MUCOADHESIVE POLYMERS IN PERORAL PEPTIDE DRUG-DELIVERY .4. POLYCARBOPHIL AND CHITOSAN ARE POTENT ENHANCERS OF PEPTIDE-TRANSPORT ACROSS INTESTINAL MUCOSAE IN-VITRO

The purpose of the study was to evaluate the inhibitory effect of the mucoadhesive polymers polycarbophil, chitosan and chitosan glutamate o n trypsin and carboxypeptidase B (CPB) activity as well as their poten tial to improve the intestinal transport of the peptide drug 9-desglyc inamide, 8-L-arginine vasopressin (DGAVP) in vitro. The degradation of the model substrates N-alpha-benzoyl-L-arginine ethylester by trypsin and hippuryl-L-arginine by CPB in the presence of the polymers was st udied. Furthermore, the effect of the polymers on intestinal DGAVP tra nsport was investigated using Caco-2 cell monolayers and the rat verti cally perfused intestinal loop model. Uniquely, polycarbophil in a con centration of 1% (w/v) was able to inhibit both trypsin and CPB activi ties. Chitosan glutamate in concentrations of 0.4 and 1% (w/v) strongl y increased the transport of DGAVP across Caco-2 cell monolayers, wher eas 1% (w/v) polycarbophil showed only low transport enhancement. All polymers in concentrations of 1% (w/v), however, showed a pronounced a nd comparable improvement of DGAVP transport across intestinal mucosae in the vertically perfused loop model. It is concluded that the chito sans enhance the transport of DGAVP solely by increasing the paracellu lar permeability due to opening of intercellular junctions. The observ ed comparable transport effect of polycarbophil in the intestinal loop model is mainly ascribed to protection of DGAVP against proteolytic d egradation in the intestinal lumen, which allows for sufficient concen tration and thus transport of the peptide drug when polycarbophil indu ced paracellular transport is less enhanced.