Studies On Polysaccharide Prodrugs Of 5-Aminosalicylic Acid As Potential Colon-Specific Delivery Systems

Oral colon-specific delivery system is naturally of value for the topical treatment of diseases of colon such as ulcerative colitis, Crohn's disease, or colorectal cancer, whereby high local concentration can be achieved while minimizing side effects. 5-aminosalicylic acid (5-ASA) is an active ingredient of agents used for the long-term maintenance therapy to prevent relapses of Crohn's disease and ulcerative colitis. However, when 5-ASA is administrated orally, a large amount of the drug is absorbed from the upper gastrointestinal tract (GIT), and causes systemic side effects.Polymeric prodrugs of 5-ASA have not been used in clinic. Natural polysaccharides have been used as tools to deliver the drugs especially to the colon. These polysaccharides remain intact in the physiological environment of stomach and small intestine but once the dosage form enters into the colon, it is acted upon by polysaccharidases, which releases the drug into colon.Three polysaccharide cyclodextrin(CyD), chitosan (ChT) and Hydroxyl propyl cellulose(HPC) were selected. We prepared several series polysaccharide prodrugs of 5-ASA toexamine the effect of solubility of prodrugs on the release characteristics of 5-ASA in thegastrointestinal contents of rats.Amino group of 5-ASA was protected by formylation, which proceeded easily in formic acid in good yield. Imidazolide of 5-fASA was prepared with excess of carbonyldimidazole (CDI), which reacted with CyD, HPC or chitosan in the presence of TEA as catalyst to form the prodrug.The results showed that the properties of conjugates were apparently different from the signal of ether CyD or 5-ASA, and having the characteristic signal of the portion of CyD and the portion of 5-ASA.It was noted that no free 5-ASA was detected regardless the value of degree substitution,...