In animal tests, this needle-free insulin acted as fast as injections

A material that slips through skin might someday make needle-free insulin possible for people with diabetes.

In mice and mini pigs, attaching the permeating polymer to insulin and applying the resulting compound like a cream normalized blood glucose levels almost as quickly as injecting insulin, researchers report November 19 in Nature. This approach, called transdermal delivery, could allow people to manage diabetes using patches rather than injections.

For many essential medications, “transdermal drug delivery has been a longtime dream,” with millions of dollars invested for insulin alone, says bioengineer Youqing Shen of Zhejiang University in Hangzhou, China. Regular insulin injections come with problems such as needle phobia, pain, skin complications and poor compliance. Insulin can’t be taken in pill form because the digestive system breaks it down.

Transdermal delivery is already used for some small molecules like nicotine, but insulin, a large protein hormone, can’t get through the skin’s complex structure. Researchers can boost skin permeability with techniques including microneedles, ultrasound or chemicals that liquidize parts of the skin’s outer barrier layer. These compromise the skin’s integrity though, raising concerns about infection and safety.

Shen and colleagues instead used a polymer designed to travel through skin by interacting with its different layers. The polymer changes state depending on pH, exploiting the fact that the pH of skin increases with depth.

The polymer starts off positively charged and so binds to negatively charged fatty acid molecules in skin’s topmost barrier layer. This surface layer is acidic, with a pH of 4 to 5, but deeper layers are neutral, with a pH around 7. The increase in pH triggers a reaction in which the polymer becomes electrically neutral. In this state, it detaches from the fatty molecules, enabling it to diffuse through deeper layers.

Shen and colleagues chemically joined insulin to this polymer. Using a fluorescent dye and an array of imaging techniques, they confirmed that the combined molecule permeates through skin into the bloodstream, where it accumulates in tissues involved in regulating glucose, including the liver. “The polymer works as a locomotive, with insulin as cargo,” Shen says.

In diabetic mice and mini pigs, whose skin is similar to humans, applying the permeable insulin lowered blood glucose to normal levels within one to two hours, comparable to injected insulin. Levels stayed normal for 12 hours, significantly longer than the four hours for insulin delivered by needle.

“The polymer hasn’t shown any side effects in mice or pigs, but humans use insulin for decades, so we need to investigate long-term toxicity,” Shen says. His team is also working on giving just the right dose, since lowering blood glucose by too much can be dangerous.

The next step then would be human testing, where evaluating effectiveness and long-term safety will be key, says chemical engineer Robert Langer of MIT, who was not involved in the study.

The team is already exploring through-skin delivery with other drugs, including the active ingredient in the weight-loss drug Ozempic, says Shen. “That also works very well.”