BIOADHESIVE POLYMERS FOR THE PERORAL DELIVERY OF PEPTIDE DRUGS

Two different classes of bioadhesive excipients which have been approved by the FDA, the anionic charged poly (acrylic acid) derivatives and the cationic charged chitosans, have been investigated with respect to 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 studies demonstrated that the two poly(acrylates) polycarbophil and Carbopol(R) 934P are able to inhibit the activity of the proteolytic enzyme trypsin at pH 6.7, which may lead to an increased stability of the peptide drug in the intestine. The depletion of Ca2+ out of the incubation medium due to the Ca2+ binding properties of the poly (acrylates) is discussed as a possible mechanism of action. Because of the observation that depletion of Ca2+ can additionally cause an opening of tight junctions, the influence of polycarbophil on the paracellular integrity of Caco-2 monolayers was also investigated by measurements of transepithelial electrical resistance (TEER) as well as by visualization studies using confocal laser scanning microscopy. At pH 4.0, apically applied polycarbophil tended to decrease TEER values stronger than the control 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 paracellular permeability of the hydrophilic model compound fluorescein-isothiocyanate-dextran (M(W) 4000) when applied to the basolateral side of the Caco-2 cell monolayer. In conclusion, bioadhesive polymers are promising absorption promoting agents for peroral delivery of peptide drugs, and their mechanism of action is probably a combination of inhibiting protease activities and modulating the intestinal epithelial permeability.