Integrative Biomedical Research
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN 3068-6326
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Volume 10 Number 2 2026
REVIEWS (Open Access)
Oral Insulin and GLP-1 Receptor Agonist Delivery Technological Advances and Physiological Barriers Toward Non-Invasive Diabetes Therapeutics
Gnanasekaran Ashok 1*, Diksha D Shroff 2, Lubna Shirin 3, Pugazhandhi Bakthavatchalam 4
Integrative Biomedical Research 10 (2) 1-8 https://doi.org/10.25163/biomedical.10210939
Submitted: 11 September 2026 Revised: 01 November 2026 Accepted: 08 November 2026 Published: 10 November 2026
Abstract
Subcutaneous injection still dominates insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, and honestly, it shows: needle-related pain, lipodystrophy, and non-adherence continue to blunt the real-world benefit of otherwise excellent molecules. This review asks a fairly simple question with a stubbornly complicated answer — can these biologics be swallowed instead of injected, and if so, how close are we? We synthesized recent formulation, device, and clinical literature (2023-2026) describing oral and transmucosal delivery of insulin and GLP-1RAs. Across the gastrointestinal tract, peptides confront a near-continuous gauntlet: gastric acid and pepsin, pancreatic and brush-border proteases, a viscoelastic mucus mesh, tight-junction-sealed epithelium, and, for whatever survives, hepatic first-pass extraction — together limiting unformulated bioavailability to well under 1%. Four broad engineering responses have emerged. Chemical permeation enhancers such as salcaprozate sodium (SNAC) and ionic liquids transiently fluidize membranes, underpinning the only currently approved product, oral semaglutide (Rybelsus®), though its bioavailability remains near 1% and its chronic gut-microbiota effects warrant continued scrutiny. Lipid, polymeric, zwitterionic, and transporter-targeted nanocarriers push relative bioavailability toward the 4-27% range in preclinical models. Ingestible micro-injectors (SOMA, LUMI), buccal and sublingual films, and engineered probiotic secretory depots bypass the gut lumen almost entirely. Meanwhile, non-peptide small-molecule GLP-1RAs sidestep the degradation problem altogether, reaching 20-30% oral bioavailability without enhancers. Taken together, the field has moved from proof-of-concept toward genuinely translatable platforms, though variable inter-subject absorption, excipient safety, and manufacturing scalability remain open questions. We argue that no single strategy is likely to “win” outright; rather, combinatorial and indication-specific approaches will probably define the next generation of non-invasive diabetes biologics.
Keywords: Oral insulin delivery; GLP-1 receptor agonists; peptide permeation enhancers; nanocarrier drug delivery; gastrointestinal barriers; oral bioavailability; diabetes mellitus
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