Researchers at Stanford University are developing a new insulin preparation that starts to work almost immediately after injection, and its working speed may be four times that of the currently available fast-acting insulin preparations.
The researchers focused on the so-called monomeric insulin. According to theory, its molecular structure should make it work faster than other forms of insulin. The problem is that monomeric insulin is too unstable for practical use. Therefore, in order to realize the ultra-fast potential of this insulin, the researchers relied on some material science magic.
Eric Appel, assistant professor of materials science and engineering at Stanford University, said: “The insulin molecule itself is very good, so we want to develop a’magic dust’ and add it to the vial, which will Helps to solve the stability problem.” “People usually focus on the therapeutic agents in drug formulations, but only focus on performance additives (the part that used to be called’inactive ingredients’), we can focus on the overall efficacy of the drug Really made great progress.”
After screening and testing a huge library of additive polymers, the researchers discovered a compound that can stabilize monomeric insulin under pressure for more than 24 hours. (In contrast, commercial fast-acting insulin can remain stable for six to ten hours under the same conditions.) Then, the researchers confirmed the ultra-fast effect of its preparation in diabetic pigs. Their results were published in “Science Translational Medicine” on July 1. Now, researchers are conducting other tests in order to qualify for clinical trials in humans.
Take one step back and two steps forward
Current commercial insulin preparations contain a mixture of three forms: monomer, dimer and hexamer. Scientists believe that the monomer will be the easiest monomer to use in the body, but in the vial, the insulin molecules are attracted to the surface of the liquid, where they gather and lose their activity. (Hexahydroanisole is more stable in the vial, but it takes longer to work in the body because they must first break down into monomers to become active.) This is “Magic Fairy Dust” (a customized polymerization Things are attracted to the air/water interface-come in.
“We are focused on polymers that preferentially enter the interface and act as a barrier between any insulin molecules that are trying to accumulate on the interface,” Joseph Mann, a graduate student at Appel’s laboratory and one of the first authors of the paper Say. Crucially, the polymer can do this without interacting with the insulin molecule itself, allowing the drug to function unimpeded.
Finding the right polymer with the desired characteristics is a long process and takes three weeks to Australia, where a fast-moving robot has created about 1500 preliminary candidates. Subsequently, separate treatments and tests were performed manually at Stanford University to identify polymers that successfully exhibited the required barrier properties. The top 100 candidates failed to stabilize commercial insulin in the test, but the researchers continued their efforts. They discovered their magic polymer a few weeks before they planned to conduct experiments on diabetic pigs.
Mann said: “It felt like nothing had happened, and then suddenly there was this wonderful moment…and the deadline for the last few months.” “When we get encouraging results, we have to step out first step.”
Superabsorbed insulin is based on a simpler insulin monomer molecule, which absorbs much faster than the more complex dimers and hexamers used in commercially available fast-acting insulin analogs. Image source: JL Mann et al., “Scientific Translational Medicine” (2020)
In commercial insulin (usually stable for about 10 hours in accelerated aging tests), the polymer greatly increases the stability period for more than a month. The next step is to observe how the polymer affects the monomeric insulin, which will aggregate on its own within 1-2 hours. When the researchers confirmed that their formula could remain stable for more than 24 hours under pressure, this was another welcome victory.
“In terms of stability, we make insulin monomer a big step. Then, by adding polymers, we achieved more than twice the stability of current commercial standards,” said Caitlin Maikawa, a graduate student in Appel’s laboratory. And the co-lead author of the paper.
With seed funding from the Stanford University Diabetes Research Center and the Stanford Maternal and Child Health Institute, researchers were able to evaluate their new monomeric insulin preparation (the most advanced non-human animal model) in diabetic pigs and found that their insulin reached 90% of its peak activity within five minutes after insulin injection. For comparison, commercially available fast-acting insulin only started to show significant activity after 10 minutes. In addition, monomeric insulin activity peaked in about 10 minutes, while commercially available insulin required 25 minutes. In humans, this difference may mean that the time required for insulin to reach peak activity is reduced by a factor of four.
Mai Chuan said: “When I took the blood test and started plotting the data, I could hardly believe how good it looked.”
Appel, senior author of the paper, said: “This is indeed unprecedented.” “For decades, this has been the main goal of many large pharmaceutical companies.”
Monomeric insulin also quickly completed its role. Both start and end activities are faster, making it easier for people to use insulin in conjunction with blood glucose levels during meals to properly manage their blood glucose levels.
The researchers plan to apply to the Food and Drug Administration for approval to test their insulin preparations in clinical trials with human subjects (although no trials have been planned and they are not currently seeking subjects). Considering how much the stability of the polymer in commercial insulin has improved, they are also considering using their polymers for other purposes.
Because their insulin formula activates so quickly (hence more like insulin in people without diabetes), researchers are excited about the possibility that it can help develop an artificial pancreas device that can Need patient intervention.
Other co-authors of Stanford University include former visiting scholar Anton Smith (from Aarhus University, Denmark); graduate students Abigail Grosskopf, Gillie Roth, Catherine Meis, Emily Gale, Celine Liong, Doreen Chan, Lyndsay Stapleton and Anthony Yu; clinical veterinarian Sam Baker; and postdoctoral fellow in Santiago Correa. Researchers at CSIRO Manufacturing in Australia are also co-authors. Appel is also a member of Stanford Bio-X, Cardiovascular Institute, Stanford Maternal and Infant Institute, and a faculty researcher at Stanford ChEM-H.