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

摘要 在过去的几十年里，fda已经批准了各种眼科产品，包括：16种药膏、4种凝胶和1种。 原位成胶。这些产品具有增加粘度和粘附性的特点，因此 增加角膜前滞留时间；传授缓释特性并改善在 行动地点。通用和创新产品的开发复杂于：1)角膜前因素；2) 病理生理学；以及3)复杂的制造过程，其中微小的产品差异可能会导致显著的 产品质量(例如粘度)的差异以及由此导致的药效学行为的差异。到目前为止 尽管没有专利和专利，但只有7种基于软膏的仿制眼科产品在美国获得批准 这些产品中的大多数都存在排他性保护壁垒。体外释放试验是FDA推荐的 在大多数仿制药的批准中，试验产品和参考产品之间的生物等效性证明的一部分 毒品。USP 37已推荐：垂直扩散池(Franz扩散池)；浸没式 具有USP装置2的单元；以及具有用于半固体体外释放测试的特殊适配器单元的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来 确定批准的半固体制剂中微小工艺和/或配方变化的可接受性。使用 这种推荐的体外释放试验方法以及文献中描述的其他方法，它是 重要的是要了解每种方法的优缺点，以便于选择方法。超过了 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长足的进步 用于复杂剂型(即微球、脂质体和植入剂)的方法。例如，一个强大的USP 已开发出具有区分配方差异的能力的装置4方法，并且 预测微球的体内性能。在这一背景下，建议开展一项 眼科药物当前体外释放方法的系统评价。Lotemax(洛替泼诺) Etabate)软膏被选为模型产品。洛替泼诺的Q1/Q2等效剂 将准备有制造差异的Etabate，并与Lotemax进行比较。稳健投放法(S) 能够检测制造差异的能力将被识别和/或开发。已识别和/或已开发的 方法(S)将在未来的研究中用于预测Q1/Q2当量眼膏的体内性能 通过使用药代动力学数据(由于时间和资金原因，不是当前提案的一部分 约束)。全面了解目前的体外释放试验方法以及对药物释放的影响 不同制造工艺对眼科药物关键理化性质和体外性能的影响 将会得到药膏。这项研究将促进制定生物等效性建议 仿制眼膏，这将有助于向公众提供安全有效的仿制药，网址为 降低了成本，而且及时。

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.