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

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.

A combined mathematical model linking the formation of amorphous solid dispersions with hot-melt-extrusion process parameters.

Hot-melt extrusion allows for the continuous production of amorphous solid dispersions, which are used to enhance bioavailability of poorly soluble drugs in pharmaceutical drug delivery. To facilitate formulation and extrusion process development, we propose a mathematical model describing the formation of amorphous solid dispersions in the context of this process. The model is based on the calculation of two key process values: (1) time to dissolution of solid drug particles in molten polymer during extrusion and (2) mean residence of material in the extruder. We suggest that their linking allows for rational process design. Experimental data support the validity of our model for both key process values as well as the overall process. This modeling approach allows for fast and cost-effective formulation and extrusion process development as well as feasibility estimations in early stages of drug development.