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UCSD alumni develop first inhaled insulin for diabetes

(L-R) Jacobs School alumni Adrian Smith (B.S. '83 engineering science), and Chris Varga (Ph.D. '02 fluid mechanics), helped optimize the spray dryers at Nektar used to develop and test insulin powder.
(L-R) Jacobs School alumni Adrian Smith (B.S. '83 engineering science), and Chris Varga (Ph.D. '02 fluid mechanics), helped optimize the spray dryers at Nektar used to develop and test insulin powder.

When UCSD AMES alumnus Adrian Smith joined start-up Inhale Therapeutics (now Nektar) in 1992, he faced one of the biggest challenges of his career. His job was to design the first inhaler to deliver insulin via the lungs, rather than by injection. Engineering this breakthrough medical delivery system would eventually involve talent from industries as varied as gas turbine, laser anemometry, and even Navy ship management.

Now, after 14 years and over $1 billion invested, partners Pfizer and Nektar Therapeutics have introduced Exubera®, an inhaled insulin therapy for treating diabetes. Exubera received FDA approval in January 2006 and in September was named the year's leading innovation in biotechnology and medicine by the Wall Street Journal. Nektar expects Exubera will transform the lives of millions of adults with Type I, and in particular Type II diabetes, by making them more willing to begin insulin therapy earlier, thus slowing the devastating complications of the disease.

Nektar was co-founded in 1990 by John S. Patton, a biology alumnus of UCSD Scripps Institution of Oceanography (Ph.D. '74). "Scientists have known for decades that large macromolecules such as insulin could be absorbed into the bloodstream through the lungs. However, no one was able to demonstrate a truly practical delivery system," says Patton. He proved that by formulating macromolecules such as insulin into tiny powder particles less than 2 microns-wide, the aerosolized medicine could be inhaled, and delivered to the deep lung.

Patton brought in Smith, an experienced product design engineer who had worked for HP and the design consulting firm IDEO, to establish and scale up the company's core technologies. Among the obstacles faced by Smith's teams was how to uniformly manufacture the insulin powder. Nektar had begun by using a relatively standard pharmaceutical spray-drying approach. To firmly establish the technology, Smith hired a dream team of atomization and thermo-science experts from the energy conversion, jet engine, and oil exploration industries.

John Patton (Ph.D. '74, biology), Nektar Therapeutics Cofounder and Chief Scientific Officer
John Patton (Ph.D. '74, biology), Nektar Therapeutics Cofounder and Chief Scientific Officer
Pictured: Exubera Inhaler. Co-developed by Pfizer and Nektar Therapeutics, Exubera is the first insulin medication that can be administered without an injection. The rapid-acting, dry powder human insulin is inhaled through the mouth into the lungs prior to eating, using the handheld Exubera Inhaler.
Pictured: Exubera Inhaler. Co-developed by Pfizer and Nektar Therapeutics, Exubera is the first insulin medication that can be administered without an injection. The rapid-acting, dry powder human insulin is inhaled through the mouth into the lungs prior to eating, using the handheld Exubera Inhaler.

"Spray drying is standard practice for making particles 20 microns or larger. It is the process commonly used to make powdered milk," says Smith. "But we were attempting to make and collect 1-5 micron particles and required very tight control over the physical morphology and solid state chemical properties that resulted."

Maintaining a repeatable time temperature history from the moment the liquid insulin formulation was atomized into droplets and as they dried into particles was critical. The powder had to dry rapidly to "freeze" insulin and other ingredients (mostly sugars) into an amorphous structure, rather than a crystal. This ensured room temperature stability of the peptide drug for its two-year shelf life. Once these particles alight on the wet surface in the deep lung, they dissolve rapidly due to their amorphous structureŚ like cotton candy on the tongueŚreleasing the insulin.

UCSD alumnus Chris Varga joined Smith's Technology Development group in 2002, leveraging his background in atomization and thermosciences from UCSD to help advance Nektar's spray drying technology.

"Controlled production of respirable-sized particles involved unique hardware refinements and engineering in each of the subprocesses of atomization, droplet drying, and particle collection," says Varga.

Another challenge was the design of the inhaler. Smith and his team personally interviewed over 300 diabetics to understand how they interacted with device prototypes. A key early observation was that patients would only reliably inhale about a liter of air at a time, even when instructed to take a deep breath.

"For this systemic treatment to work well,we needed to reproducibly create the aerosol, and then deliver it in a small volume at the beginning of what was likely to be a modest inhalation. We had to ensure that dose was delivered to the tiniest airways and alveoli of the deep lung, every time," says Smith.

A team of product design and aerospace engineers was put to the task. They created a device that uses air, compressed by the patient with a small pump, to disperse the insulin powder (contained in small foil blister packs) into an aerosol which is caught in a clear chamber. Then, as the patient inhales from the mouthpiece, the aerosol is quickly flushed out of the chamber.

"By first understanding, and then working with what people actually do, we were able to achieve reproducible delivery when the system is used in the real world," says Smith.

Now that Exubera has reached the marketplace, Smith is starting his own company, Pearl Therapeutics, to develop treatment options for asthma and COPD (chronic obstructive pulmonary disease). His goal is to better serve children (Smith's son Brendan has suffered from asthma since he was 2) and older adults whose needs are not met by current products.

"The role that engineers have played in advancing medical care is more obvious when it comes to diagnostics, devices, and surgical instruments. A compelling challenge is how we can make a difference on the therapeutics and pharmaceutics side," says Smith. "This is where UCSD, by fostering collaboration across its new pharmacy and business schools, and of course its world class biology, medicine, and engineering disciplines, stands to make a real impact."