The effect of co-amorphization of glibenclamide on its dissolution properties and permeability through an MDCKII-MDR1 cell layer.

Abstract

Co-amorphous mixtures have been demonstrated to represent a promising approach for enhancing the dissolution of poorly water-soluble drugs. However, little is known of their permeability properties, especially through biological membranes, or about the relationship between their dissolution and permeability. In the present study, co-amorphous glibenclamide (GBC) mixtures with two amino acids, arginine (ARG) and serine (SER), in molar ratios of 1:1 were prepared by cryomilling. Their dissolution and permeability properties were studied in side-by-side diffusion chambers using cell layers containing Madine Darby kidney cells overexpressing P-glycoprotein (Pgp) transporters (MDCKII-MDR1), as Pgp may influence the absorption of GBC. Furthermore, two other compounds, the flavonoid quercetin (QRT) which is a Pgp inhibitor and the surfactant, sodium lauryl sulfate (SLS), were used as excipients to investigate if they improved either passive or active diffusion of GBC. In addition, amorphous QRT and a co-amorphous mixture of GBC and QRT (1:1) were characterized with respect to their solid-state properties and physical stability. It was demonstrated that co-amorphous GBC mixtures exhibited superior dissolution properties over the corresponding physical mixtures and amorphous GBC. Furthermore, the co-amorphous GBC-ARG-SLS mixture exhibited a 9-fold increase in permeating through the MDCKII-MDR1 cell layer as compared to the corresponding physical mixture. There was a correlation between the dissolution and permeability area under curve (AUC) values, evidence that the main mechanism behind the improved permeability of co-amorphous mixtures was their improved dissolution. The simultaneous dissolution/permeation testing with side-by-side diffusion chambers and MDCKII-MDR1 cells proved to be a feasible method for evaluating the dissolution/permeation interplay of amorphous compounds.