JP7488644B2 - Pharmaceuticals - Google Patents

Description

The present invention relates to pharmaceuticals, etc.

Local anesthetic ingredients such as dibucaine, procaine, mepivacaine, meprylcaine, and lidocaine all have a similar chemical structure in which an aromatic group and an amino group are bonded via an intermediate chain. When applied locally to the skin or mucous membrane, local anesthetic ingredients are said to relieve pain and itching at the affected area by paralyzing the sensory nerves.
In addition, antihistamine ingredients such as isothipendyl, chlorpheniramine, diphenylpyraline, and diphenhydramine have a similar chemical structure to local anesthetic ingredients, in which an aromatic group and an amino group are bonded via an intermediate chain. When applied locally to the skin or mucous membrane, antihistamine ingredients exert an antipruritic effect due to their antihistamine action. Furthermore, for example, diphenhydramine has a similar chemical structure to lidocaine and is said to exert a local anesthetic effect.
For this reason, these local anesthetic and antihistamine components are widely used as active ingredients in antipruritic and anti-inflammatory drugs for the treatment of symptoms such as eczema, dermatitis, sores, heat rash, rashes, itching, chilblains, insect bites, and hives, as well as in external preparations such as medications for athlete's foot and ringworm and medications for external hemorrhoids.

When a local anesthetic component or an antihistamine component is used as an active ingredient in an external preparation, it becomes possible to flexibly administer only the required amount of drug according to the location, shape, and area of the affected area by applying the composition in a liquid or semi-solid form, such as an external application agent such as a lotion or gel, to the affected area. Up until now, liquid or semi-solid compositions containing a local anesthetic component or an antihistamine component have been sold in application containers or the like having a sponge-like application part, but the sponge-like application part has been subject to wear and deterioration over time with use.
In contrast, it has been thought that a container equipped with a plastic or metal ball in the application section, in which the composition in the container is applied by pressing and rolling the ball against the part to be applied (a so-called roll-on container), would be able to withstand longer periods of use and provide a pharmaceutical product with good quality stability.

Incidentally, Patent Document 1 describes an external preparation product that includes 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 coated ball.
However, Patent Document 1 does not disclose the combination of a local anesthetic component and a terpene, nor does it disclose any interaction between the composition and a metal coating ball.

JP 2014-193850 A

In view of the above circumstances, the present inventors have decided to develop a pharmaceutical product in which a liquid or semi-solid composition containing a local anesthetic component or an antihistamine component is contained in a roll-on container. The affected area to which the composition containing a local anesthetic component or an antihistamine component is applied is often heated due to inflammation, etc. Therefore, it was thought that using a metal ball for the roll-on container would provide a cooling sensation to the affected area and improve the feeling of use.
Therefore, in order to develop a pharmaceutical product in which a liquid or semi-solid composition containing a local anesthetic component such as lidocaine (hereinafter sometimes referred to as "component (A-1)") or an antihistamine component such as diphenhydramine (hereinafter sometimes referred to as "component (A-2)"; components (A-1) and (A-2) may be collectively referred to as "component (A)") is contained in a roll-on container equipped with a metal ball, the inventor first contacted a liquid or semi-solid composition containing a local anesthetic component or an antihistamine component with a metal member to confirm its storage stability, and found that discoloration occurred over time on the surface of the metal member due to long-term storage, causing problems with storage stability. A technology for solving such problems can be applied not only to roll-on containers equipped with metal balls, but also to containers equipped with a wide variety of metal members.
Therefore, an object of the present invention is to suppress discoloration of the surface of a metal component when a liquid or semi-solid composition containing a local anesthetic component or an antihistamine component is contained in a container equipped with the metal component.

The inventors have conducted extensive research to solve the above problems, and have found that discoloration of the surface of a metal component can be suppressed by adding terpenes such as menthol, camphor, and isopropylmethylphenol (hereinafter sometimes referred to as "component (B-1)"), glycyrrhetinic acids such as glycyrrhizinic acid (hereinafter sometimes referred to as "component (B-2)"), or steroids such as dexamethasone acetate (hereinafter sometimes referred to as "component (B-3)". Components (B-1), (B-2), and (B-3) may be collectively referred to as "component (B)") to a liquid or semi-solid composition containing a local anesthetic component and an antihistamine component, and thus completed the present invention.

That is, the present invention relates to a composition comprising the following components (A) and (B):
(A) one or more components selected from the group consisting of the following components (A-1) and (A-2):
(A-1) a local anesthetic component; (A-2) an antihistamine component; (B) one or more components selected from the group consisting of the following components (B-1) to (B-3):
The present invention provides a pharmaceutical product comprising a liquid or semi-solid composition that contains (B-1) terpenes, (B-2) glycyrrhetinic acids, and (B-3) steroids, and is contained in a container having a metal member.

According to the present invention, when a liquid or semi-solid composition containing a local anesthetic component or an antihistamine component is stored in a container equipped with a metal component, discoloration of the surface of the metal component that may occur during long-term storage can be suppressed. Therefore, a pharmaceutical product with excellent storage stability can be provided.

In this specification, "w/v %" means mass to volume percentage, specifically, the mass (g) of each component contained per 100 mL of the composition.

<Component (A-1)>
In this specification, the term "local anesthetic component" is not particularly limited as long as it has a local anesthetic effect, and specifically includes, for example, ethyl aminobenzoate, dibucaine, tetracaine, procaine, bupivacaine, propitocaine, benzocaine, mepivacaine, meprylcaine, and lidocaine themselves, as well as pharma- ceutical acceptable salts thereof, and further includes solvates of ethyl aminobenzoate, dibucaine, tetracaine, procaine, bupivacaine, propitocaine, benzocaine, mepivacaine, meprylcaine, and lidocaine themselves or pharma- ceutical acceptable salts thereof with water, alcohol, or the like. Here, the salt is not particularly limited as long as it is a pharma- ceutically acceptable salt, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide; and organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate.
These may be used alone or in appropriate combination of two or more.
These local anesthetic ingredients are known ingredients and can be produced by known methods, or commercially available products such as lidocaine hydrochloride (manufactured by Iwaki Pharmaceutical Co., Ltd.) can be used.

As component (A-1), one or more selected from the group consisting of ethyl aminobenzoate, dibucaine, procaine, mepivacaine, meprylcaine, lidocaine, and inorganic acid salts thereof and solvates thereof are preferred, one or more selected from the group consisting of ethyl aminobenzoate, dibucaine, procaine, mepivacaine, meprylcaine, lidocaine, and hydrochlorides thereof and solvates thereof are more preferred, one or more selected from the group consisting of ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, procaine, procaine hydrochloride, mepivacaine, meprylcaine hydrochloride, lidocaine, and lidocaine hydrochloride are even more preferred, and one or more selected from the group consisting of ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, lidocaine, and lidocaine hydrochloride are particularly preferred.

In the present invention, the content of component (A-1) in the liquid or semi-solid composition is not particularly limited, and may be appropriately determined depending on the desired efficacy, etc. In the present invention, component (A-1) is preferably contained in a total amount of 0.001 to 20 w/v %, more preferably 0.01 to 10 w/v %, and particularly preferably 0.1 to 3 w/v %, calculated as the free form, relative to the total volume of the composition.
In particular, when one or more members selected from the group consisting of dibucaine and its pharma- ceutically acceptable salts and solvates thereof are used as component (A-1), the content thereof, calculated as the free form, 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 %, based on the total volume of the composition.
When one or more members selected from the group consisting of lidocaine, its pharma- ceutically acceptable salts, and solvates thereof are used as component (A-1), the total amount of the member, calculated as the free form, based on the total volume of the composition 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%.
Furthermore, when ethyl aminobenzoate is used as component (A-1), it is preferably contained in a total amount of 0.01 to 5 w/v %, more preferably 0.05 to 2 w/v %, and particularly preferably 0.1 to 1 w/v %, calculated as the free form, based on the total volume of the composition.

<Component (A-2)>
In the present invention, the "antihistamine ingredient" is not particularly limited as long as it has a histamine H1 receptor antagonistic effect, and specific examples thereof include one or more selected from the group consisting of azelastine, alimemazine, isothipendyl, iproheptine, ebastine, epinastine, emedastine, oxatomide, olopatadine, carbinoxamine, clemastine, chlorpheniramine, ketotifen, difeterol, diphenylpyraline, diphenhydramine, cyproheptadine, cetirizine, triprolidine, tripelennamine, thonzylamine, fexofenadine, fenethazine, promethazine, bepotastine, homochlorcyclizine, mequitazine, methdilazine, mebhydroline, and loratadine, pharma- ceutically acceptable salts thereof, and solvates thereof. The salt is not particularly limited as long as it is a pharmacologic acceptable salt, and examples thereof include salts with inorganic acids, organic acids, inorganic bases, organic bases, etc., such as hydrochloride, tartrate, maleate, fumarate, diphenyl disulfonate, teoclate, salicylate, tannate, besylate, napadisilate, phosphate, etc. In addition, when an asymmetric carbon is present in the chemical structure of the antihistamine component, various optical isomers are present, but in the present invention, any optical isomer is included, and it may be a single optical isomer or a mixture of various optical isomers. In addition, as described above, various compounds having histamine H1 receptor antagonistic activity such as azelastine and solvates of their salts with water, alcohol, etc. are also included in the "antihistamine component".
These may be used alone or in appropriate combination of two or more.
These antihistamine ingredients are known ingredients and can be produced by known methods, or commercially available products can be used, such as diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.).

Specific examples of antihistamine components used in the present invention include azelastine or a salt thereof, such as azelastine hydrochloride; alimemazine or a salt thereof, such as alimemazine tartrate; isothipendyl or a salt thereof, such as isothipendyl hydrochloride; iproheptine or a salt thereof, such as iproheptine hydrochloride; ebastine or a salt thereof; epinastine or a salt thereof, such as epinastine hydrochloride; emedastine or a salt thereof, such as emedastine fumarate; oxatomide or a salt thereof; olopatadine, such as olopatadine hydrochloride. or its salts; carbinoxamine or its salts such as carbinoxamine diphenyl disulfonate, carbinoxamine maleate, etc.; clemastine or its salts such as clemastine fumarate, etc.; chlorpheniramine or its salts such as d-chlorpheniramine maleate, dl-chlorpheniramine maleate, etc.; ketotifen or its salts such as ketotifen fumarate, etc.; difeterol or its salts such as difeterol hydrochloride, difeterol phosphate, etc.; diphenylpyraline hydrochloride, diphenyl Diphenylpyraline or a salt thereof, such as lupyraline teoclate; diphenhydramine or a salt thereof, such as diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, etc.; cyproheptadine or a salt thereof, such as cyproheptadine hydrochloride hydrate; cetirizine or a salt thereof, such as cetirizine hydrochloride; triprolidine or a salt thereof, such as triprolidine hydrochloride; tripelennamine or a salt thereof, such as tripelennamine hydrochloride; thonzylamine or a salt thereof, such as thonzylamine hydrochloride; Examples of the drug include fexofenadine or a salt thereof; fenethazine or a salt thereof, such as fenethazine hydrochloride; promethazine or a salt thereof, such as promethazine hydrochloride, promethazine methylene disalicylate, etc.; bepotastine or a salt thereof, such as bepotastine besilate, etc.; homochlorcyclizine or a salt thereof, such as homochlorcyclizine hydrochloride, etc.; mequitazine or a salt thereof; methdilazine or a salt thereof, such as methdilazine hydrochloride, etc.; mebhydroline or a salt thereof, such as mebhydroline napadisilate, etc.; loratadine or a salt thereof, etc. In the present invention, one or more selected from the group consisting of isothipendyl, chlorpheniramine, diphenylpyraline, diphenhydramine, and salts thereof are preferred, one or more selected from the group consisting of isothipendyl hydrochloride, chlorpheniramine, chlorpheniramine maleate, diphenylpyraline hydrochloride, diphenhydramine, diphenhydramine hydrochloride, and diphenhydramine salicylate are more preferred, and one or more selected from the group consisting of isothipendyl hydrochloride, chlorpheniramine, chlorpheniramine maleate, diphenhydramine, and diphenhydramine hydrochloride are particularly preferred.

In the present invention, the content of component (A-2) in the liquid or semi-solid composition is not particularly limited, and may be appropriately determined depending on the desired efficacy, etc. In the present invention, component (A-2) is preferably contained in a total amount of 0.001 to 15 w/v %, more preferably 0.01 to 10 w/v %, and particularly preferably 0.1 to 3 w/v %, calculated as the free form, relative to the total volume of the composition.
In particular, when one or more members selected from the group consisting of chlorpheniramine, its pharma- ceutically acceptable salts, and solvates thereof are used as component (A-2), the content thereof, calculated as the free form, is preferably 0.005 to 2 w/v %, more preferably 0.05 to 1 w/v %, and particularly preferably 0.1 to 0.5 w/v %, based on the total volume of the composition.
When one or more members selected from the group consisting of diphenhydramine and its pharma- ceutically acceptable salts and solvates thereof are used as component (A-2), the total amount of the members, calculated as the free form, 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 %, based on the total volume of the composition.

<Component (B-1)>
In the present invention, "terpenes" refers to a general term (terpenoid) including terpene hydrocarbons, terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc., and the structure is not particularly limited, and examples thereof include monoterpenes, sesquiterpenes, and derivatives thereof. In addition, the terpenes may be cyclic or chain.
Specific examples of such terpenes include isopropylmethylphenol, isoborneol, irone, ocimene, carveol, carbotanacetone, carbomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineol, cymene, sylvestrene, thymol, isothujol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocampheol, pinol, piperitenone, phellandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, limonene, and the like. These may be used alone or in combination of two or more. In addition, when optical isomers exist in these terpenes, all isomers are included unless otherwise specified. In other words, in the present invention, unless a specific optical isomer is specified as the component name of a terpene, such component notation includes all of the various optical isomers alone and mixtures of these in any ratio, and may be a single optical isomer or a mixture of various optical isomers in any ratio (for example, the description "menthol" includes both dl-menthol and l-menthol).

Among the above-mentioned terpenes, from the viewpoint of the discoloration suppression effect, cyclic terpenoids are preferred, cyclic monoterpenoids are more preferred, and monocyclic or bicyclic monoterpenoids are even more preferred. Monoterpenoids having a p-menthane skeleton (e.g., unsaturated derivatives of p-menthane such as cymene, thymol, terpinene, terpinolene, phellandrene, and limonene; monoterpene alcohols having a p-menthane skeleton such as carveol, terpineol, and menthol; monoterpene ketones having a p-menthane skeleton such as carvone and menthone; monoterpene aldehydes having a p-menthane skeleton such as perillaldehyde; monoterpene ethers having a p-menthane skeleton such as cineole), monoterpenoids having an isomer of p-menthane as a skeleton (e.g., 3-methyl-4-isopropyl phenol, etc.), More preferred are monoterpenoids having a bornane skeleton (e.g., monoterpene alcohols having a bornane skeleton such as borneol; monoterpene ketones having a bornane skeleton such as camphor), and even more preferred are one or more selected from the group consisting of thymol, menthol, isopropylmethylphenol, camphor, and borneol, and even more preferred are one or more selected from the group consisting of thymol, l-menthol, dl-menthol, isopropylmethylphenol, d-camphor, dl-camphor, and d-borneol, and especially preferred are one or more selected from the group consisting of l-menthol, dl-menthol, isopropylmethylphenol, d-camphor, and dl-camphor.

When terpenes are contained in a liquid or semi-solid composition, the terpenes may be used as they are, or essential oils containing terpenes may be used.
Such essential oils include, for example, anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaputo oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, pepper oil, perilla oil, citriodora oil, citronella oil, ginger oil, cardamom oil, camphor oil, ginger grass oil, spearmint oil, peppermint oil, geranium oil, star anise oil, clove oil, Examples of oils that can be used include turpentine, spruce oil, neroli oil, basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, pennyroyal oil, henopodium oil, bergamot oil, borealis oil, hosoh oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, and Roman chamomile oil. These may be used alone or in combination of two or more.
Among these, ylang-ylang oil, fennel oil, orange oil, chamomile oil, cinnamon oil, perilla oil, citronella oil, ginger oil, camphor oil, peppermint oil, geranium oil, clove oil, turpentine, spruce oil, neroli oil, peppermint oil, palmarosa oil, bergamot oil, eucalyptus oil, lavender oil, linaloe oil, lemon oil, rose oil, rosemary oil, Roman chamomile oil, and the like are preferred, with camphor oil, peppermint oil, turpentine, peppermint oil, and eucalyptus oil being more preferred, and peppermint oil and eucalyptus oil being particularly preferred.

In the present invention, the content of component (B-1) in the liquid or semi-solid composition is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the discoloration suppression effect, however, the content of component (B-1) is preferably 0.001 to 20 w/v % in total, more preferably 0.01 to 15 w/v %, and particularly preferably 0.1 to 10 w/v %, based on the total volume of the composition.
Among them, when camphor is used as component (B-1), from the viewpoint of the discoloration suppression effect, it is preferable that camphor is contained in a total of 0.001 to 15 w/v% based on the total volume of the composition, more preferably 0.01 to 10 w/v%, and particularly preferably 0.1 to 7 w/v%. When menthol is used as component (B-1), from the viewpoint of the discoloration suppression effect, it is preferable that menthol is contained in a total of 0.05 to 10 w/v%, more preferably 0.1 to 7 w/v%, and particularly preferably 0.5 to 5 w/v% based on the total volume of the composition. Furthermore, when isopropylmethylphenol is used as component (B-1), from the viewpoint of the discoloration suppression effect, it is preferable that isopropylmethylphenol is contained in a total of 0.01 to 6 w/v%, more preferably 0.05 to 4 w/v%, and particularly preferably 0.1 to 2 w/v% based on the total volume of the composition.

In the present invention, the content ratio of component (A) and component (B-1) contained in the liquid or semi-solid composition is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the discoloration suppression effect, however, the content of component (B-1) is preferably 0.0001 to 600 parts by mass, more preferably 0.0005 to 400 parts by mass, and particularly preferably 0.005 to 200 parts by mass, per part by mass of component (A) calculated as a free form.
Among them, when component (A-1) is used as component (A), it is preferable to contain 0.005 to 50 parts by mass of component (B-1) per part by mass of component (A-1) calculated as a free form, more preferably 0.01 to 30 parts by mass, and particularly preferably 0.05 to 15 parts by mass. Also, when component (A-2) is used as component (A), it is preferable to contain 0.0005 to 500 parts by mass of component (B-1) per part by mass of component (A-2) calculated as a free form, more preferably 0.001 to 300 parts by mass, and particularly preferably 0.01 to 100 parts by mass.

<Component (B-2)>
In the present invention, the term "glycyrrhetinic acids" means one or more selected from the group consisting of glycyrrhetinic acid and its derivatives (e.g., sugar addition derivatives of glycyrrhetinic acid such as glycyrrhizinic acid) and their salts (e.g., alkali metal salts such as potassium salts and sodium salts; ammonium salts, etc.).
In the present invention, the glycyrrhetic acid-based compound is, from the viewpoint of the discoloration-inhibiting effect, preferably one or more selected from the group consisting of glycyrrhetic acid, glycyrrhizinic acid, and salts thereof, more preferably one or more selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, disodium glycyrrhizinate, and trisodium glycyrrhizinate, still more preferably one or more selected from the group consisting of glycyrrhizinic acid, glycyrrhizinic acid, and disodium glycyrrhizinate, and particularly preferably glycyrrhizinic acid.

In addition, when glycyrrhetinic acids are contained in a liquid or semi-solid composition, glycyrrhetinic acids may be used as they are, or licorice (licorice) or its extract containing glycyrrhetinic acids may be used. Here, "licorice" means the root and stolons of Glycyrrhiza uralensis Fischer or Glycyrrhiza glabra Linne (Leguminosae), and includes the root and stolons of ... Specifically, the term "licorice extract" includes liquids obtained by cutting licorice to an appropriate size as necessary, adding an appropriate infusion (extraction solvent) and infusing the infusion, liquids obtained by concentrating the infusion (soft extract, tincture, etc.), and further liquids obtained by drying these (dried extract, etc.).
In the present invention, licorice or an extract thereof is preferably licorice, licorice powder, licorice extract, or crude licorice extract as described in the 17th revised Japanese Pharmacopoeia.

There are no particular limitations on the method for producing licorice extract, and it can be produced by referring to known methods for producing plant extracts, such as those described in the General Provisions for Preparations of the 17th Revised Japanese Pharmacopoeia, under the headings "Extracts," "Infusions/Decoctions," "Tinctures," and "Liquid Extracts." Specifically, for example, licorice can be cut, heated, dried, crushed, etc. as necessary, and then extracted by adding an appropriate extraction solvent. The obtained extract may be further concentrated, dried, etc., as 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; 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, water, lower monohydric alcohols such as ethanol, or a mixture of water/lower monohydric alcohol is preferred, and water, ethanol, or a mixture of water/ethanol is particularly preferred.
The extraction procedure is not particularly limited, and any known method used for extraction from plants can be used, 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.

In the present invention, the content of component (B-2) in the liquid or semi-solid composition is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the discoloration suppression effect, however, the content of component (B-2) is preferably 0.001 to 15 w/v %, more preferably 0.01 to 4 w/v %, and particularly preferably 0.1 to 2 w/v %, calculated as the free form, relative to the total volume of the composition.
Among them, when one or more selected from the group consisting of glycyrrhetic acid and its salts are used as component (B-2), from the viewpoint of the discoloration suppression effect, the 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% in total of the composition in terms of the free form of glycyrrhetic acid. Also, when one or more selected from the group consisting of glycyrrhetic acid and its salts are used as component (B-2), from the viewpoint of the discoloration suppression effect, the 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% in total of the composition in terms of the free form of glycyrrhetic acid.

In the present invention, the content ratio of component (A) and component (B-2) contained in the liquid or semi-solid composition is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the discoloration suppression effect, however, the content of component (B-2) is preferably 0.001 to 150 parts by mass in total, more preferably 0.005 to 70 parts by mass, and particularly preferably 0.01 to 30 parts by mass, calculated as free form, per part by mass of component (A) calculated as free form.
Among them, when component (A-1) is used as component (A), it is preferable to contain 0.005 to 100 parts by mass of component (B-2) in total, calculated as a free form, per part by mass of component (A-1) in free form, more preferably 0.01 to 50 parts by mass, and particularly preferably 0.05 to 20 parts by mass. Also, when component (A-2) is used as component (A), it is preferable to contain 0.005 to 100 parts by mass of component (B-2) in total, calculated as a free form, per part by mass of component (A-2) in free form, more preferably 0.01 to 50 parts by mass, and particularly preferably 0.05 to 10 parts by mass.

<Component (B-3)>
In the present invention, the term "steroids" is not particularly limited as long as it is a compound having a steroid skeleton, and examples thereof include adrenal cortical hormones, specifically, for example, cortisone, dexamethasone, hydrocortisone, prednisolone, etc., and derivatives thereof (for example, carboxylate derivatives such as acetate, pivalate, propionate, butyrate, valerate, etc.). More specifically, examples of such steroids include amcinonide, clobetasone butyrate, clobetasol propionate, cortisone, cortisone acetate, diflucortolone valerate acetate, difluprednate, diflorasone acetate, dexamethasone, dexamethasone acetate, dexamethasone valerate, dexamethasone propionate, triamcinolone acetonide, halcinonide, hydrocortisone, hydrocortisone acetate ester, Examples of such agents include flumethasone, hydrocortisone acetate propionate, hydrocortisone butyrate, fluocinonide, fluocinolone acetonide, fludroxycortide, flumethasone pivalate, prednisolone, prednisolone acetate, prednisolone valerate acetate, beclomethasone propionate, betamethasone dipropionate, betamethasone butyrate propionate, methylprednisolone, and methylprednisolone acetate.
These may be used alone or in appropriate combination of two or more.
These steroids are known ingredients and can be produced by known methods, or commercially available products such as dexamethasone acetate (manufactured by Sanofi K.K.) may be used.

As component (B-3), one or more selected from the group consisting of cortisone, dexamethasone, hydrocortisone, prednisolone and their carboxylic acid esters (more specifically, esters of one or more carboxylic acids selected from the group consisting of acetic acid, butyric acid and valeric acid) derivatives are preferred, and one or more selected from the group consisting of cortisone, cortisone acetate, dexamethasone, dexamethasone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate and prednisolone valerate acetate are particularly preferred.

In the present invention, the content of component (B-3) in the liquid or semi-solid composition is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the discoloration suppression effect, however, the content of component (B-3) is preferably 0.001 to 10 w/v % relative to the total volume of the composition, more preferably 0.01 to 5 w/v %, and particularly preferably 0.1 to 3 w/v %.
Among them, when dexamethasone acetate is used as component (B-3), from the viewpoint of the discoloration suppression effect, it is preferably contained in a total amount of 0.01 to 15 w/v%, more preferably 0.05 to 10 w/v%, and particularly preferably 0.1 to 1.5 w/v% based on the total volume of the composition. Also, when prednisolone valerate acetate is used as component (B-3), from the viewpoint of the discoloration suppression effect, it is preferably contained in a total amount of 0.1 to 6 w/v%, more preferably 0.5 to 4 w/v%, and particularly preferably 1 to 2 w/v% based on the total volume of the composition.

In the present invention, the content ratio of component (A) and component (B-3) contained in the liquid or semi-solid composition is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the discoloration suppression effect, however, the content of component (B-3) is preferably 0.001 to 100 parts by mass in total, more preferably 0.005 to 50 parts by mass, and particularly preferably 0.01 to 30 parts by mass, per part by mass of component (A) calculated as a free form.
Among them, when component (A-1) is used as component (A), it is preferable to contain 0.005 to 60 parts by mass of component (B-3) in total, more preferably 0.01 to 40 parts by mass, and particularly preferably 0.05 to 20 parts by mass, per part by mass of component (A-1) in free form. Also, when component (A-2) is used as component (A), it is preferable to contain 0.005 to 60 parts by mass of component (B-3) in total, more preferably 0.05 to 40 parts by mass, and particularly preferably 0.1 to 20 parts by mass, per part by mass of component (A-2) in free form.

<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 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, etc. Furthermore, the type and properties of the solvent or base are not particularly limited, and may be hydrophilic or hydrophobic such as oily, and further, multiple different types of solvents and bases may be appropriately mixed and emulsified for use. Specific examples of such solvents and bases include the components exemplified as additives described below.

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

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

The composition may contain other components as medicinal ingredients in addition to those mentioned above. Such medicinal ingredients are not particularly limited, but examples include crotamiton, salicylic acids, bactericides, preservatives, astringents and protective agents, aqueous ammonia, vitamin E, panthenol, vitamin A, Scopolia extract, vasoconstrictors, sulfa drugs, anti-inflammatory agents, herbal medicines, anti-tinea fungus agents, and keratolytic agents.

Examples of the salicylic acids include glycol salicylate and methyl salicylate.
Examples of disinfectants include benzalkonium chloride, benzethonium chloride, acrinol, alkylpolyaminoethylglycine, cetylpyridinium chloride, dequalinium chloride, dequalinium acetate, berberine chloride, berberine benzoate, chlorhexidine hydrochloride, chlorhexidine gluconate solution, cetrimide, and resorcinol.
Preservatives include benzoic acid, chlorobutanol, acetic acid, phenol, tincture of iodine, and the like.
Astringent/protective agents include calamine, zinc oxide, aluminum chlorohydrate, and the like.
Examples of vitamin E include tocopherol and tocopherol acetate.
Examples of vitamin A include vitamin A oil, retinol palmitate, cod liver oil, and liver oil.

Examples of vasoconstrictors include epinephrine solution, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, and the like.
Examples of sulfa drugs include sulfadiazine, sulfisomidine, sulfisomidine sodium, homosulfamine, and the like.
Examples of anti-inflammatory agents include allantoin, aluminum chlorohydroxyallantoinate, aldioxa, ichthammol, lysozyme chloride, dry aluminum potassium sulfate, dimethylisopropylazulene, egg yolk oil, and aluminum potassium sulfate.
Examples of herbal medicines include Lithospermum root, horse chestnut seeds, witch hazel, and processed daisan.
Examples of anti-tinea fungus agents include undecylenic acid, zinc undecylenate, phenyl-11-iodo-10-undecynoate, exalamide, clotrimazole, econazole nitrate, miconazole nitrate, tioconazole, zinc diethyldithiocarbamate, ciclopirox olamine, siccanin, trichomycin, pyrrolnitrin, thianthol, 2,4,6-tribromophenylcaproic acid ester, trimethylcetylammonium pentachlorophenate, tolciclate, tolnaftate, haloprogin, sulfur, and Hibiscus bark.
Keratolytic agents include urea, diethyl phthalate, and the like.

In addition, in the present invention, the liquid or semi-solid composition may contain additives used in the pharmaceutical and cosmetic fields, etc., depending on the composition formulation, administration method, etc. Examples of such additives include gelling agents, polyhydric alcohols, oils and fats, emulsifiers, solubilizers, pH adjusters, antioxidants, softeners, thickeners, moisturizers, preservatives, stabilizers, transdermal absorption enhancers, flavoring agents, sweeteners, etc.

Examples of gelling agents include acrylic acid polymers such as carboxyvinyl polymers; water-soluble or water-swellable cellulose polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, and ethyl cellulose; polyvinyl alcohol; and polyvinylpyrrolidone.
Examples of polyhydric alcohols include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, macrogol, and polypropylene glycol.
Examples of fats and oils include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, and petrolatum; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, 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 carnauba wax, spermaceti, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, refined lanolin, and reduced lanolin; and silicone oils.

Examples of the emulsifier 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; nonionic surfactants 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 ether esters such as polyoxyethylene polyoxypropylene glycol; and ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate.
Examples of the solubilizer include, in addition to the nonionic surfactants or ionic surfactants exemplified above as the emulsifier, glycerin, liquid paraffin, crotamiton, macrogol, and the like.

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 softeners 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 thickeners include polyvinylpyrrolidone, carboxymethylcellulose, colloidal aluminum silicate, xanthan gum, locust bean gum, tragacanth gum, guar gum, gelatin, gum arabic, alginic acid, and albumin.
Moisturizing agents include sodium hyaluronate, glycerin, 1,3-butylene glycol, propylene glycol, urea, sucrose, erythritol, sorbitol, and the like.
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, hardened oil, and cysteine.
Examples of the percutaneous absorption enhancer include fatty acid esters such as diisopropyl adipate.
Examples of flavoring agents and sweeteners include acesulfame potassium, stevia, thaumatin, sucralose, panose, trehalose, erythritol, lactitol, reduced palatinose, coupling sugar, fructooligosaccharides, galactooligosaccharides, lactoferrin oligosaccharides, isomaltooligosaccharides, palatinose oligosaccharides, raffinose, aspartame, fructose, xylitol, brown sugar, saccharin or a salt thereof, sorbitol, lactose, white sugar, honey, glucose, maltitol, maltose, mannitol, and starch syrup.

In the present invention, the dosage form of the liquid or semi-solid composition is not particularly limited as long as it is liquid or semi-solid, and can be appropriately selected from, for example, dosage forms described in the General Rules for Preparations of the Japanese Pharmacopoeia, 17th Edition, etc., depending on the intended use, etc. Specific examples of such dosage forms include those described in the General Rules for Preparations of the Japanese Pharmacopoeia, 17th Edition, such as preparations for application to the skin, etc. (external liquids, sprays, ointments, creams, gels, etc.) and preparations for oral administration (oral liquids, syrups, oral jellies, etc.).
In the present invention, the pharmaceutical preparation is preferably in a dosage form selected from the group consisting of a liquid for external use, a spray, an ointment, a cream, and a gel, more preferably in a dosage form selected from the group consisting of a liniment, a lotion, an aerosol for external use, a pump spray, an ointment, a cream, and a gel, and particularly preferably in a dosage form selected from the group consisting of a lotion, an ointment, a cream, and a gel.

In the present invention, the method for producing the liquid or semi-solid composition is not particularly limited, and the composition can be produced by a known method described in, for example, the General Provisions for Preparations in the 17th Edition of the Japanese Pharmacopoeia, depending on the type and amount of the ingredients to be blended, the properties of the composition, the shape of the container, the composition dosage form, the administration route, the purpose, etc.

In the present invention, the term "container" refers to 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 contain a liquid or semi-solid composition, and may be appropriately determined depending on the specific properties, dosage form, administration route, and use of the composition.
Examples of such container shapes include aerosol containers, pump spray containers, bottle containers (more specifically, roll-on containers, jar bottle containers, bottle containers equipped with a sponge-like application member (head) and the like), tube containers, etc. In the present invention, roll-on containers are preferred from the viewpoint of the durability of the container when used for a long period of time.
All of these containers are well known (for example, a roll-on container is disclosed in JP-A-2005-186997, etc.) and may be produced by a known method, or commercially available products may be used.

The container used in the present invention is provided with a metal member.
Here, "metallic member" means a member provided on a container so that the member can at least temporarily come into contact with the liquid or semi-solid composition contained inside the container, and having a metallic part in at least a part of the area where the member can come into contact. Specific examples include the container body (preferably at least a part of the composition storage portion) and dip tube (preferably at least a part of the inner circumference) of an aerosol container or a pump spray container; the container body (preferably at least a part of the composition storage portion) and at least a part of the application ball of a roll-on container; the container body (preferably at least a part of the composition storage portion) and at least a part of the lid of a jar bottle container; the container body (preferably at least a part of the composition storage portion) and at least a part of the cap around the sponge of a bottle container equipped with a sponge-like application member (head).

In the present invention, the "metal" is not particularly limited, and examples thereof include iron, steel, stainless steel, etc. The metal may be surface-treated as necessary. Examples of such surface treatments include corrosion resistance treatment, rust prevention treatment, etc.
In the present invention, the metal is preferably steel or stainless steel from the viewpoint of workability, corrosion resistance, and usability, and particularly preferably stainless steel. The specific type of stainless steel is not particularly limited, and examples thereof include austenite, austenite-ferrite, ferrite, martensite, and precipitation hardening, and specific JIS symbols include SUS201, SUS202, SUS301, SUS302, SUS303, SUS304, SUS305, SUS316, SUS316N, SUS317, SUS317J1, SUS329J1, SUS429, SUS430, SUS440A, and SUS630. In the present invention, the stainless steel is particularly preferably SUS304 and SUS316.

In the present invention, the container having a metal member is preferably a roll-on container having a metal ball. The roll-on container having a metal ball is a container in which a metal ball is rotatably held, and when the ball is pressed against a part to be applied and rolled, the composition contained in the container is applied to the part to be applied.
The shape of the ball is not particularly limited, but from the viewpoint of facilitating rotation, a perfect sphere or a nearly perfect sphere is preferable. In addition, in a roll-on container equipped with a metal ball, the metal ball may be one or more. The diameter of the ball is preferably 1 to 20 mm, more preferably 4 to 8 mm.

In a container equipped with a metal member, the material of the portion other than 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 contained, the shape of the container, etc. Specific examples include glass, plastic, cellulose, pulp, rubber, etc., but from the viewpoints of processability, durability, etc., plastic, etc. are preferable.
In the case of a plastic container, the resin is preferably a thermoplastic resin, whether synthetic or natural, and specific examples include polyolefin-based resins, polyester-based resins, polyphenylene ether-based resins, polycarbonate-based resins, polysulfone-based resins, polyamide-based resins, polyvinyl chloride resins, and styrene-based resins. It is preferable to use one or more of these in combination, and they may also be mixtures of these (polymer alloys).
The method for placing the composition in the container is not particularly limited, and the composition can be placed in the container by any suitable means, such as pouring the composition into the container.

The pharmaceutical of the present invention is effective for antipruritic effects, etc., since it contains a local anesthetic component and an antihistamine component in the composition. Therefore, the pharmaceutical of the present invention can be used as an antipruritic and anti-inflammatory drug, athlete's foot and ringworm drug, external hemorrhoid drug, hair drug, etc., more specifically, as an antipruritic and anti-inflammatory drug for symptoms such as eczema, dermatitis, sores, heat rash, rash, itching, chilblains, insect bites, and hives; athlete's foot (athlete's foot), jock itch, and ringworm; and an external hemorrhoid drug for relieving and disinfecting the pain, itching, swelling, bleeding, and sores of anal fissures and hemorrhoids. In the present invention, it can be most suitably used as an antipruritic and anti-inflammatory drug for symptoms such as eczema, dermatitis, sores, heat rash, rashes, itchiness, chilblains, insect bites, and hives; and as a hair drug for symptoms such as premature baldness (androgenetic alopecia), alopecia areata, diffuse alopecia, pityriasis nodosum, hair growth promotion, hair restoration, prevention of hair loss (hair pulling), thinning hair, dandruff, itchiness, and hair loss after illness or childbirth.

The route of administration of the composition or pharmaceutical product is not particularly limited and can be determined appropriately depending on the disease to which it is applied, the type of preparation, and the gender, age, symptoms, etc. of the recipient, but parenteral administration, particularly topical administration, is preferred. In addition, the composition or pharmaceutical product can be taken in divided doses about 1 to 4 times a day before meals, between meals, after meals, before bedtime, etc.

In addition, the present specification discloses the following aspects, for example, although it is not limited thereto.
[1A] The following components (A) and (B):
(A) one or more components selected from the group consisting of the following components (A-1) and (A-2):
(A-1) a local anesthetic component; (A-2) an antihistamine component; (B) one or more components selected from the group consisting of the following components (B-1) to (B-3):
A pharmaceutical comprising a liquid or semi-solid composition containing (B-1) terpenes, (B-2) glycyrrhetinic acids, and (B-3) steroids, contained in a container having a metal member.
[2A] The pharmaceutical according to [1A], wherein the local anesthetic component is one or more selected from the group consisting of dibucaine, procaine, mepivacaine, meprylcaine, lidocaine, and inorganic acid salts thereof, and solvates thereof.
[3A] The pharmaceutical according to [1A] or [2A], wherein the antihistamine component is one or more selected from the group consisting of isothipendyl, chlorpheniramine, diphenylpyraline, diphenhydramine, and salts thereof.
[4A] The pharmaceutical according to any one of [1A] to [3A], wherein the terpene is one or more selected from the group consisting of monoterpenoids having a p-menthane skeleton, monoterpenoids having an isomer of p-menthane as a skeleton, and monoterpenoids having a bornane skeleton.
[5A] The pharmaceutical agent according to any one of [1A] to [4A], wherein the glycyrrhetinic acid compound is one or more selected from the group consisting of glycyrrhetic acid, glycyrrhizinic acid, and salts thereof.

[6A] The pharmaceutical agent 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 carboxylate derivatives thereof.
[7A] The pharmaceutical according to any one of [1A] to [6A], wherein component (B) is one or more selected from the group consisting of components (B-1) and (B-2).

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

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these in any way. In the following test examples, the amount of each component used is the amount of the indicated component itself, unless otherwise specified as a converted amount.

[Test Example 1] Stability test The following sample solutions (liquid compositions) 1-1 to 1-5 were prepared. The obtained sample solutions were poured into a glass bottle (standard 2K bottle) containing metal balls (metal balls made of stainless steel SUS304: stainless steel balls SUS1/4: AS ONE Corporation) so that the metal balls were about half-immersed, and then the bottle was sealed.
The glass bottle in this state was stored at room temperature for 20 days. The condition of the sample was visually checked, focusing on the presence or absence of discoloration on the surface of the metal ball after storage, and evaluated according to the following criteria. The closer the evaluation result is to "-", the better the storage stability when used as a pharmaceutical product.

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

[Sample solution 1-1]
Lidocaine hydrochloride (lidocaine hydrochloride: manufactured by Iwaki Pharmaceutical Co., Ltd.; the same applies hereinafter in this example) was dissolved as an additional component in a solution obtained by mixing ethanol and purified water in equal weight ratios (hereinafter referred to as "50% ethanol aqueous solution"), to give a content of 10% by mass relative to the total mass of the 50% ethanol aqueous solution, to give sample solution 1-1.
[Sample solution 1-2]
Lidocaine hydrochloride in an amount of 10% by mass relative to the total mass of the 50% ethanol aqueous solution and isopropyl methylphenol (isopropyl methylphenol: manufactured by Osaka Pharmaceutical Co., Ltd.; the same applies hereinafter in this example) in an amount of 10% by mass were dissolved as additional components in a 50% ethanol aqueous solution to prepare sample solution 1-2.

[Sample solution 1-3]
Lidocaine hydrochloride in an amount of 10% by mass relative to the total mass of the 50% ethanol aqueous solution and glycyrrhizinic acid (glycyrrhizinic acid K2: manufactured by Maruzen Pharmaceutical Co., Ltd.; the same applies hereinafter in this example) in an amount of 10% by mass were dissolved as additional components in a 50% ethanol aqueous solution to prepare sample solutions 1-3.
[Sample solution 1-4]
Lidocaine hydrochloride in an amount of 10% by mass relative to the total mass of the 50% ethanol aqueous solution and dexamethasone acetate (dexamethasone acetate: manufactured by Sanofi K.K.; the same applies hereinafter in this example) in an amount of 10% by mass were dispersed as additional components in a 50% ethanol aqueous solution to prepare sample solutions 1-4.
[Sample solution 1-5]
The 50% ethanol aqueous solution was used as sample solution 1-5.

A comparison of sample solutions 1-1 and 1-5 revealed that the discoloration of the metal ball surface observed in sample solution 1-1 was due to lidocaine.
Furthermore, by comparing sample solutions 1-1 with 1-2, 1-3, and 1-4, it became clear that discoloration of the metal ball surface caused by lidocaine could be suppressed by adding isopropylmethylphenol (1-2), glycyrrhizinic acid (1-3), or dexamethasone acetate (1-4) to the sample solution in addition to lidocaine.

These test results show that discoloration of the surface of metal components can be suppressed by adding terpenes such as isopropylmethylphenol, glycyrrhetinic acids such as glycyrrhizinic acid, or steroids such as dexamethasone acetate to a liquid composition containing a local anesthetic component such as lidocaine.

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

[Sample solution 2-1]
Lidocaine hydrochloride was dissolved as an additional component in a 50% ethanol aqueous solution in an amount of 1% by mass based on the total mass of the 50% ethanol aqueous solution to prepare sample solution 2-1.
[Sample solution 2-2]
Lidocaine hydrochloride in an amount of 1% by mass relative to the total mass of the 50% ethanol aqueous solution and 1% by mass of 1-menthol (L-menthol: manufactured by Takasago International Corporation; the same applies hereinafter in the present examples) were dissolved as additional components in a 50% ethanol aqueous solution to prepare sample solution 2-2.

[Sample solution 2-3]
Lidocaine hydrochloride in an amount of 1% by mass relative to the total mass of the 50% ethanol aqueous solution and isopropyl methylphenol in an amount of 1% by mass were dissolved as additional components in the 50% ethanol aqueous solution to prepare sample solution 2-3.
[Sample solution 2-4]
Lidocaine hydrochloride in an amount of 1% by mass relative to the total mass of the 50% ethanol aqueous solution and glycyrrhizinic acid in an amount of 1% by mass were dissolved as additional components in the 50% ethanol aqueous solution to prepare sample solution 2-4.
[Sample solution 2-5]
The 50% ethanol aqueous solution was used as sample solution 2-5.

In Test Example 2, as in Test Example 1, it was confirmed that discoloration of the metal ball surface caused by lidocaine can be suppressed by adding isopropylmethylphenol (2-3) or glycyrrhizic acid (2-4) to the sample solution in addition to lidocaine. A similar effect was also confirmed with l-menthol, which is a terpene like isopropylmethylphenol.

These test results confirm that discoloration of the surface of metal components can be suppressed by adding terpenes such as l-menthol or isopropylmethylphenol, or glycyrrhetinic acids such as glycyrrhizinic acid, to a liquid composition containing a local anesthetic component such as lidocaine.

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

[Sample solution 3-1]
Diphenhydramine hydrochloride (diphenhydramine hydrochloride: manufactured by Kongo Chemical Industries, Ltd.; the same applies hereinafter in the present examples) was dissolved as an additional component in a 50% ethanol aqueous solution in an amount of 1 mass % based on the total mass of the 50% ethanol aqueous solution to prepare sample solution 3-1.
[Sample solution 3-2]
In a 50% ethanol aqueous solution, diphenhydramine hydrochloride in an amount of 1 mass % based on the total mass of the 50% ethanol aqueous solution and dl-camphor (DL-camphor: Fujian Qing Pine) in an amount of 1 mass % were dissolved as additional components to prepare sample solution 3-2.
[Sample solution 3-3]
In a 50% ethanol aqueous solution, diphenhydramine hydrochloride in an amount of 10% by mass relative to the total mass of the 50% ethanol aqueous solution and 1-menthol in an amount of 1% by mass were dissolved as additional components to prepare sample solution 3-3.
[Sample solution 3-4]
In a 50% ethanol aqueous solution, diphenhydramine hydrochloride in an amount of 1% by mass relative to the total mass of the 50% ethanol aqueous solution and dexamethasone acetate in an amount of 1% by mass were dissolved/dispersed as additional components to prepare sample solution 3-4.
[Sample solution 3-5]
The 50% ethanol aqueous solution was used as sample solution 3-5.

A comparison of sample solutions 3-1 and 3-5 revealed that the discoloration of the metal ball surface observed in sample solution 3-1 was due to diphenhydramine.
Furthermore, by comparing sample solutions 3-1 with 3-2, 3-3, and 3-4, it became clear that discoloration of the metal ball surface caused by diphenhydramine could be suppressed by adding camphor (3-2), menthol (3-3), or dexamethasone acetate (3-4) to the sample solution in addition to diphenhydramine.

The above test results show that discoloration of the surface of metal components occurs when antihistamine components such as diphenhydramine are added to a liquid composition, just as in the case of local anesthetic components. It also becomes clear that discoloration of the surface of metal components can be suppressed by adding additional components to the liquid composition, such as terpenes such as camphor and menthol, and steroids such as dexamethasone acetate.

The results of Test Examples 1 to 3 above demonstrate that discoloration of the surface of metal components can be suppressed by further adding terpenes, glycyrrhetinic acids, or steroids to a liquid or semi-solid composition containing a local anesthetic component or an antihistamine component.

Production Example 1
Liquid compositions (Formulation Examples 1 to 8) containing the components and amounts (g) shown in Table 4 below per 100 g are prepared by a conventional method, and then placed in a polyethylene roll-on container (equipped with a metal ball made of SUS316), to produce the pharmaceutical products of Preparation Examples 1-1 to 1-8, respectively.

Production Example 2
Liquid compositions (Formulation Examples 9 to 10) containing the components and amounts (g) shown in Table 5 below in 100 mL were prepared by a conventional method, and placed in polyethylene containers to give pharmaceutical preparations of Preparation Examples 2-1 to 2-2, respectively.

Production Example 3
Liquid compositions (Formulation Examples 11 to 12) containing the components and amounts (g) shown in Table 6 below in 100 mL were prepared by a conventional method, and placed in polyethylene containers to give the pharmaceutical preparations of Preparation Examples 3-1 to 3-2, respectively.

Production Example 4
Semi-solid compositions (Prescription Examples 13 to 14) containing the ingredients and amounts (g) shown in Table 7 below per 100 g were prepared by a conventional method, and placed in polyethylene containers to give the pharmaceutical preparations of Preparation Examples 4-1 to 4-2, respectively.

Production Example 5
Semi-solid compositions (Prescription Examples 15 to 16) containing the ingredients and amounts (g) shown in Table 8 below per 100 g were prepared by a conventional method, and placed in polyethylene containers to give pharmaceutical preparations of Preparation Examples 5-1 to 5-2, respectively.

The present invention provides a pharmaceutical product that contains a local anesthetic component and an antihistamine component and has excellent storage stability, and can be used, for example, in the pharmaceutical industry.

Claims (8)

The following components (A) and (B):
(A) one or more components selected from the group consisting of the following components (A-1) and (A-2):
(A-1) A local anesthetic component; (A-2) One or more selected from the group consisting of diphenhydramine and its salts;
(B) one or more components selected from the group consisting of the following components (B-1) to (B-3):
A pharmaceutical product comprising a liquid or semi-solid composition containing (B-1) terpenes, (B-2) glycyrrhetinic acids, and (B-3) steroids , contained in a container equipped with a metal member, the metal member being provided on the container so as to be at least temporarily in contact with the liquid or semi-solid composition contained inside the container, except for those described in (1) to (4) below.
(1) The pharmaceutical, wherein the liquid or semi-solid composition is a liquid composition containing 2 mass% of diphenhydramine hydrochloride, 0.5 mass% of isopropylmethylphenol, 20 mass% of ethanol, 10 mass% of 1,3-butylene glycol, 1 mass% of polyoxyethylene hydrogenated castor oil (60), and 66.5 mass% of purified water.
(2) The pharmaceutical, wherein the liquid or semi-solid composition is a liquid composition containing 2 mass% of diphenhydramine hydrochloride, 0.15 mass% of prednisolone valerate acetate, 20 mass% of ethanol, 10 mass% of 1,3-butylene glycol, 1 mass% of polyoxyethylene hydrogenated castor oil (60), and 66.9 mass% of purified water.
(3) The pharmaceutical, wherein the liquid or semi-solid composition is a liquid composition containing 2 mass % of diphenhydramine hydrochloride, 0.3 mass % of dipotassium glycyrrhizinate, 20 mass % of ethanol, 10 mass % of 1,3-butylene glycol, and 67.7 mass % of purified water.
(4) When a propellant is contained. The pharmaceutical product according to claim 1, wherein component (A-1) is one or more selected from the group consisting of dibucaine, procaine, mepivacaine, meprylcaine, lidocaine, and inorganic acid salts thereof, and solvates thereof. 3. The pharmaceutical according to claim 1 or 2, wherein the component (B-1) is one or more selected from the group consisting of monoterpenoids having a p-menthane skeleton, monoterpenoids having an isomer of p-menthane as a skeleton, and monoterpenoids having a bornane skeleton. The pharmaceutical product according to any one of claims 1 to 3 , wherein the component (B-2) is at least one member selected from the group consisting of glycyrrhetic acid, glycyrrhizic acid, and salts thereof. The pharmaceutical product according to any one of claims 1 to 4 , wherein the component (B-3) is at least one member selected from the group consisting of cortisone, dexamethasone, hydrocortisone, prednisolone, and carboxylate derivatives thereof. The pharmaceutical product according to any one of claims 1 to 5 , wherein the liquid or semi-solid composition further contains water. The pharmaceutical product according to any one of claims 1 to 6 , wherein the container having a metallic member is a roll-on container having a metallic ball. The following components (A) and (B):
(A) Local anesthetic ingredient
(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) Steroids
A pharmaceutical product comprising a liquid or semi-solid composition containing the above-mentioned formula (I) contained in a container having a metal member, the metal member being provided on the container so as to be at least temporarily in contact with the liquid or semi-solid composition contained inside the container, except when a propellant is included.