酮咯酸异丙酯静脉注射脂肪乳剂的处方前研究  

Preformulation Study on the Intravenous Lipid Emulsion of Ketorolac Isopropyl Ester

作　　者：钮碧晰 尹宗宁[2] 王文博 顾尹慧 刘佳敏 王春燕 陈勇 NIU Bixi;YIN Zongning;WANG Wenbo;GU Yinhui;LIU Jiamin;WANG Chunyan;CHEN Yong(School of Pharmacy,Nantong University,Nantong 226001,China;Key Laboratory of Drug Targeting and Novel Drug Delivery Systems of Ministry of Education,West China School of Pharmacy,Sichuan University,Chengdu 610041,China;Suzhou Salupurus Pharmaceutical Technology Co.,Ltd.,Suzhou 215421,China)

机构地区：[1]南通大学药学院,江苏南通226001 [2]四川大学华西药学院靶向药物与释药系统教育部重点实验室,成都610041 [3]苏州康纯医药科技有限公司,江苏苏州215421

出　　处：《中国现代应用药学》2020年第21期2587-2593,共7页Chinese Journal of Modern Applied Pharmacy

基　　金：太仓市重点研发计划社会发展项目(TC2017SF02);中国博士后科学基金(2017M611886)。

摘　　要：目的对酮咯酸前体药物酮咯酸异丙酯进行处方前研究。方法合成酮咯酸异丙酯,建立HPLC-UV方法并进行方法学验证。对酮咯酸异丙酯溶解度、油水分配系数和降解规律等理化性质进行研究,考察加速降解实验中的原料稳定性和原辅料相容性。结果酮咯酸异丙酯在水中难溶(溶解度52.66μg·mL^-1),但可以和油相混溶,其Log P值为3.95±0.03。酮咯酸异丙酯的分析方法线性关系良好,仪器精密度良好(RSD<2%),回收率较高(>99.5%)。在给定条件下,酮咯酸异丙酯的溶液稳定性随pH和温度升高而降低。酮咯酸异丙酯可在大鼠血浆和肝匀浆溶液中迅速降解,例如,在50%大鼠血浆溶液或20%肝匀浆溶液中,酮咯酸异丙酯的降解速率常数(kobs)分别为0.51 min-1和0.15 min^-1。酮咯酸异丙酯在高温、高湿环境下较稳定,但对光照敏感;原辅料相容性同样证实了这一点。结论酮咯酸异丙酯在溶解度、分配系数、降解规律、原料稳定性和原辅料相容性方面,具备了制成静脉注射乳剂的适宜条件,为开发新型酮咯酸注射剂提供了实验依据。OBJECTIVE To conduct preformulation study of ketorolac isopropyl ester which is prodrug of ketorolac. METHODS Ketorolac isopropyl ester was synthesized. Quantification method using HPLC-UV was established and validated. Physicochemical properties including solubility, oil/water partition coefficient and degradation kinetics were investigated, followed by revealing drug stability and drug-excipients compatibility under forced degradation experiments. RESULTS Ketorolac isopropyl ester was sparingly soluble in water(52.66 μg·mL^-1) but miscible with oil phase. The Log P value of the prodrug was 3.95±0.03. Analytical method of ketorolac isopropyl ester was established with good linearity, high accuracy(RSD<2%) and high recovery yield(>99.5%). The aqueous stability of ketorolac isopropyl ester was impaired with the increase of pH value and temperature under specific conditions. Fast degradation was found when placing ketorolac isopropyl ester into the medium of rat plasma or liver homogenate solution. For example, the degradation rate constant(kobs) of the prodrug in 50% rat plasma solution or 20% liver homogenate solution was 0.51 min-1 and 0.15 min^-1, respectively. Ketorolac isopropyl ester was comparatively stable when presented in the environment with high temperature or high humidity, but it was unstable under the strong light, which was further proved by the drug-excipients stability studies. CONCLUSION The appropriate properties of ketorolac isopropyl ester on solubility, partition coefficient, degradation kinetics, chemical stability and drug-excipients compatibility enabled feasibility on preparation of intravenous lipid emulsion which provide experimental fundament to develop novel ketorolac injectables.

关 键 词：酮咯酸 酮咯酸异丙酯 前体药物 脂肪乳剂 处方前研究 

分 类 号：R943[医药卫生—药剂学]