Perspectives on Commercialisation of Oral Insulin
Main Article Content
Abstract
The objective of this paper is to demonstrate that oral insulin is potentially close to being commercialized, in light of the fact that (i) the technical, safety, and pharmacological obstacles in developing an oral insulin for clinical use for diabetes can potentially be overcome, and (ii) there are players in the field that are moving an oral insulin formulation into advanced clinical trials.
Article Details
How to Cite
NEW, Roger R C.
Perspectives on Commercialisation of Oral Insulin.
Medical Research Archives, [S.l.], v. 13, n. 11, nov. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6994>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i11.6994.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. New, RRC., 2025. Oral Insulin – Harnessing the Natural Physiology of Glucose Control in the Body. Medical Research Archives, [online] 13(1).
https://doi.org/10.18103/mra.v13i1.6180
3. Brayden DJ (2021) The Centenary of the Discovery of Insulin: An Update on the Quest for Oral Delivery. Front. Drug. Deliv. 1:726675. doi: 10.3389/fddev.2 021.726675
4. Twarog, C.; Fattah, S.; Heade, J.; Maher, S.; Fattal, E.; Brayden, D.J. Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10). Pharmaceutics 2019 11, 78-99; doi:10.3390/pharmaceutics11020078
5. Maher S, Brayden DJ, Casettari L, Illum L. Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update. Pharmaceutics 2019, 11, 41; doi:10.3390/pharmaceutics11010041
6. Ergun-Longmire B, Marker J, Zeidler A, Rapaport R, Raskin P, Bode B, Schatz D, Vargas, A, Rogers D, Schwartz S, Malone J, Krischer J, Maclaren NK. Oral Insulin Therapy to Prevent Progression of Immune-Mediated (Type 1) Diabetes. Ann. N.Y. Acad. Sci. 2004; 1029: 260–277.
7. The Diabetes Prevention Trial – Type 1. Effects of Oral Insulin in Relatives of Patients With Type 1 Diabetes. Diabetes Care. 2005;28:5 1068-1076.
8. New RRC, Ramanujam S, Chaudhari V, Bogus M, Travers GN. Namjoshi G. Safety and Efficacy of an Oral Insulin (Capsulin) in Patients with Early-Stage Type 2 Diabetes: A Dose-Ranging Phase IIb Study. Diabetes Obes Metab. 2022;1–8.
9. Zhang AMY, Wellberg EA, Kopp JL, Johnson JD. Hyperinsulinemia in Obesity, Inflammation, and Cancer. Diabetes Metab J. 2021;45:285-311. doi.org/10.4093/dmj.2020.0250.
10. Kolb H, Kempf K, Röhling M, Martin S. Insulin: too much of a good thing is bad. BMC Medicine. 2020;18:224. doi.org/10.1186/s12916-020-01688-6
11. Luzio SD, Dunseath G, Lockett A, Broke-Smith TP, New RR, Owens DR. The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes Diabetes, Obesity and Metabolism. 2009 doi: 10.1111/j.1463-1326.2009.01146.x.
12. New RRC, Bogus M, Travers GN, Hahn U, Vaiceliunaite A, Burnet M, Wang JH and Wen H. Glucagon-like peptide-1 receptor agonists for treatment of diabetes and obesity: advantage of oral delivery. Front. Drug Deliv. 2024;4:1456654. doi: 10.3389/fddev.2024.1456654.
13. Gotham D, Barber MJ, Hill A. Production costs and potential prices for biosimilars of human insulin and insulin analogues. BMJ Glob Health 2018;3: e000850. doi:10.1136/bmjgh-2018-000850
14. Barber MJ, Gotham D, Bygrave H, Cepuch C. Estimated Sustainable Cost-Based Prices for Diabetes Medicines. JAMA Network Open. 2024;7(3):e243474. doi:10.1001/jamanetworkopen.2024.3474
15. Beran D, Laing RO, Kaplan W, Knox R, Sharma A, Wirtz VJ, Frye J, Ewen M. A perspective on global access to insulin: a descriptive study of the market, trade flows and prices Diabet. Med. 2019 36: 726–733 DOI: 10.1111/dme.13947
16. Van Nuys K, Ribero R, Ryan M, Sood N. Estimation of the Share of Net Expenditures on Insulin Captured by US Manufacturers, Wholesalers, Pharmacy Benefit Managers, Pharmacies, and Health Plans From 2014 to 2018 JAMA Health Forum. 2021;2(11):e213409. doi:10.1001/jamahealthforum.2021.3409
17. Clement S, Still JG, Kosutic G, McAllister RG. Oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM2. Diabetes Technol Ther. 2002;4:459–66.
18. Kipnes M, Dandona P, Tripathy D, Still JG, Kosutic G. Control of postprandial plasma glucose by an oral insulin product (HIM2) in patients with type 2 diabetes. Diabetes Care. 2003;26:421–6.
19. Clement S, Dandona P, Still JG, Kosutic G. Oral modified insulin (HIM2) in patients with type 1 diabetes mellitus: results from a phase I/II clinical trial. Metabolism. 2004;53:54–8.
20. Heise T, Kapitza C, Nosek L, Becket P, Gelfand R, Goldberg M, Arbit E. Oral insulin as first-line therapy in type 2 diabetes: a randomized controlled pilot study. Diabetologia. 2004;47(Suppl 1):A5
21. Whitelaw DC, Kelly CA, Ironmonger W, Cunliffe C, New R, Phillips JN. Absorption of orally ingested insulin in human type 1 diabetic subjects: proof of concept study. Diabetes. 2005;54(suppl 1):5-LB.
22. Goldberg M, Dinh S, Castelli C, Majuru S, Arbit E. Improved glycemic control with oral recombinant human insulin in patients with type 2 diabetes (T2DM) inadequately controlled on metformin. Diabetes. 2007;56(suppl 2):A121.
23. Schwartz S, Geho B, Rosenberg L. Single-blind, placebo-controlled, dose-ranging trial of oral HDV-insulin in patients with type 2 diabetes mellitus. Diabetes. 2008;57(Suppl 1):A127.
24. Schwartz S, Geho B, Rosenberg L, Lau J. A 2-week randomized active comparator study of two HDV-Insulin routes (SC and oral) and SC human insulin in patients with type 1 diabetes. Diabetes. 2008;57(Suppl 1):A124.
25. Kapitza C, Zijlstra E, Heinemann L, Castelli MC, Riley G, Heise T. Oral insulin: a comparison with subcutaneous regular human insulin in patients with type 2 diabetes. Diabetes Care. 2010;33:1288-1290
26. Khedkar A, Iyer H, Anand A, Verma M, Krishnamurthy S, Savale S, et al. A dose range finding study of novel oral insulin (IN-105) under fed conditions in type 2 diabetes mellitus subjects. Diabetes Obes Metab. 2010;12:659–64.
27. Eldor, R.; Arbit, E.; Corcos, A.; Kidron, M. Glucose-Reducing Effect of the ORMD-0801 Oral Insulin Preparation in Patients with Uncontrolled Type 1 Diabetes: A Pilot Study. PLoS ONE 2013, 8, e59524.
28. Rachmiel M, Barash G, Leshem A, Sagi R, Doenyas-barak K, Koren S. OR14-1 pharmacodynamics, safety, tolerability, and efficacy of oral insulin formulation (Oshadi Icp) among young adults with type 1 diabetes: a summary of clinical studies phases I, Ib, and II. J Endocr Soc. 2019;3:OR14-1.
29. Halberg IB, Lyby K, Wassermann K, Heise T, Zijlstra E, Plum-Mörschel L. Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in type 2 diabetes: a randomised, double-blind, phase 2 trial. Lancet Diabetes Endocrinol. 2019; 7:179–88 http://dx.doi.org/10.1016/S2213-8587(18)30372-3
30. Khedkar A, Lebovitz H, Fleming A, Cherrington A, Jose V, Athalye SN, Vishweswaramurthy A. Pharmacokinetics and Pharmacodynamics of Insulin Tregopil in Relation to Premeal Dosing Time, Between Meal Interval, and Meal Composition in Patients With Type 2 Diabetes Mellitus. Clinical Pharmacology in Drug Development 2020, 9(1) 74–86 DOI: 10.1002/cpdd.730
31. Eldor R, Neutel J, Homer K, Kidron M. Efficacy and safety of 28-day treatment with oral insulin (ORMD-0801) in patients with type 2 diabetes mellitus - A randomized placebo-controlled trial. Diabetes Obes Metab. 2021 Nov;23(11):2529-2538. doi: 10.1111/dom.14499. Epub 2021 Aug 18
32. Lebovitz HE, Fleming A, Cherrington AD, Joshi S, Athalye SN, Loganathan S, Vishweswaramurthy A, Panda J, Marwah A. Efficacy and Safety of Tregopil, a Novel, Ultra-Rapid Acting Oral Prandial Insulin Analog, as Part of a Basal-Bolus Regimen in Type 2 Diabetes: A Randomized, Active Controlled Phase 2/3 Study. Expert Opinion on Pharmacotherapy. 2022; doi: 10.1080/14656566.2022.2141569.
33. Eldor R, Francis BH, Fleming A, Neutel J, Homer K, Kidron M, Rosenstock J. Oral Insulin (ORMD-0801) in Type 2 Diabetes Mellitus: Dose-Finding 12-Week Randomized Placebo-Controlled Study. Diabetes, Obesity and Metabolism 2022 doi.org/10.1111/dom.14901
34. Pechenov, S., Revell, J., Will, S. Naylor, J., Tyagi, P. et al. (2021) Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease. Sci Rep 11, 22521 doi.org/10.1038/s41598-021-01750-0
35. Low YC, Gan WL, Lai SJ, Tam RSM, Tan JF, Dietl S, Chuah LH, Voelcker N, Bakhtiar A. Critical updates on oral insulin drug delivery systems for type 2 diabetes mellitus. J Nanobiotechnology (2025) 23:16. doi.org/10.1186/s12951-024-03062-7
36. Bhattacharjee S. On the Relentless Pursuit of an Oral Insulin Delivery System: How Far is Too Far? Advanced Therapeutics (2025) doi.org/10.1002/ad tp.202400566
37. Gastaldelli A, Toschi E, Pettiti M, Frascerra S, Quiñones-Galvan A, Sironi AM, Natali A, Ferrannini E. Effect of Physiological Hyperinsulinemia on Gluconeogenesis in Nondiabetic Subjects and in Type 2 Diabetic Patients. Diabetes 2001;50:1807-12
2. New, RRC., 2025. Oral Insulin – Harnessing the Natural Physiology of Glucose Control in the Body. Medical Research Archives, [online] 13(1).
https://doi.org/10.18103/mra.v13i1.6180
3. Brayden DJ (2021) The Centenary of the Discovery of Insulin: An Update on the Quest for Oral Delivery. Front. Drug. Deliv. 1:726675. doi: 10.3389/fddev.2 021.726675
4. Twarog, C.; Fattah, S.; Heade, J.; Maher, S.; Fattal, E.; Brayden, D.J. Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10). Pharmaceutics 2019 11, 78-99; doi:10.3390/pharmaceutics11020078
5. Maher S, Brayden DJ, Casettari L, Illum L. Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update. Pharmaceutics 2019, 11, 41; doi:10.3390/pharmaceutics11010041
6. Ergun-Longmire B, Marker J, Zeidler A, Rapaport R, Raskin P, Bode B, Schatz D, Vargas, A, Rogers D, Schwartz S, Malone J, Krischer J, Maclaren NK. Oral Insulin Therapy to Prevent Progression of Immune-Mediated (Type 1) Diabetes. Ann. N.Y. Acad. Sci. 2004; 1029: 260–277.
7. The Diabetes Prevention Trial – Type 1. Effects of Oral Insulin in Relatives of Patients With Type 1 Diabetes. Diabetes Care. 2005;28:5 1068-1076.
8. New RRC, Ramanujam S, Chaudhari V, Bogus M, Travers GN. Namjoshi G. Safety and Efficacy of an Oral Insulin (Capsulin) in Patients with Early-Stage Type 2 Diabetes: A Dose-Ranging Phase IIb Study. Diabetes Obes Metab. 2022;1–8.
9. Zhang AMY, Wellberg EA, Kopp JL, Johnson JD. Hyperinsulinemia in Obesity, Inflammation, and Cancer. Diabetes Metab J. 2021;45:285-311. doi.org/10.4093/dmj.2020.0250.
10. Kolb H, Kempf K, Röhling M, Martin S. Insulin: too much of a good thing is bad. BMC Medicine. 2020;18:224. doi.org/10.1186/s12916-020-01688-6
11. Luzio SD, Dunseath G, Lockett A, Broke-Smith TP, New RR, Owens DR. The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes Diabetes, Obesity and Metabolism. 2009 doi: 10.1111/j.1463-1326.2009.01146.x.
12. New RRC, Bogus M, Travers GN, Hahn U, Vaiceliunaite A, Burnet M, Wang JH and Wen H. Glucagon-like peptide-1 receptor agonists for treatment of diabetes and obesity: advantage of oral delivery. Front. Drug Deliv. 2024;4:1456654. doi: 10.3389/fddev.2024.1456654.
13. Gotham D, Barber MJ, Hill A. Production costs and potential prices for biosimilars of human insulin and insulin analogues. BMJ Glob Health 2018;3: e000850. doi:10.1136/bmjgh-2018-000850
14. Barber MJ, Gotham D, Bygrave H, Cepuch C. Estimated Sustainable Cost-Based Prices for Diabetes Medicines. JAMA Network Open. 2024;7(3):e243474. doi:10.1001/jamanetworkopen.2024.3474
15. Beran D, Laing RO, Kaplan W, Knox R, Sharma A, Wirtz VJ, Frye J, Ewen M. A perspective on global access to insulin: a descriptive study of the market, trade flows and prices Diabet. Med. 2019 36: 726–733 DOI: 10.1111/dme.13947
16. Van Nuys K, Ribero R, Ryan M, Sood N. Estimation of the Share of Net Expenditures on Insulin Captured by US Manufacturers, Wholesalers, Pharmacy Benefit Managers, Pharmacies, and Health Plans From 2014 to 2018 JAMA Health Forum. 2021;2(11):e213409. doi:10.1001/jamahealthforum.2021.3409
17. Clement S, Still JG, Kosutic G, McAllister RG. Oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM2. Diabetes Technol Ther. 2002;4:459–66.
18. Kipnes M, Dandona P, Tripathy D, Still JG, Kosutic G. Control of postprandial plasma glucose by an oral insulin product (HIM2) in patients with type 2 diabetes. Diabetes Care. 2003;26:421–6.
19. Clement S, Dandona P, Still JG, Kosutic G. Oral modified insulin (HIM2) in patients with type 1 diabetes mellitus: results from a phase I/II clinical trial. Metabolism. 2004;53:54–8.
20. Heise T, Kapitza C, Nosek L, Becket P, Gelfand R, Goldberg M, Arbit E. Oral insulin as first-line therapy in type 2 diabetes: a randomized controlled pilot study. Diabetologia. 2004;47(Suppl 1):A5
21. Whitelaw DC, Kelly CA, Ironmonger W, Cunliffe C, New R, Phillips JN. Absorption of orally ingested insulin in human type 1 diabetic subjects: proof of concept study. Diabetes. 2005;54(suppl 1):5-LB.
22. Goldberg M, Dinh S, Castelli C, Majuru S, Arbit E. Improved glycemic control with oral recombinant human insulin in patients with type 2 diabetes (T2DM) inadequately controlled on metformin. Diabetes. 2007;56(suppl 2):A121.
23. Schwartz S, Geho B, Rosenberg L. Single-blind, placebo-controlled, dose-ranging trial of oral HDV-insulin in patients with type 2 diabetes mellitus. Diabetes. 2008;57(Suppl 1):A127.
24. Schwartz S, Geho B, Rosenberg L, Lau J. A 2-week randomized active comparator study of two HDV-Insulin routes (SC and oral) and SC human insulin in patients with type 1 diabetes. Diabetes. 2008;57(Suppl 1):A124.
25. Kapitza C, Zijlstra E, Heinemann L, Castelli MC, Riley G, Heise T. Oral insulin: a comparison with subcutaneous regular human insulin in patients with type 2 diabetes. Diabetes Care. 2010;33:1288-1290
26. Khedkar A, Iyer H, Anand A, Verma M, Krishnamurthy S, Savale S, et al. A dose range finding study of novel oral insulin (IN-105) under fed conditions in type 2 diabetes mellitus subjects. Diabetes Obes Metab. 2010;12:659–64.
27. Eldor, R.; Arbit, E.; Corcos, A.; Kidron, M. Glucose-Reducing Effect of the ORMD-0801 Oral Insulin Preparation in Patients with Uncontrolled Type 1 Diabetes: A Pilot Study. PLoS ONE 2013, 8, e59524.
28. Rachmiel M, Barash G, Leshem A, Sagi R, Doenyas-barak K, Koren S. OR14-1 pharmacodynamics, safety, tolerability, and efficacy of oral insulin formulation (Oshadi Icp) among young adults with type 1 diabetes: a summary of clinical studies phases I, Ib, and II. J Endocr Soc. 2019;3:OR14-1.
29. Halberg IB, Lyby K, Wassermann K, Heise T, Zijlstra E, Plum-Mörschel L. Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in type 2 diabetes: a randomised, double-blind, phase 2 trial. Lancet Diabetes Endocrinol. 2019; 7:179–88 http://dx.doi.org/10.1016/S2213-8587(18)30372-3
30. Khedkar A, Lebovitz H, Fleming A, Cherrington A, Jose V, Athalye SN, Vishweswaramurthy A. Pharmacokinetics and Pharmacodynamics of Insulin Tregopil in Relation to Premeal Dosing Time, Between Meal Interval, and Meal Composition in Patients With Type 2 Diabetes Mellitus. Clinical Pharmacology in Drug Development 2020, 9(1) 74–86 DOI: 10.1002/cpdd.730
31. Eldor R, Neutel J, Homer K, Kidron M. Efficacy and safety of 28-day treatment with oral insulin (ORMD-0801) in patients with type 2 diabetes mellitus - A randomized placebo-controlled trial. Diabetes Obes Metab. 2021 Nov;23(11):2529-2538. doi: 10.1111/dom.14499. Epub 2021 Aug 18
32. Lebovitz HE, Fleming A, Cherrington AD, Joshi S, Athalye SN, Loganathan S, Vishweswaramurthy A, Panda J, Marwah A. Efficacy and Safety of Tregopil, a Novel, Ultra-Rapid Acting Oral Prandial Insulin Analog, as Part of a Basal-Bolus Regimen in Type 2 Diabetes: A Randomized, Active Controlled Phase 2/3 Study. Expert Opinion on Pharmacotherapy. 2022; doi: 10.1080/14656566.2022.2141569.
33. Eldor R, Francis BH, Fleming A, Neutel J, Homer K, Kidron M, Rosenstock J. Oral Insulin (ORMD-0801) in Type 2 Diabetes Mellitus: Dose-Finding 12-Week Randomized Placebo-Controlled Study. Diabetes, Obesity and Metabolism 2022 doi.org/10.1111/dom.14901
34. Pechenov, S., Revell, J., Will, S. Naylor, J., Tyagi, P. et al. (2021) Development of an orally delivered GLP-1 receptor agonist through peptide engineering and drug delivery to treat chronic disease. Sci Rep 11, 22521 doi.org/10.1038/s41598-021-01750-0
35. Low YC, Gan WL, Lai SJ, Tam RSM, Tan JF, Dietl S, Chuah LH, Voelcker N, Bakhtiar A. Critical updates on oral insulin drug delivery systems for type 2 diabetes mellitus. J Nanobiotechnology (2025) 23:16. doi.org/10.1186/s12951-024-03062-7
36. Bhattacharjee S. On the Relentless Pursuit of an Oral Insulin Delivery System: How Far is Too Far? Advanced Therapeutics (2025) doi.org/10.1002/ad tp.202400566
37. Gastaldelli A, Toschi E, Pettiti M, Frascerra S, Quiñones-Galvan A, Sironi AM, Natali A, Ferrannini E. Effect of Physiological Hyperinsulinemia on Gluconeogenesis in Nondiabetic Subjects and in Type 2 Diabetic Patients. Diabetes 2001;50:1807-12