Enhanced In Vivo Absorption of Itraconazole via Stabilization of Supersaturation Following Acidic-to-Neutral pH Transition

Abstract

Previous attempts to improve the dissolution and absorption properties of itraconazole (ITZ) through advanced formulation design have focused only on release in acidic media; however, recent reports indicate that absorption occurs primarily in the proximal small intestine. This suggests that enhancing supersaturation of ITZ in neutral aqueous environments is essential for improving absorption. The aim of this study was to evaluate different polymeric stabilizers with either immediate release (IR) (Methocel™ E5, Methocel™ E50, Kollidon® 12, and Kollidon® 90) or enteric release (EUDRAGIT® L 100-55, HP-55, and HP-55S) properties to determine the chemical and physical attributes of the polymeric stabilizers that promote supersaturation of ITZ in neutral media. Each amorphous composition was produced by hot-melt extrusion and characterized by differential scanning calorimetry. Dissolution testing by a supersaturated acidic-to-neutral pH change method was conducted on each composition. Testing of IR compositions revealed that Methocel™ was a superior stabilizer compared with Kollidon® owing to stronger intermolecular interaction with ITZ molecules in solution. Increasing the molecular weight of polymers was found to promote ITZ supersaturation and was most likely attributable to increased solution viscosity resulting in retention of ITZ molecules in an enthalpically favored association with the polymer for extended durations. Of the enteric polymeric stabilizers, EUDRAGIT® L 100-55 was found to be superior to both HP-55 grades because of its greater permeability to acid that allowed for improved hydration of ITZ in the acid phase as well as a greater number of free hydroxyl groups on the polymer backbone that presumably helped to stabilize ITZ in solution. The Methocel™ E50 and EUDRAGIT® L 100-55 formulations were evaluated for in vivo drug absorption in male Sprague–Dawley rats and were found to produce a threefold greater ITZ absorption over our previously reported IR formulations. The results of this study confirmed the hypothesis that supersaturation of ITZ following an acidic-to-neutral pH transition in vitro correlates directly to in vivo absorption.

Keywords:

• itraconazole
• supersaturation
• in vivo
• bioavailability
• enteric
• solid dispersion
• solid solution
• hot melt extrusion
• amorphous