Polycarbophil-cysteine conjugates as platforms for oral polypeptide delivery systems

The purpose of the present study was to evaluate the potential of polycarbo phil-cysteine conjugates as carrier systems for orally administered peptide and protein drugs. Mediated by a carbodiimide, cysteine was covalently att ached to polycarbophil. The properties of resulting conjugates, displaying 35-50 mu M thiol groups per gram of polymer, to bind polypeptides and to in hibit pancreatic proteases was evaluated in vitro. Results demonstrated tha t only some polypeptides are immobilized to the polycarbophil-cysteine conj ugate. Due to the covalent attachment of cysteine to polycarbophil, the inh ibitory effect of the polymer toward carboxypeptidase A (EC 3.4.17.1) and c arboxypeptidase B (EC 3.4.17.2) could be significantly (p < 0.05) improved. As the zinc binding affinity of polycarbophil could be improved by the cov alent attachment of cysteine, the raised inhibitory effect seems to be base d on the complexation of this divalent cation from the enzyme structure. Wh ereas the covalent attachment of cysteine on polycarbophil had no influence on the enzymatic activity of trypsin (EC 3.4.21.4) and elastase (ECL 3.4.2 1.36), the inhibitory effect of the polymer-cysteine conjugate toward chymo trypsin (EC 3.4.21.1) was significantly (p < 0.05) higher than that of the unmodified polymer. Because of these inhibitory features, polycarbophil-cys teine conjugates seem to be a promising tool in protecting orally administe red therapeutic polypeptides, which are not bound to the polymer, from pres ystemic metabolism in the intestine. (C) 2000 Liss-Wiley Inc. and the Ameri can Pharmaceutical Association.