Diabetology employs the proprietary patented “Axcess” technology, in-licensed from Axcess Limited, to deliver peptides and proteins via the oral route. Using this, Diabetology’s oral insulin (Capsulin™) and oral GLP-1 receptor agonists have been tested in man in both Type 2 Diabetes Mellitus and Type 1 Diabetes Mellitus (see Pipeline )
Diabetology’s Capsulin™ oral insulin is delivered via the small intestine, and consequently is drained directly into the portal vein, before being taken up by insulin receptors on the surface of the liver cells. Only a small amount of the insulin delivered enters the peripheral blood circulation.
In contrast, injected insulin maintains high levels of insulin in the bloodstream, which is taken up principally by muscle cells and adipose tissue, very little reaching the liver. High prolonged insulinaemia in the blood circulation can lead to many undesirable side effects – eg micro- and macro-vascular abnormalities – which can occur with long-term use of injected insulin, but will be avoided with Capsulin™ oral insulin.
In addition, the liver (the organ designated by Nature to control glucose disposal under the influence of insulin) has a sensor mechanism for glucose which prevents it from removing excessive quantities of glucose from the bloodstream below the safe level, thus avoiding hypoglycaemia. Muscle cells have no such control mechanism, so use of injected insulin always comes with a risk of life-threatening hypoglycaemia. Because of the increased level of safety associated with Diabetology’s Capsulin™, as demonstrated in its phase 2b clinical trial, this treatment is suitable for use in T2DM not only in the late stages of the disease, but also in the early stages (eg together with metformin). Many studies have already demonstrated that early insulin administration improves prognosis for the disease.
| Parameters for Diabetes Therapy | Capsulin™ | Metformin | Sulphonyl Ureas | TZDs | SGLT2 inhibitors* | DPP4 inhibitors** | GLP-1 RAs† |
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Potential for improvement of prognosis (Beta Cells?) |
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Durability of effect with time, low dropouts |
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Potential to overcome insulin resistance |
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Absence of GI issues |
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Does not cause hypoglycaemia |
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No weight increase |
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Absence of cardiovascular implications |
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Insulin is a natural hormone of the body, and when administered orally in Capsulin™ it follows the same path to the liver (via the portal vein) as insulin from the pancreas, and in similar quantities to those generated naturally. Consequently, side effects are not to be expected with Capsulin™ oral insulin, and this is indeed borne out by the results of studies which Diabetology has conducted so far.
In contrast, a wide range of side effects are seen with other anti-diabetic agents, oral or otherwise (see table below).
Since these agents are acting on mechanisms in the body in an unnatural way, it is not surprising that the body adjusts to mitigate the action of these drugs, so that their activity wanes over time. This is not seen with insulin, and indeed there are indications with Capsulin™ oral insulin, in studies conducted by Diabetology, that insulin resistance may be overcome after Capsulin™ administration.
Capsulin™ outperforms other delivery technologies in terms of the biopotency it achieves, and its safety profile. It uses unmodified recombinant human insulin, and the formulation excipients are all GRAS-listed or pharmacopeial.
Whereas other technologies such as SNAC deliver via the stomach, Capsulin™ takes the insulin to the small intestine, so that it can feed directly into the liver, without high levels of insulin entering the bloodstream.
Capsulin™ achieves delivery via the transcellular route, taking advantage of natural mechanisms of intestinal uptake, while other systems (for example those using lipid-based permeation enhancers) open the tight junctions, which may prejudice the integrity of the intestinal cell wall.
Delivery direct to the liver allows Capsulin™ to benefit from the prolonged action of insulin on the liver. This means that, although insulin may be delivered with 20 minutes after administration, its action in the body lasts for 9 to 12 hours, so that two capsules (one before breakfast and one before supper) is sufficient to cover the body’s need for the day. In contrast, other technologies – including those employing modified insulins – have a short-term action, limiting their capabilities to prandial insulin only, without basal cover.
Oraglutide is able to deliver GLP-1 RAs via the small intestine. In the case of these peptides this gives Oraglutide a unique advantage, since important receptors for GLP-1 are located in the small intestine itself, which are not easily reached via the injected route, or via oral formulations which avoid the intestine altogether by crossing the stomach wall.
In normal healthy individuals GLP-1 is secreted by L cells in the gut, and interacts primarily with receptors on the Vagal Afferent Nerve (VAN), so that GLP-1/VAN interaction in the intestine is clearly an important physiological mechanism in control of glucose and satiety, which Oraglutide is harnessing.
Close proximity of intestinal cells with vagal afferents
In Oraglutide, GLP-1 RAs cross the intestinal cells via the transcellular route and come into close contact with the vagal afferent nerve cell lining the intestine, even without leaving the intestinal milieu. After binding to the GLP-1 receptors on these cells, signals are triggered, sending messages to the brain to induce satiety and weight loss, as well as improved glucose control. This mode of action is not achievable by delivery across the stomach wall.
Oral Capsule Technology for Insulin, GLP-1 and Other Protein-Based Therapies and Combinations.
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