Chemically modified chitosans as enzyme inhibitors

Because of its permeation enhancing effect (I), mucoadhesive properties (II) and the capability to provide a controlled release of incorporated drugs (III), chitosan represents an advantageous excipient in non-invasive peptide delivery. The use of chitosan for such delivery systems, however, is limited by the lack of inhibitory properties towards secreted and membrane bound enzymes. Due to the covalent attachment of enzyme inhibitors and/or complexing agents at the 2-position of this poly(beta1-4-D-glucosamine), chitosans can be transformed into polymers that exhibit inhibitory properties. The immobilization of inhibitors such as antipain, chymostatin, elastatinal and Bowman-Birk inhibitor provide a protective effect towards pancreatic serine proteases, whereas covalently attached complexing agents such as EDTA guarantee the inactivation of membrane bound Zn-dependent peptidases as well as carboxypeptidase A and B. As the inhibition of these enzymes strongly improves the bioavailability of non-invasively administered peptide drugs, chemically modified chitosans represent promising auxiliary polymers. (C) 2001 Elsevier Science B.V. All rights reserved.