JP2021088509A - Pharmaceutical - Google Patents

Abstract

To suppress the discoloration of the surface of a metal member when a liquid or semisolid composition containing a local anesthetic component and an anti-histamine component is stored in a container including the metal member.SOLUTION: In a pharmaceutical, a liquid or semisolid composition containing following components (A) and (B) is stored in a container including a metal member. The component (A) is at least one selected from the group consisting of following components (A-1) and (A-2): (A-1) a local anesthetic component and (A-2) an anti-histamine component. The component (B) is at least one selected from the group consisting of following components (B-1)-(B-3): (B-1) a terpene, (B-2) a glycyrrhetinic acid and (B-3) a steroid.SELECTED DRAWING: None

Description

The present invention relates to pharmaceutical products and the like.

Local anesthetic components such as dibucaine, procaine, mepivacaine, mepivacaine, and lidocaine all have similar chemical structures in which aromatic and amino groups are linked via an intermediate chain. When applied locally to the skin or mucous membranes, the local anesthetic component is said to relieve pain and pruritus in the affected area by paralyzing the sensory nerves.
In addition, antihistamine components such as isothipendyl, chlorpheniramine, diphenylpyraline, and diphenhydramine also have a similar chemical structure in which an aromatic group and an amino group are linked via an intermediate chain, similar to the local anesthetic component. When applied locally to the skin, mucous membranes, etc., the antihistamine component exerts an antipruritic effect due to its antihistamine effect. Furthermore, for example, diphenhydramine has a similar chemical structure to lidocaine and is said to exert a local anesthetic effect.
Therefore, these local anesthetic and antihistamine components are antipruritic and anti-inflammatory agents for symptoms such as eczema, dermatitis, sores, rashes, rashes, itching, rashes, insect bites, and hives, and topical agents for itchiness and urticaria. It is widely used as an active ingredient of external preparations such as urticaria.

When a local anesthetic component or an antihistamine component is used as an active ingredient of an external preparation, it is applied to the affected area as a liquid or semi-solid composition such as an external coating agent such as a lotion or a gel. It becomes possible to flexibly administer the required amount of the drug according to the position, shape and range of the drug. So far, liquid or semi-solid compositions containing a local anesthetic component and an antihistamine component are contained in a coating container or the like having a sponge-like coating portion, and the like has been sold. The part may be worn or deteriorated due to long-term use.
On the other hand, a container (so-called roll-on container) in which a plastic or metal ball is provided in the coating portion and the composition in the container is applied by pressing the ball against the coating target portion and rolling the ball is more suitable. It has been considered that a drug that can withstand long-term use and has good quality stability can be provided.

By the way, Patent Document 1 describes an external preparation product comprising a liquid composition containing a local anesthetic component and an antihistamine component, and a roll-on container filled with the liquid composition and having a metal coating ball. ..
However, Patent Document 1 does not disclose the combination of the local anesthetic component and the terpenes, nor does it disclose the interaction between the composition and the metal-coated balls.

Japanese Unexamined Patent Publication No. 2014-193850

In view of the above situation, the present inventor has decided to develop a pharmaceutical product in which a liquid or semi-solid composition containing a local anesthetic component and an antihistamine component is contained in a roll-on container. Affected areas to which a composition containing a local anesthetic component or an antihistamine component is applied are often heated due to inflammation or the like. Therefore, it is considered that adopting a metal ball for the roll-on container gives a cooling feeling to the affected part and improves the usability.
Therefore, the present inventor presents a local anesthetic component represented by lidocaine (hereinafter, may be referred to as "component (A-1)") or an antihistamine component represented by diphenhydramine (hereinafter, "component (A)"). -2) ", and the component (A-1) and the component (A-2) may be collectively referred to as" component (A) ") in a liquid or semi-solid state. In order to develop a drug in which the composition of the above is contained in a roll-on container equipped with a metal ball, first, a liquid or semi-solid composition containing a local anesthetic component or an antihistamine component is brought into contact with a metal member. When the storage stability was confirmed, it was clarified that the surface of the metal member was discolored over time due to long-term storage, causing a problem in storage stability. Techniques for solving such problems may be applicable not only to roll-on containers with metal balls, but also to containers with a wide variety of metal members.
Therefore, it is an object of the present invention to suppress discoloration of the surface of a metal member when a liquid or semi-solid composition containing a local anesthetic component or an antihistamine component is housed in a container containing a metal member.

Therefore, as a result of diligent studies to solve the above problems, the present inventor has made a liquid or semi-solid composition containing a local anesthetic component and an antihistamine component, and further represented by menthol, camphor, and isopropylmethylphenol. Terpenes (hereinafter, may be referred to as "component (B-1)"), glycyrrhetinic acids typified by glycyrrhizic acid (hereinafter, may be referred to as "component (B-2)"), or Steroids typified by dexamethasone acetate (hereinafter, may be referred to as "component (B-3)". In addition, component (B-1), component (B-2) and component (B-3) are referred to. The present invention has been completed by finding that discoloration of the surface of a metal member is suppressed by containing (sometimes collectively referred to as "component (B)").

That is, the present invention describes the following components (A) and (B):
(A) One or more selected from the group consisting of the following components (A-1) and (A-2);
(A-1) Local anesthetic component (A-2) Antihistamine component (B) One or more selected from the group consisting of the following components (B-1) to (B-3);
(B-1) Terpenes (B-2) Glycyrrhetinic Acids (B-3) To provide a pharmaceutical product in which a liquid or semi-solid composition containing steroids is contained in a container provided with a metal member. It is a thing.

According to the present invention, when a liquid or semi-solid composition containing a local anesthetic component or an antihistamine component is contained in a container containing a metal member, discoloration of the surface of the metal member that may occur due to long-term storage is observed. Can be suppressed. Therefore, it is possible to provide a drug having excellent storage stability.

In the present specification, "w / v%" means a mass-to-volume percentage, and specifically, means the mass (g) of each component contained in 100 mL of the composition.

<Ingredient (A-1)>
In the present specification, the "local anesthetic component" is not particularly limited as long as it has a local anesthetic action, and specifically, for example, ethyl aminobenzoate, dibucaine, tetracaine, procaine, bupivacaine, propitocaine, and the like. Benzocaine, mepivacaine, meprilcaine, lidocaine itself, as well as their pharmaceutically acceptable salts, as well as ethyl aminobenzoate, dibucaine, tetracaine, procaine, bupivacaine, propitocaine, benzocaine, mepivacaine, meprilcaine, lidocaine itself and their pharmaceuticals. It is a concept that also includes a solvent mixture of an acceptable salt and water, alcohol, or the like. Here, the salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and for example, an inorganic acid salt such as a hydrochloride, a sulfate, a nitrate, a hydrofluoride salt, and a hydrobromide; an acetate salt. , Tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate Examples thereof include organic acid salts such as acid salts.
It should be noted that these can be used alone or in combination of two or more.
These local anesthetic components are known components and can be produced by a known method, or commercially available ones may be used. Examples of commercially available products include lidocaine hydrochloride (manufactured by Iwaki Pharmaceutical Co., Ltd.).

As the component (A-1), one or more selected from the group consisting of ethyl aminobenzoate, dibucaine, procaine, mepivacaine, meprilucaine, lidocaine and their inorganic acid salts and their solvates is preferable, and aminobenzoic acid is preferable. One or more selected from the group consisting of ethyl, dibucaine, procaine, mepibacaine, meprilucaine, lidocaine and their hydrochlorides and their solvates are more preferable, and ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, procaine, procaine hydrochloride One or more selected from the group consisting of salts, mepibacaine, meprilucaine hydrochloride, lidocaine and lidocaine hydrochloride is more preferable, and one selected from the group consisting of ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, lidocaine and lidocaine hydrochloride. The above is particularly preferable.

In the present invention, the content of the component (A-1) in the liquid or semi-solid composition is not particularly limited, and may be appropriately examined and determined according to the desired medicinal effect and the like. In the present invention, the component (A-1) is preferably contained in a total amount of 0.001 to 20 w / v%, preferably 0.01 to 10 w / v%, based on the total volume of the composition in terms of free form. Is more preferable, and 0.1 to 3 w / v% is particularly preferable.
Above all, when one or more selected from the group consisting of dibucaine, a pharmaceutically acceptable salt thereof, and a solvate thereof are used as the component (A-1), the total volume of the composition is converted into a free form. The total content is preferably 0.001 to 5 w / v%, more preferably 0.01 to 1 w / v%, and particularly preferably 0.1 to 0.5 w / v%.
In addition, when one or more selected from the group consisting of lidocaine, a pharmaceutically acceptable salt thereof, and a solvate thereof are used as the component (A-1), the total volume of the composition is converted into a free form thereof. The total content is preferably 0.01 to 10 w / v%, more preferably 0.1 to 5 w / v%, and particularly preferably 0.5 to 2 w / v%.
Further, when ethyl aminobenzoate is used as the component (A-1), it is preferably contained in a total of 0.01 to 5 w / v% based on the total volume of the composition in terms of its free form, preferably 0.05. It is more preferably contained in an amount of ~ 2 w / v%, and particularly preferably 0.1 to 1 w / v%.

<Ingredient (A-2)>
In the present invention, the "antihistamine component" is not particularly limited as long as it has a histamine H1 receptor antagonism, and specifically, for example, azelastine, alimemazine, isothipendyl, iploheptadine, ebastine, epinastine, etc. Emedastine, oxatomide, olopatadine, carbinoxamine, cremastine, chlorpheniramine, ketotiphen, dipheterol, diphenylpyraline, diphenhydramine, cyproheptadine, cetirizine, triprolidine, tryperenamine, tonzilamine, fexofenadine, phenetadine, promethadine, bepotastine , Metodilazine, mebuhydrolin and loratadine, pharmaceutically acceptable salts thereof and one or more selected from the group consisting of solvates thereof. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with inorganic acids, organic acids, inorganic bases, organic bases, and the like, and examples thereof include hydrochlorides, tartrates, and maleates. , Fumarate, diphenyldisulfonate, theocruate, salicylate, tannate, besylate, napadisylate, phosphate and the like. Further, when an asymmetric carbon is present in the chemical structure of the antihistamine component, it has various optical isomers, but in the present invention, any optical isomer may be contained and a single optical isomer may be used. It may be a mixture of various optical isomers. Further, as described above, various compounds having a histamine H1 receptor antagonism such as azelastine and solvates of salts thereof and water, alcohol and the like are also included in the "antihistamine component".
It should be noted that these can be used alone or in combination of two or more.
These antihistamine components are known components, can be produced by a known method, or commercially available ones can be used. Examples of commercially available products include diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.).

Specific examples of the antihistamine component used in the present invention include azelastine such as azelastine hydrochloride or a salt thereof; alimemazine such as alimemazine tartrate or a salt thereof; isotipendyl such as isotipendyl hydrochloride or a salt thereof; iproheptin hydrochloride. Iproheptin or a salt thereof; evastin or a salt thereof; azelastine such as epinastin hydrochloride or a salt thereof; emedastine such as emedastine fumarate or a salt thereof; oxatomide or a salt thereof; olopatadine such as olopatadine hydrochloride or a salt thereof Salt; carbinoxamine such as carbinoxamine diphenyldisulfonate, carbinoxamine maleate or a salt thereof; cremastine such as cremastine fumarate or a salt thereof; d-chlorphenylamine maleate, dl-chlorphenylamine maleic acid Chlorpheniramine such as salt or a salt thereof; ketotiphen or a salt thereof such as ketotiphen fumarate; diphenylol or a salt thereof such as difeterol hydrochloride and dipheterol phosphate; diphenylpyraline hydrochloride, diphenylpyraline theocrate and the like Diphenylpyraline or a salt thereof; diphenhydramine such as diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydraminetannate or a salt thereof; cyproheptazine such as cyproheptazine hydrochloride hydrate or a salt thereof; Triprolyzine such as hydrochloride or a salt thereof; Tryperenamine such as tryperenamine hydrochloride or a salt thereof; Tondylamine such as tonzilamine hydrochloride or a salt thereof; Fexophenazine or a salt thereof; Fenetazine such as phenetazine hydrochloride or a salt thereof; Promethazine hydrochloride , Promethazine or salt thereof such as promethazine methylene disalicylate; bepotastine or salt thereof such as bepotastine besilate; homochlorcyclidine or salt thereof such as homochlorcyclidine hydrochloride; mekitadin or salt thereof; metodirazine hydrochloride Et al. Metodirazine or a salt thereof; Mebhydrolin or a salt thereof such as mebuhydrolin napadicylate; Loratazine or a salt thereof and the like can be mentioned. In the present invention, at least one selected from the group consisting of isothipendyl, chlorpheniramine, diphenylpyraline and diphenhydramine and salts thereof is preferable, and isothipendyl hydrochloride, chlorpheniramine, chlorpheniramine maleate and diphenylpyraline hydrochloride are preferable. , One or more selected from the group consisting of diphenhydramine, diphenhydramine hydrochloride and diphenhydramine salicylate, more preferably, and selected from the group consisting of isothipendyl hydrochloride, chlorpheniramine, chlorpheniramine maleate, diphenhydramine and diphenhydramine hydrochloride 1 Seeds and above are particularly preferred.

In the present invention, the content of the component (A-2) in the liquid or semi-solid composition is not particularly limited, and may be appropriately examined and determined according to the desired medicinal effect and the like. In the present invention, the component (A-2) is preferably contained in a total amount of 0.001 to 15 w / v%, preferably 0.01 to 10 w / v%, based on the total volume of the composition in terms of free form. Is more preferable, and 0.1 to 3 w / v% is particularly preferable.
Above all, when one or more selected from the group consisting of chlorpheniramine, a pharmaceutically acceptable salt thereof, and a solvate thereof are used as the component (A-2), the total volume of the composition in terms of its free form is used. It is preferably contained in a total amount of 0.005 to 2 w / v%, more preferably 0.05 to 1 w / v%, and particularly preferably 0.1 to 0.5 w / v%. ..
In addition, when one or more selected from the group consisting of diphenhydramine, a pharmaceutically acceptable salt thereof, and a solvate thereof are used as the component (A-2), the total volume of the composition is converted into a free form thereof. The total content is preferably 0.05 to 10 w / v%, more preferably 0.1 to 5 w / v%, and particularly preferably 0.5 to 2 w / v%.

<Ingredient (B-1)>
In the present invention, "terpenes" means a generic term (terpenoid) including terpene alcohol, terpene aldehyde, terpene ketone, terpene oxide, terpene lactone, etc. in addition to terpene hydrocarbons, and its structure is particularly limited. Examples thereof include monoterpenes, sesquiterpenes and derivatives thereof. Further, it may be a ring type or a chain type.
Specific examples of such terpenes include isopropylmethylphenol, isobornol, iron, osimene, carbeol, carbotanaceton, carbomenton, carbo, curene, caron, camphene, camphor, geraniol, sabinene, safranal, and cyclocitral. , Citral, citronellal, citroneric acid, citronellol, cineol, simen, silvestren, thymol, isotsjol, tsujeong, terpineol, terpinen, terpinolene, tricyclene, nerol, pinene, pinocampeol, pinol, piperitenon, ferlandral, ferlandren, Examples thereof include fenchen, fentyl alcohol, perylyl alcohol, perylaldehyde, borneol, milsen, menthol, menthone, yonor, yonon, linalool, limonene, etc., and these can be used alone or in combination of two or more. When optical isomers are present in these terpenes, any isomer is included unless otherwise specified. That is, in the present invention, unless a specific optical isomer is specified as a component name of terpenes, such component notation includes all of various optical isomers alone and a mixture thereof in an arbitrary ratio, and is a single optical. It may be an isomer or a mixture of any proportion of various optical isomers (eg, the description "menthol" includes both dl-menthol and l-menthol). ..

Among the above-mentioned terpenes, a ring-type monoterpenoid is preferable, a ring-type monoterpenoid is more preferable, and a mono-ring type or bi-ring type monoterpenoid is more preferable, and it has a p-menthan skeleton from the viewpoint of discoloration inhibitory action. Monoterpenoids (eg, unsaturated derivatives of p-menthanes such as simen, timol, terpinen, terpinolene, ferlandrene, limonene; monoterpene alcohols with p-menthane skeletons such as carbeol, terpineol, menthol; , Monoterpene ketone having a p-menthan skeleton; monoterpene aldehyde having a p-menthan skeleton such as perylaldehyde; monoterpene ether having a p-menthan skeleton such as cineole) A monoterpenoid having a monoterpenoid (eg, an unsaturated derivative of the isomer of p-menthan, such as 3-methyl-4-isopropylphenol (isopropylmethylphenol)) or a monoterpenoid having a bornan skeleton (eg, a bornan skeleton such as borneol). Monoterpene alcohols having a monoterpene alcohol; monoterpene ketones having a bornan skeleton such as camphor) are even more preferable, and one or more selected from the group consisting of timol, menthol, isopropylmethylphenol, camphor and borneol are even more preferable. , 1 or more selected from the group consisting of l-menthol, dl-menthol, isopropylmethylphenol, d-camfur, dl-camfur and d-borneol, even more preferably, l-menthol, dl-menthol, isopropylmethylphenol, One or more selected from the group consisting of d-camfur and dl-kanfur is particularly preferable.

When the terpenes are contained in the liquid or semi-solid composition, the terpenes may be used as they are, or an essential oil containing the terpenes may be used.
Such essential oils include, for example, anis oil, ylang ylang oil, iris oil, uikyo oil, orange oil, cananga oil, chamomile oil, kayapto oil, caraway oil, kubeb oil, grapefruit oil, kehi oil, coriander oil, saffron. Oil, sansho oil, perilla oil, citriodora oil, citronella oil, ginger oil, ginger oil, ginger oil, ginger glass oil, spearmint oil, peppermint oil, geranium oil, daiuikyo oil, chow oil, televisionn oil, peppermint oil , Neroli oil, basil oil, peppermint oil, palmarosa oil, piment oil, petitgrain oil, bay oil, peniroyal oil, henoposi oil, bergamot oil, boadrose oil, peppermint oil, majoran oil, mandarin oil, melissa oil, eucalyptus oil, lime Examples thereof include oil, lavender oil, linaroe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil, and these may be used alone or in combination of two or more.
Among these, Iran Iran oil, uikyo oil, orange oil, chamomile oil, keihi oil, perilla oil, citronella oil, ginger oil, citrus oil, peppermint oil, geranium oil, butterfly oil, televisionn oil, peppermint oil, neroli oil. , Hakka oil, Palmarosa oil, Bergamot oil, Eucalyptus oil, Lavender oil, Linaroye oil, Lemon oil, Rose oil, Rosemary oil, Roman chamomile oil, etc. are preferable. Is more preferable, and peppermint oil and eucalyptus oil are particularly preferable.

In the present invention, the content of the component (B-1) in the liquid or semi-solid composition is not particularly limited and may be determined by appropriate examination, but from the viewpoint of the discoloration suppressing action, the component (B-) 1) is preferably contained in a total amount of 0.001 to 20 w / v%, more preferably 0.01 to 15 w / v%, and 0.1 to 10 w / v% based on the total volume of the composition. It is particularly preferable to do so.
Above all, when camphor is used as the component (B-1), it is preferable to contain camphor in a total amount of 0.001 to 15 w / v% with respect to the total volume of the composition from the viewpoint of tarnish suppressing action. It is more preferably contained in an amount of 01 to 10 w / v%, and particularly preferably in an amount of 0.1 to 7 w / v%. When menthol is used as the component (B-1), it is preferable that menthol is contained in a total amount of 0.05 to 10 w / v% with respect to the total volume of the composition from the viewpoint of tarnish suppressing action. It is more preferably contained in an amount of 1 to 7 w / v%, and particularly preferably contained in an amount of 0.5 to 5 w / v%. Further, when isopropylmethylphenol is used as the component (B-1), isopropylmethylphenol is contained in a total amount of 0.01 to 6 w / v% based on the total volume of the composition from the viewpoint of suppressing discoloration. It is preferably contained in an amount of 0.05 to 4 w / v%, more preferably 0.1 to 2 w / v%.

Further, in the present invention, the content ratio of the component (A) and the component (B-1) contained in the liquid or semi-solid composition is not particularly limited and may be appropriately examined and determined, but it has an effect of suppressing discoloration. From this point of view, it is preferable that the component (A) is contained in an amount of 0.0001 to 600 parts by mass, preferably 0.0005 to 400 parts by mass, based on 1 part by mass of the component (A) in terms of free form. More preferably, it is particularly preferably contained in an amount of 0.005 to 200 parts by mass.
Above all, when the component (A-1) is used as the component (A), the component (A-1) is 0.005 to 50 parts by mass with respect to 1 part by mass in terms of free form. It is preferably contained, more preferably 0.01 to 30 parts by mass, and particularly preferably 0.05 to 15 parts by mass. When the component (A-2) is used as the component (A), the component (A-2) is 0.0005 to 500 parts by mass with respect to 1 part by mass in terms of free form. It is preferably contained, more preferably 0.001 to 300 parts by mass, and particularly preferably 0.01 to 100 parts by mass.

<Ingredient (B-2)>
In the present invention, "glycyrrhetinic acids" refers to glycyrrhetinic acid and its derivatives (for example, sugar-added derivatives of glycyrrhetinic acid such as glycyrrhizinic acid) and salts thereof (for example, alkali metal salts such as potassium salt and sodium salt; It means one or more species selected from the group consisting of (ammonium salt, etc.).
In the present invention, the glycyrrhetinic acid is preferably one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid and salts thereof from the viewpoint of discoloration inhibitory action, and is preferably glycyrrhetinic acid, glycyrrhizinic acid, dipotassium glycyrrhizinate, monoglycyrrhizinate. One or more selected from the group consisting of ammonium, disodium glycyrrhizinate and trisodium glycyrrhizinate is more preferable, and one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid and disodium glycyrrhizinate is further preferable. Especially preferable.

When glycyrrhetinic acid is contained in a liquid or semi-solid composition, glycyrrhetinic acid may be used as it is, or licorice (licorice) containing glycyrrhetinic acid or an extract thereof may be used. Here, "licorice" (licorice) means the root and stron of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne (Leguminosae), and is a concept that includes the one excluding its peripheral skin (peeling licorice) (10th). Seven revised Japanese Pharmacopoeia). The morphology of licorice can be adjusted as needed, and it can be cut or crushed into small pieces or lumps, or crushed into powder. For example, "licorice powder" obtained by powdering licorice can also be used. Further, in consideration of convenience of handling at the time of manufacturing the composition, "licorice extract" obtained by subjecting licorice to some kind of extraction treatment may be used. Here, the "licorice extract" includes those subjected to processing treatments such as heating, drying, and crushing in addition to the extraction treatment. Specifically, after making the elephant into an appropriate size as needed, a solution leached by adding an appropriate leachate (extraction solvent), a solution obtained by concentrating the leachate (soft extract, tincture, etc.), and further, these are added. Dried products (dried extracts, etc.) are also included in the "extract of tincture".
In the present invention, as the licorice or its extract, licorice, licorice powder, licorice extract, and licorice crude extract described in the 17th revised Japanese Pharmacopoeia are preferable.

The method for producing the extract of Kanzo is not particularly limited, and for example, the description in the sections of "extract", "immersion / decoction", "tincture", "flow extract", etc. , Can be produced with reference to a known method for producing a plant extract. Specifically, for example, licorice can be produced by cutting, heating, drying, pulverizing, etc., if necessary, and then adding an appropriate extraction solvent for extraction. The obtained extract may be further concentrated, dried or the like, if necessary.

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; benzene, toluene and the like Aromatic hydrocarbons; dimethylformamide; dimethylsulfoxide; water (including hot water) and the like. Each of these may be used alone, or two or more thereof may be used in combination. In the present invention, a lower monohydric alcohol such as water and ethanol, or a mixed solution of water / lower monohydric alcohol is preferable, and a mixed solution of water, ethanol or water / ethanol is particularly preferable.
The extraction operation is not particularly limited, and a known method used for the extraction operation from a plant can be adopted. Specifically, for example, immersion in an extraction solvent (cold immersion, warm immersion, percolation, etc.), super Extraction using a critical fluid or a subcritical fluid can be mentioned. In addition, in order to improve the extraction efficiency, it may be homogenized with stirring or in an extraction solvent.
The extraction temperature is not particularly limited and varies depending on the extraction solvent used, the extraction operation and the like, but it is preferably a temperature from about 5 ° C. to the boiling point of the extraction solvent or less.
The extraction time is not particularly limited and varies depending on the extraction solvent used, the extraction operation and the like, but is preferably about 1 hour to 14 days.

In the present invention, the content of the component (B-2) in the liquid or semi-solid composition is not particularly limited and may be determined by appropriate examination, but from the viewpoint of the discoloration suppressing action, the component (B-) 2) is preferably contained in an amount of 0.001 to 15 w / v%, more preferably 0.01 to 4 w / v%, and 0.1 to 2 w / v based on the total volume of the composition in terms of free form. % Is particularly preferable.
Above all, when one or more selected from the group consisting of glycyrrhetinic acid and a salt thereof is used as the component (B-2), from the viewpoint of discoloration inhibitory action, the total volume of the composition in terms of free form of glycyrrhetinic acid is used. The total content is preferably 0.01 to 5 w / v%, more preferably 0.05 to 3 w / v%, and particularly preferably 0.1 to 1 w / v%. Further, when one or more selected from the group consisting of glycyrrhizic acid and a salt thereof is used as the component (B-2), from the viewpoint of discoloration inhibitory action, the total volume of the composition is converted into a free form of glycyrrhizic acid. The total content is preferably 0.05 to 15 w / v%, more preferably 0.1 to 3 w / v%, and particularly preferably 0.5 to 1 w / v%.

Further, in the present invention, the content ratio of the component (A) and the component (B-2) contained in the liquid or semi-solid composition is not particularly limited and may be appropriately examined and determined, but it has an effect of suppressing discoloration. From this point of view, it is preferable that the component (A) is contained in an amount of 0.001 to 150 parts by mass in total, and the component (B-2) is contained in a total amount of 0.005 to 150 parts by mass. It is more preferably contained in an amount of 70 parts by mass, and particularly preferably contained in an amount of 0.01 to 30 parts by mass.
Above all, when the component (A-1) is used as the component (A), the component (A-1) is converted into 1 part by mass in terms of free form, and the component (B-2) is converted into a free form in total. It is preferably contained in an amount of 0.005 to 100 parts by mass, more preferably 0.01 to 50 parts by mass, and particularly preferably 0.05 to 20 parts by mass. When the component (A-2) is used as the component (A), the component (A-2) is converted to 1 part by mass in terms of free form, and the component (B-2) is converted to a free form in total. It is preferably contained in an amount of 0.005 to 100 parts by mass, more preferably 0.01 to 50 parts by mass, and particularly preferably 0.05 to 10 parts by mass.

<Ingredient (B-3)>
In the present invention, the "steroids" are not particularly limited as long as they are compounds having a steroid skeleton, and examples thereof include corticosteroids. Specific examples thereof include cortisone, dexamethasone, hydrocortisone, prednisolone and derivatives thereof. (For example, carboxylic acid ester derivatives such as acetic acid ester, pivalic acid ester, propionic acid ester, butyric acid ester, and valeric acid ester) can be mentioned. More specifically, such steroids include amcinonide, clobetazone butyrate, clobetasol propionate, cortisol, cortisol acetate, diflucortron valerate acetate, diflupredonato, diflorazone acetate, dexamethasone, and dexamethasone. Acetate, dexamethasone valerate, dexamethasone propionate, triamsinolone acetonide, halcinonide, hydrocortisol, hydrocortisol acetate, hydrocortisol acetate propionate, hydrocortisol butyrate, fluoroxycortide, fluoroxycortide Examples thereof include zombie baric acid ester, prednisolone, prednisolone acetate, prednisolone valerate acetate, bechrometasone propionate, betamethasone dipropionate, betamethasone butyrate propionate, methylprednisolone, methylprednisolone acetate and the like.
It should be noted that these can be used alone or in combination of two or more.
These steroids are known components and can be produced by a known method, or commercially available ones may be used. Examples of commercially available products include dexamethasone acetate (manufactured by Sanofi Co., Ltd.).

Ingredients (B-3) include cortisone, dexamethasone, hydrocortisone, prednisolone and carboxylic acid esters thereof (more specifically, esters of one or more carboxylic acids selected from the group consisting of acetic acid, butyric acid and valeric acid) derivatives. One or more selected from the group consisting of, preferably one or more, from the group consisting of cortisone, cortisone acetate, dexamethasone, dexamethasone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate and prednisolone valerate acetate. One or more selected are particularly preferable.

In the present invention, the content of the component (B-3) in the liquid or semi-solid composition is not particularly limited and may be determined by appropriate examination, but from the viewpoint of the discoloration suppressing action, the component (B-) 3) is preferably contained in an amount of 0.001 to 10 w / v%, more preferably 0.01 to 5 w / v%, and 0.1 to 3 w / v% based on the total volume of the composition. Is particularly preferable.
Above all, when dexamethasone acetate is used as the component (B-3), it is preferably contained in a total amount of 0.01 to 15 w / v% with respect to the total volume of the composition from the viewpoint of the effect of suppressing discoloration. It is more preferably contained in an amount of 05 to 10 w / v%, and particularly preferably 0.1 to 1.5 w / v%. When prednisolone valeric acid ester acetic acid ester is used as the component (B-3), it is preferably contained in a total amount of 0.1 to 6 w / v% with respect to the total volume of the composition from the viewpoint of suppressing discoloration. , 0.5 to 4 w / v% is more preferable, and 1 to 2 w / v% is particularly preferable.

Further, in the present invention, the content ratio of the component (A) and the component (B-3) contained in the liquid or semi-solid composition is not particularly limited and may be appropriately examined and determined, but it has an effect of suppressing discoloration. From the viewpoint of the above, it is preferable that the component (A) is contained in a total of 0.001 to 100 parts by mass, and 0.005 to 50 parts by mass is contained with respect to 1 part by mass in terms of free form. Is more preferable, and it is particularly preferable to contain 0.01 to 30 parts by mass.
Above all, when the component (A-1) is used as the component (A), the component (B-3) is 0.005 to 60 in total with respect to 1 part by mass of the component (A-1) in terms of free form. It is preferably contained in parts by mass, more preferably 0.01 to 40 parts by mass, and particularly preferably 0.05 to 20 parts by mass. When the component (A-2) is used as the component (A), the component (B-3) is 0.005 to 60 in total with respect to 1 part by mass of the component (A-2) in terms of free form. It is preferably contained in parts by mass, more preferably 0.05 to 40 parts by mass, and particularly preferably 0.1 to 20 parts by mass.

<Liquid or semi-solid composition>
In the present invention, the "liquid or semi-solid composition" means a liquid or semi-solid composition at room temperature (any temperature within the range of 15 to 25 ° C.).
In the present invention, the specific properties of the composition are not particularly limited, and may be any of a solution, a colloidal solution (sol (suspension or emulsion)), a gel and the like. The type and properties of the solvent or base are not particularly limited, and may be hydrophilic or hydrophobic such as oily, and a plurality of different solvents and bases may be appropriately mixed and emulsified. May be used. Specific examples of such a solvent / base include components exemplified as additives described later.

In the present invention, the liquid or semi-solid composition preferably contains water from the viewpoint of safety during use of the pharmaceutical product. Here, the amount of water in the composition is not particularly limited, but is preferably 1% by mass or more based on the total mass of the composition, preferably 5% by mass, from the viewpoint of safety during use of the pharmaceutical product and the effect of suppressing discoloration. % Or more, more preferably 20 to 80% by mass, and particularly preferably 30 to 60% by mass.

Further, in the present invention, it is preferable that the liquid or semi-solid composition contains a lower alcohol from the viewpoint of the usability of the pharmaceutical product. Here, the "lower alcohol" means a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples thereof include ethanol, isopropanol, n-propanol and the like. It may be used alone or in combination of two or more. Among these, ethanol, isopropanol and a mixture thereof are preferable. Here, the content of the lower alcohol in the composition is not particularly limited, but is preferably 5% by mass or more based on the total mass of the composition, from 20 to 65, from the viewpoint of the usability of the drug and the effect of suppressing discoloration. It is more preferably by mass, more preferably 30 to 60% by mass, and particularly preferably 40 to 55% by mass.
In the present invention, the liquid or semi-solid composition preferably contains both water and a lower alcohol from the viewpoint of safety and usability during use of the pharmaceutical product.

The composition may contain an ingredient other than the above as a medicinal ingredient. Such medicinal ingredients are not particularly limited, but for example, crotamitone, salicylic acid, bactericide, preservative, astringent / protective agent, aqueous ammonia, vitamin E, panthenol, vitamin A, funnel extract, vasoconstrictor, etc. Examples thereof include sulfa agents, anti-inflammatory agents, crude drugs, anti-panthenol agents, keratolytic agents and the like.

Examples of salicylic acids include glycol salicylate and methyl salicylate.
As a disinfectant, benzalkonium chloride, benzethonium chloride, acrinol, alkylpolyaminoethylglycine, cetylpyridinium chloride, decalinium chloride, decalinium acetate, velberin chloride, velberin benzoate, chlorhexidine hydrochloride, chlor Examples thereof include xidine chloride solution, cetrimid, resorcin and the like.
Examples of the preservative include benzoic acid, chlorobutanol, acetic acid, phenol, iodine tincture and the like.
Examples of the astringent / protective agent include calamine, zinc oxide, and chlorohydroxyaluminum.
Examples of vitamin E include tocopherol and tocopherol acetate.
Examples of vitamin A include vitamin A oil, retinol palmitate, cod liver oil, and cod liver oil.

Examples of the vasoconstrictor include epinephrine solution, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride and the like.
Examples of the sulfa agent include sulfadiazine, sulfisomidin, sodium sulfisomidin, homosulfamine and the like.
Examples of the anti-inflammatory agent include allantoin, aluminum / chlorohydroxyalantoinate, aldioxa, ictamol, lysozyme chloride, dry potassium aluminum sulfate, dimethylisopropylazulene, egg yolk oil, potassium aluminum sulfate and the like.
Examples of crude drugs include horse chestnut seeds, horse chestnut seeds, hamamelis, processed daisan and the like.
Anti-ringworm agents include undecylenic acid, zinc undecylenate, phenyl-11-iodo-10-undecinoate, exalamide, clotrimazole, econazole nitrate, miconazole nitrate, tioconazole, zinc diethyldithiocarbamate, cyclopyrrolnitrin, siccanine, Examples thereof include tricomycin, pyrrolnitrin, thiantol, 2,4,6-tribromphenylcaproic acid ester, trimethylcetylammonium pentachlorophenate, tolnaftate, tolnaftate, haloprodine, sulfur, and bark.
Examples of the keratolytic agent include urea, diethyl phthalate and the like.

Further, in the present invention, the liquid or semi-solid composition may contain additives used in the pharmaceutical field, cosmetics field, etc., depending on the composition dosage form, administration method, and the like. Such additives include, for example, gelling agents, polyhydric alcohols, fats and oils, emulsifiers, solubilizers, pH regulators, antioxidants, softeners, thickeners, moisturizers, preservatives, stabilizers, etc. Percutaneous absorption promoters, flavoring agents, sweeteners and the like can be mentioned.

Examples of the gelling agent include acrylic acid-based polymers such as carboxyvinyl polymers; water-soluble or water-swellable cellulosic polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and ethyl cellulose; polyvinyl alcohol; Polyvinylpyrrolidone and the like can be mentioned.
Examples of the polyhydric alcohol include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, macrogol, polypropylene glycol and the like.
Examples of fats and oils include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, and vaseline; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; behenyl alcohol, lauryl alcohol, and myristyl alcohol. Higher alcohols such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, and oleyl alcohol; higher fatty acids such as behenic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; Waxes such as paraffin wax, paraffin wax, paraffin wax, lanolin, refined lanolin, reduced lanolin; silicone oil and the like can be mentioned.

Examples of the emulsifier include polyhydric alcohols such as propylene glycol mono fatty acid ester, ethylene glycol mono fatty acid ester, glycerin mono fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methyl glucoside fatty acid ester, and alkyl polyglucoside. Fatty acid ester or polyhydric alcohol alkyl ether; polyoxyethylene ether such as polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene polyoxypropylene alkyl ether; polyoxyethylene ether; Ethylene mono fatty acid ester, polyethylene glycol di fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene Nonionic surfactants such as castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid esters, ether esters such as polyoxyethylene polyoxypropylene glycol, or ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate. And so on.
Examples of the solubilizer include glycerin, liquid paraffin, crotamitone, macrogol, and the like, in addition to the nonionic surfactant or ionic surfactant exemplified as the emulsifier described above.

Examples of the pH adjuster include 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 ice. Organic acids such as acetic acid or salts thereof; inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate, sodium hydrogen carbonate or the like; sodium hydroxide , Alkali hydroxides such as potassium hydroxide, calcium hydroxide, magnesium hydroxide; amines such as triethanolamine, diethanolamine, diisopropanolamine and the like.
Examples of the antioxidant include sodium sulfite, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, cysteine hydrochloride, citric acid, tocopherol, tocopherol acetate, soybean lecithin, propyl gallate and the like.
Examples of the softening agent include allantoin, almond oil, olive oil, glycerin, liquid paraffin, squalane, squalene, refined lanolin, medium chain fatty acid triglyceride, rapeseed oil, castor oil, propylene glycol, polybutene and the like.
Examples of the thickener include polyvinylpyrrolidone, carboxymethyl cellulose, colloidal aluminum silicate, xanthan gum, locust bean gum, tragant gum, guar gum, gelatin, arabic gum, alginic acid, albumin and the like.
Examples of the moisturizer include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, sorbitol and the like.
Examples of preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, isobutyl paraoxybenzoate, benzyl paraoxybenzoate, sodium benzoate, benzoic acid, and benzoic acid. Examples thereof include benzyl acid acid, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid and the like.
Examples of the stabilizer include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated oil, cysteine and the like.
Examples of the transdermal absorption promoter include fatty acid esters such as diisopropyl adipate.
Examples of flavoring agents and sweeteners include assesulfam potassium, stevia, somatin, sucralose, panose, trehalose, erythritol, lactitol, reduced palatinose, coupling sugar, fructo-oligosaccharide, galactooligosaccharide, milk fruit oligosaccharide, isomalto-oligosaccharide, and palatinose. Examples thereof include oligosaccharides, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or a salt thereof, sorbitol, lactose, sucrose, honey, glucose, martitol, maltose, mannitol, water candy and the like.

In the present invention, the dosage form of the liquid or semi-solid composition is not particularly limited as long as it is in the liquid or semi-solid form, and depending on the purpose of use thereof, for example, the 17th revised Japanese Pharmacopoeia. The dosage form can be appropriately selected from the dosage forms described in the general rules of formulation. Specific examples of such dosage forms include preparations applied to the skin and the like (external liquids, sprays, ointments, creams, gels, etc.) and orally administered preparations (oral liquids, syrups, oral jelly). Etc.), etc., and the dosage forms described in the 17th Amendment of the General Regulations for Pharmaceutical Formulations of the Japanese Pharmacy.
In the present invention, the pharmaceutical preparation is preferably in a dosage form selected from the group consisting of external liquids, sprays, ointments, creams and gels, and liniments, lotions, external aerosols, pump sprays, etc. The dosage form selected from the group consisting of ointments, creams and gels is more preferable, and the dosage form selected from the group consisting of lotions, ointments, creams and gels is particularly preferable.

In the present invention, the method for producing a liquid or semi-solid composition is not particularly limited, and depends on the type and amount of the components to be blended, the properties of the composition, the shape of the container, the composition dosage form, the administration route, the application, and the like. For example, it can be produced by a known method described in the 17th revised Japanese Pharmacopoeia General Rules for Formulations.

In the present invention, the "container" means a package that directly contains a liquid or semi-solid composition. The shape of the container is not particularly limited as long as it can accommodate a liquid or semi-solid composition, and is appropriately examined and determined according to the specific properties, dosage form, administration route, application, etc. of the composition. do it.
Examples of the shape of such a container include a container for an aerosol agent, a container for a pump spray agent, a bottle container (more specifically, a roll-on container, a jar bottle container, a bottle container provided with a sponge-like coating member (head), and the like. ), Tube containers, etc. In the present invention, a roll-on container is preferable from the viewpoint of durability of the container during long-term use.
All of these containers are known (for example, the roll-on container is disclosed in Japanese Patent Application Laid-Open No. 2005-186997), and may be manufactured by a known method, or a commercially available product may be used. ..

The container used in the present invention includes a metal member.
Here, the "metal member" is a contactable region provided in the container so that the member can come into contact with the liquid or semi-solid composition contained in the container at least temporarily. Means a member having a metal portion at least a part of the container, specifically, for example, a container for an aerosol agent, a container body (preferably at least a part of a composition accommodating portion) or a dip tube (preferably at least a part of a composition accommodating portion) in a pump spray container. Is at least part of the inner circumference); at least part of the container body (preferably at least part of the composition container) or coating ball in the roll-on container; at least part of the container body (preferably at least part of the composition container) in the jar bottle container. At least a part) or at least a part of a lid; a container body (preferably at least a part of a composition container) in a bottle container provided with a sponge-like coating member (head), at least a part of a cap around the sponge, and the like. ..

Further, the "metal" in the present invention is not particularly limited, and examples thereof include iron, steel, and stainless steel. The metal may be surface-treated if necessary. Examples of such surface treatments include corrosion resistance imparting treatments and rust prevention treatments.
In the present invention, as the metal, steel and stainless steel are preferable, and stainless steel is particularly preferable, from the viewpoint of workability, corrosion resistance, and usability. The specific type of stainless steel is not particularly limited, and examples thereof include austenitic stainless steel, austenitic ferrite stainless steel, ferritic stainless steel, martensitic stainless steel, and precipitation hardening stainless steel. Specific JIS symbols include, for example, SUS201 and SUS202. Examples thereof include SUS301, SUS302, SUS303, SUS304, SUS305, SUS316, SUS316N, SUS317, SUS317J1, SUS329J1, SUS429, SUS430, SUS440A and SUS630. In the present invention, SUS304 and SUS316 are particularly preferable as stainless steel.

In the present invention, as the container provided with the metal member, a roll-on container provided with a metal ball is preferable. A roll-on container equipped with a metal ball is a roll-on container in which a metal ball is rotatably held, and when the ball is pressed against a portion to be coated and rolled, the composition contained in the container is applied to the portion to be coated. It is to be applied.
The shape of the ball is not particularly limited, but a true sphere or a substantially true sphere is preferable from the viewpoint of facilitating rotation. Further, in the roll-on container provided with the metal balls, the number of the metal balls may be one or a plurality. The diameter of the ball is preferably 1 to 20 mm, more preferably 4 to 8 mm.

The material of the portion other than the metal member of the container provided with the metal member is not particularly limited, and may be appropriately selected depending on the compatibility with the liquid or semi-solid composition to be accommodated, the form of the container, and the like. Good. Specific examples thereof include glass, plastic, cellulose, pulp, rubber, etc., but from the viewpoint of processability, durability, etc., it is preferably made of plastic or the like.
The resin in the case of a plastic container is preferably a thermoplastic resin regardless of whether it is a synthetic resin or a natural resin. Specifically, for example, a polyolefin resin, a polyester resin, a polyphenylene ether resin, etc. Examples thereof include polycarbonate-based resins, polysulfone-based resins, polyamide-based resins, polyvinyl chloride resins, and styrene-based resins, and it is preferable to use one or more of these, and a mixture (polymer alloy) thereof. It may be.
The method of accommodating the composition in the container is not particularly limited, and can be achieved by an appropriate means such as putting the composition into the container.

Since the pharmaceutical product of the present invention contains a local anesthetic component and an antihistamine component in the composition, it is effective for antipruritic and the like. Therefore, the pharmaceutical agent of the present invention can be used as an antipruritic / anti-inflammatory drug, an athlete's foot / ringworm drug, a topical hemorrhoid drug, a hair drug, etc., more specifically, eczema, dermatitis, soreness, rash, rash, itching, and rash. Antipruritic and anti-inflammatory drug for symptoms such as insect bites and urticaria; medicine for ringworm (athlete's foot), ringworm, and zebra; alleviation of pain, itching, swelling, bleeding, and soreness of hemorrhoids and hemorrhoids. It can also be used as an external hemorrhoid drug for disinfection. In the present invention, an antipruritic agent for symptoms such as eczema, dermatitis, soreness, rash, rash, itching, smoldering, insect bites, and urticaria; alopecia areata, alopecia areata, and diffuse alopecia. It can be most preferably used as a hair medicine for symptoms such as alopecia areata, hair growth promotion, hair growth, prevention of hair loss (hair loss), thinning hair, dandruff, itching, and postpartum / postpartum hair loss.

The route of administration of the composition or drug is not particularly limited and can be appropriately examined and determined according to the disease to be applied, the type of preparation, the gender, age, symptoms, etc. of the user, but parenteral administration, especially external use. Administration is preferred. In addition, the composition or pharmaceutical product can be taken before meals, between meals, after meals, before bedtime, etc., in 1 to 4 divided doses per day.

The present specification is not limited to these, but discloses, for example, the following aspects.
[1A] The following components (A) and (B):
(A) One or more selected from the group consisting of the following components (A-1) and (A-2);
(A-1) Local anesthetic component (A-2) Antihistamine component (B) One or more selected from the group consisting of the following components (B-1) to (B-3);
(B-1) Terpenes (B-2) Glycyrrhetinic acids (B-3) A pharmaceutical product in which a liquid or semi-solid composition containing steroids is contained in a container provided with a metal member.
[2A] The drug according to [1A], wherein the local anesthetic component is at least one selected from the group consisting of dibucaine, procaine, mepivacaine, mepivacaine, lidocaine and their inorganic acid salts and solvates thereof.
[3A] The drug according to [1A] or [2A], wherein the antihistamine component is at least one selected from the group consisting of isothipendyl, chlorpheniramine, diphenylpyraline and diphenhydramine, and salts thereof.
[4A] The terpenes are one or more selected from the group consisting of monoterpenoids having a p-menthane skeleton, monoterpenoids having a p-menthane skeleton as a skeleton, and monoterpenoids having a bornane skeleton [1A]. -The drug according to any one of [3A].
[5A] The drug according to any one of [1A] to [4A], wherein the glycyrrhetinic acid is one or more selected from the group consisting of glycyrrhetinic acid, glycyrrhizinic acid and salts thereof.

[6A] The drug according to any one of [1A] to [5A], wherein the steroid is one or more selected from the group consisting of cortisone, dexamethasone, hydrocortisone, prednisolone and carboxylic acid ester derivatives thereof.
[7A] The drug according to any one of [1A] to [6A], wherein the component (B) is at least one selected from the group consisting of the components (B-1) and (B-2).

[8A] The pharmaceutical product according to any one of [1A] to [7A], wherein the liquid or semi-solid composition further contains water.
[9A] The drug according to any one of [1A] to [8A], wherein the liquid or semi-solid composition further contains a lower alcohol.
[10A] The pharmaceutical product according to any one of [1A] to [9A], wherein the container provided with the metal member is a roll-on container provided with a metal ball.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. In the following test examples, the amount of each component used indicates the amount of the indicated component itself unless the conversion amount is specified.

[Test Example 1] Stability test The following sample solutions (liquid compositions) 1-1 to 1-5 were prepared. Immerse the obtained sample solution in a glass bottle (2K standard bottle) with a metal ball (stainless steel SUS304 metal ball: stainless steel ball SUS1 / 4: AS ONE Co., Ltd.) installed inside so that the metal ball is about half immersed. After pouring, it was sealed.
The glass bottle in this state was stored under room temperature conditions for 20 days. The state of the sample was visually confirmed mainly by the presence or absence of discoloration on the surface of the metal sphere after storage, and evaluated according to the following criteria. It can be said that the closer the evaluation result is to "-", the better the storage stability when used as a pharmaceutical product.

(Evaluation criteria)
-: No discoloration was confirmed on the surface of the metal sphere.
±: Spots with a slight change in color tone were confirmed on the surface of the metal sphere.
+: Spots with a change to a slightly darker color tone were confirmed on the surface of the metal sphere.
++: Light brown spots were confirmed on the surface of the metal sphere.
+++: Brown spots were confirmed on the surface of the metal sphere.
++++: Dark brown spots were confirmed on the surface of the metal sphere, and coloring was also observed in the sample solution.
The results are shown in Table 1.

[Sample Solution 1-1]
A solution of ethanol and purified water mixed in equal weight (hereinafter referred to as "50% ethanol aqueous solution") is mixed with lidocaine hydrochloride (lidocane hydrochloride: Iwaki) in an amount of 10% by weight based on the total mass of the 50% ethanol aqueous solution. Pharmaceutical Co., Ltd. (hereinafter, the same applies in this example) was dissolved as an additional component to prepare a sample solution 1-1.
[Sample Solution 1-2]
In a 50% ethanol aqueous solution, an amount of lidocaine hydrochloride which is 10% by mass with respect to the total mass of the 50% ethanol aqueous solution and an amount of isopropylmethylphenol (isopropylmethylphenol: manufactured by Osaka Pharmaceutical Co., Ltd.; hereinafter, The same applies to this example) was dissolved as an additional component to prepare a sample solution 1-2.

[Sample Solution 1-3]
In a 50% ethanol aqueous solution, an amount of lidocaine hydrochloride that is 10% by mass with respect to the total mass of the 50% ethanol aqueous solution, and an amount of glycyrrhizinic acid (glycyrrhizinate K2: manufactured by Maruzen Pharmaceuticals Co., Ltd. The same applies to Examples), which was dissolved as an additional component to prepare a sample solution 1-3.
[Sample Solution 1-4]
In a 50% ethanol aqueous solution, an amount of lidocaine hydrochloride that is 10% by mass with respect to the total mass of the 50% ethanol aqueous solution, and an amount of dexamethasone acetate (dexamethasone acetate: manufactured by Sanofi Co., Ltd. The same applies to Examples), which was dispersed as an additional component to prepare a sample solution 1-4.
[Sample Solution 1-5]
The 50% aqueous ethanol solution was used as it was as the sample solution 1-5.

From the comparison between the sample solutions 1-1 and 1-5, it was clarified that the discoloration of the metal sphere surface observed in the case of the sample solution 1-1 was caused by lidocaine.
Then, by comparing the sample solutions 1-1 with 1-2, 1-3, and 1-4, in addition to lidocaine, isopropylmethylphenol (1-2) and glycyrrhizinic acid (1-3) were added to the sample solution. Alternatively, it has been clarified that discoloration of the surface of metal spheres caused by lidocaine can be suppressed by containing dexamethasone acetate (1-4).

From the above test results, a liquid composition containing a local anesthetic component typified by lidocaine, terpenes typified by isopropylmethylphenol, glycyrrhetinic acids typified by glycyrrhizic acid, or dexamethasone acetate is typified. It was clarified that the discoloration of the surface of the metal member was suppressed by containing the steroids.

[Test Example 2] Stability test The same test as in Test Example 1 was carried out using the sample solutions 2-1 to 2-5 shown below, except that the storage conditions were set at 80 ° C. for 2 days.
The results are shown in Table 2.

[Sample Solution 2-1]
Lidocaine hydrochloride in an amount of 1% by mass based on the total mass of the 50% ethanol aqueous solution was dissolved in a 50% ethanol aqueous solution as an additional component to prepare a sample solution 2-1.
[Sample Solution 2-2]
In a 50% ethanol aqueous solution, 1% by mass of lidocaine hydrochloride based on the total mass of the 50% ethanol aqueous solution, and 1% by mass of l-menthol (L-menthol: manufactured by Takasago Kagaku Kogyo Co., Ltd.) , The same applies in this example) was dissolved as an additional component to prepare a sample solution 2-2.

[Sample Solution 2-3]
In a 50% ethanol aqueous solution, 1% by mass of lidocaine hydrochloride and 1% by mass of isopropylmethylphenol were dissolved as additional components in a sample solution 2-3. And said.
[Sample Solution 2-4]
Lidocaine hydrochloride in an amount of 1% by mass and 1% by mass of glycyrrhizinic acid in an amount of 1% by mass with respect to the total mass of the 50% ethanol aqueous solution were dissolved in a 50% ethanol aqueous solution as additional components to prepare a sample solution 2-4. did.
[Sample Solution 2-5]
The 50% aqueous ethanol solution was used as it was as the sample solution 2-5.

In Test Example 2, as in Test Example 1, a metal caused by lidocaine is contained in the sample solution by further adding isopropylmethylphenol (2-3) or glycyrrhizic acid (2-4) in addition to lidocaine. It was confirmed that discoloration of the sphere surface could be suppressed. In addition, the same effect was confirmed in l-menthol, which is a terpene like isopropylmethylphenol.

Based on the above test results, the liquid composition containing a local anesthetic component typified by lidocaine is further added with terpenes typified by l-menthol and isopropylmethylphenol, or glycyrrhetinic acids typified by glycyrrhizic acid. As a result, it was confirmed that discoloration of the surface of the metal member was suppressed.

[Test Example 3] Stability test The same test as in Test Example 1 was carried out using the sample solutions 3-1 to 3-5 shown below, except that the storage conditions were set at 40 ° C. for 20 days.
The results are shown in Table 3.

[Sample Solution 3-1]
To a 50% aqueous ethanol solution, an amount of diphenhydramine hydrochloride (diphenhydramine hydrochloride: manufactured by Kongo Chemical Co., Ltd., the same applies hereinafter in this example) is added in an amount that is 1% by mass based on the total mass of the 50% ethanol aqueous solution. It was dissolved as a component to prepare a sample solution 3-1.
[Sample Solution 3-2]
In addition to the 50% ethanol aqueous solution, 1% by mass of diphenhydramine hydrochloride and 1% by mass of dl-kanfur (DL-kanfur: Fujin Aomatsu) with respect to the total mass of the 50% ethanol aqueous solution were added as additional components. It was dissolved to prepare a sample solution 3-2.
[Sample Solution 3-3]
In a 50% ethanol aqueous solution, 10% by mass of diphenhydramine hydrochloride and 1% by mass of l-menthol with respect to the total mass of the 50% ethanol aqueous solution were dissolved as additional components, and the sample solution 3-3 was dissolved. And said.
[Sample solution 3-4]
In a 50% ethanol aqueous solution, 1% by mass of diphenhydramine hydrochloride and 1% by mass of dexamethasone acetate were dissolved / dispersed as additional components with respect to the total mass of the 50% ethanol aqueous solution, and the sample solution 3 was dissolved. It was set to -4.
[Sample Solution 3-5]
The 50% aqueous ethanol solution was used as it was as the sample solution 3-5.

From the comparison between the sample solutions 3-1 and 3-5, it was clarified that the discoloration of the metal sphere surface observed in the case of the sample solution 3-1 was due to diphenhydramine.
Then, by comparing the sample solutions 3-1 and 3-2, 3-3, 3-4, in addition to diphenhydramine, camphor (3-2), menthol (3-3), or dexamethasone was added to the sample solution. It was clarified that the discoloration of the surface of the metal sphere caused by diphenhydramine can be suppressed by containing the acetic acid ester (3-4).

From the above test results, it was clarified that discoloration occurs on the surface of the metal member when the antihistamine component typified by diphenhydramine is contained in the liquid composition as in the case of the local anesthetic component. Further, by further adding additional components such as terpenes represented by camphor and menthol and steroids represented by dexamethasone acetate to the liquid composition, discoloration of the surface of the metal member can be suppressed. It became clear.

From the results of Test Examples 1 to 3 above, the surface of the metal member is formed by further adding terpenes, glycyrrhetinic acids or steroids to the liquid or semi-solid composition containing the local anesthetic component and the antihistamine component. It was clarified that the discoloration of was suppressed.

Manufacturing example 1
A liquid composition (Formulation Examples 1 to 8) containing the components and amounts (g) shown in Table 4 below in 100 g is produced by a conventional method, and a polyethylene roll-on container (metal ball made of SUS316) is provided. It is possible to produce the pharmaceutical products of Production Examples 1-1 to 1-8, respectively.

Manufacturing example 2
A liquid composition (Formulation Examples 9 to 10) containing the components and amounts (g) shown in Table 5 below in 100 mL is produced by a conventional method, and is contained in a polyethylene container, respectively, and Production Examples 2-1 to 2-1. It was used as a 2-2 pharmaceutical preparation.

Manufacturing example 3
A liquid composition (Formulation Examples 11 to 12) containing the components and the amount (g) shown in Table 6 below in 100 mL is produced by a conventional method, and is contained in a polyethylene container, respectively, and Production Examples 3-1 to 3-1. It was prepared as 3-2 pharmaceutical preparation.

Manufacturing example 4
A semi-solid composition (Formulation Examples 13 to 14) containing the components and amounts (g) shown in Table 7 below in 100 g is produced by a conventional method, and is contained in a polyethylene container. It was prepared as a pharmaceutical preparation of 1 to 4-2.

Production example 5
A semi-solid composition (Formulation Examples 15 to 16) containing the components and amounts (g) shown in Table 8 below in 100 g is produced by a conventional method, and is contained in a polyethylene container, and each of them is produced in Production Example 5- It was prepared as a pharmaceutical preparation of 1 to 5-2.

According to the present invention, since it is possible to provide a drug containing a local anesthetic component and an antihistamine component and having excellent storage stability, it can be used, for example, in the pharmaceutical industry.

Claims (8)

The following components (A) and (B):
(A) One or more selected from the group consisting of the following components (A-1) and (A-2);
(A-1) Local anesthetic component (A-2) Antihistamine component (B) One or more selected from the group consisting of the following components (B-1) to (B-3);
(B-1) Terpenes (B-2) Glycyrrhetinic acids (B-3) A pharmaceutical product in which a liquid or semi-solid composition containing steroids is contained in a container provided with a metal member. The pharmaceutical product according to claim 1, wherein the component (A-1) is at least one selected from the group consisting of dibucaine, procaine, mepivacaine, mepivacaine, lidocaine and their inorganic acid salts, and solvates thereof. The pharmaceutical product according to claim 1 or 2, wherein the component (A-2) is at least one selected from the group consisting of isothipendyl, chlorpheniramine, diphenylpyraline and diphenhydramine, and salts thereof. Claim that the component (B-1) is one or more selected from the group consisting of a monoterpenoid having a p-menthane skeleton, a monoterpenoid having a p-mentane isomer as a skeleton, and a monoterpenoid having a bornane skeleton. The drug according to any one of 1 to 3. The pharmaceutical product according to any one of claims 1 to 4, wherein the component (B-2) is at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid and salts thereof. The pharmaceutical product according to any one of claims 1 to 5, wherein the component (B-3) is at least one selected from the group consisting of cortisone, dexamethasone, hydrocortisone, prednisolone and carboxylic acid ester derivatives thereof. The pharmaceutical product according to any one of claims 1 to 6, wherein the liquid or semi-solid composition further contains water. The pharmaceutical product according to any one of claims 1 to 7, wherein the container provided with the metal member is a roll-on container provided with a metal ball.