芹菜素-哌嗪共晶的制备、表征及体外抗肿瘤药效研究  

Apigenin-piperazine co-crystal: preparation, characterization and in vitro anti-tumor efficacy

作　　者：生立嵩[1,2] 任利文[2] 杨世颖 王金华 吕扬[3] 杜冠华 SHENG Li-song;REN Li-wen;YANG Shi-ying;WANG Jin-hua;LV Yang;DU Guan-hua(Shandong Academy of Traditional Medicine,Jinan 250014,China;Beijing Key Laboratory of Drug Target and Screening Research,Beijing Key Laboratory of Polymorphic Drugs,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Research Centre of Polymorphic Drugs,Beijing Key Laboratory of Polymorphic Drugs,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]山东省中医药研究院,济南250014 [2]中国医学科学院北京协和医学院药物研究所药物筛选研究中心,药物靶点研究和新药筛选北京市重点实验室,北京100050 [3]中国医学科学院北京协和医学院药物研究所药物晶型研究中心,晶型药物研究北京市重点实验室,北京100050

出　　处：《中国新药杂志》2022年第7期679-684,共6页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(81803584);国家重点研发计划资助项目(2016YFC1000900);北京市自然科学基金资助项目(7212157);中国医学科学院医学与健康科技创新工程资助项目(2016-I2M-3-007)。

摘　　要：目的:制备和表征芹菜素-哌嗪共晶,并研究其溶出度、大鼠体内血药浓度和体外抗肿瘤药效。方法:采用加液研磨法制备芹菜素-哌嗪共晶。以密度泛函理论(DFT)计算模拟结果,与实验振动光谱进行比较,探讨共晶可能的结合模式。通过不同比例下样品的粉末X射线衍射图谱确证共晶组成比例。并在不同溶出介质中比较共晶和物理混合物的溶出度。比较口服灌胃大鼠后共晶和物理混合物的体内血药浓度水平,在不同肿瘤细胞系中比较体外抗肿瘤药效。结果:芹菜素与哌嗪形成摩尔比为1∶2的共晶。共晶溶出度较物理混合物显著提高(80.0%vs 8.56%),大鼠体内生物利用度提高252.9%,体外抗肿瘤48 h时IC;值5.19μmol·L^(-1),抗肿瘤效果明显改善。结论:芹菜素与哌嗪形成共晶后,成药性明显改善。Objective:To prepare and characterize the apigenin-piperazine co-crystal, and to study its dissolution, blood drug concentration in rats and in vitro anti-tumor efficacy. Methods:Apigenin-piperazine co-crystal was prepared by liquid grinding method. Density functional theory(DFT) calculation and simulation results were compared by experimental vibrational spectroscopy, and the possible bonding modes of co-crystal were discussed. The composition ratio of co-crystal was confirmed by PXRD. The dissolution of co-crystal and physical mixture was compared in different dissolution media. The in vitro anti-tumor efficacy was evaluated in different tumor cell lines. Results:The co-crystal of apigenin and piperazine was formed at a molar ratio of 1∶2. The dissolution of co-crystal was significantly increased(80.0%) compared with that of physical mixture in 0.5% SDS-Na solution(8.56%). The enhancement in oral bioavailability of co-crystal is 252.9% compared with physical mixture, and the anti-tumor IC;in vitro is 5.19 μmol·L^(-1). Conclusion: The druggability is significantly improved after the formation of apigenin-piperazine co-crystal.

关 键 词：芹菜素 共晶 抗肿瘤 

分 类 号：R943[医药卫生—药剂学] R965[医药卫生—药学]