Synthesis, development and in vitro evaluation of drug delivery systems with protective effect against degradation by pepsin

A (poly)peptide drug delivery system providing a protective effect against degradation by pepsin has been generated. A simplified pepstatin analogue w as thereby synthesised displaying a terminally located primary amino group allowing an easy covalent attachment to anionogenic mucoadhesive polymers b y the formation of amide bonds. The IC50 of this novel inhibitor was determ ined to be 6.65 +/- 1.05 x 10(-6) M. Mediated by a carbodiimide it was cova lently bound to polycarbophil and sodium carboxymethyl cellulose (NaCMC). I n contrast to polycarbophil-inhibitor conjugates, NaCMC-inhibitor conjugate s 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 ac cording to the Pharmacopoeia Europea. Following analysis demonstrated that 50.8 +/- 8.6% (mean +/- SD; n = 3) of insulin were degraded within the swol len carrier matrix, whereas insulin was completely metabolised in tablets w ithout the NaCMC-pepsin inhibitor conjugate. This protective effect against degradation by pepsin might make such dosage forms useful tools for a targ eted (poly)peptide delivery to the stomach.