RO134616A0 - Innovative formula with carnosine and pyrroloquinoline quinone for oral administration with the role of neutralizing free radicals in the body - food supplement - Google Patents

Abstract

The invention relates to a composition for oral administration with the role of neutralizing free radicals in the body. According to the invention, the composition comprises : 4 parts L-Carnosine, 0.13 parts Pyrroloquinoline Quinone, 11 parts L-Carnitine, 4 parts Vitamin C/ascorbic acid, 7.50 parts green tea leaf extract, 4 parts turmeric extract, 3.28 parts α lipoic acid, 1.5 parts astaxanthin, 1.25 parts Polygonum Cuspidatum root extract and maritime pine bark extract, respectively, 1 part coenzyme Q10, 0.45 parts Vitamin E , 0.16 parts zinc oxide, 0.04 parts copper bisglycenate, 0.02 parts vitamin B2 and 0.88 parts excipients for formulation as powder, capsules or tablets, the parts being expressed by mass.

Description

Description

The present invention relates to a product - AGE MANAGEMENT AOX - based on an original combination of active ingredients having as new active principles: L-carnosine and pyrroloquinone, which combines in a single formula a series of compounds known for their antioxidant effect and coenzyme. Q10, biocurcumin (turmeric), resveratrol (Polygonum Cuspidatum), alpha lipoic acid, vitamin C (ascorbic acid), pine extract, carnitine, astaxanthin, green tea polyphenols, vitamin E, Zn as zinc oxide, copper under form of copper bisgiicinate, vitamin B ₂ (riboflavin), intended for administration to adults, with antioxidant role.

There are many products on the market based on curcumin, CoQ10, resveratrol, vitamins, pycnogenol, green tea, alpha lipoic acid, for the first time we made a formula based on carnosine and Pyrroloquinoline Quinone for oral administration, in preventing biochemical changes related to radical accumulation free in the body.

AGE MANAGEMENT AOX refers to a composition for capsules or tablets characterized in that it comprises 0.88 parts (m / m) excipients of the formulation (magnesium stearate and colloidal silicon dioxide) - 2.19% m / m and principles original active LCarnosine 4 parts - 9.93% m / m, Pyrroloquinoline Quinone (PQQ) 0.13 parts - 0.31% m / m, L-Carnitine 11 parts (m / m) - 27.30% m / m , vitamin C / ascorbic acid 40 parts - 9.93% m / m, green tea leaf extract (Camellia sinensis) - standardized to 50% polyphenols 7.50 parts - 18.61% m / m of which 3.75 parts polyphenols (epigallocatechinage) 9.3% m / m, turmeric extract (Curcuma longa) 4 parts - 9.93% m / m, alpha lipoic acid 3.28 parts - 8.13% m / m, astaxanthin 1, 5 parts - 3.72% m / m, Polygonum Cuspidatum root extract 1.25 parts - 3.10% m / m with 50% resveratrol (0.625 parts - 1.6% m / m), bark extract Pinmaritim (Pinus pinaster) 1.25 parts - 3.10% m / m standardized in 99% pycnogenol (1.24 parts - 3.07%), coenzyme Q10 / ubiquinone 1 (o) part - 2.48% m / m, dry - vitamin E 50% CWS / S (solid form, deposited on starch substrate) 0.3 parts 0.74% m / m - with 0.15 parts vitamin E / tocopherol - 0.37% m / m, zinc oxide 0.16 parts - 0.39% m / m (Zinc 12.5% VNR *), copper bisgiicinate 0.04 parts - 0.11% m / m (Copper 12.50% VNR *), vitamin B2 / riboflavin 0.02 parts - 0.04% m / m (12.50% VNR *); * VNR - percentage of the Nutritional Reference Values according to Regulation 1169/2011.

and 2020 00173

01/04/2020

The action of the AGE MANAGEMENT AOX product is mainly determined by the combination of active principles in its composition.

The combination of the 15 bioactive principles in plants (turmeric, resveratrol, pycnogenol, astaxanthin), vitamins (vitamin B2, C, E) and minerals (Cu, Zn), amino acids of which two molecules for the first time - carnosine and PQQ - determine an antioxidant synergistic effect , anti-aging and neutralizing free radicals produced continuously in the human body, regulates cholesterol levels, protects the nervous system, protects eyesight, strengthens the immune system, with swarm in the prevention of degenerative diseases and cardiovascular diseases.

The invention relates to the preparation of a medicament or dietary supplement for the prevention of oxidative and nitroxative stress disorders, especially in cases where lipid peroxidation is an important component of biochemical alterations (aging, obesity, chemotherapy, dyslipidemia, chronic inflammatory status).

Bibliographical data

Antioxidants are molecules that inhibit the oxidation of other molecules and protect the body from the effects of free radicals.

Free radicals, produced either by normal cellular metabolism or as an effect of pollution and exposure to other external factors, are responsible for premature aging of the body and play a role in cardiovascular or degenerative diseases (cataracts, Alzheimer's disease, cancer). aging is the primary risk factor in Alzheimer's disease, as we age, after middle age (45-65 years), the extracellular RedOx environment changes to an "oxidized" status. Decreases mitochondrial RedOx buffer protection, increases the generation (and concentration) of reactive oxygen species (ORS) related to mitochondrial dysfunction. Oxidative status promotes neurodegeneration; ensuring the generation of NADH at this level would be a more effective therapeutic target before GSH and ORS generation.

Role in the body

Antioxidants Prevent the aging process of cells in the body, due to the action against free radicals, antioxidants are also allies of beauty, anti-aging products have various antioxidants! on the list of ingredients: vitamin C, vitamin E, green tea, grape seed extract, coenzyme Q10, SOD, etc.

The benefits of antioxidants

Antioxidants fight free radicals, reduce oxidative stress and slow down the aging process: other benefits for the body:

® regulates cholesterol levels * protects the nervous system * protects vision of 2020 00173

01/04/2020 ® strengthens the immune system * prevents degenerative diseases and cardiovascular diseases * helps in the treatment of cancer

Figure 1 link between oxy-inflammation-aging and biochemical fragility ante-disease and disease (preclinical and clinical fraiity). CVD, cardiovascular disease [Liguori & al. 2018]

Figure 2 Involvement of reactive oxygen species in various forms of cancer - endometrial cancer (after 2020 00173

01/04/2020

The ingredients that make up the product have the following benefits:

Carnosine

Carnosine or beta-alanyl-histidine is a small endogenous dipeptide containing two amino acids, beta-alanine and histidine first isolated in 1900 by Gulewitsch.

Figure 3 Carnosine-befa-alanyl-L-histidine (IUPAC (2S) -2 - [(3-Amino-1oxopropyl) amino] -3- (3H-imidazol-4-yl) propanoic acid

It is found in relatively high concentrations in many tissues of the body, especially in skeletal muscle, heart muscle and brain. The remarkable thing is that these two amino acids work much more efficiently linked than independently. While still combined, carnosine is responsible for a number of free radical detoxification activities especially produced by peroxidation of lipid membranes. Recent studies also reveal that this molecule aro a protective swarm of cell membranes, buffer capacity for protons, the formation of complexes with transition metals and the regulation of macrophage activity; Carnosine has the unique ability to rejuvenate cells in the body - to make old cells younger and to extend their life cycle.

Carnosine has strong and specific antioxidant properties, protects against radiation, improves heart function and promotes recovery from injuries. Recently, the potential of carnitine to selectively and strongly capture alpha and beta aldehydes - degradation products following lipid peroxidation of cell membranes under the attack of aggressors (oxidative and nitro-oxidative stress that generates ROSN - oxidative reagents and nitrogen species) has been demonstrated. inhibits protein-protein and DNA-protein cross-linking in neurodegenerative diseases (Alzheimer's disease) cardiomyocyte alterations in cardiac ischemic disease and in inflammatory diseases, COPD, chronic kidney disease and cancer. Products! Joking terminals (AGEs) are markers of aging processes or degenerative metabolic processes such as diabetes, atherosclerosis, chronic kidney disease, Alzheimer's disease.

and 2020 00173

01/04/2020

Figure 4 The claw process. Formation of pyrimidine derived from methyloxai and imidazolone Glycation often alters the portion of guanidine in the residues of arginine with giioxal (R = H), methyllioxai (R = Me) and 3-deoxyglucosone - which is derived from carbohydrate-rich diets. Modified these proteins contribute to the complications of diabetes

AGEs are formed predominantly from food of animal origin and are formed in addition by cooking food. Carnosine reduces the rate of formation of claw end products. The antioxidant effect of carnosine is attributed to its effect of chelating metal ions in the body, thio SOD activity and the ability to capture free radicals.

Figure 5 Oxidative stress, aging-related diseases and biomarkers (4-HNE, trans-4-hydroxy-2nonenal; 8oxodG, 7,8-dihydro-8-oxo-2 ^! -Deoxyguanosine; 8oxoGuo, 7,8-dihydro-8oxoguanosine ; ADMA, asymmetric dimethyl L-arginine; AGEs, advanced glycation end Products; CKD, chronic kidney disease; CVDs, cardiovascular diseases; F2-lsoPs, F2isoprostanes; MDA, malondialdehyde; MPO, myeloperoxidase; NDs, neurodegenerative diseases; NT, nitrotyrosine; oxLDL, oxidized low-density lipoprotein; PC, carbonyl protein; Prx, peroxyredoxins; P-VASP, phosphorylated vasodilator-stimulated phosphoprotein; Trx, thioredoxin. [Liguori et al. 2018]) to 2020 00173

01/04/2020

126 Camosine is present in human nerve and muscle tissue in concentrations up to 20 mM.

128 Its ability to neutralize toxic aldehydes resulting from metabolic pathways of oxidative degradation of endogenous compounds such as carbohydrates (carbohydrates), 130 unsaturated fatty acids and proteins is also involved in the neutralization of 4-hydroxy -2,3-nonenal (HNE) molecule that forms adducts with endogenous biomacromolecules reacting with cysteine, lysine, 132 histidine in the composition of endogenous proteins generating structural and conformational changes that underlie the alterations in degenerative processes.

Αβ-ollgomers

Acrolein 4-hydroxy-2,3-nor3enal Mayondiaidehyde

Reduced glucose axon transport metabolism

Reduced antioxidant detenses

Reduced ATP production

oxidize your synaptic stress function

134

Figure 6 Redox model in the pathogenesis of Alzheimer's disease. Beta amyloid peptide (Αβ) generated 136 by proteolytic cleavage by secretase of amyloid precursor protein (APP) that is inserted into the cell membrane (neuronal) will induce lipid peroxidation with the formation of 138 lipid oxidation products including 4-HO-2,3 -nonenal - with the most intense biological activity, acrolein - the most reactive species and methyl malon aldehyde - toxic metabolites 140 endogenously generated (20).

and 2020 00173

01/04/2020

Pyrroloquinoline Quinone (PQQ)

It is a natural redox cofactor found in the soil or in food - kiwi fruit, fermented soy with natto, tea, green pepper, parsley or (human) breast milk. Enzymes containing PQQ are called quino-proteins for example glucose dehydrogenase (GDH) also used as a glucose sensor. It was discovered by J G Hauge as the third redox cofactor after nicotinamide (NAD) and flavin in bacteria. Anthony, Zatman identified the redox cofactor PQQ in alcohol dehydrogenase and Saiisbury and Duine identified its molecular structure in 1979.

Figure Ί Chemical structure - Quinoa pyrroloquinoline (ACD / ChemSketch 10.0 & Inkscape)

PQQ pqqh ₂

Figure 8 redox reaction with PQQ substrate

Initially positioned as vitamin B (Kasahara, Nature 2003), a paper published in the National Academy of Sciences identified PQQ as a ‘vitamin’ of longevity but not essential for survival but necessary for long-term health (22) as a vitamin of longevity. Thus, PQQ has recently become a topic of interest among nutritionists and longevity specialists. Nutritional studies have shown that nutritional deficiencies in PQQ in mice and rats manifest in different ways including growth deficits, immune response deficits, poor reproductive performance, and respiratory performance disorders. PQQ activates pathways in the body that can promote cellular energy metabolism. . As a powerful antioxidant, PQQ protects and enhances the functionality of existing mitochondria. - slows down mitochondrial aging.

PQQ also promotes the generation of new myochondria (mitochondrial biogenesis).

and 2020 00173

01/04/2020

- Increased mitochondria = increased energy production, for this reason, is considered an active anti-aging compound.

in the reduced form, the neutralizing activity of free aroxyl radicals is 7.4 times higher than that of vitamin C being the most active antioxidant in the body in its water-soluble form. Studies show that PQQ amplifies mitochondrial functions, induces the regeneration of neurons and nerve cells, maintains neuronal function and fertility (24). In the reduced form the radical neutralization activity. PQQ has a protective role in the activity of the parotid gland, liver, kidney and bone tissue by inhibiting oxidative stress and DNA alteration following exposure to aggressors (25) and PQQ has recently been shown to have an inhibitory effect on osteoclast differentiation in vitro (26) and prevents estrogen deficiency-induced osteoporosis by inhibiting oxidative stress and inhibiting osteocyte senescence (Qinghe Geng, 2019) and prevents knee osteoarthritis in animal models (Qin, 2019) (27)

PQQ does not show toxicity and genotoxicity (28) when administered orally so supplementation with PQQ is a promising way to improve health status during dysmetabolic, inflammatory: or senescence-related processes.

Coenzyme Q10

It is an antioxidant that helps the immune system, nervous system and heart activity and reduces the signs of aging. As we age, the body becomes more difficult to coenzyme Q10, but we can take it from supplements and foods such as fatty fish, chicken and beef, nuts and seeds.

Turmeric biocurcumin extract

Turmeric is a plant that is related to ginger and is actually a genus that includes about 100 species of perennials in the family Zingiberaceae. This plant is native to South Asia and northern Australia, being used mainly in India for over 4000 years, due to its therapeutic salt properties. Turmeric (Curcuma longa) is one of the species of turmeric, being also known as Indian saffron.

Turmeric has long been used in Ayurvedic medicine (traditional Indian medicine), but also in traditional Chinese medicine, due to its many therapeutic properties. The benefits are due to the active substance in turmeric, curcumin, which helps treat inflammation.

* Helps improve memory - several studies of Asian populations have shown that people who ate more curry scored better on cognitive tests than those who did not eat this spice. The researchers correlated this benefit with turmeric, which is one of 2020 00173

01/04/2020 among the main ingredients of this spice mixture, but also from the Asian diet. At the same time, researchers believe that the anti-inflammatory effects of curcumin can protect the brain against degenerative diseases and can prevent Alzheimer's disease.

»Anti-inflammatory and antioxidant role - one of the most important benefits of curcumin is the ability to reduce inflammation by blocking certain enzymes involved in this process. At the same time, its antioxidant effect helps prevent arthritis, asthma or inflammatory bowel disease.

* Improves the detoxification process - due to its antioxidant properties, curcumin helps maintain the body's health and stimulates enzymes that fight free radicals, responsible for damaging cells and DNA;

Resveratrol (Polygonum Cuspidatum)

Resveratrol is naturally found in grapes, strawberries, hazelnuts, red wine, as well as in the roots and branches of Polygonum cuspidatum, a popular plant used for a long time in Asian medicine. The shells of red and black fruit species are rich in resveratrol, a derivative of stilben. Studies have shown that resevratrol has antioxidant properties, reduces the risk of cardiovascular disease, prevents cancer, reduces the plasma effects of triglycerides and cholesterol.

Resveratrol has the following effects:

- hepatic and cardiovascular protector;

- antioxidant;

- anti-aging;

- anti-cellulite;

- increases skin tone and elasticity;

- strengthens the immune system;

- adjuvant in antitumor therapies.

«Due to its antioxidant action, 20 times higher than vitamin C and 50 times higher than vitamin E, resveratrol has increased the lifespan of 60% of the organisms studied in laboratory research.

* Resveratrol inhibits the proliferation of a variety of cancer cells: breast, prostate, stomach, colon, pancreatic and thyroid cancer. In animal studies, inhibition of cell growth involved in breast, esophageal and intestinal cancer by oral resveratrol has been observed.

Alpha lipoic acid

It is one of the most important antioxidants. It is involved in the production of energy at the cellular level, protects cells from the action of free radicals, can be easily transported to the brain, 2020 00173

01/04/2020 but it also has the ability to stimulate the production of other antioxidants! in the body (glutathione, coenzyme Q10).

Lipoic acid (AL) is a fatty acid also known as: α-lipoic acid and alpha lipoic acid (AAL) and thioctic acid, is an organosulfate compound, derived from octanoic acid. Discovered in the 1980s, alpha-lipoic acid was originally classified as a vitamin.

Alpha lipoic acid is found naturally in every cell of the body (it is synthesized by the human body, but in small quantities), involved in the energy metabolism of proteins, carbohydrates and fats, having a great antioxidant action.

Alpha lipoic acid protects the structure of nerves affected by neuropathies, including diabetic neuropathy. It neutralizes free radicals in both fatty and liquid areas of the cell, compared to vitamin C which is soluble only in water and vitamin E which is soluble only in fat.

Pycnogenol

Pycnogenol is a patented extract of sea pine bark, composed of a mixture of active bioflavonoids. The over 40 years of research in the field have been dedicated to establishing safety and health benefits and have been concluded in over 100 clinical trials and over 300 scientific papers.

»Antioxidant role

65-75% of the active components of PYC are represented by procyanidins, more precisely catechin and epicatechin, and the remaining 35-25% is represented by polyphenolic monomers, phenolic or cinnamic acids and their glycosides, all of which have a high bioavailability. The combination of bioactive ingredients has much stronger biological effects than the purified extract of each component, which indicates their synergistic effect.

Due to its composition (phenolic acids, polyphenols and especially flavonoids), PYC is an effective antioxidant, helping to reduce free radical levels. Thus, it has been shown that the administration of 50 mg of PYC, for a period of 8 weeks, to a group of 78 smokers, helps to reduce the plasma concentrations of reactive oxygen species.

Carnitine

L-Carnitine is synthesized in the body from the amino acids lysine and methionine.

L-Carnitine is an effective amino acid for burning fat. It transfers long-chain fatty acids to the mitochondria, where they are oxidized and produce energy.

Dual-acting antioxidant and an amino acid known to protect nerve cells. It also facilitates the communication of the brain, eliminating the ravages produced by free radicals in it.

and 2020 00173

01/04/2020

Staxanthin

Astaxanthin is a compound in the category of carotenoids, it is partly responsible for the orange color of salmon and other aquatic life.

The human body cannot synthesize astaxanthin. In general, this compound is not converted by the body into vitamin A, however, in severe cases of deficiency, this transformation can take place.

Astaxanthin is not an essential nutrient, but eating foods rich in astaxanthin can have beneficial effects on the body. Like other carotenoids, astaxanthin is a powerful antioxidant, even stronger than other carotenoids and vitamin A. Effects:

* Reduces wrinkles and fades "old age" stains.

* Improves skin firmness and texture.

* Protects the skin from the inside from the effects of ultraviolet rays.

»Increases energy levels and improves attention and concentration.

* Supports physical endurance and recovery after exertion.

* Helps protect eyesight and joints.

Green tea extract standardized to 50% polyphenols

Green tea comes from the leaves of the plant Camellia sinensis and has been used by the Chinese for more than 2,000 years, due to the many therapeutic properties of this plant. It is one of the most famous sources of polyphenols with antioxidant properties.

Since antiquity, green tea has been used as an effective remedy in relieving headaches, for a good mood and as an energizer.

Today, scientific research attests to the special properties and confirms the benefits that the consumption of green tea brings to our lives both physically and mentally or spiritually.

* It has a diuretic and detoxifying effect. Green tea helps the kidneys function well and prevents water retention. It helps activate the metabolism, regulates the intestinal transit, stimulates the liver and the entire digestive system, thus ensuring the detoxification of the body.

• Rich in antioxidants !. The health benefits that green tea extract has are largely due to its high antioxidant content.

«Slows down aging. Green tea combats the effects of pollution due to the antioxidants it contains. Fight against free radicals produced by various noxious substances: cigarette smoke, exhaust fumes and ultraviolet rays; which age the body prematurely.

and 2020 00173

01/04/2020

Vitamin B2

Vitamin B2 or riboflavin is one of the eight vitamins belonging to the B complex. All contribute to the transformation of carbohydrates into glucose, which is then used by the body as energy. All B vitamins are water soluble. Thus, the body is not able to store them for later use.

Riboflavin works as an antioxidant, helping to protect the body against harmful particles known as free radicals. They affect cells and DNA and speed up the aging process, but also the appearance of heart or tumor diseases.

C vitamin

Vitamin C is an important substance for developing and maintaining the health of the body.

Among other things, vitamin C plays an important role in the immune response to stress and takes viral and bacterial infections (because it participates in the formation of antibodies and interferons).

Vitamin C deficiency can occur due to an inadequate diet, which lacks fruits and vegetables, but are rarely found in adults, especially in children, alcoholics and the elderly. Stress, exposure to cold, performance exercise lead to an increase in oxidative processes of plasma, so it is necessary to supplement with vitamin C.

Involved in the formation and regeneration of red blood cells, bones and tissues, vitamin C helps strengthen blood vessels, helps maintain healthy gums and faster wound healing, fights infections and strengthens the immune system. Vitamin C also has an antioxidant role, protecting the body's cells from the action of free radicals, helps the body absorb iron, contributes to the production of hormones and regulates nerve function.

Vitamin C activates many enzymes and plays an important role in cellular respiration, accelerates wound healing, is involved in collagen production and protects against cancer, stopping the formation of nitrosamines (carcinogens that form during the assimilation of amino acids in the stomach).

Vitamin C is well absorbed from the digestive tract. Absorption is decreased in those with hearing loss or accelerated intestinal transit. At the intestinal level, the absorption of vitamin C is achieved against the concentration gradient, through a specific transport system (active transport). In case of administration of high doses of vitamin C, intestinal absorption is achieved by passive transport (diffusion). The maximum intestinal absorption capacity is limited to 1200 mg in 24 hours at a dose of 3 g / day. The physiological plasma concentration is 0.7 - 1 pg / 100 ml.

and 2020 00173

01/04/2020

Vitamin C also has the great advantage of not accumulating in the body and therefore not presenting any danger of overdose or toxicity (LD ₅₀ for rats is 11900 mg / kg), thus allowing its use without restrictions.

Vitamin E

Vitamin E, also called “fertility vitamin, was discovered in wheat germ in 1922.

It represents a family of 8 antioxidant components: 4 tocopherols and 4 tocotrienols, each alpha, beta, gamma, delta. The alpha-tocopherol form is found in large amounts in the blood and tissues and is far superior to the activity of other forms of vitamin E. Vitamin E is a constituent of cell membranes that are mainly composed of fats sensitive to oxidation. Tocopherols exert a stabilizing action on cell membranes by influencing the viscosity of the permeability and flexibility of the cell wall. By protecting our cells, vitamin E protects our immune system.

It is a powerful antioxidant. It plays an important role against aging.

Copper

Essential in preventing cardiovascular disease, maintaining healthy skin and hair color and increasing fertility, copper is found in at least 15 proteins in the human body. Copper is essential in the formation of collagen, a basic protein in bones, skin and connective tissue. It plays an important role in the development of red blood cells, can help the body use stored iron and can increase immunity and fertility. Involved in the synthesis of melanin (the natural pigment found in hair, skin and eyes), copper! it also helps with good pigmentation. Copper is needed for the synthesis of many enzymes, and especially superoxide dismutase (SOD), which appears to be one of the body's most powerful antioxidants. It can also prevent bone loss that can lead to osteoporosis.

Zinc

- in the form of zinc oxide, it has a great importance in the good functioning of the human body, being a mineral with many therapeutic valences. It has been shown to be effective in: increasing immunity, colds, macular degeneration, wound healing or ADHD.

Zinc is vital to our health. This microelement has countless swarms in metabolic reactions: it participates in over 300 enzymatic reactions of cellular metabolism and is found in the content of another 50 enzymes. Zinc is important for growth and development, for cell regeneration, for sperm production and the immune system, insulin storage and protein synthesis, Zinc contributes to:

and 2020 00173

01/04/2020 r ^z maintaining normal fertility and reproduction,

376 - maintaining normal blood testosterone levels.

There are studies that support the theory that there is a link between system integrity

378 immune and the amount of zinc in the body. This mineral helps regulate the level of T lymphocytes, CD4 T lymphocytes and interieukin-2. This role in the immune system ii

380 gives zinc the ability to facilitate wound healing. Other studies have shown that changes in the level of zinc in the body can alter apoptosis, now known as “death

382 scheduled cell phone ”. Zinc has also been shown to have anti-inflammatory properties.

384 Daily dietary intake of zinc is necessary because the body does not have the ability to store zinc. Nutritionists and dietitians recommend a daily intake of zinc

386 approximately 15 mg and 25 mg for pregnant or lactating women. Increased stress or loads, to which the body is subjected, increase the need for zinc, and in these situations

388 recommends increased consumption, in addition, athletes, the elderly, patients with diabetes, women who consume estrogen preparations and people who consume

390 regular alcohol, must ensure a sufficient intake of zinc.

and 2020 00173

01/04/2020

The advantage of the formula for obtaining the product AGE MANAGEMENT AOX with L-Carnosine, Pyrroloquinoline Quinone (PQQ), resveratrol, astaxanthin, pycnogenol, curcumin, epigallocatechingalate (from Camelia sinensis) coenzyme Q10, alpha iipoic acid, vitamin C, vitamin B2 E, copper and zinc is that it includes two antioxidant molecules, a complex combination of bioactive components of natural origin, nutrients with antioxidant synergistic role, cell repairer: Vitamin C contributes to the normal functioning of the immune system and the normal formation of collagen for the normal functioning of skin, along with Vitamin E, Vitamin B2 and Zinc help protect cells against oxidative stress; Copper helps protect cellular constituents against oxidative stress. Zinc and Vitamin B2 help maintain healthy skin. AGE MANAGEMENT AOX is recommended for people over 40 years of age, cumulatively affected by cell damage.

The incorporation of the mixture of bioactive substances in herbal systems of oral administration with gastric protection (enteric soluble vegetable capsules) ensures the optimal bioavailability of gastro-sensitive active principles but also the protection of the gastric mucosa against the acidity of components (alpha Iipoic acid, ascorbic acid).

The way of making the formula is presented

Example 1. The composition for 403 mg product that can be included in an oral form (capsule) is L-carnitine-110 mg; Green Tea (Camellia sinensis) leaf extract, standardized at 50% polyphenols-75mg; Vitamin C / ascorbic acid-40mg; Lcarnosine-40mg; 25: 1 hydroethanolic extract from Turmeric (Curcuma longa) root, standardized to 95% curcuminoids-40mg; alpha lipoic acid-32.75mg; seaweed extract (Haematococcus pluvialis), with 2.5% astaxanthin-15mg; Polygonum Cuspidatum root extract, with 50% resveratroi-12.5mg; Pine bark extract (Pinus pinaster), standardized takes 99% pycnogenol-12.5mg; coenzyme Q10-10mg; anti-caking agents: magnesium stearate, colloidal silicon dioxide; vitamin E / dl-alpha tocopherol acetate 50% (maltodextrin, modified starch, silicon dioxide) -3mg; zinc oxide-1.56mg; PQQ / quinone pyrroloquinoline-1.25 mg: copper bisglycinate-0.43 mg; vitamin B2 / riboflavin0.18mg.

The raw materials are identified, the active principles are dosed. Weigh and add to the cooking vessel in descending order of mass. The mixture is homogenized in anhydrous medium and placed in the form of oral administration of hard gelatin capsules.

and 2020 00173

01/04/2020

Example 2. Proceed as in Example 1. The composition for the 403 mg product which may be included in an oral form (capsule) is L-carnitine-1 10 mg; Green Tea (Camellia sinensis) leaf extract, standardized at 50% polyphenols-75mg; Vitamin C / ascorbic acid-40mg; L-carnosine-40mg; 25: 1 hydroethanolic extract from Turmeric (Curcuma longa) root, standardized at 95% curcuminoids-40mg; alpha lipoic acid-32.75mg; seaweed extract (Haematococcus pluvialis), with 2.5% astaxanthin-15mg: Poiygonum Cuspidatum root extract, with 50% resveratroi-12.5mg; Pine bark extract (Pinus pinaster), standardized at 99% pycnogenol-12.5mg, coenzyme Q10-10mg; anti-caking agents: magnesium stearate, colloidal silicon dioxide; vitamin E / dl-aifa tocopherol acetate 50% (maltodextrin, modified starch, silicon dioxide) -3mg; zinc oxide-1.56mg; PQQ / quinone pyrroloquinoline-1.25 mg; copper bisglycinate-0.43mg; vitamin B2 / riboflavin0.18mg.

The raw materials are identified, the active principles are dosed. Weigh and add to the cooking vessel in descending order of mass. The mixture is homogenized in anhydrous medium and placed in the form of an oral administration for compression.

Stage 1

The raw materials are received according to the provisions of the Technical Specifications of the manufacturer, of the current edition of the European Pharmacopoeia.

The packaging is received qualitatively and quantitatively, according to the accompanying documentation from the manufacturer.

Stage 2

The primary and secondary weighing (control of the primary weighing) for a series of products is performed on electronic scales, in a room with controlled air conditioning (constant temperature and humidity: 21 ± 2 ° C, respectively 50% RH ± 10%).

Stage 3

The homogenization of the raw materials is performed in the Roto P machine, in a closed system.

In this step, the interphase control determines the loss by drying of the mixture, on a sample of 5 g. The practical yield of the homogenization step, which must be at least 98%, is determined.

The homogeneous mixture, as an intermediate product, is discharged into a properly labeled stainless steel container and analyzed by the Quality Control Laboratory in accordance with the provisions of S.T. and, only after obtaining the analysis bulletin, which certifies the conformity, it is possible to proceed to the next stage, encapsulation.

Step 4

The filling of the capsules with the homogeneous mixture of active ingredients and excipients is performed with a rotary machine of ZANASI 40E type (rotary encapsulation machine).

and 2020 00173

01/04/2020

The interphase control checks the average mass per capsule, the uniformity of the mass of the contents of the 462 capsule.

The yield of the capsule filling stage is at least 37%.

464 The capsules, as intermediate - bulk, are unloaded into stainless steel containers, appropriately labeled and analyzed by the Quality Control Laboratory.

466 After the issuance of the analysis bulletin, which certifies the conformity of the product, it is possible to proceed to the next stage, that of packaging.

and 2020 00173

01/04/2020

468

Testing of the product according to the invention

470 Determination of physico-chemical parameters of the prepared product

Table no. I Characteristics of the prepared product

CHARACTERISTICS ADMISSIBILITY CONDITIONS Solid powder mixture for inclusion in the transport system for oral administration The appearance of the powder Dark orange powder Smell Characteristic Taste Characteristic Average mass, mg 10 parts ± 5% (380.00 -420.00 mg) Mass uniformity Disaggregation, = Average mass ± 7.5% Max. 2 samples, out of 20 samples can vary> 7.5%, but no sample> 15%. - in gastric juice pH 1.2 It does not disintegrate for 30 minutes KF water. % max. 10 Microbial contamination * 472 Nr. total aerobic microorganisms / g: Max. 10 ⁴ UFC Nr. total yeasts and molds / g: Max. IO ² UFC Escheria coli / g: Absent

Appearance - the capsules are visually inspected for appearance, color and shape 474 on a representative number of capsules.

Smell and taste are the parameters determined by the organoleptic method.

476 The parameters of average mass and uniformity of mass are determined according to the provisions of the European Pharmacopoeia in force.

478 The disaggregation time is determined by method A provided in the European Pharmacopoeia in force.

480 Water content - is determined by titration with Karl Fischer reagent, the working method being that provided in the European Pharmacopoeia.

482 Microbiological control - determination of microbial contamination for the total number of bacteria, fungi and Escherichia coli is carried out according to 2.6.12 and 2.6.13 - FE category 3A 484 of the European Pharmacopoeia in force.

and 2020 00173

01/04/2020

Determination of the total polyphenol content in the innovative formula AOX

Spectrophotometric characterization and determination of the total polyphenol content of the innovative formula by the Folin-Ciocalteu colorimetric method is used to determine the total polyphenol content of compounds containing plant extracts.

Material and method

The principle of the method

Folin-Ciocalteu reagent contains phospho-tungsten acids as oxidants, which when reduced with slightly oxidized hydroxy phenolic groups produce a blue color with a maximum absorption at 765 nm by the formation of tungsten and molybdenum blue. Folin-Ciocalteu reagent reacts with a wide range of polyphenolic compounds; although the response may vary with the individual components, the selection of chlorogenic acid as a calibration standard allows useful data to be obtained on total polyphenols. In the present study we determined by the Folin-Ciocalteu method the total polyphenol content (Total Polyphenol Content = TPC) by establishing the content in chlorogenic acid equivalents [291.

Reagents

Distilled water, Extraction mixture: Ethyl alcohol and distilled water (75: 25% v / v). Preparation of extraction mixture: measure 750 ml of ethyl alcohol in a flask, over which 250 ml of distilled water are added and mix. Folin-Ciocalteu Reagent Solution 10%. Preparation of 10% Folin-Ciocalteu Reagent solution: pipette 10 ml of Folin-Ciocalteu Reagent in a 100 ml volumetric flask, make up to volume with distilled water and mix (Note: 10% Folin-Ciocalteu Reagent solution, prepare daily). Sodium carbonate solution 7,5% Preparation of sodium carbonate solution 7,5%: weigh 7,5 g of anhydrous sodium carbonate (Na2CO3) into the analytical balance and place in a 100 ml graduated flask, add 70 ml of distilled water and stir until completely dissolved; then it is leveled with the same solvent. - Standard solutions of chlorogenic acid Preparation Standard solutions of chlorogenic acid: Stock solution: weigh to the analytical balance 5mg chlorogenic acid is dissolved in distilled water and brought to the level in a 5ml volumetric flask. From the stock solution according to Table no. 1, dilutions are made in 10 ml volumetric flasks with distilled water and homogenized.

and 2020 00173

01/04/2020

Table no. II - Standard solutions diluted with chlorogenic acid

Chlorogenic acid standard solution Volume of chlorogenic acid stock solution, [ml] Nominal concentration of the diluted standard, ........................ Mmli ................... ... A 0.1 10 B 0.2 20 C 0.3 30 D E 0.4 40 0.5 50 F 0.7 70 G 1.0 100

Equipment - Analytical balance, accuracy of ± 0.001 g; - Water bath, to maintain the temperature at 70 ° C ± 1 ° C; - Vortex mixer, for efficient mixing during extraction. - Centrifuge, capable of achieving 4000 r I min, but this time 2500 r / min is used; - UV / VIS spectrophotometer, (Jasco-V-530); - Class A glass pipettes, to cover the volume range for standard dilutions and extracts;

- Class A volumetric flasks with a capacity of 5, 10 and 100 ml; - Extraction tubes, glass, with a capacity of 10 ml, capable of withstanding centrifugation.

Tests taken in progress

The powder contained in the capsules of the AOX movable product which was homogenized was taken to obtain a representative sample.

Extraction of polyphenols

From the AOX powder, two samples were prepared for the extraction of polyphenols, as follows: 0.200 g of test sample in an extraction tube, over which 5 ml of ethanolic extraction mixture is added and kept in the water bath for 5 minutes at 700 ° C; shake with Vortex for 10 minutes to dissolve the sample and allow to cool to room temperature; is centrifuged for 10 minutes at 2500 rpm; the supernatant is collected with a pipette from the extraction tube and the extraction is resumed with another 5 ml of extraction mixture; the filtrates are combined in a 10 ml flask with the same solvent and mixed.

Results

From each standard solution of chlorogenic acid, pipette 1 ml into 10 ml graduated flasks, then add to each flask 5 ml of 10% Folin-Ciocalteu Reagent, 4 ml of 7.5% sodium carbonate solution and make up to quota with distilled water.

and 2020 00173

01/04/2020

The solutions thus prepared are kept at room temperature for 60 minutes, then the absorbents are read on a UV / VIS Spectrophotometer (Jasco-V-530) at wavelengths of 765 ± 2 nm, in 1 cm quartz vats, with distilled water. , as compensating liquid.

Calibration curve

The tested range of chlorogenic acid concentration is 0-100 pg / ml, and the calibration curve obtained is presented in figure no. 1:

Calibration curve - chlorogenic acid

Figure 9 Chlorogenic acid calibration curve

The standard must have an absorbance of less than 0.8. It is also important that the sample is in the range of the calibration curve. if the sample has an absorbance higher than the G standard, the test is repeated by changing the dilution.

Determination of the total polyphenol content

The content was expressed as chlogenic acid equivalents (CAE) using chlorogenic acid (0-100 pg / mL, R2 = 0.9976) standard curve.

Each extract from the sample was diluted with water in a ratio of 1: 100 and then several dilutions were made, thus 1:10, 2:10; 2,5:10 and 5:10. From each sample solution, 1 ml was applied in 10 ml volumetric flasks, then 5 ml of 10% Folin-Ciocalteu Reagent, 4 ml of sodium carbonate solution 7 was added to each flask. 5% quoted with distilled water.

The prepared solutions were kept at room temperature for 60 minutes, then the absorbents were read on a UV / VIS Spectrophotometer (Jasco-V-530) at wavelengths of 765 ± 2 nm, in 1 cm quartz vats, with distilled water. , as compensating liquid.

and 2020 00173

01/04/2020

Table no. III - Diluted standard solutions from the sample of the innovative product AOX

Nr. i Sample table, i The volume Absorbent Concentration Concentration crt. mg solution of and the sample solution nominal value of the sample average of the sample sample, {ml] expressed in pg expressed in pg CAE / mg sample CAE / mg sample 1. i i 1.0 and 0.0952 31.56 2. I। ............... i 200 7 l 2.0 î 0.1487 37.99 35 80 3 : 2, b ] 0.1633 35 24 4. î | 5.0 0 2894 38.57 ---------------] ș 6.: Ș ί 2016 l 1.0 0 0983 33.98 2.0 ΐ 0.1688 37.03 36 58 7. and ί 2.5 ] 0.1685 36.81 8 ^.; t 5.0 and 0.2901 38 51

<68

570

572

574

We tested two samples of the product, AOX, from which several dilutions were made within the limits of the field studied on the calibration curve, from figure no. 1. The concentration of polyphenols in the samples was derived from the standard chlorogenic acid curve between 0 and 100 pg / mL (R ² = 0.9376). The total concentration of polyphenols in the original extracts (TPCo) was expressed as pg CAE / mg sample, following the interpretation of the samples it is found that they are homogeneous, and the results fall in the range of 31.56 38.57 pg CAE / mg sample.

conclusions

576 The product tested contains more than 30 micrograms chlorogenic acid equivalents (CAb) per milligram and 3 mg equivalents ciorogenic acid / 100 mg sample (3% CAE).

578

580 582

584 and 2020 00173

01/04/2020

SELECTIVE REFERENCES

740 CLINICAL STUDIES

742 Resveratrol, a natural antioxidant, has a protective effect on liver damage caused by inorganic arsenic exposure. Zhigang Zhang, Li Gao, Yanyan Cheng, Jing 744 Jiang, Yan Chen, Huijie Jiang, Hongxiang Yu, Anshan Shan, Baojing Cheng

746 Abstract

Resveratrol (Rev) may ameliorate chemotherapy-induced cytotoxic toxicity and oxidative stress. Arsenic trioxide (As ₂ O ₃ ) is a known cytotoxic substance and a potent chemotherapeutic agent. However, the mechanisms by which resveratrol protects the liver against the cytotoxic effects of As ₂ O ₃ are unknown. Therefore, in the present study we investigated the mechanisms involved in the action of resveratrol using a / 52 cat model in which hepatotoxicity was induced by As ₂ O _{3 treatment} . We found that pre-treatment with resveratrol, administered using a clinically comparable dose regimen, reversed changes in monologue and liver parameters induced by As ₂ O ₃ and led to a significant improvement in liver function. Resveratrol treatment 756 also improved the activities of antioxidant enzymes and attenuated As ₂ O _3- induced increases in reactive oxygen species and malondialdehyde production.

In addition, resveratrol attenuated the reduction induced by As ₂ O ₃ in the ratio of reduced glutathione to oxidized glutathione and the retention of arsenic in liver tissue.

760 These findings provide a better understanding of the mechanisms by which resveratrol modulates As ₂ O _3- induced changes in liver function and tissue morphology. They 762 also provide a stronger rationale for the clinical use of resveratrol to reduce As ₂ O _3- induced hepatotoxicity.

764

The hepatoprotective and antioxidant potential of Pycnogenol® in hepatotoxicity induced by 766 acetaminophen in rats. Raskovic A, Bukumirovic N, Paut Kusturica M, Milic N, Cabarkapa V, Borisev I, Capo I, Miljkovic D, Stilinovic N, Mikov M.

768

Abstract

770 Pycnogenol® (PYC) is already used as a food supplement and herbal medicine due to its strong antioxidant properties. The aim of the study was to examine the protective effect of PYC on acute liver damage induced by acetaminophen in rats. The effect of PYC on acetaminophen-induced hepatotoxicity in rats was 774 examined by determining biochemical parameters, in vitro antioxidant activity, histological evaluation and oxidative status in liver homogenates. The best properties of 2020 00173

01/04/2020

776 antioxidants have been demonstrated in methanolic extracts. Seven days of pre-treatment with PYC suppressed protein expression! CYP2E1 induced by the administration of a toxic dose of

778 acetaminophen. PYC at 50 mg / kg showed the ability to significantly decrease malondialdehyde (MDA) levels compared to the group in which acetaminophen was administered.

780 The enzymatic activity of xanthine oxidase (XOD) was significantly increased in the acetaminophen-treated group compared to the control group, while co-administration of 782 PYC at a dose of 50 mg / kg significantly reduced the activity of this enzyme. The significant decrease in hepatic glutathione (GSH) content in rats intoxicated with 784 acetaminophen compared to control rats was improved by concomitant administration of PYC to 50 mg / kg. The protective effect of PYC on acetaminophen-induced acute liver injury 786 in rats showed the best in vitro antioxidant potential expressed in methanolic extract and the consequent histological assessment and oxidative status in ⁷ 88 liver homogenates.

and 2020 00173

01/04/2020

BIBLIOGRAPHY

Rodriguez-Enriquez S, Pacheco-Velăzquez SC, Marin-Hernăndez Â, Gaiiardo-Perez JC, RobledoCadena DX, Hernăndez-Resendiz I, Garcia-Garcia JD, Beimont-Diaz J, Lopez-Marure R, HernăndezEsquivel L, Sănchez-Thomas R , Moreno-Sănchez R. - Resveratrol inhibits cancer cell proliferation by impairing oxidative phosphorylation and inducing oxidative stress. Toxicol Appl Pharmacoi. 2019 Mar 13. pii: S0041-008X (19) 30090-0.

2. Z. Zhang, L. Gao, Y. Cheng, J. Jiang, Y. Chen, H. Jiang, H. Yu, A. Shan and B. Cheng - Resveratrol, a Natural Antioxidant, Has a Proiective Effect on Liver Injury Induced by Inorganic Arsenic Exposure Biomed Res Int. 2014; 2014: 617202.

3. Lehninger AL (1970): Biochemistry, Worth Publisher inc. 1970

4. Sauberlich HE (1987): Nutritional Aspects of Pyridine Nucieotides, in Dolphin D, Poulson r, Avramovic O (editors): Pyridine Nucieotide Coenzymes (Part B), John Wiley & Sons, Inc. 1987, pp. 599-626.

5. A! Berts B, et al (1983): Molecular Biology of the Cell, Garland Publishing, 1983, pp. 491-495

6. Catherine C. Neto, Joe A. Vinson (2011) Herbal Medicine: Biomolecular and Clinical! Aspects. 2nd edition, Chapter6.1. Cranberry. introduction and traditional origins

7. Sebastian J. Padayatty, Arie Katz, Yaohui Wang, Peter Eck, Oran Kwon, Je-Hyuk Lee, Shenglin Chen, Christopher Corpe, Anand Dutta, Sudhir K Dutta, Mark Levine (2003) Vitamin C as an Antioxidant: Evaiuation of Its Role in Disease Prevention. Volume 22, issue 1, 18-35

8. European Food Safety Authority, Scientific Committee on Food. Toierable Upper Intake Levels for Vitamins and Minerals. 2006: ISBN: 92-9199-014-0

9. Spencer H, Norris C, Williams D. Inhibitory effects of zinc on magnesium balance and magnesium absorption in man J Am Goii Nutr. 1994; 13 (5): 479-484.

10. Shiis ME. Magnesium In: O'Deli BL, Sunde RA, eds. Handbook of nutritionally essentiai minerals. New York: Marcel Dekker, inc: 1997: 1 17-152.

11. Raskovic A, Bukumirovic N, Paut Kusturica M, MiliC N, Cabarkapa V, Borisev I, Capo I, Miljkovic D, Stiiinovic N, Mikov M. Hepatoprotective and potential antioxidant of Pycnogenol® in acetaminophen-induced hepatotoxicity in rats. Phytother Res. 2019 Mar; 33 (3): 631 -639

12. Ikemoto K, Mori S, Mukai K. Synthesis and crystai structure of pyrroloquinoline quinol (PQQH ₂ ) and pyrroloquinoline quinone (PQQ). Acta Crystallogr B Struct Sci Cryst Eng Mater. 2017 Jun 1; 73 (Pt 3): 489-497

13. Ghosh D ¹ , Brewer GJ ² . Externai cys / cySS redox state modification controis the intracellular redox state and neurodegeneration via Akt in aging and Aizheimer's disease mouse model neurons. J Alzheimers Dis. 2014,42 (1): 313-24. doi: 10.3233 / JAD-132756.

Ghosh D ¹ , Levault KR, Brewer GJ. Relative importance of redox buffers GSH and NAD (P) H in age-related neurodegeneration and Alzheimer’s disease-like mouse neurons. Aging Ceil. 2014 Aug; 13 (4): 631-40. doh 10.1111 / acel.12216. Epub 2014 Mar 21.

15. Pop, A. Pop, C, Cellular mitochondrial therapies. Coenzyme E1, (2015) Maramureș Medical, Number 59

16. Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D. Abete, P. (2018). Oxidative stress, aging, and diseases. Clinic! interventions in aging, 13, 757-772. doi: 10.2147 / CIA.S158513 17. Poulsen, Malene W .; Hedegaard, Rikke V .; Andersen, Jeanette M .; of Courten, Barbora; Bîigel, Susanne: Nieisen, John: Skibsted, Leif H .; Dragsted, Lars O. (October 2013). Advanced giycation endproducts in food and their effects on heaith. Food and Chemical Toxicoiogv. 60 '10-37. doi: 10.1016 / j.fct.2O13.06.052. ISSN 1873-6351. PMID 23867544.

18, Guney Y, et al. Carnosine may reduce lung injury caused by radiation therapy. Med Hypotheses. 2006; 66 (5): 957-9.

19. Pizzimenti, S, Ciamporcero, E. S., Daga, M., Pettazzoni, P., Arcaro, A., Cetrangolo, G.,. . & Barrera, G. (2013). Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Frontiers in physiology, 4, 242

20. Mazloumi Gavgani, F, Smith Arnesen, V., Jacobsen, R. G., Krakstad, C., Hoivik, E. A., & Lewis, A. E (2018). Class i phosphoinositide 3-Kinase PIK3CA / p110α and ΡΙΚ3ΟΒ / ρ110β isoforms in endometnai cancer. International Journal of Molecular Sciences, 79 (12), 3931.

21. Liu, Q., Raina, A. K., Smith, M. A., Sayre, L. M., & Perry, G. (2003). Hydroxynonenal, toxic carbonyls, and Alzheimer's disease. Molecular aspects of medicine, 24 (4-5), 305-313.

and 2020 00173

01/04/2020

22. Ames B. N. (2018). Prolonging healthy aging: Longevity vitamins and proteins. Proceedings of the National Academy of Sciences of the United States of America, 115 (43), 10836-10844. dor 10.1073 / pnas. 1809045115

23. Geng, Q., Gao, H., Yang, R., Guo, K., & Miao, D. (2019). Pyrroloquinolme Quinone Prevents Estrogen Deficiency-lnduced Osteoporosis by Inhibiting Oxidative Stress and Osteocyte Senescence. International Journal of Biological Sciences, 15 (1), 58-68. doi: 10.7150 / ijbs.25783

24. Akagawa, M., Nakano, M., & Ikemoto, K. (2016). Recent progress in studies on the health benefits of pyrroloquinolme quinone. Bioscience, biotechnology, and biochemistry, 80 (1), 13-22.

25. Huang, Y., Miao, D., & Chen, N. (2015). The treatment effects and mechanisms of pyrroioquinoline quinone on defective teeth and mandible in Bmi-1 knockout mice. Zhonghua kou qiang yi xue za zhiChinese Journal of stomatology, 50 (8), 496-502.

26. Kong, L, Yang, C., Yu, L., Smith, W., Zhu, S., Zhu, J., & Zhu, Q. (2013). Pyrroloquinoiine quinine inhibits RANKL-mediated expression of NFATd in part via suppression of c-Fos in mouse bone marrowcells and inhibits wear particle-induced osteolysis in mice. PLoS One, 8 (4).

Qin, R., Sun, J., Wu, J, & Chen, L. (2019). Pyrroloquinoiine quinone prevents knee osteoarthritis by inhibiting oxidative stress and chondrocyte senescence. American Journal of translational research, 11 (3), 1460-1472.

Nakano M, Suzuki H, Imamura T, Lau A, Lynch B Genotoxicity of pymoÎoquinoÎine quinone (PQQ) disodium salt (BioPQQ ™). Regul. Toxic. Pharmacol. 2013; 67: 189-197.10 1016 / j.yrtph.2013.07.007

29. Chun, O. K., & Kim, D. O. (2004). Consideration on equivalent Chemicals in total phenolic assay of chlorogenic acid-rich plums. Food Research International, 37 (4), 337-342.

Claims (4)

Claim / Claims 1. Composition for capsules or tablets characterized in that it comprises L-Carnosine 4 parts - 9.93% m / m, Pyrroloquinoline Quinone (PQQ) 0.13 parts - 0.31% m / m, L-Carnitine 11 parts (m / m) - 27.30% m / m, vitamin C / ascorbic acid 40 parts - 9.93% m / m, green tea leaf extract (Camellia sinensis) standardized to 50% polyphenols 7.50 parts - 18.61% m / m of which 3.75 parts polyphenols (epigalo catechin gaiate) 9.3% m / m, turmeric extract (Curcuma ionga) 4 parts 9.93% m / m, alpha lipoic acid 3.28 parts - 8.13% m / m, astaxanthin 1.5 parts - 3.72% m / m, Polygonum Cuspidatum root extract 1.25 parts - 3.10% m / m with 50% resveratrol (0.625 parts - 1.6% m / m), Pinus pinaster bark extract (Pinus pinaster) 1.25 parts - 3.10% m / m standardized in 99% pycnogenol (1.24 parts 3.07%), coenzyme Q10 / ubiquinone 1 (o) part - 2.48% m / m, dry - vitamin E 50% CWS / S (solid form, deposited on starch substrate) 0.3 parts 0.74% m / m - with 0, 15 parts vitamin E / tocopherol - 0.37% m / m, o zinc oxide 0.16 parts - 0.39% m / m, copper bisglycinate 0.04 parts - 0.11% m / m (Copper 12.50% VNR *), vitamin B2 / riboflavin 0.02 parts - 0.04% m / m and 0.88 parts (m / m) excipients of the formulation (magnesium stearate and colloidal silicon dioxide) - 2.19% m / m expressed by weight 2. Composition described in point 1 characterized in that it is administered orally Composition according to Claim 1, in the form of a powder, capsule or tablet 4. Composition described in point 1, characterized in that it has more than 3 mg milligrams of chlorogenic acid equivalent per 100 mg of the innovative product AOX.