JP2017132819A - Pharmaceutical composition containing loxoprofen or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition having excellent pharmaceutical effect.SOLUTION: An antipyretic pharmaceutical composition contains loxoprofen or salt thereof, chlorpheniramine or salt thereof, and at least one ephedrine selected from l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, l-methylephedrine saccharinate and dl-methylephedrine saccharinate.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof.

  Loxoprofen or its salt is a kind of non-steroidal anti-inflammatory analgesic (NSAID), rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, neck-shoulder arm syndrome, toothache, acute upper respiratory tract inflammation, after surgery It is known as effective for anti-inflammatory, analgesic and antipyretic after trauma and tooth extraction (Non-patent Document 1).

On the other hand, antihistamines include azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine diphenyldisulfonate, carbibi Noxamine maleate, clemastine fumarate, chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocluic acid salt, diphenhydramine hydrochloride, Diphenhydramine salicylate, diphenhydramine tannate, cyproheptadine hydrochloride hydrate, cetirizine hydrochloride, triprolyzine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, Exophenazine, phenetadine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besylate, homochlorcyclidine hydrochloride, mequitazine, methodirazine hydrochloride, mebhydrolinapadisilate, loratadine, etc. These are known drugs that are used in general cold medicines, oral rhinitis drugs, etc. as antiallergic drugs and antihistamine components based on antihistamine action (Non-patent Document 2).
In addition, ephedrines are known to have an antitussive effect by bronchodilating action based on sympathomimetic action. For this reason, it is a drug compounded in general cold medicine and antitussive expectorant as an antitussive component, and in a rhinitis drug for the purpose of alleviating nasal congestion due to vasoconstriction (Non-patent Documents 3 and 4).

  Loxoprofen or a salt thereof has been studied for combining with various drugs because of its excellent pharmacological action. The action obtained by the combination includes, for example, an action of enhancing anti-inflammatory, analgesic and antipyretic effects by combining with caffeine, ethenamide and acetaminophen (Patent Document 1), and a combination with bromhexine hydrochloride and ambroxol hydrochloride. A potentiating effect on cough symptoms by combining them (Patent Document 2) and an inhibitory effect on goblet cell hyperplasia (Patent Document 3) are known.

A combination of two components of loxoprofen or a salt thereof and an antihistamine, and a combination of two components of loxoprofen or a salt thereof and ephedrine are already known.
In addition, as an action of a combination of loxoprofen or a salt thereof and an antihistamine, loxoprofen is combined with epinastine hydrochloride, carbinoxamine maleate, chlorpheniramine maleate, ketotifen fumarate or mequitazine. Nasal obstruction symptom-improving action (Patent Document 4), loxoprofen and azelastine hydrochloride and mequitazine combined to inhibit goblet cell hyperplasia (Patent Document 5), loxoprofen, carbinoxamine maleate and chlorfeni Increased analgesic effect by combining lamin maleate, anti-inflammatory and antipyretic effect by combining loxoprofen and carbinoxamine maleate, loxoprofen and clemastine fumarate Potentiation of antihistaminic action by combining the Le chlorpheniramine maleate (Patent Document 6) are known.
In addition, as for the action of the combination of loxoprofen or a salt thereof and ephedrines, specifically, the anti-inflammatory action and antipyretic action enhancing action by combining loxoprofen and dl-methylephedrine hydrochloride (patent) Literature 6), anti-sneezing action enhancement effect by combining loxoprofen and pseudoephedrine (Patent Document 7), airway goblet cell hyperplasia inhibitory action by combining loxoprofen and methylephedrine hydrochloride (Patent Document 8) Are known.

  However, there is no known pharmaceutical composition containing loxoprofen or a salt thereof, an antihistamine, and ephedrines.

Japanese Patent Laid-Open No. 11-139971 JP 2001-172175 A JP 2008-13542 A JP 2001-199882 A JP 2008-169193 A JP 2000-143505 A Japanese Patent Application Laid-Open No. 2004-2362 JP 2007-314517 A

Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-4790-4759 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 230 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 290 OTC Handbook 2008-09 Academic Information Distribution Center, page 369

  The subject of this invention is providing the pharmaceutical composition which has the outstanding pharmacological action.

  Therefore, the present inventor has intensively studied, and by combining three components of loxoprofen or a salt thereof, an antihistamine, and ephedrines, the inventor has a particularly excellent pharmacological action such as an analgesic action and an antipyretic action, and is useful as a medicine. I found out.

  That is, the present invention provides a pharmaceutical composition containing loxoprofen or a salt thereof, an antihistamine, and ephedrines.

  Combined use of loxoprofen or a salt thereof, an antihistamine, and ephedrines provides excellent analgesic and / or antipyretic effects. Therefore, according to the present invention, a pharmaceutical composition having an excellent pharmacological action can be provided.

  In addition, antihistamines and / or ephedrines have an inhibitory action on gastrointestinal disorders caused by loxoprofen or a salt thereof. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition having excellent pharmacological action and excellent safety in which gastrointestinal disorders caused by loxoprofen or a salt thereof are suppressed.

The pharmaceutical composition of the present invention contains loxoprofen or a salt thereof, an antihistamine, and ephedrines.
“Loxoprofen or a salt thereof” used in the pharmaceutical composition of the present invention includes not only loxoprofen, but also a pharmaceutically acceptable salt of loxoprofen, and further, loxoprofen or a pharmaceutically acceptable salt thereof and water, alcohol, etc. Solvates are included. 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).

  The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, 10 to 300 mg, more preferably 30 to 240 mg, particularly preferably 60 to 180 mg in terms of loxoprofen sodium anhydride can be contained per day. In the present invention, loxoprofen or a salt thereof is preferably contained in an amount of 0.4 to 50% by mass, more preferably 0.8 to 25% by mass in terms of anhydrous loxoprofen, relative to the total mass of the pharmaceutical composition. 1.2 to 20% by mass is more preferable, 1.6 to 15% by mass is further more preferable, and 2.0 to 12% by mass is particularly preferable.

The “antihistamine” used in the pharmaceutical composition of the present invention is not particularly limited as long as it has a histamine H ₁ receptor antagonistic action, and specifically includes, for example, azelastine, alimemazine, isotipezil, iproheptin, Ebastine, epinastine, emedastine, oxatomide, olopatadine, carbinoxamine, clemastine, chlorpheniramine, ketotifen, dipheterol, diphenylpyraline, diphenhydramine, cyproheptadine, cetirizine, triprolidine, tripelenamine, tondylamine, fexofenadine, pronetoporazine, At least one selected from the group consisting of cyclidine, mequitazine, methodirazine, mebuhydroline, loratadine and salts thereof; It is below. Examples of the salt include salts with inorganic acids, organic acids, inorganic bases, organic bases, etc., for example, hydrochloride, tartrate, maleate, fumarate, diphenyldisulfonate, teocrate, Examples include salicylate, tannate, besylate, napadisylate, phosphate, and the like. In the chemical structure of the antihistamine, when an asymmetric carbon exists, it has various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. It may be a mixture of isomers. Further, the antihistamine may be in the form of a solvate, and solvates of the above-mentioned various compounds and salts thereof with water, alcohol, etc. are also included in the “antihistamine” (therefore, “various compounds or salts thereof” And solvates of the compounds and salts thereof).
The above-mentioned antihistamine is a known compound and can be produced by a known method, or a commercially available product can be used.

Examples of the antihistamine used in the present invention include azelastine such as azelastine hydrochloride or a salt thereof; alimemazine such as alimemazine tartrate or a salt thereof; istipendil or a salt thereof such as istipendil hydrochloride; iproheptin such as iproheptin hydrochloride or a salt thereof Evastin or a salt thereof; Epinastine or a salt thereof such as epinastine hydrochloride; Emedastine or a salt thereof such as emedastine fumarate; Oxatamide or a salt thereof; Olopatadine such as olopatadine hydrochloride or a salt thereof; Carbinoxamine diphenyldisulfonic acid Salt, carbinoxamine such as carbinoxamine maleate or the salt thereof; clemastine such as clemastine fumarate or the salt thereof; chlorphenilla such as d-chlorpheniramine maleate, dl-chlorpheniramine maleate Ketotifen such as ketotifen fumarate or salt thereof; Dipheterol such as difeterol hydrochloride or difeterol phosphate or salt thereof; Diphenylpyraline such as diphenylpyraline hydrochloride or diphenylpyraline theoclurate or the like Salt; diphenhydramine such as diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate or the salt thereof; cyproheptazine or salt thereof such as cyproheptadine hydrochloride hydrate; cetirizine such as cetirizine hydrochloride or salt thereof; triprozine such as triprolidine hydrochloride Lysine or salt thereof; tripelenamine or salt thereof such as tripelenamine hydrochloride; tonsilamine or salt thereof such as tonsilamine hydrochloride; fexofenadine or salt thereof; phenetadine such as phenetadine hydrochloride Or a salt thereof; promethazine such as promethazine hydrochloride or promethazine methylene disalicylate or a salt thereof; bepotastine or a salt thereof such as bepotastine besylate; a homochlorcyclidine such as a homochlorcyclidine hydrochloride or a salt thereof; mequitazine Or a salt thereof; methodirazine such as methodirazine hydrochloride or a salt thereof; mebhydroline such as mebhydroline napadisilate or a salt thereof; loratadine or a salt thereof is preferable.
Among these, from the viewpoint of analgesic action, clemastine or a salt thereof, chlorpheniramine or a salt thereof is preferable, and clemastine fumarate, d-chlorpheniramine maleate, or dl-chlorpheniramine maleate is more preferable. On the other hand, chlorpheniramine or a salt thereof is preferable, and d-chlorpheniramine maleate and dl-chlorpheniramine maleate are particularly preferable from the viewpoint of achieving both an excellent analgesic action and an excellent antipyretic action.

  The content of the antihistamine in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, 0.01 to 400 mg, more preferably 0.03 to 300 mg, and particularly preferably 0.1 to 200 mg of an antihistamine can be contained per day. In addition, although suitable content in the case of using a specific component as an antihistamine is illustrated below, this invention is not limited to this at all.

In the pharmaceutical composition of the present invention, when azelastine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken 0.03 to 10 mg, more preferably an amount that can be taken 0.1 to 5 mg, The amount that can be taken 0.3 to 2.5 mg is more preferable.
In the pharmaceutical composition of the present invention, when using alimemazine or a salt thereof as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 20 mg, more preferably an amount that can be taken from 0.3 to 15 mg, The amount that can be taken 1 to 10 mg is more preferable.
In the pharmaceutical composition of the present invention, when isothipentil or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 30 mg, more preferably an amount that can be taken from 0.3 to 15 mg, The amount that can be taken 1 to 7.5 mg is more preferable.
In the pharmaceutical composition of the present invention, when iproheptin or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 5 to 400 mg per day, more preferably an amount that can be taken from 10 to 300 mg, and 15 to 200 mg taken. The amount that can be produced is more preferred.

In the pharmaceutical composition of the present invention, when ebastine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 50 mg, more preferably an amount that can be taken from 0.5 to 30 mg, The amount that can be taken 1-20 mg is more preferred.
In the pharmaceutical composition of the present invention, when epinastine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken 0.3 to 50 mg, more preferably 1 to 35 mg. The amount that can be taken 5 to 25 mg is more preferable.
In the pharmaceutical composition of the present invention, when emedastine or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 0.01 to 10 mg per day, and more preferably from 0.03 to 7.5 mg. The amount that can be taken 0.1 to 5 mg is more preferable.
In the pharmaceutical composition of the present invention, when oxatomide or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken 0.3 to 200 mg per day, more preferably an amount that can be taken 1 to 100 mg, 6 to The amount that can be taken 60 mg is more preferable.

In the pharmaceutical composition of the present invention, when olopatadine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 30 mg, more preferably an amount that can be taken from 0.3 to 15 mg, The amount that can be taken 1 to 10 mg is more preferable.
In the pharmaceutical composition of the present invention, when carbinoxamine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 60 mg, more preferably an amount that can be taken from 0.5 to 30 mg, The amount that can be taken 1 to 16 mg is more preferable.
In the pharmaceutical composition of the present invention, when clemastine or a salt thereof is used as the antihistamine, the content thereof is preferably an amount that can be taken in an amount of 0.01 to 5 mg per day in terms of free form of clemastine, 0.05 to 3 mg. The amount that can be taken is more preferred, and the amount that can be taken 0.1 to 2 mg is more preferred. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
In the pharmaceutical composition of the present invention, when chlorpheniramine or a salt thereof is used as an antihistamine, its content is preferably 0.1 to 20 mg per day, more preferably 0.6 to 12 mg. preferable. In addition, when using d-chlorpheniramine maleate as chlorpheniramine or its salt, the quantity which can be taken | dosed 0.1-15 mg per day is preferable, and the quantity which can be taken | dosed 0.6-6 mg is more preferable, 1 An amount that can be taken by -5 mg is more preferred. When dl-chlorpheniramine maleate is used, the amount that can be taken from 0.5 to 20 mg per day is preferred, the amount that can be taken from 1 to 12 mg is more preferred, and the amount that can be taken from 2 to 10 mg is even more preferred.

In the pharmaceutical composition of the present invention, when ketotifen or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken 0.05 to 10 mg, more preferably an amount that can be taken 0.1 to 5 mg, The amount that can be taken 0.3 to 3 mg is more preferable.
In the pharmaceutical composition of the present invention, when dipheterol or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 1 to 300 mg per day, more preferably an amount that can be taken from 5 to 150 mg, and taken from 10 to 100 mg. The amount that can be produced is more preferred.
In the pharmaceutical composition of the present invention, when diphenylpyrine or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 0.1 to 13.5 mg per day, and an amount that can be taken from 1 to 4.5 mg. More preferred. In addition, when using a diphenyl pyraline hydrochloride as diphenyl pyraline or its salt, the quantity which can be taken | dosed 0.1-12 mg per day is preferable, and the quantity which can be taken | dosed 1-4 mg is more preferable. When using diphenylpyraline theocuroate, the amount that can be taken 0.1 to 13.5 mg per day is preferred, and the amount that can be taken 1 to 4.5 mg is more preferred.
In the pharmaceutical composition of the present invention, when diphenhydramine or a salt thereof is used as an antihistamine, the content thereof is preferably 1 to 300 mg per day, more preferably 5 to 200 mg, more preferably 15 to 150 mg. The amount that can be produced is more preferred.

In the pharmaceutical composition of the present invention, when cyproheptadine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 32 mg, more preferably an amount that can be taken from 0.3 to 20 mg, The amount that can be taken 1 to 15 mg is more preferable.
In the pharmaceutical composition of the present invention, when cetirizine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 50 mg, more preferably an amount that can be taken from 0.3 to 30 mg, The amount that can be taken 1-20 mg is more preferred.
In the pharmaceutical composition of the present invention, when triprolidine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 0.1 to 20 mg, more preferably an amount that can be taken from 0.3 to 15 mg per day. The amount that can be taken 1 to 10 mg is more preferable.
In the pharmaceutical composition of the present invention, when tripelamine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 1 to 400 mg per day, more preferably an amount that can be taken from 3 to 200 mg, and taken from 10 to 100 mg. The amount that can be produced is more preferred.

In the pharmaceutical composition of the present invention, when tongylamine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken from 1 to 300 mg per day, more preferably an amount that can be taken from 3 to 150 mg, and taken from 10 to 75 mg. The amount that can be produced is more preferred.
In the pharmaceutical composition of the present invention, when fexofenadine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.3 to 200 mg per day, more preferably an amount that can be taken from 1 to 100 mg, The amount that can be taken 6 to 60 mg is more preferable.
In the pharmaceutical composition of the present invention, when phenetazine or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 1 to 300 mg per day, more preferably an amount that can be taken from 3 to 150 mg, and 10 to 75 mg taken. The amount that can be produced is more preferred.
In the pharmaceutical composition of the present invention, when promethazine or a salt thereof is used as the antihistamine, the content thereof is preferably an amount that can be taken from 0.5 to 200 mg per day, more preferably an amount that can be taken from 1 to 100 mg, The amount that can be taken 75 mg is more preferable.

In the pharmaceutical composition of the present invention, when bepotastine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 40 mg, more preferably an amount that can be taken from 0.5 to 30 mg, The amount that can be taken 2 to 20 mg is more preferable.
In the pharmaceutical composition of the present invention, when homochlorocyclidine or a salt thereof is used as an antihistamine, the content is preferably an amount that can be taken from 0.3 to 180 mg per day, and more preferably an amount that can be taken from 1 to 90 mg. The amount that can be taken 3 to 60 mg is more preferable.
In the pharmaceutical composition of the present invention, when mequitazine or a salt thereof is used as an antihistamine, the content thereof is preferably an amount that can be taken 0.05 to 20 mg per day, more preferably an amount that can be taken 0.1 to 12 mg, The amount that can be taken 0.6 to 6 mg is more preferable.
In the pharmaceutical composition of the present invention, when methodirazine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 40 mg, more preferably an amount that can be taken from 0.3 to 20 mg, The amount that can be taken 1 to 10 mg is more preferable.

In the pharmaceutical composition of the present invention, when mebhydroline or a salt thereof is used as an antihistamine, its content is preferably 1 to 450 mg per day, more preferably 5 to 300 mg, more preferably 15 to 200 mg. The amount that can be produced is more preferred.
In the pharmaceutical composition of the present invention, when loratadine or a salt thereof is used as an antihistamine, its content is preferably an amount that can be taken from 0.1 to 30 mg, more preferably an amount that can be taken from 0.3 to 15 mg, The amount that can be taken 1 to 10 mg is more preferable.

  In the present invention, from the viewpoint of analgesic action, antipyretic action and / or inhibitory action on gastrointestinal disorders, as an antihistamine, “chlorpheniramine or a salt thereof”, “clemastine or a salt thereof”, “carbinoxamine or a salt thereof”, “ It is preferable to use “diphenylpyrine or a salt thereof” or “mequitazine or a salt thereof”, more preferably “chlorpheniramine or a salt thereof” or “clemastine or a salt thereof”, and “chlorpheniramine or a salt thereof”. It is particularly preferable to use it.

  In the present invention, “chlorpheniramine or a salt thereof” includes not only chlorpheniramine itself but also a pharmaceutically acceptable salt of chlorpheniramine. Since chlorpheniramine has an asymmetric carbon, it has an optical isomer, but in the present invention, any optical isomer may be included, which may be a single optical isomer or a mixture of various optical isomers. . Among these, in the present invention, d-form and dl-form are preferable. Preferable specific examples of the chlorpheniramine or a salt thereof include, for example, chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, etc. Can be used alone or in combination of two or more. In the present invention, d-chlorpheniramine maleate and dl-chlorpheniramine maleate are more preferable, and d-chlorpheniramine maleate is particularly preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of chlorpheniramine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. It is preferable to contain 0.004-1.5 mass% with respect to the pharmaceutical composition total mass, it is more preferable to contain 0.02-0.8 mass%, and 0.04-0.7 mass% is contained. Is particularly preferred.

  The content ratio of loxoprofen or a salt thereof, and chlorpheniramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and is determined by appropriately examining according to the daily dose of each component described above. However, it is preferable that loxoprofen or a salt thereof contains 0.0001 to 25 parts by mass of chlorpheniramine or a salt thereof with respect to 1 part by mass in terms of anhydrous loxoprofen sodium, and 0.0001 to 8 parts by mass. What contains is more preferable, and what contains 0.0001-3 mass parts is further more preferable. Among these, what contains 0.0001-1.5 mass parts of chlorpheniramine or its salt is preferable, and what contains 0.0005-0.7 mass parts is more preferable.

  In the present invention, “clemastine or a salt thereof” includes not only clemastine itself but also a pharmaceutically acceptable salt of clemastine. Specific examples of clemastine or a salt thereof include, for example, clemastine, clemastine fumarate, etc. In the present invention, clemastine fumarate is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. It is preferable to contain 0.008-0.4 mass% in conversion of the free body of clemastine with respect to mass, It is more preferable to contain 0.01-0.2 mass%, 0.015-0.15 mass% It is particularly preferable to contain it. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.

  The content ratio of loxoprofen or a salt thereof and clemastine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined according to the daily dose of each component described above. , Loxoprofen or a salt thereof is preferably contained in an amount of 0.0006 to 0.5 parts by mass of clemastine or a salt thereof in terms of a free form of clemastine relative to 1 part by mass in terms of anhydrous loxoprofen sodium. What contains 1 mass part is more preferable, and what contains 0.002-0.03 mass part is further more preferable.

  In the present invention, “carbinoxamine or a salt thereof” includes not only carbinoxamine itself but also a pharmaceutically acceptable salt of carbinoxamine. Specific examples of carbinoxamine or a salt thereof include carbinoxamine, carbinoxamine maleate, carbinoxamine diphenyl disulfonate, and the like, and carbinoxamine maleate is more preferable in the present invention. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of carbinoxamine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the above-mentioned daily dose. Carbinoxamine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.004-4 mass% with respect to mass, It is more preferable to contain 0.02-2 mass%, It is especially preferable to contain 0.04-1 mass%.

  The content ratio of loxoprofen or a salt thereof and carbinoxamine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, with respect to 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium, one containing 0.0003 to 6 parts by mass of carbinoxamine or a salt thereof is preferable, and one containing 0.002 to 1 parts by mass is more preferable. More preferably, 0.005 to 0.5 parts by mass is contained, and 0.005 to 0.3 parts by mass is particularly preferred.

  In the present invention, “diphenylpyrine or a salt thereof” includes not only diphenylpyraline itself but also a pharmaceutically acceptable salt of diphenylpyraline. Specific examples of diphenylpyraline or a salt thereof include, for example, diphenylpyraline, diphenylpyraline hydrochloride, diphenylpyraline teocrate, and the like. Diphenylpyraline hydrochloride is particularly preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of diphenylpyralin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the above-mentioned daily dose. The content is preferably 0.004 to 1% by mass, more preferably 0.004 to 0.5% by mass, and still more preferably 0.04 to 0.3% by mass based on the total mass of the product. 0.06 to 0.25% by mass is particularly preferable.

  The content ratio of loxoprofen or a salt thereof and diphenylpyraline or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. Although it is good, what contains 0.0001-3 mass parts of diphenyl pyralin or its salt is preferable with respect to 1 mass part of loxoprofen or its salt in conversion of loxoprofen sodium anhydride, 0.0005-2.5 mass part is contained. More preferable are those containing 0.001 to 1 parts by mass, and particularly preferable are those containing 0.001 to 0.3 parts by mass.

  In the present invention, “mequitazine or a salt thereof” includes not only mequitazine itself but also a pharmaceutically acceptable salt of mequitazine. Specific examples of mequitazine or a salt thereof include mequitazine and the like. These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of mequitazine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately determined and determined according to the above-mentioned daily dose. Mequitazine or a salt thereof may be added to the entire pharmaceutical composition. It is preferable to contain 0.004-1 mass% with respect to mass, It is more preferable to contain 0.008-0.5 mass%, It is especially preferable to contain 0.04-0.3 mass%.

  The content ratio of loxoprofen or a salt thereof and mequitazine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the daily dose of each component described above. However, those containing 0.0001 to 3 parts by mass of mequitazine or a salt thereof are preferred, and those containing 0.0005 to 2.5 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof in terms of anhydrous loxoprofen sodium. More preferably, one containing 0.001 to 0.3 parts by mass is particularly preferable.

  The “ephedrines” used in the pharmaceutical composition of the present invention means one or more selected from the group consisting of ephedrine, ephedrine derivatives, and salts thereof. Here, examples of derivatives of ephedrine include norephedrine (phenylpropanolamine) and methylephedrine. Examples of the salt include salts of pharmaceutically acceptable inorganic acids and organic acids, and preferred specific examples include hydrochloride, sulfate, and saccharin salt. In addition, since ephedrine has two asymmetric carbons, there are various optical isomers. In the present invention, any optical isomer may be included, and a single optical isomer may be used. A mixture of In the present invention, l-form and dl-form are preferable.

  Preferable specific examples of ephedrines in the present invention include, for example, 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine saccharin salt, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, pseudoephedrine sulfate, etc. These can be used alone or in combination of two or more. Ephedrine and pseudoephedrine are in an enantiomeric relationship with each other. In the present invention, dl-methylephedrine hydrochloride is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.

In the present invention, “ephedrines” can also be used mah (mao) containing these as ingredients.
Maou means the ground stem of Ephedra sinica Stapf, Ephedra intermedia Schrenk et CA Meyer or Ephedra equisetina Bunge (Ephedraceae), as published in the 15th Amendment Japanese Pharmacopoeia. Maow can be adjusted in its form as needed, and can be cut or crushed into small pieces, lumps, or ground into powder. For example, Maow powder is called “Maow powder”.
In addition, Maou is a liquid obtained by adding an appropriate leaching agent and concentrating the leaching liquid after being appropriately sized based on a known method described in the 15th revision of the Japanese Pharmacopoeia General Rules for Preparations, etc. It may be “extract” or “tinced”. Examples of leaching agents include lower monohydric alcohols such as methanol, ethanol and n-butanol; lower polyhydric alcohols such as ethylene glycol, propylene glycol, 1,3-butylene glycol and glycerine; ethers such as diethyl ether; acetone and ethyl Ketones such as methyl ketone; esters such as ethyl acetate; halogenoalkanes such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene and toluene; and water. These may be used alone or in combination of two or more. Furthermore, the extract can be dried.

  In the present invention, when maou is used as the ephedrines, maou powder, mao stream extract, mao soft extract, mao dry extract, mao extract and the like are preferred, and these can be used alone or in combination of two or more. Furthermore, when using maou, Chinese herbal prescriptions including maou, kakonto (Kakkonto), shosei ryoutou (Sho Seiryuto), maoutou (maoyuto), etc. can also be used. These may be produced by known methods, or commercially available products may be used.

The content of ephedrines in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user. For example, the amount of ephedrine that can be taken per day is 5 to 500 mg, more preferably 10 to 360 mg, and particularly preferably 20 to 240 mg.
In addition, a part or all of ephedrines can be substituted for the above-mentioned maou. When using maou as the ephedrines, for example, 0.1 to 25 g of maou per day (powder equivalent), more preferably 0.25 to 10 g (powder equivalent), particularly preferably 0 .4 to 4 g (concentration in bulk drug substance) can be included.
In this invention, it is preferable to contain 0.1-40 mass% of ephedrine with respect to pharmaceutical composition total mass, It is more preferable to contain 0.5-20 mass%, It contains 1-10 mass%. Is particularly preferred. Moreover, when using maou as ephedrine, it is preferable to contain 1 to 98 mass% of maou with respect to the total mass of the pharmaceutical composition, more preferably 2 to 50 mass%, and more preferably 4 to 20 mass%. It is particularly preferable to do this.

  The content ratio of loxoprofen or a salt thereof and ephedrine contained in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriate examination according to the daily dose of each component described above. , Loxoprofen or a salt thereof is preferably 0.015 to 50 parts by mass of ephedrines, more preferably 0.05 to 12 parts by mass based on 1 part by mass of loxoprofen sodium anhydride. Those containing 1 to 6 parts by mass are more preferable, and those containing 0.1 to 4 parts by mass are particularly preferable.

The pharmaceutical composition of the present invention can be produced by, for example, a known method described in the 15th 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 can be a shape that is usually used in pharmaceuticals depending on the purpose of use. . Specifically, for example, tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets), troches, drops, hard capsules, soft capsules, granules, fine granules, powders, pills, dry syrup Solid preparations such as suppositories, suppositories, poultices, plasters; lozenges, chewing gums, jelly agents, jelly drops, whipped agents, ointments, creams, foams, inhalers, nazar gels, etc. Semi-solid preparations; syrups, drinks, suspensions, spirits, liquids, eye drops, aerosols, sprays, sprays, and other liquid preparations, etc. It can be made into a dosage form.
In the present invention, it is preferably a solid preparation containing three components of loxoprofen or a salt thereof, an antihistamine and an ephedrine, from the viewpoint of ease of administration and management of drug dose, and the like. Tablets, capsules, pills, A solid preparation selected from the group consisting of granules, powders and fine granules is more preferable, and tablets or capsules are particularly preferable.

  Examples of the route of taking the pharmaceutical composition of the present invention include oral and parenteral such as rectal and vaginal administration, and oral administration is preferred. The pharmaceutical composition of the present invention can be taken, for example, before meals, between meals, after meals, before going to bed, etc., divided into about 1 to 4 times per day.

  In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof, an antihistamine and an ephedrine, such as an antipyretic analgesic, an antitussive, a noscapine, a bronchodilator, an expectorant, a hypnotic sedative, a vitamin 1 type, or 2 or more types selected from the group which consists of an anti-inflammatory agent, a gastric mucosa protective agent, an anticholinergic agent, a herbal medicine, a Chinese medicine prescription, caffeine, a xanthine type component, etc. may be included.

  Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, isopropylantipyrine, ibuprofen, ethenzamide, sazapyrine, salicylamide, sodium salicylate, thiaramide hydrochloride, lactylphenetidine, and the like.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, codeine phosphate, dihydrocodeine phosphate, dibutarate sodium, dimemorphan Examples thereof include phosphate, dextromethorphan hydrobromide, dextromethorphan / phenol phthaline salt, 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.

  As an expectorant, for example, ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, methylcysteine hydrochloride, Examples thereof include l-menthol and lysozyme hydrochloride.

Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromovalerylurea.
Examples of 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 nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, sodium riboflavin phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecoba Lamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

  Examples of the anti-inflammatory agent include glycyrrhizic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, bromelain and the like. Can be mentioned.

  Examples of the gastric mucosa protective agent include aminoacetic acid, aldioxa, magnesium silicate, gefarnate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product , Sucralfate, cetraxate hydrochloride, sofalcone, magnesium carbonate, teprenone, copper chlorophyllin potassium, copper chlorophyllin sodium, magnesium metasilicate aluminate, methylmethionine sulfate Niumukurorido, and the like.

  Examples of the anticholinergic agent include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, chipepidium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl- 1-hyostiamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodopropamide iodide, diphenylpiperidinomethyldioxolane, funnel extract, funnel root, funnel Examples include root total alkaloid citrate.

  Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyoukaku (horny lamb), fennel (yuka), turmeric (depressed gold), engosaku (yenkogyo), enmaiso (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Owaku (yellow twilight), Spruce (cherry bark), Auren (yellow ream), Onji (distant), Gajutsu (weather), valerian (deer grass), chamomile, caronin (karojin), Licorice (licorice), Kyokyo (Kikkyo), Kyonin (Kyojin), Kukoshi (Isogo), Kukoyo (Kashiwaha), Keigai (Kashiwagi), Keihi (Kinseido), Ketsumeishi (Kameko), Gentiana, Gennoshouko (current evidence), Koubushi (Kosuke), Gooh (Gyuhuang), Goshi (Gomiko), Saishin (Spicy), Salamander (Sambu), Zion (Purple), Zykopi (Peel), Peonies (Glue), Ji Jakkou, Shajin, Shazenshi (car forerunner), Shazenso (car forerunner), Beast gall (including yutan (gum gal)), Shakyo (ginger), Giryu (land dragon), Xinyi ), Sexan (Ishizuchi), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Oiso), Chixetsu carrot (bamboo ginseng), clove (clove), chimpi (chonse), touki (to home), tokong (napping root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish), bacmond (wheat) Gate winter), mint (light load), Hange (semi-summer), bankouka (banka), hampi (anti-nose), juniper (white bean), juniper (white moth), bukkuri (茯苓), button pi (peony skin), volley (Oysters), Rokujo (deer) etc. These extracts (extract, tincture, dry extract, etc.) and the like.

  Examples of Kampo prescriptions include Keishito (Katsura-yu), Kousosan (Kousosan), Psycho-keito (Shibako), Bakumondou (Bakumontoyu), Hange Examples include Kokubokuto (half-summer Koboku-yu).

  Examples of caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and citric acid caffeine.

  Examples of the xanthine component include aminophylline, diprofylline, theophylline, proxyphylline and the like.

  In addition, as a pharmaceutical composition of this invention, things other than the following (a)-(e) are preferable.

(A) Loxoprofen sodium dihydrate 60 mg (converted as an anhydride), carbinoxamine maleate 4 mg, dl-methylephedrine 20 mg, serrapeptase 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 176 mg, lactose 13 mg Agent,
(B) Loxoprofen sodium dihydrate 60 mg (converted as an anhydride), carbinoxamine maleate 4 mg, dl-methylephedrine 20 mg, serrapeptase 10 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 176 mg, lactose 13 mg ,
(C) Loxoprofen sodium dihydrate 60 mg (converted as an anhydride), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 254 mg, aspartame 30 mg, citric acid 965 mg, sodium bicarbonate 813 mg, Effervescent tablets containing 194 mg of lactose and 50 mg of magnesium stearate,
(D) Loxoprofen sodium dihydrate 60 mg (converted as an anhydride), carbinoxamine maleate 4 mg, dl-methylephedrine hydrochloride 20 mg, serrapeptase 10 mg, β-cyclodextrin 300 mg, aspartame 30 mg, mannitol 262 mg, magnesium stearate 14 mg Fast dissolving tablets and chewable tablets,
(E) A tablet having a weight of 230 mg produced by tableting the mixed powder after mixing the following components: 90 g of loxoprofen sodium, 6 g of chlorpheniramine d-maleate, 200 g of pseudoephedrine hydrochloride, 450 g of theophylline, Guaifenesin 200 g, lactose 400 g, microcrystalline cellulose 375 g, magnesium stearate 20 g, hydrogenated castor oil 19 g.

Since the pharmaceutical composition of the present invention has particularly excellent antipyretic action and / or analgesic action as shown in Test Examples 1 and 2 below, it is effective for various diseases and symptoms accompanied by fever and pain. it is obvious. Therefore, the pharmaceutical composition of the present invention is preferably an antipyretic and / or analgesic composition containing loxoprofen or a salt thereof, an antihistamine and ephedrines, and more specifically, headache, toothache, pain after extraction, pharynx One or more pain relief selected from pain, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain) and trauma pain Alleviation of one or more symptoms selected from pain, headache, joint pain and muscle pain (note that the “throat pain” includes sore throat and acute rhinitis, allergic rhinitis Including throat pain as symptoms of sinusitis, and “headache”, “joint pain” and “muscle pain” include these symptoms as cold symptoms)); Antipyretic at the time of fever And / or Akkan, alleviation of the symptoms of fever (As the said "Akkan" and "heating" includes. These symptoms as symptoms of a cold) can be suitably used as a medicament for use in.
Moreover, as a suitable specific example of the pharmaceutical composition of this invention, 1 or more types chosen from the group which consists of the following composition (A)-(D):

(A) containing loxoprofen or a salt thereof, an antihistamine and ephedrine, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, One or more pain relieving compositions selected from pain, menstrual pain, and traumatic pain,
(B) one or more relief selected from loxoprofen or a salt thereof, an antihistamine, and ephedrines from sore throat, headache, joint pain and muscle pain (sore throat as a symptom of cold, headache, Including a relief of one or more symptoms selected from joint pain and muscle pain),
(C) a composition for relief of sore throat (including relief of sore throat as symptoms due to acute rhinitis, allergic rhinitis or sinusitis), comprising loxoprofen or a salt thereof, an antihistamine and ephedrines, and (D) A composition for antipyretic (including mitigation of chills and / or fever as cold symptoms) containing loxoprofen or a salt thereof, an antihistamine, and ephedrines, including the above-mentioned composition The products (B) and (D) are preferable, and the composition (B) is particularly preferable.

Furthermore, loxoprofen is a kind of NSAID, and as a side effect, gastrointestinal disorders (gastric mucosal irritation, ulceration, etc.) are problematic, but as specifically disclosed in Test Example 3 below, antihistamines and ephedrines are It was found to have an inhibitory action on gastrointestinal disorders caused by the loxoprofen.
Therefore, the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, an antihistamine, and ephedrines has an advantageous effect of being excellent in safety because gastrointestinal disorders caused by loxoprofen or a salt thereof are suppressed.
In addition, patients with peptic ulcers that are contraindicated for drugs containing loxoprofen and patients with a history of peptic ulcers that are considered to be carefully administered can be safely taken. The pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, an antihistamine and ephedrines is also suitable as a pharmaceutical composition for administration to a patient with peptic ulcer and / or a person with a history of peptic ulcer. Available.
Furthermore, according to the present invention, an aluminoprofen, ampiroxicam, ampenac, ibuprofen, indomethacin, etodolac, epilysole, oxaprozin, ketoprofen, saltoprofen, diclofenac, sulindac, celecoxib, containing an antihistamine and / or ephedrine as an active ingredient Non-steroids such as thiaprofenic acid, thiaramide, tenoxicam, tolfenamic acid, nabumetone, naproxen, piroxicam, pranoprofen, flufenamic acid, flurbiprofen, progouritacin, mefenamic acid, meloxicam, mofezolac, loxoprofen and lornoxicam and their salts Gastrointestinal disorders (for example, NSAID ulcers) caused by persistent anti-inflammatory analgesics (preferably loxoprofen or a salt thereof) It can provide relief or inhibitor.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
[Test Example 1] Analgesic Test Test Example 1-1 Examination of analgesic action by combining three components of loxoprofen or a salt thereof, chlorpheniramine or a salt thereof and ephedrine 5 to 6-week-old Wistar male rats (weight 99) .3 to 112.0 g) of the right hind leg pain threshold was measured and designated as “the pain threshold before inflammation”.
After measurement of the pain threshold before inducing inflammation, 100 μL of 20% yeast solution was subcutaneously administered to the right hind footpad to induce inflammation. The pain threshold was measured 3 hours after the onset of inflammation and was defined as “pain threshold before drug administration”.
Immediately after the measurement of the pain threshold before drug administration, the test drug was orally administered, and the pain threshold was measured at 3 hours after the drug administration as a measurement point, which was designated as “pain threshold after drug administration”.
The pain improvement rate was calculated from the obtained pain threshold according to the following formula.

Pain improvement rate (%) = (pain threshold after drug administration−pain threshold before drug administration) / (pain threshold before inflammation induction−pain threshold before drug administration) × 100

  In addition, the pain threshold value was measured using the Randall Cerit type analgesic effect measuring apparatus (MK-201D: Muromachi Kikai Co., Ltd. product).

Each test drug was administered according to the following group composition.
1: Loxoprofen sodium hydrate alone administration group (hereinafter referred to as “LX alone”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
2: d-chlorpheniramine maleate single administration group (hereinafter referred to as “CM alone”)
d-Chlorpheniramine maleate was administered at a dose of 1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
3: dl-methylephedrine hydrochloride alone administration group (hereinafter referred to as “ME alone”)
dl-Methylephedrine hydrochloride was administered at a dose of 0.3 g / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.

4: Two-component combination administration group of loxoprofen sodium hydrate and d-chlorpheniramine maleate (hereinafter referred to as “LX + CM”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight and d-chlorpheniramine maleate was dissolved at a dose of 1 mg / kg body weight in 0.5% methylcellulose solution or administered simultaneously.
5: Loxoprofen sodium hydrate and dl-methylephedrine hydrochloride combined administration group (hereinafter referred to as “LX + ME”)
Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution simultaneously at a dose of 0.1 mg / kg body weight and dl-methylephedrine hydrochloride at a dose of 0.3 g / kg body weight.
6: Loxoprofen sodium hydrate, d-chlorpheniramine maleate and dl-methylephedrine hydrochloride combined administration group (hereinafter referred to as “LX + CM + ME”)
Loxoprofen sodium hydrate at a dose of 0.1 mg / kg body weight, d-chlorpheniramine maleate at a dose of 1 mg / kg body weight, dl-methylephedrine hydrochloride at a dose of 0.3 g / kg body weight, It was dissolved or suspended in a 0.5% methylcellulose solution and administered simultaneously.

Four rats were used for each test drug administration group.
The results are shown in Table 1. The pain improvement rate was expressed as an average value ± standard error per group.

From the test results shown in Table 1, it is clear that the combination of loxoprofen sodium hydrate, d-chlorpheniramine maleate and dl-methylephedrine hydrochloride (group 6) has an excellent analgesic action. It became.
In particular, the pain improvement rate (about 70%) is the pain improvement rate of the combination of the two components of loxoprofen sodium hydrate and d-chlorpheniramine maleate, which is known to enhance the analgesic action (Group 4: 0%), the pain improvement rate of the combination of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride, which is known to enhance the anti-inflammatory action (group 5: about 11%). It was large and exceptionally excellent even as expected from the combination of the two components.

  From the above test results, the combination of three components of loxoprofen or a salt thereof, chlorpheniramine or a salt thereof and ephedrine as an antihistamine is each component alone, loxoprofen or a salt thereof and chlorpheniramine or a salt thereof. The combination of these two components, and the combination of loxoprofen or a salt thereof and the two components of ephedrine, it was clarified that there was an exceptionally excellent analgesic action that could not be expected.

Test Example 1-2 Examination of analgesic action by combining three components of loxoprofen or a salt thereof, clemastine or a salt thereof and ephedrine According to the same method as in Test Example 1-1 except that the test drug was administered according to the following group constitution An analgesic test was performed.
1: Loxoprofen sodium hydrate alone administration group (hereinafter referred to as “LX alone”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
2: Cremastine fumarate single administration group (hereinafter referred to as “CF alone”)
Cremastine fumarate was administered at a dose of 3 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
3: dl-methylephedrine hydrochloride alone administration group (hereinafter referred to as “ME alone”)
dl-Methylephedrine hydrochloride was administered at a dose of 0.3 g / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
4: Two-component combination administration group of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride (hereinafter referred to as “LX + ME”)
Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution simultaneously at a dose of 0.1 mg / kg body weight and dl-methylephedrine hydrochloride at a dose of 0.3 g / kg body weight.
5: Three-component combination administration group of loxoprofen sodium hydrate, clemastine fumarate and dl-methylephedrine hydrochloride (hereinafter referred to as “LX + CF + ME”)
Loxoprofen sodium hydrate at a dose of 0.1 mg / kg body weight, clemastine fumarate at a dose of 3 mg / kg body weight, dl-methylephedrine hydrochloride at a dose of 0.3 g / kg body weight, 0.5% It was dissolved or suspended in a methylcellulose solution and administered simultaneously.
The results are shown in Table 2. The pain improvement rate was expressed as an average value ± standard error per group.

From the test results shown in Table 2, it was revealed that the combination of the three components of loxoprofen sodium hydrate, clemastine fumarate and dl-methylephedrine hydrochloride (group 5) has an excellent analgesic action.
In particular, the pain improvement rate (over 50%) is the pain improvement rate of a combination of two components of loxoprofen sodium hydrate and dl-methylephedrine hydrochloride, which is known to have an anti-inflammatory action enhancement effect (Group 4: approximately 11). %), Which was much larger than the combination of the two components.

  From the above test results, the combination of loxoprofen or a salt thereof, clemastine which is an antihistamine or a salt thereof and ephedrines is a combination of each component alone, or a combination of loxoprofen or a salt thereof and ephedrines. It became clear from the combination that it has an exceptionally excellent analgesic effect that cannot be predicted.

  Furthermore, from the test results of Test Example 1-1 and 1-2, by combining three components of loxoprofen or a salt thereof, chlorpheniramine or a salt thereof, an antihistamine containing clemastine or a salt thereof, and ephedrines, It became clear that there was an excellent analgesic action.

[Test Example 2] Antipyretic test An 8-week-old Wistar male rat (body weight 202.0 to 251.4 g) was used, and the test was performed as 4 to 7 animals per test drug administration group and solvent administration group, respectively. .
A micro precision thermometer (BAT-12, manufactured by Physitemp) was inserted into the rectum 4.5 cm, and the rectal temperature of the rat was measured. Next, crushed brewer's yeast (Ebios tablets, Asahi Food and Health Care) suspended in physiological saline to a concentration of 20% was administered subcutaneously at the back of the rat at a dose of 10 mL / kg body weight.
Rats were fasted after yeast administration (water was ad libitum), and about 16 hours after administration, rectal temperature was measured, and this was taken as body temperature during fever. Individuals with a calorific value (body temperature during fever-normal body temperature) of 1 ° C. or higher were grouped so that the average calorific value was approximately equal.

  Immediately after the above grouping, the test drug or solvent (0.5% methylcellulose solution: hereinafter referred to as “0.5% MC”) was orally administered, and after 1 hour, rectal temperature was measured, and the test was performed. Calculate the calorific value of the drug administration group (body temperature after administration of the test drug-normal body temperature) and the calorific value of the solvent administration group (body temperature after administration of the solvent-normal body temperature). (%) Was calculated.

Fever suppression rate (%) = (average value of calorific value of solvent administration group−average value of calorific value of test drug administration group) / average value of calorific value of solvent administration group × 100

Each test drug was administered according to the following group composition.
1: Loxoprofen sodium hydrate alone administration group (hereinafter referred to as “LX alone”)
Loxoprofen sodium hydrate was administered at a dose of 1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
2: d-chlorpheniramine maleate single administration group (hereinafter referred to as “CM alone”)
d-Chlorpheniramine maleate was administered at a dose of 3.5 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
3: dl-methylephedrine hydrochloride alone administration group (hereinafter referred to as “ME alone”)
dl-Methylephedrine hydrochloride was administered at a dose of 6 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
4: Loxoprofen sodium hydrate, d-chlorpheniramine maleate and dl-methylephedrine hydrochloride combined administration group (hereinafter referred to as “LX + CM + ME”)
Loxoprofen sodium hydrate at a dose of 1 mg / kg body weight, d-chlorpheniramine maleate at a dose of 3.5 mg / kg body weight, and dl-methylephedrine hydrochloride at a dose of 6 mg / kg body weight. It was dissolved or suspended in a 5% methylcellulose solution and administered simultaneously.
The results are shown in Table 3.

From the test results shown in Table 3, loxoprofen sodium hydrate (Group 1) showed an exothermic inhibition, that is, an antipyretic action (exothermic inhibition rate: about 50%). On the other hand, both d-chlorpheniramine maleate (group 2) and dl-methylephedrine hydrochloride (group 3) showed almost no antipyretic action (fever suppression rate: about 8% and about 3%, respectively) ).
However, the combination of the three components of loxoprofen sodium hydrate, d-chlorpheniramine maleate and dl-methylephedrine hydrochloride (group 4) shows an excellent antipyretic effect even when compared with the group 1 in particular. (Fever suppression rate: about 80%).

  From the above test results, it has been clarified that an excellent antipyretic effect can be obtained by combining three components of loxoprofen or a salt thereof, an antihistamine containing chlorpheniramine or a salt thereof, and ephedrines.

Test Example 3 Loxoprofen-Induced Gastrointestinal Disorder Inhibition Test Test Example 3-1 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Ephedrines Using 8-week-old Wistar male rats, test drug administration group, and solvent administration Each group (control group) was tested as 6 animals per group. Rats were fasted at least 16 hours before the start of the study. Water intake was free up to 1 hour before the start of the test, and then water was stopped.
As a test drug, dl-methylephedrine hydrochloride (hereinafter referred to as “ME”) is dissolved or suspended in a 0.5% methylcellulose solution and given orally (20, 60, 180 mg / 5 mL / kg body weight). did. Further, only 0.5% methylcellulose solution (hereinafter referred to as “0.5% MC”) was orally administered to the solvent administration group in the same volume (5 mL / kg).
One hour after administration of the test drug or solvent, loxoprofen sodium hydrate 120 mg / 2 mL physiological saline / kg body weight was orally administered to induce gastric mucosal damage. Five hours after administration of loxoprofen sodium hydrate, the rats were euthanized by cervical dislocation, the cardia was ligated, and the stomach was removed. After injecting 10 mL of 1% formalin solution into the stomach from the pyloric region and ligating the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and fixed lightly.

  Evaluation of the degree of gastric mucosal damage is performed by measuring the length (mm) of individual damage (erosion) occurring in the glandular stomach portion under a stereomicroscope after incising the stomach along the large curvature. The total damage per rat was taken as the ulcer index, and the ulcer index (average value ± standard error) was calculated for each group administered with the test drug and the solvent administration group. Further, according to the following formula, the ulcer suppression rate (%) by the test drug was calculated when the average value of the ulcer index of the solvent administration group was 100%.

  Ulcer inhibition rate (%) = (average value of ulcer index in solvent administration group−average value of ulcer index in test drug administration group) / average value of ulcer index in solvent administration group × 100

  The results are shown in Table 4. The ulcer index was expressed as an average value ± standard error for each group.

As is apparent from Table 4, dl-methylephedrine hydrochloride suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.
From the above test results, it has been clarified that ephedrines have an inhibitory effect on gastrointestinal disorders caused by loxoprofen or a salt thereof. In addition, ephedrines were considered to have the same inhibitory action against other NSAIDs that cause gastrointestinal disorders as well as loxoprofen.

Test Example 3-2 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Chlorpheniramine or its Salt 0.5% of d-chlorpheniramine maleate (hereinafter referred to as “CM”) as a test drug The test was carried out in the same manner as in Test Example 3-1, by dissolving or suspending in a methylcellulose solution and orally administering a predetermined amount (5, 40 mg / 5 mL / kg body weight). The results are shown in Table 5. The ulcer index was expressed as an average value ± standard error per group.

  As is apparent from Table 5, d-chlorpheniramine maleate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.

Test Example 3-3 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibition Effect of Clemastine or its Salt As a test drug, clemastine fumarate (hereinafter referred to as “CF”) is dissolved or suspended in a 0.5% methylcellulose solution. The test was carried out in the same manner as in Test Example 3-1, by turbidity and oral administration of a predetermined amount (1 mg / 5 mL / kg body weight). The results are shown in Table 6. The ulcer index was expressed as an average value ± standard error per group.

  As is apparent from Table 6, clemastine fumarate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate.

Test Example 3-4 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibition Effect by Carbinoxamine or its Salt Carbinoxamine maleate (hereinafter referred to as “CAM”) as a test drug is dissolved in a 0.5% methylcellulose solution. Alternatively, the test was carried out in the same manner as in Test Example 3-1, by suspending and orally administering a predetermined amount (0.75, 75 mg / 5 mL / kg body weight). The results are shown in Table 7. The ulcer index was expressed as an average value ± standard error per group.

  As is apparent from Table 7, carbinoxamine maleate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.

Test Example 3-5 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Diphenylpyraline or its Salt Dissolve diphenylpyraline hydrochloride (hereinafter referred to as “PP”) as a test drug in a 0.5% methylcellulose solution or The test was carried out in the same manner as in Test Example 3-1, by suspending and orally administering a predetermined amount (3, 10 mg / 5 mL / kg body weight). The results are shown in Table 8. The ulcer index was expressed as an average value ± standard error per group.

  As is apparent from Table 8, diphenylpyraline hydrochloride, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.

Test Example 3-6 Examination of Loxoprofen-induced Gastrointestinal Disorder Inhibitory Effect by Mequitazine or its Salt Mequitazine (hereinafter referred to as “MQ”) as a test drug was dissolved or suspended in a 0.5% methylcellulose solution, The test was carried out in the same manner as in Test Example 3-1, by orally administering a fixed amount (1, 3, 10 mg / 5 mL / kg body weight). The results are shown in Table 9. The ulcer index was expressed as an average value ± standard error per group.

  As is apparent from Table 9, mequitazine, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.

  From the test results of Test Examples 3-2 to 3-6, an antihistamine containing chlorpheniramine or a salt thereof, clemastine or a salt thereof, carbinoxamine or a salt thereof, diphenylpyraline or a salt thereof, mequitazine or a salt thereof is loxoprofen or a salt thereof. It was clarified that it has an inhibitory effect on gastrointestinal disorders caused by. Moreover, it is thought that an antihistamine has the same inhibitory effect also with respect to other NSAID which causes a digestive tract disorder like loxoprofen.

[Example 1] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-malein) 7 g of chlorpheniramine acid), dl-methylephedrine hydrochloride (manufactured by Alps Yakuhin Kogyo Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 120 g, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g , 486 g of carmellose calcium (manufactured by Gotoku Pharmaceutical: trade name ECG505) and 3644 g of crystalline cellulose (manufactured by Asahi Kasei Chemicals: trade name Theolas PH-101) are charged into a high-speed agitation granulator (manufactured by Paulek: model VG-25) and mixed. Next, add 1972.6 g of purified water and knead to make To obtain things. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 2] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-malein) 7 g of chlorpheniramine acid), dl-methylephedrine hydrochloride (manufactured by Alps Yakuhin Kogyo Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 120 g, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g , 486 g of carmellose calcium (product name: ECG505, manufactured by Gotoku Pharmaceutical Co., Ltd.) and 3644 g of lactose hydrate (product name: lactose 200M, manufactured by DMV) are charged into a high-speed agitation granulator (product of Paulek: model VG-25) and mixed. Then, 232 g of purified water was added to the above mixture and kneaded to obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 3] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-malein) 7 g of chlorpheniramine acid), dl-methylephedrine hydrochloride (manufactured by Alps Yakuhin Kogyo Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 120 g, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g , 486 g of carmellose calcium (product name: ECG505), lactose hydrate (product name: DMV: product name: lactose 200M) 1822 g, crystalline cellulose (product name: Theolas PH-101) 1822 g Into the machine (Paurek: VG-25) Next, 696.2 g of purified water was added to the above mixture and kneaded to obtain a granulated product. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 4] Tablet Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia Loxoprofen sodium hydrate) 408.6 g, d-chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd .: trade name D-malein) 7 g of chlorpheniramine acid), dl-methylephedrine hydrochloride (manufactured by Alps Yakuhin Kogyo Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder) 120 g, hydroxypropyl cellulose (manufactured by Nippon Soda: trade name HPC-L) 145.8 g , 486 g of carmellose calcium (product name: ECG505), lactose hydrate (product name: DMV: product name: lactose 200M) 1215 g, crystalline cellulose (product name: Asahi Kasei Chemicals: product name Theolas PH-101) 1215 g, corn starch (day Starch Chemical: Brand name Pun ST-C) 1214 g was put into a high speed agitation granulator (Powrec: VG-25 type) and mixed, and then 928.2 g of purified water was added to the above mixture and kneaded to obtain a granulated product. Obtained. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4811.4 g of this sized product and 48.6 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 5 mm punch, and 18000 tablets each having a mass of 270 mg were obtained.

[Example 5]
The tablet of Example 1 containing the following ingredients in 9 tablets (daily dose) complains of symptoms associated with colds (sore throat, chills, fever, headache, joint pain and muscle pain). An adult male (43 years old) was dosed 3 days at a time, 3 times a day, after each meal for 2 days with consent.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate): 204.3 mg (180 mg as loxoprofen sodium anhydride)
d-Chlorpheniramine maleate (manufactured by Kongo Chemical: trade name D-chlorpheniramine maleate): 3.5 mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder): 60 mg
Hydroxypropyl cellulose: 72.9mg
Carmellose calcium: 243mg
Crystalline cellulose: 1822 mg
Magnesium stearate: 24.3 mg

  After the medication, interviews were conducted regarding the various symptoms associated with the above-mentioned cold, and an answer that all symptoms were alleviated was obtained.

[Example 6]
Tablets containing the following components in 6 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate): 204.3 mg (180 mg as loxoprofen sodium anhydride)
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate): 1.34 mg
dl-Methylephedrine hydrochloride (manufactured by Alps Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia dl-methylephedrine hydrochloride powder): 60 mg
Tranexamic acid: 750mg
Bromhexine hydrochloride: 12mg
Dihydrocodeine phosphate: 24mg
Thiamine nitrate (vitamin B1 nitrate): 25mg
Riboflavin (vitamin B2): 12mg
Trehalose: 600mg
Crystalline cellulose: 467.36 mg
Macrogol 6000: 60mg
Croscarmellose sodium: 80mg
Polyvinyl alcohol: 1mg
Light anhydrous silicic acid: 24mg
Hardened oil: 65mg
Magnesium stearate: 44mg

  Combined use of loxoprofen or a salt thereof, an antihistamine, and ephedrines provides excellent analgesic and / or antipyretic effects. In addition, antihistamines and / or ephedrines have an inhibitory action on gastrointestinal disorders caused by loxoprofen or a salt thereof. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition that exhibits excellent pharmacological effects and is excellent in safety in which gastrointestinal disorders caused by loxoprofen or a salt thereof are suppressed, and can be suitably used in the pharmaceutical industry. .

Claims (7)

  At least one ephedrine selected from loxoprofen or a salt thereof, chlorpheniramine or a salt thereof, and l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, l-methylephedrine saccharin salt, and dl-methylephedrine saccharin salt An antipyretic pharmaceutical composition comprising:   The pharmaceutical composition according to claim 1, wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate.   The pharmaceutical composition according to claim 2, comprising loxoprofen sodium hydrate as a daily dose of 10 to 300 mg in terms of loxoprofen sodium anhydride.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the chlorpheniramine or a salt thereof is at least one selected from dl-chlorpheniramine maleate and d-chlorpheniramine maleate.   The dl-chlorpheniramine maleate contains 0.5 to 20 mg as a daily dose, or the d-chlorpheniramine maleate contains 0.1 to 15 mg as a daily dose. The pharmaceutical composition as described.   The pharmaceutical composition according to any one of claims 1 to 5, for relieving symptoms of chills, antipyretic fever, or chills and fever.   The pharmaceutical composition according to any one of claims 1 to 6, comprising 5 to 500 mg of ephedrine as a daily dose.