中药活性成分共晶及共无定形新物质基础设计与构建科学内涵的探索

Based on our previous fundamental studies on cocrystals and coamorphous systems, we found cocrystallization and coamorphization techniques had a great potential to be an important and innovative technology to optimize the druggability of active pharmaceutical ingredients in Traditional Chinese medicine (API-TCM). Cocrystals and coamorphous are essentially the supramolecules by connecting API-TCM and coformers through non-covalent bonds. Here, we proposed a concept to build up novel material basis of API-TCM by these technologies, via modifying physicochemical defects such as low solubility, poor dissolution as well as poor mechanical properties, in order to meet the urgent needs of innovation of TCM. However, some theoretical basis of these technologies, especially the inherent related law between coformer and outcome properties, are still unclear and limits the efficiency and applications. Accordingly, we proposed (1) to develop mathematical models by ISIS/Base and QSPR to combine the selection of coformers, properties of outcoming cocrystal or coamorphous TCM, and discover the internal relationship and principles; and (2) to build up a systematic design pathway of novel API-TCM cocrystals and coamorphous, in order to provide a innovative and promising approach for drug development of TCM. This project, matching frontier technology of pharmaceutical crystallography with new drug creation of TCM, is an ambitious exploration and attempt in drug development of TCM, and is of great significance for promoting the development and improvement of TCM in China.

前期研究发现，共晶（CC）和共无定形（CM）技术可成为优化中药活性成分（API-TCM）成药性的重要创新技术，由此提出API-TCM CC与CM新物质基础设计与构建理念。该理念通过选择合适配体（CF）与原API-TCM形成超分子复合物，改善理化性质缺陷，优化成药性，以更好地适于新药创制需要。但该理念基础研究薄弱，科学内涵及设计与构建方法不明确，限制了其深入发展。据此，本项目通过：（1）将CF结构、性质与CC或CM性质关联研究，通过建模探讨CF选择机制与内在规律，初步建立API-TCM CC与CM新物质基础设计与构建理论体系；（2）完善API-TCM CC与CM设计与构建方法，为基于该技术的新药创制提供参考。本项目以CC与CM新技术优势契合API-TCM新药创制之所需，是对API-TCM新药创制技术的大胆探索与尝试，对推动我国API-TCM新药创制的发展与水平提高具有重要意义。

前期研究发现，共晶（CC）和共无定形（CM）技术可成为优化中药活性成分（API-TCM）成药性的重要创新技术，由此提出API-TCM CC与CM新物质基础设计与构建理念。该理念通过选择合适配体（CF）与原API-TCM形成超分子复合物，改善理化性质缺陷，优化成药性，以更好地适于新药创制需要。但该理念基础研究相对薄弱，科学内涵及设计与构建方法亦不够不明确，限制了其深入发展。.据此，本项目基于CC与CM技术提出了API-TCM新物质基础设计与构建的理念，主要研究内容及重要结果包括：（1）成功筛选并制备出和厚朴酚-葡甲胺CC、杨梅素-左旋肉碱CC、多烯紫杉醇-杨梅素CM、姜黄素-绿原酸CM等API-TCM新物质，通过对CC与CM的进一步表征与深入分析，较单体而言，CC与CM能够优化API-TCM的溶解性、溶出度、流动性及可压片性，以CC或CM形式给药能够显著提高API-TCM的生物利用度；（2）进一步地，通过将CF结构、性质与CC或CM性质进行关联研究，明确了CF的加入可以显著改善API-TCM的理化性质缺陷和成药性；（3）通过理论-模型-实验相结合的方式，阐释了CF选择与API-TCM CC或CM新物质基础成药性机制和内在规律，建立了API-TCM CC与CM新物质基础设计与构建理论体系，并通过姜黄素CM的案例验证了理论体系的适用性与正确性。.本项目完成了立项时所制定的所有研究内容，共产出SCI论文12篇，中文核心期刊4篇，专利3篇，其中3篇专利获得授权，以及2部专著；培养博硕士学生17人，达到了立项时所设立的研究成果目标。本项目以CC与CM新技术优势契合API-TCM新药创制之所需，是对API-TCM新药创制技术的大胆探索与尝试，为基于该技术的新药创制提供参考，对推动我国API-TCM新药创制的发展与水平提高具有重要意义。