R esearch Center of B iom edica l Eng ineering of X iam en, X iam en , China)

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1 Chinese Journal of New D rugs 2007, Vol. 16 No. 15,,, 7, ph, 70% [ 6 ] [ ] ( ),,,, : ( 020) , E2mail: mayuzhuo66@163. com [ ] [ 1 ] SORBERA LA, RAM IS I. Cim icoxib [ J ]. D rug Fut, 2004, 29 (4) : [ 2 ] ALMANSA C, BARTROL1J, BELLOC J, et al. New W ater2solu2 ble sulfonylphosphoram idic acid derivatives of the COX22 selective inhibitor cim icoxib. A novel approach to sulfonamide p rodrugs [ J ]. J M ed Chem, 2004, 47 (22) : [ 3 ] ALMANSA C, GONZ#LEZ C. Method of p reparing 42( im idazole2 12yl) benzenesulphonamide derivatives: WO, [ P ] [ 4 ] ALMANSA C, GONZ#LEZ C, TORRES C. Novel im idazoleswith anti2inflammatory activity: WO, [ P ] [ 5 ],,,. [ J ]., 2002, 12 (5) : [ 6 ] ALMANSA C, ALF N J, DE ARR IBA AF, et al. Synthesis and structure2activity relationship of a new series of COX22 selective in2 hibitors: 1, 52diarylim idazoles[ J ]. J M ed Chem, 2003, 46 (16) : :/ : , 1, 1, 1, 1, 1, 2 (1, ; 2, ) [ ] :(methotrexate,mtx)2 ( PL2 GA), : O /W MTX2PLGA, ; HPLC; :,( )m, ( ) % ( ) %t d, K r = 01038g ml - 1 d - 1, K R = 0112g ml - 1 d - 1 :MTX2PLGA, [] ; ;2 ; ; [] R943141; R [] A [ ] (2007) Prepara tion and the in vitro and in vivo relea se of PL GA m icrospheres con ta in ing m ethotrexa te for in tra 2articular in jection Moldir 1, CHEN Han 1, L I Xue2m in 1, CHEN Hong2li 1, SH I Yan2p ing 1, ZHANG Q i2qing 1, 2 (1 Institute of B iom edical Engineering, Chinese A cadem y of M ed ical S ciences & Peking U nion M edica l College, The Key L aboratory of B iom ed ical M aterial of Tianjin, Tian jin , China; 2 Research Cen ter of B iom edical Engineering /M edical School, X iam en U niversity, Technology R esearch Center of B iom edica l Eng ineering of X iam en, X iam en , China) [ Abstract] O bjective: To p repare methotrexate (MTX) loaded poly (DL2lactide2co2glycolide) ( PLGA) m icrospheres for intra2articular adm inistration and investigate their release p rofiles. M ethods: M icrospheres were p repared by oil2in2water em ulsion solvent evaporation m ethod. The surface morpholo2 3 : (2006CB933300) ;( ) ;(3502Z ) 1187

2 Chinese Journal of New D rugs 2007, Vol. 16 No. 15 gy, size distribution, drug loading content and the encap sulation efficiency of m icrospheres were exam2 ined. The in vitro drug release p rofiles of the m icrospheres were measured in phosphate buffer saline ( PBS, ph 7140), and a rat air2pouch model was utilized to determ ine the in vivo drug release p roper2 ties. The drug concentration was assayed by high performance liquid chrom atography ( HPLC). Results: The M TX loaded m icrospheres had smooth surface w ith narrow size distribution and the average particle size was ( )m. The drug loading content and encap sulation efficiency were ( ) % and ( ) %, respectively. The drug release rate constant of m icrospheres in vitro and in vivo were g ml - 1 d - 1 and 0. 12g ml - 1 d - 1, respectively. Conclusion: The MTX2PL2 GA m icrospheres show evidently sustained release effect and may be used as a potential drug delivery sys2 tem for treatment rheumatoid arthritis [ Key words] intra2articular injection; methotrexate; PLGA; m icrospheres; in vitro & in vivo release (RA ),,,, (NSA ID s) ( disease modifying antirheumatic drugs, DMARD s) ( GC) [ 1 ], DMARD s, DMARD s, [ 2 ] (methotrexate, M TX) DMARD s, [ 3 ] MTX, [ 4 ] M TX, [ 5 ] DMARD s RA, 2 ( PLGA ), MTX,, F6 /10( FLUKO, ), RW 20. n ( IKA, ), HZQ ), DL C ( 6 (), (PH IL IPS XL 30, ),(Malvern S long bed, ),( Gilson, ) M TX ( > 99%,,, : ) ; PLGA 1188 (MW: , 50 50, ) ; ( PVA, P8136, MW : , Sigma ) ;( Sigma ) ; ( ), W istar (, : ) 1M TX2PL GA O /W [ 6 ] 100 mg PLGA 2 ml,5 mg MTX, 100 ml 2% PVA, rm in m in, 450 r m in h, 018m, 4,,,,3 2,,, 2 3PL GAM TX 311MTX PBS(pH7140),PBS nm,mtx306 nm,mtx, 306 nm MTX mg MTX PBS(pH7140)250gmL - 1, PBS 01127, 01253, 11014, 41055, , , gmL - 1

3 Chinese Journal of New D rugs 2007, Vol. 16 No. 15, HPLC [ 7 ] : C 18 (200 mm 416 mm, 5m ) ; 1% 25%2 ( ) ; 110 ml m in - 1 ; 20L 3 MTX, : Y = X ( r = ), gmL - 1 MTX, 3 ( ) %, ( ) %( ) %, RSD 1142%, 0161% 1115%, RSD 0179%, 1182%1169%, MTX2PLGA 10 mg10 ml,2 ml, 4 ml PBS,,, (0145m),, /% = / ( + ) 100; /% = / 100 MTX2PLGA,, 8 ml( PBS, ph7140, 0. 02% ), (37 1), (75 1) r m in - 1,500L,,HPLC MTX,, 3 611W istar ( g), PLGA MTX( A )MTX2PLGA ( B), [ 8 ] : 10 ml, 24 h 6 ml 1%(1 600 IUmg - 1 ) 2%, 48 h015 ml ( 10 ngmg - 1 ) 72 h 15 mg ml - 1 PLGA (011% 220 ), A 500 gml - 1 MTXPBS,B 15 mgml - 1 MTX2 PLGA(011% 220) A 2, 4, 6, 8, 12, 18, 24 h,; B 1, 3, 6, 10 d,, 612,,,, r m in m in,,0145m,, HPLC PBS (ph 7140),,, ( ), r m in m in,,,,,, HPLC : C 18 (200 mm 416 mm, 5m) ; 1% 24%2 ( ) ; 110 ml m in - 1 ; 20L,306 nm : Y = X , r = ;( ) % (n = 3) : Y = X , r = ;( ) % ( n = 3) ( gx s), t, P < 0105 MTX2PLGA,,,,, 1 2, 2 ( )m MTX2PLGA 2MTX2PLGA 2 1 MTX2PLGA, 37 3, 24 h 22% 30 d 1189

4 Chinese Journal of New D rugs 2007, Vol. 16 No %, t d, MTX2PLGA,dX /dt = - K r X K r = 01038g ml - 1 d - 1 1M TX2PL GA n = /mg /g /% /% gx s ( n = 3) A, B 4, 5 MTXPBS, 24 h,,, B MTX ( P < 0105) 4A ( n = 6) 5B ( n = 6) B 6 X 1, X 2, K R, K e : dx 1 /dt = - K R X 1 dx 2 /dt = K R X 1 - K e X 2 K R K e g ml - 1 d B 20 80, M TX RA,,, [ 5 ] Horisawa [ 9 ] PLGA,,, MTX2PLGA,10 d, MTX,, PLGA,,,,,, [ 8 ],,,24 h (715 ng ml - 1 ),, ( > 10 d), K R K r,, [ 10, 11 ],,,,,,, RA PLGA, MTX2PLGA,,,,,,

5 Chinese Journal of New D rugs 2007, Vol. 16 No. 15 [ ] ( ),, : (022) , E2mail: moldir001@yahoo. com. cn [ ] ( ),,,, : ( 022 ) , E2mail: zhangqiq@ xmu. edu. cn [ ] [ 1 ] American College of Rheumatology Subcomm ittee on Rheumatoid A rthritis Guidelines. Guidelines for the management of rheuma2 toid arthritis: 2002 Update [ J ]. A rthritis Rheum, 2002, 46 ( 2 ) : [ 2 ] ROBERTS LJ, CLELAND LG, THOMAS R, et al. Early combina2 tion disease modifying antirheumatic drug treatment for rheuma2 toid arthritis[ J ]. M ed J A ust, 2006, 184 (3) : [ 3 ] CRONSTE IN BN. Low2dose methotrexate: a mainstay in the treatment of rheumatoid arthritis [ J ]. Pharm acol Rev, 2005, 57 (2) : [ 4 ] BORCHERS AT, KEEN CL, CHEEMA GS, et al. The use of methotrexate in rheumatoid arthritis[ J ]. Sem in A rthritis Rheum, 2004, 34 (1) : [ 5 ] W IGGINTON S, CHU B,W E ISMAN M, et al. Methotrexate phar2 macokinetics after intraarticular injection in patientswith rheuma2 toid arthritis[ J ]. A rthritis Rheum, 1980, 23 (1) : [ 6 ] KIM BK, HWANG SJ, PARK JB, et al. Preparation and charac terization of drug2 loaded polymethacrylate m icrospheres by an e2 mulsion solvent evaporation method [ J ]. J M icroencapsul, 2002, 19 (6) : [ 7 ]. [ S ] :, 2005: 120. [ 8 ] OHUCH I K, H IRASAWA N. Method for the evaluation of anti2in2 flammatory and allergic drugs using experimental animal models [ M ] / / Experimental manuals for bio2pharmaceutical sciences. Tokyo: H irokawa Publishing Co, 1993: [ 9 ] HOR ISAWA E, KUBOTA K, TUBO I I, et al. Size2dependency of DL 2lactide / glycolide copolymer particulates for intra2articular de2 livery system on phagocytosis in rat synovium [ J ]. Pharm Res, 2002, 19 (2) : [ 10 ] WOO BH, KOSTANSKI JW, GEBREKIDAN S, et al. Preparation characterization and in vivo evaluation of 1202day poly (D, L 2lac2 tide) leuprolide m icrospheres [ J ]. J Control Release, 2001, 75 (3) : [ 11 ] TRACY MA,WARD KL, F IROUZABAD IAN L, et al. Factors af2 fecting the degradation rate of poly (D, L2lactic2co2glycolic acid) m icrospheres in vivo and in vitro [ J ]. B iom aterials, 1999, 20 (11) : : / : ,, (, ) [ ] : 22 ( KP2HP22CD ) :,, : (CMS2Na), 12%, ( SLS) 1%, ( ) s : T 50 = 310 m in, T d = 514 m in:2005, [] ; ; ; [] R943141; R97111 [] A [ ] (2007) Form ula tion and d issolution of the d ispersible tablets using ketoprofen hydroxypropyl22cyclodextr in inclusion com plexes L IU Yu2wen, YU Xiang2bin,WU Hong2xia (D epa rtm en t of Pha rm aceu tics, S chool of Pha rm acy, Fu jian M ed ica l U n iversity, Fuzhou , Ch ina) [ Abstract] O bjective: To develop the formulation of the dispersible tablets of ketop rofen hydroxyp ropyl22cyclodextrin ( KP2HP22CD ) inclusion comp lexes and study the dissolution. M ethods: 3 : (2004J045) 1191