Evaluation of Dissolution Methods for Complex Parenteral Liposomal Formulations

项目摘要/摘要 尽管对脂质体药物制剂进行了广泛的研究，但可靠的体外监测脂质体药物的方法 释放和预测体内表现仍然缺乏。目前，采用竞争的方法来评估 脂质体释放通常产生完全不同的、特定于方法的释放概况。在发展方面的进展 由于缺乏系统的、定量的表征，稳健的、预测性的释放方法受到了阻碍 这些复杂的药物输送系统涉及可能有助于药物释放的无数因素 剖面，所使用的广泛的溶解介质，以及缺乏能够可靠地 解释了这些影响药物释放的关键因素。建议的研究结合了明智的评估 脂质体剂型体外释药监测方法的选择 包含脂质体内微环境、溶出度的基于机理的计算模型 介质和药物形态(例如，电离状态、膜结合、络合物形成、自结合、 等)。方法的稳健性将通过统计分析关键的机械参数来评估 由项目组开发的数学模型建立的药物释放(例如，速率常数)。 拟议的基于机制的模型将使分析师能够提取这些潜在的参数 药物释放，从而统一看似相互冲突的特定方法的结果，同时科学地提供 建立体外-体内相关性(IVIVC)。尽管关注的是含有阿霉素的脂质体制剂， 基本的项目概念将适用于发布测试和其他复杂非肠外项目的IVIVC 剂型，如聚合物胶束、纳米混悬剂和其他基于纳米技术的药物输送 系统。具体目标如下：1)建立基于机理的脂质体数学模型 阿霉素的释放，模拟释放曲线，并分析目前的体外释放方法对 关键模型参数因配方不同而变化；2)脂质体的制备与表征 制剂组成与市场上销售的盐酸阿霉素脂质体注射剂相似，但在关键选择上有所不同 性质(如硫酸铵浓度、聚乙二醇化、颗粒大小等)；3)行为 用AIM确定的体外释放方法研究AIM-2脂质体制剂的溶出度/释放度 1、改变溶解条件以考察方法性能并验证/改进机理模型以 预测特定条件的发布配置文件；4)采用基于机制的发布方法和验证 以前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。这些研究的预期结果是转变 当前的基于经验的测试方法是建立在对交付的机械理解之上的方法 系统及其在任何给定环境中的发布特性。

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.