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Background <p>Oral insulin delivery offers improved patient compliance and physiological hepatic-first metabolism compared to subcutaneous injection. However, four critical barriers limit bioavailability to &lt; 1%: enzymatic degradation (70–90% loss), poor intestinal permeability (&lt; 0.5% unassisted), first-pass hepatic metabolism (60–80% loss), and rapid mucosal clearance.</p> Recent Findings <p>Current strategies employ hybrid multilayer systems combining protease inhibitors, reversible permeation enhancers, pH responsive polymers, and lipid carriers, achieving 5–15% bioavailability in human trials. Recent clinical trials (Tregopil Phase 2/3 NCT03430856; ORMD-0801 Phase 3 terminated January 2023 NCT02661932) demonstrate persistent challenges: bioavailability variability (Tregopil 18–28%; ORMD-0801 ~ 7%) and inadequate glycemic control. Emerging technologies including glucose-responsive microgels, biofilm-inspired coatings, and AI-driven optimization offer future promise within the medium to long term.</p> Summary <p>This review synthesizes quantitative data on barriers and delivery strategies, analyzes clinical trial outcomes, discusses regulatory pathways, and assesses technology readiness levels to identify near-term candidates for clinical approval. Schematic representation of the existing physiological hurdles to the delivery of oral insulin, like the acidic pH of the stomach, presence of proteolytic enzymes, mucus layer, tight junctions of the intestinal epithelial cells, first-pass metabolism of the liver, along with some prevailing technologies like encapsulation, carrier protection, surface modification for protecting the hormone from their effects to ensure intestinal delivery.</p> Graphical Abstract <p></p>

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Oral Insulin Delivery: Biological Barriers, Advanced Delivery Strategies, and Translational Limitations

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Hirthik Mageshkumar,
  • Ivana B. Hesper,
  • D. Dharani,
  • S Pandi Prabha,
  • C. Karthik

摘要

Background

Oral insulin delivery offers improved patient compliance and physiological hepatic-first metabolism compared to subcutaneous injection. However, four critical barriers limit bioavailability to < 1%: enzymatic degradation (70–90% loss), poor intestinal permeability (< 0.5% unassisted), first-pass hepatic metabolism (60–80% loss), and rapid mucosal clearance.

Recent Findings

Current strategies employ hybrid multilayer systems combining protease inhibitors, reversible permeation enhancers, pH responsive polymers, and lipid carriers, achieving 5–15% bioavailability in human trials. Recent clinical trials (Tregopil Phase 2/3 NCT03430856; ORMD-0801 Phase 3 terminated January 2023 NCT02661932) demonstrate persistent challenges: bioavailability variability (Tregopil 18–28%; ORMD-0801 ~ 7%) and inadequate glycemic control. Emerging technologies including glucose-responsive microgels, biofilm-inspired coatings, and AI-driven optimization offer future promise within the medium to long term.

Summary

This review synthesizes quantitative data on barriers and delivery strategies, analyzes clinical trial outcomes, discusses regulatory pathways, and assesses technology readiness levels to identify near-term candidates for clinical approval. Schematic representation of the existing physiological hurdles to the delivery of oral insulin, like the acidic pH of the stomach, presence of proteolytic enzymes, mucus layer, tight junctions of the intestinal epithelial cells, first-pass metabolism of the liver, along with some prevailing technologies like encapsulation, carrier protection, surface modification for protecting the hormone from their effects to ensure intestinal delivery.

Graphical Abstract