Dissolution Methods for Predicting Bioequivalence of Ocular Semi-Solid Formulations

项目总结/摘要 本提案中描述的工作介绍了评估眼用半胱氨酸生物等效性的新方法， 固体制剂。其中包括溶出度测试优化，使用人工角膜测量 眼用软膏中活性药物成分（API）的角膜转运，以及这些物质之间的相关性 体外溶解/药物释放测量。这将通过以下方法来实现： 旨在确定参考上市药物（RLD）和仿制药之间的差异 在我们的实验室生产，含有相同的活性和非活性成分（Q1），并在同一 浓度（Q2）作为RLD。本研究选择的RLD包括含有以下成分的眼用软膏： 单一API（Tobrex <$-妥布霉素眼用软膏）以及含有两种 不同的原料药（妥布霉素地塞米松眼膏）。目前唯一 这些RLD的推荐生物等效性研究是药代动力学研究和体外微生物杀灭研究 率研究。关于溶出度测试方法开发和采样时间， FDA数据库 请为该制剂的稳定性开发体外药物释放检测方法， 质量控制。质量标准将在审查申请中提交的数据后确定。 由于传统的溶出方法在预测眼用制剂的生物等效性方面表现出有限的生物相关性， 半固体产品，拟定研究的目的是（1）制备RLD的Q1/Q2仿制品 使用不同的制造工艺，并充分表征其物理化学性质，（2） 使用修改的USP比较不同Q1/Q2通用制剂中API的体外释放 溶出装置4、垂直扩散池装置和浸渍池，在改进的USP 溶出装置2，和（3）测量API从两个RLD穿过人工角膜的转运 并确定可以区分不同Q1/Q2类眼用半固体的溶出方法 制剂。将对这些研究中使用的溶出方法进行分析，以确定 每种方法的优点和缺点以及对它们检测能力的评估 生产方法的差异，以预测体内性能，并评估方法耐用性。的 这些研究的结果有望帮助FDA制定行业指南， 由含有一种或多种API的通用眼用半固体药物产品的生产商用于建立 与创新产品的生物等效性。预计这些结果将改善 通过帮助识别产品，为眼部给药开具半固体产品处方的患者 这可能导致递送超治疗剂量或亚治疗剂量的API，其后果可能是 显著

Project Summary/Abstract The work described in this proposal introduces novel methods for assessing the bioequivalence of ocular semi- solid formulations. These include dissolution test optimization, the use of an artificial cornea to measure corneal transport of Active Pharmaceutical Ingredients (APIs) in ocular ointments, and the correlation of these measurements to in vitro dissolution/drug release measurements. This will be accomplished using methods designed to determine differences between reference listed drugs (RLDs) and generic formulations manufactured in our labs that contains the same active and inactive ingredients (Q1) and in the same concentrations (Q2) as the RLDs. The RLDs chosen for this study include ocular ointments containing a single API (Tobrex¿ - tobramycin ophthalmic ointment) as well as a related ocular ointment containing two distinct APIs (Tobradex¿ - tobramycin and dexamethasone ophthalmic ointment). The only currently recommended bioequivalence studies for these RLDs are a pharmacokinetic study and an in vitro microbial kill rate study. Regarding dissolution test method development and sampling times, the recommendation in the FDA database is please develop an in vitro drug release testing method for this drug product for stability and quality controls. Specifications will be determined upon review of the data submitted in the application. Because conventional dissolution methods exhibit limited biorelevance in predicting bioequivalence of ocular semi-solid products, the aims of the proposed studies are (1) to prepare Q1/Q2 generic products of the RLDs using different manufacturing processes and to fully characterize their physicochemical properties, (2) to compare the in vitro release of the APIs from different Q1/Q2 generic preparations using a modified USP Dissolution Apparatus 4, a vertical diffusion cell apparatus, and an immersion cell in an adapted USP Dissolution Apparatus 2, and (3) to measure transport of the APIs from the two RLDs across artificial corneas and identify a dissolution method that can discriminate between different Q1/Q2 generic ocular semi-solid formulations. An analysis of the dissolution methods used in these studies will be conducted in order to identify the advantages and disadvantages of each method as well as an assessment of their capability to detect differences in manufacturing methods, to predict in vivo performance, and to assess method robustness. The results of these studies are expected to assist the FDA in developing Guidelines for Industry that can be used by manufacturers of generic ocular semi-solid drug products containing one or more APIs for establishing bioequivalence to innovator products. It is anticipated that these results will improve the health outcomes of patients who have been prescribed semi-solid products for ocular administration by helping to identify products that could lead to delivery of super- or sub-therapeutic doses of API, the consequences of which could be significant.