DISSOLUTION METHODS FOR PARENTERAL SUSTAINED RELEASE IMPLANT DRUG PRODUCTS

肠外缓释植入药物产品的溶出方法

• 批准号: 8843631
• 负责人: DIANE JANE BURGESS
• 金额: $ 25万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843631
• 关键词: DISSOLUTION; METHODS; PARENTERAL; SUSTAINED; RELEASE

ABSTRACT Over the past few decades, parenteral sustained release products (such as microspheres and implants) have emerged as an advanced alternative to traditional drug products. Currently there are more than twenty innovator microsphere and implant products on the market and several of these are either off patent or about to come off patent. Consequently, generic equivalents of these products are in various stages of development. It is crucial to ensure the quality and safety of these sustained release parenterals. In vitro release testing is important for quality control purposes as well as to predict in vivo performance and is recommended as part of the demonstration of bioequivalence between test and reference products in the approval of most generic drugs. However, due to the lack of compendial in vitro release methods available for parenteral sustained release drug products, many different procedures and non-standard apparatus are used (e.g. sample-and- separate, dialysis membrane, and flow-through methods). This makes inter-laboratory comparisons difficult and complicates the regulatory review process. However, in recent years, considerable progress has been made towards the development and acceptance of standardized in vitro release methods for parenteral microspheres. Until now, few studies have reported the development of in vitro release testing methods for parenteral implants. In particular, no in vitro release testing methods using USP standard apparatus has been reported for in situ forming implants. Over the past 16 years our laboratory has made considerable progress in the development and validation of in vitro release methods for complex parenteral products (i.e. microspheres, liposomes and implants). A robust USP apparatus 4 method for microspheres has been developed with demonstrated capability of distinguishing formulation differences and predicting in vivo performance. In addition, an accelerated USP apparatus 4 method has been developed as a rapid quality control method with discriminatory ability for implant formulations. Following these studies, it is proposed to conduct a systematic evaluation of current in vitro release methods for pre-formed and in situ forming parenteral implants that are qualitatively (Q1) and quantitatively (Q2) equivalent in inactive ingredients with manufacturing differences. The most appropriate, robust release method(s) capable of detecting manufacturing differences and predicting in vivo performance will be identified and/or developed. Dexamethasone and leuprolide acetate (drugs that are in commercial implant products) have been chosen as model drugs for pre-formed and in situ forming implants, respectively. A comprehensive understanding of current in vitro release methods, and of the effect of manufacturing differences on critical physicochemical properties and in vitro performance of both pre-formed and in situ forming implants will be obtained. This research will facilitate the development of bioequivalence recommendations for generic implant products, which will in turn help provide the public with safe and effective generic products at reduced cost and in a timely fashion.

摘要 在过去的几十年中，胃肠外持续释放产品（例如微球和植入物）已经 成为传统药品的先进替代品。目前有20多个 创新的微球和植入产品在市场上，其中一些要么是关闭专利或约 专利权被撤销因此，这些产品的通用等同物处于不同的开发阶段。 关键是要确保这些缓释胃肠外制剂的质量和安全性。体外释放测试是 对于质量控制目的以及预测体内性能很重要，建议作为 在大多数仿制药的批准中证明试验药物和参比药物之间的生物等效性 毒品然而，由于缺乏可用于胃肠外缓释的药典体外释放方法， 为了释放药物产品，使用许多不同的程序和非标准装置（例如，样品和 分离、透析膜和流通方法）。这使得实验室间的比较变得困难 并使监管审查过程复杂化。然而，近年来， 用于胃肠外给药的标准化体外释放方法的开发和接受 微球到目前为止，很少有研究报道了体外释放测试方法的发展， 肠胃外植入物特别地，还没有使用USP标准装置的体外释放测试方法被公开。 报告了原位形成植入物。在过去的16年里，我们的实验室在以下方面取得了长足的进步： 复杂的肠胃外产品（即微球， 脂质体和植入物）。已经开发了用于微球的耐用USP装置4方法， 证明了区分制剂差异和预测体内性能的能力。在 此外，已开发了加速USP装置4方法作为快速质量控制方法， 对植入物配方的辨别能力。根据这些研究，建议进行系统的 评价预成型和原位成型胃肠外植入物的当前体外释放方法， 非活性成分的定性（Q1）和定量（Q2）等同，但存在生产差异。的 能够检测生产差异并预测 将鉴定和/或开发体内性能。地塞米松和醋酸亮丙瑞林（ 商业植入物产品）已被选择作为预成型和原位成型植入物的模型药物， 分别全面了解目前的体外释放方法，以及 两种预成型材料的关键理化性质和体外性能的生产差异 并且将获得原位形成的植入物。本研究将促进生物等效性的发展 建议仿制植入产品，这反过来将有助于为公众提供安全有效的 以较低的成本和及时的方式生产通用产品。