JP2017057148A - Tyrosinase inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel tyrosinase inhibitor that is low in skin irritation and skin sensitization, and suitable for external compositions for skin, and a skin-whitening agent.SOLUTION: The present invention provides a tyrosinase inhibitor, a skin-whitening agent, and an external composition for skin comprising the following component (A), or components (A) and (B) as an active ingredient: (A) 3-(2,4-dihydroxyphenyl) propionic acid or salt thereof; and (B) ascorbic acid, a derivative thereof, or a salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a tyrosinase inhibitor and a whitening agent containing the same. The present invention also relates to an external composition for skin that can be used effectively for the prevention or improvement of blackening after sunburn and spots and freckles due to pigmentation based on these effects. Furthermore, the present invention relates to a method for increasing the tyrosinase inhibitory activity of each of 3- (2,4-dihydroxyphenyl) propionic acid or a salt thereof, and ascorbic acid, a derivative thereof or a salt thereof.

  Tyrosinase is an enzyme involved in melanin biosynthesis. Specifically, tyrosinase catalyzes the hydroxylation reaction from tyrosine to L-dopa and the oxidation reaction from L-dopa to dopaquinone in living cells, and is directly involved in the production of melanin. Yes. For example, it is known that when the skin is irradiated with ultraviolet rays, melanin is produced by the above reaction, the skin is blackened, and spots and freckles are caused by pigmentation, and there is a need for prevention from the viewpoint of beauty and health. It has been pointed out.

  For this reason, conventionally, the component which has the effect | action which suppresses the production | generation of melanin by inhibiting the activity of tyrosinase, or reduces the produced | generated melanin pigment | dye is screened, and is mix | blended with the composition for external use as a whitening agent. For example, as a whitening agent having tyrosinase inhibitory action, ascorbic acid and its derivatives, cysteine, hydroquinone, 2-hydroxy acid and their derivatives, arbutin, kojic acid, retinoid, linoleic acid, ellagic acid, lucinol, vitamin E, glutathione, Placenta extracts, plant and algae extracts, and the like are used (see, for example, Non-Patent Document 1).

  On the other hand, 3- (2,4-dihydroxyphenyl) propionic acid is conventionally known to have a function of straightening keratin fibers under heating conditions, and proposed to be used as a hair straightener. However, no tyrosinase inhibitory action or melanin production inhibitory action has been reported so far (see Patent Document 2).

Yoko Funasaka, “Blemish Treatment and Whitening Cosmetics”, Shiseido Group Homepage Information Letter Back Number 2000 No.001 (https://www.shiseidogroup.jp/rd/doctor/informationletter/backnumber/)

Special table 2009-537619 Special table 2007-186445 gazette

  An object of the present invention is to provide a novel tyrosinase inhibitor. More specifically, an object is to provide a tyrosinase inhibitor that has an excellent tyrosinase inhibitory action and has low skin irritation and skin sensitization and high safety. Another object of the present invention is to provide a whitening agent containing the tyrosinase inhibitor, that is, a novel whitening agent having a tyrosinase inhibitory action. A further object of the present invention is to provide an external composition for skin containing these tyrosinase inhibitors or whitening agents as active ingredients.

  Another object of the present invention is to provide a method for increasing the tyrosinase inhibitory activity of 3- (2,4-dihydroxyphenyl) propionic acid or a salt thereof. It is another object of the present invention to provide a method for increasing the tyrosinase inhibitory activity of ascorbic acid, a salt thereof or a derivative thereof.

  The inventors of the present invention have made extensive studies to solve the above problems, and found that 3- (2,4-dihydroxyphenyl) propionic acid has an excellent tyrosinase inhibitory action. It was confirmed that skin sensitization is extremely low and has high safety. Furthermore, when the present inventors use the 3- (2,4-dihydroxyphenyl) propionic acid in combination with ascorbic acids, the tyrosinase inhibitory action of each of them synergistically increases, and the melanin production inhibitory action increases markedly. It was found that by blending both components, it can be provided as a whitening agent that can exhibit a whitening effect far superior to a single whitening effect.

  The present invention has been completed by further studies based on these findings, and includes the following embodiments.

(I) Tyrosinase inhibitor (I-1) (A) A tyrosinase inhibitor comprising at least one selected from the group consisting of 3- (2,4-dihydroxyphenyl) propionic acid and a salt thereof as an active ingredient.
(I-2) The tyrosinase inhibitor according to (I-1), further comprising (B) at least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof.

(II) Whitening agent (II) A whitening agent comprising the tyrosinase inhibitor described in (I-1) or (I-2).

The whitening agent includes the following modes.
(II-1) (A) A whitening agent comprising at least one selected from the group consisting of 3- (2,4-dihydroxyphenyl) propionic acid and salts thereof as an active ingredient.
(II-2) The whitening agent according to (II-1), further comprising (B) at least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof.

(III) External composition for skin (III) An external composition for skin containing the tyrosinase inhibitor described in (I) or the whitening agent described in (II).

The skin external composition includes the following embodiments.
(III-1) (A) An external composition for skin containing at least one selected from the group consisting of 3- (2,4-dihydroxyphenyl) propionic acid and salts thereof as a whitening component.
(III-2) The external composition for skin according to (III-1), further comprising (B) at least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof.
(III-3) (III-1) or (III-2), which is at least one selected from the group consisting of skin cosmetics, baths, cleansing agents, external pharmaceutical compositions, and external quasi drugs A skin external composition to be described.
(III-4) The skin cosmetics, bathing agents, cleaning agents, external pharmaceutical compositions, and external quasi-drugs have the effect of preventing or improving pigmentation or whitening. (III- The external composition for skin described in 3).

(IV) Method for increasing the tyrosinase inhibitory activity of 3- (2,4-dihydroxyphenyl) propionic acids (IV-1) (A) From the group consisting of 3- (2,4-dihydroxyphenyl) propionic acid and its salts The tyrosinase inhibitory activity of the component (A) is characterized in that at least one selected from the group consisting of (B) ascorbic acid, derivatives thereof, and salts thereof is used in combination. How to increase.
(IV-2) The method according to (IV-1), wherein the degree of increase in the tyrosinase inhibitory activity is not less than the addition of the tyrosinase inhibitory activity of the component (A) and the tyrosinase inhibitory activity of the component (B).
(IV-3) The method according to (IV-1), wherein the degree of increase in the tyrosinase inhibitory activity is greater than the additive of the tyrosinase inhibitory activity of the component (A) and the tyrosinase inhibitory activity of the component (B).

(V) Method for increasing tyrosinase inhibitory activity of ascorbic acid (V-1) (B) At least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof includes (A) 3- (2 , 4-dihydroxyphenyl) propionic acid and at least one selected from the group consisting of salts thereof are used in combination, the method for increasing the tyrosinase inhibitory activity of the component (B).
(V-2) The method according to (V-1), wherein the degree of increase in the tyrosinase inhibitory activity is not less than the addition of the tyrosinase inhibitory activity of the component (B) and the tyrosinase inhibitory activity of the component (A).
(V-3) The method according to (V-1), wherein the degree of increase in the tyrosinase inhibitory activity is greater than the additive of the tyrosinase inhibitory activity of the component (B) and the tyrosinase inhibitory activity of the component (A).

(VI) Use of 3- (2,4-dihydroxyphenyl) propionic acid (VI-1) From the group consisting of (A) 3- (2,4-dihydroxyphenyl) propionic acid and its salts A method for imparting a whitening effect to an external composition for skin or enhancing the whitening effect of an external composition for skin, which comprises blending at least one selected.
(VI-2) A method for enhancing the whitening effect of an external composition for skin, wherein the external composition for skin is selected from the group consisting of (A) 3- (2,4-dihydroxyphenyl) propionic acid and a salt thereof. (B-1) The method according to (VI-1), which contains at least one selected from the group consisting of (B) ascorbic acid, derivatives thereof, and salts thereof.
(VI-3) A method for imparting a whitening effect to an external composition for skin, wherein the external composition for skin is selected from the group consisting of (A) 3- (2,4-dihydroxyphenyl) propionic acid and salts thereof In addition to at least one selected from the group consisting of (B) at least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof.

  ADVANTAGE OF THE INVENTION According to this invention, the novel tyrosinase inhibitor which has the outstanding tyrosinase inhibitory effect, and a whitening agent can be provided. In particular, (A) 3- (2,4-dihydroxyphenyl) propionic acid or a salt thereof (component (A)) and at least one selected from the group consisting of (B) ascorbic acid, a derivative thereof, and a salt thereof When (Component (B)) is used in combination, each tyrosinase inhibitory action synergistically improves. As a result, the tyrosinase inhibitor and whitening agent of the present invention containing both exhibit extremely high tyrosinase inhibitory action and whitening action. Can do.

  The tyrosinase inhibitor and whitening agent of the present invention have extremely low skin irritation and skin sensitization, and therefore are preferably used as a component of an external skin composition such as cosmetics, external skin drugs and quasi drugs. Can do.

  For this reason, the external composition for skin containing the tyrosinase inhibitor or whitening agent of the present invention is highly safe, and based on the action of the tyrosinase inhibitor or whitening agent of the present invention, suppresses excessive melanin production in the skin, It is excellent in the effect of preventing or improving pigmentation, spots or freckles caused by ultraviolet rays or the like, and can be suitably used particularly as a whitening cosmetic.

The results of measuring tyrosinase inhibitory activity for each of 3- (2,4-dihydroxyphenyl) propionic acid (compound A), ascorbic acid, and the combined use of compound A and ascorbic acid are shown (Test Example 2). The vertical axis of the graph represents the tyrosinase inhibition rate (%), and the horizontal axis represents the concentration (mg / ml) of each test compound.

(1) Active ingredient of the present invention
(A) 3- (2,4-dihydroxyphenyl) propionic acid or a salt thereof All of the tyrosinase inhibitor, whitening agent and composition for external use of the skin of the present invention are 3- (2,4-dihydroxyphenyl) propionic acid. (Hereinafter, this may be referred to as “Compound A”) or a salt thereof as an active ingredient. Hereinafter, there is a meeting that collectively refers to these active ingredients as “component (A)”.

  3- (2,4-dihydroxyphenyl) propionic acid is a known compound (CAS number: 5631-68-5), which can be obtained commercially, or chemically according to the method described in the production examples described later. It can also be synthesized.

  Examples of salts of 3- (2,4-dihydroxyphenyl) propionic acid include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium, calcium and barium; and polyvalent metals such as zinc and aluminum Various metal salts such as salts; ammonium salts such as ammonium and tricyclohexylammonium; and various alkanolamine salts such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, and triisopropanolamine. it can. Metal salts are preferred, alkali metal salts or alkaline earth metal salts are more preferred, alkali metal salts are more preferred, and sodium salts are particularly preferred.

(B) Ascorbic acid, derivatives thereof, and salts thereof In addition to the component (A), the tyrosinase inhibitor, whitening agent, and external composition for skin of the present invention include ascorbic acid, derivatives thereof, and salts thereof ( Hereinafter, these may be collectively referred to as “(B) component”) and may contain at least one selected from the group consisting of. As shown in the test examples to be described later, by using the component (B) in combination with the component (A), the tyrosinase inhibitory action of each of the component (A) and the component (B) is more than additive, preferably more than additive. More preferably, it can be synergistically improved and exhibit a very high tyrosinase inhibitory action.

  The component (B) is not particularly limited as long as it is pharmaceutically or physiologically acceptable, and is preferably one that can be blended in a composition for external use (cosmetics, external medicine, quasi-drug for external use). .

  From this viewpoint, ascorbic acid derivatives include ascorbyl phosphate, (ascorbyl / tocopheryl) phosphate, ascorbyl glucoside (for example, ascorbic acid 2-glucoside), ethyl ascorbate (for example, 2-O-ethylascorbic acid, 3- O-ethylascorbic acid), sulfuric acid ascorbic acid, 3-O-cetylascorbic acid, ascorbyl tetraisopalmitate, ascorbyl tetrahexyldecanoate, ascorbyl stearate, ascorbyl palmitate, ascorbyl dipalmitate, methylsilanol ascorbate, dehydroascorbine Examples include acid, isostearyl ascorbyl phosphate, ascorbyl palmitate, ascorbyl aminopropyl phosphate, and the like.

  As salts of ascorbic acid or ascorbic acid derivatives, for example, alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium, calcium and barium; and various metals such as polyvalent metal salts such as zinc and aluminum Salts; ammonium salts such as ammonium and tricyclohexylammonium; various alkanolamine salts such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine; chitosan salts and the like. A metal salt is preferable, an alkali metal salt or an alkaline earth metal salt is more preferable, an alkali metal salt is further preferable, and a sodium salt is particularly preferable.

  Specific examples of salts of ascorbic acid or ascorbic acid derivatives include salts of ascorbic acid such as sodium ascorbate, calcium ascorbate, magnesium ascorbate, zinc ascorbate, and chitosan ascorbic acid; and sodium ascorbyl phosphate, ascorbylline Examples include, but are not limited to, magnesium acid, disodium ascorbate sulfate, trisodium ascorbyl palmitate, disodium isostearyl ascorbyl phosphate, and potassium (ascorbyl / tocopheryl) phosphate.

  In the tyrosinase inhibitor of the present invention, one type of component (B) may be used alone, or two or more types may be used in any combination.

( 2) Tyrosinase inhibitor The tyrosinase inhibitor targeted by the present invention has an action of inhibiting the activity of tyrosinase, and is used exclusively for the purpose of inhibiting the tyrosinase activity.

  Here, the tyrosinase activity includes the activity of converting tyrosine into L-dopa (dihydroxyphenylalanine) and the activity of converting L-dopa (dihydroxyphenylalanine) into dopaquinone. Therefore, the “tyrosinase inhibition” or “tyrosinase inhibition action” referred to in the present invention has both an action of inhibiting the activity of converting tyrosine into L-dopa and an action of inhibiting the activity of converting L-dopa into dopaquinone. included. That is, those having at least one of these inhibitory actions correspond to the “tyrosinase inhibitor” of the present invention.

  The tyrosinase targeted by the present invention is not limited in its origin, but is preferably a mammalian tyrosinase, and more preferably a human tyrosinase. That is, the tyrosinase inhibitor of the present invention exhibits an action of inhibiting the activity of tyrosinase in the skin cells of the mammal (human) when applied to the skin of a mammal, preferably a human. In addition, the inhibitory action with respect to the activity of human-derived tyrosinase can be evaluated based on the inhibitory action with respect to the activity of mushroom-derived tyrosinase, and this method is an established method in the art (see test examples described later).

  As described above, the tyrosinase inhibitor of the present invention is characterized in that the component (A) is an active ingredient.

  The blending ratio of the component (A) in the tyrosinase inhibitor of the present invention is not particularly limited as long as the tyrosinase inhibitor exhibits a tyrosinase inhibitory action, and can be set as appropriate. For example, it can be appropriately set from the range of 0.001 to 10% by weight in 100% by weight of tyrosinase inhibitor. The tyrosinase inhibitor of the present invention may be composed of the above component (A) or may contain other components as long as it does not interfere with the tyrosinase inhibitory action. Such other components will be described later.

  The tyrosinase inhibitor of the present invention may contain at least one selected from the group consisting of the component (B) described above in addition to the component (A). As shown in the test examples to be described later, by using the component (B) in combination with the component (A), the tyrosinase inhibitory action of each of the component (A) and the component (B) is more than additive, preferably more than additive. More preferably, it can be synergistically improved and exhibit a very high tyrosinase inhibitory action.

  When the tyrosinase inhibitor of the present invention contains both the component (A) and the component (B), the blending ratio of the component (B) is limited to that the tyrosinase inhibitor exhibits a tyrosinase inhibitory action. There is no particular restriction. Preferably, the ratio is such that the tyrosinase inhibitory action of the tyrosinase inhibitor containing the component (A) is enhanced by the incorporation of the component (B). Although it does not restrict | limit, As an example of the quantity of this (B) component, 1-20 weight% can be illustrated in 100 weight% of tyrosinase inhibitors, for example. Moreover, although it does not restrict | limit, 20-1000 weight part can be mentioned as a mixture ratio of (B) component with respect to 1 weight part of (A) component contained in a tyrosinase inhibitor. Furthermore, although not limited, for example, the range of 20 to 50 parts by weight, and further 100 to 1000 parts by weight can be exemplified in this range. In this case, the tyrosinase inhibitor of the present invention may be composed of only the above components (A) and (B), and contains other components as long as it does not interfere with the tyrosinase inhibitory action. You may do it.

  Other components include antibacterial agents (preservatives or fungicides), antioxidants, etc., and carriers and additives that are usually used to prepare them according to the form of the tyrosinase inhibitor. Can be mentioned. For example, tyrosinase inhibitors are in the form of liquids (liquids, gels, emulsions, suspensions, extracts, tinctures, aerosols, liposomes, etc.), solids (tablets, capsules, powders, granules, etc.) And semi-solid forms (ointments, plasters, creams, etc.).

  In addition to being used as a tyrosinase inhibitor, the tyrosinase inhibitor of the present invention is used as an active ingredient of a whitening agent or an external composition for skin, which will be described later, in addition to being used as a component in the production or use thereof. (Use as additive). When used as a tyrosinase inhibitor itself, this use may be used for in vitro and in vivo use, for human and non-human animals, for therapeutic use and for non-therapeutic use. Rather, use in all cases is encompassed.

(3) Whitening Agent The whitening agent targeted by the present invention has an action of inhibiting the activity of tyrosinase and is used exclusively for the purpose of whitening the skin.

  Here, the whitening includes preventing skin darkening due to melanin production by the action of tyrosinase, or occurrence of spots and freckles due to pigmentation. Preferably, it also includes reducing or improving skin blackening and skin pigmentation (spots and freckles) caused by the melanin production.

  The whitening agent of the present invention is characterized in that the component (A) is an active ingredient as described above.

  The blending ratio of the component (A) in the whitening agent of the present invention is not particularly limited as long as the whitening agent exhibits a whitening action based on the tyrosinase inhibitory action, and can be set as appropriate. For example, it can be appropriately set from the range of 0.001 to 10% by weight in 100% by weight of the whitening agent. Although not limited, for example, a range of 0.001 to 1% by weight and 1 to 10% by weight can be exemplified in this range. The whitening agent of the present invention may be composed of the above component (A) or may contain other components as long as it does not interfere with the tyrosinase inhibitory action (whitening action). . Such other components will be described later.

  The whitening agent of the present invention may contain at least one selected from the group consisting of the component (B) described above in addition to the component (A). As shown in the test examples to be described later, by using the component (B) in combination with the component (A), the tyrosinase inhibitory action of each of the component (A) and the component (B) is more than additive, preferably more than additive. More preferably, it is improved synergistically, and as a result, an extremely high whitening effect can be exhibited.

When the whitening agent of the present invention contains both the component (A) and the component (B), the blending ratio of the component (B) indicates that the whitening agent exhibits a tyrosinase inhibitory action (whitening action). The limit is not particularly limited. Preferably, the ratio is such that the tyrosinase inhibitory action (whitening action) of the whitening agent containing the component (A) is enhanced by the blending of the component (B). Although it does not restrict | limit, As an example of the quantity of this (B) component, 1-20 weight% can be illustrated in 100 weight% of whitening agents, for example.
Moreover, although it does not restrict | limit as a compounding ratio of (B) component with respect to 1 weight part of (A) component contained in a whitening agent, 20-1000 weight part can be mentioned. Although not limited, for example, the range of 20 to 50 parts by weight, and further 100 to 1000 parts by weight can be exemplified in this range. Further, in this case, the whitening agent of the present invention may be composed only of the above components (A) and (B), and other than that it does not interfere with the tyrosinase inhibitory action (whitening action). It may contain components.

  Other components include antibacterial agents (preservatives or bactericides), antioxidants, etc., and carriers and additives that are usually used to prepare them according to the form of the whitening agent. be able to. For example, the form of the whitening agent is liquid (liquid, gel, emulsion, suspension, extract, tincture, aerosol, liposome, etc.), solid (tablet, capsule, powder, granule, etc.), Semi-solid forms (ointments, plasters, creams, etc.) can be mentioned.

  The whitening agent of the present invention is not only used as a whitening agent itself, but also as an active ingredient of a composition for external use for skin, which will be described later. ). In addition, when used as a whitening agent itself, this use is applicable regardless of whether it is used in vitro or in vivo, whether it is used for humans and non-human animals, whether it is therapeutic or non-therapeutic. , Use in all cases is encompassed.

(4) External composition for skin The external composition for skin of the present invention is characterized by containing the above-mentioned tyrosinase inhibitor or whitening agent as an active ingredient. In other words, the above-mentioned component (A) is contained as an active ingredient that exhibits a tyrosinase inhibitory action or a whitening action. Moreover, in addition to (A) component, you may contain (B) component. From the standpoint of exhibiting a higher whitening effect, the whitening component preferably contains both the component (A) and the component (B).

  The blending ratio of the component (A) in the external composition for skin of the present invention is not particularly limited as long as it exhibits a whitening action, but is usually in the range of 0.001 to 20% by weight, preferably 0.001. -5% by weight, more preferably 0.001-0.5% by weight. When the external composition for skin of the present invention contains both the component (A) and the component (B), the blending ratio of the component (B) limits that the composition for external use of the skin exhibits a whitening effect. There is no particular limitation. Although it does not restrict | limit, As an example of the quantity of this (B) component, 1-20 weight% can be illustrated in 100 weight% of skin external compositions. Moreover, although it does not restrict | limit, 20-1000 weight part can be mentioned as a mixture ratio of (B) component with respect to 1 weight part of (A) component contained in the composition for skin external application. Furthermore, although not limited, the range of 20-50 weight part, for example, and 100-1000 weight part can be illustrated in this range.

  The external composition for skin of the present invention may be an external composition applied to the skin, for example, cosmetics (including basic cosmetics and makeup cosmetics), cleansing agents, bathing agents, external medicines, and external preparations. Examples include quasi-drugs. Preferably whitening of skin (skin), in particular, cosmetics (whitening cosmetics) for the purpose of preventing, reducing or improving pigmentation on the skin, or for effect of effect, cleansing, bathing, external medicine, and external medicine It is an outside product. Of these, cosmetics, cleaning agents, and bathing agents, especially cosmetics are preferred.

  The form of the composition for external use of the skin of the present invention is not particularly limited, and can be appropriately set and prepared according to the use. For example, liquid (lotion, gel, emulsion, suspension, extract, tincture, aerosol, liposome, etc.), solid (tablet, capsule, powder, granule, solidified like soap Shape), semi-solid (ointment, plaster, cream, etc.), and patches (patches, pasta, patches, etc.) can be used. In addition, you may use a liquid agent with the form which impregnated the base material (for example, a pack, wet cotton, wet tissue etc.).

  The composition for external use of the skin of the present invention can be added to the composition for external use in the cosmetic, pharmaceutical or quasi-drug field in order to further enhance or supplement the whitening action as long as the effects of the present invention are not hindered. Conventional whitening ingredients, physiologically active substances, and useful ingredients may be used in combination. Examples of such whitening components include cysteine, hydroquinone, 2-hydroxy acid and derivatives thereof, arbutin, kojic acid, retinoid, linoleic acid, ellagic acid, lucinol, vitamin E or a derivative thereof, vitamin A or a derivative thereof, Examples thereof include pantothenic acid or a derivative thereof, glutathione, placental extract, and a plant, basidiomycete or algal extract or essential oil having a whitening effect. These whitening components can be used alone or in combination of two or more. Examples of physiologically active substances and useful ingredients include vitamins, amino acids, antibacterial agents (preservatives or bactericides), anti-inflammatory / anti-inflammatory agents, blood circulation promoting / peripheral blood flow improving agents, astringents, ultraviolet absorbers, Examples include emollients, enzyme components, antioxidants, humectants, essential oil components, plant-derived materials, and other naturally-derived materials.

  Furthermore, in the composition for external use of the present invention, a carrier, an additive, or the like can be arbitrarily selected and blended according to the shape and use form within a range not impairing the effects of the present invention. Carriers (or bases) or additives include, for example, fats and oils, mineral oils, waxes, fatty acids, silicone oils, sterols, esters, metal soaps, alcohols, sugars, polymer compounds, interfaces Activators, pH adjusters, powder components, chelating agents, colorants (colorants), water, and the like are included. These carriers and additives can be used in appropriate combination according to the shape. Specifically, when preparing an aqueous liquid composition, water can usually be used as a base, and for preparing a non-aqueous liquid composition, various oily bases such as vegetable oils (for example, olive oil) are used. , Soybean oil, sesame oil, cottonseed oil, etc.), alcohols (cetyl alcohol, propylene glycol, glycerin, etc.), mineral oil (liquid paraffin, etc.) can be used. For preparation of creamy or milky composition, aqueous base (such as water), oil base (mineral oil such as liquid paraffin and squalane; wax such as lanolin; alcohols such as cetyl alcohol and propylene glycol), A surfactant or the like can be used. For the preparation of an ointment-like composition, an oily base (hydrocarbon base, for example, mineral oil such as petrolatum, liquid paraffin; wax; alcohols such as cetyl alcohol; various ointment bases such as higher fatty acid esters) In addition, a gel base (eg, carboxyvinyl polymer, polyoxyethylene polyoxypropylene block copolymer, gum) is used for the preparation of the gel composition, and the powder composition such as a powder is used. The powder component can be used as a base for the preparation of the product.

  Since the composition for external use of the skin of the present invention has an excellent whitening effect, various parts of the outer skin (skin), such as the face, neck, arms, hands, torso, and feet, which are likely to produce melanin by external stimuli such as ultraviolet rays. Suitable for application to the outer skin of the skin. Moreover, since the composition for external use of skin of this invention has comparatively high safety | security, it can be used also about the site | parts with a possibility of contacting mucous membranes, such as the circumference of eyes and a lip.

The usage and dose of the external composition for skin of the present invention are appropriately set according to the type of product (cosmetics, bathing, cleaning, pharmaceutical, or quasi-drug), its form, user's symptoms, age, etc. You can choose. For example, in the case of cosmetics, external medicines or quasi drugs, it can be applied to a predetermined site about 1 to 5 times per day. Moreover, in the case of a bathing fee, it can be used by adding to a bathtub when bathing. Moreover, in the case of a washing | cleaning fee, it can be used for washing | cleaning of a predetermined site | part about 1 to 3 times per day.
(5) Method for Increasing Tyrosinase Inhibitory Activity of 3- (2,4-Dihydroxyphenyl) propionic Acids The present invention comprises (A) component, that is, 3- (2,4-dihydroxyphenyl) propionic acid and a salt thereof. By using at least one selected from the group consisting of component (B), that is, ascorbic acid, a derivative thereof, and a salt thereof, in combination with at least one selected from the group, tyrosinase inhibitory activity of component (A) It is a method of increasing.

  This method can be carried out by using at least one component (B) in combination with at least one component (A).

  Here, the component (A), particularly the salt of 3- (2,4-dihydroxyphenyl) propionic acid, is as described in (1) (A) above, and the description can be incorporated herein. Moreover, (B) component, especially ascorbic acid derivative, and the salt of ascorbic acid or its derivative are as having demonstrated above (1) (B), The said description can be used here. Further, the proportion of the component (A) in combination with the component (B) is also as described in the above (2). Specifically, although not limited, (B) relative to 1 part by weight of the component (A) 20-1000 weight part can be mentioned as a ratio of a component. Although there is no further limitation, for example, a range of 20 to 50 parts by weight, and further 100 to 1000 parts by weight can be exemplified in this range.

  The degree of increase in the tyrosinase inhibitory activity of the component (A) in combination with the component (B) is not limited as long as the tyrosinase inhibitory activity of the component (A) is increased, and preferably (A) The addition of the tyrosinase inhibitory activity of the component and the component (B) can be mentioned. Preferably, the degree exceeds the additive, and more preferably, the degree increases synergistically.

(6) Method for Increasing Tyrosinase Inhibitory Activity of Ascorbic Acids The present invention includes (B) component, that is, at least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof, (A) component, That is, it is a method of increasing the tyrosinase inhibitory activity of the component (B) by using at least one selected from the group consisting of 3- (2,4-dihydroxyphenyl) propionic acid and its salt.

  This method can be carried out by using at least one component (A) in combination with at least one component (B).

  Here, the component (B), particularly the ascorbic acid derivative and the salt of ascorbic acid or a derivative thereof are as described in the above (1) (B), and the description can be incorporated herein. Moreover, (A) component, especially a salt are as having demonstrated above (1) (A), The said description can be used here. Furthermore, although it does not restrict | limit about the ratio which uses (A) component together with (B) component, 0.001-1 weight part can be mentioned as a ratio of (A) component with respect to 1 weight part of (B) component. Although there is no further limitation, for example, a range of 0.001 to 0.01 parts by weight, and further 0.02 to 0.05 parts by weight can be exemplified in this range.

  The degree of increase in tyrosinase inhibitory activity by using component (A) in combination with component (B) is not limited as long as tyrosinase inhibitory activity of component (B) is increased, and preferably (B) More than the addition of the tyrosinase inhibitory activity which each of the component and the component (A) has. Preferably, the degree exceeds the additive, and more preferably, the degree increases synergistically.

  Hereinafter, the present invention will be described in more detail with reference to test examples and examples. However, the present invention is not limited to these.

Production Example 3- (2,4-Dihydroxyphenyl) propionic acid production
(1) Production of methyl 3- (2,4-dibenzyloxyphenyl) propionate Into a 500 ml three-necked flask equipped with a thermometer, a magnetic rotor and a reflux condenser, umbelliferone 20.0 g (123 mmol), tetrahydrofuran 200 ml Then, 200 ml of methanol and 1.0 g of 10% palladium carbon are added, and the inside of the system is replaced with hydrogen under stirring. After heating this mixed liquid to 30 degreeC, it is made to react under hydrogen atmosphere for 6 hours. The reaction is cooled and palladium carbon is filtered off.

  Subsequently, the obtained filtrate was transferred to a 500 ml three-necked flask equipped with a thermometer, a magnetic rotator and a reflux condenser, and 0.19 g (1 mmol) of p-toluenesulfonic acid monohydrate was added, and refluxed under nitrogen. And stirring for 2 hours. After cooling the reaction mixture to room temperature, 0.3 ml of 28% sodium methoxide in methanol is added. The reaction mixture is concentrated under reduced pressure to give 25.55 g of residue.

  Subsequently, 25.55 g of the residue obtained by the above operation, 300 ml of acetone and 34.00 g (246 mmol) of potassium carbonate were added to a 500 ml three-necked flask equipped with a thermometer, a magnetic rotor, a dropping funnel and a reflux condenser, and nitrogen was added. Under heating and stirring until acetone is refluxed. To this, 46.39 g (270 mmol) of benzyl bromide is added dropwise over 1 hour. After completion of dropping, the mixture is further stirred for 5 hours under reflux. After cooling the reaction mixture to room temperature, the by-produced salt is removed by filtration, and acetone is distilled off from the filtrate under reduced pressure. 200 ml of toluene and 200 ml of water are added to the obtained residue, and the organic layer and the aqueous layer are separated. Toluene was distilled off from the organic layer under reduced pressure, and the resulting residue was purified using silica gel column chromatography (developing solvent: hexane / ethyl acetate = 20/1) to give 3- (2,4-dibenzyl). 45.2 g (96 mmol, yield based on umbelliferone: 78%) of methyl oxyphenyl) propionate are obtained.

(2) Production of methyl 3- (2,4-dibenzyloxyphenyl) propionate In a 100 ml three-necked flask equipped with a thermometer, a magnetic rotator and a reflux condenser, 2.72 g (69.3 mmol) of sodium hydroxide, 20 g of water, 30 g of tetrahydrofuran, and 8 g (23.1 mmol) of methyl 3- (2,4-dibenzyloxyphenyl) propionate prepared in (1) were added, and the mixture was reacted at 40 ° C. for 1 hour with stirring. Reflux for 30 minutes. After cooling the reaction mixture to room temperature, 30 ml of toluene and 30 ml of water are added and stirred for 30 minutes. This is separated to obtain an aqueous layer, and 30 ml of an 8% by mass sulfuric acid aqueous solution is added to make the inner solution acidic, followed by extraction three times with 50 ml of toluene. The extracts are combined and concentrated under reduced pressure, 100 ml of tetrahydrofuran and 0.8 g of 10% palladium carbon are added to the residue, and hydrogenated over 24 hours at room temperature and atmospheric pressure. After filtering the palladium carbon, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to obtain 2.72 g of 3- (2,4-dihydroxyphenyl) propionic acid (14. 9 mmol, yield: 65%).

Test Example 1 Tyrosinase inhibitory activity of 3- (2,4-dibenzyloxyphenyl) propionic acid
According to the report by Hanamura et al. (Biosci. Biotechnol. Biochem., 72 (12), 3211-3218, 2008), the inhibitory activity against mushroom-derived tyrosinase was used as an index, and 3- (2,4-dihydroxyphenyl) The tyrosinase inhibitory activity of propionic acid (hereinafter also referred to as “Compound A”) was evaluated.

1. Test Method The following were used as test samples, completely dissolved in dimethyl sulfoxide (DMSO), diluted to 3 concentrations as shown in Table 1, and used as test sample solutions in the test.
[Test sample]
a. 3- (2,4-Dihydroxyphenyl) propionic acid (Compound A)
b. Ascorbic acid (Comparative product 1)
c. Kojic acid (Comparative product 2).

  To a 96-well microplate, 70 μL of 100 mM sodium phosphate buffer (pH 6.8) and 2 μL of a test sample solution were dispensed, and 30 μL of a 71.5 units / mL tyrosinase solution was added thereto, and then at 25 ° C. for 5 minutes. Preincubation was performed. Next, 30 μL of 10 mM L-dihydroxyphenylalanine was added thereto, and further incubated for 2 minutes under the same conditions as described above. Thereafter, the absorbance at 475 nm was immediately measured with a microplate reader.

2. The test result measurement results are shown in Table 1.

From the measurement results, the tyrosinase inhibitory activity of Compound A was IC ₅₀ = 0.08 mg / mL, the tyrosinase inhibitory activity of ascorbic acid was IC ₅₀ = 1.22 mg / mL, and the tyrosinase inhibitory activity of kojic acid was IC ₅₀ = 0.05 mg / mL. As a result, it was confirmed that Compound A greatly exceeded the tyrosinase inhibitory activity of ascorbic acid and had tyrosinase inhibitory activity almost equivalent to kojic acid.

Test Example 2 Combination with Ascorbic Acid In response to the results of Test Example 1 above, Test Example 2 measured the tyrosinase inhibitory activity when Compound A was combined with Asulbic Acid, and the effect of Ascorbic Acid on Compound A (or Ascorbine) The effect of compound A on the acid) was evaluated.

1. Test Method Tyrosinase inhibitory activity was measured according to the method described in Test Example 1 using Compound A, ascorbic acid, and a combination of Compound A and ascorbic acid as test samples.

2. Test results Tables 2 and 3 and FIG. 1 show the results of measuring tyrosinase inhibitory activity (tyrosinase inhibition rate (%)) for each of compound A, ascorbic acid, and combination of compound A and ascorbic acid.

  As shown in Tables 2 and 3 and FIG. 1, it was confirmed that the combined use of Compound A and ascorbic acid synergistically enhances the tyrosinase inhibitory activity of both.

  Due to this synergistic effect, the whitening effect can be expected with a smaller amount of compound A by using compound A in combination with ascorbic acid and with ascorbic acid in combination with compound A. In particular, Compound A, as shown in Test Example 3 below, is a compound that is inherently highly safe, but it can further reduce the risk of side effects by using a low amount in combination with ascorbic acid as described above. it can. In addition, by using ascorbic acid, which is a whitening quasi-drug approved substance, it can be provided as a safe external composition for skin whitening (whitening cosmetics, whitening quasi-drugs).

Test Example 3 A safety evaluation compound A was formulated so as to have a content of 0.5% by weight, and a cream external skin preparation was produced.

  Using this, a 24-hour occlusion patch test based on “Guidelines for Safety Evaluation of Cosmetics” (Japan Cosmetic Industry Association) was performed on 20 subjects. As a result, all 20 subjects did not respond and the skin irritation index was 0.0. From this, it was confirmed that Compound A, unlike 2-hydroxy acid known as a tyrosinase inhibitor, has no skin irritation and skin sensitization and is highly safe to the skin.

Formulation Examples Various skin whitening external preparations Formulation examples of various cosmetic compositions according to the present invention are shown below, but the present invention is not limited thereto.

Formulation Example 1 Whitening lotion Glycerin 5.0
2. 1,3-butylene glycol 5.0
3. Polyoxyethylene sorbitan monolaurate 1.0
4). Ethanol 15.0
5. Compound A 0.01
6). Glucose 1.0
7). Fructose 1.0
8). Antibacterial / preservative appropriate amount 9. Purified water Amount that makes the total amount 100.

Formulation Example 2 Whitening Emulsion Squalane 5.0
2. Olive oil 5.0
3. Jojoba oil 5.0
4). Cetyl alcohol 1.5
5. Glycerol monostearate 2.0
6). Polyoxyethylene (20) cetyl ether 3.0
7). Polyoxyethylene (20) soorbitan monooleate 2.0
8.1,3-Butylene glycol 1.0
9. Glycerin 2.0
10. Compound A 0.01
11. Preservative (paraoxybenzoic acid ester) appropriate amount 12. Purified water Amount that makes the total amount 100.

Formulation Example 3 Whitening Cream Squalane 20.0
2. Beeswax 5.0
3. Refined jojoba oil 5.0
4). Glycerol monostearate 2.0
5. Sorbitan monostearate 2.0
6). Polyoxyethylene (20) sorbitan monostearate 2.0
7). Glycerin 5.0
8). Compound A 0.01
9. Purified water Amount that makes the total amount 100.

Formulation Example 4 Whitening lotion Glycerin 5.0
2. 1,3-butylene glycol 5.0
3. Polyoxyethylene sorbitan monolaurate 1.0
4). Ethanol 15.0
5. Compound A 0.001
6). Glyceryl ascorbic acid 1.0
6). Glucose 1.0
7). Fructose 1.0
8). Antibacterial / preservative appropriate amount 9. Purified water Amount that makes the total amount 100.

Formulation Example 5 Whitening emulsion 1. Squalane 5.0
2. Olive oil 5.0
3. Jojoba oil 5.0
4). Cetyl alcohol 1.5
5. Glycerol monostearate 2.0
6). Polyoxyethylene (20) cetyl ether 3.0
7). Polyoxyethylene (20) soorbitan monooleate 2.0
8.1,3-Butylene glycol 1.0
9. Glycerin 2.0
10. Compound A 0.002
11. Glyceryl ascorbic acid 0.1
12 Preservative (paraoxybenzoic acid ester) Purified water Amount that makes the total amount 100.

Formulation Example 6 Whitening Cream Squalane 20.0
2. Beeswax 5.0
3. Refined jojoba oil 5.0
4). Glycerol monostearate 2.0
5. Sorbitan monostearate 2.0
6). Polyoxyethylene (20) sorbitan monostearate 2.0
7). Glycerin 5.0
8). Compound A 0.002
9. Glyceryl ascorbic acid 0.1
10. Purified water Amount that makes the total amount 100.

Claims (6)

  (A) A tyrosinase inhibitor comprising as an active ingredient at least one selected from the group consisting of 3- (2,4-dihydroxyphenyl) propionic acid and salts thereof.   The tyrosinase inhibitor according to claim 1, further comprising (B) at least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof.   A whitening agent comprising the tyrosinase inhibitor according to claim 1.   An external composition for skin containing the whitening agent according to claim 3.   (A) At least one selected from the group consisting of 3- (2,4-dihydroxyphenyl) propionic acid and salts thereof is selected from the group consisting of (B) ascorbic acid, derivatives thereof, and salts thereof A method for increasing the tyrosinase inhibitory activity of the component (A) above additively, wherein at least one kind is used in combination.   (B) At least one selected from the group consisting of ascorbic acid, derivatives thereof, and salts thereof is selected from the group consisting of (A) 3- (2,4-dihydroxyphenyl) propionic acid and salts thereof A method for increasing the tyrosinase inhibitory activity of the component (B) above additively, wherein at least one kind is used in combination.