Improvement of the dissolution of the antineoplastic drug regorafenib through impregnation into pullulan polysaccharide using supercritical fluid technology: Optimization of the process

Abstract

This study explores the impregnation of regorafenib monohydrate (REG MH) into microbial-based pullulan (PULL) using supercritical carbon dioxide (scCO2) for the first time, aiming to promote the oral bioavailability, water solubility and therapeutic efficacy of the drug. Pullulan was produced by Aureobasidium pullulans. A Box-Behnken design (BBD) was employed to optimize key impregnation factors including temperature (308, 318 and 328 K), pressure (200, 240 and 280 bar) and time (5, 7 and 9 h) on drug loading. Results indicated that REG MH loading into pullulan tablets ranged from 0.13% to 0.57%. The maximum drug loading was achieved at a temperature of 280 K, pressure of 328 bar and time of 7 h. The highest drug loading of 0.7% was predicted by BBD under optimum conditions of 328 K, 280 bar, and a time of 9 h. The crystalline peaks for REG MH were lost after incorporation into the pullulan proving the amorphization of the embedded drug. According to differential scanning calorimetry (DSC) results, the melting point belonging to the crystalline drug faded after impregnation into the polymer, implying that the REG MH/PULL formulation converts to a complete amorphous structure. Field emission scanning electron microscopy (FE-SEM) images indicated the semi-spherical morphology of the REG MH/PULL system. The dissolution rate of the impregnated REG MH in an aqueous medium considerably enhanced to 80% during 60 h, whereas it reached 18% for the free drug. It was found that the drug release from the polymer matrix is predominantly controlled by the Fickian diffusion mechanism.