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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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September 3, 2013

A Drug Delivery Method You Haven't Thought Of

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Posted by Derek

Word came last week that Google Ventures is funding a small outfit called Rani Biotechnology. They're trying to solve a small problem that's caught the attention of a few people now and then: making large protein drugs orally available.

Well, Google has a reputation for bankrolling some long-shot ideas, and any attempt to make proteins available this way is, by definition, a long shot. On Twitter, Andy Biotech sent around a link to this patent, which seems to have some of Rani's approach in it. If so, it's a surprising mixture of high and low tech. The drugs would be administered in a capsule, carefully formulated both chemically and physically. And when the capsule gets down into the small intestine, according to the patent, a spring-loaded mechanism is signaled to release and tiny needles pop out of its sides, delivering the protein cargo through the intestinal wall. To me, this looks less like an oral dosage than an i.v. that you swallow.

But getting that to work is probably easier than figuring out a way to make proteins survive in the gut. One can think of numerous ways that this could go wrong, but in drug development, there are always numerous ways that things could go wrong. The proof will be in the clinic, and I'm glad that someone is willing to pay to find out if this works.

Comments (55) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. Anonymous on September 3, 2013 7:12 AM writes...

Indeed, this is a long shot, it probably won't work, but...

"Google has a reputation for bankrolling some long-shot ideas"

That's precisely how, and why Google manages to innovate, while big pharma no longer does.

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2. Nick K on September 3, 2013 7:24 AM writes...

Isn't this a bit, er, dangerous? I wouldn't like to swallow what is effectively a spring-loaded syringe.

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3. Anonymous on September 3, 2013 7:32 AM writes...

What's the point of an oral formulation anyway, if the drug is effectively injected directly into the blood stream?

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4. Vanzetti on September 3, 2013 7:33 AM writes...

Just imagine the pill malfunctioning and exploding with tiny needles in your anus.

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5. Mike P. on September 3, 2013 7:43 AM writes...

@3,
The point, I think, is that a patient could take a pill at home rather going to see a nurse to get an injection. Convenient dosing is something that makes an enormous difference in whether a patient will accept and use a pharmaceutical drug or not.

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6. Grad Student on September 3, 2013 7:48 AM writes...

Seems like it would be easier to focus our efforts on making a device that can effectively deliver proteins via subQ injection and is as easy to use and as painless as swallowing a pill.

But cool idea. Are the needles biodegradable?

If they are microneedles, perhaps they could be made painless whether in the stomach or rectum.

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7. Anonymous on September 3, 2013 8:06 AM writes...

Wouldn't it be easier to use a modified/disabled enterovirus that can deliver its protein cargo via the gut without infection?

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8. johnnyboy on September 3, 2013 8:38 AM writes...

I was paying attention until the "tiny needles" bit. Google's investing ideas are sounding a lot like DARPA/BARDA's.

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9. MTK on September 3, 2013 8:46 AM writes...

There's probably dozens of alternative methods that have been, will be, or can be thought of to deliver who proteins more conveniently.

I don't think that's the point here though to be honest.

The point is someone has to fund these ideas in order for any of them to even have a chance at coming to fruition and Google is willing to do that.

Nor would I recommend that pharma companies chase every idea someone thinks of either, but what this really highlights is the unique company culture at Google.

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10. newnickname on September 3, 2013 9:57 AM writes...

This makes me think of Feynmann - Hibbs nanorobots (see wikipedia "Nanorobotics"). But let's see ... attach the head of a tapeworm (lumen delivery system) to protected ordnance (drug). (Tapeworms were once sold as diet pills!) (Other worms could also work, e.g., anasakis.) Use fullerenes as the drug delivery capsule and get the added benefit of life extension! (Pipeline, 18-Apr-12 "Buckyballs Prolong Life? Really?") The cited patent mentions using "polymers"; I didn't see carbon nanotubes as nanoneedles with a brief scan.

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11. Bill C on September 3, 2013 10:30 AM writes...

"That's precisely how, and why Google manages to innovate, while big pharma no longer does."

Puh-leeze! This capsule is an absolutely idiotic idea. Sometimes you can have a mind which is so open that your brains fall out.

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12. Anonymous on September 3, 2013 11:00 AM writes...

@11: Pharma R&D productivity has fallen by 99% over the past 60 years, precisely due to the kind of hubris and arrogance of people who think they know better, rather than testing ideas by experiment.

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13. JoJo on September 3, 2013 11:18 AM writes...

@12: what is your reference for the 99% decline over 60 years? Is it productivity, or output versus dollar spend? Or something else?

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14. Karl Laszlo on September 3, 2013 11:23 AM writes...


In my misspent youth I read a great deal of outdoor/adventure stuff. This reminds me of an antiquated, nasty method for hunting Polar Bears. It involved making a ball or pellet of cold frozen suet with a spring loaded bone shard contained therein. Once the doomed bear had swallowed it......heat would soften the fat...the sharpened bone would be released....the bear's stomach would be punctured...and eventually the natives would finish off the weakened bear.
PETA would not have been pleased.
Perhaps the patent is not as "novel" as needed ?

KL

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15. Hap on September 3, 2013 11:23 AM writes...

It sounds kind of painful to me, and I don't know that intestines are meant to take that sort of physical trauma. Whether it's worse than going to a doctor and getting injected (or less costly), I don't know. You can't find out without trying, though.

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16. Anonymous on September 3, 2013 11:31 AM writes...

@13: Inflation-adjusted R&D spend per NME, as per Eroom's law.

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17. Aarnon on September 3, 2013 11:52 AM writes...

@12, I'm sorry, but any fool can innovate for innovation's sake - the rare talent is picking only the ideas worth backing. In pharma I don't see a lack of innovation, just very inconsistent choices of where to do it.

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18. geezer on September 3, 2013 11:59 AM writes...

"......and any attempt to make proteins available this way is, by definition, a long shot"

Not quite. Avaxia are developing a bovine-derived anti-TNF antibody AVX-470 that's orally available. They are currently recruiting UC patients for a clinical trial (http://www.clinicaltrials.gov/ct2/show/NCT01759056?term=AVX-470&rank=1).

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19. Anonymous on September 3, 2013 12:03 PM writes...

@17: How can you pick the winners unless you first test them? Hubris? Hasn't worked much for big pharma...

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20. Another Derek on September 3, 2013 12:16 PM writes...

The described device doesn't seem to me to be "making large protein drugs orally available" - rather it seems merely to be making a swallowable injector. Assuming you need an injectable drug, I don't see the benefit, except to people who are too squeamish to inject themselves but are prepared to swallow a device that will do it unseen (though perhaps not unfelt; and the device has to be the size of a horse pill). There are, after all, perfectly good devices for injecting insulin - an at least decent-size protein drug - and many people use such devices often several times per day.
But it's not my money that's being spent, so good luck to them.

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21. Westlight on September 3, 2013 12:16 PM writes...

@18: You've mis-stated the Avaxia technology - it is not orally bioavailable at all - it works locally in the gut. Their website is clear on their goal of avoiding or minimizing systemic exposure, not targeting it.

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22. mad on September 3, 2013 12:22 PM writes...

Not a bad idea since oral delivery has not made any significant steps forward since the 1930s

It will obviously use microfiliments NOT sharp syringe needels.

The best thing about it is it can easily be tested in rats first with any payload as a marker so it will likely fail big or succeed big early on before the huge costs

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23. geezer on September 3, 2013 12:25 PM writes...

@21: correction, orally administered.

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24. curious george on September 3, 2013 12:56 PM writes...

Has anyone ever tried to develop a drug delivery system that uses the slow degradation of protein as the vehicle mechanism? Not sure how vicious pepsin is to most proteins/molecules, but what if you could incorporate the drug within the protein, perhaps even covalently, to have a slow release of the drug...?

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25. -=GiMP=- on September 3, 2013 1:56 PM writes...

@4
Thank you for brightening my day... :)

Every time I read your straight faced comment, I smile

:)

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26. AndD on September 3, 2013 2:09 PM writes...

@24,

I do know degradation of polysaccharides (more robust than proteins?) for drug release, e.g. by gut microflora, is a drug delivery technology that has gained some interest. Not sure if it is commercialised though.

I am skeptical about this "micro-needles in a capsule" technology though, the variability in GI motility is likely to make this pretty hit and miss, I would think.

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27. Peevester on September 3, 2013 2:15 PM writes...

This reminds me of the Monty Python "spring surprise" candy.

Hmmm, crunchy frog, heap good.

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28. oldnuke on September 3, 2013 5:31 PM writes...

Having assisted in the autopsy of a subject who died from a perforated large intestine (circa 40 years ago when I was an undergrad), this is a singularly unattractive idea. Swallowing sharp objects (or inserting them in places where they don't belong, which I've also seen) is not a very good idea!

I suppose this little nanite is going to sterilize the injection site? Maybe a small nuclear blast (borrowing from Edward Teller here) might be effective in that filthy environment? gr

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29. Pennpenn on September 3, 2013 7:50 PM writes...

"What? There's no way I'm swallowing that!"

"Good news then! It's a suppository!"

In all fairness, it's Google's money, they must be somewhat confident that something good (or at least profitable) will come from this, so I say let them roll with it.

I mean, this sort of thing sounds crazy enough to maybe work, unlike radio-water-drugs.

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30. Rahoul on September 3, 2013 10:25 PM writes...

"How can you pick the winners unless you first test them?"

It's depressing how many comments on this blog reflect a misunderstanding of the scientific method. Presumably testing is always exhaustive.

This point is not academic, many debates by commenters reduce to dogmatic rationalism versus dogmatic empiricism.

Delineating both of these important and at least conceptually separable contributions to inference, whose product is more aligned with the scientific method, will improve the quality of the discussions a lot.

Permalink to Comment

31. Anonymous on September 4, 2013 1:24 AM writes...

@30: One simply needs to understand the difference between an idea/hypothesis, and the method of testing it - by experiment.

Einstein's theory of relativity was also once considered an "absolutely idiotic idea" by many so-called "scientists" who thought they knew better without bothering to test it. Same with virtually every other scientific breakthrough.

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32. Anonymous on September 4, 2013 1:34 AM writes...

PS. And even Einstein himself once thought that quantum mechanics was a stupid idea. Hubris!

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33. Pennpenn on September 4, 2013 1:36 AM writes...

@31- There have to be limits, though, practically, physically, mentally, financially, emperically, rationally, and so on.

Einstien is a great example of an outlier which turned up gold, but honestly, how many others prior to and after Einstien have turned out to be selling complete gibberish in a science sounding package?

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34. Anonymous on September 4, 2013 1:47 AM writes...

31: your Einstein anecdote is just that.
Please read about Michelson-Morley experiment and pay attention to chronology.

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35. Anonymous on September 4, 2013 1:58 AM writes...

@33: Relativity, Quantum mechanics, Darwin's theory of evolution, Big Bang theory, virtually every other scientific breakthrough was considered absurd until it was tested.

@34: Michelson-Morley experiment was not proof of relativity, precisely because it pre-dated the theory. Science is about testing *predictions* of ideas and theories, i.e., by collecting more data from future experiments.

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36. Anonymous on September 4, 2013 2:05 AM writes...

PS. And if funding is an issue, one just needs to be creative to design cheaper experiments. But ideas *still* need to be tested before they can be called either "stupid" or "great".

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37. Anonymous on September 4, 2013 2:17 AM writes...

PPS. Obviously, any new idea/hypothesis has to be consistent with previous data, but in this case, we have no relevant data to indicate that oral capsules with micro needles cannot work in practice.

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38. sepisp on September 4, 2013 2:44 AM writes...

#4: Now that you mentioned it, administering this as a suppository should be in fact a better and safer method! This would minimize the residence time in the GI tract, all of which is potentially hazardous.

That being said, why swallowable? What's the problem with cheeks?

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39. Anonymous on September 4, 2013 3:08 AM writes...

"administering this as a suppository should be in fact a better and safer method!"

Yes, I can imagine the doctor saying: "just put this in your anus and the needles should pop out automatically"

I wonder what level of patient compliance we could expect...

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40. Anonymous on September 4, 2013 3:15 AM writes...

Will the needles still be sticking out when the device is finally passed out the body?

I think I'd rather eat raw chilli peppers.

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41. Rahoul on September 4, 2013 5:38 AM writes...

Anonymous

Without any apparent sense of irony you're making my point, and playing the role of dogmatic empiricist.

Someone else made the good point that the concept of "bad ideas" is easier to explain with a concept of trade-offs and resources, at least in the current pharma innovation uber alles fanfare.

Designing experiments requires that choices and therefore compromises are made. A point which you seem to agree.

I think you will find that the method you use to select your compromises during experimental design are logically similar to those used by people who say an experiment is a waste of time at the outset.

Your suggestion that there is no relevant data for this technology is simply wrong, again arguing the position of the dogmatic empiricist. How can a hypothesis be consistent in a vacuum?

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42. Anonymous on September 4, 2013 6:17 AM writes...

@41: And your "relevant data for this technology" is what, precisely?

Have you done any market research, or feasibility studies with this approach? Have you considered what further experiments may be done to establish whether the approach can work, and how much they may or may not cost?

Or are you simply going with your gut instinct, and rejecting the idea outright without any data or evidence?

In particular, how can you make any rational judgement and decision if have no relevant data, and no plan to test it?

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43. Anonymous on September 4, 2013 6:26 AM writes...

@41: PS. Have you even read the patent, and data described therein?

Presumably the investors at Google have done their thorough due diligence, reviewed the evidence, and decided that the risk is worth taking, whereas you may prefer to think the idea is ridiculous without even looking at the data?

Hubris!

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44. Anonymous on September 4, 2013 6:29 AM writes...

My gut instinct is that I do not want needles in my gut. Pretty sure most people feel the same.

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45. Anonymous on September 4, 2013 6:36 AM writes...

@44: Personally, I agree, but then I don't have to take daily injections. And how much would it cost to survey a few dozen doctors and patients?

Virtually nothing, and so I would be surprised if Google would have invested without such preliminary data showing that a good number of patients would prefer it to daily injections.

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46. Semichemist on September 4, 2013 11:15 AM writes...

I'm not attacking anyone in this comment so it may not get any attention or replies. Anyway,

Why is it so difficult to get these proteins into the bloodstream in another manner? This seems like an idea that's going to need a lot of optimization before it gets anywhere close to feasible. Why not inject using microneedle dermal patches? Or are the proteins in question too large for that route?

Permalink to Comment

47. Anonymous on September 4, 2013 12:06 PM writes...

@46: I actually think dermal microneedle patches are a better idea, since the proteins wouldn't go via the gut and straight to the liver.

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48. Anonymous on September 4, 2013 12:06 PM writes...

@14, Anthony Quinn uses this method -before he discovers the gun- in The Savage Innocents (1960)

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49. Anonymous on September 4, 2013 2:16 PM writes...

Whether this will "work" or not is one question, more important from a business perspective is FDA perspective, patient uptake and reimbursement. Sometimes things are perfectly feasible, but we still don't do it simply because it won't make us any money, and this smells to me like one of those cases. Would the FDA not consider this an "injection" regardless of the fact you swallow it? Do we need an all new category? (po, iv, im, sc... --> intra-jejunal?, ij?) All sorts of fun implications.

I admit I looked up the patent myself upon seeing the news headline, oral protein delivery being the "cold fusion" of the drug delivery field. Guy in the next cube heard me laughing.

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50. Anonymous on September 4, 2013 3:54 PM writes...

If _inhaled_ protein delivery failed commercially, what chance do the swallowed needles might have ?

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51. Anonymous on September 4, 2013 4:57 PM writes...

@50: The probability of success will be very low indeed, but unless you factor in how much (or little) it will cost to test and know for sure, the probability on its own is meaningless.

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52. Dr. Manhattan on September 4, 2013 5:29 PM writes...

Why not capsules with frickin' laser beams?

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53. Pennpenn on September 4, 2013 7:21 PM writes...

@35: Yes, but that doesn't negate the fact that for every Theory of Evolution, Special Relativity, and Quantum Mechanics there are countless other models that don't work.

Percieved absurdity and counter-intuitiveness is not consistently proportional to relevance.

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54. Anonymous on September 5, 2013 1:58 AM writes...

@53: Yes, that's science for you, there are many failures on the path to success, so the key is to discover the failures as quickly and cheaply as possible. But even if an idea is very likely to work, if the upside is big enough and the downside is small enough (quick and cheap testing), then it's still worth doing...

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55. NoDrugsNoJobs on September 5, 2013 5:55 PM writes...

I don't know but this would seem to risk ecoli infections. One of the concerns with chemical membrane openers (Penetration enhancers)that allow proteins in is that they might allow other things (bacterial toxins) in at the same time.

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