An oral insulin delivery system inspired by tortoises

Despite nearly a century of research, researchers have so far failed to develop an oral form of insulin that would allow patients with diabetes to avoid multiple daily injections. Now researchers from the Massachusetts Institute of Technology, Brigham and Women’s Hospital and Novo Nordisk say they have come up with an insulin pill, and it's inspired by the tortoise.

The pill is about the size of a blueberry and contains a small needle made of insulin. Once it reaches the stomach, it adjusts its orientation to ensure contact with stomach tissue before injecting the medicine. In tests in rats and pigs, the drug successfully lowered blood sugar to levels similar to those seen with insulin injections. The team reported the results in Science.

The gastrointestinal tract is not an ideal site for processing large-molecule drugs. It is acidic and full of microbiome and digestive enzymes that can attack and degrade proteins. And the thick mucus layers and dense cellular wall of the tract itself make it difficult for protein-based drugs to pass through. Because of those challenges, past attempts at oral-based large-molecule insulin platforms have only managed to deliver 1% of the drug into circulation, according to the researchers.

In fact, Novo Nordisk had previously scrapped development of an oral insulin because the low absorption rate rendered the delivery mechanism unsustainable from a commercial or manufacturing perspective. Even so, the company later reported early-stage data showing that the experimental tablet, OI388GT, was as effective as Sanofi’s injectable Lantus in controlling blood glucose levels.

For the new capsule, the researchers developed a device that has a single microneedle with a tip made of freeze-dried insulin. The injection is controlled by a compressed spring that is restrained by a sugar disc. Water in the stomach can dissolve the disc and serve as the trigger to release the spring and inject the needle into the gastric wall.

The scientists faced one major challenge: They needed to ensure that the injector wouldn’t misfire. So, they turned to the leopard tortoise for inspiration. The tortoise has a body structure that enables it to flip over when it falls onto its back. Using computer modeling, the scientists designed a pill with a similar shape. That's how the pill can reorient itself so it's always in the right position.

“What’s important is that we have the needle in contact with the tissue when it is injected,” Alex Abramson, the study’s first author, said in a statement. “Also, if a person were to move around or the stomach were to growl, the device would not move from its preferred orientation.”

The team tested needles loaded with 0.3 mg of insulin in pigs. They observed a decrease in blood glucose levels, with active drug levels in the blood comparable to those observed in the control pigs, which received insulin via subcutaneous injection, according to the study.

“We are really hopeful that this new type of capsule could someday help diabetic patients and perhaps anyone who requires therapies that can now only be given by injection or infusion,” Robert Langer, the study’s co-senior author, said in a statement.

The technology could be what Novo Nordisk has been trying to achieve in its long search for viable oral insulin. Back in November 2017, a year after it decided to pull the plug on OI388GT, Chief Science Officer Mads Krogsgaard Thomsen, Ph.D., said in a blog post that the company still believed in the potential of oral insulin.

The "missing piece of the puzzle" was "a breakthrough within drug delivery systems,” he said at the time, adding that Novo planned to work with external scientific collaborators to develop a viable delivery technology and bring it to the clinic.

Novo and the MIT scientists aren’t alone in that pursuit, though. Sanofi formed a research deal with Enteris BioPharma to leverage the latter’s oral drug delivery platform for a Type 2 diabetes therapy in 2017. A small biotech called Oramed is pushing ahead with its lead candidate, an oral insulin dubbed ORMD-0801, which is in midstage clinical trials. An earlier 28-day trial for that drug in Type 2 diabetes patients showed its ability to lower glucose levels, according to the company. And a team of researchers from Harvard University and the University of California, Santa Barbara, recently reported positive cell and animal results for their ionic liquid-based oral insulin formulation in the journal PNAS.

The Novo-MIT scientists are now working to optimize the manufacturing process for the tortoise-inspired insulin capsules. They also noted in the study that further research is needed “to determine chronic effects caused by daily gastric injections.”

Still, they believe their platform holds promise to deliver not just insulins but also a broader range of biologic drugs that traditionally have to be injected, including peptides and nucleic acids such as DNA and RNA therapies.