WO2007013290A1 - Anti-inflammatory analgesic agent - Google Patents

Abstract

Disclosed is an anti-inflammatory analgesic agent which is excellent in safety and has excellent anti-inflammatory effect and/or analgesic effect. An anti-inflammatory analgesic agent comprising a carpronium salt (3-(methoxycarbonylpropyl)trimethyl ammonium salt); a method for treatment/prevention of an inflammation and/or a pain using the analgesic agent; and use of a carpronium salt for the preparation of the anti-inflammatory analgesic agent.

Description

 Specification

 Anti-inflammatory analgesic

 Technical field

 [0001] The present invention relates to a pharmaceutical composition for anti-inflammatory analgesia characterized by containing a calpe mouth-toum salt. The present invention also relates to the use of an anti-inflammatory analgesic agent for calc mouth-um salt, and pain comprising administering an effective amount of carpronium salt to a patient having pain and Z or inflammation. And methods for treating and preventing Z or inflammation.

 Background art

 [0002] Drugs containing calp mouth-um ((3-methoxycarbopropyl) trimethylammo-muchloride) are effective for chronic gastritis and flaccid constipation with decreased gastrointestinal function as internal medicine ( Non-patent document 1) is also used as a topical medicine for alopecia areata, malignant alopecia, diffuse alopecia, erosive alopecia, juvenile alopecia and symptomatic alopecia and hair growth prevention and hair growth promotion, and Efficacy against dry seborrhea and common vitiligo (see Non-Patent Document 2 and Patent Document 1) is known. These effects are thought to be based on the action of acetylcholine muscarinic receptors stimulated by gallium chloride and gastrointestinal motility, peripheral vasodilation, and sebaceous and sweat gland function. Salt-calp mouth-um is a parasympathomimetic drug, and unlike acetylcholine, it is stable to acid that is not easily affected by cholinesterase, so it directly touches the stomach wall by oral administration and has a cholinergic effect. It acts selectively on the gastrointestinal tract, promotes the movement of the stomach and intestinal contents, corrects the decrease in gastric acid secretion, and improves the gastrointestinal function. In addition, salty calp mouth-um has a local vasodilatory effect about 10 times that of acetylcholine, and has a strong and sustained dilation effect on local blood vessels that are not easily affected by cholinesterase, and is a hair follicle. It is known that there is a function improving action against.

 [0003] Carp chloride-um has a terminal ester moiety of acetylcholine (one OCOCH) reversed.

 3 The structure (one COOCH) has excellent skin permeability and affects the wide circulation system.

 Three

It has also been reported to promote oxygen supply to local tissues such as hair roots because it acts on the microcirculatory system and exhibits local blood vessel dilation (see Non-Patent Document 3). Other actions of Calp Mouth-um include stress-induced hair loss, stress stiff shoulders, stress-induced microcirculatory dysfunction-improving agents (see Patent Document 2), and stress-related Anti-stress agent for preventing or improving rough skin (see Patent Document 3), housewife eczema that includes contact dermatitis due to detergent, etc., progressive palmokeratosis, radiant eczema (cracking, redhead) Eczema 'dermatitis group consisting of dermatitis and other skin disease treatment agents such as frostbite (see Patent Document 4) have also been reported!

[0004] On the other hand, pain associated with headache, muscular pain, trauma, etc. generally lasts for a certain period of time, and the development of better analgesics to relieve such pain is the quality of patients. 'It has also been sought to improve life (QOL). As such analgesics, steroidal anti-inflammatory analgesics such as aspirin, ibuprofen, indomethacin, piroxicam, and mefenamic acid are now widely used. However, such anti-inflammatory analgesics have a prostaglandin biosynthesis inhibitory action in common, so that the frequency of roughening the digestive organs as a side effect is a major problem. Furthermore, aspirin and the like have known side effects that worsen asthma. For this reason, the development of an analgesic agent that is useful for the relief of pain and excellent in safety is strongly desired.

 Inflammation is a biological reaction when a living body is damaged by the invasion or impact of pathogenic microorganisms, and exhibits symptoms such as redness, heat, edema, and pain. These symptoms are due to local vasodilatation and contraction, increased vascular permeability, increased blood flow, and sensitization of perivascular pain receptors. The onset mechanism is thought to be prostaglandin production. It has been. Therefore, aspirin, ibupofen, indomethacin, piroxicam, mefenamic acid, and the like, which inhibit the prostaglandin-producing enzyme cycloxinase, are known and widely used as non-steroidal anti-inflammatory agents. However, since the mechanism of action of such anti-inflammatory analgesics is a prostaglandin biosynthesis inhibitory action in common, it is a major problem that the frequency of roughening the digestive organs as a side effect is extremely high. Furthermore, aspirin and the like have known side effects that exacerbate asthma. For this reason, development of an anti-inflammatory agent that is useful for ameliorating inflammation and is excellent in safety is strongly desired.

[0005] Patent Document 1: Japanese Patent Publication No. 42-5680

Patent Document 2: JP 2002-265363 A Patent Document 3: Japanese Patent Laid-Open No. 2002-265361

 Patent Document 4: Japanese Patent Publication No. 61-30644

 Non-Patent Document 1: Shio Carpronium: Japan Pharmaceuticals, Japan Pharmaceutical Information Center, 28th edition, Jiho Co., Tokyo (2005)

 Non-Patent Document 2: Carpronium Chloride: Japan Pharmaceutical Collection, Japan Pharmaceutical Information Center, 28th Edition, Jiho Co., Tokyo (2005)

 Non-Patent Document 3: Chiyoharu Okubo, “Nippon Yakuhin Magazine”, Vol. 91, pp. 245-253, 1988 Disclosure of the Invention

 Problems to be solved by the invention

[0006] An object of the present invention is to provide an anti-inflammatory analgesic having excellent safety and having an excellent anti-inflammatory action and Z or analgesic action.

 Means for solving the problem

[0007] In the process of developing an anti-inflammatory analgesic agent that does not adversely affect the gastrointestinal tract and solves the above-mentioned problems and has excellent skin permeability, We have focused on chlorinated carb mouth which has an improving effect and excellent skin permeability. However, the relationship between carpronium chloride and its anti-inflammatory and analgesic effects is not known at all, and its use as an anti-inflammatory agent or analgesic containing these compounds has never been known. As a result of intensive studies on the action of calpe mouth-um salt in inflammation model animals and pain model animals, the present inventors have surprisingly found that calp mouth-um salt has excellent anti-inflammatory and analgesic effects. As a result, the present invention has been completed.

 That is, the present invention relates to a pharmaceutical composition for anti-inflammatory analgesia comprising a carp mouth-um salt ((3-methoxycarbo-propyl) trimethylam-um salt) as an active ingredient, that is, an anti-inflammatory analgesic. Is to provide.

 The present invention also relates to the use of a calpe mouth-um salt for producing an anti-inflammatory analgesic. The present invention also relates to a method for improving inflammation and Z or pain comprising administering an effective amount of carpronium salt to a patient having inflammation and Z or pain, and treating and preventing these symptoms.

Furthermore, the present invention contains a calpe mouth-um salt as an anti-inflammatory component and Z or an analgesic component. It is related with the pharmaceutical composition formed by this, Preferably a skin external preparation.

 [0008] Further, the present invention will be described in more detail as follows.

 (1) A pharmaceutical composition for anti-inflammatory analgesia comprising calpe mouth-um salt as an active ingredient. Strength An anti-inflammatory analgesic comprising rupro-um salt.

 (2) The pharmaceutical composition for anti-inflammatory analgesia according to (1), wherein the carpronium salt is salt carpronium. Calp mouth-to-mu salt power The anti-inflammatory analgesic according to (1) above, which is a salt carp mouth-toum.

 (3) The anti-inflammatory analgesic pharmaceutical composition further comprises another anti-inflammatory analgesic in addition to carpronium salt as an anti-inflammatory analgesic component. A pharmaceutical composition for inflammatory analgesia. The pharmaceutical composition for anti-inflammatory analgesia further contains another anti-inflammatory analgesic in addition to the calpe mouth-um salt as an effective component for anti-inflammatory analgesia. (1) or (2) A pharmaceutical composition for anti-inflammatory analgesia described in 1.

 (4) The anti-inflammatory analgesic according to (1) or (2), wherein the anti-inflammatory analgesic further contains another anti-inflammatory analgesic in addition to the carpronium salt as an anti-inflammatory analgesic component. The anti-inflammatory analgesic according to (1) or (2), wherein the anti-inflammatory analgesic further contains another anti-inflammatory analgesic in addition to carpronium salt as an active ingredient for anti-inflammatory analgesia.

(5) The pharmaceutical composition for anti-inflammatory analgesia according to any one of (1) to (4), wherein the pharmaceutical composition for anti-inflammatory analgesia is a parenteral preparation. The anti-inflammatory analgesic according to any one of (1) to (4), wherein the anti-inflammatory analgesic is a parenteral preparation.

 (6) The pharmaceutical composition for anti-inflammatory analgesia according to (5), wherein the parenteral preparation is a transdermal administration preparation. The anti-inflammatory analgesic according to (5), wherein the parenteral preparation is a preparation for transdermal administration.

 (7) The pharmaceutical composition for anti-inflammatory analgesia according to any one of (1) to (4), wherein the pharmaceutical composition for anti-inflammatory analgesia is an oral preparation. The anti-inflammatory analgesic according to any one of (1) to (4), wherein the anti-inflammatory analgesic is an oral preparation.

 [0009] (8) A pharmaceutical composition for anti-inflammation comprising calpe mouth-um salt as an active ingredient. Calp Anti-inflammatory agent containing mouth-um salt.

(9) Carpronium salt power The anti-inflammatory pharmaceutical composition according to (8) above, which is salt carpronium. Calp mouth-um salt power The anti-inflammatory according to (8) above, which is a salt mouth calm mouth-um Agent.

 (10) Pharmaceutical composition power for anti-inflammatory In addition to carpronium salt as an anti-inflammatory component, the composition further contains another anti-inflammatory analgesic agent for anti-inflammatory as described in (8) or (9) above. Medicine composition. The anti-inflammatory pharmaceutical composition according to (8) or (9), wherein the anti-inflammatory pharmaceutical composition further contains another anti-inflammatory analgesic agent in addition to the carpronium salt as an active ingredient for anti-inflammatory. Pharmaceutical composition.

 (11) The anti-inflammatory agent according to (8) or (9), wherein the anti-inflammatory agent further contains another anti-inflammatory analgesic agent in addition to the carpronium salt as an anti-inflammatory component. The anti-inflammatory agent according to the above (8) or (9), wherein the anti-inflammatory agent further contains another anti-inflammatory analgesic agent in addition to the calpe mouth-um salt as an active ingredient for anti-inflammation.

 (12) The anti-inflammatory pharmaceutical composition according to any one of (8) to (11), wherein the anti-inflammatory pharmaceutical composition is a parenteral preparation. The anti-inflammatory agent according to any one of (8) to (11), wherein the anti-inflammatory agent is a parenteral preparation.

 (13) The anti-inflammatory pharmaceutical composition according to (12), wherein the parenteral preparation is a transdermal administration preparation. The anti-inflammatory agent according to (12), wherein the parenteral preparation is a preparation for transdermal administration.

 (14) The anti-inflammatory pharmaceutical composition according to any one of the above (8) to (11), wherein the anti-inflammatory pharmaceutical composition is an oral preparation. The anti-inflammatory agent according to any one of (8) to (11), wherein the anti-inflammatory agent is an oral preparation.

(15) A pharmaceutical composition for analgesia comprising calpe mouth-um salt as an active ingredient. Calp An analgesic containing mouth-um salt.

 (16) Carpronium salt power The analgesic pharmaceutical composition according to the above (15), which is a salty carpronium. Calp mouth-to-mouth salt power The analgesic according to the above (15), which is a salt mouth-to-mouth mouth mouth.

(17) The analgesic composition according to the above (15) or (16), wherein the analgesic pharmaceutical composition further contains another anti-inflammatory analgesic agent in addition to the calpe mouth-um salt as an analgesic component. Pharmaceutical composition. The analgesic medicament according to (15) or (16) above, wherein the analgesic pharmaceutical composition further contains another anti-inflammatory analgesic agent in addition to carpronium salt as an active ingredient for analgesia. Composition. (18) The analgesic according to (15) or (16), wherein the analgesic further contains another anti-inflammatory analgesic in addition to the carpronium salt as an analgesic component. The analgesic according to (15) or (16), wherein the analgesic further contains another anti-inflammatory analgesic in addition to the calpe mouth-um salt as an active ingredient for analgesia.

 (19) The analgesic pharmaceutical composition according to any one of (15) to (18), wherein the analgesic pharmaceutical composition is a parenteral preparation. The analgesic according to any one of (15) to (18), wherein the analgesic is a parenteral preparation.

 (20) The pharmaceutical composition for analgesia according to the above (19), wherein the parenteral preparation is a preparation for transdermal administration. The analgesic according to (19), wherein the parenteral preparation is a transdermal administration preparation.

 (21) The analgesic pharmaceutical composition according to any one of (15) to (18), wherein the analgesic pharmaceutical composition is an oral preparation. The analgesic according to any one of (15) to (18), wherein the analgesic is an oral preparation.

 [0011] (22) A pharmaceutical composition for anti-inflammatory analgesia comprising an active ingredient for anti-inflammatory action and a calp-um salt as an active ingredient for Z or analgesic action, and a pharmaceutically acceptable carrier object. A pharmaceutical composition comprising a calpe mouth-um salt as an active ingredient for anti-inflammatory analgesia. More specifically, an active ingredient for anti-inflammatory action, and carpronium salt as an active ingredient for Z or analgesic action, and a thread for treating or preventing inflammation and Z or pain comprising a pharmaceutically acceptable carrier And adult.

 (23) Power of pharmaceutical composition The pharmaceutical composition according to the above (22), which further contains another anti-inflammatory analgesic agent in addition to carpronium salt as an anti-inflammatory analgesic component. The pharmaceutical composition according to the above (22), wherein the pharmaceutical composition further contains another anti-inflammatory analgesic agent in addition to the carpronium salt as an active ingredient for anti-inflammatory analgesia.

 (24) Carpronium salt power The pharmaceutical composition according to the above (22) or (23), which is carpronium chloride.

 (25) The pharmaceutical composition according to the above (22) to (24), wherein the pharmaceutical composition is a preparation for transdermal administration.

(26) The pharmaceutical composition according to any one of (22) to (24), wherein the pharmaceutical composition is an oral preparation.

[0012] (27) Administering an effective amount of carpronium salt to a patient with inflammation and epilepsy or pain Treatment and prevention of inflammation and Z or pain consisting of A method for treating and / or preventing inflammation and / or Z or pain comprising administering to a patient having inflammation and / or Z or pain a pharmaceutical composition comprising an effective amount of calpe mouth-mud salt.

 (28) The method according to the above (27), wherein the carpronium salt is carpronium chloride.

(29) Pharmaceutical composition power The method according to (27) or (28), wherein the pharmaceutical composition further comprises another anti-inflammatory analgesic agent in addition to carpronium salt as an anti-inflammatory analgesic component. The pharmaceutical composition according to the above (27) or (28), wherein the pharmaceutical composition further comprises another anti-inflammatory analgesic agent in addition to the calpe mouth-um salt as an active ingredient for anti-inflammatory analgesia. Method.

(30) The method according to any one of the above (27) to (29), wherein the pharmaceutical composition comprising an effective amount of a calpe humum salt is a parenteral preparation.

 (31) The method according to (30) above, wherein the parenteral preparation is a preparation for transdermal administration.

 (32) The method according to any one of (27) to (29) above, wherein the pharmaceutical composition comprising an effective amount of a calpe mouth-um salt is an oral preparation.

 [33] (33) A method for treating / preventing inflammation comprising administering an effective amount of carpronium salt to a patient having inflammation. A method for treating and / or preventing inflammation comprising administering a pharmaceutical composition comprising an effective amount of carpronium salt to a patient having inflammation.

 (34) Carpronium salt power The method according to (33) above, which is carpronium chloride.

(35) The method according to (33) or (34) above, wherein the pharmaceutical composition further comprises another anti-inflammatory analgesic in addition to the calpe mouth-um salt as an anti-inflammatory component. . The method according to (33) or (34) above, wherein the pharmaceutical composition is a pharmaceutical composition further containing another anti-inflammatory analgesic in addition to carpronium salt as an active ingredient for anti-inflammation.

 (36) The method according to any one of (33) to (35) above, wherein the pharmaceutical composition comprising an effective amount of a calpe mouth-um salt is a parenteral preparation.

 (37) The method according to (36) above, wherein the parenteral preparation is a preparation for transdermal administration.

 (38) The pharmaceutical composition comprising an effective amount of a calpe mouth-um salt is an oral preparation.

(33) to (35)!

[0014] (39) A method for treating and / or preventing pain comprising administering an effective amount of carpronium salt to a patient having pain. Contains effective amount of carpronium salt for patients with pain A method for treating and / or preventing pain comprising administering a pharmaceutical composition.

 (40) Carpronium salt power The method according to the above (39), which is carpronium chloride.

(41) Pharmaceutical composition strength The method according to (39) or (40) above, which is a pharmaceutical composition further containing another anti-inflammatory analgesic agent in addition to the calpe mouth-um salt as an analgesic component. Pharmaceutical composition The method according to (39) or (40) above, which is a pharmaceutical composition further containing another anti-inflammatory analgesic agent in addition to carpronium salt as an active ingredient for analgesia.

 (42) The method according to any one of (39) to (41) above, wherein the pharmaceutical composition comprising an effective amount of a calpe mouth-um salt is a parenteral preparation.

 (43) The method according to (42), wherein the parenteral preparation is a preparation for transdermal administration.

 (44) The method according to any one of (39) to (41) above, wherein the pharmaceutical composition comprising an effective amount of a calpe mouth-um salt is an oral preparation.

 [0015] (45) Use of carpronium salt for producing an anti-inflammatory analgesic.

 (46) The use (use) according to the above (45), wherein the carpronium salt is a salt carpronium.

(47) The use according to the above (45) or (46), wherein the anti-inflammatory analgesic is an anti-inflammatory analgesic containing another anti-inflammatory analgesic in addition to carpronium salt as an anti-inflammatory analgesic component (use ₀ ) The anti-inflammatory analgesic is an anti-inflammatory analgesic containing the other anti-inflammatory analgesic in addition to carpronium salt as an active ingredient for anti-inflammatory analgesia, as described in the above (45) or (46) Use.

 (48) The use according to any one of (45) to (47), wherein the anti-inflammatory analgesic is a parenteral preparation.

 (49) The use according to the above (48), wherein the parenteral preparation is a preparation for transdermal administration.

 (50) The use according to any one of (45) to (47), wherein the anti-inflammatory analgesic is an oral preparation.

 [0016] (51) Use of a calpe mouth-um salt for producing an anti-inflammatory agent.

 (52) Carpronium salt power Use according to (51) above, which is salty carpronium

(53) In addition to carpronium salt as an anti-inflammatory component, anti-inflammatory agents can also be used as other anti-inflammatory agents The use according to (51) or (52) above, which is an anti-inflammatory agent containing an analgesic. Anti-inflammatory agent power Use according to (51) or (52) above, which is an anti-inflammatory agent containing other anti-inflammatory analgesic in addition to carpronium salt as an active ingredient for anti-inflammatory.

(54) anti-inflammatory agents, the parenteral formulations (51) - (53) The use according to any displacement (u se) ₀

 (55) The use according to (54), wherein the parenteral preparation is a preparation for transdermal administration.

 (56) The use according to any one of (51) to (53) above, wherein the anti-inflammatory agent is an oral preparation

) o

 [0017] (57) Use of calpe mouth-um salt for producing an analgesic.

 (58) Carpronium salt strength Use according to (57) above, which is salty carpronium

(59) The use according to the above (57) or (58), wherein the analgesic is an analgesic further containing another anti-inflammatory analgesic in addition to the carpronium salt as an analgesic component. The use according to the above (57) or (58), wherein the analgesic is an analgesic further containing another anti-inflammatory analgesic in addition to the calpe mouth-um salt as an active ingredient for analgesia. .

 (60) The use according to any one of (57) to (59), wherein the analgesic is a parenteral preparation.

) o

 (61) The use according to (60) above, wherein the parenteral preparation is a transdermal preparation.

 (62) The use according to any one of (57) to (59), wherein the analgesic is an oral preparation

[0018] The calp mouth-mud salt used in the present invention is a calp mouth-um ((3-methoxycarbo-propyl) trimethylammonium) force cationic ammonium ion, Examples thereof include compounds having an anion as a counter ion of the ammonium ion. Examples of such anions include inorganic anions such as chlorine ions, bromine ions, iodine ions, nitrate ions, sulfate ions, phosphate ions, and carbonate ions, and organic anions such as citrate ions, oxalate ions, and lactate ions. And ions. Preferable anions of the calp mouth salt of the present invention include halogen ions such as chlorine ions, and anions that also induce organic acid power such as citrate ions. Especially preferred as anion Includes chloride ions, that is, salt-calp mouthpieces.

 The pharmaceutical composition for anti-inflammatory analgesia of the present invention is a so-called anti-inflammatory analgesic and is characterized by containing the carp mouth-mum salt of the present invention and a pharmaceutically acceptable carrier as active ingredients. Is. The “anti-inflammatory analgesia” in the present invention has an anti-inflammatory action and an analgesic action, and can treat or prevent inflammation and pain. The “anti-inflammatory analgesia” of the present invention acts on inflammation and pain, but acts on inflammation and pain individually as well as on inflammation and pain simultaneously. Cases are also included. Therefore, the “anti-inflammatory analgesic” of the present invention may be used to act on both inflammation and pain at the same time, or acts individually on each symptom on inflammation or pain. It also includes things that are intended to be made. In this sense, in the meaning of the present invention, both anti-inflammation and pain are included, including both the case where both act on inflammation and pain simultaneously and the case where each acts separately.

The terms “Z or analgesia”, “inflammation and Z or pain”, “anti-inflammatory analgesia” are used. The pharmaceutical composition of the present invention contains the carp mouth-mum salt of the present invention as an active ingredient as an active ingredient for anti-inflammatory analgesia (anti-inflammatory and Z or analgesic ingredient), and other active ingredients for pharmaceutical use. And a pharmaceutically acceptable carrier.

 There are no particular restrictions on the other active pharmaceutical ingredients that are added in addition to the calpe mouth-um salt as the analgesic ingredient of the present invention as long as they do not cause any problems when formulated as a preparation. Preferred active pharmaceutical ingredients include anti-inflammatory agents, anti-inflammatory analgesics, analgesics and the like. Specific examples of preferable pharmaceutical active ingredients include, but are not limited to, for example, non-steroidal anti-inflammatory analgesics such as indomethacin.

 The compounding amount of carpronium salt in the anti-inflammatory analgesic pharmaceutical composition (anti-inflammatory and Z or analgesic) or pharmaceutical composition of the present invention is not particularly limited, but is 0.01 to

10% by mass, preferably 0.1-5% by mass.

The anti-inflammatory analgesic of the present invention can be administered in a misaligned form of oral administration or parenteral administration. The calpe mouth-mud salt of the present invention is known to have excellent skin permeability, and can also be administered transdermally as an external preparation for skin. Examples of the dosage form of the anti-inflammatory analgesic composition or pharmaceutical composition of the present invention include oral preparations and parenteral preparations. Examples of parenteral preparations include skin preparations, eye drops, embedding agents and the like, and skin preparations are particularly preferable.

 Examples of oral preparations include tablets, granules, capsules, drinks, jelly preparations and the like. Examples of parenteral preparations include patches such as creams, gels, solutions, patches, and plasters.

 Oral preparations may be prepared using commonly used excipients, binders, disintegrants, disintegration inhibitors, absorption enhancers, humectants, adsorbents, lubricants, and the like. For example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and kainate, water, ethanol, propanol, simple syrup, glucose solution, starch solution, shellac, potassium phosphate Binders such as dry starch, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc., white sugar, stearin, Decay inhibitors such as cocoa butter, hydrogenated oil, quaternary ammonia base, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, strong oline, bentonite, colloidal Adsorbents such as caic acid, purified talc, stearate, boric acid Examples thereof include lubricants such as polyethylene glycol.

A parenteral preparation may be prepared using base components such as a thickener, an emulsifier, a neutralizer, a preservative, a stabilizer, a wetting agent, water, and fats and the like that are usually used. For example, thickeners such as carboxyvinyl polymer, hydroxyethyl cellulose, carrageenan, sodium alginate, xanthan gum, emulsifiers such as glycerin fatty acid ester, propylene glycol fatty acid ester, alkyl glyceryl ether, polyoxyethylene sorbitol fatty acid ester, polysorbate Neutralizing agents such as inorganic acids such as hydrochloric acid, alkali hydroxides such as sodium hydroxide and lithium hydroxide, amines such as triethanolamine and diethanolamine, noraoxybenzoic acid esters, and salt benzalco Preservatives such as hum, sodium sulfite, sodium hydrogen sulfite, dibutylhydroxytoluene, butylhydroxyl-sol, edetic acid or salts thereof, glycerin, ethylene glycol, propylene group Call, 1, 3-butylene glycol, isopropylene glycol, Poryechi Examples thereof include humectants such as render recall, lanolin, carnapa wax, octyldodecyl myristate, diisopropyl adipate, squalane, squalene, liquid paraffin, and silicone oils.

 [0021] The action of the analgesic in the anti-inflammatory analgesic of the present invention can be used for any of nociceptive pain, neuropathic pain, psychogenic pain and the like. Nociceptive pain is pain that occurs when a living tissue is damaged, and includes pain after surgery, pain caused by cancer, pain caused by inflammation, and the like. Neuropathic pain is pain caused by abnormalities in the nerve, spinal cord, and brain, and includes, for example, phantom limb pain, postherpetic neuralgia, reflex sympathetic dystrophy, causalgi and the like. Psychogenic pain is pain associated with psychological disorders and includes pain that does not have a physical cause.

 As the action of the analgesic in the anti-inflammatory analgesic of the present invention, it is particularly preferable to use it for pain caused by inflammation, which is preferably used for nociceptive pain. Furthermore, the anti-inflammatory analgesic of the present invention was confirmed to have an excellent anti-inflammatory action by a force-ragenin foot edema test described later. The force lagenin paw edema test has been a famous test method in the history of indomethacin development, and Winter et al. Have shown that drugs that suppress force lagenin paw edema are present in human rheumatism. It is said that it has been empirically known to have an effect and has screened many drugs using this method. Thus, the drug screened by the force ragenin paw edema test method has an anti-inflammatory action against various inflammations including rheumatism.

 Such anti-inflammation refers to the suppression of biological reactions caused by the invasion or impact of pathogenic microorganisms. Specifically, it is not only redness, heat and edema that occurs at the inflamed site, but also chills associated with infection. It refers to the suppression of fever and nerve stimulation that occurs at the site of inflammation. The anti-inflammatory action in the anti-inflammatory analgesic of the present invention includes effective actions against these various inflammations.

 The anti-inflammatory analgesic agent of the present application has anti-inflammatory action and Z or analgesic action, and each action can be used alone as an anti-inflammatory or analgesic that can only be used as an anti-inflammatory analgesic. You can also

[0022] The dose of the calpe mouth-um salt in the present invention includes a target disease and a patient symptom. It varies depending on the severity, age of the patient, complications, etc., and also varies depending on the administration route, etc. Usually 0.01 mg to 2000 mg per adult, preferably 0.1 mg to 1500 mg, The dose is preferably 1 mg to 500 mg, which can be administered orally, intravenously, intramuscularly, rectally or transdermally.

[0023] As has been clarified by various tests to be described later, the present invention has found that calpe mouth-um salt has anti-inflammatory action and Z or analgesic action. A novel pharmaceutical composition for anti-inflammatory analgesia as an active ingredient is provided. In addition, according to the present invention, it has been clarified that a pharmaceutical composition containing a calpe mouth-um salt as an active ingredient is effective for the treatment or prevention of inflammation and pain. Therefore, the present invention provides a method for treating and preventing inflammation and Z or pain, comprising administering an effective amount of carpronium salt to a patient having inflammation and Z or pain. This method of the present invention is generally used in patients with inflammation and Z or pain as carpronium salt according to the patient's symptoms, usually 0.01 mg to 2000 mg per adult, preferably 0.1 mg to The above-mentioned preparation containing 1500 mg, more preferably 1 mg to 500 mg, is administered by a method such as oral administration, intravenous administration, intramuscular administration, rectal administration or transdermal administration. .

 The present invention also provides the use of a calp mouth-um salt for producing an anti-inflammatory analgesic. As the anti-inflammatory analgesic agent in the present invention, a preparation for oral administration, intravenous administration, intramuscular administration, rectal administration or transdermal administration, which contains the above-mentioned carponium salt as an active ingredient. Is mentioned.

 The invention's effect

[0024] According to the present invention, a new anti-inflammatory analgesic for improving inflammation and pain, a method of treatment or prevention using the anti-inflammatory analgesic, and use of carpronium salt for producing the anti-inflammatory analgesic (Use) can be provided. Calp mouth-um salt used as an active ingredient of the anti-inflammatory analgesic of the present invention is highly safe and excellent in skin permeability to the gastrointestinal tract which is not easily affected by cholinesterase. The present invention provides an anti-inflammatory analgesic that is highly safe without causing gastrointestinal disorders, a method for treating and preventing the same, and a use for producing the anti-inflammatory analgesic. Brief Description of Drawings

 [0025] [FIG. 1] FIG. 1 shows that when the carpronium salt of the present invention is applied 3 hours after the onset of pain, the pain threshold before the onset of pain is 100% and the pain threshold at each time after the onset of pain is expressed as a percentage. It is a graph which shows the converted rate of change.

 [Fig. 2] Fig. 2 shows 100% of the pain threshold before the onset of pain when the carpronium salt of the present invention (white triangle mark) and indomethacin (black circle mark) were applied 3 hours later, respectively. FIG. 6 is a graph showing the rate of change in which the pain threshold value for each hour after pain induction is converted into a percentage.

 [Fig. 3] Fig. 3 is a graph showing the rate of inhibition of the area under the time-edema volume curve (AUC) when each concentration of the calp mouth-mum salt of the present invention was applied 30 minutes before the onset of inflammation. It is.

 [Fig. 4] Fig. 4 is a graph showing the change in edema volume when the carpronium salt of the present invention (black circle mark) and indomethacin (white triangle mark) are applied 30 minutes before the onset of inflammation, respectively. is there.

 [Fig. 5] Fig. 5 is a graph showing changes in edema volume when the carpronium salt of the present invention (black circle mark) and indomethacin (white triangle mark) are applied 30 minutes before the onset of inflammation, respectively. is there.

 [Fig. 6] Fig. 6 is a graph showing the results of measuring the analgesic effect when the salted calp mouthrum of the present invention was orally administered. The white circles indicate the case where only control purified water was administered, and the black circles, black triangles, and black squares indicate that 30 mgZkg, 60 mgZkg, or 120 mgZkg of salted calp mouth was administered, respectively.

 FIG. 7 is a graph showing the results of measuring the anti-inflammatory effect when the salted calp mouthrum of the present invention was orally administered. Open circles indicate the case where only control purified water was administered, and filled circles indicate the case where 120 mgZkg of salted calp mouth was administered.

 [FIG. 8] FIG. 8 shows the anti-inflammatory effect of oral administration of the salted calp mouth-mums of the present invention until 1 hour after the onset of inflammation (white circle in FIG. 8) and 1 hour later. 9 is a graph showing the results of calculating and evaluating the area under the time-one edema volume curve (AUC) from 1 to 5 hours (black circle in FIG. 8).

 [0026] Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

Example 1 [0027] A 5-week-old Wistar male rat was used to measure the pain threshold of the right hind leg before pain induction by the random cellit method. Subsequently, 0.1 mL of 20% beer yeast solution suspended in physiological saline was subcutaneously administered to the right hind footpad of the animal to induce pain, and the pain threshold was measured over time. The test substance was dissolved in a 7: 3 mixture of isopropanol and water and applied 3 hours after the onset of pain. The action of the test substance was evaluated as a percentage by converting the pain threshold value for each hour after the pain was induced into 100% as the pain threshold before the pain was induced. The analgesic effects of 2, 4 and 4% were examined. The results are shown in Fig. 1. The horizontal axis in Fig. 1 shows the time (time) of pain-inducing force, and the vertical axis shows the rate of change (%) with the pain threshold before pain induction being 100%. The white circle mark (○) in Fig. 1 indicates the case of no application, the black circle mark (參) indicates the case of 1% salty calp mouth, and the white triangle mark (△) indicates 2% salty calp. The case of mouth-um is shown, and the black triangle mark (▲) shows the case of 4% salty-calpronium.

 As a result, the pain threshold, which was lowered 3 hours after the onset of pain, was improved depending on the dose of salty calp mouth-mud, and the submaximum concentration of analgesic action (almost maximum response to analgesic action). Was 2%.

 Example 2

 [0028] The analgesic action of 2% salt hydrochloride and 1% indomethacin applied from 3 hours after the onset of pain was examined by the same method as described above. The result is shown in FIG. The horizontal axis in FIG. 2 represents the time (time) from the onset of pain, and the vertical axis represents the rate of change (%) with the pain threshold before the onset of pain being 100%. The white circle mark (○) in Fig. 2 indicates the case of no application, the black circle mark (參) indicates the case of 1% indomethacin, and the white triangle mark (△) indicates the case of 2% salty calp mouth-um. Show.

 As a result, Shio Calp Mouth-um showed a fast-acting analgesic action similar to that of indomethacin.

 Example 3

[0029] The right hind paw volume before inflammation was measured using 8-week-old Wistar male rats. Subsequently, 0.1 ml of 1% strength ragenin solution dissolved in physiological saline is subcutaneously applied to the animal's right hind paw. Inflammation was induced by administration, and then the foot volume on the inflammation-inducing side was measured from 60 minutes at 15-minute intervals and from 1 hour to 5 hours at 1-hour intervals. The test substance was dissolved in a solution of isopropanol and water mixed at a ratio of 7: 3 and applied to the inflammation-inducing foot 30 minutes before the inflammation was induced. The action of the test substance was carried out by calculating the edema volume at each hour from the difference in foot volume before and after the inflammation was induced, and calculating the area under the hour-one edema volume curve (AUC) and comparing it with the non-application group.

 Anti-inflammatory action at each concentration of 0, 01, 0, 1, 0.5 and 1% up to 60 minutes after inflammation was induced, the average value of AUC of 4 to 5 cases in each group Was calculated and shown as the inhibition rate of the control console against AUC. The results are shown in Figure 3. The horizontal axis in Fig. 3 shows the chloride concentration (%) and the vertical axis shows the AUC suppression rate (%). As a result, Shio Calp Mouth-um showed a dose-dependent anti-inflammatory effect over 0.01 force 0.5%, and the effect was almost plateau at 0.5% or more.

 Example 4

 [0030] By the same method as the experiment described in Example 3 described above, the anti-inflammatory action of salt carp mouth-um 0.5% and indomethacin 1%, the time course of edema volume of 3 cases in each group As discussed. The results are shown in Fig. 4 as the mean standard error of the edema volume. The horizontal axis in FIG. 4 indicates the time (minutes) from the onset of inflammation, and the vertical axis indicates the edema volume (mL). The white circle mark (◯) in Fig. 4 indicates the case of no application, the black circle mark (參) indicates the case of 0.5% salty carp mouth, and the white triangle mark (△) indicates 1% indomethacin. Show the case.

 As a result, Shio Calp Mouth-um exhibited a clearly stronger anti-inflammatory effect than indomethacin.

 Example 5

[0031] Next, in the same manner as in Example 4, the anti-inflammatory action of salt carp mouth-rum 0.5% and indomethacin 1% up to 5 hours after inflammation was induced was compared with the edema volume of 3 cases in each group. The change over time was examined. The results are shown in FIG. 5 as mean standard error of edema volume. The horizontal axis in FIG. 5 shows the time (hour) of inflammation-inducing force, and the vertical axis shows edema volume (mL). The white circle mark (◯) in Fig. 5 indicates the case of no coating, the black circle mark (參) indicates the case of 0.5% salty carp mouth, and the white triangle mark (△) indicates 1% indomethacin. This case is shown. As a result, Shio Calp Mouth-um exhibited a clearly stronger anti-inflammatory effect than indomethacin.

 Example 6

 [0032] The pain threshold (Pre) of the right hind paw before pain induction was measured by the Randall Cerit method using 5-week-old male Wistar rats. Subsequently, 0.1 mL of 20% brewer's yeast solution suspended in physiological saline was subcutaneously administered to the right hind paw of the animal to induce pain, and the pain threshold was measured over time. The test substance was dissolved in purified water and orally administered 3 hours after the onset of pain. The effect of the test substance was evaluated by the transition of the pain threshold after oral administration.

 After 3 hours of pain induction, the analgesic action of oral oral potassium chloride 30, 60 and 120 mgZkg was examined. The results are shown in FIG. The horizontal axis in Fig. 6 shows the time (time) from the onset of pain, and the vertical axis shows the pain threshold (mmHg) at each measurement point. The white circles (◯) in Fig. 6 indicate the control group treated with purified water, the black circles (參) indicate the salty carpronium 3 OmgZkg, and the black triangles (▲) indicate the salty carp mouth-um. The 60 mgZkg administration group is shown, and the black square (country) indicates the case of the salted calp mouth 120 mgZkg administration group.

 As a result, Shio Calp Mouth-um showed a significant analgesic effect on the control at all times when the pain threshold was measured.

 Further, when a similar test was carried out using loxoprofen, which is known as an anti-inflammatory analgesic, the same result as that of the salty calp mouth-rum of the present invention was obtained. This also suggests that the calp mouthpiece of the present invention has the same kind of analgesic effect as known loxoprofen.

 Example 7

[0033] The right hind paw volume before inflammation was measured using 8-week-old Wistar male rats. Subsequently, 0.1 mL of a 1% strength ragenin solution dissolved in physiological saline is administered subcutaneously to the right hind footpad of the animal to cause inflammation. After 30 minutes and 1 hour, from 1 hour to 5 hours later The foot volume on the inflammation-inducing side was measured at 1 hour intervals. The test substance was dissolved in purified water and administered orally 30 minutes before the inflammation occurred. The action of the test substance was carried out by calculating the edema volume for each hour, and calculating the area under the time edema volume curve (AUC) and comparing with the purified water administration group. The anti-inflammatory effect of the test substance was shown by the change in edema volume at each measurement point in 5 patients in each group. The results are shown in FIG. The horizontal axis in Fig. 7 shows the time (hours) that causes inflammation, and the horizontal axis shows the edema volume (mL). The white circles (◯) in Fig. 7 indicate the purified water administration group as the control group, and the black circles (參) indicate the case of the salt-calp mouth-mu 120mgZkg administration group.

 As a result, the salty calp mouth-um showed a significant anti-inflammatory effect on the control mouth at all times when the foot volume was measured.

 In addition, the AUC from 1 hour to 1 hour and from 1 hour to 5 hours after the onset of inflammation was determined, and the inhibition rate of salted calpe mouthrum at each dose relative to the control was calculated. The results are shown in Fig. 8. The horizontal axis of FIG. 8 shows the dose (mgZkg p. O.), And the vertical axis shows the AUC suppression rate (%). The white circles in FIG. 8 indicate the case of 0 to 1 hour after the administration of force ragenin, and the black circles indicate 1 to 5 hours later. From these results, it was found that salted calpe mouth-mud showed a dose-dependent anti-inflammatory effect even at 30 to 120 mgZkg even in oral administration, and the effect was strongly observed in the early stage of inflammation. .

 Furthermore, when a similar test was performed using loxoprofen, which is known as an anti-inflammatory analgesic, results similar to those of the salted-carp mouthpiece of the present invention were obtained. Also from this, it was considered that the calp mouthpiece of the present invention has the same kind of anti-inflammatory action as known loxoprofen.

Example 8

(Formulation example 1) (Cream formulation containing salty calp mouth-um)

 The first component, the second component, and the third component are produced according to the formulation shown below.

 [First component]

 Ingredients Amount (parts by weight)

Paraffins 15

Waxes 5

Olive oil 20

Sonorbitan sesquistearate 1.5

Glycerol monooleate 1

Stearic acid 0.3 Polyoxyethylene (20) beryl ether 1.7

 Butinoreparaben 0.1

 Carpronium chloride 0.2

 [0035] [Second component]

 Ingredient Blending amount (heavy-β I)

 Wed 30

 Canoleboxyvininole polymer 0.3

 Propylene glycol 5

 Methylparaben 0.2

 [0036] [Third component]

 Ingredient Blending amount (heavy β)

 Potassium hydroxide 0.2

 Wed 18.5

 [0037] The above three components are heated to 80 ° C, the second component is gradually added to the first component to emulsify, the third component is further added to neutralize, the particles are aligned with a homogenizer, and then stirred. Cool to get cream.

 Industrial applicability

[0038] If the pharmaceutical composition of the present invention is used, an anti-inflammatory analgesic agent characterized by containing a calp mouth-um salt is provided, and can be used in the pharmaceutical industry.

Claims

The scope of the claims  [I] A pharmaceutical composition for anti-inflammatory analgesia comprising carpronium salt. [2] A pharmaceutical composition for anti-inflammation, comprising a calpe mouth-um salt.  [3] A pharmaceutical composition for analgesia comprising calpe mouth-um salt.  [4] Calp mouth-mu salt power The pharmaceutical composition according to any one of claims 1 to 3, which is a calp mouth-um salt.  5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is a parenteral preparation. 6. The pharmaceutical composition according to claim 5, wherein the parenteral preparation is a transdermal administration preparation. 7. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is an oral preparation. [8] The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further contains another anti-inflammatory analgesic agent in addition to the calpe mouth-um salt as an anti-inflammatory component or analgesic component. Pharmaceutical composition.  [9] A pharmaceutical composition for anti-inflammation and Z or analgesia, comprising an active ingredient for anti-inflammatory action and power rupronium salt as an active ingredient for Z or analgesic action, and a pharmaceutically acceptable carrier.  [10] The pharmaceutical composition according to claim 9, which is a calpe mouth-mume salt.  [I I] A method for treating and / or preventing inflammation and pain comprising administering an effective amount of carpronium salt to a patient having inflammation and pain.  [12] A method for treating or preventing inflammation comprising administering an effective amount of carpronium salt to a patient with inflammation.  [13] A method for treating or preventing pain comprising administering an effective amount of carpronium salt to a patient with pain.  [14] Use of carpronium salt to produce anti-inflammatory analgesics. [15] Use of calpe mouth-um salt to produce anti-inflammatory agents. [16] Use of calpe mouth-um salt to produce analgesics.