Raising the CoQ10 Quotient

For a difficult compound to understand, coenzyme Q10 (CoQ10) has overcome its confusing nature, at least for consumers who rated it as their fifth most popular supplement in a November 2011 Consumerlab.com survey. The results of the 10,000-respondent survey showed about half of those polled took CoQ10, which reflected a continuing CoQ10 supplement trend, as Consumerlab.com noted it was also the fifth top-selling supplement in 2010, with 53 percent of supplement users adding it to their daily routine.

CoQ10 ingredient suppliers think its popularity is a no brainer. "There is a substantial amount of quality research on CoQ10, and consumer awareness is strong," said Rodger Rohde, president, Triarco Industries. "Whats more, the research shows CoQ10s benefits have application in a number of robust markets, including cardiovascular health, cognitive health and anti-aging."

Indeed, the Consumerlab.com survey found different demographics like CoQ10 for different health benefits. Men said they favored supplements such as CoQ10 that promise to boost energy, slow aging and lower cholesterol, and older supplement users were more likely to take CoQ10 than younger users. CoQ10 was also preferred by those who take multiple supplements; it was taken by 76.2 percent of those polled who take more than 10 supplements per day, but only by 9.8 percent of people using one supplement per day.

Alon Levy Nahoum, CEO of Herbamed, said CoQ10 has a global market of close to US$1 billion. He noted the thousands of studies performed on CoQ10 have concentrated on its benefits to heart health, but said it has recently branched out into sports performance and skin protection. "These indications are very popular, especially the use of CoQ10 for beauty-from-within and even topical skin care formulations," he said.

It offers proven health benefits, but can be difficult to explain to consumers. CoQ10 is an essential nutrient used in the production of mitochondrial energy. It comes in three main forms: ubiquinone, semiquinone and ubiquinol. Ubiquinone is the fully oxidized form (CoQ10), semiquinone is the partially reduced, free radical form (CoQ10H), and ubiquinol is the reduced form (CoQ10H2). Ubiquinone is synthesized by the body, stored in the outer membrane of the mitochondria and used in the synthesis of 95 percent of the energy (adenosine triphosphate [ATP]) the body makes. Semiquinone supports the cell by focusing on membrane characteristics. Ubiquinol is an antioxidant that protects against oxidation and helps to produce other antioxidants. Within the cells mitochondria, CoQ10 exists in a 50/50 state between oxidized and reduced form. Semiquinone is only in cell membranes.

All three form a redox (reduction-oxidation) cycle and can be converted from one form to the other in cells, lymph or blood when necessary. For example, the lymph system and blood need ubiquinol for antioxidant protection, not for energy; whereas mitochondria need ubiquinone for energy production, not protection from oxidative stress. Depending on where it is in the body, the molecule can change to fit the bodys needs. CoQ10 is in every cell, but is used most in organs that demand the highest amount of energy, such as the heart, brain and the immune system.¹

"CoQ10 has been shown to play a role in energy production, cardiovascular health, cognitive function and in keeping our cells young, healthy and happy," said Mark Anderson, director of research and development, Triarco Industries. "Research is revealing even more specific uses for CoQ10; its been shown to support healthy vision and benefit those struggling with migraines and fertility issues. In addition to its role in healthy cardiovascular function, CoQ10 may also benefit people taking certain cardiovascular medications, which can interfere with the bodys own CoQ10 production and lead to side effects such as muscle pain and weakness."

However, studies have shown that those with diseases, such as metabolic syndrome and heart disease and those who are older produce less CoQ10 and have a harder time converting between the various forms compared to their younger, healthier counterparts.² Thus, supplementation may be the answer to keeping CoQ10 levels strong.

CoQ10 supplementation has shown to help the heart in a number of studies. In an Israeli, double blind, placebo-controlled, randomized study, the administration of 60 mg/d of CoQ10 (as Ultrasome from Herbamed) to heart transplant candidates who continued their regular medication led to a significant improvement in functional status, clinical symptoms and quality of life after three months.³ The study group showed significant improvement in the six-minute walking test, and a decrease in New York Heart Association (NYHA) classification and fatigue.

Nahoum added Herbamed has performed numerous scientific studies on Ultrasome. "In humans, Ultrasome was found to improve recovery from hip fracture and chronic bed sores, and improve quality of life in patients suffering end-stage heart failure," he said.⁴

CoQ10 supplementation is also recommended for those who take statins to treat high cholesterol. CoQ10 shares the biosynthetic pathway with cholesterol, and statins are designed to block that pathway in the body. A 2004 study from Columbia University noted even brief exposure to the statin atorvastatin causes a marked decrease in blood CoQ10 concentration, and this inhibition of CoQ10 synthesis could explain the most commonly reported adverse effects of statins, especially exercise intolerance, muscle pain and muscle deterioration.⁵

Research has also found CoQ10 can reduce cholesterol and thus perhaps reduce the need for statin use. In March 2011, German researchers found ubiquinol (obtained from Kaneka) reduced low-density lipoprotein (LDL) cholesterol in healthy men after two weeks of supplementation.⁶

Supplementing with CoQ10 has also been shown to reduce hypertension⁷ and coronary atherosclerosis.⁸

The brain, like the heart, requires a lot of energy, and CoQ10 provides benefits in this part of the body as well. A Cornell University, New York, study found neuroprotection against the MPTP model of Parkinson's disease using both ubiquinone (from Tishcon) and ubiquinol (from Kaneka).⁹ The researchers found ubiquinol produced larger increases in plasma concentrations of CoQ.

The nutrient further helps the head by reducing migraine frequency and disability,¹⁰ as well as tinnitus (ringing in the ears).¹¹

CoQ10 also provides energy during sports performance. It improved swimming endurance and had an anti-fatigue effect in mice in a 2010 study.¹² And a 2010 review reported studies have confirmed CoQ10s effect in reducing fatigue and exercise-related damage, and improving physical performance.¹³

CoQ10 studies have also shown a skin health benefit. German researchers reported topical application of CoQ10 rapidly improved skins mitochondrial function in vivo,¹⁴ and a 1-percent CoQ10 cream used for five months reduced wrinkles, as observed by a dermatologist in a Japanese study.¹⁵

Different Forms and Absorption Issues

Many argue the type of CoQ10 that one takes has health consequences; some prefer ubiquinol over ubiquinone because they feel it is absorbed into the body better, but others contend ubiquinol is too unstable to process into a product effectively.

Although the molecular difference between ubiquinone (regular CoQ10) and ubiquinol (reduced CoQ10) is extremely slight, it appears that supplementing with ubiquinol can make a difference for certain groups of people," Nomura said. "Ubiquinone has been around for many years, and it has been proven to be effective for a wide variety of people at all age groups." However, he noted ubiquinone isnt exactly the "active" form because it needs to be converted to ubiquinol to be used as an antioxidant. "According to research from Kaneka [a ubiquinol ingredient supplier], ubiquinol is best suited for older people or those with specific health issues, such as diabetes or liver conditions, and may see similar results to ubiquinone, but at lower dosages."

However, Anderson pointed out ubiquinone, the oxidized form of CoQ10, is more stable and easier to formulate and store. "Its the form that has been most studied," he said. "It is difficult to keep ubiquinol stable outside of the body, therefore many manufacturers prefer ubiquinone."

Whatever the form, CoQ10 obtained in the diet needs to be properly absorbed before it can be used by the body. An April 2001 study found while supplementation with CoQ10 has potential therapeutic value in several health areas, clinical efficacy is limited due to challenges with bioavailability and absorption.¹⁶ The study, conducted by two researchers from BioActives LLC, noted more than 200 clinical trials have investigated the use of CoQ10 as a drug or dietary supplement. However, the lipophilic nature and large molecular weight of CoQ10 have adversely impacted its bioavailability. The team noted recent clinical trials on CoQ10 have looked at new formulations that may improve bioavailability.

According to William Judy, et al, in the article "Coenzyme Q10 Facts or Fabrications," CoQ10 crystals cannot be absorbed, and they must be dissolved to single molecules before absorption. Because CoQ10 crystals have a melting point 10 degrees centigrade above body temperature, they must be added to a lipid carrier molecule to facilitate absorption.

Dan Lifton, vice president of business development, Maypro Industries LLC, said CoQ10 is poorly absorbed for two primary reasons: (1) "CoQ10 molecules occur naturally in crystals, bound to each other in a form too large for cells to absorb;" and (2) "CoQ10 is also fat soluble and is relatively difficult to transport through the digestive system as compared to molecules that are water soluble." He added consumers are becoming increasingly aware of the limited bioavailability of CoQ10. "We see a very bright future for value-added forms of CoQ10 that deliver better absorption and other benefits."

Lifton said Maypro, in partnership with Bioactives LLC, markets MicroActive® CoQ10 (U.S. Patent No. 7,030,102), a water-dispersible form of CoQ10 that a study showed delivered sustained release over 24 hours and delivered three-times greater bioavailability in all of the study participants compared to crystalline and solubilized CoQ10.¹⁷ Plus, he said MicroActive CoQ10 is a stable powder that can be used in hard shell capsules and tablets, and is water dispersible so it can be used in effervescent tablets, stick packs and beverages as well.

Maypro also addressed CoQ10 absorption with its BioQ10 SA, manufactured by Mitsubishi Gas Chemical Co. BioQ10 SA combines CoQ10 with soy protein to increase bioavailability. "BioQ10 SA was designed as a viable alternative to ubiquinol based on supporting research," Lifton said.

Triarcos Aqua 10® is a patented, water-dispersible CoQ10 powder that, according to Anderson, takes on two of CoQ10s biggest challenges: absorption and stability. In a pre-clinical, unpublished study, rats that received 1 ml/100 g of body weight of Aqua 10 (the equivalent human would be 180 mg or 2.57 mg/kg) showed approximately 50-percent greater absorption compared to rats that received an equivalent dose of regular CoQ10. Additionally, Aqua 10 appeared to absorb more steadily and predictably when compared to regular CoQ10, which exhibited some random fluctuation.

Herbamed's Ultrasome also increases CoQ10 bioavailability, according to Nahoum. Like liposome, a drug-delivery technology, with Ultrasome, CoQ10 is packaged into a nano-droplet, solubilized in oil, then surrounded by a phospholipid shell. "This shell protects the CoQ10 until it is delivered to the intestinal wall, where it is delivered more effectively into the blood stream."

Nomura noted CoQ10 bioavailability can be increased using a softgel. "Since CoQ10 is a fat-soluble substance, it has shown better absorption when put into a lipid-based environment," he said. Soft Gel Technologies' CoQsol-CF formula combines CoQ10 with mixed carotenoids and mixed tocopherols, in a base of rice bran oil, which work synergistically to optimize absorption, according to Nomura.

 In a 2006 study conducted by KGK Synergize, London, Ontario, CoQsol-CF (crystal free, from Soft Gel Technologies) at a dose of 100 mg/d resulted in significantly increased plasma CoQ10 levels by the end of a 28-day treatment period compared with supplementation with standard powdered CoQ10 capsules.18 The rate of absorption at five hours following the final dose of CoQ10 was 5.5 times higher for CoQsol-CF than for the powdered CoQ10. The CoQsol-CF-supplemented group also showed increased antioxidant status and anti-atherosclerotic potential based on treatment-induced changes in the levels of selected markers, including serum levels of glutathione, C-reactive protein (CRP) and total antioxidants.

A 2009 study also conducted by KGK Synergize reported a single, 100-mg dose of reduced CoQH-CF, a softgel capsule from Soft Gel Technologies that contains Kaneka QH, was more bioavailable than a commercial formulation of CoQ10 in individuals older than 60 years.¹⁹ The area under the curve (AUC) of reduced and total CoQ10 was significantly higher in subjects administered CoQH-CF resulting in a 430-percent increase in plasma after 72 hours. Oxidized CoQ10 in plasma was higher in subjects receiving CoQH-CF compared to subjects receiving the other CoQ10, resulting in a 329-percent increase in plasma after 72 hours.

Delivery

While Nomura noted CoQ10 comes in a variety of delivery forms, such as capsules, tablets, droppers, beverages and skin creams, he said, "The most popular format is still softgels, both for ease of use and dosage concentration."

Rohde said dietary supplements in the form of capsules and tablets are still the most popular delivery forms for CoQ10. "However, CoQ10 is gaining real traction in cosmeceuticals and topical skin care formulas, especially as consumers are demanding more natural ingredients in their everyday care products."

Nahoum noted new technologies have allowed CoQ10 to be incorporated easily and with maximum stability into functional foods." Herbamed is successfully marketing nutrition bars with our Ultrasome CoQ10 ingredient in Israel," he said. "A launch for the United States is planned soon, under the NutraVida brand. The SportsAdvantage nutrition bar contains 60 mg of CoQ10 and 400 mg of L-carnitine for improved energy metabolism and sports performance. This product is unique in that it combines two ingredients that play an important role in energy metabolism and uses them in efficacious dosages."

Scott Steinford, president, ZMC-USA, pointed to Source Ones Vesi-Sorb® and Viruns Coenzyme Clear® as evidence of CoQ10 showing up in foods and beverages, and said the Derma Q-Gel® Cream product produced by Tishcon is a popular skin care cream.

If Americans are like the Japanese, Lifton predicted CoQ10 will be increasingly added into beverages in the near future.

Manufacturing

In order for all those new products with CoQ10 to hit the market, it's up to product manufacturers to hit the lab, making CoQ10 offerings that deliver on their promises. It's not an easy task.

"CoQ10 is fat soluble and can penetrate the tissues in the body, where it is needed," Anderson explained. "While this may be good for the body, it can make manufacturing a bit tricky. CoQ10 is notoriously difficult to work with because of its lipophilic nature and large molecular weight. In the past, manufacturers have struggled with CoQ10s poor solubility, often leading to a CoQ10 that falls out of solution. Options like oil carriers and softgels can help, but they limit manufacturer options in terms format, and have their own issues with absorption within the body."

Lifton said CoQ10 has to be handled carefully and protected from heat and light. "Ubiquinol is extremely unstable and on exposure to air, is rapidly converted to ubiquinone." He added MicroActive CoQ10 uses cyclodextrin to stabilize CoQ10 in heat and light.

Steinford noted manufacturers and consumers can be assured of the quality of Co10 with third-party seals. For instance, he said ZMC has an ingredient verification from the USP Ingredient Verification program. "This important third-party verification supports the quality of the product, but more importantly, the quality of the process used to make the product," he said.

With so many consumers taking CoQ10 on a daily basis to meet their energy, heart or anti-aging needs, quality CoQ10 that is bioavailable and convenient for consumers to consumeor apply in the case of cosemeceuticalsis a must in this market. Manufacturers that meet this need will certainly benefit if and when CoQ10 becomes the fourth or third most popular ingredient.

CoQ10 Patent Struggle

On March 22, 2011, the U.S. Patent and Trademark Office issued patent No. 7,910,340 to Kaneka Corp. for a process of producing ubiquinol and ubiquinone on an industrial scale. Immediately following issuance of the patent, Kaneka Corp., the Osaka, Japan-based parent of Kaneka Nutrients, filed a patent infringement lawsuit in U.S. District Court, Central District of California, Los Angeles, accusing Zhejiang Medicine Co. Ltd. (ZMC), ZMC-USA LLC, Xiamen Kingdomway Group Co., Pacific Rainbow International Inc., Mitsubishi Gas Chemical Co. Inc., Maypro Industries Inc. and ShenZhou Biology & Technology Co. Ltd. of infringing on the new patent.

Also on March 22, ZMC-USA LLC and Zhejiang Medicine Co., Hangzhou, China, filed two complaints for declaratory judgment in U.S. District Court, Southern District of Texas, and U.S. District Court, District of Columbia, against Kaneka Corp. According to ZMC, the 340 patent, offers no improvement over existing technology and is not economically feasible on a commercial scale." ZMCs complaint sought a declaration from the court that the claims of the 340 patent are not infringed by ZMC and are invalid and unenforceable.

In June 2011, Kaneka Corp. stepped up its actions by filing a complaint (No. 337-TA-2822) against the same companies it targeted before with the U.S. International Trade Commission (USITC) alleging unfair trade practices by importing and selling CoQ10 products related to the patent at issue.

Kaneka requested the USITC investigate the alleged use of the 340 patent by the defendants, issue an exclusion order banning the importation of infringing products, and halt marketing, advertising and warehousing of inventory for distribution and use in the United States. In a press statement, Kaneka also noted it was investigating the use of the allegedly infringing CoQ10 ingredients in a variety of consumer products.

At this time, Adli Law Group sent letters on behalf of Kaneka to several natural product companies advising the companies to take all necessary measures" to avoid the use of CoQ10 ingredients that may be infringing the 340 patent.

In response, ZMC released a statement on June 24 addressing both the USITC complaint and the Adli Law Group letters. ZMC continued to dispute Kanekas allegations related to patent infringement, noting it does not infringe the 340 claims and plans to defend the lawsuits to prevent any actions from being taken against its customers.

Then, in August 2011, Kaneka voluntarily dismissed the lawsuit, and the claims were transferred to U.S. District Court, Southern District of Texas, Houston. After a conference on Aug. 22, the judge ordered Kaneka to withdraw the letters Adli sent to the industry; the judge said he considered them deceptive."

Kaneka was ordered to appear before the court on Aug. 26; however, on Aug. 25, Kaneka filed notice dismissing all causes of action in the complaint against ZMC-USA and Zhejiang Medicine Co.

In a statement issued Aug. 31, Kaneka stated the letters "Constitute a valid exercise of its patent rights under controlling law;" however, instead of challenging the Aug. 22 order, it was more expedient to dismiss the district court lawsuit and focus on the USITC complaint. The company stated: "Kaneka has not relinquished any substantive rights by dismissing its lawsuit against ZMC; its claims against ZMC remain pending in the ITC investigation and in the other action filed by ZMC [in the Houston court]. Kaneka is confident of vindicating its patent rights in both actions."

"ZMC is proud to have won a non-infringement decision in Europe on the first patent complaint filed by Kaneka in 2010," said Scott Steinford, president, ZMC-USA. "ZMC and ZMC-USA are equally confident the United States judges will also find ZMC to not infringe the Kaneka patent filed in the United States in 2011."

Steinford said the biggest effect of the patent issues is on the price of CoQ10. "The cost of the litigation has been enormous," he said.

However, Alon Levy Nahoum, CEO of Herbamed, said the patent battle has caused only a little bump in the market. He added Herbamed's Ultrasome CoQ10 holds its own U.S. patents, so the company has been insulated from this issue.

Dan Lifton, vice president of business development, Maypro Industries LLC, also said it has had little impact on the market. "A small number of customers have been scared into switching their source of supply, but most companies have continued to purchase from their existing manufacturers."

This current CoQ10 patent battle may spur manufacturers to reexamine the contracts they have with suppliers to ensure that if they are sued, the supplier will cover indemnify costs and pay the lawyer fees to defend a product in court. With the intellectual property (IP) litigation that's popping up surround CoQ10 and other ingredients, this may be a crucial contract clause that helps keep a manufacturer in business.

References listed on the next page.

References for Raising the CoQ10 Quotient " by Sandy Almendarez

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18.   Evans, M. et al A randomized, double-blind trial on the bioavailability of two CoQ10 formulations Journal of Functional Foods Volume 1, Issue 1, January 2009, Pages 6573

19.   Miles L et al. Ubiquinol: a potential biomarker for tissue energy requirements and oxidative stress." Clin Chim Acta. 2005 Oct;360(1-2):87-96.