洛匹那韦混合胶束的制备与大鼠口服生物利用度研究

Preparation of lopinavir mixed micelles and study on oral bioavailability in rats

目的制备洛匹那韦混合胶束(lopinavir mixed micelles,LPV-MMs),并通过大鼠灌胃给药评价其药动学和口服生物利用度。方法以聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer,Soluplus^(■))和聚乙二醇1000维生素E琥珀酸酯(D-alpha-tocopheryl polyethylene glycol 1000 succinate,TPGS)作为载体材料,采用溶剂蒸发-薄膜水化法制备LPV-MMs,通过单因素研究方法确定了LPV-MMs的处方组成,并用透射电镜观察了LPV-MMs的微观形态;考察了LPV-MMs在不同pH介质中的药物释放速率;采用Caco-2细胞单层模型评估LPV原料药和LPV-MMs的跨膜转运特性;通过大鼠灌胃给药比较了LPV原料药和LPV-MMs的药动学和口服生物利用度。结果经实验研究确定LPV-MMs的处方中Soluplus^(■)和TPGS的质量比为70∶10,制备的LPV-MMs的粒径分布为(48.3±5.9)nm,Zeta电位为(1.38±0.04)mV,在透射电镜下可观察到LPV-MMs呈球形分布,粒径大小分布均匀;LPV-MMs在不同pH介质中的药物释放速率无明显差异;LPV-MMs能够有效提高药物的跨膜转运能力;大鼠体内药动学结果显示,将LPV制备成混合胶束后可显著提高药物的达峰浓度,增加药物口服生物利用度。结论本研究以Soluplus^(■)和TPGS作为载体材料,将洛匹那韦制备成混合胶束,显著提高了药物的跨膜转运能力,增加了药物的口服生物利用度。

Objective To prepare lopinavir mixed micelles(LPV-MMs),and evaluate their pharmacokinetics and oral bioavailability in rats.Methods The polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(Soluplus^(■))and D-alpha-tocopherol polyethylene glycol succinate(TPGS)were used as carrier materials to prepare LPV-MMs.The formulation composition of LPV-MMs was determined by single factor experiment.The microscopic morphology of LPV-MMs was observed under transmission electron microscope.The drug release rates of LPV-MMs in different pH media were investigated.The Caco-2 cell monolayer model was used to evaluate the transmembrane transport characteristics of LPV substance and LPV-MMs.The pharmacokinetics and oral bioavailability of LPV substance and LPV-MMs were compared by intragastric administration in rats.Results The experimental results determined that the mass ratio of Soluplus^(■)and TPGS in the formulation of LPV-MMs was 70∶10.The particle size distribution of LPV-MMs was(48.3±5.9)nm,and the Zeta potential was(1.38±0.04)mV.The LPV-MMs had the spherical morphology with uniform particle size in the transmission electron microscope.There was no significant difference in the drug release rate of LPV-MMs in different pH media.LPV-MMs could effectively improve the transmembrane transport ability.The pharmacokinetics in rats showed that LPV-MMs could significantly increase the peak concentration and improve the oral bioavailability of the drug.Conclusion In this study,Soluplus^(■)and TPGS are used as carrier materials to prepare lopinavir mixed micelles,which significantly improves the transmembrane transport ability and increases the oral bioavailability of lopinavir.