OBJECTIVE To develep the liposome encapsulated cyclosporine for replacing the toxic solubilizing agent present in marketed Cyclosproine(CsA) injections and prolonging the drug resident time in the body.METHODS Pegylated CsA-liposome was prepared by a modified ethanol injection method,followed by sonication and lyophilization using sucrose as cryoprotectant.After the free drug was removed from the liposome solution by Sephadex G-50 column,dialysis and super filtration respectively,entrapment efficiency(EE) of the liposome was determined by HPLC.The formulation was optimized with Central Composite Design.The pharmacokinetic behavior of the Pegylated CsA-liposome was studied following intravenous administration to rats and compared with that of commercially available injection Sandimmune.RESULTS The most desirable formulation had the composition of Phosphatidylcholine(PC),Cholesterol(CHO),CsA and Methoxy-poly(ethylene glycol)-phosphoethanolamine(mPEG-PE) in molar ratio(95/40/4.5/5).The mean volume size of the optimized liposome formulation was(50.3±5.1) nm(n=6) and entrapment efficiency was 97% by ultra filtration.There was significant difference in main pharmacokinetic parameters between the Pegylated CsA-liposome and Sandimmune.Pegylated CsA-liposome showed 30% decrease in Vc(P<0.01),30% increase in AUC(P<0.05),8% increase in MRT(P<0.01) and 59% decrease in CLt(P<0.05) compared with Sandimmune.CONCLUSION The Pegylated CsA-liposome with satisfied size and high entrapment efficiency could be obtained and could be a useful alternative dosage forms for intravenous administration of cyclosporine,which is safer and less toxicity.
WNG Y-jing;FU Xio-ning;LUN Li-io.
Preparation,Characterization and Pharmacokinetics of Long Circulated Liposome Encapsulated Cyclosproine [J]. Chinese Pharmaceutical Journal, 2008, 43(24): 1881-1885
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参考文献
[1] RICHARDSON C，EMERY P. Clinical use of cyclosporin in rh- eumatoid arthritis[J] . Drugs，1995，50 （suppl 1）：26-36.
[2] State Food and Drug Administration Center of Drug Evaluation and SiCHuan MEIKANG medical software Research and Development Company limit. Reference for Clinical drug(药物临床信息参考)[M] .1th ed. SiCHuan： SiCHuan science and technology press，2004：740-741.
[3] TIBELL A，LARSSON M，ALVESTRAND A. Dissolving intrav- enous cyclosporin A in a fat emulsion carrier prevents acute renal side effects in the rat[J] . Transpl Int，1993，6(2)：69-72.
[4] LUKE D R，KASISKE B L，MATZKE G R，et al. Effects of cyclosporine on the isolated perfused rat kidney[J] . Transplantation，1987，43(6) ：795-799.
[5] FREISE C E，LIU T，HONG K，et al. The increased efficacy and decreased nephrotoxicity of a cyclosporine liposome[J] . Transplantation，1994，57(6)：928-932.
[6] VADIEI K，LOPEZ-BERESTEIN G，PEREZ-SOLER R，et al. Tissue distribution and in vivo immunosuppressive activity of liposomal cyclosporine[J] . Drug Metab Dispos，1991，19 (6) ：1147-1151.
[7] WOODLE M C，LASIC D D. Sterically stabilized liposomes[J] . Biochim Biophys Acta，1992，1113(2) ：171-199.
[8] WU W，CUI G F，LU B. Optimization of multiple variables： application of central composite design and overall desirability[J] . Chin Pharm J(中国药学杂志)，2000，35(8)：530-533.
[9] GUO J X，PING Q N，CHEN Y. Pharmacokinetic behavior of cyclosporin A in rabbits by oral administration of lecithin vesicle and Sandimmun neoral[J] . Int J Pharm，2001，216（1-2）：17-21
[10] LI B Q，DENG Y J，YANG J W. Determination of entrapment efficiency of Topotecan liposomes by ultrafiltration-HPLC[J] . Chin J New Drugs（中国新药杂志），2007，16(1)：58-61.
[11] KIM S J，CHOI H K，LEE Y B. Pharmacokinetic and pharm- acodynamic evaluation of cyclosporin A O/W-emulsion in rats[J] . Int J Pharm，2002，249（1-2）：149-156.
[12] ARULSUDAR N, SUBRAMANIAN N, MISHRA P, et al. Prep- aration，characterization and biodistribution of 99-mTc-labeled liposome encapsulated cyclosporine[J] . J Drug Target，2003，11 (3)：187-196.
[13] LEE M K，CHOI L，KIM M H，et al. Pharmacokinetics and organ distribution of cyclosporin A incorporated in liposomes and mixed micelles[J] . Int J Pharm，1999，191(2)：87-93.
[14] FAHR A，HOLZ M，FRICKER G. Liposomal formulations of cyclosporin A： influence of lipid type and dose on pharmacokinetics[J] . Pharm Res，1995，12(8)：1189-1198.
