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Abstract:

Purpose To evaluate the effect of TPGS analogues on drug release, dissolution of UC781 was assessed from 4 SMEDDS containing either TPGS 400, 1000, 4000 or 6000. A possible interaction of the TPGS analogues with intestinal efflux carriers was illustrated by determining their effect on the absorptive transport of amprenavir, a substrate of P-glycoprotein in the Caco-2 system. Methods Each surfactant was combined with Captex200 and ethanol at different concentrations to obtain formulations resulting in oil droplet sizes < 200nm in 0.5% m/v aqueous dilutions. Droplet sizes were measured using DLS. UC781 was dissolved in the formulations and drug release was measured for 2 hours in phosphate buffer (pH 6.8). To measure the absorptive transport of amprenavir, the drug was incubated at the apical side of Caco-2 monolayers in the presence of TPGS400, 1000, 4000 or 6000 at a concentration of 0, 0.1 or 4mM. Results Dissolution results showed UC781 releases of up to 100% in case of TPGS1000 SMEDDS, while all other TPGS analogues resulted in a lower release of UC781: 90%, 45% and 31% for TPGS400, 4000 and 6000, respectively. At a concentration of 0.1 mM, inclusion of TPGS1000 increased the apparent permeability coefficient (Papp) for amprenavir. Inclusion of the other TPGS analogues did not result in a significant effect. At a concentration of 4 mM, all TPGS analogues resulted in a decrease in amprenavir permeability probably due to micellar encapsulation. The effect of TPGS1000 was further investigated in a concentration dependent way. A bell-shaped relationship was observed with a maximum inhibitory effect at 0.1mM. Conclusion Maximum UC781 releases were obtained with TPGS1000 SMEDDS. Transport results of amprenavir suggest that TPGS1000 has an inhibitory effect on P-glycoprotein activity and the concentration dependence of this effect is described by a bell-shaped relationship. All TPGS analogues can reduce the free fraction of amprenavir by micellar encapsulation.