Macromolecular Prodrug of 4-Aminosalicylic Acid for Targeted Delivery to Inflamed Colon

Gaurav      Vadnerkar; Suneela      Dhaneshwar

Abstract

Sterically hindered esters or esters of drugs with macromolecular carriers like dextran and cyclodextrin find wide applicability in colon-targeted delivery. We report here synthesis, in vitro release kinetics of macromolecular prodrug of 4-aminosalicylic acid (4-ASA) with β-cyclodextrin and its extensive pharmacological evaluation in 2, 4, 6- trinitrobenzenesulphonic acid– induced colitis in rats. Formyl 4-ASA was conjugated with β-cyclodextrin by CDI coupling followed by deprotection of the final product which was then characterized by IR, 1H-NMR and LC-MS. In vitro stability and release were studied in buffers (pH 1.2 and 7.4), stomach/small intestinal homogenates and rat cecal/fecal matters. The prodrug resisted pH-dependent hydrolysis. In stomach and small intestinal homogenates 20-23% release was observed (t1/2: 1278 and 1103 min respectively) while 68% and 92% release was furnished in rat cecal and fecal matters (t1/2: 341 and 245 min respectively). Mitigating effect of 4-AβCyd on colitis was moderate when compared with sulfasalazine or 4/5-ASA administered rectally, but it was comparable to that of aminosalicylates administered orally, suggesting incomplete delivery of 4-ASA to colon due to partial hydrolysis of 4-AβCyd in the upper GIT. The histological assessment of pancreas and liver of the prodrug-treated group showed no pathological changes indicating its better safety profile than that of sulfasalazine or oral 5-ASA. The prodrug brought about significant lowering in ulcer index compared to aminosalicylates suggesting significant improvement in gastro-protective effect than oral aminosalicylates.

Keywords: 4-Aminosalicylic acid, 4-ASA, inflammatory bowel disease, colon-targeting, macromolecular prodrug, β- cyclodextrin