Oral insulin nanoparticles could replace injections

Scientists at Nanyang Technological University, Singapore (NTU Singapore) have developed insulin nanoparticles that may one day become the basis for an oral medicine — and an alternative to insulin injections for diabetic patients. Their findings have been published in the journal Nanoscale.

A multilayered approach

Insulin is a naturally occurring hormone that is critical for the regulation of blood glucose levels, especially after a meal. In healthy individuals, insulin produced in the pancreas enters the bloodstream and is distributed to key metabolic organs, instructing the liver, muscles and fat cells to take up more glucose from the bloodstream and store it for future use. At the same time, insulin nudges the liver to lower the rate of new glucose production, serving to effectively reduce blood glucose levels.

In contrast, diabetic patients do not produce sufficient insulin to meet their body demands. In serious cases, insulin needs to be given via a needle into the fatty tissue beneath the skin. From there, it goes into the general blood circulation throughout the body before travelling to the liver.

Delivering insulin orally would be preferable over insulin jabs for patients because it causes less pain, but oral dosage remains a challenge. This is because, as insulin is a protein, it gets broken down in the gastrointestinal tract before it can even reach the bloodstream to regulate blood glucose.

To overcome this challenge, scientists from NTU’s School of Materials Science and Engineering and the Lee Kong Chian School of Medicine (LKCMedicine) designed a nanoparticle loaded with insulin at the core, then coated with alternating layers of insulin and chitosan, a natural sugar. The nanoparticle closely mimics the route by which natural insulin enters the bloodstream from the liver.

Each of the nanoparticles is about 200 nm in size — at least 1000 times smaller than a pollen grain. Insulin is first loaded into the liposome, a tiny sphere at the core of the nanoparticle. The liposome is then coated with 11 alternating layers of insulin and chitosan of three different molecular weights, an approach that allows more insulin to be loaded. Dosing is achieved by controlling the number of layers in the nanoparticle.

When the insulin nanoparticle enters an acidic environment of the stomach, its layers start to repel each other, resulting in the slow release of insulin from the outermost layer and leading inwards. While it loses some insulin as it travels down the gastrointestinal tract, the nanoparticle has enough coatings that by the time it is transported through the intestinal wall and into the bloodstream, the insulin in the remaining layers and at the liposome core is still intact.

Each nanoparticle has a tiny sphere at the core, called a liposome, which is first loaded with insulin. The liposome is then coated with 11 alternating layers of insulin and chitosan of three different molecular weights — an approach that allows more insulin to be loaded.

Proof-of-concept study

To investigate the feasibility of the insulin nanoparticle for oral delivery, the NTU team first conducted a series of lab experiments to establish the nanoparticle’s stability, its ability to pass through the intestinal wall and the efficacy of the insulin in the nanoparticles that have been transported through the intestinal wall.

After leaving the nanoparticles in fluid that simulates the stomach environment, the team found that 6% of the insulin from the nanoparticle was released in one hour and 94% remained encapsulated. It takes about one hour for food to pass through the stomach and into the small intestine, which has a less harsh environment.

When tested on the human cell line Caco-2 — a widely used model for studying the transport of molecules across the intestinal wall — the scientists found that the amount of insulin transported across was three times higher when loaded into the nanoparticle, compared to bare insulin solution. The scientists also tested the rate at which nanoparticle insulin is absorbed and cleared in the bloodstream of rats. In rats fed orally with insulin nanoparticles, the insulin concentration in the blood peaked at the 30-minute mark and was entirely eliminated in four hours.

“Taken together, these lab experiments showed that our layer-by-layer approach limited the exposure of insulin to the gastrointestinal environment, preventing premature degradation of the insulin,” said study co-author Associate Professor Yusuf Ali, from NTU LKCMedicine. “We are now studying if this peak comes earlier than the 30-minute mark — an indicator of how closely the insulin from our nanoparticle follows the ebb and flow of naturally produced insulin in the bloodstream.”

Co-lead author Dr Huang Yingying, from the School of Materials Science and Engineering, said the rapid absorption and elimination of insulin released from these multilayered nanoparticles demonstrates a proof of concept in replicating meal-related metabolic responses in individuals without diabetes. He added that the level of insulin concentration can be further increased by repeating the number of alternating insulin and chitosan layers on the nanoparticle surface.

“Efforts to develop oral insulin products have met with little success because these products either come with a safety risk or require frequent dosage due to the drug’s ability to contain only a small amount of insulin,” Dr Yingying said.

“The tests of our NTU-developed insulin nanoparticle in rats show that it can carry a large enough amount of insulin for the desired therapeutic effect and at the same time is small enough to pass through intestinal walls into the bloodstream. This indicates its potential application for oral insulin delivery in humans. We believe that the same concept could also be useful for other protein drugs that normally have to be injected.”

The NTU team is now in talks with a pharmaceutical company to further improve the nanoparticles’ function. According to Assoc Prof Ali, the team are hopeful that their work “could someday replace painful insulin injections with a simple and small pill”.

Please follow us and share on Twitter and Facebook. You can also subscribe for FREE to our weekly newsletters and bimonthly magazine.