The story of the latest development in drug administration technology — a mouth patch that can deliver peptides and proteins without injection — begins with Chinese fondue.
Researcher Zhi Luo, the lead author of a new paper detailing the patch development published in Science Translational Medicine, was enjoying the spicy fondue dish when he found himself fascinated by Sichuan peppercorns. Not their flavor — though the mouth-numbing tingling of the little berries is a thing of wonder — but the fact that they had a tendency to get stuck to the inside of the mouth and throat. As an oral drug delivery specialist, he knew that people’s mouths and throats have developed so that it’s hard for foods to get stuck to them. So what was up with Sichuan pepper?
Luo and his team, who were researching non-invasive drug delivery techniques, decided to try to answer that question by looking for other foods that can get easily stuck in one’s throat or mouth, and found another notable offender: popcorn. Both the peppercorn berry and popped corn, they realized, have a sort of suction-cup shape that can attach to the inner lining of the cheek. Perhaps they could recreate a similar mechanism to deliver peptides and proteins that otherwise need injections.
But peppercorn or popped corn weren’t the best models for a mouth patch. “This popcorn stuff has a sort of stickiness, but they were not performing so well,” recalled Luo, a researcher at the Guangdong Provincial Key Laboratory of Advanced Biomaterials in the Southern University of Science and Technology. “We wanted something that has the best suction force — which is the tentacles of the octopus.”
The holy grail of drug delivery
Peptides and proteins are contained in essential drugs like insulin or semaglutide. Their delivery can be challenging because large molecules are not easily absorbed through the digestive system, and thus are typically administered through injections.
This isn’t ideal: Needles are no fun, especially for children, and aren’t very convenient. A few innovations, for instance microneedles and nasal sprays, have attempted to make the delivery of peptides less invasive. A few peptides can also be delivered by tables (for instance, semaglutide).
But there’s still great need for alternative ways to deliver peptides and large proteins. “Oral delivery really is kind of a holy grail,” said Arturo Vegas, a professor of chemistry at Boston University, who was not involved in the patch development. “It’s still the preferred form of administration for patients […] which means higher compliance, better outcomes for the patient, less adverse effects overall.”
Luo and his team aim to get closer to the ideal delivery form. The patches, Luo explained, are inspired by the suckers on an octopus’s tentacles — not only in shape, but in the way they attach to surfaces.
Due to the slippery nature of the inside of the cheek, most suction-cup-like structures are not able to attach to it. However, said Luo, “we found that actually there are many underwater fish or creatures that can do this job very well.”Octopus suckers “can basically stick to any waxed surface or a slippery surface.”
The team designed and 3D printed a lot of different structures based on octopus suckers, trying out various shapes and plastics to arrive at the optimal product. The final product was a food-grade plastic material (polydimethylsiloxane) suction cup that features a dome-shaped top and a stretchy disk that attaches to the inside lining of the cheek. This has both the advantage of keeping the patch anchored and allowing for the infusion of peptides.
After testing various sizes, the researchers found that a 1 cm diameter — a little smaller than a penny — worked best because it was large enough for people to handle, but small enough not to feel bulky in the mouth.
A potential game changer
So far, the patch has been tested in dogs, with researchers finding that it delivered the drug desmopressin comparably to tablets. The patch remained attached to the inside of the dogs’ mouths for three hours, without falling off or causing irritation or other reactions.
The authors then ran a small human trial, albeit without drugs. They asked 40 healthy volunteers to test the patch by using it for 30 minutes while they talked, moved, and even rinsed their mouths. Most of the patches (35) remained attached. Two fell off after 10 to 15 minutes, and three after 23 to 27 minutes. The test subjects expressed preference for this potential means of drug delivery compared to injections.
This research has some limitations. One, says Luo, is that the long-term safety of the patch has not yet been studied, especially for patients who may need daily administrations and could develop sensitivity to the patch.
There may be other practical challenges, said Vegas. “The mouth is very easily accessible, so that’s kind of nice. But at the same time… it’s easily accessible, and that can also be a problem,” he said. Would the patches require people to abstain from eating while they used them, or to change their habits in other ways? Will they stay put if the patient plays with them with their tongue? These are all questions to answer, although the innovation seems promising, he said.
This is far from the first medical technology to be inspired by nature. Vegas notes that in 2008, MIT developed a similarly gecko-inspired bandage. “We can learn from other animals and other creatures,” said Luo. “I think learning from nature is always a really good resource of new and good ideas.”