ES2355342B1 - MIXTURE OF NATURAL POLYPHENOLS WITH ANTIOXIDANT CAPACITY AND HEALTHY PROPERTIES. - Google Patents

Abstract

The present invention relates to a mixture of natural polyphenols with antioxidant capacity and heart-healthy properties; The base mixture comes from the combination of natural grape extracts (including skin, seeds and grape leaves), onion and pomegranate, obtained under pressure. Being the active ingredients to be included in the final preparation; # - trans-resveratrol. # Assuming an average concentration of this compound in red wine of 5mg / liter, and that moderate consumption of red wine has been associated, in epidemiological studies, to a beneficial effect on cardiovascular mortality, a supplement of 3-5 mg daily is proposed. # - 150 mg of diarrhea quercetin. # - 300 mg of daily elagitanins in the form of punicalgins.

Description

Mixture of natural polyphenols with antioxidant capacity and heart-healthy properties.

The present invention relates to a mixture of natural polyphenols with antioxidant capacity and heart-healthy properties.

Technical sector

The present invention belongs to the field of food supplements.

Object of the invention

The base mixture of the present invention comes from the combination of natural grape extracts (including skin, seeds and grape leaves), onion and pomegranate, obtained under pressure.

The active ingredients and the desirable amounts thereof to be included in the final preparation, consisting of the base and the active ingredients that are:

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trans-resveratrol.

Assuming an average concentration of this compound in red wine of 5 mg / liter, and that moderate consumption of red wine has been associated, in epidemiological studies, with a beneficial effect on cardiovascular mortality, a supplement of 3-5 is proposed. mg daily

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150 mg of quercetin daily, a dose about 10 times higher than the usual intake, which has been associated with an improvement in cardiovascular risk markers.

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300 mg of daily elagitanins in the form of punicalgins. This dose has shown in the blood detectable levels of ellagic acid and other active metabolites in volunteers.

Advantages

The advantages of this invention are apparent from the present specification, although the most outstanding advantages are cited below with a purely enunciative and non-limiting nature;

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These compounds, independently, have antioxidant and anti-inflammatory activity, have benefits on cardiovascular risk markers and are being investigated for their effect on different types of cancer (or individually or jointly), diseases such as Alzheimer's, and on aging.

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Quercetin is also investigated as a physical capacity enhancer.

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Joint administration, in some laboratory experiments, has synergistic effects and improves its activity. In addition, quercetin slows the metabolism of resveratrol so that its bioavailability is greater.

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Many investigations have been carried out since the 1980s to identify the pharmacological properties of resveratrol. There are more than 2000 references in the scientific literature on the properties of resveratrol.

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For the aforementioned effects, it may have topical cosmetic application in skin formulations or be used as a food supplement in the form of capsules (nutraceutical), in refreshing or energy drinks, or added to certain foods such as yogurts.

Background of the prior art

The interest in polyphenols in general originates from epidemiological studies that establish the so-called "French paradox"; It refers to the fact that in a country like France, with a high-fat diet, the incidence of cardiovascular disease is relatively low. A study in 1979 showed an inverse relationship between wine consumption in France and mortality from coronary heart disease.

Subsequent research on red wine extracts identified compounds known as polyphenols as cardioprotective agents in different experiments

Drawings

In the case of a food supplement, it is not necessary to provide any shape.

Description of the polyphenols used

1. Resveratrol

Of the different polyphenols investigated, resveratrol was identified as an active component in the wine.

Resveratrol is a polyphenol found in the skin of grapes and epidermis of the leaves of the vine. The resveratrol content in the grape varies according to the conditions, since it occurs in response to parasitic attacks of the vine,

or stress of the grapes for different reasons. Artificially its content can be increased by treatment with ultraviolet light (patented procedure) in grapes already collected.

The red wine content varies between 014 mg / L, depending on the grape variety (seems to be higher in Merlot grapes) and the growing conditions.

It has been attributed a beneficial effect on cardiovascular mortality, also as a chemopreventive of cancer and an anti-aging effect and as a preventive of chronic degenerative diseases by reducing oxidative stress and acting as an antioxidant.

Effect as an antioxidant and on atherosclerosis

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As an antioxidant, it prevents the accumulation of free radicals and prevents oxidative stress. It seems to compete with Coenzyme Q and decrease the activity of the respiratory chain complex III, which is the site of free radical production. In addition to preventing the accumulation of these radicals, it increases the intracellular production of glutathione that captures these free radicals by inhibiting oxidation, and other antioxidants and enzymes in cardiac muscle cells, which protect against oxidation.

As an antioxidant it also has effects on other systems, such as respiratory. Thus, in the culture of respiratory epithelial cells subjected to oxidative stress (tobacco smoke), the decrease of the antioxidant glutathione is modified, increasing its synthesis.

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Atherosclerosis is a reversible local inflammatory phenomenon, if cells (macrophages) that are loaded with cholesterol are removed from the arterial wall. These cells get trapped by interacting with oxidized LDL particles and mobilize by adding antioxidants such as resveratrol. Oxidized LDL particles cause a series of events that make a “cement” that traps cholesterol-filled macrophages in the inflammatory lesion, through the production of free radicals. Antioxidants, including resveratrol, decrease the production of free radicals and decrease the adhesion of macrophages.

It also decreases the oxidation of LDL particles (known as "bad" cholesterol) and platelet aggregation.

In mice with a genetic predisposition to atherosclerosis, resveratrol decreases levels of LDL and total cholesterol, increases the level of HDL ("good" cholesterol), decreases the presence of atherosclerotic lesions and the deposition of periarterial fat.

In obese rats: the concentration of triglycerides, total cholesterol, free fatty acids and hypertension decreases.

It blocks the proliferation of smooth muscle cells in the arterial wall (one of the main features of arteriosclerosis) by blocking the activation of the mTOR signaling pathway induced by oxidized LDL.

Regulates vasodilation and vasoconstriction, inhibits oxidative stress and free radical production, and inhibits the modification of LDL.

Anti-cancer effect

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Since it was shown in 1997 that resveratrol can have an effect as a cancer chemopreventive, research on this effect of resveratrol has increased markedly.

It has been seen that it can act on the three phases of the cancerous process: Initiation, promotion and progression.

In fact, there are two research projects to determine the bioavailability, toxicity and possible mechanisms of action of resveratrol in patients with colorectal cancer, and another to determine its activity as a preventive of colon cancer.

Anti aging effect

Several studies suggest that resveratrol activates a gene (SIRT1), which is activated under conditions of low calorie intake and that is associated with greater longevity in some experimental models such as yeasts, worms, flies and fish.

Possible toxicity

In rats, no dose toxicity has been seen 1000 times the concentration in red wine. Nor with doses of 300 mg / kg / day for 4 weeks, equivalent to 21 grams for a 70 kg adult.

In people, a single dose of 1, 2.5 and 5 gmen and 29 volunteers did not cause adverse effects.

Clinical trials

10 studies on prevention, cancer treatment (colon and follicular lymphoma), treatment of metabolic syndrome and Alzheimer's disease, using doses between 5 mg / day (metabolic syndrome) and up to 215 mg (Alzheimer's) are under way or in the preparatory phase. .

2. Quercetin

Fluvonoids are polyphenols of a structure different from resveratrol, present in fruits, vegetables, drinks such as tea and wine. Daily consumption of fl avonoids is very high, several hundred milligrams a day; that of the most interesting compounds, fluvones and fluvonoles is 23-24 mg / day. The most abundant fl avonol (70%) in our diet is quercetin. The estimated average intake in Europe is about 10 mg / d, although in some countries it can reach 30 mg / d.

Quercetin is found in tea, wine (44% of the fluvonols of red wine and 80% of white wine, fruits (in apple peel) and especially on onions.

Beneficial Effects

In In Vitro studies it is an excellent antioxidant, and within the family of fl avonoids it is the most potent when it comes to capturing free radicals. It also inhibits lipid peroxidation and oxidation of LDL In Vitro.

Its anti-inflammatory activity seems to be due to its antioxidant and inhibitory effects on enzymes involved in inflammation (cyclooxygenases and lipoxygenases) and the consequent inhibition of leukotrienes and prostaglandins.

In epidemiological studies on the Mediterranean diet, its beneficial effect on cardiovascular mortality has been demonstrated. The intake of fruits and vegetables has been investigated in a special way.

In an epidemiological study of 10,000 people during a year, those who took more fl avonoids, especially quercetin, had less coronary heart disease. The risk of cardiovascular disease decreases with the intake of fl avonoids; the most consumed products were those with the highest amount of quercetin. A follow-up of this study also found a lower incidence of stroke.

These beneficial effects could be due to its antioxidant, anti-inflammatory, anti thrombotic activity and its vasodilator action. A large study has reviewed more than 130 clinical trials investigating the use of fl avonoids and their effect on cardiovascular risk factors, concluding that there could be beneficial effects.

At a dose of 150 mg per day, for 6 weeks, in obese patients with high cardiovascular risk, it significantly reduced systolic blood pressure, and also decreased the concentration of atherogenic particles (oxidized LDL), although without decreasing in fl ammation markers. These effects could be mediated by its action on endothelial function, as seen in hypertensive animal studies, in which it reduces blood pressure, oxidative stress and endothelial dysfunction.

Due to its anti-inflammatory activity, it has been used in clinical trials in pulmonary sarcoidosis (a chronic inflammatory disease with no known cause and also associated with oxidative damage). In these patients, high-dose quercetin (2 grams in 24 hours) improved the antioxidant capacity and decreased in fl ammation markers, suggesting a possible beneficial role of quercetin.

Other actions have recently been investigated and very high doses have been seen to increase the number of mitochondria in mouse muscle, increasing capacity and endurance in exercise.

Quercetin inhibits the metabolic transformation of resveratrol, increasing the bioavailability of free resveratrol.

Toxicity

Dose of 1000 mg / d, have been associated with nausea and headache.

3. Ellagic Acid

Ellagic acid is another natural polyphenol mainly contained in strawberries, raspberries, pomegranates and other fruits and seeds. Initial studies on this compound were directed towards effects on blood pressure and blood clotting and subsequently its anticancer effect was investigated.

Ellagic acid is a derivative of gallic acid that is free in these fruits (such as ellagic acid) or more abundantly as part of elagitanins. The latter are not well absorbed, but they are hydrolyzed in the intestine and the ellagic acid that is released is absorbed very quickly.

Most of the studies have been done with pomegranate extracts. The antioxidant capacity of pomegranate juice is three times higher than that of red wine and green tea, based on the capture of free radicals.

The main antioxidants of this extract are elagitanins and anthocyanins. Elagitanins are responsible for 92% of the antioxidant capacity of the extract.

Most of the elagitanins in this fruit are punicalgins that, as mentioned, are hydrolyzed to ellagic acid and other polyphenols in the intestine.

This antioxidant activity has been suggested that may be the basis of other beneficial effects:

In an animal model of atherosclerosis, pomegranate extract administered for 3 months reduced atherosclerotic lesion (44%) compared to a group of control animals. The antiatherogenic and vascular protective properties (lowering blood pressure, platelet aggregation and improving lipid profiles) have also been demonstrated in other animal experiments (reviewed in 32).

In patients with type 2 diabetes, pomegranate concentrate (total polyphenols 875 mg / 100 g and 100 mg elagitanins) was administered and a decrease in total cholesterol and LDL cholesterol was seen. Another similar study showed a decrease in lipid peroxidation and uptake of oxidized LDL by macrophages, which can reduce the progression of atherosclerosis.

A study on hypertensive people showed a hypotensive effect after two weeks of treatment with 50 ml (100 mg of elagitanins) per day of pomegranate extract.

There is only one study that uses purified ellagic acid (180 mg for 6 weeks) in humans and was used to counteract the adverse effects of chemotherapy in prostate cancer patients, in whom it seems that neutropenia improved.

Other areas that are being investigated are the treatment of malaria and prostate cancer.

Toxicity

Supplements between 710 and 1420 mg of elagitanins in pomegranate extracts for 4 weeks were well tolerated in volunteers.

The mixture of natural polyphenols with antioxidant capacity and heart-healthy properties consists of a base consisting of a combination of natural grape extracts (including skin, seeds and grape leaf) onion and pomegranate obtained under pressure. To which the following active principles will be added;

-Trans-resveratrol calculated at a daily dose of 3-5 mg.

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Quercitin calculated at a daily dose of 150 mgs.

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Elagitanins calculated at a daily dose of 300 mgs.

Claims (3)

one.

Mixture of natural polyphenols with antioxidant capacity and heart-healthy properties, characterized by a base consisting of the combination of natural grape extracts (including skin, seeds and grape leaves), onion and pomegranate, obtained under pressure.

2.

Mixture of natural polyphenols with antioxidant capacity and heart-healthy properties according to claim one, characterized in that the following active ingredients will be added to the base:

•

trans-resveratrol: a daily supplement of 3-5 mg is proposed.

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Quercetin, in a daily dose of 150 mgs.

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elagitanins in the form of punicalgins, in a daily dose of 300 mgs.

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 200930548 SPAIN Date of submission of the application: 31.07.2009 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

Y

BOTANICAL VITALITY. The Genesis of Good Health, 2005. [online] [retrieved on 03.10.2011] Recovered from the Internet: <URL: http: //www.botanicalvitality.com 1.2

Y

HOLLMAN, P. C. et al. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. American Journal of Clinical Nutrition, 1995. Vol. 62, pages 1276-1282. 1.2

TO

US 2008254135 A1 (HEUER, M. et al.) 16.10.2008, pages 1-3; page 4, [0035], [0036]. 1.2

TO

KR 20040044058 A (GAL SANG WAN, PARK KI HUN) 27.05.2004, (summary) [online] [retrieved on 10.03.2011] Recovered from EPO EPODOC Database. 1.2

TO

CLIFTON, P. M. Effect of grape seed extract and quercetin on cardiovascular and endothelial parameters in high-risk subjects. Journal of Biomedicine and Biotechnology, 2004. Vol. 5, No. 2004, pages 272-278. DOI: 10.1155 / S1110724304403088. 1.2

TO

US 2005048008 A1 (GUPTA, S. K.) 03.03.2005, page 3, [0027], [0028]; pages 5-6, [0052]. 1.2

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of completion of the report 14.03.2011

Examiner A. Sukhwani Page 1/5

REPORT OF THE STATE OF THE TECHNIQUE Application number: 200930548 CLASSIFICATION OBJECT OF THE APPLICATION A23L1 / 30 (01.01.2006) A61K36 / 87 (01.01.2006) A61K36 / 8962 (01.01.2006) A61K36 / 185 (01.01.2006) A61K31 / 05 (01.01.2006) A61K31 / 352 (01.01.2006) A61P9 / 00 (01.01.2006) A61P39 / 06 (01.01.2006) Minimum documentation sought (classification system followed by classification symbols) A23L, A61K, A61P Electronic databases consulted during the search (name of the database and, if possible, search terms used) INVENES, EPODOC, WPI, BIOSIS, X-FULL, NPL CAPLUS, FSTA, AGRICOLA, CABA, CROPU, SISEARCH, INTERNET  WRITTEN OPINION Application number: 200930548 Date of Completion of Written Opinion: 03/14/2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1, 2 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1, 2 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published.  WRITTEN OPINION Application number: 200930548 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

BOTANICAL VITALITY. The Genesis of Good Health, 2005. [online] [retrieved on 03.10.2011] Recovered from the Internet: <URL: http: //www.botanicalvitality.com 2005

D02

HOLLMAN, P. C. et al. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. American Journal of Clinical Nutrition, 1995. Vol. 62, pages 1276-1282. nineteen ninety five

D03

US 2008254135 A1 (HEUER, M. et al.) 16.10.2008

D04

KR 20040044058 A (GAL SANG WAN, PARK KI HUN) 05/27/2004

D05

CLIFTON, P. M. Effect of grape seed extract and quercetin on cardiovascular and endothelial parameters in high-risk subjects. Journal of Biomedicine and Biotechnology, 2004. Vol. 5, No. 2004, pages 272-278. DOI: 10.1155 / S1110724304403088. 2004

D06

US 2005048008 A1 (GUPTA, S. K.) 03.03.2005

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The present application aims at a mixture of natural polyphenols with antioxidant capacity and heart-healthy properties constituted by the combination of natural grape extracts (skin, seed and leaves), onion and pomegranate, obtained under pressure (claim 1). To the base of extracts are added active ingredients such as trans-resveratrol in 3-5 mg of daily supplement, quercetin, in a daily dose of 150 mgs and elagitanins, in the form of punicalagins, in a daily dose of 300 mgs (claim 2).  NOVELTY Documents cited D01 to D05 refer to food supplements or health compositions containing several of the antioxidant polyphenols claimed in the application under study. Indeed,

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D01 is a document that refers to the prevention of diseases with different compounds such as grapes, quercetin, pomegranate containing resveratrol and elagitanins, the stable form of ellagic acid (pages 1, 2). It expressly mentions the synergy of polyphenols, ellagic acid, resveratrol and quercetin (page 3). It also reports the preparation of capsules containing pomegranate extract, resveratrol concentrate, skin and seeds of red grapes and quercetin (pages 3-4), although it does not disclose the use of onion.

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D02 refers to the absorption of quercetin from onions and concludes with the more efficient absorption of quercetin from onions compared to other sources (page 1276; page 1280, "Comparison with previous studies"; page 1282, column 1).

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D03 discloses compositions containing resveratrol for general health and vitality that provide polyphenols and antioxidants and that are cardioprotective (page 1, column 1). The composition comprises resveratrol, red wine, pomegranate (page 2, [0011], [0012]). It discloses the resveratrol found in the skin, grape juice and red wine that are polyphenols with antioxidant capacity of Vitis vinifera (page 2, [0018] - [0019]; page 3, [0023] - [0027, [0032]) and pomegranate as a source of polyphenols that improve cardioid lipid metabolism (page 3, [0035] - [0037]).

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D04 refers to a nutritional supplement for health with quercetin that prevents cancers, angiogenesis and blood clotting. The supplement includes among other components grape juice, grape and onion mixture, quercetin, etc. (summary).

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D05 refers to the effect of grape seed extract and quercetin in subjects with high cardiovascular risk parameters.

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D06 discloses an anti-aging cosmetic that comprises a combination of antioxidants because they are more effective than just one. Antioxidants can be polyphenols such as resveratrol and ellagic acid from pomegranate, grape seed extract,

or flavones such as quercetin (page 3, [0027], [0028]; pages 5-6, [0052]).  WRITTEN OPINION Application number: 200930548  None of the documents cited disclose grape, onion and pomegranate extracts in the same polyphenol mixture. Therefore, in view of documents D01 to D06, it can be concluded that claims 1-2 are new in accordance with Article 6 LP 11/86.  INVENTIVE ACTIVITY The purpose of obtaining a mixture of polyphenols with antioxidant capacity and heart-healthy properties with the combination of grapes (skin, seeds and leaves), onion and pomegranate is obvious to the person skilled in the art in view of documents D01 and D02. So:

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D01 discloses the synergistic effect of combining polyphenols such as ellagic acid (elagitanins), resveratrol and quercetin (page 3) with cardiovascular activity and the preparation of capsules with 250 mg pomegranate extract with 20% ellagic acid, resveratrol concentrate with 40 mg of trans-resveratrol, skin and seeds of grapes, and quercetin (page 4).

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D02 refers to the quercetin content of onions and their better absorption than quercetin from another origin.

 In view of document D01 that discloses capsules with five of the components of the application under study such as grape and pomegranate extracts, resveratrol, ellagic acid (elagitanines) and quercetin, and of document D02 that discloses the best absorption of quercetin Onions, the person skilled in the art could reach, without any inventive effort, a mixture of polyphenols combining grape extract, onion and pomegranate. In this sector of the technique it is very evident to vary the quantities used and added of each component. Therefore, in view of documents D01 and D02, it can be concluded that claims 1-2 lack inventive activity according to Article 8 LP 11/86.