Chitosan and its derivatives: potential excipients for peroral peptide delivery systems

In the 1990s chitosan turned out to be a useful excipient in various pharmaceutical formulations. By modifications of the primary amino group at the 2-position of this poly(beta1-->4 D-glucosamine), the features of chitosan can even be optimised according to a given task in drug delivery systems. For peroral peptide delivery these tasks focus on overcoming the absorption (I) and enzymatic barrier (II) of the gut. On the one hand, even unmodified chitosan proved to display a permeation enhancing effect for peptide drugs. On the other hand, a protective effect for polymer embedded peptides towards degradation by intestinal peptidases can be achieved by the immobilisation of enzyme inhibitors on the polymer. Whereas serine proteases are inhibited by the covalent attachment of competitive inhibitors such as the Bowman-Birk inhibitor, metallo-peptidases are inhibited by chitosan derivatives displaying complexing properties such as chitosan-EDTA conjugates. In addition, because of the mucoadhesive properties of chitosan and most of its derivatives, a presystemic metabolism of peptides on the way between the dosage form and the absorption membrane can be strongly reduced. Based on these unique features, the co-administration of chitosan and its derivatives leads to a strongly improved bioavailability of many perorally given peptide drugs such as insulin, calcitonin and buserelin. These polymers are therefore useful excipients for the peroral administration of peptide drugs.