Development of Real-Time and Accelerated Dissolution Methods for a Long-Acting Levonorgestrel Intrauterine System

摘要 在过去几十年中，长效药物产品（如宫内避孕器/系统和皮下注射器） 植入物）已经成功地以受控的方式递送避孕类固醇多年。 在这些药物产品中，左炔诺孕酮子宫内系统（IUS）被认为是一种高效且 可逆的避孕选择，是所有年龄段女性的首选。目前，有三种长效 左炔诺孕酮宫内节育器在美国市场上，其中几个即将关闭专利。因此，委员会认为， 这些产品的仿制药预计将进入监管审查和批准程序， 不久的将来因此，至关重要的是，适当的体外性能测试方法可用于 确保产品质量和安全，并简化监管审查程序。体外释放测试是一项 一个重要的工具，不仅确保产品质量和一致的性能，而且还有助于产品 开发和监管审查流程。体外释放试验已被推荐作为 在大多数仿制药的批准中证明试验药物和参比药物之间的生物等效性。 然而，目前，缺乏药典或FDA推荐的可用于治疗的体外释放方法。 长效左炔诺孕酮IUS和文献中可用的信息非常有限。这 一直是产品开发和监管审查的主要障碍。17年来，我们的实验室 已经对体外释放方法的开发和验证做出了相当大的贡献（包括真实的- 时间和加速）用于长效复合胃肠外药物产品（如微球和植入物）。 例如，已开发了加速USP装置4方法作为快速质量控制方法 对植入物配方具有辨别能力。最近，我们的实验室与FDA合作， 一直在开发能够检测制造差异的适当体外释放方法， 预测复杂肠胃外药物产品（例如微球、原位形成 植入物以及眼用软膏）。在这些研究中获得的知识的基础上， 建议开发适当的、稳健的体外释放方法（实时和加速）， 区分左炔诺孕酮IUS（定性（Q1）和定量（Q2）等同于无活性 具有制造差异的成分），并且可以预测它们的体内性能。将努力 使用药典溶出仪开发加速释放方法。曼月乐®已被选为 参考清单药物（RLD），因为它将是第一个IUS的专利。全面了解 制造差异对关键理化和机械性能的影响 将获得左炔诺孕酮IUS及其体外和体内性能。这项研究将有助于 建立通用左炔诺孕酮IUS的生物等效性建议，这反过来将有助于 以较低的成本和及时的方式向公众提供安全有效的非专利产品。

ABSTRACT During the past few decades, long-acting drug products (such as intrauterine devices/systems and subdermal implants) have successfully delivered contraceptive steroids in a controlled manner over periods of years. Among these drug products, the levonorgestrel intrauterine system (IUS) is considered a highly effective and reversible contraception option and is preferred by women of all ages. Currently, there are three long-acting levonorgestrel IUSs on the U.S. market and several of these are about to come off patent. Consequently, generic equivalents of these products are expected to enter into the regulatory review and approval process in the near future. Therefore, it is crucial that appropriate in vitro performance testing methods are available to ensure product quality and safety and streamline the regulatory review process. In vitro release testing is an important tool that not only ensures product quality and consistent performance, but also assists in the product development and regulatory review processes. In vitro release testing has been recommended as part of the demonstration of bioequivalence between test and reference products in the approval of most generic drugs. However, at present, there is a lack of compendial or FDA recommended in vitro release methods available for the long-acting levonorgestrel IUSs and the information available in the literature is extremely limited. This has been a major obstacle to product development and regulatory review. Over the past 17 years, our laboratory has made considerable contributions to the development and validation of in vitro release methods (both real- time and accelerated) for long-acting complex parenteral drug products (such as microspheres, and implants). For example, an accelerated USP apparatus 4 method has been developed as a rapid quality control method with discriminatory ability for implant formulations. Most recently, in collaboration with the FDA, our laboratory has been developing appropriate in vitro release methods capable of detecting manufacturing differences and predicting in vivo performance for complex parenteral drug products (such as microspheres, in situ forming implants, as well as ophthalmic ointments). Building on the knowledge gained in these studies, it is now proposed to develop appropriate, robust in vitro release methods (both real-time and accelerated) that can discriminate levonorgestrel IUSs (that are qualitatively (Q1) and quantitatively (Q2) equivalent in inactive ingredients with manufacturing differences) and can predict their in vivo performance. An effort will be made to develop accelerated release method(s) using compendial dissolution apparatus. Mirena® has been chosen as the Reference List Drug (RLD) since it will be the first IUS to come off patent. A comprehensive understanding of the effect of manufacturing differences on critical physicochemical and mechanical properties of levonorgestrel IUSs and their in vitro and in vivo performance will be obtained. This research will facilitate the establishment of bioequivalence recommendations for generic levonorgestrel IUSs, which in turn will help provide the public with safe and effective generic products at reduced cost and in a timely fashion.