中药多元释药系统设计前关键技术：“组分生物药剂学分类系统”的构建

The material properties before the preparation are important factors which restrict the development of the Chinese materia medica preparation. Carrying out the in-depth study of the material basis of traditional Chinese medicine (TCM) is the basic way to solve the problem mentioned above. Based on the composition structure theory of TCM material base proposed by our research group, we put forward that the material basis "component" can be used as the basic unit of the Chinese materia medica preparation. This project aims to study the characterization techniques and methods of component properties, to build biopharmaceutics classification system of component, thus providing a scientific basis for preparation design and the choice of preparation technology. The phenolic acid component, diterpene quinone component, and monoterpene glucoside component from shuxiong prescription composed of Panax ginseng and Chinese herbaceous peony were chosen as model drugs. Based on the efficacy of anti myocardial ischemia, through the target cell affinity capture, combined with UPLC/Q-TOF-MS chromatographic analysis method, the core constitute of components were selected, namely “N” representatives. There was no statistical difference between the comprehensive effect of “N” representatives and the overall efficacy of the original extracts. The self-property parameters and its properties in the whole (multi component environment) of “N” representatives were analysised, including permeability, solubility, LogP, ADME, et al. Discrete degree was evaluated by using Cosine and Grubbs methods. The overall properties of components were characterized by assessing weight coefficients of quality, efficacy contribution and AUC exposure contribution, to build the biopharmaceutics classification system Chinese component.

成型前物料性质是制约中药制剂发展的重要因素，中药物质基础研究的深入是解决的根本途径；基于课题组提出的中药物质基础的组分结构理论，提出物质基础的“组分”可作为中药制剂的基本单元。本课题目标在于研究组分性质表征技术与方法、构建组分生物药剂学分类系统，为其剂型设计与制剂技术选择提供科学依据。课题以“参芍舒胸方”中酚酸组分、二萜醌组分、单萜苷组分作为模型药物，基于抗心肌缺血药效，通过靶细胞亲和捕集，结合UPLC/Q-TOF-MS色谱分析手段，筛选出组分的核心构成即N个代表性成分，其综合药效与原提取物整体药效无统计学差异；分析N个代表成分自身性质及其在整体(多成分环境)中的渗透性、溶解度、油水分配系数、ADME等性质参数；采用Cosine和 Grubbs法对离散度评价，综合各成分的质量权重系数、药效贡献度、AUC暴露量贡献率，整合表征组分的整体性质，从而构建“组分”生物药剂学分类系统。

本课题基于组分的生物药剂学性质，围绕“参芍舒胸方”（处方含川芎、丹参、赤芍、三七、红花等中药）展开了深入研究评价各味抗心肌缺血活性，辨识中药抗心肌缺血效应物质基础组分，优化物质基础组分间结构，并通过靶细胞亲和捕集，结合UPLC/Q-TOF-MS色谱分析、分子对接、药物血清化学等手段，筛选出组分的核心构成即N个代表性成分，其综合药效与原提取物整体药效无统计学差异；最后分析N个代表成分自身性质及其在整体(多成分环境)中的渗透性、溶解度、 油水分配系数、ADME等性质参数；采用Cosine和 Grubbs法对离散度评价，综合各成分的质量权重系数、药效贡献度、AUC暴露量贡献率，整合表征组分的整体性质，从而构建“组分”生物药剂学分类系统。结果确定了“参芍舒胸方”中6味中药抗心肌缺血活性组分以及淫羊藿抗骨质疏松活性组分，丹参、红参、川芎、三七以及红花中的抗心肌缺血活性组分分别为丹酚酸组分、人参稀有皂苷组分、川芎内酯组分、三七皂苷组分以及红花黄酮组分，淫羊藿中抗骨质疏松活性组分为低糖苷组分，并对其组分整体生物药剂学性质进行表征，并根据 “组分”生物药剂学分类系统分类方法对各组分进行分类，最终确定这6味中药中的活性组分主要为II类以及III类，即低溶解性高渗透性或高溶解性低渗透性。. 本课题在执行的过程中，博士研究生2名、硕士研究生7名。发表标注本课题基金号的学术论文17篇，其中SCI论文6篇、中文核心论文11篇。本研究建立中药组分生物药剂学性质分类系统，为明确中药物质基础及中药多元释药系统的设计提供理论和实验依据，为中药高端制剂的发展奠定研究基础。