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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Conjugation of Mycophenolic Acid with Dextran: A Potential Strategy for Colon-Targeted Delivery for Mitigation of Inflamed Colon in Ulcerative Colitis

Author(s): Suneela Dhaneshwar* and Shakuntala Chopade

Volume 20, Issue 9, 2023

Published on: 19 August, 2022

Page: [1264 - 1273] Pages: 10

DOI: 10.2174/1570180819666220430004123

Price: $65

Abstract

Background: Adverse effects induced by upper GIT release of mycophenolic acid (MPA) and its prodrug mycophenolate mofetil (MMF) have created a great deal of concern in the treatment of inflammatory bowel disease (IBD).

Objective: The goal of this work was to create a polymer-based prodrug (MDS) by attaching MPA to dextran to enable colon-targeted drug delivery and, as a result, minimize the adverse effects of MPA and MMF.

Methods: MPA was conjugated with dextran via a bio-cleavable ester bond utilizing the EDCI coupling process. MDS was characterized by spectral analysis. The degree of substitution was estimated by complete hydrolysis of the conjugate in phosphate buffer (pH= 9.0). The prodrug was screened for gastrosparing potential using TNBS-induced colitis model in Wistar rats.

Results: Physicochemical parameters, such as degree of substitution (9.32 mg MPA/100mg of MDS), DSC study (Melting point: 194.3°C), and molecular weight (70307 Da) were determined. The significant mitigating effect of MDS on quantifying parameters of TNBS-induced colitis, i.e., disease activity score rate (0.72±0.35), colon to body weight ratio (0.024±0.003), MPO activity (36.9±0.67mU/100mg of tissue), ulcerogenic potential (2.85±0.08), and histopathological data showed that prodrug restored distorted colonic architecture to normal.

Conclusion: Hydrophilicity was improved, allowing for more effective transport of MPA to the colon. In TNBS-induced colitis, the prodrug was found 1.5 times more efficient than MPA at lowering quantifiable markers of colonic inflammation. Histopathology data showed that MDS might be developed as a potential approach for directing MPA to the colon for the treatment of IBD.

Keywords: Mycophenolic acid, mycophenolate mofetil, dextran, inflammatory bowel disease, colon targeted drug delivery, macromolecular prodrug.

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[1]
Prasad, S.B.; Aeri, V.Y. Approaches targeted drug delivery to colon. Int. J. Drug Del. Tech, 2013, 3(1), 8-11.
[http://dx.doi.org/10.13140/2.1.1909.0882]
[2]
Sousa, T.; Paterson, R.; Moore, V.; Carlsson, A.; Abrahamsson, B.; Basit, A.W. The gastrointestinal microbiota as a site for the biotransformation of drugs. Int. J. Pharm., 2008, 363(1-2), 1-25.
[http://dx.doi.org/10.1016/j.ijpharm.2008.07.009] [PMID: 18682282]
[3]
Schachta, E.; Gevaerta, A.; Kenawy, E.R.; Molly, K.; Verstraete, W.; Adriaensens, P.; Carleer, R.; Gelan, J. Polymers for colon specific drug delivery. J. Control. Release, 1996, 39(2-3), 327-338.
[http://dx.doi.org/10.1016/0168-3659(95)00184-0]
[4]
Dhaneshwar, S.S.; Vadnerkar, G. Rational design and development of colon-specific prodrugs. Curr. Top. Med. Chem., 2011, 11(18), 2318-2345.
[http://dx.doi.org/10.2174/156802611797183249] [PMID: 21671865]
[5]
Palaniappan, S.; Ford, A.C.; Greer, D.; Everett, S.M.; Chalmers, D.M.; Axon, A.T.; Hamlin, P.J. Mycophenolate mofetil therapy for refractory inflammatory bowel disease. Inflamm. Bowel Dis., 2007, 13(12), 1488-1492.
[http://dx.doi.org/10.1002/ibd.20258] [PMID: 17924566]
[6]
Tandon, B.N.; Mathur, A.K.; Mohapatra, L.N.; Tandon, H.D.; Wig, K.L. A study of the prevalence and clinical pattern of non-specific ulcerative colitis in northern India. Gut, 1965, 6(5), 448-453.
[http://dx.doi.org/10.1136/gut.6.5.448] [PMID: 5294834]
[7]
Khosla, S.N.; Girdhar, N.K.; Lal, S.; Mishra, D.S. Epidemiology of ulcerative colitis in hospital and select general population of northern India. J. Assoc. Physicians India, 1986, 34(6), 405-407.
[PMID: 3771475]
[8]
Sood, A.; Midha, V.; Sood, N.; Bhatia, A.S.; Avasthi, G. Incidence and prevalence of ulcerative colitis in Punjab, North India. Gut, 2003, 52(11), 1587-1590.
[http://dx.doi.org/10.1136/gut.52.11.1587] [PMID: 14570727]
[9]
Watts, R.W. Some regulatory and integrative aspects of purine nucleotide biosynthesis and its control: An overview. Adv. Enzyme Regul., 1983, 21, 33-51.
[http://dx.doi.org/10.1016/0065-2571(83)90007-9] [PMID: 6152730]
[10]
Halloran, P.; Mathew, T.; Tomlanovich, S.; Groth, C.; Hooftman, L.; Barker, C. The International Mycophenolate Mofetil Renal Transplant Study Groups. Mycophenolate mofetil in renal allograft recipients: A pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. Transplantation, 1997, 63(1), 39-47.
[http://dx.doi.org/10.1097/00007890-199701150-00008] [PMID: 9000658]
[11]
Arns, W. Noninfectious gastrointestinal (GI) complications of mycophenolic acid therapy: A consequence of local GI toxicity? In: In: Transplantation Proceedings; Elsevier; , 2007; 39, pp. (1)88-93.
[http://dx.doi.org/10.1016/j.transproceed.2006.10.189]
[12]
Pescovitz, M.D.; Conti, D.; Dunn, J.; Gonwa, T.; Halloran, P.; Sollinger, H.; Tomlanovich, S.; Weinstein, S.; Inokuchi, S.; Kiberd, B.; Kittur, D.; Merion, R.M.; Norman, D.; Shoker, A.; Wilburn, R.; Nicholls, A.J.; Arterburn, S.; Dumont, E. Intravenous mycophenolate mofetil: Safety, tolerability, and pharmacokinetics. Clin. Transplant., 2000, 14(3), 179-188.
[http://dx.doi.org/10.1034/j.1399-0012.2000.140301.x] [PMID: 10831074]
[13]
Lipsky, J.J. Mycophenolate mofetil. Lancet, 1996, 348(9038), 1357-1359.
[http://dx.doi.org/10.1016/S0140-6736(96)10310-X] [PMID: 8918281]
[14]
Cioli, V.; Putzolu, S.; Rossi, V.; Scorza Barcellona, P.; Corradino, C. The role of direct tissue contact in the production of gastrointestinal ulcers by anti-inflammatory drugs in rats. Toxicol. Appl. Pharmacol., 1979, 50(2), 283-289.
[http://dx.doi.org/10.1016/0041-008X(79)90153-4] [PMID: 505458]
[15]
Salvadori, M.; Holzer, H.; de Mattos, A.; Sollinger, H.; Arns, W.; Oppenheimer, F.; Maca, J.; Hall, M. ERL B301 Study Groups. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am. J. Transplant., 2004, 4(2), 231-236.
[http://dx.doi.org/10.1046/j.1600-6143.2003.00337.x] [PMID: 14974944]
[16]
Bjarnason, I. Enteric coating of mycophenolate sodium: A rational approach to limit topical gastrointestinal lesions and extend the therapeutic index of mycophenolate. Transplant. Proc., 2001, 33(7-8), 3238-3240.
[http://dx.doi.org/10.1016/S0041-1345(01)02377-6] [PMID: 11750388]
[17]
Zolezzi, M. Mycophenolate Sodium versus Mycophenolate Mofetil: A Review of Their Comparative Features. Saudi J. Kidney Dis. Transpl., 2005, 16(2), 140-145.
[PMID: 18202489]
[18]
Burg, M.; Säemann, M.D.; Wieser, C.; Kramer, S.; Fischer, W.; Lhotta, K. Enteric-coated mycophenolate sodium reduces gastrointestinal symptoms in renal transplant patients. Transplant. Proc., 2009, 41(10), 4159-4164.
[http://dx.doi.org/10.1016/j.transproceed.2009.08.078] [PMID: 20005359]
[19]
Faubion, W.A., Jr; Loftus, E.V., Jr; Harmsen, W.S.; Zinsmeister, A.R.; Sandborn, W.J. The natural history of corticosteroid therapy for inflammatory bowel disease: A population-based study. Gastroenterology, 2001, 121(2), 255-260.
[http://dx.doi.org/10.1053/gast.2001.26279] [PMID: 11487534]
[20]
Campbell, S.; Travis, S.; Jewell, D. Ciclosporin use in acute ulcerative colitis: A long-term experience. Eur. J. Gastroenterol. Hepatol., 2005, 17(1), 79-84.
[http://dx.doi.org/10.1097/00042737-200501000-00016] [PMID: 15647646]
[21]
Hafraoui, S.; Dewit, O.; Marteau, P.; Cosnes, J.; Colombel, J.F.; Modigliani, R.; Cortot, A.; Lémann, M. Mycophenolate mofetil in refractory Crohn’s disease after failure of treatments by azathioprine or methotrexate. Gastroenterol. Clin. Biol., 2002, 26(1), 17-22.
[PMID: 11938035]
[22]
Ford, A.C.; Towler, R.J.; Moayyedi, P.; Chalmers, D.M.; Axon, A.T. Mycophenolate mofetil in refractory inflammatory bowel disease. Aliment. Pharmacol. Ther., 2003, 17(11), 1365-1369.
[http://dx.doi.org/10.1046/j.1365-2036.2003.01581.x] [PMID: 12786630]
[23]
Hassard, P.V.; Vasiliauskas, E.A.; Kam, L.Y.; Targan, S.R.; Abreu, M.T. Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn’s disease. Inflamm. Bowel Dis., 2000, 6(1), 16-20.
[http://dx.doi.org/10.1097/00054725-200002000-00003] [PMID: 10701145]
[24]
Lakshmi Bhavani, A.; Nisha, J. Dextran-The polysaccharide with versatile uses. Int. J. Pharma Bio Sci., 2010, 1, 569-572.
[25]
Nordmeier, E. Static and dynamic light-scattering solution behaviour of and dextran in comparison. J. Phys. Chem., 1993, 97, 5770-5785.
[http://dx.doi.org/10.1021/j100123a050]
[26]
Granath, K.A. Solution properties of branched dextrans. J. Colloid Sci., 1958, 13, 308-310.
[http://dx.doi.org/10.1016/0095-8522(58)90041-2]
[27]
Senti, F.R. Viscosity, sedimentation, and light‐scattering properties of fraction of an acid‐hydrolyzed dextran. J. Polym. Sci., 1955, 17, 527.
[http://dx.doi.org/10.1002/pol.1955.120178605]
[28]
Jung, Y.J.; Lee, J.S.; Kim, Y.M. Synthesis and in vitro/in vivo evaluation of 5-aminosalicyl-glycine as a colon-specific prodrug of 5-aminosalicylic acid. J. Pharm. Sci., 2000, 89(5), 594-602.
[http://dx.doi.org/10.1002/(SICI)1520-6017(200005)89:5<594:AID-JPS5>3.0.CO;2-8] [PMID: 10756325]
[29]
Lee, S.H.; Bajracharya, R.; Min, J.Y.; Han, J.W.; Park, B.J.; Han, H.K. Strategic approaches for colon targeted drug delivery: An overview of recent advancements. Pharmaceutics, 2020, 12(68), 1-20.
[http://dx.doi.org/10.3390/pharmaceutics12010068]
[30]
Jung, Y.J.; Kim, H.H.; Kong, H.S.; Kim, Y.M. Synthesis and properties of 5-aminosalicyl-taurine as a colon-specific prodrug of 5-aminosalicylic acid. Arch. Pharm. Res., 2003, 26(4), 264-269.
[http://dx.doi.org/10.1007/BF02976953] [PMID: 12735682]
[31]
Kim, H.; Huh, J.; Jeon, H.; Choi, D.; Han, J.; Kim, Y.; Jung, Y.N. N′-Bis(5-aminosalicyl)-L-cystine is a potential colon-specific 5-aminosalicylic acid prodrug with dual therapeutic effects in experimental colitis. J. Pharm. Sci., 2009, 98(1), 159-168.
[http://dx.doi.org/10.1002/jps.21404] [PMID: 18399548]
[32]
Nagpal, D.; Singh, R.; Gairola, N.; Bodhankar, S.L.; Dhaneshwar, S.S. Mutual azo prodrug of 5-aminosalicylic acid for colon targeted drug delivery: Synthesis, kinetic studies and pharmacological evaluation. Indian J. Pharm. Sci., 2006, 68(2), 171-178.
[http://dx.doi.org/10.4103/0250-474X.25710]
[33]
Shrivastava, P.K.; Shrivastava, A.; Sinha, S.K.; Shrivastava, S.K. Dextran carrier macromolecules for colon-specific delivery of 5-aminosalicylic acid. Indian J. Pharm. Sci., 2013, 75(3), 277-283.
[http://dx.doi.org/10.4103/0250-474X.117420] [PMID: 24082343]
[34]
Kim, W.; Yang, Y.; Kim, D.; Jeong, S.; Yoo, J.W.; Yoon, J.H.; Jung, Y. Conjugation of metronidazole with dextran: A potential pharmaceutical strategy to control colonic distribution of the anti-amebic drug susceptible to metabolism by colonic microbes. Drug Des. Devel. Ther., 2017, 11, 419-429.
[http://dx.doi.org/10.2147/DDDT.S129922] [PMID: 28243064]
[35]
Pugazhendhy, S.; Shrivastava, P.K.; Sinha, S.K.; Shrivastava, S.K. Lamaotrigine-dextran conjugates: Synthesis, characterization and biological evaluation. Med. Chem. Res., 2011, 20, 595-600.
[http://dx.doi.org/10.1007/s00044-010-9355-9]
[36]
Shrivastava, P.K.; Praveen, B.; Shrivastava, S.K. In vitro Release and pharmacological study of synthesized valproic acid-dextran conjugate. Acta Pharm Sci., 2009, 51, 169-176.
[37]
Shrivastava, P.K.; Shrivastava, S.K. Dextran carrier macromolecule for colon specific delivery of celecoxib. Curr. Drug Deliv., 2010, 7(2), 144-151.
[http://dx.doi.org/10.2174/156720110791011828] [PMID: 20158488]
[38]
Shrivastava, P.K.; Singh, R.; Shrivastava, S.K. Polyamido amine dendrimer and dextran conjugate: Preparation, characterization and in vitro-in vivo evaluation. Chem. Pap., 2010, 64, 592-601.
[http://dx.doi.org/10.2478/s11696-010-0042-6]
[39]
Iwaszkiewicz-Grzes, D.; Cholewinski, G.; Kot-Wasik, A.; Trzonkowski, P.; Dzierzbicka, K. Synthesis and biological activity of mycophenolic acid-amino acid derivatives. Eur. J. Med. Chem., 2013, 69, 863-871.
[http://dx.doi.org/10.1016/j.ejmech.2013.09.026] [PMID: 24121309]
[40]
Rasheed, A.; Aishwarya, K.; Basha, N.B.; Reddy, S.B.; Swetha, A. Dexibuprofen-dextran macromolecular prodrugs: Synthesis, characterization and pharmacological evaluation. Der Pharma Chemica, 2009, 1(2), 124-132.
[41]
Yamada, Y.; Marshall, S.; Specian, R.D.; Grisham, M.B. A comparative analysis of two models of colitis in rats. Gastroenterology, 1992, 102(5), 1524-1534.
[http://dx.doi.org/10.1016/0016-5085(92)91710-L] [PMID: 1314749]
[42]
Hartmann, G.; Bidlingmaier, C.; Siegmund, B.; Albrich, S.; Schulze, J.; Tschoep, K.; Eigler, A.; Lehr, H.A.; Endres, S. Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice. J. Pharmacol. Exp. Ther., 2000, 292(1), 22-30.
[PMID: 10604928]
[43]
Krawisz, J.E.; Sharon, P.; Stenson, W.F. Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology, 1984, 87(6), 1344-1350.
[http://dx.doi.org/10.1016/0016-5085(84)90202-6] [PMID: 6092199]
[44]
Arnhold, J.; Furtmüller, P.G.; Regelsberger, G.; Obinger, C. Redox properties of the couple compound I/native enzyme of myeloperoxidase and eosinophil peroxidase. Eur. J. Biochem., 2001, 268(19), 5142-5148.
[http://dx.doi.org/10.1046/j.0014-2956.2001.02449.x] [PMID: 11589706]
[45]
Kutter, D. Prevalence of myeloperoxidase deficiency: Population studies using Bayer-Technicon automated hematology. J. Mol. Med. (Berl.), 1998, 76(10), 669-675.
[http://dx.doi.org/10.1007/s001090050266] [PMID: 9766844]

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