A polymeric drug for treatment of inflammatory bowel disease

Abstract

Sulfasalazine (SASP) consists of salicylic acid azo linked at the 5-position to a pyridine-containing sulfonamide. This drug, currently used in inflammatory bowel disease treatment, is reductively cleaved by anaerobic bacteria in the lower bowel to 5-aminosalicylic aid (5-ASA) and sulfapyridine (SP). 5-ASA is the active therapeutic moiety and SP is responsible for a variety of adverse clinical side effects. Water-soluble sodium salicylate polymer 7, which contains salicylate residues azo linked at the 5-position to an inert polymer backbone, was synthesized for the site-specific reductive release of 5-ASA in the lower bowel. Preparations of 7 deliver (chemical reduction) > 1.96 mmol of 5-ASA/g of polymer. In vitro studies with the polymer in anaerobic rat cecal bacteria demonstrated a reduction rate of .apprx. 1 .mu.equiv of azo bond/h per ml of cecal content. A pharmacokinetic comparison of polymer and SASP showed similar deliveries of 5-ASA and metabolites to the lower bowel, blood and urine of orally dosed rats. Polymer 7 proved more active than SASP or 5-ASA in the guinea pig ulcerative colitis model. Potential therapeutic advantages of 7 include nonabsorption/nonmetabolism in the small intestine, direct 5-ASA release at the disease site and nonabsorption/nonmetabolism of the reduction-released carrier polymer.