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Diabetes and Obesity

Eat It, Breath It, Soak in It?

After Pfizer’s Exubera inhaled-insulin product died so horribly in the market last year, the other companies working in the same space had to be worried. Lilly and Alkermes have had a long-running program, as has a smaller company called Mannkind. But recently, another contender, Novo Nordisk, has announced that they and partner Aradigm have decided to cut their losses. The In Vivo Blog has an excellent roundup.
According to Novo’s CEO, they (like Pfizer) were focusing on prandial insulin because that was basically the only thing they could get to work through inhalation. Now that they’ve seen how well that went over, they’ve decided to spend the money on different proteins (basal insulin, glucagon-like-peptide 1 analogs, etc.) They have a GLP-1 analog in Phase III, but apparently are heading toward the clinic with a second-generation one that can work by the inhaled route.
I wish them luck. We really need new routes of administration for drugs, and every seemingly good candidate has some real problems. There’s a limit to how much compound you can administer transdermally through a patch, for example, and a limit to how quickly it can be administered. Long, slow, continuous delivery is fine, but no one’s going to be marketing an epinephrine patch for anaphylactic shock any time soon. Similarly, you can probably forget about antibiotic-sized total doses, too, because nobody’s skin has enough surface area. (I know, I know, on some people you might think it would work – but if you weigh a lot, you probably need more antibiotic to start with on a mg/kilo basis, and meanwhile your surface area goes up as a square while your volume goes up as a cube, and it’s a losing battle).
No, unless we find some way to make the skin crazily permeable, it’s never going to be a great delivery system. And crazily permeable is just what the skin is not, for good reason. That’s why pulmonary delivery makes sense, to a first approximation. The lungs have huge surface area, just like the small intestine does for oral dosing, because both those organs live to absorb things from the environment (as opposed to the skin). The lungs absorb a gas, unfortunately, as opposed to the small molecules absorbed by the intestines, but a gas is just a special subset of small molecule.
But there’s the downside of the idea. While an oral drug is piggybacking on machinery that’s doing what it’s supposed to be doing, lung delivery is making the organ do something it’s not. (Thus the idea of dosing peptides by this route, since the lungs aren’t a soup of proteolytic enzymes, and pulmonary circulation does not feed your compounds right into the sawmill of the liver). While the intestine absorbs all kinds of stuff, the lungs are there to absorb only one gas and excrete only one. And that primary function of oxygen / carbon dioxide transfer is rather vital, so if you’re going to horn in on it, you’d better be sure that you’re not going to degrade things.
That’s always been the worry with inhalation dosing. We can get around the acute problem of choking the patients, but the chronic problem of potential lung damage is always a worry. Lung function varies quite a bit, too, even under normal conditions, That variation is both patient-to-patient and from time to time – how do you take your inhaled medicine when you have a chest cold, or if you pull a muscle? (And that’s another reason why it’s sort of a grim cosmic joke that insulin turns out to be the big test for peptide drug delivery through the lungs, since its safe dosing window can be so narrow).
I’ll go into the ups and downs of other potential administration routes in another post. Most of them involve sharp objects, though, so they take on a certain similarity, and have the same only-if-I-have-to reputation.

3 comments on “Eat It, Breath It, Soak in It?”

  1. Russ says:

    Has the industry played with these other alternatives to inhalation/injection?
    – Insulin suppositories
    – sublingual insulin
    – insulin eyedrops
    – insulin cigarettes (pretty much the same as inhalation, but the patient looks cool doing it)

  2. Dennis says:

    I heard a guy from Syracuse give a seminar on work he was doing trying to deliver insulin orally using an insulin-vitamin B12 complex. Cool stuff.

  3. Rich Steffens says:

    There is a buccal spray insulin called Oral-lyn that was recently approved in India and is being launched by Shreya Pharma this quarter. The novel insulin spray is being developed by Generex Biotechnology. Generex has been studying the spray for approx 10 years and a recently concluded Phase II study illustrated “superior effect” over standard injection. A1C levels in the Oral-lyn group were 6.1 after 99 days. This spray is the only one that has no lung issues , with all absorbtion in the inner lining of the cheeek, and excess destroyed naturally in the stomach. Generex is preparing to begin dosing in a world wide Phase III to secure US, Canada and Western Eoropean approval- with secondary markets in the middle east, Asia, and Eastern Europe to approve this year since the safety profile is great and the efficacy data has been very positive.
    No one mentions Generex because their market cap is under $500 million, but I guess that will change. Inhalable insulin may sound like a nice idea, but buccal insulin may have rendered it as “not worth the effort” and no diabetic would choose something that may harm them over something more convenient that studies have shown will not.
    Their VP of Medical Affairs is DR Gerald Bernstein. He is the former Pres of the American Diabetes Association, who the company said (in a new presss release) was in India this week preparing Oral-lyn’s launch with Shreya.

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