pH SENSITIVE HYDROGELS WITH ADJUSTABLE SWELLING KINETICS FOR COLON-SPECIFIC DELIVERY OF PEPTIDES AND PROTEINS

摘要

A hydrogel polymeric system for the site specific delivery of peptide and protein drugs to the colon is prepared. The hydrogel protects the drug through the acid environment of the stomach, swells at a chemically controlled rate in the higher pH environment of the small intestine and is enzymatically degraded by azoreductases in the colon. pH sensitive hydrogels are formulated from monomers of N-substituted (meth)acrylamides, acrylic or methacrylic acid, a cross-linking agent containing an aromatic azo bond and an N,O-diacylhydroxylamine. Chemical control of swelling is attained by initially providing labile N,O-diacylhydroxylamine moieties in the hydrogel that are stable in the acidic medium of the stomach but that are susceptible to hydrolysis at the intestinal pH, i.e. above about pH 6.5. Upon hydrolysis, ionized -COOH groups attached to the polymer network are generated and swelling is maximized as the hydrogel reaches the colon where degradation occurs by the azoreductase cleavage of the aromatic azo cross-linking agent.