基于纳米晶体药物成药性评价的应用基础研究-纳米效应的量化表征、成药分子机制及纳米晶与生物膜相互作用

纳米药物晶体可解决多数难溶性药物的溶解度和生物利用度问题，近年来成为难溶性药物给药系统研究的热点之一。系统深入地阐明纳米晶体药物的成型机制和构效关系是该类药物制剂产业化的关键基础科学问题。本项目以难溶性药物阿瑞匹坦为模型药物，介质研磨法制备纳米晶体混悬液，建立数学模型计算吸收参数、溶解参数和剂量参数，定量地表达纳米效应，进一步阐明纳米晶体药物的分子结构特征与理化性质和生物学效应之间的相关性，以及从分子、细胞、离体、活体四个层次阐明纳米晶体药物与生物膜相互作用的机理，从而全面表征纳米制剂的成药性。本项目的顺利实施将有利于推动纳米晶体药物产业化，为其成药性评价提供充足的理论基础和实践依据，完善纳米药物质量评价标准和提升纳米药物内在稳健品质，促进高端制剂原始创新。

Nanocrystal drugs are one of the most promise strategies to improve the solubility and bioavailability of poor soluble drugs in recent years. How to deeply elucidate the forming mechanism and structure-activity relationship of nanocrystal drugs which it is the key problem of industrialization in basic science. Aprepitant, a insoluble drug, was selected as model drug which media grinding methods was used to prepare nanocrystal suspensions. Mathematical model was established for calculating absorption parameters, dissolve parameters and dose parameters in order to quantitatively express the nano effect. Moreover, we further clarify the influence of molecular structure of nanoparticles on the nano effect, as well as we elucidate the mechanism of interaction between nanocrystal drugs and biological membrane on the four levels of molecules, cells, ex vivo and in vivo. Thus, druggability of nanocrystal drugs was comprehensively characterized. The implementation of this project will significantly promote the industrialization of nanocrystal drugs, and provides theoretical and practical basis for the evaluation of druggability. Also, it can improve the evaluation criteria of nano preparations and upgrade the inner sound quality for realizing the original innovation for new dosage forms.