Bao Quanying, Wang Xiaoyi, Wan Bo, Zou Yuan, Wang Yan, Burgess Diane J
University of Connecticut, School of Pharmacy, Storrs, CT 06269, USA.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA.
Int J Pharm. 2023 Mar 5;634:122642. doi: 10.1016/j.ijpharm.2023.122642. Epub 2023 Jan 25.
Long-acting injectable (LAI) aqueous suspensions achieve extended drug release over a duration of weeks to months via slow dissolution of drug crystals with low solubility. There have been around ten LAI aqueous suspensions approved by the FDA to date and there are no generic equivalents for most of them. This may be largely due to the complex formulation development as well as the challenges in establishment of in vitro-in vivo correlation (IVIVC) for these products. Level A IVIVCs, using animal models, have been proven feasible for complex long-acting microsphere formulations with multiphasic release characteristics. Accordingly, it may be possible to develop IVIVCs for LAI aqueous drug suspensions since their release characteristics are relatively simple with only a drug dissolution phase. To establish IVIVCs for LAI drug suspensions, four compositionally equivalent medroxyprogesterone acetate LAIs with differences in processing and formulation factors (drug particle size and excipient source) were prepared using Depo-SubQ Provera 104 as the reference listed drug (RLD). Two in vitro release testing methods, modified based on USP apparatus 2 (with enhancer cells) and USP apparatus 4 (with semisolid adapters), were used. The in vivo release was investigated using a rabbit model. Level A IVIVCs were successfully established using the in vitro release profiles obtained with the USP apparatus 4. This is the first report of an IVIVC for LAI aqueous suspensions.
长效注射用（LAI）水性混悬液通过低溶解度药物晶体的缓慢溶解实现数周至数月的药物缓释。迄今为止，美国食品药品监督管理局（FDA）已批准了约十种LAI水性混悬液，其中大多数没有通用等效品。这可能主要归因于复杂的制剂开发以及为这些产品建立体外-体内相关性（IVIVC）所面临的挑战。对于具有多相释放特性的复杂长效微球制剂，使用动物模型的A级IVIVC已被证明是可行的。因此，由于LAI水性药物混悬液的释放特性相对简单，仅存在药物溶解阶段，有可能为其开发IVIVC。为了建立LAI药物混悬液的IVIVC，以Depo-SubQ Provera 104作为参比上市药品（RLD），制备了四种在加工和制剂因素（药物粒径和辅料来源）上存在差异但成分等效的醋酸甲羟孕酮LAI。使用了两种基于美国药典（USP）装置2（带有增强细胞）和USP装置4（带有半固体适配器）改进的体外释放测试方法。使用兔模型研究体内释放情况。利用USP装置4获得的体外释放曲线成功建立了A级IVIVC。这是关于LAI水性混悬液IVIVC的首次报道。
