"Smart Insulin Patch" for Diabetes Is Years From Human Trials

Veronica Hackethal, MD

June 26, 2015

A "smart insulin patch" that could potentially dispel the need for painful insulin injections for millions of people worldwide with diabetes has been developed by a team at the University of North Carolina (UNC) and North Carolina State University. It employs painless microneedles to sense the low oxygen environment created when glucose levels rise and then delivers insulin as required.

This is the first approach adopting this strategy of sensing low oxygen levels; other similar nanoparticle technologies in development rely instead on detecting changes in pH.

However, the patch has so far only been tested in murine models of type 1 diabetes; a study detailing the findings in mice was published online on June 22, 2015 in the Proceedings of the National Academy of Sciences.

"We are now moving toward preclinical, mini–pig-based studies before moving to clinical trials," said senior author Dr Zhen Gu, PhD, a professor in the joint UNC/NC State department of biomedical engineering. "If successful, we will test the patch on humans. It would take several years, most likely around 3 to 4 years, until potential clinical trials."

"If we can get these patches to work in people, it will be a game changer," said John Buse, MD, PhD, another author, in a press release. Dr Buse is director of the UNC Diabetes Care Center and past president of the American Diabetes Association.

Asked to comment, Richard Elliott, MD, research communications manager at Diabetes UK, said: "Alongside the insulin pumps that are already widely available, this 'smart patch' is one of a number of experimental approaches that are hoping to eliminate, or at least reduce, the need for insulin injections to manage diabetes effectively."

But "significant hurdles" remain in the development of many of these insulin-delivery systems, he pointed out.

And David C Klonoff, MD, medical director of the Diabetes Research Institute at Mills-Peninsula Health Services, San Mateo, California, agreed that there remains much work to be done on this new patch technology.

"It will be at least 5 years before this method could be on the market. For now, it is an interesting concept, but it is not close to being ready for clinical use."

Patch Uses Vesicles 100 Times Smaller Than Width of a Human Hair

As well as these so-called "smart insulins" that activate only when needed, other novel strategies in development to try to circumvent the problem of daily insulin injections or use of insulin pumps include nasal or oral insulins.

There is also a new inhaled insulin formulation on the market in the US, Afrezza (Sanofi/Mannkind), which was only launched in February so doctors and patients are still familiarizing themselves with its use.

In this latest research, the UNC investigators explain that their patch is made of nontoxic, biocompatible materials and measures about the size of a penny. Over 100 microneedles, made from hyaluronic acid and each about the size of an eyelash, litter its surface. Vesicles with an average diameter of 118 nm containing insulin and a bioengineered glucose-sensing enzyme, glucose oxidase, "are integrated into the microneedles, and once blood sugar goes up, the vesicles will be dissociated to release insulin correspondingly," Dr Gu explained.

"Our method is 'smart.' Our innovative microneedle-array patch provides a convenient administration method with fast glucose-responsive behavior. It reacts to body conditions and releases drug with the relevant, correct dose," he added.

The team tested how rapidly these vesicles responded to low oxygen to trigger insulin release. In vitro studies showed a "remarkably" faster release of insulin compared with other pH-sensitive glucose-responsive nanoparticles that are under development, they report.

Finally, the team tested the "smart" patches in mice models of type 1 diabetes. They compared:

  • Blank microneedles containing no insulin.

  • Microneedles containing insulin only.

  • Microneedles with vesicles containing both insulin and full-dose glucose oxidase.

  • Microneedles with vesicles containing insulin and one-half dose of glucose oxidase.

  • Microneedles with vesicles containing insulin only.

After a glucose challenge, the mice that received the patches with microneedles with vesicles containing both insulin and full-dose glucose oxidase experienced rapid declines in blood glucose (within 30 min), with blood glucose normalized for up to 4 hours. After that, their blood glucose levels gradually increased but remained lower than those of mice in the other groups for up to 9 hours.

The same group of mice also remained free of hypoglycemia even after administration of an extra dose of enzyme plus insulin. In contrast, mice given microneedles with vesicles with insulin only showed a risk of hypoglycemia, suggesting that addition of the enzyme, glucose oxidase, helps reduce the risk of hypoglycemia.

"This smart insulin patch with its novel trigger mechanism offers a clinical opportunity for closed-loop delivery of insulin in a fast glucose-responsive, pain-free, and safe manner," the researchers say.

Patch Could Be Personalized, but Still a Long Way to Go

Close-up of microneedle insulin patch [Source: Dr Zhen Gu]

In vivo and in vitro experiments also showed that the rate of insulin release could be adjusted by changing the enzyme dose, suggesting the insulin smart patches may have the potential to be tailored to different ranges of blood glucose levels. The vesicles did not show "significant" toxicity, either.

"The whole system can be personalized to account for a diabetic's weight and sensitivity to insulin, so we could make the smart patch even smarter,' said Dr Gu.

Dr Klonoff explained that other "smart insulins" that have been studied rely on direct release of insulin as triggered by pH resulting from rising glucose levels, instead of the indirect method used by this team (eg, lower oxygen levels caused by a rise in glucose).

The effectiveness of pH-based approaches has been limited by slow response to changing glucose levels, and safety and toxicity may also be an issue, Dr Gu and colleagues maintain.

But Dr Klonoff said there are plenty of unanswered questions about the sensitivity and specificity of this newest approach, too.

"What if a change in glucose failed to produce enough hypoxia to trigger sufficient insulin release? And would other things besides hypoglycemia, such as low oxygen due to lung disease, trigger a potentially dangerous release of insulin?"

And there is the issue of whether the microneedles could be tolerated long term and whether human skin reacts differently from mice skin, he explained.

"The approach might turn out to be a good one, but many questions must be answered and much human data must be collected before this can become a real product," he concluded.

The authors report no relevant financial relationships, as does Dr Elliott. Dr Klonoff reports being a consultant for Google, Insuline, Lifecare, Novartis, Roche, Sanofi, Tempramed, and Voluntis and receiving research grants from Eli Lilly, Intarcia, Novo, and Oramed. He is a stockholder in Tempramed.

Proc Natl Acad Sci. Published online June 22, 2015. Abstract

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