Projects
 

Oral Insulin

Capsulin™

Diabetology has developed a novel oral formulation of insulin using its in-licensed Axcess™ drug delivery technology. This delivery technology uses no NCE’s and has been shown to be effective as an oral delivery system for peptides in multiple animal models using not only insulin but also calcitonin and parathyroid hormone (PTH). It is reasonable to project that this product, trade-marked as Capsulin™, could replace a significant proportion of the sales of injected and infused insulin.

Oral insulin has many potential advantages over other forms of Insulin dellivery, as it most closely mimics the natural insulin secretion pathway from the pancreas to the liver. By delivering Insulin to the liver as the oral route does, the main organ of glucose regulation is solicited, and insulin side-effects in the peripheral circulation (from other routes of administration) may be avoided.

Target: Insulin replacement for diabetics
Stage: Successfully completed phase 2a

Background on Diabetes & Insulin

The inexorable spread of the western lifestyle across the world is precipitating a diabetes epidemic. Current worldwide prevalence is estimated at 2.3% (or 150 million people) and the number of diabetics is increasing by 4-5% p.a., implying that there could be over 220 million diabetics in the world by 2020. Diabetes is the most common human endocrine disease and the term covers a group of metabolic disorders whose central feature is elevated blood glucose, or hyperglycemia. Sustained hyperglycemia results in the deterioration of multiple tissue types, particularly vascular tissues, and may eventually lead to kidney failure, cardiovascular disease, leg ulcers, stroke, neuropathy and retinopathy. It is estimated that the direct medical costs of diabetes amount to nearly $92 billion annually in the US alone.

The principal regulator of blood glucose concentration is insulin, a hormone synthesized by the ß islet cells of the pancreas and secreted in response to elevated blood glucose levels. Insulin increases the uptake of glucose by multiple tissues, promotes its utilization as an energy source, reduces the production of new glucose, and slows down the production and release of alternative energy sources such as fatty acids. Its principal target organs are the liver, skeletal muscle and fat tissue. In particular, the liver plays a central role in maintaining blood glucose concentration within normal limits since it is both a major point of glucose uptake when blood levels of the substance rise and the primary source of glucose production to counter low blood glucose levels (hypoglycaemia).

Frequent Q&A on Capsulin™

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Study Results

Phase 2a study (Type 1 Diabetics):

The second clinical study of Diabetology Ltd.'s oral insulin product Capsulin™ was undertaken in the UK in 2004 to investigate the effect of administering two doses of the product in capsules to Type 1 diabetics by measuring blood glucose and circulating plasma insulin levels. This was a single-centre, open-label, two-way sequential oral dose-finding study using male Type 1 diabetic volunteers. The two doses investigated were 150iu and 300iu with the volunteers challenged with each dose on one occasion, separated by at least a 120-hour washout period. The primary endpoint was the absolute change in blood glucose after administration of Capsulin™; the secondary endpoints included its effect on plasma insulin levels.

During the course of the study, mean blood glucose levels dropped in the subjects; those receiving the higher dose showed a higher fall and blood glucose levels were continuing to fall even at the end of the 7-hour study period. Insulin levels were detectable above background in the patients’ bloodstream at various times throughout the course of the study. The main conclusions of the study are as follows:

  • Capsulin appears to be safe & well tolerated in Type 1 diabetics;
  • Capsulin produced consistent increases in blood insulin levels within 30-120 minutes after dosing;
  • Capsulin controlled blood glucose levels for an extended time period after dosing;
  • Both increases in insulin levels and control of glucose levels were dose-dependent.

The study results also supported the hypothesis made as a result of the Phase 1 study outcome that oral delivery of insulin can help restore hepatic control of the insulin regulation system.

Phase 1 study:

The first clinical study of Capsulin was undertaken in the UK in 2003 in healthy volunteers to investigate and measure the effect of orally administering insulin in the Axcess formulation on blood glucose, c-peptide and circulating insulin levels in healthy subjects. The study was open label and sequential; although there was no blinding in the study, the parameters being examined in the study were derived from blood and subjective bias in the data collected was thus minimised. The main conclusions of the study are as follows:

  • Capsulin was well tolerated by the volunteers;
  • Capsulin shows evidence of bioavailability and was biologically active in humans (fall in blood glucose levels and suppression of C-peptide levels);
  • There was a marked non-linear relationship between plasma insulin levels in the two naso-jejeunal groups suggesting that the 170iu dose may be >90% bound by the liver insulin receptors with minimal overspill of insulin into the circulation, whereas the 340iu dose floods the liver and spills over into plasma (10 times the plasma levels with 170iu).
This graph, from the phase 1 trial, illustrates the elevation in plasma insulin levels of healthy subjects following administration of 170IU Capsulin®.This allowed us to green light the progression of the development project into phase 2.

Strong pre-clinical study results:

Diabetology has studied its novel oral insulin formulations in multiple animal model systems including rats, juvenile pigs, primates and diabetic dogs. Results demonstrate:

  1. successful insulin absorption through the intestine;
  2. consistent 6-10% bioequivalence as assessed by impact upon blood glucose concentration relative to injected insulin;
  3. no chemical interaction between insulin and the carrier formulation;
  4. no unexpected toxicity or safety issues; and
  5. predictable onset of activity.

 

Poster presented at ADA 2005:

Absorption of Orally Ingested Insulin in Human Type 1 Diabetic Subjects:Proof of Concept Study

Click Here for Details (pdf)

Poster presented at ADA 2004:

Early Evaluation of a Novel Oral Insulin Delivery System in Healthy Volunteers

Click Here for Details (pdf)