Modified mucoadhesive polymers for the peroral administration of mainly elastase degradable therapeutic (poly)peptides

A number of elastatinal-polymer conjugates, having the inhibitor linked to sodium carboxymethyl cellulose (Na-CMC), poly(acrylic acid) (PAA) and poly(acrylic acid-divinyl glycol) via a 1,8-diaminooctane spacer, were synthesized and their protective effect from enzymatic degradation caused by elastase as well as their mucoadhesive properties were evaluated. Unmodified polymers did not show any inhibitory effect under our enzyme assay conditions. However, 50 mu g of modified Na-CMC, PAA and poly(acrylic acid-divinyl glycol) inhibited the proteolytic activity of elastase (6 mu g/290 mu l 50 mM Tris-HCl, pH 7.8) at 20+/-0.5 degrees C up to 77%, 41% and 44.5%, respectively. Whereas 1 mg of elastatinal-Na-CMC conjugates, resulting from reaction mixtures with a weight ratio of inhibitor to polymer of 1:10, 1:5 and 1:1, exhibited a protective effect, which was equivalent to 2.8+/-0.8 up to 9.2+/-1.2 mu g of unbound inhibitor, corresponding conjugates of elastatinal with PAA and poly(acrylic acid-divinyl glycol) were in the range between 0.8+/-0.4-3.2+/-0.4 and 1.6+/-0.4-4.2+/-0.8 mu g (n=3; +/-S.D.), respectively. Moreover, the mucoadhesive force of the polymers was not influenced by the slight modification. According to these results, the novel mucoadhesive polymers shielding from luminal enzymatic attack may be a useful tool for the peroral administration of mainly elastase degradable therapeutic (poly)peptides.