ADVANCING COLON-TARGETED BUDESONIDE DELIVERY: A REVIEW OF THE LATEST DEVELOPMENTS AND FUTURE PERSPECTIVES

AMIT KUMAR; GUNJAN DHIRWAN; PRANSHU TANGRI; YOGITA TYAGI

doi:10.22159/ajpcr.2025v18i6.54504

Authors

AMIT KUMAR Department of Pharmaceutics, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, India.
GUNJAN DHIRWAN Department of Pharmaceutics, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, India.
PRANSHU TANGRI
YOGITA TYAGI Department of Pharmaceutics, Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand, India.

DOI:

https://doi.org/10.22159/ajpcr.2025v18i6.54504

Keywords:

Corticosteroids, Inflammatory bowel disease, colon-specific delivery, Targeting approaches

Abstract

Colon-specific drug delivery is advantageous for treating various local diseases, including inflammatory bowel disease, ulcerative colitis, Crohn’s disease, chronic pancreatitis, and colonic cancer. Corticosteroids are considered as the first line drug therapy for the treatment of colon specific diseases, but also causes adverse side effects. Budesonide, a second-generation corticosteroid characterized by a relatively low side effect profile and low bioavailability resulting from extensive first-pass liver metabolism, has received approval from the Food and Drug Administration for the treatment of colon-specific diseases. Various methods have been employed for colon-targeted drug delivery. Key approaches include pH-sensitive drug delivery, time-controlled delayed release, and microbially triggered drug delivery, along with additional strategies such as prodrug delivery and pressure-controlled drug delivery. Budesonide can be given by many different formulations like coated tablets, multi-matrix tablets, pellets-based formulations, capsules, 3D-printing and nanoparticles-based formulation techniques. This detailed analysis in budesonide can help to improve the development of new techniques and treatments for colon specific drug delivery.

Downloads

Download data is not yet available.

References

Glassner KL, Abraham BP, Quigley EM. The microbiome and inflammatory bowel disease. J Allergy Clin Immunol. 2020;145(1):16- 27. doi: 10.1016/j.jaci.2019.11.003, PMID 31910984

Iswandana R, Putri KS, Putri FA, Gunawan M, Larasati SA. Challenge and development strategy for colon-targeted drug delivery system. Pharm Sci Res. 2022;9(1):17-27.

Sherlock ME, Macdonald JK, Griffiths AM, Steinhart AH, Seow CH. Oral budesonide for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2015;2015(10):CD007698. doi: 10.1002/14651858. CD007698.pub3, PMID 26497719

Muhammed RA, Mohammed S, Visht S, Yassen AO. A review on development of colon targeted drug delivery system. Int J Appl Pharm. 2024;16(2):12-27. doi: 10.22159/ijap.2024v16i2.49293

Iswandana R, Putri KS, Larasati SA, Gunawan M, Putri FA. Delivery of potential drugs to the colon: challenges and strategies. Indones J Pharm. 2022;33:307-32. doi: 10.22146/ijp.2734

Amidon S, Brown JE, Dave VS. Colon-targeted oral drug delivery systems: Design trends and approaches. AAPS PharmSciTech. 2015;16(4):731-41. doi: 10.1208/s12249-015-0350-9, PMID 26070545

Kumar P, Mishra B. Colon targeted drug delivery systems - an overview. Niet gebruiken plagiaat. Curr Drug Deliv. 2008;5(3):186-98. doi: 10.2174/156720108784911712, PMID 18673262

Davis J, Kellerman R. Gastrointestinal conditions: Inflammatory bowel disease. FP Essent. 2022;516:23-30. PMID 35507310

McCoubrey LE, Favaron A, Awad A, Orlu M, Gaisford S, Basit AW. Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics. J Control Release. 2023;353:1107-26. doi: 10.1016/j.jconrel.2022.12.029, PMID 36528195

Guo Y, Zong S, Pu Y, Xu B, Zhang T, Wang B. Advances in pharmaceutical strategies enhancing the efficiencies of oral colon-targeted delivery systems in inflammatory bowel disease. Molecules. 2018;23(7):1622. doi: 10.3390/molecules23071622, PMID 29973488

Coco R, Plapied L, Pourcelle V, Jérôme C, Brayden DJ, Schneider YJ, et al. Drug delivery to inflamed colon by nanoparticles: Comparison of different strategies. Int J Pharm. 2013;440(1):3-12. doi: 10.1016/j. ijpharm.2012.07.017, PMID 22820482

Sarangi MK, Rao ME, Parcha V. Smart polymers for colon targeted drug delivery systems: A review. Int J Polym Mater Polym Biomater. 2021;70(16):1130-66. doi: 10.1080/00914037.2020.1785455

Dunn AJ. Cytokine activation of the HPA axis. Ann N Y Acad Sci. 2000;917:608-17. doi: 10.1111/j.1749-6632.2000.tb05426.x, PMID 11268389

Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR. Transcription factor interactions: Selectors of positive or negative regulation from a single DNA element. Science. 1990;249(4974):1266-72. doi: 10.1126/ science.2119054, PMID 2119054

Vago JP, Tavares LP, Riccardi C, Teixeira MM, Sousa LP. Exploiting the pro-resolving actions of glucocorticoid-induced proteins annexin A1 and GILZ in infectious diseases. Biomed Pharmacother. 2021;133:111033. doi: 10.1016/j.biopha.2020.111033, PMID 33378946

Bruscoli S, Riccardi C, Ronchetti S. Gilz as a regulator of cell fate and inflammation. Cells. 2021;11(1):122. doi: 10.3390/cells11010122, PMID 35011684

Ayroldi E, Migliorati G, Bruscoli S, Marchetti C, Zollo O, Cannarile L, et al. Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor κB. Blood. 2001;98(3):743-53. doi: 10.1182/blood.v98.3.743, PMID 11468175

Ayroldi E, Zollo O, Macchiarulo A, Di Marco B, Marchetti C, Riccardi C. Glucocorticoid-induced leucine zipper inhibits the Raf-extracellular signal-regulated kinase pathway by binding to Raf-1. Mol Cell Biol. 2002;22(22):7929-41. doi: 10.1128/MCB.22.22.7929- 7941.2002, PMID 12391160

Vago JP, Tavares LP, Garcia CC, Lima KM, Perucci LO, Vieira ÉL, et al. The role and effects of glucocorticoid-induced leucine zipper in the context of inflammation resolution. J Immunol. 2015;194(10):4940- 50. doi: 10.4049/jimmunol.1401722, PMID 25876761

Gu R, Lei B, Shu Q, Li G, Xu G. Glucocorticoid-induced leucine zipper overexpression inhibits lipopolysaccharide-induced retinal inflammation in rats. Exp Eye Res. 2017;165:151-63. doi: 10.1016/j. exer.2017.02.011, PMID 28238753

Bereshchenko O, Migliorati G, Bruscoli S, Riccardi C. Glucocorticoid-induced leucine zipper: A novel anti-inflammatory molecule. Front Pharmacol. 2019;10:308. doi: 10.3389/fphar.2019.00308, PMID 30971930

Quatrini L, Ugolini S. New insights into the cell-and tissue-specificity of glucocorticoid actions. Cell Mol Immunol. 2021;18(2):269-78. doi: 10.1038/s41423-020-00526-2, PMID 32868909

Croxtall JD, Choudhury Q, Flower RJ. Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism. Br J Pharmacol. 2000;130(2):289-98. doi: 10.1038/ sj.bjp.0703272, PMID 10807665

Desmet SJ, De Bosscher K. Glucocorticoid receptors: Finding the middle ground. J Clin Invest. 2017;127(4):1136-45. doi: 10.1172/ JCI88886, PMID 28319043

Ramamoorthy S, Cidlowski JA. Corticosteroids-mechanisms of action in health and disease. Rheum Dis Clin North Am. 2016;42(1):15-31. doi: 10.1016/j.rdc.2015.08.002, PMID 26611548

Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17(4):233-47. doi: 10.1038/nri.2017.1, PMID 28192415

Franco LM, Gadkari M, Howe KN, Sun J, Kardava L, Kumar P, et al. Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses. J Exp Med. 2019;216(2):384-406. doi: 10.1084/jem.20180595, PMID 30674564

Ronchetti S, Migliorati G, Bruscoli S, Riccardi C. Defining the role of glucocorticoids in inflammation. Clin Sci (Lond). 2018;132(14):1529- 43. doi: 10.1042/CS20171505, PMID 30065045

Hunter AL, Poolman TM, Kim D, Gonzalez FJ, Bechtold DA, Loudon AS, et al. HNF4A modulates glucocorticoid action in the liver. Cell Rep. 2022;39(3):110697. doi: 10.1016/j.celrep.2022.110697, PMID 35443180

Lennard-Jones JE, Longmore AJ, Newell AC, Wilson CW, Jones FA. An assessment of prednisone, Salazopyrin, and topical hydrocortisone hemisuccinate used as out-patient treatment for ulcerative colitis. Gut. 1960;1(3):217-22. doi: 10.1136/gut.1.3.217, PMID 13760840

Truelove SC, Watkinson G, Draper G. Comparison of corticosteroid and sulphasalazine therapy in Ulcerattve colitis. Br Med J. 1962;2(5321):1708-11. doi: 10.1136/bmj.2.5321.1708, PMID 13994348

Ham M, Moss AC. Mesalamine in the treatment and maintenance of remission of ulcerative colitis. Expert Rev Clin Pharmacol. 2012;5(2):113-23. doi: 10.1586/ecp.12.2, PMID 22390554

Truelove SC, Watkinson G, Draper G. Comparison of corticosteroid and sulphasalazine therapy in ulcerative colitis. JAMA. 1963;184(5):1708-11. doi: 10.1136/bmj.2.5321.1708

Bello C, Goldstein F, Thornton JJ. Alternate‐day prednisone treatment and treatment maintenance in Crohn’s disease. Am J Gastroenterol. 1991;86(4):460-6. PMID 1672787

Ricketts RR. Alternate-day prednisone treatment and treatment maintenance in Crohn’s disease. J Pediatr Surg. 1992;27(3):460-466. doi: 10.1016/0022-3468(92)90920-3

Ewe K, Press AG, Singe CC, Stufler M, Ueberschaer B, Hommel G, et al. Azathioprine combined with prednisolone or monotherapy with prednisolone in active Crohn’s disease. Gastroenterology. 1993;105(2):367-72. doi: 10.1016/0016- 5085(93)90709-l, PMID 8335191

Hota SR, Mishra PP, Nanda D. Peutz-Jeghers polyp as a lead point for ileocolic intussusception in a young male: A case report. Int J Curr Pharm Res. 2024;16(4):135-7. doi: 10.22159/ijcpr.2024v16i4.4099

Dubois-Camacho K, Ottum PA, Franco-Muñoz D, De La Fuente M, Torres-Riquelme A, Díaz-Jiménez D, et al. Glucocorticosteroid therapy in inflammatory bowel diseases: From clinical practice to molecular biology. World J Gastroenterol. 2017;23(36):6628-38. doi: 10.3748/ wjg.v23.i36.6628, PMID 29085208

De Cassan C, Fiorino G, Danese S. Second-generation corticosteroids for the treatment of Crohn’s disease and ulcerative colitis: More effective and less side effects? Dig Dis. 2012;30(4):368-75. doi: 10.1159/000338128, PMID 22796798

Rocamora-Reverte L, Villunger A, Wiegers GJ. Cell-specific immune regulation by glucocorticoids in murine models of infection and inflammation. Cells. 2022;11(14):2126. doi: 10.3390/cells11142126, PMID 35883569

Bar-Meir S, Chowers Y, Lavy A, Abramovitch D, Sternberg A, Leichtmann G, et al. Budesonide versus prednisone in the treatment of active Crohn’s disease. The Israeli budesonide study group. Gastroenterology. 1998;115(4):835-40. doi: 10.1016/s0016- 5085(98)70254-9, PMID 9753485

Ghosh S, Ganguly D, Majumder S. A review on pharmacological and therapeutic insight of ozanimod for colon disease in nano-structure. Int J Pharm Pharm Sci. 2022;14(4):13-9. doi: 10.22159/ ijpps.2022v14i4.44150

Löfberg R, Danielsson A, Suhr O, Nilsson A, Schiöler R, Nyberg A, et al. Oral budesonide versus prednisolone in patients with active extensive and left-sided ulcerative colitis. Gastroenterology. 1996;110(6):1713-8. doi: 10.1053/gast.1996.v110.pm8964395, PMID 8964395

Manguso F, Bennato R, Lombardi G, Riccio E, Costantino G, Fries W. Efficacy and safety of oral beclomethasone dipropionate in ulcerative colitis: A systematic review and meta-analysis. PLOS One. 2016;11(11):e0166455. doi: 10.1371/journal.pone.0166455, PMID 27846307

Prantera C, Marconi S. Glucocorticosteroids in the treatment of inflammatory bowel disease and approaches to minimizing systemic activity. Ther Adv Gastroenterol. 2013;6(2):137-56. doi: 10.1177/1756283X12473675, PMID 23503968

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):S1-S106. doi: 10.1136/gutjnl-2019-318484, PMID 31562236

Khan MZ, Prebeg Z, Kurjaković N. A pH-dependent colon targeted oral drug delivery system using methacrylic acid copolymers. I. Manipulation of drug release using Eudragit L100-55 and Eudragit S100 combinations. J Control Release. 1999;58(2):215-22. doi: 10.1016/s0168-3659(98)00151-5, PMID 10053194

Philip AK, Philip B. Colon targeted drug delivery systems: A review on primary and novel approaches. Oman Med J. 2010;25(2):79-87. doi: 10.5001/omj.2010.24, PMID 22125706

Naeem M, Choi M, Cao J, Lee Y, Ikram M, Yoon S, et al. Colon-targeted delivery of budesonide using dual pH- and time-dependent polymeric nanoparticles for colitis therapy. Drug Des Dev Ther. 2015;9:3789-99. doi: 10.2147/DDDT.S88672, PMID 26229440

Wilding IR, Davis SS, Bakhshaee M, Stevens HN, Sparrow RA, Brennan J. Gastrointestinal transit and systemic absorption of captopril from a pulsed-release formulation. Pharm Res. 1992;9(5):654-7. doi: 10.1023/a:1015806211556, PMID 1608898

Pawar PS, Saleem MA. Formulation and evaluation of oral colon targeted tablet of budesonide. Pharm Lett. 2013;5(3):1-12.

Fukui E, Miyamura N, Uemura K, Kobayashi M. Preparation of enteric coated timed-release press-coated tablets and evaluation of their function by in vitro and in vivo tests for colon targeting. Int J Pharm. 2000;204(1-2):7-15. doi: 10.1016/s0378-5173(00)00454-3, PMID 11011980

Vassallo M, Camilleri M, Phillips SF, Brown ML, Chapman NJ, Thomforde GM. Transit through the proximal colon influences stool weight in the irritable bowel syndrome. Gastroenterology. 1992;102(1):102-8. doi: 10.1016/0016-5085(92)91789-7, PMID 1727743

Liu LS, Fishman ML, Kost J, Hicks KB. Pectin-based systems for colon-specific drug delivery via oral route. Biomaterials. 2003;24(19):3333- 43. doi: 10.1016/s0142-9612(03)00213-8, PMID 12763460

Ratner BD, Gladhill KW, Horbett TA. Analysis of in vitro enzymatic and oxidative degradation of polyurethanes. J Biomed Mater Res. 1988;22(6):509-27. doi: 10.1002/jbm.820220607, PMID 3410870

Kamath KR, Park K. Biodegradable hydrogels in drug delivery. Adv Drug Deliv Rev. 1993;11(1-2):59-84.

Sinha VR, Kumria R. Microbially triggered drug delivery to the colon. Eur J Pharm Sci. 2003;18(1):3-18. doi: 10.1016/s0928- 0987(02)00221-x, PMID 12554067

Friend DR, Chang GW. Drug glycosides: Potential prodrugs for colon-specific drug delivery. J Med Chem. 1985;28(1):51-7. doi: 10.1021/ jm00379a012, PMID 3965714

Vijaya RJ, Prabakaran L, Prushothaman M. Colon targeted drug delivery systems - an overview. Asian J Pharm Rev. 2010;8(2):25-33.

Sopyan I, Komarudin AD, Huang JA, Sunan KS. An overview: Development of colon drug delivery system and its application and limitations. Int J Appl Pharm. 2023;15(1):24-30. doi: 10.22159/ijap.2023v15i1.46681

Yamaoka T, Makita Y, Sasatani H, Kim SI, Kimura Y. Linear type azo-containing polyurethane as drug-coating material for colon-specific delivery: Its properties, degradation behavior, and utilization for drug formulation. J Control Release. 2000;66(2-3):187-97. doi: 10.1016/ s0168-3659(99)00270-9, PMID 10742579

Sahu A, Jain A, Gulbake A. Colon as target for drug delivery. Curr Drug Ther. 2014;9(1):63-73. doi: 10.2174/1574885509666140805003632

Tozaki H, Odoriba T, Okada N, Fujita T, Terabe A, Suzuki T, et al. Chitosan capsules for colon-specific drug delivery: Enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats. J Control Release. 2002;82(1):51-61. doi: 10.1016/s0168-3659(02)00084-6, PMID 12106976

Tozaki H, Komoike J, Tada C, Maruyama T, Terabe A, Suzuki T, et al. Chitosan Capsule for colon-specific drug delivery: Improvement of insulin absorption from the rat colon. J Pharm Sci. 1997;86(9):1016-21. doi: 10.1021/js970018g, PMID 9294815

Rubinstein A, Radai R, Ezra M, Pathak S, Rokem JS. In vitro evaluation of calcium pectinate: A potential colon-specific drug delivery carrier. Pharm Res. 1993;10(2):258-63. doi: 10.1023/a:1018995029167, PMID 8456074

Olaoye L, Sadraddin A, Braim S. Smart chitosan-based microbead formulation for colon-targeted delivery of lactoferrin. Int J Appl Pharm. 2024;16(5):383-8. doi: 10.22159/ijap.2024v16i5.51185

Varshosaz J, Emami J, Tavakoli N, Minaiyan M, Rahmani N, Dorkoosh F. Development and evaluation of a novel pellet-based tablet system for potential colon delivery of budesonide. J Drug Deliv. 2012;2012:905191. doi: 10.1155/2012/905191, PMID 22577558

Gite SD, Salunkhe KS, Shendge RS. Design, preparation and evaluation of colon targeted tablets of budesonide. Int J Sci Technol Res. 2020;9(3):7115-18.

Gareb B, Dijkstra G, Kosterink JG, Frijlink HW. Development of novel zero-order release budesonide tablets for the treatment of ileo-colonic inflammatory bowel disease and comparison with formulations currently used in clinical practice. Int J Pharm. 2020;155(6):366-375.

Varshosaz J, Emami J, Tavakoli N, Minaiyan M, Rahmani N, Dorkoosh F, et al. Pectin film coated pellets for colon-targeted delivery of budesonide: In-vitro/in-vivo evaluation in induced ulcerative colitis in rat. Iran J Pharm Res. 2012;11(3):733-45. PMID 24250500

Muhammed RA, Mohammed S, Visht S, Yassen AO. A review on development of colon targeted drug delivery system. Int J Appl Pharm. 2024;16(2):12-27. doi: 10.22159/ijap.2024v16i2.49293

Li C, Wang J, Wang Y, Gao H, Wei G, Huang Y, et al. Recent progress in drug delivery. Acta Pharm Sin B. 2019;9(6):1145-62. doi: 10.1016/j. apsb.2019.08.003, PMID 31867161

Homayun B, Lin X, Choi HJ. Challenges and recent progress in oral drug delivery systems for biopharmaceuticals. Pharmaceutics. 2019;11(3):129. doi: 10.3390/pharmaceutics11030129, PMID 30893852

Koleva L, Bovt E, Ataullakhanov F, Sinauridze E. Erythrocytes as carriers: From drug delivery to biosensors. Pharmaceutics. 2020;12(3):276. doi: 10.3390/pharmaceutics12030276, PMID 32197542

Carvalho PM, Makowski M, Domingues MM, Martins IC, Santos NC. Lipid membrane-based therapeutics and diagnostics. Arch Biochem Biophys. 2021;704:108858. doi: 10.1016/j.abb.2021.108858, PMID 33798534

Xu P, Wang R, Wang X, Ouyang J. Recent advancements in erythrocytes, platelets, and albumin as delivery systems. Onco Targets Ther. 2016;9:2873-84. doi: 10.2147/OTT.S104691, PMID 27274282

Sandborn WJ, Travis S, Moro L, Jones R, Gautille T, Bagin R, et al. Once-daily budesonide MMX® extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: Results from the CORE I study. Gastroenterology. 2012;143(5):1218-1226.e2. doi: 10.1053/j.gastro.2012.08.003, PMID 22892337

Gherardi A, Roze S, Kuijvenhoven J, Ghatnekar O, Yip Sonderegger YL. Budesonide with multi-matrix technology as second-line treatment for ulcerative colitis: Evaluation of long-term cost-effectiveness in the Netherlands. J Med Econ. 2018;21(9):869-77. doi: 10.1080/13696998.2018.1484371, PMID 29857775

Danese S, Siegel CA, Peyrin-Biroulet L. Review article: Integrating budesonide-MMX into treatment algorithms for mild-to-moderate ulcerative colitis. Aliment Pharmacol Ther. 2014;39(10):1095-103. doi: 10.1111/apt.12712, PMID 24641622

Katz S, Lichtenstein GR, Safdi MA. 5-ASA dose-response: Maximizing efficacy and adherence. Gastroenterol Hepatol (N Y). 2010;6(2 Suppl 3):1-16. PMID 20567558

Hua S, Marks E, Schneider JJ, Keely S. Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: Selective targeting to diseased versus healthy tissue. Nanomedicine. 2015;11(5):1117-32. doi: 10.1016/j.nano.2015.02.018, PMID 25784453

Lu H, Wang J, Wang T, Zhong J, Bao Y, Hao H. Recent progress on nanostructures for drug delivery applications. J Nanomater. 2016;2016:1-12. doi: 10.1155/2016/5762431

Wang K, Shen R, Meng T, Hu F, Yuan H. Nano-drug delivery systems based on different targeting mechanisms in the targeted therapy of colorectal cancer. Molecules. 2022;27(9):2981. doi: 10.3390/ molecules27092981, PMID 35566331

Naeem M, Awan UA, Subhan F, Cao J, Hlaing SP, Lee J, et al. Advances in colon-targeted nano-drug delivery systems: Challenges and solutions. Arch Pharm Res. 2020;43(1):153-69. doi: 10.1007/s12272-020-01219- 0, PMID 31989477

Shetty K, Bhandari A, Yadav KS. Nanoparticles incorporated in nanofibers using electrospinning: A novel nano-in-nano delivery system. J Control Release. 2022;350:421-34. doi: 10.1016/j. jconrel.2022.08.035, PMID 36002053

Lühder F, Reichardt HM. Novel drug delivery systems tailored for improved administration of glucocorticoids. Int J Mol Sci. 2017;18(9):1836. doi: 10.3390/ijms18091836, PMID 28837059

D’Haens GR, Kovács A, Vergauwe P, Nagy F, Molnár T, Bouhnik Y, et al. Clinical trial: Preliminary efficacy and safety study of a new Budesonide-MMX® 9 mg extended-release tablets in patients with active left-sided ulcerative colitis. J Crohns Colitis. 2010;4(2):153-60. doi: 10.1016/j.crohns.2009.09.007, PMID 21122499

Brunner M, Ziegler S, Di Stefano AF, Dehghanyar P, Kletter K, Tschurlovits M, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2006;61(1):31-8. doi: 10.1111/j.1365-2125.2005.02517.x, PMID 16390349

Goldstein MJ, Gelzayd EA, Kirsner JB. Some observations on the hazards of corticosteroid therapy in patients with inflammatory bowel disease. Trans Am Acad Ophthalmol Otolaryngol. 1967;71(2):254-61. PMID 4292814

D’Haens G. Systematic review: Second-generation vs. conventional corticosteroids for induction of remission in ulcerative colitis. Aliment Pharmacol Ther. 2016;44(10):1018-29. doi: 10.1111/apt.13803, PMID 27650488

Matzen P. Budesonide enema in distal ulcerative colitis: A randomized dose-response trial with prednisolone enema as positive control. The Danish budesonide study group. Scand J Gastroenterol. 1991;26(12):1225-30. doi: 10.3109/00365529108998618