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Chemistry and Industry, Feb 9, 2009 by Sarah Houlton
The incidence of diabetes is increasing at an alarming rate. According to World Health Organization estimates, at least 171m people worldwide had the condition n one of its forms in 2000, and it expects this to more than double Dy 2030. There are two main forms: in Type 1, little or no insulin is produced by the pancreas, so regular doses of insulin are required; and in Type 2, by far the most common form, the body is unable to use its insulin effectively. Type 2 can frequently De managed by diet and exercise, but often drugs are required, and sometimes insulin s needed too.
Those diabetics who require insulin face a lifetime of injections. While modern injectors are easy to use and have very fine needles which limit the pain, regular injections are intrusive, and several non-injected forms are being investigated, notably inhaled and oral forms. ‘Non-injected insulin could, potentially, improve the quality of life for many people with diabetes, particularly those with needle phobias,’ claims Pav Kalsi, care advisor at Diabetes UK. ‘Inhaled or oral insulin could reduce the need for multiple injections and therefore have less of an impact on day to day life.’
However, the lifestyle impact is not the only driver behind the search for non-injected insulin–while insulin injections are life-saving, they do not mimic the way insulin acts in the body as well as they might. Insulin pumps offer a better profile, but they are also intrusive, as the device has to be worn all the time.
One inhaled insulin product has already reached the market. Exubera, marketed by Pfizer and developed in conjunction with Nektar Therapeutics, was approved in 2006, but never gained widespread acceptance. This was partly because the extra cost was not justified by substantial advantages over standard insulin, but mainly because the delivery device was far too big. It was withdrawn from the market a year later, and in the wake of this, both Novo Nordisk working with Aradigm, and Eli Lilly with Alkermes, stopped development work on their inhaled insulin products.
This was not the end for inhaled insulin, however–MannKind has pressed ahead with the development of its own version, Afresa, in which a small organic molecule, fumaryl diketopiperazine (FDKP), is used to create inhalable particles. ‘This molecule dissolves in water under basic conditions,’ explains the company’s vice president of pharmaceutical development, Andrea Leone–Bay. ‘Subsequent acid-induced precipitation produces nanocrystals that self-assemble into microparticles. These Technosphere particles are exactly the right size for inhalation into the deep lung. We then adsorb insulin onto the particle surfaces.’ Diketopiperazines are known to self-assemble like this in solution, but FDKP is unusual as it forms particles that retain their structural integrity when dry.
FDKP is soluble at pH 7, very close to physiological pH, so when the particle hits the surface of the lung, it dissolves in the lung fluid. ‘The insulin is rapidly absorbed into the body by natural mechanisms, and the FDKP is excreted unchanged, primarily in the urine, as it is not metabolised,’ Leone-Bay says.
Another key feature is the rapidity of absorption, and the lack of variability of absorption compared with subcutaneous or other routes, chief scientific officer Peter Richardson explains. ‘The best that has been achieved with rapid-acting injected insulin analogues is an onset of action of around 40 minutes to an hour,’ he says. ‘With Afresa, the onset of insulin action is 12-14 minutes, which is much closer to the normal physiological response of 5-6 minutes or so. It’s a considerable difference.’
This is reflected in the changes in glucose production in the liver and the body, and consequently in the early changes after a meal in terms of the rate at which glucose levels rise after eating
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