Current Mesalazine Products: Differences in Enteric-Coated Dosage Forms and Pharmaceutical Risks of Clinical Efficacy Reduction (Review)

INTRODUCTION. Oral mesalazine (5-aminosalicylic acid) products are commonly used to treat inflammatory bowel disease, in particular,  ulcerative  colitis.  The  clinical  efficacy  of  these  medicinal  products  depends  directly on the composition and properties of the polymers used to deliver mesalazine to the affected areas of the colon. However, the information that has been accumulated to date suggests that the release of mesalazine from enteric-coated dosage forms in gastrointestinal tract simulations differs from that in the actual human gastrointestinal tract, which necessitates further research.

AIM. This study aimed to systematise information on the polymers used in the enteric coating of mesalazine products and to assess the pharmaceutical risks associated with the potential reduction in the efficacy of ulcerative colitis therapy.

DISCUSSION. The absorption and metabolism of mesalazine dictate the need for enteric-coated dosage forms to deliver the active substance directly to the affected areas of the colon. The most common polymer used in the manufacturing of oral mesalazine products is a methacrylic acid–methyl methacrylate copolymer with a monomer ratio of 1:1, which releases the active substance at pH 7.0. Some manufacturers use a methacrylic acid–ethyl acrylate copolymer with a monomer ratio of 1:1, which dissolves at pH 5.5. The gastrointestinal pH in patients with  inflammatory  bowel  disease  may  vary  in  wide  and  often  overlapping  ranges  depending on the organ (1.0–7.0 in the stomach, 5.0–6.2 in the duodenum, 6.1–7.1 in the jejunum, 7.4–7.5 in the ileum, and 5.7–7.5 in the colon with a possibility of acidification in ulcerative colitis patients). The rate of gastrointestinal transit varies widely as well. These factors may cause premature release of mesalazine in the stomach or the small intestine before the dosage form reaches the colon, which poses the risks of reduced clinical efficacy and systemic adverse effects.

CONCLUSIONS. In the vast majority of ulcerative colitis patients, the methacrylic acid–methyl methacrylate copolymer provides targeted delivery of 5-aminosalicylic acid from tablets and granules, facilitating its local action in the colon. However, developers and manufacturers selecting the polymer for enteric coating of oral mesalazine dosage forms should consider the pharmaceutical risks associated with reduced clinical efficacy.

1. GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17–30. https://doi.org/10.1016/S2468-1253(19)30333-4

2. Iacucci M, de Silva S, Ghosh S. Mesalazine in inflammatory bowel disease: a trendy topic once again? Can J Gastroenterol. 2010;24(2):127–33. https://doi.org/10.1155/2010/586092

3. Ciorba MA. Inflammatory bowel diseases 2024. Curr Opin Gastroenterol. 2024;40(4):233–4. https://doi.org/10.1097/MOG.0000000000001038

4. Mukherji G, Wilson CG. Biopolymers and colonic delivery. In: Rathbone MJ, Hadgraft J, Roberts MS, eds. Modified-release drug delivery technology. New York: Marcel Dekker; 2003. P. 223–32.

5. Mohylyuk V, Yerkhova A, Katynska M, Sirko V, Patel K. Effect of elevated pH on the commercial enteric-coated omeprazole pellets resistance: patent review and multisource generics comparison. AAPS PharmSciTech 2021;22(5):188. https://doi.org/10.1208/s12249-021-02038-2

6. Little RD, Jayawardana T, Koentgen S, Zhang F, Connor SJ, Boussioutas A, et al. Pathogenesis and precision medicine for predicting response in inflammatory bowel disease: advances and future directions. Gastroenterology. 2024;2:e100006. https://doi.org/10.3390/diagnostics13172797

7. Fiocchi C, Dragoni G, Iliopoulos D, Katsanos K, Ramirez VH, Suzuki K. Results of the Seventh Scientific Workshop of ECCO: precision medicine in IBD—what, why, and how. J Crohns Colitis. 2021;15(9):1410–30. https://doi.org/10.1093/ecco-jcc/jjab051

8. Svartz N. Salazopyrin, a new sulfanilamide preparation. A. Therapeutic results in rheumatic polyarthritis. B. Therapeutic results in ulcerative colitis. C. To­xic manifestations in treatment with sulfanilamide preparations. Acta Med Scand. 1942;110:577–98. https://doi.org/10.1111/j.0954-6820.1942.tb06841.x

9. Shapina MV, Khalif IL. Use of 5-aminosalicylic acid for treatment of ulcerative colitis in different dosage modes. Medical Council. 2017;(15):44–50 (In Russ.). https://doi.org/10.21518/2079-701X-2017-15-44-50

10. Perrotta C, Pellegrino P, Moroni E, De Palma C, Cervia D, Danelli P, Clementi E. Five-aminosalicylic acid: an update for the reappraisal of an old drug. Gastroenterol Res Pract. 2015;2015:456895. https://doi.org/10.1155/2015/456895

11. Serebrova SYu, Evteev VA, Demchenkova EYu, Proko­fiev AB. Compendium of pH-sensitive polymers in gastroenterology drugs: focus on enteric coatings. Medical Council. 2024;(5):134–42 (In Russ.). https://doi.org/10.21518/ms2024-039

12. Sester C, Ofridam F, Lebaz N, Gagnière E, Mangin D, Elaissari A. pH-sensitive methacrylic acid–methyl methacrylate copolymer Eudragit L100 and dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate tri-copolymer Eudragit E100. Polym Adv Technol. 2019;31:440–50. https://doi.org/10.1002/pat.4780

13. Cole ET, Scott RA, Connor AL, Wilding IR, Petereit HU, Schminke C, et. al. Enteric coated HPMC capsules designed to achieve intestinal targeting. Int J Pharm. 2002;231(1):83–95. https://doi.org/10.1016/S0378-5173(01)00871-7

14. Foppoli A, Maroni A, Moutaharrik S, Melocchi A, Zema L, Palugan L, et al. In vitro and human pharmacoscintigraphic evaluation of an oral 5-ASA delivery system for colonic release. Int J Pharm. 2019;572:118723. https://doi.org/10.1016/j.ijpharm.2019.118723

15. Ibekwe VC, Khela MK, Evans DF, Basit AW. A new concept in colonic drug targeting: a combined pH-responsive and bacterially-triggered drug delivery technology. Aliment Pharmacol Ther. 2008;28(7):911–6. https://doi.org/10.1111/j.1365-2036.2008.03810.x

16. Varum F, Freire AC, Bravo R, Basit AW. OPTICORE™, an innovative and accurate colonic targeting technology. Int J Pharm. 2020;583:119372. https://doi.org/10.1016/j.ijpharm.2020.119372

17. Preisig D, Varum F, Bravo R, Hartig C, Spleiss J, Abbes S, et al. Colonic delivery of metronidazole-loaded capsules for local treatment of bacterial infections: a clinical pharmacoscintigraphy study. Eur J Pharm Biopharm. 2021;165:22–30. https://doi.org/10.1016/j.ejpb.2021.05.002

18. Gordon H, Minozzi S, Kopylov U, Verstockt B, Chaparro M, Buskens C, et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis. 2024;18(10):1531–55. https://doi.org/10.1093/ecco-jcc/jjae091

19. Silverberg M, Satsangi J, Ahmad T, Arnott IDR, Bernstein CN, Brant SR et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005;19:5–36. https://doi.org/10.1155/2005/269076

20. Wahlgren M, Axenstrand M, Hakansson A, Marefati A, Pedersen LB. In vitro methods to study colon release: state of the art and an outlook on new strategies for better in-vitro biorelevant release media. Pharmaceutics. 2019;11(2):95. https://doi.org/10.3390/pharmaceutics11020095

21. Yamamura R, Inoue KY, Nishino K, Yamasaki S. Intestinal and fecal pH in human health. Front Microbiomes. 2023;2:1192316. https://doi.org/10.3389/frmbi.2023.1192316

22. Hua S. Advances in oral drug delivery for regional targeting in the gastrointestinal tract—influence of physiological, pathophysiological and pharmaceutical factors. Front Pharmacol. 2020;11:524. https://doi.org/10.3389/fphar.2020.00524

23. Fallingborg J, Pedersen P, Jacobsen BA. Small intestinal transit time and intraluminal pH in ileocecal resected patients with Crohn’s disease. Dig Dis Sci. 1998;43(4):702–5. https://doi.org/10.1023/A:1018893409596

24. Nugent SG, Kumar D, Rampton DS, Evans DF. Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut. 2001;48(4):571–7. https://doi.org/10.1136/gut.48.4.571

25. Sasaki Y, Hada R, Nakajima H, Fukuda S, Munakata A. Improved localizing method of radiopill in measurement of entire gastrointestinal pH profiles: colonic luminal pH in normal subjects and patients with Crohn’s disease. Am J Gastroenterol. 1997;92(1):114–8. PMID: 8995949

26. Rane K, Kukreja G, Deshmukh S, Kakad U, Jadhav P, Patole V. Robotic pills as innovative personalized medicine tools: a mini review. Recent Adv Drug Deliv Formul. 2024;18(1):2–11. https://doi.org/10.2174/0126673878265457231205114925

27. Locatelli I, Kovacic NN, Mrhar A, Bogataj M. Gastric emptying of non-disintegrating solid drug delivery systems in fasted state: relevance to drug dissolution. Expert Opin Drug Deliv. 2010;7(8):967−76. https://doi.org/10.1517/17425247.2010.495982

28. Le Vee M, Lecureur V, Stieger B, Fardel O. Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor necrosis factor-alpha or interleukin-6. Drug Metab Dispos. 2009;37(3):685–93. https://doi.org/10.1124/dmd.108.023630

29. Gong IY, Kim RB. Impact of genetic variation in OATP transporters to drug disposition and response. Drug Metab Pharmacokinet. 2013;28(1):4–18. https://doi.org/10.2133/dmpk.dmpk-12-rv-099

30. Clarke JD, Hardwick RN, Lake AD, Lickteig AJ, Goedken MJ, Klaassen CD, et al. Synergistic interaction between genetics and disease on pravastatin disposition. J Hepatol. 2014;61(1):139–47. https://doi.org/10.1016/j.jhep.2014.02.021

31. Billington S, Ray AS, Salphati L, Xiao G, Chu X, Humphreys WG, et al. Transporter expression in noncancerous and cancerous liver tissue from donors with hepatocellular carcinoma and chronic hepatitis C infection quantified by LC-MS/MS proteomics. Drug Metab Dispos. 2018;46(2):189–96. https://doi.org/10.1124/dmd.117.077289

32. Vildhede A, Kimoto E, Pelis RM, Rodrigues AD, Varma MVS. Quantitative proteomics and mechanistic modeling of transporter-mediated disposition in nonalcoholic fatty liver disease. Clin Pharmacol Ther. 2020;107(5):1128–37. https://doi.org/10.1002/cpt.1699

33. Murray M, Zhou F. Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease. Br J Pharmacol 2017;174(13):1908–24. https://doi.org/10.1111/bph.13785

34. Xu D, You G. Loops and layers of post-translational modifications of drug transporters. Adv Drug Deliv Rev. 2017;116:37–44. https://doi.org/10.1016/j.addr.2016.05.003

35. Alam K, Crowe A, Wang X, Zhang P, Ding K, Li L, et al. Regulation of organic anion transporting polypeptides (OATP) 1B1- and OATP1B3-mediated transport: an updated review in the context of OATP-mediated drug–drug interactions. Int J Mol Sci. 2018;19(3):855. https://doi.org/10.3390/ijms19030855

36. Wojtal KA, Eloranta JJ, Hruz P, Gutmann H, Drewe J, Staumann A, et al. Changes in mRNA expression levels of solute carrier transporters in inflammatory bowel disease patients. Drug Metab Dispos. 2009;37(9):1871–7. https://doi.org/10.1124/dmd.109.027367

37. König J, Glaeser H, Keiser M, Mandery K, Klotz U, Fromm MF. Role of organic anion-transporting polypeptides for cellular mesalazine (5-aminosalicylic acid) uptake. Drug Metab Dispos. 2011;39(6):1097–102. https://doi.org/10.1124/dmd.110.034991

38. Hickman D, Pope J, Patil SD, Fakis G, Smelt V, Stanley LA, et al. Expression of arylamine N-acetyltransferase in human intestine. Gut. 1998;42(3):402–9. https://doi.org/10.1136/gut.42.3.402

39. Windmill KF, Gaedigk A, Hall PM, Samaratunga H, Grant DM, McManus ME. Localization of N-acetyltransferases NAT1 and NAT2 in human tissues. Toxicol Sci. 2000;54(1):19–29. https://doi.org/10.1093/toxsci/54.1.19

40. Deloménie C, Fouix S, Longuemaux S, Brahimi N, Bizet C, Picard B, et al. Identification and functional characterization of arylamine N-acetyltransferases in eubacteria: evidence for highly selective acetylation of 5-aminosalicylic acid. J Bacteriol. 2001;183(11):3417–27. https://doi.org/10.1128/jb.183.11.3417-3427.2001

41. Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113(4):481–517. https://doi.org/10.1038/ajg.2018.27

42. Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68(Suppl 3):1–106. https://doi.org/10.1136/gutjnl-2019-318484

43. Ford AC, Kane SV, Khan KJ, Achkar J-P, Talley NJ, Marshall JK, et al. Efficacy of 5-aminosalicylates in Crohn’s disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):617–29. https://doi.org/10.1038/ajg.2011.71

44. Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T, et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis. 2020;14(1):4–22. https://doi.org/10.1093/ecco-jcc/jjz180