Oral medication is one of the most used methods of drug delivery. It’s convenient, painless, and easy to administer. However, not all drugs can be absorbed through the digestive tract.

Many recently developed drugs that tackle inflammatory diseases, diabetes, osteoporosis, and hormone imbalances must be regularly injected. This can become tiresome and inconvenient for patients. Forgotten or skipped doses, in turn, can lead to an increase in avoidable side effects and complications.

Professor Randy Mrsny and his team in the Department of Life Sciences are investigating ways to improve the oral uptake of medicines, paving the way for more convenient oral tablets to replace injections.

The team hopes that oral delivery using their novel approaches could improve patient experience and make drugs safer and more efficient.

Learning from nature to enhance safety and effectiveness

Mrsny and his team are addressing this challenge by copying processes found in nature. Some bacteria in the human gut release toxins that can secretly cross the intestine and enter the body without alerting the immune system. By studying how these toxins do this, the team has found a new way for safely delivering medicines.

They showed this approach could work for real-life treatments by delivering the powerful anti-inflammatory protein, interleukin-10, directly to the intestine. This provided a novel way to treat pouchitis. Pouchitis is a painful inflammation affecting ulcerative colitis patients who have had their colon removed and replaced with an internal pouch formed from the end of their small intestine. Around 60% of patients undergoing the procedure will experience reoccurring inflammation, requiring urgent medical treatment.

When delivered by injection, interleukin-10 can reach the intestine to reduce inflammation. However, it also spreads throughout the body, causing harmful side effects like lowering red and white blood cells. When taken orally, using the toxin uptake pathway, interleukin-10 stays in the intestine, avoiding this dangerous side effect to safely benefit pouchitis patients.

The team have also taken inspiration from the gut itself. Scientists have long thought transport proteins on the surface of intestine cells are responsible for absorbing nutrients from our food. Researchers at Harvard University later demonstrated a second pathway. This occurs between neighbouring intestinal cells and can briefly become permeable to absorb incompletely digested nutrients.

Mrsny and his team have identified how this second pathway works. They have designed small agents, called PIPs, that can switch it on. While the toxin entry pathway allows large proteins to cross the intestine, PIPs, to help smaller molecules like those used in treating certain metabolic diseases, pass through. Drugs absorbed by this route pass directly to the liver, the target for treating metabolic diseases, allowing them to work faster and more effectively than injections.

Reducing animal use

Randy’s team begins by studying human conditions, such as how bacterial toxins affect humans and the uptake of nutrients in the gut. They then use in vitro models, cell-based tests, that mimic the human intestine to ask specific questions about how these pathways and mechanisms might be applied to medicines. Some complexities, however, cannot be modelled in a dish, and the team must test their ideas in animal models.

Once they have identified specific issues that require animal testing, the researchers carry out their experiments in rats. Rats are chosen for this work because of the need to collect repeated blood samples to study how the drug is taken up by the body. Rats have a larger blood volume than mice, so fewer animals can be used to obtain the data. Rats also have a larger intestine than mice, so more material and information can be gained in this way. Limits are in place on how much and how often blood can be collected to reduce the harms to the animal. Just like in humans, there are limits on donating blood to protect their health.

When it comes to using animals in their studies, Randy believes researchers’ approach is changing. “I think there has been a paradigm shift,” he said. “We are seeing more predictive in vitro models that result in an overall reduction of animal use and a refinement of the animal models that are still necessary.”

The future of patient care

While only trialed on a small population, the first example of the toxin pathway being used to deliver interleukin-10 was taken through phase II clinical trials safely and successfully.

Looking to the future, Randy hopes to work with industry collaborators and pharmaceutical companies to run clinical trials using the PIPs. Both approaches have the potential to bring life-changing treatments to people around the world.

“Changing injected drugs to oral dosages will not only change medicine, it will greatly reduce the environmental burden of disposing of millions of needles and syringes every day,” he said.

“We believe pharmaceutical companies will invest more knowing people will take the medicines, and that improved compliance would keep people out of hospitals with more effective treatment before their condition worsens.”