Amalgam of ternary solid dispersion and P-gp efflux inhibition in development of colon-targeted tablets of rifaximin

Abstract

Background: Rifaximin, a BCS class IV drug, possesses low bioavailability due to low solubility and low permeability attributable to P-gp efflux. The studies attempted to develop pH-sensitive rifaximin tablets based on ternary solid dispersion (TSD) for spatial and temporal drug release in colon. Materials and Methods: Rifaximin TSD was prepared using Neusilin US2 as a mesoporous carrier and Poloxamer 188 as a hydrophilic carrier and P-gp inhibitor by solvent evaporation technique employing acetone at 1:5 ratio. The TSD was assessed for P-gp inhibition using the gut sac method and Caco-2 permeability studies. The TSD was compressed into tablets and coated with pH-sensitive polymers. Coating optimization was carried out using a 32 factorial design, wherein % coating and ratio of Eudragit S100:Eudragit L100 were the independent variables and % drug release at 2 h and % drug release at 8 h were the dependent variables. Results: Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy studies of rifaximin TSD suggested amorphization of the drug. Gut sac studies indicated higher mucosal to serosal permeability of rifaximin from TSD. Caco-2 permeability studies demonstrated a 4.83-fold higher permeability of rifaximin from TSD (polaxamer 25% w/w and Neusilin 55% w/w of TSD) and a significant change in efflux ratio. In-vitro release studies of the coated tablets displayed controlled and site-specific release at pH of the colon. Conclusion: Effective, stable, pH-dependent rifaximin colon-targeted tablets with enhanced dissolution, permeability, and reduced P-gp efflux were developed. The achieved merits could translate into augmented bioavailability and dose reduction. Further in-vivo studies on this novel formulation, which is cost-effective and industrially scalable, can improve the pharmacoeconomics of inflammatory bowel disease management.