Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative,enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo

The synthesis and evaluation of mono-N-carboxymethyl chitosan (MCC) as an i ntestinal permeation enhancer for macromolecular therapeutics is presented. MCCs were synthesized from two different viscosity grade chitosans to yiel d both high and low viscosity grade products. These MCCs were tested on Cac o-2 cells for their efficiency to decrease the transepithelial electrical r esistance (TEER) and to increase the paracellular permeability of the anion ic macromolecular anticoagulant low molecular weight heparin (LMWH). For in vivo studies, LMWH was administered intraduodenally with or without MCC to rats. Both types of experiments were performed at pH 7.4. Results show tha t both viscosity grade MCCs managed to significantly decrease the TEER of C aco-2 cell monolayers when they were applied apically at concentrations of 3-5% (w/v). Transport studies with Caco-2 cells revealed substantial increa ses of LMWH permeation in the presence of both viscosity grade MCCs compare d with controls. In rats, 3% (w/v) low viscosity MCC significantly increase d the intestinal absorption of LMWH, reaching the therapeutic anticoagulant blood levels of LMWH. Both in vitro and in vivo results indicate that the polyampholytic chitosan modification MCC is a suitable and functional polym er for the delivery and intestinal absorption of anionic macromolecular the rapeutics like LMWH. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceuti cal Association.