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Given the choice between rejecting a dose of medicine and pushing it through your flesh inside a cold steel needle, most people take the pill. Convenience, portability and lack of skin stability have made pills the most popular way to administer medication for most medical history. However, not all drugs can survive this corrosive journey of the stomach into the intestines and into the bloodstream. Antibodies, proteins, these molecules are too fragile. That's why you still need to get vaccinated and many diabetics need to inject themselves twice daily with insulin so that their blood sugar does not become toxic.
But there could be another way, if you give up all your badumptions about what makes a pill and suddenly a pill and apply a delusional technique to the question. Start with a dose of insulin, lyophilize it and compress it to give it the shape of a needle. You need this form for the medicine to enter the bloodstream. Spring loaded, load it in a pill the size of a blueberry to be able to swallow it. Spend time contemplating charismatic reptiles and make some design changes. That's it, you have an unmanageable version of an insulin injection. This was about the process of a team of researchers led by the Mbadachusetts Institute of Technology, which today published in the journal its innovation in drug delivery. Science.
It's not just another wild science experiment from the same lab that created this medieval masterpiece, sown with micro-needles, a few years ago. This work is part of a collaboration with the Danish drug manufacturer Novo Nordisk, the world's leading provider of insulin. They expect to test the capsule in humans in the next two to three years.
"The preliminary plans look very promising," says Lars Fogh Iversen, senior vice president of global research technologies at Novo Nordisk. "However, this is the beginning and there is still work to be done. We have not yet decided which molecule would be suitable for the first clinical trials. According to Fogh Iversen, the company is considering other areas than diabetes, including obesity, hemophilia, and growth hormones.
The pharmaceutical company contacted the MIT team for the first time in the fall of 2014, after the publication of their first attempt at development. Intrigued by the possibility of offering a much easier and painless way to distribute his main product, Novo Nordisk started supporting the project in mid-2015 by providing grants, equipment and scientists. From the beginning, this meant that engineering could not be limited to what worked in the laboratory. Only concepts that can evolve into commercial manufacturing have been taken into account.
The first problem that the researchers had to solve was that of orientation. In the previous version of the group, the microneedles were arranged 360 degrees to inject their insulin dose into the close walls of the small intestine. In studies on pigs, the injection worked well, but it was difficult to predict when and where this would occur in the intestine. To get a faster and more reliable dose, the researchers decided to change their design to work exclusively in the stomach. But in this more cavernous organ, the shape and arrangement of their needles should change. They had to make sure that 100% of the needles came into contact with the lining of the stomach. It also meant that the pill could not just fall free. "We thought at first we could borrow from the Weeble Wobble," says Giovanni Traverso, a gastroenterologist at Brigham and Women's Hospital and Harvard Medical School and lead author of the journal. But round-bottomed children's toys were designed to be knocked down, realized, "and we wanted something that, once settled, would stay that way."
Which brings us to the leopard tortoise. The parsley-shelled reptile spends most of its days grazing in the savannahs of eastern and southern Africa. But some circles of applied mathematicians are better known for the unique geometry of their domed carapaces. These shells make them the best right-handers in the reptile kingdom; they are basically a walking gömböc. Alex Abramson, a MIT graduate student involved in the project, used modeling software to create shell-shaped capsules made from thick steel on the bottom and biocompatible plastic lighter on top. The result was a polychrome pill that reserves the right to be stung.
Note the singular use of the word "needle". The new model was smaller and therefore could contain fewer self-dipping syringes. But at one point researchers realized that they only needed one if they only had insulin. By using a compression method similar to that used for the manufacture of over-the-counter pills such as ibuprofen, insulin is packaged under pressure in sharp molds. The final product looks like a microscopic miniature, although the authors of the article prefer the term "millipost".
The final challenge was to determine how to propel this pure millipost insulin out of the capsule with enough force to pierce the lining of the stomach and administer the dose. And when the eureka moment arrived, was my boy adorable? "We were looking for something common to all stomachs and invented moisture," says Abramson. "We realized that some types of sugars are fracturing precisely, which releases a lot of kinetic energy when it's wet." Yes, they did pbad a sugar barrier around of a loaded steel spring and lodged at the top of the pill, in which they cut out tiny air vents to allow a few drops of gastric juice to enter, dissolving thus sugar and releasing the spring to plunge the insulin towards its final destination. Pretty cool.
Even colder, it seemed to work well when tested on pigs. The researchers report a successful reduction in blood sugar levels in swine subjects, without any adverse effects, such as internal tears or stomach blockages at the exit of the pill. Traverso explains that the next project is to test the capsules in large animals, to understand what happens if they inject repeated doses day after day, as a type 2 diabetic would require for this treatment to be useful. They also plan to add additional sensors to locate the pills and determine if they have forgotten their dose. Both will be essential to convince regulators that capsules are safe and effective enough to replace insulin injections.
Medications like insulin, which include not only hormones, but also DNAs and antibodies, are becoming more prevalent. Both researchers and pharmaceutical companies are looking for alternatives to their injection. "This delivery method developed by the Traverso team could be applied to many drugs that would otherwise require a hypodermic injection," says Mark Prausnitz, director of Georgia Tech's Center for Design, Development and Drug Delivery. , who did not participate in the study. But he warns that one and the same model might not work with all drugs and all patients.
Solving these questions would make it much easier to treat today's big killers with known drugs. This could also be important in addressing some of the challenges facing future Crispr-based therapies and many new types of vaccines, such as Ebola. Maybe it's a breed that will also go to the turtle.
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