In vitro-In vivo correlations of parenteral microsphere drug products

肠外微球药物产品的体外-体内相关性

• 批准号: 9131455
• 负责人: STEVEN P. SCHWENDEMAN
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9131455
• 关键词: vitro; vivo; correlations; parenteral; microsphere

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.

抽象的 该项目的最终目标是了解造成影响的根本因素 用于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。总结一下这一点 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 可能限制药物到达循环的速率的过程，(b) (a)中确定的特征时间将在体外和体内测量，同时 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）将在合理的限度之间调整以涵盖速率- 控制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)，并且 (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 从植入物释放后建立IVIVC。这 将使用两种模型药物（类固醇和 LHRH）进行机制评估 激动剂。每种药物有两种配方，对应两种不同的释放方式 将选择机制进行体外和体内表征以及 IVIVC 模型的开发。如果成功，该提案有可能创造 控制释放试验标准化和合理开发的途径 IVIVC。