冰片与纳米载体促进药物口服吸收的协同作用与机制

Among the various drug delivery routes, oral administration is the most widely used and most readily accepted route as it offers numerous advantages such as being painless and easily self-administrable resulting in a comparatively high patient compliance. However, the human GI-tract forms a formidable barrier for numerous active pharmaceutical ingredients. In order to overcome the hurdles for oral delivery, many strategies have been developed both by the traditional Chinese medicine experts and the scientists in the field of pharmaceutics. Among them are nanocarrier systems and the use of borneol as “message drug”, since strong evidence being based on studies in various animal models and clinical trials is provided for the potential of nanocarrier systems and borneol in oral drug delivery. The aim of the study is to develop a novel oral delivery system which combine the use of nanocarrier and borneol into one formulation.Thus, the system can take the advantages of nanocarrier system and borneol simultaneously, and improve the absorption in GI tract synergeticly. The enhancing effect of the combination was studied in three cell models, i.e. Caco-2 cells, Caco-2/Raji co-cultured cells and Caco-2/HT29-MTX co-cultured cells. Then, the effects of borneol on the uptake and transport on nanoparticles and polymeric micelles with different size were monitored and evaluated using various approaches, and the related mechanisms were also explained. Dropping pills containing nanocarrier and borneol were fabricated to realize their synchromsized release in GI tract and promote the absorption of nanocarrier systems sustainedly. Pharmacokinetic and bioavailability study was carried out to validate the effectiveness of the system. The proposed new oral delivery system may provide an promising and useful strategy for exploring effective oral delivery of water insoluble compounds and bio-drugs.

为解决许多药物口服生物利用度低、疗效差的问题，传统中医药学和现代药剂学分别进行了大量的研究和探索，各自建立了行之有效的促吸收策略，但效果均不够理想。本项目拟将中医药中以冰片作为佐使药和药剂学中将药物包载入纳米载体中两种基于不同理论和机制的促吸收策略有机结合，在对两种手段合用对药物产生协同促吸收作用进行验证的基础上，从分子和细胞水平研究纳米载体跨膜转运的过程与机制，揭示冰片对纳米粒和聚合物胶束与生物膜结合、粘附、摄取、透过的影响。探索同时包载冰片与含药纳米载体制剂的方法，实现二者在胃肠道内的同步释放，发挥双重吸收促进作用，有效提高药物的口服生物利用度。最后分别以槲皮素和姜黄素为模型药物，进行该新型口服给药系统的药动学评价。本项目研究结果将不仅可为冰片与纳米载体两种促吸收策略的联合应用提供科学依据和理论基础，也将为更多高生物利用度口服纳米给药系统的研究提供参考。

本项目针对药物口服后生物利用度低、疗效不佳的问题，拟将传统中医药和现代制剂学促口服吸收的策略有机的结合起来，构建将冰片与纳米载体伍用以发挥双重促胃肠道吸收的新型口服给药系统，并探索其协同促吸收机制，为新型口服给系统的研究开发提供科学依据。.围绕研究目的，开展了三方面的研究。①制备了三种不同粒径的PLGA纳米粒，采用Caco-2、Caco-2/Raji、Caco-2/HT29-MTX三种体外模型评价冰片对纳米粒在三种细胞的摄取、转运的促进作用。结果表明，冰片能够显著促进小粒径纳米粒的Caco-2细胞摄取和转运，其促吸收机理为打开细胞间紧密连接，促进小粒径纳米粒细胞旁路转运；提高细胞膜流动性，促进纳米粒内吞等。大鼠药动学实验证明冰片能够显著促进载9-NC纳米粒口服生物利用度。细胞和动物安全性研究结果显示冰片作为吸收促进剂具有较好的安全性。②研究了冰片对粒径更小的纳米胶束口服吸收的影响。分别采用了体外Caco-2细胞，大鼠在体肠灌流和大鼠体内药动学模型进行研究与评价。结果显示在冰片与聚合物胶束的共同作用下，药物的AUC为原来的6.94倍，表明冰片与胶束联用能极大地促进药物的口服吸收。③进一步构建了一种将冰片、麝香和薄荷等传统芳香开窍成分与纳米系统偶联的新方法，以实现二者的同步吸收和靶向递送，提高所载药物的生物利用度和靶部位分布。以白蛋白作为载药靶向载体，通过引入活性基团，将开窍活性成分作为靶向头基以偶联到白蛋白上，构建新的药物载体。实验结果表明，芳香开窍成分的修饰可提高细胞对纳米粒的摄取，增加纳米粒的脑部递送。.基于项目研究结果，共发表标注SCI论文10篇，其中第一标注6篇，总影响因子38.43。培养博士研究生1名，硕士研究生3名。.本项目针对提高药物口服疗效这个难题，将现代药剂学技术和中医药临床经验有机结合，探索中西药技术协同改善药物口服吸收的策略，不仅可为二者的联合应用提供科学依据和理论基础，对于中西制药技术的融合具有重要的借鉴意义，也将为更多高生物利用度口服纳米给药系统的研究奠定基础。