Almost one hundred years ago, in 1922, a person received an injection of insulin to treat life-threatening diabetes for the first time. Shortly after this lucky 14-year-old boy in Toronto, Canada got his shot, researchers began to test oral insulin formulations. One hundred years later, this challenge of relieving people with diabetes of daily shots is still being tackled. All efforts failed but hope was never lost.
There have been a few research groups and companies that have made progress recently, finally shining a light on some real hope. One group, in particular, has just published their study in the journal Science. They explain how they’ve engineered a capsule that, once ingested, pokes a tiny hole in the lining of the stomach to deliver insulin or other so-called biologic medicines that normally can’t be taken by mouth. And so it seems, painful injections may become a thing of the past very soon.
“This field is really at an exciting stage. I think it’s going to completely transform how patients take drugs.” – Samir Mitragotri, a biomedical engineer at Harvard University
The environment of the stomach and intestine is extremely harsh, which is basically why all attempts to deliver complex, delicate drugs by mouth has failed thus far. The difference between traditional pharmaceuticals and biologics is the size of the molecules that make up the drug.
Traditional pharmaceuticals are those medicines that can be taken orally; and they work because the molecules are so small that the digestive tract easily absorbs them. Biologics, on the other hand, are problematic because they are large molecules making them more liable to degrade in the stomach or be blocked from entering the bloodstream by thick layers of mucus and tightly packed epithelial cells that line the stomach and gut.
“Getting past these defenses is honestly one of the biggest challenges and holy grails in drug development.” – Carlo Giovanni Traverso, a gastroenterologist and bioengineer at Harvard Medical School in Boston and the Massachusetts Institute of Technology (MIT) in Cambridge
Biologics are typically proteins: large, unwieldy molecules produced by microbes or other living cells. They are super effective because of their large size which makes them more likely to hit a target molecule in the body without side effects. Biologics are actually used the most of all drug types on the market because they work so well. Seven of the top ten selling drugs in the United States are biologics.
The closest that pharmaceutical companies have gotten to a functioning pill form of biologics is by encapsulating several small proteins (peptides) in chemicals called permeation enhancers that promote absorption by the small intestine. Granted, it does work, although most permeation enhancers allow less than 1% of peptides to cross into the bloodstream, so it doesn’t work very well.
Giovanni Traverso, with Robert Langer, a drug delivery expert at MIT, and their colleagues are working on an approach through engineering. They designed a special hollow pill with one flattened end. Its shape was inspired by a leopard tortoise shell. This shape, as well as the capsule’s center of mass being located near the flat end, ensures that the pill rights itself in the stomach, with its flat surface facing the stomach lining. It works in the same way as the leopard tortoise shell does – the steep curvature of the dome, along with the force of gravity, guarantee that the shell always rolls back to its flat side facing down.
Inside the hollow pill, just above the flat end which is made of sugar, there is a tiny tensed spring holding the needle that is made of solid insulin. As the sugar gets wet from the moisture in the stomach, it begins to dissolve. Once dissolved, the spring breaks free and okes the insulin needle into the outer stomach layer. When that happens the insulin needle dissolves and enters the bloodstream.
They tested the pill in rats and pigs and it successfully deliver almost the same insulin levels into the blood as a subcutaneous injection. Furthermore, histology studies showed no signs of lasting damage from daily internal needle punctures. Regarding the remains of the capsule itself, which is made from biodegradable polymer and stainless steel components – it just passes harmlessly through the digestive system after it has released its contents.
But some people remain skeptical. Edith Mathiowitz, a biomedical engineer at Brown University, says, “It’s a very smart design, however the team needs to ensure that creating even tiny perforations in the stomach doesn’t pose long-term health problems for patients, and that undesirable proteins or bacteria can’t wiggle their way in alongside the insulin.”
The MIT team is now continuing to work with Novo Nordisk to further develop the technology, as well as optimize the manufacturing process of the capsules. “Our motivation is to make it easier for patients to take medication, particularly medications that require an injection,” Traverso says. “The classic one is insulin, but there are many others.”