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Researchers at Stanford University are developing an ultrafast-acting insulin formulation that begins to take effect almost immediately upon injection, potentially working four times as fast as current commercial fast-acting insulin formulations. Tests in pigs indicated that the stabilized monomeric insulin formulation—which peaked in as little as nine minutes—could improve quality-of-life for patients with diabetes by allowing them to more quickly manage their blood sugar levels during mealtimes.

“In terms of stability, we took a big step backward by making the insulin monomeric,” said Caitlin Maikawa, a graduate student in the laboratory of research lead Eric Appel, assistant professor of materials science and engineering at Stanford. “Then, by adding our polymer, we met more than double the stability of the current commercial standard.” Maikawa is co-lead author of the researchers’ paper, which is published in Science Translational Medicine, and titled, “An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients.”

More than 40 million people around the world have type 1 diabetes, and rely on insulin replacement therapy, either through daily insulin injections or via an insulin infusion pump, the authors wrote. “These patients are unable to produce the insulin required to promote cellular glucose uptake in response to meals and must deliver calculated insulin boluses at mealtimes to prevent glycemic excursions.” However, even fast-acting insulins don’t work as fast as the body’s own insulin. While natural insulin produced and secreted by non-diabetic people can reach peak concentrations in just 30 minutes, rapid-acting insulin (RAI) analogs that are designed to be taken after meals don’t reach peak activity until 60–90 minutes after administration.

Current commercial formulations of insulin contain a mix of three forms: monomers, dimers, and hexamers. Scientists have assumed monomers would be the most readily useful in the body, but in practice, monomeric insulin is too unstable for practical use.

When stored in vials, the monomers are drawn to the surface of the liquid where they aggregate and become inactive. Hexamers are more stable in the vial, but take longer to work in the body because they first have to break down into monomers to become active. “Whereas monomers are rapidly absorbed into the bloodstream after injection, dimers and hexamers are absorbed more slowly on account of their size and must dissociate into monomers to become active,” the investigators wrote.

To address this problem the authors looked at how to make monomeric insulin more stable, and turned to materials science. Their approach was to develop a custom polymer that is attracted to the air/water interface. “We focused on polymers that would preferentially go to that interface and act as a barrier between any of the insulin molecules trying to gather there,” said Joseph Mann, a graduate student in the Appel lab and co-lead author of the paper. Crucially, the polymer can do this without interacting with the insulin molecules themselves, allowing the drug to take effect unimpeded.

“The insulin molecules themselves are fine, so we wanted to develop a ‘magic fairy dust’ that you add into a vial that would help to fix the stability problem,” explained Appel. “People often focus on the therapeutic agents in a drug formulation but, by focusing only on the performance additives—parts that were once referred to as ‘inactive ingredients’—we can achieve really big advancements in the overall efficacy of the drug.”

Illustration depicting how fast different forms of insulin absorb in the bloodstream, and how the polymer developed by these researchers helps stabilize ultrafast-absorbing insulin in the vial. [Joseph Mann and Caitlin Maikawa]

Finding the right polymer with the desired properties was a long process that involved a three-week trip to Australia, where approximately 1,500 preliminary candidates were created. The polymers were then tested individually by hand at Stanford to identify polymers that successfully exhibited the desired barrier behavior. They found one that could stabilize monomeric insulin for more than 24 hours in stressed conditions. By comparison, commercial fast-acting insulin stays stable for six to ten hours under the same conditions.

The polymer was identified just weeks before the team was scheduled to run experiments with diabetic pigs. “It felt like there was nothing happening and then all of the sudden there was this bright moment … and a deadline a couple of months away,” said Mann. “The moment we got an encouraging result, we had to hit the ground running.”

When tested with commercial insulin, which typically remains stable for about 10 hours in accelerated aging tests, the new polymer drastically increased the duration of stability for upwards of a month. A formulation of monomeric insulin with the polymer was shown to remain stable for more than 24 hours under stress, whereas monomeric insulin on its own aggregates in 1–2 hours.

When the team evaluated their new monomeric ultrafast-absorbing insulin lispro (UFAL) formulation in diabetic pigs they found that it reached 90% of its peak activity within five minutes of administration. By comparison, the commercial fast-acting insulin began showing significant activity only after 10 minutes. And whereas activity of the monomeric insulin peaked at about 10 minutes, the commercial rapid-acting insulin required 25 minutes. In humans, this difference could translate to a four-fold decrease in the time insulin takes to reach peak activity, the authors suggested.

“In diabetic pigs, this UFAL formulation exhibited ultrafast pharmacokinetics, with about twofold faster time to onset and twofold shorter duration of exposure than Humalog, a commercial RAI formulation using the same insulin molecule lispro,” the authors noted. “These results suggest that this UFAL formulation more closely mimics endogenous insulin secretion in healthy individuals and highlight that this formulation is promising for enhancing diabetes management.”

The ultrafast-absorbing insulin is based on simpler insulin monomer molecules, which are absorbed far faster than the more complex dimers and hexamers used in commercial rapid-acting insulin analogs. This material relates to a paper that appeared in the July 1, 2020, issue of Science Translational Medicine, published by AAAS. The paper, by J.L. Mann at Stanford University, and colleagues was titled, “An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients.” [[Credit: J.L. Mann et al., Science Translational Medicine (2020)]

“When I ran the blood tests and started plotting the data, I almost couldn’t believe how good it looked,” said Maikawa. “It’s really unprecedented,” added Appel, who is senior author of the paper. “This has been a major target for many big pharmaceutical companies for decades.” The monomeric insulin activity also finished its activity sooner. This faster start and finish should make it easier for people to coordinate their insulin with mealtime glucose levels, to better manage their blood sugar levels. “The results observed in diabetic pigs, combined with the model-predicted human UFAL pharmacokinetics, suggest that UFAL may have absorption kinetics that are unprecedented in an injectable insulin formulation,” the team concluded. “Our stable ultrafast insulin formulation has the potential to improve diabetes management and reduce patient burden around mealtime glucose management.”

The researchers plan to apply to the FDA for approval to test their insulin formulation in clinical trials, although no trials are planned yet. They are also considering other uses for their polymer, and suggest the possibility that it could aid the development of an artificial pancreas device that functions without the need for patient intervention at mealtimes.

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