DISSOLUTION METHODS FOR PARENTERAL SUSTAINED RELEASE IMPLANT DRUG PRODUCTS

摘要 在过去的几十年里，肠外缓释产品(如微球和植入物)已经 成为传统药物产品的先进替代品。目前有20多家 创新者微球和植入物产品在市场上，其中几个要么是专利过期，要么是 获得专利权。因此，这些产品的通用等价物处于不同的开发阶段。 确保这些缓释剂的质量和安全是至关重要的。体外释放试验是 对于质量控制目的以及体内性能预测都很重要，建议将其作为 在大多数仿制药的批准中，试验产品和参考产品之间的生物等效性论证 毒品。但由于缺乏有效的体外释药方法，可用于注射用缓释片 释放药物产品，使用许多不同的程序和非标准仪器(例如，样品和- 分离、透析膜和流通法)。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，近年来取得了相当大的进展。 关于注射用标准化体外释放方法的开发和验收 微球。到目前为止，很少有研究报道阿司匹林的体外释放试验方法。 肠外植入物。特别是，还没有使用USP标准仪器的体外释放测试方法 报告为原位成型植入物。在过去的16年里，我们的实验室在 开发和验证复杂的肠外制剂(即微球， 脂质体和植入物)。一种健壮的USP装置4微球的方法已经被开发出来 展示了区分配方差异和预测体内性能的能力。在……里面 此外，作为一种快速质量控制方法，已开发了加速USP装置4方法 对植入物配方的识别能力。在这些研究之后，建议进行系统的 目前预成型和原位成型非肠道植入物体外释放方法的评价 具有制造差异的非活性成分的定性(Q1)和定量(Q2)等价物。这个 最合适、稳健的发布方法(S)，能够检测制造差异并预测 将确定和/或开发活体性能。地塞米松和醋酸亮丙瑞林( 商业植入物产品)已被选为预成型和原位成型植入物的模型药物， 分别进行了分析。全面了解目前的体外释放方法，以及对药物的影响 两种预成型材料的关键理化性能和体外性能的制造差异 并将获得原位成型植入物。本研究将促进生物等效性的发展。 推荐非专利植入物产品，这将有助于为公众提供安全和有效的 以更低的成本和及时的方式生产仿制药。

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.