基于嗅区通路理论研究中医纳鼻通关机理及现代纳鼻给药系统的构建

Treating disease by the "TongGuan" route is the traditional therapeutic method.How to inherit the extraordinary concept by explainning the " TongGuan " on the basis of the olfactory transferring theory and how to overcome the common problem and build the research and application platform of the the traditional medicinal therapy are the urgent problems which need to be solved..There is a connection between the traditional “TongGuan” theory and the contemporary olfactory-route study.On the basis of preliminary work which funded by Ministry of Science and Technology,our research group selected three active components,which are baicalin，geniposide and cholic acid as the objects of this study,we plan to investigate the delivery route of drug to explain the “Guan” theory and to explore the amount and time for passing by the “Guan”.Secondly,we focus on the study of “passing” theory:the drug carrier system will be applied to increase the bypassing the olfactory mucosa of the components；and the nasal preparation will be made to increase the components'concentration in the brain.The mechanism will be investigated by the physicochemical properties study, parallel artificial membrane permeability determination, permeation mechanism of olfactory mucosa and PK-PD research which is according to the"effect,preparation and time"..All the research above are expected to explain the " TongGuan " mechanism, broaden the application of modern intranasal administration and provide the new theory for the development of new preparations.

纳鼻通关是中医传统治法。如何将其与现代嗅区递药理论进行对接，传承与建立中医独特的纳鼻通关理论；解决中药纳鼻通关技术的共性问题，搭建具有中医传统纳鼻法研究与应用平台，成为传承这种古老的用药方法亟需解决的问题。.中医纳鼻通关与嗅区递药入脑理论殊途同归，在前期科技部重大新药创制研究基础上，以黄芩苷、栀子苷及胆酸为研究对象：与现代嗅区递药理论对接，多层次、多角度探寻药物纳鼻之“关”之所在；对通“关”时间及量进行考察。以增加中药纳鼻通关之“通”量为切入点：采用现代载药系统，增加纳鼻嗅区黏膜之“通”量；在沿袭传统纳鼻法的基础上制备现代纳鼻剂；以提高纳鼻通关之“通”脑量。从物理化学性质、PAMPA模型、嗅黏膜渗透机理、整体药动学实验及“效-剂-时”对应的PK-PD研究多角度研究“通”关机理。.本研究所得结果不仅可以系统揭示纳鼻通关机理，还助于拓宽现代纳鼻给药的范围，为现代纳鼻制剂的开发提供新的理论基础。

纳鼻通关为中医传统治法，对脑部急症的治疗具有重要意义。本课题立足于中医独特的纳鼻通关理念，围绕纳鼻通“关”机理和增加纳鼻之“通”量主体，进行了相关内容的研究。本课题在中医基础理论指导下，将具安宫牛黄丸药效成分——黄芩苷、栀子苷及胆酸“量体裁衣””制备为具有现代纳米制剂特色优势的脂质体，通过单因素相关性分析，Box-behnken Design 优化等筛选了制备黄芩苷脂质体、胆酸-黄芩苷脂质体及栀子苷脂质体等现代载药系统的最佳工艺，建立了包括粒径、 Zeta 电位及外观形态在内的表征方法，并对各载药系统进行了体外释放研究。以在体蟾蜍上腭纤毛摆动法和大鼠鼻黏膜病理变化评价药物载药系统及单体成分是否可安全用于鼻腔给药。结果表明课题组制备的载药系统及其单体成分对鼻无明显毒性作用，可安全用于鼻腔给药。对通“关”时间及量进行考察，以DTE%和DTP%比较两种给药途径的脑靶向作用，结果表明鼻腔给药的靶向作用明显高于静脉给药，提示纳鼻法可增加药物入脑含量。经鼻给药后，黄芩苷脂质体组血浆的t1/2约为黄芩苷单体的2倍，且AUC0-t明显高于黄芩苷单体组，表明前者可延长药物作用时间。在组织分布中，嗅球、海马和纹状体中黄芩苷含量高于其他脑组织，其中脂质体组中嗅球的AUC0-t和MRT0-t均显著高于黄芩苷单体组，表明脂质体可延长药物在嗅球滞留时间，增强脑靶向作用，以此探寻药物纳鼻之“关”之所在，提示现代载药系统的纳鼻剂可增加中药纳鼻通关之“通”量。以神经行为学评分、TTC染色、HE染色及Nissl染色法评价鼻用黄芩苷脂质体对中动脉闭塞大鼠模型（MCAO）的作用。结果表明给药后有一定改善作用，且纳鼻组对MCAO模型大鼠的神经保护作用明显高于静脉给药组。本课题的研究结果阐明了中药有效成分纳鼻通“关”的机理及优势所在，制备了具有中医特色的现代纳米纳鼻剂，增加了纳鼻通脑之“通”量，为安宫牛黄丸中主要成分的现代纳米制剂药物研发提供依据，并为中药纳鼻法的传承与创新研究奠定了基础。