FR2942959A1 - METABOLIC STIMULATOR OF PPARS BASED ON UNSATURATED FREE FATTY ACID ESTERS, OILY COMPOSITION AND SUPPLEMENTS COMPRISING SAME. - Google Patents

Abstract

A metabolic stimulator of activated proliferative factor receptors of all types of peroxisomes (PPARs -alpha, gamma and delta (beta)) comprising at least one unsaturated free fatty acid ester, the unsaturated free fatty acid moiety being selected from oleic acid, linoleic acid, linolenic acid, DHA, EPA and mixtures thereof, and the alcohol residue being selected from C2-C5 linear alcohols, C2-C5 amino alcohols, and inositol. Oily composition and food supplement containing said peroxisome activated proliferation factor receptor (PPAR) metabolic stimulator and their use orally, topically or in sterile injectable preparation for the prevention and / or treatment of overweight , obesity and associated pathologies, adipogenesis, cardiovascular disorders, type II diabetes, and, more generally, the so-called metabolic syndrome.

Description

The present invention provides a metabolic stimulator of activated proliferative factor receptors of all types of peroxisomes (PPARs -alpha, gamma and delta (beta)) comprising at least one unsaturated free fatty acid ester, the acid fragment unsaturated free fat being selected from oleic acid, linoleic acid, linolenic acid, DHA, EPA and mixtures thereof, and the alcohol residue being selected from C 2 -C 5 linear alcohols, amino alcohols in C2-05, and inositol.

In addition, the invention relates to a peroxisome proliferative activated factor (PPAR) metabolic stimulator consisting of one or more unsaturated free fatty acid esters, wherein the unsaturated free fatty acid moiety is selected among oleic acid, linoleic acid, linolenic acid, DHA, EPA and mixtures thereof, and the alcohol residue being selected from C 2 -C 5 linear alcohols, C2-05 amino alcohols, and inositol.

The invention further relates to oily compositions as well as food supplements containing said peroxisome proliferator activated-type (PPAR) metabolic enhancer and their use orally, topically or in sterile injectable preparation for the prevention and / or treatment of overweight, obesity and associated pathologies, adipogenesis, cardiovascular disorders, diabetes and generally the so-called metabolic syndrome.

The invention further relates to a cosmetic product containing the peroxisome proliferative activated factor (PPAR) metabolic stimulator for the prevention and treatment of cellulitis. The invention also relates to an anticholesterolemic pharmaceutical composition comprising said PPAR receptor metabolic stimulator and a pharmacologically acceptable vehicle, particularly for the prevention or treatment of obesity and associated pathologies, adipogenesis, cardiovascular disorders, diabetes type II and in general what is called the metabolic syndrome.

In general, it is now recognized that the increase in the frequency of overweight and obesity, type II diabetes, cardiovascular disease and the lack of energy in many people in developed countries is due to an inadequate diet resulting from a misuse of the calories contained in the products we consume which are mostly very rich in fat. This metabolic deficiency affects nearly 50 million Americans (almost one in four adult Americans) and 30 million Europeans. About 7% of adults between the ages of 20 and 30 and 40% of adults over 40 years old have the criteria to develop this syndrome.

Metabolic syndrome is a set of factors that occur at the same time and increase the risk of cardiovascular disease, stroke and type II diabetes. Having only one of these factors - increased blood pressure, high insulin levels, excess fat around the waist, or abnormal cholesterol levels - can lead to the risk of serious illness and in the case of many factors together , the risk is even higher.

Fatty substances, by their physical, chemical and physiological properties, play an important role in the nutrition of man. In addition to the fat ingested by humans in the form of food, the body itself makes lipids essential to life.

Fatty foods, and those of adipose tissue, consist mainly of triglycerides. A triglyceride is a glycerol molecule with 3 fatty acids attached to the molecule. Triglycerides are classified in fats, but only the 3 fatty acids are fats, glycerol itself belongs rather to the class of carbohydrates. For example, it is soluble in water and not in oil; glycerol is therefore not a fat.

It is the difference in the structure of the fatty acids attached to glycerol that makes these fats different. There is thus a great diversity of triglycerides in foods such as olive, sunflower, soy, butter, tallow, lard, margarine, and so on.

These fatty acids are assimilated in the intestine according to a process common to all triglycerides that are not themselves assimilable.

They must be broken down into: - diglycerides - monoglycerides - free fatty acids,

thanks to the action of lipases that we secrete, and only these different products are assimilable, the triglycerides not being.

As soon as these products are assimilated, the body resynthesizes triglycerides in the gut cells that have been broken down by the lipases in the intestine. These new triglycerides will then bind to lipoproteins and will be stored in adipocytes (fat cells). So that the triglycerides assimilated by the organism, after decomposing them into smaller fatty substances, are stored again as triglycerides; and therefore the body does not use their energy immediately since they are stored in adipocytes. The body can metabolize fatty acids only when they are not fixed on glycerol, as in triglycerides.

This metabolic deficiency of the recomposition and storage of triglycerides has been a benefit to the early men's times thousands of years ago. Indeed, this ability to store fats was a benefit in the past. Men storing fat could then endure long periods of hunger and consumed their fat reserves during these harsh periods. All this has been well explained by Stephen Cunnane in his book The survival of the fate, World Scientific Publishing Co., New Jersey, USA, 2005. www.worldscibooks.com which explains that it is the fatest people who have survived the famine and that it is also being fatter that men have enriched their brain in omega-3 fatty acid, which has made them smarter and more advanced in the natural selection of species.

For example, Melanesians who have colonized all the Pacific islands have a very high rate of diabetes (over 60%). Indeed, when these tribes left Indonesia on outrigger canoes, it is the larger ones, keeping their reserves of fat and consuming them very little, which resisted these long journeys with often shortages on board.

But nowadays, in practically every country, where there is hardly any food left over and where we eat every day to our hunger, and sometimes more, this faculty of storage becomes harmful.

Indeed, the excess of triglycerides that we manufacture will increase the amount and density of lipoproteins, these blood transporters of triglycerides, cholesterol and phospholipids. All these fatty acids blocked in triglycerides within lipoproteins, not metabolized, increase the risk of arteriosclerosis, facilitate the formation of plaques in the arteries whose rupture can cause thromboses. The bad cholesterol becomes high. Since they can not be burned because they are prisoners of triglycerides, fatty acids can only be stored in the fat cells, which are becoming larger and more numerous.

Previous work has sought new ways to bypass this synthesis and overcome this metabolic deficiency.

So different methods have been found to destock the fat cells and have the bioavailability of the fatty acids stored in these fat cells.

Lipolytic substances were used for this purpose: • Ephedrine • Synephrine of citrus aurentium • Forskolin of coleus forskoli • Hordenine and tyramine of barley seedlings - Tea extract rich in flavonoids to block O'-methyl transferase which destroys adrenaline . • Grape seed extract rich in flavanes 3-ol and pine bark rich in pycnogenol, both of which increase thermogenesis, that is to say they release fatty acids from fat cells; likewise, the polyphenols extracted from cocoa which have the same effect.

It is to remove fatty substances prisoners fat cells that we made a very important use of amphetamines and other isomérides. But these products were very dangerous and are now all banned except Sibutramine.

We tried again to short-circuit the fat cells with CLA, modified linoleic acid, which does not enter the cycle of synthesis of TAG (Triacylglycerol) as well as with medium-chain oils that burn without passing through the cells. fat. Indeed the TAG, when stored, are not mobilized very easily. In fact, the mobilization of fatty acids from fat cells is subjected to the action of hormones that promote the release of fatty acids (catecholamines, adrenaline and norepinephrine) and hormones that oppose the mobilization (insulin and certain products - adenosine, nicotinic acid and prostaglandins, beta blockers). Thus, people, especially women, who have a genetic predisposition to the setting aside have a bad lipolysis and burn their reserves very slowly.

One of the solutions has been to propose a diet rich in DAG (Diacylglycerols) which do not enter into the synthesis of TAGs and which have many metabolic advantages. This solution has been clearly stated in the book Diacylglycerol oil (AOCS Press Edition - Yoshihisa Katsuragi et al) and some compositions have been more particularly described in the international application WO2003 / 060139 by the same authors.

The Applicant has sought to find a better way to oppose the metabolic deficiency and use the energy of the fatty substances while not promoting the formation of fatty deposits.

The solution proposed by the present invention is to consume fatty substances containing little triglycerides or no triglyceride and having a high level of free fatty acid esters.

Unsaturated free fatty acids, such as oleic, linoleic and linolenic acid, have shown in clinical trials that they have the interesting property of lowering lipoproteinemia, and of reducing insulin resistance in diabetics. In addition, they increase the metabolism of fat, they facilitate weight loss and reduce the size of fat deposits. They fight fatigue and lack of energy. All these actions stem from their activity to stimulate a set of enzymes: activating peroxisomes, which reduce cholesterol levels and stimulate fat burning.

The Applicant has surprisingly discovered that certain unsaturated fatty acid esters have the ability to activate the activated proliferation factor receptors of all types of peroxisomes.

PPAR receptor activity has been studied extensively and receptor activators of all types of PPAR have already been described as potential actives for the treatment of obesity and diabetes. By way of example, mention may be made of the application WO96 / 33724 on selective compounds of PPAR-gamma, the application WO2005 / 009958 on activators of all types of PPARs.

Thus, the present invention relates to a metabolic stimulator of activated peroxisome proliferation factor (PPAR) receptors, preferably in the form of a food supplement or a food oil, comprising at least one ester or more unsaturated free fatty acids, the unsaturated free fatty acid moiety being selected from oleic acid, linoleic acid, linolenic acid, DHA (docosahexanoic acid), EPA (acidic ecosapentanoic acid) and mixtures thereof, and the alcohol residue being selected from C2-05 linear alcohols, C2-05 amino alcohols, and inositol.

In addition, the invention relates to a peroxisome proliferative activated factor (PPAR) metabolic stimulator of one or more unsaturated free fatty acid esters, wherein the unsaturated free fatty acid moiety is selected among oleic acid, linoleic acid, linolenic acid, DHA, EPA and mixtures thereof, and the alcohol residue being selected from C 2 -C 5 linear alcohols, C2-05 amino alcohols, and inositol.

Preferably, the unsaturated free fatty acid moiety is selected from oleic acid, linoleic acid, linolenic acid and mixtures thereof.

According to another characteristic, the unsaturated free fatty acid fragment is advantageously chosen from DHA, EPA and their mixtures. Also, preferably, the alcohol residue is a C 2 -C 5 aminoalcohol selected from ethanolamine, choline, and serine.

Alternatively, according to another feature, the alcohol residue is preferably selected from ethanol and ethanolamine. The fact that the free fatty acids are esterified with an alcohol (ethanol or ethanolamine) saturates their acid function and prevents the formation of triglycerides.

In a preferred aspect of the invention, the peroxisome proliferation activated factor receptor metabolic stimulator is extracted from a vegetable oil. By the term "extracted" is meant the preparation of an unsaturated free fatty acid ester, for example according to the protocol schematized in FIG. 1.20. In particular, the vegetable oil from which the metabolic stimulator is derived is chosen from the oils of olive, sunflower, peanut, rapeseed, soya, flax, maize, rice, grape seed, walnuts, borage, raspberry seeds, evening primrose, coconut, cottonseed, palm oil, safflower, sesame or a mixture of these oils.

The invention also relates to oily compositions comprising the metabolic stimulator of activated peroxisome proliferation factor receptors of all types (PPAR) as described above. According to a first embodiment, the oily composition according to the invention is characterized in that it does not comprise triglycerides.

According to a second embodiment, the oily composition according to the invention further comprises a vegetable oil whose content of esterified free fatty acids is equal to or greater than the triglyceride content.

Advantageously, this vegetable oil is chosen from olive, sunflower, peanut, rapeseed, soya, linseed, maize, rice, grape seed, walnut, borage, bean seed oil and raspberry, evening primrose, coconut, cottonseed, palm oil, safflower, sesame or a mixture of these oils.

In the first embodiment, the oily composition of the invention comprises exclusively an esterified free fatty acid ester concentrate obtained according to a procedure described below. This oily composition is therefore characterized in that it does not comprise triglycerides.

In the second embodiment, the oil composition further comprises a vegetable oil whose esterified free fatty acid content may be greater than 50% or more of the triglycerides contained in the oil. Preferably, the oils formed contain, almost exclusively, esterified free fatty acids, and are preferably esterified with an ethyl function. Advantageously, the vegetable oil of the oily composition is chosen from olive, rapeseed and soybean oils. , flax, rice or a mixture of these oils.

Preferably, the oily composition, of the first or second embodiment, has an unsaturated free fatty acid esters content of at least 20% relative to the total weight of the composition.

And preferably the content of unsaturated free fatty acid esters is at least 20% based on the total weight of the composition, but can be 50% or even more, and in some cases up to 100%.

Advantageously, the oily composition is characterized in that the content of unsaturated free fatty acid esters is between 20% and 50% relative to the total weight of the composition.

In addition, the oily composition is presented in a form for oral, topical, or sterile injectable preparation. Advantageously, in the context of oral administration, the oily composition may be contained, by way of non-limiting example, in a biscuit, a yogurt, a meal equivalent, a food bar, an ice cream, an ice cream.

The present invention also relates to a dietary supplement comprising said peroxisome proliferator activated factor receptor (PPAR) metabolic stimulator and characterized in that said stimulator is in powder form optionally mixed with other ingredients of nutritional interest in form. In one embodiment, the other powdery ingredient is a powdered milk product, or a vegetable protein such as soybean or peas.

The present invention also relates to the use of said oily compositions as food supplements, in oral form, to prevent or reduce overweight.

Similarly, the invention relates to the use of said oily composition for topical application as an anti-cellulite cosmetic agent.

The invention also relates to the use of said oily composition in a sterile injectable preparation, for preventing or reducing weight overloads.

Finally, the invention relates to an anticholesterolemic pharmaceutical composition comprising said PPAR receptor metabolic stimulator and a pharmacologically acceptable vehicle, in particular for the prevention or treatment of obesity and associated pathologies, adipogenesis, cardiovascular disorders, diabetes and in general what is called the metabolic syndrome.

Process for Preparation The metabolic stimulators as described and claimed in the present invention are prepared according to standard techniques for the preparation of unsaturated fatty acid esters well known to those skilled in the art, namely either direct esterification or transesterification. .

Thus, for example, the preparation of the docosahexaenoic acid (DHA) ester can be carried out by transesterification of the docosahexaenoic acid ethyl ester with an alcohol selected from the group consisting of C2-05 linear alcohols, C2-05 aminoalcohols, and inositol. Advantageously, the reaction takes place on pure ethyl ester of docosahexaenoic acid (at least 95% of commercially available purity). The transesterification process is preferably carried out in the presence of a catalyst, such as an alkali metal or alkaline earth metal carbonate, advantageously K 2 CO 3. In another particular embodiment, the catalyst of the transesterification process is a lipase such as advantageously Candida antartica lipase. Similarly, the transesterification reaction can be carried out in a solvent advantageously chosen from dioxane or THF.

Experimental part

EXAMPLE 1 Oily Composition Without Triglycerides According to the first embodiment of the invention, the oily composition contains exclusively a concentrate of esterified free fatty acid esters, without triglycerides. The preparation of an oily composition containing no triglyceride is carried out according to the scheme of Figure 1, which illustrates the preparation of a rapeseed oil ethyl ester.

Such an oily composition is prepared for example from a rapeseed oil, having a fatty acid composition according to: Composition C14 fatty acids 0.1% C16 4.7% C16: 1 0.2% C18 1.6% C18: 1 62.3% C18: 2 19.1% C18: 3 9.4% C20 0.5% C20: 1 1.2% C22 0.2% C22: 1 0.2% Other 0.5% Such an oil composition may also be prepared from an olive oil, having a following fatty acid composition: C14 fatty acids 0.5% C16 fatty acids 12% C16: 1 fatty acids 1% C18 fatty acids 4% C18: 1 fatty acids 68% 11 20 12 C18: 2 fatty acids Il% C18: 3 fatty acids 0.5% C20: 1 fatty acids 0.5% Other fatty acids 2.5% From these fatty acids Ethyl esters are mainly prepared. The esterification reaction is carried out in particular with C 2 -C 5 linear alcohols, C 2 -C 5 aminoalcohols and inositol. Preferably, the esterification reaction is carried out with ethanolamine, ethanol, choline or inositol. EXAMPLE 2 Oily Food Composition According to the second embodiment of the invention, the oily composition further comprises a vegetable oil. Such a composition comprises, for example: Ethyl oleate 25% by total weight Olive oil 75% by total weight

Example 3: Oily Food Composition

Mixture (50-50) of ethyl oleate + ethyl linoleate 25 to 50% by total weight Olive oil 50 to 75% by total weight

Example 4: Oily Food Composition

Ethanolamine oleate 25% to 50% total weight Natural olive oil 50% to 75% total weight

Example 5: Capsules 600 mg Ethyl oleate 25% total weight Example 6: Bags 25 to 50% total weight Mixture (50-50) Ethyl oleate + Ethyl linoleate: Contains 20% by weight non-glycerolated fatty acids of oleic, linoleic and linolenic acids in yoghurt powder Example 7: Preparation of milk powder to be reconstituted Ethyl oleate 50 to 56% Dehydrated milk powder 44 to 50% Soy lecithin 3% Product sweetener (aspartame) Example 8: Capsule for preventing or treating the metabolic syndrome Ethyl oleate 10 to 30% Ethyl linoleate 10 to 30% Ethyl linolenate 10 to 30% Liquid soy lecithin qs 100% Example 9: Capsule for prevention or treatment of metabolic syndrome Ethyl ester of DHA 10 to 30% Ethyl ester of EPA 10 to 30% Lecithin of liquid soybean qs 100% The results of biological tests carried out using a reporter gene, such as the Luciferase, show the properties of transactivation PPAR receptors of the compositions of the invention.

All these products regularly consumed and / or absorbed by the body during determined periods of treatment exert a positive effect on the metabolism of fatty acids in humans thus making it possible to prevent or treat diseases related to overweight, the obesity and associated pathologies, adipogenesis, cardiovascular disorders, type II diabetes and in general what is known as the metabolic syndrome.

Claims (22)

1. A metabolic stimulator of activated peroxisome proliferation factor receptors of all types of peroxisomes (PPAR) comprising at least one unsaturated free fatty acid ester, the unsaturated free fatty acid moiety being selected from oleic acid, linoleic acid, linolenic acid, DHA, EPA and mixtures thereof, and the alcohol residue being selected from C 2 -C 5 linear alcohols, C 2 -C 5 amino alcohols, and inositol. A metabolic stimulator of the activated peroxisome proliferator factor receptors (PPAR) according to claim 1 consisting of one or more unsaturated free fatty acid esters, the unsaturated free fatty acid moiety being selected from oleic acid, linoleic acid, linolenic acid, DHA, EPA and mixtures thereof, and the alcohol residue being selected from C 2 -C 5 linear alcohols, C 2 -C 5 amino alcohols, and inositol. 20 3. Metabolic stimulator of activated peroxisome proliferation factor receptors of all types of peroxisomes (PPAR) according to claim 1 or 2, characterized in that the unsaturated free fatty acid moiety is selected from oleic acid, linoleic acid, linolenic acid and mixtures thereof. 4. Metabolic stimulator of activated peroxisome proliferation factor receptors according to one of claims 1 to 3, characterized in that the unsaturated free fatty acid fragment is selected from DHA, EPA and mixtures thereof. 30 5. The peroxisome proliferative activated factor receptor metabolic stimulator according to any one of claims 1 to 4, characterized in that the alcohol residue is a C 2 -C 5 aminoalcohol selected from ethanolamine, choline, and serine. 6. The peroxisome proliferation activated factor receptor metabolic stimulator according to any one of claims 1 to 5, characterized in that the alcohol residue is selected from ethanol and ethanolamine. 7. A peroxisome proliferative activated factor receptor metabolic stimulator according to any one of claims 1 to 6, characterized in that it is extracted from a vegetable oil. 8. Metabolic stimulator of activated peroxisome proliferation factor receptors according to claim 7, characterized in that the vegetable oil is chosen from olive, sunflower, peanut, rapeseed, soybean and flax oils. of corn, rice, grape seed, nuts, borage, raspberry seed, evening primrose, coconut, cottonseed, palm oil, safflower, sesame or a mixture of these oils. Oily composition, characterized in that it comprises a PPAR receptor metabolic stimulator according to one of claims 1 to 8. 10. Oily composition according to claim 9, characterized in that it does not comprise triglycerides. 25 11. Oily composition according to claim 9, characterized in that it further comprises a vegetable oil whose esterified free fatty acid content is equal to or greater than the triglyceride content. Oily composition according to claim 11, characterized in that the vegetable oil is selected from olive, rapeseed, soybean, flax, rice or a mixture of these oils. Oils composition according to one of Claims 9 to 12, characterized in that the content of unsaturated free fatty acid esters is at least 20% relative to the total weight of the composition. Oils composition according to one of claims 9 to 13, characterized in that the content of unsaturated free fatty acid esters is at least 50% relative to the total weight of the composition. 15. Oily composition according to one of claims 9 to 13, characterized in that the content of free fatty acid esters is between 20% and 100% relative to the total weight of the composition. 16. Oily composition according to any one of claims 9 to 15, characterized in that it is presented to allow oral or topical administration. 15 17. Dietary supplement comprising a peroxisome proliferator activated factor (PPAR) metabolic stimulator according to one of claims 1 to 8, characterized in that said stimulator is in powder form optionally mixed with other ingredients of Food interests in powder form of fine powder type or particulate form or granular form. 18. Dietary supplement according to claim 17, characterized in that the other powdery ingredient is a powdered milk product. 25 19. Use of an oily composition according to one of claims 9 to 16, as a dietary supplement, in oral form, to prevent or reduce overweight. 20. Use of an oily composition according to any of claims 9 to 16 for topical application as an anti-cellulite cosmetic agent. 21. Use of an oily composition according to any one of claims 9 to 16 in a sterile injectable preparation, to prevent or reduce overweight. 22. An anticholesterolemic pharmaceutical composition comprising a PPAR receptor metabolic stimulator according to one of claims 1 to 8 and a pharmacologically acceptable vehicle, in particular for the prevention or treatment of obesity and associated pathologies, adipogenesis, cardiovascular disorders, type II diabetes and in general what is called the metabolic syndrome.