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Science & Technology

May 8, 2006
Volume 84, Number 19
p. 41

A Sweet Start For Inhalable Insulin

New approach to delivering insulin scores a first for both diabetes and pulmonary drug delivery

Linda Wang

Ever since insulin was discovered some 85 years ago, researchers have been searching for needle-free ways to deliver the hormone to people who have diabetes. They've looked at oral delivery, nasal delivery, and even dermal delivery using a patch.

Now, the first of these noninvasive approaches, inhalable insulin, is about to reach the market after approval in late January by the U.S. Food & Drug Administration and the European Medicines Evaluation Agency. The product, marketed by Pfizer under the trade name Exubera, is expected to be available to consumers by midsummer.

Breathe Deeply The Exubera inhaler, which will be available midsummer, is about 6 inches long when stored and about a foot long during use.

"It's a historic event," says Tarun K. Mandal, a professor of pharmaceutics at Xavier University of Louisiana, in New Orleans. Not only will inhalable insulin offer people with diabetes more options to control their disease, it also sets a precedent for other drugs to be delivered systemically through the lungs, he points out.

According to the American Diabetes Association, 20.8 million people in the U.S. have diabetes, a disorder affecting the body's ability to produce the blood-sugar-regulating hormone insulin. People with type 1 diabetes produce virtually no insulin; people with type 2 diabetes have a form of the disease in which their bodies make too little insulin, resist its effects, or both.

Blood-sugar levels that are left unregulated can lead to heart disease, blindness, kidney failure, and lower-limb amputations.

Despite these potential complications, people who could benefit from taking insulin but don't require it, such as people with type 2 diabetes, sometimes refuse the treatment because of a fear of needles, says Peggy Odegard, a certified diabetes educator and an associate professor of pharmacy at the University of Washington, in Seattle. "Needle fears are a significant problem," she says.

Inhalable insulin, by contrast, is delivered with an inhaler, much the same way medicine to treat asthma is delivered. It can be packaged as either a powder or a liquid.

Phase III clinical trials showed that Exubera, developed by San Carlos, Calif.-based Nektar Therapeutics in partnership with Pfizer, is as effective as injections in controlling blood sugar. Exubera works by reaching the deep lung, where absorption of insulin is greatest.

"People have been trying to get around the needle for almost 100 years now, and nobody expected that if you got down into the deep lung, there would just be an open door," says John Patton, cofounder and chief scientific officer at Nektar. The deep lung houses the grapelike structures called alveoli, which offer the largest surface area for absorption.

It took researchers 15 years to bring Exubera to the market. One of the biggest challenges was making sure the formulation was safe. "You don't want to be inhaling a particle that is chemically or physically degraded because that can make it less effective or even immunogenic," Patton says.

To stabilize the formulation, researchers add biocompatible excipients, such as amino acids and sodium citrate, which interact with the insulin to keep it in a stiff, amorphous glass state, explains Nancy J. Harper, a research fellow in the pharmaceutical R&D group at Pfizer. Exubera is the first insulin product that doesn't require refrigeration, she notes.

The second challenge was getting the particles deep into the lung. This was tricky because if the particles are too large, they get lodged in the upper respiratory tract. If they're too small, they are exhaled or removed by the immune system.

It turns out that the perfect particle size is between 1 and 5 µm in diameter. Xavier's Mandal admits that creating such a particle is not easy. "We've been trying to do similar work for the past almost eight to 10 years, so we know how difficult it is," he says.

To manufacture Exubera, researchers spray liquid insulin through a fine nozzle into a high-temperature chamber, using a process known as spray-drying. The liquid evaporates into dry aerosol particles, each of which contains approximately 300 million insulin molecules. The particles are then collected and packaged into individual blister packs that are used in an inhaler. Inside blister packs, the drug remains moisture-free for two years.

Although it is the first to be approved, Exubera is just one of several inhalable insulin products moving toward commercialization. Other companies developing powder formulations include Cambridge, Mass.-based Alkermes, in collaboration with Eli Lilly & Co.; and Valencia, Calif.-based MannKind Corp. Both teams are testing their products in Phase III clinical trials and are several years from reaching the market.

One company, Aradigm, in collaboration with Danish pharmaceutical giant Novo Nordisk, is developing a liquid formulation of inhalable insulin. That drug also is in Phase III clinical trials.

A concern with all of these products is that they will cost considerably more than insulin injections. Although Pfizer has not yet released information on the price of Exubera, analysts predict that it will cost three to four times more than injectable insulin.

Another consideration is convenience. Currently, the inhaler used to dispense Exubera is about the size of an eyeglass case when stored and about a foot long when it is in use. Some diabetics say it is just too bulky to be practical. "I've had diabetes for 56 years. I've seen the device, and it just doesn't do much for me," says R. Keith Campbell, a professor of pharmacy at Washington State University.

Whether inhalable insulin catches on could also depend on personal preference. Campbell, who has type 1 diabetes, says that with the "smaller, sharper, lubricated, better-beveled needles we have now, taking a shot really isn't that big of a deal." However, he admits that if the inhalable insulin products are reasonably priced and the inhalers are compact and easy to use, he would consider switching.

For people with type 1 diabetes, inhalable insulin won't completely replace needles. These people still need daily injections of a long-acting insulin or need to use an insulin pump to mimic the body's continuous, 24-hour trickle of insulin.

Exubera and the other inhalable insulin products, by contrast, contain rapid-acting insulin, which takes care only of the sugar people consume during meals. Nektar and Alkermes are working separately on a long-acting inhalable insulin, but that product is many years from the market.

Patton points out that people with type 2 diabetes make up 95% of the diabetic population, and they are the ones who stand to benefit the most from rapid-acting insulin. These people avoid going on insulin for years because of needle fears and cause themselves irreparable damage because of it, he says. Odegard agrees, saying that rapid-acting insulin could improve treatment adherence among people with type 2 diabetes. For people with type 1 diabetes, rapid-acting insulin could reduce the number of daily injections they need to just one. The convenience itself could justify the higher cost.

As for the field of pulmonary drug delivery, inhalable insulin represents the tip of the iceberg. "This now opens the door for a lot of chemical research to formulate products that could be absorbed through the lungs," Campbell says, noting that one company is working on inhalable drugs for lung cancer. "It's going to get the thinkers thinking, and there's going to be a lot of fun things that will develop in the next 20 years."

Chemical & Engineering News
ISSN 0009-2347
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