SYNTHESIS AND CHARACTERIZATION OF AZO CONJUGATES OF FENOPROFEN FOR TREATMENT OF INFLAMMATORY BOWEL DISEASE THROUGH COLON TARGETING
Objective: The objective of this research was to synthesize azo conjugates of fenoprofen (FP) for treatment of inflammatory bowel disease through colon targeting.
Methods: Six prodrugs of FP were synthesized by diazotisation with ethyl esters of amino acids, namely, glycine, tyrosine L-phenylalanine, L-tryptophan, L-valine, L-alanine, amino acid. Methyl ester hydrochloride prepared by thionyl chloride, methanol and amino acids, followed by diazotization and then Coupling of diazotized amino acid methyl ester with fenoprofen. Six azo prodrug of fenoprofen was synthesized by using amino acid. Further, the synthesized prodrugs were characterized by TLC, IR, NMR spectroscopic analysis and subjected to in vitro drug release, TNBS induced ulcerative colitis and ulcerogenic index.
Results: All synthesized prodrugs showed excellent pharmacological response and targeting to colon. The FTIR and NMR study confirmed the structure of all azo linkage prodrugs. In vitro drug release studies revealed that FP was not release in gastric fluid. 12-15% drug were released in intestinal fluid and 65-85% drug was released in the colon because of azo reductases enzyme, secreted by colonic microflora. The azo prodrugs proved their potential in reducing the inflammation proved by the histopathology of the resected colon from every group of animals.
Conclusion: The results obtained in this research work clearly indicated a promising potential for treatment of inflammatory bowel disease through colon targeting for the effective treatment of IBD.Keywords: Fenoprofen, Prodrugs, Azo conjugates, Pharmacokinetics, Pharmacodyanamics.
2. Manjula D, Shabaraya AR, Somashekar S, Josephine LJ. Preparation and evaluation of monolithic transdermal therapeutic systems containing fenoprofen for the treatment of arthritis. Int J Pharm Sci Rev Res 2012;13:61.
3. Zovko M, Barbari M, Zorc B, Hafner A, Filipovi J. Synthesis of fenoprofen and gemfibrozil styrene-maleic acid copolymer conjugates. Acta Pharm 2005;55:169-76.
4. Alfonso RG. Remington: The science and practice of pharmacy. 19th Ed. Pennsylvaia: Mac publishing Company; 1985.
5. Garjani A, Davaran S, Rashidi M, Maleki N. Protective effects of some azo derivatives of 5-aminosalicylic acid and their pegylated Prodrugs on acetic acid-induced rat colitis. DARU 2004;12:1.
6. Peppercorn MA, Goldman P. The role of intestinal bacteria in the mechanism of Salicyl azo sulfapyridine. J Pharmacol Exp Ther 1972;181:555â€“62.
7. Jarnerol G. Newer 5-amino salicylic acid based drugs in chronic inflammatory bowel disease. Drugs 1989;37:73-86.
8. Klein A, Eliakim R. Non steroidal anti-inflammatory drugs and inflammatory bowel disease. Pharmaceuticals 2010;3:1084-92.
9. Jonkers D, StockbrÃ¼gger R. Probiotics and inflammatory bowel disease. J Soc Med 2003;96:167â€“71.
10. Dhaneshwar SS. Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease. World J Gastroenterol 2014;20:3564â€“71.
11. Rooseboom M, Commandeur JN, Vermeulen NP. Enzyme-catalyzed activation of anticancer prodrugs. Pharmacol Rev 2004;56:53.
12. Muzumdar N, Garg G, Mishra K, Singh A. Synthesis and evaluation of amino acid prodrug of naproxen. Int J Pharm Res Scholars 2014;3:678-83.
13. Makhlof A, Tozuka Y, Takeuchi H. pH-Sensitive nanospheres for colon-specific drug delivery in experimentally induced colitis rat model. Eur J Pharm Biopharm 2009;72:1-8.
14. Witaicenis A, Luchini AC, Hiruma-Lima CA, Felisbino SL, Garrido-Mesa N, Utrilla P, et al. Suppression of TNBS-induced colitis in rats by 4-methylesculetin, a natural coumarin: comparison with prednisolone and sulphasalazine. Chem Biol Interact 2012;195:76-85.
15. Rainsford KD. The comparative gastric ulcerogenic activities of non-steroid anti-inflammatory drugs. Inflammation Res 1977;7:573-7.