兽用抗菌药的共晶设计、合成与作用机制研究

The drug cocrystallization is a new technology used to improve the physical, chemical properties and biological effects of the active pharmaceutical ingredient (API). The stability, solubility, permeability and bioavailability of the cocrystal can be improved compared to pure drug. In this project, enrofloxacin, ceftiofur and florfenicol , as the representative and targeted drugs, will be selected. The appropriate cocrystal former (CCF) will be found according to the functional groups of the API and CCF which would form hydrogen bond, halogen bond or Van der Waals' force, the cocrystals of the representative drugs, will be designed and synthesized. By exploring the non-covalent force to form cocrystal between API and CCF, the crystal structure of drug cocrystal should be characterized. After the water solubility, permeability, antibacterial activity and bioavailability of the cocrystal compounds have been researched, the structure-bioactivity relationship of cocrystal drugs will then be discovered at the molecular level. With the mechanism of different CCFs to impact the molecular effects of different drugs to be developed, the directional preparation of veterinary drugs cocrystal with high bioactivity will be finally realized. This project has provided new ideas for the research and development of highly effective veterinary antibacterial drugs, and can also promote the cross combination of crystal engineering and veterinary pharmacology. It has important academic significance and industrial prospects for improving the level of veterinary drug development and reducing the use of antibiotics in China.

药物共晶可以改变药物活性成份的稳定性、溶解度、渗透性，提高药物的抗菌活性、生物利用度，已成为当前药物晶型研究的前沿和焦点。本项目以恩诺沙星、头孢噻呋、氟苯尼考为兽用抗菌药代表药，分析药物分子中能形成氢键、卤键、范德华力等非共价键的官能团，研究共晶试剂的选择、共晶的合成与稳定性；利用现代晶型分析技术，表征共晶结构，揭示药物活性成份与共晶试剂通过非共价作用力形成共晶的方式；研究共晶与药物水溶性、渗透性、抗菌活性和生物利用度等性能的关系，探讨不同共晶试剂对药物理化性质、生物效应的影响规律，实现具有高生物利用度、良好溶解性的兽药共晶定向设计。本项目将发现新的兽药共晶，为改善兽用抗菌药物水溶性、渗透性、生物利用度提供崭新的技术途径和理论借鉴；同时提升我国兽药制剂水平、降低兽用抗菌药使用风险；还可以促进晶体工程学和兽医药理学的交叉融合，引领学科发展。

本课题通过冷却结晶、溶剂蒸发结晶等方法，制备出恩诺沙星共晶9个、氟苯尼考共晶3个、头孢噻呋共晶4个，并对共晶的化学结构进行了表征，确定了晶体结构。对共晶的熔点、水溶性、稳定性进行了考察，筛选出5个水溶性好、稳定性高的恩诺沙星共晶，分别为恩诺沙星-香兰素共晶（EFC-VNL），恩诺沙星-苹果酸共晶（EFC-MLA），恩诺沙星-葵二酸共晶（EFC-SBA），恩诺沙星-酒石酸共晶（EFC-TTA），恩诺沙星-烟酸共晶（EFC-NA）；1个水溶性著提高的头孢噻呋-葵二酸共晶（CEF-SBA）和2个水溶性显著提高的氟苯尼考-丙氨酸共晶（FB-ALA）、氟苯尼考-环糊精共晶（FB-FF），发现羧基-胺基氢键、乙醇或水分子有利于提高共晶的水溶性，分子内氢键的形成对共晶水溶性的提高有限。完成了优势共晶化合物的抗菌活性研究，筛选出抗菌活性好的恩诺沙星-苹果酸共晶、头孢噻呋-葵二酸共晶。开展了恩诺沙星-苹果酸共晶在鸡、氟苯尼考-丙氨酸共晶在猪的内服药动学研究，恩诺沙星-苹果酸共晶与恩诺沙星盐酸盐的药动学参数相比，t1/2β，tmax，Cmax，AUC等统计学差异不显著（P>0.05），恩诺沙星-苹果酸共晶在鸡体内的AUC高于恩诺沙星盐酸盐，其相对生物利用度为109.9%；与氟苯尼考相比，氟苯尼考-丙氨酸共晶（FB-ALA）的t1 /2β、tmax、AUC显著增加，MRT明显延长，显示出良好的缓释作用，在体内消除缓慢，其相对生物利用度为136.1%。本项目研究出恩诺沙星-苹果酸共晶、恩诺沙星-烟酸共晶、头孢噻呋-葵二酸共晶、氟苯尼考-丙氨酸共晶、氟苯尼考-环糊精共晶等优势共晶，为进一步设计抗菌活性好、水溶性高、药代动力学特性优越的药物共晶及新制剂提供了科学依据，对开发拥有自主知识产权的新兽药和新制剂、显著提高我国兽药的研发水平、保障畜禽养殖业的健康可持续发展，具有重要的理论和实践意义。