基于胃内流体动力模拟的“药辅合一”多孔性白及胶胃内滞留行为及机制研究

Guiding ideal of “Unification of drug and adjuvant” is a wonderful application of adjuvant in traditional Chinese medicine(TCM) preparations. As a kind of active ingredient isolated from the Chinese medicine of Bletilla striata (Thunb.) Reichb.f. for hemostasia and myogenic, Bletilla striata polysaccharides gums(BSPG) has the capabilities of floating, adhesion, expansion and biocompatibility,and so on, which is the reason why BSPG may be used as a perfect drug carrier in the stomach under the guiding ideal of “Unification of drug and adjuvant”. At the same time, human stomach has complex physical structure and the phenomenon of gastric emptying movement, which leads to form the particular gastric fluid field, directly affects the dynamic state of drugs in stomach and becomes a critical scientific issues in the design of drug-delivery systems of intragastric floating-bioadhesive preparation. Therefore, in this proposal, we focus on the porous BSPG and according to the instantaneous state of gastric peristalsis, it is propose to use the computational fluid dynamics(CFD) software package FLUENT, adopt the previous model of gastric emptying during the gastric digestion and build gastric motion model to simulate movement process of BSPG in human stomach, explain the mechanisms on their gastric retention ability and investigate the influence of parameters on the gastric retention ability,such as density, viscosity, molecular weight and biodegradability, and so on. In addition, combined the base of the preliminary studies, costunolide as the tool medicine and the porous BSPG as the carrier, both will be choosed to apply in the preparation of intragastric floating-bioadhesive drug-delivery systems.Then the gastric retention capability and anti-gastric ulcers pharmacodynamics action of the complex will be evaluated. Moreover, BSPG,as the unification of drug and adjuvant as well as the functional auxiliary material of the intragastric floating-bioadhesive drug-delivery systems, whose mechanism and the scientific intension will be illustrated. Meanwhile, this study will provide a new idea for the development of gastroretentive dosage forms under the concept of “precision pharmacy” based on the computer-aided design (CAD) software.

“药辅合一”是中药制剂辅料的精妙运用。白及胶是中药白及止血、生肌之活性成分，兼具漂浮、粘附、膨胀及生物相容等特点，是理想的“药辅合一”胃部给药生物载体材料。人体胃具有复杂的生理结构加之胃排空运动，构成特殊的胃内流场环境，直接影响药物胃内运动状态，是胃内漂浮-生物粘附给药系统设计中的关键科学问题。本课题以多孔性白及胶为研究对象，基于胃蠕动的真实瞬时状态，使用计算流体力学领域FLUENT软件，采用已有研究的胃消化排空模型，模拟多孔性白及胶胃内运动轨迹，阐释其胃内滞留机理及其密度、黏度、分子量、降解性等对胃内滞留效果的影响规律；结合前期研究基础，以木香烃内酯为模型药，多孔性白及胶为载体材料，制备胃内漂浮-生物粘附协同型给药系统；评价其胃内滞留性能及抗胃溃疡药效，阐明多孔性白及胶作为 “药辅合一”胃滞留功能性辅料的机制和科学内涵，为基于计算机辅助设计的胃内滞留“精准药物”的研发提供新的研究思路。

白及为兰科植物Bletilla striata ( Thunb.)Reichb. f.的干燥块茎，始载于《神农本草经》，曰其“主胃中邪气”，使用至今已有上千年历史，自1963年为历版《中国药典》收载。白及性苦、涩、甘，微寒，入归肺、肝、胃经，具有止血生肌之功，是中医药治疗胃肺出血之要药。“药辅合一”是中药药剂学辅料的精妙运用，是区别于药学剂的重要特色。白及多糖（Bletilla striata Polysaccharide, BSP）属葡甘聚糖，具有止血、抗溃疡、创伤修复和免疫增强的多种作用，是典型的“药辅合一”中药辅料。本研究进行了BSP的提取、纯化等研究；基于胃内流体运动规律的BSP胃内运动轨迹的研究；BSP胃滞留行为的相关性分析研究、胃内漂浮-生物粘附给药系统的构建与评价；BSP基于抗胃溃疡作用的胃滞留功能性辅料机制研究；BSP对乙醇诱导的急性胃溃疡的化学表征及胃保护作用的研究；BSP可溶性微针制备、表征和释药特征的研究。结果表明：所优选的提取、纯化白及胶工艺稳定可靠，具有一定的体外抗氧化活性；冻干白及超微粉可改善兔耳创面愈合情况，吸收创面分泌物，缩短炎症反应的时间，表达大量血管内皮生长因子，加速创伤修复；制备BSP为基质的胃内漂浮-生物粘附协同型胃滞留片方法稳定可靠；BSP对乙醇诱导的胃溃疡大鼠保护作用可能是通过促炎性细胞因子和氧化应激的减少以及MAPK / NF-kappaB途径的抑制起效的；BSP具有一定的促口腔溃疡愈合的活性，可用于“药辅合一”口腔粘膜给药载体材料；BSP可用于制备可溶性微针，具有良好的生物相容性和一定的缓释性能。本项目阐明了BSP的理化特性、作用胃漂浮制剂载体、口腔粘附载体、可溶性微针载体和快速止血海绵材料初步机制，为进一进拓展BSP在医疗健康领域的新应用奠定了良好的基础。