Mucoadhesive polymers in peroral peptide drug delivery: I. Influence of mucoadhesive excipients on the proteolytic activity of intestinal enzymes

In the present study the potency of mucoadhesive excipients to inhibit intestinal proteases has been evaluated. Among the different mucoadhesive polymers investigated, uniquely the poly(acrylates) polycarbophil and carbomer 934P were able to inhibit the activities of trypsin, α-chymotrypsin, carboxypeptidase A and cytosolic leucine aminopeptidase. However, they failed to inhibit microsomal leucine aminopeptidase and pyroglutamyl aminopeptidase. Carbomer was found to be more efficient to reduce proteolytic activity than polycarbophil. The pronounced binding properties of polycarbophil and carbomer for bivalent cations such as zinc and calcium was demonstrated to be a major reason for the observed inhibitory effect. These polymers were able to deprive Ca²⁺ and Zn²⁺, respectively, from the enzyme structures, thereby inactivating their activities. Carboxypeptidase A and α-chymotrypsin activities were observed to be reversible upon addition of Zn²⁺ and Ca²⁺ ions, respectively. It is concluded that poly(acrylates) may be promising excipients to protect peptide drugs from intestinal degradation. In combination with their low toxicity risk they are expected to be suitable excipients for improved peroral delivery of peptide drugs.