注射用醋酸亮丙瑞林微球杂质控制研究  

Impurity Control of Leuprorelin Acetate Microspheres for Injection

作　　者：郭宁子 张伊洁 孙悦[1] 陈华[1] 杨化新[1] GUO Ningzi;ZHANG Yijie;SUN Yue;CHEN Hua;YANG Huaxin(National Institutes for Food and Drug Control,Beijing 102629,China;China Resources Double-Crane.Co.,Ltd.,Beijing 100102,China)

机构地区：[1]中国食品药品检定研究院,北京102629 [2]华润双鹤药业股份有限公司,北京100102

出　　处：《中国药学杂志》2023年第21期1962-1968,共7页Chinese Pharmaceutical Journal

基　　金：国家药品监督管理局化学药品质量研究与评价重点实验室项目资助。

摘　　要：目的对比分析醋酸亮丙瑞林微球制剂的杂质谱,探讨高湿条件下微球的稳定性,提出该品种微球制剂杂质控制的策略。方法采用高分辨液质联用仪(HPLC-MS/MS)对聚丙交酯(PLA)微球中杂质进行结构鉴定,采用高效液相色谱法(HPLC)对比分析不同载体辅料和不同来源微球的杂质谱,采用恒温恒湿箱考察高湿条件下微球稳定性,采用动态水分吸附分析(DVS)分析微球的吸湿特性。结果同一厂家的PLA与聚乙丙交酯(PLGA)微球制剂,杂质谱差异主要体现在酰化杂质的种类上;不同厂家的PLGA微球制剂,杂质谱差异体现在工艺杂质的种类上。高湿条件进行稳定性考察,PLA和PLGA微球中酰化杂质L的含量与存放的时间呈正相关。结论醋酸亮丙瑞林PLA和PLGA微球中分别有5种和8种制剂特有的酰化杂质,酰化位点均为肽链4位丝氨酸残基。微球载体辅料不同,酰化杂质种类亦有不同。PLA和PLGA微球均有一定引湿性,应在低湿度环境下保存。OBJECTIVE To compare and analyze the impurity profile of leuprorelin acetate microspheres,discuss the stability of microspheres under high humidity condition,and put forward the impurity control strategy.METHODS The structures of impurities in polylactic acid(PLA)microspheres were identified by high resolution liquid mass spectrometry(HPLC-MS/MS),the impurity profiles of different polymers and microspheres from different vendors were compared and analyzed by high performance liquid chromatography(HPLC),the stability of microspheres under high humidity condition was investigated in constant temperature and humidity chamber,and the hygroscopic characteristics of microspheres were analyzed by dynamic water adsorption analysis(DVS).RESULTS For PLA and PLGA microspheres from the same manufacturer,the difference in impurity profile was mainly reflected in the types of acylated impurities;for PLGA microsphere from different manufacturers,the difference in impurity profile was reflected in the type of process impurities.CONCLUSION There are 5 and 8 special kinds of acylated impurities in PLA and PLGA microspheres,and the acylation sites are the serine residue of the peptide chain.Different polymers lead to different types of acylated impurities.PLA and PLGA microspheres show hygroscopicity and should be stored in low humidity environment.

关 键 词：醋酸亮丙瑞林 缓释微球 聚丙交酯 聚乙丙交酯 杂质谱 酰化杂质 引湿性 

分 类 号：R917[医药卫生—药物分析学]