Drugs that consist of large proteins or RNA are generally not suitable for oral administration, as they are easily broken down in the digestive system. For several years, researchers at MIT (Cambridge, MA, USA) have been exploring methods to deliver these drugs orally by encasing them in small devices that protect them from degradation, delivering the drugs directly to the digestive tract lining. Most of these devices employ small needles or microneedles to inject drugs once the device reaches the digestive system. Now, the MIT researchers, along with collaborators from Brigham and Women’s Hospital (Boston, MA, USA) and Novo Nordisk (Bagsværd, Denmark), have developed a bioinspired capsule that can pump drugs directly into the walls of the GI tract. The needle-free device could be used to deliver insulin, antibodies, RNA, or other large molecules without causing any damage to the tissue.

Drawing inspiration from cephalopods, such as squids and octopuses, which use water jets to propel themselves through the water and create ink clouds to evade predators, the researchers developed an ingestible capsule that releases a burst of drugs directly into the stomach wall or other parts of the digestive tract. This innovative capsule could provide an alternative to injectable drugs, such as insulin, large proteins like antibodies, and even RNA therapies like vaccines or treatments for diseases such as diabetes, obesity, and other metabolic disorders. This needle-free strategy, detailed in a paper published in Nature, could revolutionize drug delivery.

The team designed two mechanisms to replicate the jetting action of squids and octopuses. These mechanisms use compressed carbon dioxide or tightly coiled springs to create the force needed to expel liquid drugs from the capsule. The gas or spring is kept compressed by a carbohydrate trigger, which dissolves when exposed to humidity or acidic conditions in the stomach. Once the trigger dissolves, the gas or spring is allowed to expand, propelling the drug out of the capsule. In experiments with digestive tract tissue, the researchers determined the necessary pressure to expel drugs with enough force to penetrate the submucosal tissue, creating a depot that would then gradually release the drugs.

The capsules have also been designed to target different sections of the digestive tract. One version, with a flat bottom and high dome, is intended for the stomach lining, where it sits and ejects the drug downward into the tissue. This capsule, about the size of a blueberry, holds 80 microliters of drug. Another version, shaped like a tube, aligns with longer organs such as the esophagus or small intestine, ejecting the drug toward the side wall. This version can deliver 200 microliters of drug. Made from metal and plastic, the capsules can pass through the digestive system and are excreted after delivering the drug.

In animal tests, the capsules successfully delivered insulin, a GLP-1 receptor agonist similar to the diabetes drug Ozempic, and short interfering RNA (siRNA), which can silence genes and is potentially useful for treating genetic disorders. The researchers found that the concentration of the drugs in the animals’ bloodstream was comparable to levels seen when the drugs were injected, and no tissue damage was observed. The team envisions the capsules being used by patients at home for frequent insulin or other injectable drug administration, offering a less invasive, more convenient alternative to injections. Additionally, this approach eliminates the need to dispose of sharp needles. The researchers also created a version of the device that can be attached to an endoscope, enabling doctors to administer drugs directly during endoscopies or surgeries. The team plans to further develop the capsules and hopes to begin testing them in humans soon.

“This technology is a significant leap forward in oral drug delivery of macromolecule drugs like insulin and GLP-1 agonists. While many approaches for oral drug delivery have been attempted in the past, they tend to be poorly efficient in achieving high bioavailability,” said Omid Veiseh, a professor of bioengineering at Rice University, who was not involved in the research. “Here, the researchers demonstrate the ability to deliver bioavailability in animal models with high efficiency. This is an exciting approach which could be impactful for many biologics which are currently administered through injections or intravascular infusions.” 

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