形态调控方法改善难溶性药物纳米结晶口服吸收的机制研究

It is important to improve the oral bioavailability for poorly water-soluble drugs. Nanocrystals were highly appreciated because of its high drug loading, wide application and etc. It is generally accepted that, for the nanocrystals, the dissolution rate is increased by decreasing the particle size, thereby addressing a number of issues related to poor oral bioavailability. However, in our prophase research, we found that the crystal habit of nanocrystals has a considerable influence on aqueous solubility and oral bioavailability. The aim of this project is, in the nanoscale, to systematically investigate how crystal habits can impact biopharmaceutical properties of poorly-soluble drugs. Firstly, eight model substances were selected based on their physicochemical and biological properties, and their nanocrystals with different habits were obtained by changing the formulation composition and/or preparation process, under the help of computer aided design. Secondly, the nanocrystals were characterized using advanced technologies. Finally, in order to establish the relationship between the crystal habit and oral bioavailability, the aqueous solubility and oral bioavailability were compared for different shaped nanocrystals. In addition, oral absorption studies will be carried out when necessary, in order to clarify the mechanism of in vivo behavior for different shaped nanocrystals. The results of this project will provide a solid scientific basis for selecting a superior crystal habit in nanoscale. It will also contribute a new way for the research and development for poorly water-soluble drugs.

提高难溶性药物口服生物利用度是药剂学领域的一个重要课题。纳米结晶技术由于具有载药量高、适用性广等优势而备受青睐。传统观点认为，纳米结晶通过降低粒径提高难溶性药物的溶解性和口服生物利用度。但是，本课题组前期工作表明结晶形态对纳米结晶的水溶解性和口服生物利用度也有显著影响。基于此，本课题选定性质不同的八种药物，拟通过处方和工艺调控、辅以计算机模拟技术，制备不同形态的纳米结晶；运用先进的测试手段对纳米结晶进行全面表征；通过比较不同形态纳米结晶的水溶解性和口服生物利用度，在纳米尺度上，明确系列难溶性药物纳米结晶外观形态和水溶性的关系，阐明结晶形态与生物利用度之间的关系；通过系统地评价不同形态纳米结晶的口服吸收机制，阐明结晶形态影响纳米结晶体内行为的机理。本项目将在纳米尺度范围内，为具有高生物利用度的优势晶体形态的选择提供科学依据，为纳米结晶制剂的深入研究奠定基础，为难溶性药物的研发提供一条新思路。

一般认为水溶解性和膜透过性是影响药物口服吸收的关键因素，纳米结晶由于具有载药量高、适用性广等优势已成为改善水溶性差的药物的口服生物利用度的最普遍的策略之一。由于纳米结晶必须克服粘液层以及肠道上皮细胞两层屏障才可以被吸收进入体循环，一般情况下，我们需要对粒径、带电性以及表面性质等物理化学和生物学特性进行优化从而使纳米结晶可以实现更好的吸收。近年来，研究发现纳米粒子的形状对粘液渗透能力和口服生物利用度均有较大影响，然而截止目前，纳米结晶的颗粒形状对胞饮过程、胞内转运和基底外侧胞吐过程影响的作用规律仍不明确。基于此，本研究紧紧围绕不同形态纳米结晶的吸收机制，选取洛伐他汀、螺内酯、格列本脲、艾地苯醌、拉西地平、尼群地平、阿立哌唑等作为模型药物，成功制备了球形，棒状和片状纳米结晶，并对不同形态纳米结晶的制备工艺规律进行总结；其次运用先进的现代化技术、原子力显微镜和电镜对不同形态的纳米结晶进行详细的固态表征；应用细胞模型研究了包括胞吞过程，胞内转运，胞吞过程在内的纳米结晶转运机制，发现颗粒形状可以改变纳米结晶的细胞转运过程，其中棒状纳米结晶的膜渗透性最强、球状纳米结晶次之而片层状纳米结晶最差；粘液渗透和原位肠吸收研究表明棒状纳米结晶的粘液渗透能力和在体肠段吸收均高于球状与片状纳米结晶；在药代动力学研究中发现，棒状纳米结晶可以显著提高纳米结晶在口服递送中的效率；最后本课题就纳米结晶形态对口服吸收贡献的规律进行总结并提出纳米结晶形态设计的优化思路。本课题深入研究了颗粒形状对纳米结晶口服吸收的影响，为口服递送纳米结晶设计的优化提供了坚实的基础；对后续具有特异性吸收方式的新型口服纳米结晶的开发具有指导意义。截至目前，本研究已发表7篇文章，其中SCI6篇，国内授权专利1项，达到了我们初始目标。