Mechanistic insights into effect of surfactants on oral bioavailability of amorphous solid dispersions

Abstract

Drug delivery of poorly soluble drugs in form amorphous solid dispersions (ASDs) is an appealing method to increase in vivo bioavailability. For rational formulation design, a mechanistic understanding of the impact of surfactants on the performance of ASD-based formulations is therefore of importance. In this study, we used hot-melt extrusion to prepare ASDs composed of the model drug substance efavirenz with hydroxypropyl methylcellulose phthalate (HPMCP) as the base polymer, and surfactants. Molecular dynamics simulations and in vitro dissolution studies were used to investigate formation and drug release from polymer vesicles, and their ability to maintain a supersaturation state as a function of surfactant composition. It was possible to identify main factors regulating particle formation and to modify dissolution profiles with different excipient compositions. Animal studies in the rat, in combination with physiologically based pharmacokinetic modeling, demonstrated enhanced drug absorption from formed vesicles. The surfactant composition in the ASD had a direct influence on the morphology of these vesicles, as well as kinetics of drug release, and, therefore, the oral bioavailability. ASDs, prepared by hot-melt extrusion method, were optimized for dissolution and adsorption rates increase. Our findings contribute to a better understanding of dissolution behavior of ASDs with respect to the function of surfactants, aiming to facilitate a rational formulation development and an accelerated transition from in vitro systems to in vivo applications.

Keywords: Amorphous solid dispersion; Bioavailability; Formulation development; Poorly water-soluble drugs.