Susan Aldridge

Insulin is one of the world's oldest and most well-known biological drugs, and the need for it is not going to go away as the number of patients diagnosed with diabetes continues to increase. A wealth of clinical evidence shows that good, long-term glucose control in diabetes is key to avoiding complications such as kidney disease, blindness and heart problems.

The way insulin is delivered plays a vital role in helping patients manage their condition. As with all peptide or protein drugs, insulin cannot be administered orally because it is degraded by gastric fluids, and pharma companies have long been searching for more convenient and acceptable ways of delivering insulin as opposed to the conventional syringe and needle. Pen injectors are now well-established, but other routes under investigation include inhalers, eye drops, needle-free injections, nose drops, patches and even oral formulations.

Inhaled insulin has had a tough time recently. In February this year, Novo Nordisk (Denmark) announced it had ceased clinical development of its inhaled insulin, AERx iDMS, in Phase III. The news came only a few months after Pfizer (NY, USA) dropped its own inhaled insulin, Exubera. The reasons had nothing to do with safety, although some physicians do have reservations about the long-term impact of delivering an active drug to the lungs on a chronic basis; the Exubera inhaler was rejected by patients and doctors because it was too bulky, complicated and inconvenient.

But these setbacks do not herald the end for inhaled insulin. Eli Lilly (NJ, USA), who worked with Frederick Banting and Charles Best at the University of Toronto (ON, Canada) in the 1920s to make insulin first available as a drug to diabetics, now has an inhaled insulin in Phase III. MannKind (Valencia, CA), a company focused on medical devices, is also developing an inhaled insulin. Novo is still in the game too, committed to developing long-acting inhaled insulin in liquid and powder form.

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Mads Thomsen, CSO at Novo, outlines the challenges in developing pulmonary drugs. According to him, there is plenty of experience in inhaler technology for asthma where the drug acts locally in the lung, but for diabetes, the lungs are a vehicle for transporting insulin into the blood, and this is an important difference. "The ideal insulin inhaler would look like an asthma inhaler," says Thomsen, "but it must perform much better. The amount of drug delivered in asthma is highly variable, but this doesn't matter as the patient can just take another puff. For insulin, exactly the same dose must be delivered every time."

Bioavailability is another issue, as only 10% of the inhaled drug makes it from the lungs to the blood compared with 100% for an injection. "We need to improve both the half life and the bioavailability of insulin in the inhaled form," says Thomsen.

Novo is using its background in medical device manufacture to develop a new insulin inhaler. The company has made 100 million pen injectors for insulin, which is a great advance compared with the traditional syringe, but it is, in fact, only one of many pain-free or needle-free approaches to systemic drug delivery. One of the most novel of these devices coming to market is the Solid Dose Injector (SDI) being developed by Glide Pharma (UK).

The SDI is a tiny rod of solid dose form drug — smaller than a grain of rice — with a point at the end that is pushed gently into the skin. "This pushing action is very important," claims Charles Potter, Glide's CEO. "Other needle-free systems fire the drug at the skin and the drug penetrates to a varying depth because each patient's skin is different. The push is more accurate and reaches the same depth each time."