The effect of chitosans and other excipients on the permeation of ketotifen and other drug models through Caco-2 cells

Caco-2 cells are derived from human colonic adenocarcinoma cells and exhibit morphology and functional similarities to the intestinal enterocytes. They are now considered the "gold" standard cells for in-vitro drug permeation evaluations. Caco-2 cells grown on permeable inserts have become relatively customary for screening permeability of compounds. The isolated model allows for direct evaluation of mechanisms of transport and provides great flexibility of experimentation.; We evaluated the Ketotifen, FITC-labeled dextran and Rhodamine 123 permeation across Caco-2 cells. These model drugs were chosen because they represented the three major permeation transport pathway: passive transcellular (Ketotifen), passive paracellular (FITC dextran) and active transport (Rhodamine 123). The model compounds were evaluated in the presence of various excipients such as chitosan, N, O-carboxymethyl chitosan (NOCC), Carbopol 934P, Polysorbate 80 and disodium edetate.; Samples with chitosan resulted in a concentration dependent decrease in transepithelial electrical resistance (TEER), a measure of tight junction integrity, which was not seen with the other excipients. This corresponded with significant improvement of paracellular permeation of FITC-dextran and Rhodamine 123 compared to the control (p < 0.005) where ketotifen permeation with chitosan did not show statistically significant improvement as compared to the control. Although Rhodamine 123 is a known p-glycoprotein substrate, this data would indicate that the p-glycoprotein transport system is not the rate limiting factor in Rhodamine 123 permeation. Ketotifen permeation was improved slightly when in the presence of NOCC, polysorbate 80 and edetate disodium. These excipients have been associated with improved transcellular permeation. Carbopol 934P did not improve any of the drug models' permeation.; Therefore, depending on the drug model, different excipients may improve different drug permeation. These results successfully show the effectiveness of using Caco-2 cells to help screen formulations for development.