In vitro-In vivo Correlations of Parentral Microsphere Drug Products

肠外微球药物产品的体外-体内相关性

• 批准号: 8668569
• 负责人: DIANE JANE BURGESS
• 金额: $ 48.96万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668569
• 关键词: vitro; vivo; Correlations; Parentral; Microsphere

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.

摘要 在过去的几十年里，体外-体内相关性(IVIVC)已经被成功地用于允许生物多样性 缓释口服产品。因此，消除了对未成年人进行生物等效性研究的需要 生产变更和仿制药产品应用。到目前为止，生物潜水员还没有被批准 复杂的肠外制剂(如微球)。微球被认为是高风险产品，因为它们 旨在长时间释放药物，它们有复杂的配方和工艺 方法论。微小的制造变化可能会影响微球的物理化学特性。 特征，这反过来可能会影响它们在体内的表现。体外释放测试是一种重要的工具 用于质量控制目的以及预测微球在体内的性能。虽然没有 微球的体外释药方法适用于FDA推荐使用的USP仪器 4和，如果适用，USP装置2(桨)或用于微球的任何其他适当方法。一个USP 本课题组已成功开发了微球体外释放试验的仪器4方法 含有一系列不同的小分子和蛋白质疗法。它的辨别能力 该方法已使用不同的地塞米松微球制剂进行了演示。此外，方法 使用商用利培酮(R)进行了验证(健壮性、坚固性和重复性) Consta(R)产品。已经报道了微球的体外静脉注射和体外-体内关系(IVR)。 产品。然而，这些研究没有涉及定性(Q1)和定量(Q2)的配方 无效成分的等价物，但制造差异。在我们以前标准化的基础上 利培酮(R)Consta(R)的体外释放方法，建议开发Q1/Q2等效物的IVCs 具有不同制造工艺的配方。两种模型药物(利培酮和纳曲酮)已被 之所以选择它们，是因为它们是商业上可用的微球产品，很快就会失去专利。 因此，这些产品的仿制制剂预计将进入监管程序。 开发两种模型化合物的IVIVC将使我们对物理化学有一个基本的了解 微球/药物系统的性质及其与体内外性能的关系。这 研究将有助于建立适当的体外释放方法，并将有助于推动 创新微球和仿制微球的监管审查和批准程序。此外， 建立IVIVCs的方法可以针对其他微球产品进行修改。发展中的静脉输液控制系统 对于第一季度/第二季度，使用不同制造工艺制备的等效配方将为 未来使用静脉输液控制系统，以实现生物多样性。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非专利微球产品，降低成本。