In vitro-In vivo correlations of parenteral microsphere drug products

摘要 该项目的最终目标是了解相关的潜在因素 用于体内释放的注射用微球药物制品及开发合理的 建立体外-体内相关性的基于机制的方法。综上所述， 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/或生物的特征时间 可能限制药物进入循环的过程，(B) 将在体外和体内测量(A)中确定的特征时间，而 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， 和温度)将在合理的限制之间调整，以包含速率- 控制体内观察的特征时间以确定适合的体外条件 体外-体内相关性(IVIVC)，和(D)同时PK数据将用于 确认直接测量，以确定是否存在额外的速率限制(例如组织 结合或代谢)之后从植入物释放并建立IVIVC。这个 将使用类固醇和LHRH两种模型药物进行机械性评估 激动剂。每种药物对应两种不同释放的两种剂型 机制将被选择用于体外和体内表征，以及 IVIVC模式的发展。如果成功，这项提议有可能创造出 控释检验标准化及合理发展的途径 静脉曲张。

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.