Pill May Replace Injection to Deliver Insulin, Other Peptide Drugs

It’s been the holy grail of drug delivery: a pill that can preserve the structural integrity of large, delicate proteins and peptides while carrying them past one forbidding barrier after another—the gastric acids of the gut, the protein-degrading enzymes of the intestine, the mucus layer of the intestine, and the tight junctions between the cells of the intestinal wall. Such a pill may soon be within the grasp of people with type 1 diabetes. This pill, which tucks insulin with an ionic liquid cage, which is itself tucked within an acid-resistant enteric coating, protects its fragile payload while transporting it through the gastrointestinal tract to the bloodstream.

This ionic liquid-based oral insulin formulation was developed by scientists based at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). According to these scientists, the formulation is not only safe, it significantly enhances oral insulin absorption by efficiently circumventing gastrointestinal barriers.

The scientists, led by Samir Mitragotri, Ph.D., Hiller Professor of Bioengineering and Hansjorg Wyss Professor of Biologically Inspired Engineering at SEAS, evaluated the pharmacokinetics and pharmacodynamics of the pill’s jejunal administration in rats. Detailed findings appeared June 25 in the Proceedings of the National Academy of Sciences, in an article entitled “Ionic Liquids for Oral Insulin Delivery.”

“Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid,” wrote the article’s authors. “CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning.

The formulation is biocompatible, easy to manufacture, and can be stored for up to two months at room temperature without degrading, which is longer than some injectable insulin products currently on the market.

“Low insulin doses (3–10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin,” the PNAS paper continued. “When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed.”

Mitragotri and colleagues concluded that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

Not only does oral delivery of insulin promise to improve the quality of life for up to 40 million people with type 1 diabetes worldwide, it could also mitigate many of the disease's life-threatening side effects that result from patients failing to give themselves required injections.

Insulin therapy, by injection just under the skin or delivered by an insulin pump, generally keeps the glucose levels of most diabetics in check. “But many people fail to adhere to that regimen due to pain, phobia of needles, and the interference with normal activities,” said Mitragotri. “The consequences of the resulting poor glycemic control can lead to serious health complications.”

To help diabetics avoid insulin injections, many researchers have tried various means of surmounting these barriers—by reengineering the insulin molecule, coating it in protective polymers, and introducing additives to inhibit breakdown by enzymes or to enhance absorption. However, no oral insulin delivery product is currently available in the clinic.

The newly developed ionic liquid-based oral formulation, Mitragotri explains, “is like a Swiss Army knife, where one pill has tools for addressing each of the obstacles that are encountered.”

By encapsulating the insulin–ionic liquid formulation in an enteric coating, the team overcame the first obstacle, resisting breakdown by gastric acids in the gut. This polymer coating dissolves when it reaches a more alkaline environment in the small intestine, where the ionic liquid carrying insulin is released.

The choline–geranic acid formulation also was shown to be adept at penetrating two final barriers—the layer of mucus lining the intestine and the tight cell junctions of the intestine wall, through which large-molecule drugs such as insulin cannot easily pass.

Orally ingested insulin would more closely mimic the way in which a healthy individual's pancreas makes and delivers insulin to the liver, where up to 80% is extracted and the rest is circulated through the bloodstream. It could also mitigate the adverse effects of taking injections over long period of time.

The ionic liquid-borne insulin can be prepared in a one-step process that could be readily scaled up for inexpensive industrial production, added Amrita Banerjee, Ph.D., first author of the PNAS paper, formerly a postdoctoral fellow in Mitragotri's lab, and currently an assistant professor at North Dakota State University. This one-step process could make the cost of manufacturing the oral formulation easily manageable.

Mitragotri next plans to conduct more animal tests of the formulation as well as long-term toxicological and bioavailability studies. The researchers are optimistic that if all goes well, gaining approval for eventual clinical trials in humans will be made easier by the fact that the key ingredients in their ionic liquids—choline and geranic acid—are already considered safe. The FDA has established a daily recommended dose of choline, a vitamin-like essential nutrient, and geranic acid, a chemical that naturally occurs in cardamom and lemongrass and is widely used as a food additive.

If further research progresses as hoped, the approach could be used for oral delivery of other proteins.