Development and optimization of etrasimod-loaded pH-dependent nanoparticles for colon targeted drug delivery

Background: Etrasimod-loaded pH-sensitive nanoparticles offer a promising strategy for targeted drug delivery to the colon, minimizing systemic exposure and enhancing therapeutic efficacy. A Quality-by-Design framework enables systematic optimization of formulation parameters to ensure robust performance and site-specific release. This represents the first systematic development of pH-responsive nanoparticles for etrasimod delivery and the first application of factorial design optimization for S1P receptor modulator nanoformulations. Methodology: Etrasimod-loaded pH-dependent nanoparticles were prepared via nanoprecipitation using Eudragit S100 and Eudragit RL100 polymers. The formulation was optimised using a 3² full factorial design with polymer concentrations as independent variables. The nanoparticles were characterised by particle size, zeta potential, entrapment efficiency, and drug release. The optimised formulation underwent comprehensive physicochemical characterisation (FTIR, DSC) and 6-month accelerated stability testing. Results and Discussion: The optimised formulation (TF5) containing 90% Eudragit S100 and 10% Eudragit RL100 exhibited optimal characteristics with a particle size of 142.6±5.4 nm, zeta potential of -23.5±1.8 mV, and entrapment efficiency of 73.4±3.2%. FTIR and DSC studies confirmed drug-polymer compatibility with minimal interaction. The in vitro release profile demonstrated controlled initial release (9.8% at 1 hour) followed by complete drug liberation (94.2% at 12 hrs) at pH 7.2. The formulation remained stable for 6 months at 40 °C ± 2 °C and 75% ± 5% RH, with minimal changes in critical quality attributes. Conclusion: The developed pH-dependent nanoparticulate system offers a promising platform for colon-targeted delivery of etrasimod, demonstrating optimal physicochemical properties, controlled release characteristics, and excellent stability. This formulation approach shows potential to improve therapeutic outcomes in inflammatory bowel disease by enhancing colonic drug delivery.