( ) Cys Ser T h r Phe. A sp, ,, r IL 22. M et Cys H is T rp T yr [ 4 ] A sp. A sp 2P ro A sp 2Gly

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1 Ξ ( ) ; ; ; ; ;,,,, [ 1 3 ] ( 1), A snggln A sp gglu ph 2A sn2gly2, (2),,, M et Cys H is T rp T yr (3) A sp, A sp 2P ro A sp 2Gly (4), (5) Gly, Α, A sp (6) Β2 Β2 Β Cys Ser T h r Phe T yr Β2 ph Β2, (7),,,,,,, r IL 22 [ 4 ] 1. 2 [ 1, 3 ] (1) Ξ

2 17, (2), PEG PEG,, PEG,,, [ 5 ] (3), [ 6 ],, SD S Tw een P lu ro2 n ic, (4) Β2,, [ 7 ], 1. 3 A rrhen iu s,, A rrhen iu s, : (1),, ; (2), ; (3), (T g),,, T g T g,, Yo sh ioka [ 8 ] 25,,,, 1. 4 : SD S2 [ 9 ] (Calo rim etry), ( D ifferen tiat Scann ing Calo rim etry), Chan [ 10 ] D SC rhdn ase 10 m gg m l, 1. 2 gm in rhdn ase Tm = 67. 4, Hm = J g Ca 2+ rhdn ase, M g 2+ M n 2+ rhdn ase CaC l mm o lgl, Tm = 76. 4, Hm = 20 22J g CaC l2 rhd 2 N ase 50mm o lgl CaC l2 100m ggm l, rhdn ase Tm 76. 4, Hm 21. 9J g Chang [ 11 ] D SC rh IL 2lra,,

3 , 6 2,,, : (1) ( ), ; (2), ; (3), : (PL CA ) [ 12 ], PL GA PL GA :,,,, L HRH TRH In su lin GH SOD TN F IFN IL 22 EPO L HRH leup ro lide, 1988, 40, 1993 Genetech rhgh IFN 2Χ [ 13, 14 ] 3,,, :, 3. 1,,,,,, G2CSF EPO,,, [ 15 ], (32 ), 1% 1990 N afarelin ( ), 2. 8% m 2, 5000m lgm in,,,, 20% 50%, [ 16 ] :, ;

4 19, Pu lm ozym e ( ) [ 17 ], 3. 3,, : (1),, ; (2) ; (3) ( ) ; (4), [ 18 ] Em isphere : (1) VB 12, ; (2), : (1) PEG, ; (2) ; (3) ; (4) (nanoparticle. ) ; (5) 100nm PL G [ 19 ], T echno sphere, 26% ( ), Co rtecs g,,, [ 20 ], ( ph ), CD D SC : (1), ; (2) ; (3) ; (4),,,,,,,,,, 1 M anning M C, Patel K, Bo rchardt R T. Stability of p ro tein pharm aceuticalṡ P harm R es, 1989; 6:

5 Pow elm F. Pep tide stability in aqueous parenter2 al fo rm ulations: p rediction of chem ical stability based on p rim ary sequence. A CS S ym p S er, 1994; 567: L i S, Schoneich C, Bo rchardt R T. Chem ical in2 stability of p ro tein pharm aceuticals: m echanism s of ox idation and strategies fo r stab ilization. B iotechnol B ioeng, 1995; 48: T zannis ST, H rushesky W JM,W ood PA, et al. Irreversib le inactivation of in terleuk in22 in a pump2based delivery environm enṫ P roc N atl A 2 cad S ci U SA, 1996; 93: M atsush im a A, Kodera Y, Inada Y. Chem ical modification of p ro tein drugs w ith PEG deriva2 tiveṡ D rug D elivery S y st, 1995; 10: 5 6 M anning M C,M atsuura JE, Kendrick BS, et al. A pp roaches fo r increasing the so lution stability of p ro teinṡ B iotechnol B ioeng, 1995; 48: Izutsu K, Yo sh ioka S. Stabilization of p ro tein pharm aceu ticals in freeze dried fo rm u latio ṡ D rug S tability, 1995, 1: 11 8 Yo sh ioka S, A so Y, Izutsu K, et al. A pp lication of accelerated testing to shelf2life p rediction of comm ercial p ro tein p reparationṡ J P harm S ci, 1994; 83: Jones A JS. A nalysis of po lypep tides and p ro2 teinṡ A d v D rug D el R ev, 1993; 10: Chan H, A n2yeung K, Gonda İ Effects of addi2 tives on heat denatu ration of rhdn ase in so lu2 tionṡ P harm R es, 1996; 13: Chang BS, F isher NL. D evelopem ent of an effi2 cien t single2step freeze2drying cycle fo r p ro tein fo rm ulationṡ P harm R es, 1995; 12: Couvreu r P, Pu isieux F. N ano2and m icroparticles fo r the delivery of po lypep tides and p ro tein ṡ A d v D rug D el R ev, 1993; 10: C leland JL,D uenas ET, Yang J, et al. O ne month con tinuou s release rhgh PL GA fo rm u lation ṡ P roc Int S ym p Control R el B ioact M ater, 1995; 22: C leland JL, Yang J. In vitro release of bioactive rh IFN 2Χ from PL GA m icro sphereṡ P roc Int S ym p Control R el B ioact M ater, 1995; 22: Sh imoda N,M aitani Y,M ach ida Y, et al. Effects of do se, ph and o smo larity on intranasal abso rp2 tion of rh EPO in ratṡ B iol P harm B u ll, 1995; 18: ; 23: 1 17 C ippoa D, Gonda I, Sh ire SJ. Characterizing of aero so l of rhdn ase generated by jet nebulizeṙ P harm R es, 1994; 11: F ix JA. O ral con tro lled release techno logy fo r pep tides: statu s and fu tu re p ro spectṡ R es, 1996; 13: 1760 P harm 19 Chacon M, Berges L, M o lpeceres J, et al. Op ti2 m ized p reparation of PL GA m icro spheres and nanoparticles o ral adm in istration. Int J P harm, 1996; 141: M itrago tri S, B lank sch tein D, L anger R. U ltra2 sound2m ediated tran sderm al p ro tein delivery. S cience, 1995; 269: 850 Curren t Status of Study on the Preparation s of Polypeptide D rug Fang Hongqing Institu te of B iotechnology, A cad em y of M ilita ry M ed ica l S ciences,b eij ing Abstract Po lypep tide drugs are generally characterized by the chem ical and physical in2 stab ility, sho rt b io logical half2life, and poo r perm eab ility acro ss b io logical m em b rane, w h ich are the m ain p rob lem s facing to the pharm aceu tical study. T h is paper review ed the cau ses of the in stab ility, the m ethods fo r increasing the stab ility, the determ ination of the shelf2life,

6 21 the m ethods of analysis of po lypep tide pharm aceu ticals, and the study on con tro lled release and non2paren teral adm in istration of po lypep tide drugṡ T he p ro spects of research on the p reparation s of po lypep tide drug w ere p resen ted. Key W ords Po lypep tieds P reparation s of D rug Stab ility Con tro lled release N on2 pa2ren teral adm in istration ( : ) (210009),, ( IIbgIIIa),, GPg b g a vw,, GPg b g a, GPg b g a,,, [ 1 3 ] GP g b g a, ( fib rinectin ) (vitronectin) vw GP g b g a R GD [ 4, 5 ], GPg b g a Χ 12 (HHL GGA KQA GDV ) [ 6, 7 ], GP g bg g a R GD Χ 12 : (1) ; (2) ; (3) ( ),, GPg b g a