16 replies to this topic

[malbecman]

For what its worth, here is a new paper out that compared several different vehicles on transdermal delivery. I wish they had tried DMSO like many of us have used.
I can dig up the PDF if anyone wants the more complete story.....

Biological & Pharmaceutical Bulletin
Vol. 31 (2008) , No. 5 955

Delivery of Resveratrol, a Red Wine Polyphenol, from Solutions and Hydrogels via the Skin
Chi-Feng Hung1), Yin-Ku Lin2)3), Zih-Rou Huang4) and Jia-You Fang4)
1) School of Medicine, Fu Jen Catholic University
2) Graduate Institute of Clinical Medical Sciences, Chang Gung University
3) Department of Traditional Chinese Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital
4) Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University
(Received October 29, 2007)
(Accepted February 4, 2008)
Resveratrol, the main active polyphenol in red wine, has been demonstrated to show benefits against skin disorders. The bioavailability of orally administered resveratrol is insufficient to permit high enough drug concentrations for systemic therapy. In this study, we examined the feasibility of the topical/transdermal delivery of resveratrol. The effects of vehicles on the in vitro permeation and skin deposition from saturated solutions such as aqueous buffers and soybean oil were investigated. The general trend for the delivery from solutions was: pH 6 buffer=pH 8 buffer>10% glycerol formal in pH 6 buffer>pH 9.9 buffer>pH 10.8 buffer>soybean oil. A linear relationship was established between the permeability coefficient (Kp) and drug accumulation in the skin reservoir. Viable epidermis/dermis served as the predominant barrier for non-ionic resveratrol permeation. On the other hand, both the stratum corneum (SC) and viable skin acted as barriers to anionic resveratrol. Several prototype hydrogel systems were also studied as resveratrol vehicles. The viscosity but not the polarity of the hydrogels controlled resveratrol permeation/deposition. Piceatannol, a derivative of resveratrol with high pharmacological activity, showed 11.6-fold lower skin permeation compared to resveratrol. The safety profiles of resveratrol suggested that the hydrogel caused no SC disruption or skin erythema. It was concluded that delivery via a skin route may be a potent way to achieve the therapeutic effects of resveratrol. This is the first report to establish the permeation profiles for topically applied resveratrol.
PMID: 18451526

[TianZi]

Per title; link to an article discussing the study here:

http://www.winespect...97,4407,00.html

In the past, delivery of resveratrol through the skin via a patch has been discussed and largely dismissed as potentially effective by some posters here. It will be intereresting to see if other studies confirm the essential conclusions of this team of Taiwanese researchers.

NOTE: I checked, but could not find an abstract of the study at the website for the Biological & Pharmaceutical Bulletin. If someone here finds it, please post a link here. It's possible a website like "Wine Spectator" might have misquoted or misunderstood the study results.

Edited by TianZi, 29 May 2008 - 03:02 AM.

[TianZi]

Ok, here's a link to the abstract:

http://www.jstage.js...31_955/_article

Full text:

http://www.jstage.js...b/31/5/955/_pdf

Edited by TianZi, 29 May 2008 - 03:16 AM.

[sUper GeNius]

I guess we'll see a few here rushing patches to market soon. Will Sardi be poo pooing the idea so on his website? Stay tuned.

p.s. $6800 per year? Someone give that guy Anthony's phone number...

Edited by FuLL meMbeR, 29 May 2008 - 03:41 AM.

[niner]

Per title; link to an article discussing the study here:

http://www.winespect...97,4407,00.html

In the past, delivery of resveratrol through the skin via a patch has been discussed and largely dismissed as potentially effective by some posters here. It will be intereresting to see if other studies confirm the essential conclusions of this team of Taiwanese researchers.

NOTE: I checked, but could not find an abstract of the study at the website for the Biological & Pharmaceutical Bulletin. If someone here finds it, please post a link here. It's possible a website like "Wine Spectator" might have misquoted or misunderstood the study results.

Well, you're right about the last part. "Wine Spectator" got it comically wrong. Using their best formulation, Hung et al. measured a flux of 2.32 nmol/cm**2/hr; that means that a giant patch of 200 square centimeters would deliver a tenth of a milligram of resveratrol per hour into the subcutaneous fat. The amount that would make it into systemic circulation would be insignificant. This same formulation did manage to deliver a quarter of a microgram of resveratrol to each gram of skin. I'm not sure how large an area a gram of skin is, but it's probably a couple cm**2. Since a microgram is only a thousandth of a milligram, we are still talking very small amounts, but if your aim is to deliver resveratrol to the skin, I suspect this is indeed better than pills. For everything else, forget about it.

[TianZi]

Per title; link to an article discussing the study here:

http://www.winespect...97,4407,00.html

In the past, delivery of resveratrol through the skin via a patch has been discussed and largely dismissed as potentially effective by some posters here. It will be intereresting to see if other studies confirm the essential conclusions of this team of Taiwanese researchers.

NOTE: I checked, but could not find an abstract of the study at the website for the Biological & Pharmaceutical Bulletin. If someone here finds it, please post a link here. It's possible a website like "Wine Spectator" might have misquoted or misunderstood the study results.

Well, you're right about the last part. "Wine Spectator" got it comically wrong. Using their best formulation, Hung et al. measured a flux of 2.32 nmol/cm**2/hr; that means that a giant patch of 200 square centimeters would deliver a tenth of a milligram of resveratrol per hour into the subcutaneous fat. The amount that would make it into systemic circulation would be insignificant. This same formulation did manage to deliver a quarter of a microgram of resveratrol to each gram of skin. I'm not sure how large an area a gram of skin is, but it's probably a couple cm**2. Since a microgram is only a thousandth of a milligram, we are still talking very small amounts, but if your aim is to deliver resveratrol to the skin, I suspect this is indeed better than pills. For everything else, forget about it.

The authors of the study did suggest several times that transdermal delivery may be a superior way to deliver resveratrol not only to the skin, but for systemic circulation specifically. So it seems they interpreted their own results differently than you have. It would certainly hit Sirtris hard if future studies show the same or superior results in treatment of diabetes, etc. using patches rather than an oral supplement.

But, lacking the necessary educational or professional background to comment meaningfully, I can only be a parrot here.

Someone else questioned the figure quoted as price for a year's supply of resveratrol in capsule form. US$6,800 year was for a dose of 7.5 grams resveratrol daily, which according to the study is the amount being used in some human clinical trials.

Edited by TianZi, 29 May 2008 - 04:30 AM.

[niner]

The authors of the study did suggest several times that transdermal delivery may be a superior way to deliver resveratrol not only to the skin, but for systemic circulation specifically. So it seems they interpreted their own results differently than you have. It would certainly hit Sirtris hard if future studies show the same or superior results in treatment of diabetes, etc. using patches rather than an oral supplement.

But, lacking the necessary educational or professional background to comment meaningfully, I can only be a parrot here.

Someone else questioned the figure quoted as price for a year's supply of resveratrol in capsule form. US$6,800 year was for a dose of 7.5 grams resveratrol daily, which according to the study is the amount being used in some human clinical trials.

If they said that transdermal delivery may be a superior way to deliver resveratrol systemically, I can only speculate that either they are placing way too much emphasis on "may be" or, more likely, they know a lot less about pharmacology than they do about skin. I can't fault their experimental work; it seemed quite good, but when it comes to the larger implications of the work, they are overpromoting it. They wouldn't be the first people to do that.

The $6800 figure was from an old Sinclair paper. It is now way out of date.

[TianZi]

"The $6800 figure was from an old Sinclair paper. It is now way out of date."

_____________________

1. Actually, the figure is roughly accurate, assuming a 7.5 gram per day dose, as the authors of the study have.

7.5 grams x 360 = 2,700 grams per year.

Looking at the price-per-gram resveratrol chart kindly provided by Anthony, we can see that it would be possible to obtain 2,700 grams yearly for much less than that. However, if purchasing from a reputable dealer in a 98/99% purity form, typical prices are over US$2 per gram. Revgenetics provides one of the cheapest prices available for a 98% purity product whose content claims has been confirmed by a 3rd party lab, and that comes out to US$5,400 per year. Biotivia, whose content claims have also been confirmed by a 3rd party lab, comes out to $6,723.

Whether we're talking US$5,400, US$6,723 or US$6,800, the essential point made in the article is unchanged--it's very expensive (but again, we are also assuming as the authors of the study did that a very high oral dose daily--7.5 grams--may be necessary to obtain optimal therapeutic benefits). And these prices are actually on the low end of the scale for a resveratrol product of this purity.

2. As regards whether the authors of the study are qualified to draw the conclusions made in the study, I assume they have academic and professional qualifications sufficient in the eyes of their peers to render such conclusions worthy of further study, as otherwise their work wouldn't have been considered for publication in the journal in question. Indeed, their qualifications in this regard viewed objectively are probably far superior to those of any poster on these forums.

That doesn't make them right, or demonstrate they may not be "overhyping" their results (I wonder, for example, who sponsored this study).

I'm reluctant to trudge through the full text and discover whether they tested resveratrol blood level concentrations after transdermal delivery, but I may have a go at it.

EDIT: After a search of the full text of the study, I found no references to "blood plasma". As far as I can see, only resveratrol concentrations in the skin were tested, which tells me nothing about how transdermal delivery compares to oral delivery of resveratrol.

Despite this, the potential for transdermal delivery of resveratrol as a superior vehicle for maximum systemic circulation of resveratrol was squarely mentioned once in the conclusion, and alluded to several times in the introduction and main body. So my (admittedly fairly worthless) layman's opinion is that while the claims in the study regarding effectivness for transdermal delivery of resveratrol to the skin are well-founded based on the results of study itself, the authors "overreach" by suggesting it to potentially be a superior form of delivery for systemic circulation.

With that said, I have a suspicion they likely already know something about resveratrol blood plasma levels resulting from transdermal delivery, and we'll see over the months to come whether these researchers or others publish a study specifically measuring blood plasma levels following transdermal delivery of resveratrol.

Edited by TianZi, 29 May 2008 - 06:09 AM.

[niner]

2. As regards whether the authors of the study are qualified to draw the conclusions made in the study, I assume they have academic and professional qualifications sufficient in the eyes of their peers to render such conclusions worthy of further study, as otherwise their work wouldn't have been considered for publication in the journal in question. Indeed, their qualifications in this regard viewed objectively are probably far superior to those of any poster on these forums.

That would be incorrect. Some of us have PhD's, papers in peer reviewed journals, patents, academic and industrial experience. You underestimate us. And overestimate Hung et al.

That doesn't make them right, or demonstrate they may not be "overhyping" their results (I wonder, for example, who sponsored this study).

There is overhyping going on in their paper. If I had been a reviewer, I would have requested that it be toned down. I wouldn't have flat out rejected it because the experimental work and the data appear to be good. In fact, their own data flatly contradicts the idea that transdermal delivery of resveratrol will get you a decent blood level.

I'm reluctant to trudge through the full text and discover whether they tested resveratrol blood level concentrations after transdermal delivery, but I may have a go at it.

They didn't. They only looked at skin.

[mikeinnaples]

Looking at the price-per-gram resveratrol chart kindly provided by Anthony, we can see that it would be possible to obtain 2,700 grams yearly for much less than that. However, if purchasing from a reputable dealer in a 98/99% purity form, typical prices are over US$2 per gram. Revgenetics provides one of the cheapest prices available for a 98% purity product whose content claims has been confirmed by a 3rd party lab, and that comes out to US$5,400 per year. Biotivia, whose content claims have also been confirmed by a 3rd party lab, comes out to $6,723.


Rounding up. I see 99% purity powders coming in at $.63 / gram from a reputable source. And a few others at slightly higher price points.

2700 grams = $1701.00 / Year

[enzyme]

Thanks for that ...

I have two queries:

Has anyone considered mixing resveratrol powder into an otc hydrogel & rubbing it in ... rather than ingesting the powder? Oral route seems inefficient. Mostly peed out hours later??? Any tips on diy topical hydrogel preparation if you have experimented? Anyone?


Secondly - I used to burn in the sun & never tanned much = freckly Celtic geezer, grew up in the tropics. Hair ginger/blonde until it greyed. Both parents have skin cancer. I already have lentigo & my sister has Bowen's disease (both premalignant). However, since using high dose resveratrol (+ melatonin/ALA/Carnitine etc) I never burn & tan easily. People ask if I fake tan! Is this anyone else's experience? Why would this be? Do melanocytes respond to resveratrol?

Rgds

[PWAIN]

Yep, Anthonys 99% is now $620 for 1Kg so I think your prices are pretty way out of date. By the time something like patches come to market, price will probably be lower still.

[maxwatt]

Thanks for that ...

I have two queries:

Has anyone considered mixing resveratrol powder into an otc hydrogel & rubbing it in ... rather than ingesting the powder? Oral route seems inefficient. Mostly peed out hours later??? Any tips on diy topical hydrogel preparation if you have experimented? Anyone?


Secondly - I used to burn in the sun & never tanned much = freckly Celtic geezer, grew up in the tropics. Hair ginger/blonde until it greyed. Both parents have skin cancer. I already have lentigo & my sister has Bowen's disease (both premalignant). However, since using high dose resveratrol (+ melatonin/ALA/Carnitine etc) I never burn & tan easily. People ask if I fake tan! Is this anyone else's experience? Why would this be? Do melanocytes respond to resveratrol?

Rgds

Been there done that, as a group. Google for "transdermal" in this thread. Long story short: you don't get sufficient serum levels transdermally to do diddley squat. It might result in higher levels int he skin though.

FWIW. I am using a home-made resveratrol skin cream. I believe it has eliminated the chronic acne rosacea I've had for years. Sample of one, hope someone does a study. I too don't seem to burn in the sun, but I haven't tempted fate either. I do seem to be more tanned than I would expect on sun exposure, without any redness and peeling.

Edited by maxwatt, 30 May 2008 - 02:03 AM.

[niner]

With that said, I have a suspicion they likely already know something about resveratrol blood plasma levels resulting from transdermal delivery, and we'll see over the months to come whether these researchers or others publish a study specifically measuring blood plasma levels following transdermal delivery of resveratrol.

Don't hold your breath... It will be under the limit of detection.

[TianZi]

With that said, I have a suspicion they likely already know something about resveratrol blood plasma levels resulting from transdermal delivery, and we'll see over the months to come whether these researchers or others publish a study specifically measuring blood plasma levels following transdermal delivery of resveratrol.

Don't hold your breath... It will be under the limit of detection.

I'm going to use your post as an excuse to segue to a related topic of interest to me:

What makes a particular drug, typically administered orally and not targeting a problem with the skin, a good candidate for transdermal delivery?

I ask this because my father in the past two years has been able to switch to using patches for certain of the vast number of medications he must take daily (he suffers from Types I and II diabetes, high blood pressure, cirrhosis of the liver and lungs, and a catastrophic injury to his left shoulder that essentially shattered to powder most of the bone and cartilage there years ago, requiring him to take large quantities of powerful painkillers daily).

Within the past year or two, he has been able to switch from multiple injections of insulin daily to a transdermal patch. He had in years past been informed by a doctor that transdermal delivery of insulin could never be a viable alternative to insulin injections due to the same general type of problems you have mentioned with respect to resveratrol. I guess "never" was a much shorter period of time than that physician expected. Besides insulin, he uses transdermal patches for a few other medications as well.

[enzyme]

Thanks for that ...

I have two queries:

Has anyone considered mixing resveratrol powder into an otc hydrogel & rubbing it in ... rather than ingesting the powder? Oral route seems inefficient. Mostly peed out hours later??? Any tips on diy topical hydrogel preparation if you have experimented? Anyone?


Secondly - I used to burn in the sun & never tanned much = freckly Celtic geezer, grew up in the tropics. Hair ginger/blonde until it greyed. Both parents have skin cancer. I already have lentigo & my sister has Bowen's disease (both premalignant). However, since using high dose resveratrol (+ melatonin/ALA/Carnitine etc) I never burn & tan easily. People ask if I fake tan! Is this anyone else's experience? Why would this be? Do melanocytes respond to resveratrol?

Rgds

Been there done that, as a group. Google for "transdermal" in this thread. Long story short: you don't get sufficient serum levels transdermally to do diddley squat. It might result in higher levels int he skin though.

FWIW. I am using a home-made resveratrol skin cream. I believe it has eliminated the chronic acne rosacea I've had for years. Sample of one, hope someone does a study. I too don't seem to burn in the sun, but I haven't tempted fate either. I do seem to be more tanned than I would expect on sun exposure, without any redness and peeling.

Thx mate- will do "transdermal"

The cream sounds like a good punt to me. I wanted to to mix res into a hydrogel & rub that in (rather than a patch) but was hoping a cheap/simple recipe was already out there (not DMSO = scary++)

There must be scope for an open source skin app. before big pharma hoovers up the IP or a hollywood babe corners the cosmeticeutical mkt for this.

[niner]

What makes a particular drug, typically administered orally and not targeting a problem with the skin, a good candidate for transdermal delivery?

I ask this because my father in the past two years has been able to switch to using patches for certain of the vast number of medications he must take daily (he suffers from Types I and II diabetes, high blood pressure, cirrhosis of the liver and lungs, and a catastrophic injury to his left shoulder that essentially shattered to powder most of the bone and cartilage there years ago, requiring him to take large quantities of powerful painkillers daily).

Within the past year or two, he has been able to switch from multiple injections of insulin daily to a transdermal patch. He had in years past been informed by a doctor that transdermal delivery of insulin could never be a viable alternative to insulin injections due to the same general type of problems you have mentioned with respect to resveratrol. I guess "never" was a much shorter period of time than that physician expected. Besides insulin, he uses transdermal patches for a few other medications as well.

Traditionally, one of the first requirements has been that the drug be very potent, so that the effective dose needed is very small. The painkiller Fentanyl, for example, is given in microgram quantities, and is very popular in patch form. In order to work well as a transdermal drug, the general rule is relatively low molecular weight, which is really a proxy for small molecular size. The molecule will diffuse in easiest if it's relatively lipophilic, because the stratum corneum (the outermost permeation barrier) is composed of keratinic corneocytes surrounded by lipid bilayers. Lipophilic molecules will naturally diffuse through the lipid bilayers. It is also possible to get a hydrophilic molecule in, because it can get through pores in the corneocytes. You don't want it to be too hydrophilic, though; i.e., probably not ionic. Insulin breaks all the rules, and it could never get in by itself in a simple patch. Your dad is probably using the Dermasonics device, which is an ultrasonic transducer that has been made very thin and wearable. The ultrasound might be enlarging the pores and/or driving the insulin through. This is really pretty remarkable technology, and may open up a lot of therapeutic opportunities for peptide drugs. There is also a technique called electroporation, where electric fields are used to drive molecules through the skin. In this case, you could push an ionic compound through.

There are probably a hundred different compounds that people have looked at as permeation enhancers. Some might help to fluidize the lipid membranes, others alter the properties of the corneocytes. We continue to broaden the types of compounds that can be dosed transdermally through the use of permeation enhancers and applied energy devices that go beyond simple diffusion. However, I doubt that we will see a simple transdermal dosing system that will be able to deliver more than miligram quantities in the near future.