Most discussions begin with differences in the formulation of the insulin delivered by the inhaler. Kos and Novo Nordisk/Aradigm
have liquid solutions—or, perhaps more accurately, suspensions—of recombinant human insulin, the same basic drug used in all
five medications. Lilly/Alkermes and Mannkind use a powder, but both companies distinguish their powder formulations from
the "heavy" particles of Pfizer. Lilly/Alkermes scientists like to compare Pfizer's "baseballs" to the "popcorn kernels" they
developed. Pfizer's particles are one to three microns in diameter, a size that is designed to penetrate the alveoli of the
deep lung, and that is explicitly protected in Nektar's original intellectual property. They also are fairly dense. Like baseballs,
they travel far once they are set in motion.
Time-Action Profile of Inhaled Insulins
Lilly/Alkermes' particles are light and airy like popcorn kernels. "We engineered the particles," said Bernard Silverman,
MD, vice president, clinical development at Alkermes. "We changed the geometric configuration of our particles so that some
of them under a scanning electron microscope look like crumpled paper and others like a hollow ball." Like popcorn in an air
popper, the kernels that expand the most and have the least density fly the farthest. The Lilly/Alkermes particles are larger
than Pfizer's particles, about 10 microns, but they are light in weight and still can penetrate the deep lung.
Mannkind, based in Valencia, California, uses a substrate that looks something like an airy, round shower sponge. The substrate—Mannkind
calls it a Technosphere—has a slight positive charge and creates an electrostatic bond to the negatively charged insulin peptides,
which cling to it by the thousand. The Technosphere remains a particle as long as the pH of its environment stays slightly
acidic, so it can be drawn into the lungs as powder. But in the moist, neutral-pH environment of the deep lung, the particle
liquefies and easily penetrates the lung membranes.
More provocatively, Mannkind executives claim that the unique substrate binds human recombinant insulin as monomers, or single
peptides, instead of as hexamers, or configurations of six insulin molecules. "Because of our delivery platform, you get the
insulin into the blood very quickly," explains Hakan Edstrom, the President and COO of Mannkind. "You get insulin into the
blood in monomeric form, which means it can immediately start to exert its influence on the blood glucose, whereas the other
insulin breaks down from a hexamer, to a dimer, then to a monomer before it can actually start to work." This causes the insulin
level in the blood to rise faster than with other insulin medications, including fast-acting insulin analogues.
Jay S. Skyler, MD, professor of medicine at the University of Miami, says the data from several independent studies show that
Mannkind's system does make insulin available more rapidly than other inhaled or injected products, but he remains agnostic
about the mechanism until additional studies are completed.
However, Skyler notes that the insulin profile of Mannkind's product resembles that of a healthy person more than that of
any other insulin product on the market. At the beginning of a meal, he notes, the pancreas of a non-diabetic creates a sharp
spike of insulin that signals the liver to shut down glucose production. "Most diabetics lack that rapid response of insulin
secretion from the pancreas," says Skyler, who notes that injected and inhaled insulin also act too slowly to shut down the
liver. "So the liver continues to make glucose, and the total burden of glucose after a meal is much higher in somebody with
diabetes than for somebody else when they eat the very same meal."