利格列汀自乳化释药系统的制备与大鼠体内药动学研究

Preparation of linagliptin self-nanoemulsifying drug delivery systems and evaluation of pharmacokinetics in rats

目的制备利格列汀自乳化释药系统(linagliptin self-nanoemulsifying drug delivery systems,LGP-SNEDDSs),并考察其大鼠体内药动学。方法通过测定利格列汀在不同油相、表面活性剂和助表面活性剂中的溶解度,确定LGP-SNEDDSs的处方组成;通过伪三元相图法获得其处方用量;评价了LGP-SNEDDSs的理化性质以及体外药物溶出速率;考察利格列汀混悬液和LGP-SNEDDSs经大鼠灌胃给药后的体内药动学。结果溶解度实验结果显示,分别选择辛酸/癸酸甘油三酯、辛酸癸酸聚乙二醇甘油酯和二乙二醇单乙基醚作为LGP-SNEDDSs的油相、表面活性剂和助表面活性剂,用量配比为6:3:1;LGP-SNEDDSs经水稀释后形成淡蓝色微乳液,在透射电镜下可观察到微乳呈球形或类球形,大小均匀,平均乳滴大小为(63.4±7.8)nm;体外溶出结果显示,LGP-SNEDDSs中的药物在10 min内可完全溶出,显著高于利格列汀片中药物溶出速度;稳定性结果显示LGP-SNEDDSs在加速条件下放置3个月稳定性良好。大鼠药动学结果显示,LGP-SNEDDSs可提高药物达峰浓度和生物利用度。结论将利格列汀制备成自乳化释药系统,可有效提高体内的生物利用度,对利格列汀的二次开发利用具有重要意义。

Objective To prepare linagliptin self-nanoemulsifying drug delivery systems(LGP-SNEDDSs)and to investigate their pharmacokinetics in rats.Methods By measuring the solubility of linagliptin in different oil phases,surfactants and co-surfactants,the formulation composition of LGP-SNEDDSs was determined and its formulation dosage was obtained by the pseudo-ternary phase diagram method.The physical and chemical properties and in vitro dissolution rate of LGP-SNEDDSs were evaluated.The in vivo pharmacokinetics of linagliptin suspensions and LGP-SNEDDSs after intragastric administration in rats were investigated.Results According to the solubility experiment results,Capmul MCM,Labrasol and Transcutol HP were selected as the oil phase,surfactant and co-surfactant of LGP-SNEDDSs,and the dosage ratio was 6∶3∶1.LGP-SNEDDSs were diluted with water to form a light blue microemulsion.Under the transmission electron microscope,it could be observed that the microemulsion was spherical or quasi-spherical with uniform size,and the average particle size was(63.4±7.8)nm.The drug in LGP-SNEDDSs could be completely dissolved within 10 min,which was significantly faster than the dissolution rate of linagliptin tablets.The LGP-SNEDDSs had good stability after 3 months under accelerated conditions.The results of pharmacokinetics in rats showed that LGP-SNEDDSs could increase bioavailability in vivo.Conclusion The LGP-SNEDDSs can improve the bioavailability in vivo,which is great significance to the secondary development of linagliptin.