KR20220166067A - Composition for skin whitening - Google Patents

Abstract

Disclosed is a composition for skin whitening. In one aspect, nonanoic acid, a salt thereof, hydrate or solvate of the present invention can inhibit melanin production by activating skin primary cilia. Accordingly, the nonanoic acid, a salt thereof, a hydrate, or a solvate of the present invention has an excellent whitening effect and has an advantage of being used as a raw material for a whitening effect.

Description

Composition for skin whitening {COMPOSITION FOR SKIN WHITENING}

The present specification relates to a composition for skin whitening.

The skin is the outermost organ of the human body and plays a role in protecting the human body from various external stimuli. Among the constituent layers of the skin, the epidermis serves to prevent evaporation of moisture inside the human body. The epidermis is divided into the stratum corneum, the granular layer, the spinous layer, and the basal layer in order from the outside.

External stimuli such as ultraviolet rays and fine dust and internal causes such as metabolites produced by intestinal microorganisms or stress hormones reduce the normal function of the skin, resulting in loss of elasticity, keratinization, wrinkle formation, and excessive melanin production. It is known, but there are few solutions to control it.

Primary cilia are cell structures that play an important role in helping cells behave in response to changes in the surrounding environment as bioantennas. When these primary cilia are activated in the skin, it is known to exhibit desirable effects on the skin, such as smoothing dead skin cells, strengthening the skin barrier, and preventing excessive melanin production.

While searching for a method for effectively suppressing excessive melanin production, the present inventors confirmed that nonanoic acid activates primary cilia and is effective in skin whitening, and completed the present invention.

Korean Patent Publication No. 10-2021-0050191

In one aspect, the present disclosure is to provide a composition for skin whitening.

In one aspect, the present disclosure provides a composition for skin whitening comprising nonanoid acid, a salt, hydrate or solvate thereof as an active ingredient.

In an exemplary embodiment, the nonanoic acid, salt, hydrate or solvate composition thereof may be administered at a dosage of 1.5 to 24 mg/kg/day.

In an exemplary embodiment, the composition may activate primary cilia.

In an exemplary embodiment, the composition may inhibit melanin production by fine dust.

In one aspect, the present disclosure provides a composition for activating primary cilia of skin comprising nonanoid acid, a salt, hydrate or solvate thereof as an active ingredient.

In an exemplary embodiment, the activation of skin primary cilia may be activation of skin primary cilia suppressed by fine dust.

In an exemplary embodiment, the composition may promote the production of skin primary cilia.

In an exemplary embodiment, the composition may be a food composition, a cosmetic composition or a pharmaceutical composition.

In another aspect, the present disclosure provides a composition for enhancing skin defense against fine dust containing nonanoid acid, a salt, hydrate or solvate thereof as an active ingredient.

In one aspect, the composition according to the present disclosure has an excellent skin whitening effect by suppressing excessive melanin production without side effects.

In one aspect, a composition according to the present disclosure can activate skin primary cilia.

In one aspect, the composition according to the present disclosure can enhance skin defense against fine dust.

1 is a result of measuring the cytotoxicity of nonanoic acid according to an embodiment of the present disclosure.
Figure 2 is a result of treating primary ciliary model cells with nonanoic acid according to an embodiment of the present disclosure and observing them under a confocal microscope.
3 is a graph showing the results obtained by treating primary cilia model cells with nonanoic acid according to an embodiment of the present disclosure and measuring the production rate of primary cilia and the length of primary cilia.
4 is a result of treating primary cilia model cells exposed to fine dust with nonanoic acid according to an embodiment of the present disclosure and observing them under a fluorescence microscope.
5 is a graph showing the results obtained by treating primary cilia model cells exposed to fine dust with nonanoic acid according to an embodiment of the present disclosure, and measuring the production rate of primary cilia and the length of primary cilia.
Figure 6 is a result of measuring the c-Jun phosphorylation inhibitory effect of nonanoic acid according to an embodiment of the present disclosure.
7 is a result of measuring the melanogenesis inhibitory effect of nonanoic acid according to one embodiment of the present disclosure.

Hereinafter, the present invention will be described in detail.

In one aspect, the present disclosure provides a composition for enhancing skin elasticity or improving skin wrinkles comprising nonanoid acid, a salt, hydrate or solvate thereof as an active ingredient.

In the present specification, nonanoic acid may be represented by Formula 1 below.

[Formula 1]

As used herein, "salt" means a salt according to one aspect of the present invention that is acceptable in medicine, cosmetics, and food and has the desired activity of the parent compound. These salts are (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-Toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert - acid addition salts formed with organic acids such as butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or (2) a salt formed when an acidic proton present in the parent compound is substituted. In addition, the salt may be a pharmaceutically acceptable salt.

As used herein, “pharmaceutically acceptable” means approval by the government or a regulatory body equivalent thereto that can be used in animals, more specifically in humans, by avoiding significant toxic effects when used in normal medical dosages. Received or approved, or listed in a pharmacopeia or otherwise recognized in a general pharmacopeia.

In the present specification, "hydrate" means a compound in which water is bound, and is a broad concept including an inclusion compound having no chemical bonding force between water and the compound.

As used herein, "solvate" refers to a higher order compound formed between solute molecules or ions and solvent molecules or ions.

In the present specification, "active ingredient" means a component that exhibits the desired activity alone or that can exhibit activity together with a carrier that has no activity by itself.

In the present specification, "skin" means a tissue covering the body surface of an animal, and is a concept in the broadest sense including not only the tissue covering the body surface such as the face or body, but also the scalp and hair.

In the present specification, “skin defense” is the ability to protect the skin from external stimuli and toxins, and the stimuli are a broad concept that includes all stimuli harmful to the skin such as fine dust, bacteria, viruses, ultraviolet rays, dryness, and wounds. .

In one embodiment, nonanoic acid, its salt, hydrate or solvate by administration of the composition may be administered at a dosage of 1.5 to 24 mg/kg/day. If the dosage of nonanoic acid, its salt, hydrate or solvate by administration of the composition is less than 1.5 mg / kg / day, it may be difficult to show the effect of improving skin elasticity or skin wrinkles, and more than 24 mg / kg / day If so, it may cause skin irritation. Specifically, the dosage of nonanoic acid, its salt, hydrate or solvate by administration of the composition is 1.5 mg/kg/day or more, 2 mg/kg/day or more, 2.5 mg/kg/day or more, 3 mg/kg/day or more. ≥ kg/day, ≥ 3.5 mg/kg/day, ≥ 4 mg/kg/day, ≥ 4.5 mg/kg/day, ≥ 5 mg/kg/day, ≥ 5.5 mg/kg/day, 6 mg/kg/ ≥ 6.5 mg/kg/day, ≥ 7 mg/kg/day, ≥ 7.5 mg/kg/day, ≥ 8 mg/kg/day, ≥ 8.5 mg/kg/day, ≥ 9 mg/kg/day , greater than or equal to 9.5 mg/kg/day or greater than or equal to 10 mg/kg/day, but less than or equal to 24 mg/kg/day, less than or equal to 23.5 mg/kg/day, less than or equal to 23 mg/kg/day, or less than or equal to 22.5 mg/kg/day; 22 mg/kg/day or less, 21.5 mg/kg/day or less, 21 mg/kg/day or less, 20.5 mg/kg/day or less, 20 mg/kg/day or less, 19.5 mg/kg/day or less, 19 mg /kg/day or less, 18.5 mg/kg/day or less, or 18 mg/kg/day or less.

In one embodiment, the active ingredient can activate primary cilia. In the present specification, activating primary cilia may mean promoting the production of primary cilia in a cell or increasing the length of primary cilia.

In the present specification, "primary cilia" are organelles protruding from the cell body, which sense various external stimuli including chemical stimuli, physical stimuli, light, osmotic pressure, fluid flow, and gravitational signals. When the activity of skin primary cilia is suppressed, skin pigmentation, inflammatory dermatitis, and the like may be induced.

In one embodiment, the active ingredient can increase the production of primary cilia suppressed by fine dust.

In one embodiment, the composition can inhibit melanin production by fine dust.

In this specification, "fine dust" refers to particulate matter that floats or scatters in the air for a long time as a very small substance invisible to our eyes. Specifically, the particle size of the fine dust may have a particle diameter of 10 μm or less (PM 10), more specifically, 2.5 μm or less (PM 2.5). In particular, particulate matter having a particle diameter of 2.5 μm or less (PM 2.5) is referred to as “ultrafine dust”, and in this specification, “fine dust” is intended to include “ultrafine dust”.

In one embodiment, the composition may be a cosmetic composition. The cosmetic composition, for example, softening lotion, astringent lotion, nutrient lotion, nutrient cream, massage cream, eye cream, eye essence, essence, cleansing cream, cleansing lotion, cleansing foam, cleansing water, pack, powder, body lotion , Body cream, body essence, body cleanser, hair dye, shampoo, rinse, hair styling agent, hair growth agent, ointment, gel, cream, patch, spray, powder, and skin adhesive type, but may have formulations such as, but are not limited thereto.

In addition, other ingredients in addition to the essential ingredients described above in each formulation can be appropriately selected and blended without difficulty by those skilled in the art according to the type or purpose of use of other external preparations.

The cosmetic composition may be provided in any formulation suitable for topical application. For example, it may be provided in the form of a solution, an emulsion obtained by dispersing an oil phase in an aqueous phase, an emulsion obtained by dispersing an aqueous phase in an oil phase, a suspension, a solid, a gel, a powder, a paste, a microneedle, a foam, or an aerosol composition. there is. Compositions of such formulations may be prepared according to conventional methods in the art.

The cosmetic composition according to the present specification may further include functional additives and components included in general cosmetic compositions in addition to the compounds of the present specification. The functional additive may include a component selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high-molecular peptides, high-molecular polysaccharides, sphingolipids, and seaweed extracts. The cosmetic composition according to the present specification may include other components capable of giving a synergistic effect to the main effect within a range that does not impair the main effect. In addition, the cosmetic composition according to the present specification may further include a moisturizer, an emollient agent, a surfactant, a UV absorber, a preservative, a bactericide, an antioxidant, a pH adjuster, an organic and inorganic pigment, a fragrance, a cooling agent or an antiperspirant. The blending amount of the components can be easily selected by those skilled in the art within a range that does not impair the purpose and effect of the present specification, and the blending amount may be 0.001 to 10% by weight, specifically 0.01 to 3% by weight based on the total weight of the composition. there is.

In one embodiment, the composition may be a food composition. The formulation of the food composition is not particularly limited, but may be formulated into, for example, tablets, granules, pills, powders, liquids such as drinks, caramels, gels, bars, tea bags, and the like. The food composition of each formulation can be selected and blended without difficulty by those skilled in the art according to the formulation or purpose of use other than the active ingredient, and synergistic effects can occur when applied simultaneously with other ingredients.

The food composition according to one embodiment includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like. In addition, the food compositions according to one embodiment may include natural fruit juice, fruit juice beverages, and fruit flesh for preparing vegetable beverages. These components may be used independently or in combination. The ratio of these additives is not so critical, but is generally included in the range of 0 to about 50 parts by weight per 100 parts by weight of the composition according to one embodiment.

In one embodiment, the composition may be a pharmaceutical composition. The pharmaceutical composition may be a composition for preventing or treating atopic dermatitis, psoriasis, eczema or redness. The pharmaceutical composition may be administered orally, parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, or subcutaneously. Formulations for oral administration may be tablets, pills, soft and hard capsules, granules, powders, fine granules, solutions, emulsions, or pellets, but are limited thereto. It is not. Formulations for parenteral administration may be solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches or sprays, but are not limited thereto. The formulation can be easily prepared according to a conventional method in the art, and includes surfactants, excipients, wetting agents, emulsification accelerators, suspending agents, salts or buffers for osmotic pressure control, coloring agents, spices, stabilizers, preservatives, preservatives, or Other commonly used adjuvants may be further included.

In another aspect, the present disclosure provides a composition for activating primary cilia of skin comprising nonanoic acid, a salt, hydrate or solvate thereof as an active ingredient.

In one embodiment, the skin primary cilia activation may be the activation of skin primary cilia suppressed by fine dust. When the skin is exposed to fine dust, the production of skin primary cilia is suppressed and their length is reduced. The composition according to the present disclosure prevents the suppression of the production of skin primary cilia by fine dust, enhances the production of skin primary cilia, and increases the length of skin primary cilia exposed to fine dust.

In another aspect, the present disclosure provides a composition for enhancing skin defense against fine dust containing nonanoic acid, a salt, hydrate or solvate thereof as an active ingredient.

In one embodiment, the active ingredient can enhance the production of skin primary cilia.

Hereinafter, the present invention will be described in more detail through examples and the like. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.

[Experimental Example 1] Measurement of cytotoxicity

Human-derived fibroblasts were placed in DMEM (Dulbecco's Modified Eagle's medium) containing 10% fetal bovine serum (FBS) and cultured under 5% CO ₂ conditions at 37°C. The cultured human-derived fibroblasts were treated with nonanoic acid at each concentration for 24 hours. CCK-8 reagent (Donjindo Co., CK04) was diluted 1/10 in DMEM medium, treated for 3 hours, and absorbance was measured at 450 nm, and the results are shown in FIG. 1 .

[Experimental Example 2] Primary cilia activation evaluation

In order to confirm the primary cilia activation effect of nonanoic acid, primary cilia model cells, RPE/Smo-GFP, were prepared. Specifically, human telomerase-immortalized retinal pigmented epithelial (RPE) cells (ATCC) were transformed with Smo-GFP plasmid (Addgene) to prepare RPE/Smo-GFP. RPE/Smo-GFP was treated with nonanoic acid (Sigma Aldrich) for 24 hours at each concentration (20 μM, 100 μM), and the primary cilia production rate and The length of the primary cilia was measured and the results are shown in FIGS. 2 and 3 . The production rate of primary cilia was expressed as a percentage of the number of cells having primary cilia in the total number of cells, and the length of primary cilia was a measure of the actual length of all cilia observed under a microscope. As a positive control, SAG (SMO agonist, Calbiochem Co.), a primary cilia production promoting substance, was used.

White arrows in FIG. 2 indicate primary cilia, and as can be seen in FIGS. 2 and 3, when nonanoic acid is treated, the proportion of cells with primary cilia increases statistically significantly compared to the control group, and the number of cilia increases. It was also observed that the length increased.

[Experimental Example 3] Evaluation of activation of primary cilia suppressed by fine dust

Fine dust (PM2.5) was treated with RPE/Smo-GFP, which is the primary cilia model cell of Experimental Example 2. Specifically, fine dust is directly collected from the air (37.34°N, 127.27°E, 167 m above sea level) using a Teflon filter (Zefluor, Pall Life Science, Ann Arbor, MI, USA) And this was treated with a concentration of 50 ug / ml in the cell culture medium. Thereafter, after treatment with 100 μM of nonanoic acid for 24 hours, the primary cilia generation rate and the length of primary cilia were measured using a fluorescence microscope, and the results are shown in FIGS. 4 and 5. The production rate of primary cilia was expressed as a percentage of the number of cells having primary cilia in the total number of cells, and the length of primary cilia was a measure of the actual length of all cilia observed under a microscope. As a positive control, SAG (SMO agonist, Calbiochem Co.), a primary cilia production promoting substance, was used.

As can be seen in FIGS. 4 and 5, when fine dust is treated, the production of primary cilia is suppressed, but when nonanoic acid is treated, the production of primary cilia suppressed by fine dust is restored and the length of primary cilia is also increased. I was able to confirm.

[Experimental Example 4] Evaluation of biomarker expression change

Human-derived fibroblasts (LONZA) were treated with fine dust (PM2.5). Then, after treatment with 100 μM of 2-isopropylmalic acid for 24 hours, cell lysate was made, protein was quantified, and the same amount of protein was separated by electrophoresis, and then c-Jun, p-c-Jun (phosphorylated c-Jun ) The expression of each protein was measured by an antigen-antibody reaction using an antibody specific for ), and the results are shown in FIG. 6, respectively.

As can be seen in FIG. 6, when fine dust is treated, phosphorylation of c-Jun is promoted and the amount of p-c-Jun is increased, but when nonanoic acid is treated, phosphorylation of c-Jun by fine dust is suppressed. could This effect was similar to that of SP600125 (sigma aldrich), a substance known to inhibit phosphorylation of c-Jun. When phosphorylation of c-Jun is promoted, the production of primary cilia is inhibited, and nonanoic acid inhibits phosphorylation of c-Jun to activate primary cilia.

[Experimental Example 5] Evaluation of melanin production inhibitory effect

B16 (ATCC, USA), a mouse-derived melanoma cell line, was treated with α-MSH (alpha-Melanocyte-stimulating hormone, Sigma-Aldrich, USA) at 1 μM. Then, after treatment with 1.5 mM nonanoic acid for 48 hours, the melanin content was measured and shown in FIG. 7 . Melanin content was analyzed by dissolving B16F1 cells in an aqueous solution of NaOH and then measuring the absorbance with a spectrophotometer at 475 nm as a percentage compared to the control group.

As can be seen in Figure 7, it was confirmed that the amount of melanin production, which was increased by about 3 times by α-MSH, a melanin-producing hormone, was suppressed by more than 50% when nonanoic acid was treated.

[Formulation Example 1] Liquid Ampoule

According to the composition shown in Table 1 below, liquid ampoules were prepared by a conventional method.

ingredient Content (% by weight) nonanoic acid 3.2 arginine 0.50 green tea polyphenols 0.05 indigestible maltodextrin 1.00 vitamin C 0.10 citric acid 0.10 Spices 0.05 Purified water balance Sum 100.00

[Formulation Example 2] Soap

Soap was prepared by a conventional method according to the composition shown in Table 2 below.

ingredient Content (% by weight) nonanoic acid 3.00 titanium dioxide 0.20 polyethylene glycol 0.80 glycerin 0.50 Ethylenediaminetetraacetic acid 0.05 salt 1.00 pigment 0.20 soap scent 0.20 soap base balance Sum 100.00

[Formulation Example 3] Lotion

A lotion was prepared by a conventional method according to the composition shown in Table 3 below.

ingredient Content (% by weight) nonanoic acid 3.00 L-ascorbic acid-2-phosphate magnesium salt 1.00 Collagen 1.00 sodium citrate 0.10 citric acid 0.05 licorice extract 0.20 1,3-butylene glycol 3.00 Purified water balance Sum 100.00

[Formulation Example 4] Cream

Cream was prepared in a conventional manner according to the composition shown in Table 4 below.

ingredient Content (% by weight) nonanoic acid 3.00 Polyethylene glycol monostearate 2.00 Self-emulsifying monostearate glycerin 5.00 cetyl alcohol 4.00 squalene 6.00 Glyceryl tri-2-ethylhenate 6.00 sphingoglycolipids 1.00 1,3-butylene glycol 7.00 Purified water balance Sum 100.00

[Formulation Example 5] Pack

A pack was prepared in a conventional manner according to the composition shown in Table 5 below.

ingredient Content (% by weight) nonanoic acid 3.00 polyvinyl alcohol 13.00 L-ascorbic acid-2-phosphate magnesium salt 1.00 lauroylhydroxyproline 1.00 Collagen 2.00 1,3-butylene glycol 3.00 ethanol 5.00 Purified water balance Sum 100.00

[Formulation Example 6] Beauty liquid formulation

According to the composition shown in Table 6 below, a cosmetic liquid formulation was prepared by a conventional method.

ingredient Content (% by weight) nonanoic acid 3.00 Hydroxyethylene Cellulose 12.00 xanthan gum 2.00 1,3-butylene glycol 6.00 glycerin 4.00 sodium hyaluronate 5.00 Purified water balance Sum 100.00

[Formulation Example 7] Soft capsule preparation

60 mg of nonanoic acid, 160 mg of L-carnitine, 320 mg of soybean oil, 2 mg of palm oil, 8 mg of hydrogenated vegetable oil, 4 mg of yellow wax, and 6 mg of lecithin were mixed and filled into 1 capsule according to a conventional method to prepare a soft capsule.

[Formulation Example 8] Tablets

60 mg of nonanoic acid, 500 mg of galacto-oligosaccharide, 80 mg of lactose, and 220 mg of maltose were mixed and granulated using a fluid bed dryer, and then 6 mg of sugar ester was added and tableted with a tablet press to prepare tablets.

[Formulation Example 9] Granules

60 mg of nonanoic acid, 250 mg of anhydrous crystalline glucose, and 550 mg of starch were mixed, molded into granules using a fluidized bed granulator, and filled into bags to prepare granules.

[Formulation Example 10] Drinking agent

After mixing 50 mg of nonanoic acid, 10 g of glucose, 0.6 g of citric acid, and 25 g of liquid oligosaccharide, 500 ml of purified water was added and each bottle was filled with 200 ml. After filling the bottle, it was sterilized at 130 ° C. for 4 to 5 seconds to prepare a drink beverage.

Claims (16)

A composition for skin whitening comprising nonanoic acid, a salt, hydrate or solvate thereof as an active ingredient. According to claim 1,
Wherein the nonanoic acid, its salt, hydrate or solvate is administered at a dosage of 1.5 to 24 mg/kg/day. According to claim 1,
The composition of claim 1, wherein the composition activates primary cilia. According to claim 1,
The composition is a composition that inhibits melanin production by fine dust. According to any one of claims 1 to 4,
The composition is a food composition composition. According to any one of claims 1 to 4,
The composition is a cosmetic composition composition. According to any one of claims 1 to 4,
Wherein the composition is a pharmaceutical composition. A composition for activating primary cilia of the skin, comprising nonanoid acid, a salt, hydrate or solvate thereof as an active ingredient. According to claim 8,
The skin primary cilia activation is a composition in which the activation of skin primary cilia suppressed by fine dust. According to claim 8,
Wherein the composition promotes the production of skin primary cilia. According to claim 8,
Wherein the nonanoic acid, its salt, hydrate or solvate is administered at a dosage of 1.5 to 24 mg/kg/day. According to any one of claims 8 to 11,
The composition is a food composition composition. According to any one of claims 8 to 11,
The composition is a cosmetic composition composition. According to any one of claims 8 to 11,
The composition is a pharmaceutical composition. A composition for enhancing skin defense against fine dust, comprising nonanoid acid, a salt, hydrate or solvate thereof as an active ingredient. According to claim 15,
Wherein the nonanoic acid, its salt, hydrate or solvate is administered at a dosage of 1.5 to 24 mg/kg/day.

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