Diapositiva 1

35(6(17$&,Ï1
3DPSORQDGH)HEUHURGH
(VWLPDGRVDPLJRV\FRPSDxHURV
,;&RQJUHVRGHOD6RFLHGDG(VSDxRODGH
1RVHVPX\JUDWRUHFLELURVHQOD8QLYHUVLGDGGH1DYDUUDFRQPRWLYRGHO,;&RQJUHVR
GHOD6RFLHGDG(VSDxRODGH)DUPDFLD,QGXVWULDO\*DOpQLFD
)DUPDFLD,QGXVWULDO\*DOpQLFD
7DQWRHOFRPLWpRUJDQL]DGRUFRPRHOFLHQWtILFRKDQWUDEDMDGRFRQHVPHURSDUDFRQVHJXLU
XQ SURJUDPD FLHQWtILFR FRPSHWLWLYR \ GH LQWHUpV HQ HO FDPSR GH OD 7HFQRORJtD
SDUWLFLSDFLyQ SRVLEOH GH WRGRV ORV TXH WUDEDMDPRV HQ HVWD iUHD GH LQYHVWLJDFLyQ \
)DUPDFpXWLFD %LRIDUPDFLD \ )DUPDFRFLQpWLFD \ EXVFDQGR HQWRGRPRPHQWRODPD\RU
GHVDUUROOR
8QLYHUVLGDGGH1DYDUUD
3DPSORQD±\GHIHEUHURGH
&RQILDPRV DGHPiVTXHHOGHEDWHVREUHODVH[SHFWDWLYDVGHOD6RFLHGDGHQUHODFLyQDOD
IRUPDFLyQ GH QXHYRV 3URIHVLRQDOHV GHVGH QXHVWUD ÈUHD GH &RQRFLPLHQWR QRV D\XGH D
PHMRUDUHOFDUiFWHUIRUPDWLYRGHQXHVWUDGRFHQFLD
3RU~OWLPRHVSHUDPRVTXHGXUDQWHHVWRVGtDVSRGDPRVDSUHQGHUFRPSDUWLUQXHYDVLGHDV
\SUR\HFWRVDGHPiVGHGLVIUXWDUGHODPELHQWHGHHVWDFLXGDG
%LHQYHQLGRVD3DPSORQD
(O&RPLWp2UJDQL]DGRU
&20,7e'(+2125
([FPR6U'0LJXHO6DQ]6HVPD
3UHVLGHQWHGHO*RELHUQRGH1DYDUUD
([FPR6U'ÈQJHO-RVp*yPH]0RQWRUR
5HFWRUGHOD8QLYHUVLGDGGH1DYDUUD
([FPD6UD'xD<RODQGD%DUFLQD$QJXOR
$OFDOGHVDGH3DPSORQD
([FPD6UD'xD0DUtD.XW]3HLURQFHO\
&RQVHMHUDGH6DOXGGHO*RELHUQRGH1DYDUUD
([FPR6U'/XLV0RQWXHQJD%DGtD
9LFHUUHFWRUGH,QYHVWLJDFLyQGHOD8QLYHUVLGDGGH1DYDUUD
,OPD6UD'xD,FLDU$VWLDVDUiQ$QFKLD
'HFDQDGHOD)DFXOWDGGH)DUPDFLDGHOD8QLYHUVLGDGGH1DYDUUD
6U'3HGUR&DSLOOD0DUWtQH]
3UHVLGHQWHGHO&RQVHMR*HQHUDOGH&ROHJLRV2ILFLDOHVGH)DUPDFpXWLFRV
6UD'xD03LODU*DUFtD5XL]
3UHVLGHQWDGHO&ROHJLR2ILFLDOGH)DUPDFpXWLFRVGH1DYDUUD
6U'-XDQ0DQXHO,UDFKH*DUUHWD
3UHVLGHQWHGHOD6RFLHGDG(VSDxRODGH)DUPDFLD,QGXVWULDO\*DOpQLFD
&20,7e25*$1,=$'25
35(6,'(17(+2125Ë),&2
''DQLHO)RV
35(6,'(17(
',JQDFLR)HUQiQGH]GH7URFyQL]
6(&5(7$5,$
'xD&RQFKLWD7URVGH,ODUGX\D
7(625(5$
'xD0-HV~V*DUULGR
92&$/(6
'xD0DUtD%ODQFR
'xD&DUPHQ'LRV
'xD6RFRUUR(VSXHODV
'-RDTXtQ*LUiOGH]
'xD0DUtDGHO0DU*RxL
'-XDQ0DQXHO,UDFKH
')HUQDQGR0DUWtQH]*DOiQ
'xD&ULVWLQD0DUWtQH]
'xD0DUtD-HV~V5HQHGR
'xD3LODU<JDUWXD
'xD$UDQW]D=RUQR]D
&20,7e&,(17Ë),&2
35(6,'(17(
'ÈQJHO&RQFKHLUR8QLYHUVLGDGGH6DQWLDJRGH&RPSRVWHOD
6(&5(7$5,2
'0DQXHO*X]PiQ8QLYHUVLGDGGH$OFDOiGH+HQDUHV
92&$/(6
')HUQDQGR&DUR8QLYHUVLGDG6DQ3DEOR&(8
'xD+HOHQD&RORP8QLYHUVLGDGGH%DUFHORQD
'xD5RVD-LPpQH]&DVWHOODQRV8QLYHUVLGDGGH6HYLOOD
'0DWtDV/ODEUpV8QLYHUVLGDGGH/D/DJXQD
'-RVp/XLV3HGUi]8QLYHUVLGDGGHO3DLV9DVFR
'-RVp(VWHEDQ3HULV8QLYHUVLGDGGH9DOHQFLD
'xD$GROILQD5XL]8QLYHUVLGDGGH*UDQDGD
'xD$PSDUR6iQFKH]8QLYHUVLGDGGH6DODPDQFD
'xD$QD,VDEHO7RUUHV8QLYHUVLGDG&RPSOXWHQVHGH0DGULG
'xD&RQFKLWD7URVGH,/DUGX\D8QLYHUVLGDGGH1DYDUUD
352*5$0$'(/,;&21*5(62'(/$62&,('$'
(63$f2/$'()$50$&,$,1'8675,$/<*$/e1,&$
'RPLQJRGH)HEUHUR
(QWUHJDGHGRFXPHQWDFLyQ
6HVLyQLQDXJXUDO
,OPD6UD'xD,FLDU$VWLDVDUiQ$QFKtD
'HFDQDGHOD)DFXOWDGGH)DUPDFLDGHOD8QLYHUVLGDGGH1DYDUUD
6U'5DIDHO0XJXHU]D(UDVR
'LUHFWRU GHO 6HUYLFLR GH ,QQRYDFLyQ \ 6RFLHGDG GH OD ,QIRUPDFLyQ
'HSDUWDPHQWRGH,QQRYDFLyQ(PSUHVD\(PSOHR
6U'*XLOOHUPR*DUFtDGHO%DUULR
'LUHFWRUGHO,QVWLWXWR&LHQWtILFR\7HFQROyJLFR8QLYHUVLGDGGH1DYDUUD
6U',JQDFLR)HUQiQGH]GH7URFyQL])HUQiQGH]
3UHVLGHQWH GHO ,; &RQJUHVR GH OD 6RFLHGDG (VSDxROD GH )DUPDFLD ,QGXVWULDO \
*DOpQLFD6(),*
&RQIHUHQFLD3OHQDULD6U'3DROR&RORPER8QLYHUVLW\RI3DGRYD,WDO\
³$VVHPEODJHRIPRGXOHVIRUGUXJUHOHDVHFRQWURODQGFRPELQDWLRQSURGXFWV´
0RGHUDGRUD'xD5RVD-LPpQH]&DVWHOODQRV
(QWUHJDGHO,,3UHPLRGH,QYHVWLJDFLyQ6(),*
9LQRHVSDxRO
/XQHVGH)HEUHUR
6HVLyQ,1XHYDVHVWUDWHJLDVSDUDODOLEHUDFLyQGHPHGLFDPHQWRV
&RQIHUHQFLD3OHQDULD6U'-RVp0DUWtQH]/DQDR8QLYHUVLGDGGH
6DODPDQFD
3RUWDGRUHVELROyJLFRVSDUDODYHFWRUL]DFLyQGHIiUPDFRV
0RGHUDGRUHV'$QJHO&RQFKHLUR\'-XDQ-RVp7RUUDGR
&RPXQLFDFLRQHVRUDOHV
+LGURJHOHVPLFURSDUWLFXODGRVFRQDILQLGDGSRUVDOHVELOLDUHV
)<DxH],&KLDQHOOD6$3LOHWVN\$&RQFKHLUR\&$OYDUH] /RUHQ]R
/LEHUDFLRQGH9(*)DSDUWLUGHFpOXODVPLFURHQFDSVXODGDVSDUDHO
WUDWDPLHQWRGHODHQIHUPHGDGGH$O]KHLPHU
$3RUWHUR50+HUQiQGH]*2ULYH'$QWHTXHUD&6SXFK(
&DUUR-/3HGUD]
0LFURSDUWtFXODVGH3/*$FDUJDGDVFRQDJHQWHVQHXURSURWHFWRUHV
*'1)\%'1)8QWUDWDPLHQWRSRWHQFLDOSDUDHOJODXFRPD
3&KHFD&DVDOHQJXD,%UDYR2VXQD,70ROLQD0DUWtQH]% 7XFNHU0-<RXQJ5+HUUHUR9DQUHOO
3DWFKHVIRUWUDQVGHUPDOGHOLYHU\RIVXPDWULSWDQVXFFLQDWHLQYLWUR
DQGLQYLYRSK\VLFDOFKDUDFWHUL]DWLRQ
&%DODJXHU)HUQiQGH]&3DGXOD0$&DODWD\XG3DVFXDO$ )HPHQtD)RQW90HULQR)0DUUD61LFROL36DQWL$/ySH]
&DVWHOODQR
$WRPL]DFLyQPHGLDQWHIORZIRFXVLQJDSOLFDFLRQHVIDUPDFpXWLFDV
/XFtD0DUWtQ%DQGHUDV0-RVp&y]DU%HUQDO(OHQDGH&DVWUR +HUQiQGH]$5RGUtJXH]*LO0DUtD)ORUHV0RVTXHUD-RVHID ÈOYDUH])XHQWHV0ÈQJHOHV+ROJDGR$OIRQVR*DxiQ&DOYR 0HUFHGHV)HUQiQGH]$UpYDOR
/XLV1RJXHLUDV1LHWR&DUPHQ$OYDUH]/RUHQ]R,VDEHO6DQGH] 0DFKR$QJHO&RQFKHLUR)UDQFLVFR-2WHUR(VSLQDU
3VHXGRSROLUURWD[DQRVGH3OXURQLF\FLFORGH[WULQDVSURSLHGDGHVH
LQWHUpVIDUPDFpXWLFR
&DIpVHVLyQGHSyVWHUV
0HVDUHGRQGD
6U'-RVp0DUWtQH]/DQDRPRGHUDGRU8QLYHUVLGDGGH6DODPDQFD
6U'3DROR&RORPER8QLYHUVLW\RI3DGRYD,WDO\
6U'0DQIUHG2JULV/XGZLJ0D[LPLOLDQV8QLYHUVLW\0XQLFK
$OPXHU]R
6HVLyQ ,, 9HKLFXOL]DFLyQ GH IiUPDFRV \ JHQHV WHUDSpXWLFRV HQ WHUDSLD
DQWLWXPRUDO
&RQIHUHQFLD 3OHQDULD 6U ' 0DQIUHG 2JULV 'HSDUWPHQW RI 3KDUPDF\
&HQWHURI'UXJ5HVHDUFK/XGZLJ0D[LPLOLDQV8QLYHUVLW\0XQLFK
³0DFURPROHFXODUGUXJFDUULHUVIRUWDUJHWLQJRIWKHUDSHXWLFQXFOHLFDFLGVWR
WXPRUV´
0RGHUDGRUHV'$QWRQLR5DEDVFR\'xD&RQFKLWD7URVGH,ODUGX\D
&RPXQLFDFLRQHVRUDOHV
(YDOXDFLyQGHODFDSDFLGDGGHWUDQVIHFFLyQ³LQYLYR´GH
QDQRSDUWtFXODVVyOLGDVOLStGLFDVWUDVVXDGPLQLVWUDFLyQHQUDWRQHV
SRUYtDLQWUDYHQRVD
$GHO3R]R5RGUtJXH]''HOJDGR0$6ROLQtV$5*DVFyQ( (FKHYDUUtD-05RGUtJXH]-/3HGUD]
'LVHxRGHQDQRSDUWtFXODVGHSROLİFDSURODFWRQDFRPR
VLVWHPDVWUDQVSRUWDGRUHVGH7HJDIXU
-/$ULDV0$/XTXH5DPRV0/ySH]9LRWD9*DOODUGR
(YDOXDFLyQ\FDUDFWHUL]DFLyQLQYLWURGHOHIHFWRDQWLWXPRUDOGH
GHULYDGRVGHOSODWLQRDGPLQLVWUDGRVEDMRGLIHUHQWHVIRUPDV IDUPDFpXWLFDV
'0RUHQR6=DOED,1DYDUUR&7URVGH,/DUGX\D0-*DUULGR
8WLOL]DFLyQGHOSOiVPLGR7.*)3OXFLIHUDVDHQHOHVWXGLRGHOD
ELRVHJXULGDGGHPLFURVLVWHPDVFHOXODUHVDGPLQLVWUDGRVSRU GLIHUHQWHVYtDV
(6DQWRV*2ULYH50+HUQiQGH]5&DWHQD$&DOYR-/ 3HGUD]
3RO\DQKLGULGHQDQRSDUWLFOHVIRURUDOGHOLYHU\RISDFOLWD[HO
0DLWH$JHURV3DORPD$UHVHV0LJXHO$QJHO&DPSDQHUR
*HPPD 4XLQFRFHV ,YDQ 3HxXHODV -XDQ 0DQXHO ,UDFKH
&DIpVHVLyQGHSyVWHUV
$VDPEOHDJHQHUDO6(),*
0DUWHVGH)HEUHUR
6HVLyQ,,,%LRIDUPDFLD\)DUPDFRFLQpWLFD
&RQIHUHQFLD 3OHQDULD 6U ' $OH[DQGHU 6WDDE +HDG RI 0RGHOOLQJDQG
6LPXODWLRQ%RHKULQJHU,QJHOKHLP3KDUPD*PE+&R*HUPDQ\
,PSOHPHQWDWLRQ RI SKDUPDFRPHWULFVPRGHOOLQJ DQG VLPXODWLRQ LQ FOLQLFDO
GUXJGHYHORSPHQW*HQHUDODVSHFWVDQGWKH%RHKULQJHU,QJHOKHLPH[SHULHQFH
0RGHUDGRUHV'-RVp(VWHEDQ3HULV\',JQDFLR)HUQiQGH]GH7URFyQL]
&RPXQLFDFLRQHVRUDOHV
0RGHODGRGHOWUDQVSRUWHGHOGHULYDGRGHYLQEODVWLQD.$5HQUDWD
\HQFpOXODV&$&2
*RQ]DOH]$OYDUH],*RQ]DOH]$OYDUH]02OWUD1RJXHUD'2YDGL-
0HULQR9%HUPHMR0
-HV~V9DOOH0-GH*RQ]iOH]/ySH])6iQFKH]1DYDUUR$
0RGHOL]DFLyQIDUPDFRFLQpWLFDIDUPDFRGLQiPLFDGHODHILFDFLD
DQWLWXPRUDO GHOFLVSODWLQRDGPLQLVWUDGRPHGLDQWHQDQRSDUWtFXODV
SROLPpULFDVHQXQPRGHOR[HQRJUDI
'0RUHQR,)7URFyQL]6=DOED,1DYDUUR0-*DUULGR
7UDQVSRUWHGHFRUWLVRODWUDYpVGHXQPRGHORLQYLWURGHODEDUUHUD
KHPDWRHQFHIiOLFD
&1DYDUUR,*RQ]DOH]$OYDUH]90HULQR00DQNX9*
&DVDEy0%HUPHMR
&DIpVHVLyQGHSyVWHUV
0HVDUHGRQGD
6U'9LFHQWH&DVDEyPRGHUDGRU8QLYHUVLGDGGH9DOHQFLD
6UD'xD$OLFLD5RGUtJXH]8QLYHUVLGDGGHO3DLV9DVFR839
9LWRULD
6U'-RVp'RPHQHFK8QLYHUVLGDGGH%DUFHORQD
$OPXHU]R
6U'-RVp%)DULxD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH/D/DJXQD
PRGHUDGRU
6UD'xD7HUHVD6iQFKH]$JHQFLD1DFLRQDOGH(YDOXDFLyQGHOD
&DOLGDG\$FUHGLWDFLyQ$1(&$
6U'3HUH%HUJD5HSUHVHQWDQWHGHO&RQVHMR*HQHUDOGH&ROHJLRV2ILFLDOHVGH
)DUPDFpXWLFRV
6U'-RVp&DUORV0RQWLOOD&RPLVLyQ1DFLRQDOGH(VSHFLDOL]DFLyQHQ
)DUPDFLD,QGXVWULDO\*DOpQLFD
6U'9tFWRU-LPpQH])DUPDFLD+RVSLWDODULDGHO+RVSLWDO8QLYHUVLWDULR
8QLYHUVLGDGGH9DOHQFLD
&DIpVHVLyQGHSyVWHUV
$FWRGHFODXVXUD
([FPR6U'/XLV0RQWXHQJD%DGtD
9LFHUUHFWRUGHLQYHVWLJDFLyQGHOD8QLYHUVLGDGGH1DYDUUD
([FPR6U'-RVp0DUtD5RLJ$OGDVRUR
&RQVHMHURGH,QQRYDFLyQ(PSUHVD\(PSOHRGHO*RELHUQRGH1DYDUUD
([FPD6UD'xD<RODQGD%DUFLQD$QJXOR
$OFDOGHVDGH3DPSORQD
6U'(QULTXH2UGLHUHV6DJDUPLQDJD
3UHVLGHQWHGH/DERUDWRULRV&,1)$
6U'-XDQ0DQXHO,UDFKH*DUUHWD
3UHVLGHQWHGHOD6(),*
&HQDGHJDOD
$GPLQLVWUDFLyQSXOPRQDUGHYDQFRPLFLQDHQIRUPDGHYHVtFXODV
OLStGLFDV
6HVLyQ,9'RFHQFLD
0HVDUHGRQGD)RUPDFLyQ$FDGpPLFDGHORVDOXPQRVGH)DUPDFLD3UHVHQWH\
)XWXUR
6XPDULR
,;&RQJUHVRGHOD6(),*
680$5,2
321(1&,$6
&2$720,=$&,210(',$17()/2:)2&86,1*$3/,&$&,21(6
)$50$&e87,&$6
/XFtD 0DUWtQ%DQGHUDV 0 -RVp &y]DU%HUQDO (OHQD GH &DVWUR+HUQiQGH] $
5RGUtJXH]*LO0DUtD)ORUHV0RVTXHUD-RVHIDÈOYDUH])XHQWHV0ÈQJHOHV+ROJDGR
$OIRQVR*DxiQ&DOYR0HUFHGHV)HUQiQGH]$UpYDOR
&236(8'232/,5527$;$126'(3/8521,&<&,&/2'(;75,1$6
3523,('$'(6(,17(5e6)$50$&e87,&2
/XLV1RJXHLUDV1LHWR&DUPHQ$OYDUH]/RUHQ]R,VDEHO6DQGH]0DFKR$QJHO
&RQFKHLUR)UDQFLVFR-2WHUR(VSLQDU
&2 (9$/8$&,Ï1 '( /$ &$3$&,'$' '( 75$16)(&&,Ï1 ³,1 9,92´
'(1$123$57Ë&8/$66Ï/,'$6/,3Ë',&$675$668$'0,1,675$&,Ï1
(15$721(63259Ë$,175$9(126$
$ GHO 3R]R5RGUtJXH] ' 'HOJDGR 0$ 6ROLQtV $5 *DVFyQ ( (FKHYDUUtD -0
5RGUtJXH]-/3HGUD]
3 $66(0%/$*( 2) 02'8/(6 )25 '58* 5(/($6( &21752/ $1'
&20%,1$7,21352'8&76
3DROR&RORPER
3 3257$'25(6 %,2/Ï*,&26 3$5$ /$ 9(&725,=$&,Ï1 '(
)È50$&26
-RVp0DUWtQH]/DQDR
3 0$&5202/(&8/$5 '58* &$55,(56 )25 7$5*(7,1* 2)
7+(5$3(87,&18&/(,&$&,'672780256
0DQIUHG2JULV
3 ,03/(0(17$7,21 2) 3+$50$&20(75,&602'(//,1* $1'
6,08/$7,21 ,1 &/,1,&$/ '58* '(9(/230(17 *(1(5$/ $63(&76
$1'7+(%2(+5,1*(5,1*(/+(,0(;3(5,(1&(
$OH[DQGHU6WDDE
&2081,&$&,21(625$/(6
&2 ',6(f2 '( 1$123$57Ë&8/$6 '( 32/,İ&$352/$&721$
&2026,67(0$675$163257$'25(6'(7(*$)85
-/$ULDV0$/XTXH5DPRV0/ySH]9LRWD9*DOODUGR
&2 (9$/8$&,Ï1 < &$5$&7(5,=$&,Ï1 ,19,752 '(/ ()(&72
$17,78025$/ '( '(5,9$'26 '(/ 3/$7,12 $'0,1,675$'26 %$-2
',)(5(17(6)250$6)$50$&e87,&$6
'DQLHO 0RUHQR 6DUD =DOED ,xLJR 1DYDUUR &RQFKLWD 7URV GH ,ODUGX\D
0DUtD-*DUULGR
&2+,'52*(/(60,&523$57,&8/$'26&21$),1,'$'3256$/(6
%,/,$5(6
)<DxH],&KLDQHOOD6$3LOHWVN\$&RQFKHLUR\&$OYDUH]/RUHQ]R
&2/,%(5$&,21'(9(*)$3$57,5'(&(/8/$6
0,&52(1&$368/$'$63$5$(/75$7$0,(172'(/$(1)(50('$'
'($/=+(,0(5
$3RUWHUR50+HUQiQGH]*2ULYH'$QWHTXHUD&6SXFK(&DUUR-/3HGUD]
&20,&523$57Ë&8/$6'(3/$*$&$5*$'$6&21$*(17(6
1(8523527(&725(6*'1)<%'1)8175$7$0,(172327(1&,$/
3$5$(/*/$8&20$
3 &KHFD&DVDOHQJXD , %UDYR2VXQD ,7 0ROLQD 0DUWtQH] % 7XFNHU 0- <RXQJ
5+HUUHUR9DQUHOO
&2 3$7&+(6 )25 75$16'(50$/ '(/,9(5< 2) 680$75,37$1
68&&,1$7(,19,752$1',19,923+<6,&$/&+$5$&7(5,=$7,21
& %DODJXHU)HUQiQGH] & 3DGXOD 0$ &DODWD\XG3DVFXDO $ )HPHQtD)RQW 9
0HULQR)0DUUD61LFROL36DQWL$/ySH]&DVWHOODQR
&2 87,/,=$&,Ï1 '(/ 3/È60,'2 7.*)3/XFLIHUDVD (1 (/ (678',2
'( /$ %,26(*85,'$' '(
0,&526,67(0$6 &(/8/$5(6
$'0,1,675$'26325',)(5(17(69Ë$6
(6DQWRV*2ULYH50+HUQiQGH]5&DWHQD$&DOYR-/3HGUD]
&2 32/<$1+<'5,'( 1$123$57,&/(6 )25 25$/ '(/,9(5< 2)
3$&/,7$;(/
0$JHURV3$UHVHV0$&DPSDQHUR*4XLQFRFHV,3HxXHODV-0,UDFKH
&202'(/$'2'(/75$163257('(/'(5,9$'2'(9,1%/$67,1$
.$5(15$7$<(1&e/8/$6&$&2
*RQ]DOH]$OYDUH] , *RQ]DOH]$OYDUH] 0 2OWUD1RJXHUD ' 2YDGL - 0HULQR 9
%HUPHMR0
&2$'0,1,675$&,Ï138/021$5'(9$1&20,&,1$(1)250$'(
9(6Ë&8/$6/,3Ë',&$6
-HV~V9DOOH0-GH*RQ]iOH]/ySH])6iQFKH]1DYDUUR$
&2 02'(/,=$&,Ï1 )$50$&2&,1e7,&$)$50$&2',1È0,&$ '(
/$ (),&$&,$ $17,78025$/ '(/ &,63/$7,12 $'0,1,675$'2
0(',$17( 1$123$57Ë&8/$6 32/,0e5,&$6 (1 81 02'(/2
;(12*5$)
'0RUHQR,)7URFyQL]6=DOED,1DYDUUR0-*DUULGR
6XPDULR
&275$163257('(&257,62/$75$9e6'(8102'(/2,19,752
'(/$%$55(5$+(0$72(1&()È/,&$
&1DYDUUR,*RQ]DOH]$OYDUH]90HULQR00DQNX9*&DVDEy0%HUPHMR
,;&RQJUHVRGHOD6(),*
3267(56
7(&12/2*Ë$)$50$&e87,&$
32/8&,)(5<(//2:)5(17($0$1,72/&2020$5&$'25(6'(
/$ ,17(*5,'$' '( /$6 0212&$3$6 &$&2 3$5$ (16$<26 '(
3(50($%,/,'$'
&HQWHOOHV$*RQ]DOH]$OYDUH],0HULQR9%HUPHMR09
32 $3/,&$&,Ï1 '(/ 0e72'2 %227675$3 $ /26 (678',26 '(
(67$%,/,'$' '( )È50$&26 35(3$5$'26 &20(5&,$/(6 '(
,168/,1$+80$1$
2OLYD$)DULxD-%/ODEUpV0
32 0e72'2 &$3,/$5 3$5$ (/ (678',2 '(/ &2(),&,(17( '(
',)86,Ï1$3/,&$&,Ï1'(/$1È/,6,6'((/(0(1726),1,726
0/ODEUpV$6DQWRYHxD0DWHX9
32'(7(50,1$&,Ï1'(/Ë1',&('(%8(1$&2035(6,%,/,'$''(
',6*5(*$17(6$75$9e6'(/$0(72'2/2*Ë$6('(0
-RKQQ\($JXLODU'tD](*DUFLD0RQWR\D33pUH]/R]DQR00LxDUUR-57LFy-0
6Xxp1HJUH
327+(³02=$57())(&7´,1&$1&(57+(5$3<
*RQ]DOH]$OYDUH],*RQ]DOH]$OYDUH]0$ORQVR9%HUPHOO0$%HUPHMR09
32
+,*+3(5)250$1&(
/,48,'
&+520$72*5$3+,&
'(7(50,1$7,21 2) 1$'2/2/ $)7(5 ,1 9,752 75$16'(50$/
',))86,21678',(6
0$ &DODWD\XG3DVFXDO & %DODJXHU)HUQiQGH] $ )HPHQtD)RQW 9 0HULQR $
/ySH]&DVWHOODQR
32 &2035,0,'26 ,03/$17$%/(6 '( K*+ &255(/$&,Ï1 ,1
9,752,19,92
6DQWRYHxD$)DULxD-%/ODEUpV0=KX<'DQQLHV3
32 (678',2 0,&52%,2/2*,&2 '( 9(+,&8/26 75$1'(50,&26
*(/3/8521,&<3/23OXURQLF/HFLWKLQ2UJDQRJHO
&ODUHV%5XL]0$*iOYH]3\*DOODUGR9
32 ()(&726 '( 81 &$032 0$*1e7,&2 (;7(512 (1 /$
%,2',675,%8&,Ï1'(/+,(552(181)2&2,1)/$0$725,275$6/$
$'0,1,675$&,Ï1,175$9(126$'(1$123$57Ë&8/$60$*1e7,&$6
(15$7Ï1
( (VFULEDQR 5 )HUQiQGH]3DFKHFR 0 5 ,EDUUD - * 9DOGLYLD & , 0DUTXLQD -
4XHUDOW
32 ,03/$17$&,Ï1 '( 1250$6 ,62*/3 ,'(17,),&$&,Ï1 '(
08(675$6(181/$%25$725,2'(,19(67,*$&,Ï1<'(6$552//2
)$50$&e87,&2
9'D]D7*RQoDOYHV,&DUDEDOOR
32 (/$%25$&,Ï1 < &$5$&7(5,=$&,Ï1 35(/,0,1$5 '(
1$123$57Ë&8/$6'(,168/,1$3/*$3$5$$'0,1,675$&,Ï125$/
- ÈOYDUH])XHQWHV 0- &y]DU%HUQDO / 0DUWtQ%DQGHUDV 0$ +ROJDGR 0
)HUQiQGH]$UpYDOR
32(16$<265($/,=$'26$'(6+,'5$7$'269(*(7$/(63$5$68
326,%/(87,/,=$&,Ï1(1)250$6*$/e1,&$6
0'5RPHUR%&ODUHV0$5XL]-$OFDOi3*DUFtD9*DOODUGR
32(9$/8$&,Ï1,19,752(,19,92'(',)(5(17(635272&2/26
'(
&5,235(6(59$&,Ï1
3$5$
35(6(59$5
0,2%/$6726
0,&52(1&$368/$'26
$0XUXD*2ULYH50+HUQiQGH]-/3HGUD]
32 9$/,'$&,Ï1 '( 81 0e72'2 $1$/Ë7,&2 325 +3/& 3$5$ /$
'(7(50,1$&,Ï1 '( 5$6$*,/,1$ 0(6,/$72 (1 0,&52(6)(5$6
%,2'(*5$'$%/(6'(3/*$
0)HUQiQGH](%DUFLD\61HJUR
6XPDULR
32 0,&52(1&$368/$7,21 2) 385,),(' +80$1 %,2$&7,9(
5(&20%,1$17*'1)
($QVRUHQD(*DUED\R-//DQFLHJR06$\PHULFK0-%ODQFR3UtHWR
32 (678',2 35(/,0,1$5 '( (67$%,/,'$' ),6,&248Ë0,&$ '(
81$0(=&/$,175$9(126$3$5$&(7$02/75$0$'2/
90HULQR%RKyUTXH]0-&y]DU%HUQDO66DODV-$OYDUH])XHQWHV0&DPHiQ0
'*XHUUHUR0$+ROJDGR0)HUQiQGH]$UpYDOR
32 '(6$552//2 < 9$/,'$&,Ï1 '( 81 0e72'2 '(
&8$17,),&$&,Ï1 6,08/7È1(2 325 +3/& '( 3$5$&(7$02/ <
75$0$'2/
9 0HULQR%RKyTXH] 0-&y]DU%HUQDO 6 6DODV - $OYDUH])XHQWHV 0 &DPHiQ
0'*XHUUHUR0$+ROJDGR0)HUQiQGH]$UpYDOR
32 '(9(/230(17 2) 3/*$1$123$57,&/(6 2) '2;(3,1
+<'52&+/25,'(
;*DUFLD((VFULEDQR-'RPpQHFK
32
'(6$552//2
'(
3$5&+(6
75$16'e50,&26
'(
12575,37,/,1$&21',)(5(17(60$75,&(632/,0(5,&$6
--(VFREDU&KiYH]90HULQR00HULQR6DQMXiQ$1iFKHU$*DQHP4XLQWDQDU
2'tH]6DOHV0+HUUiH]
32 '58* 5(/($6( .,1(7,&6 $1' )52176 029(0(17 678',(6
)520 0$75,&(6 &20%,1,1* 6:(//$%/( $1' ,1(57 32/<0(56
())(&72)+30&:,7+',))(5(17'(*5((62)68%67,787,21
--(VFXGHUR&)HUUHUR05-LPpQH]&DVWHOODQRV
32 /,3,' 1$123$57,&/(6 2) ('(/)26,1( $ 675$7(*< 72
,03529(,7625$/%,2$9$,/$%,/,7<
$(VWHOOD+HUPRVRGH0HQGR]D0$&DPSDQHUR)0ROOLQHGR0-%ODQFR3UtHWR
32 02'(/,=$&,21 '( /$ 0,&52(6758&785$ '( 3(/(76 $
3$57,5'('$726'(32526,0(75,$'(,17586,21'(0(5&85,2
$ *yPH]&DUUDFHGR & $OYDUH]/RUHQ]R 5 0DUWtQH]3DFKHFR $ &RQFKHLUR -/
*yPH]$PR]D
32 6,08/$&,21 '(/ 352&(62 '( &$37$&,21 '( $*8$ (1
3(/(76 0$75,&,$/(6 $ %$6( '( (8'5$*,7 620(7,'26 $
',)(5(17(675$7$0,(17263267(/$%25$&,21
/&/6i%DUUHWR/$ORQVR50DUWtQH]3DFKHFR-/*yPH]$PR]D
32 '(6$552//2 '( 81$ 9$&81$ ,175$1$6$/ )5(17( $ $ /$
',6(17(5Ë$%$&,/$50(',$17(1$123$57Ë&8/$6
$,&DPDFKR0DULD/XLVD$UD~MR-0,UDFKH&*DPD]R
32(678',2'(/$,1)/8(1&,$'(/75$7$0,(1727e50,&2<'(
/$35(6(1&,$'(393(1/$/,%(5$&,Ï1'(7(2),/,1$$3$57,5'(
&2035,0,'260$75,&,$/(6/,3Ë',&26
003XHEOD*RQ]iOH]090DUJDULW%HOOYHU070DUtQ%RVFi
32 $3/,&$&,Ï1 '( $/7$6 35(6,21(6 +,'5267È7,&$6 &202
0e72'2'((67$%,/,=$&,Ï1'(*(/(61$785$/(6'($9(5$/
+HUQiQGH]%/ODEUpV0)DULxD-%3DJiQ56RPROLQRV0
32 '(6$552//2 '( &2/2,'(6 0$*1e7,&26 '( (7,/&(/8/26$
3$5$(/75$163257('()È50$&26$17,78025$/(6
0/ySH]9LRWD-/$ULDV9*DOODUGR0$5XL]
3235(3$5$&,Ï1'(6,67(0$6&2/2,'$/(632/,0e5,&26&202
9(+Ë&8/26'(/$/&$/2,'(&$17+,121(
*&HEULiQ-/$ULDV(3RXSRQ0$5XL]
32 &+$5$&7(5,=$7,21 2) 2&8/$5 ,16(576 %$6(' 21 62',80
+<$/8521$7(+<'52;<3523</0(7+</&(//8/26(
0&DEULRXOX60XUD90HULQR00HULQR6DQMXiQ$1iFKHU00DQFRQL$0
)DGGD2'tH]6DOHV
,;&RQJUHVRGHOD6(),*
32 +,*+ 35(66685( +202*(1,6$7,21 0(7+2' 72 352'8&(
1$1216758&785(' /,3,' &$55,(56 1/&V 72 (1+$1&( 25$/
%,2$9$,/$%,/,7<2)3225/<62/8%/(&203281'6
$%HORTXL0$6ROLQtV$5*DVFyQ-/3HGUD]
32 &5,7,&$/ 32,176 2) +<'523+,/,& 0$75,&(6 %$6(' 21
+<3520(//26(./9&5
&&LIXHQWHV7*RQoDOYHV$55DMDEL6LDKERRPLDQG,&DUDEDOOR
32 ',6(f2 < &$5$&7(5,=$&,Ï1 '( 81$ 18(9$ /È*5,0$
$57,),&$/3$5$(/75$7$0,(172'(/6Ë1'520('(2-26(&2
9LFDULRGHOD7RUUH0%HQtWH]GHO&DVWLOOR-09LFR(*X]PiQ0GHODV+HUDV
%+HUUHUR9DQUHOO50ROLQD0DUWtQH],7
32 *0$27 0,&523$57,&/(6 72 75($7 ,175$&(//8/$5
3$7+2*(16
' *RQ]iOH] ( ,PEXOX]TXHWD * 3pUH] ( (OL]RQGR 1 9HQWRVD - 9HFLDQD &
*DPD]R0-%ODQFR3UtHWR
32 62/8%,/,7< %(+$9,285 2) $//2385,12/ ,1 $03+,3527,&
$1'$03+,3527,&$3527,&0,;785(6
$%6iQFKH]0$3HxD3%XVWDPDQWH%(VFDOHUD
32 5(/($6( 2) 3$0,12%(1=2,& $&,' $1' 1$352;(1 )520
(8'5$*,756320$75,&(6$65(/$7('7232/$5,7<
1$UDJyQ3%XVWDPDQWH%(VFDOHUD0$3HxD
32 7+(502*5$06 2) 7+( 62/,' 3+$6(6 2) 7+(23+<//,1(
$)7(5(48,/,%5$7,21:,7+(7+$12/:$7(5
0$3HxD3%XVWDPDQWH$5HtOOR
32 ³1(852)8==< /2*,&´ 81$ +(55$0,(17$ 87,/ (1 (/
'(6$552//2'()250$6'('26,),&$&,Ï1
0DULDQD/DQGtQ5&5RZH\3<RUN
32 32/<$1+<'5,'( 1$123$57,&/(6 $6 08&26$/ $'-89$176
)25%58&(//26,69$&&,1$7,21
5'D&RVWD0DUWLQV&*DPD]R&9DXWKLHU-0,UDFKH
32 (67$%,/,'$' < (),&$&,$ '(/ ,16(&7,&,'$ &,3(50(75,1$
,1&25325$'2(10,&52&È368/$6'(32/,85($
& 0DUWtQ 6DEURVR 3 5LYDV (VWHEDQ ' 7DYDUHV 6LOYD )HUQDQGHV 0( *LO$OHJUH
$,7RUUHV6XiUH]
32 02',),(' *(17$0,&,1 72 75($7 ,175$&(//8/$5
,1)(&7,216
(,PEXOX]TXHWD&*DPD]R'*RQ]iOH]((OL]RQGR19HQWRVD66DOD
-9HFLDQD0-%ODQFR3ULHWR
6XPDULR
32 ,1 9,752 $1' ,1 9,92 72;,&,7< 678',(6 2)
32/<$1+<'5,'(1$123$57,&/(6)2525$/'58*'(/,9(5<
32MHU$/ySH]GH&HUDLQ-0,UDFKH
32 (678',2 &203$5$7,92 '( &$5%2;,0(7,/ $/0,'21 62',&2
5(7,&8/$'2 < 48,726$126,/,&( &202 $*(17(6 ',6*5(*$17(6
(1 3(/(76 '( &(/8/26$ 0,&52&5,67$/,1$+,'52&/2527,$=,'$
(/$%25$'26325(;7586,21(6)(521,=$&,21
ÈOYDUR*R\DQHV&RQVXHOR6RXWR5DPyQ0DUWtQH]3DFKHFR
32 ,1)/8(1&,$ '( /26 $17,È&,'26 (1 /$ (67$%,/,'$' '(
20(35$=2/
0/ySH]9LRWD-/$ULDV0$5XL]9*DOODUGR
32 (1&$368/$&,Ï1 '( )È50$&26 $17,55(7529,5$/(6 (1
/(8&2&,72632/,025)218&/($5(6
&*XWLpUUH]0LOOiQ0/6D\DOHUR0DULQHUR-0/DQDR
32 +,'52*(/(6 '( 32/2;$0(5 '( *(/,),&$&,Ï1 ,1 6,78 3$5$
&(6,Ï1&21752/$'$'(3527(Ë1$6
$5H\5LFR&$OYDUH]/RUHQ]R/%DOVD06LOYD-&RXFHLUR\$&RQFKHLUR
32 +,'52*(/(6 '( &,&/2'(;75,1$6 < 32/,6$&È5,'26 &202
9(+Ë&8/26'()È50$&26$17,)Ò1*,&26
(/ySH]0RQWHUR&$OYDUH]/RUHQ]R-)5RVDGRV6DQWRV$&RQFKHLUR--7RUUHV
/DEDQGHLUD
32 )81&,21$/,=$&,Ï1 683(5),&,$/ '( 32/,(7,/(12 <
32/,3523,/(12 &21 &,&/2'(;75,1$6 3$5$ ',6326,7,926
%,20e',&260(',&$'26
&$%1DYD2UWL]*%XULOOR(%XFLR&$OYDUH]/RUHQ]R\$&RQFKHLUR
32()(&72'(/$+,'52)2%,&,'$'62%5((/&203257$0,(172
5(2/Ï*,&2 < /$ &,1e7,&$ '( /,%(5$&,Ï1 '( 81 6,67(0$
',63(562'(+,'52;,3523,/&(/8/26$
-ÈOYDUH]0'0R\D\0-/XFHUR
32 '(7(50,1$&,Ï1 '( /$6 3523,('$'(6 0(&È1,&$6 '(
6,67(0$632/,0e5,&26'(+&00$
&&ODUR&DOD05-LPpQH]&DVWHOODQR
32'(6$552//2'(18(9$6)250$6'('26,),&$&,Ï13$5$862
3(',È75,&29(7(5,1$5,2
%&ODUHV9*DOODUGR0(,EixH]0(0RUDOHV0$5XL]
32(678',2'(/$6(/(&&,Ï1'(0$7(5,$/(687,/,=$'26(1/$
&216758&&,Ï1'(81$3/$17$+,*+&217$,10(17
-RKQQ\ (GZDUG $JXLODU 'tD] 0RQWVH 0RQWDQHU (YD 3ODQDV /RUHQD 7HUUHV
,PPDFXODGD*RPH](OLDV%HQLWR
,;&RQJUHVRGHOD6(),*
32 /,%(5$&,Ï1 ,1 9,752 '( &,&/26325,1$ $ '(6'(
1$123$57Ë&8/$6 '( 3900$ )2508/$'$6 &21 ',)(5(17(6
'(5,9$'26'(&,&/2'(;75,1$6
03HFFKLR-0,UDFKH0-5HQHGR0&'LRV9LpLWH]
32 (/$%25$&,Ï1 '( 0,&523$57Ë&8/$6 %,2'(*5$'$%/(6 &21
1$/2;21$ 3$5$ $'0,1,675$&,Ï1 3$5(17(5$/ 6(/(&&,Ï1 '(/
32/Ë0(52
/%DXWLVWD&KiYH]&0DUWtQ6DEURVR-,(VSDGD*DUFtD0(*LO$OHJUH$,7RUUHV
6XiUH]
32 ,03529(0(17 2) *(1( 75$1)(5 72 78025$/ &(//6 %<
75$16)(55,1'(1'5,3/(;(6
*1DYDUUR&7URVGH,ODUGX\D02JULV(:DJQHU
32 12575,37</,1( 675$780 &251(80 3(1(75$7,21 352),/(
)520+30&3$7&+(6
$0HOHUR70*DUULJXHV0$OyV$0DUWtQ9LOORGUH8)6FKDHIHU&0/HKU
6XPDULR
32 ,17(5$&&,Ï1 '( 680$75,37$1 &21 /26 &20321(17(6 '(
81$)2508/$&,Ï1'(/,32620$6&$5*$'26&21(67($5,/$0,1$
Ï&21',+(;$'(&,/)26)$72(678',20(',$17('6&<3105
0/*RQ]iOH]5RGUtJXH]69LOODVPLO:'UKLPHXU$05DEDVFR
32
0,&52*5$18/26
'(
3(&7,1$
&217(1,(1'2
)2508/$&,21(6
08/7,3$57,&8/$5(6
&21
%8'(621,'$
&$5$&7(5,=$&,Ï1 < (9$/8$&,Ï1 '( 68 (),&$&,$ $3/,&$1'2 (/
0e72'2%227675$3
0DQXHO*X]PiQ6XVDQD6iQFKH]5DTXHO*UDJHUD
32 3523,('$'(6 9,6&26,0e75,&$6 '( )2508/$6 $5 (1
1875,&,Ï1,1)$17,/
0RUDOHV0(/ySH]*/DUD9LOORVODGD),QIDQWH'5XL]0$\*DOODUGR9
32',6(f2'((;3(5,0(1726(1)2508/$&,21'((08/6,21(6
,19(67,*$&,21'(81$18(9$9$5,$%/(5(638(67$
+6HNNDW0'&RQWUHUDV&ODUDPRQWH0'0LQJRUDQFHÈOYDUH]
32 /,%(5$&,Ï1 &21752/$'$ '( ',&/2)(1$&2 62',&2 (1
&2035,0,'26 (/$%25$'26 &21 81$ 32/,(67(5$0,'$ 12
+,1&+$%/(
5RGUtJXH]*DOiQ,&0DUJDULW09 5RGUtJXH]*DOiQ$ 0RUDOHV0/%RX]DV
35\+HUQiQGH]3-
32 ,1 9,752 *(1( 75$16)(5 72 $',326( 0(6(1&+<0$/ 67(0
&(//6 %< ,03529(' 75$16)(55,1 /,323/(;(6 $1' 32/<3/(;(6
35(/,0,1$5<678',(6&<7272;,&,7<$1'75$16)(&7,21
62OPHGLOODV$/LUDV,0LJXpOL]'*DUFtD2OPR0*DUFtD$UUDQ]DQG&7URVGH
,ODUGX\D
32(92/87,212)6,=(6,=(',675,%87,21$1'=327(17,$/2)
',63(56('3+$6('523/(76,12:(08/6,2167+528*+$*(,1*
0()UDQFR*LO$05RGUtJXH]%D\yQ
32 +,'52*(/(6 $ %$6( '( *20$6 1$785$/(6 3$5$ /$
/,%(5$&,Ï1&2/Ï1,&$'()È50$&26
*DJR*XLOODQ02WHUR(VSLQDU)-
32 (9$/8$&,Ï1 ,1 9,752,1 9,92 '( 81$ )2508/$&,Ï1 '(
/,%(5$&,Ï1 6267(1,'$ '( /29$67$7,1$ 2%7(1,'$ 0(',$17(
*5$18/$&,Ï1325)86,Ï1
2FKRD/,JDUWXD0+HUQiQGH]50*DVFyQ$56ROLQLV0$\3HGUD]-/
32 38(67$$ 38172'(81$7e&1,&$'(0,&25(1&$368/$&,Ï1
'(/352%,Ï7,&2/$&72%$&,//86)(50(1780&(&7
0(0RUDOHV+HUQiQGH]0-0DUWLQ9LOOHQD) /DUD9LOORVODGD9*DOODUGR /DUD \
0$5XL]0DUWtQH]
32 81,)250,'$' '( 81,'$'(6 '( '26,),&$&,Ï1 '(
&2035,0,'26'(3$5$&(7$02/'((/$%25$&,Ï13523,$
0,6RULDQR-%)DULxD$2OLYD
32 (678',2 )$50$&e87,&2 '( )2508/$&,21(6 *(1e5,&$6 '(
3$5$&(7$02/
+2VVpWp67RUUDGR6XVDQD67RUUDGR6DQWLDJR03%DOOHVWHURV\--7RUUDGR
32 '(7(50,1$&,Ï1 '( /$ 62/8%,/,'$' < '( /$
&203$7,%,/,'$' 35,1&,3,2 $&7,92(;&,3,(17( 3$5$ (/
'(6$552//2 '( 0,&52(6)(5$6 &202 6,67(0$6 '( /,%(5$&,Ï1
352/21*$'$'(&$11$%,12,'(6
'+HUQiQ-0ROSHFHUHV05$EHUWXUDV&0DUWtQ0(*LO$,7RUUHV
32 /,%(5$&,Ï1 ,19,752 '( /,'2&$Ë1$ %$6( '(6'(
35(3$5$&,21(6 7Ï3,&$6 $/ )2508/$'$6 &21 ',67,1726
',62/9(17(6(02/,(17(6
(%ODQFD0'&RQWUHUDV
32
%,2'(*5$'$%/(
0,&5263+(5(6
)25
9$6&8/$5
(1'27+(/,$/ *52:7+ )$&725 9(*) '(/,9(5< ,1 ,6&+(0,&
3$7+2/2*,(6
)5)RUPLJD%3HODFKR(*DUED\R*$EL]DQGD)3URVSHUDQG0-%ODQFR3ULHWR
32
,1)/8(1&,$
'(
/$
&21&(175$&,Ï1
'(
',+(;$'(&,/)26)$72 '+3 62%5( /$6 &$5$&7(5Ë67,&$6
),6,&248Ë0,&$6 '( /,32620$6 '( 68&&,1$72 '( 680$75,37È1
(/$%25$'26325',67,17$67e&1,&$6
0/*RQ]iOH]5RGUtJXH]:'KULPHXU69LOODVPLO66DODV$05DEDVFR
,;&RQJUHVRGHOD6(),*
32 '(6$552//2 < &$5$&7(5,=$&,Ï1 '( 0,&52(6)(5$6 '(
5$6$*,/,1$0(6,/$723$5$(/75$7$0,(172'(/3$5.,1621
0)HUQiQGH]61HJUR$)HUQiQGH]\(%DUFLD
32 35(/,0,1$5< 678',(6 21 '58* '(/,9(5< 2) /2:
7(03(5$785(3/$60$75($7('7(;7,/(68332576
&&DQDO-0&DQDO$1DYDUUR0-*DUFLD&HOPD
%,2)$50$&,$<)$50$&2&,1e7,&$
32 '(9(/230(17 $1' 9$/,'$7,21 2) $1 +3/& 0(7+2' )25
9$1&20<&,1 48$17,),&$7,21 $1' ,76 $33/,&$7,21 72 $
3+$50$&2.,1(7,&678'<
-HV~V9DOOH0-GH*RQ]iOH]/ySH])6iQFKH]1DYDUUR$
32 &203$5$&,Ï1 '(/ )$&725 5$=$ < *e1(52 (1 /$ 5$7$
&20202'(/2$1,0$/'($%625&,Ï1,17(67,1$/
2OWUD1RJXHUD'*RQ]DOH]$OYDUH],*RQ]DOH]$OYDUH]0&DVDER9*%HUPHMR0
32 %,2',6321,%,/,'$' 5(/$7,9$ '( /(8&,1$ 75$6
$'0,1,675$&,Ï125$/'(',(7$6'(1875,&,Ï1(17(5$/
60LUDOOHV$UQDX00HULQR6DQMXiQ$1iFKHU19-LPpQH]7RUUHV
32 %,2',6321,%,/,'$' 5(/$7,9$ '( 7$85,1$ 75$6
$'0,1,675$&,Ï125$/'(',(7$6'(1875,&,Ï1(17(5$/
60LUDOOHV$UQDX$1iFKHU00HULQR6DQMXiQ19-LPpQH]7RUUHV
32 (678',2 ,1 9,92 '( /$ ',675,%8&,Ï1 7,68/$5 < /$
&$37$&,Ï1 325 0$&5Ï)$*26 '( =,'298',1$ 87,/,=$1'2
(5,752&,7263257$'25(6
(OVD%ULRQHV&XHVWD&ODUD,VDEHO&ROLQR*DQGDULOODV-RVp0DUWtQH]/DQDR
32 9$/,'$&,Ï1 < )81&,Ï1 '(/ (5525 '( 81 0e72'2
$1$/Ë7,&2 3$5$ /$ 021,725,=$&,Ï1 '( 1,9(/(6 3/$60È7,&26
'(&$59(',/2/(13$&,(17(6&21,168),&,(1&,$&$5'Ë$&$
$-%UD]D30RGDPLR&)/DVWUD-6HEDUURMD(/0DULxR
32 35(&/,1,&$/ 678'< 2) $ 1(: 6867$,1(' 5(/($6(
)2508/$7,21 2) 0253+,1( ',6&5(3$1&,(6 %(7:((1 7+( ,1
9,752'58*5(/($6($1'7+(,19,92$%62537,21352),/(
$$UDtFR)7RUUHV0ROLQD-&iUFHO7UXOOROV$6DDGHGGLQ-(3HULV
6XPDULR
)$50$&,$&/Ë1,&$<)$50$&27(5$3,$
32 0(',&$0(1726 %,26,0,/$5(6 5(48(5,0,(1726 '(
)$50$&29,*,/$1&,$<*(67,Ï1'(5,(6*26
/=~xLJD%&DOYR
32(92/8&,Ï1'(/$,19(67,*$&,Ï1&/Ë1,&$5($/,=$'$(1(/
(67$'2(63$f2/'(6'(/$3(563(&7,9$'(81$&52
%1LFROiV30RGDPLR&)/DVWUD(/0DULxR
'2&(1&,$
32 7+( 3+$50$&< &855,&8/80 2) 7+( 81,9(56,7< 2)
)/25,'$86$
00DUWRQH'1REHO-6HEDUURMD30RGDPLR&)/DVWUD(/0DULxR
32 3+$50$&< ('8&$7,21 $7 7+( 81,9(56,7< 2) 7(;$6 $7
$867,186$
$*DUFLD&6LPLVWHU-6HEDUURMD30RGDPLR&)/DVWUD(/0DULxR
32 7(&12/2*Ë$ )$50$&e87,&$ *(67,Ï1 '(/ &212&,0,(172
0(',$17(81$,1129$&,Ï1'2&(17(%$6$'$(1(/'(6$552//2
'(8175$%$-2*583$/
0)HUQiQGH]$UpYDOR0-/HyQ:DVPHU
32 9$/25$&,Ï1 '( /$ )250$&,Ï1 5(&,%,'$ < '( /$6
&203(7(1&,$6 352)(6,21$/(6 '(/ )$50$&e87,&2 38172 '(
9,67$'(/$/8012
%HJRxD&DOYR(QULTXH(W[HEDUUtD
CONFERENCIAS PLENARIAS
&RQIHUHQFLDV3OHQDULDV
$66(0%/$*(2)02'8/(6)25'58*5(/($6(&21752/$1'&20%,1$7,21
352'8&76
3DROR&RORPER
'HSDUWPHQWRI3KDUPDF\8QLYHUVLW\RI3DUPD,WDO\
&RQIHUHQFLDV3OHQDULDV
3257$'25(6%,2/Ï*,&263$5$/$9(&725,=$&,Ï1'()È50$&26
7KH SXUSRVH RI WKH SUHVHQWDWLRQ ZLOO EH WKH LOOXVWUDWLRQ RI WKH FRQFHSW RI PRGXOH DVVHPEOLQJ IRU GUXJ
GHOLYHU\FRQWURODQGFRPELQDWLRQSURGXFWVPDQXIDFWXULQJ%\IRFXVLQJWKHGUXJUHOHDVHIURPK\GURSKLOLF
PDWULFHV WR EH XVHG DV PRGXOHV WKH GHOLYHU\ NLQHWLFV RI GLIIHUHQWO\ VKDSHG VXUIDFHV RI WKH PRGXOH DQG
GLIIHUHQWGUXJV¶UHOHDVHREWDLQHGE\DVVHPEOLQJVHYHUDOPRGXOHVLQRQHV\VWHPZHUHVWXGLHG
7KH VWXGLHG PRGXOHV DUH GLVF WDEOHWV ZLWK RQH EDVH FRQYH[ DQG WKH RWKHU FRQFDYH 0RGLILHG UHOHDVH
PDWULFHV RU LPPHGLDWH UHOHDVH WDEOHWV KDYH EHHQ IRUPXODWHG 7KH PDWUL[ VXUIDFHV ZHUH SDUWLDOO\ FRDWHG
ZLWKDQLPSHUPHDEOHILOPWRVWXG\WKHVZHOOLQJDQGGUXJUHOHDVHIURPWKHFRQYH[RUFRQFDYHVXUIDFHV
7KH VKDSH RI PRGXOH VXUIDFH LQIOXHQFHV WKH UHOHDVH UDWH ZKHQ WKH PRGXOHV DUH VZHOODEOH PDWULFHV 7KH
REVHUYHGGLIIHUHQWUHOHDVHNLQHWLFVZDVOLQNHGWRWKHPRGLILHGVZHOOLQJRIWKHGLIIHUHQWO\VKDSHGVXUIDFHV
0DWULFHVVWDFNHGZLWKWKHFRQYH[EDVHLQVHUWHGLQWKHFRQFDYHVKRZHGUHOHDVHSURILOHVGHSHQGHQWRQWKH
UDWLR$UHD9ROXPH7KH$UHD9ROXPHUDWLRRIV\VWHPVZDVFRUUHODWHGWRPHDQGLVVROXWLRQWLPH
7ZRWRVL[XQLWPRGXOHVFRXOGEHDVVHPEOHGLQRUGHUWRFUHDWHGLIIHUHQWVKDSHGV\VWHPVKDYLQJGLIIHUHQW
UHOHDVHNLQHWLFVRUFRQWDLQLQJGLIIHUHQWGUXJV7KHDVVHPEOLQJLVGULYHQE\WKHJHRPHWU\RIWKHIDFHVDQG
WKHPRVWUHFHQWWHFKQLTXHLVWKHDVVHPEODJHE\FOLFNLQJFRPSOHPHQWDU\IDFHV
6WDNHG PDWULFHV PDLQO\ H[KLELWHG DQRPDORXV UHOHDVH NLQHWLFV :KHQ WKH FRQFDYH EDVHV RI WZR PRGXOHV
ZHUHVWXFNWRJHWKHUDQDVVHPEOHGIORDWLQJV\VWHPZDVREWDLQHG
7KH PRGXOH DVVHPEODJH LQ FRPELQHG VWUXFWXUHV DOORZV WR REWDLQ GLIIHUHQW GUXJ UHOHDVH EHKDYLRXU LQ
GHSHQGHQFH RQ WKH JHRPHWU\ RI WKH DVVHPEOHG V\VWHP 'LIIHUHQW GUXJ UHOHDVH NLQHWLFV PDLQWDLQLQJ WKH
VDPH XQLW GRVDJH IRUP FRXOG EH REWDLQHG DFFRUGLQJ WR WKH DVVHPEODJH SHUIRUPHG
-RVp0DUWtQH]/DQDR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DODPDQFD
6DODPDQFD
6LVWHPDV SROLPpULFRV FRQVWLWXLGRV SRU PLFURSDUWtFXODV \ QDQRSDUWtFXODV MXHJDQ DFWXDOPHQWH XQ SDSHO
LPSRUWDQWHHQHOFDPSRGHORVVLVWHPDVGHOLEHUDFLyQ\YHFWRUL]DFLyQGHIiUPDFRV1RREVWDQWHH[LVWHQ
YHFWRUHVRSRUWDGRUHVELROyJLFRVGHIiUPDFRVTXHFRQVWLWX\HQXQDLQWHUHVDQWH\SURPHWHGRUDDOWHUQDWLYDD
HVWH WLSR GH VLVWHPDV /RV SRUWDGRUHV ELROyJLFRV SUHVHQWDQ FRPR YHQWDMD IXQGDPHQWDO VX DOWD
ELRFRPSDWLELOLGDG ELROyJLFD DVt FRPR VX FDSDFLGDG FRPR VLVWHPDV GH OLEHUDFLyQ SURORQJDGD \ VX DOWD
VHOHFWLYLGDG D GLIHUHQWHV yUJDQRV WHMLGRV \ FpOXODV GHO RUJDQLVPR SXGLHQGR YHKLFXOL]DU IiUPDFRV
VLVWHPDV HQ]LPiWLFRV \ PDWHULDO JHQpWLFR (Q HO FDPSR GH ORV SRUWDGRUHV ELROyJLFRV GH IiUPDFRV \
DOWHUQDWLYDPHQWHDODVOLSRSURWHtQDVGHEDMDGHQVLGDG\ORV SpSWLGRVGHRULJHQQDWXUDOGHEHQGHVWDFDUVH
ODV FpOXODV \ ODV FpOXODV JKRVWV FRPR ORV HULWURFLWRV \ RWUR WLSR GH FpOXODV VDQJXtQHDV ORV JKRVWV
EDFWHULDQRV ORV YHFWRUHV YLUDOHV ODV FpOXODV PDGUH PDQLSXODGDV JHQpWLFDPHQWH \ ODV FpOXODV WXPRUDOHV
HQWUHRWURV
(QHVWDSRQHQFLD VHDQDOL]DUiQORVSULQFLSDOHVSRUWDGRUHVELROyJLFRVVXVYHQWDMDVHLQFRQYHQLHQWHVVXV
PpWRGRVGHREWHQFLyQ\VXVSULQFLSDOHVDSOLFDFLRQHVWHUDSpXWLFDV
/RV HULWURFLWRV DXWyORJRV VRQ XWLOL]DGRV FRPR SRUWDGRUHV GH VXVWDQFLDV ELRDFWLYDV GHVGH ORV DxRV SXGLHQGR YHKLFXOL]DU VHOHFWLYDPHQWH OD VXVWDQFLD HQFDSVXODGD DO VLVWHPD UHWtFXOR HQGRWHOLDO 6(5 GHO
KtJDGRED]R\PpGXODyVHD([LVWHQGLIHUHQWHVPpWRGRVGHREWHQFLyQGHHULWURFLWRVSRUWDGRUHVFRPRORV
PpWRGRV RVPyWLFRV R OD HOHFWURSRUDFLyQ VLHQGR OD GLiOLVLV KLSRWyQLFD HO PpWRGR PiV XWLOL]DGR /RV
HULWURFLWRV SUHVHQWDQ SRWHQFLDOHV DSOLFDFLRQHV WHUDSpXWLFDV FRQ IiUPDFRV FRPR ORV DQWLQHRSOiVLFRV
HQ]LPDVFRPROD/DVSDUUDJLQDVDRPDWHULDOJHQpWLFRFRPRORVROLJRQXFOHyWLGRVDQWLVHQWLGR
/RV JKRVWV EDFWHULDQRV VRQ SURGXFLGRV PHGLDQWH OD OLVLV GH EDFWHULDV SHUR PDQWHQLHQGR VX PRUIRORJtD
FHOXODU \ ODV HVWUXFWXUDV DQWLJpQLFDV GH OD VXSHUILFLH GH OD EDFWHULD /RV JKRVWV EDFWHULDQRV SXHGHQ
REWHQHUVH D SDUWLU GH EDFWHULDV *UDP FRPR (VFKHULFKLD FROL 3DVWHXUHOOD PXOWRFLGD $FWLQREDFLOOXV
SOHXURSQHXPRQLDR9LEULXPFKROHUDHHQWUHRWUDV\SHUPLWHQODHQFDSVXODFLyQGHIiUPDFRVDQWtJHQRV\
$'1 \ VX FDSWDFLyQ VHOHFWLYD SRU GLIHUHQWHV WHMLGRV \ FpOXODV FRPR PDFUyIDJRV WXPRUHV R FpOXODV
HQGRWHOLDOHV /RV JKRVWV EDFWHULDQRV SUHVHQWDQ SRWHQFLDOHV DSOLFDFLRQHV WHUDSpXWLFDV HQ HO FDPSR GH ODV
YDFXQDVYHWHULQDULDVRODWHUDSpXWLFDDQWLQHRSOiVLFDRFRPRSRUWDGRUHVGH$'1\$51FRQDSOLFDFLRQHV
WHUDSpXWLFDV
9LUXV DWHQXDGRV R PRGLILFDGRV FRPR DGHQRYLUXV OHQWLYLUXV SR[YLUXV \ RWUR WLSR GH YLUXV SXHGHQ
XWLOL]DUVH FRPR SRUWDGRUHV GH PDWHULDO JHQpWLFR 6X SULQFLSDO YHQWDMD UDGLFD HQ VX DOWD HILFDFLD GH
WUDQVGXFFLyQ LQ YLYR /RV YHFWRUHV YLUDOHV FRPR SRUWDGRUHV GH PDWHULDO JHQpWLFR SUHVHQWDQ SRWHQFLDOHV
DSOLFDFLRQHV WHUDSpXWLFDV HQ FDPSRV FRPR WHUDSpXWLFD GHO FDQFHU HQIHUPHGDGHV FDUGLRYDVFXODUHV
ILEURVLVTXtVWLFDRWHUDSpXWLFDDQWL+,9
$GHPiV GH ODV \D FRQRFLGDV DSOLFDFLRQHV GH ODV FpOXODV PDGUH SDUD OD FORQDFLyQ WHUDSpXWLFD \ OD
UHJHQHUDFLyQGHWHMLGRVHVWHWLSRGHFpOXODVSXHGHQXWLOL]DUVHHQHOFDPSRGHODWHUDSLDJpQLFDUHFXUULHQGR
DFpOXODVPDGUHKHPDWRSRLpWLFDVSURFHGHQWHVGHODPpGXODyVHDVDQJUHSHULIpULFDRFRUGyQXPELOLFDOGHO
SDFLHQWH TXH VRQ PDQLSXODGDV JHQpWLFDPHQWH SDUD LQWURGXFLU XQ WUDQVJHQH WHUDSpXWLFR \ YHKLFXOL]DUOR
VHOHFWLYDPHQWH(VWDWpFQLFDWLHQHDSOLFDFLRQHVSRWHQFLDOHVHQFDPSRVFRPRODWHUDSpXWLFDDQWLQHRSOiVLFD
+,9 HQIHUPHGDGHV FDUGLRYDVFXODUHV HSLOHSVLD R HQIHUPHGDGHV QHXURGHJHQHUDWLYDV
&RQIHUHQFLDV3OHQDULDV
&RQIHUHQFLDV3OHQDULDV
0$&5202/(&8/$5'58*&$55,(56)257$5*(7,1*2)7+(5$3(87,&18&/(,&
$&,'672780256
0DQIUHG2JULV
*URXSOHDGHU9HFWRURORJ\
'HSDUWPHQWRI3KDUPDF\/XGZLJ0D[LPLOLDQV8QLYHUVLWlW0QFKHQ*HUPDQ\
$QLPSRUWDQWLVVXHIRUVXFFHVVIXOFDQFHUWKHUDS\LVWKHV\VWHPLFGHOLYHU\RIWKHUDSHXWLFGUXJVLQWRWDUJHW
FHOOVDFKLHYLQJDKLJKOHYHORIVHOHFWLYLW\E\DYRLGLQJWR[LFVLGHHIIHFWV)HDWXUHVOLNHHOHYDWHGH[SUHVVLRQ
RI GLVWLQFW UHFHSWRUV RQ WXPRXU FHOOV SUROLIHUDWLQJ WXPRXU HQGRWKHOLXP DQG D OHDN\ YDVFXODWXUH DOORZV
VHOHFWLYH WUHDWPHQW RI VROLG WXPRU WLVVXH ZLWK QXFOHLF DFLG EDVHG GUXJV :H DQG RWKHUV KDYH GHYHORSHG
SRO\PHUEDVHGGHOLYHU\V\VWHPVIRUQXFOHLFDFLGVIRUPLQJVRFDOOHGµDUWLILFLDOYLUXVHV¶3RO\FDWLRQVELQG
DQGFRQGHQVHQXFOHLFDFLGVE\HOHFWURVWDWLFLQWHUDFWLRQK\GURSKLOLFVKLHOGLQJGRPDLQVSURWHFWWKHV\VWHP
DIWHUV\VWHPLFDSSOLFDWLRQIURPXQVSHFLILFLQWHUDFWLRQZLWKEORRGFRPSRQHQWVWDUJHWLQJOLJDQGVDOORZFHOO
VSHFLILFELQGLQJDQGLQWHUQDOL]DWLRQLQWRWDUJHWFHOOVDQGPHPEUDQHDFWLYHSHSWLGHVGHULYHGIURPWR[LQVRU
YLUXVHV KDYH D IDYRXUDEOH LQIOXHQFH RQ LQWUDFHOOXODU WUDIILFNLQJ :LWK WKH KHOS RI OLYH FHOO LPDJLQJ
LPSRUWDQW VWHSV OLNH FHOO ELQGLQJ LQWUDFHOOXODU WUDIILFNLQJ DQG HQGRVRPDO UHOHDVH RI VXFK FDUULHUV DUH
UHYHDOHG ,Q YLYR LPDJLQJ DOORZV VWXG\LQJ WKH ELRGLVWULEXWLRQ DQG ELRDFWLYLW\ RI PDFURPROHFXODU GUXJ
FDUULHUVLQUHDOWLPHDQGKHOSVWRGHYHORSLPSURYHGWXPRUWDUJHWHGIRUPXODWLRQV7KHUDSHXWLFFRQFHSWVDUH
DSSOLHGLQGLIIHUHQWWXPRXUPRGHOVLQPLFHORFDODSSOLFDWLRQRIV\QWKHWLFGRXEOHVWUDQGHG51$OHDGVWR
HUDGLFDWLRQRILQWUDFUDQLDOJOLREODVWRPDV\VWHPLFDSSOLFDWLRQRIVPDOOLQWHUIHULQJ51$LQGXFHVVHOHFWLYH
DSRSWRVLVLQVXEFXWDQHRXVWXPRUVDIWHUV\VWHPLFYHFWRUDSSOLFDWLRQ
,03/(0(17$7,212)3+$50$&20(75,&602'(//,1*$1'6,08/$7,21,1
&/,1,&$/'58*'(9(/230(17*(1(5$/$63(&76$1'7+(%2(+5,1*(5
,1*(/+(,0(;3(5,(1&(
6WDDE$
7HDPOHDGHU3KDUPDFRPHWULFV'HSDUWPHQWRI'UXJ0HWDEROLVPDQG3KDUPDFRNLQHWLFV%RHKULQJHU
,QJHOKHLP3KDUPD*PE+&R.*%LUNHQGRUIHU6WU%LEHUDFK5L‰*HUPDQ\
7KH SKDUPDFHXWLFDO LQGXVWU\ FXUUHQWO\ IDFHV WKH FKDOOHQJH WKDW SURGXFWLYLW\ KDV VWDJQDWHG DQG
GHYHORSPHQWFRVWVKDYHFRQWLQXHGWRVRDU)XOOH[SORLWDWLRQLQWHJUDWLRQDQGHYDOXDWLRQRIWKHJHQHUDWHG
GDWDLQIRUPDWLRQ GXULQJ GUXJ GHYHORSPHQW YLD DSSURSULDWH WHFKQLTXHV VXFK DV SKDUPDFRPHWULF DQDO\VHV
PRGHOOLQJDQGVLPXODWLRQZLOOEHQHFHVVDU\WRJDLQNQRZOHGJHWKDWDOORZVWRHIILFLHQWO\VHOHFWWKHPRVW
SURPLVLQJ PROHFXOHVDQG WRGHYHORSWKHP LQWRVXFFHVVIXO PHGLFLQHVWKXVLQFUHDVLQJWKHSUREDELOLW\RI
WHFKQLFDOVXFFHVVIRUDGHYHORSPHQWFDQGLGDWH>@
)RU D VXFFHVVIXO LQWHJUDWLRQ RI SKDUPDFRPHWULFV LQWR WKH GUXJ GHYHORSPHQW SURFHVV WKH IROORZLQJ NH\
FKDOOHQJHVQHHGWREHWDFNOHG
7KH FXOWXUDORUJDQLVDWLRQDO FKDOOHQJH 2IWHQ LQ WKH GLIIHUHQW GLVFLSOLQHV VWXGLHV WR HYDOXDWH WKH
SKDUPDFRORJ\WR[LFRORJ\ $'0(FKDUDFWHULVWLFVVDIHW\DQGHIILFDF\RIDGUXJDUHSODQQHGFRQGXFWHG
DQGDVVHVVHGLQLVRODWLRQ7KHGHYHORSPHQWRI PRGHOVWKDW LQWHJUDWHWKH NQRZOHGJHDYDLODEOHDFURVVWKH
GLIIHUHQW GLVFLSOLQHV DQG LQ SXEOLVKHG OLWHUDWXUH LQ D TXDQWLWDWLYH ZD\ LV PLVVLQJ 7KH FRQVHTXHQW
DSSOLFDWLRQ RI WKHVH PRGHOV LQ GHFLVLRQ PDNLQJ FRXOG KHOS WR VWUHDPOLQH WKH GHYHORSPHQW SURFHVV $
FKDQJHLQPLQGVHWLQWKHGHYHORSPHQWWHDPVWRXVHSKDUPDFRPHWULFVWRJDLQNQRZOHGJHDQGPDNHPRUH
LQIRUPHG GHFLVLRQV LQVWHDG RI UHJDUGLQJ SKDUPDFRPHWULFV DV SXUHO\ VXSSRUWLYH LV QHHGHG $Q
RUJDQLVDWLRQDOVWUXFWXUHWKDWVXSSRUWVWKHLQWHUGLVFLSOLQDU\GLDORJXHRUFURVVIXQFWLRQDOPHHWLQJVVKRXOG
EH HVWDEOLVKHG )XUWKHUPRUH ZLWK SKDUPDFRPHWULF PHWKRGV DQG PHFKDQLVWLF GUXJGLVHDVH PRGHOV
JHWWLQJPRUHFRPSOH[WHDPVVSHFLDOLVHGLQSKDUPDFRPHWULFVXSSRUWDUHQHHGHG
7KH LQIUDVWUXFWXUH FKDOOHQJH 3KDUPDFRPHWULF UHVXOWV QHHG WR EH GHOLYHUHG LQ VKRUW WLPH IUDPHV ZKHQ
GHFLVLRQV DUH EHLQJ PDGH 7KXV WKH RIWHQ FRPSXWDWLRQDO UHVRXUFH LQWHQVLYH DQG QRW YHU\ XVHUIULHQGO\
SURJUDPPHVXVHGLQWKHSKDUPDFRPHWULF ILHOG QHHGWREHLPSOHPHQWHGLQDQHQYLURQPHQWHQDEOLQJIDVW
DQGFRQYHQLHQWSKDUPDFRPHWULFDQDO\VHV)XUWKHUPRUHDGDWDEDVHFRQWDLQLQJDOOGDWDREWDLQHGLQFOLQLFDO
VWXGLHV LQFOXGLQJ SKDUPDFRNLQHWLF DQG ELRPDUNHU GDWD VKRXOG EH HVWDEOLVKHG DQG D SURFHVV VKRXOG EH
GHYHORSHG WKDW DOORZV WR SURYLGH KLJK TXDOLW\ UHDG\ WR XVH GDWD VHWV FORVH WR GDWDEDVH ORFN ,Q DGGLWLRQ
VWDQGDUGJOREDOO\KDUPRQL]HGSURFHVVHVFRYHULQJSODQQLQJSHUIRUPLQJDQGUHSRUWLQJRISKDUPDFRPHWULF
DQDO\VHVQHHGWREHLPSOHPHQWHG
7KHUHVRXUFHFKDOOHQJH7KHUHLVDODFNRIWUDLQHGDQGH[SHULHQFHGSKDUPDFRPHWULFLDQV7KXVDFRQFHSW
QHHGVWREHGHYHORSHGWRGHDOZLWKWKLVVKRUWDJH
$W%,ZHDGGUHVVHGWKHDERYHPHQWLRQHGFKDOOHQJHVDVIROORZV
7KH FXOWXUDORUJDQLVDWLRQDO FKDOOHQJH $ FOLQLFDO SKDUPDFRNLQHWLFSKDUPDFRG\QDPLF SODQ ZDV
LPSOHPHQWHG DV D WRRO WR GLVFXVV VWUHDPOLQH DQG DJUHH ZLWKLQ WKH UHOHYDQW GLVFLSOLQHV RQ DFWLYLWLHV
UHJDUGLQJ SKDUPDFRNLQHWLFV DV ZHOO DV SKDUPDFRG\QDPLF LQYHVWLJDWLRQV LQFOXGLQJ WKH SKDUPDFRPHWULF
DFWLYLWLHV 7R HIILFLHQWO\ VXSSRUW SKDUPDFRPHWULF DFWLYLWLHV ZH IRUPHG D WHDP RI SKDUPDFRNLQHWLFLVWV
FRQFHQWUDWLQJRQSKDUPDFRPHWULFDQDO\VHV7KHSKDUPDFRPHWULFLDQVVSHFLDOLVHLQDWKHUDSHXWLFDUHDIRU
ZKLFKZHVWDUWHGWREXLOGDPRGHOOLQJSODWIRUPFRQVLVWLQJRIPRGHOVWKDWFDQEHXVHGDFURVVSURMHFWVLQ
WKHUHVSHFWLYHWKHUDSHXWLFDUHD
7KHLQIUDVWUXFWXUHFKDOOHQJH7RDOORZHIILFLHQWDQGFRQYHQLHQWXVHRI1210(0WKHVWDQGDUGVRIWZDUH
IRUPRGHOOLQJLQWKHSKDUPDFHXWLFDOLQGXVWU\DOLQX[JULGDUFKLWHFWXUHZDVGHYHORSHGDQGDGGLWLRQDOWRROV
ZHUH LPSOHPHQWHG IDFLOLWDWLQJ FRQYHQLHQW XVH RI 1210(0 DQG HYDOXDWLRQ RI UHVXOWV 7KH FOLQLFDO
GDWDEDVH ZDV H[WHQGHG WR KROG DOVR SKDUPDFRNLQHWLF DV ZHOO DV ELRPDUNHU GDWD DQG D 6$6 WHPSODWH
SURJUDPPH ZDVGHYHORSHGWRJHQHUDWH1210(0GDWDVHWV7KH6$6WHPSODWHSURJUDPPHFRYHUV PRVW
VWDQGDUGFDVHVDQGQHHGVRQO\VPDOODGMXVWPHQWVWRJHQHUDWHWKHGDWDVHWIRUDSDUWLFXODUVWXG\$JOREDOO\
KDUPRQL]HGSURFHVVIRUSKDUPDFRPHWULFDFWLYLWLHVZDVGHYHORSHGJXDUDQWHHLQJKLJKTXDOLW\SODQQLQJDQG
GRFXPHQWDWLRQRISKDUPDFRPHWULFDQDO\VHV
5HVRXUFH FKDOOHQJH 7R FRSH ZLWK WKH VKRUWDJH RI VWDII ZH IRFXV RXU SKDUPDFRPHWULF DFWLYLWLHV RQ
VHOHFWHGWKHUDSHXWLFDUHDVDQGRXWVRXUFHZRUNSDFNDJHVWRH[WHUQDORUJDQLVDWLRQV&52VXQLYHUVLW\7R
UHGXFH WKH VKRUWDJH RI WUDLQHG SKDUPDFRPHWULFLDQV LQ WKH IXWXUH D JUDGXDWH WUDLQLQJ SURJUDP
3KDUPDFRPHWULFV&RPSXWDWLRQDO'LVHDVH0RGHOOLQJZDVLQLWLDWHGWRJHWKHUZLWKXQLYHUVLWLHV
>@ 86 )RRG DQG 'UXJ $GPLQLVWUDWLRQ &KDOOHQJH DQG RSSRUWXQLW\ RQ WKH FULWLFDO SDWK WR QHZ PHGLFDO SURGXFWV
0DUFK$YDLODEOHDWKWWSZZZIGDJRYRFLQLWLDWLYHVFULWLFDOSDWKZKLWHSDSHUKWPO
&RPXQLFDFLRQHV2UDOHV
COMUNICACIONES ORALES
+,'52*(/(60,&523$57,&8/$'26&21$),1,'$'3256$/(6%,/,$5(6
)<DxH],&KLDQHOOD6$3LOHWVN\$&RQFKHLUR\&$OYDUH]/RUHQ]R
'HSW)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DQWLDJRGH
&RPSRVWHOD6DQWLDJRGH&RPSRVWHOD(VSDxD&UDQILHOG8QLY%HGIRUG0.'7(QJODQG
HPDLOFDUPHQDOYDUH]ORUHQ]R#XVFHV
,QWURGXFFLyQ
(O WUDWDPLHQWR IDUPDFROyJLFR GH OD
KLSHUFROHVWHUROHPLD
SODQWHD
LPSRUWDQWHV
SUREOHPDV &RPR FRQVHFXHQFLD GH HOOR VH HVWi
GHGLFDQGR XQ JUDQ HVIXHU]R DO GHVDUUROOR GH
VLVWHPDV ³WUDPSD´ TXH DFW~HQ HQ HO LQWHVWLQR
FRPR ³VHFXHVWUDQWHV´LyQLFRVRKLGURIyELFRVGH
ORV OtSLGRV R GH VXV WUDQVSRUWDGRUHV ORV iFLGRV
ELOLDUHV (OREMHWLYRGHOWUDEDMRIXHVLQWHWL]DU
QXHYRVSROtPHURVFDSDFHVGHFDSWDUiFLGRFyOLFR
)LJXUDDFXGLHQGRDXQGLVHxRUDFLRQDOTXH
HYLWHORVLQFRQYHQLHQWHVGHOPpWRGRHPStULFRGH
SUXHED \ HUURU 3DUD HOOR VH DSOLFy XQD WpFQLFD
GHPRGHOL]DFLyQTXHSHUPLWHVHOHFFLRQDUORV
PRQyPHURV FRQ PD\RU DILQLGDG SRU HO iFLGR
FyOLFR &RQ HOORV VH SUHSDUDURQ KLGURJHOHV
DOWDPHQWH UHWLFXODGRV SRU SURFHGLPLHQWRV
FRQYHQFLRQDOHV \ DSOLFDQGR OD WpFQLFD GH
LPSULQWLQJ PROHFXODU \ VH HYDOXy VX
FDSDFLGDG SDUD H[WUDHU FRODWR VyGLFR GH XQ
PHGLRDFXRVR
)LJXUD (VWUXFWXUD GHO iFLGR FyOLFR
5 5 2+
0DWHULDOHV\0pWRGRV
0DWHULDOHV
ÈFLGR FyOLFR FRODWR VyGLFR HWLOHQJOLFRO
GLPHWDFULODWR
(*'0$
ƍD]RELV
LVREXWLURQLWULOR$,%1IRVIDWRGHHWLOHQJOLFRO
PHWDFULODWR (*03 \ GLHWLODPLQRHWLO
PHWDFULODWR '($(0 GH 6LJPD$OGULFK 8.
1DPLQRSURSLO PHWDFULODPLGD $30$Â+&O
GH3RO\VFLHQFHV,QF$OHPDQLD
0RGHOL]DFLyQFRPSXWDFLRQDO
6H HVWXGLDURQ ODV LQWHUDFFLRQHV HQ '062
GLPHWLOVXOIy[LGR HQWUH HO iFLGR FyOLFR \ ORV
PRQyPHURVGHXQDDPSOLDELEOLRWHFDXWLOL]DQGR
OD SODWDIRUPD 6LOLFRQ *UDSKLFV 2FWDQH70 HO
VLVWHPD RSHUDWLYR ,5,; 6LOLFRQ *UDSKLFV
86$ HO VRIWZDUH 6<%</ 70 7ULSRV ,QF
86$ \ HO DOJRULWPR /($3)52*70 LWHUDFLRQHV
6tQWHVLVGHORVHQWUDPDGRVSROLPpULFRV
6HPH]FOyHOUHWLFXODQWH(*'0$JFRQ
ORV PRQyPHURV IXQFLRQDOHV (*03 PJ
'($(0 PJ y $30$ PJ \ VH
DxDGLHURQ PO GH '062 \ PJ GH $,%1
3DUD SUHSDUDU VLVWHPDV LPSULQWHG VH
LQFRUSRUDURQ PJ GH iFLGR FyOLFR UHODFLyQ
PRODU PROpFXOD PROGH PRQyPHUR IXQFLRQDO
6H SROLPHUL]y D ž& GXUDQWH K /RV
SROtPHURV VH SXOYHUL]DURQ VH WDPL]DURQ \ VH
UHFRJLy
OD
IUDFFLyQ
JUDQXORPpWULFD
FRUUHVSRQGLHQWH DO LQWHUYDOR μP 3DUD
HOLPLQDU ODV PROpFXODV PROGH ORV HQWUDPDGRV
SROLPpULFRVVHVRPHWLHURQDUHIOXMRFRQPHWDQRO
PO\ILQDOPHQWHVHGHVHFDURQ
,VRWHUPDVGHDGVRUFLyQGHFRODWRVyGLFR
/RV SROtPHURV PJ VH FDUJDURQ HQ
FROXPQDV GH XOWUDFHQWUtIXJD 3LHUFH &HQWULIXJH
&ROXPQV PO 7KHUPR6FLHQWLILF 86$ FRQ
μO GH GLVROXFLyQ GH FRODWR VyGLFR P0 /DV FROXPQDV VH LQWURGXMHURQ HQ YLDOHV
(SSHQGRUIVHVRPHWLHURQDDJLWDFLyQGXUDQWH
K \ VH FHQWULIXJDURQ PLQ D USP /D
FRQFHQWUDFLyQGHFRODWRVyGLFRHQHOILOWUDGRVH
GHWHUPLQy HVSHFWURIRWRPpWULFDPHQWH (O
DQiOLVLVSRUUHJUHVLyQOLQHDOGHORVSHUILOHVORJ%
FDQWLGDG GH FRODWR VyGLFR DGVRUELGR μPROJ
HQWUDPDGR IUHQWH D ORJ ) FRQFHQWUDFLyQ GH
HTXLOLEULR PROHVO SHUPLWLy HVWLPDU ORV
SDUiPHWURV GHO DMXVWH D OD HFXDFLyQ GH
)UHXQGOLFK
/RJ% PÂORJ)ORJD
/D GLVWULEXFLyQ GH DILQLGDG GH ORV OXJDUHV GH
DGVRUFLyQ VH REWXYR LQWURGXFLHQGR ORV
SDUiPHWURVP\DHQODHFXDFLyQ
1. ÂDÂPÂPHÂPÂORJ.
ILMDQGRFRPROtPLWHV
.PLQ )PD[\.PD[ )PLQ
([WUDFFLyQGHFRODWRVyGLFRGHOPHGLRDFXRVR
6H HPSDTXHWDURQ PJ GH SROtPHUR HQ
FDUWXFKRV GH PO )LOWUDWLRQ WXEHV 6XSHOFR86$SDUDH[WUDFFLyQDYDFtR9LVL3UHS
YLDO YDFXXP PDQLIROG 6XSHOFR 86$ 3DUD
DFRQGLFLRQDU ORV SROtPHURV VH KLFLHURQ SDVDU PO GH DJXD 1D2+ iF IyUPLFR 0 \
PHWDQRO $ FRQWLQXDFLyQ VH SDVDURQ DOtFXRWDV
GHPOGHGLVROXFLyQGHFRODWRVyGLFRP0
POPLQ KDVWD FRPSOHWDU PO \ VH
GHWHUPLQyODFDQWLGDGGHFRODWRVyGLFRH[WUDtGD
,;&RQJUHVRGHOD6(),*
&RPXQLFDFLRQHV2UDOHV
5HVXOWDGRV\'LVFXVLyQ
7DEOD5HVXOWDGRVGHODMXVWHGHODVLVRWHUPDV
DOPRGHORGH)UHXQGOLFK
(QWUDPDGR
(*031,3
(*030,3
'($(01,3
'($(00,3
$30$1,3
$30$0,3
&21752/1,3
&21752/0,3
P
/RJD
U
/RV HQWUDPDGRV SROLPpULFRV FRQ PRQyPHUR
IXQFLRQDO SUHVHQWDURQ XQD FDSDFLGDG GH
H[WUDFFLyQ VXSHULRU D OD GH ORV VLVWHPDV FRQWURO
)LJXUD/DFDSDFLGDGGHVDWXUDFLyQPiVDOWD
\ ORV QLYHOHV GH FRODWR VyGLFR UHPDQHQWH PiV
EDMRVVHREWXYLHURQXVDQGR$30$
$JUDGHFLPLHQWRV
0(& 6$) )('(5 \ ;XQWD GH
*DOLFLD 3*,',7&6$35 ) <DxH]
DJUDGHFH DO 0(& XQD EHFD )3, \ XQD D\XGD SDUD
XQDHVWDQFLDHQOD8QLYHUVLGDGGH&UDQILHOG8.
Control
0.15
0.10
0.05
NIP
MIP
0.00
Colato remanente (mmol/l)
0.20
0.15
0.10
0.05
NIP
MIP
0.00
0
5
10
15
20
25
30
Volumen (ml)
Colato absorbido (mmol/g)
0.20
APMA
0.15
0.10
0.05
NIP
MIP
0.00
0.20
Colato remanente (mmol/l)
/DV LVRWHUPDV GH DGVRUFLyQ VH DMXVWDURQ DO
PRGHOR GH )UHXQGOLFK \ VH HVWLPDURQ OD
KRPRJHQHLGDG GH ORV SXQWRV GH XQLyQ \ VX
DILQLGDG SRU HO DEVRUEDWR FXDQGR P HVWi
FRPSUHQGLGD HQWUH \ /RV YDORUHV GH P
PD\RU TXH GH ORV HQWUDPDGRV FRQWURO LQGLFDQ
TXH QR H[LVWHQ SXQWRV GH XQLyQ HVSHFtILFRV
7DEOD (O PRQyPHUR IXQFLRQDO LQFUHPHQWy
OD KHWHURJHQHLGDG GH ORV SXQWRV GH XQLyQ /RV
HQWUDPDGRV FRQ (*03 SUHVHQWDURQ PHQRV
SXQWRV GLVSRQLEOHV SDUD OD DGVRUFLyQ \ XQD
FRQVWDQWH GH DILQLGDG PHQRU (Q ORV VLVWHPDV
0,3 VH LQFUHPHQWy HO Q~PHUR GH SXQWRV GH
XQLyQ FRQ DOWD DILQLGDG /RV HQWUDPDGRV FRQ
$30$PRVWUDURQHOQ~PHURPiVDOWRGHSXQWRV
GHXQLyQGHDOWDDILQLGDG\QRVHGHWHFWyHIHFWR
LPSULQWLQJ
Colato absorbido (mmol/g)
0.20
/D PRGHOL]DFLyQ FRPSXWDFLRQDO SHUPLWLy
VHOHFFLRQDU WUHV PRQyPHURV IXQFLRQDOHV
$30$Â+&O(*03\'($(0FRQHQHUJtDVGH
LQWHUDFFLyQ FRQ FRODWR VyGLFR PHGLDVDOWDV \
VXSHULRUHV D ODV REWHQLGDV FRQ HO UHWLFXODQWH
(*'0$
6H
SUHSDUDURQ
HQWUDPDGRV
SROLPpULFRVFRQWURO\RWURVFRQFDGDPRQyPHUR
IXQFLRQDO \ SDUD WRGRV HOORV VH HQVD\DURQ ODV
SRVLELOLGDGHV TXH RIUHFH OD LQFRUSRUDFLyQ GHO
iFLGR FyOLFR HQ HO PRPHQWR GH OD VtQWHVLV GH
PDQHUD TXH VXV PROpFXODV SXHGDQ DFWXDU FRPR
PROGHV VLVWHPDV 0,3 /RV PRQyPHURV VH
GLOX\HURQ FRQ '062 SDUD IRUPDU SRURV TXH
IDFLOLWHQODGLIXVLyQGHOFRODWRVyGLFR
0.15
0.10
0.05
NIP
MIP
0.00
0
5
10
15
20
25
30
)LJXUD&RODWRVyGLFRH[WUDtGRSRUSDUWtFXODV
FRQWURO $ R FRQ $30$ % \ FRQFHQWUDFLyQ
UHPDQHQWHHQPHGLRDFXRVR
&RQFOXVLRQHV
Volumen (ml)
/D VHOHFFLyQ GH PRQyPHURV SRU PRGHOL]DFLyQ
FRPSXWDFLRQDO SHUPLWH LQFUHPHQWDU OD DILQLGDG
GH HQWUDPDGRV DFUtOLFRV SRU FRODWR VyGLFR \ VX
FDSDFLGDG SDUD DFWXDU FRPR VHFXHVWUDQWHV (O
LPSULQWLQJ PROHFXODU PHMRUy OLJHUDPHQWH OD
HILFDFLDGHORVVLVWHPDV
%LEOLRJUDItD
'KDO HW DO ,QG (QJ &KHP 5HV 3LOHWVN\HWDO$QDO\VW
$OYDUH]/RUHQ]R HW DO - &RQWURO 5HOHDVH )LQL\=XPDQ&ROO&]HFK&KHP&RPP
5DPSH\HWDO$QDO&KHP
/,%(5$&,21'(9(*)$3$57,5'(&(/8/$60,&52(1&$368/$'$63$5$(/
75$7$0,(172'(/$(1)(50('$''($/=+(,0(5
$3RUWHUR50+HUQiQGH]*2ULYH'$QWHTXHUD&6SXFK(&DUUR-/3HGUD]
/DERUDWRULRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGHO3DtV9DVFR839(+8
3DVHRGHOD8QLYHUVLGDGQž9LWRULD*DVWHL](VSDxD
*UXSRGH(QIHUPHGDGHV1HXURGHJHQHUDWLYDV/DERUDWRULRGH1HXURFLHQFLDV&HQWURGH
,QYHVWLJDFLyQ+RVSLWDO³GH2FWXEUH´0DGULG(VSDxD
GXUDQWH KRUDV HQ FXOWLYR \ WUDQVFXUULGR HVH
,QWURGXFFLyQ/DHQIHUPHGDGGH$O]KHLPHU
WLHPSR VH UHFRJLHURQ ORV VREUHQDGDQWHV SDUD
HV XQD GH ODV HQIHUPHGDGHV QHXURGHJHQHUDWLYDV
DQDOL]DUODFDQWLGDGGH9(*)TXHFRQWHQtDQ
PiVGHYDVWDGRUDVTXHVHFRQRFHQ6HFDUDFWHUL]D
3DUD HO HVWXGLR LQ YLYR VH XWLOL]DURQ UDWRQHV
SRU OD DSDULFLyQ GH SODFDV GH βDPLORLGH
WUDQVJpQLFRV$3336(OJUXSRFRQWUROUHFLELy
H[WUDFHOXODUHV GH RYLOORV QHXURILEULODUHV
FiSVXODVFRQFpOXODVQRWUDQVIHFWDGDV\HOJUXSR
LQWUDFHOXODUHV \ PXHUWH QHXURQDO $OJXQRV
H[SHULPHQWDO UHFLELy FiSVXODV FRQ FpOXODV
WUDEDMRVKDQUHODFLRQDGRODHQIHUPHGDGGH
VHFUHWRUDVGH9(*)(QHOFRUWH[GHFDGDUDWyQ
$O]KHLPHU FRQ XQD DOWHUDFLyQ GHO VLVWHPD
VH LPSODQWDURQ DOUHGHGRU GH PLFURFiSVXODV
YDVFXODUFHUHEUDOOOHJDQGRDSURSRQHUTXHGLFKD
/RV DQLPDOHV VH PDQWXYLHURQ HQ
DOWHUDFLyQLPSLGHODFRUUHFWDHOLPLQDFLyQGHORV
FRQGLFLRQHV GH ODERUDWRULR VLJXLHQGR OD
SpSWLGRV GH βDPLORLGH KDFLHQGR TXH HVWRV VH
QRUPDWLYDFRPXQLWDULD
DFXPXOHQSURYRFDQGROD IRUPDFLyQGHSODFDV \
(ODQiOLVLVKLVWROyJLFRVHUHDOL]y\
ODPXHUWHQHXURQDO'HKHFKRHQODHQIHUPHGDG
GtDVGHVSXpVGHODLPSODQWDFLyQGHODVFiSVXODV
GH $O]KHLPHU VH KD YLVWR TXH ORV YDVRV
VH VDFULILFDURQ ORV DQLPDOHV SDUD UHDOL]DU XQ
VDQJXtQHRVFHUHEUDOHVVHGHJHQHUDQ
DQiOLVLV LPPXQRKLVWRTXtPLFR HQ HO FXDO VH
(O IDFWRU GH FUHFLPLHQWR GHO HQGRWHOLR
DQDOL]y OD IRUPDFLyQ GH QXHYRV YDVRV
YDVFXODU 9(*) HV XQR GH ORV IDFWRUHV
VDQJXtQHRV PHGLDQWH XQ GREOH PDUFDMH FRQ
DQJLRJpQLFRV PiV SRWHQWHV TXH VH FRQRFHQ
OHFWLQD\DQWL%UG8
5HFLHQWHPHQWH VH KD GHVFXELHUWR TXH WDPELpQ
7UHV PHVHV GHVSXpV GH OD LPSODQWDFLyQ VH
SUHVHQWD IXQFLRQHV QHXURSURWHFWRUDV \
UHDOL]y XQ WHVW GH UHFRQRFLPLHQWR GH REMHWRV
QHXURJpQLFDV
257 SDUD YDORUDU OD PHPRULD D FRUWR SOD]R
/D OLEHUDFLyQ VRVWHQLGD HQ HO FHUHEUR GH XQ
(Q HVWH HQVD\R VH XWLOL]DURQ UDWRQHV & FRPR
IDFWRUDQJLRJpQLFRSRGUtDDXPHQWDUODGHQVLGDG
FRQWURO SRVLWLYR (VWH HVWXGLR FRQVWD GH GRV
GH ORV YDVRV VDQJXtQHRV \ FRQ HOOR PHMRUDU HO
IDVHV XQD SULPHUD IDVH HQ OD TXH HO DQLPDO VH
DFODUDPLHQWR GH ORV SpSWLGRV GH βDPLORLGH
IDPLOLDUL]DFRQXQREMHWR\XQDVHJXQGDIDVHHQ
GLVPLPX\HQGR OD FDQWLGDG GH SODFDV \
OD TXH HO DQLPDO WLHQH DFFHVR DO REMHWR TXH KD
PHMRUDQGR ODV IXQFLRQHV FRJQLWLYDV DIHFWDGDV
UHFRQRFLGR \ D RWUR QXHYR PLGLpQGRVH HO
3RUHOORHQHVWHWUDEDMRVHKDHVWXGLDGRHOHIHFWR
WLHPSRTXHSDVDH[SORUDQGRFDGDREMHWR
GHODOLEHUDFLyQFRQWLQXDGH 9(*) PHGLDQWHOD
WHFQRORJtDGHPLFURHQFDSVXODFLyQGHFpOXODV
5HVXOWDGRV \ GLVFXVLyQ 7RGDV ODV
PLFURFiSVXODV SUHVHQWDQ XQD IRUPD HVIpULFD \
0DWHULDO\0pWRGRV(QHVWHHVWXGLRVHKDQ
XQLIRUPH WDO \ FRPR VH SXHGH DSUHFLDU HQ OD
XWLOL]DGR ILEUREODVWRV %+. PRGLILFDGRV
ILJXUD
JHQpWLFDPHQWH SDUD VHFUHWDU 9(*) /RV
ILEUREODVWRV VH HQFDSVXODURQ PHGLDQWH XQ
JRWHDGRU HOHFWURVWiWLFR HQ FiSVXODV DOJLQDWR
SRO\/OLVLQDDOJLQDWR $3$ DOJLQDWR GH EDMD
YLVFRVLGDG ULFR HQ DFLGR JXOXUyQLFR )0&
%LRSRO\PHU
1RUZD\
VLJXLHQGR
HO
SURFHGLPLHQWR GH /LP \ 6XP FRQ OLJHUDV
PRGLILFDFLRQHV
(O GLiPHWUR \ OD PRUIRORJtD GH ODV
PLFURFiSVXODV VH HVWXGLDURQ PHGLDQWH XQ
)LJXUD )RWRJUDItD GH ODV FpOXODV VHFUHWRUDV
PLFURVFRSLR ySWLFR LQYHUWLGR 1LNRQ 706
GH9(*)PLFURHQFDSVXODGDV
HTXLSDGRFRQXQDFiPDUD
/D FDQWLGDG GH 9(*) VHFUHWDGR SRU ODV
/DFDQWLGDGGH9(*)VHFUHWDGRLQYLWURSRU
FpOXODVHQFDSVXODGDVVHGHWHUPLQyPHGLDQWHXQD
ODV FpOXODV HQFDSVXODGDV IXH SURJUHVLYDPHQWH
WpFQLFDGH(/,6$$PHUVKDP%LRWUDN9DVFXODU
DXPHQWDQGR OR FXDO GHPXHVWUD OD EXHQD
(QGRWKHOLDO *URZWK )DFWRU KXPDQ (OLVD
DGDSWDFLyQ GH ODV FpOXODV D ODV PLFURFiSVXODV
6\VWHP 6H FRORFDURQ DOUHGHGRU GH /DV FDQWLGDGHV GH 9(*) VHFUHWDGDV IXHURQ ODV
FiSVXODVHQXQDSODFDGHSRFLOORVFRQμO
VLJXLHQWHV
GH PHGLR GH FXOWLYR /D SODFD VH PDQWXYR
,;&RQJUHVRGHOD6(),*
7DEOD , &DQWLGDG GH 9(*) VHFUHWDGD ³LQ
YLWUR´ SJ PLFURFiSVXODV KRUDV D ORV
GLIHUHQWHVWLHPSRVHVWXGLDGRV9DORUHVPHGLRV ±
6'
'tD
'tD
'tD
0HGLD '6
(Q ORV HVWXGLRV LQPXQRKLVWRTXtPLFRV
UHDOL]DQGR XQD GREOH WLQFLyQ FRQ %UG8 SDUD
GHWHFWDUODVFpOXODVHQSUROLIHUDFLyQ\OHFWLQDGH
WRPDWHPDUFDGRUHVSHFLILFRSDUDFpOXODVGHORV
YDVRV VDQJXtQHRV VH REVHUYy XQ DXPHQWR
VLJQLILFDWLYR GH OD GHQVLGDG GH ORV YDVRV
VDQJXtQHRV HQ HO FRUWH[ FHUHEUDO GH ORV UDWRQHV
WUDWDGRV FRQ 9(*) UHVSHFWR D ORV UDWRQHV
FRQWURO OR FXDO SRQH GH PDQLILHVWR OD
IXQFLRQDOLGDG GHO 9(*) VHFUHWDGR D SDUWLU GH
ODVFpOXODVPLFURHQFDSVXODGDVILJXUD
$
Arbitrary Units
4
*
3
2
1
0
Control VEGF
%
&RQWURO
9(*)
&
/HFWLQ%UG8
/HFWLQ%UG8
)LJXUD $ 'HQVLGDG YDVFXODU HQ UDWRQHV
WUDWDGRV \ FRQWURO % 7LQFLyQ FRQ OHFWLQD HQ
UDWRQHVWUDWDGRV\FRQWURO&'REOHWLQFLyQHQ
UDWRQHVWUDWDGRVLPiJHQHVDGLVWLQWRDXPHQWR
(Q HO WHVW GH UHFRQRFLPLHQWR GH REMHWRV
257WDO\FRPRSXHGHREVHUYDUVHHQODILJXUD
ORV UDWRQHV WUDWDGRV FRQ ODV PLFURFiSVXODV
SURGXFWRUDV GH 9(*) REWXYLHURQ XQ YDORU
VLJQLILFDWLYDPHQWH VXSHULRU GHO tQGLFH GH
UHFRQRFLPLHQWR DO TXH SUHVHQWDEDQ ORV UDWRQHV
FRQWURO H LQFOXVR OLJHUDPHQWH VXSHULRU DO GH ORV
UDWRQHV&
Recognition index
&RPXQLFDFLRQHV2UDOHV
100
80
60
40
20
0
F 6+$0 9(*)
)LJXUD 7HVW GH FRPSRUWDPLHQWR HQ UDWRQHV
$33369DORUHVPHGLRV±6'S<
'LVFXVLyQ \ FRQFOXVLRQHV (Q HVWH HVWXGLR
VH KDQ LPSODQWDQGR HQ HO FRUWH[ GH UDWRQHV
$333V FpOXODV VHFUHWRUDV GH 9(*)
HQFDSVXODGDVHQPLFURFiSVXODV$3$
/D GHQVLGDG YDVFXODU GHWHFWDGD HQ HO FRUWH[
GH ORV UDWRQHV WUDQVJpQLFRV WUDWDGRV FRQ ODV
PLFURFiSVXODVSURGXFWRUDVGH9(*)UHVXOWyVHU
VLJQLILFDWLYDPHQWHVXSHULRUDODTXHSUHVHQWDEDQ
ORV UDWRQHV FRQWURO OR FXDO SRQH GH PDQLILHVWR
TXH HO 9(*) VHFUHWDGR SRU ODV FpOXODV
HQFDSVXODGDV HV IXQFLRQDO LQ YLYR \ TXH OD
IRUPXODFLyQ XWLOL]DGD HQ HVWH HVWXGLR HV FDSD]
GH SURGXFLU XQD OLEHUDFLyQ FRQWLQXD GXUDQWH
SURORQJDGRV SHULRGRV GH WLHPSR OR FXDO SRGUtD
SHUPLWLUUHGXFLUHOQ~PHURGHDGPLQLVWUDFLRQHV
/RV UHVXOWDGRV REWHQLGRV HQ HO WHVW GH
UHFRQRFLPLHQWR GH REMHWRV SRGUtDQ LQGLFDU TXH
HOHIHFWRDQJLRJpQLFRGHO9(*)PHMRUDDOJXQDV
GH ODV IXQFLRQHV FRJQLWLYDV FRPR OD PHPRULD D
FRUWR SOD]R QR REVWDQWH HVWD PHMRUD SRGUtD
GHEHUVH WDPELpQ DO HIHFWR QHXURSURWHFWRU GHO
9(*)\QRVRORDOHIHFWRDQJLRJpQLFR
(Q EDVH D ORV UHVXOWDGRV REWHQLGRV HQ HVWH
HVWXGLR VH SXHGH FRQFOXLU TXH OD OLEHUDFLyQ
VRVWHQLGD GH 9(*) D QLYHO GH FRUWH[ FHUHEUDO
SXHGH FRQVWLWXLU XQD KHUUDPLHQWD HILFD] SDUD
FRPEDWLUDOJXQRVVtQWRPDVGHODHQIHUPHGDGGH
$O]KHLPHUDVLPLVPRHVLPSRUWDQWHGHVWDFDUTXH
OD LQPRYLOL]DFLyQ GH FpOXODV HQ PLFURFiSVXODV
ELRFRPSDWLEOHV
HV
XQD
DSUR[LPDFLyQ
WHFQROyJLFD HILFD] SDUD FRQVHJXLU GLFKD
OLEHUDFLyQVRVWHQLGD
5HIHUHQFLDV
3HUHLUD 3$ \ FROV &XUU 'UXJ 7DUJHWV
&161HXURO'LVRUG
,DGHFROD & \ FROV 1DW 5HY 1HXURVFL =ORNRYLF %9 \ FROV $GY 'UXJ 'HOLY
5HY
=ORNRYLF%9\FROV7UHQGV1HXURVFL
6WRUNHEDXP ( \ FROV %LRHVVD\V /LP)\FROV6FLHQFH
+HUQiQGH]50\FROV3
$FNQRZOHGJPHQWV
$ 3RUWHUR DJUDGHFH D OD 8QLYHUVLGDG GHO 3DtV 9DVFR
839(+8ODEHFDFRQFHGLGD
(VWHWUDEDMRIRUPDSDUWHGHXQSUR\HFWRILQDQFLDGRSRUHO
0LQLVWHULR&LHQFLDH,QQRYDFLyQ6$)\ORV
IRQGRV)('(5
0,&523$57Ë&8/$6'(3/$*$&$5*$'$6&21$*(17(61(8523527(&725(6
*'1)<%'1)8175$7$0,(172327(1&,$/3$5$(/*/$8&20$
3&KHFD&DVDOHQJXD,%UDYR2VXQD,70ROLQD0DUWtQH]%7XFNHU0-<RXQJ5+HUUHUR
9DQUHOO
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDG&RPSOXWHQVH
GH0DGULG(VSDxD
'HSDUWDPHQWRGH2IWDOPRORJtD+DUYDUG0HGLFDO6FKRRO6FKHSHQV(\H5HVHDUFK,QVWLWXWH6WDQLIRUG
6WUHHW%RVWRQ0$
,QWURGXFFLyQ
(OJODXFRPDHVXQDQHXURSDWtDGHJHQHUDWLYDTXH
FRQVWLWX\H XQD GH ODV SULPHUDV FDXVDV GH
FHJXHUDHQORVSDtVHVGHVDUUROODGRV/DFHJXHUD
DVRFLDGD DO JODXFRPD HV GHELGD D GDxRV HQ HO
D[yQ GHO QHUYLR ySWLFR TXH SURYRFD PXHUWH
JUDGXDO GH ODV FpOXODV JDQJOLRQDUHV GH OD UHWLQD
&*5 (VWXGLRV SUHOLPLQDUHV OOHYDGRV D FDER
HQ DQLPDOHV GH H[SHULPHQWDFLyQ FRQ *'1)
)DFWRU 1HXURWUyILFR 'HULYDGR GH OD OtQHD
FHOXODU *OLDO \ %'1) )DFWRU 1HXURWUyILFR
'HULYDGR GHO &HUHEUR KDQ RIUHFLGR UHVXOWDGRV
SURPHWHGRUHV HQ OD SURWHFFLyQ GH HVWDV FpOXODV
GHELGRDTXHGLFKRVIDFWRUHVLQWHUILHUHQHQ
XQSDVRHVHQFLDOGHOSURFHVRGHDSRSWRVLV
(O WUDWDPLHQWR PiV HILFD] SDUD ODV SDWRORJtDV
TXH DIHFWDQ DO VHJPHQWR SRVWHULRU GHO RMR HV HO
GHSyVLWR GLUHFWR GH OD VXVWDQFLD DFWLYD HQ HO
OXJDUGHDFFLyQHOLPLQDQGRHIHFWRVVHFXQGDULRV
VLVWpPLFRV 6LQ HPEDUJR ODV LQ\HFFLRQHV
LQWUDRFXODUHVQRHVWiQH[HQWDVGHSUREOHPDV\VH
DVRFLDQ FRQ HIHFWRV DGYHUVRV WDOHV FRPR
FDWDUDWDV
GHVSUHQGLPLHQWR
GH
UHWLQD
HQGRIWDOPLWLV \ KHPRUUDJLDV YtWUHDV 6RQ
QHFHVDULDV SRU WDQWR IRUPDV GH DGPLQLVWUDFLyQ
FDSDFHV GH SURSRUFLRQDU FRQFHQWUDFLRQHV
WHUDSpXWLFDV GHO IiUPDFR SRU SHULRGRV
SURORQJDGRV GH WLHPSR HYLWDQGR DVt ODV
LQ\HFFLRQHV
VXFHVLYDV
/RV
VLVWHPDV
PLFURSDUWLFXODUHV ELRGHJUDGDEOHV GH OLEHUDFLyQ
FRQWURODGD VRQ XQD DOWHUQDWLYD PX\ LQWHUHVDQWH
\D TXH VH SXHGHQ DGPLQLVWUDU FRPR XQD
LQ\HFFLyQ FRQYHQFLRQDO GHVDSDUHFLHQGR GHO
OXJDU GH DFFLyQ XQD YH] HMHUFLGR HO HIHFWR
'HVSXpV GH VX DGPLQLVWUDFLyQ ODV
PLFURSDUWtFXODV IRUPDQ XQ DJUHJDGR HQ OD
FDYLGDG YtWUHD FDSD] GH FRQWURODU OD OLEHUDFLyQ
GHO IiUPDFR GXUDQWH VHPDQDV VLQ SURGXFLU
GDxRWLVXODU
(O REMHWLYR GHO SUHVHQWH WUDEDMR KD VLGR HO
GHVDUUROOR \ OD FDUDFWHUL]DFLyQ GH XQD
IRUPXODFLyQ GH PLFURHVIHUDV HODERUDGDV FRQ
iFLGR SROL OiFWLFRFRJOLFyOLFR 3/$*$
FDUJDGDVFRQ*'1)\%'1)
0DWHULDOHV\0pWRGRV
(ODERUDFLyQGHPLFURSDUWtFXODV
/DVPLFURSDUWtFXODV03VGH3/$*$FDUJDGDV
FRQ *'1) \ %'1) IXHURQ SUHSDUDGDV XVDQGR
XQD PRGLILFDFLyQ GH OD WpFQLFD GH HYDSRUDFLyQ
GHO VROYHQWH D SDUWLU GH XQD HPXOVLyQ 2$
SUHYLDPHQWH GHVFULWD /D IDVH ROHRVD HVWi
FRPSXHVWDSRUPOGHXQDVROXFLyQGH3/$*$
&+&O SY HQ OD FXDO VH DGLFLRQDURQ ȝJ GH *'1) \ μJ GH %'1) 8QD YH]
SUHSDUDGD OD IDVH ROHRVD IXH HPXOVLILFDGD HQ
PO 39$ SY D USP GXUDQWH PLQ
'HVSXpV GH K GH PDGXUDFLyQ HQ PO 39$
SY ODV 03V IXHURQ UHFRJLGDV ODYDGDV \
VHSDUDGDVHQ WUHV IUDFFLRQHV JUDQXORPpWULFDV!
ȝPȝP \ȝP)LQDOPHQWHODV
PLFURHVIHUDV IXHURQFRQJHODGDVHQ XQD PH]FOD
GH 0H2+KLHOR OLRILOL]DGDV \ FRQVHUYDGDV HQ
FRQGLFLRQHVGHYDFtRDž&DQWHVGHVXXVR
&DUDFWHUL]DFLyQGHODVPLFURSDUWtFXODV
/D PRUIRORJtD GH ODV PLFURSDUWtFXODV VH HYDOXy
SRU PLFURVFRStD HOHFWUyQLFD GH EDUULGR 6(0
-HRO -60) 7RNLR -DSyQ 3DUD HOOR
SUHYLDPHQWHDODREVHUYDFLyQVHVRPHWLHURQODV
PXHVWUDV D XQ UHFXEULPLHQWR FRQ RUR FRORLGDO
DSOLFDGRHQDWPyVIHUDGHDUJyQ
/DGHWHUPLQDFLyQGHOWDPDxRGHSDUWtFXODGHOD
IRUPXODFLyQ \ VX GLVWULEXFLyQ VH OOHYy D FDER
XWLOL]DQGRXQHTXLSR%HFNPDQ&RXOWHU/6VHULHV
&RXOWHU&RUSRUDWLRQ0LDPL)ORULGD86$
/RVHVWXGLRVGHOLEHUDFLyQLQYLWURVHUHDOL]DURQ
FRQ GRV UHSOLFDGRV GH XQD PXHVWUD GH 03V PJ TXH IXHURQ VXVSHQGLGRV HQ PO GH 3%6
S+ FRQWHQLHQGR DOE~PLQD VpULFD ERYLQD
$6% 3P N'D FRPR WUDQVSRUWDGRU \
GH D]LGD VyGLFD FRPR FRQVHUYDQWH (Q
WRGRVORVFDVRVVHHPSOHDURQ(SSHQGRUIŠ³ORZ
ELQGLQJ´ /DV PXHVWUDV VH LQWURGXMHURQ HQ XQ
EDxR WHUPRVWDWL]DGR FRQ DJLWDFLyQ FRQVWDQWH GH
USPDž&/DWRPDGHPXHVWUDVVHUHDOL]y
DLQWHUYDORVGHWLHPSRSUHHVWDEOHFLGRVKK
\ XQD YH] SRU VHPDQD GXUDQWH VHPDQDV
PHGLDQWH H[WUDFFLyQ GHO YROXPHQ GH PHGLR GH
,;&RQJUHVRGHOD6(),*
FHVLyQ \ SRVWHULRU UHSRVLFLyQ GHO PLVPR
$OtFXRWDV SURFHGHQWHV GH HVWH VREUHQDGDQWH VH
GLOX\HURQ HQ ORV FDVRV HQ TXH IXH QHFHVDULR
FRQ UHDFWLYR GLOX\HQWH FRQWHQLGR HQ HO NLW
(/,6$ HQ]\PROLQNHG LQPXQRVRUEHQW DVVD\
REWHQLHQGR DVt XQD FRQFHQWUDFLyQ GH SURWHtQD
GHQWUR GHO UDQJR GH OD FXUYD GH FDOLEUDFLyQ
HPSOHDGDSJPO
5HVXOWDGRV\'LVFXVLyQ
/DV PLFURSDUWtFXODV HODERUDGDV HQ HVWH WUDEDMR
IXHURQ HVIpULFDV SXGLpQGRVH DSUHFLDU OD
SUHVHQFLD GH DOJXQRV SRURV HQ OD VXSHUILFLH GH
ODV PLVPDV )LJXUD /D IUDFFLyQ
JUDQXORPpWULFD PD\RULWDULD VH HQFRQWUy HQ HO
UDQJRGH—P
)LJXUD 0LFURIRWRJUDItD GH ODV 03V GH
3/$*$FDUJDGDVFRQ*'1)\%'1)
/D GLVWULEXFLyQ GHO WDPDxR GH SDUWtFXOD GHQWUR
GHODIUDFFLyQVHOHFFLRQDGDȝPGDOXJDU
DFXUYDVELPRGDOHVFRQXQDPRGDSUHGRPLQDQWH
SUy[LPDDORV—P
)LJXUD 'LVWULEXFLyQ GH WDPDxR REWHQLGD HQ
ODIUDFFLyQȝP
(O UHQGLPLHQWR GH SURGXFFLyQ GH ODV
PLFURSDUWtFXODV HV GHO \ ODV HILFDFLDV GH
HQFDSVXODFLyQ GH “ SDUD *'1) \
“SDUD%'1)
7DO \ FRPR VH REVHUYD HQ ORV SHUILOHV GH
OLEHUDFLyQ)LJXUDVHSURGXFHXQHIHFWREXUVW
LQLFLDOHQODVSULPHUDVKRUDVGHOHQVD\RFRQ
YDORUHVGH“QJ*'1)PJ03V\
“ QJ %'1)PJ 03V 6HJXLGDPHQWH VH
SURGXFH XQD OLEHUDFLyQ FRQVWDQWH GH ODV
&RPXQLFDFLRQHV2UDOHV
SURWHtQDV GXUDQWH VHPDQDV FRQ XQD YHORFLGDG
GH QJPJ03GtD SDUD *'1) \ QJPJ03GtD SDUD %'1) 'HVSXpV GH VHPDQDV GH HQVD\R ODV 03V OLEHUDQ FDQWLGDGHV
GH QJ*'1)PJ 03GtD \ QJ
%'1)PJ 03GtD KDVWD HO ILQDO GHO HQVD\R
GHVSXpVGHVHPDQDV
)LJXUD 3HUILOHV GH OLEHUDFLyQ DFXPXODGRV
SDUD *'1) Ɣ \ %'1) Ŷ H[SUHVDGRV HQ
QJPJ03VQ &RQFOXVLRQHV
/DV 03V GH 3/$*$ GHVDUUROODGDV HQ HVWH
WUDEDMR SRVHHQ XQ WDPDxR VXVFHSWLEOH GH VHU
LQ\HFWDGR SRU YtD LQWUDRFXODU \ SHUPLWHQ
FRQWURODU OD OLEHUDFLyQ LQ YLWUR GH ORV GLVWLQWRV
IDFWRUHVQHXURWUyILFRV*'1)\%'1)GXUDQWH
XQ SHUtRGR GH WLHPSR GH VHPDQDV (VWRV
VLVWHPDV UHDILUPDQ OD SURPHWHGRUD SRVLELOLGDG
GH XWLOL]DU OD OLEHUDFLyQ GH DJHQWHV
QHXURSURWHFWRUHV HQ HO YtWUHR FRPR XQD
PRGDOLGDGHQHOWUDWDPLHQWRGHJODXFRPD
5HIHUHQFLDV
*DUFtD0HWDO,QYHVW2SKWKDOPRO9LV6FL
0LWWDO6HWDO1HXURUHSRUW
:RUGLQJHUHWDO0ROHFXODU9LVLRQ
5Xt]0RUHQR-0HWDO([S(\H5HV
.KRREHKLHWDO2SKWKDOPLF6XUJ
+HUUHUR9DQUHOODQG5HIRMR$GY'UXJ
'HOLY5HY
0DUWtQH]6DQFKRHWDO-0LFURHQFDSVX
ODWLRQ
$JUDGHFLPLHQWRV
(O HVWXGLR KD VLGR ILQDQFLDGR SRU %,2$9$1
352),7
6,1*8/$5
366
0LQLVWHULR GH (GXFDFLyQ \ *UXSR *58&0
&&*8&00$7
7DEOH &RPSRVLWLRQ ZZ RI WKH ZHW PL[WXUHV
XVHGWRSUHSDUHWUDQVGHUPDOSDWFKHV
393
0& 393 39$
&RPSRQHQW
39$
0&ZZ
393ZZ
39$ZZ
3ODVWRLGŠ(/
3ODVWRLGŠ(+
SURSLOHQJOLFRO
6RUELWRO
6XPDWULSWDQ
$]RQHŠ
:DWHU
0RLVWXUHXSWDNHVWXGLHV
7R FDOFXODWH PRLVWXUH XSWDNH GULHG DQG ZHLJKHG
VXPDWULSWDQ VXFFLQDWH WUDQVGHUPDO SDWFKHV ZLWKRXW
RFFOXVLYH OD\HU ZLWK XQLIRUP GLPHQVLRQV FP
ZHUH H[SRVHG WR UHODWLYH KXPLGLW\ P/ RI
VDWXUDWHGVROXWLRQRIVRGLXPFKORULGHLQDGHVLFFDWRU
XQWLODFRQVWDQWZHLJKWILOPQ :DWHU DEVRUSWLRQ FDSDFLW\ ZDV REWDLQHG DV WKH
LQFUHDVH RI ZHLJKW DIWHU WKH DVVD\ ZLWK UHVSHFW WR
LQLWLDOZHLJKW
0RLVWXUHXSWDNH >ILQDOFRQVWDQWZHLJKW±
LQLWLDOZHLJKWLQLWLDOZHLJKW@
0HFKDQLFDOSURSHUWLHVPHDVXUHPHQWV
0HFKDQLFDO SURSHUWLHV RI SDWFKHV ZHUH HYDOXDWHG
XVLQJ DQ HOHFWURQLF G\QDPRPHWHU $FTXDWL 0LODQR
,WDO\HTXLSSHGZLWKD.JORDGFHOO6WULSVQ RI
PP E\ PP VL]H ZHUH KHOG EHWZHHQ WKH WZR
FODPSV RI WKH G\QDPRPHWHU 'XULQJ PHDVXUHPHQW
WKHSDWFKHVZHUHSXOOHGDWDUDWHRIPPV
7ZRSDUDPHWHUVWKHIRUFHDQGHORQJDWLRQDWWKHSRLQW
DW ZKLFK WKH ILOPV EURNH ZHUH PHDVXUHG
0HDVXUHPHQWV ZHUH UXQ WKUHH WLPHV IRU HDFK SDWFK
7KH WHQVLOH VWUHQJWK DQG HORQJDWLRQ DW EUHDN ZHUH
FDOFXODWHGDV
7HQVLOHVWUHQJWK1PP %UHDNLQJIRUFH1&URVV
VHFWLRQDODUHDRIVDPSOHPP
(ORQJDWLRQDWEUHDN >,QFUHDVHLQOHQJWKDW
EUHDNLQJSRLQWPP2ULJLQDOOHQJWKPP@
,;&RQJUHVRGHOD6(),*
)LJXUH :DWHU DEVRUSWLRQ FDSDFLW\ REWDLQHG
ZLWKGLIIHUHQWWUDQVGHUPDOSDWFKHVIRUPXODWHG9DOXH
“6'Q ,Q UHIHUHQFH WR PHFKDQLFDO SURSHUWLHV REWDLQHG IURP
WKHVXPDWULSWDQWUDQVGHUPDOSDWFKHVIRUPXODWHGWKHVH
DUHVKRZQLQWDEOH7HQVLOHPHDVXUHFDQEHUHIOHFWHG
E\ WHQVLOH VWUHQJWK 1PP DQG HORQJDWLRQ DW EUHDN
SDUDPHWHUV
7DEOH 7HQVLOH VWUHQJWK 1PP DQG HORQJDWLRQ DW
EUHDNYDOXHVGHWHUPLQDWHZLWKSDWFKHVGHYHORSHG
9DOXH“6'Q 0HFKDQLFDOSURSHUWLHV
(ORQJDWLRQDW
7HQVLOHVWUHQJWK
EUHDN
1PP
“
“
0&
“
“
393
“
“
39$
“
39339$ “
5HVSHFW WR WHQVLOH VWUHQJWK SDUDPHWHU WUDFWLRQ
EUHDNLQJIRUFHWKHKLJKHVWYDOXHZDVREWDLQHGIRUWKH
WUDQVGHUPDOSDWFKIRUPXODWHGZLWKPHWK\OFHOOXORVH
,W FDQ EH REVHUYHG WKDW WKH XVH RI 0& LQ SDWFK
IRUPXODWLRQ SURGXFHV D VWDWLVWLFDOO\ VLJQLILFDQW
,QWURGXFWLRQ
7UDQVGHUPDODGPLQLVWUDWLRQRIIHUVDGYDQWDJHVUHVSHFW
RWKHUURXWHVRIDGPLQLVWUDWLRQ$YRLGVJDVWURLQWHVWLQDO
LQFRPSDWLELOLW\ DQG ILUVW SDVV PHWDEROLVP ZLWK WKH
FRQVHTXHQW UHGXFWLRQ RI ELRDYDLODELOLW\ RI GUXJ DQG
UHGXFHV WKH IUHTXHQF\ RI GRVLQJ LPSURYLQJ SDWLHQW
FRPSOLDQFH
6XPDWULSWDQ LV D +7 UHFHSWRU DJRQLVW XVHG LQ
DQWLPLJUDLQH WKHUDS\ 7KLV GUXJ LV DYDLODEOH WR
DGPLQLVWUDWH RUDOO\ LQWUDQDVDO RU E\ VXEFXWDQHRXV
LQMHFWLRQ DQG KDV DQ DEVROXWH ELRDYDLODELOLW\ RI
DSSUR[LPDWHO\DQGUHVSHFWLYHO\2UDO
DQG LQWUDQDVDO DGPLQLVWUDWLRQ SURGXFHV D ORZ
ELRDYDLODELOLW\ RI WKH GUXJ GXH WR SUHV\VWHPLF
PHWDEROLVPDQGLQFRPSOHWHDEVRUSWLRQDQGSDUHQWHUDO
DGPLQLVWUDWLRQ LV DVVRFLDWHG ZLWK QXPHURXV
LQFRQYHQLHQFHV IRU WKH SDWLHQW )RU WKHVH UHDVRQV D
QHZ DGPLQLVWUDWLRQ RI VXPDWULSWDQ VXFK DV
WUDQVGHUPDO URXWH FRXOG EH D JRRG DOWHUQDWLYH LQ WKH
WUHDWPHQWRIPLJUDLQH
:HKDYHREWDLQHGRFFOXVLYHELRDGKHVLYHSDWFKHVWKDW
LQFOXGHVXPDWULSWDQVXFFLQDWH7KRVHDUHQRWDGKHVLYH
LQWKHGU\VWDWHEXWDUHELRDGKHVLYHLQWKHSUHVHQFHRI
ZDWHU ,Q RUGHU WR DQDO\VH WKH SRVVLELOLW\ RI
XVLQJWKHPIRUWKHPLJUDLQHWUHDWPHQWWKHDLPRIWKH
ZRUN SUHVHQWHG ZDV WR FKDUDFWHUL]H WKH WUDQVGHUPDO
SDWFKHVSK\VLFDOSDUDPHWHUVVXFKDVPRLVWXUHXSWDNH
PHFKDQLFDOSURSHUWLHVDQGLQYLYRELRDGKHVLRQ
0DWHULDOVDQG0HWKRGV
6XPDWULSWDQ VXFFLQDWH XVHG LQ WKH SUHSDUDWLRQ RI WKH
WUDQVGHUPDOSDWFKHVZDVREWDLQHGIURPDFRPPHUFLDO
VRXUFH ,PLJUDQŠ $OO ILOPV FRQWDLQHG $]RQHŠ DV
FKHPLFDOHQKDQFHU
0HWK\OFHOOXORVH 0& SRO\Y\QLOSLUURO\GRQH 393
SRO\Y\QLODOFRKRO 39$ RU SRO\Y\QLOSLUURO\GRQH
SRO\Y\QLODOFRKRO 39339$ ZZ PL[WXUH ZDV
HPSOR\HG
)RUWKHSUHSDUDWLRQRIWKHSDWFKHVWDEOHSRO\PHUV
ZHUH K\GUDWHG DQG GLVVROYHG LQ ZDWHU a ƒ&
3ODVWRLGŠDGKHVLYHVROXWLRQ(/(+ZDVDGGHG
IROORZHG E\ WKH VROXWLRQ RI VXPDWULSWDQ VXFFLQDWH LQ
ZDWHU DQG SODVWLFL]HU > SURSLOHQJO\FROVRUELWRO
ZY@ FRQWDLQLQJ WKH SHQHWUDWLRQ HQKDQFHU
$]RQHŠ7KHPL[WXUHREWDLQHGZDVFRDWHGRQEDFNLQJ
PHPEUDQH6FRWFKSDFN70XVLQJDILOPFDVWLQJ
NQLIH :HW ILOP WKLFNQHVV ZDV —P 7UDQVGHUPDO
SDWFKHV GULHG RYHUQLJKW DW URRP WHPSHUDWXUH LQ WKH
GDUN
,QYLYRELRDGKHVLYLW\PHDVXUHPHQW
%LRDGKHVLYH VWUHQJWK RI VXPDWULSWDQ WUDQVGHUPDO
SDWFKHV ZDV HYDOXDWHG LQ YLYR XVLQJ D PRGLILFDWHG
$670TXLFNVWLFNWHVW367&
6WULSV[PPZHUHDSSOLHGWRWKHGRUVDOSDUWRI
WKH KDQG RI WKUHH YROXQWHHUV DIWHU ZHWWLQJ WKH VNLQ
ZLWK NQRZQ DPRXQW RI ZDWHU —/FP )LQDO
FRQWDFW DUHD ZDV FP $IWHU PLQXWHV VWULSV
ZHUH IL[HG WR WKH XSSHU FODPS RI DQ HOHFWURQLF
G\QDPRPHWHUHTXLSSHGZLWKDORDGFHOODQGSXOOHGDW
PPPLQ
7KH PD[LPXP IRUFH RI DGKHVLRQ SHDN GHWDFKPHQW
IRUFH 1 DQG WKH ZRUN RI DGKHVLRQ P- ZHUH
REWDLQHG
5HVXOWVDQG'LVFXVVLRQ
9DOXHV RI PRLVWXUH XSWDNH REWDLQHG IRU WKH
GLIIHUHQW WUDQVGHUPDO SDWFKHV DUH UHSUHVHQWHG LQ
)LJXUH $V H[SHFWHG WKH XVH RI GLIIHUHQW SRO\PHUV
LQ WUDQVGHUPDO SDWFKHV IRUPXODWLRQ DIIHFW LQ WKH
PRLVWXUH XSWDNH 5HVXOWV RI VWDWLVWLFDO DQDO\VLV
SHUIRUPHG VKRZHG WKDW WKH SHUFHQWDJH RI PRLVWXUH
XSWDNHSURGXFHVVWDWLVWLFDOO\VLJQLILFDQWPRGLILFDWLRQV
LQ ILOPV IRUPXODWHG ZLWK 393 SRO\PHU $129$
6FKHIIHS
3$7&+(6)2575$16'(50$/'(/,9(5<2)680$75,37$168&&,1$7(,19,752
$1',19,923+<6,&$/&+$5$&7(5,=$7,21
&%DODJXHU)HUQiQGH]&3DGXOD0$&DODWD\XG3DVFXDO$)HPHQtD)RQW90HULQR)0DUUD
61LFROL36DQWL$/ySH]&DVWHOODQR
'HSDUWDPHQWRGH)LVLRORJtD)DUPDFRORJtD\7R[LFRORJtD)DFXOWDGGH&LHQFLDV([SHULPHQWDOHV\GHOD
6DOXG8QLYHUVLGDG&(8&DUGHQDO+HUUHUD6SDLQ
'LSDUWLPHQWR)DUPDFHXWLFR)DFROWjGL)DUPDFLD8QLYHUVLWjGL3DUPD,WDO\
'HSDUWDPHQWGH)DUPjFLDL7HFQRORJLD)DUPDFqXWLFD)DFXOWDWGH)DUPjFLD8QLYHUVLWDWGH9DOqQFLD
6SDLQ
&RPXQLFDFLRQHV2UDOHV
GLIIHUHQFH UHVSHFW WR ILOPV IRUPXODWHG ZLWK 393 RU
39$393PL[WXUH$129$'XQQHWS
(ORQJDWLRQ DW EUHDN HODVWLFLW\ RI WKH SDWFKHV UHVXOWV
LQ WKH UDQJH ,Q WKLV FDVH WKHUH DUH QR
VWDWLVWLFDOO\ VLJQLILFDQW GLIIHUHQFHV DPRQJ WKH ILOPV
VWXGLHG$129$7'XQQHWS
7DEOH VKRZV WKH YDOXHV RI ELRDGKHVLYH
PHDVXUHPHQWVREWDLQHGDVSHDNGHWDFKPHQWIRUFH1
DQG ZRUN RI DGKHVLRQ P- IRU WKH WUDQVGHUPDO
SDWFKHV$OOSDWFKHVHODERUDWHGZHUHVWXGLHGEXW393
SDWFKHVGLGQRWGHWDFK IURPWKHVNLQGXULQJWKHWLPH
RIDQDO\VLV
7DEOH )RUFH 1 DQG ZRUN RI DGKHVLRQ P-
REWDLQHGZLWKSDWFKHVIRUPXODWHG9DOXH“6'Q %LRDGKHVLRQSDUDPHWHUV
:RUNRI
)RUFHRIDGKHVLRQ
DGKHVLRQ
1
P-
“
“
0&
“
“
39$
393
“
“
39$
6WDWLVWLFDO DQDO\VLV SHUIRUPHG ZLWK SHDN GHWDFKPHQW
IRUFH UHIHUV VLJQLILFDQW GLIIHUHQFHV DPRQJ DOO ILOPV
VWXGLHG$129$6FKHIIHS5HVSHFWWRZRUN
RI DGKHVLRQ SDUDPHWHU WKH VWDWLVWLFDO DQDO\VLV GLG QR
GHPRQVWUDWHGLIIHUHQFHVDPRQJSDWFKHV$129$7
'XQQHWS
&RQFOXVLRQV 393 KDV WKH PD[LPXP YDOXH RI ZDWHU
DEVRUSWLRQFDSDFLW\,QWKHRWKHUKDQGWKHXVHRI393
SURGXFHV D UHGXFWLRQ LQ WHQVLOH VWUHQJWK SDUDPHWHU
7KLV LV WUDGXFHG LQ D GHFUHDVH LQ VWUHQJWK RI SDWFKHV
REWDLQHGZLWKWKLVSRO\PHU
&RPELQDWLRQ RI WKH SRO\PHUV 39339$ OHDGV WKH
KLJKHVW VNLQ DGKHVLRQ LQ WHUPV RI SHDN GHWDFKPHQW
IRUFH+RZHYHUDOOSDWFKHV ZHUHVWLOODWWDFKHGWRWKH
VNLQVXUIDFHIRUPLQLPXPKRXUV
5HIHUHQFHV
)HPHQtD)RQW HW DO - 3KDUP 6FL %DODJXHU)HUQiQGH] HW DO - 3KDUP 6FL 3DGXOD HW DO ,QWHUQ 6\PS &RQWURO 5HO
%LRDFW0DWHU0LDPL%HDFK86$
$FNQRZOHGJPHQWV
$XWKRUV WKDQN 0LQLVWHULR GH 6DQLGDG \ &RQVXPR
3,DQG8QLYHUVLW\&(8&DUGHQDO+HUUHUDIRU
WKHLUILQDQFLDOVXSSRUW
$720,=$&,210(',$17()/2:)2&86,1*
$3/,&$&,21(6)$50$&e87,&$6
/XFtD0DUWtQ%DQGHUDV0-RVp&y]DU%HUQDO(OHQDGH&DVWUR+HUQiQGH]$5RGUtJXH]*LO0DUtD)ORUHV
0RVTXHUD -RVHIDÈOYDUH])XHQWHV0ÈQJHOHV+ROJDGR$OIRQVR*DxiQ&DOYR0HUFHGHV)HUQiQGH]$UpYDOR
'SWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH6HYLOODF3URI*DUFtD*RQ]iOH]Qž6HYLOOD
,QJHQLDWULFV7HFQRORJtDV6/$YG$PpULFR9HVSXFLRSPyG6HYLOOD'SWRGH,QJHQLHUtD
$HURHVSDFLDO\0HFiQLFDGH)OXLGRV8QLYHUVLGDGGH6HYLOOD'SWR*HQpWLFD8QLYHUVLGDGGH6HYLOOD
REWHQHU SDUWtFXODV GH GLIHUHQWH HVWUXFWXUD LQWHUQD
,QWURGXFFLyQ
PLFURHVIHUDV \ FiSVXODV YHUGDGHUDV UHVSHFWLYDPHQWH
/DWHFQRORJtDGHDWRPL]DFLyQ)ORZ)RFXVLQJ))VH
/DDWRPL]DFLyQHQHVWRVFDVRVVHOOHYyDFDERHQXQD
EDVD HQ HO HQIRFDPLHQWR GH GRV R PiV IOXLGRV
FiPDUD WHUPRVWDWL]DGD UHFRJLpQGRVH HQ OD SDUWH
LQPLVFLEOHVYHUILJXUDGHIRUPDTXHVHJHQHUDXQ
LQIHULRUODVSDUWtFXODVHQIRUPDGHSROYRVHFR
PLFURFKRUUR HVWDEOH TXH SRU LQHVWDELOLGDG FDSLODU
3RU RWUD SDUWH WDPELpQ KD VLGR SRVLEOH OD
URPSHHQJRWDVPRQRGLVSHUVDV
HQFDSVXODFLyQ GH PLFURRUJDQLVPRV GH IRUPD
HIHFWLYD 6H KDQ HQFDSVXODGR EDFWHULDV ( FROL ∼
Fluido enfocado
FIXP/ %LRPHGDO \ OHYDGXUDV 6 FHUHYLVLDH
Orificio
salida
XWLOL]DQGR XQ QHEXOL]DGRU FRQFpQWULFR /D
DWRPL]DFLyQ VH OOHYy GH LJXDO PRGR TXH ORV FDVRV
DQWHULRUHV
(Q OD DFWXDOLGDG VH HVWiQ GHVDUUROODQGR HTXLSRV
Fluido
enfocante
EDVDGRV HQ OD WHFQRORJtD )) SDUD HO DLVODPLHQWR \
)LJXUD1HEXOL]DGRU))VLPSOHPRG$YDQW,QJHQLDWULFV
DQiOLVLV DFHOHUDGR GH PLFURRUJDQLVPRV PHGLDQWH VX
7HFQRORJtDV
PLFURHQFDSVXODFLyQLQGLYLGXDOL]DGD
3DUDHOGLVHxR\GHVDUUROORGHVLVWHPDVGHGLDJQyVWLFR
PXOWLSOH[ VH KDQ HQFDSVXODGR IOXRUyIRURV HQ
/D SRVLELOLGDG GH XWLOL]DU P~OWLSOHV FRQILJXUDFLRQHV
PDWULFHVGHSROLHVWLUHQRHQHOLQWHUYDORGHWDPDxRGH
SHUPLWH DGDSWDU HVWD WHFQRORJtD D GLIHUHQWHV SURFHVRV
μP GH GLiPHWUR (Q HVWH FDVR HO IOXLGR
GRQGHVHUHTXLHUDJHQHUDUJRWDVGHIRUPDFRQWURODGD
HPSOHDGRFRPRHQIRFDQWHQRIXHJDVVLQRXQOtTXLGR
6XV DSOLFDFLRQHV VRQ P~OWLSOHV \ HQ FDPSRV WDQ
OR TXH SHUPLWH REWHQHU HVWUHFKDV GLVWULEXFLRQHV GH
GLIHUHQWHV FRPR OD DXWRPRFLyQ PD\RU UHQGLPLHQWR
WDPDxRGHSDUWtFXOD&9
HQ OD LQ\HFFLyQ GH FRPEXVWLEOH PHGLRDPELHQWH
&RQ REMHWR GH GDU XQ YDORU DxDGLGR D HVWH WLSR GH
QXHYRV PDWHULDOHV DOLPHQWDFLyQ QXHYDV WH[WXUDV
SDUWtFXODV VH KDQ HODERUDURQ SDUWtFXODV FRQWHQLHQGR
VDERUHVGLVHxRGHQXWUDFpXWLFRVLQJHQLHUtDTXtPLFD
PDWHULDOSDUDPDJQpWLFR(QHVWHFDVRVHSDUWLyGH
UHDFWRUHV GH PD\RU HILFLHQFLD DQiOLVLV TXtPLFR
XQD VXVSHQVLyQ HVWDEOH GH PDJQHWLWD HQ PHGLR
LQWURGXFFLyQ GH PXHVWUDV ELRWHFQRORJtD QDQR \
RUJiQLFR HPSOHiQGRVH $HURVLOŠ 3KDUPD
PLFURSDUWtFXODV D OD FDUWD R GRPpVWLFDV
'HJXVVDFRPRDJHQWHVXVSHQVRU
KXPLGLILFDFLyQUHIULJHUDFLyQ
)) SDUD OD LQ\HFFLyQ GH PXHVWUDV HQ HTXLSRV
(O SUHVHQWH WUDEDMR VH FHQWUD HQ VXV DSOLFDFLRQHV
DQDOtWLFRV
IDUPDFpXWLFDV HQ FRQFUHWR HQ OD HQFDSVXODFLyQ GH
6HKDQGLVHxDGR\IDEULFDGRGLIHUHQWHVQHEXOL]DGRUHV
GLIHUHQWHVVXVWDQFLDVHQVXHPSOHRFRPRKHUUDPLHQWD
SDUD VX DGDSWDFLyQ HQ HTXLSRV GH HVSHFWURPHWUtD
GHPLFURQL]DGRRSDUDODJHQHUDFLyQGHPLFHODV
DWyPLFDSDUDODLQ\HFFLyQGHPXHVWUDVOtTXLGDV
0DWHULDOHV\0pWRGRV
5HVXOWDGRV\'LVFXVLyQ
))HQSURFHVRVGHPLFURHQFDSVXODFLyQ
$ FRQWLQXDFLyQ VH PXHVWUDQ GH IRUPD UHVXPLGD \ D
(QORV~OWLPRVDxRVODWHFQRORJtD))KDVLGRYDOLGDGD
PRGR GH HMHPSOR DOJXQRV UHVXOWDGRV REWHQLGRV
FRPRXQDKHUUDPLHQWD~WLOGHEDMRFRVWH\DOWHUQDWLYD
UHIHUHQWHV D OD PLFURHQFDSVXODFLyQ GH VXVWDQFLDV
HQ ORV DFWXDOHV SURFHVRV GH PLFURHQFSDVXODFLyQ 6H
PHGLDQWH))
KDQHQFDSVXODGRIiUPDFRVGHGLIHUHQWHQDWXUDOH]D
FRPR VRQ VXOIDWR GH JHQWDPLFLQD 6* 6LJPD
7DPDxRGHSDUWtFXOD
$OGULFK DOWDPHQWH KLGURVROXEOH R OLGRFDtQD /'&
6LJPD$OGULFK OLSRVROXEOH R SURWHtQDV *)3
(O WDPDxR GH SDUWtFXOD IXH GHWHUPLQDGR PHGLDQWH
JUHHQIOXRUHVFHQWSURWHLQ%LRPHGDO6/XWLOL]DGD
PLFURVFRStDySWLFDXWLOL]DQGRXQSURJUDPDGHDQiOLVLV
FRPR PRGHOR (Q WRGRV ORV FDVRV FRQ XQD DOWD
GHLPDJHQ,PDJH-
HILFDFLDGHHQFDSVXODFLyQ
(Q OD WDEOD TXHGDQ UHFRJLGRV DOJXQRV GH ORV
(O SROtPHUR GH HOHFFLyQ HQ HVWRV FDVRV IXH 3/*$
UHVXOWDGRVREWHQLGRVHQFXDQWRDWDPDxRGHSDUWtFXOD
5HVRPHUŠ %|HKULQJHU HQ FRQFHQWUDFLRQHV
LQIHULRUHV DO SY HQ DFHWDWR GH HWLOR ($
3DQUHDF
(QORVFDVRVGH6* \ *)3VHXWLOL]DURQGRVWLSRVGH
QHEXOL]DGRUHV VLPSOH \ FRQFpQWULFR pVWRV SHUPLWHQ
,;&RQJUHVRGHOD6(),*
&RPXQLFDFLRQHV2UDOHV
LDC
0.06 –
0.5
2,5
GFP
2.88
4
12
60
5
50
2
170
5
100
2.5
5
100
10
)LJXUD(MHPSORVGHPLFURHIHUDVREWHQLGDVFRQWHQLHQGR
GLIHUHQWHVVXVWDQFLDVD6*E/'&FIOXRUyIRURVG
PDJQHWLWD
$ PRGR GH HMHPSOR VH PXHVWUDQ ORV UHVXOWDGRV
REWHQLGRV HQ IXQFLyQ GH ODV GLIHUHQWHV YDULDEOHV
FDXGDO GH OtTXLGR *)3 FRQFHQWUDFLyQ GH IiUPDFR
/'&RSUHVLyQGHJDV6*&RPRSXHGHYHUVHHQ
WRGRVORVFDVRVHREWXYRXQDHVWUHFKDGLVWULEXFLyQGH
WDPDxRV
&RPR SXHGH REVHUYDUVH HQ WRGRV ORV FDVRV VH
REWXYLHURQ SDUWtFXODV HVIpULFDV QR DJUHJDGDV FRQ
VXSHUILFLH OLVD (Q HO FDVR GH SDUWtFXODV
SDUDPDJQpWLFDV)LJGODVXSHUILFLHGHODSDUWtFXOD
IXHYDULDEOHHQIXQFLyQGHOFRQWHQLGRHQPDJQHWLWD
(VWUXFWXUDGHODSDUWtFXOD
&RQFOXVLRQHV
5HVSHFWR D OD HVWUXFWXUD GH OD SDUWtFXOD HVWD VH
GHWHUPLQy PHGLDQWH PLFURVFRStD OiVHU FRQIRFDO
&/60 (Q OD ILJXUD VH PXHVWUDQ LPiJHQHV GH
HVIHUDV HODERUDGDV D SDUWLU GH XQD GLVROXFLyQ GHO
PDWHULDO HQFDSVXODGR )LJ D R XQD HPXOVLyQ )LJ
EHPSOHDQGRXQQHEXOL]DGRUVLPSOH\FiSVXODVFRQ
Q~FOHRFRUWH]DQHEXOL]DGRUFRQFpQWULFR)LJF
0HGLDQWH HVWH WUDEDMR VH UHFRJHQ DOJXQDV GH ODV
SRVLEOHVDSOLFDFLRQHVTXHSUHVHQWD )ORZ)RFXVLQJHQ
HO FDPSR IDUPDFpXWLFR *UDFLDV D OD SRVLELOLGDG GH
FRQWURODU WDQWR HO WDPDxR FRPR OD HVWUXFWXUD GH OD
JRWDSDUWtFXOD HV SRVLEOH DGDSWDU OD WHFQRORJtD D ORV
GLIHUHQWHV SURFHGLPLHQWRV GH PLFURHQFDSVXODFLyQ
3RURWURODGRGHELGRDODVXDYLGDGGHODVFRQGLFLRQHV
GH IXQFLRQDPLHQWR HV SRVLEOH WUDEDMDU FRQ VXVWDQFLDV
OiELOHV SRU HMHPSOR PLFURRUJDQLVPRV VLQ DIHFWDU D
VXVSURSLHGDGHV
(Q UHVXPHQ VH WUDWD GH XQD WpFQLFD GH EDMR FRVWH
YHUViWLO TXH VH SUHVHQWD FRPR XQD DOWHUQDWLYD UHDO
SDUD OD SURGXFFLyQ GH PLFURSDUWtFXODV SROLPpULFDV
PRQRGLVSHUVDVGHPRUIRORJtDFRQWURODEOH
D
F
E
)LJXUD(MHPSORVGHHVWUXFWXUDVGHSDUWtFXODVREWHQLGDVHQ
IXQFLyQGHODFRQILJXUDFLyQ))HPSOHDGDD(VIHUDVGLVROXFLyQ
IOXRUyIRURV36E(VIHUDVHPXOVLyQZR*)33/*$F
&iSVXODVOHYDGXUDV3/*$
$VSHFWR\0RUIRORJtD
(O DVSHFWR \ PRUIRORJtD GH ODV SDUWtFXODV IXH
GHWHUPLQDGDPHGLDQWH6(0
(Q OD ILJXUD VH UHFRJHQ DOJXQRV HMHPSORV GH ODV
SDUWtFXODVREWHQLGDV
%LEOLRJUDItD
4
10
$ 0 *DxDQ&DOYR 3K\ 5(Y /HWW /0DUWtQ%DQGHUDV\FROV6PDOO
0$+ROJDGR\FROV,QW-3KDUP9
0HULQR \ FROV 9,, 6SDQLVK3RUWXJXHVH &RQIHUHQFH RQ
&RQWUROOHG 'UXJ 'HOLYHU\ / 0DUWtQ
%DQGHUDV \ FROV %LRVSDLQ / 0DUWtQ%DQGHUDV \
FROV$GY0DW/0DUWtQ%DQGHUDV
\ FROV 9,,, 6SDQLVK3RUWXJXHVH &RQIHUHQFH RQ &RQWUROOHG
'UXJ 'HOLYHU\ $OFDOi GH +HQDUHV % $OPDJUR
)HUQiQGH] \ FROV - $QDOO $WRPLF 6SHFWURPHWU\ $JUDGHFLPLHQWRV
3DUWH GHO WUDEDMR KD VLGR ILQDQFLDGR SRU GLIHUHQWHV
SUR\HFWRV 37523 3URJUDP 3(75, 0&\7
'3,& \ '3,3 0&\7
(8 6L[WK )UDPHZRUN 3URJUDPPH $JUDGHFLPLHQWRV D
%LRPHGDO6/6HYLOODSRUODGRQDFLyQGH(FROL\*)3
HPβCD
MβCD
8
Δπ (mN/m)
4
36(8'232/,5527$;$126'(3/8521,&<&,&/2'(;75,1$63523,('$'(6(,17(5e6
)$50$&e87,&2
/XLV1RJXHLUDV1LHWR&DUPHQ$OYDUH]/RUHQ]R,VDEHO6DQGH]0DFKR$QJHO
&RQFKHLUR)UDQFLVFR-2WHUR(VSLQDU
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJLD)DUPDFHXWLFDDQG'HSDUWDPHQWRGH4XLPLFD
)LVLFD8QLYHUVLGDGGH6DQWLDJRGH&RPSRVWHOD6DQWLDJRGH&RPSRVWHOD(VSDxD
HPDLOIUDQFLVFRRWHUR#XVFHV
0LFURVFRStDHOHFWUyQLFDGHWUDQVPLVLyQ
,QWURGXFFLyQ
/DV FLFORGH[WULQDV &' \ OD VROXELOL]DFLyQ
/DV PXHVWUDV VH REVHUYDURQ HQ XQ PLFURVFRSLR GH
PLFHOL]DU VRQ GRV WpFQLFDV PX\ ~WLOHV SDUD
WUDQVPLVLyQ3+,/,36&07(0)(,&RPSDQ\
LQFUHPHQWDU OD VROXELOLGDG \ OD HVWDELOLGDG GH
WUDVWLQFLyQFRQiFLGRIRVIRW~QJVWLFR
IiUPDFRV1RREVWDQWHFXDQGRDPERVFRPSRQHQWHV
'HVSOD]DPLHQWRGHOQDUDQMDGHPHWLOR
VH LQFRUSRUDQ FRQMXQWDPHQWH HQ GHWHUPLQDGDV
6HDxDGLHURQGLIHUHQWHVYRO~PHQHVGH3)Â
SURSRUFLRQHV VH SXHGH SURGXFLU XQ HIHFWR
0 D GLVROXFLRQHV DFXRVDV GH QDUDQMD GH PHWLOR
DQWDJyQLFR FRPR FRQVHFXHQFLD GH OD FRPSHWLFLyQ
 0 \ +3ȕ&' R 0ȕ&'  0 (O
GHOWHQVRDFWLYRFRQHOIiUPDFRSRUODXQLyQDOD&'
GHVSOD]DPLHQWR GHO FRORUDQWH SRU HO 3) GH OD
(VWD LQWHUDFFLyQ GLILFXOWD OD IRUPDFLyQ GH PLFHODV
FDYLGDG
GH OD &' VH FXDQWLILFy PLGLHQGR ORV
LQFUHPHQWDQGR OD FRQFHQWUDFLyQ FUtWLFD PLFHODU
FDPELRV GH DEVRUEDQFLD D QP +3 $
DSDUHQWH &0& /RV FRSROtPHURV DQILItOLFRV
$JLOHQW$OHPDQLD
SXHGHQSHQHWUDUHQODFDYLGDGGHODV&'VIRUPDQGR
FRPSOHMRV VXSUDPROHFXODUHV FRQRFLGRV FRPR
5HRPHWUtD
SVHXGRSROLUURWD[DQRV TXH RIUHFHQ XQ JUDQ
/RV PyGXORV HOiVWLFR *¶ \ YLVFRVR *¶¶ GH ODV
SRWHQFLDO HQ ELRPHGLFLQD 1R REVWDQWH ODV
GLVROXFLRQHV GH 3) FRQ R VLQ 0ȕ&'
FRQVHFXHQFLDV GH OD IRUPDFLyQ GH HVWRV FRPSOHMRV
SYVHGHWHUPLQDURQHQ XQUHyPHWUR5KHRO\VW
VXSUDPROHFXODUHV VREUH HO FRPSRUWDPLHQWR GH
$517$,QVWUXPHQWV*%FRQXQDQDOL]DGRU
VLVWHPDV GH OLEHUDFLyQ GH PHGLFDPHQWRV KD VLGR
GHGDWRV$5
HVFDVDPHQWH HVWXGLDGD (O REMHWLYR GHO
SUHVHQWH WUDEDMR IXH FDUDFWHUL]DU ODV LQWHUDFFLRQHV
5HVXOWDGRV\GLVFXVLyQ
HQWUH HO 3OXURQLF 3) FRQ OD KLGUR[LSURSLOȕ
/DV LVRWHUPDV ʌ$ )LJXUD PXHVWUDQ XQD
FLFORGH[WULQD +3ȕ&' \ OD PHWLOȕFLFORGH[WULQD
LQWHUDFFLyQ DWUDFWLYD HQWUH 3) \ ODV &'V $
0ȕ&' \ HYDOXDU HQ TXp PHGLDG OD SUHVHQFLD
PHGLGDTXHVHUHGXFHHOiUHDGLVSRQLEOHODV&'VVH
FRQMXQWD GH HVWRV H[FLSLHQWHV SXHGH DOWDHUDU OD
YDQRULHQWDQGRFRQVXHMHSDUDOHORDODLQWHUIDVHOR
FDSDFLGDG GH ODV &'V SDUD IRUPDU FRPSOHMRV GH
TXHIDYRUHFHODIRUPDFLyQGHORVSVHXGRUURWD[DQRV
LQFOXVLyQ FRQ PROpFXODV SHTXHxDV \ OD JHOLILFDFLyQ
(OiUHDRFXSDGDSRUHOFRPSOHMRPDFURPROHFXODUHV
LQVLWXGHO3OXURQLF
PHQRUTXHODVXPDGHODViUHDVGHFDGDFRPSRQHQWH
SRUVHSDUDGR
0DWHULDOHV\0pWRGRV
b
e
A
c
0DWHULDOHV
c
d
C
3OXURQLFŠ ) \ QDUDQMD GH PHWLOR GH 6LJPD
e
Š
e
$OGULFK +3ȕ&' '6 .OHSWRVH +3% D
b
0ȕ&' '6 .OHSWRVH &U\VPHEŠ GH
d
d
5RTXHWWH /DLVD (VSDxD $JXD XOWUDSXUD REWHQLGD
c
b
Š
SRUyVPRVLVUHYHUVD0LOOL4 0LOOLSRUH
B
,VRWHUPDVʌ$
e
c
d
a
b
/DV LVRWHUPDV VH UHJLVWUDURQ HQ XQD EDODQ]D GH
e
VXSHUILFLHGHEDUUHUDVLPSOH1,0$FRQXQiUHD
b
d
c
e
GH FP /D GLVROXFLyQ GH 3OXURQLF VH GHSRVLWy
d
c
a
b
FRQ XQD MHULQJD VREUH OD VXEIDVH DJXD R
GLVROXFLRQHVGH&'
501+\PRGHORPROHFXODU
)LJXUD ,VRWHUPDV $ REWHQLGD HQ DXVHQFLD GH 3)
/RV HVSHFWURV GH ODV GLVROXFLRQHV FRQ UHODFLyQ
FXDQGR ODV GLVROXFLRQHV GH &' VH XVDQ FRPR VXEIDVHV $
PRODU3)&'GH\
3)HQDJXDOtQHDGHSXQWRVRFRQ+3ȕ&'HQVXEIDVH%
H[FHVR GH SUHVLyQ VXSHUILFLDO SDUD ODV LVRWHUPDV 3) HQ
HQ '2 VH REWXYLHURQ HQ XQ HVSHFWUyPHWUR %UXNHU
HPSOHDQGR +3ȕ&' HQ OD VXEIDVH & 3) HQ DJXD OtQHD
$0;D0+](OPRGHORPROHFXODUFRQVWUXLGR
SXQWHDGD R FRQ 0ȕ&' HQ OD VXESKDVH ' H[FHVR GH SUHVLyQ
FRQ HO VRIWZDUH &KHP'UDZ 8OWUD &DPEULGJH
VXSHUILFLDOSDUDODVLVRWHUPDV3)HQHPSOHDQGR0ȕ&'(
6ROI &R86$VHRSWLPL]yHPSOHDQGRODVXEUXWLQD
/D FRQFHQWUDFLyQ GH &' IXH D Â E Â FG\H
00GHO+\SHU&KHP+\SHUFXEH,QF86$
6
0
-4
-8
20
4
PF127 on MβCD
16
2
0
20
PF127 on HPβCD
12
8
16
4
12
0
4
8
Δπ (mN/m)
33.33
'P±
±'(
—P
22.81 ±
7.18
11.21 ±
3.48
6.69 ± 1.23
7.9 – 8.5
CV ~ 15%
7.53 ± 1.15
10.84 ±
1.15
13.66 ±
3.03
π (mN/m)
SG
&IFR &SROP
4
3
SS SS P/K PEDU
π (mN/m)
)&2
π (mN/m)
7DEOD7DPDxRVGHPLFURHVIHUDVREWHQLGRVSDUDODVFRQGLFLRQHV
LQGLFDGDVQHEXOL]DGRU))VLPSOHJDVOtTXLGR
4
0
4
0
100
200
300
400
2
Area (cm )
500
0
-4
-8
600
E
0
100
200
300
400
2
Area (cm )
500
,;&RQJUHVRGHOD6(),*
&RPXQLFDFLRQHV2UDOHV
/DV PLFURIRWRJUDItDV GH 7(0 )LJXUD GH
PH]FODVGH3)DO\+3ȕ&'R0ȕ&'
DO PRVWUDURQ OD IRUPDFLyQ GH HVWUXFWXUDV
QDQRWXEXODUHVFRQXQJURVRUHVWLPDGRGHQP
/RV QDQRWXERV REVHUYDGRV SRGUtDQ HVWDU IRUPDGRV
SRU DVRFLDFLyQ GH PLOHV GH SVHXGRSROLUURWD[DQRV
DSLODGRV (O JURVRU GH OD HVWUXFWXUD FHQWUDO GH ORV
QDQRWXERVQPHVWiGLUHFWDPHQWHUHODFLRQDGR
FRQ HO Q~PHUR GH &' TXH IRUPDQ HO
SVHXGRSROLUURWD[DQR 3XHVWR TXH HO GLiPHWUR GH
FDGDFLFORGH[WULQDHVQPXQDORQJLWXGGH
QP UHTXLHUH XQLGDGHV GH &' HQ
FRQFRUGDQFLDFRQORVUHVXOWDGRVGH+501
B
A
C D
)LJXUD0LFURIRWRJUDILDV7(0GHGLVROXFLyQGH3)DO
$\VXPH]FODFRQGLVROXFLyQGH+3&'%R0&'&DO
UHODFLyQPRODU3)&'
/D LQFRUSRUDFLyQ GH 3) SURYRFy HO
GHVSOD]DPLHQWR GHO QDUDQMD GH PHWLOR GH ODV
FDYLGDGHVGHODV&')LJXUD(OHIHFWRIXHPiV
UHOHYDQWHHQHOFDVRGHOD0ȕ&'ORTXHUHYHODXQD
PD\RU DILQLGDG GHO 3) SRU HVWD &' /D
FDUDFWHUL]DFLyQ UHROyJLFD HYLGHQFLy FDPELRV
QRWDEOHV HQ OD WHPSHUDWXUD GH JHOLILFDFLyQ GHO
3)HQSUHVHQFLDGH&'V
0.80
0.75
A480 nm
0.70
0.65
0.60
0.55
0.00
0.05
0.10
0.15
0.20
0.25
PF127: CD molar ratio
)LJXUD&DPELRVLQGXFLGRVSRUHO3)HQODDEVRUEDQFLDGH
GLVROXFLRQHVGHOQDUDQMDGHPHWLOR0&'FXDGUDGRRQDUDQMD
GHPHWLOR+3&'WULDQJXORV
/DV &'V D ODV SURSRUFLRQHV PRODUHV HVWXGLDGDV QR
LPSLGLHURQODIRUPDFLyQGHJHOSHURLQFUHPHQWDURQ
OD WHPSHUDWXUD GH JHOLILFDFLyQ $VXPLHQGR TXH ORV
XQtPHURV GH 3) LQFRUSRUDGRV D ORV
SVHXGRSROLUURWD[DQRV QR SDUWLFLSDQ HQ OD
JHOLILFDFLyQHVSRVLEOHHVWLPDUODFRQFHQWUDFLyQGH
3)TXHQRLQWHUDFFLRQDFRQODV &'VDSDUWLUGH
ORV FDPELRV HQ OD WHPSHUDWXUD GH JHOLILFDFLyQ 3RU
HVWH SURFHGLPLHQWR VH FRQILUPy TXH OD
HVWHTXLRPHWUtD GH ORV SVHXGRSROLUURWD[DQRV GH
0ȕ&'3)HV
100
A
B
101
10-1
Moduli (Pa)
)LJXUD 0RGHOR PROHFXODU GH XQ IUDJPHQWR GH 3) XQLGDGHVGH32FRPSOHMDGRFRQ0&'
G´without CD
G´´ without CD
G´ 5% MβCD
G´´ 5%MβCD
100
10-2
10-1
10-3
10% PF127 at 25ºC
10-4
10-2
103
102
Moduli (Pa)
/RV
HVSHFWURV
GH
+501
PRVWUDURQ
GHVSOD]DPLHQWRV HQ ODV VHxDOHV GH ORV SURWRQHV +
+\+RULHQWDGRVKDFLDHOLQWHULRUGHODFDYLGDGGH
OD 0ȕ&' \ HQ OD GH ORV JUXSRV PHWLOR GH ORV
EORTXHV 332 (VWRV VXJLHUH ODV FDGHQDV GHO
FRSROtPHURVHLQWURGXFHQHQOD&'/DYDULDFLyQGH
HQ IXQFLyQ GH OD SURSRUFLyQ 0ȕ&'3)
VXJLHUH TXH FDGD XQtPHUR GH 3) LQWHUDFFLRQD
VLPXOWiQHDPHQWH FRQ PROpFXODV GH &'
(PSOHDQGR WpFQLFDV GH PRGHOL]DFLyQ PROHFXODU VH
FRQVWUX\yODHVWUXFWXUDWULGLPHQVLRQDOPiVSUREDEOH
GHO SVHXGRSROLUURWD[DQRV 0ȕ&'3) )LJXUD
103
C
101
102
100
101
10-1
D
10-2
10-1
15% PF127 at 25ºC
10-2
10-4
105
104
105
E
F
103
104
102
101
103
100
10-1
102
10-2
10-3
20% PF127 at 25ºC
101
10-4
0.1
1
10
100
Angular frequency (rad/s)
(9$/8$&,Ï1'(/$&$3$&,'$''(75$16)(&&,Ï1³,19,92´'(1$123$57Ë&8/$6
6Ï/,'$6/,3Ë',&$675$668$'0,1,675$&,Ï1(15$721(63259Ë$,175$9(126$
$GHO3R]R5RGUtJXH]D''HOJDGRE0$6ROLQtVE$5*DVFyQE((FKHYDUUtDF-05RGUtJXH]F-/3HGUD]E
D
)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD&,%(5EEQ)DFXOWDGGH)DUPDFLD8QLYGHO3DtV9DVFR9LWRULD
E
)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGHO3DtV9DVFR9LWRULD
F
/DERUDWRULRGH)LVLRORJtD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGHO3DtV9DVFR9LWRULD
,QWURGXFFLyQ (O $'1 SODVPtGLFR GHVQXGR
FROD GHO UDWyQ \ GtDV GHVSXpV GH OD
S$'1HVXQDSRWHQWHKHUUDPLHQWDSDUDODWHUDSLD
DGPLQLVWUDFLyQ VH VDFULILFDURQ ORV UDWRQHV \ VH
JpQLFD SHUR HV UiSLGDPHQWH HOLPLQDGR GH OD
H[WUDMR HO KtJDGR ORV SXOPRQHV \ HO ED]R VH
FLUFXODFLyQ VDQJXtQHD WUDV VX DGPLQLVWUDFLyQ
FRQJHODURQ LQPHGLDWDPHQWH HQ 1 OtTXLGR
LQWUDYHQRVD(QFRQVHFXHQFLDODDGPLQLVWUDFLyQ
VXPHUJLGRV HQ PHGLR GH FRQJHODFLyQ GH WHMLGRV
ORFDOHVODYtDGHDGPLQLVWUDFLyQSUHIHULGDSDUDHVWH
-XQJ/HLFD\SRVWHULRUPHQWHVHREWXYLHURQILQDV
WLSR GH WHUDSLD OR TXH OLPLWD VHULDPHQWH OD
VHFFLRQHVHQXQFULRVWDWR&U\RFXW/HLFD
DSOLFDFLyQGHOS$'1FRPR PHGLFDPHQWR3RUHVR
3DUDGHWHFWDUODSURWHtQD(*)3HQODVVHFFLRQHV
HV QHFHVDULR HO GHVDUUROOR GH VLVWHPDV GH
VHOOHYyDFDERHOPDUFDMHFRQLQPXQRIOXRUHVFHQFLD
DGPLQLVWUDFLyQ GH S$'1 TXH SHUPLWDQ VX
/DV VHFFLRQHV WHxLGDV VH PRQWDURQ FRQ
DSOLFDFLyQ XWLOL]DQGR ODV YtDV VLVWpPLFDV
)OXRURPRXQW * \ VH DQDOL]DURQ XWLOL]DQGR XQ
FRQYHQFLRQDOHVHQODSUiFWLFDFOtQLFD
PLFURVFRSLR LQYHUWLGR FRQ GLVSRVLWLYR SDUD OD
/D DGPLQLVWUDFLyQ GH JHQHV XVDQGR OtSLGRV
GHWHFFLyQ
GH
IOXRUHVFHQFLD
PRGHOR
FDWLyQLFRV HV XQD LQWHUHVDQWH DOWHUQDWLYD D ORV
(FOLSVH7(61LNRQ
YHFWRUHV YLUDOHV (VWRV OtSLGRV FDWLyQLFRV
(ODQiOLVLVHVWDGtVWLFRVHOOHYyDFDERXWLOL]DQGR
FRPELQDGRV FRQ RWUR OtSLGR VyOLGR GDQ OXJDU D OD
HO SURJUDPD 6366 SDUD UHDOL]DU XQ WHVW W
IRUPDFLyQ GH QDQRSDUWtFXODV VyOLGDV OLStGLFDV
6WXGHQW
FRQVLGHUiQGRVH
ODV
GLIHUHQFLDV
6/1V TXH FRQGHQVDQ PHGLDQWH LQWHUDFFLRQHV
HVWDGtVWLFDPHQWHVLJQLILFDWLYDVVLS
HOHFWURVWiWLFDVHO$'1FDUJDGRQHJDWLYDPHQWH
5HVXOWDGRV\'LVFXVLyQ /D 7DEODUHVXPHHO
(O REMHWLYR GH HVWH WUDEDMR HV HYDOXDU OD
WDPDxRGHSDUWtFXODHOSRWHQWFLDO]HWD\HOtQGLFHGH
FDSDFLGDG GH WUDQVIHFFLyQ GH ORV VLVWHPDV 6/1
SROLGLVSHUVLyQ ,3 GH ODV 6/1V \ ORV YHFWRUHV
$'1 ³LQ YLYR´ WUDV VX DGPLQLVWUDFLyQ LQWUDYHQRVD
6/1$'1
HQ UDWRQHV %DOEF XWLOL]DQGR HO SOiVPLGR S&06
(*)3 TXH FRGLILFD OD SURWHtQD YHUGH IOXRUHVFHQWH
(*)3
100
10-3
Moduli (Pa)
600
10
20
30
40
Temperature (ºC)
50
)LJXUD 0yGXORV HOiVWLFR *¶ \ YLVFRVR *¶¶ GH ODV
GLVROXFLRQHV GH 3) DO $% &' \ ()
FRQWHQLHQGR R QR 0&' HQ IXQFWLRQ GH OD IUHFXHQFLD
DQJXODUDž&$&\(\HQIXQFLyQGHODWHPSHUDWXUDD
UDGV%'\)
&RQFOXVLRQHV
/D LQWHUDFFLyQ GH 3) FRQ 0ȕ&' \ +3ȕ&'
FRQGXFH D OD IRUPDFLyQ GH SVHXGRSROLURWD[DQRV
VROXEOHV HQ DJXD TXH H[SHULPHQWDQ SURFHVRV GH
DJUHJDFLyQSDUDGDUOXJDUDQDQRWXERV(VWHSURFHVR
DIHFWDFRQVLGHUDEOHPHQWHDODFDSDFLGDGGHODV&'V
SDUD IRUPDU FRPSOHMRV FRQ RWUDV PROpFXODV \ D OD
WHPSHUDWXUDGHJHOLILFDFLyQGHO3)
%LEOLRJUDItD
5RGUtJXH]3HUH] HW DO - 1DQRVFL 1DQRWHFKQRO 1RJXHLUDV1LHWRHWDOWK:RUOG0HHWLQJRQ3KDUPDFHXWLFV
%LRSKDUPDFHXWLFV DQG 3KDUPDFHXWLFDO 7HFKQRORJ\ %DUFHORQD
$JUDGHFLPLHQWRV 5RTXHWWH /DLVD (VSDxD 0(&
6$) )('(5 \ ;XQWD GH *DOLFLD
3*,'7&6$35
0DWHULDO \ 0pWRGRV /RV YHFWRUHV 6/1$'1
VH REWXYLHURQ SRQLHQGR HQ FRQWDFWR HO SOiVPLGR
S&06(*)3 FRQ XQD VXVSHQVLyQ DFXRVD GH 6/1V
FRPSXHVWDV SRU 3UHFLURO $72Š '27$3 \
7ZHHQ/DUHODFLyQ6/1$'1H[SUHVDGDFRPR
UHODFLyQ'27$3$'1ZZIXH
$QWHVGHODHYDOXDFLyQGHORVYHFWRUHV³LQYLYR´
VH FDUDFWHUL]DURQ ³LQ YLWUR´ 3DUD HOOR HQ SULPHU
OXJDU VH PLGLHURQ HO WDPDxR \ FDUJD VXSHUILFLDO GH
ORV PLVPRV XWLOL]DQGR HO HTXLSR 0DOYHUQ =HWDVL]HU
3RVWHULRUPHQWH VH HYDOXy OD FDSDFLGDG GH ORV
YHFWRUHVSDUDSURWHJHUHO$'1GHODHQ]LPD'1DVD
, /DV PXHVWUDV VH SXVLHURQ HQ FRQWDFWR FRQ OD
HQ]LPD D XQD FRQFHQWUDFLyQ ILQDO GH 8 '1DVD
,μJ $'1 7DPELpQ VH HVWXGLy OD WRSRORJtD GHO
$'1XQLGRDODV6/1VXWLOL]DQGRSDUDHOOR6'6DO
TXH SHUPLWH VROWDU HO SOiVPLGR GH ODV
QDQRSDUWtFXODV 3RVWHULRUPHQWH ODV PXHVWUDV VH
VRPHWLHURQ D HOHFWURIRUHVLV HQ XQ JHO GH DJDURVD
WHxLGRFRQEURPXURGHHWLGLR
7DPELpQVHHVWXGLyODFDSDFLGDGGHWUDQVIHFFLyQ
\ OD YLDELOLGDG FHOXODU ³LQ YLWUR´ HQ FXOWLYRV GH
FpOXODV +(. D GLIHUHQWHV WLHPSRV GHVGH K
KDVWDGtDV
3DUD HO HVWXGLR ³LQ YLYR´ VH DGPLQLVWUy XQ
YROXPHQ GH μ/ GH XQD VROXFLyQ GH FRPSOHMRV
6/1$'1 μJ $'1 D WUDYpV GH OD YHQD GH OD
7DEOD 7DPDxR tQGLFH GH SROLGLVSHUVLyQ \
SRWHQFLDO]HWDGHODV6/1V\ORVYHFWRUHV6/1$'1
6/1V
6/1$'1
7DPDxRQP
,3
3RW=HWDP9
0HGLD'(SDUDQ SUHVSHFWRDODV6/1V
(OWDPDxRGHORVYHFWRUHV6/1$'1QP
HV VXILFLHQWHPHQWH SHTXHxR SDUD VHU DGPLQLVWUDGRV
SRUYtDLQWUDYHQRVD
(O JHO GH HOHFWURIRUHVLV TXH VH SUHVHQWD HQ OD
)LJXUD PXHVWUD ODV EDQGDV FRUUHVSRQGLHQWHV DO
$'1 SUHYLDPHQWH OLEHUDGR GH ORV YHFWRUHV 6/1
$'1 WUDWDGRV FRQ '1DVD , OtQHD \ QR WUDWDGRV
OtQHD/DDSDULFLyQGHODEDQGDFRUUHVSRQGLHQWH
DO $'1 OLQHDO / HQ ODV PXHVWUDV WUDWDGDV FRQ
'1DVD , LQGLFD TXH ODV QDQRSDUWtFXODV VyOR VRQ
FDSDFHVGHSURWHJHUHO$'1SDUFLDOPHQWH
,;&RQJUHVRGHOD6(),*
&RPXQLFDFLRQHV2UDOHV
SUHVHQWHV HQ HO 7ZHHQ TXH HYLWDUtDQ OD
LQWHUDFFLyQFRQFRPSRQHQWHV VDQJXtQHRVFRPRODV
SURWHtQDV SODVPiWLFDV PHGLDQWH HVWDELOL]DFLyQ
HVWpULFD'HKHFKRODVSDUWtFXODVIXHURQFDSDFHV
GH WUDQVIHFWDU ODV FpOXODV +(. ³LQ YLWUR´ D
SHVDU GH OD SUHVHQFLD GH XQ GH VXHUR HQ HO
PHGLRGHFXOWLYR
)LJXUD *HO GH HOHFWURIRUHVLV HQ DJDURVD HQ HO
TXH VH PXHVWUD OD FDSDFLGDG GH ORV YHFWRUHV SDUD
SURWHJHUHOSOiVPLGRIUHQWHDODHQ]LPD'1DVD,\
ODWRSRORJtDGHO$'1XQLGRDODV6/1V
/RV QLYHOHV GH WUDQVIHFFLyQ ³LQ YLWUR´ HQ ORV
FXOWLYRV GH FpOXODV +(. VH PLGLHURQ D
GLIHUHQWHVWLHPSRVHQWUHK\GtDV&RPRVHYHHQ
OD )LJXUD OD SURWHtQD YHUGH IOXRUHVFHQWH (*)3
VH GHWHFWy GHVGH ODV K FRQ XQ GH FpOXODV
WUDQVIHFWDGDV KDVWD ORV GtDV FRQ HO GH ODV
FpOXODVWUDQVIHFWDGDV(VWRVQLYHOHVGHWUDQVIHFFLyQ
VH REWXYLHURQ HQ SUHVHQFLD GH VXHUR HQ HO
PHGLRGHFXOWLYR
)LJXUD 1LYHOHV GH WUDQVIHFFLyQ HQ FXOWLYRV GH
FpOXODV+(.DORODUJRGHOWLHPSR/DUHODFLyQ
'27$3$'1 H[SUHVDGD FRPR '27$3$'1 IXH
/DVEDUUDVGHHUURUUHSUHVHQWDQ'(Q 7UDVODDGPLQLVWUDFLyQLQWUDYHQRVDHQUDWRQHVVH
GHWHFWy(*)3HQHOKtJDGR\HQHOED]RDORV\
GtDVWUDVODDGPLQLVWUDFLyQVLHQGRPiVDEXQGDQWHOD
SUHVHQFLDGHODSURWHtQDDORVGtDV/DWUDQVIHFFLyQ
GH FpOXODV GHO ED]R \ HO KtJDGR SXHGH VHU ~WLO VL
HVWRV WHMLGRV VRQ OD GLDQD GH OD WHUDSLD JpQLFD SRU
HMHPSORHQHOFDVRGHODVYDFXQDVGH$'1SDUDHO
WUDWDPLHQWR GH WXPRUHV HQ HVRV yUJDQRV R SDUD OD
H[FUHFLyQ DO WRUUHQWH VDQJXtQHR GH SURWHtQDV
DXVHQWHVHQHORUJDQLVPR
(QODVPXHVWUDVGHSXOPyQQRVHGHWHFWy(*)3
6LQ HPEDUJR H[LVWHQ WUDEDMRV HQ OD ELEOLRJUDItD HQ
ORVTXHVHPXHVWUDODWUDQVIHFFLyQDQLYHOSXOPRQDU
FRQVLVWHPDVFDWLyQLFRV/DDFXPXODFLyQHQORV
SXOPRQHV GH HVWRV VLVWHPDV VH UHODFLRQD FRQ OD
IRUPDFLyQ GH DJUHJDGRV FXDQGR LQWHUDFFLRQDQ FRQ
FRPSRQHQWHVVDQJXtQHRV/DDXVHQFLDGHH[SUHVLyQ
GH(*)3DQLYHOSXOPRQDUSRGUtDH[SOLFDUVHSRUOD
LQFRUSRUDFLyQ HQ ODV 6/1V GH FDGHQDV GH 3(*
)LJXUD,PiJHQHVGHVHFFLRQHVGHKtJDGR\ED]R
TXH PRVWUDURQ (*)3 D ORV \ GtDV WUDV OD
DGPLQLVWUDFLyQGHORVYHFWRUHV6/1$'1
$GHPiV ODV FDGHQDV GH 3(* HYLWDQ OD
IRUPDFLyQ GH DJUHJDGRV SXHVWR TXH LPSLGHQ OD
XQLyQ GH XQD PROpFXOD GH $'1 D PiV GH XQD
QDQRSDUWtFXOD PDQWHQLpQGRVH XQ WDPDxR GH
SDUWtFXOD LQIHULRU D QP OR TXH OHV KDFH
DGHFXDGDVSDUDODDGPLQLVWUDFLyQLQWUDYHQRVD
&RQFOXVLRQHV /RV YHFWRUHV HODERUDGRV FRQ
6/1VFRPSXHVWDVSRU3UHFLURO$72Š'27$3\
7ZHHQ VRQ FDSDFHV GH WUDQVIHFWDU WDQWR ³LQ
YLWUR´ FRPR ³LQ YLYR´ GDQGR OXJDU D OD H[SUHVLyQ
GHODQXHYDSURWHtQDGXUDQWH DO PHQRVGtDVHQHO
KtJDGR \ HQ HO ED]R WUDV XQD DGPLQLVWUDFLyQ
LQWUDYHQRVD
5HIHUHQFLDV
/LX)HWDO-*HQH0HG
.LFKOHU$HWDO-*HQH0HG66
+DUYLH3HWDO-3KDUP6FL
/LX)HWDO3KDUP5HV
$JUDGHFLPLHQWRV (VWH WUDEDMR KD VLGR
ILQDQFLDGR SRU HO 'HSDUWDPHQWR GH (GXFDFLyQ
8QLYHUVLGDGHV H ,QYHVWLJDFLyQ GHO *RELHUQR 9DVFR
,7 $QD GHO 3R]R5RGUtJXH] DJUDGHFH DO
0LQLVWHULRGH(GXFDFLyQ\&LHQFLDGH(VSDxDSRUOD
EHFD SUHGRFWRUDO RWRUJDGD /RV DXWRUHV TXLHUHQ
DJUDGHFHU D *RQW]DO *DUFtD GHSDUWDPHQWR GH
1HXURFLHQFLDV VX D\XGD HQ HO PDUFDMH FRQ
LQPXQRIOXRUHVFHQFLD
',6(f2'(1$123$57Ë&8/$6'(32/,İ&$352/$&721$&2026,67(0$6
75$163257$'25(6'(7(*$)85
-/$ULDV0$/XTXH5DPRV0/ySH]9LRWD9*DOODUGR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH*UDQDGD&DPSXV
8QLYHUVLWDULRGH&DUWXMDVQ*UDQDGD
HPDLOMODULDV#XJUHV
OLPSLH]D GHO SROtPHUR VH UHDOL]y PHGLDQWH
,QWURGXFFLyQ
FLFORV UHSHWLGRV GH FHQWULIXJDFLyQ \
/DV HQRUPHV SRVLELOLGDGHV TXH RIUHFHQ ORV
UHGLVSHUVLyQGHOVHGLPHQWRHQDJXDKDVWDTXH
PDWHULDOHVSROLPpULFRVHQHOGLVHxRGHVLVWHPDV
HO VREUHQDGDQWH WXYR XQD FRQGXFWLYLGDG WUDQVSRUWDGRUHV GH IiUPDFRV VRQ ELHQ
ȝ6ÂFP FRQRFLGDV GHVGH WLHPSR DWUiV /RV SULQFLSDOHV
EHQHILFLRV TXH RIUHFHQ HVWRV VLVWHPDV VRQ VX
FDSDFLGDG SDUD PHMRUDU ODV SURSLHGDGHV
IDUPDFRFLQpWLFDV GHO IiUPDFR YHKLFXOL]DGR
LQFUHPHQWDQGRVXDFXPXODFLyQHQHOOXJDUGH
DFFLyQODSURWHFFLyQTXHRIUHFHQDpVWHIUHQWH
D IHQyPHQRV GH ELRGHJUDGDFLyQ \ VX SURSLD
ELRGHJUDGDELOLGDG\EDMDRQXODWR[LFLGDG
/D SROLİFDSURODFWRQD 3&/ HV XQ
SROtPHUR VHPLFULVWDOLQR ELRGHJUDGDEOH \
ELRFRPSDWLEOHTXHVHFDUDFWHUL]DSRUXQDEDMD
WHPSHUDWXUD GH WUDQVLFLyQ YtWUHD 'HELGR D VX
OHQWD ELRGHJUDGDFLyQ OD 3&/ \ VXV
FRSROtPHURV SUHVHQWDQ HQRUPHV SRVLELOLGDGHV
FRPRVLVWHPDVWUDQVSRUWDGRUHVGHIiUPDFRVGH
OLEHUDFLyQ VRVWHQLGD (VWR KD KHFKR TXH VH
XWLOLFH DPSOLDPHQWH HQ OD SUHSDUDFLyQ GH
PLFURQDQRSDUWtFXODVHLPSODQWHV
(QHOSUHVHQWHWUDEDMRLQYHVWLJDPRVHOGLVHxR
GH QDQRSDUWtFXODV GH 3&/ FRPR VLVWHPDV GH
WUDQVSRUWH GH IiUPDFRV DQWLFDQFHUtJHQRV 1RV
FHQWUDPRV HQ OD RSWLPL]DFLyQ GHO SURFHVR GH
YHKLFXOL]DFLyQ GHO DQWLQHRSOiVLFR 7HJDIXU R
)WRUDIXU $QDOL]DPRV OD FDSDFLGDG GH
DEVRUFLyQDGVRUFLyQ GH pVWH SRU HO SROtPHUR \
VXSRVLEOHPHMRUDPHGLDQWHODPRGLILFDFLyQGH
ODV FRQGLFLRQHV GH SUHSDUDFLyQ )LQDOPHQWH
UHDOL]DPRV XQ DQiOLVLV SUHOLPLQDU GHO SURFHVR
GHOLEHUDFLyQLQYLWUR
0DWHULDOHV\0pWRGRV
0DWHULDOHV
(O DJXD XWLOL]DGD IXH GHVLRQL]DGD \
ILOWUDGD 0LOOL4 $FDGHPLF 0LOOLSRUH
)UDQFLD /RV UHDFWLYRV HPSOHDGRV VRQ GH
FDOLGDGDQDOtWLFD3DQUHDF(VSDxDH[FHSWR
OD 3&/ HO WHQVLRDFWLYR 3OXURQLF ® ) \HO
7HJDIXU6LJPD$OGULFK$OHPDQLD
3UHSDUDFLyQGHODVQDQRSDUWtFXODVGH3&/
/D SUHSDUDFLyQ GH ODV SDUWtFXODV GH 3&/ VH
UHDOL]y PHGLDQWH HO PpWRGR GH HPXOVLyQ 2$
± QP )LJXUD %UHYHPHQWH VH
GLVROYLy HO SROtPHUR J HQ P/ GH
GLFORURPHWDQR /D IDVH RUJiQLFD VH HPXOVLRQy
HQP/GHIDVHDFXRVD>3OXURQLF®)
ZY@EDMRDJLWDFLyQ PHFiQLFDUSP\
GXUDQWH KRUD 7UDV ORJUDU OD FRPSOHWD
HYDSRUDFLyQ GHO GLVROYHQWH HO SURFHVR GH
)LJ 0LFURIRWRJUDItD +57(0 GH ODV
QDQRSDUWtFXODV GH SROLİFDSURODFWRQD
/RQJLWXGGHEDUUDQP
$QiOLVLVGHODDGVRUFLyQDEVRUFLyQ\OLEHUDFLyQ
LQYLWURGH7HJDIXU
0HGLDQWH XQ PpWRGR HVSHFWURIRWRPpWULFR
899LV SUHYLDPHQWH YDOLGDGR Ȝ QP İ “ /ÂPRO ÂFP VH
GHWHUPLQy SRU WULSOLFDGR OD LQFRUSRUDFLyQ
GHODQWLQHRSOiVLFRDQLYHOVXSHUILFLDORHQOD
PDWUL]SROLPpULFD(OSURFHVRGHDGVRUFLyQGH
7HJDIXU WDPELpQ VH DQDOL]y FXDOLWDWLYDPHQWH
PHGLDQWH HOHFWURIRUHVLV /D OLEHUDFLyQ
LQ YLWUR GH IiUPDFR GHVGH HO FRORLGH
SROLPpULFR VH GHWHUPLQy HPSOHDQGR HO
PLVPR SURFHGLPLHQWR HVSHFWURIRWRPpWULFR
“ ž& VROXFLyQ EXIIHU 1D2+
.+ 32 GHS+ FRQGLFLRQHVVLQN
5HVXOWDGRV\'LVFXVLyQ
$GVRUFLyQGH7HJDIXUHQORVQDQRFRORLGHV
/D FRQFHQWUDFLyQ GH DQWLFDQFHUtJHQR HQ HO
PHGLR GH FRQWDFWR HMHUFH XQ HIHFWR SRVLWLYR
VREUH OD HILFLHQFLD GH DGVRUFLyQ &RPR SXHGH
DSUHFLDUVH HQ OD )LJXUD OD DGVRUFLyQ GH
7HJDIXU VH LQFUHPHQWD QRWDEOHPHQWH FRQ OD
FDQWLGDG GH DQWLQHRSOiVLFR HQ VROXFLyQ
VXJLULpQGRVH OD VDWXUDFLyQ GH HVWH SURFHVR D
FRQFHQWUDFLRQHV VXSHULRUHV D ODV LQYHVWLJDGDV
/RV GDWRV SDUHFHQ DMXVWDUVH D XQD LVRWHUPD
GHDGVRUFLyQGH/DQJPXLUī PD[ ±
ȝPROP N ±/PRO
,;&RQJUHVRGHOD6(),*
&RPXQLFDFLRQHV2UDOHV
)LJ 'HQVLGDG GH DGVRUFLyQ GH
DQWLFDQFHUtJHQRHQIXQFLyQGHOD>7HJDIXU@HQ
HOHTXLOLEULR
)LJ 'HQVLGDG GH DEVRUFLyQ GH 7HJDIXU HQ
IXQFLyQGHOD>DQWLQHRSOiVLFR@HQHOHTXLOLEULR
/RV UHVXOWDGRVGHO HVWXGLRHOHFWURIRUpWLFR
UHVSDOGDQ OD H[LVWHQFLD GH DGVRUFLyQ
VXSHUILFLDO GH 7HJDIXU HQ ODV SDUWtFXODV GH
3&/ )LJXUD XH WLHQGH D DOFDQ]DU YDORUHV
DEVROXWRVFDGDYH]PHQRUHVDOLQFUHPHQWDUVHOD
FRQFHQWUDFLyQ GH IiUPDFR HQ HO PHGLR /D
FDUJD QHJDWLYD GH ODV SDUWtFXODV WLHQGH D VHU
FDGDYH] PHQRUDOSURGXFLUVHODDGVRUFLyQGHO
DQWLWXPRUDO(VWRSXHGHGHEHUVHDODH[LVWHQFLD
GH XQD LQWHUDFFLyQ HOHFWURVWiWLFD HQWUH HO
SROtPHUR FRQ FDUJD QHJDWLYH \ ODV HVSHFLHV
SRVLWLYDV SURFHGHQWHV GH OD SURWRQDFLyQ GHO
JUXSR ±1+ GH OD PROpFXOD GH 7HJDIXU /D
SUHVHQFLD GH 1D&O DSDQWDOOD HVWH SURFHVR OR
TXHKDFHTXHHQHVWHFDVRODUHGXFFLyQGHXHQR
VHDWDQPDUFDGD
(O HVWXGLR GH OD OLEHUDFLyQ LQ YLWUR GH
7HJDIXU UHYHOD XQ SURFHVR ELIiVLFR GH
FHVLyQ GHO DQWLWXPRUDO GHVGH ORV
QDQRFRORLGHVGH3&/XQDSULPHUDHWDSDGH
OLEHUDFLyQ UiSLGD GHO 7HJDIXU YHKLFXOL]DGR
VXSHUILFLDOPHQWH ≈ HQ K VHJXLGD
GH XQD IDVH PiV OHQWD TXH UHVXOWD GH OD
GHJUDGDFLyQSROLPpULFD≈HQK
/LEHUDFLyQLQYLWURGH7HJDIXU
)LJ /LEHUDFLyQ GH 7HJDIXU GHVGH 3&/ HQ
IXQFLyQGHOWLHPSRDS+ &RQFOXVLRQHV
)LJ 0RYLOLGDG HOHFWURIRUpWLFD XH GH ODV
QDQRSDUWtFXODV GH 3&/ HQ IXQFLyQ GH OD
>7HJDIXU@ HQ HO HTXLOLEULR HQ SUHVHQFLD \ HQ
DXVHQFLDGH1D&O0
$EVRUFLyQGH7HJDIXU
/D DEVRUFLyQ GH 7HJDIXU DXPHQWD FRQ OD
FRQFHQWUDFLyQ GH pVWH HQ HO PHGLR GH VtQWHVLV
GH ODV QDQRSDUWtFXODV GH 3&/ \ FRPR SXHGH
DSUHFLDUVHHQOD)LJXUDH[LVWHXQDWHQGHQFLD
D OD VDWXUDFLyQ GHO SURFHVR D FRQFHQWUDFLRQHV
VXSHULRUHV /D LQFRUSRUDFLyQ GH 7HJDIXU HQ OD
PDWUL] SROLPpULFD SHUPLWH LQFUHPHQWDU OD
YHKLFXOL]DFLyQGHODQWLWXPRUDOHQFRPSDUDFLyQ
FRQHOPpWRGRGHDGVRUFLyQHQVXSHUILFLH
6H KDQ LGHQWLILFDGR ODV FRQGLFLRQHV LGHDOHV
SDUDODSUHSDUDFLyQGHXQVLVWHPDFRORLGDOTXH
SHUPLWHHOWUDQVSRUWH\ODOLEHUDFLyQFRQWURODGD
GHO DQWLQHRSOiVFLR 7HJDIXU (O SURFHVR GH
DEVRUFLyQGHIiUPDFRGHVFULWRSHUPLWHREWHQHU
XQDPD\RUYHKLFXOL]DFLyQGHDQWLFDQFHUtJHQR\
XQ SHUILO GH OLEHUDFLyQ ELIiVLFR DGHFXDGR SDUD
VXXWLOL]DFLyQHQWHUDSLDDQWLWXPRUDO
%LEOLRJUDItD
*H+HWDO-$SSO3RO\P6FL
6LQKD 95 HW DO ,QW-3KDUP
<DQJ-HWDO,QW-3KDUP
$ULDV-/HWDO,QW-3KDUP
$ULDV-/HWDO-&RQWURO5HOHDVH
(9$/8$&,Ï1<&$5$&7(5,=$&,Ï1,19,752'(/()(&72$17,78025$/'(
'(5,9$'26'(/3/$7,12$'0,1,675$'26%$-2',)(5(17(6)250$6
)$50$&e87,&$6
'DQLHO0RUHQR6DUD=DOED,xLJR1DYDUUR&RQFKLWD7URVGH,ODUGX\D
0DUtD-*DUULGR
'SWR)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD'HSDUWDPHQWRGH4XtPLFDVHFFLyQTXtPLFDDQDOtWLFD
8QLYHUVLGDGGH1DYDUUD3DPSORQD
FRQFLVSODWLQR\KRPRJHQL]DGDPHGLDQWHVRQGD
,QWURGXFFLyQ
GHXOWUDVRQLGRV
(O FLVSODWLQR HV XQ DJHQWH DQWLQHRSOiVLFR
XWLOL]DGR HQ XQD DPSOLD YDULHGDG GH WXPRUHV
3URWRFROR 8QD VROXFLyQ GH FLVSODWLQR HQ
VyOLGRV 6LQ HPEDUJR OD SUHVHQFLD GH
7ULV+&O PJPO VH HPXOVLRQy FRQ XQD
LPSRUWDQWHVHIHFWRVDGYHUVRVHVSHFLDOPHQWHOD
VROXFLyQ GH 3/*$ PJ GLVXHOWR HQ
QHXURWR[LFLGDG KD VXSXHVWR XQD OLPLWDFLyQ HQ
WULFORURPHWDQR PHGLDQWH XQD VRQGD GH
VX XVR >@ 'H DTXt TXH VRQ YDULDV ODV
XOWUDVRQLGRV R 8OWUD7XUUD[ GHSHQGLHQGR GHO
HVWUDWHJLDV TXH VH KDQ LGR GHVDUUROODQGR SDUD
WDPDxR EXVFDGR (VWD SULPHUD HPXOVLyQ IXH
LQWHQWDUGLVPLQXLUHVWRVHIHFWRVDGYHUVRV(QWUH
WUDQVIHULGDDXQDVROXFLyQDFXRVDGH39$DO
HOODVGHVWDFDPRVVXHQFDSVXODFLyQHQVLVWHPDV
VDWXUDGD FRQ FLVSODWLQR \ KRPRJHQL]DGD
WDOHV FRPR PLFURHVIHUDV \ OLSRVRPDV /DV
PHGLDQWH8OWUD7XUUD[
FDUDFWHUtVWLFDV ItVLFRTXtPLFDV GH HVWH DJHQWH
(QWRGRVORVFDVRVODPH]FOD$2$VHGHMyHQ
VRQXQIUHQRLPSRUWDQWHSDUDFRQVHJXLUEXHQRV
DJLWDFLyQ D 7 DPELHQWH GXUDQWH K SDUD OD
QLYHOHV GH HQFDSVXODFLyQ \ XQD OLEHUDFLyQ
FRPSOHWD HYDSRUDFLyQ GHO GLVROYHQWH \
VRVWHQLGDHQHOWLHPSR>@
WUDQVFXUULGR HVH WLHPSR ODV PXHVWUDV VH
3RU RWUR ODGR HVWi GHVFULWR TXH VX HIHFWR
FHQWULIXJDURQ VH ODYDURQ FRQ DJXD \ VH
DQWLWXPRUDO HVWi GLUHFWDPHQWH UHODFLRQDGR FRQ
OLRILOL]DURQ /DV SDUWtFXODV VH JXDUGDURQ D HO iUHD EDMR OD FXUYD GH ODV FRQFHQWUDFLRQHV
ž&SDUDVXSRVWHULRUFDUDFWHUL]DFLyQ
SODVPiWLFDV $8& VLQ HPEDUJR GDWRV GH OD
OLWHUDWXUDDSXQWDQDTXHSDUDXQDPLVPD$8&
HO UpJLPHQ GH DGPLQLVWUDFLyQ GHWHUPLQD HO
&DUDFWHUL]DFLyQGHODVSDUWtFXODV
HIHFWR\DTXHXQUpJLPHQFRQWLQXDGRGHEDMDV
(VWXGLRVItVLFRTXtPLFRV
GRVLV UHVXOWy PiV HIHFWLYR SDUD LQGXFLU
(OWDPDxR\HOSRWHQFLDO]HWDVHGHWHUPLQDURQ
DSRSWRVLV TXH XQ UpJLPHQ GH GRVLV ~QLFD \
SRU GLIUDFWRPHWUtD GH OiVHU HQ XQ =HWDVL]HU
HOHYDGD (VWH HIHFWR DQWLWXPRUDO YD
1DQR 6HULHV $TXHOODV SDUWtFXODV FRQ WDPDxRV
GLUHFWDPHQWHXQLGRDVXPHFDQLVPRGHDFFLyQ
VXSHULRUHV D P VH FXDQWLILFDURQ HQ HO
HOFXDOHVLQGHSHQGLHQWHGHOFLFORFHOXODUSHUR
0DVWHUVL]HU OHQWH 5) /RV GDWRV GH
GHSHQGLHQWH GH OD DFWLYDFLyQ GH OD YtD GH ODV
WDPDxR GH SDUWtFXOD IXHURQ FRQWUDWDGRV
FDVSDVDVFDVSDVD
PHGLDQWH 6(0 PLFURVFRStD HOHFWUyQLFD GH
3RU WDQWR HO REMHWLYR HVGHVDUUROODU HYDOXDU \
EDUULGR
FDUDFWHUL]DU LQYLWUR HO HIHFWR DQWLWXPRUDO GHO
FLVSODWLQR DGPLQLVWUDGR EDMR GLVWLQWDV IRUPDV
(VWXGLRVGHOLEHUDFLyQLQYLWUR
IDUPDFpXWLFDV
/D FDUJD GH FLVSODWLQR IXH FXDQWLILFDGD
PHGLDQWH +3/& >@ 3DUD HOOR PJ GH
SDUWtFXODV IXHURQ UHVXVSHQGLGDV HQ PO GH
0DWHULDO\PpWRGRV
1D2+ 1 \ WUDV K HQ DJLWDFLyQ VH
'HVDUUROOR GH IRUPXODFLRQHV SDUD HO
FHQWULIXJDURQ\HOVREUHQDGDQWHDQDOL]DGR
FLVSODWLQR
3RU RWUR ODGR PJ GH SDUWtFXODV VH
/DV SDUWtFXODV GHVDUUROODGDV VH SUHSDUDURQ
UHVXVSHQGLHURQHQPOGH3%6\ODPH]FODVH
VLJXLHQGR HO PpWRGR GH HYDSRUDFLyQ GHO
GHMy HQ DJLWDFLyQ FRQVWDQWH D ž& $ FDGD
GLVROYHQWH WUDV OD IRUPDFLyQ GH XQD GREOH
WLHPSR HVWDEOHFLGR HQWUH \ GtDV ODV
HPXOVLyQ$2$\XWLOL]DQGRFRPRSROtPHUR
PXHVWUDV IXHURQFHQWULIXJDGDVDJ
HO3/*$\HQFRQFUHWRHO5HVRPHU+6H
PLQ \ ORV VREUHQDGDQWHV XWLOL]DGRV SDUD
GHVDUUROODURQSURWRFRORV>@
DQiOLVLV /D WpFQLFD FURPDWRJUiILFD IXH OLQHDO
HQWUH JPO HO OtPLWH GH GHWHFFLyQ
3URWRFROR 8QD VROXFLyQ DFXRVD GH
HVWXYRHQJPO\ODSUHFLVLyQ>H[SUHVDGD
FLVSODWLQR PJPO VH HPXOVLRQy FRQ XQD
FRPR&9@IXH
VROXFLyQ GH 3/*$ PJ GLVXHOWR HQ
(VWXGLRVLQYLWUR
GLFORURPHWDQR PHGLDQWH XQD VRQGD GH
&pOXODV '+'.352E SURFHGHQWHV GH
XOWUDVRQLGRV (VWD SULPHUD HPXOVLyQ IXH
FDUFLQRPDGHFRORQGHUDWDIXHURQVHPEUDGDV
WUDQVIHULGD D XQD VROXFLyQ DFXRVD GH
HQ SODFDV \ WUDWDGDV FRQ GLVWLQWDV
SROLYLQLODOFRKRO 39$ DO SY VDWXUDGD
,;&RQJUHVRGHOD6(),*
&HOOV
*0
70
60
60
50
50
40
40
30
30
20
20
10
10
0
&HOOV
μ0
0
0
10
24
48
72
0
144
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
0
10
24
48
72
10
24
48
72
144
μ0
0
10
24
48
0
10
24
48
144
70
&HOOV
&DVSDVD DFWLYDGD PDUFDGRU DSRSWyWLFR
XWLOL]DQGR HO &DVSDVH*ORŠ /XPLQRPHWULF
$VVD\.LW3URPHJD
1LYHOHV GH 9(*) PDUFDGRU DQJLRJpQLFR
XWLOL]DQGR HO 0RXVH 9(*) ,QPXQRDVVD\ .LW
5'6\VWHPV
5HVXOWDGRV\'LVFXVLyQ
/DVSDUWtFXODVREWHQLGDVPHGLDQWHORVGLVWLQWRV
SURWRFRORVGLILULHURQGHIRUPDHVWDGtVWLFDHQHO
WDPDxR \ OD FDQWLGDG GH FLVSODWLQR
HQFDSVXODGR(OSRWHQFLDO]HWDUHVXOWyQHJDWLYR
HQWRGRVORVFDVRV3DUDODVWUHVIRUPXODFLRQHV
GHVDUUROODGDV ODV SREODFLRQHV IXHURQ
KRPRJpQHDV \ ODV SDUWtFXODV UHGRQGDV FRQ
WDPDxRV PHGLRV GH QP SDUD ODV
QDQRSDUWtFXODV $ SURWRFROR QP SDUD
ODV QDQRSDUWtFXODV % SURWRFROR \ GH
DSUR[LPDGDPHQWH P HQ HO FDVR GH ODV
PLFURSDUWtFXODV SURWRFROR /RV GLIHUHQWHV
WDPDxRV LQIOX\HURQ GH IRUPD VLJQLILFDWLYD HQ
ORV SHUILOHV GH OLEHUDFLyQ DVt ODV 13$ GH
PHQRUWDPDxRSUHVHQWDURQ XQHIHFWREXUVWGHO
D ODV K VHJXLGR GHO SDUD ODV
13% \ PHQRU DO SDUD ODV 03 (VWH
DVSHFWRFRQGLFLRQyODYLDELOLGDGFHOXODU\DTXH
VHHQFRQWUyXQDFRUUHODFLyQHQWUHODFLQpWLFDGH
OLEHUDFLyQ\HOSDUiPHWUR,& RFRQFHQWUDFLyQ
GHIiUPDFRTXHLQKLEHHOGHOFUHFLPLHQWR
FHOXODU(QHOFDVRGHOR[DOLSODWLQRpVWHPRVWUy
XQD PD\RU FLWRWR[LFLGDG GXUDQWH WRGRV ORV
WLHPSRV GH H[SRVLFLyQ FRQ XQD ,& PHQRU DO
FLVSODWLQR
3RU RWUR ODGR HO DQiOLVLV GH ODV GLVWLQWDV IDVHV
GHO FLFOR FHOXODU PRVWUy TXH OD DFXPXODFLyQ
WtSLFD GH FpOXODV HQ IDVH *0 WUDV HO
WUDWDPLHQWR FRQ FLVSODWLQR VH FXPSOtD
~QLFDPHQWH FXDQGR OD GRVLV XWLOL]DGD HVWDEDQ
SRU GHEDMR GH 0 SDUD HO DJHQWH OLEUH
PLHQWUDV TXH D GRVLV VXSHULRUHV HVWDV FpOXODV
HUDQ FDSDFHV GH VDOWDU HVWH FKHFNSRLQW
DFXPXOiQGRVH HQ ** \ HQWUDQGR
GLUHFWDPHQWH HQ DSRSWRVLV (VWD GXDOLGDG
GHVDSDUHFHSDUDORVWUDWDPLHQWRVFRQFLVSODWLQR
YHKLFXOL]DGR GRQGH LQFOXVR OD PD\RU
FRQFHQWUDFLyQSURGXMRDFXPXODFLyQFHOXODUHQ
IDVH*0ILJXUD
&XDQGR VH FXDQWLILFDURQ ORV QLYHOHV GH
FDVSDVD VH HQFRQWUy XQ SHUILO GH DFWLYDFLyQ
**
70
72
144
72
144
70
60
60
50
50
40
40
30
30
20
μ0
20
10
10
0
0
0
10
24
48
7LPHK
72
&RQWURO
144
13$
13%
03
)UHH
7LPHK
)LJXUD $QiOLVLV GHO FLFOR FHOXODU SDUD HO
FLVSODWLQR OLEUH \ YHKLFXOL]DGR WUDV GLVWLQWDV
FRQFHQWUDFLRQHV\WLHPSRVGHH[SRVLFLyQ
VH SURGXFtD XQD UiSLGD H LQWHQVD DFWLYDFLyQ D
ODV K UHODFLRQDGD FRQ ORV HIHFWRV DGYHUVRV
SULQFLSDOPHQWH HQ ULxyQ (Q HO FDVR GH ODV
GLVWLQWDV IRUPXODFLRQHV OD DFWLYDFLyQ IXH
JUDGXDOFRQXQPi[LPRHQWRGRVORVFDVRDODV
K ILJXUD (VWRV GDWRV FRUURERUDQ DO
PHQRVLQYLWURODKLSyWHVLVGHSDUWLGDVREUHOD
DFWLYDFLyQ PiV HIHFWLYD GH DSRSWRVLV WUDV XQD
OLEHUDFLyQFRQWLQXDGD\DGRVLVEDMDV
1.5
Caspase 3 activity (fg/Nº Cells)
&LFORFHOXODUPHGLDQWHPDUFDMHFRQLRGXUR
GHSURSLFLR\XWLOL]DQGRFLWRPHWUtDGHIOXMR
0. 2
0.15
0. 1
1
μ0
0.05
0
0
3
10
24
48
72
144
0.5
PDV WDUGtD HQ IDVH *0 /D DFWLYDFLyQ GH
FDVSDVD IXH VLJQLILFDWLYDPHQWH PHQRU D~Q
FXDQGR VX HIHFWR FLWRWy[LFR IXH PD\RU (VWH
GDWR DSXQWy D TXH OD FDVSDVD QR SDUHFtD VHU
HO ~QLFR GH ORV HIHFWRUHV DSRSWyWLFRV TXH HO
R[DOLSODWLQR DFWLYDED 3RU WDQWR HVWH GHULYDGR
SODWtQLFR GH WHUFHUD JHQHUDFLyQ SUHVHQWR XQ
GLVWLQWR PHFDQLVPR GH DFFLyQ FRQ UHVSHFWR DO
FLVSODWLQR
3RUXOWLPRODFXDQWLILFDFLyQ GHORVQLYHOHVGH
9(*) H[SUHVDGRV SRU ODV FpOXODV WUDV ORV
GLVWLQWRV WUDWDPLHQWRV GHPRVWUDURQ VHU XQ
H[FHOHQWH
PDUFDGRU
GHO
HIHFWR
DQWLSUROLIHUDWLYR
&RQFOXVLRQHV
$ OD YLVWD GH HVWRV UHVXOWDGRV SRGHPRV GHFLU
TXHODHQFDSVXODFLyQGHOFLVSODWLQRVXSXVRXQ
DXPHQWRGHODHILFDFLDGHHVWHDJHQWHDOPHQRV
HQHQVD\RVLQYLWUR
%LEOLRJUDItD
)XHUWHVD0$&DVWLOODE-$ORQVR&3pUH]
-0&XUU0HG&KHP
6SHQOHKDXHU*9HUW0%HQRLW-3&KDERW
) 9HLOODUG 0 - &RQWURO 5HOHDVH 0RUHQR'7URV&%DQGUpV(%XxXDOHV0
\ FROV (XU - 3KDUP %LRSKDUP $JUDGHFLPLHQWRV
(VWHWUDEDMRKDVLGRHQSDUWHILQDQFLDGRSRUHO
0LQLVWHULR GH &LHQFLD H ,QQRYDFLyQ 3&7
\OD8QLYHUVLGDGGH1DYDUUD
0RUHQR'\=DOED6KDQVLGRILQDQFLDGRVSRU
HO *RELHUQR GH 1DYDUUD 'SWR HGXFDFLyQ \
'SWRGHLQGXVWULDUHVSHFWLYDPHQWH
0
0
3
10
24
48
72
144
1.5
Caspase 3 activity (fg/Nº Cells)
9LDELOLGDG FHOXODU PHGLDQWH XQ FRORUDQWH
YLWDO GHQRPLQDGR URMR QHXWUR TXH SHUPLWH
FXDQWLILFDUODVFpOXODVYLYDV
GRVLVWLHPSRGHSHQGLHQWHHQWRGRVORVFDVRV\
DO LJXDO TXH SDUD HO FLFOR VH REVHUYy XQD
GXDOLGDG HQ HO FRPSRUWDPLHQWR GHO FLVSODWLQR
$Vt FRQFHQWUDFLRQHV PHQRUHV D 0 GHO
FRPSXHVWROLEUHSURGXFtDQXQDDFWLYDFLyQPDV
JUDGXDOHQHOWLHPSRFRQXQPi[LPRHQWUH\
KPLHQWUDVTXHSDUDFRQFHQWUDFLRQHVDOWDV
0.2
0.15
1
0.1
μ0
0.05
0
0
3
10
24
48
72
144
0.5
0
0
3
10
24
48
72
144
2.5
1
Caspase 3activity (fg/Nº Cells)
FRQFHQWUDFLRQHV GH FLVSODWLQR OLEUH \
HQFDSVXODGR0\R[DOLSODWLQR
0 GXUDQWH GLVWLQWRV WLHPSRV GH
H[SRVLFLyQ K $ FDGD WLHPSR VH
FXDQWLILFy
&RPXQLFDFLRQHV2UDOHV
2
0.75
0.5
1.5
0.25
μ0
0
1
0
3
10
24
48
72
144
0.5
0
0
3
10
24
48
72
144
7LPHK
&RQWURO
13$
13%
03
)UHH
)LJXUD 1LYHOHV GH FDVSDVD DFWLYD SRU
QXPHUR GH FpOXODV WUDV HO WUDWDPLHQWR FRQ
FLVSODWLQR OLEUH \ YHKLFXOL]DGR WUDV GLVWLQWDV
FRQFHQWUDFLRQHV\WLHPSRVGHH[SRVLFLyQ
(Q HO FDVR GHO R[DOLSODWLQR OD GLVWULEXFLyQ GH
FpOXODV HQ ODV GLVWLQWDV IDVHV SUHVHQWDED
GLIHUHQFLDV VLJQLILFDWLYDV FRQ UHVSHFWR DO
FLVSODWLQR &DEH UHVDOWDU OD DFXPXODFLyQ GH
FpOXODVHQIDVH6VHJXLGDGHXQDDFXPXODFLyQ
HQFDSVXODGDV\QRHQFDSVXODGDVORVGtDV\
SRVWLPSODQWH
/RV UHVXOWDGRV PXHVWUDQ FODUDPHQWH FRPR
HQ HO FDVR GH ODV DGPLQLVWUDFLRQHV GH ODV
FpOXODV VLQ HQFDSVXODU VH REWLHQH XQD HPLVLyQ
GH XQD JUDQ FDQWLGDG GH IRWRQHV HO SULPHU GtD
TXHSRVWHULRUPHQWHYDGHFD\HQGRKDVWDYDORUHV
LQGHWHFWDEOHVHOGtD
Día 1
3
3
CÉLULAS NO
ENCAPSULADAS
700
600
500
400
300
200
100
0
N.D.
Día 1
Día 30
3
Flujo fotones norm. (x10 )
CÉLULAS ENCAPSULADAS
30
25
20
15
10
5
0
Día 1
Día 30
)LJXUD $GPLQLVWUDFLyQ LQWUDSHULWRQHDO
,PiJHQHVGHODFiPDUDOXPLQRPpWULFDL]TGD
\ VXV YDORUHV QXPpULFRV GFKD SDUD FpOXODV
HQFDSVXODGDV\QRHQFDSVXODGDVORVGtDV\
SRVWLPSODQWH
6LQ HPEDUJR ODV FpOXODV HQFDSVXODGDV
PXHVWUDQ XQ FRPSRUWDPLHQWR EDVWDQWH
GLIHUHQWH /D HPLVLyQ GH IRWRQHV QR VROR
SHUVLVWH D OR ODUJR GH ORV GtDV VLQR TXH
DGHPiV VH LQFUHPHQWD GH IRUPD FRQVLGHUDEOH
UHVSHFWR DO SULPHU GtD (O FRPSRUWDPLHQWR GH
ODV FpOXODV HQFDSVXODGDV \ VLQ HQFDSVXODU HV
VLPLODU SDUD WRGDV ODV YtDV GH DGPLQLVWUDFLyQ
HVWXGLDGDVVF)LJLS)LJHLF)LJ
Día 1
Día 30
3
Flujo fotones norm. (x10 )
CÉLULAS NO ENCAPSULADAS
300
250
200
150
100
50
N.D.
0
Día 1
Día 30
3
Flujo fotones norm. (x10 )
CÉLULAS ENCAPSULADAS
CÉLULAS
ENCAPSULADAS
3
Flujo fotones norm. (x10 )
CÉLULAS NO
ENCAPSULADAS
CÉLULAS
ENCAPSULADAS
Flujo fotones norm. (x10 )
Flujo fotones norm. (x10 )
CÉLULAS NO ENCAPSULADAS
CÉLULAS NO ENCAPSULADAS
CÉLULAS ENCAPSULADAS
Día 30
CÉLULAS
ENCAPSULADAS
87,/,=$&,Ï1'(/3/È60,'27.*)3/8&,)(5$6$(1(/(678',2'(/$
%,26(*85,'$''(0,&526,67(0$6&(/8/$5(6$'0,1,675$'26325
',)(5(17(69Ë$6
(6DQWRV*2ULYH50+HUQiQGH]5&DWHQD$&DOYR-/3HGUD]
/DERUDWRULRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGHO3DtV9DVFR839
(+83DVHRGHOD8QLYHUVLGDGQž9LWRULD*DVWHL]6SDLQ
'LYLVLyQGH2QFRORJtD&,0$8QLYHUVLGDGGH1DYDUUD3DPSORQD6SDLQ
XQDGRVLVGHȝ/GHPLFURFiSVXODVHQ3%6
,QWURGXFFLyQ /D PLFURHQFDSVXODFLyQ GH
ȝ/GHYROXPHQILQDOELHQSRUYtDVFR
FpOXODV HV XQD WHFQRORJtD WHUDSpXWLFD FRQ XQ
SRU YtD LS HPSOHDQGR SDUD HOOR XQ FDWpWHU
JUDQ SRWHQFLDO SDUD HO WUDWDPLHQWR GH YDULRV
1LSURJDXJH1LVVKR&RUS$ORVJUXSRV
GHVRUGHQHV FUyQLFRV VLQ QHFHVLGDG GH
FRQWUROGHDPEDVYtDVVHOHVLQRFXOyHOPLVPR
LQPXQRVXSUHVLyQ
Q~PHURGHFpOXODVVLQHQFDSVXODU
6LQ HPEDUJR GHVDUUROODU XQ VLVWHPD TXH
3DUD OD YtD LF ORV UDWRQHV IXHURQ
QRV SHUPLWD FRQRFHU HQ WRGR PRPHQWR OD
DQHVWHVLDGRV PHGLDQWH LVRIOXRUDQR LQKDODGR
ORFDOL]DFLyQ H[DFWD GH ODV FpOXODV
8QD YH] UHDOL]DGD OD FUDQHRWRPtD VH OHV
PLFURHQFDSVXODGDV DVt FRPR VX HVWDGR GH
DGPLQLVWUy D QLYHO GH FRUWH]D FHUHEUDO
DFWLYLGDG IXQFLRQDO KD UHSUHVHQWDGR XQ JUDQ
ELODWHUDOPHQWH HQWUH \ PLFURSDUWtFXODV
UHWRSDUDORVGLVWLQWRV JUXSRVGHLQYHVWLJDFLyQ
SRU RULILFLR $ ORV UDWRQHV FRQWURO VH OHV
TXH WUDEDMDQ HQ HVWH FDPSR $GHPiV OD IDOWD
DGPLQLVWUDURQHOPLVPRQ~PHURGHFpOXODVVLQ
GHFRQWUROVREUHGLFKRVDVSHFWRVUHSUHVHQWDXQ
HQFDSVXODU
SUREOHPD LPSRUWDQWH D OD KRUD GH DVHJXUDU OD
/RVGtDV\WUDVODLPSODQWDFLyQVHOHV
ELRVHJXULGDG
GH
HVWD
DSUR[LPDFLyQ
DGPLQLVWUyDORVUDWRQHVXQDGRVLVGHOXFLIHULQD
ELRWHFQROyJLFD
PJHQȝ/YROXPHQPHGLDQWHLQ\HFFLyQ
(O REMHWLYR GH HVWH HVWXGLR HV OD SXHVWD D
LS \ VH GHWHUPLQy OD HPLVLyQ GH IRWRQHV
SXQWRGHXQPpWRGRGHPRQLWRUL]DFLyQLQYLYR
PHGLDQWH XQD FiPDUD OXPLQRPpWULFD
PHGLDQWH HO FXDO VH SXHGD FRQVHJXLU XQ
;HQRJHQ /RVUDWRQHV IXHURQDIHLWDGRVHQOD
H[KDXVWLYR FRQWURO VREUH ODV FpOXODV
]RQD GH LPSODQWH DQWHV GH SURFHGHU D OD
HQFDSVXODGDV H LPSODQWDGDV HQ GLVWLQWRV
FDSWDFLyQGHIRWRQHV(OWLHPSRGHFDSWXUD
OXJDUHVGHORUJDQLVPR3DUDHOORVHHQFDSVXOy
IXHGHPLQXWRVDDOWDUHVROXFLyQHQXQiUHD
XQD OtQHD FHOXODU GH PLREODVWRV &&
GH FP /DV LQWHQVLGDGHV GH HPLVLyQ IXHURQ
WUDQVIHFWDGRV FRQ XQ YHFWRU TXH FRGLILFD SDUD
GHWHUPLQDGDV PHGLDQWH HO VRIWZDUH ,JRU 3UR
ORVJHQHVWLPLGtQTXLQDVD7.SURWHtQDYHUGH
IOXRUHVFHQWH *)3 \ OXFLIHUDVD \ VH
LPSODQWy HQ UDWRQHV LQPXQRFRPSHWHQWHV SRU
5HVXOWDGRV \ 'LVFXVLyQ (O GLVHxR
YtD VXEFXWiQHD VF LQWUDSHULWRQHDO LS H
H[SHULPHQWDO VH FHQWUy HQ HO VHJXLPLHQWR GH
LQWUDFUDQHDO LF 3DUDOHODPHQWH FRPR
ORVLPSODQWHVUHDOL]DGRVXWLOL]DQGRODVWUHVYtDV
FRQWURO VH UHDOL]y HO LPSODQWH GH ODV PLVPDV
GH DGPLQLVWUDFLyQ HPSOHDQGR SDUD HOOR XQD
FpOXODV D XQD GRVLV HTXLYDOHQWH VLQ
FiPDUD OXPLQRPpWULFD 7DO \ FRPR VH KD
HQFDSVXODU
FRPHQWDGR DQWHULRUPHQWH SDUD FDGD YtD GH
DGPLQLVWUDFLyQVHGLVSRQtDGHGRVJUXSRVDORV
0DWHULDO \ 0pWRGRV /RV PLREODVWRV
TXH VH OHV DGPLQLVWUy HO PLVPR Q~PHUR GH
&& GHULYDGRV GHO P~VFXOR HVTXHOpWLFR GH
FpOXODV\DVHDHQFDSVXODGDVRVLQHQFDSVXODU
UDWyQ &+ \ JHQpWLFDPHQWH PRGLILFDGRV SDUD
Día 1
Día 30
H[SUHVDU 7. *)3 \ OXFLIHUDVD FORQ 7*/
%IXHURQHQFDSVXODGRVHQPLFURFiSVXODVGH
DOJLQDWRSROL/OLVLQDDOJLQDWR
$3$
300
250
DOJLQDWR GH EDMD YLVFRVLGDG \ DOWR FRQWHQLGR
200
150
HQ iFLGR JXOXUyQLFR )0& %LRSRO\PHU
100
50
N.D.
1RUZD\ XWLOL]DQGR SDUD HOOR XQ JRWHDGRU
0
Día 1
Día 30
HOHFWURHVWiWLFR \ VLJXLHQGR HO SURFHGLPLHQWR
GHVFULWR SRU /LP 6XQ¶V FRQ DOJXQDV
5
PRGLILFDFLRQHV
4
/DSUHVHQFLDGH*)3HQHOYHFWRUSRVLELOLWD
3
2
OD GHWHFFLyQ PHGLDQWH )$&6 GH ODV FpOXODV
1
TXHKDQVLGRWUDQVIHFWDGDV
0
Día 1
Día 30
3DUD OD DGPLQLVWUDFLyQ LQ YLYR ORV UDWRQHV
)LJXUD $GPLQLVWUDFLyQ VXEFXWiQHD
& IXHURQ DQHVWHVLDGRV FRQ XQD PH]FOD GH
,PiJHQHVGHODFiPDUDOXPLQRPpWULFDL]TGD
[LODFLQD \ TXHWDPLQD PHGLDQWH DGPLQLVWUDFLyQ
\ VXV YDORUHV QXPpULFRV GFKD SDUD FpOXODV
LQWUDSHULWRQHDO $ FDGD UDWyQ OH IXH LQRFXODGD
,;&RQJUHVRGHOD6(),*
CÉLULAS NO
ENCAPSULADAS
&RPXQLFDFLRQHV2UDOHV
10
8
6
4
2
0
Día 1
Día 30
)LJXUD $GPLQLVWUDFLyQ VXEFXWiQHD
,PiJHQHVGHODFiPDUDOXPLQRPpWULFDL]TGD
\ VXV YDORUHV QXPpULFRV GFKD SDUD FpOXODV
HQFDSVXODGDV\QRHQFDSVXODGDVORVGtDV\
SRVWLPSODQWH
/DGHVDSDULFLyQGHODVHxDOOXPLQRPpWULFD
HO GtD HQ HO FDVR GH ODV FpOXODV VLQ
HQFDSVXODU SXHGH GHEHUVH D TXH OD UHVSXHVWD
LQPXQH GHO KXpVSHG HV FDSD] GH HOLPLQDU SRU
FRPSOHWRODVFpOXODVDORJpQLFDVLPSODQWDGDV
$O LQLFLR GHO H[SHULPHQWR W GtD
SRGHPRV REVHUYDU XQD PD\RU HPLVLyQ GH
IRWRQHVSRUSDUWHGHORVLQMHUWRVFRQFpOXODVVLQ
HQFDSVXODU FRQ UHVSHFWR D ODV FpOXODV
HQFDSVXODGDV (VWR VH GHEH SULQFLSDOPHQWH D
TXH ODV FpOXODV HQFDSVXODGDV SUHVHQWDQ XQ
UHWUDVR HQ OD HPLVLyQ TXH SRGUtD VHU FDXVDGR
SRU HO WLHPSR TXH OD OXFLIHULQD QHFHVLWD SDUD
SRGHU GLIXQGLU D WUDYpV GH OD PDWUL] +D\ TXH
DxDGLU DGHPiV TXH HO RUJDQLVPR QHFHVLWD DO
PHQRVXQDVHPDQDSDUDFUHDUXQDUHGYDVFXODU
PDGXUD \ IXQFLRQDO TXH SXHGD VXSOLU SRU
FRPSOHWR OD GHPDQGD GH QXWULHQWHV \ R[tJHQR
TXH H[LJH HO LQMHUWR IDFLOLWDQGR GH HVWD IRUPD
XQ PD\RU DSRUWH GH OXFLIHULQD D ODV FpOXODV
HQFDSVXODGDV \ MXVWLILFiQGRVH SRU WDQWR HO
DXPHQWR GH OD VHxDO GH HPLVLyQ DO ILQDO GHO
H[SHULPHQWRGtDV
6HKDGHWHFWDGRXQDPHQRUVHxDOHQODYtD
LQWUDFUDQHDO GHELGR DO UHGXFLGR Q~PHUR GH
FiSVXODVLPSODQWDGDV
&RQFOXVLRQHV(VWHHVWXGLRVHFHQWUDHQOD
QHFHVLGDGGHHQFRQWUDUXQPpWRGRTXHSHUPLWD
XQD IiFLO PRQLWRUL]DFLyQ GH ODV FpOXODV
HQFDSVXODGDV LQ YLYR WUDV VX LPSODQWDFLyQ HQ
GLVWLQWDV ]RQDV GHO RUJDQLVPR &RQ HVWH
SURSyVLWR VH DGPLQLVWUDURQ SRU YtD VF LS H
LF ODV PLFURFiSVXODV GH $3$ TXH FRQWHQtDQ
PLREODVWRV && PRGLILFDGRV FRQ HO WULSOH
YHFWRU 7.*)3OXFLIHUDVD \ VH FRPSDUDURQ
FRQHOPLVPRWLSRGHFpOXODVVLQHQFDSVXODU
/RV UHVXOWDGRV GHPXHVWUDQ FODUDPHQWH OD
HILFDFLD GH HVWH PpWRGR GH PRQLWRUL]DFLyQ LQ
YLYR SDUD FpOXODV HQFDSVXODGDV H LPSODQWDGDV
XWLOL]DQGR WUHV GH ODV YtDV GH DGPLQLVWUDFLyQ
PiVKDELWXDOHV
(VWRV GDWRV LQGLFDQ TXH OD LQFRUSRUDFLyQ
GHO WULSOH YHFWRU 7.*)3OXFLIHUDVD SXHGH
UHSUHVHQWDU XQD LPSRUWDQWH PHMRUD HQ OD
PRQLWRUL]DFLyQ \ ELRVHJXULGDG GH OD
PLFURHQFDSVXODFLyQ FHOXODU SDUD ODV GLVWLQWDV
YtDVGHDGPLQLVWUDFLyQ(VWRVDYDQFHVVXSRQHQ
XQ JUDQ SDVR DGHODQWH SDUD DFHUFDU HVWD
WHFQRORJtDDIXWXURVHQVD\RVFOtQLFRV
5HIHUHQFLDV
0XUXD$\FRO%LRPDFURPROHFXOHV
&KHQJ'\FRO-%LRPHG0DWHU5HV
GRLMEPD
3RQRPDUHY9\FRO(XU-1XFO0HG0RO,
/LP)6XQ$6FLHQFH
%OXP-\FRO%LRPDWHULDOV
$JUDGHFLPLHQWRV
( 6DQWRV DJUDGHFH DO ³*RELHUQR 9DVFR
'HSDUWDPHQWR GH (GXFDFLyQ 8QLYHUVLGDGHV H
,QYHVWLJDFLyQ´SRUVXEHFDSUHGRFWRUDO
&RPXQLFDFLRQHV2UDOHV
,;&RQJUHVRGHOD6(),*
32/<$1+<'5,'(1$123$57,&/(6)2525$/'(/,9(5<2)3$&/,7$;(/
0$JHURV3$UHVHV0$&DPSDQHUR*4XLQFRFHV,3HxXHODV-0,UDFKH
'SWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH1DYDUUD,UXQODUUHDVQ
3DPSORQD
8QLGDGGH5DGLRIDUPDFLD'HSDUWDPHQWRGH0HGLFLQD1XFOHDU&OtQLFD8QLYHUVLWDULDGH1DYDUUD
8QLYHUVLGDGGH1DYDUUD3DPSORQD
7KH UHVXOWLQJ FDUULHUV ZHUH SXULILHG E\
,QWURGXFWLRQ
3DFOLWD[HO 37; LV D SRWHQW DQWLFDQFHU DJHQW
FHQWULIXJDWLRQDWUSPIRUPLQWZLFH
DSSURYHG IRU WKH WUHDWPHQW RI D ODUJH QXPEHU
DQG WKHQ WKH IRUPXODWLRQV ZHUH IUHH]HGULHG
RI VROLG WXPRUV +RZHYHU WLOO QRZ QR
*HQHVLV (/ 9LUWLV 86$ XVLQJ VXFURVH
FRPPHUFLDO IRUPXODWLRQV IRU WKH RUDO
ZZDVFU\RSURWHFWRU
DGPLQLVWUDWLRQ RI WKLV GUXJ DUH DYDLODEOH 7KLV
IDFW FDQ EH UHODWHG ZLWK WKH ORZ RUDO
&KDUDFWHUL]DWLRQRIQDQRSDUWLFOHV
ELRDYDLODELOLW\ RI SDFOLWD[HO OHVV WKDQ 6L]H DQG ]HWD SRWHQWLDO ZHUH GHWHUPLQHG E\
PDLQO\ GXH WR LWV ORZ DTXHRXV VROXELOLW\ 3
SKRWRQ FRUUHODWLRQ VSHFWURVFRS\ 36& DQG
JO\FRSURWHLQ HIIOX[ DQG ILUVW SDVV PHWDEROLVP
HOHFWURSKRUHWLF ODVHU 'RSSOHU DQHPRPHWU\
E\F\WRFKURPH3ORFDWHGLQWKHJXWDQGWKH
UHVSHFWLYHO\ XVLQJ D =HWDPDVWHU DQDO\VHU
OLYHU&<3&DQG&<3$
V\VWHP
7KH DLP RI WKLV ZRUN ZDV WR GHYHORS QHZ
7KH PRUSKRORJLFDO FKDUDFWHULVWLFV RI WKH
IRUPXODWLRQV DQG VWUDWHJLHV IRU WKH RUDO
FRPSOH[HVDQGQDQRSDUWLFOHVZHUHREVHUYHGE\
GHOLYHU\ RI SDFOLWD[HO )RU WKLV SXUSRVH WKH
VFDQQLQJ HOHFWURQ PLFURVFRS\ 6(0 DV ZHOO
DVVRFLDWLRQ EHWZHHQ F\FORGH[WULQV DQG
DV E\ WUDQVPLVVLRQ HOHFWURQ PLFURVFRS\
ELRDGKHVLYH QDQRSDUWLFOHV KDYH EHHQ VWXGLHG
7(0
5HFHQWO\ *DQWUH] $1 RU SRO\DQK\GULGH KDV
6LPLODUO\ WKH DPRXQW RI 37; ORDGHG LQWR
EHHQ SURSRVHG DV D QHZ SRO\PHU WR SUHSDUH
QDQRSDUWLFOHV ZDV FDOFXODWHG E\ +3/&89
ELRDGKHVLYH QDQRSDUWLFOHV IRU RUDO GUXJ
)LQDOO\WKH\LHOGRIWKHSURFHVVZDVFDOFXODWHG
GHOLYHU\ WKDW ZRXOG SHUPLW WR HVWDEOLVK
E\JUDYLPHWU\
DGKHVLYH LQWHUDFWLRQV ZLWK WKH JXW PXFRVD
LQGXFLQJ WKHLU LPPRELOLVDWLRQ DW WKH JXW
3KDUPDFRNLQHWLFVWXGLHV
VXUIDFHDQGWKXVLQFUHDVHWKHUHVLGHQFHWLPHRI
7KH SKDUPDFRNLQHWLF VWXG\ ZDV SHUIRUPHG E\
WKH SKDUPDFHXWLFDO GHYLFH LQ FORVH FRQWDFW
WKHRUDODGPLQLVWUDWLRQWRUDWVRIDVLQJOHGRVH
ZLWK WKH DEVRUSWLYH PHPEUDQH 2Q WKH RWKHU
RI PJNJ RI 37; LQFOXGHG LQ GLIIHUHQW
KDQG WKH XVH RI F\FORGH[WULQV ZRXOG LQFUHDVH
IRUPXODWLRQV %HVLGHV FRPPHUFLDO 7D[RO ZDV
WKH ORDGLQJ FDSDELOLW\ RI WKH QDQRSDUWLFOHV DGPLQLVWHUHG E\ LY URXWH WR UDWV DW WKH VDPH
DQG LQKLELW RU GHFUHDVH WKH DFWLYLW\ RI
GRVH PJNJ 7KHQ EORRG VDPSOHV RI F\WRFKURPH3DQG3JO\FRSURWHLQ
μOZHUHFROOHFWHGDWGLIIHUHQWWLPHVXSWRK
7KH DPRXQW RI SDFOLWD[HO ZDV GHWHUPLQHG LQ
SODVPD E\ +3/&89 GHWHFWLRQ DIWHU OLTXLG
0DWHULDOVDQGPHWKRGV
OLTXLG H[WUDFWLRQ 7KH SKDUPDFRNLQHWLF
*DQWUH]® $1 >SRO\ PHWK\O YLQ\O HWKHU
DQDO\VLV RI FRQFHQWUDWLRQWLPH GDWD REWDLQHG
FRPDOHLF DQK\GULGH@ ZDV JLIWHG E\ ,63
DIWHU WKH DGPLQLVWUDWLRQ RI WKH GLIIHUHQW 37;
6SDLQβF\FORGH[WULQ&'ZDVSURYLGHGE\
IRUPXODWLRQV ZDV DQDO\]HG XVLQJ D
6LJPD$OGULFK 6WHLQKHLP *HUPDQ\ QRQFRPSDUWLPHQWDO PRGHO XVLQJ :LQ1RQOLQ
K\GUR[\SURS\OβF\FORGH[WULQ+3&'E\5%,
VRIWZDUH3KDUVLJKW&RUSRUDWLRQ0RXQWDLQ
0DVVDFKXVHWWV 86$ DQG PRQRGHR[\
9LHZ((88
PRQRDPLQRβF\FORGH[WULQ 1+&' ZDV
SXUFKDVHGIURP&\FORODE+XQJDU\
5HVXOWVDQGGLVFXVVLRQ
1DQRSDUWLFOHVFKDUDFWHUL]DWLRQ
1DQRSDUWLFOHVSUHSDUDWLRQ
$OO WKH 37;F\FORGH[WULQ QDQRSDUWLFOHV
1DQRSDUWLFOHV ZHUH SUHSDUHG E\ VROYHQW
GLVSOD\HG VL]HV RI DERXW QP VOLJKWO\
GLVSODFHPHQW PHWKRG 7KH LQFOXVLRQ
KLJKHU WKDQ FRQWURO RQHV 37;13 ZLWKRXW
FRPSOH[HV 37;F\FORGH[WULQ SUHSDUHG LQ D
F\FORGH[WULQV QP &RQFHUQLQJ WKH 37;
PRODUUDWLRZHUHLQFXEDWHGIRUPLQXWHV
FRQWHQW LW LV LQWHUHVWLQJ WR QRWH WKDW WKH
XQGHU PDJQHWLF VWLUULQJ DW URRP WHPSHUDWXUH
DPRXQWRI37;HQWUDSSHGLQWKHQDQRSDUWLFOHV
LQ PO RI DFHWRQH FRQWDLQLQJ PJ
GHSHQGV RQ WKH W\SH RI ROLJRVDFFKDULGH XVHG
®
*DQWUH] $1 7KHQ WKH QDQRSDUWLFOHV ZHUH
WDEOH
IRUPHG E\ WKH DGGLWLRQ RI DQ HWKDQROZDWHU
PL[WXUH YY DQG WKH RUJDQLF VROYHQWV
ZHUHHOLPLQDWHGE\HYDSRUDWLRQXQGHUUHGXFHG
SUHVVXUH%FKL56ZLW]HUODQG
7DEOH3K\VLFR±FKHPLFDOFKDUDFWHULVWLFVRI
37;&' SRO\DQK\GULGH QDQRSDUWLFOHV
PHDQ“6'Q ±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
PTX HPCD NP
PTX CD NP
PTX NHCD NP
Taxol
PTX-NP
5000
4000
37;
FRQWHQW
μ
μJPJ13
“
±
±
±
±
±
±
3000
2000
1000
0
0
5
10
15
20
25
30
Time (h)
A
%
B
Taxol i.v.
PTX concentration (ng/ml)
100000
10000
1000
100
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (h)
C
)LJXUH$3DFOLWD[HOSODVPDWLFOHYHOVDIWHU
WKH RUDO DGPLQLVWUDWLRQ RID VLQJOH GRVH RI
PJNJ RI 37; ORDGHG LQ &'SRO\ DQK\GULGH
QDQRSDUWLFOHV Q % 3ODVPD SDFOLWD[HO
FRQFHQWUDWLRQWLPH SURILOHV DIWHU WKH
LQWUDYHQRXVDGPLQLVWUDWLRQRIDPJNJGRVH
RI7D[RO®Q D
C
)LJXUH $ 7UDQVPLVVLRQ HOHFWURQ
PLFURVFRS\ RI FRQYHQWLRQDO QDQRSDUWLFOHV
FRQWDLQLQJ 37; 37;13 % 6FDQQLQJ
HOHFWURQ PLFURVFRS\ 6(0 RI QDQRSDUWLFOHV
FRQWDLQLQJ β&'DQG37;37;&'13&
6(0 RI QDQRSDUWLFOHV FRQWDLQLQJ +3&' DQG
37; 37;+3&'13 ' 6(0 RI
QDQRSDUWLFOHV FRQWDLQLQJ 1+&' DQG 37;
37;1+&'13
3KDUPDFRNLQHWLFVWXGLHV
:KHQFRPPHUFLDO7D[RO® ZDVDGPLQLVWHUHGWR
UDWV E\ WKH RUDO URXWH )LJXUH $ QR 37;
SODVPDWLF OHYHOV ZHUH IRXQG 6LPLODU UHVXOWV
ZHUH REWDLQHG ZLWK WKH GLIIHUHQW FRPSOH[HV
EHWZHHQ37;DQG&'+3&'RU1+&'GDWD
QRW VKRZQ 2Q WKH FRQWUDU\ ZKHQ 37;&'
FRPSOH[HVZHUHLQFOXGHGLQWRSRO\DQK\GULGH
QDQRSDUWLFOHV IRUPXODWLRQV WKHVH IRUPXODWLRQV
GLVSOD\HG VXVWDLQHG SODVPDWLF 37; OHYHOV IRU
DW OHDVW K )LJXUH $ ,Q DQ\ FDVH WKH
37;&'13 \ 37;+3&'13 IRUPXODWLRQV
DOORZ XV WR REWDLQ IROG KLJKHU SODVPDWLF
OHYHOVWKDQ37;SODVPDWLFOHYHOVREWDLQHGZLWK
37;1+&'13 )LJXUH % VKRZV WKH GUXJ
FRQFHQWUDWLRQ WLPHSURILOH FRUUHVSRQGLQJ WR
PHDQ RI DQLPDOV DIWHU LQWUDYHQRXV
DGPLQLVWUDWLRQ RI 7D[RO® VROXWLRQ DW WKH VDPH
GRVHRIPJNJ
$
7DEOH 3KDUPDFRNLQHWLF SDUDPHWHUV RI WKH
GLIIHUHQWIRUPXODWLRQWHVWHG
$8&
&PD[
7PD[
057
7]
QJKPO
QJ
K
K
K
7D[RO LY
37;13
QG
QG
QG
QG
37;&'13
37;+3&'13
37;1+&'13
)RUPXODWLRQ
®
QG
)
S37;2+β&'13DQG37;β&'13YV37;1+β&'13
7HVW80DQQ:KLWQH\
,Q VXPPDU\ WKH REWDLQHG SKDUPDFRNLQHWLFV
SDUDPHWHUV VKRZHG LQ WKLV ZRUN GHPRQVWUDWHV
WKH KLJK FDSDELOLW\ RI SRO\ DQK\GULGH
QDQRSDUWLFOHV DVVRFLDWHG WR F\FORGH[WULQV WR
HQKDQFH WKH RUDO ELRDYDLODELOLW\ RI SDFOLWD[HO
HVSHFLDOO\ IRU 37;&'13 DQG 37;+3&'
13 IRUPXODWLRQV ZKLFK UHDFKHG DQ RUDO
ELRDYDLODELOLW\FORVHWR
$FNQRZOHGJHPHQWV
³$VRFLDFLyQGH$PLJRV´ ³)XQGDFLyQ8QLYHUVLWDULD
GH 1DYDUUD´ ³*RELHUQR GH 1DYDUUD´ 'SWR
(GXFDFLyQ ,63 &RUS ³0LQLVWHULR GH &LHQFLD \
7HFQRORJtD´6$)
5HIHUHQFHV
>@ 3 $UEyV HW DO - &RQWURO 5HOHDVH S
>@ ) .LKDUD HW DO %LRFRQMXJDWH &KHP S
>@ 6 <DQJ HW DO3KDUP 5HV S &RPXQLFDFLRQHV2UDOHV
<LHOG
02'(/$'2'(/75$163257('(/'(5,9$'2'(9,1%/$67,1$.$5(15$7$<
(1&e/8/$6&$&2
*RQ]DOH]$OYDUH],*RQ]DOH]$OYDUH]02OWUD1RJXHUD'2YDGL-0HULQR9%HUPHMR0
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH9DOHQFLD
,QVWLWXWHRI(Q]\PRORJ\+XQJDULDQ$FDGHP\RI6FLHQFHV%XGDSHVW+XQJDU\
'HSWRGH,QJHQLHUtDÈUHD)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDG0LJXHO+HUQiQGH]
(OFKH
SHUPHDELOLGDG \ FRQFHQWUDFLyQ VH XWLOL]DURQ
SDUD DMXVWDU GLIHUHQWHV PRGHORV FLQpWLFRV GH
,QWURGXFFLyQ /RV ELVLQGROHV JUXSR DO TXH
FRPSOHMLGDG FUHFLHQWH /D VHOHFFLyQ GHO PHMRU
SHUWHQHFH OD 9LQEODVWLQD VH XWLOL]DQ HQ OD
PRGHOR FLQpWLFR VH UHDOL]R HQ EDVH D ORV
WHUDSLD FRQWUD HO FDQFHU SRU VX FDSDFLGDG GH
YDORUHV GH $,& 0RGHORV GH FRPSOHMLGDG
LQKLELU OD GLYLVLyQ LQFRQWURODGD GH ODV FpOXODV
FUHFLHQWHVHFRPSDUDURQPHGLDQWHODSUXHED)
WXPRUDOHV 1R REVWDQWH VX XVR SUHVHQWD OD
GH 6QHGHFRU SDUD FRQWUDVWDU OD VLJQLILFDFLyQ
GREOH GLILFXOWDG GH VX IDOWD GH HVSHFLILFLGDG
HVWDGtVWLFDGHORVPRGHORVPiVFRPSOHMRV
SDUD FpOXODV HQ GLYLVLyQ \ OD EDMD
0RGHORV \ HFXDFLRQHV TXH LQFOX\HQ
ELRGLVSRQLELOLGDG RUDO (QWUH ORV QXHYRV
DEVRUFLyQVHFUHFLyQ VDWXUDEOH HQ FRPELQDFLyQ
GHULYDGRV GH OD 9LQEODVWLQD VH HQFXHQWUD HO
FRQGLIXVLyQSDVLYDVHXWLOL]DURQSDUDGHVFULELU
FRPSXHVWR.$5FX\RPHFDQLVPRGHDFFLyQ
ORVGDWRVH[SHULPHQWDOHV(ODMXVWHQROLQHDOVH
VH EDVD HQ VX FDSDFLGDG SDUD XQLUVH D OD
GHVDUUROOR FRQ HO SURJUDPD :LQQRQOLQ WXEXOLQDSUHVHQWDQGRPHQRUFLWRWR[LFLGDGTXH
3KDUVLJKW&RUS3DOR$OWR86$
OD 9LQEODVWLQD SHUR FRQVHUYDQGR VX SRWHQFLD
0RGHORGHDEVRUFLyQGH.$5
DQWLWXPRUDO(OREMHWLYRGHOHVWXGLR KDVLGROD
/tQHDFHOXODU
FDUDFWHUL]DFLyQ ELRIDUPDFpXWLFD GH .$5 HQ
9P B LQ
FRPSDUDFLyQ FRQ OD 9LQEODVWLQD D ILQ GH
$SLFDO%DVDO3DSS = 3GLI +
FDUDFWHUL]DU VX PHFDQLVPR GH DEVRUFLyQ
.P + &
LQWHVWLQDO \ GHWHUPLQDU OD SRVLELOLGDG GH VX
DGPLQLVWUDFLyQSRUYtDRUDO
9P B RXW
%DVDO$SLFDO3DSS = 3GLI +
.P + &
0DWHULDOHV \ 0pWRGRV /RV HVWXGLRV GH
5DWD
DEVRUFLyQ LQ YLWUR GH 9LQEODVWLQD \ .$5 VH
5DW
UHDOL]DURQ HQ PRQRFDSDV &DFR HQ GLUHFFLyQ
( I ⋅ 9 P B LQ
9 P B HIIOX[
= 6 ) ⋅ 3GLI −
3DSS
−
DSLFDO EDVDO $% \ EDVDO DSLFDO %$ /DV
.P + &
. P B HIIOX[ +
FRQFHQWUDFLRQHV GH 9LEODVWLQD DEDUFDURQ HO
0RGHORGHDEVRUFLyQGH9LEODVWLQD
iPELWR GH μ0 D μ0 \ ODV GH .$5
/tQHDFHOXODU
GHVGHDμ0
/DDEVRUFLyQLQVLWXVHFDUDFWHUL]yHQ
9P B HIIOX[
$SLFDO%DVDO3 = 3 −
UDWD :LVWDU FRQ XQ PpWRGR GH SHUIXVLyQ VLQ
DSS
GLI
$ ⋅ .P + & UHFLUFXODFLyQEDVDGRHQODWpFQLFDGH'ROXLVLR
/DV FRQFHQWUDFLRQHV GH SHUIXVLyQ RVFLODURQ
%DVDO$SLFDO3 = 3 + 9P B HIIOX[
HQWUH —0 SDUD 9LQEODVWLQD \ DSS
GLI
—0SDUD.$5
.P + &
/DV PXHVWUDV VH DQDOL]DURQ SRU
5DWD
FURPDWRJUDItD OtTXLGD +3/& GH IDVH LQYHUVD
FRQGHWHFFLyQIOXRUHVFHQWHSDUDGHWHUPLQDUODV
5DW
9P B HIIOX[
FDQWLGDGHV \ FRQFHQWUDFLRQHV GH IiUPDFR HQ
3DSS = 6 ) ⋅ 3GLI −
ODV PLVPDV /RV YDORUHV GH SHUPHDELOLGDG
$ ⋅ .P + & DSDUHQWH D FDGD FRQFHQWUDFLyQ LQLFLDO \ SDUD
FDGDFRPSXHVWRVHGHWHUPLQDURQDSDUWLUGHODV
3DSS SHUPHDELOLGDG DSDUHQWH D FDGD
FRQFHQWUDFLRQHV UHPDQHQWHV HQ OXPHQ R D
FRQFHQWUDFLyQLQLFLDO
SDUWLU GH ODV FDQWLGDGHV DFXPXODGDV HQ
3GLI&RPSRQHQWHGLIXVLRQDO
FRPSDUWLPHQWR UHFHSWRU 'H HVD IRUPD HO
9PLQ 9HORFLGDG Pi[LPD HQ OD GLUHFFLyQ
SDUiPHWUR FLQpWLFR HV HO PLVPR \ SHUPLWH VX
DSLFDOEDVDO
PRGHODGR FRQMXQWR \ HO HVWDEOHFLPLHQWR GH
9PRXW 9HORFLGDG Pi[LPD HQ OD GLUHFFLyQ
KLSyWHVLV VREUH ODV GLIHUHQFLDV HQWUH DPERV
EDVDODSLFDO
VLVWHPDV H[SHULPHQWDOHV \ HO HVFDODGR HQWUH
.P&RQVWDQWHGH0LFKDHOLVPHQWHQ
DPERV
6I IDFWRU GH FRUUHFFLyQ GHO iUHD SDUD
/DV SHUPHDELOLGDGHV DSDUHQWHV D ODV
FRQVLGHUDUODSUHVHQFLDGHSOLHJXHV\YLOOLHQOD
GLVWLQWDV
FRQFHQWUDFLRQHV
PRVWUDURQ
UDWD
GLIHUHQFLDV VLJQLILFDWLYDV HQ DPERV VLVWHPDV
H[SHULPHQWDOHV DVt SXHV ORV YDORUHV GH
=HWDSRW
P9
PTX concentration (ng/ml)
13
37;13
37;&'13
37;+3&'13
37;1+&'
13
6L]H
QP
,;&RQJUHVRGHOD6(),*
(I )DFWRU GH FRUUHFFLyQ SDUD OD GLIHUHQWH
H[SUHVLyQ GHO SRUWDGRU GH DEVRUFLyQ HQ UDWD
YHUVXVFpOXODV
9PHIIOX[ 9HORFLGDG Pi[LPD GHO VLVWHPD GH
VHFUHFLyQHQODUDWD
.PHIIOX[FRQVWDQWHGH0LFKDHOLV0HQWHQGHO
WUDQVSRUWDGRUGHVHFUHFLyQ
$ IDFWRU GH FRUUHFFLyQ SDUD OD FRQFHQWUDFLyQ
LQWUDH[WUDFHOXODU HO OXJDU GH XQLyQ GHO
WUDQVSRUWDGRUGHVHFUHFLyQHVLQWUDFHOXODU
5HVXOWDGRV\'LVFXVLyQ
/RVH[SHULPHQWRVHQODOtQHDFHOXODU&DFR\
ORV GH SHUIXVLyQ LQ VLWX HQ UDWD KDQ PRVWUDGR
TXH9LQEODVWLQD\.$5VRQDPERVVXVWUDWRV
GH WUDQVSRUWDGRUHV GH VHFUHFLyQ SHUR FRQ
GLIHUHQWHDILQLGDG3RURWURODGRHOFRPSRQHQWH
GLIXVLRQDO GH .$5 HV VXSHULRU DO GH
9LQEODVWLQD
4.00E-05
3.50E-05
3.00E-05
2.50E-05
2.00E-05
1.50E-05
1.00E-05
5.00E-06
0.00E+01
0
100
200
300
400
500
600
Concentration Micromolar
&
)LJXUD 9DORUHV GH SHUPHDELOLGDG GH
9LQEODVWLQD $% \ %$ HQ FpOXODV FDFR ǻ \
¸\HQUDWDż
1.40E-04
1.20E-04
1.00E-04
8.00E-05
6.00E-05
4.00E-05
2.00E-05
0.00E+01
0
100
200
300
400
500
Concentration Micromolar
)LJXUD9DORUHVGHSHUPHDELOLGDGGH.$5
$%\%$HQFpOXODVFDFR¸\ż\HQUDWD
ǻ
/D LQIRUPDFLyQ LQLFLDO GHO PRGHODGR
LQGHSHQGLHQWHGHORVGDWRVSHUPLWLyILQDOPHQWH
VX PRGHODGR FRQMXQWR LQFOX\HQGR ORV IDFWRUHV
GH HVFDODGR DGHFXDGRV (O PRGHOR VH YDOLGy
LQWHUQDPHQWH PHGLDQWH OD VHOHFFLyQ GHO PHMRU
PRGHOR FLQpWLFR HQ EDVH D ORV tQGLFHV GH
ERQGDGGHDMXVWH(OPRGHORXQLILFDGRSHUPLWH
GHPRVWUDU
TXH
ODV
FDUDFWHUtVWLFDV
ELRIDUPDFpXWLFDV GH .$5 VRQ PiV
IDYRUDEOHV HQ FRPSDUDFLyQ FRQ ODV GH
600
9LQEODVWLQD 3RU RWUR ODGR HO SURFHVR GH
PRGHODGRHQVLPLVPRKDPRVWUDGRODYHQWDMD
GH PD[LPL]DU OD FDQWLGDG GH LQIRUPDFLyQ TXH
SXHGHH[WUDHUVHGHORVGDWRVH[SHULPHQWDOHVHQ
FRPSDUDFLyQFRQHOPHURDQiOLVLVFRPSDUDWLYR
&RQFOXVLRQHV
9LQEODVWLQD SUHVHQWD HQ HO PRGHOR
&DFR HO SDWUyQ KDELWXDO GH XQ VXVWUDWR GH
*OLFRSURWHtQD3
.$5 PXHVWUD XQ SHUILO GLIHUHQWH
FRQVLVWHQWH FRQ OD H[LVWHQFLD GH XQ
WUDQVSRUWDGRU GH DEVRUFLyQ DXQTXH OD
FRQWULEXFLyQ GH XQ WUDQVSRUWDGRU GH VHFUHFLyQ
FRPR0USHQUDWDQRSXHGHGHVFDUWDUVH
.$5 SUHVHQWD XQ SHUILO GH
DEVRUFLyQ PiV IDYRUDEOH D OD FRQFHQWUDFLyQ
PD\RU VX SHUPHDELOLGDG HV VLPLODU D OD GH
9LQEODVWLQD SHUR FRQ XQD DILQLGDG SRU OD
*OLFRSURWHtQD3DSHQDVUHOHYDQWH
(OSURFHVRGHPRGHODGRKDSHUPLWLGR
HVWDEOHFHU KLSyWHVLV VREUH OD QDWXUDOH]D
ORFDOL]DFLyQ
\
UHOHYDQFLD
GH
ORV
WUDQVSRUWDGRUHV \ DXQTXH HVWRV UHVXOWDGRV
DLVODGRV QR SHUPLWHQ LGHQWLILFDU OD SURWHtQD
WUDQVSRUWDGRUDODPHWRGRORJtDSXHGHXWLOL]DUVH
FRPR FRPSOHPHQWDULD D ODV WpFQLFDV GH
ELRORJtDPROHFXODUDILQGHDSR\DUKLSyWHVLV\
GLVHxDUH[SHULPHQWRVFRQFOX\HQWHV
$JUDGHFLPLHQWRV
0LQLVWHULRGH(GXFDFLyQ\&LHQFLD6$)
($(
&RQVHOOHUtDGH&XOWXUD(GXFDFLyQ \&LHQFLD
\ &RQVHOOHULD GH (PSUHVD 8QLYHUVLGDG \
&LHQFLD
*HQHUDOLWDW
9DOHQFLDQD
$&203$&203
&RPLVLyQ (XURSHD 1HWZRUN RI ([FHOOHQFH
%,26,0 /6+%&7 :3 \
3KDUVLJKW &RUSRUDWLRQ SRU OD OLFHQFLD
DFDGpPLFDGH:LQQRQOLQ
,QWURGXFFLyQ
/RV OLSRVRPDV FRQVWLWX\HQ XQD LQWHUHVDQWH
DOWHUQDWLYD SDUD OD OLEHUDFLyQ SXOPRQDU GH
IiUPDFRV GHELGR D VX ELRGHJUDELOLGDG H
LQRFXLGDG DO LQFOXLU HQ VX FRPSRVLFLyQ
IRVIROtSLGRV DQiORJRV D ORV TXH IRUPDQ SDUWH
GHOVXUIDFWDQWHSXOPRQDU(VWRSRGUtDWDPELpQ
FRQWULEXLU D LQFUHPHQWDU HO WLHPSR GH
SHUPDQHQFLD GHO IiUPDFR GHQWUR GHO SXOPyQ
FRPR FRQVHFXHQFLD GH OD LQWHUDFFLyQ GH ORV
OLSRVRPDVFRQORVIRVIROtSLGRVHQGyJHQRV
1XPHURVRV IiUPDFRV SUHVHQWDQ EXHQD
DFWLYLGDGLQYLWURSHURQRVRQHIHFWLYRVSRUVX
WR[LFLGDG VLVWpPLFD \R SREUH SHQHWUDFLyQ HQ
ORVSXOPRQHVFRPRHVHOFDVRGHYDQFRPLFLQD
TXH DOFDQ]D EDMRV QLYHOHV HQ WHMLGR \
VHFUHFLRQHVSXOPRQDUHVGHORUGHQGHO
GH ORV FRUUHVSRQGLHQWHV HQ SODVPD FXDQGR
DFFHGHGHVGHODVDQJUH3DUDHVWRVFDVRV
HVWDUtD
SOHQDPHQWH
MXVWLILFDFDGD
OD
DGPLQLVWUDFLyQSXOPRQDU
El presente estudio tiene por objeto
caracterizar la disposición de vancomicina en
pulmón cuando se administra en forma de
liposomas por vía pulmonar.
0DWHULDOHV\0pWRGRV
0DWHULDOHV
/Į)RVIDWLGLOFROLQD GH \HPD GH KXHYR
6LJPD$OGULFK $OHPDQLD FROHVWHURO GH
ODQROLQD
6LJPD$OGULFK
$OHPDQLD
YDQFRPLFLQD &ORUKLGUDWR PJ &RPELQR
3KDUP %DUFHORQD FORUXUR VyGLFR %D[WHU 9DOHQFLD WLREDUELWDO %UDXQ J
%UDXQ %DUFHORQD KHSDULQD VyGLFD 0D\QH 3KDUPD 0DGULG WDPSyQ IRVIDWR
S+ \WULWRQ;0HUFN$OHPDQLD
(ODERUDFLyQGHODVYHVtFXODVOLStGLFDV
/DVYHVtFXODVOLStGLFDVVHSUHSDUDURQPHGLDQWH
HO PpWRGR FOiVLFR GH HYDSRUDFLyQ GHO
GLVROYHQWHHKLGUDWDFLyQGHORVIRVIROtSLGRV6H
SDUWLyGHODGLVROXFLyQGHOPDWHULDOOLStGLFRHQ
XQDPH]FODGHFORURIRUPR\PHWDQRO
/DPH]FODVHSUHSDUyHQXQEDOyQGHYLGULR
VXPHUJLGRHQXQEDxRGHDJXDDž&VH
FRQHFWyDXQURWDYDSRUUSPGXUDQWH
PLQXWRVSDUDODHYDSRUDFLyQGHORV
GLVRYHQWHV7UDVFXUULGRHVWHWLHPSRVH
GLVPLQX\yODWHPSHUDWXUDDž&PDQWHQLHQGR
HOYDFLRGXUDQWHKRUDV3RVWHULRUPHQWHVH
KLGUDWDURQORVIRVIROtSLGRVDGLFLRQDQGROD
GLVROXFLyQGHYDQFRPLFLQDPJPO\JGH
HVIHUDVGHYLGULR\FRORFDQGRHOUHFLSLHQWHGH
QXHYRHQHOURWDYDSRUDž&DXQDYHORFLGDG
GHUSPGXUDQWHPLQXWRV7UDVFXUULGR
HVWHWLHPSRVHPDQWXYRODPH]FODHQUHSRVR
GXUDQWHPLQXWRVSDUDFRPSOHWDUOD
IRUPDFLyQGHORVOLSRVRPDV\SRVWHULRUPHQWH
VHVRPHWLyDVRQLFDFLyQGXUDQWHPLQXWRV
$GPLQLVWUDFLyQLQKDODWRULDGHYDQFRPLFLQD
(O HVWXGLR IXH OOHYDGR D FDER XWLOL]DQGR UDWDV :LVWDU PDFKR GLVWULEXLGDV HQ WUHV
JUXSRV
*UXSR , Q DGPLQLVWUDFLyQ GH
YDQFRPLFLQD LQFRUSRUDGD HQ YHVtFXODV
OLStGLFDV
*UXSR ,, Q DGPLQLVWUDFLyQ GH
YDQFRPLFLQDLQFRUSRUDGDHQYHVtFXODVOLStGLFDV
FRQXQSHULRGRGH³ZDVKRXW´GHPLQXWRV
*UXSR ,,, Q DGPLQLVWUDFLyQ GH XQD
VROXFLyQDFXRVDGHYDQFRPLFLQD
6HUHDOL]yXQDWUDTXHRWRPtD\FDQXODFLyQGHOD
WUiTXHDFRQHFWDQGRODFiQXODDXQVLVWHPDGH
YHQWLODFLyQ DUWLILFLDO HQ IXQFLRQDPLHQWR
5HVSLUDWRU76(³$GYDQFHG´0RGHO8QDYH]
UHDOL]DGD OD WUDTXHRWRPtD HO SXOPyQ VH
PDQWXYR PHFiQLFDPHQWH YHQWLODGR GXUDQWH HO
UHVWR GHO SURFHVR 9ROXPHQ WLGDO PO \ UHVSLUDFLRQHVSRUPLQXWR
,QPHGLDWDPHQWH VH DGPLQLVWUy HO IiUPDFR D
WUDYpV GH OD YtD SXOPRQDU FRORFiQGRVH HQ HO
GHSyVLWR FRUUHVSRQGLHQWH GHO GLVSRVLWLYR GH
QHEXOL]DFLyQ 8OWUDVRQLF $HURVRO *HQHUDWRU
8976(V\VWHPODGLVROXFLyQDFXRVD
GH YDQFRPLFLQD PJPO R HO DQWLELyWLFR
LQFRUSRUDGR HQ ODV YHVtFXODV OLStGLFDV (O
HTXLSR GH QHEXOL]DFLyQ SHUPDQHFLy FRQHFWDGR
DO UHVWR GHO HTXLSR D WUDYpV GHO VLVWHPD GH
YHQWLODFLyQ DUWLILFLDO GH WDO PRGR TXH HO
SURGXFWRQHEXOL]DGRDFFHGLyDORVSXOPRQHVD
WUDYpV GH OD FiQXOD WUDTXHDO GXUDQWH PLQXWRV
6H UHFRJLHURQ PXHVWUDV GH VDQJUH DO WHUPLQDU
OD QHEXOL]DFLyQ GH YDQFRPLFLQD *UXSRV , \
,,,\PLQXWRVGHVSXpV*UXSR,,PHGLDQWH
XQD SXQFLyQ HQ HO YHQWUtFXOR L]TXLHUGR FRQ
XQDDJXMD\MHULQJDSUHYLDPHQWHKHSDULQL]DGDV
'HVSXpV VH UHFRJLy XQD PXHVWUD GH WHMLGR
SXOPRQDU TXH IXH SURFHVDGD PHGLDQWH
KRPRJHQL]DFLyQ +RPRJHQL]DWRU 352 6FLHQWLILF ,QF FRQ P0 GH WDPSyQ IRVIDWR
S+ GH 7ULWRQ ; /D
&RPXQLFDFLRQHV2UDOHV
02'(/,=$&,Ï1)$50$&2&,1e7,&$)$50$&2',1È0,&$'(/$(),&$&,$
$17,78025$/'(/&,63/$7,12$'0,1,675$'20(',$17(1$123$57Ë&8/$6
32/,0e5,&$6(18102'(/2;(12*5$)
'0RUHQR,)7URFyQL]6=DOED,1DYDUUR0-*DUULGR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH
1DYDUUD'HSDUWDPHQWRGH4XtPLFDVHFFLyQ4XtPLFD$QDOtWLFD)DFXOWDGGH&LHQFLDV8QLYHUVLGDG
GH1DYDUUD
WLHPSRVHGHVDUUROOyXQDWpFQLFDDQDOtWLFDSRU
,QWURGXFFLyQ
(O &LVSODWLQR VyOR R HQ FRPELQDFLyQ HV XQ
+3/&
DJHQWH DQWLQHRSOiVLFR PX\ XWLOL]DGR HQ XQD
DPSOLDYDULHGDGGHWXPRUHVVyOLGRV6XVHYHUD
$QLPDOHVHLPSODQWDFLyQWXPRUDO
QHIURWR[LFLGDG GHELGR D OD QHFHVLGDG GH
6H XWLOL]DURQ UDWRQHV LQPXQRGHSULPLGRV R
DGPLQLVWUDU DOWDV GRVLV SRU YtD LQWUDYHQRVD
DWK\PLF QXGH PLFHDORVTXHVHOHVLQRFXOy
SUHIHUHQWHPHQWH SDUD HYLWDU HQ SDUWH ORV
GH IRUPD VXEFXWiQHD [ '+'.352E
IHQyPHQRV GH UHVLVWHQFLD KD VXSXHVWR XQD
FpOXODV DGHQRFDUFLQRPD GH FRORQ GH UDWD
OLPLWDFLyQ SDUD VX XVR &RQ HO ILQ GH HYLWDU
(VWRV DQLPDOHV IXHURQ GLYLGLGRV HQ GRV
JUDQGHVJUXSRVSDUDORVVLJXLHQWHVHVWXGLRV
HVWRV HIHFWRV VH KDQ GHVDUUROODGR GLYHUVRV
WLSRVGHIRUPXODFLRQHVSDUDWUDWDUGHGLULJLUGH
• (VWXGLRFLQpWLFRPJNJGHFLVSODWLQR
IRUPD PiV HVSHFtILFD OD OLEHUDFLyQ GHO
EDVH VH DGPLQLVWUy VHPDQDOPHQWH
FRPSXHVWR'HQWURGHHVWDVIRUPXODFLRQHVORV
GXUDQWH WUHV FLFORV FRQVHFXWLYRV D WUHV
QDQRWUDQVSRUWDGRUHV SDUHFHQ MXJDU XQ SDSHO
JUXSRV*UXSR\UHFLELHURQ&,6HQ
LPSRUWDQWH \D TXH SDUHFHQ VHU FDSDFHV GH
VROXFLyQ
YtD
LY
H
LS
DSURYHFKDU HO GHVRUGHQ YDVFXODU GHO iUHD
UHVSHFWLYDPHQWH \ HO JUXSR UHFLELy
WXPRUDO SDUD DFFHGHU DVt PiV IiFLOPHQWH DO
&,613 SRU YtD LS /DV PXHVWUDV
SURSLRWXPRU$XQTXHKD\DOJXQRVWUDEDMRVHQ
VDQJXtQHDVVHREWXYLHURQDORODUJRGH
ODOLWHUDWXUDGRQGHVHGHPXHVWUDODHILFDFLDGH
K WUDV OD DGPLQLVWUDFLyQ /RV
DOJXQDV GH HVWDV IRUPXODFLRQHV VLQ HPEDUJR
QLYHOHV SODVPiWLFRV GH FLVSODWLQR VH
KDVWDHOPRPHQWRQRKD\QLQJ~QWUDEDMRGRQGH
PLGLHURQ PHGLDQWH XQD WpFQLFD GH
VH GHVFULED VX UHODFLyQ FLQpWLFDGLQiPLFD
DEVRUFLyQDWyPLFD
'HVGH HVWH SXQWR GH YLVWD GHVDUUROODU XQ
• (VWXGLR GLQiPLFR ORV DQLPDOHV VH
PRGHOR SDUD HVWDV QDQRSDUWtFXODV HQJOREDQGR
GLYLGLHURQHQJUXSRVFDGDXQRGHORV
FLVSODWLQR UHVXOWDUtD PX\ LQWHUHVDQWH SRUTXH
FXDOHV UHFLELy HO VLJXLHQWH WUDWDPLHQWR
QRV SHUPLWLUtD FDUDFWHUL]DU VX HILFDFLD PHGLGD
SRU YtD LS ,FRQWURO R VDOLQR ,, 13
FRPR UHVSXHVWD DQWLWXPRUDO \ UHGXFFLyQ GH
YDFtDV ,,, PJNJ GH FLVSODWLQR HQ
WR[LFLGDG HQ IXQFLyQ GH OD PHMRU H[SRVLFLyQ
VROXFLyQ\,9PJNJGH&,613
GHO RUJDQLVPR DO FRPSXHVWR $GHPiV
$WRGRVORVDQLPDOHVVHOHVHYDOXyGLDULDPHQWH
D\XGDUtD D HVWDEOHFHU XQ UpJLPHQ GH
HOWDPDxRWXPRUDO\HOSHVRFRUSRUDO$GHPiV
DGPLQLVWUDFLyQPiVVHJXUR\HIHFWLYR
HQ HO HVWXGLR GLQiPLFR VH H[WUDMHURQ PXHVWUDV
3RUWDQWRHOREMHWLYRHVGHVDUUROODUXQPRGHOR
VDQJXtQHDVSDUD PHGLUORV QLYHOHVSODVPiWLFRV
IDUPDFRFLQpWLFRIDUPDFRGLQiPLFR FDSD] GH
GH%81XUHDQLWURJHQDGDHQVDQJUH\9(*)
GHVFULELU \ SUHGHFLU OH HILFDFLD DQWLWXPRUDO GH
IDFWRUGHFUHFLPLHQWRYDVFXORHQGRWHOLDO
QDQRSDUWtFXODVSROLPpULFDVGHFLVSODWLQRHQXQ
PRGHOR[HQRJUDIGHUDWyQ
$QiOLVLVGHGDWRV
(O SURJUDPD 1210(0 YHUVLyQ 9, VH
0DWHULDO\PpWRGRV
XWLOL]y SDUD DQDOL]DU WRGRV ORV GDWRV VLJXLHQGR
)RUPXODFLyQ
XQ PpWRGRVHFXHQFLDO3ULPHURVHGHVFULELyOD
6LJXLHQGR HO PpWRGR GH HYDSRUDFLyQ GHO
IDUPDFRFLQpWLFD GHO FLVSODWLQR PHGLDQWH
GLVROYHQWH WUDV OD IRUPDFLyQ GH XQD GREOH
PRGHORV FRPSDUWLPHQWDOHV \ SRVWHULRUPHQWH
HPXOVLyQ$2$\XWLOL]DQGRFRPRSROtPHUR
VH UHDOL]y HO DQiOLVLV GH OD UHVSXHVWD
HO 3/*$ 5HVRPHU + VH GHVDUUROODURQ
DQWLWXPRUDO HYROXFLyQ WHPSRUDO GHO WDPDxR
QDQRSDUWtFXODVHQJOREDQGRFLVSODWLQR
WXPRUDO
6HFDUDFWHUL]DURQPHGLDQWH
(VWXGLRV ItVLFRTXtPLFRV HO WDPDxR \ HO
5HVXOWDGRV\GLVFXVLyQ
SRWHQFLDO ]HWD VH GHWHUPLQDURQ SRU
/DVSDUWtFXODVREWHQLGDVWXYLHURQXQWDPDxRGH
GLIUDFWRPHWUtD GH OiVHU HQ XQ =HWDVL]HU 1DQR
QPDSUR[FRQXQSRWHQFLDOQHJDWLYR\OD
6HULHV
SROLGLVSHUVLyQGHODIRUPXODFLyQIXHPHQRUGHO
(VWXGLRVGHOLEHUDFLyQLQYLWUR
/D HILFDFLD GH HQFDSXVODFLyQ HVWXYR
3DUD FXDQWLILFDU OD FDQWLGDG GH &LVSODWLQR
GHQWUR GH ORV QLYHOHV GHVFULWRV DQWHULRUPHQWH
HQFDSVXODGR \ORVSHUILOHVGHOLEHUDFLyQHQHO
SRU QXHVWUR JUXSR \ RWURV DXWRUHV SDUD RWUDV
“ \ “ YHUVXV “
S>
(VWRVUHVXOWDGRVSRQHQGHPDQLILHVWRHOLQWHUpV
GH ORV HVWXGLRV GHVWLQDGRV D SRWHQFLDU OD YtD
SXOPRQDU QR VyOR SDUD QXHYRV SURGXFWRV GH
RULJHQELRWHFQROyJLFRVLQRSDUDWRGRVDTXHOORV
IiUPDFRVFX\DELRIDVHVHORFDOLFHDHVWHQLYHO
&RQFOXVLRQHV
7UDV DO DGPLQLVWUDFLyQ SXOPRQDU OD
FDSDFLGDG
GH
WUDQVIHUHQFLD
GH
YDQFRPLFLQD D ORV HVSDFLRV \ IOXLGRV
SXOPRQDUHV HV VXSHULRU FXDQGR VH
IRUPXODHQOLSRVRPDVTXHFXDQGRVHKDFH
HQ GLVROXFLyQ VX DFFHVR DO HVSDFLR
VLVWpPLFR SRU HO FRQWUDULR QR VH
LQFUHPHQWDSDUDODVYHVtFXODVOLStGLFDV
/D LQFRUSRUDFLyQ GH YDQFRPLFLQD D ORV
OLSRVRPDV SURGXFH XQ PDQWHQLPLHQWR GH
ODV FRQFHQWUDFLRQHV GHO IiUPDFR HQ WHMLGR
\ IOXLGRSXOPRQDU PiVSURORQJDGRTXHOD
GLVROXFLyQORTXHGHPXHVWUDTXHHVWHWLSR
GH IRUPXODFLyQ IDYRUHFH OD SHUPDQHQFLD
GHOIiUPDFRHQHOHVSDFLRSXOPRQDU
/D IRUPXODFLyQ GH YDQFRPLFLQD HQ
OLSRVRPDV SDUHFH XQD DOWHUQDWLYD ySWLPD
SDUD VX DGPLQLVWUDFLyQ SXOPRQDU 'HELGR
DODFRPSRVLFLyQGHODVYHVtFXODVOtStGLFDV
IRUPXODGDV VX FRPSDWLELOLGDG HV PX\
HOHYDGD SXGLHQGR LQFOXVR IDFLOLWDU OD
UHSDUDFLyQ GHO VXUIDFWDQWH SXOPRQDU HQ
SXOPRQHVGDxDGRV
$JUDGHFLPLHQWRV
(VWH WUDEDMR IRUPD SDUWH GHO SUR\HFWR GH
LQYHVWLJDFLyQ ILQDQFLDGR SRU OD -XQWD GH
&DVWLOOD \ /HyQ 5HI 6$$ 2UGHQ
('8
%LEOLRJUDItD
*UHQKD$HWDO(XU-3KDUP%LRSKDUP
*LOEHUW%(6SULQJ
&UXFLDQL 0 HW DO - $QWLPLFURE
&KHPRWKHU
-HV~V9DOOH0-HWDO-3KDUP%LRPHG
$QDO
GHWHUPLQDFLyQ GH ODV FRQFHQWUDFLRQHV GHO
DQWLELyWLFR HQ ODV PXHVWUDV VH OOHYy D FDER
PHGLDQWH XQD WpFQLFD GH +3/& GHVDUUROODGD
SRU-HV~V9DOOH0-\FROV
5HVXOWDGRV\'LVFXVLyQ
/DILJXUDPXHVWUDORVYDORUHVPHGLRVGHORV
FRHILFLHQWHV
GH
UHSDUWR
WHMLGR
SXOPRQDUSODVPD GH YDQFRPLFLQD WUDV VX
DGPLQLVWUDFLyQSRUYtDLQKDODWRULDFXDQGRpVWD
HVLQFRUSRUDGDHQIRUPDGHYHVtFXODVOLStGLFDV
\ FXDQGR HV DGPLQLVWUDGD HQ GLVROXFLyQ /D
WDEOD LQFOX\H ODV FRUUHVSRQGLHQWHV
FRQFHQWUDFLRQHVPHGLDVGHOIiUPDFRHQSODVPD
\ WHMLGR SDUD ODV GLIHUHQWHV FRQGLFLRQHV
H[SHULPHQWDOHVHQVD\DGDV
)LJXUD 5HSDUWR WHMLGR SXOPRQDUSODVPD
SDUDORVJUXSRVH[SHULPHQWDOHVS>
7DEOD &RQFHQWUDFLRQHV GH YDQFRPLFLQD HQ
SODVPD\WHMLGRSXOPRQDU
&RQFHQWUDFLRQHV—JPO0(',$“'(
*UXSRV
3ODVPD 7HMLGRSXOPRQDU
*UXSR, “
“
*UXSR,, “
“
*UXSR,,, “
“
6H FRPSUREy TXH OD DGPLQLVWUDFLyQ GH
YDQFRPLFLQD LQFRUSRUDGD HQ ODV YHVtFXODV
OLStGLFDV SURGXFH XQ PD\RU UHSDUWR GHO
IiUPDFRHQWUHORVWHMLGRVIOXLGRVSXOPRQDUHV\
HOHVSDFLRYDVFXODUTXHFXDQGRVHLQKDODEDHQ
GLVROXFLyQ\VHGHPXHVWUDODPD\RUFDSDFLGDG
GH WUDQVIHUHQFLD GH YDQFRPLFLQD HQWUH ORV
HVSDFLRV SXOPRQDUHV FXDQGR VH LQFRUSRUD D
ORVOLSRVRPDV
&XDQGR YDQFRPLFLQD VH DGPLQLVWUD SRU
LQKDODFLyQHQIRUPDGHOLSRVRPDV VXDFFHVRD
ODFLUFXODFLyQVLVWpPLFDHVPiVUHVWULQJLGRTXH
FXDQGRVHDGPLQLVWUDHQGLVROXFLyQDXQTXHODV
GLIHUHQFLDV QR SUHVHQWDQ VLJQLILFDFLyQ
HVWDGtVWLFD 3RU HO FRQWUDULR ORV QLYHOHV
DOFDQ]DGRV HQ WHMLGR SXOPRQDU UHVXOWDURQ VHU
VXSHULRUHV D ORV TXH VH DOFDQ]DURQ FXDQGR VH
UHFXUULy D OD DGPLQLVWUDFLyQ HQ GLVROXFLyQ
,;&RQJUHVRGHOD6(),*
IRUPXODFLRQHVGH&,6\IXHGHO6XSHUILO
GH OLEHUDFLyQ SUHVHQWy XQD FXUYD WULIiVLFD GH
FDUDFWHUtVWLFDV VLPLODUHV D ODV REWHQLGDV FRQ
HVWHWLSRGHSROtPHUR
)DUPDFRFLQpWLFD)DUPDFRGLQDPLD
100
&,6,9
&''3FRQFHQUDWLRQPJ/3W
$'0,1,675$&,Ï138/021$5'(9$1&20,&,1$(1)250$'(9(6Ë&8/$6
/,3Ë',&$6
-HV~V9DOOH0-GH*RQ]iOH]/ySH])6iQFKH]1DYDUUR$
)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DODPDQFD
/LFHQFLDGR0pQGH]1LHWRVQ
HPDLODVQ#XVDOHV
,;&RQJUHVRGHOD6(),*
&,6,3
13,3
10
1
0.1
0.01
0
5
10
WLPHGD\V
15
20
)LJXUD 1LYHOHV SODVPiWLFRV GH &,6 WUDV VX
DGPLQLVWUDFLyQ HQ VROXFLyQ LY H LS \
HQFDSVXODGR LS GXUDQWH WUHV FLFORV
FRQVHFXWLYRV
(O DQiOLVLV VLPXOWiQHR GH ORV QLYHOHV
SODVPiWLFRV GH &,6 WUDV VX DGPLQLVWUDFLyQ HQ
VROXFLyQSRUYtDLYHLSVLJXLHURQXQPRGHOR
WULFRPSDUWLPHQWDO GRQGH OD YHORFLGDG GH
DEVRUFLyQSDUDODYtDLSIXH GHVFULWDFRQ XQD
FRQVWDQWH GH SULPHU RUGHQ \ OD
ELRGLVSRQLELOLGDG ) GHO &,6 QR FDPELy 6LQ
HPEDUJR ORV QLYHOHV SODVPiWLFRV GH &,6 WUDV
VX DGPLQLVWUDFLyQ HQ 13 YtD LS VLJXLy XQD
FLQpWLFD PRQRFRPSDUWLPHQWDO GRQGH OD
YHORFLGDG GH DEVRUFLyQ IXH GH RUGHQ FHUR (O
DFODUDPLHQWRSODVPiWLFR&/IXHVLPLODUSDUD
DPERV DQiOLVLV \ HVWXYR DVRFLDGR D XQD
YDULDELOLGDG LQWHUDQLPDO GHO \ UHVSHFWLYDPHQWH PLHQWUDV TXH HO YROXPHQ GH
GLVWULEXFLyQ GHO FRPSDUWLPHQWR FHQWUDO 9
DXPHQWy HQ UHODFLyQ D VX DGPLQLVWUDFLyQ HQ
13
1400
&RQWURO
1200
&''3,9
&''3,3
13%,3
UG GRVH
1000
7XPRUVL]HPP &RPXQLFDFLRQHV2UDOHV
800
600
QG GRVH
400
200
VW
GRVH
0
0
5
10
15
20
25
WLPHGD\V
)LJXUD(YROXFLyQGHOWDPDxRWXPRUDOSDUD
ORVGLIHUHQWHVJUXSRVGHWUDWDPLHQWR
(O&,6LQKLELyHOFUHFLPLHQWRWXPRUDOGHVGHHO
SULPHU FLFOR WDO \ FRPR VH UHSUHVHQWD HQ OD
ILJXUD 3DUDOHODPHQWH QR KXER GLIHUHQFLDV
VLJQLILFDWLYDVHQWUHORVWUDWDPLHQWRV
/RV SHUILOHV WHPSRUDOHV GHO YROXPHQ WXPRUDO
GH ORV GLVWLQWRV JUXSRV VH DQDOL]DURQ
VLPXOWiQHDPHQWH PHGLDQWH HO PRGHOR
SXEOLFDGRSRU%XHQR\FROV
(VWH PRGHOR EDVDGR HQ OD HFXDFLyQ GH
*RPSHUW]IXHFDSD]GHGHVFULELUODVGRVIDVHV
GHOFUHFLPLHQWRREVHUYDGDVXQDSULPHUDOLQHDO
TXHYDGHVGHTXHHVSDOSDEOHHOWXPRUKDVWDHO
GtDVHJXLGDGHRWUDH[SRQHQFLDO
/DWR[LFLGDGPHGLGDFRPRQLYHOHVVDQJXtQHRV
GH %81 XUHD QLWURJHQDGD VDQJXtQHD
DXPHQWDURQGHIRUPDHVWDGtVWLFDHQORVJUXSRV
WUDWDGRV FRQ &,6 HQ VROXFLyQ PLHQWUDV TXH OD
DGPLQLVWUDFLyQ GH 13 QR LQGXMHURQ QLQJ~Q
LQFUHPHQWRHQHVWHSDUiPHWUR)LQDOPHQWHORV
QLYHOHV SODVPiWLFRV GH 9(*) UHIOHMDURQ TXH
HVWH PDUFDGRU HUD XQ EXHQ IDFWRU GH
VHJXLPLHQWR GHO WUDWDPLHQWR DXQTXH QR
QHFHVDULDPHQWHGHSURQyVWLFR
%,%/,2*5$)Ë$
)XHUWHVD 0$ &DVWLOODE - $ORQVR & 3pUH]
-0&XUU0HG&KHP
.LP-+.LP<63DUN./HH6\FROV-
&RQWURO5HOHDVH
0RUHQR'7URV&%DQGUpV(%XxXDOHV0
\ FROV (XU - 3KDUP %LRSKDUP %XHQR/GH$OZLV'33LWRX&<LQJOLQJ-
\FROV(XU-&DQFHU
$JUDGHFLPLHQWRV
(VWHWUDEDMRKDVLGRHQSDUWHILQDQFLDGRSRUHO
0LQLVWHULR GH &LHQFLD H ,QQRYDFLyQ 3&7
\OD8QLYHUVLGDGGH1DYDUUD
0RUHQR'\=DOED6KDQVLGRILQDQFLDGRVSRU
HO*RELHUQRGH1DYDUUDGSWRHGXFDFLyQ\GSWR
GHLQGXVWULDUHVSHFWLYDPHQWH
&RPXQLFDFLRQHV2UDOHV
75$163257('(&257,62/$75$9e6'(8102'(/2,19,752'(/$%$55(5$
+(0$72(1&()È/,&$
&1DYDUUR,*RQ]DOH]$OYDUH]90HULQR00DQNX9*&DVDEy
0%HUPHMR
'HSDUWPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH9DOHQFLD(VSDxD
'HSWRGH,QJHQLHUtDÈUHD)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDG0LJXHO+HUQiQGH]
(OFKH/D[GDOH/LPLWHG5HLQR8QLGR
EDVRODWHUDO
KDFLD
OD
DSLFDO
/DV
,QWURGXFFLyQ (O WUDQVSRUWH D WUDYpV GH OD
FRQFHQWUDFLRQHV LQLFLDOHV GH FRUWLVRO IXHURQ EDUUHUDKHPDWRHQFHIiOLFDHVXQIDFWRUUHOHYDQWH
\ X0 PLHQWUDV TXH ODV GH (3$
HQ OD DFFLyQ IDUPDFROyJLFD GH PXFKDV
IXHURQ \ X0 VLHQGR OD
VXVWDQFLDVHQGyJHQDV\IiUPDFRVFX\RVLWLRGH
FRQFHQWUDFLyQ GH FRUWLVRO X0 HQ SUHVHQFLD
DFFLyQ HVWi ORFDOL]DGR HQ HO FHUHEUR $OJXQRV
GHWRGDVODVFRQFHQWUDFLRQHVGH(3$
WUDQVSRUWDGRUHV GH VHFUHFLyQ FRPR OD
JOLFRSURWHtQD3 SXHGHQ DIHFWDU D OD
5HVXOWDGRV\'LVFXVLyQ/RVH[SHULPHQWRVLQ
SHUPHDELOLGDG D WUDYpV GH GLFKD EDUUHUD GH
YLWURPRVWUDURQGLIHUHQFLDVVLJQLILFDWLYDVHQWUH
HVWDV VXVWDQFLDV LQFOX\HQGR ODV KRUPRQDV
ODV SHUPHDELOLGDGHV $% \ %$ GH FRUWLVRO
HVWHURLGHDV 3DUHFH VHUTXH XQD KLSHUDFWLYLGDG
S DVt FRPR XQ SURFHVR GH
GH OD JOLFRSURWHtQD3 HVWi UHODFLRQDGD FRQ OD
SHUPHDELOLGDGGHSHQGLHQWHGHODFRQFHQWUDFLyQ
UHVLVWHQFLD GH OD VXSUHVLyQ GHO HMH
)LJXUD
KLSRWDOiPLFRSLWXLWDULRDGUHQDO
SRU
JOXFRFRUWLFRLGHV (VWD UHVLVWHQFLD D ORV
JOXFRFRUWLFRLGHV HV XQD GH ODV DQRPDOtDV
ELROyJLFDV PHMRU GHVFULWDV HQ FLHUWRV WLSRV GH
GHSUHVLyQ $OJXQRV iFLGRV JUDVRV SROL
LQVDWXUDGRV $*3, KDQ PRVWUDGR HILFDFLD
FOtQLFD HQ HVWH JUXSR GH SDFLHQWHV DVt FRPR
XQD UHGXFFLyQ GH OD DFWLYLGDG GHO HMH DGUHQDO
HQ PRGHORV DQLPDOHV $OJXQRV PRGHORV HQ
FXOWLYRV FHOXODUHV FRPR ODV FpOXODV 0'&. \
0'&.0'5
UHSURGXFHQ
FLHUWDV
SURSLHGDGHV GH OD EDUUHUD KHPDWRHQFHIiOLFD
FRPR PDUFDGRUHV FHOXODUHV PRUIROyJLFRV
HQ]LPiWLFRV R DQWLJpQLFRV TXH WDPELpQ VH
HQFXHQWUDQHQFpOXODVHQGRWHOLDOHVFHUHEUDOHV\
KDQ VLGR DPSOLDPHQWH GHVFULWRV FRPR XQ
PRGHOR DGHFXDGR SDUD HVWD EDUUHUD /D
SURSXHVWD GH HVWH HVWXGLR IXH HYDOXDU OD
LQIOXHQFLDGHXQiFLGRJUDVRSROLLQVDWXUDGRHO
iFLGR HLFRVDSHQWDHQRLFR (3$ HQ HO
WUDQVSRUWH GHO FRUWLVRO D WUDYpV GH OD EDUUHUD
KHPDWRHQFHIiOLFDPHGLDQWHHVWXGLRVLQYLWURHQ
HO PRGHOR FHOXODU GHVFULWR DVt FRPR
)LJXUD 9DORUHV GH SHUPHDELOLGDG GH
GHVDUUROODUXQPRGHORPDWHPiWLFRJHQHUDOSDUD
FRUWLVRO D ODV GLIHUHQWHV FRQFHQWUDFLRQHV
HVWLPDU ORV SDUiPHWURV FLQpWLFRV UHODFLRQDGRV
HVWXGLDGDV HQ DPEDV OtQHDV FHOXODUHV D
FRQODSHUPHDELOLGDGGHOFRUWLVRO
0'&.\E0'&.0'5
0DWHULDOHV \ 0pWRGRV $PEDV OtQHDV
(O PHMRU PRGHOR FLQpWLFR FRUUHVSRQGH D XQ
FHOXODUHV IXHURQ VHPEUDGDV \ FUHFLGDV HQ
PRGHORGHWUHVFRPSDUWLPHQWRVDSLFDOFHOXODU
IRUPD GH PRQRFDSDV FHOXODUHV HQ PHPEUDQDV
\ EDVDO FRQ XQ WUDQVSRUWDGRU GH VHFUHFLyQ
GHSROLFDUERQDWRKDVWDVXFRQIOXHQFLDGXUDQWH
VLWXDGR HQ OD FDUD DSLFDO GH OD PHPEUDQD \
GtDV /D LQWHJULGDG GH OD PRQRFDSD VH
FX\R SXQWR GH XQLyQ VH HQFXHQWUD HQ OD SDUWH
HYDOXy PLGLHQGR OD UHVLVWHQFLD HOpFWULFD
H[WHULRUGHODPHPEUDQD'DGRTXHODVFpOXODV
WUDQVHSLWHOLDODQWHV\GHVSXpVGHOH[SHULPHQWR
0'&.0'5VRQXQFORQWUDQVIHFWDGRGHODV
8QDYH]VHDGPLQLVWUyHOIiUPDFRVHWRPDURQ
FpOXODV 0'&. GRQGH OD JOLFRSURWHtQD3 HVWi
FXDWUR PXHVWUDV GXUDQWH PLQXWRV \
VREUHH[SUHVDGDVHFRQVLGHUyTXHFDGD XQDGH
SRVWHULRUPHQWHVHDQDOL]DURQPHGLDQWH&/$5
ODV OtQHDV FHOXODUHV WHQGUtD XQ YDORU GLIHUHQWH
/RV HVWXGLRV GH WUDQVSRUWH VH UHDOL]DURQ HQ
HQ OD YHORFLGDG Pi[LPD GHO WUDQVSRUWDGRU
DPEDV GLUHFFLRQHV GHVGH OD FiPDUD DSLFDO
PLHQWUDV TXH HO UHVWR GH SDUiPHWURV VH
KDFLD OD EDVRODWHUDO \ GHVGH OD FiPDUD
,;&RQJUHVRGHOD6(),*
PDQWXYLHURQ FRPXQHV /RV SDUiPHWURV
FRUUHVSRQGLHQWHVDHVWHPRGHORVHPXHVWUDVHQ
ODWDEOD
7DEOD 3DUiPHWURV FLQpWLFRV LQ YLWUR
REWHQLGRV HQ ODV OtQHDV FHOXODUHV 0'&. \
0'&.0'5
9DORUHV&9
3DUiPHWURV
0'&.
0'&.0'5
9RO FHOXODU
Â
P/
3$&FPV
Â
3&%FPV
Â
9P
Â
Â
QPROVÂFP .P—0
Â
3RU RWUD SDUWH ORV H[SHULPHQWRV HQ SUHVHQFLD
GH(3$PRVWUDURQGLIHUHQFLDVVLJQLILFDWLYDVHQ
ORV YDORUHV GH SHUPHDELOLGDG D ODV
FRQFHQWUDFLRQHV PiV DOWDV GH (3$ S
SHUR VyOR HQ OD OtQHD FHOXODU 0'&. QR
YLpQGRVH DIHFWDGRV ORV YDORUHV GH
SHUPHDELOLGDG HQ ODV FpOXODV 0'&.0'5
7DEODV\
7DEOD 5HVXOWDGR GH OD FRPSDUDFLyQ
P~OWLSOHGHODVSHUPHDELOLGDGHVDSLFDOEDVDO\
EDVDODSLFDO
SDUD
ODV
GLVWLQWDV
FRQFHQWUDFLRQHVGH(3$HQVD\DGDVHQODOtQHD
FHOXODU0'&.
3DE
16
16
16
6
16
6
6
6
6
16
3ED
16
16
16
6
16
16
6
6
6
6
7DEOD 5HVXOWDGR GH OD FRPSDUDFLyQ
P~OWLSOHGHODVSHUPHDELOLGDGHVDSLFDOEDVDO\
EDVDODSLFDO
SDUD
ODV
GLVWLQWDV
FRQFHQWUDFLRQHVGH(3$HQVD\DGDVHQODOtQHD
FHOXODU0'&.0'5
3DE
16
16
16
16
16
16
16
16
16
16
3ED
16
16
16
16
16
16
16
16
16
16
(O FRUWLVRO HV WUDQVSRUWDGR DFWLYDPHQWH SRU OD
JOLFRSURWHtQD3HQDPEDVOtQHDVFHOXODUHVSHUR
HO WUDQVSRUWDGRU VyOR PXHVWUD VDWXUDFLyQ D ODV
FRQFHQWUDFLRQHV HQVD\DGDV HQ 0'&. (O
iFLGR JUDVR (3$ DFW~D FRPR LQKLELGRU GH OD
VHFUHFLyQ D WUDYpV GH OD JOLFRSURWHtQD3 HQ OD
OtQHD FHOXODU 0'&. PLHQWUDV TXH HQ OD OtQHD
FHOXODU WUDQVIHFWDGD OD FRQFHQWUDFLyQ GH (3$
QR HV VXILFLHQWHPHQWH DOWD SDUD PRVWUDU DOJ~Q
HIHFWR(VWRVLJQLILFDTXHODVHFUHFLyQDWUDYpV
GH OD JOLFRSURWHtQD3 SRGUtD VHU HO IDFWRU
GRPLQDQWH SDUD HO WUDQVSRUWH GH FRUWLVRO D
WUDYpV GH OD EDUUHUD KHPDRHQFHIiOLFD SXHVWR
TXHODVFRQFHQWUDFLRQHVILVLROyJLFDVGHFRUWLVRO
VH HQFXHQWUDQ HQ HO iPELWR PiV EDMR GH ODV
FRQFHQWUDFLRQHVHQVD\DGDVHQHVWHHVWXGLR
5HIHUHQFLDV
9HURQHVL%&KDUDFWHUL]DWLRQRIWKH0'&.
FHOO OLQH IRU VFUHHQLQJ QHXURWR[LFDQWV
1HXURWR[LFRORJ\
&0 3DULDQWH HW DO 'R DQWLGHSUHVVDQWV
UHJXODWH KRZ FRUWLVRO DIIHFWV WKH EUDLQ"
3V\FKRQHXURHQGRFULQRORJ\ $JUDGHFLPLHQWRV
0'&. DQG 0'&.0'5 FHOOV ZHUH
SURYLGHGE\'U0LFKDHO0*RWWHVPDQ&KLHI
/DERUDWRU\ RI &HOO %LRORJ\ 1DWLRQDO &DQFHU
,QVWLWXWH
7KLV ZRUN LV VXSSRUWHG E\ %LRVLP (8 JUDQW
/6+%&7
PÓSTERS
TECNOLOGÍA FARMACÉUTICA
7HFQRORJtD)DUPDFpXWLFD
/8&,)(5<(//2:)5(17($0$1,72/&2020$5&$'25(6'(/$,17(*5,'$'
'(/$60212&$3$6&$&23$5$(16$<26'(3(50($%,/,'$'
&HQWHOOHV$*RQ]DOH]$OYDUH],0HULQR9%HUPHMR09
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH9DOHQFLD
/DV PRQRFDSDV FHOXODUHV &DFR
UHVXOWDQ XQ EXHQ VLVWHPD SDUD HO HVWXGLR GH OD
SHUPHDELOLGDG LQWHVWLQDO VLQ HPEDUJR ORV
FRHILFLHQWHVGHSHUPHDELOLGDGDSDUHQWHV3DSS
SUHVHQWDQ XQD JUDQ YDULDELOLGDG WDQWR LQWHU
FRPR LQWUDODERUDWRULR /D YDULDFLyQ GH OD
SHUPHDELOLGDGSDUDFHOXODUFRPRFRQVHFXHQFLD
GH GDxRV HQ OD PHPEUDQD HV XQD GH ODV
SRVLEOHVFDXVDVGHGLFKDYDULDELOLGDGSXHV
XQD PRQRFDSD ELHQ IRUPDGD FRQVWLWX\H XQD
EDUUHUD SRODUL]DGD \ VHOHFWLYD FRQ XQ PtQLPR
IOXMR SDUDFHOXODU (O /XFLIHU <HOORZ /<
DWUDYLHVDODPHPEUDQDDWUDYpVGHORVHVSDFLRV
LQWHUFHOXODUHV WLJKW MXQFWLRQV GH pVWD GH
PRGR TXH HO HVWXGLR GH VX YDORU GH
SHUPHDELOLGDG SHUPLWH HYDOXDU HO HVWDGR GH OD
PRQRFDSD (O PDQLWRO FRPR VXVWDQFLD
KLGURItOLFD\GHEDMRSHVRPROHFXODUWDPELpQVH
XWLOL]DFRQHOPLVPRSURSyVLWRSHURSUHVHQWDOD
GHVYHQWDMD GH VX GHWHUPLQDFLyQ DQDOtWLFD TXH
UHTXLHUHHOPDUFDMHFRQUDGLRDFWLYLGDG3RU
WDQWRHOREMHWLYRGHHVWHWUDEDMRHVYHULILFDUHO
XVR GHO /XFLIHU <HOORZ FRPR tQGLFH GH
LQWHJULGDGGHODPRQRFDSD(QHVWHFDVROD
SHUPHDELOLGDG GH /< VH KD XWLOL]DGR SDUD
HVWDEOHFHU D TXp FRQFHQWUDFLyQ XQ IiUPDFR
HPSLH]D D DOWHUDU OD LQWHJULGDG GH OD EDUUHUD \
GH HVH PRGR HVWDEOHFHU HO OtPLWH Pi[LPR GH
FRQFHQWUDFLyQ SDUD ORV HVWXGLRV VREUH OD
SHUPHDELOLGDG GHO PLVPR (VWH PLVPR WLSR GH
HVWXGLRV VH UHDOL]y HQ XQ VHJXQGR ODERUDWRULR
XVDQGR PDQLWRO FRPR PDUFDGRU SDUDFHOXODU D
ILQ GH FRPSDUDU ORV UHVXOWDGRV GH DPERV
PpWRGRV
0DWHULDOHV\0pWRGRV
/RV HVWXGLRV GH SHUPHDELOLGDG VH
UHDOL]DURQ HQ GRV FORQHV FHOXODUHV
$7&&&DFR \ 7&&DFR /DV FpOXODV VH
FXOWLYDURQ \ FUHFLHURQ HQ PHPEUDQDV GH
SROLFDUERQDWR KDVWD DOFDQ]DU OD FRQIOXHQFLD
GXUDQWHGtDV6HHQVD\DURQVROXFLRQHVGH
/XFLIHU <HOORZ PJPO DGLFLRQDGDV GH GRV
FRPSXHVWRV ÈFLGR $FHWLOVDOLFtOLFR $$6 \
3DUDFHWDPRO 3& D GRV FRQFHQWUDFLRQHV
P0 \ P0 /RV HVWXGLRV GH WUDQVSRUWH VH
OOHYDURQ D FDER HQ GLUHFFLyQ DSLFDOEDVDO /D
YDORUDFLyQ GH ODV PXHVWUDV VH UHDOL]y SRU
FURPDWRJUDItD OtTXLGD GH DOWD UHVROXFLyQ \
GHWHFFLyQ SRU IOXRUHVFHQFLD /RV YDORUHV GH
SHUPHDELOLGDG VH REWXYLHURQ SRU UHJUHVLyQ
OLQHDO GH ODV FDQWLGDGHV DFXPXODGDV HQ HO
FRPSDUWLPHQWRUHFHSWRUIUHQWHDOWLHPSR
5HVXOWDGRV\'LVFXVLyQ
(Q OD OtQHD &DFR QR VH REVHUYD XQ
DXPHQWRGHODSHUPHDELOLGDGGHOLQGLFDGRU/<
HQ SUHVHQFLD GH ORV FRPSXHVWRV D OD
FRQFHQWUDFLyQ GH P0 SRU OR TXH GLFKD
FRQFHQWUDFLyQ QRLQWHUILHUHHQODLQWHJULGDGGH
ODPRQRFDSD)LJXUD
(Q ORV HVWXGLRV FRQ HO FORQ 7& VH
REVHUYD TXH OD DGLFLyQ GH 3DUDFHWDPRO P0
UHVXOWD Wy[LFD SDUD OD PRQRFDSD FHOXODU
SURGXFLHQGR FDPELRV HQ OD DEVRUFLyQ GHO /<
)LJXUD SRU WDQWR VH UHSLWLHURQ ORV HQVD\RV
XWLOL]DQGRXQDFRQFHQWUDFLyQYHFHVLQIHULRU
(Q HVWH FDVR ORV UHVXOWDGRV QR PRVWUDURQ
GLIHUHQFLDV VLJQLILFDWLYDV HQ ORV YDORUHV GH
SHUPHDELOLGDG GH /< REWHQLGRV HQ VROXFLyQ
OLEUH \ HQ SUHVHQFLD GH ORV FRPSXHVWRV GH
PRGR TXH SDUD 3& OD FRQFHQWUDFLyQ QR Wy[LFD
IXHP0)LJXUD
6e-7
ATCC/Caco-2
5e-7
Pemeabilidad LY (cm/s)
,QWURGXFFLyQ\REMHWLYRV
4e-7
3e-7
2e-7
1e-7
0
LY
LY + AAS 1mM
LY + PC 1mM
)LJXUD 3HUPHDELOLGDG GH /< REWHQLGD HQ
DXVHQFLD\SUHVHQFLDGHFRPSXHVWRVP0HQ
FpOXODV&DFR
3.0e-7
2.5e-7
Permeabilidad LY (cm/s)
TC7/Caco-2
2.0e-7
1.5e-7
1.0e-7
5.0e-8
0.0
LY
LY + AAS 1mM
LY + PC 1mM
)LJXUD 3HUPHDELOLGDG GH /< REWHQLGD HQ
DXVHQFLD\SUHVHQFLDGHFRPSXHVWRVP0HQ
FpOXODV7&
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
1.8e-7
Permeabilidad LY (cm/s)
1.6e-7
TC7/Caco-2
1.4e-7
1.2e-7
1.0e-7
8.0e-8
6.0e-8
4.0e-8
2.0e-8
0.0
LY
LY + AAS 0.1mM LY + PC 0.1mM
)LJXUD 3HUPHDELOLGDG GH /< REWHQLGD HQ
DXVHQFLD \ SUHVHQFLD GH FRPSXHVWRV P0
HQFpOXODV7&
6H REVHUYDQ GLIHUHQFLDV HQ PDJQLWXG
HQWUH ORV YDORUHV GH 3DSS GH /< HQ OD OtQHD
&DFRIUHQWHDODOtQHD7&(QHVWD~OWLPDORV
YDORUHV GH 3DSS VRQ LQIHULRUHV \ D VX YH] HV
PiVVHQVLEOHDODSUHVHQFLDGHFRQFHQWUDFLRQHV
HOHYDGDV GH IiUPDFR +D\ TXH UHPDUFDU TXH
SDUDXWLOL]DU /<FRPRLQGLFDGRUGHLQWHJULGDG
FHOXODU GHEH FDUDFWHUL]DUVH SUHYLDPHQWH VX
YDORU GH SHUPHDELOLGDG SURPHGLR HQ OD OtQHD
FHOXODUHQHVWXGLR
/RV UHVXOWDGRV GH H[SHULPHQWRV
VLPLODUHV UHDOL]DGRV FRQ PDQLWRO HQ HO ,QWLWXWR
6XSHULRU GH 6DQLGDG ,63 5RPD ,WDOLD
HVWDEOHFLHURQ ODV PLVPDV FRQFHQWUDFLRQHV
Wy[LFDV GH 3& \ $$6 FRQILUPDQGR OD XWLOLGDG
GHDPERVPDUFDGRUHV
&RQFOXVLRQHV
/RV HQVD\RV GH FiOFXOR GH
SHUPHDELOLGDGGH /XFLIHU<HOORZ VRQ XQEXHQ
VLVWHPD SDUD GHWHUPLQDU OD FRQFHQWUDFLyQ
Wy[LFD GH XQ FRPSXHVWR \D TXH SHUPLWH
FRQWURODU OD DOWHUDFLyQ GH OD YtD SDUDFHOXODU
LQGLFDGRUD GH OD LQWHJULGDG GH OD EDUUHUD (O
PpWRGR GHO /XFLIHU <HOORZ HV XQD EXHQD
DOWHUQDWLYD DO PDQLWRO FXDQGR OD YDORUDFLyQ
DQDOtWLFDGHHVWH~OWLPRSUHVHQWHGLILFXOWDGHV
$JUDGHFLPLHQWRV
(VWH WUDEDMR VH KD ILQDQFLDGR
SDUFLDOPHQWH FRQ IRQGRV GHO 0LQLVWHULR GH
(GXFDFLyQ \ &LHQFLD $*/&
$/,\FRQXQFRQWUDWRGHLQYHVWLJDFLyQHQ
FRODERUDFLyQ FRQ HO ,QVWLWXWR 6XSHULRUH GH
6DQLWi
5RPD
6WXG\
&RQWUDFW
&&5,+&3&;
%LEOLRJUDItD
6DLWRK 5 6XJDQR . 7DNDWD 1 7DFKLEDQD
7 +LJDVKLGD $ 1DEXFKL < $VR <
&RUUHODWLRQ RI SHUPHDELOLW\ ZLWK SRUH
UDGLXV RI WLJKW MXQFWLRQV LQ &DFR
PRQROD\HUV LPSURYHV WKH SUHGLFWLRQ RI WKH
GRVHIUDFWLRQRIK\GURSKLOLFGUXJVDEVRUEHG
E\ KXPDQV 3KDUPDFHXWLFDO 5HVHDUFK
9RO1R
.RQLVKL < +DJLZDUD . 6KLPL]X 0
7UDQVHSLWKHOLDO WUDQVSRUW RI IOXRUHVFHLQ LQ
&DFR FHOO PRQROD\HUV DQG XVH RI VXFK
WUDQVSRUWLQLQYLWURHYDOXDWLRQRISKHQROLF
DFLG DYDLODELOLW\ %LRVFL %LRWHFKQRO
%LRFKHP
6HNL++DUDGD6+RVR\D20RULPRWR.
-XQL.(YDOXDWLRQRIWKHHVWDEOLVKPHQWRID
WLJKW MXQFWLRQ LQ &DFR FHOO PRQROD\HUV
XVLQJ D SRUH SHUPHDWLRQ PRGHO LQYROYLQJ
WZR GLIIHUHQW VL]HV %LRO 3KDUP %XOO
7VXND]DNL 0 6DWVX + 0RUL $ 6XJLWD
.RQLVKL < 6KLPL]X 0 (IIHFWV RI
WULEXW\OWLQ RQ EDUULHU IXQFWLRQV LQ KXPDQ
LQWHVWLQDO &DFR FHOOV %LRFKHPLFDO DQG
%LRSK\VLFDO 5HVHDUFK &RPPXQLFDWLRQV
$3/,&$&,Ï1'(/0e72'2%227675$3$/26(678',26'((67$%,/,'$''(
)È50$&2635(3$5$'26&20(5&,$/(6'(,168/,1$+80$1$
2OLYD$)DULxD-%/ODEUpV0
'HSDUWDPHQWRGH,QJHQLHUtD4XtPLFD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD
8QLYHUVLGDGGH/D/DJXQD/D/DJXQD7HQHULIH
(QVD\RVDFHOHUDGRVQRLVRWpUPLFRV
,QWURGXFFLyQ
6H XWLOL]y XQD HVWXID +HUDHXV 0RGHOR
$FWXDOPHQWH HQ OD FDUDFWHUL]DFLyQ ItVLFR
%5 TXH SHUPLWH HO FRQWURO GH
TXtPLFD GH IiUPDFRV VH LQFOX\HQ ORV HVWXGLRV
WHPSHUDWXUDV D WUDYpV GH XQD LQWHUIDVH 56
GHHVWDELOLGDG/RVHVWXGLRVHQFRQGLFLRQHVQR
/DYDULDFLyQGHODWHPSHUDWXUDGHODHVWXIDDVt
LVRWpUPLFDV IXHURQ GHVDUUROODGRV SDUD UHGXFLU
FRPR OD DGTXLVLFLyQ GH GDWRV GH OD HYROXFLyQ
ORVHVIXHU]RVH[SHULPHQWDOHVUHTXHULGRVHQORV
GH pVWD FRQ HO WLHPSR VH UHDOL]y XWLOL]DQGR XQ
HQVD\RV LVRWpUPLFRV \ SHUPLWLU TXH ORV
3&FRQXQSURJUDPDGHVDUUROODGRHQ7HVW3RLQW
SDUiPHWURV FLQpWLFRV VHDQ HVWLPDGRV PHGLDQWH
Š
$VtODWHPSHUDWXUDLQLFLDOIXHGHž&\
XQD ~QLFD VHULH GH GDWRV GH FRQFHQWUDFLyQ GH
OD ILQDO GH ž& FRQ XQD YHORFLGDG PHGLD GH
IiUPDFR IUHQWH DO WLHPSR REWHQLGR PLHQWUDV OD
FDOHQWDPLHQWRGHž&K
WHPSHUDWXUD FDPELD FRQ HO WLHPSR (O PpWRGR
$QiOLVLVGHGDWRV
0RQWH &DUOR R WDPELpQ OODPDGR ³%RRWVWUDS´
(O PpWRGR GH OD LQWHJUDO SURSXHVWR SRU
SURSRUFLRQD XQ PpWRGR SDUD HYDOXDU OD
<RVKLRND \FROVHXWLOL]ySDUDHVWLPDU ORV
H[DFWLWXG GH ORV SDUiPHWURV HVWLPDGRV D SDUWLU
SDUiPHWURV GH $UUKHQLXV (O SURJUDPD
GH GDWRV H[SHULPHQWDOHV /D LGHD EiVLFD GHO
HVWDGtVWLFR 5Š IXH XWLOL]DGR SDUD HVWLPDU
ERRWVWUDSHVWUDWDUORVGDWRVPXHVWUDOHVFRPRVL
SRU
XQ PpWRGR LWHUDWLYR QR OLQHDO ORV
FRQVWLWX\HVHQODSREODFLyQHVGHFLUVHXWLOL]DQ
SDUiPHWURV(D$\&RDVtFRPRSDUDREWHQHU
FRPRHOXQLYHUVRGHOTXHVHH[WUDHUiQPXHVWUDV
ORVGLIHUHQWHVLQWHUYDORVGHFRQILDQ]DGHO
FRQUHHPSOD]DPLHQWR3DUDFDGDUHPXHVWUHRVH
ERRWVWUDSEiVLFRSHUFHQWLO\HOFRUUHJLGRSDUD
FDOFXODUi HO YDORU GHO HVWLPDGRU ERRWVWUDS TXH
HOVHVJR\DFHOHUDGR%FDSDUDORVSDUiPHWURV
VH XWLOL]DUi SDUD HVWLPDU OD YDULDELOLGDG
HVWLPDGRV\GHOSOD]RGHYDOLGH]
PXHVWUDO \ SRVWHULRUPHQWH JHQHUDU XQD
HVWLPDFLyQHPStULFDGHODGLVWULEXFLyQPXHVWUDO
GHOHVWDGtVWLFRHQFXHVWLyQ
(O REMHWLYR GH HVWH WUDEDMR IXH HYDOXDU OD
ILDELOLGDG GH ORV SDUiPHWURV HQHUJtD GH
DFWLYDFLyQ (D IDFWRU GH IUHFXHQFLD $
FRQFHQWUDFLyQ LQLFLDO GH IiUPDFR &R \ GHO
SOD]R GH YDOLGH] W HVWLPDGRV HQ
FRQGLFLRQHV QR LVRWpUPLFDV DSOLFDQGR HO
PpWRGR ERRWVWUDS 3DUD HOOR VH XWLOL]y XQ
SUHSDUDGRFRPHUFLDOGHLQVXOLQDKXPDQDFRPR
IiUPDFRPRGHOR
0DWHULDOHV\0pWRGRV
0DWHULDOHV
6H XWLOL]y XQ SUHSDUDGR FRPHUFLDO GH LQVXOLQD
KXPDQD GH DFFLyQ UiSLGD 7RGRV ORV GHPiV
UHDFWLYRVIXHURQGHJUDGRDQDOtWLFR
0pWRGRDQDOtWLFR
6H XWLOL]y XQ HTXLSR GH FURPDWRJUDItD GH
:DWHUV 0LOIRUG 0$ 86$ HQ XQD FROXPQD
3URWHLQ3DFN & \ XQ GHWHFWRU 899LV (O
FRQWURO DGTXLVLFLyQ \ DQiOLVLV GH GDWRV VH
UHDOL]yXWLOL]DQGRHOSURJUDPD0LOOHQLXP®
/D IDVH PyYLO IXH XQD PH]FOD 0 GH iFLGR
DFpWLFRP0GH/DUJLQLQDDFHWRQLWULOR
YYDXQIOXMRGHP/PLQ/DORQJLWXGGH
RQGD IXH GH QP VLHQGR HO YROXPHQ GH
LQ\HFFLyQ GH μ/ (O PpWRGR DQDOtWLFR IXH
YDOLGDGRGHDFXHUGRFRQODVQRUPDVSURSXHVWDV
SRUOD*XtD,&+
5HVXOWDGRV\'LVFXVLyQ
(Q OD 7DEOD VH UHFRJHQ ORV YDORUHV GH ORV
SDUiPHWURVHVWLPDGRV&R(D$\GHOSOD]RGH
YDOLGH] D XQD WHPSHUDWXUD GH ž& SDUD HO
SUHSDUDGRFRPHUFLDOGHLQVXOLQDKXPDQD
Tabla 1. Valores estimados y sus respectivos intervalos
de confianza del 95% bootstrap para los parámetros
cinéticos y el plazo de validez.
3DUiPHWUR
(VWLPDGR
%iVLFR
3HUFHQWLO
&R
/Q$
(D
.FDOPRO
W
K GtDV
%&D
/D(DHVWLPDGDHVVLPLODUDODHQFRQWUDGDHQOD
ELEOLRJUDItD SDUD HVWH WLSR GH SUHSDUDGRV
REVHUYiQGRVHGLIHUHQFLDVLQIHULRUHVDO
(O SOD]R GH YDOLGH] HVWLPDGR DVXPLHQGR XQD
FLQpWLFDGHSULPHURUGHQIXHGHGtDVXQ
YDORU OLJHUDPHQWH PD\RU TXH HO REWHQLGR HQ
FRQGLFLRQHV LVRWpUPLFDV GtDV SHUR
HQ FXDOTXLHU FDVR PX\ VXSHULRU DO GHFODUDGR
SRUHOIDEULFDQWHGtDV
3DUDFRPSUREDUODILDELOLGDGGHORVSDUiPHWURV
HVWLPDGRVXQWRWDOGHPXHVWUDVERRWVWUDS
IXHURQ FDOFXODGDV FX\RV LQWHUYDORV GH
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
-2
0
2
10000
35
8000
2
4
4
4.0
3.9
2
0
Theoretical Quantiles
3.8
3.7
Sample Quantiles
3.4
-2
3.5
500
-4
3.6
Frequency
26000
22000
S a m p le Q u a n tile s
4
18000
1000
2
2000
0
Theoretical Quantiles
500
0
Normal Q-Q Plot
1500
-2
1000
-4
Normal Q-Q Plot
Ea
-2
Theoretical Quantiles
30
35
Ln A
18000 20000 22000 24000 26000 28000
-4
Histogram of t90%
Histogram of Ea
10000
t90%
0
30
6000
25
S a m p le Q u a n tile s
1500
F requenc y
500
2000
0
25
0
F requenc y
20
6000
Sample Quantiles
4
0
Theoretical Quantiles
Normal Q-Q Plot
2000
-4
Co, %
Histogram of Ln A
4000
500
1000
Frequency
9 9 .8
9 9 .4
S a m p le Q u a n tile s
9 9 .0
2000
1000
98.8 99.0 99.2 99.4 99.6 99.8 100.0
Normal Q-Q Plot
2000
Histogram of t90%
Normal Q-Q Plot
0
F re qu enc y
Histogram of Co, %
SDUiPHWURV FLQpWLFRV HVWLPDGRV HQ HVWXGLRV GH
HVWDELOLGDG GH XQD IRUPD UiSLGD \ VHQFLOOD
SURSRUFLRQDQGR LQIRUPDFLyQ VREUH OD
GLVWULEXFLyQ HPStULFD GHO SDUiPHWUR D HVWLPDU
VLQ WHQHU TXH FRQRFHU D SULRUL HO WLSR GH OD
PLVPD
1500
FRQILDQ]DVHHQFXHQWUDQUHFRJLGRVHQOD7DEOD
/D )LJXUD PXHVWUD ORV KLVWRJUDPDV GH ODV
PXHVWUDV ERRWVWUDS DVt FRPR OD GLVWULEXFLyQ
QRUPDO GH ORV FXDQWLOHV SDUD ORV SDUiPHWURV
HVWLPDGRV&R$\(DUHVSHFWLYDPHQWH&RPR
SXHGH REVHUYDUVH OD GLVWULEXFLyQ HPStULFD GH
ORV FLWDGRV SDUiPHWURV VLJXH XQD GLVWULEXFLyQ
QRUPDO $GHPiV QR VH REVHUYDQ GLIHUHQFLDV
HQWUH ORV GLIHUHQWHV WLSRV GH LQWHUYDORV GH
FRQILDQ]DSUHVHQWDQGROtPLWHVPX\VLPLODUHV
3.4
)LJXUD +LVWRJUDPDV GH ODV UHPXHVWUDV
ERRWVWUDS \ GLVWULEXFLyQ QRUPDO GH ORV FXDQWLOHV
FRUUHVSRQGLHQWHV D OD FRQFHQWUDFLyQ LQLFLDO GH
IiUPDFR VXSHULRU IDFWRU GH IUHFXHQFLD PHGLR \
ODHQHUJtDGHDFWLYDFLyQLQIHULRU
(O PpWRGR ERRWVWUDS WDPELpQ IXH DSOLFDGD DO
SOD]R GH YDOLGH] W SDUD HVWLPDU VXV
LQWHUYDORV GH FRQILDQ]D \ FRQILUPDU VL VLJXH
XQD GLVWULEXFLyQ QRUPDO (O KLVWRJUDPD \ OD
GLVWULEXFLyQQRUPDOGHORVFXDQWLOHVVHUHFRJHQ
HQOD)LJXUD(QSULQFLSLRFDEUtDHVSHUDUXQD
GLVWULEXFLyQ QRUPDO SHUR VH REVHUYD TXH OD
GLVWULEXFLyQVHHQFXHQWUDVHVJDGDDODGHUHFKD
)LJ VXSHULRU OR TXH VXJLHUH XQD
GLVWULEXFLyQ ORJDUtWPLFRQRUPDO GDWR TXH
TXHGDUHIOHMDGRHQOD)LJXUDLQIHULRU(QHVWH
~OWLPR FDVR FRQVLGHUDQGR XQD GLVWULEXFLyQ
ORJQRUPDO ORV LQWHUYDORV GH FRQILDQ]D
DVLQWyWLFRV \ ORV HVWLPDGRV SRU HO PpWRGR
ERRWVWUDSVRQPX\VLPLODUHV
&RQFOXVLRQHV
/D WpFQLFD ERRWVWUDS FRQVWLWX\H XQ H[FHOHQWH
PpWRGR SDUD HVWLPDU OD ILDELOLGDG GH ORV
3.6
t90%
3.8
4.0
-4
-2
0
2
Theoretical Quantiles
4
)LJXUD +LVWRJUDPDV GH ODV UHPXHVWUDV
ERRWVWUDS \ GLVWULEXFLyQ QRUPDO GH ORV FXDQWLOHV
FRUUHVSRQGLHQWHV DO SOD]R GH YDOLGH] HVWLPDGR
DVXPLHQGRXQDGLVWULEXFLyQQRUPDOVXSHULRU\XQD
GLVWULEXFLyQORJQRUPDOLQIHULRU
%LEOLRJUDItD
(IURQ % 7VLELUDQL 5 - $Q
LQWURGXFWLRQ WR WKH %RRWVWUDS 1<
&KDSPDQ+DOO
,&+ 9DOLGDWLRQ RI $QDO\WLFDO 3URFHGXUHV
0HWKRGROJ\,&+4%1RYHPEHU
<RVKLRND 6 $VR < 8FKL\DPD 0 -
3KDUP6FL
6WDWLVWLFDO 'DWD $QDO\VLV 5 YHUVLRQ $XFNODQG 86$ KWWSZZZ5
SURMHFWRUJ
2OLYD$)DULxD-%//DEUpV0,QW-
3KDUP
0e72'2&$3,/$53$5$(/(678',2'(/&2(),&,(17('(',)86,Ï1
$3/,&$&,Ï1'(/$1È/,6,6'((/(0(1726),1,726
0/ODEUpV$6DQWRYHxD0DWHX9
'HSDUWDPHQWRGH,QJHQLHUtD4XtPLFD\7HFQRORJtD)DUPDFpXWLFD
8QLYHUVLGDGGH/D/DJXQD/D/DJXQD7HQHULIH
HYROXFLyQ GH OD FRQFHQWUDFLyQ PHGLD GH OD
,QWURGXFFLyQ
PROpFXOD TXH GLIXQGH GHVGH HO LQWHULRU GH XQ
(OGHVDUUROOR\DSOLFDFLyQGHPRGHORVWHyULFRV
FDSLODU KDFLD XQ UHFLSLHQWH TXH FRQWLHQH HO
EDVDGRV HQ OD WUDQVIHUHQFLD GH PDWHULD SRU
PLVPR PHGLR GH GLIXVLyQ TXH HO FDSLODU YHU
GLIXVLyQ HVWi OLPLWDGR SRU OD LQH[LVWHQFLD GH
ILJXUD (O PpWRGR TXH VH FDUDFWHUL]D SRU VX
VROXFLRQHV H[SOtFLWDV VDOYR HQ FDVRV
VHQFLOOH] \ H[DFWLWXG WLHQH XQ LQFRQYHQLHQWH
UHODWLYDPHQWH VHQFLOORV 1R GHEH H[WUDxDUQRV
HO PRGHOR PDWHPiWLFR DVXPH TXH OD ORQJLWXG
TXH D~Q KR\ GtD HO WH[WR GH &UDQN GHO FDSLODU HV WDO TXH VX GLiPHWUR HV
LPSUHVR SRU SULPHUD YH] HQ FRQWLQ~H
GHVSUHFLDEOH (VWD FRQGLFLyQ LPSRQH GLVSRQHU
VLHQGR XQ OLEUR GH UHIHUHQFLD (O GHVDUUROOR \
GH PpWRGRV DQDOtWLFRV PX\ VHQVLEOHV HQ OD
GLIXVLyQ GH OD LQYHUVLyQ QXPpULFD GH OD
SUiFWLFD PDUFDU OD PROpFXOD FRQ DOJ~Q
WUDQVIRUPDGDGH/DSODFHSHUPLWHVLPSOLILFDUOD
UDGLRLVyWRSR (O PpWRGR SURSXHVWR VH EDVD HQ
VLPXODFLyQFRQHVWRVPRGHORV/ODEUpV
FRQVWUXLU XQ VLVWHPD DQiORJR XWLOL]DQGR XQ
SHUR QR DERUGDU HO HVWXGLR GH VLVWHPDV
FDSLODUGHORQJLWXG\GLiPHWURILQLWRV
FDUDFWHUL]DGRVSRUXQDJHRPHWUtDFRPSOHMD(O
HVWXGLR GH PRGHORV PiV FRPSOHMRV VyOR HV
0RGHOR
(O PRGHOR JHRPpWULFR FRQVWD GH GRV SDUWH (O
DERUGDEOH FRQ PpWRGRV QXPpULFRV EDVDGRV HQ
FDSLODU PP GH ORQJLWXG \ PP GH
ODGLVFUHWL]DFLyQGHOVLVWHPDGLIHUHQFLDVILQLWDV
GLiPHWUR \ HO UHFLSLHQWH UHFHSWRU PP GH
\HOHPHQWRVILQLWRVHQWUHRWURV0\HUV
ORQJLWXG \ PP GH GLiPHWUR WDO FRPR VH
(O DQiOLVLV GH HOHPHQWRV ILQLWRV )($ VXHOH
PXHVWUDQ HQ OD ILJXUD (VWDV GRV SDUWHV VH
H[SOLFDUVHXWLOL]DQGRFRPRPRGHORODVIXHU]DV
FRUUHVSRQGHQ FRQ VHQGRV VXEGRPLQLRV GHO
HQ ORV QRGRV GH XQ WUXVV %UDXHU $O
PRGHOR HQ ORV TXH VRQ GH DSOLFDFLyQ OD
WUDWDUVH GH VLVWHPDV GLVFUHWRV VH REYLD HO
HFXDFLyQGH)LFNHQHVWDGRQRHVWDFLRQDULR
SULPHUSUREOHPDTXHVHQRVSODQWHDHQHO)($
OD GLVFUHWL]DFLyQ GHO VLVWHPD +R\ GtD HV XQ
∂F
+ ∇Â(' ∇F ) = DVSHFWR UHVXHOWR JUDFLDV D OD FRQWULEXFLyQ GHO
∂W
DQiOLVLVYDULDFLRQDO0\HUV
'RQGHFHVODFRQFHQWUDFLyQWHOWLHPSR'HO
(O FDPSR GH DSOLFDFLRQHV GHO DQiOLVLV GH
FRHILFLHQWHGHGLIXVLyQ \ ∇HORSHUDGRUQDEOD
HOHPHQWRV ILQLWRV HV PX\ DPSOLR WDQWR TXH
(QHOVXEGRPLQLRODFRQFHQWUDFLyQDW VH
KR\GtDVHFRQVLGHUDXQDKHUUDPLHQWDEiVLFDHQ
ILMy HQ PROP PLHQWUDV TXH HQ HO
LQJHQLHUtD6XDSOLFDFLyQHQiUHDVGHLQWHUpVHQ
VXEGRPLQLRVHILMRHQFHUR/DFRQGLFLyQGH
WHFQRORJtD IDUPDFpXWLFD WDPELpQ HV UHOHYDQWH
FRQWRUQR SDUD OD IURQWHUD HQWUH HO H[WUHPR GHO
$OJXQRV HMHPSORV ItVLFD GH OD FRPSUHVLyQ
WHUPLQDOVXPHUJLGRHQODIDVHUHFHSWRUD\HVWD
GLVROXFLyQ FRQWURODGD SRU GLIXVLyQ FHVLyQ GH
HVODGHFRQWLQXLGDGHVGHFLU
IiUPDFRV GHVGH PDWULFHV IOXMR GH IOXLGRV HQ
&
Q(1 − 1 )= WXPRUHV\FHVLyQDSDUWLUGHKLGURJHOHV
/D GLYXOJDFLyQ GHO DQiOLVLV GH HOHPHQWRV
1 L = − ' ∇ FL &
ILQLWRVKDVLGRSRVLEOHJUDFLDVDOJUDQDXPHQWR
6LHQGR Q HO YHFWRU QRUPDO D OD VXSHUILFLH TXH
GHODFDSDFLGDGGHFiOFXORGHORVRUGHQDGRUHV
VHSDUD DPERV GRPLQLRV 3DUD ODV UHVWDQWHV
SHUVRQDOHV ORV FDVRV VHQFLOORV LPSOLFDQ OD
IURQWHUDV OD FRQGLFLyQ GH FRQWRUQR HV OD GH
UHVROXFLyQ GH XQ VLVWHPD GH HFXDFLRQHV
DLVODPLHQWR
&
OLQHDOHVFRQDOJXQRVFHQWHQDUHVGHLQFyJQLWDV
Q 1L = \ GH DSOLFDFLRQHV LQIRUPiWLFDV FDSDFHV GH
$XQTXH HO PRGHOR HV D[LVLPpWULFR QR KHPRV
DXWRPDWL]DU OD GHQRPLQDGD IRUPD GpELO GHO
LQFOXLGR HVWD FRQGLFLyQ SRU VHU UHODWLYDPHQWH
PRGHOR PDWHPiWLFR &RPVRO 0XOWLSK\VLFV HV
VHQFLOOR \ QR DIHFWDU VLJQLILFDWLYDPHQWH DO
XQSURJUDPDSDUDHOHVWXGLR GHVLVWHPDVHQHO
WLHPSRGHHMHFXFLyQGHOSURJUDPD
TXHLQWHUYHQJDQVLPXOWiQHDPHQWHHOWUDQVSRUWH
8QD YH] GHILQLGR JHRPpWULFDPHQWH \
GHPDVDFDORU\PRPHQWR(VWiGRWDGRGHXQD
ItVLFDPHQWH HO PRGHOR OD HWDSD VLJXLHQWH HV
LQWHUID] JUiILFD SRWHQWH TXH OH GD DOSURJUDPD
OODPDU DO DOJRULWPR GH JHQHUDFLyQ \
XQDJUDQYHUVDWLOLGDG
UHILQDPLHQWR GH OD PDOOD (Q OD ILJXUD VH
(QHVWDFRPXQLFDFLyQVHH[SRQHHOHVWXGLRGH
PXHVWUD OD JHRPHWUtD GHO PRGHOR \ OD PDOOD
XQ VLVWHPD SDUD OD GHWHUPLQDFLyQ GHO
XQD YH] UHILQDGD 2EVpUYHVH FRPR D OD VDOLGD
FRHILFLHQWH GH GLIXVLyQ HQ XQ PHGLR FRQWLQXR
GHOFDSLODUHOQ~PHURGHQRGRVHVPX\HOHYDGR
EDVDGR HQ HO PpWRGR GHO FDSLODU &XVOOHU SDJ
SRUTXH VH HVSHUD TXH HO JUDGLHQWH GH
(VWH PpWRGR VH EDVD HQ PHGLU OD
FRQFHQWUDFLyQVHDPiVDOWRGHELGRDODGLIXVLyQ
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
HQGRVGLUHFFLRQHVVLQHPEDUJRHOQ~PHURGH
QRGRV HQ HO LQWHULRU GHO FDSLODU HV PXFKR
PHQRU SRUTXH SUHGRPLQD OD GLIXVLyQ HQ XQD
~QLFDGLUHFFLyQ
)LJXUD&RQFHQWUDFLyQ\IOXMRDORV
V
)LJXUD*HRPHWUtDGHOVLVWHPD\PDOODGR
/D UHVROXFLyQ GHO PRGHOR VH UHDOL]y HQ PRGR
WLHPSR GHSHQGLHQWH SDUD SRGHU FDOFXODU OD
FRQFHQWUDFLyQ PHGLD HQ HO VXEGRPLQLR D OR
ODUJR GHO WLHPSR /D ILJXUD VLJXLHQWH PXHVWUD
HO HVWDGR D ORV V \ V
DSUR[LPDGDPHQWH KRUDV (Q OD
JHQHUDFLyQ GH OD ILJXUD VH KDQ LQFOXLGR GRV
YDULDEOHVODFRQFHQWUDFLyQHVFDODGHFRORU\
HO IOXMR IOHFKDV 2EVpUYHVH TXH OD
FRQFHQWUDFLyQGHVXEVWDQFLDHQHOH[WUHPRGHO
FDSLODUHVSUy[LPDDODLQLFLDO\TXHHOIOXMRVH
HQFXHQWUD \D WRWDOPHQWH GHVDUUROODGR HQ HO
H[WUHPR RSXHVWR /D LQWHJUDFLyQ GH ORV
VXEGRPLQLRVSHUPLWHFDOFXODUODFRQFHQWUDFLyQ
PHGLDHQFDGDXQRGHHOORV(QODILJXUD
)LJXUD&RQFHQWUDFLyQ\IOXMRDORVV
)LJXUD &RQFHQWUDFLyQ PHGLD HQ HO FDSLODU
HQIXQFLyQGHOWLHPSR
%LEOLRJUDItD
&UDQN - 7KH 0DWKHPDWLFV RI 'LIIXVLRQ QG
HG2[IRUG6FL3XE&ODUHQGRQ
%UDXHU-5)LQLWH(OHPHQW$QDO\VLVQGHG
0DUFHO'HNNHU1<
/ODEUpV 0 &RPXQLFDFLyQ 6(),* 9LWRULD
0\HUV * ( $QDO\WLFDO 0HWKRGV LQ
&RQGXFWLRQ +HDW 7UDQVIHU 0F*UDZ 1<
'(7(50,1$&,Ï1'(/Ë1',&('(%8(1$&2035(6,%,/,'$''(',6*5(*$17(6
$75$9e6'(/$0(72'2/2*Ë$6('(0
-RKQQ\($JXLODU'tD](*DUFLD0RQWR\D33pUH]/R]DQR00LxDUUR-57LFy-06Xxp
1HJUH
*DUDQWtDGH&DOLGDG1RYDUWLV)DUPDFpXWLFD6$'RFWRUDQGRHQ)DUPDFLD\7HFQRORJtD
)DUPDFpXWLFD
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD
8QLYHUVLGDGGH%DUFHORQD$YGD-RDQ;;,,,VQ%DUFHORQD.
HPDLOHQFDUQDJDUFLD#XEHGX
6H'H0 HQ ORV GLVWLQWRV GLVJUHJDQWHV HVWiQ
,QWURGXFFLyQ
OLVWDGRVHQOD7DEOD1ž
+DELWXDOPHQWH ODV DFWLYLGDGHV GH GHVDUUROOR
IDUPDFpXWLFRVXHOHQGLYLGLUVHHQGRVJUXSRVHO
GHVDUUROORGHODIRUPXODFLyQ\HOGHVDUUROORGHO
SURFHVR GH HODERUDFLyQ DXQTXH VH OOHYDQ D
FDER D OD YH] 7UDV HO HVWXGLR SUHOLPLQDU GH
ODVFDUDFWHUtVWLFDVItVLFRTXtPLFDVGHOSULQFLSLR
DFWLYR
VROXELOLGDG
SROLPRUILVPR
JUDQXORPHWUtD LPSXUH]DV HWF R IDVH GH
SUHIRUPXODFLyQ HPSLH]D OD IDVH GH
IRUPXODFLyQ HV GHFLU ORV HVWXGLRV H[LJLGRV
SDUD TXH GH OD FRPELQDFLyQ HQWUH SULQFLSLR
DFWLYR\H[FLSLHQWHVUHVXOWHXQSURGXFWRYLDEOH
FRQ ODV FDUDFWHUtVWLFDV UHTXHULGDV (Q OD
IRUPXODFLyQ GH IRUPDV IDUPDFpXWLFDV VyOLGDV
GHEH FRQRFHUVH HO SHUILO UHROyJLFR GH OD
VXVWDQFLD DFWLYD \ GH ORV H[FLSLHQWHV SDUD WDO
ILQ HV ~WLO OD KHUUDPLHQWD 6H'H0 TXH HV XQD
QXHYD PHWRGRORJtD JDOpQLFD DSOLFDEOH D ORV
HVWXGLRV GH SUHIRUPXODFLyQ GH FRPSULPLGRV \
TXH EiVLFDPHQWH FRQVLVWH HQ OD GHWHUPLQDFLyQ
GH XQD VHULH GH SDUiPHWURV TXH
FRQYHQLHQWHPHQWH DQDOL]DGRV SURSRUFLRQDQ OD
LQIRUPDFLyQ QHFHVDULD GHO SHUILO R DSWLWXG GH
ODV VXVWDQFLDV SXOYXUHQWDV VHDQ SULQFLSLRV
DFWLYRV H[FLSLHQWHV R PH]FOD GH SULQFLSLR
DFWLYR PiV H[FLSLHQWHV UHVSHFWR D VX DSWLWXG
SDUD VHU XWLOL]DGR HQ FRPSUHVLyQ GLUHFWD HVWH
SHUILORDSWLWXGRULHQWDUiDOIRUPXODGRUVREUHOD
PD\RU R PHQRU FDSDFLGDG TXH WLHQH OD
VXVWDQFLD SDUD VHU FRPSULPLGD (Q HVWH
HVWXGLR VH SURSRQH GHWHUPLQDU HO SHUILO GH GLVJUHJDQWHV TXH VHUYLUiQ SDUD GHWHUPLQDU HO
SHUILO GH ORV PLVPRV \ TXH SRVWHULRUPHQWH
SRGUiQ VHU XWLOL]DGRV SDUD HVWXGLDUORV HQ
FRPELQDFLyQ FRQ XQ $3, DGHFXDGR \ SRGHU
REWHQHUFRPSULPLGRVSRUFRPSUHVLyQGLUHFWD
0DWHULDOHV\PpWRGRV
0DWHULDOHV
'LVJUHJDQWHV GH GLIHUHQWHV IDPLOLDV
TXtPLFDV
0pWRGRV
/RV SDUiPHWURV HVWXGLDGRV SDUD OD
GHWHUPLQDFLyQ GHO tQGLFH GH EXHQD
FRPSUHVLELOLGDG D WUDYpV GH OD PHWRGRORJtD
7DEOD 1ž 3DUiPHWURV UHTXHULGRV SRU OD PHWRORJtD
6H'H0
'LPHQVLRQ
&RPSUH
VVLELOLW\
3DUDPHWHU V\PERO 8QLW
(TXDWLRQ
%XON
GHQVLW\
'D
JPO
'D 39D
7DSSHG
GHQVLW\
'F
JPO
'F 39F
,QWHU
SDUWLFOH
3RURVLW\
,H
,H 'F±'D
'F['D
&DUU,QGH[
,&
&RKHVLRQ
,QGH[
,& 'F'D
,FG
1
H[SHULPHQWDO
+DXVQHU
5DWLR
,+
,+ 'F'D
Į
ž
WJĮ KU
W
V
([SHULPHQWDO
+5 ([SHULPHQWDO
)ORZDELOLW\
$QJOHRI
3RZGHU
UHSRVH
)ORZ
3RZGHU
)ORZ
/RVVRQ
/XEULFLW\ GU\LQJ
6WDELOLW\
+LJURVFR
SLFLW\
3DUWLFOHV
μ
+
3I
([SHULPHQWDO
,ș )Pǻ
)PQ
/XEULFLW\
'RVVDJH
+RPRJHQLW\
,ș
,QGH[
([SHULPHQWDO
5HVXOWDGRV\'LVFXVLyQ
/RVUHVXOWDGRVREWHQLGRVHVWiQGHWDOODGRVHQOD
7DEOD1ž(QOD)LJ1žHQGRQGHVHSXHGH
REVHUYDU TXH HO 3KDUPDEXVW & HV HO ~QLFR
GLVJUHJDQWH FRQ XQ SHUILO VXSHULRU DO PtQLPR
UHTXHULGR SRU OD PHWRGRORJtD 6H'H0 OR TXH
LQGLFD TXH HV LGyQHR SDUD VHU XWLOL]DGR HQ OD
REWHQFLyQ GH FRPSULPLGRV SRU FRPSUHVLyQ
GLUHFWD
(O EXHQ tQGLFH GH FRPSUHVLELOLGDG GH HVWH
H[FLSLHQWH HV GHELGR D TXH VH WUDWD GH XQ
H[FLSLHQWH FRSURFHVDGR SDUD PHMRUDU VXV
SURSLHGDGHVGLVJUHJDQWHV
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
$OJLQLF$FLG
+)'/RW
.HODFLG
/RW*8
$/0,'21
'(0$,=% /RW
/\FDWDE&
/RW*8
6WDUFK
/RWUHI
)HFXOD136XSUD
%DFW/RW$
)LJXUD 1ž 'LDJUDPD 6H'H0 GH 3KDUPDEXVW &
,*& 0DWHULDOHVDQG0HWKRGV
5HVXOWV GHPRQVWUDWH WKDW PXVLF
SURGXFH GHFUHDVH RI YLDELOLW\ RI WXPRUDO FHOOV
0RVPDQQ7-,PPXQRO0HWKRGV
9HUPHV , +DDQHQ & 6WHIIHQV1DNNHQ
+ 5HXWHOLQJVSHUJHU & - ,PPXQRO
0HWKRGV
$FNQRZOHGJHPHQWV
7KLVZRUNKDVEHHQILQDQFHE\WKH1HWZRUN
RI([FHOOHQFH%LR6LP/6+%&7
0.8
1000
0.6
5000
10000
0.4
25000
0.2
0
1 day
2 days
1 día
2 día
3 days
3 día
)LJXUH,QIOXHQFHRIWKHFODVVLFDOPXVLF
+D\GQ\0R]DUWKHDY\PXVLFDQGFKLOORXW
*UHJRULDQPXVLFKDVDQLPSRUWDQWLPSDFWRYHU
WKH FHOOV JURZWK ZKHUHDV WHFKQR PXVLF
SURGXFHOHVVHIIHFW)LJXUH
1,6
1,4
1,2
1
0,8
0,6
0,4
0,2
0
25000
10000
5000
1000
1 day1
día
2 days
2 día
3 days
3
día
)LJXUH,QIOXHQFHRIWHFKQRPXVLFDQG
*UHJRULDQFKDQW
,;&RQJUHVRGHOD6(),*
&RQFOXVLRQV
7KHVHDVVD\VLQGLFDWHWKDWWKHUHVXOWV
DUH LQIOXHQFHG IRU WKH TXDQWLW\ RI VHHGHG
FHOOVDQGWKHH[SRVLWLRQWLPH WRWKH PXVLFDO
VWLPXOL
2XU UHVHDUFK GHWHUPLQH WKDW FODVVLFDO
PXVLF FDQ EH D SRZHUIXO WRRO RQ FDQFHU
WKHUDS\ FRPELQHG ZLWK FKHPRWKHUDS\
EHFDXVH RI WKHLU EHQHILWV DW SV\FKRORJLFDO
DQGRYHUDOODWSK\VLFOHYHO
5HIHUHQFHV
1.2
1
&HOOXODU JURZWK RI O\PSKRPD FHOOV
KDV EHHQ VWXGLHG LQ WKH DEVHQFH DQG LQ WKH
SUHVHQFH RI GLIIHUHQW PXVLFDO VWLPXOL ,Q WKLV
VWXG\ GLIIHUHQW PXVLF VW\OHV ZHUH FRPSDUHG
+D\G\QDQG0R]DUWDQG&KLOORXWPXVLF
7KHHIIHFWRIWKHVRXQGWUHDWPHQWZDV
H[DPLQHGE\WKHFRORULPHWULFGHWHUPLQDWLRQRI
FHOOYLDELOLW\XVLQJWKH077DVVD\7KLVDVVD\
PHDVXUHV WKH DPRXQW RI 077 UHGXFWLRQ E\
PLWRFKRQGULDOGHK\GURJHQDVHDQGDVVXPHVWKDW
FHOO YLDELOLW\ FRUUHVSRQGLQJ WR WKH UHGXFWLYH
DFWLYLW\ LV SURSRUWLRQDO WR WKH SURGXFWLRQ RI
SXUSOH IRUPD]DQ WKDW LV PHDVXUHG
VSHFWURSKRWRPHWULFDOO\ )RU WKHVH UHDVRQ WKLV
PHWKRG SURYLGH D XVHIXO WRRO WR HYDOXDWH WKH
FHOOXODUSUROLIHUDWLRQ5HVXOWVGHPRQVWUDWHWKDW
PXVLFSURGXFHGHFUHDVHRIYLDELOLW\RIWXPRUDO
FHOOV +RZHYHU EHFDXVH RI WKH QDWXUH RI WKLV
DVVD\ LW LV QRW SRVVLEOH WR GHWHUPLQH WKH
FHOOXODUGHDWKPRGHQHFURVLVRUDSRSWRVLV
5HVXOWVDQG'LVFXVVLRQ
heavy
child
out
1\PFHO=6;
: /RW11
clasica
1\PFHO=6;
/RW11
$SSDUW IURP WKH HIIHFWV RYHU WKH
PRRGLWKDVEHHQSRVWXODWHG WKDW PXVLFFRXOG
KDYH VRPH HIIHFW RQ WKH SURJUHVVLRQ RI WKH
GLVHDVH E\ DIIHFWLQJ WKH WXPRU LWVHOI 7KH
REMHFWLYHRIWKLVVWXG\KDVEHHQWRGHWHUPLQHLI
WKH FODVVLFDO PXVLF KDV DQ HIIHFW RYHU WKH
WXPRUDOPDVV
máquina
$OJLQLF$FLG'&
/RW
gregoriano
1\PFHO
=6'
/RW11
9HHJXP
/RW(
heavy
child
out
control
1\PFHO=6%
/RW11&
control
5[FLSLHQWV
)0/RW
1\PFHO=6%
/RW11&
clasica
3ROLSODVGRQH
;/ /RW
&HNRO$
/RW113
máquina
3ROLSODVGRQH;/
/RW
gregoriano
.ROOLGRQ&/
/RW7
heavy
child
out
control
*O\FRO\V
/RWLQW6
$48$625%
$ /RW
control
.ROOLGRQ9$
ILQH /RW42
)LJXUHDQGUHSUHVHQWRSWLFGHQVLW\
YHUVXV H[SRVLWLRQ WLPH 7KH GLIIHUHQW FRORUV
UHIHU WR WKH GLIIHUHQFHV EHWZHHQ PXVLF
H[SRVXUHDQGDPRXQWRIFHOOVVHHGHG
$V FDQ EH VHHQ LQ )LJXUH UHVXOWV
LQGLFDWH WKDW H[SRVXUH SHULRGV RI KRXUV
SURGXFH DQ LQFUHDVH RI WKH FHOOXODU
SUROLIHUDWLRQ
$IWHU KRXUV WKH TXDQWLW\ RI FHOOV
IURP WKH FXOWXUHV H[SRVHG WR FODVVLFDO PXVLF
KDYHGHFUHDVHG,WLVQRWSRVVLEOHWRREVHUYHDQ
LPSRUWDQW HIIHFW RQ WKH FXOWXUHV H[SRVHG WR
RWKHU NLQG RI PXVLF KHDY\ PXVLF *UHJRULDQ
FKDQWWHFKQR)LJXUHRUFKLOORXW)LJXUH
$W KRXUV LV HYLGHQW WKDW WKH
H[SRVLWLRQ WR DQ\ PXVLFDO VWLPXOL SURGXFHV D
GHFUHDVHRIWKHFHOOXODUSUROLIHUDWLRQ7KHPRVW
HIIHFWLYH PXVLF LV WKH FODVVLFDO PXVLF ZKLFK
OHDGV WR D YLDELOLW\ UHGXFWLRQ RI HYHQ )LJXUH
clasica
%UHQFHO',6
/RW
ZD\ WR KHOS FDQFHU SDWLHQWV FRSH ZLWK WKH
HPRWLRQDO XSVHW RIWHQ FDXVHG E\ KLJKGRVH
FKHPRWKHUDS\ DQG DXWRORJRXV VWHP FHOO
WUDQVSODQWDWLRQ$FFRUGLQJWRUHVHDUFKHUVIURP
1HZ<RUN
V0HPRULDO6ORDQ.HWWHULQJ&DQFHU
&HQWHUSDWLHQWVZKR ZHUHYLVLWHGE\DWUDLQHG
PXVLFWKHUDSLVWUHSRUWHGOHVVDQ[LHW\DQGEHWWHU
RYHUDOOPRRGWKDQSDWLHQWVZKRGLGQRWUHFHLYH
PXVLFWKHUDS\;6RPHUHVHDUFKJURXSVKDYH
ZRUNHG RYHU JURXSV RI FKLOGUHQ DIIHFWHG RI
FDQFHUGLVHDVHDQGWKHWKHUDS\KDVDOORZHGDQ
LQFUHDVH RI TXDOLW\ OLIH DQG WKH VHOI VWHP RI
WKHVH SDWLHQWV ; ,W LV FOHDU WKDW PXVLF KDV D
EHQHILFLDO HIIHFW DW HPRWLRQDO OHYHO WKDW
SURGXFHVDQLPSURYHPHQWDWSK\VLFOHYHO
máquina
,*&
gregoriano
(;&,3,(17(
3ODVGRQH6
/RW
D .O.
,*&
control
(;&,3,(17(
3KDUPDEXUVW
&/RW.
D.O.
7DEOD1ž5HVXOWDGRVGHORVGLVJUHJDQWHVDQDOL]DGRV
7+(³02=$57())(&7´,1&$1&(57+(5$3<
*RQ]DOH]$OYDUH],*RQ]DOH]$OYDUH]0$ORQVR9%HUPHOO0$%HUPHMR09
'HSDUWPHQWRI(QJLQHHULQJ'LYLVLRQRI3KDUPDFHXWLFVDQG3KDUPDFHXWLFDO7HFKQRORJ\8QLYHUVLW\
0LJXHO+HUQDQGH](OFKH
'HSDUWPHQWRI'LGjFWLFDGHO
([SUHVVLy0XVLFDO3OjVWLFDL&RUSRUDO(80DJLVWHUL8QLYHUVLW\RI
9DOHQFLD
'HSDUWPHQWRI3KDUPDFHXWLFVDQG3KDUPDFHXWLFDO7HFKQRORJ\8QLYHUVLW\RI9DOHQFLD
E\LQKLELWLRQWRWKHJURZLQJDQGE\SURGXFLQJ
,QWURGXFWLRQ
FHOOXODUGHDWKIROORZLQJDQDSRSWRVLVURXWH
0XVLFWKHUDS\LVDQHDV\LQH[SHQVLYH
&RQFOXVLRQHV
3DUD HO GLVHxR GH FRPSULPLGRV D WUDYpV GH
FRPSUHVLyQ GLUHFWD HO VLJXLHQWH SDVR VHUtD
VHOHFFLRQDU XQ $3, DO FXDO VH GHWHUPLQDUi HO
ËQGLFHGHEXHQDFRPSUHVLELOLGDGDWUDYpVGHOD
PHWRGRORJtD 6H'H0 SDUD HYDOXDU OD
FRPELQDFLyQDGHFXDGDGHH[FLSLHQW\$3,SDUD
REWHQHUFRPSULPLGRVSRUFRPSUHVLyQGLUHFWD
'H DFXHUGR D ORV UHVXOWDGRV REWHQLGRV
GHWDOODGRVHQOD7DEOD1žVHFRQFOX\HTXH
D
/D PHWRGRORJtD 6H'H0 HV XQD
KHUUDPLHQWD ~WLO H LQQRYDGRUD SDUD GHWHUPLQDU
ODDSWLWXGGHH[FLSLHQWHVFRPRSRUHMHPSORORV
GLVJUHJDQWHV SDUD HYDOXDU VX FDSDFLGDG GH
REWHQHUFRPSULPLGRVSRUFRPSUHVLyQGLUHFWD
E
7RGRV ORV GLVJUHJDQWHV DQDOL]DGRV
SUHVHQWDQ YDORUHV GH ,*& LQIHULRUHV D H[FHSWR 3KDUPDEXVW & HO FXDO HV XQ
H[FLSLHQWH FRSURFHVDGR FX\DV SURSLHGDGHV
GLVJUHJUDQWHVKDQVLGRPHMRUDGDV\SUHVHQWD
XQtQGLFHGHFRPSUHVLELOLGDGVXSHULRUD
F
(O GLDJUDPD 6H'H0 HV XQD
KHUUDPLHQWDTXHSXHGHVHUXWLOL]DGDHQSDUDOD
GHWHUPLQDFLyQ GHO (VSDFLR GHO 'LVHxR GH XQD
IRUPXODFLyQDFRUGHDOD,&+4
%LEOLRJUDItD
-0 6Xxp 0 5RLJ 5 )XVWHU &
+HUQiQGH]55XKt(*DUFtD00LxDUUR
3 3pUH] -5 7LFy 1XHYD PHWRGRORJtD GH
SUHIRUPXODFLyQ
JDOpQLFD
SDUD
OD
FDUDFWHUL]DFLyQ GH VXVWDQFLDV HQ UHODFLyQ D
VX YLDELOLGDG SDUD OD FRPSUHVLyQ 'LDJUDPD
6H'H0&LHQ7HFQRO3KDUP
3 3pUH] -0 6Xxp 0 0LxDUUR 0 5RLJ
5)XVWHU(*DUFtD&+HUQiQGH]55XKt
-5 7LFy $ QHZ H[SHUW V\VWHPV 6H'H0
'LDJUDP IRU FRQWURO EDWFK SRZGHU
IRUPXODWLRQ DQG SUHIRUPXODWLRQ GUXJ
SURGXFWV (XU - 3KDUP %LRSKDUP -0 6Xxp 0 5RLJ 5 )XVWHU &
+HUQiQGH]55XKt(*DUFtD00LxDUUR
3 3pUH] -5 7LFy $SSOLFDWLRQ RI WKH
6H'H0 'LDJUDP DQG D QHZ PDWKHPDWLFDO
HTXDWLRQLQWKHGHVLJQRIGLUHFWFRPSUHVVLRQ
WDEOHWIRUPXODWLRQ(XU-3KDUP%LRSKDUP
control
&RQ UHVSHFWR D ORV GHPiV GLVJUHJDQWHV VH
REVHUYDTXHWRGRVWLHQHQYDORUHVLQIHULRUHVD
TXH HV HO YDORU PtQLPR UHTXHULGR SRU OD
PHWRGRORJtD6H'H0 ORFXDO HVOyJLFR \DTXH
HVWRVH[FLSLHQWHVVRQXWLOL]DGRVHQSRUFHQWDMHV
EDMRV GHQWUR GH ODV IRUPXODFLRQHV GH
FRPSULPLGRV\QXQFDFRPRGLOX\HQWHV
7HFQRORJtD)DUPDFpXWLFD
+,*+3(5)250$1&(/,48,'&+520$72*5$3+,&'(7(50,1$7,212)1$'2/2/
$)7(5,19,75275$16'(50$/',))86,21678',(6
0$&DODWD\XG3DVFXDO&%DODJXHU)HUQiQGH]$)HPHQtD)RQW90HULQR$/ySH]&DVWHOODQR
'HSDUWDPHQWRGH)LVLRORJtD)DUPDFRORJtD\7R[LFRORJtD)DFXOWDGGH&LHQFLDVGHOD6DOXG
8QLYHUVLGDG&(8&DUGHQDO+HUUHUD6SDLQ
'HSDUWDPHQWGH)DUPjFLDL7HFQRORJLD)DUPDFqXWLFD)DFXOWDWGH)DUPjFLD8QLYHUVLWDWGH9DOqQFLD
6SDLQ
,QWURGXFWLRQ 1DGRORO LV D EHWDEORFNHU DQG WKLV
JURXS RI PHGLFLQHV LV FRPPRQO\ XVHG DV D
PLJUDLQH SUHYHQWLYH WUHDWPHQW 1DGRORO LV
DYDLODEOH XQGHU RUDO GRVLQJ IRUP ZLWK D
ELRDYDLODELOLW\RIDERXW)RUWKLVUHDVRQWKH
GHYHORSPHQWRIQHZSKDUPDFHXWLFDOIRUPXODWLRQV
IRU DOWHUQDWLYH URXWHV RI DGPLQLVWUDWLRQ DV WKH
WUDQVGHUPDO EHFRPHV D WDUJHW RI LQWHUHVW
'LIIHUHQWDQDO\WLFDOPHWKRGVKDYHEHHQGHVFULEHG
IRU WKH GHWHUPLQDWLRQ RI QDGRORO 7KH\ LQFOXGH
+3/& ZLWK 899LVLEOH GHWHFWLRQ > @
IOXRUHVFHQFH GHWHFWLRQ >@ 06 >@ DQG
FRORULPHWULF GHWHFWLRQ >@ :H KDYH WHVWHG VRPH
RIWKHPEXWWKH\KDGWRRPDQ\LQWHUIHUHQFHVIURP
HQGRJHQRXV FRPSRXQGV SUHVHQW LQ WKH VNLQ DQG
WKXVZHUHQRWFRQVLGHUHGVXLWDEOHIRUWKHSXUSRVH
RI RXU UHVHDUFK ,Q WKLV ZRUN ZH UHSRUW WKH
YDOLGDWLRQRIDUDSLGDQGVHQVLWLYH+3/&PHWKRG
ZLWK XOWUDYLROHW GHWHFWLRQ IRU WKH TXDQWLWDWLYH
GHWHUPLQDWLRQRIQDGRORODIWHULQYLWURWUDQVGHUPDO
SHUPHDWLRQVWXGLHV
0DWHULDOVDQG0HWKRGV
3UHSDUDWLRQ RI VWDQGDUG VROXWLRQ 1DGRORO ZDV
SURYLGHGE\6LJPD$OGULFK4XtPLFD6$$
P0 QDGRORO VWRFN VROXWLRQ ZDV SUHSDUHG LQ
LVRWRQLFEXIIHU>1D&OP0+HSHVP0
S+ @ 6L[ VWDQGDUG VROXWLRQV DQG —0 ZHUH SUHSDUHG E\
IXUWKHUGLOXWLRQIURPWKHVWRFNVROXWLRQLQLVRWRQLF
EXIIHU 7KHVH VWDQGDUG IUHVK VROXWLRQV ZHUH XVHG
IRUWKHFDOLEUDWLRQFXUYHV
,QVWUXPHQWDWLRQ
DQG
FKURPDWRJUDSKLF
FRQGLWLRQV 7KH DSSDUDWXV XVHG IRU +3/&
DQDO\VLV ZDV D :DWHUV V\VWHP HTXLSSHG ZLWK D
TXDWHUQDU\ SXPS DQG D GLRGHDUUD\ GHWHFWRU
&RPSXWHUL]HGGDWDDFTXLVLWLRQDQGWUHDWPHQWZHUH
SHUIRUPHG ZLWK 0LOOHQQLXP &KURPDWRJUDSK\
6RIWZDUH $ PL[WXUH RI PRQREDVLF DPPRQLXP
SKRVSKDWH ZDWHU VROXWLRQ 0 S+ DFHWRQLWULOHYYZDVXVHGDVPRELOHSKDVH
DWDIORZRIP/PLQ6HSDUDWLRQZDVFDUULHGRXW
DW DPELHQW WHPSHUDWXUH RQ D PP [ PP
UHYHUVHSKDVH FROXPQ SDFNHG ZLWK —P &
VLOLFD SDUWLFOHV .URPDVLOŠ & $EVRUEDQFH ZDV
PHDVXUHG DW QP $OLTXRWV RI —/ ZHUH
LQMHFWHG
9DOLGDWLRQ 7KH YDOLGDWLRQ RI WKH DQDO\WLFDO
PHWKRG ZDV FDUULHG RXW ZLWK VL[ GLIIHUHQW
FRQFHQWUDWLRQV RI QDGRORO DQG —0 &DOLEUDWLRQ FXUYHV ZHUH
REWDLQHG E\ WKH OHDVW VTXDUH OLQHDU UHJUHVVLRQ
DQDO\VLVRIWKHSHDNDUHDREWDLQHGDVDIXQFWLRQRI
WKH FRQFHQWUDWLRQ RI QDGRORO $Q DYHUDJH FXUYH
ZDV EXLOW XVLQJ DOO WKH GDWD IURP WKH FDOLEUDWLRQ
FXUYHV REWDLQHG 7KH VSHFLILFLW\ RI WKH PHWKRG
ZDV LQYHVWLJDWHG E\ DQDO\]LQJ EODQN VDPSOHV
7KHLU FRPSRVLWLRQ ZDV WKH VDPH LVRWRQLF EXIIHU
XVHG WR SUHSDUH WKH VWDQGDUG VROXWLRQV IRU
FDOLEUDWLRQ>1D&OP0+HSHVP0S+
@ 7KH OLQHDULW\ RI WKH FXUYHV ZDV HYDOXDWHG
ZLWKWKHFRUUHODWLRQFRHIILFLHQW7KHVORSHDQGWKH
LQWHUFHSW RI HDFK FDOLEUDWLRQ FXUYH ZHUH
VWDWLVWLFDOO\FRPSDUHGZLWK]HUR$FFXUDF\RIWKH
PHWKRGZDVGHILQHGDVWKHUHODWLYHHUURURINQRZQ
FRQFHQWUDWLRQ VROXWLRQV 7R EH DFFHSWDEOH
PHDVXUHV VKRXOG EH ZLWKLQ “ DW DOO
FRQFHQWUDWLRQV>@3UHFLVLRQRIWKHPHWKRGZDV
WHVWHG DV ZLWKLQGD\ DQG EHWZHHQGD\
UHSURGXFLELOLW\ RI WKH DVVD\ 3UHFLVLRQ RI WKH
PHWKRG ZDV H[SUHVVHG DV WKH UHVLGXDO VWDQGDUG
GHYLDWLRQ 56' RI UHSOLFDWH PHDVXUHPHQWV 7R
EH DFFHSWDEOH WKH 56' VKRXOG EH ORZHU WKDQ
DW DOO FRQFHQWUDWLRQV DQDO\]HG > @ 7KH
OLPLW RI GHWHFWLRQ /2' ZDV HVWDEOLVKHG DW WKH
VDPSOH FRQFHQWUDWLRQ UHVXOWLQJ LQ D SHDN WKUHH
WLPHV KLJKHU WKDQ EDFNJURXQG EODQN VDPSOHV
DQDO\VLV>@7KHOLPLWRITXDQWLILFDWLRQ/24
ZDV GHILQHG DV WKH ORZHVW FRQFHQWUDWLRQ ZKLFK
FDQ EH GHWHUPLQDWHG ZLWK DQ DFFXUDF\ DQG
SUHFLVLRQEHORZ>@
6WDELOLW\ 6L[ JURXSV RI —0 QDGRORO VDOLQH
EXIIHUVROXWLRQZHUHVWRUHGLQGLIIHUHQWFRQGLWLRQV
WR GHWHUPLQH WKH VWDELOLW\ RI WKH FRPSRXQG LQ
DTXHRXVVROXWLRQ
$SSOLFDWLRQ RI WKH PHWKRG WR LQ YLWUR
WUDQVGHUPDO SHUPHDWLRQ RI QDGRORO 3LJ HDUV
ZHUH FROOHFWHG LPPHGLDWHO\ DIWHU DQLPDO GHDWK
DQGWKHSRUWLRQVRIGHUPDWRPHGVNLQZHUHVWRUHG
XQWLO XVH DW ž& 7UDQVGHUPDO SHUPHDWLRQ RI
QDGRORO ZDV LQYHVWLJDWHG DW ž& ([SHULPHQWV
ZHUH SHUIRUPHG XVLQJ )UDQ] W\SH GLIIXVLRQ FHOOV
Q 1DGROROLVIUHHO\VROXEOHLQZDWHUP/RI
P0 QDGRORO VROXWLRQ SUHSDUHG LQ D LVRWRQLF
EXIIHU 1D&O P0+(3(6 P0 S+ ZDV SODFHG LQ WKH GRQRU FRPSDUWPHQW >@ 7KH
GRQRUGLIIXVLRQDUHDZDVFP7KHUHFHSWRU
FRPSDUWPHQWP/YROXPHZDVILOOHGZLWKWKH
VDPH LVRWRQLF EXIIHU S+ 0DQXDOO\ —/
VDPSOHV IURP WKH UHFHSWRU FKDPEHU ZHUH WDNHQ
GXULQJ K 7KH VDPSOH YROXPH WDNHQ ZDV
UHSODFHG ZLWK EXIIHU S+ 7KH GUXJ FRQWDLQHG
LQHDFKVDPSOHWDNHQKDVEHHQFRQVLGHUHGLQRUGHU
WR FDOFXODWH WKH DFFXPXODWLYH DPRXQW RI QDGRORO
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
LQWKHUHFHSWRUFRPSDUWPHQW$WWKHHQGRIWKHLQ
YLWUR WUDQVGHUPDO GLIIXVLRQ H[SHULPHQWV WKH
DPRXQW RI QDGRORO UHWDLQHG LQ WKH VNLQ ZDV
H[WUDFWHGE\VKDNLQJWKHVNLQGXULQJ
K ZLWK P/ RI WKH LVRWRQLF EXIIHU S+ DQG GHWHUPLQDWHG E\ WKH +3/& PHWKRG 7KH
WUDQVGHUPDO IOX[ - RI QDGRORO ZDV HVWLPDWHG
IURP WKH VORSH RI WKH OLQHDU UHJLRQ VWHDG\VWDWH
SRUWLRQRIWKHSORWRIWKHDFFXPXODWHGDPRXQWRI
QDGRORO—JFPDJDLQVWWLPHKRXUV
5HVXOWVDQG'LVFXVVLRQ,Q WKLV ZRUNDVSHFLILF
DQGVHQVLWLYH+3/&PHWKRGWRGHWHUPLQHQDGRORO
LV GHVFULEHG 6LQFH QDGRORO VSHFWUD VKRZHG WZR
PD[LPXPSHDNVRIDEVRUEDQFHDWDQG
QP ZH KDYH VHOHFWHG QP IRU WKH GHWHFWLRQ
EHFDXVH WKHUH ZHUH WRR PXFK LQWHUIHUHQFHV IURP
VNLQDWWKHUHWHQWLRQWLPHRIQDGRORODWQP
7KH UHWHQWLRQ WLPH ZDV “ PLQXWHV. $
UHSUHVHQWDWLYH FKURPDWRJUDP RI WKH VDPSOHV
REWDLQHG IURP WUDQVGHUPDO GLIIXVLRQ VWXGLHV LV
VKRZQLQ)LJ
0,030
0,020
0,010
0,000
1,00
2,00
3,00
4,00
5,00
Minutes
1DGRORO
'D\V
/LJKW
ž&
'DUNQHVV
ž&
'DUNQHVV
ž&
'DUNQHVV
ž&
'DUNQHVV
ž&
'DUNQHVV
ž&
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
$FFXPXODWHGDPRXQWV
RIQDGRORO—JFP
“
“
%HWZHHQGD\Q :LWKLQGD\Q 5HDO
&RQFHQWUDWLRQ $FFXUDF\ &RQFHQWUDWLRQ $FFXUDF\
FRQFHQWUDWLRQ
IRXQGμ0
IRXQGμ0
μ0
7DEOH 6WDELOLW\ RI QDGRORO LQ GLIIHUHQW FRQGLWLRQ
5HFRYHU\DIWHUVWRUDJH“6'Q 7DEOH $FFXUDF\ RI WKH +3/& PHWKRG IRU GHWHUPLQLQJ
QDGROROFRQFHQWUDWLRQVLQVDOLQHEXIIHUHGVDPSOHVS+
Q :LWKLQGD\
YDULDELOLW\Q &RQFHQWUDWLRQ 56' &RQFHQWUDWLRQ 56'
IRXQGμ0
IRXQGμ0
7KHUHVXOWVREWDLQHGLQWKHVWDELOLW\WHVWDUHVKRZQ
LQ 7DEOH 7KH VDPSOHV VWRUHG DW DPELHQW
WHPSHUDWXUH VKRZHG WKH ELJJHVW GHJUDGDWLRQ RI
QDGRORO LQ VDOLQHEXIIHUHG VROXWLRQ S+ 2Q
WKHRWKHUKDQGWKHFRPSRXQGVWRUHGDWž&DQG
ž& GDUNQHVV VXIIHUHG QR GHWHFWDEOH
GHJUDGDWLRQVLQFHLW NHSWWKHVDPHFRQFHQWUDWLRQ
GXULQJGD\VRIWKHVWXG\
7KH SRWHQWLDO XVH RI WKLV PHWKRG KDV EHHQ
GHPRQVWUDWHGE\WKHVWXG\RILQYLWURWUDQVGHUPDO
GLIIXVLRQRIQDGRORO7KHDFFXPXODWHGDPRXQWVRI
QDGRORO LQ UHFHSWRU FRPSDUWPHQW —JFP DUH
SORWWHGDJDLQVWWLPHKRXUVLQ)LJ7KHDPRXQW
RI QDGRORO UHWDLQHG LQ VNLQ ZDV “
—JFP7KH WUDQVGHUPDO IOX[ HVWLPDWHG IURP WKH
VORSHRIWKHOLQHDUUHJLRQVWHDG\VWDWHSRUWLRQRI
WKHSORW ZDV IRXQGWREH ±—JFPÂK
PHDQ“6'Q )LJ&KURPDWRJUDPRIDQDGROROVDPSOHREWDLQHGIURP
LQYLWURWUDQVGHUPDOSHUPHDWLRQH[SHULPHQWV
7KH PHWKRG H[KLELWHG OLQHDULW\ EHWZHHQ WKH
UHVSRQVH\DQGWKHFRUUHVSRQGLQJFRQFHQWUDWLRQ
RI QDGRORO [ RYHU WKH —0 UDQJH RI
FRQFHQWUDWLRQV DVVD\HG 7KH UHVXOWV RI WKH OHDVW
VTXDUH OLQHDU UHJUHVVLRQ DQDO\VLV VKRZHG D
VLJQLILFDQWFRUUHODWLRQFRHIILFLHQWU•
7DEOH VXPPDUL]HV WKH UHODWLYH HUURU YDOXHV RI
WKH VWDQGDUGV $FFXUDF\ ZDV ZLWKLQ DFFHSWDEOH
OLPLWV
7KH UHVXOWV RI WKH EHWZHHQGD\ DQG ZLWKLQGD\
SUHFLVLRQ GHWHUPLQHG DUH VKRZQ LQ 7DEOH DQG
ZHUHEHORZLQDOOFDVHV
7KH OLPLW RI GHWHFWLRQ DQG WKH OLPLW RI
TXDQWLILFDWLRQ RI QDGRORO ZHUH DQG —0UHVSHFWLYHO\
%HWZHHQGD\
YDULDELOLW\Q 5HDO
FRQFHQWUDWLRQ
μ0
0,040
AU
7DEOH %HWZHHQ DQG ZLWKLQGD\ YDULDELOLWLHV RI WKH
+3/& PHWKRG IRU GHWHUPLQLQJ QDGRORO FRQFHQWUDWLRQV LQ
VDOLQHEXIIHUHGVDPSOHVS+
“
“
“
“
“
“
“
“
&RQFOXVLRQV $ VLPSOH FKURPDWRJUDSKLF PHWKRG
KDV EHHQ YDOLGDWHG IRU WKH UDSLG DQG SUHFLVH
GHWHUPLQDWLRQ RI QDGRORO 7KH UHVXOWV RI WKH
YDOLGDWLRQRIWKH+3/&PHWKRGSURYHWKHPHWKRG
DV VDWLVIDFWRU\ VLQFH WKH OLPLW RI TXDQWLILFDWLRQ
WKHVSHFLILFLW\RIWKHPHWKRGDQGLWVDFFXUDF\DQG
UHSURGXFLELOLW\ DOORZ WR TXDQWLI\ WKH DPRXQW RI
QDGRORO FRQWDLQHG LQ WKH VDPSOHV REWDLQHG IURP
WKHLQYLWURWUDQVGHUPDOSHUPHDWLRQH[SHULPHQWV
5HIHUHQFHV
3DWHO %5 HW DO - 3KDUP 6FL 'HODPRYH 0 HW DO )RUHQVLF 6FL ,QW
+RVKLQR 0 HW DO - &KURPDWRJU % %LRPHG
$SSO
6ULQLYDV 15 HW DO %LRPHG &KURPDWRJU
%HODV )- HW DO %LRPHG &KURPDWRJU
0DXUHU++HWDO-&KURPDWRJU$
$PLQ $6 HW DO - 3KDUP %LRPHG $QDO
'5 -HQNH - /LT &KURPDWRJU 5HODW
7HFKQRO
'5 -HQNH - /LT &KURPDWRJU 5HODW
7HFKQRO
$ )HPHQtD)RQW HW DO (XU - 3KDUP
%LRSKDUP
$FNQRZOHGJPHQWV 7KH DXWKRUV ZLVK WR WKDQN
0LQLVWHULR GH 6DQLGDG \ &RQVXPR 3,
0LQLVWHULR GH (GXFDFLyQ \ &LHQFLD DQG WKH
8QLYHUVLW\ &(8 &DUGHQDO +HUUHUD IRU WKH
ILQDQFLDOVXSSRUW
7LPHKRXUV
)LJ $FFXPXODWHG DPRXQW RI QDGRORO IRXQG LQ WKH
UHFHSWRU FKDPEHU YHUVXV WLPH (UURU EDUV UHSUHVHQWV
VWDQGDUGGHYLDWLRQ
&2035,0,'26,03/$17$%/(6'(K*+&255(/$&,Ï1,19,752,19,92
6DQWRYHxD$)DULxD-%/ODEUpV0=KX<'DQQLHV3
'HSDUWDPHQWRGH,QJHQLHUtD4XtPLFD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH
/D/DJXQD/D/DJXQD7HQHULIH6SDLQ'HSDUWPHQWRI3KDUPDFRORJ\<DOH6FKRRORI0HGLFLQH
1HZ+DYHQ&RQQHFWLFXW86$
6H HPSOHy XQ VLVWHPD GH FURPDWRJUDItD OtTXLGD
GH DOWD SUHFLVLyQ +3/& :DWHUV IRUPDGR SRU
XQDERPED(XQLQ\HFWRUDXWRPiWLFR
SOXVXQGHWHFWRU89GXDODQPFRQ
SURJUDPDGHDGTXLVLFLyQGHGDWRV0LOOHQLXP
FRPRIDVHHVWDFLRQDULDXQDFROXPQD3URWHLQ3DN
[ PP \ FRPR IDVH PyYLO XQD
PH]FODDFHWRQLWULORDJXDYYFRQ
GHiFLGRWULIOXRURDFpWLFRDXQIOXMRGHPOPLQ
/RV SHVRV PROHFXODUHV HQ SHVR 0Z \ HQ
Q~PHUR 0Q GH 3/*$ \ GH ORV FRPSULPLGRV
IXHURQ GHWHUPLQDGRV SRU FURPDWRJUDItD GH
SHUPHDFLyQHQJHO*3&UHODWLYDDSDWURQHVGH
SROLHVWLUHQR 'D HPSOHDQGR XQ
VLVWHPD :DWHUV 6H HPSOHy WHWUDKLGURIXUDQR
7+) FRPR IDVH PyYLO D POPLQ /D
GHJUDGDFLyQ GHO 3/*$ VH H[SUHVy PHGLDQWH OD
GHWHUPLQDFLyQGHOtQGLFHGHGHJUDGDFLyQ,'GH
DFXHUGRFRQ,' 0Q0QWGRQGH0QHVHO
0QLQLFLDO\0QWDOWLHPSRW
6H HODERUDURQ WUHV IRUPXODFLRQHV GH K*+
PHGLDQWH FRPSUHVLyQ GLUHFWD HQ XQD SUHQVD
KLGUiXOLFD &DUYHU D WHPSHUDWXUD DPELHQWH EDMR
FRQGLFLRQHV DVpSWLFDV \ FRQ GLIHUHQWHV
FRPELQDFLRQHVGHFDUJDGHKRUPRQD\SROtPHUR
\ Pi[LPD IXHU]D GH FRPSUHVLyQ HQ HO WLHPSR
HPSOHDQGR SDUD HOOR XQ PROGH FLOtQGULFR GH PPGHGLiPHWURWDEOD
7DEOD &DUDFWHUtVWLFDV GH ODV IRUPXODFLRQHV HODERUDGDV
FRQ 7Q GH IXHU]D Pi[LPD DSOLFDGD ) IRUPXODFLyQ K
K*+ 3RO 3/*$ W WLHPSR &GR FRQWHQLGR GHFODUDGR 3
SHVR(HVSHVRU
)
KPJ
3ROPJ
WV
&GR
3PJ
(PJ
$
%
&
(OFRQWHQLGRGHKRUPRQDHQORVFRPSULPLGRVQ
VH GHWHUPLQy GLVROYLHQGR FDGD XQR HQ
7+) /D HVWDELOLGDG GH OD K*+ HQ 7+) \D KD
VLGRHVWXGLDGDHQWUDEDMRVDQWHULRUHV
A
5HVXOWDGRV \ 'LVFXVLyQ /DV FDUDFWHUtVWLFDV GH
FDGD IRUPXODFLyQ VH UHVXPHQ HQ OD WDEOD /D
FHVLyQ LQ YLWUR GH K*+ GHVGH ORV FRPSULPLGRV
LPSODQWDEOHVILJXUD PXHVWUDHO PLVPRSHUILO
GH OLEHUDFLyQ XQD FHVLyQ LQLFLDO UiSLGD VHJXLGD
GHXQHVWDQFDPLHQWR(VWRVUHVXOWDGRV PXHVWUDQ
FRPR ODFHVLyQGHSULQFLSLRDFWLYRGLVPLQX\HD
PHGLGD TXH PiV FDQWLGDG GH SROtPHUR PHQRV
FDUJD GH KRUPRQD \ PiV IXHU]D GH FRPSUHVLyQ
C
DI
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
0
5
10
15
t (days)
)LJXUD&HVLyQLQYLWURGHK*+H,'GHO3/*$VHJXQGR
HMHFRQHOWLHPSR
/D ILJXUD PXHVWUD ODV SUHGLFFLRQHV
SREODFLRQDOHV HQWUH JUXSRV \ FRQFHQWUDFLRQHV
REVHUYDGDV GH KRUPRQD FRQ UHVSHFWR DO WLHPSR
SDUDFDGDUDWyQ
fixed
3DUD HVWXGLDU OD FLQpWLFD GH FHVLyQ FDGD
FRPSULPLGR VH LQWURGXMR HQ YLDOHV FRQ PO GH
WDPSyQ IRVIDWR LVRWyQLFR S+ 6|UHQVHQ HQ
XQEDxRWHUPRVWDWL]DGRDž&GXUDQWHGtDV
/RV HVWXGLRV LQ YLYR VH UHDOL]DURQ EDMR
FRQGLFLRQHV HVWpULOHV HQ HO 'HSDUWDPHQWR GH
)DUPDFRORJtD GH OD 8QLYHUVLGDG GH <DOH
HPSOHDQGR UDWRQHV KHPEUDV &% 6&,' TXH
IXHURQ WUDWDGRV FRQYHQLHQWHPHQWH GH DFXHUGR
FRQ ORV 3URWRFRORV GH &XLGDGR \ (PSOHR GH
$QLPDOHV
GH
([SHULPHQWDFLyQ
&DGD
FRPSULPLGR IXH LPSODQWDGR HQ OD FDYLGDG
SHULWRQHDO GHO UDWyQ FXDWUR GtDV GHVSXpV GH VHU
LQ\HFWDGRVFRQFpOXODV6.29LS/RVQLYHOHV
VpULFRV GH K*+ IXHURQ GHWHUPLQDGRV WUDV
VDQJUDGR GH ORV YDVRV RUELWDOHV GHO RMR \
PHGLDQWH LQPXQRHQVD\R ,PPXOLWH *URZWK
+RUPRQH 6LHPHQV 3DUD OD UHDOL]DFLyQ GHO
DQiOLVLV IDUPDFRFLQpWLFR SREODFLRQDO VH HPSOHy
XQ PRGHOR GH WDQTXHV HQ VHULH /RV
SDUiPHWURV IDUPDFRFLQpWLFRV VH HVWLPDURQ
HPSOHDQGR XQ PRGHOR QR OLQHDO GH HIHFWRV
PL[WRV 6H HVWXGLDURQ GLIHUHQWHV QLYHOHV GH
FRUUHODFLyQLQYLWURLQYLYR
B
140
120
100
80
60
40
20
0
10
mouse
60
20
0
80
11
13
9
7
8
15
12
6
1
5
2
14
60
40
20
0
80
60
40
20
0
80
60
40
20
0
0
5
10
15
20
0
tx
5
10
15
20
)LJXUD &RQFHQWUDFLRQHV SODVPiWLFDV GH K*+ GH FDGD
UDWyQGXUDQWH GtDV SXQWRV YDORUHV SUHGLFKRV SDUD FDGD
XQROtQHDURVD\SDUDFDGDJUXSRHVWXGLDGROtQHDD]XO
/DV FRQFHQWUDFLRQHV SODVPiWLFDV PXHVWUDQ XQD
FXUYD H[WUDYDVDO FRQ GLIHUHQWHV FRQFHQWUDFLRQHV
Pi[LPDV (O DQiOLVLV HVWDGtVWLFR GH ORV
UHVXOWDGRV REWHQLGRV QR UHYHOD GLIHUHQFLDV
VLJQLILFDWLYDV HQWUH IRUPXODFLRQHV S ! 3DUD HVWDEOHFHU HO QLYHO & ,9,9& UHDOL]DPRV OD
UHJUHVLyQOLQHDOHQWUHODGRVLVGHKRUPRQD;\
HO iUHD EDMR OD FXUYD $%& eVWH PRGHOR GH
FRUUHODFLyQ SRVHH XQ YDORU U GH SHUR QR
SDVDSRUHORULJHQ(VWRLQGLFDTXHODUHVSXHVWD
IDUPDFRFLQpWLFD HQWUH $%& \ ; QR HV OLQHDO
SUREDEOHPHQWH SRU OD DOWD GRVLV GH SULQFLSLR
DFWLYRDGPLQLVWUDGDHQFDGDIRUPXODFLyQ
&RQFOXVLRQHV6HHODERUDURQWUHVIRUPXODFLRQHV
GH FRPSULPLGRV LPSODQWDEOHV FRQ GLIHUHQWHV
FRPELQDFLRQHVGHK*+3/*$\Pi[LPDIXHU]D
DSOLFDGD HQ HO WLHPSR (VWDV IRUPXODFLRQHV
SRVHHQ OD SULQFLSDO YHQWDMD GH XQD IiFLO
HODERUDFLyQ TXH FRQWULEX\H D PDQWHQHU OD
HVWDELOLGDG GHO SULQFLSLR DFWLYR GXUDQWH OD
PLVPD DVt FRPR GXUDQWH VX FHVLyQ SURORQJDGD
HQ HO WLHPSR (O PRGHOR QR OLQHDO GH HIHFWRV
PL[WRV SHUPLWH DMXVWDU ORV GDWRV LQ YLYR D XQ
~QLFR PRGHOR GH WDQTXHV HQ VHULH FRQ OD GRVLV
GHKRUPRQDFRPRHO~QLFRSDUiPHWURTXHDIHFWD
DODHYROXFLyQGHODFRQFHQWUDFLyQSODVPiWLFDHQ
HO WLHPSR $XQTXH VH REWXYR XQD EXHQD
FRUUHODFLyQ LQ YLWURLQ YLYR OD HYROXFLyQ HQWUH
ORVSDUiPHWURVIDUPDFRFLQpWLFRV\GHGLVROXFLyQ
QR UHVXOWy OLQHDO GHELGR D ODV DOWDV GRVLV GH
KRUPRQD VXPLQLVWUDGDV HQ FDGD LPSODQWH eVWH
QLYHO&GHFRUUHODFLyQQRUHIOHMDHQVXWRWDOLGDG
ORV FRPSOHMRV PHFDQLVPRV GH FHVLyQ \
DEVRUFLyQ GHO SULQFLSLR DFWLYR SHUR SXHGH
HPSOHDUVH FRPR SULPHU SDVR HQ HO SURFHVR
JOREDO GH REWHQFLyQ GH UHVXOWDGRV LQ YLWURLQ
YLYR GH IRUPDV IDUPDFpXWLFDV ~WLOHV HQ OD
LQYHVWLJDFLyQ GH QXHYRV WUDWDPLHQWRV FRQWUD HO
FiQFHUGHRYDULRHQUDWRQHV
%LEOLRJUDItD
80
40
cx
0DWHULDOHV\0pWRGRVK*+ORWH,'\
3ROL'/ODFWLGDFRJOLFROLGD
3/*$
5HVRPHUŠ 5* IXHURQ VXPLQLVWUDGRV
SRU /LOO\ 6$ \ %RHKULQJHU ,QJHOKHLP
UHVSHFWLYDPHQWH 7RGRV ORV GHPiV UHDFWLYRV
HPSOHDGRVIXHURQGHJUDGRDQDOtWLFR
VH DSOLFD HQ HO WLHPSR $O FRPSUREDU HO ,' GHO
SROtPHURVHFRPSUXHEDFyPRHODXPHQWRGHOD
GHJUDGDFLyQGHOSHVRPROHFXODUGHOSROtPHURQR
FRLQFLGH FRQ XQ FDPELR HQ OD OLEHUDFLyQ GH
K*+
ID
,QWURGXFFLyQ /D OLEHUDFLyQ GH KRUPRQD GH
FUHFLPLHQWR KXPDQD K*+ GHVGH GLIHUHQWHV
WLSRV GH VLVWHPDV GH FHVLyQ FRQWURODGD KD
VLGR \ FRQWLQ~D VLHQGR DPSOLDPHQWH HVWXGLDGD
/D LQFOXVLyQ GH K*+ HQ FRPSULPLGRV
ELRGHJUDGDEOHV SDUD DGPLQLVWUDFLyQ SDUHQWHUDO
QRHVXQDSUiFWLFDFRP~QDSHVDUGHODVYHQWDMDV
TXHVXHODERUDFLyQSUHVHQWDSUHSDUDFLyQGLUHFWD
DXVHQFLDGHFRQWDFWRFRQGLVROYHQWHV\DJLWDFLyQ
PHFiQLFD DOWD HILFDFLD GH LQFRUSRUDFLyQ HWF«
5HFLHQWHPHQWHVHKDHVWXGLDGRHOHIHFWRFHOXODU
FDXVDGRWUDVODH[SUHVLyQGHK*+\GHO*+
SURWHtQDVHFUHWDGDHQODGHILFLHQFLDGHKRUPRQD
GH FUHFLPLHQWR KXPDQD WLSR ,, SRU DGHQRYLUXV
HQ OtQHDV FHOXODUHV GH FiQFHU GH RYDULR (Q
pVWHWUDEDMRVHKDHVWXGLDGRHOSHUILOGHFHVLyQGH
K*+ GHVGH FRPSULPLGRV LPSODQWDEOHV FRQ HO
REMHWR GH FRQRFHU HO HIHFWR TXH VX OLEHUDFLyQ
SURORQJDGDSURYRFDHQHOGHVDUUROORWXPRUDOGH
FiQFHUGHRYDULRHQUDWRQHV
,;&RQJUHVRGHOD6(),*
rhGH release (%)
7HFQRORJtD)DUPDFpXWLFD
9OXJW:HQVLQN .' GH 9UXHK 5 *UHVQLJW 0*
+RRJHUEUXJJH &0 YDQ %XXO2IIHUV 6& GH /HHGH /*
6WHUNPDQ /* &URPPHOLQ '- +HQQLQN :( 9HUULMN 5
3UHFOLQLFDODQGFOLQLFDOLQYLWURLQYLYRFRUUHODWLRQRIDQK*+
GH[WUDQ PLFURVSKHUH IRUPXODWLRQ 3KDUP 5HV 6DQWRYHxD$*DUFtD-7)DULxD-%/ODEUpV0$
OLQHDUPL[HGHIIHFWVVWDWLVWLFDOPRGHOIRULQYLYRHYDOXDWLRQ
RIUHFRPELQDQWKXPDQJURZWKKRUPRQHLPSODQWVLQ
K\SRSK\VHFWRPL]HG UDWV - 3KDUP 3KDUPDFRO 2NXPX ): 'DR /H 1 )LHOGHU 3- '\EGDO 1
%URRNV'6DQH6&OHODQG-/6XVWDLQHGGHOLYHU\RIKXPDQ
JURZWK KRUPRQH IURP D QRYHO JHO V\VWHP 6$%(5
%LRPDWHULDOV
(4)
Patel y Dannies, datos no publicados.
6DQWRYHxD $ *DUFtD -7 2OLYD $ /ODEUpV 0
)DULxD -% $ PDWKHPDWLFDO PRGHO IRU LQWHUSUHWLQJ LQ YLWUR
UK*+UHOHDVHIURPODPLQDULPSODQWV,QW-3KDUP
)DGG\ 0 - $ VWUXFWXUHG FRPSDUWPHQWDO PRGHO
IRUGUXJNLQHWLFV%LRPHWULFV
3LQKHUR -& %DWHV '0 /LQHDU PL[HGHIIHFWV
PRGHOV ,Q 0L[HGHIIHFWV PRGHOV LQ 6 DQG 63/86
6SULQJHU9HUODJ1HZ<RUN
(8)
USP Pharmacopeia 30, Vol.1, p. 536,
Rockville, 2006.
$JUDGHFLPLHQWRV
/RV DXWRUHV DJUDGHFHQ D $OLVRQ .D\ 9LFHQWH
+HUQiQGH] \ &DUPHQ %XHQR GH /LOO\ 6$ HO
VXPLQLVWURGH+RUPRQDGH&UHFLPLHQWR+XPDQD
5HFRPELQDQWH \ D 3DWULFLD 'RQRYDQ \ -XOLD
0HUN GH OD 8QLYHUVLGDG GH <DOH HO GHVDUUROOR
GH OD WpFQLFD GH LPSODQWDFLyQ GH ORV
FRPSULPLGRV
7HFQRORJtD)DUPDFpXWLFD
(678',20,&52%,2/2*,&2'(9(+,&8/2675$1'(50,&26*(/3/8521,&<3/2
3OXURQLF/HFLWKLQ2UJDQRJHO
&ODUHV%5XL]0$*iOYH]3\*DOODUGR9
'SWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH*UDQDGD
,QWURGXFFLyQ (Q HO GHVDUUROOR GH QXHYDV
IRUPXODFLRQHV WUDQVGpUPLFDV HO p[LWR GHSHQGH QR
VROR GH OD FRUUHFWD HOHFFLyQ GH ORV DFWLYRV \
H[FLSLHQWHVVHOHFFLRQDGRVVLQRGHODHVWDELOLGDGGH
ORV PLVPRV (Q HVWH VHQWLGR OD HVWDELOLGDG
PLFURELROyJLFD GH ODV IRUPDV GHUPRIDUPDFpXWLFDV
UHVXOWD LPSUHVFLQGLEOH FRPR JDUDQWtD GH FDOLGDG
\DTXHGHELGRDODQDWXUDOH]DGHVXVFRPSRQHQWHV
VRQ VXVFHSWLEOHV GH FRQWDPLQDFLyQ /RV
PLFURRUJDQLVPRVGDQOXJDUDGLYHUVDVDOWHUDFLRQHV
LQGHVHDEOHV TXH SXHGHQ FRQGXFLU QR VyOR D XQD
GLVPLQXFLyQGHODHVWDELOLGDGVLQRDXQDLQIHFFLyQ
SRUPLFURRUJDQLVPRVSDWyJHQRV\DODSURGXFFLyQ
GH VXVWDQFLDV PHWDEyOLFDV Wy[LFDV $Vt SXHV HO
FRQWURO PLFURELROyJLFR H[LJH XQ PD\RU ULJRU HQ
GHWHUPLQDGDV IRUPDV WySLFDV HVSHFLDOPHQWH HQ
YHKtFXORVGHOLEHUDFLyQWUDQVGpUPLFDGH IiUPDFRV
WDOHV FRPR JHOHV KLGUyILORV GH 3OXURQLF \
RUJDQRJHOHV 3/2 3OXURQLF /HFLWKLQ 2UJDQRJHO
TXH GHELGR D VX DOWR FRQWHQLGR DFXRVR
FRQVWLWX\HQ H[FHOHQWHV PHGLRV GH FXOWLYR
PLFURELROyJLFRV
(VWRV H[FLSLHQWHV SXHGHQ IDFLOLWDU HO SDVR GH
SULQFLSLRV DFWLYRV D WUDYpV GHO HVWUDWR FRUQHR
DXPHQWDQGR OD GLVSRQLELOLGDG \ HO WLHPSR GH
SHUPDQHQFLD GH XQ IiUPDFR OR TXH VXSRQH XQ
ULHVJR QR VyOR SRU VX FRPSRVLFLyQ VLQR SRU VX
OXJDU GH DFFLyQ 6LQ HPEDUJR KDVWD HO
PRPHQWR QR H[LVWHQ HYLGHQFLDV FLHQWtILFDV VREUH
ODHVWDELOLGDGPLFURELROyJLFDGHHVWRVYHKtFXORVOR
TXH OLPLWD OD HYDOXDFLyQ H[DFWD GH SRVWHULRUHV
HQVD\RV ELRIDUPDFpXWLFRV 3RU WDQWR QXHVWUR
REMHWLYR KD VLGR HO GHVDUUROOR \ HVWXGLR
PLFURELROyJLFR
GH
GRV
IRUPXODFLRQHV
WUDQVGpUPLFDVJHOSOXURQLF\3/2FRQHOREMHWRGH
GLVFULPLQDU OD QHFHVLGDG R QR GH LQFRUSRUDU XQ
FRQVHUYDQWH TXH DVHJXUH OD HVWDELOLGDG GH ODV
IyUPXODVREMHWRGHHQVD\R
7DEOD&RPSRVLFLyQGHO*HO3OXURQLF\3/2
)2508/$
)DVH
2OHRVD
&20321(17(6
/HFLWLQDGH6RMD
3DOPLWDWR
LVRSURSLOR
3/2
)DVH
$FXRVD
3OXURQLF)Š
$JXDGHVWLODGDFVS
PO
&DGDXQDGHODVPXHVWUDVVHSUHSDUDSRUWULSOLFDGR
VRPHWLpQGRVH D GLIHUHQWHV WHPSHUDWXUDV ž& ž&
\ 7 DPELHQWH SURWHJLGDV GH OD OX] (O SHULRGR GH
HVWXGLR KD VLGR GH GtDV GHWHUPLQiQGRVH D
LQWHUYDORV GH GtDV OD SUHVHQFLD GH
PLFURRUJDQLVPRV HQ DPEDV IRUPXODFLRQHV
WUDQVGpUPLFDV 3DUD HOOR VH SURFHGH D ODV VLHPEUDV
HQ PHGLR 76$ 7ULVWRQD 6RMD $JDU SDUD OD
GHWHFFLyQGHEDFWHULDV\HQPHGLR6DEXUDXQGSDUD
OD GHWHFFLyQ GH KRQJRV \ OHYDGXUDV LQFXEiQGRVH D
ž&KRUDV\ž&GtDVUHVSHFWLYDPHQWH
5)(/DGHWHUPLQDFLyQGHOUHFXHQWRGH
PLFURRUJDQLVPRV WRWDOHV VH UHDOL]D SRU UHFXHQWR HQ
SODFD 7LQFLyQ GH JUDP \ SRVWHULRU LGHQWLILFDFLyQ
FRQ $3, VHOHFWLYRV $3< &25<1( FRU\QHEDFWHULDV
$3<
67$3+
HVWDILORFRFRV$3,&$8;OHYDGXUDV\
$3,&+$3,&+%(%DFLOXV
7HFQRORJtD)DUPDFpXWLFD
'(6$552//2'(3$5&+(675$16'e50,&26'(12575,37,/,1$&21',)(5(17(6
0$75,&(632/,0(5,&$6
--(VFREDU&KiYH]90HULQR00HULQR6DQMXiQ$1iFKHU$*DQHP4XLQWDQDU
2'tH]6DOHV0+HUUiH]
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH9DOHQFLD$Y9LFHQWH$QGUpV
(VWHOOpVVQ%XUMDVVRW9DOHQFLD(VSDxD
'LYLVLyQGH(VWXGLRVGH3RVJUDGR7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH(VWXGLRV6XSHULRUHV
&XDXWLWOiQ8QLYHUVLGDG1DFLRQDO$XWyQRPDGH0p[LFR$YžGH0D\RVQ&XDXWLWOiQ,]FDOOL(VWDGRGH
0p[LFR0p[LFR
Tabla 1. Composición de parches con matriz
polimérica de EVA.
&RQFHQWUDFLyQSS
&RPSRQHQWHV 3DUFKH, 3DUFKH,, 3DUFKH,,,
(9$
7(&
7ULHWLO
FLWUDWR
&LFORKH[DQR
3(*0(
'RGHFDQRO
3OXURQLFŠ)
$OFRKROHWtOLFR
+,'52*(/
7LHPSR
GtDV
7
ž&
*HO3OXURQLF)FVS
PO
0DWHULDO\0pWRGRV
3UHSDUDFLyQGHSDUFKHV/RVSDUFKHVDGKHVLYRVVH
SUHSDUDURQ XWLOL]DQGR GRV WLSRV GH SROtPHURV
IRUPDGRUHV GH PDWUL] HWLO YLQLO DFHWDWR (9$ \
SROLLVREXWLOHQR3,%(QFDGDXQRGHORVVLVWHPDV
PDWULFLDOHV FX\D FRPSRVLFLyQ VH PXHVWUD HQ ODV
7DEODV\VHLQFRUSRUy173DODFRQFHQWUDFLyQ
GHO SS /RV FRPSRQHQWHV VH PH]FODURQ \ VH
PDQWXYLHURQ HQ DJLWDFLyQ GXUDQWH K
SRVWHULRUPHQWH IXHURQ VRPHWLGRV D VRQLFDFLyQ \
YHUWLGRV HQ SODFDV GH YLGULR GH PP GH DOWXUD
GHMiQGRVHVHFDUKDWHPSHUDWXUDDPELHQWH
\ WUDV OD IDOWD GH HIHFWLYLGDG GH OD SULPHUD
FRQFHQWUDFLyQGHFRQVHUYDQWHHVWXGLDGDVHUHDOL]D
XQ EDUULGR GH FRQFHQWUDFLRQHV FUHFLHQWHV GH
FRQVHUYDQWH
7DEOD5HFXHQWRPLFURELROyJLFR*HO3OXURQLF
5HVXOWDGRV\'LVFXVLyQ/RVUHVXOWDGRVREWHQLGRV
HQ ODV IRUPXODFLRQHV REMHWR GH HQVD\R VH
FRPSDUDURQ FRQ ORV YDORUHV OtPLWHV KDVWD DKRUD
GHWDOODGRV HQ OD 5)( SDUD IRUPXODFLRQHV
0DWHULDO\0pWRGRV/DVGLIHUHQWHVIRUPXODFLRQHV IDUPDFpXWLFDV GH XVR WySLFR 8)& 5)(
HVWXGLDGDV HQ OD HODERUDFLyQ GH ODV IRUPDV $HURELRV 0HVyILORV $(5 \ 0RKRV \
WUDQVGpUPLFDV DVt FRPR ODV FRQFHQWUDFLRQHV GH ORV /HYDGXUDV+\/5)((VFKHULFKLDFROL
$XVHQFLD 6WDSK\ORFRVFFXV DXUHXV $XVHQFLD
FRPSRQHQWHVILJXUDQHQOD7DEOD
3DUD FDGD IRUPXODFLyQ VH KDQ HODERUDGR VHLV 3VHXGRPRQDV DHUXJLQRVD $XVHQFLD &DQGLGD
IyUPXODV TXH GLILHUHQ HQ OD FRQFHQWUDFLyQ GHO DOELFDQV$XVHQFLD5)(
/RVGDWRVGHODVWDEODV\SRQHQGH PDQLILHVWR
FRQVHUYDQWH
(O FRQVHUYDQWH VHOHFFLRQDGR 0LFURFDUH 07,Š HV OD DFFLyQ DQWLEDFWHULDQD \ DQWLI~QJLFD GHO
XQD
PH]FOD
GH
0HWK\OLVRWKLD]ROLQRQH FRQVHUYDQWH HPSOHDGR 7UDQVFXUULGRV GtDV \
,RGRSURS\Q\O EXW\OFDUEDPDWH DFWLYR IUHQWH D FRQVHUYDGDV D ž& QLQJXQD GH ODV IRUPXODFLRQHV
EDFWHULDVJUDPJUDPKRQJRV\OHYDGXUDV(V HVWXGLDGDV QHFHVLWDQ FRQVHUYDGRU 6LQ HPEDUJR D
VROXEOHHQDJXDSRUORTXH VHDxDGHHQOD IDVH \ ž& VH HPSLH]D D REWHQHU UHVXOWDGRV
DFXRVD D ODV VLJXLHQWHV FRQFHQWUDFLRQHV PLFURELROyJLFRV SRVLWLYRV 3RU WDQWR VH GHGXFH OD
QHFHVLGDG GH LQFRUSRUDU GHO FRQVHUYDQWH
\
WDQWRHQHOKLGURJHOFRPRHORUJDQRJHO$VLPLVPR
,QWURGXFFLyQ
(O FRQVXPR GH WDEDFR HV XQD GH ODV SULQFLSDOHV
FDXVDV GH PXHUWH HQ HO PXQGR UHVSRQVDEOH GH OD
PXHUWH GH GH FDGD DGXOWRV /RV ULHVJRV GH
PXHUWH
DVRFLDGRV
FRQ
HQIHUPHGDGHV
FDUGLRYDVFXODUHV \ SXOPRQDUHV VH UHGXFHQ VL ORV
IXPDGRUHV LQWHUUXPSHQ VX FRQVXPR >@ 8Q
HVWXGLR PRVWUy TXH OD FRPELQDFLyQ GH QLFRWLQD
WUDQVGpUPLFD \ FORUKLGUDWR GH QRUWULSWLOLQD SRU YtD
RUDO 173+&/ UHGXFH VLJQLILFDWLYDPHQWH ORV
VtQWRPDV
SRU
GHVKDELWXDFLyQ
WDEiTXLFD
UHSUHVHQWDQGRXQDLPSRUWDQWHHLQWHUHVDQWHRSFLyQ
SDUD IXPDGRUHV FXDQGR OD PRQRWHUDSLD FRQ
QLFRWLQD WUDQVGpUPLFD QR SHUPLWH REWHQHU
UHVXOWDGRV IDYRUDEOHV >@ (O REMHWLYR GH HVWH
HVWXGLR KD VLGR HO GHVDUUROOR \ FDUDFWHUL]DFLyQ GH
GLIHUHQWHV SDUFKHV WUDQVGpUPLFRV FRQ QRUWULSWLOLQD
FRQ HO ILQ GH EXVFDU IRUPDV GH DGPLQLVWUDFLyQ
DOWHUQDWLYDVTXHSRWHQFLHQXQPD\RUFXPSOLPLHQWR
GHODWHUDSLDDQWLWDEDFR
,;&RQJUHVRGHOD6(),*
Tabla 2. Composición de parches con matriz
polimérica de PIB.
&RPSRQHQWHV
3,%
&LFORKH[DQR
3(*0(
'RGHFDQRO
3OXURQLFŠ)
&RQFHQWUDFLyQSS
3DUFKH, 3DUFKH,, 3DUFKH
,,,
(VWXGLR PLFURVFySLFR /RV SDUFKHV HODERUDGRV VH
REVHUYDURQ DO PLFURVFRSLR GH OX] SRODUL]DGD FRQ
REMHWR GH LGHQWLILFDU HQ VX FDVR OD IRUPDFLyQ GH
FULVWDOHV GXUDQWH HO DOPDFHQDPLHQWR \
FRQVHUYDFLyQ
(VWXGLRV GH SHUPHDFLyQ LQ YLWUR SRU GLIXVLyQ
SDVLYD 3DUD OOHYDU D FDER HVWRV HVWXGLRV VH
XWLOL]DURQ FHOGDV GH GLIXVLyQ WLSR )UDQ] (Q HO
GDGRU VH FRORFDURQ ORV SDUFKHV GHVDUUROODGRV
FXELHUWRV FRQ SHOtFXOD RFOXVLYD 0Š 6FRWFKSDNŠ
\ HQ HO UHFHSWRU VROXFLyQ WDPSRQDGD GH
+(3(6 S+ OD PHPEUDQD XWLOL]DGD IXH SLHO
KXPDQD FRPSOHWD SURFHGHQWH GH OD ]RQD
DEGRPLQDO /DV PXHVWUDV VH WRPDURQ D GLIHUHQWHV
LQWHUYDORV GH WLHPSR SDUD FRPSOHWDU K (O
FRQWHQLGR GH 173 VH YDORUy PHGLDQWH +3/& $
SDUWLU GH ODV FDQWLGDGHV DFXPXODGDV HQ HO
FRPSDUWLPHQWRUHFHSWRUIUHQWHDOWLHPSRVHFDOFXOy
HOIOXMRGHSDVRGH173DWUDYpVGHODSLHO
5HVXOWDGRV
0LFURVFRSLD SRODUL]DGD 'XUDQWH HO HVWXGLR
PLFURVFySLFR UHDOL]DGR LQPHGLDWDPHQWH GHVSXpV
GHODHODERUDFLyQGHORVSDUFKHV\DORVGtDVGH
DOPDFHQDPLHQWR QR VH REVHUYy OD IRUPDFLyQ GH
FULVWDOHV HQ ORV SDUFKHV FRQ PDWUL] GH (9$ 6LQ
HPEDUJR OD SUHVHQFLD GH FULVWDOHV HV HYLGHQWH HQ
ORV SDUFKHV FRQ 3,% WUDVFXUULGRVGtDVGHVGH VX
HODERUDFLyQ (Q OD )LJXUD VH PXHVWUDQ ORV
SDUFKHVGH173FRQ3)GRGHFDQRO y cada
una de las matrices usadas para elaborarlos.
&216(59$17(
02
$
1&
1&
1&
1&
1&
1&
+/
1&
1&
1&
1&
1&
1&
$
1&
1&
1&
1&
1&
1&
+/
1&
1&
1&
1&
1&
1&
$
1&
1&
1&
1&
1&
1&
+
1&
1&
1&
1&
1&
1&
$
1&
1&
1&
1&
1&
1&
+/
1&
1&
1&
1&
1&
&72
8)& 8)&
&72 &72
8)&
&72 &72
8)&
&72 &72
8)&
&72 &72
8)&
&72 &72
8)&
&72 &72
8)&
&72 &72
8)&
&72 &72
8)&
&72 &72
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
$
+/
$
+/
$
+/
$
+/
$
+/
1&
1&
8)&
8)&
8)&
8)&
1&
1&
1&
1&
1&
1&
1&
1&
1&
1&
1&
7DEOD5HFXHQWRPLFURELROyJLFR3/2
3/2
7LHPSR
GtDV
7
ž&
&216(59$17(
02
$
1&
1&
1&
1&
1&
1&
+/
1&
1&
1&
1&
1&
1&
$
1&
1&
1&
1&
1&
1&
+/
1&
1&
1&
1&
1&
1&
$
1&
1&
1&
1&
1&
1&
+/
1&
1&
1&
1&
1&
1&
$
1&
1&
1&
1&
1&
1&
+/
1&
1&
1&
1&
1&
1&
$
&72
1&
1&
+/
&72
$
&72
+/
&72
$
&72
+/
&72
$
&72
+/
&72
$
&72
+/
&72
8)& 8)&
&72
8)&
&72
8)&
&72
8)&
&72
8)&
&72
8)&
&72
8)&
&72
8)&
&72
8)&
&72
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
8)&
1&
8)&
8)&
1&
1&
8)&
8)&
8)&
8)&
1&
1&
1&
1&
1&
1&
1&
1&
1&
6H FRQILUPD HO SRGHU LQKLELWRULR WRWDO GHO
FRQVHUYDQWH HPSOHDGR DO WDQWR SDUD HO
KLGURJHO FRPR SDUD 3/2 SHUR WDPELpQ SRGHPRV
DILUPDU TXH ODV IyUPXODV HVWXGLDGDV FXPSOHQ ORV
UHTXLVLWRV GH OD OHJLVODFLyQ YLJHQWH FXDQGR VH
DGLFLRQD FDQWLGDGHV LQIHULRUHV GH FRQVHUYDQWH
HQWRGRVORVFDVRVHQVD\DGRV\SDUDODV
IyUPXODV FRQVHUYDGDV D \ ž& WUDV GtDV R
ž&WUDQVFXUULGRVGtDVGHVGHVXHODERUDFLyQ
3DUDOHODPHQWHVHUHDOL]yHOFRQWUROPLFURELROyJLFR
GH OD IDVH ROHRVD QR REVHUYDQGR FRQWDPLQDFLyQ
DOJXQD D OR ODUJR GH WRGR HO HQVD\R (Q ORV
FRQWUROHV PLFURELROyJLFRV GH ODV GLIHUHQWHV
HVSHFLHVSDWyJHQDVORVUHVXOWDGRVIXHURQDXVHQFLD
WRWDOSDUDFDGDXQRGHHOORV
&RQFOXVLRQHV
/D HVWDELOLGDG PLFURELROyJLFD GHO JHO 3OXURQLF \
3/2 VH PDQWLHQH LQDOWHUDGD GXUDQWH TXLQFH GtDV D
ƒ&6LQHPEDUJRSDUDRSWLPL]DUODHVWDELOLGDGGH
DPEDV IRUPXODFLRQHV HQ HO SHULRGR GH HVWXGLR
HQVD\DGR OD FDQWLGDG PtQLPD QHFHVDULD GH
0LFURFDUH 07,Š IXH HQ UHIULJHUDFLyQ \ FXDQGRODVIyUPXODVVHDOPDFHQDQD\ž&
%LEOLRJUDItD
5XL]0$&ODUHV%0RUDOHV0(*DOODUGR9
3KDUPDFHXWLFDO'HYHORSPHQWDQG7HFKQRORJ\
+RIIPDQ 6% <RGHU $5 7UHSDQLHU /$ - 9HW
3KDUPDFRO7KHU
0XUGDP6+RVSLWDO3KDUPDFLVW
5HDO )DUPDFRSHD (VSDxROD  (G 0LQLVWHULR
GH 6DQLGDG \ &RQVXPR SS 0DGULG
7 7HPSHUDWXUD 02 0LFURRUJDQLVPRV $
$HURELRV +/ 0RKRV \ /HYDGXUDV 8)&
8QLGDGHVIRUPDGRUDVGHFRORQLDV
1&QRFUHFLPLHQWR&72!8)&
,;&RQJUHVRGHOD6(),*
$
$
%
)LJXUD )RWRJUDItDV D DXPHQWRV GH ORV SDUFKHV
WUDQVFXUULGRVGtDVGHVGHVXHODERUDFLyQ
$3DUFKH3)3,%%3DUFKH3)(9$.
(VWXGLRV GH SHUPHDFLyQ LQ 9LWUR /RV SHUILOHV GH
SHUPHDFLyQ GH 173 REWHQLGRV D SDUWLU GH ORV
GLIHUHQWHV SDUFKHV VH PXHVWUDQ HQ OD )LJXUD $
WtWXORGHFRPSDUDFLyQHQODILJXUDVHLQFOX\HQORV
YDORUHV GH IOXMR TXH VH REWXYLHURQ SUHYLDPHQWH D
SDUWLUGHSDUFKHVTXHVHHODERUDURQFRQXQDPDWUL]
GHTXLWRVDQRHPSOHDQGRORVPLVPRVSURPRWRUHV
/RV SDUFKHV SUHSDUDGRV FRQ OD PDWUL] GH (9$
UHWLHQHQ HQ JUDQ PHGLGD OD 173 \ GLILFXOWDQ VX
OLEHUDFLyQ
,QGHSHQGLHQWHPHQWH GH OD QDWXUDOH]D GH OD PDWUL]
ORV SDUFKHV TXH FRQWLHQHQ ORV SURPRWRUHV
3OXURQLF5)'RGHFDQROPRVWUDURQHOYDORU
GH IOXMR GH 173 PiV DOWR (O Pi[LPR YDORU GH
IOXMRORSUHVHQWyHOSDUFKHFRQODPDWUL]GH3,%\
GLFKRV SURPRWRUHV “ —JKFP
FRPSDUDGR FRQ WRGRV ORV GHPiV SDUFKHV
IRUPXODGRV (O SULQFLSDO SUREOHPD GH HVWRV
VLVWHPDV HV HO YDORU GHO SHULRGR GH ODWHQFLD WODJ
DOUHGHGRUGHK
&RQFOXVLRQHV
$SHVDUGHTXHVHREVHUYDFULVWDOL]DFLyQGHOD173
HQ ORV SDUFKHV FRQ 3,% pVWRV SHUPLWHQ XQ PD\RU
SDVR GH 173 D WUDYpV GH OD SLHO /D DGLFLyQ GH
SURPRWRUHV GH SHUPHDFLyQ LQFUHPHQWD HQ WRGRV
ORVFDVRVODSHUPHDFLyQGH173DWUDYpVGHODSLHO
/DFRPELQDFLyQGH3OXURQLF5)\GRGHFDQRO
FRPR SURPRWRUHV GH SHQHWUDFLyQ HV OD TXH
SURSRUFLRQDPHMRUHVUHVXOWDGRV
&
)LJXUD 3HUILOHV GH SHUPHDFLyQ GH 173 SDUD ORV
SDUFKHVGHVDUUROODGRV$0DWUL]GHTXLWRVDQR%0DWUL]
GH3,%\&0DWUL]GH(9$ŸSDUFKHVFRQ3)
GRGHFDQROŶSDUFKHV FRQ 3(*0( \ Ƈ SDUFKHV
FRQWURO
5HIHUHQFLDV
KWWSZZZFGFJRY7REDFFRVJUVJUB
3HWR5HWDO%0-±
$QWKRQLVHQ15HWDO$QQ,QWHUQ0HG±
3URFKD]ND$9HWDO$UFK,QWHUQ0HG±
$JUDGHFLPLHQWRV
/RV DXWRUHV DJUDGHFHQ D &RQVHOOHULD G¶(PSUHVD
8QLYHUVLWDW L &LqQFLD *HQHUDOLWDW 9DOHQFLDQD SRU HO
DSR\RILQDQFLHUR*9
-RVp -XDQ (VFREDU&KiYH] DJUDGHFH OD EHFD
352),381$0
GLVVROXWLRQ DSSDUDWXV GXULQJ K 'HLRQL]HG
ZDWHU PO DW “ž& ZDV XVHG DV
GLVVROXWLRQ PHGLXP DQG WDEOHWV ZHUH WHVWHG DW USP ,Q RUGHU WR REWDLQ D ULJRURXV UDGLDO UHOHDVH
WKH WDEOHWV ZHUH ORFNHG EHWZHHQ WZR WUDQVSDUHQW
3OH[LJODVVŠ GLVFV 'UXJ UHOHDVH GDWD
0W0’” ZHUH DQDO\VHG DFFRUGLQJ WR +LJXFKL
.RUVPH\HU DQG 3HSSDV DQG 6DKOLQ
HTXDWLRQV
)URQWV PRYHPHQW VWXG\ 0HWK\OHQH EOXH
ZY ZDV DGGHG WR WKH GLVVROXWLRQ
PHGLXP LQ RUGHU WR LPSURYH WKH YLVXDOLVDWLRQ RI
WKH GLIIHUHQW IURQWV 7KH H[SHULPHQW ZDV FDUULHG
RXW LQ GXSOLFDWH LQ WKH VDPH FRQGLWLRQV DV WKH
UDGLDOUHOHDVHVWXGLHV$WGHILQHGWLPH LQWHUYDOVWKH
GHYLFHV ZHUH UHPRYHG IURP WKH GLVVROXWLRQ
DSSDUDWXV DQG SKRWRJUDSKHG 7KH SKRWRV ZHUH
DQDO\VHGXVLQJ&RUHO'UDZŠ;6RIWZDUH
5HVXOWVDQGGLVFXVVLRQ
&RQFHUQLQJ
WDEOHW
HODERUDWLRQ
+30&
GHULYDWLYHV VKRZHG KLJKHU SODVWLFLW\ DQG
HDVLHU WDEOHW HODERUDWLRQ WKDQ +&00$ %HWZHHQ
WKH FRPPHUFLDO SRO\PHUV +30& (0 SUHVHQWHG
WKH ZRUVH FRPSUHVVLRQ FKDUDFWHULVWLFV 7KH
LVRGLDPHWULFDOVKDSHRI+30&(0SDUWLFOHVOHVV
SURQHWRIUDJPHQWDWLRQFRXOGH[SODLQWKHVHUHVXOWV
7KH FRPELQDWLRQ RI WZR SRO\PHUV LQ WKH
PL[WXUHV GHFUHDVHG WKH DSSOLHG SUHVVXUH DQG
LQFUHDVHG WKH SODVWLFLW\ YDOXHV FRPSDUHG ZLWK
+&00$ ,Q WKH PL[WXUHV ZLWK 2'
+&00$ WKH SODVWLFLW\ SDUDPHWHU LQFUHDVHG LWV
YDOXH XQWLO UDWLR NHHSLQJ WKHQ FRQVWDQW
+RZHYHU VLPLODU YDOXHV ZHUH IRXQG IRU PL[WXUHV
ZLWK)'+&00$DWDOOUDWLRV0L[WXUHVZLWK)'
+&00$ QHHGHG OHVV SUHVVXUH DQG ZHUH PRUH
SODVWLF WKDQ 2'+&00$ PL[WXUHV $W VDPH
SHUFHQWDJH +30& (0 PL[WXUHV VKRZHG ZRUVH
FRPSUHVVLRQFKDUDFWHULVWLFVWKDQ+30&
.0DQG)0LQDJUHHPHQWZLWKWKHLULQGLYLGXDO
EHKDYLRXU
0HUFXU\ SRURVLPHWU\ PHDVXUHPHQWV UHYHDOHG
WKDWLQJHQHUDOWKHPDWULFHVSUHVHQWHGPHVRSRUHV
.0 DQG )0 PDWULFHV SUHVHQWHG KLJKHU
SRURVLW\ PHDQ SRUH GLDPHWHU DQG PHGLDQ SRUH
GLDPHWHU WKDQ +&00$ RQHV +30& (0
VKRZHG ORZHU SRURVLW\ WKDQ )'+&00$ DQG
KLJKHU WKDQ WKH 2' GHULYDWLYH :KHQ +&00$
SHUFHQWDJH GHFUHDVHG WKH SRURVLW\ RI WKH WDEOHWV
LQFUHDVHG
+LJKHUSHUFHQWDJHVRIGUXJUHOHDVH ZHUHREVHUYHG
IRU 2'+&00$ PDWULFHV FRPSDUHG ZLWK )'
WDEOHWV )LJ +30& (0 VKRZHG D UHOHDVH
7HFQRORJtD)DUPDFpXWLFD
/,3,'1$123$57,&/(62)('(/)26,1($675$7(*<72,03529(,7625$/
%,2$9$,/$%,/,7<
$(VWHOOD+HUPRVRGH0HQGR]D0$&DPSDQHUR)0ROOLQHGR0-%ODQFR3UtHWR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLW\RI1DYDUUD(
6SDLQ
DHVWHOOD#DOXPQLXQDYHV
6HUYLFLRGH)DUPDFRORJtD&OtQLFD&OtQLFD8QLYHUVLWDULD(3DPSORQD6SDLQ
&HQWURGH,QYHVWLJDFLyQGHO&iQFHU,QVWLWXWRGH%LRORJtD0ROHFXODU\&HOXODUGHO&iQFHU&6,&
8QLYHUVLGDGGH6DODPDQFD(6DODPDQFD6SDLQ
,QWURGXFWLRQ (GHOIRVLQH LV WKH SURWRW\SH RI WKH
JURXS RI SKRVSKROLSLG DQDORJXHV FDOOHG DON\O
O\VRSKRVSKROLSLGV $/3 ZKLFK UHSUHVHQWV D
SURPLVLQJ FODVV RI DQWLWXPRU DJHQWV >@ ZLWK
OLPLWHG VLGH HIIHFWV EXW SUHVHQWLQJ D ORZ RUDO
ELRDYDLODELOLW\ DQG ORZ HGHOIRVLQH WLVVXH OHYHOV
DIWHURUDODGPLQLVWUDWLRQWRUDWV>@
,Q DQ DWWHPSW WR LQFUHDVH WKH ELRDYDLODELOLW\ RI
GUXJVGHOLYHU\V\VWHPVKDYHEHHQGHYHORSHGVXFK
DV OLSLG QDQRSDUWLFOHV >@ 7KHVH OLSLG
QDQRSDUWLFOHV KDYH VKRZQ WR LQFUHDVH WKH RUDO
DEVRUSWLRQ RI GLIIHUHQW GUXJV DQG WR SURYLGH RI D
VXVWDLQHGUHOHDVHRIGUXJVRYHUWKHWLPH>@
7KHUHIRUHWKHDLPRIWKLVZRUNZDVWRVWXG\WKH
SKDUPDFRNLQHWLF EHKDYLRXU RI HGHOIRVLQH LQ PLFH
DQG WR GHYHORS OLSLG QDQRSDUWLFOHV PDGH RI
&RPSULWROŠ RU VWHDULF DFLG DV FDQGLGDWHV WR
LPSURYHRUDOHGHOIRVLQHDEVRUSWLRQ
0DWHULDOVDQG0HWKRGV
$QLPDOV
)HPDOH %$/%F PLFH ZHUH REWDLQHG IURP
+DUODQ ,QWHUIDXQD ,EpULFD 6/ %DUFHORQD 6SDLQ
$QLPDOV NHSW DQG KDQGOHG DFFRUGLQJ WR
LQVWLWXWLRQDO JXLGHOLQHV FRPSO\LQJ ZLWK 6SDQLVK
OHJLVODWLRQ
$Q HGHOIRVLQH VROXWLRQ ȝJ ZDV
DGPLQLVWHUHGWRPLFHQ E\RUDORULQWUDYHQRXV
URXWH %ORRG VDPSOHV ZHUH FROOHFWHG DW DQG K DIWHU DGPLQLVWUDWLRQ LQ ('7$ VXUIDFH±
FRDWHGWXEHVDQGWKHQFHQWULIXJHGDW[JIRU
PLQ ž& WR VHSDUDWH WKH SODVPD $IWHU
FHQWULIXJDWLRQ WKH SODVPD REWDLQHG ZDV VWRUHG DW
íƒ&XQWLODQDO\VLV
4XDQWLILFDWLRQ ZDV DFKLHYHG E\ XVLQJ D VOLJKWO\
PRGLILHG+3/&±06PHWKRGSUHYLRXVO\GHYHORSHG
>@
3KDUPDFRNLQHWLFDQDO\VLV
7KH SODVPD FRQFHQWUDWLRQ GDWD ZHUH DQDO\]HG
E\ QRQFRPSDUWLPHQWDO DQG FRPSDUWLPHQWDO
DQDO\VLV XVLQJ :LQ1RQOLQ 3URIHVVLRQDO (GLWLRQ
9HUVLRQ 3KDUVLJKW 0RXQWDLQ 9LHZ &$
86$
3UHSDUDWLRQRIOLSLGQDQRSDUWLFOHV
/LSLG QDQRSDUWLFOHV ZHUH SUHSDUHG E\ WKH
VLPSOH HPXOVLRQ VROYHQW HYDSRUDWLRQ PHWKRG
%ULHIO\ HGHOIRVLQH ZDV GLVVROYHG LQ DQ RUJDQLF
VROYHQWOLNHFKORURIRUP7&0FRQWDLQLQJWKHOLSLG
&RPSULWROŠ RU VWHDULF DFLG DQG HPXOVLILHG E\
VRQLFDWLRQ VHFRQGV ZLWK DQ DTXHRXV
VROXWLRQ RI VWDELOL]LQJ DJHQW 7ZHHQŠ 7KH
UHVXOWLQJHPXOVLRQZDVPDJQHWLFDOO\VWLUUHGIRU
PLQXWHV DQG WKHQ VXEMHFWHG WR URWDYDSRU IRU PLQXWHV WR FRPSOHWHO\ HYDSRUDWH WKH RUJDQLF
VROYHQW3DUWLFOHVZHUHFHQWULIXJHGDW[JIRU
PLQXWHVXVLQJDQ$PLFRQ8OWUD±ILOWHUGHYLFH
DQG ZDVKHG WZLFH ZLWK GLVWLOOHG ZDWHU 7KH
REWDLQHG SDUWLFXODU VXVSHQVLRQ ZDV IDVW IUR]HQ
XQGHU±ž&IRUDW OHDVW KRXUV IUHH]HGULHGDQG
VWRUHGDWž&
&KDUDFWHUL]DWLRQRIOLSLGQDQRSDUWLFOHV
6L]H RI SDUWLFOHV ZDV PHDVXUHG E\ SKRWRQ
FRUUHODWLRQ VSHFWURVFRS\ 3&6 XVLQJ D =HWDVL]HU
1DQR 0DOYHUQ ,QVWUXPHQWV 8. 6XUIDFH FKDUJH
ZDVPHDVXUHGXVLQJWKHVDPHHTXLSPHQWGHVFULEHG
SUHYLRXVO\ ZLWK D FRPELQDWLRQ RI ODVHU 'RSSOHU
YHORFLPHWU\ )RU HGHOIRVLQH TXDQWLILFDWLRQ PJ
RI QDQRSDUWLFOH IUHH]HGULHG SRZGHU ZHUH
GLVVROYHG LQ PO RI FKORURIRUP DQG WKHQ PL[HG
ZLWK PO RI XOWUD SXUH ZDWHU 7KH PL[WXUH ZDV
YRUWH[HGIRUPLQXWHDQGWKHQFHQWULIXJHGDW
[JIRUPLQXWHV7KHVXSHUQDWDQW ZDVDQDO\VHG
DVGHVFULEHGDERYH>@
5HVXOWVDQG'LVFXVVLRQ3KDUPDFRNLQHWLFDQDO\VLV
RI HGHOIRVLQH LQ EORRG SODVPD VKRZHG D &PD[ RI
“ ȝJPO DQG D &PLQ RI “ ȝJPO KRXUV DIWHU LQWUDYHQRXV DGPLQLVWUDWLRQ RI D VLQJOH
GRVH RI ȝJ >@7KH $8& YDOXH DVVRFLDWHG WR
WKLVSURILOHZDVȝJÂKO
(GHOIRVLQHH[KLELWHGELH[SRQHQWLDOHOLPLQDWLRQ
ZLWKDWĮYDOXHRIKRXUVLQGLFDWLQJDUDSLG
GLVWULEXWLRQ WR FHQWUDO FRPSDUWPHQW WLVVXHV
ZKHUHDV D VORZHU GLVWULEXWLRQ WR GHHS
FRPSDUWPHQWV ZDV DSSUHFLDWHG Wȕ YDOXH RI KRXUV0HDQUHVLGHQFHWLPHRIIUHHHGHOIRVLQHZDV
KRXUV
)LJXUHGHSLFWVWKHFRQFHQWUDWLRQRIHGHOIRVLQHLQ
PRXVHSODVPDSORWWHGDJDLQVWWLPH
+30& WKHUH ZHUH QR FKDQJHV LQ ZDWHU XSWDNH
IURQWVFRPSDUHGWR+30&PDWULFHV(URVLRQ
IURQWV LQFUHDVHG IRU DOO PL[WXUHV ZKHQ WKH
SURSRUWLRQ RI +&00$ GHFUHDVHG 7KH KLJKHVW
GLIIHUHQFHVZHUHREVHUYHGIRUWKHSURSRUWLRQ
)LJ &RQFHUQLQJ WKH VXEVWLWXWLRQ GHJUHH WKH
ORZHVW DGYDQFH RI HURVLRQ IURQW LQ (0 PL[WXUHV
ZDV LQ DJUHHPHQW ZLWK LWV KLJKHVW UHOHDVH 2QO\
.0 PL[WXUHV VKRZHG D GLIIXVLRQ IURQW WKDW
PRYHGRXWZDUGVZKHUHDV(0DQG)0GLIIXVLRQ
IURQW PRYHG LQZDUGV WKDW LPSOLHV WKDW WKH
IRUPDWLRQRIFOHDUJHOZDVTXLFNHULQWKHODWWHUV
3
ODK4M EROSION
2
Fronts movement (mm)
ODK4M DIFFUSION
ODK4M WATER UPTAKE
1
ODE4M EROSION
0
ODE4M DIFFUSION
ODE4M WATER UPTAKE
-1
ODF4M EROSION
ODF4M DIFFUSION
-2
ODF4M WATER UPTAKE
-3
0
100
200
300
400
500
Time (min)
600
700
)LJXUH)URQWVPRYHPHQWIURP2'+&00$+30&
&RQFOXVLRQ
7KH UHVXOWV RI WKLV VWXG\ FRQILUP WKH SRVVLELOLW\
RI PRGXODWLRQ RI WKHRSK\OOLQH UHOHDVH E\ PL[LQJ
WZR SRO\PHUV ZLWK GLIIHUHQW UHOHDVH PHFKDQLVP
)RU WKLV PRGXODWLRQ WKHVH PL[WXUHV QHHG HLWKHU
DERYH RI +&00$ RU KLJK K\GUR[\SURS\O
JURXSVGLIIHUHQFHVRI+30&LQWKHPL[WXUHV)0
RU(0.0
$FNQRZOHGJHPHQWV
7KLV ZRUN KDV EHHQ VXSSRUWHG E\ D )3, JUDQW
IURP WKH 6SDQLVK *RYHUQPHQW DQG ZDV SDUW RI D
SURMHFW 0$7 IURP WKH 6SDQLVK
0LQLVWU\RI6FLHQFHDQG7HFKQRORJ\
5()(5(1&(6
0HOLD&'&ULW5HY7KHU'UXJ&DUULHU6\VWHPV
(VFXGHUR-HWDO,QW-3KDUP
&DVWHOODQR,HWDO&DUERK\G3RO\P
%HWWLQL5HWDO(XU-3KDUP6FL
+LJXFKL7-3KDUP6FL
.RUVPH\HU5:HWDO,QW-3KDUP
3HSSDV1$DQG6DKOLQ-,QW-3KDUP
)HUUHUR&HWDO-&RQWURO5HO
%RQIHURQL0&HWDO6733KDUPD6FL
*XVWDIVVRQ&+HWDO(XU-3KDUP6FL
)RUG-/,QW-3KDUP
WKHRSK\OOLQHGLVVROYHG
,QWURGXFWLRQ
+30&V DUH FHOOXORVH HWKHUV IUHTXHQWO\ XVHG WR
SURYLGH D FRQWUROOHG UHOHDVH RI GUXJV IURP PDWUL[
WDEOHWV 7KH SRVVLELOLW\ RI PRGXODWLRQ RI
WKHRSK\OOLQHUHOHDVHE\PL[LQJ+30&RIGLIIHUHQW
YLVFRVLW\ JUDGHV ZLWK D QHZ JHQHUDWLRQ RI LQHUW
FRSRO\PHUV ZDV GHPRQVWUDWHG LQ D SUHYLRXV ZRUN
%RWK WKH VZHOOLQJ FKDUDFWHULVWLFV DQG WKH
SRURXV VWUXFWXUH RI WKH PDWULFHV ZHUH IRXQG WR
KDYH D GRPLQDQW UROH LQ WKH GUXJ UHOHDVH
PHFKDQLVP
7KH DLP RI WKH SUHVHQW ZRUN LV WR HYDOXDWH WKH
WHFKQRORJLFDO SURSHUWLHV DQG GUXJ UHOHDVH
EHKDYLRXU RI PDWUL[ WDEOHWV FRPELQLQJ +30& RI
GLIIHUHQW VXEVWLWXWLRQ GHJUHHV K\GURSKLOLF SRO\
PHU DQG K\GUR[\SURS\OFHOOXORVHPHWK\O PHWKD
FU\ODWH +&00$ LQHUW SRO\PHU $WWHQWLRQ ZLOO
EHIRFXVHGRQWKHLQIOXHQFHRIDSRO\PHUW\SHE
UDWLRRIWZRSRO\PHUVLQWKHWDEOHWVFVXEVWLWXWLRQ
GHJUHHRI+30&
0DWHULDOVDQGPHWKRGV
0DWHULDOV
+30& 0HWKRFHOŠ .0 (0 DQG )0
&RORUFRQZDVVHOHFWHGDVVZHOODEOHSRO\PHU7KH
FRSRO\PHU V\QWKHVLVHG E\ IUHH UDGLFDO
FRSRO\PHULVDWLRQ RI PHWK\O PHWKDFU\ODWH 00$
DQG K\GUR[\SURS\OFHOOXORVH +& ZDV VHOHFWHG DV
LQHUW SRO\PHU 7KH SURGXFW +&00$ ZDV GULHG
HLWKHULQDYDFXXPRYHQ2'RUIUHH]HGULHG)'
7KH2'SURGXFWZDVFUXVKHGLQDNQLYHVPLOO
WRREWDLQSRZGHU\VDPSOHV
$QK\GURXV WKHRSK\OOLQH ZDV FKRVHQ DV PRGHO
GUXJDQG6WHDULFDFLGZDVVHOHFWHGDVOXEULFDQW
0HWKRGV
0DWUL[ WDEOHW SUHSDUDWLRQ 7KHRSK\OOLQH ZZ DQG H[FLSLHQWV ZZ RI
+&00$+30& DW RU
UDWLRV ZHUH PL[HG IRU PLQ XVLQJ D
GRXEOHFRQH PL[HU DW USP $IWHU WKH DGGLWLRQ
RI VWHDULF DFLG ZZ WKH PL[LQJ SURFHGXUH
ZDV FRQWLQXHG IRU D IXUWKHU PLQ 7KH PL[WXUHV
ZHUHFRPSUHVVHGLQDQLQVWUXPHQWHGVLQJOHSXQFK
WDEOHWPDFKLQHHTXLSSHGZLWKPPIODW
IDFHGSXQFKHVWRREWDLQWDEOHWV ZHLJKLQJ PJ
DQGZLWKDFUXVKLQJIRUFHRI1
0HUFXU\SRURVLPHWU\PHDVXUHPHQWV
0HUFXU\SRURVLPHWU\UXQVZHUHXQGHUWDNHQXVLQJ
DQ $XWRSRUH ,9 SRURVLPHWHU ZRUNLQJ
SUHVVXUHVSVLZLWKDFFSHQHWURPHWHU
$ TXDQWLW\ RI VDPSOH ZDV LQFOXGHG LQ RUGHU WR
REWDLQRIPHUFXU\LQWUXVLRQ
'UXJUHOHDVHVWXG\5HOHDVHH[SHULPHQWVWKUHH
WDEOHWV ZHUH SHUIRUPHG LQ DQ DXWRPDWLF
SURILOH EHWZHHQ 2' DQG )'+&00$ ZKHUHDV
+30&.0DQG)0WDEOHWVGLVSOD\HGWKHORZHVW
UHOHDVH ,W VHHPV DSSDUHQW WKDW WKH UDWLR EHWZHHQ
PHWKR[\O DQG K\GUR[\SURS\O VXEVWLWXWLRQ LQ
+30& PD\ QRW DOZD\V EH UHSUHVHQWDWLYH RI WKH
GUXJUHOHDVHEHKDYLRXU
$VWKHFRQWHQWRI+&00$LQWKHPL[WXUHVZDV
UHGXFHG WKH DELOLW\ WR FRQWURO GUXJ UHOHDVH
LQFUHDVHG PDLQO\ IURP WR UDWLR )LJ
0L[WXUHVZLWK+30&(0DQG.0EHKDYHG
VLPLODUO\ DQG WKH PDMRU GLIIHUHQFHV ZHUH VHHQ IRU
PL[WXUHV ZLWK +30& )0 ZKLFK DOZD\V
SUHVHQWHG WKH VORZHVW WKHRSK\OOLQH UHOHDVH LQ
DJUHHPHQW ZLWK LWV ORZHVW K\GURSKLOLFLW\ 7KH
GLIIHUHQFHV ZHUH PRUH QRWLFHDEOH DW KLJKHU
SURSRUWLRQV RI +&00$ VKRZLQJ WKH KLJKHVW
UHOHDVH2'+&00$ZLWK(0DQG.0
'DWDILWWLQJ WRNLQHWLFHTXDWLRQVUHYHDOHGDGUXJ
UHOHDVH PHFKDQLVP FRQWUROOHG PDLQO\ E\ GLIIXVLRQ
IRU +&00$ PDWULFHV KRZHYHU +30&
DQG WKH PL[WXUHV VKRZHG D GUXJ UHOHDVH
PHFKDQLVPWKDWFRPELQHGLIIXVLRQDQGUHOD[DWLRQ
.0 DQG )0 W\SHV VKRZHG VLPLODU NG YDOXHV
+RZHYHUWKHODWHVWVKRZHGWKHVORZHVWNUYDOXHLQ
DJUHHPHQW ZLWK WKH VORZHVW WKHRSK\OOLQH UHOHDVH
(0 VKRZHG WKH KLJKHVW NU YDOXH DFFRUGLQJ WR LWV
ZRUVH FRPSUHVVLRQ SURSHUWLHV EHFDXVH WKH
PHWKR[\OVXEVWLWXHQWFRQWHQWPD\KDYHDQLQGLUHFW
LQIOXHQFH RYHU WKH SDUWLFOH FKDUDFWHULVWLFV RI WKH
SRZGHUV ZKLFK LQ WXUQ PD\ DIIHFW WKHLU
FRPSDFWLRQ EHKDYLRXU DQG VXEVHTXHQW GUXJ
UHOHDVH ,Q WKH PL[WXUHV WKH NG YDOXHV
UHPDLQHG PRUH RU OHVV VLPLODU WR +30& 7KH PRVW LPSRUWDQW FKDQJHV ZHUH IRXQG LQ NU
YDOXHV$OOPL[WXUHVZLWK)0GLGQRWPRGLI\WKLV
SDUDPHWHU UHVSHFW WR )0 LQ FRQFRUGDQFH
ZLWK WKH ORZHVW WKHRSK\OOLQH UHOHDVH ,Q JHQHUDO
WKHPL[WXUHVZLWK(0SUHVHQWHGVLPLODUNUYDOXHV
WR(0EXWPL[WXUHVZLWK.0VKRZHGWKH
KLJKHVWNUYDOXHVZKLFKGHFUHDVHGZKHQ+&00$
SURSRUWLRQGHFUHDVHG
)URQWV PRYHPHQW NLQHWLFV IRU +&00$ ZHUH GHVFULEHG LQ D SUHYLRXV SDSHU 1R
LPSRUWDQWGLIIHUHQFHVFRXOGEHVHHQLQWKHHURVLRQ
IURQWV IRU WKH WKUHH VZHOODEOH PDWULFHV WHVWHG
6LPLODUO\ WR )RUG HW DO GLIIHUHQFHV ZHUH QRW
IRXQGLQZDWHUXSWDNHRI+30&.0
WKHRSK\OOLQHGLVVROYHG
'58*5(/($6(.,1(7,&6$1')52176029(0(17678',(6)5200$75,&(6
&20%,1,1*6:(//$%/($1',1(5732/<0(56())(&72)+30&:,7+
',))(5(17'(*5((62)68%67,787,21
--(VFXGHUR&)HUUHUR05-LPpQH]&DVWHOODQRV
'SWR)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6HYLOOD
&3URIHVRU*DUFtD*RQ]iOH]Qž6HYLOOD6SDLQ
,;&RQJUHVRGHOD6(),*
2'+&00$
7LPHPLQ
)'+&00$
.0
(0
)0
2'.0
2'(0
7LPHPLQ
2')0
)'.0
)'(0
)')0
)LJXUH5HOHDVHSURILOHVIURPPL[WXUHVOHIWDQG
+&00$+30&PL[WXUHVULJKW
(0 DQG )0 7KH GLIIXVLRQ IURQW ZDV GLIIHUHQW
IRU +30& .0 ZKLFK PRYHG RXWZDUGV VORZO\
ZLWK WLPH )RU WKH GLIIHUHQW PL[WXUHV +&00$
,;&RQJUHVRGHOD6(),*
80
70
&RQFHQWUDWLRQXJP/
7HFQRORJtD)DUPDFpXWLFD
Intravenous administration
Oral administration
60
50
40
30
20
10
0
0
5
10
15
20
25
7LPHK
)LJXUH 7LPHFRQFHQWUDWLRQ FXUYH GDWD RI
HGHOIRVLQH DIWHU DGPLQLVWUDWLRQ RI ȝJ RI
HGHOIRVLQHQ 0HDQ“6'
7KHVWHDG\VWDWHYROXPHRIGLVWULEXWLRQ9VVRI
WKHGUXJZDVONJDSSUR[LPDWHO\WZRIROGWKDW
RI WKH WRWDO ERG\ ZDWHU RI D PRXVH VXJJHVWLQJ D
PRGHUDWHH[WUDYDVFXODUGLVWULEXWLRQRIWKHGUXJ
(GHOIRVLQHVKRZHGYHU\ORZFOHDUDQFHYDOXHVLQ
PLFH FRPSDUHG WR LWV UHVSHFWLYH OLYHU DQG NLGQH\
EORRGIORZ,WLVLQWHUHVWLQJWRQRWHWKDWWKLVYDOXH
RI /KNJ LV WUDQVODWHG EDUHO\ WR RI WKH
OLYHUEORRGIORZVXJJHVWLQJDPXFKORZHUKHSDWLF
LQWULQVLFFOHDUDQFHYDOXH
5HJDUGLQJ WKH RUDO URXWH YHU\ ORZ
FRQFHQWUDWLRQ RI HGHOIRVLQH FRXOG EH IRXQG LQ
SODVPDKDIWHURUDODGPLQLVWUDWLRQRIȝJRI
DQ HGHOIRVLQH VROXWLRQ )LJ 7KH $8& YDOXH
DVVRFLDWHG WR WKLV SURILOH ZDV ȝJÂKO 7KH
ELRDYDLODELOLW\)RIHGHOIRVLQHZDV
,Q RUGHU WR LQFUHDVH WKLV ELRDYDLODELOLW\ OLSLG
QDQRSDUWLFOHV FRQWDLQLQJ HGHOIRVLQH ZHUH SUHSDUHG
E\ WKH VLPSOH HPXOVLRQ VROYHQW HYDSRUDWLRQ
PHWKRG>@
7DEOH &KDUDFWHUL]DWLRQ RI OLSLG QDQRSDUWLFOHV
SUHSDUHG E\ VLPSOH HPXOVLRQ VROYHQW HYDSRUDWLRQ
PHWKRG
Lipid
Size (nm)
Zeta Potential
(mV)
Encapsulation
efficiency (%)
Stearic acid
312 ± 7.51
-32.4
17.10
Compritol
372 ± 18.84
-32.3
84.35
7DEOH VKRZV WKDW DOO SDUWLFOHV SUHVHQWHG D
KRPRJHQRXVVL]HDQGQHJDWLYHVXUIDFHFKDUJH6L]H
ZDV FRQILUPHG ZLWK $WRPLF )RUFH 0LFURVFRS\
LPDJLQJ )LJ 7KH KLJKHVW HQFDSVXODWLRQ
HIILFLHQF\ ZDV DFKLHYHG ZLWK &RPSULWROŠ
QDQRSDUWLFOHV
)LJXUH $WRPLF )RUFH 0LFURVFRS\ LPDJH RI
&RPSULWROŠOLSLGQDQRSDUWLFOHV
7KHKLJKHQFDSVXODWLRQHIILFLHQF\REWDLQHGZLWK
&RPSULWROŠ QDQRSDUWLFOHV LQ FRPSDULVRQ WR WKH
VWHDULFDFLGQDQRSDUWLFOHVLVOLNHO\WREHGXHWRWKH
SDUWLDOO\DPRUSKRXVVWDWHRIWKH&RPSULWROŠLQWKH
IRUPXODWLRQ ZKLFK DOORZV PRUH HGHOIRVLQH WR EH
LQFRUSRUDWHG DPRQJ OLSLG FKDLQV 7KLV VWDWHPHQW
FRXOG EH GHGXFHG IURP '6& DQG ;UD\
GLIIUDFWRPHWU\VWXGLHV>@
&RQFOXVLRQ (GHOIRVLQH SUHVHQWV D YHU\ ORZ
ELRDYDLODELOLW\ DW D VLQJOH RUDO GRVH RI ȝJ
&RQVHTXHQWO\ OLSLG QDQRSDUWLFOHV FRQWDLQLQJ
HGHOIRVLQH ZHUH GHYHORSHG DQG DUH XQGHU LQ YLYR
HYDOXDWLRQ1DQRSDUWLFOHVZHUHDGPLQLVWHUHGRUDOO\
DQG LQWUDYHQRXVO\ WR PLFH DQG ELRDYDLODELOLW\ RI
WKHYHFWRUL]HGGUXJZLOOEHGHWHUPLQHG
5HIHUHQFHV
>@ & *DMDWH ) 0ROOLQHGR &XUU 'UXJ 0HWDE >@ - .RWWLQJ HW DO 3URJ ([S 7XPRU 5HV >@5&DYDOOLHWDO-3KDUP6FL
>@ : 0HKQHUW . 0DGHU $GY 'UXJ 'HOLY 5HY
>@ $ (VWHOOD+HUPRVR GH 0HQGR]D HW DO (XU -
3KDUP%LRSKDUP
>@ . 0DQMXQDWK 9 9HQNDWHVZDUOX - 'UXJ
7DUJHW
>@ 0- %ODQFR3ULHWR HW DO - &KURPDWRJU %
$QDO\W7HFKQRO%LRPHG/LIH6FL
>@ $ (VWHOOD+HUPRVR GH 0HQGR]D HW DO &OLQ
&DQFHU5HVDFFHSWHG
$FNQRZOHGJHPHQWV 7KH DXWKRUV WKDQN
³)XQGDFLyQ &DMD 1DYDUUD´ WKH ³0LQLVWHULR GH
&LHQFLD H ,QQRYDFLyQ´ 3&7
6$) DQG WKH ³*RELHUQR 9DVFR
'HSDUWDPHQWR GH (GXFDFLyQ %),´ IRU WKHLU
ILQDQWLDOVXSSRUW
7HFQRORJtD)DUPDFpXWLFD
,;&RQJUHVRGHOD6(),*
02'(/,=$&,21'(/$0,&52(6758&785$'(3(/(76$3$57,5'('$726'(
32526,0(75,$'(,17586,21'(0(5&85,2
7DEOD 9DORUHV GH ORV SDUiPHWURV TXH GHILQHQ ODV FHOGDV XQLGDG GH ORV SHOHWV HVWLPDGRV XWLOL]DQGR HO VRIWZDUH 3RUH&RU70 \
WLHPSRVPHGLRVGHGLVROXFLyQGHWHRILOLQDREWHQLGRVDSDUWLUGHORVSHUILOHVGHFHVLyQGHORVSHOHWV'DWRVWRPDGRVGH
$*yPH]&DUUDFHGR&$OYDUH]/RUHQ]R50DUWtQH]3DFKHFR$&RQFKHLUR-/*yPH]$PR]D
/RWH
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DQWLDJR
GH&RPSRVWHOD&DPSXV8QLYHUVLWDULR6XUVQ6DQWLDJRGH&RPSRVWHOD
HPDLOMRVHOXLVJRPH]DPR]D#XVFHV
6H HODERUDURQ SHOHWV SRU H[WUXVLyQ
HVIHURQL]DFLyQ GH PH]FODV GH WHRILOLQD FDUERSRO30&&ODFWRVD
FyGLJR / \ RWURV GH FRPSRVLFLyQ VLPLODU
UHHPSOD]DQGR OD ODFWRVD SRU '&3 FyGLJR )
3RUFLRQHV GHO PDWHULDO HVIHURQL]DGR VH VHFDURQ
DHQHVWXIDGHDLUHFDOLHQWHž&K±ORWHV
/\)ESRUOLRILOL]DFLyQSUHYLDFRQJHODFLyQ
OHQWD ž& K ORWHV / \ ) R F SRU
OLRILOL]DFLyQ SUHYLD FRQJHODFLyQ UiSLGD SRU
LQPHUVLyQ HQ QLWUyJHQR OtTXLGR ž& ±ORWHV
/ \ ) (Q XQ WUDEDMR DQWHULRU VH GHVFULEH
GHWDOODGDPHQWH OD PHWRGRORJtD XWLOL]DGD SDUD
FDUDFWHUL]DU OD JUDQXORPHWUtD OD GLVWULEXFLyQ GH
WDPDxRVGHSRURHO YROXPHQ SRURVR \ ORV SHUILOHV
GHFHVLyQGHWHRILOLQD
0RGHOL]DFLyQGHODHVWUXFWXUDPLFURSRURVD
6H
XWLOL]y
HO
VRIWZDUH
3RUH&RU70
(QYLURQPHQWDO DQG )OXLG 0RGHOOLQJ *URXS
8QLYHUVLW\ RI 3O\PRXWK 8. SDUD PRGHOL]DU OD
HVWUXFWXUD SRURVD FRPR XQD VHULH GH FHOGDV
XQLGDG LQWHUFRQHFWDGDV &DGD FHOGD XQLGDG HVWi
FRQVWLWXLGDSRUQRGRV[[QRGRVHQ
ODV GLPHQVLRQHV [ \ ] (Q FDGD QRGR VH
SRVLFLRQDQSRURVF~ELFRVTXHVHFRQHFWDQHQWUH
Vt SRU SRURV FLOtQGULFRV GH PHQRU WDPDxR
HVWUDQJXODPLHQWRV $ SDUWLU GH ODV FXUYDV
DFXPXODGDV GH 3,0 FRUUHVSRQGLHQWHV D ORV
HVSDFLRV YDFLRV LQWUDJUDQXODUHV \ KDFLHQGR XVR
GH XQ DOJRULWPR VLPSOH[ VH HVWLPDURQ \
RSWLPL]DURQ VLPXOWiQHDPHQWH OD FRQHFWLYLGDG
Q~PHURPHGLRGHHVWUDQJXODPLHQWRVSRUSRUR
HO VHVJR GH SRUR SRUH VNHZ R IDFWRU GH HVFDOD
TXH DGDSWD HO WDPDxR GH ORV SRURV \ GH ORV
HVWUDQJXODPLHQWRVSDUDDMXVWDUORVDODSRURVLGDG
H[SHULPHQWDO \ HO QLYHO GH FRUUHODFLyQ TXH
DMXVWD OD DXWRFRUUHODFLyQ ORFDO HQWUH SRURV \
HVWUDQJXODPLHQWRV \ TXH YDUtD HQWUH ±
HVWUXFWXUDDOHDWRULD\±RUGHQDFLyQHQODFHOGD
XQLGDG(VWRVSDUiPHWURVSHUPLWHQJHQHUDUXQD
FHOGD XQLGDG FRQ XQDV SURSLHGDGHV GH
SHUFRODFLyQ SUy[LPDV D ODV UHDOHV HVWLPDGDV D
SDUWLUGHORVGDWRVGH3,0
$ SDUWLU GH ODV HVWUXFWXUDV PRGHOL]DGDV VH
HVWLPDURQORVVLJXLHQWHVSDUiPHWURV
• 'LiPHWUR GH SHQHWUDFLyQ YDORU PiV DOWR GHO
GLiPHWURGHORVHVWUDQJXODPLHQWRVTXHSHUPLWH
DFFHGHU D WRGRV ORV SRURV VLWXDGRV HQ XQD
FHOGDXQLGDG
• 7RUWXRVLGDG UHODFLyQ HQWUH OD GLVWDQFLD TXH
KD\ TXH UHFRUUHU SDUD DWUDYHVDU XQD FHOGD
XQLGDGHQODGLUHFFLyQGHOHMH]\HOWDPDxRGH
ODFHOGDXQLGDG3DUDFDGDFHOGDVHVLPXODURQ
UHFRUULGRV
• 3HUPHDELOLGDGDSWLWXGGHXQPDWHULDOSDUDVHU
DWUDYHVDGRSRUXQIOXLGR6HVLPXODHOSDVRGH
OtTXLGR D WUDYpV GH OD FHOGD XQLGDG HQ OD
GLUHFFLyQGHOHMH]
5HVXOWDGRV\GLVFXVLyQ
(Q OD ILJXUD VH SUHVHQWDQ FXUYDV GH LQWUXVLyQ
DFXPXODGDV GH ORV SHOHWV / REWHQLGDV D SDUWLU
GHORVGDWRVGH3,0\VLPXODGDVXWLOL]DQGRHO
SURJUDPDGHPRGHOL]DFLyQ
Volumen intruído, %
/
/
/
)
)
)
100
&RQHFWLYLGDG
6HVJRGH
SRUR
1LYHOGH
FRUUHODFLyQ
3HUPHDELOLGDG
FP
7RUWXRVLGDG
Â
Â
Â
Â
Â
Â
60
40
20
Simulado
Experimental
0.1
1
10
Diámetro, μm
)LJXUD &XUYDV DFXPXODGDV GHGLVWULEXFLyQ GH WDPDxRV GH
SRUR SDUD ORV SHOHWV / REWHQLGDV SRU 3,0 \ VLPXODGD
XWLOL]DQGRHOSURJUDPD3RUH&RU70
9DORUHV GH GLVWDQFLD HQ WRUQR D VRQ LQGLFDWLYRV
GH XQ EXHQ JUDGR GH DMXVWH HQWUH ORV GDWRV
H[SHULPHQWDOHV \ ORV VLPXODGRV &RQ ODV
IRUPXODFLRQHV UHVWDQWHV VH REWXYLHURQ FXUYDV
VLPLODUHV/RVYDORUHVGHFRQHFWLYLGDGGHORVSHOHWV
GHVHFDGRV SRU OLRILOL]DFLyQ IXHURQ VXSHULRUHV D FODUDPHQWH PD\RUHV TXH ORV GH ORV SHOHWV
GHVHFDGRV HQ HVWXID (VWR LQGLFD TXH ORV SHOHWV
GHVHFDGRVSRUOLRILOL]DFLyQFXHQWDQFRQXQDPD\RU
YDULHGDGGHFDPLQRVGHFRPXQLFDFLyQHQWUHSRURV
(O GLiPHWUR GH SHQHWUDFLyQ GH ORV SHOHWV
OLRILOL]DGRVIXHPD\RUTXHPLFUDPLHQWUDVTXHHO
GHORVSHOHWVVHFDGRVHQHVWXIDIXHYHFHVPiV
EDMR (VWRV UHVXOWDGRV H[SOLFDQ TXH HQ WpUPLQRV
FRPSDUDWLYRV \ WRPDQGR FRPR UHIHUHQFLD ORV
SHOHWV OLRILOL]DGRV OD SHUPHDELOLGDG GH ORV SHOHWV
GHVHFDGRVHQHVWXIDVHDSUiFWLFDPHQWHQXOD7DEOD
/DVGLVWULEXFLRQHVGHWDPDxRVGHORVSRURV\GH
ORV HVWUDQJXODPLHQWRV ILJXUD \ ODV
PLFURHVWUXFWXUDV
VLPXODGDV
ILJXUD
FRUUHVSRQGLHQWHV D ODV FHOGDV XQLGDG GH ORV SHOHWV
UHIOHMDQODVGLIHUHQFLDVFRPHQWDGDV
L1-est
L1-por
L2-est
L2-por
L3-est
L3-por
50
0
0.001
0.01
0.1
Diámetro, μm
1
10
)LJXUD 0RGHOL]DFLyQ GH OD HVWUXFWXUD PLFURSRURVD GH ORV
SHOHWVLQGLFDGRV/RVSRURVVHPXHVWUDQHQFRORUJULV
)LJXUD 6LPXODFLyQ GH ODV FXUYDV DFXPXODGDV GH SRURV \
HVWUDQJXODPLHQWRVGHORVSHOHWVFRQODFWRVD
7HFQRORJtD)DUPDFpXWLFD
6,08/$&,21'(/352&(62'(&$37$&,21'($*8$(13(/(760$75,&,$/(6$
%$6('((8'5$*,7620(7,'26$',)(5(17(675$7$0,(17263267
(/$%25$&,21
0.20
TMD, h
100
7HFQRORJtD)DUPDFpXWLFD
R2=0.961
0.15
70'
K
7DPDxR
FHOGD
XQLGDGμP
/RV QLYHOHV GH FRUUHODFLyQ SDUD ORV SHOHWV
GHVHFDGRVHQHVWXIDIXHURQSUy[LPRVDFHURORTXH
LQGLFDTXHORVSRURVVHGLVWULEX\HQDOHDWRULDPHQWH
(Q FDPELR ORV SHOHWV OLRILOL]DGRV SUHVHQWDURQ
YDORUHVFXDWURYHFHV VXSHULRUHVORTXHLQGLFD XQD
FLHUWD RUGHQDFLyQ HVSDFLDO TXH VH SODVPD HQ TXH
ORV SRURV GH PD\RU WDPDxR VH VLW~DQ GH PDQHUD
SUHIHUHQWH HQ ODV ]RQDV H[WHULRUHV GH OD FHOGD
XQLGDG OR TXH GHEH IDFLOLWDU OD SHQHWUDFLyQ GHO
PHGLRGHGLVROXFLyQKDFLDHOLQWHULRUGHOSHOHW/RV
SHOHWV OLRILOL]DGRV SUHYLD FRQJHODFLyQ OHQWD IXHURQ
PiV SHUPHDEOHV SRUTXH DXQTXH VX SRURVLGDG HV
PiV EDMD ORV GLiPHWURV GH SHQHWUDFLyQ VRQ
PD\RUHV (VWR H[SOLFD TXH ORV SHOHWV OLRILOL]DGRV
SUHYLD FRQJHODFLyQ OHQWD FHGDQ OD WHRILOLQD PiV
UiSLGDPHQWH 6H KD HQFRQWUDGR XQD HVWUHFKD
UHODFLyQ HQWUH OD SHUPHDELOLGDG \ ORV WLHPSRV
PHGLRVGHGLVROXFLyQ)LJXUD
Distancia=0.971
80
0
Número estrangulamientos
o poros, %
,QWURGXFFLyQ
/D PLFURHVWUXFWXUD FRQGLFLRQD HQ JUDQ PHGLGD
ODVSURSLHGDGHVGHORVSHOHWV\GHSHQGHWDQWRGH
ODV FDUDFWHUtVWLFDV GH ODV PDWHULDV SULPDV FRPR
GHO SURFHGLPLHQWR \ ODV FRQGLFLRQHV GH
HODERUDFLyQ 3DUD FDUDFWHUL]DU OD HVWUXFWXUD
PLFURSRURVDUHVXOWDPX\~WLOODSRURVLPHWUtDGH
LQWUXVLyQ GH PHUFXULR 3,0 TXH SHUPLWH
HVWLPDUODSRURVLGDGFDUDFWHUL]DUODGLVWULEXFLyQ
GH WDPDxRV GH SRUR \ REWHQHU LQIRUPDFLyQ
DFHUFD GH OD FRQHFWLYLGDG GH ORV SRURV R OD
WRUWXRVLGDG /DV KHUUDPLHQWDV
FRPSXWDFLRQDOHV SHUPLWHQ PRGHOL]DU OD
WRSRORJtD LQWHUQD GH ORV PDWHULDOHV VyOLGRV
SRURVRV
(Q HVWH WUDEDMR VH FDUDFWHUL]y SRU 3,0 OD
PLFURHVWUXFWXUD GH SHOHWV GH FHOXORVD
PLFURFULVWDOLQD 0&&FDUERSRO HODERUDGRV
XWLOL]DQGR GLIHUHQWHV SURFHGLPLHQWRV GH VHFDGR
\ VH PRGHOL]y OD JHRPHWUtD GHO HQWUDPDGR
SRURVR XWLOL]DQGR HO SURJUDPD 3RUH&RU70
)LQDOPHQWH VH DQDOL]y OD XWLOLGDG GH OD
DSUR[LPDFLyQ FRPSXWDFLRQDO SDUD SUHGHFLU ODV
SURSLHGDGHVGHFHVLyQGHIiUPDFRDSDUWLUGHORV
SHOHWV
0DWHULDOHV\0pWRGRV
0DWHULDOHV
0&& $YLFHO® 3+ )0& 3ULQFHQWRQ 1HZ
-HUVH\ 86$ FDUERPHU &DUERSRO® 3
/XEUL]RO &RUS :LFNOLIIH 2KLR 86$ ODFWRVD
DQKLGUD )DJURQ ,EpULFD (VSDxD IRVIDWR
GLFiOFLFR GLKLGUDWDGR '&3 0HUN (VSDxD \
WHRILOLQDDQKLGUD6LJPD$OGULFK(VSDxD
(ODERUDFLyQ\FDUDFWHUL]DFLyQGHORVSHOHWV
'LiPHWURGH
SHQHWUDFLyQ
μP
Â
Â
/&/6i%DUUHWR/$ORQVR50DUWtQH]3DFKHFR-/*yPH]$PR]D
0.10
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DQWLDJR
GH&RPSRVWHOD&DPSXV8QLYHUVLWDULR6XUVQ6DQWLDJRGH&RPSRVWHOD
HPDLOMRVHOXLVJRPH]DPR]D#XVFHV
0.05
0.00
1.0×10 -16
1.0×10 -14
1.0×10 -12
1.0×10 -10
,QWURGXFFLyQ
(Q ORV ~OWLPRV DxRV VH KD SXHVWR GH PDQLILHVWR OD
LPSRUWDQFLD GH OD HVWUXFWXUD PLFURSRURVD GH SHOHWV GH
HVWUXFWXUD PDWULFLDO VREUH OD OLEHUDFLyQ GH IiUPDFR HQ
HVWRVVLVWHPDV3UXHEDGHHOORHVODIXHUWHLQFLGHQFLD
GH GLVWLQWRV WUDWDPLHQWRV SRVWHODERUDFLyQ TXH
PRGLILFDQ GH IRUPD QRWDEOH OD PLFURSRURVLGDG GH ORV
SHOHWV
(O REMHWLYR GH HVWH HVWXGLR HV HYDOXDU D WUDYpV GH XQ
SURJUDPD GH VLPXODFLyQ HO DOFDQFH GHO SURFHVR GH
FDSWDFLyQGHDJXDSRUSDUWHGHODHVWUXFWXUDPLFURSRURVD
GHSHOHWVPDWULFLDOHVVREUHHOSURFHVRGHFHVLyQGH&O+
GH SURSUDQRORO D SDUWLU GH SHOHWV HODERUDGRV FRQ GRV
YDULHGDGHV GH (XGUDJLW / R 6 FRPR H[FLSLHQWH EDVH \
VRPHWLGRV D WUDWDPLHQWR WpUPLFR R GH H[SRVLFLyQ D
YDSRUHVRUJiQLFRV
Permeabilidad, cm2
)LJXUD 'HSHQGHQFLD VHPLORJ GHO WLHPSR PHGLR GH
GLVROXFLyQUHVSHFWRGHODSHUPHDELOLGDGGHORVSHOHWV
&RQFOXVLyQ
/D PRGHOL]DFLyQ GH OD PLFURHVWUXFWXUD HV XQD
DSUR[LPDFLyQ ~WLO SDUD HYDOXDU ORV FDPELRV
GHULYDGRVGHODFRPSRVLFLyQ\RODVFRQGLFLRQHVGH
HODERUDFLyQVREUHODVSURSLHGDGHVGHORVSHOHWV
$JUDGHFLPLHQWRV
;XQWDGH*DOLFLD3UR\HFWR&6$35
5HIHUHQFLDV
*yPH]&DUUDFHGR\FRO(XU-3KDUP%LRSKDUP
/DXGRQH\FRO&KHP(QJ6FL
*yPH]&DUUDFHGR\FRO$FWD0DWHUHQSUHQVD
*yPH]&DUUDFHGR\FRO(XU-3KDUP%LRSKDUP
0DWHULDOHV\0pWRGRV
0DWHULDOHV
&HOXORVD PLFURFULVWDOLQD 0&& $YLFHO® 3+ )0&
3ULQFHQWRQ1HZ-HUVH\86$(XGUDJLW/\(XGUDJLW
6 'HJXVVD $OHPDQLD SURSUDQRORO &O+ 5RLJ
)DUPD6$(VSDxD
(ODERUDFLyQ\FDUDFWHUL]DFLyQGHORVSHOHWV
6H HODERUDURQ SHOHWV SRU H[WUXVLyQHVIHURQL]DFLyQ
&DOHYDUSPPDOODGHPP&DOHYD
USPPLQGHODVLJXLHQWHFRPSRVLFLyQ0&&
SURSUDQRORO &O+ \ (XGUDJLW / ORWHV / R
(XGUDJLW6ORWHV6/DV PDVDVH[WUXtGDVVH
VHFDURQHQHVWXIDž&K0XHVWUDVGHORVSHOHWVVH
H[SXVLHURQ D YDSRUHV GH DFHWRQD HQ XQ GHVHFDGRU D
WHPSHUDWXUD DPELHQWH GXUDQWH K VXEtQGLFH D R D XQ
FDOHQWDPLHQWR D ž& GXUDQWH PLQ HQ XQD
WHUPREDODQ]D6KLPDG]X(%VXEtQGLFHW
/D FDUDFWHUL]DFLyQ PRUIROyJLFD GLiPHWUR GH )HUHW \
FLUFXODULGDG GH ORV SHOHWV VH OOHYy D FDER SRU
PLFURVFRStDySWLFD2O\PSXV6=&79/RVHVWXGLRVGH
GLVROXFLyQGHSURSUDQRORO&O+VHUHDOL]DURQGHDFXHUGR
FRQ ODV LQGLFDFLRQHV UHFRJLGDV HQ OD 863 SDUD HVWH
IiUPDFR (Q WRGRV ORV FDVRV VH HQVD\DURQ PXHVWUDV GH
SHOHWV FRQWHQLHQGR PJ GH SULQFLSLR DFWLYR \ OD
GHWHUPLQDFLyQ GH OD FRQFHQWUDFLyQ GH IiUPDFR GLVXHOWR
VHOOHYyDFDERSRUHVSHFWURIRWRPHWUtDGLUHFWDDQP
$JLOHQW /RV SHUILOHV GH GLVROXFLyQ VH DMXVWDURQ
SRU UHJUHVLyQ QR OLQHDO D OD HFXDFLyQ GH :HLEXOO
' H[SDÂWE HQ OD TXH ' UHSUHVHQWD OD IUDFFLyQ GH
GRVLV GLVXOHWD \ D \ E ORV SDUiPHWURV GH HVFDOD \ GH
IRUPD UHVSHFWLYDPHQWH $ SDUWLU GH ORV YDORUHV
HVWLPDGRV GH HVWRV SDUiPHWURV VH FDOFXOy HO WLHPSR
PHGLRGHGLVROXFLyQ70'GHDFXHUGRFRQODH[SUHVLyQ
70' DEÂΓEHQODTXH ΓUHSUHVHQWDODIXQFLyQ
JDPPD
/D HVWUXFWXUD PLFURSRURVD GH ORV SHOHWV VH HYDOXy SRU
SRURVLPHWUtD SRU LQWUXVLyQ GH PHUFXULR 3,0 HQ HO
LQWHUYDOR GH SUHVLRQHV FRPSUHQGLGR HQWUH \ 03D
0RGHOL]DFLyQGHODHVWUXFWXUDPLFURSRURVD
6H XWLOL]y HO VRIWZDUH 3RUH&RU70 (QYLURQPHQWDO DQG
)OXLG 0RGHOOLQJ *URXS 8QLYHUVLW\ RI 3O\PRXWK 8.
SDUD PRGHOL]DU OD HVWUXFWXUD SRURVD FRPR XQD VHULH GH
FHOGDV XQLGDG LQWHUFRQHFWDGDV &DGD FHOGD XQLGDG HVWi
FRQVWLWXLGD SRU QRGRV [[ QRGRV HQ ODV
GLPHQVLRQHV[\](QFDGDQRGRVHSRVLFLRQDQSRURV
F~ELFRVTXHVHFRQHFWDQHQWUHVtSRUSRURVFLOtQGULFRVGH
PHQRU WDPDxR HVWUDQJXODPLHQWRV $ SDUWLU GH ODV
FXUYDV DFXPXODGDV GH 3,0 FRUUHVSRQGLHQWHV D ORV
HVSDFLRV YDFLRV LQWUDJUDQXODUHV \ KDFLHQGR XVR GH XQ
DOJRULWPR VLPSOH[ VH HVWLPDURQ \ RSWLPL]DURQ
VLPXOWiQHDPHQWH OD FRQHFWLYLGDG Q~PHUR PHGLR GH
HVWUDQJXODPLHQWRV SRU SRUR HO VHVJR GH SRUR SRUH
VNHZ R IDFWRU GH HVFDOD TXH DGDSWD HO WDPDxR GH ORV
SRURV \ GH ORV HVWUDQJXODPLHQWRV SDUD DMXVWDUORV D OD
SRURVLGDG H[SHULPHQWDO \ HO QLYHO GH FRUUHODFLyQ TXH
DMXVWD OD DXWRFRUUHODFLyQ ORFDO HQWUH SRURV \
HVWUDQJXODPLHQWRV \ TXH YDUtD HQWUH ±HVWUXFWXUD
DOHDWRULD \ ±RUGHQDFLyQ HQ OD FHOGD XQLGDG (VWRV
SDUiPHWURVSHUPLWHQJHQHUDUXQDFHOGDXQLGDGFRQXQDV
SURSLHGDGHV GH SHUFRODFLyQ SUy[LPDV D ODV UHDOHV
HVWLPDGDVDSDUWLUGHORVGDWRVGH3,0
3DUD OD HVWLPDFLyQ GH OD YHORFLGDG GH SHQHWUDFLyQ GH
DJXD HQ ODV HVWUXFWXUDV VLPXODGDV VH XWLOL]y HO VRIWZDUH
3RUH&RU703DUDHOORVHHVWLPyDGLVWLQWRVWLHPSRVOD
GLVWDQFLD UHFRUULGD SRU HO IUHQWH OtTXLGRGH DFXHUGR FRQ
ODHFXDFLyQGH%RVDQTXHW
[[ βαÂWαÂH[SαWGRQGH
α ÂηρÂU\β 3HÂUÂγÂFRVθUÂρ
([SUHVLRQHVHQODVTXH[\[UHSUHVHQWDQODVSRVLFLRQHV
GHO IUHQWH GH OtTXLGR LQLFLDO \ WUDV XQ WLHPSR W
UHVSHFWLYDPHQWH 3H OD SUHVLyQ H[WHUQD DSOLFDGD D OD
HQWUDGDGHOWXERFDSLODUη ρ\ γ ODYLVFRVLGDGGLQiPLFD
GHQVLGDG \ WHQVLyQ VXSHUILFLDO GHO OtTXLGR
UHVSHFWLYDPHQWH θ HO iQJXOR GH FRQWDFWR OtTXLGRVyOLGR
\UHOUDGLRGHOSRUR(QWRGRVORVFDVRVVHDVXPLyTXH
η 3DÂV ρ NJÂP γ= GLQDÂFP \
θ=50ž
&RQRFLGDODSRVLFLyQGHOIUHQWHGHOtTXLGRDORVGLVWLQWRV
WLHPSRVVHFDOFXODURQORVYRO~PHQHVGHDJXDSUHVHQWHV
HQ HO LQWHULRU GH ORV HVSDFLRV YDFtRV SDUD ODV GLVWLQWDV
FHOGDV XQLGDG /D UHSUHVHQWDFLyQ GH HVWRV YRO~PHQHV D
ORV GLIHUHQWHV WLHPSRV VLPXODGRV VH DMXVWy D OD FOiVLFD
HFXDFLyQGHSRWHQFLD
Y NÂWQHQODTXHN\QUHSUHVHQWDQORVIDFWRUHVGHHVFDOD
\GHIRUPDUHVSHFWLYDPHQWH
5HVXOWDGRV\GLVFXVLyQ
(Q WRGRV ORV FDVRV ORV SHOHWV SUHVHQWDURQ XQD
JUDQXORPHWUtD \ PRUIRORJtD DGHFXDGDV GLiPHWURV GH
)HUHW\FLUFXODULGDGHVGH\μP\GH\
SDUD ORV ORWHV / \ 6 UHVSHFWLYDPHQWH /DV
GLVWULEXFLRQHV GH WDPDxRV GH SRUR )LJXUD PXHVWUDQ
TXH ORV SHOHWV HODERUDGRV FRQ (XGUDJLW 6 VRQ PiV
SRURVRV TXH ORV HODERUDGRV FRQ OD YDULHGDG / /D
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
H[SRVLFLyQGHORVSHOHWVDYDSRUHVGHDFHWRQDGXUDQWHK
SURYRFD XQD LPSRUWDQWH UHGXFFLyQ HQ HO YROXPHQ
FRUUHVSRQGLHQWH D ORV HVSDFLRV YDFtRV LQWUDJUDQXODUHV
3RU HO FRQWUDULR HVWDV PRGLILFDFLRQHV VRQ GH HVFDVD
PDJQLWXGFXDQGRORVSHOHWVVHVRPHWHQDXQWUDWDPLHQWR
WpUPLFRDž&GXUDQWHPLQ
0.3
)LJXUD 0RGHOL]DFLyQ GH OD HVWUXFWXUD PLFURSRURVD GH ORV
SHOHWVGHOORWH6(QFODURODV]RQDVKXPHFWDGDVDOFDERGHμV
L]TXLHUGD\μVGHUHFKD
La
Lt
S
Sa
St
0.1
0.0
0.01
0.1
1
10
100
1000
Diámetro poro, μ m
)LJXU
D &XUYDV DFXPXODGDV GH GLVWULEXFLyQ GH WDPDxRV GH SRUR
SDUDORVSHOHWVFRUUHVSRQGLHQWHVDORVORWHVLQGLFDGRV
L
La
Lt
S
Sa
St
400
200
10
5
0
0
2.0
L
La
Lt
0.25
0.5
S
Sa
St
1.0
500
750
1000
/D HVWUHFKD UHODFLyQ H[LVWHQWH HQWUH ORV YDORUHV GHO
H[SRQHQWH Q \ ORV WLHPSRV PHGLRV GH GLVROXFLyQ GH
SURSUDQRORO&O+)LJXUDSHUPLWHFRQFOXLUTXHHQHVWH
WLSR GH SHOHWV HO SURFHVR GH GLVROXFLyQ VH HQFXHQWUD
OLPLWDGR SRU HO PHFDQLVPR \ OD YHORFLGDG GH FDSWDFLyQ
GHDJXDSRUSDUWHGHORVSHOHWV
0.75
0.50
250
Tiempo, μs
1.00
0.00
0.0
R2=0.991
F1, 4 g.l. =401.8; α <0.01
1.5
1.0
0.5
0.0
1.5
0.20
Tiempo, h
)LJXUD3HUILOHVGHGLVROXFLyQGHSURSUDQRORO&O+\DMXVWHD
ODHFXDFLyQGH:HLEXOOFRUUHVSRQGLHQWHVDORVSHOHWVLQGLFDGRV
$ SDUWLU GH ODV PLFURHVWUXFWXUDV HVWLPDGDV FRQ HO
VRIWZDUH 3RUH&RU70 VH VLPXOy HO SURFHVR GH FDSWDFLyQ
GH DJXD SRU SDUWH GH ORVSHOHWV DVXPLHQGR TXH GXUDQWH
HO SURFHVR QR WLHQHQ OXJDU FDPELRV HVWUXFWXUDOHV
GHULYDGRV GH SURFHVRV GH KLQFKDPLHQWR HURVLyQ \R
GLVROXFLyQ
$ WtWXOR GH HMHPSOR HQ OD )LJXUD VH SUHVHQWD OD
PLFURHVWUXFWXUD GH ORV SHOHWV FRUUHVSRQGLHQWH DO ORWH 6
WUDQVFXUULGRV\μVGHOSURFHVRGHKXPHFWDFLyQ\
HQOD)LJXUDORVYRO~PHQHVGHDJXDFDSWDGDDGLVWLQWRV
WLHPSRV SRU ORV GLIHUHQWHV ORWHV GH SHOHWV 'H VX
REVHUYDFLyQ VH GHVSUHQGH ODV JUDQGHV GLIHUHQFLDV
H[LVWHQWHVHQWUHORVGLVWLQWRVORWHVGHSHOHWVWDQWRHQORV
YRO~PHQHV FRPR HQ OD ODV YHORFLGDGHV GH FDSWDFLyQ GH
DJXD
0.25
0.30
0.35
0.40
0.45
0.50
n
)LJXUD 5HODFLyQ HQWUH ORV YDORUHV GHO H[SRQHQWH Q GH OD
HFXDFLyQGHSRWHQFLD\ORVWLHPSRVPHGLRVGHGLVROXFLyQ
&RQFOXVLyQ
/DVLPXODFLyQGHOSURFHVRGHSHQHWUDFLyQGHDJXDHQOD
PLFURHVWUXFWXUD GH ORV SHOHWV FRQVWLWX\H XQD
DSUR[LPDFLyQ~WLOSDUDHYDOXDUORVFDPELRVGHULYDGRVGH
OD FRPSRVLFLyQGH ODV FRQGLFLRQHV GH HODERUDFLyQ \ GH
ORV WUDWDPLHQWRV SRVWHODERUDFLyQ VREUH ODV SURSLHGDGHV
GHFHVLyQGHORVSHOHWV
$JUDGHFLPLHQWRV
;XQWDGH*DOLFLD3UR\HFWR&6$35(YRQLN
,QGXVWULHV SRU HO VXPLQLVWUR GH ODV YDULHGDGHV GH
(XGUDJLW
5HIHUHQFLDV
*yPH]&DUUDFHGR \ FRO (XU - 3KDUP %LRSKDUP
$]DUPL\FRO,QW-3KDUP
5DR\FRO,QGLDQ-3KDUP6FL
/DXGRQH\FRO&KHP(QJ6FL
6FKRHONRSI \ FRO - &ROORLG ,QWHUI 6FL ,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
)LJXUD0LFURJUDItD6(0GHQDQRSDUWtFXODVGH
*DQWUH]
&RQFOXVLRQHV
/RV UHVXOWDGRV SUHOLPLQDUHV KDQ FRQILUPDGR OD
DILQLGDGGHOH[WUDFWRGHSURWHtQDV,SD \GH209V
SRUHOSROtPHUR\VXHIHFWLYDHQFDSVXODFLyQHQODV
QDQRSDUWtFXODV UHVXOWDQWHV (Q FXDOTXLHU FDVR HV
QHFHVDULR SURIXQGL]DU HQ OD FDUDFWHUL]DFLyQ ItVLFR
TXtPLFD GH ODV IRUPXODFLRQHV REWHQLGDV DVt FRPR
HQVXHYDOXDFLyQELROyJLFD
$JUDGHFLPLHQWRV
(VWH WUDEDMR KD VLGR UHDOL]DGR JUDFLDV D OD
³$VRFLDFLyQ GH DPLJRV GH OD 8QLYHUVLGDG GH
1DYDUUD´
5HIHUHQFLDV
6FKURHGHU*1&OLQ0LFURELRO5HY
2JDZD01DW5HY0LFURELRO
3KDOLSRQ $ 6DQVRQHWWL 3- ,PPXQRO &HOO %LRO
*yPH] 6 - 1DQRVFL 1DQRWHFKQRO 6DQVRQHWWL3-$QQ1< $FDG6FL
3000
2000
1000
)LJXUD 9RO~PHQHV GH DJXD FDSWDGD SRU ORV SHOHWV GH ORV
ORWHVLQGLFDGRVHVWLPDGRVSRUVLPXODFLyQFRQHOVRIWZDUH3RUH
&RU70\DMXVWHDODHFXDFLyQ9 NÂWQ
TMD, h
Propranolol disuelto
/DV GLIHUHQFLDV HQ OD PLFURHVWUXFWXUD GH ORV SHOHWV VH
UHIOHMDQHQODVYHORFLGDGHVGHGLVROXFLyQGHSURSUDQRORO
)LJXUD /RV SHOHWV HODERUDGRV FRQ OD YDULHGDG 6
OLEHUDQ HO IiUPDFR D PD\RU YHORFLGDG TXH ORV TXH
FRQWLHQHQ (XGUDJLW / \ DO LJXDO TXH VXFHGtD FRQ OD
PLFURHVWUXFWXUD VyOR OD H[SRVLFLyQ GH ORV SHOHWV D
YDSRUHVGHDFHWRQDSURYRFDXQDUDOHQWL]DFLyQLPSRUWDQWH
HQHOSURFHVRGHGLVROXFLyQORV70'VHLQFUHPHQWDQHQ
PiV GH FXDWUR YHFHV FRPR FRQVHFXHQFLD GH XQ FDPELR
HQHOWLSRGHFLQpWLFDSRUODTXHVHULJHHOSURFHVR
Volumen, μ m3/celda unidad
Volumen, cm3 g-1
L
0.2
'(6$552//2'(81$9$&81$,175$1$6$/)5(17($$/$',6(17(5Ë$%$&,/$5
0(',$17(1$123$57Ë&8/$6
$,&DPDFKR0DULD/XLVD$UD~MR-0,UDFKH&*DPD]R
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtDIDUPDFpXWLFD'HSDUWDPHQWRGH0LFURELRORJtD8QLYHUVLGDGGH
1DYDUUD
3DUD OD REWHQFLyQ GH YHVtFXODV GH PHPEUDQD
,QWURGXFFLyQ
H[WHUQD209V6KLJHOODIXHLQFXEDGDHQ76%D
/DVKLJHORVLVHV XQDHQIHUPHGDGHQWpULFDLQYDVLYD ž& HQ DJLWDFLyQ D USP GXUDQWH K /DV
DJXGD FDXVDGD SRU 6KLJHOOD VSS /RV FDVRV GH FpOXODV IXHURQ UHFRJLGDV SRU FHQWULIXJDFLyQ
6KLJHORVLV HQ HO PXQGR VH HVWLPDQ HQ JPLQ\ODYDGDVFRQVROXFLyQVDOLQD
PLOORQHV PLOORQHV HQ ORV SDtVHV HQ (O VREUHQDGDQWH VH ILOWUy FRQ XQ VLVWHPD GH
GHVDUUROOR TXH FDXVDQ DSUR[LPDGDPHQWH ILOWUDFLyQWDQJHQFLDOFRQXQWDPDxRGHSRURGH
PLOORQHVGHPXHUWHVHOHQQLxRVPHQRUHVGH N'D/DIUDFFLyQUHWHQLGDTXHFRQWHQtDODV209V
VH VRPHWLy D XQ SURFHVR GH FRQJHODFLyQ \
DxRV
5HFLHQWHPHQWH OD 206 KD GDGR SULRULGDG D ORV GHVFRQJHODFLyQDž&FRQREMHWRGHSURPRYHUOD
SURJUDPDV GH GHVDUUROOR GH YDFXQDV HIHFWLYDV IXVLyQ \ DJUHJDFLyQ GH ODV YHVtFXODV eVWDV VH
IUHQWH D OD 6KLJHORVLV 206 \D TXH KDVWD UHFRJLHURQSRUFHQWULIXJDFLyQDJK
OD IHFKD QLQJXQD GH ODV SURSXHVWDV KD WHQLGR XQ
p[LWRVLJQLILFDWLYR
5HVXOWDGRV\'LVFXVLyQ
(O REMHWR GH QXHVWUR WUDEDMR HV HO HPSOHR GH
H[WUDFWRV VXEFHOXODUHV GH 6KLJHOOD FDSDFHV GH /RV PpWRGRV GH H[WUDFFLyQ SDUHFHQ VHU HILFDFHV
LQGXFLU XQD UHVSXHVWD LQPXQLWDULD HILFD] /D SDUDQXHVWURREMHWLYR/DVHFUHFLyQGHSURWHtQDVVH
YDFXQD VH EDVDUi HQ HO HPSOHR GH DG\XYDQWHV RSWLPL]y DO DxDGLU DO URMR FRQJR LQGXFWRU GHO
ELRDGKHVLYRV QDQRSDUWtFXODGR SDUD DGPLQLVWUDFLyQ VLVWHPD GH VHFUHFLyQ WLSR ,,, 776 GH 6KLJHOOD
QDVDO
XQDVDOELOLDUHO'2&TXHDXQTXHQRHVLQGXFWRU
GHO 776 IDYRUHFH VX VHFUHFLyQ /RV GLVWLQWRV
H[WUDFWRV DQWLJpQLFRV )LJ IXHURQ DQDOL]DGRV
0DWHULDOHV\0pWRGRV
PHGLDQWHZHVWHUQEORWIUHQWHDGLVWLQWRVVXHURV
GLVWLQWRV
H[WUDFWRV
VXEFHOXODUHV
6HHVWiQXWLOL]DQGRGLVWLQWDVFHSDVGH6KLJHOODVSS /RV
SURFHGHQWHV GH FHQWURV KRVSLWDODULRV /DERUDWRULR LPPXQRJpQLFRV KDQ VLGR HQFDSVXODGRV HQ
1DFLRQDO GH 5HIHUHQFLD GH 0DMDGDKRQGD &OtQLFD QDQRSDUWtFXODV GH *DQWUH] (O *DQWUH] $1 HV XQ
8QLYHUVLWDULD +RVSLWDO GH 1DYDUUD &OtQLFD FRSROtPHUR HQWUH PHWLO YLQLO pWHU \ DQKtGULGR
PDOHLFR3090$)LJ
8QLYHUVLWDULDGH1DYDUUD
3RUPRWLYRVGHVHJXULGDGVHHPSOHy%(,%LQDU\
HWK\OHQHLPLQH FRPR DJHQWH LQDFWLYDQWH (O %(,
SURGXFH SRU FLFODFLyQ D SDUWLU GH %($
EURPRHWK\ODPLQHK\GUREURPLGHHQVROXFLyQ
DOFDOLQD1D2+ž&HQDJLWDFLyQK
/DV FRQGLFLRQHV JHQHUDOHV SDUD WRGDV ODV
,SD%
H[WUDFFLRQHV IXHURQ FUHFLPLHQWR HQ 76% ž&
USPK
3DUD OD H[WUDFFLyQ GH SURWHtQDV ,SD IDFWRUHV GH
,SD&
YLUXOHQFLDHVHQFLDOHVSDUDODEDFWHULD6KLJHOODIXH
LQFXEDGDHQODVFRQGLFLRQHVGHVFULWDV\VHDMXVWyVX
GHQVLGDGySWLFD'2QPD$FRQWLQXDFLyQ
VHDxDGLHURQHOLQGXFWRUGHVHFUHFLyQURMRFRQJR
\HOGHR[LFRODWR'2&TXHIDYRUHFHODVHFUHFLyQ
/DV FRQGLFLRQHV HOHJLGDV SDUD HOOR IXHURQ ODV
VLJXLHQWHV URMR FRQJR ȝJP/ \ '2&
ZY PLQ ž& USP
3RVWHULRUPHQWH ODV PXHVWUDV IXHURQ SURFHVDGDV \
DQDOL]DGDV SRU 6'63$*( H LQPXQREORWWLQJ )LJXUD$7LQFLyQGHSODWDSDUD/36\SURWHtQDV
HPSOHDQGR DQWLFXHUSRV PRQRFORQDOHV HVSHFtILFRV GH OD IUDFFLyQ GH 209V % 7LQFLyQ SODWD SDUD
IUHQWH D ,SD% H ,SD& FHGLGRV SRU $ 3KDOLSRQ SURWHtQDVGHH[WUDFFLyQGHSURWHtQDVLSD
,QVWLWXWH3DVWHXU3DULV
(678',2'(/$,1)/8(1&,$'(/75$7$0,(1727e50,&2<'(/$35(6(1&,$'(
393(1/$/,%(5$&,Ï1'(7(2),/,1$$3$57,5'(&2035,0,'260$75,&,$/(6
/,3Ë',&26
003XHEOD*RQ]iOH]090DUJDULW%HOOYHU070DUtQ%RVFi
'HSDUWPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH*UDQDGD(VSDxD
(PDLOPWPDULQ#XJUHVPGPSJ#FRUUHRXJUHV
,QWURGXFFLyQ (O %HKHQDWR GH *OLFHULOR /DV PH]FODV VH FRPSULPHQ D WRQV GH SUHVLyQ
&RPSULWROŠ PDWHULDO FpUHR XWLOL]DGR FRPR GXUDQWH PLQXWRV XVDQGR XQD SUHQVD KLGUiXOLFD
OXEULFDQWH HQ FRPSULPLGRV VH HVWi XWLOL]DQGR 6SHFDF
~OWLPDPHQWH FRPR DJHQWH PDWULFLDO SDUD SUHSDUDU &DGD IRUPXODFLyQ $ & \ ' VH SUHSDUD SRU
FRPSULPLGRVGHOLEHUDFLyQFRQWURODGD>@
GXSOLFDGR GH IRUPD TXH ORV FRPSULPLGRV GH ODV
(QHVWHHVWXGLRSUHWHQGHPRVHYDOXDUHOHIHFWRGHOD KRPyORJDV % ' \ ) VH WUDWDQ WpUPLFDPHQWH
SUHVHQFLD\FDQWLGDGGHXQDJHQWHDFHOHUDGRUGHOD GXUDQWH PLQXWRV D ž& GH WHPSHUDWXUD
GLVROXFLyQ VREUH OD OLEHUDFLyQ GH IiUPDFR D SDUWLU 'HVSXpV GH VDFDU ORV FRPSULPLGRV GH OD HVWXID VH
GHPDWULFHVOLStGLFDV\VREUHODHURVLyQTXHVXIUHQ GHMDQHQIULDUDWHPSHUDWXUDDPELHQWH/RVHQVD\RV
ODVGLVWLQWDVIRUPXODFLRQHV
GHGLVROXFLyQVHUHDOL]DQDOPHQRVKGHVSXpVGHO
7DPELpQVHLQYHVWLJDODLQIOXHQFLDTXHWLHQHVREUH WUDWDPLHQWR>@
HVWRV DVSHFWRV HO WUDWDPLHQWR WpUPLFR GH DOJXQRV eVWRVVHOOHYDQDFDERDXWRPiWLFDPHQWHXVDQGRHO
FRPSULPLGRVVHOHFFLRQDGRVWUDVVXHODERUDFLyQ
PpWRGR ,, GH SDOHWDV GH OD 863 FRQ PO GH
WDPSyQ IRVIDWR D XQ S+ GH FRPR PHGLR GH
0DWHULDOHV \ 0pWRGRV /DV IRUPXODFLRQHV
GLVROXFLyQ/DWHPSHUDWXUDVHPDQWLHQHDž&\OD
HVWXGLDGDV VH FRPSRQHQ GH ORV VLJXLHQWHV
YHORFLGDG GH ODV SDOHWDV D USP &DGD
PDWHULDOHV WHRILOLQD DQKLGUD \ ODFWRVD
IRUPXODFLyQVHDQDOL]DSRUVH[WXSOLFDGRGXUDQWH
Š
SURSRUFLRQDGDV SRU *XLQDPD &RPSULWRO KRUDV /DV PXHVWUDV VH WRPDQ HQ LQWHUYDORV GH
$72 & 393 .ROOLGRQŠ DPDEOHPHQWH
WLHPSRSUHYLDPHQWHGHWHUPLQDGRVXVDQGRILOWURVGH
VXPLQLVWUDGRV SRU *DWWHIRVVp 6 $ \ %$6)
FHOXORVD—P/DFRQFHQWUDFLyQGHIiUPDFRVH
UHVSHFWLYDPHQWHHVWHDUDWRPDJQpVLFR(VW0J\
GHWHUPLQD D XQD ORQJLWXG GH RQGD GH QP
WDOFRDGTXLULGRVDWUDYpVGH*XLQDPD6$
3HUNLQ(OPHUODPEGD
(Q OD WDEOD VH UHFRJH OD FRPSRVLFLyQ GH ODV
/RVGDWRVGHGLVROXFLyQVHDMXVWDQDODVHFXDFLRQHV
IRUPXODFLRQHVHVWXGLDGDV
FLQpWLFDV GH 3HSSDV RUGHQ FHUR SULPHU RUGHQ H
+LJXFKL
7DEOD &RPSRVLFLyQ PJ GH ODV IRUPXODFLRQHV
/RV HQVD\RV GH HURVLyQ VH UHDOL]DQ PDQWHQLHQGR
HVWXGLDGDV
ODV PLVPDV FRQGLFLRQHV TXH SDUD HO HVWXGLR GH
GLVROXFLyQSHURHQHVWHFDVRODVIRUPXODFLRQHVVH
)yUPXODV DQDOL]DQSRUWULSOLFDGR
$%&'()
/RVFRPSULPLGRVVHSHVDQDQWHVGHOHQVD\R3\
0DWHULDOHV
XQDYH]DOFDQ]DGRHOSHVRFRQVWDQWH3)HQHVWXID
D ž& $Vt VH REWLHQH HO SRUFHQWDMH GH
7HRILOLQD
FRPSULPLGRHURVLRQDGR(
&RPSULWROŠ § 3 − 3) ·
¸¸ × (F
( = ¨¨ /DFWRVD
© 3 ¹
Š
.ROOLGRQ 5HVXOWDGRV \ GLVFXVLyQ 6H SURFHGH D HVWXGLDU HO
HIHFWR GH OD SUHVHQFLD GH .ROOLGRQŠ DVt FRPR
7DOFR
GHOWUDWDPLHQWRWpUPLFRHQODOLEHUDFLyQGHWHRILOLQD
ILJ
(VW0J
6HXVD XQDFDQWLGDGGH&ILMDGHPJFRPR FRPSRQHQWHSULQFLSDOGHODVPDWULFHV
&RPR DFHOHUDGRU GH OD GLVROXFLyQ VH HVWXGLD HO
.ROOLGRQŠ HQ SRUFHQWDMHV GHO \ (O
SHVR WRWDO GH ORV FRPSULPLGRV VH PDQWLHQH
FRQVWDQWHHQPJ
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
A
B
C
D
80
60
E
F
40
20
0
0
2
4
6
Tiempo (h)
8
)LJXUD3HUILOHVGHOLEHUDFLyQGHWHRILOLQDGHVGH
PDWULFHVGH&
(VWDILJXUDQRVPXHVWUDTXHXQGH.ROOLGRQŠ
HVLQVXILFLHQWHSDUDYHUUHIOHMDGDVPRGLILFDFLRQHV
HQ OD OLEHUDFLyQ GH WHRILOLQD 6H DGYLHUWH XQ
DXPHQWR FRQVLGHUDEOH HQ OD OLEHUDFLyQ FXDQGR HO
SRUFHQWDMH GH 393 HQ OD IRUPXODFLyQ HV GHO ( 3RU RWUR ODGR OD PD\RU SURSRUFLyQ GH
.ROOLGRQŠ HQ OD IRUPXODFLyQ SURYRFD XQD PD\RU
YDULDELOLGDG LQWHULQGLYLGXDO HQ ODV SUHSDUDFLRQHV
FRQGHVYLDFLRQHVHVWiQGDUTXHQRVHKDQUHIOHMDGR
JUiILFDPHQWH SRU VRODSDUVH XQDV FRQ RWUDV
GLILFXOWDQGRVXLGHQWLILFDFLyQ
(O WUDWDPLHQWR WpUPLFR HQ WRGRV ORV FDVRV
HVWXGLDGRV%'\)GLVPLQX\HODOLEHUDFLyQGHO
IiUPDFRDSDUWLUGHODPDWUL]PiVDFXVDGDD~QHQ
HOFDVRGHODVSUHSDUDFLRQHVIRUPXODGDVFRQ393
FX\RVSHUILOHVHVWiQVLWXDGRVSRUGHEDMRLQFOXVRGH
ODIyUPXODTXHQROROOHYD%
7DEOD3DUiPHWURVFLQpWLFRV
3ULPHU 2UGHQ
3HSSDV
2UGHQ &HUR +LJXFKL
Q
Uð
$ Uð
Uð
Uð
% DXQDFLQpWLFDGHRUGHQVRQODVTXHFRQWLHQHQHO
SRUFHQWDMHPiVDOWRGH393
$~Q DVt WRGDV ODV SUHSDUDFLRQHV HVWXGLDGDV VH
DMXVWDQFRQXQFRHILFLHQWHGHFRUUHODFLyQPiVDOWR
DODFLQpWLFDSURSXHVWDSRU+LJXFKLORFXDOVXJLHUH
TXH HO PHFDQLVPR SULQFLSDO GH OLEHUDFLyQ GH
WHRILOLQD HQ QXHVWUR HVWXGLR KD VLGR YtD GLIXVLyQ
FRQWURODGD /D H[FHSFLyQ UDGLFD HQ OD IyUPXOD )
FRQXQGH.ROOLGRQŠ\WUDWDGDWpUPLFDPHQWH
TXH VH DMXVWD PiV D XQD FLQpWLFD GH SULPHU RUGHQ
(O HVWXGLR GH HURVLyQ VHxDOD FyPR D PD\RU
SURSRUFLyQGH393HOJUDGRGHHURVLyQHVPD\RU
3RU HO FRQWUDULR HO WUDWDPLHQWR WpUPLFR HQ WRGRV
ORVFDVRVUHGXFHHOHIHFWRGHODHURVLyQGXUDQWHOD
GLVROXFLyQ)LJ
100
A
B
C
D
E
F
80
Erosión (%)
Concentración (%)
100
60
40
20
0
0
2
4
6
8
Tiempo (h)
)LJXUD *UDGR GH HURVLyQ GH ODV IRUPXODFLRQHV
HVWXGLDGDV
&RQFOXVLRQHV
$O DxDGLU .ROOLGRQŠ HQ XQ SRUFHQWDMH GHO TXHGD SDWHQWH XQ DXPHQWR FRQVLGHUDEOH HQ OD
OLEHUDFLyQGHWHRILOLQD
(O WUDWDPLHQWR WpUPLFR UHGXFH OD OLEHUDFLyQ GH
WHRILOLQD HQ WRGRV ORV FDVRV DVt FRPR HO JUDGR GH
HURVLyQ GH ORV FRPSULPLGRV \ OD YDULDELOLGDG
LQWHULQGLYLGXDOGHODVIyUPXODV
%LEOLRJUDItD
>@$$2EDLGDW502EDLGDW
(XU-3KDUP%LRSKDUP
>@0g]\D]LFL(+*|NoH*(UWDQ
(XU-3KDUP%LRSKDUP
>@)HQJ4LDQ/LHWDO
,QW-3KDUP
>@<=KDQJ-%6FKZDUW]
'UXJ'HY,QG3KDUP
& ' ( ) /DVIRUPXODFLRQHVWUDWDGDVWpUPLFDPHQWHSUHVHQWDQ
DGHPiV XQD UHGXFFLyQ HQ OD YDULDELOLGDG
LQWHULQGLYLGXDO PiV DSUHFLDEOH HQ DTXHOODV TXH
FRQWLHQHQ .ROOLGRQŠ HQ VX FRPSRVLFLyQ
'HORVUHVXOWDGRVREWHQLGRVSDUDHODMXVWHFLQpWLFR
WDEODODVIRUPXODFLRQHVTXHPiVVHDSUR[LPDQ
7DEOD $QiOLVLV $129$ GH ORV GDWRV GH į GH ODV
PXHVWUDVWUDWDGDVSRU++3DXQDIUHFXHQFLDGH+]
3U!)QLYHOGHVLJQLILFDWLYLGDGGHFDGDIDFWRU
)DFWRU
F
WPLQ
S0SD
3U!)
(Q OD )LJXUD VH UHSUHVHQWD OD LQIOXHQFLD GHO
WUDWDPLHQWRSRU++3SDUDFDGDXQDGHODVPXHVWUDV
\VHREVHUYDTXHODDSOLFDFLyQGHOQLYHOVXSHULRUGH
ORVIDFWRUHVLPSOLFDGRVDIHFWDHQPD\RUPHGLGDDO
iQJXOR GH IDVH (VWH SDUiPHWUR DXPHQWD
FRQVLGHUDEOHPHQWHGHVSXpVGHOWUDWDPLHQWRFRQOD
FRQVHFXHQWH SpUGLGD GHO FRPSRQHQWH HOiVWLFR
*!* \ SUHGRPLQLR GHO FRPSRUWDPLHQWR
YLVFRVR(VGHFLUODVPXHVWUDVWUDVODDSOLFDFLyQGH
HVWD WHFQRORJtD SLHUGHQ HQ FLHUWD PHGLGD VX
QDWXUDOH]DYLVFRHOiVWLFDLQLFLDO
24
22
Delta
XFIPO
20
F
18
S03D WPLQ
7RGRV ORV WUDWDPLHQWRV SRU DOWDV SUHVLRQHV
KLGURVWiWLFDV SURGXMHURQ OD PLVPD LQDFWLYDFLyQ GH
ODIORUDPLFURELDQDLQLFLDOGHORVJHOHVGHDORH6LQ
HPEDUJR VH REVHUYDURQ GLIHUHQFLDV HQWUH ODV
PXHVWUDV WUDWDGDV \ ODV PXHVWUDV GH UHIHUHQFLD
(QWUH HVWDV ~OWLPDV VH GHWHFWD XQD PD\RU
LQDFWLYDFLyQ FXDQWR PD\RU HV OD FRQFHQWUDFLyQ GH
ORVHVWDELOL]DQWHV
3DUD HO HVWXGLR GHO FRPSRUWDPLHQWR UHROyJLFR VH
UHDOL]y XQ DQiOLVLV GH OD YDULDQ]D $129$ GHO
HIHFWR++3VREUHHOiQJXORGHIDVHTXHVHPXHVWUD
HQOD7DEOD6HDSUHFLDTXHODSUHVXUL]DFLyQ\OD
DGLFLyQ GH HVWDELOL]DQWHV DIHFWDQ GH IRUPD
VLJQLILFDWLYD)DOFRPSRUWDPLHQWRGLQiPLFR
GH ODV PXHVWUDV LQGHSHQGLHQWHPHQWH GHO WLHPSR
GXUDQWHHOFXDOVHDSOLFDGLFKDSUHVLyQ
'HSDUW,QJHQLHUtD4XtPLFD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH/D
/DJXQD'HSDUW7HFQRORJtDGHORV$OLPHQWRV)DFXOWDGGH9HWHULQDULD8QLYHUVLGDGGH=DUDJR]D
,QWURGXFFLyQ (Q OD DFWXDOLGDG OD DSOLFDFLyQ ,QVWUXPHQW,QF&UDQEXU\1-HTXLSDGRFRQSODWR
GH DOWDV SUHVLRQHV KLGURVWiWLFDV ++3 +LJK 3HOWLHU \ XQD JHRPHWUtD WLSR SODWRSODWR FRQ XQD
+\GURVWDWLF 3UHVVXUH VH HPSOHD SDUD LQFUHPHQWDU GLPHQVLyQGHPP6HXWLOL]yDSUR[LPDGDPHQWH
OD HVWDELOLGDG \ FRQVHUYDFLyQ GH DOLPHQWRV GH XQYROXPHQGHPOSRUDQiOLVLVDXQDWHPSHUDWXUD
GLVWLQWD QDWXUDOH]D (VWD WpFQLFD TXH SRGUtD VHU GH FRQVWDQWH GH ž& 6H UHDOL]DURQ EDUULGRV GH
JUDQXWLOLGDGFRPRWUDWDPLHQWRGHHVWDELOL]DFLyQGH IUHFXHQFLD GH +] D XQD IXHU]D GH FL]DOOD
JHOHVGH$ORHQRVHKDGHVFULWRHQODOLWHUDWXUDFRQ FRQVWDQWH3DUDHODQiOLVLVGHORVGDWRVVHHPSOHyHO
HVWHILQHVSHFtILFR/DFRQVHUYDFLyQGHORVJHOHVGH SURJUDPDHVWDGtVWLFR5Š$XFNODQG86$
$ORH VH YH FRPSURPHWLGD SRU VX EDMD HVWDELOLGDG 6HHVWLPyHOiQJXORGHIDVHGHOWDRįTXHHVXQ
ItVLFD\TXtPLFDVLHQGRORVSULQFLSDOHVIDFWRUHVGH SDUiPHWUR ~WLO SDUD GHVFULELU OD GLVWULEXFLyQ GH OD
VX GHJUDGDFLyQ OD FRQWDPLQDFLyQ PLFURELDQD \ OD PDVD PROHFXODU GH ORV SROtPHURV TXH FRQVWLWX\HQ
HOJHO\HOFRPSRUWDPLHQWRGLQiPLFRTXHSUHVHQWD
R[LGDFLyQHQ]LPiWLFDHQGyJHQD
/DV++3SHUPLWHQPLQLPL]DUODDOWHUDFLyQJUDFLDV 6H GHILQH FRPR OD FRUUHODFLyQ HQWUH HO PyGXOR
D VX FDSDFLGDG GH LQDFWLYDU PLFURRUJDQLVPRV YLVFRVR*\HOPyGXORHOiVWLFR*
FRQWDPLQDQWHV\HQ]LPDVHQGyJHQRVVLQQHFHVLGDG į DUFWJ**
GHXQDXPHQWRGHWHPSHUDWXUDQLGHODDGLFLyQGH
FRQVHUYDQWHVTXtPLFRV
(O REMHWLYR GH HVWH WUDEDMR HV HVWDELOL]DU JHOHV GH $PHGLGDTXHDXPHQWDHOYDORUGHGHOWDH[SUHVDGR
DORH D WUDYpV GH OD LQDFWLYDFLyQ GH HQJUDGRVVHYDSHUGLHQGRODFRQWULEXFLyQHOiVWLFD
PLFURRUJDQLVPRV/LVWHULDPRQRF\WRJHQHV(FROL GHOPDWHULDO
2+ 6DOPRQHOOD W\SKLPXULXP \ <HUVLQLD 'LVHxR H[SHULPHQWDO 3DUD OD E~VTXHGD GHO
HQWHURFROLWLFD \ REVHUYDU HO FRPSRUWDPLHQWR WUDWDPLHQWRySWLPRVHHPSOHyXQGLVHxRGHPDWUL]
FXDGUDGD GH +DGDPDUG HQ OD TXH VH KDFHQ
UHROyJLFRGHORVJHOHVWUDWDGRV
SDUWLFLSDU WUHV IDFWRUHV SUHVLyQ WLHPSR \
0DWHULDOHV\0pWRGRV6HXWLOL]DURQKRMDVGH FRQFHQWUDFLyQ GH HVWDELOL]DQWHV 7DEOD $ORHYHUD/DODVTXHVHH[WUDMRHOJHOLQFRORURSRU FRQMXJiQGRORV D GRV QLYHOHV \ VXSHULRU H
FRUWH\H[WUXVLyQPHFiQLFD(OPDWHULDOWHVWLJRHVWi LQIHULRU GRQGH FDGD ILOD UHSUHVHQWD FDGD XQR GH
GHSRVLWDGRHQHO+HUEDULRGHOD8QLYHUVLGDGGH/D ORVWUDWDPLHQWRV\ODVFROXPQDVGHILQHQORVYDORUHV
GH SUHVLyQ WLHPSR \ FRQFHQWUDFLyQ
/DJXQDFRQUHIHUHQFLD7)&
6HXWLOL]DURQiFLGRV/DVFyUELFR\FtWULFR3DQUHDF UHVSHFWLYDPHQWH
FRPR DJHQWHV FRDG\XYDQWHV HQ HO WUDWDPLHQWR SRU
++3 SRU VXV UHVSHFWLYDV SURSLHGDGHV
DQWLPLFURELDQDV \ DQWLR[LGDQWHV (Q IXQFLyQ GHO
GLVHxR H[SHULPHQWDO VH HPSOHDURQ D XQDV
FRQFHQWUDFLRQHVGH\YY
7UDWDPLHQWR ++3 (VWD WHFQRORJtD VH EDVD HQ HO
WUDWDPLHQWR GH PDWHULDOHV D SUHVLRQHV HQWUH \
03D XWLOL]DQGR HO DJXD FRPR PHGLR GH
WUDQVPLVLyQ GH GLFKD SUHVLyQ 3DUD HVWH HVWXGLR VH
XWLOL]y XQ HTXLSR ++3 GHO &HQWUR 1DFLRQDO GH
7HFQRORJtD \ 6HJXULGDG $OLPHQWDULD &17$ 1DYDUUD DSOLFDQGR XQD SUHVLyQ GH \ 03D\XQWLHPSRGHDSOLFDFLyQGH\PLQXWRV
,QDFWLYDFLyQ PLFURELDQD 6H HVWLPy D WUDYpV GHO
UHFXHQWRGHFpOXODVYLDEOHV\SDUDHOORODVPXHVWUDV
VHGLOX\HURQHQDJXDGHSHSWRQD\POVH
YHUWLy HQ XQD SODFD DJDU 76$ FRQ GH
H[WUDFWR GH OHYDGXUD <( 6H LQFXEDURQ D ž&
GXUDQWH KRUDV ( FROL 2+ 6
W\SKLPXULXP < HQWHURFROLWLFD \ KRUDV /
PRQRF\WRJHQHV
5HRORJtD /D FDUDFWHUL]DFLyQ UHROyJLFD VH UHDOL]y
XWLOL]DQGR XQ 5HyPHWUR %RKOLQ &6 %RKOLQ
7DEOD'LVHxRGHXQDPDWUL]+DGDPDUG[
5HVXOWDGRV \ 'LVFXVLyQ (Q OD 7DEOD VH
UHFRJHQ ORV GDWRV GH OD LQDFWLYDFLyQ PLFURELDQD
UHVXOWDQWHGHOWUDWDPLHQWRSRU++3/RVUHVXOWDGRV
GHOUHFXHQWRVHH[SUHVDQHQXIFPOGHODPLFURIORUD
QDWXUDOTXHFRQWDPLQDHODORHUHFLpQH[WUDtGRDQWHV
PXHVWUDV GH UHIHUHQFLD D ODV GRV FRQFHQWUDFLRQHV
HPSOHDGDV \ GHVSXpV GHO WUDWDPLHQWR FXDWUR
WUDWDPLHQWRVUHVXOWDQWHVGHOGLVHxRGRQGH[HVHO
Q~PHUR GH WUDWDPLHQWR D 5 UHIHUHQFLD S
03D HV OD SUHVLyQ KLGURVWiWLFD DSOLFDGD W PLQ
HV HO WLHPSR GH DSOLFDFLyQ F HV OD FRQFHQWUDFLyQ
GH ORV iFLGRV HQ SRUFHQWDMH \ XFIPO VRQ ODV
XQLGDGHVIRUPDGRUDVGHFRORQLDSRUPLOLOLWUR
7HFQRORJtD)DUPDFpXWLFD
7DEOD5HFXHQWRXFIPOGHLQDFWLYDFLyQPLFURELDQDHQ
JHOHVGHDORHWUDWDGRVSRU++3
+HUQiQGH]%/ODEUpV0)DULxD-%3DJiQ56RPROLQRV0
,;&RQJUHVRGHOD6(),*
[
5
5
$3/,&$&,Ï1'($/7$635(6,21(6+,'5267È7,&$6&2020e72'2'(
(67$%,/,=$&,Ï1'(*(/(61$785$/(6'($9(5$/
1
2
3
4
5
Experimento
)LJXUD 5HSUHVHQWDFLyQ GH OD LQIOXHQFLD GHO
WUDWDPLHQWR SRU ++3 VREUH HO iQJXOR GH IDVH D XQD
IUHFXHQFLD GH +] /RV WUDWDPLHQWRV VH
FRUUHVSRQGHQFRQGHOD7DEOD
&RQFOXVLRQHV /D DSOLFDFLyQ GH DOWDV
SUHVLRQHVDPXHVWUDVGHJHOHVGH$ORHSURYRFDXQD
UHGXFFLyQ VLJQLILFDWLYD GH OD IORUD LQLFLDO
PLFURELDQD HQ FRPSDUDFLyQ FRQ ODV PXHVWUDV GH
UHIHUHQFLDSRUORTXHVHFRQILUPDODFDSDFLGDGGH
LQDFWLYDFLyQ GH DO PHQRV XQR GH ORV IDFWRUHV
DOWHUDQWHV
&RQ UHVSHFWR DO HVWXGLR UHROyJLFR VH GHGXFH TXH
ORV PD\RUHV QLYHOHV GH WUDWDPLHQWR SURYRFDQ XQD
PD\RU LQIOXHQFLD VREUH OD YLVFRHODVWLFLGDG LQLFLDO
GHELGR HQ SDUWH D OD GHVHVWUXFWXUDFLyQ GH
SROLVDFiULGRVSUHVHQWHVHQODFRPSRVLFLyQTXtPLFD
GHORVJHOHVGH$ORH6HUiQHFHVDULRRSWLPL]DUODV
FRQGLFLRQHV GHO WUDWDPLHQWR SRU ++3 SDUD ORJUDU
XQ QLYHO GH LQDFWLYDFLyQ PLFURELDQD VLPLODU \
FDXVDUODPtQLPDDOWHUDFLyQSRVLEOHGHODHVWUXFWXUD
LQLFLDOGHOJHO
%LEOLRJUDItD
5DYHQWyV
0
,QGXVWULD
DOLPHQWDULD
7HFQRORJtDVHPHUJHQWHV83&(GV%DUFHORQD
/HZLV *$ 0DWKLHX ' 3KDQ7DQ/XX 5
3KDUPDFHXWLFDO ([SHULPHQWDO 'HVLJQ 1HZ
<RUN
6WHIIH -) 5KHRORJLFDO 0HWKRGV LQ )RRG
3URFHVV (QJLQHHULQJ QG HG (DVW /DQVLQJ
0,
'(6$552//2'(&2/2,'(60$*1e7,&26'((7,/&(/8/26$3$5$(/
75$163257('()È50$&26$17,78025$/(6
0/ySH]9LRWD-/$ULDV9*DOODUGR0$5XL]
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH
*UDQDGD&DPSXV8QLYHUVLWDULRGH&DUWXMDVQ*UDQDGD
HPDLOYJODUD#XJUHV
)H (& OD (& VH GLVROYLy HQ XQD PH]FOD
,QWURGXFFLyQ
(O REMHWLYR SULQFLSDO GH ODV WpFQLFDV GH
HWDQROEHQFHQR (VWD IDVH RUJiQLFD
WUDQVSRUWH DFWLYR ³DFWLYH WDUJHWLQJ´ HQ HO
VH HPXOVLRQy D ž& HQ XQD VXVSHQVLyQ
FDPSR GH OD WHUDSLD DQWLWXPRUDO HV ORJUDU TXH
DFXRVD GH )H P/ TXH FRQWHQtD /61D
ODGRVLVGHDJHQWHDQWLQHRSOiVLFRDGPLQLVWUDGD
> SY@ \ 3(* > VH ORFDOLFH H[FOXVLYDPHQWH HQ HO WHMLGR
SY@ /D HPXOVLyQ \ OD VXEVLJXLHQWH
WXPRUDO 'H HVWD PDQHUD VH ORJUD PHMRUDU OD
HYDSRUDFLyQ WRWDO GH GLVROYHQWHV VH
HILFDFLDDQWLWXPRUDO\HOSHUILOIDUPDFRFLQpWLFR
UHDOL]DURQ EDMR DJLWDFLyQ PHFiQLFD GHOTXLPLRWHUiSLFR\DGHPiVODLQFLGHQFLDGH
USP /D OLPSLH]D GH ODV SDUWtFXODV VH
HIHFWRV DGYHUVRV DVRFLDGRV DO WUDWDPLHQWR HV
UHDOL]y PHGLDQWH VHSDUDFLyQ PDJQpWLFD \
PtQLPD R QXOD /DV HVWUDWHJLDV GH ³DFWLYH
UHGLVSHUVLyQGHORVVHGLPHQWRVHQDJXD
WDUJHWLQJ´ WDPELpQ SHUPLWHQ UHYHUWLU ORV
IHQyPHQRVGHUHVLVWHQFLDDIiUPDFRVTXHVXHOH
SUHVHQWDHOWHMLGRWXPRUDO(QWUHHVWDVWpFQLFDV
GHVWDFDQ OD IXQFLRQDOL]DFLyQ VXSHUILFLDO GHO
VLVWHPD WUDQVSRUWDGRU FRQ ELROLJDQGRV
HVSHFtILFRV GH ODV FpOXODV FDQFHURVDV
FRQMXJDFLyQ FRQ DSWiPHURV IRODWRV
LQWHJULQDV SpSWLGRV HWF \ HO GLVHxR GH
PDWHULDOHV FRQ FDSDFLGDG GH UHVSXHVWD D
HVWtPXORV VHQVLELOLGDG D FDPELRV GH S+ R GH
WHPSHUDWXUDHWF'HQWURGHHVWD~OWLPD
HVWUDWHJLD XQD SURSXHVWD PX\ SURPHWHGRUD HV
)LJ 0LFURIRWRJUDItD +57(0 GH FDPSR
HO GLVHxR GH PDWHULDOHV FRQ FDSDFLGDG SDUD
RVFXUR GH ODV QDQRSDUWtFXODV FRPSXHVWDV
UHVSRQGHUDFDPSRVPDJQpWLFRV
)H (&(OUHFXEULPLHQWRGH(&DSDUHFHHQ
(QHVWHWUDEDMRGHVFULELPRVODSUHSDUDFLyQ\
EODQFR/RQJLWXGGHEDUUDQP
FDUDFWHUL]DFLyQ ILVLFRTXtPLFD GH FRORLGHV
(VWXGLR GH OD YHKLFXOL]DFLyQ GH )8 \ VX
PDJQpWLFRV GH HWLOFHOXORVD (& FDUJDGRV FRQ
OLEHUDFLyQLQYLWUR
IOXRURXUDFLOR )8 1RV FHQWUDPRV HQ HO
/D YHKLFXOL]DFLyQ GH )8 VH HVWXGLy
DQiOLVLV GH ORV SDUiPHWURV TXH GHWHUPLQDQ OD
HPSOHDQGR GRV SURFHGLPLHQWRV DGVRUFLyQ
YHKLFXOL]DFLyQ GH )8 DVt FRPR OD
VXSHUILFLDOHQSDUWtFXODVSUHIRUPDGDV)H(&
FRQWULEXFLyQ GH FDGD XQRV GH ORV PDWHULDOHV
\ )H (& \ DEVRUFLyQ R LQFRUSRUDFLyQ HQ OD
TXH FRPSRQHQ HO VLVWHPD FRORLGDO SURSXHVWR
PDWUL]GHORVFRORLGHV(&\)H (&PHGLDQWH
)LQDOPHQWH LQYHVWLJDPRV ORV IDFWRUHV
OD DGLFLyQ GHO IiUPDFR HQ HO PHGLR GH
GHWHUPLQDQWHVGHOSHUILOGHOLEHUDFLyQLQYLWUR
HPXOVLyQ DQWHV GH OD IRUPDFLyQ GH ODV
SDUWtFXODV
0HGLDQWH
XQ
PpWRGR
0DWHULDOHV\0pWRGRV
0DWHULDOHV
HVSHFWURIRWRPpWULFR YDOLGDGR Ȝ QP
İ “ /ÂPRO ÂFP VH GHWHUPLQy
/RV UHDFWLYRV VRQ GH FDOLGDG DQDOtWLFD
3DQUHDF(VSDxDH[FHSWRHO)86LJPD
SRU WULSOLFDGR OD YHKLFXOL]DFLyQ GH )8 \
$OGULFK $OHPDQLD HO SROtPHUR HWLOFHOXORVD
VXOLEHUDFLyQ“ž&VROXFLyQEXIIHU
,&1 %LRPHGLFDO ,QF ((88 \
1D2+.+ 32 GH S+ FRQGLFLRQHV
HOKLHUURFDUERQLOR)H %$6)$OHPDQLD(O
VLQN GHVGH ORV FRORLGHV GLVHxDGRV /D
DGVRUFLyQ GH )8 WDPELpQ VH HYDOXy
DJXD XWLOL]DGD IXH GHVLRQL]DGD \ ILOWUDGD
FXDOLWDWLYDPHQWH PHGLDQWH GHWHUPLQDFLRQHV
0LOOL4$FDGHPLF0LOOLSRUH)UDQFLD
HOHFWURFLQpWLFDV
3UHSDUDFLyQGHORVVLVWHPDVFRORLGDOHV
5HVXOWDGRV\'LVFXVLyQ
/DV SDUWtFXODV GH )H ± QP VH
$GVRUFLyQGH)8
VHOHFFLRQDURQ PHGLDQWH VHSDUDFLyQ SRU
(Q WRGRV ORV VLVWHPDV OD HILFLHQFLD GHO
JUDYHGDG/DVtQWHVLVGHODVSDUWtFXODVGH
SURFHVR GH DGVRUFLyQ VH LQFUHPHQWD DO
(&±QP\GH)H (&±
DXPHQWDU OD FRQFHQWUDFLyQ GH DQWLWXPRUDO HQ
QP)LJXUDVHUHDOL]yPHGLDQWHXQ
VROXFLyQ )LJXUD D (Q FRQFUHWR OD FDQWLGDG
PpWRGR GH HPXOVLILFDFLyQ SUHYLDPHQWH
Pi[LPDDGVRUELGDSRUHO)HHOOiWH[GH(&\
GHVFULWR(QHOFDVRGHODVSDUWtFXODVGH
,;&RQJUHVRGHOD6(),*
ODV SDUWtFXODV FRPSXHVWDV HV “ ȝPROP “ ȝPROP \ “ ȝPROP UHVSHFWLYDPHQWH &RPR SXHGH
DSUHFLDUVH VH VXJLHUH OD VDWXUDFLyQ GH HVWH
SURFHVR D FRQFHQWUDFLRQHV VXSHULRUHV D ODV
HQVD\DGDV /D HOHFWURIRUHVLV FRQILUPD HO
SURFHVR GH DGVRUFLyQ HO FXiO HV PX\
LQIHULRUHQHOFDVRGHO)H )LJXUDE
)LJ 'HQVLGDG GH DGVRUFLyQ GH )8 D \
PRYLOLGDG HOHFWURIRUpWLFD GH ORV FRORLGHV E
HQIXQFLyQGHOD>)8@
$EVRUFLyQGH)8
(QOD)LJXUDVHDSUHFLDFyPRODDEVRUFLyQ
DXPHQWD FRQ OD FRQFHQWUDFLyQ GH IiUPDFR
VXJLULpQGRVHXQDWHQGHQFLDDODVDWXUDFLyQSDUD
FRQFHQWUDFLRQHVVXSHULRUHV
)LJ 'HQVLGDG GH DEVRUFLyQ GH )8 HQ
IXQFLyQGHOD>)8@HQHOHTXLOLEULR
/RV UHVXOWDGRV REWHQLGRV PHMRUDQ ORV
DOFDQ]DGRVFRQHOSURFHGLPLHQWRGHDGVRUFLyQ
$GHPiV OD YHKLFXOL]DFLyQ HV VXSHULRU HQ ODV
SDUWtFXODVGH)H(&KDVWD“ȝPROJHQ
FRPSDUDFLyQ FRQ ODV GH (& KDVWD “ ȝPROJ KHFKR TXH DWULEXLPRV D TXH ORV
Q~FOHRV PDJQpWLFRV XWLOL]DGRV HQ OD REWHQFLyQ
GH ODV QDQRSDUWtFXODV FRPSXHVWDV \D WLHQHQ
IiUPDFRDGVRUELGRHQVXVXSHUILFLH
/LEHUDFLyQLQYLWURGH)8
/D )LJXUD PXHVWUD TXH HO SURFHVR GH
OLEHUDFLyQ GH )8 HV ELIiVLFR XQD IDVH GH
7HFQRORJtD)DUPDFpXWLFD
OLEHUDFLyQUiSLGDSpUGLGDGHO)8DVRFLDGRD
OD VXSHUILFLH VHJXLGD GH XQD IDVH GH
OLEHUDFLyQPiVOHQWDDWULEXLEOHDODGLIXVLyQGHO
IiUPDFR D WUDYpV GH OD PDWUL] SROLPpULFD /D
OLEHUDFLyQ GHVGH ODV SDUWtFXODV GH )H(& VH
UHDOL]DGHXQDIRUPDDOJRPiVOHQWD≈HQ
ODVSULPHUDVKRUDV\HOUHVWDQWHHQODV
VLJXLHQWHV KRUDV (VWR SXHGH H[SOLFDUVH VL
FRQVLGHUDPRVTXHSDUWHGHODQWLWXPRUDOHVWi\D
DGVRUELGR HQ HO )H FXDQGR VH IRUPD HO
UHFXEULPLHQWR GH OiWH[ VREUH pVWH $Vt HO
IiUPDFR ORFDOL]DGR HQ OD VXSHUILFLH GH ORV
Q~FOHRV PDJQpWLFRV GHEH GLIXQGLU D WUDYpV GH
OD FXELHUWD SROLPpULFD SDUD SRGHU VDOLU DO
H[WHULRU OR TXH UDOHQWL]D HO SURFHVR GH FHVLyQ
GH)8
)LJ /LEHUDFLyQ GH )8 HQ IXQFLyQ
GHOWLHPSRDS+ &RQFOXVLRQHV
6H KDQ LGHQWLILFDGR ODV FRQGLFLRQHV LGHDOHV
SDUD VtQWHWL]DU QDQRSDUWtFXODV PDJQpWLFDV
)H(&FRQFDSDFLGDGSDUDWUDQVSRUWDU)8
\DGHFXDGDVSDUDODYtDSDUHQWHUDO(OSURFHVR
GHDEVRUFLyQSHUPLWHXQDPD\RULQFRUSRUDFLyQ
GH)8HQFRPSDUDFLyQFRQODDGVRUFLyQ
%LEOLRJUDItD
9DXWKLHU & HW DO $GY 'UXJ 'HOLY 5HY -DEU0LODQH/6HWDO&DQFHU7UHDW5HY
'XUiQ-'*HWDO-3KDUP6FL
$ULDV-/HWDO/DQJPXLU
$ULDV-/HWDO-&ROORLG,QWHUIDFH6FL
$ULDV-/HWDO,QW-3KDUP
$ULDV -/ HW DO (XU - 3KDUP 6FL ,;&RQJUHVRGHOD6(),*
SUHSDUDGDV >§ SY@ IXHURQ VRQLFDGDV
GXUDQWHPLQXWRVSUHYLDPHQWH
3DUD OD GHWHUPLQDFLyQ FXDOLWDWLYD GH OD
YHKLFXOL]DFLyQ GHO DOFDORLGH VH DQDOL]y HO
HVSHFWUR GH +501 %URNHU $0
((88
REWHQLGR
XWLOL]DQGR
GLPHWLOVXOIy[LGR GHXWHUDGR '062 '
(XULVRWRSŠ6$)UDQFLD
)LQDOPHQWH OD FDUDFWHUL]DFLyQ SUHOLPLQDU
GHOWLSRGHYHKLFXODFLyQGHODOFDORLGHHQODV
SDUWtFXODV GH 32&$ DGVRUFLyQDEVRUFLyQ
FRQVLVWLy HQ OD GHWHUPLQDFLyQ GH ODV
SURSLHGDGHV HOpFWULFDV VXSHUILFLDOHV GH ODV
SDUWtFXODV \ VX GHSHQGHQFLD GHO S+
PHGLDQWHHOHFWURIRUHVLV
5HVXOWDGRV\'LVFXVLyQ
(OWDPDxRPHGLRGHODVSDUWtFXODVGH32&$HV
± QP ,3 PLHQWUDV TXH HQ ODV
SDUWtFXODV FDUJDGDV FRQ HO DOFDORLGH HV ±
QP ,3 (O DXPHQWR GH WDPDxR
SXHGH VHU GHELGR D OD YHKLFXOL]DFLyQ GH OD
FDQWKLQRQH
(QOD)LJXUDSXHGHDSUHFLDUVHHOHVSHFWURGH
+501 GH ODV QDQRSDUWtFXODV GH 32&$ FRQ
FDQWKLQRQH YHKLFXOL]DGD /D SUHVHQFLD GH
ODVEDQGDVFDUDFWHUtVWLFDVGHODOFDORLGH>į
SSP+G+SSP+G+
SSP+G+SSP+G+
SSP+G+SSP+W+
SSP+W+SSP+G+@HQHO
HVSHFWUR
GHO
SROtPHUR
GHPXHVWUD
FXDOLWDWLYDPHQWH OD HILFDFLD GH OD
YHKLFXOL]DFLyQ
)LJ(VSHFWUR +501GHODVSDUWtFXODVGH
32&$FDUJDGDVFRQFDQWKLQRQH
/D )LJXUD PXHVWUD ORV YDORUHV GH
SRWHQFLDO ]HWD HQ IXQFLyQ GHO S+ HQ
SUHVHQFLDGH1D&O 0/DVSDUWtFXODVGH
32&$ SUHVHQWDQ XQD FDUJD VXSHUILFLDO QHWD
QHJDWLYD HQ WRGR HO LQWHUYDOR GH S+V
HVWXGLDGR GH D \ VyOR ORV GDWRV
VXJLHUHQODSUHVHQFLDGHOSXQWRLVRHOpFWULFR
R S+ GH SRWHQFLDO ]HWD FHUR D S+V &RPR VH DSUHFLD QR H[LVWH GLIHUHQFLD
DOJXQD HQWUH ODV SURSLHGDGHV HOpFWULFDV
VXSHUILFLDOHV GH ODV SDUWtFXODV SROLPpULFDV
35(3$5$&,Ï1'(6,67(0$6&2/2,'$/(632/,0e5,&26&2029(+Ë&8/26'(/
$/&$/2,'(&$17+,121(
*&HEULiQ-/$ULDV(3RXSRQ0$5XL]
/DERUDWRLUHGH3KDUPDFRJQRVLH805%LR&,6)DFXOWpGH3KDUPDFLH8QLYHUVLWp3DULV6XG
&KkWHQD\0DODEU\)UDQFH
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH
*UDQDGD&DPSXV8QLYHUVLWDULRGH&DUWXMDVQ*UDQDGD
HPDLOMODULDV#XJUHV
,QWURGXFFLyQ
0DWHULDOHV\0pWRGRV
/RV SROLDOTXLOFLDQRDFULODWRV 3$&$V VRQ
0DWHULDOHV
/RV UHDFWLYRV HPSOHDGRV VRQ GH FDOLGDG
XQD IDPLOLD GH SROtPHURV PX\ XWLOL]DGD HQ
DQDOtWLFD
6LJPD$OGULFK
$OHPDQLD
%LRPHGLFLQD FRPR PDWHULDO HPEROtWLFR
H[FHSWR HO PRQyPHUR RFWLOFLDQRDFULODWR
SHJDPHQWR TXLU~UJLFR R DGKHVLYR GH WHMLGRV
UHJDOR GH +HQNHO /RFWLWH ,UODQGD (O DJXD
/DV QDQRSDUWtFXODV GH 3$&$ SUHVHQWDQ
XWLOL]DGDIXHGHVLRQL]DGD\ILOWUDGD0LOOL4
PXOWLWXG GH DSOLFDFLRQHV FRPR VLVWHPDV
$FDGHPLF0LOOLSRUH)UDQFLD
WUDQVSRUWDGRUHV GH IiUPDFRV FRQ GLIHUHQWHV
6tQWHVLVTXtPLFDGHODFDQWKLQRQH
GLDQDV \ YtDVGHDGPLQLVWUDFLyQ $FWXDOPHQWH
KDQDGTXLULGRHVSHFLDOLQWHUpVHQHOWUDWDPLHQWR
/DVtQWHVLV WRWDOGHODFDQWKLQRQHFRPLHQ]D
GHO FiQFHU \ VH HQFXHQWUDQ HQ IDVH GH
FRQ XQD UHDFFLyQ HQWUH WULSWDPLQD \ DQKtGULGR
LQYHVWLJDFLyQFOtQLFD
VXFFtQLFRHQ&+&O\DWHPSHUDWXUDDPELHQWH
/D FDQWKLQRQH &+12 )LJXUD HV
$ FRQWLQXDFLyQ OD WULSWDPLGD REWHQLGD VH
HVWHULILFD PHGLDQWH FDWiOLVLV SRU $PEHUOLVW +
XQDOFDORLGHGHRULJHQQDWXUDOTXHSHUWHQHFHDO
HQ0H2+JHQHUiQGRVHDVtXQPHWLOpVWHU(O
JUXSR GH OD ȕFDUEROLQD \ TXH SUHVHQWD OD
WUDWDPLHQWRGHODDPLGDFRQ32&OHQEHQFHQR
SHFXOLDULGDG GH WHQHU XQ FLFOR ' DGLFLRQDO HQ
VX HVWUXFWXUD (VWH DOFDORLGH VH
\DUHIOXMRGXUDQWHKRUDVRULJLQDODFLFODFLyQ
FDUDFWHUL]D SRU SUHVHQWDU XQD EDMD WR[LFLGDG \
\IRUPDFLyQGHXQDLPLQD/DHWDSDILQDOGHOD
XQD QRWDEOH DFWLYLGDG DQWLI~QJLFD SDUDVLWLFLGD
VtQWHVLV HV XQD FLFODFLyQ LQWUDPROHFXODU
DQWLWULSDQRVRPD \ OHLVKPDQLFLGD \
PHGLDQWH OD UHDFFLyQ GH %LVFKHU1DSLHUODVNL
DQWLEDFWHULDQD 6LQ HPEDUJR VX HOHYDGD
(VWHSDVRVHUHDOL]DDOH[SRQHUDODLPLQDDXQD
OLSRILOLD OLPLWD XQD SRVLEOH XWLOL]DFLyQ PiV
EDVH IXHUWH HM GLD]DELFLFORXQGHFHQR HQ
DPSOLDHQWHUDSpXWLFD
&+&O \ D WHPSHUDWXUD DPELHQWH
REWHQLpQGRVHDVtODFDQWKLQRQHUHQGLPLHQWR
≈
6tQWHVLVGHODVSDUWtFXODVSROLPpULFDVFDUJDGDV
FRQFDQWKLQRQH
/D VtQWHVLV GH QDQRHVIHUDV GH 32&$ VH
UHDOL]y
PHGLDQWH
HO
PpWRGR
GH
SROLPHUL]DFLyQ HQ HPXOVLyQ GHO PRQyPHUR
FRUUHVSRQGLHQWH %UHYHPHQWH VH DxDGH
HORFWLOFLDQRDFULODWR>SY@GLVXHOWRHQ
P/ GH DFHWRQD EDMR DJLWDFLyQ PHFiQLFD
D P/ GH XQD IDVHDFXRVD 1GH +&O
\FRQXQSYGH3OXURQLF ®)7UDV
KRUDV VH QHXWUDOL]D FRQ FDQWLGDG
)LJ (VWUXFWXUD TXtPLFD GH OD FDQWKLQ
VXILFLHQWH GH .2+ /D VtQWHVLV GH ODV
RQH
SDUWtFXODV FDUJDGDV FRQ HVWH DOFDORLGH VH
UHDOL]D GH LJXDO IRUPD FRQ OD ~QLFD
(Q HO SUHVHQWH WUDEDMR LQYHVWLJDPRV HO GLVHxR
GLIHUHQFLD GH TXH HQ OD VROXFLyQ DFHWyQLFD
GH QDQRSDUWtFXODV GH SROLRFWLOFLDQRDFULODWR
GH PRQyPHUR WDPELpQ VH HQFXHQWUD OD
32&$ FRPR VLVWHPD GH WUDQVSRUWH GH OD
FDQWKLQRQH
GLVXHOWD
S
FDQWKLQRQH FRQ HO REMHWLYR GH PHMRUDU VX
RFWLOFLDQRDFULODWRYVSFDQWKLQRQH
IRUPXODFLyQ \ GH HVWH PRGR VX
&DUDFWHUL]DFLyQ ILVLFRTXtPLFD GHO VLVWHPD
ELRGLVSRQLELOLGDG\HIHFWRWHUDSpXWLFR(QHVWH
WUDQVSRUWDGRUSROLPpULFR
HVWXGLRSUHOLPLQDU QRVFHQWUDPRVHQHOGLVHxR
/D GHWHUPLQDFLyQ GHO WDPDxR GH SDUWtFXOD
GH XQD PHWRGRORJtD DGHFXDGD GH SUHSDUDFLyQ
VH UHDOL]y D WHPSHUDWXUD DPELHQWH \
DVt FRPR HQ HO DQiOLVLV GHO WLSR GH
PHGLDQWH VFDWWHULQJ GH OX] FXDVLHOiVWLFR
YHKLFXOL]DFLyQ GH HVWH DOFDORLGH HQ ODV
4(/6 1DQRVL]HU &RXOWHU 10' &RXOWHU
SDUWtFXODVSROLPpULFDV
(OHFWURQLFV ,QF +LDOHDK )/ (O iQJXOR
VHOHFFLRQDGR IXH GH ž \ ODV VXVSHQVLRQHV
7HFQRORJtD)DUPDFpXWLFD
TXH FDUHFHQ GH DOFDORLGH YHKLFXOL]DGR \ GH
ODV SDUWtFXODV TXH OR LQFRUSRUDQ (VWR QRV
KDFH FRQFOXLU GH IRUPD SUHOLPLQDU TXH OD
FDQWKLQRQH VH HQFXHQWUD DEVRUELGD HQ HO
LQWHULRUGHOFRORLGHSROLPpULFR
)LJ3RWHQFLDO]HWDGHODVQDQRSDUWtFXODVGH
32&$ HQ IXQFLyQ GHO S+ )L FWH 0
1D&O
&RQFOXVLRQHV
6H KDQ LGHQWLILFDGR ODV FRQGLFLRQHV LGHDOHV
SDUD OD SUHSDUDFLyQ GH XQ VLVWHPD FRORLGDO
SROLPpULFR TXH SHUPLWH OD YHKLFXOL]DFLyQ GHO
DOFDORLGH FDQWKLQRQH (O WDPDxR GH
SDUWtFXOD VH YH DIHFWDGR SRU OD LQFRUSRUDFLyQ
GHODELRPROpFXOD(OHVSHFWURGH+501\OD
FDUDFWHUL]DFLyQ HOHFWURFLQpWLFD GHO FRORLGH
DSXQWDQ HIHFWLYDPHQWH D TXH HO DOFDORLGH VH
LQFRUSRUDHQODVSDUWtFXODVDQLYHOGHODPDWUL]
PHGLDQWHXQSURFHVRGHDEVRUFLyQ(VWHWUDEDMR
DEUH ODV SXHUWDV DO GHVDUUROOR GH VLVWHPDV
WUDQVSRUWDGRUHV GH OD FDQWKLQRQH \ VXV
GHULYDGRV
%LEOLRJUDItD
$ULDV -/ HW DO &ROORLGV 6XUI %
%LRLQWHUIDFHV
9DXWKLHU & HW DO $GY 'UXJ 'HOLY
5HY
0D=HWDO-3K\WRFKHPLVWU\
%U|FNHOPDQ0HWDO(XU-2UJ&KHP
6RULDQR$JDWRQ)HWDO-1DW3URG
)HUUHLUD 0( HW DO - (WKQRSKDUPDFRO
2'RQQHOO * *LEERQV 6 3K\WRWKHU
5HV
$ULDV-/HWDO,QW-3KDUP
&+$5$&7(5,=$7,212)2&8/$5,16(576%$6('2162',80
+<$/8521$7(+<'52;<3523</0(7+</&(//8/26(
0&DEULRXOX60XUD90HULQR00HULQR6DQMXiQ$1iFKHU00DQFRQL$0
)DGGD2'tH]6DOHV
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH9DOHQFLD$Y9LFHQWH$QGUpV
(VWHOOpVVQ%XUMDVVRW9DOHQFLD(VSDxD
'LSDUWLPHQWR)DUPDFR&KLPLFR7HFQRORJLFR8QLYHUVLW\RI&DJOLDUL9LD2VSHGDOH
&DJOLDUL,WDO\
FRQHSODWH ž PP GLDPHWHU 6WHDG\VWDWH
,QWURGXFWLRQ
7UDGLWLRQDO WRSLFDO RSKWKDOPLF IRUPXODWLRQV
IORZ FXUYHV ZHUH REWDLQHG ZRUNLQJ LQ
VXFK DV DTXHRXV H\H GURSV HQVXUH SRRU GUXJ
FRQWUROOHG VWUHVV PRGH 'LIIHUHQW UDQJHV RI
ELRDYDLODELOLW\GXHWRVHYHUDOSURFHVVHVVXFKDV
VKHDUVWUHVVHVLQORJDULWKPLFGLVWULEXWLRQZHUH
DUDSLGSUHFRUQHDOGUXJHOLPLQDWLRQ0RUHRYHU
XVHGLQRUGHUWRREWDLQVKHDUUDWHVEHWZHHQ
WUDGLWLRQDOH\HGURSDGPLQLVWUDWLRQDOVRVKRZV
DQG V DSSUR[LPDWHO\ 7KLV YDULDWLRQ LQ
D SRRU SDWLHQW FRPSOLDQFH &RQVHTXHQWO\
YLVFRVLW\ ZLWK VKHDU UDWH ZDV ILWWHG ZLWK WKH
VHYHUDO QRYHO RSKWKDOPLF GUXJ GHOLYHU\
VLPSOLILHG&DUUHDXPRGHO V\VWHPV KDYH EHHQ GHYHORSHG 5HFHQWO\
η
η=
RFXODU LQVHUWV RI YDULRXV RSKWKDOPLF GUXJV
F
ª § • · º
ZHUH UHSRUWHG WR LPSURYH SRRU RFXODU GUXJ
« + ¨ γ ¸ »
« ¨¨ γ ¸¸ »
ELRDYDLODELOLW\ ,Q SDUWLFXODU SURORQJHG
«¬ © F ¹ »¼
GHOLYHU\ RI GUXJV WR WKH H\H RIIHUV VHYHUDO
ZKHUHηRLVWKH]HURVKHDUYLVFRVLW\3DVWKH
DGYDQWDJHV RYHU WKH FRQYHQWLRQDO RFXODU
FRQVWDQW YLVFRVLW\ LQ WKH ORZHU 1HZWRQLDQ
WKHUDSLHV ,QGHHG FRQWUROOHG UHOHDVH RFXODU
SODWHDX γF LV WKH FULWLFDO VKHDU UDWH
LQVHUWVFDQGHOLYHUDQHIIHFWLYHGUXJDPRXQWWR
FRUUHVSRQGLQJ WR WKH WUDQVLWLRQ IURP
WKHH\HIRUDQH[WHQGHGSHULRGRIWLPH
1HZWRQLDQ WR VKHDUWKLQQLQJ EHKDYLRU V F
7KHDLPRIWKHVWXG\ZDVWRGHYHORSDQRFXODU
LV HTXDO WR Q DQG Q LV D GLPHQVLRQOHVV
ILOP IRU WKH RSKWKDOPLF FRQWUROOHG GHOLYHU\ RI
FRQVWDQW WKDW FRUUHVSRQGV WR WKH SRZHU ODZ
GLFORIHQDF
LQGH[RUIORZLQGH[
0DWHULDOVDQG0HWKRGV
,Q YLWUR SHUPHDWLRQ VWXGLHV ([FLVHG FRUQHD
3UHSDUDWLRQ RI LQVHUWV $TXHRXV GLVSHUVLRQV
IURP WKH ERYLQH H\H ZDV XVHG IRU WKH
RI 6RGLXP +\DOXURQDWH +$ DQG
GHWHUPLQDWLRQRILQYLWURFRUQHDOSHUPHDELOLW\
+\GUR[\SURS\OPHWK\OFHOOXORVH+30&ZHUH
)UDQ] GLIIXVLRQ FHOOV ZHUH XVHG 5HFHLYHU
SUHSDUHG E\ XVLQJ WKH IROORZLQJ +$+30&
FKDPEHU FRQWDLQHG SKRVSKDWH EXIIHUHG VDOLQH
ZZUDWLRV)LOP,)LOP,,DQG
S+ LQ DOO FDVHV 6DPSOHV ZHUH DQDO\]HG
)LOP ,,, 'LFORIHQDF ZDV GLVSHUVHG LQ
XVLQJ D :DWHUV +3/&89 V\VWHP DW D
WKH PL[WXUHV WR REWDLQ LQ DOO FDVHV D ZDYHOHQJWK RI QP 7KH DSSDUHQW
ZZGUXJFRQFHQWUDWLRQ7RREWDLQILOPV
FRUQHDO SHUPHDELOLW\ FRHIILFLHQW 3DSS FPK
JRIWKHVROXWLRQVZHUHSRXUHGLQWRUHFWDQJXODU
ZDVGHWHUPLQHGXVLQJWKHH[SUHVVLRQ
JODVV SODWHV [ FP 7KH GLVSHUVLRQV ZHUH
GULHGRYHUQLJKWWRFRQVWDQWZHLJKW)LOPVZHUH
Δ4
3DSS =
VWRUHGDWž&DQGDUHODWLYHKXPLGLW\5+RI
ΔW ⋅ $ ⋅ &R
7KLFNQHVV RI WKH ILOPV ZDV GHWHUPLQHG
ZKHUH4LVWKHWRWDODPRXQWSHUPHDWHGDWWLPH
XVLQJ D PLFURPHWHU 5HSRUWHG YDOXHV DUH DQ
W Δ4ΔW LV WKH VWHDG\VWDWH VORSH RI WKH OLQHDU
DYHUDJHRIPHDVXUHPHQWVIRUHDFKILOP
SRUWLRQRIWKHSORW IRUWKHDPRXQWRIWKHGUXJ
5KHRPHWULF PHDVXUHPHQWV $ +DDNH
LQWKHUHFHLYLQJFKDPEHU4YHUVXVWLPHW$
5KHRVWUHVV UKHRPHWHU 7KHUPR +DDNH
LV WKH H[SRVHG FRUQHDO VXUIDFH FP DQG
*HUPDQ\ ZLWK GDWD DFTXLVLWLRQ VRIWZDUH
&RLVWKHLQLWLDOFRQFHQWUDWLRQRIWKHGUXJLQWKH
5KHR:LQ DQG D FLUFXODWRU IRU VDPSOH
GRQRUFHOO
WHPSHUDWXUH FRQWURO ZDV XVHG 6DPSOHV ZHUH
Results and discussion
DOORZHG WR UHVW IRU DW OHDVW V SULRU WR
Homogeneous, flexible and transparent
DQDO\VLV,QDOOFDVHVWKHH[SRVHGHGJHVRIWKH
films were obtained from the prepared
VDPSOH ZHUH FRYHUHG ZLWK VLOLFRQH RLO
solutions. All films were easily removed
'LPHWKLFRQH 5)( 3K (XU WR SUHYHQW
from the cast plate and no pores or cracks
HYDSRUDWLRQRIZDWHUGXULQJPHDVXUHPHQWV$OO
were detected. Thickness of films varied
PHDVXUHPHQWVZHUHPDGHLQWULSOLFDWHDWž&
7KH IRUPXODWLRQV ZHUH VXEMHFWHG WR YLVFRVLW\
from 92.7 ± 8.9 (Film I) to 95.3 ± 9.1 (Film
PHDVXUHPHQWV DIWHU PL[LQJ ZLWK ODFKU\PDO
II) to 99.5 ± 10.2 μm (Film III).
IOXLGWRDVVHVVWKHGLOXWLRQDFWLRQRIWKHWHDUVLQ
YLYR7KHIORZFXUYHVZHUHFDUULHGRXWXVLQJD
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
Errors bars represent standard deviations
based on four experiments.
10
Viscosity (Pas)
Fim I
Film II
Film III
Conclusions
HA/HPMC films showed the capability to
control diclofenac transcorneal permeation
rate in vitro. Moreover, the drug
permeation rate was affected by the HA
concentration in the film: the higher the
concentration the slower the permeation.
Therefore, these preliminary results
indicate that HA/HPMC in appropriate ratio
can be used as drug controlled delivery
systems for topical ocular administration.
1
0.1
0.01
1
10
100
1000
Shear rate (s-1)
Fig. 1. Effect of shear rate on shear
viscosity of HA/HPMC films.
,QWURGXFWLRQ
3DUNLQVRQV GLVHDVH 3' LV RQH RI WKH PDLQ
QHXURGHJHQHUDWLQJ GLVRUGHUV DIIHFWLQJ ROG
SHRSOH 3' LV FKDUDFWHUL]HG E\ D SURJUHVVLYH
ORVVRIGRSDPLQHUJLFQHXURQVLQWKHVXVEWDQWLD
QLJUD FRPSDFWD OHDGLQJ WR DQ LPSDLUPHQW RI
WKHQLJURVWULDWDOSDWKZD\ZKLFKLVUHVSRQVLEOH
IRU WKH DEQRUPDO PRWRU EHKDYLRU RI WKHVH
SDWLHQWV 7KH PDLQVWD\ WUHDWPHQW LV /
'RSD EXW DV WKH GLVHDVH SURJUHVV SDWLHQWV
EHFRPHOHVVUHVSRQVLYHWR/'RSDDQGGHYHORS
PRWRU VLGH HIIHFWV 1R FXUUHQWO\ DYDLODEOH
WUHDWPHQW
DOWHUV
WKH
SURJUHVVLYH
QHXURGHJHQHUDWLYHFRXUVHRI3'
$SURPLVLQJVWUDWHJ\IRUWKHWUHDWPHQWRI3'LV
WKH XVH RI QHXURWURSKLF IDFWRUV WKDW FRXOG
SURWHFW WKH UHPDLQLQJ GRSDPLQHUJLF FHOOV RU
HYHQ UHJHQHUDWH WKHP LQ RUGHU WR UHYHUVH WKH
QHXURGHJHQHUDWLYH SURFHVV *OLDO FHOOOLQH
GHULYHG QHXURWURSKLF IDFWRU *'1) LV
FRQVLGHUHG WR EH RQH RI WKH VWURQJHVW
QHXURSURWHFWDQWV VSHFLILF IRU GRSDPLQHUJLF
QHXURQV %DVHG RQ WKH VXFFHVVIXO UHVXOWV LQ
DQLPDOH[SHULPHQWVSKDVH,FOLQLFDOWULDOVZHUH
SHUIRUPHG ZLWK D YHU\ SURPLVLQJ HIIHFW $OWKRXJK IXUWKHU VWXGLHV DUH QHHGHG WKH
GHOLYHU\LVVXHUHPDLQVXQVROYHG
7KH DLP RI WKLV ZRUN ZDV WR GHYHORS D
SURFHGXUH IRU WKH SXULILFDWLRQ RI KXPDQ
ELRDFWLYHJO\FRV\ODWHG*'1)DQGLWVSRVWHULRU
PLFURHQFDSVXODWLRQ LQ 3/*$ PLFURSDUWLFOHV
IRUWKHWUHDWPHQWRI3'
0DWHULDOVDQG0HWKRGV
7KH K*'1) VHFUHWLQJ FHOO OLQH 0'; ZDV
NLQGO\ SURYLGHG E\ SURIHVVRU 3DWULFN
$HELVFKHU (3)/ /DXVDQQH 6ZLW]HUODQG
7KHVH FHOOV ZHUH FXOWXUHG LQ '0(0
*OXWD0$;70,FRQWDLQLQJIRHWDOERYLQH
VHUXP :KHQ WKH FHOOV UHDFKHG FRQIOXHQFH WKH\ ZHUH ZDVKHG ZLWK 3%6 DQG
H[SRVHG WR IUHVK VHUXPIUHH PHGLXP 7KH
FRQGLWLRQHG PHGLXP ZDV FROOHFWHG IRU WKH
SXULILFDWLRQRIWKHUHFRPELQDQWK*'1)
7KH VHFUHWHG SURWHLQ ZDV SXULILHG E\ VHYHUDO
FKURPDWRJUDSK\VWHSVDVIROORZV
3XULILFDWLRQ
&DWLRQ([FKDQJH&KURPDWRJUDSK\
7KH S+ RI WKH FXOWXUH FRQGLWLRQHG PHGLXP
ZHUH DGMXVWHG WR DQG ILOWHUHG 7KH VDPSOH
SDVVHG WKURXJK D ;. FROXPQ SDFNHG
ZLWK 63 6HSKDURVH70 )DVW )ORZ XVLQJ D
5HIHUHQFHV
+RUQRI0HWDO-&RQWURO5HO
.DZDNDPL6HWDO-&RQWRO5HO
&RUULDV)HWDO-$SSO3RO\P6FL
5LHJHO 0 (OOLV 33 - &KURPDWRJU %
%LRPHG$SSO
$FNQRZOHGJHPHQW
7KH DXWKRUV WKDQN WKH &RQVHOOHULD G
(PSUHVD
8QLYHUVLWDW L &LqQFLD 9DOHQFLDQ *HQHUDOLWDW
IRUWKHILQDQFLDOVXSSRUW*9
The flow curves, which show viscosity as
a function of the shear rate, are reported
in Fig.1 for the three studied formulations.
The viscosity decreased by increasing the
shear rate, that is, these systems showed
a shear thinning or a pseudoplastic
behaviour. The Films I presents ηo values
(0.165±0.001) lower than the Film II
(0.556±0.003) and Film III (0.981±0.006).
Therefore, the viscosity increased as a
function of the HA amount.
The transcorneal permeation profiles of
diclofenac are shown in Fig. 2. Results
indicate that the Film I presented the
highest drug penetration rate across the
cornea and that the incorporation of
growing quantities of HA into the film
systems reduced the drug permeation
capacity. Permeation coefficient values
calculated for each formulation confirmed
these results: Film I (0.271±0.014), Film II
(0.119±0.003) and Film III (0.033±0.003).
These results could be explained as the
consequence of the increased film
viscosity as HA concentration increased.
Film I
Film II
Film III
-2
-1
Cumulative amount (mg.cm .h )
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0
2
4
6
0,&52(1&$368/$7,212)385,),('+80$1%,2$&7,9(5(&20%,1$17*'1)
($QVRUHQD(*DUED\R-//DQFLHJR06$\PHULFK0-%ODQFR3UtHWR
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\8QLYHUVLW\RI1DYDUUD3DPSORQD
1DYDUUD
1HXURPRUSKRORJ\7UDFLQJ/DE&,0$8QLYHUVLW\RI1DYDUUD3DPSORQD1DYDUUD.
HDQVRUHQD#XQDYHV
8
Time (h)
Fig. 2. Permeation of diclofenac through
excised cornea from the bovine eye.
SHULVWDOWLFSXPS7KHSURWHLQZDVHOXWHGXVLQJ
D OLQHDU VDOW JUDGLHQW IURP P0 WR 0
1D&O LQ P0 SKRVSKDWH EXIIHU P0
('7$ S+ 7KH IUDFWLRQV REWDLQHG ZHUH
DQDO\]HGE\6'63$*(IROORZHGE\:HVWHUQ
%ORW)LJ$7KHSUHVHQFHRIRWKHUSURWHLQV
LQ WKH VDPSOH ZDV GHWHUPLQHG E\ VWDLQLQJ WKH
6'63$*(JHOZLWKFRRPDVVLHEOXH)LJ$
7KRVH IUDFWLRQV HQULFKHG LQ *'1) DQG
SUHVHQWLQJ ORZ OHYHOV RI RWKHU SURWHLQ
FRQWDPLQDQWV ZHUH SDVVHG WKRXJK WKH VDPH
FKURPDWRJUDSK\ FROXPQ XQGHU WKH VDPH
FRQGLWLRQV7KHSXULW\RIWKHIUDFWLRQVREWDLQHG
ZDVDOVRDQDO\]HGE\FRPPDVVLHEOXH)LJ
*HO)LOWUDWLRQ&KURPDWRJUDSK\
$VL]HH[FOXVLRQFKURPDWRJUDSK\XVLQJWKH
SUHSDFNHGFROXPQ6XSHUGH[70+5
ZLWK DQ È.7$ SXULILHU ZDV ILQDOO\
SHUIRUPHG)LJ
%LRORJLFDODFWLYLW\
$ QHXURQDO FHOO ELRDVVD\ EDVHG RQ WKH DELOLW\
RI WKH SURWHLQ WR LQGXFH WKH GLIIHUHQWLDWLRQ RI
3& FHOOV WR D QHXUDO SKHQRW\SH ZDV
GHYHORSHG WR FRQILUP WKH DFWLYLW\ RI WKH
SXULILHGUHFRPELQDQWSURWHLQ)LJ
K*'1)PLFURHQFDSVXODWLRQ
3/*$ PLFURSDUWLFOHV ZHUH SUHSDUHG E\ WKH
VROYHQWHYDSRUDWLRQPHWKRGDIWHUWKHIRUPDWLRQ
RI D PXOWLSOH HPXOVLRQ :2: E\ 75206
7RWDO 5HFLUFXODWLRQ 2QH 0DFKLQH
6\VWHP7KHPHDQSDUWLFOHVL]HZDVDQDO\]HG
E\ ODVHU GLIIUDFWRPHWU\ DQG WKH HQFDSVXODWLQJ
HIILFLHQF\ ZDV PHDVXUHG E\ (/,6$ *'1)
(PD[,PPXQRDVVD\6\VWHP3URPHJD*'1)
HQFDSVXODWLRQ ZDV GHWHUPLQHG E\ GLVVROYLQJ
WKH 03 LQ GLPHWK\O VXOIR[LGH DQG WKH DPRXQW
RI QHXURWURSKLF IDFWRU HQWUDSSHG LQWR WKH
SDUWLFOHV ZDV PHDVXUHG E\ (/,6$ ,Q YLWUR
UHOHDVHVWXGLHVZHUHSHUIRUPHGDWž&XQGHU
KRUL]RQWDO DJLWDWLRQ GXULQJ PRQWKV )RU WKLV
SXUSRVH WKH SDUWLFOHV ZHUH GLVSHUVHG LQ
SKRVSKDWH EXIIHUHG VDOLQH 3%6 S+ DQG
JHQWO\ VKDNHQ $W GLIIHUHQW WLPHV VDPSOHV
ZHUHFHQWULIXJHGDQGSURWHLQLQWKHVXSHUQDWDQW
ZDVTXDQWLILHGE\(/,6$
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
5HVXOWVDQG'LVFXVVLRQ
3XULILFDWLRQ
&DWLRQ([FKDQJH&KURPDWRJUDS\
)LJXUH $ :HVWHUQ %ORW DQDO\VLV RI WKH
IUDFWLRQV REWDLQHG LQ WKH &DWLRQ([FKDQJH
&KURPDWRJUDSK\ % 6'63$*( VWDLQHG ZLWK
FRRPDVVLH EOXH %ODFN DUURZ VKRZV *'1)
:KLWHDUURZVKRZV,*)%3
:HVWHUQ%ORWDQDO\VLVRIWKHIUDFWLRQVREWDLQHG
LQ WKH ILUVW FDWLRQH[FKDQJH FKURPDWRJUDSK\
GHWHUPLQHGWKRVHLQZKLFKK*'1)KDGHOXWHG
)LJ $ $ FRRPDVVLH EOXH VWDLQ RI WKH JHO
)LJ % UHYHDOHG WKH SUHVHQFH LQ WKH VDPSOH
RI DQRWKHU SURWHLQ ZLWK D SUHGRPLQDQW
H[SUHVVLRQ LGHQWLILHG DV ,*)%3 E\ PDVV
VSHFWURPHWU\
7KH 6'63$*( VWDLQHG ZLWK FRRPDVVLH )LJ
GHPRQVWUDWHG WKDW WKLV WHFKQLTXH ZDV DEOH
WR GLVFULPLQDWH EHWZHHQ ,*)%3 DQG WKH
GLPPHU RI K*'1) REWDLQLQJ D KLJKO\ SXUH
UHFRPELQDQWSURWHLQ
%LRORJLFDODFWLYLW\
)LJXUH 6'63$*( VWDLQHG ZLWK FRRPDVVLH
EOXH RI WKH VHFRQG FDWLRQ H[FKDQJH
FKURPDWRJUDSK\ %ODFN DUURZ VKRZV *'1)
:KLWHDUURZVKRZV,*)%3
7KH VHFRQG FDWLRQH[FKDQJH FKURPDWRJUDSK\
)LJ UHGXFHG WKH DPRXQW RI ,*)% LQ WKH
VDPSOH
*HO)LOWUDWLRQ&KURPDWRJUDSK\
)LJXUH $ 3URWHLQ SURILOH IURP WKH JHO
ILOWUDWLRQ FKURPDWRJUDSK\ FROXPQ VKRZLQJ D
PDMRU SHDN WKDW FRUUHVSRQGV WR WKH IUDFWLRQV
FRQWDLQLQJ *'1) % 6'63$*( VWDLQHG ZLWK
FRRPDVVLHEOXHRIWKHIUDFWLRQLQGLFDWHG%ODFN
DUURZVKRZV*'1)
)LJXUH 'LIIHUHQWLDWLRQ RI 3& FHOOV $
&RQWUROFHOOVRUVXSSOHPHQWHGZLWKQJPORI
SXULILHG*'1)%
:H DVVD\HG WKH DELOLW\ RI SXULILHG *'1) WR
LQGXFHQHXULWHRXWJURZWKIURP3&FHOOV$V
VKRZQLQ)LJXUHFRQWUROFHOOV$GLVSOD\HG
D W\SLFDO XQGLIIHUHQWLDWHG PRUSKRORJ\ ,Q
FRQWUDVW VWULNLQJ QHXULWH RXWJURZWK ZDV
REVHUYHG LQ FXOWXUHV WUHDWHG ZLWK QJPO RI
PDPPDOLDQFHOOGHULYHGK*'1)%DWGD\
K*'1)PLFURHQFDSVXODWLRQ
K*'1)ORDGHG3/*$PLFURSDUWLFOHVSUHSDUHG
ZLWK75206SUHVHQWHGDPHDQSDUWLFOHVL]HRI
DURXQG P ZKLFK LV WRWDOO\ FRPSDWLEOH
ZLWK VWHUHRWD[LF LPSODQWDWLRQ 7KH GUXJ
HQWUDSPHQW HIILFLHQF\ ZDV PRUH WKDQ DQG WKH LQ YLWUR UHOHDVH NLQHWLFV VKRZHG D
FRQWUROOHG UHOHDVH RI WKH SURWHLQ RYHU PRQWKV UHOHDVLQJ DIWHU GD\V RI WKH
HQWUDSSHGK*'1)
&RQFOXVLRQV
$SURFHGXUHIRUWKHSXULILFDWLRQRIKLJKO\
SXUH KXPDQ UHFRPELQDQW ELRDFWLYH
JO\FRV\ODWHG*'1)KDVEHHQGHYHORSHG
K*'1) ORDGHG 3/*$ PLFURSDUWLFOHV
ZHUHVXFFHVVIXOO\GHYHORSHGE\75206
3DUWLFOHV VKRZHG DQ HIILFLHQW SURWHLQ
ORDGLQJ KDG D VXLWDEOH VL]H IRU WKHLU
DGPLQLVWUDWLRQ LQWR WKH EUDLQ DQG
SUHVHQWHGDFRQWUROOHGUHOHDVHRIK*'1)
5HIHUHQFHV
*DUED\R ( HW DO ,QW - 3KDUP 1RY
*LOO 66 HW DO 1DW 0HG 0D\
6OHYLQ -7 HW DO - 1HXURVXUJ
)HE
*DUED\R ( HW DO (XU - 3KDUP
%LRSKDUP$XJ
$FNQRZOHGJHPHQWV )XQGDFLyQ &DMD 1DYDUUD
DQG
)XQGDFLyQ
0$3)5(0HGLFLQD
*RYHUQPHQW RI 1DYDUUD 'HSDUWPHQWV RI
+HDOWKDQG(GXFDWLRQ
(678',235(/,0,1$5'((67$%,/,'$'),6,&248Ë0,&$'(81$0(=&/$
,175$9(126$3$5$&(7$02/75$0$'2/
90HULQR%RKyUTXH]0-&y]DU%HUQDO66DODV-$OYDUH])XHQWHV0&DPHiQ0'
*XHUUHUR0$+ROJDGR0)HUQiQGH]$UpYDOR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH6HYLOOD(VSDxD
6HUYLFLRGH)DUPDFLD+RVSLWDO8QLYHUVLWDULR9LUJHQ0DFDUHQD6HYLOOD(VSDxD
,QWURGXFFLyQ (O FRQWURO GHO GRORU
SRVWRSHUDWRULR GHEH GH HVWDU YLQFXODGR HQ
SULPHUDLQVWDQFLDDEULQGDUXQDPHMRUFDOLGDGGH
DWHQFLyQ KRVSLWDODULD OR TXH LPSOLFD XQ
DGHFXDGRWUDWDPLHQWR/DGHILFLHQFLDRDXVHQFLD
GHDQDOJHVLDYDDSURGXFLUHIHFWRVQHJDWLYRVHQ
HO SDFLHQWH D QLYHO GH ORV VLVWHPDV UHVSLUDWRULR
FDUGLRYDVFXODU\QHXURHQGRFULQR
/D 6RFLHGDG (VSDxROD GHO 'RORU 6(' KD
SURWRFROL]DGR XQD VHULH GH PH]FODV GH
PHGLFDPHQWRV LQWUDYHQRVDV SDUD VX HPSOHR HQ
HOWUDWDPLHQWRGHGRORUDJXGR \SRVWRSHUDWRULR
/D FRPELQDFLyQ SDUDFHWDPROWUDPDGRO SHUPLWH
HOWUDWDPLHQWRVLQWRPiWLFRGHOGRORUPRGHUDGRD
LQWHQVR DJXGR \ FUyQLFR FRQ XQD UHODFLyQ
HILFDFLD HIHFWRV LQGHVHDEOHV PX\ DOWD
SHUPLWLHQGR UHGXFLU ODV GRVLV GH WUDPDGRO
QHFHVDULDV
(OSUHVHQWHWUDEDMRGHLQYHVWLJDFLyQVXUJHFRPR
FRQVHFXHQFLD GH XQD QHFHVLGDG FOtQLFD
$FWXDOPHQWH ODV PH]FODV GH IiUPDFRV
HPSOHDGDV HQ DQDOJHVLD \ SURWRFROL]DGDV SRU OD
6(' SRU HMHPSOR SDUDFHWDPROWUDPDGRO VRQ
HODERUDGDV HQ ORV 6HUYLFLRV GH )DUPDFLD
KRVSLWDODULRV \D TXH QR VH HQFXHQWUDQ
FRPHUFLDOL]DGDV $GHPiV H[LVWH XQD HVFDVD R
QXOD LQIRUPDFLyQ VREUH OD HVWDELOLGDG
ILVLFRTXtPLFD \ FRPSDWLELOLGDG GH DOJXQDV GH
HVWDVPH]FODV
3RUORWDQWRHOREMHWLYRGHOSUHVHQWHWUDEDMRKD
FRQVLVWLGR HQ UHDOL]DU XQ HVWXGLR SUHOLPLQDU GH
OD FRPSDWLELOLGDG ItVLFD \ HVWDELOLGDG TXtPLFD
EDMRGLIHUHQWHVFRQGLFLRQHVGHFRQVHUYDFLyQGH
OD PH]FOD WUDPDGROSDUDFHWDPRO UHFRPHQGDGD
SRUOD6('SDUDHOWUDWDPLHQWRGHOGRORUFUyQLFR
\SRVWRSHUDWRULR
0DWHULDO \ 0pWRGRV (Q OD UHDOL]DFLyQ GHO
SUHVHQWH HVWXGLR VH KDQ XVDGR ORV VLJXLHQWHV
PDWHULDOHV
• 3ULQFLSLRV DFWLYRV 3DUDFHWDPRO 3HUIDOJDQŠ
%ULVWRO0\HUV
6TXLEE
\
7UDPDGRO
&ORUKLGUDWR$GRORQWDŠ*UXQHQWKDO
• 'LVROYHQWHV DFHWRQLWULOR FDOLGDG +3/&
/LFKURVROYŠ 0HUFN 6$ iFLGR IRVIyULFR
iFLGR FORUKtGULFR DO YY GLKLGURJHQR
IRVIDWRGHSRWDVLR3DQUHDF4XtPLFD6$ \
DJXDPLOOL40LOOLSRUH • 3DWURQHV GH UHIHUHQFLD 7UDPDGRO FORUKLGUDWR
&KHPVZLVV ,EpULFD 6$ 3DUDFHWDPRO
FULVWDO/DERUDWRULRV&LQID6$
$ SDUWLU GH ODV HVSHFLDOLGDGHV IDUPDFpXWLFDV
$GRORQWDŠ \ 3HUIDOJDQŠ VH SUHSDUy PHGLDQWH
PH]FODHQODEROVDGHQXWULFLyQSDUHQWHUDO1XWUL
%DJ 0XOWLFDSD *ULIROV 6$ HPSOHDQGR XQD
ERPED SHULVWiOWLFD %D[D UHSHDWHU /5
XQD GLVROXFLyQ PDGUH FRQWHQLHQGR PJP/
GHSDUDFHWDPRO\PJP/GHWUDPDGROHQXQ
YROXPHQ WRWDO GH P/ (O YHKtFXOR SDUD OD
VROXFLyQ GH SHUIXVLyQ IXH HO SURSLR GLVROYHQWH
TXH SUHVHQWD OD HVSHFLDOLGDG GH SDUDFHWDPRO \
HQHOFXDOVHDGLFLRQyHOWUDPDGRO3DUWLHQGRGH
HVWDGLVROXFLyQPDGUHVHSUHSDUDURQDOtFXRWDVGH
P/HQFDGDXQRGHORVYLDOHVKDVWDXQWRWDO
GH YLDOHV /DV GLIHUHQWHV DOtFXRWDV IXHURQ
URWXODGDV GH IRUPD DOHDWRULD HQ IXQFLyQ GH ORV
GLIHUHQWHV WLHPSRV \ FRQGLFLRQHV GH
FRQVHUYDFLyQOX]RVFXULGDGWHPSHUDWXUDHWF
6H HVWXGLy OD HVWDELOLGDG GXUDQWH XQ SHUtRGR GH
WLHPSRGHGtDVUHDOL]DQGRPHGLGDVHQHOGtD
GH SUHSDUDFLyQ GtD FHUR GH ODV PXHVWUDV GH
UHIHUHQFLDRLQLFLDOHV \DFRQWLQXDFLyQ ORVGtDV
\ /DV FRQGLFLRQHV GH
DOPDFHQDPLHQWR XWLOL]DGDV KDQ VLGR ODV
VLJXLHQWHVDWHPSHUDWXUDDPELHQWH\H[SRVLFLyQ
DOX]DPELHQWDOORWH$DWHPSHUDWXUDDPELHQWH
SUHVHUYDGD GH OX] DPELHQWDO ORWH % \ D
UHIULJHUDGDž&HQDXVHQFLDGHOX]ORWH&
(VWH SURFHVR VH UHDOL]y EDMR FRQGLFLRQHV GH
HVWHULOLGDG HQ FDPSDQD GH IOXMR ODPLQDU
KRUL]RQWDO FODVH 7HOVWDU %+ VHJ~Q
5' SRU HO TXH VH UHJXODQ ODV QRUPDV
GH FRUUHFWD HODERUDFLyQ \ FRQWURO GH FDOLGDGGH
IyUPXODV PDJLVWUDOHV \ SUHSDUDGRV RILFLQDOHV
FRQ HO ILQ GH , HYLWDU XQD SRVLEOH
FRQWDPLQDFLyQ PLFURELDQD TXH SXGLHUD DOWHUDU
ORV DQDOLWRV \ ,, UHSURGXFLU ILHOPHQWH ODV
FRQGLFLRQHV QRUPDOHV GH HODERUDFLyQ GH
PH]FODVLQWUDYHQRVDVHQXQDXQLGDGGHPH]FODV
LQWUDYHQRVDVKRVSLWDODULD
$GHPiV VH KD UHDOL]DGR XQ FRQWURO YLVXDO GH
SDUWtFXODV SRU VL DSDUHFtDQ SUHFLSLWDGRV SRU
LQFRPSDWLELOLGDG HQWUH ORV FRPSRQHQWHV GH OD
PH]FOD 7UDV DJLWDU VXDYHPHQWH SURFXUDQGR
HYLWDU OD IRUPDFLyQ GH EXUEXMDV GH DLUH H
LQYHUWLU FDGD YLDO VH REVHUYDURQ FDGD XQR
GXUDQWHVHJXQGRVSULPHURVREUHSDQHOEODQFR
\SRVWHULRUPHQWHVREUHSDQHOGHIRQGRQHJUR
(VWDH[SHULHQFLDVHOOHYyDFDERSULPHURHQ
HO PRPHQWR HQ TXH VH SUHSDUDQ ORV YLDOHV \
OXHJRHQFDGDXQRGHORVGtDVHQTXHVHKDFHHO
DQiOLVLVGH+3/&
'HQWUR GH HVWH HVWXGLR SUHOLPLQDU VH KL]R XQ
HVWXGLR GH GHJUDGDELOLGDG SDUD IRU]DU ODV
FRQGLFLRQHVFRQHOREMHWLYRGHYHUTXpIDFWRUHV
DIHFWDQ HQ PD\RU JUDGR D FDGD XQR GH ORV
IiUPDFRV 'LFKR HVWXGLR VH UHDOL]y HPSOHDQGR
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
GLVROXFLRQHV DFXRVDV LQGLYLGXDOHV GH PJP/ GH FDGD XQR GH ORV IiUPDFRV SRU
VHSDUDGR /D KLGUyOLVLV DOFDOLQD VH OOHYy D FDER
SUHSDUDQGR GLVROXFLRQHV LQGLYLGXDOHV GH FDGD
IiUPDFRHQ1D2+03DUDHOHVWXGLRGHOD
GHJUDGDELOLGDG HQ FRQGLFLRQHV R[LGDQWHV VH
HPSOHy XQD GLVROXFLyQ DFXRVD DO GH
SHUy[LGR GH KLGUyJHQR 3RU ~OWLPR VH KL]R XQ
HVWXGLR GH LQIOXHQFLD GH OD WHPSHUDWXUD SDUD
FDGD IiUPDFR HQ XQ KRUQR D ž& KRUQR
0HPPHUWŠ (Q WRGRV ORV FDVRV VH WRPy P/
GH OD GLVROXFLyQ DFXRVD GH FDGD IiUPDFR \ VH
PH]FODURQ FRQ P/ GH FDGD XQD GH ODV
GLVROXFLRQHV GHJUDGDWLYDV GXUDQWH KRUDV HQ
FRQGLFLRQHVGHWHPSHUDWXUDDPELHQWH
5HVXOWDGRV \ 'LVFXVLyQ &RPSDUDQGR OD
HYROXFLyQ GH ORV FRQWHQLGRV GH SDUDFHWDPRO \
WUDPDGRO HQ ODV WUHV FRQGLFLRQHV HVWXGLDGDV
WHPSHUDWXUD DPELHQWHSUHVHQFLD GH OX]
WHPSHUDWXUD DPELHQWHDXVHQFLD GH OX] \ ž&DXVHQFLD GH OX] VH FRPSUXHED TXH ODV
YDULDFLRQHVGHFRQWHQLGRHQWRGRVORVFDVRVVRQ
LQGHSHQGLHQWHV GH OD IRUPD GH FRQVHUYDFLyQ GH
ODVPH]FODV
$QDOL]DQGR ORV UHVXOWDGRV REWHQLGRV HQ HO
HQVD\R GH HVWDELOLGDG SODQWHDGR VH FRQFOX\H
TXHODVYDULDFLRQHVHQHOFRQWHQLGRHQWUDPDGRO
\ SDUDFHWDPRO SDUHFHQ PiV UHODFLRQDGDV FRQ OD
YDULDELOLGDG GHO SURFHGLPLHQWR RSHUDWLYR TXH
FRQ SURFHVRV UHODFLRQDGRV FRQ VX GHJUDGDFLyQ
(VWR \D VH LQWXtD DO SULQFLSLR GHO HVWXGLR DQWHV
GH DQDOL]DU ORV UHVXOWDGRV H[SHULPHQWDOHV
GHELGR D OD DXVHQFLD GH SLFRV FURPDWRJUiILFRV
QR LGHQWLILFDGRV SURFHGHQWHV GH SURGXFWRV GH
GHJUDGDFLyQ GH WUDPDGRO \R SDUDFHWDPRO HQ
FXDOTXLHUD
GH
ODV
FRQGLFLRQHV
GH
DOPDFHQDPLHQWRHVWXGLDGDV
(Q HO FDVR GHO WUDPDGRO ORV GDWRV GH
UHFXSHUDFLyQ GH FRQFHQWUDFLRQHV YDQ GHVGH XQ
KDVWDXQHQHOFDVRGHODV
PH]FODV FRQVHUYDGDV D WHPSHUDWXUD DPELHQWH \
HQSUHVHQFLDGHOX]GHVGHXQKDVWDXQ
HQ PXHVWUDV FRQVHUYDGDV D
WHPSHUDWXUDDPELHQWH\DXVHQFLDGHOX]\GHVGH
XQ KDVWD HQ PXHVWUDV
FRQVHUYDGDVDž&\HQDXVHQFLDGHOX]
(VWD YDULDELOLGDG SXHGH VHU GHELGD WDQWR D OD
YDULDELOLGDG GHO SURSLR PpWRGR HQWRUQR D XQ VHJ~QODSUHFLVLyQGHOPpWRGRLQVWUXPHQWDO
FRPR DO HUURU LQWURGXFLGR HQ ODV HOHYDGDV
GLOXFLRQHV D ODV TXH KD\ TXH VRPHWHU D ODV
PXHVWUDVSDUDSRGHUDERUGDUVXDQiOLVLV
&RQ UHVSHFWR DO SDUDFHWDPRO VH REWLHQH GDWRV
TXH YDUtDQ HQWUH XQ DO HQ
FRQGLFLRQHV GH WHPSHUDWXUD DPELHQWH \ VLQ
IRWRSURWHFFLyQGHVGHXQDOHQ
FRQGLFLRQHV GH WHPSHUDWXUD DPELHQWH \
IRWRSURWHFFLyQ\GHVGHXQDOHQ
FRQGLFLRQHV GH UHIULJHUDFLyQ D ž & \
IRWRSURWHFFLyQ
$O LJXDO TXH RFXUULy FRQ HO WUDPDGRO OD
YDULDELOLGDG HQ VXV FRQWHQLGRV SDUHFH HVWDU
UHODFLRQDGD FRQ OD YDULDELOLGDG H[SHULPHQWDO
DVRFLDGDDODGLOXFLyQGHODVPXHVWUDVQHFHVDULD
SDUD VX GHWHUPLQDFLyQ FURPDWRJUiILFD TXH D
FDPELRVTXtPLFRVUHDOHVHQODVPH]FODV
&RQ UHVSHFWR DO FRQWURO YLVXDO GH ODV PXHVWUDV
KXERDXVHQFLDWRWDOGHSDUWtFXODVHQVXVSHQVLyQ
HQ WRGDV ODV PXHVWUDV DQDOL]DGDV DVt FRPR GH
FXDOTXLHUWLSRGHFRORUDFLyQGXUDQWHORVGtDV
GHHVWXGLR
(Q FXDQWR DO HVWXGLR GH GHJUDGDFLyQ DFHOHUDGD
ODV SUHVHQFLD GH DOFDOLQL]DQWH FRQGLFLyQ GH
HVWUpVKDJHQHUDGRHQHOFDVRGHOWUDPDGROXQ
SRUFHQWDMH GH UHFXSHUDFLyQ PHQRU TXH SDUD HO
SDUDFHWDPRO HVWR KDFH SHQVDU TXH HO WUDPDGRO
VH YH PiV DIHFWDGR SRU XQDV FRQGLFLRQHV
EiVLFDV
/D SUHVHQFLD GH XQ R[LGDQWH SRWHQWH HO
SHUy[LGRGHKLGUyJHQRWDPELpQKDGHJUDGDGRDO
WUDPDGROHQ PD\RU PHGLGDTXHDOSDUDFHWDPRO
VLHQGRHVWDVFRQGLFLRQHVPiVGHJUDGDWLYDVSDUD
DPERVSULQFLSLRVDFWLYRVTXHODVFRQGLFLRQHVGH
KLGUyOLVLV DOFDOLQD DVt VH REVHUYD FRPR HO
WUDPDGRO SDUHFH PiV VHQVLEOH D HVWDV
FRQGLFLRQHV R[LGDQWHV TXH D ODV GHPiV
FRQGLFLRQHVGHHVWUpVHYDOXDGDV /DWHPSHUDWXUDSDUHFHVHUHOSULQFLSDOIDFWRUGH
HVWUpV HQ ODV FRQGLFLRQHV GHJUDGDWLYDV
HQVD\DGDVSDUDHOSDUDFHWDPROGHELGRDTXHVH
KD REWHQLGR HO PHQRU SRUFHQWDMH GH
UHFXSHUDFLyQGHWRGRHOHVWXGLRGHGHJUDGDFLyQ
SRUWDQWRGHEHH[LVWLU XQDWHPSHUDWXUDOtPLWHD
SDUWLU GH OD FXDO HO SDUDFHWDPRO HPSLH]D D
GHJUDGDUVH PiV DFHOHUDGDPHQWH 6LQ HPEDUJR
SDUD HO WUDPDGRO HO SRUFHQWDMH GH UHFXSHUDFLyQ
REWHQLGR HQ FRQGLFLRQHV GH FRQVHUYDFLyQ FRQ
DOWD WHPSHUDWXUD HV PD\RU TXH HQ FRQGLFLRQHV
R[LGDQWHV \ PHQRU TXH HQ FRQGLFLRQHV
DOFDOLQL]DQWHV
%LEOLRJUDItD
&KDUOWRQ ( ³7UHDWPHQW RI SRVWRSHUDWLYH
SDLQ´ HQ *LDPEHUDUGLQR 0 HG $Q XSGDWHG
UHYLHZUHIUHVKHUFRXUVHV\OODEXV,$636FLHQWLILF
3URJUDP&RPPLWWHH3DLQ
0XOOLFDQ :( \ /DF\ -5 75$0$3
$1$*
6WXG\
*URXS
³7UDPDGRODFHWDPLQRSKHQ FRPELQDWLRQ WDEOHWV
DQG FRGHLQHDFHWDPLQRSKHQ FRPELQDWLRQ
FDSVXOHVIRUWKHPDQDJHPHQWRIFKURQLFSDLQD
FRPSDUDWLYHWULDO´&OLQ7KHU
5HDO)DUPDFRSHD(VSDxRODHG
6DOPHUyQ*DUFtD $ 1DYDV 1 0DUWtQ $
5RPiQ ( &DEH]D - &DSLWiQ9DOOYH\ /)
³&RPSDWLELOLGDG \ HVWDELOLGDG GH PH]FODV GH
IiUPDFRV SURWRFROL]DGDV SRU OD 6RFLHGDG
(VSDxRODGHO'RORU´5HY2ILFLDO6$)+
'(6$552//2<9$/,'$&,Ï1'(810e72'2'(&8$17,),&$&,Ï16,08/7È1(2
325+3/&'(3$5$&(7$02/<75$0$'2/
90HULQR%RKyTXH]0-&y]DU%HUQDO66DODV-$OYDUH])XHQWHV0&DPHiQ0'
*XHUUHUR0$+ROJDGR0)HUQiQGH]$UpYDOR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH6HYLOOD(VSDxD
6HUYLFLRGH)DUPDFLD+RVSLWDO8QLYHUVLWDULR9LUJHQ0DFDUHQD6HYLOOD(VSDxD
,QWURGXFFLyQ (O WUDWDPLHQWR GHO GRORU
(O FURPDWyJUDIR XWLOL]DGR 0HUFN+LWDFKL
PXOWLPRGDO HV OD FRPELQDFLyQ GH GRV R PiV
/D&KURP VHULH HVWi FRPSXHVWR GH
IiUPDFRV \R PpWRGRV DQDOJpVLFRV FRQ HO ILQ
DXWRPXHVWUHDGRU 0HUFN+LWDFKL /D&KURP /
GH SRWHQFLDU OD DQDOJHVLD \ GLVPLQXLU ORV
ERPED FXDWHUQDULD 0HUFN+LWDFKL
HIHFWRV FRODWHUDOHV (O FRQFHSWR GH DQDOJHVLD
/D&KURP / LQWHUID] 0HUFN+LWDFKL
PXOWLPRGDO D SHVDU GH QR VHU QXHYR HVWi
/D&KURP ' HVSHFWURIRWyPHWUR GH
FREUDQGR FDGD GtD PiV YLJHQFLD /D HVFDOHUD
GLRGRV HQ VHULH 0HUFN+LWDFKL /D&KURP /
DQDOJpVLFD HV OD PHMRU GHPRVWUDFLyQ GH OD
\FRPSDUWLPHQWRGHWHUPRVWDWL]DFLyQGH
XWLOL]DFLyQ PXOWLPRGDO GH ORV DQDOJpVLFRV OD
ODFROXPQD+LWDFKL/D&KURP(/,7(/
FXDO UHFRPLHQGD HO PDQHMR SURJUHVLYR GH ORV
/DV FRQGLFLRQHV FURPDWRJUiILFDV IXHURQ ODV
GLIHUHQWHV WLSRV FRQ XQD HYDOXDFLyQ FRQWLQXD
VLJXLHQWHV
GHOGRORU/D6RFLHGDG(VSDxRODGHO'RORU
)DVH PyYLO .+32 0 S+ $&1
6(' KD SURWRFROL]DGR XQD VHULH GH PH]FODV
GH PHGLFDPHQWRV SDUD VX HPSOHR HQ HO
9ROXPHQGHLQ\HFFLyQȝ/
WUDWDPLHQWR GH GRORU DJXGR \ SRVWRSHUDWRULR
)OXMRP/PLQ
8QD GH HVWDV PH]FODV HV OD FRPELQDFLyQ
&ROXPQD /L&KURVSKHUŠ 53 [
SDUDFHWDPROWUDPDGRO TXH SHUPLWH HO
PPȝP0HUFN6$
WUDWDPLHQWR VLQWRPiWLFR GHO GRORU PRGHUDGR D
7HPSHUDWXUDž&
LQWHQVR DJXGR \ FUyQLFR FRQ XQD UHODFLyQ
/RQJLWXGGHRQGDGHPHGLGDGHSDUDFHWDPRO
HILFDFLD HIHFWRV LQGHVHDEOHV PX\ DOWD
QP
SHUPLWLHQGR UHGXFLU ODV GRVLV GH WUDPDGRO
/RQJLWXG GH RQGD GH PHGLGD GH WUDPDGRO
QHFHVDULDV
QP
$FWXDOPHQWH ODV PH]FODV GH IiUPDFRV
$ FRQWLQXDFLyQ VH UHDOL]y XQD UHFWD GH
HPSOHDGDVHQDQDOJHVLD\SURWRFROL]DGDVSRUOD
FDOLEUDGR SDUD GHWHUPLQDU OD OLQHDOLGDG GHO
6('SRUHMHPSORSDUDFHWDPROWUDPDGROVRQ
PpWRGR FURPDWRJUiILFR XWLOL]DQGR HO iUHD GH
HODERUDGDV HQ ORV 6HUYLFLRV GH )DUPDFLD
ORV SLFRV TXH SURSRUFLRQDEDQ GLIHUHQWHV
KRVSLWDODULRV \D TXH QR VH HQFXHQWUDQ
FRQFHQWUDFLRQHVGHOIiUPDFR6HSDUWLyGHXQD
FRPHUFLDOL]DGDV $GHPiV H[LVWH XQD HVFDVD R
GLVROXFLyQPDGUHGHWUDPDGROFRQPJGH
QXOD LQIRUPDFLyQ VREUH OD HVWDELOLGDG \
WUDPDGROHQP/GHOHOX\HQWH XWLOL]DGR \
FRPSDWLELOLGDGGHDOJXQDVGHHVWDVPH]FODV
RWUD GLVROXFLyQ PDGUH FRQ PJ GH
3RUORWDQWRHOREMHWLYRGHOSUHVHQWHWUDEDMRGH
SDUDFHWDPRO HQ P/ GHO HOX\HQWH
LQYHVWLJDFLyQ KD FRQVLVWLGR HQ YDOLGDU XQ
XWLOL]DGR (VWDV GLVROXFLRQHV PDGUH VH
PpWRGRFURPDWRJUiILFRSRU+3/&TXHSHUPLWD
GLOX\HURQ KDVWD REWHQHU ODV VLJXLHQWHV
FXDQWLILFDU HVWRV IiUPDFRV GH IRUPD
FRQFHQWUDFLRQHV GH WUDPDGRO VLPXOWiQHD HQ ODV FRQFHQWUDFLRQHV HPSOHDGDV
\ PJP/ \ GH
KDELWXDOPHQWHHQFOtQLFD
SDUDFHWDPRO \ 0DWHULDO \ 0pWRGRV (Q OD UHDOL]DFLyQ GHO
PJP/
SUHVHQWH HVWXGLR VH KDQ XVDGR ORV VLJXLHQWHV
6HJXLGDPHQWH VH HVWXGLy OD SUHFLVLyQ GH OD
PDWHULDOHV
WpFQLFD DQDOtWLFD HQ EDVH D ORV FRHILFLHQWHV GH
YDULDFLyQ&9LQ\HFWDQGRPXHVWUDVFRQXQD
• 3ULQFLSLRV
DFWLYRV
3DUDFHWDPRO
FRQFHQWUDFLyQ GH PJP/ SDUD WUDPDGRO
3HUIDOJDQŠ %ULVWRO0\HUV 6TXLEE \
\ PJP/ SDUD SDUDFHWDPRO $Vt VH
7UDPDGRO
&ORUKLGUDWR
$GRORQWDŠ
LQ\HFWDURQPXHVWUDVGHODFLWDGDGLVROXFLyQ
*UXQHQWKDO
D OR ODUJR GH XQ PLVPR GtD GH WUDEDMR
• 'LVROYHQWHV DFHWRQLWULOR FDOLGDG +3/&
SUHFLVLyQLQWUDGtD\PXHVWUDVUHSDUWLGDV
/LFKURVROYŠ 0HUFN 6$ iFLGR
HQWUHMRUQDGDVFRQVHFXWLYDVSUHFLVLyQLQWHU
IRVIyULFR iFLGR FORUKtGULFR DO YY
GtD
GLKLGURJHQR IRVIDWR GH SRWDVLR 3DQUHDF
)LQDOPHQWH VH FRPSUREy OD H[DFWLWXG R
4XtPLFD6$\DJXDPLOOL40LOOLSRUH DSUR[LPDFLyQ GHO PpWRGR SDUD GHWHUPLQDU QR
• 3DWURQHV GH UHIHUHQFLD 7UDPDGRO
VyOR ORV LQWHUYDORV GH FRQFHQWUDFLRQHV HQ ORV
FORUKLGUDWR &KHPVZLVV ,EpULFD 6$
TXHODUHVSXHVWDGHOGHWHFWRU HVOLQHDOSUHFLVD
3DUDFHWDPRO FULVWDO /DERUDWRULRV &LQID
VLQR WDPELpQ DTXpOORV HQ ORV TXH OD
6$
GHWHUPLQDFLyQ H[SHULPHQWDO GH WUDPDGRO \
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
SDUDFHWDPRO HV H[DFWD $Vt VH YDORUDURQ SRU
WULSOLFDGR XQD VHULH GH GLVROXFLRQHV GH DPERV
SULQFLSLRV DFWLYRV HQ ORV LQWHUYDORV PJP/ \ ± PJP/ SDUD WUDPDGRO \
SDUDFHWDPROUHVSHFWLYDPHQWH
5HVXOWDGRV \ 'LVFXVLyQ &RQVLGHUDQGR ORV
WLHPSRV GH UHWHQFLyQ REWHQLGRV \ OD IRUPD GH
ORV SLFRV HO HOX\HQWH FURPDWRJUiILFR
VHOHFFLRQDGR IXH OD PH]FOD .+32 0
S+ $&1 HQ SURSRUFLyQ YY
(PSOHDQGRHVWHHOX\HQWH\ILMDQGRHOIOXMRHQ
P/PLQVHFXDQWLILFDHOSDUDFHWDPROQP
\ WUDPDGRO QP FRQ XQRV WLHPSRV GH
UHWHQFLyQ GH “ PLQ S \
“ PLQ S UHVSHFWLYDPHQWH
&XDQWLILFDFLyQGHWUDPDGRO(QHOLQWHUYDORGH
FRQFHQWUDFLRQHVHVWXGLDGR\PJP/
VH REWXYR OD VLJXLHQWH UHFWD GH FDOLEUDGR Q ) S FRHILFLHQWH GH
GHWHUPLQDFLyQ U
ÈUHD
“î&RQFHQWUDFLyQ
“6HJ~QHVWRVUHVXOWDGRV
VH SXHGH FRQVLGHUDU TXH OD OLQHDOLGDG GH OD
UHVSXHVWD GHO GHWHFWRU GH GLRGR DUUD\ HV
FRUUHFWD HQ HO LQWHUYDOR GH FRQFHQWUDFLRQHV
HVWXGLDGR
(Q OR UHIHUHQWH D OD H[DFWLWXG GHO PpWRGR
FURPDWRJUiILFR HVWH SDUiPHWUR VH HYDOXy
VHJ~Q HO SRUFHQWDMH GH UHFXSHUDFLyQ REWHQLGR
DO FXDQWLILFDU HO WUDPDGRO H[SHULPHQWDOPHQWH
'LFKR HVWXGLR SURSRUFLRQy YDORUHV GH
UHFXSHUDFLyQ DGHFXDGRV HQWUH \ SDUD HO LQWHUYDOR GH FRQFHQWUDFLRQHV
FRPSUHQGLGR HQWUH ± PJP/ PHGLD
'( &9 /DSUHFLVLyQGHODWpFQLFDDQDOtWLFDSRU+3/&
VH LQYHVWLJD VREUH OD EDVH GH ORV FRHILFLHQWHV
GHYDULDFLyQ&9REWHQLGRVSDUDORVHQVD\RV
GH SUHFLVLyQ LQWUD H LQWHUGtD /RV GDWRV
LOXVWUDGRV HQ OD WDEOD VH REWXYLHURQ GHO
DQiOLVLV HVWDGtVWLFR UHDOL]DGR SDUD HVWXGLDU OD
SUHFLVLyQ FRQ XQD VROXFLyQ GH WUDPDGRO FRQ
XQDFRQFHQWUDFLyQGHPJP/
7DEOD 3UHFLVLyQ LQWUD H LQWHUGtD GHO
PpWRGR FURPDWRJUiILFR GHVDUUROODGR SDUD OD
FXDQWLILFDFLyQGHWUDPDGRO
ÈUHD0HGLD '(
,QWUDGtD Q
&9
,QWHUGtD &XDQWLILFDFLyQGHSDUDFHWDPRO(QHOLQWHUYDOR
GHFRQFHQWUDFLRQHVHVWXGLDGR\PJP/
VH REWXYR OD VLJXLHQWH UHFWD GH FDOLEUDGR Q ) S\FRHILFLHQWHGH
GHWHUPLQDFLyQ U
ÈUHD
“î&RQFHQWUDFLyQ
“ 6HJ~Q HVWRV
UHVXOWDGRV VH SXHGH FRQVLGHUDU TXH OD
OLQHDOLGDGGHODUHVSXHVWDGHOGHWHFWRUGHGLRGR
DUUD\ HV FRUUHFWD HQ HO LQWHUYDOR GH
FRQFHQWUDFLRQHVHVWXGLDGR
(Q OR UHIHUHQWH D OD H[DFWLWXG GHO PpWRGR
FURPDWRJUiILFR HVWH SDUiPHWUR VH HYDOXy
VHJ~Q HO SRUFHQWDMH GH UHFXSHUDFLyQ REWHQLGR
DO
FXDQWLILFDU
HO
SDUDFHWDPRO
H[SHULPHQWDOPHQWH
(O HVWXGLR GH H[DFWLWXG GH QXHVWUR PpWRGR GH
YDORUDFLyQ
SURSRUFLRQD
YDORUHV
GH
UHFXSHUDFLyQ DGHFXDGRV HQWUH \ SDUD HO LQWHUYDOR GH FRQFHQWUDFLRQHV
FRPSUHQGLGR HQWUH ± PJP/ PHGLD
'( &9 (OHVWXGLRGHODSUHFLVLyQLQWUDHLQWHUGtDGHOD
WpFQLFD DQDOtWLFD SRU +3/& GHVDUUROODGD SDUD
OD FXDQWLILFDFLyQ GH SDUDFHWDPRO REWHQLGRV
SDUD XQD VROXFLyQ FRQ XQD FRQFHQWUDFLyQ GH
PJP/VHPXHVWUDQHQODWDEOD
7DEOD 3UHFLVLyQ LQWUD H LQWHUGtD GHO
PpWRGR FURPDWRJUiILFR GHVDUUROODGR SDUD OD
FXDQWLILFDFLyQGHSDUDFHWDPRO
,QWUD
GtD
,QWHU
GtD
ÈUHD0HGLD
'(
Q
&9
(Q IXQFLyQ GH ORV UHVXOWDGRV REWHQLGRV SXHGH
GHFLUVH TXH VH KD YDOLGDGR XQ PpWRGR
FURPDWRJUiILFR SRU +3/& TXH SHUPLWH
FXDQWLILFDU WUDPDGRO \ SDUDFHWDPRO GH IRUPD
VLPXOWiQHD HQ ODV FRQFHQWUDFLRQHV HPSOHDGDV
KDELWXDOPHQWH HQ FOtQLFD (O PpWRGR YDOLGDGR
KDUHVXOWDGRVHUSUHFLVRH[DFWR\OLQHDOHQODV
FRQGLFLRQHVSODQWHDGDV
%LEOLRJUDItD
*RQ]iOH] GH 0HMtD 1 ³3RVWRSHUDWLYH
PXOWLPRGDO DQDOJHVLD´ 5HY 6RF (VS 'RORU
0XOOLFDQ :( \ /DF\ -5 75$0$3
$1$*
6WXG\
*URXS
³7UDPDGRODFHWDPLQRSKHQ
FRPELQDWLRQ
WDEOHWV
DQG
FRGHLQHDFHWDPLQRSKHQ
FRPELQDWLRQ FDSVXOHV IRU WKH PDQDJHPHQW RI
FKURQLFSDLQDFRPSDUDWLYHWULDO´&OLQ7KHU
=KRQJ : \ :LOOLDPV 0 ³4XDQWLWDWLYH
GHWHUPLQDWLRQRIFLVGLFKORUR1PHWK\O1
S\UUROLGLQ\OF\FORKH[\OEHQ]DPLGH DQG
WKUHHRIWKLVPHWDEROLWHVLQSODVPDE\+3/&´
-3KDUP6FL
'(9(/230(172)3/*$1$123$57,&/(62)'2;(3,1+<'52&+/25,'(
;*DUFLD((VFULEDQR-'RPHQHFK
%LRSKDUPDFHXWLFVDQG3KDUPDFRNLQHWLFVODERUDWRU\)DFXOW\RI3KDUPDF\8QLYHUVLW\RI%DUFHORQD
6SDLQ0HPEHUVRI,18%
,QWURGXFWLRQDQGREMHFWLYH
$OWKRXJK WKH QDQRSUHFLSLWDWLRQ WHFKQLTXH LV
EDVLFDOO\ DSSOLFDEOH WR OLSRSK\OLF GUXJV VLQFH
K\GURSKLOLF GUXJV VKRZHG ORZ ORDGLQJ
HIILFLHQF\ WKH REMHFWLYH RI WKH SUHVHQW
VWXG\ ZDV WR REWDLQ 3/*$QDQRSDUWLFOHV RI
GR[HSLQ K\GURFKORULGH E\ WKLV PHWKRGRORJ\
DQGWRVWXG\LWVLQYLWURUHOHDVHLQFRPSDULVRQ
ZLWKDVROXWLRQRIWKHGUXJ
0DWHULDOVDQGPHWKRGV
3UHSDUDWLRQ DQG FKDUDFWHUL]DWLRQ RI WKH
QDQRSDUWLFOHV
1DQRSDUWLFOHV ZHUH SUHSDUHG XVLQJ D
QDQRSUHFLSLWDWLRQ WHFKQLTXH DFFRUGLQJ WR WKH
PHWKRG GHYHORSHG E\ )HVVL HW DO $IWHU GLIIHUHQW IRUPXODWLRQ WHVWV WKH VHOHFWHG
VROYHQW DQG QRQVROYHQW ZHUH DFHWRQLWULOH DQG
SXULILHG ZDWHU ZLWK /XWUROŠ ) DV
VXUIDFWDQWUHVSHFWLYHO\7KHPHWKRGFRQVLVWHG
RQ D ILUVW GLVVROXWLRQ RI WKH SRO\PHU 3/*$
5* DQG WKH GUXJ ZLWK D GUXJSRO\PHU UDWLR LQ WKH RUJDQLF VROYHQW
7KH RUJDQLF SKDVH ZDV WKHQ DGGHG GURSZLVH
LQWRWKHDTXHRXVSKDVHXVLQJPRGHUDWHVWLUULQJ
)LQDOO\
WKH
RUJDQLF
VROYHQW
ZDV
URWDHYDSRUDWHGDWž&
'R[HSLQ K\GURFKORULGHORDGHG QDQRSDUWLFOHV
ZHUH FKDUDFWHUL]HG E\ PHDVXULQJ WKH PHDQ
SDUWLFOH VL]H DQG 3, =HWDVL]HU 1DQR=6
0DOYHUQ ,QV DQG E\ FDOFXODWLQJ WKH GUXJ
ORDGLQJDQGHQFDQSVXODWLRQHIILFLHQF\
)LJXUH)UDQ]GLIIXVLRQFHOO
$QDO\WLFDOSURFHGXUH
'R[HSLQ FRQFHQWUDWLRQV ZHUH GHWHUPLQHG E\
+3/&:DWHUV0LOIRUG86$
7KH FKURPDWRJUDSKLF FRQGLWLRQV ZHUH DV
IROORZV
&ROXPQ6XQILUH—P&[PP
0RELOH SKDVH 0HWDQRODFHWDWH EXIIHU S+ )ORZUDWHP/PLQ
/DPEGDQP
5HVXOWVDQGGLVFXVVLRQ
'R[HSLQ K\GURFKORULGHORDGHG QDQRSDUWLFOHV
ZHUH FKDUDFWHUL]HG VKRZLQJ D GUXJ ORDGLQJ RI
DQ HQFDSVXODWLRQ HIILFLHQF\ RI
DQG D PHDQ SDUWLFOH VL]H RI QP
3, =HWDVL]HU1DQR=60DOYHUQ,QV
$ 6(0 LPDJH RI WKH QDQRSDUWLFOHV LV VKRZHG
LQ)LJXUH
5HOHDVHVWXG\
,Q YLWUR UHOHDVH VWXGLHV RI WKH GUXJ ZHUH
SHUIRUPHG E\ PHDQV RI )UDQ]GLIIXVLRQ FHOOV
)LJXUH FP VXUIDFH DUHD DW
ž& DQG USP XVLQJ D FHOORSKDQH
PHPEUDQH 0:&2 &HOOX 6HS
7£ 0HPEUDQH )LOWUDWLRQ 3URGXFWV ,QF
86$DQGDSKRVSKDWHEXIIHUS+3%6LQ
WKH UHFHSWRU FRPSDUWPHQW DVVXULQJ VLQN
FRQGLWLRQV7KHGRQRUFRPSDUWPHQWZDVILOOHG
ZLWK PO RI D VROXWLRQ RI GR[HSLQ
K\GURFKORULGH LQ 3%6 —JP/ RU ZLWK D
VXVSHQVLRQ RI QDQRSDUWLFOHV LQ 3%6
([SHULPHQWV ZHUH SHUIRUPHG LQ UHSOLFDWHV
6DPSOHV IURP WKH UHFHSWRU FRPSDUWPHQW ZHUH
WDNHQ SHULRGLFDOO\ DQG WKH VDPH YROXPH RI
3%6 ZDV UHSODFHG 7KH GR[HSLQ FRQWHQW LQ
3%6ZDVHVWLPDWHGE\+3/&89GHWHFWLRQ
)LJXUH'R[HSLQ+&OQDQRSDUWLFOHV6(0
7KH FRPSDUDWLYH SORW RI WKH PHDQ“VG
SHUFHQWDJHRIFXPXODWLYHGRVHUHOHDVHGYVWLPH
LV VKRZQ LQ )LJXUH 5HVXOWV FRQILUPHG D
VORZHU UHOHDVH UDWH ZKHQ WKH GUXJ ZDV
HQFDSVXODWHGVLQFHORQJHUWLPHZDVQHHGHGWR
UHOHDVHRIGR[HSLQIURPWKHQDQRSDUWLFOHV
KWKDQIURPWKHVROXWLRQK
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
()(&726'(81&$0320$*1e7,&2(;7(512(1/$%,2',675,%8&,Ï1'(/
+,(552(181)2&2,1)/$0$725,275$6/$$'0,1,675$&,Ï1,175$9(126$
'(1$123$57Ë&8/$60$*1e7,&$6(15$7Ï1
((VFULEDQR5)HUQiQGH]3DFKHFR05,EDUUD-*9DOGLYLD&,0DUTXLQD-4XHUDOW
8QLGDGGH%LRIDUPDFLD\)DUPDFRFLQpWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH%DUFHORQD(VSDxD
0LHPEURGHO,18%,QVWLWXWRGH1DQRFLHQFLDGH$UDJyQ,1$8QLYHUVLGDGGH=DUDJR]D=DUDJR]D
(VSDxD,QVWLWXWRGH&LHQFLDVGH0DWHULDOHVGH$UDJyQ,&0$&6,&8QLYHUVLGDGGH=DUDJR]D
=DUDJR]D(VSDxD'SWR'H)LVLRORJtD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH%DUFHORQD(VSDxD
0LHPEURGHO,18%
KLHUUR HQ HO H[XGDGR \ HQ HO KtJDGR SRU
,QWURGXFFLyQ
/D XWLOL]DFLyQ GH QDQRSDUWtFXODV 13
HVSHFWURVFRStDGHDEVRUFLyQDWyPLFDHQ KRUQR
PDJQpWLFDV GHQWUR GHO FDPSR GH OD
GH JUDILWR $$6 =HHPDQ 6SHFWU$$
ELRPHGLFLQD HVSHFLDOPHQWH HQ HO GLDJQyVWLFR
9DULDQ SUHYLD GLJHVWLyQ GH OD PDWHULD
LQYLWURYLHQHUHDOL]iQGRVHGHVGHKDFHXQRV
RUJiQLFD HQ PHGLR iFLGR iFLGR QtWULFR DxRV /RV ~OWLPRV HVWXGLRV UHDOL]DGRV FRQ 13
3$$&6 \ iFLGR SHUFOyULFR DO 3$
PDJQpWLFDV \ VXVDSOLFDFLRQHVELRPpGLFDV QRV
$&6/RVUHVXOWDGRVVHH[SUHVDURQHQȝJ)HJ
UHYHODQ XQ IXWXUR PX\ SURPHWHGRU SDUD HVWRV
GHPDWHULDRUJiQLFD
PDWHULDOHV WDQWR HQ OD GHWHFFLyQ GH WXPRUHV \
0pWRGRVELROyJLFRV\GLVHxRH[SHULPHQWDO
PHWiVWDVLVGLDJQRVLVFRPRHQHOWUDWDPLHQWR
&RPR DQLPDO GH H[SHULPHQWDFLyQ VH
GH ORV PLVPRV PHGLDQWH DGPLQLVWUDFLyQ GH
XWLOL]DURQ UDWRQHV KHPEUD &' J
IiUPDFRV \R WUDWDPLHQWRV GH KLSHUWHUPLD
DQHVWHVLDGRV SUHYLDPHQWH FRQ LVRIOXUDQR /RV
IDUPDFRWHUDSLD 'DGR HO SDSHO UHOHYDQWH TXH
UDWRQHV IXHURQ UHSDUWLGRV DOHDWRULDPHQWH HQ
UHSUHVHQWDQ ODV 13 PDJQpWLFDV HQ HO
WUHVJUXSRV
GLDJQyVWLFR \ HQ HO WUDWDPLHQWR GHO FiQFHU OD
*UXSR ,QIODPDFLyQ , $QLPDOHV FRQ
UHODFLyQH[LVWHQWHHQWUHHOGHVDUUROORGHOFiQFHU
LQIODPDFLyQ
LQGXFLGD
SRU
OD
\ OD LQIODPDFLyQ \ OD
DGPLQLVWUDFLyQGHFDUUDJHQLQDVFHQHO
KLSHUSHUPHDELOLGDG GH OD PLFURYDVFXODWXUD
ORPRGHORVDQLPDOHV
SUHVHQWHHQDPERVSURFHVRVSRURVGH
*UXSR,QIODPDFLyQ13,1
QPUHVXOWDGHJUDQLQWHUpVHOGHVDUUROORGH
$QLPDOHVSUHSDUDGRVFRPRHQHOJUXSR
XQ PRGHOR ELROyJLFR TXH SHUPLWD HVWXGLDU OD
\TXHUHFLELHURQPJNJGH13LY
ELRGLVWULEXFLyQ
GH
13
PDJQpWLFDV
*UXSR ,QIODPDFLyQ13LPiQ ,1,
DGPLQLVWUDGDV SRU YtD LQWUDYHQRVD LY 'H
$QLPDOHVSUHSDUDGRVFRPRHQHOJUXSR
DFXHUGR FRQ OR DQWHULRUPHQWH H[SXHVWR HO
TXH VH H[SXVLHURQ D XQ FDPSR
REMHWLYR SULQFLSDO GHO SUHVHQWH WUDEDMR HV HO
PDJQpWLFRHVWiWLFRH[WHUQRGXUDQWHR
HVWXGLR GH OD ELRGLVWULEXFLyQ GH KLHUUR HQ XQ
PLQXWRV
GHVSXpV
GH
OD
IRFRLQIODPDWRULRWUDVODDGPLQLVWUDFLyQLYGH
DGPLQLVWUDFLyQLYGH13
13 PDJQpWLFDV GH KLHUUR UHFXELHUWDV GH
/D REWHQFLyQ GH ODV PXHVWUDV H[XGDGR
FDUERQRHQUDWyQ\ORVFDPELRVLQGXFLGRVSRU
LQIODPDWRULR H KtJDGR SDUD VX SRVWHULRU
OD DSOLFDFLyQ GH XQ FDPSR PDJQpWLFR H[WHUQR
YDORUDFLyQ DQDOtWLFD FRQWHQLGR HQ KLHUUR VH
SURGXFLGRVPHGLDQWHXQLPiQGHQHRGLPLR
UHDOL]y HQ SULPHU OXJDU D PLQXWRV \
SRVWHULRUPHQWH \ HQ EDVH D ORV UHVXOWDGRV
REWHQLGRVDPLQXWRV
0DWHULDOHV\0pWRGRV
0DWHULDOHV
(O HVWXGLR HVWDGtVWLFR FRPSDUDWLYR GH ODV
FDQWLGDGHVGHKLHUURHQODVPXHVWUDVELROyJLFDV
/DV 13 GH KLHUUR HQFDSVXODGDV FRQ FDUERQR
\HQORVWUHV JUXSRVGHDQLPDOHV,,1H,1,
JUDILWR QP GH ‘ IXHURQ VLQWHWL]DGDV
VH UHDOL]y PHGLDQWH XQ DQiOLVLV GH OD YDULDQ]D
PHGLDQWH HO PpWRGR DUFRGHVFDUJD \
VXPLQLVWUDGDV SRU HO ,QVWLWXWR GH 1DQRFLHQFLD
$129$GHXQIDFWRUα GH$UDJyQ,1$=DUDJR]D
6H SUHSDUy XQD VXVSHQVLyQ SDUD LQ\HFFLyQ LY
5HVXOWDGRV\'LVFXVLyQ
GH 13 PDJQpWLFDV HQ *HODIXQGLQDŠ D OD
(Q OD )LJXUD VH SUHVHQWDQ ORV YRO~PHQHV GH
FRQFHQWUDFLyQ GH PJP/ &RQ HO ILQ GH
H[XGDGR REWHQLGRV /RV YDORUHV SRQHQ GH
ORJUDU XQD ELRGLVWULEXFLyQ VHOHFWLYD GH ODV 13
PDQLILHVWRXQDXPHQWRHQORV P/GHH[XGDGR
VH DSOLFy XQ FDPSR PDJQpWLFR H[WHUQR
UHFRJLGRV UHVSHFWR DO JUXSR FRQWURO QR
PHGLDQWH OD XWLOL]DFLRQ GH XQ LPiQ GH
WUDWDGRORTXHFRQILUPDODYDOLGH]GHOPRGHOR
QHRGLPLRKLHUUR\ERUR1G)H%PP‘
LQIODPDWRULRH[SHULPHQWDOXWLOL]DGR
PPGHDOWXUD
(Q OD )LJXUD VH H[SRQHQ ORV QLYHOHV GH
0pWRGRV0pWRGRVDQDOtWLFRV
KLHUURREWHQLGRVHQHOH[XGDGR'LFKRVYDORUHV
(O HVWXGLR GH ELRGLVWULEXFLyQ GH ODV 13 HQ HO
DXPHQWDQ GH DFXHUGR FRQ HO VLJXLHQWH RUGHQ
UDWyQVHUHDOL]yDSDUWLUGHODFXDQWLILFDFLyQGHO
,!,1!,1,\HVWHLQFUHPHQWRHVPD\RUFXDQGR
)LJXUH5HOHDVHVWXG\
'LIIHUHQW PDWKHPDWLFDO UHOHDVH PRGHOV ZHUH
ILWWHG WR WKH IUDFWLRQDO UHOHDVH RI WKH GUXJ
0W0’YVWLPHWRILQGRXWWKHPHFKDQLVPRI
GUXJ UHOHDVH 7KH EHVW ILW ZDV REWDLQHG ZLWK
.RUVPH\HU3HSSDVHTXDWLRQ7KHQYDOXH
RI WKH UHSOLFDWHV ZDV EHWZHHQ LQGLFDWLQJ WKDW WKH GUXJ UHOHDVH ZDV GLIIXVLRQ
FRQWUROOHG
&RQFOXVLRQV $OWKRXJK WKH QDQRSUHFLSLWDWLRQ WHFKQLTXH LV
EDVLFDOO\DSSOLFDEOHWRK\GURSKRELFGUXJVGXH
WR WKH PLVFLELOLW\ RI WKH VROYHQW ZLWK WKH
DTXHRXV SKDVH D K\GURSKLOLF GUXJ GR[HSLQ
K\GURFKORULGH KDV EHHQ HQFDSVXODWHG ZLWK D
TXLWH FRQVLGHUDEOH GUXJ FRQWHQW $IWHU LQ YLWUR UHOHDVH VWXGLHV D VORZHU
GLIIXVLRQFRQWUROOHG UHOHDVH UDWH RI WKH GUXJ
IURPWKHQDQRSDUWLFOHVWKDQIURPDVROXWLRQKDV
EHHQREVHUYHG
5HIHUHQFHV
%LODWL8HWDO(XU-3KDUP6FL
*RYHQGHU 7 HW DO - &RQWURO 5HO )HVVL + HW DO ,QW - 3KDUP 55
)UDQ] 7 - - ,QYHVW 'HUPDWRO .RUVPH\HU 5: HW DO ,QW - 3KDUP +D\DVKL 7 HW DO ,QW - 3KDUP 5DPD5DR.HWDO-0LFURHQF
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
θP<0,05 respecto a C
C-20 min
I-20 min
IN-20
INM-20 min
Volumen exudado (mL)
2,5
C-60 min
I-60 min
IN-60
INM-60 min
2,0
θ
θ
θ
θ
θ
θ
1,5
1,0
0,5
0,0
)LJXUD 9ROXPHQ GH H[XGDGR SDUD ORV
GLVWLQWRVJUXSRVGHDQLPDOHVHQVD\DGRV
Hierro exudado (μ
μ g/g)
0,7
0,6
*P<0,05 respecto a I
I-20 min
IN-20
INM-20 min
I-60 min
IN-60
INM-60 min
φ
∗
φP<0,05 respecto a IN
∗
0,5
0,4
∗
∗
0,3
0,2
0,1
0,0
)LJXUD &RQWHQLGR GH KLHUUR HQ HO H[XGDGR
HQ ORV GLVWLQWRV ORWHV GH DQLPDOHV HQVD\DGRV
\PLQXWRVGHWRPDGHPXHVWUDV
1000
Hierro hepático (μ
μg/g)
ODV PXHVWUDV VH H[WUDHQ D ORV PLQXWRV
UHVSHFWRDORVPLQXWRV
(Q OD )LJXUD VH SUHVHQWDQ ORV QLYHOHV GH
KLHUURHQHOKtJDGR/RVUHVXOWDGRVLQGLFDQXQ
DXPHQWR HQ HO KLHUUR KHSiWLFR FXDQGR VH
DGPLQLVWUDQ ODV 13 UHVSHFWR DO JUXSR
LQIODPDFLyQ D ORV \ PLQXWRV GH
H[WUDFFLyQ GHO KtJDGR 6LQ HPEDUJR QR VH
REVHUYDQ GLIHUHQFLDV FXDQGR VH DSOLFD HO
FDPSRPDJQpWLFR\VHYDORUDHOKLHUURDORV
PLQXWRVUHVSHFWRDOJUXSRHQTXHQRVHDSOLFD
HO FDPSR PDJQpWLFR $ ORV PLQXWRV HO
LQFUHPHQWR HQ HO KLHUUR VLJXH OD VHFXHQFLD
,!,1!,1,GHIRUPDVLJQLILFDWLYD
(Q OD 7DEOD VH PXHVWUDQ ORV LQFUHPHQWRV
GHORVYDORUHVGHKLHUURREWHQLGRVHQH[XGDGR
HKtJDGRDORV\PLQGHUHFRJLGDGHODV
PXHVWUDV (O LQFUHPHQWR GHO KLHUUR HQ HO
H[XGDGRVHSURGXFHWDQWRDORVFRPRDORV
PLQXWRV SHUR HV PX\ VXSHULRU FXDQGR VH
FRQVLGHUD HO WLHPSR GH ORV PLQXWRV HQ
SUHVHQFLD GHO LPiQ H[WHUQR \ UHVSHFWLYDPHQWH5HVSHFWRDOKtJDGRWDPELpQ
VH REVHUYD XQ LQFUHPHQWR HQ ORV QLYHOHV GH
KLHUUR FXDQGR VH DGPLQLVWUDQ ODV 13 \ HQ
SUHVHQFLDGHOFDPSRPDJQpWLFRSHURQRHVGH
WDQWD PDJQLWXG FRPR HQ HO FDVR GHO H[XGDGR
UHVSHFWR DO D ORV PLQXWRV OR
FXDO FRQILUPD XQD GLVWULEXFLyQ VHOHFWLYD KDFLD
HOIRFRLQIODPDWRULR
,03/$17$&,Ï1'(1250$6,62*/3,'(17,),&$&,Ï1'(08(675$6(181
/$%25$725,2'(,19(67,*$&,Ï1<'(6$552//2)$50$&e87,&2
9'D]D7*RQoDOYHV,&DUDEDOOR
&URQRIDUPD6//$XWRYtD6HYLOOD&RULDGHO5tRNP(GLILFLR(852&(,
QDYHQž&36DQ-XDQGH$]QDOIDUDFKH6HYLOOD
*P<0,05 respecto a I
I-20 min
IN-20
INI-20 min
I-60 min
IN-60
INI-60 min
φP<0,05 respecto a IN
φ
∗
800
∗
∗
∗
600
,QWURGXFFLyQ
400
200
0
)LJXUD+LHUURHQHOKtJDGRHQORVGLVWLQWRV
ORWHVGHDQLPDOHVHQVD\DGRVDORV\
PLQXWRVGHWRPDGHPXHVWUD
7DEOD,QFUHPHQWRVHQORVYDORUHVGHKLHUUR
HQH[XGDGRHKtJDGRDORV\PLQXWRV\
HQDXVHQFLD\SUHVHQFLDGHOFDPSRPDJQpWLFR
Tiempo
%Δ
exudado
%Δ
hígado
Nanopartículas
sin
imán externo
20 min
60 min
88
52
17
18
Nanopartículas
con
imán externo
20 min
60 min
200
123
63
37
&RQFOXVLRQHV
$ ORV PLQ GH OD DGPLQLVWUDFLyQ GH 13 OD
FRQFHQWUDFLyQGHKLHUURHQHOIRFRLQIODPDWRULR
ELRIDVH VH LQFUHPHQWD HQ XQ PLHQWUDV
TXH VXV QLYHOHV HQ KtJDGR VyOR DXPHQWDQ XQ
(VWH KHFKR PXHVWUD HO JUDGR GH
ELRGLVWULEXFLyQ VHOHFWLYD REWHQLGR JUDFLDV D OD
DSOLFDFLyQGHXQFDPSRPDJQpWLFRH[WHUQR
(O PpWRGR GHVFULWR SHUPLWH HO FiOFXOR GHO
JUDGR GH GLVWULEXFLyQ VHOHFWLYD GH FDUULHUV R
IiUPDFRV IRUPXODGRV HQ QDQRSDUWtFXODV
PDJQpWLFDVGHGLVWLQWRVWDPDxRV\RGLIHUHQWHV
UHFXEULPLHQWRV HQWUH XQ IRFR LQIODPDWRULR R
WXPRU \ HO VLVWHPD UHWtFXOR HQGRWHOLDO SH
KtJDGR (Q FRQVHFXHQFLD SRGUtD VHU XQ
PpWRGR LQLFLDO SDUD HO VFUHHQLQJ GH
QDQRSDUWtFXODV
%LEOLRJUDILD
) %DONZLOO DQG $ 0DQWRYDQ /DQFHW
/0&RXVVHQVDQG=:HUE1DWXUH
65DNRII1DKRXP<DOH-%LRO0HG
+- $UUXHER HW DO 1DQRWRGD\ 5 )HUQiQGH]3DFKHFR HW DO - 0DJQ
0DJQ0DW
+/ 0D HW DO ,QW - 3KDUP $JUDGHFLPLHQWRV
(OWUDEDMRKDVLGRVXEYHQFLRQDGRSRUHO0LQLVWHULRGH
(GXFDFLyQ \ &LHQFLD (VSDxD SUR\HFWR
&2162/,'(5,1*(1,2 &6'
/DV %XHQDV 3UiFWLFDV GH /DERUDWRULR
,62*/3 VRQ XQ VLVWHPD GH QRUPDV TXH
HVWDEOHFH ODV FRQGLFLRQHV QHFHVDULDV SDUD
DVHJXUDU OD FDOLGDG \ OD WUD]DELOLGDG GH ORV
HVWXGLRVUHDOL]DGRVGHQWURGHOODERUDWRULR8QR
GH ORV SULQFLSDOHV UHTXLVLWRV SDUD OD
LPSODQWDFLyQ GH ODV */3 HV HO UHODWLYR D ORV
SURGXFWRV GH HQVD\R \ UHIHUHQFLD GRQGH VH
H[LJHQ XQD VHULH GH GDWRV SDUD OD FRUUHFWD
LGHQWLILFDFLyQ GH OD PXHVWUD (O SUHVHQWH
WUDEDMR H[SRQH XQD ILFKD GH LGHQWLILFDFLyQ GH
PXHVWUD FRQ ODV UHIHUHQFLDV PiV LPSRUWDQWHV
UHODWLYDVDOSURGXFWR\TXHUHVXOWDQQHFHVDULDV
GHQWUR GHO ODERUDWRULR SDUD VX FRUUHFWD
LGHQWLILFDFLyQ \ ORFDOL]DFLyQ GHWDOODQGR HO
PRWLYR SRU HO FXDO KHPRV KHFKR OD HOHFFLyQ
HVSHFtILFDGHFDGDXQRGHORVGDWRV
&DEH GHVWDFDU OD LPSRUWDQFLD GHO FRUUHFWR XVR
GH ORV GDWRV \ GH VX FODVLILFDFLyQ \D TXH QRV
IDFLOLWDUi PHGLDQWH XQ FULWHULR FRQFUHWR HO
UHFRQRFLPLHQWRHIHFWLYRGHXQDPXHVWUD
0DWHULDOHV\0pWRGRV
• 3URGXFWR D LGHQWLILFDU 6H HVFRJH
FRPRHMHPSOR/DFWRVDPRQRKLGUDWR
• $OEDUiQGHOOHJDGDGHSURGXFWRFRQOD
LQIRUPDFLyQ UHIHUHQWH D VX OOHJDGD \
SURYHHGRUGHOSURGXFWR
• &HUWLILFDGR GH DQiOLVLV GHO SURGXFWR
GRQGH VH GHWDOODQ FDUDFWHUtVWLFDV
FRPR HO Qž GH ORWH y OD ULTXH]D GH OD
PXHVWUD
• =RQD GH ORFDOL]DFLyQ GH OD PXHVWUD
&URQRIDUPD SRVHH iUHDV GHQWUR GH
OD
]RQD
GH
UHFHSFLyQ
\
DOPDFHQDPLHQWR
GH
PXHVWUDV
0DWHULDV SULPDV VyOLGDV 0DWHULDV
SULPDV OtTXLGDV \ 3URGXFWRV
UHIULJHUDGRV 6H HVSHFLILFDUi HO iUHD
FRQFUHWDGHOSURGXFWR\VHOHDVLJQDUi
XQQ~PHURLQWHUQRDFDGDPXHVWUD
5HVXOWDGRV\'LVFXVLyQ
&RPRKHUUDPLHQWDSDUDODLGHQWLILFDFLyQGHODV
PXHVWUDVGHQWURGHOODERUDWRULRVHGLVHxD XQD
ILFKD PRGHOR VLJXLHQGR ODV H[LJHQFLDV GH ODV
*/3 /RV GDWRV VH LPSULPHQ HQ XQ DGKHVLYR
TXH YD SHJDGR DO SURGXFWR IiFLOPHQWH YLVLEOH
\SUiFWLFRSDUDVXLQFRUSRUDFLyQDODUXWLQDGH
WUDEDMR
/DV UHIHUHQFLDV DxDGLGDV D OD ILFKD GH
LGHQWLILFDFLyQGHPXHVWUDVVRQODVVLJXLHQWHV
1RPEUH GHO SURGXFWR 6H GHILQH HO
QRPEUH FRPHUFLDO y HQ FDVR GH TXH
QRORWHQJDHOLQJUHGLHQWHFRQFUHWR
1~PHUR LQWHUQR \ ORFDOL]DFLyQ $
FDGDSURGXFWRVHOHDVLJQDXQQ~PHUR
SURSLRGHQWURGHODOPDFpQ\VHLQGLFD
HO iUHD HVSHFtILFD 6 SDUD VyOLGRV /
SDUDOtTXLGRV\SDUDUHIULJHUDGRV
&RPSRVLFLyQ 6H GHILQH HO FRQWHQLGR
GHODPXHVWUD
5LTXH]DGHOSURGXFWR
3URYHHGRU6HLQGLFDQHOQRPEUH\HO
Q~PHUR GH WHOpIRQR SDUD XQD
ORFDOL]DFLyQ UiSLGD HQ FDVR GH TXH
WHQJDPRV TXH UHDOL]DU XQ SHGLGR GH
pVWD
7pFQLFR ,QGLFD OD SHUVRQD TXH KD
UHFLELGR\DOPDFHQDGRHOSURGXFWRHQ
HOODERUDWRULR
)HFKDGHFDGXFLGDGGHOSURGXFWR
352'8&72,17(512
1RPEUH
/DFWRVD
0RQRKLGUDWR
1~PHURLQWHUQR
6
/RFDOL]DFLyQ
&RPSRVLFLyQ
'±/DFWRVH
0RQRK\GUDWH
5)(3K(XU
5LTXH]D
!
3URYHHGRU
$SKDUPD
7pFQLFR
9')
)HFKDFDGXFLGDG
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
&RQFOXVLyQ
/D RUJDQL]DFLyQ GH ORV SURGXFWRV PHGLDQWH
ILFKDV GH LGHQWLILFDFLyQ VXSRQH ODV VLJXLHQWHV
YHQWDMDVGHQWURGHOODERUDWRULR
8QDPHMRUORFDOL]DFLyQGHSURGXFWRV
JUDFLDV D OD DVLJQDFLyQ GH XQ FyGLJR
LQWHUQR\ODHVSHFLILFDFLyQGHVXiUHD
GHDOPDFHQDPLHQWR
&RQWUROGHVWRFNGHORVSURGXFWRVGHO
ODERUDWRULR \D TXH OD ILFKD HV
UHDOL]DGDDVXHQWUDGD
&RQRFLPLHQWR GH OD FDGXFLGDG GHO
SURGXFWR
(Q UHVXPHQ OD ILFKD GH LGHQWLILFDFLyQ GH
SURGXFWR IDFLOLWD HO FRUUHFWR UHJLVWUR \
DOPDFHQDPLHQWR SDUD DVHJXUDU OD FDOLGDG \
RUJDQL]DFLyQGHQWURGHOODERUDWRULR
%LEOLRJUDItD
0LQLVWHULR \ $OLPHQWDFLRQ GH $JULFXOWXUD
3HVFD \ $OLPHQWDFLRQ 3URJUDPD GH
&XPSOLPLHQWR GH ODV %XHQDV 3UDFWLFDV GH
/DERUDWRULRUHY
KWWSZZZDJHPHGHVDFWLYLGDGGRFXPHQWR
VLQIR,QWHUHVGRFV%3/ELV
(/$%25$&,Ï1<&$5$&7(5,=$&,Ï135(/,0,1$5'(1$123$57Ë&8/$6'(
,168/,1$3/*$3$5$$'0,1,675$&,Ï125$/
- ÈOYDUH])XHQWHV0-&y]DU%HUQDO/0DUWtQ%DQGHUDV0$+ROJDGR0)HUQiQGH]$UpYDOR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD
F3URIHVRU*DUFtD*RQ]iOH]Qž6HYLOOD
HPDLOIIMDOYDUH]#XVHV
GH OD GREOH HPXOVLyQ \ FRQFHQWUDFLyQ GHO
,QWURGXFFLyQ
SROtPHURIRUPDGRU3/*$
/DYtDRUDOHVODSUHIHULGDSRUORVSDFLHQWHVSRU
VHULQGRORUD\FyPRGDGHDGPLQLVWUDUSHURQR
0DWHULDOHV\0pWRGRV
VLHPSUH HV SRVLEOH XWLOL]DUOD FRPR RFXUUHQ HO
0DWHULDOHV
FDVR GH OD DGPLQLVWUDFLyQ GH SURWHtQDV
,QVXOLQD \ 7ZHHQ® 6LJPD $OGULFK
WHUDSpXWLFDV eVWDV SUHVHQWDQ P~OWLSOHV
$OHPDQLD iFLGR SROLOiFWLFRSROLJOLFyOLFR
GHVYHQWDMDVTXHREVWDFXOL]DQVXDGPLQLVWUDFLyQ
5HVRPHU® 5* YLVFRVLGDG LQKHUHQWH
SRUHVWDYtDDOVHUPDFURPROpFXODVVHQVLEOHVD
GOJ%RHUKULQJHU,QJHOKHLP$OHPDQLD
OD GHJUDGDFLyQ H[WUHPDGDPHQWH OiELOHV
DOFRKRO SROLYLQtOLFR 0RZLROŠ )OXND
DGHPiV GH SUHVHQWDU XQD EDMD FDSDFLGDG GH
$OHPDQLD\DFHWDWRGHHWLOR3DQUHDF4XtPLFD
SHQHWUDFLyQ D WUDYpV GH ORV HSLWHOLRV
6$(VSDxD
LQWHVWLQDOHV
3UHSDUDFLyQGHORVVLVWHPDV
/D LQVXOLQD PROpFXOD REMHWR GH QXHVWUR
/DV
SDUWtFXODV VH KDQ HODERUDGR XWLOL]DQGR HO
HVWXGLRVHFDUDFWHUL]DSRUXQDEDMDHVWDELOLGDG
PpWRGR GH OD GREOH HPXOVLyQHYDSRUDFLyQ GH
\D TXH HV VXVFHSWLEOH GH GHJUDGDFLyQ ItVLFD \
GLVROYHQWH
SURSXHVWR SRU %LODWL \ FROV TXtPLFD\XQDYLGDPHGLDFRUWD
FRQYHQLHQWHPHQWHPRGLILFDGR
/DV QDQRSDUWtFXODV SROLPpULFDV VRQ REMHWR GH
(O PpWRGR GH OD GREOH HPXOVLyQHYDSRUDFLyQ
HVSHFLDO DWHQFLyQ GHELGR D VX LQWHUpV SDUD
GH GLVROYHQWH HV HO PpWRGR PiV DPSOLDPHQWH
PHMRUDUODHVWDELOLGDG\SURPRYHUHOWUDQVSRUWH
XWLOL]DGR SDUD OD HQFDSVXODFLyQ GH IiUPDFRV
\ OLEHUDFLyQ FRQWURODGD GH ORV IiUPDFRV D
KLGURItOLFRV
GHWHUPLQDGDV UHJLRQHV GHO RUJDQLVPR \D TXH
/D FRPSRVLFLyQ GH ODV IDVHV GH OD GREOH
SUHVHQWDQDOWDHVWDELOLGDGEXHQDSURWHFFLyQDO
HPXOVLyQVHUHFRJHHQODWDEOD
SULQFLSLR DFWLYR \ HO XVR GH PDWHULDOHV
SROLPpULFRVSHUPLWHPRGXODUODVFDUDFWHUtVWLFDV
ILVLFRTXtPLFDV OD OLEHUDFLyQ GHO SULQFLSLR
DFWLYR \ HO FRPSRUWDPLHQWR ELROyJLFR GH
GLFKRVVLVWHPDV
(QODV~OWLPDVIHFKDVVHKDYLVWRLQFUHPHQWDGR
HO HVWXGLR VREUH QDQRSDUWtFXODV DO VHU
VXVFHSWLEOHV GH DWUDYHVDU ODV SODFDV GH 3H\HU
SULQFLSDOPHQWH D WUDYpV GH ODV FpOXODV 0
HVSHFLDOL]DGDV HQ OD DEVRUFLyQ GH SDUWtFXODV
GHVGH OD OX] JDVWURLQWHVWLQDO KDFLD OD UHJLyQ
EDVRODWHUDO ULFD HQ OLQIRFLWRV /R PiV
FDUDFWHUtVWLFR GH HVWDV FpOXODV HV TXH VRQ
FDSDFHV GH WUDQVSRUWDU PDFURPROpFXODV
SDUWtFXODV \ PLFURRUJDQLVPRV GLUHFWDPHQWH D
ODVSODFDVGH3H\HU6HKDYLVWRTXHHOWDPDxR
ySWLPRSDUDODDEVRUFLyQDWUDYpVGHODVSODFDV
GH 3H\HU VH HQFXHQWUD HQ OD HVFDOD
QDQRPpWULFD$GHPiVVRQWDPELpQIDFWRUHVGH
JUDQ LPSRUWDQFLD OD FDUJD VXSHUILFLDO OD
KLGURILOLD GHO SROtPHUR IRUPDGRU \ OD
SURSRUFLyQGHWHQVLRDFWLYRHQHOVLVWHPD
(O REMHWLYR GHO SUHVHQWH WUDEDMR KD VLGR
HODERUDU \ FDUDFWHUL]DU GH IRUPD SUHOLPLQDU
VLVWHPDV QDQRSDUWLFXODUHV D EDVH GH 3/*$
FRQWHQLHQGR LQVXOLQD SDUD VX DGPLQLVWUDFLyQ
RUDO3DUDHOORVHHVWXGLDUiODLQIOXHQFLDGHGRV
SDUiPHWURV GH IRUPXODFLyQ FRQFHQWUDFLyQ GH
DOFRKRO SROLYLQtOLFR 39$ HQ OD IDVH H[WHUQD
7DEOD&RPSRVLFLyQGHODVIDVHVGHODGREOH
HPXOVLyQ
6ROXFLyQ GH LQVXOLQD HQ iFLGR DFpWLFR
YY
$
2 6ROXFLyQGH3/*$HQDFHWDWRGHHWLOR
$ 6ROXFLyQDFXRVDGH39$
3DUD REWHQHU OD GREOH HPXOVLyQ $2$ VH
XWLOL]y XQ VRQLFDGRU %UDGVRQ : $
FRQWLQXDFLyQ HO VLVWHPD VH PDQWLHQH EDMR
DJLWDFLyQ 0DJQHWLF VWLUUHU KRWSODWH 60
GXUDQWH DSUR[LPDGDPHQWH KRUDV \ VH
VRPHWH
D
FHQWULIXJDFLyQ
ODYiQGROR
SRVWHULRUPHQWH (O SURGXFWR REWHQLGR VH
OLRILOL]D 7HOVWDU &U\RGRV REWHQLpQGRVH ODV
QDQRSDUWtFXODV
(Q OD WDEOD VH UHFRJHQ ODV GLVWLQWDV
FRQGLFLRQHVGHHODERUDFLyQ
7DEOD &RPSRVLFLyQGHORVORWHVHODERUDGRV
/RWH 39$ 3/*$
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
(Q IXQFLyQ GH ORV GDWRV REWHQLGRV VH HVWLPD
TXH HO WDPDxR PHGLR GH ODV SDUWtFXODV HV
UHGXFLGR\KRPRJpQHR/DEDMDYLVFRVLGDGGHO
SROtPHURMXVWLILFDMXQWRFRQODVFRQGLFLRQHVGH
SURGXFFLyQORVWDPDxRVREWHQLGRV
$OHVWXGLDUODLQIOXHQFLDGHODFRQFHQWUDFLyQGH
39$ ORWHV \ VH DSUHFLD FODUDPHQWH TXH
KD\ XQD GLVPLQXFLyQ GHO WDPDxR GH SDUWtFXOD
108
153
76,5
215
303
428
605
710
)LJ5HFKD]RDFXPXODWLYR IUHQWHDOtPLWH
GHGLiPHWURGHWRGRVORVYHJHWDOHV
12 0
10 0
P IM IE N T O
80
LIM O N
60
Z A N A H O R IA
40
T OM A T E
20
C EB O LLA
0
76,5
108
153
720$7(
&(%2//$
215
=$1$+25,$
303
428
GHVKLGUDWDFLyQ HQ HO GLVSRVLWLYR &5,2; HO
WDPDxR GH ORV WUR]RV GHEH VHU PiV R PHQRV
JUXHVR SDUD HYLWDU TXH TXHGHQ SHJDGRV HQ ODV
SDUHGHV
GHO
GLVSRVLWLYR
GXUDQWH
OD
GHVKLGUDWDFLyQ eVWD VH KDFH D YDFtR \ D
WHPSHUDWXUDFRQWURODGD PHQRURLJXDODž
&SDUDHYLWDUGDxRWpUPLFR\SRUWDQWRODSpUGLGD
GH ODV SURSLHGDGHV QXWULFLRQDOHV GHO YHJHWDO
3DUD OD SXOYHUL]DFLyQ XWLOL]DPRV XQ PROLQR GH
PDUWLOORV GRQGH FRQVHJXLPRV XQ WDPDxR GH
SDUWtFXODLUUHJXODU
8QD YH] REWHQLGD OD PDWHULD SULPD UHDOL]DPRV
ORVHQVD\RVGHOD5)(HOHQVD\RGHWDPDxRGH
SDUWtFXOD OD FDSDFLGDG GH IOXMR HO YROXPHQ
DSDUHQWH \ OD GHQVLGDG DSDUHQWH QRV GDQ XQD
LGHDGHODVSURSLHGDGHVGHIOXMRGHORVPLVPRV
GHODFDSDFLGDGTXHWLHQHQORVVyOLGRVGLYLGLGRV
GHIOXLUYHUWLFDOPHQWH\FRQHOWLSR\WDPDxRGH
SDUWtFXODFRQHOTXHHVWDPRVWUDEDMDQGR'HpVWD
PDQHUD SRGHPRV GHILQLU VL VRQ GHVKLGUDWDGRV
YHJHWDOHV YiOLGRV SDUD OD HODERUDFLyQ GH
GLIHUHQWHVIRUPDVJDOpQLFDV
&RPR SXHGH DSUHFLDUVH HQ OD IRWRJUDItD ORV
VLVWHPDV HODERUDGRV PRVWUDURQ KRPRJHQHLGDG
HQ HO WDPDxR FRQ IRUPD HVIpULFD \ VXSHUILFLH
OLVD
(QODWDEODVHUHFRJHQORVWDPDxRVREWHQLGRV
SDUDFDGDXQRGHORVORWHVHODERUDGRV
7DEOD7DPDxRPHGLR—PGHORVGLIHUHQWHV
ORWHVGHSDUWtFXODVHODERUDGRV
7DPDxRPHGLR
/RWH
'6
&9
—P
)LJXUD 0LFURIRWRJUDItD GH SDUWtFXODV GH
LQVXOLQD FRUUHVSRQGLHQWHV DO ORWH ORQJLWXG
GHODEDUUD—P
(16$<265($/,=$'26$'(6+,'5$7$'269(*(7$/(63$5$68326,%/(
87,/,=$&,Ï1(1)250$6*$/e1,&$6
0'5RPHUR%&ODUHV0$5XL]-$OFDOi3*DUFtD9*DOODUGR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH*UDQDGD9HUELRWHFK,'L6/
9HUELRQDW6&$
,QWURGXFFLyQ
3UHWHQGHPRV GHVDUUROODU ORV SURFHVRV GH
5HVXOWDGRV\'LVFXVLyQ
/D GHWHUPLQDFLyQ GHO WDPDxR GH SDUWtFXOD VH
REWHQFLyQGHPDWHULDVSULPDVYHJHWDOHVOOHYDGRV
UHDOL]D SRU WDPL]DFLyQ HQ FDVFDGD DVt
D FDER SRU OD LQGXVWULD IDUPDFpXWLFD FRQ OD
VHOHFFLRQDPRV ORV GLVWLQWRV WDPDxRV GH
ILQDOLGDG GH REWHQHU GHVKLGUDWDGRV YHJHWDOHV
SDUWtFXODV(QODVILJXUDV\UHSUHVHQWDPRV
SDUD VX XWLOL]DFLyQ HQ OD HODERUDFLyQ GH IRUPDV
ORV UHVXOWDGRV HQ SRUFHQWDMHV GH ORV UHFKD]RV
JDOpQLFDV2EWHQGUHPRVSROYRVGHGHVKLGUDWDGRV
ORV UHFKD]RV DFXPXODWLYRV \ HO WDPL]DGR
YHJHWDOHV \ UHDOL]DUHPRV ORV HQVD\RV JDOpQLFRV
DFXPXODWLYR TXH SUHVHQWD FDGD YHJHWDO HQ ORV
GHVFULWRV HQ OD 5HDO )DUPDFRSHD (VSDxROD
GLVWLQWRVWDPLFHV
5)( TXH QRV SHUPLWDQ GHWHFWDU VL QXHVWURV
&RQ OD PHGLGD GHO YROXPHQ DSDUHQWH OD
GHVKLGUDWDGRV YHJHWDOHV VRQ LGyQHRV SDUD HO ILQ
GHQVLGDG DSDUHQWH \ GHO iQJXOR GH UHSRVR
DOTXHYDQGHVWLQDGRV
GHWHUPLQDPRV OD FDSDFLGDG GH IOXMR TXH
SUHVHQWDQORVYHJHWDOHV
0DWHULDO\0pWRGR
45
/DV PDWHULDV SULPDV VRQ YHJHWDOHV IUHVFRV
40
SURFHGHQWHV GH OD SURGXFFLyQ DJUtFROD
35
WUDGLFLRQDO GH OD 9HJD *UDQDGLQD 6H WRPDURQ
P IM IE N T O
30
LIM O N
FRPR REMHWR GH HVWXGLR &HEROOD /LPyQ
25
Z A N A H O R IA
3LPLHQWR 7RPDWH \ =DQDKRULD TXH
2 0
T OM A T E
15
VRPHWLpQGRVH SUHYLDPHQWH PHGLDQWH PpWRGRV
C E B O LLA
10
LQGXVWULDOHV D SURFHVRV GH ODYDGR \ FRUWDGR
5
IXHURQGHVKLGUDWDGRVHQFRQGLFLRQHVGHYDFtR\
0
WHPSHUDWXUDFRQWURODGDHQHOGLVSRVLWLYR&5,2;
\ SRVWHULRUPHQWH SXOYHUL]DGRV SDUD VHU
WUDQVIRUPDGRV HQ ORV GHVKLGUDWDGRV YHJHWDOHV
)LJ5HFKD]RIUHQWHDOOtPLWHGHGLiPHWUR
TXH GHVHDPRV REWHQHU /RV YHJHWDOHV IUHVFRV
SDUDWRGRVORVYHJHWDOHV
VRQ LQWURGXFLGRV HQ XQ WUHQ GH ODYDGR SDUD
HOLPLQDU ODV LPSXUH]DV PHGLDQWH FKRUURV D
SUHVLyQ GH XQD VROXFLyQ FRQVWLWXLGD SRU
3,0,(172
KLSRFORULWR VyGLFR \ DJXD ,QPHGLDWDPHQWH
/,021
GHVSXpV VRQ WURFHDGDV SDUD VX SRVWHULRU
605
&DUDFWHUL]DFLyQGHORVVLVWHPDV
(QODILJXUDVHPXHVWUDDWtWXORGHHMHPSOR
XQDIRWRJUDItDGHOORWH
FXDQGRDXPHQWDODFRQFHQWUDFLyQGH39$/D
DGLFLyQGHOWHQVLRDFWLYRDPD\RUFRQFHQWUDFLyQ
FRQVLJXH UHGXFLU GH IRUPD PiV HIHFWLYD OD
WHQVLyQ VXSHUILFLDO GH OD IDVH FRQWLQXD
FRQVLJXLHQGRDVtUHGXFLUHOWDPDxRGHSDUWtFXOD
GHOVLVWHPD
3RU RWUR ODGR VL VH FRPSDUDQ ORV WDPDxRV
REWHQLGRVHQORVORWHV\VHDSUHFLDTXHDO
DXPHQWDU OD FRQFHQWUDFLyQ GHO SROtPHUR GHO
DODXPHQWDHOWDPDxR PHGLRGHODV
SDUWtFXODV $O DXPHQWDU OD FRQFHQWUDFLyQ GHO
SROtPHURVHLQFUHPHQWDODYLVFRVLGDGGHODIDVH
GLVSHUVD DXPHQWDQGR DVt HO WDPDxR GH
SDUWtFXOD
&RQ UHVSHFWR D ORV YDORUHV GH SRWHQFLDO ]HWD
IXHURQQHJDWLYRVSDUDORVWUHVORWHVHVWXGLDGRV
QR HQFRQWUDQGR LQIOXHQFLD VLJQLILFDWLYD SRU
FDPELRV HQ ODV FRQFHQWUDFLRQHV GH 39$ \
3/*$ $GHPiV ORV YDORUHV QHJDWLYRV GH
SRWHQFLDO ]HWD IDYRUHFHUiQ HO QR DWUDSDPLHQWR
GH ODV QDQRSDUWtFXODV SRU SDUWH GH OD FDSD GH
PXFXVTXHWDSL]DODPXFRVDLQWHVWLQDO
(Q UHODFLyQ D OD HILFDFLD GH HQFDSVXODFLyQ VH
HQFRQWUy XQ LQFUHPHQWR GH pVWD DO DXPHQWDU
WDQWR OD FRQFHQWUDFLyQ GH 39$ FRPR GH
3/*$
&RQFOXVLRQHV
&RQORVUHVXOWDGRVREWHQLGRVSXHGHFRQFOXLUVH
TXH PHGLDQWH HO PpWRGR SURSXHVWR VH KDQ
FRQVHJXLGR HODERUDU SDUWtFXODV GH LQVXOLQD GH
WDPDxR QDQRPpWULFR FRQ FDUDFWHUtVWLFDV
VXSHUILFLDOHV\FRQWHQLGRDGHFXDGRV
%LEOLRJUDItD
'H 5RVD * \ FROV - &RQWURO 5HO &y]DU 0- \ FROV ,QG )DUP 9LOD -DWR -/ $Q 5 $FDG 1DF )DUP
%LODWL8\FROV3KDUP'HY7HFK
/L0 \FROV ,QW-3KDUP
&KLDSSHWWD '$ \ FROV $FWD )DUP
%RQDHUHQVH
<DQJ<<\FROV%LRPDWHULDOV
$QGUp$EUDQW $ \ FROV (XU 3RO\P -
+DULKDUDQ6\FROV3KDUP5HV
$JUDGHFLPLHQWRV (VWH WUDEDMR VH KD
GHVDUUROODGRGHQWURGHO3UR\HFWRGH([FHOHQFLD
&76&RQVHMHUtDGH,QQRYDFLyQ&LHQFLD
\ (PSUHVD -XQWD GH $QGDOXFtD
710
&DUDFWHUL]DFLyQGHORVVLVWHPDV
(O WDPDxR PHGLR GH SDUWtFXOD IXH FDOFXODGR
PHGLDQWH XQ PpWRGR GH GLVSHUVLyQ OiVHU
3DUWLFD/$9+RULED(OHVWXGLRGHOD
IRUPD \ VXSHUILFLH VH UHDOL]y PHGLDQWH
0LFURVFRStD(OHFWUyQLFDGH%DUULGR6(0
/DV FDUDFWHUtVWLFDV HOpFWULFDV VXSHUILFLDOHV GH
ODV SDUWtFXODV VH GHWHUPLQDURQ FRQ XQ
GLVSRVLWLYR0DOYHUQ0DVWHUVL]HU
3DUD FDOFXODU OD HILFDFLD GH HQFDSVXODFLyQ PJ GH QDQRSDUWtFXODV VH GLVROYLHURQ HQ P/
GHDFHWDWRGHHWLOR6HDxDGLHURQP/GH+&O
1 \ WUDV VRPHWHU HO VLVWHPD D
FHQWULIXJDFLyQ VH FXDQWLILFy OD LQVXOLQD HQ HO
VREUHQDGDQWH
5HVXOWDGRV\'LVFXVLyQ
)LJ7DPL]DGRDFXPXODWLYRIUHQWHDOtPLWH
GHGLiPHWURGHWRGRVORVYHJHWDOHV
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
(QODWDEODVHYHQUHIOHMDGRVORVUHVXOWDGRVGH
HVWRV HQVD\RV \ HQ ODV ILJXUDV \ ORV
UHSUHVHQWDPRVJUiILFDPHQWH
SDUWtFXODV\RWUDV\TXHHOSROYRTXHGHSHJDGRD
ODVSDUHGHVGHOGLVSRVLWLYR(OUHVWRGHYHJHWDOHV
SUHVHQWDQ WDPDxR GH SDUWtFXOD JUXHVR 7RGRV
HOORVVRQDSWRVSDUDODHODERUDFLyQGHGLIHUHQWHV
IRUPDVJDOpQLFDV
%LEOLRJUDItD
5HDO)DUPDFRSHD(VSDxROD(GLFLyQ
9LOD-DWR-/7HFQRORJtD)DUPDFpXWLFD9RO, \
,,0DGULG(GLW6tQWHVLV
$XOWRQ0()DUPDFLD/DFLHQFLDGHOGLVHxRGH
ODV )RUPDV )DUPDFpXWLFDV HG 0DGULG
(OVHYLHU
7DEOD&DSDFLGDGGHIOXMRGHORVGLVWLQWRVYHJHWDOHV
,&
Ȗ
,+
3LPLHQWR
=DQDKRULD
/LPyQ
7RPDWH
&HEROOD
&DSDFLGDG
GH
IOXMR
%XHQD
%XHQD
%XHQD
$FHSWDEOH
3REUH
3REUH
PX\SREUH
,& ,QGLFH GH &DU Ȗ ÈQJXOR GH UHSRVR ,+ ,QGLFH GH
+DXVQHU
'HSHQGLHQGR GHO iQJXOR GH UHSRVR IRUPDGR OD
FDSDFLGDG GH IOXMR VHUi PD\RU R PHQRU VL pVWH
HV PHQRU D ž HO SROYR IOXLUi IiFLOPHQWH VL HV
PD\RU D ž QR H[LVWH IOXMR OLEUH \ VL VH
HQFXHQWUD FRPSUHQGLGR HQWUH ž \ ž HO IOXMR
VHUiGLItFLO
3,0,(172
/,021
=$1$+25,$
720$7(
&(%2//$
)LJ 9ROXPHQ P/ IUHQWH DO Q~PHUR GH
JROSHVUHDOL]DGRVHQHOHQVD\RGHYROXPHQ
DSDUHQWH
,&
3,0,(172
=$1$+25,$
/,021
720$7(
&(%2//$
Ȗ
)LJ ËQGLFH GH &DU IUHQWH DO iQJXOR GH
UHSRVRSDUDWRGRVORVYHJHWDOHV
&RQFOXVLRQHV
/RVGHVKLGUDWDGRVYHJHWDOHVDQDOL]DGRVFXPSOHQ
ORVHQVD\RVJDOpQLFRVSDUDSROYRVGHVFULWRVHQOD
5HDO )DUPDFRSHD (VSDxROD WRGRV HOORV
SUHVHQWDQ EXHQDV SURSLHGDGHV GH IOXMR
GHVWDFDQGR OD GHO SLPLHQWR \ OD ]DQDKRULD TXH
IOX\HQIiFLOPHQWH(VODFHEROODHO~QLFRGHHOORV
TXHSRVHHXQDFDSDFLGDGGHIOXMRSREUHGHELGRD
TXH SUHVHQWD XQ WDPDxR GH SDUWtFXOD SHTXHxR
HVWRKDFHTXHVHIRUPHQDJORPHUDGRVHQWUHXQDV
(9$/8$&,Ï1,19,752(,19,92'(',)(5(17(635272&2/26'(
&5,235(6(59$&,Ï13$5$35(6(59$50,2%/$67260,&52(1&$368/$'26
$0XUXD*2ULYH50+HUQiQGH]-/3HGUD]
)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGHO3DtV9DVFR839(+8
9LWRULD*DVWHL]$ODYD
LPSODQWDURQ ODV PLFURFiSVXODV D QLYHO
VXEFXWiQHR6& PHGLDQWH XQFDWpWHU1LSUR
JDXJH 1LVVKR &RUS (O JUXSR FRQWURO UHFLELy
+%66SRUODPLVPDYtD
,QWURGXFFLyQ
(Q OD DFWXDOLGDG SDUD SRGHU DVHJXUDU XQ
FRUUHFWR LQWHUFDPELR GH PDWHULDO GH
LQYHVWLJDFLyQ HQWUH JUXSRV FRODERUDGRUHV OD
SRVLELOLGDG GH FULRSUHVHUYDU DGHPiV GH FpOXODV
HVWUXFWXUDV ELRFRPSDWLEOHV GHVDUUROODGDV SDUD
LQPRYLOL]DUFpOXODVHVWiVLHQGRFRQVLGHUDGDSRU
PXFKRVJUXSRVGHLQYHVWLJDFLyQ
/DHQFDSVXODFLyQSURSRUFLRQDXQPpWRGRVHJXUR
\UHSURGXFLEOHSDUDODLQPRYLOL]DFLyQGHFpOXODV
REWHQLHQGR XQD OLEHUDFLyQ FRQWURODGD \
VRVWHQLGD GH SURGXFWRV WHUDSpXWLFRV VHFUHWDGRV
µGHQRYR¶
(OSUHVHQWHHVWXGLRVHOOHYyDFDERFRQHOILQGH
LGHQWLILFDU VHOHFWLYDPHQWH OD WDVD ySWLPD GH
HQIULDPLHQWR WHPSHUDWXUD \ YHORFLGDG \ OD
FRQFHQWUDFLyQ DGHFXDGD GH FULRSURWHFWRU SDUD
SURPRYHU OD FUHDFLyQ GH EDQFRV GH PLREODVWRV
HQFDSVXODGRV VHFUHWRUHV GH (SR 6H KD
VHOHFFLRQDGR HO GLPHWLO VXOIy[LGR '062
FRPRFULRSURWHFWRU
0DWHULDO\0pWRGRV
/D LQPRYLOL]DFLyQ GH ORV PLREODVWRV &&
GHULYDGRV GHO P~VFXOR HVTXHOpWLFR GH UDWRQHV
&+ \ JHQpWLFDPHQWH PRGLILFDGRV SDUD OLEHUDU
(SR PXULQD P(SR HQ PLFURFiSVXODV GH
DOJLQDWRSROL/OLVLQDDOJLQDWR $3$ VH UHDOL]y
HPSOHDQGR
XQ
JRWHDGRU
HOHFWURVWiWLFR
LQWURGXFLHQGR DOJXQDV PRGLILFDFLRQHV DO
SURWRFRORGLVHxDGRSRU/LP\6XQ
(O SULPHU HQVD\R GH HVWH HVWXGLR IXH UHDOL]DGR
FRQ XQ JUXSR GH FpOXODV PLFURHQFDSVXODGDV QR
FULRSUHVHUYDGDV \ FXDWUR JUXSRV GRQGH VH
HYDOXDURQ GLVWLQWRV SURWRFRORV GH FRQJHODFLyQ
UHFRJLGRVHQOD7DEODXWLOL]DQGRHQWRGRVORV
FDVRVXQDFRQFHQWUDFLyQGHGH'062(Q
EDVH D ORV UHVXOWDGRV REWHQLGRV HQ HVWH SULPHU
HQVD\R VH SODQWHy XQD VHJXQGD DSUR[LPDFLyQ
FRQ HO ILQ GH HYDOXDU HO HIHFWR GHO HPSOHR GH
GLVWLQWDV FRQFHQWUDFLRQHV GH '062 \ /DV FpOXODV
PLFURHQFDSVXODGDV
VH
FULRSUHVHUYDURQ
HPSOHDQGR HO SURWRFROR GH HQIULDPLHQWR
FRQWURODGRYHU&&HQ7DEOD
/DYLDELOLGDGLQYLWURGHODVFpOXODVIXHHYDOXDGD
LQGLUHFWDPHQWH SRU OD PHGLGD GH SURGXFFLyQ GH
(SR GH ODV FpOXODV PLFURHQFDSVXODGDV
HPSOHDQGR XQ NLW GH GHWHFFLyQ GH (SR 5'
6\VWHPV
3DUD ORV HVWXGLRV LQ YLYR VH XWLOL]DURQ UDWRQHV
%DOEF DGXOWRV KHPEUDV DQHVWHVLDGRV SRU
LQKDODFLyQ GH LVRIOXUDQR HQ ORV TXH VH
7DEOD3URWRFRORVGHFULRSUHVHUYDFLyQ
$JLWDFLyQ
1R
&&6K
6&
Kž&
Kž&
1OtTž&
6t
Kž&
1OtTž&
1R
0&
1OtTž&
1R
&& (QIULDPLHQWR FRQWURODGR &&6K (QIULDPLHQWR FRQWURODGR DJLWDFLyQ 6&
6XSHUHQIULDPLHQWR0&0D[LHQIULDPLHQWR
/DV PXHVWUDVGHVDQJUHVHREWXYLHURQ PHGLDQWH
SXQFLyQ UHWURRUELWDO FRQ WXERV FDSLODUHV
KHSDULQL]DGRV (O KHPDWRFULWR VH GHWHUPLQy
HPSOHDQGR XQ PpWRGR HVWiQGDU GH
PLFURKHPDWRFULWR /RV UHVXOWDGRV VH H[SUHVDQ
FRPRPHGLD±'(
(O GtD SRVWLPSODQWH DOJXQRV DQLPDOHV
IXHURQ VDFULILFDGRV \ VH H[WUDMHURQ ODV
PLFURFiSVXODV GHO HVSDFLR VXEFXWiQHR SDUD VX
ILMDFLyQ HQ XQD VROXFLyQ GH SDUDIRUPDOGHKtGR
\
SRVWHULRU
DQiOLVLV
KLVWROyJLFR+(
5HVXOWDGRV\'LVFXVLyQ
(OJUXSRGHHQIULDPLHQWRFRQWURODGRPRVWUyXQD
UHGXFFLyQ GH OD SURGXFFLyQ GH (SR VXSHULRU DO
PLHQWUDV TXH HO UHVWR GH ORV SURWRFRORV
PRVWUDURQPD\RUHVWDVDVGHUHGXFFLyQ)LJ
)LJXUD5HGXFFLyQHQODSURGXFFLyQGH(SRHQEDVH
D ORV GLVWLQWRV SURWRFRORV GH HQIULDPLHQWR '062 HPSOHDGRV HQ FRPSDUDFLyQ FRQ HO JUXSR
FRQWUROGHPLFURFiSVXODVQRFULRSUHVHUYDGDV
(O DQiOLVLV GH OD UHGXFFLyQ GH SURGXFFLyQ GH
(SRGHORVJUXSRVFULRSUHVHUYDGRVFRQGLVWLQWDV
FRQFHQWUDFLRQHVGHFULRSURWHFWRUPRVWUyTXHODV
FRQFHQWUDFLRQHVySWLPDVIXHURQ\HQ
,;&RQJUHVRGHOD6(),*
([SRVLFLyQ HQ XQ DJLWDGRU KRUL]RQWDO GH ODV PLFURFiSVXODV D OD VROXFLyQ
FULRSURWHFWRUDGXUDQWHPLQDWHPSHUDWXUDDPELHQWH
FX\RV JUXSRV VH REVHUYDURQ ODV WDVDV GH
UHGXFFLyQ PiV EDMDV \ UHVSHFWLYDPHQWH WDO \ FRPR SXHGH REVHUYDUVH
HQOD)LJXUD
&&
'062
Kž&
3URWRFRORGH
Kž&
HQIULDPLHQWR
1OtTž&
7HFQRORJtD)DUPDFpXWLFD
)LJ (VWXGLRV UHDOL]DGRV SUHYLDPHQWH KDQ
SXHVWRGHPDQLILHVWRTXHODHULWURSR\HWLQDSXHGH
DFWXDUFRPRXQIDFWRUDQJLRJpQLFRSRUGLVWLQWDV
YtDVGHVHxDOL]DFLyQ
9$/,'$&,Ï1'(810e72'2$1$/Ë7,&2325+3/&3$5$/$'(7(50,1$&,Ï1'(
5$6$*,/,1$0(6,/$72(10,&52(6)(5$6%,2'(*5$'$%/(6'(3/*$
0)HUQiQGH](%DUFLD\61HJUR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDG&RPSOXWHQVHGH0DGULG
0DGULG(VSDxD
'HSDUWDPHQWRGH)DUPDFLD8QLYHUVLGDGGH&RQFHSFLyQ&RQFHSFLyQ&KLOH
)LJXUD5HGXFFLyQHQODSURGXFFLyQGH(SRHQEDVH
D ODV GLVWLQWDV FRQFHQWUDFLRQHV GH DJHQWH
FULRSURWHFWRU HPSOHDGDV HQ FRPSDUDFLyQ FRQ HO
JUXSRFRQWUROGHPLFURFiSVXODVQRFULRSUHVHUYDGDV
&RQ UHVSHFWR D ORV HQVD\RV LQ YLYR WDO \ FRPR
VH REVHUYD HQ OD )LJXUD QR VH GHWHFWDURQ
GLIHUHQFLDV VLJQLILFDWLYDV HQWUH HO JUXSR GH
PLFURFiSVXODVQRFULRSUHVHUYDGDV\HOJUXSRGH
GH'062DOGtD±YHUVXV±
UHVSHFWLYDPHQWH33RUHOFRQWUDULR
Vt VH REVHUYDURQ DO GtD GLIHUHQFLDV
VLJQLILFDWLYDV HQWUH ORV JUXSRV FULRSUHVHUYDGRV
FRQ HO \ HO GH '062 ± YHUVXV ± UHVSHFWLYDPHQWH 3
VLHQGR SRU WDQWR OD FRQFHQWUDFLyQ GHO GH
'062ODPiVDGHFXDGDSDUDUHDOL]DUHOSURFHVR
GHFULRSUHVHUYDFLyQ
)LJXUD 1LYHOHV GH KHPDWRFULWR GH UDWRQHV %DOEF
WUDV OD DGPLQLVWUDFLyQ VXEFXWiQHD GH PLREODVWRV
&& VHFUHWRUHV GH (SR LQPRYLOL]DGRV HQ
PLFURFiSVXODV
$3$
HPSOHDQGR
GLVWLQWDV
FRQFHQWUDFLRQHV GH DJHQWH FULRSURWHFWRU /RV
UHVXOWDGRVVHH[SUHVDQFRPRPHGLD±'(
/RV LPSODQWHV GH PLFURFiSVXODV VH H[SODQWDURQ
HO GtD SRVWLPSODQWH 6H REVHUYy XQD OLJHUD
UHDFFLyQ GH FXHUSR H[WUDxR SHUR QR VH
REVHUYDURQ HIHFWRV VHFXQGDULRV DGYHUVRV
VLJQLILFDWLYRV
/RV DQiOLVLV KLVWROyJLFRV GH ODV PLFURFiSVXODV
H[SODQWDGDV PRVWUDURQ OD DSDULFLyQ GH XQD UHG
GHFDSLODUHVVDQJXtQHRVHQWUHODV PLFURFiSVXODV
)LJXUD 0LFURFiSVXODV H[SODQWDGDV GHO HVSDFLR
VXEFXWiQHR DO GtD SRVWLPSODQWH $QiOLVLV
KLVWROyJLFR+($JUXSRQRFULRSUHVHUYDGR%
JUXSRFULRSUHVHUYDGRFRQGH'062&JUXSR
FULRSUHVHUYDGRFRQGH'062
&RQFOXVLRQHV
(O REMHWLYR SULQFLSDO GH HVWH HVWXGLR IXH
HVWDEOHFHU XQD WpFQLFD GH FULRSUHVHUYDFLyQ
HFRQyPLFDPHQWH DVHTXLEOH \ ELRVHJXUD TXH
SURYRFDUD XQ PtQLPR GDxR FHOXODU GXUDQWH HO
SURFHVR GH FRQJHODFLyQGHVFRQJHODFLyQ (VWD
DSUR[LPDFLyQ SRGUtD RIUHFHU OD SRVLELOLGDG \
YHQWDMDGHOOHYDUDFDERFRQPD\RUVHJXULGDGXQ
FRUUHFWR
LQWHUFDPELR
GH
FpOXODV
PLFURHQFDSVXODGDV HQWUH ODERUDWRULRV $XQTXH
VHREVHUYDTXHODFULRSUHVHUYDFLyQSURYRFDXQD
UHGXFFLyQ GH XQ HQ OD OLEHUDFLyQ GH (SR
SRU SDUWH GH ORV PLREODVWRV PLFURHQFDSVXODGRV
HQEDVHDORVUHVXOWDGRVREWHQLGRVGHSURGXFFLyQ
GH(SRLQWHJULGDGGHODHVWUXFWXUDSROLPpULFD\
QLYHOHV GH KHPDFULWR HQ ORV HQVD\RV LQ YLYR
SRGHPRV FRQFOXLU TXH HO SURFHGLPLHQWR PiV
DGHFXDGR SDUD OD FULRSUHVHUYDFLyQ GH ODV
PLFURFiSVXODV HV HO HQIULDPLHQWR FRQWURODGR
XWLOL]DQGRXQGH'062
5HIHUHQFLDV
0XUXD$\FROV-&RQWURO5HOLQSUHVV
/LP ) \ 6XQ $0 6FLHQFH 0OOHU(KPVHQ - \ FROV - 3K\VLRO +HDUW
&LUF3K\VLRO+
GH9RV3\FROV-%LRPHG0DWHU5HV$
$JUDGHFLPLHQWRV
3UR\HFWR SDUFLDOPHQWH ILQDQFLDGR SRU HO ³0LQLVWHULR
GH (GXFDFLyQ \ &LHQFLD´ %,2 $
0XUXD DJUDGHFH DO ³*RELHUQR 9DVFR 'HSDUWDPHQWR
GH(GXFDFLyQ8QLYHUVLGDGHVH,QYHVWLJDFLyQ´SRUOD
EHFD
SUHGRFWRUDO
,QWURGXFFLyQ
/D HQIHUPHGDG GH 3DUNLQVRQ HV OD VHJXQGD
HQIHUPHGDG QHXURGHJHQHUDWLYD PiV IUHFXHQWH
GHVSXpVGHO$O]KHLPHU/DUDVDJLOLQDLQKLEH
LUUHYHUVLEOHPHQWH OD 0$2% QR RULJLQD
PHWDEROLWRV Wy[LFRV HQ FRPSDUDFLyQ FRQ RWURV
,0$2 FRPR OD VHOHJLOLQD \ WDPELpQ WLHQH
SURSLHGDGHVQHXURSURWHFWRUDV
(Q OD OLWHUDWXUD KD\ GHVFULWRV VROR GRV PpWRGRV
DQDOtWLFRV SDUD OD GHWHUPLQDFLyQ GH UDVDJLOLQD
XQRSRUFURPDWRJUDItDGHJDVHVFRQGHWHFWRUGH
HVSHFWURVFRStDGHPDVDV\RWURSRU+3/&FRQ
GHWHFFLyQ HOHFWURTXtPLFD 6LQ HPEDUJR HVWH
WLSR GH HTXLSDPLHQWR JHQHUDOPHQWH QR HVWi
GLVSRQLEOH SDUD HO DQiOLVLV IDUPDFpXWLFR GH
UXWLQD
(OREMHWLYRGHHVWHWUDEDMRKDVLGRGHVDUUROODU\
YDOLGDU XQ PpWRGR DQDOtWLFR SRU +3/& FRQ
GHWHFFLyQ89TXHVHDVLPSOHUiSLGRVHQVLEOH\
SUHFLVR SDUD OD FXDQWLILFDFLyQ GH UDVDJLOLQD
PHVLODWRHQPLFURHVIHUDVELRGHJUDGDEOHV
0DWHULDOHV \ 0pWRGRV 5DVDJLOLQD PHVLODWR
+DQJ]KRX2QLRQ&KHPLFDO&R/WGDFLFORYLU
*XLQDPD
SROtPHUR
SROLGOOiFWLFRFR
JOLFyOLFR 3/*$ 5HVRPHUŠ
%RHKULQJHU ,QJHOKHLP DOFRKRO SROLYLQtOLFR
39$ 'D 0HUFN DJXD XOWUDSXUD
0LOOLSRUH 7RGRV ORV UHDFWLYRV \ VROYHQWHV
XWLOL]DGRVIXHURQGHJUDGRDQDOtWLFR3DQUHDF
3DUDODFXDQWLILFDFLyQGHODVPXHVWUDVVHXWLOL]y
XQFURPDWyJUDIR:DWHUV86$SURYLVWRGHXQD
ERPEDPRGHORXQGHWHFWRU899LVPRGHOR
( XQ LQ\HFWRU DXWRPiWLFR PRGHOR '
:763 \ HO VRIWZDUH (PSRZHU /RJLQ +3/&
6\VWHP0DQDJHU
(ODERUDFLyQ GH ODV PLFURHVIHUDV /DV
PLFURHVIHUDV IXHURQ SUHSDUDGDV PHGLDQWH OD
WpFQLFDGHH[WUDFFLyQ\HYDSRUDFLyQGHOVROYHQWH
D SDUWLU GH XQD HPXOVLyQ $2$ 3DUD HOOR VH
SUHSDUy XQD VROXFLyQ DFXRVD GH UDVDJLOLQD
PHVLODWRPJ—OGHWDPSyQIRVIDWRDS+
TXH IXH HPXOVLILFDGD HQ XQD VROXFLyQ GH
3/*$ PJ HQ &+&O PO FRQ
XQD VRQGD GH XOWUDVRQLGRV +HDW 6\VWHPV
8OWUDVRQLFV ,QF GXUDQWH VHJXQGRV /D
HPXOVLyQ UHVXOWDQWH $2 IXH LQFRUSRUDGD HQ
POGH XQDVROXFLyQGH39$SY \
1D&O 1 DOFDOLQL]DGD FRQ 1D2+ 1 D S+
XWLOL]DQGR SDUD HOOR XQ 3RO\WURQŠ
.LQHPDWLFD *PE+ 37 GXUDQWH VHJXQGRV D USP REWHQLpQGRVH XQD
HPXOVLyQ $2$ 'LFKD HPXOVLyQ VH GHMy HQ
DJLWDFLyQ GXUDQWH KRUDV D WHPSHUDWXUD
DPELHQWH $ FRQWLQXDFLyQ ODV PLFURHVIHUDV
IXHURQ ODYDGDV \ VHFDGDV HQ XQ GHVHFDGRU DO
YDFtR
&RQGLFLRQHV FURPDWRJUiILFDV 6H HQVD\DURQ
GLVWLQWDVIDVHVPyYLOHVGLIHUHQWHVS+VGLVWLQWRV
HVWiQGDUHVLQWHUQRVDVtFRPRGLIHUHQWHVIOXMRVGH
OD IDVH PyYLO (O PpWRGR VHOHFFLRQDGR XWLOL]D
XQD FROXPQD 0HGLWHUUDQHD 6HD & μP
[PP7HNQRNURPD/DFRPSRVLFLyQGH
OD IDVH PyYLO IXH DFHWRQLWULORDJXD YY
DMXVWDGDDS+FRQiFLGRRUWRIRVIyULFRFRQ
IOXMRGHPOPLQ/DGHWHUPLQDFLyQVHUHDOL]y
D QP 6H HPSOHy DFLFORYLU FRPR HVWiQGDU
LQWHUQR(,
'HWHUPLQDFLyQ GH OD UDVDJLOLQD PHVLODWR HQ ODV
PLFURHVIHUDV 6H GLVROYLHURQ PJ GH
PLFURHVIHUDVHQPOGH&+&O(OIiUPDFRIXH
H[WUDtGRWUHVYHFHVGHVGHODIDVHRUJiQLFDFRQ
PO GH 3%6 D S+ $ FRQWLQXDFLyQ ODV
PXHVWUDVVHFHQWULIXJDURQDUSPGXUDQWH
PLQ3URFHGLpQGRVHDUHWLUDUHOVREUHQDGDQWH(O
YROXPHQWRWDOGHPXHVWUDPOVHFRPSOHWyD
PO FRQ 3%6 D S+ /DV PXHVWUDV VH
ILOWUDURQ —P \ VH SURFHGLy D OD
GHWHUPLQDFLyQGHOSULQFLSLRDFWLYRSRU+3/&
9DOLGDFLyQ GHO PpWRGR DQDOtWLFR (O PpWRGR
DQDOtWLFR IXH YDOLGDGR GH DFXHUGR D ODV QRUPDV
,&+FRQVLGHUDQGRORVFULWHULRVGHOLQHDOLGDG
SUHFLVLyQUHSHWLELOLGDG \SUHFLVLyQ LQWHUPHGLD
H[DFWLWXGVHQVLELOLGDGVHOHFWLYLGDG\UREXVWH]
5HVXOWDGRV\'LVFXVLyQ
(OPpWRGRDQDOtWLFRGHVFULWRIXHOLQHDOS
HQHOUDQJRGHFRQFHQWUDFLRQHVGH—JPO
FRQXQFRHILFLHQWHGHFRUUHODFLyQGH
/DGHVYLDFLyQHVWiQGDUUHODWLYD56'SDUDOD
UHSHWLELOLGDG LQWUDGtD \ SUHFLVLyQ LQWHUPHGLD
LQWHUGtD RVFLOy HQWUH \ OR TXH
LQGLFD XQD EDMD YDULDELOLGDG SDUD ODV GLIHUHQWHV
FRQFHQWUDFLRQHVHQVD\DGDV
/DH[DFWLWXGVHGHWHUPLQyDSDUWLUGHOSRUFHQWDMH
GH UHFXSHUDFLyQ GHO SULQFLSLR DFWLYR WUHV
FRQFHQWUDFLRQHV
REWHQLpQGRVH
YDORUHV
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
300.00
250.00
6.407
3.902
FRPSUHQGLGRV HQWUH \ FRQ
56'
/RV OtPLWHV GH GHWHFFLyQ \ FXDQWLILFDFLyQ
IXHURQ —JPO \ —JPO
UHVSHFWLYDPHQWH
/D ILJXUD PXHVWUD XQ FURPDWRJUDPD GH
UDVDJLOLQD PHVLODWR \ (, DFLFORYLU HQ XQD
PXHVWUD GH PLFURHVIHUDV GH 3/*$ 6H
SXHGHQ REVHUYDQ SLFRV VLPpWULFRV \ ELHQ
UHVXHOWRVVLQLQWHUIHUHQFLDGHRWURVFRPSXHVWRV
ORTXHFRQILUPDODVHOHFWLYLGDGGHOPpWRGR
D
E
mV
200.00
+,*+35(66685(+202*(1,6$7,210(7+2'72352'8&(1$1216758&785('
/,3,'&$55,(561/&V72(1+$1&(25$/%,2$9$,/$%,/,7<2)3225/<62/8%/(
&203281'6
$%HORTXL0$6ROLQtV$5*DVFyQ-/3HGUD]
3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\/DERUDWRU\)DFXOW\RI3KDUPDF\8QLYHUVLW\RIWKH
%DVTXH&RXQWU\839(+83DVHRGHOD8QLYHUVLGDG9LWRULD*DVWHL]6SDLQ
&RUUHVSRQGLQJHPDLO-/3MRVHOXLVSHGUD]#HKXHV
HYHU\O\RSKLOLVDWLRQSURFHVV$QLPSRUWDQWSRLQW
,QWURGXFWLRQ
WR WDNH LQWR DFFRXQW LV WKH FU\RSURWHFWRU &3
7KHUH KDV EHHQ D FRQVLVWHQW LQFUHDVH LQ WKH
FKRVHQ IRU IUHH]H GU\LQJ )' WKH VDPSOHV
QXPEHU RI SRRU ZDWHU VROXEOH GUXJ FDQGLGDWH
$PRQJ WKH PRVW FRPPRQ XVHG FU\RSURWHFWRUV
FRPSRXQGV DQG PRUH WKDQ RI QHZ
DUH WUHKDORVH VXFURVH DQG VRUELWRO ZKLFK ZH
SKDUPDFRORJLFDOO\ DFWLYH FKHPLFDO HQWLWLHV DUH
KDYH XVHG WR HYDOXDWH WKH PRVW VXLWDEOH
OLSRSKLOLF DQG H[KLELW SRRU ZDWHU VROXELOLW\ VWDELOL]HUIRUIUHH]HGU\LQJRXUQDQRVXVSHQVLRQV
7KHFKDOOHQJHLVWRPDNLQJWKHVHPROHFXOHVLQWR
:HXVHGWKHVH VWDELOL]HUVLQDGLOXWLRQ ZLWK
RUDO DGPLQLVWHUHG V\VWHPV ZLWK VXIILFLHQW
RXUVXVSHQVLRQDWWKUHHGLIIHUHQWFRQFHQWUDWLRQV
ELRDYDLODELOLW\ )RU WKLV SXUSRVH 1/&V
DQG
UHSUHVHQW DQ DOWHUQDWLYH FDUULHU V\VWHP WR
WUDGLWLRQDO FROORLGDO FDUULHUV VXFK DV HPXOVLRQV
OLSRVRPHV DQG SRO\PHULF PLFUR DQG
5HVXOWVDQG'LVFXVVLRQ
$V VKRZQ LQ ILJXUH ILYH F\FOHV ZRXOG EH
QDQRSDUWLFOHV /\RSKLOLVDWLRQ LV RQH RI WKH
HQRXJK IRU D VPDOO SDUWLFOH SRSXODWLRQ :H
PRVW HPSOR\HG PHWKRGV WR REWDLQ GHK\GUDWHG
GHFLGHGWRXVHF\FOHVWRJHWDORZ3,DVWKH
IRUPXODWLRQVZKLFKFDQEHVWRUHGDQGVKLSSHGDW
SDUWLFOH VL]H SRSXODWLRQ ZDV XQLIRUP IURP WR
URRP WHPSHUDWXUH 6WRUDJH VWDELOLW\ LQFOXGHV
F\FOHV:KHQ ZHFKRVHWKHDGHTXDWHF\FOHV
SUHYHQWLRQ RI GHJUDGDWLRQ UHDFWLRQV DQG
ZHUXQWKHKRPRJHQLVL]HUZLWKDQ631VROXWLRQ
SUHVHUYDWLRQ RI WKH LQLWLDO SDUWLFOH VL]H 7KH
IRU WHQ F\FOHV WR HQVXUH 631 ZDVQW GDPDJHG
DLP RI WKLV VWXG\ ZDV WR GHVLJQ SURGXFH DQG
ZLWK F\FOHV RU WHPSHUDWXUH :H PHDVXUHG 631
FKDUDFWHUL]H 6/1V IRU SRRUO\ VROXEOH
FRQFHQWUDWLRQ EHIRUH DQG DIWHU KRPRJHQLVDWLRQ
FRPSRXQGVHQWUDSPHQW
E\ VSHFWURSKRWRPHWU\ :H DOVR PHDVXUHG
HQWUDSPHQWHIILFDF\E\FHQWULIXJLQJWKHVDPSOHV
0DWHULDOVDQG0HWKRGV
DQG
PHDVXULQJ
WKH
ILOWUDWH
E\
$%6&FODVV,,VSLURQRODFWRQH631ZDVXVHG
VSHFWURSKRWRPHWU\ZKLFKZDVQHYHUORZHUWKDQ
DV SRRUO\ ZDWHU VROXEOH PRGHO FRPSRXQG )RU
WKH SURGXFWLRQ RI 1/&V WKH KRW SUHVVXUH
KRPRJHQL]DWLRQ+3+ PHWKRG ZDVSHUIRUPHG
3UHFLURO $72 ZDV FKRVHQ DV OLSLG
PDWUL[ IRUPHU 7ULJO\FHULGHV 0\JOLRO ZHUH DGGHG WR LQFUHDVH GUXJ HQFDSVXODWLRQ
HIILFLHQF\ DQG VWDELOLW\ 7KH VXUIDFWDQW
VROXWLRQ ZDV FRPSRVHG E\ 7ZHHQ DQG
3ROR[DPHU %ULHIO\ WKH OLSLG SKDVH
Number of homogenisation cycles
ZDV PHOWHG ž& DERYH LWV PHOWLQJ SRLQW $
KRWSUHHPXOVLRQZDVIRUPHGE\VRQLFDWLRQDQG
LQWURGXFHG LQWR WKH KRPRJHQLVL]HU 6WDQVWHG
)XLG +RPRJHQLVL]HU %DUž& 3DUWLFOH
VL]H DQG VXUIDFH FKDUJH ZHUH PHDVXUHG ZLWK D
0DOYHUQ =HWDVL]HU 7KH SURFHGXUH ZDV
Number of homogenisation cycles
RSWLPL]HG LQ WHUPV RI QXPEHU RI
KRPRJHQL]DWLRQ F\FOHV VLQFH WKLV SDUDPHWHU
)LJXUH &KDQJHV RQ SDUWLFOH VL]H DQG
KLJKO\ LQIOXHQFH WKH SDUWLFOH VL]H DQG
SRO\GLVSHUVLW\ LQGH[ 3, ZLWK DQ LQFUHDVLQJ
SRO\GLVSHUVLRQLQGH[3,
QXPEHURIKRPRJHQLVDWLRQF\FOHV
2QFHZHRSWLPL]HGWKHKRPRJHQL]DWLRQSURFHVV
ZH HYDOXDWHG WKH VWDELOLW\ RI RXU 1/&V LQ
)LQDOO\ ZH REWDLQHG 1/&V ZLWK D SDUWLFOH VL]H
GLIIHUHQWPHGLXPLQWHUPVRISDUWLFOHVL]H
RI QP DQG D VXUIDFH FKDUJH RI P9
/\RSKLOLVDWLRQ ZDV SHUIRUPHG IRU SDUWLFOHV
6XUIDFHFKDUJHGRQWFKDQJHZLWKWKHLQFUHDVLQJ
SUHVHUYDWLRQ GXULQJ VWRUDJH /\RSKLOLVDWLRQ
QXPEHURIF\FOHV
LQYROYHVIUHH]LQJRIWKHVDPSOHILUVWO\DWž&
2XU QH[W DSSURDFK ZDV WR GHPRQVWUDWH WKDW RXU
DQG VHFRQGO\ DW ž& EHIRUH WKH O\RSKLOLVDWLRQ
SDUWLFOHV ZHUH UHVLVWDQW LQ JDVWULF DQG LQWHVWLQDO
VWHS3DUWLFOHVL]HZDVPHDVXUHGEHIRUHDQGDIWHU
PHGLXP )RU WKDW SXUSRVH ZH SUHSDUHG
150.00
2.474
100.00
50.00
0.00
0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50 8.00
Minutes
0LQXWRV
Particle size(nm)
)LJXUD &URPDWRJUDPD FRUUHVSRQGLHQWH D
PLFURHVIHUDV GH 3/*$ FDUJDGDV FRQ D
UDVDJLOLQD PHVLODWR —JPO \ E (, —JPO
(O HVWXGLR GH UREXVWH] GHPRVWUy TXH ORV
UHVXOWDGRV REWHQLGRV QR YDUtDQ FRQ HO WLHPSR R
ODVFRQGLFLRQHVGHHQVD\R
(VWHPpWRGRIXHDSOLFDGRSDUDODFXDQWLILFDFLyQ
GH SULQFLSLR DFWLYR HQ PLFURHVIHUDV FDUJDGDV
FRQ UDVDJLOLQD PHVLODWR FX\D HILFDFLD GH
HQFDSVXODFLyQIXHGHO“
&RQFOXVLRQHV
6H KD YDOLGDGR XQ PpWRGR VLPSOH \ UiSLGR SRU
+3/&FRQGHWHFFLyQ89SDUDODFXDQWLILFDFLyQ
GH UDVDJLOLQD PHVLODWR HQ PLFURHVIHUDV
ELRGHJUDGDEOHVGH3/*$
%LEOLRJUDItD
%HUJDUHFKH $ HW DO - 1HXURO %DU$P2HWDO 1HXURVFL/HWW
<RXGLP0HWDO&HOO0RO1HXURELRO
9DOLGDWLRQRIDQDO\WLFDOPHWKRGV,&+WRSLFV
4%
$JUDGHFLPLHQWRV
(VWHWUDEDMRKDVLGRILQDQFLDGRSRUXQSUR\HFWR
GH LQYHVWLJDFLyQ GH OD FRQYRFDWRULD GH %HFDV \
$\XGDV GH OD )XQGDFLyQ 0XWXD 0DGULOHxD
$30DUFRV)HUQiQGH]DJUDGHFHHO
DSR\RGHO3URJUDPD$OȕDQ3URJUDPDGH%HFDV
GH $OWR 1LYHO GH OD 8QLyQ (XURSHD SDUD
$PpULFD/DWLQDEHFD1ž('&/
250
200
150
100
50
0
1
2
3
4
5
6
7
8
9
10
1
2
3
4
5
6
7
8
9
10
0,7
0,6
P.I
0,5
0,4
0,3
0,2
0,1
0
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
VLPXODWHG JDVWULF 6*) DQG LQWHVWLQDO 6,)
IOXLG 863 DQG +&O 1 ZLWK
RIVRGLXPGRGHF\OVXOSKDWH6'6ZKLFK
LV GHVFULEHG LQ 3KDUPDFRSHLD IRU 631 )RU WKH
VLPXODWHG PHGLXPV GLIIHUHQW HQ]\PHV ZHUH
XVHG SHSVLQ IRU 6*) DQG SDQFUHDWLQ IRU 6,)
ZKLFK FRQWDLQV PXOWLSOH HQ]\PHV DP\ODVH
WU\SVLQ OLSDVH ULERQXFOHDVH DQG SURWHDVH :H
ILUVWO\ DVVHVVHG WKDW 631 ZDV VWDEOH LQ WKRVH
PHGLXPVRYHUWKHWLPH:HLQWURGXFHPORI
RXUVXVSHQVLRQFRQWDLQLQJPJRI631LQWKH
GLIIHUHQW PHGLXP IRU KRXUV LQ FDVH RI +&O
DQG 6*) DQG KRXUV LQ FDVH RI 6,) DQG
PHDVXUHGSDUWLFOHVL]HWRHQVXUHWKHUHZHUHVWLOO
SDUWLFOHVLQWKHPHGLXP)LJXUH
/\RSKLOLVDWLRQ RI VDPSOHV ZLWKRXW VWDELOL]HUV
UHVXOWHG LQ WKH DJJUHJDWLRQ RI SDUWLFOHV IRUPLQJ
D FDNH ZLWK UXEEHU\ DVSHFW :KHQ VRUELWRO ZDV
XVHG DV VWDELOL]HU WKH O\RSKLOL]HG VDPSOHV
VKRZHG D SRZGHU\ DVSHFW EXW UHGLVSHUVLRQ LQ
ZDWHUZDVLPSRVLEOH7KHVDPHWKLQJKDSSHQHG
ZKHQ XVLQJ VXFURVH 2QO\ ZKHQ 1/&V ZHUH
O\RSKLOL]HG ZLWK WUHKDORVH DVSHFW ZDV SRZGHU\
DQG UHGLVSHUVLRQ ZDV SRVVLEOH )LJXUH VKRZV
WKDW WKHUH LV QR GLIIHUHQFH LQ WKH HIIHFW RI
WUHKDORVH FRQFHQWUDWLRQ RQ SDUWLFOH VL]H ,Q DOO
FDVHV VXUIDFH FKDUJH GLG QRW FKDQJHG DQG ZDV
DURXQGP9$FFRUGLQJWRWKHVHUHVXOWV
WUHKDORVHLVWKHEHVWFKRLFHIRUO\RSKLOLVDWLRQRI
RXU1/&V
&5,7,&$/32,1762)+<'523+,/,&0$75,&(6%$6('21
+<3520(//26(./9&5
&&LIXHQWHV7*RQoDOYHV$55DMDEL6LDKERRPLDQG,&DUDEDOOR
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\8QLYHUVLW\RI6HYLOOH
&3URIHVRU*DUFtD*RQ]iOH]6HYLOOH6SDLQ
&RORUFRQ0RGLILHG5HOHDVH7HFKQRORJLHV0R\HU%RXOHYDUG32%R[:HVW3RLQW3$
86$
,QWURGXFWLRQ
250
2,500
150
Final size/ Initial size
Particle Size ( nm)
200
Control
Sample 2h
100
Sample 4h
No CR
0,500
No CR
0
Control
HCl+SDS
SGF
SIF
)LJXUH &KDQJHV LQ VL]H DIWHU VWDELOLW\ DVVD\
ZLWKHQ]\PHVLQGLIIHUHQWPHGLXPV
7KLVILJXUHVKRZVWKDWSDUWLFOHVL]HLVLQFUHDVHG
DURXQG QP ZKHQ 1/&V DUH VXVSHQGHG LQ
+&/6'6 DQG 6,) PHGLXP 1R GLIIHUHQFH RQ
SDUWLFOHVL]HRYHUWLPHZDVREVHUYHGLQ6,)
$QLPSRUWDQWOLPLWDWLRQRIDTXHRXVVXVSHQVLRQV
LV WKHLU SRRU VWDELOLW\ ,Q IDFW WKH 1/&V
VXVSHQVLRQVHPSOR\HGLQWKHSUHVHQWVWXG\ZHUH
VWDEOH RQO\ IRU RQH PRQWK DW ž& +HQFH ZH
SHUIRUPHG D O\RSKLOL]DWLRQ VWXG\ ZLWK WKUHH
GLIIHUHQW FU\RSURWHFWRUV WUHKDORVH VRUELWRO DQG
VXFURVH :H O\RSKLOL]HG LQ DOO FDVHV ZLWK
O\RSURWHFWRUV DW DQG FRQFHQWUDWLRQ )LJXUH VKRZV SDUWLFOH VL]H
ZKHQO\RSURWHFWRUVZHUHXVHGDW
Particle Size (nm)
Trehalose_15%
1,000
Trehalose_5% Trehalose_10% Trehalose_15%
900,0
800,0
700,0
600,0
500,0
400,0
300,0
200,0
100,0
0,0
Before FD Trehalose Sorbitol
Sucrose
No CR
)LJXUH 7UHKDORVH ZDV WKH PRVW VXLWDEOH
FU\RSURWHFWLYHDJHQWDW
Trehalose_10%
1,500
0,000
50
Trehalose_5%
2,000
)LJXUH &RPSDULVRQ RI SDUWLFOH VL]H EHIRUH
DQG DIWHU O\RSKLOLVDWLRQ RI 1/&V ZLWK GLIIHUHQW
FRQFHQWUDWHGVROXWLRQVRIWUHKDORVH
&RQFOXVLRQV
,QWKHSUHVHQWVWXG\ZHKDYHRSWLPL]HGDQ1/&
IRUPXODWLRQIRUSRRUO\VROXEOHFRPSRXQGVPDGH
RI3UHFLURO$72DQG0\JOLRODVOLSLGVDQG
7ZHHQ DQG 3ROR[DPHU DV HPXOVLILHUV
ZKLFK LV VWDEOH LQ WKH LQ YLWUR DVVD\V IRU ERWK
JDVWULF DQG LQWHVWLQDO IOXLGV :H KDYH DVVHVVHG
WKDW OLRILOL]DWLRQ ZLWK WUHKDORVH SURYLGHG
GULHG 1/&V ZLWK SRZGHU\ DVSHFW DQG HDV\
UHGLVSHUVLRQ
5HIHUHQFHV
'DKDQ$HWDO-&RQWUROOHG5HOHDVH
0OOHU5+HWDO(XU-3KDP%LRSKDUP
0OOHU5+,QW-3KDUP
3HWNLHZLF]-HWDO,QW-3KDUP
(XURSHDQ 3KDUPDFRSHLD VXSSOHPHQW $FNQRZOHGJPHQWV
$%HORTXLWKDQNVWKH³8QLYHUVLW\RIWKH%DVTXH
&RXQWU\´IRUWKHIHOORZVKLSJUDQWV
7KH REMHFWLYHV RI WKLV VWXG\ ZHUH WR GHWHUPLQH
WKH FULWLFDO UDQJHV RI SRO\PHU FRQFHQWUDWLRQ
ZLWKLQ DQ (5 PDWUL[ DWWULEXWHG WR WKH H[FLSLHQW
SHUFRODWLRQ WKUHVKROGV DQG WR HYDOXDWH WKH UROH
RIWKHLQLWLDOSRURVLW\RIWKHV\VWHP
7KH DSSOLFDWLRQ RI WKH SHUFRODWLRQ WKHRU\ WR
VWXG\ WKH K\GUDWLRQ DQG GUXJ UHOHDVH IURP
K\GURSKLOLF PDWULFHV KDV DOORZHG IRUPXODWLRQ
VFLHQWLVWV WR H[SODLQ FKDQJHV LQ UHOHDVH NLQHWLFV
RI VZHOODEOH H[WHQGHG UHOHDVH (5 GHOLYHU\
V\VWHPV
)RUPXODWLRQV
VWXGLHG
KHUH
FRQWDLQHG
YHUDSDPLOÂ+&O DV D ZDWHU VROXEOH PRGHO GUXJ
DQG RQH K\GURSKLOLF PDWUL[ IRUPLQJ SRO\PHUV
ZLWKGLIIHUHQWYLVFRVLW\
([SHULPHQWDO0HWKRGV
0DWHULDOV
9HUDSDPLOÂ+&O
5HFRUGDWWL
,WDO\
K\SURPHOORVH 0(7+2&(/Π./9 &5
&RORUFRQ 8. PLFURFU\VWDOOLQH FHOOXORVH
0LQJWDL&KHPLFDO6SDLQ PDJQHVLXP VWHDUDWH
$FRIDUPD6SDLQFROORLGDOVLOLFRQGLR[LGH1)
$FRIDUPD6SDLQ
0HWKRGV
ƒ 7DEOHWSUHSDUDWLRQ
7DEOH VKRZV WKH FRPSRVLWLRQ RI WKH VWXGLHG
IRUPXODWLRQV ZKHUH WKH SRO\PHU ./9 &5
ZDV XVHG DW DQG ZZ
FRQFHQWUDWLRQ
7DEOH &RPSRVLWLRQ
IRUPXODWLRQV
%DWFK<
%DWFK<
RI
%DWFK<
WKH
VWXGLHG
%DWFK<
%DWFK<
7DEOHW PJ
7DEOHW PJ
7DEOHW PJ
7DEOHW PJ
9HUDSD
+30&
/DFWRVH
0&&
6L2
0J6WHDUDWH 7RWDO
7DEOHW
PJ
7KHOHWWHU<FDQEHUHSODFHGE\WKHWZROHWWHUV
LQGLFDWHGLQ7DEOHLQRUGHUWRREWDLQWKHQDPH
RIWKHWDEOHWEDWFK
,QLWLDOO\ DOO PDWHULDOV ZLWK WKH H[FHSWLRQ RI
PDJQHVLXP VWHDUDWH DQG FROORLGDO VLOLFRQ
GLR[LGH&6' ZHUHEOHQGHGIRUPLQXWHVLQ
D 7XUEXOD PL[HU 0DJQHVLXP VWHDUDWH DQG &6'
ZHUHDGGHGDQGEOHQGHGIRUDQDGGLWLRQDOPLQ
7KH WDEOHWV PJ WDUJHW ZHLJKW PP
GLDPHWHUZHUHSUHSDUHGE\GLUHFWFRPSUHVVLRQ
XVLQJ D VWDQGDUG HFFHQWULF WDEOHW PDFKLQH
%RQDOV $ 6SDLQ DW WKUHH GLIIHUHQW
FRPSUHVVLRQ IRUFHV 7DEOH 7KH PDWULFHV
FRQWDLQLQJ ZZ +30& . /9 &5
%DWFK &) ZHUH SUHSDUHG XVLQJ RQO\ WKH
KLJKHVWFRPSUHVVLRQIRUFH
7DEOH7DEOHWEDWFKHVQDPHV
0D[LPXP 0HGLXP 0LQLPXP
)RUFH
)RUFH
)RUFH
+30&. 9)
90
96
/9&5
ƒ 'UXJGLVVROXWLRQVWXG\
'LVVROXWLRQWHVWLQJZDVFRQGXFWHGLQPORI
GLVWLOOHG ZDWHU DW “ž& XVLQJ WKH 863 ,,
SDGGOH PHWKRG 7KH PDWULFHV ZHUH IL[HG WR WKH
SDGGOH RI WKH 863 GLVVROXWLRQ DSSDUDWXV EHIRUH
LWZDVLPPHUVHGLQWKHPHGLD6RWD[$7
7KH WHVWLQJ ZDV FRQGXFWHG DW D KLJK OHYHO RI
PHGLDDJLWDWLRQUSPLQ RUGHUWRVHH PRUH
FOHDUO\WKHFULWLFDOSRLQWVRIWKHV\VWHP
6DPSOHVZHUHZLWKGUDZQDIWHU
DQG KRXUV DQG DQDO\VHG YLD 89
VSHFWURSKRWRPHWU\ +LWDFKL 8 DW D
ZDYHOHQJWK RI QP 7KH WHVWLQJ ZDV
SHUIRUPHGLQWKUHHUHSOLFDWHV
ƒ 'HWHUPLQDWLRQ
RI
WKH
UHOHDVH
PHFKDQLVP
5HOHDVH GDWD DQDO\VHV ZHUH SHUIRUPHG XVLQJ
+LJXFKL .RUVPH\HU HW DO 3HSSDV6DKOLQHTXDWLRQVDQG6<67$7
SURJUDP /LQHDU +LJXFKL DQG QRQOLQHDU OHDVW
VTXDUHV ILWWLQJ PHWKRGV ZHUH XVHGWRGHWHUPLQH
WKHRSWLPXPYDOXHVIRUWKHSDUDPHWHUVLQFOXGHG
LQHDFKHTXDWLRQ
5HVXOWVDQG'LVFXVVLRQ
7KH GDWD VKRZQ LQ 7DEOHV DQG VHHP WR
LQGLFDWH D FULWLFDO SRLQW EHORZ YY
+30&./9&5LHEHWZHHQWKHEOXHDQG
\HOORZOLQHVLQ)LJXUH
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
7DEOH 3RO\PHU FRQFHQWUDWLRQ DQG LQLWLDO
SRURVLW\ IRU WKH EDWFKHV VKRZQ LQ )LJXUH FRQWDLQLQJ+30&./9&5
%DWFK
&9
&9
&9
&9
YY+30&
,QLWLDO3RURVLW\ 7DEOH .LQHWLF 3DUDPHWHUV IRU WKH EDWFKHV
VKRZQ LQ )LJXUH FRQWDLQLQJ +30& ./9
&5
90 +,*8&+,
E
U
)LJXUH'LVVROXWLRQ3URILOHVIRU%DWFK+30&
./9 &5 0D[LPXP )RUFH %DWFK 3RURVLW\
EHWZHHQDQG
7DEOH 3RO\PHU FRQFHQWUDWLRQ DQG LQLWLDO
SRURVLW\ IRU WKH EDWFKHV VKRZQ LQ )LJXUH FRQWDLQLQJ+30&./9&5
&)
%DWFK
&)
&)
ZZ+30&
&
,QLWLDO3RURVLW\ 25'(1&(52 .2560(<(5
E
U
.
Q
U
6$+/,1<3(33$6
.G
.U
U
7DEOHVDQGVKRZWKDWIRUWKHWDEOHWVSUHSDUHG
DSSO\LQJWKHORZIRUFHOHYHOWKHUHVXOWVVKRZD
FULWLFDO SRLQW EHWZHHQ DQG YY
./9&5
7DEOH .LQHWLF 3DUDPHWHUV IRU WKH EDWFKHV
VKRZQ LQ )LJXUH FRQWDLQLQJ +30& ./9
&5
+,*8&+,
E
U 25'(1
&(52
E
U .2560(<(5
.
Q
U 6$+/,1<3(33$6
.G
.U
U 7DEOHDQGVKRZQRFULWLFDOEHKDYLRXUVRZH
FRXOG H[SHFW D FULWLFDO SRLQW EHORZ YY
./9&5
$ 0LUDQGD 0 0LOOiQ , &DUDEDOOR
,QWHUQDWLRQDO-RXUQDORI3KDUPDFHXWLFV
$ 0LUDQGD 0 0LOOiQ , &DUDEDOOR -
3KDUP6FL
, )XHUWHV $ 0LUDQGD 0 0LOOiQ ,
&DUDEDOOR (XU - 3KDUP %LRSKDUP 7 *RQoDOYHV 3HUFRODWLRQ 7KUHVKROG
LQ K\GURSLOLF PDWUL[ REWDLQHG E\ 8OWUDVRQLF
$VVLVWHG &RPSUHVVLRQ DQG LQ ,QGXVWULDO
)RUPXODWLRQ3K'7KHVLV8QLYHUVLW\RI6HYLOOH
6SDLQ
7*RQoDOYHV$55DMDEL6LDKERRPLDQG,
&DUDEDOOR ,QW - 3KDUP 7+LJXFKL-3KDUP6FL
.RUVPH\HU,QW-3KDUP
)LJXUH 'UXJ GLVVROXWLRQ IURP +30& .
/9&5 0LQLPXP )RUFH EDWFK 3RURVLW\
EHWZHHQDQG
7DEOH 3RO\PHU FRQFHQWUDWLRQ DQG LQLWLDO
SRURVLW\IRUWKHEDWFKHVVKRZQLQ)LJXUH
%DWFK
&6
99+30&
&6
&6
&6
,QLWLDO3RURVLW\ 7DEOH .LQHWLF 3DUDPHWHUV IRU WKH EDWFKHV
VKRZQLQ)LJXUH
)LJXUH 'UXJ GLVVROXWLRQ IURP +30& ./9
&5 0HGLXP )RUFH %DWFK 3RURVLW\ EHWZHHQ DQG
96 +,*8&+,
E
U
25'(1
&(52
E
U
6$+/,1<3(33$6
.G
.U
U
.2560(<(5
.
Q
U
',6(f2<&$5$&7(5,=$&,Ï1'(81$18(9$/È*5,0$$57,),&$/3$5$(/
75$7$0,(172'(/6Ë1'520('(2-26(&2
9LFDULRGHOD7RUUH0%HQtWH]GHO&DVWLOOR-09LFR(*X]PiQ0GHODV+HUDV%+HUUHUR
9DQUHOO50ROLQD0DUWtQH],7
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8&00DGULG(VSDxD
'HSDUWDPHQWRGH2IWDOPRORJtD+RVSLWDO8QLYHUVLWDULR6DQ&DUORV0DGULG(VSDxD
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH$OFDOi
$OFDOiGH+HQDUHV(VSDxD
'HSDUWDPHQWRGH)DUPDFRORJtD)DFXOWDGGH)DUPDFLD8&00DGULG(VSDxD
0pWRGRGHSUHSDUDFLyQGHORVOLSRVRPDV
,QWURGXFFLyQ
/RV OLSRVRPDV VH KDQ SUHSDUDGR SRU OD WpFQLFD
(OVtQGURPHGHRMRVHFR626VHFRQVLGHUD XQ
GH
%DQJKDP PRGLILFDGD SRU %HQtWH] \ FRO
FRQMXQWRGHSUREOHPDVTXHVXUJHQDSDUWLUGHOD
&RPR FRPSRQHQWHV OLStGLFRV GH OD IRUPXODFLyQ
DOWHUDFLyQ GH OD SHOtFXOD SUHFRUQHDO (VWD
VH HPSOHDQ )& &RO \ YLW( HQ UHODFLyQ
SHOtFXODSUHFRUQHDOHVWiFRQVWLWXLGDSRUXQDFDSD
'HVSXpV GH OD H[WUXVLyQ ORV
H[WHULRUOLStGLFDTXHVHSDUDODVXSHUILFLHRFXODU
OLSRVRPDV VH GLVSHUVDURQ HQ XQD VROXFLyQ
GHO DPELHQWH H[WHUQR \ XQD FDSD LQWHUQD
KLSRWyQLFD GH iFLGR KLDOXUyQLFR /D
FRQVWLWXLGD SRU XQD PH]FOD GH FRPSRQHQWHV
WRQLFLGDG GH OD IRUPXODFLyQ “ DFXRVRSURWHLFRV\PXFLQRVRVTXHVHFRPELQDQ
P2VPO VH DMXVWy FRQ WUHKDORVD /D
GDQGROXJDUDXQJHOKLGUDWDGR/DFDSDOLStGLFD
FRQFHQWUDFLyQ ILQDO H[SUHVDGD HQ FRQWHQLGR GH
LPSLGH OD HYDSRUDFLyQ GH ORV FRPSRQHQWHV
)&GHHVWDIRUPXODFLyQHVGHPJPO
DFXRVRV
&DUDFWHUL]DFLyQ
ItVLFRTXtPLFD
GH
OD
8QD SHOtFXOD SUHFRUQHDO VDQD SHUPLWH TXH VH
IRUPXODFLyQGHOLSRVRPDV
OOHYHQ D FDER ODV IXQFLRQHV GH OXEULFDFLyQ
/DVIRUPXODFLRQHVHQVD\DGDVVHPDQWXYLHURQHQ
SURWHFFLyQ OLPSLH]D KLGUDWDFLyQ \ QXWULFLyQ GH
UHSRVR XQ PtQLPR GH KRUDV FRQ HO ILQ GH
OD VXSHUILFLH RFXODU 'H HVWD PDQHUD ODV
DVHJXUDUODKLGUDWDFLyQFRPSOHWDGHODVYHVtFXODV
SURSLHGDGHVySWLFDVGHODPLVPDVRQySWLPDV
OLStGLFDV 6H KD GHWHUPLQDGR OD WHQVLyQ
$FWXDOPHQWH ODV IRUPXODFLRQHV PiV QRYHGRVDV
VXSHUILFLDO WHQVLyPHWUR . .5h66 *PE+
GHVWLQDGDV D ORV SDFLHQWHV GH RMR VHFR YDQ
$OHPDQLD \ OD RVPRODULGDG RVPyPHWUR GH
HQFDPLQDGDV D OD HVWDELOL]DFLyQ GH OD SHOtFXOD
YDSRU .QDXHU . $OHPDQLD /DV GRV
SUHFRUQHDOPHGLDQWHODLQFRUSRUDFLyQGHDJHQWHV
GHWHUPLQDFLRQHV VH UHDOL]DURQ D ž &
OLStGLFRV\DFXRVRV
WHPSHUDWXUDGHODVXSHUILFLH FRUQHDO7DPELpQ
(O REMHWLYR GH HVWH WUDEDMR FRQVLVWH HQ HO
VH DQDOL]y HO S+ S+ 0HWHU 03 0HWWOHU
GHVDUUROORGHXQDIRUPXODFLyQGHDGPLQLVWUDFLyQ
7ROHGR (VSDxD UHDOL]DQGR ODV PHGLGDV D
WySLFD RFXODU TXH DXPHQWH OD HVWDELOLGDG GH OD
WHPSHUDWXUDDPELHQWH
SHOtFXOD SUHFRUQHDO \ SRU WDQWR PHMRUH ORV
(VWXGLRVGHWROHUDQFLDLQYLWUR
VtQWRPDV GHO 626 /D IRUPXODFLyQ HVWi
6H HVWXGLy OD WROHUDQFLD LQ YLWUR GH OD OiJULPD
FRPSXHVWD SRU OLSRVRPDV QDQRVLVWHPDV
DUWLILFLDOSURSXHVWDHQXQDOtQHDFHOXODUOtQHDGH
IDUPDFpXWLFRVTXHVHGLVSHUVDQHQXQDVROXFLyQ
FRUQHD KXPDQD +XPDQ &RUQHDO/LPEDO
DFXRVD GH iFLGR KLDOXUyQLFR SROtPHUR
(SLWKHOLDO &HOO \ HQ XQD OtQHD FHOXODU GH
ELRDGKHVLYR (O UHVXOWDGR ILQDO HV XQD
FRQMXQWLYD
,2%$1+& XWLOL]DQGR OD WpFQLFD GH
IRUPXODFLyQRIWiOPLFDFX\DVSURSLHGDGHVItVLFR
UHGXFFLyQ D QLYHO PLWRFRQGULDO GH OD VDO GH
TXtPLFDV VRQ VLPLODUHV D ODV GH OD SHOtFXOD
EURPXUR GH GLPHWLOWLD]ROLO SUHFRUQHDO
GLIHQLOWHWUD]ROLR 077 D IRUPD]iQ (O HQVD\R
VHUHDOL]yDFRUWRPLQXWRV\ODUJRSOD]R\
0DWHULDOHV\0pWRGRV
KRUDV 6H HPSOHy FRPR FRQWURO QHJDWLYR GH
&RPSRQHQWHVEiVLFRVGHORVOLSRVRPDV
YLDELOLGDG ODV FpOXODV VLQ WUDWDU \ FRPR
)RVIDWLGLOFROLQD )& SURFHGHQWH GH OHFLWLQD GH
FRQWURO SRVLWLYR ODV FpOXODV WUDWDGDV FRQ XQD
VRMD3KRVSKROLSRQ*Š 3KRVSKROLSLG*0%+
VROXFLyQGHFORUXURGHEHQ]DOFRQLRDO
&ROHVWHURO&ROαWRFRSKHUROYLW(\FORUXUR
7ROHUDQFLD LQ YLYR GH OD IRUPXODFLyQ GH
GHEHQ]DOFRQLR6LJPD&KHPLFDO&R6W/RXLV
OLSRVRPDV
7UHKDORVD GH &\PLW 4XtPLFD 6/ %DUFHORQD
(OHVWXGLRGHODWROHUDQFLDVHOOHYyDFDERHQVHLV
6SDLQ +LDOXURQDWR VyGLFR +1D JUDGR
FRQHMRV PDFKR &DGD DQLPDO HQ XQD MDXOD
RIWiOPLFR GH SHVR PROHFXODU LQGLYLGXDOFRQDFFHVROLEUHDFRPLGD\EHELGD\
'D $EDUDQ 0DWHULDV 3ULPDV 6/ &RQHMRV
FRQFLFORVFRQWURODGRVGHOX]\RVFXULGDGGH
DOELQRV PDFKR GH 1XHYD =HODQGD GH HQWUH KRUDV GH GXUDFLyQ FDGD XQR GH HOORV /RV
NJGHSHVR
HQVD\RV UHDOL]DGRV FXPSOHQ OD QRUPDWLYD GH
$592 SDUD HO XVR GH DQLPDOHV $592
,;&RQJUHVRGHOD6(),*
6WDWHPHQW IRU WKH 8VH RI $QLPDOV LQ
2SKWKDOPRORJ\ DQG 9LVLRQ 5HVHDUFK \ FRQ OD
GLUHFWLYD FRUUHVSRQGLHQWH GH OD FRPXQLGDG
HXURSHD (XURSHDQ &RPPXQLWLHV &RXQFLO
'LUHFWLYH((&
/D IRUPXODFLyQ OLSRVRPDO VH DGPLQLVWUy HQ HO
FXOGHVDFGHORVFRQHMRV6HDGPLQLVWUDURQ—O
GH OD IRUPXODFLyQ GH OLSRVRPDV HQ HO RMR
GHUHFKR\—OGHXQDVROXFLyQVDOLQDLVRWyQLFD
1D&O Å HQ HO RMR L]TXLHUGR XWLOL]DGR FRPR
FRQWURO FDGD PLQXWRV GXUDQWH KRUDV 6H
HYDOXDURQVtQWRPDV\VLJQRVFOtQLFRVGHDFXHUGR
FRQ XQ SURWRFROR SUHYLDPHQWH GHVFULWR /RV
WLHPSRV HVWXGLDGRV IXHURQ ORV VLJXLHQWHV DQWHVGHUHDOL]DUODSULPHUDLQVWLODFLyQDODV
KRUDV D ODV KRUDV \ D ODV KRUDV
GHVSXpV GH OD SULPHUD LQVWLODFLyQ (O H[DPHQ
PDFURVFySLFRGHWROHUDQFLDGHODIRUPXODFLyQVH
JUDGXyGHDLQGLFDQGRDXVHQFLDRSUHVHQFLD
GH ORV VLJXLHQWHV VLJQRV FOtQLFRV SpUGLGD GH OD
WUDQVSDUHQFLD GH OD FyUQHD DOWHUDFLRQHV HQ OD
FRQMXQWLYD KLSHUHPLD HGHPD SiUSDGRV
LQIODPDFLyQ \ SDUSDGHR LQWHQVR DXVHQFLD GH
WROHUDQFLD
5HVXOWDGRV\'LVFXVLyQ
&DUDFWHUL]DFLyQ
ItVLFRTXtPLFD
GH
OD
IRUPXODFLyQGHOLSRVRPDV
/D IRUPXODFLyQ OLSRVRPDO SUHVHQWy XQ YDORU GH
S+DGHFXDGRSUy[LPRDODQHXWUDOLGDG
(O YDORU GH WHQVLyQ VXSHUILFLDO GH OD GLVSHUVLyQ
GH OLSRVRPDV IXH GH P1P /D
KLSRWRQLFLGDGGHODIRUPXODFLyQP2VPO
SHUPLWH HTXLOLEUDU OD KLSHURVPRODULGDG TXH
DSDUHFH HQ HVWH VtQGURPH UHWRUQDQGR D YDORUHV
GHRVPRODULGDGPiVILVLROyJLFRV
7DEOD 9DORUHV GH S+ WHQVLyQ VXSHUILFLDO \
RVPRODULGDGSDUDODIRUPXODFLyQGHOLSRVRPDV
3DUiPHWUR
S+
7HQVLyQ6XSHUILFLDOP1P
2VPRODULGDGP2VPO
“
“
“
(QVD\RVLQYLWURGHODOiJULPDDUWLILFLDO
/D YLDELOLGDG FHOXODU GH OD IRUPXODFLyQ UHVXOWy
VLHPSUH VXSHULRU DO HQ ORV WUHV WLHPSRV
HQVD\DGRV
15 MINUTOS
FORMULACIÓN DE LIPOSOMAS EN CÓRNEA
1 HORA
120
4 HORAS
100
80
60
40
20
0
Control-
Formulación de
liposomas (PC=10
mg/m l)
Control+
Formulación Ensayada
)LJXUD9LDELOLGDGFHOXODUREWHQLGDHQFpOXODV
GHFyUQHDSDUDODIRUPXODFLyQGHOLSRVRPDV
15 MINUTOS
FORMULACIÓN DE LIPOSOMAS EN CONJUNTVA
1 HORA
120
% Viabilidad Celular
7HFQRORJtD)DUPDFpXWLFD
% Viabilidad Celular
9)
&RQFOXVLRQV
$OWKRXJK GLIIHUHQW SRURVLWLHV DQG FRPSUHVVLRQ
IRUFHVKDYHEHHQHPSOR\HGWKHREWDLQHGUHOHDVH
SURILOHV DUH FRPSDWLEOH ZLWK D FRPPRQ FULWLFDO
SRLQW DURXQG YY ./9 &5
LQGLFDWLQJWKHUREXVWQHVVRIWKLVSDUDPHWHU
$V SHUFRODWLRQ WKHRU\ SUHGLFWV WKH VWXGLHG
SURSHUWLHV VKRZ D FULWLFDO EHKDYLRXU DV D
IXQFWLRQ RI WKH YROXPHWULF IUDFWLRQ RI WKH
FRPSRQHQWV ZKLFK FDQ EH DWWULEXWHG WR WKH
SRO\PHUSHUFRODWLRQWKUHVKROG$ERYHWKLVSRLQW
DVDPSOHVSDQQLQJJHOOD\HUZLOOH[HUWDVWURQJHU
FRQWURORIWKHUHOHDVHUDWH
5HIHUHQFHV
4 HORAS
100
80
60
40
20
0
Control-
Formulación de
liposomas (PC=10
mg/ml)
Control+
Formulación Ensayada
)LJXUD9LDELOLGDGFHOXODUREWHQLGDHQFpOXODV
GHFRQMXQWLYDODIRUPXODFLyQGHOLSRVRPDV
7ROHUDQFLD LQ YLYR GH OD IRUPXODFLyQ GH
OLSRVRPDV
$QWHV GH OD LQVWLODFLyQ QLQJ~Q DQLPDO SUHVHQWy
VLJQRV FOtQLFRV DQRUPDOHV /D WROHUDQFLD D OD
OiJULPD DUWLILFLDO VH PDQWXYR FRQVWDQWH JUDGR
FHURSDUDWRGRVORVVLJQRVFOtQLFRVHVWXGLDGRVD
ODV KRUDV \ KRUDV GHVSXpV GH KDEHU
UHDOL]DGRODSULPHUDLQVWLODFLyQ
0ROHVWLD
&yUQHD
&RQMXQWLYD
'HVFDUJD
3iUSDGRV
*UDGR
$XVHQFLDGHPROHVWLD
1RDOWHUDFLRQHV
1RDOWHUDFLRQHV
1RVHSURGXFH
$XVHQFLDGHLQIODPDFLyQ
&RQFOXVLRQHV
/D IRUPXODFLyQ OLSRVRPDO GHVDUUROODGD SUHVHQWD
XQDV SURSLHGDGHV ILVLFRTXtPLFDV VLPLODUHV D ODV
GH OD SHOtFXOD SUHFRUQHDO /RV HVWXGLRV GH
YLDELOLGDGFHOXODU\GHWROHUDQFLDLQYLYRLQGLFDQ
XQD WROHUDQFLD ySWLPD SDUD OD OiJULPD DUWLILFLDO
SURSXHVWD
%LEOLRJUDILD
%UHZLWW+6LVWDQL)6XUY2SKWKDOPRO
66
%DQJKDP $' 6WDQGLVK 00 DQG
:DWNLQV-&-0RO%LRO
-0 %HQLWH] HW DO ,QYHVW 2SKWKDOPRO 9LV
6FL($EVWUDFW
*LSVRQ,.6SXUU0LFKDXG6 $UJHVR3
7LVGDOH $ )RQJ 1J 7 /HLJK 5XVVR & ,QYHVW
2SKWKDOPRO9LV6FL
(6DDULQHQ6DYRODLQHQ 3 -lUYLQHQ 7 $UDNL
6DVDNL . :DWDQDEH + DQG 8UWWL $ 3KDUP
5HV
'LHEROG < -DUUtQ 0 6iH] 9 &DUYDOKR (/
2UHD 0 &DORQJH 0 6HLMR % $ORQVR 0-
%LRPDWHULDOV
7RPOLQVRQ $ 7 ,QYHVW 2SKWKDOPRO 9LV
6FL2FW
$JUDGHFLPLHQWRV
*UXSR GH ,QYHVWLJDFLyQ 8&0 &&*
8&00$7 ),6 3, \ ),6
3,
7HFQRORJtD)DUPDFpXWLFD
*0$270,&523$57,&/(67275($7,175$&(//8/$53$7+2*(16
'*RQ]iOH](,PEXOX]TXHWD*3pUH]((OL]RQGR19HQWRVD-9HFLDQD&*DPD]R0-
%ODQFR3UtHWR
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\8QLYHUVLW\RI1DYDUUD3DPSORQD
6SDLQ
0ROHFXODU1DQRVFLHQFHDQG2UJDQLF0DWHULDOV'HSDUWPHQW,QVWLWXWGH&LqQFLDGH0DWHULDOVGH
%DUFHORQD&DPSXVGHOD8$%VQ%HOODWHUUD%DUFHORQD6SDLQ
'HSDUWPHQWRI0LFURELRORJ\8QLYHUVLW\RI1DYDUUD3DPSORQD6SDLQ
3DUWLFOHVL]HFKDUDFWHUL]DWLRQ
,QWURGXFWLRQ
3DUWLFOH VL]H ZDV GHWHUPLQHG E\ ODVHU
%UXFHOORVLV LV D ZRUOGZLGH ]RRQRVLV FDXVHG E\
GLIIUDFWRPHWU\ 3&6 XVLQJ D 0DVWHU6L]HU
GLIIHUHQW VSHFLHV RI WKH JHQXV %UXFHOOD ,Q YLYR
WKH SDWKRJHQ LV PDLQO\ ORFDOL]HG LQ FHOOV DQG
0DOYHUQ,QVWUXPHQWV8.
RUJDQV RI WKH PRQRQXFOHDU SKDJRF\WLF V\VWHP
VXFK DV PDFURSKDJHV RI WKH VSOHHQ DQG WKH
A OT NXSIIHU FHOOV RI WKH OLYHU 7KH DELOLW\ RI WKLV
R
C H N H 2 +R 1
SDWKRJHQ WR VXUYLYH DQG PXOWLSO\ ZLWKLQ
A OT A OT +
PDFURSKDJHVGLIILFXOWWKHDQWLELRWLFDFFHVVWRLWV
H3N
N H3+
CH 3
O
O
QLFKHDQGUHODSVHVUHPDLQDSUREOHP
OH
7R RYHUFRPH WKHVH GLIILFXOWLHV JHQWDPLFLQ
C H3
O
O
N
*P ORDGHG LQWR GUXJ GHOLYHU\ V\VWHPV KDV
H2+
NH 3 +
OH
OH
EHHQ VWXGLHG ZLWK SURPLVLQJ UHVXOWV AO
T
A OT 3UHYLRXVO\ ZH KDYH VKRZQ WKDW *P3/*$
O
>SRO\ODFWLGHFRJO\FROLGH@ PLFURSDUWLFOHV DUH
CH CH CH CH
AOT
O
VXLWDEOH IRU WKH WUHDWPHQW RI DQ H[SHULPHQWDO
CH CH
O
EUXFHOORVLVLQPLFHQHYHUWKHOHVV*PORDGLQJ
O
LPSURYHPHQW ZRXOG EH QHFHVVDU\ EHIRUH WKH
O S O
CH CH CH CH
H CH C
IRUPXODWLRQ FRXOG EH XVHG IRU WKH WUHDWPHQW RI
O
KXPDQ EUXFHOORVLV 7R DFKLHYH WKLV JRDO D
K\GURSKRELF *P *P$27 KDV EHHQ
)LJXUH&KHPLFDOVWUXFWXUHRI*P$27
V\QWKHVL]HG DQG HQFDSVXODWHG LQ 3/*$
'HWHUPLQDWLRQRIHQFDSVXODWHGJHQWDPLFLQ
PLFURSDUWLFOHVSUHSDUHGE\WKHHPXOVLRQVROYHQW
7HQ PJ RI SDUWLFOHV ZHUH GLVVROYHG LQ 0
HYDSRUDWLRQ PHWKRG 7KH DFWLYLW\ RI IUHH *P
1D2+VROXWLRQDQGVWLUUHGGXULQJK6DPSOHV
$27DQGORDGHG*P$27SDUWLFOHVZDVVWXGLHG
ZHUH FHQWULIXJHG DW [ J GXULQJ PLQ
LQ YLWUR DJDLQVW % PHOLWHQVLV 0RUHRYHU
7KHVXSHUQDWDQWZDVFHQWULIXJHGDJDLQ[
PLFURSDUWLFOHV ZHUH IXUWKHU FKDUDFWHUL]HG LQ
J PLQ LQ RUGHU WR HOLPLQDWH WKH WUDFHV RI
WHUPVRIORDGLQJDQGLQYLWURUHOHDVHNLQHWLFV
SRO\PHU 7KH HQFDSVXODWHG DPLQRJO\FRVLGHV
ZHUH TXDQWLILHG E\ D IOXRUHVFHQFH PHWKRG 7KH
([SHULPHQWDOPHWKRGV
DPLQDWHG DQWLELRWLF JHQWDPLFLQ UHDFWV ZLWK R
3UHSDUDWLRQRI*P$27SDUWLFOHV
SKWDOGHKLGH LQ SUHVHQFH RI βPHUFDSWRHWKDQRO
3/*$ + %RHULQJKHU ZDV XVHG IRU WKH
IRUPLQJ D SURGXFW WKDW LV GHWHFWHG E\
PLFURSDUWLFOH SUHSDUDWLRQ *HQWDPLFLQ$27
IOXRUHVFHQFH
VSHFWURVFRS\
FRQGLWLRQV
SDWHQW DSSOLFDWLRQ 2(3 ILJXUH H[FLWDWLRQ ZDYHOHQJWK QP HPLVVLRQ
ZDV GLVVROYHG LQ DQ RUJDQLF VROXWLRQ RI
ZDYHOHQJWKQP
GLFORURPHWKDQH FRQWDLQLQJ WKH SRO\PHU DQG
SRXUHG RQ D ZDWHU SKDVH FRQWDLQLQJ
,QYLWURUHOHDVHVWXGLHV
SRO\YLQLODOFRKRO %RWK SKDVHV ZHUH HPXOVLILHG
7KH LQ YLWUR DQWLELRWLF UHOHDVH SURILOHV ZHUH
E\ VRQLFDWLRQ DQG WKH HPXOVLRQ 2: ZDV
REWDLQHG E\ WKH LQFXEDWLRQ RI IRUPXODWLRQV LQ
VWLUUHGIRUDWOHDVWKRXUVLQRUGHUWRHYDSRUDWH
PO RI 3%6 S+ ž& SUHVHUYHG ZLWK
WKH RUJDQLF VROYHQW 0LFURSDUWLFOHV ZHUH
RIVRGLXPD]LGH
FROOHFWHGE\FHQWULIXJDWLRQZDVKHGWLPHVZLWK
7KHYLDOVZHUHIL[HGKRUL]RQWDOO\LQDVKDNHUDW
GLVWLOOHG ZDWHU DQG IUHH]HGULHG )RU
ž&6DPSOHVZHUHZLWKGUDZQDWUHJXODUWLPH
FRPSDULVRQ *P6XOIDWH PLFURSDUWLFOHV ZHUH
LQWHUYDOV DIWHU FHQWULIXJDWLRQ DQG UHSODFHG E\
DOVR SUHSDUHG E\ D ZDWHURLOZDWHU VROYHQW
IUHVK PHGLXP *P$27 DQG *P6XOIDWH
HYDSRUDWLRQWHFKQLTXH
UHOHDVHG LQWR WKH VXSHUQDWDQW ZDV TXDQWLILHG E\
IOXRUHVFHQFH
VSHFWURVFRS\ DV SUHYLRXVO\
GHVFULEHG
3
2
3
2
2
2
2
2
'HWHUPLQDWLRQRIWKHJHQWDPLFLQDFWLYLW\
,QRUGHUWRDVVHVWKHDFWLYLW\ RIERWK*PHLWKHU
IUHHRUHQFDSVXODWHGLQ3/*$PLFURSDUWLFOHVWKH
0LQLPDO ,QKLELWRU\ &RQFHQWUDWLRQ 0,& ZDV
GHWHUPLQHG IROORZLQJ WKH SURWRFRO QRUPDOL]HG
E\ WKH &/6, &OLQLFDO DQG /DERUDWRU\
6WDQGDUGV,QVWLWXWHZDVXVHG
)LUVWO\ VHULDO GRXEOH GLOXWLRQV RI WKH GLIIHUHQW
W\SHV RI JHQWDPLFLQ DQG RI ORDGHG SDUWLFOHV LQ
ZHOOSODWHVZHUHPDGH$NQRZQLQRFXOXPRI
%PHOLWHQVLV0ZDVDGGHGWRHDFKZHOOZLWK
PHGLXPWKDWZRXOGDOORZLWVJURZWK
7KHVHSODWHVZHUHLQFXEDWHGDWž&GXULQJ
GD\V DQG DIWHU EDFWHULDO JURZWK ZDV DVVHVVHG
7KHODVWZHOOZLWKQREDFWHULDOJURZWKREVHUYHG
FRUUHVSRQGVWRWKH0,&RIWKHDQWLELRWLF
5HVXOWV DQ GLVFXVVLRQ *P6XOIDWH ORDGHG
3/*$ + PLFURSDUWLFOHV SUHVHQWHG D
KRPRJHQRXVVL]HRIμPDQGDGUXJORDGLQJ
RI μJPJ SDUWLFOHV ZKHUHDV *P$27
ORDGHG 3/*$ + PLFURSDUWLFOHV VKRZHG D
VL]HRIμPDQGμJRIGUXJFKDUJHSHU
PJRISDUWLFOH7KHHQFDSVXODWLRQHIILFLHQF\IRU
*06XOIDWH ZDV ZKLOH IRU WKH *P
$27 ZDV 5HVXOWV LQGLFDWHG WKDW ZLWK
WKH *P$27 FRPSOH[ ERWK D KLJKHU
HQFDSVXODWLRQ HIILFLHQF\ DQG D KLJKHU ORDG RI
DQWLELRWLFIRUPJRISDUWLFOHZDVREWDLQHG
7KHFXPXODWLYHLQYLWURUHOHDVHSURILOHVRI*P
6XOIDWHDQG*P$27DUHVKRZQLQILJXUH
3
3
-
7HFQRORJtD)DUPDFpXWLFD
)LJXUH0ROHFXODUVWUXFWXUHRIDOORSXULQRO
7KHVROXELOLW\RIDOORSXULQROZDVPHDVXUHGDW
R& LQ ZDWHUHWKDQRO HWKDQROHWK\O DFHWDWH DQG
HWK\ODFHWDWHKH[DQH$QH[FHVVVROXWHZDVPL[HG
ZLWK P/ VROYHQW DQG DOORZHG WR UHDFK
HTXLOLEULXP LQ D FRQVWDQW WHPSHUDWXUH VKDNLQJ
EDWK +HWR 6+ 'HQPDUN “ °& 7KH
QRQGLVVROYHG VROLG SKDVH ZDV VHSDUDWH E\
ILOWUDWLRQ'XUDSRUHPHPEUDQHV—PSRUHVL]H
0LOOLSRUH,EpULFD6$6SDLQ7KHFOHDUVROXWLRQV
0.0040
0.0032
0.0024
; 0.0016
0.0008
0.0000
15
22
29
36
43
50
% Gm acumulated
40.00
35.00
30.00
25.00
20.00
Mp 752H Gm-AOT
15.00
10.00
Mp 752H Gm
5.00
0.00
0
5
10
15
20
25
30
Days
)LJXUH ,Q YLWUR UHOHDVH RI *P6XOIDWH DQG
*P$27 IURP 3/*$ PLFURSDUWLFOHV LQ 3%6 DW
ž&
)RU *P$27 DIWHU DQ LQLWLDO EXUVW RI D
FRQWLQXRV*P$27UHOHDVHZDVREVHUYHGIRUXS
WRIRXUZHHNV$WGD\VRIWKHDQWLELRWLF
ZDV UHOHDVHG 2Q WKH RWKHU KDQG WKH UHOHDVH RI
*P6XOIDWH IURP PLFURSDUWLFOHV ZDV IDVWHU
$IWHU GD\V DOPRVW RI WKH HQFDSVXODWHG
GUXJ ZDV UHOHDVHG 7KH UHVXOWV WKHQ VKRZ WKDW
WKH GUXJ UHOHDVH GHSHQGV RQ WKH SK\VLFR
δ )LJXUH ([SHULPHQWDO PROH IUDFWLRQ VROXELOLWLHV ; RI
DOORSXULQRO LQ ZDWHUHWKDQRO į WR 03D
HWKDQROHWK\O DFHWDWH į WR 03D DQG
HWK\ODFHWDWHKH[DQHį WR03DPL[WXUHV
7DEOH OLVWV WKH VROXELOLW\ SDUDPHWHU DQG WKH
DFLGLF DQG EDVLF SDUWLDO VROXELOLW\ SDUDPHWHUV IRU
WKH VROYHQW PL[WXUHV 7KH VROXELOLW\ FXUYH LV
DV\PPHWULFDO)LJXUHDQGWKHVROYHQWSRZHURI
WKH PL[WXUHVKRZLQJLQWHUPHGLDWHSRODULW\YDOXHV
HWKDQROHWK\O DFHWDWH LV ODUJHU WKDQ WKDW RI WKH
PRVW SRODU PL[WXUH HWKDQROZDWHU *RLQJ IURP
WKH ULJKW WR WKH OHIW RI )LJXUH GHFUHDVLQJ
SRODULW\ YDOXHV WKH VROXELOLW\ RI DOORSXULQRO
LQFUHDVHGWRDPD[LPXPYYHWKDQROZDWHU
į 03D 7KH SURILOH GLVSOD\HG D
PLQLPXP DW HWKDQRO 7KHQ WKH VROXELOLW\
YDOXHV LQFUHDVHG DJDLQ WR D VHFRQG PD[LPXP
YY HWK\O DFHWDWHHWKDQRO į 03D 1R PD[LPXP ZDV REVHUYHG ZKHQ WKH
SRODULW\ZDVIXUWKHUORZHUHGE\DGGLQJKH[DQHWR
HWK\O DFHWDWH 7KH VROXELOLW\ PRQRWRQLFDOO\
GHFUHDVHV LQ WKH OHDVW SRODU PL[WXUH į YDOXHV
EHWZHHQDQG03D
FKHPLFDO FKDUDFWHULVWLFV RI WKH HQFDSVXODWHG
GUXJ
,QRUGHUWRDVVHVVWKHDFWLYLW\RIHLWKHUIUHH*P
RU *P ORDGHG SDUWLFOHV D 0,& VWXG\ ZDV
SHUIRUPHG $V VKRZQ LQ ILJXUH WKH 0,&
DJDLQVW % PHOLWHQVLV 0 IRU DOO WKH WHVWHG
FRPSRXQGV *P *P$27 *P$27 ORDGHG
3/*$ + SDUWLFOHV DQG *P ORDGHG 3/*$
+ SDUWLFOHV ZDV μJP/ VXJJHVWLQJ
WKDW*P$27LVDVHIIHFWLYHDV*P6XOIDWH
MIC of Gm against B. melitensis 16M
μg of Gm
64
8
0,25
1
Gm
64
8
0,25
1
Gm-AOT
1
8
0,25
PLGA 752H Gm-AOT 64
particles
PLGA 752 H Gm 64
1
8
0,25
particles
No bacterial growth
Bacterial growth
)LJXUH7KH0LQLPDO,QKLELWLRQ&RQFHQWUDWLRQ
0,&RIIUHHDQGHQFDSVXODWHG*06XOIDWHDQG
*0$27DJDLQVW%PHOLWHQVLV0
&RQFOXVLRQ
0LFURSDUWLFOHV SUHSDUHG ZLWK *P$27
VKRZHG KLJKHU HQFDSVXODWLRQ HIILFLHQF\ DQG
ORZHU LQ YLWUR UHOHDVH NLQHWLFV DV FRPSDUHG WR
*P6XOIDWH
7KH LQGLFDWHG PRGLILHG IRUPV RI *P GLG QRW
LQWHUIHUH ZLWK WKH DQWLELRWLF DQWLEDFWHULDO
DFWLYLW\
7KH UHVXOWV REWDLQHG LQ WKLV ZRUN DUH
HQFRXUDJLQJ WR FRQVLGHU WKH XVH RI *P$27
ORDGHG 3/*$ + SDUWLFOHV DV DQ DOWHUQDWLYH
WUHDWPHQW IRU VXVFHSWLEOH LQWUDFHOOXODU EDFWHULDO
LQIHFWLRQVOLNH%UXFHOODLQIHFWLRQV
5HIHUHQFHV
& *DPD]R HW DO ([SHUW 2SLQ 'UXJ
'HOLY
&/HFDUR]HWDO-RI1DQRVFLHQFHDQG
1DQRWHFKQRORJ\
& /HFDUR] HW DO $QWPLFURE $JHQWV
&KHPRWKHU
0-%ODQFR3ULHWR,QW-3KDUP
$FNQRZZOHGJHPHQWV
7KLV ZRUN ZDV VXSSRUWHG E\ 0LQLVWHULR GH
&LHQFLD H ,QQRYDFLyQ IURP 6SDLQ 1$1
&DQG&DMD1DYDUUD)RXQGDWLRQ
,;&RQJUHVRGHOD6(),*
δD
δDE
δEF
D VROXELOLW\ SDUDPHWHU E DFLGLF SDUDPHWHU F EDVLF
SDUDPHWHU FDOFXODWHG IRU HDFK VROYHQW PL[WXUH IURP
H[SUHVVLRQįPL[ ΣįLĭLįLLVWKHYDOXHRIWKHSXUHVROYHQWDQG
ĭLWKHYROXPHIUDFWLRQRIWKHVROYHQWLQWKHVROYHQWPL[WXUH
6ROYHQWV
ZHUHDVVD\HGLQDGRXEOHEHHQVSHFWURSKRWRPHWHU
6KLPDG]X893&86$DWλ QP
7KHGHQVLWLHVRIWKHVROXWLRQVZHUHGHWHUPLQHGLQ
P/S\FQRPHWHUVDWDOOWHPSHUDWXUHV
7KH VROXELOLWLHV DUH WKH DYHUDJH RI WKUHH
GHWHUPLQDWLRQV 7KH FRHIILFLHQW RI YDULDWLRQ ZDV
ZLWKLQ
5HVXOWVDQG'LVFXVVLRQ)LJXUHVKRZVWKDWWKH
VROXELOLW\ RI DOORSXULQRO LQFUHDVHV ZLWK
WHPSHUDWXUHPHDQLQJWKDWKHDWLVDEVRUEHGLQWKH
GLVVROXWLRQ SURFHVV HQGRWKHUPLF HQWKDOS\ RI
VROXWLRQ
7KH VKDSH RI WKH VROXELOLW\ SURILOH GRHV QRW
FKDQJH ZLWK WHPSHUDWXUH DW WKH SRODULW\ UDQJH
HPSOR\HG IURP KH[DQH į 03D WR
ZDWHUį 03D
OQ; FRFįFįFįDFįEFįDδEHT
ZKHUH ; LV WKH PROH IUDFWLRQ VROXELOLW\ RI WKH
GUXJ DQG į LV WKH VROXELOLW\ SDUDPHWHU RI WKH
VROYHQW PL[WXUHV 7KH įD DQG įE SDUDPHWHUV
H[SUHVV WKH DFLGLF SURWRQ GRQRU DQG EDVLF
SURWRQ DFFHSWRU FDSDFLW\ RI WKH VROYHQW DV
GHILQHGE\.DUJHU7KHFRQVWDQWVFWRFDUH
REWDLQHGIURPPXOWLSOHUHJUHVVLRQDQDO\VLV
7KH DLP RI WKLV ZRUN LV WR SUHGLFW WKH WZRSHDN
VROXELOLW\ FXUYH IRXQG IRU DOORSXULQRO LQ WKH
SRODULW\ UDQJH FRYHUHG E\ WKH WKUHH VROYHQW
PL[WXUHVXVHG
0DWHULDOV DQG 0HWKRGV 6ROXWH DOORSXULQRO
GLK\GUR+S\UD]ROR >G@ S\ULPLGLQ
RQH 6LJPD$OGULFK *HUPDQ\ )LJXUH 6ROYHQWV ZDWHU KH[DQH HWK\O DFHWDWH DQG
HWKDQRO VSHFWURSKRWRPHWULF GHJUHH 3DQUHDF
0RQSOHW(VWHEDQ6SDLQ
45.00
7DEOH6ROXELOLW\SDUDPHWHU
62/8%,/,7<%(+$9,2852)$//2385,12/
,1$03+,3527,&$1'$03+,3527,&$3527,&0,;785(6
$%6iQFKH]0$3HxD3%XVWDPDQWH%(VFDOHUD
'HSDUWDPHQWRI)DUPDFLDDQG7HFQRORJtD)DUPDFpXWLFD)DFXOW\RI)DUPDFLD8QLYHUVLW\RI$OFDOi
$OFDOiGH+HQDUHV0DGULG6SDLQ
,QWURGXFWLRQ $OORSXULQRO LV D VWUXFWXUDO
LVRPHURIK\SR[DQWLQHXVHGLQWKHWUHDWPHQWRI
WKHJRXWSULPDU\K\SHUXULFHPLD
6ROXELOLW\ VWXGLHV FRQVWLWXWH DQ LQGLUHFW PHWKRG
IRUGHWHUPLQLQJWKHVROXELOLW\SDUDPHWHURIVROLGV
7KHVROXELOLW\RIDOORSXULQROZDVPHDVXUHGDW
VHYHUDO WHPSHUDWXUHV R& LQ VROYHQW
PL[WXUHV FRYHULQJ D ZLGH SRODULW\ UDQJH
'LIIHUHQW VROXELOLW\ SURILOHV PD\ EH REWDLQHG IRU
WKH VROXELOLW\ RI GUXJV DJDLQVW WKH VROXELOLW\
SDUDPHWHU į RI WKH VROYHQW PL[WXUHV 7KH FXUYHV
PD\ VKRZ D VLQJOH VROXELOLW\ SHDN DQG LQ RWKHU
FDVHVWZRRUPRUHPD[LPD
%XVWDPDQWH DQG FRZRUNHUV SURSRVHG D
PRGLILFDWLRQRIWKH+LOGHEUDQGHTXDWLRQWRSUHGLFW
FXUYHVZLWKWZRPD[LPD
50.00
VROYHQW
(WK\ODFHWDWH(WKDQROHWK\ODFHWDWH:DWHUHWKDQRO
+H[DQH
2
2
,;&RQJUHVRGHOD6(),*
$OORSXULQROVKRZVDFKDPDOHRQLFEHKDYLRUOLNH
WKDW+R\GHVFULEHGLQDTXDOLWDWLYHZD\IRUDFHWLF
DFLG D FRPSRXQG ZKLFK LV VROXEOH LQ KLJKHU
DQG ORZHU SRODULW\ PHGLD (TXDWLRQ WULHG WR
H[SODLQWKLVEHKDYLRULQDTXDQWLWDWLYHZD\IRUWKH
ILUVWWLPHXVLQJWKHK\GURJHQERQGLQJSDUDPHWHUV
įD DQG įE UHODWHG WR WKH /HZLV DFLG DQG /HZLV
EDVH FKDUDFWHULVWLFV RI WKH VROYHQW %HVLGHV WKH
PRGHO LQFOXGHV WKH +LOGHEUDQG VROXELOLW\
SDUDPHWHU DQG D FRQVWDQW FRQWULEXWLRQ IURP WKH
VROLG SKDVH LQ WKH LQWHUFHSW 7KH UHJUHVVLRQ
HTXDWLRQVREWDLQHGIURP(TDUH
R&
OQ; “ “ į “į “įD “įE įDįE
U Q ) W!506( HT
R&
OQ; ““į“
į“įD“įE
įDįE
U Q ) W!506( HT
7KH SUHGLFWHG YDOXHV IURP (TV DQG UHSURGXFHG WKH WZR SHDNV DW ERWK WHPSHUDWXUHV
7DEOHDQG)LJXUH
7KHVLJQVREWDLQHGRQWKHUHJUHVVLRQFRHIILFLHQWV
DJUHHZLWKWKRVHH[SHFWHGIURPWKHPRGHO(T
DOORZLQJ D SK\VLFDO LQWHUSUHWDWLRQ RI WKH IDFWRUV
WKDW LQIOXHQFH VROXELOLW\ 7KH SRVLWLYH VLJQV RQ
VRPH FRHIILFLHQWV FDQ EH UHODWHG WR IDYRUDEOH
VROXWHVROYHQWLQWHUDFWLRQVWKDWLQFUHDVHVROXELOLW\
QRQVSHFLILFδDQGK\GURJHQERQGLQJδDDQGδE
2Q WKH FRQWUDU\ WKH QHJDWLYH VLJQ RQ WKH
FRHIILFLHQWVDVVRFLDWHGWRδDQGWKHSURGXFWδD δE
DUH UHODWHG WR VROYHQWVROYHQW LQWHUDFWLRQV WKDW
GHFUHDVHVROXELOLW\
7DEOH6ROXELOLW\PROHIUDFWLRQ
;D
;E
;F
;G
R
D H[SHULPHQWDO VROXELOLW\ DW & E FDOFXODWHG VROXELOLW\
R
ZLWK HT F H[SHULPHQWDO VROXELOLW\ DW & G FDOFXODWHG
VROXELOLW\ZLWKHT
YY
0.0040
0.0032
0.0024
; 0.0016
0.0008
0.0000
15
22
29
36
43
50
δ )LJXUH 6ROXELOLW\ ; LQ VROYHQW PL[WXUHV ([SHULPHQWDO
PROHIUDFWLRQVROXELOLWLHVSZLWKHTzDQGHT„
5HIHUHQFHV
-DPHV.&,Q'UXJVDQGWKH3KDUPDFHXWLFDO
6FLHQFHVYRO0DUFHO'HNNHU1<RUN
3HxD0$HWDO,QW-3KDUP
(VFDOHUD-%HWDO-3KDUP3KDUPDFRO
%XVWDPDQWH 3 HW DO &KHP 3KDUP %XOO
.DUJHU%/HWDO-&KURPDWRJU
+R\.-3DLQW7HFK
7HFQRORJtD)DUPDFpXWLFD
7+(502*5$062)7+(62/,'3+$6(62)7+(23+<//,1($)7(5(48,/,%5$7,21
:,7+(7+$12/:$7(5
0$3HxD3%XVWDPDQWH$5HtOOR
'HSDUWDPHQWRI)DUPDFLDDQG7HFQRORJtD)DUPDFpXWLFD)DFXOW\RI)DUPDFLD8QLYHUVLW\RI$OFDOi
$OFDOiGH+HQDUHV0DGULG6SDLQ
,QWURGXFWLRQ
'LIIHUHQWLDO
VFDQQLQJ
,QGLXP]LQFOHDG VWDQGDUGV ZHUH XVHG WR
FDORULPHUWU\ '6& LV IUHTXHQWO\ WKH
FDOLEUDWH WKH '6& WHPSHUDWXUH DQG HQWKDOS\
SKDUPDFHXWLFDO WKHUPDO DQDO\VLV WHFKQLTXH RI
VFDOH
FKRLFHEHFDXVHRILWVDELOLW\WRSURYLGHGHWDLOHG
5HVXOWV DQG 'LVFXVVLRQ )LJXUH VKRZV WKH
LQIRUPDWLRQ DERXW ERWK WKH SK\VLFDO DQG
WKHUPRJUDP IRU WKH RULJLQDO SRZGHU 7KH
HQHUJHWLFSURSHUWLHVRIDVXEVWDQFH
PHOWLQJSRLQWž&RIWKHRSK\OOLQHLVPHDVXUHG
7KLV UHVHDUFK LV IRFXVHG RQ WKH LQIOXHQFH RI
DW WKH RQVHW )LJXUH EHFDXVH LW LV QRW
DTXHRXV PL[WXUHV RQ WKH '6& SDWWHUQ RI
LQIOXHQFHG E\ PDVV 7KH FRUUHVSRQGLQJ PRODU
WKHRSK\OOLQH D PHWK\O[DQWKLQH XVHG DV
KHDWRIIXVLRQLV.-PRO
EURQFKRGLODWRU
^exo
6ROYDWHV LQ SKDUPDFHXWLFV DUH JHQHUDOO\
XQZDQWHGDVRUJDQLFYDSRXUVUHPDLQDQGZRXOG
FDXVH XQQHFHVVDU\ LPSXULWLHV 8VXDOO\ WKH
WUDSSHGVROYHQWLVSUHVHQWDWDQH[DFWPRODUUDWLR
ZLWK WKH FU\VWDO HJ PRQRK\GUDWH RQH ZDWHU
PROHFXOH WR RQH FU\VWDO 7KH SURSHUWLHV JUHDWO\
GLIIHU EHWZHHQ WKH K\GUDWHV DQG DQK\GURXV
IRUPV 8QOLNH SRO\PRUSKLVP K\GUDWHV PD\
VKRZ IDVWHU RU VORZHU GLVVROXWLRQ UDWH
&RPPRQO\WKHGLVVROXWLRQUDWHRIWKHDQK\GURXV
IRUPLVIDVWHU
0DWHULDOV DQG 0HWKRGV 6ROXWH WKHRSK\OOLQH
)LJXUH7KHUPRJUDPRIWKHRSK\OOLQH
)LJXUH GLPHWK\O+SXULQHGLRQH
6LJPD$OGULFK *HUPDQ\ 6ROYHQWV ZDWHU DQG
7KHSHDNRIIXVLRQLVLPPHGLDWHO\IROORZHGE\D
HWKDQRO VSHFWURSKRWRPHWULF GHJUHH 3DQUHDF
EURDGHQGRWKHUP)LJXUH
0RQSOHW(VWHEDQ6SDLQ
7DEOH7HPSHUDWXUHDQGKHDWRIIXVLRQRI
WKHVROLGSKDVHVRIWKHRSK\OOLQH
20
mW
50
)LJXUH6WUXFWXUHRIWKHRSK\OOLQH
7KH PHOWLQJ SRLQW 7I DQG WKH PRODU KHDW RI
IXVLRQ Δ+I RI WKH RULJLQDO SRZGHU ZHUH
GHWHUPLQHG E\ '6& 0HWWOHU 7$ 6ZLW]HUODQGXVLQJSDQVZLWKDSSUR[LPDWHO\PJ
RI VDPSOHV DQG D QLWURJHQ JDV SXUJH 7KH
H[SHULPHQW ZDV ILUVW UXQ IURP URRP WHPSHUDWXUH
WRR&KHDWLQJUDWHR&PLQWRREVHUYHWKH
EHKDYLRU LQ D ZLGH WHPSHUDWXUH UDQJH LQFOXGLQJ
SRVVLEOHHQGRWKHUPLFRUH[RWKHUPLFHIIHFWVDERYH
IXVLRQ7KHWKHUPRJUDPVRIHDFKVROLGSKDVHZHUH
GHWHUPLQHG EHIRUH DQG DIWHU HTXLOLEUDWLRQ ZLWK
ZDWHUHWKDQRO PL[WXUHV WR GHWHFW SRVVLEOH VROLG
SKDVH FKDQJHV )ROORZLQJ WKH FULWHULD RI VHYHUDO
DXWKRUV LQ WKLV ILHOG DOO WKH VDPSOHV ZHUH
GULHGDWDPELHQWWHPSHUDWXUHXQWLOFRQVWDQWZHLJKW
EHIRUH EHLQJ DQDO\]HG 7KLV SURFHGXUH SUHYHQWV
WKH UHPRYDO RI VROYHQW ORRVHO\ ERXQG WR WKH
FU\VWDOWKDWPD\DIIHFWWKHWKHUPDOEHKDYLRURIWKH
VROLGSKDVH
D
100
150
200
250
300
(WKDQRO
7IR&
ǻ+I-JD
2ULJLQDOSRZGHU
350
°C
HIGUCHI MODEL
15
PABA
53,3
10
NAPROXEN
26,7
5
1.5
0.6
0,0
0,0
1,7
3,3
0
5,0
Kp
)LJXUH 'UXJ SHU FHQW UHOHDVHG YHUVXV WKH
VTXDUHURRWRIWLPHŸ3$%$Ɣ1DSUR[HQ
Square root (hours)
PEPPAS MODEL
4,0
1,7
-0,7
-3,0
-2,0
-0,3
1,3
3,0
Ln time (hours)
)LJXUH /Q RI GUXJ SHU FHQW UHOHDVHG YHUVXV
/QRIWLPHŸ3$%$Ɣ1DSUR[HQ
)LJXUHFRPSDUHVWKHYDULDWLRQRIWKHFRQVWDQWV
.SDQG.KRIERWKPRGHOV
7KHH[SRQHQWQRIWKH3HSSDVPRGHO7DEOHLV
XVHG WR DQDO\VH WKH UHODWLYH LPSRUWDQFH RI
GLIIXVLRQ DQG HURVLRQ LQ WKH GUXJ UHOHDVH
PHFKDQLVP 7KH Q YDOXHV DUH EHWZHHQ DQG LQGLFDWLQJ FRQWULEXWLRQ RI ERWK
GLIIXVLRQDQGHURVLRQSURFHVVHV'LIIXVLRQLVWKH
PDLQ PHFKDQLVP IRU QDSUR[HQ WKH H[SRQHQW LV
QHDUHU Q ZKHUHDV WKH FRQWULEXWLRQ RI
PDWUL[ HURVLRQ LV ODUJHU LQ WKH FDVH RI 3$%$
WKHQYDOXHLVKLJKHU
Kh
)LJXUH %DU &KDUW VKRZLQJ WKH YDULDWLRQ RI
WKHUHOHDVHFRQVWDQWV.SDQG.KWKHYDOXHVDUH
JLYHQLQVLGHWKHSORW
2QWKHRWKHUKDQGWKHQH[SRQHQWLVKLJKHUIRU
WKH OHDVW SRODU GUXJ QDSUR[HQ ORZHU VROXELOLW\
SDUDPHWHU YDOXH 7DEOH 7KLV UHVXOW DJUHHV
ZLWK WKDW REVHUYHG E\ .LP DQG )DVVLKL IRU
RWKHU GUXJV ZKHUH WKH Q H[SRQHQW LQFUHDVHG DV
WKHVROXELOLW\RIWKHGUXJZDVORZHUHG
5HIHUHQFHV
6PLWK $ HW DO 3KDUPDFHXWLFDO 6FLHQFH 7HFKQRORJ\7RGD\
5HDO)DUPDFRSHD(VSDxROD
$KXMD 1 (XU - 3KDUP %LR 6LHSPDQQ-HWDO$GYDQFHG'UXJ'HOLYHU\
5HYLHZV
.LP+HWDO - 3KDUP6FL ,;&RQJUHVRGHOD6(),*
IURP WKH SHDN RI IXVLRQ %HVLGHV WZR QHZ
HQGRWKHUPV DSSHDU EHIRUH PHOWLQJ )LJXUH 7R EHWWHU VHSDUDWH WKHVH WZR SHDNV WKH
H[SHULPHQWV ZHUH UXQ DW ž&PLQ XVLQJ VHDOHG
SDQV )LJXUH VKRZV D VDPSOH RI WKH '6&
SURILOHFRUUHVSRQGLQJWRHWKDQRO7KHRWKHU
WKHUPRJUDPV REWDLQHG IRU HWKDQRO UDWLRV
DUHYHU\VLPLODUWRWKDW VKRZQLQ)LJXUH7KH
RQVHW WHPSHUDWXUHV RI WKH SHDNV DUH OLVWHG LQ
7DEOH
7KH ILUVW SHDN ž& 7DEOH FDQ EH
DWWULEXWHG WR GHK\GUDWLRQ RI WKH K\GUDWH IRUPHG
LQ WKH SUHVHQFH RI WKH DTXHRXV PL[WXUHV
ZKHUHDV WKH VHFRQG SHDN ž&
FRUUHVSRQGVWRZDWHUHYDSRUDWLRQ7KHVHUHVXOWV
DUHFORVHWRWKHYDOXHVUHSRUWHGIRUWKHRSK\OOLQH
K\GUDWHV 7KH WZR SHDNV FRUUHVSRQGLQJ WR
GHK\GUDWLRQ DQG ZDWHU HYDSRUDWLRQ ZHUH IRXQG
DWR&DQGž&UHVSHFWLYHO\
$ERYH HWKDQRO LQ ZDWHU WKH '6& SURILOHV
GRQRWGLIIHUIURPWKDWREWDLQHGIRUWKHRULJLQDO
SRZGHU)LJXUH7KLVVXJJHVWVWKDWHWKDQROGR
QRW IRUP VROYDWHV ZLWK WKHRSK\OOLQH LQ WKHVH
VROYHQW PL[WXUHV ,Q RUGHU WR REVHUYH PRUH
WKRURXJKO\ WKH WUDQVIRUPDWLRQ IURP WKH K\GUDWH
WRWKHDQK\GURXVIRUPDQDGGLWLRQDOH[SHULPHQW
ZDVUXQDWHWKDQRO7KLVFRQFHQWUDWLRQZDV
FKRVHQEHFDXVHLWLV ZLWKLQ WKHUHJLRQDW ZKLFK
WKH SKDVH FKDQJH ZDV REVHUYHG HWKDQRO
7KH WZR HQGRWKHUPLF SHDNV FKDUDFWHULVWLFV RI
WKH K\GUDWH)LJXUHDUHDOPRVW LPSHUFHSWLEOH
DWHWKDQRO
^exo
7KH KHDW DQG WHPSHUDWXUHV RI IXVLRQ GLG QRW
VLJQLILFDQWO\ YDU\ DIWHU HTXLOLEUDWLRQ ZLWK WKH
VROYHQW PL[WXUHV 7DEOH 2Q WKH RWKHU KDQG
WKH KHDWLQJ UDWH GLG QRW YDU\ WKH '6& SURILOH
+RZHYHU WKH PL[WXUHV FRQWDLQLQJ HWKDQROLQZDWHULQGXFHFKDQJHVLQWKHVKDSHRI
WKH '6& SURILOH 7KH VHFRQG EURDG HQGRWKHUP
RI)LJXUHEHFRPHVVKDUSHUDQGZHOOVHSDUDWHG
19.0
2.6
20
mW
$YHUDJHRIDWOHDVWWKUHHGHWHUPLQDWLRQV
20
80,0
Released percentage
5(/($6(2)3$0,12%(1=2,&$&,'$1'1$352;(1)520(8'5$*,75632
0$75,&(6$65(/$7('7232/$5,7<
1$UDJyQ3%XVWDPDQWH%(VFDOHUD0$3HxD
'HSDUWDPHQWRI)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOW\RI)DUPDFLD8QLYHUVLW\RI$OFDOi$OFDOi
GH+HQDUHV0DGULG6SDLQ
ODZLVYDOLG7KHDPRXQWRIGLVVROYHGGUXJDVD
,QWURGXFWLRQ
IXQFWLRQ RI WLPH LV H[SUHVVHG LQ SHUFHQWDJH RI
,W LV ZHOO NQRZQ WKDW WKH FRQWUROOHG GUXJ
WKHLQLWLDOORDG
GHOLYHU\ V\VWHPV DUH NH\ LQ QHZ GRVDJH IRUP
UHVHDUFK 7KH SXUSRVH LV WR UHDFK WKH
WKHUDSHXWLFDOWDUJHWLQFUHDVLQJWKHHIIHFWLYHQHVV
5HVXOWVDQGGLVFXVVLRQ
7KH+LJXFKLDQG3HSSDV PRGHOVDUH XVHG WRILW
RI WKH GUXJ 7KHVH V\VWHPV DOORZ REWDLQLQJ
WKH GHOLYHU\ UHVXOWV 7DEOH LQFOXGHV WKH
PRUH FRPIRUWDEOH GRVLQJ LQWHUYDO UHGXFLQJ WKH
FRQVWDQWV REWDLQHG IRU WKH PRGHOV DQG WKH
LQWDNH IUHTXHQF\ DQG PLQLPL]LQJ WKH SODVPD
VROXELOLW\ SDUDPHWHU į 03D RI WKH GUXJV
GUXJ FRQFHQWUDWLRQ IOXFWXDWLRQV DW WKH VWHDG\
VWDWH 3RO\PHUV DUH RI SDUWLFXODU LPSRUWDQFH LQ
7KLV SDUDPHWHU LV XVHG DV D PHDVXUHPHQW RI
RUDOGRVDJHIRUPV
GUXJSRODULW\7KHKLJKHVWYDOXHVFRUUHVSRQGWR
7KHSXUSRVHRIWKLVZRUNLVWRUHODWHWKHGHOLYHU\
WKH PRUH SRODU VXEVWDQFHV 7KH WLPH UDQJH
RI SDPLQREHQ]RLF DFLG 3$%$ DQG QDSUR[HQ
PLQXWHVXVHGWRFDOFXODWHWKHFRQVWDQWVRIERWK
IURP(XGUDJLW5632PDWULFHVWRGUXJSRODULW\
PRGHOVLVDOVRLQFOXGHG
7KLV SRO\PHU LV XVHG IRU FRQWUROOHG GUXJ
GHOLYHU\V\VWHPV
7DEOH&RQVWDQWVRIWKHPRGHOVDQGVROXELOLW\
SDUDPHWHUįRIWKHGUXJV
0DWHULDOV
(XGUDJLW 56 32 'HJXVVD SDPLQREHQ]RLF
+LJXF
DFLG 3$%$ DQG QDSUR[HQ 6LJPD 0LOL4
W 3HSSDVPRGHO KL
'UXJ
δ PLQ
ZDWHU DQG HWKDQRO VSHFWURSKRWRPHWULF GHJUHH
PRGHO
3DQUHDF
.S
1
.K
3$%$ 0HWKRGV
1DSUR[HQ 7DEOHWSUHSDUDWLRQ
7KH WDEOHWV DUH ORDGHG ZLWK PJ RI HDFK
)LJXUH VKRZV WKH GUXJ SHU FHQW UHOHDVHG
GUXJ XVLQJ (XGUDJLW 56 32 DV GLOXHQW
DJDLQVWWKHVTXDUHURRWRIWLPHDFFRUGLQJWRWKH
H[FLSLHQWWKDWFRQWUROVWKHGHOLYHU\0DJQHVLXP
+LJXFKL PRGHO 7KH FRHIILFLHQWV RI
VWHDUDWH LV DGGHG DV WKH OXEULFDQW DQG VLOLFRQ
GHWHUPLQDWLRQ REWDLQHG DUH VLPLODU IRU ERWK
GLR[LGH $HURVLO DV DQWLDGKHUHQW 7KH UDZ
GUXJVUUDQJHVEHWZHHQDQG
PDWHULDOVDUHZHLJKHGDQGPL[HGLQDSRUFHODLQ
7KH +LJXFKL FRQVWDQW .K WKDW FRUUHVSRQGV WR
PRUWDU E\ WKH PHWKRG RI WKH VXFFHVVLYH
WKH VORSH RI WKH VWUDLJKW OLQHV RI )LJXUH LV
GLOXWLRQV 7KH PL[HG SRZGHUV DUH FRPSUHVVHG
ORZHU IRU 1DSUR[HQ .K WKDQ IRU
LQ D %RQDO HFFHQWULF PDFKLQH 7KH WDEOHW
3$%$.K 7DEOH7KDWLVWRVD\WKH
GLDPHWHULVPP
UHOHDVH UDWH LV KLJKHU IRU WKH PRVW SRODU GUXJ
ODUJHVW VROXELOLW\ SDUDPHWHU YDOXH )LJXUH ,QYLWURGUXJGLVVROXWLRQVWXGLHV
VKRZV WKH ORJDULWKPLF UHODWLRQVKLS RI WKH
7KH EDVNHW GLVVROXWLRQ DSSDUDWXV GHVFULEHG LQ
SHUFHQWDJH GUXJ UHOHDVHG DJDLQVW WLPH
WKH5)(LVXVHG7KHJODVVHVKDYHDQRPLQDO
DFFRUGLQJWRWKH3HSSDVPRGHO7KHOLQHDUILWLV
FDSDFLW\ RI PLOOLOLWUHV DQG DUH HTXLSSHG
VLPLODUWRWKDWREWDLQHGZLWKWKH+LJXFKLPRGHO
ZLWKDFRYHUWRDYRLGHYDSRUDWLRQ7KUHHWDEOHWV
U UDQJHV EHWZHHQ 7KH
IRUHDFKGUXJDUHXVHG7KHWHPSHUDWXUHLVNHSW
DQWLORJDULWKP RI WKH VWUDLJKW OLQH LQWHUFHSWV
DW “ƒ& LQ D WKHUPRVWDWHG EDWK DQG WKH
)LJXUH SURYLGHV WKH .S FRQVWDQWV RI WKH
DJLWDWLRQUDWHLVUSP7HQVDPSOHVDUHWDNHQ
H[SRQHQWLDO PRGHO 7DEOH 7KH UHOHDVH
DW WLPH LQWHUYDOV SUHYLRXVO\ VHOHFWHG UHSODFLQJ
FRQVWDQW LV ORZHU IRU QDSUR[HQ .S WKH ORVW YROXPH ZLWK GLVWLOOHG ZDWHU 7KH
WKDQ IRU 3$%$ .S 7KH UHVXOWV DUH
VDPSOHV DUH GLOXWHG ZLWK HWKDQRO DQG WKH
VLPLODU WR WKRVH REWDLQHG ZLWK WKH +LJXFKL
DEVRUEDQFH LV PHDVXUHG LQ D 89
PRGHO WKH UHOHDVH UDWH LV KLJKHU IRU WKH GUXJ
VSHFWURSKRWRPHWHU 6KLPDG]X 893&
VKRZLQJODUJHUVROXELOLW\SDUDPHWHUYDOXH
-DSDQ7KHDEVRUEDQFHXQLWVDUHFRUUHFWHG
IRU PHGLXP GLOXWLRQ 7KH DEVRUEDQFH
FRQFHQWUDWLRQ UHODWLRQVKLSV DUH REWDLQHG DW WKH
PD[LPXP DEVRUSWLRQ ZDYHOHQJWK DW WKH
FRQFHQWUDWLRQ UDQJH ZKHUH WKH /DPEHUW%HHU
,;&RQJUHVRGHOD6(),*
Ln Released percentage
7HFQRORJtD)DUPDFpXWLFD
QGSHDN
VWSHDN
50
100
150
200
250
300
350
°C
)LJXUH 7KHUPRJUDP RI WKHRSK\OOLQH ZDWHUHWKDQRO
7DEOH 7HPSHUDWXUHV ž& RI WKH QHZ SHDNV
DIWHUHTXLOLEUDWLRQZLWKZDWHUHWKDQROPL[WXUHV
(WKDQRO
VW3HDN
QG3HDN
7KH RQVHW WHPSHUDWXUHV RI WKHVH PLQXWH SHDNV
FDQQRW EH DFFXUDWHO\ PHDVXUHG DQG DUH QRW
LQFOXGHGLQ7DEOH
7KH UHVXOWV DJUHH ZLWK SUHYLRXV VWXGLHV ZLWK D
UHODWHG GUXJ FDIIHLQH DIWHU HTXLOLEUDWLRQ RI
WKH VROLG SKDVH ZLWK HWKDQROZDWHU PL[WXUHV
7KH K\GUDWHG IRUP RI FDIIHLQH DSSHDUHG DW HWKDQRO UDWLRV DQG LW FRQYHUWHG LQWR WKH
DQK\GURXVIRUPDWHWKDQROUDWLRV
7KH UHVXOWV UHPDUN WKH LPSRUWDQFH RI GHWHFWLQJ
VROLG SKDVH FKDQJHV WKDW PD\ DOWHU GLVVROXWLRQ
UDWHDQGELRDYDLODELOLW\RIVRPHGUXJVLQGRVDJH
IRUPV VXFK DV VXVSHQVLRQV ZKHUH VROLG DQG
GLVVROYHGSKDVHVDUHHTXLOLEULXP
5HIHUHQFHV
&ODV 6' HW DO +DQFRFN 3KDUPDFHXWLFDO
6FLHQFHDQG7HFKQRORJ\7RGD\
3IHLIIHU 55 HW DO - 3KDUP 6FL )O\QQ */ HW DO - 3KDUP 6FL 5XELQR -7 HW DO 3KDUP 5HV /HLWHUPDQ 59 HW DO - 3KDUP 6FL
3KDGQLV19HWDO-3KDUP6FL
%XVWDPDQWH 3 HW DO - 3KDUP 6FL 7HFQRORJtD)DUPDFpXWLFD
³1(852)8==</2*,&´81$+(55$0,(17$87,/(1(/'(6$552//2'()250$6
'('26,),&$&,Ï1
0DULDQD/DQGtQ5&5RZH\3<RUN
'HSDUWDPHQWR)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DQWLDJRGH
&RPSRVWHOD6DQWLDJRGH&RPSRVWHODHPDLOPODQGLQ#XVFHV
,QWURGXFFLyQ
3DUD HO HVWXGLR \ GHVDUUROOR GH IRUPXODFLRQHV
IDUPDFpXWLFDV VH UHFXUUH VLVWHPiWLFDPHQWH D ORV
GLVHxRV H[SHULPHQWDOHV \ D FRPSOLFDGRV
WUDWDPLHQWRV HVWDGtVWLFRV OR TXH H[LJH GHO
HVSHFLDOLVWD HQ IRUPXODFLyQ XQD SUHSDUDFLyQ GH
DOWR QLYHO HQ HVWH FDPSR 8QD GH ODV
PHWRGRORJtDV PiV XWLOL]DGDV SDUD OD
LQWHUSUHWDFLyQ GH ORV UHVXOWDGRV GHULYDGRV GH
HVWH WLSR GH DQiOLVLV HV OD GH VXSHUILFLHV GH
UHVSXHVWD 65 (Q JHQHUDO VX SUHGLFFLyQ VH
UHDOL]DHQIXQFLyQGHHFXDFLRQHVSROLQyPLFDVGH
VHJXQGR JUDGR REWHQLGDV PHGLDQWH UHJUHVLyQ
P~OWLSOHVHFXHQFLDO506
(QOD~OWLPDGpFDGDKDQFRPHQ]DGRDDSOLFDUVH
ORV PpWRGRV GH LQWHOLJHQFLD DUWLILFLDO HQ HO
FDPSRIDUPDFpXWLFR(QHVWHVHQWLGRODV³5HGHV
QHXURQDOHV DUWLILFLDOHV´ $11 KDQ UHVXOWDGR
~WLOHV SDUD GHWHFWDU FRPSOHMDV UHODFLRQHV QR
OLQHDOHV HQWUH YDULDEOHV \ UHVSXHVWDV \ \D KDQ
VLGR HPSOHDGDV FRQ p[LWR SRU HMHPSOR SDUD OD
RSWLPL]DFLyQ GH IRUPXODFLRQHV >@ 6LQ
HPEDUJR OD LQWHUSUHWDFLyQ GH ORV $11 UHVXOWD
HQ RFDVLRQHV GLItFLO OR TXH KD OOHYDGR DO
GHVDUUROOR GH QXHYDV DSUR[LPDFLRQHV FRPR ORV
VLVWHPDV ³QHXURIX]]\ ORJLF´ R GH ³OyJLFD
GLIXVD´TXHVRQPL[WRV\FRPELQDQODFDSDFLGDG
GHDSUHQGL]DMHGHORV$11FRQODSRVLELOLGDGGH
SURFHVDU LQIRUPDFLyQ LQFRPSOHWD R QR SUHFLVD
SHUR SUHVHQWDQGR VLPXOWiQHDPHQWH FDSDFLGDG
SDUDSUHGHFLUGHIRUPDH[SOtFLWD\FRPSUHQVLEOH
>@
(O WUDEDMR TXH VH SUHVHQWD SUHWHQGH SRQHU GH
PDQLILHVWRODXWLOLGDGGHXQVLVWHPD³QHXURIX]]\
ORJLF´ FRPR KHUUDPLHQWD SDUD HVWXGLDU \
GHVDUUROODUIRUPDVGHGRVLILFDFLyQ(QFRQFUHWR
VH FRPSDUDUiQ ODV FRQFOXVLRQHV GHULYDGDV GH
HVWD QXHYD PHWRGRORJtD FRQ ODV REWHQLGDV D
SDUWLUGHXQWUDWDPLHQWRHVWDGtVWLFRFRQYHQFLRQDO
SRU 506 \ DQiOLVLV GH 65 HQ HO HVWXGLR GH
FRPSULPLGRVGHFRPSUHVLyQGLUHFWD
0DWHULDOHV\0pWRGRV
6HWRPDURQFRPREDVHORVGDWRVLQFOXLGRVHQXQ
WUDEDMR SUHYLR UHDOL]DGR HQ QXHVWUR ODERUDWRULR
>@HQHOTXHVHSUHVHQWDEDQORVUHVXOWDGRVGHXQ
HVWXGLR FRPSDUDWLYR GH GRV YDULHGDGHV GH
FHOXORVD PLFURFULVWDOLQD $YLFHO 3+ DQG
3+FRPRGLOX\HQWHVGHFRPSUHVLyQGLUHFWD
/DV FDUDFWHUtVWLFDV GLIHUHQFLDOHV GH ODV IRUPXODFLRQHV HODERUDGDV KDEtDQ VLGR
HVWDEOHFLGDV VLJXLHQGR XQ GLVHxR IDFWRULDO SDUD
WUHV YDULDEOHV YDULHGDG GH FHOXORVD
PLFURFULVWDOLQD ( D GRV QLYHOHV SRUFHQWDMH GH
SUHGQLVRQD'IiUPDFR PRGHORDWUHVQLYHOHV
\IXHU]DGHFRPSUHVLyQ)DWUHVQLYHOHV
6H HYDOXDURQ ORV FRHILFLHQWHV GH YDULDFLyQ GH
SHVR&93GHODVIRUPXODFLRQHVDVtFRPRVXV
SURSLHGDGHV PHFiQLFDV \ GH FHVLyQ
$GLFLRQDOPHQWH \ FRQ HO ILQ GH LQWHUSUHWDU ORV
UHVXOWDGRV REWHQLGRV VH HVWXGLDURQ ODV
SURSLHGDGHV PLFURHVWUXFWXUDOHV GH ORV
FRPSULPLGRV
/RV PRGHORV PDWHPiWLFRV GHVDUUROODGRV SRU
UHJUHVLyQ P~OWLSOH VHFXHQFLDO WRPDURQ FRPR
EDVH OD HFXDFLyQ SROLQyPLFD GH VHJXQGR JUDGR
JHQHUDOVLJXLHQWH
< EE(E'E) E' E) E('
E()E')E()E('E')
E )' E )' E (') E (') E
(')E(')
(O DMXVWH VH UHDOL]y LQWURGXFLHQGR ~QLFDPHQWH
ORV WpUPLQRV VLJQLILFDWLYRV LQGLFDGRV SRU HO
$129$
3DUD HO WUDWDPLHQWR GH ORV GDWRV PHGLDQWH HO
VLVWHPD GH OyJLFD GLIXVD VH HPSOHy HO VRIWZDUH
)RUP5XOHV ,QWHOOLJHQV\V /WG 8. /D
SUHGLFWLELOLGDG GHO PRGHOR VH HVWDEOHFH HQ
IXQFLyQ GHO FRHILFLHQWH GH FRUUHODFLyQ 5 SDUD
FDGDSDUiPHWUR
Q
¦L = \L − \ÖL 5 = −
¦
Q
L =
\L − \L GRQGHLVODPHGLDGHODYDULDEOHGHSHQGLHQWHH
ǔ HV HO YDORU GH OD YDULDEOH TXH SUHGLFH HO
PRGHOR 9DORUHV GH 5 HQWUH \ LQGLFDQ
TXHHOPRGHORWLHQHXQDEXHQDSUHGLFWLELOLGDG
(QWUH ORV SDUiPHWURV SDUD HO DMXVWH TXH LQFOX\H
)RUP5XOHV VH VHOHFFLRQDURQ DTXHOORV SDUD ORV
TXHVHREWXYLHURQORVPHMRUHVUHVXOWDGRV
FRQFOXVLRQHV TXH OD UHJUHVLyQ P~OWLSOH
VHFXHQFLDO
'HO PRGHOR FRUUHVSRQGLHQWH VH GHGXFH OD
VXSHULRULGDGGHO$YLFHO3+DOREWHQHUVHHQ
WRGRVORVFDVRVYDORUHVGHUHVLVWHQFLDDODURWXUD
VXSHULRUHV D ORV REWHQLGRV FRQ OD YDULHGDG 3+
)LJXUD SHUR DGLFLRQDOPHQWH OD
HVWLPDFLyQGHORVYDORUHVGHSpUGLGDGHSHVRSRU
IULDELOLGDGUHVXOWyFODUDPHQWHVXSHULRU
$O LJXDO TXH HQ HO FDVR GH ODV SURSLHGDGHV
PHFiQLFDVODVFRQFOXVLRQHVTXHSHUPLWHH[WUDHU
HO WUDWDPLHQWR SRU OyJLFD GLIXVD VRQ VLPLODUHV \
HQDOJ~QFDVRVXSHULRUHVDOD506SHUPLWLHQGR
SRQHU GH PDQLILHVWR OD VXSHULRULGDG GH OD
YDULHGDG3+HQORTXHUHVSHFWDDOWLHPSRGH
GLVJUHJDFLyQ GH ORV FRPSULPLGRV \ XQD PHMRU
HVWLPDFLyQ GHO SDUiPHWUR SRUFHQWDMH GH
SUHGQLVRQDGLVXHOWRHQPLQ
$O QR UHTXHULU XQ GLVHxR H[SHULPHQWDO
GHWHUPLQDGR OD PHWRGRORJtD PHGLDQWH OyJLFD
GLIXVD SHUPLWH LQWURGXFLU FRPR YDULDEOHV
SDUiPHWURVLQWHUPHGLRVFRPRORVTXHGHILQHQHO
WUDEDMR GH FRPSUHVLyQ R OD HVWUXFWXUD
PLFURSRURVD H LQWHUSUHWDU VXV HIHFWRV VREUH ODV
FDUDFWHUtVWLFDVILQDOHVGHORVFRPSULPLGRV
7DEOD7pUPLQRVVLJQLILFDWLYRVGHULYDGRVGHOD506\
ODOyJLFDGLIXVDSDUDFDGDSDUiPHWUR
3DUiPHWURV
506>@
6XEPRGHORV
&RHILFLHQWHGH
(
('
YDULDFLyQGHSHVR
()
(
)
)
5HVLVWHQFLDDODURWXUD
'
(')
(')
('
'
)ULDELOLGDG
')
(')
)
'
7LHPSRGH
()
GLVJUHJDFLyQ
(')
(')
)
SUHGQLVRQDGLVXHOWR
')
')
DORVPLQ
)(
7DEOD9DORUHVGH5FRUUHVSRQGLHQWHVDORV
PRGHORVREWHQLGRVSRUOyJLFDGLIXVD
&RHILFLHQWHGHYDULDFLyQGHSHVR
5HVLVWHQFLDDODURWXUD.J
)ULDELOLGDG
7LHPSRGH'LVJUHJDFLyQV
SUHGQLVRQDGLVXHOWRDORVPLQ
$ PRGRGHHMHPSORVHSUHVHQWDQHQODILJXUD
RV YDORUHV HVWLPDGRV SRU DPERV PRGHORV SDUD
HOSDUiPHWUR&93TXHFRPRSXHGHREVHUYDUVH
SUHVHQWDQXQDPHMRUFRUUHODFLyQFRQORVYDORUHV
H[SHULPHQWDOHV FXDQGR VH XWLOL]D HO PRGHOR GH
OyJLFDGLIXVD
)LJ&RUUHODFLyQHQWUHORVYDORUHVH[SHULPHQWDOHV\
)LQDOPHQWH HO UD]RQDPLHQWR GLIXVR SHUPLWH
H[WUDHUFRQFOXVLRQHVFRQUHJODV6,(1721&(6
3RU HMHPSOR HO WUDWDPLHQWR GH ORV GDWRV
UHDOL]DGR UHVXOWD HQ H[SUHVLRQHV GHO WLSR 6, VH
HPSOHD OD YDULHGDG 3+ HO SRUFHQWDMH GH
SUHGQLVRQDHVDOWR\ODIXHU]DGHFRPSUHVLyQHV
DOWD (1721&(6 OD UHVLVWHQFLD D OD URWXUD HV
DOWD OD IULELOLGDG HV EDMD HO WLHPSR GH
GLVJUHJDFLyQ HV FRUWR \ HO SRUFHQWDMH GH
SUHGQLVRQDGLVXHOWRDORVPLQHVDOWR
&RQFOXVLRQHV
(O DQiOLVLV GH ORV GDWRV PHGLDQWH OyJLFD GLIXVD
SXHGHDSOLFDUVHFRQp[LWRDOHVWXGLR\GHVDUUROOR
GH FRPSULPLGRV GH FRPSUHVLyQ GLUHFWD
SHUPLWLHQGRREWHQHUFRQFOXVLRQHVVLPLODUHVDODV
GHULYDGDV GH OD 506 \ OD PHWRGRORJtD GH 65
FRQ XQ Q~PHUR PX\ OLPLWDGR GH H[SHULPHQWRV
GH XQD PDQHUD VHQFLOOD \ VLQ FRQRFLPLHQWRV
HVSHFLDOHV GH HVWDGtVWLFD (O FRQRFLPLHQWR
GHULYDGRGHVXXVRSXHGHDGHPiVDOPDFHQDUVH
HQ IRUPD GH UHJODV H[SOtFLWDV \ DPSOLDUVH FRQ
H[SHULPHQWRVDGLFLRQDOHVVLIXHUDQHFHVDULR
%LEOLRJUDItD
>@7DND\DPDHWDO3KDUP5HV
>@6KDRHWDO(XU-3KDUP6FL
>@ /DQGtQ HW DO 'UXJ 'HY ,QG 3KDUP
/RV DXWRUHV DJUDGHFHQ OD ILQDQFLDFLyQ GH OD
;XQWD GH *DOLFLD 3*,',7;$ \
3*,'7&6$35
ORVHVWLPDGRVSRUDPERVPRGHORV
3DUD ORV SDUiPHWURV TXH FDUDFWHUL]DQ ODV
SURSLHGDGHVPHFiQLFDVGHORVFRPSULPLGRVORV
UHVXOWDGRV GHO WUDWDPLHQWR PHGLDQWH OyJLFD
GLIXVD
SHUPLWLHURQ
REWHQHU
LGpQWLFDV
5HVXOWDGRV\'LVFXVLyQ
6DOYR HVFDVDV H[FHSFLRQHV ODV HFXDFLRQHV
SROLQyPLFDV REWHQLGDV SRU 506 LQFOX\HURQ XQ
HOHYDGRQ~PHURGHWpUPLQRV7DEOD
+D\ TXH VHxDODU DGHPiV TXH SDUD DTXHOORV
SDUiPHWURVFRPRHOFRHILFLHQWHGHYDULDFLyQGH
SHVR GH ORV FRPSULPLGRV R OD IULDELOLGDG TXH
FDUHFHQ GH UHSOLFDGRV ODV FRUUHODFLRQHV
REWHQLGDV SUHVHQWDURQ HVFDVR YDORU SUHGLFWLYR
6LQ HPEDUJR VX WUDWDPLHQWR PHGLDQWH OD OyJLFD
GLIXVD SHUPLWLy XQD HVWLPDFLyQ DGHFXDGD SDUD
WRGRVORVSDUiPHWURV5!7DEOD
7HFQRORJtD)DUPDFpXWLFD
32/<$1+<'5,'(1$123$57,&/(6$608&26$/$'-89$176)25%58&(//26,6
9$&&,1$7,21
5'D&RVWD0DUWLQV&*DPD]R&9DXWKLHU-0,UDFKH
,PPXQRDGMXYDQW8QLW'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\DQG'HSDUWPHQWRI
0LFURELRORJ\DQG3DUDVLWRORJ\8QLYHUVLW\RI1DYDUUD3DPSORQD6SDLQ
/DERUDWRLUHGH3K\VLFRFKLPLH3KDUPDFRWHFKQLHHW%LRSKDUPDFLH805&156)DFXOWpGH
3KDUPDFLH8QLYHUVLWp3DULV6XGDY-%&OpPHQW&KkWHQD\0DODEU\)UDQFH
,QWURGXFWLRQ
%UXFHOORVLV D ]RRQRVLV WKDW DIIHFWV ERWK
GRPHVWLFDQGRWKHUZLOGOLIHDQLPDOVLVDGLVHDVH
RIWKHUHSURGXFWLYHWUDFWWKDWPD\FDXVHDERUWLRQ
LQ IHPDOHV LQIHFWLRQ RI WKH VH[XDO RUJDQV LQ
PDOHVDQGLQIHUWLOLW\9DFFLQDWLRQLQDQLPDOVLV
XVXDOO\ SHUIRUPHG E\ DGPLQLVWUDWLRQ RI OLYH
DWWHQXDWHG %UXFHOOD VWUDLQV +RZHYHU WKHVH
YDFFLQHV DUH SDWKRJHQLF LQ KXPDQV LQWHUIHUH
ZLWKVHURORJLFDOGLDJQRVLVWHVWVDQGPD\LQGXFH
DERUWLRQV LQ SUHJQDQW DQLPDOV >@ $QRWKHU
SRVVLELOLW\WRREWDLQVDIHUDQGHIIHFWLYHYDFFLQHV
PD\ EH WKH XVH RI VXEFHOOXODU FRPSRXQGV
ORDGHG LQ QDQRSDUWLFOHV 7KLV DSSURDFK ZRXOG
SHUPLWWRRYHUFRPHWKHPDLQGUDZEDFNVUHODWHG
ZLWK WKH XVH RI OLYH YDFFLQHV DQG WR SRWHQWLDWH
WKH LPPXQH UHVSRQVH WR VXEFHOOXODU DQWLJHQV
DYRLGLQJERRVWHUGRVHV
7KH DLP RI WKLV ZRUN ZDV WR GHVLJQ
SRO\DQK\GULGH QDQRSDUWLFOHV ORDGHG ZLWK DQ
DQWLJHQLFFRPSOH[H[WUDFWHGIURP%UXFHOODRYLV
+6ZKLFKKDVDOUHDG\GHPRQVWUDWHGDELOLW\WR
LQGXFHSURWHFWLYHUHVSRQVHV DJDLQVWEUXFHOORVLV
LQ VKHHSV >@ 0DQQRV\ODWHG QDQRSDUWLFOHV >@
ZHUH GHVLJQ WR LPLWDWH FORVHO\ %UXFHOOD
FRORQR]DWLRQ SDWWHUQV DQG SURPRWH D EHWWHU
LQWHUDFWLRQ ZLWK PXFRVDO WLVVXHV )XUWKHUPRUH
WKHLQIOXHQFHRIVWHULOL]DWLRQE\γLUUDGLDWLRQ>
@ZDVHYDOXDWHG
0DWHULDOVDQG0HWKRGV
+6 ZDV REWDLQHG IURP % RYLV 5(2 FHOOV
DQGFKDUDFWHUL]HGDVGHVFULEHGSUHYLRXVO\>@
13V ZHUH SUHSDUHG E\ PRGLILFDWLRQ RI WKH
VROYHQW HYDSRUDWLRQ PHWKRG > @ %ULHIO\ WKH
SRO\PHUZDVGLVVROYHGLQDFHWRQHDQGLQFXEDWHG
ZLWK PDQRVDPLQH 7KHQ +6 ZDV DGGHG DQG
LQFXEDWHG IRU PLQ DW 57 7KH SRO\PHU
GHVROYDWLRQ ZDV LQGXFHG E\ DGGLWLRQ RI D
PL[WXUH RI HWKDQRO DQG ZDWHU 7KH RUJDQLF
VROYHQWV ZHUH HOLPLQDWHG XQGHU UHGXFHG
SUHVVXUHDQGSXULILHGE\FHQWULIXJDWLRQ)LQDOO\
13V ZHUH IUHH]HGULHG XVLQJ VXFURVH DV
FU\RSURWHFWRU&RQYHQWLRQDO13V13+6ZHUH
SUHSDUHGDVGHVFULEHGDERYHLQWKHDEVHQFHRI
PDQQRVDPLQH
1DQRSDUWLFOHVZHUHγLUUDGLDWHGE\XVLQJ&RDV
LUUDGLDWLRQ VRXUFH $UDJRJDPPD GRVHV RI .*\RU.*\ZHUHDSSOLHG
7KH SDUWLFOH VL]H DQG WKH ]HWD SRWHQWLDO ZHUH
GHWHUPLQHG E\ SKRWRQ FRUUHODWLRQ VSHFWURVFRS\
DQG HOHFWURSKRUHWLF ODVHU GRSSOHU DQHPRPHWU\
,;&RQJUHVRGHOD6(),*
7KH PRUSKRORJ\ ZDV VWXGLHG E\ 6(0 DQG WKH
SURWHLQ FRQWHQW ZDV GHWHUPLQHG E\
%&$¥3URWHLQ DVVD\ 7R HYDOXDWH WKH
PDQXIDFWXULQJHIIHFWVRQWKHSURWHLQSURILOHDQG
DQWLJHQLFLW\ SURWHLQV ZHUH H[WUDFWHG ZLWK
DFHWRQH'0) YY IURP WKH 13 DQG
DVVD\HG E\ 6'63$*( DQG LPPXQREORWWLQJ
UHVSHFWLYHO\ &RPSOHPHQW DFWLYDWLRQ ZDV
HYDOXDWHGE\TXDQWLILFDWLRQRIWKHFRQYHUVLRQRI
& E\ ' LPPXQRHOHFWURSKRUHVLV >@ )RU WKH
LQ YLWUR UHOHDVH VWXG\ 13V ZHUH UHVXVSHQGHG LQ
3%6 DW “ž& $W GHILQHG WLPH LQWHUYDOV
VDPSOHV ZHUH FHQWULIXJHG DQG WKH DQWLJHQ
FRQWHQWZDVGHWHUPLQHGE\%&$¥3URWHLQDVVD\
5HVXOWVDQG'LVFXVVLRQ
+6ORDGHG QDQRSDUWLFOHV GLVSOD\HG D VL]H RI
DERXW QP DQG DQ DQWLJHQ FRQWHQW RI —JPJ 0DQQRV\ODWLRQ RI SRO\DQK\GULGH
QDQRSDUWLFOHV\LHOGHGFDUULHUVZLWKDKLJKHUVL]H
DERXW QP DQG ORZHU DQWLJHQ FRQWHQW —JPJWKDQFRQYHQWLRQDOQDQRSDUWLFOHV
)LJ(IHFWRGHOGHSUHGQLVRQD\HOWLSRGHFHOXORVD
VREUHHOSDUiPHWURUHLVWHQFLDDODURWXUD
,;&RQJUHVRGHOD6(),*
6LPLODUO\E\FRPSDULQJ6(0SKRWRJUDSKVVHH
)LJXUH QR HYLGHQW PRGLILFDWLRQV RQ WKH
PRUSKRORJ\ RI WKH 13V ZHUH YLVXDOLVHG DIWHU
LUUDGLDWLRQ
2Q WKH VDPH ZD\ WKH
VWUXFWXUDO LQWHJULW\ DQG DQWLJHQLFLW\ RI WKH
HQWUDSSHG +6 LQ ERWK FRQYHQWLRQDO DQG
PDQQRV\ODWHG 13V ZHUH PDQWDLQHG GXULQJ WKH
SUHSDUDWLRQSURFHVVDQGDIWHUγLUUDGLDWLRQ
7KH LPPXQRHOHFWURSKRUHJUDPV RI VHUXP
LQFXEDWHG ZLWK 13V SUHVHQWHG ERWK & DQG
&D&ESHDNV7KHDUHDRI&DFWLYDWHGSHDNV
RQ ERWK 13V W\SHV ZDV KLJKHU WKDQ WKH 9%6
EDFNJURXQG DFWLYDWLRQ DQG WKH &$) YHU\
VLPLODUWDEOHLQGLFDWLQJWKDWSRO\DQK\GULGH
13V FDQ HQKDQFH WKH XSWDNH E\ PRQRQXFOHDU
SKDJRF\WLF V\VWHP 036 +RZHYHU &$) ZDV
VOLJKWO\ KLJKHU IRU VHUXP LQFXEDWHG 0$113
7KLVLVLQDJUHHPHQW ZLWKWKH PDQQRVHELQGLQJ
OHFWLQVSURSHUWLHVRIWKHPDQQRVDPLQHPRLHWLHV
ZKLFK DUH NQRZQ WR DFWLYDWH WKH FRPSOHPHQW
SDWKZD\
7DEOH $UHD PP RI & DQG & DFWLYDWHG
&D&EILUVWDQGVHFRQGSHDNUHVSHFWLYHO\DIWHU
PLQLQFXEDWLRQRIFPRIQDQRSDUWLFOHVZLWK
—/ RI KXPDQ VHUXP DW ž& 7KH FRPSOHPHQW
DFWLYDWLRQ IDFWRU &$) LV H[SUHVVHG DV
&D&E&&D&EPHDQ“VGQ &$)
7DEOH&KDUDFWHUL]DWLRQRIWKHQDQRSDUWLFOHVPHDQ
“VGQ 6L]H
QP
13+6
13+6.*\
13+6.*\
0$113+6
0$113+6.*\
0$113+6.*\
“
“
“
“
“
“
=HWD
+6FRQWHQW
SRWHQWLDO —J+6PJQS
P9
“
“
“
“
“
“
“
“
“
“
“
“
LUUDGLDWHG 7KXV E\ LQFUHDVLQJ WKH ȖGRVH WKH
EXUVWHIIHFWRIWKHQDQRSDUWLFOHVZDVIRXQGWREH
KLJKHU 7KLV IDVWHU UHOHDVH PD\ SUREDEO\
DVFULEHG WR D PRGLILFDWLRQ RI WKH PROHFXODU
ZHLJKW RI WKH SRO\DQK\GULGH GXULQJ
LUUDGLDWLRQ
9%6
13+6
0$113+6
“
“
“
)LJXUHV DQG VKRZ WKH LQIOXHQFH RI Ȗ
LUUDGLDWLRQ RQ WKH +6 UHOHDVH SURSHUWLHV 13V
VKRZHGDELSKDVLFUHOHDVHSDWWHUQFKDUDFWHUL]HG
E\DEXUVWHIIHFWW\SLFDOO\DERXWRIWKH
ORDGHG +6 IROORZHG E\ D FRQWLQRXV UHOHDVH RI
WKH DQWLJHQ IRU DW OHDVW GD\V ,QWHUHVWLQJO\
FRQYHQWLRQDO QDQRSDUWLFOHV 13+6 ZHUH QRW
DIIHFWHGE\ȖLUUDGLDWLRQ
)LJXUH Qž 6(0 SKRWRJUDSKV D 13+6 E 13
+6 .*\ F 13+6 .*\ D 0$113+6
E0$113+6.*\F0$113+6.*\
)LJXUH Qž ,QIOXHQFH RI WKH γLUUDGLDWLRQ RQ WKH
UHOHDVHSURSHUWLHVRIFRQYHQWLRQDOQDQRSDUWLFOHV13
+6{13+6.*\‘13+6.*\¡
2Q WKH FRQWUDU\ PDQQRV\ODWHG QDQRSDUWLFOHV
GLVSOD\HG GLIIHUHQW +6 UHOHDVH SURILOH ZKHQ Ȗ
&RQFOXVLRQV
3RO\DQK\GULGH QDQRSDUWLFOHV DSSHDUHG WR EH
WKH DSSURSULDWH FDUULHU WR ORDG +6 DQWLJHQLF
H[WUDFW
)RUFRQYHQWLRQDOQDQRSDUWLFOHVȖVWHULOL]DWLRQDW
D GRVH RI .*\ GLG QRW VLJQLILFDQWO\ PRGLI\
DQ\
RI
WKH
SK\VLFRFKHPLFDO
DQG
ELRSKDUPDFHXWLFDO SDUDPHWHUV DQDO\VHG LQ WKLV
ZRUN 7KH ȖLUUDGLDWLRQ RI PDQQRV\ODWHG
QDQRSDUWLFOHV LQGXFHG D IDVWHU UHOHDVH SDWWHUQ
WKDQ QRQVWHULOLVHG QDQRSDUWLFOHV $OWKRXJK
IXUWKHU LQ YLYR VWXGLHV DSSOLHG WR PXFRVDO
LPPXQL]DWLRQ DUH QHHGHG WKH QDQRSDUWLFXODWH
V\VWHPV GHYHORSHG UHYHDOHG SURPLVLQJ
FKDUDFWHULVWLFV DV DQWLJHQLF GHOLYHU\ V\VWHPV
WKURXJKRXWPXFRVDV
5HIHUHQFHV
$IWHU LUUDGLDWLRQ RI WKH QDQRSDUWLFOHV QR
VLJQLILFDQW PRGLILFDWLRQV LQ WKH VL]H RI +6
ORDGLQJRIQDQRSDUWLFOHVZHUHIRXQG7DEOH
)LJXUH Qž ,QIOXHQFH RI WKH γLUUDGLDWLRQ RQ WKH
UHOHDVH SURSHUWLHV RI PDQQRV\ODWHG QDQRSDUWLFOHV
0$113+6 z 0$113+6 .*\ … DQG
0$113+6.*\„
>@&*DPD]RHWDO,QIHFW,PPXQ
>@0(VWHYDQHWDO9DFFLQH
>@3$UEyVHWDO-&RQWURO5HOHDVH
>@+6DOPDQHWDO-1DQRVFLDQG1DQRWHFKQRO
>@'HFLVLRQ7UHHVIRUWKH6HOHFWLRQRI6WHULOL]DWLRQ
0HWKRGV&3034:3FRUU(0($
>@7KH8QLWHG6WDWHV3KDUPDFRSRHLD863WK
HG5RFNYLOOH
>@*yPH]6HWDO-1DQRVFLDQG1DQRWHFKQRO
$FNQRZOHGJPHQWV
³)XQGDomR SDUD D &LrQFLD H D 7HFQRORJLD´ LQ
3RUWXJDO 3LFDVVR JUDQW Qž 1* DQG +)
³0LQLVWHULRGH(GXFDFLyQ\&XOWXUDGH(VSDxD´
DQG ³$VRFLDFLyQ GH $PLJRV GH OD 8QLYHUVLGDG GH
1DYDUUD´LQ6SDLQ
7HFQRORJtD)DUPDFpXWLFD
,;&RQJUHVRGHOD6(),*
(67$%,/,'$'<(),&$&,$'(/,16(&7,&,'$&,3(50(75,1$,1&25325$'2(1
0,&52&È368/$6'(32/,85($
&0DUWtQ6DEURVR35LYDV(VWHEDQ'7DYDUHV6LOYD)HUQDQGHV0(*LO$OHJUH$,7RUUHV6XiUH]
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDG&RPSOXWHQVH
0DGULG
,QWURGXFFLyQ
&LSHUPHWULQD HV XQ LQVHFWLFLGD GH VtQWHVLV GHO
JUXSR GH ORV SLUHWURLGHV DPSOLDPHQWH XWLOL]DGR
HQ DJULFXOWXUD JDQDGHUtD MDUGLQHUtD \ D QLYHO
GRPpVWLFR /D PROpFXOD GH FLSHUPHWULQD
SUHVHQWD GRV WLSRV GH LVRPHUtD ILJXUD OD
LVRPHUtD ySWLFD SRU OD SUHVHQFLD GH XQ JUXSR
FLDQR \ TXH QR WLHQH WUDVFHQGHQFLD HQ HO
FRPSRUWDPLHQWR GHO SLUHWURLGH \ OD LVRPHUtD
FLVWUDQVSRUODSUHVHQFLDGHOGREOHHQODFHGHXQ
JUXSR YLQLOR \ TXH WLHQH JUDQ LQIOXHQFLD VREUH
OD DFWLYLGDG ORV LVyPHURV FLV VRQ PiV DFWLYRV
TXH ORV WUDQV SRU OR TXH HO SURGXFWR
FRPHUFLDOL]DGR KLJK FLVFLSHUPHWULQD SUHVHQWD
XQDUHODFLyQFLVWUDVGH
)LJXUD(VWUXFWXUDGH&LSHUPHWULQD
&LSHUPHWULQD DFW~D SRU FRQWDFWR D WUDYpV GH OD
FXWtFXOD GHO LQVHFWR SRU LQJHVWLyQ R SRU
LQKDODFLyQ 6H HQFXHQWUD FRPHUFLDOL]DGR HQ
IRUPD GH FRQFHQWUDGR HPXOVLILFDEOH \ SROYRV
PRMDEOHV (VWDV IRUPDV GH XWLOL]DFLyQ OOHYDQ
DVRFLDGRV LPSRUWDQWHV SUREOHPDV GH WR[LFLGDG
GHELGR QR VyOR DO FRQWDFWR GLUHFWR DFFLGHQWDO
GHO LQVHFWLFLGD FRQ SHUVRQDV DQLPDOHV R
DOLPHQWRVGXUDQWHVXDSOLFDFLyQVLQRWDPELpQDO
FRQWDFWR LQGLUHFWR GHELGR D OD FRQWDPLQDFLyQ
DWPRVIpULFDGHVXHORV\GHDJXDV
/D LQFRUSRUDFLyQ GH FLSHUPHWULQD HQ
PLFURFiSVXODV GH SROLXUHD UHVXOWDUtD XQD IRUPD
HILFD] GH GLVPLQXLU OD WR[LFLGDG \ HO LPSDFWR
PHGLRDPELHQWDO TXH OOHYD DVRFLDGD VX
DSOLFDFLyQ /D XWLOL]DFLyQ GH XQD FXELHUWD QR
ELRGHJUDGDEOH DXPHQWD OD SHUVLVWHQFLD HQ HO
DPELHQWH GHO LQVHFWLFLGD HYLWiQGRVH ODV
DSOLFDFLRQHV UHSHWLGDV PLHQWUDV TXH OD
WR[LFLGDG VH HQFXHQWUD VHQVLEOHPHQWH
GLVPLQXLGD DO HQFRQWUDUVH HO LQVHFWLFLGD
FRQILQDGR HQ HO LQWHULRU GH XQD FXELHUWD
UHVLVWHQWH DO DJXD D ORV MXJRV GLJHVWLYRV HWF
TXH LPSLGH VX FRQWDFWR GLUHFWR FRQ SLHO \
PXFRVDVDVtFRPRVXGLVROXFLyQHQHODJXD
(OREMHWLYRGHOSUHVHQWHWUDEDMRHVGHWHUPLQDUVL
OD LQFRUSRUDFLyQ GH FLSHUPHWULQD HQ
PLFURFiSVXODV VXSRQH DGHPiV XQD IRUPD GH
DXPHQWDUODHVWDELOLGDGTXtPLFDGHOLQVHFWLFLGD
\ YHULILFDU TXH HO LQVHFWLFLGD PLFURHQFDSVXODGR
5HVXOWDGRV\'LVFXVLyQ
(Q HO FURPDWRJUDPD REWHQLGR FRQ KLJK FLV
FLSHUPHWULQD ILJ VH REVHUYDQ ORV SLFRV
FRUUHVSRQGLHQWHV DO LVyPHUR WUDQV
75 PLQ\FLV75 PLQ
UHVXOWD HILFD] DO VHU LQJHULGR SRU ORV LQVHFWRV
FXDQGR URPSHQ ODV PLFURFiSVXODV FRQ VXV
PDQGtEXODV
0DWHULDOHV\0pWRGRV
6H HODERUDQ PLFURFiSVXODV 0& GH KLJK FLV
FLSHUPHWULQD PHGLDQWH OD WpFQLFD GH
SROLPHUL]DFLyQ LQWHUIDFLDO 6H XWLOL]DQ GRV
PRQyPHURV GLHWLOHQWULDPLQD \ WROXHQ
GLLVRFLDQDWR TXH UHDFFLRQDQ HQ OD LQWHUID] GH
XQDHPXOVLyQHQFX\DIDVHLQWHUQDVHHQFXHQWUD
HO LQVHFWLFLGD D HQFDSVXODU GDQGR OXJDU D OD
FXELHUWDGHSROLXUHD
(VWXGLRGHHVWDELOLGDGVHHYDO~DODHVWDELOLGDG
GH KLJK FLVFLSHUPHWULQD VLQ PLFURHQFDSVXODU \
PLFURHQFDSVXODGD IUHQWH D OD KXPHGDG
DPELHQWDO HO R[tJHQR \ OD OX] 3DUD HOOR VH
PDQWLHQHQ PXHVWUDV HQ DPELHQWH GH KXPHGDG
UHODWLYD VXSHULRU DO HQ DWPyVIHUD VDWXUDGD
GHR[LJHQR\H[SXHVWDVDODOX]VRODUGLUHFWD$
LQWHUYDORV GH WLHPSR VH GHWHUPLQD HO FRQWHQLGR
WRWDO GH FLSHUPHWULQD HQ ODV PXHVWUDV \ OD
UHODFLyQ GH LVyPHURV FLVWUDV 6H XWLOL]D XQ
PpWRGR SRU +3/& TXH SHUPLWH OD
FXDQWLILFDFLyQHVSHFtILFDGHORVGRVLVyPHURVHQ
SUHVHQFLD GH SROtPHUR \ SURGXFWRV GH
GHJUDGDFLyQ
(Q OD ILJXUD VH PXHVWUDQ ORV UHVXOWDGRV GHO
HVWXGLR GH HVWDELOLGDG IUHQWH D OD KXPHGDG
&LSHUPHWULQD VH GHJUDGD HQ DPELHQWHV GH
HOHYDGDKXPHGDGFRQXQGHJUDGDGRDODV
VHPDQDV GH DOPDFHQDPLHQWR (VWD GHJUDGDFLyQ
QROOHYDDVRFLDGRQLQJ~QFDPELRHQODUHODFLyQ
GH LVyPHURV TXH VLJXH VLHQGR SUy[LPD D OD
WHyULFD
% cipermetrina
% isómero cis
100
100
3UREOHPD
3DWUyQ
&RQ0&
&RQ0&GH
&RQLQVHFWLFLGD
WUDWDU
EODQFDV
LQVHFWLFLGD
PS
60
80
40
Cipermetrina
70
0
0
7HFQRORJtD)DUPDFpXWLFD
02',),('*(17$0,&,17275($7,175$&(//8/$5,1)(&7,216
(,PEXOX]TXHWD&*DPD]R'*RQ]iOH]((OL]RQGR19HQWRVD66DOD
-9HFLDQD0-%ODQFR3ULHWR
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\DQG'HSDUWPHQWRI0LFURELRORJ\8QLYHUVLW\
RI1DYDUUD3DPSORQD6SDLQ
0ROHFXODU1DQRVFLHQFHDQG2UJDQLF0DWHULDOV'HSDUWPHQW,QVWLWXWGH&LqQFLDGH0DWHULDOVGH
%DUFHORQD&DPSXVGHOD8$%VQ%HOODWHUUD%DUFHORQD6SDLQ
ZHUH LVRODWHG E\ FHQWULIXJDWLRQ ZDVKHG ZLWK
,QWURGXFWLRQ
ZDWHUDQGIUHH]HGULHG
*HQWDPLFLQLVDQDPLQRJO\FRVLGHZLWKDZLGH
13 VL]H SRO\GLVSHUVLW\ DQG ]HWD SRWHQWLDO ZHUH
VSHFWUXPRIDQWLEDFWHULDODFWLYLW\EXWGXHWRLWV
HYDOXDWHG E\ D G\QDPLF OLJKW VFDWWHULQJ
K\GURSKLOLFQDWXUHLWSHQHWUDWHVSRRUO\LQWRWKH
WHFKQLTXH ZLWK D =HWDVL]HU 0DOYHUQ
FHOOV7KLVFRQVWLWXWHVDSDUWLFXODUO\LPSRUWDQW
,QVWUXPHQWV8.
GUDZEDFNIRUWKHWKHUDS\RILQWUDFHOOXODU
)RU *P ORDGLQJ GHWHUPLQDWLRQ PJ RI
EDFWHULDOLQIHFWLRQVOLNHEUXFHORVLV7KHUHIRUH
SDUWLFOHV ZHUH GLVVROYHG LQ 0 1D2+
WKHXVHRISDUWLFXODWHFDUULHUVKDVEHHQSURSRVHG
VROXWLRQ DQG VWLUUHG IRU K 6DPSOHV ZHUH
WRWDUJHWWKHDQWLELRWLFVWRLQWUDFHOOXODUVLWHV
FHQWULIXJHG DW J GXULQJ PLQ DQG WKH
ZKHUHWKHEDFWHULXPLVIRXQG
VXSHUQDWDQW ZDV FHQWULIXJHG DJDLQ [ J
:H KDYH SUHYLRXVO\ VKRZQ WKDW + 3/*$
PLQWRHOLPLQDWHWKHWUDFHVRISRO\PHU
PLFURSDUWLFOHV FRQWDLQLQJ JHQWDPLFLQ VXOSKDWH
7RTXDQWLI\WKHDQWLELRWLFDQ$F4XLW\83/&Œ
*P6 ZHUH VXLWDEOH IRU WKH WUHDWPHQW RI
%(+&FROXPQμP[PP:DWHUV
H[SHULPHQWDO EUXFHOORVLV LQ PLFH +RZHYHU
WHUPRVWDWL]HG DW ž& ZDV XVHG ZLWK DQ
*PORDGLQJLPSURYHPHQW ZRXOGEHUHTXLUHGLQ
LVRFUDWLF HOXWLRQ SURILOH 7KH PRELOH SKDVH
RUGHU WR EH XVHG LQ KXPDQ WKHUDS\ 7R DFKLHYH
FRQVLVWHG RQ P0 SHQWDIOXRURSURSLRQLF DFLG
WKLV JRDO D K\GURSKRELF *P *P$27 KDV
3)3$ VROXWLRQ LQ DFHWRQLWULOHZDWHU EHHQV\QWKHVL]HG
YY 7KH IORZUDWH ZDV P/PLQ :RUNLQJ
7KHUHIRUH WKH DLP RI WKLV ZRUN ZDV WR GHVLJQ
VWDQGDUGVROXWLRQVZHUHSUHSDUHGLQDFHWRQLWULOH
GHYHORS DQG FKDUDFWHUL]H ELRGHJUDGDEOH
ZDWHUYYXVLQJWREUDP\FLQ—JP/
QDQRSDUWLFOHV13IRUWKHFRQWUROOHGGHOLYHU\RI
DVLQWHUQDOVWDQGDUG,6)RUWKHDQDO\VLVRIWKH
*P$270RUHRYHUDVEHLQJDQHZPROHFXOH
VDPSOHVVXSHUQDWDQWVZHUHGLOXWHGLQ
LW EHFRPHV QHFHVVDU\ WKH GHYHORSPHQW RI D
PRELOH SKDVH DQG ZLWK WKH ,6 DQG μ/
UHOLDEOHPHWKRGIRULWVTXDQWLILFDWLRQ'XHWRWKH
ZHUH LQMHFWHG RQWR WKH 83/& FROXPQ 7KH
ODFNRIFKURPRSKRUHJURXSVDPHWKRGEDVHGRQ
DQDO\WHV ZHUH GHWHFWHG XVLQJ DQ HOHFWURVSUD\
DQ XOWUD SHUIRUPDQFH OLTXLG FKURPDWRJUDSK\
LRQL]DWLRQWDQGHPPDVVVSHFWURPHWU\LQSRVLWLYH
FRPELQHG ZLWK WDQGHP PDVV VSHFWURPHWU\
LRQ PRGH ZLWK PXOWLSOH UHDFWLRQ PRQLWRULQJ
83/&±0606ZDVGHYHORSHG
050 7KH VHOHFWHG WUDQVLWLRQV RI WKH
SURWRQDWHG SUHFXUVRUSURGXFW LRQ SDLUV ZHUH
0DWHULDOVDQG0HWKRGV
IRU*PDQGIRU7REUDP\FLQ
*P±6 ZDV WUDQVIRUPHG LQWR D PRUH
)RU *P$27 WR[LFLW\ VWXGLHV 7+3 KXPDQ
K\GURSKRELF LRQLF FRPSOH[ *P$27 SDWHQW
PRQRF\WHV ZHUH SODWHG LQWR ZHOO SODWHV DW D
DSSOLFDWLRQ 2(37KH FRPSOH[ ZDV
GHQVLW\ RI FHOOVZHOO DQG GLIIHUHQWLDWHG LQWR
SURFHVVHG E\ WKH PHWKRG 3UHFLSLWDWLRQ ZLWK D
PDFURSKDJHV ZLWK QJP/ RI SKRUERO &RPSUHVVHG $QWLVROYHQW 3&$ $Q RUJDQLF
P\ULVWDWH
DFHWDWH 30$ LQ 530, PHGLXP
VROXWLRQ RI WKH DFWLYH FRPSRXQG LV VSUD\HG
$IWHU K μJP/ *P6 DQG ERWK QRQ
WKRXJK D QR]]OH LQWR D FRPSUHVVHG DQWLVROYHQW
SURFHVVHG DQG SURFHVVHG *P$27 ZHUH DGGHG
&2 ZKLFK UDSLGO\ GLIIXVHV LQWR WKH VSUD\HG
DQG LQFXEDWHG IRU DQG K DW ž& )RU
GURSOHWV FDXVLQJ WKH SUHFLSLWDWLRQ RI WKH VROXWH
HDFK WLPH FHOO YLDELOLW\ ZDV HYDOXDWHG E\ ERWK
7KH REWDLQHG *P LV KHUH GLILQHG DV SURFHVVHG
ODFWLF GHK\GURJHQDVH /'+ 6LJPD DQG 077
*P$27
FRORULPHWULFDVVD\V
*P$27 ZDV HQFDSVXODWHG LQWR SRO\PHULF 13
E\ XVLQJ DQ HPXOVLRQ VROYHQW HYDSRUDWLRQ
5HVXOWVDQG'LVFXVVLRQ
PHWKRG 7KH DQWLELRWLF ZDV GLVVROYHG LQ HWK\O
DFHWDWH FRQWDLQLQJ WKH SRO\PHU 3/*$ +
&KDUDFWHUL]DWLRQRIWKH13
DQG SRXUHG RQ D ZDWHU SKDVH FRQWDLQLQJ
$OO WKH IRUPXODWLRQV VKRZHG PHDQ GLDPHWHUV
SRO\YLQLODOFRKRO %RWK SKDVHV ZHUH PL[HG E\
EHORZ QP ,QFUHDVLQJ WKH QRPLQDO ORDGLQJ
XOWUDVRQLFDWLRQDQGWKHUHVXOWLQJ2:HPXOVLRQ
IURP WR PJ RI *P$27 GLG QRW DIIHFW
ZDVFRQWLQXRXVO\VWLUUHGIRUDWOHDVWKWRDOORZ
SDUWLFOH VL]H 3G, SRO\GLVSHUVLW\ LQGH[ ZDV
VROYHQW HYDSRUDWLRQ DQG SDUWLFOH IRUPDWLRQ 13
4
6
8
0
10
2
4
6
8
10
semanas
)LJXUD(VWDELOLGDGIUHQWHDODKXPHGDGDPELHQWDO
100
80
60
40
6LQHPEDUJRFXDQGRFLSHUPHWULQDVHHQFXHQWUD
PLFURHQFDSVXODGD QR VH REVHUYD DOWHUDFLyQ
DOJXQD GHVSXpV GH VHPDQDV GH
DOPDFHQDPLHQWR
5HVSHFWR D OD HVWDELOLGDG IUHQWH DO R[tJHQR
ILJXUD QR VH GHWHFWD GLVPLQXFLyQ HQ HO
FRQWHQLGR GH LQVHFWLFLGD VLQ PLFURHQFDSVXODU
SHUR Vt TXH VH REVHUYD XQD LQWHQVD UHGXFFLyQ
GHO SRUFHQWDMH GH LVyPHUR FLV \D GHVGH OD
SULPHUD VHPDQD DOPDFHQDPLHQWR &XDQGR VH
H[SRQH
DO
R[LJHQR
HO
LQVHFWLFLGD
PLFURHQFDSVXODGR QR VH REVHUYD QLQJXQD
YDULDFLyQ VLJQLILFDWLYD HQ HO SRUFHQWDMH GH
LVyPHURFLVDORODUJRGHOHVWXGLR
(Q FXDQWR DO HVWXGLR GH IRWRHVWDELOLGDG QR VH
GHWHFWyQLQJXQDDOWHUDFLyQQLHQHOFRQWHQLGRHQ
DFWLYR QL HQ OD UHODFLyQ GH LVyPHURV FXDQGR VH
DQDOL]DURQ ODV PXHVWUDV GH LQVHFWLFLGD VLQ
PLFURHQFDSVXODU
% cipermetrina
% isómero cis
)LJ (VWDELOLGDG GH FLSHUPHWULQD IUHQWH DO
R[tJHQR
MC cipermetrina
2
4
6
)LJ(VWXGLRGHHILFDFLD
&RQFOXVLRQHV
/DV PLFURFDSVXOHV GH FLSHUPHWULQD \ SROLXUHD
GHVDUUROODGDV SURWHJHQ DO LQVHFWLFLGD IUHQWH D OD
KXPHGDG \ HO R[tJHQR DWPRVIpULFR \ KDQ
GHPRVWUDGR VX HILFDFLD IUHQWH D ODUYDV GH
LQVHFWR
5HIHUHQFLDV
>@ +HUEHUW % 6FKHU &RQWUROOHG5HOHDVH
'HOLYHU\ 6\VWHPV IRU 3HVWLFLGHV 0DUFHO
'HNNHU1XHYD<RUN
>@ 1 <DQ 3 1L DQG 0 =KDQJ -
0LFURHQFDSVXODWLRQ
>@ ,3 5LYDV 0( *LO$OHJUH $, 7RUUHV
6XiUH] $QDO\WLFD &KLPLFD $FWD $JUDGHFLPLHQWRV
$O'U3HGURGHO(VWDO(76,$JUyQRPRVSRU
OD D\XGD UHFLELGD SDUD UHDOL]DU HO HVWXGLR FRQ
ODUYDV
100
90
80
70
60
50
40
30
20
10
0
Cipermetrina
20
0
2
semanas
0
20
MC cipermetrina
60
(VWXGLR GH HILFDFLD VH XWLOL]DQ ODUYDV GH
6SRGRSWHUDVSHQHVWDGLR/TXHVH PDQWLHQHQ
D XQD WHPSHUDWXUD GH ž& KXPHGDG UHODWLYD
GHO \ FLFORV OX]RVFXULGDG GHKK 6H
UHDOL]DQFXDWURJUXSRVFRQGLIHUHQWHWUDWDPLHQWR
GHODOLPHQWRDUWLILFLDOWDEOD6HGHWHUPLQDHO
SRUFHQWDMHGHPXHUWHVDODV\KGHLQLFLDUVH
HOHVWXGLR
80
90
7DEOD'LVHxRGHOHVWXGLRGHHILFDFLD
6LQ
)LJXUD&URPDWRJUDPDGHKLJKFLVFLSHUPHWULQD
&RQWURO %ODQFR
(Q HO HVWXGLR GH HILFDFLD VH REWXYLHURQ ORV
PLVPRV UHVXOWDGRV HQ HO JUXSR SDWUyQ \
SUREOHPD HO GH PXHUWHV D ODV 6LQ
HPEDUJRFXDQGRODDOLPHQWDFLyQVHPH]FOyFRQ
PLFURFiSVXODV QR FDUJDGDV EODQFR VROR
PXULHURQHOGHODVODUYDV
8
10
semanas
0
2
4
6
8
10
semanas
,;&RQJUHVRGHOD6(),*
ORZHUWKDQDQGDOOWKHQDQRSDUWLFOHVVKRZHG
DQHJDWLYHVXUIDFHFKDUJH7DEOH
7DEOH ,QIOXHQFH RI WKH *P$27 QRPLQDO
ORDGLQJLQWKHFKDUDFWHULVWLFVRI+13
*P$27
QRPLQDO
ORDGLQJPJ
6L]H
QP
3',
=HWD
SRWHQWLDO
—J*P
PJ13
((
*P$27TXDQWLILFDWLRQ
7KH 06 VSHFWUD RI *P$27 VKRZHG WKH
PROHFXODU LRQV IURP DOO *P FRPSRQHQWV &
& &D DQG &D 7KHUHIRUH WKH *P$27
FRPSOH[ ZDV GLVUXSWHG LQ WKH VRXUFH
GHVROYDWDWLRQ SURFHVV WR *P DQG $27 06
WUDQVLWLRQP]IURPWRZDVHPSOR\HG
WRTXDQWLI\*P$27LQDOOVDPSOHV
(QFDSVXODWLRQHIILFLHQF\
(QFDSVXODWHG*P$27ZDVTXDQWLILHGLQDOOWKH
SUHSDUHG13E\WKHGHYHORSHGPHWKRG13ZLWK
DQRPLQDOORDGLQJRIPJVKRZHGD*P$27
HQWUDSPHQWRIμJPJZLWKHTXLYDOHQWWRD
RIHQFDSVXODWLRQ7DEOH7KLVILJXUHLV
DSUR[ WLPHV KLJKHU WKDQ WKH DPRXQW RI
HQFDSVXODWHG XQPRGLILHG *0 μJPJ DW
WKHVDPHQRPLQDOORDGLQJ
(YHQPRUHLQFUHDVLQJWKHQRPLQDOORDGLQJIURP
PJWRPJIXUWKHULQFUHDVHGWKH*P$27
HQWUDSPHQW IURP μJPJ WR μJPJ
RISRO\PHU
*PWR[LFLW\VWXGLHVLQ7+3FHOOV
5HVXOWV VKRZHG WKDW QRQ SURFHVVHG *P$27
ZDV WR[LF DW WKH VWXGLHG FRQFHQWUDWLRQ μJP/ &RQYHUVHO\ WKH YLDELOLW\ RI WKH FHOOV
ZDV DERYH ZKHQ WUHDWHG ZLWK WKH VDPH
FRQFHQWUDWLRQRI*P6DQGSURFHVVHG*P$27
ILJXUH
$
%
)LJXUH &\WRWR[LF HIIHFW RI WKH WUHDWPHQWV RQ
7+3FHOOVPHDVXUHE\/'+$DQG077%
DVVD\V
&RQFOXVLRQV
3/*$13ORDGHGZLWK*P$27ZHUHSUHSDUHG
ZLWK D YHU\ KLJK HQWUDSPHQW HIILFLHQF\ $OVR
WKH GHYHORSHG 83/& PHWKRG LV VXLWDEOH WR
GHWHFWWKHPRGLILHG*P)LQDOO\SURFHVVHG*P
$27KDVVKRZQWREHQRQWR[LFLQ7+3FHOOV
FRPSDUHGWRWKHQRQSURFHVVHG*P$27
5HIHUHQFHV
*DPD]R&HWDO([SHUW2SLQ'UXJ'HOLY
/HFiUR] & HW DO - RI 1DQRVFLHQFH DQG
1DQRWHFKQRORJ\
/HFiUR] & HW DO $QWPLFURE $JHQWV
&KHPRWKHU
/HFiUR]&HWDO-0LFURHQFDSVXO
$FNQRZOHGJHPHQWV
7KLV ZRUN ZDV VXSSRUWHG E\ ³0LQLVWHULR GH
&LHQFLD H LQQRYDFLyQ´ IURP 6SDLQ 1$1
& DQG &DMD 1DYDUUD )RXQGDWLRQ
(,PEXOX]TXHWDWKDQNVWKH6SDQLVK³0LQLVWHULR
GH &LHQFLD H ,QQRYDFLyQ´ ³*RELHUQR GH
1DYDUUD 'HSDUWDPHQWR GH (GXFDFLyQ´ DQG
³$VRFLDFLyQ GH $PLJRV GH OD 8QLYHUVLGDG GH
1DYDUUD´ IRU WKH IHOORZVKLS JUDQWV
,19,752$1',19,9272;,&,7<678',(62)32/<$1+<'5,'(1$123$57,&/(6
)2525$/'58*'(/,9(5<
32MHU$/ySH]GH&HUDLQ-0,UDFKH
$
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\'HSDUWPHQWRI1XWULWLRQDQG)RRG6FLHQFHV
3K\VLRORJ\DQG7R[LFRORJ\8QLYHUVLW\RI1DYDUUD,UXQODUUHDVQ3DPSORQD6SDLQ
1DQRWHFKQRORJ\ LV DQ HPHUJLQJ VFLHQFH
LQYROYLQJ PDQLSXODWLRQ RI PDWHULDOV DW WKH
QDQRPHWHU VFDOH 6SHFLILFDOO\ LQ WKH FDVH RI
PHGLFLQH WKH WHUP ³QDQRPHGLFLQH´ KDV EHHQ
DSSOLHG WR GLYHUVH PHGLFDO ILHOGV VXFK DV GUXJ
GHOLYHU\V\VWHPV,QWKLVFRQWH[WRXUJURXSKDV
GHPRQVWUDWHG WKH XVH RI *DQWUH]Š $1
QDQRSDUWLFOHV LQ RUDO GUXJ GHOLYHU\
+RZHYHU WKH PDLQ SUREOHP ZLWK WKLV W\SH RI
WHFKQRORJ\ LV WKDW OLWWOH RU QRWKLQJ LV NQRZQ
DERXWWKHLUSRWHQWLDOWR[LFHIIHFWVEHFDXVHWKHUH
DUH QR VSHFLILF JXLGHOLQHV RU SURWRFROV IRU
DVVHVVLQJ WKH WR[LFLW\ RI WKHVH QHZ
QDQRPDWHULDOV )RU WKLV UHDVRQ D QHZ GLVFLSOLQH
FDOOHG QDQRWR[LFRORJ\ LV HPHUJLQJ 7KH DLP RI
WKLV ZRUN ZDV WR HYDOXDWH WKH WR[LFLW\ RI
GLIIHUHQW
3RO\DQK\GULGH
QDQRSDUWLFOHV
LQWHQGHG IRU RUDO GHOLYHU\ )RU WKLV SXUSRVH LQ
YLWUR F\WRWR[LFLW\ LQ +HS * FHOOV DQG LQ YLYR
RUDOVLQJOHGRVHVWXGLHVZHUHGHYHORSHG
0DWHULDOVDQGPHWKRGV
3RO\PHWK\O YLQ\O HWKHUFRPDOHLF DQK\GULGH
QDQRSDUWLFOHV 1S ZHUH SUHSDUHG E\ D
GHVROYDWLRQ PHWKRG SUHYLRXVO\ GHVFULEHG
6LPLODUO\
+LGUR[LSURSLOȕF\FORGH[WLQ
QDQRSDUWLFOHV +3&'1S DQG SHJ\ODWHG
QDQRSDUWLFOHV 3(*1S ZHUH SUHSDUHG E\
LQFXEDWLRQ RI HLWKHU ZLWK WKH SRO\PHU SULRU WR
IRUPDWLRQRIQDQRSDUWLFOHV
,Q RUGHU WR SUHVHUYH WKH IRUPXODWLRQV
WKURXJKRXW ZH O\RSKLOL]HG 3(*1S RU
VSUD\GULHGWKHVDPSOHV1S+3&'1S
7KH SDUWLFOH VL]H DQG WKH ]HWD SRWHQWLDO RI
QDQRSDUWLFOHV ZHUH GHWHUPLQHG E\ SKRWRQ
FRUUHODWLRQ VSHFWURVFRS\ DQG HOHFWURSKRUHWLF
ODVHU GRSSOHU DQHPRPHWU\ UHVSHFWLYHO\ 7KH
PRUSKRORJLFDOH[DPLQDWLRQRIWKHQDQRSDUWLFOHV
ZDVSHUIRUPHGE\6(0
7KHDPRXQWRI+3&'DQG3(*DVVRFLDWHG
WR WKH QDQRSDUWLFOHV ZDV TXDQWLILHG E\ +3/&
IURP WKH VXSHUQDWDQWV FROOHFWHG GXULQJ WKH
SXULILFDWLRQVWHSRIQDQRSDUWLFOHV
7KH LQ YLWUR F\WRWR[LFLW\ VWXGLHV ZHUH FDUULHG
RXW E\ 076 DVVD\ LQ +HS * FHOOV )RU WKLV
SXUSRVH GLIIHUHQW W\SHV RI SRO\DQK\GULGH
QDQRSDUWLFOHV DW GLIIHUHQW FRQFHQWUDWLRQV
DQGPJP/ZHUH
210
LQFXEDWHGIRUPLQXWHVDQGKRXUV
LQ RUGHU WR GHWHUPLQHG WKH ,& YDOXH KDOI
LQKLELWRU\FRQFHQWUDWLRQ
,Q RUGHU WRREVHUYH FKDQJHV LQ WKH PRUSKRORJ\
RIFHOOVGXHWRWKHDGGLWLRQRIWKHQDQRSDUWLFOHV
+HS * LPDJHV ZHUH WDNHQ E\ RSWLFDO
PLFURVFRS\
6LQJOH RUDO GRVH WR[LFLW\ VWXG\ ZDV SHUIRUPHG
DFFRUGLQJ WR 2&'( JXLGHOLQH %ULHIO\
ZHDGPLQLVWHUHGVLQJOHGRVHVPJ.JRI
WKHGLIIHUHQWQDQRSDUWLFOHVWRIHPDOH:LVWDUUDWV
7KH JHQHUDO V\PSWRPDWKRORJ\ RI WKH DQLPDOV
ZDV WHVWHG GXULQJ WKH H[SHULPHQW DQG IRXUWHHQ
GD\V DIWHU DGPLQLVWUDWLRQ EORRG VDPSOHV ZHUH
FROOHFWHG IRU KHPDWRORJ\ DQG EORRG FKHPLVWU\
DQDO\VLV)LQDOO\WKHDQLPDOVZHUHVDFULILFHGDQG
WKHOHWKDOGRVH/'ZDVHVWLPDWHG
80
60
40
6L]HQP
=HWD3RWHQWLDO
P9
—JOLJDQGPJ1S
1S
“
“
3(*1S
“
“
“
+3&'1S
“
“
“
Data presented are mean values and standard
deviations (n=6)
,QF\WRWR[LFLW\VWXGLHVDVVKRZQLQ)LJXUHDW
PLQXWHVDQGKRXUVWKHFHOOYLDELOLW\GLG
QRW GHFUHDVH VLJQLILFDQWO\ DIWHU WKH DGGLWLRQ RI
QDQRSDUWLFOHV 7KH SRO\ DQK\GULGH *DQWUH]Š
$1ZDVXVHGDVFRQWURO7KHQDQRSDUWLFOHVZHUH
QRQF\WRWR[LF2QO\DIWHULQFXEDWLRQIRUDQG
KRXUV D VLJQLILFDQW F\WRWR[LF HIIHFW ZDV
REVHUYHGDWWKHKLJKHVWFRQFHQWUDWLRQVWHVWHG
PJP/
7HFQRORJtD)DUPDFpXWLFD
TTO 1
TTO 2
TTO 3
TTO 4
Control 1
Control 2
190
180
170
160
0
625m
0.0
0
L
g/m
L
g/m
5m
0.12
L
g/m
5m
0.2
mL
mg/
0.5
%
2
4
6
L
g/m
2m
L
g/m
1m
10
‚
80
60
‚
&RQFOXVLRQV
40
3RO\DQK\GULGHQDQRSDUWLFOHVGLGQRWVKRZDQ\
WR[LF HIIHFWV XQGHU WKH H[SHULPHQWDO FRQGLWLRQV
XVHGKHUH
20
*
*
0.0
6
L
g/m
25m
0.1
25m
L
g/m
0.2
5m
L
g/m
0
L
g/m
.5m
L
g/m
1m
L
g/m
2m
7KHF\WRWR[LFLW\VWXGLHVGHPRQVWUDWHGWKDWWKH
QDQRSDUWLFOHV GLG QRW KDYH DQ\ WR[LF HIIHFW LQ
+HS * FHOOV DW PLQXWHV DQG KRXUV
([FHSW DW WKH KLJKHVW FRQFHQWUDWLRQV DQG WLPHV
RILQFXEDWLRQWHVWHG
HPCD NP Concentrations
† :Results were significant
and
(Kruskal Wallis-U-Mann Whitney)
at 0.05 level
7KHUHVXOWVDFKLHYHGLQWKHDFXWHRUDOWR[LFLW\
VWXG\ HVWLPDWHG WKDW WKH PHGLXP OHWKDO GRVH
/' IRU WKH GLIIHUHQW SRO\ DQK\GULGH
QDQRSDUWLFOHV IRUPXODWLRQV ZHUH JUHDWHU WKDQ
PJ.J
Figure 1. MTS assay in HepG2 cells at
different concentrations (0.0625, 0.125,
0.25, 0.5, 1 and 2 mg/mL) after incubation
for: (A) 30 minutes, 3 and 24 hous, (B) 24,
48 and 72 hours. Data presented are mean
values (all experiments were performed
triplicate) and standard deviations (n=6)
)LQDOO\GXULQJWKHDFXWHRUDOWR[LFLW\VWXG\WKDW
ODVWHG IRU GD\V QR VLJQV RI WR[LFLW\ ZHUH
REVHUYHGLQDQ\DQLPDODQGDVVKRZQLQ)LJXUH
WKH ERG\ ZHLJKW RI DOO DQLPDOV ZDV QRW
VLJQLILFDQWO\ GLIIHUHQW EHWZHHQ WKH FRQWURO
JURXSVDQGWKHWUHDWPHQWJURXSV
7KH KHPDWRORJLFDO UHVXOWV DQG EORRG FKHPLVWU\
ZHUHIRXQGZLWKLQWKHUDQJHRIQRUPDOYDOXHV
5HIHUHQFHV
6DOPDQ++HWDO-&RQWURO5HOHDVH
*RPH] 6 HW DO 9DFFLQH $UERV3HWDO-&RQWURO5HOHDVH
$JXHURV 0 HW DO - 3KDUP %LRPHG $QDO
=DEDOHWD 9 HW DO - 3KDUP %LRPHG $QDO
2&'(*XLGHOLQHVIRUWKH7HVWLQJRI
&KHPLFDOV7HVW 1R $FXWH 2UDO 7R[LFLW\
8SDQGGRZQ3URFHGXUH
$FNQRZOHGJPHQWV
3 2MHU WKDQNV WKH ³ *RELHUQR GH 1DYDUUD
'HSDUWDPHQWR GH (GXFDFLyQ´ DQG WKH
³$VRFLDFLyQ GH $PLJRV GH OD 8QLYHUVLGDG GH
1DYDUUD´IRUWKHJUDQWV
,;&RQJUHVRGHOD6(),*
0DWHULDOHV\PpWRGRV
0DWHULDOHV
([FLSLHQWHV &HOXORVD PLFURFULVWDOLQD $YLFHOŠ
3+ ORWH VRUELWRO 1HRVRUEŠ
3 ORWH ($' FDUER[LPHWLO DOPLGyQ
VyGLFR UHWLFXODGR ([SORWDEŠ ORWH (;
TXLWRVDQR 'D GHDFHWLODFLyQ
4LQJGDR 0LOHVWRQH %LRWHFK &R /7' VtOLFH
FRORLGDO $HURVLOŠ 99 3KDUPD ORWH
3ULQFLSLR DFWLYR +LGURFORURWLD]LGD ORWH
VXPLQLVWUDGD SRU *XLQDPD
(VSDxD
0pWRGRV
)RUPXODFLRQHVREMHWRGHHVWXGLR(QHOSUHVHQWH
HVWXGLR VH KDQ HODERUDGR \ HYDOXDGR IRUPXODFLRQHV TXH FRQWLHQHQ XQ GH
KLGURFORURWLD]LGD +&7 ORV SRUFHQWDMHV GH
VRUELWRO 625% FDUER[LPHWLO DOPLGyQ VyGLFR
UHWLFXODGR&0$6RTXLWRVDQRVtOLFH46TXH
VH LQGLFDQ HQ OD 7DEOD \ FHOXORVD
PLFURFULVWDOLQD
0&&
FVS
3UHSDUDFLyQ GHO GLVJUHJDQWH TXLWRVDQRVtOLFH
DFWLYR VH PH]FODURQ HQ 7XUEXODŠ7& PLQ
USP/DPH]FODVHKXPHFWyFRQDJXDHQXQD
PDOD[DGRUD SODQHWDULD .HQZRRGŠ PLQ
USP/DPDVDKXPHFWDGDVHH[WUX\yDWUDYpV
GH XQD PDOOD GH PP GH OX] HQ H[WUXVRU
&DOHYDŠ USP \ VH HVIHURQL]y HQ HTXLSR
&DOHYDŠ XWLOL]DQGR XQ SODWR GH IULFFLyQ GH
FPGHGLiPHWUR\XQDKHQGLGXUDGHPPGH
SURIXQGLGDGPLQUSP3RVWHULRUPHQWH
ORV SHOHWV VH VHFDURQ HQ HVWXID GH FLUFXODFLyQ
IRU]DGDGHDLUHK°&
&DUDFWHUL]DFLyQGHORVSHOHWV
7DPDxR\IRUPD6HGHWHUPLQySRUPLFURVFRStD
ySWLFD (VWHUHRPLFURVFRSLR 2O\PSXV6=&79
FRQHFWDGRDXQDYLGHRFiPDUD-9&7.6HO
GLiPHWURPHGLRGH)HUHW\ODFLUFXODULGDGGHDO
PHQRVSHOHWV(QWRGRVORVFDVRVORVGDWRV
VH DMXVWDURQ D XQD GLVWULEXFLyQ QRUPDO SDUD OD
TXH VH REWXYLHURQ ORV PHMRUHV UHVXOWDGRV HQ HO
DMXVWHFDOFXOiQGRVHSDUDFDGDIRUPXODFLyQORV
FRUUHVSRQGLHQWHV GLiPHWUR PHGLR \ GHVYLDFLyQ
HVWiQGDU/DIRUPDGHORVSHOHWVVHFDUDFWHUL]yD
WUDYpV GHO SDUiPHWUR FLUFXODULGDG FDOFXODGR
FRPRʌ$SGRQGH$HVHOiUHDSUR\HFWDGD\S
HO SHUtPHWUR SUR\HFWDGR $GLFLRQDOPHQWH VH
REWXYLHURQ IRWRPLFURJUDItDV GH ORV SHOHWV
XWLOL]DQGR XQ PLFURVFRSLR HOHFWUyQLFR GH
EDUULGR/HR93&DPEULGJH8.
9HORFLGDG GH GLVROXFLyQ /RV SHUILOHV GH
GLVROXFLyQGH+&7DSDUWLUGH PXHVWUDVGH
PJ GH SHOHWV VH REWXYLHURQ HQ DSDUDWR WLSR ,,
7XUX *UDX '7 %DUFHORQD (VSDxD GHVFULWR
HQOD863/RVHQVD\RVVHOOHYDURQDFDERHQ
PO GH +&O 1 D ž& FRQ ODV SDOHWDV
JLUDQGRDUSP/DFDQWLGDGGH+&7GLVXHOWD
D FDGD WLHPSR GH PXHVWUHR VH GHWHUPLQy SRU
HVSHFWURIRWRPHWUtD89GLUHFWD$JLOHQWD
QP3DUDODFDUDFWHUL]DFLyQGHODYHORFLGDG
GH GLVROXFLyQ GH +&7 D SDUWLU GH ODV GLVWLQWDV
IRUPXODFLRQHV VH XWLOL]DURQ ORV YDORUHV GH
SRUFHQWDMHGHGRVLVGH+&7GLVXHOWDHQPLQ
'
$QiOLVLVHVWDGtVWLFRGHORVUHVXOWDGRV(OWUDEDMR
H[SHULPHQWDO VH KD DGDSWDGR D OD HVWUXFWXUD GH
XQ GLVHxR IDFWRULDO SDUD WUHV YDULDEOHV DJHQWH
GLVJUHJDQWH SUHVHQFLD GH VRUELWRO \ SRUFHQWDMH
GH GLVJUHJDQWH HQ OD FRPSRVLFLyQ GH OD
IRUPXODFLyQ 3DUD OD FXDQWLILFDFLyQ GH ORV
HIHFWRVGHODVYDULDEOHVEDMRHVWXGLRVHDFXGLyD
OD UHJUHVLyQ P~OWLSOH VHFXHQFLDO 6WDWJUDSKLFV
Y
Q-S
5HVXOWDGRV\GLVFXVLyQ
(Q OD WDEOD VH KDQ DJUXSDGR ORV UHVXOWDGRV
REWHQLGRV HQ OD FDUDFWHUL]DFLyQ GH ODV GLVWLQWDV
IRUPXODFLRQHV REMHWR GH HVWXGLR 'H VX
REVHUYDFLyQFDEHGHVWDFDUHQSULPHUOXJDUTXH
ODV SURSLHGDGHV GH ORV SHOHWV GHVGH SXQWR GH
YLVWD PRUIROyJLFR VRQ DGHFXDGDV $Vt HQ
QLQJ~Q FDVR VH REVHUYDURQ HIHFWRV
VLJQLILFDWLYRV GH ORV SURFHVRV GH DJORPHUDFLyQ
HQ OD HWDSD GH HVIHURQL]DFLyQ $GHPiV ORV
YDORUHVREWHQLGRVSDUDHOSDUiPHWURFLUFXODULGDG
SHUPLWHQFRQFOXLUXQDQRWDEOHHVIHULFLGDGGHORV
SHOHWV SDUD FXDOTXLHUD GH ODV IRUPXODFLRQHV
HQVD\DGDV/DVIRWRPLFURJUDItDVGHPLFURVFRStD
HOHFWUyQLFD GH EDUULGR REWHQLGDV SDUD DOJXQDV
IRUPXODFLRQHV WLSR )LJ UDWLILFDQ ODV
DILUPDFLRQHVDQWHULRUHV
%
$
)LJ)RWRPLFURJUDItDVGHPLFURVFRStDHOHFWUyQLFDGHEDUULGR
GH625%&0$6$\625%46%
(Q ORV HVWXGLRV GH YHORFLGDG GH GLVROXFLyQ GH
+&7 VH KDQ GHWHFWDGR GLIHUHQFLDV LPSRUWDQWHV
HQWUH ODV GLIHUHQWHV IRUPXODFLRQHV )LJ /D
SUHVHQFLD GH 46 LQFUHPHQWD OD YHORFLGDG GH
GLVROXFLyQ GH SULQFLSLR DFWLYR HQ WRGDV ODV
IRUPXODFLRQHV HQ ODV TXH VH KDOOD SUHVHQWH (O
100
100
% hidroclorotiazida liberada
ÈOYDUR*R\DQHV&RQVXHOR6RXWR5DPyQ0DUWtQH]3DFKHFR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DQWLDJR
GH&RPSRVWHOD6DQWLDJRGH&RPSRVWHOD(VSDxD
HPDLOUDPRQPDUWLQH]#XVFHV
3DUD VX SUHSDUDFLyQ VH VLJXLy OD PHWRGRORJtD
,QWURGXFFLyQ
/D FHOXORVD PLFURFULVWDOLQD 0&& HV HO
GHVFULWD SRU (O%DUJKRXWKL (O TXLWRVDQR VH
H[FLSLHQWH PiV XWLOL]DGR SDUD OD HODERUDFLyQ GH
GLVSHUVDHQXQDGLVROXFLyQGH+&O0\ODVtOLFH
SHOHWVSRUH[WUXVLyQHVIHURQL]DFLyQGHELGRDTXH
FRORLGDO HQ XQD GLVROXFLyQ GH 1D2+ 0 D OD
SURSRUFLRQD
PDVDV
KXPHFWDGDV
FRQ
TXHSRVWHULRUPHQWHVHDGLFLRQDDJXDGHVWLODGD
FDUDFWHUtVWLFDV GH SODVWLFLGDG \ DGKHVLYLGDG
/DVXVSHQVLyQGHTXLWRVDQRVHDxDGHOHQWDPHQWH
~QLFDV 6LQ HPEDUJR ORV SHOHWV HODERUDGRV
DODVXVSHQVLyQGHVtOLFHEDMRDJLWDFLyQFRQWLQXD
FRQ 0&& FRPR H[FLSLHQWH EDVH QR
GXUDQWH KRUD (O FRSUHFLSLWDGR IRUPDGR VH
H[SHULPHQWDQ XQ SURFHVR GH GLVJUHJDFLyQ HQ
ODYDVHILOWUD\VHVHFDHQKRUQRDž&
PHGLR DFXRVR \ FRPR FRQVHFXHQFLD GH HOOR
7DEOD
&RPSRVLFLyQ\SURSLHGDGHVGHODVIRUPXODFLRQHVREMHWRGHHVWXGLR
H[KLEHQ XQD OHQWD YHORFLGDG GH FHVLyQ GH
7DPDxR
+7&
SULQFLSLR DFWLYR HQ HVSHFLDO VL VX
)RUPXODFLyQ
PHGLR“GV &LUFXODULGDGGV GLVXHOWD
KLGURVROXELOLGDGHVUHGXFLGD
—P
PLQ
3DUD REYLDU HVWD OLPLWDFLyQ VH KDQ SURSXHVWR
0&&
“ [ GLIHUHQWHV DOWHUQDWLYDV WHFQROyJLFDV HQWUH ODV
&0$6
“ [
TXH FDEH GHVWDFDU OD LQFRUSRUDFLyQ GH
&0$6
“ [
VXSHUGLVJUHJDQWHV R OD VXVWLWXFLyQ SDUFLDO GH OD
46
“ [
0&&SRUH[FLSLHQWHVKLGURVROXEOHV
46
“ [
(Q HO SUHVHQWH HVWXGLR VH HYDO~D GH IRUPD
625%
“ [
FRPSDUDWLYD OD HILFDFLD GH GRV DJHQWHV
GLVJUHJDQWHV XQR FRPHUFLDO FDUER[LPHWLO
625%&0$6 “ [
DOPLGyQ VyGLFR UHWLFXODGR \ RWUR TXLWRVDQR
625%&0$6
“ [
VtOLFH SURSXHVWR UHFLHQWHPHQWH SRU (O
625%46
“ [
%DUJKRXWKL \ FRO 7DPELpQ VH DQDOL]D XQ
625%46
“ [
SRVLEOH HIHFWR VLQpUJLFR DVRFLDGR D OD
GHODGLVWULEXFLyQGHWDPDxRV
LQFRUSRUDFLyQVLPXOWiQHDDORVSHOHWVGHVRUELWRO
FRPRH[FLSLHQWHGHPDUFDGDKLGURVROXELOLGDG
(ODERUDFLyQ GH SHOHWV ([FLSLHQWHV \ SULQFLSLR
16
Figure 2. Record weight to 14 days after
single oral dose of 2000 mg/kg. Error bars
represented standard deviations (n=5
100
% hidroclorotiazida liberada
14
120
CMAS
(678',2&203$5$7,92'(&$5%2;,0(7,/$/0,'2162',&25(7,&8/$'2<
48,726$126,/,&(&202$*(17(6',6*5(*$17(6(13(/(76'(&(/8/26$
0,&52&5,67$/,1$+,'52&/2527,$=,'$(/$%25$'26325(;7586,21
(6)(521,=$&,21
12
TTO 1: Gantrez® AN; TTO2: Np; TTO3: HP-ȕ-CD Np; TTO4:
PEG2000 Np; C.1: Deionized water; C.2: Lactose 66.67
mg/mL
24 h
48 h
72 h
140
8
Days
HPCD Np Concentrations
5HVXOWVDQGGLVFXVVLRQ
Table 1. Physico-chemical characterization of poly(anhydride) nanoparticles
200
20
0
7KH SK\VLFDO FKHPLFDO FKDUDFWHULVWLFV RI WKH
QDQRSDUWLFOHV DUH VKRZQ LQ 7DEOH $OO WKH
QDQRSDUWLFOH IRUPXODWLRQV GLVSOD\HG D VL]H RI
DERXW QP DQG D QHJDWLYH VXUIDFH FKDUJH
)RU +3&'1S WKH DPRXQW RI DVVRFLDWHG
F\FORGH[WULQ ZDV FDOFXODWHG WR EH DERXW —JPJ :KHUHDV IRU 3(*1S WKH DPRXQW
RI 3(* DVVRFLDWHG WR QDQRSDUWLFOHV ZDV
DERXW—JPJ
220
100
% Cell Viability
,QWURGXFWLRQ
30 min
3h
24 h
140
120
% Cell Viability
,;&RQJUHVRGHOD6(),*
Weight (grames)
7HFQRORJtD)DUPDFpXWLFD
80
60
MCC
CMAS2,5
CMAS5
SORB50
SORB50/CMAS2,5
SORB50/CMAS5
40
20
80
60
MCC
Q-S2.5
Q-S5
SORB50
SORB50/Q-S2.5
SORB50/Q-S5
40
20
0
0
0
100
200
300
Tiempo (min)
400
500
0
100
200
300
400
500
Tiempo (min)
)LJ&XUYDVDFXPXODGDVGHGLVROXFLyQGH+&7SDUDODVIRUPXODFLRQHV
LQFUHPHQWR DGLFLRQDO GH OD YHORFLGDG GH
GLVROXFLyQ GH +&7 HQ ODV IRUPXODFLRQHV TXH
LQFRUSRUDQ 625% SXHGH MXVWLILFDUVH SRU OD
UiSLGD\FRPSOHWDGLVJUHJDFLyQGHORVSHOHWV(Q
FDPELRODLQFRUSRUDFLyQGH&0$6DSHOHWVTXH
LQFOX\HQ 625% HQ VX FRPSRVLFLyQ UHGXFH OD
YHORFLGDG GH GLVROXFLyQ GH +&7 (VWH HIHFWR
QHJDWLYR GH OD &0$6 TXH DFRPSDxD D OD QR
GLVJUHJDFLyQ GH ORV SHOHWV SRGUtD DWULEXLUVH D
XQDFRPSHWLFLyQSRUODFDSWDFLyQGHDJXDFRQHO
625% H[FLSLHQWH PDUFDGDPHQWH KLGURVROXEOH
/RV HIHFWRV GH ODV YDULDEOHV EDMR HVWXGLR VREUH
HO SDUiPHWUR ' WDEOD VH KDQ FXDQWLILFDGR
SRU UHJUHVLyQ P~OWLSOH REWHQLpQGRVH OD
VLJXLHQWHHFXDFLyQ
' [&0$6[46[625%
5 TXH SRQH FODUDPHQWH GH PDQLILHVWR TXH OD
SUHVHQFLD R HO LQFUHPHQWR HQ OD SURSRUFLyQ GH
625%\46HQORVSHOHWVDIHFWDQSRVLWLYDPHQWH
DORVYDORUHVGH'
/D HFXDFLyQ WDPELpQ SRQH GH PDQLILHVWR OD
LQH[LVWHQFLDGHLQWHUDFFLRQHVHQWUHODVGLIHUHQWHV
YDULDEOHV HV GHFLU OD DGLWLYLGDG VLQ VLQHUJLDV
GHORVHIHFWRVGHODVYDULDEOHVEDMRHVWXGLRVREUH
HOSURFHVRGHGLVROXFLyQGH+&7
&RQFOXVLRQHV
(O TXLWRVDQRVtOLFH UHVXOWD FODUDPHQWH PiV
HILFD] TXH HO FDUER[LPHWLO DOPLGyQ VyGLFR
UHWLFXODGR HQ OD SURPRFLyQ GH OD YHORFLGDG GH
GLVROXFLyQ GH +&7 HQ SHOHWV HODERUDGRV FRQ
0&&FRPRH[FLSLHQWHEDVH
$GHPiV OD LQFRUSRUDFLyQ GH TXLWRVDQRVtOLFH D
SHOHWV FRQWHQLHQGR XQ GH VRUELWRO SURYRFD
VXUiSLGDGLVJUHJDFLyQHQPHGLRDFXRVR
5HIHUHQFLDV
. ( )LHOGHQ HWDO ,QW - 3KDUP &6RXWRHWDO(XU-3KDUP%LRSKDUP
0 (O%DUJKRXWKL HWDO 'UXJ 'HY ,QG 3KDUP
- 5 -RKQVRQ HWDO - 3KDUP 6FL $JUDGHFLPLHQWRV
7UDEDMR ILQDQFLDGR SRU OD ;XQWD GH *DOLFLD
&6$35 ([FLSLHQWHV GRQDGRV SRU
(YRQLN,QGXVWULHV\SRU5RTXHWWH/DLVD(VSDxD
7HFQRORJtD)DUPDFpXWLFD
)yUPXOD
0.006
0.005
0.004
AU
0.014
0.003
0.012
0.002
0.010
AU
0.001
0.008
0.006
0.000
0.004
2.00
4.00
6.00
8.00
10.00
12.00
14.00
0.002
Minutes
0.000
2.00
0.012
4.00
6.00
8.00
10.00
12.00
14.00
Minutes
0.010
0.008
0.006
0.004
0.002
0.000
2.00
4.00
6.00
8.00
10.00
12.00
14.00
Minutes
)LJXUD &URPDWRJUDPDV GH OD IyUPXOD IyUPXOD EDVH HQVD\DGD D S+ \ VLPXODFLyQGHHVWyPDJRYDFtR\OOHQRFRQORV
UHVXOWDGRVREWHQLGRVDODVGRVKRUDVGHOHQVD\R
6H REVHUYD FRPR D S+ QR H[LVWH HO SLFR
FRUUHVSRQGLHQWH D RPHSUD]RO OR TXH QRV LQGLFD
VX GHVWUXFFLyQ VL VH DSUHFLDQ GLYHUVRV SLFRV D
ORV GRV PLQXWRV FRUUHVSRQGLHQWHV D ORV
GLIHUHQWHV SURGXFWRV GH GHJUDGDFLyQ GHO
IiUPDFR
$ S+ VH GHWHFWD HO SLFR GHO RPHSUD]RO DVt
FRPRORVSLFRVGHVXV PHWDEROLWRVSHURPHQRV
DFHQWXDGRV TXH HQ HO S+ VLHQGR HO
RPHSUD]ROHQFRQWUDGRGHXQORTXHQRV
LQGLFD HQ XQD SULPHUD LQVWDQFLD TXH HO
LQFUHPHQWR GH S+ SURGXFH PHQRV DOWHUDFLyQ \
FRQILUPDODLPSRUWDQFLDGHOS+HQODHVWDELOLGDG
GHOIiUPDFR
)yUPXOD
)yUPXOD
0.012
AU
0.010
)LJXUD&URPDWRJUDPDVGHODVIyUPXODV
\ HQVD\DGDV D S+ FRQ ORV UHVXOWDGRV
REWHQLGRVDODVGRVKRUDVGHOHQVD\R
/RVFURPDWRJUDPDVQRVPXHVWUDQTXHHQWRGDV
ODVIRUPXODFLRQHVDSDUHFHHOSLFRGHRPHSUD]RO
GH IRUPD DFHQWXDGD SHUR WDPELpQ VH
HQFXHQWUDQ SURGXFWRV GH GHVFRPSRVLFLyQ SHUR
HV OD IyUPXOD OD TXH PD\RU SURWHFFLyQ KD
HMHUFLGR(QGLFKDVUHSUHVHQWDFLRQHVJUiILFDVVH
REVHUYD FRPR OD YDULDFLyQ GH FRQFHQWUDFLyQ GH
RPHSUD]ROHQHOPHGLRGHHVWXGLRWUDVPLQ
HQ IXQFLyQ GH OD YDULDFLyQ GH DQWLiFLGRV QR
PXHVWUDGLIHUHQFLDVPX\VLJQLILFDWLYDV
&RQFOXVLRQHV
/D LQFOXVLyQ GH DQWLiFLGRV HQ OD IRUPXODFLyQ
PHMRUDODHVWDELOLGDGGHOIiUPDFR
5HIHUHQFLDV
&DVWUR ' \ FROV - 3KDUP %LRPHG $QDO
5LHGHO $ \ FROV 3KDUPD]LH $JUDGHFLPLHQWRV
)LQDQFLDO VXSSRUW IURP &,&<7 6SDLQ XQGHU
3URMHFW 0$7&2 IURP -XQWD
GH $QGDOXFLD 6SDLQ XQGHU 3URMHFW )40 DQG IURP )('(5 )XQGV DUH JUDWHIXOO\
DFNQRZOHGJHG
0.008
0.006
0.004
0.002
0.000
2.00
4.00
6.00
8.00
10.00
12.00
14.00
10.00
12.00
14.00
Minutes
0.014
0.012
0.010
AU
,1)/8(1&,$'(/26$17,È&,'26(1/$(67$%,/,'$''(20(35$=2/
0/ySH]9LRWD-/$ULDV0$5XL]9*DOODUGR
MODULDV#XJUHV
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD
8QLYHUVLGDGGH*UDQDGD
,QWURGXFFLyQ
7DEOD &RPSRVLFLyQ GH WRGDV ODV
2PHSUD]RO HV XQ VXVWLWXWR EHQ]LPLGD]RO TXH
IRUPXODFLRQHVHVWXGLDGDV
LQKLEHODVHFUHFLyQJiVWULFDSRUDOWHUDFLyQHQOD
DFWLYLGDG GH OD + . $73DVD TXH HV HO SDVR
ILQDO FRP~Q GH OD VHFUHFLyQ GH iFLGR HQ ODV
2PHSUD]RO
FpOXODVSDULHWDOHV6HXVDHQHOWUDWDPLHQWR
$OPLGyQ
GH ODV ~OFHUDV SpSWLFDV OD HVRIDJLWLV SRU UHIOXMR
$O2+
\ VtQGURPH GH =ROOLQJHU(OOLVRQ (V XQD EDVH
0J2+
GpELOPHQWH OLSRItOLFD FRQ XQ S.D \ XQ
-DUDEH
3.D \ HV GHJUDGDGR D PHQRV TXH VHD
VLPSOH
SURWHJLGRGHODVFRQGLFLRQHViFLGDV
(O +3/& HV HO PpWRGR RILFLDO SURSXHVWR SRU OD
/D IRUPXOD FRUUHVSRQGH D XQ JUDQXODGR
863 SDUD OD GHWHUPLQDFLyQ \ FXDQWLILFDFLyQ
VLPSOHODVIyUPXODVLQFRUSRUDQDQWLiFLGRVD
GHO RPHSUD]RO (VWH SURFHGLPLHQWR SXHGH VHU
GLVWLQWDVFRQFHQWUDFLRQHV
XWLOL]DGR HQ ORV HVWXGLRV GH HVWDELOLGDG \D TXH
QRVHSURGXFHQLQWHUIHUHQFLDVHQWUHHOIiUPDFR\
9DORUDFLyQGHODVIRUPXODFLRQHV
VXVSURGXFWRVGHGHJUDGDFLyQ
(O REMHWLYR GH HVWH HVWXGLR HV GHWHUPLQDU OD
/RV
HQVD\RV
OOHYDGRV D FDER SHUVLJXHQ HO
HVWDELOLGDG GHO RPHSUD]RO HQ XQ PHGLR TXH
HVWXGLR GH ODV SULQFLSDOHV FDUDFWHUtVWLFDV GH ODV
SUHWHQGH VLPXODU GH XQ PRGR DSUR[LPDGR ODV
IRUPXODFLRQHVTXHGHWHUPLQDUiQVXLGRQHLGDGD
FRQGLFLRQHV GH WHPSHUDWXUD \ S+ D ODV TXH VH
ODKRUDGHVHUDGPLQLVWUDGDV
HQFXHQWUD VRPHWLGR HO IiUPDFR GXUDQWH ODV GRV
&RQRFLGD OD LQHVWDELOLGDG GHO RPHSUD]RO HQ
KRUDV VLJXLHQWHV D OD DGPLQLVWUDFLyQ RUDO GHO
PHGLR D S+ iFLGR KDEUi TXH YDORUDU OD
SUHSDUDGR
FDSDFLGDGGHODVXVSHQVLyQREWHQLGDDSDUWLUGH
ORVJUDQXODGRVSDUDFRQVHUYDUODHVWDELOLGDGGHO
IiUPDFRDXQS+GHDFLGH]HTXLYDOHQWHDODGHO
0DWHULDOHV\0pWRGRV
HVWyPDJR 6H XWLOL]DURQ GRV PHGLRV FRQ S+
GLVWLQWR FRQ HO HVWyPDJR YDFtR \ OOHQR /D
/RVSHOOHWVGH2PHSUD]ROSRVHHQXQFRQWHQLGR
YDORUDFLyQGHRPHSUD]ROVHUHDOL]DSRU+3/&
HQ RPHSUD]RO GH PJJ VXPLQLVWUDGRV SRU
DFRIDUPD 0DGULG (VSDxD (O DOPLGyQ GH
3UHSDUDFLyQGHPXHVWUDV
PDt] +LGUy[LGR GH DOXPLQLR +LGUy[LGR GH
PDJQHVLR IXHURQ VXPLQLVWUDGRV SRU *XLQDPD
6H UHDOL]D DGLFLRQDQGR J GH JUDQXODGR HQ
9DOHQFLD(VSDxD
PO GH DJXD /D GRVLV DGPLQLVWUDGD TXH VH
/D IRUPD IDUPDFpXWLFD RUDO TXH VH SUHSDUD VRQ
UHDOL]D HQ HVWH HQVD\R HV VLPLODU D OD GH XQ
JUDQXODGRV\DTXHORVHVWXGLRVKDQGHPRVWUDGR
JUDQXODGRHQVREUHVPRQRGRVLV/DGXUDFLyQGHO
TXH HO SURFHVR GH JUDQXODFLyQ HQ JHQHUDO
HQVD\R WLHQH FRPR ILQDOLGDG UHSUHVHQWDU GH
LQFUHPHQWD OD GLVROXFLyQ GH IiUPDFRV SRFR
DOJ~Q PRGR HO WLHPSR TXH RPHSUD]RO KD GH
VROXEOHV FRPR HV HO RPHSUD]RO (O XVR GH
UHVLVWLU ODV FRQGLFLRQHV GH DFLGH] GHO HVWyPDJR
GLOX\HQWHV FRPR HO DOPLGyQ GH PDt] WLHQGH D
KDVWDOOHJDUDDEVRUEHUVH
DXPHQWDU OD KLGURILOLD GH ORV LQJUHGLHQWHV
DFWLYRV \ PHMRUDU VXV FDUDFWHUtVWLFDV GH
5HVXOWDGRV\'LVFXVLyQ
GLVROXFLyQ (Q HVWH DVSHFWR HO SURFHGLPLHQWR
TXH VH XWLOL]D HV OD JUDQXODFLyQ K~PHGD
/DYDORUDFLyQSRU+3/&GHRPHSUD]ROPXHVWUD
XWLOL]DQGRMDUDEHVLPSOH
XQ FURPDWRJUDPD RULJLQDO HQ HO TXH VH REVHUYD
FRPR DJOXWLQDQWH /D GHVHFDFLyQ GHO JUDQXODGR
XQ WLHPSR GH UHWHQFLyQ SDUD RPHSUD]RO GH VHUHDOL]DDWHPSHUDWXUDDPELHQWHGXUDQWHK
PLQXWRV \ HO GH VX LPSXUH]D VXOIRQD GH
RPHSUD]ROGHPLQ
,;&RQJUHVRGHOD6(),*
0.008
0.006
0.004
0.002
0.000
2.00
4.00
6.00
8.00
Minutes
7HFQRORJtD)DUPDFpXWLFD
(1&$368/$&,Ï1'()È50$&26$17,55(7529,5$/(6(1/(8&2&,726
32/,025)218&/($5(6
&*XWLpUUH]0LOOiQ0/6D\DOHUR0DULQHUR-0/DQDR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DODPDQFD
F/LFHQFLDGR0pQGH]1LHWRVQ6DODPDQFD
,QWURGXFFLyQ
/D XWLOL]DFLyQ GH SRUWDGRUHV FHOXODUHV IUHQWH D
RWURV VLVWHPDV SRUWDGRUHV WUDGLFLRQDOHV KD VLGR
XQ FDPSR GH LQYHVWLJDFLyQ IDUPDFpXWLFD GH
DPSOLR GHVDUUROOR HQ ORV ~OWLPRV DxRV FRQ
LQWHUHVDQWHV YHQWDMDV VREUH ORV VLVWHPDV
YHFWRULDOHV WUDGLFLRQDOHV FRPR VX HYLGHQWH
ELRFRPSDWLELOLGDG\IDOWDGHWR[LFLGDG
$VtVHKDQREWHQLGRVLVWHPDVSRUWDGRUHVDSDUWLU
GH FpOXODV WDQ YDULDGDV FRPR EDFWHULDV
HULWURFLWRV OHXFRFLWRV SROLPRUIRQXFOHDUHV
FpOXODV WXPRUDOHV FpOXODV GHQGUtWLFDV R FpOXODV
PDGUHHQWUHRWUDV
8QD DGHFXDGD PDQLSXODFLyQ GH ODV GLVWLQWDV
FpOXODVHQFDGDFDVRKDSHUPLWLGRHQFDSVXODUHQ
VX LQWHULRU IiUPDFRV X RWUDV VXVWDQFLDV GH
LPSRUWDQWHXWLOLGDGWHUDSpXWLFD
(QODSUHVHQWHLQYHVWLJDFLyQVHEXVFDGHVDUUROODU
XQ
VLVWHPD
SRUWDGRU
GH
IiUPDFRV
DQWLUUHWURYLUDOHV
EDVDGR
HQ
OHXFRFLWRV
SROLPRUIRQXFOHDUHV301
5HFLHQWHPHQWH VHKDQHQFRQWUDGRHYLGHQFLDVGH
TXHORVQHXWUyILORV\RWUDVFpOXODV&'SXHGHQ
MXJDU XQ LPSRUWDQWH SDSHO HQ OD LQIHFFLyQ SRU
9,+/DHQFDSVXODFLyQHQ301GHIiUPDFRV
DQWLUUHWURYLUDOHV GHEH SHUPLWLU VX DFXPXODFLyQ
VHOHFWLYD HQ ORV PDFUyIDJRV FXDQGR ORV 301
DSRSWySLFRVVRQIDJRFLWDGRVSRUHVWRV
0DWHULDOHV\0pWRGRV
3DUD
HO
DLVODPLHQWR
GH
OHXFRFLWRV
SROLPRUIRQXFOHDUHV VH SDUWLy GH VDQJUH H[WUDtGD
SRUSXQFLyQUHWURRUELWDOGHUDWDV:LVWDUPDFKR
\VHVRPHWLyD XQIUDFFLRQDPLHQWRHQJUDGLHQWH
GHGHQVLGDG
7UDVODFHQWULIXJDFLyQVHUHFRJLyODIUDFFLyQTXH
FRQWHQtDPD\RULWDULDPHQWH301\VHVRPHWLyD
XQ SURFHGLPLHQWR GH OLVLV GH HULWURFLWRV
FRQWDPLQDQWHV SDUD DXPHQWDU VX SXUH]D HQ
OHXFRFLWRVSROLPRUIRQXFOHDUHV
3DUD HOOR VH LQFXEDURQ ODV FpOXODV FRQ XQD
VROXFLyQGHOLVLV1+&OJ/1D+&2
J/ D WHPSHUDWXUD DPELHQWH VHJXLGR GH RWUD
LQFXEDFLyQFRQ3%6OLEUHGHFDOFLR\PDJQHVLR
)LQDOPHQWH OD VXVSHQVLyQ GH FpOXODV IXH
QXHYDPHQWHFHQWULIXJDGD[JPLQXWRVHO
VREUHQDGDQWHUHWLUDGR\HOSHOOHWFRQWHQLHQGRORV
301IXHUHVXVSHQGLGRHQP/GH3%6OLEUH
GHFDOFLR\PDJQHVLR
(Q OD )LJXUD TXHGD UHFRJLGR XQ HVTXHPD GHO
PpWRGRGHDLVODPLHQWRGHORV301
Tampón de lisis
PBS
1000 x g
40 miun
7UDQVFXUULGRHOWLHPSRGHLQFXEDFLyQVHUHDOL]y
RWURODYDGRFRQ3%6OLEUHGHFDOFLR\PDJQHVLR
\ ILQDOPHQWH VH UHVXVSHQGLHURQ HQ HO PLVPR
WDPSyQ
/D FRQFHQWUDFLyQ GH DQWLUUHWURYLUDO HQFDSVXODGR
HQ301VVHGHWHUPLQyPHGLDQWHXQDWpFQLFDGH
+3/& GH IDVH UHYHUVD \ GHWHFFLyQ XOWUDYLROHWD
λ QP
XWLOL]DQGR XQD FROXPQD
/L&KUR&$57 5HVXOWDGRV\'LVFXVLyQ
/D FHQWULIXJDFLyQ HQ JUDGLHQWH GH GHQVLGDG
SHUPLWHREWHQHUXQDVHULHGHEDQGDVRIUDFFLRQHV
SHUIHFWDPHQWH GLIHUHQFLDGDV HQ ODV TXH TXHGDQ
ORV GLIHUHQWHV WLSRV GH FpOXODV VDQJXtQHDV HQ
IXQFLyQGHVXGHQVLGDG
/D XWLOL]DFLyQ GH GLVWLQWRV PHGLRV GH JUDGLHQWH
GD OXJDU D GLIHUHQWH IUDFFLRQDPLHQWR GH ODV
FpOXODV VDQJXtQHDV WDO \ FRPR UHFRJH OD )LJXUD
B
A
PBS
300 x g
7 min
sobrenadante
Suspensión de PMNs
)LJXUD 0pWRGR GH DLVODPLHQWR GH OHXFRFLWRV
SROLPRUIRQXFOHDUHVDSDUWLUGHVDQJUHSHULIpULFD
GHUDWD
6H UHDOL]DURQ HQVD\RV FRQ GLVWLQWRV PHGLRV
FRPHUFLDOHV SDUD JUDGLHQWHV GH GHQVLGDG FRPR
GH[WUDQ +LVWRSDTXH \ 3HUFROO GH GLVWLQWDV
GHQVLGDGHVVRORVRHQFRPELQDFLyQGHXQRVFRQ
RWURV
$OtFXRWDV GH ODV GLIHUHQWHV EDQGDV R IUDFFLRQHV
REWHQLGDV WUDV OD FHQWULIXJDFLyQ HQ JUDGLHQWH GH
GHQVLGDG IXHURQ DQDOL]DGDV FRQ XQ
KHPDWRDQDOL]DGRU 6\VPH[ FRQ REMHWR GH
FRQRFHU HO UHFXHQWR GLIHUHQFLDO FHOXODU GH FDGD
XQDGHHOODV
7UDV GLVWLQWDV SUXHEDV VH HVWDEOHFLy FRPR
SURFHGLPLHQWR ySWLPR GH DLVODPLHQWR GH
OHXFRFLWRV SROLPRUIRQXFOHDUHV GH UDWD HO
IUDFFLRQDPLHQWR GH VDQJUH SHULIpULFD HQ XQ
JUDGLHQWHVHQFLOORGH3HUFROODO
8QD YH] DLVODGRV ORV 301 VH SURFHGLy D
LQFXEDUORVFRQIiUPDFRVDQWLUUHWURYLUDOHVFRPR
=LGRYXGLQD \ (VWDYXGLQD D FRQFHQWUDFLRQHV
FOtQLFDPHQWH UHOHYDQWHV SDUD IDYRUHFHU OD
FDSWDFLyQGHOIiUPDFRSRUSDUWHGHODVFpOXODV
&LQFR PLOLOLWURV GH VDQJUH IXHURQ GHSRVLWDGRV
VREUH WUHV PLOLOLWURV GH 3HUFROO DO \ VH
FHQWULIXJy D [ J GXUDQWH PLQXWRV D
WHPSHUDWXUDDPELHQWH
,;&RQJUHVRGHOD6(),*
PMN
Percoll al 56 %
3DUD HOOR D OD VXVSHQVLyQ GH FpOXODV
FRQWHQLHQGRXQDFDQWLGDGFRQRFLGDGH301VVH
DxDGLy XQD GLVROXFLyQ GH IiUPDFR HQ 3%6 OLEUH
GH FDOFLR \ PDJQHVLR GXUDQWH KRUD D ž&
EDMRDJLWDFLyQVXDYH
PMNs
)LJXUD,PDJHQGHODVEDQGDVREWHQLGDVWUDV
OD FHQWULIXJDFLyQ HQ JUDGLHQWH GH GHQVLGDG
VHQFLOOR$\GREOH%
/D FRPSRVLFLyQ GH HVWDV EDQGDV YDUtD HQ
IXQFLyQ GHO PHGLR HOHJLGR VL ELHQ ORV
SROLPRUIRQXFOHDUHV
VXHOHQ
HQFRQWUDUVH
PD\RULWDULDPHQWH HQ OD PLVPD IUDFFLyQ TXH ORV
HULWURFLWRV
/DV GLIHUHQWHV EDQGDV IXHURQ UHFRJLGDV \
DQDOL]DGDVSDUDFRQRFHUODULTXH]DHQ301VGH
FDGD XQD GH HOODV FRPR TXHGD UHFRJLGR HQ OD
7DEOD
7DEOD 3RUFHQWDMH PHGLD “ '( GH
OHXFRFLWRV SROLPRUIRQXFOHDUHV UHVSHFWR D
OHXFRFLWRVWRWDOHVHQHOSHOOHWILQDO
0HGLRGHJUDGLHQWH
+LVWRSDTXH
+LVWRSDTXH\
3HUFROO\
3HUFROO
3HUFROO
301V
“
“
“
“
“
(Q YLVWD GH ORV UHVXOWDGRV VH HVWDEOHFLy HO
JUDGLHQWH VHQFLOOR GH 3HUFROO DO FRPR HO
PHMRU PHGLRGH JUDGLHQWHSDUDDLVODU OHXFRFLWRV
SROLPRUIRQXFOHDUHV D SDUWLU GH VDQJUH SHULIpULFD
GHUDWD
/D DGLFLyQ GH OD HWDSD GH OLVLV FRQ OOHYy XQ
HQULTXHFLPLHQWR GH OD IUDFFLyQ HQ 301V MXQWR
FRQ OD UHGXFFLyQ GH OD FRQWDPLQDFLyQ SRU
HULWURFLWRVREWHQLpQGRVHSRUFHQWDMHVGHKDVWDHO
GHOHXFRFLWRVSROLPRUIRQXFOHDUHVHQSHOOHW
7UDVODLQFXEDFLyQ\SRVWHULRUODYDGRGHOSHOOHW
VH REWXYR XQ EXHQ UHQGLPLHQWR GH OHXFRFLWRV
SROLPRUIRQXFOHDUHV FRQWHQLHQGR IiUPDFRV
DQWLUUHWURYLUDOHV TXH SRGUtDQ FRQVWLWXLU XQ
LQWHUHVDQWH SRUWDGRU ELROyJLFR SDUD HVWH WLSR GH
IiUPDFRV
&RQFOXVLRQHV
6HKDSXHVWRDSXQWRXQPpWRGRGHDLVODPLHQWR
GH OHXFRFLWRV SROLPRUIRQXFOHDUHV D SDUWLU GH
VDQJUHSHULIpULFDGHUDWDV
6H KD OOHYDGR D FDER OD HQFDSVXODFLyQ GH
IiUPDFRV DQWLUUHWURYLUDOHV HQ OHXFRFLWRV
SROLPRUIRQXFOHDUHVGHUDWD
%LEOLRJUDItD
/DQDR-06D\DOHUR0/&HOOVDQGFHOO
JKRVWVDVGUXJFDUULHUV,Q1DQRSDUWLFXODWHVDV
'UXJ&DUULHUV±
3LHULJp ) HW DO $GY 'UXJ 'HOLY 5HY
2OLQJHU ** HW DO - 9LURO 0XQWDQX /0 HW DO 5RPDQLDQ -
%LRSK\V
&DYDOFDQWL '0+ HW DO 0ROO &HOO
(QGRFULQRO
$JUDGHFLPLHQWRV
(O SUHVHQWH WUDEDMR KD VLGR ILQDQFLDGR FRQ ORV
SUR\HFWRVGHLQYHVWLJDFLyQHOSUR\HFWR3,
GHO 3ODQ 1DFLRQDO GH ,'L \ HO SUR\HFWR
6$$GHOD-XQWDGH&DVWLOOD\/HyQ
,QWURGXFFLyQ
/RV VLVWHPDV GH JHOLILFDFLyQ LQ VLWX WLHQHQ XQ
JUDQLQWHUpVSDUDGHVDUUROODULQ\HFWDEOHVTXHD
WHPSHUDWXUD DPELHQWH SUHVHQWDQ XQD
YLVFRVLGDG
EDMD
\
VRQ
IiFLOPHQWH
DGPLQLVWUDEOHV PLHQWUDV TXH D OD WHPSHUDWXUD
FRUSRUDO DGTXLHUHQ XQD YLVFRVLGDG HOHYDGD \
IRUPDQ GHSyVLWRV GH JHO HQ HO OXJDU GH
DSOLFDFLyQ /D JHOLILFDFLyQ LQ VLWX SHUPLWH
UHJXODUODYHORFLGDGGHOLEHUDFLyQGHVXVWDQFLDV
ELRDFWLYDV GH HVWUXFWXUD GLYHUVD /RV
FRSROtPHURV EORTXH GH SROLy[LGR GH HWLOHQR
SROLy[LGRGHSURSLOHQRSROLy[LGRGHHWLOHQR
3(23323(2 GH OD IDPLOLD GH ORV
SROR[DPHU R 3OXURQLF® H[SHULPHQWDQ
WUDQVLFLRQHV VROJHO D OD WHPSHUDWXUD FRUSRUDO
FXDQGR OD FRQFHQWUDFLyQ GH FRSROtPHUR HV
VXILFLHQWHPHQWH DOWD 1R REVWDQWH OD EDMD
FRQVLVWHQFLD\ODHOHYDGDSHUPHDELOLGDGGHORV
JHOHVGH3OXURQLFOOHYDQFRQVLJRTXHHOWLHPSR
GH SHUPDQHQFLD HQ HO OXJDU GH DSOLFDFLyQ VHD
UHODWLYDPHQWH FRUWR \ TXH VX FDSDFLGDG SDUD
UHWHQHU VXVWDQFLDV DFWLYDV UHVXOWH LQVXILFLHQWH
(OREMHWLYRGHHVWHWUDEDMRIXHHYDOXDUODV
SRVLELOLGDGHV TXH RIUHFH OD LQFRUSRUDFLyQ GH
SROtPHURV KLGURVROXEOHV GH UHFRQRFLGD
FDSDFLGDG YLVFRVL]DQWH VREUH ODV SURSLHGDGHV
UHROyJLFDVGHORVJHOHVGH3OXURQLF\VXDSWLWXG
SDUD FRQWURODU OD FHVLyQ GH SURWHtQDV
PDQWHQLHQGR OD ELRFRPSDWLELOLGDG GH ORV
VLVWHPDV
6HSUHSDUDURQGLVSHUVLRQHVGH3)DO
FRQ$%9$093$$R393DOHQPHGLR
GHFXOWLYR'0(0)+$06LJPD$OGULFK
FRQ)%6\JHQWDPLFLQD/DVGLVSHUVLRQHV
VH ILOWUDURQ D WUDYpV GH PHPEUDQDV GH μP
0LOOLSRUHVHWRPDURQ PO \VHOOHYDURQD
SODFDVGHSRFLOORVWHUPRVWDWL]DGDVDž&$
FRQWLQXDFLyQVHLQRFXODURQHQFDGDSRFLOOR
PO GH VXVSHQVLyQ GH FpOXODV &&/ %DOE7 FORQH $ R GH FpOXODV 6$26
+7% GH RVWHRVDUFRPD KXPDQR GH OD
$PHULFDQ 7\SH &XOWXUH &ROOHFWLRQ /RV
HQVD\RV VH OOHYDURQ D FDER SRU GXSOLFDGR
VLJXLHQGRODQRUPD81((1,62/D
YLDELOLGDGGHODVFpOXODV%DOE7VHFXDQWLILFy
XWLOL]DQGR HO &\WRWR[LFLW\ 'HWHFWLRQ NLW3/86
/'+ 5RFKH \ OD GH ODV 6$26 SRU WLQFLyQ
FRQFDOFHLQD\RGXURGHSURSLGLR
&DUDFWHUL]DFLyQUHROyJLFD
3DUD
FDUDFWHUL]DU
HO
FRPSRUWDPLHQWR
YLVFRHOiVWLFR GH ODV GLVSHUVLRQHV VH OOHYDURQ D
FDER EDUULGRV GH FL]DOOD RVFLODWRULD HQ XQ
UHyPHWUR
5KHRO\VW
$51
7$
,QVWUXPHQWV 8. HTXLSDGR FRQ XQ SODWR
3HOWLHU XQ DQDOL]DGRU GH GDWRV $5 \ XQ
FRQRGHFPGHGLiPHWUR/RVYDORUHVGHORV
PyGXORV HOiVWLFR *¶ \ YLVFRVR *¶¶ VH
UHJLVWUDURQ DSOLFDQGR XQD IXHU]D GH FL]DOOD GH
3DXQDIUHFXHQFLDDQJXODUGHUDGV\XQD
UDPSD GH WHPSHUDWXUD GH ž&PLQ GHVGH KDVWDž&
®
3OXURQLF )3)\SROLYLQLOSLUUROLGRQD
.ROOLGRQ® 393 GH %$6) $OHPDQLD
DOJLQDWR VyGLFR GH YLVFRVLGDGHV EDMD $%9
F3V \ PHGLD $09 F3V iFLGR
SROLDFUtOLFR VDO VyGLFD 3$$ 'D \
VHURDOE~PLQD ERYLQD %6$ GH )OXND
(VSDxD
3UHSDUDFLyQGHODVGLVSHUVLRQHV
6H SUHSDUDURQ GLVROXFLRQHV DFXRVDV GH 3)
DO SS HQ 1D&O \ VH LQFRUSRUy
$%9 $09 3$$ R 393 KDVWD XQD
FRQFHQWUDFLyQILQDOGHOSS$JGHFDGD
XQD GH HVWDV GLVROXFLRQHV VH DGLFLRQDURQ PJGH%6$
(YDOXDFLyQGHODFLWRFRPSDWLELOLGDG
/DV GLVSHUVLRQHV VH GLYLGLHURQ HQ DOtFXRWDV GH
POTXHVHLQWURGXMHURQHQWXERVGHHQVD\R\
VHFRORFDURQHQXQEDxRWHUPRVWDWL]DGRDž&
$FDGDWXERVHDxDGLHURQPOGH1D&OD
ž& \ HO FRQMXQWR VH VRPHWLy D DJLWDFLyQ
RVFLODQWH RVFPLQ $ WLHPSRV
SUHHVWDEOHFLGRVVHWRPDURQPXHVWUDVPOGH
VREUHQDGDQWH \ VH YDORUy OD FRQFHQWUDFLyQ GH
%6$ HVSHFWURIRWRPpWULFDPHQWH D QP
$JLOHQW $OHPDQLD (O PHGLR H[WUDtGR
VH UHHPSOD]y FRQ XQ YROXPHQ LJXDO GH 1D&O
Dž&
5HVXOWDGRV\'LVFXVLyQ
&RPR FRPSRQHQWHV GH ODV GLVSHUVLRQHV GH
3)VHVHOHFFLRQDURQSROtPHURVKLGURItOLFRV
DGPLWLGRV SDUD XVR LQWHUQR SRU ODV DJHQFLDV
7HFQRORJtD)DUPDFpXWLFD
+,'52*(/(6'(&,&/2'(;75,1$6<32/,6$&È5,'26&2029(+Ë&8/26'(
)È50$&26$17,)Ò1*,&26
(/ySH]0RQWHUR&$OYDUH]/RUHQ]R-)5RVDGRV6DQWRV$&RQFKHLUR--7RUUHV/DEDQGHLUD
'HSW)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DQWLDJRGH
&RPSRVWHOD6DQWLDJRGH&RPSRVWHOD
HPDLOMWRUUHV#XVFHV
,QWURGXFFLyQ
/DV LQIHFFLRQHV RSRUWXQLVWDV HQ HVSHFLDO ODV
FDXVDGDVSRU&DQGLGDDOELFDQVFRQVWLWX\HQXQ
IDFWRU LPSRUWDQWH GH PRUWDOLGDG \ PRUELOLGDG
HQ QLxRV \ HQ SDFLHQWHV FRQ VLVWHPD LQPXQH
FRPSURPHWLGR (O VHUWDFRQD]RO )LJXUD HV
XQ DJHQWH IXQJLFLGD \ IXQJLVWiWLFR FRQ XQ
DPSOLR HVSHFWUR GH DFWLYLGDG 1R REVWDQWH
VX EDMD VROXELOLGDG OLPLWD VX XWLOL]DFLyQ
SUiFWLFD (O REMHWLYR GH HVWH WUDEDMR IXH
GHVDUUROODU KLGURJHOHV GH FLFORGH[WULQDV SDUD
LQFRUSRUDU VHUWDFRQD]RO IRUPDQGR FRPSOHMRV
GH LQFOXVLyQ HQ FDQWLGDGHV WHUDSpXWLFDV (O
HQWUDPDGR GH FLFORGH[WULQDV GHEH RIUHFHU XQ
PLFURHQWRUQR ULFR HQ FDYLGDGHV GH DOWD
DILQLGDG TXH VH PDQWLHQHQ DJUXSDGDV XQD YH]
TXHHOK\GURJHOHQWUDHQFRQWDFWRFRQHOPHGLR
ELROyJLFR 3DUD SUHSDUDU ORV KLGURJHOHV VH
SDUWLy GH PH]FODV GH SROLVDFiULGRV \
FLFORGH[WULQDV\VHDSOLFyXQSURFHGLPLHQWRGH
UHWLFXODFLyQ
GLUHFWD
FRQ
HWLOHQJOLFRO
GLJOLFLGLOpWHU (*'( 6H HYDOXy OD
FDSDFLGDG GH ORV KLGURJHOHV SDUD FDUJDU
VHUWDFRQD]RO FRQWURODU VX FHVLyQ H LQKLELU HO
FUHFLPLHQWRGH&DQGLGDDOELFDQV
N
N
Cl
O
Cl
S
103
)LJXUD(VWUXFWXUDGHOVHUWDFRQD]RO
0DWHULDOHV\0pWRGRV
0DWHULDOHV
1LWUDWRGHVHUWDFRQD]ROGH)HUUHU,QW(VSDxD
+3ȕ&' GH -DQVHQ 3KDUPDFHXWLVFKH %pOJLFD
PHWLOFHOXORVD 0& 0HWKRFHO $& GH
&RORUFRQ /WG 8. KLGUR[LSURSLOFHOXORVD
+3& 1LVVR 0 GH 1LSyQ 6RGD &R -DSyQ
KLGUR[LSURSLO PHWLOFHOXORVD +30& 0HWKRFHO
.0 GH 'RZ 6WDGH *0%+ $OHPDQLD
FDUER[LPHWLO FHOXORVD VyGLFD &0&1D \
GRGHFLOVXOIDWRVyGLFR6'6GH6LJPD$OGULFK
86$ HWLOHQJOLFRO GLJOLFLGLOpWHU (*'( GH
)OXND &KHPLH *0%+ $OHPDQLD 6H XWLOL]y
DJXD SXULILFDGD SRU yVPRVLV LQYHUVD
0LOOL4®
6tQWHVLVGHORVKLGURJHOHV
6HSUHSDUDURQGLVSHUVLRQHVHQ1D2+0GH
+3ȕ&' DO SS VLQ R FRQ 0& +3&
+30&&0&RGH[WUDQRDOyDOSS
$ WXERV FRQ PO VH DxDGLHURQ PO GH
(*'( DO VH KRPRJHQHL]y \ PDQWXYR
HQHVWXIDDž&GXUDQWHK /RV KLGURJHOHV
REWHQLGRVVHODYDURQFRQ+&OP0\DJXD\
VH FRUWDURQ HQ IRUPD GH GLVFRV GH PP GH
HVSHVRU
'LVFRVFDUJDGRVGHIiUPDFRSRUFDGDWLSRGH
K\GURJHO\WUDWDPLHQWRVHFRORFDURQHQPO
GHVXVSHQVLyQGH&DQGLGDDOELFDQVHQIDVHGH
FUHFLPLHQWR H[SRQHQFLDO VRPHWLGD D DJLWDFLyQ
USPDž&3HULyGLFDPHQWHVH PLGLyOD
DEVRUEDQFLDGHOPHGLRDQP
5HVXOWDGRV\'LVFXVLyQ
(O (*'( HV XQ DJHQWH UHWLFXODQWH GH EDMD
WR[LFLGDG TXH SHUPLWH REWHQHU KLGURJHOHV D
SDUWLUGHGHULYDGRVVDFDUtGLFRVTXH PDQWHQJDQ
OLEUHV DOJXQRV GH VXV JUXSRV KLGUR[LOR (O
SURFHVRHVFDWDOL]DGRSRU2+\VHFRPSOHWDHQ
SRFDV KRUDV D ž& /DV SURSRUFLRQHV GH
16
PAA
Control
Control
101
PAA
14
PVP
12
Control
10
8
ABV
6
4
100
AMV
2
10-1
PVP
0
0
10-2
15
20
25
30
35 40 15 20 25
Temperatura (ºC)
30
35
12
24
&RQWRGDVODVGLVSHUVLRQHVVHREVHUYDURQWDVDV
GH VXSHUYLYHQFLD GH FpOXODV %DOE7 \ GH
6$26VXSHULRUHVDODOFDERGHK(Q
ORVVLVWHPDVSUHSDUDGRVFRQDOJLQDWRODWDVDGH
VXSHUYLYHQFLDVXSHUyHO)LJXUD
)LJXUD 5HVXOWDGR GH OD WLQFLyQ FDOFHLQD
\RGXURGHSURSLGLRGHFpOXODV6$26HQJHOHV
GH3)$09
/RV SHUILOHV GH FHVLyQ GH %6$ UHVXOWDURQ VHU
PX\ GHSHQGLHQWHV GH OD QDWXUDOH]D GHO
SROtPHURKLGURItOLFRLQFRUSRUDGRDO3)/DV
GLVSHUVLRQHV GH 3) VROR GDQ OXJDU D XQD
OLEHUDFLyQUiSLGDGHXQDIUDFFLyQGHODGRVLVHQ
36
48
60
72
Tiempo (horas)
40
)LJXUD0yGXORVHOiVWLFRVtPERORVKXHFRV
\YLVFRVRVtPERORVOOHQRVGHODVGLVSHUVLRQHV
GH3)DOSUHSDUDGDVHQ1D&O
VLQ FtUFXORV R FRQ 3$$ FXDGUDGRV 393
URPERV$%9WULiQJXORVKDFLDDUULED$09
WULiQJXORVKDFLDDEDMRDO
)LJXUD3HUILOHVGHFHVLyQGH%6$
&RQFOXVLRQHV
/DLQFRUSRUDFLyQGH3$$393$9%y$90
D GLVSHUVLRQHV DFXRVDV GH 3OXURQLF )
SHUPLWHREWHQHUVLVWHPDVGHJHOLILFDFLyQLQVLWX
GRWDGRV GH XQD H[FHOHQWH FLWRFRPSDWLELOLGDG
/D QDWXUDOH]D GHO SROtPHUR DIHFWD GH XQD
PDQHUD PX\ PDUFDGD D ODV SURSLHGDGHV
UHROyJLFDV GH HVWRV VLVWHPDV \ D VX HILFLHQFLD
FRPR GLVSRVLWLYRV GH OLEHUDFLyQ FRQWURODGD GH
SURWHtQDV3RUORWDQWRXQDDGHFXDGDVHOHFFLyQ
GHO SROtPHUR GHEH SHUPLWLU DMXVWDU OD
FRQVLVWHQFLD \ ORV SHUILOHV GH OLEHUDFLyQ D
QHFHVLGDGHV WHUDSpXWLFDV FRQFUHWDV /D
DSUR[LPDFLyQ GHVDUUROODGD RIUHFH LQWHUHVDQWHV
SHUVSHFWLYDVSDUDRSWLPL]DUHOFRPSRUWDPLHQWR
GHVLVWHPDVLQ\HFWDEOHVGHJHOLILFDFLyQLQVLWX
%LEOLRJUDItD
$O7DKDPL \ 6LQJK 5HFHQW 3DW 'UXJ 'HOLYHU\
)RUPXODWLRQ
%DWUDNRYD \ .DEDQRY - &RQWURO 5HOHDVH &RKQHWDO%LRPDWHULDOV±
$JUDGHFLPLHQWRV
0(& 6$) )('(5 \ ;XQWD GH
*DOLFLD3*,',7&6$35
,;&RQJUHVRGHOD6(),*
SROLVDFiULGRVHVHOHFFLRQDURQGHIRUPDTXHHQ
OD GLVSHUVLyQ UHWLFXODEOH VX FRQFHQWUDFLyQ
HVWXYLHVH IXHVH LQIHULRU D OD FRQFHQWUDFLyQ GH
HQWUHFUX]DPLHQWR \ IDYRUHFHU DVt OD
GLVWULEXFLyQ KRPRJpQHD GH ORV FRPSRQHQWHV
GHOKLGURJHO7RGRVORVKLGURJHOHVSUHVHQWDURQ
XQD HOHYDGD FODULGDG ySWLFD \ XQD VXSHUILFLH
OLVD \ KRPRJpQHD \ VH FRPSRUWDURQ FRPR
VXSHUDEVRUEHQWHV)LJXUD
800
HPβ
βCD
700
600
HPβ
βCD+dextrano
500
400
HPβ
βCD+MC
300
200
100
0
0
120
240
360
1400
Tiempo (min)
$FWLYLGDGDQWLI~QJLFD
18
102
&DUDFWHUL]DFLyQGHORVKLGURJHOHV
+LQFKDPLHQWR VH UHJLVWUy HO LQFUHPHQWR GH
SHVR H[SHULPHQWDGR SRU GLVFRV VHFRV DO
VXPHUJLUORVHQDJXD
&RPSRUWDPLHQWR ELRPHFiQLFR VH GHWHUPLQy
OD GXUH]D \ OD FRPSUHVLELOLGDG \ VH HVWLPy HO
PyGXORGHGHIRUPDELOLGDG('XWLOL]DQGR
XQ HTXLSR 7$7; 3OXV 6WDEOH 0LFURV\VWHPV
/WG8.XWLOL]DQGRXQDVRQGDGHPPTXH
VHGHVSOD]yDPPVKDVWDGHIRUPDUPPHO
K\GURJHO
&DUJD GH VHUWDFRQD]RO ORV GLVFRV VH
VXPHUJLHURQ HQ VXVSHQVLRQHV DFXRVDV GH
IiUPDFR PJ HQ PO \ DOJXQRV GH HOORV
VH VRPHWLHURQ D DXWRFODYDGR $ FRQWLQXDFLyQ
VH PDQWXYLHURQ HQ DJLWDFLyQ GXUDQWH XQD
VHPDQD /D FDQWLGDG GH VHUWDFRQD]RO
LQFRUSRUDGRVHHVWLPySRUH[WUDFFLyQHQPHGLR
6'6DO
&HVLyQ GH VHUWDFRQD]RO ORV GLVFRV FDUJDGRV
VHVXPHUJLHURQHQPOGHGLVROXFLyQGH6'6
DO \ D LQWHUYDORV SUHHVWDEOHFLGRV GH
WLHPSR VH GHWHUPLQy OD FRQFHQWUDFLyQ GH
IiUPDFR HQ HO PHGLR SRU HVSHFWURIRWRPHWUtD D
QP
ODV SULPHUDV K VHJXLGD GH XQD FHVLyQ PiV
VRVWHQLGD/DSUHVHQFLDGH393R3$$SURGXMR
XQD DFHOHUDFLyQ GHO SURFHVR GH FHVLyQ GH OD
SURWHtQD PLHQWUDV TXH HO DOJLQDWR SHUPLWLy
REWHQHU JHOHV TXH SURSRUFLRQDQ SHUILOHV GH
OLEHUDFLyQPiVOHQWRV\TXHVLJXHQFLQpWLFDVGH
RUGHQ FHUR )LJXUD (VWH FRPSRUWDPLHQWR
GHORVVLVWHPDVTXHFRQWLHQHQDOJLQDWRWLHQHVX
RULJHQ HQ OD QRWDEOH FRQVLVWHQFLD TXH
SURSRUFLRQDQ D ODV GLVSHUVLRQHV GH 3OXURQLF
JHOLILFDGDV
ABV
(QVD\RGHFHVLyQGHSURWHtQD
0DWHULDOHV\0pWRGRV
0DWHULDOHV
Cl
AMV
104
Grado de hinchamiento (%)
'HSW)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD,QVWLWXWRGH2UWRSHGLD\%DQFRGH
7HMLGRV0XVFXORHVTXHOpWLFRV8QLYHUVLGDGGH6DQWLDJRGH&RPSRVWHOD6DQWLDJRGH&RPSRVWHOD
(VSDxD
HPDLODQJHOFRQFKHLUR#XVFHV
UHJXODWRULDV \ TXH FRPELQDQ D SULRUL XQD
DGHFXDGD ELRFRPSDWLELOLGDG FRQ XQD
UHFRQRFLGD
FDSDFLGDG
FRPR
DJHQWHV
YLVFRVL]DQWHV(OUHJLVWURGHODHYROXFLyQGHORV
YDORUHV GH ORV PyGXORV HOiVWLFR \ YLVFRVR HQ
IXQFLyQ GH OD WHPSHUDWXUD SXVR GH PDQLILHVWR
OD LQIOXHQFLD GH OD QDWXUDOH]D GHO SROtPHUR
VREUHODWHPSHUDWXUDGHJHOLILFDFLyQ\VREUHOD
FRQVLVWHQFLD GH ORV KLGURJHOHV D ž& )LJXUD
/D SUHVHQFLD GH DOJLQDWR SURYRFy XQD
UHGXFFLyQ GH KDVWD ž& HQ OD WHPSHUDWXUD GH
JHOLILFDFLyQ \ FRQGXMR D OD IRUPDFLyQ GH
KLGURJHOHVPiVHVWUXFWXUDGRV
BSA cedida (mg)
$5H\5LFR&$OYDUH]/RUHQ]R/%DOVD06LOYD-&RXFHLUR\$&RQFKHLUR
)LJXUD+LQFKDPLHQWRGHORVKLGURJHOHV
/RVKLGURJHOHVSUHSDUDGRVFRQ0&
+3& y &0&1D IXHURQ ORV TXH
SUHVHQWDURQ PD\RU FRQVLVWHQFLD 7DEOD (VWR VH SXHGH DWULEXLU D XQ PD\RU JUDGR GH
UHWLFXODFLyQ HQ HO FDVR GH ORV pWHUHV GH
FHOXORVD QR LyQLFRV DO SUHVHQWDU XQ PHQRU
JUDGR GH VXVWLWXFLyQ \ SRU OR WDQWR PiV
JUXSRV KLGUR[LOR GLVSRQLEOHV SDUD UHDFFLRQDU
FRQ (*'( (Q HO FDVR GH OD &0&1D ORV
HIHFWRV RVPyWLFRV \ ODV UHSXOVLRQHV
HOHFWURVWiWLFDV GHEHQ FRQWULEXLU WDPELpQ D
KDFHUORVKLGURJHOHVPiVUtJLGRV
7DEOD 0yGXORV GH GHIRUPDELOLGDG (' \
FDQWLGDGHV GH VHUWDFRQD]RO LQFRUSRUDGR SRU ORV
KLGURJHOHVVRPHWLGRVRQRDDXWRFODYDGR
+LGURJHOHV
GH+3β
β &'
6LQ
SROLVDFiULGR
+30&
+30&
0&
0&
&0&
&0&
+3&
+3&
'H[W
'H[W
('N3D
)iUPDFRPJJ
6LQDXWRFODYH$XWRFODYH
7RGRVORVKLGURJHOHVPRVWUDURQXQDFDSDFLGDG
GH LQFRUSRUDFLyQ GH VHUWDFRQD]RO PX\ SRU
HQFLPDGHODFDQWLGDGGHIiUPDFRTXHVHSXHGH
DORMDU HQ VX IDVH DFXRVD PJJ OR
TXHSRQHGHPDQLILHVWRTXHODPD\RUSDUWHGHO
IiUPDFR VH HQFXHQWUD IRUPDQGR FRPSOHMRV GH
LQFOXVLyQ FRQ ODV FLFORGH[WULQDV DQFODGDV DO
KLGURJHO 1R REVWDQWH ORV KLGURJHOHV
SUHSDUDGRV FRQ &0& +3& R GH[WUDQR \ TXH
QR IXHURQ DXWRFODYDGRV PRVWUDURQ XQD EDMD
FDUJD GH IiUPDFR TXH VH LQFUHPHQWy
QRWDEOHPHQWH DO VRPHWHUORV D DXWRFODYDGR /D
FDOHIDFFLyQ IDFLOLWD OD VROXELOL]DFLyQ GHO
IiUPDFR \ SRU OR WDQWR VX DFFHVR D ODV
FDYLGDGHV GH OD FLFORGH[WULQD (O HVWXGLR GHO
SURFHVRGHFHVLyQGHVHUWDFRQD]ROTXHVHOOHYy
D FDER HQ GLVROXFLyQ PLFHODU GH 6'6 SDUD
DOFDQ]DU FRQGLFLRQHV VLQN HYLGHQFLy TXH ORV
KLGURJHOHV OLEHUDQ HQWUH HO \ HO GHO
IiUPDFRHQODVSULPHUDVK3RUORWDQWRVH
VHOHFFLRQy HVWH WLHPSR SDUD HYDOXDU VX
FDSDFLGDG DQWLI~QJLFD IUHQWH D &DQGLGD
DOELFDQV /RV KLGURJHOHV GH +3ȕ&' FDUJDGRV
FRQ VHUWDFRQD]RO PRVWUDURQ XQD HILFDFLD
DQWLI~QJLFDWDQDOWDFRPRODTXHSURSRUFLRQDHO
IiUPDFROLEUHORTXHLQGLFDTXHpVWHPDQWLHQH
VX DFWLYLGDG XQD YH] LQFRUSRUDGR DO KLGURJHO
)LJXUD
Absorbancia del medio con C. albicans
+,'52*(/(6'(32/2;$0(5'(*(/,),&$&,Ï1,16,783$5$&(6,Ï1
&21752/$'$'(3527(Ë1$6
,;&RQJUHVRGHOD6(),*
Módulos elástico y viscoso (Pa)
7HFQRORJtD)DUPDFpXWLFD
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0
3
5
8
24
Tiempo (h)
)LJXUD &UHFLPLHQWR GH &DQGLGD DOELFDQV HQ
PHGLRGHFXOWLYRFROXPQDVQHJUDVHQSUHVHQFLDGH
KLGURJHOHVGH+3ȕ&'VLQIiUPDFRJULVRVFXURGH
KLGURJHOHV FDUJDGRV VLQ DSOLFDU JULV FODUR R
DSOLFDQGR DXWRFODYDGR JULV FRQ UD\DV R HQ XQ
PHGLR FRQ OD PLVPD FDQWLGDG GH IiUPDFR TXH HO
KLGURJHOTXHHOKLGURJHOTXHLQFRUSRUyODGRVLVPiV
DOWDFROXPQDEODQFDFRQUD\DV
&RQFOXVLRQHV
6H KDQ GHVDUUROODGR KLGURJHOHV GH
FLFORGH[WULQDV\SROLVDFiULGRVHQXQDVRODHWDSD
VLQ XWLOL]DU GLVROYHQWHV R UHDFWLYRV Wy[LFRV /D
LQFRUSRUDFLyQ GH SROLVDFiULGRV SHUPLWH
PRGXODU ODV SURSLHGDGHV PHFiQLFDV GH
LQFRUSRUDFLyQ GH IiUPDFR \ GH FRQWURO GH OD
FHVLyQPDQWHQLHQGRODHILFDFLDDQWLI~QJLFDGHO
VHUWDFRQD]RO
%LEOLRJUDItD
3DODFtQHWDO,QW-*\QDHFRO2EVWHW
5RGUtJXH]7HQUHLUR HW DO - &RQWURO 5HOHDVH
±
$OYDUH]/RUHQ]RHWDO:2
$JUDGHFLPLHQWRV
0(&6$))('(5;XQWDGH*DOLFLD
3*,',7&6$35
7HFQRORJtD)DUPDFpXWLFD
,;&RQJUHVRGHOD6(),*
(O JUDGR GH LQMHUWR DXPHQWD FRQ HO LQFUHPHQWR
HQHOWLHPSRGHUHDFFLyQ
)81&,21$/,=$&,Ï1683(5),&,$/'(32/,(7,/(12<32/,3523,/(12&21
&,&/2'(;75,1$63$5$',6326,7,926%,20e',&260(',&$'26
&$%1DYD2UWL]*%XULOOR(%XFLR&$OYDUH]/RUHQ]R\$&RQFKHLUR
16
'HSW4XtPLFDGH5DGLDFLRQHV\5DGLRTXtPLFD,QVWLWXWRGH&LHQFLDV1XFOHDUHV8QLYHUVLGDG1DFLRQDO
$XWyQRPDGH0p[LFR0p[LFR')\'HSW)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH
)DUPDFLD8QLYHUVLGDGGH6DQWLDJRGH&RPSRVWHOD6DQWLDJRGH&RPSRVWHOD
HPDLOFDUPHQDOYDUH]ORUHQ]R#XVFHV
,QWURGXFFLyQ
,QMHUWRGH*0$VREUH3(\33
(O GLVHxR GH SURGXFWRV VDQLWDULRV 36
/DFRSROLPHUL]DFLyQGH*0$VREUH3(\33VH
PHGLFDGRV HQFLHUUD XQ QRWDEOH LQWHUpV SDUD
UHDOL]y PHGLDQWH OD WpFQLFD GH SUHLUUDGLDFLyQ
OLEHUDFLyQ ORFDOL]DGD GH IiUPDFRV TXH HYLWHQ HO
R[LGDWLYD HPSOHDQGR SDUD HOOR XQD IXHQWH GH
GHVDUUROORGHUHDFFLRQHVDGYHUVDVDVRFLDGDVDOD
&R *DPPD%HDP 37 FRQ XQD
LPSODQWDFLyQ GHO 36 SULQFLSDOPHQWH GH WLSR
LQWHQVLGDG GH .*\K XQD GRVLV GH
LQIODPDWRULR R LQIHFFLRQHV 3DUD GRWDU D ORV 36
LUUDGLDFLyQGHN*\\XQDFRQFHQWUDFLyQGH
GH DSWLWXG FRPR VLVWHPDV GH OLEHUDFLyQ UHVXOWD
PRQyPHURGHY
HVHQFLDO IXQFLRQDOL]DU VX VXSHUILFLH GH PDQHUD
,QPRYLOL]DFLyQGHȕ&'H+3ȕ&'
TXH DGTXLHUD DILQLGDG SRU HO IiUPDFR VLQ
SHUMXLFLRGHVXVSUHVWDFLRQHV FRPR36(OOR
/DV OiPLQDV LQMHUWDGDV VH VXPHUJLHURQ HQ '0)
REOLJD D XQ GHVDUUROOR UDFLRQDO GHO SURFHVR GH
K \ D FRQWLQXDFLyQ VH WUDQVILULHURQ D XQD
IXQFLRQDOL]DFLyQVXSHUILFLDOTXHWHQJDHQFXHQWD
PH]FOD GH 1D&O0'0) Y MXQWR FRQ
ODV
SHFXOLDULGDGHV
GH
FDGD
SDU
XQD FDQWLGDG HTXLPRODU GH FLFORGH[WULQD FRQ
IiUPDFRGLVSRVLWLYR (Q HVWH WUDEDMR VH DERUGD
UHVSHFWR DO *0$ LQMHUWDGR (O VLVWHPD VH
XQD QXHYD HVWUDWHJLD GH IXQFLRQDOL]DFLyQ
PDQWXYRHQDJLWDFLyQGXUDQWHKDR& /DV
VXSHUILFLDO GH SROLHWLOHQR 3( \ SROLSURSLOHQR
OiPLQDV VH ODYDURQ FRQ DJXD FDOLHQWH D ž&
33FRQFLFORGH[WULQDV)LJXUDSDUDGRWDUORV
PH]FODHWDQRODFHWRQDYGXUDQWHK \
GH FDSDFLGDG GH LQFRUSRUDFLyQ GH IiUPDFRV
ILQDOPHQWHVHDFODUDURQFRQDJXD
KLGURIyELFRV HQ JHQHUDO \ GH GLFORIHQDFR HQ
(VWXGLRVGHFDUJDGHGLFORIHQDFR
SDUWLFXODU $GHPiV GH VX FDSDFLGDG
12
n
GMA
KY
CH2
CH2
CH2
x
β-CD
CH
y
CH3
O
CH2
CH2
H2O, DMF,
NaCl
CH2
CH2
x
(VWXGLRVGHFHVLyQGHGLFORIHQDFR
CH
y
CH3
O
CH2
C
C
z
z
CO
CO
O
O
CH2
CH2
OH
HO
CH
OH
CH2
CH
O
O
HO
O
O
CH2
O
HO
OH
HO
O
HO
O
OH
O
O
OH
HO
O
OH
OH
O
OH
OH
O
OH
OH
OH O
O
O OH
HO
O
OH
)LJXUD$QFODMHGHȕ&'D3(J*0$
0DWHULDOHV\0pWRGRV
0DWHULDOHV
3( \ 33 μP \ μP GH HVSHVRU GH
3(0(; 0p[LFR *0$ GH $OGULFK 86$
ȕ&' H +3ȕ&' GH 5RTXHWWH /DLVD (VSDxD
GLFORIHQDFRVyGLFRGH9RUTXtPLFD(VSDxD
/DVPXHVWUDVGHODVOiPLQDVLQMHUWDGDVFDUJDGDV
GHGLFORIHQDFRVHODYDURQFRQDJXDGHVWLODGDVH
GHVHFDURQDYDFtRGXUDQWHK \SRVWHULRUPHQWH
HQHVWXIDDR&GXUDQWHK$FRQWLQXDFLyQVH
FRORFDURQHQP/GHWDPSyQIRVIDWRS+\
VHUHJLVWUyODDEVRUEDQFLDGHOPHGLRDQPD
LQWHUYDORV SUHHVWDEOHFLGRV GH WLHPSR /RV
HQVD\RVVHOOHYDURQDFDERSRUWULSOLFDGR
5HVXOWDGRV\'LVFXVLyQ
/D PRGLILFDFLyQ VXSHUILFLDO GH 3( \ 33 VH
UHDOL]y HQ GRV HWDSDV L LUUDGLDFLyQ Ȗ HQ
SUHVHQFLD GH GLVWLQWDV SURSRUFLRQHV GH *0$ \
LLUHDFFLyQGHORVJUXSRVJOLFLGLORGHO*0$FRQ
ȕ&' H +3ȕ&' (Q OD )LJXUD VH PXHVWUD OD
FLQpWLFD GH LQMHUWR GH *0$ VREUH 33 \ 3(
PHGLDQWHHOPpWRGRGHSUHLUUDGLDFLyQR[LGDWLYD
0
1
2
3
4
5
Tiempo de reacción (h)
)LJXUD&LQpWLFDGHLQMHUWRGH*0$VREUHŶ
3(\Ƈ33
3(J*0$ȕ&'
ȕ&'
μPROJ
'LFO
μPROJ
1.5
/D FDQWLGDG GH FLFORGH[WULQD TXH VH LQPRYLOL]y
HQ FDGD OiPLQD DXPHQWy FRQ OD SURSRUFLyQ GH
*0$LQMHUWDGRHQODVOiPLQDV)LJXUD
PP-g-GMA-β
βCD
2.0
1.0
Diclofenaco cedido (mg/g)
700
CD (μ
μ mol/ g)
600
500
400
300
200
100
4.0
0.5
8.0
5.4
14.0
0.0
1.0
PE-g-GMA-β
βCD
2.0
0
0
2
4
6
8
10
12
14
16
)LJXUD 5HQGLPLHQWR GH XQLyQ GH &'V c
33J*0$β&' • 33J*0$+3β&' 
3(J*0$β&'Ŷ3(J*0$+3β&'
&RQORVLQMHUWRV33J*0$VHREWXYRXQPD\RU
UHQGLPLHQWR HQ OD XQLyQ GH &'V TXH VH SXHGH
DWULEXLU D OD PD\RU FULVWDOLQLGDG GHO 33 \ SRU
FRQVLJXLHQWHDXQDGLVWULEXFLyQPiVKRPRJpQHD
GHO *0$ 3RU RWUR ODGR HO DQFODMH GH +3ȕ&'
IXH PHQRU TXH SDUD OD ȕ&' GHELGR
SRVLEOHPHQWH D LPSHGLPHQWRV HVWpULFRV 3DUD
FDGD LQMHUWR VH REVHUYy TXH DO DXPHQWDU OD
FDQWLGDG GH &' DQFODGD OD FDSDFLGDG GH
LQFRUSRUDFLyQ GH GLFORIHQDFR 7DEODV \ \
GHFRQWUROGHODFHVLyQ)LJXUDVHLQFUHPHQWD
GH IRUPD FRQVLGHUDEOH 7RGDV ODV OiPLQDV
SUHVHQWDURQXQPDUFDGRHIHFWREXUVWVHJXLGRGH
XQDHWDSDGHOLEHUDFLyQPiVOHQWD
7DEOD &DUJD GH GLFORIHQDFR VREUH OiPLQDV
33J*0$ FRQ FLFORGH[WULQDV DQFODGDV FRQF
LQLFLDOGHGLFORIHQDFRJO
33J*0$+3ȕ&'
33J*0$ȕ&'
*0$ +3ȕ&' 'LFO
*0$
PJFP μPROJ μPROJ PJFP
ȕ&'
μPROJ
'LFO
μPROJ
4.2
0.5
GMA (mg/ cm2)
7.9
5.0
9.7
0.0
0
4
8
12
16
20
24
60
Tiempo (horas)
)LJXUD 3HUILOHV GH FHVLyQ GH OiPLQDV
SUHSDUDGDV FRQ HO FRQWHQLGR HQ *0$ TXH VH
LQGLFDPJFP &RQFOXVLRQHV
/D PRGLILFDFLyQ VXSHUILFLDO GH 3( \ 33 FRQ
*0$ ORV GRWD GH FDSDFLGDG GH DQFODMH GH
FLFORGH[WULQDV /RV PDWHULDOHV IXQFLRQDOL]DGRV
FRPELQDQ ODV SURSLHGDGHV PHFiQLFDV GH SDUWLGD
FRQ OD FDSDFLGDG GH ODV FLFORGH[WULQDV SDUD
IRUPDUFRPSOHMRVGHLQFOXVLyQ(VWRVQRYHGRVRV
VLVWHPDV SROLPpULFRV SUHVHQWDQ XQ JUDQ
SRWHQFLDO SDUD HO GHVDUUROOR GH 36 PHGLFDGRV
GDGR TXH OD FDQWLGDG GH FLFORGH[WULQD DQFODGD
SHUPLWH UHJXODU OD FDUJD GH GLFORIHQDFR \ HO
SURFHVRGHFHVLyQ
%LEOLRJUDItD
:X \ *UDLQJHU %LRPDWHULDOV %DQGDUHHWDO&XUU(\H5HV
1DYD2UWL] HW DO 5DG 3K\V &KHP HQ
SUHQVD
$JUDGHFLPLHQWRV
0(& 6$) )('(5 ;XQWD GH *DOLFLD
3*,',7&6$35 \ '*$3$ 81$0
,10p[LFR
,;&RQJUHVRGHOD6(),*
H PCS30D F requency sweep step
H PCL30D F requency sweep step
1000
100,0
1000
100,0
G' (Pa)
100,0
10,00
100,0
10,00
10,00
G'' (Pa)
()(&72'(/$+,'52)2%,&,'$'62%5((/&203257$0,(1725(2/Ï*,&2</$
&,1e7,&$'(/,%(5$&,Ï1'(816,67(0$',63(562'(+,'52;,3523,/&(/8/26$
-ÈOYDUH]0'0R\D\0-/XFHUR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH6HYLOOD
(Q SULPHU OXJDU VH KD HIHFWXDGR XQ HVWXGLR
,QWURGXFFLyQ
/RV KLGURJHOHV VRQ UHGHV SROLPpULFDV TXH
RVFLODWRULRSDUDGHWHUPLQDUODHVWUXFWXUDIRUPDGD
DEVRUEHQ JUDQ FDQWLGDG GH DJXD PLHQWUDV
SRU ORV VLVWHPDV GLVSHUVRV 3DUD HOOR VH KDQ
SHUPDQHFHQ LQVROXEOHV HQ VROXFLyQ DFXRVD
KHFKREDUULGRVGHHVIXHU]RD3DD+]
GHELGR D HQODFHV ItVLFRV R TXtPLFRV GH ODV
\EDUULGRVGHIUHFXHQFLDDUDGVD3D
FDGHQDVSROLPpULFDVLQGLYLGXDOHV6HSXHGHQ
(QVHJXQGROXJDUVHKDQUHDOL]DGRODVFXUYDVGH
SUHSDUDU D SDUWLU GH VXVWDQFLDV SROLPpULFDV GH
YLVFRVLGDGD3D
RULJHQ VLQWpWLFR WHQLHQGR HVWUXFWXUDV ELHQ
/RV HQVD\RV GH GLVROXFLyQ VH OOHYDQ D FDER HQ
XQDSDUDWRGHGLVROXFLyQ863WLSR
GHILQLGDV TXH SXHGHQ VHU PRGLILFDGDV SDUD
(UZHND '7++ \ FRQ ORV GLVSRVLWLYRV
PHMRUDU ODV SURSLHGDGHV GH OLEHUDFLyQ GH
IiUPDFRV 8QD HVWUDWHJLD FRQVLVWH HQ
(QKDQFHU &HOO® 9DQNHO FRQ XQD VXSHUILFLH
LQFRUSRUDU JUXSRV KLGUyIRERV D PROpFXODV
HIHFWLYDGHFP\XQDPHPEUDQDGHDFHWDWR
KLGUyILODVIRUPDGRUDVGHJHO\REWHQHUSROtPHURV
GH FHOXORVD GH μP GH WDPDxR GH SRUR /D
KLGURIyELFDPHQWH PRGLILFDGRV 2WUD
WHRILOLQD VH GHWHUPLQD SRU HVSHFWURIRWRPHWUtD D
DOWHUQDWLYDUDGLFDHQHODERUDUPH]FODVItVLFDVGH
QP
SROtPHURV KLGUyOLIRV FRQ RWURV GH QDWXUDOH]D
KLGUyIRED FRQ HO ILQ GH REWHQHU VLVWHPDV
5HVXOWDGRV\'LVFXVLyQ
JHOLILFDGRV FRPSOHMRV ~WLOHV SDUD OD OLEHUDFLyQ
(O EDUULGR GH HVIXHU]R UHDOL]DGR D ORV VLVWHPDV
PRGLILFDGDGHIiUPDFRV
GLVSHUVRVHQHVWXGLR KDSHUPLWLGRGHWHUPLQDUOD
(O REMHWLYR GHO SUHVHQWH WUDEDMR VH FHQWUD HQ HO
]RQDYLVFRHOiVWLFDOLQHDOHQGRQGHHOPyGXORGH
HVWXGLR GH OD LQIOXHQFLD GHO HIHFWR KLGURIyELFR
DOPDFHQDPLHQWR \ HO PyGXOR GH SpUGLGD VRQ
GH FRSROtPHURV GH iFLGR PHWDFUtOLFR \
LQGHSHQGLHQWHV GH OD IUHFXHQFLD DSOLFDGD 6H KD
PHWDFULODWR GH PHWLOR HQ PH]FOD ItVLFD FRQ
VHOHFFLRQDGR XQ HVIXHU]R RVFLODWRULR GH 3D
KLGUR[LSURSLOFHOXORVD
SDUD VRPHWHU D ODV PXHVWUDV D XQ EDUULGR GH
IUHFXHQFLD (Q OD )LJXUD VH SXHGHQ REVHUYDU
0DWHULDOHV\0pWRGRV
ORV HVSHFWURV PHFiQLFRV GH ODV PXHVWUDV (Q
6H KDQ HODERUDGR GLIHUHQWHV VLVWHPDV GLVSHUVRV
DPERV FDVRV ORV PyGXORV GH SpUGLGDV VH
FRQ KLGUR[LSURSLOFHOXORVD +3& \ (XGUDJLW®
PDQWLHQHQ SRU HQFLPD GH ORV GH
®
DOPDFHQDPLHQWR OR TXH LQGLFD TXH VRQ IOXLGRV
/R(XGUDJLW 67DEOD
SUHGRPLQDQWHPHQWH YLVFRVRV \ TXH QR IRUPDQ
HVWUXFWXUD GH JHO $GHPiV WDQWR SDUD XQD
7DEOD &RPSRQHQWHV GH ODV GLVWLQWDV
PXHVWUDFRPRSDUDODRWUDHOiQJXORGHGHVIDVH
IRUPXODFLRQHVHQVD\DGDV
GH OD RQGD HV VXSHULRU D ž OR TXH FRUURERUD
'HQRPLQDFLyQ
&RPSRVLFLyQSS
HVWH FRPSRUWDPLHQWR /D DGLFLyQ GH WHRILOLQD D
Š
(XGUDJLW /6«««
/'
HVWRV VLVWHPDV GLVSHUVRV QR PRGLILFD OD
/66««««««««««
Š
HVWUXFWXUD YLVFRVD VLQ SXQWRV GH UHWLFXODFLyQ
7ZHHQ «««««««
6'
7ULHWDQRODPLQD««««««
REWHQLGDFRQODPH]FODGHHVWRVGRVSROtPHURV
/'
(Q HO HVWXGLR YLVFRVLPpWULFR UHFRJLGR HQ OD
7(2
$JXD
+3&
6'
)LJXUD VH SXHGH REVHUYDU SDUD DPERV IOXLGRV
+3&/'
TXHODYLVFRVLGDGGLVPLQX\HFRQODYHORFLGDGGH
+3&6'
FL]DOOD FDUDFWHUtVWLFR GH ORV VLVWHPDV QR
+3&/'7(2
+3&6'7(2
QHZWRQLDQRVGHFRPSRUWDPLHQWRSVHXGRSOiVWLFR
6H KDQ DMXVWDGR ODV FXUYDV D ORV GLVWLQWRV
PRGHORV FRQRFLGRV \ VH KD REWHQLGR XQ PHMRU
6H KDQ UHDOL]DGR HVWXGLRV UHROyJLFRV PHGLDQWH
DMXVWH SDUD HO PRGHOR GH &DUUHDX SDUD ODV GRV
XQUHyPHWUR$57$,QVWUXPHQWHTXLSDGR
PXHVWUDV OR TXH SHUPLWH GHWHUPLQDU
FRQ XQD JHRPHWUtD GH SODWR GH PP GH
PDWHPiWLFDPHQWHORVSDUiPHWURVUHFRJLGRVHQOD
GLiPHWUR \ XQJDSGH PP /DWHPSHUDWXUD VH
7DEOD
KDPDQWHQLGRDž&PHGLDQWHXQDSODFD3HOWLHU
4
0
80,0
60,0
40,0
20,0
0,0
1,000
1,000
0
250
500
750
1000
1250
1500
Tiempo (min.)
0,1000 1,000
0,1000
1,000
10,00
ang. f requency (rad/s)
HPCS30D4%TEO
0,1000
1000
100,0
)LJXUD %DUULGR GH IUHFXHQFLD D 3D GH ORV
VLVWHPDVGLVSHUVRVLQGLFDGRV
(Q HOOD VH SXHGH REVHUYDU FRPR HO VLVWHPD
+3&/' HV PiV YLVFRVR TXH HO +3&6 OR
TXH LQGLFD TXH DO DXPHQWDU HO GH JUXSRV
PHWDFULODWR GH PHWLOR VH REWLHQHQ IOXLGRV GH
PHQRUYLVFRVLGDG(QDPERVFDVRVODDGLFLyQGH
WHRILOLQDQRPRGLILFDHOFRPSRUWDPLHQWRYLVFRVR
DXQTXHSURYRFDXQDXPHQWRGHODYLVFRVLGDGHQ
HO+3&/'\XQDGLVPLQXFLyQGHODPLVPDHQ
HO+3&6'
120,0
H PC S30D Steady state f low step
H PC L30D Steady state f low step
100,0
80,00
viscosity (Pa.s)
7HFQRORJtD)DUPDFpXWLFD
6
2
8
% Teofilina liberada
CH2
3(J*0$+3ȕ&'
*0$ +3ȕ&' 'LFO
*0$
PJFP μPROJ μPROJ PJFP
10
|n*| (Pa.s)
PE-g-GMA-β
βCD
PE-g-GMA
PE
CH2
0XHVWUDVVHFDVPJGHOiPLQDVLQMHUWDGDV
FRQ GLIHUHQWHV FDQWLGDGHV GH FLFORGH[WULQD
LQPRYLOL]DGD VH FRORFDURQ HQ P/ GH
GLVROXFLyQ DFXRVD GH GLFORIHQDFR J/ GXUDQWH K HQ OD RVFXULGDG /D FDQWLGDG
GH GLFORIHQDFR FDUJDGD VH GHWHUPLQy SRU OD
GLIHUHQFLD HQWUH OD FRQFHQWUDFLyQ LQLFLDO \ ILQDO
GHFDGDGLVROXFLyQUHJLVWUDQGRODDEVRUEDQFLDD
QP /RV HQVD\RV VH OOHYDURQ D FDER SRU
WULSOLFDGR
GMA (mg/ cm2)
DQWLLQIODPDWRULDHOGLFORIHQDFRWDPELpQHYLWDOD
DGVRUFLyQ GH EDFWHULDV VREUH ELRPDWHULDOHV (Q SULPHU OXJDU VH SUHSDUDURQ LQMHUWRV GH
JOLFLGLOPHWDFULODWR *0$ VREUH 3( 3(J
*0$\3333J*0$TXHVLUYDQGHSXQWRV
GH DQFODMH GH ȕFLFORGH[WULQD ȕ&' R GH
KLGUR[LSURSLOȕFLFORGH[WULQD +3ȕ&' $
FRQWLQXDFLyQVHHYDOXyODFDSDFLGDGGHFDUJDGH
IiUPDFR\VHUHJLVWUDURQORVSHUILOHVGHFHVLyQ
7DEOD &DUJD GH GLFORIHQDFR VREUH OiPLQDV
3(J*0$ FRQ FLFORGH[WULQDV DQFODGDV FRQF
LQLFLDOGHGLFORIHQDFRJO
14
60,00
40,00
20,00
0
0
0,5000
1,000
1,500
shear rate (1/s )
2,000
2,500
3,000
)LJXUD &XUYD GH YLVFRVLGDG GH ORV VLVWHPDV
GLVSHUVRVLQGLFDGRV
7DEOD 3DUiPHWURV REWHQLGRV WUDV DSOLFDU HO
PRGHORGH&DUUHDXDODVFXUYDVGHYLVFRVLGDG
.
η η∞
Q
((
+3&/'
+3&6'
3DV
3DV
V
3RU ~OWLPR VH KD UHDOL]DGR XQ HVWXGLR GH
FLQpWLFD GH OLEHUDFLyQ (Q OD )LJXUD VH
PXHVWUDQ ORV SHUILOHV GH OLEHUDFLyQ GH ORV GRV
VLVWHPDV GLVSHUVRV \ VH REVHUYD TXH D ODV K
GH WUDQVFXUULGR HO HQVD\R VH KD REWHQLGR XQD
OLEHUDFLyQ DOUHGHGRU GHO HQ ODV GRV
PXHVWUDV
HPCL30D4%TEO
)LJXUD &LQpWLFD GH GLVROXFLyQ GH ORV
VLVWHPDVGLVSHUVRVLQGLFDGRV
6H KDQ DSOLFDGR ORV PRGHORV FLQpWLFRV GH
+LJXFKL \ .RUVPH\HU3HSSDV REWHQLpQGRVH
SDUDDPERVSROtPHURV XQU !DGHPiVGH
XQYDORUGHQGH3RUWDQWRHOPHFDQLVPR
GH OLEHUDFLyQ HV SRU GLIXVLyQ (Q OD 7DEOD VH
UHFRJHQ DOJXQRV GH ORV SDUiPHWURV REWHQLGRV
GHVSXpV GH DMXVWDU ODV FXUYDV DO PRGHOR GH
+LJXFKL
7DEOD3DUiPHWURVGHOPRGHORGH+LJXFKL
U (FXDFLyQUHFWD
+3&/'
\ ¥W±
'
FPPLQ
Â
+3&6'
\ ¥W±
Â
&RQFOXVLRQHV /RV VLVWHPDV +3&/' \
+3&6' QR WLHQHQ HVWUXFWXUD GH JHO 6RQ
VLVWHPDV VLQ UHWLFXODFLyQ YLVFRVRV \
SVHXGRSOiVWLFRV (O LQFUHPHQWR GH JUXSRV
KLGUyIRERV QR PRGLILFD HO FRPSRUWDPLHQWR GH
ORV SUHSDUDGRV DXQTXH VL GLVPLQX\H VX
YLVFRVLGDG (VWH KHFKR UHSHUFXWH HQ HO SURFHVR
GH OLEHUDFLyQ TXH VH KDFH OLJHUDPHQWH PiV
UiSLGR
%LEOLRJUDItD
/LQ&\0HWWHUV$$GY'UXJ'HOLY5HY
%RQDFXFLQD * \ FROV ,QW - 3KDUP
&DVWHOODQR , \ FRO ,QW - 3KDUP )HUUHUR & \ FROV ,QW - 3KDUP 0LOODU' \ /|IIOHU 0&ROORLGV 6XUIDFH $
(VFXGHUR-\FROV,QW-3KDUP
7HFQRORJtD)DUPDFpXWLFD
'(7(50,1$&,Ï1'(/$63523,('$'(60(&È1,&$6'(6,67(0$632/,0e5,&26
'(+&00$
&&ODUR&DOD05-LPpQH]&DVWHOODQR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD
6HYLOOD6SDLQ
,QWURGXFFLyQ
'HO HVWXGLR GH PDWHULDOHV GH RULJHQ SROLPpULFR
VH KD KDOODGR DSOLFDFLRQHV HQ HO iUHD GH
PHGLFLQD \ IDUPDFLD (VSHFLDOPHQWH DO
IRUPXODU IRUPDV IDUPDFpXWLFDV WySLFDV WDOHV
FRPR FUHPDV JHOHV HWF ORV PDWHULDOHV TXH VH
XWLOLFHQGHSHQGHUiQHQJUDQSDUWHGHODILQDOLGDG
UHTXHULGDGHOSURGXFWRILQDO(QHOGHVDUUROORGH
HVWDVIRUPDVIDUPDFpXWLFDVGHDSOLFDFLyQWySLFD
XQD VHULH GH SURSLHGDGHV PHFiQLFDV KDQ VLGR
GLUHFWDPHQWH UHODFLRQDGDV FRQ SDUiPHWURV
VHQVRULDOHV LQ YLYR SRU HMHPSOR H[WUDFFLyQ GHO
SURGXFWR GH VX FRQWHQHGRU RULJLQDO
FDUDFWHUtVWLFDV GH DSOLFDFLyQ GHO SURGXFWR 3RU
WDQWR VRQ GLUHFWDPHQWH DSOLFDEOHV DO GLVHxR GH
SUHSDUDFLRQHV IDUPDFpXWLFDV GH DGPLQLVWUDFLyQ
WySLFD
/RV SROtPHURV SXHGHQ IRUPDU LQWHUDFFLRQHV
DGKHVLYDVFRQVXEVWUDWRVELROyJLFRVVLHQGRXQD
YHQWDMD SDUD OD OLEHUDFLyQ GH IiUPDFRV
LQFOX\HQGR WLHPSR GH UHVLGHQFLD SURORQJDGR
/RVSROtPHURVGHFHOXORVDVRQHMHPSORVGHHVWH
WLSRGHVXVWDQFLDVFRQSURSLHGDGHVELRDGKHVLYDV
(OSUHVHQWHWUDEDMRVHFHQWUDHQHOHVWXGLRGHODV
SURSLHGDGHV PHFiQLFDV GH ORV VLVWHPDV
HODERUDGRV FRQ XQ FRSROtPHUR GH LQMHUWR GH
KLGUR[LSURSLOFHOXORVD\PHWDFULODWRGHPHWLOR\
XQ WHQVRDFWLYR QR LyQLFR D GLVWLQWDV
FRQFHQWUDFLRQHV
0DWHULDOHV\0pWRGR
0DWHULDOHV
&RSROtPHURGHLQMHUWRGHKLGUR[LSURSLOFHOXORVD
PHWDFULODWR GH PHWLOR +&00$ SROLR[LHWLOHQ(2 QRQLOIHQLOHWHU,JHSDO&2
Š 6LJPD$OGULFK %DUFHORQD \ 7HRILOLQD
DQKLGUD5RLJ)DUPD6$%DUFHORQD
(ODERUDFLyQGHVLVWHPDVGLVSHUVRVKLGUyILORV
6H KD SUHSDUDGR XQ VLVWHPD GLVSHUVR KLGUyILOR
FRQ+&00$SYGLVWLQWDVSURSRUFLRQHV
GH ,JHSDO &2 Š SY \ DJXD
SXULILFDGD 3DUD HOOR VH KD XWLOL]DGR XQ
KRPRJHQHL]DGRU 8OWUD7XUUD[ 7 HTXLSDGR
FRQ XQD WXUELQD 6 1 ,.$ 6WDXIHQ
$OHPDQLDDXQDYHORFLGDGGHUSP
3URSLHGDGHVPHFiQLFDV
3DUDHODQiOLVLVGHODVSURSLHGDGHVPHFiQLFDVGH
ORV VLVWHPDV SROLPpULFRV VH KD HPSOHDGR XQ
DQDOL]DGRU GH OD WH[WXUD 0RGHOR 7$;7
6WDEOH 0LFUR 6\VWHPV 5HLQR 8QLGR HQ PRGR
GH³)XHU]DHQ&RPSUHVLyQ´/DVRQGDXWLOL]DGD
KDVLGRXQGLVFRGHH[WUXVLyQHVWiQGDUGHPP
&RPSUHV
+DUGQHVV
VLELOLW\
1
1ÂPP
“ “
“ “
“ “
“ “
“ “
“ “
GH GLiPHWUR $%( /D PXHVWUD J KD VLGR
FRORFDGDHQXQUHFLSLHQWHHVWiQGDUGHPPGH
GLiPHWUR R HQ FXDOTXLHU FDVR HO UHFLSLHQWH
FRQWHQHGRURULJLQDOGHOVHPLVyOLGRGHVLPLODUHV
GLPHQVLRQHV HQ HO FDVR GH SURGXFWRV
GHUPRIDUPDFpXWLFRV (Q HQVD\R VH UHDOL]D
LQPHGLDWDPHQWH GHVSXpV GH HVWDU DOPDFHQDGR
GXUDQWH KRUDV D OD WHPSHUDWXUD GH ž& HQ
XQD KDELWDFLyQ FRQ WHPSHUDWXUD \ KXPHGDG
FRQWURODGD FRQ HO SURSyVLWR GH KDFHU
SRVWHULRUPHQWHSRVLEOHVFRPSDUDFLRQHV
/DV FDUDFWHUtVWLFDV GHO HQVD\R KDQ VLGR ODV
VLJXLHQWHV
¾
&pOXODGHFDUJD.J
¾
9HORFLGDGSUH7HVWPPV
¾
9HORFLGDG7HVWPPV
¾
9HORFLGDGSRVW7HVWPPV
¾
'LVWDQFLDPP
/DV PHGLGDV VH KDQ OOHYDGR D FDER SRU
TXLQWXSOLFDGR SDUD FDGD XQR GH ORV GRFH
VLVWHPDVSROLPpULFRVHQVD\DGRV
5HVXOWDGRV\GLVFXVLyQ
(VWH HVWXGLR LQIRUPD VREUH HO XVR GHO DQiOLVLV
GHO SHUILO GH OD WH[WXUD 73$ SDUD
FDUDFWHUL]DFLyQ PHFiQLFDPHQWH GH ORV VLVWHPDV
GLVSHUVRVIDUPDFpXWLFRVTXHFRQWLHQHQDOPHQRV
XQ SROtPHUR ELRDGKHVLYR \ SDUD GHWHUPLQDU
LQWHUDFFLRQHV HQWUH ORV FRPSRQHQWHV GH OD
IRUPXODFLyQ
'HWHUPLQDPRV OD GXUH]D ³KDUGQHVV´ IXHU]D
UHTXHULGD SDUD ORJUDU XQD GHIRUPDFLyQ DO
VLVWHPD &RPSUHVLELOLGDG ³&RPSUHVVLELOLW\´
HO WUDEDMR UHTXHULGR SDUD GHIRUPDU HO SURGXFWR
GXUDQWH OD SULPHUD FRPSUHVLyQ GH OD VRQGD R
VHQVRU
(O ³WUDEDMR GH DGKHUHQFLD´ R DGKHVLYLGDG
³DGKHVLYHQHVV´ HV GHFLU HO WUDEDMR QHFHVDULR
SDUD VXSHUDU ODV IXHU]DV DWUDFWLYDV HQWUH OD
VXSHUILFLH GH OD PXHVWUD \ OD VXSHUILFLH GH OD
VRQGD
/DV IRUPXODFLRQHV H[DPLQDGDV H[KLEHQ ODV
FDUDFWHUtVWLFDV PHFiQLFDV GHSHQGLHQWHV GHO
GLVHxRGHODIRUPXODFLyQ
7HFQRORJtD)DUPDFpXWLFD
'(6$552//2'(18(9$6)250$6'('26,),&$&,Ï13$5$862
3(',È75,&29(7(5,1$5,2
%&ODUHV9*DOODUGR0(,EixH]0(0RUDOHV0$5XL]
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH*UDQDGD
(VSDxD
6H PH]FODQ HO DJXD HO MDUDEH VLPSOH \ OD
,QWURGXFFLyQ
(QODDFWXDOLGDGODSUHRFXSDFLyQSRUGHVDUUROODU
VDFDURVD HQ ODV SURSRUFLRQHV DQWHULRUPHQWH
QXHYDVIRUPDVGHGRVLILFDFLyQGHDSOLFDFLyQHQ
LQGLFDGDV 6H OOHYDQ D HEXOOLFLyQ KDVWD TXH OD
SHGLDWUtD \ YHWHULQDULD HV XQD FRQVWDQWH HQ HO
PH]FODHVSHVH\SRVWHULRUPHQWHVHGHMDHQIULDU
iPELWRGHODWHFQRORJtDIDUPDFpXWLFD
3DUDODSUHSDUDFLyQGHODPH]FODGHJHODWLQD\
/DV JRPLQRODV VRQ SUHSDUDFLRQHV VyOLGDV SDUD
SHFWLQD DPEDV VH DGLFLRQDQ HQ FDOLHQWH \ HQ
DGPLQLVWUDFLyQ RUDO REWHQLGDV SRU PROGHR
FRQWLQXDDJLWDFLyQDODJXDGHODIyUPXOD
SUHVHQWDGDV HQ GRVLV ~QLFDV TXH YDQ D VHU
6H PH]FODQ ODV GRV VROXFLRQHV \ SRU ~OWLPR VH
IUDJPHQWDGDV FRQ ORV GLHQWHV PHGLDQWH
DGLFLRQDHOiFLGRFtWULFRSYSDUDREWHQHU
PDVWLFDFLyQ \ SRVWHULRUPHQWH GHJOXWLGDV (Q
XQ S+ GH “ HO VDERUL]DQWH \ HO
HVWH VHQWLGR SXHGHQ HVWDU GHVWLQDGDV D DTXHOORV
FRORUDQWH (VWD PH]FOD SULPDULD VH LQFRUSRUD D
SDFLHQWHV R DQLPDOHV TXH WHQJDQ GLILFXOWDGHV
ORVPROGHVSUHYLDPHQWHSDUDILQDGRV
SDUD GHJOXWLU R TXH SUHVHQWHQ UHVLVWHQFLD D RWUR
WLSRGHIRUPDVIDUPDFpXWLFDV
1XHVWURREMHWLYRKDVLGRODHODERUDFLyQ\SXHVWD
D SXQWR GH JRPLQRODV FRPR QXHYDV IRUPDV GH
GRVLILFDFLyQ HQ SHGLDWUtD \R YHWHULQDULD (O
HVWXGLRVHKDEDVDGRHQHOFXPSOLPLHQWRGHORV
OtPLWHVPtQLPRVGHDFHSWDELOLGDGHQORVHQVD\RV
GHXQLIRUPLGDGGHPDVDGLVJUHJDFLyQ\FDOLGDG
PLFURELROyJLFDGHVFULWRVHQOD5)(
0DWHULDO\0pWRGRV
)LJXUD )RWRJUDItD GH ODV JRPLQRODV VHJ~Q
0DWHULDOHV/RV SURGXFWRV XWLOL]DGRV SDUD OD
IyUPXOD,L]TGD\IyUPXOD,,GUFKD
HODERUDFLyQGHODVPH]FODVSULPDULDVIXHURQORV
VLJXLHQWHVÈFLGRFtWULFR$VSDUWDPR%HQWRQLWD
)2508/$,,
(VHQFLD GH IUHVD *OLFHULQD *RPD DUiELJD
(Q SULPHU OXJDU VH SUHSDUD XQD PH]FOD
0HWLOSDUDEHQ3HFWLQD6DFDURVD&RORUDQWHURMR
JOLFHULQDGD FDOLHQWH FRQ OD EHQWRQLWD OD JRPD
(VXPLQLVWUDGRVSRU*XLQDPD(VSDxD
DUiELJDODJHODWLQD\HOFRQVHUYDQWHHYLWDQGROD
*HODWLQD GH )DJURQ ,EpULFD (VSDxD \ $JXD
IRUPDFLyQGHJUXPRV
GHVWLODGD
$ OD PH]FOD DQWHULRU VH DGLFLRQD OD IDVH
/DV GLIHUHQWHV IRUPXODFLRQHV HPSOHDGDV HQ OD
DFXRVD MXQWR FRQ OD VDFDULQD FRORUDQWH \
HODERUDFLyQ GH ODV JRPLQRODV MXQWR FRQ ODV
VDERUL]DQWH KDVWD FRQVHJXLU YLVFRVLGDG
SURSRUFLRQHV UHODWLYDV D ORV FRPSRQHQWHV
DGHFXDGD
ILJXUDQHQODWDEOD
9HUWHPRVODSUHSDUDFLyQVREUHORVPROGHVVLQ
QHFHVLGDGGHSDUDILQDGR
7DEOD&RPSRVLFLyQGHODVIRUPXODFLRQHV
)2508/$,
)2508/$,,
5HVXOWDGRV \ GLVFXVLyQ&RQ HO ILQ GH REVHUYDU
-DUDEH VLPSOH %HQWRQLWD««
GLIHUHQFLDV VLJQLILFDWLYDV GH ODV GLIHUHQWHV
6DFDURVD«« $VSDUWDPR«
IRUPDVHQEDVHDVXFRPSRVLFLyQVHKDQOOHYDGR
*RPDDUiELJD
0H]FOD
D FDER OD UHDOL]DFLyQ GH GLIHUHQWHV HQVD\RV JHODWLQDSHFWLQD *OLFHULQD
&DGDXQDGHODVIRUPXODVVHSUHSDUDYHFHV(O
*HODWLQD« *HODWLQD««
SHULRGRGHHVWXGLRKDVLGRGHGtDV
0HWLOSDUDEHQFV
3HFWLQD««
(QFXDQWRDODVFDUDFWHUtVWLFDVRUJDQROpSWLFDVVH
&RORUDQWH
&RORUDQWHFV
KD YDORUDGR HO FRORU RORU \ VDERU DVt FRPR OD
6DERUL]DQWH
6DERUL]DQWHFV
IRUPD WDPDxR VXSHUILFLH \ FRQVLVWHQFLD GH ODV
S+ $FLGRFtWULFRS+
JRPLQRODV REMHWR GH HVWXGLR 1R VH KDQ
$JXD««««FVS $JXD««FVS
DSUHFLDGR FDPELRV VLJQLILFDWLYRV D OR ODUJR GHO
SHULRGRGHHVWXGLR
(QVD\RGHXQLIRUPLGDGGHPDVD
0pWRGRGHHODERUDFLyQ
6HSUHWHQGHGHWHUPLQDUVLODVPDVDVLQGLYLGXDOHV
)2508/$,
HVWiQ GHQWUR GH ORV OtPLWHV HVWDEOHFLGRV FRQ
3UHSDUDFLyQGHODVROXFLyQD]XFDUDGD
UHVSHFWRDODPDVDPHGLDGHODPXHVWUD
PXHVWUD\ODVXSHUILFLHGHOVHQVRU6LQHPEDUJR
DGKHVLYHQHVV HV XQD PHGLGD GHO WUDEDMR
UHTXHULGR SDUD VHSDUDU HO VHQVRU GH OD PXHVWUD
OD FXDO SXHGH HQ DOJXQRV FDVRV FRQOOHYDU D OD
IUDFWXUD GH HQODFHV FRKHVLYRV HQ OD PXHVWUD
0iV DGHODQWH VH UHDOL]DURQ ODV PHGLGDV GH ODV
SURSLHGDGHV PHFiQLFDV GH HVWRV VLVWHPDV
GLVSHUVRV HQ DXVHQFLD GH SROtPHUR PHGLDQWH OD
PLVPD WpFQLFD DQDOtWLFD SDUD H[DPLQDU
FRPSUREDU \ MXVWLILFDU ODV GLVWLQWDV SURSLHGDGHV
PHFiQLFDV
3RUWDQWRODVSULQFLSDOHVSURSLHGDGHVPHFiQLFDV
FRUUHVSRQGLHQWHV D ORV VLVWHPDV GLVSHUVRV HQ
DXVHQFLDGHSROtPHURKDQVLGRPRVWUDGDVHQOD
VLJXLHQWH7DEOD
7DEOD &DUDFWHUtVWLFDVPHFiQLFDVGHORVVLVWHPDV
7DEOD /DV FDUDFWHUtVWLFDV PHFiQLFDV GH ORV
VLVWHPDV GLVSHUVRV FRPR DQiOLVLV GHO SHUILO GH OD
WH[WXUD D ž& 0HGLD “ 6' GH DO PHQRV WUHV
UHSOLFDGRV
$GKHVLYHQH
VV1ÂPP
“
“
“
“
“
IRUPDGRVSRU,JHSDO&2FRPRDQiOLVLVGHOSHUILO
GHODWH[WXUDDž&0HGLD“6'GHDOPHQRVWUHV
UHSOLFDGRV
“
/DV SURSLHGDGHV PHFiQLFDV GH ODV GLVSHUVLRQHV
DFXRVDV VRQ SUHVHQWDGDV HQ OD 7DEOD 3DUD
HVWRV VLVWHPDV IDUPDFpXWLFRV HO LQFUHPHQWR GH
OD FRQFHQWUDFLyQ GHO WHQVLRDFWLYR PXHVWUD XQD
DOWHUDFLyQ GH ODV SURSLHGDGHV PHFiQLFDV
UHVXOWDQGR XQ LQFUHPHQWR GH OD GXUH]D
LQFUHPHQWR HO WUDEDMR QHFHVDULR SDUD FRPSULPLU
FDGD VLVWHPD KDVWD XQD GLVWDQFLD ILMDGD
&RPSUHVVLELOLW\HLQFUHPHQWDGRODDGKHVLYLGDG
GH ORV VLVWHPDV DO VHQVRU DQDOtWLFR
$GKHVVLYHQHVV
(OHVWXGLRHVWDGtVWLFRGHOHIHFWRGHOLQFUHPHQWR
GH OD FRQFHQWUDFLyQ GHO WHQVLRDFWLYR VREUH OD
KDUGQHVV FRPSUHVVLELOLW\ \ DGKHVVLYLW\ GH ODV
IRUPXODFLRQHV PHGLDQWH HO DQiOLVLV XQLIDFWRULDO
GHODYDULDQ]DSGHQRWDVLJQLILFDQFLD\
FRPSDUDFLRQHV P~OWLSOH HQWUH ODV PHGLDV FRQ
FRUUHFFLyQ GH %RQIHUURQL S GHQRWD
VLJQLILFDQFLD PXHVWUD OD H[LVWHQFLD GH
GLIHUHQFLDV VLJQLILFDWLYDV VREUH ODV SURSLHGDGHV
PHFiQLFDV FXDQGR VH SURGXFH HO LQFUHPHQWR GH
ODFRQFHQWUDFLyQGHWHQVLRDFWLYRGHORVVLVWHPDV
GLVSHUVRV$GHPiV IXH REVHUYDGD OD H[LVWHQFLD
GHXQDEXHQDFRUUHODFLyQHQWUHHOLQFUHPHQWRGH
KDUGQHVV GH ORV VLVWHPDV GLVSHUVRV DO
LQFUHPHQWDU OD FRQFHQWUDFLyQ WHQVLRDFWLYR FRQ
FRPSUHVVLELOLW\ HQWHQGLGR FRPR HO WUDEDMR
UHTXHULGRSDUDFRPSULPLUHOSURGXFWRKDVWDXQD
GLVWDQFLD ILMDGD SUHVHQWDQGR XQ FRHILFLHQWH GH
FRUUHODFLyQ OLQHDO GH 3HDUVRQ GH S<
8Q SURGXFWR GLVHxDGR SDUD XQD DSOLFDFLyQ
WySLFD FRPR PXFRVDV R SLHO GHEH
SUHIHULEOHPHQWH SRVHHU SURSLHGDGHV DGKHVLYDV
WDOHV TXH PHMRUHQ HO WLHPSR GH ORFDOL]DFLyQ HQ
HO OXJDU GH DFFLyQ \ GH HVWD IRUPD PHMRUDU OD
HILFDFLDFOtQLFD
$GKHVLYHQHVV HQ 73$ HV FRP~QPHQWH GHILQLGD
FRPR HO WUDEDMR UHTXHULGR SDUD VXSHUDU ODV
IXHU]DV DWUDFWLYDV HQWUH OD VXSHUILFLH GH OD
+DUGQHVV
1
“
“
“
“
“
“
&RPSUHVV
LELOLW\
1ÂPP
“
“
“
“
“
“
$GKHVLYHQH
VV1ÂPP
“
“
“
“
“
“
'H QXHYR FRPSUREDPRV TXH HO LQFUHPHQWR GH
WHQVLRDFWLYR GH ORV VLVWHPDV GLVSHUVRV HQ
DXVHQFLD GHO SROtPHUR SURYRFD XQ LQFUHPHQWR
VLJQLILFDWLYR HQ ORV YDORUHV GH ODV SURSLHGDGHV
PHFiQLFDV GH ORV VLVWHPDV 3DUD HOOR VH KD
UHDOL]DGR HO HVWXGLR HVWDGtVWLFR GH FRPSDUDFLyQ
HQWUH ODV PHGLDV SRU HO DQiOLVLV XQLIDFWRULDO GH
OD YDULDQ]D S GHQRWD VLJQLILFDQFLD \
FRPSDUDFLRQHV P~OWLSOH FRQ FRUUHFFLyQ GH
%RQIHUURQL S GHQRWD VLJQLILFDQFLD
PRVWUDQGR OD H[LVWHQFLD GH GLIHUHQFLDV
VLJQLILFDWLYDV (Q HVWH FDVR GHO HVWXGLR GH OD
FRUUHODFLyQ HQWUH ODV SURSLHGDGHV KDUGQHVV \
FRPSUHVVVLELOLW\ REVHUYDPRV OD DXVHQFLD GH
DVRFLDFLyQHQWUHHOODV
%LEOLRJUDItD
-RQHV',QW-3KDUP
-RQHV',QW-3KDUP
-RQHV ' -RXUQDO RI $SSOLHG 3RO\PHU
6FLHQFH
&DVWHOODQR,7HVLV'RFWRUDO8QLYHUVLGDGGHO
3DtV9DVFR6DQ6HEDVWLiQ
,;&RQJUHVRGHOD6(),*
$VLPLVPR GXUDQWH HO SHULRGR GH HVWXGLR
HQVD\DGR ODV JRPLQRODV REMHWR GH HVWXGLR QR
VXIUHQ QLQJ~Q FDPELR VLJQLILFDWLYR HQ HO YDORU
PHGLRGHPDVD
(QVD\RGHGLVJUHJDFLyQ
6H UHDOL]D HQ DJXD D ž& XWLOL]DQGR HO
GLVSRVLWLYR GH GLVJUHJDFLyQ GHVFULWR HQ 5)(
(VWH HQVD\R HVWi GHVWLQDGR D GHWHUPLQDU OD
PD\RU R PHQRU DSWLWXG GH ODV JRPLQRODV SDUD
GHVLQWHJUDUVH HQ PHGLR OtTXLGR HQ XQ WLHPSR
GHWHUPLQDGR 6H UHDOL]D HO HQVD\R SDUD ODV GRV
IRUPXODFLRQHV HODERUDGDV \ SDUD XQD FRPHUFLDO
TXHQRVVLUYHGHUHIHUHQFLD
(OWLHPSRGHGLVJUHJDFLyQSDUDODIRUPXOD,HV
GH KRUDV \ PHGLD (Q OD IyUPXOD ,, \ HQ OD
IyUPXODFRPHUFLDOSRGHPRV REVHUYDUTXHDODV
KRUDVKDQVXIULGRXQSURFHVRGHKLQFKDPLHQWR
FRQ FDPELRV HQ VX IRUPD SHUR VLQ OOHJDU D
GLVJUHJDUVHWDEOD
(VWH PLVPR HQVD\R VH KD OOHYDGR D FDER
VLPXODQGRXQDPDVWLFDFLyQSUHYLD\HOUHVXOWDGR
REWHQLGR KD VLGR HO VLJXLHQWH ODV JRPLQRWDV
HODERUDGDV FRQIRUPH D OD IyUPXOD , VH KDQ
GLVJUHJDGRHQPHQRVGHPLQXWRPLHQWUDVTXH
ODVPXHVWUDVGHODIyUPXOD,,\GHODIyUPXODGH
UHIHUHQFLD KDQ WDUGDGR PLQXWRV HQ
GHVDSDUHFHU
7DEOD(QVD\RGHGLVJUHJDFLyQ
GLVJUHJDFLyQ GLVJUHJDFLyQ
ž&
*20,12/$6
ž&
WURFHDGDV
HQWHUDV
7RPDPRV JRPLQRODV HVFRJLGDV DO D]DU GH
FDGD XQD GH ODV IyUPXODV HQ HVWXGLR \ ODV
SHVDPRV LQGLYLGXDOPHQWH /RV SHVRV PHGLRV
REWHQLGRV GH ODV XQLGDGHV IXHURQ ORV
VLJXLHQWHV
ENSAYO UNIFORMIDAD
MASA
22
21
20
19
18
17
16
Fórmula
Fórmula
1
2
1 Día
18,71
21,31
3 Días
18,63
21,25
7 Días
18,49
21,26
15 Días
18,19
21,31
30 Días
17,91
21,38
)LJXUD (YROXFLyQ XQLIRUPLGDG GH PDVD
GXUDQWHGtDV
/RV GDWRV GH PDVD REWHQLGRV QR VREUHSDVDQ HO
SRUFHQWDMH GH GHVYLDFLyQ SHUPLWLGR “ /D
PDVD LQGLYLGXDO GH FDGD XQD GH ODV JRPLQRODV
QRVHKDGHVYLDGRGHODPDVDPHGLDHQPiVGHO
GREOHGHOSRUFHQWDMHHVSHFLILFDGRILJXUD
Peso (g)
,;&RQJUHVRGHOD6(),*
)yUPXOD,
KRUDV
PLQXWR
)yUPXOD,,
!KRUDV
PLQXWRV
)yUPXOD
FRPHUFLDO
!KRUDV
PLQXWRV
(QVD\RPLFURELROyJLFR
&XPSOHODQRUPDWLYDGHVFULWDHQ5)(
%LEOLRJUDItD
6DOD]DU 5 $QiOLVLV \ FRQWURO GH
PHGLFDPHQWRV %DUFHORQD 6DOD]DU 0DFLDQ SS
)RRG +\GURFROORLGV 7H[WXUD DQG VWUXFWXUH
RIJHODWLQSHFWLQEDVHGJXPP\FRQIHFWLRQV
5HDO )DUPDFRSHD (VSDxROD HG %H0LOOHU-1*XPVK\GURFROORLGVDQDO\WLFDO
DVSHFWV ,Q $ & (OLDVVRQ &DUERK\GUDWHV LQ
IRRGV1HZ <RUN 0DUFHO 'HNNHU SS )LJXUD1ž(VWUDWHJLDSDUDODVHOHFFLyQGHPDWHULDOHV
(92/87,212)6,=(6,=(',675,%87,21$1'=327(17,$/2)',63(56('3+$6(
'523/(76,12:(08/6,2167+528*+$*(,1*
0()UDQFR*LO$05RGUtJXH]%D\yQ
%LRWUDQVIRUPDWLRQV*URXS'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\6FKRRORI
3KDUPDF\&RPSOXWHQVH8QLYHUVLW\3OD]D5DPyQ\&DMDOVQ0DGULG6SDLQ
WHPSHUDWXUH ž& DQG WKH WZR SKDVHV ZHUH
,QWURGXFWLRQ
'URSOHW VL]H DQG GURSOHW VL]H GLVWULEXWLRQ LQWR
PL[HGWRJHWKHUZLWKDURWRUVWDWRUKRPRJHQL]HU
WKH GLVSHUVHG SKDVH DUH PDLQ IDFWRUV WR
3RO\WURQ37
FRQVLGHU LQ WKH GHYHORSPHQW DQG VWRUDJH RI D
7KH WZR HPXOVLRQV REWDLQHG ZHUH ZKLWH
QHZ VHPLVROLG SKDUPDFHXWLFDO IRUP >@ 7KH
VHPLVROLGFUHDPV(ZHUHPRUHIXLGWKDQ(
EHWWHU GHVFULSWLRQ RI DQ HPXOVLRQ LV SURYLGHG
7KH HPXOVLRQV ZHUH VWRUDJHG DW URRP
E\ WKH VL]H GLVWULEXWLRQ RI LWV LQQHU GURSOHWV
WHPSHUDWXUHLQWKHGDUN
VLQFHLWLQGLFDWHVKRZWKHLQQHUSKDVHKDVEHHQ
GLYLGHG DQG GLVSHUVHG WKURXJK WKH FRQWLQXRXV
• 'URSOHWVL]HGHWHUPLQDWLRQ
SKDVH%HVLGHVGURSOHWVL]HDIIHFWVWKHVWDELOLW\
'URSOHW VL]H PHDVXUHPHQWV IRU LQWHUQDO SKDVH
RIHPXOVLRQVDQGVXVSHQVLRQVDVLQWHUSDUWLFXODU
RIERWKHPXOVLRQV((ZHUHFDUULHGRXW
IRUFHV DQG VHGLPHQWDWLRQ UDWH GHSHQGV RQ WKH
LQ WULSOLFDWH DW VL[ GLIIHUHQW DJHLQJ WLPHV VL]HRIWKHGLVSHUVHGPDWWHU>@
KRXUV DQG ZHHNV DIWHU WKH
,Q RUGHU WR FDOFXODWH JOREXOH VL]H GLVSHUVHG
SUHSDUDWLRQRIERWKHPXOVLRQVXVLQJDSDUWLFOH
GURSOHWV DUH FRQVLGHU WR EH VSKHULFDO >@
VL]HDQGVKDSHDQDO\]HU*DODL&,6DWž&
0RUHRYHU GLIIHUHQW PHDVXUHPHQW WHFKQLTXHV
RIWHPSHUDWXUH
>@DQGUHVXOWVJUDSKV>@FDQEHXVHG
7KH YDOXHV IRU GLIIHUHQW SDUDPHWHUV VXFK DV
=SRWHQWLDO PHDVXUHPHQW JLYHV XV LQIRUPDWLRQ
YROXPH HTXLYDOHQW GLDPHWHU 6DXWHU GLDPHWHU
DERXW WKH HOHFWULFDO FKDUJH RQ WKH GURSOHW
HWFZHUHJDWKHUHG$IWHUWKDWGLIIHUHQWUHVXOWV
VXUIDFH LWV VLJQ TXDQWLW\ DQG UHSHUFXVVLRQ RQ
JUDSKV QRUPDO GLVWULEXWLRQ DQG ORJQRUPDO
WKH VWDELOLW\ RI WKH GLVSHUVHG V\VWHP WKURXJK
GLVWULEXWLRQRQSUREDELOLW\SDSHUZHUHSORWWHG
VWRUDJH WLPH >@ DV WKH HOHFWULFDO VXSHUILFLDO
FKDUJH DIIHFWV WKH IORFXODWLRQ UDWH >@ DQG
• =SRWHQWLDOGHWHUPLQDWLRQ
WRWDOO\ IORFXODWHG GURSOHWV VKRZ QXOH ]
=SRWHQWLDO PHDVXUHPHQWV IRU ERWK HPXOVLRQV
SRWHQWLDO>@
ZHUH FDUULHG RXW DW ž& LQ D =HWD0DVWHU
,QWKLVZRUNWZRGLIIHUHQW2:HPXOVLRQVZHUH
SDUWLFOHDQDO\]HUDWWKHVDPHDJHLQJWLPHVDVLQ
SUHSDUHG LQFOXGLQJ VDOLF\OLF DFLG DV DFWLYH
WKH GURSOHW VL]H SHUIRUPDQFH $W OHDVW HLJKW
FRPSRXQG
VDPSOHVZKHUHWHVWHGDWHDFKDJHLQJWLPH
7KH DLPV RI WKLV ZRUN DUH D WR DFKLHYH WKH
(OHFWURSKRUHWLFPRELOLW\DQG=SRWHQWLDOYDOXHV
GURSOHW VL]H FKDUDFWHUL]DWLRQ RI WZR GLIIHUHQW
ZHUHJDWKHUHGIRUHYHU\WHVW
2:HPXOVLRQVDQGEWRVWXG\WKHVWDELOLW\RI
ERWK HPXOVLRQV WKURXJK D QLQHZHHNV SHULRG
5HVXOWVDQGGLVFXVVLRQ
DFFRUGLQJ WR WKH HYROXWLRQ RI WKH GURSOHW VL]H
•7KH GURSOHW VL]H OHQJWK GLDPHWHU
SDUDPHWHUVDQGVL]HGLVWULEXWLRQDQGRIWKH=
GLVWULEXWLRQVRIERWKHPXOVLRQVREWDLQHGDW
SRWHQWLDOYDOXH
KRXUVDQGQLQHZHHNVRIVWRUDJHDUHVKRZQLQ
WDEOH HPXOVLRQ ( DQG WDEOH HPXOVLRQ
0DWHULDOVDQGPHWKRGV
( DQG WKHLU QRUPDO GLVWULEXWLRQ JUDSKV DUH
• &RPSRVLWLRQ RI WKH HPXOVLRQV LV VKRZQ LQ
VKRZQLQILJXUHHPXOVLRQ(DQGILJXUH
WDEOH
HPXOVLRQ(
7DEOH&RPSRVLWLRQRIWKHHPXOVLRQV
(PXOVLRQ
(
0,0
-10,0
-20,0
-28,4
-0,6
Blanco placa PVC Toro
1
2,0
3,0
4,0
5,0
6,0
7,0
8,0
9,0
10,0
11,3
1,50
2,00
2,50
3,00
3,50
4,00
4,50
5,00
5,50
6,09
Blanco placa PVC Toro
UV_VIS_1
1 - SIi...
WVL:254 nm
Az
mAU
3,00
2,00
1,00
0,00
-0,75
-0,22
min
0,50
1,00
1,50
2,00
2,50
3,00
3,50
4,00
4,50
5,00
5,50
)LJXUD1ž&URPDWRJUDPD&KDSD/DFDGD
Unknown No.3 - 8,827
Unknown No.1 - 5,454
min
1,0
1,00
20080102-0 SINTROM LBH #16
4,00
UV_VIS_1
)LJXUD1ž&URPDWRJUDPD39&7RURŠ
3DUD OD FKDSD ODFDGD VH REVHUYD HQ HO
FURPDWRJUDPD GHWDOODGR HQ OD )LJXUD 1ž TXH
QR DSDUHFH QLQJ~Q SLFR FURPDWRJUiILFR
GHVFRQRFLGR\TXHHOEODQFR\HOVROYHQWHVDOHQ
PX\OLPSLRVORFXDOLQGLFDTXHQRH[LVWHQUHVWRV
GH OD VXVWDQFLD DFWLYD GHPRVWUDQGR GH HVWD
PDQHUD TXH D WUDYpV GH XQD OLPSLH]D DGHFXDGD
QRVHUiDEVRUELGRV
min
0,50
)LJXUD1ž&URPDWRJUDPD&KDSD/DFDGD
&DEHFRPHQWDUTXHHQHODQiOLVLVGHO39&$]XO
FRQGXFWLYR VH SXHGH REVHUYDU TXH QR DSDUHFHQ
SLFRV FURPDWRJUiILFRV GHVFRQRFLGRV \
FXDQWLILFDEOHVVLQHPEDUJRDSDUHFHQXQRVSLFRV
PX\SHTXHxRVQRFXDQWLILFDEOHVDXQWLHPSRGH
UHWHQFLyQ GLVWLQWRV GH OD VXVWDQFLD DFWLYD TXH
SRGUtD FRUUHVSRQGHU D OD ODFD VXSHUILFLDO TXH
FRQWLHQH HVWH 39& HO FXDO KD VLGR UHPRYLGD HQ
OD HWDSD GH OD OLPSLH]D \D TXH VH UHDOL]D XQD
LQVSHFFLyQ YLVXDO \ VHREVHUYDXQDGLVPLQXFLyQ
GHOEULOORGHOPLVPR
WVL:230 nm
Unknown No.2 - 7,334
10,0
Az
0,0
-5,0
6,00
6,50
7,00
7,50
7,98
&RQFOXVLRQHV
'HDFXHUGRDORVUHVXOWDGRVREWHQLGRVGHWDOODGRV
HQOD7DEOD1ž\ODV)LJVHFRQFOX\HTXH
G
(O 39& 7RURŠ HV HO PDWHULDO LGyQHR
SDUDODLQVWDODFLyQGHVXHORV
H
/D FKDSD /DFDGD Š HV HO PDWHULDO
LGRQHRSDUDODLQVWDODFLyQGHSDUHGHV
I
/DXWLOL]DFLyQGHPDWHULDOHVDOWHUQDWLYRV
GHVSXpVGHXQHVWXGLRDGHFXDGRHVDFHSWDEOH\D
TXH VH GHPXHVWUD VX QR UHWHQFLyQ GH VXVWDQFLDV
DOWDPHQWHWy[LFRV
%LEOLRJUDItD
6DOD]DU 0 *HVWLyQ GH OD &DOLGDG HQ HO
'HVDUUROOR \ )DEULFDFLyQ ,QGXVWULDO GH
PHGLFDPHQWRV7RPR,,7HPDSS
&)5 SDUW *03 $PHULFDQDV
KWWSZZZDFFHVVGDWDIGDJRYVFULSWVFGUKFI
GRFVFIFIU&)56HDUFKFIP"&)53DUW VK
RZ)5 YLVLWDGD
*03
(XURSHDV
&DSLWXOR
KWWSHFHXURSDHXHQWHUSULVHSKDUPDFHXWLFDOV
HXGUDOH[YROSGIVHQFDSHQSGI YLVLWDGD
(PXOVLRQ(
• 3UHSDUDWLRQDQGVWRUDJHRIWKHHPXOVLRQV
(PXOVLRQV ZHUH SUHSDUHG DFFRUGLQJ WR D
VWDQGDUG SURFHGXUH >@ 6DOLF\OLF DFLG 6$
ZDV GLVVROYHG LQ WKH PHOWHG IDWW\ SKDVH
0HOWHG ZDWHU SKDVH ZDV DGGHG DW WKH VDPH
7DEOH(PXOVLRQ(6L]HGLVWULEXWLRQ/HQJWKGLDPHWHUμP
KRXUV
ZHHNV
)UHFXHQF\
0HDQ
)UHFXHQF\
GLDPHWHU
0HDQ
GLDPHWHU
,;&RQJUHVRGHOD6(),*
7DEOH(PXOVLRQ(6L]HGLVWULEXWLRQ/HQJWKGLDPHWHUμP
KRXUV
ZHHNV
0HDQ
)UHFXHQF\
0HDQ
)UHFXHQF\
GLDPHWHU
GLDPHWHU
Figure 1. Emulsion E1.
24 hours
9 weeks
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
0,00
1,00
2,00
3,00
4,00
5,00
6,00
Droplet diameter (μm)
24 hours
9 weeks
Figure 2. Emulsion E2.
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
0,00
1,00
2,00
3,00
4,00
5,00
6,00
Droplet diameter (μm)
•,Q WDEOH HPXOVLRQ ( DQG WDEOH HPXOVLRQ ( WKH YROXPH HTXLYDOHQW PHDQ
GLDPHWHU WKH ORJQRUPDO GLVWULEXWLRQ VORSH
SORWWHG RQ SUREDELOLW\ SDSHU DQG WKH
SRO\GLVSHUVLW\GHJUHHZHUHFDOFXODWHGIURPWKH
UHVXOWV JDWKHUHG DW HYHU\ VWRUDJH WLPH KRXUVDQGZHHNV
7DEOH(PXOVLRQ(6L]HSDUDPHWHUV
9ROXPHHTXLYDOHQW
$JHLQJ
/RJQRUPDO
3RO\GLVSHUVLW\
PHDQGLDPHWHU
WLPH
GLVWULEXWLRQVORSH
GHJUHH
μP
KRXUV
“
“
“
ZHHN
“
“
“
ZHHNV
“
“
“
ZHHNV
“
“
“
ZHHNV
“
“
“
ZHHNV
“
“ “
7DEOH(PXOVLRQ(6L]HSDUDPHWHUV
9ROXPHHTXLYDOHQW
$JHLQJ
/RJQRUPDO
3RO\GLVSHUVLW\
PHDQGLDPHWHU
WLPH
GLVWULEXWLRQVORSH
GHJUHH
P
KRXUV
“
“ “
ZHHN
“
“
“
ZHHNV
“
“
“
ZHHNV
“
“
“
ZHHNV
“
“
“
ZHHNV
“
“
“
••(YROXWLRQRI=SRWHQWLDOWKURXJKWKHDJHLQJ
SHULRGLVVKRZQLQILJXUH
Figure 3. Z-Potential evolution through ageing
Ageing time (weeks)
00
2
4
6
8
10
-5
-10
-15
-20
-25
-30
-35
-40
Emulsion E1
Emulsion E2
-45
$V FDQ EH VHHQ HPXOVLRQ ( SUHVHQWV KLJKHU
GURSOHW VL]H WKDQ HPXOVLRQ ( ERWK DW WKH
EHJLQQLQJ DQG DW WKH HQG RI WKH DJHLQJ SHULRG
WDEOHV7KHVDPHREVHUYDWLRQFDPHVRXW
IURPWKHUHVXOWVVXPPDUL]HGLQWDEOHVDQG
ZKHUH WKH KLJKHVW YROXPH HTXLYDOHQW PHDQ
GLDPHWHU'YLVVKRZQE\HPXOVLRQ(DWDQ\
DJHLQJ WLPH 7KURXJK WKH QLQH DJHLQJ ZHHNV
WKHDYHUDJH'YLVμPIRUHPXOVLRQ(DQG
μPIRUHPXOVLRQ(
0RUHRYHU VL]H GLVWULEXWLRQ UDQJH LV ZLGHU IRU
HPXOVLRQ(WKDQIRUHPXOVLRQ(WDEOHV
ILJXUHV7KHUHIRUHHPXOVLRQ(VKRZV
WKH KLJKHVW ORJQRUPDO GLVWULEXWLRQ VORSH
YDOXHV DQG WKH ORZHVW SRO\GLVSHUVLW\ GHJUHH
WDEOHVILJXUHV
7KH VWDWLVWLFDO DQDO\VLV α VKRZV D
VLJQLILFDQW LQFUHDVH LQ GURSOHW VL]H RI ERWK
HPXOVLRQV GXULQJ WKH VWRUDJH WLPH 0RUHRYHU
WKHUH DUH PRUH VWDWLVWLFDOO\ VLJQLILFDQW
GLIIHUHQFHV DPRQJ UHVXOWV RI 'Y YDOXHV RI
HPXOVLRQ(WKDQWKDWRIHPXOVLRQ(
,Q PRVW FDVHV WKH YDOXHV RI =SRWHQWLDO RI
HPXOVLRQ(DUHKLJKHUWKDQWKRVHRIHPXOVLRQ
( ILJXUH ,Q JHQHUDO GURSOHW =SRWHQWLDO
YDOXHV RI ( HPXOVLRQ GHFUHDVH ZLWK VWRUDJH
WLPH ZKHUHDV WKH RSSRVLWH KDSSHQGV ZKHQ
HPXOVLRQ ( LV WHVWHG =SRWHQWLDO LQFUHDVHV
ZLWKWLPH,QERWKHPXOVLRQV=SRWHQWLDOYDOXHV
DUHQHJDWLYH
Z-Potential (mv)
7HFQRORJtD)DUPDFpXWLFD
0LQHUDORLO
:KLWHVRIWYDVHOLQH
7HIRVp+/% /DEUDILO0&6+/% 'LVWLOOHGZDWHU
7ZHHQ+/% 7HIRVp+/% 20080103-00 DIOVAN LBH #13
mAU
20,0
UV_VIS_1
WVL:305 nm
-12,8
-0,19
&RQ UHVSHFWR DO VZDEE HQ VHFR GHVSXpV GH
UHDOL]DUODOLPSLH]D\ODUHFXSHUDFLyQVHREVHUYD
HQ HO )LJXUD 1ž TXH SDUD HO 39& 7RURŠ
DSDUHFH DOJ~Q SLFR FURPDWRJUiILFR GHVFRQRFLGR
ORV FXDOHV QR VRQ FXDQWLILFDEOHV DO WUDWDUVH GH
SRUFHQWDMHVPX\SHTXHxRV
32,1
Blanco PVC Toro
1 - Fluvast...
mAU
5,0
5HVXOWDGRV\'LVFXVLyQ
'H ORV FXDWUR PDWHULDOHV VHOHFFLRQDGRV VH
REVHUYD TXH SDUD VXHORV OD UHFXSHUDFLyQ HV •
VHREWLHQHHQHO39&7RURŠ\HQSDUHGHVOD
&RPSRQHQWVRIWKHHPXOVLRQV
20080104-0 FLUVASTATINA LBH #14
12,9
7DEOD 1ž 5HVXOWDGR FRUUHVSRQGLHQWH D ORV PDWHULDOHV
VHOHFFLRQDGRV
6ZDEE+~PHGR
6ZDEE6HFR
6HF
6HF
6HF
6HF
6,
39&7RURŠ
1$
1$
39&$]XO
1$
1$
3ODFD
1$
1$
0HWDOLFD
&KDSD/DF
1$
1$
)/
39&7RURŠ
1$
1$
39&$]XO
1$
1$
3ODFD
1$
1$
0HWDOLFD
&KDSD/DF
1$
1$
9/
39&7RURŠ
39&$]XO
1$
1$
3ODFD
1$
1$
0HWDOLFD
&KDSD/DF
Probability
/D LQGXVWULD )DUPDFpXWLFD HV XQD LQGXVWULD
HVSHFLDOL]DGD HQ OD SUHSDUDFLyQ GH
PHGLFDPHQWRV (VWR TXLHUH GHFLU TXH VX
REMHWLYR SULPRUGLDO HV VXPLQLVWUDU D ORV
FRQVXPLGRUHV ILQDOHV TXH VRQ ORV SDFLHQWHV
DTXHOOD VXVWDQFLD R PH]FOD GH VXVWDQFLDV TXH
WUDQVIRUPDGDV HQ OD IRUPD IDUPDFpXWLFD
DGHFXDGD SDUD VX DGPLQLVWUDFLyQ SHUPLWHQ
GLDJQRVWLFDU SUHYHQLU DOLYLDU R FXUDU
HQIHUPHGDGHV3RUORWDQWRVWRGRVORVIDFWRUHV
H[WHUQRV FRPR ODV SHUVRQDV LQVWDODFLRQHV TXH
HVWiQ LPSOLFDGDV HQ HO FLFOR GH WUDQVIRUPDFLyQ
GHXQDPDWHULDSULPDGHVGHTXHOOHJDDODSODQWD
IDUPDFpXWLFDKDVWDHOPRPHQWRTXHVHUHDOL]DVX
OLEHUDFLyQ \ SRVWHULRU GLVWULEXFLyQ FRPR
SURGXFWRDFDEDGRMXHJDQXQSDSHOSULPRUGLDO
(VWRVPHGLFDPHQWRVUHTXLHUHQVHUIDEULFDGRVHQ
XQDVLQVWDODFLRQHVDGHFXDGDVGLVHxDGDVGHVGHXQ
SXQWR GH YLVWD GH ODV *03 *RRG
0DQXIDFWXULQJ 3UDFWLFHV \ FXPSOLHQGR FRQ ODV
QRUPDWLYDV GH +6( +HDOWK 6DIHW\ (FRORJ\
3DUD HO GLVHxR GH XQ SODQWD IDUPDFpXWLFD HV
HVHQFLDOTXHHOHTXLSRTXHFRQIRUPDHOSUR\HFWR
HO FXDO HVWDUi LQWHJUDGR SRU SHUVRQDO GH ORV
'HSDUWDPHQWRVGH*DUDQWtDGH&DOLGDGLQFOXLGR
&RQWURO GH &DOLGDG +6( ,QJHQLHUtD \
3URGXFFLyQ WHQJDQ HO FRQRFLPLHQWR HVSHFLILFR
DFHUFDGH
• /DIXQFLyQSDUDODTXHHOHGLILFLRHVGLVHxDGR
(MHPSOR ,QVWDODFLRQHV SDUD IRUPDV
IDUPDFpXWLFDV VyOLGDV KRUPRQDV FLWRVWiWLFRV
HVWpULOHVHWF
• /DV DFWLYLGDGHV \ RSHUDFLRQHV TXH VH YDQ D
OOHYDUDFDERHQHOLQWHULRUGHODVLQVWDODFLRQHV
IDUPDFpXWLFDV
• /D ,QWHUUHODFLyQ HQWUH ODV GLIHUHQWHV
DFWLYLGDGHV TXH VH YDQ D OOHYDU D FDER HQ HO
H[WHULRUGHOHGLILFLR
$KRUD VL KDEODPRV GHO GLVHxR GH XQDV
LQVWDODFLRQHV ³KLJK FRQWDLQPHQW´ TXLHUH GHFLU
TXH GHQWUR GH HVWDV LQVWDODFLRQHV VH YDQ D
IDEULFDU SURGXFWRV FX\R SULQFLSLR DFWLYR HV
DOWDPHQWHDFWLYRFRPRSRUHMHPSORFLWRVWiWLFRV
3RU WDQWR UHTXLHUH SUHVWDU HVSHFLDO DWHQFLyQ D
GHILQLU XQ VLVWHPD GH FRQWHQFLyQ WDQWR HQ
LQVWDODFLRQHV FRPR WDPELpQ HQ ODV PiTXLQDV
GRQGH XQ VLVWHPD GH SUHVLRQHV GLIHUHQFLDOHV
MXJDUiXQUROPX\LPSRUWDQWHDGHPiVGHEHPRV
HYDOXDU TXH WLSR GH (3, (TXLSR GH SURWHFFLyQ
LQGLYLGXDO VH GHEH XWLOL]DU HQ FDGD iUHD \D VHD
SURGXFFLyQDFRQGLFLRQDGR\FRQWUROGHFDOLGDG
(O IOXMR GH SHUVRQDO \ PDWHULDOHV WDPELpQ GHEH
HVWDUVROLGDPHQWHHVWUXFWXUDGRDVtFRPRXQSODQ
SDUD OD IRUPDFLyQ GHO SHUVRQDO DVHJXUiQGRQRV
GH HVWD PDQHUD TXH VROR SHUVRQDO FRQ XQ
HQWUHQDPLHQWR DGHFXDGR SXHGD DFFHGHU D HVWD
LQVWDODFLRQHVIDUPDFpXWLFDV+LJK&RQWDLQPHQW
/D FRQVWUXFFLyQ GH HVWDV LQVWDODFLRQHV GHEH GH
UHDOL]DUVH FRQ ORV PDWHULDOHV DGHFXDGRV \D TXH
DOILQDOGHFDGDFDPSDxDGHEHGHUHDOL]DUVHXQD
OLPSLH]D H[KDXVWLYD QR VROR GH ODV PiTXLQDV
VLQRGHODVLQVWDODFLRQHVSRUWDQWRVHHVSHUDTXH
HVWRV PDWHULDOHV TXH FRQIRUPDUiQ SDUHGHV
WHFKRV VXHORV QR DEVRUEDQ QL DGVRUEDQ OD
VXVWDQFLD DFWLYD \D TXH UHSUHVHQWD XQ ULHVJR
SRWHQFLDO SDUD ORV WUDEDMDGRUHV /D
UHFRPHQGDFLyQ HV XWLOL]DU HO $FHUR ,QR[LGDEOH
\D TXH HV IiFLO GH OLPSLDU SHUR HO FRVWH VHUtD
GHPDVLDGR HOHYDGR SRU WDO PRWLYR HVWH WUDEDMR
GH LQYHVWLJDFLyQ PXHVWUD OD PDQHUD GH FyPR
UHDOL]DU XQ HVWXGLR DGHFXDGR VHOHFFLRQDQGR ORV
PDWHULDOHV LGyQHRV SUHYLR D OD FRQVWUXFFLyQ GHO
HGLILFLR
0DWHULDOHV\PpWRGRV
0DWHULDOHV
PDWHULDOHV 6XHORV 39& $]XO &RQGXFWLYR
39& 7RURŠ 3DUHGHV &KDSD ODFDGD 3ODFD
0HWiOLFD
0pWRGRV
6HUHDOL]DXQHVWXGLRGHPDWHULDOHVTXHFRQVLVWH
HQ HYDOXDU HO SRUFHQWDMH GH UHFXSHUDFLyQ FRQ HO
SURGXFWR PiV LQVROXEOH 6, HO SURGXFWR
PiVSHJDMRVR)/\HOSURGXFWRPiVGLItFLO
GHOLPSLDU9/VREUHHOPDWHULDOGHVSXpVGH
XQDOLPSLH]D /DUHFXSHUDFLyQVH KDUiD WUDYpV
GH 6ZDEE +~PHGRHYDO~D UHVLGXRV GHO $3,
H[WUDtGRVFRQVROYHQWHV6ZDEEHQVHFRHYDO~D
UHVLGXRV TXH SRGUtDQ HQFRQWUDU HQ SDUHGHV \
VXHORV\TXHHORSHUDULRSRGUtDOOHYDUVHORVVREUH
OD SLHO DO WRFDUORV /D UHFXSHUDFLyQ VHUi
DFHSWDEOHFXDQGR•
Probability
,QWURGXFFLyQ
UHFXSHUDFLyQODFKDSDODFDGDODUHFXSHUDFLyQHV
• VH REWLHQH HQ OD FKDSD ODFDGD &RQ
UHVSHFWRDO6ZDEE6HFRVHREVHUYDTXHGHVSXpV
GH OD OLPSLH]D QR VH HQFRQWUDURQ UHVLGXRV GH OD
VXVWDQFLD DFWLYD PiV LQVROXEOH QL GH OD PiV
SHJDMRVD SHUR VH REVHUYDQ XQ SRUFHQWDMH PX\
EDMR FXDQGR UHDOL]DPRV OD UHFXSHUDFLyQ GHO
SURGXFWR PiV GLItFLO GH OLPSLDU HO FXDO VHUi
RSWLPL]DGRGHVSXpVGHUHDOL]DUOD YDOLGDFLyQGH
OLPSLH]D FRUUHVSRQGLHQWH XQD YH] ILQDOLFH OD
FRQVWUXFFLyQ \ OD FDOLILFDFLyQ GH ODV QXHYDV
LQVWDODFLRQHV
Az
(678',2'(/$6(/(&&,Ï1'(0$7(5,$/(687,/,=$'26(1/$&216758&&,Ï1'(
81$3/$17$+,*+&217$,10(17
-RKQQ\(GZDUG$JXLODU'tD]0RQWVH0RQWDQHU(YD3ODQDV/RUHQD7HUUHV,PPDFXODGD*RPH]
(OLDV%HQLWR
*DUDQWtDGH&DOLGDG1RYDUWLV)DUPDFpXWFLD6$'RFWRUDQGRHQ)DUPDFLD\7HFQRORJtD
)DUPDFpXWLFD
,;&RQJUHVRGHOD6(),*
= 1, RefWavelength = 600, RefBandwidth = 1, St = 0.80, Avg = On
7HFQRORJtD)DUPDFpXWLFD
&RQFOXVLRQV
$VIORFXODWLRQWDNHVSODFHGURSOHWVL]HDQGVL]H
GLVWULEXWLRQLQFUHDVHLQERWKHPXOVLRQV
7KH ORZHU WKH GURSOHW VL]H ( 'Y μP
( 'Y μP WKH KLJKHU WKH VL]H
KRPRJHQHLW\DQGWKHORZHUWKHIORFXODWLRQ
(YHQ WKRXJK HPXOVLRQ ( =SRWHQWLDO JHWV
ZHDNHU ZLWK DJHLQJ LW UHPDLQV VWURQJHU WKDQ
HPXOVLRQ(=SRWHQWLDO
'URSOHW VL]H DQG LWV GLVWULEXWLRQ DUH QRW RQO\
JRRG WRROV WR FKDUDFWHUL]H DQ HPXOVLRQ EXW
WKH\ DUH JRRG WLPHGHSHQGHQW VWDELOLW\
SDUDPHWHUVDVZHOO
7HFQRORJtD)DUPDFpXWLFD
5HIHUHQFHV
>@ ,'621%3KDUPDFHXWLFDOHPXOVLRQV(Q
3KDUPDFHXWLFDO 'RVDJH )RUPV 'LVSHUVH
6L\VWHPV YRO  HG (G /LHEHUPDQ
5LHJHU %DQNHU 0DUFHO 'HNNHU 1HZ
<RUN
>@ 6$/$*(5 - / (PXOVLRQ SURSHUWLHV
DQG UHODWHG NQRZKRZ WR DWWDLQ WKHP (Q
3KDUPDFHXWLFDO
(PXOVLRQV
DQG
6XVSHQVLRQV 0DUFHO 'HNNHU 1HZ <RUN
>@ $//(1 7 'X 3217 GH 1(02856
(, 3RZGHU VDPSOLQJ DQG SDUWLFOH VL]H
GHWHUPLQDWLRQ

HG
(OVHYLHU
$PVWHUGDP
>@ 67$1,)257+ - $QiOLVLV GHO WDPDxR
GH SDUWtFXODV (Q ³)DUPDFLD /D FLHQFLD
GHO GLVHxR GH ODV IRUPDV IDUPDFpXWLFDV 
HG (OVHYLHU (VSDxD (VSDxD ±
>@
>@
>@
7HFQRORJtD)DUPDFpXWLFD
1$6+5$3KDUPDFHXWLFDO VXVSHQVLRQV
(Q 3KDUPDFHXWLFDO 'RVDJH )RUPV
'LVSHUVH 6L\VWHPV YRO  HG (G
/LHEHUPDQ 5LHJHU %DQNHU 0DUFHO
'HNNHU<RUN±
%2:0$1 %- 2)1(5 ,,, &0
6&+277 + &ROORLGDO GLVSHUVLRQV (Q
7KH VFLHQFH DQG SUDFWLFH RI 3KDUPDF\
 HG 5HPLQJWRQV /LSSLQFRWW
:LOOLDPV :LONLQJ 3KLODGHOSKLD 52'5Ë*8(= %$<Ï1 $ 0
)5$1&2 *,/ 0 ( ,QIOXHQFLD GHO
WLSR GH (PXOVLyQ HQ OD FLQpWLFD GH
SHQHWUDFLyQ GH IiUPDFRV D WUDYpV GH
PHPEUDQDV HSLGHUPLV \ SLHO KXPDQD
/LEURGHUHV~PHQHV6RFLHGDG(VSDxRODGH
)DUPDFLD ,QGXVWULDO \ *DOpQLFD 9DOHQFLD
SS
+,'52*(/(6$%$6('(*20$61$785$/(63$5$/$/,%(5$&,Ï1&2/Ï1,&$
'()È50$&26
*DJR*XLOODQ02WHUR(VSLQDU)-
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH
6DQWLDJRGH&RPSRVWHOD&DPSXV8QLYHUVLWDULR6XUVQ6DQWLDJRGH&RPSRVWHOD
7HQLHQGR HQ FXHQWD HVWRV UHVXOWDGRV HQ HO
,QWURGXFFLyQ
SUHVHQWH WUDEDMR VH HVWXGLD OD LQIOXHQFLD GH
/DV QXHYDV IRUPDV GH OLEHUDFLyQ VHOHFWLYD GH
GLYHUVRV SDUiPHWURV HQ HODERUDFLyQ GH
IiUPDFRVHQHOFRORQKDQGHVDUUROODGRXQJUDQ
KLGURJHOHV HODERUDGRV FRQ [DQWDQD \ PH]FODV
DYDQFH HQ ORV ~OWLPRV DxRV 6X XWLOL]DFLyQ
[DQWDQDJDUURILQD VREUH OD OLEHUDFLyQ GH
SHUPLWH WUDWDU GH IRUPD PiV HIHFWLYD ODV
FLSURIOR[DFLQR \ VH DERUGDQ ORV UHVXOWDGRV
SDWRORJtDV FROyQLFDV DO SHUPLWLU DOFDQ]DU
SUHOLPLQDUHV
GHO
SURFHGLPLHQWR
GH
PD\RUHV FRQFHQWUDFLRQHV GH IiUPDFR HQ OD
UHFXEULPLHQWR GH ORV [HURJHOHV FRQ XQD
]RQD \ HYLWDU VX DEVRUFLyQ HQ HVWyPDJR H
FXELHUWD HQWpULFD HO ILQ GH HYLWDU OD OLEHUDFLyQ
LQWHVWLQR GHOJDGR UHGXFLpQGRVH GH HVWD
GHOIiUPDFRHQPHGLRViFLGRV
PDQHUD XQ JUDQ Q~PHUR GH HIHFWRV
0DWHULDOHV\0pWRGRV
VHFXQGDULRV
&LSURIOR[DFLQR848,)$*RPD;DQWDQD\
([LVWHQ GLIHUHQWHV HVWUDWHJLDV SDUD DOFDQ]DU
*RPD*DUURILQDVXPLQLVWUDGRJUDWXLWDPHQWH
HVWH REMHWLYR HQWUH OD TXH HVWDFD HO HPSOHR GH
SRU,QDJDUEH6/3DGUyQ(XGUDJLW/
SURGXFWRV UHVLVWHQWHV D ORV FRQWHQLGRV
(YRQLN
JDVWURLQWHVWLQDOHV TXH VH GHJUDGDQ HQ HO FRORQ
(ODERUDFLyQGHORV+LGURJHOHV
SRU OD DFFLyQ GH HQ]LPDV SURFHGHQWHV GH OD
/RV [HURJHOHV HPSOHDGRV SDUD HO HVWXGLR GH
IORUD EDFWHULDQD FROyQLFD (QWUH ODV
OLEHUDFLyQ VH REWXYLHURQ PHGLDQWH FRPSUHVLyQ
PDFURPROpFXODV VXVFHSWLEOHV GH VHU XWLOL]DGDV
GLUHFWDGHXQDPH]FODKRPRJpQHDFRQWHQLHQGR
SRGHPRV FLWDU GLIHUHQWHV SROLVDFiULGRV GH
PJGH&LSURIOR[DFLQR\*RPD;DQWDQDR
RULJHQ QDWXUDO HQWUH ORV TXH VH HQFXHQWUDQ ODV
PH]FODV ;DQWDQD*DUURILQD DO KDVWD
JRPDV
FRPSOHWDU HO SHVR ILQDO GH PJ SRU
(Q WUDEDMRV DQWHULRUHV VH HVWXGLDURQ ORV
FRPSULPLGR 3DUD VX HODERUDFLyQ VH KD
KLGURJHOHV HODERUDGRV FRQ JRPD ;DQWDQD
HPSOHDGRXQDPDWUL]GHLQIUDUURMRVGHPP
$OJDUURER R *DUURILQD \ VXV PH]FODV FRPR
GHGLiPHWUR\XQDSUHQVDKLGUiXOLFD0HJD
VLVWHPDV FDSDFHV GH UHVLVWLU \ HYLWDU OD
(OWLHPSRGHFRPSUHVLyQIXHYDULDEOHHQWUH\
OLEHUDFLyQGHDFHWyQLGRGHWULDPFLQRORQDHQHO
PLQXWRV \ OD IXHU]D HMHUFLGD GH R WUDFWR JDVWURLQWHVWLQDO \ GH OOHJDU HQ
WRQHODGDV
FRQGLFLRQHVDGHFXDGDVSDUDVXOLEHUDFLyQHQHO
3DUD OD HODERUDFLyQ GH ORV [HURJHOHV FRQ
FRORQ
(VWRV
SROLVDFiULGRV
IXHURQ
FXELHUWD JDVWURUUHVLVWHQWH VH DSOLFy VREUH ORV
VHOHFFLRQDGRV GHELGR D TXH VH KD GHVFULWR XQ
[HURJHOHVXQDILQDSHOtFXODGH(XGUDJLW/
FRPSRUWDPLHQWR VLQpUJLFR HQWUH HVWDV GRV
3DUD HOOR VH SUHSDUy XQD GLVROXFLyQ GHO
JRPDV QDWXUDOHV FRPR FRQVHFXHQFLD GH
SROtPHUR DFUtOLFR DO HQ HWDQRO \ IXH
LQWHUDFFLRQHV HQWUH VXV HVWUXFWXUDV /RV
DSOLFDGD FRQ D\XGD GH XQ SLQFHO VREUH OD
UHVXOWDGRV REWHQLGRV IXHURQ VDWLVIDFWRULRV
VXSHUILFLHGHORV[HURJHOHVSURFHGLpQGRVHDVX
REVHUYiQGRVH XQD DGHFXDGD UHWHQFLyQ GH
VHFDGRPHGLDQWHODXWLOL]DFLyQGHXQDFRUULHQWH
IiUPDFR HQ IOXLGRV JiVWULFR \ HQWpULFR
GH DLUH FDOLHQWH (VWH SURFHGLPLHQWR VH UHSLWLy
VLPXODGR \ HO FRPLHQ]R GH OD FHVLyQ GHO
YHFHV FRQ HO ILQ GH REWHQHU XQD FXELHUWD
PLVPR XQD YH] HQ SUHVHQFLD GH HQ]LPDV
FRQWLQXDGHVXILFLHQWHJURVRU
FROyQLFRV 6LQ HPEDUJR HVWXGLRV SUHOLPLQDUHV
(VWXGLRVOLEHUDFLyQLQYLWUR
UHDOL]DGRV FRQ KLGURJHOHV FRQWHQLHQGR
/RV HQVD\RV GH YHORFLGDG GH OLEHUDFLyQ VH
FLSURIOR[DFLQR ILJXUD PXHVWUDQ XQD
UHDOL]DURQ XWLOL]DQGR XQ DSDUDWR GH GLVROXFLyQ
OLEHUDFLyQ SUHPDWXUD GHO SULQFLSLR DFWLYR HQ
Qž 863 3URODER FRQHFWDGR GH IRUPD
IOXLGR JiVWULFR GHELGR D VX DOWD VROXELOLGDG HQ
DXWRPiWLFD D XQ HVSHFWURIRWyPHWUR +3 
PHGLRV iFLGRV VLHQGR DGHPiV ORV HODERUDGRV
ORQJLWXG GH RQGD DQDOtWLFD QP 6H
FRQ JRPD JDUURILQD ORV TXH PHQRU FRQWURO GH
HPSOHy XQD YHORFLGDG GH DJLWDFLyQ GH OLEHUDFLyQSUHVHQWDQ
USP \ XQD WHPSHUDWXUD GH ±ž& &RPR
PHGLR GH GLVROXFLyQ VH XWLOL]y LQLFLDOPHQWH
PO GH MXJR JiVWULFR DUWLILFLDO $O FDER GH
GRVKRUDVVHDGLFLRQDURQVREUHHOMXJRJiVWULFR
POGHWDPSyQIRVIDWRS+\ODFDQWLGDG
QHFHVDULDGHKLGUy[LGRVyGLFR0SDUDREWHQHU
XQS+ILQDOGH“
)LJXUD(VWUXFWXUDGHO&LSURIOR[DFLQR%DVH
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
100
5 minutos
10 minutos
20 minutos
% ciprofloxacino liberado
80
60
pH 1,2
pH 6.8
40
20
0
0
200
400
600
800
1000
1200
3RU ~OWLPR FRPSDUDQGR OD OLEHUDFLyQ GH ORV
JHOHVHODERUDGRVFRQ[DQWDQDRFRQPH]FODVVH
REVHUYD TXH PLHQWUDV TXH D SUHVLRQHV GH 7RQHODGDV ODV PH]FODV PXHVWUDQ XQ PHMRU
FRQWURO GH OD OLEHUDFLyQ HVWH FRPSRUWDPLHQWR
VHLQYLHUWHDODODXPHQWDUDWRQHODGDV
(Q WRGRV ORV FDVRV VH DSUHFLD XQD UiSLGD
OLEHUDFLyQLQLFLDOHQMXJRJiVWULFRDUWLILFLDOVLQ
HQ]LPDVS+!(VWHFRPSRUWDPLHQWR
LQGLFD TXH HQ HVWH PHGLR ORV KLGURJHOHV VRQ
LQFDSDFHVGHFRQWURODUODGLIXVLyQGHOIiUPDFR
\ HOOR GHELGR D OD HOHYDGD VROXELOLGDG GHO
FLSURIOR[DFLQRHQ PHGLRiFLGR(QHVWH PHGLR
HOIiUPDFRVHGLVXHOYH\GLIXQGHUiSLGDPHQWHD
WUDYpVGHODPDWUL]KLGURItOLFDGHOKLGURJHO
8QDYH]HQPHGLRLQWHVWLQDOHOLQFUHPHQWRGHO
S+SURYRFDXQDGLVPLQXFLyQHQODVROXELOLGDG
TXH IDYRUHFH HO FRQWURO GH OLEHUDFLyQ 7UDV KRUDVGHHQVD\RHOSRUFHQWDMHOLEHUDGRURQGDHO
HQHOPHMRUGHORVFDVRV
1400
tiempo (minutos)
100
100
100% Xantana 10 Ton 10 min con Ciprofloxacino (%)
50% Xantana y 50% Garrofina 10 Ton 10 min con Ciprofloxacino (%)
100% Xantana 7.5 Ton 10 min con Ciprofloxacino (%)
50% Xantana y 50% Garrofina 7.5 Ton 10 min con Ciprofloxacino (%)
90
% ciprofloxacion liberado
80
70
pH 6,8
60
pH 1,2
50
40
30
20
10
0
0
200
400
600
800
1000
1200
1400
tiempo (minutos)
)LJXUD&RPSDUDFLyQGHORVSHUILOHVGHOLEHUDFLyQ
GH KLGURJHOHV GH [DQWDQD GH PH]FODV DO FRQ
JRPD JDUURILQD HODERUDGRV HPSOHDQGR IXHU]DV GH
FRPSUHVLyQGHR7RQHODGDV
(OFRPSRUWDPLHQWRREVHUYDGRVHGLIHUHQFLDHQ
IXQFLyQ GH VX FRPSRVLFLyQ GH ORV [HURJHOHV
/D OLEHUDFLyQ SDUWLU GH ORV KLGURJHOHV
HODERUDGRV FRQ PH]FODV GH [DQWDQD \
JDUURILQD
D
SHQDV
GH
GLIHUHQFLDQ
LQGHSHQGLHQWHPHQWH GH IXHU]D GH FRPSUHVLyQ
XWLOL]DGD 6LQ HPEDUJR ORV HODERUDGRV D EDVH
GH [DQWDQD H[SHULPHQWDQ XQD GLVPLQXFLyQ
VLJQLILFDWLYDHQODOLEHUDFLyQGHFLSURIOR[DFLQR
(O HPSOHR GH PD\RUHV IXHU]DV V IDYRUHFH XQ
DXPHQWR GH ODV LQWHUDFFLRQHV ItVLFDV HQWUH ODV
FDGHQDV GHO SROLVDFiULGRV \ SURYRFD
PRGLILFDFLRQHV GH OD HVWUXFWXUD WULGLPHQVLRQDO
GH OD JRPD [DQWDQD TXH SXHGHQ LQIOXLU
VREUHODOLEHUDFLyQ
50% Xantana y Garrofina con cubierta Eudragit L 100
50% Xantana y Garrofina sin cubierta
90
)LJXUD&RPSDUDFLyQGHORVSHUILOHVGHOLEHUDFLyQ
GH KLGURJHOHV HODERUDGRV FRQ JRPD [DQWDQD
HPSOHDQGR XQD SUHVLyQ GH 7RQHODGDV \
GLIHUHQWHVWLHPSRVGHFRPSUHVLyQ
(QODILJXUDVHPXHVWUDQORVSHUILOHVGHOLEHUDFLyQ
GH KLGURJHOHV HODERUDGRV FRQ [DQWDQD R PH]FODV
[DQWDQDJDUURILQDO PDQWHQLHQGR OD IXHU]D GH
FRPSUHVLyQ GXUDQWH PLQXWRV HQ IXQFLyQ GH OD
IXHU]DGHFRPSUHVLyQHPSOHDGD
% ciprofloxacion liberado
80
70
60
50
40
30
20
10
0
0
100
200
300
400
500
600
700
800
900
1000
Tiempo (min)
)LJXUD 3HUILOHV GH OLEHUDFLyQ GH KLGURJHOHV
HODERUDGRV FRQ PH]FODV DO JDUURItQ[DQWDQD
FRQRVLQFXELHUWDHQWpULFD
3DUD HYLWDU OD OLEHUDFLyQ SUHPDWXUD HQ PHGLR
iFLGRVHLQFRUSRUyXQDFXELHUWDHQWpULFDVREUH
ORV KLGURJHOHV (Q OD ILJXUD VH LQFOX\HQ ORV
UHVXOWDGRV (O SURFHVR GH UHFXEULPLHQWR FRQ
(XGUDJLW / GLVPLQX\H FRQVLGHUDEOHPHQWH
HO IiUPDFR OLEHUDGR HQ PHGLR iFLGR
REWHQLpQGRVH QLYHOHV SUy[LPRV DO FRQ OD
FXELHUWD IUHQWH DO VLQ HOOD 6LQ HPEDUJR
VHUi QHFHVDULR DXPHQWDU HO JURVRU GH OD
FXELHUWDSDUDHYLWDUWRWDOPHQWHODOLEHUDFLyQHQ
HVWHPHGLR
%LEOLRJUDItD
%KDUGZDM 7 5 HW DO 'UXJ 'HY ,QG
3KDUP±
$GDZH , HW DO 9,,, &RQJUHVR 6(),* 9LWRULD
*DJR*XLOODQ0HWDOWK:RUOG0HHWLQJ
RQ
3KDUPDFHXWLFV
%LRSKDUPDFHXWLFV
DQG
3KDUPDFHXWLFDO7HFKQRORJ\%DUFHORQD
+HQULTXHV 3 HW DO 9,,, &RQJUHVR 6(),*
9LWRULD
+LJLUR-HWDO)RRG5HVHDUFK,QWHUQDWLRQDO
$JUDGHFLPLHQWRV
,QDJDUEH 6/ SRU ODV PXHVWUDV GH *RPD
;DQWDQD\*DUURILQD
(9$/8$&,Ï1,19,752,19,92'(81$)2508/$&,Ï1'(/,%(5$&,Ï16267(1,'$
'(/29$67$7,1$2%7(1,'$0(',$17(*5$18/$&,Ï1325)86,Ï1
2FKRD/,JDUWXD0+HUQiQGH]50*DVFyQ$56ROLQLV0$\3HGUD]-/
/DERUDWRULRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD
8QLYHUVLGDGGHO3DtV9DVFR839(+89LWRULD*DVWHL]$ODYD
HPDLOMRVHOXLVSHGUD]#HKXHV
,QWURGXFFLyQ
/D ORYDVWDWLQD SURIiUPDFR TXH VH KLGUROL]D
PHGLDQWH HO &LWRFURPR 3 $ D VX
FRUUHVSRQGLHQWH PHWDEROLWR DFWLYR ORYDVWDWLQD
iFLGDHVXQLQKLELGRUHVSHFtILFR\FRPSHWLWLYR
GH OD KLGUR[LPHWLOJOXWDULOFRHQ]LPD $
UHGXFWDVD HQ]LPD HVHQFLDO HQ OD ELRVtQWHVLV GHO
FROHVWHURO /D ORYDVWDWLQD SUHVHQWD EDMD
ELRGLVSRQLELOLGDG RUDO GHELGR D VX EDMD
VROXELOLGDG \ UiSLGR PHWDEROLVPR HQ HO WUDFWR
JDVWURLQWHVWLQDO \ HQ HO KtJDGR /RV UHVXOWDGRV
REWHQLGRV HQ HQVD\RV FOtQLFRV SRQHQ GH
PDQLILHVWR TXH OD DGPLQLVWUDFLyQ GH
IRUPXODFLRQHV GH OLEHUDFLyQ VRVWHQLGD GH
ORYDVWDWLQD SURGXFHQ XQD PD\RU UHGXFFLyQ GHO
FROHVWHURO/'/TXHODDGPLQLVWUDFLyQGHIRUPDV
GH OLEHUDFLyQ LQPHGLDWD 7HQLHQGR HQ FXHQWD HO
LQFUHPHQWRGHHILFDFLDDVRFLDGDDODVIRUPDVGH
OLEHUDFLyQVRVWHQLGDHOREMHWLYRGHOSUHVHQWH
HVWXGLR IXH HO GHVDUUROOR GH XQD QXHYD
IRUPXODFLyQ GH OLEHUDFLyQ VRVWHQLGD GH
ORYDVWDWLQD /RYDVWDWLQD 65 PHGLDQWH
JUDQXODFLyQ SRU IXVLyQ \ HYDOXDU VX
ELRHTXLYDOHQFLD FRQ OD IRUPXODFLyQ FRPHUFLDO
$OWRSUHYŠ 3DUD HOOR VH HVWXGLy HO
FRPSRUWDPLHQWR IDUPDFRFLQpWLFR GH DPEDV
IRUPXODFLRQHV HQ SHUURV %HDJOH WUDV VX
DGPLQLVWUDFLyQ SRU YtD RUDO HQ SUHVHQFLD \ HQ
DXVHQFLDGHDOLPHQWRVULFRVHQJUDVD
0pWRGRH[SHULPHQWDO
3UHSDUDFLyQGHODPDWUL]KLGUyILODGHOLEHUDFLyQ
VRVWHQLGD
/DIRUPXODFLyQVHSUHSDUyPHGLDQWHFRPSUHVLyQ
GH XQ JUDQXODGR HODERUDGR PHGLDQWH
JUDQXODFLyQ SRU IXVLyQ HQ XQ VROR SDVR HQ XQ
JUDQXODGRUPH]FODGRU GH DOWD YHORFLGDG
5RWRODE® =DQFKHWWD HPSOHDQGR 3(* FRPRDJHQWHDJOXWLQDQWH
(VWXGLRGHGLVROXFLyQLQYLWUR
(OHVWXGLRGHGLVROXFLyQLQYLWURVHUHDOL]yHQXQ
HTXLSR GH GLVROXFLyQ 863 ,, D USP \ “
ž&Q (OHQVD\RVHUHDOL]yHQPHGLRGH
GLVROXFLyQFRQFDPELRGHS++&O1GXUDQWH
K\WDPSyQIRVIDWR0S+KDVWDK
(OFDPELRGHS+VHUHDOL]yDGLFLRQDQGRP/
GHIRVIDWRVyGLFRWULEiVLFR0
3DUD FRPSDUDU ORV SHUILOHV GH GLVROXFLyQ
REWHQLGRVVHFDOFXOyHOIDFWRUGHVLPLOLWXGI
(VWXGLRLQYLYR
(O HVWXGLR IDUPDFRFLQpWLFR VH UHDOL]y HQ SHUURV
%HDJOHQ HQHO&HQWURGH&LUXJtDGH0tQLPD
,QYDVLyQ -HV~V 8VyQ &&0, &DGD DQLPDO
UHFLELyXQDDGPLQLVWUDFLyQLQWUDYHQRVDHQ
VROXFLyQ$GHPiVVHDGPLQLVWUDURQSRUYtDRUDO
ODIRUPXODFLyQFRPHUFLDO$OWRSUHYŠPJ\OD
QXHYD IRUPXODFLyQ GH OLEHUDFLyQ VRVWHQLGD
/RYDVWDWLQD65PJ&RQREMHWRGHHYDOXDUOD
SRVLEOH LQWHUDFFLyQ HQWUH OD ORYDVWDWLQD \
DOLPHQWRV HQ XQ SULPHU JUXSR GH HVWXGLR ODV
IRUPXODFLRQHVVHDGPLQLVWUDURQWUDVXQD\XQRGH
K\HQHOVHJXQGRJUXSRODDGPLQLVWUDFLyQVH
UHDOL]y PLQ GHVSXpV GH OD LQJHVWLyQ GH XQD
GLHWD ULFD HQ JUDVD 6H GHMy XQ SHULRGR GH
EODQTXHR GH XQD VHPDQD HQWUH ODV GLVWLQWDV
DGPLQLVWUDFLRQHV $ GLIHUHQWHV WLHPSRV VH
H[WUDMHURQ PXHVWUDV GH VDQJUH \ ORV QLYHOHV
SODVPiWLFRV GH ORYDVWDWLQD iFLGD VH DQDOL]DURQ
PHGLDQWH XQD WpFQLFD /&0606 SUHYLDPHQWH
YDOLGDGDGHDFXHUGRFRQODV JXtDVGHOD)'$ \
GHOD,&+
/RV QLYHOHV SODVPiWLFRV VH DMXVWDURQ D XQ
PRGHOR QRFRPSDUWLPHQWDO FRQ HO SURJUDPD
:LQQROLQŠ
5HVXOWDGRV\'LVFXVLyQ
(VWXGLRGHGLVROXFLyQLQYLWUR
&RPR VH REVHUYD HQ OD )LJXUD VH REWXYR XQ
SHUILOGHGLVROXFLyQGLIHUHQWHHQFDGDXQDGHODV
IRUPXODFLRQHV HQVD\DGDV /D GLVROXFLyQ GH
ORYDVWDWLQD D SDUWLU GH OD IRUPXODFLyQ
GHVDUUROODGD SUHVHQWy XQ SHUILO GH RUGHQ ]HUR
6LQHPEDUJRODIRUPXODFLyQFRPHUFLDOSUHVHQWy
XQ³WLHPSRGHODWHQFLD´GHK
(O YDORU GHO IDFWRU GH VLPLOLWXG I IXH GH LQGLFDQGRVLPLOLWXGHQWUHHOSHUILOGHGLVROXFLyQ
GHODVGRVIRUPXODFLRQHV
120
100
% Liberado
5HVXOWDGRV\'LVFXVLyQ
(Q OD ILJXUD VH PXHVWUD OD LQIOXHQFLD GHO
WLHPSR GH FRPSUHVLyQ VREUH OD OLEHUDFLyQ GH
FLSURIOR[DFLQR D SDUWLU GH ORV KLGURJHOHV
HODERUDGRV FRQ [DQWDQD 6H REVHUYD TXH HO
PDQWHQLPLHQWR GH XQD IXHU]D GH FRPSUHVLyQ
GH7RQHODGDVGXUDQWHPLQXWRVGDOXJDUD
KLGURJHOHVTXHSUHVHQWDQXQDPD\RUOLEHUDFLyQ
GHO IiUPDFR QR HQFRQWUiQGRVH GLIHUHQFLDV
VLJQLILFDWLYDV
HQWUH
ORV
HODERUDGRV
PDQWHQLHQGRODIXHU]DRPLQXWRV
80
60
40
Lovastatina SR
Altoprev
20
0
0
5
10
15
20
Tiempo (h)
)LJ3HUILOGHGLVROXFLyQLQYLWURGHORYDVWDWLQDHQPHGLR
GH GLVROXFLyQ FRQ FDPELR GH S+ GH ODV GRV IRUPXODFLRQHV
HVWXGLDGDVQ (VWXGLRLQYLYR
/DV)LJXUDV\PXHVWUDQODVFRQFHQWUDFLRQHV
SODVPiWLFDV PHGLDV GH ORYDVWDWLQD iFLGD HQ
D\XQDV \ HQ SUHVHQFLD GH DOLPHQWRV
UHVSHFWLYDPHQWH /D 7DEOD UHFRJH ORV
SDUiPHWURV IDUPDFRFLQpWLFRV REWHQLGRV SDUD
DPEDV IRUPXODFLRQHV HQ ODV GRV FRQGLFLRQHV
HVWXGLDGDV7DQWRFRQODIRUPXODFLyQFRPHUFLDO
FRPR FRQ OD QXHYD IRUPXODFLyQ VH REWXYR XQ
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
SHUILO GH QLYHOHV SODVPiWLFRV VRVWHQLGRV GH
ORYDVWDWLQDiFLGD
100
Ayunas
Lovastatina SR
Log Conc (ng/mL)
Altoprev
10
1
0
0
10
20
30
40
50
60
Tiem po (h)
)LJ &RQFHQWUDFLRQHVSODVPiWLFDV PHGLDVGHORYDVWDWLQD
iFLGD WUDV DGPLQLVWUDFLyQ RUDO GH ODV IRUPXODFLRQHV HQ
HVWDGRGHD\XQDVQ 100
Dieta
Lovastatina SR
Log Conc (ng/mL)
Altoprev
10
1
0
0
10
20
30
Tiempo (h)
40
50
60
)LJ &RQFHQWUDFLRQHVSODVPiWLFDV PHGLDVGHORYDVWDWLQD
iFLGDWUDVDGPLQLVWUDFLyQRUDOGHODVIRUPXODFLRQHVFRQXQD
GLHWDULFDHQJUDVDQ &RPR SXHGH REVHUYDUVH HQ OD )LJXUD HQ
D\XQDV ORV QLYHOHV SODVPiWLFRV GH ORYDVWDWLQD
iFLGD IXHURQ VLPLODUHV FRQ ODV GRV
IRUPXODFLRQHV HQ WRGRV ORV WLHPSRV GH
PXHVWUHR
6LQHPEDUJRWDO\FRPRVHREVHUYDHQOD)LJXUD
HQ SUHVHQFLD GH XQD GLHWD ULFD HQ JUDVD VH
REVHUYDURQ GLIHUHQFLDV HQWUH ORV SHUILOHV GH
QLYHOHVSODVPiWLFRVGHODVGRVIRUPXODFLRQHV
7DEOD 3DUiPHWURV IDUPDFRFLQpWLFRV PHGLRV GH
ORYDVWDWLQD iFLGD WUDV OD DGPLQLVWUDFLyQ RUDO GH ODV
IRUPXODFLRQHVGHOLEHUDFLyQVRVWHQLGD
$\XQDV
'LHWD
/RYDVWDWLQD65
$OWRSUHYŠ
/RYDVWDWLQD65
$OWRSUHYŠ
0HGLD'(
0HGLD'(
0HGLD'(
0HGLD'(
.HK WK
7PD[K
&PD[QJP/
$8&’
QJKP/
057K
7DO \ FRPR VH PXHVWUD HQ OD 7DEOD HQ
SUHVHQFLD GH DOLPHQWRV OD IRUPXODFLyQ
/RYDVWDWLQD 65 SUHVHQWy XQD YHORFLGDG GH
DEVRUFLyQ PiV UiSLGD \ PD\RUHV QLYHOHV
SODVPiWLFRV7PD[ “K\&PD[ “ QJP/ UHVSHFWLYDPHQWH TXH OD
IRUPXODFLyQ FRPHUFLDO 7PD[ “ K \
&PD[ “QJP/UHVSHFWLYDPHQWH
(O GLIHUHQWH FRPSRUWDPLHQWR LQ YLYR GH ODV GRV
IRUPXODFLRQHV HQ SUHVHQFLD GH DOLPHQWRV SXHGH
VHU GHELGR DO GLIHUHQWH HIHFWR GH OD GLHWD VREUH
FDGDXQDGHHOODV(QHOFDVRGHODIRUPXODFLyQ
/RYDVWDWLQD65ODSUHVHQFLDGHDOLPHQWRVSXGR
DFHOHUDU OD HURVLyQ GH OD PDWUL] LQGXFLHQGR XQD
OLEHUDFLyQ PiV UiSLGD GHO IiUPDFR HQ HO WUDFWR
JDVWURLQWHVWLQDO (VWD HURVLyQ \ HO SRVLEOH
LQFUHPHQWR GH OD VROXELOLGDG GH ORYDVWDWLQD
GHELGR D OD QDWXUDOH]D JUDVD GH ORV DOLPHQWRV \
HO DXPHQWR GH ODV VHFUHFLRQHV LQWHVWLQDOHV
SULQFLSDOPHQWH VHFUHFLyQ ELOLDU PD\RU LQFOXVR
HQSHUURVTXHHQKXPDQRVSXGLHURQGDUOXJDUD
XQDPD\RUDEVRUFLyQGHOIiUPDFR
6LQHPEDUJRODSUHVHQFLDGHDOLPHQWRVSURGXMR
XQ UHWUDVR HQ OD OLEHUDFLyQ \ DEVRUFLyQ GHO
IiUPDFR D SDUWLU GH OD IRUPXODFLyQ FRPHUFLDO
GDQGR OXJDU D QLYHOHV PiV EDMRV GH ORYDVWDWLQD
iFLGDHQSODVPD
3RU~OWLPRQR KD\GLIHUHQFLDVVLJQLILFDWLYDVHQ
HO iUHD EDMR OD FXUYD $8& ’ HQWUH DPEDV
IRUPXODFLRQHV OR TXH VXJLHUH TXH OD FRPLGD
SXHGH DIHFWDU D OD YHORFLGDG GH DEVRUFLyQ GH
ORYDVWDWLQD VLQ DIHFWDU D OD PDJQLWXG GH GLFKD
DEVRUFLyQ
(V LPSRUWDQWH VHxDODU OD DOWD YDULDELOLGDG
LQWHULQGLYLGXDOREVHUYDGDHQODVFRQFHQWUDFLRQHV
SODVPiWLFDV \ ORV SDUiPHWURV IDUPDFRFLQpWLFRV
GH DPEDV IRUPXODFLRQHV OR FXDO \D KDEtD VLGR
GHVFULWRSUHYLDPHQWHHQGLIHUHQWHVHVWXGLRV
&RQFOXVLRQHV
/RV UHVXOWDGRV REWHQLGRV HQ HVWH HVWXGLR SRQHQ
GH PDQLILHVWR OD LQIOXHQFLD GH OD SUHVHQFLD GH
DOLPHQWRVHQODDEVRUFLyQGHORYDVWDWLQDDSDUWLU
GH ODV GRV IRUPXODFLRQHV HVWXGLDGDV (Q HO
HVWXGLR UHDOL]DGR HQ FRQGLFLRQHV GH D\XQR VH
REWXYLHURQ SHUILOHV SODVPiWLFRV VLPLODUHV HQWUH
OD IRUPXODFLyQ GH /RYDVWDWLQD 65 \ $OWRSUHYŠ
6LQ HPEDUJR DPEDV IRUPXODFLRQHV SUHVHQWDQ
GLIHUHQWH FRPSRUWDPLHQWR LQ YLYR HQ SUHVHQFLD
GH DOLPHQWRV 3RU OR WDQWR VH SURFHGHUi D OD
RSWLPL]DFLyQ GH OD IRUPXODFLyQ GHVDUUROODGD
SDUD LQWHQWDU PLQLPL]DU OD LQIOXHQFLD GH ORV
DOLPHQWRVFRQREMHWRGHTXHVHDELRHTXLYDOHQWH
FRQODIRUPXODFLyQGHUHIHUHQFLD
5HIHUHQFLDV
'DYLGVRQ\FROV&OLQ7KHUDS
)'$*XLGDQFHIRU,QGXVWU\%LRDQDO\WLFDO
PHWKRGVYDOLGDWLRQIRUKXPDQVWXGLHV
,&+459DOLGDWLRQRIDQDO\WLFDO
SURFHGXUHV
$EUDKDPVVRQ\FROV'UXJ'HY,QG3KDUP
3HUVVRQ\FROV3KDUP5HV
.DODQW]L\FROV3KDUP5HV
6WHUPDQ\FROV$EVWUDFWQž-&OLQ
3KDUP
$JUDGHFLPLHQWRV
/RXUGHV 2FKRD DJUDGHFH D OD 8QLYHUVLGDG GHO
3DtV9DVFR839(+8SRUODEHFDSUHGRFWRUDO
RWRUJDGD
38(67$$38172'(81$7e&1,&$'(0,&25(1&$368/$&,Ï1'(/352%,Ï7,&2
/$&72%$&,//86)(50(1780&(&7
0(0RUDOHV+HUQiQGH]0-0DUWLQ9LOOHQD)/DUD9LOORVODGD9*DOODUGR/DUD\0$5XL]
0DUWtQH]
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH*UDQDGD&DPSXV&DUWXMDVQ
*UDQDGD&3(VSDxDPDHQ#XJUHV
'HSDUWDPHQWRGH1XWULFLyQ<6DOXG3XOHYD%LRWHFK&DPLQRGH3XUFKLOVQ*UDQDGD(VSDxD
,QWURGXFFLyQ
/D 206 GHILQH D ORV SURELyWLFRV FRPR
RUJDQLVPRV YLYRV TXH DGPLQLVWUDGRV HQ
FDQWLGDGHV DGHFXDGDV HMHUFHQ XQ HIHFWR
EHQHILFLRVRVREUHODVDOXGGHOKRVSHGDGRU
6LWHQHPRVHQFXHQWDTXHORVSURELyWLFRVVRQ
SULQFLSDOPHQWH FRQVXPLGRV SRU YtD RUDO HV
OyJLFR SHQVDU TXH VXV HIHFWRV EHQHILFLRVRV VH
SRQGUiQ GH PDQLILHVWR IXQGDPHQWDOPHQWH HQ
SDWRORJtDV LQWHVWLQDOHV 6LQ HPEDUJR OD
SRVLELOLGDG GH PRGXODU OD UHVSXHVWD LQPXQH GH
WLSRVLVWpPLFDKDFHTXHORVSURELyWLFRVWDPELpQ
SUHVHQWHQHIHFWRVSRVLWLYRVHQRWUDVDOWHUDFLRQHV
H[WUDLQWHVWLQDOHVFRPRDOHUJLDV\YDJLQLWLV
(OSURELyWLFRTXHXWLOL]DPRVIXH/DFWREDFLOOXV
IHUPHQWXP XQ EDFLOR *UDP SRVLWLYR DQDHURELR
TXHHQWUHRWUDVDSOLFDFLRQHVVHKDHPSOHDGRHQ
DOLPHQWDFLyQ LQIDQWLO \ HQ HO WUDWDPLHQWR GH
HQIHUPHGDGHV XURJHQLWDOHV HQ PXMHUHV (O
SUREOHPDTXHVHSUHVHQWDDODKRUDGHLQFRUSRUDU
SURELyWLFRV D FXDOTXLHU IRUPXODFLyQ HV OD
HVFDVDUHVLVWHQFLDGHHVWRVPLFURRUJDQLVPRVD
ORV SURFHVRV WHFQROyJLFRV \ D GLIHUHQWHV
FRQGLFLRQHV DPELHQWDOHV FRPR HO S+ HO
R[LJHQRRODWHPSHUDWXUD
3RU WRGR HVWR HV QHFHVDULR TXH ORV
PLFURRUJDQLVPRVVHLQWURGX]FDQSURWHJLGRVSRU
XQD EDUUHUD ItVLFD TXH HYLWH VX H[SRVLFLyQ D ODV
FRQGLFLRQHV DGYHUVDV GHO HQWRUQR /DV WpFQLFDV
GH PLFURHQFDSVXODFLyQ SHUPLWHQ DLVODU D ODV
EDFWHULDVPHGLDQWHXQDFXELHUWDTXHODVSURWHJH
GH HVWRV IDFWRUHV VLHQGR HVWH HO REMHWLYR GH
QXHVWURWUDEDMR
0DWHULDOHV\0pWRGRV
(O SURELyWLFR XWLOL]DGR IXH HO /DFWREDFLOOXV
IHUPHQWXP &(&7 FHGLGR SRU 3XOHYD
%LRWHFK*UDQDGD
/D WpFQLFD GH PLFURHQFDSVXODFLyQ HPSOHDGD
IXH OD *HOLILFDFLRQ LyQLFD LQWHUQD (Q FDGD XQR
GH ORV SDVRV FUtWLFRV GH OD VtQWHVLV VH WRPDURQ
PXHVWUDV SDUD HYDOXDU OD VXSHUYLYHQFLD GH ODV
EDFWHULDV
$ PLOLOLWURV GH XQD VROXFLyQ GH DOJLQDWR
FiOFLFR DO PY VH OH DGLFLRQy &D&2 \ ORV
SURELyWLFRV 0XHVWUD $ FRQWLQXDFLyQ VH
DxDGLyDFHLWHGHVRMDPOFRQ6SDQ\VH
DJLWyGXUDQWHPLQDUSPFRQHODJLWDGRU
PHFiQLFR$ODHPXOVLyQIRUPDGDVHOHDxDGLy
iFLGRDFpWLFRJODFLDOSDUDLQLFLDUODJHOLILFDFLyQ
\ VH DJLWy GXUDQWH RWURV PLQXWRV
3RVWHULRUPHQWHVHDGLFLRQy&D&O0XHVWUD\
VHDJLWyGXUDQWHPLQ\VHGHMyVHGLPHQWDU
KRUDV D ž& 7UDQVFXUULGR HVWH WLHPSR ODV
SDUWtFXODV VH FHQWULIXJDURQ D USP GXUDQWH
PLQ \ VH ODYDURQ ODV PXHVWUDV FRQ DJXD
GHVWLODGD )LQDOPHQWH ODV SDUWtFXODV VH ILOWUDURQ
DOYDFtRFRQP/GHXQDVROXFLyQDOGH
1D&O0XHVWUD
3DUDHYDOXDUODVXSHUYLYHQFLDGHORVSUHELyWLFRV
ODVPXHVWUDVVHFXOWLYDURQHQPHGLRGH0DQ
5RJRVD6KDUSH056HVSHFtILFRSDUDHVWHWLSR
GH EDFWHULDV 3DUD HOOR ODV PXHVWUDV VH
VRPHWLHURQ D GLOXFLRQHV VHULDGDV HQ DJXD GH
SHSWRQD$GHPiVHQHOFDVRGHODVPXHVWUDV\
SUHYLR D ODV GLOXFLRQHV IXH QHFHVDULR
SRQHUODV HQ FRQWDFWR GXUDQWH PLQXWRV HQ
DJLWDFLyQ USP FRQ XQ WDPSyQ IRVIDWR
0 \ S+ SDUD TXH VH SURGXMHUD OD
OLEHUDFLyQ GH ORV PLFURRUJDQLVPRV /DV
GLOXFLRQHV DGHFXDGDV VH FXOWLYDURQ HQ PHGLR
056 \ VH LQFXEDURQ D ž& \ HQ DQDHURELRVLV
GXUDQWH K /D VtQWHVLV VH OOHYy D FDER SRU
WULSOLFDGR \ VH PXHVWUDQ OD PHGLD GH ORV
UHVXOWDGRVWDEOD
5HVXOWDGRV\GLVFXVLyQ
/D ILJXUD PXHVWUD HO WDPDxR GH ODV
PLFURFiSVXODV REWHQLGDV GH DFXHUGR FRQ HO
PpWRGR GHVFULWR HQ HO DSDUWDGR DQWHULRU (O
WDPDxR WLHQH TXH VHU OR VXILFLHQWHPHQWH JUDQGH
SDUDDOEHUJDUHQVXLQWHULRUODFDUJDGHEDFWHULDV
FX\RWDPDxRRVFLODHQWRUQRDμP3RURWUD
SDUWH FRPR VH REVHUYD HQ OD ILJXUD DXQTXH
VRQ SROLGLVSHUVDV WRGDV SUHVHQWDQ XQD IRUPD
HVIpULFD
(QFXDQWRDORVHVWXGLRVUHDOL]DGRVSDUDHYDOXDU
OD VXSHUYLYHQFLD GH ORV PLFURRUJDQLVPRV ORV
UHVXOWDGRV REWHQLGRV VH PXHVWUDQ HQ OD WDEOD H[SUHVDGRV FRPR XQLGDGHV IRUPDGRUDV GH
FRORQLDVXIFSRUP/\XIFWRWDOHV$QDOL]DQGR
ORV GDWRV GH ODV PXHVWUDV LQLFLDO PXHVWUD \
ILQDO PXHVWUD VH REVHUYD XQD SpUGLGD GH
YLDELOLGDG GH DSUR[LPDGDPHQWH yUGHQHV GH
PDJQLWXG TXH VH SXHGH FRQVLGHUDU DFHSWDEOH
'H KHFKR OD FRQFHQWUDFLyQ GHO SURGXFWR ILQDO
SHUPLWLUtD DOFDQ]DU OD GRVLV GLDULD KDELWXDO
XIFGtD
FRQ
J
GHO
SURGXFWR
PLFURHQFDSVXODGR6LQHPEDUJRHQODPXHVWUD
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
VH REVHUYD XQD SpUGLGD GH FDVL yUGHQHV GH
PDJQLWXGTXHQRHVFRKHUHQWHFRQORREVHUYDGR
HQODPXHVWUD(VWRSRGUtDVHUGHELGRDTXHQR
VH KD SURGXFLGR FRUUHFWDPHQWH OD OLEHUDFLyQ GH
ODVEDFWHULDV
100
80
F (%)
60
40
20
0
0 - 0,2 0,2 0,4
0,4 0,6
0,6 0,8
Tamaño (mcm)
)LJXUD +LVWRJUDPD GH ODV PLFURFiSVXODV
VLQWHWL]DGDV
)LJXUD )RWRJUDItD GH ODV PLFURFiSVXODV GH
DOJLQDWR FiOFLFR REWHQLGDV DO PLFURVFRSLR
ySWLFR
7DEOD8QLGDGHVIRUPDGRUDVGHFRORQLDVXIF
REWHQLGDV HQ FDGD XQD GH ODV PXHVWUDV
HQVD\DGDV
XIFP/
0XHVWUD
(
XIFWRWDOHV
(
0XHVWUD
(
XIFP/
XIFWRWDOHV
(
0XHVWUD
(
XIFJ
XIFWRWDOHV
(
&RQFOXVLRQHV
/D WpFQLFD GH PLFURHQFDSVODFLyQ HPSOHDGD
SDUHFH VHU DGHFXDGD SDUD / IHUPHQWXP
&(&7\DTXHODVPLFURFiSVXODVREWHQLGDV
SUHVHQWDQ XQ WDPDxR \ IRUPD DGHFXDGD SDUD
DOEHUJDU D HVWRV PLFURRUJDQLVPRV $VLPLVPR
ORV GDWRV REWHQLGRV HQ ORV HVWXGLRV GH
VXSHUYLYHQFLDPXHVWUDQODYLDELOLGDGGHOPpWRGR
SURSXHVWR )XWXURV HQVD\RV GHEHQ FRQILUPDU OD
HVWDELOLGDGGHOSURELyWLFRDORODUJRGHOSURFHVR
DVtFRPRGXUDQWHHODOPDFHQDPLHQWR
5HIHUHQFLDV
$SOLFDFLRQHVWHUDSpXWLFDVGHORVSURELyWLFRV
%$UULVEDV%0(5RGUtJXH]'&DPXHVFR
$=DU]XHOR-*DOYH]$UV3KDUP
6XUYLYDORIIUHHDQGHQFDSVXODWHGSURELRWLF
EDFWHULDDQGWKHLUHIIHFWRQWKHVHQVRU\
SURSHUWLHVRI\RJKXUW.NDLODVDSDWK\/:7
3URELRWLFVDQGWKHVNLQ
*&DUDPLD$$W]HL9)DQRV&OLQLFVLQ
'HUPDWRORJ\
$JUDGHFLPLHQWRV
$JUDGHFHPRV D 3XOHYD %LRWHFK OD FRODERUDFLyQ
SUHVWDGD VXPLQLVWUiQGRQRV HO SUHELyWLFR
XWLOL]DGR
HQ
HVWH
HVWXGLR
81,)250,'$''(81,'$'(6'('26,),&$&,Ï1'(&2035,0,'26'(
3$5$&(7$02/'((/$%25$&,Ï13523,$
0,6RULDQR-%)DULxD$2OLYD
'HSDUWDPHQWRGH,QJHQLHUtD4XtPLFD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH
/D/DJXQD)FR6iQFKH]VQ/D/DJXQD6SDLQ
OD IXHU]D GH FRPSUHVLyQ \ HODERUDFLyQ GH OD
,QWURGXFFLyQ
3DUD JDUDQWL]DU OD XQLIRUPLGDG GH ODV XQLGDGHV
GH GRVLILFDFLyQ SUHVHQWDGDV HQ GRVLV ~QLFDV
FDGD XQLGDG GHEHUtD WHQHU XQ FRQWHQLGR GH
SULQFLSLR DFWLYR GHQWUR GH XQRV OtPLWHV
HVWDEOHFLGRV DOUHGHGRU GHO YDORU GHFODUDGR /D
XQLIRUPLGDG GH ODV XQLGDGHV GH GRVLILFDFLyQ
SXHGH VHU GHPRVWUDGD WDQWR SRU HO HQVD\R GH
XQLIRUPLGDGGHFRQWHQLGRFRPRGHXQLIRUPLGDG
GHPDVDRYDULDFLyQGHSHVR
(OWUDEDMRKDVLGRUHDOL]DGRWHQLHQGRHQFXHQWD
ODV GLVSRVLFLRQHV RILFLDOHV HVWDEOHFLGDV SRU OD
)DUPDFRSHD (XURSHD  HGLFLyQ SRU ORV
DOXPQRV GH OD DVLJQDWXUD GH 7HFQRORJtD
)DUPDFpXWLFD,,,/DVSUiFWLFDVGHODERUDWRULRGH
GLFKDDVLJQDWXUDWLHQHQFRPRILQDOLGDGHOTXHHO
DOXPQR VHD FDSD] GH HODERUDU \ DGHPiV GH
LGHQWLILFDU FXiOHV VRQ ORV FRQWUROHV GH FDOLGDG
TXH GHEHQ UHDOL]DUVH VREUH ODV IRUPDV
IDUPDFpXWLFDVVyOLGDVFRPSULPLGRV\FiSVXODV
\DFHSWDURUHFKD]DUXQORWHGHXQPHGLFDPHQWR
HQIXQFLyQGHORVUHVXOWDGRVREWHQLGRV
0DWHULDOHV\0pWRGRV
7DQWR HO SDUDFHWDPRO FRPR ORV H[FLSLHQWHV
XWLOL]DGRVIXHURQVXPLQLVWUDGRVSRU$FRIDUPD
&RPSULPLGRV
6H HODERUDURQ GRV ORWHV GH FRPSULPLGRV
FRQWHQLHQGR FDGD XQR PJ GH SDUDFHWDPRO
GH DFXHUGR FRQ OD IyUPXOD UHFRJLGD HQ OD WDEOD
FRQ )RUPXODFLyQ 393 R )RUPXODFLyQ 393 GH OD FDQWLGDG WRWDO SRU
FRPSULPLGRGHSROLYLQLOSLUUROLGRQD393
7DEOD&RPSRVLFLyQGHODIyUPXODHPSOHDGD
HQODHODERUDFLyQGHORVFRPSULPLGRV
&RPSRQHQWHV
&DQWLGDG&RPSULPLGR
3DUDFHWDPRO
PJ
6DFDURVD
PJ
393 SY HQ FV
DOFRKRO
7DOFR
PJ
$OPLGyQGHPDt]
PJ
ÈFLGRHVWHiULFR
PJ
3DUD OD SUHSDUDFLyQ GH ORV FRPSULPLGRV VH
VLJXLyODWpFQLFDGHJUDQXODFLyQSRUYtDK~PHGD
\ FRPSUHVLyQ XWLOL]DQGR XQD PiTXLQD GH
FRPSULPLU H[FpQWULFD FRQ SXQ]RQHV GH PP
-%RQDOVLQVWUXPHQWDGDSDUDFRQWURODU
FDUWDFRQWURO
'HWHUPLQDFLyQGHOSDUDFHWDPRO
(O PpWRGR DQDOtWLFR IXH SRU HVSHFWURIRWRPHWUtD
89 D QP 3DUD HOOR OD PXHVWUD DOtFXRWD R
FRPSULPLGRVHLQWURGXFHHQXQPDWUD]DIRUDGR
GHYROXPHQDSURSLDGRDOTXHVHOHDGLFLRQDQ
POGHHWDQRO\DJXDKDVWDVXHQUDVHVHILOWUD\VH
GLOX\H FRQ DJXD GHVWLODGD /RV UHVXOWDGRV VH
FRPSDUDQ FRQ SDWURQHV SULPDULRV 3K (XU
SUHYLDPHQWHSUHSDUDGRV
8QLIRUPLGDGGHPDVD
6H SHVDQ LQGLYLGXDOPHQWH \ GH IRUPD SUHFLVD
FRPSULPLGRV HVFRJLGRV DO D]DU 6H
SXOYHUL]DQ HQ XQ PRUWHUR KDVWD REWHQHU XQ
VyOLGR ILQDPHQWH GLYLGLGR \ VH KRPRJHQL]D OD
PH]FOD6HWRPDXQDDOtFXRWDGHODPH]FOD\VH
GHWHUPLQD OD FDQWLGDG GH SULQFLSLR DFWLYR GH
DFXHUGR FRQ HO PpWRGR DQDOtWLFR SURSXHVWR 3RU
~OWLPRVHFDOFXODODFDQWLGDGGHSDUDFHWDPROGH
FDGD FRPSULPLGR H[SUHVDGD FRPR SRUFHQWDMH
GHOYDORUGHFODUDGRDVXPLHQGRTXHHOSULQFLSLR
DFWLYR VH HQFXHQWUD GLVWULEXLGR GH IRUPD
KRPRJpQHD \ VHFDOFXODHO YDORUGHDFHSWDFLyQ
9$
8QLIRUPLGDGGHFRQWHQLGR
(O HQVD\R GH XQLIRUPLGDG GH FRQWHQLGR GH ODV
SUHSDUDFLRQHV SUHVHQWDGDV HQ GRVLV ~QLFDV HVWi
EDVDGR HQ HO HQVD\R GH ORV FRQWHQLGRV
LQGLYLGXDOHV GHO SULQFLSLR DFWLYR GH XQ Q~PHUR
GH XQLGDGHV SDUD GHWHUPLQDU VL ORV FRQWHQLGRV
LQGLYLGXDOHV HVWiQ GHQWUR GH ORV OtPLWHV
HVWDEOHFLGRV FRQ UHVSHFWR DO YDORU GHFODUDGR
3DUDHOORVHWRPDQXQLGDGHVGHGRVLILFDFLyQ
DO D]DU VH GHWHUPLQDQ ORV FRQWHQLGRV
LQGLYLGXDOHV TXH GHEH H[SUHVDUVH FRPR
SRUFHQWDMH GHO YDORU GHFODUDGR \ FDOFXODU HO
YDORUGHDFHSWDFLyQ
9DORUGHDFHSWDFLyQ9$\FULWHULRV
(O YDORU GH DFHSWDFLyQ VH FDOFXOD D SDUWLU GH OD
VLJXLHQWHHFXDFLyQ
9$ = 0 − ; + NV GRQGH
9$ 9DORUGHDFHSWDFLyQ
9DORUGHUHIHUHQFLDVLHQGR0LJXDOD
0 VL ; ; VL ; ; Q VL ; !
0HGLDGHORVFRQWHQLGRVLQGLYLGXDOHV
1~PHURGHPXHVWUDV
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
N )DFWRUGHWROHUDQFLD
N VLQ N VLQ V 'HVYLDFLyQHVWiQGDU
56' 'HVYLDFLyQHVWiQGDUUHODWLYD
/ /tPLWHSDUDHOLQWHUYDORGHDFHSWDFLyQ
/ / /tPLWHSDUDODVXQLGDGHVLQGLYLGXDOHV
/ 7DQWR HQ ORV HQVD\RV GH XQLIRUPLGDG GH
FRQWHQLGR FRPR GH YDULDFLyQ HQ SHVR VH GHEHQ
DSOLFDU ORV VLJXLHQWHV FULWHULRV D PHQRV TXH VH
HVSHFLILTXHORFRQWUDULRHQODPRQRJUDItD
/DSUHSDUDFLyQFXPSOHFRQHOHQVD\RFXDQGRHO
YDORU GH DFHSWDFLyQ GH ORV FRQWHQLGRV
LQGLYLGXDOHV HV PHQRU R LJXDO D / 6L HO YDORU
GHDFHSWDFLyQHVPD\RUHQWRQFHVVHGHWHUPLQDQ
ORVFRQWHQLGRVLQGLYLGXDOHVGHRWUDVXQLGDGHV
GHGRVLILFDFLyQWRPDGDVDOD]DU(QHVWHFDVRHO
YDORU GH DFHSWDFLyQ ILQDO GH ODV XQLGDGHV
GHEH VHU PHQRU R LJXDO D / Q \ ORV
FRQWHQLGRV LQGLYLGXDOHV GH QLQJXQD XQLGDG
SXHGH VHU LQIHULRU D /Â [ 0 QL PD\RU
GH /Â [ 0 $ PHQRV TXH VH
HVSHFLILTXH OR FRQWUDULR HQ OD PRQRJUDItD
LQGLYLGXDO/HV\/HV
5HVXOWDGRV\'LVFXVLyQ
/RV UHVXOWDGRV REWHQLGRV HQ HO HQVD\R GH
XQLIRUPLGDGGHPDVDSDUDORVGRVORWHVGHFDGD
XQDGHODV IRUPXODFLRQHV393 \39$
VHUHFRJHQHQODWDEOD,,
7DEOD 5HVXOWDGRV GHO HQVD\R GH XQLIRUPLGDG
GH PDVD GH ORV FRPSULPLGRV ; PHGLD
H[SUHVDGD FRPR SRUFHQWDMH GHO YDORU
GHFODUDGR 6' GHVYLDFLyQ HVWiQGDU 9$ YDORU
GHDFHSWDFLyQ
/RWH
6'
9$
;
393,
393,,
393,
393,,
WDQWRHVXQGDWRJHQHUDO\DTXHLQGLFDVLHOORWH
IDEULFDGR FRQWLHQH JOREDOPHQWH OD FDQWLGDG GH
SULQFLSLRDFWLYRSRUFRPSULPLGR/D863HV
OD ~QLFD IDUPDFRSHD TXH FRQWHPSOD XQD
PRQRJUDItD HVSHFtILFD GH FRPSULPLGRV GH
SDUDFHWDPRO \ HQ HOOD VH LQGLFD TXH ORV
FRPSULPLGRVGHEHQFRQWHQHUQRPHQRVGHO
\ QR PiV GHO GHO YDORU GHFODUDGR GH
SDUDFHWDPRO 7HQLHQGR HQ FXHQWD HVWRV OtPLWHV
GH ULTXH]D HO YDORU GH DFHSWDFLyQ FDOFXODGR
VHJ~QOD)DUPDFRSHD(XURSHDFRLQFLGLUtDFRQHO
GH OD 863 SXHVWR TXH HO YDORU GH UHIHUHQFLD 0
HV HO PLVPR DO VHU OD PHGLD GH ORV OtPLWHV GH
ULTXH]7PHQRURLJXDOTXH
7DEOD 5HVXOWDGRV GHO HQVD\R GH XQLIRUPLGDG
GH FRQWHQLGR GH ORV FRPSULPLGRV ; PHGLD
H[SUHVDGD FRPR SRUFHQWDMH GHO YDORU
GHFODUDGR 6' GHVYLDFLyQ HVWiQGDU 9$ YDORU
GHDFHSWDFLyQ
/RWH
6'
9$
;
393,
393,,
393,
393,,
/RV UHVXOWDGRV REWHQLGRV PXHVWUDQ TXH D
H[FHSFLyQGHOORWH393,ODVIRUPXODFLRQHV
FXPSOHQ HO HQVD\R GDGR TXH HO YDORU GH
DFHSWDFLyQHVLQIHULRUDOOtPLWHHVWDEOHFLGR9$
” (Q FXDQWR DO ORWH 393, HO 9$ IXH
OLJHUDPHQWH PD\RU GH (VWR HV
SUREDEOHPHQWH GHELGR D XQ HUURU H[SHULPHQWDO
DVRFLDGR FRQ HO PpWRGR DQDOtWLFR GHO
SDUDFHWDPRO \R IDOWD GH KRPRJHQHLGDG GHO
JUDQXODGR R ELHQ TXH HO SURFHVR GH PH]FOD QR
KD\D VLGR ySWLPR \ QR D SUREOHPDV
UHODFLRQDGRVFRQOHSURFHVRGHIDEULFDFLyQGDGR
TXHORVGDWRVREWHQLGRVHQODFDUWDGHFRQWUROGH
OD IXHU]D GH FRPSUHVLyQ DSOLFDGD VH PDQWXYR
GHQWURGHORVOtPLWHVHVWDEOHFLGRV
5HIHUHQFLDV
&RPR SXHGH FRPSUREDUVH GH ORV UHVXOWDGRV
REWHQLGRV WRGRV ORV ORWHV GH DPEDV
IRUPXODFLRQHV FXPSOHQ FRQ HO HQVD\R SXHV HO
YDORU GH DFHSWDFLyQ HQ QLQJ~Q FDVR HV VXSHULRU
DO OtPLWH SDUD HO LQWHUYDOR GH DFHSWDFLyQ / (Q OD WDEOD VH PXHVWUDQ ORV UHVXOWDGRV
REWHQLGRV HQ HO HQVD\R GH XQLIRUPLGDG GH
FRQWHQLGR SDUD FDGD XQR GH ORV ORWHV GH
FRPSULPLGRV
(OHQVD\RGHXQLIRUPLGDGGHFRQWHQLGRRHQVD\R
GH ULTXH]D GH XQ SULQFLSLR DFWLYR GH XQ ORWH GH
FRPSULPLGRV HV LQGLFDWLYR GH OD FRUUHFWD
GRVLILFDFLyQGHOORWH(VWHGDWRVHREWLHQHGHXQD
PXHVWUDUHSUHVHQWDWLYDGHOORWHHVWXGLDGR \SRU
3KDUPDFRSHp (XURSpHQQH  HGLWLRQ
&RQVHLOGO¶(XURSH6WUDERXUJ
7KH 8QLWHG 6WDWHV 3KDUPDFRSHLD 863
1)9ROS5RFNYLOOH
$ )ROLYHQH $OGHD -0 6Xxp 3 3pUH]
/R]DQR 0 5RLJ ( *DUFtD 0RQWR\D 0
PLxDUUR -5 7LFy (VWXGLR IDUPDFRWpFQLFR
FRPSDUDWLYR
GH
FLQFR
PHGLFDPHQWRV
LQGXVWULDOHV TXH FRQWLHQHQ J GH SDUDFHWDPRO
,, (O )DUPDFpXWLFR GH +RVSLWDOHV (678',2)$50$&e87,&2'()2508/$&,21(6*(1e5,&$6'(3$5$&(7$02/
+2VVpWp67RUUDGR6XVDQD67RUUDGR6DQWLDJR03%DOOHVWHURV\--7RUUDGR
'HSDUWPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDG&RPSOXWHQVH
GH0DGULG0DGULG6SDLQ
UHDOL]DQVHJ~QORHVWLSXODGRSRUODVIDUPDFRSHDV
,QWURGXFFLyQ
HVSDxROD 5)( QRUWHDPHULFDQD 863
(OHVWXGLRGHODFDOLGDGGHORVPHGLFDPHQWRVHV
HXURSHD (3 HG \ EULWiQLFD
VLHPSUHXQWHPDPX\LQWHUHVDQWHGHVGHHOSXQWR
%3
GH YLVWD SUiFWLFR TXH SRU VX LQFLGHQFLD HQ OD
VDOXG RFXSD XQ OXJDU GHVWDFDGR HQ OD SUHQVD
&DUDFWHUtVWLFDVGHELRGLVSRQLELOLGDG
&DGDYH]FRQPiVLQWHUpVVHHVWXGLDODUHODFLyQ
FDOLGDGSUHFLR\EDVWDQWHVYHFHVVHGXGDLQFOXVR
&RQ ODV GRV IRUPXODFLRQHV HVSDxRODV TXH
SRU DOJXQRV SURIHVLRQDOHV GH OD 6DQLGDG VREUH
SUHVHQWDQXQDPD\RUGLVSDULGDGHQYHORFLGDGGH
OD FDOLGDG ³UHDO´ GH PHGLFDPHQWRV GHO WLSR
GLVROXFLyQ VH KDFH XQ HQVD\R GH
JHQpULFRTXHKDQGHELGRVXSHUDUGHVGHHOSXQWR
ELRGLVSRQLELOLGDG HQ RQFH YROXQWDULRV VDQRV GH
GH YLVWD DGPLQLVWUDWLYR \ WpFQLFR XQD VHULH GH
HGDGFRPSUHQGLGDHQWUH\DxRV6HUHDOL]y
SUXHEDV \ FRQWUROHV (YLGHQWHPHQWH UHVROYHU
XQ GLVHxR FUX]DGR DOHDWRULR \ VH WRPDURQ
HVWDV GXGDV H[FHGH ODV SRVLELOLGDGHV GH HVWH
PXHVWUDVGHVDOLYDDORVVLJXLHQWHVWLHPSRV
WUDEDMR SHUR Vt VH KD SUHWHQGLGR PRGHVWDPHQWH
\PLQXWRV¶¶
FRQWULEXLUDXQPHMRUFRQRFLPLHQWRGHODFDOLGDG
\ KRUDV /DV PXHVWUDV VH DQDOL]DURQ SRU
GH DOJXQDV GH HVWRV PHGLFDPHQWRV 'HQWUR GH
+3/& (O WUDWDPLHQWR GH GLFKDV PXHVWUDV \ ODV
ORV GLVWLQWRV SULQFLSLRV DFWLYRV TXH VH SRGtDQ
FRQGLFLRQHV GH DQiOLVLV VRQ ODV GHVFULWDV SRU
HOHJLU KHPRV VHOHFFLRQDGR HO SDUDFHWDPRO \D
6KLP \-XQJ(OWUDWDPLHQWRGHGDWRVVH
TXHHVWHHVXQSULQFLSLRDFWLYRIiFLOGHDQDOL]DU
UHDOL]yGHIRUPDQRFRPSDUWLPHQWDO
HFRQyPLFR\VXVFHSWLEOHGHVHUXWLOL]DGRLQYLYR
FRQIDFLOLGDG\DTXHVHSXHGHDQDOL]DUHQVDOLYD
5HVXOWDGRV\GLVFXVLyQ
*DQGLD HW DO $Vt SXHV HQ HVWH WUDEDMR
VH HVWXGLDQ \ FRPSDUDQ ODV FDUDFWHUtVWLFDV
IDUPDFRWpFQLFDV \ ELRIDUPDFpXWLFDV GH YDULDV
IRUPXODFLRQHVFRPHUFLDOL]DGDVGHSDUDFHWDPRO
0DWHULDOHV\0pWRGRV
/DV IRUPXODFLRQHV FRPHUFLDOL]DGDV TXH VH KDQ
HVWXGLDGR VRQ ODV VLJXLHQWHV 7\OHQROŠ
(VSDxD 3DUDFHWDPRO (GLJHQŠ (VSDxD
3DUDFHWDPRO :LQWKURSŠ (VSDxD 3DUDFHWDPRO
0XQGRJHQŠ (VSDxD 3DUDFHWDPRO 53*Š
)UDQFLD 3DUDFHWDPRO %D\HUŠ )UDQFLD
3DUDFHWDPRO *15Š 3KDUPD )UDQFLD
3DUDFHWDPRO 0HUFNŠ )UDQFLD 3DUDFHWDPRO
5HYDQLDŠ
-RUGDQLD
3DUDFHWDPRO
5DWLRSKDUPŠ $OHPDQLD \ 3DUDFHWDPRO 0.Š
(O 6DOYDGRU $ HVWDV IRUPXODFLRQHV VH OHV
DVLJQD XQD FODYH TXH QR QHFHVDULDPHQWH
FRUUHVSRQGH FRQ HO RUGHQ DQWHV XVDGR GH ) D
) (Q HVWDV IRUPXODFLRQHV VH HVWXGLDQ VXV
FDUDFWHUtVWLFDV
IDUPDFRWpFQLFDV
\
GH
ELRGLVSRQLELOLGDG
&DUDFWHUtVWLFDVIDUPDFRWpFQLFDV
6HHVWXGLDODXQLIRUPLGDGGHPDVDXQLIRUPLGDG
GH FRQWHQLGR ULTXH]D SRU HVSHFWURIRWRPHWUtD
GLVJUHJDFLyQ UHVLVWHQFLD D OD IUDFWXUD
IULDELOLGDG HQVD\R GH GLVROXFLyQ FRQ
GHWHUPLQDFLyQ GHO IDFWRU GRV GH VLPLOLWXG \
GHWHUPLQDFLyQGHODPLQRIHQRO/RVHQVD\RVVH
(Q FXDQWR D ODV FDUDFWHUtVWLFDV IDUPDFRWpFQLFDV
WRGDV ODV IRUPXODFLRQHV FXPSOtDQ ODV
HVSHFLILFDFLRQHV GH IDUPDFRSHD HQ FXDQWR D
XQLIRUPLGDG GH PDVD XQLIRUPLGDG GH
FRQWHQLGR ULTXH]D SRU HVSHFWURIRWRPHWUtD
GLVJUHJDFLyQ UHVLVWHQFLD D OD IUDFWXUD
IULDELOLGDG HQVD\R GH GLVROXFLyQ \
GHWHUPLQDFLyQ GHO DPLQRIHQRO VDOYR GRV
IRUPXODFLRQHV XQD GH ODV FXDOHV QR FXPSOtD
HVSHFLILFDFLRQHVGHXQLIRUPLGDGGHFRQWHQLGR\
RWUD WHQtD XQD YHORFLGDG GH FHVLyQ OLJHUDPHQWH
LQIHULRU D OD HVSHFLILFDGD SRU 863 (Q
DPERV FDVRV ODV GLIHUHQFLDV FRQ UHVSHFWR D ORV
YDORUHV OtPLWHV ILMDGRV SRU OD IDUPDFRSHD HUDQ
PX\SHTXHxRVSRUORTXHQRVHFRQVLGHUDURQGH
UHOHYDQFLD 3RU HMHPSOR HQ HO HQVD\R GH
XQLIRUPLGDG GH FRQWHQLGR HO FRHILFLHQWH GH
YDULDFLyQVHJ~Q863GHEHVHUPHQRUGHO\
HQODIRUPXODFLyQTXHQRFXPSOHHVWiHQHO
(Q HO FDVR GH OD IRUPXODFLyQ TXH QR FXPSOH OD
HVSHFLILFDFLyQGHYHORFLGDGGHFHVLyQHQOD863
VH PDUFD FRPR FULWHULR XQ PtQLPR GHO
\ODFHVLyQHVGHO7DPELpQVHHVWXGLy
VL KDEtD XQD UHODFLyQ HQWUH HO SUHFLR GHO
PHGLFDPHQWR
\
DOJXQD
FDUDFWHUtVWLFD
IDUPDFRWpFQLFD LQGLFDWLYD GH OD FDOLGDG &RPR
SDUiPHWURV GH FDOLGDG VH HOLJLHURQ HO FRQWHQLGR
HQ DPLQRIHQRO \ OD YHORFLGDG GH FHVLyQ GH
SDUDFHWDPRO (Q ORV HVWXGLRV UHDOL]DGRV QR VH
HQFRQWUyUHODFLyQGLUHFWDHQWUHHOSUHFLR\HVWDV
FDUDFWHUtVWLFDVGHFDOLGDG
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
100
90
80
% d i su e lto
70
60
50
40
30
20
10
0
0
5
10
15
20
25
30
35
Tiempo (minutos)
F2
F4
)LJXUD 5HVXOWDGRV PHGLRV GH SDUDFHWDPRO
OLEHUDGR HQ ORV HVWXGLRV GH FHVLyQ GH ODV
IRUPXODFLRQHV)\)
12
C (mcg/ml)
10
8
6
4
2
0
0
100
200
300
400
500
600
Tiempo (min)
F4
F2
)LJXUD
5HVXOWDGRV
PHGLRV
GH
FRQFHQWUDFLRQHV
HQ
VDOLYD
WUDV
OD
DGPLQLVWUDFLyQ GH GRV IRUPXODFLRQHV GH
SDUDFHWDPRO
/RV UHVXOWDGRV GH iUHD EDMR OD FXUYD $8&
WPD[ \ &PD[ VH PXHVWUDQ HQ OD WDEOD &RPR
VHSXHGHREVHUYDUHQGLFKDWDEODH[LVWHXQDJUDQ
YDULDELOLGDG HQ WPD[ \ &PD[ TXH QR SHUPLWH
HVWXGLDU VL KD\ R QR GLIHUHQFLDV HQWUH GLFKDV
IRUPXODFLRQHV &RQ UHVSHFWR DO iUHD EDMR OD
FXUYD VL VH SXHGH FRQFOXLU TXH QR H[LVWHQ
GLIHUHQFLDVHQWUHDPEDVIRUPXODFLRQHV
7DEOD 5HVXOWDGRV PHGLRV GHO HVWXGLR GH
ELRGLVSRQLELOLGDG GH ODV GRV IRUPXODFLRQHV
HVWXGLDGDV
3DUiPHWUR )
)
W6WXGHQW
$8&’
ȝJKPO
7PD[K &PD[
ȝJPO
&RQFOXVLRQHV
(Q FXDQWR D ODV FDUDFWHUtVWLFDV IDUPDFRWpFQLFDV
QR VH HQFRQWUDURQ GLIHUHQFLDV UHOHYDQWHV HQ
FXDQWR D ODV GLVWLQWDV IRUPXODFLRQHV \ WDPSRFR
VH SXGR FRUUHODFLRQDU HO SUHFLR GH ORV
PHGLFDPHQWRV
FRQ
QLQJ~Q
SDUiPHWUR
IDUPDFRWpFQLFRHVWXGLDGR
'HVGHHOSXQWRGHYLVWDGHELRGLVSRQLELOLGDGHQ
HO HVWXGLR UHDOL]DGR FRQ ODV GRV IRUPXODFLRQHV
TXHPRVWUDEDQPD\RUHVGLIHUHQFLDHQYHORFLGDG
GHFHVLyQHQQXHVWUDVFRQGLFLRQHVGHHVWXGLRVH
SXHGH FRQFOXLU TXH DPEDV IRUPXODFLRQHV VRQ
ELRHTXLYDOHQWHVHQFXDQWRDODFDQWLGDGWRWDOGH
SDUDFHWDPRODEVRUELGR
5HIHUHQFLDV
%3 %ULWLVK 3KDUPDFRSRHLD +HU
0DJHVW\V6WDWLRQHU\2IILFH/RQGUHV
(3(XURSHDQ3KDUPDFRSRHLDHG
&RXQFLORI(XURSH3KDUPDFRSRHLD&RQYHQWLRQ
YRO,,,,
*DQGLD 3 %DUHLOOL 03 6DLYLQ 6 /H
7UDRQ$3/DYLW0*XHOO$+RXLQ*-
&OLQ3KDUPDFRO
5)( 5HDO )DUPDFRSHD (VSDxROD
0LQLVWHULR GH 6DQLGDG \ &RQVXPR 0DGULG
6KLP&.\-XQJ%,QW-3KDUP
8638QLWHG6WDWHV3KDUPDFRSRHLD
86 3KDUPDFRSRHLDO &RQYHQWLRQ 5RFNYLOOH
$JUDGHFLPLHQWRV
$JUDGHFHPRV OD ILQDQFLDFLyQ UHFLELGD SRU OD
8&0 DO JUXSR GH LQYHVWLJDFLyQ '(7(50,1$&,Ï1'(/$62/8%,/,'$'<'(/$&203$7,%,/,'$'35,1&,3,2
$&7,92(;&,3,(17(3$5$(/'(6$552//2'(0,&52(6)(5$6&2026,67(0$6
'(/,%(5$&,Ï1352/21*$'$'(&$11$%,12,'(6
'+HUQiQ-0ROSHFHUHV05$EHUWXUDV&0DUWtQ0(*LO$,7RUUHV
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD
8QLYHUVLGDG&RPSOXWHQVH0DGULG
8QLYHUVLGDGGH$OFDOi0DGULG
7DPELpQ VH SUHSDUDURQ PH]FODV ELQDULDV &%'
,QWURGXFFLyQ
3&/ HQ SURSRUFLyQ \
(QHOGHVDUUROORJDOpQLFRGHPLFURHVIHUDVFRPR
VLVWHPDVGHOLEHUDFLyQFRQWURODGDGHXQIiUPDFR
$QiOLVLVGHODVPXHVWUDV
UHVXOWDGHJUDQXWLOLGDGUHFXUULUDOD&DORULPHWUtD
'LIHUHQFLDO GH %DUULGR '6& (VWD WpFQLFD
6H HYDOXy SRU '6& HO SHUILO WpUPLFR GH ODV
SHUPLWH SRU XQ ODGR GHWHUPLQDU GH IRUPD
PDWHULDVSULPDV&%'\3/&GHPLFURHVIHUDV
UiSLGD LQFRPSDWLELOLGDGHV HQWUH HO SULQFLSLR
SODFHER GH ODV PH]FODV ELQDULDV \ GH ORV
DFWLYR \ ORV PDWHULDOHV SROLPpULFRV SRVLEOHV
GLIHUHQWHV WLSRV GH PLFURHVIHUDV FDUJDGDV FRQ
FRQVWLWX\HQWHVGHODIRUPXODFLyQ
&%'
3RU RWUR ODGR SRU '6& WDPELpQ VH SXHGH
7RGRV ORV HQVD\RV VH UHDOL]DURQ SRU WULSOLFDGR
REWHQHU LQIRUPDFLyQ VREUH HO HVWDGR ItVLFR GH
HQ FiSVXODV GH DOXPLQLR WDSDGDV D XQD
SULQFLSLRDFWLYR \SROtPHURXQDYH] IRUPDGDOD
YHORFLGDG GH FDOHIDFFLyQ GH ž&PLQ HQ HO
PLFURHVIHUD /D WpFQLFD SHUPLWH LQFOXVR
UDQJR GH WHPSHUDWXUDV GH ž& HQ XQ
GHWHUPLQDUODVROXELOLGDGGHOSULQFLSLRDFWLYRHQ
FDORUtPHWR GLIHUHQFLDO GH EDUULGR 0HWWOHU
HOSROtPHURGDWRHVSHFLDOPHQWHLPSRUWDQWHSDUD
7ROHGR'6&
HO GHVDUUROOR GH VLVWHPDV GH OLEHUDFLyQ
$ SDUWLU GHO iUHD GH ORV SLFRV GH IXVLyQ VH
FRQWURODGD \D TXH HO SHUILO GH OLEHUDFLyQ GHO
GHWHUPLQD HO FDORU GH IXVLyQ ǻ+P TXH VH
DFWLYR D SDUWLU GHO VLVWHPD HVWi IXHUWHPHQWH
UHODFLRQD FRQ HO JUDGR GH FULVWDOLQLGDG ȜP GH
LQIOXHQFLDGR SRU VX GLVSRVLFLyQ DO HVWDGR
ODPXHVWUDVHJ~QODHFXDFLyQ
PROHFXODU R HQ IRUPD GH PLFURFULVWDOHV HQ HO
PLVPR
ȜP ǻ+Pǻ+FP
(Q HO SUHVHQWD WUDEDMR VH GHWHUPLQD PHGLDQWH
GRQGH
ǻ+FP
HV OD HQWDOStD GH IXVLyQ GH XQD
'6&ODFRPSDWLELOLGDGHQWUHXQSULQFLSLRDFWLYR
PXHVWUDFRQXQDFULVWDOLQLGDGGHO
GHO JUXSR GH ORV FDQQDELQRLGH &DQQDELGLRO \
5HVXOWDGRV\'LVFXVLyQ
XQ SROtPHUR SROLİFDSURODFWRQD DVt FRPR OD
VROXELOLGDG GHO SULQFLSLR DFWLYR HQ GLFKR
/D ILJXUD UHVXPH ORV UHVXOWDGRV REWHQLGRV HQ
SROtPHUR(VWRVGDWRVVHDSOLFDQDOGHVDUUROORGH
HODQiOLVLVWpUPLFRGH&%'\3&/PS\GHORV
PLFURHVIHUDV GH FDQQDELGLRO FRPR VLVWHPDV GH
GLIHUHQWHVWLSRVGHPLFURHVIHUDVHODERUDGRV
OLEHUDFLyQ FRQWURODGD GH DGPLQLVWUDFLyQ SRU YtD
SDUHQWHUDO
0DWHULDOHV\0HWRGRV
6HXWLOL]D&DQQDELGLRO&%'SXUH]DGHO
7+& 3KDUP )UDQNIXUW $OHPDQLD \ SRO\İ
FDSURODFWRQD3&/3P6LJPD$OGULFK
6W/RXLV((88
3UHSDUDFLyQGHODVPXHVWUDV
6H SUHSDUDURQ PLFURHVIHUDV SODFHER \ FRQ
GLVWLQWD UHODFLyQ SULQFLSLR DFWLYRSROtPHUR
\ 6H
XWLOL]yODWpFQLFDGHHPXOVLyQ2$HYDSRUDFLyQ
GHVROYHQWH
0
-5
Endo
/DV IRUPXODFLRQHV FRPHUFLDOL]DGDV HQ (VSDxD
TXH PXHVWUDQ XQD PD\RU GLVSDULGDG HQ FHVLyQ
VRQODVGHVFULWDVFRPR)\)\VXVUHVXOWDGRV
VHPXHVWUDQHQODILJXUD
(Q FXDQWR D ODV FDUDFWHUtVWLFDV GH
ELRGLVSRQLELOLGDGHQODILJXUDVHPXHVWUDQORV
UHVXOWDGRV PHGLRV GH ODV GRV IRUPXODFLRQHV
HVWXGLDGDV
(8)
(7)
(6)
-10
(5)
(4)
-15
-20
Raw CBD (1)
Raw PCL (2)
Placebo PCL MS (3)
MS CBD-PCL 5/150 (4)
MS CBD-PCL 10/150 (5)
MS CBD-PCL 15/150 (6)
MS CBD-PCL 30/150 (7)
MS CBD-PCL 50/150 (8)
(2)
(3)
(1)
-25
0
20
40
60
80
100
)LJXUD7HUPRJUDPDVGHODVPDWHULDVSULPDV
\GHODVPLFURHVIHUDV
&%' PXHVWUD XQ SLFR GH IXVLyQ D ž&
FRQILUPDQGRVXQDWXUDOH]DFULVWDOLQD'LFKRSLFR
QRDSDUHFHHQORVWHUPRJUDPDVGHODVGLIHUHQWHV
IRUPXODFLRQHV GH PLFURHVIHUDV VXJLULHQGR TXH
HO &%' VH HQFXHQWUD GLVXHOWR HQ OD PDWUL]
SROLPpULFD
Temperature (ºC)
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
Raw PCL(1)
Placebo PCL MS (2)
Mixture 1:3 (3)
Mixture 1:2 (4)
Mixture 1:1 (5)
Mixture 1.5:1 (6)
Mixture 2:1 (7)
Mixture 3:1 (8)
Mixture 4:1 (9)
Mixture 5:1 (10)
Mixture 6:1 (11)
Endo
-15
-20
(2)
(1)
-25
0
20
40
60
80
100
Temperature (ºC)
)LJXUD 7HUPRJUDPDV GH ODV PH]FODV
ELQDULDV
(QODILJXUDVHUHSUHVHQWDQORVYDORUHVGHFDORU
GH IXVLyQ GH &%' HQ ODV PH]FODV /D
FRQFHQWUDFLyQ GH &%' H[WUDSRODGD SDUD XQ
FDORU GH IXVLyQ ³FHUR´ VH FRUUHVSRQGH FRQ OD
VROXELOLGDG GH &%' HQ HO SROtPHUR (VWH YDORU
Estudio de solubilidad CBD-PCL (DSC)
HVGH
6
relació n C B D : PC L
5
4
y = 0,1048x + 1,5341
3
R2 = 0,9606
2
1
0
10,00
20,00
30,00
40,00
50,00
0,00
AH (J/g)
)LJXUD(VWXGLRGHVROXELOLGDG
&RQFOXVLRQHV
&%' \ 3&/ VRQ VXVWDQFLDV TXtPLFDPHQWH
FRPSDWLEOHV (O IDFWRU TXH OLPLWD OD FDUJD GH
&%' HQ ODV PLFURHVIHUDV GH 3&/ HV HO HIHFWR
SODVWLILFDQWHTXHHOSULQFLSLRDFWLYRHMHUFHVREUH
HO SROtPHUR \ TXH D FRQFHQWUDFLRQHV
VHQVLEOHPHQWH SRU GHEDMR GH OD VROXELOLGDG GH
&%' HQ HO SROtPHUR OOHJD D LPSHGLU OD
PLFURHQFDVSXODFLyQ 3RU HVWH PRWLYR HQ ODV
PLFURHVIHUDV &%' VH HQFXHQWUD VLHPSUH
GLVSHUVRDOHVWDGRPROHFXODU
5HIHUHQFLDV
'XEHUQHW & 7KHUPRDQDO\VLV RI
PLFURVSKHUHV 7HUPRFKLP $FWD ±
0XQGDUJL5&HWDO-&RQWURO5HO
/L==/L4-3KDUP6FL
$JUDGHFLPLHQWRV
(VWH WUDEDMR VH KD UHDOL]DGR FRQ XQD EHFD GH
)380LQLVWHULRGH(GXFDFLyQ\&LHQFLD\FRQ
OD ILQDQFLDFLyQ GH OD 8QLYHUVLGDG &RPSOXWHQVH
GH0DGULG
/,%(5$&,Ï1,19,752'(/,'2&$Ë1$%$6('(6'(35(3$5$&,21(67Ï3,&$6$/
)2508/$'$6&21',67,1726',62/9(17(6(02/,(17(6
(%ODQFD0'&RQWUHUDV
HYDEODQL#XJUHV
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH*UDQDGD
*UDQDGD(VSDxD
D S+ LJXDO D GHO FXDO KHPRV FRPSUREDGR
,QWURGXFFLyQ
SUHYLDPHQWH TXH FXPSOH ODV FRQGLFLRQHV VLQN
6H IRUPXODQ SUHSDUDFLRQHV WySLFDV FRQ
>@
OLGRFDtQD EDVH DO PP XWLOL]DQGR HQ FDGD
/DV DOtFXRWDV H[WUDtGDV FRQ UHHPSOD]DPLHQWR
XQD GH HOODV XQ GLVROYHQWH HPROLHQWH QR SRODU
KDQ
VLGR
FXDQWLILFDGDV
PHGLDQWH
$GLSDWR GH GLHWLO KH[LOR )RUPXODFLyQ $
HVSHFWURIRWRPHWUtD
2FWLOGRGHFDQRO)RUPXODFLyQ%$GLSDWRGH
&DGD IyUPXOD KD VLGR HQVD\DGD YHFHV
GLEXWLOR )RUPXODFLyQ & \ 0LULVWDWR GH
FRPSDUiQGRODFRQXQEODQFR
LVRSURSLOR)RUPXODFLyQ'GHXVRKDELWXDOHQ
SUHSDUDFLRQHV GHUPDWROyJLFDV 3UHYLDPHQWH VH
5HVXOWDGRV\'LVFXVLyQ
GHWHUPLQy WHyULFD \ H[SHULPHQWDOPHQWH OD
VROXELOLGDG GHO IiUPDFR HQ FDGD XQR GH GLFKRV
7RGDV ODV SUHSDUDFLRQHV VH KDQ PDQWHQLGR
GLVROYHQWHV /DV IRUPXODFLRQHV GLVHxDGDV
HVWDEOHVDOPHQRVGXUDQWHXQDxR
VRQ HPXOVLRQHV 2$ &RPR IDVH ROHRVD VH
(O HQVD\R GH OLEHUDFLyQ VH UHDOL]y GXUDQWH XWLOL]DQ ORV GLVROYHQWHV QR SRODUHV HQ FDQWLGDG
KRUDV GH HOODV VROR ORV UHVXOWDGRV UHIHUHQWHV D
VXILFLHQWH SDUD PDQWHQHU OD OLGRFDtQD HQ
ODVSULPHUDVKRUDVIXHURQUHSUHVHQWDWLYRV
VROXFLyQ \ D VDWXUDFLyQ &RPR HPXOJHQWH VH
VHOHFFLRQy XQ SROtPHUR SROLDFUtOLFR 3HPXOHQ
7,0
75TXHRULJLQDHPXOVLRQHVHVWDEOHVGXUDQWHOD
6,0
UHSRVLFLyQ GH ODV IRUPXODFLRQHV H LQHVWDEOHV DO
5,0
H[WHQGHUODVVREUHODSLHO IDYRUHFLHQGRODUiSLGD
HYDSRUDFLyQGHODIDVHDFXRVD\ODVDWXUDFLyQGHO
4,0
SUHSDUDGR (O REMHWLYR IXQGDPHQWDO HV TXH OD
3,0
OLGRFDtQD VH HQFXHQWUH HQ VROXFLyQ \ D
A
B
VDWXUDFLyQ SDUD GH HVWD PDQHUD DXPHQWDU VX
2,0
C
ELRGLVSRQLELOLGDG>@HLQLFLDUXQUiSLGRHIHFWR\
1,0
D
SURORQJDUORHQHOWLHPSR
0,0
7RGDV ODV IRUPXODFLRQHV WLHQHQ OD PLVPD
0,0
1,0
2,0
3,0
4,0
5,0
FDQWLGDG GH SROtPHUR \ S+ SDUD HOOR VH
Tiempo (h)
DGLFLRQR WULHWDQRODPLQD H[FHSWR HQ HO FDVR GH
)LJXUD &DQWLGDG DFXPXODWLYD GH OLGRFDtQD
ODV IRUPXODFLRQHV % \ & /D LQFRUSRUDFLyQ GH
OLEHUDGD SRU XQLGDG GH VXSHUILFLH GHVGH OD
XQD SHTXHxD FDQWLGDG GH WHQVLRDFWLYR IXH
IRUPXODFLyQFRQ$GLSDWRGHGLHWLOKH[LOR$
QHFHVDULDHQODIRUPXODFLyQ'
2FWLOGRGHFDQRO%$GLSDWRGHGLEXWLOR&\
0HGLDQWH HQVD\RV YLVFRHOiVWLFRV >@ ODV
0LULVWDWRGHLVRSURSLOR'
IRUPXODFLRQHV IXHURQ FDUDFWHUL]DGDV FRPR JHO
FUHPDJHO \ GH OD FRPSDUDFLyQ GH ORV
(Q OD ILJXUD VH REVHUYD OD OLEHUDFLyQ GH OD
SDUiPHWURVFDUDFWHUtVWLFRV*\*´FRQORVTXH
OLGRFDtQD HQ IXQFLyQ GHO WLHPSR 'H VX DQiOLVLV
SUHVHQWDEDQIRUPXODFLRQHVDQiORJDVVLQIiUPDFR
VHGHGXFH
VHGHWHFWyODLQWHUDFFLyQGHOSROtPHURDQLyQLFR
/D DXVHQFLD GH WLHPSR GH UHWDUGR
FRQ OD OLGRFDtQD FDWLyQLFD KDFLHQGR GXGDU
([SHULPHQWDOPHQWH VH FRPSUREy OD UiSLGD
VREUH OD LGRQHLGDG GH OD HOHFFLyQ GHO SROtPHUR
FHVLyQGHODOLGRFDtQDDOPHGLRUHFHSWRU
FRPRHPXOJHQWH
/RV SHUILOHV GH ODV FXUYDV VRQ PX\ VLPLODUHV
(QHVWHWUDEDMRVHHVWXGLDFRPRHVWDLQWHUDFFLyQ
(Q HOORV VH GLVWLQJXHQ GRV ]RQDV ELHQ
HQWUH HO SROtPHUR \ HO IiUPDFR DIHFWD D OD
GLIHUHQFLDGDV GHVGH D KRUD GRQGH OD
OLEHUDFLyQGHODOLGRFDtQD
OLEHUDFLyQHVWDUHJLGDSRUORVFRPSRQHQWHVGHOD
HPXOVLyQ \ GHVGH D KRUDV GHVSXpV GH
0DWHULDOHV\0pWRGRV
LQLFLDGRHOHQVD\RGRQGHH[LVWHODSRVLELOLGDGGH
(OHQVD\RGHOLEHUDFLyQLQYLWURVHKDUHDOL]DGR
OD UXSWXUD GH OD HPXOVLyQ (Q DPERV FDVRV VH
HQFpOXODVWLSR)UDQ]>@)'&GHFPGH
REVHUYD ILJXUD TXH OD IRUPXODFLyQ ' HV OD
GLiPHWUR D ž& /D FDQWLGDG GH PXHVWUD HV
TXH SUHVHQWD PD\RU OLEHUDFLyQ (Q HOOD VH
FRQVWDQWH \FRPR PHPEUDQD GHVHSDUDFLyQFRQ
SUHVXSRQtD TXH OD LQWHUDFFLyQ GH OD OLGRFDtQD
ODIDVHUHFHSWRUDVHXWLOL]DXQDGHPHWLOFHOXORVD
FRQHOSROtPHURVHUtDGHPHQRULQWHQVLGDG\VROR
/DVROXFLyQUHFHSWRUDKDVLGRXQWDPSyQIRVIDWR
2
0
-5
-10
Lidocaína (mg/cm )
3&/ PS \ ODV 03V SODFHER PXHVWUDQ XQD
HQWDOStD GH IXVLyQ GH “ -J \
“-JUHVSHFWLYDPHQWHORTXHVXJLHUH
TXH HO SROtPHUR PDQWLHQH VXV FDUDFWHUtVWLFDV
VHPLFULVWDOLQDVHQODV03VQRHVWDQGRDIHFWDGDV
SRU HO SURFHVR GH PLFURHQFDSVXODFLyQ SYDOXH
6LQHPEDUJRDQDOL]DQGRODHQGRWHUPDGHIXVLyQ
GH3&/HQODVPLFURHVIHUDVFDUJDGDVVHREVHUYD
TXH DO DXPHQWDU OD FDUJD GLVPLQX\H
SURJUHVLYDPHQWHWDQWRODWHPSHUDWXUDFRPROD
HQWDOStDGHIXVLyQGHOSROtPHURWDEOD
7DEOD 3DUiPHWURV FDORULPpWULFRV GH ODV
PXHVWUDVǻ+FP -J
0XHVWUD 7Pž& ǻ+P ȜP
-J
3&/PS
0VSODFHER 06 06 06 06 06 /D GLVPLQXFLyQ GH OD HQWDOStD GH IXVLyQ VH
FRUUHVSRQGH FRQ XQD GLVPLQXFLyQ GHO JUDGR GH
FULVWDOLQLGDGȜPGHODVPXHVWDVTXHMXQWRFRQ
OD GLVPLQXFLyQ GH OD WHPSHUDWXUD GH IXVLyQ
LQGLFDQ XQ HIHFWR SODVWLILFDQWH GHO SULQFLSLR
DFWLYRVREUHHOSROtPHUR
(QHIHFWRHQODVIRWRJUDILDVGHODVPLFURHVIHUDV
FRQ &%' ILJ VH REVHUYD TXH DO DXPHQWDU OD
UHODFLyQ &%' 3/& ODV PLFURHVIHUDV WLHQGH D
SHJDUVH GH PDQHUD TXH SDUD XQD UHODFLyQ
OD DJUHJDFLyQ HV WDQ LQWHQVD TXH
FRPSURPHWHODPLFURHQFDSVXODFLyQ
(a)
(b)
)LJXUD)RWRJUDItD6(0GHODVPLFURHVIHUDV
D\E
(Q OD ILJXUD VH UHFRJHQ ORV WHUPRJUDPDV
REWHQLGRVDSDUWLUGHODVPH]FODVELQDULDV(VWDV
FXUYDVSUHVHQWDQGRVSLFRVHQGRWpUPLFRVTXHVH
FRUUHVSRQGHQ FRQ &%' \ 3&/ OR TXH LQGLFD
TXH QR VH GHWHFWD LQFRPSDWLELOLGDG TXtPLFD
HQWUHDPERV
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
SRGUtD DIHFWDUVH HO UHSDUWR GH OD OLGRFDtQD HQWUH
DPEDV IDVHV FRPR FRQVHFXHQFLD GHO
WHQVLRDFWLYR6LQHPEDUJRODIRUPXODFLyQ%HQ
ODTXHODOLGRFDtQDDFWXyFRPRQHXWUDOL]DQWHHV
OD GH PHQRU OLEHUDFLyQ HQ HOOD VH SUHVXSRQH OD
PD\RU LQWHQVLGDG GH LQWHUDFFLyQ HQWUH OLGRFDtQD
\SROtPHUR
/RV FRHILFLHQWHV GH GLIXVLyQ 7DEOD VH
HQFXHQWUDQ GHQWUR GH ORV YDORUHV QRUPDOHV
UHIHUHQWHV D IRUPXODFLRQHV SDUD DSOLFDFLyQ
WySLFD
7DEOD &RHILFLHQWH GH GLIXVLyQ ' GH OD
OLGRFDtQDEDVHHQODVGLVWLQWDVIRUPXODFLRQHV
'
)RUPXODFtyQ
FPV
Â
$
5,60
D
6,12
C
5,42
B
5,92
A
4,0
4,5
5,0
5,5
6,5
Lidocaína (mg/cm 2)
(QWRGRVORVFDVRVODOLEHUDFLyQGHOLGRFDtQD
IXH SUy[LPD FRPR SRGHPRV REVHUYDU HQ OD
ILJXUDLQFOXVRHQODIRUPXOD%
100
% Lidocaína
80
76,9
74,4
70,4
68,1
70
60
50
40
30
20
10
0
A
B
C
D
)LJXUD 3RUFHQWDMH GH OLGRFDtQD OLEHUDGD HQ
ODVKRUDV
/DV REVHUYDFLRQHV DQWHULRUHV TXHGDQ
UHIOHMDGDVHQORVYDORUHVGHYHORFLGDG7DEOD
\ HQ ORV FRHILFLHQWHV GH GLIXVLyQ 7DEOD
DPERVREWHQLGRVDSDUWLUGHODFLQpWLFDGH
+LJXFKL SUHYLD FRPSUREDFLyQ GH RWUDV
+HPRV FRPSUREDGR WUDVHO DQiOLVLV GH HVWRV
GDWRV TXH OD IyUPXOD TXH PiV UiSLGDPHQWH
OLEHUDHOIiUPDFRHVOD'
7DEOD &LQpWLFD GH OLEHUDFLyQ < D E[
D PJ\ PJFP[ WVE PJFPÂVò
)RUP
$
U
\ ÂW
(FXDFLyQ
%
\ ÂW
&
\ ÂW
'
\ ÂW
(UURUHVWiQGDUGHHVWLPDFLyQ
Â
Â
'
Â
6,0
)LJXUD &DQWLGDG GH OLGRFDtQD DFXPXODWLYD
OLEHUDGDDODVKRUDV
90
%
&
&RQFOXVLRQHV
/DOLEHUDFLyQGHODOLGRFDtQDHQWRGRVORVFDVRV
HVDGHFXDGDDSHVDUGHTXHVHSRGtDLQWXLUXQD
JUDQLQWHUDFFLyQHQWUHODVPROpFXODVGHOIiUPDFR
\ ORV JUXSRV iFLGRV GHO 3HPXOHQ 75 \ FRPR
FRQVHFXHQFLD XQD EDMD FHVLyQ GH IiUPDFR (VWR
KDFH SUHYHU XQ UiSLGR LQLFLR GH HIHFWR \ GH
LQWHQVLGDGDGHFXDGD
5HIHUHQFLDV
:LHFKHUV-:HWDO,QW-&RVP6FL
%ODQFD ( &RQWUHUDV 0 ' DQG 6HNNDW
+³0RGLILFDWLRQ
RI
SK\VLFDOFKHPLFDO
SDUDPHWHUV RI WRSLFDO HPXOVLRQV E\ OLGRFDLQH
EDVH DQG 3HPXOHQ 75 LQWHUDFWLRQ´ WK :RUOG
0HHWLQJ RQ 3KDUPDFHXWLFV %LRSKDUPDFHXWLFV
DQG3KDUPDFHXWLFOD7HFKQRORJ\
)UDQ] 7 - - ,QYHVWLJDWLYH 'HUPDWRORJ\
'RPpQHFK - HW DO %LRIDUPDFLD \
IDUPDFRFLQpWLFD
%,2'(*5$'$%/(0,&5263+(5(6)259$6&8/$5(1'27+(/,$/*52:7+
)$&7259(*)'(/,9(5<,1,6&+(0,&3$7+2/2*,(6
)5)RUPLJD%3HODFKR(*DUED\R*$EL]DQGD)3URVSHUDQG0-%ODQFR3ULHWR
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\
'HSDUWPHQWRI+HPDWRORJ\DQG&HOO7KHUDS\
&OLQLFD8QLYHUVLWDULDDQG'LYLVLRQRI&DQFHU8QLYHUVLW\RI1DYDUUD,UXQODUUHDVQ3DPSORQD
6SDLQ
ƒ& J PLQ )LQDOO\ WKH SDUWLFOHV
,QWURGXFWLRQ
ZHUH UHVXVSHQGHG LQ PO RI XOWUDSXUH ZDWHU
&DUGLRYDVFXODU GLVHDVHV DUH WKH ZRUOGZLGH
IUR]HQ DW ƒ& O\RSKLOLVHG *HQHVLV (/
OHDGLQJFDXVHRIGHDWKLQERWKPHQDQGZRPHQ
9LUWLV DQG VWRUHG DW ƒ& 3DUWLFOH VL]H
H[WHQGLQJDFURVVDOOUDFLDODQGHWKQLFJURXSV
GLVWULEXWLRQ ZDV GHWHUPLQHG E\ ODVHU
&XUUHQWO\ DYDLODEOH DSSURDFKHV IRU WUHDWLQJ
GLIIUDFWRPHWU\ XVLQJ D 0DVWHUVL]HUŠ 0DOYHUQ
SDWLHQWV ZLWK LVFKHPLF GLVHDVH LQFOXGH GUXJV
,QVWUXPHQWV 8. 7KH HQFDSVXODWLRQ HIILFLHQF\
SHUFXWDQHRXVLQWHUYHQWLRQDQGYDVFXODUVXUJHU\
DQG WKH LQ YLWUR UHOHDVH RI 9(*) LQ 3%6 ZHUH
+RZHYHUDVLJQLILFDQWQXPEHURIWKHVHSDWLHQWV
FRQGXFWHG
XVLQJ
DQ
HQ]\PHOLQNHG
DUH
QRW
FDQGLGDWHV
IRU
FRURQDU\
LPPXQRVRUEHQW DVVD\ (/,6$ VSHFLILF IRU
UHYDVFXODUL]DWLRQ SURFHGXUHV ,Q RUGHU WR ORRN
UK9(*) 5' 6\VWHPV 7KH ELRDFWLYLW\
IRUFXUDWLYHPRUHWKDQSDOLDWLYHWKHUDSLHVHDUO\
RI WKH UHOHDVHG 9(*) ZDV HYDOXDWHG LQ YLWUR
VWUDWHJLHV WR LPSURYH WKH UHJHQHUDWLRQ RI WKH
GHWHUPLQLQJ WKH SUROLIHUDWLRQ FDSDFLW\ RI D
GDPDJHG WLVVXH DUH EHLQJ H[SORUHG OLNH WKH
KXPDQLOLDFDUWHU\HQGRWKHOLDOFHOOOLQH+,$(&
GHOLYHU\ RI JURZWK IDFWRUV WR SURPRWH
DIWHU9(*)VWLPXODWLRQE\XVLQJWKH&HOO7LWHU
QHRYDVFXODUL]DWLRQRUVWLPXODWHFHOOSUROLIHUDWLRQ
*ORŠ /XPLQHVFHQW &HOO 9LDELOLW\ $VVD\
DQGSURWHFWLRQ7KXVVHYHUDOFOLQLFDOWULDOV
3URPHJD $OVR 9(*) ELRDFWLYLW\ ZDV
KDYH EHHQ DOUHDG\ SHUIRUPHG LQ SDWLHQWV ZLWK
FRQILUPHG E\ GHWHUPLQLQJ LWV FDSDELOLW\ WR
FDUGLDF DQG OLPE LVFKHPLD E\ LQMHFWLRQ RI SUR
DFWLYDWHLWVUHFHSWRU.'5E\PHDVXULQJ.'5
DQJLRJHQLF IDFWRUV OLNH 9(*) RU E)*) W\URVLQH SKRVSKRU\ODWLRQ E\ (/,6$ 5'
+RZHYHU SRVLWLYH UHVXOWV KDYH QRW EHHQ
6\VWHPV
REWDLQHGEHLQJSDUWRIWKLVIDLOXUHDWWULEXWDEOHWR
VXERSWLPDOGHOLYHU\VWUDWHJLHVDQGLQVWDELOLW\RI
WKHSURWHLQ7KHDLPRIWKLVZRUNZDVWRGHYHORS
3RO\ODFWLGHFRJO\FROLGH
3/*$
ELRGHJUDGDEOH PLFURSDUWLFOHV ORDGHG ZLWK WKH
YDVFXODU HQGRWKHOLDO JURZWK IDFWRU 9(*)
WKDWFRXOGEHDSSOLFDEOHWRWKHVHSDWKRORJLHV
0DWHULDOVDQG0HWKRGV
9(*) ZDV HQFDSVXODWHG E\ VROYHQW
H[WUDFWLRQHYDSRUDWLRQ PHWKRG XVLQJ WKH 7RWDO
5HFLUFXODWLRQ 2QH0DFKLQH 6\VWHP 75206
%ULHIO\ PJ RI 3/*$ ZLWK D PRQRPHU
UDWLR ODFWLF DFLGJO\FROLF DFLG RI 5HVRPHU 5* + %RHKULQJHU ZHUH
GLVVROYHG LQ PO RI D GLFKORURPHWDQHDFHWRQH
PL[WXUH7KLVSRO\PHUVROXWLRQZDVLQMHFWHGLQWR
WKH LQQHU DTXHRXV SKDVH : FRQWDLQLQJ WKH
UK9(*) 5' 6\VWHPV 1H[W WKH
SUHYLRXVO\ IRUPHG LQQHU HPXOVLRQ :2 ZDV
UHFLUFXODWHGWKURXJKWKHV\VWHPIRUPLQXQGHU
D WXUEXOHQW UHJLPH $IWHU WKLV VWHS WKH ILUVW
HPXOVLRQ ZDV LQMHFWHG LQWR WKH RXWHU DTXHRXV
SKDVH:FRPSRVHGRIPORID3RO\
YLQ\ODOFRKROUHVXOWLQJLQDPXOWLSOHHPXOVLRQ
:2: ZKLFK ZDV KRPRJHQL]HG E\
FLUFXODWLRQ WKURXJK WKH V\VWHP IRU PLQ 7KH
PXOWLSOH HPXOVLRQ ZDV VWLUUHG IRU K
0LFURSDUWLFOHV ZHUH ZDVKHG WKUHH WLPHV ZLWK
XOWUDSXUHZDWHUE\FRQVHFXWLYHFHQWULIXJDWLRQDW
5HVXOWVDQG'LVFXVVLRQ
75206SURGXFHGPLFURVSKHUHVZLWKDGLDPHWHU
RI—PZKLFKUHVXOWHGWREHPRUHFRPSDWLEOH
ZLWKDLQYLYRDGPLQLVWUDWLRQ7KHHQFDSVXODWLRQ
HIILFLHQF\ZDVDURXQGDQGWKHGUXJORDGLQJ
—J 9(*)PJ SRO\PHU &RQFHUQLQJ LQ
YLWUR UHOHDVH RI 9(*) LQ 3%6 RI WKH
HQWUDSSHG SURWHLQ ZDV UHOHDVHG ZLWKLQ WKH ILUVW
KRXUV DQG DURXQG E\ GD\ )LJXUH
9(*) UHOHDVHG IURP PJ RI PLFURSDUWLFOHV
VWLPXODWHG WKH SUROLIHUDWLRQ RI +,$(&V LQ
FXOWXUH )LJXUH LQGLFDWLQJ WKDW WKH SURWHLQ
UHPDLQVDFWLYHDIWHULWVHQFDSVXODWLRQ'LIIHUHQW
FRQFHQWUDWLRQV RI UHOHDVHG 9(*) IURP WKH
PLFURSDUWLFOHV GLG QRW LQGXFH SURPLQHQW VKLIWV
RQ WKH SUROLIHUDWLRQ SURILOH GDWD QRW VKRZQ
$OVR ELRDFWLYLW\ RI 9(*) ZDV FRQILUPHG E\
GHWHFWLRQ RI LWV UHFHSWRU .'5 DFWLYDWLRQ LQ
+,$(&FHOOVZKHQWUHDWHGZLWKQJPORIIUHH
9(*) RU ZLWK PJ RI 9(*) PLFURSDUWLFOHV
)LJXUH
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
&RQFOXVLRQV
,1)/8(1&,$'(/$&21&(175$&,Ï1'(',+(;$'(&,/)26)$72'+362%5(/$6
&$5$&7(5Ë67,&$6),6,&248Ë0,&$6'(/,32620$6'(68&&,1$72'(
680$75,37È1(/$%25$'26325',67,17$67e&1,&$6
0/*RQ]iOH]5RGUtJXH]:'KULPHXU69LOODVPLO66DODV$05DEDVFR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH6HYLOOD6HYLOOD(VSDxD
(VWRV SDUiPHWURV IXHURQ GHWHUPLQDGRV D ž&
HQ XQ HTXLSR ]HWDPDVWHU 0DOYHUQ ,QVWUXPHQWV
,QWURGXFFLyQ
0DOYHUQ8.
6XPDWULSWiQ 680 HV XQ IiUPDFR DJRQLVWD
7DEOD&RPSRVLFLyQGHORVORWHVHVWXGLDGRV
VHOHFWLYR GH ORV UHFHSWRUHV VHURWRQLQpUJLFRV +7%\+7' PX\ XWLOL]DGRHQHOWUDWDPLHQWR
/RWHV
'&3
7/(
5(9
)$7
68
GHORVHSLVRGLRVDJXGRVGHPLJUDxD
(VWHWUDEDMRGHLQYHVWLJDFLyQIRUPDSDUWHGHXQ
SUR\HFWR GHVWLQDGR DO GHVDUUROOR GH XQD
IRUPXODFLyQ ySWLPD GH OLSRVRPDV GH 680 FRQ
ODILQDOLGDGGHSRGHUDGPLQLVWUDUHOIiUPDFRSRU
YtD QDVDO HYLWDQGR ODV WtSLFDV UHFXUUHQFLDV
SURGXFLGDVSRUODVIRUPDVFRQYHQFLRQDOHV
(VWXGLRV SUHYLRV UHDOL]DGRV SRU QXHVWUR JUXSR
GH LQYHVWLJDFLyQ KDQ SXHVWR GH PDQLILHVWR OD
LPSRUWDQFLD GH DGLFLRQDU FDUJD D ODV
IRUPXODFLRQHV GH OLSRVRPDV SDUD SRGHU LQFOXLU
680 HQ HO LQWHULRU GH ODV YHVtFXODV >@ /D
DGLFLyQ GH HVWHDULODPLQD OtSLGR FDUJDGR
SRVLWLYDPHQWHKDSHUPLWLGR REWHQHUOLSRVRPDV
5(9 FRQ XQD FDUJD GH IiUPDFR GH
DSUR[LPDGDPHQWH SY >@ $XQTXH ODV
GLVSHUVLRQHV FRORLGDOHV UHVXOWDQWHV WUDV OD
DGLFLyQ GH '+3 PRVWUDURQ HILFDFLDV GH
/DPHODULGDG
HQFDSVXODFLyQ PHQRUHVVLQHPEDUJRHQEDVHD
/D PRUIRORJtD GH ODV YHVtFXODV IXH YLVXDOL]DGD
ORV GDWRV GH SRWHQFLDO ]HWD SUHVHQWDURQ XQD
XWLOL]DQGR WpFQLFDV GH FRQIRFDOLGDG &/60
PD\RU HVWDELOLGDG TXH ORV OLSRVRPDV FRQ FDUJD
PHGLDQWH OD DGLFLyQ GH URGDPLQD D OD IDVH
SRVLWLYD
DFXRVD
3RUHOORHOREMHWLYRGHOSUHVHQWHWUDEDMRFRQVLVWH
(ILFDFLDGHHQFDSVXODFLyQ
HQ HYDOXDU ODV SURSLHGDGHV ILVLFRTXtPLFDV GH
(VWH SDUiPHWUR IXH GHWHUPLQDGR PHGLDQWH
GLVWLQWDV IRUPXODFLRQHV HODERUDGDV FRQ '+3 D
GLiOLVLV GLQiPLFD TXH SHUPLWH HO FiOFXOR GH OD
GLVWLQWDV FRQFHQWUDFLRQHV \ PHGLDQWH GLVWLQWDV
FRQFHQWUDFLyQ GH SULQFLSLR DFWLYR QR
WpFQLFDVGHHODERUDFLyQFRQHOILQGHHVFODUHFHU
HQFDSVXODGR>@
HO FRPSRUWDPLHQWR GHO IiUPDFR FXDQGR VH
&RQGLFLRQHVFURPDWRJUiILFDV
PRGLILFDODFDUJDVXSHUILFLDOGHODVYHVtFXODV
- &ROXPQD GH DFHUR LQR[LGDEOH :DWHUV
6SKHULVRUE —P 2'6 GH PP GH
0DWHULDOHV\0pWRGRV
ORQJLWXG\PPGHGLiPHWUR
)RVIDWLGLOFROLQD 3& &ROHVWHURO &+
- )DVH PyYLO WDPSyQ IRVIDWR 0 'LKH[DGHFLOIRVIDWR'+3&ORURIRUPRWDPSyQ
DFHWRQLWULOR YY DMXVWDGR D S+ +(3(6 P0 S+ VXFFLQDWR GH
FRQKLGUy[LGRGHVRGLR0
VXPDWULSWDQRIUHFLGRSRU*OD[R6PLWK.OLQH
- )OXMR P/PLQ 9ROXPHQ GH LQ\HFFLyQ /RV OLSRVRPDV IXHURQ SUHSDUDGRV VLJXLHQGR ORV
—/
PpWRGRVUHFRJLGRVHQHVWXGLRVSUHYLRV>@
$QiOLVLVHVWDGtVWLFR
(Q HVWH WUDEDMR WRGRV ORV ORWHV IXHURQ
(O WUDWDPLHQWR GH ORV GDWRV VH KD UHDOL]DGR
SUHSDUDGRVFRQPJGH680\XVDQGRFLQFR
XWLOL]DQGRHOSURJUDPD6366YHUVLyQ
FRQFHQWUDFLRQHVGH'+3
\P0FRPRVHUHFRJHHQODWDEOD
5HVXOWDGRV\'LVFXVLyQ
(IHFWRGHODWpFQLFDGHHODERUDFLyQ
7DPDxR YHVLFXODU tQGLFH GH SROLGLVSHUVLyQ \
/DV GLVWLQWDV IRUPXODFLRQHV KDQ VLGR
SRWHQFLDO]HWD
FDUDFWHUL]DGDV SRU FRQIRFDOLGDG 6H SXHGH
REVHUYDUDSDUWLUGHODVLPiJHQHVREWHQLGDVSRU
HO &/60 TXH ORV PpWRGRV 7/( \ )$7
SURSRUFLRQDQ YHVtFXODV PXOWLODPLQDUHV )LJXUD
•
•
•
)LJXUH 9(*) LQ YLWUR UHOHDVH SURILOH IURP
3/*$PLFURSDUWLFOHV
)LJXUH +,$(& SUROLIHUDWLRQ DVVD\ +,$(&
VWLPXODWHG E\ GDLO\ DGPLQLVWUDWLRQ RI SXUH
9(*) DW QJPO GXULQJ RU GD\V RU E\
9(*)UHOHDVHGIURPWKHPLFURSDUWLFOHV9(*)
03 &XOWXUH PHGLXP &R DQG QRQORDGHG
PLFURSDUWLFOHV ZHUH XVHG DV FRQWUROV 3RUH
WUDQVZHOOVRI—P
9(*)3/*$
PLFURSDUWLFOHV
ZHUH
VXFFHVVIXOO\ GHYHORSHG E\ 75206 ZLWK D
VXLWDEOHVL]HIRULQYLYRDGPLQLVWUDWLRQ
7KH 9(*) UHPDLQHG DFWLYH DIWHU WKH
PLFURHQFDSVXODWLRQ SURFHVV DFWLYDWLQJ LWV
UHFHSWRU.'5LQHQGRWKHOLDOFHOOV+,$(&
DQG DV D FRQVHTXHQFH RI LW SURPRWLQJ WKH
FHOOSUROLIHUDWLRQ
9(*)PLFURSDUWLFOHVFRXOGEHDSURPLVLQJ
VWUDWHJ\ IRU LVFKHPLF FDUGLRYDVFXODU
GLVHDVHV
5HIHUHQFHV
103DQG\DHWDO9DVF3KDUPDFRO
±
6*UXQGPDQQHWDO(XU-&OLQ,QYHVW
3&DUPHOLHWHWDO1DW0HG
06LPRQVHWDO&LUF
(*DUED\RHWDO(XU-3KDUP%LRSKDUP
,QSUHVV
$FNQRZOHGJPHQWV
7KLV ZRUN ZDVVXSSRUWHGE\ $JHQFLD(VSDxROD
GH &RRSHUDFLyQ ,QWHUQDFLRQDO SDUD HO
'HVDUUROOR $(&,' )XQGDFLyQ &DMD 1DYDUUD
DQG 0LQLVWHULR GH &LHQFLD H ,QQRYDFLyQ 366
)LJXUH .'5 DFWLYDWLRQ E\ 9(*) QJPO
VWLPXODWLRQ
5HFHSWRU
DFWLYDWLRQ
E\
SKRVSKRULODWLRQ LQ W\URVLQH UHVLGXHV ZDV
GHWHUPLQHGE\(/,6$WHFKQLTXH
,;&RQJUHVRGHOD6(),*
$
-62,00
-64,00
%
40,00
38,00
36,00
Media de EE
Media de ZETA
$ \% PLHQWUDVTXHODWpFQLFD5(9SHUPLWH
OD IRUPDFLyQ GH YHVtFXODV XQLODPLQDUHV )LJXUD
&
$%&
7HFQRORJtD)DUPDFpXWLFD
-66,00
34,00
32,00
30,00
28,00
-68,00
26,00
10,0
12,5
15,0
20,0
30,0
10,0
12,5
DCP
15,0
20,0
30,0
DCP
&
620,00
600,00
580,00
'
0,600
0,550
Media de IP
)LJXUD ,PiJHQHV GH ODV YHVtFXODV REWHQLGDV
SRU HO PLFURVFRSLR FRQIRFDO $ 7/( % )$7
&5(9
$O DQDOL]DU ODV YDULDEOHV GHSHQGLHQWHV ((
WDPDxRYHVLFXODUSRWHQFLDO]HWDH,3QRVHKD
REVHUYDGRQLQJXQDGLIHUHQFLDVLJQLILFDWLYDQLHQ
OD(()SQLHQHOSRWHQFLDO]HWD
) 3 HQWUH ODV GLVWLQWDV
IRUPXODFLRQHV /D PD\RU (( REWHQLGD
FRUUHVSRQGLy D ODV YHVtFXODV 5(9 GHELGR IXQGDPHQWDOPHQWH DO PD\RU HVSDFLR
DFXRVR GH ORV OLSRVRPDV XQLODPLQDUHV >@
5HVSHFWR DO WDPDxR YHVLFXODU HO $129$
GHPRVWUy GLIHUHQFLDV VLJQLILFDWLYDV HQWUH ODV
WpFQLFDVREWHQLpQGRVHXQDYDULDFLyQSRVLWLYDGH
S HQWUH ORV PpWRGRV 7/( \
5(9LQGLFDWLYRGHOPHQRUWDPDxRGHORV5(9
(QFXDQWRDO,3ODSUXHED7GH'XQQHW PRVWUy
XQD GLIHUHQFLD VLJQLILFDWLYD HQWUH ORV PpWRGRV
7/( \ 5(9 FRQ XQD GLIHUHQFLD GH S
TXH LQGLFDED XQD PD\RU KRPRJHQHLGDG
GHODGLVSHUVLyQHQODVIRUPXODFLRQHV5(9
(IHFWRGHODFRQFHQWUDFLyQGH'+3
(QHVWHWUDEDMRVHHODERUDURQIRUPXODFLRQHVFRQ
FLQFR FRQFHQWUDFLRQHV GLVWLQWDV GH '+3 SDUD
PRGLILFDU OD FDUJD VXSHUILFLDO GH ODV
IRUPXODFLRQHV /D SUXHED $129$ QR PRVWUy
GLIHUHQFLDV VLJQLILFDWLYDV VREUH ODV YDULDEOHV
HVWXGLDGDV 6LQ HPEDUJR HQ OD ILJXUD GRQGH
VH UHFRJH OD HYROXFLyQ GH ODV UHVSXHVWDV HQ
IXQFLyQ GH OD FRQFHQWUDFLyQ GH '+3 SXHGH
REVHUYDUVH OD HYROXFLyQ GH ODV GLVWLQWDV
UHVSXHVWDV (Q FRQFUHWR OD (( PXHVWUD XQD
WHQGHQFLD DVFHQGHQWH D PHGLGD TXH VH
LQFUHPHQWDODGHQVLGDGGHFDUJDQHJDWLYDHQODV
YHVtFXODVKDVWDHOSXQWRFRUUHVSRQGLHQWHD
P0 GH '+3 D SDUWLU GHO FXDO QR DXPHQWD
VLJQLILFDWLYDPHQWH 8QD KLSyWHVLV TXH VH EDUDMD
HV OD SRVLELOLGDG GH TXH HO 680 TXH DO S+
IRUPXODGRVHHQFXHQWUDLRQL]DGRSRVLWLYDPHQWH
LQWHUDFFLRQH FRQ HO '+3 IDYRUHFLHQGR OD
HQFDSVXODFLyQ GHO IiUPDFR KDVWD XQ OtPLWH D
SDUWLUGHOFXDOQRVHSURGXFHODLQWHUDFFLyQ(VWH
KHFKRGDUtDOXJDUDXQDHYROXFLyQHQORVYDORUHV
GHSRWHQFLDO]HWDFRPRHOUHIOHMDGRHQODILJXUD
Media de SIZE
0,500
560,00
540,00
0,450
0,400
520,00
0,350
500,00
480,00
0,300
10,0
12,5
15,0
DCP
20,0
30,0
10,0
12,5
15,0
20,0
30,0
DCP
)LJXUD 9DULDFLyQ GH ODV UHVSXHVWDV HQ
IXQFLyQ GH OD FRQFHQWUDFLyQ GH '+3 $
3RWHQFLDO]HWD%((&7DPDxR',3
(IHFWRGHODSUHVHQFLDGH680
*OREDOPHQWH ODV IRUPXODFLRQHV HODERUDGDV
SUHVHQWDURQ XQ WDPDxR YHVLFXODU TXH RVFLOy
HQWUH\QP KDELpQGRVHREVHUYDGR
DO DSOLFDU ODV SUXHEDV QR SDUDPpWULFDV SDUD
YDULDEOHV LQGHSHQGLHQWHV 8 GH 0DQQ:KLWQH\
: GH :LOFR[RQ \ HVWDGtVWLFR = GLIHUHQFLDV
HVWDGtVWLFDPHQWH VLJQLILFDWLYDV FXDQGR VH
LQFRUSRUDED HO IiUPDFR HO WDPDxR DXPHQWy S
5HVSHFWR DO SRWHQFLDO ]HWD LJXDOPHQWH VH
REVHUYDURQ GLIHUHQFLDV HQWUH ORV OLSRVRPDV
EODQFR\ORVIRUPXODGRVFRQ680S
&RQFOXVLRQHV
'H WRGRV ORV UHVXOWDGRV REWHQLGRV SRGHPRV
FRQFOXLUTXHODFRQFHQWUDFLyQGH'+3QRDIHFWy
DORVSDUiPHWURVHVWXGLDGRVDXQTXHVtVHREWXYR
XQDUHODFLyQGLUHFWDFRQOD((KDVWDXQYDORUGH
P0 GH '+3 (Q FXDQWR D OD WpFQLFD GH
HODERUDFLyQ SRGHPRV FRQFOXLU TXH OD WpFQLFD
5(9HVODTXHSURSRUFLRQDODPD\RUFDQWLGDGGH
IiUPDFRHQFDSVXODGRORTXHSXHGHVHUGHELGRD
OD KRPRJHQHLGDG \ DO SHTXHxR WDPDxR GH ODV
YHVtFXODV 3RU ~OWLPR OD SUHVHQFLD GHO IiUPDFR
HQ ODV IRUPXODFLRQHV LQFUHPHQWD HO WDPDxR
YHVLFXODU \ GLVPLQX\H HO YDORU GHO SRWHQFLDO
]HWDORTXHSRGUtDFRQWULEXLUDXQLQFUHPHQWRGH
ODHVWDELOLGDGGHODIRUPXODFLyQ
5HIHUHQFLDV
*RQ]iOH]5RGUtJXH] HW DO 9,,, 6SDQLVK
3RUWXJXHVH &RQIHUHQFH RQ &RQWUROOHG 'UXJ
'HOLYHU\
*RQ]iOH]5RGUtJXH] HW DO 9,,, 6SDQLVK
3RUWXJXHVH &RQIHUHQFH RQ &RQWUROOHG 'UXJ
'HOLYHU\
0DHVWUHOOLHWDO,QW-3KDUP
$EUDKDPHWDO0HWKRGV(Q]LPRO
,17(5$&&,Ï1'(680$75,37$1&21/26&20321(17(6'(81$)2508/$&,Ï1
'(/,32620$6&$5*$'26&21(67($5,/$0,1$Ï&21',+(;$'(&,/)26)$72
(678',20(',$17('6&<3105
0/*RQ]iOH]5RGUtJXH]69LOODVPLO:'UKLPHXU$05DEDVFR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6HYLOOD&
3URI*DUFtD*RQ]iOH]6HYLOOD
EDUULGR FRQ XQD YHORFLGDG GH FDOHQWDPLHQWR GH
,QWURGXFFLyQ
6XPDWULSWiQ 680 HV XQ IiUPDFR DJRQLVWD
ž& PLQ HQ XQ LQWHUYDOR GH WHPSHUDWXUDV
VHURWRQLQpUJLFR PX\ XWLOL]DGRHQHOWUDWDPLHQWR
FRPSUHQGLGRHQWUH\ž&REWHQLHQGRDVt
GHORVHSLVRGLRVDJXGRVGHPLJUDxD
ORVWHUPRJUDPDVFRUUHVSRQGLHQWHVDODVGLVWLQWDV
([LVWHQ FRPHUFLDOL]DGRV HQ OD DFWXDOLGDG
IRUPXODFLRQHV
SUHSDUDGRV GH 680 GHVWLQDGRV D VX
DGPLQLVWUDFLyQSRUYtDVXEFXWiQHDRUDORQDVDO
0LFURVFRStDGHSODWLQDFDOLHQWH+60
6LQ HPEDUJR VH HVWiQ HVWXGLDQGR RWUDV YtDV
DOWHUQDWLYDVFRQHOILQGHPLQLPL]DUHOIHQyPHQR
(O SURFHVR GH IXVLyQ GH ODV PXHVWUDV VH UHDOL]y
GH UHFXUUHQFLD GHO IiUPDFR >@ 1XHVWUR JUXSR
PHGLDQWH XQD SODWLQD FDOLHQWH 0HWWOHU )3
GH LQYHVWLJDFLyQ HVWi GHVDUUROODQGR XQD
+7DFRSODGDDXQPLFURVFRSLR2O\PSXV%+
IRUPXODFLyQ LQWUDQDVDO GH 680 YHKLFXODGR HQ
REMHWLYR [ FRQ XQ GLVSRVLWLYR GH UHJLVWUR
OLSRVRPDV 5HVXOWDGRV SUHYLRV KDQ GHPRVWUDGR
IRWRJUiILFRGLJLWDO/DWHPSHUDWXUDLQLFLDO\ILQDO
TXHHVQHFHVDULRDSRUWDUFDUJDDODVXSHUILFLHGH
GH SURJUDPDFLyQ VH HOLJLy HQ EDVH D ORV
ODV YHVtFXODV SDUD IRUPDU OLSRVRPDV GH 680
WHUPRJUDPDVREWHQLGRVHQHO'6&
HVWDEOHV>@(VSRUHOORSRUORTXHHQHOSUHVHQWH
(VSHFWURVFRStDGH3105
WUDEDMR VH YD D UHDOL]DU XQ DQiOLVLV GHO
/RV HVSHFWURV GH 3105 VH REWXYLHURQ HQ XQ
FRPSRUWDPLHQWR ItVLFR GH ODV YHVtFXODV FXDQGR
HVSHFWUyPHWUR %UXNHU $YDQFH D 0+]
pVWDV HVWiQ HQ SURFHVR GH IRUPDFLyQ HQ
FRQXQDVRQGD413GHGHWHFFLyQGLUHFWDSDUDHO
SUHVHQFLD GH OtSLGRV FDUJDGRV SRVLWLYD R
3 \ RSHUDQGR D XQD WHPSHUDWXUD GH žN \
QHJDWLYDPHQWH FRPSDUDQGR ORV UHVXOWDGRV FRQ
žN FRQ XQ GHOD\ GH UHODMDFLyQ G ORVREWHQLGRVFRQODVYHVtFXODVVLQFDUJDU
PLOLVHJXQGRVSXOVRGHž\HOQ~PHURGHSXQWRV
SDUDODDGTXLVLFLyQN 1~PHUR
GH
DFXPXODFLRQHV VFDQV N /RV YDORUHV GHO
0DWHULDOHV\0pWRGRV
)RVIDWLGLOFROLQD 3& FROHVWHURO &+
FDPELRTXtPLFRHVWiQH[SUHVDGRVHQSSP
HVWHDULODPLQD ($ GLKH[DGHFLOIRVIDWR '+3
FORURIRUPRWDPSyQ+(3(6DMXVWDGRDS+
5HVXOWDGRV\'LVFXVLyQ
\ VXFFLQDWR GH VXPDWULSWiQ 680 TXH IXH
(VWXGLRWpUPLFRSRU'6&\+60
GRQDGRSRU*OD[R6PLWK.OLQH
(Q HVWH HVWXGLR VH KD HYDOXDGR HO
3UHSDUDFLyQGHORVOLSRVRPDV
FRPSRUWDPLHQWR WpUPLFR GHO 680 GH ORV
OtSLGRVIRUPDGRUHVGHSHOtFXODLQGLYLGXDOPHQWH
/DV IRUPXODFLRQHV GH OLSRVRPDV IXHURQ
GH ODV PH]FODV ItVLFDV ELQDULDV GHO
SUHSDUDGDV XWLOL]DQGR OD WpFQLFD GH HYDSRUDFLyQ
IiUPDFR FRQ ORV GLVWLQWRV FRPSRQHQWHV DVt
HQFDSDILQD7/(>@6HSUHSDUDURQOLSRVRPDV
FRPR GH PXHVWUDV REWHQLGDV GH OD SHOtFXOD
FDUJDGRV SRVLWLYD \ QHJDWLYDPHQWH XVDQGR GXUDQWH HO SURFHVR GH IRUPDFLyQ GH ORV
P0 GH ($ < '+3 UHVSHFWLYDPHQWH /D
OLSRVRPDVFRQ\VLQIiUPDFR
FDQWLGDG GH 680 IXH GH PJ HQ P/ GH
/D ILJXUD PXHVWUD ORV WHUPRJUDPDV GH FDGD
IDVHDFXRVDSRUORWH
XQR GH ORV FRPSRQHQWHV GH OD IRUPXODFLyQ SRU
/DV PXHVWUDV TXH IXHURQ XWLOL]DGDV SDUD HO
VHSDUDGR6HREVHUYDTXH680SUHVHQWDXQSLFR
HVWXGLR SRU '6& FRUUHVSRQGLHURQ D OLSRVRPDV
ELHQ GHILQLGR D XQD WHPSHUDWXUD GH WUDQVLFLyQ
HQIDVHGHIRUPDFLyQGRQGHODKLGUDWDFLyQGHOD
7P GH ž& HO FXDO FRUUHVSRQGH D VX
SHOtFXODOLStGLFDIXHSDUFLDO
IXVLyQ&RQUHVSHFWRDORVOtSLGRVIRUPDGRUHVGH
3DUD HO HVWXGLR GH 3105 OD SHOtFXOD OLStGLFD
SHOtFXODUHVXOWDGHLQWHUpVOD3&TXHSUHVHQWDXQ
FRPSRUWDPLHQWRLUUHJXODUHOFXDOVHDSUHFLDSRU
VH KLGUDWy FRQ P/ GH XQD VROXFLyQ IRUPDGD
OD DXVHQFLD GH SLFRV HQ HO WHUPRJUDPD
SRU P/ GH DJXD GHXWHUDGD \ P/ GHO
SUREDEOHPHQWH GHELGR D TXH VH WUDWD GH XQD
WDPSyQ+(3(6
PH]FOD GH IRVIROtSLGRV (Q ORV WHUPRJUDPDV
UHVXOWDQWHV GH ODV PH]FODV ELQDULDV VH REVHUYy
&DORULPHWUtDGLIHUHQFLDOGHEDUULGR'6&
FyPRGHVDSDUHFtDHOSLFRGH680HQODPH]FOD
3&680 OR FXDO VH GHEH D XQD GLVROXFLyQ GHO
(O HTXLSR TXH VH XWLOL]y IXH XQ '6& 680 HQ OD IRVIDWLGLOFROLQD D XQD WHPSHUDWXUD
6HWDUDP/DVPXHVWUDVVHVRPHWLHURQDXQ
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
SRU GHEDMR GH VX WHPSHUDWXUD GH IXVLyQ KHFKR
TXHIXHFRUURERUDGRSRU+60 \ORTXHH[SOLFD
OD LPSRVLELOLGDG GH SUHSDUDU OLSRVRPDV QHXWURV
GH680
100
SUM AT
TLE neutro 50:50
31P NMR a 303K
D
E
F
G
H
)LJXUD (VSHFWURV GH 3105 D žN D
OLSRVRPDV QHXWURV E OLSRVRPDV SRVLWLYRV F
OLSRVRPDV SRVLWLYRV FRQ 680 G OLSRVRPDV
QHJDWLYRVHOLSRVRPDVQHJDWLYRVFRQ680
100
80
100
80
Heatflow mV/min
PC
CH
60
80
100
0
-20
80
100
-40
-60
50
100
150
200
250
300
350
400
40
20
0
-20
-40
-60
-80
-100
ppm
20
0
-20
-40
-60
-80
-100
ppm
60
60
40
40
20
0
-20
-40
-60
-80
-100
ppm
20
0
-20
-40
-60
-80
-100
ppm
0
-20
-40
-60
-80
-100
ppm
TLE negativo con sumatriptan
31P NMR a 303 K
EA
0
40
TLE negativo 50:40:10
31P NMR a 303 K
DAP
40
20
60
TLE positivo con sumatriptan
31P NMR a 303 K
100
80
60
TLE positivo 50:40:10
31P NMR a 303 K
450
)LJXUD'6&GHOVXPDWULSWiQ\GHFDGDOtSLGR
(Q FXDQWR D ORV OLSRVRPDV WDQWR ORV FDUJDGRV
QHJDWLYD FRPR SRVLWLYDPHQWH FRQ 680
SUHVHQWDQ XQD DOWHUDFLyQ HQ VXV 7P \ HQ VXV
HQWDOStDV FRQ UHVSHFWR D ORV OLSRVRPDV EODQFR
WDEOD)LJ\ORFXDOHVLQGLFDWLYRGHXQD
SRVLEOH LQWHUDFFLyQ GHO 680 FRQ OD SHOtFXOD
OLStGLFD
TemperaturaºC
30
40
20
neutro 50:50
NMR a 338 K
100
-70
60
)LJXUD(VWUXFWXUDGHELFDSD\KH[DJRQDO+,,
GHOLSRVRPDV
(OOR KDFH SHQVDU TXH HO IiUPDFR SRGUtD
HVWDELOL]DU D ORV OLSRVRPDV VREUH WRGR D ORV
FDUJDGRVSRVLWLYDPHQWH
D
E
F
G
H
)LJXUD (VSHFWURV GH 3105 DW žN
DEFGH \ I VRQ ODV PLVPDV PXHVWUDV GH OD
ILJXUD
&RQFOXVLRQHV
/DVPROpFXODVGH680\ODFDUJDVXSHUILFLDOGH
ODVYHVtFXODVDOWHUDQHORUGHQHQHOLQWHULRUGHODV
ELFDSDV OLStGLFDV /RV OLSRVRPDV FDUJDGRV
SRVLWLYDPHQWH VRQ PiV HVWDEOHV TXH ORV TXH
SRVHHQ FDUJD QHJDWLYD 0LHQWUDV TXH OD ($
LQGXFLUtDODIRUPDFLyQGHODHVWUXFWXUDGHELFDSD
HQ ORV OLSRVRPDV >@ HO '+3 RULJLQD GRV WLSRV
GH FRQIRUPDFLRQHV ELFDSD \ KH[DJRQDO +,,
FRQWULEX\HQGR D OD GHVHVWDELOL]DFLyQ GH OD
IRUPXODFLyQ
5HIHUHQFLDV
)HPHQtD)RQWHWDO,QW-3KDUP
±
:HLGPDQQ HW DO &OLQ 7KHUDS ±
&XOOLV DQG 'H .UXLMII %LRFKLP %LRSK\V
$FWD±
0DHVWUHOOLHWDO,QW-RI3KDUP
±
/ySH]*DUFtD HW DO %LRFKLP HW %LRSK\V
$FWD±
TLE
31P
-20
80
80
60
40
20
0
-20
-40
-60
-80
-100
ppm
20
0
-20
-40
-60
-80
-100
ppm
20
0
-20
-40
-60
-80
-100
ppm
20
0
-20
-40
-60
-80
-100
ppm
0
-20
-40
-60
-80
-100
ppm
TLE positivo 50:40:10
31P NMR a 338 K
-120
100
0
100
200
300
400
80
Temper atur a ºC
100
80
TLE negativo
31P a 338 K
l i ponegati voSUM
Li ponegat.bl anco
)LJXUD 7HUPRJUDPDV GH OLSRVRPDV EODQFR \
FRQ680FDUJDGRVQHJDWLYDPHQWH
40,000
20,000
0,000
-20,000
-40,000
0
100
200
300
400
500
-60,000
-80,000
Temper atur a ºC
Li poposi tSUM
60
40
TLE positivo con sumatriptan
31P NMR a 338 K
500
Li poposi tbl anco
)LJXUD 7HUPRJUDPDV GH OLSRVRPDV EODQFR \
FRQ680FDUJDGRVSRVLWLYDPHQWH
(VSHFWURVFRStDGH3105
(Q ORV HVSHFWURV UHFRJLGRV HQ OD ILJXUD VH
REVHUYDODHVWUXFWXUDGHELFDSDHQORVHVSHFWURV
D E \ F D žN ORV FXDOHV PXHVWUDQ XQ SLFR
GHILQLGRDFRPSDxDGRGHXQKRPEURODWHUDOEDMR
6LQHPEDUJRHQORVHVSHFWURVG\HDSDUHFHXQ
SLFR DGLFLRQDO TXH HV FDUDFWHUtVWLFR GH OD
HVWUXFWXUD GH IDVH KH[DJRQDO +,, SURSLD GH
OLSRVRPDVFRQFDUJDQHJDWLYD)LJXUD
$ ž )LJXUD VH REVHUYD HO HIHFWR
GHJUDGDWLYR GH OD WHPSHUDWXUD VREUH ORV
OLSRVRPDV DFHQWXiQGRVH pVWH HQ ODV
IRUPXODFLRQHVTXHQRFRQWLHQHQ680
100
80
60
60
TLE negativo con
31P NMR a 338 K
100
80
40
50:40:10
60
40
sumatriptan
40
20
0,&52*5$18/26'(3(&7,1$&217(1,(1'2)2508/$&,21(6
08/7,3$57,&8/$5(6&21%8'(621,'$&$5$&7(5,=$&,Ï1<(9$/8$&,Ï1'(
68(),&$&,$$3/,&$1'2(/0e72'2%227675$3
0DQXHO*X]PiQ6XVDQD6iQFKH]5DTXHO*UDJHUD
'SWR)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD
'SWR(VSHFLDOLGDGHV0pGLFDV+LVWRORJtD)DFXOWDGGH0HGLFLQD
8QLYHUVLGDGGH$OFDOi$OFDOiGH+HQDUHV0DGULG(VSDxD
GLVWULEXFLyQ WHyULFD (VWD VH GHWHUPLQD
VLPXODQGR XQ HOHYDGR Q~PHUR GH PXHVWUDV
,QWURGXFFLyQ
DOHDWRULDV FRQVWUXLGDV GLUHFWDPHQWH D SDUWLU GH
6HJ~Q SUHFLVD OD *XtD GH OD (0($ SDUD HO
ORVGDWRVREVHUYDGRV
GHVDUUROOR GH SURGXFWRV PHGLFLQDOHV GHVWLQDGRV
DOWUDWDPLHQWRGHODVHQIHUPHGDGHVLQIODPDWRULDV
0DWHULDOHV\0pWRGRV
LQWHVWLQDOHV FRPR OD GH &URKQ HV PX\
/DV 03 13 \ 1& VH SUHSDUDURQ PHGLDQWH ODV
LPSRUWDQWHTXHHOIiUPDFROOHJXHHILFLHQWHPHQWH
WpFQLFDV GH HPXOVLyQHYDSRUDFLyQ GHO GLVROYHQWH
DO FRORQ (YLWDQGR OD DEVRUFLyQ HQ HO WUDFWR
QDQRSUHFLSLWDFLyQ \ GHSRVLFLyQ LQWHUIDFLDO
JDVWURLQWHVWLQDO 7*, SUR[LPDO \ ORJUDQGR XQD
UHVSHFWLYDPHQWH HPSOHDQGR FRPR SROtPHUR OD
HOHYDGD FRQFHQWUDFLyQ HQ ODV UHJLRQHV
SROLİFDSURODFWRQD
/DV
SDUWtFXODV
VH
LQIODPDGDV VH LQFUHPHQWD OD HIHFWLYLGDG GHO
LQFRUSRUDURQDGLVSHUVLRQHVDFXRVDVGHSHFWLQD
IiUPDFR /D SHFWLQD HV XQ SROLVDFiULGR QDWXUDO
FRQODVTXHVHREWXYLHURQORVPLFURJUiQXORVSRU
GHULYDGR GHO iFLGR α'JDODFWXUyQLFR
JHOLILFDFLyQLyQLFD$FRQWLQXDFLyQVHVHFDURQ\
SDUFLDOPHQWH PHWR[LODGR (V ELRGHJUDGDGR SRU
VH UHFXEULHURQ FRQ XQ FRSROtPHUR PHWDFUtOLFR
OD PLFURIORUD FROyQLFD D S+! WLHQH XQD
JDVWURUUHVLVWHQWH (XGUDJLW 6 \ XQ
FDUJDQHWDQHJDWLYDSyVHVHELRDGKHVLYLGDG\VXV
SROLVDFiULGR FRQ OR TXH VH REWLHQH XQ VLVWHPD
GLVSHUVLRQHV DFXRVDV JHOLILFDQ HQ SUHVHQFLD GH
GHOLEHUDFLyQFRQWURODGDGHHQWUHJDGHOIiUPDFR
LRQHVFDOFLRSRUORTXHSUHVHQWDXQDVFXDOLGDGHV
''6HQHOLQWHVWLQRJUXHVR
PX\ LQWHUHVDQWHV SDUD HO GHVDUUROOR GH
/D FDUDFWHUL]DFLyQ GH ODV IRUPXODFLRQHV VH
IRUPXODFLRQHVGLULJLGDVDORVWUDPRVILQDOHVGHO
UHDOL]y SRU PLFURVFRStD ySWLFD \ HOHFWUyQLFD
7*, 3RU VX SDUWH ORV VLVWHPDV
=HLVV'60ODGLVWULEXFLyQGHWDPDxRSRU
PXOWLSDUWLFXODUHVFRPRODVQDQRSDUWtFXODV13
GLVSHUVLyQ GH OD OX] /HHGV¤1RUWKUXS OD
PLFURSDUWtFXODV 03 \ QDQRFiSVXODV 1&
HILFDFLD GH HQFDSVXODFLyQ SRU FURPDWRJUDItD
SUHVHQWDQ DILQLGDG SRU ORV WHMLGRV LQIODPDGRV
OtTXLGD +3/& :DWHUV D QP SUHYLD
(Q WUDEDMRV SUHYLRV KHPRV HODERUDGR \
H[WUDFFLyQFRQHWDQRODO/DFDUDFWHUL]DFLyQ
FDUDFWHUL]DGR PLFURJUiQXORV 0* GH
VH FRPSOHWy FRQ FDORULPHWUtD '6& 0HWWOHU
SROLVDFiULGRV UHFXELHUWRV FRQ SROtPHURV
HVSFHWURPHWUtD )7,5 6SHFWUXP 3HUNLQ
PHWDFUtOLFRV LQFOX\HQGR VLVWHPDV PXOWL
(OPHU GLIUDFWRPHWUtD 5D\ ;SHUW 3UR \
SDUWLFXODUHV TXH SHUPLWHQ VX OLEHUDFLyQ \
HVWXGLRV GH OLEHUDFLyQ HQ IOXMR FRQWLQXR FRQ
YHFWRUL]DFLyQDOFRORQ
JUDGLHQWHGHS+HQXQDFpOXODGHXOWUDILOWUDFLyQ
(O REMHWLYR GH HVWH WUDEDMR KD FRQVLVWLGR HQ OD
P/
SUHSDUDFLyQ FDUDFWHUL]DFLyQ \ HYDOXDFLyQ GH OD
3DUD OD HYDOXDFLyQ GH OD HILFDFLD ³LQ YLYR´ VH
HILFDFLD³LQYLYR´GH0*GHSHFWLQDUHFXELHUWRV
XWLOL]DURQ UDWDV 6SUDJXH'DZOH\ PDFKRV
FRQ(XGUDJLW6FRQWHQLHQGR1303R1&
DQLPDODULR 8$+ Qž KRPRORJDFLyQ (& GH
SROLİFDSURODFWRQD
FDUJDGDV
FRQ
$ /RV DQLPDOHV VH GLYLGLHURQ HQ JUXSRV
%XGHVRQLGD 'HELGR D OD JUDQ YDULDELOLGDG
XQRFRQWURO\DOUHVWRVHOHVLQGXMRXQDUHDFFLyQ
LQWHULQGLYLGXDO \ DO UHGXFLGR Q~PHUR GH
LQIODPDWRULD
DJXGD
FRQ
iFLGR
DQLPDOHV XWLOL]DGR QRV SURSXVLPRV H[SORUDU OD
WULQLWUREHQFHQRVXOIyQLFR 71%6 $ ODV PHWRGRORJtD %RRWVWUDS SDUD PHMRUDU OD
KRUDV GH LQGXFLU OD UHDFFLyQ LQIODPDWRULD VH
ILDELOLGDG GH OD HYDOXDFLyQ GH ORV UHVXOWDGRV GH
DGPLQLVWUDURQ GLDULDPHQWH GXUDQWH GtDV FRQ
HILFDFLD
XQD FiQXOD EXFRJiVWULFD ODV IRUPXODFLRQHV
(OPpWRGR%RRWVWUDSSURSXHVWRSRU(IURQHQ
ȝJ%'6.JDORVJUXSRV*VXHURVDOLQR
HV XQ SURFHGLPLHQWR GH UHPXHVWUHR
FRQWURO*GLVSHUVLyQGH%'6HQ&0&*D
FRQVLGHUDGR FRPR XQD EXHQD DOWHUQDWLYD D ODV
* 0LFURJUiQXORV GH SHFWLQD FRQ 03 13 R
SUXHEDV SDUDPpWULFDV \ QR SDUDPpWULFDV
1& FDUJDGDV FRQ %'6 * D *
FRQYHQFLRQDOHVSDUDHOFRQWUDVWHGHKLSyWHVLV6H
0LFURJUiQXORV GH SHFWLQD FRQ SDUWtFXODV VLQ
EDVDHQFRQVWUXLUXQPRGHORGHGLVWULEXFLyQSDUD
FDUJD $O TXLQWR GtD \ VLJXLHQGR HO SURWRFROR
HO HVWDGtVWLFR D SDUWLU GH OD LQIRUPDFLyQ
HVWDEOHFLGR ORV DQLPDOHV IXHURQ VDFULILFDGRV \
SURSRUFLRQDGD SRU OD PXHVWUD \ QR UHTXLHUH
VHH[WUDMRHOLQWHVWLQR&RPRtQGLFHVGHODOHVLyQ
DVXPLUQLQJ~QVXSXHVWRSUHYLRVREUHVX
VH KD FRQVLGHUDGR HO GDxR PDFURVFySLFR
REVHUYDGRODUHODFLyQSHVRFRORQGLVWDOFPSHVR
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
Mg-NP-Bd
Mg-NC-Bd
Mg-NP
Mg-NC
Mg-MP-Bd
BDS
TNBS
Mg-MP
Indice del Daño
Salino
Mg-NC-Bd
Mg-NP-Bd
Mg-MP-Bd
Mg-NP
Mg-NC
)LJXUH 3HVR VHJPHQWR FRORQSHVR FRUSRUDO GHO
DQLPDO
(Q OD )LJXUD VH PXHVWUDV PLFURIRWRJUDItDV
REWHQLGDV FRQ 6(0 GH ORV 0* VLQ UHFXEULU VX
IRUPD \ Q~FOHR D \ XQ GHWDOOH GH OD FXELHUWD
E
SIZE= 1153 ȝm
80
70
60
50
40
30
20
10
0
Mg-NP-Bd
2,098±0,43
2,63±0,36
5,16±0,37
Mg-NC-Bd
92,59±4,49
82,26±3,93
92,15±2,42
Mg-MP-Bd
1,203±0,112
1,220±0,063
1,222±0,133
0
Mg-NP
CONTENIDO
(BDS ȝg/ mg)
4
2
Mg-NC
RENDIMIENTO
(%)
6
Mg-MP
Micropartículas
Nanopartículas
Nanocápsulas
TAMAÑO
(mm)
8
BDS
MICROGRANULOS
Conteniendo
10
Mg-MP
7DEOD0LFURJUiQXORVGH3HFWLQDFRQ%'6
12
BDS
16
14
TNBS
RENDIMIENTO
(%)
18
Salino
E.E.
(BDS%)
)LJXUD $FWLYLGDG PLHORSHUR[LGDVD 032 P8PJ
PXFRVD
SIZE= 50 nm
)LJXUD,PDJHQDO6(0GH0*D;E;
'HORVUHVXOWDGRVGH'6&5D\RV;\)7,5VH
GHGXFH TXH OD %'6 QR IRUPD HQODFHV QL FRQ OD
3İ&/ QL FRQ OD 3HFWLQD 6X OLEHUDFLyQ
FRPLHQ]D D ODV K FXDQGR HO S+ GHO IOXLGR
FDPELDGHD
/D DSOLFDFLyQ GH XQ FRQWUDVWH SDUDPpWULFR
FRQYHQFLRQDO SDUD DQDOL]DU ORV UHVXOWDGRV LQ YLYR
UHTXLHUH FRPSUREDU OD QRUPDOLGDG GH ODV
YDULDEOHV SHUR FXDQGR OD YDULDEOH QR WLHQH HVWD
GLVWULEXFLyQ R HO WDPDxR GH OD PXHVWUD HV
LQVXILFLHQWH DQLPDOHV VH HVWDUtD
FRPHWLHQGR XQ HUURU HQ OD LQIHUHQFLD 0HGLDQWH
OD WpFQLFD %RRWVWUDS VH REYLDQ HVWRV
LQFRQYHQLHQWHV&RQHVWHPpWRGRVHKDUHDOL]DGR
XQ DQiOLVLV GH OD YDULDQ]D \ XQ WHVW GH
FRPSDUDFLRQHV P~OWLSOHV JHQHUDGR PXHVWUDV ERRWVWUDS PHGLDQWH HO SDTXHWH GH OLEUH
GLIXVLyQ5
3DUD YDORUDU OD HILFDFLD GH ORV WUDWDPLHQWRV VH
DVLJQDURQ SXQWXDFLRQHV GH D D OD OHVLyQ
KLVWROyJLFD GH OD SDUHG LQWHVWLQDO HYDOXDGD SRU
PLFURVFRStD\DOGDxRPDFURVFySLFRREVHUYDGR
YLVXDOPHQWH HQ WRGR HO 7*, REWHQLpQGRVH XQ
tQGLFHJOREDOGHGDxRILJXUD/DVILJXUDV\
UHSUHVHQWDQORVRWURVGRVtQGLFHVFRQVLGHUDGRV
0RUDOHV0(/ySH]*/DUD9LOORVODGD),QIDQWH'5XL]0$\*DOODUGR9
3
TNBS
DISTRIBUCIÓN
AMPLITUD (nm)
4
Salino
TAMAÑO
(nm)
2460±130
300±30 87,38±2,91 63,53±6,3
175,1±14,9 67,2±7,9 90,77±2,22 93,42±5,35
244,3±25,1 81,6±25,6 97,41±0,24 92,48±1,26
3523,('$'(69,6&26,0e75,&$6'()2508/$6$5(11875,&,Ï1,1)$17,/
5
MPO (mU/mg mucosa)
SISTEMAS
Multiparticulares
Micropartículas
Nanopartículas
Nanocápsulas
2
1
0
)LJXUH ËQGLFH GHO GDxR PDFURVFySLFR H
KLVWROyJLFR
6
Indice P COLON/ PANIMAL
FRUSRUDO OD DFWLYLGDG PLHORSHUR[LGDVD 032 \
GDxR KLVWROyJLFR GH OD SDUHG LQWHVWLQDO D QLYHO GHO
FRORQ
5HVXOWDGRV\'LVFXVLyQ
/RV GDWRV GH WDPDxR \ (ILFDFLD GH
(QFDSVXODFLyQ (( SDUD OD %'6 HQ ORV
VLVWHPDV PXOWLSDUWLFXODUHV 03 13 \ 1& \ HQ
ORV PLFURJiQXORV GH SHFWLQD UHFXELHUWRV FRQ
(XJUDJLW6VHPXHVWUDQUHVSHFWLYDPHQWHHQ
ODV7DEODV\
7DEOD7DPDxR\FDUJDGH0313\1&FRQ%'6
(Q ORV WUHV tQGLFHV VH DSUHFLDQ GLIHUHQFLDV
HVWDGtVWLFDPHQWH VLJQLILFDWLYDV S! GH
WRGRV ORV JUXSRV FRQ HO FRQWURO VDOLQR \ FRQ
UHVSHFWR D OD DFWLYLGDG 032 FRQ HO JUXSR VLQ
WUDWDU (Q JHQHUDO ORV VLVWHPDV PXOWLSDUWLFXODUHV
0313\1&SUHVHQWDQPD\RUHIHFWLYLGDGTXH
OD%'6OLEUH/DIRUPXODFLyQGH0*FRQ1&HV
OD TXH PiV FDUJD GH IiUPDFR SHUPLWH
FRDG\XYDQGR D VX DFFLyQ ORV iFLGRV JUDVRV
LQVDWXUDGRVGHODIRUPXODFLyQ
5HIHUHQFLDV
'RF5HI&303(:3(0($
/LX/HWDO%LRPDWHULDOV
%KDUGZDM9HWDO-%LRPHG1DQRWHFKQRO
6iQFKH]67HVLVGRFWRUDO8QLY$OFDOi
*X]PDQ0HWDO3URFWK$QQ0HHWLQJ
([SRVRI&RQWURO5HOHDVH6RF32
*DUFtD3pUH]$FDSHQ0pWRGRVDYDQ]DGRV
GHHVWDGtVWLFDDSOLFDGD0DGULG81('
*X]PDQ0HWDO3DWQž(6
KWWSFUDQUSURMHFWRUJ
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH*UDQDGD
&DPSXVGH&DUWXMDVQ*UDQDGD
HPDLOPDHQ#XJUHV
'HSDUWDPHQWRGH1XWULFLyQ\6DOXG3XOHYD%LRWHFK*UDQDGD
'HSDUWDPHQWRGH3HGLDWUtD+RVSLWDO9DOO'¶+HEUyQ%DUFHORQD
,QWURGXFFLyQ
5HFLHQWHPHQWH HQ QXWULFLyQ LQIDQWLO VH KDQ
FRPHUFLDOL]DGR ODV OODPDGDV IyUPXODV $5
VLQyQLPR GH DQWLUHJXUJLWDFLyQ FRQ OD
LQGLFDFLyQ DSUREDGD SDUD ODFWDQWHV FRQ
UHJXUJLWDFLRQHV UHIOHMR GH OD LQPDGXUH] GHO
VLVWHPDQHUYLRVRHQWpULFR\GHOWRQRGHOHVItQWHU
HVRIiJLFRLQIHULRUGXUDQWHORVSULPHURVPHVHVGH
YLGD
/DV PRGLILFDFLRQHV PiV IUHFXHQWHV HQ ODV
IyUPXODV $5 VH EDVDQ HQ DxDGLU DOJXQD
VXVWDQFLD HVSHVDQWH WDOHV FRPR OD KDULQD GH OD
VHPLOOD GH DOJDUURER \ DOPLGRQHV OD
DPLORSHFWLQDFRPRDOPLGyQGHDUUR]\DOPLGyQ
SUHFRFLGRGHPDt](OREMHWLYRGHHVWHWUDEDMRHV
FRQRFHUODYLVFRVLGDGGHDOJXQDVGHODVIyUPXODV
$5 GHO PHUFDGR WUDV VX UHFRQVWLWXFLyQ VHJ~Q
UHFRPHQGDFLyQ GHO IDEULFDQWH \ HQ FRQGLFLRQHV
GH VLPLOLWXG ILVLROyJLFD JiVWULFD WUDV VX
KLSRWpWLFDLQJHVWD
3DUDHOORKHPRVUHDOL]DGRXQH[KDXVWLYRHVWXGLR
UHROyJLFR GH IyUPXODV $5 FRQ GLIHUHQWH
FRPSRVLFLyQHQFXDQWRDOHVSHVDQWHHPSOHDGR
0DWHULDOHV\0pWRGRV
6H GHWHUPLQy OD YLVFRVLGDG H[SUHVDGD HQ P3DÂV
GH IyUPXODV $5 GH LQLFLR UHFRQVWLWXLGDV
VLJXLHQGR ODV UHFRPHQGDFLRQHV GHO IDEULFDQWH \
VH FRPSDUy FRQ XQD IyUPXOD GH LQLFLR HVWiQGDU
VLQHVSHVDQWH
/RV HQVD\RV UHROyJLFRV VH UHDOL]DURQ FRQ XQ
UHyPHWUR%ROKLP&6GHHVIXHU]RFRQWURODGR
/D JHRPHWUtD GH PHGLGD HVFRJLGD IXH OD GH
FLOLQGURVFRD[LDOHV&7L
$VLPLVPRORVHVWXGLRVIXHURQUHDOL]DGRVWDQWRD
WHPSHUDWXUD DPELHQWH “ž & FRPR D
“ž & S+ “ \ XQ GH SHSVLQD
VLPXODQGR ODV FRQGLFLRQHV JiVWULFDV GXUDQWH O
KRUDWUDVODDGPLQLVWUDFLyQ
5HVXOWDGRV\'LVFXVLyQ
8QSDVRSUHYLRDODUHDOL]DFLyQGHHVWDVPHGLGDV
FRQVLVWH HQ VRPHWHU WRGDV ODV PXHVWUDV D ODV
PLVPDV SUHFRQGLFLRQHV /DV PXHVWUDV VH
VRPHWHQ D XQ GHWHUPLQDGR HVIXHU]R GXUDQWH XQ
WLHPSRHVWDEOHFLGR\VHJXLGDPHQWHVHGHMDQHQ
UHSRVR &RQ HVWR VXSRQHPRV TXH VH URPSH OD
HVWUXFWXUDLQWHUQDGHOVLVWHPDTXHFRPLHQ]DD
IRUPDUVH GXUDQWH HO WLHPSR GH UHSRVR 'H HVWH
PRGR DVHJXUDPRV REWHQHU VLHPSUH UHVXOWDGRV
UHSURGXFLEOHV
7RGDV ODV PXHVWUDV HVWXGLDGDV PXHVWUDQ XQ
FRPSRUWDPLHQWR QHZWRQLDQR D ž& 'H PRGR
TXH HO GDWR GH YLVFRVLGDG DSRUWDGR HV HO
FRUUHVSRQGLHQWH DO DMXVWH OLQHDO GH ORV GDWRV
H[SHULPHQWDOHVFRQIRUPHD OH\GH1HZWRQSDUD
IOXLGRVOtTXLGRVWDEOD
7DEOD9LVFRVLGDGGHODVIyUPXODVHVWXGLDGDV
Dž&
)Ï508/$
&RQWURO
$OPLGyQGHPDL]\
SDWDWD
$OPLGyQGHDUUR]
SUHJHODWLQL]DGR
+DULQDVHPLOOD
DOJDUURER
+DULQDVHPLOOD
DOJDUURER
$OPLGyQGHPDL]
*RPDJDUURItQ
ηP3DÂV
'(
(Q OD WDEOD REVHUYDPRV TXH OD IyUPXOD TXH
FRQWLHQH KDULQD GH VHPLOOD GH DOJDUURER D XQD
FRQFHQWUDFLyQ GHO PP HV OD TXH
SUHVHQWD YDORUHV PiV DOWRV GH YLVFRVLGDG (VWR
YLHQH DEDODGR SRU ORV WUDEDMRV UHDOL]DGRV SRU
RWURV DXWRUHV 3RU OR WDQWR HVWD IyUPXOD \D
HVSHVDHQHOELEHUyQ
/D WDEOD PXHVWUD ORV UHVXOWDGRV REWHQLGRV HQ
FRQGLFLRQHV JiVWULFDV SDUD ORV WUHV WLHPSRV
HVWXGLDGRV WLHPSR FHUR \ PLQXWRV
7RGDVODVIyUPXODVH[KLEHQXQFRPSRUWDPLHQWR
QHZWRQLDQRVDOYRODPXHVWUDTXHFRQWLHQHFRPR
HVSHVDQWH KDULQD GH DOJDUURER D XQD
FRQFHQWUDFLyQ GH HV SVHXGRSOiVWLFD 3RU
HVWHPRWLYRODYLVFRVLGDGGHHVWDPXHVWUDHVHO
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
UHVXOWDGRGHODMXVWHOLQHDOGHORVGDWRVREWHQLGRV
FXDQGRODIyUPXODFRPLHQ]DDIOXLU
(QWRGRVORVFDVRVODYLVFRVLGDGGHODVPXHVWUDV
HQVD\DGDV HV PD\RU HQ FRQGLFLRQHV JiVWULFDV
TXH D ž& \ S+ QDWXUDO (VWR SXHGH GHEHUVH D
OD FRDJXODFLyQ TXH H[SHULPHQWDQ HQ HVWDV
FRQGLFLRQHV SULQFLSDOPHQWH GHELGR D OD DFFLyQ
GHORVHVSHVDQWHV
7DEOD9LVFRVLGDGGHODVIyUPXODVDž&S+
\GHSHSVLQD
)Ï508/$
&RQWURO
$OPLGyQGH
PDL]\SDWDWD
$OPLGyQGH
DUUR]
SUHJHODWLQL]DGR
+DULQDVHP
DOJDUURER!
+DULQDVHP
DOJDUURER
$OPLGyQGH
PDL]
*RPDJDUURItQ
&RQFOXVLRQHV
ηP3DÂV
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
PLQ
%LEOLRJUDItD
6XiUH]/%RO3HGLDWU
$JRVWHQL & (63(+$1 &RPPLWWHH
RQ1XWULWLRQ$FWD3HGULDWU
0DFRVNR&:5KHRORJ\3ULQFLSOHV
DQGDSSLFDWLRQV1XHYD<RUN9&+S
'(
'H DFXHUGR FRQ ORV UHVXOWDGRV REWHQLGRV
SRGHPRV DILUPDU TXH WRGRV ORV HVSHVDQWHV
DQDOL]DGRV LQFUHPHQWDQ OD YLVFRVLGDG GHO
SURGXFWR VREUH WRGR HQ FRQGLFLRQHV JiVWULFDV
/D KDULQD GH VHPLOOD GH DOJDUURER HV HO
YLVFRVL]DQWHTXHPD\RUYLVFRVLGDGFRQILHUHDOD
IyUPXOD HQ ODV GRV FRQGLFLRQHV HQ ODV TXH VH
UHDOL]y HO HVWXGLR DXQTXH HVWH GDWR HV PD\RU D
OD FRQFHQWUDFLyQ PiV EDMD (VWR VH GHEH D OD
SUHVHQFLD GH RWURV FRPSRQHQWHV FRPR OD
FDVHLQD )XWXURV HVWXGLRV GHEHUiQ GHWHUPLQDU VL
ODV GLIHUHQFLDV HQ OD YLVFRVLGDG WLHQHQ XQD
LPSOLFDFLyQ HQ OD HILFDFLD FOtQLFD GH ODV
IyUPXODV
',6(f2'((;3(5,0(1726(1)2508/$&,21'((08/6,21(6,19(67,*$&,21'(
81$18(9$9$5,$%/(5(638(67$
+6HNNDW0'&RQWUHUDV&ODUDPRQWH0'0LQJRUDQFHÈOYDUH]
PGFRQWUH#XJUHV
'HSDUWDPHQWR)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH*UDQDGD
*UDQDGD(VSDxD
(VWDFLyQ([SHULPHQWDO'HO=DLGLQ&6,&*UDQDGD(VSDxD
,QWURGXFFLyQ
/D IRUPXODFLyQ GH HPXOVLRQHV HV IUHFXHQWH HQ
5HVXOWDGRV\'LVXFXVLyQ
7RGDV ODV IRUPXODFLRQHV RULJLQDQ HPXOVLRQHV
7HFQRORJtD )DUPDFpXWLFD &RQ HVWD ILQDOLGDG \
HVWDEOHV DO PHQRV GXUDQWH XQ DxR H[FHSWR ODV
HQ OD ~OWLPD GpFDGD VH DSOLFD HO GLVHxR GH
IRUPXODFLRQHV 1 1 1 \ 1 TXH VH
H[SHULPHQWRV FRPR KHUUDPLHQWD GH WUDEDMR
VHSDUDURQ ODV IDVHV DQWHV GH KRUDV VLHQGR
$KRUUD WLHPSR \ GLQHUR \ SHUPLWH GHWHFWDU
H[FOXLGDV GHO GLVHxR (VWH IHQyPHQR VXFHGH
LQWHUDFFLRQHV
HQWUH
ORV
FRPSRQHQWHV
VLHPSUHTXHH[LVWHQDOWDSURSRUFLyQGHDFHLWH \
GLItFLOPHQWH DSUHFLDEOHV FRQ OD WpFQLFD GH
SROtPHURSUREDEOHPHQWHGHELGRDODLQWHUDFFLyQ
³HQVD\R \ HUURU´ &RPR YDULDEOH UHVSXHVWD ODV
HVWpULFDGHODVFDGHQDVGHOSROtPHUR
XVXDOHVVRQPHGLGDVGHYLVFRVLGDG\WDPDxRGH
7UDQVFXUULGDV DO PHQRV K GH OD SUHSDUDFLyQ
JRWD HQWUH RWUDV (O REMHWLYR GH HVWH WUDEDMR HV
VH GHWHUPLQD OD FRQGXFWLYLGDG GH FDGD XQD GH
HYDOXDU OD FRQGXFWLYLGDG GH ODV HPXOVLRQHV
ODV HPXOVLRQHV 7DEOD ORV YDORUHV YDUtDQ GH
FRPR YDULDEOH UHVSXHVWD HQ HO GLVHxR GH
H[SHULPHQWRV >@ /D FRQGXFWLYLGDG WLHQH OD
D μ6FP FRQILUPDQGR TXH ODV
YHQWDMD GH REWHQHUVH IiFLO \ UiSLGDPHQWH
IRUPXODFLRQHVVRQHPXOVLRQHV2$
DGHPiVGHVXJUDQVHQVLELOLGDG(VWDHYDOXDFLyQ
VH DSOLFD DO GLVHxR GH OD IRUPXODFLyQ GH XQD
7DEOD &RPSRVLFLyQ GH ODV IRUPXODFLRQHV
HPXOVLyQ FRQ DFHLWH GH ROLYD \ XQ DJHQWH
VHJ~QXQGLVHxR'2SWLPDOHQWDQWRSRUXQR\
ODFRQGXFWLYLGDG
SROLPpULFR [] (O GLVHxy IXH XWLOL]DGR
SUHYLDPHQWH LQFOX\HQGR OD YLVFRVLGDG FRPR
)RUPX
&RQGXF
YDULDEOH UHVSXHVWD (O REMHWLYR IXH GHWHUPLQDU
$FHLWH
S+
3HPXOHQ $JXD WLYLGDG
ODV SURSRUFLRQHV GH DFHLWH GH ROLYD SROtPHUR
2OLYD
ODFLyQ
ȝVFP
SROLDFUtOLFR 3HPXOHQ 75 \ DJXD DVt FRPR HO
1
S+ TXH RULJLQDQ IRUPXODFLRQHV HVWDEOHV 6H
1
LQFOX\y HO S+ GHELGR D TXH HO SROtPHUR
1
SROLDFUtOLFRQRWLHQHSURSLHGDGHVWHQVLRDFWLYDV\
1
OD HVWDELOLGDG GHO SUHSDUDGR GHSHQGH HO S+ GHO
1
PHGLR6HDSOLFyXQGLVHxRGHPH]FODV>@
1
FRQ YDULDEOH GH SURFHVR FRQ UHVWULFFLRQHV
EDVDGR HQ HO FULWHULR '2SWLPDO GHELGR D OD
1 5RWD
LUUHJXODULGDG GHO GRPLQLR H[SHULPHQWDO /RV
1 5RWD
FRPSRQHQWHV\VXVLQWHUYDORVIXHURQ$FHLWHGH
1
ROLYD $F $F 3HPXOHQ 3P
1 3P $TXD FRQVHUYDQV $J
1 $J (O S+YDULD S+ 1 5RWD
FRPSDWLEOHFRQODSLHO
1 1 0DWHULDOHV\0pWRGRV
1 (O GLVHxR GH PH]FODV FRQ YDULDEOH GH SURFHVR
1 5RWD
FRQ UHVWULFFLRQHV '2SWLPDO IXH JHQHUDGR
1 02''( GDQGR OXJDU D IRUPXODFLRQHV
1 GLIHUHQWHV 7DEOD 'H HOODV 11
1 FRQVWLWX\HQORVYpUWLFHV\SXQWRVFHQWUDOHVGHODV
1 DULVWDV GH ORV ODGRV \ HO SXQWR FHQWUR IXH
UHSHWLGRFXDWURYHFHV11
/DHYDOXDFLyQGHODFRQGXFWLYLGDGSRUPHGLRGH
/D HODERUDFLyQ GH ODV HPXOVLRQHV VH UHDOL]DQ
DQiOLVLV GH UHJUHVLyQ P~OWLSOH LQGLFD TXH OD
VHJ~QHOPpWRGRGHVFULWRHQ6HNNDW\&RQWUHUDV
FRPSRVLFLyQ GH ODV PH]FODV LQIOX\H
[] VLJXLHQGR XQ RUGHQ DOHDWRULR SDUD HYLWDU
VLJQLILFDWLYDPHQWH HQ HOOD 3DUD HOOR VH KL]R HO
HUURUHVVLVWHPiWLFRV
DMXVWHGHORVGDWRVPHGLDQWHUHJUHVLyQOLQHDOSRU
/D FRQGXFWLYLGDG VH GHWHUPLQD PHGLDQWH XQ
PtQLPRV FXDGUDGRV SDUFLDOHV LQGLFDQGR TXH OD
FRQGXFWtPHWUR&ULVRO%DUFHORQD
SURSRUFLyQGHDJXD\ODLQWHUDFFLyQGHpVWDFRQ
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
HO S+ QR LQIOX\H GH IRUPD VLJQLILFDWLYD )LJXUD
HQODFRQGXFWLYLGDG(QFDPELRHOFRQWHQLGR
HQ DFHLWH \ SHPXOHQ VL WLHQHQ XQ HIHFWR
VLJQLILFDWLYR3DXQTXHFRQWUDULR \DVX
YH] SUHVHQWDQ XQD LQWHUDFFLyQ WDPELpQ
VLJQLILFDWLYD
3
FRQ
HO
S+
)LJXUD,QIOXHQFLDGHODLQWHUDFFLyQ$FHLWHS+
VREUHODFRQGXFWLYLGDGGHODVSUHSDUDFLRQHV
'HODQiOLVLVGHODLQWHUDFFLyQDFHLWHS+)LJXUD
VH GHGXFH TXH OD FRQGXFWLYLGDG SDUD YDORUHV GH
S+ EDMR HV LQGHSHQGLHQWH GH OD FRQFHQWUDFLyQ
GHDFHLWH6LQHPEDUJRSDUDYDORUHVGHS+DOWR
GHSHQGH GH OD FRQFHQWUDFLyQ GH DFHLWH (V DOWD
ȝ6FP SDUD FRQFHQWUDFLRQHV UHGXFLGDV GH
DFHLWH \ EDMD ȝ6FP SDUD FRQFHQWUDFLRQHV
HOHYDGDVGHDFHLWH
)LJXUD,QIOXHQFLDGHODLQWHUDFFLyQ3HPXOHQ
S+ VREUH OD FRQGXFWLYLGDG GH ODV
SUHSDUDFLRQHV
'H OD LQWHUDFFLyQ 3HPXOHQS+ )LJXUD VH
GHGXFHTXHODFRQGXFWLYLGDGSDUDYDORUHVGHS+
EDMRHVLQGHSHQGLHQWHGHODFRQFHQWUDFLyQGH
SROtPHUR 6LQ HPEDUJR OD FRQGXFWLYLGDG SDUD
YDORUHV GH S+ DOWR GHSHQGH GH OD
FRQFHQWUDFLyQ GH SHPXOHQ VLHQGR EDMD ȝ6FP SDUD FRQFHQWUDFLRQHV HGXFLGDV GH
SROtPHUR \ DOWD ȝ6FP SDUD
FRQFHQWUDFLRQHVHOHYDGDVGHSROtPHUR
&RQFOXVLRQHV
/D YDULDEOH UHVSXHVWD FRQGXFWLYLGDG WLHQH
OLPLWDFLRQHV 9D D VHU DGHFXDGD VLHPSUH \
FXDQGRVHTXLHUDQREWHQHUHPXOVLRQHVTXHWHQJDQ
XQS+HOHYDGRFRQFDQWLGDGHVLQIHULRUHVDHQ
DFHLWH PP \ VXSHULRUHV D HQ
3HPXOHQ PP 6X XWLOL]DFLyQ HQ GLVHxR
GHH[SHULPHQWRVUHTXLHUHHVWXGLRVDGLFLRQDOHV
%LEOLRJUDItD
-*DEULHOVRQ\FROV-&KHPRPHWULFV
%)*RRGULFK7'65
1RYHRQ7'6
6 &DIDJJL \ FROV &KHP ,QWHO /DE 6\VW
±
5$)LVKHU-RIWKH0LQLVWU\RI$JULF
3*DR\FROV3KDUP'HY7HFKQ
±
+6HNNDW\FROV,;&RQJUHVR&LHQWtILFR,
&RQJUHVR,QWHUQDFLRQDOGH)RUPXODFLyQ
0DJLVWUDO&LXGDG5HDO1RY
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD
'HSDUWDPHQWRGH(VWDGtVWLFDH,QYHVWLJDFLyQ2SHUDWLYD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH*UDQDGD
&DPSXV8QLYHUVLWDULRGH&DUWXMDVQ*UDQDGD
'HSDUWDPHQWRGH,QJHQLHUtD4XtPLFD(76(,%8QLYHUVLGDG3ROLWpFQLFDGH&DWDOXxD$YG'LDJRQDO
%DUFHORQDHPDLOPDUJDULW#XJUHV
,QWURGXFFLyQ
(OXVRGHH[FLSLHQWHVSROLPpULFRVHVXQUHFXUVR
WHFQROyJLFR HQ HO FRQWURO GH OLEHUDFLyQ GH
IiUPDFRV /RV SROLpVWHUHV VRQ XQD IDPLOLD GH
SROtPHURV ELRGHJUDGDEOHV PX\ LPSRUWDQWH HQ
IRUPXODFLyQ GH OLEHUDFLyQ FRQWURODGD VLQ
HPEDUJR VH HQFXHQWUDQ HVFDVDV SXEOLFDFLRQHV
TXH HPSOHHQ SROLHVWHUDPLGDV FRQ HVWH REMHWLYR
(QHVWHWUDEDMRVHIRUPXODQFRPSULPLGRV
GH GLFORIHQDFR VyGLFR FRQ XQD SROLHVWHUDPLGD
3$'$6\VHHVWXGLDVXLQIOXHQFLDHQHOFRQWURO
GH OLEHUDFLyQ GHO IiUPDFR PRGHOR DVt FRPR ODV
PRGLILFDFLRQHV LQGXFLGDV SRU OD SUHVHQFLD GH
GLOX\HQWHV WLSR \ FDQWLGDG 3$'$6 HV
ELRFRPSDWLEOH ELRGHJUDGDEOH GH HVWUXFWXUD
TXtPLFDUHJXODU\FRQWLHQHHOPLVPRQ~PHURGH
JUXSRVpVWHU\DPLGDILJ
(VWXGLRVGHOLEHUDFLyQLQ9LWUR
&RPSULPLGRVGHFDGDIRUPXODFLyQVHVRPHWHQD
HQVD\RV GH OLEHUDFLyQ HQ GLVSRVLWLYR GH
GLVROXFLyQ6RWDV$76PDUWDSDUDWRGHSDOHWD
GH 5)(  HG FRQ USP GH YHORFLGDG GH
URWDFLyQ GH ODV SDODV \ P/ GH WDPSyQ GH
IRVIDWRV S+ D “ ž & FRPR PHGLR GH
OLEHUDFLyQ
(O HVWXGLR GH OLEHUDFLyQ VH UHDOL]D GXUDQWH XQ
SHULRGR GH KRUDV \ ODV FDQWLGDGHV OLEHUDGDV
DFXPXODGDV GH GLFORIHQDFR VyGLFR VH HYDO~DQ
SRU HVSHFWURIRWRPHWUtD 89 D QP 3HUNLQ
(OPHU/DPEGD/RVUHVXOWDGRVPHGLDGHVHLV
UpSOLFDV VH H[SUHVDQ HQ FXUYDV UHSUHVHQWDWLYDV
GHOSRUFHQWDMHGHGRVLVOLEHUDGDWLHPSR
3DUD HVWXGLDU OD FLQpWLFD GHO SURFHVR GH
OLEHUDFLyQVHDSOLFDQGLIHUHQWHVIXQFLRQHVRUGHQ
FHURSULPHURUGHQ+LJXFKL\3HSSDV
[NHCHCO-O(CH2)12O-OCCHNH-OC(CH2)8CO-]n
CH3
CH3
)LJXUD 3ROLHVWHUDPLGD 3$'$6 /DODQLQD
GRGHFDQRO/DODQLQDiFLGRVHEiFLFR
0DWHULDO\0pWRGRV
0DWHULDO 'LFORIHQDFR VyGLFR *XLQDPD
9DOHQFLD 3$'$6 /DODQLQDGRGHFDQRO/
DODQLQDiFLGR VHEiFLFR SUHSDUDGD SRU
SROLPHUL]DFLyQ LQWHUIDFLDO VLJXLHQGR HO PpWRGR
GHVFULWR SRU 3DUHGHV HW DO FRQ XQ WDPDxR
PHGLR GH SDUWtFXOD GH ȝP ȝP
FHOXORVD PLFURFULVWDOLQD $YLFHO 3+ ODFWRVD PRQRKLGUDWR *XLQDPD 9DOHQFLD
IRVIDWR
FiOFLFR
GLEiVLFR
GLKLGUDWDGR
(PFRPSUHV)DUPDTXtPLFR6XU0iODJD
(ODERUDFLyQGHFRPSULPLGRV
/DV IRUPXODFLRQHV HVWXGLDGDV VH HVSHFLILFDQ HQ
ODWDEOD
5HVXOWDGRV\'LVFXVLyQ
7RGDV ODV IRUPXODFLRQHV RULJLQDQ FRPSULPLGRV
FRQ FDUDFWHUtVWLFDV JDOpQLFDV LGyQHDV /D ILJ PXHVWUD ODV FXUYDV PHGLDV GH OLEHUDFLyQ GH
GLFORIHQDFR VyGLFR SROYR FRPSULPLGRV FRQ
IiUPDFR \ 3$'$6 UHIHUHQFLD 3 \
IRUPXODFLRQHVDGLFLRQDGDVGHGLOX\HQWHV
100
7DEOD)RUPXODFLRQHVGHFRPSULPLGRV
80
60
40
150 CM
150 L
150 F
DF polvo
20
COMPOSICIÓN POR COMPRIMIDO (mg)
200 P 150 CM 100 CM 150 L 100 L 150 F 100 F
DICLOFENACO SÓDICO (DF)
100
100
100
100
100
100
100
PADAS (P)
150
200
150
100
100
150
100
CELULOSA MICROCRISTALINA (CM)
---
47
97
---
---
---
---
LACTOSA (L)
---
---
---
47
97
---
---
FOSFATO CÁLCICO (F)
---
---
---
---
---
47
97
ESTEARATO MAGNÉSICO
---
3
3
3
3
3
3
0H]FODGRV ORV FRPSRQHQWHV VH HODERUDQ SRU
FRPSUHVLyQ GLUHFWD 7RQVPLQ HQ SUHQVD
KLGUiXOLFDFRPSULPLGRVSODQRVGHPJ\
PPGHGLiPHWUR
CONCENTRACIÓN (%)
)LJXUD ,QIOXHQFLD GHO DFHLWH GH ROLYD
SHPXOHQ\DJXD\VXLQWHUDFFLyQFRQHOS+HQOD
FRQGXFWLYLGDGGHODVSUHSDUDFLRQHV
/DFRQGXFWLYLGDGVHDMXVWDDOPRGHOR
&RQGXFWLYLGDGȝ6FP S+$F
3PS+$FS+3P (OYDORUGHOFRHILFLHQWHGHGHWHUPLQDFLyQ5 MXQWR FRQ HO YDORU GHO SDUiPHWUR
³YDOLGH]´ TXH LQGLFDQ OD IUDFFLyQ GH OD
YDULDFLyQ GH OD FRQGXFWLYLGDG TXH HV H[SOLFDGD
SRUHOPRGHORFRUURERUDQODERQGDGGHODMXVWH
$GLFLRQDOPHQWHODYDULDQ]DGHELGDDODIDOWDGH
DMXVWHQRHVVLJQLILFDWLYDIUHQWHDOHUURUSXUR3
(OFRHILFLHQWH4LQGLFDODDOWD
FDSDFLGDG GH SUHGLFFLyQ GH GLFKR PRGHOR 3RU
XOWLPRODSUHFLVLyQGHORVSXQWRVFHQWUDOHVQ HVGHO
/,%(5$&,Ï1&21752/$'$'(',&/2)(1$&262',&2(1&2035,0,'26
(/$%25$'26&2181$32/,(67(5$0,'$12+,1&+$%/(
5RGUtJXH]*DOiQ,&0DUJDULW095RGUtJXH]*DOiQ$0RUDOHV0/%RX]DV35\
+HUQiQGH]3-
100
100
100
200
CM
L
F
P
0
0
2
4
6
8
10
12
14
16
18
20
22
24
TIEMPO (h)
)LJXUD 3HUILOHV GH OLEHUDFLyQ GH GLFORIHQDFR
VyGLFRHQSROYR\IRUPXODFLRQHVFRQ3$'$6
,;&RQJUHVRGHOD6(),*
7HFQRORJtD)DUPDFpXWLFD
/DWDEODUHFRJHORVSDUiPHWURVGHOHVWXGLRGH
OLEHUDFLyQLQYLWUR/DSROLHVWHUDPLGDGHPXHVWUD
HQWRGRVODVIyUPXODVHVWXGLDGDVFDSDFLGDGSDUD
FRQWURODUODOLEHUDFLyQGHGLFORIHQDFRVyGLFR(Q
DXVHQFLD GH GLOX\HQWHV 3 HO SROtPHUR
RULJLQD FRPSULPLGRV PDWULFLDOHV LQHUWHV QR
GHIRUPDEOHV GH OLEHUDFLyQ OHQWD \ SURJUHVLYD
FRQ XQD HILFDFLD GH GLVROXFLyQ GHO /D
VXVWLWXFLyQ SDUFLDO GH SROtPHUR SRU IRVIDWR
FiOFLFRGLEiVLFRQRPRGLILFDVXVWDQFLDOPHQWHHO
FRPSRUWDPLHQWR GH OLEHUDFLyQ GH ORV
FRPSULPLGRV PDWULFLDOHV FRQ HVFDVD YDULDFLyQ
HQWUH ODV GRV FRQFHQWUDFLRQHV GH 3$'$6
HVWXGLDGDV WDEOD /D LQFRUSRUDFLyQ GH
FHOXORVD PLFURFULVWDOLQD \ ODFWRVD LQFUHPHQWD OD
FHVLyQGHGLFORIHQDFRKDVWDXQ\GHOD
GRVLVDOILQDOGHOHQVD\R
PLFURFULVWDOLQD &0 \ &0
GHVW \ ORV TXH FRQWLHQHQ ODFWRVD
PRQRKLGUDWR/\/GHVW (O DQiOLVLV FLQpWLFR GH ORV UHVXOWDGRV WDEOD LQGLFD TXH OD OLEHUDFLyQ GH GLFORIHQDFR VyGLFR
GH ORV FRPSULPLGRV UHVSRQGH D XQD FLQpWLFD GH
WLSR+LJXFKL
7DEOD&LQpWLFDVGHOLEHUDFLyQGHGLFORIHQDFR
VyGLFRGHVGHODVIRUPXODFLRQHVGHFRPSULPLGRV
HIGUCHI
PEPPAS
100 CM
150 L
100L
150 F
100 F
ABC in vitro
838,62
(122,09)
1471,75
(108,59)
1545,26
(244,58)
2188,09
(974,63)
2004,43
(217,66)
839,44
(97,31)
907,33
(126,68)
ED (%)
25,36
(4,44)
44,19
(3,05)
49,41
(9,79)
96,28
(53,64)
73,16
(9,17)
26,40
(3,18)
28,08
(3,64)
TMD (h)
8,96
(0,53)
6,70
(0,36)
6,07
(1,17)
0,45
(5,88)
3,22
(1,10)
8,83
(0,38)
8,63
(0,44)
% LIBERACIÓN (T=8H)
Lactosa
100 L
150 F
100 F
K
1,9433
3,5181
3,4430
2,7463
3,4896
1,8983
2,0389
r2
0,9150
0,8934
0,8448
0,8531
0,6097
0,8639
0,8791
K
-0,0281
-0,0803
r2
-0,0811
-0,0479
-0,1331
-0,0265
-0,0302
0,9597
0,9846
0,9693
0,9432
0,8686
0,9127
0,9403
K 10,4209
19,033
19,0007
15,0907
20,8941
10,4065
11,1048
r2
0,9886
0,9728
0,9739
0,8264
0,9817
0,9949
0,9860
K
0,4824
0,6129
0,5688
0,6011
0,5428
0,5567
0,5291
n
0,9960
0,9831
0,9755
0,9643
0,8559
0,9839
0,9679
&RQFOXVLRQHV
5HDOL]DGR XQ DQiOLVLV HVWDGtVWLFR GH ORV GDWRV
$129$PXOWLIDFWRUDW KWDQWRODFDQWLGDG
GH SROLHVWHUDPLGD FRPR HO WLSR GH GLOX\HQWH
LQIOX\HQ VLJQLILFDWLYDPHQWH HQ OD FDQWLGDG GH
IiUPDFR GLVXHOWR S \ S UHVSHFWLYDPHQWH 6H OOHJD D GHGXFFLRQHV
VLPLODUHV SDUD W K /D ILJ PXHVWUD OD
UHODFLyQHQWUHFDGDGLOX\HQWH\ODFRQFHQWUDFLyQ
GH3$'$6UHVSHFWRDODOLEHUDFLyQGHIiUPDFR
150 L
100 C
ORDEN UNO
PARÁMETROS IN VITRO
150 CM
150 C
ORDEN CERO
7DEOD3DUiPHWURVGHOLEHUDFLyQ
200 P
200 P
CINÉTICAS
Celulosa
microcristalina
Fostato cálcico
dibásico
100
150
PADAS (mg)
)LJXUD *UDILFR GH UHODFLyQ HQWUH 3$'$6 \
ORVGLOX\HQWHVGHODVIRUPXODFLRQHV
3DUD XQ QLYHO GH VLJQLILFDFLyQ GH \
FRPSDUDQGR 3 FRQ FDGD GLOX\HQWH QR VH
HQFXHQWUDQ GLIHUHQFLDV VLJQLILFDWLYDV SDUD ORV
FRPSULPLGRVFRQIRVIDWRFiOFLFRGLEiVLFR)
\)GLIHUHQFLDHVWLPDGD'HVW SHUR
VRQVLJQLILFDWLYDVODVGLIHUHQFLDVHQODOLEHUDFLyQ
GH
ORV
FRPSULPLGRV
FRQ
FHOXORVD
,19,752*(1(75$16)(572$',326(0(6(1&+<0$/67(0&(//6%<,03529('
75$16)(55,1/,323/(;(6$1'32/<3/(;(635(/,0,1$5<678',(6
&<7272;,&,7<$1'75$16)(&7,21
62OPHGLOODV$/LUDV,0LJXpOL]'*DUFtD2OPR0*DUFtD$UUDQ]DQG&7URVGH,ODUGX\D
'HSDUWPHQWRI3K\VLRORJ\6FKRRORI%LRORJ\&RPSOXWHQVH8QLYHUVLW\RI0DGULG6SDLQ
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\6FKRRORI3KDUPDF\8QLYHUVLW\RI1DYDUUD
6SDLQ
&HOO7KHUDS\/DERUDWRU\/D3D]8QLYHUVLW\+RVSLWDORI0DGULG6SDLQ
/D SROLHVWHUDPLGD 3$'$6 /DODQLQD
GRGHFDQRO/DODQLQDiFLGR VHEiFLFR SHUPLWH
HODERUDU FRPSULPLGRV GH OLEHUDFLyQ FRQWURODGD
FRQFLQpWLFDGHOLEHUDFLyQGHODUDt]FXDGUDGD(O
WLSR \ FDQWLGDG GH GLOX\HQWH PRGLILFD OD
OLEHUDFLyQ GH GLFORIHQDFR VLHQGR OD ODFWRVD OD
GHHIHFWRPiVDFXVDGR
$JUDGHFLPLHQWRV
7UDEDMR ILQDQFLDGR SRU OD -XQWD GH $QGDOXFtD
3UR\HFWR([FHOHQFLD)40\SRUOD
&,&<73UR\HFWR0$7
%LEOLRJUDItD
7DUYDLQHQ 7 HW DO - &RQWURO 5HO 7DUYDLQHQ7HWDO,QW-3KDUP±
5RGUtJXH]*DOiQ,&HWDO$FWDV;5HXQLyQ
GHO *UXSR (VSHFLDOL]DGR GH 3ROtPHURV 0DUJDULW 09 HW DO $FWDV ; 5HXQLyQ GHO
*UXSR(VSHFLDOL]DGRGH3ROtPHURV
0DUJDULW 09 HW DO  :RUOG 0HHWLQJ RQ
3KDUPDFHXWLFV
%LRSKDUPDFHXWLFV
3KDUPDFHXWLFDO 7HFKQRORJ\ %DUFHORQD DEULO
3DUHGHV 1 HW DO - $SSO 3RO\PHU 6FL ,QWURGXFWLRQ
6WHP FHOOV DUH D VHOIUHQHZLQJ SRSXODWLRQ ZLWK
ORQJWHUP YLDELOLW\ DQG PXOWLOLQHDJH SRWHQWLDO
7KHVH SURSHUWLHV WXUQ VWHP FHOOEDVHG JHQH
WKHUDS\ LQWR D SURPLVLQJ VWUDWHJ\ IRU WKH
WUHDWPHQW RI LQKHULWHG GLVHDVHV VXFK DV
KDHPRSKLOLD
7KH DLP RI WKLV VWXG\ ZDV WR LVRODWH DGLSRVH
PHVHQFK\PDO VWHP FHOOV $6& IURP
OLSRDVSLUDWH VDPSOHV WR H[SDQG WKHP LQ YLWUR
&KDUDFWHUL]DWLRQ RI FXOWXUHG FHOOV EDVHG RQ FHOO
VXUIDFH PDUNHUV H[SUHVVLRQ SDWWHUQV DQG
GLIIHUHQWLDWLRQDVVD\VZDVSHUIRUPHG
'27$3 OLSRSOH[HV DQG 3(, DQG 3$0$0
SRO\SOH[HV ZLWK RU ZLWKRXW WUDQVIHUULQ FDUU\LQJ
S&09/XF SODVPLG ZHUH SUHSDUHG IRU SDUWLFOH
VL]H DQG ]HWD SRWHQWLDO FKDUDFWHUL]DWLRQ 7KHQ
SUHOLPLQDU\LQYLWURWUDQVIHFWLRQVWXGLHVLQ$6&
ZHUH GHYHORSHG HYDOXDWLQJ FHOO YLDELOLW\ DQG
JHQHH[SUHVVLRQ
0DWHULDOVDQG0HWKRGV
,VRODWLRQ FXOWXUH DQG FKDUDFWHUL]DWLRQ RI VWHP
FHOOV $GLSRVH VWHP FHOOV ZHUH REWDLQHG DQG
FXOWXUHGDVGHVFULEHGE\*DUFLD2OPRHWDO
5DZOLSRDVSLUDWHVZHUHZDVKHGH[WHQVLYHO\ZLWK
VWHULOH SKRVSKDWH EXIIHUHG VDOLQH 3%6 WR
UHPRYH EORRG FHOOV VDOLQH DQG ORFDO DQHVWKHWLF
7KH H[WUDFHOOXODU PDWUL[ ZDV GLJHVWHG ZLWK
FROODJHQDVHW\SH,*LEFR%5/8.7KHFHOOV
UHVXVSHQGHG LQ '0(0 '0(0 ZLWK IHWDO
ERYLQH
VHUXP
DQG
SHQLFLOOLQVWUHSWRP\FLQ ZHUH SODWHG RQWR PP WLVVXHFXOWXUH GLVKHV DQG LQFXEDWHG DW
ž&&2 LQ DLU WR VXEFRQIOXHQFH )ORZ
F\WRPHWULF DQDO\VLV RI $6& LQFXEDWHG ZLWK
VSHFLILF SK\FRHU\WKULQFRQMXJDWHG PRQRFORQDO
DQWLERGLHV &' &' 0LOOLSRUH 6SDLQ
&' &' DQG IOXRUHVFHLQ LVRWK\RFLDQDWHG
FRQMXJDWHG &' %HFWRQ 'LFNLQVRQ 6SDLQ
ZDV SHUIRUPHG RQ D )$&6FDQ DUJRQ ODVHU
F\WRPHWHU%HFWRQ'LFNLQVRQ6SDLQ&RQIOXHQW
FHOOV ZHUH LQGXFHG WR GLIIHUHQWLDWH ZLWK
DGLSRJHQLF PHGLXP '0(0 ZLWK P0
LVREXW\OPHWK\O[DQWKLQH —0 GH[DPHWKDVRQH
—0LQVXOLQDQG—0LQGRPHWKDFLQXQWLO
GD\ 7KHQ WKH\ ZHUH PDLQWDLQHG LQ '0(0
ZLWK —0 LQVXOLQ IRU GD\V /LSLG
,;&RQJUHVRGHOD6(),*
GHWHUPLQHG E\ G\QDPLF OLJKW VFDWWHULQJ XVLQJ D
=HWDVL]HU 1DQR 6HULHV 0DOYHUQ ,QVWUXPHQWV
8. DQG D =HWD3OXV =HWD 3RWHQWLDO $QDO\]HU
%URRNKDYHQ,QVWUXPHQWV&RUSRUDWLRQ86$
,Q YLWUR FHOO WUDQVIHFWLRQ &HOOV ZHUH VHHGHG LQ
ZHOOFXOWXUHSODWHVKEHIRUHDGGLWLRQRIWKH
FRPSOH[HV7KHQP/RI'0(0DQG
P/ RI FRPSOH[HV ZHUH DGGHG JHQWO\ WR HDFK
ZHOO $IWHU D K LQFXEDWLRQ WKH PHGLXP ZDV
UHSODFHG DQG WKH FHOOV ZHUH IXUWKHU LQFXEDWHG
IRU K &HOO YLDELOLW\ ZDV TXDQWLILHG E\ D
PRGLILHG $ODPDU%OXH*LEFR%5/8.DVVD\
&HOOVZHUHO\VHGXVLQJUHSRUWHUO\VLVEXIIHU
3URPHJD 86$ IROORZHG E\ WZR DOWHUQDWLQJ
IUHH]HWKDZ F\FOHV $ OXPLQRPHWHU 6LULXV
%HUWKROG'HWHFWLRQ6\VWHPV6SDLQZDVXVHGWR
PHDVXUHOXFLIHUDVHDFWLYLW\ZLWKOXFLIHUDVHDVVD\
UHDJHQW 3URPHJD 86$ 7KH SURWHLQ FRQWHQW
ZDVPHDVXUHGE\WKH'&3URWHLQ$VVD\UHDJHQW
%LR5DG86$XVLQJERYLQHVHUXPDOEXPLQDV
WKH VWDQGDUG7KH GDWD ZHUH H[SUHVVHG DV QJ RI
OXFLIHUDVHSHUPJRISURWHLQ
5HVXOWVDQG'LVFXVVLRQ
/LJKW SKDVH FRQWUDVW PLFURVFRS\ RI LVRODWHG
$6& IURP WZR OLSRDVSLUDWH GRQRUV VKRZV D
PRQROD\HU RI DGKHULQJ ILEUREODVWOLNH FHOOV
7KHVH REVHUYDWLRQV DUH FRQVLVWHQW ZLWK =XN HW
DO$VVKRZQLQ)LJXUH$6&H[SUHVVHG
PHVHQFK\PDO VWHP FHOO VXUIDFH PDUNHUV &'
&' DQG &' ,Q
FRQWUDVW QR H[SUHVVLRQ RI WKH KDHPDWRSRLHWLF
OLQHDJHPDUNHUV&'DQG&'ZDVREVHUYHG
,QGXFWLRQ RI $6& ZLWK DGLSRJHQLF PHGLXP
UHVXOWHG LQ D VLJQLILFDQW IUDFWLRQ RI WKH FHOOV
FRQWDLQLQJ PXOWLSOH LQWUDFHOOXODU OLSLGILOOHG
GURSOHWV VWDLQHG E\ 2LO5HG 2 VROXWLRQ )LJXUH
$
%
&
'
(
)LJXUH6XUIDFHDQWLJHQVRI$6&VGHWHFWHGE\
IORZ F\WRPHWU\ +XPDQ $6&V ZHUH SRVLWLYH IRU
DFFXPXODWLRQ ZDV DVVHVVHG E\ 2LO5HG 2
VWDLQLQJ
/LSRVRPH
OLSRSOH[HV
DQG
SRO\SOH[HV
SUHSDUDWLRQ
GLROHR\O
WULPHWK\ODPPRQLXPSURSDQH '27$3 $YDQWL
3RODU/LSLGV86$OLSRVRPHVZHUHSUHSDUHGE\
GU\LQJ D FKORURIRUP VROXWLRQ RI WKH OLSLG E\
URWDU\ HYDSRUDWLRQ XQGHU UHGXFHG SUHVVXUH DQG
WKHQ E\ K\GUDWLQJ WKH ILOP ZLWK D P0
+(3(6 ZY JOXFRVH EXIIHU S+ +%* 7KH UHVXOWLQJ PXOWLODPHOODU YHVLFOHV
ZHUH
H[WUXGHG
WKURXJK
SRO\FDUERQDWH
PHPEUDQHV ZLWKQPSRUHGLDPHWHUXVLQJD
/LSRVRIDVWGHYLFH$YHVWLQ&DQDGDWRREWDLQD
XQLIRUP VL]H GLVWULEXWLRQ 7KH OLSLG WR '1$
FKDUJHUDWLRZDVFDOFXODWHGDVWKHPROHUDWLRRI
'27$3 RQH FKDUJH SHU PROHFXOH WR
QXFOHRWLGHUHVLGXHDYHUDJH0:
%UDQFKHG SRO\HWK\OHQLPLQH 3(, .'D
6LJPD$OGULFK 6SDLQ ZDV GLOXWHG LQ GLVWLOOHG
ZDWHU DW S+ WR D ILQDO FRQFHQWUDWLRQ RI PJP/7KH3(,FRQFHQWUDWLRQVZHUHFDOFXODWHG
WRPDNHWKHGHVLUHG13FKDUJHUDWLRIRUȝJRI
SODVPLG '1$ DVVXPLQJ WKDW JPRO
FRUUHVSRQGHG WR HDFK UHSHDWLQJ XQLW RI 3(,
FRQWDLQLQJ RQH QLWURJHQ DWRP DQG JPRO
FRUUHVSRQGHG WR HDFK UHSHDWLQJ XQLW RI '1$
FRQWDLQLQJRQHSKRVSKRUXVDWRP
*HQHUDWLRQ SRO\DPLGRDPLQH 3$0$0
6LJPD$OGULFK 6SDLQ FDWLRQLF GHQGULPHU ZDV
SUHSDUHGE\GU\LQJDPHWK\ODOFRKROVROXWLRQRI
WKH GHQGULPHU E\ URWDU\ HYDSRUDWLRQ XQGHU
UHGXFHGSUHVVXUHDQGWKHQE\K\GUDWLQJWKHILOP
ZLWK +%* 7KH 3$0$0 FRQFHQWUDWLRQV ZHUH
FDOFXODWHGWRDFKLHYHGLIIHUHQWFKDUJHUDWLRV
WDNLQJ LQWR DFFRXQW WKH DPRXQW RI SRVLWLYH
DPLQHV RQ WKH GHQGULPHU RYHU QHJDWLYH
SKRVSKDWHVRQWKH'1$
&RPSOH[HV IRU LQ YLWUR H[SHULPHQWV ZHUH
SUHSDUHG E\ ILUVW PL[LQJ +%* ZLWK 7I
OLSRSOH[HVSRO\SOH[HV RU ZLWKRXW SODLQ
OLSRSOH[HVSRO\SOH[HV LURQ VDWXUDWHG KHDW
LQDFWLYDWHG KXPDQ WUDQVIHUULQ %HFWRQ
'LFNLQVRQ %LRVFLHQFHV 6SDLQ ZLWK WKH
FRUUHVSRQGLQJ DPRXQW RI '27$3 3(, RU
3$0$0
7KH
S&09/XF
%LR6HUYH
%LRWHFKORJLHV86$ZDVWKHQDGGHGDQGJHQWO\
PL[HG 3DUWLFOH VL]H DQG ]HWD SRWHQWLDO ZHUH
7HFQRORJtD)DUPDFpXWLFD
&' $ &' % DQG &' ( DQG
QHJDWLYHIRU&'&DQG&''
$
%
)LJXUH2LO5HG2VWDLQLQJVKRZVOLSLGILOOHG
GURSOHWV DFFXPXODWHG E\ $6& XSRQ WUHDWPHQW
ZLWK DGLSRJHQLF PHGLXP $ 8QGLIIHUHQWLDWHG
$6&PDLQWDLQHGLQFRQWUROPHGLXPZHUHVWDLQHG
DVDQHJDWLYHFRQWURO%
&HOO YLDELOLW\ IROORZLQJ WUDQVIHFWLRQ ZDV
DVVHVVHG WR HYDOXDWH ZKHWKHU WUDQVIHUULQ DQG
SODLQ FRPSOH[HV DW YDULRXV OLSLG'1$ FKDUJH
UDWLRVZHUHWR[LFWR$6&7KH$ODPDUEOXH
DVVD\ VKRZHG D YLDELOLW\ KLJKHU WKDQ IRU
'27$3OLSRSOH[HVZKLOHWUDQVIHFWLRQZLWK3(,
DQG 3$0$0 SRO\SOH[HV UHGXFHG WKH
SHUFHQWDJH RI YLDEOH FHOOV WR 7KH
F\WRWR[LFLW\ RI FDWLRQLF SRO\PHUV LV WKRXJKW WR
EH D UHVXOW RI SHUPHDELOL]DWLRQ HIIHFWV RI
SRVLWLYHFKDUJHVWRFHOOXODUPHPEUDQHV7KH
UHODWLYH F\WRWR[LFLW\ RI FRPSOH[HV ZDV DOVR
DVVHVVHG E\ WKH WRWDO DPRXQW RI H[WUDFWDEOH
FHOOXODUSURWHLQVLQWKHFHOOO\VDWHSHU ZHOODQG
FRQILUPHG WKH UHVXOWV ZLWK WKH $ODPDU EOXH
DVVD\GDWDQRWVKRZQ
*HQH H[SUHVVLRQ PHDVXUHPHQWV DIWHU RXU
SUHOLPLQDU\ LQ YLWUR WUDQVIHFWLRQ DVVD\V VXJJHVW
WKDW WUDQVIHUULQ SURPRWHV FHOOXODU HQWU\ RI WKH
3(, FRPSOH[HV LQWR WKH $6& DOWKRXJK OHYHOV
DFKLHYHG DUH YHU\ ORZ OHVV WKDQ QJ RI
OXFLIHUDVH SHU PJ RI SURWHLQ 3(, SRO\SOH[HV
FRQMXJDWHGZLWKȝJRIWUDQVIHUULQJDYHKLJKHU
OHYHOV RI WUDQVIHFWLRQ WKDQ SODLQ SRO\SOH[HV
&KDUDFWHUL]DWLRQ RI WKH FRPSOH[HV XVHG IRU
WUDQVIHFWLRQ LQ WHUPV RI SDUWLFOH VL]H DQG ]HWD
SRWHQWLDOVKRZHGWKDW7IFRPSOH[HVZHUHELJJHU
WKDQ SODLQFRPSOH[HV DQG WKH SUHVHQFH RI
WUDQVIHUULQ DOVR VHHPHG WR WXUQ OLSRVRPHV DQG
3(,'1$ FRPSOH[HV LQWR OHVV SRVLWLYHO\
FKDUJHG SDUWLFOHV 7KHVH UHVXOWV DUH FRQVLVWHQW
ZLWK SUHYLRXV UHSRUWV DERXW 3(,7I FRQMXJDWHV
)XUWKHU H[SHULPHQWV DUH LQ SURJUHVV WR
FRQILUP WKHVH UHVXOWV LQ D UHSURGXFLEOH PDQQHU
DQG WR HVWDEOLVK WKH RSWLPDO FRQGLWLRQV IRU
WUDQVIHFWLRQRI$6&
&RQFOXVLRQ
,Q VXPPDU\ KXPDQ SURFHVVHG OLSRDVSLUDWHV
\LHOG D SRSXODWLRQ RI DGXOW PHVHQFK\PDO VWHP
FHOOV ZKLFK FDQ EH KRPRJHQHRXVO\
FKDUDFWHUL]HG E\ WKHLU FHOO VXUIDFH PDUNHUV
H[SUHVVLRQSDWWHUQVDQGGLIIHUHQWLDWLRQSRWHQWLDO
7KLV SRSXODWLRQ LV DQ LGHDO FDQGLGDWH IRU VWHP
FHOOEDVHGJHQHWKHUDS\DQG 3(,7IFRQMXJDWHG
SRO\SOH[HV DSSHDU WR EH QRQF\WRWR[LF HIILFLHQW
JHQH FDUULHUV IRU $6& LQ YLWUR WUDQVIHFWLRQ
+RZHYHU IXUWKHU LQYHVWLJDWLRQV DUH QHHGHG WR
LPSURYH WKH WUDQVIHFWLRQ DFWLYLW\ DQG LWV
UHSURGXFLELOLW\
5HIHUHQFHV
=XN 3$ HW DO 0RO %LRO &HOO *DUFtD2OPR ' HW DO ,QW - &RORUHFWDO 'LV
0DGVHQ / HW DO %LRFKHP - 7URV GH ,ODUGX\D & HW DO %LRFKLP %LRSK\V
$FWD
$KQ ++ HW DO %LRPDWHULDOV =XN3$HWDO7LVVXH(QJ
/HH.0HWDO$UFK3KDUP5HV
$FNQRZOHGJPHQWV
7KLVZRUNZDVILQDQFLDOO\VXSSRUWHGE\DJUDQW
IURP WKH *RYHUQPHQW RI 1DYDUUD 'HSDUWPHQW
RI (GXFDWLRQ IURP 8QLYHUVLW\ RI 1DYDUUD
)RXQGDWLRQ)815R\DO)RXQGDWLRQ³9LFWRULD
(XJHQLD´ %D[WHU %LR6FLHQFH 6SDLQ DQG IURP
6SDQLVK6RFLHW\RI7KURPERVLVDQG+HPRVWDVLV
$
%
&V$
PJ
7DPDxR
QP
3ROLGLV
SHUVLyQ
3RWHQFLDO
=HWDP9
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
(O((RVFLODHQWUHHO\PLHQWUDV
TXH OD FDQWLGDG GH &V$ DVRFLDGD DO SROtPHUR
H[SUHVDGD HQ μJ GH &V$ PJ SROtPHUR YDUtD
HQWUH \ 7DEOD /D UHFXSHUDFLyQ GHO
SROtPHURUHQGLPLHQWRHVLJXDORVXSHULRUDO
)RUPXODFLyQ$1DQRSDUWtFXODVGH3900$FRQKLGUR[LSURSLOαFLFORGH[WULQD\FLFORVSRULQD$
)RUPXODFLyQ%1DQRSDUWtFXODVGH3900$FRQKLGUR[LSURSLOβFLFORGH[WULQD\FLFORVSRULQD$
/RVGDWRVPXHVWUDQODPHGLD±6'Q 7DEOD&DQWLGDGGH&V$DVRFLDGDDOSROtPHUR((\GH
UHQGLPLHQWR
)RUPXOD
FLyQ
$
%
&V$
PJ
μJPJGH
3900$
“
“
“
“
“
“
“
“
“
“
“
“
((
5HQGLPLHQWR
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
“
&V$/LEHUDGR
((
,,
&RQFOXVLRQHV
$O LQFOXLU KLGURSURSLOβFLFORGH[WULQD HQ HO
SURFHVR GH SUHSDUDFLyQ GH QDQRSDUWtFXODV GH
3900$ FRQ &V$ OD FDQWLGDG GH IiUPDFR
DVRFLDGD DO SROtPHUR VH LQFUHPHQWD GH IRUPD
QRWDEOH HQ FRPSDUDFLyQ FRQ OR TXH RFXUUH DO
XWLOL]DU KLGUR[LSURSLOαFLFORGH[WULQD 7DPELpQ
DXPHQWD OD HILFDFLD GH HQFDSVXODFLyQ (Q DPEDV
IRUPXODFLRQHV ODV QDQRSDUWtFXODV SUHVHQWDQ
WDPDxRV \ FDUJDV VXSHUILFLDOHV DGHFXDGDV SDUD OD
DGPLQLVWUDFLyQRUDO
(OIiUPDFRVHOLEHUDLQLFLDOPHQWHGHIRUPDUiSLGD
GHVGH ODV GRV IRUPXODFLRQHV SRVWHULRUPHQWH PiV
OHQWDPHQWH SHUR VLHPSUH GH IRUPD FRQWLQXD D OR
ODUJRGHOWLHPSR
/D IRUPXODFLyQ TXH FRQWLHQH KLGUR[LSURSLOβ
FLFORGH[WULQDOLEHUDPHQRVGHOGHOWRWDOGHOD
&V$WUDVKGHLQFXEDFLyQHQORVPHGLRV*6H,6
\WUDVKGHLQFXEDFLyQHQPHGLR3%6
(Q PHGLR 3%6 S+ ILJXUD OD OLEHUDFLyQ
GHO IiUPDFR HV FRQWLQXD HQ HO WLHPSR GHVGH ODV
GRVIRUPXODFLRQHV'HVSXpVGHPLQVHOLEHUD
DSUR[LPDGDPHQWH HO \ HO GH &V$
GHVGH ODV IRUPXODFLRQHV $ \ %
UHVSHFWLYDPHQWH7UDVKHVWRVSRUFHQWDMHVVRQ
FHUFDQRVDO\DO
5HIHUHQFLDV
7LHPSR0LQXWRV
)LJXUD,QIOXHQFLDGHODUHODFLyQ&V$3900$VREUHOD
FDQWLGDG GH &V$ DVRFLDGD DO SROtPHUR μJ &V$ PJ
3900$ \ OD HILFDFLD GH HQFDSVXODFLyQ (( /DV
EDUUDV GH HUURU UHSUHVHQWDQ ODV GHVYLDFLRQHV HVWiQGDU HQ
EDVH D GHWHUPLQDFLRQHV UHDOL]DGDV SRU WULSOLFDGR ,
)RUPXODFLyQ$,,)RUPXODFLyQ%
PJ&V$PJ*DQWUH]
((
—J&V$PJ390 0 $
)LJXUD 3HUILOHV GH OLEHUDFLyQ LQ YLWUR GH &V$ GHVGH ODV
IRUPXODFLRQHV $ Ɣ \ % Ŷ HQ PHGLR ,6 S+ D
ž & /RV GLVWLQWRV YDORUHV UHSUHVHQWDQ OD PHGLD ± 6'
Q —J&V$PJ390 0 $
PJ&V$PJ3900$
7LHPSR0LQXWRV
)LJXUD 3HUILOHV GH OLEHUDFLyQ LQ YLWUR GH &V$ GHVGH ODV
IRUPXODFLRQHV$Ɣ\%ŶHQPHGLR*6S+ D
ž & /RV GLVWLQWRV YDORUHV UHSUHVHQWDQ OD PHGLD ± 6'
Q 7DEOD7DPDxRSROLGLVSHUVLyQ\FDUJDVXSHUILFLDOGHODV
QDQRSDUWtFXODVGH3900$FDUJDGDVFRQ&V$
)RUPXOD
FLyQ
,
&V$/LEHUDGR
0HGLRV *iVWULFR 6LPXODGR S+ *6
,QWHVWLQDO 6LPXODGR S+ ,6 \ 3%6
S+ 3DUD HVWXGLDU OD OLEHUDFLyQ LQ YLWUR VH
DxDGHQPJHQHOFDVRGHODIRUPXODFLyQ$R
PJ HQ HO FDVR GH OD % D P/ GHO PHGLR
VHOHFFLRQDGR/DPXHVWUDVHLQFXEDDž&HQ
XQEDxRFRQDJLWDFLyQ$WLHPSRVSUHILMDGRVOD
PXHVWUD VH FHQWULIXJD PLQ D USP \
VH GHWHUPLQD OD &V$ OLEHUDGD SRU +3/&89
XWLOL]DQGRXQPpWRGRWRWDOPHQWHYDOLGDGR
5HVXOWDGRV\'LVFXVLyQ
(OWDPDxRGHODVQDQRSDUWtFXODVRVFLODHQWUH
\QP\ORVYDORUHVGHSROLGLVSHUVLyQIXHURQ
LQIHULRUHVDORTXHLQGLFDKRPRJHQHLGDGHQ
HOWDPDxRGHODVSDUWtFXODV/DFDUJDVXSHUILFLDO
RVFLODHQWUH\P97DEOD
((
&V$/LEHUDGR
,QWURGXFFLyQ
/D FLFORVSRULQD $ &V$ KD VLGR H[WHQVDPHQWH
XWLOL]DGD SDUD OD SURILOD[LV \ HO WUDWDPLHQWR GHO
UHFKD]RHQODPD\RUtDGHORVWLSRVGHWUDQVSODQWH
GHyUJDQRV7DPELpQHVXQIiUPDFRHIHFWLYRHQ
HOWUDWDPLHQWRGHYDULRVWUDVWRUQRVDXWRLQPXQHV
>@ /D DEVRUFLyQ GH OD &V$ HQ HO WUDFWR
JDVWURLQWHVWLQDO HV PX\ YDULDEOH /D HVWUXFWXUD
FtFOLFDUtJLGD\HODOWRSHVRPROHFXODUFRQILHUHQ
D HVWH IiUPDFR EDMD SHUPHDELOLGDG D WRGDV ODV
EDUUHUDV ELROyJLFDV > @ /D IRUPXODFLyQ GHO
IiUPDFR HQ QDQRSDUWtFXODV KD UHFLELGR PXFKD
DWHQFLyQ HQ ORV ~OWLPRV DxRV GHELGR D VX
SRWHQFLDO GH PHMRUDU OD ELRGLVSRQLELOLDG \
PDQWHQHU XQD OLEHUDFLyQ FRQWURODGD (Q HVWH
FRQWH[WR KHPRV GHVDUUROODGR GLVWLQWDV
IRUPXODFLRQHV GH QDQRSDUWtFXODV GH SROLPHWLO
YLQLOpWHUFRDQKtGULGR PDOHLFR 3900$
FDUJDGDV FRQ &V$ FRQ HO ILQ GH HYDOXDU VX
FDSDFLGDGFRPRWUDQVSRUWDGRUHVSRUYtDRUDO
0DWHULDOHV\0pWRGRV
3UHSDUDFLyQ\RSWLPL]DFLyQGHODVQDQRSDUWtFXODV
/DV QDQRSDUWtFXODV GH 3900$ VH KDQ
SUHSDUDGRPHGLDQWHGHVROYDWDFLyQGHOSROtPHUR
3DUD PHMRUDU ODHILFDFLD GH HQFDSVXODFLyQ GH OD
&V$ VH KD DxDGLGR KLGUR[LSURSLOα R
KLGUR[LSURSLOβ FLFORGH[WULQD +3α&' R
+3β&' 7UDV HYDSRUDU ORV GLVROYHQWHV
RUJiQLFRV ODV QDQRSDUWtFXODV REWHQLGDV VH
SXULILFDQ PHGLDQWH GRV FLFORV GH FHQWULIXJDFLyQ
USP PLQ )LQDOPHQWH HO DJXD VH
HOLPLQDPHGLDQWHOLRILOL]DFLyQ
&RQ HVWH SURFHGLPLHQWR VH KDQ REWHQLGR ODV
VLJXLHQWHV IRUPXODFLRQHV )RUPXODFLyQ $
QDQRSDUWtFXODV GH 3900$ FRQ &V$ \
+3α&' \ )RUPXODFLyQ % QDQRSDUWtFXODV GH
3900$FRQ&V$\+3β&'
3DUD RSWLPL]DUODV ~QLFDPHQWH VH KD YDULDGR OD
FDQWLGDG GH IiUPDFR XWLOL]DGD SHUPDQHFLHQGR
FRQVWDQWHV ODV FDQWLGDGHV GH 3900$ GH
+3α&'RGH+3β&'
&DUDFWHUL]DFLyQGHODVQDQRSDUWtFXODV
7DPDxR \ 3RWHQFLDO =HWD 6H KDQ GHWHUPLQDGR
SRU HVSHFWURVFRSLD GH FRUUHODFLyQ IRWyQLFD
36& XWLOL]DQGR XQ VLVWHPD GH DQiOLVLV
=HWDVL]HU1DQR
(ILFDFLD GH HQFDSVXODFLyQ GH &V$ (( +D
VLGRGHWHUPLQDGDSRU+3/&89
/LEHUDFLyQ LQ YLWUR GH &V$ GHVGH ODV
QDQRSDUWtFXODV
SULPHURV PLQ \ D ODV K HO SRUFHQWDMH RVFLOD
HQWUHXQ\UHVSHFWLYDPHQWH
)LQDOPHQWHHQORTXHKDFHUHIHUHQFLDDOPHGLR,6
ILJXUD ODV IRUPXODFLRQHV $ \ % OLEHUDQ
UHVSHFWLYDPHQWHHQORVSULPHURV PLQDOUHGHGRU
GHO\GHOGHOIiUPDFR'HVSXpVGHK
GH LQFXEDFLyQ HVWRV SRUFHQWDMHV VRQ
DSUR[LPDGDPHQWHGHO\
((
03HFFKLR-0,UDFKH0-5HQHGR0&'LRV9LpLWH]
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH1DYDUUD
3DPSORQD(VSDxD
'XUDQWH OD RSWLPL]DFLyQ GH ODV GRV
IRUPXODFLRQHV VH REVHUYDURQ IHQyPHQRV GH
SUHFLSLWDFLyQ FXDQGR OD FDQWLGDG GH &V$ HUD
LJXDORVXSHULRUDPJ
$ YLVWD GH ORV UHVXOWDGRV REWHQLGRV WUDV OD
RSWLPL]DFLyQ VH REVHUYy TXH SDUD OD
IRUPXODFLyQ $ ODV QDQRSDUWtFXODV SUHSDUDGDV
FRQ PJ HUDQ ODV TXH SUHVHQWDEDQ ODV
SURSLHGDGHVPiVLQWHUHVDQWHV\HQHOFDVRGHOD
IRUPXODFLyQ % HUDQ ODV TXH FRQWHQtDQ PJ
GHIiUPDFR7DEODV\\)LJXUD3RUHOOR
VH HVWXGLy OD OLEHUDFLyQ GHO IiUPDFR GHVGH ODV
PLVPDVHQPHGLRV*6H,6DVtFRPRHQ3%6
—J&V$PJ3900$
/,%(5$&,Ï1,19,752'(&,&/26325,1$$'(6'(1$123$57Ë&8/$6
'(3900$)2508/$'$6&21',)(5(17(6'(5,9$'26'(
&,&/2'(;75,1$6
,;&RQJUHVRGHOD6(),*
—J&V$PJ3900$
7HFQRORJtD)DUPDFpXWLFD
7LH PSR0LQXWRV
)LJXUD 3HUILOHV GH OLEHUDFLyQ LQ YLWUR GH FLFORVSRULQD $
GHVGHODVIRUPXODFLRQHV$Ɣ\%ŶHQPHGLR3%6
S+ Dž&/RVGLVWLQWRVYDORUHVUHSUHVHQWDQODPHGLD
±6'Q 3RURWUDSDUWHODVIRUPXODFLRQHV$\%OLEHUDQHQ
PHGLR*6ILJXUDHQWUHXQ\HQORV
>@-/,WDOLDHWDO.XPDU'UXJ'LVFRY7RGD\
±
>@-&.RODUVHWDO/DQFHW±
>@ 0) +HEHUW $GY 'UXJ 'HOLY 5HY ±
$JUDGHFLPLHQWRV
(VWH WUDEDMR KD VLGR ILQDQFLDGR SRU )81'$&,Ï1 &$-$
1$9$55$ \ 0 3HFFKLR DFWXDOPHQWH UHFLEH XQD EHFD GH
6(1$&<7,)$5+8GHO*2%,(512GH3$1$0$
)RUPXODFLyQ$1DQRSDUWtFXODVGH3900$FRQKLGUR[LSURSLOαFLFORGH[WULQD\FLFORVSRULQD$
)RUPXODFLyQ%1DQRSDUWtFXODVGH3900$FRQKLGUR[LSURSLOβFLFORGH[WULQD\FLFORVSRULQD$
/RVGDWRVPXHVWUDQODPHGLD±6'Q 7HFQRORJtD)DUPDFpXWLFD
(/$%25$&,Ï1'(0,&523$57Ë&8/$6%,2'(*5$'$%/(6&211$/2;21$3$5$
$'0,1,675$&,Ï13$5(17(5$/6(/(&&,Ï1'(/32/Ë0(52
/%DXWLVWD&KiYH]&0DUWtQ6DEURVR-,(VSDGD*DUFtD0(*LO$OHJUH$,7RUUHV6XiUH]
'SWR)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDG&RPSOXWHQVH0DGULG
6H UHDOL]D XQD SULPHUD VHOHFFLyQ HQ IXQFLyQ GH
,QWURGXFFLyQ
ODFRPSDWLELOLGDGHQWUHHOSROtPHUR\QDOR[RQD
1DOR[RQD HV XQ DQWDJRQLVWD RSLiFHR ~WLO HQ OD
GHVKDELWXDFLyQ GH GURJRGHSHQGLHQWHV \D TXH
'6& &RQ ORV SUHVHOHFFLRQDGRV VH HODERUDQ
SHUPLWHXQEORTXHRIDUPDFROyJLFRHIHFWLYRDQWH
03 6H VHOHFFLRQD DTXHO TXH PHMRUHV
XQD QXHYD GRVLV GH KHURtQD 6X FRUWD VHPLYLGD
FDUDFWHUtVWLFDVSURSRUFLRQHDODV03HQFXDQWRD
SODVPiWLFD KRUDV \ VX EDMD
WDPDxRFDSDFLGDGGHWUDQVSRUWH\FRQWUROGHOD
ELRGLVSRQLELOLGDG RUDO DFRQVHMDQ VX
OLEHUDFLyQGH1DOR[RQD)LJXUD
LQFOXVLyQHQXQVLVWHPDGHOLEHUDFLyQFRQWURODGD
GHDGPLQLVWUDFLyQSRUYtDSDUHQWHUDO6HSODQWHD
3 R Ot P H U R E L R F R P S D WL E OH \ E L R G H J U D G D E OH
OD HODERUDFLyQ GH PLFURSDUWtFXODV 03 FRQ
QDOR[RQD TXH WUDV VX DGPLQLVWUDFLyQ SRU YtD
12
VXEFXWiQHD VHDQ FDSDFHV GH OLEHUDU IiUPDFR
& R P S D W L E OH F R Q ) i U P D F R
) LQ
GXUDQWH XQD VHPDQD 3DUD HOOR HV QHFHVDULR
6Ë
FRQWDUFRQXQPDWHULDOLQWHJUDQWHGHOD03TXH
VHDFDSD]GHFRQWURODUODOLEHUDFLyQGHOIiUPDFR
( OD E R U D F L y Q G H 0 LF U R S D U W tF X OD V 0 3 ([LVWH XQD JUDQ YDULHGDG GH PDWHULDOHV
WUDQVSRUWDGRUHV FRQ GLVWLQWDV FDUDFWHUtVWLFDV
SHVR PROHFXODU JUDGR GH FULVWDOLQLGDG SHUR
QR VLHPSUH VRQ YiOLGRV SDUD REWHQHU 03 3RU
7 D P D x R G H 0 3 D G H F X D G R
12
S D U D V X D G P L Q L V W U D F Ly Q S D U H Q W H U D O
WDQWR OD DGHFXDGD VHOHFFLyQ GH HVWH PDWHULDO
) LQ
P H G LD Q W H LQ \ H F F L y Q V X E F X Wi Q H D
FRQWURODGRUHVGHJUDQLPSRUWDQFLD
— P 0DWHULDOHV\0pWRGRV
6Ë
(Q HO SUHVHQWH WUDEDMR GDGD OD YtD GH
DGPLQLVWUDFLyQ GH ODV 03 VH HPSOHD PDWHULDO
FRQWURODGRU GH OD OLEHUDFLyQ GH 1DOR[RQD
& D U J D G H OD V 0 3 D G H F X D G D ELRFRPSDWLEOH \ ELRGHJUDGDEOH 6H SDUWH GH
12
S D U D V X D G P LQ LV W U D F L y Q V X V S H Q G LG D V H Q
) LQ
SROtPHURV FRQ DPEDV FDUDFWHUtVWLFDV REWHQLGRV
X Q Y R OX P H Q P i [ L P R G H P /
GHO iFLGR OiFWLFR 3/$ iFLGR JOLFyOLFR \ GH
FDSURODFWRQD 3&/ \ GH VXV FRSROtPHURV /D
6Ë
7DEOD UHFRJH ORV SROtPHURV HPSOHDGRV \ VXV
FDUDFWHUtVWLFDV 7RGDV ODV 03 VH HODERUDQ D
SDUWLUGHODPLVPDFDQWLGDGGHSROtPHUR\SRUHO
12
/ L E H U D F L y Q G H 1 D OR [ R Q D
) LQ
G X U D Q W H D O P H Q R V V H P D Q D
PLVPR PpWRGR GH PLFURHQFDSVXODFLyQ 6H
UHFXUUHDODWpFQLFDGHGREOHHPXOVLyQ$2$
HYDSRUDFLyQ GHO VROYHQWH GDGD OD HOHYDGD
6Ë
KLGURVROXELOLGDGGH1DOR[RQD+&O
0 3 V H OH F F L R Q D G D V S D U D S R V W H U L R U H V W U D E D M R V
7DEOD3ROtPHURVHPSOHDGRV
)LJXUD ÈUERO GH GHFLVLyQ SDUD OD VHOHFFLyQ
GHOSROtPHURHQODV03GH1DOR[RQD
3ROtPHURV
9LG/J 7IXVLyQ
7J
ž&
ž&
3DUD D\XGDU HQ OD LQWHUSUHWDFLyQ GHO SURFHVR GH
3RO\'//iFWLFR $PRUIR
FHVLyQ LQ YLWUR GHO IiUPDFR VH GHWHUPLQD HO
3RO\'//iFWLFR $PRUIR
HVWDGRItVLFRGH1DOR[RQDHQODV03'6&\VH
3ε&DSURODFWRQD
UHDOL]DQIRWRVDODV03WUDVHOHQVD\RGHFHVLyQ
3&/
6(0 3RU ~OWLPR VH UHDOL]D XQ HVWXGLR GH
'/3/*$ $PRUIR
VROXELOLGDGGH1DOR[RQDHQFDGDSROtPHURSDUD
'/3/*$ $PRUIR
HYDOXDU VX FDSDFLGDG GH WUDQVSRUWH DQDOL]DQGR
'/3/*$
$PRUIR
PH]FODV ItVLFDV FRQ SURSRUFLRQHV FUHFLHQWHV GH
'/3/&/ $PRUIR
IiUPDFR SRU '6& 6L H[LVWH XQD UHODFLyQ
HQWUHODSURSRUFLyQGH1DOR[RQDHQODPH]FOD\
HO YDORU GH HQWDOStD GH IXVLyQ VH H[WUDSROD DO
,;&RQJUHVRGHOD6(),*
YDORU GH HQWDOStD FHUR RUGHQDGD HQ HO RULJHQ
HV GHFLU D OD SURSRUFLyQ HQ OD TXH HO IiUPDFR
HVWiGLVXHOWRHQHOSROtPHUR
5HVXOWDGRV\'LVFXVLyQ
7RGRV ORV SROtPHURV HQVD\DGRV UHVXOWDURQ VHU
FRPSDWLEOHV FRQ 1DOR[RQD 6H SURFHGLy D OD
HODERUDFLyQGH03FRQWRGRVHOORV(OGLiPHWUR
GH ODV 03 HVWXYR FRPSUHQGLGR HQWUH \ —P VHJ~Q HO SROtPHUR HPSOHDGR 3RU WDQWR
WRGDV ODV 03 SUHVHQWDURQ XQ WDPDxR DGHFXDGR
SDUD VX DGPLQLVWUDFLyQ SDUHQWHUDO PHGLDQWH
LQ\HFFLyQ VXEFXWiQHD (Q OD )LJXUD VH
PXHVWUDQIRWRV6(0GHDOJXQDVGHODV03
XQDOLEHUDFLyQGH1DOR[RQDGXUDQWHXQDVHPDQD
SHUR FRQ GLIHUHQWH YHORFLGDG GH OLEHUDFLyQ
)LJXUD (O PHFDQLVPR GH OLEHUDFLyQ HV
SULQFLSDOPHQWHGLIXVLyQ VHJ~QHODVSHFWRGHODV
03GHVSXpVGHOHQVD\RGHFHVLyQ)LJXUD
Vel oci dad de Li ber aci ón de Nal oxona
( ug/ dí a)
1000
800
600
400
200
0
0,5
00/01 /00
1
01 /01 /00
2
3
02 /01 /00
03 /01 /00
4
04 /01 /00
5
05 /01 /00
6
7
06 /01 /00
07 /01 /00
ti empo (días)
MSde PLGA 50/ 50 0,45-0,60 dL/ g
MSde PLGA 50/ 50 0,16-0,24 dL/ g
MSde DL-PLA 0,55-0,75 dL/ g
)LJXUD&HVLyQ³LQYLWUR´GH1DOR[RQD
3/*$
3/$&/
3/*$G/J'/3/$G/J
)LJXUD 03 WUDV HO HQVD\R GH FHVLRQ ³LQ
9LWUR´
6H DQDOL]DURQ ODV 03 SRU '6& \ QR VH GHWHFWy
SUHVHQFLD GH 1DOR[RQD DO HVWDGR VyOLGR 6H
REVHUYy TXH ORV SROtPHURV HQ ORV TXH OD
VROXELOLGDG GH 1DOR[RQD HV PD\RU
SURSRUFLRQDURQ 03 FRQ PD\RU FDUJD GH
IiUPDFR /D )LJXUD PXHVWUDORVUHVXOWDGRVGH
VROXELOLGDG GH 1DOR[RQD HQ SROtPHURV
'/3/$G/JQ'/3/$G/J
Proporción Naloxona:polímero
3/*$G/J3&/
)LJXUD)RWRVGHODV03REWHQLGDV6(0
/D )LJXUD PXHVWUD OD FDQWLGDG GH 1DOR[RQD
HQFDSVXODGDVHJ~QHOSROtPHURHPSOHDGR
6
4
3
2
1
0
DL-P LGA
0,24dL/ g)
DL-P LGA
0, 60dL/ g)
DL-P LGA
1,0dL/ g)
DL-P LA
DL-P LA
80/ 20 P LA -
(0,55-
(1,3-
P CL
0, 75dL/ g)
1,7dL/ g)
P CL
)LJXUD&DQWLGDGGH1DOR[RQDHQODV03
6H FDOFXOD SDUD FDGD SROtPHUR OD FDQWLGDG GH
03 TXH FRQWLHQH XQD GRVLV VHPDQDO GH
1DOR[RQD 6ROR FRQ SROtPHURV GH ORV HVWXGLDGRVVHFRQVLJXHTXHHVWDFDQWLGDGGH03
VHSXHGDVXVSHQGHUHQ P/3/*$ORV
GRVHVWXGLDGRV\'/3/$GHPHQRUYLVFRVLGDG
LQKHUHQWH &RQ ODV 03 GH HVWRV SROtPHURV VH
OOHYD D FDER HO HQVD\R GH FHVLyQ 6H FRQVLJXH
60
40
20
0
0
5
y = 5,3948x + 7,3561
R2 = 0,9591
5
50/ 50 (0, 16- 50/ 50 (0,45- 75/ 25 (0, 7-
80
PCL
—J1DOR[RQDPJGH03
7
100
10
15
20
DL-PLA
y = 3,4165x + 13,252
R2 = 0,973
25
30
35
AH (J/g)
PLGA 50/50
y = 2,3274x + 14,855
R2 = 0,8773
)LJXUD6ROXELOLGDGGH1DOR[RQDHQSROtPHURV
%LEOLRJUDItD
%DXWLVWD/\FRO(Q/LEUR$FWDV,,&RQJUHVR
1DFLRQDO ,QYHVWLJDFLyQ $OXPQRV 3UHJUDGR
&LHQFLDV6DOXG0DGULG$EULO
/DUHR07RUUHV$,*LO0(-6HS6FL
7KHHXZHV)+XVVDLQ$+LJXFKL7-3KDUP
6FL
$JUDGHFLPLHQWRV
,9 3ODQ 5HJLRQDO GH ,QYHVWLJDFLyQ &&*
8&0%,2*UXSRGHLQYHVWLJDFLyQ8&0
&0 $GPLQLVWUDFLyQ SDUHQWHUDO GH
PHGLFDPHQWRV
HOHFWURQHXWUDOLW\ UHVXOWHG LQ DQ HQKDQFHG
WUDQVIHFWLRQ
30
&KDUJHUDWLR
20
G5/Tf-G5/DNA complexes at charge ratio 2/1 (+/-)
- TF
25
+ TF
20
15
10
5
0
G5
G5 / G5-Tf 50%
6/1 (+/-)
)LJXUH 7UDQVIHFWLRQ HIILFLHQF\ *7I*
FRPSOH[HVRQ.FHOOV
'LIIHUHQFHV EHWZHHQ IRUPXODWLRQ SHUIRUPDQFHV
FDQQRWEHH[SODLQHGE\WKHHIIHFWRISDUWLFOHVL]H
RQ WUDQVIHFWLRQ UDWH 7KH LQFRUSRUDWLRQ RI
WUDQVIHUULQ ZLWKLQ WKH GHQGULSOH[HV GLG QRW
VLJQLILFDQWO\ DIIHFW WKHLU VL]H DURXQG QP LQ
PRVW FDVHV ZKHUHDV WKH SRVLWLYH VXUIDFH FKDUJH
RIFRPSOH[HVZDVVKLHOGHGE\WUDQVIHUULQHYHQDW
ORZ FRQFHQWUDWLRQV 7DEOH 1R VLJQV RI
DJJUHJDWLRQ ZHUH REVHUYHG VLQFH WKH
SRO\GLVSHUVLRQLQGH[3',ZDV”
7RGHPRQVWUDWHZKHWKHUWKHXSWDNHRI*7I*
FRPSOH[HV LV IDFLOLWDWHG YLD LQWHUDFWLRQ ZLWK WKH
WUDQVIHUULQ UHFHSWRU D FRPSHWLWLYH LQKLELWLRQ
H[SHULPHQWZDVSHUIRUPHGXVLQJFKDUJH
UDWLR FRPSOH[HV $V VKRZQ LQ )LJXUH WKH
LQFUHDVH RI WUDQVIHFWLRQ PHGLDWHG E\ *7I*
FRPSOH[HV FRXOG EH ODUJHO\ EORFNHG E\ WKH
DGGLWLRQ RI IUHH WUDQVIHUULQ WR WKH PHGLXP WKXV
GHPRQVWUDWLQJ WKDW 7IFRPSOH[HV PHGLDWHG
OLJDQGGHSHQGHQWJHQHWUDQVIHU
G5/Tf-G5 5% G5/Tf-G5 16% G5/Tf-G5 25% G5/Tf-G5 50% )LJXUH &RPSHWLWLYH LQKLELWLRQ ZLWK IUHH
WUDQVIHUULQ*7I*'1$FRPSOH[HVDWFKDUJH
UDWLR ZHUH DGGHG WR . FHOOV LQ WKH
SUHVHQFH RU DEVHQFH RI IUHH WUDQVIHUULQ
PJP/
&KDUJHUDWLR
4/1 (+/-)
G5 / G5-Tf 25%
G5
G5 / G5-Tf 5%
G5 / G5-Tf 16%
G5 / G5-Tf 50%
G5 / G5-Tf 25%
G5
G5 / G5-Tf 5%
G5 / G5-Tf 16%
G5 / G5-Tf 50%
G5 / G5-Tf 25%
G5
G5 / G5-Tf 5%
10
G5 / G5-Tf 16%
ng luciferase/mg protein
40
n g lu c ife ra s e /m g p ro te in
50%
0%
25%
16%
50%
25%
0%
16%
0%
50%
25%
16%
LPEI N/P 6
BPEI N/P 6
12575,37</,1(675$780&251(803(1(75$7,21352),/()520+30&
3$7&+(6
$0HOHUR70*DUULJXHV0$OyV$0DUWtQ9LOORGUH8)6FKDHIHU&0/HKU
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\)DFXOW\RI3KDUPDF\8QLYHUVLW\RI9DOHQFLD
6SDLQ
,QVWLWXWHRI%LRSKDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\8QLYHUVLW\RI6DDUODQG*HUPDQ\
7KHZKROHDSSDUDWXVLVWHPSHUDWHGDWƒ&LQDQ
,QWURGXFWLRQ
1RUWULSW\OLQHK\GURFKORULGH17+LVDWULF\FOLF
RYHQ
DQWLGHSUHVVDQW GUXJ ZKLFK KDV VKRZQ WR EH DV
HIIHFWLYHDVEXSURSLRQLQWKHVXSSRUWWKHUDS\IRU
$IWHU WKH LQFXEDWLRQ WLPH WKH 3ODVWLEDVHŠ LV
VPRNLQJ FHVVDWLRQ >@ )LYH SDWFKHV FRQWDLQLQJ
UHPRYHGZLWKSDSHUDQGWKHLQFXEDWLRQGHYLFHLV
WKH GUXJ KDYH EHHQ WHVWHG WR VHH WKH HIIHFWV RI
RSHQHG7KHIRUPXODWLRQLVFRPSOHWHO\UHPRYHG
WKH YHKLFOH LQ WKH GUXJ GLVWULEXWLRQ 7KH
IURPWKHVNLQZLWKWKHDLGRIDFRWWRQEDOO7KH
LQIOXHQFH RI GLIIHUHQW LQFXEDWLRQ WLPHV K DQG
VNLQ LV WKHQ WUDQVIHUUHG RYHU D ILOWHU SDSHU
K KDYH EHHQ HYDOXDWHG RQ WKH SHQHWUDWLRQ
VRDNHG ZLWK 5LQJHU VROXWLRQ WR DQ DOXPLQLXP
SURILOHV RI 17+ ZLWKLQ WKH VWUDWXP FRUQHXP
EORF ZKHUH LW LV IL[HG ZLWK QDLOV 7KH VNLQ LV
FRYHUHG ZLWK D 7HIORQ PDVN ZLWK D FP RI
6&
GLDPHWHU KROH 7KH XQFRYHUHG DUHD ZLOO EH WKH
([SHULPHQWDOPHWKRGV
VWULSSLQJDUHD7KHEORFNLVWKHQSODFHGXQGHUD
3UHSDUDWLRQRIWKHSDWFKHV
7HIORQSXQFKVWULSVDUHSUHSDUHG(DFKVWULS
ZLOOEHIL[HGRYHUWKHVNLQDQGSUHVVXUHGZLWKD
)LYH GLIIHUHQW SDWFKHV ZHUH SUHSDUHG 7KHLU
NJ ZHLJKW SODFHG RYHU WKH SXQFK IRU FRPSRVLWLRQ LV SUHVHQWHG LQ 7DEOH VHFRQGV ,W LV D FULWLFDO VWHS RI WKH WHFKQLTXH WR
)RUPXODWLRQ RI WKH SDWFKHV LV VXPPDUL]HG LQ
DVVXUH WKH VDPH FRQWDFW WLPH DQG SUHVVXUH IRU
)LJXUH
HYHU\ VWULS 7KH VWULS LV WKHQ UHPRYHG DQG
FROOHFWHG LQ VFLQWLOODWLRQ YLDOV IROORZLQJ WKH
VHTXHQFH 6 6 6 6 6 6 6
6 7KH UHPRYDO VSHHG VKRXOG DOVR EH
FRQVWDQW7KHVWULSVDUHWKHQH[WUDFWHGZLWK&O+
VROXWLRQDQGDQDO\]HGIRU17+FRQWHQW>@
0HDVXUHPHQWRIWKH6&7KLFNQHVV
)LJXUH)RUPXODWLRQRIWKHSDWFKHV
6& WKLFNQHVV KDV EHHQ FDOFXODWHG E\ LQIUDUHG
7DEOH&RPSRVLWLRQRIWKHSDWFKHV
GHQVLWRPHWU\ XVLQJ D 7KH 6TXDPH6FDQ70
)LOP$
)LOP%
)LOP&
)LOP'
)LOP(
$ GHYLFH 7KH 6TXDPH6FDQ GHYLFH LV
17+
HTXLSSHG ZLWK D GLRGH HPLWWLQJ OLJKW ZLWK D
(W2+
ZDYHOHQJWKRIQPLHLQWKHLQIUDUHGUDQJH
3*
(DFK WDSH FDQ EH PHDVXUHG E\ WKH UHGXFWLRQ LQ
2$
36
OLJKW LQWHQVLW\ ZKLFK LV OLQHDUO\ UHODWHG WR WKH
+30&
VWUDWXP FRUQHXP GHQVLW\ RQ WKH WDSH DQG LV
+ 2
H[SUHVVHG LQ WHUPV RI SHUFHQWDJH WUDQVPLVVLRQ
7 7KH FRUUHVSRQGLQJ FDOLEUDWLRQ FXUYH FDQ
,QYLWURWDSHVWULSSLQJVWXG\
EHXVHGIRUDQLQGLUHFWHYDOXDWLRQRISURWHLQVRQ
WDSHV 7DSHVWULSSLQJ LQYLYR VWXGLHV VKRZHG D
7KH SHQHWUDWLRQ SURILOH RI 1+7 IURP WKH
KLJKO\ VLJQLILFDQW FRUUHODWLRQ EHWZHHQ 7 DQG
SDWFKHV ZLWKLQ WKH VWUDWXP FRUQHXP KDV EHHQ
WKHSURWHLQFRQWHQWSHUVWULS
HYDOXDWHG LQ YLWUR E\ PHDQV RI WKH VR FDOOHG
6DDUEUFNHQ 6% PRGHO ,W FRQVLVWV RI
(YDOXDWLRQ RI FKDQJHV LQ WKH 6& DIWHU
LQFXEDWLRQ DQG D WDSHVWULSSLQJ )RU WKH
LQFXEDWLRQZLWKWKHSDWFKHVE\&/60
LQFXEDWLRQ D PP GLDPHWHU SLHFH RI VNLQ LV
SXWRQDILOWHUSDSHUVRDNHGZLWK5LQJHUVROXWLRQ
6NLQ VDPSOHV RI WKH VDPH IHPDOH KDYH EHHQ
RQ D WHIORQ EORF 7KH IRUPXODWLRQ LV SODFHG RQ
LQFXEDWHGIRUKKDQGKZLWKSDWFKHV$WR
WKH WRS RI WKH VNLQ DQG D WHIORQ SXQFK LV IL[HG
( $IWHU WKH LQFXEDWLRQ WLPH WKH IRUPXODWLRQ
RYHUWKHIRUPXODWLRQ7KHSXQFKKDVDFDYLW\RI
ZDV UHPRYHG DQG VNLQ FXWV ZHUH SUHSDUHG DQG
PPGHSWKZKHUHWKHIRUPXODWLRQUHPDLQV7KH
HYDOXDWHG E\ &RQIRFDO /DVHU 6FDQQLQJ
WZR SDUWV RI WKH GHYLFH DUH VHDOHG ZLWK
PLFURVFRS\&/60
3ODVWLEDVHŠWRDYRLGZDWHUORVVIURPWKHVNLQ
50
2/1 (+/-)
50%
0%
25%
16%
0%
50%
25%
16%
50%
0%
25%
16%
LPEI N/P 6
BPEI N/P 6
lg RLU/10 000 cells
7HFQRORJtD)DUPDFpXWLFD
60
0
% metabolic activity
7DEOH %LRSK\VLFDO SURSHUWLHV RI *7I*
S'1$ FRPSOH[HV $OO FRPSOH[HV ZHUH SUHSDUHG
LQ +%* S+ DQG WKH ILQDO '1$
FRQFHQWUDWLRQZDV—JP/
70
PEI 25 N/P 6
,03529(0(172)*(1(75$1)(57278025$/&(//6%<75$16)(55,1
'(1'5,3/(;(6
*1DYDUUR&7URVGH,ODUGX\D02JULV(:DJQHU
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\6FKRRORI3KDUPDF\8QLYHUVLW\RI1DYDUUD
3DPSORQD6SDLQ
3KDUPDFHXWLFDO%LRORJ\%LRWHFKQRORJ\'HSDUWPHQWRI3KDUPDF\/XGZLJ0D[LPLOLDQV8QLYHUVLWlW
0XQLFK*HUPDQ\
DQG LQFUHDVLQJ DPRXQWV RI * ZHUH
UHSODFHGE\7I*LQWKHFRPSOH[
,QWURGXFWLRQ
7KHPDMRUGUDZEDFNVRIQRQYLUDOYHFWRUVDUHWKH
1E+07
ODFNRIFHOOVSHFLILFLW\DQGWKHLUOLPLWHGDELOLW\WR
1E+06
WUDQVIHFW FHOOV &RXSOLQJ RI FHOOELQGLQJ OLJDQGV
VXFK DV WUDQVIHUULQ 7I WR SRO\FDWLRQV FDQ EH D
1E+05
UHOHYDQW VWUDWHJ\ WR RYHUFRPH WKHVH EDUULHUV 1E+04
7UDQVIHUULQ UHFHSWRU LV H[SUHVVHG RQ WKH VXUIDFH
RI FHUHEUDO HQGRWKHOLDO FHOOV KHSDWRF\WHV DQG
1E+03
KLJKO\ SUROLIHUDWLQJ FHOOV VXFK DV HU\WKUREODVWV
DQGWXPRUFHOOV7KHLQFOXVLRQRIWUDQVIHUULQLQWR
1E+02
SRO\SOH[HV HQKDQFHV WKHLU VSHFLILFLW\ WRZDUGV
WDUJHW VLWHV HJ WXPRU EUDLQ OLYHU DQG DW WKH
2/1 (+/-)
4/1 (+/-)
6/1 (+/-)
VDPH WLPH VKLHOGV WKHLU SRVLWLYH FKDUJH VXUIDFH
OHDGLQJWRDQLQKLELWLRQRIXQVSHFLILFLQWHUDFWLRQV
120
DIWHU V\VWHPLF DSSOLFDWLRQ ,Q RXU H[SHUL
100
PHQWVZHXVHGDJHQHGHOLYHU\V\VWHPFRQVLVWLQJ
80
RI 3$0$0 GHQGULPHUV DQG SODVPLG '1$ WKDW
60
PHGLDWHVHIILFLHQWWUDQVJHQHH[SUHVVLRQLQ1HXUR
40
$WXPRUVDIWHULQWUDYHQRXVDGPLQLVWUDWLRQ*1
HW DO PDQXVFULSW LQ SUHSDUDWLRQ ,Q WKLV VWXG\
20
ZH JR D VWHS EH\RQG DQG SUHVHQW SUHOLPLQDU\
0
ELRSK\VLFDO DQG WUDQVIHFWLRQ VWXGLHV FDUULHG RXW
ZLWK 3$0$07I3$0$0 FRPSOH[HV LQ RUGHU
2/1 (+/-)
4/1 (+/-)
6/1 (+/-)
WR LQYHVWLJDWH ZKHWKHU KLJK WXPRU H[SUHVVLRQ
REWDLQHG ZLWK SODLQ GHQGULSOH[HV FDQ EH
)LJXUH 7UDQVIHFWLRQ HIILFLHQF\ RI *7I*
UHLQIRUFHGE\WKHLQFRUSRUDWLRQRIWUDQVIHUULQ
FRPSOH[HVDQGPHWDEROLFDFWLYLW\LQ1HXUR$
0DWHULDOVDQG0HWKRGV
$V VKRZQ LQ )LJXUH SODLQ FRPSOH[HV RU WKHLU
7UDQVIHUULQ3$0$0 FRQMXJDWH V\QWKHVLV ZDV
PL[WXUHV ZLWK 7IFRQMXJDWHV WXUQ RXW WR EH
SHUIRUPHG VLPLODUO\ DV SUHYLRXVO\ GHVFULEHG QRQWR[LF +RZHYHU QR LPSURYHPHQW E\ XVLQJ
,Q DOO H[SHULPHQWV JHQHUDWLRQ RI 3$0$0
WUDQVIHUULQ ZDV REVHUYHG ,W PLJKW EH WKDW IRU
GHQGULPHU* ZDVSDUWLDOO\ UHSODFHGE\7I*
1HXUR$ FHOOV DGVRUSWLYH HQGRF\WRVLV E\
FRQMXJDWHV PRODU UDWLR 7I* DQG
HOHFWURVWDWLF LQWHUDFWLRQV RI FKDUJHG FRPSOH[HV
FRQGHQVHGZLWKSODVPLG'1$DWGLIIHUHQWFKDUJH
ZLWKFHOOPHPEUDQHKHSDUDQHVXOIDWHVLVPDVNLQJ
UDWLRV 7KH GHJUHH RI UHSODFHPHQW LV UHSUHVHQWHG
WUDQVIHUULQPHGLDWHGJHQHWUDQVIHU7KHUHIRUHZH
DV SHUFHQWDJH HJ PHDQV SDUW RI 7I*
VHOHFWHG HU\WKURLG OHXNHPLF . FHOOV IRU
SOXVSDUWVRI*
IXUWKHU H[SHULPHQWV 7KHVH FHOOV DUH NQRZQ WR
'HQGULSOH[HV VL]HV DQG ]HWDSRWHQWLDOV ZHUH
H[SUHVVHOHYDWHGQXPEHUVRIWUDQVIHUULQUHFHSWRUV
PHDVXUHG E\ ODVHU GLIUDFWRPHWU\ LQ D =HWDVL]HU
*HQH WUDQVIHU HIILFLHQF\ RQ . FHOOV ZDV
QDQRSDUWLFOHDQDO\]HU
VWXGLHG DV D IXQFWLRQ RI *'1$ FKDUJH UDWLR
,Q YLWUR WUDQVIHFWLRQ HIILFLHQF\ ZDV GHWHUPLQHG
DQG LQFUHDVLQJ DPRXQWV RI * LQ WKH FRPSOH[
RQ QHXUREODVWRPD 1HXUR$ DQG HU\WKURLG
ZHUHUHSODFHGE\7I*FRQMXJDWH$VVKRZQLQ
OHXNHPLF . FHOOV /XFLIHUDVH DFWLYLW\ DQG
)LJXUH ERWK IDFWRUV KDYH DQ LQIOXHQFH RQ
SURWHLQ FRQWHQW ZHUH PHDVXUHG &HOO YLDELOLW\
WUDQVIHFWLRQ HIILFLHQF\ 2Q WKH RQH KDQG
ZDVGHWHUPLQHGE\077DVVD\
FRPSOH[HV FRQWDLQLQJ ERWK * DQG 7I*
PHGLDWHG WR IROG KLJKHU WUDQVIHFWLRQ
5HVXOWVDQG'LVFXVVLRQ
HIILFLHQFLHV FRPSDUHG WR SODLQ GHQGULSOH[HV
*HQH WUDQVIHU HIILFLHQF\ RQ 1HXUR$ FHOOV ZDV
GHSHQGLQJRQWKHSHUFHQWDJHRIWUDQVIHUULQXVHG
VWXGLHGDVDIXQFWLRQRI*'1$FKDUJHUDWLR
2Q WKH RWKHU KDQG ORZ FKDUJH UDWLRV QHDU
,;&RQJUHVRGHOD6(),*
&KDUJHUDWLR
7HFQRORJtD)DUPDFpXWLFD
3RO\SOH[HV
6L]HQP
3',
3$0$0
*
*7I*
*7I*
*7I*
*7I*
3$0$0
*
*7I*
*7I*
*7I*
*7I*
3$0$0
*
*7I*
*7I*
*7I*
*7I*
=HWD
SRWHQWLDO
P9
5HIHUHQFHV
0HUGDQ 7 HW DO $GY'UXJ 'HO 5HY .LUFKHLV5HWDO*HQH7KHUDS\
+XDQJ54HWDO)$6(%-
&RWWHQ0HWDO3URF1DWO$FDG6FL86$
,;&RQJUHVRGHOD6(),*
5HVXOWVDQGGLVFXVVLRQ
,Q )LJXUHV DQG WKH DPRXQWV RI 17+ SHU
SRRO RI VDPSOHV DUH UHSUHVHQWHG IRU WKH ILYH
SDWFKHVXQGHUWKHLQFXEDWLRQWLPHV
K
K
K
K
)LJXUH &/60 SKRWRJUDSKV RI VNLQ FURVV
VHFWLRQVDIWHULQFXEDWLRQZLWKSDWFK'
)LJXUH17+$PRXQWVSHUSRRORIVWULSVDIWHU
KLQFXEDWLRQWLPH
)LJXUH17+$PRXQWVSHUSRRORIVWULSVDIWHU
KLQFXEDWLRQWLPH
,WFDQEHVHHQWKDWWKHDPRXQWRIGUXJGHFUHDVHV
ZKHQ WKH 6& WKLFNQHVV LQFUHDVHV XQGHU HYHU\
LQFXEDWLRQWLPH DV LW LV WKH FRPPRQ WHQGHQF\
REVHUYHGLQWKHOLWHUDWXUH>@7KHDPRXQWRI
GUXJ SHUPHDWHG LQFUHDVHV IRU DOO IRUPXODWLRQV
ZKHQ LQFUHDVLQJ WKH LQFXEDWLRQ WLPH DV LW ZDV
H[SHFWHG
&RPSDULQJ WKH GLIIHUHQW YHKLFOHV DIWHU K DQG
KSDWFK&SURYLGHVKLJKHVWDPRXQWRI17+LQ
WKH 6WUDWXP &RUQHXP 7KHVH UHVXOWV DUH QRW LQ
DFFRUGDQFH ZLWK SUHYLRXVO\ UHSRUWHG UHVXOWV >@
DV )'& H[SHULPHQWV HVWLPDWHG PRUH HIILFLHQF\
IRU SDWFK ' WKDQ IRU SDWFK & 7KLV FRXOG EH
H[SODLQHGLQOLJKWWRWKHFRQWDFWWLPH7KHUHIRUH
IXUWKHU VWXGLHV ZLWK K LQFXEDWLRQ WLPH DUH
QHHGHG
&RQFHUQLQJ WKH RWKHU SDWFKHV WKH HQKDQFLQJ
HIIHFWRI2$LVSDWHQWDJDLQ3DWFK(KDYLQJWKH
GRXEOH DPRXQW RI 17+ EXW QR 2$ SURYLGHV D
ZRUVHSHQHWUDWLRQRIGUXJWKDQSDWFKHV$DQG%
7KH LQIOXHQFH RI WKH LQFUHDVH RI GUXJ
FRQFHQWUDWLRQRIWKHSDWFKHVLQ17+SHQHWUDWLRQ
WKRXJK WKH 6& FDQ DOVR EH VHHQ LQ WKHVH
H[SHULPHQWVE\FRPSDULVRQRISDWFKHV$ZLWK&
DQG%ZLWK'
7KH HYDOXDWLRQ RI WKH FKDQJHV LQ WKH VWUDWXP
FRUQHXP E\ PHDQV RI &/60 DIWHU LQFXEDWLRQ
ZLWKSDWFK'LVSUHVHQWHGLQ)LJXUH
7KHVH SKRWRJUDSKV UHYHDOHG D WLPHGHSHQGHQW
LQFUHDVHRIWKHZDWHUFRQWHQWLQWKHFRUQHRF\WHV
EHFDXVHWKHLUVL]HLQFUHDVHGFRQVLGHUDEO\
&RQFOXVLRQV
17+SHQHWUDWLRQDQGGLVWULEXWLRQZLWKLQWKH6&
LV VWURQJO\ LQIOXHQFHG E\ WKH YHKLFOH DQG
LQFXEDWLRQ WLPH 7KH WDSHVWULSSLQJ WHFKQLTXH
DOORZV WKH HYDOXDWLRQ RI GLIIHUHQFHV LQ UDWH DQG
DPRXQW RI GUXJ SHQHWUDWHG 7KHUH LV D WLPH
GHSHQGHQW LQFUHDVH RI WKH K\GUDWLRQ RI WKH 6&
DIWHULQFXEDWLRQ3DWFK'FDQEHFRQVLGHUHGDVD
JRRGFDQGLGDWHIRUWUDQVGHUPDOGHOLYHU\RI17+
DQG LV ZRUWK WR SURFHHG ZLWK IXUWKHU LQ YLYR
VWXGLHV
$FNQRZOHGJPHQWV
7KH DXWKRUV ZRXOG OLNH WR WKDQN WKH '$$'
JUDQW IRU $ 0HOHUR WKH *DOHQRV 1HWZRUN
0DULH &XULH)HOORZVKLS DJUHHPHQW LQ WKH
IUDPHZRUN RI WKH (8 3URMHFW ³7RZDUGV D
(XURSHDQ 3K' LQ $GYDQFHG 'UXJ 'HOLYHU\´
0(67&7 DQG WKH SURMHFW ),6
,QVWLWXWR GH 6DOXG 6DQ &DUORV ,,, ), 5HIHUHQFHV
+XJKHV -5 0HFKDQLVP RI DFWLRQ RI D
GHFLVLRQDLGIRUVPRNLQJFHVVDWLRQWUHDWPHQW
$GGLFWLRQ DXWKRU UHSO\
0HOHUR $ *DUULJXHV 70 $OPXGHYHU 3
0DUWtQ9LOORGUH$/HUK&06FKlIHU8
1RUWULSW\OLQH+\GURFKORULGH3HUPHDWLRQWKURXJK
+XPDQ 6NLQ ,QIOXHQFH RI S+ DQG 3HQHWUDWLRQ
(QKDQFHUV 'HYHORSPHQW RI D QRUWULSW\OLQH
7'6
(XU-3KDUP%LRSKDUP±
/DGHPDQQ - 5LFKWHU + 7HLFKPDQQD $
2WEHUJ1%OXPH3H\WDYL8/XHQJR-:HL‰%
6FKDHIHU8)/HKU&0:HSI56WHUU\:
1DQRSDUWLFOHV ± $Q HIILFLHQW FDUULHU IRU GUXJ
GHOLYHU\LQWRWKHKDLUIROOLFOHV
(XU-3KDUP%LRSKDUP
:DJQHU+.RVWND .+ /HKU&06FKDHIHU
8)S+SURILOHVLQKXPDQVNLQLQIOXHQFHRIWZR
LQYLWURWHVWV\VWHPVIRUGUXJGHOLYHU\WHVWLQJ
(XU - 3KDUP %LRSKDUP 7HFQRORJtD)DUPDFpXWLFD
35(/,0,1$5<678',(621'58*'(/,9(5<2)/2:7(03(5$785(3/$60$
75($7('7(;7,/(68332576
&&DQDO-0&DQDO$1DYDUUR0-*DUFLD&HOPD
'HSDUWPHQW3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\)DFXOW\RI3KDUPDF\8QLYHUVLGDGGH
%DUFHORQD$YGD-RDQ;;,,,VQ%DUFHORQD6SDLQ
7H[WLOHDQG3DSHU(QJLQHHULQJ'HSDUWPHQW8QLYHUVLGDG3ROLWpFQLFDGH&DWDOXxDF&RORP
7HUUDVVD6SDLQ
E\WKHPROHFXODUGLDO\VLVPHWKRGUHSRUWHGLQ
DQGDQDO\]HGE\VSHFWURSKRWRPHWU\
,QWURGXFWLRQ
/73WUHDWPHQWVZHUHFDUULHGRXWRQRQHVLGHRI
0HGLFDO WH[WLOHV DUH RQH RI WKH PRVW
WKHIDEULFVLQDFRURQDUHDFWRUDWDWPRVSKHULF
G\QDPLFDOO\ H[SDQGLQJ VHFWRUV LQ WKH WHFKQLFDO
WH[WLOH PDUNHW $FFRUGLQJWRWKHOLWHUDWXUHRYHU
SUHVVXUHDQG:XVLQJDPELHQWDLUDVSODVPD
PQWRQVRIWH[WLOH PDWHULDOV ZLWKDYDOXHRI
JDV
86EQ ZHUH FRQVXPHG ZRUOGZLGH LQ WKH
6WDWLF FRQWDFW DQJOH RQ WKH IDEULFV ZDV
PDQXIDFWXUHRIPHGLFDODQGK\JLHQHSURGXFWVLQ
GHWHUPLQHGZLWKD.UVV'6$JRQLRPHWHU
7KLV LV SUHGLFWHG WR LQFUHDVH LQ YROXPH
WHUPV E\ SHU DQQXP WR WR UHDFK
5HVXOWVDQGGLVFXVVLRQ
PQWRQVZLWKDYDOXHRI86EQ
7KH LQFUHDVH LQ K\GURSKLOLFLW\ E\ YHU\ VKRUW
&DWHJRULHVRIPHGLFDOWH[WLOHVLQFOXGH
/73WUHDWPHQWWLPHVDQGVRIWKHWUHH
• QRQLPSODQWDEOHPDWHULDOV
PDWHULDOVVWXGLHGLVUHSRUWHGLQ)LJXUH
• ҏLPSODQWDEOHPDWHULDOV
PP
CO
WO
110
100
90
θs (º)
80
70
60
50
40
0,0
0,2
0,4
0,6
0,8
1,0
t (s)
1,2
(O DQiOLVLV PRUIROyJLFR SRU 6(0 PXHVWUD TXH
ODV PLFURHVIHUDV FDUJDGDV FRQ UDVDJLOLQD
PHVLODWR SUHVHQWDQ VXSHUILFLHV LUUHJXODUHV FRQ
LQYDJLQDFLRQHVPLHQWUDVTXHODVQRFDUJDGDVVRQ
HVIpULFDV\FRQVXSHUILFLHOLVD
/RV HVWXGLRV GH FHVLyQ PXHVWUDQ XQD FHVLyQ
LQLFLDOGHO“HUGtDVHJXLGDGHXQD
OLEHUDFLyQFRQVWDQWHGXUDQWHDSUR[LPDGDPHQWH
GtDV $GLFKR WLHPSRHOSRUFHQWDMHOLEHUDGRIXH
GH “ $ SDUWLU GH HVH WLHPSR VH
SURGXFH XQD OLEHUDFLyQ PiV OHQWD KDVWD HO ILQDO
GHOSURFHVRILJXUD
)LJXUD 3HUILO GH FHVLyQ GH UDVDJLOLQD
PHVLODWRGHVGHPLFURHVIHUDVGH3/*$
(Q OD ILJXUD VH PXHVWUDQ ORV UHVXOWDGRV
REWHQLGRVHQHODQiOLVLVGHUD\RV;
/DV LQWHQVLGDGHV Pi[LPDV HQ HO HVSHFWUR GH
UD\RV ; SDUD OD UDVDJLOLQD PHVLODWR VH
REWXYLHURQ D ž ž ž \ ž
&XDQGR VH DQDOL]y HO HVSHFWUR FRUUHVSRQGLHQWH
DO SROtPHUR \ PLFURVIHUDV VLQ FDUJDU QR VH
REVHUYy QLQJ~Q Pi[LPR OR TXH LQGLFD TXH HO
SROtPHUR VH HQFXHQWUD DO HVWDGR DPRUIR \
DGHPiV HO SURFHVR GH HQFDSVXODFLyQ QR
PRGLILFD VXV FDUDFWHUtVWLFDV (Q HO SHUILO
FRUUHVSRQGLHQWHDODVPLFURHVIHUDVFDUJDGDVFRQ
SULQFLSLR DFWLYR QR VH REVHUYDQ GH IRUPD WDQ
DFXVDGD ORV Pi[LPRV GH LQWHQVLGDG
FRUUHVSRQGLHQWHVDODUDVDJLOLQDPHVLODWR
'HSHQGLQJ ERWK RQ WKHLU VXUIDFH FKHPLFDO
SURSHUWLHV WKH ' VWUXFWXUH RI WKH IDEULFV DQG
WKHLUVSHFLILFVXUIDFHGLUHFWO\GHSHQGDQWRQWKH
ILEUH GLDPHWHU WKH PDWHULDOV LQFRUSRUDWH
GLIIHUHQWSHUFHQWDJHRINHWRSURIHQ
VKRZV LQWHUPHGLDWH NHWRSURIHQ LQFRUSRUDWLRQ
EHWZHHQ WKH RWKHU WZR PDWHULDOV %HLQJ DOUHDG\
DQK\GURSKLOLFILEUHQRGUXJXSWDNHLQFUHDVHLV
REVHUYHGZKLOHLQ:2DQG33SODVPDWUHDWPHQW
WHQGV WR LPSURYH NHWRSURIHQ XSWDNH RQ WKH
IDEULF 7ZR PHFKDQLVPV PD\ EH WDNHQ LQWR
DFFRXQW D VXSHUILFLDO DEVRUSWLRQ ZKLFK PD\
WDNH SODFH LQ :2 RU 33 GXH WR WKHLU
K\GURSKRELF SURSHUWLHV RU D GLIIXVLRQ LQWR WKH
ILEUHLQPRUHK\GURSKLOLFPDWHULDOVVXFKDV&2
8QWUHDWHG
/73V
/73V
NHWRSURIHQZWLQFRUSRUDWHGWRWKHIDEULF
33
“
“
“
&2
“
“
“
:2
“
“
“
7KHFRPSDULVRQRIWKHGUXJLQFRUSRUDWHG7DEOH
WR WKH PRVW K\GURSKRELF PDWHULDOV :2 DQG
33 UHYHDOV D KLJKHU GUXJ DEVRUSWLRQ LQ 33
ZKLFK FDQ EH H[SODLQHG E\ D KLJKHU VSHFLILF
VXUIDFH RI 33 GXH WR WKH SUHVHQFH RI D OD\HU RI
ILEUHVRIQDQRPHWULFGLDPHWUHRQWKHQRQZRYHQ
VWUXFWXUH 8QWUHDWHG &2 ZKLFK LV K\GURSKLOLF
ZLWK ILEUH GLDPHWHUV VLPLODU WR WKRVH RI :2
120
110
100
90
80
70
60
50
40
30
20
10
0
D
E
F
G
1
)LJXUD D 5DVDJLOLQD PHVLODWR E 3/*$
F PLFURHVIHUDV GH 3/*$ G
PLFURHVIHUDV GH 3/*$ FDUJDGDV FRQ
UDVDJLOLQDPHVLODWR
&RQFOXVLRQHV
/D WpFQLFD GH H[WUDFFLyQ \ HYDSRUDFLyQ GHO
VROYHQWH D SDUWLU GH XQD HPXOVLyQ $2$ KD
PRVWUDGR UHVXOWDGRV DGHFXDGRV SDUD OD
PLFURHQFDSVXODFLyQ GH UDVDJLOLQD PHVLODWR
REWHQLpQGRVH UHQGLPLHQWRV GH SURGXFFLyQ \
HQFDSVXODFLyQ HOHYDGRV DVt FRPR XQ EXHQ
FRQWUROHQODOLEHUDFLyQGHOSULQFLSLRDFWLYR
%LEOLRJUDItD
%HUJDUHFKH $ HW DO - 1HXURO 6KDVWU\%1HXURVFL5HV
%DU$P2HWDO 1HXURVFL/HWW
<RXGLP0HWDO&HOO0RO1HXURELRO
$JUDGHFLPLHQWRV
(VWH WUDEDMR IXH ILQDQFLDGR SRU XQ SUR\HFWR GH
LQYHVWLJDFLyQ )XQGDFLyQ 0XWXD 0DGULOHxD
$30DUFRV)HUQiQGH]DJUDGHFHHO
DSR\RGHO3URJUDPD$OȕDQ3URJUDPDGH%HFDV
GH $OWR 1LYHO GH OD 8QLyQ (XURSHD SDUD
$PpULFD/DWLQDEHFD1ž('&/
0
-10
20
50
80
110
140
170
200
230
ºC
120
Wool
100
80
60
40
Untreated
LTP 0.35 s
LTP 1.05 s
20
0
5
10
15
20
25
)LJXUH .HWRSURIHQ UHOHDVHG IURP WKUHH
GLIIHUHQWXQWUHDWHG87WH[WLOHVXSSRUWV
7KH NLQHWLFV RI NHWRSURIHQ UHOHDVH RQ WKH
XQWUHDWHGPDWHULDOV)LJXUHUHYHDOVVLJQLILFDQW
GLIIHUHQFHV LQ WKH NHWRSURIHQ UHOHDVHGIURP &2
LQ K DQG IURP :2 DURXQG LQ
K
/73 WUHDWPHQW SUHYLRXV WR GUXJ LQFRUSRUDWLRQ
SURGXFHV VLJQLILFDQW GLIIHUHQFHV LQ WKH
NHWRSURIHQUHOHDVHZLWKUHVSHFWWRWKHXQWUHDWHG
PDWHULDOVLQ&2DQG:2IDEULFV
120
Cotton
100
80
60
40
Untreated
LTP 0.35s
LTP 1.05s
20
0
0
5
10
15
20
5
10
15
t (h)
Untreated CO
Untreated WO
t (h)
25
t (h)
)LJXUH (IIHFW RI DLU /73 WUHDWPHQW RQ WKH
NHWRSURIHQUHOHDVHRI&2IDEULFV
7KH GUXJ UHOHDVH RI XQWUHDWHG &2 IDEULFV
LQFUHDVHV IURP WR DIWHU /73
WUHDWPHQW )LJXUH 7KLV FDQ EH H[SODLQHG
WDNLQJLQWRDFFRXQWWKHHWFKLQJHIIHFWDWWULEXWHG
WR /73 ZKLFK PD\ KDYH HOLPLQDWHG RFFOXVLYH
FHULFVXEVWDQFHVRQWKHVXUIDFHRI&2WKHUHIRUH
IDYRXULQJWKHUHOHDVHRIWKHGUXJ
,Q WKH FDVH RI :2 IDEULFV )LJXUH /73
WUHDWPHQW UHGXFHV WKH SHUFHQWDJH RI NHWRSURIHQ
UHOHDVHG 7KLV FRXOG EH H[SODLQHG E\ WKH
SUHVHQFH RI WKH FKDUDFWHULVWLF IDWW\ DFLGV
PRQROD\HU FRYDOHQWO\ ERXQG WR WKH SURWHLQ
PDWUL[ RI ZRRO 7KLV K\GURSKRELF OD\HU PD\
LPSDLU SHQHWUDWLRQ RI WKH GUXJ LQWR WKH ILEUH LQ
WKHXQWUHDWHGPDWHULDOZKLOHLWVHOLPLQDWLRQPD\
IDYRXU WKH DEVRUSWLRQ LQ WKH EXON RI WKH ILEUH
WKHUHIRUHGLIILFXOWLQJLWVODWWHUOLEHUDWLRQ
0
0
7DEOH NHWRSURIHQ ZW LQFRUSRUDWHG WR WKH
GLIIHUHQWPDWHULDOVRQZHLJKWRIIDEULF
G
E
F
D
)LJXUD D 5DVDJLOLQD PHVLODWR E
PLFURHVIHUDV GH 3/*$ FDUJDGDV FRQ
UDVDJLOLQD PHVLODWR F PLFURHVIHUDV GH 3/*$
G3/*$
)LQDOPHQWHHQHOHVWXGLRGH'6&VHREVHUYDOD
DSDULFLyQ GHO SLFR GH IXVLyQ GH UDVDJLOLQD
PHVLODWR D ž& ILJXUD D DVt FRPR OD 7J
FDUDFWHUtVWLFD GHO 3/*$ D ž& ILJXUD
E (Q HO '6& FRUUHVSRQGLHQWH D ODV
PLFURHVIHUDV FDUJDGDV VH REVHUYD OD 7J
FDUDFWHUtVWLFD GHO 3/*$ \ XQ SLFR D
ž&
,;&RQJUHVRGHOD6(),*
)LJXUH(YROXWLRQRIVWDWLFFRQWDFWDQJOHRIWKH
PDWHULDOVZLWKDLU/73WUHDWPHQW
% ketoprofen released
• H[WUDFRUSRUHDOGHYLFHV
• KHDOWKFDUHDQGK\JLHQHSURGXFWV
:LWKLQWKHVHFDWHJRULHVDQLQWHUHVWLQJSRLQWLVWR
SURYLGH WKH PHGLFDO WH[WLOHV ZLWK FRQWUROOHG
GUXJ UHOHDVH SURSHUWLHV WR LPSURYH ZRXQG
KHDOLQJLQWKHFDVHRIQRQLPSODQWDEOHPDWHULDOV
VXFKDVSDQVHPHQWVRULQWKHFDVHRILPSODQWDEOH
PDWHULDOVVXFKDVVWHQWV
7R LPSURYH WKH K\GURSKLOLF SURSHUWLHV RI WKH
PDWHULDOV WR SRWHQFLDOO\ LPSURYH ZHWWLQJ ZLWK
WKH VROXWLRQV RI DFWLYH SULQFLSOH RU PRGXODWLQJ
WKHLU UHOHDVH SURSHUWLHV WKH\ ZHUH WUHDWHG ZLWK
ORZ WHPSHUDWXUH SODVPD /73 /73 LV D
SDUWLDOO\ LRQL]HG JDV FRPSRVHG RI FKDUJHG DQG
QHXWUDO SDUWLFOHV ZKLFK FDQ LQWHUDFW HLWKHU
SK\VLFDOO\ RU FKHPLFDOO\ ZLWK WKH VXEVWUDWH
VXUIDFHWRDGHSWKRIDIHZWHQVRIQPGXHWR
LWV KLJK UHDFWLYLW\ /73 KDV EHHQ H[WHQVLYHO\
VWXGLHGIRUWKHVXUIDFHPRGLILFDWLRQRISRO\PHUV
RU WH[WLOHV EXW QRW IRU GUXJ GHOLYHU\ SXUSRVHV
7KHUHIRUH WKH DXWKRUV KDYH LGHQWLILHG D
SRWHQWLDOO\ LQWHUHVWLQJ QHZ SDWK IRU PRGLI\LQJ
WKH LQFRUSRUDWLRQ DQG UHOHDVH SURSHUWLHV RI
SRO\PHULFWH[WLOH
PDWHULDOV ZKLFK LV SUHOLPLQDULO\ VWXGLHG LQ WKLV
ZRUN
0DWHULDOVDQG0HWKRGV
7KUHH GLIIHUHQW IDEULFV ZHUH VHOHFWHG IRU WKHLU
PRUSKRORJLFDO DQG FKHPLFDO GLIIHUHQFHV D
SRO\SURS\OHQH QRQZRYHQ 33 D FRWWRQ ZRYHQ
IDEULF&2DQGDZRROZRYHQ:2IDEULF
,QFRUSRUDWLRQDQGGUXJUHOHDVHSURSHUWLHVRIWKH
PDWHULDOV EHIRU DQG DIWHU /73 WUHDWPHQW ZHUH
VWXGLHGE\XVLQJNHWRSURSKHQHDVDPRGHOGUXJ
HVWXGLR VH UHDOL]y FRQ PJ GH FDGD SURGXFWR
HQWUH ž& FRQ XQD YHORFLGDG GH
FDOHQWDPLHQWRGHž&PLQ
5HVXOWDGRV\GLVFXVLyQ
/RVUHQGLPLHQWRVPiVHOHYDGRVGHSURFHVR\GH
HQFDSVXODFLyQ VH REWXYLHURQ FRQ HO PpWRGR GH
HPXOVLyQ$2$WDEOD
7DEOD 5HQGLPLHQWRV GH SURFHVR \
HQFDSVXODFLyQ REWHQLGRV HQ OD SUHSDUDFLyQ GH
ODVPLFURHVIHUDV
(PXOVLyQ 5HQGLPLHQWR
(ILFDFLDGH
GHOSURFHVR
HQFDSVXODFLyQ
2$
“
“
$2$
“
“
% ketoprofen released
'(6$552//2<&$5$&7(5,=$&,Ï1'(0,&52(6)(5$6'(5$6$*,/,1$0(6,/$72
3$5$(/75$7$0,(172'(/3$5.,1621
0)HUQiQGH]61HJUR$)HUQiQGH]\(%DUFLD
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDG&RPSOXWHQVHGH0DGULG
0DGULG(VSDxD
'HSDUWDPHQWRGH)DUPDFLD8QLYHUVLGDGGH&RQFHSFLyQ&RQFHSFLyQ&KLOH
3RO\WURQŠ5(&2.LQHPDWLFD*PE+37
,QWURGXFFLyQ
GXUDQWH PLQDUSP /DHPXOVLyQ2$
/DHQIHUPHGDGGH3DUNLQVRQ(3HVODVHJXQGD
UHVXOWDQWH IXH DGLFLRQDGD D PO GH 39$
HQIHUPHGDG QHXURGHJHQHUDWLYD PiV IUHFXHQWH
SY\VHGHMyHQDJLWDFLyQGXUDQWHKRUDV
GHVSXpV GHO $O]KHLPHU 6H WUDWD GH XQD
D WHPSHUDWXUD DPELHQWH 3RU ~OWLPR ODV
SDWRORJtD FUyQLFD TXH GH PRPHQWR QR WLHQH
PLFURHVIHUDVIXHURQODYDGDV\OLRILOL]DGDV
FXUD SRU OR TXH HO REMHWLYR GHO WUDWDPLHQWR HV
0pWRGRGHHPXOVLyQ$2$
UHGXFLU VX SURJUHVLyQ DVt FRPR FRQWURODU ORV
6H SUHSDUy XQD VROXFLyQ DFXRVD GH UDVDJLOLQD
VtQWRPDV \HIHFWRVVHFXQGDULRVGHORV IiUPDFRV
PHVLODWRPJ—OGHWDPSyQIRVIDWRDS+
TXHVHXVDQSDUDWUDWDUOD
TXH IXH HPXOVLILFDGD HQ XQD VROXFLyQ GH
/DUDVDJLOLQDLQKLEHLUUHYHUVLEOHPHQWHOD0$2
3/*$ PJ HQ &+&O PO FRQ
% \ QR RULJLQD PHWDEROLWRV Wy[LFRV HQ
XQD VRQGD GH XOWUDVRQLGRV +HDW 6\VWHPV
FRPSDUDFLyQ FRQ RWURV ,0$2 FRPR OD
8OWUDVRQLFV ,QF GXUDQWH VHJXQGRV /D
VHOHJLOLQD /D UDVDJLOLQD \ VX PHWDEROLWR
HPXOVLyQ UHVXOWDQWH $2 IXH LQFRUSRUDGD HQ
PD\RULWDULR
5DPLQRLQGDQR
SRVHHQ
POGH XQDVROXFLyQGH39$SY \
SURSLHGDGHV QHXURSURWHFWRUDV OR TXH KDFH TXH
1D&O 1 DOFDOLQL]DGD FRQ 1D2+ 1 D S+
VHDQ KR\ FRQVLGHUDGRV FRPR SRWHQFLDOPHQWH
XWLOL]DQGR SDUD HOOR XQ 3RO\WURQŠ
PX\ ~WLOHV HQ HO WUDWDPLHQWR QR VROR GH OD (3
.LQHPDWLFD *PE+ 37 GXUDQWH VLQR GH RWURV SURFHVRV QHXURGHJHQHUDWLYRV
VHJXQGRV D USP REWHQLpQGRVH XQD
DVRFLDGRVDOHQYHMHFLPLHQWR
HPXOVLyQ $2$ 'LFKD HPXOVLyQ VH GHMy HQ
/DV FDUDFWHUtVWLFDV ELRIDUPDFpXWLFDV \
DJLWDFLyQ GXUDQWH KRUDV D WHPSHUDWXUD
IDUPDFRFLQpWLFDV GH OD UDVDJLOLQD MXQWR FRQ HO
DPELHQWH $ FRQWLQXDFLyQ ODV PLFURHVIHUDV
KHFKR GH TXH VH XWLOLFH HQ XQ WUDWDPLHQWR
IXHURQ ODYDGDV \ VHFDGDV HQ XQ GHVHFDGRU DO
FUyQLFR \ GH TXH QR H[LVWD QLQJ~Q VLVWHPD GH
YDFtR
OLEHUDFLyQ FRQWURODGD GHO PLVPR KDFH TXH HVWH
(ILFDFLDGHHQFDSVXODFLyQ6HGLVROYLHURQPJ
FRPSXHVWR VHD XQ FDQGLGDWR LGyQHR SDUD HO
GHPLFURHVIHUDVHQPOGH&+&O(OIiUPDFR
GHVDUUROORGHGLFKRWLSRGHVLVWHPDV
IXH H[WUDtGR WUHV YHFHV GHVGH OD IDVH RUJiQLFD
3RU WDQWR HO REMHWLYR GH HVWH WUDEDMR KD VLGR
FRQ PO GH 3%6 S+ $ FRQWLQXDFLyQ ODV
GHVDUUROODU XQD QXHYD IRUPXODFLyQ SDUD HO
PXHVWUDVVHFHQWULIXJDURQDUSPGXUDQWH
WUDWDPLHQWR GH OD (3 FRQVLVWHQWH HQ
PLQ3URFHGLpQGRVHDUHWLUDUHOVREUHQDGDQWH(O
PLFURHVIHUDV ELRGHJUDGDEOHV GH UDVDJLOLQD
YROXPHQWRWDOGHPXHVWUDPOVHFRPSOHWyD
PHVLODWR
PO FRQ 3%6 S+ /DV PXHVWUDV VH
ILOWUDURQ —P \ VH SURFHGLy D OD
0DWHULDOHV\0pWRGRV
GHWHUPLQDFLyQ GHO SULQFLSLR DFWLYR SRU +3/& D
/DV PLFURHVIHUDV IXHURQ SUHSDUDGDV XWLOL]DQGR
QP
3/*$ 5HVRPHUŠ %RHKULQJHU
(VWXGLR GH FHVLyQ 6H GLVSHUVDURQ PJ GH
,QJHOKHLP PHGLDQWH OD WpFQLFD GH H[WUDFFLyQ \
PLFURHVIHUDV HQ PO GH 3%6 S+ /DV
HYDSRUDFLyQ GHO VROYHQWH D SDUWLU GH XQD
PXHVWUDV VH PDQWXYLHURQ D ž& EDMR DJLWDFLyQ
HPXOVLyQ2$RGHXQDHPXOVLyQ $2$3DUD
FRQVWDQWH WRPiQGRVH PXHVWUDV D GLIHUHQWHV
HOGHVDUUROOR\RSWLPL]DFLyQGHFDGDPpWRGRVH
WLHPSRVTXHIXHURQFXDQWLILFDGDVSRU+3/&
PRGLILFDURQORVVLJXLHQWHVSDUiPHWURVFDQWLGDG
(VWXGLRPRUIROyJLFR(OHVWXGLRVHOOHYyDFDER
GH SULQFLSLR DFWLYR FDQWLGDG GH SROtPHUR
PHGLDQWH PLFURVFRSLD HOHFWUyQLFD GH EDUULGR
YROXPHQ GH &+&O FRQFHQWUDFLyQ GH 39$ \
6(0-HRO-60WDQWRHQ PLFURHVIHUDV
S+GHODIDVHDFXRVDLQWHUQD\H[WHUQDPpWRGR
FDUJDGDVFRPRQRFDUJDGDV
$2$ )LQDOPHQWH VH GHVDUUROODURQ ORV
5D\RV;6HXWLOL]yXQGLIUDFWyPHWURDXWRPiWLFR
VLJXLHQWHVPpWRGRV
GH SROYR 3KLOLSV ;¶3HUW 03' HQ
0pWRGRGHHPXOVLyQ2$
FRQILJXUDFLyQ șș HQ HO UDQJR DQJXODU ž
6HGLVSHUVDURQ PJGHUDVDJLOLQD PHVLODWRHQ
ș WDPDxR GH SDVR ž ș \ WLHPSRV GH
XQDVROXFLyQGH3/*$PJHQP/GH
FRQWHRVHJSDVR
&+&O/DGLVSHUVLyQIXHHPXOVLILFDGDHQPO
&DORUtDGLIHUHQFLDOGHEDUULGR'6&6HXWLOL]y
GHXQDVROXFLyQGH39$DOSYXWLOL]DQGRXQ
XQ HTXLSR 0HWWOHU 7ROHGR '6& (O
,;&RQJUHVRGHOD6(),*
% ketoprofen released
7HFQRORJtD)DUPDFpXWLFD
20
25
)LJXUH (IIHFW RI DLU /73 WUHDWPHQW RQ WKH
NHWRSURIHQUHOHDVHRI:2IDEULFV
1R VLJQLILFDQW GLIIHUHQFHV ZHUH IRXQG LQ WKH
GUXJUHOHDVHSURSHUWLHVRIWKH33IDEULFVHLWKHU
XQWUHDWHGRU/73WUHDWHG
&RQFOXVLRQV
7KHSUHOLPLQDU\VWXGLHVFDUULHGRXWLQWKLVZRUN
UHYHDO WKDW LW LV SRVVLEOH WR PRGXODWH WKH
LQFRUSRUDWLRQ DQG GUXJ UHOHDVH RI GLIIHUHQW
IDEULFVE\WKHXVHRIYHU\VKRUWWUHDWPHQWWLPHV
E\ /73 7KH FKHPLFDO DQG PRUSKRORJLFDO
SURSHUWLHVRIWKHPDWHULDOVDUHRIKLJKUHOHYDQFH
LQWKHVHNLQGRIVWXGLHV
5HIHUHQFHV
5LJE\'DVVRFLDWHV7HFKQLFDO7H[WLOHVDQG
,QGXVWULDO 1RQZRYHQV :RUOG 0DUNHW )RUHFDVW
WR¶KWWSZZZGDYLGULJE\DVVRFLDWHVFRP
*ULOO $ &ROG 3ODVPD LQ 0DWHULDOV
)DEULFDWLRQ
)URP
)XQGDPHQWDOV
WR
$SSOLFDWLRQV,(((3UHVV1HZ<RUN
-RKDQ)HWDO-$SSO3RO\P6FL
5DNRZVNL:HWDO0HOOLDQG7H[WLOEHULFKWH
,QW7H[WLOH5HSRUWV
<DVXGD 7 HW DO - $SSO 3RO\PHU 6FL +HVVH+HWDO7H[WLOH5HV-
&DOGHUy * HW DO /DQJPXLU $FNQRZOHGJPHQWV
7KH DXWKRUV DFNQRZOHGJH WKH VXSSRUW RI
'HSDUWDPHQW G¶(GXFDFLy L 8QLYHUVLWDWV RI
*HQHUDOLWDW GH &DWDOXQ\D IRU WKH SRVWGRF
IHOORZVKLS RI && DQG WR WKH IXQGLQJ RI SURMHFW
&74&334
%LRIDUPDFLD\)DUPDFRFLQpWLFD
'(9(/230(17$1'9$/,'$7,212)$1+3/&0(7+2')259$1&20<&,1
48$17,),&$7,21$1',76$33/,&$7,2172$3+$50$&2.,1(7,&678'<
-HV~V9DOOH0-GH*RQ]iOH]/ySH])6iQFKH]1DYDUUR$
)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DODPDQFD
/LFHQFLDGR0pQGH]1LHWRVQ
HPDLODVQ#XVDOHV
BIOFARMACIA Y FARMACOCINÉTICA
([SHULPHQWDO
0DWHULDOVDQGUHDJHQWV
9DQFRP\FLQ ZDV SURYLGHG E\ &RPELQR 3KDUP
%DUFHORQD 6SDLQ +3/& JUDGH DFHWRQLWULOH
ZDV XVHG WR SUHSDUH WKH PRELOH SKDVH DQG ZDV
VXSSOLHG E\ 0HUFN 'DUPVWDGW *HUPDQ\
8OWUDSXUH ZDWHU ZDV REWDLQHG ZLWK D 0LOOL4
0LOOLSRUH V\VWHP $OO RWKHU FKHPLFDO UHDJHQWV
ZHUH RI DQDO\WLFDO JUDGH DQG ZHUH XVHG DV
UHFHLYHGSHUFKORULFDFLG3DQUHDF4XtPLFD
6$ %DUFHORQD 6SDLQ 7ULWRQ ; 0HUFN
'DUPVWDGW *HUPDQ\ DQG 1++32 6LJPD
$OGULFK4XtPLFD6$0DGULG6SDLQ
,QVWUXPHQWV
7KH 6KLPDG]X +3/& V\VWHP 6&/$ [ /
FRPSULVHG D SXPS PRGHO /&$' D
.RQWURQ D YDULDEOHZDYHOHQJWK 89 GHWHFWRU
*URβ =LPPHUQ *HUPDQ\ DQG D .RQWURQ
FROXPQ RYHQ )RU GDWD SURFHVVLQJ D &ODVV 93
'DWD V\VWHP 6KLPDG]X 'XLVEXUJ *HUPDQ\
ZDVXVHG
&KURPDWRJUDSKLF FRQGLWLRQV DQG VDPSOH
SUHSDUDWLRQ
6HSDUDWLRQ ZDV DFFRPSOLVKHG XVLQJ D 1XFOHRVLO
& μP FROXPQ ZLWK D OHQJWK RI FP
DQG DQ LQQHU GLDPHWHU RI FP $ PL[WXUH RI
P0 1++32 S+ DFHWRQLWULOH YYDVWKHPRELOHSKDVHDWDIORZUDWHP/PLQ
DQGDFROXPQWHPSHUDWXUHRIž&ZHUHVHOHFWHG
DV WKH EHVW FRQGLWLRQV 5HJDUGLQJ VDPSOH
WUHDWPHQWWKHIROORZLQJSURFHGXUHSURYHGWREH
RSWLPXP D PL[WXUH RI μ/ RI VDPSOH ZLWK
μ/ RI SHUFKORULF DFLG ZDV YRUWH[HG IRU
V IROORZHG E\ FHQWULIXJDWLRQ DW USP
WRVHSDUDWHSURWHLQVDIWHUZKLFKWKHVXSHUQDWDQW
ZDVFROOHFWHG2IWKLVDQDOLTXRWRIμ/ZDV
LQMHFWHGLQWRWKHFKURPDWRJUDSKLFV\VWHP
9DOLGDWLRQ
9DOLGDWLRQ ZDV SHUIRUPHG IROORZLQJ WKH )'$
JXLGHOLQHV IRU ELRDQDO\WLFDO PHWKRGV >@ 7KH
PHWKRG ZDV YDOLGDWHG DV UHJDUGV LWV VSHFLILFLW\
OLQHDULW\ DFFXUDF\ SUHFLVLRQ ZLWKLQ DQG
EHWZHHQGD\VHQVLWLYLW\DQGVWDELOLW\
7KH VWDELOLW\ RI YDQFRP\FLQ VDPSOHV DQDO\VHG
ZDV LQYHVWLJDWHG DIWHU WKUHH FRQVHFXWLYH F\FOHV
RIIUHH]LQJWKDZLQJ
5HVXOWVDQGGLVFXVVLRQ
:LWKWKLVVLPSOHIDVWDQGLQH[SHQVLYHSURFHGXUH
DQ H[FHOOHQW FKURPDWRJUDSKLF VSHFLILFLW\ ZDV
REWDLQHGILJXUHZLWKQRLQWHUIHUHQFHVGXHWR
WKH FRPSRQHQWV RI WKH ELRORJLFDO VDPSOHV
DQDO\VHG SHUIXVLRQ IOXLG DQG OXQJ WLVVXH
KRPRJHQDWH 7KH PHWKRG ZDV FKHFNHG ZLWK
UHVSHFW WR EODQNV RI GLIIHUHQW RULJLQV DV
UHFRPPHQGHGE\WKH)'$
YDQFRP\FLQ
9ROWV
,QWURGXFWLRQ
$PRQJ WKH PHWKRGV GHYHORSHG WR GDWH IRU WKH
TXDQWLILFDWLRQ RI YDQFRP\FLQ LQ ELRORJLFDO
IOXLGV
LPPXQRHQ]\PDWLF
WHFKQLTXHV
)3,$7'[ (0,7 DQG 5,$ >@ DQG
FKURPDWRJUDSKLFPHWKRGVDUHWKHPRVWUHOHYDQW
7KH IRUPHU DOWKRXJK ZLGHO\ XVHG LQ FOLQLFDO
SUDFWLFH IRU PRQLWRULQJ VHUXP OHYHOV RZLQJ WR
WKHLU VLPSOLFLW\ DQG VSHHG GR KDYH VRPH
GUDZEDFNV VXFK DV WKH ORZ SUHFLVLRQ RI WKH
(0,7 DVVD\ IRU FRQFHQWUDWLRQV KLJKHU WKDQ PJ/ 7KH ODWWHU ZLWK JUHDWHU DFFXUDF\ DQG
SUHFLVLRQ DQG JUHDWHU VHQVLWLYLW\ XVH FRPSOH[
SURFHGXUHV IRU VDPSOH SUHSDUDWLRQ LQFOXGLQJ
OLTXLGOLTXLGH[WUDFWLRQ//(>@RUVROLGSKDVH
H[WUDFWLRQ 63( >@ H[FHSW IRU WKH FDVH RI
/XVND HW DO ZKRVH VDPSOH WUHDWPHQW LV VLPSOH
EXWVKRZLQJDOLPLWRITXDQWLILFDWLRQRIWKHRUGHU
RIμJP/ZKLFKLVLQVXIILFLHQWLQFHUWDLQFDVHV
>@
7KH SUHVHQW ZRUN UHSRUWV WKH VHWWLQJ XS DQG
YDOLGDWLRQ RI DQ +3/& PHWKRG IRU WKH
TXDQWLILFDWLRQ RI YDQFRP\FLQ FRQFHQWUDWLRQV LQ
ELRORJLFDOIOXLGVLQDUDSLGVLPSOHZD\XVLQJD
EDVLF +3/& V\VWHP 7KH PHWKRG VKRZV KLJKHU
VHQVLWLYLW\ WKDQ RWKHU WHFKQLTXHV RI VLPLODU
FRPSOH[LW\GHVFULEHGWRGDWH7KHDSSOLFDWLRQRI
WKH PHWKRG WR D SKDUPDFRNLQHWLF VWXG\ RI
YDQFRP\FLQ LQ LVRODWHG UDW OXQJ LV DOVR
GHVFULEHG
EODQN
7LPHPLQ
)LJXUH6SHFLILFLW\&KURPDWRJUDPVKRZLQJDEODQN
RI D .UHEV+HQVHOHLW PHGLXP VDPSOH DQG D .UHEV
+HQVHOHLWPHGLXPVDPSOHVSLNHGZLWKYDQFRP\FLQ
,;&RQJUHVRGHOD6(),*
%LRIDUPDFLD\)DUPDFRFLQpWLFD
7DEOHVXPPDUL]HVWKHUHVXOWVRIWKHUHJUHVVLRQ
DQDO\VLV
7DEOH /LQHDU UHJUHVVLRQ DQG VWDWLVWLFDO
DQDO\VLV
&
UDQJH
—JPO
6ORSH
,QWHUFHSW
U
S6ORSH
(
(
(
S,QWHUFHSW
$FFXUDF\ ZDV GHWHUPLQHG XVLQJ VWDQGDUG
FDOLEUDWLRQ FXUYHV RI YDQFRP\FLQ ZLWKLQ WKH
UDQJHV RI DQG —JP/ IRU
HDFK GD\ 7KH GDWD RQ DFFXUDF\ VKRZQ
FRHIILFLHQWVRIYDULDWLRQDYDOXHEHORZWKH
OLPLWDFFHSWHGE\WKH)'$
7KH PHDQV “ 6' RI WKH UHFRYHULHV ZHUH
“ “ “ IRU
VWDQGDUG FXUYHV —JP/ —JP/ DQG —JP/ UHVSHFWLYHO\ ,Q
WKH UDQJH DFFXUDF\ ZDV FDOFXODWHG IRU
FRQFHQWUDWLRQV RI DQG —JP/
LQVWHDG RI WKH ORZHU OLPLW —JP/
FRQVLGHULQJ WKLV DV WKH TXDQWLILFDWLRQ OLPLW DQG
KHQFHDGPLWWLQJJUHDWHUYDULDELOLW\LQLW
)RU WKH μJP/ FRQFHQWUDWLRQ WKH UHVXOWV
ZHUH PHDQ±6' ± &9 HUURU $ VOLJKW XQGHUHVWLPDWLRQ FDQ EH
VHHQLQWKHUHVXOWVIRUFRQFHQWUDWLRQVFORVHWRWKH
OLPLWRITXDQWLILFDWLRQZLWKDQHUURURI
LHORZHUWKDQWKDWVWLSXODWHGE\WKH)'$
IRUWKHOLPLWRITXDQWLILFDWLRQ
7KHYDOXHVRIWKHFRHIILFLHQWVRIYDULDWLRQRIWKH
UHVSRQVHREWDLQHGLQWKHWKUHHYDOLGDWLRQUDQJHV
ZHUHOHVVWKDQLQWKHVWXGLHVRQUHSHDWDELOLW\
DQGZLWKLQGD\SUHFLVLRQPD\EHVHHQLQWDEOHV
DQGUHVSHFWLYHO\
7DEOH5HSHDWDELOLW\ZLWKLQGD\SUHFLVLRQ
&RQFHQWUDWLRQV
—JPO
0HDQ5HVSRQVH
±6'
±
±
±
±
±
±
±
±
±
&9
7DEOH5HSURGXFLELOLW\EHWZHHQGD\SUHFLVLRQ
&RQFHQWUDWLRQV
—JPO
0HDQ5HVSRQVH
±6'
±
±
±
±
±
±
±
±
±
&9
7KH VWDELOLW\ RI WKH GUXJ DW WKUHH FRQFHQWUDWLRQ
OHYHOV DQG —JPO GXULQJ WKUHH
F\FOHV RI IUHH]LQJWKDZLQJ ZDV DVVHVVHG 7KH
UHVXOWV REWDLQHG FRQILUPHG WKH DEVHQFH RI DQ\
HIIHFWRIWKUHHWKDZLQJDQGIUHH]LQJF\FOHV
7KH OLPLW RI TXDQWLILFDWLRQ ZDV μJP/
VLQFHWKLVFRQFHQWUDWLRQFDQEHGHWHUPLQHGZLWK
DQHUURURIDQGKHQFHOHVVWKDQWKH
OLPLW SHUPLWWHG E\ WKH )'$ 7KH DQDO\WLFDO
PHWKRGSURSRVHGDQGYDOLGDWHGKHUHZDVDSSOLHG
LQ D SKDUPDFRNLQHWLF VWXG\ RI WKH SXOPRQDU\
GLVWULEXWLRQ RI YDQFRP\FLQ LQ LVRODWHG UDW OXQJ
>@ 7KLV W\SH RI VWXG\ UHTXLUHV WKH
TXDQWLILFDWLRQ RI YDQFRP\FLQ LQ SHUIXVDWH
VDPSOHV ZKRVH FRQFHQWUDWLRQV GHFUHDVH UDSLGO\
IURP YHU\ KLJK PD[LPXP YDOXHV DV ZHOO DV LQ
OXQJ WLVVXH 7KH DYDLODELOLW\ RI D UDSLG VLPSOH
DQG LQH[SHQVLYH PHWKRG RI DQDO\VLV WKDW DOORZV
SUHFLVH DQG DFFXUDWH TXDQWLILFDWLRQ RI WKH GUXJ
DFURVV D EURDG UDQJH RI YDOXHV IDFLOLWDWHV WKH
FKDUDFWHULVDWLRQ RI WKH NLQHWLF SURILOH LQ DOO LWV
SKDVHV DQG WKH PHFKDQLVPV LQYROYHG LQ
YDQFRP\FLQ GLVSRVLWLRQ LQ WKH SXOPRQDU\
V\VWHP
&RQFOXVLRQV
7KH SURSRVHG DQDO\WLFDO PHWKRGRORJ\ LQ
FRPSDULVRQZLWKSUHYLRXVO\UHSRUWHGPHWKRGVRI
VLPLODUFRPSOH[LW\DQGHTXLSPHQWUHTXLUHPHQWV
SURYLGHV D ORZHU TXDQWLILFDWLRQ OLPLW WRJHWKHU
ZLWKDVKRUWHUVDPSOHDQDO\VLVWLPH
7KHVH FKDUDFWHULVWLFV DUH YHU\ LQWHUHVWLQJ DQG
KHOSIXO IRU UHVHDUFK VWXGLHV UHODWHG WR GUXJ
SKDUPDFRNLQHWLFV LQYROYLQJ D KLJK QXPEHU RI
VDPSOHVZLWKLQDEURDGFRQFHQWUDWLRQUDQJHDQG
WLVVXHOHYHOVLQIRUPDWLRQ
$FNQRZOHGJPHQWV
7KH DXWKRUV DFNQRZOHGJH WKH &RQVHMHUtD GH
(GXFDFLyQ GH OD -XQWD GH &DVWLOOD \ /HyQ IRU
3K'JUDQW2UGHQ('8
5HIHUHQFHV
<HR.7HWDO&OLQ&KHP
+X0:HWDO7KHU'UXJ0RQLW
*UHHQH69HWDO-&KURPDWRJU
/XNVD - HW DO - &KURPDWRJU % %LRPHG
$SSO
*XLGDQFH IRU ,QGXVWU\ %LRDQDO\WLFDO
0HWKRG
9DOLGDWLRQ
KWWSZZZIGDJRYFGHUJXLGDQFHIQO
SGI
'H -HV~V 0- HW DO $QWLPLFURE $JHQWV
&KHPRWKHU
&203$5$&,Ï1'(/)$&7255$=$<*e1(52(1/$5$7$&20202'(/2$1,0$/
'($%625&,Ï1,17(67,1$/
2OWUD1RJXHUD'*RQ]DOH]$OYDUH],*RQ]DOH]$OYDUH]0&DVDER9*%HUPHMR0
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDGGH9DOHQFLD
'HSWRGH,QJHQLHUtDÈUHD)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD8QLYHUVLGDG0LJXHO+HUQiQGH](OFKH
,QWURGXFFLyQ (Q HO PRGHODGR GH SURFHVRV
SDUWLU GH ODV FRQFHQWUDFLRQHV UHPDQHQWHV HQ
FLQpWLFRV FRPR OD DEVRUFLyQ SDUD HVWDEOHFHU
OXPHQ /DV FRQVWDQWHV GH YHORFLGDG GH
FRUUHODFLRQHV HVWUXFWXUD DFWLYLGDG HV IUHFXHQWH
DEVRUFLyQ DSDUHQWHV GH SULPHU RUGHQ HQ FDGD
FRPELQDU \ FRPSDUDU GDWRV REWHQLGRV HQ OD
FRQGLFLyQ VH REWXYLHURQ SRU DMXVWDGR GH OD
PLVPDHVSHFLHDQLPDOHQGLIHUHQWHVODERUDWRULRV
HFXDFLyQ PRQRH[SRQHQFLDO D ODV FRQFHQWUDFLR
DILQGHLQFUHPHQWDUODVLJQLILFDFLyQGHOPRGHOR
QHV UHPDQHQWHV HQ OXPHQ D FDGD WLHPSR
\ VX iPELWR GH DSOLFDFLyQ D PD\RU Q~PHUR GH
(FXDFLyQ
(F
PROpFXODV 1R REVWDQWH HV IUHFXHQWH REVHUYDU
∂&
= − ND Â&
GLVSDULGDG HQ ORV YDORUHV REWHQLGRV SDUD XQ
PLVPRIiUPDFRHQGLVWLQWRVODERUDWRULRVDSHVDU
∂W
GH XWLOL]DU WpFQLFDV H[SHULPHQWDOHV VLPLODUHV
5HVXOWDGRV \ 'LVFXVLyQ /D FRQVWDQWH GH
(VWHWUDEDMRHVSDUWHGHXQSUR\HFWRHQHOTXHVH
YHORFLGDG GH DEVRUFLyQ GH 0HWRSURORO GLILHUH
SUHWHQGH FDUDFWHUL]DU OD YDULDELOLGDG DVRFLDGD D
FXDQGRXVDPRVPDFKRV\KHPEUDVH[FHSWRHQOD
ORVH[SHULPHQWRVGHSHUIXVLyQLQVLWXHQUDWDHQ
UD]D:LVWDU8QLOHYHU7DEOD)LJXUD
GLVWLQWRV ODERUDWRULRV \ HVWLPDU FXDOHV VRQ ORV
IDFWRUHVSULQFLSDOHVUHVSRQVDEOHVGHODPLVPD\
7DEOD &RQVWDQWHV DSDUHQWH GH YHORFLGDG GH
GH TXH PRGR SXHGHQ HVWDQGDUL]DUVH \R
DEVRUFLyQ REWHQLGRV WUDV XQD SHUIXVLyQ GH
SRQGHUDUVHORVGLVWLQWRVUHVXOWDGRVVLVHGLVSRQH
0HWRSUROROμ0
GHLQIRUPDFLyQVREUHHOSURWRFRORH[SHULPHQWDO
&RQ HVWH ILQ HQ HVWH WUDEDMR SUHOLPLQDU VH KD
.D“'(K
FDUDFWHUL]DGRODSHUPHDELOLGDGLQWHVWLQDOGHGRV
0(72352/2/
μ0
IiUPDFRV PRGHOR 0HWRSURORO \ 9HUDSDPLOR HQ
0$&+2
+(0%5$
WUHVUD]DVGHUDWDXWLOL]DQGRHQDPEDVPDFKRV\
KHPEUDV
:+DQ
“
“
6H VHOHFFLRQy 0HWRSURORO SRUTXH HV HO SDWUyQ
XWLOL]DGRSDUDFODVLILFDUORVFRPSXHVWRVHQDOWDR
:8QLOHYHU
“
“
EDMD SHUPHDELOLGDG \ 9HUDSDPLOR FRPR
FRQRFLGRVXVWUDWRGHJOLFRSURWHLQD3
&',*6
“
“
0DWHULDOHV\0pWRGRV/DGHWHUPLQDFLyQGHOD
::LVWDU
FRQVWDQWH GH YHORFLGDG GH DEVRUFLyQ VH UHDOL]y
SRU XQ PpWRGR GH SHUIXVLyQ ³LQ VLWX´ HQ
METOPROLOL
LQWHVWLQR FRPSOHWR GH UDWD VLQ UHFLUFXODFLyQ 100 uM
FRPRVHPXHVWUDHQODILJXUD6HXWLOL]DURQ
6
DQLPDOHV GH SHVR FRPSUHQGLGR HQWUH Ka
JUDPRVWUDVKRUDVGHD\XQR /DV
5
FRQFHQWUDFLRQHV GH SHUIXVLyQ IXHURQ —0
SDUD DPERV FRPSXHVWRV 0HWRSURORO \
4
9HUDSDPLOR
3
)LJXUD
5HSUHVHQWDFLyQ
2
JUiILFDGHOPpWRGR
1
GHSHUIXVLyQLQVLWX
VLQUHFLUFXODFLyQ
0
W UNI M W UNI H W HAN M W HAN H CD*IGS M CD*IGS H
Raza / Sexo
)LJXUD
&RQVWDQWHV
DSDUHQWH GH YHORFLGDG GH
/DV PXHVWUDV VH DQDOL]DURQ SRU FURPDWRJUDItD
DEVRUFLyQ
REWHQLGRV
WUDV
XQD
SHUIXVLyQ
GH
OtTXLGD +3/& GH IDVH LQYHUVD FRQ GHWHFFLyQ
0HWRSUROROμ0
IOXRUHVFHQWHSDUDGHWHUPLQDUODVFRQFHQWUDFLRQHV
GH IiUPDFR HQ ODV PLVPDV /RV YDORUHV GH
(O DQiOLVLV GH YDULDQ]D GH XQD YtD \ OD
FRQVWDQWH GH YHORFLGDG GH DEVRUFLyQ DSDUHQWH
SUXHED QR SDUDPpWULFD GH .UXVNDO :DOOLV
SDUDFDGDFRPSXHVWRVHGHWHUPLQDURQD
α SRQHQ GH PDQLILHVWR TXH H[LVWHQ
,;&RQJUHVRGHOD6(),*
%LRIDUPDFLD\)DUPDFRFLQpWLFD
GLIHUHQFLDV VLJQLILFDWLYDV HQWUH ORV YDORUHV GH
YHORFLGDGGHDEVRUFLyQSDUDODVGLVWLQWDVUD]DVH
LQFOXVR HQWUH PDFKR \ KHPEUDV GHQWUR GH OD
PLVPDUD]D7DEOD
/D SUXHED QR SDUDPpWULFD GH .UXVNDO :DOOLV
α SRQHQ GH PDQLILHVWR TXH H[LVWHQ
GLIHUHQFLDV VLJQLILFDWLYDV HQWUH ORV YDORUHV GH
YHORFLGDGGHDEVRUFLyQSDUDODVGLVWLQWDVUD]DVH
LQFOXVR HQWUH PDFKR \ KHPEUDV GHQWUR GH OD
PLVPDUD]D7DEOD
7DEOD $QiOLVLV GH YDULDQ]D 3UXHED QR
SDUDPpWULFDGH.UXVNDO:DOOLV
:81,
0(72352/2/
μ0
:+$1
&',*6
0
+
0
+
0
+
:
81,
0
+
16
:
+$1
0
6
16
+
16 16
6
&'
,*6
0
16 16 16 16
7DEOD $QiOLVLV GH YDULDQ]D 3UXHED QR
SDUDPpWULFDGH.UXVNDO:DOOLV
9(5$3$0,/2
μ0
+
6
6
6
6
6
(Q HO FDVR GH SHUIXQGLU 9HUDSDPLOR D XQD
FRQFHQWUDFLyQ GH μ0 /D FRQVWDQWH GH
YHORFLGDG
GH
DEVRUFLyQ
GLILHUH
VLJQLILFDWLYDPHQWH FXDQGR VH FRPSDUD HO
UHVXOWDGR REWHQLGR HQ PDFKRV \ KHPEUDV SDUD
WRGDVODVUD]DVHVWXGLDGDV7DEOD)LJXUD
VERAPAMILO
100 uM
Ka
5
4
3
2
1
0
W UNI H W HAN M W HAN H CD*IGS M CD*IGS H
Raza / Sexo
)LJXUD &RQVWDQWH DSDUHQWH GH YHORFLGDG GH
DEVRUFLyQ REWHQLGRV WUDV XQD SHUIXVLyQ GH
9HUDSDPLORμ0
7DEOD&RQVWDQWHDSDUHQWHGHYHORFLGDGGH
DEVRUFLyQREWHQLGRVWUDVXQDSHUIXVLyQGH
9HUDSDPLORμ0::LVWDU
.D“'(K
9(5$3$0,/2
μ0
0$&+2
+(0%5$
:+DQ
“
“
:8QLOHYHU
“
“
&',*6
“
“
:81,
&',*6
+
0
+
0
+
:
81,
0
+
6
:
+$1
0
6
16
+
6
16 16
&'
,*6
0
16
6
6
6
+
6
6
6
6
6
&RQFOXVLyQ $ OD YLVWD GH ORV UHVXOWDGRV OD
YDULDELOLGDG QR HV KRPRJpQHD HQWUH UD]DV QL
JpQHUR 1R REVWDQWH ORV UHVXOWDGRV GH
SHUPHDELOLGDG SURPHGLD SDUD HO FRPSXHVWR GH
SHUPHDELOLGDG SDVLYD PHWRSURORO VRQ PDV
SDUHFLGRV TXH ORV GH YHUDSDPLOR SDUD HO TXH OD
GLIHUHQWH H[SUHVLyQ GHO SRUWDGRU DxDGH XQD
IXHQWHDGLFLRQDOGHYDULDFLyQ(QHOFDVRGHODV
GRV UD]DV ZLVWDU ORV UHVXOWDGRV VRQ VLPLODUHV
LQFOX\HQGR ORV REWHQLGRV FRQ KHPEUDV TXH
FOiVLFDPHQWH VH FRQVLGHUDEDQ PiV YDULDEOHV
3DUD HO YHUDSDPLOR HQ FDPELR DPEDV UD]DV
ZLVWDU SURSRUFLRQDQ HQ ORV PDFKRV UHVXOWDGRV
PX\ GLVWLQWRV PLHQWUDV TXH ODV KHPEUDV GH ODV
WUHV UD]DV RIUHFHQ PHQRV GLIHUHQFLDV (V SRU
HOOR LPSRUWDQWH GHWDOODU DO SXEOLFDU ORV
UHVXOWDGRV OD UD]D SDUWLFXODU XWLOL]DGD \ HQ HO
FDVR GH FRPSXHVWRV FRQ SRUWDGRUHV LQWHVWLQDOHV
VHUtD FRQYHQLHQWH XWLOL]DU XQ FRPSXHVWR SDWUyQ
TXH SHUPLWD FRUUHJLU SDUD ORV GLIHUHQWHV QLYHOHV
HQ GLVWLQWDV UD]DV \ R ODERUDWRULRV DVRFLDGRV DO
PpWRGRGHFUtDDOLPHQWDFLyQ
%LEOLRJUDItD
'ROXLVLR - 7 %LOOXSV 1 ) 'LWWHUW / :
6XJLWD(76ZLQWRVN\-9 -3KDUP6FL
0DUWtQ 9LOORGUH HW DO -
3KDUPDFRNLQ%LRSKDUP
6
W UNI M
:+$1
0
$JUDGHFLPLHQWRV 0LQLVWHULR GH (GXFDFLyQ \
&LHQFLD 6$)( $( &RQVHOOHUtD GH &XOWXUD (GXFDFLyQ \ &LHQFLD \
&RQVHOOHULD GH (PSUHVD 8QLYHUVLGDG \ &LHQFLD
*HQHUDOLWDW 9DOHQFLDQD $&203
$&203 &RPLVLyQ (XURSHD 1HWZRUN
RI ([FHOOHQFH %,26,0 /6+%&7
:3\3KDUVLJKW&RUSRUDWLRQSRU
ODOLFHQFLDDFDGpPLFDGH:LQQRQOLQ %,2',6321,%,/,'$'5(/$7,9$'(/(8&,1$75$6$'0,1,675$&,Ï125$/'(
',(7$6'(1875,&,Ï1(17(5$/
60LUDOOHV$UQDX00HULQR6DQMXiQ$1iFKHU19-LPpQH]7RUUHV
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLWDWGH9DOqQFLD
$YGD9LFHQW$QGUpV(VWHOOpVVQ%XUMDVVRW9DOHQFLD
(QVD\RVLQYLYR6HKDQXWLOL]DGRUDWDVPDFKRGH
,QWURGXFFLyQ
OD UD]D :LVWDU FRQ XQ SHVR FRPSUHQGLGR HQWUH
/DV SURWHtQDV VRQ HO SULQFLSDO FRPSRQHQWH
\ J /RV HQVD\RV KDQ VLGR DSUREDGRV
HVWUXFWXUDO \ IXQFLRQDO GH WRGDV ODV FpOXODV GHO
SRUHO&RPLWpeWLFRGHOD)DFXOWDGGH)DUPDFLD
RUJDQLVPR 8Q DSRUWH GLHWpWLFR DGHFXDGR GH
8QLYHUVLWDWGH9DOqQFLD
SURWHtQDHVHVHQFLDOSDUDPDQWHQHUODLQWHJULGDG
/RV DQLPDOHV VH DVLJQDURQ GH IRUPD DOHDWRULD D
\ OD IXQFLyQ FHOXODU \ SDUD ORJUDU XQ EXHQ
ORVJUXSRV
HVWDGRGHVDOXG
&RQWURO DGPLQLVWUDFLyQ RUDO GH P/ GH
/D OHXFLQD HV XQ DPLQRiFLGR HVHQFLDO
DJXD1 UDPLILFDGRVHORFDOL]DSUHIHUHQWHPHQWHHQWHMLGR
PXVFXODU \ FRQGLFLRQD HO GHVDUUROOR \
3UREOHPD DGPLQLVWUDFLyQ RUDO GH P/
IXQFLRQDPLHQWR GH OD PDVD PXVFXODU $GHPiV
GHOSUHSDUDGRHQWHUDOSUREOHPD1 HVXQDPLQRiFLGRSUHFXUVRUGHODJOXWDPLQD\GH
5HIHUHQFLD DGPLQLVWUDFLyQ SRU YtD RUDO GHO
OD DODQLQD FX\R UHTXHULPLHQWR DXPHQWD HQ
SUHSDUDGRHQWHUDOGHUHIHUHQFLD1 HVWDGRV FUtWLFRV GH VHSVLV KHULGDV LQIODPDFLyQ
3DUD OD REWHQFLyQ GH ODV PXHVWUDV GH VDQJUH VH
>@
KDXWLOL]DGRODWpFQLFDGHFDQXODFLyQGHODYHQD
/D QXWULFLyQ HQWHUDO HV HO PHMRU UHFXUVR SDUD
\XJXODU GH OD UDWD /D WRPD GH PXHVWUDV VH
DOLPHQWDU R FRPSOHPHQWDU OD DOLPHQWDFLyQ GH
SURORQJy GXUDQWH KRUDV HQ ORV WLHPSRV SHUVRQDV FRQ GHILFLHQFLDV R FRQ DOJXQD
SUHYLD DGPLQLVWUDFLyQ SDWRORJtD FXDQGR VH FRQVHUYD WRWDO R
\KRUDV(OYROXPHQ
SDUFLDOPHQWH OD IXQFLRQDOLGDG GHO WUDFWR
GH VDQJUH H[WUDtGR D FDGD WLHPSR IXH GH JDVWURLQWHVWLQDO
P/TXHXQD YH]REWHQLGRVHFHQWULIXJDD
(O REMHWLYR GH HVWH WUDEDMR KD VLGR YDORUDU HQ
JGXUDQWHPLQDž&(OSODVPDVREUHQDGDQWH
UDWDVQRUPRQXWULGDVVLHODSURYHFKDPLHQWRGHOD
VH GHVSURWHLQL]D FRQ ÈFLGR 6XOIRVDOLFtOLFR
OHXFLQDHVWiFRQGLFLRQDGRSRUODFRPSRVLFLyQGH
66$ \VHDOPDFHQDGXUDQWHXQ PtQLPRGH
OD PH]FOD SURWHLFD GHO SUHSDUDGR GH QXWULFLyQ
KRUDVDWHPSHUDWXUDGHž&KDVWDHOPRPHQWR
HQWHUDO 3DUD HOOR VH KD GHWHUPLQDGR OD
GHVX YDORUDFLyQ /DGHWHUPLQDFLyQFXDQWLWDWLYD
ELRGLVSRQLELOLGDG UHODWLYD GH OD OHXFLQD WUDV OD
GH OHXFLQD VH KD UHDOL]DGR SRU FURPDWRJUDItD
DGPLQLVWUDFLyQ RUDO GH XQD GRVLV ~QLFD GH XQD
OtTXLGD GH DOWD UHVROXFLyQ SRU GHWHFFLyQ
IRUPXODFLyQ SUREOHPD XWLOL]DQGR FRPR
IOXRULPpWULFD PHGLDQWH GHULYDWL]DFLyQ GH ODV
UHIHUHQFLD XQD IRUPXODFLyQ DPSOLDPHQWH
PXHVWUDV FRQ 23$0&$ ȜH[ QP \ ȜHP LQWURGXFLGDHQODSUiFWLFDDVLVWHQFLDO
QP\XQDFROXPQDFURPDWRJUiILFDGHIDVH
LQYHUVD 8OWUD%DVH & ȝP [ PP /D
0DWHULDOHV\0pWRGRV
IDVH PyYLO HPSOHDGD KD FRQVLVWLGR HQ XQD
(O HVWXGLR VH KD UHDOL]DGR FRQ GRV SUHSDUDGRV
PH]FOD GH WDPSyQ IRVIDWR . P0 FRQ HQWHUDOHV FRPHUFLDOL]DGRV SRU GLIHUHQWHV
P// GH WLHWLODPLQD D S+ \ XQD PH]FOD
ODERUDWRULRV /D PH]FOD SURWHLFD GHO SUHSDUDGR
RUJiQLFD GH PHWDQRO DFHWRQLWULOR HQ
SUREOHPD HVWi FRQVWLWXLGD SRU FDVHtQD SURWHtQD
SURSRUFLyQYY>@6HKDXWLOL]DGRXQ
GH VXHUR OiFWHR \ SURWHtQD GH JXLVDQWH ORWH
IOXMRFRQVWDQWHGHP/PLQ\XQYROXPHQGH
\ OD GHO SUHSDUDGR GH UHIHUHQFLD SRU
LQ\HFFLyQGHμ/
FDVHtQD SURWHtQD GH VXHUR OiFWHR \ SURWHtQD GH
(O WUDWDPLHQWR PDWHPiWLFR GH ORV GDWRV
VRMDORWH
H[SHULPHQWDOHV GH FRQFHQWUDFLyQ SODVPiWLFD GH
(QVD\R GH GLJHVWLyQ LQ YLWUR P/ GHO
OHXFLQD \ WLHPSR GH WRPD GH PXHVWUD VH KD
SUHSDUDGR HQWHUDO DFRQGLFLRQDGRV HQ XQ EDxR
UHDOL]DGR PHGLDQWH HO SURJUDPD LQIRUPiWLFR
GHDJXDDž&EDMRDJLWDFLyQVHKDQVRPHWLGR
:LQ1RQOLQŠXWLOL]DQGRODPHWRGRORJtDQR
D XQ SURFHVR GH GLJHVWLyQ LQ YLWUR GXUDQWH XQ
FRPSDUWLPHQWDO (O DQiOLVLV HVWDGtVWLFR GH ORV
SHULRGRGHKRUDV>@(VWHHQVD\RKDSHUPLWLGR
UHVXOWDGRV VH KD UHDOL]DGR FRQ D\XGD GHO
FRQRFHU OD FDQWLGDG GH OHXFLQD HQ FDGD XQR GH
SURJUDPD6366
ORVSUHSDUDGRVGHHVWXGLR/DWRPDGHPXHVWUDV
VHKDUHDOL]DGRHQWLHPSRKRUDVPRPHQWRHQ
5HVXOWDGRV\'LVFXVLyQ
HO TXH QR VH KD LQLFLDGR OD GLJHVWLyQ GHO
(Q OD 7DEOD VH LQGLFD OD FRQFHQWUDFLyQ GH
SUHSDUDGR \ KRUDV WLHPSRV TXH FRPSOHWDQ
OHXFLQD HQ ORV SUHSDUDGRV GH HVWXGLR
HO SHULRGR GH GLJHVWLyQ JiVWULFD H LQWHVWLQDO
GHWHUPLQDGDHQFDGDXQDGHODVIDVHVGHOHQVD\R
UHVSHFWLYDPHQWH
GH GLJHVWLyQ LQ YLWUR 1R VH GHWHFWDURQ
FRQFHQWUDFLRQHVDSUHFLDEOHVGHODPLQRiFLGRHQODV
,;&RQJUHVRGHOD6(),*
%LRIDUPDFLD\)DUPDFRFLQpWLFD
FRQGLFLRQHV GH HQVD\R VLQ GLJHULU \ GLJHVWLyQ
JiVWULFD S+ 3RU HO FRQWUDULR HQ OD HWDSD GH
GLJHVWLyQLQWHVWLQDOHQODTXHVHRULJLQDHOSURFHVR
GHSURWHyOLVLVODFRQFHQWUDFLyQGHDPLQRiFLGRHV
HOHYDGD (VWH UHVXOWDGR FRQILUPD OD FRPSRVLFLyQ
UHIHULGDHQHOHWLTXHWDGRGHORVSUHSDUDGRV\DTXH
QR FRQWLHQHQ OHXFLQD GHFODUDGD HQ IRUPD GH
DPLQRiFLGR OLEUH VLQR TXH VX SURFHGHQFLD HV
H[FOXVLYDPHQWH GH OD PH]FOD SURWHLFD /D
FRPSDUDFLyQ HVWDGtVWLFD GH ORV YDORUHV GH ODV
FRQFHQWUDFLRQHV GH OHXFLQD REWHQLGDV D S+ LQGLFD TXH ODV GLIHUHQFLDV QR VRQ
HVWDGtVWLFDPHQWHVLJQLILFDWLYDVS FDOFXODGRV
QRUPDOL]DQGR
OD
$8&
FRQFHQWUDFLyQ
SODVPiWLFDWLHPSR
GHO
DPLQRiFLGR SRU OD FRQFHQWUDFLyQ SODVPiWLFD
EDVDOLQGLYLGXDO
7DEOD 9DORUHV LQGLYLGXDOHV GHO $8&
QRUPDOL]DGD GH OHXFLQD REWHQLGD WUDV OD
DGPLQLVWUDFLyQGHXQDGRVLV~QLFDGHORVSUHSDUDGRV
HQWHUDOHVHQVD\DGRV
$8&
$8&
$QLPDO 1RUPDOL]DGD $QLPDO 1RUPDOL]DGD
SUREOHPD
UHIHUHQFLD
7DEOD0HGLD0\GHVYLDFLyQHVWiQGDU'(GHOD
FRQFHQWUDFLyQGHOHXFLQDPPRO/HQORVSUHSDUDGRV
HQWHUDOHV HVWXGLDGRV REWHQLGD HQ FDGD XQD GH ODV
IDVHVGHOHQVD\RGHGLJHVWLyQ1'1RGHWHFWDGR
&RQFHQWUDFLyQGH/HXFLQDPPRO
/SUHSDUDGRHQWHUDO0“'(
3UREOHPD
5HIHUHQFLD
1'
1'
1'
1'
“
“
6LQGLJHVWLyQ
S+ S+ (Q OD )LJXUD VH UHSUHVHQWD HO FRFLHQWH GH ODV
PHGLDVJHRPpWULFDV\VXLQWHUYDORGHFRQILDQ]D
,& GH OD FRQFHQWUDFLyQ SODVPiWLFD
Pi[LPD&Pi[\GHO$8&REWHQLGDVSDUDORV
SUHSDUDGRVGHHVWXGLR
/D ILJXUD PXHVWUD ODV FRQFHQWUDFLRQHV
SURPHGLR GH OHXFLQD HQ SODVPD ȝ0 GH
OHXFLQDJUDWDIUHQWHDORVWLHPSRVGHPXHVWUHR
REWHQLGDV WUDV OD DGPLQLVWUDFLyQ RUDO GH DJXD
$GHOSUHSDUDGRSUREOHPD%\GHOSUHSDUDGR
GHUHIHUHQFLD&
1.6
1.2
0.8
&Pi [ SURE&Pi[ UHI
$
2.00
1.80
1.60
ta1.40
a
r1.20
g
/
M1.00
o
r0.80
c
i
%
2.00
1.80
1.60
ta1.40
a
r
1.20
/g
M1.00
o
r 0.80
c
i
m0.60
0.40
0.20
0.00
-0.25
0.75
1.75
2.75
3.75
4.75
5.75
6.75
7.75
8.75
Horas
0.40
0.20
0.00
-0.25 0.75
1.75
2.75
3.75
4.75
Horas
5.75
6.75
7.75
8.75
&
2.00
1.80
1.60
ta1.40
a
r
1.20
/g
M1.00
o
r 0.80
ic0.60
m
0.40
0.20
0.00
-0.25
0.75
1.75
2.75
3.75
4.75
5.75
6.75
7.75
Horas
)LJXUD&RQFHQWUDFLyQSODVPiWLFDGHOHXFLQDWUDVOD
DGPLQLVWUDFLyQRUDOGHXQDGRVLV~QLFDGHP/GH
DJXD $ SUHSDUDGR HQWHUDO SUREOHPD % \
SUHSDUDGRHQWHUDOGHUHIHUHQFLD&
/D YDULDELOLGDG GH ODV FRQFHQWUDFLRQHV
SODVPiWLFDVGHOHXFLQDWUDVODDGPLQLVWUDFLyQGH
DJXDHVPD\RUTXHOD
REWHQLGD FXDQGR VH DGPLQLVWUD XQD GRVLV ~QLFD
GH SUHSDUDGR HQWHUDO (VWH UHVXOWDGR SRQH GH
PDQLILHVWRTXHHOSHULRGRGHD\XQRLQIOX\HHQOD
HILFLHQFLD GH OD DXWRUUHJXODFLyQ ILVLROyJLFD GH
ODVFRQFHQWUDFLRQHVSODVPiWLFDVGHDPLQRiFLGR
(Q OD 7DEOD VH PXHVWUDQ ORV YDORUHV
LQGLYLGXDOHV GHO iUHD EDMR OD FXUYD GH
FRQFHQWUDFLyQ SODVPiWLFD GH OHXFLQD ± WLHPSR
$8&SURE $8&UHI
0.4
0
$
m0.60
%LEOLRJUDItD
*DUFLD GH /RUHQ]R$ 0HWDEROLVPR HQ OD
DJUHVLyQ ,QGLFDFLRQHV GHO VRSRUWH
QXWULFLRQDO HVSHFLDOL]DGR (Q 6(13(
6(0,&<8& *DOHQLWDV7ULD 1LJUD HGV
$VSHFWRV PHWDEyOLFRV \ QXWULFLRQDOHV HQ HO
SDFLHQWH EDMR DJUHVLyQ DJXGD JUDYH KWWSZZZIGDJRYFDHUJXLGDQFHLQGH[
7HHUOLQN7<FRO&OLQ&KHP
2O]D 0HQHVHV - \ FRO 1XWULFLyQ
+RVSLWDODULD
$JUDGHFLPLHQWRV
/RVDXWRUHVDJUDGHFHQDODHPSUHVD9HJHQDW6
$ OD ILQDQFLDFLyQ UHDOL]DGD SDUD GHVDUUROODU HO
SUR\HFWR
³&DUDFWHUL]DFLyQ
GH
OD
ELRGLVSRQLELOLGDG GH QXWULHQWHV GHO SUHSDUDGR
7'LHW 3OXVŠ´ D WUDYpV GHO FRQWUDWR FRQ OD
8QLYHUVLWDW GH 9DOqQFLD 6&3-3 5HI
8.75
)LJXUD &RFLHQWH HQWUH ODV PHGLDV JHRPpWLFDV GH
ORV YDORUHV GH &Pi[ \ $8& /tQHD SXQWHDGD
,QWHUYDOR DFHSWDFLyQ (0($ /tQHD
FRQWtQXD,QWHUYDORDFHSWDFLyQ)'$
&RQFOXVLRQHV
/DV FRQFHQWUDFLRQHV GH OHXFLQD REWHQLGDV WUDV
HOSHULRGRGHGLJHVWLyQLQWHVWLQDOLQYLWURS+
HQ DPERV SURGXFWRV VRQ HTXLYDOHQWHV
LQGLFDQGR TXH OD XWLOL]DFLyQ GLJHVWLYD GH OD
PH]FOD SURWHLFD GH DPERV SUHSDUDGRV HV
VLPLODU
6HGHPXHVWUDELRHTXLYDOHQFLDHQWUHHOSUHSDUDGR
SUREOHPD\HOGHUHIHUHQFLDFXDQGRVHXWLOL]DOD
OHXFLQD FRPR ELRPDUFDGRU (VWH UHVXOWDGR
FRQILUPD TXH OD IXHQWH SURWHLFD QR FRQGLFLRQD
VXDSURYHFKDPLHQWRSRUHORUJDQLVPR
7DEOD0HGLD0\GHVYLDFLyQHVWiQGDU'(GHOD
FRQFHQWUDFLyQ GH WDXULQD —PRO/ GH SUHSDUDGR
HQWHUDO
6LQGLJHVWLyQ
S+ S+ &RQFHQWUDFLyQGH7DXULQD—PRO/
SUHSDUDGRHQWHUDO0“'(
3UREOHPD
5HIHUHQFLD
“
“
“
“
“
“
(VWRV UHVXOWDGRV LQGLFDQ TXH HO SUHSDUDGR
SUREOHPD FRQVWLWX\H XQD IXHQWH HQULTXHFLGD GH
WDXULQD XQDV YHFHV VXSHULRU DO SUHSDUDGR GH
UHIHUHQFLD $VLPLVPR OD FRQFHQWUDFLyQ GH
WDXULQD SURSRUFLRQDGD LQLFLDOPHQWH SRU HO
SUHSDUDGR SUREOHPD VH HQFXHQWUD GHQWUR GH ODV
UHFRPHQGDFLRQHV HVWDEOHFLGDV SDUD SURGXFWRV
HQULTXHFLGRVHQGLFKRDPLQRiFLGRSRUHMHPSOR
HQIyUPXODVLQIDQWLOHV“—PRO/>@
/D ILJXUD PXHVWUD ODV FRQFHQWUDFLRQHV
SURPHGLRGHWDXULQDHQSODVPDȝ0GHWDXULQDJ
UDWD IUHQWH D ORV WLHPSRV GH WRPD GH PXHVWUD
REWHQLGDVWUDVODDGPLQLVWUDFLyQGHDJXD$GHO
SUHSDUDGRSUREOHPD%\GHOSUHSDUDGRHQWHUDO
GH UHIHUHQFLD & 6H REVHUYD TXH OD
FRQFHQWUDFLyQ SODVPiWLFD GH DPLQRiFLGR VH
PDQWLHQHPiVSUy[LPDDVXYDORUEDVDO\HVPiV
VRVWHQLGD HQ HO WLHPSR SDUD ORV DQLPDOHV GHO
JUXSR%(VWHUHVXOWDGRSXHGHGHEHUVHDTXHHQ
DXVHQFLDGHDSRUWHH[yJHQRHQULTXHFLGRJUXSRV
FRQWURO \ UHIHUHQFLD HO UHWRUQR GHO DPLQRiFLGR
GHVGH ORV UHVHUYRULRV PXVFXODUHV KDFLD HO
WRUUHQWHFLUFXODWRULRVHDJRWD
(O $129$ UHDOL]DGR FRQ OD FRQFHQWUDFLyQ
SODVPiWLFDEDVDOGHWDXULQDREWHQLGDSDUDWRGRV
ORV DQLPDOHV GHO HVWXGLR LQGLFD TXH QR H[LVWHQ
GLIHUHQFLDV HVWDGtVWLFDPHQWH VLJQLILFDWLYDV
S 2.0
%
1.8
1.6
1.4
1.4
1.2
1.0
1.2
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
-0.25 0.75 1.75 2.75 3.75 4.75 5.75 6.75 7.75 8.75
0.0
-0.25 0.75 1.75 2.75 3.75 4.75 5.75 6.75 7.75 8.75
Horas
Horas
2.0
&
)LJXUD&RQFHQWUDFLyQSODVPiWLFDGHWDXULQDWUDVOD
DGPLQLVWUDFLyQRUDOGHXQDGRVLV~QLFDGHP/GH
DJXD $ SUHSDUDGR HQWHUDO SUREOHPD % \
SUHSDUDGRHQWHUDOGHUHIHUHQFLD&
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
-0.25
0.75
1.75
2.75
3.75
4.75
5.75
6.75
7.75
8.75
Horas
(Q OD 7DEOD VH PXHVWUDQ ORV YDORUHV
LQGLYLGXDOHV GHO iUHD EDMR OD FXUYD GH
FRQFHQWUDFLyQ SODVPiWLFD GH WDXULQD ± WLHPSR
$8& (VWRV YDORUHV VH KDQ FDOFXODGR
QRUPDOL]DQGR OD FRQFHQWUDFLyQ SODVPiWLFD GHO
DPLQRiFLGRREWHQLGDDFDGDWLHPSRGHWRPDGH
PXHVWUD SRU OD FRQFHQWUDFLyQ SODVPiWLFD EDVDO
REWHQLGDSDUDFDGDDQLPDOHQVD\DGR$VLPLVPR
VH LQGLFD HO FRFLHQWH HQWUH ODV PHGLDV
JHRPpWULFDV GHO SDUiPHWUR \ HO LQWHUYDOR GH
FRQILDQ]D,&FX\RVOtPLWHVH[FHGHQ
ORVGHDFHSWDFLyQ
7DEOD 9DORUHV LQGLYLGXDOHV FRFLHQWH GH OD PHGLD
JHRPpWULFD H ,& GHO $8& QRUPDOL]DGD GH
WDXULQDREWHQLGDWUDVODDGPLQLVWUDFLyQGHXQDGRVLV
~QLFDGHORVSUHSDUDGRVHQWHUDOHVHQVD\DGRV
$8&1RUPDOL]DGD
$8&1RUPDOL]DGD
SUREOHPD
UHIHUHQFLD
3DUiPHWUR
SUREUHI
,&
/Q$8&
&RQFOXVLRQHV
(OSUHSDUDGRSUREOHPDSUHVHQWDXQDFDQWLGDGGH
WDXULQD WUHV YHFHV PD\RU TXH HO SUHSDUDGR GH
UHIHUHQFLD
(O HQULTXHFLPLHQWR GH SUHSDUDGR HQWHUDO
SUREOHPD FRQ WDXULQD DGPLQLVWUDGR HQ GRVLV
~QLFDDUDWDVQRUPRQXWULGDVQRVHWUDGXFHHQXQ
DXPHQWRGHODVFRQFHQWUDFLRQHVSODVPiWLFDVGHO
DPLQRiFLGR
/DYDULDELOLGDGHQHO$8&GHWDXULQDGLILFXOWD
OD DSOLFDFLyQ GHO FULWHULR GH ELRHTXLYDOHQFLD
%LRIDUPDFLD\)DUPDFRFLQpWLFD
HQWUHORVSUHSDUDGRVHQVD\DGRVDGPLQLVWUDGRVHQ
GRVLV~QLFDDUDWDVQRUPRQXWULGDV
%LEOLRJUDItD
6WLSDQXN 0+ +RPRF\VWHLQH F\VWHLQH DQG
2.0
$
1.8
1.6
m i c ro M /g r a t a
5HVXOWDGRV\'LVFXVLyQ
(Q OD 7DEOD VH LQGLFD OD FRQFHQWUDFLyQ GH
WDXULQD HQ ORV SUHSDUDGRV GH HVWXGLR
GHWHUPLQDGDHQFDGDXQDGHODVIDVHVGHOHQVD\R
GHGLJHVWLyQLQYLWUR
&XDQGRVHFRPSDUDQGRVDGRVORVYDORUHVGHODV
FRQFHQWUDFLRQHV GH WDXULQD SURFHGHQWHV GH ORV
SUHSDUDGRV SUREOHPD \ UHIHUHQFLD REWHQLGRV HQ
ODVWUHVFRQGLFLRQHVGHHQVD\RVLQGLJHULUS+
\ S+ VH REWLHQHQ HQ WRGRV ORV FDVRV
GLIHUHQFLDV HVWDGtVWLFDPHQWH VLJQLILFDWLYDV
7DEODS m ic r o M / g ra t a
%,2',6321,%,/,'$'5(/$7,9$'(7$85,1$75$6$'0,1,675$&,Ï125$/'(
',(7$6'(1875,&,Ï1(17(5$/
60LUDOOHV$UQDX$1iFKHU00HULQR6DQMXiQ19-LPpQH]7RUUHV
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLWDWGH9DOqQFLD
$Y9LFHQW$QGUpV(VWHOOpVVQ%XUMDVVRW9DOHQFLD
,QWURGXFFLyQ
(QVD\RV LQ YLYR +DQ SHUPLWLGR FRQRFHU HO
(O REMHWLYR SULQFLSDO GH ODV WpFQLFDV GH VRSRUWH
DFFHVR GHO ELRPDUFDGRU DO SODVPD VDQJXtQHR
QXWULFLRQDO HV VDWLVIDFHU ODV QHFHVLGDGHV
WUDV OD DGPLQLVWUDFLyQ SRU YtD RUDO GH ORV
HQHUJpWLFDV GH FXDOTXLHU SDFLHQWH LQFDSD] GH
SUHSDUDGRVHQWHUDOHV
LQJHULUSRUYtDRUDOORVQXWULHQWHVQHFHVDULRV/D
6H KDQ XWLOL]DGR UDWDV PDFKR GH OD UD]D :LVWDU
SUHSDUDFLyQ GH XQ SUHSDUDGR QXWULFLRQDO
FRQ XQ SHVR FRPSUHQGLGR HQWUH \ J
LQGLYLGXDOL]DGRUHTXLHUHUHDOL]DUXQDYDORUDFLyQ
/RV HQVD\RV KDQ VLGR DSUREDGRV SRU HO &RPLWp
LQLFLDO GH ORV SDUiPHWURV DQWURSRPpWULFRV
eWLFR GH OD )DFXOWDG GH )DUPDFLD 8QLYHUVLWDW
ELRTXtPLFRV \ QXWULFLRQDOHV GHO SDFLHQWH (VWD
GH9DOqQFLD
LQGLYLGXDOL]DFLyQ
FRQGXFH
D
HODERUDU
/RV DQLPDOHV VH DVLJQDURQ GH IRUPD DOHDWRULD D
IRUPXODFLRQHV HQULTXHFLGDV FRQ QXWULHQWHV FRQ
ORVJUXSRV
HO ILQ GH FRPSHQVDU FDUHQFLDV ILVLROyJLFDV
&RQWURO DGPLQLVWUDFLyQ RUDO GH P/ GH
HVSHFtILFDV GH ORV LQGLYLGXRV GHVQXWULGRV (Q
DJXD1 HVWHFRQWH[WRGHWHUPLQDUODELRHTXLYDOHQFLDGHO
SUHSDUDGR HQWHUDO HQULTXHFLGR UHVSHFWR D RWUR
3UREOHPD DGPLQLVWUDFLyQ RUDO GH P/
SUHSDUDGR DPSOLDPHQWH LQWURGXFLGR HQ HO
GHO
SUHSDUDGR
HQWHUDO
SUREOHPD
PHUFDGR FRQVWLWX\H XQ DVSHFWR HVHQFLDO SDUD
HQULTXHFLGRFRQWDXULQD1 SURFHGHUDOLQWHUFDPELRGHSURGXFWRVGLHWpWLFRV
5HIHUHQFLD DGPLQLVWUDFLyQ SRU YtD RUDO GHO
JDUDQWL]DQGR OD FDOLGDG QXWULFLRQDO GHO
SUHSDUDGRHQWHUDOGHUHIHUHQFLD1 SUHSDUDGRDGPLQLVWUDGR
3DUD OD REWHQFLyQ GH ODV PXHVWUDV GH VDQJUH VH
/D WDXULQD HV XQ DPLQRiFLGR VXOIXUDGR GH
KDXWLOL]DGRODWpFQLFDGHFDQXODFLyQGHODYHQD
³HVHQFLDELOLGDGDGTXLULGD´TXHVHLQFRUSRUDFRQ
\XJXODU GH OD UDWD /D WRPD GH PXHVWUDV VH
IUHFXHQFLDDODVIRUPXODFLRQHVQXWULFLRQDOHV>@
SURORQJy GXUDQWH KRUDV HQ ORV WLHPSRV (V XQ DPLQRiFLGR HVHQFLDO SDUD ORV SDFLHQWHV
SUHYLD DGPLQLVWUDFLyQ FRQ DOWHUDFLRQHV KHSiWLFDV \D TXH VXUJH FRPR
\KRUDV(OYROXPHQ
SURGXFWR ILQDO GHO PHWDEROLVPR GH ORV
GH VDQJUH H[WUDtGR D FDGD WLHPSR IXH GH DPLQRiFLGRVPHWLRQLQD\FLVWHtQD
P/TXHXQD YH]REWHQLGRVHFHQWULIXJDD
(OREMHWLYRGHHVWHHVWXGLRKDVLGRGHWHUPLQDUHQ
JGXUDQWHPLQDž&(OSODVPDVREUHQDGDQWH
UDWDVQRUPRQXWULGDVODELRGLVSRQLELOLGDGUHODWLYD
VH GHVSURWHLQL]D FRQ ÈFLGR 6XOIRVDOLFtOLFR
GH OD WDXULQD WUDV OD DGPLQLVWUDFLyQ RUDO GH XQD
66$ \VHDOPDFHQDGXUDQWHXQ PtQLPRGH
GRVLV ~QLFD GH XQD IRUPXODFLyQ SUREOHPD
KRUDVDWHPSHUDWXUDGHž&KDVWDHOPRPHQWR
HQULTXHFLGD FRQ HVWH DPLQRiFLGR XWLOL]DQGR
GHVX YDORUDFLyQ /DGHWHUPLQDFLyQFXDQWLWDWLYD
FRPRUHIHUHQFLDXQDIRUPXODFLyQVLQHQULTXHFHU
GH WDXULQD VH KD UHDOL]DGR SRU FURPDWRJUDItD
OtTXLGD GH DOWD UHVROXFLyQ SRU GHWHFFLyQ
0DWHULDOHV\0pWRGRV
IOXRULPpWULFD PHGLDQWH GHULYDWL]DFLyQ GH ODV
(O HVWXGLR VH KD UHDOL]DGR FRQ GRV SUHSDUDGRV
PXHVWUDV FRQ 23$0&$ ȜH[ QP \ ȜHP HQWHUDOHV FRPHUFLDOL]DGRV SRU GLIHUHQWHV
QP\XQDFROXPQDFURPDWRJUiILFDGHIDVH
ODERUDWRULRV 6H GHQRPLQD SUREOHPD DO
LQYHUVD 8OWUD%DVH & ȝP [ PP /D
SUHSDUDGR HQULTXHFLGR ORWH \ UHIHUHQFLD
IDVH PyYLO HPSOHDGD KD FRQVLVWLGR HQ XQD
DOQRHQULTXHFLGRORWH
PH]FOD GH WDPSyQ IRVIDWR . P0 FRQ (QVD\R GH GLJHVWLyQ LQ YLWUR P/ GHO
P// GH WLHWLODPLQD D S+ \ XQD PH]FOD
SUHSDUDGR HQWHUDO DFRQGLFLRQDGRV HQ XQ EDxR
RUJiQLFD GH PHWDQRO DFHWRQLWULOR HQ
GHDJXDDž&EDMRDJLWDFLyQVHKDQVRPHWLGR
SURSRUFLyQYY >@6HKDXWLOL]DGRXQ
D XQ SURFHVR GH GLJHVWLyQ LQ YLWUR GXUDQWH XQ
IOXMRFRQVWDQWHGHP/PLQ\XQYROXPHQGH
SHULRGRGHKRUDV>@(VWHHQVD\RKDSHUPLWLGR
LQ\HFFLyQGHμ/
FRQRFHU OD FDQWLGDG GH WDXULQD HQ FDGD XQR GH
(O WUDWDPLHQWR PDWHPiWLFR GH ORV GDWRV
ORVSUHSDUDGRVGHHVWXGLR/DWRPDGHPXHVWUDV
H[SHULPHQWDOHV GH FRQFHQWUDFLyQ SODVPiWLFD GH
VHKDUHDOL]DGRHQWLHPSRKRUDVPRPHQWRHQ
WDXULQD \ WLHPSR GH WRPD GH PXHVWUD VH KD
HO TXH QR VH KD LQLFLDGR OD GLJHVWLyQ GHO
UHDOL]DGR PHGLDQWH HO SURJUDPD LQIRUPiWLFR
SUHSDUDGR \ KRUDV WLHPSRV TXH FRPSOHWDQ
:LQ1RQOLQŠXWLOL]DQGRODPHWRGRORJtDQR
HO SHULRGR GH GLJHVWLyQ JiVWULFD H LQWHVWLQDO
FRPSDUWLPHQWDO (O DQiOLVLV HVWDGtVWLFR GH ORV
UHVSHFWLYDPHQWH
UHVXOWDGRV VH KD UHDOL]DGR FRQ D\XGD GHO
SURJUDPD6366
,;&RQJUHVRGHOD6(),*
m ic ro M /g ra t a
%LRIDUPDFLD\)DUPDFRFLQpWLFD
%LRIDUPDFLD\)DUPDFRFLQpWLFD
(678',2,19,92'(/$',675,%8&,Ï17,68/$5</$&$37$&,Ï1325
0$&5Ï)$*26'(=,'298',1$87,/,=$1'2(5,752&,7263257$'25(6
(OVD%ULRQHV&XHVWD&ODUD,VDEHO&ROLQR*DQGDULOODV-RVp0DUWtQH]/DQDR
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6DODPDQFD
$YGD/LFHQFLDGR0pQGH]1LHWRVQ6DODPDQFD
,QWURGXFFLyQ
$=7
/RV HULWURFLWRV SUHVHQWDQ FDUDFWHUtVWLFDV TXH ORV
KDFHQ DGHFXDGRV FRPR VLVWHPDV SRUWDGRUHV
FRPRODFDSDFLGDGGHSURSRUFLRQDUXQHIHFWRGH
(ULWURFLWRV
6DQJUH
+HPDWRFULWR OLEHUDFLyQFRQWURODGDRGHGLULJLUHOIiUPDFRDO
$=7PJP/
VLVWHPD UHWtFXORHQGRWHOLDO GHELGR D VX UiSLGR
DFODUDPLHQWR GH OD VDQJUH SRU HO VLVWHPD
PRQRFLWRPDFUyIDJR
([LVWH XQD JUDQ YDULHGDG GH IiUPDFRV
5(6(//$'2
(ULWURFLWRV
FRQWHQLHQGR
',È/,6,6+,327Ï1,&$
GLVSRQLEOHV SDUD HO WUDWDPLHQWR GH OD LQIHFFLyQ
$=7
SRU 9,+ SHUR VX LQVXILFLHQWH FDSDFLGDG GH
SHQHWUDFLyQ HQ ORV PDFUyIDJRV \ VX EDMD
)LJXUD 3URFHGLPLHQWR GH GLiOLVLV KLSRWyQLFD
ELRGLVSRQLELOLGDG GDQ OXJDU D OD DSDULFLyQ GH
SDUDODHQFDSVXODFLyQGH='9HQHULWURFLWRVGH
UHVLVWHQFLDV \ HIHFWRV Wy[LFRV GHELGR D OD
UDWD
DFXPXODFLyQ HQ RWURV yUJDQRV 7HQLHQGR HQ
FXHQWD OD LPSRUWDQFLD GHO VLVWHPD PRQRFLWR
(OHVWXGLRVHUHDOL]yHQGRVJUXSRVGHUDWDV
PDFUyIDJRHQODLQIHFFLyQSRU+,9TXHDFW~D
:LVWDU TXH KDEtDQ UHFLELGR WUHV GtDV DQWHV XQD
FRPR XQ LPSRUWDQWH UHVHUYRULR GHO YLUXV OD
LQ\HFFLyQ
GH WLRJOLFRODWR DO SRU YtD
YHFWRUL]DFLyQ HVSHFtILFD GH HVWRV DJHQWHV KDFLD
LQWUDSHULWRQHDO XQR UHFLELy XQD VROXFLyQ GH
ORVPDFUyIDJRVWLHQHXQJUDQLQWHUpVWHUDSpXWLFR
='9DXQDGRVLVGHPJ.J\HORWURP/GH
3RU HVWDV UD]RQHV ORV IiUPDFRV
HULWURFLWRV FRQWHQLHQGR ='9 HQ DPERV FDVRV
DQWLUUHWURYLUDOHVVRQEXHQRVFDQGLGDWRVSDUDVHU
SRU YtD LQWUDSHULWRQHDO $
WLHPSRV
HQFDSVXODGRVHQHULWURFLWRVSRUWDGRUHV
SUHGHWHUPLQDGRV VH H[WUDMHURQ ORV PDFUyIDJRV
(O REMHWLYR GHO SUHVHQWH WUDEDMR KD VLGR HO
SHULWRQHDOHV PHGLDQWH ODYDGR SHULWRQHDO $
HVWXGLR GH OD ELRGLVWULEXFLyQ GH =LGRYXGLQD
FRQWLQXDFLyQORVDQLPDOHV IXHURQVDFULILFDGRV \
='9 FXDQGR VH DGPLQLVWUD HQFDSVXODGD HQ
VH WRPDURQ PXHVWUDV GH SODVPD KtJDGR ED]R
HULWURFLWRVSRUWDGRUHV
ULxyQSXOPyQFHUHEUR\PHGXODyVHD
/DV FRQFHQWUDFLRQHV GH ='9 HQ ODV
0DWHULDOHV\0pWRGRV
GLVWLQWDVPXHVWUDVVHGHWHUPLQDURQPHGLDQWHXQD
WpFQLFD GH +3/& FRQ GHWHFFLyQ GH 89 λ /RV HULWURFLWRV SRUWDGRUHV GH ='9 VH
QPWUDVXQDSUHFLSLWDFLyQSURWHLFD\H[WUDFFLyQ
SUHSDUDURQ PHGLDQWH XQ PpWRGR GH GLiOLVLV
OLTXLGROLTXLGR /D WpFQLFD VH YDOLGy VLJXLHQGR
KLSRWyQLFD XWLOL]DQGR XQ WDPSyQ KLSRRVPyWLFR
ODVQRUPDVGHOD)'$SDUDPXHVWUDVELROyJLFDV
GH P2VPNJ \ XQ WDPSyQ GH UHVHOODGR GH
6H REWXYLHURQ YDORUHV GH FRHILFLHQWH
P2VPNJ (O SURFHGLPLHQWR GH
YDULDFLyQSDUDODH[DFWLWXG\SUHFLVLyQLQIHULRUHV
HQFDSVXODFLyQ VH PXHVWUD HQ OD ILJXUD \ IXH
DO
RSWLPL]DGR SUHYLDPHQWH HQ QXHVWUR ODERUDWRULR
VHOHFFLRQiQGRVH ODV VLJXLHQWHV FRQGLFLRQHV
5HVXOWDGRV\'LVFXVLyQ
FRQFHQWUDFLyQ LQLFLDO GH ]LGRYXGLQD GH PJPO WLHPSR GH LQFXEDFLyQ GH PLQXWRV \
(OSURFHGLPLHQWRGHGLiOLVLVKLSRWyQLFDXWLOL]DGR
UHODFLyQ GH YRO~PHQHV VDFR GH GLiOLVLVWDPSyQ
SDUD OD HQFDSVXODFLyQ GH ='9 HQ HULWURFLWRV
GHP/
SHUPLWLy REWHQHU XQ EXHQ UHQGLPLHQWR GH
HQFDSVXODFLyQ REWHQLpQGRVH FRQFHQWUDFLRQHV GH
='9 HQ HULWURFLWRV GH “ PJP/ \
UHQGLPLHQWRVGHHQFDSVXODFLyQGHO
/DV ILJXUDV \ PXHVWUDQ ODV FRQFHQWUDFLRQHV
GH='9HQSODVPD\ED]RWUDVODDGPLQLVWUDFLyQ
GH ]LGRYXGLQD HQ VROXFLyQ R LQFRUSRUDGD D
HULWURFLWRV /RV UHVXOWDGRV REWHQLGRV UHIOHMDQ
WDXULQH(Q6KLOV0(6KLNH0DQG5RVV&DEDOOHUR%
&RXVLQV 5- HGV 0RGHUQ 1XWULWLRQ LQ +HDOWK DQG
'LVHDVHWKHG3KLODGHOSKLD3$/LSSLQFRWW:LOOLDQV
:LONLQV
KWWSZZZIGD JRYFDHUJXLGDQFHLQGH[KWP
.XOS.6\FRO
7HHUOLQN7\FRO&OLQ&KHP
2O]D 0HQHVHV - \ FRO 1XWULFLyQ
+RVSLWDODULD
&HQWULIXJDFLyQ
/DYDGR
$JUDGHFLPLHQWRV
/RVDXWRUHVDJUDGHFHQDODHPSUHVD9HJHQDW6
$ OD ILQDQFLDFLyQ UHDOL]DGD SDUD GHVDUUROODU HO
SUR\HFWR
³&DUDFWHUL]DFLyQ
GH
OD
ELRGLVSRQLELOLGDG GH QXWULHQWHV GHO SUHSDUDGR
7'LHW 3OXVŠ´ D WUDYpV GHO FRQWUDWR FRQ OD
8QLYHUVLWDW GH 9DOqQFLD 6&3-3 5HI
0HPEUDQD GHGLiOLVLV
/DYDGR
7DPSyQ KLSHUWyQLFR
P2VP.J
PLQž&
7DPSyQ KLSRWyQLFR P2VP.J
ž&PLQ
,;&RQJUHVRGHOD6(),*
%LRIDUPDFLD\)DUPDFRFLQpWLFD
C o n cen tració n
(m g /kg )/D o sis(m g /kg )
FDPELRV HQ OD IDUPDFRFLQpWLFD GH ='9
LQFRUSRUDGD HQ HULWURFLWRV SRUWDGRUHV /D
VHPLYLGD GH HOLPLQDFLyQ \ HO WLHPSR PHGLR GH
UHVLGHQFLD GH ='9 VH LQFUHPHQWDQ FXDQGR HO
IiUPDFRVHDGPLQLVWUDLQFRUSRUDGRHQHULWURFLWRV
SRUWDGRUHV /D VHPLYLGD GH HOLPLQDFLyQ
HVWLPDGD SDUD ]LGRYXGLQD HQFDSVXODGD HQ
HULWURFLWRV IXH GH KRUDV IUHQWH D XQ YDORU
SDUD HVWH SDUiPHWUR GH KRUDV FXDQGR VH
DGPLQLVWUyHQIRUPDGHVROXFLyQ
1
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
$JUDGHFLPLHQWRV
(O SUHVHQWH WUDEDMR KD VLGR ILQDQFLDGR HQ HO
PDUFR GHO 3ODQ 1DFLRQDO GH ,'L UHI
3,\SRUOD-XQWDGH&DVWLOOD\/HyQUHI
6$$
Control
Eritrocitos
0
10
20
30
40
50
60
Tiempo (h)
Concentración(m g/kg)
/D(m g/kg )
)LJXUD &RQFHQWUDFLRQHV GH ]LGRYXGLQD HQ
SODVPDSDUDHOJUXSRFRQWUROƔ\HOJUXSRTXH
UHFLELy='9HQFDSVXODGDHQHULWURFLWRVŶ
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0
Control
Eritrocitos
0
10
20
30
40
50
60
Tiempo (h)
)LJXUD &RQFHQWUDFLRQHV GH ]LGRYXGLQD HQ
ED]R SDUD HO JUXSR FRQWURO Ɣ \ HO JUXSR TXH
UHFLELy='9HQFDSVXODGDHQHULWURFLWRVŶ
/DHQFDSVXODFLyQGH='9HQHULWURFLWRVSURGXFH
XQ LQFUHPHQWR HQ ODV FRQFHQWUDFLRQHV GH
IiUPDFR HQ FpOXODV IDJRFtWLFDV \ HQ WHMLGRV GHO
VLVWHPDUHWtFXORHQGRWHOLDOFRPRED]RHKtJDGR
%LEOLRJUDItD
&* 0LOOiQ 0/ 0DULQHUR $=
&DVWDxHGD -0 /DQDR 'UXJ HQ]\PH DQG
SHSWLGH GHOLYHU\ XVLQJ HU\WKURF\WHV DV FDUULHUV
-&RQWURO5HOHDVH
-0/DQDR(%ULRQHV&,&ROLQR5HFHQW
DGYDQFHV LQ GHOLYHU\ V\VWHPV IRU DQWL+,9
WKHUDS\-'UXJ7DUJHW
& *XWLpUUH] 0LOOiQ 0 $UpYDOR $
=DU]XHOR&DVWDxHGD)*/ySH]0/6D\DOHUR
-0 /DQDR (QFDSVXODWLRQ DQG LQ YLWUR
HYDOXDWLRQ RI DPLNDFLQORDGHG HU\WKURF\WHV
'UXJ'HOLYHU\
*XLGDQFHIRU,QGXVWU\%LRDQDO\WLFDO0HWKRG
9DOLGDWLRQKWWSZZZIGDJRYFYP
,;&RQJUHVRGHOD6(),*
%LRIDUPDFLD\)DUPDFRFLQpWLFD
/RV UHVXOWDGRV REWHQLGRV HQ HO HQVD\R GH
OLQHDOLGDG SHUPLWLHURQ FRPSUREDU OD H[LVWHQFLD
GH XQD EXHQD FRUUHODFLyQ HQWUH HO iUHD \ OD
FRQFHQWUDFLyQ GHQWUR GHO UDQJR GH
FRQFHQWUDFLRQHVHVWXGLDGR
/RVUHVXOWDGRVREWHQLGRVHQODSUHFLVLyQ&9\
H[DFWLWXG(UURU5HODWLYR(5LQWUDHLQWHUGtDD
OD FRQFHQWUDFLyQ DOWD PHGLD \ EDMD
VHOHFFLRQDGDV VH PXHVWUDQ HQ ODV WDEODV \ UHVSHFWLYDPHQWH
7DEOD 5HVXOWDGRV GHO HQVD\R GH SUHFLVLyQ \
H[DFWLWXGLQWUDGtD
)LJXUD 5HSUHVHQWDFLyQ JUiILFD GH OD IXQFLyQ GHO
HUURUDQDOtWLFRREWHQLGDSDUDODGHWHUPLQDFLyQGHORV
QLYHOHV SODVPiWLFRV GH FDUYHGLORO FRQ HVWH PpWRGR
DQDOtWLFR
&WHRU
&H[S
&9
(5
QJPO
QJPO
&RQFOXVLRQHV
$ OD YLVWD GH ORV UHVXOWDGRV REWHQLGRV HQ ORV
HQVD\RV GH YDOLGDFLyQ WRGRV ORV YDORUHV VH
HQFXHQWUDQ GHQWUR GH ORV DFHSWDGRV FXDQGR VH
WUDEDMD FRQ PXHVWUDV ELROyJLFDV SRU OR TXH VH
GLVSRQH GH XQD PHWyGLFD DQDOtWLFD DSWD SDUD OD
FXDQWLILFDFLyQ DGHFXDGD GH QLYHOHV SODVPiWLFRV
GH FDUYHGLORO D FRQFHQWUDFLRQHV WHUDSpXWLFDV
SURFHGHQWHVGHSDFLHQWHV
%LEOLRJUDItD
%DHN,+HWDO$UFK3KDUP5HV
7DEOD 5HVXOWDGRV GHO HQVD\R GH SUHFLVLyQ \
H[DFWLWXGLQWHUGtD
&WHRU
&H[S
&9
(5
QJPO
QJPO
5HVSHFWRDODSUHFLVLyQLQWUDGtDHO&9SUHVHQWy
VX YDORU PiV HOHYDGR SDUD OD
FRQFHQWUDFLyQ GH QJPO (Q HO HQVD\R GH
SUHFLVLyQ LQWHUGtD VH REWXYR HO PD\RU &9
SDUDODFRQFHQWUDFLyQGHQJPO
(O (5 LQWUD H LQWHUGtD SUHVHQWy XQ YDORU
Pi[LPR GH \ GH UHVSHFWLYDPHQWH DPERV SDUD OD FRQFHQWUDFLyQ
GHQJPO
/RVUHVXOWDGRVGHORVHVWXGLRVGHHVWDELOLGDGHQ
GLIHUHQWHVFRQGLFLRQHVVHHQFRQWUDURQGHQWURGH
ORVOtPLWHVHVWDEOHFLGRV
/D IXQFLyQ GHO HUURU DQDOtWLFR TXH PHMRU
UHSUHVHQWDED ORV GDWRV H[SHULPHQWDOHV VH
GHWHUPLQy HVWDGtVWLFDPHQWH PHGLDQWH UHJUHVLyQ
SROLQRPLDO /D IXQFLyQ REWHQLGD IXH OD TXH VH
LQFOX\H D FRQWLQXDFLyQ \ FX\D UHSUHVHQWDFLyQ
JUiILFDVHPXHVWUDHQOD)LJXUD
'(QJPO &
9$/,'$&,Ï1<)81&,Ï1'(/(5525'(810e72'2$1$/Ë7,&23$5$/$
021,725,=$&,Ï1'(1,9(/(63/$60È7,&26'(&$59(',/2/(13$&,(17(6&21
,168),&,(1&,$&$5'Ë$&$
$-%UD]D30RGDPLR&)/DVWUD-6HEDUURMD(/0DULxR
8QLGDGGH)DUPDFLD&OtQLFD\)DUPDFRWHUDSLDKWWSZZZXEHVIDUFOLZSKWP
'SWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD
8QLYHUVLGDGGH%DUFHORQD$Y-RDQ;;,,,VQ%DUFHORQD
TXH FRPSUHQGtD FRQFHQWUDFLRQHV GHQWUR GHO
,QWURGXFFLyQ
UDQJR QJPO 6H GHWHUPLQDURQ ORV
&DUYHGLORO HV XQ DJHQWH EORTXHDQWH β
YDORUHV GH FRQFHQWUDFLyQ H[SHULPHQWDO ODV
DGUHQpUJLFR QR VHOHFWLYR FRQ DFWLYLGDG DOID
PHGLDV\ODVGHVYLDFLRQHVHVWiQGDUHV6'GHODV
DGUHQpUJLFD
EORTXHDQWH
\
DFWLYLGDG
UHFWDV DQDOL]DGDV 3RVWHULRUPHQWH VH EXVFy OD
VLPSDWLFRPLPpWLFD QR LQWUtQVHFD 7LHQH
PHMRU IXQFLyQ HQWUH OD GHVYLDFLyQ HVWiQGDU
SURSLHGDGHV
YDVRGLODWDGRUHV
GHELGR
YDULDEOH GHSHQGLHQWH \ OD FRQFHQWUDFLyQ
SULQFLSDOPHQWHDVXDFWLYLGDGDOID&DUYHGLORO
WHyULFD GH OD FXUYD GH FDOLEUDGR YDULDEOH
KDGHPRVWUDGRVXXWLOLGDGHQHOWUDWDPLHQWRGHOD
LQGHSHQGLHQWH (O DQiOLVLV VH FRPHQ]y FRQ XQ
KLSHUWHQVLyQDUWHULDO\FRPRFRDG\XYDQWHHQHO
SROLQRPLRGHRUGHQFX\DHFXDFLyQJHQHUDOHV
WUDWDPLHQWR GH OD LQVXILFLHQFLD FDUGtDFD \ HQ OD
HQIHUPHGDGFRURQDULD
6' $$&$&$&
/RV PpWRGRV GH HVWLPDFLyQ SDUDPpWULFD HQ
HVWXGLRV
IDUPDFRFLQpWLFRV
JHQHUDOPHQWH
5HVXOWDGRV\'LVFXVLyQ
UHTXLHUHQODSRQGHUDFLyQGHORVGDWRVSULPDULRV
/D SUREOHPiWLFD GH OD HOHFFLyQ GHO PpWRGR GH
(Q OD ILJXUD VH PXHVWUD XQ FURPDWRJUDPD
SRQGHUDFLyQQRHVWiGHOWRGRUHVXHOWD\QRH[LVWH
UHSUHVHQWDWLYR GHO DQiOLVLV GH FDUYHGLORO
XQDVROXFLyQXQLYHUVDOSDUDWRGRVORVFDVRV
REWHQLGRFRQHOPpWRGRDQDOtWLFRGHVDUUROODGR
0DWHULDO\0pWRGRV
&RPR WpFQLFD DQDOtWLFD VH XWLOL]y OD
FURPDWRJUDItD OtTXLGD GH DOWD HILFDFLD HQ IDVH
UHYHUVDDFRSODGDDXQGHWHFWRUGHIOXRUHVFHQFLD
3UHYLDPHQWHDODQiOLVLVODV PXHVWUDVELROyJLFDV
VH SURFHVDURQ PHGLDQWH H[WUDFFLyQ OtTXLGR
OtTXLGR XWLOL]DQGR HQ OD SULPHUD IDVH FRPR
GLVROYHQWH pWHU HWtOLFR \ HQ OD VHJXQGD iFLGR
VXOI~ULFR0
(O DQiOLVLV FURPDWRJUiILFR VH UHDOL]y D
WHPSHUDWXUD DPELHQWH FRQ XQD FROXPQD
1XFOHRVLO & IDVH UHYHUVD μP × PP
)LJXUD &URPDWRJUDPD UHSUHVHQWDWLYR GH
3KHQRPHQH[£ \ XQD SUHFROXPQD & 2'6
FDUYHGLORODXQDFRQFHQWUDFLyQGHQJPO
2FWDGHF\O × PP 3KHQRPHQH[£ /D IDVH
PyYLO FRQVLVWLy HQ DFHWRQLWULORWDPSyQ IRVIDWR
(O WLHPSR GH UHWHQFLyQ DSUR[LPDGR GH
DMXVWDGR FRQ iFLGR IRVIyULFR D S+ \ HOXLGD
FDUYHGLOROUHVXOWyVHUGHPLQ
LVRFUiWLFDPHQWHDPOPLQ
(O SRUFHQWDMH GH H[WUDFFLyQ PHGLR GHO IiUPDFR
/DYDOLGDFLyQGHOPpWRGRDQDOtWLFRVHLQLFLy
IXH GH /RV UHVXOWDGRV GHO HQVD\R GH
FRQ HO HQVD\R GH OLQHDOLGDG 3DUD pVWH VH
OLQHDOLGDG SDUD HO UDQJR GH FRQFHQWUDFLRQHV
SUHSDUDURQYDULDVUHFWDVGHFDOLEUDGRHQSODVPD
VHOHFFLRQDGDV VH PXHVWUDQ HQ OD WDEOD GRQGH
KXPDQR SURYHQLHQWH GH GLIHUHQWHV GRQDQWHV
HOFRHILFLHQWHGHYDULDFLyQ&9VHUHILHUHDOGH
GHQWUR GHO UDQJR GH FRQFHQWUDFLRQHV
ORVIDFWRUHVUHVSXHVWD
VHOHFFLRQDGRGHQJPO
3DUDORVHQVD\RVGHSUHFLVLyQ\H[DFWLWXGLQWUDH
LQWHUGtD VH HVFRJLHURQ WUHV FRQFHQWUDFLRQHV
7DEOD 5HVXOWDGRV GHO HQVD\R GH OLQHDOLGDG GH
DOWD PHGLD \ EDMD GHQWUR GHO UDQJR GH
FDUYHGLOROHQSODVPDKXPDQR
FRQFHQWUDFLRQHV GH OD UHFWD GH FDOLEUDGR
7DPELpQ VH UHDOL]DURQ ORV HQVD\RV GH
&9
(UURUHVWiQGDU
5
)
HVWDELOLGDGFRUUHVSRQGLHQWHV
GHODSHQGLHQWH
7UDV GH OD YDOLGDFLyQ GHO PpWRGR VH FDOFXOy OD
IXQFLyQ GHO HUURU DQDOtWLFR 'XUDQWH GtDV
GLIHUHQWHV VH DQDOL]y XQD FXUYD GH FDOLEUDGR
%UD]D $- HW DO %LRPHG &KURPDWRJ 0RGDPLR 3 HW DO (Q 5 6DOD]DU (GLWRU
$QiOLVLV \ FRQWURO GH PHGLFDPHQWRV 5RPDUJUDI
/
+RVSLWDOHW GH /OREUHJDW %DUFHORQD 35(&/,1,&$/678'<2)$1(:6867$,1('5(/($6()2508/$7,212)
0253+,1(',6&5(3$1&,(6%(7:((17+(,19,752'58*5(/($6($1'7+(,1
9,92$%62537,21352),/(
$$UDtFR)7RUUHV0ROLQD-&iUFHO7UXOOROV$6DDGHGGLQ-(3HULV
'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO7HFKQRORJ\)DFXOW\RI3KDUPDF\8QLYHUVLW\RI9DOHQFLD
$YGD9$QGUpV(VWHOOpVVQ%XUMDVVRW9DOHQFLD6SDLQ
E\ PHDQV RI D FRPELQDWLRQ RI WKH UHJXODU
,QWURGXFWLRQ
WUDSH]RLGDO DQG WKH ORJDULWKPLF WUDSH]RLGDO
$ QHZ VXVWDLQHG UHOHDVH IRUPXODWLRQV RI
UXOHV 7KH PD[LPXP SODVPD PRUSKLQH
PRUSKLQH KDV EHHQ GHYHORSHG ZKLFK LQYROYHV
FRQFHQWUDWLRQ &PD[ DQG WKH WLPH WR &PD[
WKH IRUPDWLRQ RI D FRPSOH[ EHWZHHQ PRUSKLQH
7PD[ ZHUHREVHUYHG YDOXHV3KDUPDFRNLQHWLF
DQG (XGUDJLW® / DQ DFU\OLF SRO\PHU LQVROXEOH
SDUDPHWHUV RI PRUSKLQH ZHUH FRPSDUHG E\
DW ORZ S+ YDOXHV DQG VROXEOH DERYH S+ ,Q
PHDQV RI D ZD\ $129$ WHVW IDFWRUV
YLWURVWXGLHVRIWKHFRPSOH[KDYHGHPRQVWUDWHG
WUHDWPHQWGRJDQGSHULRG
WKDWPRUSKLQHUHOHDVHGHSHQGVRQWKHS+RIWKH
GLVVROXWLRQ PHGLXP 7KH SUHVHQW ZRUN
5HVXOWVDQG'LVFXVVLRQ
FRQVWLWXWHV DQ LQ YLYR SUHFOLQLFDO VWXG\ RI WKH
7KHDEVRUSWLRQDQGWKHHOLPLQDWLRQRIPRUSKLQH
VXVWDLQHG UHOHDVH IHDWXUHV RI WKH SURSRVHG QHZ
ZDV UDSLG LQ IDVWHG GRJV )LJXUH UHJDUGOHVV
PRUSKLQH(XGUDJLW®/ FRPSOH[ IRUPXODWLRQ
RI WKH NLQG RI FDSVXOH XVHG LH ILOOHG ZLWK
7KH VWXG\ KDV EHHQ FRQGXFWHG LQ GRJV
0+7 RU 0(& ,Q IDFW WKH PHDQ YDOXHV RI
FRPSDULQJWKHSODVPDFRQFHQWUDWLRQYHUVXVWLPH
SKDUPDFRNLQHWLF SDUDPHWHUV FRUUHVSRQGLQJ WR
SURILOH RI PRUSKLQH DGPLQLVWHUHG DV PRUSKLQH
ERWKIRUPXODWLRQVZHUHQRWVWDWLVWLFDOO\GLIIHUHQW
(XGUDJLW®/ FRPSOH[ ZLWK WKH SURILOH REWDLQHG
7DEOH
DIWHU WKH DGPLQLVWUDWLRQ RI PRUSKLQH DORQH
)XUWKHUPRUH VLQFH PRUSKLQH UHOHDVH IURP WKH
FRPSOH[ LV LQIOXHQFHG E\ WKH LRQLF VWUHQJWK
ERWK SURILOHV ZHUH FRPSDUHG LQ IHG DQG IDVWHG
DQLPDOV
0DWHULDOVDQG0HWKRGV
6L[ SXUSRVHEUHG EHDJOHV PDOHV DQG IHPDOHV DSSUR[LPDWHO\ RQH \HDU RI DJH ZHUH
XVHG LQ WKH H[SHULPHQWV UDQJH NJ
'RJV ZHUH DGPLQLVWHUHG ZLWK FDSVXOHV ILOOHG
ZLWK PJ RI PRUSKLQH K\GURFKORULGH
WULK\GUDWH 0+7 RU PJ RI PRUSKLQH
(XGUDJLW®FRPSOH[0(&HTXLYDOHQWWRPJ
RI PRUSKLQH K\GURFKORULGH WULK\GUDWH ,Q VWXG\
, GRJV ZHUH IDVWHG RYHUQLJKW DQG WKH FDSVXOHV
FRQWDLQLQJ 0+7 RU 0(& ZHUH DGPLQLVWHUHG DW
DP XVLQJ D WZRSHULRG FURVVRYHU GHVLJQ
ZLWKDZDVKRXWSHULRGRIRQHZHHN,QVWXG\,,
GRJV ZHUH FRQGLWLRQHG WR HDW RQFH D GD\
)LJXUH 0HDQ PRUSKLQH SODVPD
EHWZHHQ DQG DP GXULQJ VHYHUDO
FRQFHQWUDWLRQV REWDLQHG LQ IDVWHG GRJV Q GD\V2QWKHGD\RIWKHDGPLQLVWUDWLRQRI0+7
DIWHU RUDO DGPLQLVWUDWLRQ RI RQH FDSVXOH
RU0(&GRJVZHUHDOORZHGWRHDWQRUPDOO\DQG
FRQWDLQLQJ 0+7 ο RU 0(& • 6WDQGDUG
WKH GUXJ ZDV DGPLQLVWHUHG DW DP
GHYLDWLRQ EDUV KDYH QRW EHHQ UHSUHVHQWHG WR
DFFRUGLQJWRWKHVDPHH[SHULPHQWDOGHVLJQXVHG
LPSURYHILJXUHFODULW\
LQVWXG\,
%ORRG VDPSOHV ZHUH ZLWKGUDZQ WKURXJK D
:KHQ0+7DQG0(&ZHUHDGPLQLVWHUHGWRIHG
FDWKHWHU SODFHG LQ WKH FHSKDOLF YHLQ XQWLO DQLPDOV WKH PHDQ SODVPD PRUSKLQH
PLQDIWHUGRVLQJDQGSODFHGLQKHSDULQL]HGWXEHV
FRQFHQWUDWLRQV ZHUH DJDLQ VLPLODU IRU ERWK
WRREWDLQSODVPD0RUSKLQHZDVH[WUDFWHGIURP
IRUPXODWLRQV )LJXUH ZLWKRXW VWDWLVWLFDOO\
SODVPD VDPSOHV ZLWK FKORURIRUPLVRSURSDQRO
VLJQLILFDQW GLIIHUHQFHV LQ WKH SKDUPDFRNLQHWLF
YY DQG TXDQWLILHG E\ +3/& ZLWK 89
SDUDPHWHUVRIPRUSKLQH7DEOH
GHWHFWLRQ
7KH DUHD XQGHU WKH SODVPD PRUSKLQH
FRQFHQWUDWLRQYHUVXVWLPHFXUYHIURPWLPH]HUR
WR WKH ODVW WLPH ZLWK D GHWHFWDEOH FRQFHQWUDWLRQ
RIPRUSKLQHSDUWLDODUHD$8&SZDVHVWLPDWHG
,;&RQJUHVRGHOD6(),*
7DEOH 3KDUPDFRNLQHWLF SDUDPHWHUV RI
PRUSKLQHPHDQ ±6'REWDLQHGLQIDVWHGGRJV
Q 3DUDPHWHU
0+7
0(&
&PD[QJPO
±
±D
7PD[PLQ
±
±D
$8&S
± ±D
QJPLQPO
D
6WDWLVWLFDOO\ QRW GLIIHUHQW IURP PHDQ YDOXH
REWDLQHGZLWK0+7
)LJXUH 0HDQ PRUSKLQH SODVPD
FRQFHQWUDWLRQV REWDLQHG LQ IHG GRJV Q DIWHU RUDO DGPLQLVWUDWLRQ RI RQH FDSVXOH
FRQWDLQLQJ0+7οRU0(&•
7DEOH 3KDUPDFRNLQHWLF SDUDPHWHUV RI
PRUSKLQHPHDQ ±6'REWDLQHGLQIHGGRJVQ
3DUDPHWHU
0+7
0(&
±D
&PD[QJPO
±
7PD[PLQ
± ±D
$8&S
± ±D
QJPLQPO
D
6WDWLVWLFDOO\ QRW GLIIHUHQW IURP PHDQ YDOXH
REWDLQHGZLWK0+7
$OO WKLV LQGLFDWHV WKDW WKH FRPSOH[ 0(& LV
XQDEOH WR DIIRUG VXVWDLQHG UHOHDVH RI PRUSKLQH
LQ YLYR 7KHVH UHVXOWV FRQWUDVW ZLWK WKRVH
REWDLQHGLQYLWUR$OYDUH])XHQWHVHWDO
DQG VXJJHVWV WKH OLPLWHG XVHIXOQHVV RI LQ YLWUR
DVVD\V IRU WKLV NLQG RI VXVWDLQHG UHOHDVH
IRUPXODWLRQVLQZKLFKS+DQGLRQLFVWUHQJWKDUH
LPSRUWDQW IDFWRUV LQ GUXJ UHOHDVH IURP WKH
SRO\PHULFVWUXFWXUH
7KH DGPLQLVWUDWLRQ RI 0+7 DQG 0(& WR IHG
GRJV JDYH ULVH WR SODVPD PRUSKLQH
FRQFHQWUDWLRQV ORZHU WKDQ WKRVH REWDLQHG LQ
IDVWHGGRJVWKRXJKWKHSODVPDPRUSKLQHOHYHOV
ZHUHGHWHFWDEOHIRUDORQJHUWLPHXSWRKRXUV
DIWHU GRVLQJ ILJXUH 7KH SDUWLDO DUHD XQGHU
WKH SODVPD PRUSKLQH FRQFHQWUDWLRQV $8&S
ZDV VOLJKWO\ ODUJHU LQ IHG GRJV WKDQ LQ IDVWHG
DQLPDOVIRUERWKPRUSKLQHIRUPXODWLRQVWKRXJK
WKHGLIIHUHQFHVZHUHQRWVWDWLVWLFDOO\VLJQLILFDQW
7KH DSSDUHQWO\ SURORQJHG DEVRUSWLRQ RI
PRUSKLQH LQ IHG GRJV FRXOG EH GXH WR WKH
SUHVHQFH RI IRRG LQ WKH JDVWURLQWHVWLQDO WUDFW
ZKLFKGHFUHDVHVWKHPRUSKLQHGLIIXVLRQUDWHEXW
DOVRWRWKHHQWHURKHSDWLFUHF\FOLQJRIWKHGUXJDV
D FRQVHTXHQFH RI IRRGLQGXFHG JDOOEODGGHU
HPSW\LQJ ,Q IDFW PRUSKLQH JOXFXURQLGHV DUH
WKHPDLQPRUSKLQHPHWDEROLWHVLQUDWVGRJVDQG
KXPDQV DQG IROORZLQJ ELOLDU\ H[FUHWLRQ
WKH\ FRXOG EH K\GURO\VHG EDFN WR WKH SDUHQW
FRPSRXQGDQGUHDEVRUEHGIURPWKHLQWHVWLQH
&RQFOXVLRQV
,Q YLWUR GLVVROXWLRQ DVVD\V FDQ EH RI OLPLWHG
XVHIXOQHVV IRU VXVWDLQHG UHOHDVH IRUPXODWLRQV LQ
ZKLFK S+ DQG LRQLF VWUHQJWK DUH LPSRUWDQW
IDFWRUV LQ GUXJ UHOHDVH IURP WKH SRO\PHULF
VWUXFWXUH
5HIHUHQFHV
$OYDUH])XHQWHV-HWDO'UXJ'HY,QG
3KDUP
)HUQiQGH]$UpYDOR0HWDO673
6FLHQFHV
-DFT](HWDO'UXJ0HWDE'LVSRV
2XHOOHW'0HWDO'UXJ0HWDE'LVSRV
*RXUOD\*.HWDO&OLQ3KDUPDFRNLQHW
$FNQRZOHGJHPHQWV
7KLVZRUNLVSDUWRIDUHVHDUFKSURMHFWVXSSRUWHG
E\ D JUDQW IURP WKH &RPLVLyQ ,QWHUPLQLVWHULDO
GH &LHQFLD \ 7HFQRORJtD &,&<7
RI WKH
0LQLVWU\RI(GXFDWLRQDQG&XOWXUHRI6SDLQDQG
WKH(XURSHDQ&RPLVVLRQ)'&
FARMACIA CLÍNICA Y FARMACOTERAPIA
)DUPDFLD&OLQLFD\)DUPDFRWHUDSLD
0(',&$0(1726%,26,0,/$5(6
5(48(5,0,(1726'()$50$&29,*,/$1&,$<*(67,Ï1'(5,(6*26
/=~xLJD%&DOYR
/DERUDWRULRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGHO3DtV9DVFR
3ž8QLYHUVLGDG9LWRULD
,QWURGXFFLyQ
8QPHGLFDPHQWRELRVLPLODUQRSXHGHDSUREDUVH
HQ EDVH D ORV PLVPRV UHTXHULPLHQWRV TXH VH
H[LJHQ SDUD XQ IiUPDFR JHQpULFR VLQR TXH HV
SUHFLVR UHDOL]DU HQVD\RV FOtQLFRV GHVWLQDGRV D
HVWDEOHFHU VX HILFDFLD \ VHJXULGDG HQ XQD
LQGLFDFLyQ GHILQLGD DVt FRPR GHVDUUROODU XQ
SURJUDPD GH IDUPDFRYLJLODQFLD \ JHVWLyQ GH
ULHVJRVGHVSXpVGHVXFRPHUFLDOL]DFLyQ
(O ODERUDWRULR VROLFLWDQWH GHEH SUHVHQWDU D OD
$JHQFLD (XURSHD GH (YDOXDFLyQ GH
0HGLFDPHQWRV (0($ HO PHQFLRQDGR SODQ GH
JHVWLyQ GH ULHVJRV \ HO SURJUDPD GH
IDUPDFRYLJLODQFLD MXQWR FRQ OD VROLFLWXG GH
DXWRUL]DFLyQGHOSURGXFWRELRVLPLODULQFOX\HQGR
XQD GHVFULSFLyQ GH ORV LQFLGHQWHV GH VHJXULGDG
TXH SXHGDQ GHULYDUVH GH ODV GLIHUHQFLDV
H[LVWHQWHVHQHOSURFHVRGHIDEULFDFLyQUHVSHFWR
DOPHGLFDPHQWRGHUHIHUHQFLD(ODVSHFWRGH
VHJXULGDGPiVLPSRUWDQWHDWHQHUHQFXHQWDHVOD
LQPXQRJHQLFLGDG
&RQVLGHUDFLRQHV UHVSHFWR DO SURFHVR GH
IDEULFDFLyQ
/D QHFHVLGDG GH UHIRU]DU OD IDUPDFRYLJLODQFLD
HQORVELRIiUPDFRVVHKL]RPiVHYLGHQWHWUDVHO
SUREOHPD REVHUYDGR HQ DOJXQRV SDFLHQWHV TXH
KDEtDQ UHFLELGR XQD HULWURSR\HWLQD LQQRYDGRUD
(SUH[Š TXH SUHVHQWDURQ $SODVLD (ULWURFLWDULD
3XUD (VWH HIHFWR DGYHUVR QR KDEtD VLGR
GHWHFWDGR HQ ORV HQVD\RV FOtQLFRV GXUDQWH HO
GHVDUUROOR GHO SURGXFWR GHELGR D TXH VX
LQFLGHQFLD HV H[WUDRUGLQDULDPHQWH EDMD SRU
(OORIXHGHELGRD XQOLJHURFDPELRHQ
HO SURFHVR GH SURGXFFLyQ GH HVWD HSRHWLQD DOID
HO XVR XQ QXHYR HVWDELOL]DQWH XWLOL]DGR HQ OD
IRUPXODFLyQ GHO SURGXFWR LQWHUDFFLRQy FRQ ORV
WDSRQHV GH JRPD GHO HQYDVH TXH FHGLHURQ
DOJXQRV FRPSRQHQWHV TXH VH WUDGXMR HQ HO
GHVDUUROORGHDQWLFXHUSRVQHXWUDOL]DQWHV QRVROR
SDUD HO PHGLFDPHQWR VLQR WDPELpQ SDUD OD
HULWURSR\HWLQD HQGyJHQD HQ DOJXQRV SDFLHQWHV
6L ORV SURGXFWRV ELRVLPLODUHV VH IDEULFDQ
XWLOL]DQGRXQSURFHVRWRWDOPHQWHGLIHUHQWHDOGHO
IiUPDFRGHUHIHUHQFLDSUREDEOHPHQWHGHQOXJDU
D GLIHUHQFLDV HVWUXFWXUDOHV \ ELRTXtPLFDV HQ OD
PROpFXOD SRU OR TXH QR SXHGH JDUDQWL]DUVH VX
VHJXULGDG VLQ OOHYDU D FDER HVWXGLRV FOtQLFRV
DPSOLRV
3XQWRV FODYH HQ HO SHULRGR GH SRVW
FRPHUFLDOL]DFLyQ GH PHGLFDPHQWRV ELR
VLPLODUHV
/RV SULQFLSDOHV DVSHFWRV D FRQVLGHUDU HQ OD
VHJXULGDGGHORVPHGLFDPHQWRVELRVLPLODUHVXQD
YH]FRPHUFLDOL]DGRVVRQORVVLJXLHQWHV
3ODQHVGHJHVWLyQGHULHVJRV
/DV GLUHFWULFHV &+03 GH OD (0($ VREUH
ELRVLPLODUHV H[SOLFDQ TXH ORV GDWRV GH ORV
HQVD\RV FOtQLFRV SUHYLRV D VX DXWRUL]DFLyQ
QRUPDOPHQWH VRQ LQVXILFLHQWHV SDUD LGHQWLILFDU
ODV SRVLEOHV GLIHUHQFLDV FRQ HO SURGXFWR GH
UHIHUHQFLD 3RU OR WDQWR OD VHJXULGDG FOtQLFD GH
ORV ELRVLPLODUHV GHEH PRQLWRUL]DUVH PX\ GH
FHUFDGXUDQWHODIDVHGHSRVWFRPHUFLDOL]DFLyQ\
GHEH UHDOL]DUVH XQD HYDOXDFLyQ FRQWLQXD GHO
EDODQFHULHVJREHQHILFLR
(OREMHWLYRGHEHVHUFDUDFWHUL]DU\FXDQWLILFDUHO
ULHVJRSDUDORVFRPSXHVWRVQXHYRVRFRPSUREDU
TXH HO ULHVJR GH OD SURWHtQD ELRVLPLODU QR HV
PD\RUTXHHOGHOSURGXFWRGHUHIHUHQFLD
/RV SODQHV GH JHVWLyQ GH ULHVJRV SDUD XQ
ELRVLPLODUGHEHQFHQWUDUVHHQ
ƒ 5HIRU]DUODVPHGLGDVGHIDUPDFRYLJLODQFLD
ƒ 3ODQLILFDU FyPR LGHQWLILFDU HO ULHVJR GH
LQPXQRJHQLFLDGDG SpUGLGD VHFXQGDULD GH
HIHFWR HQ SDFLHQWHV QDLYH FXDOTXLHU SpUGLGD
GHHIHFWRHQSDFLHQWHVQRQDLYHHYLGHQFLDGH
OD SUHVHQFLD GH DQWLFXHUSRV QHXWUDOL]DQWHV
DQiOLVLVGHDQWLFXHUSRVHWF
ƒ ,PSOHPHQWDUXQVLVWHPDHVSHFLDOGHYLJLODQFLD
SRVWFRPHUFLDOL]DFLyQ
)DUPDFRYLJLODQFLD
/DVGLUHFWULFHVGHO&RPLWpGH0HGLFDPHQWRVGH
8VR+XPDQRGHOD(0($&+03HQIDWL]DQOD
QHFHVLGDG GH SUHVWDU HVSHFLDO DWHQFLyQ D OD
IDUPDFRYLJLODQFLD HVSHFLDOPHQWH SDUD GHWHFWDU
HIHFWRVDGYHUVRVVHULRV\UDURV
/RVSXQWRVDFRQVLGHUDUVRQ
ƒ /RV VLVWHPDV GH IDUPDFRYLJLODQFLD GHEHQ
GLIHUHQFLDU HQWUH HO SURGXFWR LQQRYDGRU \ HO
ELRVLPLODUGHWDOIRUPDTXHORVHIHFWRVGHORV
ELRVLPLODUHVQRVHSLHUGDQHQORVLQIRUPHVGH
ORVSURGXFWRVGHUHIHUHQFLD
ƒ $VHJXUDUODWUD]DELOLGDG
,;&RQJUHVRGHOD6(),*
6XVWLWXFLyQ GH PHGLFDPHQWRV '&, 'HQRPL
QDFLRQHV&RPXQHV,QWHUQDFLRQDOHV
/DV 'HQRPLQDFLRQHV &RPXQHV ,QWHUQDFLRQDOHV
'&, R QRPEUHV JHQpULFRV LGHQWLILFDQ ODV
VXVWDQFLDV IDUPDFpXWLFDV R SULQFLSLRV DFWLYRV
&DGDSURGXFWRJHQpULFRWLHQHXQ~QLFRQRPEUH
TXHHVUHFRQRFLGRJOREDOPHQWH\HVGHGRPLQLR
S~EOLFR
(O SURSyVLWR GHO SURJUDPD '&, HV DVLJQDU
QRPEUHV JHQpULFRV VHOHFFLRQDGRV SRU OD
2UJDQL]DFLyQ0XQGLDOGHOD 6DOXG206DODV
VXVWDQFLDV IDUPDFpXWLFDV SDUD TXH FDGD XQD
SXHGD UHFRQRFHUVH JOREDOPHQWH /RV '&,V
WDPELpQ IRUPDQ SDUWH HVHQFLDO GHO SURFHVR
UHJXODWRULRHQPXFKRVSDtVHVGRQGHVHUHTXLHUH
XQQRPEUHJHQpULFRSDUDODOLFHQFLD
/D 206 QR HYDO~D GDWRV GH FRPSDUDELOLGDG \
SRU WDQWR QR SXHGH DVLJQDU XQ '&, D XQ
ELRVLPLODU VLQ OD DXWRUL]DFLyQ SUHYLD GH ODV
DXWRULGDGHV /D HYDOXDFLyQ \ DSUREDFLyQ GH ORV
ELRVLPLODUHV GHEH UHDOL]DUVH GH PDQHUD
LQGHSHQGLHQWH DO SURFHVR GH DVLJQDFLyQ GH
QRPHQFODWXUDGHOD206
(OWpUPLQR³ELROyJLFR´HVXQFRQFHSWRFLHQWtILFR
PLHQWUDV TXH ³ELRVLPLODU´ VLJQLILFD XQD UXWD
UHJXODWRULD\OHJDOSDUDODDXWRUL]DFLyQ\ORVGRV
GHEHQ GLIHUHQFLDUVH FODUDPHQWH 3RU WDQWR VH
UHFRPLHQGD QR LQFOXLU QLQJXQD GLVWLQFLyQ TXH
LQGLTXH HO WpUPLQR UHJXODWRULR ELRVLPLODU HQ HO
'&,SDUDHVWRVSURGXFWRV'HKHFKRVHSURSRQH
TXH OD SROtWLFD VREUH '&, GH QRPHQFODWXUD GH
ORV ELRVLPLODUHV VHD OD PLVPD TXH OD GH ORV
SURGXFWRVELROyJLFRVRULJLQDOHV
/D DVLJQDFLyQ GH ORV '&,V GHEH VHU
LQGHSHQGLHQWH GHO SURFHVR UHJXODWRULR R GH ODV
FRQVLGHUDFLRQHV VREUH OD VXVWLWXFLyQ GH
PHGLFDPHQWRV HQ OD SUHVFULSFLyQ PpGLFD R GHO
XVR GH '&,V HQ IDUPDFRYLJLODQFLD $ SHVDU GH
VHUFRQRFLGRTXHORV'&,VVRQGHJUDQ XWLOLGDG
HQ IDUPDFRYLJLODQFLD QR GHEHQ VHU HO ~QLFR
PHGLR GH LGHQWLILFDFLyQ GHO SURGXFWR R HO
LQGLFDGRU ~QLFR SDUD OD VXVWLWXFLyQ GH
PHGLFDPHQWRVHQHOFDVRGHORVELRVLPLODUHV/D
WUD]DELOLGDGGHSHQGHGH P~OWLSOHVIDFWRUHV'&,
IDEULFDQWH Q~PHUR GH ORWH VLVWHPD GH
IDUPDFRYLJLODQFLDELHQGHILQLGRUHTXLVLWRVSRVW
FRPHUFLDOL]DFLyQ GH LQIRUPDFLyQ VREUH
DFRQWHFLPLHQWRV DGYHUVRV HWF \ OD VXVWLWXFLyQ
GHEH VHU UHVSRQVDELOLGDG GH OD DXWRULGDG
UHJXODWRULD QDFLRQDO \ EDVDUVH HQ GDWRV
FLHQWtILFRV\FOtQLFRVDSURSLDGRV
&RQFOXVLRQHV
/RV PHGLFDPHQWRV ELRVLPLODUHV SXHGHQ DSRUWDU
EHQHILFLRV LPSRUWDQWHV SHUR QR VLQ ULHVJR
DxDGLGR(OXVRGHHVWRVSURGXFWRVSURSRUFLRQD
OD RSRUWXQLGDG GH PHMRUDU HO VLVWHPD GH
IDUPDFRYLJLODQFLD H LPSOHPHQWDU XQD PHWR
GRORJtDHIHFWLYDHQODSUiFWLFDFOtQLFD
8Q SURJUDPD GH IDUPDFRYLJLODQFLD HV HVHQFLDO
HQ OD XWLOL]DFLyQ GH ORV ELRVLPLODUHV GHELGR D
TXHHVGLItFLOSUHGHFLUODVFRQVHFXHQFLDVFOtQLFDV
GH ORV FDPELRV DSDUHQWHPHQWH LQRFXRV HQ VX
SURFHVR GH IDEULFDFLyQ DVt FRPR DO YDFtR GH
LQIRUPDFLyQFLHQWtILFDH[LVWHQWH
(V HVHQFLDO GLVSRQHU GH XQD LQIRUPDFLyQ
H[KDXVWLYD GH ORV SDFLHQWHV OD FXiO GHEH
UHFRJHUVH HQ XQD EDVH GH GDWRV QDFLRQDO
,PSOHPHQWDU HVWH VRILVWLFDGR HVTXHPD GH
IDUPDFRYLJLODQFLD HV FRPSOHMR \ FRVWRVR \ SRU
WDQWR QR HVWi DO DOFDQFH GH OD PD\RUtD GH ORV
ODERUDWRULRVIDEULFDQWHVGHELRVLPLODUHV
'HELGR D ODV H[LJHQFLDV HVSHFLDOHV ORV
IDEULFDQWHV GH ELRVLPLODUHV GHEHQ LQYHUWLU PiV
GH OR QHFHVDULR HQ ORV PHGLFDPHQWRV JHQpULFRV
WUDGLFLRQDOHV SRU OR TXH OD JUDQ UHGXFFLyQ GH
SUHFLRV TXH QRUPDOPHQWH VH REVHUYD FRQ ODV
SHTXHxDV PROpFXODV JHQpULFDV GH VtQWHVLV
TXtPLFD QR VH REVHUYDUi HQ ORV SURGXFWRV
ELRVLPLODUHV
5HIHUHQFLDV
$
'RPtQJXH]*LO
%LRWHFQROyJLFRV
FDUDFWHUtVWLFDV
,1(60(0DGULG
0HGLFDPHQWRV
GLIHUHQFLDOHV
% $ /LDQJ 5HJXODWLQJ )ROORZ2Q %LRORJLFV
+DUYDUG-/HJLVO
,&0DFGRXJDOO$QWLERG\PHGLDWHGSXUHUHGFHOO
DSODVLD 35&$ HSLGHPLRORJ\ ,PPXQRJHQLFLW\ DQG
ULVNV 1HSKURO 'LDO 7UDQVSODQW 6XSSO 6'5RJHU$0LNKDLO%LRVLPLODUV2SSRUWXQLW\
RU &DXVH IRU &RQFHUQ - 3KDUP 3KDUPDFHXW 6FL
9ROXPH $ RI WKH 5XOHV *RYHUQLQJ 0HGLFLQDO
3URGXFWV LQ WKH (XURSHDQ 8QLRQ *XLGHOLQHV RQ
3KDUPDFRYLJLODQFH IRU 0HGLFLQDO 3URGXFWV IRU
+XPDQ
8VH
0DUFK
KWWSHFHXURSDHXHQWHUSULVHSKDUPDFHXWLFDOVHXGUDO
H[HXGUDOH[BHQKWP
:+2 ,QIRUPDO &RQVXOWDWLRQ RQ ,QWHUQDWLRQDO
1RQSURSULHWDU\ 1DPHV ,11 3ROLF\ IRU
%LRVLPLODU 3URGXFWV :+2 *HQHYD KWWS
ZZZZKRLQWPHGLFLQHVVHUYLFHVLQQ%LRVLPLODUV,11
B5HSRUWSGI
)DUPDFLD&OLQLFD\)DUPDFRWHUDSLD
(92/8&,Ï1'(/$,19(67,*$&,Ï1&/Ë1,&$5($/,=$'$(1(/(67$'2(63$f2/
'(6'(/$3(563(&7,9$'(81$&52
%1LFROiV30RGDPLR&)/DVWUD(/0DULxR
&52'\QDPLF6ROXWLRQV6/&6DQW$QWRQL0D&ODUHW%DUFHORQD
8QLGDGGH)DUPDFLD&OtQLFD\)DUPDFRWHUDSLD'SWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD
$Y-RDQ;;,,,VQ%DUFHORQDKWWSZZZXEHVIDUFOLZSKWP
5HVXOWDGRV\'LVFXVLyQ
(Q LQYHVWLJDFLyQ FOtQLFD H[LVWHQ GRV JUDQGHV
JUXSRV GH HVWXGLRV ORV H[SHULPHQWDOHV \ ORV
REVHUYDFLRQDOHV /RVHQVD\RVFOtQLFRV(&VRQ
HVWXGLRV H[SHULPHQWDOHV TXH VHJ~Q OD IDVH GH
GHVDUUROOR FOtQLFR GHO PHGLFDPHQWR VH
FODVLILFDQ HQ (& GH IDVH , ,, ,,, \ ,9 R SRVW
DXWRUL]DFLyQ /RV HVWXGLRV REVHUYDFLRQDOHV VRQ
HVWXGLRVSRVWDXWRUL]DFLyQ(3$\SRUWDQWRVH
UHDOL]DQ VHJ~Q ODV FRQGLFLRQHV GH XVR
HVWDEOHFLGDV
HQ
OD
DXWRUL]DFLyQ
GH
FRPHUFLDOL]DFLyQ
'HDFXHUGRFRQHO5'GHGHIHEUHUR
SRU HO TXH VH UHJXODQ ORV HQVD\RV FOtQLFRV FRQ
PHGLFDPHQWRV
XQD
RUJDQL]DFLyQ
GH
LQYHVWLJDFLyQ SRU FRQWUDWR R ³FRQWUDFW UHVHDUFK
RUJDQL]DWLRQ´ &52 HV XQD SHUVRQD ItVLFD R
MXUtGLFDFRQWUDWDGDSRUHOSURPRWRUSDUDUHDOL]DU
IXQFLRQHV R GHEHUHV GHO SURPRWRU HQ UHODFLyQ
FRQ HO (& /DV &52 DSRUWDQ UHFXUVRV QR
VRORHQODJHVWLyQGH(&VLQRHQJHQHUDOGHOD
LQYHVWLJDFLyQELRPpGLFD
(O REMHWLYR SULQFLSDO GHO HVWXGLR IXH DQDOL]DU OD
HYROXFLyQ GH OD LQYHVWLJDFLyQ FOtQLFD UHDOL]DGD
HQHOHVWDGRHVSDxROGHVGHODSHUVSHFWLYDGHXQD
&52
(O Q~PHUR WRWDO GH HVWXGLRV GH LQYHVWLJDFLyQ
FOtQLFDUHJLVWUDGRVHQOD&52GXUDQWHHOSHULRGR
IXHGH(QOD)LJXUDVHPXHVWUDQ
ORVHVWXGLRVFODVLILFDGRV\VXSUHYDOHQFLD
/RV (& FRQ PiV SDFLHQWHV \ FRQ PiV FHQWURV
IXHURQ ORV GH IDVH ,9 &RQ UHODFLyQ D ORV
HVWXGLRV REVHUYDFLRQDOHV ORV (3$SURV IXHURQ
ORV TXH WXYLHURQ PHQRU Q~PHUR GH SDFLHQWHV \
FHQWURVGHUHFOXWDPLHQWRSUREDEOHPHQWHGHELGR
D VX HVWULFWD OHJLVODFLyQ FRQ REMHWR GH LPSHGLU
OD UHDOL]DFLyQ GH HVWXGLRV GH LQGXFFLyQ D OD
SUHVFULSFLyQ\GHPDUNHWLQJ
(Q OD )LJXUD VH UHSUHVHQWDQ ODV iUHDV
WHUDSpXWLFDV FXELHUWDV HQ IXQFLyQ GHO WLSR GH
HVWXGLRFOtQLFR
N º e s t u d io s s e g ú n á r e a te r a p é u tic a
,QWURGXFFLyQ
,;&RQJUHVRGHOD6(),*
Ensayo Clínico (EC)
18%
25%
EPA prospectivo
(EPApros)
EPA transversal /
retrospectivo
(EPAtrans / retros)
12%
INFECCIOSAS
CARDIOVASCULAR
CARDIOLOGÍA
20
NEFROLOGÍA
HEMATOLOGÍA
15
UROLOGÍA
ENDOCRINOLOGÍA
10
NEUROLOGÍA
ALERGOLOGÍA
5
GINECOLOGÍA
0
PSIQUIATRÍA
EC
EPApros
EPAtrans/retros
EPI
CC
'HVGHODSHUVSHFWLYDGHOD&52VHREVHUYyXQD
WHQGHQFLD
FODUD
KDFLD
ORV
HVWXGLRV
REVHUYDFLRQDOHVHQGHWULPHQWRGHORV(&
/RV HVWXGLRV REVHUYDFLRQDOHV VH
FRQVWLWX\HQHQXQDKHUUDPLHQWDSURGXFWLYDSDUD
OD LQGXVWULD IDUPDFpXWLFD WDQWR SRU PRWLYRV GH
PDUNHWLQJ FRQWDFWR FRQ PpGLFRV SURPRFLyQ
GHO XVR GH GHWHUPLQDGRV PHGLFDPHQWRV HWF
FRPRFRQHOREMHWRGHFRQWLQXDUODLQYHVWLJDFLyQ
GH XQ PHGLFDPHQWR \D FRPHUFLDOL]DGR
IDUPDFRYLJLODQFLD SREODFLRQHV HVSHFLDOHV
FDOLGDGGHYLGDHWF
(QOD)LJXUDVHUHSUHVHQWDHOQ~PHURWRWDOGH
FHQWURV \ VXMHWRV SDUWLFLSDQWHV HQ IXQFLyQ GHO
WLSRGHLQYHVWLJDFLyQFOtQLFD
TRAUMATOLOGÍA
OTRAS
)LJXUD ÈUHDV WHUDSpXWLFDV HQ IXQFLyQ GHO WLSR GH
HVWXGLR
2QFRORJtD IXH HO iUHD WHUDSpXWLFD SUHGRPLQDQWH
HQ ORV (& (Q ORV HVWXGLRV REVHUYDFLRQDOHV
GHVWDFDURQODViUHDVGHRQFRORJtDHQIHUPHGDGHV
LQIHFFLRVDV WUDQVSODQWHV HQGRFULQRORJtD \
FDUGLRYDVFXODU
&RQFOXVLRQHV
'HVGH OD SHUVSHFWLYD GH OD &52 \ GXUDQWH HO
SHULRGR HVWXGLDGR VH REVHUYy XQ
DXPHQWR GH ORV HVWXGLRV REVHUYDFLRQDOHV HQ
GHWULPHQWRGHORV(&
(ORUJDQLVPRSURPRWRUSULQFLSDOGHORVHVWXGLRV
GH OD &52 IXH OD LQGXVWULD IDUPDFpXWLFD
GLULJLHQGR VX LQYHUVLyQ KDFLD ORV HVWXGLRV
REVHUYDFLRQDOHV \ HQ iUHDV WHUDSpXWLFDV GH
PD\RU LQFLGHQFLD HQ ORV ~OWLPRV DxRV
RQFRORJtD
HQIHUPHGDGHV
LQIHFFLRVDV
WUDVSODQWHVHQGRFULQRORJtD\FDUGLRYDVFXODU
/RV HVWXGLRV REVHUYDFLRQDOHV VRQ HQ OD
DFWXDOLGDG XQ LQVWUXPHQWR DPSOLDPHQWH
XWLOL]DGR SDUD VHJXLU SRWHQFLDQGR HO GHVDUUROOR
FOtQLFR GH XQ PHGLFDPHQWR WUDV VX
FRPHUFLDOL]DFLyQ
%LEOLRJUDItD
ÈOYDUH]'DUGHW & HW DO 0HG &OLQ %DUF
5'GHGHIHEUHURSRUHOTXHVH
UHJXODQORVHQVD\RVFOtQLFRVFRQPHGLFDPHQWRV
%2(Q~PGHIHEUHURGH
$ODPL 0 HW DO (Q (O HQVD\R FOtQLFR HQ
(VSDxD6HFFLyQ,9&DStWXOR
/D GLVWULEXFLyQ GHO WLSR GH LQYHVWLJDFLyQ FOtQLFD
HQ OD TXH SDUWLFLSy OD &52 GXUDQWH ORV FLQFR
DxRVGHHVWXGLRVHPXHVWUDHQOD)LJXUD
42
40
38
36
34
32
30
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
Nº de estudios
Casos Clínicos (CC)
)LJXUD 7LSRV \ SUHYDOHQFLD GH HVWXGLRV GH
LQYHVWLJDFLyQ FOtQLFD UHJLVWUDGRV HQ OD &52 GXUDQWH
HOSHULRGR
(VWXGLR WUDQVYHUVDO GHVFULSWLYR VREUH ORV
HVWXGLRV GH LQYHVWLJDFLyQ FOtQLFD HQFDUJDGRV D
XQD&52GHOHVWDGRHVSDxROGXUDQWHHOSHULRGR
/DVIXHQWHVGHREWHQFLyQGHORVGDWRV
IXHURQORVDUFKLYRV\ODSURSLDEDVHGHGDWRVGH
OD&52
/DVYDULDEOHVGHOHVWXGLRIXHURQWLSRGHHVWXGLR
iUHD WHUDSpXWLFD Q~PHUR GH FHQWURV \ VXMHWRV
SDUWLFLSDQWHV GXUDFLyQ HYROXFLyQ GHO Q~PHUR
HQHOWLHPSR\RUJDQLVPRSURPRWRU
6H GLVHxy XQD EDVH GH GDWRV HQ OD TXH VH
UHFRJLy LQIRUPDFLyQ VREUH FDGD XQR GH ORV
HVWXGLRV OOHYDGRV D FDER HQ HO SHULRGR
HVWDEOHFLGR
/RV WLSRV GH HVWXGLRV VH FODVLILFDURQ HQ (& \
GHQWURGHpVWRVHQIDVH,,,,,,y,9\HVWXGLRV
REVHUYDFLRQDOHV \ GHQWUR GH pVWRV SRVW
DXWRUL]DFLyQ SURVSHFWLYR (3$SURV SRVW
DXWRUL]DFLyQ UHWURVSHFWLYR (3$UHWURV SRVW
DXWRUL]DFLyQWUDQVYHUVDO(3$WUDQVFDVRV
FOtQLFRV && \ RWURV HVWXGLRV HSLGHPLROyJLFRV
(3,
ONCOLOGÍA
25
Tipos de estudios
38%
0DWHULDO\0pWRGRV
TRASPLANTE
30
Epidem iológico (EPI)
7%
35
EC
EPApros
EPAtrans /retros
EPI
CC
2003
2004
2005
2006
2007
2008
Año
)LJXUD 'LVWULEXFLyQ GHO WLSR GH HVWXGLR FOtQLFR
GXUDQWHORVDxRVDO
70
60
50
% Centros
%
40
% Pacientes
30
% Estudios
20
10
os
EP
I
so
s
Clí
n ic
EP
Ap
ro
s
an
s/r
etr
os
EP
Ca
A tr
EC
0
Tipo de estudio
)LJXUD 1~PHUR GH FHQWURV \ VXMHWRV SDUWLFLSDQWHV
HQIXQFLyQGHOWLSRGHLQYHVWLJDFLyQFOtQLFD
(OQ~PHURWRWDOGHHVWXGLRVHQORVTXHSDUWLFLSy
OD&52HQWUHORVDxRVDOIXHGH
\ UHVSHFWLYDPHQWH IXH
HODxRHQHOTXHWXYRPD\RUQ~PHURGHHVWXGLRV
FXDQWLILFiQGRVHXQWRWDOGHREVHUYDFLRQDOHV\
(& GHVWDFy SRU HO LQFUHPHQWR GHO
Q~PHURGH&&TXHVXPyXQWRWDOGHIUHQWHD
VyOR(&
(ORUJDQLVPRSURPRWRUSULQFLSDOGHORVHVWXGLRV
GHOD&52IXHODLQGXVWULDIDUPDFpXWLFD
'RFHQFLD
7+(3+$50$&<&855,&8/802)7+(81,9(56,7<2))/25,'$86$
00DUWRQH'1REHO-6HEDUURMD30RGDPLR&)/DVWUD(/0DULxR
&ROOHJHRI3KDUPDF\DWWKH8QLYHUVLW\RI)ORULGD86$
&OLQLFDO3KDUPDF\DQG3KDUPDFRWKHUDS\8QLW'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO
7HFKQRORJ\
)DFXOW\RI3KDUPDF\8QLYHUVLW\RI%DUFHORQD
$YGD-RDQ;;,,,VQ%DUFHORQD6SDLQKWWSZZZXEHGXIDUFOLZSKWP
DOCENCIA
2EMHFWLYH
7RSUHVHQWWKH3KDUPDF\FXUULFXOXPDQGW\SLFDO
FRXUVH RI VWXG\ DW WKH 8QLYHUVLW\ RI )ORULGDV
&ROOHJHRI3KDUPDF\
%DFNJURXQG
7KH 8QLYHUVLW\ RI )ORULGD 8) 3KDUPDF\
SURJUDP LV D ULJRURXV IRXU \HDU FXUULFXOXP
6WXGHQWVZLOODFTXLUHDWRWDORIFUHGLWKRXUV
DQG KRXUV RI FOHUNVKLS H[SHULHQFH 7KH
PHDQDWWULWLRQUDWHLVRYHU\HDUVDQGWKH
PHDQUHWHQWLRQUDWHLVRYHU\HDUV7KH
HGXFDWLRQDO SKLORVRSK\ FDQ EH GHVFULEHG DV
&DVH$VVLVWHG6WXGHQW&HQWHUHG/HDUQLQJ7KLV
DSSURDFK IDFLOLWDWHV DFWLYH OHDUQLQJ WKURXJK
SDWLHQWFDVHVLQZKLFKVWXGHQWVDUHSURPSWHGWR
PDNHSKDUPDFRWKHUDSHXWLFGHFLVLRQV
0HWKRGV
$GHVFULSWLYHPHWKRGEDVHGRQWKHFXUULFXOXPDW
WKH8)&ROOHJHRI3KDUPDF\RUJDQL]HGE\\HDU
&ODVV WLWOHV ZLOO EH LWDOLFL]HG ZLWK D EULHI
GHVFULSWLRQIROORZLQJWKHFRUHFODVVHV
5HVXOWVDQG'LVFXVVLRQ
%HIRUH VWDUWLQJ SKDUPDF\ VWXGLHV VRPH
SUHUHTXLVLWHVDUHUHTXLUHGWRDSSO\WRWKHFROOHJH
RI SKDUPDF\ 7KDW LQFOXGHV WDNLQJ SUH
SURIHVVLRQDOFRXUVHVZKLFKDUHVKRZQLQ7DEOH
7DEOH3UHSURIHVVLRQDOFRXUVHUHTXLUHPHQWV
7DEOH)LUVWSURIHVVLRQDO\HDUFRXUVHV
•
&OLQLFDO%LRFKHPLVWU\
•
'RVDJH)RUPV,DQG,,
•
)XQGDPHQWDOVRI0HGLFLQDO&KHPLVWU\
•
3K\VLRORJLFDO%DVLVRI'LVHDVH,,,
•
,QWURWR3KDUPDFLVWV3KDUPDFHXWLFDOVDQGWKH
+HDOWK&DUH6\VWHP
•
0LFURELRORJLFDODQG,PPXQRORJLFDO%DVLVIRU
7KHUDS\
•
&KHPLVWU\,,,ZLWKODEV
•
2UJDQLF&KHPLVWU\,DQG,,ZLWKODEV
•
3UDFWLFXP,DQG,,
•
%LRORJLFDO6FLHQFHV,,,ZLWKODEV
•
6WUXFWXUHDQG)XQFWLRQRI1XFOHRWLGHV
•
3K\VLFV,,,ZLWKODEV
•
3KDUPDFRWKHUDS\,
•
$QDWRP\DQG3K\VLRORJ\ZLWKODEV
•
%DVLF3ULQFLSOHVRI3KDUPDFRORJ\
•
0DWK$QDO\WLFDO*HRPHWU\DQG&DOFXOXV
•
3XEOLF6SHDNLQJ
,Q DGGLWLRQ WR FRPSOHWLQJ WKHVH FRXUVHV DQ
DSSOLFDQW PXVW DOVR WDNH WKH 3KDUPDF\ &ROOHJH
$GPLVVLRQV 7HVW 3&$7 7KH 3&$7 LV D
VSHFLDOL]HG WHVW WKDW KHOSV LGHQWLI\ TXDOLILHG
DSSOLFDQWV WR SKDUPDF\ FROOHJHV ,W PHDVXUHV
JHQHUDO DFDGHPLF DELOLW\ DQG VFLHQWLILF
NQRZOHGJHQHFHVVDU\IRUWKHFRPPHQFHPHQWRI
SKDUPDFHXWLFDO HGXFDWLRQ 7KH 3&$7 LV
FRQVWUXFWHG VSHFLILFDOO\ IRU FROOHJHV RI
SKDUPDF\ DQG FRQVLVWV RI PXOWLSOHFKRLFH
LWHPV DQG WZR ZULWLQJ WRSLFV &DQGLGDWHV DUH
JLYHQIRXUKRXUVWRFRPSOHWHWKHWHVW
0RUHRYHU LW LV QHFHVVDU\ WR ZULWH D SHUVRQDO
SURILOHDQGDQHVVD\WRFRPPXQLFDWHPRWLYDWLRQ
JRDOVFLUFXPVWDQFHVDQGH[SHULHQFHVUHODWHGWR
DSKDUPDF\FDUHHUWZRUHFRPPHQGDWLRQOHWWHUV
IURP VHSDUDWH UHIHUHQFHV D SKDUPDFLVW DQG D
VFLHQFH SURIHVVRU DQG H[WUDFXUULFXODU DFWLYLWLHV
LQYROYHPHQW LQ VWXGHQW RUJDQL]DWLRQV
FRPPXQLW\ VHUYLFH YROXQWHHULQJ DQG ZRUN
H[SHULHQFH $OWKRXJK SKDUPDF\ H[SHULHQFH LV
QRW D UHTXLUHPHQW IRU DGPLVVLRQ LW LV VWURQJO\
UHFRPPHQGHG
7KH 8) &ROOHJH RI 3KDUPDF\ DGPLWV PRUH RU
OHVVVWXGHQWVRQFHSHU\HDUDQGWKHUHZHUH
DSSUR[LPDWHO\DSSOLFDWLRQV
)LUVW3URIHVVLRQDO<HDU
7KH ILUVW \HDU RI WKH 3KDUPDF\ SURJUDP LV
GHVLJQHG WR JLYH VWXGHQWV DQ LQWURGXFWLRQ WR
SKDUPDFHXWLFDO
FRQFHSWV
LQFOXGLQJ
ELRFKHPLVWU\ PHGLFLQDO FKHPLVWU\ DQG GRVDJH
IRUPV 6WXGHQWV DFFUXH FUHGLW KRXUV WKURXJK
FRPSOHWLRQRIWKHFRXUVHVLQFOXGHGLQ7DEOH
3KDUPDFRWKHUDS\ , LV WKH ILUVW RI D FRXUVH
VHTXHQFH6WXGHQWVDUHFDOOHGRQLQFODVVWRGRD
SDWLHQW LQWHUYLHZ LQFOXGLQJ FRPSOHWH SDWLHQW
KLVWRU\ DVVHVVPHQW RI V\PSWRPV DQG
SKDUPDFRWKHUDSHXWLF UHFRPPHQGDWLRQ $QRWKHU
FRUH FODVV WDNHQ LV %DVLF 3ULQFLSOHV RI
3KDUPDFRORJ\ ZKLFK LV WKH ILUVW RI D WKUHH
FRXUVH VHTXHQFH WKDW H[DPLQHV WKH
SKDUPDFRORJLFDOSULQFLSOHVRIFKHPLFDOVXVHGLQ
WKHUDSHXWLFV ZLWK KHDY\ HPSKDVLV RQ
PHFKDQLVPRIDFWLRQDQGPDMRUVLGHHIIHFWV
3UDFWLFXP,DQG,,LQWURGXFHVSDWLHQWFDUHQHHGV
IURP KHDOWK FDUH V\VWHP DQG VRFLRORJLFDO
SHUVSHFWLYHV 6WXGHQWV DUH DVVLJQHG LQ D JURXS
,;&RQJUHVRGHOD6(),*
'RFHQFLD
ZLWKDYROXQWHHUSDWLHQWDQGDUHDOVRDVVLJQHGWR
VKDGRZVHQLRUSKDUPDF\VWXGHQWV
6HFRQG3URIHVVLRQDO<HDU
'XULQJWKLV\HDUVWXGHQWVDUHLQWURGXFHGWRPRUH
LQ GHSWK GUXJVSHFLILF LQIRUPDWLRQ DQG WRSLFV
DUH RUJDQL]HG E\ GLVHDVH VWDWH 6WXGHQWV WDNH
,QWURGXFWLRQ WR 4XDQWLWDWLYH 0HWKRGV LQ
3KDUPDF\ ZKLFK HPSKDVL]HV WKH DSSOLFDWLRQ RI
ELRVWDWLVWLFV LQ UHVHDUFK DQG SKDUPDF\ SUDFWLFH
,PSRUWDQW FRQFHSWV RI SKDUPDFRNLQHWLFV
LQFOXGLQJ DEVRUSWLRQ GLVWULEXWLRQ PHWDEROLVP
DQG HOLPLQDWLRQ DUH WDXJKW LQ %DVLF 3ULQFLSOHV
RI 'RVH 2SWLPL]DWLRQ , DQG ,, 0HGLFLQDO
&KHPLVWU\ , ,, WHDFK VWXGHQWV WR SUHGLFW
VROXELOLW\ PHWDEROLVP DQG SKDUPDFRORJLFDO
DFWLYLW\SRWHQF\ RI GUXJ FODVVHV EDVHG RQ WKH
FRQWULEXWLRQ RI WKHLU IXQFWLRQDO JURXSV WR WKHLU
VWUXFWXUHV)LQDOO\3URIHVVLRQDO&RPPXQLFDWLRQV
LQ 3KDUPDF\ 3UDFWLFH FDOOV RQ VWXGHQWV WR KRQH
WKHLU VNLOOV LQFOXVLYH RI HPSDWK\ DQG
DVVHUWLYHQHVV VSHFLILF WR IXQFWLRQV SKDUPDFLVWV
SHUIRUP2WKHUFODVVHVGXULQJWKLV\HDULQFOXGH
•
3KDUPDFRORJLFDO %DVLV RI 7KHUDSHXWLFV ,, ,,,
ZKLFKH[DPLQHVWKHSKDUPDFRORJLFDOSULQFLSOHVRI
FKHPLFDOVXVHGLQWKHUDSHXWLFV
3KDUPDFRWKHUDS\,,,,,WKDWSURYLGHVIUDPHZRUN
IRU WKH WKHUDSHXWLF PDQDJHPHQW DQG IRFXVHV RQ
VSHFLILF GLVHDVH VWDWHV E\ XWLOL]LQJ D FDVHDVVLVWHG
VWXGHQWFHQWHUHGOHDUQLQJIRUPDW
3UDFWLFXP ,,, ,9 ZKLFK SURYLGH VWXGHQWV
H[SHULHQFH LQ FRPPXQLW\ SKDUPDF\ RU KRVSLWDO
SKDUPDF\RSHUDWLRQV
•
•
7KLUG3URIHVVLRQDO<HDU
6WXGHQWV ZLOO FRPSOHWH WKHLU FRXUVHZRUN LQ
SUHSDUDWLRQIRUEHJLQQLQJFOHUNVKLSV,QWKHIDOO
VHPHVWHU VWXGHQWV WDNH WKH FRXUVHV VKRZQ LQ
7DEOH
7DEOH7KLUGSURIHVVLRQDO\HDUFRXUVHVIDOOVHPHVWHU
•
'RVDJH)RUPVDQG&RQWHPSRUDU\3UDFWLFH
•
3KDUPDFHXWLFDO6NLOOV/DERUDWRU\,
•
'UXJ7KHUDS\0RQLWRULQJDQG3KDUPDFRJHQRPLFV
•
(YLGHQFHG%DVHG3KDUPDF\
•
3KDUPDFRWKHUDS\,9
•
/HJDODQG2UJDQL]DWLRQDO(QYLURQPHQWRI0HGLFLQHV
8VH
,QWKHVSULQJVWXGHQWVVWDUWFOHUNVKLSVDQGEHJLQ
ZRUNLQJ LQ KRVSLWDOV FRPPXQLW\ SKDUPDFLHV
DQG RXWSDWLHQW SKDUPDFLHV DV LQGHSHQGHQW
SUDFWLWLRQHUV ZLWK WKH JXLGDQFH RI SUHFHSWRUV
7KURXJKRXW WKH WKLUG DQG IRXUWK \HDU RI VFKRRO
FOHUNVKLSVZLOOSURYLGHPRQWKURWDWLRQVZLWK
D WRWDO RI KRXUV RI SURIHVVLRQDO SUDFWLFH
7KLV H[SRVHV WKH VWXGHQW WR D YDULHW\ RI
SKDUPDFHXWLFDO HQYLURQPHQW 6WXGHQWV ZLOO
FRPSOHWH PRQWKV RI UHTXLUHG URWDWLRQV
LQFOXGLQJ $GXOW 0HGLFLQH PRQWK
$PEXODWRU\&DUHPRQWK'UXJ,QIRUPDWLRQ
DQG3HGLDWULFV2QFRORJ\*HURQWRORJ\DQGKDYH
PRQWKVRIHOHFWLYHURWDWLRQVRIWKHLUFKRLFH
,QVSULQJVHPHVWHUVWXGHQWVDUHDOVRUHTXLUHGWR
DWWHQG WKH IROORZLQJ FODVVHV 3KDUPDFHXWLFDO
6NLOOV /DERUDWRU\ ,, 3KDUPDFRWKHUDS\ 9 DQG
&ULWLFDO $SSUDLVDO RI 3KDUPDFRHFRQRPLFV
6WXGLHV7KH\ ZLOODOVRDFFUXHFUHGLWKRXUVLQ
WKLV VHPHVWHU WKURXJK WKHLU FKRLFH RI HOHFWLYH
FRXUVHV VXFK DV 3HGLDWULF 3KDUPDF\ DQG
&OLQLFDO7R[LFRORJ\
)RXUWK3URIHVVLRQDO<HDU
6WXGHQWV FRQWLQXH FOHUNVKLSV WKURXJKRXW WKH
VXPPHU IDOO DQG VSULQJ RI WKHLU IRXUWK \HDU
$IWHU FRPSOHWLQJ WKHLU FOHUNVKLSV LQ )HEUXDU\
VWXGHQWV UHWXUQ WR WKHLU FDPSXV DQG DWWHQG WZR
PRUHPRQWKVRIFODVV
3KDUPDFRWKHUDS\ 9, WKH ODVW FRXUVH LQ WKH SDUW VHTXHQFH ZKHUH VWXGHQWV DVVLPLODWH DQG
FRPELQH WKHLU GLGDFWLF DQG FOLQLFDO NQRZOHGJH
WKURXJKUHDOOLIHSDWLHQWFDVHSUHVHQWDWLRQV
+HUEDO 0HGLFLQHV D SUDFWLFHRULHQWHG
LQWURGXFWLRQ LQWR KHUEDO PHGLFLQHV IRFXVHV RQ
ERWDQLFDO RU KHUEDO SURGXFWV 7KDW ZLOO DOORZ
VWXGHQWV WR PDNH MXGJPHQWV DERXW FOLQLFDO
HIIHFWLYHQHVV DQG SRWHQWLDO IRU DGYHUVH
FRQVHTXHQFHVLQSDWLHQWV
6WXGHQWVZLOODOVRDFTXLUHFUHGLWKRXUVWKURXJK
WKHLUFKRLFHRIWZRHOHFWLYHV
&RQFOXVLRQ 7KH 8QLYHUVLW\ RI )ORULGD
3KDUPDF\'HJUHHLVDIRXU\HDUSURJUDPZLWKD
ULJRURXVFXUULFXOXP7KHILUVWWKUHH\HDUVRIWKH
SURJUDPDUHPRVWO\FDVHEDVHGLQFODVVOHDUQLQJ
GHVLJQHGWRSUHSDUHVWXGHQWVIRUWKHLUILQDO\HDU
RIVFKRROZKHUHWKH\ZLOOHDUQH[SHULHQWLDO
KRXUV WKURXJK FOHUNVKLS ZRUN 7KH JRDO RI WKH
8QLYHUVLW\ RI )ORULGD¶V 3KDUPDF\ 'HJUHH LV WR
SURYLGH D VWURQJ HGXFDWLRQDO IRXQGDWLRQ VR WKDW
VWXGHQWVZLOOEHFRPHSKDUPDFLVWVZKRHPEUDFH
WKHFRQFHSWRIEHLQJDOLIHORQJOHDUQHU
5HIHUHQFHV
7KH 8QLYHUVLW\ RI )ORULGD¶V &ROOHJH RI
3KDUPDF\
KWWSZZZFRSXIOHGXURRWLQGH[KWP
1RYHPEHU
3+$50$&<('8&$7,21$77+(81,9(56,7<2)7(;$6$7$867,186$
$*DUFLD&6LPLVWHU-6HEDUURMD30RGDPLR&)/DVWUD(/0DULxR
&ROOHJHRI3KDUPDF\DWWKH8QLYHUVLW\RI7H[DVDW$XVWLQ86$
&OLQLFDO3KDUPDF\DQG3KDUPDFRWKHUDS\8QLW'HSDUWPHQWRI3KDUPDF\DQG3KDUPDFHXWLFDO
7HFKQRORJ\
)DFXOW\RI3KDUPDF\8QLYHUVLW\RI%DUFHORQD
$YGD-RDQ;;,,,VQ%DUFHORQD6SDLQKWWSZZZXEHGXIDUFOLZSKWP
2EMHFWLYH
LQWHUHVW LQ SKDUPDF\ DQG SURYLGH OHWWHUV RI
7RGHVFULEHWKHFXUULFXOXPDWWKH8QLYHUVLW\RI
UHFRPPHQGDWLRQZULWWHQE\SUHYLRXVSURIHVVRUV
7H[DV 87 DW $XVWLQ¶V &ROOHJH RI 3KDUPDF\
DQGSKDUPDF\HGXFDWLRQLQWKH8QLWHG6WDWHVRI
HPSOR\HUVRUSKDUPDFLVWV$IWHUWKHILUVWURXQGLQ
$PHULFD86$
WKHVHOHFWLRQSURFHVVWKHDSSOLFDQWZLOOEHLQYLWHG
0DWHULDODQG0HWKRGV
IRU DQ LQWHUYLHZ ZLWK D IDFXOW\ PHPEHU DQG D
$GHVFULSWLYHPHWKRGEDVHGRQWKHFXUULFXOXPDW
FXUUHQW SKDUPDF\ VWXGHQW 7KLV DSSOLFDWLRQ
WKH 87 DW $XVWLQ¶V &ROOHJH RI 3KDUPDF\ DQG
SURFHVVLVYHU\FRPSHWLWLYH$WWKH87&ROOHJHRI
SRVW JUDGXDWLRQ SKDUPDF\ HGXFDWLRQ SURJUDPV
3KDUPDF\DERXW PDQ\ DSSOLFDWLRQV DUHUHFHLYHG
LQ86$ZDVDSSOLHGIRUWKLVVWXG\
HDFK \HDU EXW RQO\ DSSOLFDQWV FDQ EH
DFFHSWHGDVFDQEHVHHQLQ)LJXUH
5HVXOWVDQG'LVFXVVLRQ
7KH87SKDUPDF\VFKRROFXUULFXOXPFRQVLVWVRI
WKUHHPDLQFRPSRQHQWV)LUVWDUHWKHSUHUHTXLVLWHV
UHTXLUHGWRDSSO\WRWKHFROOHJHRISKDUPDF\7KH
FRXUVHV LQFOXGH WKH EDVLF VFLHQFHV ZLWK WKHLU
FRUUHVSRQGLQJ ODERUDWRU\ FRPSRQHQWV JHQHUDO
DQG RUJDQLF FKHPLVWU\ FHOOXODU ELRORJ\
PLFURELRORJ\ JHQHWLFV LPPXQRORJ\ DQG
SK\VLFV&DOFXOXVDQGVWDWLVWLFVDUHDOVRUHTXLUHG
$OO VWXGHQWV DWWHQGLQJ 87 PXVW WDNH WKH ³FRUH´
KXPDQLW\ FODVVHV DV SDUW RI WKHLU GHJUHH
UHTXLUHPHQWV 7KHVH ³FRUH´ FODVVHV LQFOXGH
(QJOLVK OLWHUDWXUH ZULWLQJ JRYHUQPHQW KLVWRU\
ILQHDUWVDQGDVRFLDOVFLHQFHVXFKDVSV\FKRORJ\
%HFDXVH WKH SUHSKDUPDF\ FODVVHV RQO\ WDNH D
PLQLPXP RI \HDUV WR FRPSOHWH D SKDUPDF\
DSSOLFDQWYDULHVLQDJHDQGGHJUHHEDFNJURXQGDV
FDQEHVHHQLQ)LJXUH
)LJXUH ,OOXVWUDWLQJ WKH DGPLVVLRQ VWDWLVWLFV DW WKH
&ROOHJHRI3KDUPDF\DW87
$IWHU VWXGHQWV DUH DFFHSWHG LQWR WKH &ROOHJH RI
3KDUPDF\WKH\EHJLQDIRXU\HDUSURJUDPWRHDUQ
WKHLU3KDUP'GHJUHH7KH ILUVW WKUHH \HDUVDUH
GLGDFWLF DQG WKH IRXUWK \HDU LV GHGLFDWHG WR
SUDFWLFDOH[SHULHQFH
7KHILUVW\HDURIFRXUVHZRUN³3´\HDULVYHU\
LQWHQVH DQG LQFOXGHV WKH EDVLF SKDUPDF\
FRXUVHV 7KHVH FODVVHV EXLOG XSRQ WKH EDVLF
VFLHQFH RU SUHSKDUPDF\ FRXUVHV WDNHQ
SUHYLRXVO\ 6WXGHQWV WDNH WKH VXEMHFW VKRZQ LQ
7DEOH
7DEOH6XEMHFWVRI3
)LJXUH &RPSDULQJ WKH HGXFDWLRQDO EDFNJURXQG RI
VWXGHQWVHQWHULQJWKH&ROOHJHRI3KDUPDF\DW87
,Q DGGLWLRQ WR FRPSOHWLQJ WKHVH FRXUVHV DQ
DSSOLFDQW PXVW DOVR WDNH WKH 3KDUPDF\ &ROOHJH
$GPLVVLRQV 7HVW 3&$7 7KLV LV D QDWLRQDO
VWDQGDUGL]HG H[DP WR WHVW DQG HTXDOO\ FRPSDUH
WKHDSSOLFDQWV¶DELOLWLHVLQPDWKVFLHQFHUHDGLQJ
DQG ZULWLQJ $Q DSSOLFDQW PXVW DOVR ZULWH DQ
HVVD\RU³SHUVRQDOVWDWHPHQW´GHFODULQJWKHLU
)DOO6HPHVWHU
• %LRFKHPLVWU\DQG/DE
• 3K\VLFDO&KHPLFDO
3ULQFLSOHVRI'UXJV
• $QDWRP\
3K\VLRORJ\
• 3KDUPDF\
$GPLQLVWUDWLRQDQGODE
• 0HGLFLQDO&KHPLVWU\
3ULQFLSOHVDQGODE
• ,QWURGXFWLRQWR
3KDUPDF\
6SULQJ6HPHVWHU
• 0DFUR0ROHFXODU
&KHPLVWU\DQG
%LRWHFKQRORJ\
• $QDWRP\3K\VLRORJ\
,,
• %LRSKDUPDF\.LQHWLFV
DQGODE
• *HQHUDO3DWKRORJ\
• 3KDUPDFRORJ\3ULQFLSOHV
• 3KDUPDFHXWLFVDQGODE
• ,QWURGWR3KDUPDF\,,
,;&RQJUHVRGHOD6(),*
'RFHQFLD
6RPHRIWKHVHFRXUVHVDOVRLQFOXGHDODERUDWRU\
FRPSRQHQW7KHVWXGHQWVDUHLQFODVVIRUDWOHDVW
VL[WHHQKRXUVSHUZHHNGXULQJERWKVHPHVWHUV
7KH 3 \HDU¶V SULPDU\ IRFXV LV RQ WKH
SKDUPDFRWKHUDS\ FRXUVHV DV LW LV VKRZQ LQ
7DEOH (DFK FODVV IRFXVHV RQ D GLIIHUHQW
GLVHDVH VWDWHV DQG WKH GUXJV XVHG WR WUHDW WKHP
7KHVHFRXUVHVUHTXLUHDWOHDVWILIWHHQFODVVURRP
KRXUV LQ WKH IDOO DQG VSULQJ DQG VL[ LQ WKH
VXPPHU
7DEOH6XEMHFWVRI3
3KDUPDFRWKHUDS\&RXUVHV
• $OOHUJ\DVWKPDDQG
DXWRQRPLFV
• &DUGLRYDVFXODUDQGUHQDO
V\VWHPV
• $QWLPLFURELDOV
• 1RQEDFWHULDOUHWURYLUDO
WKHUDSLHVDQG
RQFRORJ\DQWLFDQFHU
WKHUDSLHV
• +RUPRQDOUHSODFHPHQW
'LDEHWHVSUHJQDQF\
FRQWUDFHSWLRQWK\URLG
G\VIXQFWLRQJURZWK
KRUPRQHDQG
LQIODPPDWRU\GLVRUGHUV
• 1HXURORJLFDOSV\FKRORJ\
GLVRUGHUV
• /RFDODQDHVWKHWLFVDQGSDLQ
PDQDJHPHQW
• 3KDUPDFRWKHUDS\ODE
$GGLWLRQDO&RXUVHV
• &RPPXQLFDWLRQDQG
HWKLFV
• ,QWURGXFWLRQWRGUXJ
LQIRUPDWLRQ
• 3KDUPDF\
DGPLQLVWUDWLRQ,,
• 3URIHVVLRQDO
HOHFWLYHVKRXUV
• ([SHULHQWLDOSUDFWLFH
LQWKHSKDUPDF\DW
WKH87VWXGHQW
KHDOWKVFLHQFH
FHQWHU
7KH ODERUDWRU\ FRPSRQHQW DVVRFLDWHG ZLWK WKH
SKDUPDFRWKHUDS\FRXUVHVGHDOVZLWKUHDOSDWLHQW
FDVHV 7KH VWXGHQWV PXVW HYDOXDWH WKH SDWLHQW¶V
FXUUHQW GUXJ WUHDWPHQW PDNH FKDQJHV ZKHQ
QHHGHG DQG SURYLGH UHFRPPHQGDWLRQV IRU WKH
SURSHU FRXUVH RI WUHDWPHQW IRU HDFK FDVH (DFK
JURXS SUHSDUHV D VXEMHFWLYH REMHFWLYH
DVVHVVPHQW DQG SODQ QRWH 62$3 LQ RUGHU WR
WKRURXJKO\DVVHVVDQGHYDOXDWHWKHSDWLHQW7KLV
ODEKHOSVSUHSDUHVWXGHQWVIRUFOLQLFDOSUDFWLFH
3 \HDU LQFOXGHV FRXUVHV WKDW JR EH\RQG GUXJ
LQIRUPDWLRQWRSUHSDUHWKHVWXGHQWVIRUURWDWLRQV
WKHIROORZLQJ\HDUDQGLQFUHDVHWKHLUNQRZOHGJH
LQDOODUHDVRISKDUPDF\7KHVHYHQWHHQKRXUVRI
FXUULFXOXPLQWKH3\HDULVVKRZQLQ7DEOH
7DEOH6XEMHFWVRI3
3&RXUVHV
• 3KDUPDF\/DZ
•
• 2YHUWKH&RXQWHU
0HGLFDWLRQV
,QWUDYHQRXVPHGLFDWLRQV
DQG,9SUHSDUDWLRQODE
•
$SSOLHG.LQHWLFV
• 'UXJ/LWHUDWXUHDQG
%LRVWDWLVWLFV
•
3DWLHQWDVVHVVPHQWDQG
/DE
• $GYDQFHG
SKDUPDFRWKHUDS\ODE
•
3KDUPDFRHFRQRPLFV
• 3KDUPDFRJHQRPLFV
• 3URIHVVLRQDOHOHFWLYH
7KH 3 \HDU LV FRPSRVHG RI VHYHQ URWDWLRQV
VWDUWLQJ LQ -XO\ DQG HQGLQJ LQ 0D\ RI WKH
IROORZLQJ \HDU6WXGHQWVDUHGLYLGHGDPRQJVL[
GLIIHUHQW UHJLRQV LQ 7H[DV WR FRPSOHWH WKHP
7KH VHYHQ URWDWLRQV FRQVLVW RI WZR DFXWH FDUH
RQH DPEXODWRU\ FDUH RQH LQVWLWXWLRQDO SUDFWLFH
RQH VHOHFWLYH IRFXVHG RQ SDWLHQW FDUH DQG WZR
HOHFWLYH 7KH PLQLPXP WLPH FRPPLWPHQW IRU
WKHVHURWDWLRQVLVKRXUVSHUZHHN
$IWHU FRPSOHWLQJ WKHVH IRXU \HDUV HDFK VWXGHQW
PXVW WDNH WZR VWDQGDUGL]HG H[DPV WR EHFRPH
OLFHQVHG SKDUPDFLVWV WKH 1RUWK $PHULFDQ
3KDUPDFLVW /LFHQVXUH ([DPLQDWLRQ 1$3/(;
DQG WKH 0XOWLVWDWH 3KDUPDF\ -XULVSUXGHQFH
([DPLQDWLRQ 03-( 7KH SKDUPDF\ OLFHQVH LV
RQO\ JRRG LQ WKH VWDWH WKDW WKH WHVWV ZHUH WDNHQ
LQ EXW VWXGHQWV KDYH WKH RSWLRQ WR SD\ WR KDYH
WKHLUWHVWVFRUHVWUDQVIHUUHGWRRWKHUVWDWHV
,I D VWXGHQW ZRXOG OLNH WR IXUWKHU WKHLU FOLQLFDO
NQRZOHGJH WKH\ KDYH WKH RSWLRQ WR DSSO\ IRU
UHVLGHQFLHV DIWHU JUDGXDWLRQ $ UHVLGHQF\ LV D
RQH\HDUSURJUDPWKDWLVVLPLODUWRDQLQWHUQVKLS
RUWKHURWDWLRQVGXULQJWKH3\HDU$UHVLGHQF\
SURYLGHV D IDVW SDFHG OHDUQLQJ HQYLURQPHQW WR
SURYLGHWKHVWXGHQWZLWKWKHHTXLYDOHQWRIWKUHH
\HDUVRISUDFWLFHH[SHULHQFHLQMXVWRQH\HDU$OO
SKDUPDFLVWV LQWHUHVWHG LQ SXUVXLQJ D UHVLGHQF\
FRPSOHWH WKH ILUVW SRVWJUDGXDWH \HDU 3*<
UHVLGHQF\ZKLFKLVDJHQHUDOUHVLGHQF\
$IWHU WKH 3*< D SKDUPDFLVW FDQ FKRRVH WR
VSHFLDOL]H LQ D FHUWDLQ DUHD RI SKDUPDF\ DQG
SXUVXH D VHFRQG SRVWJUDGXDWH \HDU 3*<
UHVLGHQF\ DOORZLQJ WKHP WR VSHFLDOL]H LQ D
IRFXVHG DUHD RI SDWLHQW FDUH VXFK DV RQFRORJ\
LQIHFWLRXV GLVHDVHV RU SV\FKLDWU\ 3KDUPDFLVWV
PXVW DSSO\ IRU WKHVH UHVLGHQFLHV DQG FRPSOHWH
WKH LQWHUYLHZ SURFHVV WR EH DFFHSWHG LQWR D
UHVLGHQF\ SURJUDP 5HVLGHQFLHV DUH YHU\
FRPSHWLWLYH EHFDXVH PRVW SURJUDPV DUH OLPLWHG
DQGFDQRQO\DFFHSWSKDUPDFLVWVD\HDU
,Q86$WKHUHDUHDERXWUHVLGHQF\SURJUDPV
LQ KRVSLWDOV FOLQLFV FRPPXQLW\ SUDFWLFH RU
PDQDJHG FDUH VHWWLQJV 7KHVH UHVLGHQFLHV
SURYLGH VWXGHQWV ZLWK WKH TXDOLILFDWLRQV IRU
SRVLWLRQV LQ KRVSLWDOV DQG RWKHU KHDOWK FDUH
V\VWHPV DQG DOVR GLVWLQJXLVK WKHP IURP RWKHU
3KDUP ' JUDGXDWHV 7KH W\SLFDO SD\ IRU
UHVLGHQWV LV D \HDU DQG D
W\SLFDOSKDUPDFLVW¶VVDODU\LV
5HIHUHQFHV
7KH8QLYHUVLW\RI7H[DVDW$XVWLQ&ROOHJHRI3KDUPDF\
ZZZXWH[DVHGXSKDUPDF\1RYHPEHU
$PHULFDQ 6RFLHW\ RI +HDOWK6\VWHP 3KDUPDFLVWV
,QWHUQHWZZZDVKSRUJ1RYHPEHU
7(&12/2*Ë$)$50$&e87,&$*(67,Ï1'(/&212&,0,(1720(',$17(81$
,1129$&,Ï1'2&(17(%$6$'$(1(/'(6$552//2'(8175$%$-2*583$/
0)HUQiQGH]$UpYDOR0-/HyQ:DVPHU
'HSDUWDPHQWRGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGH6HYLOOD
(VSDxD
,QWURGXFFLyQ
(O HQWRUQR JHQHUDGR SRU OD LQPLQHQWH
LPSODQWDFLyQ GHO (((6 KD VXSXHVWR XQ UHWR HQ
QXPHURVDV XQLYHUVLGDGHV HXURSHDV \ DOJXQDV
DPHULFDQDVHQFXDQWRDDVSHFWRVPX\GLYHUVRV
(QHOiUHDGHODGRFHQFLDHVWHUHWRKDLPSOLFDGR
TXH XQD EXHQD SDUWH GHO SURIHVRUDGR KD\D
DSURYHFKDGR OD RSRUWXQLGDG RIHUWDGD SRU HVWD
QXHYD FRQFHSFLyQ GH OD XQLYHUVLGDG SDUD GDU
IRUPD D PXFKDV GH ODV LQLFLDWLYDV TXH HQ OD
LQQRYDFLyQGRFHQWHVHKDQLGROOHYDQGRDFDERD
ORODUJRGHORVDxRVSHURTXHHQODPD\RUtDGH
ODV RFDVLRQHV QR KDEtDQ VLGR SODVPDGDV HQ
HVWUXFWXUDVIRUPDOHV
(O iUHD GH OD 7HFQRORJtD )DUPDFpXWLFD UHVXOWD
VHU HVSHFLDOPHQWH LQWHUHVDQWH SDUD LPSODQWDU
QXPHURVDV DFWLYLGDGHV GH LQQRYDFLyQ GRFHQWH
TXH OHV SHUPLWD DO HVWXGLDQWH XQLYHUVLWDULR
VXSHUDU DOJXQRV GH ORV SUREOHPDV TXH
KDELWXDOPHQWH VH OH DFKDFDQ FRPR VRQ FLHUWR
JUDGRGHDSDWtDHQHODOXPQDGR\ODFRQVHFXHQWH
IDOWD GH GHVDUUROOR GH GHWHUPLQDGDV KDELOLGDGHV
QHFHVDULDVSDUDVXGHVHQYROYLPLHQWRDFDGpPLFR
SHUVRQDOHLQFOXVRDYHFHVSURIHVLRQDO
&RQ OD LQWHQFLyQ GH DFWXDU VREUH HVWDV
FXHVWLRQHV
OD
DVLJQDWXUD
7HFQRORJtD
)DUPDFpXWLFD GH OD )DFXOWDG GH )DUPDFLD GH OD
8QLYHUVLGDG GH 6HYLOOD GHVDUUROOy GXUDQWH HO
FXUVR SDVDGR XQ FDPELR HQ VX HVWUDWHJLD
GRFHQWHFX\RREMHWLYREiVLFRHUDLQWHQWDUSDOLDU
HQ OD PHGLGD GH OR SRVLEOH ODV FDUHQFLDV
LQGLFDGDV DQWHULRUPHQWH /D HVWUDWHJLD FRQVLVWLy
HQHOGHVDUUROORSRUSDUWHGHORVDOXPQRV\SRU
PHGLR GH XQD DFWLYLGDG JUXSDO GH XQ FDVR
SUiFWLFRSODQWHDGRSRUHOORVPLVPRV
&RPR QRSRGtDVHGHRWUD PDQHUDHVWHFDPELR
IXHLQLFLDOPHQWHWtPLGRQRREVWDQWHYLVWRVORV
UHVXOWDGRV REWHQLGRV GXUDQWH HO FXUVR SDVDGR
SUHVHQWDGRVHQGLYHUVRVIRURVVH
KD GHFLGLGR DPSOLDU OD GXUDFLyQ UHTXHULGD SDUD
GHVDUUROODU HVWD DFWLYLGDG GXUDQWH HO SUHVHQWH
FXUVRDFDGpPLFR
$ VX YH] HVWLPDPRV TXH UHVXOWD IXQGDPHQWDO
UHIOH[LRQDU DFHUFD GH FXDOTXLHU LQLFLDWLYD HQ OD
GRFHQFLD GH XQD PDWHULD HQ SDUWLFXODU FRQ HO
REMHWRGHTXHQRVHSURGX]FDQSHUWXUEDFLRQHVHQ
HO WUDQVFXUVR GHO DxR DFDGpPLFR (Q HVWH
VHQWLGR HO SURIHVRUDGR GHEH VHU FRQVFLHQWH GH
TXH OD GXUDFLyQ GHO FXUVR HVOLPLWDGD \ TXH HQ
pO GHEHQ FDEHU WRGDV ODV DFWLYLGDGHV
SURJUDPDGDV UHVSHFWR D ODV WDUHDV GRFHQWHV GHO
DOXPQRUHODWLYDVDWRGDVODVPDWHULDV6LHVWRQR
VHWLHQHHQFXHQWDVHFRUUHHOULHVJRGHTXHXQD
DVLJQDWXUDDEVRUEDORVUHFXUVRVGHODOXPQDGRHQ
GHWULPHQWR GH ODV GHPiV FRQ HO FRQVLJXLHQWH
IUDFDVR DFDGpPLFR GH DOXPQDGR 1R GHEHPRV
GHMDUGH SHQVDU TXH WRGDV ODV LQLFLDWLYDV TXH VH
OOHYHQDFDERHQODVGLYHUVDVPDWHULDVTXHGHEH
FXUVDUHODOXPQDGRWHQGUiQXQUHIOHMRQRVyORHQ
HO GHVDUUROOR GH FRPSHWHQFLDV YDULDV VLQR
WDPELpQHQVXVH[SHGLHQWHVDFDGpPLFRV<HVWR
VHUiDVtWDQWRSDUDORVUHVXOWDGRVSRVLWLYRVFRPR
SDUDORVQHJDWLYRV
0HWRGRORJtD
6H KD GLVHxDGR XQD HVWUDWHJLD QXHYD FRQ
UHODFLyQ D FRQVHJXLU XQD LPSOLFDFLyQ PiV
IRUPDO \ HILFD] GHO DOXPQDGR HQ VX IRUPDFLyQ
GHQWURGHOiUHDGHOD7HFQRORJtD)DUPDFpXWLFD
/DLQLFLDWLYDVHKDHVWUXFWXUDGRVREUHODEDVHGH
FRQVHJXLU TXH HO DOXPQR GHVDUUROOH FLQFR
FRPSHWHQFLDV JHQpULFDV GH JUDQ LPSRUWDQFLD
SDUD VX SRVWHULRU GHVHQYROYLPLHQWR SHUVRQDO \
SURIHVLRQDO EXVFDU LQIRUPDFLyQ D WUDYpV GH
ODV QXHYDVWHFQRORJtDV WUDEDMDU HQ HTXLSR
WRPDU GHFLVLRQHV HODERUDU LQIRUPHV GH
PDQHUDFRUUHFWD\GHEDWLUHQS~EOLFR
(O REMHWLYR ~OWLPR FRQVLVWH HQ TXH HO DOXPQR
DERUGH OD DVLJQDWXUD GH PDQHUD TXH VHD FDSD]
GH XQD YH] FRQRFLGRV \ GRPLQDGRV ORV
FRQFHSWRV WHyULFRV GH OD PDWHULD SRGHU UHDOL]DU
XQDERUGDMHSUiFWLFRGHODPLVPD
3DUDHOORGHEHUiQWUDEDMDQGRHQHTXLSRUHFDEDU
\ PDQHMDU OD LQIRUPDFLyQ QHFHVDULD SDUD VHU
FDSDFHV HQWUH WRGRV GH SODQWHDU HVWUXFWXUDU \
UHVROYHU XQ FDVR UHDO HQ HO FDPSR GH OD
7HFQRORJtD)DUPDFpXWLFD
&DGDJUXSRGHWUDEDMRHVWDUiFRRUGLQDGRSRUXQ
DOXPQR HOHJLGR HQWUH HOORV TXH DFWXDUi HQ
FDOLGDGGHSRUWDYR]GHJUXSR(QODILJXUDVH
UHFRJHQ ORV SRUWDYRFHV GH JUXSRV GHO FXUVR
SDVDGR
)LJXUD3RUWDYRFHVGHJUXSRVGHWUDEDMR
+DELGD FXHQWD TXH VRQ HOORV PLVPRV TXLHQHV
GHEHUiQ VHU FDSDFHV GH GHWHUPLQDU FXiO VHUi VX
FDPSR FRQFUHWR GH WUDEDMR GHEHUiQ LU
HVWXGLDQGR OD PDWHULD WUDWDGD KDVWD IHFKDV
HVWDEOHFLGDV GH DQWHPDQR SDUD UHDOL]DU HVWD
DFWLYLGDG SDUD HVWDEOHFHU FXiOHV VRQ ORV
,;&RQJUHVRGHOD6(),*
'RFHQFLD
FRQRFLPLHQWRV GH ORV TXH GLVSRQHQ \ FXiOHV
QHFHVLWDQ ORFDOL]DU SDUD SRGHU HVWUXFWXUDU \
UHVROYHU ORV FDVRV TXH HO JUXSR YD SODQWHDQGR
/yJLFDPHQWH HVWRV FDVRV LUiQ DXPHQWDQGR VX
FRPSOHMLGDG \ VX QHFHVLGDG GH UHODFLRQDU
FRQFHSWRV D PHGLGD TXH VH YD\D DYDQ]DQGR HQ
HOSURJUDPD
&RQHOREMHWLYRGHFRPSDWLELOL]DUHVWDDFWLYLGDG
FRQODWRWDOLGDGGHOWUDEDMRTXHGHEHDERUGDUHO
DOXPQR GXUDQWH HO FXUVR DFDGpPLFR VH KDQ
WHQLGR HQ FRQVLGHUDFLyQ ORV VLJXLHQWHV
FRQGLFLRQDQWHV
6HKDHVWDEOHFLGRUHGXFLUHQXQODVFODVHV
PDJLVWUDOHV SDUD SRGHU OOHYDU D FDER HVWD
LQLFLDWLYD $VtODDFWLYLGDGVHSRGUiUHDOL]DUHQ
OD IUDQMD KRUDULD \ HQ HO DXOD DVLJQDGD D HVWD
DVLJQDWXUDYHUILJXUD(VWLPDPRVTXHHVWRHV
OR TXH SRVLELOLWD OD FRPSDWLELOLGDG FRQ OD
WRWDOLGDG GH ODV DFWLYLGDGHV LQYROXFUDGDV HQ HO
FXUVRDFDGpPLFR/yJLFDPHQWHHVWRLPSOLFDSRU
SDUWH GHO SURIHVRUDGR XQD UHIOH[LyQ DFHUFD GH
TXp SDUWH GH ORV FRQWHQLGRV GH FLHUWRV WHPDV HO
DOXPQDGRGHEHUiVHUFDSD]GHEXVFDUHQIXHQWHV
GHVROYHQFLDUHFRQRFLGDFRQHOREMHWRGHSRGHU
OOHYDU D FDER XQD UHGXFFLyQ SURSRUFLRQDO GHO
SURJUDPD \ OLEHUDU DVt HO WLHPSR QHFHVDULR
SDUDUHDOL]DUODDFWLYLGDG
WUDEDMR FRQ XQD FRPSRVLFLyQ PHGLD GH ± DOXPQRV
7RGRVORVFDVRVWHUPLQDURQHQWLHPSR \ IRUPD
\ IXHURQ HQWUHJDGRV D WRGRV ORV DOXPQRV SRU
PHGLR GH ORV SRUWDYRFHV GH JUXSR /RV JUXSRV
WXYLHURQWLHPSRGHDQDOL]DUORVSDUDVHOHFFLRQDU
SRU PHGLR GH YRWDFLyQ ORV WUHV WUDEDMRV
ILQDOLVWDVGHHQWUHWRGRVORVFDVRVHQWUHJDGRV
/RV SRUWDYRFHV GH ORV JUXSRV ILQDOLVWDV
GHIHQGLHURQVXVFDVRV\ILQDOPHQWHYROYLHURQD
YRWDU SDUD GHWHUPLQDU HO FDVR JDQDGRU D FX\RV
FRPSRQHQWHV VH OHV KL]R HQWUHJD GH XQ SUHPLR
GH FDUiFWHU LQVWLWXFLRQDO RWRUJDGRU SRU HO
5HFWRUDGR GH OD 8QLYHUVLGDG GH 6HYLOOD ILJXUD
)LJXUD0RGHORXQLILFDGRGHLQIRUPH
)LJXUD 3XQWXDFLyQ RWRUJDGD SDUD HO JUDGR GH
VDWLVIDFFLyQGHODDFWLYLGDGL]GD\FDSDFLGDGSDUD
UHODFLRQDUFRQFHSWRVGFKD
&RPR GDWR REMHWLYR VH PXHVWUD OD VLJXLHQWH
ILJXUDILJXUD
&RQODLQWHQFLyQGHOOHYDUDFDERHOSURFHVRGH
PDQHUD IRUPDO QRUPDOL]DQGR ORV LQIRUPHV VH
OHV KL]R HQWUHJD GH XQD SODQWLOOD TXH GHEtDQ
HPSOHDU SDUD OD HQWUHJD GH ORV FDVRV HQ VXV
GLIHUHQWHV HVWDGtRV GH GHVDUUROOR (O PRGHOR VH
UHFRJHHQODILJXUD
)LJXUD 5HVXOWDGRV FRUUHVSRQGLHQWHV DO VHJXQGR
SDUFLDOGHODDVLJQDWXUD
5HVSHFWRDOLPSDFWRGHODDFWLYDGTXHUHPRVUHVDOWDU
TXHHOGHORVSUHVHQWDGRVDOžSDUFLDODSUREy
HO H[DPHQ \ GH HOORV HO IXHURQ DOXPQRV
SHUWHQHFLHQWHVDORVJUXSRVGHWUDEDMR
%LEOLRJUDItD
0 )HUQiQGH] $UpYDOR 0- /HyQ :DVPHU ) )HUQiQGH] &RUWpV
³,QQRYDFLyQGRFHQWHHQWHFQRORJtDIDUPDFpXWLFD´,-RUQDGDGHLQQRYDFLyQ
GRFHQWHHQFLHQFLDVGHODVDOXG6HYLOODGHPDU]RGH
0 )HUQiQGH] $UpYDOR 0- /HyQ :DVPHU ³7HFQRORJtD )DUPDFpXWLFD \
(((6(VSRVLEOH´,QWHUFDPELRGHH[SHULHQFLDV(&76GHODV)DFXOWDGHV
GH)DUPDFLD$QGDOX]DV*UDQDGDGHMXQLRGH
0 )HUQiQGH] $UpYDOR 0- /HyQ :DVPHU ³7HFQRORJtD )DUPDFpXWLFD
FyPR JHVWLRQDU HO FRQRFLPLHQWR D WUDYpV GH DFWLYLGDGHV (((6´ QG
,QWHUQDWLRQDO &RQJUHVV LQ +LJK (GXFDWLRQ LQ 3KDUPDFHXWLFDO 6FLHQFHV
6DQWLDJRGH&RPSRVWHOD±GHMXOLRGH
5HVXOWDGRV\'LVFXVLyQ
&HUFD GHO GH ORV DOXPQRV PDWULFXODGRV
WHUPLQDURQODDFWLYLGDGJUXSDOFXPSOLHQGRFRQ
ODV IHFKDV GH HQWUHJD HVWDEOHFLGDV SUHYLDPHQWH
(VWR VXSXVR WUDEDMDU FRQ XQRV JUXSRV GH
HQODDGTXLVLFLyQGHFRPSHWHQFLDVSURIHVLRQDOHV
SURSLDVGHOIDUPDFpXWLFR
,QWURGXFFLyQ
$ PRGR GH GDWRV VXEMHWLYRV YDOJDQ FRPR
HMHPSORVORUHFRJLGRHQODILJXUD
)LJXUD*UXSRWUDEDMDQGRHQHODXOD
)LJXUD0RGHORXQLILFDGRGHLQIRUPH
9$/25$&,Ï1'(/$)250$&,Ï15(&,%,'$<'(/$6&203(7(1&,$6
352)(6,21$/(6'(/)$50$&e87,&238172'(9,67$'(/$/8012
%HJRxD&DOYR(QULTXH(W[HEDUUtD
$UHDGH)DUPDFLD\7HFQRORJtD)DUPDFpXWLFD'HSDUWDPHQWRGH)LVLRORJtD
)DFXOWDGGH)DUPDFLD8QLYHUVLGDGGHO3DtV9DVFR
3ž8QLYHUVLGDG9LWRULD
/D 8QLYHUVLGDG HVSDxROD VH HQFXHQWUD LQPHUVD
HQODHODERUDFLyQ\DGDSWDFLyQGHORVSODQHVGH
HVWXGLR SDUD DMXVWDUVH D ORV UHTXHULPLHQWRV GHO
QXHYR(VSDFLR(XURSHRGH(GXFDFLyQ6XSHULRU
(O REMHWLYR HVHQFLDO GH HVWRV QXHYRV SODQHV HV
JDUDQWL]DU OD DGTXLVLFLyQ GH FRPSHWHQFLDV
SURIHVLRQDOHV SRU SDUWH GH ORV DOXPQRV SDUD OR
FXiO HV SUHFLVR FDPELDU HO HQIRTXH WUDGLFLRQDO
EDVDGR H[FOXVLYDPHQWH HQ OD PHPRUL]DFLyQ GH
FRQWHQLGRV \ PRGLILFDU ORV PpWRGRV GH
DSUHQGL]DMH DVt FRPR ORV SURFHGLPLHQWRV GH
HYDOXDFLyQ
$VLPLVPRODV'LUHFWULFHVSDUDODHODERUDFLyQGH
WtWXORV GH *UDGR \ 0iVWHU´ GHO 0LQLVWHULR GH
(GXFDFLyQ \ &LHQFLD HVWDEOHFHQ TXH HVWDV
HQVHxDQ]DV WHQGUiQ FRPR ILQDOLGDG HQWUH RWUDV
³XQD IRUPDFLyQ RULHQWDGD D OD SUHSDUDFLyQ
SDUDHOHMHUFLFLRGHODVDFWLYLGDGHVGHFDUiFWHU
SURIHVLRQDO´
/D ILFKD WpFQLFD GHO WtWXOR GH )DUPDFpXWLFR HVWDEOHFH XQ OLVWDGR GH FRPSHWHQFLDV FX\D
DGTXLVLFLyQ GHEH VHU JDUDQWL]DGD SRU ODV
XQLYHUVLGDGHV 'LH] GH HOODV SUHVHQWDQ XQ
HQIRTXHGHODODERUSURIHVLRQDOGHOIDUPDFpXWLFR
FHQWUDGD HQ HO SDFLHQWH PLHQWUDV TXH ODV VHLV
UHVWDQWHV HVWiQ HQIRFDGDV D OD SURGXFFLyQ \
FRQWURO GH PHGLFDPHQWRV DVt FRPR D ORV
DQiOLVLV FOtQLFRV GH DOLPHQWRV H KLJLpQLFR
VDQLWDULRVHQWUHRWUDV (VWDGLVWULEXFLyQHVWDUtD
HQ FRQFRUGDQFLD FRQ OD GLVWULEXFLyQ GH ODV
VDOLGDVSURIHVLRQDOHVGHOIDUPDFpXWLFR
6HJ~QGDWRVSURFHGHQWHVGHO /LEUR%ODQFRGH OD
7LWXODFLyQGH)DUPDFLD\GHO&RQVHMR*HQHUDOGH
&ROHJLRV GH )DUPDFpXWLFRV HO Q~PHUR GH
&ROHJLDGRV DFWXDO HQ (VSDxD HV GH
DSUR[LPDGDPHQWH 'H HOORV HO WUDEDMDQ HQ 2ILFLQDV GH )DUPDFLD HO HQ OD
LQGXVWULD IDUPDFpXWLFD HO HQ 6HUYLFLRV GH
)DUPDFLD +RVSLWDODULD \ HO UHVWR HQ RWUDV
PRGDOLGDGHVSURIHVLRQDOHV
3RU RWUD SDUWH HQ OD PD\RU SDUWH GH ORV SODQHV
GH HVWXGLR HVSDxROHV ORV FUpGLWRV GH ORV WUHV
SULPHURVDxRVHVWiQGHVWLQDGRVSULQFLSDOPHQWHD
DVLJQDWXUDV UHODFLRQDGDV FRQ OD 4XtPLFD \ OD
)tVLFDUHGXFLHQGRODSRVLELOLGDGGHSURIXQGL]DU
2EMHWLYR\0HWRGRORJtD
&RQHOILQGHFRQWULEXLUDODHYDOXDFLyQ\PHMRUD
GHO3ODQGH(VWXGLRVGH*UDGXDGRHQ)DUPDFLD
VH KD UHDOL]DGR XQD YDORUDFLyQ GH OD IRUPDFLyQ
UHFLELGD GXUDQWH OD /LFHQFLDWXUD PHGLDQWH OD
UHFRJLGDGHRSLQLRQHVGHORVDOXPQRVGHO~OWLPR
FXUVR GH )DUPDFLD GH OD 8QLYHUVLGDG GHO 3DtV
9DVFRHQHOFXUVR
3DUDHOORVHKDOOHYDGRDFDERXQDHQFXHVWDHQOD
TXH VH KD VROLFLWDGR D ORV DOXPQRV TXH YDORUHQ
ORV GLIHUHQWHV PpWRGRV GH HQVHxDQ]D
DSUHQGL]DMH XWLOL]DGRV \ SXQWXHQ OD XWLOLGDG GH
FDUD D VX IXWXUR SURIHVLRQDO GH OD IRUPDFLyQ
UHFLELGDHQODVGLIHUHQWHVDVLJQDWXUDVGHVXSODQ
GH HVWXGLRV HQIRTXH GH OD PDWHULD \ VX
DSOLFDELOLGDG D OD DGTXLVLFLyQ GH FRPSHWHQFLDV
SURIHVLRQDOHV WDQWR SDUD ODV FRPSHWHQFLDV
HVSHFtILFDVFRPRWUDQVYHUVDOHV
5HVXOWDGRV
(Q FXDQWR D OD PHWRGRORJtD XWLOL]DGD HQ VX
SURFHVR GH HQVHxDQ]DDSUHQGL]DMH XQD DPSOLD
PD\RUtDGHORVDOXPQRVHQFXHVWDGRVVHxDODTXH
VHKDFHEDVWDQWHRPXFKRpQIDVLVHQODV7HRUtDV
\FRQFHSWRVSRUHOFRQWUDULRHOpQIDVLV
HQ&RQRFLPLHQWRVSUiFWLFRV\PHWRGROyJLFRVHV
FRQVLGHUDEOHPHQWH PHQRU DVt FRPR HO
$SUHQGL]DMH EDVDGR HQ SUREOHPDV )LJXUD
3RU OR TXH VH UHILHUH D ODV IXHQWHV GH
LQIRUPDFLyQ OD PD\RUtD LQGLFDQ DO
3URIHVRU FRPR OD SULQFLSDO IXHQWH GH
LQIRUPDFLyQ
/D PD\RUtD GH ORV DOXPQRV XWLOL]D SRFR OD
ELEOLRJUDItD UHFRPHQGDGD \ DSHQDV FRQVXOWDQ
,QWHUQHW SDUD VXV HVWXGLRV /RV TXH XWLOL]DQ
,QWHUQHWORKDFHQSDUDFRQVXOWDUODVSiJLQDVZHE
GHODVGLIHUHQWHVDVLJQDWXUDV
&RPR PDWHULDO GH DSR\R XWLOL]DQ IXQGD
PHQWDOPHQWH ODV IRWRFRSLDV GH ORV HVTXHPDV GH
FODVHSURSRUFLRQDGRVSRUORVSURIHVRUHV
,;&RQJUHVRGHOD6(),*
Valora la importancia que se ha dado en tus estudios
a los distintos métodos utilizados
Teorías y Conceptos
Conocimientos prácticos
17
0
20
40
60
80
Porcentaje de alumnos que respondió “bastante” o “mucho”.
)LJ0HWRGRORJtDGHHQVHxDQ]DXWLOL]DGD
Aprendizaje
basado en problemas
(QODWDEODVHUHFRJHODYDORUDFLyQHVFDODGH
D GH ORV DOXPQRV GH OD XWLOLGDG SDUD VX
IXWXUR SURIHVLRQDO GH ODV DVLJQDWXUDV WURQFDOHV
GHODWLWXODFLyQ
&RQFOXVLRQHV
/RVDOXPQRVFRQVLGHUDQPX\LPSRUWDQWHSDUDVX
IXWXUR SURIHVLRQDO OD IRUPDFLyQ RULHQWDGD D OD
FOtQLFD \ D OD REWHQFLyQ \ FRQWURO GH
PHGLFDPHQWRV PLHQWUDV TXH OD H[FHVLYD
IRUPDFLyQ TXH UHFLEHQ HQ HO FDPSR GH OD
4XtPLFD OD )tVLFD \ RWUDV PDWHULDV QR
HVSHFtILFDPHQWH ELRVDQLWDULDV OHV UHVWDUtD
WLHPSRSDUDFRPSOHWDUVXIRUPDFLyQDFRUGHDODV
QHFHVLGDGHVGHOIDUPDFpXWLFR
6yOR XQ SLHQVD TXH ORV HVWXGLRV GH
)DUPDFLDVRQXQDEXHQDEDVHSDUDOOHYDUDFDER
VXWUDEDMRSURIHVLRQDOHQHOIXWXURSRUORTXHHQ
VXRSLQLyQGHEHUHRULHQWDUVHORVFRQWHQLGRV
/RV FRQWHQLGRV IRUPDWLYRV QR FXEUHQ ODV
FRPSHWHQFLDVUHTXHULGDVDORVWLWXODGRV
%LEOLRJUDItD
5'GHGH2FWXEUHSRUHOTXH
VHHVWDEOHFHOD2UGHQDFLyQGHODVHQVHxDQ]DV
XQLYHUVLWDULDVRILFLDOHV%2(2FWXEUH
2UGHQ &,1 GH GH MXOLR SRU OD
TXH VH HVWDEOHFHQ ORV UHTXLVLWRV SDUD OD
YHULILFDFLyQGHORVWtWXORVXQLYHUVLWDULRVRILFLDOHV
TXHKDELOLWDQSDUDHOHMHUFLFLRGHODSURIHVLyQGH
)DUPDFpXWLFR%2(-XOLR
7DEOD9DORUDFLyQDGHORVDOXPQRVGH
OD XWLOLGDG GH ODV PDWHULDV SDUD VX IXWXUR
SURIHVLRQDO
67
34
100
9DORUDFLyQ
$VLJQDWXUDV
&UpGLWRV
100
)tVLFDDSOLFDGD
0DWHPiWLFD
DSOLFDGD
3VLFRORJtD\6RFLRO
6DQLWDULD
3XQWXDFLyQ %LRORJtDYHJHWDO
4XtPLFD
,QRUJiQLFD
&LWRORJtDH
+LVWRORJtD
7pFQLFDV
LQVWUXPHQWDOHV
)tVLFR4XtPLFD
%LRTXtPLFD
1XWULFLyQ\
%URPDWRORJtD
7R[LFRORJtD
*HVWLyQ\
3ODQLILFDFLyQ
4XtPLFD
2UJiQLFD
)DUPDFRJQRVLD
3XQWXDFLyQ $QDWRPtD
)LVLRORJtD
• 4XtPLFD$QDOtWLFD
)LVLRSDWRORJtD
4XtPLFD
)DUPDFpXWLFD
%LRTXtPLFD
&OtQLFD
,QPXQRORJtD
0LFURELRORJtD\
3DUDVLWRORJtD
/HJLVODFLyQ\
'HRQWRORJtD
6DOXG3~EOLFD
7HFQRORJtD
)DUPDFpXWLFD
%LRIDUPDFLD\
3XQWXDFLyQ
)DUPDFRFLQpWLFD
)DUPDFLD&OtQLFD
•
\)DUPDFRWHUDSLD
)DUPDFLD
*DOpQLFD
)DUPDFRORJtD
ÍNDICE DE AUTORES
ËQGLFHGH$XWRUHV
Ë1',&('($8725(6
$
$EHUWXUDV05 32
$EL]DQGD*32
$JHURV0 &2
$JXLODU'tD]-( 323232
$OFDOi-32
$ORQVR/ 32
$ORQVR9 32
$OyV032
ÈOYDUH]-32
ÈOYDUH])XHQWHV- &2323232
$OYDUH]/RUHQ]R& &2&232323232
$QVRUHQD( 32
$QWHTXHUD' &2
$UDJyQ1 32
$UDtFR$ 32
$UD~MR0/32
$UHVHV3 &2
$ULDV-/ &2323232
$\PHULFK06 32
%
%DODJXHU)HUQiQGH]& &232
%DOOHVWHURV03 32
%DUFLD( 3232
%DXWLVWD&KiYH]/ 32
%HORTXL$ 32
%HQtWH]GHO&DVWLOOR-0 32
%HQLWR(32
%HUPHMR0 &2&2323232
%HUPHOO0$32
%ODQFD( 32
%ODQFR3ULHWR0- 3232323232
%RX]DV35 32
%UDYR2VXQD, &2
%UD]D$- 32
%ULRQHV&XHVWD( 32
%XFLR(32
%XULOOR*32
%XVWDPDQWH3 323232
&
&DEULRXOX0 32
&DODWD\XG3DVFXDO0$&232
&DOYR$ &2
&DOYR% 3232
&DPDFKR$,32
&DPHiQ0 3232
&DPSDQHUR0$ &232
&DQDO&32
&DQDO-0 32
&DUDEDOOR, 3232
&iUFHO7UXOOROV- 32
&DUUR( &2
&DVDEy9* &232
&DVWUR+HUQiQGH]( &2
&DWHQD5 &2
&HEULiQ* 32
&HQWHOOHV$ 32
ËQGLFHGH$XWRUHV
*DVFyQ$5 &23232
*LO$OHJUH0( 323232
*RPH], 32
*yPH]$PR]D-/ 3232
*yPH]&DUUDFHGR$32
*RQoDOYHV7 3232
*RQ]iOH]/ySH])&232
*RQ]iOH]' 3232
*RQ]DOH]$OYDUH], &2&2323232
*RQ]DOH]$OYDUH]0 &23232
*RQ]iOH]5RGUtJXH]0/ 3232
*R\DQHV$ 32
*UDJHUD5 32
*XHUUHUR0' 3232
*XWLpUUH]0LOOiQ&32
*X]PiQ0 3232
+
+HUQiQ' 32
+HUQiQGH]3-32
+HUQiQGH]% 32
+HUQiQGH]50 &2&23232
+HUUiH]032
+HUUHUR9DQUHOO5&232
+ROJDGR0$ &2323232
,
,EixH]0( 32
,EDUUD05 32
,JDUWXD0 32
,PEXOX]TXHWD( 3232
,QIDQWH'32
,UDFKH-0&232323232
-
-HV~V9DOOH0-GH &232
-LPpQH]7RUUHV19 3232
-LPpQH]&DVWHOODQRV05 3232
/
/DQDR-033232
/DQFLHJR-/ 32
/DQGtQ0 32
/DUD9LOORVODGD) 3232
/DVWUD&) 32323232
/HKU&0 32
/HyQ:DVPHU0- 32
/LUDV$32
/ODEUpV0 32323232
/ySH]GH&HUDLQ$32
/ySH]* 32
/ySH]&DVWHOODQR$ &232
/ySH]0RQWHUR( 32
/ySH]9LRWD0 &23232
/XFHUR0- 32
/XTXH5DPRV0$ &2
0
0DQFRQL0 32
0DQNX0 &2
0DUJDULW%HOOYHU09 3232
0DUtQ%RVFi07 32
0DULxR(/ 32323232
0DUTXLQD&, 32
,;&RQJUHVRGHOD6(),*
&KHFD&DVDOHQJXD3 &2
&KLDQHOOD, &2
&LIXHQWHV& 32
&ODUHV% 323232
&ODUR&DOD&32
&ROLQR*DQGDULOODV&,32
&RORPER33
&RQFKHLUR$ &2&232323232
&RQWUHUDV&ODUDPRQWH0' 3232
&y]DU%HUQDO0- &2323232
'
'D&RVWD0DUWLQV5 32
'DQQLHV332
'D]D932
'HODV+HUDV%32
'HO3R]R5RGULJXH]$ &2
'HOJDGR' &2
'KULPHXU:32
'tH]6DOHV2 3232
'LRV9LpLWH]0& 32
'RPpQHFK- 32
(
(FKHYDUUtD( &2
(OL]RQGR( 3232
(VFDOHUD% 3232
(VFREDU&KiYH]--32
(VFULEDQR( 3232
(VFXGHUR--32
(VSDGD*DUFtD-,32
(VWHOOD+HUPRVRGH0HQGR]D$32
(W[HEDUUtD(32
)
)DGGD$032
)DULxD-% 32323232
)HPHQtD)RQW$&232
)HUQiQGH]$ 32
)HUQiQGH]0 3232
)HUQiQGH]$UpYDOR0&232323232
)HUQiQGH]3DFKHFR5 32
)HUUHUR& 32
)ORUHV0RVTXHUD0 &2
)RUPLJD)5 32
)UDQFR*LO0(32
*
*DJR*XLOODQ032
*DOODUGR9 &232323232323232
*iOYH]3 32
*DPD]R& 32323232
*DxiQ&DOYR$ &2
*DQHP4XLQWDQDU$ 32
*DUED\R( 3232
*DUFLD$ 32
*DUFtD3 32
*DUFLD; 32
*DUFtD$UUDQ]032
*DUFtD&HOPD0-32
*DUFLD0RQWR\D( 32
*DUFtD2OPR' 32
*DUULGR0- &2&2
*DUULJXHV70 32
,;&RQJUHVRGHOD6(),*
0DUUD) &2
0DUWtQ6DEURVR& 323232
0DUWLQ9LOOHQD0- 32
0DUWtQ%DQGHUDV/ &232
0DUWtQ9LOORGUH$32
0DUWtQH]3DFKHFR5 323232
0DUWRQH032
0DWHX932
0HOHUR$ 32
0HULQR9 &2&2&2323232323232
0HULQR%RKyUTXH]9 3232
0HULQR6DQMXiQ0 32323232
0LJXpOL], 32
0LxDUUR0 32
0LQJRUDQFHÈOYDUH]0'32
0LUDOOHV$UQDX6 3232
0RGDPLR3 32323232
0ROLQD0DUWLQH],7 &232
0ROOLQHGR) 32
0ROSHFHUHV-32
0RQWDQHU032
0RUDOHV0( 323232
0RUDOHV0/32
0RUHQR' &2&2
0R\D0' 32
0XUD6 32
0XUXD$ 32
1
1iFKHU$ 32323232
1DYD2UWL]&$%32
1DYDUUR$ &23232
1DYDUUR& &2
1DYDUUR*32
1DYDUUR, &2&2
1HJUR6 3232
1LFROiV% 32
1LFROL6 &2
1REHO' 32
1RJXHLUDV1LHWR/ &2
2
2FKRD/ 32
2JULV0 332
2MHU332
2OLYD$ 3232
2OPHGLOODV6 32
2OWUD1RJXHUD'&232
2ULYH* &2&232
2VVpWp+ 32
2WHUR(VSLQDU)-&232
2YDGL- &2
3
3DGXOD& &2
3DJiQ5 32
3HFFKLR032
3HGUD]-/ &2&2&2323232
3HODFKR%32
3HxD0$ 323232
3HxXHODV, &2
3pUH]* 32
3pUH]/R]DQR332
ËQGLFHGH$XWRUHV
3HULV-(32
3LOHWVN\6$ &2
3ODQDV( 32
3RUWHUR$ &2
3RXSRQ( 32
3URVSHU) 32
3XHEOD*RQ]iOH]00 32
4
4XHUDOW- 32
4XLQFRFHV* &2
5
5DEDVFR$0 3232
5DMDEL6LDKERRPL$5 32
5HtOOR$ 32
5HQHGR0-32
5H\5LFR$32
5LYDV(VWHEDQ3 32
5RGUtJXH]%D\yQ$0 32
5RGUtJXH]*DOiQ$ 32
5RGUtJXH]*DOiQ,&32
5RGUtJXH]-0 &2
5RGUtJXH]*LO$ &2
5RPHUR0'32
5RVDGRV6DQWRV-) 32
5RZH5& 32
5XL]0$ 323232
6
6i%DUUHWR/&/ 32
6DDGHGGLQ$ 32
6DOD632
6DODV6 323232
6iQFKH]1DYDUUR$&232
6iQFKH]$% 32
6iQFKH]6 32
6DQGH]0DFKR, &2
6DQWL3 &2
6DQWRV( &2
6DQWRYHxD$ 3232
6D\DOHUR0DULQHUR0/ 32
6FKDHIHU8)32
6HEDUURMD- 323232
6HNNDW+ 32
6LPLVWHU& 32
6ROLQtV0$ &232
6RPROLQRV0 32
6RULDQR0,32
6RXWR&32
6SXFK& &2
6WDDE$ 3
6Xxp1HJUH-032
7
7DYDUHV6LOYD)HUQDQGHV' 32
7HUUHV/ 32
7LFy-5 32
7RUUDGR--32
7RUUDGR6DQWLDJR632
7RUUHV6XiUH]$, 3232
7RUUDGR6XVDQD6 32
7RUUHV$, 32
7RUUHV/DEDQGHLUD-- 32
,;&RQJUHVRGHOD6(),*
7RUUHV0ROLQD) 32
7URFyQL],) &2
7URVGH,ODUGX\D& &23232
7XFNHU% &2
9
9DOGLYLD-*32
9DXWKLHU& 32
9HFLDQD- 3232
9HQWRVD1 3232
9LFDULRGHOD7RUUH032
9LFR(32
9LOODVPLO6 3232
:
:DJQHU(32
<
<DxH]) &2
<RUN3 32
<RXQJ0- &2
=
=DOED6 &2&2
=KX<32
=~xLJD/ 32