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WO2019009627A1 - Composition pour le blanchiment de la peau - Google Patents

Composition pour le blanchiment de la peau Download PDF

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Publication number
WO2019009627A1
WO2019009627A1 PCT/KR2018/007597 KR2018007597W WO2019009627A1 WO 2019009627 A1 WO2019009627 A1 WO 2019009627A1 KR 2018007597 W KR2018007597 W KR 2018007597W WO 2019009627 A1 WO2019009627 A1 WO 2019009627A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
melanin
skin whitening
tyrosinase
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PCT/KR2018/007597
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English (en)
Korean (ko)
Inventor
배명애
양정윤
황규석
신대섭
Original Assignee
한국화학연구원
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Publication of WO2019009627A1 publication Critical patent/WO2019009627A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic 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
    • 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
    • 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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat

Definitions

  • the present invention relates to a composition for whitening skin.
  • the skin whitening composition includes a skin whitening pharmaceutical composition, a skin whitening cosmetic composition, and a skin whitening health functional health functional food.
  • Melanin Human skin color is largely determined by melanin, hemoglobin, carotene, etc. Melanin plays the most important role. Melanin is a black pigment found in animals, plants and microorganisms. It is not essential for growth or development, but it is a substance that enhances the survival and competitiveness of the environment. Melanin is a stable pigment among the pigments found in organisms and does not dissolve in almost all solvents and the process of melanogenesis occurs in melanosomes, the organelles of specially differentiated cells, melanocytes . In other words, the skin color is determined by the content and distribution of melanin, and is related to the number and distribution of melanosomes released into the outside of the cell after being produced in melanocytes. Melanin protects skin from ultraviolet light (J. Drugs Dermatol., 2004, 3, 668-678). However, it is known that hyperpigmentation and melanomas such as spots and freckles are caused by excessive production.
  • the in vivo synthesis process of melanin is as follows. Melanocyte Melanocyte Melanocyte Melanocyte Melosis Melanocyte Melanocyte Melanosome Melanosome Melanocyte (tyrosinase) by the enzyme tyrosine (Tyrosine) as a substrate Dopa (DOPA), Dopaquinone (DOPA quinone) through the wave DOPA chrome), and melanin is produced as a copolymer. The resulting melanin is transferred to the keratinocyte through the bag of melanomas and is brought up to the skin surface through a keratinocyte keratinization process for 28 days.
  • DOPA Dopa
  • DOPA quinone Dopaquinone
  • melanin is produced as a copolymer.
  • the resulting melanin is transferred to the keratinocyte through the bag of melanomas and is brought up to the skin surface through a keratinocyte keratinization process for 28 days.
  • melanin is overproduced by a factor promoting melanin production, and the period of keratinization process becomes physiologically long, so that melanin is not lost in the skin together with keratin, and pigmentation phenomenon appears. Therefore, it can be suppressed by controlling some processes in the melanin production process to prevent such pigment deposition phenomenon.
  • tyrosinase (EC 1.14.18.1) converts tyrosine to the key precursor of melanin biosynthesis (DOPA Quinone) as the most important enzyme of melanin biosynthesis in plants, microbes, and mammalian cells.
  • the enzyme has a monophenolase function to convert L-tyrosine to DOPA (3,4-dihydroxyphenylalanine) and a diphenolase (DOPA) to convert L-dopa to L-dopaquinone diphenolase function (J. Appl. Microbiol., 2006, 100, 219-232; Int. J. Biochem. Cell Biol., 2004, 36, 235-246).
  • DOPA diphenolase
  • the dopaquinone created here is automatically converted to melanin without the aid of enzymatic action. Therefore, inhibition of the activity of tyrosinase inhibits melanin biosynthesis.
  • Typical inhibition of melanin synthesis inhibits the activity of tyrosinase, an important enzyme of melanin synthesis.
  • Representative components that are commercialized include chelates such as kojic acid, which inhibit the activity of tyrosinase having copper ion as an active site chelator, and arbutin, which are similar to tyrosine as a tyrosinase substrate, are used in combination with tyrosinase and tyrosine to inhibit the production of melanin, which is also widely used as a pigment inhibitor .
  • chelates such as kojic acid, which inhibit the activity of tyrosinase having copper ion as an active site chelator
  • arbutin which are similar to tyrosine as a tyrosinase substrate, are used in combination with tyrosinase and tyrosine to inhibit the production of melanin, which is also widely used as a pigment inhibitor .
  • compositions for whitening skin are Korean Patent No. 266740, which discloses extracts of three or more natural substances selected from among propolis, blueberry, camellia, tosaja, japonica, Korean Patent No. 406124 discloses kojic acid or its derivative which inhibits tyrosinase in melanocytes of skin, arbutin or its derivative, melanin, (3-aminopropane phosphoric acid) -L-ascorbate), albutin, mulberry extract, and ascorbyl 3-aminopropyl phosphate (L-ascorbate) Rubus coreanum leaf or fruit extract which reduces the amount of substance prostaglandin, Rubus idaeus leaf or fruit A whitening cosmetic composition which improves the whitening function without adding skin irritation by adding at least one selected from the group consisting of an extract, a Vitisvinifera stem extract and a Cola nitida leaf extract.
  • Japanese Patent No. 266740 and Japanese Patent No. 406124 disclose a natural whitening agent for exhibiting a whitening effect, but the whitening agent is a mixture of various natural products, and it is difficult to confirm which extract has a whitening effect, The whitening agent has a problem that it is difficult to expect a sufficient whitening effect even with a small amount of use, which is disadvantageous in that it is used in an excessive amount.
  • the composition for skin whitening according to the present invention is excellent in the inhibitory effect of tyrosinase activity and has an excellent effect of inhibiting melanin synthesis and exhibits skin whitening effect and thus can be usefully used as a skin whitening composition
  • Another object of the present invention is to provide a cosmetic composition for skin whitening.
  • the present invention provides a pharmaceutical composition for skin whitening comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • A is S, NH or O
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or C 1-10 alkyl of straight chain or side chain.
  • the present invention also provides a cosmetic composition for skin whitening comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • A is S, NH or O
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or C 1-10 alkyl of straight chain or side chain.
  • the present invention provides a health functional food for skin whitening comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • A is S, NH or O
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or C 1-10 alkyl of straight chain or side chain.
  • the composition for skin whitening according to the present invention suppresses the expression of proteins associated with melanin production and inhibits the activity of tyrosinase even when a small amount is used, so that it has an excellent effect of inhibiting the production of melanin, , And is excellent in inhibiting pigment deposition. Therefore, it can be effectively used as a composition for skin whitening, specifically, a pharmaceutical composition for skin whitening, a cosmetic composition for skin whitening, and a health functional food for skin whitening.
  • FIG. 1 is an image showing the effect of inhibiting melanin synthesis in a zebrafish-generated embryo of a compound (compound of Example 1) which is excellent in the effect of suppressing melanin synthesis performed in the screening method 1 described above.
  • FIG. 2 is an image of the melanin synthesis-inhibiting compound (compound of Example 1) performed in the above screening method 2, and then the melanin synthesis recovery ability in the zebrafish-generated embryo was photographed.
  • FIG. 3 is a graph showing the results of the evaluation of the amount of melanin performed in the screening method 3.
  • FIG. 5 is a graph showing the results of evaluation of tyrosinase inhibitory activity in HMV-II cells performed in Experimental Example 2 according to the present invention.
  • FIG. 6 is a graph showing the results of evaluation of inhibition of melanin biosynthesis in HMV-II cells performed in Experimental Example 2 according to the present invention.
  • FIG. 7 is a graph showing the amount of melanin-forming protein expressed by the compound of Example 1 in Experimental Example 4 according to the present invention by western blotting.
  • FIG. 8 is a graph showing the expression levels of melanin-related proteins expressed by the compound of Example 1 in Experimental Example 4 according to the present invention.
  • Figure 8a Graph showing the amount of expression of MITF by the treatment of the compound of Example 1
  • Figure 8b Graph of measurement of tyrosinase expression level by compound 1 treatment of Example 1
  • Fig. 8d Measurement of TRP-2 expression level by the treatment of the compound of Example 1
  • FIG. 9 is a graph showing the expression levels of genes related to melanin formation by the treatment of the compound of Example 1 in Experimental Example 5 according to the present invention.
  • FIG. 9a Graph of gene expression amount of MITF by treatment of compound of Example 1
  • Figure 9b Graph of expression of tyrosinase gene expression by compound 1 treatment of Example 1
  • FIG. 9d is a graph showing the amount of TRP-2 gene expression measured by the compound of Example 1
  • the skin whitening composition according to the present invention includes a skin whitening pharmaceutical composition, a skin whitening cosmetic composition, and a skin whitening health functional food.
  • the present invention provides a pharmaceutical composition for skin whitening comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • A is S, NH or O
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or C 1-10 alkyl of straight chain or side chain.
  • A may be S.
  • the A may be NH.
  • the A may be O.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or straight or branched C 1-6 alkyl.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or straight or branched C 1-3 alkyl.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen.
  • the pharmaceutical composition for skin whitening represented by Chemical Formula (1) according to the present invention is a protein for producing a precursor which is necessary for the production of melanin by using a small amount of tyrosinase, TRP 1, TRP 2 Tyrosinase-related protein 2) or MITF (Microphthalmia-associated transcription factor), and the effect of inhibiting the production of melanin is also excellent (Example 1, Experimental Examples 1-5 and Figures 1-9)
  • the compound represented by the formula (1) according to the present invention inhibits the expression of proteins associated with melanin production and inhibits the activity of tyrosinase even when a small amount is used, so that the effect of inhibiting the production of melanin is excellent, And is excellent in inhibiting the pigment deposition, so that it can be usefully used as a pharmaceutical composition for skin whitening.
  • the compound represented by the formula (1) can be used in the form of a pharmaceutically acceptable salt.
  • an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, And organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like are obtained from non-toxic organic acids such as dicarboxylic acids, Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound represented by the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, The precipitate may be filtered and dried, or the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like
  • bases can be used to make pharmaceutically acceptable metal salts.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt.
  • the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
  • the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be administered orally or parenterally in various formulations at the time of clinical administration. More preferably, Lt; / RTI >
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like.
  • excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate.
  • the present invention can also provide a formulation for external skin preparation for skin whitening effect comprising the compound of Formula 1 as an active ingredient.
  • the compound of formula (1) when used as an external preparation for skin, it may further comprise at least one selected from the group consisting of fatty substances, organic solvents, solubilizers, thickeners and gelling agents, softeners, antioxidants, suspending agents, stabilizers, foaming agents, , Water, ionic or nonionic emulsifiers, fillers, sequestering agents and chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or external preparations for skin And any other ingredients used in the skin sciences.
  • the components can also be introduced in amounts commonly used in the field of dermatology.
  • the compound of Formula 1 when provided as an external preparation for skin, it may have a formulation such as, but not limited to, ointments, patches, gels, creams or sprays.
  • the pharmaceutical composition of the present invention is particularly preferably used as a parenteral preparation.
  • the external preparation for skin may be a pharmaceutically acceptable base such as vaseline or stearyl alcohol; Suitable pharmaceutically acceptable surfactants such as polysorbate, sorbitan sesquioleate, and the like; A suitable pharmaceutically acceptable humectant such as glycerin; A suitable pharmaceutically acceptable solvent; And a conventional external preparation for skin preparation in which a flavoring agent, a coloring agent, a stabilizer, a tackifier and the like are homogeneously mixed.
  • the compound of Chemical Formula 1 of the present invention when used as a medicine, it may further contain one or more active ingredients showing the same or similar functions.
  • a known skin whitening component may be included.
  • the addition of an additional skin whitening ingredient may further enhance the skin whitening effect of the composition of the present invention.
  • the composition is a whitening ingredient known in the art and includes a substance inhibiting tyrosinase enzyme activity such as kojic acid, arbutin, etc., hydroquinone, vitamin C (L-Ascorbic acid); And derivatives thereof, and various plant extracts. ≪ Desc / Clms Page number 2 >
  • the additional component may be included in an amount of 0.0001 to 10% by weight based on the total weight of the composition, and the content range may be adjusted according to requirements such as skin safety, ease of formulation of the compound of Formula 1 .
  • the pharmaceutical composition of the present invention can provide a desired skin whitening effect when an effective amount of the compound of Formula 1 is included.
  • the term "effective amount” means the amount of a compound capable of exhibiting a skin whitening effect.
  • an effective amount of the compound of formula (1) contained in the composition of the present invention will vary depending on the form in which the composition is commercialized, how the compound is applied to the skin, and the time on the skin.
  • the compound of Formula 1 may be contained at a higher concentration than that of a cosmetic product that is routinely applied to skin. Accordingly, the daily dosage is 0.1 to 100 mg / kg, preferably 30 to 80 mg / kg, more preferably 50 to 60 mg / kg, based on the amount of the compound of formula (1) 6 times a day.
  • formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols).
  • the tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.
  • the present invention also provides a cosmetic composition for skin whitening comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • A is S, NH or O
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or C 1-10 alkyl of straight chain or side chain.
  • A may be S.
  • the A may be NH.
  • the A may be O.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or straight or branched C 1-6 alkyl.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or straight or branched C 1-3 alkyl.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen.
  • the melanin production inhibitory activity, tyrosinase activity inhibiting activity, and melanin formation-related protein expression inhibiting activity were measured,
  • the cosmetic composition for skin whitening represented by Chemical Formula (1) according to the present invention is characterized in that it comprises proteins such as tyrosinase, tyrosinase-related protein 1 (TRP 1), and tyrosinase (TRP 2) that produce a precursor required for the production of melanin, -related protein 2) or MITF (Microphthalmia-associated transcription factor), and has an excellent effect of suppressing the production of melanin (Example 1, Experimental Example 1-5 and Fig. 1 -9)
  • proteins such as tyrosinase, tyrosinase-related protein 1 (TRP 1), and tyrosinase (TRP 2) that produce a precursor required for the production of melanin, -related protein 2) or MITF (Microphthalmia-associated transcription factor), and has an excellent effect of suppressing the production of melanin (Example 1, Experimental Example 1-5 and Fig. 1 -9)
  • the compound represented by the formula (1) according to the present invention inhibits the expression of proteins associated with melanin production and inhibits the activity of tyrosinase even when a small amount is used, so that the effect of inhibiting the production of melanin is excellent, And is excellent in inhibiting the pigment deposition, so that it can be usefully used as a cosmetic composition for skin whitening.
  • the cosmetic composition for skin whitening represented by the formula (1) of the present invention 3 to 30 parts by weight of the compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof is added to the whitening cosmetic composition, , Preferably 5 or 20 parts by weight.
  • the cosmetic composition of the present invention may further contain, in addition to the compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof, a lipid, an organic solvent, a solubilizing agent, a thickening agent and a gelling agent, a softening agent, Stabilizers, foaming agents, fragrances, surfactants, water, ionic or nonionic emulsifiers, fillers, sequestering and chelating agents, preservatives, vitamins, barrier agents, wetting agents, essential oils, dyes, pigments, A lipid vesicle, or any other ingredient conventionally used in cosmetic compositions for skin whitening, which are commonly used in the skin science field.
  • the components can be introduced in amounts commonly used in the dermatology field.
  • the cosmetic composition for skin whitening according to the present invention can be used as a skin whitening cosmetic composition in the form of a solution, an external ointment, a cream, a foam, a nutritional lotion, a softening longevity pack, a pack, May be formulated into a formulation selected from the group consisting of solid oils, suspensions, emulsions, pastes, gels, lotions, powders, soaps, surfactant-containing cleansing, oils, powder foundations, emulsion foundations, wax foundations, patches and sprays But is not limited thereto.
  • the cosmetic composition of the present invention may further comprise at least one cosmetically acceptable carrier incorporated in a cosmetic composition for general skin, and examples thereof include oil, water, a surfactant, a moisturizer, a lower alcohol, A thickening agent, a chelating agent, a coloring matter, an antiseptic, a perfume, and the like may be appropriately compounded, but the present invention is not limited thereto.
  • the cosmetically acceptable carrier to be contained in the cosmetic composition of the present invention varies depending on the formulations.
  • the carrier component may be an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide Mixtures of these may be used.
  • lactose When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder or a mixture thereof may be used as the carrier component, Propellants such as fluorohydrocarbons, propane / butane or dimethyl ether.
  • a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl benzoate, -Butyl glycol oil, and in particular fatty acid esters of cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.
  • the formulation of the present invention is a suspension
  • a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
  • the formulation of the present invention is a soap
  • alkali metal salts of fatty acids fatty acid hemiesters, fatty acid protein hydrolizates, isethionates, lanolin derivatives, aliphatic alcohols, vegetable oils, glycerol, sugars and the like are used as carrier components .
  • the present invention also provides a method of skin whitening comprising the step of applying the compound of formula 1 to the skin of a subject.
  • the subject includes, without limitation, mammals including rats, livestock, humans, and the like.
  • the present invention provides a health functional food for skin whitening comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • A is S, NH or O
  • R 1 , R 3 , R 4 , R 5 , R 6 R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or C 1-10 alkyl of straight chain or side chain.
  • A may be S.
  • the A may be NH.
  • the A may be O.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or straight or branched C 1-6 alkyl.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen or straight or branched C 1-3 alkyl.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen.
  • health functional food refers to a food prepared by adding the compound of Formula 1 to food materials such as beverage, tea, spices, gum, confectionery, etc., encapsulation, powdering, suspension, etc., But it has the advantage that there are no side effects that can occur when a drug is taken for a long time using a food as a raw material, unlike a general medicine.
  • the health functional food of the present invention thus obtained can be ingested on a daily basis, so that a high skin whitening effect can be expected, which is very useful.
  • the compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof can be used as it is in food or can be used together with other food or food ingredients, and can be suitably used according to a conventional method.
  • the amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health functional food may be 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
  • the health functional beverage composition of the present invention has no particular limitation on other components other than the above-mentioned compounds as essential components in the indicated ratios, and may contain various flavoring agents or natural carbohydrates as additional components such as ordinary beverages have.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • Natural flavors can be advantageously used as flavors other than those described above
  • the ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
  • the compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof may be in the form of a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), a preparation flavoring agent and a natural flavoring agent, Cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols and carbonating agents used in carbonated beverages.
  • the compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.
  • composition for skin whitening according to the present invention can be used as a skin whitening composition which is a combination of proteins such as tyrosinase, tyrosinase-related protein 1 (TRP 1), tyrosinase-related protein 2 (TRP 2) It has an effect of inhibiting the production of MITF (Microphthalmia-associated transcription factor) and ultimately has an effect of inhibiting the production of melanin.
  • MITF Microphthalmia-associated transcription factor
  • the composition for skin whitening according to the present invention suppresses the expression of proteins associated with melanin production and inhibits the activity of tyrosinase even when a small amount is used, so that the composition exerts an effect of suppressing the production of melanin, And is excellent in inhibiting pigment deposition, so that it can be usefully used as a composition for skin whitening, more specifically, a pharmaceutical composition for skin whitening, a cosmetic composition for skin whitening, and a health functional food for skin whitening.
  • Melanin synthesis in zebrafish melanocytes is known to have the same mechanism among vertebrates. Melanin synthesis and melanocyte formation begin from 24 hours after fertilization and black melanocytes can be observed through a dissecting microscope.
  • the breeding equipment used was a LEICA MZ10F fluorescence microscope, LEICA DFC425 camera and Leica Application Suite software (v4.5).
  • egg water was used to dissolve 60 mg / L sea salt (Sigma-Aldrich, S9883) in the third distilled water.
  • Control groups were untreated control, solvent control (0.4% DMSO), and phenylthiourea (200 ⁇ M PTU) known as tyrosinase inhibitor. An image photographed in Fig. 1 is shown.
  • Fig. 1 is an image showing the effect of inhibiting melanin synthesis in a zebrafish-generated embryo of a compound (compound of Example 1 below) that is excellent in the effect of suppressing melanin synthesis performed in the screening method 1 described above.
  • FIG. 2 is an image of the melanin synthesis-inhibiting compound (compound of Example 1) performed in the above screening method 2, and then the melanin synthesis recovery ability in the zebrafish-generated embryo was photographed.
  • FIG. 3 is a graph showing the results of the evaluation of the amount of melanin performed in the screening method 3.
  • the compound of Example 1 according to the present invention had an excellent melanin synthesis inhibitory effect.
  • the compound of Example 1 of the present invention can inhibit the synthesis of melanin in a similar manner to that of PTU, even when treated with less than 10, 20 and 40 ⁇ M of PTU, compared with 200 ⁇ M of PTU .
  • the compound of Example 1 according to the present invention has excellent ability to inhibit melanin synthesis.
  • the compound of Example 1 of the present invention Showed that melanin synthesis inhibition similar to that of PTU was confirmed by confirming that the amount of melanin was reduced similarly to that of PTU even when 10, 20, and 40 ⁇ M were treated at a smaller amount.
  • the compound derived from the above screening is a compound represented by the formula (A) shown in the following Example 1.
  • Tyrosinase is an enzyme involved in determining the most important initial rate in the melanin biosynthetic pathway in the human body. Many whitening ingredients inhibit the enzyme. This test is a method for evaluating the degree of inhibition of the activity of tyrosinase enzyme in vitro.
  • the compound of Example 1 according to the present invention had an excellent ability to inhibit tyrosinase activity, and in particular, the compound of Example 1 of the present invention Suggesting that treatment with smaller amounts of 10, 20 and 40 ⁇ M inhibits tyrosinase activity similar to that of PTU.
  • Tyrosinase is an enzyme involved in determining the most important initial rate in the melanin biosynthetic pathway in the human body. Many whitening ingredients inhibit the enzyme.
  • Experimental Example 2 was carried out to evaluate the expression and inhibition of tyrosinase enzyme.
  • the cell line used in this experiment is human malignant melanoma cell line HMV-II (human malignant melanoma, Sigma-aldrich).
  • HMV-II cells were cultured in DME / F-12 medium supplemented with 10% FBS (Fetal Bovine Serum) and 100 ⁇ g / mL of antibiotics. The cells were cultured in a humidified incubator at 37 ° C, 5% CO 2 . Cells were washed 2-3 times with PBS (Phosphate Buffer Solution) at 70-80% of culture dishes and subcultured with Trypsin-EDTA (Gibco, USA).
  • PBS Phosphate Buffer Solution
  • the tyrosinase activity of the HMV-II cell line was inoculated at 2 x 10 4 cells / well, and then 100 ⁇ M of each of Arbutin and Kojic acid was used as a positive control. , 5, 10 ⁇ M) and cultured for up to 10 days. After washing with PBS, the cells were dissolved in PBS containing 0.1% Triton X-100. After centrifugation at 1000 rpm for 5 minutes, the supernatant was used as the active enzyme solution. In 96 wells, 10 mM L-dopa was reacted with the substrate and enzyme solution at 37 ° C for 3 hours, and the absorbance was measured at 405 nm. The results are shown in Fig.
  • FIG. 5 is a graph showing the results of evaluation of tyrosinase inhibitory activity in HMV-II cells performed in Experimental Example 2 according to the present invention.
  • the compound of Example 1 according to the present invention is excellent in the ability to inhibit tyrosinase activity, and in particular, compared to albutine and cochinear acid, which are well known as inhibitors of tyrosinase, 1 shows a superior ability to inhibit tyrosinase activity even when a significantly smaller amount of the compound is treated.
  • HMV-II cells The melanin production of HMV-II cells was measured by inoculating cells at 1 ⁇ 10 5 cells / well and incubated with samples (positive control, Arbutin, Kojic acid; 100 ⁇ M, compound of Example 1; ) And cultured for up to 10 days. After washing with PBS, the cells were dissolved in PBS containing 0.1% Triton X-100. After dissolving in 1 N NaOH at 80 ° C for 2 hours, absorbance was measured at 405 nm. The results are shown in Fig.
  • FIG. 6 is a graph showing the results of evaluation of inhibition of melanin biosynthesis in HMV-II cells performed in Experimental Example 2 according to the present invention.
  • the compound of Example 1 according to the present invention is excellent in the ability to inhibit melanin biosynthesis, and in particular, compared to arbutin and coric acid, which are well known as inhibitors of tyrosinase, 1 shows a superior ability to inhibit melanin biosynthesis even when a significantly smaller amount of the compound is treated.
  • Example 1 In order to analyze the degree of expression of the melanin-related protein according to the compound treatment of Example 1 according to the present invention, the following experiment was performed through Western blotting.
  • Human-derived malignant melanoma HMV-II cells were seeded at 5 ⁇ 10 5 on 100-mm cell culture plates and cultured for one day. (Arbutin; 1 mM, Kojic acid; 100 ⁇ M, compound of Example 1; 1, 5, and 10 ⁇ M) as a positive control (DMSO solution) and then cultured in a 37 ° C CO 2 incubator for 5 days. Cells were detached with 0.1% trypsin-EDTA, and then centrifuged to collect the cells.
  • Cells were resuspended in RIPA lysis buffer (50 mM Tris, pH 7.4, 0.1% SDS, 1% NP-40, 150 mM NaCl, 1 mM PMSF, 10 mM NaF, 10 ⁇ g / ml aprotinin, 10 ⁇ g / ml leupeptin, 10 mM Na 3 VO 4 ), followed by centrifugation to obtain a cell lysate. The obtained cell lysate was quantitated and the cell lysate containing the same amount of protein (40 ⁇ g) was separated by electrophoresis on a 4-12% Bis-Tris acrylamide gel.
  • RIPA lysis buffer 50 mM Tris, pH 7.4, 0.1% SDS, 1% NP-40, 150 mM NaCl, 1 mM PMSF, 10 mM NaF, 10 ⁇ g / ml aprotinin, 10 ⁇ g / ml leupeptin, 10 mM Na
  • PVDF membrane Polyvinylidene difluoride membrane
  • Blocking of the PVDF membrane was carried out for 1 hour in TBST (25 mM tris-buffered saline (TBS), pH 7.5, 150 mM NaCl, 0.1% Tween-200) containing 5% Anti-tyrosinase antibody, anti-TRP-1 antibody, anti-TRP-2 antibody and anti-TRIP-2 antibody were used as the primary antibodies.
  • -MITF antibody was used.
  • Anti-GAPDH anti-GAPDH was used as an internal standard protein. The primary antibody was reacted at room temperature for 3 hours.
  • the cells were washed three times with TBST buffer solution and reacted with a secondary antibody (horseradish peroxidase-conjugated anti-goat IgG) at room temperature for 2 hours. All antibodies used in the experiments were purchased from Santacruz.
  • the PVDF membrane was washed three times with TBST buffer and reacted with the ECL solution, and then the chemiluminescence was obtained using an imaging device. The result of Western blot analysis is shown in Fig. 7, and the expression rate of protein is shown in Fig.
  • FIG. 7 is a graph showing the amount of melanin-forming protein expressed by the compound of Example 1 in Experimental Example 4 according to the present invention by western blotting.
  • FIG. 8 is a graph showing the expression levels of melanin-related proteins expressed by the compound of Example 1 in Experimental Example 4 according to the present invention.
  • Figure 8a Graph showing the amount of expression of MITF by the treatment of the compound of Example 1
  • Figure 8b Graph of measurement of tyrosinase expression level by compound 1 treatment of Example 1
  • Fig. 8d Measurement of TRP-2 expression level by the treatment of the compound of Example 1
  • Human-derived malignant melanoma HMV-II cells were seeded at 5 ⁇ 10 5 on 100-mm cell culture plates and cultured for one day. (100 ⁇ M each of Arbutin, Kojic acid, and 1, 5, and 10 ⁇ M of each of the compounds of Example 1) were treated with DMSO nuclei and then cultured in a 37 ° C CO 2 incubator for 5 days. Cells were detached with 0.1% trypsin-EDTA, and then centrifuged to collect the cells. RNA was isolated using a triazole solution (Trizol reagent) for cell precipitation. The amount of isolated RNA was determined by measuring the absorbance at 260 nm.
  • Trizol reagent Trizol reagent
  • Real-time PCR was performed using a real-time PCR instrument (ABI 7500 fast-real time PCR, Applied biosystem, or PCR) after mixing approximately 100 ng of RNA with Verso SYBR Green 1-Step qRT-PCR Low ROX Mix according to the manufacturer's manual. USA). Genes used for real-time PCR were ordered from Bioneer. The polymerase reaction was carried out at 50 ° C for 15 minutes and at 95 ° C for 15 minutes, followed by 15 cycles of denaturation at 95 ° C for 15 seconds, annealing at 60 ° C for 15 seconds, and enzyme reaction at 72 ° C for 40 cycles. The results of the above experiment are shown in Fig.
  • FIG. 9 is a graph showing the expression levels of genes related to melanin formation by the treatment of the compound of Example 1 in Experimental Example 5 according to the present invention.
  • FIG. 9a Graph of gene expression amount of MITF by treatment of compound of Example 1
  • Figure 9b Graph of expression of tyrosinase gene expression by compound 1 treatment of Example 1
  • FIG. 9d is a graph showing the amount of TRP-2 gene expression measured by the compound of Example 1
  • composition for skin whitening according to the present invention can be used as a skin whitening composition, such as tyrosinase, TRP 1 (Tyrosinase-related protein 1), TRP 2 (Tyrosinase- protein 2) or MITF (Microphthalmia-associated transcription factor), and ultimately inhibits the production of melanin.
  • TRP 1 Teyrosinase-related protein 1
  • TRP 2 Teyrosinase- protein 2
  • MITF Microphthalmia-associated transcription factor
  • the composition for skin whitening according to the present invention suppresses the expression of proteins associated with melanin production and inhibits the activity of tyrosinase even when a small amount is used, so that the composition exerts an effect of suppressing the production of melanin, And is excellent in inhibiting pigment deposition, so that it can be usefully used as a composition for skin whitening, more specifically, a pharmaceutical composition for skin whitening, a cosmetic composition for skin whitening, and a health functional food for skin whitening.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
  • an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.
  • the ointment was prepared by incorporating the above ingredients in the prescribed amounts according to the usual preparation method of ointment.
  • Vitamin A acetate 70 mg
  • Vitamin E 1.0mg
  • Vitamin B6 0.5mg
  • Vitamin B12 0.2mg
  • composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a component suitable for a health functional food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above components may be mixed , Granules may be prepared and used in the manufacture of a health functional food composition according to a conventional method.
  • the above components were mixed in accordance with a conventional health functional beverage manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour with stirring, and the solution thus prepared was filtered to obtain a sterilized container, which was sealed and sterilized, Were used to prepare beverage compositions.
  • composition ratio is relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional or national preference such as the demand class, demand country, use purpose, and the like.
  • Sorbitol sesquioleate 1.4 parts by weight
  • Methylpolysiloxane 0.4 part by weight
  • Glycerin monostearate of pro-type 1.8 parts by weight
  • Carboxyvinyl polymer 18.0 wt%
  • composition ratio is appropriately adjusted according to the preferred embodiment, the composition or the mixing ratio may be arbitrarily varied according to the local or national preference such as the demand level, the demanded country, the intended use, and the like.
  • composition for skin whitening according to the present invention can be effectively used as a skin whitening composition, specifically a pharmaceutical composition for skin whitening, a skin whitening cosmetic composition and a skin whitening health functional food.

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Abstract

La présente invention concerne une composition de blanchiment de la peau. La composition de blanchiment de la peau de la présente invention inhibe l'expression d'une protéine liée à la mélanogénèse et bloque l'activité de la tyrosinase même en petite quantité, conduisant à un excellent effet inhibiteur de la mélanogénèse, et peut ainsi faire preuve d'un effet de blanchiment de la peau et avoir un excellent effet inhibiteur sur la pigmentation, de telle sorte que la présente invention peut être efficacement utilisée comme composition de blanchiment de la peau, en particulier, comme composition pharmaceutique pour le blanchiment de la peau, composition cosmétique pour le blanchiment de la peau, et aliment fonctionnel de santé pour le blanchiment de la peau.
PCT/KR2018/007597 2017-07-05 2018-07-04 Composition pour le blanchiment de la peau WO2019009627A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
JPH0761919A (ja) * 1993-08-26 1995-03-07 Kao Corp 美白剤
KR20130010480A (ko) * 2010-03-23 2013-01-28 바이어스도르프 악티엔게젤샤프트 하나 이상의 티아졸 유도체를 함유하는 화장품 또는 피부학적 제제
WO2015037891A1 (fr) * 2013-09-10 2015-03-19 주식회사 알엔에스 Agent de blanchiment de la peau contenant un nouveau composé cyclique
CN105272912A (zh) * 2015-11-12 2016-01-27 济宁医学院 具有巯基喹啉骨架结构的酪氨酸酶抑制剂及其应用
US20170035672A1 (en) * 2010-01-06 2017-02-09 Elc Management Llc Skin lightening compositions

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Publication number Priority date Publication date Assignee Title
JPH0761919A (ja) * 1993-08-26 1995-03-07 Kao Corp 美白剤
US20170035672A1 (en) * 2010-01-06 2017-02-09 Elc Management Llc Skin lightening compositions
KR20130010480A (ko) * 2010-03-23 2013-01-28 바이어스도르프 악티엔게젤샤프트 하나 이상의 티아졸 유도체를 함유하는 화장품 또는 피부학적 제제
WO2015037891A1 (fr) * 2013-09-10 2015-03-19 주식회사 알엔에스 Agent de blanchiment de la peau contenant un nouveau composé cyclique
CN105272912A (zh) * 2015-11-12 2016-01-27 济宁医学院 具有巯基喹啉骨架结构的酪氨酸酶抑制剂及其应用

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MANIVEL, P.: "Thiourea-mediated regioselective synthesis of symmetrical and unsymmetrical diversified thioethers", INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, 2014, pages 7866 - 7870, XP055680319 *

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