JP2007291067A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition enhanced in anti-inflammatory action and having anti-influenza virus action. <P>SOLUTION: It is found that the excellent anti-inflammatory action and the excellent anti-influenza virus action are expressed by using tranexamic acid or its salt, clemastine or its salt, bromhexine or its salt and ibuprofen together with dihydrocodeine or its salt, methyl ephedrine or its salt, vitamin B<SB>1</SB>, its derivative or its salt and vitamin B<SB>2</SB>, its derivative or its salt. The preventive and/or therapeutic composition for inflammation containing the components, the preventive and/or therapeutic composition for influenza virus infectious diseases containing the components and the pharmaceutical composition useful as a cold medicine are provided. <P>COPYRIGHT: (C)2008,JPO&amp;INPIT

Description

  The present invention relates to a pharmaceutical composition having an anti-inflammatory action and an anti-influenza virus action.

  Tranexamic acid or a salt thereof, particularly tranexamic acid, is known to have an antiplasmin action, an antiallergic action, an anti-inflammatory action, and the like (see Non-Patent Document 1). Furthermore, the anti-influenza virus action of tranexamic acid is also known (see Patent Document 1).

  Also, clemastine or its salt, especially clemastine fumarate, enhances the anti-inflammatory effect of tranexamic acid when used in combination with tranexamic acid in addition to antihistamine, sedation, anticholinergic, antiserotonin, antiadrenergic, etc. It is known (see Patent Document 2).

  In addition, bromhexine or its salt, especially bromhexine hydrochloride, enhances the anti-inflammatory effect of tranexamic acid in addition to the secretory activation action of airway mucosa and submucosal tracheal gland, the action of dissolving and degrading acidic glycoprotein fiber network. It is known to do (refer patent document 3). The present inventors have already found that a pharmaceutical composition containing tranexamic acid or a salt thereof, clemastine or a salt thereof, and / or bromhexine or a salt thereof exhibits an excellent anti-inflammatory action, and further added ibuprofen. It was found that the pharmaceutical composition exhibits an excellent anti-inflammatory action (see Patent Document 4).

  On the other hand, dihydrocodeine or a salt thereof, particularly dihydrocodeine phosphate, is known to have analgesic action, mental function-suppressing action, hypnotic action, respiratory-suppressing action, antitussive action, and antipruritic action by suppressing intestinal peristaltic movement, etc. 2). However, it is not known that this has an anti-inflammatory effect. In addition, it is not known to enhance the action of other drugs having anti-inflammatory action.

  Further, methylephedrine or a salt thereof, particularly methylephedrine hydrochloride is known to have a central antitussive action, bronchodilator action, and the like (see Non-Patent Document 3). However, it is not known that this has an anti-inflammatory effect. In addition, it is not known to enhance the action of other drugs having anti-inflammatory action.

Moreover, it is known that vitamin B ₁ or a derivative thereof or a salt thereof, particularly thiamine nitrate, is effective for debilitating diseases, hyperthyroidism, beriberi and the like (see Non-Patent Document 4). However, it is not known that this has an anti-inflammatory effect. In addition, it is not known to enhance the action of other drugs having anti-inflammatory action.

Moreover, it is known that vitamin B ₂ or a derivative thereof or a salt thereof, particularly riboflavin, is effective for riboflavin deficiency, debilitating disease, and the like (see Non-Patent Document 5). However, it is not known that this has an anti-inflammatory effect. In addition, it is not known to enhance the action of other drugs having anti-inflammatory action.

Further, tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, further dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof Or there exists a patent application which described the pharmaceutical composition containing those salts (refer the formulation example 3-2 of patent document 4). However, there is no description or suggestion that it has an anti-influenza virus action.

International Publication No. 04/032915 Pamphlet Japanese Patent Application Laid-Open No. 2004-339211 JP 2004-331660 A Japanese Patent Application No. 2005-283709 Japan Pharmaceutical Information Center JAPAN Pharmaceuticals Collection of Medical Drugs 2006 Page 1491 14th Amendment Japanese Pharmacopoeia Manual Sasakawa Shoten Co., Ltd. C-3193-C-3194 14th Amendment Japanese Pharmacopoeia Manual Sasakawa Shoten Co., Ltd. C-731 14th Amendment Japanese Pharmacopoeia Manual Sasakawa Shoten Co., Ltd. C-1283 14th Amendment Japanese Pharmacopoeia Manual Yodogawa Shoten Co., Ltd. C-3034

  The present invention is more effective than previously known anti-inflammatory pharmaceutical compositions, and more effective than conventional anti-influenza virus action of tranexamic acid alone. In other words, it provides a pharmaceutical composition useful as a true total cold medicine.

As a result of intensive studies, the present inventors have found that in addition to tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, and ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a salt thereof The present inventors have found that an excellent anti-inflammatory action and anti-influenza virus action are exhibited by using a derivative or a salt thereof and vitamin B ₂ or a derivative thereof or a salt thereof in combination, thereby completing the present invention.

That is, the present invention relates to the following inventions.
(1) Tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof Or a pharmaceutical composition for anti-inflammatory and / or anti-influenza viruses, comprising a salt thereof.
(2) The pharmaceutical composition according to the above (1), wherein the compounding ratio of tranexamic acid or a salt thereof and clemastine or a salt thereof is 10,000: 1 to 2: 1.
(3) The pharmaceutical composition according to the above (1) or (2), wherein the compounding ratio of tranexamic acid or a salt thereof and bromhexine or a salt thereof is 1500: 1 to 10: 1.
(4) The pharmaceutical composition according to any one of (1) to (3) above, wherein the compounding ratio of tranexamic acid or a salt thereof and ibuprofen is 100: 1 to 1: 200.
(5) The pharmaceutical composition according to any one of (1) to (4) above, wherein the compounding ratio of tranexamic acid or a salt thereof and dihydrocodeine or a salt thereof is 3000: 1 to 1: 5.
(6) The pharmaceutical composition according to any one of the above (1) to (5), wherein the compounding ratio of tranexamic acid or a salt thereof and methylephedrine or a salt thereof is 300: 1 to 1:15.
(7) The pharmaceutical according to any one of the above (1) to (6), wherein the compounding ratio of tranexamic acid or a salt thereof and vitamin B ₁ or a derivative thereof or a salt thereof is 30000: 1 to 1:50. Composition.
(8) The medicament according to any one of (1) to (7) above, wherein the compounding ratio of tranexamic acid or a salt thereof, and vitamin B ₂ or a derivative thereof or a salt thereof is 30000: 1 to 1:10. Composition.
(9) As a daily dose, tranexamic acid or a salt thereof is 10 to 3000 mg as tranexamic acid, clemastine or a salt thereof is 0.4 to 5 mg as clemastine, bromhexine or a salt thereof is 2 to 24 mg as bromhexine, and 30 as ibuprofen -2000 mg, dihydrocodeine or a salt thereof as 1-50 mg as dihydrocodeine, methylephedrine or a salt thereof as 10-150 mg as methylephedrine, vitamin B ₁ or a derivative thereof or a salt thereof as 0.1 mg of vitamin B ₁ or a derivative thereof The pharmaceutical composition according to any one of (1) to (8) above, wherein vitamin B ₂ or a derivative thereof or a salt thereof contains 0.1 to 1000 mg as vitamin B ₂ or a derivative thereof.
(10) The pharmaceutical composition according to any one of (1) to (9), wherein the tranexamic acid or a salt thereof is tranexamic acid.
(11) The pharmaceutical composition according to any one of (1) to (10), wherein clemastine or a salt thereof is clemastine fumarate.
(12) The pharmaceutical composition according to any one of (1) to (11) above, wherein the bromhexine or a salt thereof is bromhexine hydrochloride.
(13) The pharmaceutical composition according to any one of (1) to (12) above, wherein the dihydrocodeine or a salt thereof is dihydrocodeine phosphate.
(14) The pharmaceutical composition according to any one of (1) to (13), wherein the methylephedrine or a salt thereof is methylephedrine hydrochloride.
(15) The pharmaceutical composition according to any one of (1) to (14) above, wherein the vitamin B ₁ or a derivative thereof or a salt thereof is thiamine nitrate.
(16) The pharmaceutical composition according to any one of (1) to (15) above, wherein the vitamin B ₂ or a derivative thereof or a salt thereof is riboflavin.
(17) The pharmaceutical composition according to any one of (1) to (16) above, which is used for prevention and / or treatment of inflammation.
(18) The pharmaceutical composition according to any one of (1) to (16) above, which is used for prevention and / or treatment of influenza virus infection.
(19) The pharmaceutical composition according to any one of (1) to (16) above, which is a cold medicine.
(20) The pharmaceutical composition according to any one of (1) to (19), wherein the preparation is an oral administration preparation.
(21) The pharmaceutical composition according to any one of the above (1) to (20), wherein the preparation is a solid preparation.
(22) The pharmaceutical composition according to any one of (1) to (20) above, wherein the dosage form is a tablet, capsule, powder, granule, fine granule, liquid, troche or jelly.
(23) An anti-inflammatory action-enhancing composition containing dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof or a salt thereof.

As will be apparent from the examples below, in addition to tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, and ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof, or The anti-inflammatory action of a pharmaceutical composition containing tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, and ibuprofen by combining those salts and vitamin B ₂ or a derivative thereof or a salt thereof Further enhancement was shown. That is, a pharmaceutical composition containing dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof or a salt thereof includes tranexamic acid or a salt thereof, clemastine Or a salt thereof, a bromhexine or a salt thereof and a pharmaceutical composition containing ibuprofen, which enhances the anti-inflammatory effect, an anti-inflammatory effect-enhancing composition, tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen , Dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and a vitamin B ₂ or a derivative thereof or a salt thereof are excellent anti-inflammatory It was shown to have an effect.

Tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof or Pharmaceutical compositions containing these salts also showed excellent anti-influenza virus activity.

Therefore, tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof or The pharmaceutical composition containing these salts is useful as a pharmaceutical composition for preventing and / or treating inflammation, a pharmaceutical composition for preventing and / or treating influenza virus infection, a cold medicine, and the like.

  Tranexamic acid or a salt thereof according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, or it can be produced based on a known method. Examples of salts of tranexamic acid include mineral salts such as hydrochloride, nitrate and sulfate, organic acid salts such as fumarate and methanesulfonate, alkali metal salts such as sodium, potassium, calcium and magnesium. And alkaline earth metal salts. In the present invention, tranexamic acid or a salt thereof is preferably tranexamic acid.

  Clemastine or a salt thereof according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, or it can be produced based on a known method. Examples of the salt of clemastine include mineral salts such as hydrochloride, nitrate and sulfate, and organic acid salts such as fumarate and methanesulfonate. In the present invention, clemastine or its salt is preferably clemastine fumarate.

  Bromohexine or a salt thereof according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, or it can be produced based on a known method. Examples of the salt of bromhexine include mineral acid salts such as hydrochloride, nitrate and sulfate, and organic acid salts such as methanesulfonate. In the present invention, bromhexine or a salt thereof is preferably bromhexine hydrochloride.

  The ibuprofen according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, or it can be produced based on a known method.

Dihydrocodeine or a salt thereof according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used, or it can be produced based on a known method. Examples of the salt of dihydrocodeine include phosphates, hydrochlorides, nitrates, mineral salts such as sulfates, and organic acid salts such as methanesulfonate. In the present invention, dihydrocodeine or a salt thereof is preferably dihydrocodeine phosphate.
The methylephedrine or a salt thereof according to the present invention is a known compound, and as a method for obtaining the methylephedrine, a commercially available product may be used, or it can be produced based on a known method. Examples of the salt of methylephedrine include mineral acid salts such as hydrochloride, nitrate and sulfate, and organic acid salts such as methanesulfonate. In the present invention, methylephedrine hydrochloride is preferred as methylephedrine or a salt thereof.

Examples of vitamin B ₁ or a derivative thereof according to the present invention include thiamine, bis-thiamine, bis-butyamine, bis-benchamine, thiamine disulfide, octothiamine, fursultiamine, and benfotiamine. Moreover, mineral salts, such as nitrate, hydrochloride, a sulfate, can be mentioned as those salts. These are known compounds, and as a method for obtaining them, commercially available products may be used, or they can be produced based on known methods. In the present invention, vitamin B ₁ or a derivative thereof or a salt thereof is preferably thiamine nitrate.

The vitamin B ₂ or derivatives thereof according to the present invention, may include, for example, riboflavin, flavin adenine dinucleotide or the like. Moreover, as those salts, mineral acid salts, such as phosphoric acid, organic acid salts, such as butyric acid, metal salts, such as a sodium salt, etc. can be mentioned. These are known compounds, and as a method for obtaining them, commercially available products may be used, or they can be produced based on known methods. In the present invention, riboflavin is preferable as vitamin B ₂ or a derivative thereof or a salt thereof.

The pharmaceutical composition of the present invention includes tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and besides vitamin B ₂ or derivatives thereof, or salts thereof, may be formulated pharmaceutical components further below. Components that can be combined include antipyretic analgesics such as aspirin, aspirin aluminum, sazapyrine, etenzamide, salicylamide, acetaminophen, isopropylantipyrine, central nervous stimulants such as caffeine, anhydrous caffeine, sodium benzoate caffeine, Sedatives such as bromvalerylurea, allyl isopropyl acetyl urea, chlorpheniramine maleate, diphenhydramine, diphenhydramine salicylate, carbinoxane maleate, mequitazine, alimemazine tartrate, diphenylpyraline hydrochloride, triprolidine hydrochloride and other antihistamines, lysozyme chloride, bromelain, Serrapeptase, semi-alkaline proteinase, glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid Anti-inflammatory drugs such as sodium azulene sulfonate, codeine phosphate, noscapine hydrochloride, noscapine, dextromethorphan hydrobromide, dextromethorphan phenolphthalein salt, dimemorphan phosphate, tipepidine hibenzate, tipidin citrate, epradinone hydrochloride, Antitussives such as methoxyphenamine hydrochloride, trimethquinol hydrochloride, phenylpropanolamine hydrochloride, L-ethylcysteine hydrochloride, potassium guaiacol sulfonate, potassium cresolate, expectorants such as guaifenesin, carbocysteine, ambroxol hydrochloride, theophylline, Bronchodilators such as aminophylline and diprofylline, belladonna (total) alkaloids, belladonna extract, isopropamide iodide, scopolamine hydrobromide, funnel extract, butyl bromide Anti-acetylcholine agents such as poramine, methylbenactidium bromide, timepidium bromide, pirenzepine, cetylpyridinium, cetylpyridinium chloride, popidone iodine, chlorhexidine gluconate, benzalkonium chloride, decalinium chloride, thymol, iodine / potassium iodide, phenol , Disinfectants such as chlorhexidine hydrochloride, creosote, benzethonium chloride, local anesthetics such as dibucaine hydrochloride, ethyl aminobenzoate, lidocaine, lidocaine hydrochloride, oxesazein, vitamin A, liver oil, vitamin B ₆ , vitamin B ₁₂ , vitamin C , Vitamins such as calcium ascorbate, vitamin D, vitamin E, calcium tocopherol succinate, pantothenic acid, panthenol, sodium pantothenate, calcium pantothenate Metabolic components such as pantethine, nicotinic acid, nicotinamide, glucuronic acid, glucuronolactone, aminoethyl sulfonic acid, biotin, γ-oryzanol, earth dragon, keihi, gohi, gyoza, kyou, maoh, licorice, gyonin, Examples include herbal medicines such as Hange, Shazenso, Senega, Psycho, Bukuryo, Shinyi, and extracts (extracts, tinctures, etc.) of these herbal medicines, but should not be limited to the above. These pharmaceutical ingredients may be blended with a single ingredient or in combination of two or more.
The pharmaceutical composition of the present invention can be administered orally or parenterally. The preparations for parenteral administration include injections, plasters, spirits, extracts, suppositories, suspensions, tinctures, ointments, poultices, nasal drops, inhalants, liniments, and lotions. And dosage forms such as aerosols. Examples of the preparation to be administered orally include dosage forms such as tablets, capsules, powders, granules, fine granules, solutions, troches, and jelly. Moreover, you may mix | blend the pharmaceutical composition of this invention with a mouthwash, a throat spray, a mouthwash, etc. In the present invention, a preparation for oral administration is preferred. Among these, solid preparations in dosage forms such as tablets, capsules, powders, granules, fine granules, troches, and jelly are preferable.

  Formulation can be performed by known formulation techniques, and appropriate formulation additives can be added to the formulation. What is necessary is just to add a formulation additive suitably in the range which does not impair the effect of this invention. Examples of formulation additives include excipients, disintegrants, binders, sweeteners, flavoring agents, lubricants, and the like.

  Examples of the excipient include crystalline cellulose, powdered cellulose, corn starch, potato starch, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate and silicic acid. Examples include calcium, magnesium aluminate metasilicate, synthetic hydrotalcite, synthetic aluminum silicate, sucrose fatty acid ester, hydrogenated oil, lactose, sucrose, D-mannitol, erythritol, trehalose, glucose, fructose and the like.

  Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, alginic acid, partially pregelatinized starch, and bentonite.

  Examples of the binder include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, povidone, macrogol, gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, aminoalkyl methacrylate. Mention may be made of copolymers, pullulan and the like.

  Examples of sweetening agents include aspartame, xylitol, erythritol, sorbitol, mannitol, saccharin and the like.

  Examples of the flavoring agent include menthol, mint water, mint oil, ascorbic acid, citric acid, cinnamon oil, clove oil, lactic acid, honey, borneol, rose oil and the like.

  Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, and hardened oil. These formulation additives may be used alone or in combination of two or more.

The blending ratio of each component in the pharmaceutical composition of the present invention may be determined as appropriate. For example, the blending ratio of tranexamic acid or a salt thereof and clemastine or a salt thereof is preferably 10,000: 1 to 2: 1, 1500: 1. More preferred is ~ 200: 1.
Moreover, the compounding ratio of tranexamic acid or a salt thereof and bromhexine or a salt thereof is preferably 1500: 1 to 10: 1, and more preferably 100: 1 to 20: 1.
The compounding ratio of tranexamic acid or a salt thereof and ibuprofen is preferably 100: 1 to 1: 200, more preferably 5: 2 to 2: 3.
The compounding ratio of tranexamic acid or a salt thereof and methylephedrine or a salt thereof is preferably 300: 1 to 1:15, and more preferably 30: 1 to 6: 1.

  Moreover, the compounding ratio of tranexamic acid or a salt thereof and dihydrocodeine or a salt thereof is preferably 3000: 1 to 1: 5, and more preferably 75: 1 to 40: 3.

The compounding ratio of tranexamic acid or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof is preferably 30000: 1 to 1:50, and more preferably 750: 1 to 8: 1.

The compounding ratio of tranexamic acid or its salts and vitamin _{B 2} or derivatives thereof, or a salt thereof, is 30000: 1 to 1: 10 preferably, 375: 1 to 40: 3 is more preferable.

The dosage of the pharmaceutical composition of the present invention to a patient may be appropriately determined by appropriately examining the patient's sex, age, symptoms, administration method, number of administrations, administration timing, and the like. For example, in the case of oral administration, tranexamic acid or a salt thereof is preferably administered as tranexamic acid in an amount of 10 to 3000 mg per day, more preferably 400 to 750 mg, and particularly preferably 750 mg. As for clemastine or a salt thereof, 0.4 to 5 mg is preferably administered as clemastine per day, more preferably 0.5 to 2 mg is administered, and 1 mg (for example, when the salt is a fumarate salt, clemastine fumarate is added). 1.34 mg) is particularly preferred. About bromhexine or its salt, it is preferable to administer 2-24 mg per day as bromhexine, it is more preferable to administer 4-12 mg, and when the salt of bromhexine is hydrochloride, it is especially preferable to administer 12 mg as bromhexine hydrochloride. About ibuprofen, it is preferable to administer 30-2000 mg per day, It is more preferable to administer 300-600 mg, It is especially preferable to administer 450 mg. As for dihydrocodeine or a salt thereof, it is preferable to administer 1 to 50 mg per day as dihydrocodeine, more preferably 10 to 30 mg, and when the salt of dihydrocodeine is a phosphate, 24 mg as dihydrocodeine phosphate may be administered. Particularly preferred. As for methylephedrine or a salt thereof, 10 to 150 mg is preferably administered as methylephedrine per day, more preferably 25 to 75 mg is administered. When the salt of methylephedrine is hydrochloride, 60 mg is administered as methylephedrine hydrochloride. It is particularly preferred. For vitamin _{B 1} or a derivative or a salt thereof, preferably administered 0.1~100mg per day as vitamin _{B 1} or a derivative thereof, more preferably be 1~50mg administration, vitamin _{B 1} or a derivative thereof Alternatively, when the salt is thiamine nitrate, it is particularly preferable to administer 25 mg as thiamine nitrate. For vitamin _{B 2} or derivatives thereof, or a salt thereof, preferably administered 0.1~1000mg per day as vitamin _{B 2} or derivatives thereof, more preferably be 2~30mg administration, vitamin _{B 2} or derivatives thereof Or when those salts are riboflavin, it is especially preferable to administer 12 mg as riboflavin.

That is, tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof or In the pharmaceutical composition of the present invention containing these salts, the compounding amount is 10 to 3000 mg of tranexamic acid or its salt as tranexamic acid, 0.4 to 5 mg of clemastine or its salt as clemastine per day, bromhexine or its 2-24 mg of salt as bromohexine, 30-2000 mg of ibuprofen, 1-50 mg of dihydrocodeine or its salt as dihydrocodeine, methylephedrine or its salt as methyl ester 10~150mg as Edorin, 0.1-100 mg of vitamin _{B 1} or a derivative thereof or a salt thereof as vitamin _{B 1} or a derivative thereof, vitamin _{B 2} or derivatives thereof, or a salt thereof as vitamin _{B 2} or derivatives thereof 0. 1 to 1000 mg is preferably formulated (taken), preferably 400 to 750 mg of tranexamic acid or its salt as tranexamic acid per day, 0.5 to 2 mg of clemastine or its salt as clemastine, bromohexine or its 4-12 mg of salt as bromhexine, 300-600 mg of ibuprofen, 10-30 mg of dihydrocodeine or its salt as dihydrocodeine, 25-75 as methylephedrine or its salt as methylephedrine g, to 1~50mg vitamin _{B 1} or a derivative thereof or a salt thereof as vitamin _{B 1} or a derivative thereof, 2～30Mg administered vitamin _{B 2} or derivatives thereof or their salts as vitamin _{B 2} or derivatives thereof (dose) More preferably, 750 mg as tranexamic acid per day, 1 mg as clemastine (for example, when salt is fumarate, 1.34 mg of clemastine fumarate) and when bromhexine is hydrochloride , 12 mg, ibuprofen 450mg as bromhexine hydrochloride, when the salt of dihydrocodeine is phosphate, if 24mg of phosphorus acid dihydrocodeine, salts of methyl ephedrine hydrochloride, 60 mg as the hydrochloride methylephedrine, vitamin _{B 1} or its When derivatives or salts thereof of thiamine mononitrate, 25 mg as thiamine mononitrate, when vitamin B ₂ or derivatives thereof or their salts of riboflavin, is particularly preferred formulated so as to be 12mg administered (dose) as riboflavin .

  The pharmaceutical composition of the present invention may be produced as a single preparation containing a plurality of components according to the present invention and administered (taken), or each component according to the present invention may be divided into different preparations. The kit preparation may be such that these preparations can be simultaneously or sequentially administered (taken).

  The pharmaceutical composition of the present invention is preferably used for prevention and / or treatment of inflammation, prevention and / or treatment of influenza virus infection, and / or cold medicine. The effects and effects of cold medicines include relief of cold symptoms (such as runny nose, nasal congestion, sneezing, sore throat, cough, sputum, chills, fever, headache, joint pain, muscle pain, etc.) Can do.

  Hereinafter, the present invention will be described with reference to examples. However, the present invention should not be limited to these examples.

1. Anti-inflammatory test (bradykinin-plasmin edema method)
1-1. Test Method Six 6-week-old male Crj: Wistar rats (Nippon Charles River Co., Ltd.) were examined in one group. Samples 1, 2 and 3 shown below were administered. For the sample 1 administration group, the necessary amount of tranexamic acid was weighed and orally dissolved or suspended in a 0.5 w / v% methylcellulose solution. In the sample 2 administration group, necessary amounts of tranexamic acid, clemastine fumarate, bromhexine hydrochloride, and ibuprofen were weighed and dissolved or suspended in the above 0.5 w / v% methylcellulose solution orally. Further, for the sample 3 administration group, necessary amounts of tranexamic acid, clemastine fumarate, bromhexine hydrochloride, ibuprofen, dihydrocodeine phosphate, methylephedrine hydrochloride, thiamine nitrate, and riboflavin were weighed and added to the above 0.5 w / v% methylcellulose solution. Those dissolved or suspended were orally administered.
Sample 1: tranexamic acid (500 mg / kg)
Sample 2: tranexamic acid (500 mg / kg) + clemastine fumarate (0.89 mg / kg) + bromhexine hydrochloride (8 mg / kg) + ibuprofen (300 mg / kg)
Sample 3: tranexamic acid (500 mg / kg) + clemastine fumarate (0.89 mg / kg) + bromhexine hydrochloride (8 mg / kg) + ibuprofen (300 mg / kg) + dihydrocodeine phosphate (16 mg / kg) + methylephedrine hydrochloride ( 40 mg / kg) + thiamine nitrate (16.7 mg / kg) + riboflavin (8 mg / kg)
Thirty minutes after oral administration, a solution of 1 mg bradykinin and 0.5 U plasmin dissolved in 20 ml of physiological saline was subcutaneously administered to the right hind footpad, at 0.1 ml / animal, and inflammation occurred. The volume of the right hind footpad was measured with a mouse / rat hindlimb footpad edema volume measuring device (TK-101 CMP, Unicom Co., Ltd.) before inflammation and at 15, 30, 45 and 60 minutes after inflammation. The edema rate at each measurement time (the ratio of the footpad volume at each measurement time to the footpad volume before inflammation) was calculated by the following equation, and the area under the edema rate curve (AUC) was calculated. Edema rate (%) = {(footpad volume (ml) for each measurement time−footpad volume before inflammation (ml)) / footpad volume before inflammation (ml)} × 100

ｐ＜０．０５、ｐ＜０．０１ 検体１投与群に対して有意差あり
ｎｓ 有意差なし 1-2. Test results The results are shown in Table 1.

p <0.05, p <0.01 Significantly different from sample 1 administration group ns Not significant

  As is apparent from the results (Table 1), the group (sample 2) that was combined with tranexamic acid, clemastine fumarate, bromhexine hydrochloride, and ibuprofen was more anti-inflammatory than the group that received tranexamic acid (sample 1). The effect was significantly expressed 30 minutes after inflammation and showed a superior anti-inflammatory effect, but in addition to tranexamic acid, clemastine fumarate, bromhexine hydrochloride, and ibuprofen, dihydrocodeine phosphate, methylephedrine hydrochloride, nitric acid nitrate The group using thiamine and riboflavin in combination (Specimen 3, the pharmaceutical composition of the present invention) significantly expressed its anti-inflammatory effect 15 minutes after inflammation. That is, the anti-inflammatory action of the specimen 3 showed an effect earlier than the anti-inflammatory action shown in the specimen 2, and further showed an excellent anti-inflammatory action.

  Therefore, the pharmaceutical composition according to the present invention containing tranexamic acid, clemastine fumarate, bromhexine hydrochloride, ibuprofen, dihydrocodeine phosphate, methylephedrine hydrochloride, thiamine nitrate, and riboflavin exhibits an excellent anti-inflammatory action. I understood.

2. 2. Anti-influenza virus test 2-1. Test Method Influenza virus A / PR / 8/34 was diluted with phosphate buffered saline (PBS) containing 0.1% bovine serum albumin (BSA) to prepare a virus dilution. BALB / c mice were anesthetized and 20 μL of virus dilution was inoculated nasally and infected with virus.
The mice were divided into 4 groups with 6 mice per group, and the following specimens 1 to 4 were respectively administered.

1 hour before virus inoculation, 6 hours after the last administration after virus inoculation, 2 days after the next day after virus inoculation, twice a day for a total of 5 days. Administered.
Sample 1 (control group): Water sample 2 (low concentration group): tranexamic acid 50 mg / kg + ibuprofen 30 mg / kg + bromhexine hydrochloride 0.8 mg / kg + clemastine fumarate 0.1 mg / kg + methylephedrine hydrochloride 4 mg / kg + dihydrocodeine phosphate 1 .6 mg / kg + thiamine nitrate 1.65 mg / kg + riboflavin 0.8 mg / kg
Specimen 3 (high concentration group): tranexamic acid 100 mg / kg + ibuprofen 60 mg / kg + bromhexine hydrochloride 16 mg / kg + clemastine fumarate 0.2 mg / kg + methylephedrine hydrochloride 8 mg / kg + dihydrocodeine phosphate 3.2 mg / kg + thiamine nitrate 3.3 mg / kg + Riboflavin 1.6mg / kg
Sample 4 (positive control group): oseltamivir phosphate (trade name: Tamiflu) 1 mg / kg
For 14 days after virus inoculation, the survival rate of mice was observed, and the control group, low concentration group, high concentration group and positive control group were compared, and the anti-influenza virus action of the pharmaceutical composition of the present invention was evaluated.

2-2. Test Results Control group mice administered with water (specimen 1) began to die on day 7 after virus inoculation, and 83% of mice died on that day. All mice died 8 days after inoculation. The mice in the low concentration group to which the low concentration pharmaceutical composition of the present invention (Sample 2) was administered began to die from the seventh day after inoculation. Seven days after inoculation, 50% of the mice survived and 8% after inoculation, 33% of the mice survived, but 9 days after inoculation all mice died. The mice in the high concentration group to which the high concentration pharmaceutical composition of the present invention (Sample 3) was administered began to die from the 7th day of inoculation, but 33% of the mice survived until the 10th day after the inoculation. The positive control group to which Sample 4 was administered began to die on the 8th day after inoculation. On day 8 after inoculation, 50% of mice survived, but by day 10 after inoculation, all mice died. The results are shown in Table 2.

  From the results in Table 2, it was found that the pharmaceutical composition of the present invention (Samples 2 and 3) had a life-prolonging effect on mice infected with influenza virus and had an excellent anti-influenza virus action.

3. Formulation Example 3-1. Granules Granules were produced by the usual method with the following composition (3 capsules per day).
Tranexamic acid 750mg
Clemastine fumarate 1.34 mg (1 mg as clemastine)
Bromhexine hydrochloride 12mg
Ibuprofen 450mg
Dihydrocodeine phosphate 24mg
Methylephedrine hydrochloride 60mg
Thiamine nitrate 25mg
Riboflavin 12mg
Erythritol 50mg
Trehalose 590.2mg
Crystalline cellulose appropriate amount Pullulan 184mg
Croscarmellose sodium 40mg
Eudragit 10mg
Aspartame 82mg

3-2. Tablets Tablets were produced by the usual method with the following composition (daily dose).
Tranexamic acid 750mg
Clemastine fumarate 1.34 mg (1 mg as clemastine)
Bromhexine hydrochloride 12mg
Ibuprofen 450mg
Methylephedrine hydrochloride 60mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate 25mg
Riboflavin 12mg
Lactose appropriate amount crystalline cellulose appropriate amount macrogol 30mg
Croscarmellose sodium 80mg
Polyvinyl alcohol 1mg
Light anhydrous silicic acid 24mg
Sucrose fatty acid ester 20mg
Hardened oil 10mg
Magnesium stearate

As is clear from the above examples, tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a pharmaceutical composition containing the derivative or a salt thereof exhibited an anti-inflammatory and anti-influenza virus activity superior.

Therefore, tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof or Pharmaceutical compositions containing these salts show excellent effects, and are useful as compositions for preventing and / or treating inflammation, compositions for preventing and / or treating influenza virus infections, cold medicines, and the like. Is.

Claims (23)

Tranexamic acid or a salt thereof, clemastine or a salt thereof, bromhexine or a salt thereof, ibuprofen, dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof or a derivative thereof A pharmaceutical composition for anti-inflammatory and / or anti-influenza viruses, comprising a salt. The pharmaceutical composition according to claim 1, wherein the compounding ratio of tranexamic acid or a salt thereof and clemastine or a salt thereof is 10,000: 1 to 2: 1. The pharmaceutical composition according to claim 1 or 2, wherein the compounding ratio of tranexamic acid or a salt thereof and bromhexine or a salt thereof is 1500: 1 to 10: 1. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compounding ratio of tranexamic acid or a salt thereof and ibuprofen is 100: 1 to 1: 200. The pharmaceutical composition according to any one of claims 1 to 4, wherein a mixing ratio of tranexamic acid or a salt thereof and dihydrocodeine or a salt thereof is 3000: 1 to 1: 5. The pharmaceutical composition according to any one of claims 1 to 5, wherein the compounding ratio of tranexamic acid or a salt thereof and methylephedrine or a salt thereof is 300: 1 to 1:15. The pharmaceutical composition according to any one of claims 1 to 6, wherein the compounding ratio of tranexamic acid or a salt thereof, and vitamin B ₁ or a derivative thereof or a salt thereof is 30000: 1 to 1:50. Tranexamic acid or a salt thereof and vitamin _{B 2} or blending ratio of the derivative or a salt thereof, is 30000: 1 to 1: 10 is the pharmaceutical composition according to any one of claims 1 to 7. As a daily dose, tranexamic acid or a salt thereof is 10 to 3000 mg as tranexamic acid, clemastine or a salt thereof is 0.4 to 5 mg as clemastine, bromhexine or a salt thereof is 2 to 24 mg as bromhexine, 30 to 2000 mg as ibuprofen, Dihydrocodeine or a salt thereof is 1 to 50 mg as dihydrocodeine, methylephedrine or a salt thereof is 10 to 150 mg as methylephedrine, vitamin B ₁ or a derivative thereof or a salt thereof is 0.1 to 100 mg as vitamin B ₁ or a derivative, vitamin B ₂ or a derivative thereof or a pharmaceutical composition according to any one of claims 1 to 8, their salts are 0.1~1000mg contained as vitamin _{B 2} or derivatives thereof. The pharmaceutical composition according to any one of claims 1 to 9, wherein the tranexamic acid or a salt thereof is tranexamic acid. The pharmaceutical composition according to any one of claims 1 to 10, wherein clemastine or a salt thereof is clemastine fumarate. The pharmaceutical composition according to any one of claims 1 to 11, wherein the bromhexine or a salt thereof is bromhexine hydrochloride. The pharmaceutical composition according to any one of claims 1 to 12, wherein the dihydrocodeine or a salt thereof is dihydrocodeine phosphate. The pharmaceutical composition according to any one of claims 1 to 13, wherein the methylephedrine or a salt thereof is methylephedrine hydrochloride. The pharmaceutical composition according to any one of claims 1 to 14, wherein the vitamin B ₁ or a derivative thereof or a salt thereof is thiamine nitrate. Vitamin B ₂ or a derivative thereof or a salt thereof, a pharmaceutical composition according to any one of claims 1 to 15 is riboflavin. The pharmaceutical composition according to any one of claims 1 to 16, which is used for prevention and / or treatment of inflammation. The pharmaceutical composition according to any one of claims 1 to 16, which is used for prevention and / or treatment of an influenza virus infection. It is a cold medicine, The pharmaceutical composition of any one of Claims 1-16. The pharmaceutical composition according to any one of claims 1 to 19, wherein the preparation is an oral administration preparation. The pharmaceutical composition according to any one of claims 1 to 20, wherein the preparation is a solid preparation. The pharmaceutical composition according to any one of claims 1 to 20, wherein the dosage form is a tablet, capsule, powder, granule, fine granule, solution, troche or jelly. A composition for enhancing anti-inflammatory action comprising dihydrocodeine or a salt thereof, methylephedrine or a salt thereof, vitamin B ₁ or a derivative thereof or a salt thereof, and vitamin B ₂ or a derivative thereof or a salt thereof.