FR2773484A1 - Micronutritional compositions having a therapeutic effect containing polyunsaturated fatty acids, trace elements, and vitamins - Google Patents

Abstract

Micronutritional compositions having a therapeutic effect containing a base material having a nonspecific effect combining polyunsaturated fatty acids (I), essential trace elements (II), vitamins and, optionally, amino acids. The base material having a nonspecific effect is preferably added to a vegetable or animal material having a specific effect on living creatures, such as ginseng, gingko biloba, myrtle, witch hazel, passion flower, artichoke, Harpagophytum procumbens, blackcurrant, propolis and royal jelly. (I) is a polyunsaturated fatty acid of the n-3 series, especially docosahexaenoic acid (Ia) and eicosapentaenoic acid (Ib), the ratio of (Ia)/(Ib) preferably being 0.9 or more. Preferably, (I) is obtained from egg yolk made rich in (Ia) by feeding the birds with a feed that is rich in fish oil containing polyunsaturated n-3 acids. (Ia) is then present in the form of phospholipids. The essential trace elements (II) include Ca, Mg, Fe, Cr, Ni, Co, Cu, Mn, Mo, V, Zn, Se, F and I. Selenium is preferably present in organic form. The vitamins added are preferably vitamin E and vitamin C. Amino acids that may be included are preferably at least one sulfur-containing amino acid and proline or hydroxyproline.

Description

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  NEW COMPOSITIONS WITH SYNERGISTIC EFFECT BETWEEN

  MICRONUTRIENTS AND SUBSTANCES OF LIVING ORIGIN

  The subject of the present invention is new compositions with a therapeutic effect, making it possible to associate with a synergistic effect, micronutrients and substances of living origin, that is to say: * plants such as traditional medicinal plants recognized for their effectiveness in human or animal diseases,

  * or animal like secretions from insects such as royal jelly or propolis.

  The nutritional aspect of the invention consists of imbalanced intakes of polyunsaturated fatty acids, hereinafter called AGPI, in essential trace elements, hereinafter called ETE, in vitamins, hereinafter called VIT, and optionally in amino acids, hereinafter referred to as AAm. This micronutritional association proposed by

  the invention has real synergistic effects in its therapeutic action.

  In the prior art, combinations have been proposed comprising * minerals * vitamins * and, optionally, PUFAs, in particular of the n-3 series; these n-3 PUFAs are generally supplied in the form of fish or vegetable oils, and can be

  natural, artificial or synthetic.

  Reference will be made in particular to French applications N 96 07 020 of 04/06/96 and N 96 10 285 of 13/08/96 from the same inventors. Thus, has it been proposed to administer conventional fish oils or those enriched in eicosapentaenoic acid (C20: 5n-3), hereinafter referred to as EPA, or as docosahexaenoic or cervonic acid (C ,, 22: 6n-3), hereinafter referred to as ADH, to which vegetable oils containing proportions or not were added notable gamma-linolenic acid (C18: 3n-6). These include evening primrose oil, borage oil or

blackcurrant seeds.

  The administration of PUFAs can be done by PUFAs grafted chemically on lecithin or cholesterol esters which are real medicinal active substances, and cannot be used as being natural, since they do not constitute not nutraceutical raw materials and they must

  in most countries follow marketing authorization procedures.

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  We have also proposed in the prior art joint contributions in ETE, VIT and AAm, possibly associated with plants in very numerous forms.

galenic possible.

  These compositions according to the prior art have defects linked essentially to the source of n-3 PUFA that is fish oil: * Very poor tolerance, whatever its mode of purification, patients often stopping the treatment of discomfort from taste, smell and regurgitation. Attempts have been made to reduce this intolerance, either by gentle hydrogenation, but this damages PUFAs which lose their structural membrane properties, or by microencapsulation in gelatin, which partly masks the odor, but increases the surface area offered to the body. 'oxidation, which reduces the stability time; * The large excess of EPA compared to the DHA provided by fish oil when the needs of the body for EPA are very low; the only cells containing EPA, in a significant quantity, are platelets, and, in a lesser quantity, erythrocytes, whereas practically all cells contain DHA; EPA has long been regarded as the really useful n-3 series PUFA. At present, although beneficial as in hypercoagulability problems, it is considered to have drawbacks, in particular as a powerful inhibitor of the synthesis of arachidonic acid, hereinafter referred to as AA, absolutely essential as the ADH to the biological activity of all cell membranes; * DHA from fish oils or other sources is in the form of triglycerides and not in the form directly assimilated by the cell membranes that are glycerophospholipids, hereinafter called GPL; in fact, in membranes, PUFAs are only in the form of LPG, the hydrophilic part of which is oriented towards the periphery, while the lipophilic part is found in the membrane bilayer; the immediate integration of LPG supplies guarantees faster efficiency, avoids additional work for the body, and better restores membrane functioning

  thus promoting the therapeutic effect of plants or bee secretions.

  The present invention therefore has, among other aims, to avoid these defects encountered in

prior art.

  The invention provides micronutrient compositions with therapeutic effect, characterized in that they comprise a base with non-specific effect combining polyunsaturated fatty acids PUFA, in particular PUFA n-3, essential trace elements.

  ETE, and vitamins VIT, and possibly AAm amino acids.

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  At least one basic composition according to the invention can be added at least one complementary substance with specific effect of living, plant or animal origin.

  According to another characteristic of the invention, the composition contains n-PUFAs

  3 having docosahexaenoic acid ADH and eicosapentaenoic acid AEP in an ADH / (ADH + AEP) ratio greater than or equal to 0.9, of which at least part of

  ADH is in the form of phospholipids.

  A composition according to the invention can also jointly contain selenium in organic form, vitamin E and vitamin C. It can also

  contain AA arachidonic acid.

  According to an important characteristic of the invention, the n-3 PUFAs used are obtained from egg yolk enriched in DHA by biotechnological process, by modifying the food of avian species, by providing n-3 PUFAs in the form of fish oil, the eggs laid by these species having all the PUFAs, including DHA, necessary, the DHA being in the form of phospholipids. In particular, we can mix these PUFAs rich in AA and poor in ADH, on the one hand, and PUFAs rich in ADH and poor in AA, on the other hand, in proportions defined by calculation from

  compositions of the starting materials to obtain the desired ratio between ADH and AA.

  The essential trace elements can be: calcium Ca, magnesium Mg, iron Fe, chromium Cr, nickel Ni, cobalt Co, copper Cu, manganese Mn, molybdenum

  Mo, vanadium V, zinc Zn, selenium Se, fluorine F and iodine 1.

  A composition according to the invention may also contain: * at least one substance of plant origin from the following species: ginseng, ginkgo biloba, blueberry, witch hazel, passionflower, artichoke, harpagophytum and blackcurrant,

  * at least one substance of animal origin such as propolis or royal jelly.

  The amino acids used can be sulfur or else proline or

hydroxyproline.

  The compositions in accordance with the invention find their applications

  therapeutic, especially in cases involving degeneration and / or aging.

  It can be added that, according to another technical characteristic of the invention, in a common basic composition is combined with Il'ADH (PUFA for membrane reconstruction), possibly AA, antioxidant agents, in adequate quantity and quality. the base of which is preferably the above-mentioned combined contribution of selenium in organic form, of VIT E and of VIT C. The inventors have carefully studied the pathophysiology of degenerative diseases and aging and have observed that evolution of healthy individuals towards pathology, whatever its location, results from two concomitant phenomena and

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  intimately linked which constitute a common pathological core allowing to define the basic composition with therapeutic effect in accordance with the invention: 1) A first phenomenon is the dysfunction of cell membranes, due to a

  imbalance of dietary PUFA intake, very common with modern food.

  The supply of n-3 PUFA, in particular ADH, essential to cell membranes, is deficient. This means that the structure of the membranes is very rich in AA arachidonic acid which gives rise to mediators (such as prostaglandins and

  leukotrienes) generators of oxygenated free radicals, hereinafter called RLO.

  It may be that, under certain conditions, the AA is not in great excess, which can appear in particular due to an insufficient endogenous synthesis and the disaffection in the consumption of red meats and offal which results from the fear of KREUTZFELD-JACOB disease due to prions. These foods are an important source of PUFAs with very long chains. If the situation persists,

  AA deficiencies may appear over time.

  2) A second phenomenon results from the excess of AA in the membranes causing the excess of RLO which attack the membrane phospholipids, thus weakening the structure of the cell, and causing its dysfunction, which constitutes an increasingly vicious circle.

  more destructive, the capacity for regeneration decreasing until cell death.

  According to a characteristic of the invention, the n-3 PUFAs used can be obtained from egg yolk enriched in DHA by a biotechnological process, by modifying the

  feed for hens, guinea fowl, quail or other avian species, by supplying n PUFA

  3 in the form of fish oil or single-celled organisms in quantity and quality 2 5 carefully defined. Thus we can obtain, in the eggs laid by these birds, the

  PUFAs including the necessary DHA being in the form of phospholipids.

  According to an important characteristic of the invention, to obtain PUFAs, two kinds of egg powder are used: a) one rich in DHA and relatively poor in AA, birds of birds fed partially with fish oil , rich in lafamillen-3 fatty acids b) the other rich in AA and relatively poor in DHA, birds of fed birds

  partially with seeds or vegetable oil rich in n-6 fatty acids.

  From the contents in each PUFA, a simple calculation makes it possible to determine the

  adequate mixing to finally obtain the desired AA / ADH ratio.

  The DHA is preferably in the form of phospholipids, which are found, for example, around 200 mg per chicken egg, which corresponds to an optimum of

  the metabolic capacity of said volatile.

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  This constitutes a characteristic advantage of the invention, since, moreover, there are situations where the enzymatic systems allowing the metabolism of PUFAs are lowered, even inhibited, in particular the delta-6 desaturase. We can cite in particular the following situations: age (lowering of delta-6-desaturase and elongase), * important carbohydrate intakes, * abundant lipid intakes, * zinc, iron, copper deficiency , * secretion of glucagon, thyroxine, adrenaline, * administration of corticosteroids,

* liver failure.

  According to another characteristic of the invention, the combination of ADH, anti-free radicals and substances corresponding to the common base, makes it possible to treat the pathophysiological field, in a non-specific manner. This field treatment becomes specific when it is associated, in addition, with two types of supplements: 1) Specific micronutrients The pathologies present a common origin treated by the substance linked to the common trunk, they are differentiated by specific biological alterations that the 'study

  of the pathophysiology of each of them allows us to understand.

  Thus, according to a characteristic of the invention, one can provide in addition to the components of the common base, minerals, vitamins, PUFAs, and possibly the amino acids necessary for the complete restoration of the biological terrain. 2 5 For example: In the case of premature or accelerated aging, in addition to the LPGs providing PUFAs such as the ADH / (ADH + EPA) ratio is greater than 0.9, and the AA, selenium preferably under organic form, and VIT E and C, we will bring chromium Cr, zinc Zn, magnesium Mg, manganese Mn, copper Cu, which prove to be deficient in the elderly, as well as VIT B3, B6 , B9, B12, beta-carotene, and,

  possibly glutathione (or cysteine).

  In the case of atherosclerosis, in addition to the common base, chromium Cr, magnesium Mg, zinc Zn, manganese Mn, VIT BI, B2, B3, and possibly

glutathione and / or carnitine.

  3 5 In the case of rheumatic joint, ligament or muscle inflammation, always in addition to the common base, copper Cu, zinc Zn,

  manganese Mn, silicon Si, as well as proline, hydroxyproline and VIT B6.

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  2) Plants and / or secretions of insects They are presented in the most varied galenical forms: for example fluid or dry extracts, powders, suspensions, essential oils, macerates, mother tinctures

  alcoholic or not, alcoholates, alcoholates, hydrolysates, extracts, mellites, propyl extracts

  glycolic, nebulized, etc ... We will choose them taking into account their concentrations in

active subtances.

  Thus, by using the common basic composition, added with specific micronutrients, the biological terrain is restored and experience has shown that, as a result, the therapeutic efficacy of the associated substance (s) of living origin, such as plants, propolis, or royal jelly, was potentiated, in particular, from

  fact that it can be practiced on a balanced ground.

  The selection criteria for these components of living origin are essentially the following: * Possess a recognized therapeutic effect at precise, well-defined doses, which can be standardized; * Have been the subject of recent and indisputable studies according to the most recent criteria of pharmacognosy; * Be used in their most concentrated dosage form, therefore occupying the smallest possible space in the pharmaceutical form considered, which is

generally the case of extracts.

  Thus, the inventors of the present application have studied and successfully used the following plants, the list of which is not exhaustive:

VARIETIES NAMES LATINS FAMILIES

  Ginseng Panax ginseng CA MEYER Araliaceae Blueberry Vaccinium myrtillus Ericaceae Witch hazel Hamamelis Virginiana Hamamelidaceae Passionflower Passiflora incarnata Passifloraceae Artichoke Cynara scolymus Compounds Harpagophytum Harpagophytum procumbens Pedaliacs Cassis Ribes nigrum sausage, non-animal products list may not include this product, can be listed as blackcurrants Ribes nigrum nigrum Saxifragus among others, propolis and royal jelly whose effectiveness has been

also successfully tested.

  The essential trace elements of the compositions in accordance with the invention must have good bioavailability, that is to say, in general, they must preferably be in organic form:

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  * For metalloids, such as selenium Se, they can be integrated, for example, in

  proteins, or in yeasts.

  * For metals, we will use, among others, amino acid chelates, picolinates, proteinates, peptonates, gluconates, pidolates (5-oxoprolinates), enriched yeasts, enriched microalgae. Can be selected, among others, as ETA, in accordance with the invention: calcium Ca, magnesium Mg, iron Fe, chromium Cr, nickel Ni, cobalt Co, copper Cu, manganese Mn, molybdenum Mo, Vanadium V, zinc Zn, selenium Se,

  fluorine F. iodine I. They can be used alone or in combination.

  In accordance with the invention, the vitamins are used as cofactors of essential trace elements, by promoting the digestive absorption of these TEEs, and this under

  form of vitamins co-active with each other or with certain TEEs.

  For example, in a disturbed carbohydrate metabolism, a mixture of chromium 111 is used with vitamin B3, its cofactor, and vitamins B 1 and B2, which leads to a synergy between these micronutrients in the field and with d other substances

  in terms of treatment (especially insulin).

  The amino acids AAm, in the compositions in accordance with the invention, belong to the two categories defined below. Experience has shown that the addition of AAm is complex to grasp, due in particular to the interactions between them which are very numerous and often poorly understood. The essential AAm must be present, and in correct proportions for a satisfactory assimilation, but this is still poorly understood, hence the circumspection of the rule in this area of AAm in micronutrition, and the serious essential experimentation that the inventors are carrying out. . On the filing date of this application and on the basis of their experiments, the inventors define the following two categories: 1) First category of AAm These are sulfur AAm, in particular cysteine for its detoxifying function and anti-free radical. Cysteine or its derivatives such as carbocysteine, N-acetyl-cyste does, allows the body to carry out the synthesis of glutathione, tripeptide which allows the

  synthesis of an antioxidant key, the selenium enzyme, glutathionperoxidase.

  2) Second category of AAm These are proline or hydroxyproline, non-essential AAm, but

  major constituents of cartilage.

  To better understand the technical characteristics and advantages of the present invention, we will describe examples of embodiment and experimental studies, it being understood that these are not limiting as to their mode of

  implementation and applications that can be made.

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  First example of study: immunostimulating effect We study the following common basic composition, supplemented with ginseng extract, that is to say, by taking: * glycerophospholipids very rich in ADH, with ADH / (ADH + EPA) greater than or equal to 0.9, in an amount corresponding to 5 to 50 mg of DHA, * 25 mg of organic selenium, * 3 mg of FAST * 5 mg of zinc * 25 mg of VITC * 1 mg of VITB6

  * 100 mg of standardized extract of Ginseng panax C.A. MEYER.

  The composition according to the invention was compared with a placebo and a commercial composition containing ginseng alone. They were administered to 30 volunteers comparable to each other, divided into three groups of ten subjects receiving

  respectively the three compositions for eight weeks.

  The following immunological parameters were studied: * leukocyte chemotaxis: the migration of leukocytes was measured in millimeters after deduction of spontaneous migration; * phagocytic index: phagocytosed microorganisms have been counted; * naturaikillers or killer cells expressed as a percentage of microorganisms killed; * total T lymphocytes in percentage; With T4 helper lymphocytes as a percentage; * T8 suppressor lymphocytes in percentage;

* report T41T8.

  The results obtained are indicated in the table below at times to (at times

  0), t4 (at four weeks) and t0 (at eight weeks).

  Overall, all the checks carried out show that the compositions in accordance with the invention are superior to placebo and even to good quality ginseng

  standardized, which confirms the synergy obtained.

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  PARAMETERS t AVERAGE VALUES placebo ginseng only invention chemotaxis to 2.03 + 0.6 1.74 + 0.5 1.75 + 0.4 t4 2.01 0.6 2.20 + 0.5 2.25 0, 5 t8 2.00 + 0.5 2.50 0.5 2.65 + 0.5 phagocytic index to 0.42 + 0.2 0, 40+ 0.1 0.42 + 0.2 t4 0.46 + 0.2 0.56 + 0.1 0.57 + 0.2 t8 0.44 + 0.2 0.63 + 0.1 0.70 + 0.2 cellulosic t 37.7 + 19 30.7 + 11 31.2 + 11l t4 42.2+ 15 40.2 14 41.2 + 15 t8 40.5 + 14 44.8 + 13 47.1 + 14 T cells to 83.7 + 7 80.9 + 5 82.2 + 5 t4 80.8 + 12 87.7 + 8 89.0 + 5 t 82.8 + 10 88.6 + 9 92.0 + 5 T4 helpers to 52.7 + 8 57.6 + 4 54.7 + 6 t4 51.6 + 7 61.7 + 4 62.0 +5 t8 52.7 + 8 65.2 + 4 67.1 + 4 T8 suppressor to 26.1 + 5 30.7 + 3 30.5 + 4 t4 26.0 + 5 29.8 + 4 30.1 + 4 t8 26.7 + 5 30.7 + 3 31.4 + 4 T41 / T8 in values to 2.02 1.87 1 , 79 means t4 1.98 2.07 2.05 t8 1.97 2.12 2.13 Second study example: retinopathy in the elderly A more limited study was carried out on ten elderly people with vision problems due to a retinopathy. All had undergone exams for measuring visual acuity (ETDRS scale), reading speed (ZEISS board) and near acuity measurement (PARINAUD scale). In addition, the eye examinations proper were performed with a slit lamp, the microscopic examination of the fundus, the

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  taking retinography shots and monochromatic shots, defining the field

visual and electroretinogram.

  Five people received, for three months, a standardized extract of Vaccinium myrtillus (Ericaceae) at a dose of 100 mg per dose. Five people received, for three months, a composition in accordance with

  the invention constituted by the common base as defined in the first study above

  above, but added here, not ginseng, but standardized Vaccinium extract

  myrtillus (Ericaceae) 100 mg per dose.

  At the end of the three months of experimentation, the vision of the five people treated with the composition in accordance with the invention improved markedly, while the other five people treated with the blueberry extract only improved significantly less, and , in particular, both at the back of the eye and at the level of the retina and the electroretinogram. The synergistic effect of the composition according to the invention is

again demonstrated here.

  Third example: immunological activity The following composition comprising the common base supplemented with ginseng has been successfully tested. The daily dose is quantified, and the possible range of the contents of the various components has been added: COMPONENT DOSE / day in mg FORK / day in mg glycerophospholipids of ADH 404-60 10-200 seleniummetalloid 0.05 0.0005 -0.30 zinc metal 10 0.01-100 vitamin E 10 0.01-100 vitamin C 80 0.5-10000 ginseng extract (white roots), titrated to 4% ginsenoside 200 20 400 Fourth example: aging and brain function Similarly, we have successfully experimented with the following composition in its two

additional component variants.

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  COMPONENT DOSE / day in mg FORK / day in mg glycerophospholipids of DHA 40-60 10-200 selenium 0.05 0.0005-0.30 chromium 0.025 0.0002-0, 40 magnesium 50 5-1000 zinc 10 0 , 01-100 manganese 2 0.005-20 vitamin B6 2 0.2-20 vitamin B 1 1 0.1-10 vitaminB2 1.4 0.1-15 vitamin B9 0.04 0.0001-4 vitamin B3 16 1- 60 ginseng extract (white roots), titrated to 4% ginsenoside 200 20-400 or ginkgo biloba extract 7 0.1-70

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Claims (15)

  1) Micronutrient composition with therapeutic effect, characterized in that it comprises a base with non-specific effect associating polyunsaturated fatty acids, essential trace elements, and vitamins. 2) Composition according to claim 1 characterized in that it comprises amino acids.   3) Composition according to one of claims 1 or 2 characterized in that at the   non-specific basic composition is added at least one substance   complementary to specific effect of living origin.   4) Composition according to claim3 characterized in that it comprises at least   a complementary substance of plant origin.   ) Composition according to one of claims 3 or 4 characterized in that it   includes at least one complementary substance of animal origin.   6) Composition according to one of claims I to 5 characterized in that it contains   n-3 polyunsaturated fatty acids having a mass ratio of docosahexaenoic acid divided by the sum of the masses of docosahexaenoic acid and acid   eicosapentaenoic greater than or equal to 0.9.   7) Composition according to one of claims I to 6 characterized in that it contains   docosahexaenoic acid mainly in the form of phospholipids.   8) Composition according to one of claims I to 7 characterized in that it contains   together selenium in organic form, vitamin E and vitamin C.   9) Composition according to one of claims 1 to 8 characterized in that the acids   n-3 polyunsaturated fats used are obtained from egg yolk enriched in docosahexaenoic acid by biotechnological process, by modifying the food of avian species, by contribution of n-3 polyunsaturated fatty acids in the form of fish oil, eggs laid by these species having polyunsaturated fatty acids including the necessary docosahexaenoic acid, docosahexaenoic acid being in the form of phospholipids.   10) Composition according to one of claims 1 to 9 characterized in that it contains arachidonic acid.   11) Composition according to claim 10 characterized in that one mixes polyunsaturated fatty acids rich in arachidonic acid and poor in docosahexaenoic acid, on the one hand, and polyunsaturated fatty acids rich in docosahexaenoic acid and poor in acid arachidonic, on the other hand, in proportions defined by calculation from the compositions of the starting materials to obtain the   desired ratio of docosahexaenoic acid to arachidonic acid.   12) Composition according to one of claims 1 to 10 characterized in that it   contains at least one essential trace element among the following: calcium Ca, 13 2773484   magnesium Mg, iron Fe, chromium Cr, nickel Ni, cobalt Co, copper Cu, manganese Mn, molybdenum Mo, vanadium V, zinc Zn, selenium Se, fluorine F and iodine 1.   13) Composition according to one of claims I to 12 characterized in that it   contains at least one substance of plant origin from the following species: ginseng,   ginkgo biloba, blueberry, witch hazel, passionflower, artichoke, harpagophytum and blackcurrant.   14) Composition according to one of claims I to 13 characterized in that it contains propolis.   ) Composition according to one of claims 1 to 14 characterized in that it contains royal jelly.   16) Composition according to one of claims 2 to 15 characterized in that it   contains at least one sulfur amino acid.   17) Composition according to one of claims 2 to 16 characterized in that it   contains proline or hydroxyproline.   18) Therapeutic application of the composition according to one of claims 1 to 17 to   pathologies involving degeneration and / or aging.