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WO2005058878A1 - Preventive and/or remedy for dysmenorrhea - Google Patents

Preventive and/or remedy for dysmenorrhea Download PDF

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Publication number
WO2005058878A1
WO2005058878A1 PCT/JP2004/018714 JP2004018714W WO2005058878A1 WO 2005058878 A1 WO2005058878 A1 WO 2005058878A1 JP 2004018714 W JP2004018714 W JP 2004018714W WO 2005058878 A1 WO2005058878 A1 WO 2005058878A1
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WO
WIPO (PCT)
Prior art keywords
dysmenorrhea
symptoms
therapeutic agent
pranlukast hydrate
prophylactic
Prior art date
Application number
PCT/JP2004/018714
Other languages
French (fr)
Japanese (ja)
Inventor
Kenzo Nakao
Ken Mizushima
Hajime Yamamotoya
Toshio Takakuwa
Original Assignee
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Priority to JP2005516318A priority Critical patent/JPWO2005058878A1/en
Publication of WO2005058878A1 publication Critical patent/WO2005058878A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a preventive and / or therapeutic agent for dysmenorrhea, comprising pranlukast hydrate as an active ingredient.
  • Dysmenorrhea is a pathological condition that accompanies menstruation before the onset of menstruation and that accompanies menstruation, and mainly includes pain (for example, menstrual pain, lower abdominal pain, back pain, etc.). This is a syndrome that appears as a symptom.
  • lower abdominal symptoms eg, lower abdominal tension, lower abdominal discomfort, etc.
  • lower back symptoms eg, lower back malaise, etc.
  • digestive symptoms eg, Stomach pain, nausea, vomiting, diarrhea, anorexia, loss of appetite, etc.
  • vascular neurological symptoms eg, headache, heavy headache, cold sweat, palpitations, etc.
  • mental symptoms eg, frustration, irritability, depression, etc.
  • Symptoms such as general symptoms (eg, general malaise, fatigue), dizziness, nausea, flushing of the face, sweating or increased salivary secretion are also observed.
  • Dysmenorrhea is a frequent gynecological disease, and the number of dysmenorrhea patients is on the rise at present.
  • Dysmenorrhea is classified into two types: organic (secondary) dysmenorrhea and functional (primary) dysmenorrhea.
  • Organic dysmenorrhea is dysmenorrhea in which an organic lesion causing pain is present in the pelvic cavity.
  • functional dysmenorrhea has no organic lesions, and many etiologies such as theories of endocrine ataxia, dysgenesis, and neurological factors have been advocated, but the cause is still unknown. is there.
  • dysmenorrhea is mainly caused by pain
  • nonsteroidal anti-inflammatory drugs are mainly used to relieve analgesia.
  • NSAIDs have side effects such as gastrointestinal disorders, patient compliance is poor and long-term administration is difficult.
  • many patients do not have sufficient analgesic effects with the use of NSAIDs. Therefore, development of a preventive / therapeutic agent for dysmenorrhea (particularly functional dysmenorrhea) which is excellent in efficacy and safety and can be administered for a long period of time has been eagerly desired.
  • Patent Document 1 JP 2002-187855 A
  • An object of the present invention is to provide a prophylactic and / or therapeutic agent for dysmenorrhea (particularly functional dysmenorrhea) which is excellent in efficacy and safety and can be administered to a patient for a long period of time.
  • a preventive and / or therapeutic agent for dysmenorrhea comprising plannorecast hydrate as an active ingredient
  • the dysmenorrhea is at least one selected from pain, lower abdominal symptoms, lumbar symptoms, gastrointestinal symptoms, vascular nerve symptoms, psychiatric symptoms, systemic symptoms, dizziness, nausea, hot flush, sweating, and increased salivation.
  • the prophylactic and / or therapeutic agent or the therapeutic agent according to the above (1) which is accompanied by the above-mentioned symptoms and ameliorates at least one of the symptoms.
  • the daily dosage of pranlukast hydrate for a patient is 450 mg, and 2 capsules containing 112.5 mg of pranlukast hydrate should be administered twice a day, two capsules at a time.
  • (11) a method for preventing and / or treating dysmenorrhea in a mammal, which comprises administering an effective amount of pranlukast hydrate to the mammal,
  • the present invention provides a safe and more effective agent for preventing and / or treating dysmenorrhea, and can prevent and / or treat various symptoms of dysmenorrhea.
  • Prevention and / or treatment of dysmenorrhea includes suppression, alleviation, mild Includes reduction or improvement.
  • the “dysmenorrhea” in the present invention includes organic dysmenorrhea and functional dysmenorrhea.
  • Plannorecast hydrate which is the active ingredient of the present invention, has the formula (A)
  • Production of pranlukast hydrate can be carried out, for example, according to the method described in JP-A-61-050977.
  • the toxicity of pranlukast hydrate was extremely low, confirming that it is safe enough for use as a pharmaceutical.
  • the minimum lethal dose was 2000 mg / kg or more when administered orally or subcutaneously to mice or rats (both male and female).
  • Pranlukast hydrate is a symptom of dysmenorrhea pain (eg, menstrual pain, lower abdominal pain, lower back pain, etc.), lower abdominal symptoms (eg, lower abdominal tension, lower abdominal discomfort, etc.), lower back symptoms ( For example, lumbar fatigue, gastrointestinal symptoms (eg, stomach pain, nausea, vomiting, diarrhea, loss of appetite, loss of appetite, etc.), vascular nerve symptoms (eg, headache, severe headache, cold sweat, increased palpitation, etc.), mental disorders It can prevent and / or treat symptoms (eg, frustration, irritability, depression, etc.), systemic symptoms (eg, general malaise, easy fatigue, etc.), dizziness, nausea, hot flush, sweating, increased salivation, and the like.
  • symptoms eg, frustration, irritability, depression, etc.
  • systemic symptoms eg, general malaise, easy fatigue, etc.
  • dizziness nausea, hot flush, sweating, increased salivation, and the like.
  • hydrates is useful as a treatment for various symptoms of dysmenorrhea and may also be useful as a root treatment for dysmenorrhea.
  • 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, but may be individually and specifically administered so as to obtain the desired effect of the present invention.
  • the daily dose of a human patient is preferably about 25 mg to about 25 OO mg, more preferably 112.5 mg strength, about 450 mg, more preferably about 225 mg strength, and even more preferably about 225 mg strength, 450 mg strength.
  • oral administration either oral administration or parenteral administration is preferably used, but oral administration is more preferred.
  • the daily dose per patient may be less than or greater than the above range.
  • pranlukast hydrate 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.
  • Examples of the solid preparation for oral administration for oral administration include tablets, pills, capsules, powders, and granules.
  • plannorecast hydrate is mixed or granulated with force as it is (e.g., stirring granulation method, fluidized bed granulation method, dry granulation method, tumbling stirring fluidization).
  • Layer granulation method, etc. and manufactured according to a conventional method (for example, capsule filling for capsules, tableting for tablets, etc.).
  • the above additives may be used alone or in combination of two or more.
  • additives include excipients (eg, ratatose, mannitol, darcos, microcrystalline cellulose, corn starch, etc.), binders (eg, hydroxypropyl cellulose, polybutylpyrrolidone, magnesium aluminate metasilicate, etc.), Dispersant (example For example, corn starch and the like), disintegrants (for example, calcium cellulose glycolate), lubricants (for example, magnesium stearate), stabilizers, dissolution aids (for example, daltamic acid, aspartic acid, etc.), Water-soluble polymers [for example, celluloses (for example, hydroxypropinoresenorelose, hydroxypropinolemethinoresenorelose, methinoresenorelose, etc.), synthetic polymers (for example, polyethylene glycol, polyvinylinolepyrrolidone, polybutyla) Or sweeteners (eg, sucrose, powdered sugar, sucrose, fructose,
  • Reduced maltose water powdered reduced maltose water, glucose fructose liquid sugar, fructose dextrose liquid sugar, honey, sonorebitone, manoletitone, mannitore, xylitotone, erythritone, aspartame, saccharin, saccharin sodium and the like.
  • the granules or tablets may be coated with a coating agent (eg, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.) if necessary, or the coating may be made up of two or more layers. There may be.
  • the above excipients are appropriately selected, uniformly mixed with plannorecast hydrate, or in the form of granules, or in the form of granules coated with an appropriate coating agent.
  • May be filled into a forceps capsule, or glycerin, sorbitol, or the like may be added to a suitable capsule base (eg, gelatin) to form an encapsulation with a plastic base having increased plasticity.
  • a suitable capsule base eg, gelatin
  • coloring agents or preservatives sulfur dioxide, parabens (methyl paraoxybenzoate, ethyl ethyl paraoxybenzoate, propyl paraoxybenzoate)] and the like can be added.
  • Capsules include hard capsules or soft capsules.
  • one or more tablets, or capsules be administered at a time, preferably one to about two.
  • tablets or capsules are prepared so as to contain pranlukast hydrate in an amount of about 50-250 mg, preferably 100-120 mg, especially about 112.5 mg per 1 capsule or capsule. Is preferred.
  • Liquid preparations for oral administration include liquid preparations, suspensions, emulsions, syrups, dissolving preparations (for example, dry syrup lj) and elixirs.
  • a liquid preparation for internal use pranlukast hydrate is dissolved, suspended or emulsified in a diluent generally used for the liquid preparation for internal use (for example, purified water, ethanol or a mixture thereof).
  • this solution can be used as wetting agents, suspending agents, emulsifiers, sweeteners, flavors, Agents, preservatives or buffers, and the like.
  • dry syrup IJ can be produced by, for example, mixing pranlukast hydrate with, for example, sucrose, powdered sugar, sucrose, fructose, glucose or lactose.
  • the dry syrup IJ may be granulated according to a conventional method.
  • 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.
  • the ointment is manufactured 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 or commonly used ones.
  • 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 (beetle, spermaceti, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphate ester, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oil (dimethyl Polysiloxanes), hydrocarbons (hydrophilic petrolatum, white petrolatum,
  • the gel is produced by a known method.
  • the gel is produced, for example, by melting plannorecast hydrate in a gel base.
  • the gel base is selected from known or commonly used ones.
  • the gel base include lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropinoresenorelose, ethinoresenorelose, etc.), neutralization Agents (triethanolanolamine, diisopropanolamine, etc.), surfactants (polyethylene glycol monostearate, etc.) ), Gums, water, absorption enhancers or rash preventive agents, and one or more selected from these are used in combination.
  • the gel preparation may contain a preservative, an antioxidant or a flavoring agent.
  • 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. Examples of the cream base include higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.). , Emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption promoters, anti-rash agents, etc., and one or more selected from these are used in combination. . Further, the cream may contain a preservative, an antioxidant or a flavoring agent.
  • 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.
  • the compress base examples include 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, a solubilizing agent, a tackifier or an anti-rash agent, and one or more selected from these are used. 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 known or commonly used ones. Examples of the base for application include a polymer base, oils and fats, higher fatty acids, tackifiers and rash preventives, and one or two or more selected from these are used.
  • the liniment is manufactured by a known method.
  • liniment is prepared by adding pranlukast hydrate to water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acid, It is manufactured by dissolving, suspending or emulsifying one or more selected from serine, soap, emulsifier, suspending agent and the like.
  • the liniment may contain a preservative, an antioxidant or a flavoring agent.
  • Examples of injections for parenteral administration include solutions, suspensions or emulsions, and solid injections that are dissolved or suspended in a solvent before use.
  • the injection is used by dissolving, suspending or emulsifying pranlukast hydrate in a solvent.
  • the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, and alcohols such as ethanol. These solvents are used alone or in combination of two or more.
  • the injection may contain a stabilizer, a solubilizing agent (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer or a preservative. Good.
  • a stabilizer 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.
  • dosage forms for parenteral administration include, for example, sprays, inhalants and sprays. These preparations may contain a buffering agent other than commonly used diluents to provide isotonicity with stabilizers such as sodium bisulfite, for example, isotonic agents such as sodium chloride, sodium citrate or citric acid. May contain an agent. Methods for producing sprays are described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.
  • Examples of the inhalant include an aerosol, a powder for inhalation, and a liquid for inhalation.
  • the inhalant may be in the form of being dissolved or suspended in water or another suitable medium before use. These inhalants are manufactured according to a known method.
  • Inhalants include, for example, in the case of liquids for inhalation, preservatives (benzalkonium chloride, paraben, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), tonicity agents (sodium chloride, sodium chloride, etc.). Concentrated glycerin), a thickener (such as a carboxyvinyl polymer), or an absorption enhancer, if necessary.
  • Powders for inhalation include lubricants (stearic acid and its salts, etc.) and binders (starch, It is manufactured by appropriately selecting an excipient (eg, a string), an excipient (eg, lactose, cellulose), a coloring agent, a preservative (eg, salt of Hibenzalkonidum, paraben) or an absorption enhancer, as necessary.
  • lubricants stearic acid and its salts, etc.
  • binders starch, It is manufactured by appropriately selecting an excipient (eg, a string), an excipient (eg, lactose, cellulose), a coloring agent, a preservative (eg, salt of Hibenzalkonidum, paraben) or an absorption enhancer, as 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 suppositories for rectal administration and pessaries for vaginal administration, which contain pranlukast hydrate and are formulated in a conventional manner.
  • the agent for preventing and / or treating dysmenorrhea of the present invention can be used in combination with other agents.
  • the other drugs are: 1) supplement and / or enhance the therapeutic effect of plannorecast hydrate, 2) kinetics of pranlukast hydrate 'improved absorption, reduced dosage, And / or 3) it is preferably used to reduce the side effects of pranlukast hydrate.
  • the concomitant preparation of pranlukast hydrate and another drug may be in the form of a combination preparation containing both components in one preparation, or may be in the form of separate preparations.
  • the preparations may be administered simultaneously with a time difference between the administrations of the two preparations.
  • administration with a time difference may be performed by administering plannorecast hydrate first and then administering another drug, or administering another drug first and administering plannorecast hydrate later.
  • Each administration method may be the same or different.
  • the other drug may be a small molecule compound or a high molecular weight protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy or antibody, or vaccine. And so on.
  • 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 arbitrarily administered in combination of one or more of the following homologous groups and heterogeneous groups at appropriate ratios.
  • Other drugs include, for example, analgesics [eg, non-steroidal anti-inflammatory drugs (NSAIDs)], muscle relaxants, tranquilizers, herbal medicines and the like.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Analgesics include, for example, sazapyrine, sodium salicylate, aspirin, aspirin'dialuminate, diflunisal, indomethacin, suprofen, ⁇ fenamate, dimethyl isopropyl azulene, bufexamac, fuerbinac, diclofenac sodium, tramethine sodium , Crinolinole, fenbufen, napmetone, proglumetacin, indomethacin pharmacin, inacemethasin, proglumetasin maleate, ampfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil Ketoprofen, Fenoprofen Calcium, Thiaprofen, Oxaprozin, Pranoprofen, Loxop Fennamidine, alumin
  • Examples of the muscle relaxant include triperisone hydrochloride, chlorzoxazone, chlormezanone, metocanolebamol, fenprobamate, pridinol mesylate, clofenesin rubbamate, baclofen, eperisone hydrochloride, afloqualone, tizanidine hydrochloride, alclodinum chloride, and chloride.
  • Examples of the tranquilizer include chlordiazepoxide, diazepam, cloxazolam, oxazepam, oxazolam, medazepam, bromazepam, lorazepam, prazepam, fludiazepam, dipotassium chlorazepate, mexazolam, alprazolame, flutazolameframepramazepam And ethyl mouth frazepate, clotiazebam, etizolam or hydroxyzine.
  • herbal medicines include, for example, Tokishakuyakusan, Kamishoyosan, Keishibukuryogan, Kyukyogaito, Tokikenchuto, Tokakujokito, Sankoshashinto, Orenjokutoto, Hanatsu Koboku-to, Saiko Keishi-to, Shimotsu-yu, Juzen-taiho-yu, Gozoku-san, girls' flower, Onkyo-to, Onsen-shi, etc. are mentioned.
  • other drugs include those that have been discovered to date as well as those that will be discovered based on the mechanism described above.
  • pranlukast hydrate (trade name: ONON capsules) was administered at 450 mg / day (2 capsules containing 112.5 mg after breakfast and 2 capsules after dinner) for 8 weeks He examined the effectiveness of the chief complaint against menstrual pain. The efficacy of menstrual pain was evaluated using the visual analogue scale (VAS) of pain and the amount of anti-inflammatory analgesic (sodium oral xoprofen, trade name: loxonin). The VAS evaluates the degree of menstrual pain on a 10-point scale.
  • VAS visual analogue scale
  • the left end (Ocm) is 0 (no pain at all) and the right end (10cm) is 10 (the strongest you can imagine).
  • the pain at the time of measurement was measured in cm.
  • the number of anti-inflammatory analgesics used per menstrual pain was evaluated.
  • the patient required about 34 tablets / day X 4 days during the period of menstruation.
  • the VAS before taking pranlukast hydrate was 10 points, 8 points after 4 weeks and 6 points after 8 weeks, and the degree of menstrual pain was reduced.
  • the use of anti-inflammatory analgesics was 11 tablets before taking the drug, but it was possible to reduce it to 6 tablets after 4 weeks and 1 tablet after 8 weeks.
  • Pranlukast hydrate is very useful as a preventive and / or therapeutic agent for dysmenorrhea (particularly functional dysmenorrhea).

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Abstract

A preventive and/or a remedy for dysmenorrhea containing pranlukast hydrate as the active ingredient which are excellent in efficacy and safety and make it possible to prevent and/or treat symptoms of dysmenorrhea such as pain, lower abdominal symptoms, lumbar symptoms, digestive symptoms, vascular nerve symptoms, mental symptoms, systemic symptoms, vertigo, nausea, facial flush, perspiration and accelerated saliva secretion.

Description

明 細 書  Specification
月経困難症の予防および Zまたは治療剤  Dysmenorrhea prevention and Z or treatment
技術分野  Technical field
[0001] 本発明は、プランルカスト水和物を有効成分として含有する月経困難症の予防およ び/または治療剤に関する。  The present invention relates to a preventive and / or therapeutic agent for dysmenorrhea, comprising pranlukast hydrate as an active ingredient.
背景技術  Background art
[0002] 月経困難症とは、月経開始前から月経時にぉレ、て、月経に随伴して起こる病的症 状であり、主として疼痛 (例えば、月経痛、下腹部痛、腰痛等）が主症状として現われ る症候群である。また、上記疼痛以外にも多種多様の症状を呈し、例えば下腹部症 状 (例えば、下腹部緊張感、下腹部不快感等）、腰部症状 (例えば、腰部倦怠感等） 、消化器症状 (例えば、胃痛、嘔気、嘔吐、下痢、食欲不振、食欲減退等）、血管神 経症状 (例えば、頭痛、頭重感、冷汗、心悸亢進等）、精神症状 (例えば、イライラ、 神経過敏、憂鬱等）、全身症状 (例えば、全身倦怠感、易疲労感等）、めまい、悪心、 顔面紅潮、発汗または唾液分泌亢進等の症状も見られる。月経困難症は婦人科疾 患として頻度の高い疾患であり、現在、月経困難症患者は増加傾向にある。  [0002] Dysmenorrhea is a pathological condition that accompanies menstruation before the onset of menstruation and that accompanies menstruation, and mainly includes pain (for example, menstrual pain, lower abdominal pain, back pain, etc.). This is a syndrome that appears as a symptom. In addition to the above-mentioned pain, it presents a wide variety of symptoms, such as lower abdominal symptoms (eg, lower abdominal tension, lower abdominal discomfort, etc.), lower back symptoms (eg, lower back malaise, etc.), digestive symptoms (eg, Stomach pain, nausea, vomiting, diarrhea, anorexia, loss of appetite, etc.), vascular neurological symptoms (eg, headache, heavy headache, cold sweat, palpitations, etc.), mental symptoms (eg, frustration, irritability, depression, etc.) Symptoms such as general symptoms (eg, general malaise, fatigue), dizziness, nausea, flushing of the face, sweating or increased salivary secretion are also observed. Dysmenorrhea is a frequent gynecological disease, and the number of dysmenorrhea patients is on the rise at present.
[0003] 月経困難症は器質性 (続発性)月経困難症と機能性 (原発性)月経困難症の二つ に分類される。器質性月経困難症とは、疼痛の原因となる器質性病変が骨盤腔内に 存在する月経困難症を言う。それに対し、機能性月経困難症は器質性病変が認めら れず、例えば内分泌失調症説、子宮発育不全説または神経的要因説など多くの成 因説が唱えられているが、いまだに原因が不明である。  [0003] Dysmenorrhea is classified into two types: organic (secondary) dysmenorrhea and functional (primary) dysmenorrhea. Organic dysmenorrhea is dysmenorrhea in which an organic lesion causing pain is present in the pelvic cavity. In contrast, functional dysmenorrhea has no organic lesions, and many etiologies such as theories of endocrine ataxia, dysgenesis, and neurological factors have been advocated, but the cause is still unknown. is there.
月経困難症は疼痛を主症状とするため、その治療薬としては、鎮痛の緩解を目的 に非ステロイド系抗炎症薬（NSAID)が主に用いられている。し力、し、 NSAIDは消 化器障害等の副作用があるため、患者コンプライアンスが悪ぐ長期投与も困難なた め、対処療法にならざるを得なかった。さらに、 NSAIDを用いても十分な鎮痛効果 が得られない患者も多い。そのため、有効性や安全性に優れ、長期投与可能な月経 困難症 (特に機能性月経困難症)の予防'治療剤の開発が切望されていた。  Since dysmenorrhea is mainly caused by pain, nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly used to relieve analgesia. Because NSAIDs have side effects such as gastrointestinal disorders, patient compliance is poor and long-term administration is difficult. In addition, many patients do not have sufficient analgesic effects with the use of NSAIDs. Therefore, development of a preventive / therapeutic agent for dysmenorrhea (particularly functional dysmenorrhea) which is excellent in efficacy and safety and can be administered for a long period of time has been eagerly desired.
[0004] 一方、 4一ォキソ _8_[4_ (4—フエニルブトキシ）ベンゾィルァミノ] _2_ (テトラゾール _5—ィル)一 4H_1—べンゾピラン 1/2水和物（一般名：プランルカスト水和物；商品 名オノン）は気管支喘息やアレルギー性鼻炎の治療剤として用いられており、十分な 安全性が確認されている薬剤である。また、特開 2002-187855号明細書 (特許文 献 1参照）には、プランルカスト水和物が器質性 (続発性)子宮内膜症に有用であるこ とが記載されているが、月経困難症、特に機能性月経困難症に関する記載は全くな されていない。 [0004] On the other hand, 4-oxo _8_ [4_ (4-phenylbutoxy) benzoylamino] _2_ (tetrazole 4H_1-Benzopyran 1/2 hydrate (generic name: pranlukast hydrate; trade name onon) is used as a therapeutic agent for bronchial asthma and allergic rhinitis, and is sufficiently safe It is a drug whose properties have been confirmed. Japanese Patent Application Laid-Open No. 2002-187855 (see Patent Document 1) discloses that pranlukast hydrate is useful for organic (secondary) endometriosis, There is no mention of dysfunction, especially functional dysmenorrhea.
特許文献 1 :特開 2002 - 187855号公報  Patent Document 1: JP 2002-187855 A
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0005] 本発明の目的は有効性や安全性に優れ、患者に長期投与可能な月経困難症 (特 に機能性月経困難症）の予防および/または治療剤を提供することにある。 An object of the present invention is to provide a prophylactic and / or therapeutic agent for dysmenorrhea (particularly functional dysmenorrhea) which is excellent in efficacy and safety and can be administered to a patient for a long period of time.
課題を解決するための手段  Means for solving the problem
[0006] 前記課題に鑑み、本発明者らは鋭意検討を行なった結果、プランノレカスト水和物 が驚くべき事に、上記課題を臨床的に解決することを初めて見出し、本発明を完成し た。 [0006] In view of the above problems, the present inventors have conducted intensive studies. As a result, the present inventors have found that plannorecast hydrate surprisingly solves the above problems clinically for the first time, and completed the present invention. Was.
すなわち、本発明は  That is, the present invention
(1) プランノレカスト水和物を有効成分として含有することを特徴とする月経困難症の 予防および/または治療剤、  (1) a preventive and / or therapeutic agent for dysmenorrhea, comprising plannorecast hydrate as an active ingredient;
(2) 月経困難症が機能性月経困難症であることを特徴とする前項（1)記載の予防 および/または治療剤、  (2) the prophylactic and / or therapeutic agent according to (1), wherein the dysmenorrhea is functional dysmenorrhea;
(3) 月経困難症が、疼痛、下腹部症状、腰部症状、消化器症状、血管神経症状、 精神症状、全身症状、めまい、悪心、顔面紅潮、発汗および唾液分泌亢進から選択 される少なくとも 1種以上の症状を伴うものであって、前記症状の少なくとも 1種を改善 することを特徴とする前項（1)記載の予防および Zまたは治療剤、  (3) The dysmenorrhea is at least one selected from pain, lower abdominal symptoms, lumbar symptoms, gastrointestinal symptoms, vascular nerve symptoms, psychiatric symptoms, systemic symptoms, dizziness, nausea, hot flush, sweating, and increased salivation. The prophylactic and / or therapeutic agent or the therapeutic agent according to the above (1), which is accompanied by the above-mentioned symptoms and ameliorates at least one of the symptoms.
(4) 疼痛が月経痛、下腹部痛、または腰痛であることを特徴とする前項（3)記載の 予防および/または治療剤、  (4) the prophylactic and / or therapeutic agent according to the above (3), wherein the pain is menstrual pain, lower abdominal pain, or back pain;
(5) プランルカスト水和物の患者 1日当たりの投与量が 112. 5— 450mgであること を特徴とする前項（1)記載の予防および/または治療剤、 (6) プランルカスト水和物の患者 1日当たりの投与量が 450mgであることを特徴と する前項（5)記載の予防および/または治療剤、 (5) The prophylactic and / or therapeutic agent according to (1), wherein the daily dose of pranlukast hydrate to the patient is 112.5 to 450 mg. (6) The prophylactic and / or therapeutic agent according to (5), wherein the daily dose of pranlukast hydrate for a patient is 450 mg.
(7) プランルカスト水和物の患者 1日当たりの投与量が 450mgであって、プランル カスト水和物 1回当たり 225mgを 1日 2回投与することを特徴とする前項（6)記載の 予防および/または治療剤、  (7) The prophylaxis described in (6) above, wherein the daily dose of the patient is 450 mg of pranlukast hydrate, and 225 mg of pranlukast hydrate is administered twice a day. And / or therapeutic agents,
(8) プランルカスト水和物の、患者 1日当たりの投与量が 450mgであって、プランル カスト水和物を 112. 5mg含有するカプセル剤を 1回当たり 2カプセル、 1日 2回投与 することを特徴とする前項（6)記載の予防および Zまたは治療剤、  (8) The daily dosage of pranlukast hydrate for a patient is 450 mg, and 2 capsules containing 112.5 mg of pranlukast hydrate should be administered twice a day, two capsules at a time. The prophylactic and Z or therapeutic agent according to (6) above,
(9) 前項（1)記載の月経困難症の予防および Zまたは治療剤と、鎮痛薬、筋弛緩 薬、精神安定薬、および漢方薬から選択される 1種または 2種以上とを組み合わせる ことを特徴とする医薬、  (9) A combination of the preventive and / or therapeutic agent for dysmenorrhea described in (1) of the preceding paragraph with one or more selected from analgesics, muscle relaxants, tranquilizers, and Chinese herbs. Medicine,
(10) プランルカスト水和物を、患者 1日当たり、 225mgまたは 450mg投与すること を特徴とする、月経痛、悪心、嘔吐、下痢、頭痛、顔面紅潮、発汗および唾液分泌亢 進から選択される少なくとも 1種以上の月経困難症の随伴症状の予防および/また は治療剤、  (10) Selective from menstrual pain, nausea, vomiting, diarrhea, headache, hot flush, sweating, and increased salivary secretion, characterized by administering 225 mg or 450 mg of pranlukast hydrate per patient per day A prophylactic and / or therapeutic agent for at least one or more concomitant symptoms of dysmenorrhea;
(11) プランルカスト水和物の有効量を哺乳動物に投与することを特徴とする、哺乳 動物における月経困難症の予防および/または治療方法、  (11) a method for preventing and / or treating dysmenorrhea in a mammal, which comprises administering an effective amount of pranlukast hydrate to the mammal,
(12) プランノレカスト水和物と、鎮痛薬、筋弛緩薬、精神安定薬、および漢方薬から 選択される 1種または 2種以上を哺乳動物に投与することを特徴とする、哺乳動物に おける月経困難症の予防および/または治療方法、  (12) In mammals, characterized in that plannorecast hydrate and one or more selected from analgesics, muscle relaxants, tranquilizers, and herbal medicines are administered to mammals A method of preventing and / or treating dysmenorrhea,
(13) 月経困難症の予防および/または治療剤を製造するためのプランノレカスト水 和物の使用、  (13) Use of plannorecast hydrate for producing a prophylactic and / or therapeutic agent for dysmenorrhea,
に関する。  About.
発明の効果  The invention's effect
[0007] 本発明によって、安全かつより効果的な月経困難症の予防および/または治療剤 が提供され、月経困難症の諸症状を予防および/または治療することができる。 発明を実施するための最良の形態  [0007] The present invention provides a safe and more effective agent for preventing and / or treating dysmenorrhea, and can prevent and / or treat various symptoms of dysmenorrhea. BEST MODE FOR CARRYING OUT THE INVENTION
[0008] 「月経困難症の予防および/治療」には、月経困難症の諸症状の抑制、緩和、軽 減または改善等が含まれる。 [0008] "Prevention and / or treatment of dysmenorrhea" includes suppression, alleviation, mild Includes reduction or improvement.
本発明における「月経困難症」には器質性月経困難症と機能性月経困難症が含ま れる。  The “dysmenorrhea” in the present invention includes organic dysmenorrhea and functional dysmenorrhea.
本発明の有効成分であるプランノレカスト水和物は式 (A)  Plannorecast hydrate, which is the active ingredient of the present invention, has the formula (A)
[化 1]  [Chemical 1]
Figure imgf000005_0001
Figure imgf000005_0001
で示される 4_ォキソ _8_[4_ (4_フエニルブトキシ）ベンゾィルァミノ ]_2—(テトラゾ 一ノレ一 5—ィル）_4H_1_ベンゾピラン 1/2水和物である。  It is 4_oxo_8_ [4_ (4_phenylbutoxy) benzoylamino] _2- (tetrazo-mono-ole-5-yl) _4H_1_benzopyran hemihydrate represented by
[0009] [本発明化合物の製造方法] [Method for producing the compound of the present invention]
プランルカスト水和物の製造は、例えば特開昭 61—050977号明細書記載の方法 に準じて行なうことができる。  Production of pranlukast hydrate can be carried out, for example, according to the method described in JP-A-61-050977.
[0010] [毒性] [0010] [toxicity]
プランルカスト水和物の毒性は極めて低いものであり、医薬品として使用するため に十分安全であることが確認された。例えばプランノレカスト水和物の急性毒性として 、最小致死量は、マウスまたはラット（いずれも雌雄）に対して経口または皮下投与し た場合、 2000mg/kg以上であった。  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 plannorecast hydrate, the minimum lethal dose was 2000 mg / kg or more when administered orally or subcutaneously to mice or rats (both male and female).
[0011] [医薬品への適用] [0011] [Application to pharmaceutical products]
プランルカスト水和物は月経困難症の症状である疼痛（例えば、月経痛、下腹部痛 、腰痛等）、下腹部症状 (例えば、下腹部緊張感、下腹部不快感等)、腰部症状 (例 えば、腰部倦怠感等）、消化器症状 (例えば、胃痛、嘔気、嘔吐、下痢、食欲不振、 食欲減退等）、血管神経症状 (例えば、頭痛、頭重感、冷汗、心悸亢進等）、精神症 状 (例えば、イライラ、神経過敏、憂鬱等）、全身症状 (例えば、全身倦怠感、易疲労 感等）、めまい、悪心、顔面紅潮、発汗、唾液分泌亢進等を予防および/または治療 できる。月経困難症の予防および/または治療剤として有用である。プランルカスト 水和物を用いることによって、月経困難症の諸症状に対する対処療法として有用で あり、さらに月経困難症の根治療法としても有用である可能性がある。 Pranlukast hydrate is a symptom of dysmenorrhea pain (eg, menstrual pain, lower abdominal pain, lower back pain, etc.), lower abdominal symptoms (eg, lower abdominal tension, lower abdominal discomfort, etc.), lower back symptoms ( For example, lumbar fatigue, gastrointestinal symptoms (eg, stomach pain, nausea, vomiting, diarrhea, loss of appetite, loss of appetite, etc.), vascular nerve symptoms (eg, headache, severe headache, cold sweat, increased palpitation, etc.), mental disorders It can prevent and / or treat symptoms (eg, frustration, irritability, depression, etc.), systemic symptoms (eg, general malaise, easy fatigue, etc.), dizziness, nausea, hot flush, sweating, increased salivation, and the like. It is useful as a prophylactic and / or therapeutic agent for dysmenorrhea. Pranlukast The use of hydrates is useful as a treatment for various symptoms of dysmenorrhea and may also be useful as a root treatment for dysmenorrhea.
[0012] プランルカスト水和物を有効成分として含有する医薬は、全身的または局所的に用 レ、ることができる。  [0012] A medicament containing pranlukast hydrate as an active ingredient can be used systemically or locally.
プランルカスト水和物の投与量は、年齢、体重、症状、治療効果、投与方法または 処理時間等により異なるが、本発明の所望の効果が得られるよう個別具体的に投与 すればよい。例えば、ヒト患者 1日当たりの投与量として好ましくは約 25mgから約 25 OOmg、より好ましくは糸勺 112. 5mg力、ら約 450mg、さらに好ましくは約 225mg力、ら糸勺 450mgである。  The dose of pranlukast hydrate varies depending on age, body weight, symptom, therapeutic effect, administration method or treatment time, but may be individually and specifically administered so as to obtain the desired effect of the present invention. For example, the daily dose of a human patient is preferably about 25 mg to about 25 OO mg, more preferably 112.5 mg strength, about 450 mg, more preferably about 225 mg strength, and even more preferably about 225 mg strength, 450 mg strength.
[0013] 投与方法としては、経口投与または非経口投与のいずれも好ましく用いられるが、 経口投与がより好ましい。また、投与は、例えば経口投与の場合、上記投与量を、一 日 1回から数回、好ましくは 1日 1回から約 4回、さらに好ましくは 1日 1回力 約 2回に 分けるのが好ましい。  [0013] As an administration method, either oral administration or parenteral administration is preferably used, but oral administration is more preferred. In addition, for example, in the case of oral administration, it is preferable to divide the above dose once to several times a day, preferably once to about four times a day, more preferably about twice a day once a day. .
もちろん前記したように、投与量、投与方法または投与回数は種々の条件により変 動するので、患者 1日当たりの投与量は、上記範囲より少なくてもよぐまた範囲を越 えてもよい。  Of course, as described above, the dose, the administration method, or the number of administrations vary depending on various conditions. Therefore, the daily dose per patient may be less than or greater than the above range.
[0014] プランルカスト水和物を上記の医薬として製造する場合、自体公知の製剤とするこ とができる。製剤は、経口投与のための内服用固形剤もしくは内服用液剤、または非 経口投与のための注射剤、外用剤、坐剤または吸入剤等とすることができる。  [0014] 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.
[0015] 経口投与のための内服用固形剤としては、錠剤、丸剤、カプセル剤、散剤または顆 粒剤等が挙げられる。  [0015] Examples of the solid preparation for oral administration for oral administration include tablets, pills, capsules, powders, and granules.
このような内服用固形剤においては、プランノレカスト水和物はそのまま力 \添加剤と 混合または造粒 (例えば、攪拌造粒法、流動層造粒法、乾式造粒法、転動攪拌流動 層造粒法等）され、常法 (例えばカプセル剤の場合はカプセル充填、錠剤の場合は 打錠剤等）に従って製造される。上記添加剤は 1種あるいは 2種以上を適宜配合して もよレ、。添加剤としては、例えば賦形剤（例えば、ラタトース、マンニトール、ダルコ一 ス、微結晶セルロース、トウモロコシデンプン等）、結合剤（例えば、ヒドロキシプロピル セルロース、ポリビュルピロリドン、メタケイ酸アルミン酸マグネシウム等）、分散剤（例 えば、トウモロコシデンプン等）、崩壊剤（例えば、繊維素グリコール酸カルシウム等） 、滑沢剤（例えば、ステアリン酸マグネシウム等）、安定剤、溶解補助剤（例えば、ダル タミン酸、ァスパラギン酸等）、水溶性高分子 [例えば、セルロース類 (例えば、ヒドロキ シプロピノレセノレロース、ヒドロキシプロピノレメチノレセノレロース、メチノレセノレロース等）、 合成高分子類（例えば、ポリエチレングリコール、ポリビニノレピロリドン、ポリビュルァ ルコール等)など]または甘味剤 (例えば、白糖、粉糖、ショ糖、果糖、ブドウ糖、乳糖In such solid preparations for internal use, plannorecast hydrate is mixed or granulated with force as it is (e.g., stirring granulation method, fluidized bed granulation method, dry granulation method, tumbling stirring fluidization). Layer granulation method, etc.) and manufactured according to a conventional method (for example, capsule filling for capsules, tableting for tablets, etc.). The above additives may be used alone or in combination of two or more. Examples of additives include excipients (eg, ratatose, mannitol, darcos, microcrystalline cellulose, corn starch, etc.), binders (eg, hydroxypropyl cellulose, polybutylpyrrolidone, magnesium aluminate metasilicate, etc.), Dispersant (example For example, corn starch and the like), disintegrants (for example, calcium cellulose glycolate), lubricants (for example, magnesium stearate), stabilizers, dissolution aids (for example, daltamic acid, aspartic acid, etc.), Water-soluble polymers [for example, celluloses (for example, hydroxypropinoresenorelose, hydroxypropinolemethinoresenorelose, methinoresenorelose, etc.), synthetic polymers (for example, polyethylene glycol, polyvinylinolepyrrolidone, polybutyla) Or sweeteners (eg, sucrose, powdered sugar, sucrose, fructose, glucose, lactose)
、還元麦芽糖水ァメ、粉末還元麦芽糖水ァメ、ブドウ糖果糖液糖、果糖ブドウ糖液糖 、ハチミツ、ソノレビトーノレ、マノレチトーノレ、マンニトーノレ、キシリトーノレ、エリスリトーノレ、 アスパルテーム、サッカリン、サッカリンナトリウム等）などが挙げられる。また、顆粒剤 または錠剤は、必要によりコーティング剤（例えば、白糖、ゼラチン、ヒドロキシプロピ ルセルロース、ヒドロキシプロピルメチルセルロースフタレート等）などで被覆されてレヽ てもよいし、また前記コーティングは 2以上の層であってもよい。カプセル剤として製 造する場合には、上記賦形剤を適宜選択し、プランノレカスト水和物と均等に混和また は粒状、もしくは粒状としたものに適当なコーティング剤で剤皮を施したものを力プセ ルに充填するか、適当なカプセル基剤（ゼラチン等）にグリセリンまたはソルビトール 等をカ卩えて塑性を増したカプセル基剤で被包成形してもよい。これらカプセル基剤に は必要に応じて、着色剤または保存剤 [二酸化イオウ、パラベン類 (パラォキシ安息 香酸メチル、パラォキシ安息香酸ェチル、パラォキシ安息香酸プロピル) ]等を加える こと力 Sできる。カプセル剤には、ハードカプセルまたはソフトカプセルが含まれる。 また、錠剤またはカプセル剤は、一回当たり、 1一数個、好ましくは 1一約 2個投与さ れるのが好ましい。このため、錠剤またはカプセル剤には、プランルカスト水和物が、 1§定または 1カプセノレ当たり、約 50— 250mg、好ましくは糸勺 100— 120mg、とりわけ 約 112. 5mg含まれるよう製造されるのが好ましい。 , Reduced maltose water, powdered reduced maltose water, glucose fructose liquid sugar, fructose dextrose liquid sugar, honey, sonorebitone, manoletitone, mannitore, xylitotone, erythritone, aspartame, saccharin, saccharin sodium and the like. The granules or tablets may be coated with a coating agent (eg, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.) if necessary, or the coating may be made up of two or more layers. There may be. When manufactured as capsules, the above excipients are appropriately selected, uniformly mixed with plannorecast hydrate, or in the form of granules, or in the form of granules coated with an appropriate coating agent. May be filled into a forceps capsule, or glycerin, sorbitol, or the like may be added to a suitable capsule base (eg, gelatin) to form an encapsulation with a plastic base having increased plasticity. To these capsule bases, if necessary, coloring agents or preservatives [sulfur dioxide, parabens (methyl paraoxybenzoate, ethyl ethyl paraoxybenzoate, propyl paraoxybenzoate)] and the like can be added. Capsules include hard capsules or soft capsules. In addition, it is preferable that one or more tablets, or capsules, be administered at a time, preferably one to about two. For this reason, tablets or capsules are prepared so as to contain pranlukast hydrate in an amount of about 50-250 mg, preferably 100-120 mg, especially about 112.5 mg per 1 capsule or capsule. Is preferred.
経口投与のための内服用液剤としては、水剤、懸濁剤'乳剤、シロップ剤、用時溶 解型製剤（例えば、ドライシロップ斉 lj)またはエリキシル剤等が挙げられる。このような 内服用液剤においては、プランルカスト水和物は、内服用液剤で一般的に用いられ る希釈剤（例えば、精製水、エタノールまたはそれらの混液等）に溶解、懸濁または 乳化される。さらにこの液剤は、湿潤剤、懸濁化剤、乳化剤、甘味剤、風味剤、芳香 剤、保存剤または緩衝剤等を含有していてもよい。また、ドライシロップ斉 IJは、例えば プランルカスト水和物と、例えば白糖、粉糖、ショ糖、果糖、ブドウ糖または乳糖等と を混合等して製造することができる。また、ドライシロップ斉 IJは、常法に従って顆粒とし てもよい。 Liquid preparations for oral administration include liquid preparations, suspensions, emulsions, syrups, dissolving preparations (for example, dry syrup lj) and elixirs. In such a liquid preparation for internal use, pranlukast hydrate is dissolved, suspended or emulsified in a diluent generally used for the liquid preparation for internal use (for example, purified water, ethanol or a mixture thereof). You. In addition, this solution can be used as wetting agents, suspending agents, emulsifiers, sweeteners, flavors, Agents, preservatives or buffers, and the like. Further, dry syrup IJ can be produced by, for example, mixing pranlukast hydrate with, for example, sucrose, powdered sugar, sucrose, fructose, glucose or lactose. The dry syrup IJ may be granulated according to a conventional method.
[0017] 非経口投与のための剤形としては外用剤または注射剤等が挙げられる。外用剤の 剤形としては、例えば、軟膏剤、ゲル剤、クリーム剤、湿布剤、貼付剤、リニメント剤、 噴霧剤、吸入剤またはスプレー剤等が挙げられる。  [0017] 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.
[0018] 軟膏剤は公知の方法により製造される。軟膏剤は、例えば、プランルカスト水和物 を基剤に混和または溶融させて製造される。軟膏基剤は公知あるいは通常使用され てレ、るもの力ら選ばれる。軟膏基剤としては、例えば、高級脂肪酸または高級脂肪酸 エステル（アジピン酸、ミリスチン酸、パルミチン酸、ステアリン酸、ォレイン酸、アジピ ン酸エステル、ミリスチン酸エステル、パルミチン酸エステル、ステアリン酸エステル、 ォレイン酸エステル等）、ロウ類 (ミツロウ、鯨ロウ、セレシン等）、界面活性剤（ポリオキ シエチレンアルキルエーテルリン酸エステル等）、高級アルコール（セタノール、ステ ァリルアルコール、セトステアリルアルコール等）、シリコン油（ジメチルポリシロキサン 等）、炭化水素類 (親水ワセリン、白色ワセリン、精製ラノリン、流動パラフィン等）、ダリ コール類（エチレングリコール、ジエチレングリコール、プロピレングリコール、ポリェチ レングリコール、マクロゴール等）、植物油（ヒマシ油、ォリーブ油、ごま油、テレビン油 等）、動物油（ミンク油、卵黄油、スクヮラン、スクワレン等）、水、吸収促進剤またはか ぶれ防止剤等が挙げられ、これらから選ばれる 1種または 2種以上を混合して用いら れる。さらに、軟膏剤は、保湿剤、保存剤、安定化剤、抗酸化剤または着香剤等を含 んでいてもよい。  The ointment is manufactured 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 or commonly used ones. 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 (beetle, spermaceti, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphate ester, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oil (dimethyl Polysiloxanes), hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), dalicols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), plants (Castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oil (mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancer or anti-rash agent, etc., and one or more selected from these. A mixture of more than one species is used. Further, the ointment may contain a humectant, a preservative, a stabilizer, an antioxidant or a flavoring agent.
[0019] ゲル剤は公知の方法により製造される。ゲル剤は、例えば、プランノレカスト水和物を ゲル基剤に溶融させて製造される。ゲル基剤は公知あるいは通常使用されているも のから選ばれる。ゲル基剤としては、例えば、低級アルコール（エタノール、イソプロピ ノレアルコール等）、ゲル化剤（カルボキシメチルセルロース、ヒドロキシェチルセル口 ース、ヒドロキシプロピノレセノレロース、ェチノレセノレロース等）、中和剤（トリエタノーノレア ミン、ジイソプロパノールアミン等）、界面活性剤（モノステアリン酸ポリエチレングリコ ール等）、ガム類、水、吸収促進剤またはかぶれ防止剤等が挙げられ、これらから選 ばれる 1種または 2種以上を混合して用いられる。さらに、ゲル剤は、保存剤、抗酸化 剤または着香剤等を含んでいてもよい。 [0019] The gel is produced by a known method. The gel is produced, for example, by melting plannorecast 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, hydroxypropinoresenorelose, ethinoresenorelose, etc.), neutralization Agents (triethanolanolamine, diisopropanolamine, etc.), surfactants (polyethylene glycol monostearate, etc.) ), Gums, water, absorption enhancers or rash preventive agents, and one or more selected from these are used in combination. Further, the gel preparation may contain a preservative, an antioxidant or a flavoring agent.
[0020] クリーム剤は公知の方法により製造される。クリーム剤は、例えば、プランルカスト水 和物を基剤に溶融または乳化させて製造される。クリーム基剤は公知あるいは通常 使用されているものから選ばれる。クリーム基剤としては、例えば、高級脂肪酸エステ ノレ、低級アルコール、炭化水素類、多価アルコール（プロピレングリコール、 1， 3—ブ チレングリコール等）、高級アルコール（2—へキシルデカノール、セタノール等）、乳 化剤 (ポリオキシエチレンアルキルエーテル類、脂肪酸エステル類等）、水、吸収促 進剤またはかぶれ防止剤等が挙げられ、これらから選ばれる 1種または 2種以上を混 合して用いられる。さらに、クリーム剤は、保存剤、抗酸化剤または着香剤等を含んで いてもよい。 [0020] 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. Examples of the cream base include higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.). , Emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption promoters, anti-rash agents, etc., and one or more selected from these are used in combination. . Further, the cream may contain a preservative, an antioxidant or a flavoring agent.
[0021] 湿布剤は公知の方法により製造される。湿布剤は、例えば、プランルカスト水和物 を基剤に溶融させ、練合物とし支持体上に展延塗布して製造される。湿布基剤は公 知あるいは通常使用されているものから選ばれる。湿布基剤としては、例えば、増粘 剤（ポリアクリル酸、ポリビニルピロリドン、アラビアゴム、デンプン、ゼラチン、メチルセ ルロース等）、湿潤剤（尿素、グリセリン、プロピレングリコール等）、充填剤（カオリン、 酸化亜鉛、タルク、カルシウム、マグネシウム等）、水、溶解補助剤、粘着付与剤また はかぶれ防止剤等が挙げられ、これらから選ばれる 1種または 2種以上を混合して用 レ、られる。さらに、湿布剤は、保存剤、抗酸化剤または着香剤等を含んでいてもよい  [0021] 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. Examples of the compress base include 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, a solubilizing agent, a tackifier or an anti-rash agent, and one or more selected from these are used. Further, the poultice may contain a preservative, an antioxidant or a flavoring agent.
[0022] 貼付剤は公知の方法により製造される。貼付剤は、例えば、プランルカスト水和物 を貼付用基剤に溶融させ、支持体上に展延塗布して製造される。貼付剤用基剤は 公知あるいは通常使用されているものから選ばれる。貼付用基剤としては、例えば、 高分子基剤、油脂、高級脂肪酸、粘着付与剤またはかぶれ防止剤等が挙げられ、こ れらから選ばれる 1種または 2種以上を混合して用いられる。 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 known or commonly used ones. Examples of the base for application include a polymer base, oils and fats, higher fatty acids, tackifiers and rash preventives, and one or two or more selected from these are used.
リニメント剤は公知の方法により製造される。リニメント剤は、例えば、プランルカスト 水和物を水、アルコール（エタノール、ポリエチレングリコール等）、高級脂肪酸、ダリ セリン、セッケン、乳化剤、懸濁化剤等から選ばれるもの単独または 2種以上に溶解、 懸濁または乳化させて製造される。さらに、リニメント剤は、保存剤、抗酸化剤または 着香剤等を含んでいてもよい。 The liniment is manufactured by a known method. For example, liniment is prepared by adding pranlukast hydrate to water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acid, It is manufactured by dissolving, suspending or emulsifying one or more selected from serine, soap, emulsifier, suspending agent and the like. Further, the liniment may contain a preservative, an antioxidant or a flavoring agent.
[0023] 非経口投与のための注射剤としては、溶液、懸濁液もしくは乳濁液または用時溶剤 に溶解もしくは懸濁して用いる固形の注射剤が挙げられる。注射剤は、プランルカス ト水和物を溶剤に溶解、懸濁または乳化させて用いられる。溶剤としては、例えば、 注射用蒸留水、生理食塩水、植物油、プロピレングリコール、ポリエチレングリコール 、エタノールのようなアルコール類等が挙げられる。これら溶剤は、 1種または 2種以 上を組み合わせて用レ、られる。さらにこの注射剤は、安定剤、溶解補助剤（グルタミン 酸、ァスパラギン酸、ポリソルベート 80 (登録商標）等）、懸濁化剤、乳化剤、無痛化 剤、緩衝剤または保存剤等を含んでいてもよい。これらは最終工程において滅菌す るか無菌操作によって製造されるのが好ましい。また無菌の固形剤、例えば、凍結乾 燥品を製造し、その使用前に無菌化または無菌の注射用蒸留水または他の溶剤に 溶解して使用することもできる。  [0023] Examples of injections for parenteral administration include solutions, suspensions or emulsions, and solid injections that are dissolved or suspended 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, and alcohols such as ethanol. 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 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.
[0024] 非経口投与のためのその他の剤形としては、例えば噴霧剤、吸入剤またはスプレ 一剤等が挙げられる。これら製剤は、一般的に用いられる希釈剤以外に亜硫酸水素 ナトリウムのような安定剤と等張性を与えるような緩衝剤、例えば、塩化ナトリウム、ク ェン酸ナトリウムあるいはクェン酸のような等張剤を含有していてもよレ、。スプレー剤 の製造方法は、例えば、米国特許第 2, 868, 691号および同第 3, 095, 355号に 詳しく記載されている。  [0024] Other dosage forms for parenteral administration include, for example, sprays, inhalants and sprays. These preparations may contain a buffering agent other than commonly used diluents to provide isotonicity with stabilizers such as sodium bisulfite, for example, isotonic agents such as sodium chloride, sodium citrate or citric acid. May contain an agent. Methods for producing sprays are described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.
[0025] 吸入剤としては、エアゾル剤、吸入用粉末剤または吸入用液剤が挙げられる。当該 吸入剤は用時に水または他の適当な媒体に溶解または懸濁させて使用する形態で あってもよレ、。これらの吸入剤は公知の方法に準じて製造される。  [0025] Examples of the inhalant include an aerosol, a powder for inhalation, and a liquid for inhalation. The inhalant may be in the form of being dissolved or suspended in water or another suitable medium before use. These inhalants are manufactured according to a known method.
吸入剤は、例えば、吸入用液剤の場合には、防腐剤 (塩化ベンザルコニゥム、パラ ベン等）、着色剤、緩衝化剤（リン酸ナトリウム、酢酸ナトリウム等）、等張化剤 (塩化ナ トリウム、濃グリセリン等）、増粘剤（カルボキシビ二ルポリマー等）または吸収促進剤 等を必要に応じて適宜選択して製造される。  Inhalants include, for example, in the case of liquids for inhalation, preservatives (benzalkonium chloride, paraben, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), tonicity agents (sodium chloride, sodium chloride, etc.). Concentrated glycerin), a thickener (such as a carboxyvinyl polymer), or an absorption enhancer, if necessary.
[0026] 吸入用粉末剤は、滑沢剤 (ステアリン酸およびその塩等）、結合剤（デンプン、デキ ストリン等）、賦形剤（乳糖、セルロース等）、着色剤、防腐剤 (塩ィヒベンザルコニゥム、 パラベン等）または吸収促進剤等を必要に応じて適宜選択して製造される。 [0026] Powders for inhalation include lubricants (stearic acid and its salts, etc.) and binders (starch, It is manufactured by appropriately selecting an excipient (eg, a string), an excipient (eg, lactose, cellulose), a coloring agent, a preservative (eg, salt of Hibenzalkonidum, paraben) or an absorption enhancer, as necessary.
吸入用液剤を投与する際には通常噴霧器 (アトマイザ一、ネブライザ一）が使用さ れ、吸入用粉末剤を投与する際には通常粉末薬剤用吸入投与器が使用される。 非経口投与のためその他の組成物としては、プランルカスト水和物を含み、常法に より処方される直腸内投与のための坐剤および膣内投与のためのペッサリー等が含 まれる。  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 suppositories for rectal administration and pessaries for vaginal administration, which contain pranlukast hydrate and are formulated in a conventional manner.
[0027] また、本発明の月経困難症の予防および/または治療剤は、他の薬剤との併用剤 とすることもできる。他の薬剤と併用する場合、他の薬剤は、 1)プランノレカスト水和物 の治療効果の補完および/または増強、 2)プランルカスト水和物の動態'吸収改善 、投与量の低減、および/または 3)プランルカスト水和物の副作用の軽減のために 使用されることが好ましい。  [0027] Further, the agent for preventing and / or treating dysmenorrhea of the present invention can be used in combination with other agents. When used in combination with other drugs, the other drugs are: 1) supplement and / or enhance the therapeutic effect of plannorecast hydrate, 2) kinetics of pranlukast hydrate 'improved absorption, reduced dosage, And / or 3) it is preferably used to reduce the side effects of pranlukast hydrate.
プランルカスト水和物と他の薬剤との併用剤は、 1つの製剤中に両成分を配合した 配合剤の形態であってもよぐまた別々の製剤とする形態であってもよい。この別々の 製剤とする場合の投与方法は、両製剤を同時に投与してもよぐ両製剤の投与時間 に時間差を設けて投与してもよい。また、時間差による投与は、プランノレカスト水和物 を先に投与し、他の薬剤を後に投与してもよいし、他の薬剤を先に投与し、プランノレ カスト水和物を後に投与しても力まわず、それぞれの投与方法は同じでも異なってい てもよい。  The concomitant preparation of pranlukast hydrate and another drug may be in the form of a combination preparation containing both components in one preparation, or may be in the form of separate preparations. When administering these separate preparations, the preparations may be administered simultaneously with a time difference between the administrations of the two preparations. In addition, administration with a time difference may be performed by administering plannorecast hydrate first and then administering another drug, or administering another drug first and administering plannorecast hydrate later. Each administration method may be the same or different.
[0028] 他の薬剤は、低分子化合物であってもよぐまた高分子の蛋白、ポリペプチド、ポリ ヌクレオチド（DNA、 RNA、遺伝子）、アンチセンス、デコイまたは抗体である力、ま たはワクチン等であってもよい。他の薬剤の投与量は、臨床上用いられている用量を 基準として適宜選択することができる。また、プランルカスト水和物と他の薬剤の配合 比は、投与対象の年齢および体重、投与方法、投与時間、対象疾患、症状または他 の薬剤の種類等により適宜選択することができる。例えば、プランルカスト水和物 1重 量部に対し、他の薬剤を 0. 01乃至 100重量部用いればよい。他の薬剤は以下に示 す同種群および異種群から任意に 1種または 2種以上を適宜の割合で組み合わせ て投与してもよい。 他の薬剤としては、例えば鎮痛薬 [例えば、非ステロイド系抗炎症薬 (NSAID) ]等） 、筋弛緩薬、精神安定薬または漢方薬等が挙げられる。 [0028] The other drug may be a small molecule compound or a high molecular weight protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy or antibody, or vaccine. And so on. 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 arbitrarily administered in combination of one or more of the following homologous groups and heterogeneous groups at appropriate ratios. Other drugs include, for example, analgesics [eg, non-steroidal anti-inflammatory drugs (NSAIDs)], muscle relaxants, tranquilizers, herbal medicines and the like.
[0029] 鎮痛薬としては、例えばサザピリン、サリチル酸ナトリウム、アスピリン、アスピリン'ダ ィアルミネート配合、ジフル二サル、インドメタシン、スプロフェン、ゥフエナマート、ジメ チルイソプロピルァズレン、ブフエキサマク、フエルビナク、ジクロフェナクナトリウム、ト ルメチンナトリウム、クリノリノレ、フェンブフェン、ナプメトン、プログルメタシン、インドメタ シンフアルネシル、ァセメタシン、マレイン酸プログルメタシン、アンフエナクナトリウム 、モフエゾラク、エトドラク、イブプロフェン、イブプロフェンピコノール、ナプロキセン、 フルルビプロフェン、フルルビプロフェンアキセチル、ケトプロフェン、フエノプロフェン カルシウム、チアプロフェン、ォキサプロジン、プラノプロフェン、ロキソプロフェンナトリ ゥム、アルミノプロフェン、ザルトプロフェン、メフエナム酸、メフエナム酸アルミニウム、 トルフエナム酸、フロクタフェニン、ケトフエ二ルブタゾン、ォキシフェンブタゾン、ピロキ シカム、テノキシカム、アンピロキシカム、ナパゲルン軟膏、ェピリゾール、塩酸チアラ ミド、塩酸チノリジン、ェモルファゾン、スルピリン、ミグレニン、サリドン、セデス G、アミ ピロ一 N、ソルボン、ピリン系感冒薬、ァセトァミノフェン、フエナセチン、メシル酸ジメト チアジン、シメトリド配合剤または非ピリン系感冒薬等が挙げられる。  [0029] Analgesics include, for example, sazapyrine, sodium salicylate, aspirin, aspirin'dialuminate, diflunisal, indomethacin, suprofen, ゥ fenamate, dimethyl isopropyl azulene, bufexamac, fuerbinac, diclofenac sodium, tramethine sodium , Crinolinole, fenbufen, napmetone, proglumetacin, indomethacin pharmacin, inacemethasin, proglumetasin maleate, ampfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil Ketoprofen, Fenoprofen Calcium, Thiaprofen, Oxaprozin, Pranoprofen, Loxop Fennamidine, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamic acid, tolfenamic acid, floctafenin, ketophenirbutazone, oxifenbutazone, piroxicam, tenoxicam, ampiroxicam, napageln ointment, epirisol, tiaramid hydrochloride, hydrochloric acid Examples include tinolidine, emorfazone, sulpyrine, migrenine, salidone, cedes G, amypyro-I-N, sorbone, pilin-based cold remedies, acetoaminophen, phenacetin, dimethothiazine mesylate, a combination drug of simetride or a non-pyrine-based cold pill.
[0030] 筋弛緩薬としては、例えば塩酸トリペリゾン、クロルゾキサゾン、クロルメザノン、メトカ ノレバモール、フェンプロバメート、メシル酸プリジノール、力ルバミン酸クロフエネシン、 バクロフェン、塩酸エペリゾン、アフロクァロン、塩酸チザニジン、塩化アルクロ二ゥム、 塩化スキサメトニゥム、塩化ッボクラリン、ダントロレンナトリウム、臭化パンクロ二ゥム、 臭化べクロニゥムまたは臭化ブチルスコポラミン等が挙げられる。  [0030] Examples of the muscle relaxant include triperisone hydrochloride, chlorzoxazone, chlormezanone, metocanolebamol, fenprobamate, pridinol mesylate, clofenesin rubbamate, baclofen, eperisone hydrochloride, afloqualone, tizanidine hydrochloride, alclodinum chloride, and chloride. Suxametonium, carbocurarine chloride, dantrolene sodium, panclodium bromide, vecuronium bromide or butyl scopolamine bromide.
[0031] 精神安定薬としては、例えばクロルジァゼポキシド、ジァゼパム、クロキサゾラム、ォ キサゼパム、ォキサゾラム、メダゼパム、ブロマゼパム、ロラゼパム、プラゼパム、フル ジァゼパム、クロラゼプ酸二カリウム、メキサゾラム、アルプラゾラム、フルタゾラム、フ ノレトプラゼパム、口フラゼプ酸ェチル、クロチアゼバム、ェチゾラムまたはヒドロキシジ ン等が挙げられる。  [0031] Examples of the tranquilizer include chlordiazepoxide, diazepam, cloxazolam, oxazepam, oxazolam, medazepam, bromazepam, lorazepam, prazepam, fludiazepam, dipotassium chlorazepate, mexazolam, alprazolame, flutazolameframepramazepam And ethyl mouth frazepate, clotiazebam, etizolam or hydroxyzine.
[0032] 漢方薬としては、例えば当帰芍薬散、加味逍遥散、桂枝茯苓丸、きゅう帰膠艾湯、 当帰建中湯、桃核承気湯、三黄瀉心湯、黄連解毒湯、半夏厚朴湯、柴胡桂枝湯、 四物湯、十全大補湯、五積散、婦人華、温経湯または温清飲等が挙げられる。 また、他の薬剤には、上記したメカニズムに基づいて、現在までに見出されているも のだけでなく今後見出されるものも含まれる。 [0032] Examples of herbal medicines include, for example, Tokishakuyakusan, Kamishoyosan, Keishibukuryogan, Kyukyogaito, Tokikenchuto, Tokakujokito, Sankoshashinto, Orenjokutoto, Hanatsu Koboku-to, Saiko Keishi-to, Shimotsu-yu, Juzen-taiho-yu, Gozoku-san, Ladies' flower, Onkyo-to, Onsen-shi, etc. are mentioned. In addition, other drugs include those that have been discovered to date as well as those that will be discovered based on the mechanism described above.
[0033] 以下、実施例（臨床薬理試験)および製剤例によって本発明を詳述するが、実施例 等は、本発明をよく理解するためのものであり、本発明はこれらに限定されるものでは ない。  Hereinafter, the present invention will be described in detail with reference to examples (clinical pharmacology tests) and formulation examples. However, the examples and the like are provided for better understanding of the present invention, and the present invention is not limited thereto. is not.
実施例  Example
[0034] 機能性月経困難症患者に、プランルカスト水和物（商品名：オノンカプセル)を 450 mg/日（112. 5mg含有カプセルを朝食後 2カプセルおよび夕食後 2カプセル）で 8 週間投与し、主訴である月経痛に対する有効性を検討した。月経痛に対する薬効評 価は、痛みのビジュアルアナログスケール（visual analogue scale ;VAS)および 消炎鎮痛剤（口キソプロフェンナトリウム、商品名：ロキソニン）の使用量で実施した。 V ASは、月経痛の程度を 10段階の数値で評価し、 10cmの直線上で、左端 (Ocm)を 0点 (全く痛みがなく幸せ)から右端（10cm)を 10点 (想像できる最も強い痛み）として 、測定時点の痛みを cmで測定した。消炎鎮痛剤の使用量は、月経痛毎に使用した 消炎鎮痛剤の錠数を評価した。なお、当患者は月経の期間中、消炎鎮痛剤を 3 4 錠/日 X 4日程度必要としていた。その結果、下表のように、プランルカスト水和物服 薬前の VASは 10点であった力 4週間後 8点、 8週間後 6点と、月経痛の程度は軽 減された。また、消炎鎮痛剤の使用量も服薬前は 11錠であつたが、 4週間後は 6錠、 8週間後は 1錠に減らすことが可能となった。  [0034] For patients with functional dysmenorrhea, pranlukast hydrate (trade name: ONON capsules) was administered at 450 mg / day (2 capsules containing 112.5 mg after breakfast and 2 capsules after dinner) for 8 weeks He examined the effectiveness of the chief complaint against menstrual pain. The efficacy of menstrual pain was evaluated using the visual analogue scale (VAS) of pain and the amount of anti-inflammatory analgesic (sodium oral xoprofen, trade name: loxonin). The VAS evaluates the degree of menstrual pain on a 10-point scale. On a 10cm straight line, the left end (Ocm) is 0 (no pain at all) and the right end (10cm) is 10 (the strongest you can imagine). The pain at the time of measurement was measured in cm. For the amount of anti-inflammatory analgesic used, the number of anti-inflammatory analgesics used per menstrual pain was evaluated. The patient required about 34 tablets / day X 4 days during the period of menstruation. As a result, as shown in the table below, the VAS before taking pranlukast hydrate was 10 points, 8 points after 4 weeks and 6 points after 8 weeks, and the degree of menstrual pain was reduced. The use of anti-inflammatory analgesics was 11 tablets before taking the drug, but it was possible to reduce it to 6 tablets after 4 weeks and 1 tablet after 8 weeks.
[表 1]  [table 1]
Figure imgf000013_0001
Figure imgf000013_0001
プランルカスト水和物を投与することにより、月経痛の程度を抑制し、かつ消炎鎮痛 剤の使用量を軽減できることが明らかとなった。  It has been clarified that administration of pranlukast hydrate can reduce the level of menstrual pain and reduce the use of anti-inflammatory analgesics.
[製剤例] 製剤例 1 :カプセル剤の製造 [Formulation example] Formulation Example 1: Production of capsules
プランルカスト水和物（40kg)、乳糖（19kg)および添加剤（適量）を常法に従って 噴霧乾燥造粒し、造粒物 lg中、プランルカスト水和物を 625mg含有する造粒物を得 た。得られた造粒物を 1カプセル中、プランルカスト水和物の含量が 112. 5mgにな るように 3号カプセルに常法に従って充填することにより、プランルカスト水和物を含 有するカプセル剤を得た。  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.
産業上の利用可能性 Industrial applicability
プランルカスト水和物は月経困難症（特に機能性月経困難症）の予防および/また は治療剤として非常に有用である。  Pranlukast hydrate is very useful as a preventive and / or therapeutic agent for dysmenorrhea (particularly functional dysmenorrhea).

Claims

請求の範囲 The scope of the claims
[1] プランルカスト水和物を有効成分として含有することを特徴とする月経困難症の予 防および/または治療剤。  [1] A prophylactic and / or therapeutic agent for dysmenorrhea, which comprises pranlukast hydrate as an active ingredient.
[2] 月経困難症が機能性月経困難症であることを特徴とする請求の範囲第 1項記載の 予防および/または治療剤。  [2] The prophylactic and / or therapeutic agent according to claim 1, wherein the dysmenorrhea is functional dysmenorrhea.
[3] 月経困難症が、疼痛、下腹部症状、腰部症状、消化器症状、血管神経症状、精神 症状、全身症状、めまい、悪心、顔面紅潮、発汗および唾液分泌亢進から選択され る少なくとも 1種以上の症状を伴うものであって、前記症状の少なくとも 1種を改善す ることを特徴とする請求の範囲第 1項記載の予防および/または治療剤。 [3] At least one dysmenorrhea selected from pain, lower abdominal symptoms, lumbar symptoms, gastrointestinal symptoms, vascular nerve symptoms, psychiatric symptoms, systemic symptoms, dizziness, nausea, hot flush, sweating, and increased salivation 2. The prophylactic and / or therapeutic agent according to claim 1, which is accompanied by the above-mentioned symptoms and ameliorates at least one of the symptoms.
[4] 疼痛が月経痛、下腹部痛、または腰痛であることを特徴とする請求の範囲第 3項記 載の予防および/または治療剤。 [4] The preventive and / or therapeutic agent according to claim 3, wherein the pain is menstrual pain, lower abdominal pain, or back pain.
[5] プランルカスト水和物の患者 1日当たりの投与量が 112. 5— 450mgであることを特 徴とする請求の範囲第 1項記載の予防および/または治療剤。 [5] The prophylactic and / or therapeutic agent according to claim 1, wherein the daily dose of pranlukast hydrate for a patient is 112.5 to 450 mg.
[6] プランルカスト水和物の患者 1日当たりの投与量力 50mgであることを特徴とする 請求の範囲第 5項記載の予防および/または治療剤。 [6] The preventive and / or therapeutic agent according to claim 5, wherein the dosage strength of pranlukast hydrate per patient is 50 mg per day.
[7] プランルカスト水和物の患者 1日当たりの投与量が 450mgであって、プランルカスト 水和物 1回当たり 225mgを 1日 2回投与することを特徴とする請求の範囲第 6項記載 の予防および Zまたは治療剤。 [7] The claim 6, wherein the daily dose of pranlukast hydrate to a patient is 450 mg, and 225 mg of pranlukast hydrate is administered twice a day twice a day. Prophylactic and Z or therapeutic agents as described.
[8] プランルカスト水和物の、患者 1日当たりの投与量が 450mgであって、プランルカ スト水和物を 112. 5mg含有するカプセル剤を 1回当たり 2カプセル、 1日 2回投与す ることを特徴とする請求の範囲第 6項記載の予防および/または治療剤。 [8] The daily dose of pranlukast hydrate for patients is 450 mg, and 2 capsules containing 112.5 mg of pranlukast hydrate are administered twice a day, 2 capsules each 7. The prophylactic and / or therapeutic agent according to claim 6, characterized in that:
[9] 請求の範囲第 1項記載の月経困難症の予防および Zまたは治療剤と、鎮痛薬、筋 弛緩薬、精神安定薬、および漢方薬から選択される 1種または 2種以上とを組み合わ せることを特徴とする医薬。 [9] Combining the preventive and / or therapeutic agent for dysmenorrhea described in claim 1 with one or more selected from analgesics, muscle relaxants, tranquilizers, and herbal medicines A medicament characterized in that:
[10] プランルカスト水和物を、患者 1日当たり、 225mgまたは 450mg投与することを特 徴とする、月経痛、悪心、嘔吐、下痢、頭痛、顔面紅潮、発汗および唾液分泌亢進か ら選択される少なくとも 1種以上の月経困難症の随伴症状の予防および/または治 療剤。 [10] Select from menstrual pain, nausea, vomiting, diarrhea, headache, hot flush, sweating, and increased salivation, characterized by 225 mg or 450 mg of pranlukast hydrate administered per patient per day A prophylactic and / or therapeutic agent for at least one or more concomitant symptoms of dysmenorrhea.
[11] プランルカスト水和物の有効量を哺乳動物に投与することを特徴とする、哺乳動物 における月経困難症の予防および/または治療方法。 [11] A method for preventing and / or treating dysmenorrhea in a mammal, which comprises administering an effective amount of pranlukast hydrate to the mammal.
[12] プランルカスト水和物と、鎮痛薬、筋弛緩薬、精神安定薬、および漢方薬から選択 される 1種または 2種以上を哺乳動物に投与することを特徴とする、哺乳動物におけ る月経困難症の予防および/または治療方法。  [12] A mammal characterized by administering pranlukast hydrate and one or more selected from an analgesic, a muscle relaxant, a tranquilizer, and a Chinese medicine to a mammal A method for preventing and / or treating dysmenorrhea.
[13] 月経困難症の予防および/または治療剤を製造するためのプランノレカスト水和物 の使用。  [13] Use of plannorecast hydrate for producing a prophylactic and / or therapeutic agent for dysmenorrhea.
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JP2011519870A (en) * 2008-05-21 2011-07-14 テイコク ファーマ ユーエスエー インコーポレーテッド Treatment of dysmenorrhea by transdermal administration of non-steroidal anti-inflammatory drugs

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