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(如宫内节育器/系统和皮下注射) 植入物)多年来以受控方式成功地提供了避孕类固醇。 在这些药物中，左旋诺孕酮宫内系统(IUS)被认为是一种高效和 可逆的避孕选择，受到所有年龄段女性的青睐。目前，有三种长效机制 美国市场上的左旋诺孕酮宫内节育器，其中几种即将失去专利。因此， 这些产品的仿制药预计将于#年进入监管审查和批准程序。 在不久的将来。因此，关键是要有合适的体外性能测试方法 确保产品质量和安全，简化监管审查流程。体外释放试验是一种 重要的工具，不仅确保产品质量和一致的性能，而且还帮助产品 发展和监管审查流程。体外释放试验已被推荐为 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的论证。 然而，目前还缺乏药典或FDA推荐的体外释放方法可供选择 长效左旋诺孕酮宫内节育器和文献中可获得的信息极其有限。这有 是产品开发和监管审查的主要障碍。在过去的17年里，我们实验室 在体外释放方法的开发和验证方面做出了相当大的贡献(包括真实的 时间和加速)用于长效复杂的非肠道药物产品(如微球和植入物)。 例如，已经开发了加速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，在与FDA的合作下，我们的实验室 一直在开发合适的体外释放方法，能够检测制造差异和 预测复杂肠外药物制品(如微球、原位成型)的体内性能 植入物以及眼膏)。在这些研究中获得的知识的基础上，现在 建议开发合适的、强大的体外释放方法(实时和加速)，以 鉴别左炔诺孕酮宫内节育器(不活跃时定性(Q1)和定量(Q2)等同 具有制造差异的成分)，并可以预测它们在体内的表现。我们将努力 采用药典溶出仪建立S加速释放法。Mirena®已被选为 参考清单药物(RLD)，因为它将是第一个专利到期的IUS。全面了解 制造差异对材料关键物理化学和机械性能的影响 将获得左炔诺孕酮宫内节育器及其体内外性能。这项研究将有助于 为左旋诺孕酮宫内节育器建立生物等效性建议，这反过来将有助于 以较低的成本和及时的方式为公众提供安全有效的仿制药。

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.