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

Abstract

Regorafenib is administered orally for the treatment of metastatic colorectal cancer. However, its limited water solubility hinders its clinical efficacy. This study explores the impregnation of regorafenib monohydrate (REG MH) into pullulan (PULL) using supercritical carbon dioxide (scCO₂), aiming to promote the oral bioavailability, water solubility and therapeutic efficacy of the drug. Pullulan was first produced by Aureobasidium pullulans. A Box-Behnken design (BBD) was employed to optimize 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. The maximum drug loading (0.57 %) 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 optimal conditions of 328 K, 280 bar, and 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. The drug release from the polymer matrix is predominantly controlled by the Fickian diffusion mechanism.