坎格列净纳米晶体冻干粉的制备及其药动学和药效学评价

Preparation of canagliflozin nanocrystals lyophilized powder and evaluation of its pharmacokinetics and pharmacodynamics

目的制备坎格列净纳米晶体(CFZ-NCs),并考察其在大鼠体内的药动学以及控制血糖的效果。方法以维生素E聚乙二醇1000琥珀酸酯(TPGS)和十二烷基硫酸钠(SDS)作为稳定剂,采用高压均质法制备CFZ-NCs,并通过冷冻干燥工艺将其固化成固体粉末;分别考察了CFZ-NCs及其冻干粉的粒径分布、Zeta电位;并在扫描电镜下观察CFZ-NCs的微观结构;比较坎格列净(CFZ)混悬剂及其纳米晶体的体外药物溶出速率;评价CFZ混悬剂和CFZ-NCs经大鼠口服给药后的体内药动学以及对糖尿病大鼠血糖水平的控制效果。结果CFZ-NCs及其冻干粉复溶后的粒径分布分别为(281.7±15.5)、(297.7±13.9)nm,Zeta电位分别为(-36.1±1.0)、(-36.9±0.7)mV,在扫描电镜下可观察到CFZ-NCs呈不规则块状分布;CFZ-NCs冻干粉的体外溶出速率显著高于CFZ混悬剂;大鼠口服CFZ-NCs冻干粉后,其药物达峰质量浓度和口服生物利用度显著高于CFZ混悬剂,对血糖控制水平效果也明显优于CFZ混悬剂。结论将CFZ制备成CFZ-NCs冻干粉,能显著提高药物的口服生物利用度,达到良好的控制血糖效果,对CFZ的二次开发奠定实验基础。

Objective To prepare canagliflozin nanocrystals(CFZ-NCs)and investigate their pharmacokinetics in rats and blood glucose control effects in diabetic rats.Methods By using vitamin E polyethylene glycol 1000 succinate(TPGS)and sodium lauryl sulfate(SDS)as stabilizers,CFZ-NCs were prepared by a high-pressure homogenization method,and solidified CFZ-NCs into solid powder by freeze-drying process.The particle size distribution and Zeta potential of CFZ-NCs and their lyophilized powders were investigated,respectively.The microstructure of CFZ-NCs was observed under scanning electron microscope(SEM).The in vitro dissolution rates of canagliflozin(CFZ)suspensions and CFZ-NCs were compared.The in vivo pharmacokinetics of CFZ suspensions and CFZ-NCs after oral administration in rats and the control effect on blood glucose levels in diabetic rats were evaluated.Results The particle size distributions of CFZ-NCs and CFZ-NCs lyophilized powder after reconstitution were(281.7±15.5)and(297.7±13.9)nm,and the Zeta potentials were(-36.1±1.0)and(-36.9±0.7)mV,respectively.The CFZ-NCs were irregularly distributed under SEM.The in vitro dissolution rate of CFZ-NCs lyophilized powder was significantly higher than that of CFZ suspensions.After oral administration of CFZ-NCs lyophilized powder in rats,the peak plasma concentration and oral bioavailability were significantly higher than CFZ suspensions,and the effect on blood glucose control level was significantly better than CFZ suspensions.Conclusion CFZ was prepared into CFZ-NCs lyophilized powder,which could significantly improve the oral bioavai-lability and achieve a good blood glucose control effect.It was of great significance for the secondary development of CFZ.