WO2005058879A1 - Preventive and/or remedy for exudative otitis media - Google Patents

Abstract

A preventive and/or a remedy for exudative otitis media containing pranlukast hydrate as the active ingredient. The pranlukast hydrate contained in the above preventive and/or remedy for exudative otitis media has an effect of reducing middle ear exudate and, therefore, is useful as a drug for ameliorating various symptoms such as hearing disorder, ringing in the ear and ear obstruction.

Description

 Specification

 Prophylaxis and treatment of otitis media with effusion

 Technical field

 The present invention relates to a preventive and / or therapeutic agent for exudative otitis media containing pranlukast hydrate as an active ingredient.

 Background art

 [0002] The number of patients with otitis media (medical care) is 350,000 (Ministry of Health, Labor and Welfare patient survey: 2001), of which about 40 to 50% is considered to be otitis media with effusion.

 Exudative otitis media is a common otitis media in children and the elderly.If the function of the Eustachian tube connecting the middle ear and the back of the nose is poor, the pressure inside and outside the eardrum will be poorly adjusted, and the middle ear will become negative pressure, resulting in mucoid The liquid oozes and accumulates. As a result, symptoms such as hearing loss and a feeling of ear obstruction are exhibited. Patients with acute upper respiratory tract inflammation, chronic sinusitis, allergic rhinitis and adenoid hypertrophy are prolonged and intractable because inflammation of the nose and throat always affects the middle ear through the Eustachian tube. It will be easier. When exudative otitis media becomes intractable, sequelae such as hearing loss remain and necessitate surgery, so early treatment is regarded as important. For children, it is difficult to perform frequent surgical procedures such as tympanic incision and placement of a tympanic membrane tube. Drugs are needed to minimize surgical procedures.

 [0003] In general, the therapeutic agent for exudative otitis media is mainly an expectorant (eg, carbocysteine) or a macrolide antibiotic (eg, erythromycin etylsuccinate, clarithromycin, etc.). Since no effect has been obtained, development of a highly effective oral preparation has been desired.

[0004] On the other hand, 4-oxo-1-8- [4_ (4-phenylbutoxy) benzoylamino] -1- (tetrazol-5-yl) -1 4H-1_benzopyran 1 / 2hydrate (generic name: pranlukast) Hydrate (trade name ONON) is used as a therapeutic agent for bronchial asthma and allergic rhinitis and is a drug that has been confirmed to be sufficiently safe. In addition, there has been a report showing the efficacy of pranlukast hydrate in rat pathological models of rat exudative otitis media (see Non-Patent Document 1), but this document does not describe any efficacy in humans . Non-Patent Document 1: Auris i "Auris Nasus Larynx, (Netherlands), 2002, p. 127—132

 Disclosure of the invention

 Problems to be solved by the invention

 An object of the present invention is to provide a prophylactic and / or therapeutic agent for otitis media or otitis media that is highly effective and can be orally administered to human patients.

 '' Means to solve the problem

 [0006] In view of the above problems, the present inventors have conducted intensive studies and as a result, surprisingly, pranlukast hydrate surprisingly reduces the middle ear fluid, and further improves hearing, ear sensation and the like. Therefore, they have found for the first time clinically that they are useful as preventive and / or therapeutic agents for human otitis media or otitis media, especially exudative otitis media, and completed the present invention. .

 [0007] That is, the present invention provides

 (1) Prevention of otitis media or otitis media characterized by containing pranlukast hydrate and Z or therapeutic agent,

 (2) the prophylactic and / or Z or therapeutic agent according to (1), wherein the otitis media is exudative otitis media;

 (3) Hearing loss, tinnitus and ear obstruction sensation The prophylactic and / or therapeutic agent or the therapeutic agent according to the above (1) which ameliorates one or more selected symptoms,

 (4) The prophylactic and / or therapeutic agent according to the above (1), which is an exudate reducing agent,

 (5) a prophylactic and / or therapeutic agent for deafness, tinnitus or ear sensation characterized by containing pranlukast hydrate;

 (6) The prophylactic and / or therapeutic agent according to (1) or (5), wherein the daily dose of pranlukast hydrate for a patient is 50 to 450 mg.

 (7) The prophylactic and Z or therapeutic agent according to (6), wherein the daily dose of plannorecast hydrate to the patient is 112.5 mg, 225 mg or 450 mg,

(8) The patient's daily dose of pranlukast hydrate is 450 mg, and 225 mg

The prophylactic and Z or therapeutic agent according to (7), which is administered twice a day,

(9) Patients with pranlukast hydrate Dosage capacity per day The prophylactic and / or therapeutic agent or therapeutic agent according to (8), wherein the capsule containing 112.5 mg of caste hydrate is administered twice a day, two capsules twice a day,

 (10) The prophylactic and / or therapeutic agent or the Z or therapeutic agent according to the above (1) or (5), wherein the daily dose of pranlukast hydrate per lkg of the patient's body weight is 2 to: L0 mg. ,

(11) The prophylactic and / or Z or therapeutic agent according to (10), wherein the daily dose of plannorecast hydrate is 7 mg / kg of the patient's body weight.

 (12) The prophylactic agent or therapeutic agent according to (6), wherein the daily dose of plannorecast hydrate is 50 mg, 70 mg, 100 mg, 140 mg, 200 mg, or 280 mg. , '

 (13) Pranlukast hydrate and one or more selected from expectorants, antibiotics, antihistamines, antiallergic drugs, steroids, nonsteroidal anti-inflammatory drugs, anti-inflammatory enzymes and herbal medicines A medicine characterized by being combined with

 (14) A method for preventing and / or treating otitis media with effusion in a mammal, which comprises administering plannorecast hydrate to a mammal at a dose of 2 to 10 mg / kg per day.

(15) a prophylactic and / or therapeutic agent for hearing loss, tinnitus or ear sensation in a mammal, which comprises administering 2 to 10 mgZkg of pranlukast hydrate per day to the mammal;

 (16) Plannorecast hydrate per day: 2 to: LOmg / kg, expectorant, antibiotic, antihistamine, antiallergic, steroid, nonsteroidal anti-inflammatory, anti-inflammatory enzyme, and A method for preventing and / or treating otitis media with effusion in a mammal, which comprises administering one or more selected ones to a mammal;

 (17) Pranlukast hydrate at a daily rate of 2 to: LOmg / kg, expectorant, antibiotic, antihistamine, antiallergic, steroid, nonsteroidal anti-inflammatory, anti-inflammatory enzyme, and A method for preventing and / or treating hearing loss, tinnitus or ear sensation in a mammal, which comprises administering one or more selected ones to a mammal; and

(18) Use of pranlukast hydrate for the manufacture of a prophylactic and / or therapeutic agent for the prevention of hearing loss, tinnitus or ear obstruction, About.

 The invention's effect

 [0008] The present invention provides an effective preventive and / or therapeutic agent for otitis media or otitis media, especially otitis media with effusion, and prevents and / or treats various symptoms of otitis media or otitis media, especially otitis media with effusion. can do. In addition, the present invention can improve hearing loss, tinnitus, and feeling of ear obstruction associated with exudative otitis media.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0009] Pranlukast hydrate used in the present invention has the formula (A)

 [Chemical 1]

 4-oxo-1- [4- (4-phenylbutoxy) benzoylamino] '-2- (tetrazol-5-yl) -1 4H-1-benzopyran hemihydrate represented by the formula:

 [0010] [Method for producing the compound of the present invention]

 Production of pranlukast hydrate can be carried out, for example, according to the method described in JP-A-61-050977.

 [0011] [toxicity]

 The toxicity of pranlukast hydrate was extremely low, confirming that it is safe enough for use as a pharmaceutical. For example, as acute toxicity of pranlukast hydrate, the minimum lethal dose was 2000 mgZkg or more when administered orally or subcutaneously to mice or rats (both male and female).

[0012] [Application to pharmaceutical products]

Pranlukast hydrate is useful as a medicament for preventing and / or treating otitis media or otitis media, especially exudative otitis media. In addition, pranlukast hydrate is exudative It is useful as a medicine for the prevention of hearing loss, tinnitus and ear sensation or as a therapeutic drug because it improves various symptoms such as hearing loss or tinnitus associated with otitis.

[0013] A medicament containing pranlukast hydrate as an active ingredient can be used systemically or locally.

 The dose of pranlukast hydrate varies depending on age, body weight, symptom, therapeutic effect, administration method or treatment time, etc., but it is only necessary to individually and specifically administer to obtain the desired effect of the present invention. . For example, the dose per day for a human patient is preferably about 25 mg strength, about 25 OO mg, more preferably 112.5 mg strength, et al. About 450 mg, even more preferably 225 mg strength, et al. 450 mg.

 [0014] In addition, the daily dose when administering plannorecast hydrate to a child is preferably about 2 to: LOmg, more preferably about 5 to about 5 mg / kg body weight of a pediatric patient. 8 mg, more preferably about 7 mg. In addition, when administered to pediatric patients weighing 12 kg or more and less than 18 kg, the daily dose of pranlukast hydrate should be about 50-: LOOmg strength S, more preferably about 50 mg or about 50 mg / day. lOOmg. Weight 18k

When administered to pediatric patients weighing at least 25 g and weighing less than 25 kg, the daily dose of pranlukast hydrate is preferably about 70-140 mg per day, more preferably about 70 mg or about 140 mg. When administered to pediatric patients weighing 25 kg or more and less than 35 kg, the daily dose of pranlukast hydrate is preferably about 100 mg to about 200 mg per day, more preferably about 100 mg or about 200 mg per day. . When administered to pediatric patients weighing 35 kg or more and less than 45 kg, the daily dose of pranlukast hydrate is preferably about 140 to 280 mg strength S per day, more preferably about 140 mg or about 280 mg. .

 [0015] As an administration method, either oral administration or parenteral administration is preferably used, but oral administration is more preferred. In the case of oral administration, for example, the above dose is divided into one to several times a day, preferably about four times a day, more preferably once to about twice a day. preferable.

[0016] Of course, as described above, the dose, the administration method, or the number of administrations vary depending on various conditions. Therefore, the daily dose of the patient may be smaller or larger than the above range. You may get.

 When pranlukast hydrate is produced as the above-mentioned medicament, it can be made into a formulation known per se. The preparation can be a solid preparation or liquid for oral administration or an injection, an external preparation, a suppository or an inhalant for parenteral administration.

 17] Solid preparations for internal administration for oral administration include tablets, pills, capsules, powders, and granules.

 In such solid preparations for internal use, pranlukast hydrate is mixed or granulated as such with excipients (e.g., stirring granulation, fluidized bed granulation, dry granulation, tumbling stirred fluidized bed). Granulation method), and manufactured according to a conventional method (for example, capsule filling for capsules and tableting for tablets). One or more of the above additives may be appropriately blended. Examples of additives include excipients IJ (eg, ratatose, mannitol, darcos, microcrystalline cellulose, corn starch, etc.) and binders (eg, hydroxypropinole cellulose, polybutylpyrrolidone, magnesium aluminate metasilicate, etc.) ), Dispersants (eg, corn starch, etc.), disintegrants (eg, calcium cellulose glycolate, etc.), lubricants (eg, magnesium stearate, etc.), stabilizers, solubilizing agents (eg, dartamine Acid, aspartic acid, etc.), water-soluble polymers [eg, celluloses (eg, hydroxypropylsenorelose, hydroxypropylmethinoresenorelose, methylsenorelose, etc.)] and synthetic polymers (eg, polyethylene glycol, polybutyl) (Pyrrolidone, Polyvinyl alcohol, etc.) Etc.] or sweetening agents (e.g., sucrose, powdered sugar, sucrose, fructose, glucose, lactose

, Reduced maltose water, powdered reduced maltose water, glucose fructose liquid sugar, fructose dextrose liquid sugar, honey, sorbitol, maltitol, mannitol, xylitol, erythritol, aspartame, saccharin, saccharin sodium, etc.). The granules or tablets may be coated with a coating agent (eg, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.) if necessary, and the coating may be made up of two or more layers. There may be. When manufactured as capsules, the above-mentioned excipients are appropriately selected, uniformly mixed with pranlukast hydrate, or in the form of granules, or granules, coated with an appropriate coating agent and coated. In a capsule, or add glycerin or sorbitol to a suitable capsule base (gelatin, etc.). It may be encapsulated with a capsule base that has increased plasticity by kneading it. These capsule bases may contain colorants or preservatives [sulfur dioxide, sulfur,. Ravens (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl nonoxybenzoate)] and the like can be added. Capsules' include hard capsules or soft capsules. Also, it is preferable that one to several, preferably one to about two tablets or capsules are administered at one time. For this reason, tablets or capsules are prepared to contain pranlukast hydrate in an amount of about 50-250 mg, preferably about 100-120 mg, especially about 112.5 mg per coagulant or capsule. preferable.

[0018] As oral liquids for oral administration, 7 agents, suspensions? Excipients, syrups, solution-in-use preparations (eg, dry syrups) or elixirs. In such a liquid for internal use, pranlukast hydrate is dissolved, suspended or emulsified in a diluent generally used for a liquid for internal use (for example, purified water, ethanol or a mixture thereof). You. Further, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative or a buffering agent. The dry syrup can be produced by mixing, for example, pranlukast hydrate with, for example, sucrose, powdered sugar, sucrose, fructose, glucose or lactose. The dry syrup may be granulated according to a conventional method.

 [0019] Dosage forms for parenteral administration include external preparations and injections. Examples of the dosage form of the external preparation include an ointment, a gel, a cream, a compress, a patch, a liniment, a spray, an inhalant, and a spray.

[0020] The ointment is produced by a known method. An ointment is produced, for example, by mixing or melting pranlukast hydrate with a base. The ointment base is selected from known ones and those commonly used. Ointment bases include, for example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester) ), Waxes (beeswax, spermaceti, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphate, etc.), higher alcohols (cetanol, stearinole alcohol, cetostearyl alcohol, etc.), silicone oils ( Dimethyl polysiloxane ), Hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (castor oil, olive oil) Sesame oil, turpentine oil, etc.), animal oils (mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers or anti-rash agents, etc. For Further, the ointment may contain a humectant, a preservative, a stabilizer, an antioxidant or a flavoring agent.

 [0021] The gel is produced by a known method. Gels are produced, for example, by melting pranlukast hydrate in a gel base. The gel base is selected from known or commonly used ones. Examples of the gel base include 'lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), Ethanolamine, diisopropanolamine, etc.), surfactants (polyethylene glycol monostearate, etc.), gums, water, absorption enhancers, anti-rash agents, etc., and one or two selected from these. These are used in combination. Further, the 'gel' may contain a preservative, an antioxidant, a flavoring agent, and the like.

 [0022] The cream is produced by a known method. Creams are produced, for example, by melting or emulsifying pranlukast hydrate in a base. The cream base is selected from those known or commonly used. Cream bases include, for example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (such as propylene glycol, 1,3-butylethylene glycol), higher alcohols (such as 2-hexyldecanol and cetanol). ), Emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption enhancers or rash preventives, etc., and one or more selected from these are used as a mixture. Can be Further, the cream may contain a preservative, an antioxidant or a flavoring agent.

[0023] The poultice is produced by a known method. The poultice is produced by, for example, melting pranlukast hydrate in a base, forming a kneaded product, and spreading and applying the mixture on a support. The compress base is selected from those known or commonly used. As a compress base, for example, Agents (polyacrylic acid, polybutylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium, etc.), Examples thereof include water, a solubilizing agent, a tackifier and an anti-rash agent, and one or more of these can be used in combination. Further, the poultice may contain a preservative, an antioxidant or a flavoring agent.

The patch is produced by a known method. The patch is produced, for example, by dissolving pranlukast hydrate in a patch base and spreading it on a support. The base for the patch is selected from those known or commonly used. Examples of the sticking base include a polymer base, oils and fats, higher fatty acids, tackifiers and rash preventives, and one or more of these selected from a mixture are used.

 The liniment is manufactured by a known method. As the liniment, for example, pranlukast hydrate is dissolved in one or more selected from water, alcohols (ethanol, polyethylene glycol, etc.), higher fatty acids, dalyserin, soap, emulsifier, suspending agent and the like. It is manufactured by suspending or emulsifying. Further, the liniment may contain a preservative, an antioxidant or a flavoring agent.

 [0025] Examples of injections for parenteral administration include solutions, suspensions or emulsions, and solid injections used by dissolving or suspending in a solvent before use. The injection is used by dissolving, suspending or emulsifying pranlukast hydrate in a solvent. Examples of the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and the like. These solvents are used alone or in combination of two or more. Further, this injection may contain a stabilizer, a solubilizer (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer or a preservative. Good. These are preferably produced by sterilization or aseptic operation in the final step. In addition, a sterile solid preparation, for example, a freeze-dried product can be produced, and then sterilized or dissolved in sterile distilled water for injection or other solvents before use.

[0026] Other dosage forms for parenteral administration include, for example, nebulizers, inhalants or sprays. One agent and the like can be mentioned. These preparations may contain a buffering agent that provides isotonicity with stabilizers such as sodium bisulfite other than commonly used diluents, for example, sodium chloride, sodium citrate, and citric acid. Contains isotonic agent! / You can do it. Methods for producing sprays are described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.

 [027] Inhalants include aerosols, powders for inhalation, and liquids for inhalation. The inhalant may be in the form of being dissolved or suspended in water or another appropriate medium before use. These inhalants are manufactured according to a known method.

 '' For inhalants, for example, in the case of liquids for inhalation, preservatives (salts such as salt, paraben, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), tonicity agents (Sodium chloride, concentrated glycerin, etc.), a thickener (carboxyvinyl polymer, etc.) or an absorption enhancer, etc., as appropriate, if necessary.

 [0O28] Powders for inhalation include lubricants (stearic acid and its salts), binders (starch, dextrin, etc.), excipients (lactose, cellulose, etc.), coloring agents, p-preservatives (chlorinated Benzalkonium, benzene, etc.) or an absorption enhancer, etc., if necessary. A nebulizer (atomizer, nebulizer) is usually used to administer the inhalable liquid, and a powder inhaler is usually used to administer the inhalable powder. Other compositions for parenteral administration include pranlukast hydrate and include suppositories for rectal administration and pessaries for vaginal administration, formulated in a conventional manner. It is.

 [0029] Also, the prophylactic and / or therapeutic agent for otitis media or otitis media, particularly exudative otitis media of the present invention, or the prophylactic and / or therapeutic agent for preventing hearing loss, tinnitus and ear occlusiveness (hereinafter, the preventive or therapeutic agent of the present invention May be used in combination with other drugs. When used in combination with other pharmacological agents, other drugs can be used to: 1) supplement and / or enhance the therapeutic effect of pranlukast hydrate; 2) improve the kinetics and absorption of pranlukast hydrate, reduce the dosage And / or 3) it is preferably used to reduce the side effects of pranlukast hydrate. '

The combination drug of the prophylactic or therapeutic agent of the present invention and another drug contains both components in one preparation. It may be in the form of a combined preparation or in the form of separate preparations. In the case of the separate preparations, the rain preparations may be administered simultaneously, or the preparations may be administered with a time difference between the administration times of the two preparations. In addition, administration with a time lag may be performed by administering pranlukast hydrate first and then administering another drug, or administering another drug first and then administering planlankast hydrate later. Each administration method may be the same or different. ,

[0030] The other drug may be a low molecular weight compound, and may be a high molecular weight protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy or antibody. May be a vaccine or the like. The dose of the other drug can be appropriately selected based on the dose clinically used. The mixing ratio of pranlukast hydrate and other drugs can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, target disease, symptoms, types of other drugs, and the like. For example, 0.01 to 100 parts by weight of another drug may be used for 1 part by weight of pranlukast hydrate. Other drugs may be administered in the same or different groups as shown below. Any one or more of them may be administered in combination at an appropriate ratio.

 [0031] Examples of the other drugs include expectorants, antibiotics, antihistamines, antiallergic drugs, steroid drugs, nonsteroidal anti-inflammatory drugs, anti-inflammatory enzyme drugs, and herbal medicines. Examples of expectorants include carbocysteine, ammonia whiskey semen, sodium bicarbonate, bromide hexate, ambroxol hydrochloride, ambroxol hydrochloride sustained release IJ, methyl cysteine hydrochloride, acetyl cysteine, Examples include L-ethyl cysteine hydrochloride or tyloxapol.

 [0032] Examples of the antibiotic include penicillin antibiotics (eg, amoxicillin), cephem antibiotics (eg, cefaclor) or macrolide antibiotics (eg, erythromycin ethyl succinate). Can be

[0033] Antihistamines include, for example, cyproheptadine hydrochloride, chlorfeniramine d-maleate, mequitazine, azelastine hydrochloride, xanthomid, terfenadine, emedastine fumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepotastine , Fexofenadine, mouth latadine, death mouth latadine, olopatadine hydrochloride, TAK—427, Z CR-2060, NIP-530, mometasonefo mouth, mizolastine, BP-294, andlast, auranofin or atarivastin.

 Examples of the antiallergic agent include ketotifen fumarate and the like.

 [0034] Examples of steroid drugs include clobetasol propionate, diflorazone acetate, fluocinonide, mometasone furanolevonate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, and diflucorto valerate Ron, .amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodone propionate, prednisolone valerate, fluocinolone propisonide acetate Beclomethasone, triamcinolone acetonide, flumethasone pivalate, alclomethasone propionate, clobetasone butyrate, preduzolone, Xantho xyconoretide, cortisone acetate, hydrocortisone, sodium hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludomouth cortisone acetate, prednisolone acetate, prednisolone sodium succinate, prednisolone butyl acetate, prednisolone sodium phosphate, halopredone acetate, methylprednisolone, Methylprednisolone acetate, sodium methylprednisolone succinate, triamcinolone, triamcinolone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramesazone acetate, betamethasone, flutizone dipropionate propionate, pudesonide, funorenizolide, ST-126P, ciclesonideol Nate, mometasone furan carbonate, plasterone sulfone , Deflazacort, methylprednisolone sulphonate or methylprednisolone sodium succinate.

Non-steroidal anti-inflammatory drugs include, for example, sazapyrine, sodium salicylate, aspirin, aspirin / dialuminate, diflunisal, indomethacin, suprofen, ゥ fenamate, dimethylisopropylazulene, bufexamac, fuerbinac, diclofenac Sodium, tonolemetin sodium, crinolinole, fempfen, napmetone, prognole methacine, indomethacin fanesyl, acamethasine, proglamatacin maleate, anfenac sodium, mofuezorakku, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, Furenorebiprofen axetil, ketoprofen, Phenoprofen calcium, thiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, aluminoprofen, zanoletoprofen, mefenamic acid, aluminum mefenamic acid, tolfenamic acid, floctafenin, ketofenilptazone, xyfenfenbutazone, Examples include piroxicam, tenoxicam, ampiroxicam, epirizonole, thialamide hydrochloride, tinolidine hydrochloride, emorfazone, sulpyrine, migrenine, sorbone, acetaminophen, phenacetin, dimethothiazine mesinoleate, and cimetride. Examples of the anti-inflammatory enzyme include lysozyme chloride, promelain, pronase, cerapeptase, or a combination preparation of streptokinase and streptodornase.

 Examples of herbal medicines include Shosaikoto, Kososan, Ryokeijutsukanto, Orokikenchuto, Shoseiryuto, Mapokanto, Eppikajutsuto, Rikkunshito, Mao-bushi-saishinto or Shiba Reinto and the like. In addition, other drugs include not only those that have been discovered to date and those that will be discovered in the future, based on the mechanism described above. ■ Hereinafter, the present invention will be described in detail with reference to examples (clinical pharmacology tests) and production examples. However, the examples and the like are for better understanding of the present invention, and the present invention is not limited thereto. . '

Example

 For 21 children with otitis media with effusion, pranlukast hydrate (trade name: onondry syrup) at 7.Omg / kg / day (70mgZkg / day as dry syrup) for at least 4 weeks (up to 14 weeks) ) Was administered and the efficacy was confirmed. Efficacy (drug efficacy) was evaluated comprehensively, mainly on hearing tests and tympanograms, with reference to tympanic membrane findings and subjective symptoms (deafness, tinnitus, ear sensation, etc.). As a result, 13 (61.9%) of 21 children with otitis media with effusion showed efficacy. The efficacy of pranlukast hydrate for otitis media with effusion in children is based on the efficacy of existing drugs (combination of anti-inflammatory enzymes and antihistamines, antiallergic drugs, herbal medicines, antibiotics, etc.). 5, 713-720 (1992)). In addition, pranlukast hydrate was also effective for patients who did not show efficacy with the antibiotic erythromycin ethylsuccinate '(brand name: erythro-mouth syndry syrup) or for patients who had been prolonged for a long time.

Based on the above results, administration of pranlukast hydrate improved hearing and eardrum findings. As a result, pranlukast hydrate was found to be effective as a treatment for otitis media with effusion.

 [0040] [Preparation example]

 Formulation Example 1: Production of capsules

 Spray-dry granulation of pranlukast hydrate (40 kg), lactose (19 kg) and additives (suitable amount) according to a conventional method, and granulation containing 625 mg of pranlukast hydrate in lg Obtained. Capsules containing pranlukast hydrate are filled by filling the obtained granules into No. 3 capsules according to a conventional method so that the content of pranlukast hydrate in one capsule is 112.5 mg. Agent was obtained.

Formulation Example 2: Production of dry syrup

 Granules are prepared from pranlukast hydrate (10 kg), sucrose (80 kg) and additives (appropriate amount) according to a conventional method to obtain a dry syrup containing lOOmg of pranlukast hydrate in lg of granules. Was.

 Industrial applicability

[0042] Pranlukast hydrate is very useful as a prophylactic and / or therapeutic agent for otitis media with effusion. '

Claims

The scope of the claims  [I] A prophylactic and / or therapeutic agent for otitis media or otitis media comprising pranlukast hydrate.  [2] The agent of claim 1, wherein the otitis media is exudative otitis media.  [3] Hearing loss, tinnitus and ear obstruction sensation The preventive aid Z or therapeutic agent according to claim 1, which ameliorates one or more selected symptoms.  [4] The prophylactic and / or therapeutic agent according to claim 1, which is an agent for reducing exudate. [5] A preventive and / or therapeutic agent for preventing hearing loss, tinnitus or ear sensation, which comprises pranlukast hydrate. [6] The prophylactic and / or Z or therapeutic agent according to claim 1 or 5, wherein the dose of plannorecast hydrate per patient is 50 to 450 mg. [7] The preventive and / or therapeutic agent or therapeutic agent according to claim 6, wherein the daily dose of pranlukast hydrate to a patient is 112.5 mg, 225 mg or 450 mg. [8] Patients with pranlukast hydrate dose power per day S450mg, 225mg daily 8. The preventive and / or therapeutic agent according to claim 7, wherein the agent is administered twice. [9] Patients to administer pranlukast hydrate twice a day, twice daily, in capsules containing 450 mg of pranlukast hydrate and containing 112.5 mg of pranlukast hydrate The prophylactic agent Z or the therapeutic agent according to claim 7, which is characterized in that: [10] The prophylactic and / or therapeutic agent according to claim 1 or 5, wherein the daily dose of plannorecast hydrate per lkg of the patient's body weight is 2 to 10 mg. [II] The agent according to claim 10, wherein the daily dose of pranlukast hydrate is 7 mg / kg of the patient's body weight.  [12] The patient's daily dosage strength of pranlukast hydrate is Omg, 70 mg, 100 mg, 140 mg, 200 mg, or 280 mg, and the prophylaxis and Z or Therapeutic agent.  [13] Pranlukast hydrate and expectorants, antibiotics, antihistamines, antiallergic drugs, HIE was used for echiseki A medicament characterized in that it is a combination of one or two or more selected from a loyd drug, a nonsteroidal anti-inflammatory drug, an anti-inflammatory enzyme drug and a Chinese medicine. [14] A method for preventing and / or treating otitis media with effusion in a mammal, comprising administering 2 to 10 mg / kg of pranlukast hydrate per day to the mammal. [15] A prophylactic and / or therapeutic agent for the prevention of hearing loss, tinnitus or ear sensation in a mammal, which is administered at a dose of 2 to 10 mg / kg per day of pranlukast hydrate to the mammal.  [16] Pranlukast hydrate from 2 to per day: LOmg / kg, expectorant, antibiotic, antihistamine, antiallergic, steroid, nonsteroidal anti-inflammatory, anti-inflammatory, And one or more selected Chinese medicines are administered to mammals A method of preventing and treating otitis in a mammal.  [17] Pranlukast hydrate from 2 to 2 per day: LOmg / kg, expectorant, antibiotic, antihistamine, antiallergic, steroid, nonsteroidal anti-inflammatory, anti-inflammatory enzyme, A method for preventing and / or treating hearing loss, tinnitus or ear sensation in a mammal, which comprises administering one or more selected ones to a mammal.  [18] Use of pranlukast hydrate for the manufacture of a prophylactic and / or therapeutic agent for hearing loss, tinnitus or ear obstruction.