WO2020095979A1 - Agent thérapeutique pour une maladie du système nerveux central comprenant de la tipépidine - Google Patents

Agent thérapeutique pour une maladie du système nerveux central comprenant de la tipépidine Download PDF

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WO2020095979A1
WO2020095979A1 PCT/JP2019/043606 JP2019043606W WO2020095979A1 WO 2020095979 A1 WO2020095979 A1 WO 2020095979A1 JP 2019043606 W JP2019043606 W JP 2019043606W WO 2020095979 A1 WO2020095979 A1 WO 2020095979A1
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tipepidine
disorder
pharmaceutical composition
acceptable salt
central
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Japanese (ja)
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剛志 辻村
瞬 林
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大日本住友製薬株式会社
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    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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

Definitions

  • the present invention relates to a therapeutic agent for central diseases containing tipepidine.
  • Tipepidine is widely used in Japan as a central antitussive. Tipepidine is a cough medicine approved in 1959 and is a commonly used safe drug for pediatric patients. Tipepidine has a wide range of pharmacological actions, including central antitussive action, mood disorder, pain, schizophrenia, dysuria associated with cerebral infarction, attention deficit / hyperactivity disorder, cerebral dysfunction caused by environmental chemicals, Alzheimer's disease, It is also reported to be effective for obsessive-compulsive disorder. Further, it has been clarified from a small-scale clinical study that it is effective against attention deficit / hyperactivity disorder and depression (Patent Documents 1, 2, 3, 4, 5, Non-Patent Documents 1 and 2).
  • tipepidine has a very short half-life in vivo of 1.8 hours, and it is necessary to take it three times a day. Therefore, when used in a central disease, there is a problem that it is difficult to maintain the blood concentration, and furthermore, the intracerebral concentration that exhibits a drug effect cannot be sufficiently reached (Non-patent Document 3).
  • Non-Patent Documents 4 and 5 Non-Patent Documents 4 and 5).
  • Non-Patent Document 6 Non-Patent Document 6
  • Depression is classified as one of mood disorders, and one of the most common mental illnesses with a lifetime prevalence rate of 10% or higher.
  • the main symptoms are strong depressive mood, decreased motivation / interest / joy, psychomotor disorders (frustration / inhibition of mental activity), decreased appetite, insomnia, etc., and significantly deteriorates the quality of life of patients. ..
  • the treatment of depression includes cognitive-behavioral therapy, drug therapy, and electroconvulsive therapy (ECT), and drug therapy with antidepressants is actively used for moderate to moderate depression.
  • Antidepressants include tricyclic antidepressants (TCA), tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), serotonin / noradrenaline reuptake inhibitors, noradrenergic / selective serotonergic
  • TCA tricyclic antidepressants
  • SSRI selective serotonin reuptake inhibitors
  • NaSSA antidepressants
  • these drugs take 3 weeks or more for the onset of antidepressant action, and there is a problem that only about one-third of patients reach remission with the initial monotherapy.
  • ADHD Attention deficit / hyperactivity disorder
  • ICD10 ICD10
  • ICD10 ICD10
  • the main symptoms are hyperactivity, impulsivity, and carelessness, which make life difficult in school.
  • adolescence it causes severe mental illness such as depression and addiction, and significantly deteriorates the quality of life of the patient.
  • central stimulants dopain / noradrenaline reuptake inhibitors
  • non-central stimulants noradrenaline reuptake inhibitors, ⁇ 2 adrenergic agonists
  • central stimulants dopain / noradrenaline reuptake inhibitors
  • non-central stimulants noradrenaline reuptake inhibitors, ⁇ 2 adrenergic agonists
  • the central stimulants have a strong effect of suppressing the symptoms of ADHD, but have a risk of forming dependence and may be abused.
  • a non-central stimulant has a low risk of forming dependence, but a problem is that the effect of suppressing the symptoms of ADHD is weak. Therefore, there is a demand for a drug that can suppress ADHD symptoms to the same level as existing central stimulants without forming dependence.
  • it is also required to alleviate the symptoms of ADHD by using it together with a non-central stimulant or a central stimulant.
  • JP-A-2009-227631 Japanese Patent Laid-Open No. 2011-246446 JP2012-62272A Japanese Patent Laid-Open No. 2013-63958 JP, 2017-36242, A
  • Neuropsychiatric Disease and Treatment 2014, 10, 10, 147-151 Neuropsychiatric Disease and Treatment, 2014, 10, 10, 719-722 Asverin Tablets Drug Interview Form Experimental Physiology, 2007, 92, 67-78 Movement Disorders, 2001, 16, 16, 507-510 Neurology, 2000, 54, 1166-11756
  • the problem to be solved by the present invention is to provide a method and a medicine for treating or preventing central diseases caused by tipepidine.
  • the present invention relates to a therapeutic or prophylactic agent for central diseases, a method for treating or preventing central diseases, characterized in that tipepidine or a pharmaceutically acceptable salt thereof is used in combination with a CYP2D6 inhibitor.
  • Pharmaceutical compositions and kits are included in the present invention.
  • the present invention also includes tipepidine or a pharmaceutically acceptable salt thereof, Parkinson's disease, Parkinson's disease syndrome due to the use of antipsychotic drugs, sleep disorders, chronic fatigue syndrome, fatigue associated with neurodegeneration and central diseases, overeating.
  • the present invention provides a therapeutic or prophylactic agent for addiction, fibromyalgia, or a group of trauma and stress-related disorders, a method for treating or preventing, a pharmaceutical composition and a kit.
  • the present invention relates to the following.
  • Item 1 A pharmaceutical composition for treating or preventing a central disease, which comprises tipepidine or a pharmaceutically acceptable salt thereof in combination with a CYP2D6 inhibitor.
  • Item 2 A pharmaceutical composition for treating or preventing a central disease, comprising a CYP2D6 inhibitor, which is used in combination with tipepidine or a pharmaceutically acceptable salt thereof.
  • Item 3 A pharmaceutical composition for treating or preventing a central disease, comprising tipepidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor.
  • CYP2D6 inhibitors are quinidine, paroxetine, bupropion, fluoxetine, terbinafine, cinacalcet, dacomitinib, duloxetine, mirabegron, celecoxib, escitalopram, moclobelatil, clavitone, fluvoxamine, abiraterabalone, mirabedalone, amiodarone, fluvoxamine, abiraterabalone, amiodalone, amiodala. 4.
  • composition according to any one of the above items 1 to 3, which is one or more drugs selected from the group consisting of, ritonavir, sertraline, vemurafenib, and deramciclane, or a pharmaceutically acceptable salt thereof. ..
  • the CYP2D6 inhibitor is one or more pharmaceutical agents selected from the group consisting of quinidine, paroxetine, bupropion, fluoxetine, terbinafine, cinacalcet, dacomitinib, duloxetine, mirabegron, celecoxib, escitalopram, moclobemide, cimetidine, and fluvoxamine; Item 4.
  • the pharmaceutical composition according to any one of Items 1 to 3, wherein the pharmaceutical composition is a salt acceptable for.
  • CYP2D6 inhibitor is one or more drugs selected from the group consisting of quinidine, paroxetine, bupropion, fluoxetine, terbinafine, cinacalcet, and dacomitinib, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition according to any one of claims.
  • the CYP2D6 inhibitor is one or more drugs selected from the group consisting of quinidine, paroxetine, bupropion, and fluoxetine, or a pharmaceutically acceptable salt thereof, according to any one of items 1 to 3 above.
  • Pharmaceutical composition is one or more drugs selected from the group consisting of quinidine, paroxetine, bupropion, and fluoxetine, or a pharmaceutically acceptable salt thereof, according to any one of items 1 to 3 above.
  • Item 8 The pharmaceutical composition according to any one of Items 1 to 3, wherein the CYP2D6 inhibitor is quinidine or a pharmaceutically acceptable salt thereof.
  • Central diseases are Parkinson's disease, Parkinson's disease syndrome due to antipsychotic use, sleep disorders, chronic fatigue syndrome, fatigue associated with neurodegenerative and central diseases, overeating, addiction, or fibromyalgia, the above-mentioned item
  • Item 10 The pharmaceutical composition according to any one of Items 1 to 8, wherein the central disease is a sleep disorder.
  • Item 11 The pharmaceutical composition according to any one of items 1 to 8 and 10, wherein the central disease is hypersomnia, idiopathic hypersomnia disorder, or narcolepsy.
  • Item 12. The pharmaceutical composition according to any one of items 1 to 8, wherein the central disease is a depressive disorder group.
  • Central disorders include anxiety-related depressive disorders, depressive disorders with mixed features, depressive disorders with melancholic features, depressive disorders with mood-matching psychotic features, mood Depressive disorders with inconsistent psychotic features, depressive disorders with catatonic disorders, seasonal depressive disorders, severe dysregulation, depression, persistent depressive disorder, premenstrual dysphoric disorder, or substances / medicines 13.
  • the pharmaceutical composition according to any one of the above items 1 to 8 and 12, which is an induced depressive disorder.
  • Item 14 The pharmaceutical composition according to any one of items 1 to 8 and 12, wherein the central disease is a group of depressive disorders in children.
  • Central disorders are anxiety-affected depressive disorders in children, depressive disorders with mixed features in children, depressive disorders with melancholic features in children, psychotic features that match mood in children Depressive disorder group with illness, depressive disorder group with psychotic features inconsistent with mood in children, depressive disorder group with catatonic disorders in children, seasonal depressive disorder group in children, severe mood regulation in children, in children 15.
  • Item 16 9. The pharmaceutical composition according to any one of items 1 to 8 above, wherein the central disease is an anxiety group.
  • Item 17. 17 The pharmaceutical composition according to any one of the above items 1 to 8 and 16, wherein the central disease is separation anxiety disorder, localized phobia, social anxiety disorder, panic disorder, or substance / drug-induced anxiety disorder. ..
  • Item 18. The pharmaceutical composition according to any one of items 1 to 8 and 16 above, wherein the central disease is an anxiety group in children.
  • the central disease is separation anxiety in children, localized phobia in children, social anxiety in children, panic disorder in children, or substance / drug-induced anxiety in children.
  • the pharmaceutical composition according to any one of claims.
  • Item 20 The pharmaceutical composition according to any one of Items 1 to 8, wherein the central disease is a neurodevelopmental group.
  • Item 21 Central diseases include autism spectrum disorder, attention deficit / hyperactivity disorder, localized learning disorder, intellectual disability, speech disorders, speech disorders, childhood-onset fluency, social (pragmatic) communication disorders, development 21.
  • Item 22 The pharmaceutical composition according to any one of items 1 to 8 above, wherein the central disease is a group of obsessive-compulsive disorder and related disorders.
  • Item 23 The pharmaceutical composition according to any one of the above items 1 to 8 and 22, wherein the central disease is obsessive-compulsive disorder, dysphoric phobia, dentosis, hair loss, or plucking skin.
  • Item 24 The pharmaceutical composition according to any one of items 1 to 8, wherein the central disease is a group of disorders related to trauma and stress factors.
  • Item 25 The medicine according to any one of the above items 1 to 8 and 24, wherein the central disease is post-traumatic stress disorder, reactive attachment disorder, disinhibition-type interpersonal interaction disorder, acute stress disorder, or adaptation disorder. Composition.
  • Item 26 The pharmaceutical composition according to any one of the above items 1 to 25, wherein the dose of tipepidine or a pharmaceutically acceptable salt thereof is 2 mg to 2000 mg per day.
  • Item 27 The pharmaceutical composition according to any one of items 1 to 26 above, wherein the dose of the CYP2D6 inhibitor is 1 mg to 1000 mg per day.
  • Item 28 A method for treating or preventing a central disease comprising administering to a mammal a therapeutically effective amount of tipepidine or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CYP2D6 inhibitor.
  • Item 29 Tipepidine or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of central diseases in combination with a CYP2D6 inhibitor.
  • Item 30 A CYP2D6 inhibitor for use in the treatment or prevention of central diseases, which is used in combination with tipepidine or a pharmaceutically acceptable salt thereof.
  • Item 31 Use of tipepidine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing central diseases, which is used in combination with a CYP2D6 inhibitor.
  • Item 32 Use of a CYP2D6 inhibitor for the manufacture of a medicament for treating or preventing central diseases, which is used in combination with tipepidine or a pharmaceutically acceptable salt thereof.
  • Item 33 Use of tipepidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor for the manufacture of a medicament for treating or preventing central diseases.
  • Item 34 A kit for the treatment or prevention of central diseases, which comprises tipepidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor.
  • Parkinson's disease due to antipsychotic use, sleep disorder, chronic fatigue syndrome, fatigue associated with neurodegeneration and central illness, overeating, addiction, fiber containing tipepidine or a pharmaceutically acceptable salt thereof
  • Item 36 Including tipepidine or a pharmaceutically acceptable salt thereof, Parkinson's disease, Parkinson's disease syndrome due to antipsychotic use, sleep disorder, chronic fatigue syndrome, fatigue associated with neurodegeneration and central diseases, overeating, addiction, or A therapeutic or preventive agent for fibromyalgia.
  • Item 37 The therapeutic or prophylactic agent according to Item 35 or 36, wherein the disease is a sleep disorder.
  • Item 39 The therapeutic or prophylactic agent according to Item 35 or 36 above, wherein the disease is a group of trauma and stress-related disorders.
  • Item 40 37.
  • the therapeutic or prophylactic agent according to the above item 35 or 36, wherein the disease is post-traumatic stress disorder, reactive attachment disorder, disinhibition-type interpersonal interaction disorder, acute stress disorder, or adaptation disorder.
  • the invention also relates to: Fatigue associated with Parkinson's disease, Parkinson's disease syndrome due to antipsychotic drug use, sleep disorders, chronic fatigue syndrome, neurodegeneration and central illness, including administration of tipepidine or a pharmaceutically acceptable salt thereof to a mammal , A method for treating or preventing hyperphagia, addiction, fibromyalgia, or trauma and stress-related disorders.
  • Parkinson's disease Parkinson's syndrome due to antipsychotic use, sleep disorders, chronic fatigue syndrome, fatigue associated with neurodegenerative and central illness, overeating, addiction, fibromyalgia, or trauma and stress-related disorders
  • a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of Parkinson's disease, Parkinson's syndrome due to antipsychotic use, sleep disorders, chronic fatigue syndrome, fatigue associated with neurodegenerative and central illness, overeating, addiction, fibromyalgia, or trauma and stress-related disorders
  • tipepidine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis; and if the disease is a sleep disorder (especially hypersomnia, idiopathic hypersomnia disorder, or narcolepsy).
  • the present invention by combining tipepidine or a pharmaceutically acceptable salt thereof with a CYP2D6 inhibitor, the pharmacokinetics of tipepidine having a short half-life in vivo were improved, and a new central action of tipepidine was found.
  • Parkinson's disease, Parkinson's disease syndrome due to the use of antipsychotics, sleep disorders, chronic fatigue syndrome, fatigue associated with neurodegeneration and central diseases, overeating, dependence, or therapeutic agents for central diseases such as fibromyalgia
  • the present invention can be expected to improve sleep disorders.
  • tipepidine or a pharmaceutically acceptable salt thereof comprising tipepidine or a pharmaceutically acceptable salt thereof, Parkinson's disease, Parkinson's disease syndrome due to the use of antipsychotic drugs, sleep disorders, chronic fatigue syndrome, fatigue associated with neurodegeneration and central diseases, overeating.
  • therapeutic or prophylactic agents for addiction, or fibromyalgia methods for treating or preventing, pharmaceutical compositions and kits.
  • tipepidine or a pharmaceutically acceptable salt thereof in combination with a CYP2D6 inhibitor, a depressive disorder group, anxiety group, neurodevelopmental group, obsessive-compulsive and related disease group, or heart.
  • therapeutic agents or prophylactic agents for the group of trauma and stress-related disorders methods for treating or preventing, pharmaceutical compositions and kits.
  • a therapeutic or prophylactic agent for a group of disorders related to trauma and stress factors a method, a pharmaceutical composition and a kit for treating or preventing, comprising tipepidine or a pharmaceutically acceptable salt thereof.
  • FIG. 1 shows the metabolic stability of tipepidine in human hepatocytes, and shows the residual rates of tipepidine in the treated and non-treated groups to which 1-ABT, a CYP inhibitor, was added.
  • the horizontal axis shows the reaction time, and the vertical axis shows the residual ratio of tipepidine.
  • FIG. 2 shows simulated changes in plasma concentration of tipepidine when orally administered to humans alone with tipepidine or with combined use of a CYP2D6 inhibitor and tipepidine.
  • the horizontal axis shows the time from administration, and the vertical axis shows the plasma concentration of tipepidine.
  • FIG. 1 shows the metabolic stability of tipepidine in human hepatocytes, and shows the residual rates of tipepidine in the treated and non-treated groups to which 1-ABT, a CYP inhibitor, was added.
  • the horizontal axis shows the reaction time, and the vertical axis shows the residual ratio of tipepidine.
  • FIG. 2 shows simulated changes in
  • FIG. 3 shows plasma of tipepidine when orally administered to human hepatocyte-transplanted mice (PXB mice) with 20 mg / kg of tipepidine hibenzate alone and with 100 mg / kg of CYP2D6 inhibitor quinidine and 20 mg / kg of tipepidine hibenzate.
  • the figure shows the transition of medium concentration.
  • the horizontal axis shows the time from administration, and the vertical axis shows the plasma concentration of tipepidine.
  • FIG. 4 shows changes in plasma concentrations of tipepidine when SD rats were orally administered with 20 mg / kg of tipepidine hibenzate alone, and combined with 20 mg / kg of CYP inhibitor 1-ABT and 100 mg / kg of tipepidine hibenzate. It is a thing.
  • FIG. 5 shows the total amount of locomotor activity from 30 minutes after administration to 1.5 hours after intraperitoneal administration of solvent or tipepidine hibenzate (2 groups of 25 mg / kg and 80 mg / kg) to SD rats. It was done.
  • the bar graph shows the average value of each treatment group, and ** means that the risk rate (P) calculated by Dunnett's test is less than 0.01.
  • FIG. 6 shows that SD rats were intraperitoneally administered with a solvent, imipramine 10 mg / kg was subcutaneously administered, or tipepidine hibenzate (2 groups of 8.0 mg / kg and 80 mg / kg) was intraperitoneally administered 30 minutes later.
  • the forced swimming test was performed, and the immobility time (seconds) of the rat was displayed.
  • the bar graph shows the average value of each treatment group, and ** means that the risk rate (P) calculated by the Tukey-Kramer test is less than 0.01.
  • FIG. 7 shows that SD rats were forcibly orally administered with vehicle, tipepidine hibenzate 20 mg / kg, or tipepidine hibenzate 20 mg / kg and CYP inhibitor 1-ABT 100 mg / kg, and 30 minutes after the administration of tipepidine, 1.5 hours. It is a display of the total sum of the spontaneous locomotor activity of.
  • the bar graph shows the average value of each treatment group.
  • S. Means that the risk factor (P) calculated by the Tukey-Kramer test is 0.05 or more.
  • FIG. 8 shows that SD rats were forcibly orally administered with solvent, tipepidine hibenzate 20 mg / kg, or tipepidine hibenzate 20 mg / kg and CYP inhibitor 1-ABT 100 mg / kg, and a forced swimming test was conducted 1 hour after the administration. , The immobility time of the rat (second) is displayed. The bar graph shows the average value of each treatment group.
  • S. Means that the risk factor (P) calculated by the Tukey-Kramer test is 0.05 or more, and ** means that the risk factor (P) calculated by the Tukey-Kramer test is less than 0.01.
  • FIG. 10A shows that Wistar rats were intraperitoneally administered with a solvent, tipepidine hibenzate (2 groups of 8.0 mg / kg and 80 mg / kg), sleep EEG was measured 4 hours after the administration, and the awakening time of the rats was measured. It is displayed.
  • FIG. 10B is a graph showing the total wakeup time 4 hours after the administration of the solvent, tipepidine hibenzate (2 groups of 8.0 mg / kg and 80 mg / kg) to the Wistar rat, intraperitoneally.
  • the bar graph shows the average value of each treatment group, ** means that the risk rate (P) calculated by Dunnett's test is less than 0.01, and * indicates the risk rate (P) calculated by Dunnett's test. Means less than 0.05.
  • FIG. 11A shows that Wistar rats were intraperitoneally administered with a solvent, tipepidine hibenzate (2 groups of 8.0 mg / kg and 80 mg / kg). REM sleep EEG was measured 4 hours after administration, and the REM sleep time of the rat was displayed.
  • FIG. 11B is a graph showing the total REM sleep time of 4 hours after the intraperitoneal administration of the vehicle, tipepidine hibenzate (2 groups of 8.0 mg / kg and 80 mg / kg), to Wistar rats.
  • the bar graph shows the average value of each treatment group, ** means that the risk rate (P) calculated by Dunnett's test is less than 0.01, and * indicates the risk rate (P) calculated by Dunnett's test. Means less than 0.05.
  • FIG. 12 shows the immobility time by the forced swimming test 60 minutes after the administration, which was subcutaneously administered to a chronically fatigued SD rat at a dose of 1 mg / kg of solvent and tipepidine citrate or 5 mg / kg. It is a thing. ** means that the risk rate (P) calculated by Dunnett's test is less than 0.01.
  • FIG. 13A shows that on the day before the test, Wistar rats were forcibly orally administered with the solvent or the CYP inhibitor 1-ABT 100 mg / kg, and 15 minutes before the start of the test, the solvent or tipepidine hibenzate 40 mg / kg was orally administered, and the test was started. The sleep electroencephalogram was measured 6 hours later, and the awakening time of the rat was displayed.
  • FIG. 13A shows that on the day before the test, Wistar rats were forcibly orally administered with the solvent or the CYP inhibitor 1-ABT 100 mg / kg, and 15 minutes before the start of the test, the solvent or tipepidine hibenzate
  • FIG. 13B shows that on the day before the test, Wistar rats were gavaged with the solvent or the CYP inhibitor 1-ABT 100 mg / kg, and 15 minutes before the start of the test, the vehicle or the tipepidine hibenzate 40 mg / kg was gavaged, and the test was started. It shows the total awakening time of the next 6 hours.
  • the bar graph shows the average value of each treatment group.
  • S. Means that the risk factor (P) calculated by the Tukey-Kramer test is 0.05 or more, and ** means that the risk factor (P) calculated by the Tukey test is less than 0.01.
  • FIG. 14A shows that on the day before the test, Wistar rats were gavaged with the solvent or the CYP inhibitor 1-ABT 100 mg / kg, and 15 minutes before the start of the test, the vehicle or the tipepidine hibenzate salt 40 mg / kg was gavaged orally, and the test was started. The REM sleep electroencephalogram was measured 6 hours later, and the REM sleep time of the rat was displayed.
  • FIG. 14B shows that on the day before the test, Wistar rats were gavaged with the solvent or the CYP inhibitor 1-ABT 100 mg / kg, and 15 minutes before the start of the test, the vehicle or the tipepidine hibenzate 40 mg / kg was gavaged, and the test was started.
  • One aspect of the present invention relates to a combination of tipepidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor.
  • Another aspect of the present invention comprises tipepidine or a pharmaceutically acceptable salt thereof, Parkinson's disease, Parkinson's disease syndrome due to antipsychotic use, sleep disorders, chronic fatigue syndrome, fatigue associated with neurodegenerative and central diseases.
  • the present invention relates to a therapeutic or preventive agent for feeling, overeating, addiction, or fibromyalgia.
  • Tipepidine in the present invention has a chemical name of 3- (dithien-2-ylmethylene) -1-methylpiperidine and has already been used as an active ingredient of a commercially available antitussive drug. And, as tipepidine, it can be used in a free base form or a pharmaceutically acceptable acid addition salt and / or hydrate and / or solvate thereof (in the present specification, these are collectively referred to as tipepidine Or its pharmaceutically acceptable salt).
  • Suitable acid addition salts are, for example, selected from succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid, citric acid and hibenzic acid. Examples thereof include salts of acids, preferably salts of hibenzic acid or citric acid.
  • cytochrome P450 (hereinafter referred to as CYP) is known as an enzyme that plays a major role.
  • CYP cytochrome P450
  • the major molecular species are CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 / 5. Since the CYP2D6 inhibitor has an action of suppressing the enzymatic activity of CYP2D6, it increases blood exposure of the CYP2D6 substrate drug when used in combination with a drug metabolized by CYP2D6 (hereinafter referred to as CYP2D6 substrate drug).
  • the “CYP2D6 inhibitor” in the present invention means a plasma exposure (AUC) of a CYP2D6 substrate drug susceptible to interaction in a clinical drug interaction test by 1.25 times or more, preferably 2 times or more, more preferably 5 times or more. It means a drug having an inhibitory ability to increase more than twice.
  • CYP2D6 inhibitor in the present invention, specifically, “Drug Interaction Guideline for Drug Development and Proper Information Provision (Final Draft)” issued on July 8, 2014 or September 26, 2016 Drug Development and Drug Interactions: Table of of Substrates, Inhibitors and and Inducers Table 3-2: Examples of clinical inhibitors for P450-mediated metabolisms (for concomitant use priorical and D quinidine, paroxetine, bupropion, fluoxetine, terbinafine, cinacalcet, dacomitinib, which are classified as strong inhibitors of CYP2D6 in drug labeling), duloxetine, mirabegron, celecoxib, escitalopram, moclobemide, which are classified as moderate inhibitors.
  • CYP2D6 inhibitor any two or more of these drugs may be used in combination. Although these drugs have different main actions, they also have a CYP2D6 inhibitory action, and are therefore referred to as “CYP2D6 inhibitors” in the present specification.
  • Suitable acid addition salts are selected, for example, from succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid, citric acid and hibenzic acid. Acid salts may be mentioned.
  • quinidine, paroxetine, bupropion, fluoxetine, terbinafine, cinacalcet, dacomitinib or pharmaceutically acceptable salts thereof which are classified as strong inhibitors of CYP2D6, and more preferably have few side effects and are easy to clinically Quinidine, paroxetine, bupropion, fluoxetine, or a pharmaceutically acceptable salt thereof, wherein quinidine is a sulfate hydrate, paroxetine is a hydrochloride hydrate, bupropion is a hydrochloride, and fluoxetine is a hydrate. It is preferably used as the hydrochloride salt. Even more preferably, quinidine or a pharmaceutically acceptable salt thereof, which is different from the effective dose exhibiting the main drug effect by 10 times or more the effective dose exhibiting the inhibitory effect, is exemplified.
  • Parkinson's disease As one embodiment of the central diseases in the present invention, Parkinson's disease, Parkinson's disease syndrome due to the use of antipsychotic agents, sleep disorders (including hypersomnia, idiopathic hypersomnia disorder, narcolepsy), chronic fatigue syndrome, neurodegeneration and central nervous system Fatigue associated with sexual disorders, overeating, addiction, or fibromyalgia.
  • sleep disorders including hypersomnia, idiopathic hypersomnia disorder, narcolepsy
  • chronic fatigue syndrome neurodegeneration and central nervous system Fatigue associated with sexual disorders, overeating, addiction, or fibromyalgia.
  • Preferred examples include hypersomnia, idiopathic hypersomnia disorder, or sleep disorders including narcolepsy.
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
  • DSM-5 Depressive disorders
  • category V anxiety Anxiety Disorders
  • category I neurodevelopmental disorders Neurodevelopmental disorders
  • Depressive Disorders include Depressive Disorders With With anxious distress, Depressive Disorders With Mixed features, and depression with melancholic features. Depressive Disorders With melancholicfeatures, Depressive Disorders With-moog-congruent psychoticfeatures, Depressive Disorders with non-mood psychotic features With-mood-incongruent psychotic features, Depressive Disorders With Catatonia, Depressive Disorders, With seasonal pattern, Severe Mood Dysregulation Disorder, Depression.
  • Depressive Disorder Major Depressive Disorder
  • persistent depressive disorder dysthymia
  • disiste nt Depressive Disorder Dysthymia
  • premenstrual dysphoric disorder Premenstrual Dysphoric Disorder
  • substance / drug-induced depressive disorder Substance / Medication-Induced Depressive Disorder
  • Anxiety Disorders include Separation Anxiety Disorder, Specific Phobia, Social Anxiety Disorder (Social Phobia), and Panic Disorder. ), Or substance / drug-induced anxiety disorder (Substance / Medication-Induced Anxiety Disorder).
  • Neurodevelopmental Disorders include Autism Spectrum Disorder, Attention-Deficit / Hyperactivity Disorder, Specific Learning Disorder, and intellectual disability IntellectualDisability), Language Disorder, Speech Sound Disorder, Childhood-Onset Fluency Disorder (Stuttering), Social (Pragmatic) Communication (Pragmatic) Communication Disorder), Developmental Coordination Disorder, Tic Disorders.
  • depression disorders in children include depressive disorders with anxious distress in children, depressive disorders with mixed features in children, depressive disorders with melancholic features in children, and psychosis consistent with mood in children.
  • Depressive disorder group with sexual characteristics depressive disorder group with psychotic features that do not match mood in children, depressive disorder group with catatonic disorders in children, seasonal depressive disorder group in children, severe mood regulation in children , Depression in children, persistent depressive disorder in children (dysthymia), premenstrual dysphoric disorder in children, or substance-drug-induced depressive disorder in children.
  • Anxiety groups in children include isolated anxiety in children, localized phobia in children, social anxiety in children (social phobia), panic disorder in children, or substance-drug-induced anxiety in children.
  • the term “children” used in the present invention generally means 6 to 15 years old.
  • the therapeutic or prophylactic agent for a depressive disorder group, anxiety group, or neurodevelopmental group by combining tipepidine or a pharmaceutically acceptable salt thereof with a CYP2D6 inhibitor according to the present invention has immediate effect. It is a safe medicine that is effective, persistent, does not form addiction, and does not cause suicide attempts, and is therefore applicable not only to adult patients but also to pediatric patients.
  • a group VI according to DSM-5 is obsessive-compulsive and related disorders (Obsessive-Compulsive and Related Related Disorders), or a group VII of trauma and stress-related disorders. (Trauma- and Stressor-Related Disorders).
  • Obsessive-compulsive Disorder Obsessive-Compulsive Disorder, Body Dysmorphic Disorder, Hoarding Disorder, Trichotillomania (Hair-Pulling Disorder), or skin Exclusion (Skin-Picking) Disorder is mentioned.
  • Post-traumatic stress disorder including post-traumatic stress disorder in children under 6 years old
  • Posttraumatic StressDisorder reactive attachment disorder
  • Reactive AttachmentDisorder Disinhibited social interaction disorder
  • acute stress disorder acute Stress Disorder
  • adjustment disorder Adjustment Disorders
  • a "therapeutically effective amount” means an amount of a drug or drug that elicits a biological or pharmaceutical response required by a researcher or physician in a tissue, system, animal or human.
  • “treatment” and “treatment” refer to any treatment of a disease (eg, amelioration of symptoms, alleviation of symptoms, suppression of progression of symptoms, etc.) and any prevention of diseases (eg, onset and / or development of a disease). Or prevention of progress) is included.
  • pharmaceutical composition As used herein, “pharmaceutical composition,” “pharmaceutical formulation,” and “pharmaceutical product” refer to products that contain the specified ingredients in the specified amounts, as well as directly or indirectly from combinations of the specified ingredients in the specified amounts. It is intended to encompass any product that results.
  • the definition of sleep disorder used in the present invention is "a state in which excessive sleepiness or actual falling into sleep during the day is seen repeatedly every day, which lasts for at least one month, As a result, social life or occupational function is disturbed, or one feels distressed, even if the duration of one session is shorter than one month and repeated sleep periods are observed. ”
  • both agents may be administered separately or may be administered together as one pharmaceutical composition.
  • one component of the combination of the invention may be administered prior to, simultaneously with, or after the other component.
  • These components may be prepared as a pharmaceutical preparation in a single preparation form or separate preparation forms, or may be a kit.
  • the active ingredient of the present invention is orally or parenterally (for example, intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or implant).
  • parenterally for example, intramuscular, intraperitoneal, intravenous, transdermal or subcutaneous injection or implant.
  • it may be formulated alone or in combination with other drugs that can be used in combination in a suitable formulation containing a vehicle.
  • Pharmaceutical products suitable for oral administration according to the invention comprise the active compound tipepidine of the invention, a pharmaceutically acceptable salt thereof and / or a CYP2D6 inhibitor, in a dose adapted to the individual needs of the active ingredient. It can be administered orally in the usual dosage forms, such as tablets, capsules, syrups, suspensions and the like. Alternatively, the solution, emulsion, suspension or the like in the form of a liquid preparation can be administered parenterally in the form of injection, or can be made into a patch. Also, the above suitable dosage forms can be prepared by incorporating the active compound into an acceptable conventional carrier, excipient, binder, stabilizer and the like. When used in an injection dosage form, an acceptable buffering agent, solubilizing agent, isotonic agent, pH adjusting agent and the like can be added.
  • the dose of the active ingredient of the present invention is not particularly limited, but the dose and frequency of administration of the therapeutic agent vary depending on the administration form or the degree of disease state requiring treatment.
  • tipepidine or a pharmaceutically acceptable salt thereof is administered as a single agent, 2-2000 mg, preferably 20-200 mg per day for an adult is orally or parenterally administered once or in several divided doses. be able to.
  • tipepidine or a pharmaceutically acceptable salt thereof when tipepidine or a pharmaceutically acceptable salt thereof is administered in combination with a CYP2D6 inhibitor, the dose is 2-2000 mg, preferably 20-200 mg per day for an adult, orally or
  • the CYP2D6 inhibitor may be orally administered, and the combined CYP2D6 inhibitor may be 1-1000 mg, preferably 1-300 mg per day for an adult, and may be orally or parenterally administered once or in several divided doses.
  • quinidine or a pharmaceutically acceptable salt thereof can be administered orally or parenterally per day for an adult at 1 to 200 mg, preferably 1 to 50 mg, once or in several divided doses. ..
  • paroxetine or a pharmaceutically acceptable salt thereof can be orally or parenterally administered to an adult per day at 1 to 200 mg, preferably 1 to 50 mg, once or in several divided doses. ..
  • bupropion or a pharmaceutically acceptable salt thereof can be administered orally or parenterally in an amount of 1 to 1000 mg, preferably 1 to 300 mg per day for an adult, or once or in several divided doses. ..
  • fluoxetine or a pharmaceutically acceptable salt thereof can be administered orally or parenterally in an adult daily dose of 1-200 mg, preferably 1-50 mg, once or in several divided doses. ..
  • the weight ratio of tipepidine (free form equivalent): CYP2D6 inhibitor (free form equivalent) when administering in combination with tipepidine or a pharmaceutically acceptable salt thereof and the CYP2D6 inhibitor is 1: 500 to 2000: 1.
  • free form equivalent means the weight as it is when the main drug is used in the free form, and the free weight excluding the weight of the salt when the main drug is used in the form of a pharmaceutically acceptable salt.
  • the CYP2D6 inhibitor is quinidine or a pharmaceutically acceptable salt thereof
  • tipepidine or a pharmaceutically acceptable salt thereof and quinidine or a pharmaceutically acceptable salt thereof are administered in combination.
  • the weight ratio of tipepidine (free body conversion): quinidine (free body conversion) is 1: 100 to 2000: 1.
  • the weight ratio of tipepidine (calculated as free form): paroxetine is 1: 100 to 2000: 1.
  • the CYP2D6 inhibitor is bupropion or a pharmaceutically acceptable salt thereof
  • tipepidine or a pharmaceutically acceptable salt thereof and bupropion or a pharmaceutically acceptable salt thereof are administered in combination.
  • the weight ratio of tipepidine (free form conversion): bupropion is 1: 500 to 2000: 1.
  • the CYP2D6 inhibitor is fluoxetine or a pharmaceutically acceptable salt thereof
  • tipepidine or a pharmaceutically acceptable salt thereof and fluoxetine or a pharmaceutically acceptable salt thereof are administered in combination.
  • the weight ratio of tipepidine (free form conversion): fluoxetine is 1: 100 to 2000: 1.
  • the lower limit value of tipepidine (free body conversion) per day for adults when tipepidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor are administered in combination is in the range of 2 to 20 mg.
  • the lower limit of the daily dose of the CYP2D6 inhibitor for an adult is any weight in the range of 1 to 20 mg, for example, 1 mg, 2 mg, 5 mg, 10 mg. , Or 20 mg.
  • the lower limit of the weight ratio of tipepidine (free form conversion): CYP2D6 inhibitor is, for example, 1: 500, 1: 250, 1: 100, 1:50, 1:25, 1:10, 1: 5, 1: 2.
  • the CYP2D6 inhibitor when the CYP2D6 inhibitor is quinidine or a pharmaceutically acceptable salt thereof, 1 mg, 2 mg, or 5 mg can be mentioned as the lower limit of quinidine (free form conversion) per day for an adult.
  • the lower limit of the weight ratio of tipepidine (converted free form): quinidine (converted free form) may be 1: 100, 1:50, 1:25, 1:10, 1: 5 or 1: 2.
  • the lower limit of paroxetine (free body conversion) for an adult per day is 1 mg, 2 mg, or 5 mg.
  • the lower limit of the weight ratio of tipepidine (converted to free form): paroxetine (converted to free form) includes 1: 100, 1:50, 1:25, 1:10, 1: 5 or 1: 2.
  • the CYP2D6 inhibitor is bupropion or a pharmaceutically acceptable salt thereof
  • 1 mg, 10 mg, or 20 mg may be mentioned as the lower limit of bupropion (free form conversion) per day for an adult.
  • the lower limit of the weight ratio of tipepidine (converted free form): bupropion (converted free form) includes 1: 500, 1: 300, 1: 150, 1: 100, 1:50 or 1:25.
  • the lower limit of fluoxetine (free form conversion) per day for an adult is 1 mg, 2 mg, or 5 mg.
  • the lower limit of the weight ratio of tipepidine (free form conversion): fluoxetine (free form conversion) may be 1: 100, 1:50, 1:25, 1:10, 1: 5 or 1: 2.
  • the upper limit of the amount of tipepidine (free body conversion) per day for an adult when the tipepidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor are administered in combination is in the range of 200 to 2000 mg.
  • the upper limit of the daily dose of the CYP2D6 inhibitor for an adult is any weight in the range of 50 to 1000 mg, for example, 50 mg, 100 mg, 200 mg, 500 mg. , Or 1000 mg.
  • the upper limit of the weight ratio of tipepidine (free form conversion): CYP2D6 inhibitor is, for example, 2000: 1, 1000: 1, 800: 1, 400: 1, 200: 1, 100: 1, 50: 1, 25: 1 or 10: 1.
  • the CYP2D6 inhibitor is quinidine or a pharmaceutically acceptable salt thereof, 50 mg, 100 mg, or 200 mg may be mentioned as the upper limit of quinidine (free body conversion) per day for an adult.
  • the upper limit of the weight ratio of tipepidine (converted free form): quinidine (converted free form) is 2000: 1, 1000: 1, 400: 1, 200: 1, 100: 1, 50: 1, 25: 1 or 10: 1 can be mentioned.
  • the CYP2D6 inhibitor when the CYP2D6 inhibitor is paroxetine or a pharmaceutically acceptable salt thereof, 50 mg, 100 mg, or 200 mg may be mentioned as the upper limit of paroxetine (free form conversion) per day for an adult.
  • the upper limit of the weight ratio of tipepidine (converted free form): paroxetine (converted free form) is 2000: 1, 1000: 1, 400: 1, 200: 1, 100: 1, 50: 1, 25: 1 or 10: 1 can be mentioned.
  • the CYP2D6 inhibitor when the CYP2D6 inhibitor is bupropion or a pharmaceutically acceptable salt thereof, the upper limit of bupropion (free body conversion) for an adult per day is 300 mg, 600 mg, or 1000 mg.
  • the upper limit of the weight ratio of tipepidine (free form conversion): bupropion (free form conversion) is 2000: 1, 1000: 1, 400: 1, 200: 1, 100: 1, 50: 1, 25: 1 or 10: 1 can be mentioned.
  • the CYP2D6 inhibitor is fluoxetine or a pharmaceutically acceptable salt thereof
  • 50 mg, 100 mg, or 200 mg may be mentioned as the upper limit of fluoxetine (free body conversion) per day for an adult.
  • the upper limit of the weight ratio of tipepidine (free form conversion): fluoxetine (free form conversion) is 2000: 1, 1000: 1, 400: 1, 200: 1, 100: 1, 50: 1, 25: 1 or 10: 1 can be mentioned.
  • the pharmaceutical composition of the present invention is used as a solid preparation for oral administration, a liquid preparation for oral administration, and an injection, an external preparation, a suppository, an inhalant, a nasal preparation, etc. for parenteral administration.
  • the solid preparations for oral administration include tablets, pills, capsules, powders and granules. Capsules include hard capsules and soft capsules. In addition, tablets include sublingual tablets, buccal tablets, and rapidly disintegrating buccal tablets.
  • one or more active substances may be used as they are, or excipients (lactose, mannitol, glucose, crystalline cellulose, dextrin, starch, etc.), binders (hydroxypropylcellulose, polyvinylpyrrolidone). , Magnesium metasilicate, etc.), disintegrant (calcium fibrin glycolate, etc.), lubricant (magnesium stearate, talc, etc.), stabilizer, solubilizer (glutamic acid, aspartic acid, etc.), etc. It is used by formulating it according to a conventional method.
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • capsules of absorbable material such as gelatin.
  • additives such as preservatives, antioxidants, colorants, sweeteners and the like which are commonly used can be added if necessary.
  • Sublingual tablets, buccal patches, rapidly disintegrating buccal tablets, and oral liquid preparations for oral administration are mixed with usual carriers, excipients, binders, stabilizers, etc. suitable for each dosage form. It is manufactured according to a known method.
  • the dosage form of the external preparation for parenteral administration includes, for example, ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops, and Includes nasal drops and the like. These contain one or more active substances and are produced by a known method or a commonly used formulation.
  • a poultice, a patch, and an injection for parenteral administration are manufactured by a known or commonly used formulation by mixing with a usual pharmaceutical additive suitable for each dosage form.
  • the term “effective amount” refers to tipepidine or a pharmaceutical preparation thereof, which completely or partially inhibits the progression of central diseases, or at least partially alleviates one or more symptoms of central diseases. Or a combination of tipepidine or a pharmaceutically acceptable salt thereof and a CYP2D6 inhibitor.
  • An effective amount can be a therapeutically or prophylactically effective amount.
  • An effective amount will be determined by the age and sex of the patient, the condition being treated, the severity of the condition, the results sought, and the like. For a given patient, the effective amount can be determined by methods known to those of ordinary skill in the art.
  • Example 1 Estimation of CYP metabolism contribution of tipepidine using human hepatocytes The contribution of CYP metabolism to the metabolism of tipepidine by human hepatocytes was confirmed by the following method.
  • Human frozen hepatocytes used were those manufactured by Sekisui XenoTech. Human frozen hepatocytes were seeded in KHB buffer at a concentration of 1 million cells / mL, and tipepidine was added thereto at a concentration of 1 ⁇ mol / L.
  • a treatment group to which 1-aminobenzotriazole (1-ABT) (2.5 mmol / L), which is a CYP inhibitor, was added and a non-treatment group to which no CYP inhibitor was added were provided, and the conditions were 37 ° C. and 5% CO 2 And incubated for 1 hour or 2 hours.
  • the residual rate of tipepidine after the reaction was measured by LC-MS.
  • Example 2 Calculation of Various CYP Metabolism Contribution Ratios of Tipepidine Using Human Liver Microsomes
  • the metabolic contribution ratios of various CYPs involved in the metabolism of tipepidine were calculated using human liver microsomes.
  • Human liver microsomes used were manufactured by Sekisui XenoTech. Human liver microsomes were added at a concentration of 0.1 mg / mL, NADPH at 3 mmol / L, and tipepidine at a concentration of 0.1 ⁇ mol / L in a 50 mmol / L phosphate buffer (pH 7.4), and various CYPs were added.
  • the selective inhibitors were mixed at the concentrations shown below and incubated at 37 ° C for 30 minutes.
  • CYP1A2 Concentration of selective inhibitor of various CYPs Furafylline (CYP1A2): 10 ⁇ mol / L, montelukast (CYP2C8): 10 ⁇ mol / L, sulfaphenazole (CYP2C9): 10 ⁇ mol / L, N-benzylnilvanol ( N-benzylnirvanol; CYP2C19): 5 ⁇ mol / L, quinidine (CYP2D6): 1 ⁇ mol / L, azamulin (CYP3A4): 5 ⁇ mol / L
  • Table 1 shows the survival rate at the time of inhibition of various CYPs in the metabolism of tipepidine in human liver microsomes, the metabolic clearance, and the metabolic contribution rate of various CYPs calculated from the metabolic clearance. For the first time, it was revealed that tipepidine was mainly metabolized by CYP2D6, and its contribution rate was calculated to be 83%.
  • Example 3 Simulation of Tipepidine Plasma Concentration Changes in Humans and PK Parameters in Combination with Tipepidine Alone, CYP2D6 Inhibitor and Tipepidine Combined Commercially-Containing Tipepidine as an Active Ingredient in Plasma Concentration Changes and PK Parameters after Oral Administration of Tipepidine It was calculated by applying the information described in the Asverin Tablet Interview Form (IF) to the following 1-compartment model formula.
  • IF Asverin Tablet Interview Form
  • FIG. 2 shows the simulation results of changes in the plasma concentration of tipepidine when orally administered to humans alone with tipepidine alone, or when orally administered with the combination of CYP2D6 inhibitor and tipepidine
  • Table 2 shows the simulation results of PK parameters. It was simulated that the C max of tipepidine when the CYP2D6 inhibitor and tipepidine were combined was increased by a maximum of 3.1 times, the AUC was increased by a maximum of 9.4 times, and the t 1/2 was increased by a maximum of 4.0 times as compared with the case of administration of tipepidine alone. It was shown that the combination of tipepidine with a CYP2D6 inhibitor can be expected to increase plasma exposure and half-life of tipepidine.
  • Example 4 Evaluation of Tipepidine Blood Kinetics of Tipepidine Alone in PXB Mice and in Combination with CYP2D6 Inhibitor Quinidine and Tipepidine.
  • PXB mice which are human hepatocyte transplanted mice. It is known that there are species differences in drug metabolism in general, and the contribution ratio of various CYPs to metabolism is also different. Therefore, PXB mice transplanted with human hepatocytes are used instead of using wild-type mice or rats. It is considered that the use of is more suitable for verifying the combined effect of CYP2D6 inhibitors in humans.
  • tipepidine hibenzate alone was orally administered to male PXB mice (18-20 weeks old), which are human liver transplantation mice, or 100 mg / kg of CYP2D6 inhibitor quinidine was orally administered, and 2 hours after that, tipepidine hibenzic acid was administered. 20 mg / kg of salt was orally administered. Blood was collected at 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, and 24 hours after administration of tipepidine hibenzate. Plasma was obtained from the collected blood, the plasma tipepidine concentration was measured by LC-MS, and the concentration transition was subjected to non-compartmental analysis using Phoenix WinNonlin (Certara), and C max , AUC, t 1 / as PK parameters. 2 was calculated.
  • tipepidine By co-administering tipepidine with CYP2D6 inhibitor quinidine, it was clarified that the C max of tipepidine was increased by 1.5 times, AUC was increased by 3.2 times, and t 1/2 was increased by 3.0 times. It has been shown that increased plasma exposure and increased half-life are expected.
  • the rate of increase shown in this Example was lower than the rate of increase simulated in Example 3, but this was due to the fact that the liver of PXB mouse was not completely humanized and the residual hepatocytes of the mouse were It is presumed that the metabolism of the drug was not affected by chidinin.
  • Example 5 Evaluation of Tipepidine Blood Kinetics of Tipepidine Alone and CYP Inhibitor 1-ABT in Combination with Tipepidine in SD Rats
  • Example 4 by combining tipepidine with CYP2D6 inhibitor quinidine in PXB mice, increase and halve in plasma exposure of tipepidine Although an increase in the period was confirmed, PXB mice are not suitable for pharmacological evaluation. Therefore, an oral administration test of tipepidine using SD rats was carried out for the purpose of confirming the exposure-increasing effect of the combined use of CYP inhibitors in rats suitable for pharmacological evaluation.
  • 1-ABT that inhibits all CYPs was used instead of the CYP2D6 inhibitor.
  • a solvent or CYP inhibitor 1-ABT 100 mg / kg was orally administered to SD male rats (7 weeks old). Two hours after the administration of the solvent or 1-ABT, 20 mg / kg of tipepidine hibenzate was orally administered. Blood was collected 30 minutes, 1 hour, 2 hours, 4 hours, and 6 hours after administration.
  • Plasma was obtained from the collected blood, the plasma tipepidine concentration was measured by LC-MS, and the concentration transition was subjected to non-compartmental analysis using Phoenix WinNonlin (Certara), and C max , AUC, t 1 / as PK parameters. 2 was calculated.
  • PK parameters are shown in Table 4. It was revealed that coadministration of tipepidine with 1-ABT increased C max 16-fold, AUC 93-fold, and t 1/2 12-fold.
  • Example 6 Examination of central side effects of tipepidine The evaluation of locomotor activity in a new environment is an evaluation system generally used for evaluating side effects of drugs acting on the central nervous system. Thirty-two SD male rats (7 weeks old) were intraperitoneally administered with a solvent or tipepidine hibenzate 25 mg / kg or 80 mg / kg. From 30 minutes after the administration, the spontaneous locomotor activity of the rats was measured for 90 minutes by a SUPERMEX apparatus (Muromachi Kikai).
  • Example 7 Antidepressant-like Action of Tipepidine Using Forced Swim Test on Wistar Rats
  • the forced swim test is widely used as a behavioral test to evaluate depression-like behavior of rats and mice, including screening for antidepressant drugs.
  • Thirty-six Wistar male rats (7 weeks old) were placed in the swimming training room on the day before the test to get accustomed to the environment. Then, the animal was put into a water tank filled with tap water at a water temperature of 25 ⁇ 1 degree, and a forced swimming training test was conducted for 15 minutes.
  • the antidepressant drug imipramine 10 mg / kg was subcutaneously administered before swimming training. After swimming, the animals were removed from the aquarium and water droplets were wiped off and returned to their cages.
  • the body weight was measured and brought into a swimming training room to get accustomed to the environment.
  • imipramine was subcutaneously administered 1 hour and 5 hours before the start of the test.
  • tipepidine administration group tipepidine hibenzate 8 mg / kg or 80 mg / kg was intraperitoneally administered 30 minutes before the start of the test.
  • Internal administration was performed. The animal was placed in a water tank filled with tap water at a water temperature of 25 ⁇ 1 ° C., a forced swimming training test was conducted for 5 minutes, and a video camera was photographed from the front. The immobility time was measured visually after blinding the moving image.
  • Example 8 Examination of central side effects of tipepidine, or a combination of tipepidine and a CYP inhibitor, SD male rats (7 weeks old) were forcibly orally administered with a solvent or the CYP inhibitor 1-ABT 100 mg / kg.
  • the vehicle-administered rat group was defined as the solvent-administered group
  • the 1-ABT-administered rat group was defined as the 1-ABT-administered group.
  • Two hours after the administration of the solvent or 1-ABT in each group the solvent or the tipepidine hibenz was 20 mg / kg of the acid salt was administered, and 20 mg / kg of tipepidine hibenzate was forcibly orally administered to the 1-ABT administration group. From 30 minutes after administration of 20 mg / kg of the solvent or tipepidine hibenzate, the spontaneous locomotor activity of the rat was measured by SUPERMEX apparatus (Muromachi Kikai) for 90 minutes.
  • Example 9 Antidepressant-like action of tipepidine by tipepidine or a combination of tipepidine and a CYP inhibitor Wistar male rats (9 weeks old) were placed in a swimming training room on the day before the test to acclimate to the environment. Then, the animal was put into a water tank filled with tap water at a water temperature of 25 ⁇ 1 degree, and a forced swimming training test was conducted for 15 minutes. After swimming, the animals were removed from the aquarium and water droplets were wiped off and returned to their cages. On the day of the test, the body weight was measured and brought into a swimming training room to get accustomed to the environment. Vehicle or CYP inhibitor 1-ABT 100 mg / kg was administered by oral gavage.
  • the solvent-administered rat group was defined as the solvent-administered group, and the 1-ABT-administered rat group was defined as the 1-ABT-administered group.
  • the solvent or tipepidine 20 mg / kg was administered as the 1-ABT-administered group.
  • tipepidine 20 mg / kg was forcibly orally administered.
  • the animal was placed in a tank filled with tap water at a water temperature of 25 ⁇ 1 ° C., and one hour after the administration of tipepidine hibenzate, or four hours later, a forced swimming training test was conducted for 5 minutes. , Taken from the front with a video camera. The immobility time was measured visually after the video was blinded.
  • Example 8 it was shown that central side effects were not observed by the combined administration of tipepidine hibenzate and a CYP inhibitor (FIG. 7). From these results, in the combined administration of tipepidine hibenzate and CYP inhibitor, compared to the administration of tipepidine hibenzate alone, central side effects are not expressed and a strong antidepressant-like action can be maintained for a long time. It became clear. In addition, since it showed a strong antidepressant effect 1 hour after administration, it was clarified that it has immediate effect.
  • Example 10 Awakening Effect of Tipepidine on Wistar Male Rats Wistar male rats (9 weeks old) were bred in a dark room with a 12-hour cycle. Rats were anesthetized by intraperitoneal administration of pentobarbital 50 mg / kg, and EEG Electrode WIRES was transplanted to the skull for measuring EEG, and EMG Electrode WIRES was transplanted around the back neck for EMG Recording. After a one week recovery period, EEG / EMG recordings were measured using Ponemah (Data Sciences International, Inc.). The Sleep stage software (KISSEI COMTEC CO., LTD) was used for the determination of the sleep stage. On the day of the test, tipepidine hibenzate 8 mg / kg and 80 mg / kg were intraperitoneally administered 30 minutes before the start of the test, and the sleep state for 4 hours thereafter was determined by software.
  • KISSEI COMTEC CO., LTD The Sleep stage software
  • FIGS. 10A, 10B, 11A and 11B The results are shown in FIGS. 10A, 10B, 11A and 11B.
  • the administration of tipepidine hibenzate 8 mg / kg and 80 mg / kg maintained the wake time as compared with the vehicle administration group. Furthermore, shortening of REM sleep time was observed at 8 mg / kg and 80 mg / kg administration. That is, it was revealed that tipepidine has a strong wakefulness effect.
  • Example 11 Effect of tipepidine for improving chronic fatigue syndrome on SD rats SD rats were bred for 3 days in a breeding box in which water kept at 23 degrees was placed at a height of 1.5 cm to prepare a model of chronic fatigue syndrome associated with sleep deprivation. .. The rats were subcutaneously administered with a solvent and tipepidine citrate at a dose of 1 mg / kg or 5 mg / kg, and 60 minutes after that, a forced swimming test was performed.
  • Example 12 Awakening Effect of Tipepidine on Wistar Rats by Tipepidine and a Combination of Tipepidine and CYP Inhibitor Wistar male rats (9 weeks old) were bred in a light-dark room with a 12-hour cycle. Rats are anesthetized by intraperitoneal administration of pentobarbital 50 mg / kg, and EEG Electrode WIRES is transplanted to the skull to measure EEG, and EMG Electrode WIRES is transplanted around the back neck for EMG Recording. After a one week recovery period, EEG / EMG recordings were measured using Ponemah (Data Sciences International, Inc.). The Sleep stage software (KISSEI COMTEC CO., LTD) was used for the determination of the sleep stage.
  • the day before the test 100 mg / kg of vehicle or CYP inhibitor 1-ABT was orally administered by gavage.
  • the vehicle-administered rat group was defined as the solvent-previous day administration group
  • the 1-ABT-administered rat group was defined as the 1-ABT previous-day administration group
  • the solvent-previous day administration group and the 1-ABT previous-day administration group were tested with solvent or tipepidine 40 mg / kg Gavage was administered 15 minutes before the start, and the sleep state for 6 hours thereafter was determined by software.
  • the results are shown in Figures 13A, 13B, 14A and 14B.
  • tipepidine hibenzate 40 mg / kg single administration group significant maintenance of wakefulness and shortening of REM sleep time were not observed as compared with the vehicle administration group.
  • the CYP inhibitor 1-ABT 100 mg / kg and tipepidine hibenzate 40 mg / kg administration groups significant awakening time maintenance and shortening of REM sleep time were observed as compared with 1-ABT 100 mg / kg and vehicle administration groups. Admitted. From these results, it was revealed that the combined administration of tipepidine hibenzate and the CYP inhibitor maintains a strong wakefulness for a long time, as compared with the administration of tipepidine hibenzate alone.
  • Example 13 Amelioration of chronic fatigue syndrome on SD rats by tipepidine or a combination of tipepidine and a CYP inhibitor.
  • SD rats were bred for 3 days in a breeding box with water kept at 23 degrees and a height of 1.5 cm. Create a chronic fatigue syndrome model.
  • vehicle or CYP inhibitor was administered by oral gavage 1 hour before the administration of tipepidine or a pharmaceutically acceptable salt thereof, and subcutaneous administration of tipepidine or a pharmaceutically acceptable salt thereof was conducted 1 hour before the start of the test. To do. A forced swimming test is carried out 60 minutes later.
  • Example 14 Awakening effect and cataplexic inhibitory effect of tipepidine on narcolepsy mouse Intraperitoneal or subcutaneous administration of solvent and tipepidine or a pharmaceutically acceptable salt thereof to narcolepsy mouse, and then videographed electroencephalogram, electromyogram and behavior for several hours. To do. Awakening time is calculated from EEG, and the frequency of cataplexy is measured from EEG electromyography and video recording.
  • Example 15 Awakening action and cataplexy inhibitory action on narcolepsy mouse by tipepidine or a combination of tipepidine and CYP inhibitor , a solvent or CYP inhibitor is forcibly orally administered 1 hour before administration of a solvent or a CYP inhibitor to tipepidine or a pharmaceutically acceptable salt thereof.
  • the oral administration of tipepidine or a pharmaceutically acceptable salt thereof is performed by oral gavage. After that, for several hours, videographs of EEG, EMG, and behavior will be taken. Awakening time is calculated from EEG, and the frequency of cataplexy is measured from EEG electromyography and video recording.
  • Example 16 Evaluation of wakefulness in narcolepsy patients by combined use of tipepidine and CYP2D6 inhibitors
  • Narcolepsy patients exhibit excessive daytime sleepiness, emotional weakness, paralysis of sleep, etc., and the prevalence in Japan is reported to be about 0.16%. ing. Although modafinil is effective against excessive daytime sleepiness, it has been reported that about 20% of patients do not respond, and further drugs are required.
  • Patients with narcolepsy are dosed with CYP2D6 inhibitor (1-300 mg) and 1-3 times daily with tipepidine or a pharmaceutically acceptable salt thereof (20-200 mg). Thereafter, a sleep maintenance test for 4 sections and 20 minutes is performed every 2 hours, and sleep latency until sleep is measured.
  • Example 17 Evaluation of emotional weakness seizures in narcolepsy patients by combination use of tipepidine and CYP2D6 inhibitors It is known that narcolepsy patients suffer from emotional weakness seizures due to excessive emotional stimulation such as emotions. Modafinil is reportedly ineffective for emotional weakness attacks. Further, gamma-hydroxybutyric acid (GBH) is used in the United States for the treatment of emotional weakness attacks in patients with narcolepsy, but it requires two doses at night, which poses a major problem in compliance. CYP2D6 inhibitor (1-300mg) and tipepidine or its pharmaceutically acceptable salt (20-200mg) were administered to patients with narcolepsy for 14 days, and the number of emotional weakness attacks for 14 days was measured. To do.
  • GSH gamma-hydroxybutyric acid
  • Example 18 Evaluation of wakefulness in sleep apnea patients by combined use of tipepidine and CYP2D6 inhibitors Sleep apnea patients become hypopnea at night, and sleep at night is subdivided so that they cannot sleep deeply and are strong in the daytime of the next day. Drowsiness, malaise, and poor concentration are required.
  • a treatment method there is used a method of improving a hypopnea state by sending pressured air using nasal continuous positive pressure breathing therapy (referred to as CPAP method). When no improvement is observed by the CPAP method, modafinil or the like suppresses excessive daytime sleepiness, but it is reported that its action is not sufficient.
  • a sleep apnea patient is administered a CYP2D6 inhibitor (1-200 mg), and is further administered 1-3 times daily with tipepidine or a pharmaceutically acceptable salt thereof (20-200 mg). Then, for 20 minutes, a 4-section sleep maintenance test is performed every 2 hours to measure sleep latency.
  • Example 19 Evaluation of wakefulness effect in Parkinson's disease patients by combined use of tipepidine and CYP2D6 inhibitors It is said that about 80% of Parkinson's disease patients have sleep disorders, which is the most frequent non-motor symptom. Particularly in patients with Parkinson's disease, strong drowsiness is observed in the daytime, which is known as one of the factors that significantly reduce the quality of life of patients. Although off-label for excessive daytime sleepiness, modafinil is recommended for use. However, the efficacy of modafinil has not been fully verified.
  • CYP2D6 inhibitor (1-300 mg) is administered to patients with Parkinson's disease, and further tipepidine or a pharmaceutically acceptable salt thereof (20-200 mg) is administered 1 to 3 times a day. Then, for 20 minutes, a 4-section sleep maintenance test is performed every 2 hours to measure sleep latency.
  • Example 20 Obsessive-compulsive effect of tipepidine for mice using the marble burying test. A cage is covered with bedding, and 20 marbles are placed on each cage. The mice are intraperitoneally or subcutaneously administered with a solvent and tipepidine or a pharmaceutically acceptable salt thereof. After administration, the mouse is placed in a cage, allowed to move freely for 15 minutes, and the number of filled glass beads is counted visually.
  • Example 21 Obsessive-compulsive amelioration effect on SD rats by tipepidine or a combination of tipepidine and a CYP inhibitor using a glass bead masking test.
  • a cage is covered with bedding, and 20 glass beads are placed on each cage.
  • the vehicle or the CYP inhibitor is orally administered by gavage to the mouse, and 1 hour after that, tipepidine or a pharmaceutically acceptable salt thereof is orally administered by gavage. After administration, the mouse is placed in a cage, allowed to move freely for 15 minutes, and the number of filled glass beads is counted visually.
  • Example 22 Post-traumatic stress disorder improving effect of tipepidine on rats using fear conditioning test Rats are placed in a chamber, and electric shock is presented from the floor grid to perform conditioning. After a fixed time (24 hours) of conditioning, the rats are intraperitoneally or subcutaneously administered with a solvent and tipepidine or a pharmaceutically acceptable salt thereof. After administration, the rat is placed in a conditioning chamber and the rate of freezing behavior in the absence of electrical stimulation is measured.
  • Example 23 Post-traumatic stress disorder ameliorative effect on SD rats by tipepidine or a combination of tipepidine and a CYP inhibitor using a fear conditioning test. Rats are placed in a chamber, and electric shock is presented from the floor grid to perform conditioning. After a certain period of conditioning (24 hours), the rats are gavaged with solvent or CYP inhibitor, and 1 hour after that, gipipidine or a pharmaceutically acceptable salt thereof is gavaged. After administration, the rat is placed in a conditioning chamber and the rate of freezing behavior in the absence of electrical stimulation is measured.
  • the present invention can be used in the fields of pharmaceuticals and the like, for example, in the fields of development or production of therapeutic and prophylactic agents for central diseases.

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Abstract

La présente invention concerne : un agent thérapeutique ou un agent prophylactique pour une maladie du système nerveux central, dans laquelle de la tipépidine ou un sel pharmaceutiquement acceptable de celle-ci et un inhibiteur de CYP2D6 sont utilisés en combinaison ; ou un agent thérapeutique ou un agent prophylactique, dans lequel la tipépidine seule est utilisée, pour la maladie de Parkinson, le syndrome de la maladie de Parkinson provoqué par l'utilisation d'un médicament antipsychotique, de troubles du sommeil, d'un syndrome de fatigue chronique et également pour la fatigue, la toxicomanie, la toxicomanie, ou la fibromyalgie associée à la dégénérescence nerveuse et à un trouble du système nerveux central, ou à un traumatisme émotionnel et à des troubles liés au stress.
PCT/JP2019/043606 2018-11-08 2019-11-07 Agent thérapeutique pour une maladie du système nerveux central comprenant de la tipépidine WO2020095979A1 (fr)

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JP2003523936A (ja) * 1999-04-07 2003-08-12 ファイザー・プロダクツ・インク 併用療法におけるｃｙｐ２ｄ６インヒビターの使用
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