基于中药药剂复方药性传递假说的白虎汤液中多成分纳米相态解析及其与原方立法意图和功效相关性研究

The drug property, such as the treating principle, reasonable collocation medicinal and clinical efficacy of Chinese Materia Medica(CMM) compound formula, can be affected by active ingredient, drug process, dosage form and internal function etc. In the last study, this is not well recognized, and don't know how to conduct research. In this topic, the hypothesis of compound formula drug property delivered by CMM medicament is innovatively proposed and used as the main line. Baihu Decoction is chosen as object and split according to phase. Then, the phase is analyzed and the essence of the drug property delivery is revealed from the perspectives including disperse system, chemical component and drug release profile. This research is designed to give a scientific explanation for the CMM compound formula drug property deliver process, deeply study the microstructure and formation mechanism of the particles in complex dispersion, and discuss the contribution of the component to the drug property delivery. The purpose of the research is to effectively inherit the theory of “prescription-disease-dose-effect”, trace the origin of maximum therapeutic effect of decoction, and strive to create a modern CMM preparation theory, transform Traditional Chinese Medicines theory from “philosophical thought” to “scientific research”, and scientifically guide the modernization research of CMM.

中药复方的理法方药、药性和合、临床功效等药性特征受到有效成分、药物处理、施药形式及体内作用等因素影响。以往研究中，对中药复方药性的存在认识不足，不清楚如何对其进行研究。本课题创新性提出“中药药剂复方药性传递假说”，并以此为主线，以白虎汤为对象，根据其立法意图和功效，采用整体动物、活体荧光成像、荧光内窥式显微及药效动力学等技术建立复方药性评价体系，对白虎汤液按相态拆分及解析，从分散体系、化学成分、释药行为等视角揭示其药性传递的实质。本课题旨在对中药复方药性传递过程作以科学阐释，对复杂分散体系中粒子的微观形态及形成机理进行深入研究，并探讨体系中各组成对药性传递的贡献。该研究有效传承“方-证-剂-效”理论，追溯汤剂中协同作用和治疗效果最大化的根源，力图创建源于传统并高于传统的现代中药制剂理论，实现中医药理论由“哲学思想”到“科学探究”的转变，并给予中药现代化研究以科学指导。

本项目在中药传统汤剂白虎汤中发现纳米相态，平均粒径100 nm，形态圆整，负载难溶性解热有效成分芒果苷和大量无机离子。课题选取较有争议的煎煮时间、加水量、煎煮次数进行考察，参考指标主要降热成分芒果苷、新芒果苷含量变化及EDTA法滴定Ca2+含量变化确定最终煎煮工艺。课题根据白虎汤的立法意图和功效建立白虎汤复方药性评价指标体系为：温病气分热证（内毒素静脉注射）模型、干酵母致热模型、2,4-二硝基苯酚致热模型。白虎汤各相态拆分方法的建立、白虎汤复方药性传递有效相态的确定研究、白虎汤复方药性传递有效相态的形成机制及组成解析研究、白虎汤有效相态与白虎汤复方药性传递的相关性研究。课题采用Box-Behnken效应面法优化还原纳米相态的处方，并对还原纳米相态进行TEM、粒度分布、差示热扫描、红外光谱、X射线衍射等性能指标进行表征，同时对还原纳米相态进行体外释药性能考察，完成白虎汤纳米相态的还原研究。采用整体动物、活体荧光成像、液质联用及药效动力学等技术建立复方药性评价体系，对白虎汤液按相态拆分及解析，从分散体系、化学成分、释药行为等视角证明中药复方药性的可表达性和可评价性、汤液基于相态的可拆分性及有效相态与复方药性的相关性，阐明其表达和传递白虎汤复方药性的机制，揭示其传递白虎汤复方药性的本质，使课题组的“中药药剂复方药性传递假说”得到了强有力的支持和验证。