JP5525324B2 - Loxoprofen-containing pharmaceutical preparation - Google Patents

Description

  The present invention relates to a pharmaceutical preparation comprising loxoprofen or a salt thereof and chlorpheniramine 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, for example, an anti-inflammatory / analgesic / antipyretic effect-enhancing action (Patent Document 1), carbinoxamine maleate, chlorpheniramine maleate, Examples include nasal congestion ameliorating action by combining with ketotifen fumarate, mequitazine and epinastine hydrochloride (Patent Document 2), goblet cell hyperplasia suppressing action by combining with azelastine hydrochloride and mequitazine (Patent Document 3), etc. .
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 the said patent document, the combination of a loxoprofen and various drugs is examined, and the formulation example which combined the loxoprofen and various drugs is described.

  On the other hand, chlorpheniramine or a salt thereof is a drug that has an antihistamine action and is used as a general cold medicine, a rhinitis medicine, or the like as an antihistamine component (Non-Patent Document 2, etc.) As described above, as an action obtained by combining chlorpheniramine maleate and loxoprofen, an improvement action of nasal obstruction symptoms (Patent Document 2) and an enhancement action of antihistamine action (Patent Document 6) are known. ing.

  However, it is not known whether or not loxoprofen or a salt thereof and chlorpheniramine or a salt thereof interact in the preparation.

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

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

The present inventors first examined the storage stability of a solid preparation containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof, and as a result, examined the storage stability of the loxoprofen or a salt thereof and chlorpheniramine or a salt thereof. It has been found that when a salt is mixed or formulated and stored, an interaction occurs between these compounds, and this interaction causes solidification, discoloration, and the like, resulting in a problem in stability.
Accordingly, an object of the present invention is to provide a stable solid preparation containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof.

  Therefore, the present inventors have studied to solve this problem. As a result, loxoprofen or a salt thereof, and chlorpheniramine or a salt thereof are mixed with silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve). It was found that the interaction can be suppressed by storing in the presence of a desiccant such as calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride, magnesium oxide.

That is, the present invention provides a pharmaceutical preparation comprising loxoprofen or a salt thereof, chlorpheniramine or a salt thereof, and a desiccant in a container.
The present invention further includes a step of storing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in the presence of a desiccant, wherein the interaction between loxoprofen and chlorpheniramine or a salt thereof is suppressed. The manufacturing method of the solid formulation to contain is provided.
The present invention also includes a step of storing a solid preparation containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in the presence of a desiccant, wherein the loxoprofen or a salt thereof and chlorpheniramine or a salt thereof The manufacturing method of the pharmaceutical formulation which contains the solid formulation and desiccant containing this in a container is provided.

According to the present invention, the interaction between loxoprofen or a salt thereof and chlorpheniramine or a salt thereof can be suppressed. Therefore, a solid preparation containing loxoprofen or a salt thereof and chlorpheniramine 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 chlorpheniramine 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, chlorpheniramine 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).

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

The chlorpheniramine or a salt thereof used in the pharmaceutical preparation of the present invention includes chlorpheniramine itself and a pharmaceutically acceptable salt of chlorpheniramine. Since chlorpheniramine has an asymmetric carbon, it has an optical isomer. In the present invention, it includes an optical isomer, and may be a single optical isomer or a mixture of various optical isomers. Among these, in the present invention, d-form and dl-form are preferable.
Preferable specific examples of the chlorpheniramine or a salt thereof include chlorpheniramine, chlorpheniramine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, and the like. More preferred are chlorpheniramine maleate and dl-chlorpheniramine maleate.
These are known compounds, and can be produced by known methods, or commercially available products can be used.

  The content of chlorpheniramine or a salt thereof in the pharmaceutical preparation of the present invention may be determined by appropriate examination according to the sex, age, symptom, etc. of the user, but is 0.1 to 20 mg per day. The amount that can be taken is preferred, and the amount that can be taken 0.6 to 12 mg is more preferred. In addition, when using d-chlorpheniramine maleate as chlorpheniramine or its salt, the quantity which can be taken | dosed 0.1-15 mg per day is preferable, and the quantity which can be taken | dosed 0.6-6 mg is more preferable, 1 An amount that can be taken by -5 mg is more preferred. When dl-chlorpheniramine maleate is used, the amount that can be taken from 0.5 to 20 mg per day is preferred, the amount that can be taken from 1 to 12 mg is more preferred, and the amount that can be taken from 2 to 10 mg is even more preferred.

  The content ratio of loxoprofen or a salt thereof and chlorpheniramine or a salt thereof contained in the pharmaceutical preparation of the present invention may be determined by appropriately examining according to the daily dose of each component described above, Loxoprofen or a salt thereof is preferably one containing 0.0001 to 1.5 parts by mass of chlorpheniramine or a salt thereof relative to 1 part by mass in terms of loxoprofen sodium anhydride, containing 0.0005 to 0.7 parts by mass More preferred are those containing 0.001 to 0.5 parts by mass.

Loxoprofen or a salt thereof and chlorpheniramine or a salt thereof contained in the pharmaceutical preparation of the present invention include loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in terms of convenience of administration and management of drug dosage. A solid preparation is preferred.
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.
As the solid preparation, in view of interaction inhibition, loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in the solid preparation are preferably contained so as not to contact each other, and 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) Powders or granules produced by granulating any one of loxoprofen or a salt thereof, and chlorpheniramine 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 chlorpheniramine or a salt thereof are each granulated by an appropriate method to form a granular material, a powder or a granule prepared by containing these, and the granular material are further suitable. Formulation coated by the 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 chlorpheniramine 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. As the multi-layered tablet, those in which loxoprofen or a salt thereof and chlorpheniramine or a salt thereof are located in different layers are preferable. As a multi-layered tablet having three or more layers, a layer containing loxoprofen or a salt thereof and chlorpheniramine Or it is more preferable that the layers containing the salt are positioned so as not to contact each other. In addition, the granular material manufactured by said (i) and (b) can be used as a loxoprofen or its salt, and a chlorpheniramine or its salt.
(F) A dry-coated tablet in which any one of loxoprofen or a salt thereof and chlorpheniramine 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, the granular material manufactured by said (i) and (b) can be used as a loxoprofen or its salt, and a chlorpheniramine or its salt.
The content of loxoprofen or a salt thereof in the solid preparation of the present invention is not particularly limited and may be appropriately determined according to the above-mentioned daily dose, but relative to the total mass of the solid preparation, converted to loxoprofen sodium anhydride It is preferable to contain 0.4 to 55% by mass, more preferably 0.4 to 50% by mass, even more preferably 1.2 to 30% by mass, and 1.2 to 25% by mass. It is particularly preferable to contain it. Among these, it is preferable to contain 1.2-20 mass%, it is more preferable to contain 2.4-15 mass%, and it is especially preferable to contain 2.4-12 mass%.

  The content of chlorpheniramine or a salt thereof in the solid preparation of the present invention is not particularly limited and may be appropriately determined and determined according to the above-mentioned daily dose, but chlorpheniramine or a salt thereof may be solid. It is preferable to contain 0.004-8 mass% with respect to a formulation total mass, It is more preferable to contain 0.004-1.5 mass%, It is further containing 0.02-0.8 mass% The content is preferably 0.04 to 0.7% by mass.

  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 according to 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 chlorpheniramine 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.
Moreover, 0.001-1 mass part is preferable with respect to 1 mass part of solid preparation containing loxoprofen or its salt and chlorpheniramine or its salt, and 0.004-0.4 mass part is more preferable.

  In the pharmaceutical preparation of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof and chlorpheniramine or a salt thereof, such as an antipyretic analgesic, an antihistamine, an antitussive, a noscapine, a bronchodilator, an expectorant, a hypnotic sedative , Vitamins, anti-inflammatory agents, gastric mucosal 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, ketotifen fumarate, dipheterol hydrochloride, dipheterol phosphate, diphenylpyraline hydrochloride, diphenylpyraline theocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelenamine Hydrochloride, tondylamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, mequitazine, methodirazine hydrochloride, mebhydrolina Jishiru acid salts.

  Antitussives include, for example, aloclamide hydrochloride, eprazinone hydrochloride, carbetapentane enoate, cloperastine hydrochloride, cloperastine phendizoate, codeine phosphate, dihydrocodeine phosphate, dibunato 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, and l-menthol.

Examples of the hypnotic sedative include allyl isopropyl acetyl urea, bromvalerylurea and the like.
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 anti-inflammatory agents include lysozyme chloride, glycyrrhizic acid and derivatives thereof, and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), seaprose, semi-alkaline proteinase, serrapeptase, tranexamic acid, proctase, pronase, Bromelain etc. are mentioned.

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

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

  Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyoukaku (horny lamb), fennel (yuka), turmeric (depressed gold), engosaku (yenkogyo), enmaiso (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Owaku (yellow twilight), Spruce (cherry bark), Auren (yellow ream), Onji (distant), Gajutsu (weather), valerian (deer grass), chamomile, caronin (karojin), Licorice, licorice, bellflowers, kokushi (coconut), cucumber (cucumber leaves), keigai (cocoon), keihi (cinnamon), ketsumeishi (actual child), gentian, gennoshouko (current evidence), Koubushi (Kosuke), Gooh (Gyuhuang), Goshi (Gomiko), Saishin (Spicy), Salamander (Sambu), Zion (Purple), Zykopi (Peel), Peonies (Glue), Ji Jakkou, Shajin, Shazenshi (car forerunner), Shazenso (car forerunner), Beast gall (including yutan (gum gal)), Shakyo (ginger), Giryu (land dragon), Xinyi ), Sexan (Ishizuchi), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Oiso), Chixetsu carrot (bamboo ginseng), clove (clove), chimpi (chonse), touki (to home), tokong (napping root), Nantenjitsu (southern), carrot (carrot), baimo (shellfish), bacmond (wheat) Gate winter), mint (light load), Hange (semi-summer), bankouka (banka), hampi (anti-nose), juniper (white bean), juniper (white moth), bukkuri (茯苓), button pi (peony skin), volley (Oyster), maou (mao), rokjo (deer moth) ) And their extracts (extracts, tinctures, dried extracts, etc.) and the like.

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, and anhydrous 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, etc., and 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 of storing loxoprofen or a salt thereof, chlorpheniramine 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 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 chlorpheniramine or a salt thereof can be stored in a bottle. When storing in a bottle, loxoprofen or a salt thereof and chlorpheniramine 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, plate-shaped or bag-shaped sheet type), loxoprofen or a salt thereof, and chlorpheniramine or a salt thereof in the bag. When storing in a bag, loxoprofen or a salt thereof and chlorpheniramine or a salt thereof are preferably solid preparations containing these.

  Further, 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 desiccant may be enclosed in a container. For example, a form containing a solid preparation containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in a stick package, PTP package or SP package, and a desiccant packaged in a pillow package or a stick package. More specifically, the form etc. which carry out pillow packaging of the solid formulation which carried out SP packaging or PTP packaging, and a plate-shaped or bag-shaped sheet type desiccant etc. are mentioned. Further, the pillow packaging form may be stored in a box or the like.

Since the pharmaceutical preparation of the present invention contains loxoprofen or a salt thereof, which is a kind of NSAID, and chlorpheniramine or an salt thereof having an antihistamine action, headache, toothache, pain after tooth extraction, sore throat, ear pain, Arthralgia, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain, menstrual pain, pain relief, chills, fever during fever, cold symptoms (nasal nose, nose) Stuffiness, sneezing, sore throat, chills, fever, headache, joint pain, muscle pain), symptoms of acute rhinitis, allergic rhinitis or sinusitis (sneezing, runny nose, nasal congestion, nasal discharge) Efficacy or effect on eyes, sore throat, head weight), etc., and is useful as a cold medicine or an internal medicine for rhinitis.
Further, chlorpheniramine or a salt thereof according to the pharmaceutical preparation of the present invention reduces or suppresses gastrointestinal disorders (gastric mucosal irritation, ulcer formation in the small intestine, etc.) caused by loxoprofen. Therefore, the solid preparation of the present invention containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof can be used in patients with peptic ulcer or a patient with a history of gastrointestinal tract without any risk of gastrointestinal disorders caused by loxoprofen. The salt can be taken and is useful.

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 0.584 g of loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name, Japanese Pharmacopoeia, loxoprofen sodium hydrate) and 10 mg of d-chlorpheniramine maleate (manufactured by Kongo Chemical: product) Name D-chlorpheniramine maleate) was mixed, put into a glass bottle (3K standard bottle), and stored at 60 ° C. for 1 week. Separately, 1 g of synthetic zeolite (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name MS-W1506) was further added as a desiccant and similarly stored at 60 ° C. for 1 week. For each, the state of the mixture immediately after the start of storage, 1 day, 2 days and 1 week, ie, the presence or absence of interaction, was evaluated, and the results are shown in Table 1.

  As is apparent from Table 1, the mixture of loxoprofen and chlorpheniramine that had been preserved by mixing was wet, solidified, and further discolored as a result of interaction. On the other hand, it was found that the addition of the desiccant can maintain the same state as at the start and suppress and improve the interaction.

[Test Example 2] Inhibition of loxoprofen-induced gastrointestinal damage by chlorpheniramine Using Wistar rats (Std: Wistar / ST, male, 8 weeks old, body weight 219.3 to 244.4 g), tested as 6 animals per group Carried out. Rats were fasted from the day before the test (16 hours or longer). Water intake was free up to 1 hour before the start of the test, and then water was stopped.
As a test drug, d-chlorpheniramine maleate (CM) was suspended in a 0.5% methylcellulose (MC) solution and orally administered in a predetermined amount (5, 40 mg / 5 mL / kg). In the control group, only the solvent (0.5% MC solution) was orally administered in the same volume (5 mL / kg).
One hour after administration of the test drug, loxoprofen sodium hydrate 120 mg / 2 mL saline / kg was orally administered to each group of rats to induce gastric mucosal damage. Five hours after administration of loxoprofen sodium hydrate, the rats were euthanized by cervical dislocation, the cardia was ligated, and the stomach was removed. After injecting 10 mL of 1% formalin solution into the stomach from the pyloric region and ligating the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and fixed lightly.
Evaluation of the degree of gastric mucosal damage is performed by measuring the length (mm) of individual damage (erosion) occurring in the glandular stomach portion under a stereomicroscope after incising the stomach along the large curvature. The total damage per rat was calculated as the ulcer index. The ulcer suppression rate (%) in the test drug was calculated according to the following formula. The results are shown in Table 2.

  Ulcer inhibition rate (%) = {1− (ulcer index of test drug / ulcer index of control group)} × 100

  From Table 2, it was found that d-chlorpheniramine maleate suppresses gastrointestinal disorders caused by loxoprofen.

[Production Example 1]
Loxoprofen sodium hydrate 1123.7 g (manufactured by Daiwa Pharmaceutical Co., Ltd., trade name: Japanese Pharmacopoeia Loxoprofen sodium hydrate), d-chlorpheniramine maleate 19.3 g (manufactured by Kongo Chemical Co., Ltd .: trade name D-chlorfeni maleate) Lamin), hydroxypropylcellulose 123.8 g (manufactured by Nippon Soda: trade name HPC-M), carmellose calcium 412.5 g (product name: ECG505), crystalline cellulose 2404.4 g (manufactured by Asahi Kasei Chemicals: trade name Theolas) PH-101) was put into a high-speed agitation 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 (manufactured by Taihei Kagaku Kogyo: trade name magnesium stearate (vegetable)) were introduced into a mixer (manufactured by Kotobuki: PM50 type) and mixed, and then the diameter 8 Tableting was performed using a tableting machine (manufactured by Hata Iron Works: HT-AP18SS type) equipped with a 0.0 mm punch, and 16500 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.

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

Claims (13)

  A pharmaceutical preparation comprising loxoprofen or a salt thereof, chlorpheniramine or a salt thereof, and a desiccant in a container.   A pharmaceutical preparation comprising a container containing a solid preparation containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof and a desiccant.   The pharmaceutical preparation according to claim 1 or 2, wherein the container is a bottle.   The pharmaceutical preparation according to claim 2 or 3, comprising a solid preparation containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof, and a desiccant packaged in a pillow or stick package, which is packaged in stick packaging, PTP packaging or SP packaging. .   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 It is a seed | species or 2 or more types, The pharmaceutical formulation of any one of Claims 1-4.   The pharmaceutical preparation according to any one of claims 1 to 5, wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate.   The pharmaceutical preparation according to claim 6, 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 7, wherein the chlorpheniramine or a salt thereof is dl-chlorpheniramine maleate or d-chlorpheniramine maleate.   The pharmaceutical preparation according to claim 8, comprising 0.5 to 20 mg of dl-chlorpheniramine maleate as a daily dose.   The pharmaceutical preparation according to claim 8, containing 0.1 to 15 mg of d-chlorpheniramine maleate as a daily dose.   A solid containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof with suppressed interaction, comprising the step of storing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in the presence of a desiccant Preparation method of the preparation.   The manufacturing method according to claim 11, wherein the storage is storage in a container.   A solid preparation containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof, comprising a step of storing a solid preparation containing loxoprofen or a salt thereof and chlorpheniramine or a salt thereof in the presence of a desiccant. And a desiccant in a container.