04-07:Layout 1
19.12.2007
12:59
Seite 3
Scientia Pharmaceutica (Sci. Pharm.) 75, 147-163 (2007)
© Österreichische Apotheker-Verlagsgesellschaft m. b. H., Wien, Printed in Austria
147
)DFWRUV ,QIOXHQFLQJ 'UXJ 'LVVROXWLRQ &KDUDFWHULVWLF IURP
+\GURSKLOLF 3RO\PHU 0DWUL[ 7DEOHW
.LDWWLVDN 6DHLR <DQHH 3RQJSDLEXO +HOPXW 9LHUQVWHLQ
6LULSRUQ 2NRQRJL
'HSDUWPHQW RI 3KDUPDFHXWLFDO 6FLHQFHV )DFXOW\ RI 3KDUPDF\ &KLDQJ 0DL
8QLYHUVLW\ &KLDQJ 0DL 7KDLODQG
'HSDUWPHQW RI 3KDUPDFHXWLFDO 7HFKQRORJ\ DQG %LRSKDUPDFHXWLFV 8QLYHUVLW\ RI
9LHQQD $ $XVWULD
$EVWUDFW
7KH DLP RI WKLV ZRUN ZDV WR LQYHVWLJDWH WKH IDFWRUV LQIOXHQFLQJ WKH GLVVROXWLRQ
FKDUDFWHULVWLFV RI GUXJ VXEVWDQFHV IURP K\GURSKLOLF SRO\PHU PDWUL[ WDEOHWV 9DULRXV
NLQGV RI FHOOXORVH GHULYDWLYH SRO\PHUV ZHUH XVHG IRU PDWUL[ IRUPDWLRQ 7KHLU VZHOOLQJ
SURSHUWLHV ZHUH PHDVXUHG 7KH HIIHFWV RQ GUXJ UHOHDVH ZHUH VWXGLHG LQ FRPSDULVRQ
ZLWK ODFWRVH 5HVXOWV LQGLFDWH WKDW GUXJ UHOHDVH FKDUDFWHULVWLFV IURP SRO\PHU PDWUL[
WDEOHWV IROORZ +LJXFKL VTXDUH URRW WLPH NLQHWLFV ,W ZDV IRXQG WKDW WKH SRO\PHUV
FRXOG UHWDUG WKH UHOHDVH RI GUXJV LQ ERWK VLPXODWHG JDVWULF IOXLG 6*) DQG
VLPXODWHG LQWHVWLQDO IOXLG 6,) EXW DW GLIIHUHQW OHYHOV 7KH GLVVROXWLRQ FRQVWDQWV RI
GUXJV ZHUH KLJKHU ZKHQ WKH S+ RI WKH GLVVROXWLRQ PHGLXP ZDV LQFUHDVHG 5HVXOWV
DOVR LQGLFDWH D OLQHDU FRUUHODWLRQ EHWZHHQ WKH SURSRUWLRQV RI PDWUL[IRUPLQJ
VWUXFWXUHV LQ WKH WDEOHWV DQG WKH H[WHQW RI GLVVROXWLRQ UHWDUGDWLRQ ,W ZDV IRXQG WKDW
QRW RQO\ WKH VZHOOLQJ SURSHUW\ RI WKH SRO\PHU EXW DOVR LWV K\GURSKRELFLW\ DQG WKH
KDUGQHVV RI WKH WDEOHW SOD\HG DQ LPSRUWDQW UROH LQ WKH UHWDUGDWLRQ RI GUXJ UHOHDVH
5HVXOWV DOVR LQGLFDWH WKDW 393 . VXSSRUWV FHOOXORVH SRO\PHUV VR DV WR LPSURYH
WKH UHOHDVH EHKDYLRU LQ RUGHU WR EHWWHU NHHS GUXJ UHOHDVH FRQVWDQW LQ HDFK WLPH
LQWHUYDO
04-07:Layout 1
19.12.2007
148
12:59
Seite 4
Kiattisak Saeio, Yanee Pongpaibuil, Helmut Viernstein, Siriporn Okonogi
.H\ZRUGV
3HQWR[LI\OOLQH .HWRSURIHQ VXVWDLQHG UHOHDVH WDEOHW +30& 393
,QWURGXFWLRQ
'UXJ PRGLILFDWLRQ DQG GRVDJH IRUPV KDYH EHHQ LQYHVWLJDWHG WR FRQWURO WKH
WLPH FRXUVH RI GUXJ UHOHDVH DQG WR PDLQWDLQ FRQVWDQW GUXJ ELRDYDLODELOLW\ 6XVWDLQHG
UHOHDVH RUDO GRVDJH IRUPV KDYH EHHQ GHPRQVWUDWHG WR LPSURYH WKHUDSHXWLF
HIILFLHQF\ E\ PDLQWHQDQFH RI D VWHDG\ GUXJ SODVPD FRQFHQWUDWLRQ >@ 0RUHRYHU
WKHUH DUH PDQ\ DGYDQWDJHV RI VXVWDLQHG UHOHDVH GRVDJH IRUPV VXFK DV
PLQLPL]DWLRQ RI SDWLHQW FRPSOLDQFH SUREOHPV UHGXFWLRQ RI ERWK ORFDO DQG V\VWHPLF
VLGH HIIHFWV DYRLGDQFH RI QLJKW WLPH GRVLQJ DQG PLQLPL]DWLRQ RI ³SHDNV´ DQG
³YDOOH\V´ LQ GUXJ EORRG OHYHOV :LWK GUXJV RI VKRUW KDOI OLIH WKDW UHTXLUH IUHTXHQW
GRVLQJ WR PDLQWDLQ FRQVWDQW WKHUDSHXWLF OHYHOV WKH QXPEHU RI GRVH DGPLQLVWUDWLRQV
FDQ EH UHGXFHG >@
,Q JHQHUDO ODFWRVH LV WKH PRVW FRPPRQ H[FLSLHQW LQ WDEOHW FRPSUHVVLRQ
+RZHYHU ³GRVH ± GXPSLQJ´ PD\ RFFXU ZLWK VROXEOH GUXJV ZKHQ FRPSUHVVHG LQ
ODFWRVH WDEOHWV >@ 7KH XVH RI SRO\PHUV LQ FRQWUROOLQJ WKH UHOHDVH RI GUXJV KDV
EHFRPH LPSRUWDQW LQ WKH IRUPXODWLRQ RI SKDUPDFHXWLFDO GRVDJH IRUPV >@ 2QH RI
WKH HIIHFWLYH VWUDWHJLHV WR DYRLG WKH GRVHGXPSLQJ HIIHFW LV WKH IDEULFDWLRQ RI
VXVWDLQHG UHOHDVH WDEOHWV E\ LQFRUSRUDWLQJ WKH GUXJ VXEVWDQFH LQ D PDWUL[ FRQWDLQLQJ
D VXLWDEOH UDWH ± FRQWUROOLQJ SRO\PHU >@ ,Q WDEOHW PDWUL[ V\VWHPV WKH WDEOHW LV LQ
WKH IRUP RI D FRPSUHVVHG FRPSDFW FRQWDLQLQJ DQ DFWLYH LQJUHGLHQW DQG WDEOHW
H[FLSLHQWV VXFK DV ILOOHU DQWLDGKHUHQW DQG OXEULFDQW 7KH PDWUL[ PD\ EH WDEOHWHG E\
GLUHFW FRPSUHVVLRQ RI WKH GULHG SRZGHU PL[WXUH RU JUDQXOHV >@
+\GURSKLOLF SRO\PHUV ZLWK KLJK JHOOLQJ FDSDFLW\ DUH RI SDUWLFXODU LQWHUHVW LQ WKH
ILHOG RI FRQWUROOHG UHOHDVH :KHQ WKH WDEOHWV FRQWDFW ZLWK ZDWHU SRO\PHU K\GUDWLRQ
DW WKH VROLG±OLTXLG LQWHUIDFH RFFXUV DQG LV IROORZHG E\ IRUPDWLRQ RI D YLVFRXV OD\HU
ZKLFK UHWDUGV WKH UHOHDVH RI GUXJ IURP WKH WDEOHWV >@ +RZHYHU WKHUH KDYH
EHHQ IHZ UHSRUWV RQ FRPSDULVRQ DPRQJ WKH SRO\PHU W\SHV WKH GLVVROXWLRQ PHGLD
DQG RWKHU IDFWRUV ZKLFK FDQ LQIOXHQFH WKH UHWDUGDWLRQ RI GUXJ UHOHDVH
04-07:Layout 1
19.12.2007
12:59
Seite 5
Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet
149
,Q WKLV VWXG\ SHQWR[LI\OOLQH 37) DQG NHWRSURIHQ .7) ZHUH XVHG DV PRGHO
GUXJV 37) LV DQ RUDOO\ DFWLYH KDHPRUUKHRORJLFDO DJHQW ,W LV LQGLFDWHG IRU LPSURYLQJ
WKH IORZ SURSHUWLHV RI EORRG E\ GHFUHDVLQJ LWV YLVFRVLW\ >@ ,W VKRZV KLJK VROXELOLW\
LQ ZDWHU ZLWK DSSUR[LPDWHO\ PJPO DW & DQG PJPO DW & 7KH KDOI OLIH
RI WKH GUXJ LV RQO\ K IRU WKH FDSVXOH GRVDJH IRUP >@ ,W ZDV UHSRUWHG WKDW
RI 37) LV HOLPLQDWHG LQ K >@ +HQFH LW LV GLIILFXOW WR PDLQWDLQ HIIHFWLYH GUXJ
FRQFHQWUDWLRQV LQ EORRG .7) LV D QRQVWHURLGDO DQWLLQIODPPDWRU\ GUXJ ZLWK ZHOO
HVWDEOLVKHG DQDOJHVLF DQG DQWLS\UHWLF SURSHUWLHV >@ ,W LV ZLGHO\ XVHG IRU WKH
WUHDWPHQW RI UKHXPDWLF GLVRUGHUV EXW UHTXLUHV IUHTXHQW DGPLQLVWUDWLRQV WR PDLQWDLQ
WKHUDSHXWLF
SODVPD
FRQFHQWUDWLRQV
>@
,Q
FRQYHQWLRQDO
SURPSWUHOHDVH
IRUPXODWLRQV NHWRSURIHQ LV UDSLGO\ DQG HIILFLHQWO\ DEVRUEHG ZLWK SHDN SODVPD OHYHOV
RFFXUULQJ ZLWKLQ ± K DIWHU ZKLFK WKH WKHUDSHXWLF SODVPD FRQFHQWUDWLRQ DEUXSWO\
IDOOV WR YHU\ ORZ OHYHOV 7KH UHODWLYHO\ KLJK JDVWURLQWHVWLQDO FRQFHQWUDWLRQ DQG
SODVPD SHDNV DVVRFLDWHG ZLWK FRQYHQWLRQDO IRUPXODWLRQV UHVXOW LQ LQFUHDVHG
LQFLGHQFH RI VLGH HIIHFWV >@ ZKLFK GHPDQG WKH XVH RI D VXVWDLQHG UHOHDVH GRVDJH
IRUP 9DULRXV DSSURDFKHV KDYH EHHQ DGRSWHG LQFOXGLQJ WKH XVH RI S+GHSHQGHQW
EDUULHU ILOPV RU FDSVXOHV GLVSHQVHG ZLWK PLFURJUDQXOHV PDWUL[ SHOOHWV RI
QDQRFU\VWDOOLQH NHWRSURIHQ DQG WDEOHWV +RZHYHU WKH HIIHFWV RI SRO\PHU SURSRUWLRQ
LQ WKH PDWUL[ WDEOHW DQG RI WKH S+ RI WKH PHGLXP RQ GUXJ GLVVROXWLRQ KDYH QRW EHHQ
GHVFULEHG LQ GHWDLO
7KH DLPV RI WKH SUHVHQW VWXG\ ZHUH WR LQYHVWLJDWH WKH UROH RI K\GURSKLOLF
SRO\PHUV LQ VXVWDLQLQJ WKH UHOHDVH RI GUXJV LQ WDEOHW GRVDJH IRUP DQG WR VWXG\ WKH
HIIHFWV RQ RWKHU GUXJ GLVVROXWLRQ FKDUDFWHULVWLFV
([SHULPHQWDO
0DWHULDOV
3HQWR[LI\OOLQH 37) ZDV SXUFKDVHG IURP /DERUDWRULR &KLPLFR ,QWHUQD]LRQDOH
,WDO\ +\GUR[\HWK\O FHOOXORVH +(& :3 YLVFRVLW\ UDQJH RI P3DV DQG
+(& 43 YLVFRVLW\ UDQJH RI P3DV ZHUH IURP $OGULFK &KHPLFDO
&RPSDQ\ ,QF 86$ +\GUR[\SURS\O PHWK\OFHOOXORVH +30& (0 DQG +30& )0
04-07:Layout 1
19.12.2007
150
12:59
Seite 6
Kiattisak Saeio, Yanee Pongpaibil, Helmut Viernstein, Siriporn Okonogi
ERWK ZLWK YLVFRVLW\ UDQJH RI P3DV ZHUH VXSSOLHG IURP &RORUFRQ 86$
3RO\YLQ\OS\UUROLGRQH 393 . 0: RI DQG 393 . 0: RI ZHUH
IURP )OXND &KHPLND 6ZLW]HUODQG 0HWKRORVH 6+ +30& ZLWK 0: RI
ZDV IURP 6KLQ (WVX -DSDQ $QK\GURXV ODFWRVH ZDV IURP 0HJJOH *HUPDQ\
.HWRSURIHQ .7) DQG RWKHU LQJUHGLHQWV ZHUH RI WKH KLJKHVW JUDGHV DYDLODEOH
6ZHOOLQJ SURSHUW\ RI WKH SRO\PHU
7KH VZHOOLQJ SURSHUW\ RI FHOOXORVH GHULYDWLYH SRO\PHUV ZDV VWXGLHG E\
PHDVXULQJ WKH FKDQJH LQ YROXPH &HUWDLQ DPRXQWV RI HDFK SRO\PHU ZHUH SODFHG LQ
PO JUDGXDWHG F\OLQGHUV DW DQ LQLWLDO DSSDUHQW YROXPH RI PO 6XEVHTXHQWO\
ZDWHU ZDV DGGHG WR D YROXPH RI PO 7KH VZHOOLQJ SURSHUW\ RI WKH SRO\PHU
REVHUYHG ZLWKLQ K ZDV H[SUHVVHG ERWK DV WKH VZHOOLQJ UDWLR DQG VZHOOLQJ UDWH
7KH VZHOOLQJ UDWLR 4G IRU HDFK SRO\PHU ZDV FDOFXODWHG IURP WKH IROORZLQJ
HTXDWLRQ
4G 9V 9G
9G
ZKHUH 9G DQG 9V UHSUHVHQW WKH YROXPH RI WKH LQLWLDO GULHG SRO\PHU DQG WKH ILQDO
YROXPH RI VZROOHQ SRO\PHU UHVSHFWLYHO\ 7KH VZHOOLQJ UDWH ZDV FDOFXODWHG DV WKH
YROXPH LQFUHDVH 9 V 9G SHU K 7KH H[SHULPHQW ZDV GRQH LQ WULSOLFDWH
3UHSDUDWLRQ RI WDEOHWV
3RZGHU PL[WXUHV RI 37) DQG SRO\PHU RU ODFWRVH DW D ZHLJKW UDWLR RI ZHUH
PRLVWHQHG DQG VLHYHG WKURXJK D PP ZLUH PHVK $IWHU GU\LQJ ƒ& K WKH
JUDQXOHV ZHUH VLHYHG DJDLQ WKURXJK D PP ZLUH PHVK WKHQ PL[HG ZLWK WDOFXP DQG PDJQHVLXP VWHDUDWH 7KH PL[WXUH ZDV FRPSUHVVHG E\ XVH RI D
VLQJOH SXQFK WDEOHWLQJ PDFKLQH WR \LHOG WDEOHWV RI PJ HDFK 7KH KDUGQHVV RI
37) WDEOHWV REWDLQHG ZDV PHDVXUHG E\ XVH RI D KDUGQHVV WHVWHU 3KDUPD 7HVWŠ
W\SH 37% *HUPDQ\ )RU WKH IRUPDWLRQ RI .7) PDWUL[ WDEOHWV SDUWV RI .7)
DQG SDUW RI ODFWRVH ZHUH PL[HG ZLWK JUDGHG SURSRUWLRQV RI PL[WXUHV FRPSRVHG RI
+30& 0HWKRORVH 6+ DQG FDOFLXP K\GURJHQ SKRVSKDWH GLK\GUDWH PDVV
04-07:Layout 1
19.12.2007
12:59
Seite 7
Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet
151
UDWLR 7KH ZHW PL[WXUH ZDV JUDQXODWHG DQG VLHYHG WKURXJK D PP ZLUH PHVK
$IWHU GU\LQJ ƒ& K WKH JUDQXOHV ZHUH VLHYHG DJDLQ WKURXJK D PP ZLUH
PHVK WKHQ PL[HG ZLWK RI PL[WXUH RI WDOFXP DQG PDJQHVLXP VWHDUDWH 7KH
PL[WXUH ZDV FRPSUHVVHG LQWR GRXEOH FRQYH[ PP GLDPHWHU WDEOHWV DW D SUHVVXUH
RI .EDU XVLQJ D +DQVHDWHQ ( ([FHQWHU SUHVV 7KH FRQWHQW RI .7) LQ HDFK WDEOHW
ZDV PJ
'LVVROXWLRQ VWXGLHV
'LVVROXWLRQ VWXGLHV ZHUH SHUIRUPHG DFFRUGLQJ WR 0HWKRG RI 863 DW
“ ƒ& ,Q FDVH RI 37) PO RI VLPXODWHG JDVWULF IOXLG 6*) RU VLPXODWHG
LQWHVWLQDO IOXLG 6,) ZDV ILOOHG LQWR D JODVV GLVVROXWLRQ YHVVHO DQG WKH SDGGOH ZDV
URWDWHG DW WKH VSHHG RI USP 7KH WDEOHW ZDV SXW LQ WKH VLQNHU )LJ SULRU WR
FRQWDFW ZLWK WKH PHGLXP WR SUHYHQW WDEOHW IORDWLQJ 'HWHUPLQDWLRQ RI GUXJ UHOHDVH
ZDV GRQH E\ VSHFWURSKRWRPHWU\ DW QP ,Q FDVH RI .7) PO RI GLVVROXWLRQ
PHGLXP 0 +&O RU EXIIHU S+ RU EXIIHU S+ ZDV XVHG DW D SDGGOH VSHHG
RI USP %XIIHU S+ FRPSULVHG PO 0 1D+32 DQG PO 0
FLWULF DFLG VROXWLRQ %XIIHU S+ ZDV IRUPHG E\ QHXWUDOL]DWLRQ RI 0 +&O DV
IROORZV $ PL[WXUH ZDV SUHSDUHG RI PO 0 +&O 0 1D+32 0
1D2+ DV UHTXLUHG 4XDQWLILFDWLRQ RI OLEHUDWHG GUXJ ZDV SHUIRUPHG E\ SKRWRPHWULF
PHDVXUHPHQW DW D ZDYHOHQJWK RI QP
D
E
)LJ 7DEOHW VLQNHU D DQG WKH VLQNHU ZLWK D 37) WDEOHW GXULQJ GLVVROXWLRQ E
04-07:Layout 1
19.12.2007
152
12:59
Seite 8
Kiattisak Saeio, Yanee Pongpaibil, Helmut Viernstein, Siriporn Okonogi
(IIHFW RI 393 DV D GUXJ UHOHDVH PRGLILHU
7KLV H[SHULPHQW ZDV SHUIRUPHG ZLWK WKH 37)FHOOXORVH SRO\PHU WDEOHW 7KH
DPRXQW RI SRO\PHU RI WKH VHOHFWHG IRUPXODWLRQ ZDV UHSODFHG ZLWK 393 . RU
393 . 7DEOHW SUHSDUDWLRQ DQG GLVVROXWLRQ VWXG\ ZHUH SHUIRUPHG DV GHVFULEHG
DERYH
5HVXOWV DQG 'LVFXVVLRQ
6ZHOOLQJ SURSHUWLHV RI SRO\PHUV
7KH VZHOOLQJ RI WKH K\GURSKLOLF SRO\PHUV LV DVVRFLDWHG ZLWK PROHFXODU
K\GUDWLRQ DQG DOZD\V RFFXUV ZKHQ SRO\PHUV FRPH LQ FRQWDFW ZLWK ZDWHU
3URJUHVVLYH VZHOOLQJ RI SRO\PHUV FDXVHV FRQVLGHUDEOH VWUXFWXUDO FKDQJHV 7KHVH
LQFOXGH WKH PRGLILFDWLRQ RI SRURVLW\ DQG WRUWXRVLW\ RI WKH SRO\PHUV ZKLFK DIIHFW WKH
GLIIXVLRQDO UHOHDVH RI D GUXJ > @ 7KH VZHOOLQJ SURSHUW\ RI SRO\PHUV FDQ EH
H[SUHVVHG DV VZHOOLQJ UDWLR RU UDWH RI VZHOOLQJ 7KH VZHOOLQJ UDWLR VXJJHVWV WKH
DELOLW\ RI D SRO\PHU WR H[SDQG LWV YROXPH DIWHU K\GUDWLRQ ZKHUHDV WKH UDWH RI
VZHOOLQJ LQGLFDWHV KRZ IDVW WKH ZDWHU FDQ SHQHWUDWH LQWR WKH SRO\PHU FU\VWDO ODWWLFH
,Q WKH SUHVHQW H[SHULPHQWV IRXU FHOOXORVH GHULYDWLYH SRO\PHUV H[KLELWHG GLIIHUHQW
VZHOOLQJ OHYHOV DV VKRZQ LQ 7DE ,W ZDV GHPRQVWUDWHG WKDW +(& 43
H[KLELWV WKH PRVW VZHOOLQJ ZLWK WKH KLJKHVW VZHOOLQJ UDWLR DQG UDWH RI VZHOOLQJ RI
DQG POK UHVSHFWLYHO\ IROORZHG E\ WKH LQVLJQLILFDQWO\ OHVVHU OHYHO RI
VZHOOLQJ RI +(& :3 DQG +30& (0 7KH SRRUHVW VZHOOLQJ SURSHUW\ ZDV IRXQG
ZLWK +30& )0
3RO\PHUV
+(& :3
+(& 43
6ZHOOLQJ 5DWLR
5DWH RI 6ZHOOLQJ POK
+30& (0
+30& )0
7DE 6ZHOOLQJ UDWLR RI DOO SRO\PHUV ZLWKLQ K
04-07:Layout 1
19.12.2007
12:59
Seite 9
Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet
153
3K\VLFDO DSSHDUDQFH DQG KDUGQHVV RI 37) WDEOHWV
7KH SK\VLFDO DSSHDUDQFH RI 37) WDEOHWV SUHSDUHG ZLWK GLIIHUHQW W\SHV RI
SRO\PHUV RU ODFWRVH ZHUH REORQJ VKDSH DQG ZKLWH LQ FRORU ,W ZDV IRXQG WKDW 37)
PDWUL[ WDEOHWV SUHSDUHG ZLWK WKH WHVW SRO\PHUV RU ODFWRVH FRXOG EH HDVLO\
FRPSUHVVHG LQWR WDEOHWV 7KH WDEOHWV ZHUH HDVLO\ UHPRYDEOH IURP WKH GLH FDYLW\
UHJDUGOHVV RI WKH DGGLWLRQ RI D VPDOO TXDQWLW\ RI WDOFXP DQG PDJQHVLXP VWHDUDWH
7KH WDEOHWV FRPSUHVVHG ZLWK +(& VKRZHG UDWKHU URXJK VXUIDFH ZKLOH WKRVH ZLWK
+30& RU ODFWRVH SRVVHVVHG VPRRWK DQG JOLWWHU VXUIDFHV DV VKRZQ LQ )LJ )LJ 7KH VXUIDFH FKDUDFWHULVWLFV RI D +(& WDEOHW OHIW DQG D +30& WDEOHW ULJKW
7KH WDEOHWV REWDLQHG IURP SRO\PHU PDWUL[ H[KLELWHG GLIIHUHQW KDUGQHVV YDOXHV
LQ WKH UDQJH RI 1 DV VKRZQ LQ 7DE ZKLOH WKRVH IURP ODFWRVH DOVR IHOO ZLWKLQ
WKLV UDQJH ,Q FRPSDULVRQ DPRQJ WKRVH H[FLSLHQWV +30& (0 JDYH WKH WDEOHWV
ZLWK WKH KLJKHVW KDUGQHVV 7KH KDUGQHVV DOZD\V LQIOXHQFHV WKH FRPSDFWLRQ RI
VXEVWDQFHV LQVLGH WKH WDEOHWV WKH KLJKHU WKH KDUGQHVV WKH KLJKHU WKH FRPSDFWLRQ
RI WKH WDEOHWV 7KH KLJK FRPSDFWLRQ FDXVHV D GHFUHDVH LQ SRURVLW\ RI WKH SRO\PHU
PDWUL[ +HQFH WKH WDEOHWV ZLWK KLJK FRPSDFWLRQ KDYH D KLJK DELOLW\ WR UHWDUG WKH
ZDWHU SHQHWUDWLRQ LQWR WKHLU FRUH 7KH KLJKHVW KDUGQHVV RI +30& (0 FRQWDLQLQJ
WDEOHWV LQGLFDWHG WKDW WKH\ VKRXOG KDYH WKH KLJKHVW DELOLW\ WR UHWDUG ZDWHU SHQHWUDWLRQ
UHVXOWLQJ LQ VORZ UHOHDVH RI GUXJ PROHFXOHV IURP WKLV PDWUL[
04-07:Layout 1
154
19.12.2007
12:59
Seite 10
Kiattisak Saeio, Yanee Pongpaibil, Helmut Viernstein, Siriporn Okonogi
([FLSLHQWV
$YHUDJH +DUGQHVV 1
+(& :3
+(& 43
+30& (0
+30& )0
/DFWRVH
YDOXHV UHSUHVHQW DYHUDJH 6' Q 7DE +DUGQHVV RI 37) WDEOHWV IURP GLIIHUHQW H[FLSLHQWV
'LVVROXWLRQ RI GUXJV IURP FHOOXORVH SRO\PHU WDEOHWV
7KH GLVVROXWLRQ EHKDYLRU RI 37) IURP WDEOHWV FRQWDLQLQJ GLIIHUHQW W\SHV RI
FHOOXORVH SRO\PHUV LV LOOXVWUDWHG LQ )LJ 5HVXOWV UHYHDOHG D VLJQLILFDQW GLIIHUHQFH LQ
GUXJ GLVVROXWLRQ EHKDYLRU EHWZHHQ WDEOHWV ZLWK ODFWRVH DQG WKRVH ZLWK WKH SRO\PHUV
$ YHU\ UDSLG UHOHDVH RI GUXJ IURP ODFWRVH WDEOHWV ZDV IRXQG ZLWKLQ PLQ LQ ERWK
6*) DQG 6,) ZKHUHDV WKH SRO\PHU WDEOHWV VKRZHG WKH UHWDUGDWLRQ RI GUXJ UHOHDVH
7KLV ZDV GXH WR WKH KLJK ZDWHU VROXELOLW\ RI ODFWRVH DQG WKH UHODWLYHO\ ORZ
FRPSDFWLRQ RI VXFK WDEOHWV DFFRUGLQJ WR LWV LQIHULRU KDUGQHVV $V D FRQVHTXHQFH
ZDWHU HDVLO\ SHQHWUDWHV LQWR WKH WDEOHWV DQG WKH VROXEOH 37) PROHFXOHV DUH UDSLGO\
UHOHDVHG 7KH SRO\PHUV DUH OHVV ZDWHU VROXEOH WKDQ ODFWRVH +HQFH WKH ZDWHU
SHQHWUDWLRQ LQWR WKH SRO\PHU PDWUL[ WDEOHW LV PRUH GLIILFXOW 7KLV OHDGV WR WKH
UHWDUGDWLRQ RI GUXJ UHOHDVH 5HVXOWV DOVR LQGLFDWH WKDW LQ 6*) WKH DPRXQW RI GUXJ
UHOHDVHG LV OHVV WKDQ LQ 6,) ZKRVH S+ LV KLJKHU 7KH HIIHFW RI S+ ZDV FRQVLVWHQW
ZKHQ .7) ZDV XVHG DV D PRGHO GUXJ DQG +30& ZDV XVHG DV D PRGHO SRO\PHU DV
VKRZQ LQ )LJ 7KH KLJKHU WKH S+ WKH KLJKHU WKH GUXJ GLVVROXWLRQ FRQVWDQW \
± [ \
± [ DQG \
± [ LQ 0
+&O EXIIHU S+ DQG EXIIHU S+ UHVSHFWLYHO\ ,Q DGGLWLRQ WKHUH LV D OLQHDU
FRUUHODWLRQ EHWZHHQ WKH SURSRUWLRQ RI SRO\PHU LQ WKH WDEOHWV DQG WKH H[WHQVLRQ RI
GUXJ UHWDUGDWLRQ LQ DOO WKUHH GLVVROXWLRQ PHGLD U DQG LQ 0
+&O EXIIHU S+ DQG EXIIHU S+ UHVSHFWLYHO\
04-07:Layout 1
19.12.2007
12:59
Seite 11
Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet
E
F
G
H
D
'UXJ 5HOHDVH PJ
'UXJ 5HOHDVH PJ
D
E
F
G
155
H
7LPH PLQ
7LPH PLQ
$
%
)LJ 'LVVROXWLRQ SURILOHV RI 37) UHOHDVH IURP WDEOHWV RI GLIIHUHQW H[FLSLHQWV
ODFWRVH D +(& :3 E +(& 43 F +30& (0 G DQG
+30& (0 H LQ 6*) $ DQG 6,) %
'LVVROXWLRQ FRQVWDQW PJPLQ
+30&7DEOHW
)LJ 7KH UHODWLRQVKLS RI SRO\PHU FRQWHQW DQG GLVVROXWLRQ FRQVWDQW RI .7) LQ
EXIIHU S+ §EXIIHU S+ S DQG 0 +&O 04-07:Layout 1
19.12.2007
156
12:59
Seite 12
Kiattisak Saeio, Yanee Pongpaibil, Helmut Viernstein, Siriporn Okonogi
+RZHYHU WKH WRWDO DPRXQW RI GUXJ UHOHDVHG IURP SRO\PHU WDEOHWV ZKHQ
SORWWHG YHUVXV WLPH GLG QRW ILW WKH UHJUHVVLRQ OLQH 7KLV ZDV PRUH REYLRXVO\ VHHQ
ZKHQ GLVVROXWLRQ WRRN SODFH LQ 6,) 7KHLU UHOHDVH EHKDYLRU VHHPHG WR IROORZ WKH
+LJXFKL HTXDWLRQ DV IROORZV
: NW : LV WKH WRWDO DPRXQW RI GUXJ UHOHDVH DW D WLPH W DQG N LV WKH UHOHDVH
ZKHUH
FRQVWDQW 7KH +LJXFKL SORWV RI DOO GUXJ SRO\PHU WDEOHWV LQ 6*) DQG 6,) DUH VKRZQ LQ
)LJ DQG )LJ UHVSHFWLYHO\
D
6TXDUH 5RRW 7LPH PLQ
5 . 6TXDUH 5RRW 7LPH PLQ
5 . 'UXJ 5HOHDVH PJ
G
'UXJ 5HOHDVH PJ
F
5 . 'UXJ 5HOHDVH PJ
'UXJ 5HOHDVH PJ
E
5 . 6TXDUH 5RRW 7LPH PLQ
6TXDUH 5RRW 7LPH PLQ
)LJ +LJXFKL SORWV RI 37) UHOHDVH IURP WDEOHWV FRQWDLQLQJ +(& :3 D
+(& 43 E +30& (0 F DQG +30& )0 G LQ 6*)
7KH GLVVROXWLRQ UDWH RI 37) IURP HDFK SRO\PHU WDEOHW FRXOG EH GHWHUPLQHG
IURP WKH VORSH RI WKH +LJXFKL SORW ,W ZDV REYLRXVO\ VHHQ SDUWLFXODUO\ LQ 6,) WKDW WKH
GUXJ UHOHDVH ZDV EHWWHU VXVWDLQHG LQ WKH WDEOHWV ZLWK +30& WKDQ +(& 7KLV PD\ EH
GXH WR WKH ZDWHU VROXELOLW\ RI WKH SRO\PHUV %DVHG RQ WKH FKHPLFDO VWUXFWXUH +(&
04-07:Layout 1
19.12.2007
12:59
Seite 13
Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet
157
SRO\PHU VKRXOG EH PRUH ZDWHU VROXEOH WKDQ +30& 7KH ZDWHU FRXOG WKXV SHQHWUDWH
PRUH HDVLO\ WR GLVVROYH 37) LQ WKH +(& WDEOHWV 0RUHRYHU WKH YLVFRVLW\ RI D
SRO\PHU JHO LV D UDWHFRQWUROOLQJ IDFWRU LQ GUXJ GLVVROXWLRQ >@ 7KH KLJKHU WKH
YLVFRVLW\ WKH PRUH UHVLVWDQW WKH PDWUL[ WR GLVVROXWLRQ DQG HURVLRQ 6LQFH WKH +30&
SRO\PHUV XVHG LQ WKLV VWXG\ DUH PXFK PRUH YLVFRXV WKDQ +(& WKLV FRXOG H[SODLQ
WKH UHOHDVH UHWDUGDWLRQ SURSHUW\ RI WKH +30& SRO\PHUV +RZHYHU LW ZDV QRWLFHG
WKDW VRPH UHWDUGDWLRQ RI GUXJ UHOHDVH RFFXUUHG LQ +(& 43 WDEOHWV 7KLV PD\
EH GXH WR WKH KLJK VZHOOLQJ SURSHUW\ RI WKLV SRO\PHU 2QFH WKH WDEOHWV FRQWDFW WKH
PHGLXP WKH SHQHWUDWHG ZDWHU FDXVHV WKLV SRO\PHU WR VZHOO UDSLGO\ 7KH WKLFNQHVV
DQG GHFUHDVHG SRURVLW\ RI WKH GLIIXVLRQ OD\HU LQKLELWV WKH SDVVDJH RI WKH GUXJ
PROHFXOHV UHVXOWLQJ LQ UHWDUGDWLRQ RI GUXJ UHOHDVH
'UXJ 5HOHDVH PJ
D
E
6TXDUH 5RRW 7LPH PLQ
5 . G
6TXDUH 5RRW 7LPH PLQ
5 . 'UXJ 5HOHDVH PJ
'UXJ 5HOHDVH PJ
F
5 . 'UXJ 5HOHDVH PJ
5 . 6TXDUH 5RRW 7LPH PLQ
6TXDUH 5RRW 7LPH PLQ
)LJ +LJXFKL SORWV RI 37) UHOHDVH IURP WDEOHWV FRQWDLQLQJ +(& :3 D
+(& 43 E +30& (0 F DQG +30& )0 G LQ 6,)
04-07:Layout 1
19.12.2007
158
12:59
Seite 14
Kiattisak Saeio, Yanee Pongpaibil, Helmut Viernstein, Siriporn Okonogi
&RPSDULQJ +30& (0 ZLWK +30& )0 WKHUH ZDV QR VLJQLILFDQW GLIIHUHQFH
LQ VXVWDLQHG UHOHDVH RI GUXJ +RZHYHU WDEOHWV ZLWK +30& (0 H[KLELWHG
VLJQLILFDQWO\ KLJKHU KDUGQHVV DFFRPSDQLHG E\ KLJK FRPSDFWLRQ $V GHVFULEHG
SUHYLRXVO\ WKH KLJKHU WKH FRPSDFWLRQ WKH KLJKHU WKH UHWDUGDWLRQ RI GUXJ UHOHDVH
7KHUHIRUH WKH GUXJ UHWDUGDWLRQ VHHPHG WR EH DVVXUHG ZKHQ GUXJV ZHUH
LQFRUSRUDWHG LQ +30& (0 WDEOHWV 0RUHRYHU WKH KLJKHU KDUGQHVV SURYLGHG WDEOHWV
ZLWK EHWWHU SURWHFWLRQ SRZHU IURP IUDJLOLW\ GXH WR ZHLJKW RU VWUHVV IRUFHV 7KXV
KDUGQHVV LV RQH RI WKH UHTXLUHPHQWV IRU WDEOHWV WKDW VKRXOG EH PHW IRU WKHP WR
ZLWKVWDQG KDQGOLQJ LQ WKH ORJLVWLF FKDLQ IURP SURGXFHU WR SDWLHQW )RU WKHVH UHDVRQV
+30& (0 ZDV VHOHFWHG WR EH WKH PRVW VXLWDEOH H[FLSLHQW IRU GUXJ WDEOHW
IRUPXODWLRQ
(IIHFW RI 393 DV GUXJ UHOHDVH PRGLILHU
,QLWLDO UHVXOWV LQGLFDWHG WKDW +30& (0 ZDV WKH PRVW VXLWDEOH SRO\PHU EDVH
IRU GUXJ PDWUL[ WDEOHWV +RZHYHU WKH DPRXQW RI GUXJ UHOHDVH LQ HDFK WLPH LQWHUYDO
G4GW ZKHQ SORWWHG YHUVXV WLPH W ZDV IOXFWXDWHG FRQVLGHUDEO\ DV VKRZQ LQ )LJ
D 7KLV LQFRQVWDQW GUXJ UHOHDVH VXJJHVWHG D WUHQG RI XQVWHDG\ GUXJ
FRQFHQWUDWLRQ LQ SODVPD DIWHU RUDO DGPLQLVWUDWLRQ RI WKLV W\SH RI WDEOHW
E
F
G4GW PJPLQ
G4GW PJPLQ
G4GW PJPLQ
D
7LPH PLQ
7LPH PLQ
7LPH PLQ
)LJ 'LVVROXWLRQ SURILOH RI GUXJ UHOHDVH LQ HDFK WLPH LQWHUYDO G4GW RI
37)+30& (0 WDEOHWV ZLWKRXW 393 D ZLWK 393 . E DQG ZLWK
393 . F
04-07:Layout 1
19.12.2007
12:59
Seite 15
Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet
159
$V PHQWLRQHG DERYH WKH UHOHDVH RI GUXJ IURP WKH WHVWHG SRO\PHU PDWUL[ ZDV
LQIOXHQFHG E\ WKH GXDO HIIHFWV RI WKH K\GURSKLOLFLW\ RI SRO\PHU DQG WKH VZHOOLQJ RI WKH
PDWUL[ XSRQ K\GUDWLRQ 7KH K\GURSKLOLFLW\ RI WKH SRO\PHU FDXVHG WKH PDWUL[ WR EH
HURGHG GXULQJ GUXJ GLVVROXWLRQ 7KLV XQFRQWUROOHG HURVLRQ ZDV FRQVLGHUHG WR EH D
PDMRU IDFWRU IRU GUXJ GLVVROXWLRQ ,I JUDGXDO FRQVWDQW HURVLRQ RFFXUUHG WKH VWHDG\
GUXJ FRQFHQWUDWLRQ LQ HDFK WLPH LQWHUYDO ZDV REVHUYHG 7KHUHIRUH WKH IOXFWXDWHG
GUXJ UHOHDVHG ZDV GXH WR WKH XQFRQWUROOHG FRPSRVLWLRQ RI WKH SRO\PHU PDWUL[
7KH UHSODFHPHQW RI +30& (0 ZLWK 393 . LQ WKH WDEOHW IRUPXODWLRQ
VKRZHG QR HIIHFW RQ WKLV UHOHDVH PHFKDQLVP +RZHYHU ZKHQ 393 . ZDV XVHG
LQVWHDG RI 393 . WKHUH ZDV VRPH VLJQLILFDQW PRGLILFDWLRQ DV VKRZQ LQ )LJ F
,QGHHG LW ZDV REVHUYHG WKDW WKH GUXJ UHOHDVH SURILOH SDUWLFXODUO\ DIWHU PLQ RI
GLVVROXWLRQ ZDV PRUH FRQVWDQW ZLWK WKH GUXJ UHOHDVH DW DERXW PJ GXULQJ WKH
GLVVROXWLRQ SHULRG RI PLQ 7KHVH UHVXOWV VXJJHVW WKDW 393 . LV DQ HIILFLHQW
UHOHDVH PRGLILHU LPSURYLQJ WKH UHOHDVH EHKDYLRU RI 37) WDEOHWV WRZDUG PRUH
FRQVWDQW GUXJ UHOHDVH GXULQJ D VXIILFLHQW OHQJWK RI WLPH
&RQFOXVLRQ
,W ZDV FRQFOXGHG WKDW WKH EHVW VXVWDLQHG UHOHDVH WDEOHW FRXOG EH SURGXFHG
XVLQJ +30& DV K\GURSKLOLF FRQWUROOLQJ SRO\PHU 7KH +LJXFKL PRGHO FRXOG EH XVHG
IRU SUHGLFWLRQ RI GUXJ UHOHDVH 7KH S+ RI GLVVROXWLRQ PHGLD DQG WKH SURSRUWLRQ RI
SRO\PHU LQ WKH WDEOHW DIIHFWHG WKH GLVVROXWLRQ FKDUDFWHULVWLFV RI WKH GUXJ ,W ZDV
IRXQG WKDW QRW RQO\ WKH VZHOOLQJ SURSHUW\ RI WKH SRO\PHU EXW DOVR LWV K\GURSKRELFLW\
DQG WKH KDUGQHVV RI WKH WDEOHW SOD\HG DQ LPSRUWDQW UROH LQ UHWDUGDWLRQ RI GUXJ
UHOHDVH 7KH DGGLWLRQ RI 393 . WR WKH +30& WDEOHWV LPSURYHG WKH +30& PDWUL[
VWUXFWXUH VR DV WR UHOHDVH WKH GUXJ LQ FRQVWDQW DPRXQWV LQ HDFK WLPH LQWHUYDO
$FNQRZOHGJHPHQW
$SSUHFLDWLRQ LV H[SUHVVHG WR 6LDP 3KDUPDFHXWLFDO &R /WG 7KDLODQG IRU
VXSSO\ RI FKHPLFDOV DQG SDUWLDO ILQDQFLDO VXSSRUW
04-07:Layout 1
19.12.2007
160
12:59
Seite 16
Kiattisak Saeio, Yanee Pongpaibil, Helmut Viernstein, Siriporn Okonogi
5HIHUHQFHV
>@ 7XUQHU 6 )HGHULFL & +LWH 0 )DVVLKL 5
)RUPXODWLRQ 'HYHORSPHQW DQG +XPDQ ,Q 9LWUR,Q 9LYR &RUUHODWLRQ IRU D 1RYHO
0RQROLWKLF &RQWUROOHG 5HOHDVH 0DWUL[ 6\VWHP RI +LJK /RDG DQG +LJKO\ :DWHU
6ROXEOH 'UXJ 1LDFLQ
'UXJ 'HY ,QG 3KDUP >@ )HUQDQGHV &0 5DPRV 3 $PLOFDU &) 9HLJD )%
+\GURSKLOLF DQG K\GURSKRELF F\FORGH[WULQV LQ D QHZ VXVWDLQHG UHOHDVH RUDO
IRUPXODWLRQ RI QLFDUGLSLQH LQ YLWUR HYDOXDWLRQ DQG ELRDYDLODELOLW\ VWXGLHV LQ
UDEELWV
- &RQWURO 5HOHDVH >@ *UHHQEODWW '-
3KDUPDFRNLQHWLF GHWHUPLQDQWV RI K\SQRWLF GUXJ DFWLRQ 7KH DUW DQG VFLHQFH RI
FRQWUROOLQJ UHOHDVH
6OHHS 0HGLFLQH 66
>@ 3DWKHU 6, 5XVVHOO , 6\FH -$ 1HDX 6+
6XVWDLQHG UHOHDVH WKHRSK\OOLQH WDEOHWV E\ GLUHFW FRPSUHVVLRQ 3DUW IRUPXODWLRQ DQG LQ YLWUR WHVWLQJ
,QW - 3KDUP >@ 6DNR . 6DZDGD 7 1DNDVKLPD + <RNRKDPD 6 6RQREH 7
,QIOXHQFH RI ZDWHU VROXEOH ILOOHUV LQ K\GUR[\SURS\OPHWK\OFHOOXORVH PDWULFHV RQ LQ
YLWUR DQG LQ YLYR GUXJ UHOHDVH
- &RQWURO 5HOHDVH >@ &KRZGDU\ .3 6DQNDU **
(XGUDJLW PLFURFDSVXOHV RI QLIHGLSLQH DQG LWV GLVSHUVLRQV LQ +30&0&&
SK\VLFRFKHPLFDO FKDUDFWHUL]DWLRQ DQG GUXJ UHOHDVH VWXGLHV
'UXJ 'HY ,QG 3KDUP 04-07:Layout 1
19.12.2007
12:59
Seite 17
Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet
161
>@ (EXEH 1. +LNDO $+ :\DQGW &0 %HHU '& -RQHV $%
(IIHFW RI 'UXJ )RUPXODWLRQ DQG 3URFHVV 9DULDEOHV RQ *UDQXODWLRQ DQG
&RPSDFWLRQ &KDUDFWHULVWLFV RI +HWHURJHQHRXV 0DWULFHV 3DUW +30& DQG
393 6\VWHPV
'UXJ 'HY ,QG 3KDUP >@ /RWILSRXU ) 1RNKRGFKL $ 6DHHGL 0 1RURX]L6DQL 6 6KDUEDIL -
6LDKL6KDGEDG 05
7KH HIIHFW RI K\GURSKLOLF DQG OLSRSKLOLF SRO\PHUV DQG ILOOHUV RQ WKH UHOHDVH UDWH
RI DWHQRORO IURP +30& PDWULFHV
,/ )DUPDFR ±
>@ 9D]TXH] 0- 3HUH]0DUFRV % *RPH]$PR]D -/ 0DUWLQH]3DFKHFR 5 6RXWR
& &RQFKHLUR $
,QIOXHQFH RI 7HFKQRORJLFDO 9DULDEOHV RQ 5HOHDVH RI 'UXJ IURP +\GURSKLOLF
0DWULFHV
'UXJ 'HY ,QG 3KDUP >@ +DUFXP :: 6NLQQHU *: $OWHNDU 0 -RQHMD 6. %DUQXP 3( *XR -+
0RGHOOLQJ WKH (IIHFWV RI +\GUR[\SURS\OFHOOXORVH LQ $FHWDPLQRSKHQ 7DEOHW
)RUPXODWLRQ
'UXJ 'HY ,QG 3KDUP >@ 3DERQ &9 )UXWRV 3 /DVWUHV -/ )UXWRV *
,Q YLWUR VWXG\ RI PL[HG FRQWUROOHG UHOHDVH PDWUL[ WDEOHWV FRQWDLQLQJ +03& DQG
SRO\DPLGH 'UXJ 'HY ,QG 3KDUP >@ &KLULFR 6 'DOPRUR $ /DPEHUWL * 5XVVR * 7LWRPDQOLR *
$QDO\VLV DQG PRGHOLQJ RI VZHOOLQJ DQG HURVLRQ EHKDYLRU IRU SXUH +30& WDEOHW
- 3KDUP 6FL 04-07:Layout 1
19.12.2007
162
12:59
Seite 18
Kiattisak Saeio, Yanee Pongpaibil, Helmut Viernstein, Siriporn Okonogi
>@ 9D]TXH] 0- &DVDOGHUUH\ 0 *RPH]$PR]D -* 0DUWLQH]3DFKHFR 5
6RXWR & DQG &RQFKHLUR $
$WHQRORO
UHOHDVH
IURP
K\GURSKLOLF
PDWUL[
WDEOHWV
ZLWK
K\GUR[\SURS\OPHWK\OFHOOXORVH +30& PL[WXUHV DV JHOOLQJ DJHQW HIIHFWV RI WKH
YLVFRVLW\ RI +70/ PL[WXUH
(XU - 3KDUP 6FL >@ $ODQ : 6WHSKHQ 3&
3HQWR[LI\OOLQH ± $ 5HYLHZ RI LWV 3KDUPDFRG\QDPLF DQG 3KDUPDFRNLQHWLF
3URSHUWLHV DQG LWV 7KHUDSHXWLF (IILFDF\
'UXJ ± >@ 0DNRWR 2 <RVKLKLGD 0
&RQWUROOHG 'UXJ 5HOHDVH RI +LJKO\ :DWHU 6ROXEOH 3HQWR[LI\OOLQH IURP 7LPH
/LPLW 'LVLQWHJUDWLRQ 7\SH :D[ 0DWUL[ 7DEOHW
3KDUP 5HV >@ 0DNRWR 2 <RVKLKLGD 0
3URJUDPDEOH 'UXJ 5HOHDVH RI +LJKO\ :DWHU6ROXEOH 3HQWR[LI\OOLQH IURP 'U\ ±
&RDWHG :D[ 0DWUL[
- 3KDUP 6FL >@ *OHL[QHU . 0XOOHU 5 /HKUDFK )
3KDUPDFHXWLFDO FRPSRVLWLRQV
86 3DWHQW )HE >@ )RVVJUHHQ - .LUFKKHLQHU % 3HWHUVHQ )2 7RSK¡M ( =DFKDULDH (
&OLQLFDO HYDOXWDWLRQ RI NHWRSURIHQ 53
,Q UKHXPDWRLG DUWKULWLVGRXEOHEOLQG FURVVRYHU FRPSDULVRQZLWK LQGRPHWKDFLQ
6FDQG - 5KHXPDWRO 6XSSO ±
>@ &DWKFDUW %- 9LQFH -' *RUGRQ $- %HOO 0 &KDOPHUV ,0
6WXGLHV RQ EHQ]R\OSKHQ\O SURSLRQLF DFLG µ2UXGLV¶
$QQ 5KHXP 'LV ±
04-07:Layout 1
19.12.2007
12:59
Seite 19
Factors Influencing Drug Dissolution Characteristic from Hydrophilic Polymer Matrix Tablet
163
>@ /LYHUVLGJH **
.HWRSURIHQ
,Q )ORUH\ . (G $QDO\WLFDO 3URILOHV RI 'UXJ 6XEVWDQFHV
1HZ <RUN$FFDGHPLF 3UHVV ±
>@ *UDKDP ** 'D\ 52 &KDPSLRQ *' /HH ( 1HZWRQ .
$VSHFWV RI WKH FOLQLFDO SKDUPDFRORJ\ RI QRQVWHURLGDO DQWLLQIODPPDWRU\ GUXJV
&OLQ 5KHXP 'LV ±
>@ .RUVPH\HU 5: *XUQ\ 5 'RHONHU ( %XUL 3 3HSSDV 1$
0HFKDQLVPV RI VROXWH UHOHDVH IURP SRURXV K\GURSKLOLF SRO\PHUV
,QW - 3KDUP >@ .RUVPH\HU 5: 3HSSDV 1$
(IIHFW RI WKH PRUSKRORJ\ RI K\GURSKLOLF SRO\PHULF PDWULFHV RQ WKH GLIIXVLRQ DQG
UHOHDVH RI ZDWHU VROXEOH GUXJV
- 0HPEUDQH 6FL >@ (PHMH 02 .XQOH 22 2IRHIXOH 6,
7KH HIIHFW RI WKH PROHFXODU VL]H RI FDUER[\PHWK\OFHOOXORVH RQ WKH UDWH RI
K\GUDWLRQ PDWUL[ HURVLRQ DQG GUXJ UHOHDVH
'UXJ 'HOLYHU\ 7HFK Received October 28th, 2007
Accepted December 1st, 2007