Insulin is a hormone naturally produced by the pancreas, playing a central role in regulating blood sugar levels. It helps move glucose from the bloodstream into cells, where it is used for energy or stored for later use. When the body does not produce enough insulin or cannot use it effectively, blood glucose levels rise, leading to diabetes. For over a century, managing diabetes has involved administering insulin, with a long-standing aspiration to develop an oral form for easier treatment.
The Need for Oral Insulin
Traditional insulin administration involves subcutaneous injections, which have several drawbacks. Daily injections can cause discomfort, pain, and needle phobia. Side effects include weight gain, low blood sugar (hypoglycemia), and injection site reactions like rashes or lumps.
Multiple daily injections impact quality of life and treatment adherence. An oral alternative would offer increased convenience and a non-invasive method. This could improve patient compliance and mimic the body’s natural insulin secretion, delivering insulin directly to the liver.
Challenges of Oral Delivery
Developing an oral form of insulin faces biological and chemical obstacles. As a protein, insulin is highly susceptible to degradation within the gastrointestinal (GI) tract. The stomach’s acidic environment (pH 1-3) can readily cleave insulin’s disulfide bonds, leading to denaturation and inactivation.
Beyond stomach acid, digestive enzymes like pepsin in the stomach and proteases (trypsin, chymotrypsin, carboxypeptidases) in the small intestine further break down insulin. These enzymes degrade proteins, leaving little intact insulin for absorption. Even if insulin survives degradation, its large molecular size and hydrophilic nature hinder passage across the intestinal wall into the bloodstream. Finally, absorbed insulin must navigate “first-pass metabolism” in the liver, where a significant portion is metabolized before reaching systemic circulation, reducing its bioavailability to less than 1%.
Strategies for Oral Absorption
To overcome these challenges, various scientific approaches are being explored for oral insulin absorption. One strategy involves encapsulating insulin in protective coatings to shield it from harsh GI conditions. For instance, nanoparticles and microspheres, often made from biodegradable polymers like chitosan, can protect insulin from enzymatic degradation and acidic environments.
These nanocarriers also facilitate insulin’s uptake across the intestinal lining by enhancing paracellular transport (between cells) or transcellular transport (through cells). Another approach involves incorporating permeation enhancers, compounds that temporarily open tight junctions between intestinal cells, allowing larger molecules like insulin to pass through. Researchers are also developing enzyme inhibitors that can be co-administered to reduce proteolytic enzyme activity in the GI tract, preserving insulin’s integrity.
Current Progress and Future Prospects
Progress has been made in oral insulin research, with several formulations in clinical trials. While a widely available oral insulin product is not yet on the market, advancements in nanotechnology and formulation science offer promising pathways. For example, early formulations like Nodlin™ have shown glucose-lowering effects comparable to injected insulin in Phase I trials, though efficacy variability remains a challenge.
Researchers are developing “smart insulin” formulations encapsulated in nanocarriers that could release insulin only when blood sugar levels are high, reducing the risk of hypoglycemia. This technology is anticipated to enter human clinical trials as early as 2025, with hopes for market availability within two to three years if successful. The approval of an effective oral insulin could revolutionize diabetes management, offering a patient-friendly treatment option and improving the quality of life for millions globally.