Preliminary evaluation of hot melt extrusion for improving the oral bioavailability of substrates of P-glycoprotein (P-gp) efflux pump

With the aim of developing an oral formulation of a drug substrate of P-glycoprotein (P-gp) transporter and an inhibitor/modulator of this efflux pump by Hot Melt Extrusion (HME), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) - Eudragit® E PO (EPO) mixtures of differing concentrations (0-25%) were extruded at 110 °C after assessing TPGS miscibility in the polymer by melt rheology and thermal analysis. The resulting extrudates were also characterized in terms of TPGS dissolution behaviour in 0.1M HCl. EPO-TPGS melts showed a pseudoplastic behaviour at all concentrations. Apparent viscosity extrapolated to zero wall shear rate (consistency index) was progressively reduced by the addition of TPGS suggesting that the inhibitor is miscible and might exert a plasticizing effect within melted EPO. The latter effect was also confirmed by DSC data that however revealed a small residual crystallinity in samples with 20-25% inhibitor content. Extrudates of acceptable quality were obtained at all concentrations except for samples with 25% TPGS that are hardly handled as tend to stick together. In addition, TPGS-EPO formulations with 5 and 20% inhibitor content showed a fast inhibitor liberation in acidic conditions (≥ 70% in 15 min) irrespective of inhibitor content.