注射用噻吩诺啡缓释微球加速稳定性研究  

Accelerated stability test of sustained-release thienorphine loaded microspheres for injection

作　　者：代旭栋 王珊 邸金威 李明媛 郁彭[1] 郑爱萍 高静 DAI Xu-dong;WANG Shan;DI Jin-wei;LI Ming-yuan;YU Peng;ZHENG Ai-ping;GAO Jing(College of Biotechnology,Tianjin University of Science&Technology,Tianjin 300457,China;Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Academy of Military Sciences,Beijing 100850,China)

机构地区：[1]天津科技大学生物工程学院,天津300457 [2]军事科学院军事医学研究院毒物药物研究所,北京100850

出　　处：《药学学报》2022年第8期2503-2511,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82173788);河北省科技重点研发计划项目(19272701D).

摘　　要：为满足噻吩诺啡长效缓释的临床需求,研制注射用噻吩诺啡微球,本研究进行了其加速稳定性研究,探究该微球适宜的贮存运输条件。以丙交酯乙交酯共聚物[poly(lactic-co-glycolic acid),PLGA]为载体材料,使用乳化溶剂挥发法,制备了3批中试规模的噻吩诺啡微球。通过考察37、45、52、60℃下微球的体外释放,应用阿伦尼乌斯方程,建立释放速率常数(lgk)与温度(1/T)之间的线性关系,得到方程:lgk=−8.073/T+24.35(R2=0.9853)。结果显示,可使用高温下微球释放预测37℃体外释放,选择52.0±0.5℃作为体外加速释放条件。建立质量研究方法,考察微球形貌、载药量、粒径及粒径分布、聚合物分子质量、有关物质等关键质量属性在加速条件下的变化,并以差异因子f1与相似因子f2比较加速条件下释放行为的相似性。结果发现,注射用噻吩诺啡缓释微球在25±2℃、相对湿度(relative humidity,RH)60%±5%的加速稳定性试验条件下,6个月各关键质量属性均未发生显著变化,提示微球可短期贮存于室温,长期贮存可放置在5±3℃条件下。In order to meet the clinical needs of long-acting sustained-release thienorphine,injectable thienorphine loaded microspheres were developed,and the accelerated stability study was carried out to explore the suitable storage and transportation conditions of the microspheres.Using poly(lactic-co-glycolic acid)(PLGA)as carrier material,3 batches of microspheres were prepared in pilot scale with emulsion solvent evaporation method.By investigating the in vitro release of thienorphine loaded microspheres at 37,45,52,and 60℃,and applying the Arrhenius equation,the linear relationship between the release rate constant(lgk)and the temperature(1/T)was established to obtain the equation:lgk=−8.073/T+24.35(R2=0.9853),which showed that the release of microspheres at high temperature can be used to predict the release in vitro at 37℃,and 52.0±0.5℃was selected as the accelerated release condition in vitro.The quality research methods were established to investigate the changes of critical quality attributes such as microsphere morphology,drug loading,particle size and distribution,polymer molecular weight,and the related substances under accelerated conditions.The difference factor f1 and similarity factor f2 were used to assess the similarity of release behavior under accelerated conditions.The results showed that under the accelerated experimental conditions of 25±2℃and relative humidity(RH)60%±5%,the critical quality attributes of injectable thienorphine loaded microspheres had no significant change in 6 months,suggesting that the long-term storage condition could be 5±3℃.

关 键 词：噻吩诺啡 丙交酯乙交酯共聚物 微球 加速稳定性试验 关键质量属性 

分 类 号：R943[医药卫生—药剂学]