基于"药辅合一"理念薯蓣皂苷元-莱鲍迪苷A自组装胶束的制备、药动学及降血糖作用评价OA

Objective To prepare diosgenin-rebaudioside A self-assembled nanomicelles(Dio-Reb A-SNM),and evaluate its oral pharmacokinetics and hypoglycemic effects in vivo.Methods Single factor experiment was employed to investigate the prescriptions of Dio-Reb A-SNM.The amounts ratio of rebaudioside A to diosgenin,diosgenin concentration and ultrasonic time were selected as main influencing factor,the overall desirability of envelopment efficiency and drug loading was employed as optimization index,and Box-Behnken response surface design method(BBD-RSM)was employed to optimize prescriptions of Dio-Reb A-SNM.Transmission electron microscope(TEM)was employed to observe the microscopic appearance of Dio-Reb A-SNM,and X-ray powder diffraction(XRPD)was employed to analyze the crystal form of diosgenin in Dio-Reb A-SNM powder.The saturated solubility and release behavior of Dio-Reb A-SNM were determined in different pH media.SD rats were administered intragastrically with diosgenin and Dio-Reb A-SNM,respectively.Blood drug concentration was determined,and the relative oral bioavailability of Dio-Reb A-SNM was calculated.The model of type 2 diabetes mellitus(T2DM)in rats was established,and the effects of diosgenin and Dio-Reb A-SNM on hypoglycemic effects,serum aspartate aminotransferase(AST),alanine aminotransferase(ALT),urea nitrogen and creatinine level were compared.The histopathological state of liver and kidney was observed by HE staining method.Results The optimal formulations of Dio-Reb A-SNM:amounts ratio of rebaudioside A to diosgenin was 12.32∶1,diosgenin concentration was 1.97 mg/mL and ultrasonic time was 20.20 min.Envelopment efficiency,drug loading,particle size and ζ potential were(93.59±0.63)％,(5.65±0.07)％,(25.66±1.76)nm and(-24.59±1.18)mV,respectively.The appearance of Dio-Reb A-SNM were spherical.The crystal form of diosgenin changed into an amorphous form in Dio-Reb A-SNM powder.Dio-Reb A-SNM greatly improved the saturated solubility of diosgenin in different pH media.Drug release behavior of Dio-Reb A-SNM in vitro had obvious sustained-release characteristics,the cumulative release rate was increased to 90.94％in 18 h,and the drug release process conformed to Weibull model.Pharmacokinetics showed that tmax of Dio-Reb A-SNM was shortened to(2.06±0.29)h,t1/2 was increased to(8.39±1.94)h,Cmax and oral relative bioavailability were increased to 3.59-fold and 6.82-fold,respectively.Compared with diosgenin group(30 mg/kg),Dio-Reb A-SNM(30 mg/kg)could significantly reduce the blood glucose of T2DM rats at the fourth week(P＜0.01),and effectively reduced the AST,ALT,urea nitrogen and creatinine level in serum(P＜0.01).The pathological damage of liver and kidney was further alleviated by Dio-Reb A-SNM.Conclusion Dio-Reb A-SNM significantly promoted the oral absorption of diosgenin and improved hypoglycemic efficacy in vivo.