The effect of solubility enhancer and P-gp inhibitor excipients on rat jejunal permeability of sirolimus from self-microemulsifying formulations

Abstract

Objective: The aim of this study was to investigate the effect of solubility enhancer and P-gp inhibitor excipients on rat jejunal permeability of sirolimus from self-microemulsifying (SMEDDS) formulations. The applicability of SMEDDS formulations in enhancing physicochemical properties, in vitro release and intestinal absorption was investigated and compared. Materials and Methods: Surface properties of vehicles, formulations and prepared nanoemulsions were investigated. A Box-Behnken design was run to evaluate the effect of independent factors (amounts of oil, surfactant and cosurfactant) on responses (Transmittance, droplet size, polydispersity index, refractive index, and zeta potential). Optimized formulations prepared containing different excipients and their dissolution profiles and intestinal permeabilities were determined and compared. Results: Nanoemulsion prepared from formulation containing more Cremophor RH 40, exhibits the lowest surface tension. Droplet size of optimized SNEDDS formulation containing Capryol PGMC, Cremophor RH 40 and Transcutol was 45.38 nm. Optimized formulations revealed significant increase in drug release (more than 85% release in 5 min). The best results in terms of droplet size, drug release and intestinal permeability enhancement was observed applying Capryol PGMC, Cremophor RH 40 and Transcutol. The intestinal permeability of sirolimus in formulation with best obtained results (F5) was 3.46 fold higher than that of sirolimus solution. The Peff values of formulations F2, F4 and F5, all containing Cremophor RH 40 and Capryol PGMC, were significantly higher than that of control sirolimus solution. Discussion and conclusion: Statistical design allowed us to screen the effect of each component in formation of nano-emulsions and to obtain Sirolimus self-nanoemulsifying formulations with desirable physicochemical characteristics. Incorporating sirolimus in SNEDDS formulations could promisingly enhance the intestinal permeability of sirolimus. Application of Capryol PGMC and Cremophor RH 40 P-gp inhibitor and solubility enhancer excipients could significantly improve the intestinal absorption of sirolimus.