The Need for Oral Insulin

Abstract

Type 1 Diabetes Mellitus (T1DM) is a chronic autoimmune disorder characterized by immune-mediated destruction of pancreatic ?-cells, resulting in absolute insulin deficiency. Conventional insulin therapy, administered via subcutaneous injections, is effective but associated with limitations such as patient discomfort, poor compliance, storage challenges, and unpredictable absorption. Oral insulin represents a promising alternative, potentially improving patient adherence and mimicking physiological insulin delivery through the portal-hepatic system. However, oral administration is hindered by multiple barriers, including enzymatic degradation in the gastrointestinal tract, acidic gastric environment, poor intestinal absorption, and first-pass metabolism, which inactivate the protein. Recent advances in nanotechnology have demonstrated that nanoparticles can overcome these challenges by protecting insulin from degradation, enhancing intestinal uptake, and enabling controlled drug release. This review highlights the need for oral insulin, discusses the limitations of conventional therapy, explores recent developments in novel oral delivery systems, and examines regulatory and commercial aspects, emphasizing the future potential of oral insulin to transform diabetes management.

Introduction

Diabetes mellitus affects more than 500 million people worldwide and continues to rise. Insulin therapy is essential for Type 1 diabetes and advanced Type 2 diabetes, but current subcutaneous injections are painful, inconvenient, and fail to mimic the body’s natural insulin pathway, which normally delivers insulin first to the liver via the portal vein. These drawbacks reduce compliance, create non-physiological insulin distribution, and impose storage and cost burdens—highlighting the need for an effective oral insulin formulation.

Oral insulin has the potential to replicate physiological insulin delivery, improve patient adherence, reduce systemic side effects, and eliminate needle-related problems. However, the gastrointestinal tract creates major challenges: insulin is degraded by enzymes, destroyed by stomach acid, poorly absorbed across the intestinal barrier, and has extremely low bioavailability (<1%). Successful development therefore requires protecting insulin and enhancing its absorption.

To overcome these barriers, various delivery strategies are being explored, including protease inhibitors, permeation enhancers, nanoparticle/lipid carriers, mucoadhesive and pH-responsive polymers, microencapsulation, self-emulsifying systems, and receptor-mediated transport approaches. Multiple academic and industrial programs—such as Oramed’s ORMD-0801, Biocon’s insulin tregopil, and Diasome’s hepatic-directed vesicles—have shown partial success, though none have yet achieved FDA approval due to limited bioavailability and inconsistent glycemic control.

Regulatory development of oral insulin involves stringent preclinical toxicity and stability studies, followed by multi-phase clinical trials assessing safety, absorption, and long-term efficacy. Manufacturing must be GMP-compliant and ensure formulation stability and batch consistency.

Commercially, oral insulin has strong global demand, with over 530 million people living with diabetes and high patient preference for non-injectable therapies. It also offers potential economic benefits by improving compliance, reducing complications, and lowering medical waste. However, challenges include high R&D costs, complex formulation requirements, regulatory hurdles, and slow clinical progress.

Overall, oral insulin remains a highly promising but technically demanding innovation. Advances in material science, nanotechnology, and drug-delivery research continue to bring it closer to becoming a practical and commercially viable therapy.

Conclusion

Insulin remains the cornerstone in the management of diabetes mellitus, yet its injectable route poses significant limitations such as pain, inconvenience, and poor compliance. The concept of oral insulin emerges as a patient-friendly and physiologically superior alternative, capable of mimicking the natural insulin pathway through the liver. Despite numerous scientific and regulatory challenges- such as instability in the GI tract, poor absorption, and complex manufacturing – recent advances in nanotechnology, formulation science, and drug delivery systems are bringing this vision closer to reality. Regulatory bodies are cautiously optimistic, and several late-stage clinical trials indicate that oral insulin could soon become a viable therapeutic option. Once commercialized, it is expected to improve patient compliance, enhance quality of life, and reduce the healthcare burden associated with injectable therapy.

References

[1] Thomas N, Kapoor N, Velavan J, Vasan KS, editors. A practical guide to diabetes mellitus. 7th ed. New Delhi: Jaypee Brothers Medical Publishers; 2016. [2] Brown AM. One hundred years of insulin. London: The Physiological Society; 2021. [3] Holt RI, Cockram CS, Flyvbjerg A, Goldstein BJ, editors. Textbook of Diabetes. 4th ed. West Sussex: Wiley-Blackwell; 2010. [4] Carino GP, Mathiowitz E. Oral insulin delivery. Advanced drug delivery reviews. 1999 Feb 1;35(2-3):249-57. [5] Xiao Y, Tang Z, Wang J, Liu C, Kong N, Farokhzad OC, Tao W. Oral insulin delivery platforms: strategies to address the biological barriers. Angewandte Chemie International Edition. 2020 Nov 2;59(45):19787-95. [6] Fonte P, Araújo F, Reis S, Sarmento B. Oral insulin delivery: how far are we?. Journal of diabetes science and technology. 2013 Mar;7(2):520-31. [7] Iyer G, Dyawanapelly S, Jain R, Dandekar P. An overview of oral insulin delivery strategies (OIDS). International Journal of Biological Macromolecules. 2022 May 31;208:565-85. [8] Wong TW. Design of oral insulin delivery systems. Journal of drug targeting. 2010 Feb 1;18(2):79-92. [9] Gedawy A, Martinez J, Al-Salami H, Dass CR. Oral insulin delivery: existing barriers and current counter-strategies. Journal of pharmacy and pharmacology. 2018 Feb;70(2):197-213. [10] Zhang E, Zhu H, Song B, Shi Y, Cao Z. Recent advances in oral insulin delivery technologies. Journal of Controlled Release. 2024 Feb 1;366:221-30. [11] Sonia TA, Sharma CP. An overview of natural polymers for oral insulin delivery. Drug discovery today. 2012 Jul 1;17(13-14):784-92. [12] Arbit E, Kidron M. Oral insulin delivery in a physiologic context. Journal of diabetes science and technology. 2017 Jul;11(4):825-32. [13] Mukhopadhyay P, Mishra R, Rana D, Kundu PP. Strategies for effective oral insulin delivery with modified chitosan nanoparticles: a review. Progress in polymer science. 2012 Nov 1;37(11):1457-75. [14] Sarmento B, Martins S, Ferreira D, Souto EB. Oral insulin delivery by means of solid lipid nanoparticles. International journal of nanomedicine. 2007 Dec 1;2(4):743-9. [15] Sarmento B, Ribeiro A, Veiga F, Sampaio P, Neufeld R, Ferreira D. Alginate/chitosan nanoparticles are effective for oral insulin delivery. Pharmaceutical research. 2007 Dec;24(12):2198-206. [16] Shah RB, Patel M, Maahs DM, Shah VN. Insulin delivery methods: Past, present and future. International journal of pharmaceutical investigation. 2016 Jan;6(1):1. [17] Luo YY, Xiong XY, Tian Y, Li ZL, Gong YC, Li YP. A review of biodegradable polymeric systems for oral insulin delivery. Drug delivery. 2016 Jul 23;23(6):1882-91. [18] Fonte P, Araújo F, Silva C, Pereira C, Reis S, Santos HA, Sarmento B. Polymer-based nanoparticles for oral insulin delivery: Revisited approaches. Biotechnology advances. 2015 Nov 1;33(6):1342-54. [19] Shetty SS, Halagali P, Johnson AP, Spandana KA, Gangadharappa HV. Oral insulin delivery: Barriers, strategies, and formulation approaches: A comprehensive review. International Journal of Biological Macromolecules. 2023 Jul 1;242:125114. [20] Oramed Pharmaceuticals. Oramed announces top-line results from Phase 3 trial of ORMD-0801 for the treatment of type 2 diabetes [Internet]. New York: Oramed Pharmaceuticals; 2023 Jan 11 [cited 2025 Oct 30]. Available from: https://www.oramed.com [21] ClinicalTrials.gov. Phase II safety and efficacy study of oral ORMD-0801 in subjects with type 2 diabetes mellitus [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2023 [cited 2025 Oct 30]. Available from: https://clinicaltrials.gov/ct2/show/NCT02496000 [22] Joshi SR, Vora JP, Kalra S. Insulin tregopil: an ultra-fast oral recombinant human insulin—clinical development overview. Drugs. 2023;83(6):527–536. doi:10.1007/s40265-023-01890-5 [23] Lebovitz HE, Ghosh S, Dandona P, Gupta Y, et al. Efficacy and safety of Tregopil, a novel, ultra-rapid acting oral prandial insulin tablet. Diabetes Obes Metab. 2022;24(10):2068–2078. doi:10.1111/dom.14760 [24] ClinicalTrials.gov. Evaluation of pharmacokinetics, safety and tolerability of orally administered insulin Tregopil in type 1 diabetes [Internet]. Bethesda (MD): U.S. National Library of Medicine; 2024 [cited 2025 Oct 30]. Available from: https://clinicaltrials.gov/ct2/show/NCT04141423 [25] Diasome Pharmaceuticals. Diasome completes enrollment in Phase 2b OPTI-2 trial of HDV-Insulin Lispro for type 1 diabetes [Internet]. Cleveland (OH): Diasome Pharmaceuticals; 2025 Feb [cited 2025 Oct 30]. Available from: https://www.diasome.com [26] Hunt NJ, Bunnag N, Singh SP, Nguyen LC, et al. Oral nanotherapeutic formulation of insulin with reduced immunogenicity and improved bioavailability. Nat Nanotechnol. 2024;19(3):224–233. doi:10.1038/s41565-024-01790-7 [27] World Health Organization (WHO). Global report on diabetes [Internet]. Geneva: World Health Organization; 2023 [cited 2025 Oct 30]. Available from: https://www.who.int/diabetes

Copyright

Copyright © 2025 Varun Kumar, Tarkeshwar Prasad Shukla, Pramod Mishra, Sujeet Pratap Singh. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.