JP2008231007A - Cell death inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cell death inhibitor to inhibit the death of a cell caused by a lipid peroxide. <P>SOLUTION: A cell death inhibitor suppresses the death of a cell caused by a lipid peroxide and contains at least one kind of oil selected from olive oil, squalane, jojoba oil and perilla oil, and fullerenes. Another cell death inhibitor suppresses the cell death caused by a lipid peroxide and contains at least one kind of vitamin selected from ascorbic acid tetraisopalminate and d1-α-tocopherol, and fullerenes. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a cell death inhibitor that suppresses cell death caused by lipid peroxide.

  The cells are covered with a cell membrane composed of intercellular lipids, and the interstitial lipids contain unsaturated fatty acids. Unsaturated fatty acids are characterized by being easily oxidized, and are converted to lipid peroxides when oxidized by ultraviolet rays or free radicals generated in the body. On the skin surface, when oil contained in sebum or cosmetics is oxidized by ultraviolet rays or outside air, it changes to lipid peroxide. Thus, in the skin, lipid peroxide is generated both inside and outside.

  Lipid peroxide has a peroxide bond OO in its molecule. The peroxide bond OO has a smaller bond energy than a bond such as C—H, C—C, C—O, etc., is easily decomposed by heat or light, and changes to a free radical. As described above, free radicals are also involved in the generation of lipid peroxides, while causing oxidative damage to DNA / proteins and causing cell death. A decrease in the number of cells due to an increase in cell death decreases the cell proliferative ability, and it becomes impossible to replenish new cells sufficiently, so that aging of the skin is promoted.

Conventionally, a technique for preventing skin aging by suppressing the generation of lipid peroxide by an antioxidant substance has been proposed.
JP 2006-057011 A

  However, it is difficult to completely suppress the generation of lipid peroxide, and a technique for suppressing skin cell death in an environment where lipid peroxide is present is required. This invention is made | formed in view of the said subject, and aims at provision of the cell death inhibitor which suppresses the cell death by a lipid peroxide.

  One embodiment of the present invention is a cell death inhibitor that suppresses cell death caused by lipid peroxide. The cell death inhibitor includes at least one oil agent selected from the group consisting of olive oil, squalane, jojoba oil, and shiso oil, and fullerenes. According to this aspect, it becomes easy to suppress cell death in an environment where lipid peroxide is present.

  In the above embodiment, the oil agent is olive oil, and the concentration of fullerenes may be 0.5 μM or more and 10 μM or less. In the above embodiment, the oil agent is olive oil, and the concentration of fullerenes may be 7.5 μM or more and 10 μM or less. The cell death inhibitor is expected to be applied to cosmetics and the like. According to this aspect, cell death can be more effectively suppressed in an environment where lipid peroxide is present.

  Another embodiment of the present invention is a cell death inhibitor that suppresses cell death caused by lipid peroxide. Including at least one vitamin selected from the group consisting of the cell death inhibitor, ascorbic acid tetraisopalmitate (hereinafter simply referred to as “VCIP”), d1-α-tocophenol, and fullerenes. It is characterized by. According to this aspect, it becomes easy to suppress cell death in an environment where lipid peroxide is present.

  In the above embodiment, the cell may be a skin cell. According to this aspect, cell death of skin cells can be easily suppressed, and skin aging can be easily suppressed.

  The fullerenes may be one or more of fullerenes, fullerene derivatives, or fullerenes modified or clathrated with organic compounds or fullerene derivative complexes. The fullerene derivative may be a fullerene that integrates one or more of an oxygen-containing group, a nitrogen-containing group, and a hydrocarbon group that may have a substituent. Further, the fullerenes may be one or more of salts with metals. The salt of fullerenes may be one or more of sodium, potassium, magnesium, calcium, and aluminum salts. Furthermore, the fullerenes may be one or more of hydroxylated fullerenes and esters thereof. In addition, the fullerene may be a complex of at least one of fullerene and a fullerene derivative and one or more of organic oligomers, organic polymers, cyclodextrins, crown ethers, and related compounds thereof. It may be a composite of one or more of fullerenes and fullerene derivatives and polyvinylpyrrolidone (PVP). According to these embodiments, fullerenes are easily dissolved in water. Therefore, various forms such as an external preparation, an ointment, a patch, a powder, a suspension, and a liquid are possible, and the degree of freedom of the form of the cell death inhibitor tends to increase.

  A combination of the above-described elements as appropriate can also be included in the scope of the invention for which patent protection is sought by this patent application.

  According to the present invention, cell death due to lipid peroxide is easily suppressed.

  Hereinafter, the best mode for carrying out the present invention will be described in detail.

  The fullerene in the cell death inhibitor of the present embodiment may be fullerene, a fullerene derivative, or a fullerene or a complex of fullerene derivatives modified or clathrated with an organic compound, among which fullerene is Cn (n Is an integer greater than or equal to 60), including C60 fullerene, C70 fullerene, and the like, and also having a carbon skeleton structure such as a spherical shape such as a carbon tube fullerene and a tube, and a conventionally known one. One is given as an example.

  The fullerenes used in this embodiment include various substituents in such a carbon skeleton structure, for example, a hydrocarbon group, an oxygen crosslinking group, a hydroxyl group, an acyl group, and an ether group, which may have a substituent. Further, fullerene derivatives having an oxygen-containing group such as a carboxyl group, an amino group, a nitrogen-containing group such as a cyano group, and the like are also included.

  In addition, for example, the fullerene used in the present embodiment is a combination of a plurality of fullerenes via an alkylene chain such as a methylene chain, or a fullerene 60 derivative having one modifying group for one fullerene molecule. For example, as a derivative of fullerene 70, it is sufficient that 1 to 50 modifying groups are bonded to one fullerene molecule, and each of these modifying groups is independently a hydroxyl group or a group thereof. It may be an ester group of a hydroxyl group and an inorganic or organic acid or a glycoside group of a sugar, a ketal group of a hydroxyl group and a ketone, or an acetal group of an aldehyde, and is selected from the fullerene-modified compound or a salt thereof and the salt thereof. It may be at least one kind. Furthermore, the fullerene used in the present embodiment may be C60 fullerene, C70 fullerene, or nanotube fullerene, or one or more mixtures selected from them. Further, fullerene in which carbon black (soot containing fullerenes), which is a fullerene non-product, remains may be used.

  As for the fullerene oxygen-containing derivative, a compound in which an oxygen atom is bonded directly to a carbon atom of a fullerene skeleton or via a carbon chain such as an alkylene chain is considered. For example, a fullerene hydroxide having an —OH group having a hydroxylation rate of about 50 / mol · fullerene or less is directly bonded.

  For example, organic compounds that modify or include fullerenes or fullerene derivatives as described above include organic oligomers, organic polymers, and inclusion compounds or inclusion complexes or cyclodextrins (CD), crown ethers, or similar compounds thereof. One type or two or more types are exemplified as suitable ones.

  Examples of the organic oligomer or organic polymer include polyalkylene glycols or polyhydric alcohols such as carboxylic acid esters, alcohols, saccharides, polysaccharides, polyhydric alcohols, polyethylene glycol, butylene glycol, polypropylene glycol, polyvinyl alcohol, and the like. Nonionic water-soluble polymers including starch derivatives such as polymers, dextran, pullulan, starch, hydroxyethyl starch and hydroxypropyl starch, alginic acid, hyaluronic acid, chitosan, chitin derivatives, and the anionic nature of these polymers Or cationic derivatives and their polymeric glycerin and fatty acids, oils, propylene carbonate, lauryl alcohol, ethoxylated castor oil, polysorbates, and esters or ethers thereof , And polymers thereof, polyester polymers thereof, pyrrolidone polymers such as polyvinylpyrrolidone, esters or ethers of unsaturated alcohol polymers, and polyoxyethylene polyoxypropylene block copolymers Are preferably bonded to fullerene or a derivative thereof, and may be a mixture of one or more thereof. Especially, various things, such as polyalkylene glycols, such as polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP), are illustrated as a preferable thing. In the case of polymers such as PEG and PVP, the average molecular weight is generally preferably about 2000 to 100,000. Suitable fullerenes in this embodiment include hydroxylated fullerene, esters of hydroxylated fullerene, for example, one or more selected from monoesters, diesters, triesters, polyesters and salts thereof. A mixture of

  These fullerenes are already known as substances and have known uses in cosmetic raw materials, feed raw materials and the like.

  The fullerene salts used in the present embodiment may be selected from, for example, hydroxylated fullerenes, salts of fullerene esters, polyhydroxylated fullerenes, fullerene esters, fullerene triesters, fullerene polyesters, and the like, The salts only need to form a physiologically acceptable salt. Examples of these salts include inorganic salts and organic salts.

  These salts may be salts of metals such as alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), or trimethylamine, triethylamine, pyridine, picoline, It may be a salt with an organic base such as N, N-dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine or the like. From the viewpoint of high safety and economy, one or more metal salts selected from sodium, potassium, magnesium, calcium, and aluminum are suitable as the salts of the fullerene hydroxides and fullerene monoesters. Yes.

  Fullerene derivatives that are water-soluble as fullerenes, modified or clathrates with organic compounds, and fullerene salts are highly stable, easily soluble in water, and have a pH that can be adjusted, resulting in low cytotoxicity and biocompatibility. It is more suitable for use in this embodiment because of its high performance. For example, fullerenes and polymers such as PEG (polyethylene glycol), PVP (polyvinyl pyrrolidone), CD (cyclodextrin), or inclusions, and monovalent salts are more soluble in water than divalent salts. It is preferable because it is high. In particular, fullerene-PVP, sodium fullerenes and sodium fullerene esters, and potassium fullerenes and fullerene monoesters are suitable.

  For example, there is a water-soluble PVP-fullerene complex as one of attention. PVP (polyvinylpyrrolidone) has the following formula:

で表わされるものであって、本実施形態においては、その重量平均分子量（Ｍｗ）が３，０００〜３，０００，０００程度の範囲のもの、さらには、６，０００〜１，５００，０００程度のものが好適なものとして考慮される。ＰＶＰは、合成したものでもよいし、市販品であってもよい。この場合のフラーレンは上記のとおりのフラーレン誘導体であってもよい。

In the present embodiment, the weight average molecular weight (Mw) is in the range of about 3,000 to 3,000,000, and further about 6,000 to 1,500,000. Are considered suitable. PVP may be a synthesized product or a commercially available product. The fullerene in this case may be a fullerene derivative as described above.

  And the fullerenes with high solubility to water are desirable for the cell death inhibitor containing the fullerenes used in the present embodiment as an active ingredient.

  Further, a water adduct or a crystal water adduct of fullerenes is useful because it is more soluble in water than its anhydride.

  The water content or water content of the fullerenes or crystal water adduct used in the present embodiment is not particularly limited, but the water content is 1% to 50% by weight in order to maintain better solubility. More preferably 5% to 20% by weight, and in the case of crystal water, a water adduct or crystal water adduct of fullerenes holding water molecules in the range of 1 to 20 water salt, more preferably 1 to 10 water salt. desirable.

  The cell death inhibitor used in the present embodiment has low toxicity and can be administered.

  The form of the cell death inhibitor used in the present embodiment is not particularly limited, and examples include an external preparation, an ointment, a patch, a powder, a granule, a suspension, and a liquid.

  It can be formulated as a mixture with pharmaceutically acceptable inert carriers or diluents and / or other pharmacological agents, or in dosage unit form.

  Further, it may be formulated as a complex according to a known pharmaceutical manufacturing method. For example, the main component used in this embodiment may be used as a complex with cyclodextrin or maltosyl-cyclodextrin for the purpose of enhancing solubility by increasing solubility in water and enhancing pharmacological activity.

  In the present embodiment, these active ingredients are listed in the 12th revised Japanese Pharmacopoeia Heisei 3 (Hakushoku Shoten) etc., which can be pharmaceutically acceptable if desired according to known pharmaceutical manufacturing methods. It can be administered as a single agent by mixing with diluents, excipients, and the like.

  When the preparation of this embodiment is a solution, a water-soluble agent (for example, distilled water), a water-soluble preparation (for example, physiological saline, Ringer's solution, etc.), an oil-based solvent (for example, sesame oil, corn oil, olive oil) Etc.) can be prepared by conventional means using a solvent. At this time, a solubilizing agent (for example, sodium salicylate, sodium acetate, etc.), a buffering agent (for example, sodium citrate, glycerin, etc.), an isotonic agent (for example, glucose, etc.), a stabilizer (for example, human serum albumin, Polyethylene glycol etc.), preservatives (eg benzyl alcohol, phenol etc.), soothing agents (eg benzalkonium chloride, procaine hydrochloride etc.) etc. can also be used.

  Pharmacologically and pharmaceutically acceptable additives as desired (eg, diluents, excipients, binders, disintegrants, colorants, stabilizers, extenders, wetting agents, surfactants, lubricants) , Dispersants, buffering agents, flavoring agents, flavoring agents, fragrances, preservatives, solubilizers, solvents, coating agents, sugar coatings, etc.) or those formulated using these can also be used.

  The diluent used for the adjustment is pharmaceutically acceptable, but means a material other than the compound used in the present embodiment, and includes various materials such as solid, semi-solid, and liquid.

  For example, the cell death inhibitor obtained by this embodiment may be produced by any known method.

  For parenteral administration, for example, a patch or an external preparation can be used, and as an injection, for example, a subcutaneous injection, an intramuscular injection, or the like is used. Examples of the external preparation include ointments, nasal administration agents, transdermal preparations and the like.

  In order to obtain an external preparation, the composition of the present embodiment can be made into a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the solid state, the composition of the present embodiment is used as it is or an excipient (eg, glycol, mannitol, starch, microcrystal, cellulose, etc.), a thickener (eg, natural gums, cellulose derivatives, Acrylic polymer or the like) is added and mixed to obtain a powdery composition.

  The liquid form is an oily or aqueous suspension. In the case of a semi-solid, an aqueous or oily gel or ointment is preferable.

  In addition, these are all pH adjusters (eg, carbonic acid, monoester, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), etc. May be added. According to a method known per se, the composition of this embodiment can be made into an oily or aqueous solid, semi-solid or liquid.

  Hereinafter, application of fullerenes as an external preparation will be described in detail.

<A> Administration method of fullerenes as an external preparation Administration form Examples of the form of the external composition for skin are not particularly limited. For example, all external preparations such as aqueous solvents, ointments, emulsions, creams, gels, packs, bath preparations, cleaning agents, poultices, dispersions, etc. The dosage form is not particularly limited, and is solid, paste, mousse, gel, powder, solution, solubilization, emulsification, powder dispersion, multilayer It can be. Especially for aqueous solutions, emulsions, ointments, gels, water-soluble preparations, cosmetics, and packs, use these humidifiers, vibration introducers, iontophoresis devices, sound wave introducers, and electromagnetic wave introducers after applying these agents externally. As a result, the penetration of fullerenes into the skin can be promoted, and a greater effect can be exhibited.

As the application method, in the case of a liquid agent, all physically possible methods such as spraying, sticking, poultice, dipping, and masking can be used.
<B> External Preparation Containing Fullerenes The external composition used in the present embodiment is basically realized as a combination with various components constituting conventionally known cosmetics and external preparations.

  In the following, these components in general will be outlined.

1. Oil agent Fullerenes used in the present embodiment are oils, preferably natural oils, more preferably orange oil, beaver oil, olive oil, jojoba oil, shiso oil, pine oil or one or more oils selected from pine oil. It is preferable to disperse the oil in oil containing it and administer it to a living body, particularly the skin.

  As an oil agent, as long as it is used for normal cosmetics, it is a natural oil, a synthetic oil, or a solid, semi-solid, liquid, etc. , Waxes, fatty acids, higher alcohols, ester oils, silicone oils, fluorinated oils, and the like can be used. For example, hydrocarbons such as squalane, squalene, ceresin, paraffin, paraffin wax, liquid paraffin, pristane, polyisobutylene, microcrystalline wax, petroleum jelly, waxes such as beeswax, carnauba wax, candelilla wax, whale wax; beef tallow, cow Animal oils such as leg fat, beef bone fat, hard beef fat, hard oil, turtle oil, pork fat, horse fat, mink oil, liver oil, egg yolk oil; lanolin, liquid lanolin, reduced lanolin, lanolin alcohol, hard lanolin, lanolin acetate, Lanolin derivatives such as lanolin fatty acid isopropyl, POE lanolin alcohol ether, POE lanolin alcohol acetate, lanolin fatty acid polyethylene glycol, POE hydrogenated lanolin alcohol ether; lauric acid, myristic acid, palmitic acid, steari Acid, behenic acid, undecylenic acid, oleic acid, arachidonic acid, docosahexaenoic acid (DHA), isostearic acid, fatty acids such as 12-hydroxystearic acid.

  As oils, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, behenyl alcohol, hexadecyl alcohol, oleyl alcohol, isostearyl alcohol, hexyl decanol, octyldodecanol, cetostearyl alcohol, 2-decyltetradecinol Higher alcohols such as cholesterol, phytosterol, sitosterol, lanosterol, POE cholesterol ether, monostearyl glycerol ether (batyl alcohol); diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, mono Isostearic acid-N-alkylglycol, isocetyl isostearate, trimethylol triisostearate Lopan, ethylene glycol di-2-ethylhexanoate, cetyl 2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, pentaerythritol tetra-2-ethylhexanoate, cetyl octanoate, octyldodecyl gum ester, olein Oleyl acid, octyldodecyl oleate, decyl oleate, neopentyl glycol dicaprate, triethyl citrate, 2-ethylhexyl succinate, amyl acetate, ethyl acetate, butyl acetate, isocetyl stearate, butyl stearate, diisopropyl sepacate, Di-2-ethylhexyl sepacate, cetyl lactate, myristyl lactate, isopropyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptyl palmitate Ndecyl, cholesteryl 12-hydroxystearylate, dipentaerythritol fatty acid ester, isopropyl myristate, octyldodecyl myristate, 2-hexyldecyl myristate, myristyl myristate, hexyldecyl dimethyloctanoate, ethyl laurate, hexyl laurate, Examples include ester oils such as N-lauroyl-L-glutamic acid-2-octyldodecyl ester and diisostearyl malate. Further, as oil agents, acetoglyceride, triisooctanoic acid glyceride, triisostearic acid glyceride, triisopalmitic acid glyceride, tri-2-ethylhexanoic acid glyceride, monostearic acid glyceride, di-2-heptylundecanoic acid glyceride, trimyristic acid Glyceride oil such as glyceride; dimethylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, tetramethyltetrahydrogencyclotetrasiloxane, stearoxy Higher alkoxy-modified silicones such as silicone; higher fatty acid-modified silicones, silicone resins, silicone rubber, Silicone oil corn oil; perfluoropolyether, perfluorodecalin, fluorine-based oils of perfluoro octane.

2. Surfactant The fullerene preparation / cosmetic used in the present embodiment may contain caprylic acid monoglyceride and / or capric acid monoglyceride, and may further contain lauric acid monoglyceride. Caprylic acid monoglyceride, capric acid monoglyceride and lauric acid monoglyceride (hereinafter also simply referred to as glycerides) are all designated as food additives; glycerin fatty acid esters, their safety has been confirmed, and there is no problem even if they are eaten. It is a food emulsifier.

  In order to disperse the fullerenes used in this embodiment in water, an emulsifier can be added. For example, the emulsifier may be a nonionic surfactant such as polyoxyethylene sorbitan fatty acid ester or polyglycerin fatty acid ester such as polyoxyethylene sorbitan monooleate having an HLB of 10 or more, or an anionic system such as sodium lauryl sulfate. A surfactant can also be used.

  As the surfactant, anionic, cationic, nonionic and amphoteric active agents are used. Examples of anionic surfactants include fatty acid soaps such as sodium stearate and triethanolamine palmitate, alkyl ether carboxylic acids and salts thereof, carboxylates such as condensates of amino acids and fatty acids, alkyl sulfonic acids, and alkene sulfonates. Sulfonates of fatty acid esters, sulfonates of fatty acid amides, sulfonates of alkyl sulfonates and their formalin condensates, alkyl sulfate esters, secondary higher alcohol sulfates, alkyl and allyl ether sulfates , Sulfate ester of fatty acid ester, sulfate ester of fatty acid alkylolamide, sulfate ester salt such as funnel oil, alkyl phosphate, ether phosphate, alkyl allyl ether phosphate, amide phosphate, N-acyl amino acid System active agents It is.

  Examples of the cationic surfactant include amine salts such as alkylamine salts, polyamines and aminoalcohol fatty acid derivatives, alkyl acid quaternary ammonium salts, aromatic quaternary ammonium salts, pyridium salts, imidazolium salts and the like. Nonionic surfactants include sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyethylene glycol fatty acid ester, sucrose fatty acid ester, polyoxyethylene alkyl ether, polyoxypropylene alkyl ether, poly Oxyethylene alkyl phenyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene propylene glycol fatty acid ester, polyoxyethylene castor oil, polyoxyethylene Hydrogenated castor oil, polyoxyethylene phytostanol ether, polyoxyethylene Down phytosterol ether, polyoxyethylene cholestanol ether, polyoxyethylene cholesteryl ether, polyoxyalkylene-modified organopolysiloxane, polyoxyalkylene-alkyl co-modified organopolysiloxane, alkanolamide, sugar ethers, and sugar amides. Examples of amphoteric surfactants include betaines, aminocarboxylates, imidazoline derivatives, and the like.

  As the metal soap, 12-hydroxy aluminum stearate, zinc stearate, aluminum stearate, calcium stearate, magnesium stearate, zinc myristate, magnesium myristate, zinc cetyl phosphate, calcium cetyl phosphate, zinc sodium cetyl phosphate, zinc laurate And zinc undecylenate.

3. Pigment Since most of the fullerenes used in the present embodiment are colored, it is desirable to adjust the color tone so as not to cause a sense of incongruity by appropriately adding a pigment as a cosmetic. As colored pigments, inorganic red pigments such as iron oxide, iron hydroxide and iron titanate, inorganic brown pigments such as γ-iron oxide, inorganic yellow pigments such as yellow iron oxide and loess, black iron oxide, carbon black, etc. Lake inorganic black pigments, inorganic purple pigments such as manganese violet and cobalt violet, inorganic green pigments such as chromium hydroxide, chromium oxide, cobalt oxide and cobalt titanate, inorganic blue pigments such as bitumen and ultramarine blue, and tar dyes Pigments, pigments obtained by lacquering natural pigments, and composite powders obtained by combining these powders. Examples of the pearl pigment include titanium oxide-coated mica, titanium oxide-coated mica, bismuth oxychloride, titanium oxide-coated bismuth oxychloride, titanium oxide-coated talc, fish scale foil, and titanium oxide-coated colored mica. Examples of the metal powder pigment include aluminum powder, copper powder, and stainless steel powder.

  As tar pigments, Red No. 3, Red No. 104, Red No. 106, Red No. 201, Red No. 202, Red No. 204, Red No. 205, Red No. 220, Red No. 226, Red No. 227, Red No. 228, Red 230, Red 401, Red 505, Yellow 4, Yellow 5, Yellow 202, Yellow 203, Yellow 204, Yellow 401, Blue 1, Blue 2, Blue 201, Blue 404 , Green No. 3, Green No. 201, Green No. 204, Green No. 205, Orange No. 201, Orange No. 203, Orange No. 204, Orange No. 206, Orange No. 207 and the like. Examples of natural pigments include carminic acid, laccaic acid, calsamine, bradylin, and crocin. The above-mentioned powders such as inorganic powder, organic powder, pigment, and tar dye may be composited or surface-treated with an oil agent, silicone, or fluorine compound.

4). Moisturizer Polyhydric alcohols such as propylene glycol, glycerin, polyglycerin, sorbitan and sorbitol are added to relieve skin moisturizing and irritation. As the moisturizing agent, alkaline simple hot spring water, deep layer water, hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin and keratan sulfate, or salts thereof, proteins such as collagen, elastin and keratin Derivatives and salts thereof, phospholipids derived from soybeans and eggs, glycolipids, ceramides, mucins, honey, erythritol, maltose, maltitol, xylitol, xylose, pentaerythritol, fructose, dextrin and its derivatives, mannitol, sorbitol, inositol, Sugars such as trehalose and glucose, urea, asparagine, aspartic acid, alanine, arginine, isoleucine, ortinin, glutamine, glycine, glutamic acid and derivatives thereof, and their Amino acids such as cysteine, cystine, citrulline, threonine, serine, tyrosine, tryptophan, theanine, valine, histidine, hydroxylysine, hydroxyproline, pyrrolidone carboxylic acid and salts thereof, proline, phenylalanine, methionine, lysine and the like or their derivatives And the like.

  Furthermore, as a humectant, D-panthenol, avocado extract, almond oil, carob extract, rice extract, strawberry extract, fennel extract, euglena extract, olive oil extract, olive oil, odorifera extract, cacao butter, Oat extract, Kizuta extract, Kumaza extract, Gardenia extract, Grapefruit extract, Gentian shochu extract, Gentian extract, Burdock extract, Kokopachiru extract, Sesame extract, Cactus extract, Cactus extract, Ginger extract , Diou extract, Shea butter, Citrus extract, Senkyu extract, Zeniaoi extract, Perilla extract, Camellia extract, Corn extract, Delicatum extract, Tormentilla extract, Dokudami extract, Pakmondou extract, Hauchi bean extract, ham Squirrel extract, mint extract, green mint extract, Atlantic mint extract, parsley extract, rose extract, sunflower extract, cypress extract, loofah extract, prune extract, butcher's bloom extract, borage oil, button Extract, Jojoba oil, Bodaige extract, Hop extract, Pine extract, Maronier extract, Macadamia nut oil, Quince extract, Murasaki extract, Meadow home oil, Melissa extract, Cornflower extract, Lily extract, Yuzu Examples include an extract, a lime extract, a lavender extract, a gentian extract, a bitumen extract, and an apple extract. One or two or more moisturizers listed above can be appropriately selected and blended.

5. Excipients / Bases Gelling agents include amino acid derivatives such as N-lauroyl-L-glutamic acid, α, γ-di-n-butylamine, dextrin palmitate, dextrin stearate, dextrin 2-ethylhexanoic acid Dextrin fatty acid esters such as palmitic acid esters, sucrose palmitic acid esters, sucrose fatty acid esters such as sucrose stearic acid esters, benzylidene derivatives of sorbitol such as monobenzylidene sorbitol, dibenzylidene sorbitol, dimethylbenzyl dodecyl ammonium montmorillonite clay, dimethyldi Examples include organically modified clay minerals such as octadecyl ammonium montmorillonite clay.

  Examples of alcohols include lower alcohols such as ethanol and isopropanol, polyhydric alcohols such as glycerin, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, and polyethylene glycol. It is done.

  Examples of water-soluble polymers include plant-based polymers such as gum arabic, tragacanth, galactan, carob gum, guar gum, caraya gum, carrageenan, pectin, agar, algae colloid, trant gum, locust bean gum, galactomannan; xanthan gum, dextran, succino Microbial polymers such as glucan and pullulan; animal polymers such as casein, albumin and gelatin; starch polymers such as starch, carboxymethyl starch and methylhydroxypropyl starch; methylcellulose, ethylcellulose, methylhydroxypropylcellulose and carboxymethylcellulose , Hydroxymethylcellulose, hydroxypropylcellulose, nitrocellulose, sodium cellulose sulfate, carboxymethylcellulose sodium Cellulose polymers such as crystalline cellulose and cellulose powder; Alginate polymers such as sodium alginate and propylene glycol alginate; Vinyl polymers such as polyvinyl methyl ether, carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer; Polyoxyethylene Polymer: Polyoxyethylene polyoxypropylene copolymer-based polymer; Acrylic polymer such as sodium polyacrylate, polyethyl acrylate, polyacrylamide; Inorganic water-soluble such as polyethyleneimine, cationic polymer, bentonite, laponite, hectorite Functional polymers. Also included are film forming agents such as polyvinyl alcohol and polyvinyl pyrrolidone.

  As powder, if it is used for normal cosmetics, its shape (spherical, needle-like, plate-like, etc.), particle size (smoke-like, fine particles, pigment grade, etc.), particle structure (porous, Any material such as inorganic powder, organic powder, and pigment can be used regardless of whether it is nonporous or the like. For example, as the inorganic powder, magnesium oxide, barium sulfate, calcium sulfate, magnesium sulfate, calcium carbonate, magnesium carbonate, talc, synthetic mica, mica, kaolin, sericite, muscovite, synthetic mica, phlogopite, saucite, Biotite, lithia mica, silicic acid, anhydrous silicic acid, aluminum silicate, magnesium silicate, magnesium aluminum silicate, sulfur-containing aluminum silicate, calcium silicate, barium silicate, strontium silicate, metal tungstate, hydroxy Examples thereof include apatite, permiculite, hygielite, montmorillonite, zeolite, ceramic powder, dicalcium phosphate, alumina, aluminum hydroxide, boron nitride, boron nitride and the like.

  Organic powders include polyamide powder, polyester powder, polyethylene powder, polypropylene powder, polystyrene powder, polyurethane, benzoguanamine powder, polymethylbenzoguanamine powder, tetrafluoroethylene powder, polymethylmethacrylate powder, silk powder, nylon powder, 12 nylon, 6Nylon, styrene / acrylic acid copolymer, divinylbenzene / styrene copolymer, vinyl resin, urea resin, phenol resin, fluororesin, silicon resin, acrylic resin, melamine resin, epoxy resin, polycarbonate resin, microcrystalline fiber powder Body, lauroyllysine and the like.

6). Cell Activator To administer the fullerenes used in the present embodiment to a living body or skin to promote the drug effect, it is preferable to simultaneously administer a drug for activating cells to be administered. Cell activators include deoxyribonucleic acid and salts thereof, adenylate derivatives such as adenosine triphosphate and adenosine monophosphate and salts thereof, ribonucleic acid and salts thereof, cyclic AMP, cyclic GMP, flavin adenine nucleotide, guanine Nucleic acid-related substances such as adenine, cytosine, thymine, xanthine and their derivatives caffeine, theopherin and salts thereof, calf blood extract, serum deproteinized extract, spleen extract, egg components such as birds, Chicken crown extract, shell extract, shellfish extract, royal jelly, silk protein and its degradation product or derivatives thereof, hemoglobin or its degradation product, lactoferrin or its degradation product, mollusc extract such as squid, fish meat extract, etc. , Mammals, birds, shellfish, insects, fish, molluscs, crustaceans, etc. Extracts from yeast extract, lactic bacteria extract, extracts derived from microorganisms selected from fermentation metabolites of bifidobacteria extract, and the like.

  Further, as cell activators, retinol and its derivatives (retinol palmitate, retinol acetate, etc.), retinal and its derivatives, vitamin A such as carotenoids such as dehydroretinal, tretinoin, carotene, thiamines (thiamine hydrochloride, thiamine sulfate) Salt), riboflavin (riboflavin, riboflavin acetate, etc.), pyridoxine (pyridoxine hydrochloride, pyridoxine dioctanoate, etc.), flavin adenine nucleotide, cyanocobalamin, folic acid, nicotinic acid (nicotinamide, benzyl nicotinate, etc.), choline Vitamin B such as apricot, apricot extract, ginkgo biloba extract, ginseng extract, barley extract, orange extract, cucumber extract, kiwi extract, shiitake extract, cedar extract, assembly extract, taiso Extract, Capsicum extract, Garlic extract, Carrot extract, Bud extract, Peach extract, Lettuce extract, Lemon extract, Ganoderma extract, Rosemary extract, Asparagus extract, Ibukitorano extract , Pea extract, Age extract, Ogon extract, Ononis extract, Seaweed extract, Raspberry extract, Kujin extract, Caiquet extract, Sesame extract, Vegetable oil containing linoleic acid, Saisin extract, Hawthorn Extract, Sunpens extract, Shirayuri extract, Peonies extract, Sempukuka extract, Sakuhakuhi extract, Soybean extract, Tea extract, Toki extract, Molasses extract, Juniper extract, Beech tree extract, Grape seed extract , Flow demanita extract, hop extract, micaika extract, mokka extract, yukinoshita extract , Yokuinin extract and Rakan fruit extract, as well as Akane, Red grape, Akamegashiwa, Akebi, Asa, morning glory, Azuki, Asenyaku, Achacha, Achacharu, Itadori, Fig, Ginkgo biloba, Ylang-ilan, Moray-brush, Ume, Uwa-urushi Ezoukogi, Ebisu, Enju, Pea, Psyllium, Okra, Oguruma, Onigurumi, Omuraeshi, Dutch Strawberry, Oyster, Kakidoushi, Kashi, Cashew, Valerian, Calla Lily, Karin, Guarana, Oxalis, Chrysanthemum, Gypsophila, Gimnesi , Guava, wolfberry, kudzu, camphor tree, chestnut, caquette, bay geese, keihi, gosho strawberry, pepper, coffee, licorice, colombo, sasanqua, salamander, saffron, saffron Kura, Pomegranate, Sandscon, Sunpens, Zion, Shobu, Watermelon, Stevia, Plum, Pepper, Pear, Achillea millefolium, Pepper, Horseradish, Pepper, Seri, Senegal, Senna, Daio, Daidai, Tamarind, Taranoki, Dandelion, Chicory, clove, ginseng, chorei, primrose, azalea, communis, tsuruna, teuchigurumi, togan, eucommia, taro aoi, nazuna, jujube, nanten, nigaki, cabbage, pineapple, hibiscus, papaya, basil, hasp , Hikiokoshi, Hishi, Pistachio, Hiba, Japanese matsutake, Bakaku, Biwa, Japanese dandelion, Fushinoki, Fujibakama, Blueberry, Bow-fu, Physalis, Honoki, Mushroom, Maikai, Maou, Mango, Mannentake, Mishima Saiko, Misohagi, Mitsuba, Mimosa, Merilot, Melon, Mokuren, Momordica Grosvenori, Morohaya, Moyashi, Yakuchi, Yakumoso, Gagurumasou, Palm, Yashajitsu, Yardhi, Yamota Yuzuriha, mugwort, rye, orchid, longan, apple, litchi, forsythia and other extracts, hinokitiol, cephalanthin and other plant-derived extracts, α- and γ-linolenic acid, eicosapentaenoic acid and their derivatives, estradiol and its derivatives Derivatives and salts thereof, organic acids such as glycolic acid, succinic acid, lactic acid, salicylic acid, and derivatives thereof, and salts thereof. One or two or more cell activators listed above can be appropriately selected and blended.

  Examples of vitamins include vitamin Ks such as phytonadione, menaquinone, menadione and menadiol, vitamins P such as eriocitrin and hesperidin, biotin, carcinine and ferulic acid. Furthermore, provitamins such as vitamin E such as d1-α-tocophenol and VCIP can be mentioned. Examples of the blood circulation promoter include nonyl acid wallenyl amide, capsaicin, gingerone, cantalis tincture, ictamol, α-borneol, inositol hexanicotinate, cyclantelate, cinnarizine, trazoline, acetylcholine, pelapamil, γ-oryzanol and the like. Examples of skin astringents include tannic acid, examples of antiseborrheic agents include thianthol, and examples of enzymes include lipase and papain.

  As amino acids, glycine, alanine, valine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cystine, methionine, phenylalanine, tyrosine, proline, hydroxyproline, ortinin, citrulline, Examples include amino acids such as theanine and derivatives thereof and salts thereof, amino acid derivatives such as pyrrolidone carboxylic acid, and derivatives thereof. Examples of nucleic acid-related substances include deoxyribonucleic acid and salts thereof, adenylic acid derivatives selected from adenosine triphosphate, adenosine diphosphate and adenosine monophosphate and salts thereof, ribonucleic acid and salts thereof, cyclic AMP, and cyclic GMP Examples of flavin adenine nucleotides, guanine, adenine, cytosine, thymine, xanthine and their derivatives caffeine, deophylline, and salts and hormones thereof include estradiol, etenyl estradiol, and the like.

7). Ascorbic acid In the composition for external use of the present embodiment, ascorbic acid or a derivative thereof is preferably used.

  Especially, what is necessary is just at least 1 type selected from the compound or its salt represented by a following formula, or there.

  In the formula, R1, R2, R3 and R4 each independently represent a hydroxyl group or an ester group of a hydroxyl group with an inorganic or organic acid or a glycoside group of a sugar, or two adjacent hydroxyl groups and ketones of the hydroxyl group. Or acetal group with an aldehyde. However, R1 and R2 are not simultaneously hydroxyl groups.

  Ascorbic acid itself can also be used, and ascorbic acid may be either L-form, D-form or DL-form, among ester with inorganic acid or organic acid, glycoside with sugar, or hydroxyl group of ascorbic acid It may be an acetal bonded to a ketal or aldehyde bonded to two adjacent hydroxyl groups and ketone.

  In this case, examples of the inorganic acid include phosphoric acid, diphosphoric acid, triphosphoric acid, sulfuric acid and the like, and phosphoric acid is preferable. Examples of the organic acid include acetic acid, propionic acid, butyric acid, isobutyric acid, stearic acid, myristic acid, and palmitic acid, and higher fatty acids such as palmitic acid are particularly preferable. Examples of the sugar include glucose, sucrose, fructose and the like, and glucose is particularly preferable. Examples of the ketone include acetone and methyl ethyl ketone, and examples of the aldehyde include acetaldehyde, propyne aldehyde, and benzaldehyde. Examples of the salt include sodium, potassium, magnesium, calcium and the like, and sodium salt and magnesium salt are particularly preferable.

  Specific examples of such ascorbic acid derivatives include ascorbic acid 2-phosphate, ascorbic acid 2-diphosphate, ascorbic acid 2-triphosphate, ascorbic acid 2-polyphosphate, ascorbic acid 2-phosphate diester. , Ascorbic acid 2-phosphate 6-palmitic acid, ascorbic acid 2-phosphate 6-myristic acid, ascorbic acid 2-phosphate 6-stearic acid, ascorbic acid 2-phosphate 6-oleic acid, ascorbic acid 2-glucoside Ascorbic acid such as ascorbic acid 2-glucoside 6-palmitic acid, ascorbic acid 2-glucoside 6-myristic acid, ascorbic acid 2-glucoside 6-stearic acid, ascorbic acid 2-glucoside 6-oleic acid, ascorbic acid 2-sulfate Esters, alkyl esters of L-ascorbic acid , Derivatives of L-ascorbic acid phosphate, L-ascorbic acid sulfate, etc., and alkali metal salts such as sodium salts and potassium salts, calcium salts, magnesium salts and the like Etc. More specifically, palmitic acid L-ascorbic acid, dipalmitic acid L-ascorbic acid, isopalmitic acid L-ascorbic acid, diisopalmitic acid L-ascorbic acid, tetraisopalmitic acid L-ascorbic acid, stearic acid L Ascorbic acid, distearic acid L-ascorbic acid, isostearic acid L-ascorbic acid, diisostearic acid L-ascorbic acid, myristic acid L-ascorbic acid, dimyristic acid L-ascorbic acid, isomyristic acid L-ascorbic acid, diiso Myristic acid L-ascorbic acid, oleic acid L-ascorbic acid, dioleic acid L-ascorbic acid 2-ethylhexanoic acid L-ascorbic acid, L-ascorbic acid phosphate sodium, L-ascorbic acid phosphate potassium, L Magnesium ascorbate phosphate, calcium L-ascorbate phosphate, aluminum L-ascorbate phosphate, sodium L-ascorbate sulfate, potassium L-ascorbate sulfate, magnesium L-ascorbate sulfate, L -Calcium ascorbate sulfate, aluminum L-ascorbate sulfate, sodium L-ascorbate, potassium L-ascorbate, magnesium L-ascorbate, calcium L-ascorbate, aluminum L-ascorbate, and the like Sodium salt, potassium salt, magnesium salt, calcium salt, zinc salt, ammonium salt, alkyl-substituted ammonium salt, hydroxyalkyl-substituted ammonium salt, etc. And the like.

  Moreover, the shape which these ascorbic acid derivatives couple | bonded with the polymer chain may be sufficient. In particular, ascorbic acid 2-phosphate and ascorbic acid 2-glucoside, and particularly the above-mentioned salts thereof are preferable from the viewpoint of formulation convenience such as water solubility, chemical stability of the derivative, and effect.

8). pH adjuster Preferred examples of the pH adjuster include a storage stabilizer, an organic acid having a chelating effect, or a salt thereof. These include erythorbic acid and its salts, dibutylhydroxytoluene, tocopherol and its derivatives, porphyrin, butylhydroxyanisole, sodium bisulfite, anhydrous sodium sulfite, gallic acid and its derivatives, alanine, ethylenediaminehydroxyethyl sodium triacetate, ethylenediaminetetraacetic acid And a salt thereof, citric acid and a salt thereof, gluconic acid, tartaric acid, phytic acid, sodium polyphosphate, sodium metaphosphate, at least one selected from the group consisting of the total amount of the composition for external use In the range of 0.01% to 50% by weight, preferably in the range of 0.1% to 5% by weight. The salt is not particularly limited, but metals other than transition metals are desirable from the viewpoint of safety to the skin, and sodium, potassium, magnesium, and calcium are particularly desirable.

9. Active oxygen scavenger It is preferred to co-administer an active oxygen scavenger. As active oxygen scavengers, superoxide dismutase, mannitol, bilirubin, cholesterol, tryptophan, histidine, quercetin, quercitrin, catechin, catechin derivatives, rutin, rutin derivatives, taurine, thiotaurine, eggshell membrane extract, gallic acid, gallic acid Derivatives, yeast extract, ganoderma biloba extract, yashajitsu extract, genus shochu extract, button pi extract, melissa extract, parsley extract and dicoppi extract, retinol and its derivatives (retinol palmitate, retinol acetate, etc.), retinal And its derivatives, vitamin A such as dehydroretinal; thiamines (thiamine hydrochloride, thiamine sulfate, etc.), riboflavins (riboflavin, riboflavin acetate, etc.), pyridoxines (pyridoxine hydrochloride, Vitamin Bs such as doxin dioctanoate, flavin adenine nucleotide, cyanocoparamine, folic acid, nicotinic acid (nicotinic acid amide, benzyl nicotinate), choline, etc .; ergocalciferol, cholecalciferol, dihydroxystad Vitamin Ds such as nal; tocopherol and its derivatives (dl-α (β, γ) -tocopherol, dl-α-tocopherol acetate, nicotinic acid-dl-α-tocopherol, linoleic acid-dl-α-tocopherol, succinic acid dl-α-tocopherol etc.), vitamin E such as ubiquinones; dibutylhydroxytoluene, butylhydroxyanisole and the like.

10. Other compounding agents For the purpose of preserving the composition for external use containing the fullerenes used in this embodiment or a diluted solution thereof, a preservative such as ethanol can be added. Further, the pH can be adjusted by adding a pH adjusting agent such as an organic acid such as citric acid, fumaric acid, succinic acid or lactic acid, or NaOH or KOH.

  In any case, in the composition for external use containing the fullerenes used in the present embodiment, components that are usually used in preparations such as external preparations, that is, water (purified water, Hot spring water, deep water, etc.), oil agent, surfactant, metal soap, gelling agent, powder, alcohol, water-soluble polymer, film forming agent, resin, UV protection agent, inclusion compound, antibacterial agent, perfume , Deodorant, salt, pH adjuster, freshener, animal / microbe-derived extract, plant extract, blood circulation promoter, astringent, antiseborrheic agent, active oxygen scavenger, cell activator, moisturizer, keratin One or more solubilizers, enzymes, hormones, vitamins and the like can be added as appropriate.

  In addition, as UV protection agents, 2-methoxyhexyl paramethoxycinnamate, isopropyl paramethoxycinnamate, diethanolamine paramethoxyhydrocinnamate, glyceryl di-2-methoxycinnamate mono-2-ethylhexanoate, methoxycinnamate Cinnamic acid UV absorbers such as octyl and methyl diisopropylcinnamate-2-hydroxy-4-methoxybenzophenone-2-hydroxy-4-methoxybenzophenone-5-sulfuric acid 2-hydroxy-4-methoxybenzophenone-5-sulfuric acid Sodium, 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2 ', 4,4'-tetrahydroxybenzophenone- 2-hydroxy- Benzoic acids such as n-octoxybenzophenone and other benzophenone ultraviolet absorbers, paraaminobenzoic acid, ethyl paraaminobenzoate, butyl paraaminobenzoate, 2-ethylhexyl paradimethylaminobenzoate, glyceryl paraaminobenzoate, and amyl paraaminobenzoate UV absorbers, salicylic acid-2-ethylhexyl, triethanolamine salicylate, homomenthyl salicylate, dipropylene glycol salicylate, methyl salicylate, ethylene glycol salicylate, phenyl salicylate, amyl salicylate, benzyl salicylate, isopropylbenzyl salicylate, potassium salicylate, etc. UV absorber; 4-t-butyl-4'-methoxydibenzoylmethane, 4-isopropyldibenzoylmethane, 4-methyl Dibenzoylmethane UV absorbers such as xyldibenzoylmethane, 4-t-butyl-4'-hydroxydibenzoylmethane; menthyl-O-aminobenzoate, 2-phenyl-benzimidazol-5-sulfate, 2-phenyl -5-methylbenzoxazole, 3- (4-methylbenzylidene) camphor, 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate, 2-ethyl-2-cyano-3,3'-diphenyl acrylate, 2 -(2'-hydroxy-5-methylphenyl) benzotriazole, anthranilic acid UV absorbers such as menthyl anthranilate; urocanic acid UV absorbers such as ethyl urocanate; titanium oxide, zirconium oxide, cerium oxide and the like It is done. These metal oxides may be silica-coated. The blending amount of the UV protection agent may be 0.001 to 50% by weight, and preferably 0.01 to 10%.

  Antibacterial agents include benzoic acid, sodium benzoate, coalic acid, sorbic acid, potassium sorbate, paraoxybenzoic acid ester, parachlorometacresol, hexachlorophene, benzalkonium chloride, chlorhexidine chloride, trichlorocarbanilide, photosensitizer, Bis (2-pyridylthio-1-oxide) zinc, phenoxyethanol and thianthol, isopropylmethylphenol and the like can be mentioned. Examples of the pH adjusting agent include potassium carbonate, sodium hydrogen carbonate, ammonium hydrogen carbonate and the like. Examples of the refreshing agent include L-menthol and camphor.

  As an anti-inflammatory agent, glycyrrhizic acid such as dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, β-glycyrrhetinic acid, stearyl glycyrrhetinate, disodium 3-succinyloxyglycyrrhetinate, or glycyrrhetinic acid and derivatives thereof and salts thereof, Panthenol and derivatives thereof such as mefenamic acid, phenylbutazone, indomethacin, ibuprofen, ketoprofen, allantoin, guaiazulene, calcium pantetonate, D-pantothenyl alcohol, pantothenyl ethyl ether, acetyl pantothenyl ethyl ether, and salts thereof, ε-aminocaproic acid, diclofenac sodium, tranexamic acid and the like can be mentioned. The blending amount is 0.001 to 10% by weight, more preferably 0.01 to 5% by weight.

  Antioxidants include superoxide dismutase, mannitol, histidine, tryptophan, bilirubin, quercetin, quercitrin, polyphenol, proanthocyanidins, tocotrienol, catechin, catechin derivatives, rutin and its derivatives, gallic acid and its derivatives, ubiquinone, astaxanthin , Carotene, and other retinols such as retinol palmitate and retinol acetate, retinal and derivatives thereof, dehydroretinal, carotenoids such as carotene, lycopene and astaxanthin, carotenoids; thiamine hydrochloride, thiamine sulfate, riboflavin, acetic acid Pyridoxine such as riboflavin, pyridoxine hydrochloride, pyridoxine dioctanoate, flavin adenine nucleotide, cyano Vitamin B such as nicotinic acid such as paramine, folic acid, nicotinic acid amide, benzyl nicotinate, choline, etc .; Vitamin D such as ergocalciferol, cholecalciferol, dihydroxystannal; dl-α (β, γ) -Tocopherols such as tocopherol, dl-α-tocopherol acetate, nicotinic acid-dl-α-tocopherol, linoleic acid-dl-α-tocopherol, succinic acid dl-α-tocopherol and vitamin E such as ubiquinones; Examples include dibutylhydroxytoluene and butylhydroxyanisole.

  Hereinafter, in the Examples, the composition for external use combined with fullerenes is specified, and the effect will be described in more detail. Of course, the invention is not limited by the following examples.

(Example 1: Production example of fullerenes)
For example, PVP-fullerene, which is a PVP (polyvinylpyrrolidone) modified composite fullerene, is prepared by the following method.

  First, mixed fullerene (C60: C70 = 3.5: 1 mol / mol) (0.8 mg) is added to toluene (1.0 ml) and stirred. This stirred solution was filtered to remove mixed fullerenes that were not dissolved in toluene, and then this solution was added to an ethanol solution of PVP: weight average molecular weight 60,000 (100 mg) at room temperature. After thorough blending, the solvent was evaporated under reduced pressure. The residue was dissolved in 2.0 ml of Milli-Q water and the suspension concentration was azeotropically distilled to distill off toluene.

  As a result, an aqueous PVP-fullerene complex solution was obtained. Also, water was removed by evaporation to obtain a powder.

(Example 2: Preparation example of a solution containing fullerene and olive oil)
The cell death inhibitory action was verified using solutions having fullerene concentrations of 0.5 μM, 7.5 μM, and 10.0 μM. The external composition used in combination with fullerene is olive oil. As fullerenes, PVP-fullerene obtained by the method of Example 1 was used. Hereinafter, preparation of a solution containing fullerene and olive oil will be described by taking a 0.5 μM solution as an example.

  First, PVP-fullerene was dissolved in olive oil to obtain an oily mixture of fullerene and olive oil. This oily mixture is dissolved in purified water so that the concentration of fullerene is 0.5 μM and the concentration of olive oil is 0.053 mg / ml. Further, ethyl alcohol is added to this solution to adjust the concentration of ethyl alcohol to 0.0024 ml / ml. Ethyl alcohol plays a role as a preservative for preventing deterioration of the composition for external use combined with fullerene.

(Example 3: Test example of cell death inhibitory action by fullerene and olive oil)
The obtained fullerene concentration 0.5 μM solution is applied to human epidermal cells cultured for 24 hours. The application amount of the solution is adjusted to 0.5 ml / cm ^{2 based} on the area of human epidermal cells. Human epidermal cells coated with a solution having a fullerene concentration of 0.5 μM are placed at a constant temperature of 25 ° C. for 3 hours. Thereafter, t-BuOOH (tertiary butyl hydroperoxide) having a concentration of 60 μM as lipid peroxide is applied to human epidermal cells and allowed to stand at a constant temperature of 25 ° C. for 24 hours.

  Next, the degree of cell death of the human epidermal cells thus obtained is evaluated. The degree of cell death was evaluated using a spectrophotometer utilizing the property that light with a wavelength of 450 nm is absorbed by dehydrogenase in mitochondria. In other words, the higher the absorbance of light having a wavelength of 450 nm, the more active dehydrogenases are present and the larger number of cells are alive. Conversely, the lower the absorbance, the fewer active dehydrogenases and the smaller the number of living cells. Solutions with fullerene concentrations of 7.5 μM and 10 μM were also prepared by the same method as in Example 2, and the degree of cell death was evaluated. A spectrophotometer manufactured by JASCO Corporation and an absorption plate reader manufactured by Bio-Rad were used for the measurement.

  FIG. 1 is a graph showing the cell death inhibitory effect when solutions having different fullerene concentrations are applied to human epidermal cells. The vertical axis shows cell death inhibition relative activity. Cell death inhibition relative activity was determined by taking the fullerene solution and then measuring the human epidermis cells without t-BuOOH as 100% absorbance, without applying the fullerene solution and applying only t-BuOOH. The absorbance at the time of measuring epidermal cells is 0%, and the absorbance of human epidermal cells coated with a solution of each fullerene concentration is shown as a relative value. The unit is%. If the relative activity of inhibiting cell death is 50%, the absorbance of human epidermal cells is an intermediate value between the absorbances of 100% and 0% as a reference. The horizontal axis indicates the fullerene concentration of the solution applied to human epidermal cells, and the unit is μM. The value of the relative activity of inhibiting cell death at each fullerene concentration shows an average value calculated from a large number of samples.

  The cell death inhibitory relative activities of human epidermal cells coated with solutions having fullerene concentrations of 0.5 μM, 7.5 μM, and 10.0 μM are 7.1%, 11.5%, and 19.4%, respectively. From the test, it was confirmed that as the fullerene concentration increased, the cell death inhibitory effect increased. When the fullerene concentration is 10.0 μM, it is considered that the effect of suppressing cell death is the highest and the effect of suppressing aging of the skin is the highest. Although the cell death inhibitor according to this embodiment is expected to be applied to cosmetics and the like, most of fullerenes are colored, and in order to adjust the color tone so that it does not feel strange when applied to the skin, 10 It is desirable to incorporate fullerene at a concentration lower than 0.0 μM. On the other hand, when the fullerene concentration was lower than 0.5 μM, the cell death inhibitory effect was hardly observed.

(Example 4: Test example of cell death inhibitory action by an external composition other than olive oil)
FIG. 2 is a graph showing the cell death inhibitory effect when various oils and vitamins are applied to human epidermal cells together with fullerene. Based on the results of Example 3, the cell death inhibitory effect was verified using an external composition different from olive oil. All fullerene concentrations were 10 μM, and the measurement was performed. The vertical axis shows the cell death inhibiting relative activity as in FIG. 1, and the unit is%. The horizontal axis shows the composition for external use used in combination with fullerene. The value of the relative activity of inhibiting cell death in each oil or vitamin shows the average value calculated from a large number of samples.

  The cell death suppression relative activities of human epidermis cells of olive oil, squalane, jojoba oil, and shiso oil applied with fullerene as an oil agent are 19.4%, 20.0%, 40.0%, and 19.0%, respectively. . The cell death inhibitory relative activities of VCIP and d1-α-tocophenol applied together with fullerene as vitamins are 8.2% and 24.0%, respectively. The value of the relative activity of olive oil for cell death inhibition refers to the value at the fullerene concentration of 10 μM in FIG.

  As for oils, squalane and jojoba oil have a cell death inhibitory effect that exceeds olive oil, and jojoba oil has a cell death inhibitory relative activity that is at least twice that of olive oil. From these results, it is considered that jojoba oil is more preferable than olive oil in order to suppress cell death and skin aging. On the other hand, squalane and shiso oil have the same effect of suppressing cell death as olive oil. Therefore, these oil agents can be used as an alternative oil agent for olive oil.

  For vitamins, VCIP shows a cell death inhibitory effect lower than that of olive oil, whereas d1-α-tocophenol shows a cell death inhibitory effect over olive oil. If the oil agent cannot be used in the preparation of the cell death inhibitor, these vitamins can be used instead of the oil agent. At that time, it is desirable to use d1-α-tocophenol having a higher cell death inhibitory effect.

  In this example, a test was performed using PVP-modified composite fullerene, which is a composite of mixed fullerene and PVP, as fullerenes. However, the fullerenes may be one or more of fullerenes, fullerene derivatives, or fullerenes or complex of fullerene derivatives modified or included by an organic compound. The fullerene derivative may be a fullerene that integrates one or more of an oxygen-containing group, a nitrogen-containing group, and a hydrocarbon group that may have a substituent.

  Further, the fullerenes may be one or more of salts with metals. The salt of fullerenes may be one or more of sodium, potassium, magnesium, calcium, and aluminum salts. Furthermore, the fullerenes may be one or more of hydroxylated fullerenes and esters thereof.

  In addition, the fullerene may be a complex of at least one of fullerene and a fullerene derivative and one or more of organic oligomers, organic polymers, cyclodextrins, crown ethers, and related compounds thereof. It may be a composite of at least one fullerene derivative and polyvinylpyrrolidone (PVP).

  These fullerenes are processed to make fullerenes soluble in water, and the same effects as the fullerenes used in the above examples are presumed.

  The present invention is not limited to the above-described embodiments, and various modifications and changes can be made based on the knowledge of those skilled in the art, and the embodiments to which such modifications are added. Can also be included in the scope of the present invention.

It is a graph which shows the cell death inhibitory effect at the time of apply | coating the solution in which fullerene density | concentration differs to a human epidermal cell. It is a graph which shows the cell death inhibitory effect at the time of apply | coating various oil agents and vitamins to human epidermal cells with fullerene.

Claims (12)

A cell death inhibitor that suppresses cell death caused by lipid peroxide,
At least one oil selected from the group consisting of olive oil, squalane, jojoba oil and shiso oil;
A cell death inhibitor comprising fullerenes. The oil is olive oil;
The cell death inhibitor according to claim 1, wherein the concentration of the fullerenes is 0.5 µM or more and 10 µM or less. The oil is olive oil;
The cell death inhibitor according to claim 1 or 2, wherein the concentration of the fullerene is 7.5 µM or more and 10 µM or less. A cell death inhibitor that suppresses cell death caused by lipid peroxide,
At least one vitamin selected from the group consisting of ascorbic acid tetraisopalmitate and d1-α-tocophenol;
A cell death inhibitor comprising fullerenes.   The cell death inhibitor according to any one of claims 1 to 4, wherein the cells are skin cells.   The fullerene is one or more of fullerene, a fullerene derivative, a fullerene modified with or including an organic compound, or a complex of fullerene derivatives, according to any one of claims 1 to 5. The cell death inhibitor described.   The fullerene derivative is a fullerene that integrates at least one of an oxygen-containing group, a nitrogen-containing group and a hydrocarbon group which may have a substituent. Agent.   The cell death inhibitor according to any one of claims 1 to 7, wherein the fullerene is one or more of salts with metal.   The cell death inhibitor according to claim 8, wherein the salt of fullerene is at least one of sodium, potassium, magnesium, calcium, and aluminum salts.   The cell death inhibitor according to any one of claims 1 to 9, wherein the fullerene is at least one of hydroxylated fullerenes and esters thereof.   The fullerene is a complex of at least one of fullerene and a fullerene derivative, and one or more of organic oligomers, organic polymers, cyclodextrins, crown ethers, and one or more of those similar compounds. Item 11. The cell death inhibitor according to any one of Items 6 to 10.   The cell death inhibitor according to claim 11, which is a complex of at least one of fullerene and a fullerene derivative and polyvinylpyrrolidone (PVP).

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