POLYMERS FOR COLON-SPECIFIC DRUG DELIVERY

New types of synthetic water soluble polymeric systems for the treatment of colon disease are described. These systems are based on the concept of binding of polymeric carriers containing carbohydrate moieties complementary to colonic mucosal lectins and on the concept of site-specific release of drug (5-aminosalicylic acid) from the polymeric carrier by the degrading action of microbial enzymes present in the colon. New synthetic pathways have been developed for the synthesis of N-(2-hydroxypropyl)methacrylamide copolymers containing high amounts of both the bioadhesive moiety (fucosylamine) and 5-aminosalicylic acid. Fucosylamine containing copolymers bind to the colonic mucosa of guinea pigs. The higher the content of fucosylamine, the higher the binding. The binding can be inhibited by unbound fucose indicating the presence of specific lectin-like structures in the guinea pig colon. New biodegradable hydrogels containing both acidic comonomers and enzymatically degradable azoaromatic crosslinks were synthesized. These hydrogels are suitable for site-specific delivery of peptides (proteins) into the colon. In the low pH range of the stomach, the gels have a low equilibrium degree of swelling and the drug is protected against digestion by enzymes. The degree of swelling increases as the hydrogel passes down the gastrointestinal tract due to increased pH. In colon, the hydrogels have reached a degree of swelling that makes the crosslinks accessible to azoreductases and mediators. The rate of degradation depends on the structure of the hydrogels. Total dissolution in vivo can be achieved in less than 48 h. Brush border membrane and luminal enzymes were isolated from guinea pig small intestine and colon. Their enzymatic activity towards insulin and insulin B-chain was compared. It was shown that the extent of peptide degradation is substantially lower with colonic enzymes when compared to those isolated from the small intestine.