基于PK-PD模型的葛根芩连结肠靶向给药系统药效物质基础及制备工艺研究

Modernization of Chinese materia medica preparation is an important part of modernization of Chinese materia medica and one of the key links in development of industrialization of Chinese materia medica. At present, pharmaceutical dosage forms have been developed to the targeted drug delivery system which is characterized by drug carrier modification on the international. But domestic modernization of Chinese materia medica preparation still has three major bottlenecks. Firstly, the pharmacodynamic material basis of the compound is not clear, in other words, “active compounds” which can show major functions of original prescription are uncertain. Secondly, the study of Chinese materia medica tends to be pattern of western medicine, “active compounds” which can characterize the efficacy often be replaced by a single chemical composition in particular. Thirdly, the system of evaluation is lack of characteristic of traditional Chinese medicine.For example, the system of targeting evaluation only makes use of the system of western medicine evaluation, which means the system of targeting evaluation of a a single composition. It never evaluate the targeting of “active compounds” which can show the overall concept of traditional Chinese medicine so that characteristic of traditional Chinese medicine is less prominent.. The group will try to regard Gegen Qinlian Decoction as the object of study and illuminate pharmacodynamic material basis of Gegen Qinlian Decoction on the basis of establishing the system of the chemical fingerprint-pharmacokinetic fingerprint-pharmacodynamic fingerprint.Then, it can represent the change of “active compounds” during the process of extraction、refining and concentration and establish the overall concept of traditional Chinese medicine to prepare the new colon-targeted preparation with the characteristic of traditional Chinese medicine.

中药制剂现代化是中药现代化的重要组成部分，是中药产业化发展的关键环节之一，目前，国际上，药物剂型已经发展到以控制药物释放为特征的缓控释给药系统，以药物载体修饰为特征的靶向给药系统。而国内中药制剂的现代化一直存在着三大瓶颈：一是药效物质基础不清楚，即体现原方剂功能主治的“活性混合物”不明确；二是中药研究西药化，突出地表现为，表征药效的“活性混合物”在提取过程中往往被单一的化学成分所替代；三是评价体系没有中医特色，如靶向性评价体系套用西药的评价体系，即单一成分的靶向评价体系，没有对体现中医整体药物观的“活性混合物”进行靶向性评价，中医特色不突出。本课题将以葛根芩连汤为研究对象，在构建体外化学指纹-药代指纹-药效指纹三维指纹体系的基础上，阐明葛根芩连汤药效物质基础，动态表征“活性混合物”在复方提取、精制、浓缩中的变化，创建能体现中医整体药物观的靶向评价体系，制备具有中医特色的结肠靶向新制剂。

项目背景：.课题组研究发现葛根芩连汤口服后，药物难以到达结肠病灶部位，并且治疗溃疡性结肠炎的药效物质不清楚；中药复方研究从前处理到成型、从体外到体内的变化既不客观，也不能体现中医整体药物观；靶向性评价套用西药的评价体系。课题组提出建立葛根芩连汤三维指纹图谱体系及谱效关系模型，确定活性混合物并制备具有中医药特色，且符合中医整体药物观的新型给药系统。.主要研究内容：.1.葛根芩连汤药效物质基础研究：包括药效学试验，建立葛根芩连汤化学-药代-药效三维指纹图谱，建立谱效关系模型。2.结肠定位释药系统的制备：以活性混合物及权重系数为评价指标，优化工艺参数，制备结肠定位释药系统。3.结肠定位释药系统评价体系研究：分别进行体外释放度试验、体内药动学试验和组织分布试验。.重要结果：.建立葛根芩连汤全方及各拆方组体外-药代-药效指纹图谱和谱效关系模型，构建葛根芩连结肠定位释药系统并结合体外释放度试验、家兔体内药代动力学试验和组织分布试验，创建符合中医整体药物观的靶向评价体系，为中药复方新型给药系统制备与评价研究提供体现出中医特色的思路。.关键数据：.建立葛根芩连汤全方及各拆方组体外-药代-药效指纹图谱和谱效关系模型，有效成分与药效之间的关联度均大于0.5。优化工艺参数后，制备的结肠定位片口服给药后，葛根芩连有效成分在家兔体内的血药浓度达峰时间明显延迟，且分布于各组织内，其中结肠组织药物浓度最高。表明结肠定位片大部分药物集中在结肠局部释放，进一步印证了葛根芩连结肠定位释药系统体内过程与中医归经理论之间的关联性。.科学意义：.为探索并制备具有中医药特色，且符合中医整体药物观的新型给药系统，课题组提出创新研究思路：首先，阐明葛根芩连汤药效物质基础；其次，制备符合中医药特色、多成分、多途径、多靶点整体作用的新型给药系统；最后，构建符合中医整体药物观的靶向评价体系，为葛根芩连结肠靶向制剂的体内外研究提供评价依据。