基于释药动力学的多组分缓释制剂评价方法学研究

With the changes of human diseases and their treatment, combination drugs have become to be hotspot of innovation drugs, and development of their drug delivery system has also become to be focus. Current evaluation methods of drug-release in vitro for one ingredient sustained and controlled release preparations are difficultly to characterize the release behaviors and mechanism of multi-ingredient sustained and controlled release preparations in vitro and in vivo. To resolve this problem, evaluation methods of drug-release with high fitting precision, good predicting ability, reliable and good correlation in vitro and in vivo, need to be established for multi-ingredient sustained and controlled release preparations...To establish the evaluation methods of drug-release in vitro for multi-ingredient sustained release preparations, main active components and ingredients from Chinese herbal medicines are selected as targets, and the popular and reliable antioxidation models, such as DPPH, ABTS, FRAP and DMPD assay, are introduced into the evaluation in-line or at-line of drug release for multi-ingredient sustained release preparations. Systemic methodological investigation are designed, such as specificity, accuracy, precision (repeatability, intermediate precision and reproducibility), detection limit, quantitation limit, linearity, range, robustness and system suitability testing. The mthods are validated by the relationships between drug release in vitro and in vivo, pharmadynamics and pharmacology.

随着疾病谱和治疗模式的改变，"复方药物"以其独有优势已成为国际上新药研发的热点，其缓控释制剂的研究也成为药剂学发展的重要方向。缓控释制剂体外释药的现行评价方法难以全面表征多成分制剂释药过程中的总体行为，无法细微刻画多组分制剂的体内外释放行为特征，因此亟待建立预测能力强、可靠性高、与体内过程相关性强的评价方法。.本课题以构建适宜于多组分特点的缓释制剂体外释药评价方法为目的，选择临床疗效确切的常用中药为研究对象，以其主要有效成分及其有效组分等为切入点，引进抗氧化生物测定的最新技术和方法作为链接多成分间量比和效价的桥梁，重点研究拟建立方法（DPPH法、ABTS法、FRAP法、DMPD法）的可靠性和耐受性，并进行系统的方法学验证，通过体内-体外评价的相关性研究，进而构建适宜于多组分缓释制剂释药评价的生物测定法，制定相应的SOP和技术要求。

建立了一种基于生物测定法的中药多组分缓释制剂释药评价方法，以临床疗效确切的中药——丹参为研究对象，选取与其疗效密切相关的抗氧化活性为生物测定指标，分别采用DPPH、ABTS及FRAP法测定了丹参中各单一成分及不同配伍情况下，抗氧化活性的变化情况。在阐明成分间相互作用情况的基础上，对抗氧化生物测定在制剂释药评价中的影响因素、方法的可靠性和耐受性等情况进行系统研究、分析。最终确定了方法的适宜性，并对其适宜范围进行规定。采用所建立的基于抗氧化生物测定法对丹参多组分缓释制剂的整体释药行为进行评价，并与目前的各成分的释药动力学进行相关性及相似因子分析，结果表明所建立的方法能够很好地表征各成分的释药行为，且相对于绘制各单一成分的释药动力学曲线的方法，该方法更为简便、快捷，且可大大节约成本。因此，该方法建立对于多组分制剂的研究和开发具有积极的促进作用。