Development and in vitro evaluation of a drug delivery system protecting from trypsinic degradation

We have been developing a delivery system based on a novel polymer conjugate protecting perorally administered (poly)peptide drugs from trypsinic degradation. The trypsin inhibitor antipain was, therefore, covalently attached to the mucoadhesive polymer chitosan. The protective effect of resulting chitosan-antipain conjugates was quantified by an enzyme assay. In contrast to the unmodified polymer, chitosan-antipain conjugates exhibited a significant inhibitory effect towards enzymatic activity of trypsin (EC 3.4.21.4). Moreover, the mucoadhesive force of chitosan was not influenced by the slight modification. Based on a chitosan-antipain conjugate, a drug delivery system was generated using insulin as model drug. Tablets containing 5% polymer conjugate demonstrated after incubation with trypsin (180 spectrophotometric BAEE units/ml) for 1.5 h in lateral parts of the swelled dosage form a 13.3 +/- 2.3% (mean +/- S.D., n = 3) minor proteolysis of matrix embedded insulin compared to tablets lacking the polymer conjugate. In the inner part of the swelled dosage form containing the conjugate proteolysis was completely inhibited, whereas in control tablets 11.3 +/- 9.5% (mean +/- S.D., n = 3) insulin was degraded. Furthermore, a controlled drug release over a period of 6 h was guaranteed by the delivery system. According to these results, the novel chitosan-antipain conjugates shielding from luminal enzymatic attack may be a useful tool for the peroral administration of mainly trypsinic degraded peptide and protein drugs. (C) 1997 Elsevier Science B.V.