Development and evaluation of regorafenib loaded liquid suppository for rectal delivery: In vitro, in vivo analyses

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 water solubility, extensive hepatic metabolism, low oral bioavailability, and serious side effects like Hand-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 study 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 study of RG release behavior from liquid suppository [RG/P188/P407/T80/distilled water: 1.25/15/11/10/62.75; %] were investigated followed by in vitro cell lines study on Caco-2 and HCT 116 cell lines. Additionally, pharmacokinetics, in vivo safety and in vivo localization studies were carried out following rectal administration in Sprague-Dawley rats. Results showed that increased P407 and T80 concentrations significantly lowered the temperature and time required 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 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. It can be concluded from the results that RG loaded liquid suppository has a great potential to target CRC with enhanced drug localization, improved bioavailability and no toxic effects at the application's site.