Synthesis of a novel PEGylated colon-specific azo-based 4- aminosalicylic acid prodrug

Document Type : Original Article

Authors

1 Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Food Science and Technology, Ferdowsi University of Mashhad, Mashhad, Iran

4 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

5 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): 4-aminosalicylic acid (4-ASA) is an isomer of mesalazine that has recently been shown to be effective against inflammatory bowel disease (IBD), and more specifically, ulcerative colitis. However, the majority of orally administered 4-ASA is readily and extensively absorbed from the stomach and small intestine, so only a small amount is transported to the colon. A mutual ester and azo prodrug of 4-ASA was synthesized with polyethylene glycol (PEG) and dimethylaniline, respectively , to overcome this issue.
Materials and Methods: The 4-ASA prodrug was synthesized via a two-step process and then characterized by 1H-NMR. The stability of the prodrug was evaluated in simulated gastric fluid (pH 1.2). Furthermore, the in vitro release profiles of the drug conjugate was evaluated at pH 1.2, as well as pH 6.8 in the absence or presence of rat cecal content.
Results: The prepared prodrug was stable at pH 1.2, indicating that it could be protected from the acidic environment of the stomach. Also, the results of drug release at pH 6.8 showed that the amount of 4-ASA released was 63% within 12 hr in the absence of rat cecal content, while in the presence of rat cecal content, 97% of 4-ASA was released from the prodrug in 6 hr.
Conclusion: Overall, the synthesized PEGylated azo-based 4-ASA prodrug could be a potential candidate for targeted drug delivery to the inflamed gut tissue in IBD.

Keywords

References

1. Mura C, Valenti D, Floris C, Sanna R, De Luca MA, Fadda AM, et al. Metronidazole prodrugs: Synthesis, physicochemical properties, stability, and ex vivo release studies. Eur J Med Chem 2011;46:4142–4150.
2. Sharma R, Rawal RK, Malhotra M, Sharma AK, Bhardwaj TR. Design, synthesis and ex-vivo release studies of colon-specific polyphosphazene–anticancer drug conjugates. Bioorg Med Chem 2014;22:1104–1114.
3. Heylen M, E.Ruyssers N, M.Gielis E, Vanhomwegen E, A.Pelckmans P, G.Moreels T, et al. Of worms, mice and man: An overview of experimental and clinical helminth-based therapy for inflammatory bowel disease. Pharmacol Ther 2014;143:153–167.
4. Klotz U, Schwab M. Topical delivery of therapeutic agents in the treatment of inflammatory bowel disease. Adv Drug Deliv Rev 2005;57:267–279.
5. Jung Y, Kim H, Kim H, Kong H, Choi B, Yang Y, et al. Evaluation of 5-aminosalicyltaurine as a colon-specific prodrug of 5-aminosalicylic acid for treatment of experimental colitis. Eur J Pharm Sci 2006;28:26–33.
6. Vadnerkar G, Dhaneshwar S. Macromolecular prodrug of 4-aminosalicylic acid for targeted delivery to inflamed colon. Curr Drug Discov Technol 2013;10:16–24.
7. Friend DR. New oral delivery systems for treatment of inflammatory bowel disease. Adv Drug Deliv Rev 2005;57:247–265.
8. Kandice L.Knigge. Inflammatory bowel disease. Clin Cornerstone 2002;4:49–57.
9. Abdei-alim AM, El-shorbagi AA, Abdei-moty SG, Abdei-allah HHM. Synthesis and Anti-Inflammatory Testing of Some New Compounds Incorporating 5-Aminosalicylic Acid (5-ASA) as Potential Prodrugs. Arch Pharm Res 2005;28:637–638.
10. Cestari SH, Bastos JK, Di Stasi LC. Intestinal anti-inflammatory activity of baccharis dracunculifolia in the trinitrobenzenesulphonic acid model of rat colitis. Evidence-based Complement Altern Med 2011;2011:1-9.
11. Deore V, Yewalkar N, Bhatia D, Desai N, Gupte RD, Dadarkar SS, et al. Synthesis and therapeutic evaluation of pyridyl based novel mTOR inhibitors. Bioorganic Med Chem Lett 2009;19:2949–2952.
12. Tuleu C, Basit AW, Waddington WA, Ell PJ, Newton JM. Colonic delivery of 4-aminosalicylic acid using amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsules. Aliment Pharmacol Ther 2002;16:1771–1779.
13. McConnell EL, Liu F, Basit AW. Colonic treatments and targets: issues and opportunities. J Drug Target. 2009;17:335–363.
14. Dhaneshwar S, Vadnerkar G. Rational Design and Development of Colon-Specific Prodrugs. Curr Top Med Chem 2011;11:2318–2345.
15.    Dhaneshwar SS. Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease. World J Gastroenterol 2014;20:3564–3571.
16. Goyanes A, Buanz ABM, Hatton GB, Gaisford S, Basit AW. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur J Pharm Biopharm 2015;89:157–162.
17. Dhaneshwar SS, Chail M, Patil M, Naqvi S, Vadnerkar G. Colon-specific mutual amide prodrugs of 4-aminosalicylic acid for their mitigating effect on experimental colitis in rats. Eur J Med Chem 2009;44:131–142.
18. Daniel F, Seksik P, Cacheux W, Jian R, Marteau P. Tolerance of 4-aminosalicylic acid enemas in patients with inflammatory bowel disease and 5-aminosalicylic-induced acute pancreatitis. Inflamm Bowel Dis 2004;10:258–260.
19.     Schreiber S, Howaldt S, Raedler A. Oral 4-Aminosalicylic acid versus 5-Aminosalicylic acid slow release tablets. Double blind, controlled pilot study in the maintenance treatment of Crohn’s ileocolitis. Gut 1994;35:1081–1085.
20. Karrout Y, Neut C, Wils D, Siepmann F, Deremaux L, Flament MP, et al. Novel polymeric film coatings for colon targeting: Drug release from coated pellets. Eur J Pharm Sci 2009;37:427–433.
21.  Rajguru V V., Gaikwad PD, Bankar VH, Pawar SP. An overview on colonic drug delivery system. Int J Pharm Sci Rev Res 2011;6:197–204.
22.  Sinha VR, Kumria R. Polysaccharides in colon-specific drug delivery. Int J Pharm 2001;224:19–38.
23. Dai XP, Yu CC, Shen SK. Biodegradable polyphosphazenes for drug delivery applications. Adv Drug Deliv Rev 2003;55:467–482.
24. 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;12:24–30.
25. Bertram GK, Katzung BG. Basic and Clinical Pharmacology. Int Ed 2006.
26. Sousa T, Yadav V, Zann V, Borde A, Abrahamsson B, Basit AW. On the colonic bacterial metabolism of Azo-bonded prodrugs of 5-aminosalicylic acid. J Pharm Sci 2014;103:3171–3175.
27. Cesar ALA, Abrantes FA, Farah L, Castilho RO, Cardoso V, Fernandes SO, et al. New mesalamine polymeric conjugate for controlled release: Preparation, characterization and biodistribution study. Eur J Pharm Sci 2018;111:57–64.
28. Hartzell AL, Maldonado-Gómez MX, Yang J, Hutkins RW, Rose DJ. In vitro digestion and fermentation of 5-formyl-aminosailcylate-inulin: A potential prodrug of 5-aminosalicylic acid. Bioact Carbohydrates Diet Fibre 2013;2:8–14.
29. Trombino S, Cassano R, Cilea A, Ferrarelli T, Muzzalupo R, Picci N. Synthesis of pro-prodrugs l-lysine based for 5-aminosalicylic acid and 6-mercaptopurine colon specific release. Int J Pharm 2011;420:290–296.
30. Mahkam M. Novel pH-sensitive hydrogels for colon-specific drug delivery. Drug Deliv 2010;17:158–163.
31. Kim H, Kim D, Choi D, Jeon H, Han J, Jung Y, et al. Synthesis and Properties of N,N ′-Bis(5-Aminosalicyl)-L-Cystine as a Colon-Specific Deliverer of 5-Aminosalicylic Acid and Cystine. Drug Deliv 2008;15:37–42.
32. Zou M, Cheng G, Okamoto H, Hao X-HH, An F, Cui F-D De, et al. Colon-specific drug delivery systems based on cyclodextrin prodrugs: In vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates. World J Gastroenterol [Internet] 2005;11:7457–7460.
33. Wiwattanapatapee R, Lomlim L, Saramunee K. Dendrimers conjugates for colonic delivery of 5-aminosalicylic acid. J Control Release 2003;88:1–9.
34. Li F, Wu G, Zheng H, Wang L, Zhao Z. Synthesis, colon-targeted studies and pharmacological evaluation of an anti-ulcerative colitis drug 4-Aminosalicylic acid-β-O-glucoside. Eur J Med Chem 2016;108:486–494.
35. Suneela D, Gaurav V, Samuel S. Azo reductase- activated colon- targeting prodrugs of aminosalicylates for inflammatory bowel disease: preparation, pharmacokinetic and pharmacodynamic profile. Inflamm Allergy Drug Targets 2013;12:419–432.
36. Suneela D, Gaurav V, Himanshu R. Design and development of novel azo prodrugs using various permutations and combinations of 5- and 4-aminosalicylic acids for inflammatory bowel disease: a colon-targeted approach. Inflamm Allergy Drug Targets 2013;12:328–340.
37.  Jilani J, Shomaf M, Alzoubi KH, Press D. Synthesis and evaluation of mutual azo prodrug of 5-aminosalicylic acid linked to 2-phenylbenzoxazole-2-yl-5-acetic acid in ulcerative colitis. Drug Des Devel Ther 2013;7:691–698.
38.   Yan Y, Ren F, Wang P, Sun Y, Xing J. Synthesis and evaluation of a prodrug of 5-aminosalicylic acid for the treatment of ulcerative colitis. Iran J Basic Med Sci. 2019; 22:1452–61.
39. Jilani J, Shomaf M, Alzoubi KH, Press D. Synthesis and evaluation of mutual azo prodrug of 5-aminosalicylic acid linked to 2-phenylbenzoxazole-2-yl-5-acetic acid in ulcerative colitis. Drug Des Devel Ther. 2013; 7:691–698.
Iranian Journal of Basic Medical Sciences
Volume 23, Issue 6
June 2020
Pages 781-787

Files

Share

How to cite

Statistics