目的 制備利格列汀(LGP)殼聚糖-磷脂自組裝納米粒(LGP-CS/LC-NPs),并考察其在大鼠體內(nèi)的藥動學(xué)以及對糖尿病模型大鼠的血糖控制效果。方法 采用溶劑滴入法制備LGP-CS/LC-NPs,通過單因素實驗篩選LGP-CS/LC-NPs處方中LGP與磷脂(LC)的質(zhì)量比,CS與LC的質(zhì)量比,以及醋酸溶液pH值;考察LGP-CS/LC-NPs的粒徑分布、Zeta電位、微觀形態(tài),以及體外藥物溶出速率;采用Caco-2細(xì)胞單層模型評價LGP-CS/LC-NPs的細(xì)胞跨膜轉(zhuǎn)運(yùn);考察LGP原料藥混懸液和LGP-CS/LC-NPs經(jīng)大鼠ig給藥后的體內(nèi)藥動學(xué)以及對糖尿病大鼠的血糖控制效果。結(jié)果 優(yōu)化得到LGP-CS/LC-NPs的最優(yōu)處方:LGP與LC的質(zhì)量比為1∶3,CS與LC的質(zhì)量比為1∶20,醋酸溶液pH值為4~5;制備的LGP-CS/LC-NPs的粒徑為(195.5±7.8)nm,Zeta電位為(35.6±0.8)mV,在透射電鏡下可觀察到LGP-CS/LC-NPs為球形“核-殼”結(jié)構(gòu);LGP-CS/LC-NPs的體外溶出速率顯著高于LGP混懸液;LGP-CS/LC-NPs能有效提高LGP的跨膜轉(zhuǎn)運(yùn)能力;與LGP混懸液相比,大鼠ig LGP-CS/LC-NPs后可顯著提高LGP生物利用度,且可較好地控制糖尿病模型大鼠的血糖水平。結(jié)論 以CS和LC作為載體材料,將LGP制備成LGP-CS/LC-NPs,能夠顯著提高LGP口服生物利用度,達(dá)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

江蘇省藥學(xué)會科研基金項目(A202033); 南京市藥學(xué)會科研基金項目(2021YX007);南京市藥學(xué)會科研基金項目(2021YX019)