目的 制备利格列汀(LGP)壳聚糖-磷脂自组装纳米粒(LGP-CS/LC-NPs),并考察其在大鼠体内的药动学以及对糖尿病模型大鼠的血糖控制效果。方法 采用溶剂滴入法制备LGP-CS/LC-NPs,通过单因素实验筛选LGP-CS/LC-NPs处方中LGP与磷脂(LC)的质量比,CS与LC的质量比,以及醋酸溶液pH值;考察LGP-CS/LC-NPs的粒径分布、Zeta电位、微观形态,以及体外药物溶出速率;采用Caco-2细胞单层模型评价LGP-CS/LC-NPs的细胞跨膜转运;考察LGP原料药混悬液和LGP-CS/LC-NPs经大鼠ig给药后的体内药动学以及对糖尿病大鼠的血糖控制效果。结果 优化得到LGP-CS/LC-NPs的最优处方:LGP与LC的质量比为1∶3,CS与LC的质量比为1∶20,醋酸溶液pH值为4~5;制备的LGP-CS/LC-NPs的粒径为(195.5±7.8)nm,Zeta电位为(35.6±0.8)mV,在透射电镜下可观察到LGP-CS/LC-NPs为球形“核-壳”结构;LGP-CS/LC-NPs的体外溶出速率显著高于LGP混悬液;LGP-CS/LC-NPs能有效提高LGP的跨膜转运能力;与LGP混悬液相比,大鼠ig LGP-CS/LC-NPs后可显著提高LGP生物利用度,且可较好地控制糖尿病模型大鼠的血糖水平。结论 以CS和LC作为载体材料,将LGP制备成LGP-CS/LC-NPs,能够显著提高LGP口服生物利用度,达到良好的控糖效果。

Objective To prepare ligagliptin self-assembled chitosan-lecithin nanoparticles(LGP-CS/LC-NPs) and investigate its pharmacokinetics in rats and its effect on blood glucose control in diabetic model rats.Methods LGP-CS/LC-NPs was prepared by solvent injection method. The mass ratio of LGP to lecithin, the mass ratio of chitosan to lecithin, and the pH value of acetic acid solution in LGP-CS/LC-NPs formulation were screened by single factor experiment. The particle size distribution, Zeta potential,microstructure and dissolution of LGP-CS/LC-NPs in vitro were investigated. The transmembrane transport of LGP-CS/LC-NPs was evaluated using Caco-2 cell monolayer model. The pharmacokinetics and pharmacodynamics of LGP suspensions and LGP-CS/LCNPs after oral administration in rats were evaluated.Results The optimal formulation of LGP-CS/LC-NPs was as followed: the mass ratio of LGP to lecithin was 1∶3, the mass ratio of chitosan to lecithin was 1∶20, the pH of acetic acid solution was 4—5.The particle size of LGP-CS/LC-NPs was(195.5 ±7.8) nm, the Zeta potential was(35.6 ±0.8) mV. The spherical "core-shell" structure of LGP-CS/LC-NPs was observed under Transmission Electron Microscope. The dissolution rate of LGP-CS/LC-NPs in vitro was significantly higher than that of LGP suspensions. LGP-CS/LC-NPs could effectively improve the transmembrane transport capacity of drugs. Compared with LGP suspensions, after ig LGP-CS/LC-NPs, the bioavailability could be significantly improved, and the blood glucose level of diabetic model rats could be better controlled.Conclusion Chitosan and lecithin were used as carrier materials to prepare LGP-CS/LC-NPs, which could significantly improve the oral bioavailability and achieve good sugar control effect.

R944.2

江苏省药学会科研基金项目(A202033); 南京市药学会科研基金项目(2021YX007);南京市药学会科研基金项目(2021YX019)