A (poly)peptide drug delivery system providing a protective effect against degradation by pepsin has been generated. A simplified pepstatin analogue was thereby synthesised displaying a terminally located primary amino group allowing an easy covalent attachment to anionogenic mucoadhesive polymers by the formation of amide bonds. The IC50 of this novel inhibitor was determined to be 6.65+/-1.05x10(-6) M. Mediated by a carbodiimide it was covalently bound to polycarbophil and sodium carboxy-methyl cellulose (NaCMC). In contrast to polycarbophil-inhibitor conjugates, NaCMC-inhibitor conjugates displayed a high inhibitory effect towards pepsin. The protective effect of tablets containing a NaCMC-pepsin inhibitor conjugate (10%), NaCMC (56.7%), insulin (3.3%), and mannitol (30%) was evaluated in vitro. Tablets were therefore incubated for 2 h at 37 degrees C with simulated gastric fluid according to the Pharmacopoeia Europea. Following analysis demonstrated that 50.8+/-8.6% (mean +/- SD; n = 3) of insulin were degraded within the swollen carrier matrix, whereas insulin was completely metabolised in tablets without the NaCMC-pepsin inhibitor conjugate. This protective effect against degradation by pepsin might make such dosage forms useful tools for a targeted (poly)peptide delivery to the stomach.