JP2015098469A - Pharmaceutical composition comprising chili pepper - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition comprising chili pepper or an extract thereof and having excellent storage stability, as well as agents for stabilizing storage property of the pharmaceutical composition and methods for stabilizing the pharmaceutical composition.SOLUTION: The pharmaceutical composition of the invention comprises: (A) one or more kinds of chili pepper (fruits of Capsicum annuum Linne (Solanaceae)) and extracts thereof; (B) loxoprofen or a salt thereof; (C) one or more ingredients selected from the group consisting of the following (C-1) and (C-2) compounds, where (C-1) is a compound represented by the formula (1) or a salt thereof [X is a single bond or O; Y is a methine group or N; Ris H, a hydroxyl group or alkyl group; Ris a substituted/unsubstituted cyclic amino group or a substituted/unsubstituted aminoalkyl group; Ris H or a halogen atom], and (C-2) is a polyalcohol.

Description

  The present invention relates to a pharmaceutical composition containing a red pepper or an extract thereof, and a storage stabilizer and a stabilization method for a pharmaceutical composition containing a red pepper or an extract thereof.

  Herbal medicines such as chili peppers and extracts thereof are widely used as components of pharmaceuticals because they have various pharmacological actions. However, in a pharmaceutical composition containing a crude drug or an extract thereof, storage stability tends to be a problem, and development of a technique for improving storage stability is required. In particular, pharmaceuticals should be stored, stored, transported, etc. under temperature controlled conditions (at least 30 ° C., so-called room temperature), but they are not always sufficiently temperature controlled in the hands of consumers. Considering the recent climate change and the trend of power saving due to the world situation, it is often assumed that it is often placed under a high temperature that greatly exceeds 30 ° C, so ensuring storage stability under high temperature conditions is extremely important. .

  Examples of the problem of storage stability in a pharmaceutical composition containing a crude drug or an extract thereof include, for example, the formation of a precipitate in a liquid pharmaceutical composition due to a low-solubility component contained in a large amount thereof. In order to solve the problem, a technique of blending a solubilizer has been studied. For example, Patent Document 1 describes blending a polyoxyethylene hydrogenated castor oil and a polyoxyethylene polyoxypropylene condensate with a crude drug extract. Patent Document 2 describes a solubilized liquid composition in which a polyglycerin fatty acid ester and a polyoxyethylene nonionic surfactant are blended at a specific ratio in addition to a herbal extract and an oil component. .

By the way, loxoprofen is a kind of non-steroidal anti-inflammatory analgesic (NSAID) also known as an active ingredient of Loxonin (registered trademark) (Non-patent Document 1), osteoarthritis, myalgia, swelling after trauma It is used as an active ingredient of external preparations such as gels, poultices, tapes and the like, which are effective for treating diseases such as pain and symptom anti-inflammatory and analgesic (Non-patent Document 2).
However, in the pharmaceutical composition containing a herbal medicine, especially a pepper and its extract, what kind of influence Loxoprofen has on the storage stability has not been examined until now.

Japanese Patent Publication No. 5-9408 JP 2002-128703 A

The 16th revision Japanese Pharmacopoeia Manual Sasakawa Shoten Co., Ltd. C-5359-5364 Loxonin (registered trademark) gel 1% pharmaceutical interview form Daiichi Sankyo Co., Ltd. Revised October 2010 (3rd edition)

  An object of the present invention is to provide a pharmaceutical composition containing a capsicum or an extract thereof and having excellent storage stability, and a storage stabilizer and a stabilization method for the pharmaceutical composition containing the capsicum or an extract thereof. There is.

  Therefore, the present inventors have intensively studied to solve the above-mentioned problems, and as a result, loxoprofen or a salt thereof has an action of improving the storage stability of a pharmaceutical composition containing a red pepper or an extract thereof, and loxoprofen or a salt thereof. In addition to the salt, any one of the following components (C-1) and (C-2):

(C-1) The following general formula (1) including chlorpheniramine or a salt thereof

[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R ¹ represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ² may have a substituent. A good cyclic amino group or an aminoalkyl group which may have a substituent, and R ³ represents a hydrogen atom or a halogen atom. ]
In combination with a compound represented by the formula (I) or a salt thereof (C-2) polyhydric alcohol, the effect of improving the above storage stability is improved, and the mixture is preserved for a long time under a high temperature condition while containing a capsicum or an extract thereof. In this case, it was found that an insoluble matter is hardly generated and a pharmaceutical composition excellent in storage stability can be obtained, and the present invention has been completed.

That is, the present invention includes the following components (A), (B) and (C):
(A) One or more selected from pepper and its extract (B) Loxoprofen or a salt thereof (C) One or more selected from the group consisting of the following components (C-1) and (C-2) (C- 1) The following general formula (1)

[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R ¹ represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ² may have a substituent. A good cyclic amino group or an aminoalkyl group which may have a substituent, and R ³ represents a hydrogen atom or a halogen atom. ]
Or a salt thereof (C-2) A pharmaceutical composition containing a polyhydric alcohol is provided.

In addition, the present invention is a storage stabilizer for a pharmaceutical composition containing at least one selected from pepper and an extract thereof, and comprises the following components (B) and (C):
(B) Loxoprofen or a salt thereof (C) A storage stabilizer containing at least one selected from the group consisting of the above components (C-1) and (C-2) is provided.

The present invention also relates to a method for stabilizing a pharmaceutical composition comprising at least one selected from pepper and an extract thereof, wherein the pharmaceutical composition comprises the following components (B) and (C):
(B) Loxoprofen or a salt thereof (C) Provided is a stabilization method comprising at least one selected from the group consisting of the above components (C-1) and (C-2).

  According to the present invention, it is possible to provide a pharmaceutical composition excellent in long-term storage stability, which contains a red pepper or an extract thereof and hardly generates insoluble matter even when stored for a long time under high temperature conditions. it can.

<Component (A)>
“Capsicum” (蕃 椒) means the fruit of Capsicum annuum Linne (Solanaceae) as described in the 16th revision Japanese Pharmacopoeia. The shape of the pepper can be adjusted as needed, and can be cut or crushed into small pieces, small clumps, or pulverized into a powder. For example, “powder powder” made from pepper is also used in the present invention. Can do. In addition, in consideration of the convenience of handling at the time of manufacturing the pharmaceutical composition, a product obtained by subjecting the pepper to some kind of extraction treatment (hereinafter referred to as a “pepper extract”) may be used.
In addition, the above “pepper extract” includes those subjected to processing such as heating, drying and pulverization in addition to the extraction. Specifically, after the capsicum is appropriately sized as required, an appropriate leaching solution (extraction solvent) is added and leached, or the leaching solution is concentrated (soft extract, tincture, etc.), A dried product (dried extract or the like) is also included in the “capsicum extract” of the present invention.
Moreover, you may use the well-known capsaicinoid which is a main component of a pepper as said pepper extract. As the capsaicinoid, capsaicin and nonanoic acid vanillylamide are preferable.

  Among the above components (A), capsicum soft extract, capsaicin, nonanoic acid vanillylamide and capsicum, capsicum powder, capsicum tincture described in the 16th revision Japanese Pharmacopoeia are preferable, and capsicum soft extract and nonanoic acid vanillylamide are particularly preferable. preferable.

In addition, as the above-mentioned pepper and its extract, commercially available products such as pepper extract B, (local) pepper powder (manufactured by Nippon Powder Chemical Co., Ltd.), nonyl acid vanillylamide (Nagaoka Jitsugyo Co., Ltd.), etc. can be used. The extract may be produced according to a known method.
The method for producing the above extract of capsicum is not particularly limited. For example, the description of “Extract”, “Dipping Agent / Decoach”, “Tincture”, “Flower Extract” in the 16th revised Japanese Pharmacopoeia General Rules for Preparations It can manufacture with reference to the manufacturing method of a well-known plant extract. Specifically, for example, the pepper can be cut, heated, dried, pulverized, 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; benzene, toluene and the like And amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide; water (including hot water) and the like. These may be used alone or in combination of two or more. In the present invention, water, ethanol, or a water / ethanol mixture is preferred.
The extraction operation is not particularly limited, and a known method used for the extraction operation from plants can be adopted. Specifically, for example, immersion in extraction solvent (cooling, digestion, percolation, etc.), super For example, extraction using a critical fluid or a subcritical fluid may be mentioned. In addition, in order to raise extraction efficiency, you may homogenize in stirring or an extraction solvent.
The extraction temperature is not particularly limited and varies depending on the extraction solvent to be used, the extraction operation, and the like, but is preferably set to a temperature from about 5 ° C. to the boiling point of the extraction solvent.
The extraction time is not particularly limited and varies depending on the extraction solvent to be used, the extraction operation, and the like, but is preferably about 1 hour to 14 days.

  Although content of a component (A) is not specifically limited, 0.001-15 mass% is preferable with respect to the pharmaceutical composition total mass, and 0.005-10 mass% is more preferable, and is 0.005-10 mass% with respect to a pharmaceutical composition total mass. 01-8 mass% is still more preferable. Moreover, when using a capsaicinoid such as nonanoic acid vanillylamide as the component (A), the capsaicinoid content is preferably 0.001 to 1% by mass, more preferably 0.005, based on the total mass of the pharmaceutical composition. It is -0.75 mass%, More preferably, it is 0.01-0.5 mass%.

<Component (B)>
In the present invention, “loxoprofen or a salt thereof” includes loxoprofen itself, a pharmaceutically acceptable salt of loxoprofen, and a solvate of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol, or the like. It is. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).

  Although content of a component (B) is not specifically limited, From a viewpoint of a storage stability improvement effect, 0.01-30 mass% is preferable in conversion of loxoprofen sodium anhydride with respect to the pharmaceutical composition total mass, and 0.0. 1 to 25% by mass is more preferable, 0.5 to 20% by mass is further preferable, 0.5 to 10% by mass is further preferable, 0.5 to 5% by mass is further preferable, and 0.5 to 3% by mass is preferable. Particularly preferred.

  The content ratio of component (A) and component (B) contained in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of storage stability, component (B) is added to 1 part by mass in terms of loxoprofen sodium anhydride. On the other hand, the component (A) is preferably 0.01 to 15 parts by mass in terms of bulk drug substance, more preferably 0.05 to 10 parts by mass, and 0.1 to 8 parts by mass. Particularly preferred. When using capsaicinoid such as nonanoic acid vanillylamide as component (A), from the viewpoint of storage stability, component (B) is 1 part by mass in terms of loxoprofen sodium anhydride, and capsaicinoid is 0.001 to 1 part by mass. The amount is preferably 0.005 to 0.75 parts by mass, and more preferably 0.01 to 0.5 parts by mass.

<Ingredient (C)>
(Component (C-1))
In the present invention, the general formula (1)

[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R ¹ represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ² may have a substituent. A good cyclic amino group or an aminoalkyl group which may have a substituent, and R ³ represents a hydrogen atom or a halogen atom. ]
In addition to the compound itself represented by the general formula (1), a pharmaceutically acceptable salt of the compound represented by the general formula (1) is also included in the compound represented by general formula (1).

  Specific examples of the compound represented by the general formula (1) or a salt thereof include, for example, a compound represented by the general formula (1), an inorganic acid salt or an organic acid salt of the compound represented by the general formula (1) ( For example, hydrochloride, maleate, fumarate, diphenyl disulfonate, theocrate, salicylate, tannate, besylate, phosphate, etc.). In addition, when an asymmetric carbon exists in the chemical structure of the compound represented by the general formula (1), it has various optical isomers. In the present invention, any optical isomer is included, Or a mixture of various optical isomers. Furthermore, the compound represented by the general formula (1) or a salt thereof may be in the form of a solvate, and a solvate of the compound represented by the general formula (1) or a salt thereof with water, alcohol or the like. Are also included in the “compound represented by the general formula (1) or a salt thereof”.

In the above R ¹ , the alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, and a methyl group is preferable.
Further, as the R ^1, a hydrogen atom or a methyl group.

In the above R ² , the “cyclic amino group” in the cyclic amino group which may have a substituent is a 5- to 7-membered fat having at least 1, preferably 1 or 2, nitrogen atoms as ring-constituting atoms. Means a cyclic group.
Specific examples of such cyclic amino groups include pyrrolidinyl group, pyrazolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, homopiperidinyl group, homopiperazinyl group and the like. Among these, piperidinyl group, piperazinyl group and homopiperazinyl group are preferable, and piperidinyl group and piperazinyl group are more preferable.

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

In the above R ² , the “cyclic amino group optionally having substituent (s)” includes 1-methylpiperidin-4-yl group, 4-methylhomopiperazin-1-yl group, 1- [3- (4- tert-butylbenzoyl) propyl] piperidin-4-yl group, 4- [3- (1,3-dihydro-2H-benzimidazol-2-one-1-yl) propyl] piperazin-1-yl group, 4- [2- (carboxymethoxy) ethyl] piperazin-1-yl group, 1- {4- [4- (2-carboxypropan-2-yl) phenyl] -4-hydroxybutyl} piperidin-4-yl group, 1 A-(3-carboxypropyl) piperidin-4-yl group is preferred.

In the above R ² , the “aminoalkyl group” in the aminoalkyl group which may have a substituent is an amino group, a monoalkylamino group, a dialkylamino group or a cyclic amino group (the “cyclic amino group” is as described above). It means an alkyl group substituted with the same meaning as “cyclic amino group” in “cyclic amino group optionally having substituent (s)”. Among these, an alkyl group substituted with a dialkylamino group or a cyclic amino group is preferable. The cyclic amino group is preferably a pyrrolidinyl group.
Specific examples of such an aminoalkyl group include 2- (dimethylamino) ethyl group, 2- (pyrrolidin-2-yl) ethyl group, 2-[(isopropyl) (methyl) amino] ethyl group, and the like. Is mentioned. Examples of the “substituent” in the aminoalkyl group which may have a substituent include a hydroxyl group, a phenyl group, and an alkyl group.

In the above R ² , the “aminoalkyl group optionally having substituent (s)” is 2- (dimethylamino) ethyl group, 2- (1-methylpyrrolidin-2-yl) ethyl group, 2-[(methyl ) (1-Phenyl-1-hydroxypropan-2-yl) amino] ethyl group is preferred.

In the above R ² , as the alkyl group moiety in the “alkyl group”, “alkylbenzoyl group”, “carboxyalkylphenyl group”, “aminoalkyl group”, “monoalkylamino group”, “dialkylamino group”, A linear or branched alkyl group having 1 to 6 carbon atoms is preferable, and specific examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
In the above R ² , the alkoxy group moiety in the “carboxyalkoxy group” is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, and a propoxy group. , Butoxy group, pentyloxy group, hexyloxy group and the like.

In the above R ³ , examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In the present invention, a chlorine atom is preferable. In the general formula (1), the substitution position on the phenyl group of R ³ is not particularly limited, but substitution at the 4-position is preferable.

In the present invention, specific examples of the compound represented by the general formula (1) or a salt thereof include ebastine or a salt thereof; oxatomide or a salt thereof; carbinoxamine diphenyl disulfonate, carbinoxamine maleate Carbinoxamine such as clemastine fumarate or the like; Clemastine such as clemastine fumarate or a salt thereof; Chlorpheny such as chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate Lamin or salt thereof; dipheterol or salt thereof such as dipheterol hydrochloride or dipheterol phosphate; diphenylpyrine or salt thereof such as diphenylpyraline hydrochloride or diphenylpyraline theocrate; diphenhydramine, diphenhydramine hydrochloride or diphenhydramine Diphenhydramine or a salt thereof such as lithylate or diphenhydramine tannate; cetirizine or a salt thereof such as cetirizine hydrochloride; fexofenadine or a salt thereof; bepotastine or a salt thereof such as bepotastine besylate; homochlorcyclidine hydrochloride Examples thereof include homochlorocyclidine such as a salt or a salt thereof, and these compounds can be produced by known methods, and commercially available products can also be used.
Among these, chlorpheniramine or a salt thereof, diphenhydramine or a salt thereof is preferable, and chlorpheniramine or a salt thereof is particularly preferable from the viewpoint of long-term storage stability improving action.

In addition, preferred specific examples of the chlorpheniramine or a salt thereof include d-chlorpheniramine maleate and dl-chlorpheniramine maleate, and particularly preferably d-chlorpheniramine maleate. is there.
Specific examples of the diphenhydramine or a salt thereof include diphenhydramine, diphenhydramine hydrochloride, diphenhydramine salicylate, and particularly preferred are diphenhydramine and diphenhydramine salicylate.

  Chlorpheniramine has the following formula:

Diphenhydramine is represented by the following formula:

It is a compound represented by these.

  Although content of a component (C-1) is not specifically limited, From a viewpoint of a long-term storage stability improvement effect, 0.01-10 mass% is preferable with respect to pharmaceutical composition total mass, 0.05-5 mass % Is more preferable, and 0.1 to 3% by mass is particularly preferable.

  Although the content ratio of component (A) and component (C-1) contained in the pharmaceutical composition of the present invention is not particularly limited, from the viewpoint of long-term storage stability, relative to 1 part by mass of component (C-1) The component (A) is preferably 0.1 to 100 parts by mass, more preferably 0.5 to 50 parts by mass, and particularly preferably 1 to 20 parts by mass in terms of the active ingredient. Moreover, when using a capsaicinoid such as nonanoic acid vanillylamide as the component (A), from the viewpoint of long-term storage stability, the capsaicinoid is 0.01 to 10 parts by mass with respect to 1 part by mass of the component (C-1). Is more preferable, 0.05 to 5 parts by mass is more preferable, and 0.1 to 1 part by mass is particularly preferable.

(Ingredient (C-2))
In the present invention, “polyhydric alcohol” means an alcohol having two or more hydroxyl groups in the same molecule, and specifically, for example, propylene glycol, glycerin, 1,3-butylene glycol, sorbitol, mannitol, dithiol. Examples include lower polyhydric alcohols such as propylene glycol; higher polyhydric alcohols such as polyvinyl alcohol, polyglycerin, macrogol, and polypropylene glycol. As the polyhydric alcohol, a polyhydric alcohol selected from glycerin, 1,3-butylene glycol, sorbitol, mannitol, dipropylene glycol and polyvinyl alcohol is preferable from the viewpoint of improving the storage stability. In addition, these can be manufactured by a well-known method and a commercially available thing can also be used.

  The content of the component (C-2) is not particularly limited, but is preferably 0.001 to 80% by mass with respect to the total mass of the pharmaceutical composition from the viewpoint of long-term storage stability improving action, 50 mass% is more preferable and 0.01-5 mass% is especially preferable.

  The content ratio of the component (A) and the component (C-2) contained in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of storage stability, the component is contained in 1 part by mass of the component (C-2). (A) is preferably 0.01 to 1000 parts by mass, more preferably 0.05 to 100 parts by mass, and particularly preferably 0.1 to 15 parts by mass in terms of bulk drug substance. Moreover, when using a capsaicinoid such as nonanoic acid vanillylamide as the component (A), from the viewpoint of long-term storage stability, the capsaicinoid is 0.0001 to 1000 parts by mass with respect to 1 part by mass of the component (C-2). Is more preferable, 0.0005 to 100 parts by mass is more preferable, and 0.001 to 10 parts by mass is particularly preferable.

  In the present invention, the polyhydric alcohol is particularly preferably polyvinyl alcohol. “Polyvinyl alcohol” is a polymer obtained by saponifying polyvinyl acetate, and can be produced by a known method, or a commercially available product can also be used. The degree of polymerization of vinyl acetate used as a raw material for polyvinyl alcohol can be adjusted as appropriate, and the degree of saponification can also be adjusted as appropriate.

  The polymerization degree and saponification degree of vinyl acetate are not particularly limited, and may be determined by appropriate examination. The degree of polymerization is preferably about 200 to 3500, and particularly preferably about 300 to 2200. Moreover, as a saponification degree, 65 mol% or more is preferable and 78 mol% or more is more preferable. Among them, those having a saponification degree of 78 to 96 mol% (referred to as polyvinyl alcohol (partially saponified product)) and those having 97 mol% or more (referred to as polyvinyl alcohol (completely saponified product)) are more preferable, 78 Those with ˜96 mol% are particularly preferred.

Moreover, when using polyvinyl alcohol as a component (C-2), the content is not specifically limited, From a viewpoint of a long-term storage stability improvement effect, it is 0.05-10 mass with respect to pharmaceutical composition total mass. % Is preferable, 0.1 to 7% by mass is more preferable, and 0.2 to 5% by mass is particularly preferable.
Moreover, the content ratio of the component (A) and polyvinyl alcohol contained in the pharmaceutical composition of the present invention is not particularly limited, but from the viewpoint of long-term storage stability, the component (A) is added to 1 part by mass of polyvinyl alcohol. The amount of the active ingredient is preferably 0.005 to 200 parts by mass, more preferably 0.01 to 100 parts by mass, and particularly preferably 0.02 to 5 parts by mass. When a capsaicinoid such as nonanoic acid vanillylamide is used as the component (A), from the viewpoint of long-term storage stability, the capsaicinoid is preferably 0.001 to 20 parts by mass with respect to 1 part by mass of polyvinyl alcohol. The amount is more preferably 002 to 10 parts by mass, and particularly preferably 0.005 to 5 parts by mass.

The pharmaceutical composition of the present invention can be produced by, for example, a known method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
The dosage form is not particularly limited, and may be any of solid, semi-solid, and liquid shapes, and may be a shape usually used in pharmaceuticals depending on the purpose of use and the like. it can. For example, preparations for oral administration (tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, etc.), preparations for application to the vagina (vagina tablets, vaginal suppositories, etc.), skin, etc. The dosage form described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations such as preparations (solid preparations for external use, liquid preparations for external use, sprays, ointments, creams, gels, patches, etc.) can be used. Among these, a semi-solid or liquid preparation is preferable, and in particular, a dosage form selected from oral liquids, syrups, liquids for external use, sprays, ointments, creams, gels and patches. It is more preferable that the dosage form is selected from liniment, lotion, external aerosol, pump spray, ointment, cream, gel, tape and poultice, liniment, lotion, and external use. Particularly preferred is a dosage form selected from aerosols, pump sprays, ointments, creams, gels and poultices.

  Further, the pharmaceutical composition of the present invention is preferably a semi-solid or liquid composition as described above, and a water-containing composition (in the present invention, “water-containing composition” means a semi-solid containing water). More specifically, it means a shape or liquid composition, and more specifically, 1% by mass or more, more preferably 5% by mass or more, further preferably 10 to 90% by mass, particularly preferably 15 to 80% by mass of water in the composition. %) Is more preferable. The semi-solid or liquid composition can be formulated as the semi-solid or liquid preparation. As specifically disclosed in the examples described later, it was confirmed that the combination of the component (B) and the component (C) suppresses the generation of insoluble matter in the solution caused by the component (A). It is inferred to be solubilized.

  Examples of the route of taking the pharmaceutical composition of the present invention include oral, transdermal, and parenteral such as transvaginal. In the present invention, parenteral is preferred, and transdermal administration is particularly preferred.

  In the pharmaceutical composition of the present invention, as a pharmaceutical component, a drug other than the above components, for example, analgesic component, anti-inflammatory component, antihistamine component, bactericidal component, astringent / protective component, blood circulation promoting component, local anesthetic component, antitussive agent, One or two selected from the group consisting of noscapine, bronchodilator, expectorant, hypnotic sedative, vitamins, anti-inflammatory agent, gastric mucosa protective agent, antacid, anticholinergic agent, herbal medicine, herbal medicine, etc. It may contain more than seeds.

As an analgesic component, for example, aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrine, salicylamide, salicylic acid, ethylene glycol salicylate, glycol salicylate, sodium salicylate, methyl salicylate, thiaramide hydrochloride, lactylphenetidine Etc.
Examples of the anti-inflammatory component include sodium guaiazulene sulfonate.

  Antihistamine components include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, ketotifen fumarate, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine Examples thereof include hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, and mebhydroline napadisilate.

  Examples of the sterilizing component include benzalkonium chloride. Examples of the astringent / protective component include zinc oxide. Examples of the blood circulation promoting component include tocopherol acetate, benzyl nicotinate, heparin-like substances, sodium polyethylene sulfonate, and the like. Examples of the local anesthetic component include lidocaine, clove oil, belladonna extract and the like.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, dibutate sodium, dimemorphan phosphate, tipepidine citrate, And tipepidine hibenzate.

Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of the bronchodilator include trimethquinol hydrochloride, phenylephrine hydrochloride, methoxyphenamine hydrochloride and the like.

  Examples of expectorants include ammonia, fennel, ammonium chloride, and 1-menthol.

Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromvalerylurea.
Vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, thiamine nitrification) , Dicetiamine hydrochloride, cetothiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisivethiamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavin phosphate , Riboflavin butyrate, sodium riboflavin phosphate, panthenol, panthetin, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecobalamin, ascorbic acid, ascorb Sodium binate, calcium ascorbate, hesperidin, etc.).

  Examples of the anti-inflammatory agent include seaprose, semi-alkaline proteinase, serrapeptase, proctase, pronase, bromelain and the like.

Examples of the gastric mucosa protective agent include gefarnate, cetraxate hydrochloride, sofalcone, teprenone, methylmethionine sulfonium chloride and the like.
Antacids include aminoacetic acid, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, magnesium alumina hydroxide, aluminum hydroxide gel, dry hydroxide Aluminum gel, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide, magnesium hydroxide / sulfuric acid Co-precipitation product of aluminum potassium, magnesium carbonate, sodium hydrogen carbonate, precipitated calcium carbonate, magnesium metasilicate magnesium aluminate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, bandit bone, stone decision, Rei, and the like.

  Examples of the anticholinergic agents include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, chipepidium bromide, methylbenactidium bromide, pirenzepine hydrochloride, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, etc. .

  Herbal medicines include Akamegashiwa (red buds), Asenyaku (Asenyaku), Arnica, Yinakukaku (Oyakukan), Fennel (Yellow), Turmeric (Yongyin), Engosaku (Yankou), Ogon (Yellow), Ousei (Yellow) , Ohi (cherry bark), Ouren (yellow ream), Onji (distant), Gajutsu (Iso), Kanokosou (Deer herb), Chamomile, Caronin (Karojin), Kyokyo (Kikkyo), Kyonin (Kyojin), Kokushi (Lion), cucumber (leaf), kei-gu (silk), keihi (cinnamon), katsumeishi (Keiko), gentian, gennoshouko (current evidence), kouka (safflower), kobushi (kosuke), goo (cow yellow), Goshi (Gomiko), Saishin (Spicy), Sanshishi (Yamako), Zion (Purple), Zicopi (Puricle), Shikon (Purple), Peonies (Glue), Musk (Chinese), Shaji (Shasan), shazenshi (car front child), shazenso (car front grass), beast gall (including yutan (bear gall)), gyoza (ginger), giryu (land dragon), shin ii (hot potato), sexan (stone wall) ), Senega, Senkyu (river cucumber), Zenko (mae-hu), Senburi (Senhwa), Sojutsu (蒼朮), Sohakuhi (mulberry white skin), Soyo (Soba), Taisan (Daegu), Chiksetsu carrot (Bamboo ginseng) ), Chinpi (Chinese skin), Toki (homecoming), Tokon (Nanten), Nantenjitsu (Nan Tenji), Carrot (Ginseng), Baimo (Shell mother), Bakumondou (Bakumon winter), Hange (half-summer), Bankouuka Herbal medicines such as (Banka), Hampi (anti-nasal), peony (white), peanut (white moth), bukkuri (茯苓), button pi (peony skin), yellow bay (pepper skin), loquat (deer moth) and their extraction Product (extract, tincture, dry extract, etc.) etc. Is mentioned.

  Herbal formulas include Keishito (Keishaeyu), Kousosan (Kousosan), Psychokeito (Shibako Keiedo), Shosai Koto (Koshisaifuto), Bakumondou (Bakumon Fuyuto), Hangekou Bokuto (Hankatsu Koboku-yu).

  The pharmaceutical composition of the present invention can be used as appropriate for the treatment or alleviation of the corresponding disease / symptom according to the known efficacy of various components. Among them, since the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, or a salt thereof, it can be used as a medical drug or an OTC drug. Specifically, for example, osteoarthritis, myalgia and It is effective as an analgesic / anti-inflammatory agent, etc. because it has a disease selected from swelling / pain after trauma and symptom anti-inflammatory / analgesic effect.

  EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[Reference Example 1] Examination of the effect of improving the storage stability of loxoprofen or a salt thereof The following samples 1-A and 1-B were prepared, and the appearance (generation of insoluble matter) immediately before the start of storage and after storage at 80 ° C. for 1 day. The presence or absence) was evaluated visually.
The results are shown in Table 1.

<Sample 1-A>
Pepper extract (Nippon Powder Pharmaceutical Co., Ltd .: trade name Pepper extract B) 0.5 g (pure drug equivalent 6.25 g) was dissolved and suspended in purified water to obtain 100 g of sample 1-A in a total amount.
<Sample 1-B>
Pepper extract (Nippon Powder Pharmaceutical Co., Ltd .: trade name Pepper extract B) 0.5g (pure drug equivalent 6.25g) and loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium water 20 g of the product was dissolved and suspended in purified water to obtain a total amount of 100 g of Sample 1-B.

As is clear from the test results described in Table 1, in the sample solution containing only the pepper extract alone (Sample 1-A), a small amount of insoluble matter was observed immediately before the start of storage, and after storage at 80 ° C. for 1 day. In the sample solution containing loxoprofen sodium hydrate in addition to the pepper extract, no precipitation was observed even after storage at 80 ° C. for 1 day. .
From such test results, it was revealed that loxoprofen or a salt thereof has an action of suppressing the formation of a precipitate of a water-containing composition containing a red pepper or an extract thereof and improving storage stability. This is presumably because loxoprofen or a salt thereof solubilizes pepper or an extract thereof in the water-containing composition.

[Test Example 1] Examination of the storage stability improving action of the combination of loxoprofen or a salt thereof and the compound represented by the general formula (1) The following samples 2-A and 2-B were prepared, The appearance after storage for a week (presence or absence of insoluble matter) was evaluated visually.
The results are shown in Table 2.

<Sample 2-A>
Pepper extract (Nippon Powder Pharmaceutical Co., Ltd .: trade name Pepper extract B) 0.5g (pure drug equivalent 6.25g) and loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium water 1.1 g of the product was dissolved and suspended in a solvent (mixed solution obtained by mixing equal amounts of Briton-Robinson broad buffer (pH 8.0) and absolute ethanol) to obtain 100 g of Sample 2-A.
<Sample 2-B>
Pepper extract (Nippon Powder Pharmaceutical Co., Ltd .: trade name Pepper extract B) 0.5 g (Powder equivalent amount 6.25 g), loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium water 1.1 g and 0.5 g of chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name: D-chlorpheniramine maleate) in the same solvent as Sample 2-A, and a total amount of 100 g sample 2-B was obtained.

As apparent from the test results shown in Table 2, in the sample solution containing the red pepper extract and loxoprofen sodium hydrate (Sample 2-A), insoluble matter was generated after storage at 80 ° C. for 1 week. In the sample solution (Sample 2-B) further containing chlorpheniramine maleate in addition to the pepper extract and loxoprofen sodium hydrate, no insoluble matter was observed after storage at 80 ° C. for 1 week.
From these test results, when the compound represented by the above general formula (1) containing chlorpheniramine or a salt thereof or a salt thereof is combined with loxoprofen or a salt thereof, the storage stability improving action confirmed in Reference Example 1 is confirmed. It has become clear that this is further improved.

[Test Example 2] Examination of the storage stability improving action of the combination of loxoprofen or a salt thereof and the compound represented by the general formula (1) Part 2
Sample 2-C below was prepared, and the appearance (presence or absence of insoluble matter) after storage at 80 ° C. for 1 week was visually evaluated.
The results are shown in Table 3.

<Sample 2-C>
Sample 2-C with a total amount of 100 g was obtained by the same method as Sample 2-B, except that the pepper extract was replaced with 0.5 g of nonanoic acid vanillylamide (Nagaoka Business Co., Ltd .: trade name nonyl acid vanillylamide).

  As is clear from the test results shown in Table 3, when using nonanoic acid vanillylamide, the storage stability is good by combining loxoprofen sodium hydrate and chlorpheniramine maleate as in the case of using capsicum extract. It became clear that.

[Test Example 3] Examination of the storage stability improving action of a combination of loxoprofen or a salt thereof and a polyhydric alcohol The following samples 3-A and 3-B were prepared, and the appearance (insoluble) after storage at 80 ° C. for 1 week The presence or absence of product formation was evaluated visually.
The results are shown in Table 4.

<Sample 3-A>
Sample 3-A was obtained in the same manner as Sample 2-A.
<Sample 3-B>
Sample 3-B was prepared in the same manner as Sample 2-B except that chlorpheniramine maleate was replaced with polyvinyl alcohol (partially saponified product) (manufactured by Nippon Synthetic Chemical Industry Co., Ltd .: trade name Gohsenol EG-05). Obtained.

As apparent from the test results shown in Table 4, in the sample solution containing the red pepper extract and loxoprofen sodium hydrate (Sample 3-A), insoluble matter was generated after storage at 80 ° C. for 1 week. In the sample solution (Sample 3-B) further containing polyvinyl alcohol in addition to the pepper extract and loxoprofen sodium hydrate, no insoluble matter was produced even after storage at 80 ° C. for 1 week.
From such test results, it was revealed that the storage stability improving action confirmed in Reference Example 1 was further improved by combining loxoprofen or a salt thereof with a polyhydric alcohol such as polyvinyl alcohol.

[Test Example 4] Examination of the storage stability improving action of a combination of loxoprofen or a salt thereof and a polyhydric alcohol, part 2
Sample 3-C below was prepared, and the appearance (presence or absence of insoluble matter) after storage at 80 ° C. for 1 week was visually evaluated.
The results are shown in Table 5.

<Sample 3-C>
Sample 3-C with a total amount of 100 g was obtained by the same method as Sample 3-B, except that the pepper extract was replaced with 0.5 g of nonanoic acid vanillylamide (Nagaoka Kogyo Co., Ltd .: trade name nonyl acid vanillylamide).

  As is apparent from the test results shown in Table 5, storage stability can be improved by combining loxoprofen sodium hydrate and polyvinyl alcohol even when nonanoic acid vanillylamide is used, as in the case of using capsicum extract. It became clear.

Production Example 1 (Gel)
By a conventional method, a gel containing the following components in 100 g was produced.
Loxoprofen sodium hydrate 1.13g
Glycyrrhetinic acid 0.2g
Nonanoic acid vanillylamide 0.025 g
l-Menthol 3g
Chlorpheniramine maleate 0.1g
Hydroxypropyl methylcellulose 1g
Carboxyvinyl polymer 1.2g
1,3-butylene glycol 5g
Triethanolamine 1.5g
Ethanol 20g
100g of purified water

Production Example 2 (Gel)
By a conventional method, a gel (gel cream) containing the following components in 100 g was produced.
Loxoprofen sodium hydrate 1.13g
Pepper extract 0.4g (Drug substance equivalent: 4g)
l-Menthol 2g
Polyvinyl alcohol 0.2g
Salicylic acid glycol ester 2g
Carboxy vinyl polymer 1g
Glycerin 10g
Octyldodecanol 10g
0.5 g of glyceryl monostearate
Polyoxyl stearate 0.5g
5g isopropyl myristate
Lauro Macrogol 1.5g
Triethanolamine 1g
100g of purified water

Production Example 3 (Powder)
By a conventional method, a cataplasm containing 100% of the following components was produced.
Loxoprofen sodium hydrate 1.13g
Nonanoic acid vanillylamide 0.025 g
1g of salamander
Horse chestnut seed 3g
l-Menthol 3g
Polyvinyl alcohol 0.8g
7g of partially neutralized polyacrylic acid
Carmellose sodium 5g
N-methyl-2-pyrrolidone 2g
Concentrated glycerin 25g
Polysorbate 80 0.3g
Aluminum hydroxide gel 0.05g
Titanium oxide 1g
Talc 2g
Tartaric acid 0.6g
Edetate sodium hydrate 0.1g
Kaolin 2.5g
Sodium bisulfite 0.3g
100g of purified water

Production Example 4 (Lotion)
By a conventional method, a lotion preparation containing the following components in 100 g was produced.
Loxoprofen sodium hydrate 1.13g
Glycyrrhetinic acid 0.1g
Nonanoic acid vanillylamide 0.1 g
Peppermint oil 6g
Chlorpheniramine maleate 0.5g
Diisopropyl adipate 5g
Isopropanol 40g
Hydroxypropyl methylcellulose 0.1g
Polyethylene glycol 1g
Sodium bisulfite 0.2g
100g of purified water

Production Example 5 (Cream)
A cream containing the following components in 100 g was produced by a conventional method.
Loxoprofen sodium hydrate 1.13g
Horse chestnut seed extract 0.3g (Drug equivalent: 3g)
Nonanoic acid vanillylamide 0.12 g
dl-Camphor 4g
Polyvinyl alcohol 0.2g
Carboxy vinyl polymer 0.8g
Edetate sodium hydrate 1g
Sodium bisulfite 0.1g
Octyldodecyl myristate 10g
Diisopropyl adipate 5g
2g glyceryl monostearate
Sorbitan monostearate 0.5g
1g polyoxyethylene sorbitan monostearate
Paraben 0.2g
Sodium hydroxide 0.1g
100g of purified water

Production Example 6 (cataplasm)
By a conventional method, a cataplasm containing 100% of the following components was produced.
Loxoprofen sodium hydrate 1.13g
Horse chestnut seed extract 0.3g (Drug equivalent: 3g)
Nonanoic acid vanillylamide 0.1 g
l-Menthol 3g
Polyvinyl alcohol 1g
7g of partially neutralized polyacrylic acid
Methyl acrylate and 2-ethylhexyl acrylate copolymer resin emulsion
5g
Carmellose sodium 5g
Crotamiton 2g
Concentrated glycerin 25g
Polysorbate 80 0.3g
Aluminum hydroxide gel 0.05g
Titanium oxide 1g
Talc 2g
Tartaric acid 0.6g
Edetate sodium hydrate 0.1g
Kaolin 2.5g
Sodium bisulfite 0.3g
100g of purified water

Production Example 7 (cataplasm)
By a conventional method, a cataplasm containing 100% of the following components was produced.
Loxoprofen sodium hydrate 1.13g
Nonanoic acid vanillylamide 0.025 g
l-Menthol 3g
Polyvinyl alcohol 0.8g
7g of partially neutralized polyacrylic acid
Carmellose sodium 5g
N-methyl-2-pyrrolidone 2g
Concentrated glycerin 25g
Polysorbate 80 0.3g
Aluminum hydroxide gel 0.05g
Titanium oxide 1g
Talc 2g
Tartaric acid 0.6g
Edetate sodium hydrate 0.1g
Kaolin 2.5g
Sodium bisulfite 0.3g
100g of purified water

  ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition which contains a crude drug etc. and was excellent in storage stability (especially storage stability in high temperature conditions) can be provided, and can be utilized in the pharmaceutical industry etc.

Claims (5)

The following components (A), (B) and (C):
(A) One or more selected from pepper and its extract (B) Loxoprofen or a salt thereof (C) One or more selected from the group consisting of the following components (C-1) and (C-2) (C- 1) The following general formula (1)

[In Formula (1), X represents a single bond or an oxygen atom, Y represents a methine group or a nitrogen atom, R ¹ represents a hydrogen atom, a hydroxyl group or an alkyl group, and R ² may have a substituent. A good cyclic amino group or an aminoalkyl group which may have a substituent, and R ³ represents a hydrogen atom or a halogen atom. ]
Or a salt thereof (C-2) A pharmaceutical composition comprising a polyhydric alcohol.   The pharmaceutical composition according to claim 1, wherein the component (C) is one or more selected from the group consisting of chlorpheniramine and a salt thereof, diphenhydramine and a salt thereof, and polyvinyl alcohol.   The pharmaceutical composition according to claim 1 or 2, which is a semi-solid or liquid composition.   The pharmaceutical composition according to any one of claims 1 to 3, which is a hydrous composition.   The pharmaceutical composition according to any one of claims 1 to 4, which is a liniment, lotion, external aerosol, pump spray, ointment, cream, gel, tape or poultice.