Macromolecular prodrug of 4-aminosalicylic acid for targeted delivery to inflamed colon.
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.
Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune-411 038, Maharashtra, India.
Gaurav
G
Vadnerkar
Suneela
S
Dhaneshwar
D020003:1-Octanol / Q000737:chemistry; D010131:Aminosalicylic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004355:Drug Stability; D005243:Feces / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D014302:Trinitrobenzenesulfonic Acid; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry
D000893:Anti-Inflammatory Agents; D011355:Prodrugs; D047392:beta-Cyclodextrins; D014867:Water; D010131:Aminosalicylic Acid; D014302:Trinitrobenzenesulfonic Acid; C031215:betadex; D020003:1-Octanol