Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability

Purpose. To investigate the effect of vitamin E-TPGS, d-alpha-tocopheryl po lyethylene glycol 1000 succinate, on the solubility and permeability of amp renavir, a potent HIV protease inhibitor. Methods. The aqueous solubility of amprenavir was measured as a function of vitamin E-TPGS concentration. Directional transport through Caco-2 cell mo nolayers was determined in the presence and absence of vitamin E-TPGS and P -glycoprotein inhibitors. Absorption flux was estimated from Caco-2 cell pe rmeability and aqueous solubility. Results. The solubility of amprenavir in a pH 7 buffer at 37 degrees C was 0.036 +/- 0.007 mg/mL. The solubility linearly increased with increasing vi tamin E-TPGS concentration (above 0.2 mg/mL). Polarized transport was demon strated in the basolateral to apical direction, exceeding apical to basolat eral transport by a factor of 6. The active efflux system was inhibited by vitamin E-TPGS and known P-glycoprotein inhibitors verapamil and GF120918. Conclusions. The solubility of amprenavir was improved in the presence of v itamin E-TPGS through micelle solubilization. Vitamin E-TPGS inhibits the e fflux system and enhances the permeability of amprenavir. Overall. vitamin E-TPGS enhanced the absorption flux of amprenavir by increasing its solubil ity and permeability. The enhancement is essential to the development of th e novel soft gelatin capsule formulation of amprenavir for use in the clini c.