KR101702441B1 - Cosmetic composition for skin whitening - Google Patents

Abstract

The compound contained as an active ingredient in the cosmetic composition or the pharmaceutical composition of the present invention is excellent in solubility in a solvent so that it can be easily compounded with other ingredients to be added and inhibits the activity of tyrosinase to inhibit the production of melanin The skin whitening effect is excellent. Also, since it is safe because it is free of irritation and toxicity to the human body, it can be utilized as an effective ingredient of a skin external preparation for treating, alleviating or preventing cosmetic and / or pigmented skin lesions for skin whitening.

Description

COSMETIC COMPOSITION FOR SKIN WHITENING

This patent application was carried out under the support of the "Business Development of a Leading Business in the Greater Economy Region (R0001536)" by the "Industry and Commerce Ministry", "Korea Industrial Technology Development Agency" and "Honam Regional Industrial Evaluation Institute".

The present invention relates to a skin whitening composition, and more particularly to a skin whitening cosmetic composition containing a compound having good solubility and no fear of irritation or toxicity to the skin as an active ingredient, a cosmetic composition containing the same, And an external preparation for skin containing the same.

In Northeast Asian society including Korea and China and Japan, white and clean skin like white is one of criteria for judging beauty of women. Therefore, there is a high interest in materials having a whitening effect, and development of such materials is actively pursued. For example, skin whitening cosmetics are whitening skin, and according to the domestic "Cosmetic Act", it is possible to prevent melanin pigment from depositing on the skin to inhibit the formation of spots and freckles, or to suppress the color of melanin pigment To help skin whitening function.

The skin of the human body is a tissue that protects the human body from external environment and functions biochemically. The skin can be largely divided into epidermis, dermis and hypodermis. The epidermis is composed of stratum corneum, granular layer, stratum spinosum, (stratum basal). Melanin is a phenolic polymer compound widely found in the natural world and is a black pigment present in the epidermis of the skin. Melanin absorbs ultraviolet (UV) light energy to protect the skin from UV damage and protects skin from external harmful factors such as amines, free radicals, harmful oxygen and free radicals that are found in the skin.

When such melanin is produced less, skin lesions such as vitiligo are induced, whereas when melanin is overly synthesized or keratinization of the skin is not normally performed, the melanin is not removed and not only the skin is damaged but also the pigment of the skin is deposited, , Freckles, and may cause skin cancer. Therefore, in order to prevent deposition of skin pigment, it is necessary to inhibit a part of the melanin generation mechanism to reduce the production of melanin.

Melanocytes, which are melanocytes, are present in the basal layer located at the bottom of the epidermis. When the skin is stimulated by an excess of ultraviolet rays, an enzyme called tyrosinase oxidizes tyrosine in the melanocytes, and oxidized tyrosine Makes melanin. As new skin cells push up old skin cells, the old skin cells become keratinized, and skin appears black as new skin cells containing melanin are passed through the granules and the superficial layer, through the granules and into the stratum corneum. Since there is no enzymes that degrade melanin in the body, melanin is removed from the skin when keratinocyte is separated from the epidermis.

The darkness of the skin is caused by melanin generated by stimulation with ultraviolet rays or the like. In order to prevent the skin from becoming dark, it is necessary to reduce the melanin pigment or inhibit melanin generation. In order to reduce the melanin pigment produced for skin whitening effect, tocopherol, vitamins and the like have been developed. However, since the whitening agent containing these components is known to have little discoloration effect of the melanin pigment, .

On the other hand, currently available skin whitening cosmetics do not produce melanin from skin cells after receiving ultraviolet light. The registered ingredients of whitening cosmetics in Korea Food and Drug Administration are Niacinamide (C ₆ H ₆ N ₂ O), Broussonetia Extract, Ascorbyl Glucoside (C ₁₂ H ₁₈ O ₁₁ ) , ascorbyl tetra isopropyl palmitate (ascorbyl Tetraisopalmitate, 2,3,5,6-tetra- 2-hexyldecanonyl-L-ascorbyl acid, C 70 H 128 O 10), arbutin (arbutin, 4- hydroxyphenyl -β- D-glucopyranoside, C ₁₂ H ₁₆ O ₇ ), alpha-bisabolol, 6-methyl-2- (4-methyl-3-cyclohexen- - an extract), etc. - all, C ₁₅ H ₂₆ O), ethyl ascorbyl ether (ethyl ascorbyl _{bait, C 8 H 12 O 6)} , oil-soluble licorice extract (Oil Soluble licorice (Glycyrrhiza ascorbyl ethyl ether, 3- O). These components inhibit the activation of tyrosinase, an enzyme involved in the production of melanin in skin cells (mulberry extract, arbutin, alpha-bisabolol, and soluble licorice extract), ii) tyrosine stimulated by tyrosinase, (Iii) inhibiting the step of transferring melanin from melanocytes to keratinocytes (niacinamide) by skin whitening (ibuprofen) . ≪ / RTI >

On the other hand, a typical pharmaceutical ingredient related to skin whitening is hydroquinone. Hydroquinone is sold as an ointment-type medicinal product. Unlike whitening cosmetics, which inhibit melanin production, it is known that skin cells with melanin are directly destroyed to help new skin cells grow.

However, these components are limited in their use as raw ingredients for cosmetics due to their low stability or problems of skin side effects, or they have poor efficacy and / or efficacy and are toxic to skin cells, cause carcinogenesis or allergy, Due to this, only limited concentration is allowed.

In order to solve the problems of the conventional skin whitening materials, new whitening ingredients have been researched and developed. Korean Patent No. 10-0755742, for example, proposes a skin whitening composition containing an acrylate-based compound having an excellent whitening effect and no toxicity as an active ingredient. However, there is a need to develop a substance having a skin-whitening effect that can be safely used in a human body because of its good solubility in a solvent and no irritation or toxicity to the skin, for example, in combination with other ingredients added to cosmetics or medicines .

Disclosure of the Invention The present invention has been proposed in order to solve the problems of the prior art described above, and an object of the present invention is to provide a cosmetic composition for skin whitening, And to provide an external preparation for skin comprising the same.

Another object of the present invention is to provide a skin whitening cosmetic composition containing as an active ingredient a compound having excellent solubility in a solvent so that it can be easily compounded with other components because of its excellent solubility in a solvent, cosmetics containing the same, And to provide an external preparation for skin comprising the same.

According to an aspect of the present invention, there is provided a skin whitening cosmetic composition comprising a compound represented by the following formula (I), a cosmetically acceptable salt thereof, or a possible isomer thereof as an active ingredient: to provide.

(I), R ¹ to R ⁶ are each independently a hydrogen atom, a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkoxy group, a C ₄ -C ₁₀ cycloalkyl group or a C ₅ -C ₁₀ aryl group; a is an amino acid or the peptide coupled (conjugation) through an ester bond, said amino acid is a basic amino acid, an acidic amino acid or a hydrophilic amino acid, wherein the peptide is a basic amino acid which is connected via a hydrophobic amino acid, acidic amino acid or a hydrophilic Amino acids)

In an exemplary embodiment, in formula (I), R ¹ to R ⁶ are each independently a hydrogen atom or a C ₁ -C ₁₀ alkyl group, and A is a basic amino acid or a basic amino acid connected through a hydrophobic amino acid Lt; / RTI >

For example, in one specific embodiment, the active ingredient may comprise a compound represented by the formula (II), a cosmetically acceptable salt thereof, or a possible isomer thereof.

(In the formula (II), A ¹ is arginine (Arg) or arginyl glycine linked through an ester bond)

At this time, the active ingredient may be contained at a concentration of 0.1 to 1000 μM.

The present invention also provides a cosmetic comprising the aforementioned cosmetic composition for skin whitening.

According to another aspect of the present invention, there is provided a method of treating, alleviating, and / or preventing a pigmented skin abnormality lesion containing the compound represented by the above-mentioned formula (I) or (II), a pharmaceutically acceptable salt thereof, Or prevention of < / RTI >

The present invention also provides an external preparation for skin containing such a pharmaceutical composition.

The compound added as an active ingredient according to the present invention has no stimulation or toxicity to the human body, and thus safety can be secured. In addition, the effect on skin whitening is superior to that of existing materials, and the solubility in solvents is also good.

Accordingly, the compound of the present invention is useful as a cosmetic composition for skin whitening and a cosmetic composition containing the cosmetic composition as well as a pharmaceutical composition for treating and / or preventing pigmented skin lesions, . In particular, as a harmless component to the human body, since there is no irritation or toxicity to human body, safety is ensured and thus it can be utilized as a medicine for treating and / or preventing skin whitening cosmetic products and pigmented skin lesions.

FIG. 1 is a graph showing the content of melanin secreted by the culture medium after treating the animal cell line with a spirosenol derivative and culturing for 72 hours according to an exemplary embodiment of the present invention. FIG.
FIG. 2 is a graph showing the content of melanin in cells after treatment with a spirostenol derivative in an animal cell line for 72 hours according to an exemplary embodiment of the present invention. FIG.
FIG. 3 is a graph showing the activity of tyrosinase in a cell after treatment with a spirostenol derivative in an animal cell line for 72 hours according to an exemplary embodiment of the present invention. FIG.
4A is a graph showing the degree of inhibition of melanogenesis in a state where the spirosenol derivative synthesized according to the exemplary embodiment of the present invention and spirosol not substituted are dissolved in water and ethanol. This is a photograph of the degree of whitening measured in the dissolved state. In Fig. 4B, SS represents unsubstituted spirosenol, and ASS represents spirosenol derivatives substituted with arginine.
FIG. 5 is a graph showing a result of measuring the V value of a hyperpigmentation site over time after application of a skin whitening cosmetic product manufactured according to an exemplary embodiment of the present invention to a human body.
FIG. 6 is a graph showing a result of measuring the V value of a normal skin area over time after application of skin whitening cosmetics manufactured according to an exemplary embodiment of the present invention to a human body.

Hereinafter, the present invention will be described in detail with reference to the accompanying drawings where necessary.

The present invention relates to a composition for treating / preventing skin whitening and / or pigmented skin abnormal lesions containing, as an active ingredient, a compound which is effective for skin whitening effect and for treatment and / or prevention of abnormal pigmented skin lesions. The compound to be added and contained as an active ingredient in a pharmaceutical composition for treating / preventing a skin whitening cosmetic composition and / or a pigmented skin abnormal lesion according to the present invention is a compound represented by the following formula (I), its pharmaceutical and / Or a cosmetically acceptable salt, or a possible isomer thereof.

(I), R ¹ to R ⁶ are each independently a hydrogen atom, a C ₁ -C ₁₀ alkyl group, a C ₁ -C ₁₀ alkoxy group, a C ₄ -C ₁₀ cycloalkyl group or a C ₅ -C ₁₀ aryl group; a is an amino acid or the peptide coupled (conjugation) through an ester bond, said amino acid is a basic amino acid, an acidic amino acid or a hydrophilic amino acid, wherein the peptide is a basic amino acid which is connected via a hydrophobic amino acid, acidic amino acid or a hydrophilic Amino acids)

With respect to the amino acids or peptides that are linked to compounds linked by multiple rings that are matrixes according to the present invention, the basic amino acids are lysine (Lys, K), arginine (Arg, R ) And histidine (His, H). Acidic amino acids are glutamic acid (Glu, E) or aspartic acid (Asp, D), which are amino acids with negative charge at neutral pH. Hydrophilic amino acids are serine (Ser, S), threonine (Thr, T), tyrosine (Tyr, Y), thiol groups (-SH (Cys, C), carboxyamide (Asn, N), and glutamine (Gln, Q). Hydrophobic amino acids include glycine (Gly, G), alanine (Ala, A), valine (Val), isoleucine (Ile, I), leucine (Leu, L) Methionine (Met, M) having a thioether bond, proline (Pro, P) having a side chain forming a ring structure, phenylalanine (Phe, F) having an aromatic ring as a side chain, and tryptophan (Trp, W) ≪ / RTI >

As an exemplary form of the compound represented by the above-mentioned formula (I) as an active ingredient contained in a composition for treating / preventing a skin whitening and pigmentation abnormal skin lesion according to the present invention, R ¹ to R ⁶ in the formula (I) are each independently a hydrogen atom or an alkyl group C ₁ -C _10, and a is may be a peptide consisting of the basic amino acid coupled through a basic amino acid, or a hydrophobic amino acid. For example, an effective ingredient which can be added to a pharmaceutical composition for the treatment / prevention of skin whitening and / or pigmented skin abnormal lesions is a compound represented by the following formula (II), its pharmaceutical and / or cosmetic engineering Acceptable salt, or a possible isomer thereof.

(In the formula (II), A ¹ is arginine (Arg) or arginyl glycine linked through an ester bond)

The cosmetically and / or pharmaceutically acceptable salts of compounds of formula (I) or (II) include acid addition salts formed by cosmetic and / or pharmaceutically acceptable free acids useful. For example, an acid addition salt may be prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile can do. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration. As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, Gluconic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glucuronic acid, aspartic acid, ascorbic acid, Hydroquinone, vanillylic acid, hydroiodic acid, and the like.

In addition, bases can be used to make cosmetic and / or pharmaceutically acceptable metal salts. For example, an alkali metal salt or an alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. The corresponding silver salt can also be obtained by reacting an alkali metal salt or an alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

The cosmetically and / or pharmaceutically acceptable salts of the compounds of formula (I) or (II), unless otherwise indicated, can be present in the compounds of formula (I) or (II) Lt; RTI ID = 0.0 > acid / basic < / RTI > For example, the cosmetically and / or pharmaceutically acceptable salts may include the sodium, calcium and potassium salts of the hydroxy group, and the other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate (Hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p- toluenesulfonate Can be prepared through a process for preparing a salt.

The compound represented by the formula (I) or (II) has at least one asymmetric carbon. The asymmetric carbon atoms contained in these compounds may independently represent the configuration of R, S or RS independently from each carbon atom, and therefore the compound of formula (I) or (II) may be either a pure enantiomer or a pure diastereomer May be in the form of a diastereoisomer, or in the form of a mixture of enantiomers, in particular racemates, or in the form of a mixture of diastereoisomers. The separation of enantiomers and diastereoisomers can be carried out by techniques known to those of ordinary skill in the art, particularly chromatography.

The compound according to the present invention can be synthesized by introducing and linking an appropriate amino acid or peptide to one end of a parent compound having a plurality of ring structures. Illustratively, by introducing a basic / acidic / hydrophilic amino acid through an ester bond to one end of the compound represented by the formula (I) or (II), or introducing a peptide composed of a basic / acidic / hydrophilic amino acid via a hydrophobic amino acid can do.

For example, (3β, 25R) -spirost-5-en-3-ol (spirosol) can be used as a starting material having a plurality of ring structures for synthesizing a compound represented by the formula (II) . Spirostenol, also called diosgenin, is a steroid sapogenin that is obtained by hydrolysis of wild yam saponins with strong acids, bases or enzymes. Spirostenol induces angiogenesis through estrogen receptor-related phosphatidylinositol 3-kinase, p38 mitogen-activated protein kinase pathway in osteoblasts. However, spirosol is low in solubility in solvents such as water (0.02 mg / L) and difficult to absorb in vivo.

In an exemplary embodiment of the present invention, a hydroxy group formed at one end of spirosenol to increase the solubility of spirosenol in water, which is a starting material, and a basic amino acid, an acidic amino acid, or a polar functional group having charge (Ii) a peptide consisting of a hydrophobic amino acid and a polar amino acid such as a basic / hydrophobic / hydrophilic amino acid, for example, by forming an ester bond with a carboxyl group of a hydrophobic amino acid to form an ester bond with the carboxyl group of the hydrophilic amino acid, To synthesize the spirosolene derivative to be displayed.

Illustratively, a spirostanol derivative in which a basic / acidic / hydrophilic amino acid is directly linked to a hydroxyl group located at one end of spirostanol via a carboxyl group of a basic / acidic / hydrophilic amino acid through an ester bond is synthesized by the following method (See Synthesis Example 1). For example, a basic / acidic / hydrophilic amino acid in which a polar functional group (e.g., an amine group (or amino group), a hydroxyl group, a thiol group, a carboxyl group, etc.) is protected by a suitable protecting group is reacted with spirosenol, An intermediate compound in which a basic / acidic / hydrophilic amino acid protected with a protecting group is esterified to a hydroxyl group at one end is obtained. At this time, for example, Boc (t-butyloxycarbonyl) or Fmoc (9-fluorenyl methoxycarbonyl) can be used as a protecting group for protecting the polar functional group of the basic / acidic / hydrophilic amino acid. However, the present invention is limited only to these exemplified protecting groups no. In one preferred embodiment, spirosol is low in solubility in water, and therefore can be dissolved in an appropriate organic solvent such as an organic solvent such as p-toluoyl chloride, triethylamine (TEA), tetrahydrofuran (THF) Can be used. Once the synthesis of the intermediate compound is complete, a deprotection reaction is carried out using trifluoroacetic acid and methylene chloride (TFA / MC) to remove the protecting group attached to the polar functional group of the basic / acidic / hydrophilic amino acid linked to the spirostenone end , A spirostanol derivative into which a basic / acidic / hydrophilic amino acid is directly introduced via an ester bond can be obtained.

According to an alternative embodiment, in order to link a peptide composed of a hydrophobic amino acid-basic / acidic / hydrophilic amino acid to a hydroxy group located at one end of spirosenol, the carboxyl group of the hydrophobic amino acid and the hydroxy group of spirostanol react to form an ester bond (See Synthesis Example 2). For example, a hydrophobic amino acid protected with a protecting group of an amine group and spirosenol are reacted with a suitable solvent to form a hydrophobic amino acid protected with a protecting group to form a ester bond with the hydroxyl group of spirosol, and a deprotection reaction An intermediate compound in which a hydrophobic amino acid forms an ester bond at one end of spirosol can be obtained. This intermediate compound and a basic / acidic / hydrophilic amino acid in which a polar functional group (for example, an amine group, a hydroxyl group, a thiol group, a carboxyl group, etc.) are protected by a suitable protecting group are reacted in a suitable organic solvent and then a basic / acidic / The protecting group attached to the polar functional group of the compound of formula (I) is removed to obtain a compound in which a basic / acidic / hydrophilic amino acid is linked to one end of spirosol through a hydrophobic amino acid.

According to an exemplary embodiment of the present invention, a compound represented by formula (I) or formula (II) inhibits the production of melanin in a culture medium of an animal cell line (see FIG. 1) (See FIG. 2). In particular, these compounds added as an active ingredient in accordance with the present invention lower the activity of tyrosinase, which is closely related to the production of melanin (see FIG. 3).

With regard to the deposition of melanin pigment in the skin, it is known that tyrosinase is produced by excessive production of melanin polymer through a series of enzymatic oxidation steps and accumulated in the skin. Tyrosinase is the most important enzyme in the melanogenesis process that converts tyrosine (Tyr) into DOPA (3,4-dihydroxy phenylalanine) and dopaquinone (DOPA-quinone), intermediates for the production of melanin polymers. According to an exemplary embodiment of the present invention, the compound of the present invention inhibits the activity of tyrosinase involved in the initial process of producing melanin, so that effective treatment and / or prevention of skin whitening and pigmentation abnormal skin lesions It is possible.

In particular, unlike spirostenol, in which an amino acid or a peptide is not introduced, in accordance with an exemplary embodiment of the present invention, a peptide having a basic / acidic / hydrophilic amino acid linked thereto via a basic / acidic / hydrophilic amino acid and / The stanol derivatives have improved solubility in organic solvents such as water or ethanol. Therefore, whilst spirostenol not substituted with an amino acid or a peptide has no whitening activity when added to water or an organic solvent, the spirostanol derivative according to the present invention exhibits far superior whitening activity (See Figs. 4A and 4B). Therefore, according to the present invention, a spirostanol derivative in which an amino acid or a peptide is bound to a hydroxy group at one end via an ester bond is useful as a skin whitening cosmetic composition containing a solvent and a pharmaceutical composition for the treatment and / And can also be used in a composition.

In addition, as a result of administration to a human body after preparation of a formulation containing the compound used in accordance with the present invention, skin brightness was greatly increased not only in hyperpigmentation sites but also in normal skin tissues (see FIGS. 5 and 6) It has been found that adverse effects such as erythema and itching are not reported in the administration, which is harmless to the human body (see Examples below).

Accordingly, according to one aspect of the present invention, there is provided a skin whitening cosmetic composition comprising a compound represented by the above-mentioned formula (I) or (II), a cosmetically acceptable salt thereof, or a possible isomer thereof as an active ingredient And cosmetics containing the cosmetic composition. According to an exemplary embodiment, the active ingredient may be contained in the cosmetic composition of the present invention in a concentration of 0.1 to 1000 μM, preferably 1 to 10 μM.

The skin whitening cosmetic composition according to the present invention may further comprise an excipient for cosmetic use. The effect of the present invention, that is, the effect of the present invention can be attained by using known components used in ordinary cosmetics such as moisturizing agent, powder component, ultraviolet absorber, antioxidant, cosmetic ingredient, glycolipid, plant extract, preservative, , a pH adjusting agent, a coloring matter, a viscosity adjusting agent or a gelling agent as an auxiliary component.

Nonlimiting examples of the moisturizing agent include propylene glycol, isoprene glycol, 1,2-heptanediol, 1,3-butylene glycol, dipropylene glycol, hexanediol, polyethylene glycol glycerin, glycerin, diglycerin, triglycerin, polyglycerin, Neopentyl glycol, sorbitol, erythritol, pentaerythritol, glucose, and galactose; fructose, sucrose, maltose, xylose, xylobiose, reduced products of oligosaccharide, protein, mucopolysaccharide, collagen, elastin, Triethanolamine, and the like.

Examples of the powder component include, but are not limited to, white inorganic pigments such as titanium oxide, silicon-treated titanium oxide, zinc oxide and barium sulfate, iron oxide pigments such as iron oxide, carbon black, titanium oxide sintered product, There may be mentioned calcium carbonate, calcium carbonate, magnesium carbonate, hydroxyapatite, and boron nitride, such as talc, muscovite, kaolin, silicon carbide, bentonite, smectite, anhydrous silicic acid, aluminum oxide, magnesium oxide, zirconium oxide, diatomaceous earth, calcium silicate, barium silicate, magnesium silicate, An organic polymer resin powder such as a white sieve powder, a titanium dioxide coated mica, a titanium oxide mica titanium oxide, a siliconized mica titanium, a young resin, a polyethylene resin, a fluorine resin, a cellulose resin and a silicone resin, zinc stearate and N- Natural low molecular weight powder, starch powder, silk powder and cellulose powder, red No. 201, red No. 202, etc. 203, No. 204, No. 402, No. 404 and No. 401, red No. 3, No. 104, No. 106, No. 205, No. 4, No. 5, No. 3 and No. 1 Zirconium such as zirconium, barium or aluminum lake, gold powder such as mica and gold powder, and composite powder such as titanium oxide coated with mica titanium oxide.

Non-limiting examples of ultraviolet absorbers may be benzophenone derivatives, paraamino benzoic acid derivatives, methoxycinnamic acid derivatives, urocanic acid, and the like. Non-limiting examples of antioxidants include BHT, BHA, vitamin C, vitamin E, derivatives thereof, salts thereof, and the like. Non-limiting examples of cosmetic ingredients may include vitamins including the above-mentioned vitamins, derivatives thereof, salts thereof, anti-inflammatory agents and herbal medicines. Non-limiting examples of glycolipids may be sphingoglycolipids and the like. Non-limiting examples of plant extracts may be extracts of aloe vera, locusts, hamamelis, cucumber, lemon, lavender, rose, and the like. Non-limiting examples of preservatives can be methyl p-hydroxybenzoate, ethyl p-oxybenzoate, butyl p-hydroxybenzoate, propyl pamooxybenzoate, phenoxyethanol and ethanol.

Non-limiting examples of flavorings may be camphor oil, tangerine oil, peppermint oil, jasmine absolute, pine oil, lime oil, lavender oil, rose oil and musk oil. Non-limiting examples of pH adjusting agents may be edetic acid, sodium edetate, sodium chloride, citric acid, sodium citrate, sodium hydroxide, potassium hydroxide and triethanolamine. Non-limiting examples of pigments may be Blue No. 1, Blue No. 204, Red No. 3, and Yellow No. 201. Non-limiting examples of viscosity modifiers include polyvinyl alcohol (PVA), methyl cellulose (MC), ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, other cellulose derivatives, polyvinyl pyrrolidone (PVP) (Alkylated) acrylic acid polymers (chain type, crosslinked type) and acrylic acid alkyl methacrylate copolymers such as carboxymethyl cellulose, xanthan gum, alginic acid or its salts, carrageenan, queen seeded paw, alkaline generous polysaccharides, carboxyvinyl polymer, acrylate, And so on. Non-limiting examples of gelling agents include glyceryl (behenic acid / eicosanic acid) glyceryl and (behenic acid / eicosanic acid) polyglyceryl-10, fatty acid metal salts, hydroxystearic acid, dextrin fatty acid esters, inulin fatty acid esters, Hydrocarbon waxes such as ester, acylated cellobiose, dibenzylidene sorbitol, amino acid gelling agent, silicic anhydride, organic modified clay mineral, silica, alumina, crosslinked organopolysiloxane, polyethylene wax or paraffin wax, carnauba wax or Vegetable wax such as candelilla wax, agar, gelatin and the like.

The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used as a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, a powder, a soap, , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a cream, a nutritional 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.

In addition, the cosmetic composition of the present invention may further comprise at least one cosmetically acceptable carrier to be incorporated in a general skin cosmetic composition, and examples thereof include oil, water, a surfactant, a moisturizer, 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.

When the formulation of the present invention is a paste, cream or gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component . When 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. In the case of a spray, in particular, / Propane or dimethyl ether. When the formulation of the present invention is a solution or emulsion, 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 alcohol, benzyl benzoate, Glycol, and 1,3-butyl glycol oil, in particular, cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol aliphatic ester, polyethylene glycol or fatty acid esters of sorbitan have.

In addition, when 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, Microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used. When the formulation of the present invention is an interface-active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, 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.

As another embodiment of the present invention, the present invention provides a cosmetic comprising the above cosmetic composition. Cosmetics are used in a similar way, for example, by applying the "Cosmetics Act" to clean and glamorize the human body, adding charm, brightly changing appearance, or applying, rubbing or spraying the human body to maintain or improve the health of the skin As an article, the action on the human body can be defined as being mild. For example, the cosmetic according to the present invention may be a functional cosmetic having a skin whitening effect. The cosmetic according to the present invention is a kind of functional cosmetics because it has been confirmed that it shows the effect of skin whitening when applied to human body.

For example, the cosmetic according to the present invention may be used as a skin lotion, a skin softener, a skin toner, an astringent, a lotion, a milk lotion, a moisturizing lotion, a nutrition lotion, a massage cream, a nutritive cream, , Soap, shampoo, cleansing foam, cleansing lotion, cleansing cream, body lotion, body cleanser, emulsion, press powder, loose powder or eye shadow formulation.

According to another embodiment of the present invention, there is also provided a pharmaceutical composition comprising a compound represented by the formula (I) or (II), a pharmaceutically acceptable salt thereof, or a possible isomer thereof as an active ingredient, To a therapeutic composition for treating, alleviating and / or preventing a lesion. As a lesion of pigmented skin abnormalities, for example, freckles, melasma, cafe au lait spot, chloasma, black speckles, etc., which are excessively formed of melanin pigment and are pathologically deposited on the skin, , Lentigo and hyperpigmentation of the skin after inflammation or irritation, but the present invention is not limited thereto. According to an exemplary embodiment, the active ingredient may be included in the pharmaceutical composition of the present invention at a concentration of 0.1 to 1000 μM, for example, 10 to 1000 μM.

The pharmaceutical composition for the treatment / prevention of pigmented skin disorder lesions according to the present invention may further comprise a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" of the present invention means that it exhibits properties that are not toxic to the cells or humans exposed to the composition. Such carriers may be used without limitation as long as they are known in the art such as buffers, preservatives, wetting agents, solubilizers, isotonic agents, stabilizers, bases, excipients and lubricants. In addition, the pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method have. Furthermore, it can be used in the form of an external preparation for skin in the form of ointments, lotions, spray agents, patches, creams, powders, suspensions, gels or gels.

Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used.

For example, solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, Sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use may include various excipients, wetting agents, sweetening agents, fragrances, preservatives, etc. in addition to water and liquid paraffin, which are simple diluents commonly used in suspension agents, solutions, emulsions and syrups.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.

As yet another embodiment of the present invention, the present invention provides an external preparation for skin comprising a pharmaceutical composition for treating / preventing a pigmented skin abnormality lesion. The term "external preparation for skin" of the present invention is a comprehensive concept including general substances generally used for external skin application. Non-limiting examples of formulations comprising the above pharmaceutical compositions include, but are not limited to, an agent such as a warning agent, a lotion, a liniment, a liquid, an aerosol, an excipient, an ointment, a fluid excipient, an emulsion, a suspension, a capsule, a cream, Gelatin capsules, pastes, and sustained release preparations.

The external preparation for skin according to the present invention may be a parenteral dosage form which is formulated in solid, semi-solid or liquid form by adding a compatible inorganic or organic carrier, excipient and diluent. The preparation for parenteral administration may be a transdermal dosage form selected from the group consisting of drops, ointments, lotions, gels, creams, patches, sprays, suspensions, and emulsions.

Examples of carriers, excipients and diluents that can be contained in the external preparation include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In the external preparation for skin according to each formulation, the components other than the composition of the present invention may be mixed and selected without difficulty by those skilled in the art according to the formulation or use purpose of the external preparation for skin, etc. In this case, A synergistic effect can occur.

In addition, when the composition according to the present invention is used as a pharmaceutical composition, it may further contain a preservative, a stabilizer, a wetting agent or an emulsifying accelerator, a pharmaceutical adjuvant such as a salt or buffer for controlling osmotic pressure and other therapeutically useful substances And can be formulated into parenteral administration forms according to conventional methods. It should be understood that the actual dosage of the active ingredient should be determined in light of various relevant factors such as the severity of the symptoms, the route of administration selected, the age, sex, weight and health status of the subject. In general, the dosage of active ingredient is in the range of from 0.001 [mu] g / kg / day to about 2000 [mu] g / kg / day. A more preferred dosage is 0.5 [mu] g / kg / day to 2.5 [mu] g / kg / day. External administration may be administered once a day or divided into several doses.

Hereinafter, the present invention will be described in detail with reference to exemplary embodiments, but the present invention is not limited to the invention described in the following embodiments.

Synthesis Example 1: Synthesis of arginyl-spiroselen derivative

(1) Synthesis of an ester-bonded intermediate with Boc-protected arginine

(Boc-Arg (Boc) _2- OH protected with Boc) and 3 amine groups were protected with Boc (3β, 25R) -spirost-5-en-3-ol (spirosol, 7.92 g, 19.01 mmol, , 9.02 g, 19.01 mmol) was dissolved in 100 ml of triethylamine (TEA) (5.3 ml, 38.04 mmol), p-Toluoyl chloride (2.53 ml, 19.01 mmol) and tetrahydrofuran (THF) after 4-dimethylaminopyridine (DMAP, 2.3 g, 19.01 mmol) was added thereto, followed by stirring at room temperature for about 12 hours. Spirostenol, the starting material, was completely disappeared on TLC, and then the solvent was removed and extracted with saturated KHSO ₃ (aq) solution and methylene chloride. The solvent was removed by drying with MgSO ₄ . The crude product was separated by silica gel chromatography (hexane: ethylacetate = 5: 1) to give an intermediate ((3)) in white solid (yield: 87%).

(2) Synthesis of arginyl-O-spirostenol

The purified intermediate compound ((2)) was stirred under 30% TFA / MC (trifluoroacetic acid / methylene chloride) for about 1 hour to remove the protected Boc group. The solvent was removed on a rotary evaporator and a white solid was obtained. The compound was dissolved in acetone and treated with 2M-HCl / Ether to replace TFA salt with HCl salt. At this time, a white precipitate was formed. The precipitate was filtered with a glass filter, washed several times with acetone and ether, and dried to obtain a clean compound ((3)) having a purity of 95% or more. NMR analysis results are shown below.

^One ≪ 1 > H NMR (500 MHz, CDCl3 ₃ (m, 2H), 1.89 (m, 2H), 1.89 (m, 2H), 1.84 ), 1.65 (m, 12H), 1.25 (m, 7H), 1.01 (s, 3H), 1.96 (m, 4H), 0.74 (s, 3H), 0.73 LRMS (ESI): m / z = 571.5 [M + 1] < ⁺

Synthesis Example 2: Synthesis of arginyllylisyl-spiroselen derivative

(1) Synthesis of glycyl-spirostanol ester

(100 ml) was added to a mixture of Boc-Gly-OH (4.6 g), spirosol (10 g, (1)), triethylamine (TEA) (6.7 ml) and p- And stirred for about 2 minutes. 4-Dimethylaminopyridine (DMAP, 2.93 g) was added and stirred at room temperature for about 12 hours. Spirostenol, a starting material, was completely disappeared on TLC, and then the solvent was removed and extracted with saturated KHSO ₃ (aq) solution and methylene chloride (MC). The solvent was removed by drying with MgSO ₄ . The crude product was separated by silica gel chromatography (hexane: ethylacetate = 5/1) to give a white solid (yield 90%). The purified intermediate N-Boc-Glycyl spirostanol ester was stirred under 10% TFA / MC for about 3 hours to remove the protected Boc group. The solvent was removed on a rotary evaporator and ether was added to give a white solid. MR analysis results are shown below.

¹ H-NMR (500.13 MHz, DMSO-d ₆ ): d 8.18 (bs, 3H), 5.37 (d, IH), 4.60-4.58 (m, IH), 4.28 ), 3.41-3.39 (m, 1H), 3.20 (t, 1H), 2.33-2.22 (m, 2H), 1.97-0.86 (m, 28H), 0.74 (s, (ESI): m / z = 472.6 [M + H] < ^{+ &}

(2) Synthesis of arginyllylisyl-O spirostanol

Boc-Arg-OH (7.24 g) was dissolved in 50 ml of dimethylformamide (DMF), and ethylene dichloride (EDC, 6.33 g) and hydroxybenzotriazole (HOBt, 3.57 g) were added and stirred for about 20 minutes . The intermediate compound ((2), 12 g) obtained above and TEA (3.7 ml) were dissolved in 100 ml of CH ₂ Cl ₂ , and this mixed solution was added to the solution and stirred at room temperature for about 6 hours. The solvent was removed by concentration under reduced pressure, and water was poured into the resulting residue to obtain a white solid. The resulting white solid was washed several times with water and dried to give Gly-N-BOC-Arg spirosol in 90% yield. The purified ester was stirred under 10% TFA / MC for about 3 hours to remove the protected Boc group. The solvent was removed on a rotary evaporator and ether was added to give a white solid. This compound was dissolved in 100 ml of acetone and 2M HCl / Ether (30 ml) was added to obtain a white precipitate. The precipitate was filtered with a glass filter, washed several times with acetone, and dried. NMR analysis results are shown below.

¹ H-NMR (500.13 MHz, DMSO-d ₆ ): d 9.09 (s, IH), 8.33 (s, 2H), 7.81 ), 4.30 (qt, IH), 3.96-3.89 (m, 3H), 3.43-3.40 (m, IH), 3.24-3.16 ), 0.75 (s, 3H), 0.74 (s, 3H) LRMS (ESI): m / z = 701.7 [M ⁺

Example 1: Measurement of inhibitory effect on melanin formation

(1) Measurement of the melanin content secreted in the culture medium

B16F10 mouse melanoma used as a cell line was seeded at 2 × 10 ⁵ / well in each well of a 6-well plate, and cultured in a 37 ° C. 5% CO ₂ incubator for 24 hours. The medium of each well was removed and fresh DMEM 10% FBS). The spirosenol derivatives synthesized in Synthesis Example 1 and Synthesis Example 2 were treated for each concentration in each well, treated with 100 pg / ml of alpha-melanocyte stimulating hormone (alpha-MSH), and then cultured for 72 hours. After the culture, the melanin content secreted by the culture medium was measured. A negative control (NT), which had no treatment for comparison, and arbutin, hydroquinone, and spirostenol, which are known to have a whitening effect, were used as positive control. Arbutin and hydroquinone, positive control groups, were selected and treated at the most effective concentrations to the extent that no toxicity was observed. The measurement results are shown in Table 1 and Fig. The content of melanin secreted into the medium was significantly lowered in the 10 μM treated group of arginyl-spiroselen and arginyllysyl-spiroselen derivative, compared with spirosenol not substituted with the peptide.

(2) Measurement of intracellular melanin content

The culture solution obtained above was removed, 1 ml of PBS was added, each well was scraped with a cell scraper to remove the cells, and then transferred to a 1.5 ml tube. Subsequently, the supernatant was removed by centrifugation at 8,000 rpm for 3 minutes at 4 DEG C, and the cell pellet was recovered. The cell pellet was recovered and washed with 200 L of lysis buffer (1 mM Triton X-100, 1 mM PMSF (phenylmethylsulfonyl fluoride) phosphate buffer (pH 6.8)). Cells were lysed by vortexing for 30 min at 10 min intervals and centrifuged at 13,000 rpm for 30 min at 4 ° C to remove the supernatant. The melanin-containing cell pellets were recovered and resuspended in 100 l of ether / isopropanol 1: And washed once. The supernatant was removed by centrifugation at 13,000 rpm for 10 minutes. After drying at 60 ° C for about 3 hours, 110 l of 1N NaOH was added to dissolve the melanin in the cells at 60 ° C for 1 hour. The supernatant obtained by dissolving in each well of a 96-well plate was added in an amount of 100 L, and absorbance was measured at 490 nm. The measurement results are shown in Table 2 and FIG. The intracellular melanin content also showed a much better effect in the arginyl-spirosenol and arginyl-glyceryl-spiroselenes treated groups compared to spirosenols.

Example 2: Inhibition of intracellular tyrosinase activity

B16F10 mouse melanoma was seeded into each well of a 6-well plate at 2 × 10 ⁵ and incubated in a 5% CO2 incubator at 37 ° C. for 24 hours. After removing the medium from each well, fresh DMEM (containing 10% FBS) . Each well was treated with the active material by concentration, followed by treatment with 100 pg / ml of? -MSH, followed by incubation for 72 hours. Then, the culture solution was removed, 1 ml of PBS was added, each well was scraped with a cell scraper to remove the cells, and then transferred to each 1.5 ml tube. Subsequently, the supernatant was removed by centrifugation at 8,000 rpm for 3 minutes at 4 ° C, and the cell pellet was recovered. The cell pellet was recovered and washed with 200 L of lysis buffer (1% Triton X-100, 100 mM sodium phosphate buffer 6.8). The cells were vortexed at 10 minute intervals for 30 minutes and then centrifuged at 13,000 rpm for 30 minutes at 4 ° C to transfer the supernatant to a new 1.5-ml tube. The total amount of protein was quantified using a BCA protein assay kit (PIERCE, USA). The same amount of the sample was added to each well of a 96-well plate in an amount of 40 L, followed by 2 mg / 6.8) containing 160 L of L-3,4-dihydroxyphenylalanine (L-DOPA). After reacting at 37 ° C for 10 minutes to 30 minutes, the absorbance was measured at 475 nm. The measurement results are shown in Table 3 and FIG. Similar to the case of measuring the melanin content, it was confirmed that the tyrosinase activity was further inhibited in the arginyl-spiroselen derivative and the arginyllysyl-spirosenol derivative as compared with the un-substituted spirosenol.

Example  3: Melanin formation inhibition and whitening effect in a state dissolved in a solvent

The arginyl-spirosenol derivative synthesized in Synthesis Example 1 and the non-substituted spirosenol were dissolved in distilled water (DW) and ethanol (EtOH), and the degree of inhibition of melanin formation and the whitening effect Were measured. The melanin production inhibitory effect is shown in Fig. 4A and the whitening effect is shown in Fig. 4B. The unsubstituted spirosol was low in solubility in solvents and no whitening activity appeared after mixing in solvent. On the other hand, arginyl-spirosol novolak derivatives showed better whitening activity when dissolved in a solvent and dissolved in a solvent.

Preparation Example: Preparation of external preparation for skin

An external skin preparation containing arginyl-spiroselen derivatives prepared according to Synthesis Example 1 was prepared according to the content ratios shown in Table 4 below.

Example 4: Improvement of skin brightness according to human body application

The skin external preparation made in the manufacturing example was continuously administered to 23 adult women aged 23-55 years with a hyperpigmentation site on the face, and the degree of improvement in skin brightness over time was evaluated. The selected test subject was a woman who had no skin disease or allergic specific disease and used the skin external preparation made in the manufacturing example twice a day (morning / evening). Before applying to the human body (0 week), 3 weeks And skin brightness after 6 weeks of use. The subjects were prohibited to use basic cosmetics and cosmetics 12 hours before the test, and prohibited the use of cosmetics, such as skin care products, which could affect the evaluation results 1 week before the start of the human body application test. The human body test was carried out under the condition of constant temperature and humidity (20 ~ 24 ℃, relative humidity 40 ~ 60%) and stable for 30 minutes after washing.

In order to evaluate the skin brightness of the sample, the face of the subject was photographed at 3 weeks and 6 weeks before use, using Visia-CR (Canfiled Imaging System, USA). The ball portion of the facial photograph taken in the cross-polarized mode was determined as the test site and the average value of the V (Value) of the test site was obtained using image analysis software (Image-Pro Plus, USA). The V value was used to evaluate the skin brightness using the mean value as a factor associated with skin brightness. The instrumental values were confirmed by repeated measures ANOVA with a mean difference of 5% (p <0.05) between before and after use of the sample. Statistical analysis program was PASW statistics 21 (SPAA, USA).

Table 5 shows the results of analysis of hypercholesterolemic sites and V-values of normal skin areas for each subject. Meanwhile, FIG. 6 shows the results of the mean V-value analysis of the entire test subjects for hyperpigmentation sites and normal skin areas, and FIGS. 5 and 6 show the results of the mean V value measurement results.

As a result of analyzing the V value of hyperpigmentation site and normal skin area using Visa-CR and image analysis software, the skin external preparation prepared in the preparation example was statistically significant after 6 weeks (p <0.05 ) Showed 0.64% and 0.65% increase in hyperpigmentation site and normal skin area, respectively. Therefore, this sample is considered to help improve the skin color of the hyperpigmented area and normal skin area.

On the other hand, the increase rate of V value using Visia-CR and image analysis software was calculated using the following equation, and the calculation results are shown in Table 7 below.

Example 5: Skin Irritation Test

The test subjects of Example 5 were checked with the help of a dermatologist for skin adverse reaction according to the application of the external preparation obtained according to the preparation example, and when the adverse reaction occurred, the grade was displayed according to the severity. If there is no adverse reaction, the score is indicated as 0, weakly 1, middle 2, and severe 3. The evaluation results are shown in Table 8 below. During the evaluation period, the patient did not show any special skin reactions such as itching symptoms and blister symptoms.

Claims (10)

A cosmetic composition for skin whitening comprising a compound represented by the following formula (II) as an active ingredient.

(In the formula (II), A ¹ is arginine (Arg) or arginyl glycine linked through an ester bond) The cosmetic composition for skin whitening according to claim 1, further comprising a cosmetically acceptable carrier. The cosmetic composition for skin whitening according to claim 1, wherein the active ingredient is added to a solvent which is water or ethanol. The cosmetic composition for skin whitening according to claim 1, wherein the effective ingredient is contained at a concentration of 0.1 to 1000 μM. A cosmetic comprising the cosmetic composition for skin whitening as set forth in any one of claims 1 to 4. An external preparation for skin comprising the cosmetic composition for skin whitening as set forth in any one of claims 1 to 4. delete delete delete delete

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