Dissolution Methods for Predicting Bioequivalence of Ocular Semi-Solid Formulations

项目摘要/摘要 本提案中描述的工作介绍了新的方法来评价眼内半乳糖的生物等效性。 固体配方。这些措施包括溶出度测试的优化，使用人工角膜来测量 活性药物成分在眼膏中的角膜转运及其相关性 测量到体外释放/药物释放测量。这将使用方法来完成 旨在确定参考上市药物(RLD)和仿制药之间的差异 由我们的实验室制造，含有相同的活性和非活性成分(第一季度)和相同的 浓度(Q2)作为RLDs。为这项研究选择的RLD包括含有 单一原料药(妥布霉素眼膏)以及相关的含有两种 不同的原料药(妥布霉素和地塞米松眼膏)。目前唯一的 推荐的这些RLD的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。 速率研究。关于溶出度试验方法的发展和采样时间， FDA数据库正在开发一种该药品的体外药物释放测试方法，以确保稳定性和 质量控制。规格将在审查申请书中提交的数据后确定。 因为传统的溶出法在预测眼球生物等效性方面表现出有限的生物利用度。 半固体产品，拟议研究的目的是(1)制备RLD的Q1/Q2仿制产品 使用不同的制造工艺，并充分表征它们的物理化学性质，(2) 用改良USP比较不同Q1/Q2非专利制剂中原料药的体外释放 适用于USP的溶解装置4、垂直扩散池装置和浸没池 溶解装置2，和(3)测量来自两个RLD的原料药通过人工角膜的传输 并确定了一种能够区分不同Q1/Q2类眼部半固体的溶出度方法 配方。将对这些研究中使用的溶解方法进行分析，以确定 每种方法的优缺点以及对其检测能力的评估 制造方法的差异，以预测体内性能，并评估方法的稳健性。这个 这些研究的结果有望帮助FDA制定可供使用的行业指南 由含有一种或多种原料药的非专利眼科半固体药物产品制造商 与创新者产品的生物等效性。预计这些结果将改善以下人群的健康状况 通过帮助识别产品而开出半固体产品用于眼部给药的患者 这可能导致超治疗剂量或亚治疗剂量的API的交付，其后果可能是 意义重大。

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.