仿制盐酸多柔比星脂质体注射液药学技术要求解析  

Research and analysis of CMC requirements for generic PEGylated liposomal doxorubicin

作　　者：张宁[1] 

机构地区：[1]国家食品药品监督管理总局药品审评中心,北京100038

出　　处：《中国新药杂志》2014年第8期896-900,911,共6页Chinese Journal of New Drugs

摘　　要：盐酸多柔比星脂质体注射液(Doxil)已上市多年,但成功上市的仿制产品却寥寥无几,原因主要在于该产品技术难度较大——处方工艺的微小改变都可能导致安全有效性的差异。文中调研分析了FDA和EMA对于盐酸多柔比星脂质体注射液仿制药的技术要求,并同我国现阶段的技术要求进行对比。FDA的相关技术要求强调:相同的处方组成(药脂比、游离和包封药物的量及比例、其他辅料类型和用量)、相同的制剂特性(粒径及粒径分布、形态、表面电荷、PEG层厚度、PEG层结合位置和结合量)、相同的脂质体内部环境(采用硫酸铵梯度包封技术、内部pH、内部包封药物的沉淀状态)、相同的体外释放行为(在不同的生理条件下进行考察)。EMA除强调以上药学对比研究外,还强调临床前药代、组织分布的对比研究。考虑到现阶段脂质体药学对比研究的局限性,在我国当前的技术评价中,强调药学对比、临床前和临床比较并重的评价思路。In spite of the long-marketing history of Doxil, there are few approved generic ＂Doxils＂ availa- ble, which boils down to technical hurdle even minor changes in the formulation and manufacturing process may cause different in vivo performance. Research and analysis was carried out on FDA and EMA＇s relevant guide- line and comparison was made between those two agency＇s requirements and CFDA＇s current requirements. It＇s con- cluded that as to generic liposomal doxorubicin, FDA focus on the same formulation（drug/lipid ratio, free and en- trapped drug amount, other inactive ingredients amount）, the same characteristics （particle size and distribution, morphology, grafeted PEG at the liposome surface, electrical surface potential or charge）, the same internal envi- ronment（ ammonium sulfate gradient remote loading ,internal pH,state of encapsulated drug） ,the same in vitro re- lease（under multiple conditions）. Besides those mentioned above, EMA also focus on comparative investigation of pharmacokinetics（including tissue distribution） ,toxicology and pharmacodynamics. Because of limitations of CMC comparison of liposomes, CFDA also focus on non-clinical and clinical comparison at present.

关 键 词：多柔比星 脂质体 仿制 药学对比 

分 类 号：R95[医药卫生—药学]