by John Walsh, P.A., C.D.E.
The FDA approved the first inhaled version of insulin called Exubera from Pfizer Inc. in January 2006. It became available in September 2006, 84 years after the first insulin injections were given. By October 2007, Pfizer announced it would be dropping Exubera, citing that the drug had failed to gain the acceptance of patients and physicians
The Real Thing
Artist's Concept, 1996
Over the years, various attempts have been made to capture the $3 billion injected insulin market. Three alternative sites of delivery have fared well in the competition: into upper nasal pathways or the lungs and through the stomach.
Delivery of an insulin pill through the stomach has two hurdles to overcome: getting intact insulin molecules past acidity and digestive enzymes in the stomach and intestines, and then opening the intestinal membranes to insulin transport. These problems have stymied researchers for at least 40 years, although a new novel approach discussed below offers some hope.
Delivery of insulin to the small bath towel size area of the upper nasal airways suffers from poor transport across the nasal membranes. Delivery this way requires very large doses of insulin or use of a chemical to enhance insulin transport. Chemicals used to enhance insulin transport often cause nasal irritation and a runny nose. Even a mild cold or stuffiness could easily change the intended insulin dose. About 100 units of insulin must be deposited into the nose to deliver 10 units into the blood. Insulin production costs would seem prohibitive except that a similar ratio applies to lung delivery, a method that is rapidly progressing.
Compared to nasal delivery, transport of insulin through the lungs allows delivery across a surface area the size of a singles tennis court. Absorption into the bloodstream occurs through the thin alveolar walls of the lungs. This appears to be the most promising approach for delivery at this time. However, there is concern about the long-term effects of inhaling a growth protein into the lungs. It is hoped the large surface area over which it is spread will minimize negative effects, but small decreases in oxygen transport have already been noted in some research studies.
Several companies are working on providing inhaled insulin with varioius delivery systems.
Eli Lilly - AIR Insulin
Eli Lilly is seen as the next company to step into the inhaled insulin market. Its AIR Insulin is expected to be submitted for approval in 2009. The AIR Insulin System is currently undergoing Phase III clinical trials as a potential treatment for Type 1 and Type 2 diabetes. Lilly, which is developing the product alongside drug delivery specialist Alkermes, has been working on developing an inhaled insulin product since 2001. Alkermes will be the exclusive commercial manufacturer of insulin powder for AIR.
Mannkind Corporation - Technosphere Insulin System
Mannkind is taking part in the inhaled insulin competition with their Technosphere Insulin System, a palm sized inhaler device. According to them, their system allows insulin to be rapidly absorbed into the bloodstream and reach peak levels in 12 to 14 minutes. They attribute this to their carrier molecule and their formulation of a faster acting insulin than is currently on the market. In their system, insulin is loaded onto pH-sensitive carrier particles, dried to a powder and loaded into plastic cartridges and packaged. Due to the aerodynamic properties of the particles, the powder is scattered deep into the lungs when the patient inhales. When these pH sensitive particles come into contact with the neutral pH of the lungs, the particles dissolve immediately, becomes a liquid and absorb into the lungs. The name of the insulin they plan to use is Afrezza. This rapid acting mealtime insulin therapy is being studied for use in adult patients with type 1 and type 2 diabetes. The Afrezza Inhalation Powder is pre-metered into single use dose cartridges and the light, discreet and easy to use Afrezza Inhaler. A new drug application requesting approval to market Afrezza was accepted by the FDA in May 2009.
Novo Nordisk recently recruited people for their Phase III trials for its AERx Insulin Diabetes Management System. Novo Nordisk has partnered with Aradigm to produce the only inhaled insulin in clinical trials that uses a liquid formulation. Their device uses a breath-guidance system that only delivers insulin to the lung when breathing is "correct". It uses strips with liquid insulin. This makes dosage adjustments possible to the nearest unit. Along with making data downloading available, Novo Nordisk is focused on producing a simple and convenient device for both healthcare professionals and patients.
Pfizer - Exubera
Exubera was the first of the inhaled insulins to be released. It was approved for those over 18 years of age with diabetes, but realistically was only appropriate for those with Type 1 who were on larger doses of insulin, such as 60 or more units per day, or those with Type 2 who can tolerate larger doses of insulin. It was a short-acting powder form of insulin that was inhaled before each meal. A long-acting insulin was still needed to be given each day by injection for Type 1's and some Type 2's. To create an inhaler, Pfizer and Aventis collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specializes in finding delivery solutions for oral, injectable and pulmonary drug administration. The Exubera inhaler weighed about 4 ounces and was about the size of an eyeglass case when closed. It opened to about 12 inches for delivery. The lack of discreet delivery was another issue repeatedly brought up by detractors of the device.
Similar to other inhaled insulins, a number of side effects were reported. They included coughing, shortness of breath, sore throat and dry mouth. Exubera is not approved for smokers or anyone who has smoked in the last six months because almost twice as much of the inhaled insulin can enter the bloodstream and increase the possibility of an overdose. It was also not approved for anyone with a lung disorder, such as asthma, emphysema, or chronic obstructive pulmonary disease. Exercise also increases transport and likelihood of lows.
Another major problem with Exubera was the inability to deliver precise insulin doses. The smallest blister pack available contains the equivalent of 3 units of Regular insulin. A 3 unit dose would make it difficult for many people using insulin to achieve accurate control which is the real goal of any insulin therapy. Using the 1800 Rule for Regular insulin, someone on 60 units of insulin per day would lower their blood sugar about 90 mg/dl (5 mmol) per 3 unit pack, while someone on 30 units a day would drop 180 mg/dl (10 mmol) per pack. Precise control flies out the window with this sledge hammer approach, especially compared to an insulin pump that can deliver one twentieth of a unit with precision.
Aradigm Corporation of Hayward, California, working with Novo Nordisk, is developing a similar approach with its patented AERxTM Diabetes Management System. They also report that inhaled U250 and U500 Regular insulins are absorbed more quickly than injected Regular using their controlled breathing device. Action times of the inhaled Regular aerosol appear to be between that of injected Humalog and Regular insulins. Novo is planning to offer 1 unit dose increments in its product.
Andaris, a privately-held company with about 70 employees in Nottingham, England, was purchased in 2003 by Cambridge-based Quadrant. Started in 1994, Andaris began developing injectable microscopic contrast agents for diagnostic tests with ultrasound. In the process, they also developed a 5 micron hollow microcapsule of insulin using a low temperature, spray drying technique that preserves the insulin structure. This insulin microcapsule can be inhaled directly into the lungs for absorption. Quadrant is now working with Innovata, MicroDose Technologies, and Bristol-Meyers Squibb to develop the QDose inhaled insulin product. They are planning a more discreet inhaler for delivery.
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