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

总结/摘要 美国批准了四种左炔诺孕酮宫内释放系统（LNG-IUS）。 FDA.然而，到目前为止，还没有批准的通用LNG-IUS。LNG-IUSs的发展是 挑战性：1）长效（长达5年）; 2）局部作用; 3）药械联合 产品.在美国FDA的资助下（RFA-FD-15-006），我们成功开发了 优化了定性定量（Q1/Q2）等效LNG IUSs的处理方法 使用Mirena®作为参考产品。物理化学表征方法，以及 可靠的实时释放测试方法与歧视的能力，已经开发。这 允许确定药物粒度、物理结构（尺寸和 装置的配置）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。与这些 方法在手，下一个合乎逻辑的步骤，使通用等效的液化天然气的发展- IUSs是根据质量目标产品概况了解LNG-IUSs的设计空间 （QTPP）。因此，现在有必要系统地调查关键的 工艺参数（CPP）、配方变化和器件物理结构（尺寸 和配置）。这将需要开发非Q1/Q2 等效LNG-IUS，因为Q1/Q2等效配方在组成方面受到限制 和赋形剂的浓度。在过去的20年里，我们的实验室 对制剂开发和体外释放测试（均为真实的- 时间和加速）。在 与FDA合作，我们开发了适当的体外方法， 通过评价为这些复杂的胃肠外制剂提供生物等效性建议 原材料属性以及工艺和配方参数对其 性能基于这些知识，现在提出开发一种制造方法， 适用于商业化生产的LNG IUS，可识别 CPP及其对关键质量属性（CQA）的影响评价。的影响 工艺参数、制剂变化和器械物理结构对释放速率的影响 将定量测定LNG-IUS。此外，稳健的加速放行检测 将开发一种方法来减少体外性能测试的时间。Liletta®（类似 将作为第二个商业比较产品进行研究。这项研究将 促进建立LNG-IUS仿制药的生物等效性建议。

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.