Mechanistic analysis of chemical permeation enhancers for oral drug delivery

Purpose. Traditionally, the oral route cannot be employed for the delivery of macromolecular drugs such as proteins and peptides due, in large part, to limited transport across the epithelial membrane. This particular challenge can potentially be addressed through the use of chemical permeation enhancers, which affect transcellular and/or paracellular transport routes. Although certain permeation enhancers have been proposed for use in oral delivery, potential for application is often unclear when the route of enhancer action is unknown. Methods. A combination of theory and experiments was developed for determining mechanism of enhancer action. The effect of 51 enhancers on Caco-2 cells was studied using TEER, MTT, and LDH assays. Results. The mechanistic details of intestinal permeability enhancement were uncovered for a broad set of enhancers in vitro. Understanding gained from enhancer mechanisms enabled the deduction of structure-function relationships for hydrophilic and hydrophobic permeation enhancers as well as the identification of a transcellular enhancer, 0.01% (w/v) palmityldimethyl ammonio propane sulfonate, which enabled the non-cytotoxic intracellular delivery of a model drug. Conclusions. The results presented here emphasize the importance of understanding enhancer mechanism and uncover a zwitterionic surfactant capable of safely and effectively achieving intra-epithelial drug delivery in vitro.