JP2016014064A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition with reduced interaction between clemastine or salt thereof and a xanthine derivative.SOLUTION: A method for improving the storage stability of a pharmaceutical composition is characterized in that a pharmaceutical composition comprising clemastine or salt thereof and caffeine further comprises tranexamic acid or salt thereof.

Description

  The present invention relates to a pharmaceutical composition having excellent storage stability, containing clemastine or a salt thereof and a xanthine derivative.

  Clemastine such as clemastine fumarate or a salt thereof has an antihistaminic action, and is used for various medicines such as oral medicine for rhinitis and allergy medicine in addition to general cold medicine (Non-patent Document 1).

  On the other hand, xanthine derivatives such as caffeine have central nervous excitability and are used in various pharmaceuticals such as general cold medicines and antipyretic analgesics. Caffeine exhibits central excitatory action, cardiotonic / diuretic action, gastric acid secretion enhancing action, smooth muscle relaxing action, etc., and is a drug used for antipyretic analgesics, antitussive expectorants, etc. in addition to general cold medicine (Non-patent Document 2) ). In addition, other xanthine derivatives such as theophylline, paraxanthine, theobromine, aminophylline, diprofylline, and proxyphylline having a structure similar to caffeine have pharmacological effects similar to caffeine. Theophylline exhibits central excitatory action, cardiotonic / diuretic action, smooth muscle relaxing action, etc., and is a drug used for antitussive expectorant, antipruritics and the like. Aminophylline is a double salt of theophylline and ethylenediamine, and exhibits the same action as theophylline, and diprofylline also exhibits the same action as theophylline (Non-patent Document 3). Proxyphyrin also shows the same action as theophylline (Non-patent Document 4), and paraxanthine and theobromine show the same action.

  A combination of clemastine or a salt thereof and a xanthine derivative is already known. For example, Example 5 of Patent Document 1 discloses a tablet containing clemastine fumarate and caffeine. Further, Examples 4 to 11 and Comparative Examples 4 to 7 in Patent Document 2 disclose tablets containing clemastine fumarate and anhydrous caffeine.

JP 2005-330245 A JP 2010-1111589 A

OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 231 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. pp. 198-199 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Pages 292-294 OTC Handbook 2008-09 Academic Information Distribution Center, Inc. Page 688 Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-2743-2749 OTC Handbook 2008-09 Academic Information Distribution Center Co., Ltd. Pages 693-694

However, it is not known at all whether or not an interaction that affects storage stability occurs between clemastine or a salt thereof and a xanthine derivative.
Therefore, the present inventor has intensively studied the storage stability of both components, and surprisingly, when clemastine or a salt thereof and a xanthine derivative are mixed and stored for a long time under a high temperature condition, unexpectedly, between these components, It has been found that an interaction occurs, and this interaction causes a change in the state of the mixture over time (wetting, etc.), resulting in a problem in storage stability.
In the process of distribution and storage of pharmaceuticals, there is a possibility of being exposed to high temperatures for a long period of time. Therefore, pharmaceutical compositions are required to have improved storage stability during storage at high temperatures and for long periods.

  Accordingly, an object of the present invention is to provide a pharmaceutical composition in which the interaction between clemastine or a salt thereof and a xanthine derivative is suppressed.

  Therefore, the present inventor conducted further studies to solve this problem, and found that the interaction can be suppressed by allowing tranexamic acid or a salt thereof to coexist in clemastine or a salt thereof and a xanthine derivative. Completed the invention.

  That is, the present invention provides a pharmaceutical composition containing clemastine or a salt thereof, a xanthine derivative and tranexamic acid or a salt thereof.

According to the present invention, the interaction between clemastine or a salt thereof and a xanthine derivative can be suppressed. Therefore, a pharmaceutical composition containing clemastine or a salt thereof, and a xanthine derivative having excellent storage stability can be provided.
Moreover, the pharmaceutical composition containing the clemastine or its salt, and the xanthine derivative which suppressed the interaction can be provided easily and cheaply without passing through a complicated process.

  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, a mineral salt of clemastine (hydrochloride, nitrate, sulfate, etc.), an organic acid salt of clemastine (fumarate, methanesulfonate, etc.), 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 determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, per day, clemastine or a salt thereof in an amount of 0.01 to 5 mg, more preferably 0.05 to 3 mg, particularly preferably 0.1 to 2 mg in terms of free form of clemastine should be included. Can do. In this invention, it is preferable to contain 0.008-0.4 mass% of clemastine or its salt with respect to the pharmaceutical composition total mass in conversion of the free body of clemastine, 0.01-0.2 mass% is contained. It is more preferable to contain 0.015 to 0.15% by mass. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.

  In the present invention, the “xanthine derivative” is preferably a compound represented by the following general formula (1).

[In Formula (1), R ¹ and R ² each independently represent a hydrogen atom or a methyl group, and R ³ represents a hydrogen atom, a methyl group, a monohydroxypropyl group, or a dihydroxypropyl group. ]

In formula (1), in R ³ , the monohydroxypropyl group is preferably a 2-hydroxypropyl group. The dihydroxypropyl group is preferably a 2,3-dihydroxypropyl group.

In the above general formula (1),
(1) R ¹ is a methyl group, R ² is a methyl group, and R ³ is a methyl group means caffeine.
(2) R ¹ is a methyl group, R ² is a methyl group, and R ³ is a hydrogen atom means theophylline.
(3) R ¹ is a hydrogen atom, R ² is a methyl group, and R ³ is a methyl group means theobromine.
(4) R ¹ is a methyl group, R ² is a hydrogen atom, and R ³ is a methyl group means paraxanthine.
(5) A compound in which R ¹ is a methyl group, R ² is a methyl group, and R ³ is a 2-hydroxypropyl group means proxyphylline.
(6) The case where R ¹ is a methyl group, R ² is a methyl group, and R ³ is a 2,3-dihydroxypropyl group means diprofylline.

The compounds of the general formula (1), especially the above-mentioned compounds are known, and in the present invention, commercially available products can be used in addition to those produced by known methods.
As the xanthine derivative, in addition to the compound represented by the above general formula (1), a pharmaceutically acceptable salt thereof (for example, a double salt formed (sodium benzoate caffeine (sodium benzoate and sodium benzoate)) Caffeine double salt), aminophylline (double salt of theophylline and ethylenediamine)), etc.), a compound represented by the general formula (1) or a salt thereof and solvate of water, alcohol, etc. can also be used. These are also included in the “xanthine derivative”, and the above-mentioned compounds (caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprofylline) also include the compound, a salt thereof, and a solvate thereof. In the present invention, one or more of these xanthine derivatives can be used.

  In the present invention, the xanthine derivative is preferably one or more selected from the group consisting of caffeine, theophylline, theobromine, paraxanthine, proxyphylline, and diprofylline. In particular, the pharmaceutical composition of the present invention is used as an antipyretic analgesic or a general cold medicine. Caffeine is preferred from the standpoint of use as, for example. Specific examples of the caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and caffeine citrate. Among these, caffeine hydrate, caffeine anhydride, benzoic acid are preferable. Sodium caffeine is particularly preferred.

  The content of the xanthine derivative 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 1000 mg, more preferably 20 to 800 mg, particularly preferably 30 to 600 mg of xanthine derivative can be contained per day. In the present invention, the xanthine derivative is preferably contained in an amount of 0.4 to 65% by mass relative to the total mass of the pharmaceutical composition, more preferably 0.8 to 50% by mass, and 1.6 to 40% by mass. It is particularly preferable to contain it.

  In the present invention, “tranexamic acid or a salt thereof” includes tranexamic acid itself, a pharmaceutically acceptable salt of tranexamic acid, and a solvent of tranexamic acid or a pharmaceutically acceptable salt thereof, water, alcohol, and the like. Japanese products are also included. Tranexamic acid or its salts have antiplasmin, antiallergic, and antiinflammatory effects, and tend to be associated with increased systemic fibrinolysis, sore throat, redness, and hyperemia in diseases such as tonsillitis and sore throat -Known compounds (Non-Patent Documents 5 and 6) that are used for symptoms such as swelling and sore throat in stomatitis, and also used for liver pigmentation, senile pigmentation, post-inflammation pigmentation, etc. In addition to the above, commercially available products can be used. In the present invention, tranexamic acid or a salt thereof is preferably tranexamic acid (chemical name: trans-4- (Aminomethyl) cyclohexanecarboxylic acid).

  The content of tranexamic acid 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, per day, tranexamic acid or a salt thereof can be contained in an amount that can be taken from 50 to 2000 mg, more preferably from 70 to 750 mg, particularly preferably from 400 to 750 mg in terms of free form of tranexamic acid. In the present invention, tranexamic acid or a salt thereof is preferably contained in an amount of 1 to 90% by mass, more preferably 1 to 80% by mass, in terms of free form of tranexamic acid, based on the total mass of the pharmaceutical composition. More preferably, it is contained in an amount of 1 to 75% by mass. Among these, considering the pharmacological action exhibited by the pharmaceutical composition, it is preferably contained in an amount of 5 to 70% by mass, more preferably 5 to 60% by mass, and particularly preferably 7 to 50% by mass.

  The content ratio of clemastine or a salt thereof and tranexamic acid or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the inhibitory effect of the interaction between clemastine or a salt thereof and a xanthine derivative. However, from the viewpoint of suppressing interaction, one containing 10 to 200,000 parts by mass of tranexamic acid or a salt thereof in terms of free form of tranexamic acid with respect to 1 part by mass of clemastine or a salt thereof in terms of free form of clemastine. What contains 20-15000 mass parts is more preferable, What contains 200-7500 mass parts is further more preferable, What contains 200-1000 mass parts is especially preferable.

  In addition, the content ratio of the xanthine derivative and tranexamic acid or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined depending on the inhibitory effect of the interaction between clemastine or a salt thereof and the xanthine derivative. However, from the viewpoint of suppressing the interaction, it is preferable to contain 0.05 to 200 parts by mass of tranexamic acid or a salt thereof in terms of free form of tranexamic acid with respect to 1 part by mass of the xanthine derivative, and 0.08 to What contains 40 mass parts is more preferable, and what contains 0.5-25 mass parts is especially preferable.

In addition to clemastine or a salt thereof, a xanthine derivative and tranexamic acid, the pharmaceutical composition of the present invention preferably further contains an NSAID (nonsteroidal anti-inflammatory analgesic). When taking medicines containing NSAIDs, gastrointestinal disorders (gastric mucosal irritation, ulceration, etc.), which are side effects caused by NSAIDs, are problematic, but as specifically disclosed in Test Example 2 below, clemastine Alternatively, it has been found that a salt thereof has an inhibitory action on gastrointestinal disorders caused by loxoprofen, which is a kind of NSAID.
Therefore, a pharmaceutical composition containing NSAID in addition to clemastine or a salt thereof, xanthine derivative and tranexamic acid or a salt thereof has an advantageous effect of being excellent in safety because digestive tract disorders caused by NSAID are suppressed. In particular, when NSAID is loxoprofen or a salt thereof, there is a history of peptic ulcers that have been conventionally treated with peptic ulcers that have been contraindicated in drugs containing loxoprofen and peptic ulcers that have been carefully administered. It is preferable because it can be safely taken even by a patient and can also be used as a pharmaceutical composition for administration to a person suffering from peptic ulcer and / or a person with a history of peptic ulcer.

  Specific examples of NSAIDs that can be suitably blended in the pharmaceutical composition of the present invention include, for example, aluminoprofen, ampiroxicam, ampenac, ibuprofen, indomethacin, etodolac, epilysole, oxaprozin, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib , Thiaprofenic acid, thiaramide, tenoxicam, tolfenamic acid, nabumetone, naproxen, piroxicam, pranoprofen, flufenamic acid, flurbiprofen, progouritacin, mefenamic acid, meloxicam, mofezolac, loxoprofen and lornoxicam and their salts These 1 type or 2 types or more can be used in combination.

Examples of the NSAID that can be suitably blended in the pharmaceutical composition of the present invention include ibuprofen, loxoprofen or a salt thereof, and loxoprofen or a salt thereof is particularly preferable.
As specifically disclosed in Test Example 3, when loxoprofen or a salt thereof and clemastine or a salt thereof or a xanthine derivative are mixed and stored, an interaction occurs between these components, and this interaction causes a mixture. It has been found that changes in state such as wetting and solidification occur, causing problems in stability, and that the interaction can be suppressed by further coexisting tranexamic acid or a salt thereof in the mixture.
Therefore, the pharmaceutical composition of the present invention includes, in addition to clemastine or a salt thereof, a xanthine derivative and tranexamic acid or a salt thereof, from the viewpoint that the interaction between loxoprofen or a salt thereof and clemastine or a salt thereof or a xanthine derivative is also suppressed. Furthermore, the pharmaceutical composition of the present invention which further contains loxoprofen or a salt thereof is preferred.

Further, as specifically disclosed in Test Example 4, it was found that a combination of loxoprofen or a salt thereof and clemastine or a salt thereof has a particularly excellent analgesic effect.
Therefore, in addition to clemastine or a salt thereof, a xanthine derivative and tranexamic acid or a salt thereof, the pharmaceutical composition of the present invention further containing loxoprofen or a salt thereof has an excellent analgesic action, and is an analgesic composition. More specifically, headache, toothache, post-extraction pain, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain) and Relief of one or more pains selected from traumatic pain; relief of one or more symptoms selected from sore throat, headache, joint pain and muscle pain. And sore throat as symptoms of acute rhinitis, allergic rhinitis or sinusitis, and "headache", "joint pain" and "muscle pain" Cold symptoms and Can be suitably used as a medicament for use in containing.) These symptoms Te.

Moreover, as a suitable specific example of the pharmaceutical composition of this invention of the aspect containing a clemastine or its salt, a xanthine derivative, tranexamic acid or its salt, and loxoprofen or its salt, the following composition (A)-(C) One or more selected from the group consisting of:
(A) Headache, toothache, pain after tooth extraction, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, containing clemastine or a salt thereof, xanthine derivative, tranexamic acid or a salt thereof, and loxoprofen or a salt thereof Pain relief pain, bruise pain, fracture pain, sprain pain, menstrual pain (menstrual pain) and trauma pain analgesic composition for one or more types of pain,
(B) one or more types of relief selected from throat pain, headache, joint pain and muscle pain, containing clemastine or a salt thereof, xanthine derivative, tranexamic acid or a salt thereof, and loxoprofen or a salt thereof A composition for alleviating one or more symptoms selected from throat pain, headache, joint pain and muscle pain as symptoms, and (C) clemastine or a salt thereof, a xanthine derivative, tranexamic acid or the like And a composition for the relief of sore throat (including relief of sore throat as symptoms of acute rhinitis, allergic rhinitis or sinusitis), which contains a salt and loxoprofen or a salt thereof, (B) is particularly preferred.

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

  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 1.2 to 30% by mass, in terms of anhydrous loxoprofen sodium, based on the total mass of the pharmaceutical composition. Preferably, the content is 1.2 to 25% by mass. Among these, it is more preferable to contain 1.2-20 mass%, it is still more preferable to contain 2.4-15 mass%, and it is especially preferable to contain 2.4-12 mass%.

  The content ratio of loxoprofen or a salt thereof and 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 daily dose of each component described above. Alternatively, it is preferable to contain 0.0006 to 0.5 parts by mass of clemastine or a salt thereof in terms of a free form of clemastine with respect to 1 part by mass of loxoprofen sodium anhydride in terms of its salt. More preferably, it contains 0.002 to 0.03 parts by mass.

  In addition, the content ratio of loxoprofen or a salt thereof and a xanthine derivative in the pharmaceutical composition of the present invention is not particularly limited, and may be appropriately determined and determined according to the daily dose of each component described above. Or the salt thereof preferably contains 0.03 to 100 parts by mass of a xanthine derivative, more preferably 0.08 to 27 parts by mass relative to 1 part by mass in terms of loxoprofen sodium anhydride. What contains 10 mass parts is further more preferable.

  Further, the content ratio of loxoprofen or a salt thereof and tranexamic acid or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, depending on the inhibitory effect of the interaction between loxoprofen or a salt thereof and clemastine, a salt thereof, or a xanthine derivative. However, from the viewpoint of suppressing the interaction, loxoprofen or a salt thereof is 1 part by mass in terms of loxoprofen sodium anhydride, and tranexamic acid or a salt thereof is reduced to 0. Those containing 1 to 25 parts by mass are preferred, those containing 0.2 to 15 parts by mass are more preferred, and those containing 0.5 to 10 parts by mass are particularly preferred.

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 from the viewpoint of ease of administration and management of drug dosage, and is selected from the group consisting of tablets, powders, granules, fine granules, pills and capsules. A solid preparation is more preferable, and a tablet or capsule is particularly preferable.

  In the case where the pharmaceutical composition of the present invention is a solid preparation, from the viewpoint of suppressing interaction, clemastine or a salt thereof and a xanthine derivative in the solid preparation are contained so as not to substantially contact each other, and are manufactured and formulated. Also good. The preparations prepared so as to be substantially in contact with each other can be easily understood by general pharmaceutical technology researchers, using appropriate formulation additives based on known methods. Can be manufactured and formulated. Specifically, as the form of the solid preparation, the following (a) to (f) can be exemplified, and these can be produced and formulated by a known method.

(I) A powder or granule produced by granulating any one of clemastine or a salt thereof and a xanthine derivative into a granule by an appropriate method and containing the other without granulation, and the like A preparation in which the granular material is further coated by an appropriate method. In addition, the tranexamic acid or its salt used by this invention may be contained in a granular material, and may be contained separately from a granular material.
(B) Klemastine or a salt thereof and xanthine derivative are granulated separately by an appropriate method to form granules, and powders and granules produced by containing them, and the granules by further appropriate methods Coated formulation.
In addition, tranexamic acid or a salt thereof used in the present invention may be contained in any one of the granular materials, or may be included in both granular materials, and separately from these granular materials. You may make it contain.
Moreover, when the granule manufactured by (i) or (b) contains clemastine fumarate, cellulose or a derivative thereof may be contained in the granule.
(C) A capsule filled with the powder or granule prepared in (i) or (b) above.
(D) Tablets obtained by tableting the granular material produced in (b) or (b) above.
(E) A multilayer tablet prepared so that clemastine or a salt thereof and a xanthine derivative do not contact each other, and a preparation in which the multilayer tablet is further coated by an appropriate method. As the multilayer tablet, clemastine or a salt thereof and a xanthine derivative are preferably located in different layers, and as a multilayer tablet of three or more layers, a layer containing clemastine or a salt thereof and a layer containing a xanthine derivative are mutually What was located so that it may not contact | connect is more preferable. In addition, the granular material manufactured by said (i) and (b) can be used as a clemastine or its salt, and a xanthine derivative. In the multilayer tablet, tranexamic acid or a salt thereof may be located in either a layer containing clemastine or a salt thereof or a layer containing a xanthine derivative, or may be located separately in both layers. Furthermore, you may locate in the intermediate | middle layer of either layer.
(F) A dry-coated tablet in which one of clemastine or a salt thereof and a xanthine derivative is arranged in a core tablet and the other is arranged in an outer shell, and a preparation in which the dry-coated tablet is further coated by an appropriate method. In addition, the granular material manufactured by said (i) and (b) can be used as a clemastine or its salt, and a xanthine derivative. In the dry-coated tablet, tranexamic acid or a salt thereof may be located in the nuclear tablet, may be located in the outer shell, or may be separately located in either the nuclear tablet or the outer shell.
The above-mentioned solid preparation may be coated with sugar coating, film coating or the like by a known method.

  Examples of the route of administration of the pharmaceutical composition of the present invention include oral and parenteral such as transrectal and vaginal. In the present invention, an oral administration preparation is preferred. In addition, the pharmaceutical composition of the present invention can be taken about 1 to 4 times per day before meals, between meals, after meals, before going to bed.

  In the pharmaceutical composition of the present invention, clemastine or a salt thereof, xanthine derivative, tranexamic acid or a salt thereof, a drug other than NSAID, such as an antihistamine, an antitussive, a noscapine, a bronchodilator, an expectorant, a hypnotic sedative It may contain one or more selected from the group consisting of agents, vitamins, anti-inflammatory agents, gastric mucosa protective agents, antacids, anticholinergic agents, herbal medicines, Kampo prescriptions and the like.

  Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine diphenyldisulfonate, carbibi Noxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, difeterol hydrochloride, difeterol phosphate, diphenylpyraline hydrochloride, diphenylpyralineteocric acid Salt, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cyproheptadine hydrochloride hydrate, cetirizine hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, Dilamine hydrochloride, fexofenadine, phenetadine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besylate, homochlorcyclidine hydrochloride, mequitazine, methodirazine hydrochloride, mebhydroline napadisilate , Loratadine and the like.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibub Examples thereof include sodium sodium, dimemorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, and the like.

Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of bronchodilators include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, l-methylephedrine. Saccharin salt, dl-methylephedrine saccharin salt, methoxyphenamine hydrochloride and the like can be mentioned.

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

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

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

  Anticholinergic agents include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipidium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl-1- Hyoscyamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloid, belladonna extract, belladonna total alkaloid, iodide isopropamide, diphenylpiperidinomethyldioxolane iodide, funnel extract, funnel root, funnel root total Examples include alkaloid citrate.

  Herbal medicines include Akamegashiwa (red buds), Asenyaku (Asen Yaku), Inyo-kaku (Ryokan), Fennel (Yongxiang), Engosaku (Yancho), Ogon (Yellow), Ousei (Yellow), Oubak (Yellow), Spruce (Cherry bark), auren (yellow ream), onji (distant), gadgets (garbage), valerian grass (kashikoshi), chamomile, caronin (karojin), kyokyo (kikyo), kyonin (kyojin), kokushi (枸杞) Child), Kukoyo (Kashiwaha), Keigai (Kashiwa), Keihi (Katsuhashi), Ketsumeishi (Kemeko), Gentiana, Gennoshouko (current evidence), Koubushi (Katsukiko), Gooh (oxen yellow), Goshi (Gomiko), Saishin ( Spicy, Salamander, Zion, Zipoppi, Peonies, Shako, Shajin, Shazenshi, Shazenso, Car Grass), animal gall (including yutan (bear gall)), gyoza (ginger), giraffe (earth dragon), shin ii (spicy potato), sexan (stone urn), senega, senkyu (river cucumber), zenko (maehu) ), Sembli (Senri), Sojutsu (蒼朮), Sohakuhi (mulberry bark), Soyo (Soba), Taisan (Daegu), Chiksetsu carrot (Bamboo ginseng), Clove (clove), Chimpi (Chen), Toki ( Toko (Togyo), Nantenjitsu (Nan Tenji), Carrot (Ginseng), Baimo (Scarlet mother), Bacmondou (Wheat Gate Winter), Hange (Halfsummer), Bankouka (Banka Flower), Hampi (Antinas) ), Peony (white bean), peanut (white cocoon), bukuryo (pepper), button pi (peony skin), mao (mao), rokjo (deer moth), and their extracts (extract, tincture, dried extract, etc.) Etc.

  Chinese herbal prescriptions include Kakonto (Kakkonto), Keishito (Katsurayu), Kousosan (Kososan), Psychokeito (Saiko Keitou), Shosai Koto (Koshisaikoyu), Shosei Ryuto (Sho Seiryuto) ), Bakumondou (Bakumon Fuyuto), Hangekoubokuto (Hankatsu Kobokuto), Maoutou (Maoyuto) and the like.

The pharmaceutical composition of the present invention preferably does not contain a combination of bromohexine hydrochloride and an anticholinergic agent. Moreover, things other than the following (a)-(c) are preferable.
(A) Clemastine fumarate 1.34 parts by mass, low-substituted hydroxypropylcellulose 150 parts by mass and hydroxypropylcellulose 60 parts by mass 211.34 parts by mass, acetaminophen 900 parts by mass, dl- Contains 60 parts by weight of methylephedrine hydrochloride, 250 parts by weight of potassium guaiacol sulfonate, 420 parts by weight of tranexamic acid, 75 parts by weight of anhydrous caffeine, 700 parts by weight of lactose, 50 parts by weight of croscarmellose sodium and 30 parts by weight of magnesium stearate 1 tablet about 300mg.
(B) Granules having the following composition (3 capsules per day).
Tranexamic acid 420 mg, clemastine fumarate 1.34 mg, bromhexine hydrochloride 12 mg, belladonna total alkaloid 0.3 mg, acetaminophen 900 mg, dihydrocodeine phosphate 24 mg, methylephedrine hydrochloride 60 mg, benfotiamine 24 mg, anhydrous caffeine 60 mg Erythritol 50 mg, corn starch 50 mg, crystalline cellulose appropriate amount, aspartame 82 mg.
(C) Tablets having the following composition (daily dose).
Tranexamic acid 420 mg, clemastine fumarate 1.34 mg, bromhexine hydrochloride 12 mg, belladonna total alkaloid 0.3 mg, acetaminophen 900 mg, dihydrocodeine phosphate 24 mg, methylephedrine hydrochloride 60 mg, benfotiamine 24 mg, anhydrous caffeine 60 mg , Lactose appropriate amount, crystalline cellulose appropriate amount, polyvinyl alcohol 1 mg, light anhydrous silicic acid 24 mg, magnesium stearate trace amount.

  The pharmaceutical composition of the present invention may be further stored in the presence of a desiccant from the viewpoint of interaction inhibition. Hereinafter, what contains the pharmaceutical composition and desiccant of this invention in a container may be called "pharmaceutical formulation" of this invention.

  In the pharmaceutical preparation of the present invention, the desiccant is not particularly limited. Of course, the shape is not limited, for example, a plate-shaped or bag-shaped sheet type, a cylindrical shape (tablet type), etc., and a cylindrical shape with paper wrapping or film coating. But you can.

  Specific examples of the desiccant include silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride, magnesium oxide. Etc., and a mixture of these and activated carbon may be used. Among these, one or more selected from the group consisting of silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve), and calcium chloride is more preferable.

  Commercially available products can be used as the desiccant. Examples of commercially available products include Shiblet, MS-Tablet, MS-Serum W, Tokai Gel, Decikait 25, Alp Sheet, Yamanishi Pharmaceutical Co., Ltd., manufactured by Tokai Chemical Industry Co., Ltd. Dryan (registered trademark) packaged product, Dryan (registered trademark) tablet, Dryan (registered trademark) sheet, Sekawa, Allosheet, Zeosheet manufactured by Shinagawa Kasei Co., Ltd., OZO manufactured by OZO Chemical Engineering Co., Ltd. An ID sheet made by the company ID, an ID packing desiccant, etc.

  In the pharmaceutical preparation of the present invention, the content of the desiccant may be appropriately determined and determined, but is preferably 0.001 to 1 part by weight, preferably 0.004 to 1 part by weight with respect to 1 part by weight of the pharmaceutical composition of the present invention. 0.4 parts by mass is more preferable.

  The container used for the pharmaceutical preparation of the present invention is not particularly limited as long as it can be used as a container for foods, supplements, pharmaceuticals, health foods, and the like, but any of a fixed container and an amorphous container can be used and sealed. What is possible is preferred. Examples of the fixed container include bottles, cans, and boxes. Examples of the amorphous container include bags (pillow packaging, stick packaging, PTP packaging, SP packaging, etc.) and the like. Of these containers, specifically, bottles and bags are preferable.

The forming member of the container is not particularly limited, and examples thereof include paper, glass, a resin or a resin film, or a member such as a metal or metal film. It may be a thing. Moreover, it is preferable that moisture permeation prevention processing is performed about the member which has moisture permeability, such as paper.
The container may be transparent, translucent, or opaque.

  The method for storing the pharmaceutical composition and the desiccant of the present invention in a container is not particularly limited, and both can be achieved by arranging them by appropriate means such as charging into the container.

  For example, when the container is a bottle, the desiccant (preferably, a columnar shape (tablet shape)) is placed in the bottle, or stored in the back side (inner cap) of the bottle lid, and stored in the container. This can be achieved by storing the pharmaceutical composition in a bottle or the like. When stored in a bottle, the pharmaceutical composition of the present invention is preferably a solid preparation.

  Further, when the container is a bag, it can be achieved by storing the desiccant (preferably, a plate-like or bag-like sheet type) and the pharmaceutical composition of the present invention in the bag. When stored in the bag, the pharmaceutical composition of the present invention is preferably a solid preparation.

  Further, the pharmaceutical composition of the present invention may be once packaged by SP packaging, PTP packaging or a bag, and then the packaged pharmaceutical composition and desiccant may be enclosed in a bag. More specifically, the form which carries out pillow packaging, combining the pharmaceutical composition which carried out SP packaging or PTP packaging, and a plate-shaped or bag-shaped sheet type desiccant etc. is mentioned. Further, the pillow packaging form may be stored in a box or the like. When the pharmaceutical composition is once packaged by SP packaging, PTP packaging or a bag, the pharmaceutical composition of the present invention is preferably a solid preparation.

  Since the pharmaceutical composition of the present invention contains clemastine having an antihistamine action or a salt thereof, a xanthine derivative having a central nervous excitatory action, and tranexamic acid having an anti-inflammatory action or a salt thereof, a general cold medicine (cold medicine) It is useful as a medicine for nasal inflammation and rhinitis.

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
[Test Example 1] Examination of interaction between clemastine fumarate and anhydrous caffeine Samples 1-A to 1-B shown below were each prepared and stored at 60 ° C for 19 days, immediately after the start of storage, 1 day later, 2 days later The state of the mixture in the sample after 6 days and 19 days was evaluated to confirm the presence or absence of interaction. The results are shown in Table 1.

[Sample 1-A]
Clemastine fumarate (manufactured by Daito: trade name: clemastine fumarate) 10 mg and anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name: anhydrous caffeine) 1866 mg were mixed to obtain a mixture, which was put into a glass bottle (3K standard bottle). And sample 1-A was obtained.
[Sample 1-B]
Clemastine fumarate (manufactured by Daito: trade name: clemastine fumarate) 2 mg, anhydrous caffeine (manufactured by Shizuoka Caffeine Kogyosho: trade name: anhydrous caffeine) 373.2 mg and tranexamic acid (Daiichi Sankyo Propharma: product) Name Japanese Pharmacopoeia Tranexamic acid) 1119.4 mg was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 1-B.

From the test results shown in Table 1, it was found that in a mixture in which only clemastine fumarate and anhydrous caffeine were mixed, interaction occurred and the mixture became wet as time passed.
On the other hand, in a mixture obtained by adding tranexamic acid to clemastine fumarate and anhydrous caffeine and mixing, it was found that the state of white powder was maintained even after storage for 19 days, just after the start of storage.
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between clemastine or a salt thereof and a xanthine derivative including anhydrous caffeine.

Test Example 2 Examination of Loxoprofen-Induced Gastrointestinal Disorder Inhibitory Effect by Clemastine Fumarate Using 8-week-old Wistar male rats, each of the test drug administration group and the solvent administration group (control group), 4 to 4 The test was carried out as 8 animals. 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, clemastine fumarate (hereinafter referred to as “CF”) was dissolved or suspended in a 0.5% methylcellulose solution, and a predetermined amount (1 mg / 5 mL / kg body weight) was orally 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 sum of the length of damage per rat was taken as the ulcer index, and the ulcer index (mean value ± standard error) was calculated for each of the test drug administration group 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 2. The ulcer index was expressed as an average value ± standard error for each group.

  As is apparent from Table 2, it was revealed that administration of clemastine fumarate can suppress gastric mucosal damage caused by loxoprofen sodium hydrate.

  From the above test results, it was revealed that clemastine or a salt thereof has an inhibitory action on gastrointestinal disorders caused by loxoprofen or a salt thereof. In addition, clemastine or a salt thereof was considered to have the same inhibitory action on other NSAIDs that cause gastrointestinal disorders as well as loxoprofen.

[Test Example 3] Examination of interaction between loxoprofen sodium hydrate and other components Test Example 3-1 Examination of interaction between loxoprofen sodium hydrate and clemastine fumarate Samples 3-1 to A-3 shown below Each of -1-C was stored at 60 ° C. for 1 week after preparation, and the state of the mixture in the sample immediately after the start of storage, 1 day, 3 days, and 1 week was evaluated to confirm the presence or absence of interaction. The results are shown in Table 3.

[Sample 3-1A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg and clemastine fumarate (Dite: trade name: clemastine fumarate) 1.34 mg Obtained and put into a glass bottle (3K standard bottle), sample 3-1-A was obtained.
[Sample 3-1-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, clemastine fumarate (trade name: clemastine fumarate) 1.34 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: trade name: Japanese Pharmacopoeia Tranexamic acid (750 mg) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 3-1-B.
[Sample 3-1-C]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3 mg, clemastine fumarate (trade name: clemastine fumarate) 1.34 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: Trade name Pharmacopeia Tranexamic acid (750 mg) was mixed to obtain a mixture, and 1 g of synthetic zeolite (product name: MS-W1506), a desiccant, glass bottle (3K standard bottle) And sample 3-1-C was obtained.

From the test results shown in Table 3, it was found that in a mixture in which only loxoprofen sodium hydrate and clemastine fumarate were mixed, an interaction occurred and the mixture became wet.
On the other hand, in the mixture of loxoprofen sodium hydrate and clemastine fumarate added with tranexamic acid, it was found that the white powder state was maintained even after storage for 1 week, just after the start of storage. .
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and clemastine or a salt thereof.

Test Example 3-2 Examination of interaction between loxoprofen sodium hydrate and anhydrous caffeine Samples 3-2-A to 3-2-C shown below were prepared and stored at 40 ° C. and 75% RH for 1 week. Immediately after the start, the state of the mixture in the sample after 1 day, 3 days and 1 week was evaluated, and the presence or absence of interaction was confirmed. The results are shown in Table 4.

[Sample 3-2-A]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg and anhydrous caffeine (Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 250 mg were mixed to obtain a mixture. Obtained and put in a glass bottle (3K standard bottle) to obtain Sample 3-2-A.
[Sample 3-2-B]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg, anhydrous caffeine (Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 250 mg and tranexamic acid (Daiichi Sankyo Propharma's product name: Japanese Pharmacopoeia Tranexamic acid (750 mg) was mixed to obtain a mixture, which was put in a glass bottle (3K standard bottle) to obtain Sample 3-2-B.
[Sample 3-2-C]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen Sodium Hydrate) 204.3 mg, anhydrous caffeine (Shizuoka Caffeine Industry: trade name: anhydrous caffeine) 250 mg and tranexamic acid (Daiichi Sankyo Propharma Co., Ltd .: Trade name Pharmacopeia Tranexamic acid (750 mg) was mixed to obtain a mixture, and 1 g of synthetic zeolite (product name: MS-W1506), a desiccant, glass bottle (3K standard bottle) And sample 3-2-C was obtained.

From the test results shown in Table 4, it was found that in a mixture in which only loxoprofen sodium hydrate and anhydrous caffeine were mixed, an interaction occurred and the mixture solidified.
On the other hand, it was found that a mixture of loxoprofen sodium hydrate and anhydrous caffeine added with tranexamic acid was kept in a white powder state even after storage for 1 week, just after the start of storage.
From the above test results, it was revealed that tranexamic acid or a salt thereof has an action of suppressing the interaction between loxoprofen or a salt thereof and a xanthine derivative including anhydrous caffeine.

[Test Example 4] Examination of analgesic effect by combination of clemastine fumarate and loxoprofen sodium hydrate The pain threshold value of right hind paw of Wistar male rats of 5-6 weeks old was measured, and "the pain threshold value before inflammation was induced" It was.
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 with 1 hour after the drug administration as a measurement point, and was defined as “pain threshold after drug administration”.
In addition, the pain threshold value was measured using the Randall Cerit type analgesic effect measuring apparatus (MK-201D: Muromachi Machine 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: Cremastine fumarate 3 mg / kg single administration group (hereinafter referred to as “CF alone (3 mg / kg)”)
Cremastine fumarate was administered at a dose of 3 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
3: Clemastine fumarate 30 mg / kg single administration group (hereinafter referred to as “CF alone (30 mg / kg)”)
Cremastine fumarate was administered at a dose of 30 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
4: Two-component combination administration group of loxoprofen sodium hydrate and clemastine fumarate 3 mg / kg (hereinafter referred to as “LX + CF (3 mg / kg)”)
Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution at a dose of 0.1 mg / kg body weight and clemastine fumarate at a dose of 3 mg / kg body weight and administered simultaneously.
5: Two-component combination administration group of loxoprofen sodium hydrate and clemastine fumarate 30 mg / kg (hereinafter referred to as “LX + CF (30 mg / kg)”)
Loxoprofen sodium hydrate was dissolved or suspended in a 0.5% methylcellulose solution at a dose of 0.1 mg / kg body weight and clemastine fumarate at a dose of 30 mg / kg body weight and administered simultaneously.

  From the pain threshold obtained in the above test, the pain improvement rate was calculated 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

Four rats were used for each test drug administration group.
The results are shown in Table 5. The pain improvement rate was expressed as an average value ± standard error for each group.

  From the test results shown in Table 5, it became clear that the combination of loxoprofen sodium hydrate and clemastine fumarate has an excellent analgesic effect (pain improvement rate of the fourth group: about 41%, the fifth group Pain improvement rate: about 68%).

  From the above test results, it became clear that a particularly excellent analgesic effect was achieved by combining loxoprofen or a salt thereof and clemastine or a salt thereof.

[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.
Cremastine fumarate 1.34mg
Anhydrous caffeine 150mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1188.46mg
Magnesium stearate 24.3mg

[Example 2]
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.
Cremastine fumarate 1.34mg
Anhydrous caffeine 75mg
Tranexamic acid 750mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1263.46mg
Magnesium stearate 24.3mg

[Example 3]
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.
Cremastine fumarate 1.34mg
Anhydrous caffeine 75mg
Tranexamic acid 750mg
Loxoprofen sodium hydrate 204.3mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 1059.16mg
Magnesium stearate 24.3mg

  An adult male (33 years old) complaining of symptoms associated with cold (sore throat, headache, joint pain and muscle pain) with consent, 3 tablets of Example 3 once a day 3 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 4]
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.
Cremastine fumarate 1.34mg
Anhydrous caffeine 75mg
Tranexamic acid 750mg
Ibuprofen 450mg
Hydroxypropylcellulose 72.9mg
Carmellose calcium 243mg
Crystalline cellulose 813.46mg
Magnesium stearate 24.3mg

[Example 5]
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.
Tranexamic acid 750mg
Loxoprofen sodium hydrate 204.3mg
Cremastine fumarate 1.34mg
Bromhexine hydrochloride 12mg
dl-Methylephedrine hydrochloride 60mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate (vitamin B1 nitrate) 25mg
Riboflavin (vitamin B2) 12mg
Anhydrous caffeine 150mg
Trehalose 440mg
Crystalline cellulose 317.36mg
Macrogol 6000 60mg
Croscarmellose sodium 240mg
Polyvinyl alcohol 1mg
Light anhydrous silicic acid 24mg
Hardened oil 65mg
Magnesium stearate 44mg

[Example 6]
Tablets containing the following components in 6 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Tranexamic acid 750mg
Ibuprofen 450mg
Cremastine fumarate 1.34mg
Bromhexine hydrochloride 12mg
dl-Methylephedrine hydrochloride 60mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate (vitamin B1 nitrate) 25mg
Riboflavin (vitamin B2) 12mg
Anhydrous caffeine 150mg
Trehalose 440mg
Crystalline cellulose 71.66mg
Macrogol 6000 60mg
Croscarmellose sodium 240mg
Polyvinyl alcohol 1mg
Light anhydrous silicic acid 24mg
Hardened oil 65mg
Magnesium stearate 44mg

[Example 7]
Fifteenth revision Japanese Pharmacopoeia Preparation of A granule and B granule according to the “Granule” section of the General Rules for Preparations and mixing them, and usually containing the following ingredients in 3 capsules (daily dose) Manufactured by the method.
<A granule>
Tranexamic acid 750mg
Cremastine fumarate 1.34mg
Bromhexine hydrochloride 12mg
dl-Methylephedrine hydrochloride 60mg
Dihydrocodeine phosphate 24mg
Riboflavin (vitamin B2) 6.5mg
Anhydrous caffeine 75mg
Erythritol 973.5mg
Crystalline cellulose 445.7mg
Pullulan 120mg
Aminoalkyl methacrylate copolymer RS 96mg
Croscarmellose sodium 40mg
Aspartame (L-phenylalanine compound) 18mg
<B granule>
Loxoprofen sodium hydrate 204.3mg
Thiamine nitrate (vitamin B1 nitrate) 25mg
Riboflavin (vitamin B2) 5.5mg
Trehalose 590.2mg
Crystalline cellulose 100mg
Pullulan 64mg
Aspartame (L-phenylalanine compound) 64mg

[Example 8]
Fifteenth revision Japanese Pharmacopoeia Preparation of A granule and B granule according to the “Granule” section of the General Rules for Preparations and mixing them, and usually containing the following ingredients in 3 capsules (daily dose) Manufactured by the method.
<A granule>
Ibuprofen 450mg
Bromhexine hydrochloride 12mg
dl-Methylephedrine hydrochloride 60mg
Dihydrocodeine phosphate 24mg
Riboflavin (vitamin B2) 6.5mg
Anhydrous caffeine 75mg
Erythritol 973.5mg
Crystalline cellulose 200mg
Pullulan 120mg
Aminoalkyl methacrylate copolymer RS 96mg
Croscarmellose sodium 40mg
Aspartame (L-phenylalanine compound) 18mg
<B granule>
Tranexamic acid 750mg
Cremastine fumarate 1.34mg
Thiamine nitrate (vitamin B1 nitrate) 25mg
Riboflavin (vitamin B2) 5.5mg
Trehalose 590.2mg
Crystalline cellulose 100mg
Pullulan 64mg
Aspartame (L-phenylalanine compound) 64mg

[Example 9]
Thirty tablets obtained in Example 1 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 10]
30 tablets obtained in Example 2 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 11]
Thirty tablets obtained in Example 3 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 12]
Thirty tablets obtained in Example 4 and 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) were placed in a glass bottle (3K standard bottle) to prepare a pharmaceutical preparation.

[Example 13]
Twelve tablets obtained in Example 5 were packaged in aluminum PTP.

[Example 14]
Twelve tablets obtained in Example 6 were packaged in aluminum PTP.

  According to the present invention, the interaction between clemastine or a salt thereof and a xanthine derivative can be suppressed. Therefore, a pharmaceutical composition comprising clemastine or a salt thereof and a xanthine derivative having excellent storage stability can be provided.

Claims (1)

  A method for improving the storage stability of a pharmaceutical composition, which further comprises tranexamic acid or a salt thereof in a pharmaceutical composition containing clemastine or a salt thereof and caffeine.