基于脱卷积原理和时辰给药同步丹参主成分体内过程的多元释药系统构建及其量化整合研究

The synergistic therapeutic effects produced by compatibility of Chinese medicine components reflect the overall concept and the idea of Chinese medicine treatment. Due to the difference of physicochemical properties of the constituents, both the ideal in vivo process and therapeutic effects can not be achieved easily. In our research, Danshen (salvia miltiorrhiza) is chosen as the model drug. Because of the significantly different in vivo process of major effective constituents, it is hard for them to exist in the body simultaneously, so the interactive effects on their respective targets are restricted. Thus, the view of synchronous in vivo process of major effective constituents is proposed in this project. Danshen exhibits a variety of cardiovascular activities, including prevention and treatment of angina pectoris. The substance basis of Danshen are Salvianolic acid B, Danshensu, TanshinoneⅡA, TanshinoneⅠand Protocatechuic aldehyde. The expected plasma concentration-time curves of these effective components will be simulated by computer program according to the occurrence frequency of angina pectoris in 24h based on chronopharmacology. Then, the relevant desired release profiles will be calculated using deconvolution method and used to guide the design of controlled-release pellets. The pharmacokinetic parameters MRT and Tmax will be chosen to evaluate the synchronization of in vivo process. In addition, multi-index comprehensive evaluation will be used to determine the best dosage proportion of these effective components. Finally, a reconstructive Danshen with synchronous in vivo performance and better comprehensive therapeutic effects will be obtained.

中药组（成）分配伍产生协同治疗作用体现了中医药的整体观和用药思想。由于各成分性质的差异，往往不能产生理想的体内过程和治疗效果。本项目选择中药丹参，针对其主要活性成分体内过程差异较大，很难保证同一时段共同存在于体内，制约在各自靶点产生交互作用的现象，提出单味中药主要成分体内同步驻留，共同存在的观点，以达峰时间和平均驻留时间等药动学参数作为体内同步性评价指标。根据心绞痛发作频率及时辰给药原理，通过模拟计算得到理想的血药浓度，运用脱卷积理论预测主要成分的体外释药行为，采用微丸技术调控各成分的释放、吸收与消除速度，使其具有基本一致的体内过程。在此基础上，以归一化加权的多效应指标研究同步微丸的量化配比。从一个全新的角度塑造体内命运和综合效应更加优良的"重组丹参"。这种既保留中药有效成分的完整性，又经人工改造与重组形成理想中药的尝试，希望能为中药配伍和多成分给药系统的设计与研制提供新的思路与借鉴。

本项目以丹参为模型药物，根据心绞痛发作频率及时辰给药原理，模拟计算得到丹参各成分的理想血药浓度，运用脱卷积理论预测主要成分的体外释药行为，采用微丸技术调控丹参各成分的释放、吸收和消除速度，使其具有基本一致的体内过程。并在此基础上，以归一化加权的多效应指标研究同步微丸的量化配比。. 研究结果表明，根据脱卷积理论预测得到的理想体外释药曲线，制备得到的各组分缓释微丸均能符合心绞痛时辰治疗的要求；丹参的多种活性组分微丸（如丹参酮IIA，丹参素，丹酚酸B和原儿茶醛）的体内过程较为一致，且组合给药后能达到更好的治疗效果；对上述四种组分的量化配比研究表明，当四种组分的配比分别为丹酚酸B： 10 %，丹参酮IIA： 41%，丹参素：42 %，原儿茶醛：7 %时，心绞痛的治疗效果最好。. 项目研究成果如下：.1、已发表SCI收载论文6篇，接收SCI收载论文1篇；.2、申请发明专利2项，公开2项；.3、主办或参与国际学术交流4次、国内学术交流3次，发表会议论文1篇。. （详见附件）