FR2691616A1 - Nutritional compsns. for dietetic, pharmaceutical, veterinary and cosmetic purposes - contain trace elements complex with aminoacid(s), unsatd. fatty acids and vitamin(s) - Google Patents

Abstract

Nutritional compsns. ('biovectors') comprise unsatd. fatty acid, essential trace elements, vitamins and aminoacids. The trace elements are at least partially complexed with the amino acids, by ionic and/or covalent bonding to form complexes with 5-membered rings contg. at least one trace element. Pref. fatty acids are in the form of vegetable or fish oils and/or are 'grafted' onto lecithin, phospholipids and/or cholesterol esters and opt. microencapsulated. USE/ADVANTAGE - The compsns. may be used for dietetic, pharmaceutical, veteinary and cosmetic purposes. They provide efficient intestinal absorption of trace elements.

Description

NUTRITIONAL BIO-VECTORS
The present invention relates to new compositions rich in micronutrients, in proportions balanced to the physiological needs in order to increase their absorption, transport and fixation on the receptor sites; 1 invention also relates to their manufacturing process. In what follows, these compositions will be referred to as nutritional bio-vectors.

 The micronutrients essential to the maintenance of a normal life of the human and animal organism (mammals) are well known. Their insufficiency or absence results in a set of severe symptoms and may, in the event of a true absence, become incompatible with life.

Micronutrients are four types
10. Unsaturated fatty acids, whether monounsaturated (such as oleic acid) or polyunsaturated (hereinafter referred to as PUFA)
PUFAs have two essential series
the series W6 or n-6, the first term of which is linoleic acid (C18,2n-6), which by successive desaturations and elongations lead the body to synthesize prostaglandin precursor PUFAs (hereinafter referred to as PGs): C20,3n-6 dihomogammalinolenic acid for PG1 and C20,4n-6 arachidonic acid for PG2 (for convenience of printing in the present description and the claims which follow, the lowercase omega-letter has been replaced by the letter W) .

the series W3 or n-3 resulting from the alphalinolenic acid C18,3n-3 which by the same set of desaturations and successive elongations will lead to two essential polyunsaturated fatty acids
eicosapentaenoic acid C20,5n-3 precursor of prostaglandins G3,
the docosahexaenoic acid C22,6n-3 or cervonic acid which exerts a fundamental structural function at the level of the nerve and retinal brain cells.

 Fatty acids should therefore be considered as precursors of prostaglandins, which is well known, and / or as essential structural elements of cell membranes.

 As the desaturation, essential for the passage of a polyunsaturated fatty acid to a higher level of desaturation, is inhibited with age and under the effect of certain drugs (corticosteroids, adrenaline, etc.), PUFAs are essential to maintenance of good health and also in certain pathological situations (particularly inflammatory diseases); it is also necessary to provide unsaturated unsaturated and longer-chain unsaturated fatty acids directly to individuals in order to ensure that prostaglandin and leukotriene synthesis remains assured.

So the sources of fatty acids must be carefully chosen
- Monounsaturated fatty acids: oleic acid present in vegetable oils, mainly olive oil.

- Polyunsaturated fatty acids:
a) PUFA n-6 are found in a large number of vegetable oils such as for example: sunflower oils, grape seed oil, blackcurrant, wheat germ, etc ...

These oils provide mainly linoleic acid and quite a lot of more desaturated PUFAs with longer chains.

 In subjects whose desaturation capacity is reduced, it may be useful to provide vegetable oils containing mainly gamma linolenic acid (C18,3n-6) which will directly elongate C20,3n-6 (dibromo acid). gamma linolenic).

 It is then about borage oil, evening primrose etc ...

b) PUFA n-3 can be found in two types of oils
vegetable oils, such as rapeseed or soya bean oil, which contain appreciable amounts of alpha-linolenic acid (C20, 3n-3) in an amount of about 8 to 9%.

- marine oils, in particular fish oils, in which we can distinguish
(bb) fish-fleshed fish caught in cold seas where the species are mixed and which contain on the order of 30 to 60% n-3 PUFAs and even 80% in the form of a mixture of
C20.5n-3 and C22.6n-3.

 (b2) fish-specific fish oil, as is the case with mackerel oil, salmon, sardines, sharks, anchovies, tuna, rainbow trout, etc. which PUFA levels vary greatly as a percentage of C20.5n-3 and C22.6n-3. These variations make it possible to modulate dietary formulas according to their destinations.

 For example, the use of American shark oil or Japanese tuna is better suited to a product for the elderly because very rich in C22f6n-3 thus providing benefits in terms of maintaining the brain structure.

 b3) specific n-3 fatty acids grafted onto vectors such as phospholipids, lecithins, cholesterol esters provided that these fatty acids retain the only "cis" optical form physiological.

20- Essential trace elements
Trace elements can be used in different forms
a) in the form of inorganic salts whose bioavailability is not optimal, but remaining chemically free, allowing for some of them (mainly magnesium and zinc) to complex drug molecules by covalent bonds masking their hydrophilic radicals for the make lipophilic therefore better adaptable to the receptors. Once made lipophilic, the molecules have an increased bioavailability (this is true for many molecules including antibiotics, anti-inflammatories, etc.).
b) in form already complexed by two or three specific amino acids allowing maximum absorption of the trace elements themselves
The complexes obtained comprise a metal ion and a ligand comprising at least two atoms of atoms, capable of combining with the ion by giving a block of electrons
The donor atoms in the ligand are the most electronegative (phosphorus, oxygen, nitrogen, sulfur)
The absorption of the trace elements in the form of the complexes described above is greater than that of the trace elements introduced into yeasts (even when this introduction is possible, which is true for selenium, chromium, molybdenum and a little zinc for the other elements the enriched yeast culture does not seem to be able to be done now)
Complexed ETEs are less toxic than salt-free mineral ions because of their chemical nature because the suspended mineral between two heterocycles is protected from reactions with tissues and blood. These molecules behave in the body like dipeptides.

c) a mixture of the two forms (mineral and organic) to have excellent bioavailability of trace elements and achieve a complexation by covalent bond of certain drug molecules if they include hydrophilic functions
The trace elements concerned are mainly calcium, magnesium, iron, cobalt, copper, nickel, chromium, manganese, molybdenum, fluorine, iodine, vanadium, zinc, selenium, rubidium, potassium and bromine.

30- Vitamins
The vitamins used according to the invention are:
or cofactors to the biological activity of the trace elements by activation of the metallo-dependent enzymes.

for example: zinc or magnesium and vitamins B6 and B1; selenium and vitamins E
- are essential for the digestive absorption of certain traces in connection with other trace elements.

for example: iron and vitamins C
- either biologically active in the same metabolisms as a trace element
for example: B1, B2, B3 in carbohydrate metabolism
for example: vanadium and vitamin B1, B2, B3 also in carbohydrate metabolism
for example: selenium and vitamins E, A and C (in the capture of free radicals).

40- Amino acids
Amino acids are all usable for complexing metals. They are excellent electron donors, since by definition they contain oxygen and nitrogen atoms.

The sulfur-containing amino acids are also good electron donors, therefore excellent complexing agents, but especially their sulfur atom has the advantages
to be able to be replaced by selenium (selenomethionine, selenocysteine, etc.) and to constitute a source of selenium directly capturing free oxygen radicals.

 - to be in themselves scavengers (literal translation of English "scavengers") that is to say free radical sensors.

 In the prior art, it is well known to use, in nutritional compositions, fatty acids as is the case in particular of the French patent 2,600,890 (in the name of one of the applicants of the present) filed on July 3, 1986 as well as European patents 440,307; 440,308; 440,309,440,341; 440,347 (Efamol limited) all with priority from 1990 which describe families of compositions based on fatty acid.

 Some of these documents and in particular the French Patent 2,600,890 and the European Patent 440,341 also provide for the use of zinc and selenium. But in fact these patents consider only simple mixtures whose efficiency is extremely irregular on certain subjects while the nutritional biovector compositions according to the present invention have a considerably improved efficiency.

The present therefore relates to new compositions rich in micronutrients so one of the main characteristics is to constitute nutritional biovectors particularly effective and which are characterized in that they comprise, in quantities by weight
trace elements in the form of salts or metal oxides and / or complexes of ETE with at least one amino acid in an amount of 0.002 to 0.7% (as free element),
water-soluble and / or fat-soluble vitamins in an amount of 0.0001 to 10%,
monounsaturated and / or polyunsaturated fatty acids in an amount of 10 to 97%,
specific amino acids in an amount of 10 to 50%.

According to an advantageous embodiment, the polyunsaturated fatty acids are provided
either by mixing vegetable oils and fish,
either in the form of vegetable oil alone,
either in the form of fish oil alone,
either in the form of lecithin-grafted unsaturated fatty acids, phospholipids, or cholesterol esters in order to make a specific fatty acid contribution.

 These fatty acids grafted can be an oleic fatty acid and / or eicosapentaenoic acid and / or a docosahexaenoic acid, which allows to control very precisely the nature of unsaturated fatty acids administered so as to best respect the normal physiological balance.

 In addition, according to the invention, the fatty acids may be microencapsulated, which has the advantage of making them powdery, and, at the time of absorption, to reduce or even eliminate the taste of fish that is often unpleasant.

 According to the invention the trace elements (0.002 to 1.4% by weight of the composition) are provided in the form of inorganic salts or oxides of calcium, magnesium, iron, copper, cobalt, nickel, manganese, molybdenum, fluorine , iodine, vanadium, zinc, selenium, rubidium, bromine, alone or in combination and in the form of complexes or chelates of the elements mentioned above obtained by ionic and covalent bonding with one or more amino acids (and preferably 2 or 3 amino acids ) so as to form a ring with 5 vertices, having a sufficient stability, and so as to have a molecular weight of the order of 1500 daltons, including metal. This low molecular weight is the express condition for optimal absorption without intestinal transformation, similar to dipeptides or tripeptides.

 The natural amino acids that can complex the cations are 23, which is normal since it is sufficient that their structure is of the form R-CH-COOH for the chelation is done. The choice of amino acids depends on the metal to be complexed, the stability of the complex obtained, and its ability to be destructured at the level of the recaptors for a biologically useful fixation.

a) These complexes or chelates affect forms of the following type, M being the trace element, R and R 'of the optionally substituted, identical or different amino acid radicals

 Some examples of complex structures thus obtained allows a better understanding of the invention.

- pour le fer, avec une molécule de glycine et une de méthionine

- for copper, with two molecules of glycine

- for iron, with one molecule of glycine and one of methionine

This complex with glycine and methionine, thanks to its thiol function, is a free radical scavenger preventing ferrous iron from catalyzing the Haber Weiss cycle by oxidation and promoting the production of the highly reactive hydroxyl radical.
(b) complexes may have different structures, for example
- for zinc, with a molecule of cysteine:

 In all cases we find pentagonal cycles closed on the element.

 The overall content of metallic trace elements in the complexes ranges from 0.5 to 25% (weight equivalent of free element).

The invention provides for associating the trace elements in the form of oxides, metal salts and complexes of trace elements, it makes it possible to promote the complexation of certain hydrophilic drug molecules because of their chemical functions (carboxyl -COOH). , hydroxyl -OH, and amine -NH2) creating the same type of complex according to the reaction

 M being a metal, mainly magnesium and zinc.

 The resulting products of the invention can therefore advantageously be associated with medicinal treatments provided that the molecules concerned are hydrophilic.

 This concerns antibiotics, anxiolytics and antidepressants, anti-inflammatories, etc ... carrying COOH, OH and NH2 functions.

 In accordance with the invention, the vitamins added at the same time as the fatty acids and the trace elements may be of animal, plant or synthetic origin. They must be chosen according to their recognized complementarity with the essential elements (ETE) used as indicated above to ensure the best possible efficiency for the whole.

 These are fat-soluble vitamins A and E, and water-soluble vitamins B1, B2, B3, BS, B6, B8, B9, B12, and the like.

 To better understand the technical characteristics and advantages of the present invention, will be described examples of embodiments being understood that they are not limiting as to their mode of implementation and the applications that can be made. make.

EXAMPLE 1
A zinc chelate is prepared from one molecule of cysteine for one zinc atom.

 A magnesium chelate is also prepared at the rate of one molecule of glycine and one of aspartic acid for a magnesium atom.

 Finally, a selenium complex is prepared at the rate of one molecule of methionine and one of L-cysteine (or taurine).

 In a mixer, the following compounds are introduced, the water-soluble vitamins being introduced last.

- zinc chelate 45 mg (free zinc) - zinc sulphate 45 mg (free zinc) - magnesium chelate 100 mg (free magnesium) - magnesium oxide 120 mg (free magnesium) - selenium 50 mg complex (free selenium) - Vitamin B1 7 mg - Vitamin B6 10 mg - Vitamin B9 120 mcg - Vitamin C 100 mg - Lecithin 5 mg
These components are thoroughly mixed and then milled to the appropriate size.

In addition, oils and fat-soluble vitamins are mixed - Hydrogenated soybean oil 35 mg - Borage oil 160 mg - Blackcurrant seed oil 160 mg - Fish oils 160 mg - Vitamins E 50 mg - Vitamins A 1250 IU - Beta carotene 1250 units
After carefully mixing, the two preparations are combined and worked until a homogeneous paste is dispensed in capsules or capsules.

EXAMPLE 2
A copper chelate is prepared at the rate of two molecules of glycine for a copper atom and a manganese chelate at the rate of two L-cysteine atoms for one manganese atom.

In a blender the following components are mixed - Copper Chelate 45 mg (free copper) - Manganese Chelate 45 mg (free copper) - Vitamin B1 10 mg - Vitamin B6 15 mg - Vitamin C 130 mg
Mix and grind thoroughly at 20 ° C. Then add - Hydrogenated Soybean Oil 30 mg - Blackcurrant Seed Oil 300 mg
and it is always carefully mixed at 200C until a paste is obtained.

We then add
Eicosapentaenoic acid grafted on lecithin 300 mg
It is mixed for a long time and divided into capsules or capsules.

EXAMPLE 3
An iron chelate is prepared from one molecule of glycine and one methionine for one iron atom and the zinc chelate of Example 1.

Mixed in a blender - Iron chelate 60 mg (free iron) - Zinc chelate 50 mg (free iron) - Vitamin B1 7 mg - Vitamin B9 120 mg - Vitamin C 120 mg - Lecithin 6 mg
We grind, then granulate and crush again. In addition, the following mixture is microencapsulated with gelatin: - Hydrogenated soybean oil 40 mg - Blackcurrant seed oil 160 mg - Vitamin A 1250 IU - Vitamin E 50 mg
A pulverulent product is thus obtained which is combined with the first mixture, the whole being divided into capsules.

EXAMPLE 4
The zinc chelate, the iron chelate and the selenium complex are prepared as in the previous examples.

The following components are mixed: - zinc chelate 45 mg (free zinc) - iron chelate 60 mg (free iron) - selenium complex 50 mcg (free selenium) - vitamin C 180 mg
The following mixture prepared separately is added - Fish oil 300 mg - Vitamin A 1300 IU
This mixture is microencapsulated with gelatin and combined with the first mixture to which emulsifier and perfume are added, if necessary, and emulsified.

 It is divided into pots or tubes.

EXAMPLE 5
Copper chelate and manganese chelate are prepared as above.

The following components are mixed - Copper Chelate 60 mg - Manganese Chelate 50 mg - Magnesium Oxide 140 mg - Vitamin B1 8 mg - Vitamin B6 15 mg - Vitamin C 60 mg - Lecithin 6 mg
We mix carefully. The following mixture is also prepared: - Eicosapentaenoic acid 300 mg grafted on phosphatidyl ester - Hydrogenated soybean oil 30 mg - Blackcurrant seed oil 180 mg - Vitamin A 1400 IU - Beta-carotene 1200 Units
It is mixed and microencapsulated with gelatin. The two mixtures are combined in a gel, an ointment or a stick paste.

Report of experiments demonstrating the interest of the invention
These experiments focused on the absorption of ETEs and that of n-3 fatty acids in tissues.

1.- Trace elements
a) Intestinal absorption of ETE at the general level
The results of the mixture according to the invention are particularly significant in terms of intestinal absorption.

The following table shows the numbers obtained on jejunum of male Sprague Dawsey albino rats after incubation around 370C in Ringer's solution and then measured by atomic absorption spectrophotometry. After supply of 50 mcg of copper, iron, magnesium and zinc in the form of salts or according to the invention and with respect to untreated animals.

<Tb>

Elements <SEP> S04 <SEP> 02 <SEP> C03 <SEP> Control <SEP> Mixture <SEP> according to
<tb> traces <SEP> the invention
<tb><SEP> Cm <SEP> 8 <SEP> 11 <SEP> 6 <SEP> 0 <SEP> 34
<tb><SEP> Mg <SEP> 36 <SEP> 23 <SEP> 51 <SEP> 7 <SEP> 90
<tb><SEP> Fe <SEP> 78 <SEP> 61 <SEP> 82 <SEP> 53 <SEP> 279
<tb><SEP> Zu <SEP> 84 <SEP> 66 <SEP> 87 <SEP> 14 <SEP> 181
<tb> lb) Example of distribution of a trace element in the blood
This study investigated the distribution of zinc in the blood over time by comparing, in the rat, the levels of radioactive zinc after administration of 5 mcg (microgram) of 65Zn as Zn C12 or mixture according to the invention .

The analysis was performed every half hour after administration by gamma ray spectrophotometry; the count is done per minute and per gram of tissue.

<Tb>

<SEP> Time <SEP> Zn <SEP> C12 <SEP> Zn <SEP> of <SEP> blend
<tb><SEP> after <SEP> according to <SEP> invention
<tb> 90 <SEP> minutes <SEP> 20 <SEP> 17
<tb> 120 <SEP> minutes <SEP> 18 <SEP> 23
<tb> 150 <SEP> minutes <SEP> 20 <SEP> 34
<tb> 180 <SEP> minutes <SEP> 21 <SEP> 38
<Tb>
lc. Example of distribution of two trace elements in different tissues
Tissue levels were measured after precise doses: 5 mcg 65Zn and 30 mcg 54Mn and are expressed as counts per minute per gram of tissue in the rat.

(1) Zinc levels in certain tissues (5 mcg of 65zn)

<tb><SEP> Tissues <SEP> 65ZnC12 <SEP> 65Zn <SEP>
<tb><SEP> according to <SEP> invention
<tb> Muscle <SEP> 150 <SEP> 190
<tb> Heart <SEP> 1.42 <SEP> 1.52
<tb> Liver <SEP> 7.53 <SEP> 10.40
<tb> Kidney <SEP> 7.6 <SEP> 8.9
<tb> Brain <SEP> 420 <SEP> 575
<tb> (2) Manganese content in tissues (30 mcg of 54Mn)

<tb><SEP> Tissues <SEP> S4MnCl2 <SEP> 54Mn
<tb><SEP> according to <SEP> invention
<tb> Muscle <SEP> 21 <SEP> 31
<tb> Heart <SEP> 34 <SEP> 105
<tb> Liver <SEP> 48 <SEP> 110
<tb> Kidney <SEP> 81 <SEP> 95
<tb> Rate <SEP> 180 <SEP> 391
<tb> Lung <SEP> 53 <SEP> 55
<tb> Intestine <SEP> 83 <SEP> 137
<tb> Os <SEP> 110 <SEP> 282
<tb> 2) N-3 Polvinsaturated Fatty Acids in Nerve Tissues
Since PUFAs of the n-3 series have an essential role in nerve tissue, a comparative study was carried out on n-3 deficient rats receiving n6, and rats treated with the n-3 products. invention.

The results after two months of study are presented in the following table:

<tb><SEP> cells and
<tb><SEP> organelles <SEP>% <SEP> total <SEP>% <SEP><SEP> of <SEP>% <SEP> of
<tb><SEP> Brain <SEP> from APGI <SEP> C20 <SEP> 4n-6 <SEP> C22 :: 6n-3 <SEP>
<tb><SEP> normal <SEP> n-6 <SEP> n-3 <SEP> normal <SEP> Exp <SEP> Normal <SEP> Exp
<tb><SEP> Exp <SEP> Exp <SEP> Batch <SEP> n-6 <SEP> Batch <SEP> n-3
<tb> Neurons <SEP> 32 <SEP> 37 <SEP> 33 <SEP> 15 <SEP> 19 <SEP> 8 <SEP> 9
<tb> Capillary <SEP> 35 <SEP> 38 <SEP> 35 <SEP> 16 <SEP> 17 <SEP> 10 <SEP> 10
<tb> Mitochondria <SEP> 30 <SEP> 33 <SEP> 30 <SEP> 16 <SEP> 19 <SEP> 12 <SEP> 12
<tb> Retin <SEP> 45 <SEP> 47 <SEP> 46 <SEP> 5 <SEP> 8 <SEP> 35 <SEP> 36
<Tb>
From this table, it appears that the diet rich in n-6 PUFA (column n-6 exp of the table) increases the content of tissue C20,4n-6 promoting inflammation (the PGI2 being proinflammatory) while the products according to the invention maintain the balance of composition C22,6n-3 which is physiological and, moreover, without inflammatory properties.

 The present invention is particularly directed to compositions for dietetic, pharmaceutical, veterinary or cosmetological use, rich in micronutrients which are very largely assimilated and in physiological proportions. It is obvious that the nutritional biovectors according to the invention can be included in a wide variety of formulations thus serving as a basis for more elaborate forms, galenic, cosmetic or dietetic, for example.

Claims (17)

 1.- Nutrient biovectors based on unsaturated fatty acids, essential trace elements, vitamins and amino acids, characterized in that at least a part of the trace elements are complexed, thanks to ionic bonds and / or covalently, by at least a portion of the amino acids to give molecules at least one pentagonal ring including at least one trace element atom.  2. Biovectors according to claim 1 characterized in that at least a portion of the unsaturated fatty acids are grafted onto lecithin, and / or phospholipids, and / or cholesterol esters.  3. Biovectors according to one of claims 1 or 2 characterized in that at least a portion of the fatty acids or their derivatives are microencapsulated.  4. Biovectors according to one of claims 1 to 3 characterized in that at least a portion of the trace elements are in the form of metal salts.  5. Biovectors according to one of claims 1 to 4 characterized in that the trace elements represent (in free equivalent) from 0.002 to 0.7% by weight of the entire composition.  6. Biovectors according to one of claims 1 to 5 characterized in that the vitamins represent from 0.0001 to 10% by weight of the entire composition.  7. Biovectors according to one of claims 1 to 6 characterized in that the fatty acids represent from 10 to 97% by weight of the entire composition.  8. Biovectors according to one of claims 1 to 7 characterized in that the amino acids (in free equivalent) represent from 3 to 50% by weight of the entire composition.  9. Biovectors according to one of claims 1 to 8 characterized in that at least a portion of the fatty acids is in the form of vegetable oils.  10. Biovectors according to one of claims 1 to 9 characterized in that at least a portion of the fatty acids is in the form of fish oils.  11. A method of producing nutritional bivoectors according to one of claims 1 to 10 characterized in that at least one essential trace element is complexed with at least one amino acid and then all the other components are mixed together.  12. Process according to claim 11, characterized in that at least a portion of the fatty acids are grafted onto lecithin and / or phospholipids and / or cholesterol esters.  13.- Method according to one of claims 11 or 12 characterized in that microencapsule at least a portion of optionally grafted fatty acids.  14.- Method according to one of claims 11 to 13 characterized in that the compositions comprise trace elements which represent (in free equivalent) from 0.002 to 0.7% by weight of the entire composition.  15.- Method according to one of claims 11 to 14 characterized in that the vitamins represent from 0.0001 to 10% by weight of the entire composition.  16. A process according to one of claims 11 to 15 characterized in that the fatty acids represent from 10 to 97% by weight of the entire composition.  17.- Method according to one of claims 11 to 16 characterized in that the amino acids (in free equivalent) represent from 3 to 50% by weight of the entire composition.