In vitro-In vivo correlations of parenteral microsphere drug products

摘要 这个项目的最终目标是了解造成这种情况的潜在因素 用于胃肠外微球药物产品的体内释放，并开发合理的 基于机制的方法来创建体外-体内相关性。来概括这种 方法-为了确定潜在的释放机制，我们建议（a） 确定控制关键物理-化学和/或生物 可以限制药物到达循环的速率的过程，（B） 将在体外和体内测量（a）中确定的特征时间， 监测模型载药微球的释放（和/或保留）动力学， 阐明释放机制，（c）体外条件（溶液化学，混合， 温度）将在合理的范围内进行调整，以涵盖费率- 控制在体内观察到的特征时间，以确定合适的体外条件 体外-体内相关性（IVIVC），和（d）同时PK数据将用于 确认直接测量，以确定是否存在附加速率限制（例如，组织 结合或代谢），并建立IVIVC。的 将使用两种模型药物类固醇和LHRH进行机制评估 激动剂每种药物的两种制剂对应于两种不同的释放 将选择用于体外和体内表征的机制， IVIVC模式的发展。如果成功的话，这一提议有可能创造 控制释放测定的标准化和合理开发的途径 IVIVCs

Abstract The ultimate goal of this project is to understand the underlying factors responsible for in vivo release of parenteral microsphere drug products and to develop a rational mechanism-based approach to create in vitro-in vivo correlations. To summarize this approach-In order to identify potential release mechanisms we propose to (a) determine the characteristic times governing key physical-chemical and/or biological processes that could be rate-limiting to the drug reaching the circulation, (b) the characteristic times identified in (a) will be measured both in vitro and in vivo while monitoring the release (and/or retention) kinetics of model drug-loaded microspheres to elucidate the release mechanism, (c) the in vitro conditions (solution chemistry, mixing, and temperature) will be adjusted between reasonable limits to encompass the rate- controlling characteristic times observed in vivo to identify suitable in vitro conditions for an in vitro-in vivo correlation (IVIVC), and (d) at the same time PK data will be used to confirm direct measurements, to determine if additional rate limits exist (e.g., tissue binding or metabolism) after release from the implant and to establish an IVIVC. The mechanistic evaluation will be conducted using two model drugs a steroid and LHRH agonist. Two formulations for each drug corresponding to two different release mechanisms will be selected for in vitro and in vivo characterization and the development of the IVIVC model. If successful, this proposal has the potential to create a path toward standardization of controlled release assays and rational development of IVIVCs.