WO2012010624A2 - Topical use of steviol or derivatives in hair care - Google Patents

Topical use of steviol or derivatives in hair care Download PDF

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Publication number
WO2012010624A2
WO2012010624A2 PCT/EP2011/062425 EP2011062425W WO2012010624A2 WO 2012010624 A2 WO2012010624 A2 WO 2012010624A2 EP 2011062425 W EP2011062425 W EP 2011062425W WO 2012010624 A2 WO2012010624 A2 WO 2012010624A2
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WO
WIPO (PCT)
Prior art keywords
hair
group
formula
alkyl
saturated
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PCT/EP2011/062425
Other languages
French (fr)
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WO2012010624A3 (en
Inventor
Regina Goralczyk
Remo Graeub
Annis Olivia Mayne-Mechan
Jenny Piussi
Henry Rieger
Hasan Mohajeri
Original Assignee
Dsm Ip Assets B.V.
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Application filed by Dsm Ip Assets B.V. filed Critical Dsm Ip Assets B.V.
Priority to JP2013520137A priority Critical patent/JP5850266B2/en
Priority to BR112013000762-1A priority patent/BR112013000762B1/en
Priority to US13/809,265 priority patent/US20130115182A1/en
Priority to ES11735642.8T priority patent/ES2659407T3/en
Priority to KR1020137004345A priority patent/KR101842734B1/en
Priority to EP11735642.8A priority patent/EP2595598B1/en
Priority to CN201180034657.4A priority patent/CN103002866B/en
Publication of WO2012010624A2 publication Critical patent/WO2012010624A2/en
Publication of WO2012010624A3 publication Critical patent/WO2012010624A3/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365Hydroxycarboxylic acids; Ketocarboxylic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60Sugars; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/002Preparations for repairing the hair, e.g. hair cure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/10Preparations for permanently dyeing the hair
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00Preparations for affecting hair growth
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/006Antidandruff preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/06Preparations for styling the hair, e.g. by temporary shaping or colouring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/06Preparations for styling the hair, e.g. by temporary shaping or colouring
    • A61Q5/065Preparations for temporary colouring the hair, e.g. direct dyes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/12Preparations containing hair conditioners

Definitions

  • the present invention relates to the use of steviol and/or isosteviol, and/ or a salt, an ester, a diester, or an ether thereof for application to skin, skin having hair, scalp, hair of a human, or fur of an animal for the overall enhancement of the hair, particularly for restoring hair color and delaying the onset of greyness in hair, lessening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age-associated hair thinning, prevent- ing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning, maintaining of the natural hair color, increasing hair shininess, glossiness or volume.
  • This invention also relates to a method for stimulating hair growth, and/or preventing the graying of hair, or restoring or maintaining the natural hair color.
  • the hair is composed of a protein called keratin.
  • the hair itself is arranged in three layers, an outer cuticle, middle cortex and central medulla. If the hair is colored, it is due to the presence of pigments - either eumelanin (black or brown) or pheomelanin (red or yellow). If these pigments are lacking, the hair is white. Can- ites is the term given to grey hair, it is an illusion created by the mixture of white and colored hairs. Hair grows from a follicle. The walls of the follicle form the outer root sheath of the hair. The lower part of the follicle widens out to form the hair bulb that contains the germinal matrix, the source of hair growth.
  • Dermal tissue projects into the follicle base to form the dermal papilla, and this has a network of capillary blood vessels to supply oxygen, energy, and the amino-acids needed for growth. Correcting the effects of aging as far as possible is a preoccupation of ever- increasing importance.
  • Stevia extracts have been described in (JP 1 1 193219 A) as having hair growing and regeneration effect, however, steviol as well as phloretin, which are known inhibitors of cellular glucose transport have been claimed to also inhibit hair growth when applied topically (EP 0 71 1 541 A1 ).
  • one aspect of this invention is a method of enhancing an animal's, including a human's, hair comprising administering a topically applied composition comprising steviol and/or isosteviol, an ester, a diester, or an ether derivative for a time sufficient and in an amount effective to enhance the overall appearance, eg. thickness, volume, shini- ness and glossiness of hair in an animal including human, and observing or appreciating the result.
  • Another embodiment of this invention is the use of steviol and/or isosteviol, an ester, a diester, or an ether derivative thereof in the manufacture of topical or cos- metic composition which stimulates hair growth and enhances the overall appearance of hair of an animal including human, eg. thickness, volume, shininess and glossiness.
  • the compound of formula (I) below is combined with at least one additional active substance selected from the group consisting of: antioxidants, light screening agents, colorants, and biological actives.
  • the present invention provides the topical use of a compound of formula (I) or a salt thereof,
  • R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
  • R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i- Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C 8 alkyl) group, and
  • R3 is independently CH 2 , O, or CH-(Ci-C 7 alkyl),
  • the enhancement of the appearance of hair is selected from the group consisting of: restoring hair color and delaying the onset of greyness in hair, less- ening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age-associated hair thinning, preventing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning, maintaining of the natural hair color, increasing hair shininess, glossiness or volume.
  • formula (I) as depicted above encompasses all possible stereoisomers.
  • alkoxy refers to methoxy- and ethoxy- groups.
  • alkyl amino and dialkylamino refers to methylamino-, dimethylamino-, ethylamine- or diethylamino- groups.
  • preferred R1 groups are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec.
  • R2 groups are, methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, pentyl, neopentyl, hexyl, 2-ethyl-hexyl, heptyl, octyl, hydroxy, methyloxy, ethyloxy, propy- loxy, isopropyloxy, butyloxy, sec.
  • butyloxy isobutyloxy, pentyloxy, neopentyloxy, hexyloxy, 2-ethyl-hexyloxy, heptyloxy, octyloxy, -O-C(O) methyl, -O-C(O) ethyl, -0- C(O) propyl, -O-C(O) isopropyl, -O-C(O) butyl, -O-C(O) sec.
  • R3 groups are oxygen, CH 2 , CH-CH 3 , CH-C 2 H 5 , CH-C 3 H 7 , CH-C4H9. It is well understood that any lower alkyl group containing three or more carbon atoms can be either straight chain or branched chain.
  • R1 is selected from hydrogen and a saturated, straight C1-C5 alkyl group
  • preferred R2 groups are selected from hydroxy, methyl, ethyl, propyl, methyloxy, ethyloxy, propyloxy, -O-CO-CH3, -O-CO-C 2 H 5 , and -O-CO- C3H 7
  • preferred R3 groups are selected from CH 2 , CH-CH 3 , and O.
  • R1 is selected from hydrogen or a saturated, straight C1-C3 alkyl group
  • R2 is selected from hydroxy, methyl, methyloxy, ethyloxy, and propyloxy
  • preferred R3 groups are selected from CH 2 , CH-CH 3 , and O.
  • R1 is hydrogen or a saturated, straight or branched C1-C3 alkyl group
  • R2 is hydroxy or a methyl group
  • R3 is a CH 2 or O group.
  • R1 is hydrogen, R2 is hydroxy, and R3 is CH 2 , or R2 is methyl and R3 is 0 corresponding to the compound of formula (II) steviol (CAS number: 471 -80-7) and the compound of formula (III) Isosteviol (CAS number 27975-19-5).
  • the salts of steviol, steviol derivatives and/or isosteviol, and isosteviol derivatives may be formed by any cosmetically acceptable cation which means any metal cation as well as any organic cation that is not toxic to the skin and/or does not cause allergic reactions.
  • cosmetically acceptable cation means any metal cation as well as any organic cation that is not toxic to the skin and/or does not cause allergic reactions.
  • cations are ammonium salts and alkyl ammonium salts, alkali cations such as sodium and potassium ions and alkaline earth metal cations such as calcium and magnesium ions.
  • Steviol, isosteviol, salts and esters thereof are particularly preferred as they can then be easily transported to hair follicles.
  • the compounds used according to the present invention can either be sourced from chemical suppliers like e.g. Sigma or can be prepared by chemical synthesis according to known methods to a person skilled in the art such as e.g. : by degly- cosylation of the respective glucosides (e.g. : stevioside or rebaudiosides A and C) and, in case of the derivatives or salts, further derivatisation (esterification/ amida- tion, etherification/ salt formation).
  • Such methods are well known in the art and are e.g.
  • compositions according to the invention are especially attractive, since many people, including animal owners and handlers, have a special interest in cosmetic treatments considered as "natural" with mild effects and without major side effects.
  • the term "effective amount” means an amount necessary to obtain a desired physiological effect.
  • the term "Hair” as used according to the invention refers to both, hair of a human being as well as animal fur.
  • the term 'hair of an animal including human' relates to all parts of the body of an animal as well as of a human having hair such as the fur of animals as well as the eyelashes, the eyebrows, the beard or the scalp hair of a human.
  • Most preferably the term relates to the hair on the scalp of humans (male or female of any age).
  • skin having hair relates to all parts of the skin of a human having hair such as in particular the scalp and the face (eyelashes, the eyebrows, beard).
  • Most preferably the topical compositions are applied to the scalp of humans (male or female of any age).
  • Topical composition as used herein denotes any composition suitable for the topical application to mammalian keratinous tissue such as skin having hair, particularly to the human scalp or to animal skin having fur.
  • Preventing as used herein is not intended to mean that the event will never oc- cur, but means delaying the onset of the condition or event, and/or lessening the severity of the condition or event when it does occur.
  • “Chronic administration” is meant to convey that administration of the active ingredient regularly occurs over an extended period of time, for example once or twice per day for a time of at least about two weeks, preferably for at least one month, and more preferably at least two months.
  • the regular administration can be every two days, every three days, or once per week or twice per week.
  • Extended period of time means substantially daily for a period of time of at least about two weeks, preferably at least about a month, and even more preferably for at least about two months.
  • "Observing” or “appreciating” may be done by either the individual who administers or applies the active ingredient topically, or may be done by a third party.
  • the post-administration condition may be compared with the pre-administration condition and analyzed either using a standard test, or by subjective analysis.
  • “Enhanced Appearance” means that the hair has improved at least one of the following qualities:
  • Hair alopecia i.e. hair is retained, hair loss is stopped or slowed; or hair is re- growing
  • the invention provides the use of compounds of formula (I) according to the present invention for the enhancement of the appearance of hair, wherein the enhancement of the appearance of hair is selected from the group consisting of: lessening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age- associated hair thinning, preventing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning. More preferably, the enhancement of the appearance of hair is selected from the group consisting of: restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, and counteracting age-associated hair thinning.
  • Compounds of formula (I) according to the present invention may either be used in therapeutic or non-therapeutic topical applications. In a preferred embodiment, the use according to the present invention is non therapeutic.
  • the compound of formula (I) is combined with at least one additional active substance selected from the group consisting of antioxidants, light screening agents, colorants, and biological actives.
  • antioxidants used for formulated into hair care compositions.
  • antioxidants chosen from the group consisting of amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazole (e.g. urocanic acid) and derivatives, peptides such as D, L-carnosine, D-carnosine, L-carnosine and derivatives (e.g. anserine), carote- noids, carotenes (e.g. a-carotene, ⁇ -carotene, lycopene) and derivatives, chloro- genic acid and derivatives, lipoic acid and derivatives (e.g.
  • amino acids e.g. glycine, histidine, tyrosine, tryptophan
  • imidazole e.g. urocanic acid
  • peptides such as D, L-carnosine, D-carnosine, L-carnosine and derivatives (e.
  • thiols e.g. thioredoxine, glutathione, cystine, cystamine and its glycosyl-, N-acetyl-, methyl-, ethyl-, propyl-, amyl- butyl- and lauryl-, palmitoyl-; oleyl-, y-linoleyl-, cholesteryl- and glycerylester
  • salts thereof dilaurylthiodipropionate, distearylthiodipropionate, thiodipropi- onic acid and its derivatives (ester, ether, peptides, lipids, nucleotides, nucleosides and salts) as well as sulfoximine compounds (such as buthioninsulfoxi- mine, homocysteinesulfoximine, buthioninsulfone
  • ⁇ / kg pmol to ⁇ / kg
  • metal-chelators such as a-hydroxyfatty acids (citric acid, lactic acid, malic acid), palmic-, phytinic acid, , lactoferrin), ⁇ -hydroxyacids, huminic acid, gallic acid, gallic extracts, bilirubin, biliverdin, EDTA, EGTA and its derivatives, unsaturated fatty acids and their derivatives (such as ⁇ -linoleic acid, linolic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and their deriva- tives, tocopherol and derivates (such as vitamin-E-acetate), mixtures of nat.
  • metal-chelators such as a-hydroxyfatty acids (citric acid, lactic acid, malic acid), palmic-, phytinic acid, , lactoferrin), ⁇ -hydroxyacids, huminic
  • vitamin E vitamin E, vitamin A and derivatives (vitamin-A-palmitate and -acetate) as well as coniferylbenzoate, rutinic acid and derivatives, a-glycosylrutin, ferulic acid, fur- furylideneglucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, trihy- droxybutyrophenone, urea and its derivatives, mannose and derivatives, zinc and derivatives (e.g. ZnO, ZnSO 4 ), selen and derivatives (e.g.
  • One or more preservatives/ antioxidants may be present in an amount of at least 0.01 wt.-% of the total weight of the composition. Preferably about 0.01 to about 10 wt.-% of the total weight of the composition of the present invention is present. Most preferred, one or more preservatives/ antioxidants are present in an amount about 0.1 to about 1 wt. -%.
  • Light screening agents are advantageously selected from UV-A, UV-B and/or broadband filters.
  • UV-B or broad spectrum screening agents i.e. substances having absorption maximums between about 290 and 340 nm may be organic or inorganic compounds.
  • Organic UV-B or broadband screening agents are e.g.
  • acrylates such as 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340), ethyl 2-cyano-3,3-diphenylacrylate and the like; camphor deriva- tives such as 4-methyl benzylidene camphor (PARSOL® 5000), 3-benzylidene camphor, camphor benzalkonium methosulfate, polyacrylamidomethyl benzylidene camphor, sulfo benzylidene camphor, sulphomethyl benzylidene camphor, therephthalidene dicamphor sulfonic acid and the like; Cinnamate derivatives such as ethylhexyl methoxycinnamate (PARSOL® MCX), ethoxyethyl methoxycinna- mate, diethanolamine methoxycinnamate (PARSOL® Hydro), isoamyl methoxyc
  • 2-phenyl benzimidazole sulfonic acid and its salts PARSOL®HS.
  • Salts of 2-phenyl benzimidazole sulfonic acid are e.g. alkali salts such as sodium- or potassium salts, ammonium salts, morpholine salts, salts of prim. , sec. and tert.
  • salicylate derivatives such as isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, ethylhexyl salicylate (PARSOL® EHS, NEO Heliopan OS), isooctyl salicylate or homomenthyl salicylate (homosalate, PARSOL® HMS, NEO Heliopan OS) and the like; triazine derivatives such as ethylhexyl triazone (Uvinul T-150), diethylhexyl butamido triazone (Uvasorb HEB).
  • salicylate derivatives such as isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, ethylhexyl salicylate (PARSOL® EHS, NEO Heliopan OS), isooctyl salicylate or homomenthyl salicylate (homosalate, PARSOL® HMS, NEO Heli
  • Encapsulated UV-filters such as encapsulated ethylhexyl methoxycinnamate (Eusolex UV-pearls) or microcapsules loaded with UV-filters as e.g. disclosed in EP 1 471 995 and the like.
  • Inorganic compounds are pigments such as microparticulated ⁇ 2, ZnO and the like.
  • micropar- ticulated refers to a particle size from about 5 nm to about 200 nm, particularly from about 15 nm to about 100 nm.
  • the T1O2 particles may also be coated by metal oxides such as e.g. aluminum or zirconium oxides or by organic coatings such as e.g. polyols, methicone, aluminum stearate, alkyl silane. Such coatings are well known in the art.
  • Examples of broad spectrum or UV A screening agents i.e. substances having absorption maximums between about 320 and 400 nm may be organic or inorganic compounds e.g. dibenzoylmethane derivatives such as 4-tert. butyl-4'- methoxydibenzoyl-methane (PARSOL® 1789), dimethoxydibenzoylmethane, iso- propyldibenzoylmethane and the like; benzotriazole derivatives such as 2,2'- methylene-bis-(6-(2H-benzotriazole-2-yl)-4-(1 , 1 ,3,3,-tetramethylbutyl)-phenol (TINOSORB M) and the like; bis-ethylhexyloxyphenol methoxyphenyl triazine (Ti- nosorb S) and the like; phenylene-1 ,4-bis-benzimidazolsulfonic acids or salts such as 2,2-(1 ,4
  • microparticulated refers to a particle size from about 5 nm to about 200 nm, particularly from about 15 nm to about 100 nm.
  • the particles may also be coated by other metal oxides such as e.g. aluminum or zirconium oxides or by organic coatings such as e.g. polyols, me- thicone, aluminum stearate, alkyl silane. Such coatings are well known in the art.
  • dibenzoylmethane derivatives have limited photostability it may be desirable to photostabilize these UV-A screening agents.
  • the term "conventional UV-A screening agent” also refers to dibenzoylmethane derivatives such as e.g.
  • PARSOL® 1789 stabilized by, e.g. 3,3-Diphenylacrylate derivatives as described in EP 0 514 491 B1 and EP 0 780 1 19 A1 ; Benzylidene camphor derivatives as de- scribed in the US Patent No. 5,605,680; Organosiloxanes containing benzmalo- nate groups as described in the EP 0 358 584 B1 , EP 0 538 431 B1 and EP 0 709 080 A1 .
  • all colorants usually formulated into hair care compositions which have an absorption in the visible light of electromagnetic radiation (400 nm to 800 nm) can be used.
  • the absorption is often caused by the following chromophores: Azo- (mono-, di-, tris- or poly-)stilbene-, carotenoide-, diaryl- methane-, triarylmethane-, xanthene-, acridine-, quinoline-, methine- (also polyme- thine-) thiazol-, indamine-, indophenol-, azin-, oxazine-, thiazine-, anthraquinone-, indigo-, phthalocyanin and further synthetic, natural and/or inorganic chromophores.
  • FD & C and D & C which can be used in hair care compositions according to the invention are e.g. curcumin, riboflavin, lactoflavin, tartrazine, quinoline yellow, co- chenille, azorubin, amaranth, ponceau 4R, erythrosine, red 2G, indigotin, chlorophyll, chlorophyllin, caramel, carbo medicinalis, carotenoids, carotin, bixin, nor- bixin, annatto, orlean, capsanthin, capsorubin, lycopin, xanthophyll, flavoxanthin, lutein, kryptoaxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, bet- anin, anthocyans without being limited thereto.
  • curcumin e.g. curcumin, riboflavin, lactoflavin, tartrazine,
  • dyes are e.g. inorganic pigments such as iron oxide (iron oxide red, iron oxide yellow, iron oxide black etc.) ultramarines, chromium oxide green or carbon black.
  • inorganic pigments such as iron oxide (iron oxide red, iron oxide yellow, iron oxide black etc.) ultramarines, chromium oxide green or carbon black.
  • Other colorants and dyes which can be used in the compositions according to the invention com- prise natural or synthetic organic pigments, disperse dyes which may be solubi- lized in solvents like direct hair dyes of the HC type, for example HC red No. 3, HC Blue No.
  • Biological actives are advantageously selected from general activators of melano- genesis like tyrosinase activators, peptide hormones, cAMP-activators (caffeine) and neurotrophins.
  • Preferred tyrosinase activators are any substance which increases tyrosinase expression or enzyme activity, like e.g. glycyrrhizin from the root of licorice.
  • Peptide hormones belonging to the group of melanocortins are the preferred pep- tide hormones including ACTH, alpha-MSH, beta-MSH and gamma-MSH; these peptides are all cleavage products of a large precursor peptide called proopiomelanocortin (POMC).
  • POMC proopiomelanocortin
  • Alpha-MSH is the most important melanocortin for pigmentation.
  • the melanocyte-stimulating hormones (collectively referred to as MSH or intermedins) are a class of peptide hormones that in nature are produced by cells in the intermediate lobe of the pituitary gland. They stimulate the production and release of melanin (melanogenesis) by melanocytes in skin and hair. Therefore, they will be advantageously combined with the compounds of the present invention.
  • the compounds of the present invention are used topically on hair, wherein hair is a mammal's fur. Preferred mammals are horses, dogs and cats.
  • the compound of formula (I) is used in an effective amount selected in the range of 0.00001 to 20 wt.-%, preferably, 0.0001 to 5 wt.-%, more preferably, 0.001 to 0.5 wt.-% based on the total weight of the topical composition.
  • the compound of formula (I) is used in a topical composition in an amount in the range of 0.00001 to 20 wt.-%, preferably, 0.0001 to 5 wt.-%, more preferably, 0.001 to 0.5 wt.-% based on the total weight of the topical composition.
  • the present invention also relates to the use of compounds of formula (I) for increasing the total number of melanocytes in hair follicles and/or for increasing the differentiation and migration of melanocytes from the hair sheath to the hair matrix and/or increasing proliferation of hair cells, and/or increasing the production of melanin, and/or for lengthening hair growth phase (anagen) and/or shortening hair resting phase (telogen).
  • Number of melanocytes in the hair follicle can be evaluated by standard methods e.g. immunohistochemical staining of the melanocytes with the pan-melanocyte marker NKI-beteb following by counting the NKI-beteb+ cells. Differentiation and migration of melanocytes from the hair sheath to the hair matrix can be measured by immunohistochemical staining of c-kit+ melanocytes in the hair follicle, and by assessing their distribution within the hair follicle.
  • the invention further provides the use of a compound of formula (I) according to the present invention, in combination with the use of other ingredients which are conventionally used in topical compositions, such as in particular hair care compositions, generally enhance the appearance of hair, eg. thickness, volume, shininess and glossiness, to prevent the graying of hair and/or restore or maintain the natural hair color, such as 5,6-dihydroxyindoline HBr, 5,6- dihydroxyindoline HBr in combination with 2-methylresorcinol and/or arginine.
  • a compound of formula (I) according to the present invention in combination with the use of other ingredients which are conventionally used in topical compositions, such as in particular hair care compositions, generally enhance the appearance of hair, eg. thickness, volume, shininess and glossiness, to prevent the graying of hair and/or restore or maintain the natural hair color, such as 5,6-dihydroxyindoline HBr, 5,6- dihydroxyindoline HBr in combination with 2-methylre
  • the present invention further provides the use of compounds of formula (I) as described in this invention for elongation of hair follicles, increasing the proliferation of hair follicle cells (outer/inner root sheet, dermal papilla fibroblasts).
  • the present invention provides the use of compound of formula (I) for restoring hair color and delaying the onset of greyness in hair, and/or maintaining of the natural hair color.
  • this invention relates to a method for stimulating hair growth, and/or preventing the greying of hair or restoring or maintaining the natural hair color comprising the steps of applying to skin having hair, for a sufficient time, a to ical composition comprising an effective amount a compound of formula (I),
  • R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
  • R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i- Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C 8 alkyl) group,
  • R3 is independently CH 2 , O, or CH-(Ci-C 7 alkyl),
  • the topical composition for the method according to the present invention is a hair care composition, and more preferably, it is a hair tonic, a conditioner, a shampoo, or a styling gel.
  • the topical composition may further comprise at least one additional active substance selected from the group consisting of antioxidants, light screening agents, colorants, and biological actives.
  • One embodiment of this invention is the prevention of the graying of hair for resto- ration and/or maintenance of the natural hair color, as shown by the ability of said compounds and derivatives to increase total number of melanocytes in hair follicles, as well as, to increase the differentiation and migration of melanocytes from the hair sheath to the hair matrix.
  • This invention relates to a method for preventing the graying of hair, delaying the onset of graying, and/or restoring and/or maintaining the natural hair color which comprises the step of applying a topical composition comprising an effective amount of steviol and/or isosteviol, or a salt, an ester, a diester, or an ether thereof as depicted in formula (I) to human or animal skin having hair, and observing the prevention, restoration, or maintenance of natural hair color.
  • the present invention also encompasses a method of topically administering an amount of steviol and/or isosteviol or a salt, an ester, a diester, or an ether thereof and observing or appreciating an increase in the number of melanocytes in hair follicles, and/or increasing the differentiation or migration of melanocytes from the hair sheath to the hair matrix.
  • the observation or appreciation can be done by noticing a decrease in grayness, maintenance of original hair color, or by observing a restoration of original hair color.
  • a sample of a topical composition (2 to 10 ml_ or mg/ cm 2 , depending on the type of formulation; preferably a leave-on product such as hair tonic, lotion or cream) containing a preferred amount of a compound of formula (I) is then applied at least once a day on the scalp, typically from 1 to 4 times daily for at least three months, especially six months (because normal hair growth rate is about 1 cm/ month) and distributed equally with a massage on the scalp.
  • the product is not washed out after application.
  • a second hair sample is taken from the same place on the scalp and analyzed as described above.
  • a comparison of the melanin content, hair color or degree of graying is made intra- individually before and after the treatment period.
  • topical applications of steviol and/or isosteviol can:
  • o preventing or counteracting premature hair loss o delaying the onset or seventy of age-associated hair loss, and/or o delaying the onset or seventy of hair thinning.
  • Another aspect of this invention is a method of enhancing hair appearance selected from the group consisting of:
  • the present invention also relates to the use of steviol and/or isosteviol or a salt, an ester, a diester, or an ether thereof as depicted in formula (I) for stimulating dermal papilla region and keratinocytes within the hair follicle in order to increase the total number of keratinocytes responsible for hair growth and/or releasing growth stimulating molecular signals from surrounding cells of the hair follicle and/or migration of progenitor keratinocytes to rebuild hair follicles.
  • the topical formulation of a compound of formula (I) is administered to a non-human animal, which is preferably a mammal.
  • the non-human animal is a mammal, such as a companion animal (dog, cat, ferret) or an animal which is used in the fur industry (minks, chinchillas or the like), or an animal which is shown in competition (such as dogs, horses, cats, rabbits and other farm animals).
  • Supplementing the animal's normal bathing or grooming regime with steviol and or isosteviol, a salt, an ester, a diester, or an ether -containing compositions of this invention will enhance the appearance of the animals' fur.
  • a veterinary topical composition containing a fur-enhancing amount of steviol and/or isosteviol or a salt, an ester, a diester, or an ether derivative thereof.
  • Another aspect of this invention is a shampoo or other topical formulation espe- cially designed for a show animal which comprises steviol and/or isosteviol or a salt, an ester, a diester, or an ether derivative thereof.
  • This should be applied to the animal daily for at least one month, and preferably for at least two months prior to the competition in order for its fur to be at its optimal condition.
  • the invention relates to the use of a compound of formula (I) such as particularly steviol and/or isosteviol or a salt thereof for fur grooming (so the fur no longer appears neglected, and looks better groomed).
  • the physiological effect may be achieved by one single dose or by repeated doses.
  • the dosage administered may, of course, vary depending upon known factors, such as the physiological characteristics of the particular composition; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and/or the effect desired and can be adjusted by a person skilled in the art.
  • an effective amount will typically be at least 0.00001 wt.-% based on the total weight of the topical composition.
  • the topical compositions contain the compound of formula (I) according to the present invention in an amount of 0.00001 to 20 wt.-%, more preferably in an amount from 0.0001 to 5 wt.-%, even more preferably in an amount from 0.001 to 0.5 wt.-%, based on the total weight of the composition.
  • the topical compositions are applied at least several times per week, preferably at least once per day, and more preferably applied at least twice a day such as e.g. once in the morning and once in the evening. Applications should be for a chronic period of time, i.e. at least one week, preferably for at least two weeks, and more preferably for at least 4 weeks in order to observe results.
  • the present invention is also providing a hair care composition comprising pound of formula (I),
  • R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
  • R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i- Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C 8 alkyl) group,
  • R3 is independently CH 2 , O, or CH-(Ci-C 7 alkyl),
  • the present invention is also providing a hair care composition
  • a hair care composition comprising a compound of formula (I) as described above, and at least one conventional hair care carrier, wherein the pH of the composition is below 7, preferably below 6, more preferably below 5, even more preferably below 4.
  • the hair care composition according to the present inven- tion further comprises an antioxidant selected from the group of antioxidants usually formulated in hair care, and as described above, and/or, a light screening agent selected from UV-A, UV-B, and/or broad band UV filters as described in the present application.
  • an antioxidant selected from the group of antioxidants usually formulated in hair care, and as described above, and/or, a light screening agent selected from UV-A, UV-B, and/or broad band UV filters as described in the present application.
  • the present invention is also providing a hair care composition comprising pound of formula (I),
  • R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
  • R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i- Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C 8 alkyl) group,
  • R3 is independently CH 2 , O, or CH-(Ci-C 7 alkyl),
  • an antioxidant selected from the group of antioxidants usually formulated into hair care and/or a light screening agent selected from UV-A, UV-B and/or broadband filters as described in the present application.
  • the present invention further provides a composition as described above which is a gel, a lotion, a tincture, a spray, a mousse, a cleansing composition, a shampoo, or a foam.
  • topical compositions are hair care compositions such as conditioners, treatments, tonics, styling gels, mousses, shampoos, hair sprays, pomades, setting lotions, coloring and permanent waving compositions.
  • hair care compositions such as conditioners, treatments, tonics, styling gels, mousses, shampoos, hair sprays, pomades, setting lotions, coloring and permanent waving compositions.
  • tonics, conditioners, treatments, and styling gels which may be in the form of a gel, a lotion, a tincture, a spray, a mousse, a cleansing composition or a foam and which may be applied according to individual needs, e.g., once daily as a lotion, tincture, mousse or spray; or once or twice weekly as a conditioner or treatment.
  • the typical composition used in the method for preventing the graying of hair as well as for restoring and/or maintaining the natural hair color according to the present invention may further comprise other ingredients which are conventionally used in topical compositions such as 5,6-dihydroxyindoline HBr, 5,6- dihydroxyindoline HBr in combination with 2-methylresorcinol and/or arginine.
  • a compound of formula (I) with the definitions and preferences as given above is useful in topical compositions such as in particular hair care compositions which further contain carriers and/or excipients or diluents conventionally used in topical, respectively, hair care compositions.
  • the compound of formula (I) may be combined with suitable auxiliary agents which are conventionally used in hair care compositions such as disclosed in general terms in Ullmann's Encyclopedia of Industrial Chemistry (1989), Vol. A 12, Hair Preparations, and more specifically, e.g., in International Patent Application No. WO 00/06094, WO 00/07550 and WO 01/06994.
  • a compound of formula (I) according to the present invention may be combined with the use of further ingredients to protect the hair against detri- mental environmental impact and to improve the health of the hair.
  • the compounds of formula (I) according to the present invention may be incorporated into conventional hair care compositions as described below:
  • the hair care compositions may comprise additional cosmetic or dermatological adjuvants and/or additives (cosmetic carrier) which are preferably selected from
  • the hair care compositions can contain further adjuvants and additives such as preservatives, antioxidants, silicones, thickeners, softeners, anionic, cationic, non- ionic or amphoteric emulsifiers, light screening agents, antifoaming agents, moisturizers, fragrances, surfactants, fillers, sequestering agents, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or ba- sifying agents, dyes, colorants, pigments or nanopigments, light stabilizers, insect repellents, antibacterial agents, or any other ingredients usually formulated into hair care compositions.
  • the necessary amounts of the adjuvants and additives can, based on the desired product, easily be chosen by a skilled artisan in this field and will be illustrated in the examples, without being limited hereto.
  • the hair care compositions are in the form of cosmetic hair-treatment preparations, e.g. hair tonics, conditioners, hair-care preparations, e.g. pre- treatment preparations, styling creams, styling gels, pomades, hair rinses, treatment packs, intensive hair treatments e.g. leave-on and rinse-off deep condition- ers, hair-structuring preparations, e.g. hair-waving preparations for permanent waves (hot wave, mild wave, cold wave), hair-straightening preparations, liquid hair-setting preparations, hair foams, hairsprays, bleaching preparations, e.g.
  • cosmetic hair-treatment preparations e.g. hair tonics, conditioners, hair-care preparations, e.g. pre- treatment preparations, styling creams, styling gels, pomades, hair rinses, treatment packs, intensive hair treatments e.g. leave-on and rinse-off deep condition- ers, hair-structuring preparations, e.g. hair-waving preparations for permanent
  • Preferred hair care compositions are leave-on compositions selected from hair tonics, conditioners, treatments, and styling gels.
  • the hair care preparations may be in the form of a (aerosol) spray, (aerosol) foam, gel, gel spray, cream, lotion, liquid or a wax.
  • Hair sprays comprise as well aerosol sprays as pump sprays without propellant.
  • Hair foams comprise as well aerosol foams as pump foams without propellant.
  • Hair sprays and hair foams comprise mainly or exclusively water soluble or water dis- persible components. If the components used in hair sprays or hair foams according to the invention are water dispersible, then they may be in the form of micro dispersions with particle sizes of usually 1 -350 nm, preferably 1 -250 nm. The solid content of such preparations is typically in the range of 0.5 to 20 wt.-% of the total weight of the preparation. Such micro dispersions normally do not need further emulsifiers or tensides for their stabilization.
  • An exemplary hair gel with the compound of the present invention may comprise:
  • An exemplary conditioner preparation according to the present invention may comprise:
  • An exemplary styling composition with the compound of the present invention may comprise:
  • An exemplary styling gel with the compound of the present invention may comprise:
  • An exemplary hair care composition (spray) with the compound of the present in- vention may comprise:
  • Another hair care composition with the compound of the present invention may comprise:
  • An exemplary composition for aerosol foams with the compound of the present invention may comprise:
  • An exemplary shampoo preparation with the compound of the present invention may comprise:
  • the hair care composition according to the invention can comprise at least a water-soluble or water-dispersible hair polymer.
  • Typical hair polymers for use in the present invention are commercially available polymers for hair care such as hair styling or conditioning polymers such as e.g. copolymers of vinyl acetate and cro- tonic acid, copolymers of methyl vinyl ether and maleic anhydride, copolymers of acrylic acid or methacrylic acid with other monomers, polyurethanes, N- vinylpyrrolidone and silicone polymers.
  • the content of the hair polymer is generally from about 0.1 to 10 % by weight, based on the total weight of the composition.
  • water- soluble or water-dispersible polyurethanes which, if desired, additionally comprise siloxane groups in copolymerized form.
  • composition according to the invention can further comprise, at least one water-insoluble silicone, in particular a polydimethylsiloxane, e.g. the Abil ® grades from Goldschmidt.
  • the content of the silicone is then generally from about 0.0001 to about 2 % by weight, preferably from about 0.001 to about 1 % by weight, based on the total weight of the composition.
  • Preferred waxes according to the present invention are fatty acid amides, such as, for example, erucamide.
  • the hair care compositions according to the present invention can, where appropriate, additionally comprise an antifoaming agent, e.g. based on silicone.
  • the amount of antifoaming agent is generally up to 0.001 % by weight, based on the total amount of the composition.
  • the compositions according to the invention have the advantage that, on the one hand, they impart the desired hold to the hair and, on the other hand, the polymers are easy to wash out (redispersible). Generally, a natural appearance and shine is imparted to the hair, even when the hair is by its very nature especially thick and/or dark.
  • alcohol refers to all alcohols usually used in cosmetic compositions such as ethanol, n-propanol, isopropanol.
  • Other ingredients are cosmetic adjuvants and additives such as propellants, antifoaming agents, surface active ingredients e.g. tensides, emulsifiers, foam former and solubilisators.
  • the used surface active ingredients may be anionic, cationic, amphoteric or neutral.
  • Further ingredients may be preservatives, antioxidants, perfume oils, lipidic refatters, active and/or caring ingredients such as panthenol, col- lagen, vitamins, protein hydrolysates, alpha- and beta hydroxyl carbonic acids, stabilisators, pH regulators, opacifiers, colorants, dyes, gel formers, salts, moisturizers, complex formers, viscosity regulators or light screening agents without being limited thereto.
  • the hair care compositions may additionally comprise conditioning compounds based on silicone such as polyalkylsiloxane, polyarylsiloxane, polyarylalkylsiloxane, silicone resins, polyethersiloxane or di- methicone copolyole (CTFA) and amino functionalized silicone compounds such as amodimethicone (CTFA), GP 4 Silicone fluid® and GP 7100® (Genesee), Q2 8220® (Dow Corning), AFL 40® (Union Carbide) or polymers as disclosed in EP 0 852 488.
  • CTFA amodimethicone
  • GP 4 Silicone fluid® and GP 7100® Genesee
  • Q2 8220® Denst Control
  • AFL 40® Union Carbide
  • Other suitable ingredients comprise silicone propfpolymers having a polymeric silicone backbone and non-silicone containing side chains or a non silicone containing polymeric backbone and silicone side chains such as Luviflex® Silk or polymers disclosed in
  • Typical propellants for hair sprays or aerosol foams may be used. Preferred are mixtures of propane/ butane, pentane, dimethylether, 1 , 1 -difluoroethane (HFC- 152a), carbon dioxide, nitrogen or compressed air.
  • HFC- 152a 1 , 1 -difluoroethane
  • All emulsifiers for aerosol foams or surfactants for shampoo preparations may be conventionally used non-ionic, cationic, anionic or amphoteric emulsifi- ers/surfactants.
  • non-ionic emulsifiers are (INCI-nomenclature) Laureths, e.g. Laureth-4; Ceteths, e.g. Ceteth-1 , polyethyleneglycolcetylether; ceteareths, e.g. ceteareth-25, polyglycol fatty acid glycerides, hydroxylated lecithins, lactyl esters of fatty acids, alkylpolyglycosides.
  • non-ionic surfactants are e.g. reaction products of aliphatic alcohols or alkylphenols with 6 to 20 C-Atoms of a linear or branched alkyl chain with ethyleneoxide and/or propyleneoxide.
  • the amount of alkyleneoxide is about 6 to 60 mol to one mol alcohol.
  • alkylaminox- ide, mono- or dialkylalkanolamide, fatty esters of polyethylene glycols, alkylpolyglycosides or sorbitan ester are suitable for the incorporation of hair care compositions according to the invention.
  • cationic emulsifiers/surfactants are quaternised ammonium compounds e.g. cetyltrimethylammoniumchloride or bromide (INCI: cetrimoniumchlo- ride or bromide), stearyl benzyl dimethyl ammonium chloride, distearyldimethyl- ammonium chloride, stearamidopropyldimethylamine, hydroxyethylcetyldimonium phosphate (INCI: Quaternium-44), Luviquat ® Mono LS (INCI: Cocotrimoniumme- thosulfate), poly(oxy-1 ,2-ethandiyl), (octadecylnitrilio) tri-2, 1 -Ethandiyl) tris- (hydroxy)-phosphate (INCI Quaternium-52).
  • cationic guar derivatives such as guarhydroxypropyltrimoniumchloride (INCI) may be used in conditioner/s
  • Anionic emulsifiers/surfactants can be selected from alkylsulfate, alkylethersulfate, alkylsulfonate, alkylarylsulfonate, alkylsuccinate, alkylsulfosuccinate, N- alkylsarkosinate, acyltaurate, acylisethionate, alkylphosphate, alkyletherphos- phate, alkylethercarboxylate, alpha-olefinsulfonate, especially the alkali-und earth alkali salts, e.g. sodium, potassium, magnesium, calcium, as well as ammonium- and triethanol amine-salts.
  • the alkylethersulfate, alkyletherphosphate and alkylethercarboxylate may comprise between 1 to 10 ethyleneoxide or propyleneox- ide units, preferably 1 to 3 ethyleneoxide-units per molecule.
  • Suitable anionic surfactants are e.g. sodium laurysulfate, ammonium laury sulfate, sodium laurylethersulfate, ammonium laurylethersulfate, sodium lauroylsarkon- isate, sodiumoleylsuccinate, ammonium laurylsulfosuccinate, sodium dodecylben- zolsulfonate, triethanolamidodecylbenzolsulfonate.
  • Suitable amphoteric surfactants are e.g. alkylbetaine, alkylamidopropylbetaine, al- kylsulfobetaine, alkylglycinate, alkylcarboxyglycinate, alkylamphoacetate or propionate, alkylamphodiacetate or dipropionate such as cocodimethylsulfopropylbe- taine, laurylbetaine, cocamidopropylbetaine or sodium cocamphopropionate.
  • gel formers all typical cosmetic gel formers can be used such as slightly cross linked polyacrylic acid e.g. Carbomer (INCI), cellulose derivatives, polysaccarides e.g. xanthan gum, caprylic/ capric triglyceride (INCI), sodiumacrylate-copolymers, polyquaternium-32 (and) paraffinum liquidum (INCI), sodiumacrylate-copolymers (and) paraffinum liquidum (INCI) (and) PPG-1 trideceth-6, polyquaternium-37 (and) propyleneglycoldicapratdicarylate (and) PPG-1 trideceth-6, polyquaternium- 7, polyquaternium-44.
  • slightly cross linked polyacrylic acid e.g. Carbomer (INCI), cellulose derivatives, polysaccarides e.g. xanthan gum, caprylic/ capric triglyceride (INCI), sodiumacrylate-copolymers, polyquaternium-32 (and) par
  • the hair care composition may additionally comprise opacifiers and/or pearly gloss-imparting substances, such as soaps or salts of carboxylic acids, cationics including cationic polymers, dimethicone (INCI) or amodimethicone (INCI).
  • opacifiers and/or pearly gloss-imparting substances such as soaps or salts of carboxylic acids, cationics including cationic polymers, dimethicone (INCI) or amodimethicone (INCI).
  • customary additives are for example long chain fatty alcohols such as cetyl alcohol, stearyl alcohol, cetylstearyl alcohol, dimethylstearamine.
  • the hair care composition may contain lipids such as dimethicone, amodimethicone, mineral oil, or silicon derivatives such as Dimethicone Copolyol.
  • the present invention also relates to a dual-vial packaging system as described in WO2008049443 containing the compound of formula (I) as a dried powder in a compartment, and a cosmetically acceptable carrier in the other compartment.
  • Human hair follicles were obtained from human skin fragments (obtained by plastic surgery) and grown in supplemented William's E medium supplemented with penicillin/streptomycin, L-glutamine (2 mM), insulin (10 pg/ml and hydrocortisone (8 nM). Hair follicle growth was assessed via length measurements (day 0, 4, 7). Triiodothyronine (T3, 30 ⁇ ) was used as positive control. The effect of steviol (at 0.625 to 5 pg/ml) was tested in parallel. At day 7, RNA was extracted from hair follicles that had been subjected to different treatments (control, T3, steviol).
  • Fibroblast growth factor 7 Keratino- 2.91 0.0006 cyte growth factor
  • TIMP metallopeptidase inhibitor 3 2.32 0.0001
  • Chemokine (C-X-C motif) ligand 12 2.22 0.0005
  • the genes regulated by steviol were further mapped to biological pathways using statistical tools provided with the Genedata software package.
  • Steviol modulated gene expression of the pathways of the epidermal development, ectoderm development and keratinocyte differentiation with a high statistical significance (indicated by p- value in Table 2); other pathways were not significantly affected.
  • This data is in line with the observed effect of steviol on hair follicle elongation (see Table 1 ) and corroborate that steviol modulates molecular pathways that lead to changes in hair growth.
  • Integrin alpha-6 Steviol (0.625 pg/mL) 1 .62 ⁇ 0.06
  • the present invention such as in particular steviol 0.5
  • Dissolve PVP in the rest of the water. Premix the perfume with PEG-40 hydrogenated castor oil. Mix all parts, and finally add preservative and tocopheryl acetate.
  • Example 13 Permanent hair tinting formulation
  • Dissolve compound of formula (I) according to the present invention in particular steviol
  • water add Methylcellulose and stir until dissolved; mix Ethylparaben with Sodium Laureth Sulfate.
  • Example 15 Induction of melanin synthesis by Steviol: Quantification of melanin synthesis in cell culture: Normal human melanocytes NHM (HEMn-MP, Clonetics) were seeded in 96 well cell culture plates and grown to sub-confluence for two days in a mixture of M2- Medium (Clonetics) and Medium (Promocell). Culture medium was exchanged with Culture Medium containing Steviol and melanogenesis progressed for another three days at 37 °C with another medium exchange on day two. Including cell layer and culture supernatant the total melanin was extracted using 1 .7M KOH with vigorous shaking at RT. We measured melanin content at 405 nm in an ab- sorbance plate reader. The data is normalized to 100 % for the un-treated control sample, and expressed as percentage of the control.
  • Glycyrrhizin is used as a positive control since it is a known inducer of melano- genesis. Steviol shows a clear dose dependent positive effect on the production of melanin in human melanocytes.
  • A/B Heat part A and part B separately to 70°C.
  • Viscosity 3500-5000 mPas (Brookfield, #4 / 10 rpm)
  • Example 19 2-Phase leave-on Conditioner:
  • part C Add all ingredients of part C successively and mix with moderate propeller agitation.
  • Viscosity spray able 2-phases
  • Example 20 Solid product which needs to be dissolved prior to the application:
  • the solid part contains Steviol, and the liquid part contains 0 to 100 % water or/and ethanol (0 to 100 %), and/or other compounds required to dissolve the solid part in a comfortable/convenient time (1 -8 min), e.g. emulsifiers, glycerine, propylene glycol, butylene glycol, rheological modifier, e.g. Carbomers, Hydroxyethyl cellulose, pH-regulators.
  • emulsifiers e.g. emulsifiers, glycerine, propylene glycol, butylene glycol, rheological modifier, e.g. Carbomers, Hydroxyethyl cellulose, pH-regulators.
  • Solid part (0.01 to 10g) are mixed with the liquid part (5 mL-30ml_) prior to application in an appropriated system by shaking.
  • Example 21 Stabilization of steviol in acidic aqueous solution: Steviol was dissolved at 1 wt.-% in water and the pH adjusted at different values as shown below. At pH 9, the solution turns brown within 1 day demonstrating instability of Steviol. However, the more acidic the pH, the less discoloration was observed as reported by the patone color index. Color index of 1 % Steviol solution in water at different pH:
  • the proximal two thirds of anagen hair follicles located in the subcutaneous fat were isolated using watchmakers forceps and subsequently collected in Petri dishes containing complete hair follicle culture medium (Williams E, Biochrom KG seromed, Berlin, Germany); 1 % Penicillin-Streptomycin; 1 % L-Glutamine 200mM; 0.02 % hydrocortisone; 0.1 % Insulin.
  • Three hair follicles per well were then randomly distributed and cultured in 24 well plates (Costar, NY, USA) containing 500 ml of complete hair follicle culture medium per well.
  • Steviol was tested at two different concentrations (0.625 and 1 .25 ⁇ ). Macro- scopic analysis of hair follicle pigmentation showed a slow loss of active pigmentation in the control group over the seven day culture period (in vitro graying) remaining pigmentation is scored minimal (+) in the table below. Sphingosyl phos- phorylcholine at 1 ⁇ was used as a positive control as it is known from previous work to reduce the speed of in vitro hair graying. Remaining pigmentation is scored (+++). As shown in the table below, a clear and significant improvement of hair follicle pigmentation was observed when steviol was used. This remaining pigmentation was superior when steviol was used at 0.625 ⁇ (+++) when compared to steviol 1 .25 ⁇ (++). c

Abstract

The present invention relates to the use of steviol and/or isosteviol, or a salt, ester, a diester, or an ether thereof as depicted in formula (I), wherein R1 is hydrogen (H) or a saturated, straight or branched C1-C8 alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups, R2 is independently a saturated, straight or branched C1-C8 alkyl group, -O-C1-C8 alkyl group, -OH group, a -O-C(O)-C1-C8 alkyl, or, -COO(C1-C8 alkyl) group, R3 is independently CH2, O, or CH-(C1-C7 alkyl), wherein the enhancement of the appearance of hair is selected from the group consisting of: restoring hair color and delaying the onset of greyness in hair, lessening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age-associated hair thinning, preventing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning, maintaining of the natural hair color, increasing hair shininess, glossiness or volume.

Description

Topical Use of Steviol or Derivatives in Hair Care
The present invention relates to the use of steviol and/or isosteviol, and/ or a salt, an ester, a diester, or an ether thereof for application to skin, skin having hair, scalp, hair of a human, or fur of an animal for the overall enhancement of the hair, particularly for restoring hair color and delaying the onset of greyness in hair, lessening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age-associated hair thinning, prevent- ing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning, maintaining of the natural hair color, increasing hair shininess, glossiness or volume. This invention also relates to a method for stimulating hair growth, and/or preventing the graying of hair, or restoring or maintaining the natural hair color.
BACKGROUND OF THE INVENTION
The hair is composed of a protein called keratin. The hair itself is arranged in three layers, an outer cuticle, middle cortex and central medulla. If the hair is colored, it is due to the presence of pigments - either eumelanin (black or brown) or pheomelanin (red or yellow). If these pigments are lacking, the hair is white. Can- ites is the term given to grey hair, it is an illusion created by the mixture of white and colored hairs. Hair grows from a follicle. The walls of the follicle form the outer root sheath of the hair. The lower part of the follicle widens out to form the hair bulb that contains the germinal matrix, the source of hair growth. Dermal tissue projects into the follicle base to form the dermal papilla, and this has a network of capillary blood vessels to supply oxygen, energy, and the amino-acids needed for growth. Correcting the effects of aging as far as possible is a preoccupation of ever- increasing importance.
It therefore remains a long awaited need in the hair care industry to prevent hair loss, to stimulate hair growth, to prevent age related graying of the hair, to prevent loss of natural coloration of the hair, and to promote restoration of the natural hair color.
Stevia extracts have been described in (JP 1 1 193219 A) as having hair growing and regeneration effect, however, steviol as well as phloretin, which are known inhibitors of cellular glucose transport have been claimed to also inhibit hair growth when applied topically (EP 0 71 1 541 A1 ).
DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present application now surprisingly found that steviol and/or isosteviol and derivatives as described below with formula (I) have a great potential for use in topical hair care applications for stimulating hair growth, preventing hair loss, and enhancing the overall appearance, eg. thickness, volume, shininess and glossiness of hair of an animal including human. Thus, one aspect of this invention is a method of enhancing an animal's, including a human's, hair comprising administering a topically applied composition comprising steviol and/or isosteviol, an ester, a diester, or an ether derivative for a time sufficient and in an amount effective to enhance the overall appearance, eg. thickness, volume, shini- ness and glossiness of hair in an animal including human, and observing or appreciating the result.
Another embodiment of this invention is the use of steviol and/or isosteviol, an ester, a diester, or an ether derivative thereof in the manufacture of topical or cos- metic composition which stimulates hair growth and enhances the overall appearance of hair of an animal including human, eg. thickness, volume, shininess and glossiness.
In a further embodiment, the compound of formula (I) below is combined with at least one additional active substance selected from the group consisting of: antioxidants, light screening agents, colorants, and biological actives.
Therefore, the present invention provides the topical use of a compound of formula (I) or a salt thereof,
Figure imgf000005_0001
wherein
R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i- Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C8 alkyl) group, and
R3 is independently CH2, O, or CH-(Ci-C7 alkyl),
for enhancement of the appearance of hair of an animal including human, wherein the enhancement of the appearance of hair is selected from the group consisting of: restoring hair color and delaying the onset of greyness in hair, less- ening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age-associated hair thinning, preventing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning, maintaining of the natural hair color, increasing hair shininess, glossiness or volume.
It is to be understood that formula (I) as depicted above encompasses all possible stereoisomers. In the above definition of compounds of formula (I), the term alkoxy refers to methoxy- and ethoxy- groups. Preferably, the term alkyl amino and dialkylamino refers to methylamino-, dimethylamino-, ethylamine- or diethylamino- groups. In the above definition of compounds of formula (I), preferred R1 groups are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, pentyl, neopen- tyl, hexyl, 2-ethyl-hexyl, heptyl, and octyl. Independently of R1 , preferred R2 groups are, methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, pentyl, neopentyl, hexyl, 2-ethyl-hexyl, heptyl, octyl, hydroxy, methyloxy, ethyloxy, propy- loxy, isopropyloxy, butyloxy, sec. butyloxy, isobutyloxy, pentyloxy, neopentyloxy, hexyloxy, 2-ethyl-hexyloxy, heptyloxy, octyloxy, -O-C(O) methyl, -O-C(O) ethyl, -0- C(O) propyl, -O-C(O) isopropyl, -O-C(O) butyl, -O-C(O) sec. butyl, -O-C(O) isobutyl, -O-C(O) pentyl, -O-C(O) neopentyl, -O-C(O) hexyl, -O-C(O) 2-ethyl-hexyl, -0- C(O) heptyl, -O-C(O) octyl. -COO methyl, -COO ethyl, -COO propyl, -COO isopro- pyl, -COO butyl, -COO sec. butyl, -COO isobutyl, -COO pentyl, -COO neopentyl, - COO hexyl, -COO 2-ethyl-hexyl, -COO heptyl, and -COO octyl. Independently of R1 and R2, preferred R3 groups are oxygen, CH2, CH-CH3, CH-C2H5, CH-C3H7, CH-C4H9. It is well understood that any lower alkyl group containing three or more carbon atoms can be either straight chain or branched chain.
In a preferred embodiment, R1 is selected from hydrogen and a saturated, straight C1-C5 alkyl group, preferred R2 groups are selected from hydroxy, methyl, ethyl, propyl, methyloxy, ethyloxy, propyloxy, -O-CO-CH3, -O-CO-C 2H5, and -O-CO- C3H7, and preferred R3 groups are selected from CH2, CH-CH3, and O.
In another preferred embodiment, R1 is selected from hydrogen or a saturated, straight C1-C3 alkyl group, R2 is selected from hydroxy, methyl, methyloxy, ethyloxy, and propyloxy, and preferred R3 groups are selected from CH2, CH-CH3, and O.
In a further preferred embodiment, R1 is hydrogen or a saturated, straight or branched C1-C3 alkyl group, R2 is hydroxy or a methyl group, and R3 is a CH2 or O group. In the most preferred embodiment, R1 is hydrogen, R2 is hydroxy, and R3 is CH2 , or R2 is methyl and R3 is 0 corresponding to the compound of formula (II) steviol (CAS number: 471 -80-7) and the compound of formula (III) Isosteviol (CAS number 27975-19-5).
formula (II):
Figure imgf000007_0001
Figure imgf000007_0002
Even more preferred compounds according to the present invention are steviol and isosteviol with the stereochemistry as depicted in formula (IV) and formula (V).
Figure imgf000007_0003
Figure imgf000008_0001
Most preferred compound for all embodiments of the present invention is steviol. The salts of steviol, steviol derivatives and/or isosteviol, and isosteviol derivatives may be formed by any cosmetically acceptable cation which means any metal cation as well as any organic cation that is not toxic to the skin and/or does not cause allergic reactions. Examples of such cations are ammonium salts and alkyl ammonium salts, alkali cations such as sodium and potassium ions and alkaline earth metal cations such as calcium and magnesium ions.
Steviol, isosteviol, salts and esters thereof are particularly preferred as they can then be easily transported to hair follicles. The compounds used according to the present invention can either be sourced from chemical suppliers like e.g. Sigma or can be prepared by chemical synthesis according to known methods to a person skilled in the art such as e.g. : by degly- cosylation of the respective glucosides (e.g. : stevioside or rebaudiosides A and C) and, in case of the derivatives or salts, further derivatisation (esterification/ amida- tion, etherification/ salt formation). Such methods are well known in the art and are e.g. : disclosed in Yingyong Huaxue (1993), 10(4), 35-8: Synthesis of steviol derivatives and their bioactivity, Russian Journal of General Chemistry (2009), 79(10), 2197-2200: O-Alkylation of diterpenoid steviol in the system KOH-DMSO, or Tao et al. Synthesis and bioactivity of Isosteviol derivatives; Chinese Chemical Letters (2005) 16: 1441 -1444.
The compositions according to the invention are especially attractive, since many people, including animal owners and handlers, have a special interest in cosmetic treatments considered as "natural" with mild effects and without major side effects. As used throughout the specification and claims, the following definitions apply:
The term "effective amount" means an amount necessary to obtain a desired physiological effect.
The term "Hair" as used according to the invention refers to both, hair of a human being as well as animal fur. The term 'hair of an animal including human' relates to all parts of the body of an animal as well as of a human having hair such as the fur of animals as well as the eyelashes, the eyebrows, the beard or the scalp hair of a human. Most preferably the term relates to the hair on the scalp of humans (male or female of any age). The term "skin having hair" relates to all parts of the skin of a human having hair such as in particular the scalp and the face (eyelashes, the eyebrows, beard). Most preferably the topical compositions are applied to the scalp of humans (male or female of any age). "Topical composition" as used herein denotes any composition suitable for the topical application to mammalian keratinous tissue such as skin having hair, particularly to the human scalp or to animal skin having fur.
"Preventing" as used herein is not intended to mean that the event will never oc- cur, but means delaying the onset of the condition or event, and/or lessening the severity of the condition or event when it does occur.
"Chronic administration" is meant to convey that administration of the active ingredient regularly occurs over an extended period of time, for example once or twice per day for a time of at least about two weeks, preferably for at least one month, and more preferably at least two months. Alternatively, the regular administration can be every two days, every three days, or once per week or twice per week. "Extended period of time" means substantially daily for a period of time of at least about two weeks, preferably at least about a month, and even more preferably for at least about two months. "Observing" or "appreciating" may be done by either the individual who administers or applies the active ingredient topically, or may be done by a third party. The post-administration condition may be compared with the pre-administration condition and analyzed either using a standard test, or by subjective analysis. "Enhanced Appearance" means that the hair has improved at least one of the following qualities:
o Color (i.e. retention/restoration of natural color vs. greyness),
o Hair alopecia (i.e. hair is retained, hair loss is stopped or slowed; or hair is re- growing),
o Hair thickness (progression of hair thinning is slowed, halted, or reversed), o Skin wounds/injuries are healing or healed,
o Hair shininess or glossiness (hair appears less dull and more shiny/glossy), o Hair has more volume. In a preferred embodiment, the invention provides the use of compounds of formula (I) according to the present invention for the enhancement of the appearance of hair, wherein the enhancement of the appearance of hair is selected from the group consisting of: lessening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age- associated hair thinning, preventing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning. More preferably, the enhancement of the appearance of hair is selected from the group consisting of: restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, and counteracting age-associated hair thinning.
Compounds of formula (I) according to the present invention may either be used in therapeutic or non-therapeutic topical applications. In a preferred embodiment, the use according to the present invention is non therapeutic.
In a further embodiment, the compound of formula (I) is combined with at least one additional active substance selected from the group consisting of antioxidants, light screening agents, colorants, and biological actives.
Antioxidants Based on the invention all known antioxidants usually formulated into hair care compositions can be used. Especially preferred are antioxidants chosen from the group consisting of amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazole (e.g. urocanic acid) and derivatives, peptides such as D, L-carnosine, D-carnosine, L-carnosine and derivatives (e.g. anserine), carote- noids, carotenes (e.g. a-carotene, β-carotene, lycopene) and derivatives, chloro- genic acid and derivatives, lipoic acid and derivatives (e.g. dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g. thioredoxine, glutathione, cystine, cystamine and its glycosyl-, N-acetyl-, methyl-, ethyl-, propyl-, amyl- butyl- and lauryl-, palmitoyl-; oleyl-, y-linoleyl-, cholesteryl- and glycerylester) and the salts thereof, dilaurylthiodipropionate, distearylthiodipropionate, thiodipropi- onic acid and its derivatives (ester, ether, peptides, lipids, nucleotides, nucleosides and salts) as well as sulfoximine compounds (such as buthioninsulfoxi- mine, homocysteinesulfoximine, buthioninsulfone, penta-, hexa-, heptathioninsul- foximine) in very low compatible doses (e.g. pmol to μΓηοΙ/ kg), additionally (metal)-chelators (such as a-hydroxyfatty acids (citric acid, lactic acid, malic acid), palmic-, phytinic acid, , lactoferrin), β-hydroxyacids, huminic acid, gallic acid, gallic extracts, bilirubin, biliverdin, EDTA, EGTA and its derivatives, unsaturated fatty acids and their derivatives (such as γ-linoleic acid, linolic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and their deriva- tives, tocopherol and derivates (such as vitamin-E-acetate), mixtures of nat. vitamin E, vitamin A and derivatives (vitamin-A-palmitate and -acetate) as well as coniferylbenzoate, rutinic acid and derivatives, a-glycosylrutin, ferulic acid, fur- furylideneglucitol, carnosine, butylhydroxytoluene, butylhydroxyanisole, trihy- droxybutyrophenone, urea and its derivatives, mannose and derivatives, zinc and derivatives (e.g. ZnO, ZnSO4), selen and derivatives (e.g. selenomethionin), stil- benes and derivatives (such as stilbenoxide, trans-stilbenoxide) and suitable derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids) of the named active ingredients, or enzymes such as superoxide dismutase, catalase or similar, or activators of such enzymes. One or more preservatives/ antioxidants may be present in an amount of at least 0.01 wt.-% of the total weight of the composition. Preferably about 0.01 to about 10 wt.-% of the total weight of the composition of the present invention is present. Most preferred, one or more preservatives/ antioxidants are present in an amount about 0.1 to about 1 wt. -%.
Light screening agents
Light screening agents are advantageously selected from UV-A, UV-B and/or broadband filters. Examples of UV-B or broad spectrum screening agents, i.e. substances having absorption maximums between about 290 and 340 nm may be organic or inorganic compounds. Organic UV-B or broadband screening agents are e.g. acrylates such as 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL® 340), ethyl 2-cyano-3,3-diphenylacrylate and the like; camphor deriva- tives such as 4-methyl benzylidene camphor (PARSOL® 5000), 3-benzylidene camphor, camphor benzalkonium methosulfate, polyacrylamidomethyl benzylidene camphor, sulfo benzylidene camphor, sulphomethyl benzylidene camphor, therephthalidene dicamphor sulfonic acid and the like; Cinnamate derivatives such as ethylhexyl methoxycinnamate (PARSOL® MCX), ethoxyethyl methoxycinna- mate, diethanolamine methoxycinnamate (PARSOL® Hydro), isoamyl methoxycinnamate and the like as well as cinnamic acid derivatives bond to siloxanes; p- aminobenzoic acid derivatives, such as p-aminobenzoic acid, 2-ethylhexyl p- dimethylaminobenzoate, N-oxypropylenated ethyl p-aminobenzoate, glyceryl p- aminobenzoate; benzophenones such as benzophenone-3, benzophenone- 4,2,2',4,4'-tetrahydroxy-benzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophe- none and the like; esters of benzalmalonic acid such as di-(2-ethylhexyl) 4- methoxybenzalmalonate; esters of 2-(4-ethoxy-anilinomethylene)propandioic acid such as 2-(4-ethoxy anilinomethylene) propandioic acid diethyl ester as described in the European Patent Publication EP 0 895 776; organosiloxane compounds containing benzmalonate groups as described in the European Patent Publications EP 0 358 584 B1 , EP 0 538 431 B1 and EP 0 709 080 A1 such as polysilicone-15 (PARSOL® SLX); drometrizole trisiloxane (Mexoryl XL); imidazole derivatives such as e.g. 2-phenyl benzimidazole sulfonic acid and its salts (PARSOL®HS). Salts of 2-phenyl benzimidazole sulfonic acid are e.g. alkali salts such as sodium- or potassium salts, ammonium salts, morpholine salts, salts of prim. , sec. and tert. amines like monoethanol amine salts, diethanol amine salts and the like; salicylate derivatives such as isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, ethylhexyl salicylate (PARSOL® EHS, NEO Heliopan OS), isooctyl salicylate or homomenthyl salicylate (homosalate, PARSOL® HMS, NEO Heliopan OS) and the like; triazine derivatives such as ethylhexyl triazone (Uvinul T-150), diethylhexyl butamido triazone (Uvasorb HEB). Encapsulated UV-filters such as encapsulated ethylhexyl methoxycinnamate (Eusolex UV-pearls) or microcapsules loaded with UV-filters as e.g. disclosed in EP 1 471 995 and the like. Inorganic compounds are pigments such as microparticulated ΤΊΟ2, ZnO and the like. The term "micropar- ticulated" refers to a particle size from about 5 nm to about 200 nm, particularly from about 15 nm to about 100 nm. The T1O2 particles may also be coated by metal oxides such as e.g. aluminum or zirconium oxides or by organic coatings such as e.g. polyols, methicone, aluminum stearate, alkyl silane. Such coatings are well known in the art.
Examples of broad spectrum or UV A screening agents i.e. substances having absorption maximums between about 320 and 400 nm may be organic or inorganic compounds e.g. dibenzoylmethane derivatives such as 4-tert. butyl-4'- methoxydibenzoyl-methane (PARSOL® 1789), dimethoxydibenzoylmethane, iso- propyldibenzoylmethane and the like; benzotriazole derivatives such as 2,2'- methylene-bis-(6-(2H-benzotriazole-2-yl)-4-(1 , 1 ,3,3,-tetramethylbutyl)-phenol (TINOSORB M) and the like; bis-ethylhexyloxyphenol methoxyphenyl triazine (Ti- nosorb S) and the like; phenylene-1 ,4-bis-benzimidazolsulfonic acids or salts such as 2,2-(1 ,4-phenylene)bis-(1 H-benzimidazol-4,6-disulfonic acid) (Neoheliopan AP); amino substituted hydroxybenzophenones such as 2-(4-diethylamino-2-hydroxy- benzoyl)-benzoic acid hexylester (Uvinul A plus) as described in EP 1 046 391 ; Ionic UV-A filters as described in WO 2005/080341 A1 ; pigments such as microparticulated ZnO or T1O2 and the like. The term "microparticulated" refers to a particle size from about 5 nm to about 200 nm, particularly from about 15 nm to about 100 nm. The particles may also be coated by other metal oxides such as e.g. aluminum or zirconium oxides or by organic coatings such as e.g. polyols, me- thicone, aluminum stearate, alkyl silane. Such coatings are well known in the art. As dibenzoylmethane derivatives have limited photostability it may be desirable to photostabilize these UV-A screening agents. Thus, the term "conventional UV-A screening agent" also refers to dibenzoylmethane derivatives such as e.g. PARSOL® 1789 stabilized by, e.g. 3,3-Diphenylacrylate derivatives as described in EP 0 514 491 B1 and EP 0 780 1 19 A1 ; Benzylidene camphor derivatives as de- scribed in the US Patent No. 5,605,680; Organosiloxanes containing benzmalo- nate groups as described in the EP 0 358 584 B1 , EP 0 538 431 B1 and EP 0 709 080 A1 .
Colorants
Based on the invention, all colorants usually formulated into hair care compositions which have an absorption in the visible light of electromagnetic radiation (400 nm to 800 nm) can be used. The absorption is often caused by the following chromophores: Azo- (mono-, di-, tris- or poly-)stilbene-, carotenoide-, diaryl- methane-, triarylmethane-, xanthene-, acridine-, quinoline-, methine- (also polyme- thine-) thiazol-, indamine-, indophenol-, azin-, oxazine-, thiazine-, anthraquinone-, indigo-, phthalocyanin and further synthetic, natural and/or inorganic chromophores. FD & C and D & C which can be used in hair care compositions according to the invention are e.g. curcumin, riboflavin, lactoflavin, tartrazine, quinoline yellow, co- chenille, azorubin, amaranth, ponceau 4R, erythrosine, red 2G, indigotin, chlorophyll, chlorophyllin, caramel, carbo medicinalis, carotenoids, carotin, bixin, nor- bixin, annatto, orlean, capsanthin, capsorubin, lycopin, xanthophyll, flavoxanthin, lutein, kryptoaxanthin, rubixanthin, violaxanthin, rhodoxanthin, canthaxanthin, bet- anin, anthocyans without being limited thereto. Examples of dyes are e.g. inorganic pigments such as iron oxide (iron oxide red, iron oxide yellow, iron oxide black etc.) ultramarines, chromium oxide green or carbon black. Other colorants and dyes which can be used in the compositions according to the invention com- prise natural or synthetic organic pigments, disperse dyes which may be solubi- lized in solvents like direct hair dyes of the HC type, for example HC red No. 3, HC Blue No. 2 and all other hair dyes listed in International Cosmetic Ingredient Dictionary Handbook, 1 1 th edition, 2006) or the dispersion dyes listed in Color Index International Society of Dyers and Colorist, color varnishes (insoluble salts of soluble dyes, like many Ca-, Ba- or Al-salts of anionic dyes), soluble anionic or cationic dyes such as acid dyes (anionic), basic dyes (cationic), direct dyes, reactive dyes or solvent dyes, fluorescent dyes, fluorescein and isothiocyanates. Biological actives.
Biological actives are advantageously selected from general activators of melano- genesis like tyrosinase activators, peptide hormones, cAMP-activators (caffeine) and neurotrophins.
Preferred tyrosinase activators are any substance which increases tyrosinase expression or enzyme activity, like e.g. glycyrrhizin from the root of licorice.
Peptide hormones belonging to the group of melanocortins are the preferred pep- tide hormones including ACTH, alpha-MSH, beta-MSH and gamma-MSH; these peptides are all cleavage products of a large precursor peptide called proopiomelanocortin (POMC). Alpha-MSH is the most important melanocortin for pigmentation. The melanocyte-stimulating hormones (collectively referred to as MSH or intermedins) are a class of peptide hormones that in nature are produced by cells in the intermediate lobe of the pituitary gland. They stimulate the production and release of melanin (melanogenesis) by melanocytes in skin and hair. Therefore, they will be advantageously combined with the compounds of the present invention. In yet another embodiment, the compounds of the present invention are used topically on hair, wherein hair is a mammal's fur. Preferred mammals are horses, dogs and cats.
In a further embodiment, the compound of formula (I) is used in an effective amount selected in the range of 0.00001 to 20 wt.-%, preferably, 0.0001 to 5 wt.-%, more preferably, 0.001 to 0.5 wt.-% based on the total weight of the topical composition. According to the present invention, the compound of formula (I) is used in a topical composition in an amount in the range of 0.00001 to 20 wt.-%, preferably, 0.0001 to 5 wt.-%, more preferably, 0.001 to 0.5 wt.-% based on the total weight of the topical composition. The present invention also relates to the use of compounds of formula (I) for increasing the total number of melanocytes in hair follicles and/or for increasing the differentiation and migration of melanocytes from the hair sheath to the hair matrix and/or increasing proliferation of hair cells, and/or increasing the production of melanin, and/or for lengthening hair growth phase (anagen) and/or shortening hair resting phase (telogen). Number of melanocytes in the hair follicle can be evaluated by standard methods e.g. immunohistochemical staining of the melanocytes with the pan-melanocyte marker NKI-beteb following by counting the NKI-beteb+ cells. Differentiation and migration of melanocytes from the hair sheath to the hair matrix can be measured by immunohistochemical staining of c-kit+ melanocytes in the hair follicle, and by assessing their distribution within the hair follicle.
In another embodiment, the invention further provides the use of a compound of formula (I) according to the present invention, in combination with the use of other ingredients which are conventionally used in topical compositions, such as in particular hair care compositions, generally enhance the appearance of hair, eg. thickness, volume, shininess and glossiness, to prevent the graying of hair and/or restore or maintain the natural hair color, such as 5,6-dihydroxyindoline HBr, 5,6- dihydroxyindoline HBr in combination with 2-methylresorcinol and/or arginine.
The present invention further provides the use of compounds of formula (I) as described in this invention for elongation of hair follicles, increasing the proliferation of hair follicle cells (outer/inner root sheet, dermal papilla fibroblasts). Thus, the present invention provides the use of compound of formula (I) for restoring hair color and delaying the onset of greyness in hair, and/or maintaining of the natural hair color.
In another embodiment, this invention relates to a method for stimulating hair growth, and/or preventing the greying of hair or restoring or maintaining the natural hair color comprising the steps of applying to skin having hair, for a sufficient time, a to ical composition comprising an effective amount a compound of formula (I),
Figure imgf000017_0001
wherein R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i- Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C8 alkyl) group,
R3 is independently CH2, O, or CH-(Ci-C7 alkyl),
and observing the result.
More preferred compounds are steviol and isosteviol in any isomeric form, most preferred are compounds of formula (IV) and formula (V), even most preferred is steviol. Preferred amounts of the compound of formula (I) are selected in the range of 0.00001 to 20 wt.-%, preferably, 0.0001 to 5 wt.-%, more preferably, 0.001 to 0.5 wt.-% based on the total weight of the topical composition. Preferably, the topical composition for the method according to the present invention is a hair care composition, and more preferably, it is a hair tonic, a conditioner, a shampoo, or a styling gel. The topical composition may further comprise at least one additional active substance selected from the group consisting of antioxidants, light screening agents, colorants, and biological actives.
Graving of the Hair
One embodiment of this invention is the prevention of the graying of hair for resto- ration and/or maintenance of the natural hair color, as shown by the ability of said compounds and derivatives to increase total number of melanocytes in hair follicles, as well as, to increase the differentiation and migration of melanocytes from the hair sheath to the hair matrix. This invention relates to a method for preventing the graying of hair, delaying the onset of graying, and/or restoring and/or maintaining the natural hair color which comprises the step of applying a topical composition comprising an effective amount of steviol and/or isosteviol, or a salt, an ester, a diester, or an ether thereof as depicted in formula (I) to human or animal skin having hair, and observing the prevention, restoration, or maintenance of natural hair color.
Thus the present invention also encompasses a method of topically administering an amount of steviol and/or isosteviol or a salt, an ester, a diester, or an ether thereof and observing or appreciating an increase in the number of melanocytes in hair follicles, and/or increasing the differentiation or migration of melanocytes from the hair sheath to the hair matrix. The observation or appreciation can be done by noticing a decrease in grayness, maintenance of original hair color, or by observing a restoration of original hair color. The efficacy of the use of compounds of formula (I) in accordance with the present invention for prevention of the greying of hair and/or for restoration and/or maintenance of the natural hair color can be shown by procedures described below: As a reference (control) a hair tress containing approximately 100 hairs is cut neatly above the scalp. The color of the hair within the tress is measured from the near-root part to the tip. This could be either done 1 ) visually by scoring, 2) with high density photo documentation and scoring, 3) by pigment analysis and deter- mination of the melanin content from hair following hair degradation and melanin extraction. In this later case, melanin can be measured by photometric means, or by chemical reaction (i.e. formation of pyrrole-2,3,5 tricarboxylic acid from eumela- nin, and formation of aminohydroxyphenylalanine isomers for pheomelanin, followed by quantitative chromatographic, spectroscopic, or spectrophotometric analysis. It can also be done directly by assessing the pigment status of the hair bulb of plucked hair using light microscopy and the Lickert-Scale of pigmentation.
A sample of a topical composition (2 to 10 ml_ or mg/ cm2, depending on the type of formulation; preferably a leave-on product such as hair tonic, lotion or cream) containing a preferred amount of a compound of formula (I) is then applied at least once a day on the scalp, typically from 1 to 4 times daily for at least three months, especially six months (because normal hair growth rate is about 1 cm/ month) and distributed equally with a massage on the scalp. In one method, the product is not washed out after application. At the end of the treatment period, a second hair sample is taken from the same place on the scalp and analyzed as described above.
A comparison of the melanin content, hair color or degree of graying is made intra- individually before and after the treatment period.
Hair Loss
Also according to this invention, topical applications of steviol and/or isosteviol can:
o lessening hair loss,
o restoring hair growth after the onset of baldness has occurred,
o increasing the thickness of hair,
o counteracting age-associated hair thinning,
o preventing or counteracting premature hair loss, o delaying the onset or seventy of age-associated hair loss, and/or o delaying the onset or seventy of hair thinning.
Thus another aspect of this invention is a method of enhancing hair appearance selected from the group consisting of:
o lessening of hair loss,
o restoring hair growth after the onset of baldness has occurred,
o increasing the thickness of hair,
o counteracting age-associated hair thinning,
o preventing or counteracting premature hair loss,
o delaying the onset or severity of age-associated hair loss, and/or
o delaying the onset or severity of hair thinning
comprising topically administering steviol and/or isosteviol, and observing the enhancement.
The present invention also relates to the use of steviol and/or isosteviol or a salt, an ester, a diester, or an ether thereof as depicted in formula (I) for stimulating dermal papilla region and keratinocytes within the hair follicle in order to increase the total number of keratinocytes responsible for hair growth and/or releasing growth stimulating molecular signals from surrounding cells of the hair follicle and/or migration of progenitor keratinocytes to rebuild hair follicles.
Veterinary Uses In another aspect of this invention, the topical formulation of a compound of formula (I) is administered to a non-human animal, which is preferably a mammal. In a preferred aspect of this invention, the non-human animal is a mammal, such as a companion animal (dog, cat, ferret) or an animal which is used in the fur industry (minks, chinchillas or the like), or an animal which is shown in competition (such as dogs, horses, cats, rabbits and other farm animals). Supplementing the animal's normal bathing or grooming regime with steviol and or isosteviol, a salt, an ester, a diester, or an ether -containing compositions of this invention will enhance the appearance of the animals' fur. Thus another aspect of this invention is a veterinary topical composition containing a fur-enhancing amount of steviol and/or isosteviol or a salt, an ester, a diester, or an ether derivative thereof.
Another aspect of this invention is a shampoo or other topical formulation espe- cially designed for a show animal which comprises steviol and/or isosteviol or a salt, an ester, a diester, or an ether derivative thereof. This should be applied to the animal daily for at least one month, and preferably for at least two months prior to the competition in order for its fur to be at its optimal condition. In a further embodiment the invention relates to the use of a compound of formula (I) such as particularly steviol and/or isosteviol or a salt thereof for fur grooming (so the fur no longer appears neglected, and looks better groomed).
Dosages
The physiological effect may be achieved by one single dose or by repeated doses. The dosage administered may, of course, vary depending upon known factors, such as the physiological characteristics of the particular composition; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and/or the effect desired and can be adjusted by a person skilled in the art.
An effective amount will typically be at least 0.00001 wt.-% based on the total weight of the topical composition. Preferably, the topical compositions contain the compound of formula (I) according to the present invention in an amount of 0.00001 to 20 wt.-%, more preferably in an amount from 0.0001 to 5 wt.-%, even more preferably in an amount from 0.001 to 0.5 wt.-%, based on the total weight of the composition. The topical compositions are applied at least several times per week, preferably at least once per day, and more preferably applied at least twice a day such as e.g. once in the morning and once in the evening. Applications should be for a chronic period of time, i.e. at least one week, preferably for at least two weeks, and more preferably for at least 4 weeks in order to observe results. Formulations
The present invention is also providing a hair care composition comprising pound of formula (I),
formula (I):
Figure imgf000022_0001
wherein
R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i- Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C8 alkyl) group,
R3 is independently CH2, O, or CH-(Ci-C7 alkyl),
and at least one conventional hair care carrier.
In a preferred embodiment, the present invention is also providing a hair care composition comprising a compound of formula (I) as described above, and at least one conventional hair care carrier, wherein the pH of the composition is below 7, preferably below 6, more preferably below 5, even more preferably below 4.
In another embodiment, the hair care composition according to the present inven- tion further comprises an antioxidant selected from the group of antioxidants usually formulated in hair care, and as described above, and/or, a light screening agent selected from UV-A, UV-B, and/or broad band UV filters as described in the present application. The present invention is also providing a hair care composition comprising pound of formula (I),
formula (I):
Figure imgf000023_0001
wherein
R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i- Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C8 alkyl) group,
R3, is independently CH2, O, or CH-(Ci-C7 alkyl),
and at least one conventional hair care carrier, and an antioxidant selected from the group of antioxidants usually formulated into hair care and/or a light screening agent selected from UV-A, UV-B and/or broadband filters as described in the present application.
The present invention further provides a composition as described above which is a gel, a lotion, a tincture, a spray, a mousse, a cleansing composition, a shampoo, or a foam.
In particular the topical compositions are hair care compositions such as conditioners, treatments, tonics, styling gels, mousses, shampoos, hair sprays, pomades, setting lotions, coloring and permanent waving compositions. Of particular interest for the purpose of the present invention are tonics, conditioners, treatments, and styling gels which may be in the form of a gel, a lotion, a tincture, a spray, a mousse, a cleansing composition or a foam and which may be applied according to individual needs, e.g., once daily as a lotion, tincture, mousse or spray; or once or twice weekly as a conditioner or treatment. The typical composition used in the method for preventing the graying of hair as well as for restoring and/or maintaining the natural hair color according to the present invention may further comprise other ingredients which are conventionally used in topical compositions such as 5,6-dihydroxyindoline HBr, 5,6- dihydroxyindoline HBr in combination with 2-methylresorcinol and/or arginine.
In accordance with the present invention, a compound of formula (I) with the definitions and preferences as given above is useful in topical compositions such as in particular hair care compositions which further contain carriers and/or excipients or diluents conventionally used in topical, respectively, hair care compositions.
The compound of formula (I) may be combined with suitable auxiliary agents which are conventionally used in hair care compositions such as disclosed in general terms in Ullmann's Encyclopedia of Industrial Chemistry (1989), Vol. A 12, Hair Preparations, and more specifically, e.g., in International Patent Application No. WO 00/06094, WO 00/07550 and WO 01/06994.
Thus, the use of a compound of formula (I) according to the present invention may be combined with the use of further ingredients to protect the hair against detri- mental environmental impact and to improve the health of the hair.
The compounds of formula (I) according to the present invention may be incorporated into conventional hair care compositions as described below: The hair care compositions may comprise additional cosmetic or dermatological adjuvants and/or additives (cosmetic carrier) which are preferably selected from
1 . ) Water
2. ) Water soluble organic solvents, preferably C1 -C4-Alkanols
3. ) Oils, fatty substances, waxes
4.) Various esters different to 3) of C6-C30 monocarboxylic acids with mono-, di-, or trivalent alcohols
5. ) Saturated acyclic and cyclic hydrocarbons
6. ) Fatty acids
7. ) Fatty alcohols 8. ) Silicone oils
9. ) Surface active ingredients
and mixtures thereof. The hair care compositions can contain further adjuvants and additives such as preservatives, antioxidants, silicones, thickeners, softeners, anionic, cationic, non- ionic or amphoteric emulsifiers, light screening agents, antifoaming agents, moisturizers, fragrances, surfactants, fillers, sequestering agents, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or ba- sifying agents, dyes, colorants, pigments or nanopigments, light stabilizers, insect repellents, antibacterial agents, or any other ingredients usually formulated into hair care compositions. The necessary amounts of the adjuvants and additives can, based on the desired product, easily be chosen by a skilled artisan in this field and will be illustrated in the examples, without being limited hereto.
Preferably the hair care compositions are in the form of cosmetic hair-treatment preparations, e.g. hair tonics, conditioners, hair-care preparations, e.g. pre- treatment preparations, styling creams, styling gels, pomades, hair rinses, treatment packs, intensive hair treatments e.g. leave-on and rinse-off deep condition- ers, hair-structuring preparations, e.g. hair-waving preparations for permanent waves (hot wave, mild wave, cold wave), hair-straightening preparations, liquid hair-setting preparations, hair foams, hairsprays, bleaching preparations, e.g. hydrogen peroxide solutions, lightening shampoos, bleaching creams, bleaching powders, bleaching pastes or oils, temporary, semi-permanent or permanent hair colorants, preparations containing self-oxidizing dyes, or natural hair colorants, such as henna or chamomile.
Preferred hair care compositions are leave-on compositions selected from hair tonics, conditioners, treatments, and styling gels.
Based on the application the hair care preparations may be in the form of a (aerosol) spray, (aerosol) foam, gel, gel spray, cream, lotion, liquid or a wax. Hair sprays comprise as well aerosol sprays as pump sprays without propellant. Hair foams comprise as well aerosol foams as pump foams without propellant. Hair sprays and hair foams comprise mainly or exclusively water soluble or water dis- persible components. If the components used in hair sprays or hair foams according to the invention are water dispersible, then they may be in the form of micro dispersions with particle sizes of usually 1 -350 nm, preferably 1 -250 nm. The solid content of such preparations is typically in the range of 0.5 to 20 wt.-% of the total weight of the preparation. Such micro dispersions normally do not need further emulsifiers or tensides for their stabilization.
An exemplary hair gel with the compound of the present invention may comprise:
1 . 0.1 to 20 wt.-% preferably 1 to 10 wt.-% of at least one hair polymer;
2. 0 to 10 wt.-% of at least one carrier (solvent), selected from C2-C5 alcohols, preferably ethanol;
3. 0.01 to 5 wt.-%, preferably 0.2 to 3 wt.-% of at least one thickener;
4. 0 to 50 wt.-% of a propellant;
5. 0 to 10 wt.-%, preferably 0.1 to 3 wt.-% of a styling polymer different to 1 . ), preferably a water soluble non-ionic polymer;
6. 0 to 1 wt.-% of at least one refatter, preferably selected from glycerine and glycerine derivatives;
7. 0 to 30 wt.-% of other customary additives e.g. a silicone component
8. 0.005 to 5 wt.-% of a compound of formula (I) according to the present invention,
9. water ad 100 wt.-%
An exemplary conditioner preparation according to the present invention may comprise:
1 . 0.05 to 10 wt.-% of a hair polymer
2. 5 to 95 wt.-% of water
3. 5 to 50 wt.-% of surfactant
4. 0 to 5 wt.-% of an additional conditioning agent
5. 0 to 10 wt.-% other customary additives
6. up to 20 wt.-% of a compound of formula (I)
all ingredients adding up to 100 wt.-%. An exemplary styling composition with the compound of the present invention may comprise:
1 . 0.1 to 10 wt.-% of at least one hair polymer;
2. 20 to 99 wt.-% water and/or alcohol;
3. 0 to 70 wt.-% of at least one propellant;
4. 0 to 20 wt.-% of customary additives;
5. 0.005 to 5 wt.-% of a compound of formula (I) according to the present invention. An exemplary styling gel with the compound of the present invention may comprise:
1 . 0.1 to 10 wt.-% of a hair polymer;
2. 60 to 99.85 wt.-% of water and/or alcohol;
3. 0.05 to 10 wt.-% of a gel former;
4. 0 to 20 wt.-% of other customary additives.
5. 0.005 to 5 wt.-% of a compound of formula (I) according to the present invention.
An exemplary hair care composition (spray) with the compound of the present in- vention may comprise:
1 . 0.005 to 5 wt.-% of a compound of formula (I) according to the present invention,
2. 30 to 99.5 wt.-%, preferably 40 to 99 wt.-%, of at least one solvent chosen from water, water-miscible solvents and mixtures thereof;
3. 0 to 70 wt.-% of propellant;
4. 0.1 to 10 wt.-% of at least one water-soluble or water-dispersible hair polymer
5. 0 to 0.3 % by weight of at least one water-insoluble silicone;
6. 0 to 0.5 wt.-% of at least one wax, preferably at least one fatty acid amide;
7. customary additives.
Another hair care composition with the compound of the present invention may comprise:
1 . 0.05 to 20 wt.-% of at least one hair polymer;
2. 20 to 99.95 wt % of water and/or alcohol; 3. 0 to 79.5 wt.-% of customary additives;
4. 0.005 to 5 wt.-% of a compound of formula (I) according to the present invention. An exemplary composition for aerosol foams with the compound of the present invention may comprise:
1 . 0.1 to 10 wt.-% of at least one hair polymer;
2. 55 to 99.8 wt.-% water and/or alcohol;
3. 5 to 20 wt.-% of a propellant;
4. 0.1 to 5 wt.-% of an emulsifier;
5. 0 to 10 wt.-% of customary additives.
6. 0.005 to 5 wt.-% of a compound of formula (I) according to the present invention. An exemplary shampoo preparation with the compound of the present invention may comprise:
1 . 0.05 to 10 wt.-% of a hair polymer;
2. 25 to 94.95 wt.-% of water;
3. 5 to 50 wt.-% of surfactant;
4. 0 to 5 wt.-% of an additional conditioning agent;
5. 0 to 10 wt.-% other customary additives.
6. 0.005 to 5 wt.-% of a compound of formula (I) according to the present invention,
7. 0 to 5 wt.-% opacifiers and/or pearly gloss-imparting substances
The hair care composition according to the invention can comprise at least a water-soluble or water-dispersible hair polymer. Typical hair polymers for use in the present invention are commercially available polymers for hair care such as hair styling or conditioning polymers such as e.g. copolymers of vinyl acetate and cro- tonic acid, copolymers of methyl vinyl ether and maleic anhydride, copolymers of acrylic acid or methacrylic acid with other monomers, polyurethanes, N- vinylpyrrolidone and silicone polymers. The content of the hair polymer is generally from about 0.1 to 10 % by weight, based on the total weight of the composition. Here, it is preferable to use water- soluble or water-dispersible polyurethanes which, if desired, additionally comprise siloxane groups in copolymerized form.
The composition according to the invention can further comprise, at least one water-insoluble silicone, in particular a polydimethylsiloxane, e.g. the Abil® grades from Goldschmidt. The content of the silicone is then generally from about 0.0001 to about 2 % by weight, preferably from about 0.001 to about 1 % by weight, based on the total weight of the composition. Preferred waxes according to the present invention are fatty acid amides, such as, for example, erucamide.
The hair care compositions according to the present invention can, where appropriate, additionally comprise an antifoaming agent, e.g. based on silicone. The amount of antifoaming agent is generally up to 0.001 % by weight, based on the total amount of the composition. The compositions according to the invention have the advantage that, on the one hand, they impart the desired hold to the hair and, on the other hand, the polymers are easy to wash out (redispersible). Generally, a natural appearance and shine is imparted to the hair, even when the hair is by its very nature especially thick and/or dark.
The term alcohol refers to all alcohols usually used in cosmetic compositions such as ethanol, n-propanol, isopropanol. Other ingredients are cosmetic adjuvants and additives such as propellants, antifoaming agents, surface active ingredients e.g. tensides, emulsifiers, foam former and solubilisators. The used surface active ingredients may be anionic, cationic, amphoteric or neutral. Further ingredients may be preservatives, antioxidants, perfume oils, lipidic refatters, active and/or caring ingredients such as panthenol, col- lagen, vitamins, protein hydrolysates, alpha- and beta hydroxyl carbonic acids, stabilisators, pH regulators, opacifiers, colorants, dyes, gel formers, salts, moisturizers, complex formers, viscosity regulators or light screening agents without being limited thereto. In order to obtain certain properties the hair care compositions may additionally comprise conditioning compounds based on silicone such as polyalkylsiloxane, polyarylsiloxane, polyarylalkylsiloxane, silicone resins, polyethersiloxane or di- methicone copolyole (CTFA) and amino functionalized silicone compounds such as amodimethicone (CTFA), GP 4 Silicone fluid® and GP 7100® (Genesee), Q2 8220® (Dow Corning), AFL 40® (Union Carbide) or polymers as disclosed in EP 0 852 488. Other suitable ingredients comprise silicone propfpolymers having a polymeric silicone backbone and non-silicone containing side chains or a non silicone containing polymeric backbone and silicone side chains such as Luviflex® Silk or polymers disclosed in EP 0 852 488.
Typical propellants for hair sprays or aerosol foams may be used. Preferred are mixtures of propane/ butane, pentane, dimethylether, 1 , 1 -difluoroethane (HFC- 152a), carbon dioxide, nitrogen or compressed air.
All emulsifiers for aerosol foams or surfactants for shampoo preparations may be conventionally used non-ionic, cationic, anionic or amphoteric emulsifi- ers/surfactants. Examples of non-ionic emulsifiers are (INCI-nomenclature) Laureths, e.g. Laureth-4; Ceteths, e.g. Ceteth-1 , polyethyleneglycolcetylether; ceteareths, e.g. ceteareth-25, polyglycol fatty acid glycerides, hydroxylated lecithins, lactyl esters of fatty acids, alkylpolyglycosides. Examples of non-ionic surfactants are e.g. reaction products of aliphatic alcohols or alkylphenols with 6 to 20 C-Atoms of a linear or branched alkyl chain with ethyleneoxide and/or propyleneoxide. The amount of alkyleneoxide is about 6 to 60 mol to one mol alcohol. Furthermore alkylaminox- ide, mono- or dialkylalkanolamide, fatty esters of polyethylene glycols, alkylpolyglycosides or sorbitan ester are suitable for the incorporation of hair care compositions according to the invention.
Examples of cationic emulsifiers/surfactants are quaternised ammonium compounds e.g. cetyltrimethylammoniumchloride or bromide (INCI: cetrimoniumchlo- ride or bromide), stearyl benzyl dimethyl ammonium chloride, distearyldimethyl- ammonium chloride, stearamidopropyldimethylamine, hydroxyethylcetyldimonium phosphate (INCI: Quaternium-44), Luviquat® Mono LS (INCI: Cocotrimoniumme- thosulfate), poly(oxy-1 ,2-ethandiyl), (octadecylnitrilio) tri-2, 1 -Ethandiyl) tris- (hydroxy)-phosphate (INCI Quaternium-52). Furthermore, cationic guar derivatives such as guarhydroxypropyltrimoniumchloride (INCI) may be used in conditioner/shampoo preparations.
Anionic emulsifiers/surfactants can be selected from alkylsulfate, alkylethersulfate, alkylsulfonate, alkylarylsulfonate, alkylsuccinate, alkylsulfosuccinate, N- alkylsarkosinate, acyltaurate, acylisethionate, alkylphosphate, alkyletherphos- phate, alkylethercarboxylate, alpha-olefinsulfonate, especially the alkali-und earth alkali salts, e.g. sodium, potassium, magnesium, calcium, as well as ammonium- and triethanol amine-salts. The alkylethersulfate, alkyletherphosphate and alkylethercarboxylate may comprise between 1 to 10 ethyleneoxide or propyleneox- ide units, preferably 1 to 3 ethyleneoxide-units per molecule.
Suitable anionic surfactants are e.g. sodium laurysulfate, ammonium laury sulfate, sodium laurylethersulfate, ammonium laurylethersulfate, sodium lauroylsarkon- isate, sodiumoleylsuccinate, ammonium laurylsulfosuccinate, sodium dodecylben- zolsulfonate, triethanolamidodecylbenzolsulfonate.
Suitable amphoteric surfactants are e.g. alkylbetaine, alkylamidopropylbetaine, al- kylsulfobetaine, alkylglycinate, alkylcarboxyglycinate, alkylamphoacetate or propionate, alkylamphodiacetate or dipropionate such as cocodimethylsulfopropylbe- taine, laurylbetaine, cocamidopropylbetaine or sodium cocamphopropionate.
As gel formers, all typical cosmetic gel formers can be used such as slightly cross linked polyacrylic acid e.g. Carbomer (INCI), cellulose derivatives, polysaccarides e.g. xanthan gum, caprylic/ capric triglyceride (INCI), sodiumacrylate-copolymers, polyquaternium-32 (and) paraffinum liquidum (INCI), sodiumacrylate-copolymers (and) paraffinum liquidum (INCI) (and) PPG-1 trideceth-6, polyquaternium-37 (and) propyleneglycoldicapratdicarylate (and) PPG-1 trideceth-6, polyquaternium- 7, polyquaternium-44. In order to provide the formulation a pearlescent appearance or to give the impression of a richer or creamier product, the hair care composition may additionally comprise opacifiers and/or pearly gloss-imparting substances, such as soaps or salts of carboxylic acids, cationics including cationic polymers, dimethicone (INCI) or amodimethicone (INCI).
Other customary additives are for example long chain fatty alcohols such as cetyl alcohol, stearyl alcohol, cetylstearyl alcohol, dimethylstearamine. Furthermore the hair care composition may contain lipids such as dimethicone, amodimethicone, mineral oil, or silicon derivatives such as Dimethicone Copolyol.
In another embodiment, the present invention also relates to a dual-vial packaging system as described in WO2008049443 containing the compound of formula (I) as a dried powder in a compartment, and a cosmetically acceptable carrier in the other compartment.
The invention is further illustrated by the Examples which follow without being limited thereto. EXAMPLES
Example 1: Growth of Human Hair Follicle
Human hair follicles were obtained from human skin fragments (obtained by plastic surgery) and grown in supplemented William's E medium supplemented with penicillin/streptomycin, L-glutamine (2 mM), insulin (10 pg/ml and hydrocortisone (8 nM). Hair follicle growth was assessed via length measurements (day 0, 4, 7). Triiodothyronine (T3, 30 μΜ) was used as positive control. The effect of steviol (at 0.625 to 5 pg/ml) was tested in parallel. At day 7, RNA was extracted from hair follicles that had been subjected to different treatments (control, T3, steviol). RNA was processed for Affymetrix® DNA microarray analysis in order to identify effects of compounds on gene expression. Where appropriate, RNA expression levels were further quantified by RT-PCR using the ABI 7900 Taqman instrumentation. In all procedures the protocols suggested by the manufacturers were strictly followed.
Results
Effects on hair follicle growth:
Steviol dose-dependently favoured the elongation of hair follicles. At low concentrations the effect was significant, whereas at higher concentrations the compound did not significantly contribute to growth.
Table 1
Figure imgf000033_0001
Effect on gene expression:
Global effects of steviol on gene expression were determined by transcriptomics i.e. DNA microarray analysis. The obtained data were processed with Genedata software tools. This resulted in a list of genes that had significantly different expression levels in steviol-treated hair follicles (compared to untreated hair follicles). Examples of genes that were differentially up-regulated by steviol and which are involved in epidermal physiology are given in Table 2. Only genes directly or indirectly involved in epidermal proliferation or differentiation and which were at least 2-fold up-regulated are listed. Table 2
Ratio of steviol-
Gene treated/untreated p - value
Transmembrane protein with EGF-like 3.10 0.0001 and two follistatin-like domains 2
Fibroblast growth factor 7 (keratino- 2.91 0.0006 cyte growth factor)
CASP8 and FADD-like apoptosis 2.58 0.0004 regulator
Topoisomerase (DNA) II alpha 2.45 0.0004
170kDa
TIMP metallopeptidase inhibitor 3 2.32 0.0001
Chemokine (C-X-C motif) ligand 12 2.22 0.0005
(stromal cell-derived factor 1 )
Integrin, alpha 6 2.15 0.0004
Collagen, type IV, alpha 6 2.04 0.0008
Insulin-like growth factor 1 receptor 2.00 0.001
The genes regulated by steviol were further mapped to biological pathways using statistical tools provided with the Genedata software package. Steviol modulated gene expression of the pathways of the epidermal development, ectoderm development and keratinocyte differentiation with a high statistical significance (indicated by p- value in Table 2); other pathways were not significantly affected. This data is in line with the observed effect of steviol on hair follicle elongation (see Table 1 ) and corroborate that steviol modulates molecular pathways that lead to changes in hair growth.
The mRNA level of some marker genes involved in growth and/or differentiation of cells in the skin and in hair follicle was further determined by RT-PCR and is shown in Table 3. Table 3
Treatment of human hair Fold changes (versus
Gene
follicle (concentration) control)
All genes Control (untreated) 1
Keratin 6 Steviol (10 Mg/mL) 1 .33 ± 0.1 1
COX-2 Steviol (1 .25 Mg/mL) 0.46 ± 0.17
Integrin alpha-6 Steviol (0.625 pg/mL) 1 .62 ± 0.06
HO-1 Steviol (1 .25 Mg/mL) 0.64 ± 0.08
Involucrin Steviol (1 .25 Mg/mL) 0.51 ± 0.22
The importance of these genes in epidermal and therefore also hair development is described and discussed in detail e.g. by Adriani et al. J. Invest Dermatol 120: 923-931 (2003); Grochot-Preczek et al. Thromb Haemost 104 (on-line 10-June 2010); Li et al. Exp Dermat 9: 431 -438 (2000); Ma et al. Ann Acad Med Singapore 33: 784-8 (2004); Neufang et al. Proc Nat Acad Sci (USA) 98: 7629-7634 (2001 ).
Example 2: Anti Dandruff Shampoo
INCI NOMENCLATURE wt.-%
Aqua Ad 100
Ammonium Laureth Sulphate (28 %) 35.00
Ammonium Lauryl Sulphate (25 %) 15.00
Glycol Distearate 1 .00
Dimethicone 1 .00
Cetyl Alcohol 0.50
Cocamide MEA 3.00
Zinc Pyrithione 1 .00
Guar Hydroxipropyltrimonium Chloride 0.20
Hydrogenated Polydecene 1 .00
Polyquaternium-10 0.10
PEG 7m 0.50
Trimethylpropane Tricaprylate/Tricaprate 1 .00
Preservative q.s.
Fragrance 0.30
E 104.E 1 10.E 132 0.02 INCI NOMENCLATURE wt.-%
Compound of formula (1), in particular steviol 0.01
Combine all ingredients and mix intensively until a homogeneous solution is obtained. At the end, add the water under slow agitation and wait until the foam has disappeared.
Example 3: Conditioning Shampoo
INCI NOMENCLATURE wt.-%
Aqua Ad 100
Sodium Laureth Sulphate (28 %) 25.00
Cocamidopropyl Betaine (40 %) 5.00
Sodium Chloride 2.50
Glycol Distearate 1 .00
Glycerin 2.00
Dimethiconol 0.50
Parfum 0.50
Coco-Glucoside (40%) 3.00
Carbomer 0.10
Arginine 0.05
Glyceryl Oleate 0.05
Glyceryl Stearate 1 .00
Guar Hydroxypropyltrimonium Chloride 0.10
Panthenol 1 .00
Disodium EDTA 0.05
Preservative q.s.
Hydrolyzed Keratin 0.10
Citric Acid/ Sodium Hydroxide q.s
Compound of formula (1) according to the
present invention such as in particular steviol 0.005
E 102, E 1 10, FD&C blue 0.01 Combine all ingredients and mix intensively until a homogeneous solution is obtained. At the end, add the water under slow agitation and wait until the foam has disappeared. Then carefully add the thickening agent (sodium chloride). Example 4: Shine Shampoo
Figure imgf000037_0001
Combine all ingredients and mix intensively until a homogeneous solution is obtained. At the end, add the water under slow agitation and wait until the foam has disappeared. Than add carefully the thickening agent (sodium chloride). Example 5: Extra Shine Revitalizing Hair Cream
Figure imgf000038_0002
Heat part A and part B separately to 65 °C under moderate agitation. When both have the same temperature, add part B into part A under agitation. Let cool to 40 °C and add part C under agitation, homogenize. Cool to ambient temperature.
Example 6: Hair Repair Treatment
Figure imgf000038_0001
Compound of formula (1) according to
the present invention such as in particular steviol 0.5
Parfum q.s.
Alcohol denat. 10.00
Citric Acid q.s.
Heat Part A to 70 °C. Add part B to part A under stirring. Add the mixture to part C and homogenize. Add part D and let cool down under moderate agitation. Example 7: Color Balm
Figure imgf000039_0001
Heat parts A and B separately to 70°C. Add part A to B and homogenize. Add part C under stirring. Example 8: Silky Hair Cocktail
Figure imgf000040_0001
Heat parts A and B separately to 70°C. Add part A to B and homogenize. Let cool down under stirring.
Example 9: Oil Sheen Moisturizer
INCI NOMENCLATURE wt.-%
A Cetyl Alcohol 2.00
PEG-75 Lanolin 1 .00
Glyceryl Stearate 4.00
Ceteareth-25 1 .00
Cetearyl Octanoate 4
B Glycerin 10.00
Figure imgf000041_0001
Heat parts A and B separately to 70°C. Add part A to B and homogenize. Add part C under stirring. Example 10: Setting Cream High Gloss
Figure imgf000041_0002
Heat parts A and B separately to 70°C. Add part A to B and homogenize. Add part C under stirring. Example 11: Hair Gel
Figure imgf000042_0001
Disperse carbomer in about 50% of the water amount and add AMP under stirring till a clear gel is formed. Dissolve PVP in the rest of the water. Premix the perfume with PEG-40 hydrogenated castor oil. Mix all parts, and finally add preservative and tocopheryl acetate.
Example 12: Hair Gel
Figure imgf000042_0002
Combine all ingredients of part 1 and mix intensively until a homogeneous gel is obtained. Example 13: Permanent hair tinting formulation
Part I
Figure imgf000043_0001
Heat phase A and B of Part I separately to 70 °C. Add phase A to phase B under stirring. Adjust the pH to 1 1 .2. Heat phase A and B of Part II separately to 70 °C. Add phase A to phase B under stirring. Adjust the pH. Combine Parts I and II shortly before use.
Example 14: Pharmaceutical Shampoo
Part I
Figure imgf000044_0001
Dissolve compound of formula (I) according to the present invention (in particular steviol) in water, add Methylcellulose and stir until dissolved; mix Ethylparaben with Sodium Laureth Sulfate.
Mix part 1 with part 2.
Example 15: Induction of melanin synthesis by Steviol: Quantification of melanin synthesis in cell culture: Normal human melanocytes NHM (HEMn-MP, Clonetics) were seeded in 96 well cell culture plates and grown to sub-confluence for two days in a mixture of M2- Medium (Clonetics) and Medium (Promocell). Culture medium was exchanged with Culture Medium containing Steviol and melanogenesis progressed for another three days at 37 °C with another medium exchange on day two. Including cell layer and culture supernatant the total melanin was extracted using 1 .7M KOH with vigorous shaking at RT. We measured melanin content at 405 nm in an ab- sorbance plate reader. The data is normalized to 100 % for the un-treated control sample, and expressed as percentage of the control.
The results are summarized in the table below:
Figure imgf000045_0002
Glycyrrhizin is used as a positive control since it is a known inducer of melano- genesis. Steviol shows a clear dose dependent positive effect on the production of melanin in human melanocytes.
Example 16: Silk & Shine Conditioning Fluid:
Figure imgf000045_0001
Procedure:
A/B Heat part A and part B separately to 70°C.
When both have reached the same temperature, add part B to part A.
C Add. Ingredients of part C and homogenize balanced.
D Water phase II cold: Add. all ingredients of part D in water. Add. the cold solution under stirring into the product.
E Add. Preservative and Parfum. Homogenize thoroughly and then with continued mixing cool down to ambient temperature.
Technical Data:
pH: 4.8 Viscosity: 30.000 mPas (# 6/5 RPM)
Example 17: Sulfate Free Shampoo:
Figure imgf000046_0001
Procedure:
1 Mix part A under stirring.
2 Add ingredients of part B step by step to A under stirring until equal distribu- tion is optioned.
3 Add ingredients of part C step by step to the first part under stirring.
6 Mixing separate: all ingredients of part D and add to the shampoo.
7 Addition ingredients of part E. The batch will thicken. Technical Data:
Viscosity: 3500-5000 mPas (Brookfield, #4 / 10 rpm)
Example 18: Color Protection Shampoo:
Figure imgf000047_0001
Procedure:
A Mix part A under stirring.
B Add. ingredients of part B step by step to part A, under stirring. Neutralize with NaOH.
C Add. all ingredients of part C step by step to the mixture.
D Mixing separate: ingredients of part D all in perfume and add. into the shampoo.
E/F Then add. the thickening agent until desired viscosity is reached. Add preservative. pH: 6.10 Viscosity: 8.000 mPas (S 4/ 10 Rpm)
Example 19: 2-Phase leave-on Conditioner:
Figure imgf000048_0001
Procedure:
A Add the polymer in water and mix thoroughly until a homogeneous solution is obtained.
Add lactic acid
B Add all ingredients of part B successively and mix until clear and uniform.
C Add all ingredients of part C successively and mix with moderate propeller agitation.
D Mixing separate : all ingredients of part D dissolve in ethanol.
Add the solution into the product.
Homogenize moderate!
Technical Data:
Viscosity: spray able 2-phases
Example 20: Solid product which needs to be dissolved prior to the application:
Product forms to treat the hair or the scalp consisting of
a) a solid part
b) a liquid part,
wherein the solid part and the liquid part are mixed prior to application.
The solid part contains Steviol, and the liquid part contains 0 to 100 % water or/and ethanol (0 to 100 %), and/or other compounds required to dissolve the solid part in a comfortable/convenient time (1 -8 min), e.g. emulsifiers, glycerine, propylene glycol, butylene glycol, rheological modifier, e.g. Carbomers, Hydroxyethyl cellulose, pH-regulators.
Composition:
Solid parts:
Nr ingredient Wt-%
1 Mannitol 30
2 Ascorbyl Glucoside 20
3 Sodium Citrate 10 Ceratonia Siliqua Gum 25
5 Steviol 15
Liquid phase:
Nr ingredient Wt-%
1 Ethanol 45
2 Water 50
3 Sorbitol 3
Polysorbate-40 0.4
5 frangrance q.n. Solid part (0.01 to 10g) are mixed with the liquid part (5 mL-30ml_) prior to application in an appropriated system by shaking.
Example 21: Stabilization of steviol in acidic aqueous solution: Steviol was dissolved at 1 wt.-% in water and the pH adjusted at different values as shown below. At pH 9, the solution turns brown within 1 day demonstrating instability of Steviol. However, the more acidic the pH, the less discoloration was observed as reported by the patone color index. Color index of 1 % Steviol solution in water at different pH:
Figure imgf000050_0001
Example 22: Effect on Steviol on hair follicle melanogenesis: Material & Method:
For optimal quality of hair follicles with an intact pigmentary-unit, normal human scalp skin hair follicles in the anagen VI stage of the hair cycle were isolated from scalp skin biopsies obtained from elective plastic surgery after obtaining informed consent from patients following the protocol published by Philpott and colleagues with slight modifications (Philpott et al. 1990, Philpott 1999). Briefly, after separation of epidermis and dermis from subcutaneous fat the dermis just above the dermis/subcutis border under a binocular dissecting microscope, the proximal two thirds of anagen hair follicles located in the subcutaneous fat were isolated using watchmakers forceps and subsequently collected in Petri dishes containing complete hair follicle culture medium (Williams E, Biochrom KG seromed, Berlin, Germany); 1 % Penicillin-Streptomycin; 1 % L-Glutamine 200mM; 0.02 % hydrocortisone; 0.1 % Insulin. Three hair follicles per well were then randomly distributed and cultured in 24 well plates (Costar, NY, USA) containing 500 ml of complete hair follicle culture medium per well.
Per experiment, a minimum of three wells (containing three hair follicles each) was assigned to each test group, and was supplemented with different concentrations of test substances pre-diluted in the respective dissolvent 100 x concentrated. An equal number of control follicles were cultured in complete hair follicle culture medium alone. Each experiment was repeated with hair follicles from at least three different age, pigmentation and sex matched donors. Every second day, each well was photo-documented, the pigmentation degree of each hair follicle determined, medium replaced and fresh supplements added. After 7 days hair follicles were snap frozen and stored at -80 °C.
Steviol was tested at two different concentrations (0.625 and 1 .25 μΜ). Macro- scopic analysis of hair follicle pigmentation showed a slow loss of active pigmentation in the control group over the seven day culture period (in vitro graying) remaining pigmentation is scored minimal (+) in the table below. Sphingosyl phos- phorylcholine at 1 μΜ was used as a positive control as it is known from previous work to reduce the speed of in vitro hair graying. Remaining pigmentation is scored (+++). As shown in the table below, a clear and significant improvement of hair follicle pigmentation was observed when steviol was used. This remaining pigmentation was superior when steviol was used at 0.625 μΜ (+++) when compared to steviol 1 .25 μΜ (++). c
o
CO
Q_
CD o
E
CD
Q_ Q
Control + -
Sphingosylphosphorylcholine 1 microM +++ -
Steviol 0.625 microM +++ -
Steviol 1 .25 microM ++ -
tsr y

Claims

Claims
1 . Topical use of a compound of formula (I) or a salt thereof,
formula (I):
Figure imgf000053_0001
wherein
R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i-
Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C8 alkyl) group, and
R3 is independently CH2, O, or CH-(Ci-C7 alkyl),
for enhancement of the appearance of hair in an animal including human, wherein the enhancement of the appearance of hair is selected from the group consisting of: restoring hair color and delaying the onset of greyness in hair, lessening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age-associated hair thinning, preventing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning, maintaining of the natural hair color, increasing hair shininess, glossiness or volume.
2. The use according to claim 1 , wherein
R1 is hydrogen (H) or a saturated, straight or branched C1-C5 alkyl group, R2 is independently a saturated, straight or branched C1-C3 alkyl group, -O-C1- C3 alkyl group, -OH group, a -O-C(O)-Ci-C3 alkyl group, and
R3 is independently CH2, O, or CHCH3.
3. The use according to any of claims 1 or 2, wherein
R1 is hydrogen (H) or a saturated, straight or branched C1 -C3 alkyl group,
R2 is independently a -OH group or a methyl group, and
R3 is independently CH2 or O.
4. The use according to any of claims 1 to 3, wherein
R1 is hydrogen (H),
R2 is hydroxyl (OH), and
R3 is CH2.
or
R1 is hydrogen (H),
R2 is methyl (CH3), and
R3 is oxygen (O).
5. The use according to any of claims 1 to 4, wherein the compound of formula (I) is steviol or isosteviol with the stereochemistry as depicted in of formula (IV) and formula (V).
Figure imgf000054_0001
6. The use according to any of claims 1 to 5, wherein the enhancement of the appearance of hair is selected from the group consisting of: lessening hair loss, restoring hair growth after the onset of baldness has occurred, increasing the thickness of hair, counteracting age-associated hair thinning, preventing premature hair loss, or delaying the onset or severity of age-associated hair loss and thinning.
7. The use according to any of the claims 1 to 6, wherein the compound of formula (I) as defined by any of the claims 1 to 5 is combined with the use of at least one additional active substance selected from the group consisting of antioxidants, light screening agents, colorants and biological actives.
8. The use according to any of the claims 1 to 7 wherein hair is a mammal's fur.
9. The use according to any of the claims 1 to 8, wherein the effective amount of compound of formula (I) is selected in the range of 0.00001 to 20 weight- %, based on the total weight of the topical composition.
10. Use of a compound of formula (I) according to any of the claims 1 to 5 for increasing the total number of melanocytes in hair follicles, and/or for increasing the differentiation and migration of melanocytes from the hair sheath to the hair matrix and/or increasing proliferation of hair cells, and/or increasing the production of melanin, and/or for lengthening hair growth phase and/or shortening hair resting phase.
1 1 . Method for stimulating hair growth, and/or preventing the graying of hair or restoring or maintaining the natural hair color comprising the steps of applying to skin having hair, for a sufficient time, a topical composition comprising an effective amount of a compound of formula (I),
Figure imgf000056_0001
wherein
R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i-
Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C8 alkyl) group,
R3 is independently CH2, O, or CH-(Ci-C7 alkyl),
and observing the result.
12. The method as in claim 1 1 , wherein the compound of formula (I) is steviol and/or isoteviol of claims 4 or 5.
13. The method as in claims 1 1 or 12, wherein the effective amount of the compound of formula (I) is selected in the range of 0.00001 to 20 wt.-% based on the total weight of the topical composition.
14. The method according to any one of claims 1 1 to 13, wherein the topical composition is a hair care composition.
15. The method as in claim 14, wherein the hair care composition is a hair tonic, a conditioner, a shampoo, or a styling gel.
16. The method according to any one of claims 1 1 to 15, wherein the topical composition further comprises at least one additional active substance selected from the group consisting of antioxidants, light screening agents, colorants and biological actives.
17. Hair care composition comprising a compound of formula (I),
Figure imgf000057_0001
formula (I): R1 wherein
R1 is hydrogen (H) or a saturated, straight or branched d-Cs alkyl group non substituted or substituted with up to 3 hydroxyl-, alkoxy- amino-, alkylamino- or dialkylamino- groups,
R2 is independently a saturated, straight or branched d-Cs alkyl group, -O-C-i-
Cs saturated straight or branched alkyl group, -OH group, a -O-C(O) d-Cs alkyl, or, -COO(Ci-C8 alkyl) group,
R3 is independently CH2, O, or CH-(Ci-C7 alkyl),
and at least one conventional hair care carrier
18. A hair care composition according to claim 1 7, wherein the pH of the composition is below 7.
19. Hair care composition as in any of the claims 17 or 18, further comprising an antioxidant and/or a light screening agent selected from UV-A, UV-B and/or broadband UV filters.
20. A composition as in claim 17 to 19 which is a gel, a lotion, a tincture, a spray, a mousse, a cleansing composition, a shampoo, or a foam.
* * *
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BR112013000762-1A BR112013000762B1 (en) 2010-07-23 2011-07-20 Topical use of steviol or derivatives in hair treatment and method, cosmetic, non-therapeutic, for stimulation of hair growth and / or prevention of grayish appearance in hair or restoration or maintenance of natural hair color
US13/809,265 US20130115182A1 (en) 2010-07-23 2011-07-20 Topical use of steviol or derivatives in hair care
ES11735642.8T ES2659407T3 (en) 2010-07-23 2011-07-20 Topical use of steviol or isosteviol in hair care
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EP11735642.8A EP2595598B1 (en) 2010-07-23 2011-07-20 Topical use of steviol or isosteviol in hair care
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012116992A3 (en) * 2011-03-01 2013-01-10 Dsm Ip Assets B.V. Oral use of a composition comprising steviol or isosteviol
WO2012116990A3 (en) * 2011-03-01 2014-05-01 Dsm Ip Assets B.V. Novel use
WO2016077581A1 (en) * 2014-11-12 2016-05-19 University Of Florida Research Foundation, Inc. Isosteviol triazoles and uses thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3169303A4 (en) * 2014-07-14 2018-01-17 Greene, Michael, V. Volume boosting molding hair coloring creme formulation
KR102604920B1 (en) * 2021-06-14 2023-11-21 동덕여자대학교 산학협력단 Composition for hair growth and/or for inhibiting hair loss
CN113476321B (en) * 2021-07-07 2023-09-22 珠海沅芷健康科技有限公司 Application of isosteviol in preparing cosmetic preparation for whitening skin and resisting melanin generation
CN114933554B (en) * 2022-06-01 2023-09-29 新乡医学院 Isotevelol-based injectable supermolecular hydrogel and preparation method and application thereof

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0358584B1 (en) 1988-09-09 1992-09-16 Rhone-Poulenc Chimie Diorganopolysiloxanes containing functional benzal malonate groups
EP0514491B1 (en) 1990-02-14 1993-11-03 L'oreal Light-resistant filtering cosmetic composition containing a uv-a filter and an alkyl beta, beta-diphenylacrylate or an alkyl alpha-cyano-beta, beta-diphenylacrylate
EP0538431B1 (en) 1991-05-10 1996-02-28 Givaudan-Roure (International) S.A. Organosiloxanes for use as sunscreen agents
EP0709080A1 (en) 1994-10-14 1996-05-01 Givaudan-Roure (International) S.A. Photostable cosmetic light screening compositions
EP0711541A1 (en) 1994-11-11 1996-05-15 Harry H. Leveen Use of glucose blockers for inhibiting hair growth
US5605680A (en) 1986-12-08 1997-02-25 L'oreal Photostable cosmetic composition containing a UV-A screen and a UV-B screen and a process for stabilizing the UV-A screen with the UV-B screen
EP0780119A1 (en) 1995-12-18 1997-06-25 Givaudan-Roure (International) S.A. Light screening compositions
EP0852488A1 (en) 1995-09-29 1998-07-15 L'oreal Topical composition containing a silicone-grafted polymer and an amine silicone and/or a silicone gum or resin
EP0895776A2 (en) 1997-08-05 1999-02-10 F. Hoffmann-La Roche Ag Cosmetic light-screening composition
JPH11193219A (en) 1997-12-26 1999-07-21 Ichimaru Pharcos Co Ltd Hair growing and regenerating agent with formulated plant extract
WO2000006094A1 (en) 1998-07-29 2000-02-10 The Procter & Gamble Company Hair care composition comprising antioxidants
WO2000007550A1 (en) 1998-08-05 2000-02-17 Revlon Consumer Products Corporation Method for improving the fade resistance of hair and related compositions
EP1046391A2 (en) 1999-04-20 2000-10-25 Basf Aktiengesellschaft Use of aminosubstituted hydroxybenzophenones as photostable UV-filters in cosmetic and pharmaceutical preparations
WO2001006994A1 (en) 1999-07-23 2001-02-01 Unilever Plc Method of reducing colour loss from dyed hair using organic amino compounds
EP1471995A1 (en) 2002-02-07 2004-11-03 Dow Corning Corporation Encapsulation process and encapsulated compositions
WO2005080341A1 (en) 2004-02-13 2005-09-01 Dsm Ip Assets B.V. Ionic uv-a sunscreens and compositions containing them
WO2008049443A1 (en) 2006-10-24 2008-05-02 Cadorit Ag Container system for lyophilized active substances

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5110801A (en) * 1984-08-13 1992-05-05 Leveen Harry H Treatment of acne
JPH0713022B2 (en) * 1991-09-10 1995-02-15 文夫 堂園 Veterinary medicine
JPH05213721A (en) * 1992-02-05 1993-08-24 Sansho Seiyaku Co Ltd External preparation for hair
JPH1036229A (en) * 1996-07-18 1998-02-10 Mandamu:Kk Stevia extract and hair growth composition
JP2002037716A (en) * 2000-07-24 2002-02-06 Shiseido Co Ltd Kaurenes-containing composition, hair-growing agent and skin care agent
US7585514B2 (en) * 2002-06-11 2009-09-08 L'oreal Administration of agents mimicking DOPAchrome tautomerase (TRP-2) activity for protecting hair follicle melanocytes
JP2004269430A (en) 2003-03-10 2004-09-30 Ichimaru Pharcos Co Ltd Composition for hair treatment and hair cosmetic for damaged hair
JP2006045170A (en) * 2004-08-09 2006-02-16 Yukihiro Hirose Hair-growing composition and eating or drinking type hair growth promotor containing the composition
JP5073451B2 (en) 2007-10-26 2012-11-14 ホソカワミクロン株式会社 Hair restorer for scalp
WO2009071277A1 (en) * 2007-12-03 2009-06-11 Dsm Ip Assets B.V. Novel nutraceutical compositions containing stevia extract or stevia extract constituents and uses thereof
US8759405B2 (en) * 2009-07-21 2014-06-24 Dsm Ip Assets B.V. Stevia extract or steviol for hair care
JP5017386B2 (en) * 2009-12-03 2012-09-05 株式会社シャローム Method for producing melanin synthesis promoting substance, melanin synthesis promoting substance, external preparation for skin, method for producing tyrosinase active substance, tyrosinase active substance, and pharmaceutical

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5605680A (en) 1986-12-08 1997-02-25 L'oreal Photostable cosmetic composition containing a UV-A screen and a UV-B screen and a process for stabilizing the UV-A screen with the UV-B screen
EP0358584B1 (en) 1988-09-09 1992-09-16 Rhone-Poulenc Chimie Diorganopolysiloxanes containing functional benzal malonate groups
EP0514491B1 (en) 1990-02-14 1993-11-03 L'oreal Light-resistant filtering cosmetic composition containing a uv-a filter and an alkyl beta, beta-diphenylacrylate or an alkyl alpha-cyano-beta, beta-diphenylacrylate
EP0538431B1 (en) 1991-05-10 1996-02-28 Givaudan-Roure (International) S.A. Organosiloxanes for use as sunscreen agents
EP0709080A1 (en) 1994-10-14 1996-05-01 Givaudan-Roure (International) S.A. Photostable cosmetic light screening compositions
EP0711541A1 (en) 1994-11-11 1996-05-15 Harry H. Leveen Use of glucose blockers for inhibiting hair growth
EP0852488A1 (en) 1995-09-29 1998-07-15 L'oreal Topical composition containing a silicone-grafted polymer and an amine silicone and/or a silicone gum or resin
EP0780119A1 (en) 1995-12-18 1997-06-25 Givaudan-Roure (International) S.A. Light screening compositions
EP0895776A2 (en) 1997-08-05 1999-02-10 F. Hoffmann-La Roche Ag Cosmetic light-screening composition
JPH11193219A (en) 1997-12-26 1999-07-21 Ichimaru Pharcos Co Ltd Hair growing and regenerating agent with formulated plant extract
WO2000006094A1 (en) 1998-07-29 2000-02-10 The Procter & Gamble Company Hair care composition comprising antioxidants
WO2000007550A1 (en) 1998-08-05 2000-02-17 Revlon Consumer Products Corporation Method for improving the fade resistance of hair and related compositions
EP1046391A2 (en) 1999-04-20 2000-10-25 Basf Aktiengesellschaft Use of aminosubstituted hydroxybenzophenones as photostable UV-filters in cosmetic and pharmaceutical preparations
WO2001006994A1 (en) 1999-07-23 2001-02-01 Unilever Plc Method of reducing colour loss from dyed hair using organic amino compounds
EP1471995A1 (en) 2002-02-07 2004-11-03 Dow Corning Corporation Encapsulation process and encapsulated compositions
WO2005080341A1 (en) 2004-02-13 2005-09-01 Dsm Ip Assets B.V. Ionic uv-a sunscreens and compositions containing them
WO2008049443A1 (en) 2006-10-24 2008-05-02 Cadorit Ag Container system for lyophilized active substances

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"International Cosmetic Ingredient Dictionary Handbook", 2006
"Synthesis of steviol derivatives and their bioactivity", RUSSIAN JOURNAL OF GENERAL CHEMISTRY, vol. 79, no. 10, 2009, pages 2197 - 2200
ADRIANI ET AL., J. INVEST DERMATOL, vol. 120, 2003, pages 923 - 931
GROCHOT-PRECZEK ET AL., THROMB HAEMOST, vol. 104, 10 June 2010 (2010-06-10)
LI ET AL., EXP DERMAT, vol. 9, 2000, pages 431 - 438
MA ET AL., ANN ACAD MED SINGAPORE, vol. 33, 2004, pages 784 - 8
NEUFANG ET AL., PROC NAT ACAD SCI, vol. 98, 2001, pages 7629 - 7634
TAO ET AL., SYNTHESIS AND BIOACTIVITY OF ISOSTEVIOL DERIVATIVES; CHINESE CHEMICAL LETTERS, vol. 16, 2005, pages 1441 - 1444
YINGYONG HUAXUE, vol. 10, no. 4, 1993, pages 35 - 8

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012116992A3 (en) * 2011-03-01 2013-01-10 Dsm Ip Assets B.V. Oral use of a composition comprising steviol or isosteviol
WO2012116990A3 (en) * 2011-03-01 2014-05-01 Dsm Ip Assets B.V. Novel use
WO2016077581A1 (en) * 2014-11-12 2016-05-19 University Of Florida Research Foundation, Inc. Isosteviol triazoles and uses thereof

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