中药传统丸剂溶出/释放动力学特征的整体表征与机制研究

The research is based on feature of "the holism concept" and "the compound prescriptions" of traditional Chinese medicine (TCM), with materiomic release kinetics theory of TCM as the foundation and the exactly clinical effective Liuwei Dihuang Pill as the representative drug. In the early study period, we have established a quantitative method of materiome of TCM and an evaluation method of synchronicity and visualization of multi-component release. In this research, through comparing the difference of overall drug release behavior of traditional Chinese medicine pills (Honeyed Pill, Water-bindered Pill, Wax-wrapped pill, Paste pill etc.) by the methods outlined above, the characterization of overall release kinetics could be showed comprehensibly, dynamically and multidimensionally. Using the Liuwei Dihuang Pill as an example, by studying the influences of herbal powder wall-breaking rate, honey refining degree and dosage, the dry degree and disintegrating time of the preparation, the associated rules of materiomic dissolution/release kinetics characteristics, the theory composed of drug release characterization of traditional Chinese medicine pills could be analyzed. The study is expected to characterize release kinetics characteristics of traditional Chinese medicine pill integrally, and to express the influence on its release kinetics behaviors of dosage forms and raw materials and adjuvant differently, to reveal scientific connotations of theory of traditional Chinese medicine preparations, such as "Pill - Sustained release drug" etc., to provide a new model for qualitative evaluation and control of Chinese medicine pills（traditional Chinese medicine compound solid dosage forms），to provide evaluative methods and standards for upgrading formulations of traditional Chinese medicine pills and processing transformations of traditional Chinese medicine pills, and to provide basis for clinical reasonable selection and application of traditional Chinese medicine pills.

本课题基于中医药的"整体观念"与"复方用药"特色，以中药物质组释放动力学理论为基础，选择临床疗效确切的六位地黄丸等为代表，采用前期建立的中药物质组定量方法、多组分释放同步性与可视化评价方法，系统比较蜜丸、水丸、蜡丸、糊丸整体释药行为的相似性与差异性，全面、动态、多维表征中药传统丸剂的整体释放动力学特征；并以六位地黄丸（蜜丸）为例，研究饮片粉体细胞破壁率、蜂蜜炼制程度及其用量、制剂干燥程度与其溶散时间、物质组溶出/释放动力学特征的关联规律，以期解析中药传统丸剂释药特征的构成原理。该研究可望整体表征中药传统丸剂释放动力学特征，差异化表达剂型、原辅料等对其释放动力学行为的影响，揭示"丸者缓也"等传统中药制剂理论的科学内涵，将为中药丸剂（中药复方固体剂型）的质量评价与控制提供一种全新模式，为中药传统丸剂的处方设计、剂型升级与工艺改造提供评价方法与标准，还可为临床合理选择与应用中药丸剂提供依据。

中药传统丸剂的独特防治优势与其释药特征密切相关，传统中药制剂理论认为：水丸“易化”，蜜丸“缓化”，糊丸“迟化”，蜡丸“难化”；而中国药典规定“小蜜丸、水蜜丸与水丸的溶散时限均为1小时，糊丸与浓缩丸的溶散时限为2小时”，表征蜜丸、水丸、蜡丸、糊丸等中药传统丸剂的的释放动力学特征，阐明“易化”、“缓化”、“迟化”与“难化”的科学内涵，对剂型选择与指导临床应用具有实际意义。.本项目基于中医药的“整体观念”与“复方用药”特色，选择疗效确切的六味地黄丸等为中药传统丸剂的代表，采用前期建立的中药物质组定量方法、多组分释放同步性（异步性）与直观可视化等评价方法，全面表征中药丸剂（蜜丸、水丸、蜡丸、糊丸等类型）的整体释放动力学特征；以六味地黄丸（蜜丸）为例，通过研究饮片粉碎程度（植物细胞破壁率）、辅料（炼蜜及其用量）、工艺（丸剂干燥程度）等对中药蜜丸释放动力学特征的影响，以解析中药蜜丸释药机理。.本项目制备了水蜜丸、大蜜丸、小蜜丸、浓缩丸、水泛丸、糊丸和蜡丸等不同类型的六味地黄丸，释放动力学研究发现，不同类型的六味地黄丸中的指标成分（马钱苷和丹皮酚）与中药物质组的释放特征，在4种不同释放介质中均有较大的差异；大蜜丸、糊丸、蜡丸等均有一定的缓释特征；与古语所述“水丸取其易化，蜜丸取其缓化，糊丸取其迟化，蜡丸取其难化”，基本相符。结果表明中药物质组释放动力学评价方法可整体、可视化表征中药传统丸剂的释药特征的差异。六味地黄丸（蜜丸）的释放动力学特征与药材粉粹度及粉体细胞破壁率，蜂蜜炼制程度及其用量，丸粒大小，丸剂干燥程度等因素有关。.该研究整体、动态、量化表征了蜜丸、水泛丸、糊丸、蜡丸等中药传统丸剂（剂型）的释放动力学特征，实现对蜜丸“缓化”、水丸“易化”、蜡丸“迟化”、糊丸“难化”等的差异化表达，从中药饮片粉末粒径、辅料、工艺等角度解析了中药蜜丸释药特征的影响因素，一定程度上揭示了“丸者缓也”、“大毒者须用丸”、“水丸取其易化，蜜丸取其缓化，糊丸取其迟化，蜡丸取其难化”等传统中药制剂理论的科学内涵，为中药丸剂（中药复方固体剂型）的质量评价与控制提供一种全新模式，为中药传统丸剂的剂型升级与工艺改造提供评价方法与标准。