12 replies to this topic

[Wilmore Labs]

I wanted to post the proof of concept poster from the resveratrol 2012 conference: yes it's mine. We were able to get about 3 grams worth of resveratrol into the bloodstream out of 0.140 Grams of a buccal dose or about 15 fold increase over oral dose.

 Picture1 Figure 2 OTM poster 2012.jpg   41.36KB   53 downloads

I am trying to find feedback. If it's wanted, then speak up. If we go to http://www.indiegogo.com/ would anyone help fund the next step for a t-shirt, (product would be expensive, but if there's a strong response we can get a small batch produced) etc? If we put it on a Croudfunding investment site would there be interest?

Just speaking up, posting a "yes we want it", sending messages to GNC and Supplement companies would help get this picked up. Supplement companies are worried about this, but not for the way you think. They're worried about putting investment into it when they don't know if there's demand. They don't know if anyone would want to buy it, so I'm asking.

I'm just trying to keep the lights on, do science, and keep adding to the patent application.

Leave feedback, ask questions, follow on twitter @renegadesci.


 Blanchard Smoliga OTM Delivery Resveratrol 2012.pdf   471.2KB   29 downloads

Edited by Wilmore Labs, 21 December 2012 - 07:21 PM.

[Kevnzworld]

There are many companies that sell sublingual resveratrol . It's widely available. What am I missing?

http://www.resveratr...of-resveratrol/

http://www.prnewswir...t-90376494.html

[Wilmore Labs]

The problem with serious research into OTM dosages is the solubility issue. Resveratrol is not soluble alone in the mouth, which is why the little buccal experiment worked in alcohol (alcohol is a good universal solvent). Most supplement binders are sugar alcohols, which will reduce the solubility from our exploration into the literature. That's most of the compression lozenges and the gums. Gum Arabic is very hydrophilic, and will reduce resveratrol aqueous solubility in gums and prevent transmucosal delivery. It will also require a robust dose size. 150mg is large, but we ended up with 140mg and plan to walk it back to a lower dose so we don't waste so much.

 Blanchard Smoliga OTM resveratrol 2012 introduction.jpg   419.87KB   23 downloads

We needed to double the solubility, and we showed we can at least do that with ribose. That's important because when a molecule isn't soluble it self associates, or stacks like a roll of quarters. Getting a molecule through a membrane, like in the mouth, require single molecules to pass through between the lipid membrane. Without solubility it'd be like trying to throw a roll of quarters into a coin slot. Solubility allows it to get into the slot(s). This is why no research lab has used these products: researchers don't think they'll work. The we're working with to test them with the research, of course, and force them to support their claims.

One thing that was reported was the taste of the lozenges. It gave subjects a cinnamon or black pepper taste with the solubolized resveratrol lozenge. We hypothesize there is a link between solubility for absorption and the solubility for the strong taste. We had to run the raw ingredients through the mass spec to ensure it wasn't contaminants.

 Blanchard Smoliga OTM resveratrol 2012.jpg   403.31KB   21 downloads

Edited by Wilmore Labs, 21 December 2012 - 08:36 PM.

[Kevnzworld]

Interesting, I assume you are Otis Blanchard. I found your patent application and read it. ( I'm not a scientist )

http://www.google.co...eratrol&f=false

I would call Life Extension foundation. ( LEF.org ). They have funded many small start ups with novel nutriceutical formulations.
Good luck.

Edited by Kevnzworld, 21 December 2012 - 08:50 PM.

[Wilmore Labs]

Yeah, I'm Otis. I'm just getting some feedback. I appreciate it.

Edited by Wilmore Labs, 21 December 2012 - 08:53 PM.

[niner]

I think that was some cool science, Otis. It's pretty brilliant to use ribose as a molecular chaperone. You got a pretty impressive Cmax. (Why are the peaks so broad in the Fig 1 chromatogram?) Boocock's resveratrol was essentially unformulated, but there are now micronized versions for sale, and even a micronized version in Tween 80. If the lozenge form is going to be expensive, then you should probably view this product as the competition, rather than Boocock. Then there's the question of whether the key thing is Cmax or AUC. Is there any evidence that Cmax is the important number, or is that derived from theory? Considering that there are probably multiple mechanisms of action, deriving that from theory alone would be tough.

[Wilmore Labs]

"(Why are the peaks so broad in the Fig 1 chromatogram?)": It's zoomed in for about 60-90s of elution from the column and it took 30 minutes per sample to get good seperation.

The thing with tween 80 and micronised is that solubolized oral doses of resveratrol has been tested, even with cyclic dextrose. Bile in the small intestines does fairly well in the gut bringing polyphenols into solution, better than tween, or we wouldn't have good absorption in the first place.

The third question: "Is bioavalibility or Cmax more important?"

I don't know. From Sinclair and Baur's 2006 review "the in vivo evidence" they mentioned that resveratrol's effects on COX is poorly reversible". Right now I've not gone into the background on it, but this would be key if it held up with ER-alpha, etc. If resveratrol's effects on cells are poorly reversible, the effects are concentration dependent to have more interaction with more targets on more cells, then the effects last after the switches are agonised and the molecule is gone.

If it's like a testosterone the effect will be dependent on the continual interaction with cells, a quick switch, then this will be a clever novelty.

We don't know which it is for resveratrol. We'd like to find out.

Love the questions. This is what my desk and bed looks like on any given day. I love to go over this data.  IMG_1905.JPG   111.79KB   17 downloads

Attached Files

•  P7. The Impact of Aqueous Solubility and Dose on the Pharmacokinetic Profiles.pdf   183.25KB   7 downloads

Edited by Wilmore Labs, 21 December 2012 - 10:27 PM.

[hav]

Doesn't adding sugar to resveratrol turn it into piceid, aka polydatin? I seem to recall that polydatin has somewhat better water solubility compared to resveratrol, but still fairly low. I take it together with resveratrol and it seems to make a more effective mix. Just did a little poking around on pubmed and I see this study which mentions using grafting techniques to cause hexose, another monosaccharide, to make polydatin appear in the fruit in place of resveratrol in growing apple trees:

Piceid (resveratrol glucoside) synthesis in stilbene synthase transgenic apple fruit.

A stilbene synthase gene along with the selectable marker gene bar for herbicide resistance was transferred via Agrobacterium tumefaciens mediated transformation into apple (Malus domesticaBorkh.) cvs. 'Elstar' and 'Holsteiner Cox'. The stilbene synthase catalyzes the conversion of 1 molecule of p-coumaroyl-CoA and 3 molecules of malonyl-CoA into 3,4',5-trihydroxystilbene, commonly known as resveratrol. This phytoalexin has implications in both phytopathology and human health. Greenhouse-grown transgenic and nontransformed control plants were grafted onto dwarfing rootstock M27. Flowering and fruiting occurred within the following years, offering the opportunity to analyze transgenic apple fruit and fertility of transgenic plants as well as inheritance of the transgenes into the seedling progeny. Molecular analysis revealed that the stilbene synthase is expressed in transgenic plants and in the skin and flesh of transgenic apple fruit. After formation, resveratrol is modified by the addition of a hexose sugar. The resulting component was characterized as piceid. With the aim of characterizing the influence of the novel biosynthetic pathway on the accumulation of other phenolic compounds naturally present in apple fruit, the amounts of flavanols, flavonols, phloretin derivatives and hydroxycinnamic acids in wild type and transgenic fruit were determined by HPLC. In all investigated transformed lines that accumulated piceid, no negative correlation between levels of piceid and the above-mentioned compounds was observed, except for the flavonol contents, which slightly decreased. Inheritance of the transgenes was confirmed in the seedling progeny, which were obtained after pollination of transgenic plants with nontransgenic pollen and vice versa after pollination of nontransgenic plants with pollen obtained from transgenic plants. The fertility of stilbene synthase transgenic plants was demonstrated. To the authors' knowledge this is the first time that data are available on piceid synthesis in transgenic apple fruit and the effects of its accumulation on levels of other phenolic compounds present in the fruit.

Howard

[Wilmore Labs]

Well, this is getting into enzyme kinetics. I didn't incubate at a high enough temperature or a long enough time for this reaction to occur spontaneously in manufacturing. The lozenges were tested for only resveratrol, and we had all the yield returning that we received. I don't have access to the library over christmas break, but the tree is a living organism with many enzymes. Apparently the tree has enzymes to transfer a Glucose molecule to Resveratrol to detoxify it. It's a hydrolysis reaction that, if the same as the sulfa metabolites which requires two ATP for the sulfotransferase to add one sulfate to a polyphenol, will require an input of ATP. I'd printed this one up and cited it in old correspondence, but those files are in NC right now.

http://www.ncbi.nlm..../pubmed/9566730

What else we'll require in addition to ATP is the enzymes involved, or we'll have to add a large amount of energy. The only time we're possibly making Piceid is in our subjects. Which we'll be sending old and new samples off to quantify metabolites in 1Q.

[Morris Luo]

Otis, it seems that you are do research on resveratrol solubility? Right?

[blood]

Did anything ever come of this approach to resveratrol delivery (i.e., can it be purchased)?

[Wilmore Labs]

We're still working. I was recently published. Will try and keep everyone posted of developments.


http://www.longecity...exercise-study/

http://www.ncbi.nlm....atrol blanchard

[Wilmore Labs]

http://www.prweb.com...web11274730.htm