JP2012062304A - Activity inhibitor for trpa1, method for inhibiting activity of trpa1, and external preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an activity inhibitor for TRPA1, and an external preparation which has low stimulability to the skin.SOLUTION: The activity inhibitor for TRPA1 contains a compound expressed by formula (I): (wherein, Rdenotes a hydrogen atom, a hydroxy group, 1 to 4C alkyl group, a carboxyl group, an amino group or an aldehyde group; Rand Rindependently a hydrogen atom, a hydroxy group respectively, 1 to 4C alkyl group, a carboxyl group, an amino group or an aldehyde group; and Rdenotes an oxygen atom or a sulfur atom). Further, the external preparation contains the activity inhibitor.

Description

  The present invention relates to an activity inhibitor for TRPA1, a method for inhibiting the activity of TRPA1, and an external preparation.

  If external preparations such as cosmetics that are applied directly to the skin, or external preparations such as hair external preparations that may come into contact with the skin contain cooling agents, parabens, alkaline agents, etc., depending on the user When the external preparation is used, uncomfortable irritation may be felt on the skin.

  For example, the present inventors have found that the parabens and alkaline agents activate TRPA1, which is one of the transient receptor potential channels, and cause unpleasant stimulation via the activated TRPA1. (For example, see Patent Documents 1 to 3).

  However, in recent years, due to the increase in safety awareness of users, external preparations that do not give such unpleasant stimuli or have few unpleasant stimuli tend to be preferred.

JP 2008-79528 A JP 2009-82053 A JP 2009-225733 A

  This invention is made | formed in view of the said prior art, and it aims at providing the activity inhibitor of TRPA1 which suppresses the activity of TRPA1 effectively. Another object of the present invention is to provide a method for inhibiting the activity of TRPA1 that effectively inhibits the activity of TRPA1. Furthermore, an object of this invention is to provide the external preparation with few unpleasant irritation | stimulation with respect to skin.

That is, the gist of the present invention is as follows.
(1) An activity inhibitor that suppresses the activity of TRPA1, which is represented by the formula (I):

(In the formula, R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a carboxyl group, an amino group or an aldehyde group, R ² and R ³ are each independently a hydrogen atom, a hydroxyl group, and 1 to 4 carbon atoms. Alkyl group, carboxyl group, amino group or aldehyde group, R ⁴ represents an oxygen atom or a sulfur atom)
An activity inhibitor of TRPA1, comprising a compound represented by:
(2) An activity suppression method for suppressing the activity of TRPA1, comprising the formula (I):

(In the formula, R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a carboxyl group, an amino group or an aldehyde group, R ² and R ³ are each independently a hydrogen atom, a hydroxyl group, and 1 to 4 carbon atoms. Alkyl group, carboxyl group, amino group or aldehyde group, R ⁴ represents an oxygen atom or a sulfur atom)
A method for inhibiting the activity of TRPA1, which comprises contacting a compound represented by formula (2) with TRPA1, and (3) an external preparation formulated with a component that activates TRPA1, The present invention relates to an external preparation characterized by containing an activity inhibitor.

  The TRPA1 activity inhibitor of the present invention has an excellent effect of effectively suppressing the activity of TRPA1. Moreover, the TRPA1 activity suppression method of the present invention has an excellent effect of effectively suppressing the activity of TRPA1. Furthermore, the external preparation of this invention has the outstanding effect that there are few unpleasant irritation | stimulation with respect to skin.

In Test Example 1, it is a graph showing the results of examining the relationship between the type of sample and the inhibition rate. In Test Example 2, it is a graph showing the results of examining the relationship between the sample and the inhibition rate.

1. TRPA1 activity inhibitor The TRPA1 activity inhibitor of the present invention (hereinafter referred to as "activity inhibitor") is represented by the formula (I):

(In the formula, R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a carboxyl group, an amino group or an aldehyde group, R ² and R ³ are each independently a hydrogen atom, a hydroxyl group, and 1 to 4 carbon atoms. Alkyl group, carboxyl group, amino group or aldehyde group, R ⁴ represents an oxygen atom or a sulfur atom)
It contains the compound represented by these, It is characterized by the above-mentioned.

  The compound represented by the formula (I) suppresses the activation of TRPA1 by the TRPA1 agonist and suppresses the activity of TRPA1. Therefore, since the activity inhibitor of the present invention contains the compound represented by the formula (I), the activity of TRPA1 can be suppressed by bringing the activity inhibitor into contact with TRPA1.

In the formula (I), R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a carboxyl group, an amino group, or an aldehyde group. The number of carbon atoms of the alkyl group is 1 or more from the viewpoint of sufficiently expressing the inhibitory action on the activity of TRPA1, and in the case of using the activity inhibitor in humans, from the viewpoint of ensuring sufficient affinity for human skin. 4 or less, preferably 3 or less. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group. Among R ¹ , a methyl group is preferable from the viewpoint of sufficiently exhibiting an inhibitory action on the activity of TRPA1 and ensuring sufficient affinity for human skin when the activity inhibitor is used in humans.

In the formula (I), R ² and R ³ are each independently a hydroxyl group, a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a carboxyl group, an amino group, or an aldehyde group. The alkyl group is the same as the alkyl group in R ¹ . Among R ² and R ³ , a methyl group is sufficiently expressed from the viewpoint of sufficiently exhibiting an inhibitory action on the activity of TRPA1 and ensuring sufficient affinity for human skin when the activity inhibitor is used in humans. preferable.

In the formula (I), R ⁴ is an oxygen atom or a sulfur atom. Among R ⁴ , it is sufficient to express an inhibitory effect on the activity of TRPA1 and, when the activity inhibitor is used in humans, it is an oxygen atom from the viewpoint of ensuring sufficient affinity for human skin. preferable.

Among the compounds represented by formula (I), R ¹ , R ² and R ³ are methyl groups and R ⁴ is an oxygen atom from the viewpoint of sufficiently expressing the inhibitory action on the activity of TRPA1. 8-Cineol is preferred.

  The compound represented by the formula (I) can be isolated by, for example, distilling eucalyptus oil, distilling an extract obtained from Laurier, mugwort, basil, sagebrush, rosemary, sage and the like. .

  The content of the compound represented by the formula (I) in the activity inhibitor of the present invention is preferably 0.0001% by mass or more, preferably 0.001% by mass or more, from the viewpoint of sufficiently expressing the inhibitory action on the activity of TRPA1. In the case where the activity inhibitor is used in humans, it is preferably 100% by mass or less, more preferably 1% by mass or less, from the viewpoint of ensuring sufficient affinity for human skin.

  The activity inhibitor of the present invention may contain other components such as water, a pH adjuster, a chelating agent, and a stabilizer within a range that does not hinder the object of the present invention. In addition, when the activity inhibitor of this invention contains the said component, in the activity inhibitor of this invention in the range which does not prevent the objective of this invention, the compound and said component which are represented by Formula (I) A complex may be formed.

  Examples of the activity of TRPA1 include the ability to regulate ion flux in cells and the ability to regulate membrane potential in cells. Examples of the ability to regulate ion flux in cells include the ability to transport cations from outside the cell into the cell. Examples of the ability to regulate membrane potential in cells include the ability to generate current. These activities are expressed when a TRPA1 agonist binds to TRPA1 and activates the TRPA1. Examples of the cation include calcium ion and sodium ion.

  Examples of the TRPA1 agonist include menthol, ethanol, 1,3-butylene glycol, propylene glycol, alkaline agents (eg, ammonia, monoethanolamine, potassium hydroxide, etc.), allyl isothiocyanate, methyl paraben, allicin, and icilin. , Hydrogen peroxide, bradykinin, acrolein, and perfume oil components (for example, citral, eugenol, cinnamaldehyde, etc.), but the present invention is not limited to such examples.

  The inhibitory action of the activity inhibitor of the present invention on the activity of TRPA1 is based on, for example, the calcium ion concentration in cells expressing TRPA1 (hereinafter referred to as “TRPA1 expressing cells”), the current in the TRPA1 expressing cells, etc. Can be evaluated.

When the calcium ion concentration in the TRPA1-expressing cell is used, the inhibitory action is, for example,
(A1) a step of contacting a TRPA1-expressing cell, a test substance (activity inhibitor) and a TRPA1 agonist, and measuring a calcium ion concentration in the TRPA1-expressing cell [referred to as “calcium ion concentration (A)”];
(A2) a step of bringing a TRPA1-expressing cell into contact with a TRPA1 agonist and measuring a calcium ion concentration in the TRPA1-expressing cell [referred to as “calcium ion concentration (B)”]; and (A3) obtained in the step (A1) Evaluation can be performed by performing a step of comparing the obtained calcium ion concentration (A) with the calcium ion concentration (B) obtained in the step (A2) (referred to as “evaluation method A”). In step (A3), when the calcium ion concentration (A) is decreased as compared with the calcium ion concentration (B), the test substance can be evaluated as having an inhibitory action on the activity of TRPA1. Moreover, it can be evaluated that the said test substance has a high inhibitory effect, so that the difference between the said calcium ion concentration (A) and a calcium ion concentration (B) is large.

  The calcium ion concentration is, for example, by introducing a fluorescent reagent based on a calcium chelator (hereinafter also referred to as “fluorescent calcium indicator”) into a TRPA1-expressing cell, and binding the fluorescent calcium indicator to the calcium ion in the cell, It can be measured by a method for examining the fluorescence intensity of a fluorescent calcium indicator bound to calcium ions. The fluorescent calcium indicator is not particularly limited as long as it binds to calcium ions and its fluorescence characteristics change depending on the amount of the fluorescent calcium indicator, and examples thereof include FURA 2, FURA 2-AM, and Fluo-3. .

When using a current in a TRPA1-expressing cell, the inhibitory action is, for example,
(B1) contacting a TRPA1-expressing cell, a test substance (activity inhibitor) and a TRPA1 agonist, and measuring a current [referred to as “current (A)”] at a constant potential in the TRPA1-expressing cell;
(B2) contacting a TRPA1-expressing cell with a TRPA1 agonist, and measuring a current [referred to as “current (B)”] under the same potential as in (1) in the TRPA1-expressing cell; and (B3 It can be evaluated by performing a step of comparing the current (A) obtained in step (B1) with the current (B) obtained in step (B2) (referred to as “evaluation method B”). . In the step (B3), when the current (A) is smaller than the current (B), the test substance can be evaluated as having an inhibitory action on the activity of TRPA1. Moreover, it can be evaluated that the said test substance has a high inhibitory effect, so that the difference between the said electric current (A) and an electric current (B) is large. The current can be measured by, for example, a patch clamp method.

  According to the activity inhibitor of the present invention, since the activity of TRPA1 associated with an unpleasant irritation in skin is suppressed, unpleasant irritation in skin can be suppressed. Therefore, the activity inhibitor of this invention can be used suitably for the external preparation used with respect to the sensitive skin which is easy to feel the unpleasant irritation | stimulation in skin.

2. TRPA1 activity suppression method The TRPA1 activity suppression method of the present invention (hereinafter referred to as "activity suppression method") is an activity suppression method for suppressing the activity of TRPA1, wherein the compound represented by formula (I) is defined as TRPA1. It is made to contact.

  According to the activity-suppressing method of the present invention, since the compound represented by the formula (I) is used, for example, TRPA1 contained in sensory nerves existing in human skin, sensations existing under mucous membranes such as oral cavity. Activities such as TRPA1 contained in nerves can be effectively suppressed.

  The contact between the compound represented by the formula (I) and TRPA1 can be performed by supplying the compound represented by the formula (I) to a site containing TRPA1, for example, a cell constituting the skin.

Since the amount of the compound represented by the formula (I) to be contacted with the TRPA1 varies depending on the application target of the activity suppression method of the present invention and cannot be determined unconditionally, the activity suppression method of the present invention It is preferable to set appropriately according to the application target. The amount of the compound represented by the formula (I) to be contacted with the TRPA1 is usually relative to the activity of the TRPA1 when the application target of the activity suppression method of the present invention is TRPA1 contained in the sensory nerve existing in the skin. From the viewpoint of sufficiently expressing the suppressive action, it is preferably 10 μg or more, more preferably 100 μg or more per 10 cm ^{2 of} skin, and from the viewpoint of suppressing the load on the skin, it is preferably 100 mg or less, more preferably 10 mg or less. .

  The inhibitory effect of the activity suppression method of the present invention on the activity of TRPA1 can be evaluated by the same technique as the evaluation of the inhibitory effect on the activity of TRPA1 by the activity inhibitor.

  Since the activity suppression method of the present invention suppresses the activity of TRPA1 which is related to an unpleasant irritation in the skin, there is a possibility that, for example, the activity suppression method gives an unpleasant irritation when contacting the skin. When an external preparation containing a certain component is used, the activity of TRPA1 contained in cells in the skin is suppressed by performing the activity suppression method using the compound represented by formula (I) and the external preparation in combination. And unpleasant stimuli can be suppressed. Therefore, the method for suppressing the activity of TRPA1 of the present invention is suitable to be applied when a human having sensitive skin uses the external preparation.

3. External preparation The external preparation of the present invention is an external preparation in which a component for activating TRPA1 is blended, and is characterized by containing the activity inhibitor of TRPA1.

  Since the external preparation of this invention contains the said activity inhibitor, it suppresses activation of TRPA1. Therefore, according to the external preparation of the present invention, unpleasant stimuli based on activation of TRPA1, such as unpleasant stimuli due to a component that activates TRPA1, can be reduced. The external preparation of the present invention is preferably an external preparation for sensitive skin.

  In this specification, “sensitive skin” means that the barrier function of the skin is lowered, and it reacts sensitively to substances, irritation, etc. that do not react on the average skin, itching of the skin, skin roughness, etc. The skin that tends to occur.

  Moreover, in this specification, "component which activates TRPA1" means the component which can be used for an external preparation among TRPA1 agonists. As a component that activates TRPA1, for example, when the same operation as in the evaluation method A is performed, the calcium ion concentration (A) increases in step (A3) as compared with the calcium ion concentration (B). And a component indicating that the current (A) is larger than the current (B) in step (B3) when the evaluation method B is performed. Examples of the component that activates TRPA1 include menthol, ethanol, 1,3-butylene glycol, propylene glycol, alkaline agents (eg, ammonia, monoethanolamine, potassium hydroxide, etc.), allyl isothiocyanate, methyl paraben, and allicin. , Icilin, hydrogen peroxide, acrolein, perfume oil components (for example, citral, eugenol, cinnamaldehyde, etc.), but the present invention is not limited to such examples.

Among the compounds represented by the formula (I) contained in the activity inhibitor in the external preparation of the present invention, R ¹ , R ² and R ³ are selected from the viewpoint of sufficiently expressing the inhibitory action on the activity of TRPA1. 1,8-cineole which is a methyl group and R ⁴ is an oxygen atom is preferable.

  The dosage form of the external preparation of the present invention can be appropriately selected depending on the use of the external preparation of the present invention. Examples of the dosage form of the external preparation of the present invention include lotions, creams, foams, emulsions, gels, packs, powders, aerosols, patches and the like, but the present invention is limited only to such examples. is not.

  The external preparation of the present invention includes a skin external preparation such as cosmetics directly applied to the skin, a hair external preparation that may come into contact with the skin, and the like.

  Examples of the external preparation for skin include body lotion, deodorant cosmetics (for example, deodorant lotion, deodorant gel, deodorant spray, deodorant roll-on, deodorant paper, etc.), lotion, emulsion, skin care cream, tonic, stick cosmetic, lip Skin bleaching agents (body bleaching agents), cleaning agents (eg body shampoos, cleansing agents, facial cleansers, bar soaps), sheet cosmetics (eg wipes, sheet packs etc.), patches (eg And shaving cosmetics (for example, shaving gel).

  Examples of the hair external preparation include hair washing cosmetics (eg, shampoo, rinse, etc.), hair restorers, hair colors, hair bleach, perm solution, hair styling agents (eg, hair tonic), and the like. .

  Since the content of the activity inhibitor in the external preparation of the present invention varies depending on the type and amount of the component that activates the TRPA1, the use of the external preparation, etc., it cannot be determined unconditionally. It is preferable to set appropriately depending on the type and amount of the component to be activated, the use of the external preparation, and the like. Usually, the content of the activity inhibitor in the external preparation of the present invention is such that the content of the compound represented by the formula (I) in the external preparation of the present invention sufficiently exhibits the inhibitory action on the activity of TRPA1. From the viewpoint of suppressing the load on the skin, preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, further preferably 0.05% by mass or more, particularly preferably 0.1% by mass or more. It is desirable that the content is adjusted to be preferably 10% by mass or less, more preferably 8% by mass or less.

  Since the amount of the activity inhibitor relative to the component that activates TRPA1 varies depending on the type and amount of the component that activates TRPA1, the application of the external preparation, and the like, it cannot be determined in a general manner. It is preferable to set appropriately depending on the type and amount of the component that activates the agent, the use of the external preparation, and the like. Usually, the amount of the activity inhibitor relative to the component that activates TRPA1 depends on the amount of the compound represented by formula (I) per 100 parts by mass of the component that activates TRPA1, depending on the component that activates TRPA1. From the viewpoint of suppressing unpleasant irritation, it is preferably 1 part by mass or more, more preferably 10 parts by mass or more, and from the viewpoint of obtaining an appropriate cooling feeling, preferably 500 parts by mass or less, more preferably 200 parts by mass or less. It is desirable to adjust so that.

  In the external preparation of the present invention, in addition to the above-mentioned “component that activates TRPA1,” for example, higher alcohols, waxes, hydrocarbon oils other than the component that activates TRPA1, within the range where the object of the present invention is not hindered Oils such as fatty acids, oils and fats, ester oils and silicone oils; surfactants such as anionic surfactants, cationic surfactants, nonionic surfactants and amphoteric surfactants; activates TRPA1 Moisturizers such as polyhydric alcohols other than the components, sugars, hyaluronic acid, hyaluronic acid derivatives; thickeners, antioxidants, chelating agents, pH adjusters other than the components that activate TRPA1, and components that activate TRPA1 Other ingredients such as preservatives and water other than the ingredients for activating the perfume, coloring matter, ultraviolet absorber, ultraviolet scattering agent, vitamin, amino acid and TRPA1 may be blended.

  Examples of the oil include wax such as carnauba wax, candelilla wax, beeswax, rice bran wax, shellac wax, whale wax, lanolin; ceresin, light isoparaffin, light liquid isoparaffin, synthetic squalane, vegetable squalane, squalane, paraffin, microcrystalline wax. , Hydrocarbon oils such as liquid isoparaffin, liquid paraffin, polyethylene powder, polyethylene wax, Fischer-Tropsch wax, petrolatum; lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, lanolin alcohol, behenyl alcohol, cetostearyl alcohol, etc. Higher alcohol; lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, behenic acid Fatty acids such as undecylenic acid, lanolinic acid, isostearic acid; coconut oil, palm oil, hydrogenated palm oil, avocado oil, sesame oil, olive oil, kukui nut oil, grape particle oil, safflower oil, almond oil, corn oil, cottonseed oil, sunflower oil Oils such as seed oil, grape seed oil, hazelnut oil, macadamia nut oil, meadow foam oil, rosehip oil, jojoba oil; ethyl oleate, isopropyl myristate, isopropyl palmitate, myristyl myristate, cetyl palmitate, oleyl oleate Octyldodecyl myristate, isocetyl stearate, octyldodecyl oleate, ethyl isostearate, isopropyl isostearate, cetyl 2-ethylhexanoate, cetostearyl 2-ethylhexanoate, Glyceryl 2-ethylhexanoate, glyceryl tri (capryl / caprate), glyceryl triisopalmitate, pentaerythritol tetra-2-ethylhexanoate, isocetyl octoate, isostearyl octoate, isocetyl isostearate, octyldodecyl isostearate, Ester oils such as isononyl isononanoate and octyldodecyl dimethyloctanoate; methylpolysiloxane, highly polymerized methylpolysiloxane, methylphenylpolysiloxane, octamethyltrisiloxane, decamethyltetrasiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane , Dodecamethylcyclohexasiloxane, methylcyclopolysiloxane, alcohol-modified silicone, alkyl-modified silicone, amino Examples include silicone oils such as modified silicones and epoxy-modified silicones, but the present invention is not limited to such examples. The said oil agent can be used individually or in mixture of 2 or more types.

  Examples of the surfactant include higher fatty acid soaps, alkyl sulfate esters, alkyl phosphates, polyoxyethylene alkyl ether sulfates, polyoxyethylene alkyl phenyl ether sulfates, alkyl ether phosphates, alkyl ether carboxylic acids. Salt, acylmethyltaurine salt, N-acyl-N-methyl-β-alanine salt, N-acylglycine salt, N-acylglutamate, polyoxyethylene alkylcarboxylate, alkylphenyl ether sulfonate, alkylsulfosuccinic acid And its salts, N-acyl sarcosine and its salts, polyoxyethylene coconut oil fatty acid monoethanolamide sulfate and other anionic surfactants; alkylamine salts, fatty acid amidoamine salts, amine salts such as ester-containing tertiary amine salts, Alkyl quaternary ammonium salts such as noalkyl quaternary ammonium salts, dialkyl quaternary ammonium salts, trialkyl quaternary ammonium salts, benzalkonium quaternary ammonium salts, cyclic quaternary ammonium salts such as alkyl pyridinium salts, Cationic surfactants such as benzethonium chloride; sorbitan fatty acid ester, glycerin fatty acid ester, castor oil, hydrogenated castor oil and their alkylene oxide adducts, polyglycerin fatty acid ester, polyoxyalkylene alkyl ether, polyoxyalkylene fatty acid ester, poly Oxyalkylene alkylphenols, polyoxyethylene sorbite fatty acid esters, polyoxyethylene alkylphenyl formaldehyde condensates, polyoxyethylene sterols and derivatives thereof Nonionic surfactants such as conductors, polyoxyethylene lanolin and derivatives thereof, polyoxyethylene beeswax derivatives, sugar esters; alkyl glycine salts, carboxymethyl glycine salts, N-acylaminoethyl-N-2-hydroxyethyl glycine salts Glycine-type amphoteric surfactants such as, aminopropionic acid-type amphoteric surfactants such as alkylaminopropionate and alkyliminodipropionate, betaine aminoacetates such as alkyldimethylaminoacetic acid betaine and fatty acid amidopropyldimethylaminoacetic acid betaine Examples include amphoteric surfactants such as type amphoteric surfactants and sulfobetaine type amphoteric surfactants such as alkylhydroxysulfobetaines, but the present invention is not limited to such examples. The surfactants can be used alone or in admixture of two or more.

  Examples of the humectant include diglycerin, polyglycerin, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, 3-methyl-1,3-butanediol, and 1,2-pentanediol. , 1,2-hexanediol, 1,2-heptanediol, 1,2-octanediol, 1,2-nonanediol, 1,2-decanediol and other polyhydric alcohols; sorbitol, mannitol, glucose, sucrose, Sugars such as fructose, xylitol, lactose, maltose, maltitol, trehalose; hyaluronic acid, hydrolyzed hyaluronic acid, propylene glycol hyaluronic acid and the like are included, but the present invention is limited only to such examples Not to. The humectants can be used alone or in admixture of two or more.

  Examples of the thickener include natural polymer compounds such as gum arabic, tragacanth gum, guar gum, locust bean gum, carrageenan, alginic acid, agar, pectin, caraya gum, iris moss, quince seed, gelatin, shellac, rosin, and casein; Semi-synthetic polymer compounds such as sodium carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, ethylserose, sodium alginate, ester gum, nitrocellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose; polyvinyl alcohol, sodium polyacrylate, carboxyvinyl polymer, Acrylic acid / alkyl methacrylate copolymer, polyvinyl methyl cellulose, polyamide resin, acrylate / Polyoxyethylene cetyl ether copolymer, acrylates / polyoxyethylene stearyl ether copolymer, acrylates / polyoxyethylene behyl ether copolymer, acrylates / polyoxyethylene cetyl ether copolymer, acrylates / itaconate poly Examples thereof include synthetic polymer compounds such as oxyethylene stearyl ether copolymer, acrylates / polyoxyethylene stearyl ether cross polymer of methacrylic acid, and alkyl acrylate / vinyl neodecanoate cross polymer, but the present invention is limited to such examples only. It is not a thing. The said thickener can be used individually or in mixture of 2 or more types.

  Examples of the antioxidant include ascorbic acid, sodium ascorbate, potassium ascorbate, magnesium ascorbate, calcium ascorbate, aluminum ascorbate, sodium ascorbate phosphate, sodium ascorbate phosphate, potassium ascorbate phosphate Ascorbic acid and / or its derivatives such as aluminum ester, sodium ascorbate sulfate, potassium ascorbate sulfate, magnesium ascorbate sulfate, calcium ascorbate sulfate, calcium ascorbate sulfate; aluminum; squalene, saponin, limonin, cameliagenin , Hopane, lanosterol, facyclol, ursolic acid, oleonolic acid, betulinic acid Triterpenes; tocopherol, tocopherol acetate, astaxanthin, coenzyme Q10, but such colloidal platinum and the like, and the present invention is not limited only to those exemplified. The said antioxidant can be used individually or in mixture of 2 or more types.

  Examples of the chelating agent include ethylenediaminetetraacetic acid and its salt, ethylenediaminehydroxyethyl triacetic acid and its salt, citric acid and its salt, gluconic acid and its salt, tartaric acid and its salt, phytic acid and its salt, polyphosphoric acid and Although the salt etc. are mentioned, this invention is not limited only to this illustration. The chelating agents can be used alone or in admixture of two or more.

When the compound represented by the formula (I) contained in the activity inhibitor is 1,8-cineol in which R ¹ , R ² and R ³ are methyl groups and R ⁴ is an oxygen atom, Such an activity inhibitor gives a refreshing feeling to human skin. Therefore, the activity inhibitor containing the 1,8-cineole can be used as a cooling agent in the external preparation of the present invention.

For example, when an external preparation containing a component that activates TRPA1 such as menthol as a cooling agent is further added to the activity inhibitor containing 1,8-cineole, an unpleasant stimulus based on the activation of TRPA1 Can be suppressed. Moreover, when the activity inhibitor containing the said 1, 8- cineol is mix | blended with an external preparation instead of the component which activates TRPA1 like a menthol as a refreshing agent, unpleasant irritation | stimulation based on activation of TRPA1 is carried out. Moreover, it can be suppressed and a refreshing feeling can be given to human skin. Therefore, in the external preparation of the present invention, the compound represented by the formula (I) contained in the activity inhibitor is a compound in which R ¹ , R ² and R ³ are methyl groups, and R ⁴ is an oxygen atom. , 8-cineole can be suitably used.

  The activity inhibitor containing 1,8-cineole contains the 1,8-cineole even when it is impregnated in a support used in a sheet cosmetic that is an external preparation of the present invention. The activity inhibitor can suppress unpleasant irritation based on the activation of TRPA1 even when it is incorporated into an adhesive plaster layer formed on a support used for a patch or the like.

  It is preferable that the support is made of a flexible material that adapts to unevenness and expansion / contraction of human skin. Examples of the support include woven fabric, non-woven fabric, and film, but the present invention is not limited to such illustration. The support is preferably stretchable because it can be easily applied to human skin or wiped on the skin. Examples of the material of the woven fabric and non-woven fabric include natural fibers such as cotton, jute manila hemp, wool, silk fiber, and feather fibers; regenerated fibers such as viscose rayon fibers; and half fibers such as acetate fibers, triacetate fibers, and promix fibers. Synthetic fibers; Synthetic fibers such as polyamide fibers, acrylic fibers, and polyester fibers can be mentioned, but the present invention is not limited to such examples. Examples of the material for the film include polyamide; polyester; acrylic resin; polyolefin such as polyethylene and polypropylene; and synthetic resin such as polyvinyl chloride. However, the present invention is not limited only to such examples. . The said support body can be suitably selected according to the use etc. of the said sheet cosmetics or a patch.

  The thickness of the support varies depending on the use of the sheet cosmetic or the patch, and therefore cannot be determined unconditionally. Therefore, the thickness of the support is appropriately set according to the use of the sheet cosmetic or the patch. It is preferable to do. Usually, the thickness of the support is preferably 0.1 to 2.5 mm, more preferably 0.5 to 2 mm, from the viewpoint of ensuring ease of use.

  As described above, according to the external preparation of the present invention, unpleasant irritation to human skin can be reduced.

  The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to the examples.

Example 1
In the formula (I), R ¹ , R ² and R ³ are methyl groups, and R ⁴ is an oxygen atom. 1,8-cineol is dissolved in a solvent A [composition: 140 mM at 25 ° C. so that its concentration becomes 5 mM. Sodium chloride, 5 mM potassium chloride, 2 mM magnesium chloride, 2 mM calcium chloride, 10 mM glucose, 10 mM Hepes hydrochloride buffer (pH 7.4)] to obtain an activity inhibitor.

  Menthol, an agonist of TRPA1, was dissolved in the obtained activity inhibitor at 25 ° C. so as to have a concentration of 1 mM to obtain a sample.

(Comparative Example 1)
Example 1 except that ruthenium red, which is an antagonist of TRPA1, was used in place of 1,8-cineole in Example 1, and was dissolved in solvent A at 25 ° C. so that the concentration of the ruthenium red was 10 μM. The same operation as in 1 was performed to obtain a sample.

(Comparative Example 2)
In Example 1, instead of 1,8-cineole, glycerin as a control having no relation to the activity of TRPA1 was used and dissolved in solvent A at 25 ° C. so that the concentration of the glycerin was 5 mM. A sample was obtained in the same manner as in Example 1 except for.

(Production Example 1)
A cDNA encoding human TRPA1 [polynucleotide at positions 63 to 3888 of the nucleotide sequence shown in SEQ ID NO: 1 (GenBank accession number: NM_007332)] is a vector for mammalian cells (trade name: pcDNA3, manufactured by Invitrogen). .1 (+)] to obtain a human TRPA1 expression vector. 1 μg of the obtained human TRPA1 expression vector was mixed with 6 μl of a gene introduction reagent [manufactured by Invitrogen, trade name: PLUS Reagent, catalog number: 11514-015] to obtain a mixture I. In addition, 4 μl of cationic lipid for gene introduction [manufactured by Invitrogen, trade name: Lipofectamine (registered trademark), catalog number: 18324-012] and medium for reducing serum use [trade name: OPTI-MEM (manufactured by Invitrogen), registered (Trademark) I Reduced-Serum Medium (Cat. No. 11058021) 200 μl was mixed to obtain a mixture II.

Further, 5 × 10 ⁵ cells of HEK293 cells were cultured in a DMEM medium containing 10% by mass FBS on a petri dish having a diameter of 35 mm maintained at 37 ° C. in a 5% by volume carbon dioxide atmosphere until 70% confluency. did.

  By adding the mixture I and the mixture II to the obtained cell culture, the human TRPA1 expression vector was introduced into HEK293 cells to obtain TRPA1-expressing cells.

(Test Example 1)
The TRPA1-expressing cells obtained in Production Example 1 were cultured at room temperature in a DMEM medium containing 10% by weight fetal calf serum containing FURA 2-AM (manufactured by Invitrogen), a reagent for measuring intracellular calcium ions, at a final concentration of 5 μM. By incubating for a minute, FURA 2-AM was introduced into the TRPA1-expressing cells to obtain FURA 2-AM-introduced TRPA1-expressing cells.

  The obtained FURA 2-AM-introduced TRPA1-expressing cells were placed in each chamber of a fluorescence measuring apparatus with a circulating constant temperature chamber [manufactured by Hamamatsu Photonics, Inc., trade name: ARGUS-50]. Thereafter, FURA 2-AM-introduced TRPA1-expressing cells in the chamber were mixed with solvent A [composition: 140 mM sodium chloride, 5 mM potassium chloride, 2 mM magnesium chloride, 2 mM calcium chloride, 10 mM glucose, 10 mM hepes hydrochloride buffer (pH 7.4)]. Washed with.

  Next, an agonist of TRPA1 was placed in the chamber containing the FURA 2-AM-introduced TRPA1-expressing cells after washing, and the FURA 2-AM-introduced TRPA1-expressing cells were mixed with the agonist. As the agonist, solvent A containing 1 mM menthol was used.

Thereafter, in the chamber, the fluorescence intensity based on FURA 2-AM introduced into the TRPA1-expressing cells at the excitation wavelength of 340 nm and bound to intracellular calcium ions (hereinafter referred to as “fluorescence intensity _{340 nm} ”) and TRPM1 at the excitation wavelength of 380 nm. The intensity of fluorescence based on FURA 2-AM introduced into the expression cells (hereinafter referred to as “fluorescence intensity _{380 nm} ”) was measured.

From the measured fluorescence intensity of _{340 nm} and fluorescence intensity of _{380 nm} , a Δfluorescence intensity ratio _agonist was calculated. The Δ fluorescence intensity ratio _sample has the formula (II):

Calculated based on The control is solvent A.

Further, instead of using the agonist alone, the agonist and a test sample (a sample obtained in Example 1, a sample obtained in Comparative Example 1, or a sample obtained in Comparative Example 2) were used in combination. Except for this, the fluorescence intensity _{340 nm} and the fluorescence intensity _{380 nm} were measured in the same manner as in the case of using the agonist.

From the measured fluorescence intensity of _{340 nm} and fluorescence intensity of _{380 nm} , a Δfluorescence intensity ratio _agonist was calculated. The Δ fluorescence intensity ratio _{agonist + test sample} is represented by the formula (III):

Calculated based on

From the calculated Δ fluorescence intensity ratio _agonist and Δ fluorescence intensity ratio _{agonist + test sample} , the inhibition rate for the activity of TRPA1 was calculated. In addition, the inhibition rate is represented by the formula (IV):

Inhibition rate (%) = (Δ fluorescence intensity ratio _agonist− Δ fluorescence intensity ratio _{agonist + test sample} ) / Δ fluorescence intensity ratio _agonist × 100 (IV)

Calculated according to

  In Test Example 1, the results of examining the relationship between the type of sample and the inhibition rate are shown in FIG. In the figure, 1 is the inhibition rate when using the sample obtained in Example 1, 2 is the inhibition rate when using the sample obtained in Comparative Example 1, and 3 is the sample obtained in Comparative Example 2. The suppression rate when used is shown.

  From the results shown in FIG. 1, it can be seen that the inhibition rate (1 in the figure) when using the sample obtained in Example 1 is about 40%. Since the inhibition rate (3 in the figure) when using the sample obtained in Comparative Example 2 containing glycerin as a control is 0% or less, it is included in the sample obtained in Example 1. It is suggested that 1,8-cineole acts as a blocker and suppresses the activity of TRPA1 expressed by the activation of TRPA1 caused by menthol. In addition, it can be seen that the inhibition rate (1 in the figure) for the activity of TRPA1 by 1,8-cineole is comparable to the inhibition rate (2 in the figure) for the activity of TRPA1 by a known antagonist of TRPA1.

From these results, it can be seen that 1,8-cineole in which R ¹ , R ² and R ³ are methyl groups and R ⁴ is an oxygen atom in the formula (I) suppresses the activity of TRPA1.

(Test Example 2)
In Test Example 1, instead of menthol, allyl isothiocyanate which is a known agonist for TRPA1 was used, and the same operation as in Test Example 1 was performed except that the concentration of allyl isothiocyanate was adjusted to 20 μM. The inhibition rate when using the sample obtained in Example 1 was calculated.

  In Test Example 2, the result of examining the relationship between the sample and the inhibition rate is shown in FIG. In the figure, 1 indicates the inhibition rate when the sample obtained in Example 1 was used.

  From the results shown in FIG. 2, it can be seen that the inhibition rate (1 in the figure) when using the sample obtained in Example 1 is about 25%. Therefore, it is suggested that 1,8-cineole contained in the sample obtained in Example 1 acts as a blocker and suppresses the activity of TRPA1 expressed by the activation of TRPA1 caused by allyl isothiocyanate.

(Example 2)
Among the compounds represented by the formula (I), a compound other than 1,8-cineole and menthol are dissolved in solvent A at 25 ° C. so that the concentration of the compound becomes 5 mM and the concentration of menthol becomes 1 mM. Obtain a sample.

(Test Example 3)
In Test Example 1, when the sample obtained in Example 2 was used instead of the sample obtained in Example 1, the same operation as in Test Example 1 was performed, and the sample obtained in Example 2 was used. Calculate the inhibition rate.

  As a result, the same result as that obtained when using the sample obtained in Example 1 is obtained.

  From the above results, the compound represented by the formula (I) suppresses the activity of TRPA1, suggesting that it is useful as an activity inhibitor of TRPA1. Further, the compound represented by the formula (I) is suitable for use in an external preparation, particularly an external preparation for sensitive skin, because it suppresses the activity of TRPA1 and suppresses unpleasant irritation based on the activity of TRPA1. It is suggested that there is.

(Example 3 and Comparative Example 3)
Menthol, ethanol and 1,8-cineole were dissolved in purified water at 25 ° C. so that the respective concentrations were 1% by volume, 10% by volume and 0.5% by volume to obtain a sample (Example 3). .

  On the other hand, a sample was obtained in the same manner as in Example 3 except that 1,8-cineole was not used (Comparative Example 3).

(Example 4 and Comparative Example 4)
Ethanol and 1,8-cineole were dissolved in purified water at 25 ° C. so that the respective concentrations were 50% by volume and 0.5% by volume to obtain a sample (Example 4).

  On the other hand, a sample was obtained in the same manner as in Example 4 except that 1,8-cineole was not used (Comparative Example 4).

(Example 5 and Comparative Example 5)
Ammonia, ethanol and 1,8-cineole were dissolved in purified water at 25 ° C. so that the respective concentrations were 1% by volume, 10% by volume and 0.5% by volume to obtain a sample (Example 5). .

  On the other hand, a sample was obtained in the same manner as in Example 5 except that 1,8-cineole was not used (Comparative Example 5).

(Test Example 4)
(1) Selection of Stinger 86 healthy male subjects whose face was washed around the lower periphery of the eyes were acclimated for 5 minutes in a test room at room temperature 25 ° C. and relative humidity 45-60%.

  Next, 750 μL of 0.2 vol% octanol aqueous solution was impregnated into a nonwoven fabric [manufactured by Sansho Paper Industry Co., Ltd., product number: KP9560, length 1 cm × width 3 cm] to obtain a test sheet.

  On the other hand, a control sheet was obtained in the same manner as described above except that 750 μL of a 10% by volume ethanol aqueous solution was used instead of the 0.2% by volume octanol aqueous solution.

The test sheet and the control sheet were pasted under the eyes of both eyes. _Stinging scores S _A2.5 , S _A5, and S _A8 are sequentially applied to the intensity of stimulation at 2.5 minutes, 5 minutes, and 8 minutes after application according to the following stimulus evaluation methods. I put on.

In addition, after completion of the evaluation of the intensity of stimulation after 10 minutes from the time of application, each of the test sheet and the control sheet was removed from under the eyes of both eyes. Then, after the elapse of a period of one week or more from the removal of each of the test sheet and the control sheet, each of the test sheet and the control sheet is pasted under the eyes of both eyes. _Stinging scores S _B2.5 , S _B5, and S _B8 were _assigned to the intensity of stimulation at the time of 2.5 minutes, 5 minutes, and 8 minutes, respectively.

For each subject, the maximum value S _A max is calculated from the _sting score S _{A2.5 to} S _A8 , and the maximum value S _B max is calculated from the _sting score S _{B2.5 to} S _B8 to determine the maximum value of each subject. The average value of S _A max and the maximum value S _B max was determined.

[Stimulation evaluation method]
Based on the following evaluation criteria, each subject evaluated the intensity of stimulation for each of the test sheet and the control sheet as time passed.

[Evaluation criteria]
0 point: I do not feel any stimulation.
1 point: I feel a faint stimulus.
2 points: I feel a stimulus with an intermediate strength between "subtle stimulus" and "clear stimulus".
3 points: I feel a clear stimulus.
4 points: I feel a stimulus with an intermediate strength between "clear stimulus" and "unbearable stimulus".
5 points: I feel unsatisfactory stimulation.

[Select Stinger]
Among the test subjects, a test subject having the average value of 3 or more for the test sheet and the average value of 1 or less for the control sheet was employed as a stinger.

(2) Sting test on the face In the above (1), the stinger selected in (1) was used as a subject, and the samples obtained in Examples 3 to 5 and Comparative Examples 3 to 5 were used. ) And the intensity of the stimulation was evaluated in the same manner. The results are shown in Table 1.

  From the results shown in Table 1, the average value of the sting score when menthol and ethanol and 1,8-cineole were used in combination (see Example 3) was determined using menthol and ethanol without using 1,8-cineole. It can be seen that it is smaller than the average value of the sting score when using (see Comparative Example 3). Moreover, the average value of the sting score when ethanol and 1,8-cineole were used in combination (see Example 4) was the average value of the sting score when ethanol was used without using 1,8-cineole. It can be seen that it is small compared to (see Comparative Example 4). Furthermore, the average value of the sting score when ammonia and ethanol are used in combination with 1,8-cineole (see Example 5) is sting when ammonia and ethanol are used without using 1,8-cineole. It can be seen that it is smaller than the average score (see Comparative Example 5). From these results, according to 1,8-cineole, it is suggested that menthol, ethanol or ammonia can suppress unpleasant stimuli caused by activating TRPA1. Therefore, since 1,8-cineole suppresses the activity of TRPA1 and suppresses unpleasant irritation based on the activity of TRPA1, it is suggested that it is suitable for use in an external preparation, particularly an external preparation for sensitive skin. Is done.

(Test Example 5)
In Test Example 4, the same procedure as in Test Example 4 was performed except that a compound other than 1,8-cineole among the compounds represented by formula (I) was used instead of 1,8-cineole. Was evaluated for strength. As a result, the same result as when 1,8-cineole is used is obtained.

  From the above results, it is suggested that the compound represented by the formula (I) can suppress unpleasant stimuli caused by activating menthol, ethanol or ammonia with TRPA1. Therefore, since the compound represented by the formula (I) suppresses the activity of TRPA1 and suppresses unpleasant irritation based on the activity of TRPA1, it is suitable for use in an external preparation, particularly an external preparation for sensitive skin. It is suggested that there is.

(Examples 6 to 10 and Comparative Examples 6 to 10)
Each component was mixed so that it might become a composition of Table 2, and the stock solution of the aerosol spray was prepared. The obtained stock solution and liquefied petroleum gas as propellant are filled into an aerosol container from the stem so that the stock solution / propellant (volume ratio) is 5/95, and an aerosol spray is attached with a button suitable for the stem. (Example 6 and Comparative Example 6) were obtained.

  Moreover, each component was mixed so that it might become a composition of Table 3, and lotion (Example 7 and Comparative Example 7) was prepared.

  Each component was mixed so that it might become a composition of Table 4, and the cleaning material (Example 8 and Comparative Example 8) was prepared.

  Each component was mixed so that it might become a composition of Table 5, and the washing | cleaning material (Example 9 and Comparative Example 9) was prepared.

  Each component was mixed so that it might become a composition of Table 6, and the patch (plaster) (Example 10 and Comparative Example 10) was prepared.

(Test Example 6)
Eight test subjects who had wiped the lower part of the ear of the neck with a wet towel and removed sebum stains and the like were allowed to stand still for about 10 minutes in a test room at room temperature of 23 to 27 ° C. and relative humidity of 45 to 60%.

[Stinging test of aerosol spray]
The following operation was performed without notifying the subject which of the stock solution obtained in Example 6 and the stock solution obtained in Comparative Example 6 was used.

A cylindrical body (length: 10 cm) having an inner diameter of 3 cm was placed between the spray portion of the aerosol container containing the stock solution and the propellant obtained in Example 6 and the skin of the left neck (under the ear). Next, the contents in the aerosol container were sprayed for 1 second toward the skin of the left neck (under the ear) located inside the cylinder. According to the following evaluation methods for stimuli, respectively, in order to the intensity of stimulation at the lapse of 1 minute, 3 minutes, 5 minutes, 7 minutes, 10 minutes, 13 minutes, 17 minutes and 20 minutes from the end of spraying, respectively. Sting scores S ₁ , S ₃ , S ₅ , S ₇ , S ₁₀ , S ₁₃ , S ₁₇ and S ₂₀ were assigned.

On the other hand, the fact that the stock solution obtained in Comparative Example 6 was used instead of the stock solution obtained in Example 6 and that the contents in the aerosol container were sprayed toward the right neck (under ear) skin. Except for the above, the same operation as described above was performed, and sting scores S ₁ , S ₃ , S ₅ , S ₇ , S ₁₀ , S ₁₃ , S ₁₇ and S ₂₀ were assigned.

[Stinging test for other external preparations]
1000 μL of each external preparation obtained in Examples 7 and 9 to 10 and Comparative Examples 7 and 9 to 10 μm on a non-woven fabric (Futamura Chemical Co., Ltd., trade name: TCF # 404WJ-M, length 3 cm × width 3 cm) A test sheet was obtained by impregnation.

  In addition, about each external preparation obtained in Example 8 and Comparative Example 8, first, it melt | dissolved in purified water so that the density | concentration of an external preparation might be 5 mass%, and obtained aqueous solution. The obtained aqueous solution (1000 μL) was impregnated into a non-woven fabric [trade name: TCF # 404WJ-M, length 3 cm × width 3 cm, manufactured by Futamura Chemical Co., Ltd.] to obtain a test sheet.

  Next, the following operation was performed for each type of external preparation without notifying the subject which of the test sheet obtained in the example and the test sheet obtained in the comparative example was used.

Each test sheet obtained in Examples 7 to 10 was attached to the left neck (under the ear). Stinging scores S ₁ , S _3, and S ₅ are given to the intensity of stimulation at the time of application for 1 minute, 3 minutes, and 5 minutes, respectively, according to the following stimulation evaluation method. It was.

After evaluation of the intensity of stimulation after 5 minutes from the time of application, the test sheet was removed from the left neck (under the ear). Subsequently, in accordance with the stimulation evaluation method described below, the stints were sequentially applied to the intensity of stimulation at the time of 7 minutes, 10 minutes, 13 minutes, 17 minutes, and 20 minutes after the test sheet was applied. Ging scores S ₇ , S ₁₀ , S ₁₃ , S ₁₇ and S ₂₀ were assigned.

Instead of the test sheets obtained in Examples 7 to 10, the test sheets obtained in Comparative Examples 7 to 10 were used, and the test sheets were attached to the right neck (under the ear). except that performs the same operation was with a stinging scores _{S 1, S 3, S 5} , S 7, S 10, S 13, S 17 and S _20.

[Totaling Sting Score]
For each external preparations obtained in Examples 6-10 and Comparative Examples 6-10, for each subject, and aggregate the maximum value Smax from stinging scores S ₁ to S _20, an average value of the maximum value Smax of each subject Asked.

[Stimulation evaluation method]
Based on the same evaluation criteria as in Test Example 4, each subject evaluated the strength of stimulation for the test sheet when each time passed. The results are also shown in Tables 2-6.

  From the results shown in Tables 2 to 6, the average value of the sting score of aerosol spray (Example 6) when menthol and 1,8-cineole were used in combination was not using 1,8-cineole, but menthol. It can be seen that it is smaller than the average value of the sting score of the aerosol spray (Comparative Example 6) when using. Moreover, the average value of the sting score of the skin lotion (Example 7) when 1,3-butylene glycol and ethanol were used in combination with 1,8-cineole was 1,3 without using 1,8-cineole. -It turns out that it is small compared with the average value of the sting score of the lotion (comparative example 7) when using butylene glycol and ethanol. Furthermore, the average value of the sting score of the cleaning material (Example 8) when 1,3-butylene glycol and potassium hydroxide and 1,8-cineole were used in combination was 1,8-cineole not used. It can be seen that it is smaller than the average value of the sting score of the cleaning material (Comparative Example 8) when 1,3-butylene glycol and potassium hydroxide are used. The average sting score of the cleaning material (Example 9) when 1,3-butylene glycol and 1,8-cineole were used in combination was 1,3-butylene without using 1,8-cineole. It can be seen that it is smaller than the average value of the sting score of the cleaning material (Comparative Example 9) when glycol is used. In addition, the average value of the sting score of the patch (Example 10) when menthol and 1,8-cineole were used in combination was the patch when menthol was used without using 1,8-cineole (comparison) It can be seen that it is smaller than the average value of the sting score in Example 10).

  These results suggest that according to 1,8-cineole, menthol, ethanol, 1,3-butylene glycol or potassium hydroxide can suppress unpleasant stimuli caused by activating TRPA1. The

  Therefore, since 1,8-cineole suppresses the activity of TRPA1 and suppresses unpleasant irritation based on the activity of TRPA1, it is suggested that it is suitable for use in an external preparation, particularly an external preparation for sensitive skin. Is done. In addition, since 1,8-cineole gives a refreshing feeling to the human skin after washing, 1,8-cineole is used as a component that suppresses unpleasant irritation and gives a refreshing feeling to the human skin. It is suggested that it is suitable for use in an agent, particularly an external preparation for sensitive skin.

(Example 11 and Comparative Example 11)
Each component was mixed so that it might become a composition of Table 7, and the 1st agent and 2nd agent of the hair decoloring agent were prepared.

(Test Example 7)
(1) Selection of Stinger A test subject sensitive to an alkaline agent was selected by the method described in Japanese Patent Application Laid-Open No. 2007-191212. Then, the 8 subjects who wiped the lower part of the ear of the neck with a wet towel and removed sebum stains were allowed to stand quietly for 5 minutes in a test room at a room temperature of 23 to 27 ° C. and a relative humidity of 45 to 60%.

  The hair bleaching agent 1st agent and 2nd agent which consist of a composition of Table 7 were mixed so that 1st agent / 2nd agent (mass ratio) might be 80/20, and the hair bleaching agent was prepared. .

Next, 1 g of the hair bleaching agent obtained in Example 11 was applied in an area of about 3 cm × 3 cm square near the skin segments C2 to C3 that deviated leftward from the midline of the subject's neck. In accordance with the following evaluation method of stimulation, the stiffness at the time of 1 minute, 3 minutes, 5 minutes, 7 minutes, 10 minutes, 13 minutes, 15 minutes and 20 minutes from the time of application, respectively, Ging scores S ₁ , S ₃ , S ₅ , S ₇ , S ₁₀ , S ₁₃ , S ₁₇ and S ₂₀ were assigned.

On the other hand, except that 1 g of the hair bleaching agent obtained in Comparative Example 11 was applied in an area of about 3 cm × 3 cm square near the skin segments C2 to C3 that deviated rightward from the midline of the subject's neck, The same operation as described above was performed, and sting scores S ₁ , S ₃ , S ₅ , S ₇ , S ₁₀ , S ₁₃ , S ₁₇ and S ₂₀ were assigned.

For each hair bleaching agent obtained in Example 11 and Comparative Example 11, the maximum value Smax was totaled from the sting scores S _{1 to} S ₂₀ for each subject, and the average value of the maximum values Smax of each subject was determined.

[Stimulation evaluation method]
Based on the same evaluation criteria as in Test Example 4, each subject evaluated the intensity of stimulation with respect to the hair bleaching agent as time passed. The results are also shown in Table 7.

  From the results shown in Table 7, the average sting score of the hair bleaching agent (Example 11) when ammonia, monoethanolamine, hydrogen peroxide, and 1,8-cineole were used together was 1,8. -It turns out that it is small compared with the average value of the sting score of the hair bleaching agent (Comparative Example 11) when ammonia, monoethanolamine and hydrogen peroxide are used without using cineole. From these results, according to 1,8-cineole, it is suggested that ammonia, monoethanolamine and hydrogen peroxide can suppress unpleasant stimuli caused by activating TRPA1. Therefore, since 1,8-cineole suppresses the activity of TRPA1 and suppresses unpleasant irritation based on the activity of TRPA1, it is suggested that it is suitable for use in an external preparation, particularly an external preparation for sensitive skin. Is done.

(Prescription example)
Hereinafter, the formulation example of the external preparation which concerns on this invention is shown. Note that “EO” in parentheses in the raw material name represents an oxyethylene group. The number described before “EO” indicates the number of added moles of oxyethylene group.
(Prescription example 1 lotion for sensitive skin)
The following raw materials were mixed so as to have the following composition to obtain a skin lotion for sensitive skin.
1,8-cineole 0.1% by mass
Polyoxyethylene hydrogenated castor oil (50 EO) 1.0 mass%
Glycerin 1.5% by mass
1,3-butylene glycol 15.0% by mass
Citric acid 0.05% by mass
Sodium citrate 0.1% by mass
1,2-octanediol 0.2% by mass
Purified water balance 100.0% by mass

(Formulation Example 2 Sensitive Skin Latex)
The following raw materials were mixed so as to have the following composition to obtain an emulsion for sensitive skin.
1,8-cineole 0.1% by mass
Liquid paraffin 15.0% by mass
Beeswax 2.0% by mass
Lanolin 1.5% by mass
Sorbitan sesquioleate 2.5% by mass
Polyoxyethylene sorbitan monooleate 1.0% by mass
1,2-octanediol 0.05% by mass
1,3-butylene glycol 13.0% by mass
Xanthan gum 0.5% by mass
Purified water balance 100.0% by mass

(Prescription example 3 cream for sensitive skin)
The following raw materials were mixed so as to have the following composition to obtain a cream for sensitive skin.
1,8-cineole 0.3% by mass
Stearyl alcohol 5.0 mass%
Stearic acid 2.0% by mass
Vaseline 5.0% by mass
Squalane 5.0% by mass
Glyceryl tri-2-ethylhexanoate 1.0% by mass
Jojoba oil 1.0% by mass
Olive oil 1.0% by mass
1.3-Butylene glycol 15.0% by mass
Propylene glycol monostearate ester 2.5% by mass
Polyoxyethylene cetyl ether (20E.O.) 3.0 mass%
Triethanolamine 1.0% by mass
1,2-hexanediol 0.15% by mass
1,2-octanediol 0.1% by mass
Purified water balance 100.0% by mass

(Prescription Example 4 Deodorant Gel)
The following raw materials were mixed so as to have the following composition to obtain a deodorant gel.
1,8-cineole 0.5% by mass
Menthol 0.5% by mass
Acrylic acid / alkyl methacrylate copolymer 0.2% by mass
Potassium hydroxide 0.02% by mass
Isononyl isononanoate 1.5% by mass
Triclosan 0.1% by mass
Ethanol 30.0% by mass
Perfume Appropriate amount of purified water, remaining total 100.0% by mass

(Prescription Example 5 Shaving Gel)
The following raw materials were mixed so as to have the following composition to obtain a shaving gel.
Carboxyvinyl polymer 0.6% by mass
Acrylic acid / alkyl methacrylate copolymer 0.1% by mass
Sodium hydroxide 0.25 mass%
Polyoxyethylene hydrogenated castor oil (50 EO) 0.5% by mass
Polyoxyethylene / methylpolysiloxane copolymer 3.0% by mass
Glycerin 3.0% by mass
Polyethylene glycol (PEG-32) 3.0% by mass
70% by weight sorbite solution 5.0% by weight
Acrylamide / acrylic acid / dimethyldiallylammonium chloride copolymer solution
0.1% by mass
Menthol 0.4% by mass
1,8-cineole 0.4% by mass
Ethanol 2.0% by mass
Methyl paraoxybenzoate appropriate amount edetate appropriate amount perfume appropriate amount purified water balance 100.0% by mass

(Formulation example 6 lotion)
The following raw materials were mixed so as to have the following composition to obtain a lotion.
1,8-cineole 0.3% by mass
1,3-butylene glycol 6.0% by mass
Glycerin 4.0% by mass
Hydrolyzed hyaluronic acid 0.1% by mass
Polyoxyethylene polyoxypropylene 2-decyltetradecyl ether
0.2% by mass
Phenoxyethanol 0.3% by mass
Perfume proper amount ethanol 3.0 mass%
Purified water balance 100.0% by mass

(Prescription Example 7 Deodorant Roll-on)
The following raw materials were mixed so as to have the following composition to obtain a deodorant roll-on.
1,8-cineole 0.3% by mass
Menthol 0.1% by mass
Triclosan 0.1% by mass
Chlorhydroxyaluminum 10.0% by mass
Isononyl isononanoate 1.0% by mass
Hydroxypropyl cellulose 1.0% by mass
Ethanol 60.0% by mass
Perfume Appropriate amount of purified water, remaining total 100.0% by mass

(Prescription Example 8 Wipe sheet cosmetic)
A sheet cosmetic for wiping was prepared by impregnating 1 g of a nonwoven fabric with 5 g of a composition having the following composition.
[Sheet composition for wiping off]
1,8-cineole 0.3% by mass
Menthol 0.1% by mass
Talc 10.0% by mass
Polyoxyethylene polyoxypropylene 2-decyltetradecyl ether
0.2% by mass
Ethanol 40.0% by mass
Perfume Appropriate amount of purified water The balance 100.0%

(Prescription Example 9 Skin Care Gel)
The following raw materials were mixed so as to have the following composition to obtain a skin care gel.
1,8-cineole 0.5% by mass
1,3-butylene glycol 10.0% by mass
Glycerin 3.0% by mass
Dipropylene glycol 5.0% by mass
Acrylic acid / alkyl methacrylate copolymer 0.4% by mass
Xanthan gum 0.01% by mass
Potassium hydroxide 0.15% by mass
Decamethylpolysiloxane 5.0% by mass
Trimethylglycine 10.0% by mass
1.2-pentanediol 0.1% by mass
Glycerin mono 2-ethylhexyl ether 0.05% by mass
Dipotassium glycyrrhizinate 0.1% by mass
Ethanol 3.0% by mass
Edetate disodium appropriate amount perfume appropriate amount purified water balance 100.0% by mass

(Formulation Example 10 Skin Care Cream)
The following raw materials were mixed so as to have the following composition to obtain a skin care cream.
Liquid paraffin 5.0% by mass
Paraffin 5.0% by mass
Hydrogenated palm oil 3.0% by mass
Behenyl alcohol 3.0% by mass
Stearic acid 1.0% by mass
Glyceryl tri-2-ethylhexanoate 5.0% by mass
Xanthan gum 0.05% by mass
Carboxyvinyl polymer 0.4% by mass
1.5% by mass of polyoxyethylene sorbitan monostearate
Glyceryl stearate 0.5% by mass
1,3-butylene glycol 10.0% by mass
1,2-octanediol 0.2% by mass
1,8-cineole 0.5% by mass
Glycerin mono-2-ethylhexyl ether 0.35% by mass
Glycerin 5.0% by mass
Potassium hydroxide Appropriate amount Tocopherol Appropriate amount Disodium edetate Appropriate perfume Appropriate amount Purified water Remaining Total 100.0% by mass

(Formulation Example 11 Body lotion)
The following raw materials were mixed so as to have the following composition to obtain a body lotion.
1,8-cineole 0.5% by mass
Menthol 0.5% by mass
1,3-butylene glycol 5.0% by mass
Nylon powder 5.0% by mass
Ethanol 50.0% by mass
Perfume Appropriate amount of purified water, remaining total 100.0% by mass

(Prescription Example 12 Tonic)
The following raw materials were mixed so as to have the following composition to make a tonic.
1,8-cineole 0.5% by mass
Menthol 0.5% by mass
D-pantothenyl alcohol 0.2% by mass
Nicotinamide 0.1% by mass
Dl-α-tocopherol acetate 0.1% by mass
Camphor 0.001% by mass
Polyoxyethylene hydrogenated castor oil (50 EO) 0.3% by mass
Sodium lactate 0.5% by mass
Citric acid 0.05% by mass
Ethanol 50.0% by mass
Perfume Appropriate amount of purified water, remaining total 100.0% by mass

(Prescription Example 13 Deodorant Spray)
Deodorant spray by filling the aerosol container from the stem with the stock solution consisting of the following composition and the propellant consisting of the following composition so that the mass ratio (stock solution / propellant) is 5/95 and attaching the appropriate button to the stem. It was.
(Composition of stock solution)
Talc 20.0% by mass
Silic anhydride 20.0% by mass
Chlorhydroxyaluminum 10.0% by mass
1,8-cineole 0.5% by mass
Menthol 1.5% by mass
Triclosan 0.1% by mass
Dimethylpolysiloxane 15.0% by mass
Perfume Appropriate amount Isopropyl myristate balance (propellant composition)
LPG 100.0% by mass

(Prescription Example 14 Deodorant Stick)
The following raw materials were mixed so as to have the following composition to obtain a deodorant stick.
Isopropyl methylphenol 0.2% by mass
Potassium aluminum sulfate 20.0% by mass
Chlorohydroxyaluminum 10.0% by mass
Stearyl alcohol 5.0 mass%
Glycerol monostearate 3.0% by mass
Silica anhydride 35.0% by mass
Candelilla wax 0.5% by mass
Castor oil 0.1% by mass
1,8-cineole 0.5% by mass
Citral 0.04% by mass
Eugenol 0.05% by mass
Decamethylcyclopentasiloxane balance 100.0% by mass

(Prescription Example 15 Lip)
The following raw materials were mixed so as to have the following composition to obtain a lip.
Isocetyl stearate 25.0% by mass
Paraffin 20.0% by mass
Trioctanoin 10.0% by mass
Ceresin 5.0% by mass
Microcrystalline wax 5.0% by mass
Vaseline 1.0% by mass
Citral 0.04% by mass
Eugenol 0.05% by mass
1,8-cineole 0.5% by mass
Liquid paraffin remainder Total 100.0% by mass

(Prescription Example 16 Cleansing Agent)
The following raw materials were mixed so as to have the following composition to obtain a cleansing agent.
Polyoxyethylene (capryl / capric acid) glyceryl
3.0% by mass
Polyoxyethylene coconut oil fatty acid glyceryl 2.0% by mass
N- [3-alkyl (12,14) oxy-2-hydroxypropyl]
-L-Arginine hydrochloride
0.2% by mass
1,3-butylene glycol 5.0% by mass
1,2-octanediol 0.1% by mass
1,8-cineole 0.3% by mass
Sodium dihydrogen phosphate Appropriate amount Disodium hydrogen phosphate Appropriate amount Tocopherol acetate Appropriate amount Phenoxyethanol Appropriate amount Purified water Remaining Total 100.0% by mass

(Prescription Example 17 Face Wash)
The following raw materials were mixed so as to have the following composition to obtain a face wash.
30% by mass Lauryldimethylaminoacetic acid betaine solution 3.0% by mass
Lauric acid 5.0% by mass
Myristic acid 6.0% by mass
Palmitic acid 4.0% by mass
Stearic acid 9.0% by mass
Polyethylene glycol distearate (150 EO)
5.0% by mass
10% by weight vinylpyrrolidone / dimethylaminopropylmethacrylamide / lauryldimethylaminopropylmethacrylamide chloride copolymer solution
10.0% by mass
Polyethylene glycol 20.0% by mass
Propylene glycol 3.0% by mass
Glycerin 5.0% by mass
1,2-octanediol 0.5% by mass
Hydroxypropyl methylcellulose 0.5% by mass
Potassium hydroxide 5.0% by mass
1,8-cineole 0.6% by mass
Edetate salt proper amount perfume appropriate amount purified water balance 100.0% by mass

(Prescription Example 18 Body Shampoo)
The following raw materials were mixed so as to have the following composition to obtain a body shampoo.
Lauric acid 5.0% by mass
Myristic acid 7.0% by mass
Propylene glycol 4.0% by mass
Lauryldimethylaminoacetic acid betaine 3.5% by mass
Potassium hydroxide 3.6% by mass
Sodium sulfite 0.03% by mass
Methyl paraoxybenzoate 0.3% by mass
Phenoxyethanol 0.8% by mass
1,8-cineole 0.5% by mass
Edetate salt proper amount perfume appropriate amount purified water balance 100.0% by mass

(Prescription Example 19 Shampoo)
The following raw materials were mixed so as to have the following composition to obtain shampoo.
Sodium polyoxyethylene lauryl ether sulfate 6.0% by mass
Lauryldimethylaminoacetic acid betaine 2.0% by mass
Polyoxyethylene lauryl ether sodium acetate 3.0% by mass
Disodium lauryl sulfosuccinate 1.0% by mass
Palm oil fatty acid diathanamide 5.0% by mass
O- [2-hydroxy-3- (trimethylammonio) propyl] chloride
Hydroxyethyl cellulose
0.2% by mass
Dipotassium glycyrrhizinate 0.2% by mass
Menthol 1.0% by mass
1,8-cineole 0.5% by mass
Ethanol 3.0% by mass
Sodium chloride Appropriate amount edetate salt Appropriate amount Sodium benzoate Appropriate perfume Appropriate amount Purified water Remaining Total 100.0% by mass

(Prescription Example 20 Hair Color)
The following raw materials were mixed so as to have the following composition to obtain a first and second agent for hair color. At the time of use, the 1st agent and the 2nd agent were mixed so that mass ratio (1st agent / 2nd agent) might be set to 80/20, and it was set as the hair color. In the following, the percentage of each component means the percentage of each component in the hair color (mixture of the first agent and the second agent).
[First agent]
Cetyl alcohol 5.0% by mass
Polyoxyethylene cetyl ether (20E.O.) 5.0 mass%
1,3-butylene glycol 3.0% by mass
Monoethanolamine 14.0% by mass
1,8-cineole 0.5% by mass
Paraaminophenol Appropriate amount Resorcinol Appropriate amount of purified water Remaining part 1st total 80.0% by mass
[Second agent]
35% by volume hydrogen peroxide 9.0% by mass
Purified water 11.0% by mass
Total 20.0% by weight of second agent
[Hair color]
Total 100.0 mass% of 1st agent and 2nd agent

(Prescription Example 21 Patch)
A plaster having the following composition was applied on a support to obtain a patch.
[Composition of plaster of patch]
Polyacrylic acid 5.0% by mass
Sodium polyacrylate 2.0% by mass
Glycerin 15.0% by mass
Polyoxyethylene hydrogenated castor oil 0.7% by mass
Methyl salicylate 0.2% by mass
Menthol 0.5% by mass
1,8-cineole 0.5% by mass
Purified water balance 100.0% by mass

Claims (3)

An activity inhibitor that suppresses the activity of TRPA1, comprising the formula (I):

(In the formula, R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a carboxyl group, an amino group or an aldehyde group, R ² and R ³ are each independently a hydrogen atom, a hydroxyl group, and 1 to 4 carbon atoms. Alkyl group, carboxyl group, amino group or aldehyde group, R ⁴ represents an oxygen atom or a sulfur atom)
A TRPA1 activity inhibitor comprising a compound represented by the formula: An activity suppression method for suppressing the activity of TRPA1, comprising the formula (I):

(In the formula, R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, a carboxyl group, an amino group or an aldehyde group, R ² and R ³ are each independently a hydrogen atom, a hydroxyl group, and 1 to 4 carbon atoms. Alkyl group, carboxyl group, amino group or aldehyde group, R ⁴ represents an oxygen atom or a sulfur atom)
A method for inhibiting the activity of TRPA1, which comprises contacting a compound represented by the formula with TRPA1.   An external preparation containing an ingredient for activating TRPA1 and comprising the TRPA1 activity inhibitor according to claim 1.