Efficacious Intestinal Permeation Enhancement Induced by the Sodium Salt of 10-undecylenic Acid, A Medium Chain Fatty Acid Derivative

10-undecylenic acid (UA) is an OTC antifungal therapy and a nutritional supplement. It is an unsaturated medium chain fatty acid (MCFA) derivative, so our hypothesis was that its 11-mer sodium salt, uC(11), would improve intestinal permeation similar to the established enhancer, sodium caprate (C-10), but without the toxicity of the parent saturated MCFA, decylenic acid (C-11). MTT assay and high-content screening (HCS) confirmed a cytotoxicity ranking in Caco-2 cells: C-11 > C-10 = uC(11). Five to ten millimolars of the three agents reduced TEER and increased the Papp of [C-14]-mannitol across Caco-2 monolayers and rat intestinal mucosae, a concentration that matched increases in plasma membrane permeability seen in HCS. Although C-11 was the most efficacious enhancer in vitro, it damaged monolayers and tissue mucosae more than the other two agents at similar concentrations and exposure times and was therefore not pursued further. Rat jejunal and colonic in situ intestinal instillations of 100 mM C-10 or uC(11) with FITC-dextran 4000 (FD4) solutions yielded comparable regional enhancement ratios of similar to 10 and 30%, respectively, for each agent with acceptable tissue histology. Mini-tablets of uC(11) and FD4 however delivered more FD4 compared to C-10-FD-4 mini-tablets in both regions, as reflected by a statistically higher AUC, and with no evidence of membrane perturbation. The unsaturated bond in uC(11) therefore confers a reduction in lipophilicity and cytotoxicity compared to C-11, and the resulting permeation enhancement is on a par with or superior to that of C-10, a key component of formulations in current phase II oral peptide clinical trials.