Optimization of Sirolimus Micelles by Response Surface Methodology and Its Effect on Small Intestinal Absorption

OBJECTIVE To prepare sirolimus(SRL) polymer micelles and investigate its effects on the absorption kinetics of rat intestine. METHODS The SRL CS-DCA micelles were prepared by solvent evaporation using deoxycholic acid grafted chitosan(CS-DCA) as carrier. The encapsulation efficiency, drug loading, particle size and potential were taken as the evaluation indexes, and the formulation was optimized by the central composite design-response surface optimization method. In situ single pass perfusion model of rat was set up to investigate intestinal absorption characteristics of SRL CS-DCA micelles with different concentrations. Meanwhile, the intestinal absorption coefficient(P_eff), absorption rate constant(K_a) and the dose fraction(f_a) were used to evaluate drug absorption. RESULTS The optimum formulation of SRL CS-DCA micelles was as follows:the concentration of CS-DCA was 10 mg·mL^-1, and the mass ratio of drug to carrier was 20%. Under this condition, the system had the positive charge of (37.0±2.7)mV, particle size of (182.2±5.7)nm, the encapsulation efficiency greater than 90%, and the drug loading of (15.80±0.5)%. After the SRL CS-DCA micelles passed through the rat intestine, the P_eff, K_a and f_a were significantly higher than those of SRL(P<0.05). There was no significant difference in the P_eff, K_a and f_a values of SRL CS-DCA micelles with different concentration in the whole intestine of rats, suggesting that the micelles had no concentration inhibition at 10-100 μg·mL^-1, and the absorption characteristics were linear dynamics of passive transport. It was speculated that its possible absorption mechanism was passive diffusion. CONCLUSION The SRL CS-DCA micelles can enhance effect on intestine absorption of SRL monomer, which proves that SRL CS-DCA can effectively improve the oral bioavailability of sirolimus.