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 t_max of Dio-Reb A-SNM was shortened to (2.06 ±0.29) h, t_1/2 was increased to (8.39 ±1.94) h, C_max 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.

diosgenin  /  rebaudioside A  /  self-assembled nanomicelles  /  Box-Behnken response surface design method  /  pharmacokinetic  /  bioavailability  /  hypoglycemic effects