基于热力学/分子动力学技术与PK/PD相结合的中药滴丸主/客体物相结构-药效相关性研究

Represented by compound Danshen dropping pills, traditional Chinese medicine (TCM) solid dispersion (SD) preparation has attracted much attention because of its distinctive curative effect. With water-soluble matrixes as the carrier, such as PEG and PVP, these preparations mix their compound multi-compositions to make the SD in order to improve the stability, release rate and bioavailability of the drugs. However, at present, few people have studied the SD, mixed by multi-compound compositions and carrier, on its combining ways and methods, its fusion state of the host/guest molecules, the mutual interference during the fusion of different components and the influence of the factors above on the drug efficacy, which has delayed the depth development of such preparations. Thermodynamic/Molecular Dynamics Analysis can reflect the combining methods and mutual interaction of each component in the system, and can analyze the fusion mechanism of this kind of dropping pills and the carriers. This subject is planning to use techniques, such as “Multi-component Melting Phase State Analysis”, “Molecular Dynamics Simulation” to analyze the state of each component in the compound Danshen dropping pills simulative preparation while in the PEG carrier, to investigate the influences of the state change on the PK of each active ingredient, to explore the correlation of the state change of host/guest molecules and the drug, and in order to reveal the relationship of the internal structure of the SD type traditional Chinese medicine dropping pills between its drug efficacy and provide the theoretical support for the development of traditional Chinese medicine dropping pills.

以复方丹参滴丸为代表的中药固体分散体（SD）制剂因其疗效显著而备受关注。这类制剂多以PEG或PVP等水溶性基质为载体，将其复方多成分与基质形成共融体作为提高药物稳定性、释放速率和生物利用度的手段。但目前少有人对这种复方多成分与水溶性基质形成SD的结合途径与方式、主/客分子的融合状态、多成分在融合过程中的相互干扰以及上述因素对药效的影响等进行研究，迟滞了此类制剂的深度开发。热力学/分子动力学解析可以反映体系内各组分之间的结合方式及相互作用，从客体分子/基质融合行为角度解析此类滴丸中成分与基质融合的机制。本课题拟应用“多元熔融相态解析”、“分子动力学模拟”等技术，对复方丹参滴丸模型制剂中各成分在PEG基质中的状态进行解析，考察其状态变化对各活性成分PK的影响，探索主/客分子状态变化与药效的相关性，进而揭示SD类中药滴丸的内部结构及其与药效的关系，为中药滴丸的研制提供理论支撑。

本项目通过对复方丹参滴丸制剂物相结构及其形成机理的解析，阐明滴丸结构特征及其对复方中特征性成分药动学（PK）的影响；建立模型制剂的“物相结构-特征性成分PK-特征性药效学指标PD”相关性联系，从而揭示中药多成分滴丸固体分散体（SD）制剂内部结构及其对制剂临床疗效的影响。热力学参数（TD）可以表征体系内分子无序化程度、分子间作用力、分子结构稳定性等微观结构性质。结果表示，原儿茶醛结晶复原性较强，丹参素则展示了在PEG介入下的无定形稳定状态。分子动力学模拟计算（MD）通过分子间的矢量对接计算体系能量变化，从而与TD分析的结果形成参照对比，解析分子间作用的全过程。LibDock模块分析表明，丹参素的羟基与模型受体蛋白氨基酸残基形成了大量氢键，进而与FT-IR结果共同证明药物组分与基质材料的结合形式可以影响其与蛋白氨基酸残基的氢键形成，影响药物与靶蛋白结合效率，最终影响药效。在代谢产物的富集途径分析中，我们发现复方丹参组分药物对冠心病的药理活性影响主要涉及三个生命代谢途径，包括甘油磷脂代谢、鞘脂代谢和花生四烯酸代谢。鉴定出二十六个潜在的生物标志物来表达脂质代谢紊乱。最后，通过心肌梗死率与凝血抑制率作为特征性药效指标，对复方组分进行PK-PD拟合，发现丹参素及丹酚酸B存在PK-PD对应关系。并且，基质PEG的存在会影响不同组分PK-PD的拟合参数。多数情况这种影响对于药效是正向的，推测是由于PEG改变了组分药动学行为及其与受体蛋白的接触效率。. 综上所述，本项目应用“多元熔融相态解析”、“分子动力学模拟”等技术，对复方丹参滴丸模型制剂中各成分在PEG基质中的状态进行解析，考察其状态变化对各活性成分PK的影响，探索主/客分子状态变化与药效的相关性，进而揭示SD类中药滴丸的内部结构及其与药效的关系，为中药滴丸的研制提供理论支撑。.总结项目内容包括.（1）采用TD/MD技术联合物化性质检测手段解析复方丹参滴丸SD模型制剂的物相结构，阐明复方丹参滴丸SD的形成机理。.（2）探寻复方丹参滴丸主要组分在保护心肌及治疗冠心病过程中的重要代谢途径及生物标志物。.（3）建立代表性组分丹参素、原儿茶醛、丹酚酸B及其模型制剂的PK方程，选取心肌梗死率及凝血抑制率作为PD指标，进行相关性拟合。