JP2010126476A - Pharmaceutical composition containing loxoprofen - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new means for ameliorating or suppressing digestive tract disorder caused by loxoprofen. <P>SOLUTION: The pharmaceutical composition contains loxoprofen or its salt and copper chlorophyllin or its salt. Preferably, the loxoprofen or its salt is loxoprofen sodium hydrate. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition containing loxoprofen.

Loxoprofen is a non-steroidal anti-inflammatory analgesic (NSAID), rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, neck-shoulder arm syndrome, toothache, acute upper respiratory tract, post-surgical / post-traumatic It is known as effective for anti-inflammatory, analgesic and antipyretic after tooth extraction (Non-patent Document 1).
In addition, loxoprofen is considered less likely to cause gastrointestinal disorders (gastric mucosal irritation, ulcer formation in the small intestine, etc.) as a side effect than other NSAIDs such as ketoprofen, naproxen, and indomethacin. However, in fact, loxoprofen is not completely free from gastrointestinal disturbances, and various measures for reducing gastrointestinal disorders caused by loxoprofen have been studied. For example, a composition in which loxoprofen is combined with a herbal medicine (Patent Document 1), a proton pump inhibitor (Patent Document 2), or an antacid (Patent Document 3) having a gastric / gastric mucosa protecting action is known.

On the other hand, copper chlorophyllin sodium, which is a kind of copper chlorophyllin salt, is known to suppress pepsin activity in gastric juice and promote healing of the ulcer wound surface by granulation proliferation action (Non-Patent Documents 2 and 3). . In addition, it is known to be used for removing bad breath based on the deodorizing action.
However, it is not known how the action on the digestive tract changes when copper chlorophyllin and loxoprofen are used in combination.
That is, it is not known that copper chlorophyllin or a salt thereof reduces gastrointestinal disorders caused by loxoprofen, and further, a pharmaceutical composition containing loxoprofen and copper chlorophyllin or a salt thereof is not known.
JP 2004-161667 A Special table 2007-522217 gazette JP 2006-52210 A Fifteenth revised Japanese Pharmacopoeia explanation book Yodogawa Shoten Co., Ltd. C-4790-4759 Clinical Gastroenterology, 2,663 (1954) J. et al. Lab. Clin. Med. , 29, 241 (1944)

  An object of the present invention is to provide a new means for reducing or suppressing a digestive tract disorder caused by loxoprofen.

  As a result of diligent research on the reduction and suppression of the expression of gastrointestinal disorders of loxoprofen, the present inventors can reduce or suppress the gastrointestinal disorders caused by loxoprofen by adding copper chlorophyllin or a salt thereof to loxoprofen or a salt thereof. The present invention has been completed.

That is, the present invention provides a pharmaceutical composition containing loxoprofen or a salt thereof and copper chlorophyllin or a salt thereof.
Moreover, this invention provides the reduction or suppression agent of the digestive tract disorder | damage | failure resulting from loxoprofen or its salt which uses copper chlorophyllin or its salt as an active ingredient.

  As will be apparent from the Examples below, copper chlorophyllin reduces gastrointestinal disorders caused by loxoprofen. Therefore, by using a pharmaceutical composition containing loxoprofen or a salt thereof and copper chlorophyllin or a salt thereof, there is no risk of gastrointestinal tract disorder, and an excellent NSAID effect of loxoprofen is exhibited, and an excellent anti-pepsin of copper chlorophyllin Since it can also have an effect | action, a bad breath removal effect, etc., it can become a very outstanding pharmaceutical composition.

The present invention relates to a pharmaceutical composition containing loxoprofen or a salt thereof and copper chlorophyllin or a salt thereof.
The loxoprofen or a salt thereof contained in the pharmaceutical composition 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 ones and can be produced by a known method, or commercially available ones 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 proportion of loxoprofen or a salt thereof contained in the pharmaceutical composition of the present invention may be determined by appropriate examination according to the daily dose described below, but in terms of loxoprofen sodium anhydride relative to the whole pharmaceutical composition. 1-70 mass% is preferable, 5-60 mass% is still more preferable, and 7-50 mass% is especially preferable.

  The copper chlorophyllin or a salt thereof contained in the pharmaceutical composition of the present invention includes not only copper chlorophyllin but also a pharmaceutically acceptable salt of copper chlorophyllin, and further a solvate with water, alcohol or the like. These are known ones and can be produced by a known method, or commercially available ones can be used. In the present invention, suitable examples of copper chlorophyllin or a salt thereof include copper chlorophyllin alkali metal salts such as copper chlorophyllin sodium and copper chlorophyllin potassium. Only one type of copper chlorophyllin sodium and copper chlorophyllin potassium may be used, or two types may be used in combination.

  The proportion of copper chlorophyllin or a salt thereof contained in the pharmaceutical composition of the present invention may be appropriately determined and determined according to the daily dose described later, but is 1 to 70% by mass with respect to the entire pharmaceutical composition. Is preferable, 5-60 mass% is still more preferable, and 7-50 mass% is especially preferable.

  The compounding ratio of loxoprofen or a salt thereof and copper chlorophyllin or a salt thereof in the pharmaceutical composition of the present invention is 0.001 to 10 parts by mass of copper chlorophyllin or a salt thereof relative to 1 part by mass of loxoprofen sodium anhydride. Is preferable, 0.01-5 mass parts is more preferable, 0.1-1 mass part is further more preferable.

The dose of the pharmaceutical composition of the present invention may be appropriately determined and determined. However, in the case of oral administration, loxoprofen or a salt thereof is preferably 30 to 180 mg in terms of loxoprofen sodium anhydride as a daily dose. 60-180 mg is more preferable.
The daily dose of copper chlorophyllin or a salt thereof is preferably 5 to 200 mg, more preferably 10 to 120 mg. These dosages can be appropriately increased or decreased depending on age, sex, symptoms, etc., and may be taken in 1 to 4 times a day.

  In the pharmaceutical composition of the present invention, as a pharmaceutical ingredient, a drug other than loxoprofen or a salt thereof and copper chlorophyllin or a salt thereof, for example, an antipyretic analgesic, 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.

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

  Antihistamines include, for example, azelastine hydrochloride, isothipentyl hydrochloride, iproheptin hydrochloride, clemastine fumarate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, Tondylamine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyl disulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocrate, mebhydrolinapadisyl Acid salt, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine male And phosphate, mequitazine, epinastine hydrochloride, difeterol phosphate and the like.

  Antitussives include, for example, aloclamide hydrochloride, cloperastine hydrochloride, carbetapentane citrate, tipepidine citrate, dibutate sodium, dextromethorphan hydrobromide, dextromethorphan / phenolphthaline salt, tipepidine hibenz And acid salts, cloperastine phendizoate, codeine phosphate, dihydrocodeine phosphate, dimethylmorphane phosphate, and eprazinone hydrochloride.

  Examples of noscapine include noscapine hydrochloride and noscapine.

  Examples of bronchodilators include, for example, methylephedrine, dl-methylephedrine hydrochloride, l-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, trimethquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, Examples thereof include pseudoephedrine hydrochloride and pseudoephedrine sulfate.

  As an expectorant, for example, potassium guaiacol sulfonate, guaifenesin, potassium cresol sulfonate, ammonium chloride, l-menthol, ammonia fennel, ethylcysteine hydrochloride, methylcysteine hydrochloride, bromhexine hydrochloride, ambroxol hydrochloride And carbocysteine.

  Examples of the hypnotic sedative include bromvalerylurea and allylisopropylacetylurea.

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

  Anti-inflammatory agents include lysozyme chloride, serrapeptase, bromelain, semi-alkaline proteinase, pronase, seaprose, proctase, glycyrrhizic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate), tranexamic acid, etc. Is mentioned.

As gastric mucosa protective agents, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate (aluminum glycinate), aluminum hydroxide gel, aluminum hydroxide / magnesium carbonate Mixed dried gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium hydroxide / potassium aluminum sulfate coprecipitation product, magnesium carbonate, metasilicic acid Examples thereof include magnesium aluminate, aldioxa, methylmethionine sulfonium chloride, sucralfate, cetraxate hydrochloride, sofalcone, gefarnate, and teprenone.
Anticholinergic drugs include oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, scopolamine hydrobromide, datsura extract, tipidium bromide, methyl atropine bromide, methyl anisotropin bromide, methyl scopolamine bromide, methyl-1- Hyoscyamine bromide, methylbenactidium bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna extract, belladonna alkaloid, belladonna total alkaloid, iodopropamide, diphenylpiperidinomethyldioxolane iodide, funnel extract, funnel root, funnel root total Examples include alkaloid citrate.

  Herbal medicines include Akamegashiwa (red buds), Asenyaku (Asenyaku), Yinakukaku (Ryokan), Fennel (Yongxiang), Engosaku (Yankou), Ogon (Yellow), Ousei (Yellow), Oubak (Yellow), Spruce (Cherry bark), auren (yellow ream), onji (distant), gajutsu (weather), valerian (kashikusa), chamomile, caronin (karojin), licorice (licorice), kyokyo (kikyo), kyonin (kyojin) ), Kukoshi (Kushiko), Kukoyo (Kashiwaha), Keigai (Kashiwagi), Keihi (Kinshikashi), Ketsumeishi (Keiko), Gentiana, Gennoshouko (current evidence), Koubushi (Katsukiko), Gouou (cow yolk), Goshishi ( Goshiko, Saishin, Sansho, Shion, Zikopi, Hakuyaku, Shakuyaku, Shako, Shajin, Shazenshi ), Shazenso (car in front of the car), Beast gall (including Yutan (bear gall)), Syougyo (ginger), Giryu (land dragon), Shinyi (spicy potato), Sexan (stone wall), Senega, Senkyu Zenko (mae-hu), assembly (Senhwa), Sojutsu (蒼朮), Sohakuhi (mulberry white skin), Soyo (Soyo), Taisan (Otsuchi) Chikutsutsujinjin (Takebushi ginseng), clove (chome), chimpi (Chen) , Toki (homecoming), Tokon (Nanten), Nantenjitsu (Nan Tenji), Carrot (Ginseng), Baimo (Shell), Bakumondou (Bakumon winter), Hange (half-summer), Bankouka (Bankaka), Hampi (Anti-nasal), peony (white bean), peanut (white moth), bukuryo (、), button pi (peony skin), borei (oyster), maou (mao yellow), rokjo (deer moth) and other extracts and their extracts ( Extract, tincture, dried extract, etc.) I can get lost.

  The Kampo prescriptions include Kakkon-yu, Katsue-yu, Kosou-san, Saiko-Kei-do, Sho-saiko-to, Shosei-ryu, Mumon-tou-yu, Hanka-kopaku-to, Mao-to, 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.

  The pharmaceutical composition of the present invention can be produced by a known method described in the 15th revision Japanese Pharmacopoeia General Rules for Preparation, etc., and includes excipients, binders, disintegrants, lubricants, etc. It can be manufactured using pharmaceutical additives.

  Examples of the dosage form of the pharmaceutical composition of the present invention include, for example, capsules, pills, granules, fine granules, powders, tablets, solutions, syrups, jellies, lozenges and the like, orally administered preparations, and external preparations, Examples include parenteral preparations such as ointments, creams, gel creams, cataplasms, transdermal preparations, patches, liniments, lotions and suppositories. In the present invention, a preparation for oral administration is preferable, and a solid preparation is more preferable. The solid preparation may be coated with sugar coating, film coating or the like by a known method.

  When an orally administered preparation is uncoated, coloring due to copper chlorophyllin may occur on the tongue of the user depending on the manner of taking and the properties of the preparation. In order to solve this, the pharmaceutical composition of the present invention preferably contains an acid such as ascorbic acid, tartaric acid, citric acid, malic acid, phosphoric acid or hydrochloric acid.

  Since the pharmaceutical composition of the present invention contains loxoprofen, which is a kind of NSAID, and copper chlorophyllin, headache, toothache, pain after tooth extraction, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, shoulder pain, Pain pain, fracture pain, cramp pain, menstrual pain, menstrual pain, trauma pain relief, chills, fever during fever, cold symptoms (throat pain, chills, fever, headache, joint pain, muscle pain Pain), alveolar pyorrhea, gingivitis, stomatitis, removal of bad breath, and the like.

  The pharmaceutical composition of the present invention is excellent due to copper chlorophyllin or a salt thereof without any risk of gastrointestinal disturbance caused by loxoprofen.

  Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

Example 1. Inhibition of loxoprofen-induced gastrointestinal disorders
Using Wistar rats (Std: Wistar / ST, male, 8 weeks old, body weight 195.1 to 215.8 g), the test was carried out as 6 animals per group. 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, copper chlorophyllin sodium (SCC) was suspended in a 0.5% methylcellulose (MC) solution and orally administered in a predetermined amount (25, 50 mg / 5 mL / kg). In the control group, only the solvent (0.5% MC) was orally administered in the same volume (5 mL / kg).
One hour after administration of the test drug, loxoprofen sodium hydrate 100 mg / 2 mL physiological 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. 10 mL of a 1% formalin solution was injected into the stomach from the pyloric region, and after ligation of 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) that occurred in the glandular stomach under a stereomicroscope after incising the stomach along the large curvature. The total damage per rat was calculated as the Ulcer Index (UI).
Taking the ulcer index of the control group as 100%, the ulcer inhibition rate (%) in the test drug was calculated. The results are shown in Table 1.

  As is clear from Table 1, copper chlorophyllin or a salt thereof alleviated gastric mucosal damage caused by loxoprofen.

The present invention provides a pharmaceutical composition comprising loxoprofen or a salt thereof and copper chlorophyllin or a salt thereof, and the pharmaceutical composition of the present invention comprises loxoprofen, which is a kind of NSAID, and copper having an anti-pepsin action and the like. Contains chlorophyllin.
Therefore, the pharmaceutical composition of the present invention has a headache, toothache, pain after extraction, sore throat, ear pain, joint pain, neuralgia, low back pain, muscle pain, stiff shoulder pain, bruise pain, fracture pain, sprain pain, menstrual pain ( Menstrual pain), pain relief, trauma, antipyretic fever, cold symptoms (throat pain, chills, fever, headache, joint pain, muscle pain), alveolar abscess, gingivitis, stomatitis, Efficacy or effect in removing bad breath.
According to the present invention, copper chlorophyllin or a salt thereof alleviated gastrointestinal disorders caused by loxoprofen. Therefore, the gastrointestinal disorder caused by loxoprofen can be reduced, and a pharmaceutical composition exhibiting the above-described excellent efficacy or effect can be provided and is useful.

Claims (8)

  A pharmaceutical composition comprising loxoprofen or a salt thereof and copper chlorophyllin or a salt thereof.   The pharmaceutical composition according to claim 1, wherein loxoprofen or a salt thereof is loxoprofen sodium hydrate.   The pharmaceutical composition according to claim 2, comprising 30 to 180 mg of loxoprofen sodium hydrate as a daily dose in terms of anhydrous loxoprofen sodium.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the copper chlorophyllin or a salt thereof is one or two kinds of copper chlorophyllin salts selected from copper chlorophyllin sodium and copper chlorophyllin potassium.   The pharmaceutical composition according to any one of claims 1 to 4, comprising 5 to 200 mg of copper chlorophyllin or a salt thereof as a daily dose.   The pharmaceutical composition according to any one of claims 1 to 5, which is an orally administered preparation.   The pharmaceutical composition according to any one of claims 1 to 6, which is a solid preparation.   An agent for reducing or suppressing gastrointestinal disorders caused by loxoprofen or a salt thereof, comprising copper chlorophyllin or a salt thereof as an active ingredient.