Written by Qingyang Li
When I was in high school, I had a friend named Lily. Generally speaking, she was no different from the average adolescent girl, except when she was eating. Before eating lunch with us, she always needed to inject insulin, and pay special attention to her diet. She was never able to eat much of our favorite rice. Lily was diagnosed with type 1 diabetes at the age of thirteen, and since then she has lived a life that requires insulin injections every day. Like most people, insulin injections cause Lily pain.
Diabetes is not an emerging disease for humans. As early as 1500 BC, there were written records describing the symptoms of diabetic patients with “rapid weight loss and frequent urination” in ancient Egypt. There are also descriptions of “diarrhea” in ancient Chinese medical books. Although the history of the disease is very long, humans have also struggled to treat diabetes for a long time. It was not until the emergence of insulin that the status quo was really changed.
Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion or impaired biological response to insulin, or both. There are two types of diabetes: type one and type two. Despite the prevalence of type 1 diabetes, sufferers can only be treated with insulin or insulin analogue injections. This is very painful for the patient. Long-term subcutaneous injections are often accompanied by adverse reactions such as pain, local tissue necrosis, infection and nerve damage. Therefore, improving drug delivery methods is a hot topic for research.
Towards oral insulin medication
For decades, scientists have been experimenting with developing oral insulin, but no product has been approved for market use by patients. “The reason why insulin cannot be taken orally is because it is too ‘large’. Insulin molecules cannot pass through the epithelial cells of the stomach and intestines into the blood. At the same time, the gastric juice in the stomach cuts the insulin molecule into small segments, making it unable to maintain its original structure and thus unable to function,” said Professor Akhter Hossain, Head of Insulin Peptide Group at the Howard Florey Institute, the University of Melbourne.
But all of that might be about to change. In order to solve the limiting factors that hinder the oral administration of insulin, recently, Professor Robert Langer’s team at MIT and scientists from Danish pharmaceutical company, Novo Nordisk, have designed a new type of drug capsule that can carry insulin or other protein drugs. This capsule can protect the drug contained within it from the harsh environment of the gastrointestinal tract. When the capsule reaches the small intestine, it breaks down, exposing soluble microneedles. These tiny needles are inserted into the intestinal wall and release insulin into the bloodstream.
Animal experiments have confirmed that this capsule can be loaded with the same dose of insulin as the standard injection, and the released insulin can quickly enter the blood.
“Most drugs are absorbed through the small intestine, partly because the small intestine has a very large surface area – 250 square meters, about the size of a tennis court. In addition, because this part of the body lacks pain receptors, it may be possible to achieve painless injection,” Professor Hossain explained.
In order to allow the capsules to reach the small intestine smoothly and achieve microneedle injection in the small intestine, the researchers covered the capsule with a polymer that can survive the acidic environment of the stomach (pH between 1.5 and 3.5). When the capsule reaches the small intestine, the high pH environment (pH about 6) in the small intestine will trigger its decomposition, which will eject the three folding arms hidden in the capsule. On each arm is a patch containing 1 mm long microneedles, which carry insulin. When the arms are opened, the force they release will cause the microneedles to penetrate the outermost layer of the small intestine tissue, after which the needle will dissolve and release the drug. To ensure that the microneedle will not pierce too deeply, cause perforation or other serious adverse events, researchers have conducted a large number of safety tests in animal and human tissues. They also designed the arm so that it can be broken after the microneedle has deployed, to reduce intestinal blockage, and it dissolves within a few hours. Tests conducted in pigs show that this 9mm diameter and 30mm long capsule can effectively release insulin and immediately produce a blood sugar lowering response.
Professor Hossain believes this is a convincing paper. “This new capsule represents an important step towards achieving oral protein medicine, and I am also optimistic about the follow-up clinical trials of oral insulin,” he said.
The future is bright and painless
Aside from Novo Nordisk’s new type of drug capsule, several other modes of insulin delivery, such as inhalation and skin patch, are currently being trialed.
In 2014, an inhalable form of insulin was marketed, and the FDA approved it for the administration of meal insulin in diabetic patients. The benefits of such a delivery system are obvious, but the drug cannot replace long-acting insulin and faces several other drawbacks. “For inhaled insulin, controlling the dose is difficult.” Professor Hossain said, “If an overdose occurs, it readily causes the patient’s blood sugar to be too low, which is very dangerous.”
Earlier this year, Nature Biomedical Engineering published an article reporting on the research progress of the “smart insulin patch”. This patch is about the size of a dollar coin. Hundreds of tiny needles (less than 1 mm in length) that can sense blood sugar levels are neatly arranged on the patch and loaded with insulin. When worn, these tiny needles can penetrate the epidermis to sense the blood sugar level near the subcutaneous tissue, and act like a supplementary pancreas; when the blood sugar level rises, it releases insulin into the body to reduce blood sugar. When the blood sugar level drops, it will slow down the release of insulin to prevent hypoglycemia.
At present, the ability of the “smart insulin patch” to regulate blood sugar has been confirmed in rat and pig models. The researchers claim that if this intelligent insulin delivery method can finally be applied to the clinic, it will completely change the patient’s diabetes management experience and quality of life.
Promisingly, these new insulin delivery technologies are set to significantly reduce the suffering of type 1 diabetes patients. In the near future, my friend Lily will soon be able to take insulin without the painful injections. Instead she will take a capsule as simply as swallowing a lolly, or perhaps even by wearing a small sticker on her arm.
Qingyang Li is a Masters student at the University of Melbourne. This story was written as part of a Science Communication internship project with the Royal Society of Victoria under the mentorship of Dr Renee Beale.
Image credit: Artem Podrez from Pexels