EP1165620A1 - INCLUSION COMPLEXES OF POLYUNSATURATED FATTY ACIDS AND THEIR DERIVATIVES WITH $g(g)-CYCLODEXTRIN - Google Patents

INCLUSION COMPLEXES OF POLYUNSATURATED FATTY ACIDS AND THEIR DERIVATIVES WITH $g(g)-CYCLODEXTRIN

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Publication number
EP1165620A1
EP1165620A1 EP00909441A EP00909441A EP1165620A1 EP 1165620 A1 EP1165620 A1 EP 1165620A1 EP 00909441 A EP00909441 A EP 00909441A EP 00909441 A EP00909441 A EP 00909441A EP 1165620 A1 EP1165620 A1 EP 1165620A1
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EP
European Patent Office
Prior art keywords
cyclodextrin
fatty acids
aqueous solution
complex
polyunsaturated fatty
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP00909441A
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German (de)
French (fr)
Inventor
Florence Djedaini Pilard
Bruno Perly
Jean-Pierre Dalbiez
Quitterie Michon
Béatrice ROUSSEAU
Pascale Barrier
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Sea Oil
Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Original Assignee
Commissariat a lEnergie Atomique CEA
Sea Oil
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Application filed by Commissariat a lEnergie Atomique CEA, Sea Oil filed Critical Commissariat a lEnergie Atomique CEA
Publication of EP1165620A1 publication Critical patent/EP1165620A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
    • 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
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/738—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/925—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of animal origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms

Definitions

  • the invention relates to solubilization
  • Polyunsaturated fatty acids such as arachidonic or eicosatetraenoic (AA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids are long chain polyunsaturated fatty acids
  • DHA Docosahexaenoic acid
  • Triglycerides RR 2 , R 3 represent the fatty acid hydrocarbon group such as EPA, DHA or the like. These n-3 series polyunsaturated fatty acids (PUFA) have very interesting properties in the prevention of certain inflammatory pathologies (psoriasis, arthritis) and cardiovascular diseases.
  • PUFA polyunsaturated fatty acids
  • n-3 PUFAs exert their beneficial effect by intervening at two levels:
  • the period of perinatal development is special in that it corresponds to the most active phase of incorporation of long chain PUFAs (22: 6 n-3; i.e. 22 carbon atoms, 6 ethylenic unsaturations , the first being on carbon n-3) in the structural lipids of the central nervous system, but also the most sensitive to dietary intake of PUFAs.
  • this period of rapid growth extends from the last three months of fetal life until the age of two. During the first year, the newborn's brain will take two grams per day mainly due to the phenomenon of myelinization. This implies that dietary intake of PUFA must be quantitatively and qualitatively correct.
  • document FR-A-2 547 829 [1] provides a stable composition containing compounds of unsaturated fatty acids and a stabilizing organic compound corresponding to the formula:
  • R 1 and R 2 represent Ls respectively fatty acid residues while R represents H 3 or
  • Document EP-A-0 470 452 [3] also describes the production of a product comprising ⁇ -cyclodextrin and an oleaginous substance containing EPA or DHA, by precipitation from a solution.
  • the present invention specifically relates to formulations in the form of aqueous solutions containing in solution at least one oleaginous substance belonging to the group of polyunsaturated fatty acids and their derivatives (salts, esters and triglycerides), which are suitable for such incorporation.
  • the subject of the invention is an aqueous solution comprising at least one oleaginous substance chosen from polyunsaturated fatty acids and the salts, esters and triglycerides of polyunsaturated fatty acids, in which the said substance (s) are in the form of an inclusion complex in ⁇ -cyclodextrin.
  • natural cyclodextrins are cyclic oligosaccharides consisting of D-glucopyranosyl units linked in ⁇ -1,4.
  • ⁇ -cyclodextrin which is a natural cyclodextrin, comprises eight D-glycopyranosyl units.
  • the oleaginous substances used in the invention can be of different types and from various origins, for example from fish or plants.
  • the polyunsaturated fatty acids AA, EPA and DHA mentioned above are used, in particular in the form of triglycerides. It is possible to use a mixture of one or more of these acids with other saturated or unsaturated fatty acids, for example a fish oil.
  • the solution comprises several oleaginous substances, these being constituted by a fish oil.
  • the fish oil can in particular be a sardine oil or a tuna oil.
  • Such an oil comprises unsaturated fatty acids having from 1 to 6 ethylenic unsaturations as well as fatty acids without ethylenic unsaturation.
  • the invention also relates to a process for the preparation of an aqueous solution comprising at least one oleaginous substance chosen from polyunsaturated fatty acids and the salts, esters and triglycerides of polyunsaturated fatty acids.
  • ⁇ -cyclodextrin is used to dissolve these substances and the process comprises the following steps: a) dissolving ⁇ -cyclodextrin in water, b) adding to the solution obtained in a) oleaginous substance (s) to be dissolved, and c) separating the precipitated complex of ⁇ -cyclodextrin and of oleaginous substance (s)
  • the precipitated complex can also be recovered, dried, then put back into an aqueous solution.
  • the complex obtained can be recovered and dried in the supernatant and then put back into an aqueous solution.
  • the method may further comprise a step of recovering and drying at least one of the complexes obtained in step c) followed by the re-solution in aqueous solution of the dried complex (s). .
  • one begins by dissolving the ⁇ -cyclodextrin in water with stirring using an amount of ⁇ -cyclodextrin which can go to the saturation of the. solution, i.e. 230 g / 1.
  • step b) which follows, the oleaginous substance (s) are added in an amount such that it corresponds to a slight excess relative to the amount of ⁇ -cyclodextrin necessary to form the equimolar complex. It is also subjected to agitation.
  • step c) the supernatant is separated from the precipitate, for example by centrifugation.
  • oleaginous substances in ⁇ -cyclodextrin overcomes the following problems: the polymerization of polyunsaturated fatty acids, the migration of cis double bonds in trans, and peroxidation.
  • Such aqueous formulations can be used to include these polyunsaturated fatty acids and / or their triglycerides, salts and esters in food compositions and in cosmetic compositions.
  • the subject of the invention is also pharmaceutical, food or cosmetic compositions comprising an aqueous solution of at least one oleaginous substance chosen from polyunsaturated fatty acids and the salts, esters and triglycerides of polyunsaturated fatty acids, in which the (said) substance (s) are in the form of an inclusion complex in ⁇ -cyclodextrin.
  • FIG. 1 is the spectrum obtained by nuclear magnetic resonance of the proton, in pyridine, of the ⁇ -cyclodextrin-fish oil complex, precipitated in the example given below.
  • the following example illustrates the solubilization of fish oil using ⁇ -cyclodextrin.
  • 9.9931 g of ⁇ -cyclodextrin and 87 ml of water are introduced into a container to obtain a solution of 114.86 g / 1 of ⁇ -cyclodextrin, which corresponds substantially to half of the maximum solubility (230 g / 1) ⁇ -cyclodextrin.
  • the mixture is stirred on a turntable at 300 revolutions / minute until the ⁇ -cyclodextrin is completely dissolved, which is obtained in a few minutes.
  • TGL (noted TGL in the figure) which are unambiguously attributed to triglycerides from fish oil.
  • the amount of triglycerides included in the supernatant is quite large and the amount included in the precipitate is even greater.
  • the solubility of the lyophilized complexes is then examined by re-solution in water. To this end, the quantity of water necessary to obtain the dissolution of 0.0846 g of lyophilized complex is added; this is 47.08 ml and it leads to an opalescent solution, the complex concentration of which is 1.79 g / l.
  • the lyophilized complex obtained from the supernatant and the lyophilized complex obtained from the precipitate are dissolved in a minimum volume of dimethylformamide DMF, which denatures the complex by separating the two species which constitute it. Having taken a mass of 1 g of complex, a volume of DMF of 4 ml is necessary to dissolve everything. About 60 ml of ether are added to each sample because the triglycerides are soluble therein but not the cyclodextrin which precipitates instantly.
  • the fraction of the triglycerides which have been included in the ⁇ -cyclodextrin is thus recovered.
  • the fluid obtained is oily in appearance.
  • the mass of triglycerides recovered is 0.1178 g per 1 g of the complex from the supernatant and 0.2164 g for 1 g of the complex from the precipitate.
  • the samples are stored under argon to avoid any degradation in air, before their analysis by gas chromatography, which will give their characteristic fatty acid profile.
  • fatty acids are identified by their number of carbon atoms, followed by the number of ethylenic unsaturations and the location in the chain of the first unsaturation.
  • EPA corresponds to 20: 5 n-3.

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Abstract

The invention concerns an aqueous solution comprising at least an oleaginous substance selected among the polyunsaturated fatty acids and their salts, esters and triglycerides of polyunsaturated fatty acids, wherein said substance(s) are in the form of an inclusion complex in gamma -cyclodextrin. The oleaginous substance(s) can be selected among arachidonic acid (AA), eicosapentanoic acid (EPA), docosahexanoic acid (DHA) and their triglycerides as well as among fish oils.

Description

COMPLEXES D'INCLUSION D'ACIDES GRAS POLYINSATURES ET DE LEURS DERIVES AVEC LA 7-CYCLODEXTRINEINCLUSION COMPLEXES OF POLYUNSATURATED FATTY ACIDS AND THEIR DERIVATIVES WITH 7-CYCLODEXTRIN
DESCRIPTIONDESCRIPTION
Domaine techniqueTechnical area
L'invention concerne la solubilisation etThe invention relates to solubilization and
10 la stabilisation d'acides gras polyinsaturés et des sels, esters et triglycérides correspondants, par inclusion dans la γ-cyclodextrine en vue d'obtenir des formulations solubles dans l'eau, incorporables à des compositions pharmaceutiques, alimentaires ou10 stabilization of polyunsaturated fatty acids and the corresponding salts, esters and triglycerides, by inclusion in γ-cyclodextrin with a view to obtaining formulations which are soluble in water, can be incorporated into pharmaceutical, food or
15 cosmétiques.15 cosmetics.
Les acides gras polyinsaturés tels que les acides arachidonique ou eicosatétraénoïque (AA) eicosapentaénoique (EPA) et docosahexaénoique (DHA) sont des acides gras polyinsaturés à longue chaîne dePolyunsaturated fatty acids such as arachidonic or eicosatetraenoic (AA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids are long chain polyunsaturated fatty acids
20 la série n-3. Ils sont contenus dans les produits issus de la mer, c'est-à-dire principalement dans les huiles de poissons, mais aussi dans certaines micro-algues. Ils sont obtenus par hydrolyse-estérification des triglycérides. Ces acides et les triglycérides20 the n-3 series. They are contained in products from the sea, that is to say mainly in fish oils, but also in certain micro-algae. They are obtained by hydrolysis-esterification of triglycerides. These acids and triglycerides
25 correspondants répondent aux formules : 25 correspondents respond to the formulas:
Acide arachidonique (AA)Arachidonic acid (AA)
Acide eicosapentaénoïque (EPA)Eicosapentaenoic acid (EPA)
Acide docosahexaenoïque (DHA)Docosahexaenoic acid (DHA)
Triglycérides : R R2, R3 représentent le groupe hydrocarboné acide gras tel que EPA, DHA ou autre. Ces acides gras polyinsaturés de la série n-3 (AGPI) présentent des propriétés très intéressantes dans la prévention de certaines pathologies inflammatoires (psoriasis, arthrite) et des maladies cardio-vasculaires.Triglycerides: RR 2 , R 3 represent the fatty acid hydrocarbon group such as EPA, DHA or the like. These n-3 series polyunsaturated fatty acids (PUFA) have very interesting properties in the prevention of certain inflammatory pathologies (psoriasis, arthritis) and cardiovascular diseases.
Les premières études épidémiologiques suggérant l'existence d'effets potentiellement bénéfiques de ces acides gras sur la mortalité cardio- vasculaire, remontent aux observations effectuées chez les Esquimaux groenlandais . Dans cette population, consommatrice quasi-exclusive de mammifères marins et de poissons, environ 14 g d'AGPI n-3 sont ingérés quotidiennement, et les décès par maladies cardio- vasculaires sont rares. La relation entre le niveau de consommation de poissons (et à fortiori d'AGPI n-3) et l'incidence des maladies cardio-vasculaires a été retrouvée au Japon et dans certaines études prospectives .The first epidemiological studies suggesting the existence of potentially beneficial effects of these fatty acids on cardiovascular mortality date back to observations made in Greenlandic Eskimos. In this population, an almost exclusive consumer of marine mammals and fish, around 14 g of n-3 PUFA are ingested daily, and deaths from cardiovascular diseases are rare. The relationship between the level of consumption of fish (and a fortiori of PUFA n-3) and the incidence of cardiovascular disease has been found in Japan and in certain prospective studies.
Les AGPI n-3 exercent leur effet bénéfique en intervenant à deux niveaux :The n-3 PUFAs exert their beneficial effect by intervening at two levels:
1) ils abaissent la triglycéridémie (et non la cholestérolémie) , cette diminution résultant pour l'essentiel d'une synthèse des lipoprotéines de basse densité et de leurs constituants ;1) they lower triglyceridemia (and not cholesterolemia), this reduction resulting essentially from a synthesis of low density lipoproteins and their constituents;
2) ils inhibent les phénomènes d'agrégation plaquettaire, de coagulation et d'inflammation en jouant sur la synthèse d'un grand nombre de molécules (thromboxanes, prostacylines, leucotriènes, PAF, fibrinogène, PDGF, cytokines, ... ) . Dans le souci de limiter le taux de mortalité coronarienne pour l'ensemble de la population, il semble prudent de recommander la consommation de poisson. Les AGPI présentent également d'autres intérêts notamment au niveau de la peau et des structures nerveuses au cours du développement périnatal.2) they inhibit the phenomena of platelet aggregation, coagulation and inflammation by playing on the synthesis of a large number of molecules (thromboxanes, prostacylins, leukotrienes, PAF, fibrinogen, PDGF, cytokines, ...). In order to limit the coronary mortality rate for the whole population, it seems prudent to recommend the consumption of fish. PUFAs also have other interests, particularly in the skin and nerve structures during perinatal development.
En effet, des modifications apparaissent lors de déficience en AGPI au niveau de l'épiderme : perméabilité à l'eau augmentée, hyperprolifération cellulaire (problème de kératinisation) , augmentation de l'épaisseur et du nombre de couches, eczémas, irritations, érythèmes...In fact, modifications appear during PUFA deficiency in the epidermis: increased water permeability, cellular hyperproliferation (keratinization problem), increased thickness and number of layers, eczema, irritations, erythemas. ..
Sur le plan nutritionnel, la période de développement périnatal est particulière en ce sens qu'elle correspond à la phase la plus active d'incorporation des AGPI à longue chaîne (22 : 6 n-3 ; soit 22 atomes de carbone, 6 insaturations éthyléniques, la première étant sur le carbone n-3) dans les lipides de structure du système nerveux central, mais également la plus sensible aux apports alimentaires en AGPI. Pour le cerveau humain, cette période de croissance rapide s'étend des trois derniers mois de la vie fœtale jusqu'à l'âge de deux ans. Au cours de la première année, le cerveau du nouveau-né va prendre deux grammes par joiir en raison principalement du phénomène de myelinisation. Cela implique que les apports alimentaires en AGPI doivent être corrects quantitativement et qualitativement.From a nutritional point of view, the period of perinatal development is special in that it corresponds to the most active phase of incorporation of long chain PUFAs (22: 6 n-3; i.e. 22 carbon atoms, 6 ethylenic unsaturations , the first being on carbon n-3) in the structural lipids of the central nervous system, but also the most sensitive to dietary intake of PUFAs. For the human brain, this period of rapid growth extends from the last three months of fetal life until the age of two. During the first year, the newborn's brain will take two grams per day mainly due to the phenomenon of myelinization. This implies that dietary intake of PUFA must be quantitatively and qualitatively correct.
En raison d'une consommation moyenne faible de ces acides gras dans les pays industrialisés (200 à 400 mg/jour) , un certain nombre d'industriels commencent à se pencher sur la façon d' enrichir certains aliments en ces acides gras en y additionnant des huiles de poisson (pain, margarine, mayonnaise...)Due to the low average consumption of these fatty acids in industrialized countries (200 to 400 mg / day), a number of manufacturers are starting to look into how to enrich certain foods with these fatty acids by adding them fish oils (bread, margarine, mayonnaise ...)
Cependant l'incorporation de ces acides gras à longue chaîne dans des compositions alimentaires ou cosmétiques est rendue difficile en raison de l'insolubilité dans l'eau, de l'odeur indésirable et du manque de stabilité de ces acides gras.However, the incorporation of these long chain fatty acids into food or cosmetic compositions is made difficult due to the insolubility in water, the undesirable odor and the lack of stability of these fatty acids.
En effet, ceux-ci sont sensibles à la température et à la lumière. Ils sont instables et s'oxydent très facilement.Indeed, they are sensitive to temperature and light. They are unstable and oxidize very easily.
Etat de la technique antérieureState of the art
Pour surmonter ces difficultés, le document FR-A-2 547 829 [1] propose une composition stable contenant des composés d'acides gras insaturés et un composé organique stabilisant répondant à la formule :To overcome these difficulties, document FR-A-2 547 829 [1] provides a stable composition containing compounds of unsaturated fatty acids and a stabilizing organic compound corresponding to the formula:
H2COR1 H 2 COR 1
I R2— O— CH 0 | ||IR 2 - O— CH 0 | ||
H2C — 0 — P — OCH2CH2N+R3 H 2 C - 0 - P - OCH 2 CH 2 N + R 3
dans laquelle R 1 et R 2 repré Lsentent respectivement des restes d'acides gras alors que R représente H3 ouin which R 1 and R 2 represent Ls respectively fatty acid residues while R represents H 3 or
(CH3)3. On peut aussi ajouter à la composition une cyclodextrine dont le rôle est de réduire très fortement l'odeur déplaisante et l'amertume propres aux composés d' acides gras polyinsaturés et dont le rôle est également de rendre la composition agréable au palais.(CH 3 ) 3 . You can also add to the composition a cyclodextrin whose role is to very strongly reduce the unpleasant odor and bitterness specific to polyunsaturated fatty acid compounds and whose role is also to make the composition pleasant to the palate.
Dans le document FR-A-2 550 445 [2], on a proposé d' inclure un acide gras polyinsaturé tel que EPA dans la γ-cyclodextrine. Dans ce but, on mélange les deux composés sous forme de pâte en présence de petits volumes d'eau, ce qui conduit à l'obtention d'une poudre contenant un composé d'inclusion γ- cyclodextrine-EPA.In document FR-A-2 550 445 [2], it has been proposed to include a polyunsaturated fatty acid such as EPA in γ-cyclodextrin. For this purpose, the two compounds are mixed in the form of a paste in the presence of small volumes of water, which leads to the production of a powder containing an inclusion compound γ-cyclodextrin-EPA.
Le document EP-A-0 470 452 [3] décrit également l'obtention d'un produit comprenant de la γ- cyclodextrine et une substance oléagineuse contenant EPA ou DHA, par précipitation à partir d'une solution.Document EP-A-0 470 452 [3] also describes the production of a product comprising γ-cyclodextrin and an oleaginous substance containing EPA or DHA, by precipitation from a solution.
Toutes ces techniques ont l'inconvénient de conduire à des produits solides qui ne conviennent pas pour l'incorporation dans toutes les compositions pharmaceutiques, alimentaires ou cosmétiques.All these techniques have the disadvantage of leading to solid products which are not suitable for incorporation into all pharmaceutical, food or cosmetic compositions.
La présente invention a précisément pour objet des formulations sous forme de solutions aqueuses contenant en solution au moins une substance oléagineuse appartenant au groupe des acides gras polyinsaturés et de leurs dérivés (sels, esters et triglycérides), qui conviennent pour une telle incorporation. Exposé de l'inventionThe present invention specifically relates to formulations in the form of aqueous solutions containing in solution at least one oleaginous substance belonging to the group of polyunsaturated fatty acids and their derivatives (salts, esters and triglycerides), which are suitable for such incorporation. Statement of the invention
Aussi, l'invention a pour objet une solution aqueuse comprenant au moins une substance oléagineuse choisie parmi les acides gras polyinsaturés et les sels, esters et triglycérides d'acides gras polyinsaturés, dans laquelle la (les) dite (s) substance (s) sont sous la forme de complexe d'inclusion dans la γ-cyclodextrine.Also, the subject of the invention is an aqueous solution comprising at least one oleaginous substance chosen from polyunsaturated fatty acids and the salts, esters and triglycerides of polyunsaturated fatty acids, in which the said substance (s) are in the form of an inclusion complex in γ-cyclodextrin.
On rappelle que les cyclodextrines naturelles sont des oligosaccharides cycliques constitués d'unités D-glucopyranosyle liées en α-1,4. La γ-cyclodextrine qui est une cyclodextrine naturelle, comprend huit unités D-glycopyranosyle .It is recalled that natural cyclodextrins are cyclic oligosaccharides consisting of D-glucopyranosyl units linked in α-1,4. Γ-cyclodextrin which is a natural cyclodextrin, comprises eight D-glycopyranosyl units.
Elle répond à la formule :It responds to the formula:
avec n = 8with n = 8
Les substances oléagineuses utilisées dans l'invention peuvent être de différents types et d'origines diverses, par exemple provenir de poissons ou de végétaux. On utilise avantageusement les acides gras polyinsaturés AA, EPA et DHA mentionnés précédemment, en particulier sous forme de triglycérides. On peut utiliser un mélange d'un ou plusieurs de ces acides avec d'autres acides gras saturés ou insaturés, par exemple une huile de poisson.The oleaginous substances used in the invention can be of different types and from various origins, for example from fish or plants. Advantageously, the polyunsaturated fatty acids AA, EPA and DHA mentioned above are used, in particular in the form of triglycerides. It is possible to use a mixture of one or more of these acids with other saturated or unsaturated fatty acids, for example a fish oil.
Dans ce cas, la solution comprend plusieurs substances oléagineuses, celles-ci étant constituées par une huile de poisson. L'huile de poisson peut être en particulier une huile de sardine ou une huile de thon. Une telle huile comprend des acides gras insaturés ayant de 1 à 6 insaturations éthyléniques ainsi que des acides gras sans insaturation éthylénique. L'invention a également pour objet un procédé de préparation d'une solution aqueuse comprenant au moins une substance oléagineuse choisie parmi les acides gras polyinsaturés et les sels, esters et triglycérides d'acides gras polyinsaturés. Selon l'invention, on utilise la γ- cyclodextrine pour solubiliser ces substances et le procédé comprend les étapes suivantes : a) dissoudre la γ-cyclodextrine dans de l'eau, b) ajouter à la solution obtenue en a) la (les) substance (s) oléagineuse (s) à solubiliser, et c) séparer le complexe précipité de γ- cyclodextrine et de substance (s) oléagineuse (s)In this case, the solution comprises several oleaginous substances, these being constituted by a fish oil. The fish oil can in particular be a sardine oil or a tuna oil. Such an oil comprises unsaturated fatty acids having from 1 to 6 ethylenic unsaturations as well as fatty acids without ethylenic unsaturation. The invention also relates to a process for the preparation of an aqueous solution comprising at least one oleaginous substance chosen from polyunsaturated fatty acids and the salts, esters and triglycerides of polyunsaturated fatty acids. According to the invention, γ-cyclodextrin is used to dissolve these substances and the process comprises the following steps: a) dissolving γ-cyclodextrin in water, b) adding to the solution obtained in a) oleaginous substance (s) to be dissolved, and c) separating the precipitated complex of γ-cyclodextrin and of oleaginous substance (s)
/ du surnageant qui contient également le complexe en solution. Ainsi, on peut obtenir directement une solution aqueuse de la ou (des) substance (s) oléagineuse (s) ./ of the supernatant which also contains the complex in solution. Thus, an aqueous solution of the oil-producing substance (s) can be obtained directly.
On peut aussi récupérer le complexe précipité, le sécher, puis le remettre en solution aqueuse. De même, on peut récupérer et sécher le complexe obtenu dans le surnageant et le remettre ensuite en solution aqueuse.The precipitated complex can also be recovered, dried, then put back into an aqueous solution. Similarly, the complex obtained can be recovered and dried in the supernatant and then put back into an aqueous solution.
Aussi, le procédé peut comprendre en outre une étape de récupération et de séchage d'au moins l'un des complexes obtenus dans l'étape c) suivie de la remise en solution aqueuse du (des) complexe (s) séché (s) .Also, the method may further comprise a step of recovering and drying at least one of the complexes obtained in step c) followed by the re-solution in aqueous solution of the dried complex (s). .
Pour mettre en œuvre le procédé décrit ci- dessus, on commence par dissoudre la γ-cyclodextrine dans de l'eau sous agitation en utilisant une quantité de γ-cyclodextrine qui peut aller jusqu'à la saturation de la. solution, soit 230 g/1.To implement the method described above, one begins by dissolving the γ-cyclodextrin in water with stirring using an amount of γ-cyclodextrin which can go to the saturation of the. solution, i.e. 230 g / 1.
Dans l'étape b) qui suit, on ajoute la (les) substance (s) oléagineuse (s) en quantité telle qu'elle corresponde à un léger excès par rapport à la quantité de γ-cyclodextrine nécessaire pour former le complexe équimolaire. On soumet également à une agitation. Dans l'étape c) , on sépare le surnageant du précipité, par exemple par centrifugation.In step b) which follows, the oleaginous substance (s) are added in an amount such that it corresponds to a slight excess relative to the amount of γ-cyclodextrin necessary to form the equimolar complex. It is also subjected to agitation. In step c), the supernatant is separated from the precipitate, for example by centrifugation.
Lorsque l'on opère avec un excès de substance (s) oléagineuse (s) , on élimine tout d'abordWhen operating with an excess of oleaginous substance (s), we first eliminate
/ cet excès avant d'effectuer la séparation par centrifugation. Lorsque l'on soumet ensuite le (s) complexe (s) obtenu (s) à un séchage, celui-ci peut être effectué par lyophilisation ou encore par un procédé de déshydratation utilisant des zéolithes ou « Zéodratation »./ this excess before separation by centrifugation. When the complex (s) obtained is then subjected to drying, this can be carried out by lyophilization or else by a dehydration process using zeolites or “zeodratation”.
L'inclusion des substances oléagineuses précitées dans la γ-cyclodextrine permet de surmonter les problèmes suivants : la polymérisation des acides gras polyinsaturés, la migration des doubles liaisons cis en trans, et la peroxydation.The inclusion of the aforementioned oleaginous substances in γ-cyclodextrin overcomes the following problems: the polymerization of polyunsaturated fatty acids, the migration of cis double bonds in trans, and peroxidation.
L'inclusion des acides gras polyinsaturés ou de leurs triglycérides, sels et/ou esters dans la γ-cyclodextrine, conformément à l'invention, permet d'obtenir des formulations aqueuses contenant ces acides gras en supprimant et en réduisant fortement les problèmes liés à leur oxydabilité et à leur instabilité.The inclusion of polyunsaturated fatty acids or their triglycerides, salts and / or esters in γ-cyclodextrin, in accordance with the invention, makes it possible to obtain aqueous formulations containing these fatty acids by eliminating and greatly reducing the problems associated with their oxidability and their instability.
De telles formulations aqueuses peuvent être utilisées pour inclure ces acides gras polyinsaturés et/ou leurs triglycérides, sels et esters dans des compositions alimentaires et dans des compositions cosmétiques.Such aqueous formulations can be used to include these polyunsaturated fatty acids and / or their triglycerides, salts and esters in food compositions and in cosmetic compositions.
Aussi, l'invention a encore pour objet des compositions pharmaceutiques, alimentaires ou cosmétiques comprenant une solution aqueuse d'au moins une substance oléagineuse choisie parmi les acides gras polyinsaturés et les sels, esters et triglycérides d'acides gras polyinsaturés, dans laquelle la (lesdites) substance (s) sont sous la forme de complexe d'inclusion dans la γ-cyclodextrine.Also, the subject of the invention is also pharmaceutical, food or cosmetic compositions comprising an aqueous solution of at least one oleaginous substance chosen from polyunsaturated fatty acids and the salts, esters and triglycerides of polyunsaturated fatty acids, in which the (said) substance (s) are in the form of an inclusion complex in γ-cyclodextrin.
L'invention sera mieux comprise à la lecture de la description qui suit, donnée bien entendu à titre illustratif et non limitatif, en référence au dessin annexé.The invention will be better understood on reading the description which follows, given of course by way of illustration and not limitation, with reference to the appended drawing.
Brève description du dessinBrief description of the drawing
La figure 1 est le spectre obtenu par résonance magnétique nucléaire du proton, dans la pyridine, du complexe γ-cyclodextrine-huile de poisson, précipité dans l'exemple donné ci-après.FIG. 1 is the spectrum obtained by nuclear magnetic resonance of the proton, in pyridine, of the γ-cyclodextrin-fish oil complex, precipitated in the example given below.
Exposé détaillé des modes de réalisation de l'inventionDetailed description of the embodiments of the invention
L'exemple qui suit illustre la solubilisation d'huile de poisson au moyen de γ-cyclodextrine. On introduit dans un récipient 9,9931 g de γ-cyclodextrine et 87 ml d'eau pour obtenir une solution à 114,86 g/1 de γ-cyclodextrine, ce qui correspond sensiblement à la moitié de la solubilité maximale (230 g/1) de la γ-cyclodextrine. On agite le mélange sur un plateau tournant à 300 tours/minute jusqu'à complète dissolution de la γ-cyclodextrine, ce qui est obtenu en quelques minutes.The following example illustrates the solubilization of fish oil using γ-cyclodextrin. 9.9931 g of γ-cyclodextrin and 87 ml of water are introduced into a container to obtain a solution of 114.86 g / 1 of γ-cyclodextrin, which corresponds substantially to half of the maximum solubility (230 g / 1) γ-cyclodextrin. The mixture is stirred on a turntable at 300 revolutions / minute until the γ-cyclodextrin is completely dissolved, which is obtained in a few minutes.
On ajoute alors 10 ml d'huile de poisson brute (référence SO 30 qui/ contient au moins 30 % d'acide ω-3), et on maintient une agitation constante à10 ml of crude fish oil are then added (reference SO 30 which / contains at least 30% ω-3 acid), and constant stirring is maintained at
300 tours/minute sur plateau tournant pendant 24 heures. Il se forme un précipité blanc qui se dépose au fond du récipient, et on observe une phase aqueuse opalescente intermédiaire et une suspension huileuse en surface. On élimine la suspension huileuse et on sépare la phase aqueuse du précipité par centrifugation deux fois successivement à 1000 tours/minute pendant 15 minutes, à la température ambiante. On lyophilise séparément le surnageant (phase aqueuse) et le précipité, après congélation dans l'azote liquide. On examine ensuite les produits lyophilisés par résonance magnétique nucléaire du proton (RMN XH) après dissolution dans la pyridine deutériée, à 298 K, à l'aide d'un spectromètre BRUKER DRX 500, opérant à 500, 13 MHz. La figure 1 illustre le spectre de résonance magnétique nucléaire H du précipité. La comparaison de ce spectre avec celui de la γ-cyclodextrine seule montre la présence de signaux300 rpm on a turntable for 24 hours. A white precipitate forms which settles at the bottom of the container, and an intermediate opalescent aqueous phase is observed and an oily suspension on the surface. The oily suspension is removed and the aqueous phase is separated from the precipitate by centrifugation twice successively at 1000 revolutions / minute for 15 minutes, at room temperature. The supernatant (aqueous phase) and the precipitate are lyophilized separately, after freezing in liquid nitrogen. Then examines the freeze-dried products by proton nuclear magnetic resonance (NMR X H) after being dissolved in deuterated pyridine at 298 K using a Bruker DRX 500 operating at 500, 13 MHz. Figure 1 illustrates the nuclear magnetic resonance spectrum H of the precipitate. Comparison of this spectrum with that of γ-cyclodextrin alone shows the presence of signals
(notés TGL sur la figure) qui sont attribués sans ambiguïté aux triglycérides issus de l'huile de poisson.(noted TGL in the figure) which are unambiguously attributed to triglycerides from fish oil.
Le spectre RMN H obtenu avec le surnageant est identique à celui de la figure 1.The H NMR spectrum obtained with the supernatant is identical to that of FIG. 1.
La quantité de triglycérides inclus dans le surnageant est assez importante et la quantité incluse dans le précipité est encore plus importante.The amount of triglycerides included in the supernatant is quite large and the amount included in the precipitate is even greater.
On examine ensuite la solubilité des complexes lyophilisés, par remise en solution dans l'eau. A cet effet, on ajoute la quantité d'eau nécessaire pour obtenir la dissolution de 0,0846 g de complexe lyophilisé ; celle-ci est de 47,08 ml et elle conduit à une solution opalescente dont la concentration en complexe est de 1,79 g/1.The solubility of the lyophilized complexes is then examined by re-solution in water. To this end, the quantity of water necessary to obtain the dissolution of 0.0846 g of lyophilized complex is added; this is 47.08 ml and it leads to an opalescent solution, the complex concentration of which is 1.79 g / l.
On précise que dans le cas de la β- cyclodextrine, le complexe formé dans les mêmes conditions a une solubilité trois fois plus faible (0,65 g/1) .It is specified that in the case of β-cyclodextrin, the complex formed under the same conditions has a solubility three times lower (0.65 g / 1).
Ceci est très intéressant en vue d'une utilisation dans des compositions alimentaires ou cosmétiques, car on peut limiter à des valeurs très faibles la quantité de solution aqueuse de complexe ajoutée .This is very advantageous for use in food or cosmetic compositions, since the amount of aqueous complex solution added can be limited to very low values.
On vérifie maintenant que le complexe du surnageant et le complexe du précipité sont tous deux des complexes d'inclusion des triglycérides dans la γ- cyclodextrine.It is now verified that the complex of the supernatant and the complex of the precipitate are both complexes of inclusion of the triglycerides in the γ-cyclodextrin.
Dans ce but, on dissout le complexe lyophilisé obtenu à partir du surnageant et le complexe lyophilisé obtenu à partir du précipité dans un volume minimum de dimethylformamide DMF, ce qui dénature le complexe en séparant les deux espèces qui le constituent. Ayant prélevé une masse de 1 g de complexe, il faut un volume de DMF de 4 ml pour tout dissoudre. On ajoute environ 60 ml d'éther à chaque échantillon car les triglycérides y sont solubles mais pas la cyclodextrine qui précipite instantanément.For this purpose, the lyophilized complex obtained from the supernatant and the lyophilized complex obtained from the precipitate are dissolved in a minimum volume of dimethylformamide DMF, which denatures the complex by separating the two species which constitute it. Having taken a mass of 1 g of complex, a volume of DMF of 4 ml is necessary to dissolve everything. About 60 ml of ether are added to each sample because the triglycerides are soluble therein but not the cyclodextrin which precipitates instantly.
Afin de bien isoler la phase organique contenant les triglycérides de la γ-cyclodextrine précipité, on a recours à une centrifugation pendant 10 minutes, à 1000 tours/minute, à la température ambiante. On transfère la partie liquide récupérée dans une ampoule à décanter. On lave quatre fois successivement à l'eau pour extraire les traces de γ- cyclodextrine restées éventuellement dans la phase organique. On sèche cette phase sur Na2S04 et on bouche le flacon. Après environ 1 heure, on filtre les échantillons sur fritte sous le vide de la trompe à eau, puis on élimine le solvant organique d'extraction (éther) à l' évaporateur rotatif.In order to properly isolate the organic phase containing the triglycerides of the precipitated γ-cyclodextrin, centrifugation is used for 10 minutes, at 1000 revolutions / minute, at room temperature. The recovered liquid part is transferred to a separatory funnel. We wash four times successively with water to extract the traces of γ-cyclodextrin possibly remaining in the organic phase. This phase is dried over Na 2 S0 4 and the bottle is capped. After about 1 hour, the samples are filtered on a frit under the vacuum of the water pump, then the organic extraction solvent (ether) is removed on a rotary evaporator.
On récupère ainsi la fraction des triglycérides qui ont été inclus dans la γ- cyclodextrine. Le fluide obtenu est d'aspect huileux. La masse de triglycérides récupérée est de 0,1178 g pour 1 g du complexe provenant du surnageant et de 0,2164 g pour 1 g du complexe issu du précipité.The fraction of the triglycerides which have been included in the γ-cyclodextrin is thus recovered. The fluid obtained is oily in appearance. The mass of triglycerides recovered is 0.1178 g per 1 g of the complex from the supernatant and 0.2164 g for 1 g of the complex from the precipitate.
Les échantillons sont stockés sous argon pour éviter toute dégradation à l'air, avant leur analyse par chromatographie en phase gazeuse, qui donnera leur profil en acides gras caractéristique.The samples are stored under argon to avoid any degradation in air, before their analysis by gas chromatography, which will give their characteristic fatty acid profile.
Les résultats obtenus, exprimés en pourcentage des acides gras identifiés sont donnés dans le tableau qui suit. The results obtained, expressed as a percentage of the fatty acids identified are given in the table below.
Tableau 1Table 1
Dans ce tableau, les acides gras sont identifiés par leur nombre d'atomes de carbone, suivi du nombre d' insaturations éthyléniques et de l'emplacement dans la chaîne de la première insaturation. Ainsi, EPA correspond à 20 : 5 n-3. In this table, fatty acids are identified by their number of carbon atoms, followed by the number of ethylenic unsaturations and the location in the chain of the first unsaturation. Thus, EPA corresponds to 20: 5 n-3.
Les résultats du tableau montrent que l'huile issue du surnageant a la même composition en acides gras que l'huile provenant du précipité. C'est bien la preuve que l'on trouve du complexe à l'état dissous dans le surnageant.The results in the table show that the oil from the supernatant has the same fatty acid composition as the oil from the precipitate. This is proof that we find the dissolved complex in the supernatant.
REFERENCES CITEESREFERENCES CITED
[1] FR-A-2 547 829. [2] FR-A-2 550 445. [3] EP-A-0 470 452, [1] FR-A-2 547 829. [2] FR-A-2 550 445. [3] EP-A-0 470 452,

Claims

REVENDICATIONS
1. Solution aqueuse comprenant au moins une substance oléagineuse choisie parmi les acides gras polyinsaturés et les sels, esters et triglycérides d'acides gras polyinsaturés, dans laquelle la (les) dite (s) substance (s) sont sous la forme de complexe d'inclusion dans la γ-cyclodextrine.1. Aqueous solution comprising at least one oleaginous substance chosen from polyunsaturated fatty acids and the salts, esters and triglycerides of polyunsaturated fatty acids, in which the said substance (s) are in the form of a complex 'inclusion in γ-cyclodextrin.
2. Solution aqueuse selon la revendication 1 dans laquelle la (les) substance (s) oléagineuse (s) sont choisies parmi l'acide arachidonique' (AA) , l'acide eicosapentaénoïque (EPA), l'acide docosahexaenoïque (DHA) et leurs triglycérides.2. An aqueous solution according to claim 1 in which the oil-producing substance (s) are chosen from arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and their triglycerides.
3. Solution aqueuse selon la revendication 1 comprenant plusieurs substances oléagineuses, dans laquelle lesdites substances sont constituées par une huile de poisson.3. An aqueous solution according to claim 1 comprising several oleaginous substances, in which said substances consist of a fish oil.
4. Procédé de préparation d'une solution aqueuse selon la revendication 1, qui comprend les étapes suivantes : a) dissoudre la γ-cyclodextrine dans de l'eau, b) ajouter à la solution obtenue en a) la (les) substance (s) oléagineuse (s) à solubiliser, et c) séparer le complexe précipité de γ- cyclodextrine et de substance (s) oléagineuse (s) du surnageant qui contient également le complexe en solution.4. Process for the preparation of an aqueous solution according to claim 1, which comprises the following steps: a) dissolving the γ-cyclodextrin in water, b) adding to the solution obtained in a) the substance (s) ( s) oilseed (s) to be dissolved, and c) separating the precipitated complex of γ-cyclodextrin and of oilseed substance (s) from the supernatant which also contains the complex in solution.
5. Procédé selon la revendication 4, qui comprend de plus le séchage d'au moins l'un des complexes obtenus dans l'étape c) suivi de la remise en solution aqueuse du (des) complexe(s) séché(s). 5. Method according to claim 4, which further comprises the drying of at least one of the complexes obtained in step c) followed by the re-solution in aqueous solution of the dried complex (s).
6. Composition alimentaire comprenant une solution aqueuse selon l'une quelconque des revendications 1 à 3.6. Food composition comprising an aqueous solution according to any one of claims 1 to 3.
7. Composition cosmétique comprenant une solution aqueuse selon l'une quelconque des revendications 1 à 3.7. Cosmetic composition comprising an aqueous solution according to any one of claims 1 to 3.
8. Composition pharmaceutique comprenant une solution aqueuse selon l'une quelconque des revendications 1 à 3. 8. Pharmaceutical composition comprising an aqueous solution according to any one of claims 1 to 3.
EP00909441A 1999-03-09 2000-03-07 INCLUSION COMPLEXES OF POLYUNSATURATED FATTY ACIDS AND THEIR DERIVATIVES WITH $g(g)-CYCLODEXTRIN Withdrawn EP1165620A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9902881 1999-03-09
FR9902881A FR2790758A1 (en) 1999-03-09 1999-03-09 SOLUBILIZATION OF POLYUNSATURATED FATTY ACIDS AND DERIVATIVES THEREOF BY FORMATION OF INCLUSION COMPLEXES WITH A CYCLODEXTRIN AND THEIR USE IN PHARMACEUTICAL, COSMETIC OR FOOD COMPOSITIONS
PCT/FR2000/000560 WO2000053637A1 (en) 1999-03-09 2000-03-07 INCLUSION COMPLEXES OF POLYUNSATURATED FATTY ACIDS AND THEIR DERIVATIVES WITH η-CYCLODEXTRIN

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EP1165620A1 true EP1165620A1 (en) 2002-01-02

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EP00909441A Withdrawn EP1165620A1 (en) 1999-03-09 2000-03-07 INCLUSION COMPLEXES OF POLYUNSATURATED FATTY ACIDS AND THEIR DERIVATIVES WITH $g(g)-CYCLODEXTRIN

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EP (1) EP1165620A1 (en)
JP (1) JP2002539138A (en)
CA (1) CA2366719A1 (en)
FR (1) FR2790758A1 (en)
NO (1) NO20014341D0 (en)
WO (1) WO2000053637A1 (en)

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DE10253042A1 (en) 2002-11-14 2004-06-03 Wacker-Chemie Gmbh Cosmetic preparation containing a complex of cyclodextrin and vitamin F.
ES2209658B1 (en) * 2002-12-05 2005-10-01 Proyecto Empresarial Brudy, S.L. USE OF DOCOSAHEXAENOIC ACID AS AN ACTIVE PRINCIPLE FOR THE TREATMENT OF LIPODYSTROPHY.
FR2850040B1 (en) * 2003-01-20 2005-03-11 Centre Nat Rech Scient SYSTEMS FOR MICROENCAPSULATION AND THEIR APPLICATIONS
US7105195B2 (en) 2003-07-25 2006-09-12 General Mills, Inc. Reduced trans fat product
US20040180125A1 (en) * 2003-03-11 2004-09-16 Plank David W. Cyclodextrin-containing compositions and methods
US7335386B2 (en) 2003-07-30 2008-02-26 Gerneral Mills, Inc. Method for preventing acrylamide formation in food products and food intermediates
EP1637134A4 (en) * 2003-06-20 2010-01-27 Mochida Pharm Co Ltd Composition for prevention/treatment for varicose veins
EP2049083A2 (en) * 2006-12-27 2009-04-22 Cargill, Incorporated Stabilisation by preparing cyclodextrin inclusion complexes
FR2915901A1 (en) * 2007-05-07 2008-11-14 In Cyclo Soc Par Actions Simpl HOMOGENEOUS AND STABLE COMPOSITION, RICH IN OLEAGINOUS SUBSTANCES BASED ON A MILK PRODUCT, PROCESS FOR PREPARING SAME AND USES THEREOF.
GB0710439D0 (en) * 2007-05-31 2007-07-11 Uni I Oslo Oral dosage form
GB0808479D0 (en) * 2008-05-09 2008-06-18 Uni I Oslo Topical compositions
FR3048177B1 (en) * 2016-02-25 2020-10-30 Fabre Pierre Dermo Cosmetique BIPHASE COSMETIC COMPOSITION AND ITS USE BY TOPICAL APPLICATION

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JPS5941395A (en) * 1982-09-01 1984-03-07 マルハ株式会社 Stabilization of fish oils
JPS6034156A (en) * 1983-08-08 1985-02-21 Hayashibara Biochem Lab Inc Eicosapentaenoic acid clathrate compound and food and drink containing the same
IT1243192B (en) * 1990-08-09 1994-05-24 Staroil Ltd LONG CHAIN POLYUNSATURATED FATTY ACIDS AND THEIR DERIVATIVES, WITH CYCLODESTRINE
JPH0725816A (en) * 1993-07-08 1995-01-27 Yoshihisa Matsuda Polyenoic acid clathrate

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Publication number Publication date
CA2366719A1 (en) 2000-09-14
JP2002539138A (en) 2002-11-19
NO20014341L (en) 2001-09-06
FR2790758A1 (en) 2000-09-15
NO20014341D0 (en) 2001-09-06
WO2000053637A1 (en) 2000-09-14

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