Oral nanotherapeutic formulation of insulin with reduction of hypoglycemic episodes. Summary Injectable insulin is a widely used medication with life-threatening hypoglycemic events. Here we report insulin-conjugated silver sulfide quantum dots coated with a chitosan/glucose polymer to produce a responsive oral insulin nanoformulation . This formulation is pH responsive, insoluble in acidic environments and shows greater absorption in human duodenum and Caenorhabditis elegans explants at neutral pH. The formulation is sensitive to glucosidase enzymes to trigger insulin release. The formulation has been found to distribute to the liver of mice and rats after oral administration and promote a dose-dependent reduction in blood glucose without promoting hypoglycemia or weight gain in diabetic rodents. Non-diabetic baboons also show a dose-dependent reduction in blood glucose. No biochemical or hematological toxicity or adverse events were observed in mice, rats, and non-human primates. The formulation demonstrates the potential to control oral blood glucose without hypoglycemic episodes. |
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Researchers have found a new way to deliver insulin to the body. The drug, which can be taken orally , has already been tested on baboons and has been found to lower blood sugar levels without causing hypoglycemia . The new insulin will be ready for human testing in 2025. If all goes well, diabetics will have an easier life without injections.
There are approximately 425 million people worldwide with diabetes. Approximately 75 million of them inject insulin daily. Now they may soon have a new alternative to syringes or insulin pumps. Scientists have found a new way to supply the body with smart insulin.
The new insulin can be consumed by taking a capsule or better yet, inside a piece of chocolate.
Inside we find tiny nanocarriers in which insulin is encapsulated. The particles are 1/10,000th the width of a human hair and are so small that they cannot even be seen with a normal microscope.
"This way of delivering insulin is more precise because it delivers it quickly to the areas of the body that need it most. When insulin is given with a syringe, it is distributed throughout the body, where it can cause unwanted side effects," he explains. Professor Peter McCourt from the Arctic University of Norway UiT. He is one of the researchers behind the study.
The research was recently published in Nature Nanotechnology .
Delivering directly to the liver
It was researchers from the University of Sydney and the Sydney Local Health District who, in collaboration with UiT, discovered many years ago that it was possible to deliver drugs to the liver using nanocarriers. The method was later developed further in Australia and Europe.
Many medications can be taken orally, but until now people had to inject insulin into their bodies. McCourt explains that the problem with nanocarrier insulin is that it breaks down in the stomach and therefore does not reach where it is needed in the body. This has been a big challenge to develop a diabetes drug that can be taken orally. But now researchers have solved this challenge.
"We created a layer to protect insulin from being broken down by stomach acid and digestive enzymes on its way through the digestive system, keeping it safe until it reaches its destination, that is, the liver ," says McCourt, a biologist. hepatic.
The coating is then broken down in the liver by enzymes that are activated only when blood sugar levels are high , releasing insulin where it can then act on the liver, muscles and fat to remove sugar from the blood.
"This means that when blood sugar is high, there is a rapid release of insulin and, more importantly, when blood sugar is low, no insulin is released," says Nicholas J. Hunt from the University of Sydney, who, along with Victoria Cogger, is leading the project.
He explains that this is a more practical and patient-friendly method of managing diabetes because it greatly reduces the risk of a hypoglycemic event occurring and allows controlled release of insulin depending on the patient’s needs, unlike injections. where all the insulin is released at once.
Fewer side effects
The new method works similar to how insulin works in healthy people. The pancreas produces insulin that first passes through the liver, where much of it is absorbed and keeps blood sugar levels stable. In the new insulin method, the nanocarrier releases insulin into the liver, where it can be absorbed or entered into the blood to circulate throughout the body.
"When insulin is injected under the skin with a syringe, much more of it reaches the muscles and fatty tissue than would normally happen if it were released from the pancreas, which can lead to fat buildup . It can also lead to hypoglycemia. , which can be potentially dangerous for people with diabetes.
With the new method, there will be fewer side effects.
Plus, you don’t need to prick yourself with a needle and you can take the medication you need in a slightly more discreet way. Additionally, this form of insulin does not require refrigeration.
Tested on baboons
Oral insulin has been tested in nematodes, mice and rats. And finally, the drug has been tested on baboons in Australia’s National Baboon Colony. "To make oral insulin more palatable, we incorporated it into unsweetened chocolate. This approach was well received," says Hunt. According to him, 20 baboons participated in this study. When they received the drug, their blood sugar level decreased.
The baboons were normal, healthy baboons, but oral insulin was also tested on mice and rats that actually had diabetes . The mice and rats did not have low blood sugar events (hypoglycemia), gain weight, or accumulate fat in the liver, overcoming current challenges with injectable insulins and other oral insulins.
What remains now is to test the new method on humans.
Ready to use in 2-3 years
"Human trials will begin in 2025 led by spin-off company Endo Axiom Pty Ltd. The clinical trials are conducted in 3 phases; in the phase I trial we will investigate the safety of oral insulin and critically analyze the incidence of hypoglycemia in healthy patients and with type 1 diabetes. Our team is very excited to see if we can reproduce in humans the absent hypoglycemia results observed in baboons, as this would be a big step forward. The experiments follow strict quality requirements and must be carried out collaboratively with doctors to ensure they are safe for test subjects," Hunt says.
"After this phase I we will know that it is safe for humans and we will investigate how it can replace injections for diabetic patients in phase 2 trials," says the researcher.
Researchers hope that the new drug can be ready for everyone to use in 2 to 3 years.
Final message In conclusion, Ag 2 S QD-conjugated insulin with a CS/GS polymeric coating was simple to fabricate and reproducible at CSIRO. The product facilitated oral absorption and hepatic targeting of insulin. In mice, rats and baboons, it demonstrated a dose-dependent effect with a reduced incidence of hypoglycemia and no toxicity. These studies form the basis for evaluating this formulation in humans, ongoing toxicity and clinical investigations. This technology is designed to be a platform for oral peptide delivery. It is applicable to peptides and proteins that act in the liver (for example, interferon-α) or other specific organs (for example, the pancreas for the glucagon-like peptide 1 agonist (liraglutide). |
Reference : Hunt, NJ, Lockwood, GP, Heffernan, SJ et al. Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-023-01565-2
