Contributions of dissolution and intestinal permeation to oral drug product quality

Abstract

Dissolution and intestinal permeation are the primary biopharmaceutical factors controlling oral drug product performance. The objective of this research was to develop in vitro dissolution and Caco-2 cell monolayers, both separately and in combination, as tools to characterize the biopharmaceutical performance of oral drug products. Firstly, in vitro dissolution methods were developed to elucidate the degree of drug solubility-controlled or formulation-controlled drug dissolution from immediate release dosage forms. Results indicate dissolution from formulations may be controlled by disintegration or diffusion through the aqueous boundary layer. Drug solubility and formulation design dictated the degree of disintegration or diffusion control. Secondly, Caco-2 monolayer permeability was quantitatively related to human drug absorption kinetics. Results suggest a rank-order relationship between Caco-2 permeability and in vivo intestinal permeation rate, providing a kinetic interpretation of Caco-2 monolayer permeability. Caco-2 monolayer methods were also used to develop a simple kinetic model to elucidate P-glycoprotein effects on intestinal drug transport. Results suggest P-glycoprotein substantially reduced net fexofenadine transport, which was well characterized by the simple kinetic model. Thirdly, "static" and "dynamic" dissolution/Caco-2 systems were developed. Each system integrated in vitro dissolution and Caco-2 monolayers to predict the relative contributions of dissolution and intestinal permeation to overall drug absorption kinetics. Results indicate the "static" system accurately predicted the relative contributions of dissolution and intestinal permeation to overall drug absorption and the "dynamic" system simultaneously assessed the effect of formulation changes on dissolution and intestinal permeation. Hence, in vitro dissolution and Caco-2 cell monolayer methods were successfully developed to characterize the biopharmaceutical performance of oral drug products. Separately, these methods identified factors controlling drug product dissolution, estimated the absorption potential of oral drug candidates and elucidated P-glycoprotein effects on intestinal drug transport. In combination, these methods elucidated the degree to which dissolution and intestinal permeation limits overall drug product performance and characterized excipient effects on dissolution and intestinal permeation.