Insulin pill for diabetes

Millions of people worldwide are afflicted by diabetes and regularly have to inject the insulin they lack to control their blood sugar. Now scientists have developed a way to package the drug into a pill and protect it from digestion. Chris Smith spoke to Samir Mitragotri from Harvard University...

Samir - In diabetes insulin is not produced by the pancreas, or not used very well by the cells, so the sugar level in the body goes up and that has significant long term complications, such as loss of eyesight, loss of sensation. The main therapy is to take insulin. Now insulin is a protein, which means it gets digested by the stomach and, even if some insulin remains in the stomach intact, it goes into the intestine, and it cannot be absorbed from the intestine into the blood circulation. So, a long story short, you cannot take insulin as a pill, it’ll just get digested so that’s why people have to inject it into the body.

Chris - What have you done to try and surmount the problem?

Samir - We figured that if wanted to deliver insulin orally, which would tremendously help diabetics, we had to figure out three things:
We had to protect insulin in the stomach from the enzymes and the acidity in the stomach.

When insulin reaches the intestine we had to make sure that it can cross the mucus layer which is present on the inner lining of the intestine.

We had to make sure that insulin can cross the cell layer which is also present on the intestine and is connected by tight junctions.

These are the barriers which are designed by the body to keep large molecules out and we had to overcome them to be able to deliver insulin into the blood circulation.

Chris - How do you think you can do it?

Samir - That’s where ionic liquids came into the picture. Ionic liquids are a very interesting class of materials. These are basically liquid salts, so just think about your table salt which is sodium chloride. In the case of sodium chloride, the sodium and the chloride ions are very small so they form a solid. Now, imagine a large positive charge and a large negative charge molecule, when they form a salt they are a liquid, and that’s basically ionic liquid. These ionic liquids have very interesting properties; they can stabilise proteins like insulin, they can overcome the barrier of the mucus, and they can also open the tight junctions by acting on the cells of the intestine. We tried a number of ionic liquids and it turned out one in particular is very effective in overcoming all three barriers in a single formulation and that’s what allowed oral delivery of insulin in our study.

Chris - My question is then, what is the liquid in question and how do you mix it up with the insulin so that you end up with a form of insulin that will get in via mouth into the bloodstream?

Samir - The ionic liquid that we used has two components. The first component is choline, which is basically a dietary supplement that many people take. And the second molecule in the ionic liquid is geranic acid, which is also a naturally occurring molecule present in lemongrass and cardamom. When we combine them they form this ionic liquid that we call CAGE which stands for choline and geranic acid eutectic, and we add insulin to it and essentially make a suspension and fill that liquid in a capsule, and that’s the formulation that we deliver.

Chris - Does it work? I mean, when you take this, does the insulin get protected from the stomach acid and does it end up getting into the bloodstream?

Samir - It works very well. We did a number of studies. We looked at the ability of CAGE to protect insulin against the enzymes and it was quite effective. We also looked at the ability of CAGE to reduce the mucus barrier by lowering its viscosity and it worked very well. And the third set of studies we also looked at how well this CAGE worked in opening the tight junctions of the intestine, and that also worked very well. When we delivered this insulin pill to rats, we saw a significant reduction of the glucose levels, which is an indication of insulin getting into blood circulation.

Chris - Was it as good or better than if you inject insulin? Does it work equivalently well?

Samir - You had to deliver a little bit more insulin by oral route compared to an injection, but the end result is much better than what we got with injection. And what I mean by that is when you inject insulin by needles it is all delivered very quickly into the blood, so the glucose level goes down quickly and the insulin is eventually cleared and the glucose level comes up quickly. So there is a big jump in insulin concentration and a big reduction as opposed to that when you deliver it orally you see a long lasting effect of  insulin on the blood glucose level. So a a single oral pill can reduce the glucose levels for a much longer time than an injection can.

Chris - And is this safe? Because if you’re capable of bypassing the normal defences of the intestine which are there to keep things that shouldn’t be going in out, is there a possibility that other things will end up sneaking in alongside the insulin that you do want and that could be bad for the patient?

Samir - In the study we did a very interesting experiment. We gave the ionic liquid CAGE to the rat by itself first, we waited for half an hour and then gave insulin by itself. And, interestingly, what we found is that the treatment where one is followed by the other does not work as well as both delivering simultaneously. What that tells us is that insulin has to be dispersed in CAGE, in the ionic liquid, for it to work. And what it means for safety is that now if you think about other molecules, which are present in the intestine but are not part of the CAGE insulin formulation, they have a much less chance of getting into the circulation compared to insulin.