Biomedical engineers create an oral insulin capsule to improve diabetes treatment
The leopard tortoise is a lumbering creature weighing up to 50 pounds. But its tall, peaked shell makes it surprisingly nimble: If it lands on its back, it automatically rolls to its side, where it can flip itself onto its feet with relative ease.
This ability was the inspiration behind a groundbreaking oral insulin-delivery capsule developed by a team of biomedical researchers from Massachusetts Institute of Technology, Harvard Medical School, KTH Royal Institute of Technology in Sweden, and Novo Nordisk in Denmark.
Dubbed a self-orienting millimeter-scale applicator (SOMA), the pea-sized capsule self-orients on the stomach lining, where it injects a needle of insulin. After the insulin fully dissolves in the tissue, the capsule passes out of the system. The team published these results in the journal Science.
More than 30 million people suffer from diabetes in the United States. Many rely on insulin injections to control their blood sugar. Yet drug adherence remains low: People must learn how to use needles; the injections can be painful; the insulin must be refrigerated; and used needles are biohazards.
As a result, doctors often delay prescribing insulin injections for years, and instead offer less effective oral medications, such as glucose pills.
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The first attempts to create an oral alternative started less than a year after injection therapy began in 1922. The problem is that stomach acid and enzymes break down insulin in the digestive system, and what does survive is poorly absorbed because the large molecules have trouble penetrating the walls of the gastrointestinal tract.
And it’s not just a problem for insulin therapies. Other macromolecule biologics suffer a similar fate in the gut. Some approaches for delivering biologics have included altering intestinal membranes or chemically altering a target drug.
The SOMA applicator is composed of low-density polycaprolactone and high-density 316L grade stainless steel. Like the leopard tortoise, it is high-domed, flat-bellied, and bottom heavy like a weeble-wobble toy (another inspiration).
This enables the applicator to orient its flat side to the stomach lining within milliseconds. Getting the capsule to face the stomach wall reproducibly was one of the major challenges the team overcame, said Robert Langer of the MIT Department of Chemical Engineering, who specializes in developing controlled-release systems for large molecules.
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Then researchers had to devise a way to get the insulin into the stomach lining. So they created a biodegradable 7-mm needle with a 1.7-mm tip of solid insulin, driven by a compressed stainless steel spring.
To release the needle, they “looked for materials that could change their behavior relatively quickly in the presence of increased moisture,” said Giovanni Traverso, assistant professor of medicine at Harvard Medical School.
They landed on sugar, which “is interesting in that it has brittle fracture mechanics,” Traverso said. They used sugar to plug the needle. It takes about 10 minutes for the plug to dissolve in the moist environment of the stomach. Once it begins to go, the force from the spring fractures it and pops the needle into the lining.
They also compressed the insulin into a super-concentrated solid that delivered 100 times the active pharmaceutical ingredient as liquid or solvent-cast forms generally do. “That’s the way to get the most amount of drug per unit volume, and it provides enhanced stability,” Traverso said.
In 300 tests on ex vivo pig stomachs and 60 on live pigs, the capsule consistently plunged the needle into the lining, released the insulin in about an hour, and lowered blood sugar levels at a rate to comparable to injected insulin.
SOMA worked only on an empty stomach, since food blocked it. Traverso compared using the capsule after eating to trying to give someone an injection through their jacket.
After the needle dissolved, the capsule passed through the gastrointestinal tract and out of the body. In humans, this would take about one day.
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After testing, the pigs were monitored twice daily and showed no ill effects. Endoscopies performed a week later revealed no tissue damage.
Maria José Alonso, a pioneer in nanopharmaceutical technology at University of Santiago de Compostela in Spain and the current president of the Controlled Release Society, called this SOMA a “radically new” technology.
“We are not talking about incremental improvements in insulin absorption, which is what most researchers in the field have done so far,” Alonso said. “This is by far the most realistic and impactful breakthrough technology disclosed until now for oral peptide delivery.”
Traverso said that SOMA could potentially deliver other biologics, including proteins, peptides, monoclonal antibodies, and RNA- and DNA-based therapeutics that cannot be taken orally now.
With an eye on optimizing the device for large-scale manufacturing with Novo Nordisk, the team is now looking to understand the effects of chronic use and test its safety through long-term experiments and preclinical models on primates and dogs.
SOMA is not the only next-generation oral delivery system in the works. Novo Nordisk’s oral Semaglutide is in phase three clinical trials.
“Lots of people have been working on ways of doing this, and it has been accomplished in different ways, but perhaps not to the levels that were demonstrated in our study,” Traverso said.
“I do hope this technology, based on the efficacy and tolerability data, will reach the market soon,” Alonso said. “Many patients from around the world will benefit from such an extraordinary achievement.”
Jen Pinkowski is a science journalist.
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