Evaluation of Dissolution Methods for Complex Parenteral Liposomal Formulations

项目总结/摘要 尽管对脂质体药物制剂进行了广泛的研究，但用于监测脂质体药物制剂的可靠的体外方法仍然存在不足。 释放和预测体内性能仍然缺乏。目前，用于评估的竞争方法 脂质体释放通常产生不同的方法特异性释放曲线。的发展进度 由于缺乏系统的定量表征， 这些复杂的药物递送系统涉及可能有助于药物释放的无数因素 分布，广泛的溶出介质，以及缺乏可靠的机制模型， 解释了药物释放的这些关键因素。拟议的研究结合了明智的评价 选择的方法来监测从脂质体剂型的体外药物释放， 基于机制的计算模型，包括脂质体内微环境、溶解 介质和药物形态（例如，电离态，膜结合，复合物形成，自缔合， 等）。方法耐用性将通过对控制的关键机制参数进行统计分析来评估。 药物释放（例如，速率常数），如项目小组开发的数学模型所确定。 拟议的机制为基础的模型将使分析师能够提取这些基本参数驱动 药物释放，从而统一看似矛盾的方法特定的结果，同时提供科学的 体外-体内相关性（IVIVC）。虽然集中于含有阿霉素的脂质体制剂， 基本的项目概念将适用于其他复杂的胃肠外制剂的放行检测和IVIVC 剂型如聚合物胶束、纳米悬浮液和其它基于纳米技术的药物递送 系统.具体目标如下：1）建立基于机理的脂质体数学模型 多柔比星释放，模拟释放曲线，并分析目前的体外释放方法的敏感性， 由于配方差异导致的关键模型参数的改变; 2）制备和表征脂质体 制剂的组成与市售盐酸多柔比星脂质体注射剂相似，但在关键选择方面有所不同 特性（例如，硫酸铵浓度、聚乙二醇化、粒度等）; 3)进行 使用AIM中确定的体外释放方法对来自AIM 2的脂质体制剂进行溶出/释放研究 1、改变溶出条件以探测方法性能并验证/完善机理模型， 预测特定条件下的释放曲线; 4）调整释放方法并验证基于 在先前的研究中开发的数学模型旨在建立体外-体内相关性，从而预测 来自体外实验数据的体内释放曲线。这些研究的预期成果是将 目前的经验为基础的测试方法，一个建立在机械的理解交付 系统及其在任何给定环境中的释放特性。

PROJECT SUMMARY/ABSTRACT Despite extensive study of liposomal drug formulations, reliable in vitro methods to monitor liposomal drug release and predict in vivo performance are still lacking. Currently, competing methods employed to assess liposomal release often produce disparate, method-specific release profiles. Progress in the development of robust, predictive release methods has been hindered by lack of systematic, quantitative characterization of these complex drug delivery systems with respect to the myriad of factors that may contribute to drug release profiles, the wide range of dissolution media employed, and a lack of mechanistic models that can reliably account for these critical factors on drug release. The proposed study combines evaluation of judiciously selected methods to monitor in vitro drug release from liposomal dosage forms with comprehensive mechanism-based computational models that incorporate the intra-liposomal microenvironment, dissolution media, and drug speciation (e.g., ionization state, membrane binding, complex formation, self-association, etc.). Method robustness will be assessed by statistical analyses of key mechanistic parameters that govern drug release (e.g., rate constants) as established by the mathematical models developed by the project team. The proposed mechanism-based models will enable analysts to extract those underlying parameters driving drug release, thereby unifying seemingly conflicting method-specific results, while providing scientifically founded in vitro-in vivo correlations (IVIVC). Though focused on liposomal formulations containing doxorubicin, the underlying project concepts will be applicable to release testing and IVIVC for other complex parenteral dosage forms such as polymeric micelles, nanosuspensions, and other nanotechnology-based drug delivery systems. Specific aims are as follows: 1) Construct mechanism-based mathematical models for liposomal doxorubicin release, simulate release profiles, and analyze the sensitivity of current in vitro release methods to alterations in key model parameters due to formulation differences; 2) Prepare and characterize liposome formulations similar in composition to marketed doxorubicin HCl liposome injections but varying in key selected properties (e.g., ammonium sulfate concentration, pegylation, particle size, etc.); 3) Conduct dissolution/release studies of liposome formulations from aim 2 using in vitro release methods identified in aim 1, varying dissolution conditions to probe method performance and to validate/refine the mechanistic models to predict condition-specific release profiles; 4) Adapt the release methods and validated mechanism-based mathematical models developed in previous aims to establish in vitro-in vivo correlations and thereby predict in vivo release profiles from in vitro experimental data. The expected outcome of these studies is to transform current empirically based testing approaches to one founded on a mechanistic understanding of the delivery system and its release characteristics in any given environment.