WO2004047564A1 - Novel pharmaceutical compositions in particular for preventing cardiovascular pathologies - Google Patents

Novel pharmaceutical compositions in particular for preventing cardiovascular pathologies Download PDF

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Publication number
WO2004047564A1
WO2004047564A1 PCT/FR2003/003425 FR0303425W WO2004047564A1 WO 2004047564 A1 WO2004047564 A1 WO 2004047564A1 FR 0303425 W FR0303425 W FR 0303425W WO 2004047564 A1 WO2004047564 A1 WO 2004047564A1
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vitamin
compositions according
new pharmaceutical
tocopherol
dietetic
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PCT/FR2003/003425
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French (fr)
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Ludovic Predal
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Synergia Holding
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A61K47/6895—Rescue therapy; Agonist-antagonist; Antidotes; Targeted rescue or protection, e.g. by folic acid-folinic acid or conjugated to antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to the field of chemistry and more particularly to the field of therapeutic chemistry.
  • compositions containing at least one vitamin from the group of vitamin B and of vitamin C, associated or in mixture with an excipient or an inert, non-toxic, pharmaceutically acceptable vehicle.
  • vitamins of group B used in the compositions of the present invention there may be mentioned in particular vitamin B6 or Pyridoxine, vitamin B12 or Cobalamin, vitamin B9 or folic acid, vitamin E or Tocopherol, vitamin B1 or thiamine and the vitamin B2 or ziboflavin.
  • vitamin C is defined as being by ascorbic acid itself, but it is understandable that it can be substituted for iso-ascorbic acid or salts of ascorbic acid (sodium, calcium or tromethamine salts ), or esters such as palmitate or ascorbyl stearate. Vitamin C can also be used in the form of lactone or alternatively in the form of an enol ester. Ascorbic acid and its derivatives can be racemic or split. Each epimer is part of the scope of the invention. Vitamin B6 called pyridoxine has the following chemical formula
  • Vitamin E is defined as a tocopherol. This term is called ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol and ⁇ -tocopherol. Also included in this family are tocotrienols of which two representatives are known ( ⁇ and ⁇ ). However, in the context of the present invention, it is alpha or gamma tocopherol which are the preferred constituents, ⁇ -tocopherol has the formula:
  • tocopherol can exist in racemic or split form, in the form of all cis (R, R, R) or all trans isomers.
  • ⁇ -tocopherol occurs in the form (4R, 8R).
  • Tocopherol can also be in the form of esters such as nicotinate, ⁇ -linolenate, acetate or acid succinate of tocopherol.
  • Vitamin B9 is the name given to folic acid and its derivatives and more particularly to folinic acid, free or in salt form, in racemic form or in split form, in particular for folinic acid which is in RR form. and RS.
  • Vitamin B12 designates a large class of cobalt complexes linked to a tetraporphyric nucleus and carrying phosphorylated residues of ribofuranose.
  • the central cobalt atom is linked to an anion which can be a cyanide (cyano cobalamin) a sulfite (sulfitocobalamin), an acetate (acetocobalamin) a hydroxo (hydroxocobalam) a chloride (chlorocobalamin), a methyl radical (methylcobalamin) or under internal salt form with phosphoric groups (co-enzyme B12).
  • the compositions according to the invention represent a synergy which finds particular use in the cardiovascular field, in particular as a protective agent for the arteries and the heart.
  • compositions according to the invention have many other therapeutic applications, in particular in the prevention of atheroma and the treatment of hyperlipidemias, disorders of the metabolism of carbohydrates and also for the treatment of nervous disorders linked to alcohol consumption.
  • compositions according to the invention contain from 50 to 250 mg of ascorbic acid and preferably from 80 to 160 mg, per unit dose.
  • compositions according to the invention contain tocopherol (vitamin E) in a unit dose ranging from 5 to 25 mg and preferably from 8 to 16 mg.
  • compositions according to the invention contain vitamin B6 (pyridoxine) in a unit dose ranging from 3 to 20 mg and preferably from 4 to 10 mg.
  • vitamin B6 pyridoxine
  • compositions according to the invention contain vitamin B9 in the form of folic acid at a unit dose of 0.4 to 1 mg and preferably from 0.5 to 2 mg.
  • Vitamin B 12 is present in the compositions according to the invention, in particular in the form of cyanocobalamin or of hydroxocobalamin, at a unit dose ranging from 100 ⁇ g to 1,000 ⁇ g and preferably from 150 to 250 ⁇ g per unit dose.
  • a composition according to the invention contains: vitamin C at a dose of 100 mg natural vitamin E ( ⁇ -tocopherol) at a dose of 10 mg vitamin B6 at a dose of 5 mg - vitamin B9 at a dose of 500 ⁇ g vitamin B 12 at a dose of 200 ⁇ g
  • the compositions according to the invention are mainly intended for the oral route. However, other routes of administration are possible such as the transcutaneous or percutaneous route or the parenteral route.
  • the physiologically acceptable non-toxic inert excipient is a diluting agent, a bulking agent, a binding agent, a disintegrating agent, a flavoring agent, a structuring agent, a release agent or a lubricating agent.
  • mineral or organic fillers such as microcrystalline cellulose, diluents such as microcrystalline cellulose or starch, disintegrating agents such as carboxyl methyl starch, mannitol or cross-linked polyvinyl pyrrolidone, flavoring agents such as a natural or synthetic sweetener, for example acesulfame, aspartame or stevioside, one or more structuring agents such as citric acid, disodium citrate or disodium phosphate, a mold release agent such as talc , sodium soap, magnesium stearate, calcium stearate or stearic acid, and / or a lubricating agent such as mineral oil, paraffin oil or silicone oil.
  • compositions according to the invention will be presented for oral administration in the form of capsules, capsules, tablets, coated tablets, pills, cachets, granules, bars or powders, flavored or not.
  • composition will be presented in liquid form, in particular in the form of capsules, oil in water emulsion or water in oil.
  • the preferred dosage ranges from 1 to 3 unit doses per day.
  • compositions according to the invention have protective effects with respect to arterial diseases and heart diseases. They regulate the metabolic pathways involved in cardiovascular disease, in particular the regulation of the metabolism of sulfur amino acids such as methionine and homocysteine.
  • compositions according to the invention show real effectiveness in preventing restenosis after angioplasty, in particular after removal of a stent.
  • Vitamins B6, B9 (folic acid) and B12 are important in several metabolic pathways involved in cardiovascular disease.
  • these 3 vitamins regulate the metabolism of sulfur amino acids, in particular the synthesis of methionine and the degradation (or recycling) of homocysteine.
  • Methionine is essential in the processes of methylation (of nucleic acids), protein synthesis and cell multiplication.
  • Homocysteine is toxic to the endothelium of the arteries as soon as its concentration in the blood increases beyond the so-called physiological values.
  • Folic acid in addition to its role in the metabolism of homocysteine, is important in cardiovascular physiology because it is one of the co-factors of endothelial NO synthase.
  • NO nitric oxide
  • Endothelial NO synthase is a versatile enzyme which, in the event of a substrate deficiency (arginine) or in the presence of an arginine competitor (dimethyl-arginine) or even in the event of a deficiency in one of the co-factor ( zinc, folic acid, tetrahydrobiopterin or BH4), stops producing NO and generates free oxygen radicals (especially the superoxide ion) toxic to the endothelium and pro-inflammatory.
  • arginine substrate deficiency
  • dimethyl-arginine dimethyl-arginine
  • BH4 zinc, folic acid, tetrahydrobiopterin or BH4
  • B vitamins (especially folic acid) are therefore at the crossroads of several pathophysiological mechanisms involving homocysteine, NO synthase, superoxide ion and its derivative (peroxide-nitrite) and finally some classic risk factors (diabetes , Hypertension, syndrome X, cholesterol) which promote the accumulation of dimethyl arginine.
  • the B vitamins must be considered in the general context of the correction of these risk factors (smoking cessation, correction of dyslipidemia and diabetes, treatment of high blood pressure) and in the part of eating habits that protect both the heart (the myocardium proper) and the arteries (and their walls).
  • a preventive approach based on the use of B vitamins should take into account not only very serious events (ventricular arrhythmias, myocardial infarction) endangering the lives of patients in the very short term but also symptoms or syndromes (angina pectoris). chest, exercise tolerance, restenosis after angioplasty, endothelial dysfunction) which condition the quality of life of patients and / or significantly influence the prognosis in the medium and long term.
  • vitamin B6 and vitamin B12 can also have a direct protective effect, also partly independent of homocysteine.
  • Figure 1 represents before and after administration of folic acid the variation of the diameter of the arteries (EDD) in response to the lifting of a tourniquet (cuff.release). This diameter is measured by ultra sonometry of the maximum arterial flow or FMD (Flow Mediated Dilation).
  • EDD diameter of the arteries
  • FMD Flow Mediated Dilation

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Abstract

The invention concerns the field of chemistry and more particularly the field of therapeutic chemistry. More precisely, the invention concerns novel pharmaceutical and/or dietetic compositions containing vitamins of the group of vitamins B, and vitamin C, associated or mixed with an inert, non toxic and physiologically acceptable excipient or vehicle. The invention is useful in particular as preventive agent against arterial diseases and heart diseases.

Description

NOUVELLES COMPOSITIONS PHARMACEUTIQUES NOTAMMENT POUR LA PREVENTION DES PATHOLOGIES CARDIO-VASCULAIRES NEW PHARMACEUTICAL COMPOSITIONS IN PARTICULAR FOR THE PREVENTION OF CARDIOVASCULAR CONDITIONS
La présente invention se rapporte au domaine de la chimie et plus particulièrement au domaine de la chimie thérapeutique.The present invention relates to the field of chemistry and more particularly to the field of therapeutic chemistry.
Elle plus a particulièrement pour objet de nouvelles compositions pharmaceutiques et/ou diététiques à base de composés vitaminiques possédant des effets protecteurs vis-à-vis du système cardio-vasculaire.It more particularly relates to new pharmaceutical and / or dietetic compositions based on vitamin compounds having protective effects vis-à-vis the cardiovascular system.
Elle se rapporte plus précisément à de nouvelles compositions pharmaceutiques et/ou diététiques renfermant au moins une vitamine du groupe de la vitamine B et de la vitamine C, associées ou en mélange avec un excipient ou un véhicule inerte, non-toxique, pharmaceutiquement acceptable.It relates more precisely to new pharmaceutical and / or dietetic compositions containing at least one vitamin from the group of vitamin B and of vitamin C, associated or in mixture with an excipient or an inert, non-toxic, pharmaceutically acceptable vehicle.
Parmi les vitamines du groupe B utilisées dans les compositions de la présente invention on citera en particulier la vitamine B6 ou Pyridoxine, la vitamine B12 ou Cobalamine, la vitamine B9 ou acide folique, la vitamine E ou Tocophérol, la vitamine Bl ou thiamine et la vitamine B2 ou ziboflavine.Among the vitamins of group B used in the compositions of the present invention, there may be mentioned in particular vitamin B6 or Pyridoxine, vitamin B12 or Cobalamin, vitamin B9 or folic acid, vitamin E or Tocopherol, vitamin B1 or thiamine and the vitamin B2 or ziboflavin.
Cependant ces termes doivent conserver une très grande généralité car de nombreux dérivés chimiques, des isomères ou des énantiomères sont connus et possèdent des propriétés similaires.However, these terms must remain very general since many chemical derivatives, isomers or enantiomers are known and have similar properties.
De même la vitamine C est définie comme étant par l'acide ascorbique lui-même mais il est compréhensible qu'on puisse lui substituer l'acide iso-ascorbique ou des sels d'acide ascorbique (sels de sodium, de calcium ou de trométhamine), ou des esters comme le palmitate ou le stéarate d'ascorbyle. On peut également utiliser la vitamine C sous forme de lactone ou bien encore sous forme d'ester d'enol. L'acide ascorbique et ses dérivés peuvent être racémiques ou dédoublés. Chaque épimère fait partie du cadre de l'invention. La vitamine B6 dénommée pyridoxine possède la formule chimique suivanteLikewise vitamin C is defined as being by ascorbic acid itself, but it is understandable that it can be substituted for iso-ascorbic acid or salts of ascorbic acid (sodium, calcium or tromethamine salts ), or esters such as palmitate or ascorbyl stearate. Vitamin C can also be used in the form of lactone or alternatively in the form of an enol ester. Ascorbic acid and its derivatives can be racemic or split. Each epimer is part of the scope of the invention. Vitamin B6 called pyridoxine has the following chemical formula
CH2 OHCH 2 OH
Figure imgf000003_0001
Figure imgf000003_0001
II est évident que des dérivés chimiques proches tels que la pyridoxamine et ses sels, de formuleIt is obvious that close chemical derivatives such as pyridoxamine and its salts, of formula
Figure imgf000003_0002
Figure imgf000003_0002
le pyridoxal de formulethe pyridoxal of formula
Figure imgf000003_0003
Figure imgf000003_0003
et ses sels le pyridoxal 5-phosphate et ses sels ou l'acide 4-pyridoxiqueand its salts pyridoxal 5-phosphate and its salts or 4-pyridoxic acid
COOHCOOH
Figure imgf000003_0004
et ses sels et sa lactone (β-pyracine) rentrent également dans la définition du terme vitamine B6 selon la présente invention. La vitamine E est définie comme étant un tocophérol. On dénomme sous ce terme l'α- tocophérol, le β-tocophérol, le γ-tocophérol, le δ-tocophérol et l'ε-tocophérol. On englobe également dans cette famille les tocotriénols dont on connaît deux représentants (α et β). Cependant dans le cadre de la présente invention c'est l'alpha ou le gamma tocophérol qui sont les constituants préférés, l'α-tocopherol a pour formule :
Figure imgf000003_0004
and its salts and its lactone (β-pyracin) also fall within the definition of the term vitamin B6 according to the present invention. Vitamin E is defined as a tocopherol. This term is called α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and ε-tocopherol. Also included in this family are tocotrienols of which two representatives are known (α and β). However, in the context of the present invention, it is alpha or gamma tocopherol which are the preferred constituents, α-tocopherol has the formula:
Figure imgf000004_0001
Figure imgf000004_0001
Il est bien connu que le tocophérol peut exister sous forme racémique ou dédoublée, sous forme d'isomères tout cis (R, R, R) ou tout trans. Dans les huiles de soja et de blé le γ- tocophérol se présente sous forme (4R, 8R).It is well known that tocopherol can exist in racemic or split form, in the form of all cis (R, R, R) or all trans isomers. In soybean and wheat oils γ-tocopherol occurs in the form (4R, 8R).
Le tocophérol peut également se présenter sous forme d'esters comme le nicotinate, le γ- linolénate, l'acétate ou le succinate acide de tocophérol.Tocopherol can also be in the form of esters such as nicotinate, γ-linolenate, acetate or acid succinate of tocopherol.
Tous ces dérivés rentrent dans la définition du terme tocophérol.All these derivatives fall within the definition of the term tocopherol.
La vitamine B9 est le nom donné à l'acide folique et ses dérivés et plus particulièrement à l'acide folinique, libre ou sous forme de sel, sous forme racémique ou sous forme dédoublée notamment pour l'acide folinique qui se présente sous forme RR et RS.Vitamin B9 is the name given to folic acid and its derivatives and more particularly to folinic acid, free or in salt form, in racemic form or in split form, in particular for folinic acid which is in RR form. and RS.
Le terme Vitamine B12 désigne une vaste classe de complexes du cobalt lié à un noyau tétraporphyrique et portant des résidus phosphorylés de ribofuranosé.The term Vitamin B12 designates a large class of cobalt complexes linked to a tetraporphyric nucleus and carrying phosphorylated residues of ribofuranose.
L'atome de cobalt central est lié à un anion qui peut être un cyanure (cyano cobalamine) un sulfite (sulfitocobalamine), un acétate (acétocobalamine) un hydroxo (hydroxocobalamme) un chlorure (chlorocobalamine), un radical méthyle (methylcobalamine) ou sous forme de sel interne avec les groupements phosphoriques (co-enzyme B12). Les compositions selon l'invention représentent une synergie qui trouve notamment une pleine utilisation dans le domaine cardiovasculaire, en particulier comme agent protecteur des artères et du cœur.The central cobalt atom is linked to an anion which can be a cyanide (cyano cobalamin) a sulfite (sulfitocobalamin), an acetate (acetocobalamin) a hydroxo (hydroxocobalam) a chloride (chlorocobalamin), a methyl radical (methylcobalamin) or under internal salt form with phosphoric groups (co-enzyme B12). The compositions according to the invention represent a synergy which finds particular use in the cardiovascular field, in particular as a protective agent for the arteries and the heart.
Néanmoins les compositions selon l'invention possèdent beaucoup d'autres applications thérapeutiques notamment dans la prévention de l'athérome et le traitement des hyperlipidémies, des troubles du métabolisme des glucides et encore pour le traitement des troubles nerveux liés à la consommation d'alcool.However, the compositions according to the invention have many other therapeutic applications, in particular in the prevention of atheroma and the treatment of hyperlipidemias, disorders of the metabolism of carbohydrates and also for the treatment of nervous disorders linked to alcohol consumption.
Les compositions selon l'invention contiennent de 50 à 250 mg d'acide ascorbique et de préférence de 80 à 160 mg, par prise unitaire.The compositions according to the invention contain from 50 to 250 mg of ascorbic acid and preferably from 80 to 160 mg, per unit dose.
Les compositions selon l'invention renferment du tocophérol (vitamine E) à une dose unitaire allant de 5 à 25 mg et de préférence de 8 à 16 mg.The compositions according to the invention contain tocopherol (vitamin E) in a unit dose ranging from 5 to 25 mg and preferably from 8 to 16 mg.
Les compositions pharmaceutiques selon l'invention renferment de la vitamine B6 (pyridoxine) à une dose unitaire s'échelonnant de 3 à 20 mg et de préférence de 4 à 10 mg.The pharmaceutical compositions according to the invention contain vitamin B6 (pyridoxine) in a unit dose ranging from 3 to 20 mg and preferably from 4 to 10 mg.
Les compositions selon l'invention renferment de la vitamine B9 sous forme d'acide folique à une dose unitaire de 0,4 à 1 mg et de préférence de 0,5 à 2 mg.The compositions according to the invention contain vitamin B9 in the form of folic acid at a unit dose of 0.4 to 1 mg and preferably from 0.5 to 2 mg.
La vitamine B 12 est présente dans les compositions selon l'invention, notamment sous forme de cyanocobalamine ou d'hydroxocobalamine, à une dose unitaire allant de 100 μg à 1.000 μg et de préférence de 150 à 250 μg par prise unitaire.Vitamin B 12 is present in the compositions according to the invention, in particular in the form of cyanocobalamin or of hydroxocobalamin, at a unit dose ranging from 100 μg to 1,000 μg and preferably from 150 to 250 μg per unit dose.
D'une manière préférée une composition selon l'invention contient : la vitamine C à la dose de 100 mg la vitamine E naturelle (γ-tocophérol) à la dose de 10 mg la vitamine B6 à la dose de 5 mg - la vitamine B9 à la dose de 500 μg la vitamine B 12 à la dose de 200 μg Les compositions selon l'invention sont principalement destinées à la voie orale. Cependant d'autres voies d'administration sont possibles comme la voie transcutanée ou percutanée ou la voie parentérale.In a preferred manner, a composition according to the invention contains: vitamin C at a dose of 100 mg natural vitamin E (γ-tocopherol) at a dose of 10 mg vitamin B6 at a dose of 5 mg - vitamin B9 at a dose of 500 μg vitamin B 12 at a dose of 200 μg The compositions according to the invention are mainly intended for the oral route. However, other routes of administration are possible such as the transcutaneous or percutaneous route or the parenteral route.
L'excipient inerte non toxique physiologiquement acceptable est un agent diluant, un agent de charge, un agent liant, un agent de désagrégation, un agent de sapidité, un agent de structuration, un agent de démoulage ou un agent lubrifiant. On pourra citer à cet égard des produits de charge minéraux ou organiques comme la cellulose microcristalline, des agents diluants comme le la cellulose microcristalline ou l'amidon, des agents de désagrégation comme le carboxyl méthyl amidon, le mannitol ou la polyvmyl pyrrolidone réticulée, des agents de sapidité comme un édulcorant naturel ou synthétique, par exemple l'acésulfame, l'aspartame ou le stévioside, un ou plusieurs agents de structuration comme l'acide citrique, le citrate disodique ou le phosphate disodique, un agent de démoulage comme le talc, le savon sodique, le stéarate de magnésium, le stéarate de calcium ou l'acide stéarique, et/ou un agent lubrifiant comme une huile minérale, une huile de paraffine ou une huile de silicone.The physiologically acceptable non-toxic inert excipient is a diluting agent, a bulking agent, a binding agent, a disintegrating agent, a flavoring agent, a structuring agent, a release agent or a lubricating agent. Mention may be made in this regard of mineral or organic fillers such as microcrystalline cellulose, diluents such as microcrystalline cellulose or starch, disintegrating agents such as carboxyl methyl starch, mannitol or cross-linked polyvinyl pyrrolidone, flavoring agents such as a natural or synthetic sweetener, for example acesulfame, aspartame or stevioside, one or more structuring agents such as citric acid, disodium citrate or disodium phosphate, a mold release agent such as talc , sodium soap, magnesium stearate, calcium stearate or stearic acid, and / or a lubricating agent such as mineral oil, paraffin oil or silicone oil.
Les compositions selon l'invention seront présentées pour l'administration orale sous forme de capsules, de gélules, de comprimés, de comprimés enrobés, de pilules, de cachets, de granulés, de barres ou de poudres aromatisées ou non.The compositions according to the invention will be presented for oral administration in the form of capsules, capsules, tablets, coated tablets, pills, cachets, granules, bars or powders, flavored or not.
Eventuellement la composition sera présentée sous forme liquide notamment sous forme de capsules, d'émulsion huile dans l'eau ou eau dans l'huile.Optionally, the composition will be presented in liquid form, in particular in the form of capsules, oil in water emulsion or water in oil.
La posologie préférée s'échelonne de 1 à 3 prises unitaires par jour.The preferred dosage ranges from 1 to 3 unit doses per day.
Les compositions selon l'invention possèdent des effets protecteurs vis-à-vis des maladies artérielles et des maladies cardiaques. Elles assurent la régulation des voies métaboliques impliquées dans les maladies cardiovasculaires en particulier la régulation du métabolisme des acides aminés soufrés comme la méthionine et l'homocystéine.The compositions according to the invention have protective effects with respect to arterial diseases and heart diseases. They regulate the metabolic pathways involved in cardiovascular disease, in particular the regulation of the metabolism of sulfur amino acids such as methionine and homocysteine.
Elles interviennent pour assurer une amélioration de la fonction endothéliale artérielle par supplémentation en vitamines du groupe B. Les compositions selon l'invention manifestent une réelle efficacité pour prévenir la resténose après angioplastie notamment après prélèvement d'un stent.They are involved in ensuring an improvement in arterial endothelial function by supplementation with group B vitamins. The compositions according to the invention show real effectiveness in preventing restenosis after angioplasty, in particular after removal of a stent.
Les exemples suivants illustrent l'invention sans toutefois la limiter.The following examples illustrate the invention without, however, limiting it.
EXEMPLE IEXAMPLE I
Comprimés à 100 mg de vitamine C100 mg vitamin C tablets
- vitamine C 100 mg- vitamin C 100 mg
- vitamine E naturelle (γ-tocophérol) 10 mg- natural vitamin E (γ-tocopherol) 10 mg
- vitamine B6 5 mg- vitamin B6 5 mg
- vitamine B9 500 μg- vitamin B9 500 μg
- vitamine B 12 200 μg- vitamin B 12 200 μg
Cellulose micro cristalline 40 mgMicro crystalline cellulose 40 mg
Silice colloïdale 5 mgColloidal silica 5 mg
- Lactose 25 mg- Lactose 25 mg
Talc 2 mgTalc 2 mg
Stéarate de magnésium 2 mg pour un compriméMagnesium stearate 2 mg for one tablet
EXEMPLE IIEXAMPLE II
Etude pharmacologique des compositions selon l'inventionPharmacological study of the compositions according to the invention
1 - Les vitamines du groupe B et l'acide folique1 - B vitamins and folic acid
Les vitamines B6, B9 (acide folique) et B12 sont importantes dans plusieurs voies métaboliques impliquées dans les maladies cardiovasculaires. En particulier, ces 3 vitamines régulent le métabolisme des acides aminés soufrés, notamment la synthèse de la méthionine et la dégradation (ou recyclage) de l'homocystéine. La méthionine est indispensable dans les processus de méthylation (des acides nucléiques), la synthèse des protéines et la multiplication cellulaire. L'homocystéine est, quand à elle, toxique pour l'endothélium des artères dès que sa concentration dans le sang augmente au-delà des valeurs dites physiologiques. L'acide folique, outre son rôle dans le métabolisme de l'homocystéine, est important en physiologie cardiovasculaire car il est un des co-facteurs de la NO-synthase endothéliale. Cette enzyme, via la génération d'oxyde nitrique (NO), est un médiateur important de la vasomotricité artérielle (le NO est vasodilatateur) et des interactions endothélium-plaquettes (risque thrombotique) et endothélium-leucocytes (inflammation) qui sont inhibées par le NO. La NO-synthase endothéliale est un enzyme versatile qui, en cas de déficience en substrat (arginine) ou en présence d'un compétiteur de l'arginine (la diméthyl-arginine) ou encore en cas de déficience en un des co-facteur (zinc, acide folique, tétrahydrobioptérine ou BH4), cesse de produire du NO et génère des radicaux libres de l'oxygène (notamment l'ion superoxyde) toxiques pour l'endothélium et pro-inflammatoires.Vitamins B6, B9 (folic acid) and B12 are important in several metabolic pathways involved in cardiovascular disease. In particular, these 3 vitamins regulate the metabolism of sulfur amino acids, in particular the synthesis of methionine and the degradation (or recycling) of homocysteine. Methionine is essential in the processes of methylation (of nucleic acids), protein synthesis and cell multiplication. Homocysteine is toxic to the endothelium of the arteries as soon as its concentration in the blood increases beyond the so-called physiological values. Folic acid, in addition to its role in the metabolism of homocysteine, is important in cardiovascular physiology because it is one of the co-factors of endothelial NO synthase. This enzyme, via the generation of nitric oxide (NO), is an important mediator of arterial vasomotricity (NO is vasodilator) and endothelium-platelet interactions (thrombotic risk) and endothelium-leukocytes (inflammation) which are inhibited by NO. Endothelial NO synthase is a versatile enzyme which, in the event of a substrate deficiency (arginine) or in the presence of an arginine competitor (dimethyl-arginine) or even in the event of a deficiency in one of the co-factor ( zinc, folic acid, tetrahydrobiopterin or BH4), stops producing NO and generates free oxygen radicals (especially the superoxide ion) toxic to the endothelium and pro-inflammatory.
Les vitamines B (surtout l'acide folique) sont donc au carrefour de plusieurs mécanismes physiopathologiques impliquant l'homocystéine, la NO-synthase, l'ion superoxyde et son dérivé (le peroxyde-nitrite) et enfin certains facteurs de risque classiques (diabète, HTA, syndrome X, cholestérol) qui favorisent l'accumulation de diméthyl-arginine. En cardiologie préventive, du fait de ces interactions, les vitamines B doivent être envisagées dans le contexte général de la correction de ces facteurs de risque (arrêt du tabac, correction des dyslipidémies et du diabète, traitement de l'hypertension artérielle) et dans le cadre d'habitudes alimentaires qui permettent de protéger aussi bien le cœur (le myocarde proprement dit) que les artères (et leur paroi).B vitamins (especially folic acid) are therefore at the crossroads of several pathophysiological mechanisms involving homocysteine, NO synthase, superoxide ion and its derivative (peroxide-nitrite) and finally some classic risk factors (diabetes , Hypertension, syndrome X, cholesterol) which promote the accumulation of dimethyl arginine. In preventive cardiology, because of these interactions, the B vitamins must be considered in the general context of the correction of these risk factors (smoking cessation, correction of dyslipidemia and diabetes, treatment of high blood pressure) and in the part of eating habits that protect both the heart (the myocardium proper) and the arteries (and their walls).
Enfin, une approche préventive basée sur l'utilisation des vitamines B devra prendre en compte non seulement les événements gravissimes (arythmies ventriculaires, infarctus du myocarde) mettant en péril la vie des patients à très court terme mais aussi des symptômes ou syndromes (angine de poitrine, tolérance à l'effort, resténose après angioplastie, dysfonctionnement endothélial) qui conditionnent la qualité de vie des patients et/ou influencent de façon significative le pronostic à moyen et long terme.Finally, a preventive approach based on the use of B vitamins should take into account not only very serious events (ventricular arrhythmias, myocardial infarction) endangering the lives of patients in the very short term but also symptoms or syndromes (angina pectoris). chest, exercise tolerance, restenosis after angioplasty, endothelial dysfunction) which condition the quality of life of patients and / or significantly influence the prognosis in the medium and long term.
2 - Epidémiologie des maladies cardiovasculaires, homocystéine, vitamines B L'augmentation des concentrations dans le sang de l'homocystéine au carrefour de 2 voies métaboliques, reméthylation en méthionine (qui nécessite l'acide folique et la vitamine B12) ou trans-sulfuration en • cystathionine (qui nécessite de la vitamine B6) est associé à une augmentation du risque cardiovasculaire. En dehors des sévères hyperhomocystéinmies dues à des maladies génétiques rarissimes, les élévations modérées de l'homocystéine sont dues en général à un déficit de la voie de méthylation, elle-même secondaire à une déficience relative ou absolue, en acide folique et/ou en vitamine B12 et associé ou non à une particularité génétique [polymorphisme génétique (forme TT thermolabile) de la méthylènetétrahydrofolate réductase (MTHFR), l'enzyme qui permet le recyclage de la forme active de l'acide folique].2 - Epidemiology of cardiovascular diseases, homocysteine, B vitamins Increasing blood concentrations of homocysteine at the crossroads of 2 metabolic pathways, methionine remethylation (which requires folic acid and vitamin B12) or trans-sulfurization into • cystathionine (which requires vitamin B6) is associated with an increased cardiovascular risk. Apart from severe hyperhomocysteinemia due to extremely rare genetic diseases, moderate elevations of homocysteine are due general to a deficiency in the methylation pathway, itself secondary to a relative or absolute deficiency in folic acid and / or vitamin B12 and associated or not with a genetic characteristic [genetic polymorphism (thermolabile TT form) of methylenetetrahydrofolate reductase (MTHFR), the enzyme that allows recycling of the active form of folic acid].
De nombreuses études épidémiologiques ont corrélées l'homocystéine avec le risque de maladies cardiovasculaires. Rares ont été les études négatives. Pour résumer l'information apportée par l'épidémiologie d'observation, on peut se référer à l'une des études les plus importantes conduites de façon prospective chez des patients porteurs d'une maladie des coronaires et suivis pendant 5 ans. La mortalité de ceux ayant une concentration en homocystéine <9.0 μM fut de 3,6 % tandis que la mortalité de ceux ayant une concentration en homocystéine >15 μM fut de 24.7 %. Cette différence est considérable, et pour certains investigateurs, l'homocystéine est un facteur de risque au moins aussi important que le cholestérol ou l'HTA.Many epidemiological studies have correlated homocysteine with the risk of cardiovascular disease. Few studies have been negative. To summarize the information provided by the epidemiology of observation, one can refer to one of the most important studies conducted prospectively in patients with coronary artery disease and followed for 5 years. The mortality of those with a homocysteine concentration <9.0 μM was 3.6% while the mortality of those with a homocysteine concentration> 15 μM was 24.7%. This difference is considerable, and for some investigators, homocysteine is a risk factor at least as important as cholesterol or hypertension.
Au-delà du problème spécifique posé par la toxicité de l'homocystéine pour les artères, des études récentes ont montré que des concentrations basses en acide folique dans le sang (en relation avec des apports insuffisants) étaient également corrélées à la mortalité cardiovasculaire. Cette corrélation pouvait être indépendante de l'homocystéine, et suggère un effet direct (indépendant de son effet sur l'homocystéine) et protecteur, de l'acide folique.Beyond the specific problem posed by the toxicity of homocysteine to the arteries, recent studies have shown that low concentrations of folic acid in the blood (in relation to insufficient intakes) are also correlated with cardiovascular mortality. This correlation could be independent of homocysteine, and suggests a direct effect (independent of its effect on homocysteine) and protective, of folic acid.
D'autres études ont indiqué que la vitamine B6 et la vitamine B12 pouvaient aussi avoir un effet protecteur direct, également en partie indépendante de l'homocystéine.Other studies have indicated that vitamin B6 and vitamin B12 can also have a direct protective effect, also partly independent of homocysteine.
Malgré le nombre et la qualité des études épidémiologiques montrant une relation positive entre homocystéine et mortalité cardiovasculaire ou des relations négatives entre vitamines B et mortalité cardiovasculaire, la question d'une relation de causalité reste entière tant que l'on ne dispose pas des résultats d'essais randomisés testant spécifiquement l'hypothèse selon laquelle une réduction du taux d'homocystéine et/ou une augmentation des taux de vitamines B réduit la mortalité. 3 - Essais cliniques randomisésDespite the number and quality of epidemiological studies showing a positive relationship between homocysteine and cardiovascular mortality or negative relationships between B vitamins and cardiovascular mortality, the question of a causal relationship remains unresolved until the results are available. '' randomized trials specifically testing the hypothesis that a reduction in homocysteine levels and / or an increase in vitamin B levels reduces mortality. 3 - Randomized clinical trials
On dispose des résultats de trois types d'essai clinique randomisé testant les effets d'une supplémentation en vitamine B chez des patients coronariens ou avec des facteurs de risque vasculaires majeurs :We have the results of three types of randomized clinical trial testing the effects of vitamin B supplementation in patients with coronary artery disease or with major vascular risk factors:
1. Dans une étude publiée dans le Lancet en 2000, des investigateurs hollandais ont testé, sur des sujets appartenant à des familles présentant une maladie coronarienne très précoce, l'effet de 5 mg d'acide folique + 250 mg de vitamine B6 sur la survenue d'un test d'effort anormal (ECG pathologique) pendant un suivi de 2 ans. Les concentrations d'homocystéine ont été réduites de 14.7 à 7.4 μmol/L dans le groupe traité. Surtout, le risque de présenter un test d'effort pathologique (témoin d'une maladie coronaire active) a été réduit à 60 % suggérant que les vitamines B6 et B9 (acide folique), ou bien la diminution de l'homocystéine, avaient effectivement ralenti la progression de la maladie coronarienne chez ces sujets à risque élevé.1. In a study published in The Lancet in 2000, Dutch investigators tested, on subjects belonging to families with very early coronary artery disease, the effect of 5 mg of folic acid + 250 mg of vitamin B6 on occurrence of an abnormal stress test (pathological ECG) during a 2-year follow-up. Homocysteine concentrations were reduced from 14.7 to 7.4 μmol / L in the treated group. Above all, the risk of presenting a pathological stress test (witness to an active coronary disease) was reduced to 60% suggesting that the vitamins B6 and B9 (folic acid), or even the reduction of homocysteine, had indeed slowed the progression of coronary artery disease in these high-risk subjects.
2. Plusieurs études randomisées ont mené des investigations avant et après supplémentation en vitamine B sur la fonction endothéliale artérielle de patients porteurs de pathologies variables (coronariens, patients avec hypercholestérolémie familiale). La fonction endothéliale était évaluée en général par des techniques non invasives et les compositions selon l'invention à base de vitamines B étaient administrées par voie orale sur des périodes allant de 4 semaines à plusieurs années. Les doses administrées étaient en général très élevées. Les résultats obtenus sont étonnamment concordants (aucune étude négative) et montrent une amélioration importante de la fonction endothéliale artérielle après avoir reçu les vitamines B. Les chiffres correspondants sont représentés sous forme de graphique à la figure 1.2. Several randomized studies have carried out investigations before and after vitamin B supplementation on the arterial endothelial function of patients with variable pathologies (coronaries, patients with familial hypercholesterolemia). The endothelial function was generally evaluated by non-invasive techniques and the compositions according to the invention based on B vitamins were administered orally over periods ranging from 4 weeks to several years. The doses administered were generally very high. The results obtained are surprisingly consistent (no negative study) and show a significant improvement in arterial endothelial function after receiving the B vitamins. The corresponding figures are represented in the form of a graph in FIG. 1.
La figure 1 représente avant et après administration d'acide folique la variation du diamètre des artères (EDD) en réponse à la levée d'un garrot (cuff.release). Ce diamètre est mesuré par ultra sonométrie du débit artériel maximal ou FMD (Flow Médiated Dilation).Figure 1 represents before and after administration of folic acid the variation of the diameter of the arteries (EDD) in response to the lifting of a tourniquet (cuff.release). This diameter is measured by ultra sonometry of the maximum arterial flow or FMD (Flow Mediated Dilation).
Les résultats obtenus montrent le retour à la normale du diamètre des artères après administration d'acide folique The results obtained show the return to normal of the diameter of the arteries after administration of folic acid

Claims

REVENDICATIONS
1. Nouvelles compositions pharmaceutiques et/ou diététiques caractérisées en ce qu'elles contiennent au moins une vitamine du groupe des vitamines B et de la vitamine C1. New pharmaceutical and / or dietetic compositions characterized in that they contain at least one vitamin from the group of vitamins B and vitamin C
-associées ou en mélange avec un excipient ou un véhicule inerte, non toxique, physiologiquement acceptable.-associated or mixed with an excipient or an inert, non-toxic, physiologically acceptable vehicle.
2. Nouvelles compositions pharmaceutiques et/ou diététiques selon la revendication 1, caractérisées en ce que les vitamines du groupe B sont choisies parmi la vitamine B6, la vitamine B12, la vitamine B9 et la vitamine E.2. New pharmaceutical and / or dietetic compositions according to claim 1, characterized in that the vitamins of group B are chosen from vitamin B6, vitamin B12, vitamin B9 and vitamin E.
3. Nouvelles compositions pharmaceutiques et/ou diététiques selon la revendication 1 ou la revendication 2, caractérisées en ce que la vitamine B6 est choisie parmi la pyridoxine, la pyridoxamine, le pyridoxal, le pyridoxal 5-phosphate, l'acide pyridoxique et sa lactone.3. New pharmaceutical and / or dietetic compositions according to claim 1 or claim 2, characterized in that the vitamin B6 is chosen from pyridoxine, pyridoxamine, pyridoxal, pyridoxal 5-phosphate, pyridoxic acid and its lactone .
4. Nouvelles compositions pharmaceutiques et/ou diététiques selon la revendication 1 ou la revendication 2, caractérisées en ce que la vitamine E est choisie parmi l'α- tocophérol, le β-tocophérol, le γ-tocophérol;; le δ-tocophérol, l'ε-tocophérol et les tocotriénols.4. New pharmaceutical and / or dietetic compositions according to claim 1 or claim 2, characterized in that vitamin E is chosen from α-tocopherol, β-tocopherol, γ-tocopherol; δ-tocopherol, ε-tocopherol and tocotrienols.
5. Nouvelles compositions pharmaceutiques et/ou diététiques selon la revendication 1 ou la revendication 2, caractérisées en ce que la vitamine B9 est choisie parmi l'acide folique et ses dérivés, l'acide folinique et leurs sels.5. New pharmaceutical and / or dietetic compositions according to claim 1 or claim 2, characterized in that vitamin B9 is chosen from folic acid and its derivatives, folinic acid and their salts.
6. Nouvelles compositions pharmaceutiques et/ou diététiques selon la revendication 1 ou la revendication 2, caractérisées en ce que la vitamine B12 est choisie dans le groupe formé de la cyanocobalamine, de la sulfitocobalamine, de l'acétocobalamine, de l'hydroxocobalamine, de la méthyl cobalamine, de la chlorocobalamine et du co- enzyme B12.6. New pharmaceutical and / or dietetic compositions according to claim 1 or claim 2, characterized in that vitamin B12 is chosen from the group formed by cyanocobalamin, sulfitocobalamin, acetocobalamin, hydroxocobalamin, methyl cobalamin, chlorocobalamin and co-enzyme B12.
7. Nouvelles compositions pharmaceutiques et/ou diététiques selon la revendication 1 ou la revendication 2, caractérisées en ce que la vitamine C est présente sous forme d'acide ascorbique, l'acide isoascorbique, leurs sels, leurs esters, leur lactone et les esters d'enol.7. New pharmaceutical and / or dietetic compositions according to claim 1 or claim 2, characterized in that the vitamin C is present in the form ascorbic acid, isoascorbic acid, their salts, their esters, their lactone and the enol esters.
8. Nouvelles compositions pharmaceutiques et/ou diététiques selon l'une des revendications 1 à 7, caractérisées en ce qu'elles contiennent de 50 à 250 mg d'acide ascorbique par prise unitaire.8. New pharmaceutical and / or dietetic compositions according to one of claims 1 to 7, characterized in that they contain from 50 to 250 mg of ascorbic acid per unit intake.
9. Nouvelles compositions pharmaceutiques et/ou diététiques selon l'une des revendications 1 à 7, caractérisées en ce qu'elles contiennent de 5 à 25 mg de tocophérol par prise unitaire.9. New pharmaceutical and / or dietetic compositions according to one of claims 1 to 7, characterized in that they contain from 5 to 25 mg of tocopherol per unit dose.
10. Nouvelles compositions pharmaceutiques et/ou diététiques selon l'une des revendications 1 à 7, caractérisées en ce qu'elles contiennent de 0,4 à 1 mg d'acide folique par prise unitaire.10. New pharmaceutical and / or dietetic compositions according to one of claims 1 to 7, characterized in that they contain 0.4 to 1 mg of folic acid per unit dose.
11. Nouvelles compositions pharmaceutiques et/ou diététiques selon l'une des revendications 1 à 7, caractérisées en ce qu'elles contiennent de 100 à 1.000 μg de vitamine B12 par prise unitaire.11. New pharmaceutical and / or dietetic compositions according to one of claims 1 to 7, characterized in that they contain from 100 to 1,000 μg of vitamin B12 per unit intake.
12. Nouvelles compositions pharmaceutiques et/ou diététiques selon l'une des revendications 1 à 7, caractérisées en ce qu'elles contiennent la vitamine C à la dose de 100 mg la vitamine E naturelle à la dose de 10 mg la vitamine B6 à la dose de 5 mg la vitamine B9 à la dose de 500 μg la vitamine B 12 à la dose de 200 μg12. New pharmaceutical and / or dietetic compositions according to one of claims 1 to 7, characterized in that they contain vitamin C at the dose of 100 mg natural vitamin E at the dose of 10 mg vitamin B6 at the 5 mg dose vitamin B9 at 500 μg dose vitamin B 12 at 200 μg dose
13. Nouvelles compositions pharmaceutiques et/ou diététiques selon l'une des revendications 1 à 12, contenant des vitamines du groupe B et de la vitamine C, caractérisées en ce qu'elles contiennent un excipient ou un véhicule choisi parmi ceux destinés à l'administration par voie orale. 13. New pharmaceutical and / or dietetic compositions according to one of claims 1 to 12, containing group B vitamins and vitamin C, characterized in that they contain an excipient or a vehicle chosen from those intended for oral administration.
14. Utilisation des compositions selon l'une des revendications 1 à 13, en tant que médicament ou d'un produit diététique, possédant des effets protecteurs vis-à-vis des maladies artérielles et des maladies cardiaques .14. Use of the compositions according to one of claims 1 to 13, as a drug or a dietetic product, having protective effects with respect to arterial diseases and heart diseases.
Utilisation des compositions selon l'une des revendications 1 à 13, en tant que médicament ou d'un produit assurant une amélioration de la fonction endothéliale par supplémentation en vitamine du groupe B.. Use of the compositions according to one of claims 1 to 13, as a medicament or of a product ensuring an improvement in endothelial function by supplementation with vitamin B group.
PCT/FR2003/003425 2002-11-22 2003-11-19 Novel pharmaceutical compositions in particular for preventing cardiovascular pathologies WO2004047564A1 (en)

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