Composition

Abstract

To provide means for suppressing discoloration of a liquid or semi-solid composition comprising urea and a plant of the genus Arnica or an extract thereof at high temperature storage.SOLUTION: There is provided a liquid or semi-solid composition comprising following components (A), (B) and (C): (A) urea; (B) a plant of the genus Arnica or an extract thereof; (C) one or more kinds selected from a group consisting of following components (C-1), (C-2) and (C-3): (C-1), for example, chlorpheniramine, a salt of chlorpheniramine, diphenhydramine, and a salt of diphenhydramine; (C-2) local anesthetic, and (C-3) glycyrrhetinic acids. The liquid or semi-solid composition can be suppressed in discoloration during high-temperature storage.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition and the like. [Background technology]

[0002] Urea has a high moisture-retaining capacity as well as keratolytic and antibacterial properties, and has been used as an active ingredient in topical preparations for dry skin diseases such as ichthyosis, senile xerosis, atopic dermatitis, etc. Furthermore, due to its mild effects and safety, it is used not only in pharmaceuticals but also as an ingredient in quasi-drugs and cosmetics, and is widely used in ordinary households.

[0003] On the other hand, liquid or semi-solid compositions such as topical solutions, ointments, creams, gels, etc., have the advantage that they can be flexibly administered in the required amount depending on the location, shape, and area of ​​the affected area. Urea-containing preparations have also been available on the market in the form of emulsions, creams, etc. (e.g., Non-Patent Documents 1 and 2).

[0004] Dry skin is often accompanied by inflammation and itching caused by inflammation. Therefore, the development of pharmaceuticals and quasi-drugs containing urea and an ingredient that suppresses inflammation is thought to be useful for treating skin diseases accompanied by dryness. Plants of the Asteraceae family, such as Arnica, are known to be one of the ingredients that suppress inflammation. Plants of the Arnica genus and their extracts not only have excellent anti-inflammatory properties, but are also expected to be gentle on the skin as they are plant-derived ingredients. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Keratinamin Kowa 20% Urea Cream, Kowa Company, Limited [Retrieved July 10, 2020] (https: / / hc.kowa.co.jp / wp-content / uploads / 2014 / 03 / %E3%82%B1%E3%83%A9%E3%83%81%E3%83%8A%E3%83%9F%E3%83%B320%EF%BC%85%E3%82%AF%E3%83%AA%E3%83%BC%E3%83%A0.pdf) [Non-patent document 2] Keratinamin Kowa Emulsion 20, Kowa Company, Limited [Retrieved July 10, 2020] (https: / / hc.kowa.co.jp / wp-content / uploads / 2017 / 08 / %E3%82%B1%E3%83%A9%E3%83%81%E3%83%8A%E3%83%9F%E3%83%B3%E4%B9%B3%E7%8A%B6%E6%B6%B2100g%E6%B7%BB%E4%BB%98%E6%96%87%E6%9B%B8.pdf) Summary of the Invention [Problem to be solved by the invention]

[0006] Under the above circumstances, it would be meaningful to develop and market a liquid or semi-solid composition containing urea and a plant of the genus Lacertilia or its extract. Therefore, the present inventors investigated the properties of a liquid or semi-solid composition containing urea together with a plant of the genus Lagophthalmus or an extract thereof in order to develop such a composition. They found that although urea, a plant of the genus Lagophthalmus or an extract thereof are each stable on their own, discoloration occurs when the two components are stored at high temperatures when they are present together. Therefore, an object of the present invention is to provide a means for suppressing discoloration of a liquid or semi-solid composition containing urea and a plant of the genus Lacertilia or an extract thereof during storage at high temperatures. [Means for solving the problem]

[0007] Therefore, the present inventors have conducted extensive research to solve the above problems, and have found that a liquid or semi-solid composition containing urea and a plant of the genus Lagophthalmus or an extract thereof can be further treated with one or more components selected from the group consisting of the following Component 1, Component 2, and Component 3: Component 1: A compound represented by the following general formula (1), such as chlorpheniramine or a salt thereof, or diphenhydramine or a salt thereof

[0008] [ka]

[0009] [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, and R 1 represents a hydrogen atom, a hydroxyl group, or an alkyl group, and R 2 represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom.]

[0010] A compound represented by the formula (I) or a salt thereof; Component 2. Local anesthetics such as lidocaine or its salts, dibucaine or its salts; Component 3. Glycyrrhetinic acids such as glycyrrhetinic acid or its salts, glycyrrhizinic acid or its salts; The present inventors have found that when a composition containing the component (I) is contained, discoloration during high-temperature storage can be suppressed compared to when the component (I) is not contained, and have completed the present invention.

[0011] That is, the present invention provides a composition comprising the following components (A), (B) and (C): (A) Urea; (B) a plant of the genus Lacertilia or an extract thereof; (C) one or more selected from the group consisting of the following components (C-1), (C-2), and (C-3): (C-1) The following general formula (1)

[0012] [ka]

[0013] [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, and R 1 represents a hydrogen atom, a hydroxyl group, or an alkyl group, and R 2 represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom.]

[0014] A compound represented by the formula (I) or a salt thereof; (C-2) Local anesthetics; (C-3) glycyrrhetinic acids; The present invention provides a liquid or semi-solid composition comprising:

[0015] The present invention also provides a composition comprising the following components (A) and (B): (A) Urea; (B) a plant of the genus Lacertilia or an extract thereof; a liquid or semi-solid composition containing the above, and one or more selected from the group consisting of the following components (C-1), (C-2), and (C-3); (C-1) a compound represented by the above general formula (1) or a salt thereof; (C-2) Local anesthetics; (C-3) glycyrrhetinic acids; The present invention provides a method for inhibiting discoloration of a composition, the method comprising the step of incorporating [Effects of the Invention]

[0016] According to the present invention, discoloration of a liquid or semi-solid composition containing urea and a plant of the genus Lagerstroemia or an extract thereof during high-temperature storage can be suppressed, thereby providing a pharmaceutical product, quasi-drug, cosmetic, or the like for treating skin diseases accompanied by dryness, which has excellent storage stability. DETAILED DESCRIPTION OF THE INVENTION

[0017] First, the invention in the form of a "liquid or semi-solid composition" will be described below. <Component (A)> In the present invention, commercially available products can be used as "urea", and specific examples of commercially available products include urea (Fujifilm Wako Pure Chemical Industries, Ltd.) and urea (Takasugi Pharmaceutical Co., Ltd.).

[0018] In the present invention, the content of urea in the liquid or semi-solid composition is not particularly limited and may be determined appropriately. In the present invention, the content of urea is preferably 1 to 40 mass % relative to the total mass of the composition, more preferably 2 to 30 mass %, even more preferably 3 to 25 mass %, and particularly preferably 4 to 22.5 mass %.

[0019] <Ingredient (B)> In the present invention, "plants of the genus Arnica" refers to plants belonging to the genus Arnica (Arnica genus) of the Asteraceae family. The specific species is not particularly limited as long as it belongs to the genus, and examples thereof include plants with the following scientific names: Arnica montana, Arnica chamissonis, Arnica fulgens, Arnica cordifolia, Arnica latifolia, Arnica longifolia, and Arnica sachalinensis. In the present invention, a single species of Arnica may be used, or multiple different species of Arnica may be used in combination. In the present invention, Arnica montana is preferred from the viewpoint of its anti-discoloration effect. Furthermore, in the present invention, the parts of the Arnica plant used are not particularly limited, and the whole plant or parts (flowers, inflorescences, spikes, buds, leaves, branches, roots, etc.) or a combination of two or more thereof may be used.

[0020] The form of the Lagophthalmus plant can be adjusted as needed, and it can be cut or crushed into small pieces or chunks, or crushed into powder. In addition, in consideration of ease of handling during the production of the composition, a Lagophthalmus plant that has been subjected to some kind of extraction treatment (referred to in this specification as an "extract of a Lagophthalmus plant") may also be used. The term "extract of a plant of the genus Lagarcia" also encompasses those that have been subjected to processing such as heating, drying, pulverization, etc. in addition to extraction. Specifically, the "extract of a plant of the genus Lagarcia" of the present invention includes a liquid obtained by cutting a plant of the genus Lagarcia into an appropriate size as needed and then adding an appropriate infusion (extraction solvent), a liquid obtained by concentrating the infusion (soft extract, tincture, etc.), and further a liquid obtained by drying these (dried extract, etc.).

[0021] The method for producing an extract of a plant of the genus Lagerstroemia is not particularly limited, and it can be produced by referring to known methods for producing plant extracts, such as those described in the "Extracts," "Infusions / Decoctions," "Tinctures," and "Liquid Extracts" sections of the General Provisions for Preparations of the Seventeenth Edition of the Japanese Pharmacopoeia. Specifically, for example, the extract can be produced by cutting, heating, drying, or pulverizing a plant of the genus Lagerstroemia as needed, and then adding an appropriate extraction solvent to carry out extraction. The resulting extract may be further concentrated, dried, or the like, as needed.

[0022] Examples of the extraction solvent include lower monohydric alcohols such as methanol, ethanol, isopropanol, and n-butanol; lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol, and glycerin; ethers such as diethyl ether; ketones such as acetone and ethyl methyl ketone; esters such as ethyl acetate; nitriles such as acetonitrile; alkanes such as pentane, hexane, cyclopentane, and cyclohexane; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; dimethylformamide; dimethyl sulfoxide; and water (including hot water). These may be used alone or in combination of two or more. In the present invention, lower monohydric alcohols such as ethanol, water, propylene glycol, 1,3-butylene glycol, or a mixture of two or more of these are preferred, with water, a monohydric alcohol having 1 to 6 carbon atoms, or a mixture of these being more preferred, and water, ethanol, or a mixture of water and ethanol being particularly preferred. The extraction procedure is not particularly limited, and any known method used for extraction from plants can be appropriately adopted, specifically, for example, immersion in an extraction solvent (cold immersion, hot immersion, percolation, etc.), extraction using a supercritical fluid or subcritical fluid, etc. In order to increase the extraction efficiency, stirring or homogenization in the extraction solvent may be performed. The extraction temperature is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but is preferably from about 5°C to a temperature below the boiling point of the extraction solvent. The extraction time is not particularly limited and varies depending on the extraction solvent used, the extraction procedure, etc., but is preferably about 1 hour to 14 days.

[0023] In the present invention, the "plant of the genus Lacertilia or an extract thereof" is preferably arnica (Arnica montana) or an extract thereof. Examples of the extract of arnica include arnica tincture and arnica extract. As the plant of the genus Lacertilia or an extract thereof, one or more arnica extracts selected from arnica tincture and arnica extract (soft extract, dry extract) are more preferred, arnica tincture and arnica extract listed in the 2006 Standards for Quasi-drug Ingredients are even more preferred, and arnica tincture is particularly preferred.

[0024] In the present invention, commercially available products can be used as plants of the genus Lacertilia or extracts thereof, and specific commercially available products include, for example, Arnica Tincture (Alps Pharmaceutical Co., Ltd.), Arnica Extract (Maruzen Pharmaceutical Co., Ltd.), Falcorex Arnica (Ichimaru Pharcos Co., Ltd.), Arnica Extract, Arnica Tincture (all Nippon Powder Pharmaceutical Co., Ltd.), etc.

[0025] In the present invention, the content of a plant of the genus Lagerstroemia or an extract thereof in a liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration inhibitory effect, the plant of the genus Lagerstroemia or an extract thereof is preferably contained in an amount of 0.00001 to 4 mass%, more preferably 0.0005 to 3.5 mass%, and particularly preferably 0.003 to 3 mass%, based on the total mass of the composition, in terms of the amount of the plant of the genus Lagerstroemia, in terms of the amount of the plant of the genus Lagerstroemia, in terms of the amount of the plant of the genus Lagerstroemia, in terms of the amount of the plant of the genus Lagerstroemia, in terms of the amount of the plant of the genus Lagerstroemia, is preferably contained in an amount of 0.005 to 2.5 mass%, more preferably 0.01 to 2 mass%, and particularly preferably 0.02 to 1.9 ...%.

[0026] In the present invention, the content ratio of urea to a plant of the genus Lagerstroemia or an extract thereof in a liquid or semi-solid composition is not particularly limited and may be determined as appropriate, but from the viewpoint of discoloration inhibition, the content of a plant of the genus Lagerstroemia or an extract thereof, in terms of the amount of the herbal drug, is preferably 0.000005 to 1.75 parts by mass, more preferably 0.00005 to 1.5 parts by mass, and particularly preferably 0.0001 to 1.25 parts by mass, per part by mass of urea. In particular, when arnica is used as the plant of the genus Lagerstroemia, from the viewpoint of discoloration inhibition, the content of arnica or an extract thereof, in terms of the amount of the herbal drug, is preferably 0.0005 to 1 part by mass, more preferably 0.001 to 0.75 parts by mass, and particularly preferably 0.002 to 0.5 parts by mass, per part by mass of urea.

[0027] <Component (C-1)> In the present invention, "general formula (1)

[0028] [ka]

[0029] [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, and R 1 represents a hydrogen atom, a hydroxyl group, or an alkyl group, and R 2represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom.]

[0030] The term "compound represented by general formula (1) or a salt thereof" includes not only the compound represented by general formula (1) itself but also pharmaceutically acceptable salts of the compound represented by general formula (1). Specific examples of the compound represented by general formula (1) or a salt thereof include the compound represented by general formula (1), inorganic acid salts or organic acid salts of the compound represented by general formula (1) (e.g., hydrochloride, maleate, fumarate, diphenyldisulfonate, teoclate, salicylate, tannate, besylate, phosphate, etc.). Furthermore, when an asymmetric carbon is present in the chemical structure of the compound represented by general formula (1), various optical isomers exist. In the present invention, any of the optical isomers is included, and the compound represented by general formula (1) or a salt thereof may be a single optical isomer or a mixture of various optical isomers. Furthermore, the compound represented by general formula (1) or a salt thereof may be in the form of a solvate, and solvates of the compound represented by general formula (1) or a salt thereof with water, alcohol, etc. are also included in the term "compound represented by general formula (1) or a salt thereof."

[0031] R 1 In the above, the alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, with a methyl group being preferred. In addition, the R 1 is preferably a hydrogen atom or a methyl group.

[0032] R 2 In the above, the "cyclic amino group" in the cyclic amino group which may have a substituent means a 5- to 7-membered alicyclic group having at least one, preferably 1 or 2, nitrogen atoms as a ring-constituting atom. Specific examples of such cyclic amino groups include a pyrrolidinyl group, a pyrazolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a homopiperidinyl group, a homopiperazinyl group, etc. Among these, a piperidinyl group, a piperazinyl group, and a homopiperazinyl group are preferred, and a piperidinyl group and a piperazinyl group are more preferred.

[0033] Furthermore, examples of the "substituent" in the cyclic amino group which may have a substituent include an alkyl group which may be substituted with one or more groups selected from an alkylbenzoyl group, a 1,3-dihydro-2H-benzimidazol-2-one-1-yl group, a carboxyalkoxy group, a carboxyl group, a carboxyalkylphenyl group, and a hydroxyl group. Among these, an alkyl group, a carboxyalkoxyalkyl group, and a carboxyalkylphenyl(hydroxy)alkyl group are preferred. Specific examples of the "substituent" include a methyl group, a 3-(4-tert-butylbenzoyl)propyl group, a 3-(1,3-dihydro-2H-benzimidazol-2-one-1-yl)propyl group, a 2-(carboxymethoxy)ethyl group, a 4-[4-(2-carboxypropan-2-yl)phenyl]-4-hydroxybutyl group, and a 3-carboxypropyl group.

[0034] R 2 In the above, the "cyclic amino group which may have a substituent" is preferably a 1-methylpiperidin-4-yl group, a 4-methylhomopiperazin-1-yl group, a 1-[3-(4-tert-butylbenzoyl)propyl]piperidin-4-yl group, a 4-[3-(1,3-dihydro-2H-benzimidazol-2-one-1-yl)propyl]piperazin-1-yl group, a 4-[2-(carboxymethoxy)ethyl]piperazin-1-yl group, a 1-{4-[4-(2-carboxypropan-2-yl)phenyl]-4-hydroxybutyl}piperidin-4-yl group, or a 1-(3-carboxypropyl)piperidin-4-yl group.

[0035] R 2In the above, the "aminoalkyl group" in the aminoalkyl group which may have a substituent means an alkyl group substituted with an amino group, a monoalkylamino group, a dialkylamino group, or a cyclic amino group (the "cyclic amino group" has the same meaning as the "cyclic amino group" in the above-mentioned "cyclic amino group which may have a substituent"). Among them, an alkyl group substituted with a dialkylamino group or a cyclic amino group is preferred. Note that the cyclic amino group is preferably a pyrrolidinyl group. Specific examples of such aminoalkyl groups include a 2-(dimethylamino)ethyl group, a 2-(pyrrolidin-2-yl)ethyl group, a 2-[(isopropyl)(methyl)amino]ethyl group, etc. Furthermore, examples of the "substituent" in the optionally substituted aminoalkyl group include a hydroxyl group, a phenyl group, an alkyl group, etc.

[0036] R 2 In the above, the "aminoalkyl group which may have a substituent" is preferably a 2-(dimethylamino)ethyl group, a 2-(1-methylpyrrolidin-2-yl)ethyl group, or a 2-[(methyl)(1-phenyl-1-hydroxypropan-2-yl)amino]ethyl group.

[0037] In addition, the above R 2 In the above, the alkyl group moiety in the "alkyl group", "alkylbenzoyl group", "carboxyalkylphenyl group", "aminoalkyl group", "monoalkylamino group" and "dialkylamino group" is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group. In addition, the R 2 In the formula (I), the alkoxy group portion in the "carboxyalkoxy group" is preferably a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, and specific examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, and a hexyloxy group.

[0038] R 3In the general formula (1), examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like, and in the present invention, a chlorine atom is preferred. 3 The substitution position on the phenyl group is not particularly limited, but substitution at the 4-position is preferred.

[0039] In the present invention, specific examples of the "compound represented by general formula (1) or a salt thereof" include ebastine or a salt thereof; oxatomide or a salt thereof; carbinoxamine or a salt thereof such as carbinoxamine diphenyldisulfonate, carbinoxamine maleate, etc.; clemastine or a salt thereof such as clemastine fumarate, etc.; chlorpheniramine or a salt thereof such as d-chlorpheniramine maleate, dl-chlorpheniramine maleate, etc.; difeterol hydrochloride, difeterol phosphate, etc. difeterol or a salt thereof; diphenylpyraline or a salt thereof such as diphenylpyraline hydrochloride, diphenylpyraline teoclate, etc.; diphenhydramine or a salt thereof such as diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, etc.; cetirizine or a salt thereof such as cetirizine hydrochloride; fexofenadine or a salt thereof; bepotastine or a salt thereof such as bepotastine besilate, etc.; homochlorcyclidine or a salt thereof such as homochlorcyclidine hydrochloride, etc. These may be used alone or in combination of two or more. The compounds represented by the general formula (1) and salts thereof, particularly the compounds and salts thereof described above, are known and can be produced by known methods, or commercially available products can be used.

[0040] In the present invention, the total content of the compound represented by general formula (1) or a salt thereof in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibiting effect. In the present invention, from the viewpoint of the discoloration inhibiting effect, the compound represented by general formula (1) or a salt thereof is contained in an amount of preferably 0.1 to 15 mass %, more preferably 0.5 to 12.5 mass %, and particularly preferably 0.75 to 10 mass %, based on the total mass of the composition.

[0041] In the present invention, the content ratio of urea to the compound represented by general formula (1) or a salt thereof in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration-inhibiting effect. From the viewpoint of the discoloration-inhibiting effect, the content of the compound represented by general formula (1) or a salt thereof in total is preferably 0.005 to 10 parts by mass, more preferably 0.01 to 5 parts by mass, and particularly preferably 0.04 to 3 parts by mass, per part by mass of urea.

[0042] In the present invention, it is preferable to use "chlorpheniramine or a salt thereof" or "diphenhydramine or a salt thereof" as the compound represented by general formula (1) or a salt thereof.

[0043] In the present invention, "chlorpheniramine or a salt thereof" includes not only chlorpheniramine itself but also pharmaceutically acceptable salts of chlorpheniramine.

[0044] [ka]

[0045] It is a compound represented by the formula: Chlorpheniramine has an asymmetric carbon atom, and therefore has optical isomers. In the present invention, any optical isomer is included, and it may be a single optical isomer or a mixture of various optical isomers. Of these, the d- and dl-forms are preferred in the present invention. Specific examples of chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, and dl-chlorpheniramine maleate. In the present invention, chlorpheniramine maleate is preferred, with d-chlorpheniramine maleate and dl-chlorpheniramine maleate being more preferred, and d-chlorpheniramine maleate being particularly preferred. These are known compounds and can be produced by known methods, or commercially available products can be used.

[0046] When chlorpheniramine or a salt thereof is used, the content of chlorpheniramine or a salt thereof in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration inhibitory effect, the content of chlorpheniramine or a salt thereof is preferably 0.5 to 12.5 mass%, more preferably 0.75 to 10 mass%, and particularly preferably 0.8 to 9 mass%, relative to the total mass of the composition.

[0047] When chlorpheniramine or a salt thereof is used, the content ratio of urea to chlorpheniramine or a salt thereof in the liquid or semi-solid composition is not particularly limited. From the viewpoint of the discoloration-inhibiting effect, the content of chlorpheniramine or a salt thereof is preferably 0.01 to 5 parts by mass, more preferably 0.04 to 3 parts by mass, and particularly preferably 0.04 to 2.5 parts by mass per part by mass of urea.

[0048] In the present invention, "diphenhydramine or a salt thereof" includes not only diphenhydramine itself but also pharmaceutically acceptable salts of diphenhydramine.

[0049] [ka]

[0050] It is a compound represented by the formula: Specific examples of diphenhydramine or a salt thereof include diphenhydramine, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, etc. In the present invention, diphenhydramine, diphenhydramine hydrochloride, and diphenhydramine salicylate are preferred. These are known compounds and can be produced by known methods, or commercially available products can be used.

[0051] When diphenhydramine or a salt thereof is used, the content of diphenhydramine or a salt thereof in the liquid or semi-solid composition is not particularly limited. From the viewpoint of the discoloration-inhibiting effect, however, the content of diphenhydramine or a salt thereof is preferably 0.5 to 12.5% ​​by mass, more preferably 0.75 to 10% by mass, and particularly preferably 0.8 to 9% by mass, relative to the total mass of the composition.

[0052] When diphenhydramine or a salt thereof is used, the content ratio of urea to diphenhydramine or a salt thereof contained in the liquid or semi-solid composition is not particularly limited. From the viewpoint of the discoloration-inhibiting effect, the content of diphenhydramine or a salt thereof is preferably 0.01 to 5 parts by mass, more preferably 0.04 to 3 parts by mass, and particularly preferably 0.04 to 2.5 parts by mass per part by mass of urea.

[0053] <Component (C-2)> In the present invention, examples of "local anesthetics" include one or more selected from the group consisting of dibucaine, tetracaine, bupivacaine, procaine, propitocaine, benzocaine, mepivacaine, meprylcaine, and lidocaine, as well as salts thereof. Examples of salts include, but are not limited to, inorganic acid salts (e.g., hydrochloride, phosphate, sulfate, nitrate, etc.), organic acid salts (e.g., acetate, citrate, tartrate, etc.), etc. Local anesthetics may also be in the form of solvates, and solvates of various compounds or their salts with water, alcohol, etc. are also encompassed by the term "local anesthetic." In the present invention, specific examples of local anesthetics include dibucaine or salts thereof such as dibucaine and dibucaine hydrochloride; procaine or salts thereof such as procaine and procaine hydrochloride; and lidocaine or salts thereof such as lidocaine and lidocaine hydrochloride, but are not limited to these. In the present invention, from the viewpoint of the discoloration inhibitory effect, dibucaine or lidocaine or a salt thereof is preferred, and one or more selected from the group consisting of dibucaine, dibucaine hydrochloride, lidocaine, and lidocaine hydrochloride are particularly preferred. Local anesthetics are known and can be produced by known methods, or commercially available local anesthetics can be used.

[0054] In the present invention, the content of the local anesthetic in the liquid or semi-solid composition is not particularly limited. However, from the viewpoint of the discoloration suppression effect, the content of the local anesthetic, calculated as the free form, is preferably 0.01 to 20% by mass, more preferably 0.025 to 17.5% by mass, and particularly preferably 0.05 to 15% by mass, based on the total mass of the composition. In particular, when lidocaine or a salt thereof is used as the local anesthetic, from the viewpoint of the discoloration suppression effect, the content of the local anesthetic, calculated as the free form of lidocaine, is preferably 0.1 to 12% by mass, more preferably 0.5 to 10% by mass, and particularly preferably 1 to 9% by mass, based on the total mass of the composition. Furthermore, when dibucaine or a salt thereof is used as the local anesthetic, from the viewpoint of the discoloration suppression effect, the content of the local anesthetic, calculated as the free form of dibucaine, is preferably 0.1 to 12% by mass, more preferably 0.5 to 10% by mass, and particularly preferably 1 to 9% by mass, based on the total mass of the composition.

[0055] In the present invention, the ratio of urea to local anesthetic in the liquid or semi-solid composition is not particularly limited and may be determined appropriately from the viewpoint of the discoloration inhibitory effect, but from the viewpoint of the discoloration inhibitory effect, the local anesthetic is contained in an amount of preferably 0.0005 to 15 parts by mass, more preferably 0.001 to 12.5 parts by mass, and particularly preferably 0.01 to 10 parts by mass, calculated as the free form, per part by mass of urea. In particular, when lidocaine or a salt thereof is used as the local anesthetic, from the viewpoint of the discoloration inhibitory effect, the local anesthetic is contained in an amount of preferably 0.005 to 7.5 parts by mass, more preferably 0.01 to 2.5 parts by mass, and particularly preferably 0.02 to 1 part by mass, calculated as the free form of lidocaine per part by mass of urea. Furthermore, when dibucaine or a salt thereof is used as the local anesthetic, from the viewpoint of inhibiting discoloration, the amount of dibucaine contained is preferably 0.005 to 7.5 parts by mass, more preferably 0.015 to 5 parts by mass, and particularly preferably 0.03 to 3 parts by mass, calculated as the free form, per part by mass of urea.

[0056] <Component (C-3)> In the present invention, "glycyrrhetinic acids" means one or more selected from glycyrrhetinic acid and its derivatives (e.g., sugar-added derivatives of glycyrrhetinic acid such as glycyrrhizinic acid) and salts thereof (e.g., alkali metal salts such as potassium salts and sodium salts; ammonium salts, etc.). In the present invention, from the viewpoint of the discoloration inhibiting effect, the glycyrrhetinic acid is preferably one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, and salts thereof, more preferably one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate, and trisodium glycyrrhizinate, still more preferably one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, and dipotassium glycyrrhizinate, and particularly preferably one or more selected from the group consisting of glycyrrhetinic acid and dipotassium glycyrrhizinate.

[0057] When glycyrrhetinic acids are incorporated into a liquid or semi-solid composition, glycyrrhetinic acids may be used as they are, or licorice (liquorice) or an extract thereof containing glycyrrhetinic acids may be used. Here, "licorice" (liquorice) refers to the roots and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne (Leguminosae), and also encompasses the roots and stolons from which the periderm has been removed (peeled licorice) (Japanese Pharmacopoeia, 17th Edition). The form of licorice can be adjusted as needed, for example, by cutting or crushing into small pieces or chunks, or by grinding into powder. For example, "licorice powder," which is licorice powder, can also be used. Furthermore, for ease of handling during the manufacture of pharmaceutical compositions, "licorice extracts" obtained by subjecting licorice to some extraction treatment may also be used. Here, the "licorice extract" also encompasses those that have been subjected to processing such as heating, drying, or grinding in addition to extraction. Specifically, "licorice extract" includes the liquid obtained by cutting licorice to an appropriate size as needed, adding an appropriate infusion (extraction solvent), and infusing the infusion, as well as concentrated liquids (soft extracts, tinctures, etc.) from the infusion, and further drying these (dried extracts, etc.). In the present invention, the licorice or extract thereof is preferably the licorice, licorice powder, licorice extract, or crude licorice extract described in the 17th revised Japanese Pharmacopoeia.

[0058] The method for producing the licorice extract is not particularly limited, and it can be produced, for example, by the same method as the above-mentioned method for producing the extract of a plant of the genus Lagophthalmus.

[0059] In the present invention, commercially available products can be used as glycyrrhetinic acids, and specific commercially available products include glycyrrhetinic acid fine powder (Alps Pharmaceutical Co., Ltd.), non-standard dipotassium glycyrrhizinate, and non-standard monoammonium glycyrrhizinate (Maruzen Pharmaceutical Co., Ltd.).

[0060] In the present invention, the content of glycyrrhetinic acids in the liquid or semi-solid composition is not particularly limited, but from the viewpoint of the discoloration suppression effect, the content of glycyrrhetinic acids is preferably 0.01 to 2 mass%, more preferably 0.05 to 1.5 mass%, and particularly preferably 0.1 to 1 mass%, calculated as the free form, relative to the total mass of the composition.

[0061] In the present invention, the content ratio of urea to glycyrrhetinic acids in the liquid or semi-solid composition is not particularly limited, and may be determined by appropriate consideration from the viewpoint of the discoloration-inhibiting effect. From the viewpoint of the discoloration-inhibiting effect, the content of glycyrrhetinic acids is preferably 0.001 to 0.7 parts by mass, more preferably 0.005 to 0.5 parts by mass, and particularly preferably 0.01 to 0.3 parts by mass, calculated as the free form, per part by mass of urea.

[0062] Furthermore, among component (C), from the viewpoint of discoloration suppression effect, diphenhydramine, salts of diphenhydramine, lidocaine, salts of lidocaine, glycyrrhetinic acid, and salts of glycyrrhetinic acid are preferred, and lidocaine, salts of lidocaine, glycyrrhetinic acid, and salts of glycyrrhetinic acid are particularly preferred.

[0063] <Liquid or semi-solid composition> In the present invention, the term "liquid or semi-solid composition" means a composition that is liquid or semi-solid at room temperature (any temperature within the range of 15 to 25°C). In the present invention, the properties of the composition are not particularly limited, and may be any of a solution, a colloidal solution (sol (suspension or emulsion)), a gel, etc. Furthermore, the type and properties of the solvent or base are not particularly limited, and they may be hydrophilic or hydrophobic such as oily, and multiple different types of solvents and bases may be appropriately mixed and emulsified for use. Furthermore, when an emulsion system is used, the continuous phase may be an aqueous phase (oil-in-water type, etc.) or an oil phase (water-in-oil type, etc.), and may also be a composite emulsifier system such as a water-in-oil-in-water type or an oil-in-water-in-oil type. Among these compositions, those containing at least an oily solvent / base are preferred from the viewpoint of the feel when applied to dry skin, etc. Specific examples of such solvents / bases in the present invention include the components exemplified below as additives.

[0064] In the present invention, from the viewpoint of safety during use of the liquid or semi-solid composition, the liquid or semi-solid composition preferably contains water. Here, the content of water in the composition is not particularly limited, but from the viewpoint of safety during use of the liquid or semi-solid composition and the effect of inhibiting discoloration, it is preferably 15 to 80 mass % relative to the total mass of the composition, more preferably 20 to 70 mass %, and particularly preferably 23 to 60 mass %.

[0065] The liquid or semi-solid composition of the present invention may also contain a lower alcohol. Here, "lower alcohol" refers to a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples include ethanol, isopropanol, n-propanol, etc., with ethanol, isopropanol, and mixtures thereof being preferred. The content of the lower alcohol in the composition is preferably 0.01 to 70% by mass, more preferably 0.05 to 65% by mass, and particularly preferably 0.1 to 60% by mass, relative to the total mass of the composition.

[0066] In the present invention, in addition to components (A) to (C), the liquid or semi-solid composition may contain additives used in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc., depending on the dosage form, administration method, etc. Examples of such additives include oils, emulsifiers, gelling agents, thickeners, polyhydric alcohols, solubilizers, pH adjusters, antioxidants, preservatives, stabilizers, etc. These may be used alone or in appropriate combinations of two or more.

[0067] The oil component is not particularly limited as long as it is an oily component commonly used in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc., and examples thereof include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, and petrolatum; waxes such as white beeswax, carnauba wax, candelilla wax, and lanolin; fats and oils such as soybean oil, hard fat, castor oil, olive oil, and triacylglycerol; behenyl alcohol, lauryl alcohol, myristyl alcohol, isostearyl alcohol, cetanol, stearyl alcohol, and oleic acid; Examples of suitable oils include alcohols such as methyl alcohol and cholesterol; fatty acids such as palmitic acid, stearic acid and oleic acid; fatty acid esters such as cetyl 2-ethylhexanoate, hexadecyl isostearate, isopropyl myristate, isopropyl palmitate and octyldodecyl myristate; polybasic acid esters such as diethyl sebacate, diisopropyl adipate and diisopropyl sebacate; silicone oils such as methylpolysiloxane; and vitamin derivatives such as retinol palmitate and tocopherol acetate. Among these, one or more oils selected from the group consisting of hydrocarbons, waxes, oils and fats, alcohols, fatty acids, fatty acid esters, silicone oils, and vitamin derivatives are preferred, and one or more oils selected from the group consisting of hydrocarbons, oils and fats, fatty acids, and fatty acid esters are more preferred. The content of the oil is not particularly limited, but is preferably from 1 to 40% by mass, more preferably from 5 to 30% by mass, and particularly preferably from 10 to 25% by mass, relative to the total mass of the composition.

[0068] The emulsifier may be a nonionic surfactant or an ionic surfactant. Examples of nonionic surfactants include polyhydric alcohol fatty acid esters or polyhydric alcohol alkyl ethers such as propylene glycol mono-fatty acid esters, ethylene glycol mono-fatty acid esters, glycerin mono-fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, methyl glucoside fatty acid esters, and alkyl polyglucosides; polyoxyethylene ethers such as polyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, and polyoxyethylene polyoxypropylene alkyl ethers; ether esters such as polyoxyethylene mono-fatty acid esters, polyethylene glycol di-fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene methyl glucoside fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene vegetable oils, polyoxyethylene alkyl ether fatty acid esters, and polyoxyethylene polyoxypropylene glycol. Examples of ionic surfactants include sodium lauryl sulfate and sodium cetyl sulfate. The content of the emulsifier is not particularly limited, but is preferably from 0.01 to 15% by mass, more preferably from 0.1 to 10% by mass, and particularly preferably from 1 to 5% by mass, relative to the total mass of the composition.

[0069] Examples of gelling agents include acrylic acid polymers such as carboxyvinyl polymers; polyvinyl alcohol; and polyvinylpyrrolidone. Examples of thickeners include polyvinylpyrrolidone, colloidal aluminum silicate, xanthan gum, locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, and albumin. Examples of polyhydric alcohols include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, macrogol, and polypropylene glycol. Examples of solubilizers include the nonionic surfactants or ionic surfactants exemplified above as emulsifiers, as well as glycerin, liquid paraffin, crotamiton, macrogol, and the like.

[0070] Examples of pH adjusters include organic acids or salts thereof such as citric acid, sodium citrate, anhydrous citric acid, malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, acetic acid, sodium acetate, and glacial acetic acid; inorganic acids or salts thereof such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, and sodium hydrogen carbonate; alkali hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide; and amines such as triethanolamine, diethanolamine, and diisopropanolamine. Examples of antioxidants include sodium sulfite, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, cysteine ​​hydrochloride, citric acid, tocopherol, tocopherol acetate, soybean lecithin, and propyl gallate. Examples of preservatives include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, and aminoethylsulfonic acid. Examples of stabilizers include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated oil, and cysteine.

[0071] In addition, the liquid or semi-solid composition of the present invention may contain other medicinal ingredients, such as wound healing agents, moisturizing agents, anti-inflammatory ingredients, antipruritic agents, whitening ingredients, etc., depending on the purpose of use, dosage form, etc.

[0072] Examples of wound healing agents include allantoin, allantoin chlorohydroxyaluminum, allantoin hydroxyaluminum, panthenol, and the like. Examples of moisturizing agents include heparinoids; polyhydric alcohols such as glycerin, 1,3-butylene glycol, and propylene glycol; polymeric compounds such as collagen and chitosan; amino acids such as glycine, alanine, and aspartic acid; natural moisturizing factors such as sodium lactate and ceramide; and plant extracts such as chamomile extract and aloe extract. Examples of anti-inflammatory ingredients include hydrocortisone, prednisolone, methylprednisolone, clobetasone, betamethasone, dexamethasone, cortisone, flumethasone, beclomethasone, fluticasone, calamine, zinc oxide, guaiazulene, tocopherol acetate, pyridoxine hydrochloride, menthol, camphor, turpentine oil, indomethacin, ibuprofen, ketoprofen, felbinac, piroxicam, salicylic acid, and derivatives thereof. Examples of antipruritic agents include nonylic acid vanillylamide, capsaicin, benzyl nicotinate, and capsicum tincture.

[0073] Examples of whitening ingredients include ascorbic acid and its derivatives and salts thereof, vitamin A and its derivatives, pantothenic acid and its derivatives, hydroquinones such as arbutin and its derivatives, resorcinol and its derivatives such as ellagic acid, kojic acid, and rucinol, chamomilla recutita (chamomilla ET), cysteine ​​and its derivatives and salts thereof, glabridin, glabrene, liquiritin, isoliquiritin, ferulic acid and its derivatives and salts thereof, caffeic acid and its derivatives and salts thereof, etc. Extracts that exhibit whitening activity may also be used as whitening ingredients. Examples of such extracts include cicada extract, placenta extract, chamomile extract, animal and plant extracts containing carotenoids, asparagus extract, pea extract, Chinese laurel extract, Scutellaria root extract, Ononis extract, raspberry extract, Sophora root extract, Chinese laurel extract, Gokahi extract, coffee extract, rice bran extract, wheat germ extract, Chinese rhizome extract, hawthorn extract, sunflower extract, white lily extract, peony extract, Japanese laurel extract, soybean extract, tea extract, molasses extract, tomato extract, white angelica extract, beech bud extract, grape extract, flordemanita extract, hop extract, squid extract, mokka extract, saxifrage extract, eucalyptus extract, coix seed extract, and monk fruit extract.

[0074] The pH of the liquid or semi-solid composition of the present invention is not particularly limited, but is preferably 5 to 9, and particularly preferably 6 to 8, when measured at 25°C. The consistency of the liquid or semi-solid composition of the present invention is not particularly limited, but is preferably 1 to 70 gf, more preferably 1 to 50 gf, and particularly preferably 3 to 30 gf. Here, the consistency represents the maximum stress when a metal ball with a diameter of 1 cm is thrust 1 cm into the composition at a speed of 300 mm / min at 25°C, and can be measured using a small tabletop tester (EZ TEST, manufactured by Shimadzu Corporation).

[0075] The liquid or semi-solid composition of the present invention can be produced in accordance with known methods described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 17th Edition, etc., except for using components (A), (B), and (C).

[0076] The method of administration or application of the liquid or semi-solid composition of the present invention is not particularly limited, and includes oral and parenteral administration such as transdermal and vaginal administration. In the present invention, parenteral administration is preferred, and transdermal administration is particularly preferred, due to the properties of the liquid or semi-solid composition (such as the ability to flexibly apply only the required amount depending on the location, shape, and area of ​​the affected area).

[0077] In the present invention, the dosage form of the liquid or semi-solid composition is not particularly limited and can be appropriately selected from dosage forms described in, for example, the General Rules for Preparations in the Japanese Pharmacopoeia, Seventeenth Edition, etc., depending on the intended use, etc. Specific examples of such dosage forms include those described in the General Rules for Preparations in the Japanese Pharmacopoeia, Seventeenth Edition, such as preparations to be applied to the skin, etc. (external liquid preparations, sprays, ointments, creams, gels, patches, etc.). In the present invention, the dosage form is preferably selected from the group consisting of external liquid preparations, sprays, ointments, creams, gels, and patches, and more preferably selected from the group consisting of external liquid preparations, sprays, ointments, creams, and gels. More specifically, examples of the dosage form include a dosage form selected from the group consisting of liniments, lotions, external aerosols, pump sprays, ointments, creams, gels, tapes, and poultices. Among these, a dosage form selected from the group consisting of lotions, ointments, creams, and gels is preferred, and an emulsion lotion is particularly preferred. The emulsion lotion refers to a lotion prepared as an emulsion, and may be either an oil-in-water type or a water-in-oil type, with the oil-in-water type being preferred.

[0078] The liquid or semi-solid composition of the present invention contains urea and a plant of the genus Lagerstroemia or an extract thereof, and therefore can be used as a medicine, quasi-drug, cosmetic, etc., for example, as a medicine, quasi-drug, cosmetic, etc. for the treatment of skin diseases accompanied by dryness. The composition is preferably useful as a medicine having as its efficacy and effect the treatment of diseases and symptoms selected from ichthyosis, senile xerosis, atopic skin, keratoderma tylodes palmaris progressiva (dry type of housewives' eczema), plantar fissured dermatitis, palmoplantar keratosis, and lichen pilaris; a medicine having as its efficacy and effect the treatment of dry skin accompanied by itching (xerosis in adults and the elderly, dry skin in children, etc.); and a medicine having as its efficacy and effect the treatment of diseases and symptoms selected from dry fingers, keratosis of the elbows, knees, heels, and ankles, xerosis in the elderly, and cold skin.

[0079] Next, the invention in the form of a "method" will be described below. The present invention comprises the following components (A) and (B): (A) Urea; (B) a plant of the genus Lacertilia or an extract thereof; a liquid or semi-solid composition containing the above, and one or more selected from the group consisting of the following components (C-1), (C-2), and (C-3); (C-1) a compound represented by the above general formula (1) or a salt thereof; (C-2) Local anesthetics; (C-3) glycyrrhetinic acids; The present invention also relates to a method for inhibiting discoloration of a composition, which comprises the step of incorporating In such an embodiment of the invention, the order of the step of blending component (A), the step of blending component (B), and the step of blending one or more selected from the group consisting of components (C-1), (C-2), and (C-3) is not particularly limited, as long as a liquid or semi-solid composition containing component (A), component (B), and component (C) is produced directly or indirectly. In this embodiment of the invention, the meanings of various terms, the amounts of each component, etc. are all the same as those explained for the "liquid or semi-solid composition."

[0080] This specification discloses the invention exemplified below in relation to the above embodiments, but is not limited to these in any way.

[0081] [1-1] The following components (A), (B), and (C): (A) Urea; (B) a plant of the genus Lacertilia or an extract thereof; (C) one or more selected from the group consisting of the following components (C-1), (C-2), and (C-3): (C-1) The following general formula (1)

[0082] [ka]

[0083] [In formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, and R 1 represents a hydrogen atom, a hydroxyl group, or an alkyl group, and R 2 represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent, and R 3 represents a hydrogen atom or a halogen atom.]

[0084] A compound represented by the formula (I) or a salt thereof; (C-2) Local anesthetics; (C-3) glycyrrhetinic acids; A liquid or semi-solid composition comprising:

[0085] [1-2] The composition according to [1-1], wherein component (B) is arnica or an extract thereof. [1-3] The composition according to [1-1] or [1-2], wherein component (B) is an arnica extract using a lower monohydric alcohol, water, propylene glycol, 1,3-butylene glycol, or a mixture of two or more of these as the extraction solvent. [1-4] The composition according to any one of [1-1] to [1-3], wherein component (B) is arnica, arnica tincture, or arnica extract.

[0086] [1-5] The composition according to any one of [1-1] to [1-4], wherein the component (C-1) is one or more selected from the group consisting of chlorpheniramine, salts of chlorpheniramine, diphenhydramine, and salts of diphenhydramine. [1-6] The composition according to any one of [1-1] to [1-5], wherein component (C-2) is one or more selected from the group consisting of dibucaine, tetracaine, bupivacaine, procaine, propitocaine, benzocaine, mepivacaine, meprylcaine, lidocaine, and salts thereof. [1-7] The composition according to any one of [1-1] to [1-6], wherein the component (C-2) is one or more selected from the group consisting of dibucaine, a salt of dibucaine, lidocaine, and a salt of lidocaine. [1-8] The composition according to any one of [1-1] to [1-7], wherein the component (C-3) is one or more members selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, and salts thereof. [1-9] The composition according to any one of [1-1] to [1-8], wherein the dosage form is selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel.

[0087] [2-1] The following components (A) and (B): (A) Urea; (B) a plant of the genus Lacertilia or an extract thereof; a liquid or semi-solid composition containing the above, and one or more selected from the group consisting of the following components (C-1), (C-2), and (C-3); (C-1) a compound represented by the above general formula (1) or a salt thereof; (C-2) Local anesthetics; (C-3) glycyrrhetinic acids; A method for inhibiting discoloration of a composition, comprising the step of incorporating [2-2] The method according to [2-1], wherein component (B) is arnica or an extract thereof. [2-3] The method according to [2-1] or [2-2], wherein component (B) is an arnica extract using a lower monohydric alcohol, water, propylene glycol, 1,3-butylene glycol, or a mixture of two or more of these as the extraction solvent. [2-4] The method according to any one of [2-1] to [2-3], wherein component (B) is arnica, arnica tincture, or arnica extract.

[0088] [2-5] The method according to any one of [2-1] to [2-4], wherein the component (C-1) is at least one member selected from the group consisting of chlorpheniramine, a salt of chlorpheniramine, diphenhydramine, and a salt of diphenhydramine. [2-6] The method according to any one of [2-1] to [2-5], wherein the component (C-2) is one or more selected from the group consisting of dibucaine, tetracaine, bupivacaine, procaine, propitocaine, benzocaine, mepivacaine, meprylcaine, lidocaine, and salts thereof. [2-7] The method according to any one of [2-1] to [2-6], wherein the component (C-2) is at least one selected from the group consisting of dibucaine, a salt of dibucaine, lidocaine, and a salt of lidocaine. [2-8] The method according to any one of [2-1] to [2-7], wherein the component (C-3) is at least one member selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid, and salts thereof. [2-9] The method according to any one of [2-1] to [2-8], wherein the composition is in a dosage form selected from the group consisting of an external solution, a spray, an ointment, a cream, and a gel. [Example]

[0089] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0090] [Test Example 1] Storage test Liquid compositions having the formulations shown in Table 1 were prepared by a conventional method. Each of the resulting compositions was placed in a glass bottle (No. 5 screw tube bottle: Maruem Co., Ltd.) and stored at 60°C for 1 day. The degree of discoloration (yellowing) before and after storage was evaluated by measuring the color difference (ΔYI) of the composition before and after storage using a color difference meter (spectrophotometer CM-700d: Konica Minolta Sensing Inc.). The results are shown in Table 1.

[0091] [Table 1]

[0092] As shown in the results in Table 1, the compositions containing urea and arnica tincture alone in the solvent (Reference Examples 1 and 2) had low ΔYI values ​​and virtually no discoloration was observed, whereas the composition containing both urea and arnica tincture (Comparative Example 1) had a ΔYI value that was more than 30 times higher, demonstrating that the coexistence of these two components causes discoloration when stored at high temperatures. On the other hand, in the compositions (Examples 1 and 2) containing diphenhydramine hydrochloride or chlorpheniramine maleate in addition to urea and arnica tincture, the ΔYI value was less than half that of Comparative Example 1, demonstrating that discoloration during high-temperature storage was suppressed.

[0093] From the above test results, it was revealed that when a plant of the genus Lacertilia, such as arnica tincture, or an extract thereof is further mixed with a compound represented by general formula (1), such as diphenhydramine or a salt thereof, or chlorpheniramine or a salt thereof, the product is relatively resistant to discoloration (yellowing) even when stored at high temperatures, and has excellent storage stability.

[0094] [Test Example 2] Storage test Liquid compositions having the formulations shown in Table 2 were prepared by conventional methods, and tests were carried out in the same manner as in Test Example 1. The results are shown in Table 2.

[0095] [Table 2]

[0096] As shown in the results in Table 2, the compositions containing urea and arnica tincture alone in the solvent (Reference Examples 1 and 2) had low ΔYI values ​​and virtually no discoloration was observed, whereas the composition containing both urea and arnica tincture (Comparative Example 1) had a ΔYI value that was more than 30 times higher, demonstrating that the coexistence of these two components causes discoloration when stored at high temperatures. On the other hand, in the compositions (Examples 3 and 4) containing dibucaine hydrochloride or lidocaine hydrochloride in addition to urea and arnica tincture, the ΔYI value was less than half that of Comparative Example 1, demonstrating that discoloration during high-temperature storage was suppressed.

[0097] From the above test results, it was revealed that when urea, a plant of the genus Lacertilia, such as arnica tincture, or an extract thereof is further mixed with a local anesthetic, such as dibucaine or its salt, or lidocaine or its salt, the product is relatively resistant to discoloration (yellowing) even when stored at high temperatures, and has excellent storage stability.

[0098] [Test Example 3] Storage test Liquid compositions having the formulations shown in Table 3 were prepared by conventional methods, and tests were carried out in the same manner as in Test Example 1. The results are shown in Table 3.

[0099] [Table 3]

[0100] As shown in the results in Table 3, the compositions containing urea and arnica tincture alone in the solvent (Reference Examples 1 and 2) had low ΔYI values ​​and virtually no discoloration was observed, whereas the composition containing both urea and arnica tincture (Comparative Example 1) had a ΔYI value that was more than 30 times higher, demonstrating that the coexistence of these two components causes discoloration when stored at high temperatures. On the other hand, in the compositions (Examples 5 and 6) containing urea, arnica tincture, and further containing glycyrrhetinic acid or dipotassium glycyrrhizinate, the ΔYI value was less than half that of Comparative Example 1, demonstrating that discoloration during high-temperature storage was suppressed.

[0101] From the above test results, it was revealed that when urea, a plant of the genus Lacertilia, such as arnica tincture, or an extract thereof is further mixed with glycyrrhetinic acid, such as dipotassium glycyrrhizinate, discoloration (yellowing) is relatively unlikely to occur even when stored at high temperatures, and the product has excellent storage stability.

[0102] Examples of the preparation of the liquid or semi-solid compositions of the present invention are shown below. The content of the extract of a plant of the genus Lacertilia is expressed in terms of the amount (g) of the crude drug unless otherwise specified.

[0103] Production Example 1 (packaged lotion) Liquid compositions (Formulation Examples 1 to 8: oil-in-water emulsion lotions) containing the ingredients and amounts (g) shown in Tables 4 to 5 below per 100 g were prepared by a conventional method and placed in polypropylene bottle containers to produce the packaged lotions of Preparation Examples 1-1 to 1-8, respectively.

[0104] [Table 4]

[0105] [Table 5]

[0106] Production Example 2 (Packaged cream) Semi-solid compositions (Formulation Examples 9 to 16: oil-in-water creams) containing the ingredients and amounts (g) shown in Tables 6 to 7 below per 100 g were prepared in a conventional manner, and placed in tube containers (laminated tubes) made of laminated film, with a low-density polyethylene film as the innermost layer, a nylon film on the outer side (middle layer), and a low-density polyethylene film on the outer side thereof, to give packaged creams of Preparation Examples 2-1 to 2-8, respectively.

[0107] [Table 6]

[0108] [Table 7]

[0109] Production Example 3 (Emulsion Lotion) A liquid composition (oil-in-water emulsion lotion) containing the following ingredients in the amounts listed below per 100 g was prepared in a conventional manner and placed in a polyethylene bottle. urea 20g Arnica tincture 0.2g (equivalent to 44mg of crude drug) Diphenhydramine hydrochloride 1g Glycyrrhetinic acid 0.3g Tocopherol acetate 0.5g White petrolatum, stearyl alcohol, olive oil, squalane, octyldodecyl myristate, concentrated glycerin, carboxyvinyl polymer, xanthan gum, polysorbate 60, polyoxyethylene hydrogenated castor oil 50, sorbitan monostearate, sodium edetate hydrate, DL-alanine, glycine, citric acid hydrate, sodium hydroxide, purified sodium hyaluronate and purified water (appropriate amount)

[0110] Production Example 4 (Cream) A semi-solid composition (oil-in-water cream) containing the following ingredients and amounts per 100 g was prepared in a conventional manner and placed in a laminated tube container made of polyethylene and polyvinyl alcohol. urea 20g Arnica tincture 0.2g (equivalent to 44mg of crude drug) Glycyrrhetinic acid 0.3g Tocopherol acetate 0.5g White petrolatum, light liquid paraffin, octyldodecyl myristate, cetanol, stearyl alcohol, dimethylpolysiloxane, concentrated glycerin, carboxyvinyl polymer, xanthan gum, polysorbate 60, polyoxyethylene hydrogenated castor oil 50, sorbitan monostearate, sodium edetate hydrate, glycine, DL-alanine, potassium dihydrogen phosphate, sodium hydroxide, purified sodium hyaluronate and purified water (as needed)

[0111] Production Example 5 (Cream) A cream preparation of Production Example 5 was obtained in exactly the same manner as in Production Example 4, except that the container was changed to a polypropylene bottle container.

[0112] Production Example 6 (Cream) A semi-solid composition (oil-in-water cream) containing the following ingredients in the amounts listed below per 100 g was prepared in a conventional manner and placed in a polypropylene bottle. urea 20g Arnica tincture 0.2g (equivalent to 44mg of crude drug) Diphenhydramine hydrochloride 1g Glycyrrhetinic acid 0.3g Tocopherol acetate 0.5g White petrolatum, light liquid paraffin, octyldodecyl myristate, cetanol, stearyl alcohol, dimethylpolysiloxane, concentrated glycerin, carboxyvinyl polymer, xanthan gum, polysorbate 60, polyoxyethylene hydrogenated castor oil 50, sorbitan monostearate, sodium edetate hydrate, glycine, DL-alanine, potassium dihydrogen phosphate, sodium hydroxide, purified sodium hyaluronate and purified water (as needed)

[0113] Production Example 7 (Emulsion Lotion) A liquid composition (oil-in-water emulsion lotion) containing the following ingredients in the amounts listed below per 100 g was prepared in a conventional manner and placed in a polyethylene bottle. urea 20g Arnica tincture 0.2g (equivalent to 44mg of crude drug) Diphenhydramine hydrochloride 1g Glycyrrhetinic acid 0.3g Crotamiton 5g Lidocaine 2g Liquid paraffin, squalane, cetanol, isopropyl myristate, polysorbate 60, polyoxyethylene hydrogenated castor oil, glycerin, propylene glycol, paraben, carboxyvinyl polymer, triethanolamine and purified water (appropriate amount)

[0114] Production Example 8 (Cream) A semi-solid composition (oil-in-water cream) containing the following ingredients and amounts per 100 g was prepared in a conventional manner and placed in a laminated tube container made of polyethylene and polyvinyl alcohol or a polypropylene bottle container. urea 20g Arnica tincture 0.2g (equivalent to 44mg of crude drug) Glycyrrhetinic acid 0.3g Tocopherol acetate 0.5g Crotamiton 5g Squalane, petrolatum, liquid paraffin, dimethylpolysiloxane, isopropyl myristate, cetanol, stearyl alcohol, self-emulsifying glycerin stearate, polysorbate 60, polyoxyethylene hydrogenated castor oil, glycerin, propylene glycol, xanthan gum, paraben, glycine, triethanolamine and purified water (appropriate amount)

[0115] Manufacturing Example 9 (Cream) A semi-solid composition (cream) containing the following ingredients in the amounts listed below per 100 g was prepared in a conventional manner and placed in a polypropylene bottle. urea 20g Arnica tincture 0.2g (equivalent to 44mg of crude drug) Diphenhydramine hydrochloride 1g Glycyrrhetinic acid 0.3g Crotamiton 5g Lidocaine 2g Squalane, petrolatum, liquid paraffin, dimethylpolysiloxane, isopropyl myristate, cetanol, stearyl alcohol, self-emulsifying glycerin stearate, polysorbate 60, polyoxyethylene hydrogenated castor oil, glycerin, propylene glycol, xanthan gum, paraben, glycine, triethanolamine and purified water (appropriate amount) [Industrial Applicability]

[0116] According to the present invention, discoloration of a liquid or semi-solid composition containing urea and a plant of the genus Lagerstroemia or an extract thereof during high-temperature storage can be suppressed. Therefore, it is possible to provide drugs, quasi-drugs, cosmetics, etc. for treating skin diseases accompanied by dryness, which have excellent storage stability, and can be suitably used in the pharmaceutical industry, etc.

Claims

1. The following components (A), (B), and (C): (A) Urea; (B) a plant of the genus Lacertilia or an extract thereof; (C) one or more selected from the group consisting of the following components (C-1) and (C-2): (C-1) one or more selected from the group consisting of chlorpheniramine, salts of chlorpheniramine, diphenhydramine, and salts of diphenhydramine; (C-2) one or more selected from the group consisting of dibucaine, a salt of dibucaine, lidocaine, and a salt of lidocaine; A liquid or semi-solid composition comprising:

2. 2. The composition of claim 1, wherein component (B) is arnica or an extract thereof.

3. 3. The composition according to claim 1 or 2, wherein component (B) is arnica, arnica tincture or arnica extract.

4. The composition according to any one of claims 1 to 3, which is in a dosage form selected from the group consisting of an external liquid, a spray, an ointment, a cream, and a gel.

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