Insulin pill may soon be a reality

Daily jabs of insulin are a painful reality for many with diabetes. That may change if researchers who have successfully tested oral insulin in rats are able to replicate those results in humans.

Nearly 350m people worldwide suffer from diabetes and that number is predicted to grow to more than 500m by 2030. While the more common form, type-2 diabetes, does not always need insulin treatment, nearly quarter of all diabetes patients depend on insulin jabs. Oral insulin’s estimated annual sales could be somewhere between $8 billion and $17 billion.

The benefits of an insulin pill are more than just ease of taking the drug. The pill will mean that patients can start taking insulin earlier in the development of the disease, which could reduce some of the secondary complications, which can include blindness and impaired healing that leads to amputations.

The idea of oral insulin has been around since the 1930s, but the difficulties of making it seemed too big to overcome. First, insulin is a protein – when it comes in contact with stomach enzymes, it is quickly destroyed. Second, if insulin can pass through the stomach safely, it is too big a molecule (about 30 times the size of aspirin) to be absorbed into the bloodstream, where it needs to be in order to regulate blood-sugar levels.

Sanyog Jain at India’s National Institute of Pharmaceutical Education and Research and his colleagues have been working on delivering insulin in the oral form for many years. Their first fully-successful attempt came in 2012, when they developed a formulation that successfully controlled blood-sugar level in rats. But the materials used were too expensive to consider commercialising the technology.

Now, in a paper published in the journal Biomacromolecules, they have found a cheaper and more reliable way of delivering insulin. They overcome the two main hurdles by, first, packing insulin in tiny sacs made of lipids (fats), and, second, attaching to it folic acid (vitamin B9) to help improve its absorption into the bloodstream.

The lipids they use are cheap and have been successfully employed to deliver other drugs before. These help to protect insulin from being digested by stomach enzymes, which gets it to the small intestine. When the lipid-covered sacs enter the small intestine, special cells on its lining called microfold cells are attracted to the folic acid in them. The folic acid helps activate a transport mechanism that can let big molecules pass through into the blood. The amount of folic acid used in the formulation also seems to be in the safe region.

In rats, Jain’s formulation was as effective as injected insulin, although the relative amounts that entered the blood stream differed. However, it was better in one key aspect. Whereas the effects of an injection are quickly lost (in less than 6 to 8 hours), Jain’s formulation helped control blood-sugar level for more than 18 hours.

The most important part of the research comes after successful testing in animals – the formulation needs to be given to human volunteers. But, Jain said, “at a government institute like ours, we don’t have the sort of money needed for clinical trials.”

He may not have to wait for long, as big pharma companies have been searching for an insulin pill formulation for decades. Two of them, Danish pharma giant Novo Nordisk and Israeli upstart Oramed are in a race to come up with a solution. Google’s venture capital arm, Google Ventures, recently invested $10m in Rani Therapeutics with the hope it will help develop oral insulin. Indian firm Biocon also does oral insulin research, and it recently signed an agreement with pharma giant Bristol-Myers Squibb.

Oramed is ahead, with their oral insulin product soon to enter phase-II clinical trials, which is the most advanced stage any oral insulin formulation has ever reached. Its chief scientist, Miriam Kidron, said of Jain’s research: “Most people have the same basic idea to develop an insulin pill, but its the little differences that will determine ultimate success.”

While Kidron did not reveal Oramed’s formulation, she said, “we attempted liposomal delivery before, just like Jain’s work, but we weren’t successful.” She warned that translating success from rats to humans is very difficult. And she is right – most drugs have a high cull-rate at each stage of their development. Even so, research like Jain’s give hope that an insulin pill may not remain a dream for long.The Conversation

First published at The Conversation.

Medical technology: A silent healer

Researchers have developed novel ways to tap the pharmacological potential of an infamous and deadly gas

Carbon monoxide gets a bad rap. The gas, produced by incomplete combustion of hydrocarbons, causes hundreds of deaths every year by poisoning and sends many thousands to hospital. Most of these are the result of leaking cooking and heating equipment, but the colourless, odourless and tasteless substance, known to chemists as CO, has also aided many a suicide. Most horrifically, Nazis used it in gas chambers.

But there is more to the “silent killer”, as CO is sometimes called. It is produced by many cells in the human body, where its molecules play a crucial role in activating enzymes involved in controlling the dilation of blood vessels, and thus blood flow. Mice in which the gene for producing the compound has been knocked out develop faulty organs and die young.

Exploiting this insight, researchers have successfully used CO to treat a number of ailments in lab animals. These include pulmonary hypertension, an otherwise incurable disease in which thickened arteries obstruct the flow of blood, leading to heart failure. The gas can also keep inflammation in check, in particular after organ transplants.

Frederick Montgomery and Duncan Bathe think they have come up with a way to hit the sweet spot. Their Coke-can-sized gizmo, which they devised while working at Ikaria, an American drug firm that both have since left, contains a cartridge of pressurised CO, a tube to deliver the gas to the patient’s nose, and a few buttons to set the required dose. A sensor connected to a nozzle at the end of the tube constantly measures the patient’s breathing rate and adjusts the amount of CO dispensed with each breath. Safety features, including automatic shutdown if anything seems amiss, are meant to eliminate the risk of CO overdose and ensure that none leaks out, endangering others.

Scientists at another American pharmaceutical company, Sangart, meanwhile, have been encasing the gas—or, strictly speaking, CO-ferrying haemoglobin—in a polymer pouch. Kim Vandegriff and her colleagues have been using polymer wrappers a mere nanometre (a billionth of a metre) across. These can be designed to break open only where their payload is needed. Early trials have shown promise in treating sickle-cell anaemia, a disease caused by a faulty haemoglobin gene.

Unlike most drugs, CO is not broken down by the body. Instead, once its job is done, it is transported to the lungs and exhaled. As a result, it produces no side-effects. Given the right dose, then, it can heal silently, too.

First published on economist.com. Also appeared in The Economist. Also available in audio here.

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