A Polymeric Drug for Treatment of Inflammatory Bowel Disease

Article abstract of DOI:10.1021/jm00363a015

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 acid (5-ASA) and sulfapyridine (SP).Recent reports indicate that 5-ASA is the active therapeutic moiety and that SP is responsible for a variety of adverse clinical side effects.Water-soluble polymer 7, which contains salicylate residues azo linked at the 5-position to an inert polymer backbone, has been synthesized for the side-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 approximately 1 μequiv of azo bond h^-1 (mL of cecal content)^-1.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 pigs 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.