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WO1999056740A1 - Dosage d'identification de composes favorisant la production de melanine, et composes de type retinoide identifies par ce dosage - Google Patents

Dosage d'identification de composes favorisant la production de melanine, et composes de type retinoide identifies par ce dosage Download PDF

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Publication number
WO1999056740A1
WO1999056740A1 PCT/US1999/009845 US9909845W WO9956740A1 WO 1999056740 A1 WO1999056740 A1 WO 1999056740A1 US 9909845 W US9909845 W US 9909845W WO 9956740 A1 WO9956740 A1 WO 9956740A1
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WO
WIPO (PCT)
Prior art keywords
compound
tetrahydro
compounds
naphthalen
pentamethyl
Prior art date
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PCT/US1999/009845
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English (en)
Inventor
Deepa Rungta
Original Assignee
Galderma Research & Development, S.N.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Galderma Research & Development, S.N.C. filed Critical Galderma Research & Development, S.N.C.
Priority to AU38829/99A priority Critical patent/AU762364B2/en
Priority to IL13877299A priority patent/IL138772A0/xx
Priority to JP2000546767A priority patent/JP3669925B2/ja
Priority to CA002324001A priority patent/CA2324001C/fr
Priority to EP99921689A priority patent/EP1082111A4/fr
Priority to BR9909599-8A priority patent/BR9909599A/pt
Publication of WO1999056740A1 publication Critical patent/WO1999056740A1/fr
Priority to NO20004723A priority patent/NO20004723L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/04—Preparations for care of the skin for chemically tanning the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4933—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having sulfur as an exocyclic substituent, e.g. pyridinethione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/673—Vitamin B group
    • A61K8/675—Vitamin B3 or vitamin B3 active, e.g. nicotinamide, nicotinic acid, nicotinyl aldehyde
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/08—Preparations for bleaching the hair

Definitions

  • melanin is synthesized by specialized cells, melanocytes, which are found within the epidermis. Melanocytes synthesize melanin within organelles, which are called melanosomes. As the melanosomes become saturated with melanin, they are transported to the dendritic arms of the melanosomes and are transferred to the surrounding keratinocytes. The keratinocytes then migrate to the surface of the skin causing the skin to exhibit a brown pigmentation. The amount of melanin in keratinocytes determines the extent of pigmentation in the skin and hair.
  • melanin melanocyte stimulating hormone
  • compounds such as theophylline
  • MSH melanocyte stimulating hormone
  • analogs of MSH are being tested for clinical efficacy for promoting skin pigmentation.
  • alpha-lipoproteins can stimulate melanin production in the skin.
  • melanin preferably human melanocytes.
  • Figure 1 contains the structures for compounds identified according to the invention which affect melanin production
  • FIGS 2 through 4 list pigmentary diseases that may be treated using the compounds of the invention.
  • the present invention provides a novel assay for identifying compounds that alter (increase or inhibit) the expression of melanin by human melanocytes, preferably compounds that increase melanin production by human melanocytes.
  • the subject assay will test the effect of a particular compound or combination of compounds on the growth or proliferation of human melanocytes in culture, and also the effect of said same compound on melanin production by said cultured human melanocytes, normalizing melanin content based on the number (proliferation) of said cultured human melanocytes, and identifying a compound or compounds which affects melanin production based on an increase or decrease in melanin production per cell. -5-
  • the subject assay will comprise:
  • step (v) further comparing the data obtained in steps (ii) and (iii) to the proliferation and melanin production in control human melanocyte cultures which are cultured under identical conditions as the previous cultures except in the absence of said compound;
  • identifying a screened compound as one that alters (increases or decreases) melanin expression by human melanocytes based on an increase or decrease in melanin production by melanocytes cultured in the presence of said compound relative to control cultures not contacted with said compound.
  • This method will preferably be effected by obtaining human melanocytes, e.g., neonatal skin melanocytes, from a suitable source. These melanocytes are then seeded simultaneously into two cell culture chambers, e.g., a 96-well plate and a 24-well plate.
  • the respective wells are then incubated with a fixed amount of a particular compound or compounds, the effect of which on melanin expression is to be determined. Such incubation will be effected for a time period sufficient to -6- evaluate the effect, if any, of such compound or compounds on melanin production by such cultured melanocytes.
  • the incubation then will vary from about one minute to about one month, more preferably from about one hour to about two weeks, and most preferably from about 12 hours to one week.
  • the proliferation of cells in one of said cultures is then evaluated. This can be effected by suitable methods, e.g., by absorbence.
  • the cells in the 96-well plate are treated with 3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium (a tetrazolium dye conventionally used to colormetrically determine proliferation of cells) (MTS) and the absorbence of the plate read at 490 nm to determine the proliferation of cells in said 96-well plate.
  • MTS colormetrically determine proliferation of cells
  • the second culture e.g., a 24-well plate, containing a human melanocyte culture which has been incubated with the test compound under the same conditions, is then tested to determine the amount of melanin expressed by cells contained therein.
  • This can be effected by known methods. In the present invention, this will preferably be effected by washing such cells, e.g., with phosphate buffered saline (PBS), lysing said washed cells with an alkaline solution, e.g., with IN NaOH, and measuring the amount of alkali soluble melanin contained therein, e.g., by measuring absorbence of alkali soluble melanin at 405 nm.
  • PBS phosphate buffered saline
  • an alkaline solution e.g., with IN NaOH
  • This data is then preferably compared to a control melanocyte culture, grown under identical conditions but in the absence of said tested compound.
  • the data obtained from both melanocyte cell cultures is then normalized based on melanocyte proliferation (cell number) in order to determine the effect, -7- if any, of the particular compound or compounds on melanin production and accumulation of melanin by melanocytes.
  • Compounds which alter melanin expression according to the invention are those compounds which affect melanin production and accumulation in cultured human melanocytes.
  • such compound will alter melanin expression by at least 10% relative to control melanocyte cultures. More preferably, such compound will affect melanin production by at least 20%. Most preferably, the compound will affect melanin production and accumulation on the order of 150 to 250%, or greater. Therefore, the subject invention is directed to the identification of compounds or combinations thereof that increase or decrease melanin production and accumulation by human melanocytes.
  • Compounds which increase melanin production and accumulation can be used, e.g., to promote tanning or browning of skin, and to treat or prevent graying of hair.
  • Such compounds can be used to treat diseases or conditions associated with hypopigmentation, e.g., vitiligo.
  • Compounds which decrease melanin production can be utilized for treatment of subjects having diseases or conditions associated with hyperpigmentation.
  • diseases and conditions include melasma or age-related hyperpigmentation, and chloasma.
  • compounds which inhibit melanin production and/or accumulation may be used to treat and/or prevent hyperpigmentation associated with aging, e.g., "liver spots" often observed on the hands and face of older persons.
  • a list of disease and conditions associated with pigmentation disorders may be found in Dermatology in General Medicine (Fitzpatric, T. B., et al) which are incorporated by reference in their entirety herein.
  • the compounds of the present invention can be useful in the treatment of hypopigmentation afflications such as vitiligo, post-inflammatory -8- hypopigmentations or depigmentations, for the treatment of hypopigmentations or depigmentations after skin grafts, for the treatment of hypopigmentations or depigmentations due to overexposure to ultraviolet rays, for treating post- cicatrisation hypopigmentations or depigmentations, or for treating hypopigmentations or depigmentations due to aging or lentigo.
  • hypopigmentation afflications such as vitiligo, post-inflammatory -8- hypopigmentations or depigmentations
  • hypopigmentations or depigmentations after skin grafts for the treatment of hypopigmentations or depigmentations due to overexposure to ultraviolet rays
  • post- cicatrisation hypopigmentations or depigmentations for treating post- cicatrisation hypopigmentations or depigmentations due to aging or lentigo.
  • the subject assay can be used to identify combinations of compounds that affect (increase or decrease) melanin production or accumulation by human melanocytes, in particular combinations having synergistic effects on melanin production or accumulation.
  • the present invention is directed to pham aceutical/dermatological/cosmetic compounds that contain at least one melanin-affecting compound according to the invention.
  • a novel class of compounds has been discovered using the subject assay methods which promote melanin production and/or accumulation by normal human melanocytes. These compounds are advantageous also in that they are well tolerated and non-irritating to the skin. This is surprising because many other retinoid compounds screened using the subject assay did not affect pigmentation under similar conditions. These compounds are hypothesized to affect melanin production and/or accumulation via the retinoid signaling pathway.
  • the present invention provides pharmaceutical/cosmetic/dermatological compounds that comprise an amount of at least one substituted aromatic or heterocyclic carboxylic acid, or a derivative thereof, with the proviso that such carboxylic acid does not contain a phenol, naphthol, thiophenol, or thionaphthol function, in free or protected form.
  • Such -9- carboxylic acids include, by way of example, benzoic acid, propiolic acid, nicotinic acid, acrylic acid, butenoic acid and naphtoic acid.
  • the substituted aromatic or heterocyclic carboxylic acids of the present invention will display activity for RXRs.
  • a compound displaying RXR activity is a compound which exhibits a binding for RXR less than 5000 nM, and preferably less than 1000 nM.
  • the determination of the binding for RXRs is well known by those skilled in the art and is reported in, for example: (1) "Selective Synthetic Ligands for Nuclear Retinoic Acid Receptor Subtypes" in RETINOIDS, Progress in Research and Clinical Applications, Chapitre 10 (pp 261-267), Marcel Dekker Inc, published by Maria A.
  • the compound displaying activity for RXRs exhibits an agonsit activity for RXRs.
  • This agonist activity for RXRs may be determined for instance by the method reported in U.S. Patent No. 5,696,104, the entire contents of which are hereby incorporated by reference.
  • compounds which have been surprisingly discovered to promote melanin production and/or accumulation by human melanocytes according to the invention include: -10-
  • compositions will be in a form suitable for topical application to the skin and/or hair.
  • these compositions will be in a form suitable for artificial tanning and/or browning of the skin.
  • These compositions may comprise other pharmaceutically, cosmetically,
  • compositions typically formulated into these types of compositions, such as ionic or non-ionic thickeners, softeners, antioxidants, opacifiers, stabilizers, emollients, organic sunscreens which are active in the UN- A and/or UN-B region, photoprotective inorganic pigments, and non-pigments, moisturizers, vitamins, fragrances, preservatives, fillers, sequestering agents, dyestuffs, and colorants.
  • ionic or non-ionic thickeners such as ionic or non-ionic thickeners, softeners, antioxidants, opacifiers, stabilizers, emollients, organic sunscreens which are active in the UN- A and/or UN-B region, photoprotective inorganic pigments, and non-pigments, moisturizers, vitamins, fragrances, preservatives, fillers, sequestering agents, dyestuffs, and colorants.
  • compositions may comprise one or more compounds that affect melanin production and/or accumulation by melanocytes, e.g., synergistic combinations.
  • compositions may comprise other compounds which promote or inhibit pigmentation, e.g., dihydroxyacetone (DHA), or derivatives thereof.
  • DHA dihydroxyacetone
  • Suitable compounds are disclosed in U.S. Serial No. 08/819,084, filed March 18, 1997 by Tuloup et al, and assigned to L'OREAL.
  • MSH and analogs thereof which promote pigmentation may be included.
  • compounds which inhibit pigmentation such as HQ, monobenzene ether and arbutin may be included with compounds identified using the subject assay that inhibit pigmentation.
  • compositions will be in a form suitable for topical application to human skin and/or hair.
  • suitable forms include a cream, a milk, a cream-gel, -12- a fluid lotion, an oil-in-water emulsion or water-in-oil emulsion, a vesicle dispersion, or any other form typically employed in the art.
  • the amount of the at least one melanin-affecting compound contained in the subject compositions will typically range from about 0.0001% to about 30% by weight relative to the total weight of the composition, and preferably will range in concentration from about 0.5% to about 15% by weight relative to the total weight of the composition, and more preferably will range in concentration from about 0.001%) to 5% by weight relative to the total weight of the composition.
  • the present invention also encompasses a regimen of treatment, cosmetic, dermatological, or therapeutic, comprising topical application of an amount of a melanin-affecting compound according to the invention.
  • An effective amount is an amount sufficient to affect (increase or decrease) pigmentation of the skin and/or hair. Such regimen may be effected in conjunction with other compounds that affect pigmentation of the skin and/or hair. Such regimen can be effected repeatedly until the desired effect on pigmentation is achieved. Chronic administration should be suitable as the subject compounds are not irritating to the skin.
  • compositions which contain at least one compound according to the invention that are suitable for promoting coloration of the hair.
  • Such compositions may include other constituents typically included in hair formulations, e.g., conditioning agents, pigments and color ingredients, straighteners, permanents, surfactants, perfumes, alcohols, et seq.
  • Normal human melanocytes from neonatal skin were used for the assay.
  • the cells were seeded simultaneously into 96-well plates and 24-well plates appropriately according to the surface area of the wells, and treated with the test compound for 5 days.
  • the addition of the compound to the plates was done using a Robot to ensure accuracy (same amount in each well).
  • the cells in the 96-well plate were treated with MTS solution and the plate was read at 490 nm to determine the effect of the compounds on the growth of the cells.
  • the cells in the 24-well plates were rinsed with PBS, and then lysed with IN NaOH, and the absorbence of alkali soluble melanin was measured at 405 nm.
  • the data from the 96-well plate was analyzed to determine the effect of each compound on the proliferation of the cells, and the data from the 24-well plate was used to determine the effect of the compound on the melanin content of the cells. The melanin content was then normalized to the proliferation of the cells.
  • the inventors Using this method, the inventors have identified the following compounds that increase the melanin content of normal human melanocytes. It is anticipated, based on these results, that other compounds, e.g., retinoids, can be identified which alter (increase or decrease) melanin production by human melanocytes.
  • the inventors have identified a novel class of pro-pigmentory compounds for normal human melanocytes (increase melanin production thereby). It is hypothesized that these molecules may work through the retinoid signaling pathway.
  • the discovery of a class of retinoid-like molecules having pro-pigmentory activity is surprising especially because other retinoid signaling molecules do not induce pigmentation under similar conditions. This discovery is further advantageous because these compounds are very well tolerated, and are not irritating to the skin. Accordingly, they have potential application in altering pigmentation in skin and/or hair of human subjects. -15-
  • composition is prepared in the form of a 0.8 g tablet:
  • 1 to 3 tablets are given to an adult individual per day for three to six months depending on the severity of the case treated.
  • one vial is given to an adult individual per day for three months depending on the severity of the case treated.
  • the gelatin capsules used consist of gelatin, titanium oxide, and a preserving agent.
  • one gelatin capsule is given to an adult individual per day for 30 days.
  • a gel is prepared by making the following formulations:
  • Hydroxypropylcellulose sold by the company Hercules under the name "Klucel HF" 2.000 g Ethanol (95 °) qs 100.000 g
  • This gel is applied to a hypopigmented grafted skin one to three times a day for six to twelve weeks depending on the severity of the case treated. -17-
  • a lotion is prepared for correcting post-inflammatory hypopigmentation by mixing together the following ingredients:
  • This lotion is applied twice a day and a significant improvement is observed within a period of two to six weeks.
  • a cosmetic composition to combat the harmful effects of sunlight is prepared by mixing together the following ingredients:
  • Demineralized water qs 100.000 g This composition is applied daily and makes it possible to combat light- inducing aging.
  • (e) The following non-ionic oil-in-water cream is prepared:
  • Vitamin D3 0.020 g -18-
  • Glyceryl monostearate 2.500 g
  • This cream is applied to a skin affected with vitiligo once or twice a day for thirty days.
  • a topical gel is prepared by mixing together the following ingredients:
  • Carboxyvinyl polymer sold under the name Carbopol 941® by
  • Triethanolamine as a 20% by weight aqueous solution 3.800 g
  • a hair lotion for repigmenting the hair is prepared by mixing together the following ingredients:
  • Polyethylene glycol (molecular mass — 400) 40.00 g
  • a post-cicatrization cream is prepared by mixing together the following ingredients:
  • Disodium salt of ethylenediamine- tetraacetic acid 0.050 g
  • Purified water qs 100.000 g -20-
  • This cream is applied one to three times a day for six to twelve weeks.
  • An oil-in-water cream is prepared by making the following formulation:
  • Miglyol 812® Mixture of caprylic/capric triglycerides sold under the name Miglyol 812® by
  • Triethanolamine (99% by weight) 2.500 g
  • Perhydrosqualene 18.000 g Mixture of caprylic/capric triglycerides sold under the name Miglyol 812® by "Dynamit Nobel” 4.000 g
  • This lotion is applied to the scalp once or twice a day at a rate of 1 ml per application.
  • Hydroxypropylcellulose (Klucel G® from Hercules) 3.500 g
  • This thickened lotion is applied to the scalp once or twice a day at a rate of
  • Niosomal lotion Chimexane ML® 0.475 g
  • Propylene glycol monomethyl ether (Dowanol PM® from Dow Chemical) 20.000 g -23-
  • Hydroxypropylcellulose (Klucel G® from Hercules) 3.000 g
  • This thickened lotion is applied to the scalp once or twice a day at a rate of

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un dosage in vitro permettant de sélectionner des composés modifiant la pigmentation de la peau. L'invention concerne également une nouvelle catégorie de composés pro-pigmentaires comprenant des acides carboxyliques hétérocycliques ou aromatiques substitués, des dérivés de ceux-ci, ou des sels pharmaceutiquement acceptables, lesquels composés ne renferment pas de fonction phénol, naphtol, thiophénol, ou thionaphtol sous forme libre ou protégée. Selon un mode de réalisation préféré, ces composés présentent une activité vis-à-vis des récepteurs RXR. Ces composés peuvent être utilisés dans des compositions cosmétiques ou dermatologiques destinées à modifier la pigmentation de la peau et/ou les cheveux de l'homme, ainsi que pour traiter des troubles et des états pathologiques ayant une incidence sur la pigmentation de la peau et des cheveux.
PCT/US1999/009845 1998-05-06 1999-05-06 Dosage d'identification de composes favorisant la production de melanine, et composes de type retinoide identifies par ce dosage WO1999056740A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU38829/99A AU762364B2 (en) 1998-05-06 1999-05-06 Assay for identification of compounds that promote melanin production and retinoid-like compounds identified by said assay
IL13877299A IL138772A0 (en) 1998-05-06 1999-05-06 Assay for identification of compounds that promote melanin production and retinoid-like compounds identified by said assay
JP2000546767A JP3669925B2 (ja) 1998-05-06 1999-05-06 メラニン産生を促進する化合物を同定するためのアッセイおよび当該アッセイにより同定されたレチノイド様化合物
CA002324001A CA2324001C (fr) 1998-05-06 1999-05-06 Composes de type retinoide pour la promotion de la production de melanine
EP99921689A EP1082111A4 (fr) 1998-05-06 1999-05-06 Dosage d'identification de composes favorisant la production de melanine, et composes de type retinoide identifies par ce dosage
BR9909599-8A BR9909599A (pt) 1998-05-06 1999-05-06 Método cosmético, dermatológico e/ou terapêutico para alterar (promover ou inibir) a pigmentação da pele e/ou dos cabelos de um ser humano, composição farmacêutica/cosmética/dermatológica que altera a pigmentação da pele e/ou dos cabelos humanos com aplicação tópica e método in vitro para selecionar composto ou combinação de composto que alteram (aumentam ou diminuem) a pigmentação da pele e/ou dos cabelos humanos
NO20004723A NO20004723L (no) 1998-05-06 2000-09-21 Analyse for identifikasjon av forbindelser som fremmer melaninproduksjon og retinoid-liknende forbindelser identifisert ved nevnte analyse

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US8447898P 1998-05-06 1998-05-06
US60/084,478 1998-05-06

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US10/346,054 Continuation US20030113281A1 (en) 1998-05-06 2003-01-17 Assay for identification of compounds that promote melanin production and retinoid-like compounds identified by said assay

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EP (1) EP1082111A4 (fr)
JP (1) JP3669925B2 (fr)
KR (1) KR100538417B1 (fr)
CN (1) CN1247192C (fr)
AR (1) AR018340A1 (fr)
AU (1) AU762364B2 (fr)
BR (1) BR9909599A (fr)
CA (1) CA2324001C (fr)
ID (1) ID26632A (fr)
IL (1) IL138772A0 (fr)
NO (1) NO20004723L (fr)
WO (1) WO1999056740A1 (fr)
ZA (1) ZA200005026B (fr)

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EP1059082A1 (fr) * 1999-06-11 2000-12-13 Basf Aktiengesellschaft Utilisation de vinyltetrahydrohydronaphthalènes et vinylbenzotetrahydropyrannes substituées comme filtres solaires
FR2831439A1 (fr) * 2002-02-14 2003-05-02 Oreal Composition comprenant au moins un autobronzant et au moins un compose activteur de la melanogenese
WO2006088310A1 (fr) * 2005-02-15 2006-08-24 Stiefel Laboratories Korea Composition pharmaceutique contenant un retinoide dans la prevention et le traitement du vitiligo
WO2008025965A3 (fr) * 2006-08-29 2008-10-02 Reinnervate Ltd Composés rétinoïdes et leur utilisation
WO2008121850A3 (fr) * 2007-03-30 2008-11-27 Univ Rochester Modulateurs de type petite molécule, de l'expression de la mélanine
US7604949B2 (en) 1999-06-29 2009-10-20 New York University Methods and compositions that affect melanogenesis
WO2013040227A3 (fr) * 2011-09-15 2013-07-25 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of Arizona State University Composés thérapeutiques
US10231947B2 (en) 2017-01-23 2019-03-19 Arizona Board Of Regents On Behalf Of Arizona State University Isochroman compounds and methods of use thereof
US10238655B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Dihydroindene and tetrahydronaphthalene compounds
US10238626B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
WO2019110212A1 (fr) * 2017-12-06 2019-06-13 Unilever N.V. Composition d'assombrissement de la peau
US10328040B2 (en) 2014-01-17 2019-06-25 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic methods
US11433012B2 (en) 2017-11-14 2022-09-06 Conopco, Inc. Peptides for increasing melanin in melanocytes

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JP4303616B2 (ja) * 2004-03-01 2009-07-29 花王株式会社 メラノソーム転送の検出法
SG10202102348YA (en) * 2016-09-08 2021-04-29 Agency Science Tech & Res Use of polyamines in compositions and methods for inducing or promoting skin darkening and regulating melanogenesis

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US5696104A (en) * 1995-06-19 1997-12-09 Centre International De Recherches Dermatologiques Galderma Process for identifying RXR-receptor-agonist compounds
US5824685A (en) * 1995-02-01 1998-10-20 The Johns Hopkins University School Of Medicine Method of preventing proliferation of retinal pigment epithelium by retinoic acid receptor agonists

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FR2735367B1 (fr) * 1995-06-19 1997-07-18 Cird Galderma Utilisation de ligands specifiques des recepteurs rxrs
WO1997000892A2 (fr) * 1995-06-23 1997-01-09 The Government Of The United States Of America, Represented By The Secretary Department Of Health And Human Services Activite de depigmentation de la proteine-signal d'agouti et ses peptides
FR2746101B1 (fr) * 1996-03-14 1998-04-30 Composes bicycliques-aromatiques
CA2250000C (fr) * 1996-03-28 2010-06-15 Trustees Of Boston University Techniques de modulation de la synthese de la melanine
FR2755965B1 (fr) * 1996-11-19 1998-12-18 Cird Galderma Composes biaromatiques, compositions pharmaceutiques et cosmetiques les contenant et utilisations

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US5470577A (en) * 1993-07-07 1995-11-28 Trustees Of Boston University Stimulation of tanning by DNA fragments or single-stranded DNA
US5824685A (en) * 1995-02-01 1998-10-20 The Johns Hopkins University School Of Medicine Method of preventing proliferation of retinal pigment epithelium by retinoic acid receptor agonists
US5696104A (en) * 1995-06-19 1997-12-09 Centre International De Recherches Dermatologiques Galderma Process for identifying RXR-receptor-agonist compounds

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1059082A1 (fr) * 1999-06-11 2000-12-13 Basf Aktiengesellschaft Utilisation de vinyltetrahydrohydronaphthalènes et vinylbenzotetrahydropyrannes substituées comme filtres solaires
US7604949B2 (en) 1999-06-29 2009-10-20 New York University Methods and compositions that affect melanogenesis
FR2831439A1 (fr) * 2002-02-14 2003-05-02 Oreal Composition comprenant au moins un autobronzant et au moins un compose activteur de la melanogenese
WO2006088310A1 (fr) * 2005-02-15 2006-08-24 Stiefel Laboratories Korea Composition pharmaceutique contenant un retinoide dans la prevention et le traitement du vitiligo
US8293803B2 (en) 2006-08-29 2012-10-23 Reinnervate Limited Retinoid compounds and their use
WO2008025965A3 (fr) * 2006-08-29 2008-10-02 Reinnervate Ltd Composés rétinoïdes et leur utilisation
US9162984B2 (en) 2007-03-30 2015-10-20 University Of Rochester Small-molecule modulators of melanin expression
WO2008121850A3 (fr) * 2007-03-30 2008-11-27 Univ Rochester Modulateurs de type petite molécule, de l'expression de la mélanine
WO2013040227A3 (fr) * 2011-09-15 2013-07-25 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of Arizona State University Composés thérapeutiques
AU2012308582B2 (en) * 2011-09-15 2016-11-24 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of Arizona State University Therapeutic compounds
US9573906B2 (en) 2011-09-15 2017-02-21 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona Acting For And On Behalf Of Arizona State University Therapeutic compounds
US10391093B2 (en) 2011-09-15 2019-08-27 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University Therapeutic compounds
US10328040B2 (en) 2014-01-17 2019-06-25 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic methods
US10231947B2 (en) 2017-01-23 2019-03-19 Arizona Board Of Regents On Behalf Of Arizona State University Isochroman compounds and methods of use thereof
US10238655B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Dihydroindene and tetrahydronaphthalene compounds
US10238626B2 (en) 2017-01-23 2019-03-26 Arizona Board Of Regents On Behalf Of Arizona State University Therapeutic compounds
US11433012B2 (en) 2017-11-14 2022-09-06 Conopco, Inc. Peptides for increasing melanin in melanocytes
WO2019110212A1 (fr) * 2017-12-06 2019-06-13 Unilever N.V. Composition d'assombrissement de la peau
US11419803B2 (en) 2017-12-06 2022-08-23 Conopco, Inc. Skin darkening composition

Also Published As

Publication number Publication date
EP1082111A4 (fr) 2004-03-10
JP3669925B2 (ja) 2005-07-13
CA2324001C (fr) 2007-08-07
CA2324001A1 (fr) 1999-11-11
AU3882999A (en) 1999-11-23
JP2002513756A (ja) 2002-05-14
IL138772A0 (en) 2001-10-31
AU762364B2 (en) 2003-06-26
AR018340A1 (es) 2001-11-14
EP1082111A1 (fr) 2001-03-14
NO20004723L (no) 2000-11-06
ID26632A (id) 2001-01-25
ZA200005026B (en) 2001-05-22
KR100538417B1 (ko) 2005-12-22
CN1247192C (zh) 2006-03-29
CN1299274A (zh) 2001-06-13
BR9909599A (pt) 2001-09-25
NO20004723D0 (no) 2000-09-21
KR20010043147A (ko) 2001-05-25

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