Decanoate-induced permeation enhancement: Distinct membrane effects of micellar and vesicular colloids

Sodium decanoate (C10) is a medium-chain fatty acid widely studied as a permeation enhancer and considered a benchmark compound for improving the intestinal permeability of poorly absorbed drugs. However, although the mechanism of action of C10 has been extensively investigated, the effect of its colloidal structure on this mechanism remains incompletely understood. This study investigates how pH-dependent colloidal forms of C10, i.e., micelles (pH 8.5) and vesicles (pH 6.5), modulate drug permeation across intestinal mucosae. Ex vivo permeation studies using rat intestinal mucosa were performed with atenolol and 4 kDa fluorescein isothiocyanate (FITC)–dextran as paracellular markers, and metoprolol as a transcellular marker. A pH EpiStat unit was integrated with the Ussing chamber system to allow continuous pH monitoring and precise titration. C10 micelles, at 30 mM, enhanced marker permeation across the intestinal mucosa, particularly metoprolol, whereas vesicles caused minimal enhancement. Using an epithelial-mimetic artificial membrane, micelles were found to cause rapid and complete barrier disruption, while vesicles slowly increased membrane permeability, resulting in a sustained increase in marker permeation. Furthermore, C10 vesicles displayed stronger interactions with mucin and promoted greater retention of marker compounds within the mucosa. Collectively, these findings suggest that both micellar and vesicular C10 enhance permeation primarily via the transcellular route but through different mechanisms: micelles disrupt lipid membrane integrity, while vesicles fluidize membranes without compromising barrier function and interacting with the mucus layer. This work provides new mechanistic insight into C10-mediated permeation enhancement and informs the rational design of more effective oral delivery systems. • pH-dependent C10 colloids exhibit distinct permeation enhancement mechanisms. • C10 micelles rapidly disrupt epithelial barriers to enhance drug permeation. • C10 vesicles fluidize membranes and interact with mucus for sustained uptake. • Vesicular C10 interacts strongly with mucin, promoting mucosal retention. • Mechanistic insight on how colloidal states of C10 governs absorption-enhancement.