Development of optimized supersaturable self-nanoemulsifying systems of ezetimibe: Effect of polymers and efflux transporters

摘要

Objectives: To develop an optimized supersaturable self-nanoemulsifying drug delivery system (S-SNEDDS) in order to control drug precipitation along with surmounting poor aqueous solubility and P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2) efflux activity. Methods: Long-term stability of a previously reported formulation (OPT-LCT) consisting of Maisine 35-1 and Labrasol indicated rapid precipitation of ezetimibe. In vitro supersaturation test was carried out for selection of apt polymeric precipitation inhibitor (PPI). Following incorporation of the selected PPI, the precipitates from various formulations were differentiated employing optical microscopy, differential scanning calorimetry (DSC) and X-ray diffraction techniques. The S-SNEDDS was evaluated for globule size distribution. Also, lipid-lowering activity of S-SNEDDS was compared in relation to marketed product and optimized-long chain triglyceride. Subsequently, in situ perfusion studies were carried out for calculating various permeability and absorptivity parameters with specific focus on P-gp and MRP2 inhibition. Results: Supersaturation test facilitated the selection of HPMC E5LV as the best PPI. The precipitates from the S-SNEDDS were identified as amorphous while crystalline ezetimibe precipitates were found when HPMC was absent in the formulation. Owing to heterogeneous distribution, globule size analysis was not practicable. Plasma lipid estimations showed that S-SNEDDS had considerable influence in increasing the high-density lipid levels. The single-pass intestinal perfusion parameters, namely fraction absorbed and effective permeability demonstrated significant improvement in rate and extent of absorption from S-SNEDDS. Co-administration of itraconazole and indomethacin as P-gp and MRP2 inhibitors, respectively revealed the potential of S-SNEDDS in reducing the efflux activities. Conclusions: The studies revealed that the systemic exposure of ezetimibe following oral administration can be substantially improved using S-SNEDDS.