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“Ultrafast” insulin may be four times faster than regular

 


It may function four times faster than current commercial fast-acting insulin preparations.

"...I wanted to develop a "magic fairy powder" to add to the vial that would help fix stability issues. "

The researchers focused on so-called monomeric insulin, which theoretically has a molecular structure that allows it to act faster than other forms of insulin. The problem is that monomeric insulin is too unstable for practical use. Therefore, researchers have relied on some material science magic to realize the ultrafast potential of this insulin.

“The insulin molecule itself is great, so I wanted to develop a “magic fairy powder” to add to the vial that would help solve the stability problem,” University.

"People often focus on the therapeutic agents in their formulations, but by focusing only on the performance additives that were once called "inactive ingredients," we are able to improve the overall effectiveness of the drug. Really great progress can be achieved. "

After screening and testing a large library of additive polymers, researchers found one that could stabilize monomeric insulin for more than 24 hours under stress conditions. (By comparison, commercially available fast-acting insulin is stable for 6-10 hours under the same conditions.)

We then confirmed the ultrafast effect of the formulation in diabetic pigs.

Stabilization of ultra-fast insulin

Current commercial formulation Insulin contains a mixture of three forms: monomeric, dimeric and hexameric. Scientists assume that monomers are the easiest to help the body, but in vials, insulin molecules are attracted to the surface of liquids where they aggregate and become inactive. (Hexamers are more stable in vials, but they take longer to work in the body because they first need to be broken down into monomers in order to be active.) Where'Magic Fairy Powder' , That is, a custom polymer/water interface that attracts to the air-coming in.

"We focused on the polymer that acts as a barrier between insulin molecules that preferentially go to that interface and gather there," said co-author, a graduate student in the Appel lab. Says Joseph Mann. Importantly, the polymer can do this without interacting with the insulin molecule itself, allowing the drug to exert its effect unhindered.

Finding the right polymer with the desired properties was a long process that involved a three-week trip to Australia, and a fast-moving robot created about 1500 preliminary candidates. They were then manually processed and tested individually to identify polymers that showed the desired barrier behavior.

The first 100 candidates did not stabilize over-the-counter insulin in the test, but researchers sought for it. They found their magical polymer just a few weeks before they were going to experiment with diabetic pigs.

"I felt like nothing had happened, but suddenly there was this bright moment...and the deadline a few months ahead," says Mann. “At the moment we got promising results, we had to hit the ground.”

"When I ran a blood test and started plotting data, I could hardly believe how nice it was."

In commercial insulin (which normally remains stable for about 10 hours in accelerated aging studies), the polymer dramatically increases the duration of stability by over a month. The next step was to see how the polymer affects insulin alone. It was another welcome victory when researchers confirmed that their prescription could remain stable for more than 24 hours under stress.

“In terms of stability, we have taken a big step by turning insulin into a monomer. After that, we added a polymer that was more than twice as stable as current commercial standards,” Appel Labs said. Says Caitlin Maikawa, a co-author of a graduate student at.

Researchers then evaluated a new monomeric insulin formulation in diabetic pigs (a state-of-the-art non-human animal model) and found that insulin reached 90% of peak activity within 5 minutes. injection..

In comparison, over-the-counter fast-acting insulin began to show significant activity only after 10 minutes. In addition, monomeric insulin activity peaked at approximately 10 minutes, whereas commercial insulin required 25 minutes. In humans, this difference leads to a one-quarter reduction in the time it takes insulin to reach peak activity.

“When I ran a blood test and started plotting data, I could hardly believe how nice it looked,” says Maikawa.

“This is unprecedented,” Appel says. “This has been a major goal of many large pharmaceutical companies for decades.”

Monomeric insulin also finished its action earlier. The faster you both start and end your activity, the easier it will be to use insulin in conjunction with your dietary glucose levels to help you manage it properly. Blood glucose level..

Advance

Researchers plan to apply to the Food and Drug Administration for approval to test insulin preparations in clinical trials with human participants (the trial is not planned at this time and we are not looking for participants). Hmm). They are also exploring other uses for polymers, given how much the stability of commercial insulin has improved significantly.

The researchers say that their insulin preparations activate so quickly that they resemble insulin in people without diabetes and could help to develop artificial pancreatic devices that function without dietary patient intervention. I am excited.

Researchers are conducting additional trials in hopes of eligibility for human clinical trials.

Result is Science Translational Medicine.. Additional co-authors are Stanford and CSIRO Manufacturing, Australia.

Funding for research is provided by the National Institutes of Health, Stanford Diabetes Research Center, Stanford Institute for Maternal and Child Health, American Diabetes Association, PhRMA Foundation, US Department of Defense, Stanford Graduate Fellowship, Canadian Natural Sciences and Engineering Research Council, Stanford Bio X Bowes Graduate School. Student Fellowship, Novo Nordisk Foundation, Stanford Bio X, and Danish Independent Research Council.

Source: Stanford University


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