In vitro-In vivo Correlations of Parentral Microsphere Drug Products

摘要 在过去的几十年中，体外-体内相关性（IVIVC）已成功用于允许生物豁免， 缓释口服产品。因此，无需进行生物等效性研究， 生产变更和仿制药申请。到目前为止，生物豁免尚未获得批准， 复合肠胃外剂型（例如微球）。微球被认为是高风险产品， 设计用于长时间释放药物，并且它们具有复杂的配方和加工过程 方法论。微小的生产变更可能会影响微球的理化性质 特性，这反过来可能会影响其体内性能。体外释放测试是一个重要的工具 用于质量控制目的以及预测微球的体内性能。虽然没有 微球可用的药典体外释放方法，FDA建议使用USP装置 4和，如果适用的话，USP装置2（桨法）或用于微球的任何其他适当的方法。的USP 本课题组已成功地开发了一种用于微球体外释放测试的装置4方法 含有一系列不同的小分子以及蛋白质治疗剂。这种辨别能力 已经使用不同的地塞米松微球制剂证明了该方法。此外，方法 使用市售利培酮进行了验证（耐用性、耐用性和再现性） Consta（R）产品。已经报道了微球的IVIVCs和体外-体内关系（IVIVIVRs） 产品.然而，这些研究不涉及定性（Q1）和定量（Q2） 非活性成分等同，但生产差异。在我们之前标准化的基础上 利培酮（R）Consta（R）的体外释放方法，建议开发Q1/Q2等效的IVIVIVCs 不同制造工艺的配方。两种模型药物（利培酮和纳培酮）已被 之所以选择它们，是因为它们是商业上可获得的微球产品，很快就会失去专利。 因此，预计这些产品的通用制剂将进入监管程序。 为两种模型化合物开发IVIVC将使人们对IVIVC的物理化学性质有一个基本的了解。 微球/药物系统的性质及其与体外和体内性能的关系。这 研究将有助于建立适当的体外释放方法，并将有助于促进 创新药和仿制药微球的监管审查和批准流程。而且 用于建立IVIVC的方法可以被修改用于其它微球产品。开发的IVIVIVC 对于Q1/Q2，使用不同生产工艺制备的等效制剂将为 未来使用IVIVVC以允许生物豁免。这些研究将有助于减少对人体研究的需求， 及时为公众提供安全有效的低成本通用微球产品。

ABSTRACT In the past decades, in vitro-in vivo correlation (IVIVC) has been successfully used to allow biowaivers for extended release oral products. Therefore eliminating the need for bioequivalence studies for minor manufacturing changes and generic drug product applications. Until now, biowaivers have not been granted for complex parenteral dosage forms (e.g. microspheres). Microspheres are considered high risk products as they are designed to release drug over long periods of time and they have complex formulations and processing methodologies. Minor manufacturing changes have the potential to affect microsphere physicochemical characteristics, which in turn may affect their in vivo performance. In vitro release testing is an important tool for quality control purposes as well as to predict microsphere in vivo performance. Although there is no compendial in vitro release method available for microspheres, FDA has recommended using USP apparatus 4 and, if applicable, USP apparatus 2 (Paddle) or any other appropriate method for microspheres. A USP apparatus 4 method has been successfully developed by our group for in vitro release testing of microspheres containing a range of different small molecules as well as protein therapeutics. The discriminatory ability of this method has been demonstrated using different dexamethasone microsphere formulations. In addition, method validation (robustness, ruggedness, and reproducibility) has been performed using the commercial Risperdal(R) Consta(R) product. IVIVCs and in vitro-in vivo relationships (IVIVRs) have been reported for microsphere products. However, these studies did not involve formulations that are qualitatively (Q1) and quantitatively (Q2) equivalent in inactive ingredients with manufacturing differences. Building on our previously standardized in vitro release method for Risperdal(R) Consta(R), it is proposed to develop IVIVCs for Q1/Q2 equivalent formulations with different manufacturing processes. Two model drugs (risperidone and naltrexone) have been chosen since they are in commercially available microsphere products that will shortly come off patent. Accordingly, generic formulations of these products are expected to enter into the regulatory process. Developing IVIVC for two model compounds will allow a fundamental understanding of the physicochemical properties of the microsphere/drug system and its relationship with in vitro and in vivo performance. This research will facilitate the establishment of appropriate in vitro release methods, and will help advance the regulatory review and approval processes for both innovator and generic microspheres. Moreover, the approaches taken to establish IVIVCs may be modified for other microsphere products. The developed IVIVCs for Q1/Q2 equivalent formulations prepared using different manufacturing processes will pave the way for the future use of IVIVCs to allow biowaivers. These studies will help reduce the need for human studies and provide the public with safe and effective generic microsphere products at reduced cost in a timely fashion.