Evaluation of alkylmaltosides as intestinal permeation enhancers: Comparison between rat intestinal mucosal sheets and Caco-2 monolayers

Alkylmaltosides are a class of non-ionic surfactant currently in clinical trials to improve nasal permeation of peptide drugs, however few studies have detailed their potential effects on intestinal permeation enhancement. Tetradecyl maltoside (TDM, C14), was examined in Caco-2 monolayers and in isolated rat jejunal and colonic mucosae mounted in Ussing chambers. Dodecyl maltoside (DDM, C12) was examined in mucosae. Parameters measured included critical micelle concentration (CMC), transepithelial electrical resistance (TEER), and apparent permeability coefficients (Papp) of paracellular and transcellular flux markers. TDM and DDM decreased TEER and increased the Papp of [14C]-mannitol and FD-4 across Caco-2 monolayers and colonic mucosae in the concentration range of 0.01–0.1% w/v, concentrations much higher than the CMC. Remarkably, neither agent had any effect on the TEER or fluxes of jejunal mucosae. Histopathology, cell death assays (MTT and LDH) and sub-lethal high content cytotoxicity analyses (HCA) were carried out with TDM. Exposure of colonic mucosae to high concentrations of TDM had no major effects on gross histology and ion transport function was retained. In Caco-2, HCA data at sub-lethal concentrations of TDM was consistent with the action of a mild non-ionic surfactant. In conclusion, alkylmaltosides are effective non-toxic permeation enhancers in isolated colonic tissue and their inclusion in oral peptide formulations directed to that intestinal region warrants further study.

Tetradecyl maltoside (TDM) increases the flux of paracellular markers across rat colonic mucosae.Figure optionsDownload high-quality image (121 K)Download as PowerPoint slide