拉洛他赛自乳化释药系统的制备及大鼠体内药动学研究

Preparation and evaluation of larotaxel self-emulsifying drug delivery system and pharmacokinetic study in rats

目的研制拉洛他赛自乳化释药系统并对其在大鼠体内的药代动力学进行考察。方法考察拉洛他赛在不同油相、乳化剂中的溶解度,同时加入一种肠道黏膜黏附剂单油酸甘油酯用于增加口服的吸收量,再通过绘制伪三元相图,并通过均匀设计表设计处方,进一步筛选确定最优的处方,制备拉洛他赛自乳化释药系统;考察自乳化制剂的外观、粒径、电位、自乳化时间、含药量和稳定性,并比较拉洛他赛口服溶液剂与自乳化制剂的大鼠体内生物利用度。结果以三辛酸甘油酯-单油酸甘油酯-吐温80(m∶m∶m=15∶55∶30)形成均一稳定的拉洛他赛自乳化制剂。偏光显微镜下无药物析出,拉洛他赛自乳化制剂经pH值1.2的模拟胃液、蒸馏水及pH值6.8的模拟肠液的不同倍数稀释后,稳定性无明显变化;外观呈现淡蓝色略带乳光溶液,粒径为(169.7±15.36)nm(n=3),多分散性指数PDI为0.169,zeta电位为(-24.2±1.23)mV(n=3),含药量质量分数为(0.987±0.0183)%(n=3);相比于溶液剂,自乳化制剂生物利用度显著提高,约是溶液剂的4.7倍。结论拉洛他赛自乳化释药系统易于制备、质量稳定,可显著增加拉洛他赛的口服生物利用度,为口服拉洛他赛新型制剂的研发提供了思路。

Objective To develop a self-emulsifying drug delivery system of larotaxel and to investigate its pharmacokinetics in rats.Methods The solubility of larotaxel in different oil phases and emulsifiers was determined and an intestinal mucoadhesive monoglyceride was added to increase the oral absorption.The final formulations for larotaxel self-emulsifying drug delivery system were optimized based on the pseudo-ternary phase diagrams.The appearance,particle size,potential,self-emulsification time,drug content and stability of the self-emulsifying preparation were investigated,and the bioavailability of solution and self-emulsifying formulation of larotaxel were compared.Results A homogeneously stable self-emulsifying formulation of larotaxel was prepared with tricaprylinmonoolein-Tween 80(m∶m∶m=15∶55∶30).No drug precipitation was observed under polarized light microscopy.The stability of the LTX-SEDDS did not significantly change after being diluted by simulated gastric fluid of pH 1.2,distilled water and simulated intestinal fluid of pH 6.8.The preparation is a slightly opalescent solution with bluish color.The particle size was(169.7±15.36)nm(n=3)with the polydispersity index(PDI)of 0.169.The zeta potential was(-24.2±1.23)mV(n=3),and the drug content was(0.987±0.0183)%(n=3);The bioavailability of self-emulsified formulation was increased by 4.7 times compared to that of solution group.Conclusion The self-emulsifying drug delivery system of larotaxel is easy to prepare and shows excellent storage stability.The oral bioavailability of larotaxel increases significantly,which provides a thought for the development of new formulations of oral larotaxel.