Novel bioadhesive drug delivery system protecting (poly)peptides from gastric enzymatic degradation

We have been developing a new generation of a drug delivery system based on the covalent attachment of a pepsin inhibitor (pepstatin A) to a bioadhesive carrier matrix. This approach involves covalent coupling of pepstatin to sodium carboxymethyl cellulose with the use of an appropriate spacer (1,8-diaminooctane). The protective effect of this novel matrix system was quantified by an enzyme assay, determining the degree of pepsinic degradation of inserted horseradish peroxidase. The result demonstrated a reduction of only 18.5 +/- 4% (mean of three experiments; +/- S.D.) of enzyme activity after 8 h of incubation with 0.05 N HCl containing 1.25 mg of pepsin per mi. Substitution of the conjugate with sodium carboxymethyl cellulose led to a 83 +/- 15% (mean of three experiments; +/- S.D.) loss of enzyme activity with the same approach. Inhibition of pepsinic degradation of inserted (poly)peptides could also be demonstrated by SDS-Page analysis. The pepstatin-matrix conjugate formed the basis for the development of a bioadhesive drug delivery system providing a controlled release of incorporated peptide drugs. Epidermal growth factor is a potent candidate for our system, which, when perorally administered, should maximize therapy in the treatment of gastric ulcers.