DoE-guided comparison of SNEDDS, solid dispersion, and polymeric nanoparticles for enhancing apparent epithelial transport and oral exposure of sorafenib.

Sorafenib is an orally administered multikinase inhibitor whose clinical utility is limited by extremely low aqueous solubility and poor oral bioavailability. Although sorafenib is generally considered dissolution-limited, its oral absorption may also be affected by formulation-dependent epithelial transport behavior. In this study, three nanotechnology-based oral delivery platforms-self-nanoemulsifying drug delivery systems (SNEDDS), spray-dried solid dispersions (SD), and polymeric nanoparticles (PN)-were developed and directly compared using a unified design of experiments (DoE)-guided optimization framework. Component selection was guided by solubility screening, and each platform was optimized to improve colloidal or solid-state performance. The optimized formulations-solidified SNEDDS (S-SNEDDS), SD, and lyophilized PN-were characterized by PXRD and DSC, indicating a marked reduction in detectable sorafenib crystallinity. All formulations increased apparent solubility in aqueous, pH-adjusted, and biorelevant media, with S-SNEDDS showing the greatest enhancement. In Caco-2 monolayers, S-SNEDDS achieved the highest apparent permeability, showing a 13.4-fold increase over raw sorafenib. In beagle dogs, S-SNEDDS also produced the highest systemic exposure, with a Cmax of 2,948.23 ± 530.68 ng/mL and an AUC0-48h of 30,958 ± 2,092 ng·h/mL, corresponding to a 6.2-fold AUC increase. The rank order of in vivo exposure aligned more closely with Caco-2 permeability than with apparent solubility alone. These findings suggest that formulation architecture influences sorafenib absorption through combined effects on luminal solubilization and epithelial transport-related behavior.