External preparation and kit

Abstract

To provide an external preparation and a kit that can suppress inactivation of an antioxidant during storage and exhibit antioxidative effect of the antioxidant when applied to a target site.SOLUTION: An external preparation containing an antioxidant having a thiol group or a hydroxy group protected with a photolabile protecting group. A kit comprising the external preparation and a light-shielding container accommodating the external preparation.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to an external preparation and a kit. [Background technology]

[0002] Skin and hair are often exposed to ultraviolet rays and are susceptible to oxidative stress. Reactive oxygen species generated by exposure to ultraviolet rays damage cells, which is thought to be one of the causes of skin blemishes and wrinkles, and hair dryness, split ends, and bleaching.

[0003] For the purpose of preventing damage caused by reactive oxygen species, a technique has been proposed for capturing free iron or copper, which can catalyze reactions causing oxidative damage by reactive oxygen species, in which the chelating agent is blocked with a photocleavable substituent so that the scavenger itself exerts its scavenging ability upon exposure to ultraviolet light, while suppressing the side effects of the scavenger itself until exposure to ultraviolet light, which causes oxidative damage (see, for example, Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 8-92081 Summary of the Invention [Problem to be solved by the invention]

[0005] Meanwhile, research is being conducted into topical preparations containing antioxidants in the hope of preventing or repairing oxidative damage caused by antioxidants. However, during the storage stage before application of the topical preparation to the target site, the antioxidant may react with dissolved oxygen and lose its antioxidant properties. Therefore, topical preparations are required to suppress the deactivation of the antioxidant during storage while still exhibiting the antioxidant's antioxidant properties when applied to the target site, but such a technology has not been discovered.

[0006] In view of the above problems, the present invention aims to provide an external preparation and kit that can suppress the inactivation of the antioxidant during storage while exerting the antioxidant's antioxidant properties when applied to the target site. [Means for solving the problem]

[0007] In one embodiment, the present invention relates to an external preparation containing an antioxidant having a thiol group or a hydroxy group protected with a photolabile protecting group.

[0008] In one embodiment, the photolabile protecting group may be a group that dissociates upon irradiation with ultraviolet light having a wavelength of 320 nm or more and 400 nm or less.

[0009] In one embodiment, the photolabile protecting group may have a partial structure represented by any one of the following formulas (a) to (d). [ka] (In the above formula, * represents a bond to the sulfur atom of the thiol group or the oxygen atom of the hydroxy group. The dashed line represents a bond to another structure in the photolabile protecting group.)

[0010] In one embodiment, the photolabile protecting group may have at least one group selected from the group consisting of a nitro group, a hydroxy group, an alkoxy group, an acyl group, and a substituted or unsubstituted amino group.

[0011] In one embodiment, the photolabile protecting group may be a coumarinylmethyl group, a coumarinylcarbonylmethyl group, a nitrobenzyl group, a hydroxyphenacyl group, or a group in which some or all of the hydrogen atoms of these groups have been substituted with substituents.

[0012] In one embodiment, the antioxidant may be water-soluble or oil-soluble.

[0013] In one embodiment, the antioxidant may be an antioxidant containing a thiol group.

[0014] In one embodiment, the antioxidant may be glutathione, ascorbic acid, dihydrolipoic acid, or a derivative thereof.

[0015] In one embodiment, the topical preparation may be for cosmetic use.

[0016] In one embodiment, the topical agent may be for hair.

[0017] In one embodiment, the present invention relates to a kit comprising the topical preparation and a light-shielding container that contains the topical preparation.

[0018] In this specification, the term "protected hydroxy group" includes an amide bond or an ester bond (carboxylic acid ester bond or sulfonic acid ester bond) that is cleaved or decomposed by light irradiation to generate COOH or SO3H. [Effects of the Invention]

[0019] According to the topical preparation of the present invention, the thiol group or hydroxyl group, which is the active site of the antioxidant, is protected by a photolabile protecting group, thereby suppressing reaction with dissolved oxygen during storage and preventing deactivation of the antioxidant. Furthermore, after application of the topical preparation to the target site, the photolabile protecting group is dissociated and deprotected by irradiation with light, particularly ultraviolet light, thereby allowing the preparation to exhibit good antioxidant properties. [Brief explanation of the drawings]

[0020] [Figure 1] 1 is a graph showing the change in absorbance at 600 nm in a resazurin reduction test depending on whether or not an antioxidant is protected with a photolabile protecting group. [Figure 2] 1 is a graph showing the spectroscopic spectra of the antioxidants of Examples 1 to 6 protected with a photolabile protecting group. [Figure 3]1 is a graph showing absorbance at 600 nm in a resazurin reduction test using protected forms of the antioxidants of Examples 1 to 6 protected with a photolabile protecting group. [Figure 4] 1 is a graph showing absorbance at 600 nm in a resazurin reduction test using a protected form of the antioxidant of Example 7 protected with a photolabile protecting group. [Figure 5] 1 is a graph showing absorbance at 600 nm in a resazurin reduction test using a protected form of the antioxidant of Example 8 protected with a photolabile protecting group. [Figure 6] 1 is a graph showing absorbance at 600 nm in a resazurin reduction test for the antioxidant of Example 9 in a protected form protected with a photolabile protecting group and in an unprotected state. [Figure 7] 1 is a graph showing absorbance at 600 nm in a resazurin reduction test using a protected form of the antioxidant of Example 10 protected with a photolabile protecting group. DETAILED DESCRIPTION OF THE INVENTION

[0021] Hereinafter, the embodiments of the present invention will be described in detail, but the present invention is not limited to these embodiments. Combinations of preferred aspects in the embodiments are also preferred.

[0022] <External preparations> The topical preparation according to this embodiment contains an antioxidant having a thiol group or a hydroxyl group protected by a photolabile protecting group. The topical preparation may contain other optional ingredients as long as the effects of the present invention are not impaired.

[0023] (antioxidant) The antioxidant is not particularly limited as long as it is a compound containing a thiol group (-SH moiety) or a hydroxyl group (-OH moiety) as an active site that exhibits antioxidant properties (electron-donating reducing properties). The antioxidant may be a water-soluble antioxidant or an oil-soluble antioxidant. From the viewpoint of ease of application as a topical agent, the antioxidant is preferably a water-soluble antioxidant.

[0024] In this specification, "water-soluble" means that the solubility in water at 25° C. is 1% or more, and "oil-soluble" means that the solubility in water at 25° C. is less than 1%. Note that "oil-soluble" and "poorly water-soluble" are treated as synonyms.

[0025] Examples of water-soluble antioxidants include thiol group-containing antioxidants such as glutathione, ergothioneine, coenzyme A, dihydrolipoic acid, and penicillamine, and hydroxyl group-containing antioxidants such as ascorbic acid, anthocyanin, saponin, theaflavin, and uric acid. Among these, glutathione, ascorbic acid, dihydrolipoic acid, or derivatives thereof are preferred, with glutathione or its derivatives being more preferred. Glutathione is a linear oligopeptide (tripeptide) composed of L-glutamine, L-cysteine, and glycine, as represented by the following formula: As with other thiol group-containing antioxidants, the thiol group (derived from L-cysteine ​​in glutathione) exhibits electron-donating properties, thereby exerting antioxidant properties.

[0026] [ka]

[0027] Examples of oil-soluble antioxidants include hydroxy group-containing antioxidants such as tocopherol, sesamol, astaxanthin, terephthalylidene dicamphorsulfonic acid, oxybenzone-3, oxybenzone-4, diethylaminohydroxybenzoylhexylbenzoate, phenylbenzimidazole sulfonic acid, drometrizole trisiloxane, bisethylhexyloxyphenol methoxyphenyl triazine, ferulic acid, homosalate, and methylenebisbenzotriazolyltetramethylbutylphenol.

[0028] The thiol or hydroxyl group contained as the active site of the antioxidant is protected by a photolabile protecting group. The photolabile protecting group dissociates (deprotects) upon irradiation with light, generating a thiol or hydroxyl group as the active site of the antioxidant. This allows the dissociation of the photolabile protecting group to proceed upon exposure to natural light, particularly ultraviolet light contained in sunlight, allowing the topical preparation to rapidly exert its antioxidant properties after application to the target site. Furthermore, because the active site is protected, the antioxidant can be prevented from being inactivated by dissolved oxygen during storage of the topical preparation in a container.

[0029] The light is not particularly limited and may be natural light or artificial light. The wavelength of the light is also not particularly limited and wavelengths ranging from near ultraviolet to near infrared can be suitably used. The photolabile protecting group is preferably a group that dissociates upon irradiation with ultraviolet light having a wavelength of 320 nm or more and 400 nm or less.

[0030] As a result of investigations, the present inventors have come up with the idea that the factors that cause a photolabile protecting group to dissociate (deprotect) upon irradiation with light are mainly influenced by (1) the presence of a conjugated structure in which double bonds (C=C, C=O) are connected to a certain extent, (2) the distance between the dissociating portion and the conjugated structure, and (3) the stability of the cation generated upon dissociation.

[0031] Regarding the above factor (1), by introducing the conjugated structure into the photolabile protecting group, sensitivity to natural ultraviolet light (≧320 nm) can be exhibited as the light absorption wavelength. The absorption wavelength can be adjusted by introducing a polar group in addition to the conjugated structure. The combined use of the conjugated structure and the polar group allows for efficient design of a structure for dissociation of the photolabile protecting group.

[0032] Regarding the above factor (2), it is effective to adopt a structure in which the moiety (carbon atom) that dissociates from the active site (S of SH, O of OH) of the antioxidant in the photolabile protecting group and the conjugated structure are close to each other, preferably adjacent to each other.

[0033] Regarding the factor (3), it is possible to utilize the fact that the carbon atoms adjacent to the conjugated structure are stable in a state where they maintain a positive charge (i.e., the energy barrier for dissociation of the photolabile protecting group is low).

[0034] The photolabile protecting group may have a partial structure represented by any one of the following formulae (a) to (d) (hereinafter, each may be referred to as "partial structure (a)" or the like). By introducing the following partial structure into the photolabile protecting group, the above factors (1) to (3) can be preferably satisfied, and efficient dissociation (deprotection) of the photolabile protecting group can be induced. Note that in partial structure (d), although C=C and C=O are not adjacent, the nitrogen atom is sandwiched between C=C and C=O, providing a stable receptacle for the positive charge generated on the carbonyl carbon. It is presumed that dissociation proceeds due to stabilization of the reaction intermediate, similar to the carbon adjacent to the conjugated system.

[0035] [ka] (In the formulas (a) to (c), * represents a bond to the sulfur atom of the thiol group or the oxygen atom of the hydroxy group. In the formula (d), ** represents a bond to another atom constituting the antioxidant that generates COOH upon dissociation. The dashed lines represent bonds to other structures in the photolabile protecting group. The bonds indicated by the wavy lines are dissociated upon irradiation with light.)

[0036] As the photolabile protecting group, photolabile protecting groups having the partial structures (a) to (d) can be suitably used. Examples of photolabile protecting groups having the partial structure (a) include coumarinyl protecting groups and nitrobenzyl protecting groups. Examples of photolabile protecting groups having the partial structure (b) include coumarinyl protecting groups and hydroxyphenacyl protecting groups. Examples of photolabile protecting groups having the partial structure (c) include styrylmethyl protecting groups. Examples of photolabile protecting groups having the partial structure (d) include nitroindoline protecting groups. Derivatives of these photolabile protecting groups are also suitable. As the photolabile protecting group, coumarinyl protecting groups, nitrobenzyl protecting groups, and derivatives thereof are preferred in terms of absorption wavelength, photodissociation efficiency, etc. Among these, the photolabile protecting group is preferably a coumarinylmethyl group, a coumarinylcarbonylmethyl group, a nitrobenzyl group, a hydroxyphenacyl group, or a group in which some or all of the hydrogen atoms of these groups have been substituted with a substituent. These protecting groups can stabilize the radical on the carbon atom adjacent to the conjugated system (including the carbonyl group), and can exhibit good photolabile properties. Furthermore, the introduction of these protecting groups can impart the ability to reach deep layers of the skin, which is difficult to achieve with water-soluble antioxidants alone.

[0037] Examples of the photolabile protecting group include structures represented by the following formula (1) or (2). [ka] (In formula (1), R 1 R is a cyano group, a nitro group, a hydroxy group, an amino group, an alkyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an acyl group, an acyloxy group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. 1 If there are multiple R 1 are the same or different. 1 teeth, ** -CH2- or **It is -CO-CH2-. ** is a bond on the ring side. n is an integer of 0 to 4. * is a bond to the sulfur atom of a thiol group or the oxygen atom of a hydroxy group. In formula (2), R 2 R is a cyano group, a nitro group, a hydroxy group, an amino group, an alkyl group, an alkoxy group, an alkoxycarbonyl group, an alkoxycarbonyloxy group, an acyl group, an acyloxy group, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. 2 If there are multiple R 1 are the same or different. m is an integer of 0 to 4. R 3 is a hydrogen atom, a cyano group, a nitro group, or a carboxy group. * is a bond to the sulfur atom of a thiol group or the oxygen atom of a hydroxyl group.

[0038] In formula (1), L 1 When attached to the 4th position, L 1 teeth, ** -CH2- is preferred. 1 When attached to the 3rd position, L 1 teeth, ** -CO-CH2- is preferred.

[0039] In formula (2), the nitro group (-NO2) is preferably located at the o-position relative to the benzylic carbon bonded to the benzene ring.

[0040] R 1 and R 2In the formula (I), examples of the amino group include N,N-dialkylamino groups such as N,N-dimethylamino and N,N-diethylamino, N,N-dicarboxyamino groups, and -NH2 groups. Examples of the alkyl group include linear or branched alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, propyl, and isopropyl groups. Examples of the alkoxy group include alkoxy groups having 1 to 10 carbon atoms such as methoxy, ethoxy, and propoxy groups. Examples of the alkoxycarbonyl group include alkoxycarbonyl groups having 2 to 10 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl groups. Examples of the alkoxycarbonyloxy group include alkoxycarbonyloxy groups having 2 to 10 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl groups. Examples of the acyl group include aliphatic or aromatic acyl groups having 2 to 12 carbon atoms, such as an acetyl group, a propionyl group, a benzoyl group, and an acryloyl group. Examples of the acyloxy group include aliphatic or aromatic acyloxy groups having 2 to 12 carbon atoms, such as an acetyloxy group, a propionyloxy group, a benzoyloxy group, and an acryloyloxy group.

[0041] R 1 and R 2 As the alkyl group, an alkoxy group, an N,N-dialkylamino group, or an acyloxy group is preferred.

[0042] n and m are each independently preferably an integer of 0 to 3, more preferably an integer of 0 to 2, and even more preferably 0 or 1.

[0043] Specific examples of the photolabile protecting group include structures represented by the following formulas (1-1) to (1-8) and (2-1) to (2-6). [ka]

[0044] [ka] (In the above formula, * has the same meaning as in formulas (1) and (2) above.)

[0045] The lower limit of the amount of antioxidant (in a deprotected antioxidant state) in the topical preparation is preferably 0.03% by mass, more preferably 0.05% by mass, and even more preferably 0.1% by mass. The upper limit of the amount is preferably 10% by mass, more preferably 8% by mass, and even more preferably 7% by mass. By setting the amount of antioxidant in the above range, the antioxidant can be suitably exhibited during light irradiation.

[0046] (Method for synthesizing protected antioxidants) The synthesis method of an antioxidant in which a thiol group or a hydroxy group is protected is not particularly limited, and it can be synthesized by a known method. The following scheme shows a representative example in which glutathione is used as the antioxidant. As shown in the following scheme, it can be synthesized by a nucleophilic reaction between a halide of a photolabile protecting group and the antioxidant in an appropriate solvent.

[0047] [ka] (In the formula, G is a structure other than the thiol group of glutathione, X is a halogen atom, and Prot is a structure corresponding to a photolabile protecting group.)

[0048] Examples of the solvent include known organic solvents such as ethanol, water, and mixtures thereof. A mixture of water and ethanol is preferred as the solvent. The pH of the solvent and the ethanol content may be adjusted to enhance reaction efficiency. The lower limit of the pH of the solvent is preferably 7.7, more preferably 8.0. The upper limit of the pH is preferably 12.0, more preferably 11.0. By controlling the pH of the solvent within the above range, the reaction can be efficiently promoted while suppressing the generation of by-products due to excess hydroxy groups. The lower limit of the ethanol content in the solvent is preferably 5% by mass, more preferably 8% by mass. The upper limit of the ethanol content is preferably 20% by mass, more preferably 15% by mass. By controlling the ethanol content within the above range, the solubility of the component that provides the photolabile protecting group can be increased, thereby promoting the reaction, and the generation of by-products due to excess hydroxy groups can be suppressed.

[0049] Specifically, the process of protecting glutathione with the photolabile protecting group represented by formula (2-1) and a representative process of dissociating (deprotecting) glutathione by irradiation with light are shown in the following scheme. For other photolabile protecting groups, each process proceeds according to a similar scheme. However, the dissociation of the photolabile protecting group is not limited to the following scheme, and dissociation may proceed according to a different scheme.

[0050] [ka]

[0051] (Other ingredients) In addition to the antioxidant, the topical preparation may contain other ingredients used in topical preparations, such as oily ingredients, surfactants (synthetic or natural), moisturizers, thickeners, emulsifiers or emulsifier aids, preservatives / disinfectants, powder ingredients, ultraviolet absorbers, other antioxidants, pigments, fragrances, anti-wrinkle agents, other physiologically active ingredients, sequestering agents, pH adjusters, water, etc., as needed.

[0052] Examples of oily components include plant-derived oils such as olive oil, jojoba oil, castor oil, soybean oil, rice oil, rice germ oil, coconut oil, palm oil, cocoa oil, meadowfoam oil, shea butter, tea tree oil, avocado oil, macadamia nut oil, bergamot oil, lavender oil, rose oil, bergamot oil, and chamomile oil; vitamin A oil; animal-derived oils such as mink oil and turtle oil; waxes such as beeswax, carnauba wax, rice wax, and lanolin; hydrocarbons such as liquid paraffin, petrolatum, paraffin wax, and squalane (e.g., sugar squalane and olive squalane); myristic acid, palmitic acid, stearic acid, oleic acid, isostearic acid, and cis-11-eicosene. fatty acids such as PEG-14 hydroxybenzoates; higher alcohols such as lauryl alcohol, cetanol, pantothenyl alcohol, and stearyl alcohol; synthetic esters and synthetic triglycerides such as isopropyl myristate, isopropyl palmitate, butyl oleate, 2-ethylhexylglyceride, glyceryl tri-2-ethylhexanoate, trimethylpropane tri-2-ethylhexanoate, caprylic / capric triglyceride, caprylic / capric / myristate / stearic triglyceride, and higher fatty acid octyldodecyl (octyldodecyl stearate, etc.); and silicones such as cyclopentasiloxane, dimethicol, and dimethicone (methylpolysiloxane).

[0053] Examples of surfactants include nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitol fatty acid esters; fatty acid salts, alkyl sulfates, alkylbenzene sulfonates, polyoxyethylene alkyl ether sulfates, polyoxyethylene fatty amine sulfates, polyoxyethylene alkylphenyl ether sulfates, polyoxyethylene alkyl ether phosphates, α-sulfonated fatty acid alkyl ester salts, polyoxyethylene Examples of surfactants that can be used include anionic surfactants such as ethylene alkyl phenyl ether phosphates; cationic surfactants such as quaternary ammonium salts, primary to tertiary fatty amine salts, trialkylbenzylammonium salts, alkylpyridinium salts, 2-alkyl-1-alkyl-1-hydroxyethylimidazolinium salts, N,N-dialkylmorpholinium salts, and polyethylene polyamine fatty acid amide salts; and amphoteric surfactants such as N,N-dimethyl-N-alkyl-N-carboxymethylammoniobetaine, N,N,N-trialkyl-N-alkyleneammoniocarboxybetaine, and N-acylamidopropyl-N',N'-dimethyl-N'-β-hydroxypropylammoniosulfobetaine.

[0054] Examples of emulsifiers and / or emulsifying aids that can be blended include stevia derivatives such as enzyme-treated stevia, saponin or derivatives thereof, casein or its salts (sodium, etc.), sugar and protein complexes, sucrose or esters thereof, lactose, soybean-derived water-soluble polysaccharides, soybean-derived protein and polysaccharide complexes, lanolin or derivatives thereof, cholesterol, stevia derivatives (enzyme-treated stevia, etc.), silicates (aluminum, magnesium, etc.), carbonates (calcium, sodium, etc.), saponin and derivatives thereof, lecithin and derivatives thereof (hydrogenated lecithin, etc.), lactic acid bacteria-fermented rice, lactic acid bacteria-fermented germinated rice, lactic acid bacteria-fermented grains (wheat, beans, millet, etc.), etc.

[0055] Examples of moisturizing agents include glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, xylitol, sodium pyrrolidone carboxylate, and the like, as well as sugars such as trehalose and raffinose, mucopolysaccharides (e.g., hyaluronic acid and its derivatives, hyaluronic acid fermentation liquid, chondroitin and its derivatives, heparin and its derivatives, etc.), elastin and its derivatives, collagen and its derivatives, collagen peptides, NMF-related substances, lactic acid, urea, higher fatty acid octyldodecyl, seaweed extract, estradiol, various amino acids and their derivatives.

[0056] Examples of thickeners include components derived from brown algae, green algae, or red algae, such as alginic acid, agar, carrageenan, and fucoidan; polysaccharides such as pectin and aloe polysaccharide; gums such as tragacanth gum, locust bean gum, xanthan gum, and guar gum; cellulose derivatives such as carboxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose; synthetic polymers such as carboxyvinyl polymers, alkyl-modified carboxyvinyl polymers, polyvinyl alcohol, polyvinylpyrrolidone, and acrylic acid-methacrylic acid copolymers; hyaluronic acid and its derivatives; polyglutamic acid and its derivatives, and polyacrylic acid.

[0057] Anti-inflammatory agents include allantoin, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, β-glycyrrhetinic acid, stearyl glycyrrhetinate, ε-aminocaproic acid, d-camphor, dl-camphor, zinc oxide, panthenol, pyridoxine hydrochloride, and riboflavin or a derivative thereof.

[0058] Examples of antiseptics and disinfectants include urea; benzoic acid or its salts, parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate; phenoxyethanol, dichlorophene, hexachlorophene, chlorhexidine hydrochloride, benzalkonium chloride, salicylic acid, sodium salicylate, zinc pyrithione, benzalkonium chloride, ethanol, undecylenic acid, phenols, and alkane bromide. Examples include chrysoquinolinium, resorcinol, jamal (imidazolidinyl urea), isopropyl methylphenol, triclosan, trichlorocarbanide, trichlorohydroxydiphenol ether, hinokitiol, 1,2-pentanediol, propanediol, concentrated benzalkonium chloride solution 50, essential oils such as peppermint oil and eucalyptus oil, bark distillate, radish fermented liquid, ethanol derived from plants such as sugar cane and corn, or 1,3-butylene glycol.

[0059] Examples of cell activators include pantothenyl alcohol, menthol, dl-menthol, and γ-oryzanol.

[0060] Anti-acne agents include sulfur, salicylic acid or its salts, photosensitizer No. 201, pyridoxine dicaprylate, and the like.

[0061] Examples of powder components include sericite, titanium oxide, talc, kaolin, bentonite, zinc oxide, magnesium carbonate, magnesium oxide, zirconium oxide, barium sulfate, silicic anhydride, mica, nylon powder, polyethylene powder, silk powder, cellulose-based powder, powder of grains (rice, wheat, corn, millet, etc.), powder of beans (soybean, adzuki bean, etc.), etc.

[0062] Examples of ultraviolet absorbers include ethyl paraaminobenzoate, ethylhexyl paradimethylaminobenzoate, amyl salicylate and its derivatives, 2-ethylhexyl paramethoxycinnamate, octyl cinnamate, oxybenzone, 2,4-dihydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate, 4-tert-butyl-4-methoxybenzoylmethane, 2-(2-hydroxy-5-methylphenyl)benzotriazole, urocanic acid, ethyl urocanate, and aloe extract.

[0063] Other antioxidants include, for example, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, carotenoids such as astaxanthin, vitamin E and its derivatives (e.g., tocopherol acetate, tocopherol nicotinate), vitamin A or its derivatives (retinol palmitate, etc.), and the like.

[0064] In addition, examples of whitening agents that can be used include kojic acid or its derivatives, ascorbic acid or its derivatives, tranexamic acid or its derivatives, ellagic acid and its derivatives, resorcinol derivatives (e.g., 4-n-butylresorcinol, 4-isoamylresorcinol, etc.), 4-methoxysalicylic acid potassium salt, 2,5-dihydroxybenzoic acid derivatives (e.g., 2,5-diacetoxybenzoic acid, 2-acetoxy-5-hydroxybenzoic acid, 2-hydroxy-5-propionyloxybenzoic acid, etc.), magnolignan ( 5,5'-dipropyl-biphenyl-2,2'-diol), hydroxybenzoic acid and its derivatives, vitamin E and its derivatives, α-hydroxy acids (e.g., lactic acid, malic acid, succinic acid, citric acid, α-hydroxyoctanoic acid, etc.), AMP (adenosine monophosphate, adenosine monophosphate), t-cycloamino acid derivatives, mulberry bark extract, chamomile extract, hydrolyzed rice bran extract, saxifrage extract, and white mustard extract or hydrolyzed products thereof.

[0065] Anti-wrinkle agents include vitamin A or its derivatives, vitamin E or its derivatives, pantothenyl alcohol, allantoin, and the like.

[0066] Examples of the kojic acid derivatives include kojic acid esters such as kojic acid monobutyrate, kojic acid monocaprate, kojic acid monopalmitate, and kojic acid dibutyrate, kojic acid ethers, and kojic acid sugar derivatives such as kojic acid glucoside. Examples of the ascorbic acid derivatives include sodium L-ascorbic acid 2-phosphate, magnesium L-ascorbic acid 2-phosphate, sodium L-ascorbic acid 2-sulfate, and sodium L-ascorbic acid 2-sulfate. Ascorbic acid ester salts such as ester magnesium, ascorbic acid sugar derivatives such as L-ascorbic acid-2-glucoside, L-ascorbic acid-5-glucoside, ascorbyl tocopheryl maleate, ascorbyl tocopheryl phosphate K, myristyl 3-glyceryl ascorbate, caprylyl 2-glyceryl ascorbate, 6-acylated products of these ascorbic acid sugar derivatives (the acyl group is a hexanoyl group, an octanoyl group, a decanoyl group, etc.), L-ascorbyl tetraisopalmitate, ascorbic acid esters, L-ascorbic acid tetrafatty acid esters such as L-ascorbic acid tetralaurate, 3-O-ethyl ascorbic acid, L-ascorbic acid-2-phosphate-6-O-sodium palmitate, glyceryl ascorbic acid or its acylated derivatives, ascorbic acid glycerin derivatives such as bisglyceryl ascorbic acid, L-ascorbic acid aminopropyl phosphate, hyaluronic acid derivatives of L-ascorbic acid, 3-OD lactose-L-ascorbic acid, isostearyl ascorbic acid, hydroxybenzoates ... Examples of the hydroquinone derivatives include arbutin (hydroquinone-β-D-glucopyranoside) and α-arbutin (hydroquinone-α-D-glucopyranoside). Examples of the tranexamic acid derivatives include tranexamic acid esters (e.g., tranexamic acid lauryl ester, tranexamic acid hexadecyl ester, tranexamic acid cetyl ester or a salt thereof), tranexamic acid amides (e.g., tranexamic acid methylamide), etc. Examples of vitamin E derivatives include sodium α-tocopheryl phosphate and tocopherol acetate.

[0067] Examples of sequestering agents include edetic acid, edetate salts, trisodium ethylenediaminehydroxyethyltriacetate, diethylenetriaminepentaacetic acid, pentasodium diethylenetriaminepentaacetate, ethylenediaminetetrakis(2-hydroxyisopropyl)dioleate, hydroxyethanedisulfonic acid, tetrasodium hydroxyethanedisulfonate, and phytic acid.

[0068] Examples of pH adjusters include lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, malic acid and salts thereof, potassium carbonate, sodium bicarbonate, ammonium bicarbonate, potassium hydroxide, sodium hydroxide, monoethanolamine, triethanolamine, and 2-amino-2-methylpropanediol.

[0069] Examples of water include water commonly used in external preparations, such as distilled water, filtered water, electrolyzed water, and ultrapure water.

[0070] The application site of topical preparations (including cosmetics, quasi-drugs, topical medicines, and hair preparations) is not particularly limited, and includes the entire human body, including skin, hair, and mucous membranes. Therefore, examples of dosage forms include, but are not limited to, emulsions, creams, lotions, essences, packs, lipsticks, foundations, liquid foundations, makeup press powders, blushers, face powders, facial cleansers, body shampoos, soaps, mask preparations, hair tonics, gels, and bath additives.

[0071] <Kit> The kit according to this embodiment comprises the topical agent and a light-shielding container for storing the topical agent. The light-shielding container is not particularly limited as long as it is a container with light-shielding properties. Examples of the container include a plastic container, a glass container, and a metal container. The method for imparting light-shielding properties is also not limited, and examples include a method of molding a container by blending a light-shielding agent (filler, dye, pigment, etc.) into the material that constitutes the container, a method of covering the container with a light-shielding paint or light-shielding film, etc., and a combination of these methods. Metal containers generally have light-shielding properties themselves. [Example]

[0072] The present invention will be described in detail below using examples, but the present invention is not limited to the following examples as long as it does not depart from the gist of the invention.

[0073] <Example> Antioxidants in which the thiol group was protected with a photolabile protecting group were synthesized according to the following procedure. The antioxidants used and the compounds for introducing the photolabile protecting group are shown below.

[0074] (antioxidant) A-1: Glutathione (a compound represented by the following formula (A-1)) A-2: Ergothioneine (a compound represented by the following formula (A-2)) A-3: Coenzyme A (a compound represented by the following formula (A-3)) A-4: Ascorbic acid (a compound represented by the following formula (A-4)) A-5: Dihydrolipoic acid (compound represented by the following formula (A-5))

[0075] [ka]

[0076] (Compound for introducing a photolabile protecting group) B-1: A compound represented by the following formula (B-1): B-2: A compound represented by the following formula (B-2): B-3: A compound represented by the following formula (B-3): B-4: A compound represented by the following formula (B-4): B-5: A compound represented by the following formula (B-5): B-6: A compound represented by the following formula (B-6):

[0077] [ka]

[0078] Example 1 82.9 mg of antioxidant (A-1), 58.3 mg of compound (B-1), and 13.5 mL of 90 mM Tris-HCl buffered 10% ethanol aqueous solution as a solvent were placed in a flask and stirred at 25°C for 3 hours to synthesize a protected compound represented by the following formula (P-1) in which the thiol group of the antioxidant was protected with a photolabile protecting group.

[0079] [ka]

[0080] Example 2 74.8 mg of antioxidant (A-1), 65.5 mg of compound (B-2), and 12.2 mL of 90 mM Tris-HCl buffered 10% ethanol aqueous solution as a solvent were placed in a flask and stirred at 25°C for 3 hours to synthesize a protected compound represented by the following formula (P-2) in which the thiol group of the antioxidant was protected with a photolabile protecting group.

[0081] [ka]

[0082] Examples 3 to 10 Protected compounds represented by the following formulae (P-3) to (P-10) in which the thiol group of an antioxidant was protected with a photolabile protecting group were synthesized in the same manner as in Example 2, except that the types and amounts of antioxidants and compounds for introducing a photolabile protecting group shown in Table 1 below were used. In Example 10, the antioxidant (A-5) was reacted with compound (B-3) according to the procedure described in Wolfgang Dunge et al., Fresenius Z. Anal. Chem. 288, 361-368 (1977). The two types of protected compounds shown in the following formulae (P-9) and (P-10) each existed in either one or both forms.

[0083] [ka]

[0084] [ka]

[0085] [ka]

[0086] [Table 1]

[0087] <Evaluation> The protected products obtained in Examples 1 to 10 were evaluated according to the following procedure.

[0088] (Storage stability) 6.0572 g of Tris(hydroxymethyl)aminomethane (Tokyo Chemical Industry Co., Ltd.) was dissolved in approximately 400 mL of D / W (ultrapure water), and 12 M HCl (WAKO) was added to adjust the pH to 8.201. This was then diluted to 500 mL with D / W to create a Tris-HCl stock solution. 93.8 mg of Glutathione Reduced Form (WAKO) was dissolved in 6104 μL of the above Tris-HCl stock solution to create a GSH solution. This solution was designated the "unprotected" sample.

[0089] Separately, a protector solution was prepared by dissolving 5.7 mg of the protector of Example 3 in 1 mL of a solution prepared by mixing the above Tris-HCl stock solution and ethanol in a ratio of 6:4. This solution was designated as sample "protected."

[0090] 90 μL of each sample was mixed with 10 μL of cell assay resazurin solution (Tokyo Kasei) on a microplate. The absorbance at 600 nm was measured using a plate reader (Corona Electric, Grating Microplate Reader "SH-1300Lab"). Figure 1 shows the absorbance measurement results. The addition of glutathione unprotected with a photolabile protecting group reduced resazurin, resulting in a rapid decrease in absorbance at 600 nm. In other words, the thiol group at the active site of unprotected glutathione is exposed, allowing it to react with dissolved oxygen and resulting in reduced storage stability. On the other hand, the thiol group at the active site of protected glutathione is protected, preventing it from reacting with dissolved oxygen and providing excellent storage stability.

[0091] (spectrophotometric measurement) The protected products obtained in Examples 1 to 6 (the protected product in Example 1 is referred to as "NBB," and the protected products in Examples 2 to 5 are referred to as "C1" to "C5," respectively) were subjected to spectrophotometric measurement. Specifically, the measurements were performed using a spectrophotometer ("NanoDrop," manufactured by Thermo Fisher Scientific). The obtained spectroscopic spectra are shown in FIG. 2. It was found from FIG. 2 that all of the protected products exhibited absorption in the wavelength range of 320 nm or more and 400 nm or less.

[0092] (Resazurin reduction test) The protected compounds obtained in Examples 1 to 8 were mixed with resazurin, a reduction indicator, and then the mixture was subjected to irradiation at 365 nm and 11.5 J / cm 2The photolabile protecting groups were then exposed to light to promote dissociation of the photolabile protecting groups, resulting in deprotection of the protected compounds. The mixtures were then subjected to absorbance measurement at 600 nm using the spectrophotometer. When resazurin was reduced due to exposure of the thiol groups of the antioxidants caused by deprotection, the absorbance at 600 nm of the resazurin before reduction decreased. The results of Examples 1 to 6 are shown in Figure 3, those of Example 7 in Figure 4, those of Example 8 in Figure 5, those of Example 9 in Figure 6, and those of Example 10 in Figure 7 (in Examples 7 and 8, "untreated" indicates the results before light irradiation, and "treated" indicates the results after light irradiation, respectively. For Example 9, the absorbance of the antioxidant without protected thiol groups before and after light irradiation is also shown). Figures 3 to 5 show that the absorbance at 600 nm decreased after light irradiation for all protected compounds, confirming that resazurin was reduced.

[0093] The above-mentioned light exposure amount corresponds to an exposure time of approximately 3,300 seconds converted into sunlight exposure. This exposure time is approximately the same as the time it takes for oxidative damage to occur in cells, their internal organs, genes, etc. due to ultraviolet rays from sunlight. Therefore, the protected antioxidants exhibit antioxidant properties that are sufficient to compensate for oxidative damage that occurs after exposure to ultraviolet rays, and are insensitive to ultraviolet rays that do not cause oxidative damage, thereby maintaining their reducing properties.

Claims

1. An external preparation containing an antioxidant having a thiol group or a hydroxyl group protected with a photolabile protecting group.

2. The topical preparation according to claim 1 , wherein the photolabile protecting group is a group that dissociates upon irradiation with ultraviolet light having a wavelength of 320 nm or more and 400 nm or less.

3. The topical preparation according to claim 1, wherein the photolabile protecting group has a partial structure represented by any one of the following formulas (a) to (d): 【Chemical 1】 (In the above formula, * represents a bond to the sulfur atom of the thiol group or the oxygen atom of the hydroxy group. The dashed line represents a bond to another structure in the photolabile protecting group.)

4. The topical preparation according to claim 1 , wherein the photolabile protecting group comprises an aromatic ring.

5. The topical preparation according to claim 1, wherein the photolabile protecting group has at least one group selected from the group consisting of a nitro group, a hydroxy group, an alkoxy group, an acyl group, and a substituted or unsubstituted amino group.

6. 2. The topical preparation according to claim 1, wherein the photolabile protecting group is a coumarinylmethyl group, a coumarinylcarbonylmethyl group, a nitrobenzyl group, a hydroxyphenacyl group, or a group in which some or all of the hydrogen atoms of these groups have been substituted with substituents.

7. The topical preparation according to claim 1 , wherein the antioxidant is water-soluble or oil-soluble.

8. The topical preparation according to claim 1, wherein the antioxidant is an antioxidant containing a thiol group.

9. 2. The topical preparation according to claim 1, wherein the antioxidant is glutathione, ascorbic acid, dihydrolipoic acid, or a derivative thereof.

10. The external preparation according to claim 1, which is for use in cosmetics.

11. The external preparation according to claim 1, which is for hair.

12. A kit comprising the topical preparation according to any one of claims 1 to 11 and a light-shielding container for containing the topical preparation.

Images