L. Yu et al., Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability, PHARM RES, 16(12), 1999, pp. 1812-1817
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.