JPWO2005058879A1 - Preventive and / or therapeutic agent for exudative otitis media - Google Patents

Abstract

The present invention relates to a preventive and / or therapeutic agent for exudative otitis media containing pranlukast hydrate as an active ingredient. In the preventive and / or therapeutic agent for exudative otitis media of the present invention, pranlukast hydrate has a function of reducing middle ear exudate, and is a medicament for improving various symptoms such as hearing loss, tinnitus, and ear obstruction. Useful.

Description

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

The number of patients with otitis media (medical treatment) is 305,000 (Ministry of Health, Labor and Welfare patient survey: 2001), of which about 40-50% is exudative otitis media.
Exudative otitis media is a common otitis media in children and the elderly.If the function of the eustachian tube that connects the middle ear and the back of the nose deteriorates, the regulation of the pressure inside and outside the eardrum is poor, and the middle ear becomes negative pressure. Liquid oozes and accumulates. Therefore, it presents symptoms such as hearing loss and a feeling of ear obstruction. When patients have acute upper respiratory tract inflammation, chronic sinusitis, allergic rhinitis, and adenoid hypertrophy, inflammation of the nose and throat always affects the middle ear through the ear canal, making it protracted and intractable. When exudative otitis media becomes intractable, sequelae such as hearing loss remain and the need for surgery arises, so early treatment is regarded as important. In the case of children, it is difficult to frequently perform surgical procedures such as tympanic incision and tympanic tube placement, and drugs for minimizing surgical procedures are required.

  In general, therapeutic agents for exudative otitis media are mainly expectorants (eg, carbocysteine) and macrolide antibiotics (eg, erythromycin ethyl succinate, clarithromycin, etc.), but sufficient effects are obtained. However, the development of a highly effective oral preparation has been eagerly desired.

On the other hand, 4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran 1/2 hydrate (generic name: pranlukast water) Japanese product (trade name Onon) is used as a therapeutic agent for bronchial asthma and allergic rhinitis, and has been confirmed to be sufficiently safe. In addition, it has been reported that pranlukast hydrate is effective in a pathological model of exudative otitis media in rats (see Non-Patent Document 1), but this document does not describe any effectiveness in humans. .
Auris Nasus Larynx, (Netherlands), 2002, p. 127-132

  An object of the present invention is to provide a prophylactic and / or therapeutic agent for otitis media or otitis media which is excellent in effectiveness and can be administered orally to human patients.

  In view of the above problems, the present inventors have conducted extensive studies, and as a result, pranlukast hydrate surprisingly reduces the middle ear fluid and further improves hearing and ear obstruction. The present invention was found for the first time clinically and usefully as an agent for the prevention and / or treatment of otitis media or otitis media, particularly exudative otitis media.

That is, the present invention provides (1) a prophylactic and / or therapeutic agent for otitis media or otitis media, comprising pranlukast hydrate,
(2) The preventive and / or therapeutic agent according to (1) above, wherein the otitis media is exudative otitis media,
(3) The preventive and / or therapeutic agent according to the above item (1), which improves at least one symptom selected from hearing loss, tinnitus, and ear obstruction;
(4) The preventive and / or therapeutic agent according to (1) above, which is an exudate reducing agent,
(5) A preventive and / or therapeutic agent for hearing loss, tinnitus or ear obstruction, characterized by containing pranlukast hydrate,
(6) The prophylactic and / or therapeutic agent according to (1) or (5) above, wherein the daily dose of pranlukast hydrate is 50 to 450 mg,
(7) The prophylactic and / or therapeutic agent according to (6) above, wherein the daily dose of pranlukast hydrate is 112.5 mg, 225 mg or 450 mg,
(8) The prophylactic and / or therapeutic agent according to (7) above, wherein the daily dose of pranlukast hydrate is 450 mg and 225 mg is administered twice a day,
(9) The daily dose of pranlukast hydrate is 450 mg, and the capsule containing 112.5 mg of pranlukast hydrate is to be administered 2 capsules at a time, twice a day. A prophylactic and / or therapeutic agent according to (8) above, characterized by:
(10) The prophylactic and / or therapeutic agent according to (1) or (5) above, wherein the daily dose of pranlukast hydrate is 2 to 10 mg per kg of the patient's body weight,
(11) The prophylactic and / or therapeutic agent according to (10) above, wherein the daily dose of pranlukast hydrate is 7 mg per kg of the patient's body weight,
(12) The prophylactic and / or therapeutic agent according to (6) above, wherein the daily dose of pranlukast 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 agents, steroids, non-steroidal anti-inflammatory drugs, anti-inflammatory enzymes, and traditional Chinese medicines A medicine characterized by being combined with
(14) A method for preventing and / or treating exudative otitis media 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 hearing loss, tinnitus or ear obstruction in a mammal, characterized by administering 2-10 mg / kg of pranlukast hydrate per day to the mammal,
(16) Pranlukast hydrate 2-10 mg / kg per day, expectorant, antibiotic, antihistamine, antiallergic, steroid, nonsteroidal anti-inflammatory, anti-inflammatory enzyme, and Chinese medicine A method for preventing and / or treating exudative otitis media in a mammal, which comprises administering to the mammal one or more selected from
(17) Pranlukast hydrate at 2-10 mg / kg per day, expectorant, antibiotic, antihistamine, antiallergic, steroid, nonsteroidal anti-inflammatory, anti-inflammatory enzyme, and Chinese medicine A method for preventing and / or treating hearing loss, tinnitus or ear obstruction in a mammal, characterized by administering to the mammal one or more selected from: and (18) deafness, tinnitus or ear obstruction Use of pranlukast hydrate for the manufacture of a prophylactic and / or therapeutic agent
About.

  The present invention provides an effective preventive and / or therapeutic agent for otitis media or otitis media, particularly exudative otitis media, and can prevent and / or treat various symptoms of otitis media or otitis media, particularly exudative otitis media. In addition, the present invention can improve hearing loss, tinnitus, and ear obstruction associated with exudative otitis media.

で示される４−オキソ−８−［４−（４−フェニルブトキシ）ベンゾイルアミノ］−２−（テトラゾール−５−イル）−４Ｈ−１−ベンゾピラン １／２水和物である。The pranlukast hydrate used in the present invention has the formula (A)

4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran 1/2 hydrate represented by the formula:

[Method for producing compound of the present invention]
The production of pranlukast hydrate can be carried out in accordance with, for example, the method described in JP-A 61-050977.

[toxicity]
The toxicity of pranlukast hydrate was extremely low and confirmed to be sufficiently safe for use as a pharmaceutical product. For example, as the acute toxicity of pranlukast hydrate, the minimum lethal dose was 2000 mg / kg or more when administered orally or subcutaneously to mice or rats (both male and female).

[Application to pharmaceutical products]
Pranlukast hydrate is useful as a medicament for the prevention and / or treatment of otitis media or otitis media, particularly exudative otitis media. In addition, pranlukast hydrate improves various symptoms such as deafness or tinnitus associated with exudative otitis media and is therefore useful as a medicament for the prevention and / or treatment of hearing loss, tinnitus, and ear obstruction.

A medicament containing pranlukast hydrate as an active ingredient can be used systemically or locally.
The dose of pranlukast hydrate varies depending on age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but may be specifically administered individually so as to obtain the desired effect of the present invention. For example, the daily dose per human patient is preferably about 25 mg to about 2500 mg, more preferably about 112.5 mg to about 450 mg, and even more preferably 225 mg to 450 mg.

  In addition, the daily dose when pranlukast hydrate is administered to children is preferably about 2 to 10 mg, more preferably about 5 mg to about 8 mg per kg body weight of the pediatric patient, Preferably it is about 7 mg. In addition, when administered to a pediatric patient having a body weight of 12 kg or more and less than 18 kg, the daily dose of pranlukast hydrate is preferably about 50 to 100 mg, more preferably about 50 mg or about 100 mg per day. is there. When administered to a pediatric patient weighing 18 kg or more and less than 25 kg, the daily dose of pranlukast hydrate is preferably about 70 to 140 mg, more preferably about 70 mg or about 140 mg. When administered to a pediatric patient having a body weight of 25 kg or more and less than 35 kg, the daily dose of pranlukast hydrate is preferably about 100 mg to about 200 mg, more preferably about 100 mg or about 200 mg. When administered to a pediatric patient weighing 35 kg or more and less than 45 kg, the daily dose of pranlukast hydrate is preferably about 140 to 280 mg, more preferably about 140 mg or about 280 mg.

  As an administration method, either oral administration or parenteral administration is preferably used, but oral administration is more preferable. In the case of oral administration, for example, the above dose is divided into once to several times a day, preferably once to about 4 times a day, more preferably once to about 2 times a day. preferable.

Of course, as described above, since the dose, administration method, and number of administrations vary depending on various conditions, the dose per patient per day may be less than or exceeding the above range.
When manufacturing pranlukast hydrate as said pharmaceutical, it can be set as a formulation known per se. The preparation can be a solid preparation or liquid for internal use for oral administration, or an injection, external preparation, suppository or inhalant for parenteral administration.

Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders or granules.
In such a solid preparation for internal use, pranlukast hydrate is used as it is, mixed with additives or granulated (for example, stirring granulation method, fluidized bed granulation method, dry granulation method, rolling stirring flow) Layered granulation method, etc.), and is produced according to conventional methods (for example, capsule filling in the case of capsules, tableting in the case of tablets, etc.). The said additive may mix | blend 1 type (s) or 2 or more types suitably. Examples of additives include excipients (eg, lactose, mannitol, glucose, microcrystalline cellulose, corn starch, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), dispersing agents ( For example, corn starch, etc.), disintegrating agents (for example, calcium calcium glycolate), lubricants (for example, magnesium stearate), stabilizers, solubilizers (for example, glutamic acid, aspartic acid, etc.), water-soluble Polymer [eg, celluloses (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, etc.), synthetic polymers (eg, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, etc.)] or sweet (For example, sucrose, powdered sugar, sucrose, fructose, glucose, lactose, reduced maltose water candy, powdered reduced maltose water candy, glucose fructose liquid sugar, fructose glucose liquid sugar, honey, sorbitol, maltitol, mannitol, xylitol, erythritol , Aspartame, saccharin, sodium saccharin, etc.). The granules or tablets may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.) if necessary, and the coating is composed of two or more layers. Also good. When manufacturing as a capsule, the above excipients are selected as appropriate, and capsules that are evenly mixed with pranlukast hydrate or granulated or coated with an appropriate coating agent Or may be encapsulated with a capsule base whose plasticity is increased by adding glycerin or sorbitol to a suitable capsule base (gelatin or the like). If necessary, a colorant or a preservative [sulfur dioxide, parabens (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate)] or the like can be added to these capsule bases. Capsules include hard capsules or soft capsules.
Moreover, it is preferable that 1 to several, preferably 1 to about 2 tablets or capsules are administered at a time. For this reason, tablets or capsules are prepared so that pranlukast hydrate is contained in an amount of about 50 to 250 mg, preferably about 100 to 120 mg, especially about 112.5 mg per tablet or capsule. preferable.

  Examples of liquids for internal use for oral administration include solutions, suspensions / emulsions, syrups, dissolution-type preparations (for example, dry syrups) or elixirs. In such a liquid for internal use, pranlukast hydrate is dissolved, suspended or emulsified in a diluent generally used in liquids for internal use (for example, purified water, ethanol or a mixture thereof). . Furthermore, this liquid agent 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 preparation can be produced, for example, by mixing pranlukast hydrate with, for example, sucrose, powdered sugar, sucrose, fructose, glucose or lactose. The dry syrup may be granulated according to a conventional method.

  Examples of dosage forms for parenteral administration include external preparations and injections. Examples of the dosage form of the external preparation include ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, and sprays.

  The ointment is produced by a known method. The ointment is produced, for example, by mixing or melting pranlukast hydrate in a base. The ointment base is selected from known or commonly used ones. Examples of the ointment base include 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, etc. ), Waxes (such as beeswax, whale wax, ceresin), surfactants (such as polyoxyethylene alkyl ether phosphates), higher alcohols (such as cetanol, stearyl alcohol, cetostearyl alcohol), silicone oils (such as dimethylpolysiloxane) ), Hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol etc.), vegetable oil ( Mashi oil, olive oil, sesame oil, turpentine oil, etc.), animal oil (mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption promoter or anti-rash agent, etc., and one or more selected from these Are used as a mixture. Furthermore, the ointment may contain a humectant, a preservative, a stabilizer, an antioxidant or a flavoring agent.

  The gel is produced by a known method. The gel is 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 (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.), Surfactants (polyethylene glycol monostearate, etc.), gums, water, absorption promoters or anti-rash agents and the like may be mentioned, and one or more selected from these may be used in combination. Furthermore, the gel may contain a preservative, an antioxidant, a flavoring agent, or the like.

  The cream is produced by a known method. The cream is produced, for example, by melting or emulsifying pranlukast hydrate in a base. The cream base is selected from known or commonly used ones. Examples of cream bases include higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (such as propylene glycol and 1,3-butylene glycol), higher alcohols (such as 2-hexyldecanol and cetanol), and emulsifiers (polyoxy). Ethylene alkyl ethers, fatty acid esters, etc.), water, absorption accelerators or rash prevention agents, and the like, and one or two or more selected from these are used. Furthermore, the cream may contain a preservative, an antioxidant or a flavoring agent.

  The poultice is produced by a known method. The poultice is manufactured, for example, by melting pranlukast hydrate in a base, and spreading and applying it as a kneaded material on a support. The poultice base is selected from known or commonly used ones. As the poultice base, for example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, Talc, calcium, magnesium, etc.), water, solubilizers, tackifiers or anti-rash agents, and the like. One or more selected from these may be used in combination. Furthermore, 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 melting pranlukast hydrate in a patch base and spreading and coating it on a support. The base for patch is selected from known or commonly used ones. Examples of the base for sticking include polymer bases, fats and oils, higher fatty acids, tackifiers, anti-rash agents, and the like, and one or more selected from these are used in combination.
The liniment is produced by a known method. The liniment is, for example, pranlukast hydrate dissolved in one or more selected from water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, Manufactured by suspension or emulsification. Furthermore, the liniment may contain a preservative, an antioxidant, a flavoring agent, or the like.

  Examples of injections for parenteral administration include solutions, suspensions or emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An 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, the injection may contain a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent or a preservative. . These are preferably sterilized in the final step or manufactured by aseptic operation. In addition, a sterile solid preparation such as a freeze-dried product can be produced and used by dissolving in sterilized or sterile distilled water for injection or other solvent before use.

  Examples of other dosage forms for parenteral administration include sprays, inhalants, sprays and the like. In addition to the commonly used diluents, these preparations contain a buffer that provides isotonicity with a stabilizer such as sodium bisulfite, for example, an isotonic agent such as sodium chloride, sodium citrate or citric acid. You may contain. The production method of the spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355.

Inhalants include aerosols, inhalable powders or inhalable solutions. The inhalant may be used in the form of being dissolved or suspended in water or other suitable medium at the time of use. These inhalants are produced according to known methods.
Inhalants, for example, in the case of inhalation solutions, preservatives (benzalkonium chloride, parabens, etc.), colorants, buffering agents (sodium phosphate, sodium acetate, etc.), isotonic agents (sodium chloride, Concentrated glycerin and the like), thickener (carboxyvinyl polymer and the like), absorption accelerator and the like are appropriately selected as necessary.

Powders for inhalation include lubricants (stearic acid and its salts), binders (starch, dextrin, etc.), excipients (lactose, cellulose, etc.), coloring agents, preservatives (benzalkonium chloride, parabens, etc.) ) Or an absorption enhancer or the like as necessary.
A nebulizer (atomizer or nebulizer) is usually used when administering an inhalation solution, and an inhalation administration device for powder medicine is usually used when administering an inhalable powder.
Other compositions for parenteral administration include pranlukast hydrate and include suppositories for rectal administration, pessaries for intravaginal administration, etc., formulated in a conventional manner.

In addition, the preventive and / or therapeutic agent for inner otitis or otitis media of the present invention, particularly exudative otitis media, or the preventive and / or therapeutic agent for hearing loss, tinnitus and ear obstruction (hereinafter abbreviated as the preventive or therapeutic agent of the present invention). .) Can also be used in combination with other drugs. When used in combination with other drugs, the other drugs are: 1) supplementation and / or enhancement of the therapeutic effect of pranlukast hydrate, 2) improvement of kinetics and absorption of pranlukast hydrate, reduction of dosage, And / or 3) It is preferably used for reducing the side effects of pranlukast hydrate.
The combination agent of the preventive or therapeutic agent of the present invention and another drug may be in the form of a combination drug containing both components in one preparation, or may be in the form of separate preparations. As the administration method in the case of separate preparations, both preparations may be administered simultaneously, and administration may be performed with a time difference between the administration times of both preparations. In addition, administration by time difference may be performed by administering pranlukast hydrate first and other drugs later, or administering other drugs first and pranlukast hydrate later. Of course, each administration method may be the same or different.

  The other drug may be a low molecular weight compound, and may be a high molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy or antibody, or a vaccine, etc. Also good. The dosage of other drugs can be appropriately selected based on the clinically used dose. In addition, the blending ratio of pranlukast hydrate and the other drug can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, target disease, symptom, or other drug type. 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 by combining one or two or more from the same group and different groups shown below in an appropriate ratio.

Examples of the other drugs include expectorants, antibiotics, antihistamines, antiallergic drugs, steroid drugs, nonsteroidal anti-inflammatory drugs, anti-inflammatory enzymes, and traditional Chinese medicines.
Examples of expectorants include carbocysteine, ammonia fennel, sodium bicarbonate, bromhexine hydrochloride, ambroxol hydrochloride, ambroxol hydrochloride sustained release agent, methylcysteine hydrochloride, acetylcysteine, L-ethylcysteine hydrochloride or tyloxapol. Can be mentioned.

  Examples of antibiotics include penicillin antibiotics (eg, amoxiline), cephem antibiotics (eg, cefaclor), and macrolide antibiotics (eg, erythromycin ethyl succinate).

Antihistamines include, for example, cyproheptadine hydrochloride, chlorpheniramine d-maleate, mequitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepotastine, fexofenadine, loratadine, desalt Examples include loratadine, olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, andlast, auranofin or acribastine.
Examples of the antiallergic agent include ketotifen fumarate.

  Examples of steroid drugs include clobetasol propionate, diflorazone acetate, fluocinonide, mometasone furanate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, diflucortron valerate, amsinonide, halsinonide, dexamethasone, Dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodon propionate, prednisolone valerate acetate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide, pivalic acid flumetazone Alclomethasone acid, clobetasone butyrate, prednisolone, fludroxycol Cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, fludrocortisone acetate, prednisolone acetate, sodium prednisolone succinate, prednisolone butyl acetate, sodium prednisolone phosphate, halopredon acetate, methylprednisolone acetate, methyl prednisolone acetate Methylprednisolone sodium, triamcinolone, triamcinolone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, betamethasone, fluticasone propionate, budesonide, flunisolide, ST-126P, ciclesonide, dexamethasone paromithonate, mometasone furanzone Teronsulfonate, Deflazaco , And the like methylprednisolone thread descriptor sulphonate or methylprednisolone sodium succinate.

  Non-steroidal anti-inflammatory drugs include, for example, Sazapyrine, sodium salicylate, aspirin, aspirin dialuminate, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac sodium, tolmetin sodium, clinolyl, fenbufen, Napumetone, Progouritacin, Indomethacin Farnesyl, Acemetacin, Progouritacin Maleate, Ampenac Sodium, Mofezolac, Etodolac, Ibuprofen, Ibuprofen Piconol, Naproxen, Flurbiprofen, Flurbiprofen Axetil, Ketoprofen, Fenoprofen Calcium, thiaprofen, oxaprozin, pranoprofen, Soprofen sodium, aluminoprofen, zaltoprofen, mefenamic acid, mefenamic acid aluminum, tolfenamic acid, fructaphenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, epilysole, thiaramide hydrochloride, tinolidine hydrochloride, emorphazone, Examples include sulpyrine, migrenin, sorbone, acetaminophen, phenacetin, dimethothiazine mesylate, and cimetrid compounding agent.

  Examples of the anti-inflammatory enzyme include lysozyme chloride, bromelain, pronase, serrapeptase, or a streptokinase / streptodornase combination agent.

Herbal medicines include, for example, Sho-saiko-to, Kosou-san, Sakai-Kai-San-yu, Hakuen-kenchu-yu, Kosei-ryu, Ma-an-yu, Yue-ka-ka-to, Rikkunshi-yu, Mao-bushi-saishin-to or Shiba For example, Tsukuyu.
In addition, other drugs include not only those found so far, but also those that will be found in the future based on the above-described mechanism.

  Hereinafter, the present invention will be described in detail with reference to examples (clinical pharmacological tests) and production examples. However, the examples and the like are for understanding the present invention well, and the present invention is not limited thereto.

In 21 pediatric patients with exudative otitis media, pranlukast hydrate (trade name: Onon dry syrup) is 7.0 mg / kg / day (70 mg / kg / day as dry syrup) for 4 weeks or more (maximum 14 weeks) ) And confirmed the effectiveness. Efficacy (drug efficacy) was evaluated comprehensively with reference to the eardrum findings and subjective symptoms (deafness, tinnitus, ear obstruction, etc.), with a focus on hearing tests and tympanograms. As a result, effectiveness was recognized in 13 (61.9%) of 21 pediatric patients with exudative otitis media. The effectiveness of pranlukast hydrate for exudative otitis media in children is based on the effectiveness of existing drugs (combination of anti-inflammatory enzyme and antihistamine, antiallergic drugs, traditional Chinese medicines, antibiotics, etc.). 5, 713-720 (1992)) or higher. In addition, pranlukast hydrate was also effective in patients who did not show efficacy with the antibiotic erythromycin succinate (trade name: erythrosine dry syrup) or who had been prolonged for a long time.
From the above results, it was clarified that pranlukast hydrate is effective as a therapeutic agent for exudative otitis media because administration of pranlukast hydrate has improved hearing and tympanic findings.

[Formulation example]
Formulation Example 1: Production of capsules Pranlukast hydrate (40 kg), lactose (19 kg) and additives (appropriate amount) are spray-dried and granulated according to a conventional method, and pranlukast hydrate in 1 g of the granulated product. Of 625 mg was obtained. Capsules containing pranlukast hydrate by filling the obtained granulated product into No. 3 capsules in a usual manner so that the content of pranlukast hydrate is 112.5 mg in one capsule Got.

Formulation Example 2: Manufacture of dry syrup preparation Granules are prepared according to a conventional method with pranlukast hydrate (10 kg), sucrose (80 kg) and additives (appropriate amount), and pranlukast hydrate is added to 1 g of the granule. A dry syrup containing 100 mg was obtained.

Pranlukast hydrate is very useful as a preventive and / or therapeutic agent for exudative otitis media.

Claims (18)

  A prophylactic and / or therapeutic agent for otitis media or otitis media, comprising lanlucast hydrate.   The preventive and / or therapeutic agent according to claim 1, wherein the otitis media is exudative otitis media.   The prophylactic and / or therapeutic agent according to claim 1, which improves at least one symptom selected from hearing loss, tinnitus, and ear obstruction.   The preventive and / or therapeutic agent according to claim 1, which is an exudate reducing agent.   A prophylactic and / or therapeutic agent for hearing loss, tinnitus or ear obstruction, characterized by containing pranlukast hydrate.   6. The prophylactic and / or therapeutic agent according to claim 1 or 5, wherein the daily dose of pranlukast hydrate is 50 to 450 mg per patient.   The prophylactic and / or therapeutic agent according to claim 6, wherein the daily dose of pranlukast hydrate is 112.5 mg, 225 mg or 450 mg.   The prophylactic and / or therapeutic agent according to claim 7, wherein the daily dose of pranlukast hydrate is 450 mg, and 225 mg is administered twice a day.   The daily dose of pranlukast hydrate is 450 mg, and the capsule containing 112.5 mg of pranlukast hydrate is administered twice a day, twice a day. The preventive and / or therapeutic agent according to claim 7.   6. The prophylactic and / or therapeutic agent according to claim 1 or 5, wherein the daily dose of pranlukast hydrate is 2 to 10 mg per kg body weight of the patient.   11. The prophylactic and / or therapeutic agent according to claim 10, wherein the daily dose of pranlukast hydrate is 7 mg per 1 kg body weight of the patient.   The prophylactic and / or therapeutic agent according to claim 5, wherein the daily dose of pranlukast hydrate is 50 mg, 70 mg, 100 mg, 140 mg, 200 mg, or 280 mg.   A combination of pranlukast hydrate and one or more selected from expectorants, antibiotics, antihistamines, antiallergic drugs, steroids, nonsteroidal anti-inflammatory drugs, anti-inflammatory enzymes, and traditional Chinese medicines The medicine characterized by comprising.   A method for preventing and / or treating exudative otitis media in a mammal, comprising administering 2 to 10 mg / kg of pranlukast hydrate per day to the mammal.   A prophylactic and / or therapeutic agent for hearing loss, tinnitus or ear obstruction in mammals, comprising administering 2 to 10 mg / kg of pranlukast hydrate per day to the mammal.   Pranlukast hydrate per day, 2-10 mg / kg, selected from expectorants, antibiotics, antihistamines, antiallergic drugs, steroid drugs, nonsteroidal anti-inflammatory drugs, anti-inflammatory enzymes, and traditional Chinese medicines A method for preventing and / or treating otitis in a mammal, which comprises administering one or more kinds to the mammal.   Pranlukast hydrate per day, 2-10 mg / kg, selected from expectorants, antibiotics, antihistamines, antiallergic drugs, steroid drugs, nonsteroidal anti-inflammatory drugs, anti-inflammatory enzymes, and traditional Chinese medicines A method for preventing and / or treating hearing loss, tinnitus, or ear obstruction in a mammal, comprising administering one or more of the above to the mammal. Use of pranlukast hydrate for the manufacture of an agent for the prevention and / or treatment of hearing loss, tinnitus or ear obstruction.