Chitosan-TPP modification of SNEDDS enhances mucin interaction, apparent epithelial transport, and oral exposure of ezetimibe.

Poor aqueous solubility limits the oral absorption of ezetimibe, and conventional self-nanoemulsifying drug delivery systems (SNEDDS) primarily address the solubilization barrier. In this study, ezetimibe-loaded SNEDDS were associated with a chitosan-tripolyphosphate (TPP) ionic network to generate chitosan-TPP-modified SNEDDS colloids (CS-SNEDDS) with additional mucin-interactive characteristics. The resulting CS-SNEDDS had a mean particle size of approximately 142 nm and a positive zeta potential, while retaining the apparent solubilization and rapid dispersion properties of the SNEDDS component. Compared with conventional SNEDDS, CS-SNEDDS showed markedly greater mucin association and increased apparent apical-to-basolateral transport across Caco-2 monolayers. Following oral administration to rats, CS-SNEDDS produced an AUC₀-₂₄h of 4715.62 ± 854.07 ng·h/mL, compared with 3647.39 ± 753.54 ng·h/mL for SNEDDS and 2176.84 ± 426.58 ng·h/mL for crystalline ezetimibe. The AUC₀-₂₄h of CS-SNEDDS was significantly higher than that of SNEDDS, whereas no significant difference in Cmax was detected between the two nanoformulations. These findings indicate that chitosan-TPP modification of ezetimibe-loaded SNEDDS introduced mucin-interactive cationic properties and was associated with an additional improvement in apparent epithelial transport and systemic exposure beyond that achieved by SNEDDS alone. This lipid-polymer interfacial modification strategy may provide a useful formulation approach for improving the oral delivery of poorly water-soluble drugs.