Composition

Abstract

To provide a liquid or semi-solid composition comprising prednisolone valerate acetate in an amount of more than 0.15 w / v% based on the total volume of the composition, which suppresses crystal precipitation when stored under low-temperature conditions.SOLUTION: A liquid or semi-solid composition comprises: (A) prednisolone valerate acetate in an amount of more than 0.15 w / v% based on the total volume of the composition; and (B) a salicylic acid.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Prednisolone valerate acetate, an adrenal corticosteroid, exhibits excellent anti-inflammatory activity at the affected area while being a highly safe prodrug that converts to a less active substance in the body. Such excellent efficacy and high safety characteristics are consistent with the concept of self-medication. Therefore, in Japan, prednisolone valerate acetate is widely used as an active ingredient in over-the-counter (OTC) drugs that are effective against eczema, dermatitis, rashes, insect bites, itching, heat rash, hives, and other conditions (e.g., Non-Patent Documents 1 and 2). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Package insert: "Eczema and Dermatitis Treatment Drug Livmex Kowa Cream," Kowa Company, Ltd., October 2011 [Non-patent document 2] Package insert: "Eczema and Dermatitis Treatment Drug Livmex Kowa Ointment," Kowa Company, Ltd., October 2012 Summary of the Invention [Problem to be solved by the invention]

[0004] All OTC medications containing prednisolone valerate acetate that have been sold to date are liquid or semi-solid compositions (e.g., ointments and creams) containing 1.5 mg of prednisolone valerate acetate per mL of composition (i.e., 0.15 w / v% of the total volume of the composition). However, since the anti-inflammatory effect is basically dose-dependent, it is believed that if the content of prednisolone valerate acetate is more than 0.15 w / v%, it will be possible to produce a pharmaceutical product with stronger anti-inflammatory effect and superior efficacy.

[0005] The present inventors therefore investigated the storage stability of liquid or semi-solid compositions containing more than 0.15 w / v% prednisolone valerate acetate in order to develop such compositions. They found that liquid or semi-solid compositions containing 0.3 w / v% prednisolone valerate acetate, based on the total volume of the composition, developed crystal precipitation problems after storage at -20°C for one week. Liquid or semi-solid compositions containing 0.15 w / v% prednisolone valerate acetate, such as conventional over-the-counter (OTC) pharmaceuticals, did not develop crystal precipitation problems under the same storage conditions. Therefore, it was determined that crystal precipitation during storage at such low temperatures occurs when the composition contains more than 0.15 w / v% prednisolone valerate acetate, based on the total volume of the composition. Therefore, an object of the present invention is to provide a liquid or semi-solid composition which contains more than 0.15 w / v % of prednisolone valerate acetate based on the total volume of the composition and which is inhibited from forming crystals when stored at low temperatures. [Means for solving the problem]

[0006] Therefore, the present inventors have conducted further intensive studies to solve the above-mentioned problems, and have found that a liquid or semi-solid composition containing more than 0.15 w / v % of prednisolone valerate acetate (hereinafter, in this specification, this may be simply referred to as "component (A)") relative to the total volume of the composition, further contains any one of the following components 1 to 7 (hereinafter, in this specification, components 1 to 6 will be referred to as "component (B-1)," "component (B-2)," "component (B-3)," "component (B-4)," "component (B-5)," "component (B-6)," and "component (B-7)," respectively, and "one or more selected from the group consisting of components (B-1) to (B-7)" will be referred to as "component (B)"):

[0007] 1. Local anesthetic ingredients, such as lidocaine and lidocaine hydrochloride 2: Crotamitons, represented by crotamiton 3. Antihistamine ingredients, such as diphenhydramine and diphenhydramine hydrochloride 4: Salicylic acids, such as glycol salicylate 5: Terpenes, such as l-menthol, dl-camphor, and isopropylmethylphenol 6: Panthenols, typified by panthenol 7: Hydroxycarboxylic acids, such as sodium citrate

[0008] The present inventors have found that by incorporating component (B), crystal precipitation during storage at low temperatures is relatively suppressed compared to when component (B) is not incorporated, and have completed the present invention.

[0009] That is, the present disclosure provides a composition comprising the following components (A) and (B): (A) prednisolone valerate acetate in an amount greater than 0.15 w / v% based on the total volume of the composition; (B) one or more selected from the group consisting of the following components (B-1) to (B-7): (B-1) Local anesthetic ingredient (B-2) Crotamiton (B-3) Antihistamine ingredients (B-4) Salicylic acids (B-5) Terpenes (B-6) Panthenols (B-7) Hydroxycarboxylic acids The present invention provides a liquid or semi-solid composition comprising: [Effects of the Invention]

[0010] According to the present disclosure, it is possible to provide a liquid or semi-solid composition containing prednisolone valerate acetate, which exhibits good storage stability, excellent efficacy, and is relatively inhibited from crystallizing when stored under low-temperature conditions. DETAILED DESCRIPTION OF THE INVENTION

[0011] <Component (A)> In the present disclosure, the content of "prednisolone valerate acetate" in the liquid or semi-solid composition exceeds 0.15 w / v%, preferably 0.3 w / v% or more, more preferably 0.3 to 0.5 w / v%, and particularly preferably 0.3 w / v%. As specifically disclosed in the test examples below, OTC drugs containing prednisolone valerate acetate at a content (0.15 w / v%) that have been sold up to now do not cause any particular problems even after storage for one week at -20°C, whereas liquid or semi-solid compositions containing more than 0.15 w / v% prednisolone valerate acetate cause the problem of crystal precipitation when stored under the same conditions. However, by further adding component (B) to a liquid or semi-solid composition, crystal precipitation can be relatively suppressed compared to when component (B) is not added.

[0012] <Component (B-1)> In the present disclosure, 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, oxypolyethoxydodecane, dibucaine, tetracaine, procaine, bupivacaine, propitocaine, benzocaine, mepivacaine, meprylcaine, and lidocaine themselves, as well as pharmaceutically acceptable salts thereof, and further includes solvates of ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, tetracaine, procaine, bupivacaine, propitocaine, benzocaine, mepivacaine, meprylcaine, and lidocaine themselves or pharmaceutically acceptable salts thereof with water, alcohol, or the like. Here, the salt is not particularly limited as long as it is a pharmaceutically 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 (manufactured by Delta Pharmaceuticals) and lidocaine hydrochloride (manufactured by Iwaki Pharmaceutical Co., Ltd.) can be used.

[0013] From the viewpoint of the crystal precipitation inhibitory effect, component (B-1) is preferably one or more selected from the group consisting of ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, procaine, mepivacaine, meprylcaine, lidocaine, salts thereof, and solvates thereof, and particularly preferably ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, procaine, mepivacaine, meprylcaine, lidocaine, hydrochlorides thereof, and solvates thereof. More preferred is one or more selected from the group consisting of ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, dibucaine hydrochloride, procaine, procaine hydrochloride, mepivacaine, meprylcaine hydrochloride, lidocaine, and lidocaine hydrochloride, and particularly preferred is one or more selected from the group consisting of ethyl aminobenzoate, dibucaine, dibucaine hydrochloride, lidocaine, and lidocaine hydrochloride.

[0014] The content of component (B-1) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, however, the content of component (B-1) is preferably 0.01 to 20 w / v % relative to the total volume of the composition, more preferably 0.1 to 10 w / v %, and particularly preferably 0.5 to 2 w / v %. Furthermore, the mass ratio of component (A) to component (B-1) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, the content of component (B-1) is preferably 0.01 to 50 parts by mass, more preferably 0.1 to 30 parts by mass, and particularly preferably 2 to 7 parts by mass, of component (B-1) per part by mass of component (A).

[0015] <Component (B-2)> In the present disclosure, the term "crotamiton derivatives" refers to one or more compounds selected from the group consisting of crotamiton, its salts, and solvates thereof. The salts are not particularly limited as long as they are pharmaceutically acceptable, and crotamiton and its salts may be solvates such as hydrates. These may be used alone or in appropriate combination of two or more. These crotamitons are known compounds and can be produced by known methods, or commercially available products such as crotamiton (Sumitomo Chemical Co., Ltd.) can be used.

[0016] The content of component (B-2) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, however, the content of component (B-2) is preferably 0.1 to 30 w / v % relative to the total volume of the composition, more preferably 0.5 to 20 w / v %, and particularly preferably 2 to 10 w / v %. Furthermore, the mass ratio of component (A) to component (B-2) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, the content of component (B-2) is preferably 0.1 to 70 parts by mass, more preferably 1 to 50 parts by mass, and particularly preferably 5 to 35 parts by mass, of component (B-2) per part by mass of component (A).

[0017] <Component (B-3)> In the present disclosure, the "antihistamine ingredient" is not particularly limited as long as it has histamine H1 receptor antagonistic activity, and specific examples 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, pharmaceutically acceptable salts thereof, and 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, and organic bases, such as hydrochloride, tartrate, maleate, fumarate, diphenyldisulfonate, teoclate, salicylate, tannate, besylate, napadisylate, and phosphate. Furthermore, when an asymmetric carbon is present in the chemical structure of an antihistamine component, various optical isomers exist. In the present invention, any of these optical isomers is included, and it may be a single optical isomer or a mixture of various optical isomers. Furthermore, as described above, solvates of various compounds having histamine H1 receptor antagonistic activity, such as azelastine, and their salts with water, alcohol, and the like, are also encompassed by the term "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 such as diphenhydramine (manufactured by Kongo Chemical Co., Ltd.) and diphenhydramine hydrochloride (manufactured by Kongo Chemical Co., Ltd.) can be used.

[0018] Specific examples of component (B-3) 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 or a salt thereof, such as olopatadine hydrochloride; Carbinoxamine or its salts, such as carbinoxamine diphenyldisulfonate and carbinoxamine maleate; clemastine or its salts, such as clemastine fumarate; chlorpheniramine or its salts, such as d-chlorpheniramine maleate and dl-chlorpheniramine maleate; ketotifen or its salts, such as ketotifen fumarate; difeterol or its salts, such as difeterol hydrochloride and difeterol phosphate; diphenylpyraline hydrochloride, diphenylpyraline Diphenylpyraline or its salts such as teoclate; Diphenhydramine or its salts such as diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate; Cyproheptadine or its salts such as cyproheptadine hydrochloride hydrate; Cetirizine or its salts such as cetirizine hydrochloride; Triprolidine or its salts such as triprolidine hydrochloride; Tripelennamine or its salts such as tripelennamine hydrochloride; Thonzylamine or its salts such as thonzylamine hydrochloride; Feki Examples include sofenadine 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; bepotastine or a salt thereof such as bepotastine besilate; homochlorcyclizine or a salt thereof such as homochlorcyclizine hydrochloride; mequitazine or a salt thereof; methdilazine or a salt thereof such as methdilazine hydrochloride; mebhydroline or a salt thereof such as mebhydroline napadisilate; loratadine or a salt thereof, etc. From the viewpoint of the crystal precipitation inhibitory effect, component (B-3) is preferably one or more selected from the group consisting of isothipendyl, chlorpheniramine, diphenylpyraline, diphenhydramine, and salts thereof, more preferably one or more selected from the group consisting of isothipendyl hydrochloride, chlorpheniramine, chlorpheniramine maleate, diphenylpyraline hydrochloride, diphenhydramine, diphenhydramine hydrochloride, and diphenhydramine salicylate, and particularly preferably one or more selected from the group consisting of isothipendyl hydrochloride, chlorpheniramine, chlorpheniramine maleate, diphenhydramine, and diphenhydramine hydrochloride.

[0019] The content of component (B-3) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, however, the content of component (B-3) is preferably 0.01 to 10 w / v % relative to the total volume of the composition, more preferably 0.1 to 5 w / v %, and particularly preferably 0.2 to 2 w / v %. Furthermore, the mass ratio of component (A) to component (B-3) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, the content of component (B-3) is preferably 0.01 to 30 parts by mass, more preferably 0.1 to 20 parts by mass, and particularly preferably 0.5 to 10 parts by mass, of 1 part by mass of component (A).

[0020] <Component (B-4)> In the present disclosure, the term "salicylic acids" refers to one or more compounds selected from the group consisting of salicylic acid and its derivatives (for example, esters of salicylic acid (specifically, for example, methyl salicylate, ethyl salicylate, glycol salicylate, etc.)) and salts thereof. The salts are not particularly limited as long as they are pharmaceutically acceptable, and examples thereof include salts with inorganic acids, organic acids, inorganic bases, organic bases, etc., such as alkali metal salts such as potassium salts and sodium salts; and ammonium salts. From the viewpoint of the crystal precipitation inhibitory effect, component (B-4) is preferably one or more selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate, and methyl salicylate, more preferably one or more selected from the group consisting of glycol salicylate and methyl salicylate, and particularly preferably glycol salicylate. These compounds are all known compounds and can be produced by known methods, or commercially available products can be used, such as glycol salicylate (manufactured by API Corporation).

[0021] The content of component (B-4) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, however, the content of component (B-4) is preferably 0.01 to 20 w / v%, more preferably 0.1 to 10 w / v%, and particularly preferably 0.4 to 5 w / v%, relative to the total volume of the composition. Furthermore, the mass ratio of component (A) to component (B-4) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, the content of component (B-4) is preferably 0.1 to 50 parts by mass, more preferably 0.5 to 30 parts by mass, and particularly preferably 1 to 20 parts by mass, of component (B-4) per part by mass of component (A).

[0022] <Component (B-5)> In the present disclosure, "terpenes" refers to a general term (terpenoid) that includes terpene hydrocarbons as well as terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc., and the structure is not particularly limited, and examples include monoterpenes, sesquiterpenes, and derivatives thereof. In addition, terpenes may be cyclic or chain-like. Specific examples of such terpenes include isopropylmethylphenol, isoborneol, irone, ocimene, carveol, carbotanacetone, carvomenthone, carvone, carene, calone, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, cineole, cymene, silvestrene, 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, the component name includes all of the various optical isomers alone and mixtures of these optical isomers in any ratio, and may be a single optical isomer or a mixture of various optical isomers in any ratio (for example, the term "menthol" includes both dl-menthol and l-menthol). Furthermore, when terpenes are incorporated into a liquid or semi-solid composition, the terpenes may be used as they are, or essential oils containing terpenes may be used. These terpenes are known compounds and can be produced by known methods, or commercially available products such as isopropylmethylphenol (Sumitomo Chemical Co., Ltd.), dl-camphor (Fujian Seishun Co., Ltd.), and l-menthol (Takasago International Corporation) can be used.

[0023] As component (B-5), from the viewpoint of the crystal precipitation inhibitory effect, a cyclic terpenoid is preferred, a cyclic monoterpenoid is more preferred, a monocyclic or bicyclic monoterpenoid is even more preferred, and examples thereof include monoterpenoids having a p-menthane skeleton (for example, 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; and monoterpene ethers having a p-menthane skeleton such as cineole), monoterpenoids having an isomer of p-menthane as a skeleton (for example, 3-methyl-4-isopropyl Phenol (e.g., unsaturated derivatives of p-menthane isomers such as isopropylmethylphenol) or 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) are even more preferred, and one or more selected from the group consisting of thymol, menthol, isopropylmethylphenol, camphor and borneol are even more preferred, and one or more selected from the group consisting of thymol, l-menthol, dl-menthol, isopropylmethylphenol, d-camphor, dl-camphor and d-borneol are even more preferred, and one or more selected from the group consisting of l-menthol, dl-menthol, isopropylmethylphenol, d-camphor and dl-camphor are particularly preferred.

[0024] The content of component (B-5) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, however, component (B-5) is preferably contained in an amount of 0.01 to 30 w / v%, more preferably 0.05 to 15 w / v%, and particularly preferably 0.1 to 7 w / v%, relative to the total volume of the composition. Furthermore, the mass ratio of component (A) to component (B-5) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, the content of component (B-5) is preferably 0.01 to 60 parts by mass, more preferably 0.05 to 40 parts by mass, and particularly preferably 0.2 to 25 parts by mass, of 1 part by mass of component (A).

[0025] <Component (B-6)> In the present disclosure, "panthenols" refers to one or more selected from the group consisting of panthenol and its derivatives (pantothenic acid, pantothenyl ethyl ether, acetylpantothenyl ethyl ether, pantethine, pantetheine, coenzyme A, etc.) and their salts (alkali metal salts such as sodium salts; salts with Group 2 elements such as calcium salts, etc.). In the present disclosure, these may be used alone or in combination of two or more. From the viewpoint of the crystal precipitation inhibitory effect, component (B-6) is preferably one or more selected from the group consisting of panthenol, pantothenic acid, acetylpantothenyl ethyl ether, pantothenyl ethyl ether, and salts thereof, more preferably one or more selected from the group consisting of panthenol, sodium pantothenate, calcium pantothenate, acetylpantothenyl ethyl ether, and pantothenyl ethyl ether, and particularly preferably one or more selected from the group consisting of panthenol and pantothenyl ethyl ether. Panthenols are known ingredients and may be produced by known methods, or commercially available products may be used. Specific examples of commercially available products include D-panthenol 50P (BASF Japan Ltd.), D-panthenol 75W (BASF Japan Ltd.), D-panthenol USP (BASF Japan Ltd.), calcium pantothenate (Kyowa Pharma Chemical Co., Ltd.), calcium pantothenate (BASF Japan Ltd.), calcium pantothenate (Alps Pharmaceutical Co., Ltd.), Viewplex VH (DSM Nutrition Japan Ltd.), D-pantothenyl alcohol (DSM Nutrition Japan Ltd.), D-pantothenyl alcohol (Alps Pharmaceutical Co., Ltd.), DL-pantothenyl alcohol (Alps Pharmaceutical Co., Ltd.), and pantothenyl ethyl ether (Kyowa Pharma Chemical Co., Ltd.).

[0026] The content of component (B-6) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, however, component (B-6) is preferably contained in an amount of 0.01 to 20 w / v%, more preferably 0.1 to 10 w / v%, and particularly preferably 1 to 5 w / v%, relative to the total volume of the composition. Furthermore, the mass ratio of component (A) to component (B-6) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, the content of component (B-6) is preferably 0.1 to 50 parts by mass, more preferably 1 to 30 parts by mass, and particularly preferably 3 to 20 parts by mass, of component (B-6) per part by mass of component (A).

[0027] <Component (B-7)> In the present disclosure, "hydroxycarboxylic acids" refers to organic compounds having a carboxyl group and a hydroxyl group in one molecule, and specifically includes at least one selected from the group consisting of citric acid, tartaric acid, lactic acid, fumaric acid, malic acid, their salts, and solvates thereof. The salts are not particularly limited as long as they are pharmaceutically acceptable, and examples include alkali metal salts such as sodium salts and potassium salts; salts with Group II elements such as calcium salts and magnesium salts; and ammonium salts. Furthermore, the hydroxycarboxylic acids and their salts may be solvates such as hydrates. From the viewpoint of the crystal precipitation inhibitory effect, component (B-7) is preferably one or more selected from the group consisting of citric acid, sodium citrate, tartaric acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, fumaric acid, and malic acid, and particularly preferably one or more selected from the group consisting of citric acid and sodium citrate.

[0028] The content of component (B-7) in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined by appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, however, component (B-7) is preferably contained in an amount of 0.01 to 20 w / v%, more preferably 0.05 to 10 w / v%, and particularly preferably 0.1 to 5 w / v%, relative to the total volume of the composition. Furthermore, the mass ratio of component (A) to component (B-7) contained in the liquid or semi-solid composition of the present disclosure is not particularly limited and may be determined through appropriate consideration. From the viewpoint of the crystal precipitation inhibitory effect, the content of component (B-7) is preferably 0.01 to 50 parts by mass, more preferably 0.1 to 30 parts by mass, and particularly preferably 0.3 to 20 parts by mass, of component (B-7) per part by mass of component (A).

[0029] <Liquid or semi-solid composition> In the present disclosure, a "liquid or semi-solid composition" refers to a composition that is liquid or semi-solid at room temperature (any temperature within the range of 15 to 25°C). Here, the properties of the composition are not particularly limited, and it may be any of a solution, colloidal solution (sol (suspension or emulsion)), gel, etc. Furthermore, the type and properties of the solvent or base are not particularly limited, and it may be hydrophilic or hydrophobic such as oily, and multiple different types of solvents and bases may be appropriately mixed, emulsified, etc. for use. Specific examples of such solvents and bases include the components exemplified below as additives.

[0030] In the present disclosure, the liquid or semi-solid composition preferably contains water in addition to components (A) and (B) from the viewpoints of safety during use and ease of use. Here, the content of water in the composition is not particularly limited, but from the viewpoint of safety during use and improving the stability of prednisolone valerate acetate, it is preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 10 to 90% by mass, even more preferably 20 to 80% by mass, even more preferably 25 to 70% by mass, and particularly preferably 30 to 65% by mass, based on the total mass of the composition.

[0031] In addition, in the present disclosure, the liquid or semi-solid composition preferably contains a lower alcohol in addition to components (A) and (B) from the viewpoint of usability. It is to be noted that both water and a lower alcohol may be contained. In the present disclosure, the liquid or semi-solid composition preferably contains both water and a lower alcohol from the viewpoint of safety during use and usability. Here, "lower alcohol" means a linear or branched monohydric alcohol having 1 to 6 carbon atoms, and specific examples thereof include ethanol, isopropanol, n-propanol, etc., and one of these may be used alone or two or more may be used in combination. Among these, ethanol, isopropanol, and mixtures thereof are preferred. The content of the lower alcohol in the composition is not particularly limited, but from the viewpoint of the feel when used, it is preferably 5% by mass or more, more preferably 10 to 80% by mass, even more preferably 15 to 75% by mass, even more preferably 20 to 70% by mass, even more preferably 25 to 65% by mass, and particularly preferably 30 to 60% by mass, relative to the total mass of the composition.

[0032] In the present invention, the liquid or semi-solid composition may contain, as a medicinal ingredient, drugs other than those mentioned above, such as one or more drugs selected from the group consisting of glycyrrhizic acid derivatives, allantoin, disinfectants, astringents / protectants, aqueous ammonia, vitamin E derivatives, and vitamin A derivatives.

[0033] Examples of glycyrrhizinic acids include glycyrrhizinic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), glycyrrhetinic acid, etc. Examples of disinfectants 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, and benzethonium chloride. Astringent and protective agents include, for example, calamine and zinc oxide. Examples of vitamin E include tocopherol, tocopherol succinate, tocopherol acetate, and tocopherol nicotinate. Examples of vitamin A include vitamin A oil and retinol palmitate.

[0034] In addition, in the present disclosure, liquid or semi-solid compositions may be blended with additives used in the pharmaceutical field, etc., depending on the dosage form, administration method, etc. of the composition. 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. These may be used alone or in combination of two or more.

[0035] 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; and polyvinylpyrrolidone. Examples of polyhydric alcohols include glycerin, ethylene glycol, propylene glycol, 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, purified lanolin, and reduced lanolin; and silicone oil.

[0036] Examples of emulsifiers 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 alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, and polyoxyethylene polyoxypropylene alkyl ethers; and nonionic surfactants such as ether esters of 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, and polyoxyethylene alkyl ether fatty acid esters. In addition, ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate can be mentioned. Examples of solubilizers include the nonionic surfactants and ionic surfactants exemplified above as emulsifiers, as well as liquid paraffin, crotamiton, and the like.

[0037] Examples of pH adjusters include organic acids or salts thereof such as 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 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, purified lanolin, medium-chain fatty acid triglycerides, rapeseed oil, castor oil, propylene glycol, and polybutene. 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, and sorbitol. Examples of stabilizers include adipic acid, ascorbic acid, sodium sulfite, sodium hydrogen sulfite, sodium chloride, hydrogenated 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 its salt, sorbitol, lactose, white sugar, honey, glucose, maltitol, maltose, mannitol, and starch syrup.

[0038] In the present disclosure, the pH of the liquid or semi-solid composition is not particularly limited, but from the viewpoints of the stability and usability of the composition, the pH at 25°C is preferably 3 to 8, and particularly preferably 4 to 6.

[0039] In the present disclosure, the method for producing a 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 18th Edition of the Japanese Pharmacopoeia, etc., depending on the types and amounts of the ingredients to be blended, the properties of the composition, the dosage form, the route of administration, the intended use, etc.

[0040] In the present disclosure, the method of administration or application of the liquid or semi-solid composition is not particularly limited, and examples include oral administration and parenteral administration such as transdermal and vaginal administration. In the present invention, parenteral administration is preferred, and transdermal administration is particularly preferred, in view of the pharmacological action of prednisolone valerate acetate and the properties of the liquid or semi-solid composition (which allow for flexible application of only the required amount depending on the location, shape, and area of ​​the affected area).

[0041] In the present disclosure, the dosage form of the liquid or semi-solid composition is not particularly limited as long as the composition is in a liquid or semi-solid form, and can be appropriately selected from dosage forms described in, for example, the General Provisions for Preparations in the 18th Edition of the Japanese Pharmacopoeia, etc., depending on the intended use, etc. Specific examples of such dosage forms include preparations to be applied to the skin, etc. (external liquid preparations, sprays, ointments, creams, gels, etc.), preparations to be administered orally (oral liquid preparations, syrups, oral jellies, etc.), etc. In the present disclosure, the dosage form of the liquid or semi-solid composition is preferably 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 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, even more preferably a dosage form selected from the group consisting of a lotion, an ointment, a cream, and a gel, and particularly preferably a lotion.

[0042] The liquid or semi-solid composition of the present disclosure may be contained in a container, such as a bottle or a tube. The material of the container is not particularly limited and may be appropriately selected from the viewpoint of usability, etc. Specific examples of such materials include aluminum foil, glass, and plastics (polyesters such as polyethylene terephthalate; polyethylenes such as LDPE and HDPE; and polyolefins such as polypropylene), with aluminum foil being preferred. In the present invention, the means for storing the liquid or semi-solid composition in a container is not particularly limited, and the container may be filled or otherwise processed in a conventional manner depending on the shape of the container, the properties of the composition, etc., thereby producing the container-packed composition of the present invention.

[0043] The liquid or semi-solid composition of the present disclosure contains prednisolone valerate acetate, which has excellent anti-inflammatory activity, and therefore can be used as a pharmaceutical or quasi-drug, and can be suitably used, for example, as an antipruritic and anti-inflammatory drug, more specifically, as an antipruritic and anti-inflammatory drug having efficacy or effects of one or more selected from eczema, dermatitis, sores, heat rash, rash, itch, chilblains, insect bites, and hives.

[0044] The present disclosure provides a composition comprising the following component (A): (A) prednisolone valerate acetate in an amount greater than 0.15 w / v% based on the total volume of the composition; A liquid or semi-solid composition containing the following component (B): (B) one or more selected from the group consisting of the following components (B-1) to (B-7): (B-1) Local anesthetic ingredient (B-2) Crotamiton (B-3) Antihistamine ingredients (B-4) Salicylic acids (B-5) Terpenes (B-6) Panthenols (B-7) Hydroxycarboxylic acids The present invention also relates to a method for inhibiting crystal precipitation, which includes the step of incorporating (A) and (B) into a liquid or semi-solid composition. Here, "inhibition of crystal precipitation" means that, when stored for the same period under low-temperature storage conditions (a temperature below 0°C, preferably below 0°C, particularly preferably -20°C), no visible crystal precipitation is observed or the amount of crystal precipitation is small, compared to when the composition does not contain component (B). Furthermore, the "method for inhibiting crystal precipitation" means that, by incorporating components (A) and (B) into a liquid or semi-solid composition, a situation can be created in which the "inhibition of crystal precipitation" can be achieved (a situation in which the "inhibition of crystal precipitation" would occur if the composition were stored under low-temperature storage conditions).

[0045] In such an embodiment, the order of the step of blending component (A) and the step of blending component (B) is not particularly limited, as long as a liquid or semi-solid composition containing components (A) and (B) is produced directly or indirectly. In this embodiment, the meanings of various terms, the amounts of each component, etc. are all the same as those explained for the "liquid or semi-solid composition."

[0046] This specification discloses the invention exemplified below in relation to the above embodiments, but is not limited to these in any way. <a1>The following components (A) and (B): (A) prednisolone valerate acetate in an amount greater than 0.15 w / v% based on the total volume of the composition; (B) one or more selected from the group consisting of the following components (B-1) to (B-7): (B-1) Local anesthetic ingredient (B-2) Crotamiton (B-3) Antihistamine ingredients (B-4) Salicylic acids (B-5) Terpenes (B-6) Panthenols (B-7) Hydroxycarboxylic acids A liquid or semi-solid composition comprising:

[0047] <a2>Component (A) is prednisolone valerate acetate in an amount of 0.3 w / v% based on the total volume of the composition. <a1>The composition described.

[0048] <a3>The component (B-1) is one or more selected from the group consisting of ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, procaine, mepivacaine, meprylcaine, lidocaine, salts thereof, and solvates thereof. <a1>or <a2>The composition described. <a4>Component (B-2) is one or more selected from the group consisting of crotamiton, a salt thereof, and a solvate thereof. <a1> ~ <a3>The composition described in any one of the above. <a5>The component (B-3) is one or more selected from the group consisting of isothipendyl, chlorpheniramine, diphenylpyraline, diphenhydramine, and salts thereof. <a1> ~ <a4>The composition described in any one of the above.

[0049] <a6>The component (B-4) is at least one selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate, and methyl salicylate. <a1> ~ <a5>The composition described in any one of the above. <a7>the component (B-5) is one or more selected from the group consisting of cymene, thymol, terpinene, terpinolene, phellandrene, limonene, carveol, terpineol, menthol, carvone, menthone, perillaldehyde, cineole, monoterpene ether, 3-methyl-4-isopropylphenol (isopropylmethylphenol), borneol, and camphor; <a1> ~ <a6>The composition described in any one of the above. <a8>The component (B-6) is one or more selected from the group consisting of panthenol, pantothenic acid, acetylpantothenyl ethyl ether, pantothenyl ethyl ether, and salts thereof. <a1> ~ <a7>The composition described in any one of the above. <a9>The component (B-7) is one or more selected from the group consisting of citric acid, sodium citrate, tartaric acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, fumaric acid, and malic acid. <a1> ~ <a8>The composition described in any one of the above.

[0050] <a10>No crystal precipitation occurs when stored at -20°C for one week. <a1> ~ <a9>The composition described in any one of the above. <a11>The dosage form is selected from the group consisting of lotions, ointments, creams, and gels. <a1> ~ <a10>The composition described in any one of the above.

[0051] <b1>The following component (A): (A) prednisolone valerate acetate in an amount greater than 0.15 w / v% based on the total volume of the composition; A liquid or semi-solid composition containing the following component (B): (B) antihistamine components; A method for inhibiting crystal precipitation, comprising the step of incorporating:

[0052] <b2>Component (A) is prednisolone valerate acetate in an amount of 0.3 w / v% based on the total volume of the composition. <b1>The method described.

[0053] <b3>The component (B-1) is one or more selected from the group consisting of ethyl aminobenzoate, oxypolyethoxydodecane, dibucaine, procaine, mepivacaine, meprylcaine, lidocaine, salts thereof, and solvates thereof. <b1>or <b2>The method described. <b4>Component (B-2) is one or more selected from the group consisting of crotamiton, a salt thereof, and a solvate thereof. <b1> ~ <b3>Any of the methods described above. <b5>The component (B-3) is one or more selected from the group consisting of isothipendyl, chlorpheniramine, diphenylpyraline, diphenhydramine, and salts thereof. <b1> ~ <b4>Any of the methods described above.

[0054] <b6>The component (B-4) is at least one selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate, and methyl salicylate. <b1> ~ <b5>Any of the methods described above. <b7>the component (B-5) is one or more selected from the group consisting of cymene, thymol, terpinene, terpinolene, phellandrene, limonene, carveol, terpineol, menthol, carvone, menthone, perillaldehyde, cineole, monoterpene ether, 3-methyl-4-isopropylphenol (isopropylmethylphenol), borneol, and camphor; <b1> ~ <b6>Any of the methods described above. <b8>The component (B-6) is one or more selected from the group consisting of panthenol, pantothenic acid, acetylpantothenyl ethyl ether, pantothenyl ethyl ether, and salts thereof. <b1> ~ <b7>Any of the methods described above. <b9>The component (B-7) is one or more selected from the group consisting of citric acid, sodium citrate, tartaric acid, sodium tartrate, lactic acid, calcium lactate, sodium lactate, fumaric acid, and malic acid. <b1> ~ <b8>Any of the methods described above. <b10>The dosage form of the composition is selected from the group consisting of lotions, ointments, creams, and gels. <b1> ~ <b9>Any of the methods described above. [Example]

[0055] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0056] [Test Example 1] Preservation test Part 1 Various liquid compositions containing the components and amounts (g) shown in Table 1 below per 100 mL were prepared by a conventional method and placed in glass bottles (2K standard bottles). The resulting compositions were stored for one week at −20° C. After storage, the presence or absence of crystal precipitation in the composition was visually confirmed, and the composition was evaluated as ◯ when no crystal precipitation was observed, and × when crystal precipitation was observed. The results are shown in Table 1 together with the content (w / v%) of prednisolone valerate acetate in each composition.

[0057] [Table 1]

[0058] The results shown in Table 1 indicate that the composition of Reference Example 1, which contained 0.15 w / v% prednisolone valerate acetate based on the total mass of the composition, showed no crystal precipitation even after storage at −20° C. for 1 week, whereas the composition of Comparative Example 1, which contained 0.3 w / v%, showed crystal precipitation. This indicates that such crystal precipitation is a problem that occurs when the content of prednisolone valerate acetate exceeds 0.15 w / v%. However, it was revealed that the composition of Example 1, which further contains lidocaine in addition to 0.3 w / v% prednisolone valerate acetate, and the composition of Example 2, which also contains lidocaine hydrochloride, did not undergo crystal precipitation even after storage at -20°C for one week.

[0059] The above test results demonstrate that by further adding a local anesthetic component, such as lidocaine or lidocaine hydrochloride, to a liquid or semi-solid composition containing more than 0.15 w / v% prednisolone valerate acetate, crystal precipitation is relatively suppressed compared to when such a component is not added.

[0060] [Test Example 2] Preservation test Part 2 Various liquid compositions containing the ingredients and amounts (g) shown in Table 2 below per 100 mL were prepared by a conventional method, and tests were carried out in the same manner as in Test Example 1. The results are shown in Table 2.

[0061] [Table 2]

[0062] The test results shown in Table 2 reveal that the composition of Example 3, which contains crotamiton in addition to 0.3 w / v% prednisolone valerate acetate, also does not exhibit crystal precipitation even after storage at -20°C for one week, similar to the compositions of Examples 1 and 2.

[0063] The above test results demonstrate that the inclusion of a crotamiton congener, such as crotamiton, in a liquid or semi-solid composition containing more than 0.15 w / v% prednisolone valerate acetate can relatively suppress crystal precipitation compared to a composition that does not contain such a component.

[0064] [Test Example 3] Preservation test No. 3 Various liquid compositions containing the ingredients and amounts (g) per 100 mL shown in Table 3 below were prepared by a conventional method, and tests were carried out in the same manner as in Test Example 1. The results are shown in Table 3.

[0065] [Table 3]

[0066] The test results shown in Table 3 reveal that, similar to the compositions of Examples 1 and 2, the composition of Example 4, which contains diphenhydramine in addition to 0.3 w / v % prednisolone valerate acetate, and the composition of Example 5, which contains diphenhydramine hydrochloride, do not produce crystal precipitation even after storage at -20°C for one week.

[0067] The above test results demonstrate that by further adding an antihistamine component, such as diphenhydramine or diphenhydramine hydrochloride, to a liquid or semi-solid composition containing more than 0.15 w / v % prednisolone valerate acetate, crystal precipitation is relatively suppressed compared to when such an component is not added.

[0068] [Test Example 4] Preservation test No. 4 Various liquid compositions containing the ingredients and amounts (g) shown in Table 4 below per 100 mL were prepared by a conventional method, and tests were carried out in the same manner as in Test Example 1. The results are shown in Table 4.

[0069] [Table 4]

[0070] The test results shown in Table 4 reveal that the composition of Example 6, which contains glycol salicylate in addition to 0.3 w / v% prednisolone valerate acetate, also does not produce crystal precipitation after storage at -20°C for 1 week, similar to the compositions of Examples 1 and 2.

[0071] The above test results demonstrate that by further adding a salicylic acid, such as glycol salicylate, to a liquid or semi-solid composition containing more than 0.15 w / v % of prednisolone valerate acetate, crystal precipitation is relatively suppressed compared to when such a component is not added.

[0072] [Test Example 5] Preservation test No. 5 Various liquid compositions containing the ingredients and amounts (g) shown in Table 5 below per 100 mL were prepared by a conventional method, and tests were carried out in the same manner as in Test Example 1. The results are shown in Table 5.

[0073] [Table 5]

[0074] The test results shown in Table 5 reveal that, similar to the compositions of Examples 1 and 2, the composition of Example 7 containing 1-menthol in addition to 0.3 w / v% prednisolone valerate acetate, the composition of Example 8 containing dl-camphor, and the composition of Example 9 containing isopropylmethylphenol also do not cause crystal precipitation after storage at -20°C for one week.

[0075] From the above test results, it was revealed that by further adding terpenes, such as l-menthol, dl-camphor, or isopropylmethylphenol, to a liquid or semi-solid composition containing more than 0.15 w / v % of prednisolone valerate acetate, crystal precipitation is relatively suppressed compared to when these components are not added.

[0076] [Test Example 6] Storage test No. 6 Various liquid compositions containing the ingredients and amounts (g) per 100 mL shown in Table 6 below were prepared by a conventional method, and tests were carried out in the same manner as in Test Example 1. The results are shown in Table 6.

[0077] [Table 6]

[0078] The test results shown in Table 6 reveal that the composition of Example 10, which contains panthenol in addition to 0.3 w / v% prednisolone valerate acetate, also does not exhibit crystal precipitation even after storage at -20°C for one week, similar to the compositions of Examples 1 and 2.

[0079] The above test results demonstrate that by further adding a panthenol, such as panthenol, to a liquid or semi-solid composition containing more than 0.15 w / v % prednisolone valerate acetate, crystal precipitation is relatively suppressed compared to when such a component is not added.

[0080] [Test Example 7] Preservation test No. 7 Various liquid compositions containing the ingredients and amounts (g) shown in Table 7 below per 100 mL were prepared by a conventional method, and tests were carried out in the same manner as in Test Example 1. The results are shown in Table 7.

[0081] [Table 7]

[0082] The test results shown in Table 7 reveal that the composition of Example 11, which contains sodium citrate in addition to 0.3 w / v% prednisolone valerate acetate, also does not produce crystal precipitation even after storage at -20°C for 1 week, similar to the compositions of Examples 1 and 2.

[0083] The above test results demonstrate that by further adding an oxycarboxylic acid, such as sodium citrate, to a liquid or semi-solid composition containing more than 0.15 w / v % prednisolone valerate acetate, crystal precipitation is relatively suppressed compared to when such an ingredient is not added.

[0084] [Manufacturing Example 1] A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, inner stopper: polyethylene, bottle: polyethylene or polypropylene) to obtain the lotion of Preparation Example 1. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Allantoin 0.2g Isopropylmethylphenol 0.1g Additives: edetate sodium hydrate, citric acid hydrate, benzyl alcohol, ethanol and purified water

[0085] [Manufacturing Example 2] A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, inner stopper: polyethylene, bottle: polyethylene or polypropylene) to obtain a lotion of Preparation Example 2. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Allantoin 0.2g Tocopherol acetate 0.5g Additives: edetate sodium hydrate, citric acid hydrate, benzyl alcohol, ethanol and purified water

[0086] [Manufacturing Example 3] A liquid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, inner stopper: polyethylene, bottle: polyethylene or polypropylene) to obtain a lotion of Preparation Example 3. Prednisolone valerate acetate 0.3g Lidocaine 1.0g Isopropylmethylphenol 0.1g l-menthol 5.0g Additives: edetate sodium hydrate, citric acid hydrate, benzyl alcohol, ethanol and purified water

[0087] [Manufacturing Example 4] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, inner stopper: polyethylene, bottle: polyethylene or polypropylene) to obtain the lotion of Preparation Example 4. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Allantoin 0.2g Tocopherol acetate 0.5g Additives: Polyoxyethylene arachidyl ether / stearyl alcohol mixture, medium-chain fatty acid triglyceride, xanthan gum, hydroxyethyl cellulose, carboxyvinyl polymer, sodium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium hydroxide, fragrance, purified water

[0088] [Manufacturing Example 5] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene or polyethylene, tube: metal or polyethylene) to obtain the ointment of Preparation Example 5. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Allantoin 0.2g Tocopherol acetate 0.5g Additives: methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum and liquid paraffin

[0089] [Manufacturing Example 6] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene or polyethylene, tube: metal or polyethylene) to obtain the ointment of Preparation Example 6. Prednisolone valerate acetate 0.3g dl-Camphor 1.0g l-menthol 5.0g Tocopherol acetate 0.5g Additives: methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum and liquid paraffin

[0090] [Manufacturing Example 7] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene or polyethylene, tube: metal or polyethylene) to obtain the ointment of Preparation Example 7. Prednisolone valerate acetate 0.3g Crotamiton 5.0g Allantoin 0.2g Tocopherol acetate 0.5g Additives: methyl parahydroxybenzoate, propyl parahydroxybenzoate, white petrolatum and liquid paraffin

[0091] [Manufacturing Example 8] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene or polyethylene, tube: metal or polyethylene) to obtain the ointment of Preparation Example 8. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Allantoin 0.2g Tocopherol acetate 0.5g Additives: Glycerin monostearate, citric acid hydrate, sodium citrate hydrate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, liquid paraffin, white petrolatum, purified water

[0092] [Manufacturing Example 9] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene or polyethylene, tube: metal or polyethylene) to obtain the cream of Preparation Example 9. Prednisolone valerate acetate 0.3g Crotamiton 5.0g Glycol salicylate 1.0g Tocopherol acetate 0.5g Additives: Medium chain fatty acid triglyceride, diisopropyl adipate, dimethylpolysiloxane, concentrated glycerin, behenyl alcohol, polyoxyethylene arachidyl ether-stearyl alcohol mixture, xanthan gum, sodium alginate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium citrate hydrate and purified water.

[0093] [Manufacturing Example 10] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene or polyethylene, tube: metal or polyethylene) to obtain the cream of Preparation Example 10. Prednisolone valerate acetate 0.3g Glycol salicylate 1.0g dl-Camphor 1.0g l-menthol 5.0g Additives: Medium chain fatty acid triglyceride, diisopropyl adipate, dimethylpolysiloxane, concentrated glycerin, behenyl alcohol, polyoxyethylene arachidyl ether-stearyl alcohol mixture, xanthan gum, sodium alginate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium citrate hydrate and purified water.

[0094] [Manufacturing Example 11] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene or polyethylene, tube: metal or polyethylene) to obtain the cream of Preparation Example 11. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Allantoin 0.2g Tocopherol acetate 0.5g Additives: Medium chain fatty acid triglyceride, diisopropyl adipate, dimethylpolysiloxane, concentrated glycerin, behenyl alcohol, polyoxyethylene arachidyl ether-stearyl alcohol mixture, xanthan gum, sodium alginate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium citrate hydrate and purified water.

[0095] [Manufacturing Example 12] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene or polyethylene, tube: metal or polyethylene) to obtain the cream of Preparation Example 12. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Allantoin 0.2g Tocopherol acetate 0.5g Additives: Light liquid paraffin, Macrogol 6000, α-monoisostearyl glyceryl ether, polyoxyethylene behenyl ether, citric acid hydrate, sodium citrate hydrate, concentrated glycerin, Macrogol 400, magnesium sulfate hydrate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, fragrance, purified water

[0096] [Manufacturing Example 13] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, tube: innermost layer is linear low-density polyethylene) to obtain the cream of Preparation Example 13. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Methyl salicylate 1.0g l-menthol 3.0g dl-Camphor 2.0g Additives: Medium-chain fatty acid triglyceride, diisopropyl adipate, dimethylpolysiloxane, concentrated glycerin, behenyl alcohol, polyoxyethylene arachidyl ether-stearyl alcohol mixture, sorbitan monostearate, xanthan gum, hypromellose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium citrate hydrate and purified water.

[0097] [Manufacturing Example 14] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, tube: innermost layer is linear low-density polyethylene) to obtain the cream of Preparation Example 14. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Glycol salicylate 1.0g l-menthol 3.5g dl-Camphor 1.0g Additives: Medium-chain fatty acid triglyceride, diisopropyl adipate, dimethylpolysiloxane, concentrated glycerin, behenyl alcohol, polyoxyethylene arachidyl ether-stearyl alcohol mixture, sorbitan monostearate, xanthan gum, hypromellose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium citrate hydrate and purified water.

[0098] [Manufacturing Example 15] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, tube: innermost layer is linear low-density polyethylene) to obtain the cream of Preparation Example 15. Prednisolone valerate acetate 0.3g Glycol salicylate 2.0g Lidocaine 1.0g Crotamiton 5.0g Additives: Medium-chain fatty acid triglyceride, diisopropyl adipate, dimethylpolysiloxane, concentrated glycerin, behenyl alcohol, polyoxyethylene arachidyl ether-stearyl alcohol mixture, sorbitan monostearate, xanthan gum, hypromellose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium citrate hydrate and purified water.

[0099] [Manufacturing Example 16] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, tube: innermost layer is linear low-density polyethylene) to obtain the cream of Preparation Example 16. Prednisolone valerate acetate 0.3g Methyl salicylate 2.0g dl-Camphor 4.0g Crotamiton 2.0g Isopropylmethylphenol 0.1g Additives: Medium-chain fatty acid triglyceride, diisopropyl adipate, dimethylpolysiloxane, concentrated glycerin, behenyl alcohol, polyoxyethylene arachidyl ether-stearyl alcohol mixture, sorbitan monostearate, xanthan gum, hypromellose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium citrate hydrate and purified water.

[0100] [Manufacturing Example 17] A semi-solid composition containing the following ingredients and amounts in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, tube: innermost layer is linear low-density polyethylene) to obtain the cream of Preparation Example 17. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 1.0g Lidocaine 0.5g l-menthol 4.0g Additives: Medium-chain fatty acid triglyceride, diisopropyl adipate, dimethylpolysiloxane, concentrated glycerin, behenyl alcohol, polyoxyethylene arachidyl ether-stearyl alcohol mixture, sorbitan monostearate, xanthan gum, hypromellose, methyl parahydroxybenzoate, propyl parahydroxybenzoate, citric acid hydrate, sodium citrate hydrate and purified water.

[0101] [Manufacturing Example 18] A semi-solid composition containing the following ingredients in the amounts listed below in 100 mL was prepared by a conventional method and placed in a container (cap: polypropylene, tube: metal or polyethylene) to obtain a gel of Preparation Example 18. Prednisolone valerate acetate 0.3g Diphenhydramine hydrochloride 2.0g Glycyrrhetinic acid 1.0g Tocopherol acetate 0.5g Additives: benzyl alcohol, hypromellose, citric acid hydrate, sodium edetate hydrate, ethanol, purified water [Industrial Applicability]

[0102] According to the present invention, there is provided a liquid or semi-solid composition containing prednisolone valerate acetate, which exhibits good storage stability, excellent efficacy, and is relatively inhibited from crystallizing when stored at low temperatures, and which can be suitably used in the pharmaceutical industry, etc. < / b1> < / b1> < / b1> < / b1> < / b1> < / b1> < / b1> < / a1> < / a1> < / a1> < / a1> < / a1> < / a1> < / a1> < / a1>

Claims

1. The following components (A) and (B): (A) more than 0.15 w / v% prednisolone valerate acetate based on the total volume of the composition; (B) salicylic acids; A liquid or semi-solid composition comprising:

2. 2. The composition according to claim 1, wherein component (A) is prednisolone valerate acetate in an amount of 0.3 w / v % based on the total volume of the composition.

3. 2. The composition of claim 1, wherein component (B) is at least one member selected from the group consisting of salicylic acid, glycol salicylate, sodium salicylate, and methyl salicylate.

4. 2. The composition according to claim 1, which does not undergo crystal precipitation when stored at −20° C. for one week.

5. The composition according to any one of claims 1 to 4, which is in a dosage form selected from the group consisting of lotions, ointments, creams and gels.

6. The following component (A): (A) more than 0.15 w / v% prednisolone valerate acetate based on the total volume of the composition; A liquid or semi-solid composition containing the following component (B): (B) salicylic acids; A method for inhibiting crystal precipitation, comprising the step of incorporating:

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