SYNTHESIS AND EVALUATION OF A MODIFIED MUCOADHESIVE POLYMER PROTECTING FROM ALPHA-CHYMOTRYPSINIC DEGRADATION

A number of chymostatin-poly(acrylic acid) conjugates, having the inhi bitor linked via a 1,8-diaminooctane spacer, and a Bowman-Birk inhibit or (BBI)-poly(acrylic acid) conjugate were synthesised and their prote ctive effect from enzymatic degradation caused by alpha-chymotrypsin a s well as their mucoadhesive properties were evaluated. Whereas unmodi fied neutralised poly(acrylic acid) did not show any inhibitory effect under our enzyme assay conditions, 1 mg of the chymostatin-polymer co njugate exhibiting the highest protective effect was capable of inhibi ting the proteolytic activity of 4 +/- 0.7 U (BTEE) of alpha-chymotryp sin by 50% (n = 3; +/- S.D.). This inhibitory effect was equivalent to 4.6 mu g +/- 0.6 mu g (n = 4; +/- S.D.) of unbound chymostatin which was added to the unmodified neutralised polymer in the same assay. Alt hough the protective effect of the BBI-poly(acrylic acid) conjugate wa s even 17% higher, its mucoadhesive strength was 35.2% lower than the unmodified polymer. However, the mucoadhesive force of the chymostatin -poly(acrylic acid) conjugate exhibiting the highest protective effect was not influenced by the ligand. According to these results, the nov el mucoadhesive chymostatin-poly(acrylic acid) conjugate protecting in serted therapeutic agents from alpha-chymotrypsinic degradation may be a useful tool for the peroral peptide and protein administration. (C) 1997 Elsevier Science B.V.