JP2001097888A - Composition for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a stable radical-eliminating composition for external use, effective to the human skin tissue, capable of exhibiting radical-eliminating activities, manifesting high effects on various kinds of radical diseases. SOLUTION: This radical-eliminating composition for external use containing two or more kinds of components and having water-soluble components providing pH >=7.1 is obtained by formulating a stable activity-type radical-eliminating material so as to have the highest wt.% compared to those of all other components except water in the components for an agent for the external use. The radical-eliminating composition for external use having the water-soluble components providing pH >=7.1 simultaneously contains the stable activity-type radical-eliminating material, one or more, preferably two or more kinds of natural moisture- keeping components, and one or more kinds, preferably two or more kinds of nonsteroidal antiinflammatory components. The radical-eliminating composition for the external use further simultaneously contains an ultraviolet-scattering agent having a low photocatalystic toxicity therewith. The dermal radical-eliminating composition for the external use contains plural stable activity-type radical-eliminating materials selected from the stable activity-type radical- eliminating materials having different times for activating the activities of the radical- eliminating materials in the cells, when the stable activity-type radical-eliminating materials are added to a culturing liquid, and a cell is cultured therein.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an external composition having an excellent radical scavenging effect.

[0002]

2. Description of the Related Art The skin is susceptible to the attack of radicals such as active oxygen.
She has been receiving it for four hours and is aging little by little every day. Cells breathe oxygen and burn and oxidize it slowly to oxidize and produce energy, but this oxygen also produces toxic substances such as active oxygen and damages skin cells, which is one of the causes of aging It is said that it is. For this reason, it has been pointed out that, for example, animal species with more active oxygen metabolism generate more active oxygen and have a shorter life span. In addition, it is estimated that an average of 1000 or more DNA molecules per cell are damaged by active oxygen per day. It is said that the accumulation of biological damage due to this active oxygen becomes a phenomenon called "aging", which eventually leads to death. Active oxygen also oxidizes skin lipids, breaking peptide bonds in proteins and producing melanin pigments, wrinkles,
It is being clarified that it contributes to the occurrence of tarmi. In addition, it is pointed out that it causes various skin inflammations, skin disorders and accelerated aging such as destruction of cells and tissues, inflammation such as acne and atopic dermatitis, and DNA damage, skin cancer and promotion of cleavage of telomere gene. Have been. Hydrogen peroxide, hydroxyl radicals, superoxides, and the like are known as active oxygen generated in the living body, but radicals are also included, including lipid hydroperoxide (lipid peroxide), which is an oxidized and damaged oil. It has been pointed out that a group of substances is a causative substance that promotes skin aging. Radicals such as lipid hydroperoxides need to be scavenged as soon as possible in order to cause a chain reaction and successively generate new radicals. Active oxygen and radicals are also produced in large quantities by factors such as exposure to ultraviolet light, chlorine in tap water, lipid peroxide in foods, and radical producing components contained in cosmetic raw materials. In recent years, metal oxides such as titanium oxide, which is a general component of an ultraviolet scattering agent in cosmetics, are said to release a large amount of hydroxyl radicals into sweat due to ultraviolet rays. The problem is that a large amount of radicals are generated from the ultraviolet scattering agent that originally reduces the toxicity of ultraviolet light

Exposure to radical generating factors contained in such cosmetics for a long time not only accelerates aging of the skin and accelerates the formation of wrinkles and sagging, but also exacerbates acne, atopy and other dermatitis, It induces pigmentation and, in severe cases, necroses skin cells, damaging DNA and inducing skin cancer. It has also been pointed out that many skin diseases are caused by radicals. For example, skin diseases caused by radicals include, for example, actinic inflammation and pigmentation caused by light and ultraviolet irradiation, irradiation, and other inflammations, aging and necrosis of skin tissue cells, acne, athlete's foot, beetles, spirochetes, and syphilis. Infectious inflammation associated with the concentration of leukocytes induced by various staphylococci, skin inflammation such as atopic dermatitis, skin cell necrosis or skin tissue wounds caused by burns, frostbite, bedsores, wounds, etc. It is said that radicals are also involved in skin diseases such as insect bites, makeup rash, metal rash, pesticide rash, chemical rash, jellyfish toxin, and chemical inflammation due to acid-alkali dermatitis. As a defense mechanism against these radicals, the living body has a defense system that eliminates the toxicity of active oxygen and radicals. Glutathione peroxidase, catalase, superoxide dismutase (SO
D) and the like are known. Many other natural radical scavengers such as vitamin C, vitamin E, carotenoids, polyphenols of tea and grape, and raspberry extract are known.

[0004]

The radical scavenging component of the conventional external preparation composition for scavenging radicals does not pay attention to the effect of radical scavenging activity on human cells or the stability of radical scavenging substances. In experimental animals such as rats and mice, even if a high radical scavenging effect is recognized, a component with low radical scavenging activity is used as a radical scavenging component on actual human skin tissue, or radical scavenging activity exists In addition, because of its poor stability, many of its effects were low or did not persist even when it was added to external compositions such as cosmetics.On the other hand, recent advances in ESR and other radical detection technologies have made it possible to detect even trace amounts of harmful radicals to the human body. Sources have also been found in substances that were not previously recognized as radical sources. For example, metal oxides such as titanium oxide are frequently added to external compositions such as cosmetics for the purpose of ultraviolet reflection and scattering in order to prevent harm to the skin due to ultraviolet rays. In recent years, metal oxides containing titanium oxide in cosmetics have been added. It has been found that the photocatalysis during ultraviolet irradiation can be a serious radical generation source. It is difficult to check for the presence of radical sources due to the large number of types of substances added to the external composition, and the government does not specifically mandate safety tests on radical sources when selling cosmetics Therefore, unknown external sources of radicals other than metal oxides exist in external preparations such as cosmetics, which contribute to problems such as photosensitivity and photoallergy. Also, in the conventional external compositions such as cosmetics, a group of polyphenols having a radical scavenging action and a group of hydroxy compounds having a reducing action having a plurality of hydroxyl groups such as AG have been often used, but these hydroxy compounds are used as an external preparation. When added to and applied to the skin, it has a high affinity for water molecules, so that it feels sticky to the touch and remarkably reduces the commercial value of an external preparation having a radical scavenging action. In addition, radicals are said to be involved in the cause and exacerbation of the disease state, pigmentation caused by photostimulation, ultraviolet rays, radiation, and other inflammation, apoptosis and aging of skin tissue cells, acne, athlete's foot, psyllium, spirochetes, syphilis ,
Skin inflammation such as infectious inflammation, actinic inflammation, atopic dermatitis, etc. due to concentration of blood cells induced by various staphylococci, skin cell necrosis due to burns, frostbite, bedsores, wounds, etc. An external composition that can exert an effective radical scavenging effect against radical skin diseases such as sweat, insect rash, makeup rash, metal rash, pesticide rash, chemical rash, jellyfish toxin, chemical inflammation due to acid-alkali dermatitis, etc. A variety of radical scavengers have been developed and used to scavenge radicals on the skin, which has no problem.However, radical scavengers themselves are generally unstable and do not last long enough. The amount of radicals in the skin tissue could not be eliminated. Therefore, a sufficient effect could not be exhibited. In particular, since skin tissue is widely present on the human body surface, it is susceptible to attack by common radical-generating factors such as oxygen, light, ultraviolet rays, and various other chemicals that promote oxidation. Sustainable and effective radical scavenging was not possible. For example, AsA
And AsA sulfate, one of the derivatives of tocopherol, is a stable AsA derivative and its AsA activity has been reported by experiments using animals. However, it is almost converted to AsA by the hydrolase of human skin tissue. However, it was ineffective as a radical scavenging composition component of an external preparation. In addition, inflammation and burns due to severe ultraviolet irradiation,
In infectious diseases, the generation of radicals continues for a long time, for example, skin cells are continuously exposed to the generation of continuous radicals for several days, so that in a conventional topical composition, the radical scavenging effect decreases in a short time. Therefore, the effect of preventing and treating radical diseases of the skin due to the radical scavenging effect could not be sufficiently exerted. In addition, there are a number of substances that have an effective radical scavenging effect in test tubes that are difficult to be absorbed from human skin and cannot be used due to cytotoxicity problems. It has been demanded to select a tissue exhibiting a radical scavenging action and apply it to a composition for external use.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a composition for external use for radical elimination, which is provided with a measure for an unknown radical-generating substance which has not been considered in a conventional external use composition.
In addition, we devised a method for selecting a radical scavenging component that can exert its effect on human skin tissue and the stability of radical scavenging components, and contains a component that exhibits a radical scavenging effect that can effectively prevent and treat radical diseases of human skin And a method for preventing and treating radical diseases. The problem with radical scavengers used on the skin is
As described above, skin tissues are more susceptible to chemicals and ultraviolet rays than other human organs, and radicals are extremely likely to be generated and the generated radicals are easily sustained. There is a problem that radicals are decomposed and metabolized within a time, and radicals cannot be sufficiently eliminated from skin tissue. The present inventors have tried to solve this problem by selecting and using a stable radical scavenger instead of a normal radical scavenger, but even a stable type is hydrolyzed in skin tissue and becomes a normal type. It has been found that a sufficient radical scavenging effect cannot be obtained because it is a radical scavenger. In other words, when a stable radical scavenger that is so strong that it is not hydrolyzed in skin tissue was tested, no effect was seen in the skin, so a stable active radical scavenger that had both stability and activity in skin tissue was used. I decided to use it. The stable active radical scavenging substance that can be used in the present invention refers to a substance that is stable in the following experiment and has activity as a radical scavenging substance in skin tissue by a hydrolase or the like in skin tissue. That is, the activity of the stable active radical scavenger usable in the present invention is determined by adding AAPH to a homogenate solution of living human epidermis.
(2,2'-azobis (amidinopropa
ne) Dihydrochloride) Add 10 mM, measure the radical strength by ESR, and then add 10 mM of a radical scavenger to this solution. When measuring the suppressed radical strength, the radical strength is reduced to 80% or less before the addition of the radical scavenger. It is limited to radical scavengers having inhibitory activity. The stability of the stable active radical scavenging substance usable in the present invention is such that when the 1% aqueous solution or squalane oil solution is left at 40 ° C. for 1 month, the radical scavenging substance has a stability of 50% or more. It is limited to a single or a plurality of stable active radical scavengers. Next, as a measure against unknown radical generating sources, the present inventors have conducted various studies and as a result, even if there is any unknown radical generating source, if there is an excess amount of a stable active radical scavenger, it can counter the unknown radical generating material It was presumed that it was considered to be the case. When the stable active radical scavenging substance having the above-mentioned stability and activity was used and the weight% in this external preparation component was compared with that of all other components, components other than water were used. When the compound was added at the highest weight percentage among the above, radicals from unknown radical-generating substances could be completely eliminated and an external composition for radical scavenging effective for prevention and treatment of radical diseases could be obtained. In addition, in the case of external preparation products such as cosmetics, the fact that the amount of the radical scavenger added is the largest among the components other than water has a psychological effect of increasing the added value of the external preparation. In other words, consumers who purchase external preparations often decide whether or not to purchase the product by labeling the components, because there is a psychological tendency to seek the highest content of radical scavenging components at that time. . The present inventors applied a stable radical scavenger to the skin, tested its effect on radical diseases of the skin, and measured the amount of the radical scavenger on the skin. We examined exploration. These experiments revealed that the permeability of the radical scavenger to the skin was a very important factor. We tried various substances to improve the penetration of radical scavengers into the skin. By using a stable active radical scavenger and a moisturizer together, the skin permeability of the stable active radical scavenger increased dramatically. I found a thing. This is because most of the formulated stable active radical scavengers are applied in the form of an emulsifier or an aqueous solution, and a large amount of water is present in the formulation system and the components are dispersed. This is considered to be due to the fact that the residual amount remains on the skin and the skin permeability of the stable active radical scavenger decreases.

In patients suffering from radical diseases, the use of a synthetic humectant tends to cause irritation rather than aggravation, and the use of a natural humectant can alleviate this problem. We were able to. Thus, the present inventors have found that the effect can be remarkably improved by using a natural humectant in combination with a stable active radical scavenger. Furthermore, when two or more kinds of natural humectants were used in combination, the use of a natural humectant as a single agent made it possible to absorb a much more stable active radical scavenger into the skin. In addition, in the case of special radical disorders associated with allergic reactions caused by ultraviolet rays or chemical substances generated by allergic predisposed patients and radical infectious diseases such as acne bacteria, blood cells are concentrated on the affected area and an inflammatory reaction is observed. There is. Among blood cells, leukocytes are known to be a strong radical generating source, and under such conditions, radical diseases are further deepened and deteriorated. It was thought that the combined use of an anti-inflammatory agent was effective in reducing and eliminating the source of radicals caused by these leukocytes. Was found to be improved. Furthermore, the combined use of two or more kinds of anti-inflammatory agents could significantly enhance the effect of the stable active radical scavenger on radical diseases, compared to the use of a single agent. This seems to be because the administration of the adjunct agent is more effective than the single agent for the inflammatory response having a different mechanism of action. However, even with this prescription, it is possible to obtain a satisfactory effect for severe radical diseases caused by ultraviolet irradiation damage including ultraviolet B wave which is exposed to the skin exposed to seawater on the seashore in the summertime during the daytime. Did not. Therefore, the present inventor focused on the fact that radical dermatosis is harder to cure on the face and arms etc., which are more likely to be exposed to light such as solar ultraviolet rays than inside clothes, etc., and a stable active radical scavenger and a light absorber or a light reflector. Was considered. Unexpectedly, many organic light absorbers and organic ultraviolet light absorbers did not sufficiently improve the skin radical disease, but rather worsened. Although the cause is unknown, it is considered that the stimulus of the organic ultraviolet absorber itself or the decomposition of the organic ultraviolet absorber by ultraviolet rays and the like to convert it to a stimulant are considered. Next, when the present inventors used an inorganic ultraviolet scattering agent, under indoor visible light, it was effective in combination with a stable active radical scavenger, but under light including an ultraviolet region such as sunlight. In some cases, radical diseases of the skin were not sufficiently improved, but rather worsened. When the cause was investigated, a large amount of radicals were detected from the inorganic ultraviolet scattering agent under a high energy wavelength light such as ultraviolet light. The amount of radicals increased in the presence of water, and extremely high amounts of radicals were detected in seawater, sweat, and tap water in which chlorine remained. The present inventors considered that the increase in skin disease when using an inorganic ultraviolet scattering agent under sunlight was attributed to the photocatalytic activity of the inorganic ultraviolet scattering agent. Thus, surprisingly good results were obtained when a photocatalytically active inorganic ultraviolet scattering agent developed in recent years as a cosmetic raw material was used. That is, the present invention can strongly and continuously reduce radicals on the skin by simultaneously containing an existing stable active radical scavenger, a photocatalytically active inorganic ultraviolet scattering agent and a natural humectant. The present invention was found to be extremely effective as an external composition for radical scavenging of the present invention, and completed the present invention. The stable active radical scavenger of the present invention, which simultaneously contains three components of a stable active radical scavenger, a photocatalytically active inorganic ultraviolet scattering agent, and a natural humectant, a photocatalytically active inorganic ultraviolet scattering agent, and a natural system The external composition containing the three moisturizing components is compared with the conventional stable active radical scavenger, the photocatalytically active inorganic ultraviolet scattering agent and the natural moisturizing agent alone or in combination with the two agents. It has excellent radical scavenging ability, and has an extremely high effect as a preventive and therapeutic agent for radical diseases. In addition, it has been found that when the pH of the external preparation composition of the present invention is 7.1 or more, the radical scavenging effect of the stable active radical scavenger is enhanced. Furthermore, as a result of conducting research to enhance the effect,
Plural stable active radical scavengers selected from different stable active radical scavengers in which the activity of radical scavengers in cells is activated at different times when culturing skin cells by adding a stable active radical scavenger to the culture solution It has been confirmed that an external composition for radical scavenging of the skin containing a radical scavenger has a long-lasting radical scavenging ability in the skin and exhibits an excellent preventive and therapeutic effect for radical diseases. From this, the present inventors have found that when a stable active radical scavenger is added to a culture solution and the skin cells are cultured, the activity of the radical scavenger in the cells is activated at different times, and different stable active radical scavengers are activated. Invented a composition for external use for skin containing simultaneously a plurality of stable active radical scavengers selected from the group consisting of a photocatalytically active inorganic ultraviolet scattering agent and a natural moisturizer. An extremely high effect was confirmed as a preventive and therapeutic agent for. The basic three components of the stable active radical scavenger of the present invention, the photocatalytically active inorganic ultraviolet scattering agent and the natural humectant are independent of each other when a three-component compounding agent is not available due to dermatological outpatients. The same effect can also be exhibited by a method of simultaneously applying different preparations added to the radical disease applicable to the present invention is effective for all pigmentation of the skin, and inflammatory or post-inflammatory pigment It is effective for deposition, but is particularly effective when the cause is radical damage caused by photostimulation, ultraviolet light, or radiation. In addition, since the shortening speed of the telomere gene in skin cells is delayed to increase telomerase activity, it has an effect of suppressing apoptosis and aging. Acne, athlete's foot, beetles, spirochetes,
Suppresses inflammation of infectious inflammation of bacteria, protozoa and viral skin caused by syphilis and the like. It is considered that this is to suppress cell damage due to excessive radicals generated by blood cells. Suppresses exacerbation by radicals during inflammation such as atopic dermatitis and allergic dermatitis. This is because human skin suffers many radical damages such as ultraviolet rays and tap water chlorine even under normal conditions, and inflamed skin such as atopic dermatitis rapidly deteriorates when affected by these radicals It is thought to be. In addition, the composition for external use of the present invention is effective for cell necrosis or wound due to burns, frostbite, bedsores, wounds and the like. This is because radicals are generated when skin tissues and cells are destroyed. Further, the composition for external use of the present invention is effective against various chemical skin inflammations such as sweat, insect rash, makeup rash, metal rash, pesticide rash, chemical rash, jellyfish toxin and acid-alkali dermatitis.
In addition, for a hydroxy compound group having a plurality of hydroxyl groups having a high sticky feeling and having a reducing action, which has been blended in a conventional external composition such as cosmetics, a fine particle silica or collagen is used in combination with the external preparation. By doing so, a high value-added external composition for radical scavenging which can reduce the stickiness can be completed.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to an external composition for radical scavenging of skin, comprising a stable active radical scavenger, a phototoxic inorganic ultraviolet scattering agent and a natural humectant, and a method therefor. About. The stability of the radically active radical scavenger usable in the present invention is one of the radical scavengers.
When the percent aqueous solution or the squalane oil solution is left at 40 ° C. for one month, a substance in which 50% or more of the radical scavenging substance remains can be used as a passing substance. The stable active radical scavenging substance that can be used in the present invention may be one whose activity has been confirmed by the following method. That is, AAPH (2,2′-azobis (amidi) which is a radical generator is added to the homogenate solution of the epidermis.
nopropane) dihydrochloride
e) Add 10 mM to generate hydroxyl radical and
Measure the radical strength by SR, then add 10 mM of a radical scavenger to this solution and measure the suppressed radical strength. When measuring the suppressed radical strength, it has the ability to suppress to less than 90% of the radical strength before adding the radical scavenger. It is an active radical scavenger. According to the present invention, the stable active radical scavenging substance having the above stability and activity is contained in a weight% of the external preparation component.
Is more complex than cosmetics by providing an external composition for radical scavenging of the skin consisting of three or more components, characterized in that it is compounded at the highest weight percentage besides water when compared with that of all other components. Even radicals generated from an unknown radical generating substance made of a compound can be sufficiently eliminated. The topical composition for radical scavenging of the present invention is effective for the following radical diseases. Radical diseases include pigmentation, photoallergy and allergic dermatitis, dermatitis due to light rays, dermatitis due to ultraviolet rays, dermatitis due to radiation, aging of skin cells, apoptosis of skin cells, infectious dermatitis, acne , Oily sickness, athlete's foot, athlete's foot, beetle, spirochetes, syphilis, other skin inflammations, atopic dermatitis, skin cell necrosis or wounds, burns, frostbite, bedsores, wounds, chemical dermatitis, sweat, insects, makeup These include rash, metal rash, pesticide rash, chemical rash, jellyfish toxin, acid-alkali dermatitis, hair loss, alopecia, baldness, gray hair, rosacea, and dry skin.

The stable active radical scavenger of the present invention includes ascorbic acid (hereinafter referred to as AsA), α-tocopherol (the TOC may be any of the dl form, the d form, and the 1 form), carotenoids (the above-mentioned carotenoids). , Carotenoids such as β-carotene, α-carotene, astaxanthin, retinol, retinoic acid, tretinoin, lycopene, lutein, cryptoxanthin and optical isomers thereof), catechin, polyphenol, plant extract, seed extract, mold extract , Seaweed extract, yeast extract, stable extract of organic radicals such as organic acid esters, sugar esters, etc. of radical scavengers selected from cell extracts, etc. What is necessary is just what passed the activity test. As the organic acid constituting the organic acid ester, phosphoric acid, acetic acid, sulfuric acid,
α-hydroxy acids, amino acids and the like may be used, and sugars constituting sugar esters include glucose, fructose,
Any natural monosaccharide or natural polysaccharide such as sialic acid may be used.
The amino acid constituting the amino acid ester may be any amino acid selected from essential amino acids such as glycine, alanine, lysine, cysteine, cystine and arginine. The salt may be a highly safe salt such as an alkali metal, an alkaline earth metal or an amine salt. Specific examples thereof include sodium (hereinafter abbreviated as Na), potassium (hereinafter abbreviated as K), calcium, Aluminum, magnesium (hereinafter abbreviated as Mg), zinc, iron,
Bismuth, triethanolamine salts and the like may be used. The following substances can be used as specific examples of the stable active radical scavenging substance that can be used in the present invention. Ascorbic acid-2-phosphate (hereinafter referred to as AP) salt, APNa,
APNa, APK, AP calcium, ascorbic acid-
2-glucoside (hereinafter referred to as AG), AG-6-palmitic acid, AG-6-stearic acid, AG-6-fatty acid,
AsA-2-polyglucoside, AsA-2-diglucoside, AsA tetraisopalmitic acid, AsA-6-palmitic acid, AsA-2,6-dipalmitic acid, AsA-6-stearic acid, AsA-6-fatty acid, AsA liposome capsule, AsA1 , 3, butylene glycol (hereinafter abbreviated as BG) dispersion, AsA propylene glycol (hereinafter abbreviated as PG) dispersion, AsA ethanol, AsA
Cetanol dispersion, AsA polyhydric alcohol dispersion, As
A alcohol dispersion, AsA glycerin dispersion, AsA
Jojoba oil coating, AsA room temperature hardened oil coating, AsA vegetable oil dispersion, TOC, TOC liposome capsule, TOC1,3, BG dispersion, TOCPG dispersion, TOC ethanol, TOC cetanol dispersion, TO
C polyhydric alcohol dispersion, TOC alcohol dispersion, T
OC glycerin dispersion, TOC jojoba oil coating, TOC room temperature hardened oil coating, TOC vegetable oil dispersion (the TOC may be any of dl form, d form and l form), β-carotene, α-carotene, astaxanthin, retinol, Carotenoids such as retinoic acid, tretinoin, lycopene, lutein, cryptoxanthin and optical isomers thereof, retinol acetate, retinol palmitate, carotenoid liposome capsule, carotenoid 1,3, BG dispersion, carotenoid PG dispersion, carotenoid ethanol, carotenoid cetanol Dispersion,
Carotenoid polyhydric alcohol dispersion, carotenoid alcohol dispersion, carotenoid glycerin dispersion, carotenoid jojoba oil coating, carotenoid room temperature hardened oil coating, carotenoid vegetable oil dispersion can be used. Further, the following natural antioxidants can also be used as the stable active radical scavenger of the present invention. Epigallocatechin gallate, epicatechin, proanthocyanidins, catechins, succinic acid, plant-derived polyphenols, glutathione, superoxydismutase, metalthionene, kojic acid, cysteine, cystine, dipotassium glycyrrhizinate, catalase, plant seed extract, Grape seed extract, licorice extract. Liposomal capsules of natural antioxidants of these natural products, solvent dispersions of natural antioxidants such as 1,3, BG dispersion, PG dispersion, ethanol dispersion, cetanol dispersion, polyhydric alcohol dispersion, Alcohol dispersions, glycerin dispersions and the like can be used. In addition, jojoba oil coatings of these natural products, room temperature hardened oil coatings, vegetable oil dispersions and the like can also be used.

As the stable active radical scavenger of the present invention, a radical scavenger which is unstable alone such as AsA or tocopherol and its salts or a mixture thereof is coated with a coating agent such as gelatin or fats and oils for the purpose of stabilization. It is also possible to use those prepared with microcapsules, liposomes, or dextrin, or those obtained by intercalating with diatomaceous earth. As the phototoxic inorganic ultraviolet scattering agent of the present invention, a metal oxide powder having ordinary photocatalytic activity, such as a commercially available titanium oxide, zinc oxide, or iron oxide powder, cannot be used. The phototoxic inorganic ultraviolet scattering agent that can be used in the present invention irradiates cells with ultraviolet rays in the presence of metal oxide powder to generate radicals from the metal, and counts the number of cells that undergo apoptosis under the influence of the following evaluation method. 4/5 of the number of cells causing control potosis without UV irradiation
(0.8) or less can be used. Specific examples of the phototoxic inorganic ultraviolet scattering agent that can be used in the present invention include, for example, tetraethoxysilane, ammonia, an organic alkali, an ammonium salt of an inorganic acid and / or an organic acid, or an inorganic acid and / or an organic acid. An aqueous solution for forming a silica film containing at least one or more alkalis and having a pH of 7.1 to 10.0 and a silicon concentration of 0.002 to 0.02 mol / L selected from organic alkali salts of And silica-coated metal particles having a diameter of 1 to 1000 nm in which a silica coating is formed by contacting a substrate. The metal particles of the silica-coated metal particles are coated with titanium oxide, zirconium oxide, zinc oxide, aluminum oxide, iron oxide, aluminum / cobalt oxide, aluminum oxide hydrate / silica treated titanium oxide, calcium oxide, chromium oxide, and chromium oxide. Metal oxides such as titanium mica, zirconium oxide, cerium oxide, titanium oxide sol, titanium oxide coated reduced mica titanium, titanium oxide coated sericite, titanium oxide / silicic anhydride composite, iron oxide / titanium oxide sintered product, and Mg oxide And one or more kinds of single or mixed metal particles selected from inorganic substances.

Examples of the phototoxic inorganic ultraviolet scattering agent usable in the present invention include fragrance journal, 19
Silica-coated titanium oxide, silica-coated zinc oxide (TS01, TS04, ZS032) manufactured by Showa Denko KK (product name: Maxlite) described in p.110 of December 1998, and the like can be used. The phototoxic inorganic ultraviolet scattering agent according to the present invention can be incorporated into various compositions in addition to the above-mentioned compositions, and is also incorporated into general compositions such as cosmetics. Other ingredients, such as fats and oils, waxes,
Contains hydrocarbons, fatty acids, alcohols, polyhydric alcohols, sugars, esters, metal soaps, water-soluble polymer compounds, surfactants, antioxidants, bactericidal / preservatives, vitamins, hormones, coloring materials, etc. can do. As the natural humectant that can be used in the present invention, substances selected from the following can be used: N-stearoyl phytosphingosine, ceramide, elastin, hydrolyzed elastin solution, water-soluble Elastin, methylsilanol / N-acetylmethionine / hydrolyzed elastin condensate, methylsilanol / hydrolyzed elastin condensate, methylsilanol / lactic acid / hydrolyzed elastin condensate, N-lauroyl-L-glutamate di (cholesteryl, octyldodecyl) ), N- [2-hydroxy-3- (stearyldimethylammonio) propyl] chloride hydrolyzed silk, hydrolyzed silk compound, water-soluble silk compound, water-soluble wheat protein-containing material,
Water-soluble soy protein-containing material, water-soluble casein-containing material, sodium pyrrolidone carboxylate, dl-pyrrolidone carboxylic acid N
a, glycyrrhizin, dipotassium glycyrrhizinate, sodium pyrrolidonecarboxylate, water-soluble cellulose compounds such as hydroxyethylcellulose, monosaccharides, pectins, water-soluble keratin-containing substances, proleoglycans, peptidoglycans, dimethylsilanol / hyaluronic acid condensation which is mucopolycephalic Liquid, hyaluronic acid, dermatan sulfate, N- [2-
Hydroxy-3- [3- (dihydroxymethylsilyl)
Propoxy] propyl] hydrolyzed collagen, myristoyl hydrolyzed collagen solution, myristoyl succinyl atelocollagen solution, coconut oil fatty acid hydrolyzed collagen,
Or its Na, K or triethanolamine salt, oleoyl hydrolyzed collagen, taurine or compounds thereof,
Hydrolyzed collagen-alanine myristyl condensate, hydrolyzed corn protein, hydrolyzed tosaka solution, hydrolyzed potato protein, hydrolyzed porcine fibronectin, hydrolyzed eggshell membrane, hydrolyzed egg white, hydrolyzed lanolin, casein, casein Na, succinyl Atelocollagen solution, succinylated bovine serum albumin-treated sicon extract, succinylcarboxymethylchitosan solution, succinylchitosan, succinylchitosan solution, water-soluble chitosan, casein Na, hydrolyzed collagen solution, oil-soluble collagen extract, lauric acid-hydrolyzed collagen Na, Lauroyl hydrolyzed collagen K, isostearoyl hydrolyzed collagen, isostearoyl hydrolyzed collagen / aminomethylpropanediol salt, undecylenoyl hydrolyzed collagen K, chloride -[2-Hydroxy-3- (stearyldimethylammonio) propyl] hydrolyzed collagen, collagen, elastin, lecithin, sodium polyaspartate, polyglycine, surfactin, polyglutamic acid, polyamino acid and the like. Manufactured by Eldew, Eldew CL-202, Aquadew, Aquadew SPA-30, and the like. Furthermore, the present inventors have found that a plurality of combinations of certain kinds of stable active radical scavengers particularly enhance the radical scavenging activity of the skin, and have completed the following invention. The present invention relates to a method of adding a stable active radical scavenger to a culture solution and culturing skin cells, wherein the activity of the radical scavenger in the cells is activated at different times, and a plurality of different stable active radical scavengers selected from the different scavengers. An external composition for radical scavenging of the skin, comprising a stable active radical scavenger comprising a combination of the above stable active radical scavengers. This will be described in detail below with reference to specific examples. The present inventors have found that a special combination of different derivatives of AsA clearly enhances the radical scavenging activity of AsA as compared with the single use, even when the concentration in terms of AsA is the same. For example, APMg (hereinafter referred to as APM) and APNa
(Hereinafter APS) and AG (hereinafter APG) when combined, 2% APM, 2% APS and 1% A
It was known that the radical scavenging activity of PM + 1% APS was almost the same, but the activity of 2% AG was inferior to these. However, 2% APM and 1% APM +
1% APM + 1% AG or 1% APS compared to 1% APS
It was found that + 1% AG had higher skin radical scavenging activity.

When the cause was investigated, AsA derivatives were added to the culture solution and As cells in the cells were cultured when the skin cells were cultured.
It has been found that a combination of derivatives in which the activity of A is activated at different times increases the radical scavenging effect synergistically. For example, the approximate time at which the activity of the radical scavenging agent in the cell was maximized could be verified by the following method. Approximately 6 × 10 5 skin cells selectively cultured from human skin tissue including human dermal fibroblasts or dermal basal cells were spread on a 60 mmφ plate, and dialyzed fetal bovine serum (Moregate) was added to the plate.
The cells were cultured for 24 hours in a minimum essential medium containing 0% and 5% of human serum, then replaced with the same medium containing 50 μM of AsA or a derivative thereof, cultured for 2 hours, 6 hours, and 18 hours, and then subjected to trypsin treatment. Was collected and the number of cells was counted using a Coulter Counter DN type (Coulter Electronics Co., Ltd., trade name). The cells were washed with Hanks' balanced salt solution and disrupted with an ultrasonic homogenizer. This is filtered through Morcut II (UFFPLCC) (Nippon Millipore Co., Ltd., trade name), and analyzed by HPLC and colorimetry to quantify a stable active radical scavenging substance (for example, AsA derivative etc.) Was determined as the activity value. Table Culture time and activity of radical scavenger (intracellular concentration)
It was shown by the amount of intracellular accumulation of sA (pmole / cell). The AsA derivatives used in this example and their abbreviations are shown below. L-ascorbic acid-2-phosphate-6-palmitate sodium salt (hereinafter abbreviated as APP), L-
Ascorbic acid (hereinafter abbreviated as AsA), L-ascorbic acid-2-phosphate magnesium salt (hereinafter abbreviated as APM), L-ascorbic acid-2-phosphate sodium salt (hereinafter abbreviated as APS) L-ascorbic acid -2-sulfate sodium salt (hereinafter AS
S), 2-OD-glucopyranosyl-L-ascorbic acid (hereinafter abbreviated as AG), L-ascorbic acid-2,6-dipalmitate (hereinafter ADP)
Abbreviated).

From these results, when a stable active radical scavenger such as an AsA derivative is added to a culture solution and the skin cells are cultured, the activity of the radical scavenger in the cells (here, AsA
Activity) was activated at different times due to differences in the rate of hydrolysis of the ester of the derivative. The time at which the maximum concentration was reached was compared as a standard for activation. In the above example, APM and APS are both activated at the same time with the maximum value of 6 hours measured, but AG shows the maximum value at 18 hours, and is activated at a different time from APM and APS. Can be confirmed. Therefore, APM and A
PM belongs to the same group, but AG belongs to a different group while being the same AsA derivative. In the present invention, a combination selected from the same group (for example, AP
M and APS) and a combination of substances selected from different groups (for example, a combination of APM and AG) can far more sustainably increase radical scavenging activity in cells, and a radical having a high effect The composition for external use for erasure was able to be invented. 24 hours and 48 hours
The same experiment was performed for all of the following radical generators by adding an item for measuring the cell concentration after time, and the substances having a tendency to increase the intracellular accumulation concentration in the same time zone were arranged in the same group and classified into 5 groups. . Furthermore, substances having different basic skeletons are classified into different groups even if they have the property of increasing the intracellular concentration within the same time, and finally the following groups are obtained based on the results of various radical scavenging effects experiments. The present inventors have found that the synergistic effect is maximized by classifying the group from A into 11 groups of group K, and completed the present invention.

Group A: AsAs) APNa, APN
a, APK, group B: tocopherols) TOC,
TOC acetate, TOC phosphate, TOC uric acid, TOC citrate
C, (the TOC may be any of a dl form, a d form, and an l form), group C: carotenoids) β-carotene, α
Carotenoids such as carotene, astaxanthin, retinol, retinoic acid, tretinoin, lycopene, lutein, and cryptoxanthin, and their optical isomers. Group D: AsA) AG, AG-6-palmitic acid, AG-6-stearic acid , AG-6-fatty acids, group E: tocopherols) glucoside TOC, TOC succinate (the TOC is dl
Group F: AsA class) AsA-2-polyglucoside,
AsA-2-diglucoside, AsA phosphate TOC Group G: AsA) AsA tetraisopalmitic acid, AsA-6-palmitic acid, AsA-2,6-dipalmitic acid, AsA-6-stearic acid, AsA-6-fatty acid group H : Polyphenols) epigallocatechin gallate, epicatechin, proanthocyanidins, catechins, polyphenols Group I: amino acid and protein radical scavengers) glutathione, superoxydimustase, metalthionene, cysteine, cystine, catalase Group J: organic Acids) Kojic acid, dipotassium glycyrrhizinate, Group K: Other natural radical scavengers of unknown structure having radical scavenging ability) Plant seed extract

The topical composition containing the nonsteroidal anti-inflammatory agent of the present invention refers to a topical composition which does not contain corticosteroids, derivatives thereof and salts thereof. Corticosteroids are produced in the body and are known to act to suppress inflammation.However, when steroids are used for a long period of time, if they suddenly stop using topical drugs, they will become more symptomatic than before. Has become a problem. It is known that atopic dermatitis, which is one of the radical diseases, complicates or worsens the same radical disease, such as cataract. Eyelid dermatitis, which has been reported as a complication of atopic dermatitis,
Cataract, retinal detachment, keratoconjunctivitis, keratoconus and the like are known, and it is said that they occur in about 30% of patients with atopic dermatitis. It is known that these inflammations are further exacerbated by radical production by ultraviolet rays. It has been reported that administration of steroids to these radical disease patients promotes their medical condition. Patients with atopic dermatitis with strong rash on the face are more likely to develop atopic cataract and a study reported in the American Journal of Ophthalmology in 1994 found that prednisolone (a steroid hormone)
It has been reported that cataracts occur in as many as 75% of patients after one year of oral administration of Species (> 16 mg / day). In other words, steroids were considered to be extremely likely to promote radical diseases. In the present invention, in order to solve the problem of habit of these steroids and the problem that steroids promote radical diseases, non-steroidal anti-inflammatory agents are used in the radical scavenging external composition of the present invention. A dramatic effect was found when an inflammatory agent was used, and the present invention was completed. Adrenocortical hormones and their derivatives and salts thereof are roughly classified into three types: glucocorticoids, electrolyte corticoids (mineralcorticoids), and adrenal androgens (adrenal hormones). The agent cannot be used. Glucocorticoids include cortisol (hydrocortisone), deoxycortisol, and corticosterone. A typical glucocorticoid is cortisol, which is secreted mainly from the bundle layer of the adrenal cortex. Electrolyte hormones include aldosterone and deoxycorticosterone (DOC). As a natural synthetic steroid having enhanced action of an electrolyte, there is a 9α-fluoro compound fludrocortisone acetate (florinef). It has strong electrolyte corticoid action (nearly comparable to aldosterone) and relatively strong glucocorticoid action. Adrenal androgens include dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, but these anti-inflammatory agents cannot be used. Further in the present invention, Delmobate ointment, Diacoat ointment, full meta ointment, Mesaderm ointment, topsym ointment, Texmetene ointment, Boala ointment, Ecler ointment, Almeta ointment, lidomex Kowa ointment, locoid ointment,
It is not possible to use the steroidal anti-inflammatory components used in Kindbate ointment, Rinderone A ointment, and prednin ophthalmic ointment. Glycyrrhizic acid and its derivatives, salicylic acid derivative-type anti-inflammatory agents, aniline derivative-type anti-inflammatory agents, antitussive agents, pyrazolone derivative-type anti-inflammatory agents, as anti-inflammatory anti-inflammatory agents that can be added to the radical disease preventive / treatment composition of the present invention, There are indomethacin-based anti-inflammatory agents, mefenamic acid-based anti-inflammatory agents, antihistamines, anti-allergic agents, inflammatory enzyme agents and the like. Specific examples thereof include ε-aminocaproic acid, allantoin, allantoin acetyl-DL-methionine, allantoin β-glycyrrhetinic acid, allantoin chlorohydroxyaluminum, allantoin dihydroxyaluminum, allantoin DL-pantothenyl alcohol, allantoin polygalacturonic acid, and succinyl glycyrrhetinic acid. 2Na, glycyrrhizic acid, triNa glycyrrhizinate, dipotassium glycyrrhizinate,
Disodium glycyrrhizinate, monoammonium glycyrrhizinate, monoammonium α-glycyrrhizinate, β-
Glycyrrhetinic acid, glyceryl glyceryl retinate, stearyl glycyrrhetinate, pyridoxine glycyrrhetinate, glycyrrhetinyl stearate, lysozyme chloride,
Guaiazulene, ethyl guaiazulene sulphonate, Na guaiazulene sulphonate etc. can be used

The concentration of the stable active radical scavenger in the present invention may be 0.5 to 10% by weight in terms of dry matter in the composition for external use. In the present invention, the addition concentration of the three components of the phototoxic inorganic ultraviolet scattering agent is such that the weight% of the composition for external use is 1 to 1 in terms of dry matter.
It may be in the range of 5% by weight. The concentration of the three components of the natural humectant exfoliating agent in the present invention may be such that the weight% in the external composition is in the range of 0.01 to 10% by weight in terms of dry matter. In order to obtain a radical scavenging effect on the skin by the radical disease preventing / treating composition of the present invention, the externally applied composition of the present invention adjusted in the above range is 0.05 to 5 ml / cm 2 or 0 per day. It is desirable to apply it to the skin in 1 to 3 divided doses at a concentration in the range of 0.05 to 5 g cm2. As a stabilizer that can be added to the composition for preventing and treating radical diseases of the present invention, a substance having antioxidant ability can be added, for example, vitamin A, vitamin B, vitamin C, vitamin E, vitamin E nicotinate, vitamin E acetic acid Add antioxidants such as esters, ubiquinone and their vitamin derivatives or salts, carotenoids such as astaxanthin, cysteine, glutathione, glutathione peroxidase, SOD, citric acids, phosphoric acids, polyphenols, nucleic acids, herbal medicines, seaweeds, and inorganic substances. If so, the stability can be improved. Further, the composition for preventing or treating a radical disease of the present invention can be used in combination with a generally used whitening cosmetic material. Examples of whitening ingredients that can be used in combination include kojic acid, placenta extract, arbutin and the like. In addition, when an anti-inflammatory component or an anti-inflammatory component is used in combination or in combination, the anti-inflammatory effect is promoted by a synergistic effect with tocopherol phosphate. Therefore, these existing anti-inflammatory components or anti-inflammatory components can be added to the cosmetic of the present invention. . The other components of the composition for preventing or treating radical diseases which can be added to the present invention are not particularly limited. For example, if necessary, the cosmetic raw material standard second edition (198)
4) Pharmaceutical Daily and Cosmetic Ingredients Standards
93) The Pharmaceutical Daily, and the Japanese Pharmacopoeia Law and the Official Manual of Food Additives, 6th Edition (1992) Hirokawa Shoten, and the Japan Cosmetic Industry Federation (2-9-14 Toranomon, Minato-ku, Tokyo
F) Natural lipids such as surfactants, humectants, thickeners, squalane, etc., listed in the “List of Ingredients” updated by the All Ingredients Name Committee on August 31, 1999;
Oils and fats, preservatives, ultraviolet absorbers, anti-inflammatory agents such as glycyrrhizic acid, analgesics, whitening agents, chelating agents, pigments, antioxidants, pigments, fragrances, pH adjusters, organic acids, medicinal ingredients, and other cosmetic ingredients The fungicides, stabilizers, preservatives, and emulsifiers to be blended can be appropriately added together in the range of 0.0001 to 90% by weight. In addition, the possible forms of the radical disease prevention / treatment composition of the present invention include creams, ointments, essences, lotions, emulsions, nail varnishes, lip balms, packs, gels, masks, packs, foundations, lipsticks, soaps, Body shampoo, shampoo, rinse, hair restorer, hair styling agent, hair dye, bath agent, toothpaste, mouthwash, bandage, patch, toothpaste, mouthwash, troche, bath agent, hair tonic, hair cream, hair restorer, hair restorer The preparation can be in the form of any external preparation such as a preparation and a scalp preparation. Examples will be described below.

An external preparation was prepared by a conventional method according to the following formulation. The figures below are expressed in weight%.

Example 1 A lotion was prepared according to the following formulation by a conventional method. APMg2.0, AG2.0, dl-TOC1.
0, silica-coated titanium oxide (Maxlite) 0.5
Silica-coated zinc oxide (Maxlite) 0.5, polyaspartic acid Na1.0, hyaluronic acid Na0.0,
1, allantoin 0.5, sodium citrate 2.0, dipotassium glycyrrhizinate 0.3 ethyl alcohol 5.0,
Eldew CL202: 8.0, Aqua Dew SPA3
0: 8.0, PG 5.0, Na hydroxide 0.1, xanthan gum 0.3, 1,3BG 3.0, citric acid 0.1, d
1-pyrrolidone carboxylate Na0.3, NaOH 0.
1, xanthan gum 0.3, castor oil 1.0, methyl paraben 0.2, fine particle silica 0.01, water-soluble collagen 0.01, purified water residue

Example 2 An emulsion was prepared according to the following formulation by a conventional method. APNa 1.0, APMg 1.0, AsA glucoside 1.0, dl-TOC 1.0, silica-coated titanium oxide (maxlite) 1.0, silica-coated zinc oxide (maxlite) 1.0, sodium polyaspartate
3.0, Na hyaluronate 0.1 Na citrate 1.0,
10. dipotassium glycyrrhizinate 0.3, avocado oil
0, behenyl alcohol 0.6, stearic acid 0.4,
Glycerin fatty acid ester 0.9, polyoxyethylene sorbitan fatty acid ester 1.1, polyoxyethylene alkyl ether 0.4, 1,3BG 10.1, methyl paraben 0.2, fragrance 0.4, purified water residue

Example 3 A cream was produced by a conventional method according to the following formulation. APNa1.0, APMg1.0, AG1.0,
dl-TOC 1.0, silica-coated titanium oxide (Maxlite) 1.0, silica-coated zinc oxide (Maxlite) 1.0, sodium polyaspartate 3.0, sodium hyaluronate 0.1, sodium citrate 2.0, glycyrrhizin Dipotassium acid 0.3, squalane 11.1, stearic acid 7.8, stearyl alcohol 6.0, beeswax 1.9, PG monostearate 3.1, polyoxyethylene cetyl ether 1.1, 1,3BG 11.9 , Methyl paraben 0.2, fragrance 0.4, purified water residue

Example 4 A pack was produced according to the following recipe by a conventional method. APNa 1.0, APMg 1.0, AsA glucoside 1.0, dl-TOC 1.0, silica-coated titanium oxide (maxlite) 1.0, silica-coated zinc oxide (maxlite) 1.0, sodium polyaspartate
3.0, Na hyaluronate 0.1, dipotassium glycyrrhizinate 0.3, polyvinyl alcohol 14.5, carboxymethylcellulose Na 4.8, 1,3BG2.9
Whale run powder 3.0, ethyl alcohol 10.0,
Methyl paraben 0.1, purified water: residue

Example 5 A lipstick was produced according to a conventional method according to the following formulation. APNa 1.0, APMg 1.0, AsA glucoside 1.0, dl-TOC 1.0, silica-coated titanium oxide (maxlite) 1.0, silica-coated zinc oxide (maxlite) 1.0, sodium polyaspartate
1.0, dipotassium glycyrrhizinate 0.3, hexadecyl alcohol 25.2, lanolin 3.9, beeswax 4.8, ozokerite 3.4, candelilla wax 6.
2, Carnauba wax 2.1, methyl paraben 0.1, cetane powder 3.0, titanium oxide 2.1, red pigment 4.8, fragrance 0.1, appropriate amount of castor oil residue moisture

Example 6 A foundation was produced by a conventional method according to the following formulation. APNa1.0, APMg1.0, As
A glucoside 1.0, dl-TOC 1.0, silica-coated titanium oxide (Maxlite) 7.0, silica-coated zinc oxide (Maxlite) 7.0, sodium polyaspartate 3.0, sodium hyaluronate 0.1 liquid paraffin 23.5, isopropyl palmitate 14.3, lanolin alcohol 1.8, lanolin acetate 2.9, microcrystalline wax 6.5, ozokerite 7.7, candelilla wax 0.4, methyl paraben 0.1, talc 5. 0, coloring pigment 3.9, fragrance 0.5, kaolin residue

Example 7 A hair restorer was produced by a conventional method according to the following formulation. APNa 1.0, APMg 1.0, AsA glucoside 1.0, dl-TOC 1.0, silica-coated titanium oxide (Maxlite) 1.0, silica-coated zinc oxide (Maxlite) 1.0, dipotassium glycyrrhizinate 0.3 , Polyaspartic acid Na3.0, ethyl alcohol 60.0, castor oil 4.3, resorcinol 0.7,
Methyl paraben 0.1, pepper tincture 0.4, purified water: residue

Example 8 Sunscreen emulsion APNa1.0, APMg
1.0, AG1.0, dl-TOC1.0, silica-coated titanium oxide (Maxlite) 2.0, silica-coated zinc oxide (Maxlite) 5.0, sodium polyaspartate 3.0, dipotassium glycyrrhizinate 0. 3, stearic acid 2.0, cetyl alcohol 1.0, petrolatum 5.0, silicone oil 2.0, liquid paraffin 10.0,
Glycerin monostearate (self-emulsifying type)
1.0, polyoxyethylene (25 mol) monooleate 1.0, polyethylene glycol 1500:
5.0, Vegum 0.5, Purified water: Residue, appropriate amount of flavor, proper amount of preservative

Embodiment 9 In the following examples, the names of substances and their abbreviations are abbreviated as follows. L-ascorbic acid-2-phosphate-
6-palmitate sodium salt (hereinafter APP)
L-ascorbic acid (hereinafter abbreviated as AsA), L-ascorbic acid PG dispersion (hereinafter abbreviated as PGAs)
A), L-ascorbic acid-2-phosphate magnesium salt (hereinafter abbreviated as APM), L-ascorbic acid-2-phosphate sodium salt (hereinafter abbreviated as APS), L-ascorbic acid-2-phosphate Sulfate sodium salt (hereinafter abbreviated as ASS), 2-OD
-Glucopyranosyl-L-ascorbic acid (hereinafter referred to as AG
L-ascorbic acid-2,6-dipalmitate (hereinafter abbreviated as ADP), dl-TOC
The radical scavenging activity and stability were measured by the following method (abbreviated as DLT), and a stable active radical scavenging substance usable in the present invention was selected. AAPH (2,2'-azobis (amidin) was added to the homogenate solution of living human epidermis.
o propane) dihydrochloride
e) Add 10 mM, measure the radical strength by ESR, and then add 10 mM of the following radical scavenger to this solution. When measuring the suppressed radical strength, the radical strength is reduced to 80% or less before the addition of the radical scavenger. A radical scavenger having an inhibitory activity can be used in the present invention +
The results are summarized in the table below. Further, the stability of the radical scavenger usable in the present invention was evaluated by the following method. When a 1% aqueous solution of the following radical scavenger or a squalane oil solution is allowed to stand at 40 ° C. for one month, the radical scavenger having a stability in which 50% or more of the radical scavenger remains remains usable as + in the present invention. , And those which are not-are summarized in the table below. As a result, the stable active radical scavenger of the present invention is L-ascorbic acid-2-phosphate-6-palmitate sodium salt (hereinafter referred to as AP).
P), L-ascorbic acid PG dispersion (hereinafter referred to as P
GAsA), L-ascorbic acid-2-phosphate magnesium salt (hereinafter abbreviated as APM), L-
Ascorbic acid-2-phosphate sodium salt
(Hereinafter abbreviated as APS), 2-OD-glucopyranosyl-L-ascorbic acid (hereinafter abbreviated as AG), L-
Ascorbic acid-2,6-dipalmitate
(Hereinafter abbreviated as ADP), dl-TOC (abbreviated as DLT)
Turned out to be suitable. However, the stable active radical scavenger of the present invention is not limited to this.

Example 10 Using this stable active radical scavenger, the weight% of the stable active radical scavenger in the external preparation component
The following experiment was conducted to examine the effect of suppressing the radical generating substance in the external preparation component blended at the highest weight% other than water when compared with that of all the other blend components. Randomly purchase 30 items of commercially available external lotion and 10g
This was used as a control lotion. Next, 10 g of the same lotion is measured accurately, and the water content is reduced to 3 with a freeze dryer.
Dried to within -5%. The weight of the residue after drying is measured, and this is defined as Ag. Next, the radical scavenger confirmed in the above test was mixed with Ag and the dried product, and finally water was added (10-
A) Add g to make lotion for test. 5 μl / cm 2 of a lotion of a control and a lotion of a test group are applied on a collagen sheet which is assumed to be artificial skin. Next, UV (UV lamp HP-1) is applied to this epidermis from a distance of 15 cm.
5M, 280-400 nm manufactured by ATTO)
cm2). When the radical intensity was measured by ESR, the lotion in which a measurable radical peak was generated in the control was 12 lotions out of 30 lotions tested. In the 12 lotions, the test plot showed that the control radical reduction rate was 8
Those with an activity to suppress radical strength to 0% or less +
The results are summarized in the table below. The radical suppression rate was determined by the following formula. Radical decrease rate = (radical strength of test plot / radical strength of control plot) × 100 From this experimental result, only when the stable active radical scavenging substance confirmed in the above experiment was used, the weight% in the external preparation component was the highest weight% other than water when compared with that of all the other components. It has been confirmed that the compounding agent can sufficiently eliminate radicals from unknown radical generating sources of the external preparation component.

Example 11 The skin on the back of a hairless mouse was peeled off, cut to an appropriate size, and the skin and parafilm were removed for 7 minutes each.
After sterilizing by gently immersing 0% ethanol, parafilm is adhered to the dermis side. Next, a solution (2 μl / cm 2) dispersed in squalane so that the phototoxic inorganic ultraviolet scattering agent of the present invention becomes 3% is applied onto the epidermis of the test plot. On the other hand, a squalane solution (2 μl / cm 2) containing no phototoxic inorganic ultraviolet scattering agent of the present invention on the epidermis of the control section
Is applied. The epidermis is irradiated with UV (UV lamp HP-15M, manufactured by 280-400 nm Atto) at a dose of 2 J / cm2 from a distance of 15 cm. Then 50 mM
The skin applied with PBS is thoroughly washed. Place a piece of lens paper on two pieces of sterilized nylon mesh on a petri dish of φ6 cm and place DMEM on the center of the lens paper.
2 ml of the medium is dropped and immersed. Next, place the epidermis on the lower side so as to be in close contact with the lens paper, cover the Petri dish,
Incubate in a CO2 incubator for 24 hours. After culturing, the sections are stained using a staining kit, and then observed under a microscope, and the number of apoptotic cells in the test section and the control is counted. As a result, the photo-toxic inorganic ultraviolet scattering agent of the present invention whose apoptotic cell number (A) is 5 minutes 4 (0.8) or less of the control apoptotic cell number (B) can be used in the present invention. The results are summarized in the table below as + and those not so as −. Examples of the low phototoxic inorganic ultraviolet scattering agent usable in the present invention used in this experiment include silica coated titanium oxide (TS01, TS04) manufactured by Showa Denko KK (product name: Maxlite), and silica coated oxide. Zinc (hereinafter abbreviated as ZS032) was used. From the above results, the present invention shows that TS01, TS04, ZS0
32 could be used. From this test result, the phototoxic inorganic ultraviolet scattering agent that can be used in this experiment is
The radical scavenging ability of the external preparation of the anti-invention can be extremely enhanced by selecting the apoptotic cell number of which is less than 4/5 (0.8) of the control apoptotic cell number in the present invention. .

Embodiment 12 One or more, preferably two or more, of the stable active radical scavenger and the natural moisturizing component and one or more, preferably two or more, of the nonsteroidal anti-inflammatory components are simultaneously contained. The following experiment was conducted in order to examine the effect of the water-soluble component to suppress the radical of the external composition for radical scavenging having a pH of 7.5 or more. A back skin section of a nude mouse simultaneously contains one or more, preferably two or more, of the stable active radical scavenger of the present invention, a natural moisturizing component, and one or more, preferably two or more non-steroidal anti-inflammatory components. A liquid (2 μl / cm 2) in which purified water is applied to a composition for external use for radical scavenging having the following pH, wherein the water-soluble component has the following pH, is applied (test section). On the other hand, purified water (2 μl / cm 2) is applied to the back skin section of the nude mouse as a control. Next, both skin sections were irradiated with UV (UV lamp HP-15M, manufactured by 280-400 nm Atto) at an irradiation dose (2 J / cm2) from a distance of 15 cm. After sufficiently washing the surface of the skin section with purified water, the skin section was homogenized, and the extract was measured for its radical strength by ESR. The radical decrease rate was determined by the following formula. Radical decrease rate = (radical strength of test plot / radical strength of control plot) × 100. AR: Allantoin (Non-steroidal anti-inflammatory agent) GR: Dipotassium glycyrrhizinate (Non-steroidal anti-inflammatory agent) The mixing ratio of AG + AR in the following table was added at a weight ratio of 1: 1. PAS: 10% sodium polyaspartate solution (natural humectant 1) PCS: 10% sodium dl-pyrrolidonecarboxylate solution (natural humectant 2) The mixing ratio of PAS + PCS in the table below was added at a weight ratio of 1: 1. . According to these experiments, an aqueous solution characterized by simultaneously containing one or more, preferably two or more, stable active radical scavengers and natural moisturizing components and one or more, preferably two or more non-steroidal anti-inflammatory components. It was confirmed that the composition for external use for radical scavenging having a pH of 7.1 or more had an extremely high radical scavenging ability.

Example 13 The following experiment was conducted to examine the effect of suppressing the radical-generating substance in the external preparation component by using the stable active radical scavenger and the phototoxic inorganic ultraviolet scattering agent. A hairless mouse back skin section was prepared by using a radical scavenger of the present invention, 0.5% by weight of allantoin and 0.5% by weight of dipotassium glycyrrhizinate, which are nonsteroidal anti-inflammatory drugs, and the following natural humectants and phototoxicity. A liquid (2 μl / cm 2) in which the type ultraviolet scattering agent is dispersed in purified water so as to have a weight percentage shown in the following table is applied (test section). On the other hand, purified water (2 μl / cm 2) is applied to the back skin section of the hairless mouse in the control section. Next, both skin sections were exposed to UV (UV lamp HP-15) from a distance of 15 cm.
M, 280-400 nm manufactured by ATTO)
cm2). After thoroughly washing the surface of the skin section with purified water, the skin section is homogenized, and the extract is subjected to ESR to measure the respective radical intensities. And +
When the radical intensity is reduced to 0% or less, it is ++,
The results are summarized in the table below, with the results being 80% or more.
The radical decrease rate was determined by the following formula. Radical decrease rate = (radical strength of test plot / radical strength of control plot) × 100. In addition, the test preparation used in this experiment was applied to 10 patients with acne vulgaris known to have a radical disease between the ages of 15 and 43 years, three times a day in the morning, noon, and evening using a normal lotion. The stimulus and effect were confirmed by the method used. As a result, if there was no change in the medical condition, 0
5 and 5 with some improvement and 10 with significant improvement. PAS: polyaspartic acid sodium (natural humectant) PG: PG (non-natural humectant) It was confirmed that the radical scavenging action of the external preparation of the present invention containing the three components of the stable active radical scavenger, the phototoxic ultraviolet scattering agent and the natural moisturizer at the same time was extremely strong as compared with the other formulations. Was.

Example 14 The concentration of 0.1 to 5% by weight of the stable active radical scavenger of the present invention, 1 to 10% by weight of the natural moisturizing component, and the non-steroidal anti-inflammatory component 0. The following experiments were performed to examine the effectiveness of the formulations at different concentrations, each from 01% to 5% weight.
A stable active radical scavenger concentration of 0.1 to 5% by weight, a natural moisturizing component of 1 to 10% by weight, and a nonsteroidal anti-inflammatory component of 0.01% to 5% by weight are dispersed in purified water at different concentrations. (2 μl / cm 2) is applied (test plot). On the other hand, purified water (2 μl / cm 2) is applied to the back skin section of the nude mouse as a control.
Next, UV (U) was applied to both skin sections from a distance of 15 cm.
V lamp HP-15M, 280-400nm ATTO)
Was irradiated at an intensity of the irradiation dose (2 J / cm2). After sufficiently washing the surface of the skin section with purified water, the skin section was homogenized, and the extract was measured for its radical strength by ESR. The radical decrease rate was determined by the following formula.
Radical decrease rate = (radical strength of test plot / radical strength of control plot) × 100. AR: Allantoin (Non-steroidal anti-inflammatory agent) GR: Dipotassium glycyrrhizinate (Non-steroidal anti-inflammatory agent) The mixing ratio of AG + AR in the following table was added at a weight ratio of 1: 1. PAS: Na polyaspartate (natural humectant 1) PCS: dl-pyrrolidone carboxylate Na (natural humectant 2) PAS + PCS in the table below was added at a weight ratio of 1: 1. As a result of the experiment, the total added concentration of the stable active radical scavenger was 1% or more, preferably 2% or more, more preferably 3% or more, and the total concentration of the natural moisturizing component was 2% or more, preferably 4%. Radical lowering rate of a preparation containing simultaneously at least 8% by weight, more preferably at least 8% by weight, and a total concentration of non-steroidal anti-inflammatory components of at least 0.1% by weight, preferably at least 0.5% by weight, more preferably at least 2% by weight. Was confirmed to be extremely low.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/375 A61K 31/375 A61P 17/00 A61P 17/00 39/06 39/06 // A61K 7 / 00 A61K 7/00 U W 7/06 7/06 7/42 7/42 7/48 7/48 F term (reference) 4C076 AA12 BB31 CC18 DD29 DD37R DD43 EE26 EE30 EE37 EE43 EE53 FF68 4C083 AA082 AA112 AB172 AB212 AB242 AC022 AC072 AC102 AC402 AC432 AC482 AC841 AC842 AD042 AD072 AD152 AD272 AD332 AD391 AD411 AD412 AD531 AD532 AD621 AD622 AD641 AD642 AD661 AD662 CC04 CC05 CC13 CC19 DD11 DD27 DD33 EE12 EE13 EE17 4C084 AA17 MA63 NA05 NA10 ZC411 ZA01 MA0A0MA0MA04A0 4C206 AA01 AA02 CA10 DA12 ZA89

Claims (9)

[Claims] 1. Two or more kinds of the stable active radical scavengers, wherein the weight% in the external preparation component is higher than that of all the other components by weight, except for water. A composition for external use for radical scavenging wherein the aqueous component comprising the component has a pH of 7.1 or more 2. The composition according to claim 1, wherein at least one, preferably at least two, of a stable active radical scavenger and a natural moisturizing component and at least one, preferably at least two, of non-steroidal anti-inflammatory components are simultaneously contained. External use composition for radical scavenging whose water component is pH 7.1 or more 3. The external composition for radical elimination according to claim 2, further comprising an ultraviolet light scattering agent having low photocatalytic toxicity. 4. When a cell is cultured by adding a stable active radical scavenger to a culture solution, a plurality of stably active radical scavengers selected from different stable active radical scavengers in which the activity of the radical scavenger in the cell is activated at different times. Topical composition for radical scavenging of skin containing a stable active radical scavenger 5. The external composition for radical scavenging of the skin according to claim 1, which comprises the plurality of stable active radical scavenging substances according to claim 4. 6. The stable active radical scavenger according to claim 1, wherein the stable active radical scavenger comprises one or more stable active radical scavengers selected from the following groups A to H. External use composition for radical scavenging. Group A: ascorbic acid-2-sodium phosphate, ascorbic acid-2-sodium phosphate, ascorbic acid-2-potassium phosphate. Group B: α-tocopherol acetate, α-tocopherol acetate, α-tocopherol phosphate, α-tocopherol urate, α-tocopherol citrate, (the α-tocopherol is d1 body, d
Body or one). Group C: Carotenoids such as β-carotene, α-carotene, astaxanthin, retinol, retinoic acid, tretinoin, lycopene, lutein, cryptoxanthin, and optical isomers thereof may be used. Group D: ascorbic acid-2-glucoside, ascorbic acid-2-glucosido 6-palmitic acid, ascorbic acid-2-glucosidol 6-stearic acid, ascorbic acid-2-glucosido 6-fatty acid.
Group E: Glucoside α-tocopherol, succinic α
Tocopherol (the α-tocopherol is dl
Body, d body, and l body). Group F: ascorbic acid-2-polyglucoside, ascorbic acid-2-
Diglucoside, α-tocopherol phosphate ascorbate. Group G: ascorbic acid tetraisopalmitic acid, ascorbic acid-6-palmitic acid, ascorbic acid-2,6-dipalmitic acid, ascorbic acid-6-stearic acid, ascorbic acid-6-fatty acid. Group H: epigallocatechin gallate, epicatechin, proanthocyanidins, catechins, polyphenols. Group I: amino acid and protein radical scavengers, glutathione, superoxydimustase, metalthionene, cysteine, cystine, catalase. Group J:
Kojic acid, arbutin, dipotassium glycyrrhizinate.
Group K: plant seed extract, plant fruit extract, plant germ extract. 7. A method for preventing and treating radical diseases using the components of the composition for external use for radical scavenging according to claims 1 to 7. 8. An external composition for radical scavenging of the skin, characterized in that silica or collagen is added to the external composition for radical scavenging of the skin according to any one of claims 1 to 8, thereby suppressing stickiness of the external preparation. 9. The total concentration of the stable active radical scavenger added is 1% by weight or more, preferably 2% by weight or more, more preferably 3% by weight or more, and the total concentration of natural moisturizing components is 2% by weight or more, preferably 4% by weight or more. % Or more, more preferably 8% or more, and the total concentration of the non-steroidal anti-inflammatory component is 0.1% or more, preferably 0.5% or more, more preferably 2% or more at the same time. 3. An external composition for radical scavenging according to claim 2