JP5794807B2 - Pharmaceutical composition containing loxoprofen and clemastine - Google Patents

Description

  The present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof and clemastine or a salt thereof.

  Loxoprofen or its salt is a kind of non-steroidal anti-inflammatory analgesic (NSAID), rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, neck-shoulder arm syndrome, toothache, acute upper respiratory tract inflammation, after surgery It is known as effective for anti-inflammatory, analgesic and antipyretic after trauma and tooth extraction (Non-patent Document 1).

  On the other hand, clemastine or a salt thereof has an antihistamine action, and is a drug used as a general cold medicine, a rhinitis medicine or the like as an antihistamine component (Non-patent Document 2).

  Loxoprofen or a salt thereof 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, ketotifen fumarate , Improvement of nasal congestion by combining with mequitazine and epinastine hydrochloride (Patent Document 2), inhibition of goblet cell hyperplasia by combining with azelastine hydrochloride and mequitazine (Patent Document 3), bromhexine hydrochloride and ambrox A potentiating effect on cough symptoms (Patent Document 4) and an inhibitory effect on goblet cell hyperplasia (Patent Document 5) are known.

A combination of two components of loxoprofen or a salt thereof and clemastine or a salt thereof is already known. Specifically, an antihistaminic action enhancing action (Patent Document 6) by combining loxoprofen and clemastine fumarate is known.
Furthermore, Patent Document 6 discloses that the analgesic action is enhanced in the combination of loxoprofen and chlorpheniramine maleate, which is also known to have an antihistaminic action enhancing action.

  However, nothing is known about the enhancement of analgesic action when loxoprofen or a salt thereof and clemastine or a salt thereof are combined.

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 Co., Ltd. 231-232

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

  Therefore, the present inventor has intensively studied, and the combination of loxoprofen or a salt thereof and clemastine or a salt thereof has a particularly excellent analgesic action that cannot be predicted from the combination of loxoprofen and chlorpheniramine, and is used as a medicine. I found it useful.

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

  A combination of loxoprofen or a salt thereof and clemastine or a salt thereof exhibits excellent analgesic action. Therefore, according to the present invention, a pharmaceutical composition having an excellent pharmacological action can be provided.

  Moreover, clemastine or a salt thereof has an inhibitory action against gastrointestinal disorders caused by loxoprofen or a salt thereof. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition having excellent pharmacological action and excellent safety in which gastrointestinal disorders caused by loxoprofen or a salt thereof are suppressed.

  “Loxoprofen or a salt thereof” used in the pharmaceutical composition of the present invention includes not only loxoprofen, but also a pharmaceutically acceptable salt of loxoprofen, and further, loxoprofen or a pharmaceutically acceptable salt thereof and water, alcohol, etc. Solvates are included. These are known compounds, and can be produced by known methods, or commercially available products can be used. In the present invention, loxoprofen or a salt thereof is preferably loxoprofen sodium hydrate (chemical name: Monosodium 2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoate dihydrate).

The content of loxoprofen or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, 10 to 300 mg, more preferably 30 to 240 mg, particularly preferably 60 to 180 mg in terms of loxoprofen sodium anhydride can be contained per day.
In the present invention, loxoprofen or a salt thereof is preferably contained in an amount of 0.4 to 50% by mass, more preferably 0.8 to 25% by mass in terms of anhydrous loxoprofen, relative to the total mass of the pharmaceutical composition. 1.2 to 20% by mass is more preferable, 1.6 to 15% by mass is further more preferable, and 2.0 to 12% by mass is particularly preferable.

  In the present invention, “clemastine or a salt thereof” includes not only clemastine itself but also a pharmaceutically acceptable salt of clemastine. Specific examples of clemastine or a salt thereof include, for example, clemastine, clemastine fumarate, etc. In the present invention, clemastine fumarate is preferred. These are known compounds, and can be produced by known methods, or commercially available products can be used.

The content of clemastine or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, 0.01 to 5 mg, more preferably 0.05 to 3 mg, more preferably 0.1 to 2 mg, particularly preferably 0.2 to 2 mg of clemastine free form per day It can be shown. In addition, 1.34 mg of clemastine fumarate corresponds to 1 mg as a free form of clemastine.
In the present invention, clemastine or a salt thereof is preferably contained in an amount of 0.008 to 0.4 mass% in terms of free form of clemastine with respect to the total mass of the pharmaceutical composition, and 0.01 to 0.2 mass% is contained. It is more preferable to contain 0.015 to 0.15% by 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 determined by appropriate examination according to the daily dose of each component described above. Or it is preferable to contain 0.0006 to 300 parts by mass of clemastine or a salt thereof in terms of free form of clemastine with respect to 1 part by mass of loxoprofen sodium anhydride in terms of its salt, or 0.001 to 0.5 parts by mass More preferably, 0.0012 to 0.1 parts by mass is more preferable, and 0.002 to 0.03 parts by mass is particularly preferable.

The pharmaceutical composition of the present invention can be produced by, for example, a known method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations. The dosage form is not particularly limited, and may be any of solid, semi-solid, and liquid shapes, and may be a shape usually used in pharmaceuticals depending on the purpose of use and the like. it can. Specifically, for example, tablets (including chewable tablets, effervescent tablets, orally disintegrating tablets), troches, drops, hard capsules, soft capsules, granules, fine granules, powders, pills, dry syrup Solid preparations such as suppositories, suppositories, poultices, plasters; lozenges, chewing gums, jelly agents, jelly drops, whipped agents, ointments, creams, foams, inhalers, nazar gels, etc. Semi-solid preparations; syrups, drinks, suspensions, spirits, liquids, eye drops, aerosols, sprays, sprays, and other liquid preparations, etc. It can be made into a dosage form.
In the present invention, it is preferably a solid preparation containing loxoprofen or a salt thereof and clemastine or a salt thereof from the viewpoints of ease of administration and management of drug dosage, etc. Tablets, capsules, pills, granules More preferably, it is a solid preparation selected from the group consisting of powders and fine granules, and tablets and capsules are particularly preferable.

  Examples of the route of taking the pharmaceutical composition of the present invention include oral and parenteral such as rectal and vaginal administration, and oral administration is preferred. The pharmaceutical composition of the present invention can be taken, for example, before meals, between meals, after meals, before going to bed, etc., divided into about 1 to 4 times per day.

  In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof, clemastine or a salt thereof, such as an antipyretic analgesic agent, an antihistamine, an antitussive agent, a noscapine, a bronchodilator, an expectorant, a hypnotic sedative, It may contain one or more selected from the group consisting of vitamins, anti-inflammatory agents, gastric mucosa protective agents, anticholinergics, herbal medicines, Chinese herbal formulas, caffeine, xanthine components and the like.

  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, 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 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, 1-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, 1-methylephedrine saccharin salt, dl-methylephedrine saccharin. Examples thereof include salts, pseudoephedrine hydrochloride, pseudoephedrine sulfate, methoxyphenamine hydrochloride, and the like.

  As an expectorant, for example, ambroxol hydrochloride, ammonia fennel, ethylcysteine hydrochloride, ammonium chloride, carbocysteine, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, bromhexine hydrochloride, methylcysteine hydrochloride, Examples thereof include l-menthol and lysozyme hydrochloride.

Examples of the hypnotic sedative include allyl isopropyl acetyl urea and bromovalerylurea.
Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B ₁₂ , vitamin C, hesperidin and derivatives thereof, and salts thereof (for example, thiamine, thiamine chloride hydrochloride, Thiamine nitrate, dicetiamine hydrochloride, sethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octothiamine, chicotiamine, thiamine disulfide, bisibutamine, bisbenchamine, prosultiamine, benfotiamine, riboflavin, riboflavinline Acid ester, riboflavin butyrate, sodium riboflavin phosphate, panthenol, pantethine, calcium pantothenate, sodium pantothenate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, mecoba Lamin, ascorbic acid, sodium ascorbate, calcium ascorbate, hesperidin, etc.).

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

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

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

  Herbal medicines include, for example, akamegashiwa (red buds), asenyaku (asenyaku), inyoukaku (horny lamb), fennel (yuka), turmeric (depressed gold), engosaku (yenkogyo), enmaiso (extended herb), ogon (yellow jade) ), Ousei (yellow spirit), Owaku (yellow twilight), Spruce (cherry bark), Auren (yellow ream), Onji (distant), Gajutsu (weather), valerian (deer grass), chamomile, caronin (karojin), Licorice, licorice, bellflowers, kokushi (coconut), cucumber (cucumber leaves), keigai (cocoon), keihi (cinnamon), ketsumeishi (actual child), gentian, gennoshouko (current evidence), Koubushi (Kosuke), Gooh (Gyuhuang), Goshi (Gomiko), Saishin (Spicy), Salamander (Sambu), Zion (Purple), Zykopi (Peel), Peonies (Glue), Ji Jakkou, Shajin, Shazenshi (car forerunner), Shazenso (car forerunner), Beast gall (including yutan (gum gal)), Shakyo (ginger), Giryu (land dragon), Xinyi ), Sexan (Ishizuchi), Senega, Senkyu (Ryukyu), Zenko (Mae-Hu), Senburi (Senshu), Sojutsu (蒼朮), Sohakuhi (Mulberry white skin), Soyo (Soba), Taisan (Oiso), Chixetsu carrot (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 (Oysters), maou (mao), lokjo ( Mushroom) Crude drugs and extracts thereof such as (extract, tincture, dry extract, etc.) and the like.

  As Kampo prescriptions, for example, Kakonto (Kakkontoyu), Keishito (Katsurayu), Kousosan (Kososan), Psychokeito (Saiko Keitou), Shosai Koto (Koshibakoto), Shosei Ryuto (Sho Blue) Ryuyu), Bakumondou (Bakumon Fuyu), Hangekou Bokuto (Half Summer Kobuke), Maoutou (Maoyu), and the like.

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

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

  In addition, as a pharmaceutical composition of this invention, things other than the following (a) are preferable.

(A) A tablet containing loxoprofen sodium dihydrate 60 mg (converted as an anhydride), clemastine fumarate 5 mg, magnesium stearate 7 mg, crystalline cellulose 60 mg, starch 205 mg, and lactose 13 mg.

Since the pharmaceutical composition of the present invention has an excellent analgesic action as shown in Test Example 1 below, it is clearly effective for various diseases and symptoms accompanied by pain.
Therefore, the pharmaceutical composition of the present invention is preferably an analgesic composition containing loxoprofen or a salt thereof and clemastine or a salt thereof, and more specifically, headache, toothache, pain after extraction, sore throat, ear One or more pain relief selected from pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain, and trauma pain; throat pain, headache Alleviation of one or more symptoms selected from joint pain and muscle pain (in addition, the “throat pain” includes sore throat and acute rhinitis, allergic rhinitis or sinusitis as symptoms of cold) (It includes throat pain as a symptom due to the above. Also, “headache”, “joint pain” and “muscle pain” include these symptom as cold symptoms.) Available to:
Moreover, as a suitable specific example of the pharmaceutical composition of this invention, 1 or more types chosen from the group which consists of the following composition (A)-(C):
(A) Headache, toothache, pain after extraction, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, shoulder pain, bruise pain, fracture pain, containing loxoprofen or a salt thereof and clemastine or a salt thereof One or more pain-relieving compositions selected from pain, menstrual pain (menstrual pain) and trauma pain,
(B) Alleviation of one or more symptoms selected from loxoprofen or a salt thereof and clemastine or a salt thereof selected from sore throat, headache, joint pain and muscle pain (throat pain as various symptoms of cold) , Including relief of one or more symptoms selected from headache, joint pain and muscle pain), and (C) relief of throat pain containing loxoprofen or a salt thereof and clemastine or a salt thereof (Including relief of sore throat as various symptoms due to acute rhinitis, allergic rhinitis or sinusitis), and the above composition (B) is particularly preferable.

Loxoprofen is a kind of NSAID and causes gastrointestinal disorders (gastric mucosal disorder, ulceration, etc.) as a side effect. As specifically disclosed in Test Example 2 below, clemastine or a salt thereof is And having an inhibitory action on gastrointestinal disorders caused by the loxoprofen, particularly about 1 part by mass of loxoprofen or a salt thereof in about 140 parts by mass in terms of anhydrous loxoprofen sodium, and about 0. Gastrointestinal disorders when administered in combination at a ratio of 5 parts by weight or more, more preferably about 1 part by weight or more, even more preferably 1 to 200 parts by weight, particularly preferably 1 to 8.5 parts by weight It was found that the inhibitory action is significant.
Therefore, the pharmaceutical composition of the present invention containing loxoprofen or a salt thereof and clemastine or a salt thereof has an advantageous effect that the gastrointestinal disorder caused by loxoprofen or a salt thereof is suppressed and thus has excellent safety.
In addition, even patients with peptic ulcers that have been contraindicated for drugs containing loxoprofen and those with a history of peptic ulcers that have been treated with caution may be safely taken. The pharmaceutical composition of the present invention comprising loxoprofen or a salt thereof and clemastine or a salt thereof is a pharmaceutical composition for administration to a patient suffering from peptic ulcer and / or a person with a history of peptic ulcer. Can also be suitably used.
Furthermore, according to the present invention, aluminoprofen, ampiroxicam, ampenac, ibuprofen, indomethacin, etodolac, epilysole, oxaprozin, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib, thiaprofenic acid containing clemastine or a salt thereof as an active ingredient , Non-steroidal anti-inflammation such as, thiramide, tenoxicam, tolfenamic acid, nabumetone, naproxen, piroxicam, pranoprofen, flufenamic acid, flurbiprofen, progouritacin, mefenamic acid, meloxicam, mofezolac, loxoprofen and lornoxicam and their salts Reducing or suppressing gastrointestinal disorders (for example, NSAID ulcers) caused by analgesics (preferably loxoprofen or a salt thereof) It can be provided.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
[Test Example 1] Analgesic test The pain threshold value of the right hind leg of a 5-6 week-old Wistar male rat (body weight 102.7-120.5 g) was measured and defined as a "pre-inflammation pain threshold value".
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: d-chlorpheniramine maleate single administration group (hereinafter referred to as “CM alone”)
d-Chlorpheniramine maleate was administered at a dose of 1 mg / kg body weight dissolved or suspended in a 0.5% methylcellulose solution.
3: Two-component combination administration group of loxoprofen sodium hydrate and d-chlorpheniramine maleate (hereinafter referred to as “LX + CM”)
Loxoprofen sodium hydrate was dissolved or suspended in 0.5% methylcellulose solution at a dose of 0.1 mg / kg body weight and d-chlorpheniramine maleate at a dose of 1 mg / kg body weight. .

4: 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.
5: 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.
6: 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.
7: 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

  Furthermore, in order to evaluate the enhancement of analgesic action by combining with loxoprofen sodium hydrate, the two-component combination administration groups (“LX + CM”, “LX + CF (3 mg / kg)” and “LX + CF (30 mg / kg)”) Shows the rate of increase in pain improvement compared to the corresponding group of antihistamines alone (“CM alone”, “CF alone (3 mg / kg)” and “CF alone (30 mg / kg)”). Was calculated according to the following formula.

Increased rate of analgesic activity = average value of pain improvement rate in the two-component combination administration group / average value of pain improvement rate in the single administration group of the antihistamine

Four rats were used for each test drug administration group.
The results are shown in Table 1. The pain improvement rate was expressed as an average value ± standard error for each group.

From the test results shown in Table 1, in the combination of loxoprofen sodium hydrate and d-chlorpheniramine maleate (group 3), the single administration group (group 2) of d-chlorpheniramine maleate and In comparison, almost no increase in pain improvement rate was observed (an increase of about 1.4 times).
On the other hand, the combination of loxoprofen sodium hydrate and clemastine fumarate (groups 5 and 7) was compared with the corresponding single administration group of clemastine fumarate (groups 4 and 6 respectively). An increase in pain improvement rate of more than about 30 times was observed (about 32 times in the fifth group and about 34 times in the seventh group).
This indicates that the combination of loxoprofen sodium hydrate and clemastine fumarate has an enhanced analgesic effect that cannot be expected from the combination of loxoprofen sodium hydrate and d-chlorpheniramine maleate. It became clear that.
Further, it was revealed that the combination of loxoprofen sodium hydrate and clemastine fumarate has an excellent analgesic action (group 5 pain improvement rate: about 41%, group 7 pain improvement rate: About 68%).

  From the above test results, by combining loxoprofen or a salt thereof and clemastine or a salt thereof, an extremely excellent analgesic effect that cannot be expected from a combination of loxoprofen or a salt thereof and chlorpheniramine or a salt thereof is obtained. It became clear that it was played.

[Test Example 2] Loxoprofen-induced gastrointestinal tract disorder inhibitory test Using 8-week-old Wistar male rats, the test drug administration group and the solvent administration group (control group) were each tested as 4 to 8 animals per group. Rats were fasted at least 16 hours before the start of the study. Water intake was free up to 1 hour before the start of the test, and then water was stopped.
As a test drug, 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 body weight).
One hour after administration of the test drug or solvent, loxoprofen sodium hydrate 120 mg / 2 mL physiological saline / kg body weight was orally administered to induce gastric mucosal damage. Five hours after administration of loxoprofen sodium hydrate, the rats were euthanized by cervical dislocation, the cardia was ligated, and the stomach was removed. After injecting 10 mL of 1% formalin solution into the stomach from the pyloric region and ligating the pyloric region, the entire stomach was immersed in the formalin solution for about 20 minutes and fixed lightly.

  Evaluation of the degree of gastric mucosal damage is performed by measuring the length (mm) of individual damage (erosion) occurring in the glandular stomach portion under a stereomicroscope after incising the stomach along the large curvature. The total damage per rat was taken as the ulcer index, and the ulcer index (average value ± standard error) was calculated for each group administered with the test drug and the solvent administration group. Further, according to the following formula, the ulcer suppression rate (%) by the test drug was calculated when the average value of the ulcer index of the solvent administration group was 100%.

  Ulcer inhibition rate (%) = (average value of ulcer index in solvent administration group−average value of ulcer index in test drug administration group) / average value of ulcer index in solvent administration group × 100

  The results are shown in Table 2. The ulcer index was expressed as an average value ± standard error for each group.

  As apparent from Table 2, at least 1 mg / kg of clemastine fumarate (for clemastine) was observed for gastric mucosal damage caused by administration of 120 mg / kg of loxoprofen sodium hydrate (about 106 mg / kg in terms of loxoprofen sodium anhydride). Administration (ie, about 0.75 mg / kg in terms of free form) (ie, the combination ratio is about 141 parts by weight of loxoprofen or its salt in terms of anhydrous loxoprofen sodium, and clemastine or its salt is a free form of clemastine) It became clear that it can be suppressed by about 1 part by mass).

  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.

[Example 1]
Tablets containing the following ingredients in 9 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg hydroxypropylcellulose 72.9 mg
Carmellose calcium 243mg
Crystalline cellulose 1884.16mg
Magnesium stearate 24.3mg

  For adult male (30 years old) complaining of various symptoms associated with colds (sore throat, headache, joint pain and muscle pain) with consent, 3 tablets of Example 1 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 2]
Tablets containing the following components in 6 tablets (daily dose) were produced by a conventional method in accordance with the section of “Tablets” of the 15th revised Japanese Pharmacopoeia General Rules for Preparations.
Loxoprofen sodium hydrate (manufactured by Yamato Pharmaceutical Co., Ltd .: trade name Japanese Pharmacopoeia Loxoprofen sodium hydrate) 204.3mg
Clemastine fumarate (manufactured by Daito: trade name clemastine fumarate) 1.34 mg tranexamic acid 750 mg
dl-Methylephedrine hydrochloride 60mg
Bromhexine hydrochloride 12mg
Dihydrocodeine phosphate 24mg
Thiamine nitrate (vitamin B1 nitrate) 25mg
Riboflavin (vitamin B2) 12mg
Trehalose 600mg
Crystalline cellulose 467.36mg
Macrogol 6000 60mg
Croscarmellose sodium 80mg
Polyvinyl alcohol 1mg
Light anhydrous silicic acid 24mg
Hardened oil 65mg
Magnesium stearate 44mg

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

Claims (9)

An analgesic pharmaceutical composition comprising loxoprofen or a salt thereof and clemastine or a salt thereof for alleviating one or more cold symptoms selected from sore throat, headache, joint pain and muscle pain A pharmaceutical composition to be used .   The pharmaceutical composition according to claim 1, wherein the loxoprofen or a salt thereof is loxoprofen sodium hydrate.   The pharmaceutical composition according to claim 1 or 2, wherein loxoprofen or a salt thereof is contained in an amount of 10 to 300 mg per day in terms of anhydrous loxoprofen sodium.   The pharmaceutical composition according to any one of claims 1 to 3, wherein clemastine or a salt thereof is clemastine fumarate.   The pharmaceutical composition according to any one of claims 1 to 4, comprising clemastine or a salt thereof as a daily dose of 0.01 to 5 mg in terms of clemastine free form. The pharmaceutical composition according to any one of claims 1 to 5 , which is for administration to a person suffering from peptic ulcer and / or a person with a history of peptic ulcer. An analgesic potentiator comprising loxoprofen or a salt thereof and clemastine or a salt thereof. The agent according to claim 7, which is used for alleviating one or more symptoms selected from sore throat, headache, joint pain and muscle pain. The agent according to claim 8, wherein one or more symptoms selected from sore throat, headache, joint pain and muscle pain are symptoms of cold.