| Darkhorse |
Rank: Light Heavyweight
Experience: 7-10 Years
Join Date: Mar 2005
This quote from BulkNut:
Potassium-R-Lipoic Acid is R-Lipoic Acid attached to Potassium. Once the Potassium is attached it forms a salt, which is much more stable than regular r-ALA. |
Potassium-r-ALA does not require refrigeration or cool temperatures to remain effective. Potassium-r-ALAis stable, readily dissolvable, is relatively tasteless, and has a high bioavailability.
I found this from Avant that is an email response with studies done on R-ala vs. ala attached to a salt like K (potassium). It's interesting.
Here is the reply I got from gerobova - thanks Karyn |
I feel a bit awkward entering a forum as a representative of a company, but if that's what it takes to set the record straight, I'll do it.
I don't know if you are aware of all the info that is on our website, some of things I will say here (different color or font) are taken from various pages of the site (or it would take me forever to write it all out).
Starting out, I would like to say that R-lipoic acid is just about the only thing we are involved in, as well as some intermediates and a few research chemicals. We now manufacture the product ourselves and although we used to import it from China, we no longer do so now that we can produce it ourselves. This has taken a long time to develop (believe me) and there is no other company in North America manufacturing this material. Given this fact, I hope I don't sound boastful when I say that we probably know more about working with this material than almost anyone around.
We have been involved with RLA for over 3 years now, and when we started out, although somewhat aware the polymerization problems, had no idea as to the extent of the issue.
We now supply several large companies who are aware of these issues from direct experience with RLA, or from studying the PK studies (which are available if you enjoy technical reading) as well as encapsulators who refuse to handle non-stabilized RLA and have come to us for their RLA for their customers' RLA products.
If you look online, or through product catalogues, you will see several companies now using 'potassium-R-lipoate, including Life Extension, all with our stabilized product. Some people call it K-RALA, which is our trademarked name, and make reference to our company, and some prefer to call it Potassium-R-lipoate and leave us out of it. We are fine either way. FYI, the reason it is called lipoate is that when you make a salt, or an ester, from an acid, the "ic" of lipoic becomes "oate'. as in lipoate.
The most recent company to launch our product is Swanson, (pls. see their newest catalog insert for details) Some of these companies have done their own testing of RLA and our product in stability chambers with significant results (their testing, not ours). This is certainly not about hype, nor about discrediting anyone. It is about telling the truth about what is actually going on, both before the product is consumed, and, more recently and very significantly, what happens in the stomach with dissolution and bioavailability, which will explain why the results you are seeing in yourself are working/not working.
To address that issue in particular, which is very interesting, is because racemic ALA is more stable than either one of the 2 isomers on their own, both as a powder, and inside the body, when it is consumed, the RLA from the ALA is more bioavailable than consuming pure, non-polymerized RLA.
We have done plasma studies measuring RLA and SLA with both racemic ALA and RLA that show that you actually get more RLA out of taking 600 mg ALA than out of taking 1 gm of pure RLA powder! When you then put it in a capsule, or even worse, a tablet, the amount of RLA from a 600 mg dose was undetectable in the plasma. This is not a theory or hype. It is based on clinical trials (to be published in a per-reviewed medical journal later this year).
So, the results you are getting, even though, as you say, on paper, should be the opposite, validate these findings, or perhaps better said, our findings validate what you have experienced. Actually, on paper as well, we have proven what we suspected all along, that what you are experiencing is due to the non-bioavailability of non-stabilized RLA. Even more than taking polymerized or non-polymerized material to begin with, by the time RLA hits the stomach environment, it turns to polymer, cannot be absorbed, and is worse than useless. We wouldn't go to all this trouble to do the stabilization, especially now that we are manufacturing RLA, if we thought just selling straight RLA was a good idea. It would save us a lot of time and trouble.
We are also currently manufacturing stabilized RLA (using a different salt form than potassium) for a large and well-known company who has stayed away from it in the past because they are aware of these stability and polymerization issues but now will be coming out with an RLA product as they are satisfied with the stability of our material.
Okay, now here's some more technical data: (Hope all of this isn't too much for you, I just want to make sure you have all the ammo you need and that I don't leave anything out)
From our site:
Racemic lipoic acid is a relatively unstable molecule due its propensity to form polymeric chains. There are significant stability problems, especially with the pure enantiomers which have a lower melting point and polymerize more readily than the racemic mixture. It is not surprising that some people doubt our claims concerning this problem on a product that has only been commercially available as a nutritional supplement for a few years.
Most supplement companies have no experience with the actual doing of the chemistry on the products they manufacture. Consumers and supplement manufacturers are bombarded with so much hype that suspicion is a natural result. It can be difficult to discriminate between scientific fact and “marketing hype”. Since most people do not have the time to dig out old chemistry journals, we decided to publish what we have discovered from both the library and the laboratory.
GeroNova did not invent the problem of RLA polymerization as a marketing ploy, although we have been frequently accused of this. In fact, we were shocked, and dismayed when we discovered (several years ago) that our very first batch of capsules (made from 99.5% enantiomerically pure RLA) contained 22% polymer! Subsequent research revealed that what was new to us is actually a well known characteristic of disulfides and was observed from the very first laboratory preparations of racemic ALA in the early 50's. (see JACS references below and Characterization and Stability of Cyclic Disulfides and Cyclic Dimeric Bis (Disulfides) Tetrahedron 45, 91 (1989).
Lior, these refs are available to look up and 1 is from the 1950's. It is not our own "idea".
Following is more technical info. (Just tell me when to stop) I don't know if anyone in your forum will care to take the time to read about it, but some of this info is from sources other than us that I felt important to include with this letter. We are reporting what others have found that all say basically the same thing.
While vitamin resellers are still largely unaware of the stability problems of RLA, primary manufacturing companies know all too well about its reality. Asta Medica (now Viatris), BASF, Degussa, Labochim and Antibioticos, have developed novel methods of dealing with this annoying property of an otherwise valuable supplement.
Asta Medica [US Patent 5,455,264] modified the usual isolation and crystallization of ALA or RLA to yield a product with a novel crystalline structure, characterized by a novel x-ray diffraction pattern and dissolution profile. It was also easy to isolate the product from polymeric starting materials.
The next Asta Medica invention [US Patent 5,994,393] utilized a special resolution technique to alter the R/S ratio. The resulting products have varying melting points depending on the how much of the S isomer is present. The more SLA present, the higher the melting point, so that a R/S mixture of 65.8 % RLA: 34.2% SLA has a melting point of 54-58 degrees C and is less prone to polymerize. Labochim (Italy) has a dosage form commercially available containing a 70:30 mixture of RLA: SLA and that is more stable and less prone to polymerization than the usually encountered RLA.
BASF jumped in on the act [US 6,441,024] and developed a process (similar to Asta Medica 's) utilizing a mixed solvent system and precise temperature control which modified the crystalline structure and physical properties of RLA.
GeroNova did not set out to gain a market advantage over our competitors by publicizing this problem. We actually set out to discover what they were doing that we were not in order to prevent polymerization. This sticky elastomer was the cause of many sleepless nights, and two years of subsequent R&D to develop a stable/heat resistant dosage form. It was only after testing competitors products (by third party HPLC analysis) that we discovered that not only were most companies not doing anything to prevent polymerization, but were obviously also not doing any quality control on their finished products, since they were not delivering anything close to their label claims.
We brought the issue of RLA instability and our test results to the attention of vitamin companies as well as to the public in an attempt to raise the quality of products reaching the consumer. While many companies choose to deny any problem exists, we reported it from the beginning and have subsequently discovered novel ways to overcome the limiting physical properties.
I wouldn't call this discrediting, we are presenting the facts, period.
Since we believe the old philosophy of business (bashing your competitors) is outdated, GeroNova endorses any of our "competitors" involved with this fascinating molecule, and support them in their attempts to bring it to the public, as long as they are delivering what they claim. Since we believe that every living, breathing human being needs RLA, there is room for quite a few good RLA companies, and we believe RLA will outgrow CoQ10 and Vitamin E within 10 years.
On the other hand, it makes no sense to report all the health benefits of RLA if you cannot deliver it into the body in a usable form.
GeroNova will not endorse companies selling products containing largely polymerized RLA, with poor dissolution properties and low bioavailability, even at discount prices. If you are using a cheap RLA product, with no mention of the polymer content, or if the companies that produce finished tablets and capsules deny the reality of RLA instability, you may be better off to use or take high quality racemic ALA .
Which, by the way, you are doing! (This was in response to the following)
I usually stick with the racemic version of ala because it seems to make me more hypoglycemic and refills glycogen better than does rala for me, even though on paper it should be opposite.
According to Asta Medica, [6,348,490] RLA tablets were characterized by poor disintegration and dissolution profiles, such that RLA was only 9% dissolved in simulated gastric juice after 30 minutes, whereas racemic ALA was 100 % dissolved after 30 minutes. This means that unless the product has been stabilized and is not polymeric, use racemic ALA .
This also suggests the possibility that the insoluble polymer may accumulate in the GI tract over time, since it is essentially insoluble in water or gastric juice. In the lab it is insoluble in strong acids or any of the common organic solvents (even powerful solvents like DMF and DMSO). Strong base will depolymerize it in time and under forceful conditions but requires much more heat and alkalinity than what is found in the intestinal environment. This could be significant for diabetics, Alzheimer's sufferers, MS patients or the HIV infected who take high daily doses (up to 6 gm per day).
Many people consider Bruce Ames the guru of lipoic acid. (He patented the combo of ALCAR and ALA/RLA and)
The revolutionary research (and subsequent media coverage) of Bruce Ames, Lester Packer and Tory Hagen has been largely responsible for the consumer demand for lipoic acid products in the US (which consumes most of the lipoic acid in the world).
Ame's group has shown the role of mitochondrial decay in age-related disease and how it can be reversed with ALC, lipoic acid, and the "spin trap", PBN. Dr Ames has recently filed a patent called:
“Stability of Lipoic Acid” (US Application 20040044046, March 4, 2004)
 LA suffers from certain disadvantages, however. In particular, the natural form R-LA is unstable above 40° C., so it can degrade under some warehousing conditions. Also LA is hygroscopic. What is needed is stabilization of this natural form of LA with a natural salt.
The natural salt in the patent is a salt pair formed by reacting RLA with nicotinamide. This was an example of a fortuitous discovery that may ultimately be commercially successful. As an incidental note, the salt was actually made by a famous local organic chemist and friend of Ames who found it in a vial on a lab shelf 17 months after he synthesized it. He decided to re-test it utilizing IR spectrophotometry and realized that the spectral data was identical to the original, indicating that it was stable.
He then reported his finding to Ames .
According to Juvenon (the patent holder of Ames ’ ALC / ALA cocktail) RLA is not used in their formulas, even though the research was done with the R-form because,
“The R form can be purified from the S form. However, the major problem with this compound, when separated from the S form, is stability. The compound deteriorates relatively rapidly at room temperature. The R form is also significantly more expensive. Work is ongoing to solve the stability problem, and when we feel this is complete to our satisfaction, Juvenon will offer a product containing only the R form.
Here are a few more patents mentioning the polymer problem, innovative solutions, the problems of RLA tablet dissolution, poor bioavailability and the enhanced bioavailability of the salt forms.
Alpha-Lipoic Acid with Novel Modification. (US Patent 5,994,393 Nov 30, 1999 )
“The melting range of the pure enantiomers of thioctic acid (47-49° C) is lower compared to the racemic compound (58-61° C). In the production of solid galenic formulations, the use of pressure on the material is indispensable so that on the one hand a heating and on the other hand a melting of thioctic acid takes place. Concentrated solutions of thioctic acid or its melts polymerize immediately and can no longer be converted into a crystalline form by cooling.”
According to "Method of Producing Flowable R, S-Thioctic Acid, R,S-Thioctic Acid and its Use" (US Patent 5,705,192 Jan 6, 1998 )
…it is possible to make a thioctic acid form available which does not adhere to the pressing tool or exhibit a tendency to form fissures on the tablet, even when tablets with 600mg or more active substance content are prepared.”
According to “Dosage Forms containing thioctic acid or solid salts of thioctic acid with improved release and bioavailability” ( US Patent 6,348,490)
“In contrast with dosage forms prepared from free R-thioctic acid, the dosage forms prepared from salts of R-Thioctic acid have not only the advantage of better release and bioavailability of the active ingredient, but are moreover more easily produced.”
According to the article "Disulfide Polymers of DL-alpha-lipoic Acid" by Thomas and Reed (JACS 78, 6148 (1956)
“The ease with which ALA polymerizes has been noted. The several lipoic acids described in this paper polymerized to various extents during their distillation and recrystallisation. The liquid esters of lipoic acid polymerized with extreme ease”.
The previous note referred to by Reed was reported by his group at the University of Texas in JACS 77, 416 (1955) and about the same time by a team from Merck Sharp & Dohme [JACS 78, 5079 (1956)]. The polymer problem was recognized from the very first laboratory preparations of lipoic acid because the oxidation of DHLA produced not only the disulfide (ALA ) but also an insoluble chain of oligomeric disulfides.
This polymer is the same polymer found in commercial dosage forms of RLA.
It is important to realize that Reed was working with the racemic ALA, i.e. DL-Lipoic acid” and not RLA, which was not yet available in any sizeable quantities. (In 1957 he isolated RLA by classical resolution in 60% yield).
The optical isomers were first made by Merck in 1955 [JACS 77, 416 (1955)] and later by DuPont [JACS 79, 6483 (1957)].
HEAT AND POLYMER FORMATION
Extreme heat is NOT a necessary requisite for polymer formation, as indicated in the above patents and the citation by Reed. Reed heated the product to 65°C because he knew heat would accelerate the polymerization, but in the case of RLA this occurs instantly at 46°C.
A key point that needs recognition is that even the so called “stable” ALA used extensively in the nutritional supplement industry is still prone to polymerization, and is also hygroscopic, although more heat stable than RLA. Anyone that has worked with this material knows how sticky it gets during its conversion into solid dosage forms. The pure enantiomers are even more unstable since they melt at a lower temperature, lose crystallinity and form a non-recrystallizable glass. Technically, a “glass” is an amorphous substance, i.e. without crystallinity. The isolation of crystalline R-Lipoic is a formidable problem during commercial production, and one of the key factors influencing the cost of the product. Even processed under high vacuum and below room temperature, it is very common to get a pot of “rubber” rather than “golden crystals”.
MELTING POINT TEST, POLYMERIC STRUCTURE
The best methods to prove the structure of the polymer conclusively is by x-ray diffraction, and by UV spectrophotometry which has a spectral profile distinct from the crystalline forms [JACS 78, 5079 (1956)].
The heat of friction during encapsulation and the compression of tableting are sufficient to initiate this process. Polymerization is also catalyzed by light and acid, and de-polymerized by strong base and more heat. The rate of polymerization is slower in acid than by light or heat.
"In the solid state ALA appears to be stable. In the cases noted above the instability of the compound was apparent only when it was in a dissolved or fluid state. It appears therefore that once the crystal lattice of ALA is broken the molecules tend to polymerize under certain conditions. These conditions must provide for the opening the 1,2 dithiolane ring of lipoic acid. The necessary energy for opening or at least loosening the disulfide bond comes from the absorption of light in the visible or on the edge of the visible spectrum. Once these bonds are activated, the molecules in a non rigid state tend to polymerize." [JACS 78, 5079 (1956)]
While ALA is more stable in the solid form than in solution, the hygroscopic nature of ALA initiates polymerization. Even a partially polymerized product can pose significant problems in the manufacturing and stability of a dosage form. The polymer reduces dintegration, dissolution of tablets or capsules, GI absorption and lowers the bioavailability, since it is so poorly absorbed from the GI tract.
We placed RLA capsules of known RLA and Polymer contents in simulated gastric juice in a dissolution tester, and tested concentrations of active RLA over time by HPLC. In five runs, the amount of detectable RLA was significantly less than the assay result of the same dosage forms, suggesting that the polymer is trapping active material.
The results of our experiment supported our intuitive hunches, i.e. even if the entire dosage form has not become polymeric, the stickiness of the material will limit the dissolution, absorption and bioavailability of RLA.
The fact that the product has not been completely polymerized, and that there is some material still available to enter the circulation can account for the positive (albeit limited) results obtained with the preparations.
You must be exhausted by now. I'm just getting going...
Another issue is that, even without the polymerization issue, there is the fact of the solubility factor of weak acids. R-lipoic is a weak acid [pKa=4.7]) and does not have good solubility. Try putting some RLA powder..open a cap if you have one) in a glass of water or vinegar (or anything, for that matter) and see what happens. This is happening in your stomach. It is a well established principle in pharmacology that salts of weak acids generally have much higher aqueous solubility than the free acid.
Therefore, if the material can be taken as a salt (K-RALA® is the potassium salt of R-lipoic acid), the solubility can be increased and there is improved dissolution. See a First Course in Pharmacokinetics and Biopharmaceutics. David Bourne, Ph.D. Drug dissolution.
If you haven't heard enough by now, there is one more piece of info I would like to add.
Our newest product, RALA-Gel, is what I believe, is the best we have, and even better than K-RALA, although there is nothing wrong with the powder, or liquid K-RALA (I have always liked the liquid best and you can "feel" it within 10 minutes). We just came out with RALA-Gel a few months ago, and it is superior to K-RALA (powder) in terms of bioavailability, according to our plasma studies. The key to success with any supplement, be it for bodybuilding or general health or rejuvenation, is the amount of material that is actually being absorbed, and, how long it is sustained in the plasma.
Personally, RALA-gel, K-RALA-10 (and other happy guinea pigs at GeroNova) is the only from of RLA I will take now (and, of course the Mito-GOLD product, but that is more $, with the delta tocotrienol and R-DHLA). It is the product we are selling to the doctors and the response has been overwhelmingly positive. I am not surprised, as the effects are noticeable.
We are also selling the bulk liquid-filled caps for private label, so stay tuned for plenty of those on the market in this year. I don't see how anyone (and even if I wasn't in the business) would want to take regular RLA caps after knowing all this.
I will quote from our site again to give you the info:
RALA-Gel® is dissolved in medium chain triglycerides (MCT) to enhance G.I. absorption and increase plasma levels of RLA.
MCT contain 8-10 carbon fatty acids esterified with glycerin, and function as a carrier of RLA into the hepatic (liver) portal system.
The portal system is a specialized portion of the systemic circulatory system. It is unique in that blood from the spleen, stomach, pancreas, and intestine first passes through the liver before it moves on to the heart.
Prior to the MCT delivery system, the most bio-available forms of RLA were as salts, (K-RALA™) or aqueous solutions of the salts (K-RALA-10™).
Numerous factors affect G.I. absorption. Racemic-ALA has poor solubility in stomach acid and RLA polymerizes on contact in low pH environments. The MCT delivery system allows most of the RLA to bypass the harsh environment and be delivered into the intestines-liver (entero-hepatic system) and can appear in the circulation within several minutes of consumption .
MCT also compete with RLA for entero-hepatic transport systems, allowing higher levels of RLA to reach the plasma and tissues. (See Mito-GOLD™ more details on MCT).
GeroNova recently performed dissolution and bioavailability studies utilizing HPLC analysis of the plasma.
The absorption of commercial RLA powder, capsules and tablets is less than 1%, due to extensive polymerization during manufacturing and in the stomach.
Stabilized against polymerization through a proprietary process, RALA-Gel® contains no excipients, chemical surficants or detergents that compromise gut integrity to achieve their result.
RALA-Gel®, GeroNova's new liquid-filled, Bio-Enhanced™ oil-based 100mg R-lipoic acid capsules with D-Biotin are now available in bottles of 60 and 120 at our online store.
Although it costs more than some of the RLA caps out there, what's the point of paying anything for something that is not having the effect that it claims to?
Whew! Now I'm exhausted.
Please feel free to post this info on your forum. (Also please try, if you don't post all of it, which I don't expect you to, who wants to read for an hour? to keep things in context)
If you would like to try a bottle of RALA-Gel, I will be happy to offer you a money back guarantee if you are not satisfied.
Please let me know if you have any questions. (and what you think of all this)