JP2015172092A - Pharmaceutical composition containing loxoprofen or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition having an excellent pharmacological effect.SOLUTION: An analgesic pharmaceutical composition contains loxoprofen or salt thereof, one or more antihistamine selected from the group consisting of chlorpheniramine, diphenylpyraline and mequitazine and salt thereof, and one or more codeine selected from the group consisting of codeine, dihydrocodeine and salt and solvate thereof.

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).
Codeine is also known to be a narcotic antitussive component having an antitussive effect by suppressing the function of the cough center, and based on the effect, codeine is used for general cold medicine, antitussive expectorant, etc. It is a drug (Non-patent Document 3).

  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 codeines are already known.
Regarding the action of the combination of loxoprofen or a salt thereof and an antihistamine, specifically, with loxoprofen, epinastine hydrochloride, carbinoxamine maleate, chlorpheniramine maleate, ketotifen fumarate and mequitazine For improving nasal obstruction symptoms (PTL 4), combination of loxoprofen with azelastine hydrochloride and mequitazine (PTL 5), loxoprofen and carbinoxamine maleic acid Increased analgesic effect by combining salt and chlorpheniramine maleate, anti-inflammatory and antipyretic effect by combining loxoprofen and carbinoxamine maleate, loxoprofen and clemastine fuma Potentiation of antihistaminic action by combining the salt and chlorpheniramine maleate (Patent Document 6) are known.
In addition, as for the action of the combination of two components of loxoprofen or a salt thereof and codeine, specifically, the anti-inflammatory action enhancing action by combining loxoprofen and dihydrocodeine phosphate (Patent Document 6), loxoprofen A goblet cell hyperplasia inhibitory effect (Patent Document 7) is known by combining phenoline and codeine phosphate.

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

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 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 289

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

  Therefore, the present inventor conducted intensive studies and found that a combination of three components of loxoprofen or a salt thereof, an antihistamine, and codeines exhibits a particularly excellent analgesic action and is useful as a medicine.

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

When three components of loxoprofen or a salt thereof, an antihistamine and codeine are used in combination, an excellent analgesic effect is exhibited. Therefore, according to the present invention, a pharmaceutical composition having an excellent pharmacological action can be provided.
In addition, the antihistamine has 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 codeines. First, the loxoprofen or a salt thereof will be described.
“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 more preferable, and 2.0 to 12% by mass is particularly preferable.

Next, the antihistamine used in the present invention will be described in detail.
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; 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.

  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 quantity which can be taken | dosed 0.1-13.5 mg per day is preferable, and the quantity which can be taken | dosed 1-4.5 mg is more preferable.
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.

  Among the antihistamines as described above, 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 from the viewpoint of an analgesic action and / or a gastrointestinal disorder inhibiting action. From the viewpoint of analgesic action, chlorpheniramine or a salt thereof, clemastine or a salt thereof is particularly preferable.

  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 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 more preferable, and what contains 0.0005-0.7 mass part is especially 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, but clemastine or a salt thereof may be added to the entire pharmaceutical composition. 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, diphenylpyralin or a salt thereof includes not only diphenylpyralin itself but also a pharmaceutically acceptable salt of diphenylpyralin. Specific examples of diphenylpyraline or a salt thereof include, for example, diphenylpyraline, diphenylpyraline hydrochloride, diphenylpyraline theocuroate and the like. In the present invention, diphenylpyraline hydrochloride and diphenylpyraline theocuroate are preferable, 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.

Next, codeines used in the present invention will be described.
In the present invention, “codeines” means one or more selected from the group consisting of codeine, dihydrocodeine and salts thereof, and solvates thereof. This group includes codeine and dihydrocodeine itself, as well as pharmaceutically acceptable salts of codeine and dihydrocodeine and solvates thereof. Specific examples of codeines include codeine, dihydrocodeine, codeine phosphate hydrate, dihydrocodeine phosphate, and the like. Among these, codeine phosphate hydrate and dihydrocodeine phosphate are preferable, and dihydrocodeine phosphate is particularly preferable. These are known compounds, and can be produced by known methods, or commercially available products can be used.

The content of codeine 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, 2-60 mg, more preferably 4 to 48 mg, particularly preferably 6 to 36 mg of codeine can be contained per day. When codeine phosphate hydrate is used as codeine, 4-60 mg, more preferably 8-48 mg, particularly preferably 12-36 mg of codeine phosphate hydrate should be included per day. Is preferred. Moreover, when using dihydrocodeine phosphate, it is preferable to contain 2-30 mg of dihydrocodeine phosphate per day, more preferably 4-24 mg, and particularly preferably 6-24 mg.
In this invention, it is preferable to contain 0.08-4 mass% of codeines with respect to the pharmaceutical composition total mass. Moreover, when codeine is codeine phosphate hydrate, it is preferable to contain 0.15-4 mass% with respect to the pharmaceutical composition total mass from a viewpoint of an analgesic effect | action, and 0.3-3 mass% is contained. It is more preferable to contain 0.5 to 2.5% by mass. Furthermore, when codeine is dihydrocodeine phosphate, it is preferable to contain 0.08-2 mass% with respect to a pharmaceutical composition total mass from a viewpoint of an analgesic effect | action, 0.16-1.5 mass% containing It is more preferable to contain, and it is especially preferable to contain 0.24-1.5 mass%.

  The content ratio of loxoprofen or a salt thereof and codeines 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 one containing 0.005 to 4 parts by mass of codeine, more preferably 0.01 to 2 parts by mass based on 1 part by mass in terms of anhydrous loxoprofen sodium. What contains 0.02-1 mass part is especially 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 may be a shape usually used in pharmaceuticals depending on the purpose of use and the like. it can. 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 codeines, from the viewpoint of ease of administration and management of drug dosage, etc., and 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 codeine, 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 chosen 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, dibutate sodium, dimemorphan phosphate, dextromethorphan bromide Examples thereof include hydroacid salts, dextromethorphan / phenolphthalin salts, tipepidine citrate, and tipepidine hibenzate.

Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of bronchodilators include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine saccharin salt, dl-methylephedrine saccharin. Examples thereof include salts, pseudoephedrine hydrochloride, pseudoephedrine sulfate, 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.

  Anticholinergic agents include, for example, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipidium 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, bellflowers, kokushi (coconut), cucumber (cucumber leaves), keigai (cocoon), keihi (cinnamon), ketsumeishi (actual child), gentian, 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 (Takebushi Ginseng), Clove (Chiko), Chimp (Chan), Toki (Toki), Tokon (Nanten), Carrot (Ginseng), Baimo (Shell), 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), maou (mao), lokjo ( Mushroom) Crude drugs and extracts thereof such as (extract, tincture, dry extract, etc.) and the like.

  As Kampo prescriptions, for example, Kakonto (Kakkontoyu), Keishito (Katsurayu), Kousosan (Kososan), Psychokeito (Saiko Keitou), Shosai Koto (Koshibakoto), Shosei Ryuto (Sho Blue) Ryuyu), Bakumondouto (Bakumon Fuyuto), Hangekoubokuto (Half summer Kobokuto), Maoutou (Maoyuto) and the like.

  Examples of caffeine include caffeine, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate.

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

Since the pharmaceutical composition of the present invention has a particularly excellent analgesic action as shown in Test Example 1 below, it is clear that it is effective for various diseases and symptoms accompanied by pain. Therefore, the pharmaceutical composition of the present invention is preferably an analgesic composition containing loxoprofen or a salt thereof, an antihistamine and codeine, and more specifically, headache, toothache, post-extraction pain, sore throat, ear pain. Analgesia of one or more types of pain selected from the group consisting of: 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 joint pain and muscle pain (Note that the “throat pain” refers to sore throat and acute rhinitis, allergic rhinitis or sinusitis as symptoms of cold) (It includes throat pain as various symptoms. Also, “headache”, “joint pain” and “muscle pain” include these symptoms as cold symptoms.) Available
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)-(C):

(A) containing loxoprofen or a salt thereof, an antihistamine and codeine, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, shoulder pain, bruise pain, fracture pain, One or more pain relieving compositions selected from pain, menstrual pain, and traumatic pain,
(B) at least one kind of relief selected from loxoprofen or a salt thereof, an antihistamine and codeine, from a sore throat, headache, joint pain and muscle pain (sore throat as a symptom of cold, headache, A composition for relieving one or more symptoms selected from joint pain and muscle pain), and (C) alleviation of sore throat (acute rhinitis, comprising loxoprofen or a salt thereof, an antihistamine and codeines) (Including relief of sore throat as various symptoms due to allergic rhinitis or sinusitis), and the above composition (B) is particularly preferable.

Loxoprofen is a kind of NSAID, and as a side effect, gastrointestinal disorders (stomach mucosal irritation, ulceration, etc.) become a problem. As specifically disclosed in Test Example 2 below, antihistamine is used as an antihistamine. It was found to have an inhibitory effect on gastrointestinal disorders caused by.
Therefore, the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, an antihistamine, and codeines has an advantageous effect that it is excellent in safety because gastrointestinal disorders caused by loxoprofen or a salt thereof are suppressed.
In addition, patients with peptic ulcers that have been conventionally contraindicated for drugs containing loxoprofen and patients with a history of peptic ulcers that have been carefully administered can be safely taken. The pharmaceutical composition of the present invention containing loxoprofen or a salt thereof, an antihistamine and codeine can also be used as a pharmaceutical composition for administration to a patient with peptic ulcer and / or a person with a history of peptic ulcer. It can be suitably used.
Furthermore, according to the present invention, an antihistamine is contained as an active ingredient, aluminoprofen, ampiroxicam, ampenac, ibuprofen, indomethacin, etodolac, epilysole, oxaprozin, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib, thiaprofenic acid, thiaramide, Nonsteroidal anti-inflammatory analgesics such as tenoxicam, tolfenamic acid, nabumetone, naproxen, piroxicam, pranoprofen, flufenamic acid, flurbiprofen, progouritacin, mefenamic acid, meloxicam, mofezolac, loxoprofen and lornoxicam and their salts Preferably, an agent for reducing or suppressing gastrointestinal disorders (for example, NSAID ulcer) caused by loxoprofen or a salt thereof can be provided. That.

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 codeine 5 to 6 weeks old Wistar male rats (weight 102) 7-120.5 g) of the right hind paw pain threshold was measured and was defined as the “pre-inflammation pain threshold”.
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: Dihydrocodeine phosphate single administration group (hereinafter referred to as “DP alone”)
Dihydrocodeine phosphate was administered at a dose of 0.1 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 dihydrocodeine phosphate two-component combination administration group (hereinafter referred to as “LX + DP”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight and dihydrocodeine phosphate was dissolved or suspended in a 0.5% methylcellulose solution at a dose of 0.1 g / kg body weight.
6: Loxoprofen sodium hydrate, d-chlorpheniramine maleate and dihydrocodeine phosphate combined administration group (hereinafter referred to as “LX + CM + DP”)
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 and dihydrocodeine phosphate at a dose of 0.1 g / kg body weight. It was dissolved or suspended in a 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 for each group.

From the test results shown in Table 1, it is clear that the combination of loxoprofen sodium hydrate, d-chlorpheniramine maleate and dihydrocodeine phosphate (group 6) has an excellent analgesic effect. became.
In particular, the pain improvement rate (about 60%) is the pain improvement rate of a combination of two components of loxoprofen sodium hydrate and d-chlorpheniramine maleate, which is known to enhance analgesic action (Group 4: about 4%). 0%), and the pain improvement rate of the combination of two components of loxoprofen sodium hydrate and dihydrocodeine phosphate, which is known to enhance anti-inflammatory action (Group 5: about 32%) is much larger The combination of the two components was exceptionally excellent as could not be expected.

  From the above test results, the combination of loxoprofen or a salt thereof, chlorpheniramine or a salt thereof as an antihistamine, and codeine is divided into each component alone, loxoprofen or a salt thereof and chlorpheniramine or a combination thereof. It was clarified that the combination of the two components of the salt and the combination of the two components of loxoprofen or a salt thereof and codeine exhibit an exceptionally excellent analgesic action that cannot 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 codeine The test drug was administered in the same manner 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: Dihydrocodeine phosphate single administration group (hereinafter referred to as “DP alone”)
Dihydrocodeine phosphate was administered at a dose of 0.1 g / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.

4: Two-component combination administration group of loxoprofen sodium hydrate and dihydrocodeine phosphate (hereinafter referred to as “LX + DP”)
Loxoprofen sodium hydrate was administered at a dose of 0.1 mg / kg body weight and dihydrocodeine phosphate was dissolved or suspended in a 0.5% methylcellulose solution at a dose of 0.1 g / kg body weight.
5: Loxoprofen sodium hydrate, clemastine fumarate and dihydrocodeine phosphate combined administration group (hereinafter referred to as “LX + CF + DP”)
Loxoprofen sodium hydrate at a dose of 0.1 mg / kg body weight, clemastine fumarate at a dose of 3 mg / kg body weight, dihydrocodeine phosphate at a dose of 0.1 g / kg body weight, 0.5% methylcellulose solution It was dissolved or suspended in 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 became clear that the combination of the three components (group 5) of loxoprofen sodium hydrate, clemastine fumarate and dihydrocodeine phosphate has excellent analgesic activity.
In particular, the pain improvement rate (about 54%) is the pain improvement rate of the combination of loxoprofen sodium hydrate and dihydrocodeine phosphate, which is known to enhance the anti-inflammatory effect (Group 4: about 32%). ), Which was much larger than expected, and could not be expected from the combination of the two components.

  From the above test results, the combination of three components of loxoprofen or a salt thereof, clemastine or a salt thereof as an antihistamine, and codeine is the combination of each component alone and two components 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 Examples 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 codeines, It became clear that there was an excellent analgesic action.

Test Example 2 Loxoprofen-Induced Gastrointestinal Disorder Inhibition Test Test Example 2-1 Examination of Loxoprofen-Induced Gastrointestinal Inhibitory Effect by Chlorpheniramine or its Salt Using 8-week-old Wistar male rats and study drug administration group , And the solvent administration group (control group), the test was carried out 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, d-chlorpheniramine maleate (hereinafter referred to as “CM”) is dissolved or suspended in a 0.5% methylcellulose solution, and a predetermined amount (5, 40 mg / 5 mL / kg body weight) is orally administered. Administered. 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 3. The ulcer index was expressed as an average value ± standard error for each group.

  As is apparent from Table 3, d-chlorpheniramine maleate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.

Test Example 2-2 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory 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 2-1, by turbidity and oral administration of a predetermined amount (1 mg / 5 mL / kg body weight). The results are shown in Table 4. The ulcer index was expressed as an average value ± standard error per group.

  As is clear from Table 4, clemastine fumarate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate.

Test Example 2-3 Examination of Loxoprofen-induced Gastrointestinal Disorder Inhibitory Effect by Carbinoxamine or its Salt Carbinoxamine maleate (hereinafter referred to as “CAM”) as a test drug was dissolved in a 0.5% methylcellulose solution. Alternatively, the test was carried out in the same manner as in Test Example 2-1, by suspending and orally administering a predetermined amount (0.75, 75 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, carbinoxamine maleate, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.

Test Example 2-4 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Diphenylpyrine 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 2-1 by suspending and orally administering a predetermined amount (3, 10 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, diphenylpyraline hydrochloride, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.

Test Example 2-5 Inhibition of Loxoprofen-Induced Gastrointestinal Disorder 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 2-1, by orally administering a fixed amount (1, 3, 10 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 clear from Table 7, mequitazine, an antihistamine, suppressed gastric mucosal damage caused by loxoprofen sodium hydrate in a dose-dependent manner.

  From the test results of Test Examples 2-1 to 2-5, 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 was thought that an antihistamine has the same inhibitory effect also with respect to other NSAIDs that cause gastrointestinal dysfunction in the same manner as loxoprofen.

[Example 1]
Tablets containing the following ingredients in 9 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) 204.3mg
d-Chlorpheniramine maleate (manufactured by Kongo Chemical Co., Ltd., trade name: D-chlorpheniramine maleate) 3.5 mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1858mg
Magnesium stearate 24.3mg

  An adult male (38 years old) complaining of various symptoms associated with cold (sore throat, headache, joint pain and muscle pain) with consent, three tablets of Example 1 once a day, three times a day Dosage for 2 days in later usage. After the medication, interviews were conducted regarding the above symptoms, and an answer that all symptoms were alleviated was obtained.

[Example 2]
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) 204.3mg
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg
Dihydrocodeine phosphate (manufactured by Shionogi & Co., Ltd., trade name: dihydrocodeine phosphate “Shionogi”) 24 mg
dl-Methylephedrine hydrochloride 60mg
Tranexamic acid 750mg
Bromhexine hydrochloride 12mg
Thiamine nitrate (vitamin B1 nitrate) 25mg
Riboflavin (vitamin B2) 12mg
Trehalose 600mg
Crystalline cellulose 467.36mg
Macrogol 6000 60mg
Croscarmellose sodium 80mg
Polyvinyl alcohol 1mg
Light anhydrous silicic acid 24mg
Hardened oil 65mg
Magnesium stearate 44mg

  When three components of loxoprofen or a salt thereof, chlorpheniramine or a salt thereof and codeine are used in combination, an excellent analgesic effect is exhibited. Therefore, according to the present invention, a pharmaceutical composition having an excellent pharmacological action can be provided and can be suitably used in the pharmaceutical industry.

Claims (5)

  One or more antihistamines selected from the group consisting of loxoprofen or a salt thereof, chlorpheniramine, diphenylpyralin and mequitazine and their salts, and selected from the group consisting of codeine, dihydrocodeine and their salts and solvates thereof An analgesic pharmaceutical composition comprising one or more codeines.   The pharmaceutical composition according to claim 1, wherein the antihistamine is diphenylpyralin.   The pharmaceutical composition according to claim 1 or 2, wherein the codeines are at least one selected from the group consisting of codeine phosphate hydrate and dihydrocodeine phosphate.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate.   The pharmaceutical composition according to any one of claims 1 to 4, which is used for alleviating one or more symptoms selected from sore throat, headache, joint pain and muscle pain.