木犀草素过饱和自乳化释药系统的制备与大鼠药动学的研究

Preparation and in vivo pharmacokinetics of luteolin supersaturated self-microemulsifying drug delivery systems

目的制备木犀草素过饱和自微乳化给药系统(luteolin supersaturation self microemulsifying drug delivery system,LUT-S-SMEDDS),以提高木犀草素的口服生物利用度。方法根据木犀草素在不同种类油相、乳化剂和助乳化剂中的溶解度、配伍相容性以及伪三元相图确定了LUT-SMEDDS的处方,并加入沉淀抑制剂制备成LUT-S-SMEDDS;评价了LUT-SMEDDS和LUT-S-SMEDDS的理化性质;比较了LUT-混悬剂、LUT-SMEDDS和LUT-S-SMEDDS经大鼠口服后体内药动学。结果选择单亚油酸甘油酯(maisine)为油相,辛酸/癸酸聚乙二醇甘油酯(labrasol)为乳化剂,二乙二醇单乙基醚(transcutol,HP)为助乳化剂,配比为体积比4∶4.5∶1.5,制备的LUT-SMEDDS和LUT-S-SMEDDS具有较强的自乳化性和分散稳定性;使用Soluplus作为沉淀抑制剂制备的LUT-S-SMEDDS可以在长时间内维持药物处于较高浓度状态;与LUT-混悬剂和LUT-SMEDDS相比,LUT-S-SMEDDS显著提高了大鼠的口服生物利用度。结论将木犀草素制备成过饱和自乳化释药系统,可加快药物溶出,抑制药物析晶,显著提高药物口服生物利用度。

Objective To prepare Luteolin supersaturated self-microemulsifying drug delivery system(LUT-S-SMEDDS)to improve the oral bioavailability.Methods The solubility of Luteolin in different kinds of oil phases,surfactants and co-surfactants was determined.According to the compatibility experiment and pseudo-ternary phase diagram,the formulation of LUT-SMEDDS and the amount of each excipient were determined.The LUT-S-SMEDDS was prepared by adding precipitation inhibitor.The physical and chemical properties of LUT-SMEDDS and LUT-S-SMEDDS were evaluated.The in vivo pharmacokinetics of Luteolin-suspension,LUT-SMEDDS and LUT-S-SMEDDS after oral administration in rats were compared.Results Maisine was selected as the oil phase,Labrasol as the surfactant,Transcutol HP as the co-surfactant,and the ratio was 4∶4.5∶1.5.The prepared LUT-SMEDDS and LUT-S-SMEDDS had strong self-emulsification and dispersion stability.LUT-S-SMEDDS prepared with Soluplus as a precipitation inhibitor could maintain the drug at a higher concentration state for a long time.Compared with LUT-suspension and LUT-SMEDDS,LUT-S-SMEDDS significantly improved the oral bioavailability in rats.Conclusion In this study,Luteolin was prepared as a supersaturated self-emulsifying drug delivery system,which could increase drug dissolution,inhibit drug crystallization,and significantly improve oral bioavailability.