Development and Characterization of Regorafenib loaded Liquid Suppository for Rectal Delivery

Abstract

Regorafenib (RG), a multi-targeting kinase inhibitor, has recently been used in the colorectal cancer (CRC) treatment. However, its clinical effectiveness is severely constrained by its poor aqueous solubility, low oral bioavailability, extensive hepatic metabolism, and serious side effects like Hand and foot skin reaction (HFSR), rashes, fatigue, stomatitis, diarrhea, dizziness and hypertension. Therefore, it is necessary to investigate alternative administration routes in order to increase RG efficacy. The aim of this research was to develop RG loaded liquid suppository with enhanced bioavailability and reduced toxicity. RG loaded liquid suppository was optimized using Design Experts® software, with various quantities of drug (RG), polymers [poloxamer 407 (P407), and poloxamer 188 (P188)], surfactant [tween® 80, (T80)] and distilled water. Physicochemical characterization and in vitro drug release behavior of the RG loaded liquid suppository were investigated followed by in vitro cell lines study. Additionally, pharmacokinetics, in vivo safety and in vivo localization studies carried out following rectal administration in Sprague-Dawley rats. Results showed that increased P407 and T80 concentrations significantly lowered the temperature and time for gelation, while the strength and mucoadhesion of gel was meaningfully enhanced. However, RG concentration increased didn’t show significant effect on all these parameters. RG loaded liquid suppository displayed a significantly improved in vitro release, augmented in vivo localization, and enhanced bioavailability, when compared with the RG suspension. In vitro cell lines data demonstrated that unlike normal saline treated Caco-2 and HCT 116 cell lines, the RG loaded liquid suppository and RG suspension has significantly reduced the cancer cell burden, which was also observed through their lower IC50 values. Histopathology study confirmed the formulation's safety for rectal administration, whereas RG suspension instigated severe damage to the rectal tissues. Concluded from the results that RG loaded liquid suppository has a great potential to target CRC with enhanced drug localization, improved bioavailability and no toxicity at the application’s site.