BIOADHESIVE POLYMERS FOR THE PERORAL DELIVERY OF PEPTIDE DRUGS

Two different classes of bioadhesive excipients which have been approv ed by the FDA, the anionic charged poly (acrylic acid) derivatives and the cationic charged chitosans, have been investigated with respect t o their ability to improve intestinal peptide drug absorption. It was found that both polycarbophil and the chitosan derivatives Daichitosan (R) VH and chitosan-glutamate (SeaCure(R) +210) enhance the absorption of the peptide drug 9-desglycinamide, 8-arginine vasopressin (DGAVP) in the vertically perfused intestinal loop model of the rat. Recent st udies demonstrated that the two poly(acrylates) polycarbophil and Carb opol(R) 934P are able to inhibit the activity of the proteolytic enzym e trypsin at pH 6.7, which may lead to an increased stability of the p eptide drug in the intestine. The depletion of Ca2+ out of the incubat ion medium due to the Ca2+ binding properties of the poly (acrylates) is discussed as a possible mechanism of action. Because of the observa tion that depletion of Ca2+ can additionally cause an opening of tight junctions, the influence of polycarbophil on the paracellular integri ty of Caco-2 monolayers was also investigated by measurements of trans epithelial electrical resistance (TEER) as well as by visualization st udies using confocal laser scanning microscopy. At pH 4.0, apically ap plied polycarbophil tended to decrease TEER values stronger than the c ontrol solution, whereas at pH 7.0 no pronounced changes of TEER could be observed. At pH 7.4, polycarbophil was only able to increase the p aracellular permeability of the hydrophilic model compound fluorescein -isothiocyanate-dextran (M(W) 4000) when applied to the basolateral si de of the Caco-2 cell monolayer. In conclusion, bioadhesive polymers a re promising absorption promoting agents for peroral delivery of pepti de drugs, and their mechanism of action is probably a combination of i nhibiting protease activities and modulating the intestinal epithelial permeability.