藤黄酸长循环脂质体制备及药动学研究

Preparation and pharmacokinetics of gambogic acid long-circulating liposomes

目的优化藤黄酸长循环脂质体制备工艺,并对其体外释放及体内药动学进行研究。方法建立藤黄酸定量测定方法;以藤黄酸包封率作为考察指标,采用Box-Behnken试验设计优化脂质体组方,得到藤黄酸包封率最高的处方;采用电镜扫描观察藤黄酸脂质体表面形态,采用透析法对脂质体体外释放进行研究,测定藤黄酸在15 d内的稳定性;雄性Wistar大鼠尾静脉分别注射1 mg/m L藤黄酸、藤黄酸脂质体后,采用UPLC-MS/MS方法测定血药浓度,比较2种药物药动学参数差异。结果 Box-Behnken优化后脂质体最优处方为胆固醇444 mg、蛋黄磷脂酰胆碱1 823 mg和二硬脂酰基磷脂酰乙醇胺-聚乙二醇705 mg,脂质体包封达到92.3%,脂质体粒径均一,表面光滑;体外释放结果表明脂质体可以平缓释放,且具有长效作用,在15 d内储存稳定;脂质体中藤黄酸的体内半衰期为9.97 h,是藤黄酸的4.43倍;脂质体中藤黄酸的AUC0~24 h为22.55μg·h/m L,是藤黄酸的4.73倍。结论藤黄酸脂质体与原料药相比具有长循环、血药浓度高、释放平缓等特点。

Objective To optimize the preparation process of gambogic acid（GA） liposomes and study the in vitro and in vivo release. Methods The detection method of GA was established, using the Box-Behnken experiment design to optimize liposomes formula, GA liposomes were obtained with the highest encapsulation efficiency; Using scanning electron micrographs（SEM） to observe liposome surface morphology, using the dialysis method to study the liposome release in vitro, we also measured the stability of liposome in 15 d; Male Wistar rats were injected with GA or GA liposomes（1 mg/m L） via tail vein, UPLC-MS/MS method was used to determine the drug concentration, and differences in pharmacokinetic parameters of the two drugs were compared. Results After Box-Behnken optimization, the encapsulation efficiency of liposomes was 92.3%, and the optimized liposomes formula is cholesterol of 440 mg, egg phosphatidylcholine of 1823 mg,,and istearoyl phosphoethanolamine-PEG 2000 of 705 mg, liposomes had uniform particle size and smooth surface; In vitro release results showed that the liposomes could be gentle and slowly release and had a longterm effect. The liposomes were stable keeping in 4 ℃ within 15 d; In in vivo study, the half-life of GA liposome was 9.97 h, 4.43 times of GA; AUC0—24 h of GA liposome was 22.55 μg·h/m L, 4.73 times of GA. Conclusion Compared with GA, GA liposome has the characteristics of long-circulating, high blood drug concentration, and could release smoothly.