酮咯酸异丙酯静脉注射脂肪乳剂的处方前研究

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52.66 μg·mL^-1），但可以和油相混溶，其LogP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（k_obs）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。

Preformulation Study on the Intravenous Lipid Emulsion of Ketorolac Isopropyl Ester

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 LogP 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(k_obs) 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.