57 replies to this topic

[malbecman]

Well, I tried out my daily dose of t-resv. w/ soy lecithin from my local health food store as an emulsifier.

I usually mix my 5mg/kg BAC 50% powder in warm water and chug it down. Not too bad tasting but it definitely has some issues going into solution and is more like a slurry.

Mixing in ~ 1 tsp lecithin as a guesstimate dose and getting it dissolved first, then adding the BAC powder, my BAC powder definitely goes into solution. It looks more just like a cup of coffee now with no visible grains or small chunks like before. The taste is actually more pleasant as well although the lecithin coats the mouth a little, kind of like a real oil and vinegar salad dressing. 1 T = 70 kcal so I'm guessing I got ~15-20 kcal. I will try less next time as I think there was plenty of lecithin in there this time.

No idea how it might affect bioavailability, I'm not up for doing a PK study on myself (n=1?) but I figure having the t-resv. in solution has got to be a good thing. [thumb]

[health_nutty]

Well I disolved some 98% extract in miralax and it worked really well, no foam or anything at the top. Hopefully I get that 200% increased bioavailability. I can't imagine that the sirtris patent is as simple as that, but I'm not in the mood to read a patent right now And if it is, power to informed consumers!

Why did you do that?

[bugmenot.com]

I still have not found the patent application. Has anyone actually read it? What is the URL?

The problem with this is that we don't have micronized powder, and we don't know how much solvent to use, and we don't know exactly how they are mixing them. So we actually have no idea what the increased bioavailability will be with any formulation we make.

This means that if you go through this process and take 200mg, you have no idea if you're taking the equivalent of 250mg or 800mg.

So what's the point? If you want 200% more, take 200% more. I think it's easier until we can quantify things.

[maxwatt]

I still have not found the patent application. Has anyone actually read it? What is the URL?

The problem with this is that we don't have micronized powder, and we don't know how much solvent to use, and we don't know exactly how they are mixing them. So we actually have no idea what the increased bioavailability will be with any formulation we make.

This means that if you go through this process and take 200mg, you have no idea if you're taking the equivalent of 250mg or 800mg.

So what's the point? If you want 200% more, take 200% more. I think it's easier until we can quantify things.

Because there's an upper limit on the serum level; the excipient allows a higher serum level. If I understand the patent data, higher doses will increase the area under the curve, and only increase the peak concentration in the blood up to a certain point.

Go back to the beginning of this thread; I think the patent link is there.

The 98% resveratrol powder I use, and that Proteomist experimented with, is an extremely fine powder. Most of the particles a re sufficiently fine to work with this method. I doubt it will work with a 50% resveratrol extract.

[proteomist]

Here is a link to the patent in which they discuss some formulation issues:

http://www.wipo.int/.....Y=wo/06127987

[bugmenot.com]

The patent is for

a composition that includes nanoparticles comprising a sirtuin modulator, or a pharmaceutically acceptable salt, prodrug or metabolic derivative thereof. Such particles typically have a mean diameter of 50 nm to 500 nm, such as 100 nm to 200 nm.

I really doubt that your powder is anything like nanoparticles. Here is a link to an FDA document regarding a resveratrol product. Note that the powder is 100 mesh, which is typical.

Here we can find a chart detailing what 100 mesh means: average particle size of 0.149mm. That's 149,000nm or roughly 500 times larger than what is called for in the patent. Even if your powder is 10 times finer (which I doubt), that's still 50 times larger than you want it to be.

No, I really think you are wasting your time with this until a micronized resveratrol is available.

[maxwatt]

The patent  is for

I really doubt that your powder is anything like nanoparticles. Here is a link to an FDA document regarding a resveratrol product. Note that the powder is 100 mesh, which is typical.

Here we can find a chart detailing what 100 mesh means: average particle size of 0.149mm.  That's 149,000nm or roughly 500 times larger than what is called for in the patent. Even if your powder is 10 times finer (which I doubt), that's still 50 times larger than you want it to be.

No, I really think you are wasting your time with this until a micronized resveratrol is available.

The powder is specified for an 80 mesh screen, and most of the particles are much smaller than 80 mesh, but still would not qualify as mirconized, I am sure. However. all but the largest particles remain in suspension indefinitely, which would seem to show the detergent effect of the PEG3325 is effectively solubulizing most of the resveratrol. The use of similar excipients, such as cyclodextrin, with other non-watter soluble supplements, specifically non-micronized CoQ10, lead me to believe that it does increase serum levels. There are studies showing such solubized Q10 reaches higher serum levels than Q10 powder alone.

From what I have gathered about the drying process for the 98% resveratrol I use, it is spray-dried from a fine nozzle, and precipitates from a mist. The larger particles are from clumping of the particles. Most of them are very fine. I will see if I can get someone with access to the proper microscope to try and measure the particle size.

Judging from the subjective effects of consuming resveratrol in this manner, I believe it is a more effective delivery system than just swallowing the powder.

[bugmenot.com]

However. all but the largest particles remain in suspension indefinitely, which would seem to show the detergent effect of the PEG3325 is effectively solubulizing most of the resveratrol. 

A suspension has nothing to do with a solution.

[proteomist]

But it dramatically increases surface area, which will drive the surrounding solution to saturation much more quickly, and will serve to maintain saturation in the face of other solution-depleting factors such as cellular uptake. Similarly, dissaggregation of the particles makes them much more able to interact with epithelial microvili.

I don't understand your argument against using these agents, could you clarify what issue you have with this?

Also, did you look at the charts I posted? Sirtris' internal data clearly shows elevated rates of uptake in the presence of these excipients. Yes they were using micronized particles, but there's no reason to think that small particle size was absolutely necessary, rather than just synergistic, for acheiving these effects.

However. all but the largest particles remain in suspension indefinitely, which would seem to show the detergent effect of the PEG3325 is effectively solubulizing most of the resveratrol. 

A suspension has nothing to do with a solution.

[bugmenot.com]

There's no way to know what portion of the increased uptake was due to particle size and what portion was due to the solvent.

Merely mixing large particles into a carrier does nothing to the surface area. Particle size controls the surface area.

We also don't know that the particles would be disaggregated.

And without being able to calculate the effects of particle size, we not only have no idea how much solvent to use, we also have no idea what effect it actually has on uptake.

So we go from being able to rely somewhat on the calculation that 4.7mg/kg is equivalent to the dosing of the mice in Sinclair's study to having no idea at all of how much we're getting.

This somehow doesn't seem like an improvement to me.

If polysorbate 80 is actually a good solvent for resveratrol, it seems as if the better idea would be to take a whole lot of resveratrol, micronize it, and then dissolve it, then take it in the form of softgels, etc. The idea would be to have it completely dissolved.

Taking an 80 mesh powder with some arbitrary amount of some solvent without giving the resveratrol a chance to dissolve doesn't seem to make much sense. It will all be diluted in your stomach anyway.

[proteomist]

First of all, Polysorbate 80 isn't a solvent, it's a surfactant. Secondly, yes it does make a difference to surface area. If you have small particles densely packed, most of their surface is facing other particles rather than solvent. A surfactant stabilizes their deaggregated state by forming a amphipathic interface with the water. So yes, it makes a big difference. This is easily seen by mixing resveratrol in water with or without surfactant. With it, it disperses and stays suspended. Without it, it forms clumps and tries like hell to exclude itself from water. You also make the mistaken assumption that the resveratrol dissolves in the gut/stomach. This is very unlikely to be the case. It's never going to be fully dissolved in aqueous solution because the solubility is so low. Rather, a small amount goes into solution or is directly absorbed by cells from the surface of particles. Therefore maximizing their dispersion is desireable. This is standard operating procedure for many, many drugs. I work in a drug lab. We deal with this kind of thing every day. I know whereof I speak.

Why don't you tell us all the details of your own dosing regimen, and the logic behind it? Perhaps your strategy for micronizing it without spending huge amounts of money? What do you think it might dissolve in that's biocompatible? How are you going to keep it from reprecipitating when that solvent gets diluted into water in the stomach?

There's no way to know what portion of the increased uptake was due to particle size and what portion was due to the solvent.

Merely mixing large particles into a carrier does nothing to the surface area.  Particle size controls the surface area.

We also don't know that the particles would be disaggregated.

And without being able to calculate the effects of particle size, we not only have no idea how much solvent to use, we also have no idea what effect it actually has on uptake.

So we go from being able to rely somewhat on the calculation that 4.7mg/kg is equivalent to the dosing of the mice in Sinclair's study to having no idea at all of how much we're getting.

This somehow doesn't seem like an improvement to me.

If polysorbate 80 is actually a good solvent for resveratrol, it seems as if the better idea would be to take a whole lot of resveratrol, micronize it, and then dissolve it, then take it in the form of softgels, etc. The idea would be to have it completely dissolved.

Taking an 80 mesh powder with some arbitrary amount of some solvent without giving the resveratrol a chance to dissolve doesn't seem to make much sense. It will all be diluted in your stomach anyway.

[maxwatt]

Proteomist took the words out of my mouth. But why the anonymous mailinator account, Noway?

[bugmenot.com]

The regimen I'm using is based on what a friend who knows Sinclair said that he said he was taking (a year ago), which was 600-800mg per day.

With regard to precipitation, you could ask the same question about when it's in the blood. Blood is composed mostly of water, so if you can't get it to dissolve in water, it won't circulate well and won't get around the body. The reason to dissolve it is because then you should get really good dispersion and not have any clumps that pass through the digestive tract intact.

If you really can get better dispersion with a bit of polysorbate 80, it would be useful to get a good method for doing so, including how to mix it, how much to use, and how to package it.

But if it is true that resveratrol may have deleterious effects if taken to excess, as some have claimed, it would be important to be able to quantify exactly what equivalent dose you're getting with any particular method.

[proteomist]

With regard to precipitation, you could ask the same question about when it's in the blood. Blood is composed mostly of water, so if you can't get it to dissolve in water, it won't circulate well and won't get around the body. The reason to dissolve it is because then you should get really good dispersion and not have any clumps that pass through the digestive tract intact.

Blood is a lot more complicated than that. In particular, you have huge amounts of serum albumin that acts a
carrier for hydrophobic molecules that would otherwise precipitate.

But if it is true that resveratrol may have deleterious effects if taken to excess, as some have claimed, it would be important to be able to quantify exactly what equivalent dose you're getting with any particular method.

I'd love to have exact human PKPD data for various resveratrol formulations. But Sirtris isn't sharing that yet, and nobody else has published it.

[inawe]

The last posts dealt with ways to improve absorption of resveratrol in water, where the solubility is poor. On the other hand, solubility in ethanol is good. Wouldn't a solution in ethanol have small enough resveratrol particles for better absorption?

[niner]

The last posts dealt with ways to improve absorption of resveratrol in water, where the solubility is poor. On the other hand, solubility in ethanol is good. Wouldn't a solution in ethanol have small enough resveratrol particles for better absorption?

I think the problem with this is that as soon as it hits the stomach, it will be diluted in water to the point that the resveratrol will precipitate out. The question then is what is the particle size? Beats me, though I'd expect a lot of clumping. On the other hand, if you have a small particle of resveratrol that is lined with the hydrophobic end of a surfactant, it will remain stable when it hits the stomach. The surfactant will not dissociate rapidly from the particle.

[inawe]

Is it not a situation similar to fat-soluble substances that are taken in oil? What happens when they reach the stomach?

[proteomist]

In that case they stay in the oil, because it doesn't mix with water. Ethanol, however, is freely soluble in water and will rapidly be diluted below the concentration where it can dissolve resveratrol, which is upward of about 60% or 120 proof.

And no, resveratrol doesn't dissolve into oils, unfortunately.

Is it not a situation similar to fat-soluble substances that are taken in oil? What happens when they reach the stomach?

[inawe]

In that case they stay in the oil, because it doesn't mix with water. Ethanol, however, is freely soluble in water and will rapidly be diluted below the concentration where it can dissolve resveratrol, which is upward of about 60% or 120 proof.

And no, resveratrol doesn't dissolve into oils, unfortunately.

Is it not a situation similar to fat-soluble substances that are taken in oil? What happens when they reach the stomach?

OK. So we can compare 2 situations:
1) In the stomach water a big clump of oil with vitamin E molecules inside.
2) In that same stomach water, smaller clumps of resveratrol.
Why should 1 get a better treatment than 2 as far as transport on the GI system?

[maxwatt]

Resveratrol does dissolve in oils, but poorly. Here's a study on drug delivery of resveratrol in emulsions from the

International Journal of Pharmaceutics

The abstract seems to state that an aqueous system using PEG as an excipient, showed a superior release rate to lipid emulsions.

The effect of oil components on the physicochemical properties and drug delivery of emulsions: Tocol emulsion versus lipid emulsion
Chi-Feng Hunga, Chia-Lang Fangb, Mei-Hui Liaoc and Jia-You Fangc, , 
aSchool of Medicine, Fu-Jen Catholic University, Taipei, Taiwan
bDepartment of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan
cPharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan 333, Taiwan
Available online 11 November 2006
Abstract

An emulsion system composed of vitamin E, coconut oil, soybean phosphatidylcholine, non-ionic surfactants, and polyethylene glycol (PEG) derivatives (referred to as the tocol emulsion) was characterized in terms of its physicochemical properties, drug release, in vivo efficacy, toxicity, and stability. Systems without vitamin E (referred to as the lipid emulsion) and without any oils (referred to as the aqueous micelle system) were prepared for comparison. A lipophilic antioxidant, resveratrol, was used as the model drug for emulsion loading. The incorporation of Brij 35 and PEG derivatives reduced the vesicle diameter to <100 nm. The inclusion of resveratrol into the emulsions and aqueous micelles retarded the drug release. The in vitro release rate showed a decrease in the order of aqueous micelle system > tocol emulsion > lipid emulsion. Treatment of resveratrol dramatically reduced the intimal hyperplasia of the injured vascular wall in rats. There was no significant difference in this reduction when resveratrol was delivered by either emulsion or the aqueous micelle system. The percentages of erythrocyte hemolysis by the emulsions and aqueous micelle system were 0 and 10%, respectively. Vitamin E prevented the aggregation of emulsion vesicles. The mean vesicle size of the tocol emulsion remained unchanged during 30 days at 37 °C. The lipid emulsion and aqueous micelle system, respectively, showed 11- and 16-fold increases in vesicle size after 30 days of storage.

[proteomist]

Sorry, I meant to indicate that it isn't freely soluble, which is what we'd want for an oral oil delivery system.

The abstract seems to imply this is i.v. delivery, since they are concerned about hemolysis.

Resveratrol does dissolve in oils, but poorly.  Here's a study on drug delivery of resveratrol in emulsions from the

International Journal of Pharmaceutics

The abstract seems to state that an aqueous system using PEG as an excipient, showed a superior release rate to lipid emulsions.

The effect of oil components on the physicochemical properties and drug delivery of emulsions: Tocol emulsion versus lipid emulsion
Chi-Feng Hunga, Chia-Lang Fangb, Mei-Hui Liaoc and Jia-You Fangc, , 
aSchool of Medicine, Fu-Jen Catholic University, Taipei, Taiwan
bDepartment of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan
cPharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan 333, Taiwan
Available online 11 November 2006
Abstract

An emulsion system composed of vitamin E, coconut oil, soybean phosphatidylcholine, non-ionic surfactants, and polyethylene glycol (PEG) derivatives (referred to as the tocol emulsion) was characterized in terms of its physicochemical properties, drug release, in vivo efficacy, toxicity, and stability. Systems without vitamin E (referred to as the lipid emulsion) and without any oils (referred to as the aqueous micelle system) were prepared for comparison. A lipophilic antioxidant, resveratrol, was used as the model drug for emulsion loading. The incorporation of Brij 35 and PEG derivatives reduced the vesicle diameter to <100 nm. The inclusion of resveratrol into the emulsions and aqueous micelles retarded the drug release. The in vitro release rate showed a decrease in the order of aqueous micelle system > tocol emulsion > lipid emulsion. Treatment of resveratrol dramatically reduced the intimal hyperplasia of the injured vascular wall in rats. There was no significant difference in this reduction when resveratrol was delivered by either emulsion or the aqueous micelle system. The percentages of erythrocyte hemolysis by the emulsions and aqueous micelle system were 0 and 10%, respectively. Vitamin E prevented the aggregation of emulsion vesicles. The mean vesicle size of the tocol emulsion remained unchanged during 30 days at 37 �C. The lipid emulsion and aqueous micelle system, respectively, showed 11- and 16-fold increases in vesicle size after 30 days of storage.

[Fredrik]

There is a commercial Resveratrol polyethylene glycol product available, PEGylated liposome resveratrol. What do you think of this approach, a marketing ploy or something viable?

From the commercial website:

"Encapsulating resveratrol in PEGlyated liposomes enables resveratrol to pass readily into the bloodstream and then protect it from agents that might alter them, thus allowing excellent bioavailability. Formulated as a liquid suspension, the liposomes can be easily absorbed through the mucous membranes of the mouth by holding the liquid in your mouth without swallowing it."


http://www.life-enha...duct.asp?ID=565

[maxwatt]

There is a commercial Resveratrol polyethylene glycol product available, PEGylated liposome resveratrol. What do you think of this approach, a marketing ploy or something viable? 

From the commercial website:

"Encapsulating resveratrol in PEGlyated liposomes enables resveratrol to pass readily into the bloodstream and then protect it from agents that might alter them, thus allowing excellent bioavailability. Formulated as a liquid suspension, the liposomes can be easily absorbed through the mucous membranes of the mouth by holding the liquid in your mouth without swallowing it."


http://www.life-enha...duct.asp?ID=565

The amount of resveratrol per dose is so low, even if this were superior delivery system, it would do diddley-squat for your health.

[Fredrik]

Yes, I know the dose is too low. I was more interested in the delivery method than the actual product. I´m not taking resveratrol until a specific extract or product is made available that has been tested on man or mice and been shown to actually do something. I´m not doubting the beneficial effects of resveratrol on metabolism (even if I don´t think it will extend maximum lifespan a diddley-squat in humans). But I´m worried about poor fomulations and too low bioavailability.

If I lived in the americas I would have joined the group purchase of Orchids synthetic resveratrol that Sinclair used in his published studies.

Edited by fredrik, 25 June 2007 - 03:32 PM.

[sUper GeNius]

Is there any data in the patent regarding the effectiveness of Peg?

Has anyone found a good supplier of Tween 80? I have had my doubts as to the freshness and preservation and purity of some I have seen available.

[yucca06]

About Tween 80 (PS80), I read it could have carcinogenic effects ??!!
Try a google search with E433, you'll see....
Is there any study to back this ?

I bought a few bottles of PS80 3 weeks ago, but I still not began to use it because of this...

[lucid]

About Tween 80 (PS80), I read it could have carcinogenic effects ??!!

Doesn't bother us miralax users, not sure about tween though.

PEG(3350-8000) has been shown to strongly prevent colon cancer (not surprisingly).
http://cancerres.aac...full/60/12/3160

[yucca06]

thanks for the info about PEG/miralax.
I never saw it was used as an OTC laxative. The PEG 4000 is very cheap also, not bad (about $5 for 20 x 10g in every pharmacy in France). But in powder form only...
How do you take it ? Mixed with water/alcool ? Or could I cap the PEG with resv, and still have improved absorption ? Something like a 100mg resv/750mg PEG4000 cap maybe ?