JP5896645B2 - Pharmaceutical preparation containing loxoprofen or a salt thereof - Google Patents

Description

  The present invention relates to a pharmaceutical preparation comprising loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof.

  Loxoprofen is a type of non-steroidal anti-inflammatory analgesic (NSAID), including rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, cervical-shoulder arm syndrome, toothache, acute upper respiratory inflammation, post-surgical / post-traumatic It is known as effective for anti-inflammatory, analgesic and antipyretic after tooth extraction (Non-patent Document 1).

Loxoprofen has been studied for combining with various drugs because of its excellent pharmacological action. Examples of the action obtained by the combination include enhancement of anti-inflammatory, analgesic and antipyretic effects by combining with caffeine, ethenamide and acetaminophen (Patent Document 1), carbinoxamine maleate, chlorpheniramine malee Of nasal congestion by combining with acid salt, ketotifen fumarate, mequitazine and epinastine hydrochloride (Patent Document 2), inhibitory effect on goblet cell hyperplasia by combining with azelastine hydrochloride and mequitazine (Patent Document 3), etc. Is mentioned.
Further, combining loxoprofen with bromhexine hydrochloride or ambroxol hydrochloride enhances the effect on cough symptoms (Patent Document 4) and suppresses goblet cell hyperplasia (Patent Document 5), and combines loxoprofen with bromhexine hydrochloride. There are known anti-inflammatory, analgesic and antipyretic effects (Patent Document 6).

  It is also known that loxoprofen enhances the antihistamine action of chlorpheniramine maleate and clemastine fumarate (Patent Document 6). In this patent document, combinations of loxoprofen with various drugs are studied. In addition, formulation examples in which loxoprofen and various drugs are combined are described. Furthermore, in order to suppress gastric mucosal damage caused by loxoprofen, it is known to combine one kind of cycloalkane derivatives (Patent Document 7).

Soft capsules filled with a liquid containing loxoprofen and one kind of cycloalkane derivative are known (Patent Documents 8 to 10), but it is not known whether loxoprofen and cycloalkane derivatives interact with each other. . Of course, no solution is known about the solution.
In addition, a solid preparation containing loxoprofen and a cycloalkane derivative has not been known so far.

Japanese Patent Laid-Open No. 11-139971 JP 2001-199882 A JP 2008-169193 A JP 2001-172175 A JP 2008-13542 A JP 2000-143505 A JP 2010-83882 A JP 2009-242360 A JP 2009-242365 A JP 2009-242366 A

15th Amendment Japanese Pharmacopoeia Manual C-4790-4495 Sasakawa Shoten Co., Ltd.

The present inventors first studied the storage stability of loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof in order to develop a solid preparation containing the loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof. Surprisingly, it has been found that when the salt is mixed and stored, an interaction occurs between these compounds, and this interaction causes discoloration, solidification, and the like, resulting in problems in stability.
Accordingly, an object of the present invention is to provide a stable solid preparation containing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof.

  Therefore, the present inventors further studied to solve this problem, and suppressed the interaction by storing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof in the presence of a desiccant. I found out that I can.

That is, the present invention provides a pharmaceutical preparation containing loxoprofen or a salt thereof, a cycloalkane derivative or a salt thereof, and a desiccant in a container.
The present invention also provides a pharmaceutical preparation comprising a solid preparation containing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof and a desiccant in a container.
Further, the present invention relates to loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof with suppressed interaction, characterized by storing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof in the presence of a desiccant. The manufacturing method of the solid formulation containing this is provided.
The present invention also includes a step of storing a solid preparation containing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof in the presence of a desiccant, wherein the loxoprofen or a salt thereof and a cycloalkane derivative or a mixture thereof A method for producing a pharmaceutical preparation comprising a solid preparation containing a salt and a desiccant in a container is provided.

According to the present invention, the interaction between loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof can be suppressed. Therefore, a solid preparation containing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof having excellent storage stability can be provided.
Moreover, the solid formulation with which interaction was suppressed including the loxoprofen or its salt, and the cycloalkane derivative or its salt can be provided easily and cheaply without passing through a complicated process.

The pharmaceutical preparation of the present invention contains loxoprofen or a salt thereof, a cycloalkane derivative or a salt thereof and a desiccant.
Loxoprofen or a salt thereof used in the pharmaceutical preparation of the present invention includes not only loxoprofen but also a pharmaceutically acceptable salt of loxoprofen, and further a solvate with water, alcohol or the like. 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).

  Further, the content of loxoprofen or a salt thereof may be determined by appropriate examination according to the sex, age, symptoms, etc. of the user, but the amount that can be taken 10 to 300 mg in terms of loxoprofen sodium anhydride per day The amount that can be taken 30 to 240 mg is more preferable. The amount that can be taken 60 to 180 mg is more preferable.

The cycloalkane derivative or salt thereof used in the pharmaceutical preparation of the present invention includes the following general formula (I)
_{H 2 N-CH 2 -A-} CO-O-Q (I)
[Wherein, A represents a cycloalkylene group having 5 to 8 carbon atoms, and Q represents a carboxyalkylphenyl group or a hydrogen atom. ]
Or a salt thereof (hereinafter also referred to as compound (I)) is preferred. In addition, when compound (I) has an asymmetric carbon atom, any optical isomer may be sufficient and a mixture may be sufficient.
In general formula (I), the cycloalkylene group having 5 to 8 carbon atoms in A is preferably a cyclohexylene group. The binding site in the cycloalkylene group is not particularly limited, but the 1 and 4 positions are preferred.
Q is a hydrogen atom or a carboxyalkylphenyl group, and the alkyl group in the carboxyalkylphenyl group is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably an ethyl group.

  Examples of the salt of the cycloalkane derivative include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; hydrochlorides, sulfates, nitrates, phosphates, carbonates, etc. Inorganic acid salts; organic acid salts such as tartrate, maleate, tosylate, and mesylate. In the present invention, the cycloalkane derivative or a salt thereof includes these solvates.

As compound (I), 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid or a hydrochloride thereof, and trans-4- (aminomethyl) cyclohexanecarboxylic acid is preferable. Among them, from the viewpoint of using the solid preparation of the present invention as an antipyretic analgesic or a general cold medicine, 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid monohydrochloride, trans -4- (Aminomethyl) cyclohexanecarboxylic acid is preferred.
In addition, the compound represented by the general formula (I) or a salt thereof is a known compound described in JP-B-47-23535, JP-B-59-134758, JP-B-60-6353, or the like. In addition to production by known methods, commercially available products can be used.

Further, the content of the cycloalkane derivative or a salt thereof may be appropriately determined and determined according to the sex, age, symptoms, etc. of the user, but an amount that can be taken 10 to 2000 mg per day is preferable. The amount that can be taken -1000 mg is more preferred, and the amount that can be taken 100-800 mg is more preferred.
In addition, when a cycloalkane derivative or a salt thereof is 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] -phenyl} propanoic acid monohydrochloride, 10 to 1500 mg of the compound per day The amount that can be taken is preferred, the amount that can be taken 50 to 1000 mg is more preferred, and the amount that can be taken 100 to 800 mg is more preferred. In addition, when the cycloalkane derivative or a salt thereof is trans-4- (aminomethyl) cyclohexanecarboxylic acid or a salt thereof, an amount that can be taken in an amount of 50 to 2000 mg per day in terms of a free form of the compound is preferable. The amount which can be taken -750 mg is more preferable, and the amount which can be taken 400-750 mg is more preferable.

  In addition, the content ratio of loxoprofen or a salt thereof, and a cycloalkane derivative or a salt thereof may be appropriately determined and determined according to the daily dose of each component described above, but loxoprofen or a salt thereof is One containing 0.03 to 200 parts by mass, more preferably 0.2 to 40 parts by mass of cycloalkane derivative or a salt thereof is preferable with respect to 1 part by mass in terms of anhydrous loxoprofen sodium. Those containing ˜20 parts by mass are particularly preferred.

In addition, loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof are solid preparations containing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof in terms of convenience of administration and management of a drug dose. preferable. According to the present invention, the interaction can be suppressed even in the form of such a solid preparation.
The solid preparation of the present invention can be produced and formulated based on a known method described in the 15th revision Japanese Pharmacopoeia General Rules for Preparations. Examples of the dosage form of the solid preparation include tablets, powders, granules, fine granules, pills, capsules and the like.

In the present invention, it is preferable to contain loxoprofen or a salt thereof in an amount of 0.4 to 55 mass% in terms of anhydrous loxoprofen sodium based on the total mass of the solid preparation, and more preferably 1.2 to 50 mass%. The content is preferably 1.2 to 45% by mass.
Moreover, it is preferable to contain 0.4-90 mass% of cycloalkane derivatives or its salt with respect to solid formulation total mass, It is more preferable to contain 2-70 mass%, It contains 3-60 mass%. It is more preferable to contain 4 to 55% by mass.

  As the solid preparation, in view of interaction inhibition, it is more preferable to contain loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof in the solid preparation so that they do not substantially contact each other, and are manufactured and formulated. 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 loxoprofen or a salt thereof, and a cycloalkane derivative or a salt thereof by an appropriate method, and containing the other without granulation. Etc., as well as a preparation in which the granular material is further coated by an appropriate method.
(B) Loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof are separately granulated by an appropriate method to form a granular material, and a powder or a granule prepared by containing them, and the granular material further. Formulation coated by an appropriate method.
(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 multi-layer tablet prepared so that loxoprofen or a salt thereof, and a cycloalkane derivative or a salt thereof do not contact each other, and a preparation in which the multi-layer tablet is further coated by an appropriate method. The multi-layered tablet preferably has loxoprofen or a salt thereof and a cycloalkane derivative or salt thereof positioned in different layers, and the multi-layered tablet has a layer containing loxoprofen or a salt thereof and a cycloalkane derivative. Or it is more preferable that the layers containing the salt are positioned so as not to contact each other. In addition, as the loxoprofen or a salt thereof, and the cycloalkane derivative or the salt thereof, the granular material produced in (i) or (b) above can be used.
(F) A dry-coated tablet in which any one of loxoprofen or a salt thereof, and a cycloalkane derivative or a salt thereof is arranged in a nuclear tablet, and a preparation in which the dry-coated tablet is further coated by an appropriate method. In addition, as the loxoprofen or a salt thereof, and the cycloalkane derivative or the salt thereof, the granular material produced in the above (a) or (b) can be used.

  Examples of the route of administration of the solid preparation of the present invention include oral and parenteral such as rectal and vaginal, and the solid preparation of the present invention is preferably an oral administration preparation. In addition, when administered orally, the solid preparation according to the present invention can be divided into about 1 to 4 times per day and taken before meals, between meals, after meals, and before going to bed.

  In the present invention, the desiccant is not particularly limited as long as it can suppress or improve the interaction when stored together with loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof. Also, the shape is not limited, and examples thereof include a plate-shaped or bag-shaped sheet mold, a cylinder (tablet mold), etc., and a cylinder with paper wrapping or film coating. But you can.

  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 and magnesium oxide. 1 type or 2 types or more can be mentioned, and these and activated carbon may be mixed. Among these, one or more selected from silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve) and calcium chloride are more preferable, and synthetic zeolite is particularly preferable from the viewpoint of interaction suppression.

  Various desiccants are commercially available. For example, Shiblet, MS-Tablet, MS-Serum W, Tokai Gel, Decite Kite 25, Alp sheet, Toray Chemical Co., Ltd. ) Packaged items, Dryan (registered trademark) tablets, Dryan (registered trademark) sheets, Sekawa, Allosheet, Zeosheet, Shinzo Kasei Co., Ltd., OZO Co., Ltd. OZO, IDi Co., Ltd. IDi-packing desiccant and the like.

The content of the desiccant may be determined as appropriate, but is preferably 0.05 to 35 parts by mass, more preferably 0.15 to 17 parts by mass with respect to 1 part by mass of loxoprofen or a salt thereof.
In addition, for 1 part by mass of the solid preparation containing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof, 0.001 to 1.5 parts by mass is preferable, and 0.004 to 1 part by mass is more preferable. 0.004-1 mass part is further more preferable.

  In the pharmaceutical preparation of the present invention, a drug other than loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof, for example, an antipyretic analgesic agent, an antihistamine, an antitussive, a noscapine, a bronchodilator, an expectorant, a hypnotic sedative , Vitamins, anti-inflammatory agents, gastric mucosa protective agents, anticholinergic agents, herbal medicines, Chinese herbal formulas, caffeine, xanthine components and the like may be included. These components are preferably contained in the solid preparation.

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

  Antihistamines include, for example, azelastine hydrochloride, alimemazine tartrate, istipendil hydrochloride, iproheptin hydrochloride, epinastine hydrochloride, emedastine fumarate, carbinoxamine diphenyl disulfonate, carbinoxamine maleate, clemastine fumarate. Acid salt, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine Hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelenamine hydrochloride, tondilamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethad Methylene two salicylates, mequitazine, methdilazine hydrochloride, main blanking hydro Linna Paji sill acid salts.

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

Examples of noscapine include noscapine hydrochloride and noscapine.
Examples of bronchodilators include trimethquinol hydrochloride, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl. -Methylephedrine saccharin salt, methoxyphenamine hydrochloride, etc. are 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 bromovalerylurea.
Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, sodium riboflavin phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecoba Lamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

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

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

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

  Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyoukaku (horny lamb), fennel (yuka), turmeric (depressed gold), engosaku (yenkogyo), enmaiso (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Owaku (yellow twilight), Spruce (cherry bark), Auren (yellow ream), Onji (distant), Gajutsu (weather), valerian (deer grass), chamomile, caronin (karojin), Licorice, licorice, bellflowers, kokushi (coconut), cucumber (cucumber leaves), keigai (cocoon), keihi (cinnamon), ketsumeishi (actual child), gentian, gennoshouko (current evidence), Koubushi (Kosuke), Gooh (Gyuhuang), Goshi (Gomiko), Saishin (Spicy), Salamander (Sambu), Zion (Purple), Zykopi (Peel), Peonies (Glue), Ji Jakkou, Shajin, Shazenshi (car forerunner), Shazenso (car forerunner), Beast gall (including yutan (gum gal)), Shakyo (ginger), Giryu (land dragon), Xinyi ), Sexan (Sekiyu), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Otsuchi) Chiku Ginseng (bamboo ginseng), clove (clove), chimpi (Chen), Toki (to home), Tokon (root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish mother), Bakumondou (baramon) Winter), mint (thin load), Hange (half-summer), bankouka (banka), hampi (anti-nose), juniper (white bean), juniper (white moth), bukkuri (茯苓), button pi (peony skin), volley ( Oyster), Maou (mao), Rokjo (deer moth) And herbal medicines such as these and extracts thereof (extracts, tinctures, dry extracts, etc.).

The Kampo prescription includes, for example, Kakkon-to, Katsue-yu, Koso-san, Saiko-Kei-to, Sho-saiko-to, Shosei-ryu, Mumon-tou-yu, Hanka-kopaku-to, Mao-to, and the like.
Examples of caffeine include sodium benzoate caffeine, caffeine hydrate, anhydrous caffeine, and citric acid caffeine.
Examples of the xanthine component include aminophylline, diprofylline, theophylline, proxyphylline and the like.

  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 a metal film, and a composite structure or a multilayer structure in which these members are appropriately combined. 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 loxoprofen or a salt thereof, a cycloalkane derivative or a salt thereof, and a desiccant used in the present invention in the container is not particularly limited, and any suitable means such as charging all of them into the container. This can be achieved by arranging according to

  For example, when the container is a bottle, a desiccant (preferably a cylindrical shape (tablet shape)) is placed in the bottle or stored in the back side (inner cap) of the bottle lid, and loxoprofen or The salt and the cycloalkane derivative or the salt thereof can be achieved by storing in a bottle. When storing in a bottle, loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof are preferably solid preparations containing these.

  In the case where the container is a bag, it can be achieved by storing a desiccant (preferably, a plate-type or bag-shaped sheet type), loxoprofen or a salt thereof, and a cycloalkane derivative or a salt thereof in the bag. When storing in a bag, loxoprofen or a salt thereof, and a cycloalkane derivative or a salt thereof are preferably solid preparations containing these.

  Furthermore, the solid preparation of the present invention may be once packaged by SP packaging, PTP packaging, a bag or the like, and then the packaged solid preparation and a desiccant may be enclosed in a bag. For example, a form containing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof in stick packaging, SP packaging or PTP packaging, and a desiccant packaged in pillow packaging or stick packaging. More specifically, a form in which the solid preparation packed in SP or PTP and a plate-like or bag-like sheet-type desiccant are combined in a pillow package is included. Further, the pillow packaging form may be stored in a box or the like.

  The pharmaceutical preparation of the present invention includes loxoprofen or a salt thereof, which is a kind of NSAID, and trans-4- (aminomethyl) cyclohexanecarboxylic acid having an anti-inflammatory action or a loxoprofen-induced gastric mucosal disorder inhibiting action or the like. [Trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid Since it contains cycloalkane derivatives including monohydrochloride, headache, toothache, pain after tooth extraction, sore throat, ear pain, joint pain, Neuralgia, low back pain, muscle pain, shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain, menstrual pain, pain relief, chills, antipyretic fever, cold symptoms (sore pain, chills, Fever, headache, joint pain, muscle pain, etc.) and is useful as a cold medicine, antipyretic analgesic, and the like.

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 Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 0.5 g and 3- {4- [trans-4- (aminomethyl) cyclohexyl Carbonyloxy] phenyl} propanoic acid monohydrochloride (manufactured by Daiichi Sankyo Propharma Co., Ltd .: Japan Pharmacopoeia Setraxate hydrochloride) 0.5 g was mixed, put into a glass bottle (3K standard bottle), and stored at 60 ° C.
Separately, in addition to the mixture of loxoprofen sodium hydrate and 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid monohydrochloride, a synthetic zeolite (Shinetsu Made by Kasei Kogyo Co., Ltd .: Trade name MS-W1506) 1 g was added and stored in the same manner at 60 ° C.
For each, the state of the mixture immediately after the start of storage, 1 day, 3 days, and 1 week later, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 1.

As is clear from Table 1, what was preserved by simply mixing loxoprofen sodium hydrate with 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] -phenyl} propanoic acid monohydrochloride As a result of the interaction, the mixture turned discolored 1 day after the start of storage and changed to a solidified state.
On the other hand, when a desiccant is added, the mixture is found to be less affected and discolored even after one week, and the powder state is maintained, compared to the mixture just mixed. did.

[Production Example 1]
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 1123.7 g, 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid monohydrochloride Salt (Daiichi Sankyo Propharma, trade name: Japanese Pharmacopoeia Setraxate hydrochloride) 1650 g, Hydroxypropylcellulose (Nippon Soda, trade name: HPC-M) 123.8 g, Carmellose calcium (Gotoku Pharmaceutical: trade name ECG505) ) 412.5 g, crystalline cellulose (Asahi Kasei Chemicals: trade name Theorus PH-101) 773.7 g was charged into a high-speed agitation granulator (Fukae Kogyo: FS-10 type), mixed, and then purified water 206.3 g. And kneaded. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4083.7 g of this sized product and 41.3 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 0.0 mm punch, and tablets each having a mass of 250 mg were obtained.

[Production Example 2]
Loxoprofen sodium hydrate (manufactured by Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate) 1123.7 g, trans-4- (aminomethyl) cyclohexanecarboxylic acid (manufactured by Daiichi Sankyo Propharma: trade name, Japanese Pharmacy) Way Tranexamic acid (2200 g), hydroxypropyl cellulose (Nippon Soda: trade name HPC-M) 123.8 g, carmellose calcium (product name: ECG505), 412.5 g, crystalline cellulose (Asahi Kasei Chemicals: trade name Theolas) PH-101) 223.7 g was added to a high-speed stirring granulator (Fukae Kogyo Co., Ltd .: FS-10 type) and mixed, and then 206.3 g of purified water was added and kneaded. The granulated product was put into a fluidized bed dryer (Freund Sangyo: FLO-5 type), dried, and then granulated using a granulator (Okada Seiko: ND-10 type). 4083.7 g of this sized product and 41.3 g of magnesium stearate (trade name: magnesium stearate (vegetable)) manufactured by Taihei Kagaku Kogyo Co., Ltd. were introduced into a blender (manufactured by Kotobuki: PM50 type) and mixed. Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 0.0 mm punch, and tablets each having a mass of 250 mg were obtained.

[Example 1]
Thirty tablets obtained in Production 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 2]
Thirty tablets obtained in Production 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.

  According to the present invention, the interaction between loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof can be suppressed. Therefore, a solid preparation containing loxoprofen or a salt thereof and a cycloalkane derivative or a salt thereof having excellent storage stability can be provided.

Claims (13)

Loxoprofen or a salt thereof, general formula (I)
_{H 2 N-CH 2 -A-} CO-O-Q (I)
[Wherein, A represents a cycloalkylene group having 5 to 8 carbon atoms, and Q represents a carboxyalkylphenyl group or a hydrogen atom. ]
Compound or pharmaceutical formulation comprising a salt, and the desiccant in the container in represented. Loxoprofen or a salt thereof, and general formula (I)
_{H 2 N-CH 2 -A-} CO-O-Q (I)
[Wherein, A represents a cycloalkylene group having 5 to 8 carbon atoms, and Q represents a carboxyalkylphenyl group or a hydrogen atom. ]
The pharmaceutical formulation which contains the solid formulation containing the compound or its salt represented by these, and a desiccant in a container. Loxoprofen or a salt thereof and general formula (I)
_{H 2 N-CH 2 -A-} CO-O-Q (I)
[Wherein, A represents a cycloalkylene group having 5 to 8 carbon atoms, and Q represents a carboxyalkylphenyl group or a hydrogen atom. ]
The pharmaceutical formulation which contains the solid formulation and desiccant which contain the compound or its salt represented by these so that it may not contact substantially mutually. The compound represented by the general formula (I) or a salt thereof is 3- {4- [trans-4- (aminomethyl) cyclohexylcarbonyloxy] phenyl} propanoic acid or a hydrochloride thereof, or trans-4- (aminomethyl) 4. The pharmaceutical preparation according to any one of claims 1 to 3, which is cyclohexanecarboxylic acid. The pharmaceutical preparation according to any one of claims 1 to 4 , wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate. The pharmaceutical preparation according to claim 5 , comprising loxoprofen sodium hydrate in an amount of 10 to 300 mg per day in terms of anhydrous loxoprofen sodium. The pharmaceutical preparation according to any one of claims 1 to 6 , comprising 10 to 2000 mg of the compound represented by the general formula (I) or a salt thereof as a daily dose. The desiccant is selected from the group consisting of silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride and magnesium oxide 1 the pharmaceutical formulation of claim 1 to 7 any one of claims is kind or two or more. The pharmaceutical preparation according to any one of claims 1 to 8 , wherein the container is a bottle. A solid preparation containing loxoprofen or a salt thereof and a compound represented by the general formula (I) or a salt thereof in stick packaging, PTP packaging or SP packaging, and a desiccant packaged in pillow packaging or stick packaging. 1 to 9. The pharmaceutical preparation according to any one of 9 to 9 . Loxoprofen or a salt thereof, and general formula (I)
_{H 2 N-CH 2 -A-} CO-O-Q (I)
[Wherein, A represents a cycloalkylene group having 5 to 8 carbon atoms, and Q represents a carboxyalkylphenyl group or a hydrogen atom. ]
The compound represented by or a salt thereof, characterized in that it comprises a step of storing a drying agent presence, or a salt thereof loxoprofen interaction is inhibited or a salt thereof and the general formula (I) The manufacturing method of the solid formulation containing this. The production method according to claim 11 , wherein the preservation is preservation in a container. Loxoprofen or a salt thereof, and general formula (I)
_{H 2 N-CH 2 -A-} CO-O-Q (I)
[Wherein, A represents a cycloalkylene group having 5 to 8 carbon atoms, and Q represents a carboxyalkylphenyl group or a hydrogen atom. ]
Containing loxoprofen or a salt thereof and a compound represented by the general formula (I) or a salt thereof, comprising a step of storing a solid preparation containing the compound represented by the formula or a salt thereof in the presence of a desiccant A method for producing a pharmaceutical preparation comprising a solid preparation and a desiccant in a container.