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    Mentor  Pharmaceutical Consulting


 
 
 

Oral Delivery of Insulin

Diabetes is the world’s fastest growing chronic disease. It currently affects 246 million people worldwide and this number is expected to rise to 380 million by 2025. Treatment of diabetes generally involves thrice daily monitoring of blood glucose levels and injection of insulin, sometimes four times per day, for the rest of the diabetic patient’s life. Administration is still generally by sub-cutaneous injection.

The sub-cutaneous route of administration has lead to several treatment-associated sequelae. Insulin therapy or intensification of insulin therapy commonly results in weight gain. This weight gain can be excessive, adversely affecting the patient’s cardiovascular risk profile. This is possibly due to the ‘unphysiological' pharmacokinetic and metabolic profile following SC administration. Thus, injected insulin can avoid first-pass metabolism, and so large quantities of insulin are available to stimulate adipocytes and increase glucose and lipid uptake into these cells. High local concentrations of insulin result in lipodystrophy, possibly due to areas of local down-regulation of insulin receptors in adjacent adipocytes. Additionally, diabetic patients also show an unconscious increase in calorie intake due perhaps, to fear or the experience of hypoglycaemia such as that encountered by “overdosing? with injected insulin.

 Despite years of experience with injected insulin, it is often impossible to achieve strict glycaemic control, and so patients often have poorly controlled, unpredictable blood glucose levels due to the variable release from the site of injection, which leads to a high variability between and within individuals.  Many patients are needle-phobic, and there is a high rate of non-compliance (around 30%) in diabetic patients, which leads to improper treatment and the development undesirable sequelae that could have been prevented with correct treatment.

 Oral insulin administration would help to circumvent many of the above problems.

  • The oral route of administration of insulin is a more natural route of administration, and as such would result in delivery to the hepatic portal vein, which is the normal route for insulin to be delivered to the body.

  • Oral delivery of insulin would avoid the lipodistrophy often seen with injected insulin

  • Oral delivery of insulin avoids the continued insulin-stimulation of adipocytes would be avoided resulting in reduced or negligible weight gain.

  • Episodes of  hypoglycaemia could be reduced or avoided all together when insulin is administered via the oral route.

  • A tablet of oral form of insulin should result in greater patient comfort and patient compliance would go up.

  • Oral insulin delivery would also "provide a new life" for several of the more popular insulin analogues currently nearing the end of their patent life.

Studies on Oral Delivery of Insulin

There are many studies which have claimed to show effective oral delivery of insulin when administered orally. The majority of these studies have concentrated on protection of insulin from proteolysis through either chemical modification of the insulin with PEG, or vitamin B12, or by incorporation of the insulin within protective matrices such as nanoparticles, nanolattices, liposomes, or various excipients. Whilst the main aim of these studies was to protect the insulin from proteolysis, little attention has been given to the mechanism of uptake of the protected insulin from the gut. Similarly studies looking at insulin delivery to the lung have concentrated on different modes of formulation of the insulin for effective pulmonary delivery, but no mechanism of uptake has been cited.

Several studies have now shown the presence of an insulin receptor in the gut and in the alveolar epithelial cells. in at least some of the studies, it has been shown that binding of insulin to the insulin receptor leads to uptake and transcytosis of the insulin. Whilst there have been many claims of effective oral delivery of insulin in different permeation enhancers, mucoadhesive polymers, or nanoparticles, a common requirement for all of these methods, is still transcytosis across the gut wall. The possibility exists therefore, that the aforementioned oral delivery technologies have utilized the normal insulin RMT process in the gut.

Presence of the Insulin Receptor in adult mouse intestine

Experiments with  Rhodamine-labelled insulin have demonstrated functional insulin receptor in mouse small intestine.

Rhodamine-labelled insulin (red) can be seen binding to the tips of the enterocytes (nuclei stained blue)

Mentor has identified a novel strategy for oral insulin delivery, which combines a natural targeting agent with a protective formulation to provide a commercially viable oral insulin formulation. The resultant formulation would be delivered as an insulin tablet.

Mentor can provide technical advice on:

  • The identification of suitable insulin preparation for oral insulin administration

  • The preparation of a suitable oral insulin formulation.

  • Appropriate in vitro and in vivo models to study oral delivery of insulin.