Evaluation and Development of Dissolution Testing Methods for Semisolid Ocular Drug Products

半固体眼科药品溶出度测试方法的评价和开发

• 批准号: 8844139
• 负责人: DIANE JANE BURGESS
• 金额: $ 34.84万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8844139
• 关键词: Evaluation; Development; Dissolution; Testing; Methods

ABSTRACT In the past few decades, FDA has approved various ophthalmic products including: 16 ointments, four gels and one in situ forming gel. These products have features of increased viscosity as well as mucoadhesion and therefore increased pre-corneal residence time; imparting sustained release characteristics and improved availability at the site of action. Development of generic and innovator products is complicated by: 1) pre-corneal factors; 2) pathophysiology; and 3) complex manufacturing processes, where small product variations can result in significant differences in product quality (e.g. viscosity) with consequent differences in pharmacodynamic behavior. Until now only seven ointment-based generic ophthalmic products have been approved in the US in spite of no patent and exclusivity protection barriers for the majority of these products. In vitro release testing is recommended by FDA as part of the demonstration of bioequivalence between test and reference products in the approval of most generic drugs. The USP 37 NF <1724> has recommended: the vertical diffusion cell (Franz diffusion cells); the Immersion cell with USP apparatus 2; and USP apparatus 4 with a special adapter cell for in vitro release testing of semisolid dosage forms. The FDA has recommended the use of Franz diffusion cells or any other appropriate method to determine the acceptability of minor process and/or formulation changes in approved semisolid dosage forms. With this variety of recommended in vitro release testing methods as well as other methods described in the literature, it is important to understand the advantages and disadvantages of each method to facilitate method selection. Over the past 16 years our laboratory has made considerable progress in the development and validation of in vitro release methods for complex dosage forms (i.e. microspheres, liposomes and implants). For example, a robust USP apparatus 4 method has been developed with demonstrated capability of distinguishing formulation differences, and predicting in vivo performance for microspheres. Following on this background, it is proposed to conduct a systematic evaluation of current in vitro release methods for ophthalmic drug products. Lotemax¿ (loteprednol etabonate) ointment has been selected as the model product. Q1/Q2 equivalent formulations of loteprednol etabonate with manufacturing differences will be prepared and compared to Lotemax¿. Robust release method(s) capable of detecting manufacturing differences will be identified and/or developed. The identified and/or developed method(s) will be used in future studies to predict the in vivo performance of Q1/Q2 equivalent ophthalmic ointment formulations through use of pharmacokinetic data (not a part of the current proposal due to time and financial constraints). A comprehensive understanding of current in vitro release testing methods, as well as the effect of manufacturing differences on the critical physicochemical properties and in vitro performance of ophthalmic ointments will be obtained. This research will facilitate the development of bioequivalence recommendations for generic ophthalmic ointments, which will in turn help provide the public with safe and effective generic products at reduced cost and in a timely fashion.

摘要 在过去的几十年里，FDA批准了各种眼科产品，包括：16种软膏剂，4种凝胶剂和1种 原位形成凝胶。这些产品具有增加的粘度以及粘膜粘附的特征，因此 增加的角膜前停留时间;赋予持续释放特性和改善的在 行动现场。仿制药和创新药的开发因以下因素而变得复杂：1）角膜前因素; 2） 病理生理学;以及3）复杂的制造工艺，其中小的产品变化可导致显著的 产品质量（例如粘度）的差异导致药效学行为的差异。直到现在 尽管没有专利，但在美国只有七种基于软膏的通用眼科产品获得批准， 这些产品中的大多数都有排他性保护壁垒。FDA建议进行体外释放试验， 在批准大多数仿制药时， 毒品USP 37 NF<1724>推荐：垂直扩散池（Franz扩散池）;浸入式扩散池（浸入式扩散池） 用于半固体体外释放试验的USP装置2和USP装置4， 剂型。FDA建议使用Franz扩散池或任何其他适当的方法， 确定批准的半固体剂型中微小工艺和/或处方变更的可接受性。与 这些推荐的体外释放测试方法以及文献中描述的其它方法， 重要的是要了解每种方法的优点和缺点，以便于选择方法。来 在过去的16年里，我们的实验室在体外释放的开发和验证方面取得了相当大的进展。 用于复杂剂型（即微球、脂质体和植入物）的方法。例如，稳健的USP 已经开发了装置4方法，其具有区分配方差异的证明能力，并且 预测微球的体内性能。在这一背景下，建议进行一次 眼用药品现行体外释放方法的系统评价。氯替麦松（氯替泼诺 依碳酸盐）软膏已被选为模型产品。氯替泼诺的Q1/Q2等效制剂 将制备具有生产差异的依碳酸盐，并与Lotemax进行比较。耐用放行方法 将识别和/或开发能够检测制造差异的方法。已确定和/或已开发的 将在未来研究中使用方法预测Q1/Q2等效眼膏的体内性能 通过使用药代动力学数据（由于时间和财务原因， 约束）。全面了解目前的体外释放测试方法，以及 眼用制剂关键理化性质和体外性能的生产差异 将获得软膏。这项研究将促进生物等效性建议的发展， 仿制眼药膏，这将有助于为公众提供安全有效的仿制产品， 降低成本，及时。