Composition for skin whitening

Abstract

The present invention relates to a cosmetic composition for skin whitening and, specifically, to: a cosmetic composition for skin whitening, comprising, as an active ingredient, at least one compound selected from the group consisting of chemical formulas 1 to 12 according to the present invention or a salt thereof; a pharmaceutical composition for preventing or treating pigmentation or hyperpigmentation; and a health functional food for skin whitening or alleviating hyperpigmentation diseases. The compound according to the present invention can effectively inhibit the activity of tyrosinase, and at the same time, has the activity of inhibiting melanin production and melanin secretion, and thus can be used not only in the manufacture of functional cosmetics and health functional foods for skin whitening, but also as a therapeutic agent for diseases caused by melanin hyperpigmentation.

Description

Skin whitening composition

[0001] The present invention relates to a composition for skin whitening.

[0002] The skin serves the primary function of protecting the body from external physical and chemical stimuli. Melanin, present in the skin, is a complex of black pigment and protein, consisting of phenolic biopolymers widely distributed in nature. Melanin is known to protect the body from external environments, such as ultraviolet rays, and enhances the viability and competitiveness of cells against the environment.

[0003] However, the overproduction of melanin is reported to cause melasma, freckles, and age spots, accelerate skin aging, and be associated with the development of skin cancer.

[0004] Pigmentation, which is closely related to skin whitening, occurs in melanocytes located in the basal layer of the skin's epidermis. Pigmentation is known to be significantly influenced by the activity of tyrosinase, and is primarily induced into hyperpigmentation by ultraviolet rays, inflammation, DNA damage, and reactive oxygen species.

[0005] Factors that promote the production of melanin include sunlight and ultraviolet rays, as well as estrogen or prostaglandins. The biosynthesis of melanin occurs through a series of oxidative reactions of specific enzymes, such as tyrosinase, TRP-1 (tyrosinase related protein-1), and DCT (dopachrome tautomerase), in the melanosomes of melanocytes located in the basal layer of the epidermis. Among these, inhibition of tyrosinase activity, the main enzyme in melanin synthesis, is being adopted in the early stages of developing melanin polymerase inhibitors.

[0006] Meanwhile, as a means to treat or alleviate skin pigmentation abnormalities such as melasma, freckles, and hyperpigmentation, as well as excessive melanin pigmentation caused by exposure to ultraviolet rays, substances having tyrosinase inhibitory activity, such as ascorbic acid, kojic acid, arbutin, hydroquinone, glutathione, or their derivatives, have been incorporated into cosmetics or pharmaceuticals. However, their use is restricted due to insufficient whitening effects and safety issues regarding the skin.

[0007] Therefore, there is a need to develop new skin whitening agents that possess excellent whitening activity while having few side effects.

[0008] Accordingly, while researching to discover a new substance with excellent skin whitening activity, the inventors confirmed that compounds of the following chemical formulas 1 to 12 can effectively inhibit the activity of tyrosinase and simultaneously inhibit the production and secretion of melanin, thereby confirming that these compounds can be used as skin whitening agents, and thus completed the present invention.

[0009] Therefore, the object of the present invention is to provide a cosmetic composition for skin whitening comprising one or more compounds selected from the group consisting of the following chemical formulas 1 to 12 or a salt thereof as an active ingredient.

[0010]

[0011] Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of pigmentation or hyperpigmentation, comprising as an active ingredient one or more compounds selected from the group consisting of formulas 1 to 12 or a pharmaceutically acceptable salt thereof.

[0012] Another objective of the present invention is to provide a health functional food for skin whitening or improvement of hyperpigmentation disorders, comprising as an active ingredient one or more compounds selected from the group consisting of formulas 1 to 12 or a salt thereof.

[0013] Therefore, the present invention provides a cosmetic composition for skin whitening comprising one or more compounds selected from the group consisting of Formulas 1 to 12 of the present invention or a salt thereof as an active ingredient.

[0014] In addition, the present invention provides a pharmaceutical composition for the prevention or treatment of pigmentation or hyperpigmentation, comprising as an active ingredient one or more compounds selected from the group consisting of formulas 1 to 12 or a pharmaceutically acceptable salt thereof.

[0015] In addition, the present invention provides a health functional food for skin whitening or improvement of hyperpigmented diseases, comprising as an active ingredient one or more compounds selected from the group consisting of the formulas 1 to 12 or a salt thereof.

[0016] In one embodiment of the present invention, the compound can inhibit the activity of tyrosinase.

[0017] In one embodiment of the present invention, the compound can inhibit the production and secretion of melanin.

[0018] In one embodiment of the present invention, the pigmentation or hyperpigmentation may be one or more diseases selected from the group consisting of post-inflammatory hyperpigmentation, melasma, freckles, café au lait spots, other hyperpigmentation of melanin, melanoma, albinism not otherwise classified, other disorders with reduced melanin formation, pigmented purpura, serpentine angioma, other specified disorders of pigmentation, iron pigmentation, tattoo pigmentation, and pigmentation disorders of unspecified type.

[0019] One or more compounds selected from the group consisting of formulas 1 to 12 according to the present invention, or salts thereof, can effectively inhibit the activity of tyrosinase and simultaneously have the activity of inhibiting the production and secretion of melanin into the extracellular space. Therefore, they can be used not only in the manufacture of functional cosmetics and health functional foods for skin whitening but also as a therapeutic agent for diseases caused by excessive melanin pigmentation.

[0020] Figure 1 is a result of confirming the inhibition of tyrosinase activity for the compounds of the present invention, confirming the inhibition of tyrosinase activity using L-tyrosine as a substrate.

[0021] Figure 2 is a result of confirming the inhibition of tyrosinase activity for the compounds of the present invention, confirming the inhibition of tyrosinase activity using L-DOPA as a substrate.

[0022] Figure 3 shows the results of confirming the inhibitory effect of the compound of the present invention on intracellular melanin production and extracellular secretion of melanin on melanin production increased by α-MSH in mouse-derived melanoma cells (B16F10).

[0023] The present invention is characterized by providing a composition for skin whitening.

[0024] Specifically, the present invention is characterized by providing a cosmetic composition for skin whitening that comprises one or more compounds selected from the group consisting of the following chemical formulas 1 to 12 or a salt thereof as an active ingredient.

[0025]

[0026] Regarding compounds having the structural formulas of Chemical Formulas 1 to 12 above, nothing is known about their relationship with conventional skin whitening.

[0027] Meanwhile, the inventors confirmed through experiments of an embodiment of the present invention that compounds having the structural formulas of Chemical Formulas 1 to 12 can effectively inhibit the activity of tyrosinase and inhibit the production and secretion of melanin, and thus can be used as new skin whitening agents.

[0028] Tyrosinase is a copper-containing enzyme that exists naturally in mammals, plants, and fungi and accepts substrates such as phenols and catechols. This enzyme is involved in the first two steps of melanin biosynthesis, hydroxylating L-tyrosine into L-DOPA (L-3,4-dihydroxyphenylalanine) and oxidizing it to o-quinone (dopaquinone). Dopaquinone is converted into melanin through several reaction steps, acting as a causative agent for skin pigmentation. Furthermore, in the food industry, tyrosinase serves as a target enzyme that controls the stability of fruits and vegetables. Accordingly, the development of safer and more effective tyrosinase inhibitors is recognized as a critical challenge for the food and cosmetics industries.

[0029] According to one embodiment of the present invention, in order to confirm the tyrosinase activity inhibitory efficacy of the compounds of Formulas 1 to 12 of the present invention, the inhibition of tyrosinase activity by treatment with the compounds of the present invention was analyzed in a reaction process in which L-tyrosine and L-DOPA were substrates to tyrosinase, and it was confirmed that the compounds of the present invention effectively inhibit the activity of tyrosinase.

[0030] Furthermore, in another embodiment of the present invention, when the compounds of the present invention were tested on melanoma cell lines to determine whether they could inhibit melanin production increased by α-MSH treatment, it was found that in the groups treated with the compounds of the present invention, melanin production was significantly inhibited and melanin secretion out of the cells was also inhibited.

[0031] Through these results, the inventors found that the compounds of the present invention having the structural formulas of Chemical Formulas 1 to 12 can be usefully used in pharmaceuticals, cosmetics, and health functional foods for skin whitening.

[0032] Therefore, the present invention can provide a cosmetic composition for skin whitening comprising one or more compounds selected from the group consisting of the above chemical formulas 1 to 12 or a salt thereof as an active ingredient.

[0033] In the present invention, “skin whitening” refers to suppressing changes in skin color or pigmentation caused by excessive production of pigment within the skin due to external environmental changes such as ultraviolet rays, stress, abnormal hormone secretion, and pregnancy. It includes the effect of improving, preventing, or avoiding dark skin, melasma, freckles, and dark circles caused by the various factors mentioned above, the effect of increasing skin transparency, and the effect of improving skin dullness to increase shine and firmness. In other words, it refers to all actions that inhibit the production of melanin to suppress or prevent the deposition of melanin in the skin.

[0034] The cosmetic composition of the present invention may include a salt of the above-mentioned compound. The term "salt" used in the present invention refers to a form of salt that can be used as a cosmetic, among salts in which a cation and an anion are bonded by electrostatic attraction. Typically, it may be a metal salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. For example, metal salts include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, barium salt, etc.), aluminum salt, etc.; salts with organic bases include salts with triethylamine, pyridine, picoline, 2,6-rutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.; salts with inorganic acids include salts with hydrochloric acid, hydrobromide, nitric acid, sulfuric acid, phosphoric acid, etc. Salts with organic acids may include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; salts with basic amino acids may include salts with arginine, lysine, ornithine, etc.; and salts with acidic amino acids may include salts with aspartic acid, glutamic acid, etc. Furthermore, the cosmetic composition of the present invention may be prepared in any formulation conventionally manufactured in the art, and may be formulated, for example, as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, and spray, but is not limited thereto. More specifically, the cosmetic composition of the present invention may be prepared in the form of a softening lotion, a nourishing lotion, a nourishing cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray, or a powder.

[0035] In the case where the formulation of the present invention is a paste, cream, or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as a carrier component.

[0036] When the formulation of the present invention is a solution or an emulsion, a solvent, a solubilizing agent, or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, or fatty acid ester of sorbitan.

[0037] In the case where the formulation of the present invention is a suspension, liquid diluents such as water, ethanol, or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tracant may be used as carrier components.

[0038] In the case where the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, it may additionally include a propellant such as hydrochlorofluorocarbon, propane / butane, or dimethyl ether.

[0039] In the case where the formulation of the present invention is a cleansing agent containing a surfactant, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamidobetaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester, etc. may be used as a carrier component.

[0040] In addition, the present invention may provide a pharmaceutical composition for the prevention or treatment of pigmentation or hyperpigmentation, comprising as an active ingredient one or more compounds selected from the group consisting of formulas 1 to 12 or a pharmaceutically acceptable salt thereof.

[0041] The term "pigmentation" as used in the present invention generally refers to excessive pigmentation caused by an increase in melanin in the skin, fingernails, toenails, or mucous membranes surrounding the oral or nasal cavity. The pigmentation subject to prevention, improvement, or treatment by the present invention is not specifically limited to a particular disease name as long as it falls within the category of pigmentation in a medical or cosmetic sense; however, it may be post-inflammatory hyperpigmentation, melasma, freckles, café-au-lait spots, other melanin hyperpigmentation, lentigo, albinism not otherwise classified, other disorders with reduced melanin formation, pigmented purpura, serpentine angioma, other specified pigmentation disorders, iron pigmentation, tattoo pigmentation, or pigmentation disorders of unspecified type.

[0042] In this invention, the term "prevention" refers to any act of suppressing or delaying the occurrence of pigmentation by administering the composition of this invention, and the term "treatment" refers to any act of improving or beneficially altering the symptoms of pigmentation by the composition of this invention.

[0043] The term "pharmaceuticalally acceptable salt" used in the present invention refers to a salt in a form that can be used pharmaceutically among salts in which cations and anions are bonded by electrostatic attraction, and specific examples of such types include examples of "salts" described above in cosmetic compositions.

[0044] As the above pharmaceutically acceptable salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, or phosphoric acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, and aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chloride, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, butyne-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, and phthalates. Includes terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate.

[0045] The composition of the present invention may include pharmaceutically acceptable additives, and pharmaceutically acceptable additives may include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, malt syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropylene cellulose, Opadry, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, sucrose, etc.

[0046] The pharmaceutically acceptable additive according to the present invention is preferably included in an amount of 0.1 to 90 parts by weight with respect to the composition, but is not limited thereto.

[0047] In the present invention, the composition may be administered in various oral or parenteral formulations during actual clinical administration. When formulating, it may be prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. It is preferable to use a suitable formulation known in the art that is disclosed in the literature (Remington's Pharmaceutical Science, recently Mack Publishing Company, Easton, PA). Carriers, excipients, and diluents that may be included in the above composition include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc.

[0048] The above-mentioned solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms are prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium styrate and talc are also used. Furthermore, the above-mentioned liquid dosage forms for oral administration include suspensions, liquid formulations, emulsions, syrups, etc., and may include various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.

[0049] To formulate the pharmaceutical composition of the present invention for parenteral administration, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, topical agents, etc. may be used, and as the non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used.

[0050] In addition, when the pharmaceutical composition of the present invention is formulated into an ointment, cream, topical powder, oil, external skin preparation, etc., it may be formulated using animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc. as a carrier.

[0051] The pharmaceutical effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time and / or administration route, etc., and may vary depending on various factors including the type and degree of response to be achieved by administering the pharmaceutical composition, the type of individual to be administered, age, body weight, general health condition, symptoms or degree of disease, gender, diet, excretion, and components of other compositions used simultaneously or at different times with the individual, as well as similar factors well known in the pharmaceutical field, and a person with ordinary knowledge in the art can easily determine and prescribe an effective dosage for the intended treatment.

[0052] The pharmaceutical composition of the present invention may be administered once a day or divided into several doses. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Taking all of the above factors into consideration, the amount administered can be an amount that obtains maximum effect with a minimum amount without side effects, and this can be easily determined by a person skilled in the art.

[0053] The administration route and method of administration of the pharmaceutical composition of the present invention may each be independent, and any administration route and method may be followed without special limitation as long as the pharmaceutical composition can reach the intended site. The pharmaceutical composition may be administered orally or parenterally.

[0054] Methods of parenteral administration of the pharmaceutical composition of the present invention may include intravenous administration, intraperitoneal administration, intramuscular administration, transdermal administration, or subcutaneous administration, and methods of applying, spraying, or inhaling the composition to a diseased area may also be used, but are not limited thereto.

[0055] The pharmaceutical composition of the present invention can exhibit excellent effects even when used alone, but it may be used in combination with various methods such as hormone therapy and drug therapy to increase therapeutic efficiency.

[0056] In addition, the present invention may provide a method for preventing or treating pigmentation, comprising the step of administering a compound according to the present invention to an individual suspected of having pigmentation.

[0057] In the present invention, the subject suspected of pigmentation refers to all animals, including humans, in which pigmentation has occurred or may occur, and the subject can be efficiently treated by administering the compound of the present invention to the subject suspected of pigmentation. Pigmentation is as described above.

[0058] The treatment method of the present invention may include administering a pharmaceutically effective amount of the compound of the present invention. A suitable total daily dose may be determined by the treating physician within the scope of proper medical judgment and may generally be administered in amounts of 0.005 to 4000 mg / kg, 0.001 to 2000 mg / kg, 0.01 to 1000 mg / kg, 0.05 to 200 mg / kg, or 0.1 to 100 mg / kg, divided into one or several doses per day. However, for the purposes of the present invention, it is preferable to apply a specific therapeutically effective dose for a specific patient differently depending on various factors and similar factors well known in the pharmaceutical field, including the type and degree of response to be achieved, the specific composition including whether other preparations are used in some cases, the patient's age, weight, general health condition, gender and diet, time of administration, route of administration and secretion rate of the composition, duration of treatment, and drugs used together or concurrently with the specific composition.

[0059] Furthermore, the present invention may provide a health functional food for skin whitening or improvement of hyperpigmentation disorders, comprising as an active ingredient one or more compounds selected from the group consisting of the formulas 1 to 12 of the present invention or a pharmaceutically acceptable salt thereof.

[0060] The health functional food of the present invention comprises the active ingredient of the present invention. Examples of said foods include drinks, meat, sausages, bread, biscuits, rice cakes, powdered grains, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, alcoholic beverages, vitamin complexes, dairy products, and dairy processed products, and also include all health functional foods in the conventional sense. As an active ingredient, the active ingredient of the present invention may be added directly to food or used together with other foods or food ingredients, and may be used appropriately according to conventional methods. The effective content may be appropriately determined according to the purpose of use (for prevention or improvement) and may be included in a range of 0.001 to 70 weight percent relative to the total weight of the health food. However, in the case of long-term consumption for the purpose of health and hygiene or for health control, the above amount may be less than the above range, and if there are no issues regarding safety, the active ingredient may be used in an amount greater than the above range. For example, when manufactured as a health drink, in addition to the above active ingredients, it may contain natural carbohydrates or flavoring agents as additives commonly used in beverage manufacturing. The above natural carbohydrates may include conventional sugars such as monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.), and polysaccharides (e.g., dextrin, cyclodextrin, etc.), as well as sugar alcohols such as xylitol, sorbitol, and erythritol. The above natural carbohydrates may be contained in a range of 1 to 20 weight%, preferably 5 to 10 weight%, relative to the total weight of the health food. The above flavoring agents may include natural flavoring agents (taumatin, stevia extract, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).In addition, it may contain various nutritional supplements, vitamins, minerals (electrolytes), flavoring agents (synthetic or natural flavoring agents), coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Furthermore, it may contain fruit pulp for the production of natural fruit juices, fruit juice beverages, and vegetable beverages. Although there are no specific limitations on the content of these additives, they may be included in a range of 0.1 to 20 weight percent relative to the total weight of the health food.

[0061] Furthermore, the present invention may provide a skin whitening external preparation composition comprising, as an active ingredient, one or more compounds selected from the group consisting of Formulas 1 to 12 of the present invention or a pharmaceutically acceptable salt thereof.

[0062] The topical skin composition according to the present invention may be formulated containing a cosmetically or dermatologically acceptable medium or base. This may be provided in any formulation suitable for topical application, for example, in the form of a solution, gel, solid, paste anhydrous product, emulsion obtained by dispersing an oil phase in an aqueous phase, suspension, microemulsion, microcapsule, microgranule, or ionic (liposome) and non-ionic vesicular dispersants, or in the form of a cream, skin toner, lotion, powder, ointment, spray, pack, or concealer stick. It may also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant. These compositions may be prepared according to conventional methods in the art.

[0063] In addition, the topical skin composition according to the present invention may contain adjuvants commonly used in the field of cosmetics or dermatology, such as fatty substances, organic solvents, solvents, thickeners, gelling agents, emollients, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants, water, ionic or nonionic emulsifiers, fillers, metal ion chelating agents, chelating agents, preservatives, vitamins, blockers, humectants, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles, or any other ingredients commonly used in cosmetics. The adjuvants are introduced in amounts commonly used in the field of cosmetics or dermatology.

[0064] The present invention will be explained in more detail below through examples. These examples are intended to explain the invention more specifically, and the scope of the invention is not limited to these examples.

[0065]

[0066] <Experimental Method>

[0067] (1) In Vitro tyrosinase inhibition assay

[0068] The effect of the test substance on tyrosinase activity inhibition was analyzed by reacting the test substance, purified tyrosinase, and the substrate tyrosine in a test tube. Specifically, 110 μL of 0.1 M phosphate buffer (pH 6.5), 10 μL of the sample solution containing the test substance, and 10 μL of mushroom tyrosinase solution (1500 U / mL) were added sequentially to a test tube. Then, 20 μL of 1.5 mM tyrosine solution was added, and the mixture was reacted at 37 ℃ for 10 minutes, after which the absorbance was measured at 490 nm. To calculate accurate values, the data values ​​were corrected by using the solvent in which the sample was dissolved as the blank solution instead of the sample solution, and the tyrosinase activity inhibition rate was calculated using the following formula.

[0069]

[0070] Tyrosinase activity inhibition rate (%) = 100 - (b - b' / a - a') × 100

[0071] a : Absorbance of the blank solution after reaction

[0072] b: Absorbance of the sample solution after reaction

[0073] a' and b': Absorbance measured by replacing tyrosinase with buffer solution

[0074]

[0075] (2) In Vitro DOPA oxidation inhibition assay

[0076] The L-DOPA-based tyrosinase activity inhibition test was conducted based on relevant research papers and the guidelines for the efficacy evaluation of functional cosmetics that aid in skin whitening provided by the Ministry of Food and Drug Safety. The specific experimental method is as follows. The reagents used in the test were primarily diluted in 20 mM sodium phosphate buffer (pH 6.5). Since the test substances were dissolved at high concentrations in DMSO, they were diluted to a low concentration in the buffer, and then further diluted to a concentration where the final DMSO concentration would have minimal effect on the test. In a 96-well plate, 40 µl of the test substance, 40 µl of mushroom tyrosinase (200 units / ml), and 80 µl of phosphate buffer were added to each well. 40 µl of either L-DOPA (8 mM) or phosphate buffer was added to bring the total volume to 200 µl. The reaction was carried out at 37°C for 30 minutes, and changes were measured every minute at a wavelength of 475 nm. In this case, arbutin was used as a positive control. The percentage of diphenolase activity inhibition was calculated as follows, and the highest measured value was shown in the graph.

[0077] % of inhibition = (AB) / A×100

[0078] A = Absorbance at 475 nm without addition of test substance

[0079] B = Absorbance at 475 nm with added test substance

[0080]

[0081] (3) Cell culture and treatment of test substance (compound of the present invention)

[0082] To verify the effect of measuring melanin concentration, B16F10, a mouse-derived Murin melanoma cell, was placed in a 6-well plate at a rate of 7 x 10 per well. 4 Gaero Cells were aliquoted and cultured for use. For cell culture, DMEM (Dulbecco's Modified Eagle's Medium) containing 1% penicillin / streptomycin (100 µg / ml) and 10% fetal bovine serum was used as the base medium, and the cells were cultured at 37°C in an incubator maintained at 5% carbon dioxide. After 24 hours of culture, the cells were treated with the test substance and α-MSH, a drug that induces melanin production, for 72 hours to confirm the results.

[0083]

[0084] (4) Measurement of melanin concentration

[0085] After 24 hours of cell culture, the test substance to be evaluated and α-MSH, a drug that induces melanin production, were added. After 72 hours, the culture medium and cells were collected separately for analysis. To avoid affecting the measurement of melanin secreted into the medium, a phenol red-free medium was used for the experiment, and arbutin, a substance notified by the Ministry of Food and Drug Safety, was used as the control drug. After the reaction was complete, the culture medium of the experimental group was collected as is. To remove suspended solids, centrifugation was performed at 1500 rpm (330 g force) for 5 minutes, and the supernatant was collected to measure the amount of melanin secreted into the medium (extracellular amount). Additionally, the cells remaining in the culture dish were washed twice with 1X DPBS (Dulbecco's phosphate buffered saline), and 1N NaOH was added to scrape the cells together. The collected cells were incubated at 60°C for 30 minutes, after which the amount of melanin (intracellular amount) was measured. The amount of melanin was measured using a microplate reader at 490 nm absorbance, and the values ​​were compared after correcting for protein amount using a BCA assay.

[0086]

[0087] <Example 1>

[0088] Confirmation of inhibition of tyrosinase activity following compound treatment of the present invention

[0089] Tyrosinase is the most important enzyme in melanin biosynthesis occurring in plant, microbial, and mammalian cells, converting tyrosine into dopaquinone, the key precursor of melanin biosynthesis. This enzyme performs monophenolase functions, converting L-tyrosine into L-DOPA (3,4-dihydroxyphenylalanine), and diphenolase functions, converting L-DOPA into L-dopaquinone; the dopaquinone produced is automatically converted into melanin without the aid of enzymatic action. Therefore, tyrosinase inhibitors induce a skin whitening effect by inhibiting melanin biosynthesis.

[0090] Accordingly, the inventors performed an in vitro tyrosinase activity inhibition analysis as in the experimental method (1) to determine whether the compounds of the present invention can inhibit the activity of tyrosinase.

[0091]

[0092] As a result, as shown in Figure 1, it was confirmed that the compounds of the present invention W001, W003, W004, W005, W006, W009, W017, M004, and M006 inhibit monophenolase activity using L-tyrosine as a substrate.

[0093]

[0094] In addition, the inventors analyzed whether the compound of the present invention inhibits diphenolase activity through the experiment of the above experimental method (2).

[0095] As a result, as shown in Figure 2, the compounds W001, W003, W004, W005, W006, W008, W010, W017, M004, and M007 of the present invention were found to be able to effectively inhibit diphenolase activity using L-DOPA as a substrate.

[0096]

[0097] Through these results, the inventors confirmed that the compounds of the present invention can inhibit the activity of monophenolase and diphenolase, thereby inhibiting the activity of tyrosinase.

[0098]

[0099] <Example 2>

[0100] Confirmation of inhibition of melanin production and secretion

[0101] Furthermore, the inventors confirmed through experiments of the above experimental methods (3) and (4) whether the compound of the present invention can inhibit the production of melanin in melanocytes and the secretion of melanin out of the cell.

[0102]

[0103] As a result, as shown in Figure 3, the compound treatment groups of the present invention were found to inhibit melanin production increased by α-MSH, and were also found to be able to inhibit extracellular secretion of melanin.

[0104]

[0105] Through this, the inventors found that the compounds of the present invention can effectively inhibit the activity of tyrosinase and inhibit the production and secretion of melanin, and thus can be usefully used not only in the manufacture of cosmetics for skin whitening but also as health functional foods for skin whitening and as treatments for skin diseases caused by pigment abnormalities.

[0106]

[0107] The present invention has been described above with reference to its preferred embodiments. Those skilled in the art will understand that the present invention may be embodied in modified forms without departing from the essential characteristics of the invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the invention is defined by the claims, not by the foregoing description, and all variations within the scope of the claims should be interpreted as being included in the invention.

Claims

1. A cosmetic composition for skin whitening comprising, as an active ingredient, one or more compounds selected from the group consisting of the following chemical formulas 1 to 12 or a salt thereof.

2. In Paragraph 1, A cosmetic composition for skin whitening characterized by the above compound inhibiting the activity of tyrosinase.

3. In Paragraph 1, A cosmetic composition for skin whitening characterized by the above compound inhibiting the production and secretion of melanin.

4. A pharmaceutical composition for the prevention or treatment of pigmentation or hyperpigmentation, comprising as an active ingredient one or more compounds selected from the group consisting of the following chemical formulas 1 to 12 or a pharmaceutically acceptable salt thereof.

5. In Paragraph 4, A pharmaceutical composition for the prevention or treatment of pigmentation or hyperpigmentation, characterized by the above compound inhibiting the activity of tyrosinase.

6. In Paragraph 4, A pharmaceutical composition for the prevention or treatment of pigmentation or hyperpigmentation, characterized by the above compound inhibiting the production and secretion of melanin.

7. In Paragraph 4, A pharmaceutical composition for the prevention or treatment of pigmentation or hyperpigmentation, characterized in that the above pigmentation or hyperpigmentation is one or more conditions selected from the group consisting of post-inflammatory hyperpigmentation, melasma, freckles, café-au-lait spots, other melanin hyperpigmentation, lentigo, albinism not otherwise classified, other disorders with reduced melanin formation, pigmented purpura, serpentine angioma, other specified pigmentation disorders, iron pigmentation, tattoo pigmentation, and pigmentation disorders of unspecified type.

8. A health functional food for skin whitening or improvement of hyperpigmentation disorders, comprising as an active ingredient one or more compounds selected from the group consisting of the following chemical formulas 1 to 12 or a salt thereof.

9. In Paragraph 8, The above compound is a health functional food for skin whitening or improvement of hyperpigmented disorders, characterized by inhibiting the activity of tyrosinase.

10. In Paragraph 8, The above compound is a health functional food for skin whitening or improvement of hyperpigmented disorders, characterized by inhibiting the production and secretion of melanin.

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