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Ionic liquid formulation makes oral insulin pill

29 Jun 2018 Belle Dumé
A capsule with an acid-resistant enteric coating
The end of insulin injections?

Diabetes mellitus is becoming a serious worldwide health problem. This auto-immune disease leads to β-cells being destroyed in type-1 diabetes and progressive β-cell dysfunction in type-2 diabetes. The result is insulin insufficiency in the patient.

Current treatments rely on closely monitoring blood glucose levels and then injecting insulin to simulate natural insulin secretion by pancreatic β-cells. Not only are repeated injections painful, this approach is far from ideal in itself and often fails to keep glucose levels within the tight physiological range required. Complications such as potentially fatal hypoglycaemia can ensue, as well as various pathologies (such as cardiovascular disease, kidney failure, retinopathy and neuropathy) linked to repeated hyperglycaemic episodes.

An insulin capsule that can be swallowed would be much better because not only would it make patients’ lives easier, the delivered insulin would closely mimic the natural physiological path that pancreatic insulin takes (via the portal vein to the liver and then on into the systemic circulation).

Researchers have been working on such a pill for a few decades now, but no formulation has successfully passed clinical trials yet. “One of the main problems to overcome is the fact that insulin is degraded in the stomach by enzymes and gastric acids,” explains Samir Mitragotri of Harvard University. “And even if some insulin survives and enters the intestine, it cannot be absorbed into the bloodstream because of the viscous mucus layer on the intestinal wall and the tight junctions of the intestine cells, through which large molecules such as insulin cannot easily pass.

“In our work, we have overcome these hurdles using ionic liquids.”

CAGE for oral insulin delivery

Ionic liquids consist of organic/inorganic salts and are widely used in various novel chemical and pharmaceutical technologies. In their work, Mitragotri and colleagues suspended insulin in an ionic liquid comprising choline and geranic acid (CAGE). This formation has already proved itself to be efficient for delivering antibiotics and insulin through skin.

“CAGE is good for three reasons for when it comes to oral insulin delivery,” says Mitragotri. “First, it protects insulin against enzyme degradation. Second, it reduces the viscosity of the mucus layer on the intestine, which improves how the insulin permeates across it. Finally, it can pass through the tight junctions of the intestine wall.”

The researchers filled capsules with an acid-resistant enteric coating with 80 microlitres of the formulation and orally administered these to nondiabetic male Wistar rats that had fasted overnight. They then measured blood glucose using a commercial glucose meter every hour for 12 hours and found that a relatively low dose of 10 U/kg dose brings about a 45% decrease in blood glucose levels. The blood glucose drops rapidly within the first two hours and then steadies out, reaching a plateau after 10 hours. In comparison with injected insulin, a dose of 2 U/kg of insulin produces a sharp drop of 49% in one hour, which rises steadily and subsequently peaks at 88% of the initial value in four hours.

Biocompatible and stable

The formulation is also biocompatible, and, according to circular dichroism measurements on its structure, is stable for up to two months at room temperature and up to four months in the fridge (at 4°C).

“Our work demonstrates the feasibility of oral delivery of insulin,” Mitragotri tells Physics World. “The same technology might also be used to deliver other proteins.”

Reporting the work in PNAS 1722338115, the team, which includes researchers from the University of California at Santa Barbara, is now busy with longer term safety and efficacy studies in larger animals. These will pave the way for subsequent human trials.



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