EP4167935A1 - Association of natural actives ingredients to fight skin aging - Google Patents

Association of natural actives ingredients to fight skin aging

Info

Publication number
EP4167935A1
EP4167935A1 EP20734351.8A EP20734351A EP4167935A1 EP 4167935 A1 EP4167935 A1 EP 4167935A1 EP 20734351 A EP20734351 A EP 20734351A EP 4167935 A1 EP4167935 A1 EP 4167935A1
Authority
EP
European Patent Office
Prior art keywords
resveratrol
composition
hyaluronic acid
component
advantageously
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.)
Pending
Application number
EP20734351.8A
Other languages
German (de)
French (fr)
Inventor
Mathilde THOMAS
Bertrand Thomas
David Sinclair
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CAUDALIE GROUP LIMITED
Harvard College
Original Assignee
Tomcat International Ltd
Harvard College
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tomcat International Ltd, Harvard College filed Critical Tomcat International Ltd
Publication of EP4167935A1 publication Critical patent/EP4167935A1/en
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • 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
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • 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
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • 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
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the present invention relates to a composition
  • a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof.
  • the present invention also relates to a cosmetic care method for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing, comprising administering an effective amount of the composition of the invention.
  • Resveratrol (3, 5, 4'-trihydroxystilbene) is a natural polyphenolic antioxidant of the stilbene family that is found in more than 70 plant species.
  • One of the most common botanical sources is the vine; more specifically vine shoot is particularly rich in resveratrol.
  • resveratrol is a phytoalexin that protects plants from stress, UV light, microbial infections.
  • Resveratrol exists in two isomeric forms, the cis and trans forms, and is presented in monomeric form, or as an oligomer containing several monomeric units.
  • resveratrol is a powerful antioxidant and anti-inflammatory agent and has cardiovascular and anti-carcinogenic effects.
  • One of its most promising actions is its anti-aging action due to its ability to increase the activity of sirtuins which are longevity genes capable of prolonging the life of cells and organisms (Sinclair D. et al ., Nature, 2003, 425: 191 -196; Steegborn C. et al., PLoS One, 2012, 7 (11 ); Wood JG et al. Nature 430: 686-689).
  • WO 99/03816 discloses extraction methods leading to extracts enriched in monomeric and/or oligomeric resveratrol, using groups which protect phenolic functions, more particularly ester groups. These extraction methods allow to confer stability in air and in the light to monomeric and oligomeric resveratrol and render them liposoluble. These protective groups can be then eliminated under determined conditions, which makes it possible to exploit the properties of resveratrol in a controlled manner.
  • Resveratrol-Oleyl not only has a protective effect against carbonyl stress (a type of protein modification which occurs during aging) but also has improved skin bioavailability thanks to its stabilization and solubilization by oleic acid.
  • Hyaluronic acid is a ubiquitous natural polysaccharide which is formed from repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine, linked together by alternating glycosidic bonds 6-1 ,4 and 6-1 .3. It is widely distributed in various tissues of the body, such as connective, epithelial and nervous tissues. It is therefore suitable for biomedical applications targeting these tissues and is for example used to treat osteoarthritis of the knee. Hyaluronic acid is often used in the form of intra-articular injections, as it would protect the joints by increasing the viscosity of the synovial fluid and making the cartilage more elastic.
  • Hyaluronic acid is naturally present in the skin where it plays an important role in hydration and in the biomechanical properties of the skin. Hyaluronic acid, however, decreases in quantity and quality with age, resulting in drying the skin and a decrease in its biomechanical properties, leading thus to wrinkles. Hyaluronic acid is metabolically extremely active. The degradation of hyaluronic acid is first catalyzed by hyaluronidases. Furthermore, polymeric hyaluronic acid can be degraded non- enzymatically by free radicals. The enzymes responsible for the synthesis of hyaluronic acid are the hyaluronan synthases HAS-1 , HAS-2 and HAS-3.
  • HAS-2 seems to play a crucial role during development since the deletion of the has-2 gene in mice is lethal at mid-gestation due to numerous cardiovascular malformations (Camenisch TD. Et al., J. Clin. Invest., 2000, 106 (3): 349-60).
  • Hyaluronic acid is widely used in dermatology and dermoesthetics to treat the signs of aging. It is injected into the dermis to fill in wrinkles as described in document Kogan, G. et al. (6iotechno. Letter, 2007, 29: 17-25). It has the advantage of being absorbable in the event of bad injection and without side effect, even in treatment over several years. Treatment requires repeated injections at regular intervals, usually 6 to 12 months, in order to maintain a filling action.
  • the application FR 3 036 956 relates to compositions comprising resveratrol and hyaluronic acid and in particular to the use of such a composition to stimulate the synthesis of hyaluronic acid.
  • These compositions are capable of stimulating the production of hyaluronic acid in order to restore or maintain the biological and biomechanical properties of tissues and having improved properties for the treatment of dysfunctions linked to a deficit in the synthesis of hyaluronic acid, in particular for the treatment and protection of tissues containing hyaluronic acid (skin, cartilage. .), even more particularly for the treatment, slowing down and prevention of skin aging.
  • International application WO 2012/116391 discloses a cosmetic or pharmaceutical formulation comprising a crosslinked polymer of hyaluronate and one or more compounds selected from a group comprising in particular resveratrol or one of its derivatives. These compositions stimulate the formation of collagen in the dermis and regulate cell turnover. These compositions can be used against oxidative damage to the dermis and pigmentation problems.
  • US 2014/363502 relates to compositions containing resveratrol and their use for modulating the expression of certain genes involved in particular in aging.
  • US 2014/363502 discloses a combination of resveratrol and hyaluronic acid. According to this document, the more significant effect of the compositions according to the invention is attributed to better stability of the combined resveratrol compared to resveratrol alone.
  • These compositions can be useful in the treatment and prevention of cancers, and age-related diseases, including macular degeneration.
  • Khaya senegalensis is a tree also referred to as cailcedrat, belonging to the Meliaceae family and found in several African countries, especially Benin, Cameroon, Senegal, Guinea, Ivory Coast or else Burkina Faso. It is also found in northern Australia and New Caledonia.
  • Khaya senegalensis is a plant used for the large-scale construction of dugout canoes in Africa. In addition, its seeds are rich in oleic acid, making therefrom an oil used in West African cuisine. Khaya senegalensis is moreover known as a medicinal plant: the seeds and leaves are used to combat fever and headaches, and the bark is known for its anti-inflammatory properties. Khaya senegalensis bark is used in the treatment of arthritis, lumbago and other joint pains, and also in the treatment of dermatoses. Decoctions of bark of the plant have also been used as disinfectants.
  • WO 2017/178751 discloses that an extract of the plant Khaya senegalensis is capable of maintaining and/or increasing the expression of collagen XVIII of the skin and/or the mucous membranes and/or the scalp and/or the skin appendages, in particular at the dermoepidermal junction.
  • Such an extract allows thus to increase both the firmness and/or elasticity of the skin and/or the mucous membranes and/or the scalp, and also to decrease the visibility of the pores, that is to say decrease the opening thereof, and/or to make skin smoother and/or to limit and/or reduce perspiration and/or to limit and/or reduce the loss of head hair and/or body hair and/or increase the growth of head hair and/or body hair and/or reduce or limit the production of sebum.
  • Patent application WO2012033634 discloses cosmetic anti-aging compositions which may be applied topically, comprising, among other plant extracts, a Khaya senegalensis extract for inhibiting synthesis of metalloproteases 1 (ALMR1 s) and stimulating the synthesis of procollagen I.
  • a Khaya senegalensis extract for inhibiting synthesis of metalloproteases 1 (ALMR1 s) and stimulating the synthesis of procollagen I.
  • Patent application EP1019016 also discloses a synergistic anti-aging complex intended especially for topical application to the skin and comprising a dehydrated extract of Khaya senegalensis bark, said complex making it possible to combat UV radiation, the inflammatory processes generated by this radiation, and to reduce lipid peroxidation of fibroblasts.
  • the inventors have shown a specific effect of the association of a Khaya Senegalensis extract with resveratrol or one of its derivatives and hyaluronic acid or one of its derivatives or a salt thereof, in comparison with each compound alone and with the association of resveratrol or one of its derivatives and hyaluronic acid or one of its salts (without the Khaya Senegalensis extract).
  • the present invention thus relates to a composition
  • a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof.
  • the present invention also relates to the use of a composition
  • a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof, for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing.
  • the present invention also relates to a cosmetic care method for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing, comprising topically administering to a subject in need thereof, an effective amount of a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof.
  • a cosmetic care method for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing
  • Figure 1 illustrates the effect of Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) alone (H), Oligo-Resveratrol alone (0), Khaya Senegalensis extract alone (C), an association of Low Molecular Weight Hyaluronic Acid (50 kDa) + Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) + Oligo- Resveratrol (HOR), or an association of Low Molecular Weight Hyaluronic Acid (50 kDa) + Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) + Oligo-Resveratrol + Khaya Senegalensis extract (HORC), on the expression of HAS-2 Genes.
  • Sample V corresponds to fibroblasts that were untreated, i.e. that were incubated in the absence of products to be tested.
  • Figure 2 illustrates the effect of Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) alone (H), Oligo-Resveratrol alone (O), Khaya Senegalensis extract alone (C), an association of Low Molecular Weight Hyaluronic Acid (50 kDa) + Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) + Oligo- Resveratrol (HOR), or an association of Low Molecular Weight Hyaluronic Acid (50 kDa) + Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) + Oligo-Resveratrol + Khaya Senegalensis extract (HORC), on the expression of COL4A1 Genes.
  • Sample V corresponds to fibroblasts that were untreated, i.e. that were incubated in the absence of products to be tested.
  • alkyl group refers to a linear or branched saturated hydrocarbon chain.
  • alkylene group refers to a linear or branched, divalent, saturated hydrocarbon chain.
  • aryl group refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more, notably 1 or 2, fused rings, such as, for example, a phenyl or naphtyl group.
  • arylene group refers to an divalent aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more, notably 1 or 2, fused rings, such as, for example, a phenyl or naphtyl group.
  • alkylaryl group refers to an aryl group as defined above bound to the molecule via an alkyl group as defined above.
  • arylalkyl group refers to an alkyl group as defined above bound to the molecule via an aryl group as defined above.
  • heterocycle refers to a saturated, unsaturated or aromatic hydrocarbon monocycle or polycycle (comprising fused, bridged or spiro rings), such as a bicycle, in which one or more, advantageously 1 to 4, and more advantageously 1 or 2, carbon atoms have each been replaced with a heteroatom selected from nitrogen, oxygen and sulphur atoms.
  • the heterocycle comprises 5 to 15, notably 5 to 10 atoms in the ring(s).
  • Each ring of the heterocycle has advantageously 5 or 6 members.
  • “increasing the expression of genes” is intended to mean an increase in the level of genes expression, preferably of at least 1.5-fold, more preferably still of at least 2-fold, relative to the gene expression detected in the absence of treatment.
  • the invention relates to a composition
  • a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or one of its salts, hyaluronic acid derivatives or one of its salts, or mixtures thereof.
  • the Khaya Senegalensis extract may be any extract of all or part of the plant Khaya Senegalensis.
  • the Khaya Senegalensis extract is an extract of the root, bark, flower, seed, seedling, aerial parts, in particular the stem of the branches and/or the leaf, and mixtures thereof.
  • the Khaya Senegalensis extract according to the invention is a bark extract.
  • the Khaya Senegalensis extract may be obtained by plant extraction methods known by the one skilled in the art, in particular by solid/liquid extraction, for example maceration.
  • the Khaya Senegalensis extract is obtained by solid/liquid extraction, for example maceration, of at least one part of the plant in a solvent such as water, alcohol, polyol, glycol and mixtures thereof.
  • the Khaya Senegalensis extract is obtained by solid/liquid extraction of at least one part of the plant, in particular the bark, in a solvent selected from the group consisting of water, alcohol, polyol, glycol or mixtures thereof, more advantageously in a solvent selected for the group consisting of water/alcohol, water/glycol or water/polyol mixtures in proportion of between 0/100 and 100/0 (v/v) of water/alcohol, polyol or glycol, preferably between 20/80 and 100/0 (v/v), more preferably between (60/40 and 100/0).
  • the extract of Khaya Senegalensis is obtained by aqueous solid/liquid extraction.
  • aqueous solid/liquid extraction is intended to mean any solid/liquid extraction as defined above with an aqueous solvent comprising at least 60% by weight, advantageously at least 70% by weight, in particular at least 80% by weight, more particularly at least 90% by weight, particularly at least 95% by weight, of water relative to the total weight of the aqueous solvent, even more advantageously 100 % by weight of water.
  • the extract of Khaya Senegalensis is obtained by solid/liquid extraction of an amount of 10% to 20% by weight of bark relative to the total weight of bark and of solvent, in an aqueous solvent, in particular in water as sole solvent.
  • the extract of Khaya Senegalensis is obtained by solid /extraction as disclosed in the international application WO 2017/178751 , in particular from page 12, line 31 to page 15, line 22 and in example 1.
  • the extract of Khaya Senegalensis used in the invention is advantageously enriched in oligo- proanthocyanidins (OPC).
  • OPC oligo- proanthocyanidins
  • the extract of Khaya Senegalensis used in the invention comprises advantageously at least 3%, more advantageously between 3 % to 7 % by weight of OPC, in relation with the total weight of the extract.
  • the extract of Khaya Senegalensis used in the invention is also advantageously enriched in polyphenols.
  • the extract of Khaya Senegalensis used in the invention comprises advantageously at least 10 %, more advantageously between 10 % to 14 % by weight of polyphenols, expressed in Gallic acid equivalent.
  • the composition also comprises as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof.
  • component b) can be a compound selected from the group of resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters; a mixture of two or more of said compounds; or an extract enriched in said compounds, preferably a vine extract.
  • resveratrol (3, 5, 4'-trihydroxystilbene) can exist in two isomeric forms, the c/ ' s and trans forms (see formula (I) and (II) respectively):
  • component b) comprises resveratrol
  • it is in the form of trans- resveratrol (formula (II)).
  • resveratrol monomers are resveratrol derivatives, in particular trans- resveratrol derivatives, comprising one monomer unit, such as E-piceid, E-astringin, E-pterostilbene or E-piceatannol.
  • resveratrol oligomers are resveratrol derivatives comprising two or more resveratrol monomer units, in particular 2, 3 or 4 resveratrol monomer units, such as e-viniferin, d-viniferin, pallidol, a-viniferin, miyabenol C, E-vitisin B, or hopeaphenol.
  • resveratrol esters are monomers or oligomers of resveratrol, wherein the monomers comprises at least one ester group of formula (III), and the oligomers are formed of two or more monomer units, in particular 2, 3 or 4 monomer units, comprising at least one ester group of formula (III), the monomer units being joined by carbon-carbon bonds, or ether, and/or the oligomers are formed of monomers crosslinked by at least one group of formula (IV):
  • A represents an alkyl group of at least two carbon atoms, linear or branched, saturated or unsaturated; an aryl group; arylalkyl group; or an alkylaryl group, and
  • R represents an alkylene group from 0 to 10 carbon atoms, saturated or unsaturated; an arylene group having 1 to 3 rings; a heterocyclic group, and the diastereoisomers of these units.
  • resveratrol esters according to the invention are as disclosed in the international application WO 99/03816, in particular from page 2 line 18, to page 5 line 2.
  • the method of preparation of the resveratrol esters is also disclosed in WO 99/03816.
  • resveratrol esters are resveratrol esters of fatty acid. More advantageously, resveratrol esters are of one of the following fatty acids: butyric acid C4:0; valeric acid C5:0; hexanoic acid C6:0; sorbic acid C6:2(n-2); lauric acid C12:0; palmitic acid C16:0; stearic acid C18:0; oleic acid C18: 1 (n-9); linoleic acid C18:2(n-6); linolenic acid C18:3(n-6); a-linolenic acid C18:3(n-3); arachidonic acid C20:4(n-3), eicosapentaenoic acid C20:5(n-3); and docosahexanoic acid C22:6(n-3).
  • A is advantageously a (C4-C2s)-alkyl group, more advantageously a (C4-C22)- alkyl group, more advantageously a Ci 6 -alkyl group (i.e. C16-fatty acid).
  • resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters can be chemically synthesized or obtained from various plant sources selected from the following group: Vitaceae, Umbelliferae, Myrtaceae, Dipterocarpaceae, Cyperaceae, Gnetaceae, Legumes, Grasses, Seraceae, Haemodoraceae, Musaceae, Polygonaceae, Pinaceae, Cupressaceae, Cesalpiniaceae, Poaceae, and Solanaceae.
  • the resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters are obtained by extracting grape vines using water and/or an organic solvent, by techniques known to the one skilled in the art, such as techniques disclosed in WO 99/03816.
  • the resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters can also be obtained by use of genetically modified microorganisms from animal tissue or by bioproduction from plants, in particular from suspensions of vine cells ( Study of the synthesis of resveratrol and its derivatives by
  • the component b) is in the form of an extract rich in resveratrol from grape vines, in particular in the form of an extract rich in resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters.
  • the component b) is an extract of grape vines enriched in trans- resveratrol and/or resveratrol oligomers, preferably enriched in trans- resveratrol and resveratrol oligomers such as e- viniferin, d-viniferin, and a-viniferin. More advantageously, the component b) is an extract of grape vines comprising trans- resveratrol and e-viniferin.
  • the component b) is an extract of grape vines comprising frans-resveratrol in a content of between 10 and 30 % by weight, and e-viniferin in a content of between 10 and 20 % by weight, in relation to the total weight of the extract.
  • the component b) is a mixture of resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters.
  • the component b) is a mixture comprising at least resveratrol, in particular frans- resveratrol and/or resveratrol oligomers, in particular e-viniferin, d-viniferin, and a-viniferin.
  • the component b) is a mixture comprising mainly frans-resveratrol and/or e- viniferine. More advantageously, the component b) is a mixture comprising frans-resveratrol in a content of between 10 and 30 % by weight, and e-viniferin in a content of between 10 and 20 % by weight, in relation to the total weight of the extract.
  • composition of the invention also comprises as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof.
  • hyaluronic acid refers to a linear polymer consisting of the repetition of the disaccharides of D-glucuronic acid and N-acetyl-D- glucosamine, linked together via alternating 6-1 ,4 and 6-1 ,3 glycosidic bonds ([-6(1 ,4)-GlcUA-6(1 ,3)- GlcNAc-]n).
  • Hyaluronic acid is a naturally occurring, not sulphated glycosaminoglycan (GAG).
  • GAG sulphated glycosaminoglycan
  • Hyaluronic acid is widely available commercially or may be prepared or extracted by any technique known to those skilled in the art. This polymer may be natural or synthetic.
  • Hyaluronic acid derivatives means its counterparts, analogs, derivatives, complexes, esters, fragments and subunits.
  • Hyaluronic acid exists naturally in the form of unsaturated disaccharides (Acta Vet Scand. 2015 Mar 4; 57(1 ): 12) and can also be chemically modified so as to improve its absorption characteristics, such as for example by modifications of the hydroxyl groups by an ether bond to obtain a cysteine conjugate-hyaluronic acid (Chem Commun (Camb). 2015 51 (47): 9662-5) or the formation of an ethyl ether of l-cysteine (C) via an amide bond (J Pharm Sci. 2015 Apr 21. doi: 10.1002/jps.24456).
  • hyaluronic acid salt or ‘hyaluronic acid derivatives salt” is understood to mean the sodium, potassium, magnesium, aluminium, or ammonium salts, in particular sodium or potassium salts.
  • the average molecular weight of the hyaluronic acid or derivatives thereof used varies according to the administration mode.
  • the average molecular weight of hyaluronic acid or derivatives thereof is advantageously at most 100 kDa, more advantageously between 0.5 kDa and 100 kDa, more advantageously between 0.5 kDa and 50 kDa, and even more advantageously between 5 kDa and 50 kDa.
  • high molecular weight hyaluronic acid or derivatives thereof is advantageously used, such as more than 1 Million Dalton, in particular between 1.2 and 2.1 Millions Da.
  • component c) is hyaluronic acid and/or hydrolysed hyaluronic acid of average molecular weight of at most 100 kDa, more advantageously between 0.5 kDa and 100 kDa, even more advantageously between 0.5 kDa and 50 kDa, and even more advantageously between 5 kDa and 50 kDa.
  • the amounts of components a), b) and c) in the composition will be determined by those skilled in the art in the light of their general knowledge.
  • the composition is advantageously formulated so that component b) is administered at a dose of between 10 mg per day and 5 g per day.
  • the cosmetic or dermatological composition is advantageously formulated so that component a) represents from 0.05 to 5% by weight of the composition, component b) represents from 0.01 to 1% by weight of the composition and component c) represents 0.01 to 0.4% by weight of the composition.
  • the composition is advantageously formulated in the form of an aqueous solution comprising advantageously between 1 pg/ml and 100 mg/ml of component a), between 1 pg/ml and 100 mg/ml of component b) and between 1 pg/ml and 100 mg/ml of component c).
  • These doses can be administered once or several times a day.
  • the composition of the invention comprises between 0.02 % and 5 %, more advantageously between 0.5 and 2%, by weight of component a), in relation to the total weight of the composition.
  • the composition of the invention comprises between 0.01 % and 1 %, more advantageously between 0.3 and 1%, by weight of component b), in relation to the total weight of the composition.
  • the composition of the invention comprises between 0.01 % and 0.4 %, more advantageously between 0.01 and 0.2 %, by weight of component c), in relation to the total weight of the composition.
  • the composition of the invention comprises between 0.5 % and 2 % of component a), between 0.3 % and 1 % of component b), and between 0.01 % and 0.2 % of component c).
  • the composition of the invention comprises an extract of Khaya Senegalensis bark as component a), a mixture comprising at least trans- resveratrol or resveratrol oligomers as component b), and hyaluronic acid or hydrolysed hyaluronic acid of average molecular weight of at most 100 kDa as component c).
  • the composition of the invention comprises an aqueous extract of Khaya Senegalensis bark as component a), a mixture comprising mainly trans- resveratrol and e-viniferin, as component b), and hyaluronic acid or hydrolysed hyaluronic acid of average molecular weight of at most 100 kDa as component c).
  • the composition of the invention comprises an aqueous extract of Khaya Senegalensis bark as component a), a grape vine extract comprising mainly trans- resveratrol or resveratrol oligomers, in particular e-viniferin, as component b), and hyaluronic acid or hydrolysed hyaluronic acid of average molecular weight of between 5 and 100 kDa as component c).
  • the composition of the invention further comprises other active principles, in particular active principles with anti-aging properties such as b-carotene, vitamin E or vitamin C, Oligo-ProanthoCyanidines (OPC), retinol, cis-retinoic acid, trans-retinoic acid, retinyl palmitate salicylic acid, niacinamide, nicotinic acid, phytic acid, N-acetyl L-cysteine, azelaic acid, lipoic acid, lactic acid, glycolic acid, panthenol, arbutin, deoxyarbutin, kojic acid, allantoin, cholesterol, C10- C30 cholesterol/lanosterol esters, tocopherol, tocopheryl acetate, and mixtures thereof.
  • active principles with anti-aging properties such as b-carotene, vitamin E or vitamin C, Oligo-ProanthoCyanidines (OPC), retinol, cis-retinoic
  • composition of the invention may be formulated in the form of various preparations for oral, parenteral or topical administration, preferably for topical administration.
  • the composition of the invention is a cosmetic composition, a food composition, a pharmaceutical composition, a dermatological composition or a veterinary composition.
  • the modes of administration, dosing schedules and optimal galenic forms of the components and composition of the invention may be determined according to the criteria generally taken into account in the establishment of a pharmaceutical, dermatological, cosmetic, food or veterinary treatment suitable for a patient or an animal, such as for example the age or the body weight of the patient or animal, the severity of the general condition of the patient or animal, tolerance to the treatment, noted side effects, skin type.
  • the composition and/or components of the invention may further include at least one acceptable carrier, in particular a pharmaceutically acceptable, a dermatologically acceptable carrier, a cosmetically acceptable carrier, a food acceptable carrier, or a veterinary acceptable carrier.
  • composition according to the present invention may furthermore comprise at least one known excipient commonly used in those fields, chosen from oils, waxes, emollients, solvents, pigments, dyes, polymers, surfactants, rheological agents, perfumes, electrolytes, adjusters of pH, fillers, chemical or mineral filters, chelating agents, odor absorbers, thermal spring water, antioxidants, gelling agents, for example hydrophilic or lipophilic gelling agents, moisturizing agents, thickeners, and preservatives.
  • excipient commonly used in those fields, chosen from oils, waxes, emollients, solvents, pigments, dyes, polymers, surfactants, rheological agents, perfumes, electrolytes, adjusters of pH, fillers, chemical or mineral filters, chelating agents, odor absorbers, thermal spring water, antioxidants, gelling agents, for example hydrophilic or lipophilic gelling agents, moisturizing agents, thickeners, and preservatives.
  • the composition is a cosmetic composition for topical use comprising an effective amount of components a), b) and c), and further comprising at least one cosmetically acceptable excipient chosen from oils, waxes, emollients, solvents, pigments, dyes, polymers, surfactants, rheological agents, perfumes, electrolytes, adjusters of pH, fillers, chemical or mineral filters, chelating agents, odor absorbers, thermal spring water, antioxidants, gelling agents, for example hydrophilic or lipophilic gelling agents, moisturizing agents, thickeners, and preservatives.
  • the amounts of these various excipients are those traditionally used in cosmetics.
  • the amount of each excipient may vary from 0.01 % to 20 % by weight, in relation to the total weight of the cosmetic composition.
  • the cosmetic composition is a skin care or makeup product and is for example in the form of a gel, a cream, a pomade, a lotion, an emulsion, a milk, an oil, an ointment, a foam, a serum, a hydrogel, a mask, an aerosol, a stick, for example for a lipstick, an aqueous or water-alcoholic or glycolic solution, a powder, or a patch.
  • the composition is a pharmaceutical, dermatological or veterinary composition, for topical, oral or parenteral administration. It can also be in the form of a food composition, in particular a food supplement.
  • a composition comprises an effective amount of components a), b) and c), and further comprises a physiologically acceptable carrier.
  • the pharmaceutical, dermatological, veterinary or food composition comprises an effective amount of components a), b) and c), and a suitable excipient chosen from oils, waxes, emollients, solvents, pigments, dyes, polymers, surfactants, rheological agents, perfumes, electrolytes, adjusters of pH, fillers, chemical or mineral filters, chelating agents, odor absorbers, thermal spring water, antioxidants, gelling agents, for example hydrophilic or lipophilic gelling agents, moisturizing agents, thickeners, and preservatives.
  • a suitable excipient chosen from oils, waxes, emollients, solvents, pigments, dyes, polymers, surfactants, rheological agents, perfumes, electrolytes, adjusters of pH, fillers, chemical or mineral filters, chelating agents, odor absorbers, thermal spring water, antioxidants, gelling agents, for example hydrophilic or lipophilic gelling agents, moisturizing agents, thickeners, and preservatives.
  • the composition for oral administration is advantageously in the form of tablets, capsules, powders, granules, lyophilisates, solutes, suspensions, syrups, drinks, pastes, chewing gum or candy.
  • the composition for parenteral administration is advantageously in the form of an aqueous solution or of a lyophilized powder.
  • the pharmaceutical, dermatological, cosmetic, veterinary or food compositions according to the invention are for use for treating and/or preventing disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes.
  • the cosmetic composition of the invention is for use for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing; advantageously for maintaining or restoring hydration of the skin and the biomechanical properties of the skin and/or to prevent or delay the appearance of signs of aging of the skin, in particular the appearance of wrinkles and the loss of firmness of the skin or to slow down the effects; in particular for preventing, slowing down or correcting skin aging, in particular for firming the skin, and/or promoting the attenuation or resorption of wrinkles.
  • the cosmetic composition of the invention is for use for increasing the expression of HAS2 genes or COL4A1 genes.
  • the present invention also relates to a cosmetic care method for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing, comprising topically administering an effective amount of a composition according to the invention to a subject in need thereof.
  • the cosmetic care method is for maintaining or restoring hydration of the skin and the biomechanical properties of the skin and/or to prevent or delay the appearance of signs of aging of the skin, in particular the appearance of wrinkles and the loss of firmness of the skin or to slow down the effects.
  • the cosmetic care method is for preventing, slowing down or correcting skin aging, in particular for firming the skin, and/or promoting the attenuation or resorption of wrinkles.
  • the present invention also relates to the cosmetic use of the cosmetic composition of the invention for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing, advantageously for maintaining or restoring hydration of the skin and the biomechanical properties of the skin and/or to prevent or delay the appearance of signs of aging of the skin, in particular the appearance of wrinkles and the loss of firmness of the skin or to slow down the effects, in particular for preventing, slowing down or correcting skin aging, more particularly for firming the skin, and/or promoting the attenuation or resorption of wrinkles.
  • compositions according to the invention are more particularly for use for treating and/or preventing osteoarthritis and skin aging.
  • the pharmaceutical, dermatological, veterinary or food compositions may also be for use for preventing and/or treating pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome, or digestive disorders, in particular gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa.
  • the pharmaceutical, dermatological, veterinary or food compositions according to the invention can be for use for treating ocular disorders, in particular dryness of corneal lesions and keratopathies.
  • the present invention thus also relates to the composition of the invention for use as a drug, in particular for preventing and/or treating osteoarthritis; skin aging; pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome; digestive disorders, such as gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa; or ocular disorders, such as dryness of corneal lesions and keratopathies.
  • the present invention also relates to the composition of the invention for use for preventing and/or treating disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes.
  • the present invention thus also relates to a method for preventing and/or treating osteoarthritis; skin aging; pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome; digestive disorders, such as gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa; or ocular disorders, such as dryness of corneal lesions and keratopathies; comprising administering to a subject in need thereof, an effective amount of the composition of the invention.
  • the present invention thus also relates to a method for preventing and/or treating disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes, comprising administering to a subject in need thereof, an effective amount of the composition of the invention.
  • the present invention also relates to the use of the composition of the invention for the manufacture of a drug for preventing and/or treating osteoarthritis; skin aging; pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome; digestive disorders, such as gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa; or ocular disorders, such as dryness of corneal lesions and keratopathies.
  • the present invention also relates to the use of the composition of the invention for the manufacture of a drug for preventing and/or treating disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes.
  • Example 1 Effect of the composition of the invention on the expression of the has2 genes and COL4A1 genes in human skin fibroblasts - Comparison with each compound individually.
  • GOAL To determine the activity of Oligo-Resveratrol (OR, R), Low Molecular Weight Hyaluronic Acid (50 kDa) (HHA, H), Very Low Molecular Weight-Hyaluronic Acid (0.5-10 kDa) (OHA, 0), Khaya Senegalensis extract (CL, C) and their combination on the expression of the has2 genes and COL4A1 genes in human skin fibroblasts.
  • RNA extraction kit (Zymo Research; Cat #: ZR1057) iScript kit (Biorad; Cat #: 170-8891 )
  • the vegan collagen booster (Khaya Senegalensis extract), a hydrophilic liquid (1 g; from Caudalie, stored at room temperature)
  • Very Low Molecular Weight HA (0.5-10 kDa), a hydrophilic powder.
  • Hyaluronic Acid 50 kDa
  • the solubility is 100 g/L (500 mg; from Caudalie, stored at 4°C)
  • Oligo-resveratrol (Batch BX1191834), a hydrophobic powder.
  • RNA extraction is carried out using the Omega RNA extraction kit. 1 mg of RNA is used and transcribed into complementary DNA using the Bio-Rad iScriptTM cDNA synthesis kit followed by quantification by quantitative real-time PCR.
  • PCR reactions were carried out using the FastStartTM DNA Master SYBR Green I real-time PCR kit (Roche Molecular Biochemicals). Each PCR was carried out in a final volume of 20 pi containing 10 m ⁇ of SYBR Green mix 2X (Fast start DNA master SYBR green + Taq DNA polymerase), 2 m ⁇ of the primer mixture and 8 m ⁇ of cDNA solution.

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Abstract

The invention relates to a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or one of its salts, hyaluronic acid derivatives or one of its salts, or mixtures thereof. The invention also relates to a cosmetic care method for maintaining or restoring hydration of the skin and/or the biomechanical properties of the skin, and/or for preventing or delaying skin ageing, comprising topically administering an effective amount of the composition of the invention. The invention also relates to a composition of the invention for use as a drug.

Description

ASSOCIATION OF NATURAL ACTIVES INGREDIENTS TO FIGHT SKIN AGING
FIELD OF THE INVENTION
The present invention relates to a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof. The present invention also relates to a cosmetic care method for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing, comprising administering an effective amount of the composition of the invention.
PRIOR ART
Resveratrol (3, 5, 4'-trihydroxystilbene) is a natural polyphenolic antioxidant of the stilbene family that is found in more than 70 plant species. One of the most common botanical sources is the vine; more specifically vine shoot is particularly rich in resveratrol. In nature, resveratrol is a phytoalexin that protects plants from stress, UV light, microbial infections.
Resveratrol exists in two isomeric forms, the cis and trans forms, and is presented in monomeric form, or as an oligomer containing several monomeric units.
The study of the properties of resveratrol has made it possible to highlight 20 multiple biological activities of interest. Thus, resveratrol is a powerful antioxidant and anti-inflammatory agent and has cardiovascular and anti-carcinogenic effects. One of its most promising actions is its anti-aging action due to its ability to increase the activity of sirtuins which are longevity genes capable of prolonging the life of cells and organisms (Sinclair D. et al ., Nature, 2003, 425: 191 -196; Steegborn C. et al., PLoS One, 2012, 7 (11 ); Wood JG et al. Nature 430: 686-689).
The studies carried out by the applicant have demonstrated that resveratrol extracted from vine shoots naturally intensifies the firmness and youthfulness of the skin. Resveratrol from vine shoots overactivated by alkylation is the subject-matter of international application WO 99/03816. WO 99/03816 discloses extraction methods leading to extracts enriched in monomeric and/or oligomeric resveratrol, using groups which protect phenolic functions, more particularly ester groups. These extraction methods allow to confer stability in air and in the light to monomeric and oligomeric resveratrol and render them liposoluble. These protective groups can be then eliminated under determined conditions, which makes it possible to exploit the properties of resveratrol in a controlled manner.
International application WO 2009/063440 relates in particular to resveratrol-oleyl, alkylated resveratrol stabilized by the addition of a chain of fatty acids capable of countering the formation of glycated molecules. Resveratrol-Oleyl not only has a protective effect against carbonyl stress (a type of protein modification which occurs during aging) but also has improved skin bioavailability thanks to its stabilization and solubilization by oleic acid.
Hyaluronic acid is a ubiquitous natural polysaccharide which is formed from repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine, linked together by alternating glycosidic bonds 6-1 ,4 and 6-1 .3. It is widely distributed in various tissues of the body, such as connective, epithelial and nervous tissues. It is therefore suitable for biomedical applications targeting these tissues and is for example used to treat osteoarthritis of the knee. Hyaluronic acid is often used in the form of intra-articular injections, as it would protect the joints by increasing the viscosity of the synovial fluid and making the cartilage more elastic.
Hyaluronic acid is naturally present in the skin where it plays an important role in hydration and in the biomechanical properties of the skin. Hyaluronic acid, however, decreases in quantity and quality with age, resulting in drying the skin and a decrease in its biomechanical properties, leading thus to wrinkles. Hyaluronic acid is metabolically extremely active. The degradation of hyaluronic acid is first catalyzed by hyaluronidases. Furthermore, polymeric hyaluronic acid can be degraded non- enzymatically by free radicals. The enzymes responsible for the synthesis of hyaluronic acid are the hyaluronan synthases HAS-1 , HAS-2 and HAS-3. HAS-2 seems to play a crucial role during development since the deletion of the has-2 gene in mice is lethal at mid-gestation due to numerous cardiovascular malformations (Camenisch TD. Et al., J. Clin. Invest., 2000, 106 (3): 349-60).
Hyaluronic acid is widely used in dermatology and dermoesthetics to treat the signs of aging. It is injected into the dermis to fill in wrinkles as described in document Kogan, G. et al. (6iotechno. Letter, 2007, 29: 17-25). It has the advantage of being absorbable in the event of bad injection and without side effect, even in treatment over several years. Treatment requires repeated injections at regular intervals, usually 6 to 12 months, in order to maintain a filling action.
To date, various works have been reported regarding combinations of resveratrol and hyaluronic acid.
The application FR 3 036 956 relates to compositions comprising resveratrol and hyaluronic acid and in particular to the use of such a composition to stimulate the synthesis of hyaluronic acid. These compositions are capable of stimulating the production of hyaluronic acid in order to restore or maintain the biological and biomechanical properties of tissues and having improved properties for the treatment of dysfunctions linked to a deficit in the synthesis of hyaluronic acid, in particular for the treatment and protection of tissues containing hyaluronic acid (skin, cartilage. .), even more particularly for the treatment, slowing down and prevention of skin aging.
International application WO 2014/210308 discloses the use of resveratrol in combination with high molecular weight hyaluronic acid for wound healing.
International application WO 2012/116391 discloses a cosmetic or pharmaceutical formulation comprising a crosslinked polymer of hyaluronate and one or more compounds selected from a group comprising in particular resveratrol or one of its derivatives. These compositions stimulate the formation of collagen in the dermis and regulate cell turnover. These compositions can be used against oxidative damage to the dermis and pigmentation problems.
Application US 2014/363502 relates to compositions containing resveratrol and their use for modulating the expression of certain genes involved in particular in aging. In particular, US 2014/363502 discloses a combination of resveratrol and hyaluronic acid. According to this document, the more significant effect of the compositions according to the invention is attributed to better stability of the combined resveratrol compared to resveratrol alone. These compositions can be useful in the treatment and prevention of cancers, and age-related diseases, including macular degeneration.
Khaya senegalensis is a tree also referred to as cailcedrat, belonging to the Meliaceae family and found in several African countries, especially Benin, Cameroon, Senegal, Guinea, Ivory Coast or else Burkina Faso. It is also found in northern Australia and New Caledonia.
Khaya senegalensis is a plant used for the large-scale construction of dugout canoes in Africa. In addition, its seeds are rich in oleic acid, making therefrom an oil used in West African cuisine. Khaya senegalensis is moreover known as a medicinal plant: the seeds and leaves are used to combat fever and headaches, and the bark is known for its anti-inflammatory properties. Khaya senegalensis bark is used in the treatment of arthritis, lumbago and other joint pains, and also in the treatment of dermatoses. Decoctions of bark of the plant have also been used as disinfectants.
WO 2017/178751 discloses that an extract of the plant Khaya senegalensis is capable of maintaining and/or increasing the expression of collagen XVIII of the skin and/or the mucous membranes and/or the scalp and/or the skin appendages, in particular at the dermoepidermal junction. Such an extract allows thus to increase both the firmness and/or elasticity of the skin and/or the mucous membranes and/or the scalp, and also to decrease the visibility of the pores, that is to say decrease the opening thereof, and/or to make skin smoother and/or to limit and/or reduce perspiration and/or to limit and/or reduce the loss of head hair and/or body hair and/or increase the growth of head hair and/or body hair and/or reduce or limit the production of sebum. Patent application WO2012033634 discloses cosmetic anti-aging compositions which may be applied topically, comprising, among other plant extracts, a Khaya senegalensis extract for inhibiting synthesis of metalloproteases 1 (ALMR1 s) and stimulating the synthesis of procollagen I.
Patent application EP1019016 also discloses a synergistic anti-aging complex intended especially for topical application to the skin and comprising a dehydrated extract of Khaya senegalensis bark, said complex making it possible to combat UV radiation, the inflammatory processes generated by this radiation, and to reduce lipid peroxidation of fibroblasts.
To date, no works have been reported regarding combinations of resveratrol, hyaluronic acid and Khaya senegalensis extract.
SUMMARY OF THE INVENTION
Unexpectedly, the inventors discovered that the association of a Khaya Senegalensis extract with resveratrol or one of its derivatives and hyaluronic acid or one of its derivatives or a salt thereof, shows a significant increase in collagen 4 gene and Has2 (Hyaluronic Acid Synthase 2) gene.
The inventors have shown a specific effect of the association of a Khaya Senegalensis extract with resveratrol or one of its derivatives and hyaluronic acid or one of its derivatives or a salt thereof, in comparison with each compound alone and with the association of resveratrol or one of its derivatives and hyaluronic acid or one of its salts (without the Khaya Senegalensis extract).
The present invention thus relates to a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof.
The present invention also relates to the use of a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof, for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing.
The present invention also relates to a cosmetic care method for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing, comprising topically administering to a subject in need thereof, an effective amount of a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof. DESCRIPTION OF THE FIGURES
Figure 1 illustrates the effect of Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) alone (H), Oligo-Resveratrol alone (0), Khaya Senegalensis extract alone (C), an association of Low Molecular Weight Hyaluronic Acid (50 kDa) + Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) + Oligo- Resveratrol (HOR), or an association of Low Molecular Weight Hyaluronic Acid (50 kDa) + Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) + Oligo-Resveratrol + Khaya Senegalensis extract (HORC), on the expression of HAS-2 Genes. Sample V corresponds to fibroblasts that were untreated, i.e. that were incubated in the absence of products to be tested.
Figure 2 illustrates the effect of Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) alone (H), Oligo-Resveratrol alone (O), Khaya Senegalensis extract alone (C), an association of Low Molecular Weight Hyaluronic Acid (50 kDa) + Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) + Oligo- Resveratrol (HOR), or an association of Low Molecular Weight Hyaluronic Acid (50 kDa) + Very Low Molecular Weight Hyaluronic Acid (0,5-10 KDa) + Oligo-Resveratrol + Khaya Senegalensis extract (HORC), on the expression of COL4A1 Genes. Sample V corresponds to fibroblasts that were untreated, i.e. that were incubated in the absence of products to be tested.
DEFINITIONS
The terms “alkyl group”, as used in the present invention, refers to a linear or branched saturated hydrocarbon chain. A “(Cx-Cy)alkyl group”, as used in the present invention, refers to a linear or branched saturated hydrocarbon chain containing from x to y carbon atoms wherein x and y are an integer.
The terms “alkylene group”, as used in the present invention, refers to a linear or branched, divalent, saturated hydrocarbon chain.
The term “aryl group”, as used in the present invention, refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more, notably 1 or 2, fused rings, such as, for example, a phenyl or naphtyl group.
The term “arylene group”, as used in the present invention, refers to an divalent aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more, notably 1 or 2, fused rings, such as, for example, a phenyl or naphtyl group.
The term “alkylaryl group”, as used in the present invention, refers to an aryl group as defined above bound to the molecule via an alkyl group as defined above. The term “arylalkyl group” as used in the present invention, refers to an alkyl group as defined above bound to the molecule via an aryl group as defined above.
The term “heterocycle” as used in the present invention refers to a saturated, unsaturated or aromatic hydrocarbon monocycle or polycycle (comprising fused, bridged or spiro rings), such as a bicycle, in which one or more, advantageously 1 to 4, and more advantageously 1 or 2, carbon atoms have each been replaced with a heteroatom selected from nitrogen, oxygen and sulphur atoms. Advantageously, the heterocycle comprises 5 to 15, notably 5 to 10 atoms in the ring(s). Each ring of the heterocycle has advantageously 5 or 6 members.
For the purpose of the present invention, “increasing the expression of genes” is intended to mean an increase in the level of genes expression, preferably of at least 1.5-fold, more preferably still of at least 2-fold, relative to the gene expression detected in the absence of treatment.
DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect, the invention relates to a composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or one of its salts, hyaluronic acid derivatives or one of its salts, or mixtures thereof.
Regarding component a), the Khaya Senegalensis extract may be any extract of all or part of the plant Khaya Senegalensis. Advantageously, the Khaya Senegalensis extract is an extract of the root, bark, flower, seed, seedling, aerial parts, in particular the stem of the branches and/or the leaf, and mixtures thereof. More advantageously, the Khaya Senegalensis extract according to the invention is a bark extract.
The Khaya Senegalensis extract may be obtained by plant extraction methods known by the one skilled in the art, in particular by solid/liquid extraction, for example maceration.
Advantageously, the Khaya Senegalensis extract is obtained by solid/liquid extraction, for example maceration, of at least one part of the plant in a solvent such as water, alcohol, polyol, glycol and mixtures thereof.
Advantageously, the Khaya Senegalensis extract is obtained by solid/liquid extraction of at least one part of the plant, in particular the bark, in a solvent selected from the group consisting of water, alcohol, polyol, glycol or mixtures thereof, more advantageously in a solvent selected for the group consisting of water/alcohol, water/glycol or water/polyol mixtures in proportion of between 0/100 and 100/0 (v/v) of water/alcohol, polyol or glycol, preferably between 20/80 and 100/0 (v/v), more preferably between (60/40 and 100/0). Advantageously, the extract of Khaya Senegalensis is obtained by aqueous solid/liquid extraction. For the purpose of the present invention, “aqueous solid/liquid extraction” is intended to mean any solid/liquid extraction as defined above with an aqueous solvent comprising at least 60% by weight, advantageously at least 70% by weight, in particular at least 80% by weight, more particularly at least 90% by weight, particularly at least 95% by weight, of water relative to the total weight of the aqueous solvent, even more advantageously 100 % by weight of water.
Advantageously, the extract of Khaya Senegalensis is obtained by solid/liquid extraction of an amount of 10% to 20% by weight of bark relative to the total weight of bark and of solvent, in an aqueous solvent, in particular in water as sole solvent.
In a particularly advantageous embodiment of the invention, the extract of Khaya Senegalensis is obtained by solid /extraction as disclosed in the international application WO 2017/178751 , in particular from page 12, line 31 to page 15, line 22 and in example 1.
The extract of Khaya Senegalensis used in the invention is advantageously enriched in oligo- proanthocyanidins (OPC). In particular, the extract of Khaya Senegalensis used in the invention comprises advantageously at least 3%, more advantageously between 3 % to 7 % by weight of OPC, in relation with the total weight of the extract.
The extract of Khaya Senegalensis used in the invention is also advantageously enriched in polyphenols. In particular, the extract of Khaya Senegalensis used in the invention comprises advantageously at least 10 %, more advantageously between 10 % to 14 % by weight of polyphenols, expressed in Gallic acid equivalent.
According to the invention, the composition also comprises as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof.
In the context of the invention, component b) can be a compound selected from the group of resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters; a mixture of two or more of said compounds; or an extract enriched in said compounds, preferably a vine extract.
In the context of the invention, resveratrol (3, 5, 4'-trihydroxystilbene) can exist in two isomeric forms, the c/'s and trans forms (see formula (I) and (II) respectively):
Advantageously, when component b) comprises resveratrol, it is in the form of trans- resveratrol (formula (II)).
In the context of the invention, resveratrol monomers are resveratrol derivatives, in particular trans- resveratrol derivatives, comprising one monomer unit, such as E-piceid, E-astringin, E-pterostilbene or E-piceatannol.
In the context of the invention, resveratrol oligomers are resveratrol derivatives comprising two or more resveratrol monomer units, in particular 2, 3 or 4 resveratrol monomer units, such as e-viniferin, d-viniferin, pallidol, a-viniferin, miyabenol C, E-vitisin B, or hopeaphenol.
In the context of the invention, resveratrol esters are monomers or oligomers of resveratrol, wherein the monomers comprises at least one ester group of formula (III), and the oligomers are formed of two or more monomer units, in particular 2, 3 or 4 monomer units, comprising at least one ester group of formula (III), the monomer units being joined by carbon-carbon bonds, or ether, and/or the oligomers are formed of monomers crosslinked by at least one group of formula (IV):
-0-C0-A (III) -O-CO-R-CO-O- (IV) wherein
A represents an alkyl group of at least two carbon atoms, linear or branched, saturated or unsaturated; an aryl group; arylalkyl group; or an alkylaryl group, and
R represents an alkylene group from 0 to 10 carbon atoms, saturated or unsaturated; an arylene group having 1 to 3 rings; a heterocyclic group, and the diastereoisomers of these units.
Advantageously, resveratrol esters according to the invention are as disclosed in the international application WO 99/03816, in particular from page 2 line 18, to page 5 line 2. The method of preparation of the resveratrol esters is also disclosed in WO 99/03816.
Advantageously, resveratrol esters are resveratrol esters of fatty acid. More advantageously, resveratrol esters are of one of the following fatty acids: butyric acid C4:0; valeric acid C5:0; hexanoic acid C6:0; sorbic acid C6:2(n-2); lauric acid C12:0; palmitic acid C16:0; stearic acid C18:0; oleic acid C18: 1 (n-9); linoleic acid C18:2(n-6); linolenic acid C18:3(n-6); a-linolenic acid C18:3(n-3); arachidonic acid C20:4(n-3), eicosapentaenoic acid C20:5(n-3); and docosahexanoic acid C22:6(n-3). Therefore, in formula (III), A is advantageously a (C4-C2s)-alkyl group, more advantageously a (C4-C22)- alkyl group, more advantageously a Ci6-alkyl group (i.e. C16-fatty acid).
In the context of the invention, resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters can be chemically synthesized or obtained from various plant sources selected from the following group: Vitaceae, Umbelliferae, Myrtaceae, Dipterocarpaceae, Cyperaceae, Gnetaceae, Legumes, Grasses, Seraceae, Haemodoraceae, Musaceae, Polygonaceae, Pinaceae, Cupressaceae, Cesalpiniaceae, Poaceae, and Solanaceae.
Advantageously, the resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters are obtained by extracting grape vines using water and/or an organic solvent, by techniques known to the one skilled in the art, such as techniques disclosed in WO 99/03816. The resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters can also be obtained by use of genetically modified microorganisms from animal tissue or by bioproduction from plants, in particular from suspensions of vine cells ( Study of the synthesis of resveratrol and its derivatives by
In an advantageous embodiment of the invention, the component b) is in the form of an extract rich in resveratrol from grape vines, in particular in the form of an extract rich in resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters.
Advantageously, the component b) is an extract of grape vines enriched in trans- resveratrol and/or resveratrol oligomers, preferably enriched in trans- resveratrol and resveratrol oligomers such as e- viniferin, d-viniferin, and a-viniferin. More advantageously, the component b) is an extract of grape vines comprising trans- resveratrol and e-viniferin. More advantageously, the component b) is an extract of grape vines comprising frans-resveratrol in a content of between 10 and 30 % by weight, and e-viniferin in a content of between 10 and 20 % by weight, in relation to the total weight of the extract.
In another advantageous embodiment, the component b) is a mixture of resveratrol, resveratrol monomers, resveratrol oligomers, and/or resveratrol esters.
Advantageously, the component b) is a mixture comprising at least resveratrol, in particular frans- resveratrol and/or resveratrol oligomers, in particular e-viniferin, d-viniferin, and a-viniferin.
Advantageously, the component b) is a mixture comprising mainly frans-resveratrol and/or e- viniferine. More advantageously, the component b) is a mixture comprising frans-resveratrol in a content of between 10 and 30 % by weight, and e-viniferin in a content of between 10 and 20 % by weight, in relation to the total weight of the extract.
The composition of the invention also comprises as component c) hyaluronic acid or a salt thereof, hyaluronic acid derivatives or a salt thereof, or mixtures thereof.
In accordance with the present invention, the term "hyaluronic acid" (or hyaluronan) refers to a linear polymer consisting of the repetition of the disaccharides of D-glucuronic acid and N-acetyl-D- glucosamine, linked together via alternating 6-1 ,4 and 6-1 ,3 glycosidic bonds ([-6(1 ,4)-GlcUA-6(1 ,3)- GlcNAc-]n). Hyaluronic acid is a naturally occurring, not sulphated glycosaminoglycan (GAG). Hyaluronic acid is widely available commercially or may be prepared or extracted by any technique known to those skilled in the art. This polymer may be natural or synthetic.
For the purposes of the present invention, the term “hyaluronic acid derivatives” means its counterparts, analogs, derivatives, complexes, esters, fragments and subunits. Hyaluronic acid exists naturally in the form of unsaturated disaccharides (Acta Vet Scand. 2015 Mar 4; 57(1 ): 12) and can also be chemically modified so as to improve its absorption characteristics, such as for example by modifications of the hydroxyl groups by an ether bond to obtain a cysteine conjugate-hyaluronic acid (Chem Commun (Camb). 2015 51 (47): 9662-5) or the formation of an ethyl ether of l-cysteine (C) via an amide bond (J Pharm Sci. 2015 Apr 21. doi: 10.1002/jps.24456).
For the purposes of the present invention, the term “hyaluronic acid salt” or ‘hyaluronic acid derivatives salt” is understood to mean the sodium, potassium, magnesium, aluminium, or ammonium salts, in particular sodium or potassium salts.
According to the invention, the average molecular weight of the hyaluronic acid or derivatives thereof used varies according to the administration mode. Thus, for topical administration, the average molecular weight of hyaluronic acid or derivatives thereof is advantageously at most 100 kDa, more advantageously between 0.5 kDa and 100 kDa, more advantageously between 0.5 kDa and 50 kDa, and even more advantageously between 5 kDa and 50 kDa. For oral or parenteral administration, high molecular weight hyaluronic acid or derivatives thereof is advantageously used, such as more than 1 Million Dalton, in particular between 1.2 and 2.1 Millions Da.
Advantageously, component c) is hyaluronic acid and/or hydrolysed hyaluronic acid of average molecular weight of at most 100 kDa, more advantageously between 0.5 kDa and 100 kDa, even more advantageously between 0.5 kDa and 50 kDa, and even more advantageously between 5 kDa and 50 kDa.
The amounts of components a), b) and c) in the composition will be determined by those skilled in the art in the light of their general knowledge. For oral administration, the composition is advantageously formulated so that component b) is administered at a dose of between 10 mg per day and 5 g per day. For topical administration, the cosmetic or dermatological composition is advantageously formulated so that component a) represents from 0.05 to 5% by weight of the composition, component b) represents from 0.01 to 1% by weight of the composition and component c) represents 0.01 to 0.4% by weight of the composition. For the parenteral route, the composition is advantageously formulated in the form of an aqueous solution comprising advantageously between 1 pg/ml and 100 mg/ml of component a), between 1 pg/ml and 100 mg/ml of component b) and between 1 pg/ml and 100 mg/ml of component c).
These doses can be administered once or several times a day.
Advantageously, the composition of the invention comprises between 0.02 % and 5 %, more advantageously between 0.5 and 2%, by weight of component a), in relation to the total weight of the composition.
Advantageously, the composition of the invention comprises between 0.01 % and 1 %, more advantageously between 0.3 and 1%, by weight of component b), in relation to the total weight of the composition.
Advantageously, the composition of the invention comprises between 0.01 % and 0.4 %, more advantageously between 0.01 and 0.2 %, by weight of component c), in relation to the total weight of the composition.
Advantageously, the composition of the invention comprises between 0.5 % and 2 % of component a), between 0.3 % and 1 % of component b), and between 0.01 % and 0.2 % of component c).
Advantageously, the composition of the invention comprises an extract of Khaya Senegalensis bark as component a), a mixture comprising at least trans- resveratrol or resveratrol oligomers as component b), and hyaluronic acid or hydrolysed hyaluronic acid of average molecular weight of at most 100 kDa as component c).
Advantageously, the composition of the invention comprises an aqueous extract of Khaya Senegalensis bark as component a), a mixture comprising mainly trans- resveratrol and e-viniferin, as component b), and hyaluronic acid or hydrolysed hyaluronic acid of average molecular weight of at most 100 kDa as component c).
Advantageously, the composition of the invention comprises an aqueous extract of Khaya Senegalensis bark as component a), a grape vine extract comprising mainly trans- resveratrol or resveratrol oligomers, in particular e-viniferin, as component b), and hyaluronic acid or hydrolysed hyaluronic acid of average molecular weight of between 5 and 100 kDa as component c). Advantageously, the composition of the invention further comprises other active principles, in particular active principles with anti-aging properties such as b-carotene, vitamin E or vitamin C, Oligo-ProanthoCyanidines (OPC), retinol, cis-retinoic acid, trans-retinoic acid, retinyl palmitate salicylic acid, niacinamide, nicotinic acid, phytic acid, N-acetyl L-cysteine, azelaic acid, lipoic acid, lactic acid, glycolic acid, panthenol, arbutin, deoxyarbutin, kojic acid, allantoin, cholesterol, C10- C30 cholesterol/lanosterol esters, tocopherol, tocopheryl acetate, and mixtures thereof.
The composition of the invention may be formulated in the form of various preparations for oral, parenteral or topical administration, preferably for topical administration.
Advantageously, the composition of the invention is a cosmetic composition, a food composition, a pharmaceutical composition, a dermatological composition or a veterinary composition.
The modes of administration, dosing schedules and optimal galenic forms of the components and composition of the invention may be determined according to the criteria generally taken into account in the establishment of a pharmaceutical, dermatological, cosmetic, food or veterinary treatment suitable for a patient or an animal, such as for example the age or the body weight of the patient or animal, the severity of the general condition of the patient or animal, tolerance to the treatment, noted side effects, skin type. Depending on the type of administration desired, the composition and/or components of the invention may further include at least one acceptable carrier, in particular a pharmaceutically acceptable, a dermatologically acceptable carrier, a cosmetically acceptable carrier, a food acceptable carrier, or a veterinary acceptable carrier. In particular, the composition according to the present invention may furthermore comprise at least one known excipient commonly used in those fields, chosen from oils, waxes, emollients, solvents, pigments, dyes, polymers, surfactants, rheological agents, perfumes, electrolytes, adjusters of pH, fillers, chemical or mineral filters, chelating agents, odor absorbers, thermal spring water, antioxidants, gelling agents, for example hydrophilic or lipophilic gelling agents, moisturizing agents, thickeners, and preservatives. The person skilled in the art knows how to adapt the formulation of the composition according to the invention using his general knowledge.
In a particular embodiment of the invention, the composition is a cosmetic composition for topical use comprising an effective amount of components a), b) and c), and further comprising at least one cosmetically acceptable excipient chosen from oils, waxes, emollients, solvents, pigments, dyes, polymers, surfactants, rheological agents, perfumes, electrolytes, adjusters of pH, fillers, chemical or mineral filters, chelating agents, odor absorbers, thermal spring water, antioxidants, gelling agents, for example hydrophilic or lipophilic gelling agents, moisturizing agents, thickeners, and preservatives. The amounts of these various excipients are those traditionally used in cosmetics. For example, the amount of each excipient may vary from 0.01 % to 20 % by weight, in relation to the total weight of the cosmetic composition. According to a particularly preferred embodiment, the cosmetic composition is a skin care or makeup product and is for example in the form of a gel, a cream, a pomade, a lotion, an emulsion, a milk, an oil, an ointment, a foam, a serum, a hydrogel, a mask, an aerosol, a stick, for example for a lipstick, an aqueous or water-alcoholic or glycolic solution, a powder, or a patch.
In a particular embodiment of the invention, the composition is a pharmaceutical, dermatological or veterinary composition, for topical, oral or parenteral administration. It can also be in the form of a food composition, in particular a food supplement. Such a composition comprises an effective amount of components a), b) and c), and further comprises a physiologically acceptable carrier. In particular, the pharmaceutical, dermatological, veterinary or food composition comprises an effective amount of components a), b) and c), and a suitable excipient chosen from oils, waxes, emollients, solvents, pigments, dyes, polymers, surfactants, rheological agents, perfumes, electrolytes, adjusters of pH, fillers, chemical or mineral filters, chelating agents, odor absorbers, thermal spring water, antioxidants, gelling agents, for example hydrophilic or lipophilic gelling agents, moisturizing agents, thickeners, and preservatives. The amounts of these various excipients are those traditionally used in pharmaceutical, dermatological, veterinary or food compositions. For example, the amount of each excipient may vary from 0.01 % to 20 % by weight, in relation to the total weight of the composition
According to the invention, the composition for oral administration is advantageously in the form of tablets, capsules, powders, granules, lyophilisates, solutes, suspensions, syrups, drinks, pastes, chewing gum or candy.
According to the invention, the composition for parenteral administration is advantageously in the form of an aqueous solution or of a lyophilized powder.
In a particular embodiment of the invention, the pharmaceutical, dermatological, cosmetic, veterinary or food compositions according to the invention are for use for treating and/or preventing disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes.
Advantageously, the cosmetic composition of the invention is for use for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing; advantageously for maintaining or restoring hydration of the skin and the biomechanical properties of the skin and/or to prevent or delay the appearance of signs of aging of the skin, in particular the appearance of wrinkles and the loss of firmness of the skin or to slow down the effects; in particular for preventing, slowing down or correcting skin aging, in particular for firming the skin, and/or promoting the attenuation or resorption of wrinkles.
Advantageously, the cosmetic composition of the invention is for use for increasing the expression of HAS2 genes or COL4A1 genes. The present invention also relates to a cosmetic care method for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing, comprising topically administering an effective amount of a composition according to the invention to a subject in need thereof.
Advantageously, the cosmetic care method is for maintaining or restoring hydration of the skin and the biomechanical properties of the skin and/or to prevent or delay the appearance of signs of aging of the skin, in particular the appearance of wrinkles and the loss of firmness of the skin or to slow down the effects.
Advantageously, the cosmetic care method is for preventing, slowing down or correcting skin aging, in particular for firming the skin, and/or promoting the attenuation or resorption of wrinkles.
The present invention also relates to the cosmetic use of the cosmetic composition of the invention for maintaining or restoring hydration of the skin and/or for preventing or delaying skin ageing, advantageously for maintaining or restoring hydration of the skin and the biomechanical properties of the skin and/or to prevent or delay the appearance of signs of aging of the skin, in particular the appearance of wrinkles and the loss of firmness of the skin or to slow down the effects, in particular for preventing, slowing down or correcting skin aging, more particularly for firming the skin, and/or promoting the attenuation or resorption of wrinkles.
The pharmaceutical, dermatological, veterinary or food compositions according to the invention are more particularly for use for treating and/or preventing osteoarthritis and skin aging.
In another aspect of the invention, the pharmaceutical, dermatological, veterinary or food compositions may also be for use for preventing and/or treating pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome, or digestive disorders, in particular gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa.
In another aspect of the invention, the pharmaceutical, dermatological, veterinary or food compositions according to the invention can be for use for treating ocular disorders, in particular dryness of corneal lesions and keratopathies.
The present invention thus also relates to the composition of the invention for use as a drug, in particular for preventing and/or treating osteoarthritis; skin aging; pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome; digestive disorders, such as gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa; or ocular disorders, such as dryness of corneal lesions and keratopathies. The present invention also relates to the composition of the invention for use for preventing and/or treating disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes.
The present invention thus also relates to a method for preventing and/or treating osteoarthritis; skin aging; pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome; digestive disorders, such as gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa; or ocular disorders, such as dryness of corneal lesions and keratopathies; comprising administering to a subject in need thereof, an effective amount of the composition of the invention.
The present invention thus also relates to a method for preventing and/or treating disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes, comprising administering to a subject in need thereof, an effective amount of the composition of the invention.
The present invention also relates to the use of the composition of the invention for the manufacture of a drug for preventing and/or treating osteoarthritis; skin aging; pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome; digestive disorders, such as gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa; or ocular disorders, such as dryness of corneal lesions and keratopathies.
The present invention also relates to the use of the composition of the invention for the manufacture of a drug for preventing and/or treating disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes.
The following examples aim to illustrate the present invention.
EXAMPLES
Example 1 : Effect of the composition of the invention on the expression of the has2 genes and COL4A1 genes in human skin fibroblasts - Comparison with each compound individually.
GOAL: To determine the activity of Oligo-Resveratrol (OR, R), Low Molecular Weight Hyaluronic Acid (50 kDa) (HHA, H), Very Low Molecular Weight-Hyaluronic Acid (0.5-10 kDa) (OHA, 0), Khaya Senegalensis extract (CL, C) and their combination on the expression of the has2 genes and COL4A1 genes in human skin fibroblasts. Materials
Human skin fibroblasts (Age 31 , from Coriell Institute for Medical Research)
EMEM (ATCC; Cat # 30-2003; Lot: 80410888)
15% FBS (Seradigm; Cat #: 1400-500)
1% Penicillin-Streptomycin Solution, 100X (Corning; Cat # 30-002-CI)
RNA extraction kit (Zymo Research; Cat #: ZR1057) iScript kit (Biorad; Cat #: 170-8891 )
PowerUp SYBR Green Master Mix (Thermo Fisher Scientific)
SYBR Green (Roche)
LightCylcer 480 (Roche)
QuantStudio 7 Pro (Thermo Fisher Scientific)
The vegan collagen booster (Khaya Senegalensis extract), a hydrophilic liquid (1 g; from Caudalie, stored at room temperature)
The two hyaluronic acids:
Very Low Molecular Weight HA (0.5-10 kDa), a hydrophilic powder. A stock solution at 1% (10 g/L) (500 mg; from Caudalie, stored at 4°C)
Low Molecular Weight Hyaluronic Acid (50 kDa), a hydrophilic powder. The solubility is 100 g/L (500 mg; from Caudalie, stored at 4°C)
Oligo-resveratrol (Batch BX1191834), a hydrophobic powder. A stock solution at 60 g/L in DMSO (300 mg; from Caudalie, stored at 4°C).
Method
HAS2 gene expression
Human skin fibroblasts cells were plated in 10 cm2 plate in such that they were 60% confluent (Passage 4). The old medium was removed and replaced with new medium (EMEM + 15% FBS + 1X Pen/Strep) containing the respective small molecules at the listed concentration. Cells were incubated at 37° C with 5% CO2 for 22 h. RNA was extracted using the RNA extraction kit (Zymo Research). One microgram of RNA was used to generate cDNA using the iScript kit (Biorad). The cDNA was diluted with water and 1 pL was used for each qPCR reaction on a 96 well LightCycler (Roche) with SYBR Green reagent from Roche.
COL4A1 gene expression
Human skin fibroblasts cells were plated in 10 cm2 plate in such that they were 60% confluent (Passage 4). The old medium was removed and replaced with new medium (EMEM + 15% FBS + 1X Pen/Strep) containing the respective small molecules at the listed concentration. Cells were incubated at 37° C with 5% CO2 for 22 h. RNA was extracted using the RNA extraction kit (Zymo Research). One microgram of RNA was used to generate cDNA using the iScript kit (Biorad). The cDNA was diluted with water and 8 pL was used for each qPCR reaction on a 384 well QuantStudio 7 Pro with PowerUP SYBR Green reagent from Thermo Fisher Scientific. Table 1 below indicates the different conditions tested and the concentrations used
TABLE 1 .
RNA extraction is carried out using the Omega RNA extraction kit. 1 mg of RNA is used and transcribed into complementary DNA using the Bio-Rad iScript™ cDNA synthesis kit followed by quantification by quantitative real-time PCR.
The PCR reactions were carried out using the FastStart™ DNA Master SYBR Green I real-time PCR kit (Roche Molecular Biochemicals). Each PCR was carried out in a final volume of 20 pi containing 10 mΐ of SYBR Green mix 2X (Fast start DNA master SYBR green + Taq DNA polymerase), 2 mΐ of the primer mixture and 8 mΐ of cDNA solution.
Results Expression Levels of HAS2 Genes
The results are given in Table 2 and Figure 1 .
Table 2. Quantitative results of Expression Levels of HAS2 Genes
These results show that the combination of all four components (HORC) activate has2 gene expression up to 2-fold. Expression Levels of COL4A1 genes The results are given in Table 3 and Figure 2.
Table 3. Quantitative results of Expression Levels of COL4A1 gene
These results show that combination of all four components (HORC) activate COL4A1 gene expression up to 5-fold.

Claims

1. A composition comprising as component a) a Khaya Senegalensis extract, as component b) resveratrol, resveratrol monomers, resveratrol oligomers, resveratrol esters, or mixtures thereof, and as component c) hyaluronic acid or one of its salts, hyaluronic acid derivatives or one of its salts, or mixtures thereof.
2. The composition of claim 1 , wherein the component a) is an extract of Khaya Senegalensis barks, advantageously an aqueous extract of Khaya Senegalensis barks.
3. The composition of claim 1 or 2, wherein resveratrol is c/'s- resveratrol or trans-resveratrol, advantageous ly trans- resve ratro l .
4. The composition of any one of claims 1 to 3, wherein resveratrol monomers are E-piceid, E- astringin, E-pterostilbene or E-piceatannol.
5. The composition of any one of claims 1 to 4, wherein resveratrol oligomers are e-viniferin, d- viniferin, pallidol, a-viniferin, miyabenol C, E-vitisin B, or hopeaphenol.
6. The composition of any one of claims 1 to 5, wherein resveratrol esters are monomers or oligomers of resveratrol, wherein the monomers comprise at least one ester group of formula (III), and the oligomers are formed of two or more monomer units, in particular 2, 3 or 4 monomer units, comprising at least one ester group of formula (III), the monomer units being joined by carbon-carbon bonds or ether and/or the oligomers are formed of monomers crosslinked by at least one group of formula (IV):
-O-CO-A (III) -O-CO-R-CO-O- (IV), wherein
A represents an alkyl group of at least two carbon atoms, linear or branched, saturated or unsaturated; an aryl group; arylalkyl group; or an alkylaryl group, and
R represents an alkylene group from 0 to 10 carbon atoms, saturated or unsaturated; an arylene group having 1 to 3 rings; an heterocyclic group, or the diastereoisomers of these units.
7. The composition of any one of claims 1 to 6, wherein the component b) is a mixture of resveratrol and resveratrol oligomers or a grape vine extract comprising resveratrol and resveratrol oligomers, advantageously trans- resveratrol and e-viniferin, d-viniferin, and/or a-viniferin, more advantageously trans-resveratrol and e-viniferin.
8. The composition of any one of claims 1 to 7, wherein the component c) is hyaluronic acid or hydrolysed hyaluronic acid, or a salt thereof.
9. The composition of any one of claims 1 to 8, wherein the component c) is hyaluronic acid or hydrolysed hyaluronic acid, or a salt thereof, having an average molecular weight of at most 100 kDa, more advantageously of between 0.5 kDa and 100 kDa.
10. The composition of any one of claims 1 to 9, wherein the composition is for oral, parenteral or topical administration, advantageously for topical administration.
11. The composition of any one of claims 1 to 10, wherein the composition is a cosmetic composition, a food composition, a pharmaceutical composition, a dermatological composition or a veterinary composition.
12. A cosmetic care method for maintaining or restoring hydration of the skin and/or the biomechanical properties of the skin, and/or for preventing or delaying skin ageing, comprising topically administering an effective amount of a composition according to any one of claims 1 to 11 to a subject in need thereof.
13. Non therapeutic use of a composition according to any one of claims 1 to 11 for increasing the expression of HAS2 genes or COL4A1 genes.
14. A composition as defined in any one of claims 1 to 11, for use as a drug, in particular for preventing and/or treating osteoarthritis; skin aging; pathologies affecting the mucous membranes of the respiratory tract, such as asthma, respiratory allergies, respiratory distress syndrome; digestive disorders, such as gastroenteritis, ischemic necrosis and ulcerations of the intestinal mucosa; or ocular disorders, such as dryness of corneal lesions and keratopathies.
15. A composition as defined in any one of claims 1 to 11 , for use as a drug for preventing and/or treating disorders associated to a reduction in hyaluronic acid, a decrease of the expression of HAS2 genes, and/or a decrease in the expression of COL4A1 genes.
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FR2758984B1 (en) 1997-02-03 1999-04-16 Serobiologiques Lab Sa ACTIVE SYNERGISTIC COMPLEX AND COSMETIC AND / OR PHARMACEUTICAL PRODUCT COMPRISING THIS COMPLEX
FR2766176B1 (en) 1997-07-15 1999-10-29 Caudalie COMPOSITIONS BASED ON RESVERATROL DERIVATIVES
US20090169585A1 (en) 2003-10-23 2009-07-02 Resveratrol Partners, Llc Resveratrol-Containing Compositions And Their Use In Modulating Gene Product Concentration Or Activity
FR2923717B1 (en) 2007-11-15 2015-01-16 Caudalie COMPOSITIONS OF STILBENIC POLYPHENOLIC DERIVATIVES AND THEIR APPLICATIONS FOR COMBATING PATHOLOGIES AND ENHANCING LIVING ORGANISMS
WO2012033634A2 (en) 2010-09-09 2012-03-15 Mary Kay Inc. Topical skin care formulations comprising plant extracts
US9931289B2 (en) 2011-02-09 2018-04-03 Forward Scout Enterprises Pty Ltd Cosmetic or pharmaceutical formulation
US20150005391A1 (en) 2013-06-26 2015-01-01 COLE Research & Design, Inc. Method of reducing scarring
US10470987B2 (en) * 2015-06-05 2019-11-12 Tomcat International Limited Process for stimulating hyaluronic acid synthesis
FR3036956B1 (en) 2015-06-05 2019-12-20 President And Fellows Of Harvard College METHOD OF STIMULATING THE SYNTHESIS OF HYALURONIC ACID
FR3049859B1 (en) 2016-04-12 2023-11-03 Basf Beauty Care Solutions France Sas COSMETIC USE OF KHAYA SENEGALENSIS EXTRACT

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