Alternative routes of insulin delivery

Conventional insulin therapy requires subcutaneous injection or, in the case of pump therapy, subcutaneous infusion of insulin. The requirement for injection is a deterrent for anyone contemplating insulin therapy, and a major obstacle for some. Furthermore, subcutaneous injection is associated with the problems of delayed and variable insulin absorption, plus the relative disadvantage of delivery into the systemic circulation. It follows that many attempts have been made to explore other routes of delivery, including intranasal, intrapulmonary, intraperitoneal oral and rectal administration. Of these, the only route currently approved for clinical use (in the USA) is intrapulmonary insulin. All alternative routes suffer from the disadvantage of low bioavailability, thus increasing the cost of insulin and reducing precision in dosing. A further limitation is that alternative routes do not eliminate the need for injection, since there is currently no alternative way of giving long-acting insulins. This page of Diapedia provides a brief overview of alternative delivery systems, and more detailed consideration of the oral, nasal and inhalational routes of delivery is provided on daughter pages.

Background

Insulin injections have always been unpopular, and dominate the popular perception of life with diabetes. Modern injection technology has greatly improved the convenience and comfort of insulin injections, but efforts dating back to the very early days of insulin use have been made to examine alternative routes of insulin delivery[1].

The basic principles of conventional Insulin administration are considered elsewhere. Advantages include speed and ease of administration plus confidence about the dose of insulin that will enter the circulation. A further advantage is that long-acting insulin can be given by this route. Disadvantages include delayed and sometimes erratic absorption, and delivery of insulin into the systemic rather than portal circulation.

Intraperitoneal insulin overcomes this limitation, since molecules crossing the peritoneal membrane enter the portal circulation. It can be used in patients who already have intraperitoneal access, especially those with renal failure treated with continuous intraperitoneal dialysis (CAPD). In this situation insulin is simply added to the dialysis fluid. It is also used, albeit rarely, in continuous intraperitoneal insulin infusion therapy; see CIPII Intraperitoneal insulin

Other Routes of Administration

Insulin is able to cross mucous membranes, whether in the nose, lungs or intestine, but bioavailability is low. Since this approach appears to offer the prospect of injection-free insulin delivery, all routes have been actively investigated, and have proved irresistibly attractive to generations of investors. In the event, the results have generally been disappointing.

Nasal Insulin: Intranasal insulin administration offers the advantage of very rapid insulin delivery into the circulation coupled with the avoidance of pre-meal insulin injections, and was intensively investigated in the 1970s and early 1980s.

The first report of long-term use tested three daily intranasal doses of insulin plus injected Ultratard insulin at night. In the event the study provided an omen of future events, since HbA1c rose rapidly, and 3/9 volunteers failed on treatment; another complained of nasal irritation[2]. Subsequent experience with the addition of an absorption enhancer confirmed that intranasal insulin therapy required a twenty-fold increase in insulin dose and was associated with a high rate of treatment failure[3].

Intranasal insulin has also been tested as a possible means of inducing immune tolerance to insulin in autoimmune diabetes[4], and as a possible means of improving cognitive function in Alzheimer's disease.

Inhaled insulin. As with intranasal insulin, inhaled insulin potentially offers rapid absorption of needle-free insulin. The lung has a surface area of ~100 m2, and small molecules such as insulin (molecular mass 5700, diameter 2.2 nm) are readily absorbed via the alveoli. Pfizer launched an inhaled insulin under the trade name of Exubera in 2006 but withdrew it in 2008, citing poor demand.

Problems with inhaled insulin included poor bioavailability, (much of the inhaled insulin is lost in the "dead space" of the bronchial tree), and associated high costs. The inhaler proved bulky and inconvenient. Furthermore, use of inhaled insulin was associated with evidence of a mild induced restrictive lung defect[5]. A greater concern was that 6/4,740 patients on Exubera developed lung cancer during the trial, as against 1/4,292 in the comparison group.

Despite this unpromising experience, the FDA gave its approval in June 2014 for clinical use of Afrezza, a new formulation of inhaled insulin developed by MannKind[6].

Oral Insulin: Insulin, being a peptide chain, is rapidly broken down by acids in the stomach or digested by proteolytic enzymes. Early experiments suggested that oral insulin had some effect on lowering circulating glucose if given in very high doses or instilled into the duodenum via a tube. Many subsequent attempts have been made to deliver insulin in a form capable of bypassing the stomach, including liposomes, capsules and nanoparticles[7]. Low and erratic bioavailability remain major problems, and the utility of this approach remains to be demonstrated.

Summary

After 90 years of endeavour, subcutaneous insulin injection (or infusion) remains the preferred route of insulin administration. Despite the limitations of insulin delivery into the systemic circulation, this route of administration can offer substantial protection against the long-term complications of diabetes, and no better alternative seems likely to emerge in the near future.

References

  1. ^ Jensen HF. Insulin. Its chemistry and physiology. Commonwealth Fund, New York, 1938

  2. ^ Frauman AG et al. Long-term use of intranasal insulin in insulin-dependent patients. Diabetes Care 1987;573-8

  3. ^ Hilsted J et al. Intranasal insulin, the clinical realities. Diabetologia 1995;680-4

  4. ^ Fourlanos S et al. Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 2011;1237-45

  5. ^ Mathieu C, Gale EAM. Inhaled Gone with the wind? Diabetologia 2008;1-5

  6. ^ //www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403122.htm

  7. ^ Fonte P et al. Oral insulin how far are we? J Diabetes Sci Technol 2013;520-31

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