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

摘要/摘要 目前美国已批准了四种左炔诺孕酮宫内缓释系统(LNG-IUSS)。 美国食品和药物管理局。然而，到目前为止，还没有获得批准的通用LNG-IUS。LNG-IUSs的发展 挑战：1)长期作用(长达5年)；2)局部作用；3)药物-装置组合 产品。在我们的美国FDA拨款(RFA-FD-15-006)下，我们成功地开发和 定性和定量(Q1/Q2)当量LNG-IUSS加工方法的优化 使用Mirena®作为参考产品。物理化学表征方法和一种 建立了可靠的具有判别能力的实时释药检测方法。这 允许测定药物颗粒大小、物理结构(尺寸和 设备的配置)以及外膜的来源对体外药物释放的影响。 我们还建立了使用水有机介质的加速测试方法。有了这些 方法在手，能够开发LNG的通用等价物的下一个合乎逻辑的步骤是- IUSS是基于质量目标产品简介来理解LNG-IUSS的设计空间 (QTPP)。因此，现在有必要系统地调查关键技术的影响 工艺参数(CPP)、配方变化和设备物理结构(尺寸 和配置)。这将需要开发非第一季度/第二季度 当量LNG-Ius，因为Q1/Q2当量配方在组成方面受到限制 辅料的浓度。在过去的二十年里，我们的实验室已经取得了 在制剂开发和体外释放试验方面做出了重大贡献(两者都是真实的 时间和加速)许多不同的长效复杂的肠外药物产品。在……里面 与FDA合作，我们已经开发出适当的体外方法，以使 通过评价对这些复杂的非肠道药物产品提出生物等效性建议 原材料属性以及加工和配方参数对其的影响 性能。基于这一知识，现在建议开发一种制造方法 对于适合商业制造的LNG-IUS，将允许识别 CPP及其对关键质量属性(CQA)的影响的评估。的影响 工艺参数、配方变化和器件物理结构对释放率的影响 将定量测定LNG-IUS的含量。此外，强大的加速版本测试 将开发一种方法来减少体外性能测试的时间。Liletta®(类似的 Mirena®的产品)将作为第二个商业比较对象进行调查。这项研究将 促进制定通用液化天然气-IUS的生物等效性建议。

SUMMARY/ABSTRACT There are four levonorgestrel-releasing intrauterine systems (LNG-IUSs) approved by the U.S. FDA. However, to date, there are no approved generic LNG-IUSs. Development of LNG-IUSs is challenging: 1) long acting (up to 5 years); 2) locally acting; and 3) drug-device combination products. Under our U.S. FDA grant (RFA-FD-15-006), we have successfully developed and optimized a processing method for qualitatively and quantitatively (Q1/Q2) equivalent LNG-IUSs using Mirena® as the reference product. Physicochemical characterization methods, and a reliable real-time release testing method with discriminatory capability, have been developed. This allowed determination of the impact of drug particle size, physical structure (dimensions and configuration of the device) as well as the source of the outer membrane on in vitro drug release. We have also established accelerated testing methods using hydro-organic media. With these methods in hand, the next logical step to enable development of generic equivalents of the LNG- IUSs is to understand the design space of LNG-IUSs based on the quality target product profiles (QTPPs). Accordingly, it is now necessary to systematically investigate the impact of critical process parameters (CPPs), formulation variations, and the device physical structure (dimensions and configuration) on the release profiles. This will require the development of non-Q1/Q2 equivalent LNG-IUSs, since Q1/Q2 equivalent formulations are limited in terms of the composition and concentration of the excipients. Over the past two decades, our laboratory has made considerable contributions to the formulation development and in vitro release testing (both real- time and accelerated) of many different long-acting complex parenteral drug products. In collaboration with the FDA, we have developed appropriate in vitro approaches to enable bioequivalence recommendations for these complex parenteral drug products, through evaluation of the impact of raw material attributes, as well as processing and formulation parameters on their performance. Building on this knowledge, it is now proposed to develop a manufacturing method for LNG-IUSs suitable for adaption to commercial manufacturing that will allow identification of the CPPs and evaluation of their impact on the critical quality attributes (CQAs). The influence of processing parameters, formulation variations and device physical structure on the release rate of LNG-IUSs will be quantitatively determined. In addition, a robust accelerated release testing method will be developed to reduce the time for in vitro performance testing. Liletta® (a similar product to Mirena®) will be investigated as a second commercial comparator. This research will facilitate the establishment of bioequivalence recommendations for generic LNG-IUSs.