13 replies to this topic

[bixbyte]

I am not advocating the use of Transdermal Patch and I have no monetary interest in the company.
Anyone know if a Resveratrol patch would benefit?
Years ago we were testing out Res mixed DMSO and applying this to our skin.
But, I did not notice any benefits.

$50 month for only 75 mg / day. Think this link is Hype?

http://www.ageforce....nts/resveratrol

[hav]

I don't know if its hype or not but I don't believe their claim that it injects 100% of the resveratrol through your skin into your bloodstream. Not without any supporting research proving that. Their only research link points to the wikipedia page on resveratrol which contains no such study or claim for transdermal administration of resveratrol.

I did a little digging in pubmed myself and there is some support for transdermal resveratrol delivery. Into the skin and into fat layers beneath the skin for benefits there. But I don't see any measurement in this study of amounts of resveratrol going into the bloodstream from there... the closest is this speculation based on measured amounts in removed skin samples:

Delivery of Resveratrol, a Red Wine Polyphenol, from Solutions and Hydrogels via the Skin

Resveratrol delivery by skin route may avoid the degradation because the low metabolism in the skin, resulting in the possible prolongation of half-life and sufficient concentration in the systemic circulation.

Howard

Edited by hav, 19 February 2014 - 10:25 PM.

[cudBwrong]

Some measurements of resveratrol cream, applied topically, delivering to the bloodstream:

http://www.ncbi.nlm....pubmed/24381018

J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Feb 1;947-948:23-31. doi: 10.1016/j.jchromb.2013.12.005. Epub 2013 Dec 17.
In vitro drug release and ex vivo percutaneous absorption of resveratrol cream using HPLC with zirconized silica stationary phase.

Polonini HC¹, Bastos Cde A², Oliveira MA³, Silva CG⁴, Collins CH⁴, Brandão MA⁵, Raposo NR⁶.
Author information

• ¹Núcleo de Pesquisa e Inovação em Ciências da Saúde (NUPICS), Federal University of Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil. Electronic address: h.c.polonini@gmail.com.
• ²Grupo de Química Analítica e Quimiometria (GQAQ), Federal University of Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil.
• ³Grupo de Química Analítica e Quimiometria (GQAQ), Federal University of Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil. Electronic address: marcone.oliveira@ufjf.edu.br.
• ⁴Institute of Chemistry, University of Campinas, PO Box 6154, 13083-970 Campinas, SP, Brazil.
• ⁵Núcleo de Pesquisa e Inovação em Ciências da Saúde (NUPICS), Federal University of Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil. Electronic address: marcosbrand2012@gmail.com.
• ⁶Núcleo de Pesquisa e Inovação em Ciências da Saúde (NUPICS), Federal University of Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil. Electronic address: nadiafox@gmail.com.

Abstract

Since the designs of optimal formulations for resveratrol permeation via the skin are lacking, the aim of this study was to establish the profile of resveratrol permeability into and across human skin. For that, a laboratory-made chromatographic column was used (Zr-PMODS), with its performance being compared to a traditional C18 column. In vitro drug release was conducted with polysulfone membranes, and the flux (JS) was 30.49μgcm(-2)h(-1)), with a lag time (LT) of 0.04h, following a pseudo-first-order kinetics. For ex vivo percutaneous absorption using excised female human skin, the kinetic profile was the same, but JS was 0.87μgcm(-2)h(-1) and LT was 0.97h. From the initials 49.30μg applied to the skin, 9.50μg were quantified in the receptor medium, 20.48μg was retained at the stratum corneum (do not account as permeated) and 21.41μg was retained at the viable epidermis+dermis (account as permeated), totalizing 30.90μg of resveratrol permeated after 24h of application (62.6%). From these results, one can conclude that a person using the 1-g emulsion dose released by the pump containing 20mg of resveratrol will have, theoretically, 12.53mg of it liberated into his bloodstream, gradually and continuously for 24h.

[hav]

No blood tests at all in that study. Just in vitro skin sample absorption measurements. And no logic at all to their theory resveratrol might travel from the skin into the blood stream. I would expect it to either stay in the skin or at best be trapped in the fatty layers beneath it. I've tried resveratrol mixed with dmso and it just precipitates onto the surface and gets left behind. Jojoba would probably absorb better but would not likely penetrate into the blood stream.

Howard

[cudBwrong]

No blood tests at all in that study. Just in vitro skin sample absorption measurements. And no logic at all to their theory resveratrol might travel from the skin into the blood stream.

Howard

You are absolutely right Howard. Looking at some other studies of how resveratrol reacts with the skin, I found one which may interest you:

http://www.ncbi.nlm....les/PMC3601074/

PLoS One. 2013; 8(3): e59632.
Published online 2013 March 18. doi: 10.1371/journal.pone.0059632


PMCID: PMC3601074
Resveratrol Induces Long-Lasting IL-8 Expression and Peculiar EGFR Activation/Distribution in Human Keratinocytes: Mechanisms and Implications for Skin Administration

They review a number of methods for topical administration, and show some surprising effects on normal keratinocytes, with the effects changing with dose, but also over time.

With regard to possible preventive/clinical feasibility of Resv for skin administration, we observed that Resv at pharmacologically relevant concentration (5–50 µM) caused serious and long lasting deregulation of adaptive reactions to inflammatory (TNFα) and growth (TGFα) stimuli in normal human skin keratinocytes. These Resv-associated effects could bring both beneficial and deleterious outcomes: from one side, they could aim at the enforcement of intrinsic skin cell survival mechanisms (IL-8 over-production, enhanced ERK1/2 and NFκB phosphorylation, and AP-1 transactivation), and from the other side, they could damage sensitive, ageing or ailing skin, thus enhancing the risk of tumorigenesis (EGFR activation, its nuclear retention, and AP-1 transactivation), augmenting inflammatory burden (IL-8 overproduction, enhanced EGFR/ERK and NFκB phosphorylation), and diminishing physiological skin regeneration and wound healing (decreased keratinocyte proliferation), like it has been shown previously

In humans, only a small fraction of the nutritional Resv reaches the body fluids as free Resv, due to its active enterohepatic metabolism [80]. The amount of Resv ingested from dietary sources such as wine and fruit juices (containing not more than 5 mg/ml resveratrol) often results in plasma levels that are either not detectable or several orders of magnitude below the micromolar concentrations that are typically employed in vitro (32 nM–100 µM) [81]. Administration of 25 mg Resv results in plasma concentrations of the free form that range from 1 to 5 ng/ml [82], and administration of higher doses (up to 5 g) increased the plasma Resv concentrations to about 500 ng/ml [83]. Reasonably, the concentrations of free Resv in peripheral tissues such as the epidermis must be much lower, although its lipophilicity could dramatically affect its distribution. In the last years, the possibility to introduce free Resv transcutaneously has been explored. Topical application of Resv as its triphosphate salt derivative resveratrate was shown to protect human skin from damage due to repetitive ultraviolet irradiation significantly better than application of free Resv or an antioxidant preparation used as a control [84]. Resveratrate is a transient derivative of Resv, since free Resv is released at the level of stratum corneum where dephosphorylating enzymes reside. Experiments performed on biopsies of pig skin demonstrated that treatment with resveratrate compared to the parent compound led to a more homogeneous distribution of Resv throughout the stratum corneum and viable epidermis [85]. However, no data on the concentrations reached by Resv or its bioactive metabolites in the epidermis in vivo are available. By using mouse skin, transcutaneous penetration and accumulation of free Resv in the viable epidermis was shown to be highly favoured by the use of acqueous, mildly acidic (pH 6) buffers in the form of topically applied, adherent hydrogels [86]. Finally, the investigation on the possible topical administration of Resv via nonoparticles is presently very active, although technical limitations, such as the use of organic solvents, are still to be overcome

Edited by cudBwrong, 22 February 2014 - 09:02 PM.

[hav]

Been studying skin graphics and this one shows a close up of some of the outermost epidermis layers:


Looks like the melanocytes reach the furthest down through the epidermis to the junction of the dermis. Here's another graphic showing where the blood and lymph vessels are. Looks like the largest are blood vessels but they're pretty far down in subcutaneous area embedded in a fatty layer.


There seem to be some really small blood and lymph vessels that get near the junction of the epidermis and dermis but the big-time blood vessels look like they're much further down an pretty well insulated.

Howard

[LucidMind]

Howard,

Based on your reasoning how would you explain the effectiveness of other skin path delivery systems such as nicotine patches?

[cudBwrong]

Howard,

Based on your reasoning how would you explain the effectiveness of other skin path delivery systems such as nicotine patches?

This is a good point, there are a lot of drugs delivered, or which we are trying to find a way to deliver, by transdermal patches. The short answer is that our ability to do this depends on the properties of the target drug.

Many molecules cannot permeate intact skin, which is actually a major reason why the skin is there. The primary indicator is molecular weight. Molecules above 400 g/mol or Daltons generally can't get through. Resveratrol is about half that, which is still pretty large so it might make it, at least sometimes. Nicotine is a bit smaller. The weight is not the only factor, but it's important.

Encapsulating molecules in highly deformable vesicles, or, alternatively, vesicles with highly fluid layers, allows many things to permeate that cannot do so otherwise. There is a lot of research, including Howard's experiments, in this area.

A nice fulltext review of the topic is here:

http://www.ncbi.nlm....?report=classic

Edited by cudBwrong, 25 February 2014 - 02:00 AM.

[cudBwrong]

Here is a group that experimented with resveratrol and different types of nanovesicles, including transferomes, which are deformable, and ethanol-based vesicles, which have the fluid layers. Using porcine skin, they found enhanced permeability with the ethanol vesicles only.

http://www.ncbi.nlm....pubmed/22909994

Int J Pharm. 2013 Jan 20;440(2):179-87. doi: 10.1016/j.ijpharm.2012.08.009. Epub 2012 Aug 14.
Nanocarriers for topical administration of resveratrol: a comparative study.

Scognamiglio I¹, De Stefano D, Campani V, Mayol L, Carnuccio R, Fabbrocini G, Ayala F, La Rotonda MI, De Rosa G.
Author information

• ¹Department of Pharmaceutical and Toxicological Chemistry, Faculty of Pharmacy, University of Naples Federico II, via Montesano 49, Naples, Italy.

Abstract

The trans-resveratrol (t-res), a non-flavonoid polyphenol extracted from different plants, has recently earned interest for application on the skin for different applications. In this work, the potential of nanocarriers, namely transfersomes and ethanol-containing vesicles, to deliver t-res into/through the skin was investigated. Thus, transfersomes with different surfactants, namely polysorbate 80 (Tw80), sodium cholate (SC) and sodium deossicholate (SDC) and ethanol-containing vesicles with different lipid composition, namely soy phosphatidylcholine (SPC) and cholesterol (chol), encapsulating t-res were prepared and characterized. The nanocarriers had a mean diameter ranging between 83 and 116 nm with a high t-res encapsulation efficiency (≥ 70%). Moreover, cytotoxicity as well as the inhibition of production of reactive oxygen species (ROS) and lipid peroxidation, following incubation of H(2)O(2)-stimulated human keratinocyte (HaCaT) with t-res, as free or encapsulated into the nanocarriers, were investigated. Only blank nanocarriers containing Tw80 or ethanol were cytotoxic and led to increase of ROS, but this effect was not observed when using nanocarriers encapsulating t-res. Finally, permeation studies on porcine skin carried out on Franz diffusion cells, showed that only ethanol-containing vesicles based SPC were able to promote t-res permeation through the skin.

Edited by cudBwrong, 25 February 2014 - 01:56 AM.

[niner]

One factor in skin permeation, as mentioned above, is size. Smaller is better. However, there are other factors, or we would have a very hard time in the shower, what with water being only 18 daltons. Another major factor is hydrophobicity. Hydrophilic molecules do not penetrate skin very well, while hydrophobic molecules are better. The molecules that work well with transdermal dosage forms are those that are very potent, so you don't need to get a large dose. Fentanyl, for example, is dosed in micrograms, and nicotine doses are only a couple mg. High-dose drugs are rarely used transdermally, because it is usually hard to deliver a large dose. A characteristic of transdermal dosing is that the drug is delivered slowly over an extended period of time. Sometimes that's what we want, but not with resveratrol. With resveratrol, we want a large bolus dose in order to overwhelm the conjugative enzymes that are poised to deactivate it by attaching a glucuronide or sulfate group. Pharmacokinetic data has shown that larger doses are more efficient than small doses, Doubling the dose will more than double the blood level of free resveratrol. Allowing resveratrol to trickle in slowly is the worst possible scenario, since there would be plenty of conjugative capacity to gobble up the resveratrol that slowly leaked in. The one exception that I can imagine would be a situation where you wanted to specifically dose the skin, or possibly something that was directly under the skin.

[cudBwrong]

One factor in skin permeation, as mentioned above, is size. Smaller is better. However, there are other factors, or we would have a very hard time in the shower, what with water being only 18 daltons. .....

Allowing resveratrol to trickle in slowly is the worst possible scenario, since there would be plenty of conjugative capacity to gobble up the resveratrol that slowly leaked in. The one exception that I can imagine would be a situation where you wanted to specifically dose the skin, or possibly something that was directly under the skin.

niner makes me laugh. I was wondering why I was so squishy after a shower.

In general, "time release" of resveratrol is the worst way to try to get it into the bloodstream. Patches make sense only in the context of specific targets.

Encapsulation and the transdermal patch are two techniques that can work together on specific drug delivery problems.

A lot of the work on encapsulation -- not just on resveratrol -- is focused on cancer, particularly skin cancer, but there are other targets. I've even seen studies (I can't locate them at the moment) where they are developing drug delivery methods inside the eye using encapsulation.

One other possible reason for encapsulation is to protect the drug from metabolism while it is inside the capsule. I'm not clear about this, but I think the idea is that the capsules may circulate, either in blood or lymph, before the drug "decloaks" in the vicinity of its target.

[hav]

Based on your reasoning how would you explain the effectiveness of other skin path delivery systems such as nicotine patches?

The only one I've read up on in depth is dmso. It's believed to work so well transdermally do to a super affinity for water leading it to literally suck out and replace water molecules within cells in the skin until it reaches the small blood vessels which penetrate above the fat layer below the skin and contain even higher water levels. And drags anything water soluble along with it. I think the reason dmso doesn't work with resveratrol is because resveratrol is not water soluble.

Howard

[Wilmore Labs]

Other than the limitations of trans-dermal to a few mg over long release. Nicotine is the highest concentration in a patch which is approved by the FDA at 31mg (Large patch), and that has a low absorption of about 10-20% with nicotine. Patches aren't efficient, and importantly the FDA requires approval of patches as medical devices (combination products).

http://www.fda.gov/C...s/ucm101496.htm

[hav]

There's a company called Respro Labs that markets caffeine, b12, and melatonin patches. But I have no idea how they operate. I've tried their caffeine patches and they do work but were not as potent as home brewing my own with dmso. Caffeine seems to be unusually well suited for transdermal delivery being small in size and both hydro and lipophilic.

Here's a study of c60 dissolved in squalene that showed that combo was unable to penetrate the barrier between the epidermis and dermis:

Biological safety of LipoFullerene composed of squalane and fullerene-C60 upon mutagenesis, photocytotoxicity, and permeability into the human skin tissue.

In human skin biopsy built in a diffusion chamber, C60 permeated into the epidermis at 33.6 nmol/g tissue (24.2 ppm), on administration with LF-SQ containing 223 ppm of C60, but not detected in the dermis even after 24 hrs, as analysed by HPLC. It is presumed that LF-SQ can permeate into the epidermis via the corneum but can not penetrate the basement membrane, and so can not reach into the dermis

I expect that resveratrol in a straight oil solution would be similar. But I've noticed that c60 in jojoba seems to be very well absorbed by the skin. Here's a study that supports adding jojoba to olive oil for enhanced transdermal delivery of a lipophilic drug:

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone

Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug.

Resveratrol probably isn't as lipophilic as risperidone but it might dissolve and absorb with jojoba to some extent.

Howard