Topical skin components

Abstract

The objective is to provide a composition with enhanced histamine-independent anti-itch properties. Let's assume that. [Solution] (A) Contains camphor and (B) one or more antihistamines A topical composition is prepared. Such a topical composition is, in particular, in the form of a skin topical composition. Such topical compositions can also inhibit TRPA1 activity.

Description

Technical Field

[0001] The present invention relates to a topical skin composition containing camphor and an antihistamine agent.

Background Art

[0002] Skin diseases such as atopic dermatitis, senile pruritus, urticaria, eczema, and chafing, or the itching of the skin associated with dry skin, is very uncomfortable for patients and may interfere with daily life. When unable to bear such skin itching and scratching causes stimuli such as scratches to be added to the scratched area, the symptoms may further worsen, often leading to a vicious cycle of stronger itching. Therefore, in order to improve such diseases and conditions accompanied by itching, it is important to first

[0003] suppress itching. As antipruritic agents, there are those containing an antihistamine agent or those

[0004] containing a steroid, but they cannot cope with all itching, and the development of new antipruritic agents is desired. Regarding the mechanism of itching, TRPA1 (transient receptor potential ankyrin 1), one of the ion channels, has been studied as a channel related to pain in the past, but in recent years, it has been reported to be related to the transmission pathway of histamine-independent itching (Non-Patent

Prior Art Documents

[0005]

Non-Patent Document 1

[0006] The present invention aims to provide a topical skin composition that acts on histamine-independent itching. Let's assume that. [Means for solving the problem]

[0007] As a result of diligent research into the above issues, the present inventors have found that camphor can be used with an antihistamine. We discovered that the combined composition suppresses the activation of TRPA1, and thus the present invention It has now been completed.

[0008] In other words, the present invention provides the following skin external compositions or agents. Section 1. (A) Camphor and (B) One or more antihistamines are included in the topical composition. Section 2. Furthermore, prednisolone, prednisolone derivatives, allantoin, and allantoin derivatives Conductor, glycyrrhizic acid, glycyrrhetinic acid, glycyrrhizic acid or glycyrrhetinic acid The product contains one or more selected from the group consisting of derivatives and salts thereof, as specified in item 1. The external composition described. Section 3. The external application mixture described in item 1 or 2, wherein the water content is 85% by mass or less of the total amount of the composition. Finished product. Section 4. Furthermore, it contains one or more antioxidants, in addition to the products described in any one of items 1 to 3. Composition for use. Item 5. A skin coolant containing (A) camphor and (B) one or more antihistamines. Item 6. Furthermore, prednisone, a derivative of prednisone, allantoin, a derivative of allantoin, glycyrrhizic acid, glycyrrhetinic acid, a derivative of glycyrrhizic acid or glycyrrhetinic acid, and one or more selected from the group consisting of salts thereof, the skin coolant according to Item 5. Furthermore, the present invention relates to the following method. Item 7. A method for imparting a cooling effect on the skin to a topical composition by co-existing (B) one or more antihistamines to a topical composition containing (A) camphor.

[0009] Item 8. A method for imparting an itch-suppressing effect independent of histamine by co-existing (B) one or more antihistamines to a topical composition containing (A) camphor. Item 9. A method for imparting an inhibitory effect on the activity of TRPA1 (transient receptor potential ankyrin 1) by co-existing (B) one or more antihistamines to a topical composition containing (A) camphor. Item 10. Furthermore, at least one selected from the group consisting of prednisone, a derivative of prednisone, allantoin, a derivative of allantoin, glycyrrhizic acid, glycyrrhetinic acid, a derivative of glycyrrhizic acid or glycyrrhetinic acid, and salts thereof is co-existing, the method according to any one of Items 7 to 9. <The effects of the invention>

[0010] ​​​​​​​​​​The present invention makes it possible to provide a composition that can suppress the activity of TRPA1. This is the result. [Modes for carrying out the invention]

[0011] [Skin external composition] The topical skin composition of the present invention contains (A) camphor and (B) an antihistamine. .

[0012] ((A) Camphor) The camphor used in this invention is the camphor used in pharmaceuticals or quasi-drugs. Therefore, it is not particularly limited. Both natural and synthetic products can be used, including d-isomers and l-isomers. Either the dl-isomer or the camphor is acceptable. Use an essential oil containing camphor as the camphor. It is also possible. Examples of such essential oils include camphor oil. In particular, dl-camphor, d-camphor, and camphor oil are preferred.

[0013] In the present invention, the content of component (A) relative to the total amount of the composition is in balance with the other components. The appropriate amount is set by the following. The amount of component (A) relative to the total amount of the composition is preferably , 0.001% by mass or more, more preferably 0.01% by mass or more, even more preferably 0 The content of component (A) is preferably 0.1% by mass or more. It is less than or equal to mass%, more preferably 5% by mass or less, and even more preferably 3% by mass or less. The concentration is below, and is particularly preferably 1.5% by mass or less. Furthermore, essential oils containing camphor are used. If present, the amount of camphor in the blended essential oils will be set to fall within the above range. ru.

[0014] ((B) Antihistamines) The antihistamine used in the present invention is used in pharmaceuticals or quasi-drugs. It is not particularly limited as long as it is something that can be used. Commercially available products can also be used.

[0015] Examples of antihistamines include diphenhydramine, bromodifenhydramine, and clemas. Chlorphenoxamine, diphenylpyraline, doxylamine, orphenadrine, Ethanolamine-based antihistamines such as phenyltroxamine, chlorpheniramine , dimethindene, propylamine-based antihistamines such as tarastine, mepyramine, me Ethylenediamine antihistamines such as tapirylene and triperenamine, and alimethazine Hydroxyethyl promethazine, isotipendyl, mequitazine, oxomemazine, pro Phethiazine antihistamines such as metazine, buclidine, cetirizine, homochlorochlorothin Lucyclizine, Cyclizine, Hydroxyzine, Levocetirizine, Meclizine, Oxatom Piperazine-based antihistamines such as ketotifen, olopatadine, and fexofenacin Zin, loratadine, terfenadine, antazoline, azatadine, vamipine, cyprohep Tagine, Deptropin, Ebastine, Emedastine, Epinastine, Mebhydrorin, Mi Zolastine, pimethixen, pyrobutamine, quifenadine, rupatadine, triprolidine , acrivastine, astemizole, azelastine, bilastine, desloratadine, and These salts are examples. Among these, ethanolamine-based, propylamine-based, and ethanolamine-based salts are examples. Amine-based antihistamines such as ethylenediamines are preferred, and ethanolamine-based or p Lopyramine-based antihistamines are more preferred.

[0016] Here, the salt can be any pharmaceutically or physiologically acceptable salt, including inorganic and organic salts. Examples include the following. Inorganic salts include hydrochloride, hydrobromide, nitrate, sulfate, and phosphate. Examples include acetate, trifluoroacetate, butyrate, and palmitate. Salts, monocarboxylates such as stearate, fumarates, maleates, succinates Polycarboxylic acid salts such as salts, malonates, lactates, tartrates, and citrates Luvonate, methanesulfonate, toluenesulfonate, tosylate, napadisylate Examples include organic sulfonates.

[0017] Specifically, diphenhydramine hydrochloride, bromodifenhydramine hydrochloride, clemas Tin maleate, chlorphenoxamine hydrochloride, diphenylpyraline hydrochloride, Doxylamine Min succinate, orphenadrine hydrochloride, chlorpheniramine maleate, dimethine Denmaleate, Metapyrylene hydrochloride, Triperenamine hydrochloride, Alimemazine tartrate Isotipendyl hydrochloride, cetirizine hydrochloride, homochlorcyclizine hydrochloride, cyclizine Hydrochloride, hydroxyzine hydrochloride, levocetirizine hydrochloride, meclizine hydrochloride, ketotifen Fumarate, olopatadine hydrochloride, fexofenadine hydrochloride, antazoline hydrochloride, Azatadine maleate, cyproheptadine hydrochloride, deptropin cetone, emedas Tin fumarate, epinastine hydrochloride, mebhydrolin napadisylate, pimethixenma Leate, pyrobutamine phosphate, quifenadine hydrochloride, rupatadine fumarate, tri Examples include prolysine hydrochloride and azelastine hydrochloride.

[0018] While not limited to these, antihistamines include diphenhydramine or its salts, or Chlorpheniramine or a salt thereof is particularly preferred.

[0019] Antihistamines can be used individually or in combination of two or more types.

[0020] In the present invention, the content of component (B) relative to the total amount of the composition is in balance with the other components. The appropriate amount is set by the following. The amount of component (B) relative to the total amount of the composition is preferably 0.1% by mass or more, more preferably 0.2% by mass or more, even more preferably 0.5% by mass The amount is % or more. The content of component (B) relative to the total amount of the composition is preferably 3% by mass. The following, more preferably 2% by mass or less, even more preferably 1.5% by mass or less, and further More preferably, the content is 1.1% by mass or less. The amount is preferably 0.1 to 3% by mass, more preferably 0.2 to 2.5% by mass or less. More preferably, it is 0.5 to 2% by mass.

[0021] The content of diphenhydramine or its salt relative to the total amount of the composition may be 1% by mass. The content of chlorpheniramine or its salt relative to the total amount of the composition may be 0.5% by mass. good.

[0022] In the present invention, the ratio of the content of component (B) to component (A) enhances the effects of the present invention. From this perspective, the content of component (B) is 0.01 to 300 parts by mass of component (A). It is 0 parts by mass, preferably 0.02 to 1000 parts by mass, more preferably 0.04 to 200 parts by mass, more preferably 0.1 to 100 parts by mass, and especially preferably 0.3 to 5 parts by mass The amount is 0 parts by mass, most preferably 1 to 15 parts by mass.

[0023] In the present invention, the ratio of the content of diphenhydramine or its salt to component (A) is From the viewpoint of enhancing the effects of the present invention, the content of component (B) is such that the amount of component (B) is equal to 1 part by mass of component (A). The amount is 0.01 to 3000 parts by mass, preferably 0.02 to 1000 parts by mass, more preferably More preferably 0.04 to 200 parts by mass, more preferably 0.1 to 100 parts by mass, particularly preferred More preferably, it is 0.3 to 50 parts by mass, most preferably 1 to 15 parts by mass.

[0024] In the present invention, the ratio of the content of chlorpheniramine or its salt to component (A) is From the viewpoint of enhancing the effects of the present invention, the content of component (B) is such that the amount of component (B) is equal to 1 part by mass of component (A). The amount is 0.01 to 3000 parts by mass, preferably 0.02 to 1000 parts by mass, more preferably More preferably 0.04 to 200 parts by mass, more preferably 0.1 to 100 parts by mass, particularly preferred More preferably, it is 0.3 to 50 parts by mass, most preferably 1 to 10 parts by mass.

[0025] (water) The composition of the present invention may be a liquid composition containing water, but may also be a composition that does not contain water. It is also acceptable. The amount of water to be added is not limited, but preferably relative to the total amount of the composition. The amount is 85% by mass or less. More preferably, 20 to 70% by mass, even more preferably, It is 35-65% by mass. If the composition is in the form of a cream, the amount relative to the total amount of the composition is It is also possible to set it to 50-85% by mass. If the dosage form of the composition is an ointment, the formulation The water content is preferably 10% by mass or less, and more preferably, based on the total amount of the composition. The amount is 5% by mass or less, more preferably 1% by mass or less, and particularly preferably 0.1% by mass or less. It is below.

[0026] (ethanol) The composition of the present invention preferably has an ethanol concentration of 10% by mass or less of the composition. It is more preferable that the amount is 5% by mass or less. The composition of the present invention is a composition containing ethanol. It may be a composition that contains substantially no ethanol or none at all. Here, "effectively not included" means 0.1% by mass or less.

[0027] (Other ingredients) The pharmaceutical composition of the present invention further contains, in addition to the above components (A) and (B), prednisolone Lon, prednisolone derivatives, allantoin, allantoin derivatives, glycyrrhizin Acids, glycyrrhetinic acid, glycyrrhizic acid or derivatives of glycyrrhetinic acid, and their It may contain one or more types selected from the group consisting of salts.

[0028] Prednisolone, prednisolone derivatives, or salts thereof are used in pharmaceuticals or quasi-drugs. The prednisolone derivative is preferably one used in the context of [the application of the prednisolone derivative]. It is a derivative esterified with an organic acid, more preferably valeric acid, acetic acid, butyric acid, and p A derivative esterified with lopionic acid and / or furanic acid, and more preferably a derivative esterified with lopionic acid and / or furanic acid. These are derivatives esterified with valeric acid, acetic acid, butyric acid, and / or propionic acid. The tellated derivative is any esterified derivative such as monoester, diester, or triester. It is common to have it, for example, prednisolone valerate acetate (prednisolone valerate acetate). It may also be a derivative esterified with two or more organic acids, such as zolon. Particularly preferred is prednisolone valerate acetate (prednisolone valerate acetate). (Also known as Zolon)

[0029] The content of prednisolone, prednisolone derivatives, or salts thereof relative to the total amount of the composition is The amount is set appropriately based on the balance with other components, etc. Preferably, relative to the total amount of the composition. 0.05% by mass or more, more preferably 0.1% by mass or more, even more preferably 0.1 The content of component (B) is 5% by mass or more. The content of component (B) relative to the total amount of the composition is preferably 0. It is 5% by mass or less, more preferably 0.25% by mass or less, and even more preferably 0.1% by mass. It is 5% by mass or less. Preferably, it is 0.05 to 0.5% by mass of the total amount of the composition. Preferably, the amount is 0.1 to 0.25% by mass. Prednisolone or prednisolone derivative. The body content may be, for example, 0.1% by mass, 0.15% by mass, or 0.25% by mass.

[0030] In the present invention, prednisolone, a prednisolone derivative, or the same for component (A). From the viewpoint of enhancing the effects of the present invention, the ratio of the salt content is as follows: (A) 1 part by mass The amount is 0.007 to 500 parts by mass, preferably 0.02 to 100 parts by mass, and more preferably 0.02 to 100 parts by mass. The amount is 0.05 to 50 parts by mass, more preferably 0.08 to 25 parts by mass, and particularly preferably The amount is 0.1 to 10 parts by mass, most preferably 0.1 to 1.5 parts by mass.

[0031] Allantoin or allantoin derivatives are used in pharmaceuticals or quasi-drugs. It is not particularly limited as long as it is possible.

[0032] The content of allantoin or allantoin derivatives relative to the total amount of the composition is determined by the other components. The amount is set appropriately depending on the balance of the elements. Preferably, it is 0.0 by mass relative to the total amount of the composition. 1% or more, more preferably 0.1% or more by mass, even more preferably 0.2% or more by mass Yes. The content of component (B) relative to the total amount of the composition is preferably 3% by mass or less. More preferably, the amount is 1% by mass or less, and even more preferably, 0.5% by mass or less. The amount may be 0.2% by mass or 0.5% by mass relative to the total amount.

[0033] In the present invention, the content of allantoin or an allantoin derivative relative to component (A) The ratio is such that, from the viewpoint of enhancing the effects of the present invention, it is 0.002 to 1 part by mass of component (A). The amount is 3000 parts by mass, preferably 0.01 to 1000 parts by mass, more preferably 0. 0.3 to 100 parts by mass, more preferably 0.05 to 50 parts by mass, particularly preferably 0. The amount is 1 to 25 parts by mass, most preferably 0.13 to 5 parts by mass.

[0034] Glycyrrhizic acid, derivatives of glycyrrhizic acid, or salts thereof are used as pharmaceuticals or medicines. It is not particularly limited as long as it is used in non-drug products. Examples include dipotassium glycyrrhizinate and monoammonium glycyrrhizinate. It is possible.

[0035] The total amount of glycyrrhizic acid, a derivative of glycyrrhizic acid, or a salt thereof in the composition The amount is set appropriately based on the balance with other components, etc. Preferably relative to the total amount of the composition. More preferably 0.1% by mass or more, more preferably 0.2% by mass or more, even more preferably, The amount is 0.3% or more. Glycyrrhizic acid and glycyrrhizic acid derivative relative to the total amount of the composition The content of the conductor or its salt is preferably 1% by mass or less, and more preferably 0% by mass. The amount is 7% by mass or less, more preferably 0.5% by mass or less. The content of licyrrhizic acid, a derivative of glycyrrhizic acid, or a salt thereof is preferably 0. The amount is 1 to 1% by mass, more preferably 0.2 to 0.5% by mass. Glycyrrhizic acid or so The salt content may be 0.2% by mass or 0.5% by mass.

[0036] In the present invention, glycyrrhizic acid, a derivative of glycyrrhizic acid, and component (A) Alternatively, the ratio of the salt content is such that, from the viewpoint of enhancing the effects of the present invention, (A) 1 part by mass = The amount is 0.01 to 1000 parts by mass, preferably 0.04 to 100 parts by mass, more preferably More preferably 0.06 to 70 parts by mass, more preferably 0.1 to 50 parts by mass, and especially preferably The amount is 0.2 to 10 parts by mass, most preferably 1 to 5 parts by mass.

[0037] Glycyrrhetinic acid, glycyrrhetinic acid derivatives, or salts thereof are used as pharmaceuticals or drugs. It is not particularly limited as long as it is used in quasi-drugs. Glycyrrhetinic acid derivatives and Examples include stearyl glycyrrhetinate.

[0038] The total amount of glycyrrhetinic acid, a derivative of glycyrrhetinic acid, or a salt thereof in the composition The amount is set appropriately based on the balance with other components, etc. Preferably relative to the total amount of the composition. Or, 0.1% by mass or more, more preferably 0.2% by mass or more, even more preferably 0 It is 0.3% by mass or more. The amount of a glycyrrhetinic acid derivative or salt thereof relative to the total amount of the composition The content is preferably 1% by mass or less, more preferably 0.7% by mass or less, and Preferably, the amount is 0.5% by mass or less. The amount of glycyrrhetinic acid, and glycyrrhetinic acid relative to the total amount of the composition. The content of lycyrrhetinic acid derivatives or salts thereof is preferably 0.1 to 1% by mass. Preferably, it is 0.2 to 0.5% by mass. Glycyrrhetinic acid, derivative of glycyrrhetinic acid The content of the substance or its salt may be as low as 0.5% by mass.

[0039] In the present invention, glycyrrhetinic acid, a derivative of glycyrrhetinic acid, and component (A) Alternatively, the ratio of the salt content is such that, from the viewpoint of enhancing the effects of the present invention, (A) 1 part by mass = The amount is 0.01 to 1000 parts by mass, preferably 0.04 to 100 parts by mass, more preferably More preferably 0.06 to 70 parts by mass, more preferably 0.1 to 50 parts by mass, and especially preferably The amount is 0.2 to 10 parts by mass, most preferably 1 to 8 parts by mass.

[0040] The pharmaceutical composition of the present invention further contains, in addition to the above components (A) and (B), an antioxidant. It may contain. Antioxidants are not limited to those used in pharmaceuticals or quasi-drugs. It is not determined. Examples of antioxidants include citric acid hydrate, anhydrous citric acid, sulfites, and pi. Sulfite, phosphoric acid, sorbate, erythorbate, succinic acid, tranexamic acid, Water-soluble substances such as ujic acid, edetic acid, ascorbic acid, ascorbic acid derivatives, and L-cysteine. Antioxidants, soy lecithin, tocopherol, tocopherol derivatives, or salts thereof; Butylhydroxytoluene (hereinafter abbreviated as BHT), butylhydroxyanisole, ben Examples of lipid-soluble antioxidants include zotriazole, propyl gallate, and tocotrienol. Lipid-soluble antioxidants are particularly preferred.

[0041] Dibutylhydroxytoluene, tocopherol, or their salts are particularly preferred as antioxidants. It seems so.

[0042] The amount of antioxidants in the total composition is set appropriately based on the balance with other components. Preferably, 0.01% by mass or more, more preferably 0% of the total amount of the composition. 0.05% by mass or more, more preferably 0.1% by mass or more, relative to the total amount of the composition. The antioxidant content is preferably 2% by mass or less, and more preferably 1% by mass or less. The amounts are as follows. The amounts may also be 0.05% by mass, 0.1% by mass, or 1% by mass relative to the total amount of the composition.

[0043] For example, if dibutylhydroxytoluene is included as an antioxidant, The amount is preferably 0.05 to 0.1% by mass. As an antioxidant, tocopherol or If it contains a salt of that salt, in particular tocopherol acetate, the content thereof is preferable. The mass percentage is between 0.1 and 1%.

[0044] In the present invention, the ratio of the antioxidant content to component (A) enhances the effects of the present invention. From this viewpoint, (A) is preferably 0.001 to 2000 parts by mass per 1 part by mass of component More preferably, 0.01 to 1000 parts by mass, more preferably 0.015 to 100 parts by mass, and further Preferably 0.03 to 50 parts by mass, particularly preferably 0.05 to 25 parts by mass, most preferably More specifically, it is 0.1 to 15 parts by mass.

[0045] In addition to the above components (A) and (B), the pharmaceutical composition of the present invention further contains various active ingredients. One or more components can be used in combination. Preferably, an antihistamine It is also possible to combine antipruritic agents other than antacids, antibacterial / antiseptic ingredients, local anesthetics, etc.

[0046] Examples of antipruritic agents other than antihistamines include crotamiton.

[0047] Examples of antibacterial and antiseptic ingredients include benzalkonium chloride, acrinol, and benzyl chloride. Thonium, cetyltrimethylammonium chloride, cresol, povidone-iodine, iodide Iodine, isopropylmethylphenol, parabens, phenoxyethanol, salt Cetylpyridinium, miconazole or its salts, chlorobutanol or plants (for example) (These are derived from aloe, sophora, rosemary, mulberry, eucalyptus, cinchona, clove, etc.) Ingredients and other components are listed.

[0048] Examples of local anesthetics include lidocaine, dibucaine, and ethyl aminobenzoate. .

[0049] (Base, carrier, additives, etc.) The composition of the present invention, from the viewpoint of improving usability, stability, etc., is provided that it does not hinder the effects of the present invention. Even if the product contains a base, carrier, or additive in addition to the above components (A) and (B), good.

[0050] Examples of bases, carriers, or additives include surfactants, higher fatty acids, and higher alcohols. Oils, hydrocarbons, fats and oils, waxes, ester oils, silicone oils, moisturizing ingredients, polyhydric alcohols Examples include thickeners, cooling agents, preservatives or antimicrobials, pH adjusters, chelating agents, etc. These ingredients can be used individually or in any combination of two or more.

[0051] Surfactants can contribute to the stabilization of components. Examples of surfactants include nonionic surfactants. Any of the following may be used: surfactant, cationic surfactant, anionic surfactant, amphoteric surfactant, etc. .

[0052] Here, an anionic surfactant is, for example, fatty acid soap (for example, lauric acid). Sodium palmitate, sodium palmitate, potassium laurate, potassium myristate, Potassium palmitate, potassium stearate, etc.; alkyl sulfate salts (for example, Sodium lauryl sulfate, potassium lauryl sulfate, etc.; alkyl ether sulfate salts (For example, POE-lauryl sulfate triethanolamine, POE-lauryl sulfate sodium (e.g., sodium laureth sulfate); N-acyl sarcosinate (e.g., lauroyl sarcosinate) Synthodium, etc.); higher fatty acid amide sulfonates (e.g., N-myristoyl-N- Sodium methyl taurate, sodium methyl taurate (coconut oil fatty acid), lauryl methyl taurate Sodium urinate, etc.); phosphate ester salt (POE-oleyl ether sodium phosphate) POE-stearyl ether phosphate, sodium lauryl phosphate, polyoxyethylene Sodium lauryl ether phosphate, etc.); sulfosuccinates (e.g., alkyl sulfosuccinates) Sodium succinate, sodium di-2-ethylhexyl sulfosuccinate, polio Sodium xyethylene sulfosuccinate, lauryl polypropylene glycol sulfosuccinate Sodium citrate, etc.; alkylbenzene sulfonates (e.g., linear dodecylbenzene); Sodium sulfonate, linear dodecylbenzenesulfonate triethanolamine, lin Addecylbenzenesulfonic acid, etc.; amino acid-based surfactants (e.g., cocoyl glutamate) Sodium phosphate, N-acyl glutamate, etc.); N-acyl glutamate (for example, Potassium lauroyl glutamate, monosodium N-lauroyl glutamate, N- Disodium thearoyl glutamate, monosodium N-myristoyl-L-glutamate (e.g., um); higher fatty acid ester sulfate salts (e.g., hydrogenated coconut oil fatty acid glycerin sulfate) Sodium phosphate, etc.); sulfurized oil (e.g., funnel oil, etc.); ether carboxylate (e.g., polyphosphate). Polyoxyethylene alkyl ether carboxylic acid, polyoxyethylene alkyl allyl ether telcarboxylate salts, sodium polyoxyethylene lauryl ether acetate, etc.; α-ole Fin sulfonates; higher fatty acid ester sulfonates; secondary alcohol sulfates ;Higher fatty acid alkylolamide sulfate salt;Lauroyl monoethanolamide sugar Sodium citrate; N-palmitoyl aspartate ditriethanolamine; casein Examples include thorium.

[0053] Examples of nonionic surfactants include sorbitan fatty acid esters (e.g., sorbitan fatty acid esters). Sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate , sorbitan monostearate, diglycerol penta-2-ethylhexyl sorbita (e.g., diglycerol sorbitan tetra-2-ethylhexylate); propylene glycol) Fatty acid esters (e.g., propylene glycol monostearate); hydrogenated castor oil Oil derivatives (e.g., polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxy Ethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (H CO-60), polyoxyethylene hydrogenated castor oil 80, etc.; polyoxyethylene sorbita Fatty acid esters (for example, polyoxyethylene (20) sorbitan monolaurate) Polysorbate 20), Polyoxyethylene (20) Sorbitan Monostearate (Poly Sorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate (80%), polyoxyethylene (20) sorbitan isostearate, etc.; glycerin Derivatives (e.g., polyoxyethylene monococonut oil fatty acid glyceryl, glycerin alkyl) Ethers); polyoxyalkylene alkyl ethers (e.g., polyoxyethylene ethers) Ethers, etc.; silicone-based surfactants (e.g., polyoxyethylene methylpolysaccharide) Roxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, PEG Examples include polydimethylsiloxyethyl dimethicone, alkyl glucoside, etc. .

[0054] Examples of higher fatty acids include saturated or unsaturated straight-chain or branched-chain fatty acids with 12 to 2 carbon atoms. Two fatty acids can be used, for example, preferably lauric acid, myristic acid, and palladium. Linear saturated fatty acids such as mitic acid, stearic acid, or behenic acid (solid at room temperature); oleic acid Acids, linoleic acid, linolenic acid, palmitoleic acid, eicosapentaenoic acid, paxenic acid or is an unsaturated fatty acid such as docosahexaenoic acid (liquid at room temperature); or isostearic acid or Examples include branched fatty acids such as lanolin fatty acids, or 12-hydroxystearic acid. .

[0055] Examples of higher alcohols include higher alcohols with 12 to 22 carbon atoms and sterols. Examples include lauryl alcohol, myristyl alcohol, and cetanol. Cetostearyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol Alcohol, and other straight-chain saturated alcohols (solid at room temperature); oleyl alcohol, ceracyl alcohol Unsaturated alcohols such as ethanol (liquid at room temperature); or hexyldecanol, isosyl Tearyl alcohol, octyldodecanol, decyltetradecanol, lanolin alcohol Examples include [mention specific examples].

[0056] Examples of hydrocarbons include petrolatum, paraffin, ceresin, isoparaffin, and Cord fat, microcrystalline wax, polybutene, polyethylene powder, liquid parabens Fins, squalane, gelling hydrocarbons (such as Plastibase), ozokerite, α-ole Examples include fin oligomers, light liquid paraffins, and hydrocarbons such as light liquid paraffins. It is possible.

[0057] Oils and fats include avocado oil, linseed oil, camellia oil, macadamia nut oil, and corn oil. Oils: oat oil, olive oil, safflower oil, apricot kernel oil, jojoba oil, grape seed oil, sunflower oil Almond oil, camellia oil, rapeseed oil, sesame oil, castor oil, cocoa butter, coconut oil, hydrogenated oil Japanese oak oil, palm oil, palm kernel oil, Japanese wax kernel oil, Japanese wax, wheat germ oil, rice germ oil, rice bran Oils, cottonseed oil, soybean oil, peanut oil, tea seed oil, evening primrose oil, kukui nut oil, hazelnut oil Examples include oils and fats such as shea butter, orange oil, and chamomile oil.

[0058] Examples of waxes include candelilla wax, rice bran wax, cotton wax, carnauba wax, and lanoli wax. Lanolin fatty acid isopropyl, POE lanolin alcohol ether, POE lanolin Alcohol acetate, lanolin fatty acid polyethylene glycol, POE hydrogenated lanolin Examples include alcohol ethers, shellac wax, and waxes such as beeswax.

[0059] Examples of ester oils include isopropyl myristate, butyl myristate, and myristic acid. Decyl, myristyl myristate, cetyl myristate, isopropyl palmitate, Cetyl lumitate, ethyl stearate, butyl stearate, stearyl stearate Isocetyl stearate, hexyl laurate, ethyl oleate, ethyl linoleate Isopropyl linoleate, cetyl caprylate, decyl oleate, oleyl oleate Isodecyl oleate, cetyl octanoate, 2-octyldodecyl myristate, dimethyl 2-Octyldodecyl Dimethyloctanoate, Hexyldecyl Dimethyloctanoate, Myristic 2-Hexyldecyl Acid, 2-Hexyldecyl Palmitate, Diisopropyl Adipate, 2-hexyldecyl adipic acid, diethyl sebacate, diisopropyl sebacate, iso Isocetyl stearate, isostearyl isostearate, isononyl isononanoate, Isotridecyl isononanoate, cholesteryl 12-hydroxystearylate, stearin Cholesteryl acid, cholesteryl oleate, macadamia nut fatty acid phytosteryl, o Phytosteryl leate, inulin stearate, ethylene di-2-ethylhexyl ester Recall, cetyl 2-ethylhexanoate, N-alkyl glycol monoisostearate Neopentyl glycol dicaprate, glyceryl di-2-heptylundecanoate, Tri-2-ethylhexyl rimellitate, Tri-tridecyl trimellitate, Tri-2-ethylhexyl Trimethylolpropane xylate, trimethylolpropane triisostearate, tetra Pentaerythritol 2-ethylhexanoate, glyceryl tri-2-ethylhexanoate N, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, Glyceryl trimyristate, Caprylic / Capric Triglyceride, Caprylic / Capric Triglyceride Glyceryl glycerate (lylic acid / capric acid / myristic acid / stearic acid), medium-chain triglyceride Lido, castor oil fatty acid methyl ester, lauroyl glutamate di(phytosteryl / o Octyldodecyl, Lauroyl Glutamate Di(Octyldodecyl / Phytosteryl / B) Henyl, cetyl lactate, myristyl lactate, bis-cyclohexane-1,4-dicarboxylic acid Toxydiglycol, lanolin acetate, ethyl acetate, butyl acetate, amyl acetate, citrate Diethyl dimer dilinoleate (phytosteryl / isostearyl / cetyl / stearyl) (L / Behenyl), Dimer Dilinoleyl Dimer Dilinoleate, Tripolyhydroxyste Dipentaerythrityl alloate, tri(behenic acid / isostearate / eicosanedioic acid) Examples include glyceryl.

[0060] Examples of silicone oils include methylpolysiloxane, methylphenylpolysiloxane, and decane. Methyltetrasiloxane, methylcyclopentasiloxane, highly polymerized methylpolysiloxane Octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, methyl Hydrogen polysiloxane, methyl trimethicone, dimethiconol, dimethiconol Rospolymers, siloxanes such as caprylyl methicone, alkyl-modified silicones, Amino-modified silicones such as minopropyl dimethicone and amodimethicone, cross-linked methyl polymer Risiloxane, cross-linked alkyl-modified silicone, amino-modified silicone, polyether-modified Silicone, polyglycerin-modified silicone, cross-linked polyether-modified silicone, Bridged alkyl polyether modified silicone, silicone-alkyl chain comodified polyether Modified silicone, silicone-alkyl chain comodified polyglycerin, poly Polyglycerin-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, Examples include silicone-modified silicones and silicone oils such as silicone resins.

[0061] Examples of moisturizing ingredients include hyaluronic acid (hydrolyzed hyaluronic acid, low molecular weight hyaluronic acid). (Contains acids, etc.); Salts of hyaluronic acid (e.g., sodium hyaluronate, zinc hyaluronate) , low molecular weight zinc hyaluronate, etc.); hyaluronic acid derivatives (acetylated hyaluronic acid or similar) Salt (e.g., sodium acetylated hyaluronate, zinc acetylated hyaluronate, etc.), frame Bridge-type hyaluronic acid derivatives (e.g., sodium hyaluronate crosspolymer), carboxymethyl hyaluronic acid Sodium hyaluronate, unsaturated hyaluronic acid or its salt, hydrolyzed alkyl hyaluronate (C12 -13) Glyceryl, cationized hyaluronic acid derivative (hydroxypropyl hyaluronate) Trimonium, etc.; dimethylsilanol hyaluronate, etc.); chondroitin sulfate or the Salt (chondroitin sulfate sodium, chondroitin sulfate potassium, dermatan sulfate sodium Potassium diuretic, dermatan sulfate, etc.; heparin-like substances, alanine, serine, asparagus Ginic acid, glycine, proline, hydroxyproline, glucosamine, theanine, arginine Amino acids and their derivatives such as ; polyhydric alcohols; PPG-17, buteth-17, PPG -25 Sorbitol, Polyoxyalkylene Alkyl Glucoside, PEG / PPG / Poly Butylene glycol-8 / 5 / 3 glycerin, polyoxyalkylenediglyceryl, etc. Alkylene oxide; glycosyltrehalose, trehalose; ceramide, glucosyl trehalose Lamide, cholesterol, phytosterol, cholesterol derivatives, phytosterol Derivatives; 2-methacryloyloxyethyl phosphorylcholine / butyl methacrylate copolymer Combined solution, polymethacryloyloxyethyl phosphorylcholine, etc. 2-methacryloyloxy Phosphorylcholine-containing polymer; lactic acid, sodium lactate, sodium pyrrolidone carboxylate , NMF-derived components such as urea; collagen, elastin, keratin, chitin, chitosan, etc. and their hydrolysates; hydroxyethyl urea; plants (e.g., aloe, seaweed, cuttlebone) Corn, chlorella, lemongrass, chamomile, witch hazel, tea, perilla, grapefruit Examples include components derived from plants such as Gynostemma pentaphyllum.

[0062] Examples of polyhydric alcohols include low-molecular-weight substances having two or more hydroxyl groups, for example, Glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol 1,3-Butanediol, Ethylene Glycol, Diethylene Glycol, Isopropyl 1,3-butylene glycol, 1,3-propanediol, 1,2- tanediol, 1,2-hexanediol, 1,2-octanediol, decanediol Neopentyl glycol, sorbitol, xylitol, erythritol, mannitol One example is [the rule].

[0063] Examples of thickening agents include polyvinyl alcohol, polyvinylpyrrolidone, and polyvinyl Methyl ether, vinyl-based thickeners such as carboxyvinyl polymer, methylcellulose, etc. Hydroxycellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxy hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose Cellulose, carboxyethylcellulose, hydrophobized hydroxypropylmethylcellulose, etc. Lulurose-based thickeners, guar gum, sclerotium gum, tamarind gum, xanthan gum Dextran, pectin, pullulan, gelatin, locust bean gum, carrageenan Agar, biosaccharide gum, alkyl acrylate methacrylate copolymer, polyacrylic acid Sodium acid, bentonite, dextrin fatty acid ester, dimethyl distearyl ammonium compound Monium hectorite, sodium alginate, polyethylene glycol, trimethyl chloride Ammonium hydroxypropyl guar gum, trimethylammonium hydroxypropyl chloride (hydroxyethyl cellulose, (hydroxyethyl acrylate / acryloyl hydrate) (Sodium taurate) copolymer, (ammonium acryloyldimethyltaurate / vinyl Examples include pyrrolidone copolymers.

[0064] Examples of cooling agents include menthol and its derivatives, chlorobutanol, and Borneo. Terpenes such as ol, geraniol, cineole, anethole, limonene, and eugenol. (These may be d-isomers, l-isomers, or dl-isomers.); Eucalyptus oil, bergamot oil, Peppermint oil, cool mint oil, spearmint oil, fennel oil, peppermint oil, cinnamon oil Examples include essential oils such as rose oil and turpentine oil.

[0065] Examples of preservatives or antimicrobials include benzoic acid, sodium benzoate, dehydroacetic acid, Sodium dehydroacetate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate Pill, butyl parahydroxybenzoate, ethyl parahydroxybenzoate, pro parahydroxybenzoate Pills, benzyl parahydroxybenzoate, methyl parahydroxybenzoate, phenoxyethanol , benzyl alcohol, methylisothiazoline, iodide propynyl butylcarbamate, 1,3-propanediol, 1,2-pentanediol, 1,2-hexanediol, or Examples include 1,2-octanediol.

[0066] Examples of pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, etc.) and organic acids (lactic acid, citric acid, etc.) Tartaric acid, malic acid, succinic acid), organic bases (triethanolamine, diisopropanol) Amines, triisopropanolamine, etc., as well as their salts, inorganic bases (hydroxylated ammonium compounds) Examples include sodium hydroxide, sodium ammonium sulfate, etc.

[0067] Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA), ethylenediaminetetraacetic acid, etc. 4-acetic acid (sodium salt (sodium edetate: Japanese Pharmacopoeia, EDTA-2Na, etc.) Examples include potassium salts, phytic acid, gluconic acid, polyphosphate, and metaphosphate. .

[0068] [Manufacturing method] The method for producing the pharmaceutical composition of the present invention is not particularly limited and can be set as appropriate.

[0069] Specifically, each component is heated and dissolved as needed, then mixed, and cooled in a water bath while stirring. One possible method is to leave it undisturbed at room temperature, but this is not the only option.

[0070] [Formulation] The compositions of the present invention include, for example, bases or carriers commonly used in pharmaceuticals or quasi-drugs, and It can be mixed with additives as needed to form a topical skin composition.

[0071] The form of the composition of the present invention is not particularly limited, but it is preferably in the form of a topical skin composition. Such forms include, for example, suspensions, emulsions, creams, ointments, gels, Liniment agents, lotions, patches, solid preparations contained in containers (stick preparations, spherical preparations, Examples include hemispherical preparations. These preparations are as described in the General Provisions of the 18th Revised Japanese Pharmacopoeia. It can be manufactured in accordance with laws and regulations. Among these, creams or ointments are preferred.

[0072] [pH] The pH of the composition of the present invention is typically pH 3.0 to 7.5, and is pH 3.0 to 7.0. It is preferable that the pH is 3.0 to 6.5, and more preferably that the pH is 3.5 to 6.0 It is even more preferable that the pH is between 3.8 and 5.5. This pH can be adjusted, for example, by using a pH adjusting agent. However, pH measurement This shall not apply to formulations that cannot or cannot be determined.

[0073] [container] The composition of the present invention is housed in a container of a shape and material appropriately selected according to the intended use and application. , can be used. Specific containers include, for example, containers with nozzles and containers with pumps. Containers, jar containers, tube containers, containers with holes in the inner stopper, and containers with hinged caps. Examples include containers, sponge-head containers, roll-on containers, and stick-type containers. By housing the composition of the present invention in these containers, it can be applied directly or indirectly to the desired affected area. It can be applied to a small or large area of ​​the affected area. It is also possible to design it to be tapered or have a large diameter. Apply the composition according to this embodiment to the affected area. After application, it can also be spread using a non-woven fabric or your fingers.

[0074] Furthermore, the container material is polyethylene terephthalate, polybutylene terephthalate. Polyethylene naphthalate, polypropylene, polyethylene (HDPE, LDPE, LLDPE, etc.), ABS resin, polycarbonate, fluororesin, polyvinyl chloride, polya Microwaves, ethylene vinyl alcohol resin, polystyrene, glass, and metals (aluminum, etc.) Examples can be given. Furthermore, these materials are selected considering factors such as strength, flexibility, weather resistance, and component stability. Considering this, various coating treatments are applied, or these materials are combined, for example, by mixing them. They can be combined or laminated and used as container materials.

[0075] [Skin cooling agents, methods for imparting a cooling effect] The present invention also contains (A) camphor and (B) one or more antihistamines. A skin cooling agent; or (A) an external composition containing camphor, (B) one or more of the following: This includes a method for imparting a cooling effect to the composition, which involves coexisting with an antihistamine. Therefore, the content, ratio, and other conditions of each component are as described in [Skin Topical Composition]. It depends on the size.

[0076] [Method for imparting an anti-itch effect] The present invention also includes (A) a topical composition containing camphor, and (B) one or more antihypertensive agents. This includes a method for imparting an antipruritic effect to the composition, which involves the coexistence of a stamina-inhibiting agent. Here, the content, ratio, and other conditions of each component are described in [Skin Topical Composition]. It will be in accordance with the content.

[0077] [Method for imparting histamine-independent anti-itch effects] The present invention also includes (A) a topical composition containing camphor, and (B) one or more antihypertensive agents. By co-administering staminaxin, a histamine-independent anti-itch effect can be achieved. This includes the law. Here, the content, ratio, and other conditions of each component are defined as [Composition for topical use on skin]. The contents will be as described in [Item].

[0078] The present invention also includes (A) a topical composition containing camphor, and (B) one or more antihypertensive agents. By coexisting with stamina-inducing drugs, TRPA1 (transient receptor This includes methods for suppressing the activity of or potential ankyrin 1). Therefore, the content, ratio, and other conditions of each component are as described in [Skin Topical Composition]. It depends on the size.

[0079] [Application] The compositions of the present invention are particularly useful for suppressing itching, suppressing redness, or for histamine-independent itching. It is effective for suppressing symptoms and conditions, and by inhibiting TRPA1 activity, the symptoms and conditions are improved. It may also be used for conditions. While not limited to these, the compositions of the present invention may be used for, for example, atopic dermatitis. Sexual dermatitis, senile skin pruritus, eczema (skin eczema including scalp eczema and hand eczema), dermatitis, Itching, rash, hives, sores, heat rash, chilblains, insect bites, or caused by dryness, etc. It has an effect against itching, etc. Furthermore, it can also have a skin repair function. This invention The composition also causes stinging, burning, and itching that spreads redness when scratched. It is also effective against recurring itching and severe itching.

[0080] Due to its effects on the skin, the present invention is applicable to products used as topical skin preparations (formulations for the skin). It is preferable to use it. Suitable skin application sites include the hands (palms, backs of hands, fingers), Examples of areas affected include the skin on the face, feet, head, neck, chest, armpits, back, waist, back of the elbows, and back of the knees. According to Akira, because it enhances histamine-independent anti-itch effects, it can be used not only as a topical skin preparation but also in the eyes. It can also be used in various dosage forms such as oral ointments, nasal ointments, and nasal creams. The drug composition is taken once to several times a day, depending on the intended use, using known or commonly used methods. It can be used according to the prescribed dosage and usage. [Examples]

[0081] Next, the present invention will be specifically described with reference to examples, but the present invention is limited to the following examples. It's not that.

[0082] [Test Example 1: TRPA1 Activity Inhibition Test] <Cells used> Preparation of a T-REx-293 cell line containing the hTRPA1 gene hTRPA1 mRNA was extracted from human WI38 cells. Stable hTRPA1 The HEK cells that expressed this gene were developed using Invitrogen's tetracycline-regulated T-REx gene. The sample was prepared using the current system. The hTRPA1 mRNA was used as a template for RT-PCR. The amplified hTRPA1 cDNA is expressed using pcDN, a gene expression vector for mammalian cells. Incorporated into A4 / TO (manufactured by Invitrogen), Invitrogen's gene T-RE using the introduction reagent Lipofectamin 2000 reagent It was introduced into x-293 cells. Zeocin is incorporated into pcDNA4 / TO. Plasmids (Blastos) for maintaining the T-Rex system in T-REx-293 cells The idin resistance gene is retained. The antibiotic Zeocin 500 μg / mL and T- cells that stably retain the hTRPA1 gene using blastosidine 10 μg / mL We established the REx-293 cell line.

[0083] <Cell culture> T-REx-293 cells that stably express hTRPA1 were 10% FBS, 100 units. / mL penicillin,100mg / mL streptomysin,250 Using DMEM medium containing ng / mL amphotericin B, at 37°C and 5% The culture was performed in the presence of carbon dioxide. During subculturing, 200 μg / mL Zeocin, 5 μg / mL of blastosidine was added, and the procedure was carried out at a maximum of 60 passages. Specifically, as a pre-culture, TR is used in a 60mm dish to achieve semi-confluence. After culturing Ex-293 cells, they were washed with PBS(-). 1×Trypsin / EDTA treatment was performed. The cells were then detached from the dish by force and DMEM medium was added. Then, a 15 mL tube was inserted. Transferred to a container and centrifuged at 800 rpm at room temperature for 4 minutes. Only the DMEM medium was aspirated and removed. After loosening the cells by tapping, fresh DMEM medium is added, and approximately 40 × 10 4 ce A cell suspension was prepared by adjusting the cell number to achieve ll / mL. At this time, receptor expression was 1 μg / mL tetracycline was added for this purpose. The prepared cell suspension was 96 watts. Dispense 100 μL into individual plates and incubate overnight in a 37°C, 5% CO2 incubator. I adapted it and used it in the test.

[0084] <Test to confirm the inhibition of TRPA1 activity by camphor and antihistamines> Cinnamaldehyde induces the activity of TRPA1, and together with cinnamaldehyde, The test samples (examples and comparative examples) were administered to the above cells, and the TRPA1 activity was determined by the test sample. We checked whether inhibition occurred. Each test sample is shown in Tables 1 and 2. Units in Tables 1 and 2. Unless otherwise specified, all values ​​are in μg / ml. Here, all camphor used is dl-camphor. I have the flu.

[0085] [Table 1]

[0086] [Table 2]

[0087] Ca 2+ Concentration indicator (Fluo-8 (manufactured by AAT Bioquest, Inc.) We used this to observe changes in TRPA1 activity. Ca 2+ The concentration indicator is pre-treated to maintain hTRPA1 The T-REx-293 cells were taken up and then scanned with a microplate reader. The amount of light was measured. Specifically, the procedure was carried out according to the following protocol. Cell culture was performed on cell 96U the day before. Remove the cell plate from the incubator and decant the DMEM medium. 100 μL / well buffer (pH 7.4, 5.37 mM KCl, 0.44 mM) mM KH2PO4, 137 mM NaCl, 0.34 mM Na2HPO4, 5 .56mM D-glucose, 20mM HEPES, 1mM CaCl2, 0.1% bovine serum albumin, 2.5mM probene Gently wash with cid. (residual purified water), and then dissolve in 3 μM Fluo-8. After adding 50 μL of buffer solution to each well, incubate in a 37°C, 5% CO2 incubator for 1 hour. Processed. After incubator treatment, the same buffer containing Fluo-8 was decanted. Removed with a suction device and gently washed with 100 μL / well of the same buffer solution. Then, 180 μL The same buffer solution was added in L / well. The test sample solution added to the cells was 10 times the final concentration. The solution was prepared at a concentration of 1000 times the final concentration. Specifically, the test sample was prepared using DMS. After dissolving in O, the DMSO solution of the test sample was prepared by adding 1 / 100th of the solution to the buffer. Flexstation II (Registered Trademark) or Flexs Station III (Registered Trademark) Microplate Reader Measurements were opened at Molecular Devices (Sunnyvale, CA, USA). It started. 30 seconds after the start of the microplate reader measurement, a 10x concentrated sample solution was applied to each plate. 20 μL was added to each gel, and the maximum fluorescence intensity was measured 160 to 200 seconds after addition. The ΔF value was then calculated. The ΔF value was calculated using the following formula. ΔF = (Maximum fluorescence intensity from 160 to 200 seconds) / (Average fluorescence intensity from 0 to 30 seconds) Measurements were taken three times, and after calculating the average value of the ΔF value, a comparison was made with only cinnamaldehyde added. For example (for Comparative Example 1-2 and Examples 1-1 to 6, Comparative Example 1-1 is used as the reference, and Comparative Example 1-4 (For Examples 1-7 to 12, Comparative Example 1-3 is used as the basis.) Each component was simultaneously The inhibition rate (%) when the substance is added was calculated. The inhibition rate (%) was calculated based on the following formula. Inhibition rate (%) = (ΔF value of cinnamaldehyde only - ΔF value of each comparative example or example) / cinnamaldehyde ΔF value of namaldehyde only × 100

[0088] As shown in Tables 1 and 2, when added simultaneously with cinnamaldehyde, camphor 50 μg / mL and the addition of chlorpheniramine maleate or diphenhydramine hydrochloride TRPA1 activity was suppressed. This trend was observed when camphor concentration was reduced from 50 μg / mL to 25 μg / mL. Aside from the change, the results were the same when using the same test solution (Tables 3 and 4). The addition of lorpheniramine maleate or diphenhydramine hydrochloride alone does not suppress the activity. No control was observed. As with Tables 1 and 2, all camphor used was dl-camphor. ru.

[0089] [Table 3] [Table 4]

[0090] Next, camphor and chlorpheniramine maleate or diphenhydramine hydrochloride Both contain allantoin, dipotassium glycyrrhizinate, or prednisolone valerate. The effect of adding acetate on the activity of TRPA1 was investigated. The camphor used was All are dl-camphor. Examples of each standard and example are shown in Tables 5 to 10. Tables 5 to 10 Unless otherwise specified, all units are μg / ml. The inhibition rate is shown in the leftmost column of each table as an example. The value was calculated based on this. Suppression rate (%) = (ΔF value of the reference example - ΔF value of each example) / ΔF value of the reference example × 100 The results are shown in Tables 5-10.

[0091] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0092] Together with camphor and chlorpheniramine maleate or diphenhydramine hydrochloride, Allantoin, dipotassium glycyrrhizinate, or prednisolone valerate acetate It was found that the activity of TRPA1 was further suppressed when sterol was added.

[0093] Therefore, camphor and chlorpheniramine maleate or diphenhydramine hydrochloride This combination suppresses the activity of TRPA1, and furthermore, allantoin and gu Add dipotassium lycyrrhizinate or prednisolone valerate acetate. It was found that this strengthens the inhibitory effect on activity. Furthermore, allantoin and glycyrrhizin... When dipotassium valerate or prednisolone valerate acetate is added alone, activity No suppression was observed.

[0094] [Test Example 2. Sensory Evaluation Test 1] The compositions of the test examples shown in Table 11 were prepared by conventional methods. All units in Table 11 are in mass percent. Similar to Test Example 1, all the camphor used was dl-camphor. Each test example was taken with micros parter and applied to the forearm of 4 healthy adults, and the cool feeling and fragrance immediately after application were evaluated. The evaluation was carried out in 5 grades, and the average values were calculated and compared. 1: Not felt, 2: Slightly felt, 3: Felt, 4: Well felt, 5: Very felt

[0095] Also, for 1 adult who felt itchy with redness on the tibia of the leg, for Comparative Example 2-1 and Examples 2-6 and 2-7, the improvement degree of itching and redness 5 minutes after application was evaluated in 1-5 grades . Furthermore, for 1 adult who felt itchy with redness on the outer side of the left forearm and 1 adult who felt itchy with redness on the back of the left hand and fingers , for Comparative Example 2-1 and Examples 2-6 and 2-7, the improvement degree of redness 5 minutes after application was evaluated in 1-5 grades . Note that 1 indicates no improvement at all, and 5 indicates very improved. The results are shown together in Table 11. The results are shown in Table 11.

[0096]

Table 11

[0097] Compared with camphor alone, the combination of chlorpheniramine maleate or diphenhydramine hydrochloride makes it easier to feel the cool feeling and the fragrance of camphor. Furthermore, by adding proprednisolone valerate acetate, allantoin or dipotassium glycyrrhizinate to these, the effect was further enhanced. Also, a similar tendency was confirmed for itching and redness . was confirmed.

[0098] [Test Example 3. Sensory Evaluation Test 2] The compositions of the test examples shown in Tables 12 and 13 were prepared. Note that Comparative Examples 3-1, 3-2, and 3- For step 3, commercially available products were used. The compositions shown in Table 12 are creams, and Table 13 is... The compositions shown are ointments. All units in Tables 12 and 13 are in mg / g. Take the length from the tip of an adult's index finger to the first joint (1 FTU = approximately 0.5g), and measure the weight of a healthy adult 11 Apply to the forearm area and spread the applied composition over a 5cm x 5cm area until it becomes slightly shiny. Gently spread it over the skin. Immediately after application, and 20 minutes later, a "cooling / refreshing / soothing sensation" and "medicinal effect" were observed. The "feeling" was rated on a 5-point scale. 1: I don't feel it at all, 2: I don't feel it much, 3: Neither, 4: I feel it, 5: I feel it very much The results are shown in Table 10. Note that the feeling of efficacy refers to the feeling that the itching subsides when it occurs. It indicates a feeling of something being good or that it might be effective.

[0099] [Table 12] [Table 13]

[0100] The cream formulation contains camphor and diphenhydramine hydrochloride, compared to Comparative Example 3-1. In Example 3-1, it was confirmed that a cooling sensation and a medicinal effect could be felt. Furthermore, with the ointment... Compared to Comparative Examples 3-2 and 3-3, it contains camphor and chlorpheniramine maleate. In Example 3-2, it was confirmed that a cooling sensation and a medicinal effect could be felt.

[0101] [Test Example 4. Cooling Effect Evaluation Test] The compositions shown in Table 14 were prepared. All units in Table 14 are mg / g. Test area: medial forearm. Mark the area (2cm x 2cm) and use a surface thermometer (HORIBA INFRARED TH The skin temperature of the test site was measured using an ERMOMETER IT-545). Then, about 18 mg of the preparation was applied to the test site, and the skin temperature immediately after application was measured to calculate the cooling effect (%). The cooling effect (%) was calculated as shown in the following formula (1). The preparation was applied to the test site, and the skin temperature immediately after application was measured to calculate the cooling effect (%). The cooling effect (%) was calculated as follows. Cooling effect (%) = (Skin temperature before application - Skin temperature immediately after application) / Skin temperature before application × 100 The results are shown in Table 14.

[0102]

Table 14

[0103] Compared with the composition containing only camphor and additives, the cooling effect could be confirmed in Examples 4-1 to 4-2 containing camphor and an antihistamine. Furthermore, by adding prednisolone valerate acetate, allantoin or dipotassium glycyrrhizinate to these, the effect was enhanced. Compared with the composition containing only camphor and additives, the cooling effect could be confirmed in Examples 4-1 to 4-2 containing camphor and an antihistamine. Furthermore, by adding prednisolone valerate acetate, allantoin or dipotassium glycyrrhizinate to these, the effect was enhanced. Furthermore, by adding prednisolone valerate acetate, allantoin or dipotassium glycyrrhizinate to these, the effect was enhanced. The effect was enhanced.

[0104] [[ID=,30]] [Formulation Example] Formulation examples are shown in Tables 15-16 below. All units are in mass %. Table 15 is a cream, and Table 16 is an ointment. Formulation examples are shown in Tables 15-16 below. All units are in mass %. Table 15 is a cream, and Table 16 is an ointment.

[0105]

Table 15

[0106]

Table 16

Claims

[Claim 1] (A) Camphor and (B) One or more antihistamines are included in this topical composition.

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