Improvement of the pharmaceutical availability and membrane permeability of furosemide by formulation design

Abstract

Furosemide is a well-known loop diuretic having weak acidic chemical properties. Furosemide belongs to the Biopharmaceutical Classification System (BCS) class IV because it has poor aqueous solubility and poor membrane permeability characteristics. In this study, the effect of different combinations of functional excipients (i.e. chitosan, sodium lauryl sulphate, NaHCO3 and CaCO3) in the formulation of multiple-unit pellet system (MUPS) tablets has been investigated. Spherical beads (0.5 mm, 0.75 mm and 1 mm) were produced by extrusion-spheronisation consisting of different combinations of excipients, which were compressed to form flat faced, bevelled edge MUPS tablets. Three control MUPS tablet formulations (i.e. containing 0.5 mm, 0.75mm and 1 mm beads) were prepared without the functional excipients. A commercial product (Lasix®) was also included in the study as a reference for purposes of comparison. Each MUPS tablet formulation was evaluated for physical properties (hardness, disintegration, mass variation and friability), whereasthe bead formulations were tested for mucoadhesiveness. Dissolution evaluations were conducted on each MUPS tablet formulation in media with three different pH environments, namely 0.1 M HCl (pH 1.2), citric acid buffer (pH 4.6) and a phosphate buffer (pH 7.4). Ex-vivo permeability studies were performed across excised pig tissues of the pyloric antrum and the duodenal region on selected experimental MUPS tablet formulations; the control MUPS tablet formulations, and (or as well as) the commercial product. Histological analysis was conducted on the tissues after exposure to the selected experimental MUPS tablet formulations, the control MUPS tablet formulation and the commercial product. The dissolution results in the 0.1 M HCl (pH 1.2) showed the highest effect of the excipients on furosemide release when compared to the control formulations and the commercial product. This phenomenon was expected due to the acidic nature of furosemide. All the dissolution parameters showed increased dissolution of furosemide for the MUPS tablet formulations containing the functional excipients as compared to that of the control MUPS tablet formulations as follow: the AUC values of the dissolution curves showed a 4.5–10 fold increase, the %max showed a 60–70% increase and the DRi exhibited up to a 19 fold increase. Permeability results revealed the selected MUPS tablet formulations had a 2.5 fold higher cumulative percentage transport than the control MUPS tablet formulation without a cytotoxic effect on the tissues. The results from this study showed that the combination of selected functional excipients incorporated into beads that were compressed into MUPS tablet formulations not only increased furosemide release, but also its permeation across excised intestinal tissues.