Monday, May 5, 2008

A Brief Personal Update: Plus, Insulin By Mouth? (Kinda)

After several panic-filled weeks of last-minute cramming for final exams, N.B. is finally "free" for the summer (aside from all those lick-and-stick hours at the local pharmacy where he earns his keep). The goal at this point is to finally find things I enjoy doing--like blogging--instead of shoving medicinal chemistry into my head so that I can pass the semester-end exam.

It also gives me time to do less academic (but arguably no less cerebral) things to do, like finally beating Metal Gear Solid 2 on the "extreme" difficulty. Preferably without using hundreds of continues. No, I haven't done it yet, but it's a by-end-of-summer goal.

In any case.

This particular story apparently isn't breaking news--and if you've been following it, it's a saga that has dragged on for several years, reportedly with the intervention of Big Pharma trying to shut down Little Biotech, or at least buy them out. But here's the exciting news for patients and investors alike. An oral insulin spray is still in development and has apparently performed well in trials. The medication is approved for use in Ecuador and India, and it is currently undergoing phase III trials in the U.S., suggesting that we may see some sort of release in the states in the next one or two years.

Buccal administration is a complicated-sounding way of giving medicine by having it absorb through the cheek. The cheeks and area underneath the tongue have a rich blood supply and fairly thin barriers between the bloodstream and the outside world, permitting specially-formulated drugs to cross easily. While a lot of buccal drugs are used for their local effect (like anesthetics), some are intended to effect the whole body, like the opioid pain-reliever fentanyl, which is available as what amounts to a sucker.

Another major advantage of buccal administration is that it bypasses both the stomach and the liver, preventing the drug from being broken down before it enters the bloodstream (in the case of the liver, this is called first-pass metabolism). Protein drugs, such as insulin, cannot normally be taken by mouth because the stomach and intestine will digest them like any other protein, rendering them inactive. To prevent insulin from being reduced to useless amino acid bits, it must normally be given by injection.

The reason inhalation was considered as a route of administration for insulin was because it, too, bypasses the breakdown that takes place in the stomach. Theoretically, the rectal route partially bypasses first-pass metabolism (it actually depends how far up you insert the suppository), but I can't imagine rectal insulin would be very popular, and there are other complications.

For the pharmacologists in the audience, now I'm trying to imagine what sort of formulation barriers might exist to insulin suppositories. Base incompatibility? Temperature/storage problems? I've never even heard of a protein drug being given by that route. But I digress.

The product that the article I linked is talking about is a spray--think something like breath spray--that is applied to the inside of the cheek. The spray would be metered to provide a precise dose, but fine-tuning might be difficult unless the spray can be "dialed" to spray different amounts of insulin. The details are still fuzzy, but the research is still very exciting.

Patient compliance--the ability and willingness of a patient to properly use his or her medications--is a huge obstacle for patients with diabetes. Anything that makes administration of insulin easier for adults and children alike is definitely a good idea, assuming of course that there are no long-term drawbacks and that the system is practical (inhaled insulin turned out not to be). I'm looking forward to seeing where this research goes.

2 comments:

qetzal said...

Hadn't looked at this for a while, but your post prompted me to look again. I definitely wish them success in developing this, but as always, there are reasons to avoid being too optimistic.

Based on the Phase III trial description (http://www.clinicaltrials.gov/ct2/show/NCT00668850?spons=generex&rank=1), the trial is expected to complete in Dec. 2010. So, US approval seems unlikely before late 2011 at best.

The article you link says a Phase II study showed "superior effect" relative to Humulin R injection. That news seems to have been announced in Nov. 2006, but I can't find a published reference. That's a bit bothersome.

What I do see is that bioavailability and biopotency are quite low - looks like around 5%. So a patient would need to administer 20U by buccal spray to get an effect equivalent to 1U by sc injection. That could be a cost of goods issue.

For comparison, Exubera was around 7-10% biopotency. Obviously, they thought it could still be profitable at that level. (They were wrong, of course, but not due to cost of goods problems.)

It also seems that dosing with the buccal spray is by number of "puffs". A typical dose for a Type 1 diabetic appears to be 8-12 puffs immediately before a meal, and another 8-12 puffs immediately after. That starts to make the whole procedure sound a bit cumbersome. I'm not sure if they can improve that, since it would require either higher insulin concentration or more spray per puff. Either of those might be a big challenge.

On the plus side, the buccal spray appears to act sooner and clear faster. If they can show that translates to better efficacy or safety, it could be huge. If not, and they have to compete based on convenience, I suspect it will be much tougher.

N.B. said...

That's some great stuff, qetzal. I should've done some more digging; you managed to pull together some excellent information there.