WO2022045336A1 - パーキンソン病の運動合併症治療薬 - Google Patents

パーキンソン病の運動合併症治療薬 Download PDF

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Publication number
WO2022045336A1
WO2022045336A1 PCT/JP2021/031722 JP2021031722W WO2022045336A1 WO 2022045336 A1 WO2022045336 A1 WO 2022045336A1 JP 2021031722 W JP2021031722 W JP 2021031722W WO 2022045336 A1 WO2022045336 A1 WO 2022045336A1
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Prior art keywords
tandospirone
pharmaceutically acceptable
acceptable salt
levodopa
item
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Ceased
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PCT/JP2021/031722
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English (en)
French (fr)
Japanese (ja)
Inventor
光將 栗田
友紀 池田
充宏 中塔
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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Priority to CN202180053119.3A priority Critical patent/CN116113402A/zh
Priority to EP21861757.9A priority patent/EP4218764A4/en
Priority to MX2023002422A priority patent/MX2023002422A/es
Priority to CA3189670A priority patent/CA3189670A1/en
Priority to AU2021332775A priority patent/AU2021332775A1/en
Priority to KR1020237005487A priority patent/KR20230058615A/ko
Priority to JP2022545758A priority patent/JPWO2022045336A1/ja
Publication of WO2022045336A1 publication Critical patent/WO2022045336A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

  • the present disclosure contains tandospirone useful as a medicine and a pharmaceutically acceptable salt or prodrug thereof as an active ingredient, and parenterally administers motor complications such as motor fluxuations of Parkinson's disease (for example, via trans). It relates to a preparation to be treated or prevented by skin administration), or a treatment method thereof.
  • Parkinson's disease is one of the progressive neurodegenerative diseases whose main symptom is abnormal extrapyramidal function. Pathologically, dopaminergic neuronal shedding and Alpha-synuclein deposition in the substantia nigra pars compacta are observed. Clinically, it presents with various motor symptoms such as akinesia, tremor at rest, rigidity, and loss of postural reflexes.
  • Parkinson's disease treatment is drug therapy aimed at supplementing dopamine in the brain, and drugs containing the dopamine precursor levodopa (L-dopa, levodopa) are used as the first-line drug for the initial treatment of Parkinson's disease. Will be done. However, with the progression of the disease, in almost all patients undergoing levodopa treatment, diurnal variation of Parkinson's disease (motor fluxuations) and levodopa-induced dystonia in Parkinson's disease (hereinafter, "PD-LID" (Parkinson's disease levodopa induced)) Motor complications such as dystonia) and dystonia appear.
  • PD-LID Parkinson's disease levodopa induced
  • PD-LID The incidence of PD-LID is 30 to 50% 5 years after the start of levodopa treatment, increases with the progression of the pathological condition, and reaches 50 to 100% 10 years after the start of treatment.
  • Peak-dose dyskinesia is known as a typical symptom of PD-LID, and involuntary movements appear on the face, tongue, neck, limbs, trunk, etc. when the blood concentration of levodopa is high. It is an exercise.
  • Patent Document 1 discloses a transdermal absorbent of tandospirone.
  • tandospirone or a pharmaceutically acceptable salt thereof causes a rapid increase in the amount of dopamine in the synaptic cleft of the striatum in various situations such as when levodopa is administered to Parkinson's disease. It has been found to have both an inhibitory effect and an effect of delaying the decrease over time, and is preferable treatment, improvement, progression suppression (delay or support) and progression suppression (delay or support) of motor complications as seen in the treatment of levodopa of Parkinson's disease. We have found that we can provide preventive technology.
  • parenteral administration of tandospirone results in motor complications as seen in Parkinson's disease compared to oral administration.
  • tandospirone eg, transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, etc.
  • targets for improving these motor complications are wearing-off, on-off, no-on, and delayed on phenomena.
  • diurnal fluctuations motor fluctuations
  • dyskinesia in Parkinson's disease such as levodopa-induced dyskinesia (PD-LID), etc. are included.
  • compositions of the present disclosure have an adverse effect on non-motor symptoms in the treatment of motor complications such as dyskinesia improvement as compared to other therapeutic agents for motor symptoms of Parkinson's disease (eg, amantadine sustained release agents, etc.). There is also the advantage that there is no. Depending on the patient, improvement of non-motor symptoms can be expected in addition to improvement of dyskinesia and improvement of motor complications such as chronotype.
  • non-motor symptoms examples include mental symptoms, sleep disorders, sensory disorders, pain, olfactory disorders, autonomic nervous system symptoms and the like.
  • Psychiatric symptoms include depression, anxiety, apathy, agitation, irritability, hallucinations, delusions, cognitive dysfunction and the like.
  • sleep disorders include daytime hypersomnia, insomnia, restless legs syndrome, and REM sleep behavioral abnormalities.
  • Autonomic nervous system symptoms include constipation, dysuria, orthostatic hypotension and the like.
  • the compositions of the present disclosure are particularly depressed, anxious, irritable, itchy leg syndrome, REM sleep behavioral abnormalities, as compared to other therapeutic agents for motor symptoms of Parkinson's disease (eg, amantazine sustained release agents, etc.). , It is expected not to worsen the illusion, and it can be expected to improve depression, anxiety, irritability, itchy leg syndrome, or REM sleep behavior abnormality.
  • the present disclosure includes: [Item H1] A composition for treating, ameliorating or preventing motor complications, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used. A composition characterized in that the salt is administered parenteral.
  • [Item H1C] A composition for treating, ameliorating or preventing dyskinesia in a subject, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is parenteral.
  • (Parental) A composition that is administered and characterized in that the subject is receiving drug therapy for Parkinson's disease.
  • [Item H1D] A composition for treating, ameliorating or preventing dyskinesia in a subject, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is parenteral.
  • (Parenteral) A composition characterized by being administered and the subject receiving levodopa therapy.
  • [Item H1E-1] A composition for reducing the OFF time in a subject who is a Parkinson's disease patient, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • [Item H1E] A composition for reducing the OFF time in a subject who is a Parkinson's disease patient, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • [Item H1F] A composition containing tandospirone or a pharmaceutically acceptable salt thereof for reducing the OFF time and increasing the ON time in a subject who is a Parkinson's disease patient, the tandospirone or a composition thereof.
  • the refractory time (off time) is reduced and the ON time without troublesome dyskinesia is increased.
  • a composition for which the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral and the subject is receiving drug therapy.
  • a composition comprising a parenteral administration of an acceptable salt.
  • a composition for treating, ameliorating or preventing motor complications of Parkinson's disease which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • a composition characterized in that an acceptable salt is administered parenteral and the subject is receiving drug therapy for Parkinson's disease.
  • a composition for treating, ameliorating or preventing motor complications of Parkinson's disease which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • a parenteral dose of acceptable salt the subject of which is a drug therapy for Parkinson's disease such as a levodopa-containing preparation, a levodopa metabolic enzyme inhibitor, a dopamine receptor agonist, and an adjunct to Parkinson's disease.
  • a composition for treating, ameliorating or preventing motor complications of Parkinson's disease which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • a composition characterized in that an acceptable salt is administered parenteral and the subject is receiving Dopamine replacement therapy for Parkinson's disease.
  • a composition for treating, ameliorating or preventing motor complications of Parkinson's disease which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • a composition for treating, ameliorating or preventing motor complications of Parkinson's disease which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • An effective amount of acceptable salt is administered parenteral to maintain sustained dopamine levels in the striatal synaptic cleft, suppress sudden fluctuations in dopamine levels, and / or intermittently in the subject.
  • a composition characterized by suppressing dopamine receptor stimulation [Item H8] The composition according to any one of the preceding items, which is administered to the subject so as not to cause rebound symptoms. [Item H9] The composition according to any one of the preceding items, wherein the motor complications include chronotypes. [Item H10] The composition according to any one of the preceding items, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • [Item H15] The composition according to any one of the preceding paragraphs, wherein the treatment, amelioration or prevention ameliorate chronotypes without exacerbating the dyskinesia symptoms in Parkinson's disease. thing.
  • the treatment, amelioration or prevention is any one of the preceding items, characterized in that the levodopa-induced dyskinesia (PD-LID) symptoms are ameliorated without exacerbating the diurnal variation (motor fluctuations).
  • the treatment, amelioration or prevention of the preceding item is characterized by ameliorating motor complications or chronotypes without exacerbating the dyskinesia symptoms in Parkinson's disease.
  • the treatment, amelioration or prevention is characterized by ameliorating motor complications or chronotypes without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID).
  • the chronotypes include a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and a delayed on phenomenon.
  • the composition according to any one of the preceding paragraphs which comprises, and a combination thereof.
  • the treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof.
  • composition according to any one of the following items [Item H21] The composition according to any one of the preceding items, wherein the motor complication further comprises a dyskinesia symptom in Parkinson's disease. [Item H22] The composition according to any one of the preceding items, wherein the motor complication further comprises levodopa-induced dyskinesia (PD-LID). [Item H23] The composition according to any one of the preceding paragraphs, wherein the dyskinesia symptom in Parkinson's disease comprises peak-dose dyskinesia, diphasic dyskinesia, and a combination thereof.
  • Levodopa-induced dyskinesia (PD-LID) is described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof.
  • Composition [Item H25] The composition according to any one of the preceding paragraphs, wherein the treatment, amelioration or prevention is characterized by ameliorating chronotypes without dyskinesia symptoms.
  • the treatment, amelioration or prevention is characterized by ameliorating chronotypes without painful dyskinesia symptoms. ..
  • the composition is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally without exacerbating diurnal variation.
  • the composition precedes for ameliorating or preventing levodopa-induced dyskinesia (PD-LID) symptoms, shortening levodopa-induced dyskinesia (PD-LID) expression time, or a combination thereof.
  • the composition according to any one of the items.
  • the composition does not reduce the duration of action (on-time) of anti-Parkinson's disease associated with the treatment of Levodopa for Parkinson's disease beyond clinically significant time, and / or the time of non-response (off time).
  • the composition is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally without prolonging the treatment beyond a clinically significant time.
  • the composition is a composition for improving or preventing levodopa-induced dyskinesia (PD-LID) symptoms, shortening the expression time of levodopa-induced dyskinesia (PD-LID), or achieving a combination thereof.
  • the composition does not reduce the duration of action (on-time) of anti-Parkinson's disease associated with levodopa treatment of Parkinson's disease beyond clinically significant time, and / or reduces the duration of response (off-time).
  • the composition according to any one of the preceding paragraphs, characterized in that it does not prolong beyond a clinically significant time.
  • composition according to any one of the preceding items which is a transdermal pharmaceutical product.
  • composition according to any one of the preceding items which is provided as a patch formulation.
  • transdermal pharmaceutical product is a tape / patch agent.
  • drug dose of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg per day as a free form of tandospirone. ..
  • drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 100 mg per day as a free form of tandospirone. ..
  • drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 1 to 60 mg per day as a free form of tandospirone.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2 The composition according to any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 9 to 60 cm. 2 The composition according to any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.5 to 15 ng / mL for 12 hours or more per day.
  • the tandospirone or a pharmaceutically acceptable salt thereof is a tandospirone concentration in human blood (plasma) for 12 to 30 hours after a single administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • composition according to any one of the preceding paragraphs wherein the composition is administered so as to be 0.05 to 20 ng / mL.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. .
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • composition according to any one of the preceding paragraphs characterized in that it is administered so as to be 10 to 100% of the subsequent maximum blood concentration.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. It is administered so that the ratio of the minimum concentration when the subsequent maximum blood concentration is 100% is 10 to 95%, and the maximum blood concentration after administration is 1 to 15 ng / mL.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the composition according to any one of the preceding paragraphs, which is administered so that the ratio of the minimum concentration to the subsequent maximum blood concentration is 100% is 10 to 95%.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a maximum blood concentration of tandospirone in human blood (plasma) in a steady state after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • composition is 1 to 15 ng / mL, and is characterized by being administered so that the ratio of the minimum concentration when the maximum concentration of tandospirone in human blood (plasma) is 100% is 30 to 95%.
  • the composition according to any one of the following items. [Item H55] The tandospirone or a pharmaceutically acceptable salt thereof is used in the striatum after administration of the tandospirone or a pharmaceutically acceptable salt thereof, before administration of levodopa, and 1 hour after administration. 11 11 C] The composition according to any one of the preceding paragraphs, wherein the raclopride receptor binding change amount (change amount B / 1h) is administered so as to be less than 10%.
  • composition according to any one of the preceding items which is provided as an adjunct of levodopa.
  • composition according to any one of the preceding items which is used in combination with the same preparation as levodopa or a separate preparation.
  • a drug for treating or preventing Parkinson's disease with or without motor complications wherein the drug is tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa.
  • a drug comprising a combination of levodopa and a levodopa metabolic enzyme inhibitor wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally.
  • PD-LID levodopa-induced dyskinesia
  • a drug for treating or preventing Parkinson's disease with or without motor complications wherein the drug is (1) levodopa or (2) levodopa and levodopa metabolic enzyme inhibition.
  • the agent comprising (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and tandospirone or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical characterized in that it is administered parenterally.
  • a composition comprising tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response of a Parkinson's disease patient to levodopa treatment, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • the improvement comprises an improvement in chronotypes.
  • the improvement comprises an improvement in dyskinesia.
  • the improvement comprises an improvement in drug-induced dyskinesia.
  • [Item H73] The composition according to any one of the preceding paragraphs, wherein the improvement comprises an improvement in levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • [Item J1] The use for the manufacture of a pharmaceutical agent containing tandospirone or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of motor complications, the use thereof. Use, characterized in that tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral.
  • [Item J1B] Use for the manufacture of a pharmaceutical agent for the treatment, amelioration or prevention of dyskinesia, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the use is the tandospirone or its pharmaceutically acceptable salt.
  • Use characterized in that the acceptable salt is administered parenteral.
  • [Item J1C] Use for the manufacture of a pharmaceutical agent for the treatment, amelioration or prevention of dyskinesia in a subject, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the use is the tandospirone or a pharmaceutical product thereof.
  • Use characterized in that a pharmaceutically acceptable salt is administered parenteral and the subject is receiving drug therapy for Parkinson's disease.
  • Use Use for the manufacture of a pharmaceutical agent for the treatment, amelioration or prevention of dyskinesia in a subject, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the use is the tandospirone or a pharmaceutical product thereof.
  • a pharmaceutically acceptable salt is administered parenteral and the subject is receiving levodopa therapy.
  • [Item J1E] A use for the manufacture of a pharmaceutical agent containing tandospirone or a pharmaceutically acceptable salt thereof for reducing the OFF time in a subject who is a patient with Parkinson's disease, wherein the use is the tandospirone or Use, characterized in that the pharmaceutically acceptable salt is administered parenteral and the subject is receiving drug therapy.
  • [Item J1F] The use for producing a drug containing tandospirone or a pharmaceutically acceptable salt thereof for reducing the OFF time and increasing the ON time in a subject who is a Parkinson's disease patient. The use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral and the subject is receiving drug therapy.
  • Use characterized by receiving therapy.
  • [Item J2] Use for the manufacture of a pharmaceutical agent containing tandospirone or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of motor complications of Parkinson's disease. Is used, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral.
  • tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral and the subject is receiving drug therapy for Parkinson's disease.
  • a pharmaceutical product for the treatment, amelioration or prevention of motor complications of Parkinson's disease which comprises tandospirone or a pharmaceutically acceptable salt thereof.
  • a drug therapy for Parkinson's disease such as a levodopa-containing preparation, a levodopa metabolic enzyme inhibitor, a dopamine receptor agonist, and the like.
  • Use characterized by receiving medication selected from the group consisting of adjuvants for Parkinson's disease.
  • [Item J5] Use for the manufacture of a pharmaceutical agent containing tandospirone or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of motor complications of Parkinson's disease. Is used, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral and the subject is receiving dopamine replacement therapy for Parkinson's disease.
  • tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral and the subject is receiving levodopa therapy for Parkinson's disease.
  • an effective amount of the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral, the dopamine amount in the striatal synaptic cleft is continuously maintained in the subject, and the dopamine amount is abruptly changed.
  • Use characterized by suppression and / or suppression of intermittent dopamine receptor stimulation.
  • the treatment, amelioration or prevention is any one of the preceding items, characterized in that the levodopa-induced dyskinesia (PD-LID) symptoms are ameliorated without aggravating the diurnal variation (motor fluctuations). Use as described in section.
  • the treatment, amelioration or prevention of the preceding item is characterized by ameliorating motor complications or chronotypes without exacerbating the dyskinesia symptoms in Parkinson's disease. Use as described in any one paragraph.
  • the treatment, amelioration or prevention is characterized by ameliorating motor complications or chronotypes without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). Use as described in any one of the preceding paragraphs.
  • the chronotypes include a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and a delayed on phenomenon. And the use described in any one of the preceding paragraphs, including combinations thereof.
  • the treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof. Use as described in any one of the items.
  • the use according to any one of the preceding items, wherein the motor complication further includes dyskinesia symptoms in Parkinson's disease.
  • the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • the dyskinesia symptom in Parkinson's disease includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof.
  • Levodopa-induced dyskinesia (PD-LID) is described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. Use of.
  • the preceding item is for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of levodopa-induced dyskinesia (PD-LID) expression time, or a combination thereof.
  • PD-LID levodopa-induced dyskinesia
  • PD-LID levodopa-induced dyskinesia
  • the use does not reduce the duration of action (on-time) of anti-Parkinson's disease associated with the treatment of Levodopa for Parkinson's disease beyond clinically significant time, and / or the duration of failure.
  • Use characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally without prolonging (off time) beyond a clinically significant time.
  • the use is for improving or preventing levodopa-induced dyskinesia (PD-LID) symptoms, shortening the onset time of levodopa-induced dyskinesia (PD-LID), or achieving a combination thereof.
  • the use does not reduce the duration of action (on time) of anti-Parkinson's disease associated with the treatment of levodopa in Parkinson's disease beyond clinically significant time, and / or the time of non-response (off time) clinically.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2 The use described in any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 9 to 60 cm. 2 The use described in any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.5 to 15 ng / mL for 12 hours or more per day. Characteristic use as described in any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is a tandospirone concentration in human blood (plasma) for 12 to 30 hours after a single administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. ..
  • the use according to any one of the preceding paragraphs characterized in that it is administered to be 1-15 ng / mL.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the use according to any one of the preceding paragraphs characterized in that it is administered so as to be 10 to 100% of the subsequent maximum blood concentration.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. It is administered so that the ratio of the minimum concentration when the subsequent maximum blood concentration is 100% is 10 to 95%, and the maximum blood concentration after administration is 1 to 15 ng / mL. Use as described in any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a maximum blood concentration of tandospirone in human blood (plasma) in a steady state after administration of the tandospirone or a pharmaceutically acceptable salt thereof. It is 1 to 15 ng / mL, and is characterized by being administered so that the ratio of the minimum concentration when the maximum concentration of tandospirone in human blood (plasma) is 100% is 30 to 95%. Use as described in any one of the items.
  • the tandospirone or a pharmaceutically acceptable salt thereof is a striatum of the striatum after administration of the tandospirone or a pharmaceutically acceptable salt thereof, before administration of levodopa, and 1 hour after administration.
  • 11 11 C The use according to any one of the preceding paragraphs, characterized in that the raclopride receptor binding change (change B / 1h) is administered to be less than 10%.
  • the motor complications include chronotypes.
  • the motor complication further comprises dyskinesia.
  • levodopa metabolic enzyme inhibitors said (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors, administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, tandospirone or a pharmaceutical thereof.
  • Use characterized by parenteral administration of an acceptable salt.
  • Tandospirone or a pharmaceutically acceptable salt thereof characterized in that it is administered.
  • [Item K1B] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of dyskinesia, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral. Characterized by tandospirone or a pharmaceutically acceptable salt thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of dyskinesia in a subject, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral. Tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the subject is receiving medication for Parkinson's disease.
  • [Item K1E-1] A tandospirone or a pharmaceutically acceptable salt thereof for reducing the OFF time in a subject who is a patient with Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is parenteral. ) Tandospirone or a pharmaceutically acceptable salt thereof, which is administered and characterized in that the subject is receiving drug therapy.
  • [Item K1E] Tandospirone or a pharmaceutically acceptable salt thereof for reducing the OFF time in a subject who is a patient with Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral.
  • Tandospirone or a pharmaceutically acceptable salt thereof characterized in that the subject is receiving drug therapy.
  • [Item K1G] In patients with Parkinson's disease, tandospirone or a pharmaceutically acceptable salt thereof for reducing the response time (off time) and increasing the ON time without troublesome dyskinesia.
  • Tandospirone or a pharmaceutically acceptable salt thereof characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral and the subject is receiving drug therapy.
  • tandospirone or tandospirone for reducing the response time (off time) and increasing the anti-Parkinson's disease action time (on time) without troublesome dyskinesia.
  • Tandospirone or a pharmacy thereof which is a pharmaceutically acceptable salt, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenteral, and the subject is receiving levodopa therapy. Tandospirone.
  • a drug therapy selected from the group consisting of a drug therapy for Parkinson's disease such as a levodopa-containing preparation, a levodopa metabolic enzyme inhibitor, a dopamine receptor agonist, and an adjunct to Parkinson's disease.
  • Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of motor complications of Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is not.
  • Tandospirone or a pharmaceutically acceptable salt thereof which is administered orally (parenteral) and is characterized in that the subject is receiving levodopa therapy for Parkinson's disease.
  • the dose is parenteral to maintain sustained dopamine levels in the striatal synaptic cleft, suppress sudden fluctuations in dopamine levels, and / or intermittent dopamine receptor stimulation in the subject.
  • Tandospiron or a pharmaceutically acceptable salt thereof characterized in that it suppresses.
  • [Item K8] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items, which is administered so as not to cause rebound symptoms to the subject.
  • [Item K9] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, wherein the motor complications include chronotypes.
  • the parenteral administration is tandospirone according to any one of the preceding items, which is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof. Acceptable salt.
  • the treatment, amelioration or prevention is any one of the preceding items, characterized in that the levodopa-induced dyskinesia (PD-LID) symptoms are ameliorated without aggravating the diurnal variation (motor fluctuations).
  • Tandospirone or a pharmaceutically acceptable salt thereof as described in Section.
  • the treatment, amelioration or prevention of the preceding item is characterized by ameliorating motor complications or diurnal fluctuations without exacerbating the dyskinesia symptoms in Parkinson's disease. Tandospirone according to any one item or a pharmaceutically acceptable salt thereof.
  • the treatment, amelioration or prevention is characterized by ameliorating motor complications or diurnal fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID).
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs.
  • the chronotypes include a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and a delayed on phenomenon. Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, which comprises, and combinations thereof.
  • the treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the following items.
  • the dyskinesia symptom in Parkinson's disease includes tandospirone or a combination thereof according to any one of the preceding paragraphs, which comprises peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof.
  • a pharmaceutically acceptable salt is formulated.
  • Levodopa-induced dyskinesia (PD-LID) is described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. Tandospirone or a pharmaceutically acceptable salt thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof [Item K25] The tandospirone or pharmaceutical thereof according to any one of the preceding paragraphs, wherein the treatment, amelioration or prevention is characterized by ameliorating chronotypes without dyskinesia symptoms. Tolerable salt.
  • the pharmaceutically acceptable salt thereof does not exacerbate diurnal variation and is characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally, the tandospirone or the pharmaceutically acceptable salt thereof. .. [Item K28]
  • the tandospirone or a pharmaceutically acceptable salt thereof improves or prevents levodopa-induced dyskinesia (PD-LID) symptoms, shortens the expression time of levodopa-induced dyskinesia (PD-LID), or a combination thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs for achieving the above.
  • its pharmaceutically acceptable salt does not reduce the duration of action (on-time) of anti-Parkinson's disease associated with the treatment of Levodopa in Parkinson's disease beyond clinically significant time, and / or the duration of non-response (off).
  • a tandospirone or a pharmaceutically acceptable salt thereof characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally without prolonging the time) beyond a clinically significant time.
  • the tandospirone or a pharmaceutically acceptable salt thereof improves or prevents levodopa-induced dyskinesia (PD-LID) symptoms, shortens the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof.
  • Tandospiron or a pharmaceutically acceptable salt thereof for achieving the above and the tandospirone or a pharmaceutically acceptable salt thereof clinically indicates the anti-Parkinson's disease action duration (on-time) associated with the treatment of levodopa in Parkinson's disease.
  • on-time the anti-Parkinson's disease action duration associated with the treatment of levodopa in Parkinson's disease.
  • Tandospirone or a pharmaceutically acceptable salt thereof wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally.
  • [Item K35] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, wherein the improvement in chronotypes is more than a clinically significant improvement.
  • [Item K36] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, wherein the improvement of the chronotypes is at a level sufficient to obtain a clinical effect.
  • [Item K38] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items, which is provided as a patch.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 9 to 60 cm. 2 Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. Characteristically, the tandospirone according to any one of the preceding paragraphs or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.5 to 15 ng / mL for 12 hours or more per day. Characteristically, the tandospirone according to any one of the preceding paragraphs or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof is a tandospirone concentration in human blood (plasma) for 12 to 30 hours after a single administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, which is administered so as to be 0.05 to 20 ng / mL.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. . Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, characterized in that it is administered to be 1 to 15 ng / mL.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, which is administered so as to be 10 to 100% of the subsequent maximum blood concentration.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. It is administered so that the ratio of the minimum concentration is 10 to 95% when the maximum blood concentration is 100%, and the maximum blood concentration after administration is 1 to 15 ng / mL. Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmacy thereof according to any one of the preceding paragraphs, which is characterized in that the tandospirone is administered so that the ratio of the minimum concentration to the subsequent maximum blood concentration of 100% is 10 to 95%. Tandospirone.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a maximum blood concentration of tandospirone in human blood (plasma) in a steady state after administration of the tandospirone or a pharmaceutically acceptable salt thereof. It is 1 to 15 ng / mL, and is characterized by being administered so that the ratio of the minimum concentration when the maximum concentration of human blood (plasma) tandospirone is 100% is 30 to 95%. Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the following items.
  • tandospirone or a pharmaceutically acceptable salt thereof is used in the striatum after administration of the tandospirone or a pharmaceutically acceptable salt thereof, before administration of levodopa, and 1 hour after administration.
  • 11 11 C Tandospirone according to any one of the preceding paragraphs or pharmaceutically acceptable thereof, characterized in that the change in raclopride receptor binding (change B / 1h) is less than 10%. Salt to be done.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items provided as an adjunct of levodopa.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items, which is used in combination with the same preparation as levodopa or a separate preparation.
  • [Item K62] The tandospirone according to any one of the preceding paragraphs or a pharmaceutically acceptable salt thereof, wherein the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • [Item K63] The tandospirone according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the (1) or (2) are administered simultaneously or at different times.
  • a pharmaceutically acceptable salt A levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitor for treating or preventing Parkinson's disease with or without motor complications, said (1).
  • Levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally.
  • the motor complication is (1) levodopa, or (2) levodopa and a metabolic enzyme inhibitor of levodopa according to any one of the preceding paragraphs, which comprises dyskinesia.
  • the motor complication is (1) levodopa, or (2) levodopa and a metabolic enzyme inhibitor of levodopa according to any one of the preceding paragraphs, which comprises drug-induced dyskinesia.
  • the motor complications include (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors according to any one of the preceding paragraphs, including levodopa-induced dyskinesia (PD-LID). ..
  • PD-LID levodopa-induced dyskinesia
  • [Item L1] A method for treating, ameliorating or preventing motor complications in a subject, which comprises parentally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof. ..
  • [Item L1B] A method for treating, ameliorating or preventing dyskinesia in a subject, comprising parentally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof.
  • [Item L1C] A method for treating, ameliorating or preventing dyskinesia in a subject, comprising parentally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof.
  • [Item L1D] A method for treating, ameliorating or preventing dyskinesia in a subject, comprising parentally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof.
  • [Item L1E-1] A method for reducing OFF time in a subject who is a Parkinson's disease patient, which comprises parentally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof. The method, characterized in that the subject is receiving drug therapy.
  • [Item L1E] A method for reducing OFF time in a subject who is a Parkinson's disease patient, comprising parentally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof. A method comprising the subject receiving drug therapy.
  • [Item L1F] Decreasing OFF time and increasing ON time in subjects who are Parkinson's disease patients, including parenteral administration of tandospirone or a pharmaceutically acceptable salt thereof to the subject.
  • a method for causing the subject to be treated characterized in that the subject is receiving drug therapy.
  • a method for increasing the duration of action (on-time) of anti-Parkinson's disease without troublesome dyskinesia characterized in that the subject is receiving levodopa therapy.
  • [Item L2] For the treatment, amelioration or prevention of motor complications of Parkinson's disease, which comprises parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject.
  • Method. For the treatment, amelioration or prevention of motor complications of Parkinson's disease, which comprises parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject.
  • a method characterized in that the subject is receiving medication for Parkinson's disease.
  • amelioration or prevention of motor complications of Parkinson's disease which comprises parentally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof.
  • the method wherein the subject receives drug therapy selected from the group consisting of levodopa-containing preparations, levodopa metabolic enzyme inhibitors, drug therapy for Parkinson's disease such as dopamine receptor agonists, and adjuvants for Parkinson's disease.
  • drug therapy selected from the group consisting of levodopa-containing preparations, levodopa metabolic enzyme inhibitors, drug therapy for Parkinson's disease such as dopamine receptor agonists, and adjuvants for Parkinson's disease.
  • a method characterized by being.
  • amelioration or prevention of motor complications of Parkinson's disease which comprises parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject.
  • a method characterized in that the subject is receiving dopamine replacement therapy for Parkinson's disease.
  • [Item L6] For the treatment, amelioration or prevention of motor complications of Parkinson's disease, which comprises parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject.
  • a method characterized in that the subject is receiving levodopa therapy for Parkinson's disease.
  • amelioration or prevention of motor complications of Parkinson's disease which comprises parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject.
  • the method is characterized by sustained dopamine levels in the striatal synaptic clefts, suppression of rapid fluctuations in dopamine levels, and / or suppression of intermittent dopamine receptor stimulation in the subject. And how.
  • [Item L8] The method according to any one of the preceding items, which is administered to the subject so as not to cause rebound symptoms.
  • [Item L9] The method according to any one of the preceding items, wherein the motor complications include chronotypes.
  • the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • the parenteral administration is persistent or is continuously administered.
  • the parenteral administration includes transdermal administration.
  • the treatment, amelioration or prevention is any one of the preceding items, characterized in that the levodopa-induced dyskinesia (PD-LID) symptoms are ameliorated without exacerbating the chronotype fluctuations.
  • [Item L17] The preceding item, wherein the treatment, amelioration or prevention ameliorate motor complications or chronotypes without exacerbating the dyskinesia symptoms in Parkinson's disease.
  • the treatment, amelioration or prevention is characterized by ameliorating motor complications or chronotypes without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). The method according to any one of the preceding paragraphs.
  • the chronotypes include a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and a delayed on phenomenon. And the method according to any one of the preceding paragraphs, including combinations thereof.
  • the treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof. The method described in any one of the items to be described.
  • the motor complication further comprises a dyskinesia symptom in Parkinson's disease.
  • the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • the dyskinesia symptom in Parkinson's disease comprises peak-dose dyskinesia, diphasic dyskinesia, and a combination thereof.
  • Levodopa-induced dyskinesia (PD-LID) is described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. the method of.
  • the preceding item is for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of levodopa-induced dyskinesia (PD-LID) expression time, or a combination thereof. The method described in any one of the above.
  • PD-LID levodopa-induced dyskinesia
  • PD-LID levodopa-induced dyskinesia
  • Amelioration or prevention of dyskinesia symptoms in Parkinson's disease patients including parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to the subject, of the time of dyskinesia onset in Parkinson's disease patients.
  • the method is a method for improving or preventing levodopa-induced dyskinesia (PD-LID) symptoms, shortening the onset time of levodopa-induced dyskinesia (PD-LID), or achieving a combination thereof.
  • PD-LID levodopa-induced dyskinesia
  • the method does not reduce the duration of action (on-time) of anti-Parkinson's disease associated with the treatment of levodopa in Parkinson's disease beyond clinically significant time, and / or the time of non-response (off-time) clinically.
  • the method according to any one of the preceding paragraphs characterized in that it does not extend beyond a meaningful time.
  • the method according to any one of the preceding items wherein the shortening of the non-responder time (off time) is longer than a clinically significant time.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. The method according to any one of the preceding paragraphs, which is characteristic.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.5 to 15 ng / mL for 12 hours or more per day. The method according to any one of the preceding paragraphs, which is characteristic.
  • the tandospirone or a pharmaceutically acceptable salt thereof is a tandospirone concentration in human blood (plasma) for 12 to 30 hours after a single administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the method according to any one of the preceding paragraphs characterized in that it is administered so as to be .05 to 20 ng / mL.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered by a human blood (plasma) tandospirone concentration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a maximum blood concentration of tandospirone in human blood (plasma) in a steady state after administration of the tandospirone or a pharmaceutically acceptable salt thereof. It is 1 to 15 ng / mL, and is characterized by being administered so that the ratio of the minimum concentration when the maximum concentration of tandospirone in human blood (plasma) is 100% is 30 to 95%.
  • the tandospirone or a pharmaceutically acceptable salt thereof is a striatum of the striatum after administration of the tandospirone or a pharmaceutically acceptable salt thereof, before administration of levodopa, and 1 hour after administration.
  • 11 11 C The method according to any one of the preceding paragraphs, characterized in that the raclopride receptor binding change amount (change amount B / 1h) is administered so as to be less than 10%.
  • [Item L58] A method for treating or preventing Parkinson's disease with or without motor complications, wherein the method is with an effective amount of tandospirone or a pharmaceutically acceptable salt thereof.
  • a method comprising administering 1) levodopa, or (2) levodopa and a combination of levodopa and a metabolic enzyme inhibitor, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. ..
  • the motor complications include chronotypes.
  • the motor complication further comprises dyskinesia.
  • the (1) levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, including administration of the agent.
  • the motor complication includes dyskinesia.
  • the motor complication comprises drug-induced dyskinesia.
  • the motor complication comprises levodopa-induced dyskinesia (PD-LID).
  • [Item 1] A composition for treating, ameliorating or preventing motor complications associated with the treatment of levodopa in Parkinson's disease, which comprises tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or A composition characterized in that the pharmaceutically acceptable salt is administered parenterally.
  • [Item 2] The composition according to Item 1, wherein the motor complications include diurnal fluctuations.
  • [Item 3] The composition according to Item 1 or 2, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • [Item 4] The composition according to any one of the preceding items, wherein the parenteral administration is persistent or is continuously administered.
  • the treatment, amelioration or prevention is characterized by ameliorating motor complications without exacerbating levodopa-induced dyskinesia (PD-LID) symptoms.
  • the treatment, amelioration or prevention is any one of the preceding items, characterized in that the levodopa-induced dyskinesia (PD-LID) symptoms are ameliorated without aggravating the diurnal variation (motor fluctuations).
  • the composition according to paragraph 8 Any of the preceding items characterized by ameliorating motor complications or chronotypes without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID).
  • the chronotypes include a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and a delayed on phenomenon.
  • the treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof.
  • composition according to any one of the preceding items, wherein the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • Item 13 The composition according to any one of the preceding sections, wherein the treatment, amelioration or prevention is characterized by ameliorating chronotypes without dyskinesia symptoms.
  • the treatment, amelioration or prevention is characterized by ameliorating chronotypes without painful dyskinesia symptoms.
  • the improvement of the chronotypes is at a level sufficient to obtain a clinical effect.
  • composition according to any one of the preceding items which is provided as a patch formulation.
  • transdermal pharmaceutical product is a tape / patch agent.
  • drug dose of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as a free form of tandospirone. ..
  • drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone. ..
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the composition according to any one of the preceding paragraphs which is administered so as to be .05 to 20 ng / mL.
  • the composition according to any one of the preceding items which is provided as an adjunct of levodopa.
  • a drug for treating or preventing Parkinson's disease with or without motor complications wherein the drug is tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa.
  • the motor complications include chronotypes.
  • the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • a drug for treating or preventing Parkinson's disease with or without motor complications wherein the drug is (1) levodopa or (2) levodopa and levodopa metabolic enzyme inhibition.
  • the agent comprising (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and tandospirone or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical characterized in that it is administered parenterally. 37.
  • the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • a composition comprising tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response of a Parkinson's disease patient to levodopa treatment, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • the chronotypes of Parkinson's symptoms are a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and delayed on. ) Described in any one of the preceding paragraphs, including the phenomenon and combinations thereof.
  • Composition. [Item 8A] The treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof.
  • [Item 9A] The composition according to any one of the preceding items, wherein the shortening of the off time is more than or equal to a clinically significant time.
  • [Item 10A] The composition according to any one of the preceding items, wherein the shortening of the off time is a time sufficient to obtain a clinical effect.
  • [Item 11A] The composition according to any one of the preceding items, wherein the improvement of the chronotype (motor fluctuations) is more than a clinically significant improvement.
  • [Item 12A] The composition according to any one of the preceding items, wherein the improvement of the chronotypes is at a level sufficient to obtain a clinical effect.
  • [Item 13A] The composition according to any one of the preceding items, which is a transdermal pharmaceutical product.
  • [Item 14A] The composition according to any one of the preceding items, which is provided as a patch formulation.
  • composition according to any one of the preceding items, wherein the transdermal pharmaceutical product is a tape / patch agent.
  • the drug dose of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as a free form of tandospirone. ..
  • the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone. ..
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day.
  • PD-LID levodopa-induced dyskinesia
  • the levodopa-induced dyskinesia (PD-LID) is described in any one of the preceding sections, comprising peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof.
  • Composition. [Item 22A]
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • [Item 23A] The composition according to any one of the preceding items, which is provided as an adjunct of levodopa.
  • [Item 24A] The composition according to any one of the preceding items, which is used in combination with the same preparation as levodopa or a separate preparation.
  • [Item 25A] A drug for treating or preventing Parkinson's disease with or without diurnal fluctuations (motor fluctuations), wherein the drug is tandospirone or a pharmaceutically acceptable salt thereof (1).
  • [Item 26A] The pharmaceutical agent according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • [Item 27A] A drug for treating or preventing Parkinson's disease with or without diurnal fluctuations (motor fluctuations), wherein the drug is (1) levodopa, or (2) levodopa and levodopa.
  • a pharmaceutical comprising a metabolic enzyme inhibitor, wherein the (1) levodopa, or (2) levodopa and the levodopa metabolic enzyme inhibitor is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof. ..
  • [Item 28A] The pharmaceutical agent according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • [Item 29A] A composition comprising tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response of a Parkinson's disease patient to levodopa treatment, wherein the improvement is chronotype (motor fluctuations). ) The composition, including the improvement.
  • [Item 30A] The pharmaceutical or composition according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone.
  • the parenteral administration is persistent or is continuously administered.
  • the item according to any one of the preceding items which improves motor complications or chronotypes without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID).
  • Method. The chronotypes include a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and a delayed on phenomenon. And the method according to any one of the preceding paragraphs, including combinations thereof.
  • the treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof. The method described in any one of the items to be described.
  • PD-LID Improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, including parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof, levodopa-induced dyskinesia (PD-LID).
  • the shortening of the non-response time (off time) is longer than a clinically significant time.
  • the shortening of the non-response time (off time) is a time sufficient for obtaining a clinical effect.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • a method for treating or preventing Parkinson's disease with or without the need for parenteral administration of tandospirone or a pharmaceutically acceptable salt thereof is provided.
  • the motor complications include chronotypes.
  • the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • Exercise complications including administration of an effective amount of (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, in combination with tandospirone or a pharmaceutically acceptable salt thereof.
  • the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone.
  • Treatment of motor fluctuations associated with levodopa treatment of Parkinson's disease in a subject including parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to the subject. , Methods for improvement or prevention.
  • parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • Treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof.
  • [Item A10A] The method according to any one of the preceding items, wherein the shortening of the off time is a time sufficient to obtain a clinical effect.
  • [Item A11A] The method according to any one of the preceding items, wherein the improvement of the chronotype (motor fluctuations) is more than a clinically significant improvement.
  • [Item A12A] The method according to any one of the preceding items, wherein the improvement of the chronotypes is at a level sufficient to obtain a clinical effect.
  • [Item A13A] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product.
  • [Item A17A] The method according to any one of the preceding paragraphs, wherein the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2 The method according to any one of the preceding paragraphs.
  • [Item A19A] The tandospirone or a pharmaceutically acceptable salt thereof is administered for 12 hours or more per day so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the method according to any one of the preceding items provided as an adjunct of levodopa.
  • [Item A25A] Within the day, comprising administering to a subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof in combination with (1) levodopa or (2) levodopa and a metabolic enzyme inhibitor of levodopa.
  • [Item A26A] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • An effective amount of (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, and the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitor is tandospirone or A method for treating or preventing Parkinson's disease with or without diurnal fluctuations (motor fluctuations), including administration in combination with the pharmaceutically acceptable salt.
  • tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • [Item A29A] A method for improving the deterioration of the quality of response to levodopa treatment in Parkinson's disease patients containing tandospirone or a pharmaceutically acceptable salt thereof, the improvement being chronotype (motor fluctuations). Methods, including improvements.
  • [Item A30A] The method according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone.
  • [Item B1] The use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the treatment, amelioration or prevention of motor complications associated with the treatment of levodopa in Parkinson's disease.
  • tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally.
  • the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • the parenteral administration is persistent or is administered continuously.
  • the parenteral administration includes transdermal administration.
  • the treatment, amelioration or prevention is any one of the preceding items, characterized in that the levodopa-induced dyskinesia (PD-LID) symptoms are ameliorated without aggravating the diurnal variation (motor fluctuations). Use as described in section.
  • the chronotypes include a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and a delayed on phenomenon. And the use described in any one of the preceding paragraphs, including combinations thereof.
  • the treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof. Use as described in any one of the items.
  • the use according to any one of the preceding items, wherein the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • PD-LID Amelioration or prevention of symptoms, shortening of levodopa-induced dyskinesia (PD-LID) expression time, or use for the manufacture of a drug to achieve a combination thereof, wherein the tandospirone or a pharmaceutical thereof is used.
  • Use characterized by parenteral administration of a generally acceptable salt.
  • the improvement of the chronotype motor fluctuations
  • the improvement of the chronotypes is at a level sufficient to obtain a clinical effect.
  • the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2 The use described in any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the motor complications include chronotypes.
  • the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and tandospirone or a pharmaceutically acceptable salt thereof.
  • Use characterized in that the salt is administered parenterally.
  • the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical agent for improving the deterioration of the quality of response to levodopa treatment in a patient with Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used.
  • Use characterized by parenteral administration of an acceptable salt to.
  • the improvement includes an improvement in chronotypes.
  • the improvement comprises an improvement in levodopa-induced dyskinesia (PD-LID).
  • tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone.
  • Item B1A Use for the manufacture of a drug containing tandospirone or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of motor fluctuations associated with the treatment of levodopa in Parkinson's disease. , The use is characterized by being administered parenterally.
  • parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • [Item B7A] The diurnal fluctuations of the Parkinson's symptom are wearing-off phenomenon, on-off phenomenon, no-on phenomenon, and delayed on. ) Phenomena, and the use described in any one of the preceding paragraphs, including combinations thereof.
  • Treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof. Use as described in any one of the items.
  • [Item B9A] The use according to any one of the preceding items, wherein the shortening of the off time is more than a clinically significant time.
  • the drug dose of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as a free form of tandospirone.
  • the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone.
  • tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2 The use described in any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. Characteristic use as described in any one of the preceding paragraphs.
  • PD-LID levodopa-induced dyskinesia
  • tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • [Item B26A] The use according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • [Item B27A] The combination of tandospirone or a pharmaceutically acceptable salt thereof with (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, with or without diurnal fluctuations.
  • Use characterized by being administered in combination with salt.
  • [Item B28A] The use according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • [Item B29A] The use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical agent for improving the deterioration of the quality of response to levodopa treatment in patients with Parkinson's disease, wherein the improvement is diurnal variation. Use, including improvements in (motor fluctuations).
  • [Item B30A] The use according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone.
  • a tandospirone or a pharmaceutically acceptable salt thereof for the treatment, amelioration or prevention of motor complications associated with the treatment of Levodopa of Parkinson's disease which is the tandospirone or a pharmaceutically acceptable salt thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof characterized in that the salt is administered parenteral.
  • Tandospirone Any of the preceding items characterized by ameliorating motor complications or diurnal fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). Tandospirone according to paragraph 1 or a pharmaceutically acceptable salt thereof.
  • the chronotypes include a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, and a delayed on phenomenon. Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, which comprises, and combinations thereof.
  • Treatment, amelioration or prevention of the chronotypes includes prolongation of the anti-Parkinson's disease action time (on time), shortening of the non-response time (off time), or a combination thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the following items.
  • Levodopa-induced dyskinesia (PD-LID) is described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof.
  • Tandospirone or its pharmaceutically acceptable salt [Item C13] The tandospirone or pharmaceutical thereof according to any one of the preceding paragraphs, wherein the treatment, amelioration or prevention is characterized by ameliorating chronotypes without dyskinesia symptoms. Tolerable salt. [Item C14] The tandospirone or tandospirone according to any one of the preceding paragraphs, wherein the treatment, amelioration or prevention is characterized by ameliorating chronotypes without painful dyskinesia symptoms.
  • tandospirone-induced dyskinesia (PD-LID) symptoms, shortening of levodopa-induced dyskinesia (PD-LID) expression time, or their pharmaceutically acceptable salts.
  • Tandospirone or a pharmaceutically acceptable salt thereof characterized in that it is administered parenterally.
  • Tandospirone or pharmaceutically acceptable thereof to achieve improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of levodopa-induced dyskinesia (PD-LID) expression time, or a combination thereof.
  • PD-LID levodopa-induced dyskinesia
  • PD-LID levodopa-induced dyskinesia
  • the salt, the tandospirone or a pharmaceutically acceptable salt thereof does not reduce the duration of action (on-time) of anti-Parkinson's disease associated with the treatment of Levodopa in Parkinson's disease beyond clinically significant time, and /
  • tandospirone or a pharmacy thereof characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally without prolonging the refractory time (off time) beyond a clinically significant time.
  • Acceptable salt is not reduce the duration of action (on-time) of anti-Parkinson's disease associated with the treatment of Levodopa in Parkinson's disease beyond clinically significant time.
  • Tandospirone or a pharmaceutically acceptable salt thereof for ameliorating or preventing sex dyskinesia (PD-LID) symptoms, shortening levodopa-induced dyskinesia (PD-LID) expression time, or a combination thereof.
  • a tandospirone or a pharmaceutically acceptable salt thereof characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. Characteristically, tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • tandospirone or pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, which is administered to be .05 to 20 ng / mL.
  • the motor complications include chronotypes.
  • the motor complication further comprises levodopa-induced dyskinesia (PD-LID).
  • [Item C35] The combination according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • Levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally.
  • the motor complication comprises (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibition according to any one of the preceding paragraphs, further comprising levodopa-induced dyskinesia (PD-LID).
  • Agent [Item C38] The (1) according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times. Levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors.
  • Tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response to levodopa treatment in patients with Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally.
  • Tandospirone or a pharmaceutically acceptable salt thereof characterized by being.
  • the salt is tandospirone or a pharmaceutically acceptable salt thereof, characterized in that it is administered parenterally.
  • [Item C6A] The tandospirone or pharmaceutical thereof according to any one of the preceding paragraphs, wherein the treatment, amelioration or prevention is characterized by ameliorating chronotypes without exacerbating dyskinesia. Tolerable salt.
  • the chronotypes of Parkinson's disease are wearing-off phenomenon, on-off phenomenon, no-on phenomenon, and delayed on.
  • Treatment, amelioration or prevention of the chronotypes includes prolongation of anti-Parkinson's disease action time (on time), shortening of non-response time (off time), or a combination thereof.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the following items.
  • [Item C16A] The tandospirone or the tandospirone according to any one of the preceding paragraphs, wherein the drug dose of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as a free form of tandospirone. Its pharmaceutically acceptable salt.
  • [Item C17A] The tandospirone or the tandospirone according to any one of the preceding paragraphs, wherein the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone. Its pharmaceutically acceptable salt.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2 Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. Characteristically, tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs.
  • Tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items, which is used for treating, ameliorating or preventing levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • PD-LID Levodopa-induced dyskinesia
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • [Item C27A] A (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitor for treating or preventing Parkinson's disease with or without diurnal fluctuations (motor fluctuations).
  • the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, characterized by (1) levodopa or (2).
  • Levodopa and levodopa metabolic enzyme inhibitors [Item C28A] The item (1) according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • Levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors.
  • C29A Tandospirone or a pharmaceutically acceptable salt thereof for ameliorating the deterioration of the quality of response to levodopa treatment in Parkinson's disease patients, the improvement comprising improving diurnal fluctuations (motor fluctuations).
  • Tandospirone or a pharmaceutically acceptable salt thereof [Item C30A] The pharmaceutical or tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone, a combination thereof.
  • levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors.
  • the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • parenteral administration is persistent or is administered continuously.
  • parenteral administration comprises transdermal administration.
  • the treatment or amelioration of the PD-LID is characterized by ameliorating the PD-LID without causing rebound symptoms.
  • the PD-LID comprises peak-dose dyskinesia, diphasic dyskinesia, and a combination thereof.
  • the treatment, improvement or prevention of PD-LID includes any one of the preceding items including treatment, improvement or prevention of PD-LID symptoms, shortening of PD-LID expression time, or a combination thereof.
  • the composition according to. [Item 9D] The composition according to any one of the preceding items, wherein the treatment or improvement of the PD-LID is for a clinically significant time or longer.
  • [Item 11D] The composition according to any one of the preceding items, wherein the treatment or improvement of PD-LID is more than clinically significant improvement.
  • [Item 12D] The composition according to any one of the preceding items, wherein the treatment or improvement of the PD-LID is at a level sufficient to obtain a clinical effect.
  • [Item 13D] The composition according to any one of the preceding items, which is a transdermal pharmaceutical product.
  • [Item 14D] The composition according to any one of the preceding items, which is provided as a patch formulation.
  • [Item 15D] The composition according to any one of the preceding items, wherein the transdermal pharmaceutical product is a tape / patch agent.
  • the composition according to any one of the preceding paragraphs [Item 19D] The tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day.
  • the composition according to any one of the preceding paragraphs which is characteristic.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • composition according to any one of the preceding paragraphs which is administered so as to be .05 to 20 ng / mL.
  • composition according to any one of the preceding items which is provided as an adjunct of levodopa.
  • composition according to any one of the preceding items which is used in combination with the same preparation as levodopa or a separate preparation.
  • PD-LID levodopa-induced dyskinesia
  • levodopa or (2) levodopa and a combination of levodopa metabolic enzyme inhibitors.
  • PD-LID levodopa-induced dyskinesia
  • a levodopa metabolic enzyme inhibitor is characterized by administration in combination with tandospirone or a pharmaceutically acceptable salt thereof.
  • Do medicine.
  • a composition comprising tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response of a Parkinson's disease patient to levodopa treatment, wherein the improvement is levodopa-induced dyskinesia.
  • a composition comprising an improvement in PD-LID).
  • the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone, according to any one of the preceding paragraphs, the tandospirone or a pharmaceutically acceptable salt thereof, a composition, or a composition thereof. Medicine.
  • parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • parenteral administration is persistent or is administered continuously.
  • [Item D4D] The method according to any one of the preceding items, wherein the parenteral administration has little fluctuation in blood concentration.
  • [Item D5D] The method according to any one of the preceding items, wherein the parenteral administration includes transdermal administration.
  • [Item D6D] The method according to any one of the preceding paragraphs, wherein the treatment or amelioration of the PD-LID improves the PD-LID without causing rebound symptoms.
  • [Item D7D] The method according to any one of the preceding items, wherein the PD-LID comprises peak-dose dyskinesia, diphasic dyskinesia, and a combination thereof.
  • the treatment, improvement or prevention of PD-LID includes any one of the preceding items including treatment, improvement or prevention of PD-LID symptoms, shortening of PD-LID expression time, or a combination thereof.
  • the method described in. [Item D9D] The method according to any one of the preceding items, wherein the treatment or improvement of the PD-LID is for a clinically significant time or longer.
  • the drug dose of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as a free form of tandospirone.
  • the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as a free form of tandospirone.
  • the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal pharmaceutical product, and the total application area per application is 1 to 100 cm. 2 The method according to any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. The method according to any one of the preceding paragraphs, which is characteristic.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the method according to any one of the preceding paragraphs characterized in that it is administered so as to be .05 to 20 ng / mL.
  • [Item D21D] The method according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as an adjunct of levodopa.
  • [Item D22D] The method according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used in combination with the same preparation as levodopa or a separate preparation.
  • [Item D23D] A test comprising administering to a subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof in combination with (1) levodopa or (2) levodopa and a levodopa metabolic enzyme inhibitor.
  • PD-LID levodopa-induced dyskinesia
  • the present invention comprises administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof in combination with an effective amount of (1) levodopa or (2) levodopa and a levodopa metabolic enzyme inhibitor.
  • [Item D26D] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • [Item D27D] A method for improving the quality of response to levodopa treatment in Parkinson's disease patients, which comprises administering to Parkinson's patients an effective amount of tandospirone or a pharmaceutically acceptable salt thereof. Improvements include improvement of levodopa-induced dyskinesia (PD-LID).
  • PD-LID levodopa-induced dyskinesia
  • [Item D28D] The method according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone.
  • [Item E1D] Use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical agent for the treatment, amelioration or prevention of levodopa-induced dyskinesia (PD-LID) in Parkinson's disease. Is used, characterized by being administered parenterally.
  • [Item E2D] The use according to Item E1D, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and a combination thereof.
  • [Item E3D] The use according to Item E1D or E2D, wherein the parenteral administration is persistent or is administered continuously.
  • the treatment, improvement or prevention of PD-LID includes any one of the preceding paragraphs including treatment, improvement or prevention of PD-LID symptoms, shortening of PD-LID onset time, or a combination thereof. Use as described in.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. Characteristic use as described in any one of the preceding paragraphs.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • the use according to any one of the preceding paragraphs characterized in that it is administered to be 0.05 to 20 ng / mL.
  • PD-LID levodopa-induced dyskinesia
  • [Item E24D] The use according to any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof and the above (1) or (2) are administered simultaneously or at different times.
  • [Item E25D] To treat or prevent Parkinson's disease with or without levodopa-induced dyskinesia (PD-LID) of (1) levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors.
  • the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof. And use.
  • the treatment, amelioration or prevention of PD-LID includes any one of the preceding items including treatment, improvement or prevention of PD-LID symptoms, shortening of PD-LID expression time, or a combination thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. Characteristically, the tandospirone according to any one of the preceding paragraphs or a pharmaceutically acceptable salt thereof.
  • the tandospirone or a pharmaceutically acceptable salt thereof has a human blood (plasma) tandospirone concentration of 0 for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.
  • tandospirone or pharmaceutically acceptable salt thereof according to any one of the preceding paragraphs, which is administered to be .05 to 20 ng / mL.
  • the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, (1) levodopa, or (2) Levodopa and levodopa metabolic enzyme inhibitors.
  • tandospirone or a pharmaceutically acceptable salt thereof (1) levodopa, or (2) Levodopa and levodopa metabolic enzyme inhibitors.
  • Tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response to levodopa treatment in Parkinson's disease patients, the improvement of which is an improvement of levodopa-induced dyskinesia (PD-LID).
  • Tandospirone or a pharmaceutically acceptable salt thereof including.
  • the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone, according to any one of the preceding paragraphs, the tandospirone or a pharmaceutically acceptable salt thereof, tandospirone or a pharmaceutical product thereof.
  • the present disclosure can be provided as a patch (also referred to as a tape agent).
  • a patch also referred to as a tape agent.
  • the tape agent of the present disclosure When the tape agent of the present disclosure is attached, wearing-off, on-off phenomenon, no-on associated with drug treatment of Parkinson's disease (for example, levodopa treatment), etc. More preferably treat, improve or treat diurnal variation (motor fluctuations) such as phenomena, delayed on phenomena, and / or motor complications such as dyskinesias including levodopa-induced dyskinesia (PD-LID). It is possible to treat, improve or prevent diurnal fluctuations (motor fluxuations) without preventing or exacerbating dyskinesia symptoms. As described above, when the tape agent of the present disclosure is applied, chronotype (motor fluctuations) is treated, improved or prevented more preferably without treating, ameliorating or preventing motor complications in Parkinson's disease or exacerbating dyskinesia symptoms. can.
  • diurnal variation motor
  • the tape agent of the present disclosure when applied to more preferably treat, improve or prevent motor complications associated with drug treatment (for example, levodopa treatment) for Parkinson's disease, the dyskinesia symptom does not worsen.
  • the treatment of Parkinson's disease in which the dose of a drug such as levodopa is increased once and / or daily as compared with the treatment using the tape agent of the present disclosure, is performed in clinical practice. Can be done. In the current treatment, it is attempted to treat patients with Parkinson's disease expressing dyskinesia with Levodopa at low and frequent doses (Parkinson's disease clinical practice guideline 2018 version (Vol. III). Q & A on Parkinson's disease medical care Chapter 3 Treatment of motor symptoms)), but this disclosure may be applied in other cases as well.
  • wearing-off, on-off phenomenon, no-on phenomenon, delayed on (delayed) on Suppresses the occurrence of motor complications such as dyskinesia as seen in Parkinson's disease including diurnal variation (motor fluxuations) such as phenomena and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID).
  • diurnal variation motor fluxuations
  • drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID).
  • the levodopa-containing preparation can be adjusted to the optimum amount. That is, diurnal variation (motor fluctuations) such as wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon, etc., and levodopa-induced dyskinesia.
  • Parkinson's disease patients who have or are at risk of developing motor complications such as dyskinesia as seen in Parkinson's disease including drug-induced dyskinesia such as (PD-LID). Wearing-off, on-off phenomenon, no-on (no-) even if the dose of Levodopa is increased to reduce the number of doses or the daily dose of Levodopa is increased. Exercise complications such as on) phenomenon, diurnal variation (motor fluxuations) such as delayed on phenomenon, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID) as seen in Parkinson's disease. It does not aggravate the symptoms (motor complications) and enables more preferable treatment of Parkinson's disease symptoms.
  • Levodopa-induced motor complications associated with daily doses especially wearing-off, on-off, no-on, delayed on Treatment with reduced motor complications such as dyskinesia as seen in Parkinson's disease including diurnal variation (motor fluxuations) such as phenomena and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID). It can be improved or prevented.
  • the present inventors have diurnal fluctuations (motor fluctuations) such as wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon, etc.
  • Oral administration of tandospirone with the expectation of improving motor complications such as dyskinesia as seen in Parkinson's disease including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID) is temporarily administered.
  • motor complications such as dyskinesia as seen in Parkinson's disease including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID) are exacerbated.
  • oral administration of tandospirone is accompanied by "rebound symptoms" of dyskinesia, so wearing-off, on-off phenomenon, no-on phenomenon, delayed on (delayed on).
  • As a therapeutic agent for improving motor complications such as dyskinesia as seen in Parkinson's disease including diurnal variation (motor fluctuations) such as phenomena and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID). Found unfavorable.
  • the "rebound symptom” in the present disclosure is the symptom described in [0052].
  • oral administration of tandospirone causes "rebound symptoms", so it is not preferable to increase the dose of the levodopa-containing preparation.
  • dyskinesia in the present disclosure is the state described in [0041].
  • This disclosure describes dyskinesias of chronotypes such as wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon, etc. Can be improved without aggravating.
  • the tandospirone parenteral compositions of the present disclosure are wearing-off, on-off, no-on, without the "rebound symptoms" of dyskinesia.
  • Exercise complications such as dyskinesias such as on) and drug-induced dyskinesias such as levodopa-induced dyskinesias (PD-LID) and Parkinson's disease such as diurnal fluctuations (motor fluxuations) such as delayed on phenomena.
  • PD-LID drug-induced dyskinesias
  • Parkinson's disease such as diurnal fluctuations (motor fluxuations) such as delayed on phenomena.
  • diurnal fluctuations motor fluctuations
  • diurnal fluctuations such as wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon, and levodopa-induced dyskinesia.
  • AIMs score The score of motor complications such as dyskinesia as seen in Parkinson's disease including drug-induced dyskinesia such as (PD-LID) is "AIMs score” (AIMs) by the method described in [0140]. It can be measured as "abnormal involuntary movements”).
  • compositions of the present disclosure for both diurnal variation and dyskinesias such as those found in Parkinson's disease, including drug-induced dyskinesias such as levodopa-induced dyskinesias (PD-LID). Or, it was found that a preventive effect can be expected. This means that it is excellent as a therapeutic drug for motor complications. No approved drug is effective against both chronotype and dyskinesias such as those found in Parkinson's disease, including drug-induced dyskinesias such as levodopa-induced dyskinesias (PD-LID).
  • PD-LID drug-induced dyskinesias
  • the present disclosure may be implemented in the following specific embodiments: (1) (A) Parenteral administration step of tandospirone and (B) A method for treating, ameliorating or preventing Parkinson's disease, including a step of administering levodopa at a higher dose than the conventional dose, a wearing-off phenomenon, an on-off phenomenon, Dyskinesias such as those found in Parkinson's disease, including no-on, delayed on, and other motor fluctuations, and drug-induced dyskinesias such as levodopa-induced dyskinesia (PD-LID).
  • PD-LID drug-induced dyskinesias
  • Diurnal fluctuations such as on-off phenomenon, no-on phenomenon, delayed on phenomenon, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID).
  • How to treat, ameliorate or prevent motor complications such as dyskinesia as seen in Parkinson's disease, including wearing-off, on-off phenomenon, no-on ( Diurnal fluctuations such as no-on phenomenon, delayed on phenomenon, and dyskinesia such as those seen in Parkinson's disease including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID).
  • a method of treating, ameliorating or preventing Parkinson's disease with improved motor complications (PD-LID).
  • How to treat, ameliorate or prevent Parkinson's disease, wearing-off, on-off phenomenon, no-on phenomenon in patients who have or are at risk of developing Parkinson's disease Motor fluctuations such as delayed on phenomenon, motor complications such as dyskinesia as seen in Parkinson's disease including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID).
  • PD-LID drug-induced dyskinesia
  • Parkinson's disease In patients who have or are at risk of developing motor complications such as dyskinesia, as seen in Parkinson's disease, including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID). How to treat, improve or prevent Parkinson's disease, daily fluctuations such as wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon, etc. (Motor fluctuations), methods for treating, ameliorating or preventing motor complications such as dyskinesia as seen in Parkinson's disease, including drug-induced dyskinesia (PD-LID), or wear.
  • PD-LID drug-induced dyskinesia
  • Diur-day fluctuations such as ring-off (wearing-off), on-off (on-off) phenomenon, no-on (no-on) phenomenon, delayed on (delayed on) phenomenon, and Levodopa-induced dyskinesia (PD-)
  • PD- Levodopa-induced dyskinesia
  • (A) A step of maintaining the plasma concentration of tandospirone at 0.05 to 20 ng / mL
  • (B) A method of treating, ameliorating or preventing Parkinson's disease, a method of improving dyskinesia, or a wearing-off, on-off phenomenon, including the step of administering levodopa.
  • Dyskinesias such as those found in Parkinson's disease, including no-on, delayed on, and other motor fluctuations, and drug-induced dyskinesias such as levodopa-induced dyskinesia (PD-LID).
  • Motor complications such as dyskinesia, as seen in Parkinson's disease, including drug-induced dyskinesia such as circadian fluctuations, levodopa-induced dyskinesia (PD-LID), are present or are present.
  • How to prevent, or diurnal fluctuations (motor fluctuations) such as wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon, Levodopa A method for treating, ameliorating or preventing Parkinson's disease in which motor complications such as dyskinesia are improved as seen in Parkinson's disease including drug-induced dyskinesia such as induced dyskinesia (PD-LID).
  • motor complications such as dyskinesia are improved as seen in Parkinson's disease including drug-induced dyskinesia such as induced dyskinesia (PD-LID).
  • levodopa has a short half-life and the effect is not long-lasting, it is usually taken multiple times a day. Blood levels of tandospirone are maintained. Therefore, in the case of a transdermal preparation, levodopa is taken with exposure to tandospirone regardless of the timing of administration of levodopa. On the other hand, for example, if Cedir tablets and levodopa are taken three times a day at the same timing (oral administration), levodopa will be taken in a state where the tandospirone concentration is lowered. In other words, it can be said that it is characterized by being different from oral preparations. In addition, it is considered preferable that the blood concentration of tandospirone is maintained at the time of administration of levodopa.
  • composition comprising tandospirone or a pharmaceutically acceptable salt or prodrug thereof for the treatment, amelioration or prevention of motor fluxuations associated with the treatment of levodopa in Parkinson's disease.
  • the composition provides a composition characterized by being administered parenterally.
  • the present disclosure can be used for various purposes (indications / effects), such as wearing-off, on-off phenomenon, no-on (no).
  • Exercise such as dyskinesia as seen in Parkinson's disease including drug-induced dyskinesia such as -on) phenomenon, diurnal variation (motor fluxuations) such as delayed on phenomenon, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID).
  • Parkinson's disease Improvement of complications, wearing-off, on-off phenomenon, no-on phenomenon, delayed on (delayed) in Parkinson's disease patients treated with levodopa on)
  • Treatment of motor complications such as dyskinesia as seen in Parkinson's disease including diurnal variation (motor fluxuations) such as phenomena and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID) (brain)
  • PD-LID levodopa-induced dyskinesia
  • exercise complications such as diurnal variation and dyskinesia mean drug treatment such as levodopa treatment for Parkinson's disease or symptoms associated with the same situation.
  • a symptom derived from another disease and associated with drug treatment of Parkinson's disease such as levodopa or a treatment other than the equivalent situation
  • motor complications such as chronotype and dyskinesia include those derived from Parkinson's disease (coexistence), they are included in the scope of the present disclosure.
  • the pharmaceutical compositions of the present disclosure include drug-induced motor complications (eg, wearing-off, on-off) such as levodopa-induced dyskinesia (PD-LID) for Parkinson's disease.
  • drug-induced motor complications eg, wearing-off, on-off
  • Parkinson's disease including -off) phenomenon no-on phenomenon, diurnal variation such as delayed on phenomenon, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID).
  • PD-LID drug-induced dyskinesia
  • It can be expected to treat, improve or prevent motor complications such as dyskinesia as seen.
  • the present disclosure is also expected as a therapeutic, ameliorating or prophylactic agent for motor fluctuations that does not exacerbate dyskinesia symptoms.
  • the present disclosure is also expected to reduce the wear-off time without dyskinesia symptoms and / or prolong the on-time without dyskinesia symptoms.
  • the disclosure also presents the treatment of motor complications such as dyskinesias as seen in Parkinson's disease, including drug-induced dyskinesias such as levodopa-induced dyskinesias (PD-LID), which do not exacerbate diurnal variation. , Can be expected as an improvement or preventive drug.
  • FIG. 1 shows the ON time (Parkinson's disease) by measuring the rotation behavior (total number of rotations for 5 minutes) after administration of levodopa in Parkinson's disease model rats (6-OHDA-lesioned rats) by oral administration of tandospirone for 180 minutes.
  • the results of measuring the anti-Parkinson's disease action effect time (on time) associated with the treatment of levodopa of the disease are shown.
  • the ON time was defined as a time indicating a rotation speed of 20% or more of the peak value of the total rotation speed for 5 minutes by administration of levodopa.
  • FIG. 2 shows the ON time by measuring the rotational behavior (total rotation speed for 5 minutes) after administration of levodopa in Parkinson's disease model rats (6-OHDA-lesioned rats) by transdermal administration of tandospirone for 180 minutes. The measurement result is shown.
  • the ON time was defined as a time indicating a rotation speed of 20% or more of the peak value of the total rotation speed for 5 minutes by administration of levodopa.
  • a tandospirone tape 60 cm 2 / kg (6.5% W / V containing a tandospirone-free form)
  • an extension of the ON time of 120 to 180 minutes of levodopa administration was observed compared to the solvent-administered group (Fig.). 2A)
  • a significant prolongation of the 180-minute total ON time was observed (FIG. 2B).
  • 3 shows the results of measuring dyskinesia-like symptoms and rotational behavior (ON score) by administering levodopa to PD-LID model rats by oral administration of tandospirone and measuring for 180 minutes every 20 minutes.
  • Behavioral observation evaluation was performed from 20 minutes after intraperitoneal administration of levodopa to 1 minute in a transparent acrylic cage every 20 minutes until 3 hours after administration.
  • Behavioral observations include Limb AIMs (involuntary bending and stretching of the forelimbs on the opposite side of the disorder, opening and closing of the palm, up and down wrists, chorea-like shaking, dystonia-like rigidity), and Axial AIMs (upper body and neck on the opposite side of the disorder).
  • 3 shows the results of measuring dyskinesia-like symptoms and rotational behavior (ON score) by administering levodopa to PD-LID model rats by oral administration of tandospirone and measuring for 180 minutes every 20 minutes.
  • Behavioral observation evaluation was performed from 20 minutes after intraperitoneal administration of levodopa to 1 minute in a transparent acrylic cage every 20 minutes until 3 hours after administration.
  • Behavioral observations include Limb AIMs (involuntary bending and stretching of the forelimbs on the opposite side of the disorder, opening and closing of the palm, up and down wrists, chorea-like shaking, dystonia-like rigidity), and Axial AIMs (upper body and neck on the opposite side of the disorder).
  • levodopa was administered to PD-LID model rats by transdermal administration of tandospirone (without stripping), and dyskinesia-like symptoms and rotational behavior (ON score) were measured every 20 minutes for 180 minutes. The measurement result is shown.
  • tandospirone tape was transdermally administered to PD-LID model rats, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms (FIG. 4A) and rotational behavior (FIG. 4B), and the results were averaged. It is shown by ⁇ standard error.
  • the application of tandospirone tape increased the total ON score (Fig.
  • FIG. 4C levodopa was administered to PD-LID model rats by transdermal administration of tandospirone (without stripping), and dyskinesia-like symptoms and rotational behavior (ON score) were measured every 20 minutes for 180 minutes. The measurement result is shown. Specifically, tandospirone tape was transdermally administered to PD-LID model rats, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms (FIG. 4A) and rotational behavior (FIG. 4B), and the results were averaged.
  • tandospirone tape was transdermally administered to PD-LID model rats that had undergone keratin stripping treatment at the tape application site, and levodopa was administered 4 hours later to administer dyskinesia-like symptoms (Fig. 5A) and rotational behavior. (FIG. 5B) was evaluated and the results are shown as mean ⁇ standard error.
  • Fig. 5C total ON score
  • Fig. 5D significantly extended the 180-minute dyskinesia-free ON time
  • levodopa was administered to PD-LID model rats by transdermal administration of tandospirone (with stripping), and dyskinesia-like symptoms and rotational behavior (ON score) were measured every 20 minutes for 180 minutes. The measurement result is shown.
  • tandospirone tape was transdermally administered to PD-LID model rats that had undergone keratin stripping treatment at the tape application site, and levodopa was administered 4 hours later to administer dyskinesia-like symptoms (Fig. 5A) and rotational behavior. (FIG. 5B) was evaluated and the results are shown as mean ⁇ standard error. Tandospirone tape application after keratin stripping treatment increased the total ON score (Fig.
  • FIG. 6A shows the results of intraperitoneal administration of levodopa to PD-LID model rats and measurement of changes in dopamine over time in the striatum by the microdialysis method.
  • FIG. 6B is a result of calculating the time when the amount of change in free dopamine is 0.2 pg or more. By applying the tandospirone tape, the effect of prolonging the release time of striatal dopamine was observed as compared with the placebo group.
  • FIG. 6C shows the results of total dopamine release after levodopa administration.
  • FIG. 7 shows an evaluation of changes in plasma concentration when the tandospirone tape agent of Example 4 was applied to normal rats. Specifically, the transition of the plasma tandospirone concentration obtained by applying the tandospirone tape to normal rats (9 cm 2 : 31 ⁇ 2 cm 2 / kg) is shown by the average value ⁇ standard deviation. The x-axis shows the time from application, and the y-axis shows the tandospirone plasma concentration. FIG.
  • Example 8 shows the results of administration condition 1 of Example 5, and a tandospirone tape (formulation 2: drug dose 37 mg / kg) was attached by transdermal administration (condition 1) to allow tandospirone to be transdermally absorbed.
  • the total dyskinesia-like symptom (AIMs) score was 12.6.
  • the total AIMs score decreased by 17.7 as compared with the placebo tape containing no tandospirone, and a significant improvement in dyskinesia-like symptoms was observed.
  • tandospirone tape was transdermally administered to PD-LID model rats, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms, and the results were shown by mean ⁇ standard error.
  • FIG. 9 shows the results of the administration condition 2 of Example 5. Under the keratin stripping condition, a tandospirone tape (formulation 3: drug dose 45 mg / kg) was applied to transdermally absorb the highly exposed tandospirone. The total dyskinesia-like symptom (AIMs) score was 5.8.
  • tandospirone tape was transdermally administered to PD-LID model rats that had undergone keratin stripping treatment at the tape application site, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms, and the results were averaged. Value ⁇ standard error. ** indicates p ⁇ 0.01, which means that there is a significant difference compared to the placebo tape application group (Wilcoxon rank sum test).
  • FIG. 9-A shows the total AIMs score for 180 minutes.
  • FIG. 9-B shows the total AIMs score for 100-180 minutes.
  • FIG. 10 shows an evaluation of improvement of dyskinesia-like symptoms by continuous subcutaneous administration of tandospirone in Example 6.
  • tandospirone was continuously administered subcutaneously to PD-LID model rats, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms, and the results were shown by mean ⁇ standard error. * Indicates p ⁇ 0.05, which means that there is a significant difference compared to the solvent-administered group (Steel test).
  • Subcutaneous continuous administration of tandospirone improved dyskinesia-like symptoms in a dose-dependent manner, and 1.25 mg / kg / hour showed a significant improvement (FIGS. 10-A, B).
  • FIG. 10 shows an evaluation of improvement of dyskinesia-like symptoms by continuous subcutaneous administration of tandospirone in Example 6. Specifically, tandospirone was continuously administered subcutaneously to PD-LID model rats, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms, and the results were shown by mean ⁇ standard error.
  • FIG. 11 shows an evaluation of long-term dyskinesia-like symptom improvement of continuous subcutaneous administration of tandospirone in Example 7.
  • FIG. 12 shows an evaluation of the preventive / suppressive effect of continuous subcutaneous administration of tandospirone in Example 8 on dyskinesia-like symptoms.
  • FIG. 12-A shows the results over time of repeated administration of levodopa
  • FIG. 12-B shows the results on the day after the administration of tandospirone citrate was completed (day 16).
  • Statistical analysis of test results was performed by comparing with the solvent-administered group by Steel test using the total AIMs score on the 16th day of repeated administration of levodopa as an index.
  • FIG. 13 shows an evaluation of the dyskinesia symptom of oral administration of tandospirone in Comparative Example 1. Behavioral observation evaluation was performed using the same method as in Example 2. Tandospirone citrate is suspended in a 0.5% methylcellulose solution and orally administered to rats (citrate concentration: 10, 30 mg / kg), and after 5 minutes, a levodopa combination solution is intraperitoneally administered for behavioral observation evaluation. Carried out. The results in the figure are shown as mean ⁇ standard error. Using the 3-hour total dyskinesia-like symptom (AIMs) score (Fig.
  • AIMs 3-hour total dyskinesia-like symptom
  • FIG. 14 shows an evaluation of the dyskinesia symptom of oral administration of tandospirone in Comparative Example 1. Behavioral observation evaluation was performed using the same method as in Example 2. Tandospirone citrate is suspended in a 0.5% methylcellulose solution and orally administered to rats (citrate concentration: 30, 100 mg / kg), and after 5 minutes, a levodopa combination solution is intraperitoneally administered for behavioral observation and evaluation.
  • FIG. 15 shows the evaluation of the tandospirone metabolite of Comparative Example 2 for dyskinesia symptoms. Behavioral observation evaluation was performed using the same method as in Example 2.
  • FIG. 15 shows the evaluation of the tandospirone metabolite of Comparative Example 2 for dyskinesia symptoms. Behavioral observation evaluation was performed using the same method as in Example 2. 1-PP dihydrochloride (Tokyo Chemical Industry) was dissolved in physiological saline and administered subcutaneously to rats (10, 30 mg / kg), and after 5 minutes, levodopa compound solution was intraperitoneally administered for behavioral observation and evaluation. (Fig. 15-A). The results in the figure are shown by mean ⁇ standard error. Using the 3-hour total dyskinesia-like symptom (AIMs) score (Fig. 15-B) and the 100-180 minute total dyskinesia-like symptom score (Fig.
  • FIG. 16 is a diagram showing powder X-ray diffraction patterns of tandospirone-free form, tandospirone citrate (hydrate) and tandospirone citrate (anhydride).
  • FIG. 17 shows the results in Example 9. The predicted value (average value) of the plasma tandospirone-free body concentration when the tandospirone tape agent was once transdermally administered for 24 hours is shown. In FIG. 17B, the value predicted and analyzed from the measured value of 17.6 mg is shown.
  • FIG. 18 also shows the results in Example 9.
  • FIG. 19 also shows the results in Example 9.
  • the predicted value of the plasma tandospirone concentration transition in a steady state at the time of repeated transdermal administration of a tandospirone tape once a day is shown.
  • FIG. 20 shows the results in Example 10.
  • the back of the rhesus monkey was shaved, 19 hours before the test, an ointment was applied to an area of 4 cm ⁇ 10 cm, covered with tape and a clean cloth, and the jacket was put on.
  • the evaluation of dyskinesia was performed by analyzing a video of a model monkey and scoring it by an evaluator who is skilled in behavioral evaluation. The dyskinesia score was evaluated based on the Revised non-human primate dyskinesia ratting scale (J Neuroscience 2001; 21: 6853-6861.).
  • the score is 0, and if less than 30% of the evaluation time is observed, the score is considered to be mild dyskinesia, and the score is 1, and it is normal even if 30% or more of the evaluation time is seen. If the behavior is not inhibited, it is regarded as moderate dyskinesia and the score is 2, and if less than 70% of the evaluation time and 30% or more of the dyskinesia is observed and the normal behavior is inhibited, it is marked as remarkable dyskinesia. The deemed score was set to 3, and when dyskinesia was observed in 70% or more of the evaluation time and normal behavior was impaired, the deemed score was set to 4 as severe dyskinesia.
  • systemic dyskinesia was evaluated as a particularly severe dyskinesia.
  • UDysRS which is a clinical evaluation scale that incorporates site-specific dyskinesia into the evaluation
  • dyskinesia occurs in 4 or more of the 6 locations of the face, right arm, left arm, trunk, right leg, and left leg.
  • the case was defined as systemic dyskinesia, and the score was 1 if systemic dyskinesia occurred in 30% or more of the evaluation time, and 2 if systemic dyskinesia occurred in 70% or more of the evaluation time.
  • tandospirone [chemical name: (1R, 2S, 3R, 4S) -N- [4- ⁇ 4- (pyrimidine-2-yl) piperazine-1-yl ⁇ butyl] -2,3-bicyclo [ 2.2.1] Heptane dicarboxyimide] has the following structure. Cedir tablets containing tandospirone citrate as an active ingredient are used therapeutically as serotoninergic anxiolytics (eg, Cedir Attachment Revised April 2016, 14th Edition, Sumitomo Dainippon Pharma Co., Ltd .; See JP-A-58-126865).
  • Tandospirone has a beneficial effect on the memory of chronic schizophrenia, and cognitive function is administered by administering tandospirone or a pharmaceutically acceptable salt thereof while continuing maintenance therapy with a typical antipsychotic drug such as haloperidol. It is known that the disorder can be improved (see JP-A-2002-20291; the powder X-ray diffraction pattern is shown in FIG. 16).
  • tandospirone (free form) is preferable, and a pharmaceutically acceptable salt of tandospirone or a prodrug of tandospirone can also be used in the same manner as tandospirone.
  • Pharmaceutically acceptable salts or prodrugs of tandospirone include salts with inorganic acids such as hydrochlorides, hydrobromates, sulfates, phosphates, acetates, butyrates, tartrates, citrates, Includes salts with organic acids such as maleate and fumarate.
  • a prodrug of tandospirone is an arbitrary ingredient that has a different structure from that of tandospirone, but can exert its medicinal effect by being metabolized to tandospirone or an active ingredient based on it after administration.
  • the prodrug of tandospirone is a compound that is converted to tandospirone by a reaction with an enzyme or the like under physiological conditions in the living body, that is, a compound that enzymatically undergoes oxidation, reduction, hydrolysis, etc. to change to tandospirone, or is hydrolyzed by an acid or the like.
  • the tandospirone prodrug may be one that changes to tandospirone under physiological conditions as described in Hirokawa Shoten, 1990, "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198.
  • the tandospirone of the present disclosure or a salt thereof or a prodrug thereof (hereinafter, also referred to as tandospirones) has an excellent serotonin 5-HT1A receptor activating effect.
  • the tandospirone disclosed in the present disclosure has low toxicity and is safe.
  • Tandospirone citrate Drugs containing "tandospirone citrate” as an active ingredient include (1) depression and fear in neurosis, and (2) physical symptoms and depression in psychosomatic disorders (autonomous hypertension, essential hypertension, digestive ulcers). It is clinically applied as an oral preparation as a therapeutic agent for anxiety, irritation, and sleep disorders. Tandospirone has high selectivity for serotonin 1A receptor (hereinafter, also referred to as "5-HT1A receptor”) in the evaluation of in vitro receptor binding to various neurotransmitter receptors, while it is highly selective. It has a low affinity for dopamine 2 receptors (also referred to as "D2 receptors").
  • D2 receptors dopamine 2 receptors
  • tandospirone is effective for neurosis and the like by activating 5-HT1A receptors and selectively acting on serotonin nerves.
  • pharmacotherapy for Parkinson's disease means receiving treatment with a therapeutic agent for Parkinson's disease.
  • Drug therapy for Parkinson's disease includes dopamine replacement therapy (levodopa therapy, drug therapy for Parkinson's disease such as levodopa metabolic enzyme inhibitor, dopamine receptor agonist (dopamine agonist)), and treatment with adjuvants for Parkinson's disease. Can be mentioned.
  • levodopa therapy includes levodopa therapy in a narrow sense (also referred to as treatment with a levodopa-containing preparation), drug therapy of a metabolic enzyme inhibitor of levodopa, and the like.
  • the pharmaceutical compositions of the present disclosure can be expected as therapeutic, ameliorating or prophylactic agents for motor complications in patients receiving these Parkinson's disease drug therapies. Among them, it is known that exercise complications are likely to occur in patients receiving levodopa therapy, and the pharmaceutical composition of the present disclosure is useful for these patients.
  • levodopa (broad definition) is levodopa (L-3,4-dihydroxyphenylalanine (IUPAC name is (S) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid) in a narrow sense. It also includes L-dopa) and any other drug that has the same efficacy as L-3,4-dihydroxyphenylalanine.
  • Such other agents include, but are not limited to, for example, esters of L-3,4-dihydroxyphenylalanine and salts thereof.
  • esters of L-3,4-dihydroxyphenylalanine are levodopa ethyl ester (LDEE; ethyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate), levodopapropyl ester; levodopapropyl ester (propyl).
  • LEE levodopa ethyl ester
  • (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate levodopamethyl ester (methyl (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoate) and the like.
  • the ester of L-3,4-dihydroxyphenylalanine can be, for example, a salt containing a hydrated salt.
  • the salt of levodopaester is one of octanate, myristate, succinate, succinate dihydrate, fumarate, fumarate dihydrate, mesylate, tartrate and hydrochloride. May include, but are not limited to.
  • the succinate or succinate dihydrate of the ester of L-3,4-dihydroxyphenylalanine is levodopaethyl ester succinate (LDEE-S) or levodopaethyl ester succinate dihydrate (LDEE). -S-dihydrate or LDEE-S (d)) can be mentioned.
  • levodopa metabolic enzyme inhibitor refers to any drug having an action of inhibiting its metabolism so as to strengthen the action of levodopa in a broad sense, and levodopa becomes dopamine in the intestine, liver and blood vessels.
  • Examples thereof include dopa decarboxylase (decarboxylase) inhibitors (DCI) (carbidopa, ⁇ -methyldopa, benzeradide (Ro4-4602), ⁇ -difluoromethyl-DOPA (DFMD)) or salts thereof that prevent change.
  • DCI dopa decarboxylase
  • DCI dopa decarboxylase inhibitors
  • DFMD ⁇ -difluoromethyl-DOPA
  • a catecholamine-O-methyltransferase inhibitor (exemplified by Entakapon), which prevents levodopa from being degraded before it enters the brain, which prevents dopamine from being degraded in the brain.
  • Examples include monoamine oxidase inhibitors (MAO-I) (exemplified by selegiline) and the like to prevent.
  • the term "motor complications” refers to any therapeutic problem observed in patients with advanced Parkinson's disease, and is an involuntary movement associated with levodopa treatment.
  • Levodopa-induced dyskinesia PD-LID
  • wearing-off and on-off phenomena that are diurnal and motor fluctuations
  • no-on phenomenon / delayed on (no-on) Delayed on Symptoms such as phenomena can be mentioned.
  • On / off is a phenomenon in which symptoms change suddenly as if the switch is turned on and off, and while wearing off is predictable, on / off is unpredictable. ..
  • Dyskinesia ⁇ involuntary movements> is a type of motor complication that appears in patients with Parkinson's disease, etc., and refers to involuntary movements in which the limbs and body move freely. Similar to Parkinson's disease, it includes dyskinesias in patients with neurodegenerative diseases associated with a deficiency of dopamine levels in the striatum. Dyskinesia is said to be caused by various causes, and examples thereof include those induced by various drugs (for example, levodopa) and dyskinesias caused by drug administration.
  • levodopa-induced dyskinesia ⁇ involuntary movement>(PD-LID) refers to involuntary movements in which the limbs and body are caused by overdose of levodopa.
  • Dyskinesias are more likely to appear if you continue to take more than necessary levodopa from the early stages of the disease, and once dyskinesias have appeared, it is very difficult to control even if you adjust the dose of levodopa afterwards.
  • Etc. are known.
  • Peak-dose dyskinesia is known as a typical symptom of PD-LID, and symptoms appear on the face, tongue, neck, limbs, trunk, etc. when the blood concentration of levodopa is high. ..
  • chronotype and “exercise fluctuation” can be used interchangeably, which means that the effective time of the drug is shortened and the effect disappears by the next dose. It is believed to be due to a decrease in nerve endings that retain dopamine.
  • Typical chronotypes include the wear-off phenomenon.
  • “not” to exacerbate chronotype means, for example, wearing-off, on-off phenomenon, no-on phenomenon, and delayed onset. It means that the on (delayed on) phenomenon does not worsen, the ON time is not shortened, the OFF time is not extended, and the like.
  • progression inhibition means that the progression of motor complications in Parkinson's disease is delayed, stopped, or ameliorated (including sensing) compared to no treatment. include. In the case of motor complications in Parkinson's disease, it can be determined by confirming the effect of prolonging the ON time without dyskinesia, but it is not limited to this. Treatment, prevention or amelioration of the various diseases, disorders or symptoms of the present disclosure may include inhibition of the progression of motor complications in Parkinson's disease.
  • the "wearing-off phenomenon” refers to a phenomenon caused by shortening the drug efficacy time of levodopa, and means a phenomenon in which the effect of levodopa expires.
  • the time zone when levodopa is effective is called the on period, and the time zone when the levodopa effect disappears is called the off period.
  • the on-off phenomenon means that the symptoms suddenly improve (on) or worsen (off) regardless of the time taken for levodopa, and the no-on phenomenon refers to levodopa. It means that the effect is not recognized even if it is taken, and the delayed on phenomenon means that it takes time for the effect of levodopa to appear.
  • the rotational behavior is indicated by the rotational behavior time in the direction opposite to the destruction or the total number of rotational movements, and is an behavior that reflects the increase in striatal dopamine.
  • Involuntary movements are those in which a part of the body moves freely and does not stop, bites the lips, is difficult to talk, cannot stay still, is difficult to move the limbs as expected, and the limbs and / or the oral and facial parts and / Or a movement disorder in which involuntary movements of the axial part of the body are observed.
  • the dyskinesias observed in PD patients treated with levodopa called levodopa-induced dyskinesias (LIDs)
  • LIDs levodopa-induced dyskinesias
  • not exacerbating dyskinesia symptoms means that, for example, no new dyskinesia symptoms occur as compared with the case before the start of the treatment of the present disclosure or the case where the therapeutic agent of the present disclosure is not administered. , It means a state in which the dyskinesia symptom is not aggravated or the dyskinesia symptom accompanied by rebound is not accompanied.
  • Peak-dose dyskinesia is an involuntary movement that occurs when the antiparkinsonian drug is in excess.
  • Biphasic dyskinesia is a dyskinesia that appears in two phases, before the onset of the antiparkinsonian drug and when the effect disappears.
  • the ON time without dyskinesia refers to the total time of the "ON time” which is the anti-Parkinson's disease action time, in which dyskinesia does not occur. It can be defined as the time when the dyskinesia symptom (AIMs) score is 0 and the Locomotive behavior score is 1 or more at each evaluation time point after administration of levodopa in the PD-LID model animal. If a model of is present, it can also be evaluated using such a model.
  • AIMs dyskinesia symptom
  • pharmaceutically acceptable salt includes acids and / or base salts formed by inorganic and / or organic acids and bases, including acid addition salts and base addition salts. Be done.
  • an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, phthalate, etc.
  • examples thereof include organic acid salts such as salts and camphor sulfonates.
  • the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt and aluminum salt, or trimethylamine, triethylamine, pyridine, picolin, 2,6-lutidine, ethanolamine and diethanolamine.
  • Triethanolamine Triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylamine, organic base salts and the like.
  • examples of the "pharmaceutically acceptable salt” include amino acid salts with basic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid or acidic amino acids.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. Pharmaceutical Sciences (1977) 66: 1-19 describes in detail pharmaceutically acceptable salts.
  • the pharmaceutical containing the tandospirone of the present disclosure or a pharmaceutically acceptable salt or prodrug thereof may contain a carrier, if necessary.
  • carrier relates to, for example, transporting or transporting a pharmaceutical compound of interest from one organ / tissue or part of the body to another organ / tissue or part of the body, or A pharmaceutically acceptable substance, composition, or excipient such as a liquid or solid bulking agent, diluent, additive, solvent, base or skin penetration enhancer that makes it possible.
  • “Pharmaceutically acceptable” means that it is compatible with other ingredients in the pharmaceutical product and is not harmful to the subject.
  • Diseases treatable in the present invention include any motor complications of Parkinson's disease.
  • Diseases treatable in this disclosure include any levodopa-induced motor complications of Parkinson's disease and associated chronotypes.
  • the treatable patients in the present disclosure include Parkinson's disease patients who have levodopa-induced motor complications or who may develop levodopa-induced motor complications.
  • Levodopa-induced motor complications include levodopa-induced dyskinesias.
  • the improving effect on Parkinson's disease dyskinesia such as levodopa-induced dyskinesia in the present invention is clinically known as Unified dyskinesia Racing Scale (UDysRS), Clinical dyskinesia Racing Scale (CDRS), , Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Abnormal Involuntary Movement Scale (AIMS), EuroQol 5 Dimensions (EQ-5D-5L), PDQ-39 (Parkinson's Disease Questionnarie-39), Confirm by clinical evaluation scales such as Clinical Global Expressions (CGI) and Patient Global Impactions (PGI), and scales calculated from mobile motion information acquired by wearable devices such as patient diaries, accelerometers and / or angular velocimeters.
  • CGI Clinical Global Expressions
  • PKI Patient Global Impactions
  • the improvement effect of dyskinesia can be confirmed by the evaluation of abnormal involuntary movement behavior like dyskinesia.
  • PD-LID levodopa-induced dyskinesia
  • PD-LID levodopa-induced dyskinesia
  • the action time (ON time) of the anti-Parkinson's disease therapeutic agent such as levodopa and the non-action time (OFF time) of the anti-Parkinson's disease therapeutic agent such as levodopa are clinically, for example, Unified, which is a clinical evaluation scale. Acquired by clinical evaluation scales such as Parkinson's Disease Racing Scale (UPDRS), MDS-UPDRS, EQ-5D-5L, PDQ-39, CGI, PGI, and wearable devices such as patient diaries, accelerometers and / or angular velocimeters. It can be confirmed by the scale calculated from the moving motion information. In addition, in non-clinical model 6-OHDA unilaterally treated rats, the therapeutic effect on ON time can be confirmed by prolonging the rotational behavior time induced by levodopa.
  • UDRS Parkinson's Disease Racing Scale
  • MDS-UPDRS MDS-UPDRS
  • EQ-5D-5L EQ-5D-5L
  • the "rebound symptom" of dyskinesia in a patient with Parkinson's disease or the like is treated with a dyskinesia improving drug after the peak time (for example, 1 hour) of the anti-Parkinson's disease action of levodopa during treatment with the dyskinesia improving drug. It is a phenomenon in which dyskinesia worsens than in the absence, and is expected to appear 1 to 6 hours after administration of levodopa.
  • PD-LID levodopa-induced dyskinesia
  • improving dyskinesia for example, levodopa-induced dyskinesia (PD-LID)
  • PD-LID levodopa-induced dyskinesia
  • improving dyskinesia for example, levodopa-induced dyskinesia (PD-LID)
  • PD-LID levodopa-induced dyskinesia
  • PD-LID levodopa-induced dyskinesia
  • the rebound symptom of levodopa-induced dyskinesia is, for example, a clear dyskinesia-like symptom (AIMs score) observed at 120-140 minutes after levodopa administration. Can be evaluated using 2 or more) and the total dyskinesia-like symptom score for 100 to 180 minutes as an index. Improvement of dyskinesia can be assessed by total AIMs score 180 minutes after levodopa administration.
  • an anti-Parkinson's disease therapeutic agent eg, levodopa
  • a patient with Parkinson's disease or the like in the present disclosure is clinically UPDRS.
  • the ON time without dyskinesia in the present disclosure is clinically determined is clinically UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-.
  • Check with clinical evaluation scales such as 39, CGI, PGI, and scales calculated from moving motion information acquired by wearable devices such as ON time, OFF time, accelerometer and / or angular velocity meter described in the patient's diary. be able to.
  • UDysRS and patient diary can be combined and evaluated.
  • the ON time (On time without troublesome dyskinesia) without painful dyskinesia in the present disclosure is extended clinically is UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS in the clinical evaluation scale and patient diary.
  • UDysRS and patient diary can be combined and evaluated.
  • the ON time is extended without the rebound symptom of dyskinesia in the present disclosure can be confirmed, for example, by comparing the following with the case where the therapeutic agent of the present disclosure is not administered.
  • Clinically it is described in clinical evaluation scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, PGI in the clinical evaluation scale and patient diary, and patient diary. It can be confirmed by the scale calculated from the moving motion information acquired by the wearable device such as the ON time, the OFF time, the accelerometer and / or the angular velocity meter. Further, for example, in a non-clinical model PD-LID model rat, it can be confirmed by evaluation of dyskinesia and rotational behavior time. For example, UDysRS and patient diary can be combined and evaluated.
  • the diurnal variation (motor complications) of motor symptoms in the present disclosure is clinically a clinical evaluation scale or a clinical evaluation scale such as UPDRS, MDS-UPDRS, EQ-5D-5L, PDQ-39, CGI, PGI in the patient's diary. It can be confirmed by the scale calculated from the moving motion information acquired by the wearable device such as the ON time, the OFF time, the accelerometer and / or the angular velocity meter described in the patient's diary. If the improvement of the clinical evaluation scale or the shortening of the OFF time can be confirmed by the patient's diary, it can be considered that the chronotype has improved.
  • the clinical evaluation scale can be evaluated by a known method in the art.
  • improving diurnal variation (motor complications) without causing dyskinesia rebound symptoms is temporary as compared with the case where treatment with a diurnal variation (motor complications) improving drug is not performed after administration of levodopa.
  • diurnal fluctuations (motor complications) will improve without worsening dyskinesia.
  • tandospirone improves diurnal fluctuations (motor complications), preferably without aggravating dyskinesia. Improving dyskinesia without exacerbation includes new onset of dyskinesia symptoms, deterioration of clinical score of dyskinesia, improvement without dyskinesia alibound symptoms, and the like. Furthermore, we found that parenteral administration of tandospirone improved diurnal variation (motor complications) better than oral administration of tandospirone, specifically, ON time without dyskinesia. It was found that the prolongation effect of Tandospirone was excellent.
  • parenteral administration showed the effect of prolonging the ON time without dyskinesia regardless of the dose, but oral administration did not involve dyskinesia at the normal dose (rat 10,30 mg / kg). No prolongation of the ON time was observed, and the ON time without dyskinesia was prolonged only after the dose was increased to a dose (100 mg / kg in rats) where central side effects were a concern.
  • One of ordinary skill in the art can calculate an appropriate dose in humans in light of these doses. (For example, see Cedir Tablets Pharmaceutical Interview Form, Revised December 2017, 10th Edition, Sumitomo Dainippon Pharma Co., Ltd.).
  • tandospirone can be orally administered, but parenteral administration is preferable, and continuous parenteral administration or continuous parenteral administration is more preferable, and tandospirone is transdermally administered. It is most preferable to administer.
  • levodopa-induced “dystonia” is also called dystonia, and is a general term for movement disorders related to involuntary and continuous muscle contraction due to central nervous system disorders caused by levodopa administration. It refers to symptoms such as abnormal posture, twisting of the whole body or part of the body, rigidity, and convulsions. Levodopa-induced dystonia can be clinically evaluated by MDS-UPDRS (Part IV), UDysRS and the like.
  • the term "adjunct" refers to a drug other than a drug having a main action, and in the present disclosure, for example, if levodopa is the main agent, tandospirone or the like is an auxiliary agent. Can be done.
  • the daily dose of the antiparkinson's disease drug is the usual dose of the antiparkinson's disease drug described in the 2018 version of the Parkinson's disease clinical practice guideline or the corresponding guideline in the United States and Europe.
  • the daily dose of levodopa the main agent, is the usual dose of levodopa treatment described in the Parkinson's Disease Practice Guidelines 2018 version or the corresponding guidelines in the United States and Europe. ..
  • the usual daily dose of levodopa is 50 to 1200 mg / day, preferably 100 mg to 600 mg / day, in combination with or as a combination drug with a peripheral dopa decarboxylase inhibitor (DCI). It's a day.
  • DCI peripheral dopa decarboxylase inhibitor
  • FDA-approved SINEMET® (Carbidopa-Levodopa Combination Tablets) (New Drag Application (NDA) # 017555) is a 1: 4 ratio combination tablet (Carbidopa 25 mg-Levodopa 100 mg) and 1: 10. It is provided as a ratio combination tablet (Carbidopa 10 mg-Levodopa 100 mg, Carbidopa 25 mg-Levodopa 250 mg).
  • the daily maintenance dose is administered SINEMET® from 70 mg to 100 mg of Carbidopa, and the maximum daily dose is 200 mg of SINEMET®.
  • Tandospirone or a pharmaceutically acceptable salt or prodrug or treatment thereof herein can be used to reduce or prevent motor complications associated with the administration of conventional doses of levodopa treatment. ..
  • the dose of levodopa can be adjusted as appropriate. For example, it can be increased within the range of single dose and daily dose specified in the 2018 version of the Parkinson's disease clinical practice guideline published by the Japanese Society of Neurology or the corresponding guideline in the United States and Europe.
  • sustained can be determined by a person skilled in the art in consideration of the description in the present specification and by utilizing the knowledge known in the art. Specifically, if the blood drug concentration is maintained for a long period of time and the effect of prolonging the biological half-life is shown, it can be defined as having a long-lasting effect.
  • the persistent composition include various percutaneous absorption preparations described in [0076], various persistent injections described in [0117], various implantants described in [0118], and the like.
  • continuous administered means that the active ingredient in the present disclosure is continuously administered from outside the body into the body. It can be selected from the parenteral routes of administration described in [0071] and can be achieved by percutaneous absorption, injection or infusion.
  • “persistent” can mean less variation in blood levels of tandospirone.
  • the fluctuation of the blood concentration is small means that the ratio of the maximum value (Cmax) and the minimum value (Cmin) of the tandospirone concentration at the time of the final administration after reaching the steady state is within a certain range. It means to be within, and a certain range thereof is referred to to those skilled in the art with reference to the disclosure of the present specification, depending on the purpose to be achieved (for example, suppression of motor complications (for example, suppression of diurnal variation), etc.).
  • the ratio of the maximum value (Cmax) to the minimum value (Cmin) of the tandospirone concentration at the time of the final administration after reaching the steady state is 1.0 to 3.0, 1.0 to 1.0. It means that it is 2.0, 1.0 to 1.8, and 1.0 to 1.7.
  • “clinically significant time” can be determined by one of ordinary skill in the art, taking into account the description herein and utilizing knowledge known in the art. Specifically, if a significant effect is shown in the prevention, treatment or alleviation of motor complications covered by the present disclosure, the time can be defined as a clinically significant time. .. Similarly, if "clinically significant improvement” as used herein has a significant effect on the prevention, treatment or alleviation of motor complications covered by the present disclosure, the condition is clinical. Can be defined as a significant improvement. Such methods of measuring time and improvement are matters that can be appropriately selected by those skilled in the art, and for example, any method described herein is considered, but is limited thereto.
  • the 2018 version of the Parkinson's disease clinical practice guideline published by the Japanese Society of Neurology can be used.
  • the clinical evaluation index of dyskinesia is 2.32 points (Parkinsonism Relat Disord 21: 1349, 2015)), (1) comparison with placebo, (2) before and after treatment of each patient. It can be decided as appropriate in consideration of such matters.
  • "sustainably maintaining the amount of dopamine in the synaptic cleft of the striatum” means that the amount of dopamine in the synaptic cleft of the striatum is maintained above a certain concentration.
  • the amount of change in the amount of [ 11 C] raclopride receptor binding in the striatum 1h / 4h is less than 5%.
  • / or the rate of change in the amount of [ 11 C] raclopride receptor binding in the striatum 1h / 4h is 90% or less, preferably 80% or less, more preferably 70% or less.
  • the effect of the pharmaceutical composition can be confirmed.
  • the amount of change in the [ 11 C] raclopride receptor binding of the striatum before and 1 hour after the administration of levodopa is referred to as the amount of change B / 1h.
  • “suppressing abrupt fluctuations in the amount of dopamine in the synaptic cleft of the striatum” means that the amount of dopamine in the synaptic cleft of the striatum does not change significantly in a short period of time.
  • the amount of change B / 1h in the amount of [ 11 C] raclopride receptor binding in the striatum is less than 10%, and /
  • the effect of the pharmaceutical composition of the present invention can be confirmed by the change rate B / 1h of 90% or less, preferably 80% or less, more preferably 70% or less.
  • "suppressing intermittent dopamine receptor stimulation” means suppressing an increase or decrease in the amount of dopamine in the synaptic cleft of the striatum over time.
  • the pharmaceutical composition of the present invention can be confirmed by checking whether or not it is used.
  • sufficient time for a clinical effect and “sufficient level for a clinical effect” are also known to those of skill in the art in light of the description herein. It can be decided by using the knowledge of. Specifically, if it is possible to measure the time and level at which clinical effects such as prevention, treatment or alleviation of motor complications covered by the present disclosure can be obtained, the time and level can obtain clinical effects. It can be evaluated that it is enough time. Such methods of measuring time and level are items that can be appropriately selected by those skilled in the art, and for example, any method described herein is considered, but is limited thereto. However, for example, the Parkinson's disease clinical practice guideline 2018 version published by the Japanese Society of Neurology or the corresponding guideline in the United States and Europe can be used.
  • dyskinesia symptoms for example, levodopa-induced dyskinesia (PD-LID) symptoms
  • Parkinson's disease is clinically significant for already developing dyskinesia symptoms. Does not worsen to some extent or significantly, does not prolong dyskinesia onset time, does not significantly worsen even if it is primary like dyskinesia rebound symptoms, does not develop new dyskinesia symptoms, side effects of dyskinesia It means that the frequency does not increase significantly as compared to the case where the composition of the present invention is not administered.
  • Dyskinesia symptoms are, for example, ON time, OFF time described in clinical evaluation scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, PGI, etc. It can be confirmed by a scale calculated from moving motion information acquired by a wearable device such as an accelerometer and / or an angular velocity meter.
  • deterioration of the quality of response of a Parkinson's disease patient to levodopa treatment refers to any deterioration in the patient's responsiveness to levodopa treatment, such deterioration of the quality of response is diurnal variation or dyskinesia. It can be measured from symptoms and the like.
  • “improvement” of “deterioration of response quality to levodopa treatment of Parkinson's disease patients” means improvement of diurnal variation and degree of dyskinesia symptoms in levodopa treatment of each patient, UPDRS, MDS-UPDRS, UDysRS.
  • parenteral administration refers to any form of administration that is not oral administration, preferably tandospirone in an effective form and level for levodopa-induced motor complications of Parkinson's disease.
  • the means of parenteral administration include administration by transdermal absorption or transmucosal absorption, including injection or injection, and combinations thereof.
  • a percutaneous absorption preparation such as a coating agent, a patch, or a spray agent is brought into contact with the skin or mucous membrane, and the drug in the preparation is transferred into the body through the skin or mucous membrane. Is effective.
  • Administration by injection or infusion includes intravenous, intradermal, subcutaneous, intramuscular, enteral (enema) administration, and may be bolus administration and / or continuous infusion. They may use suspensions, liquids, emulsions, embeddings in oily or aqueous media containing other pharmaceuticals such as suspending agents, stabilizers and / or dispersants.
  • percutaneous endoscopic gastrostomy can be performed for continuous delivery to the proximal small intestine using a tube and a portable infusion pump.
  • parenteral administration may be performed in the form of continuous administration. Such continuous administration can be achieved with patches, injections or infusions and the like.
  • tandospirone or a pharmaceutically acceptable salt or prodrug thereof is preferably administered by a method capable of maintaining the blood drug concentration for a long period of time, and is administered by a method capable of suppressing the production of metabolites. Is even more preferable.
  • the administration method include percutaneous administration and subcutaneous, intradermal and intramuscular injection administration. In the case of subcutaneous, intradermal and intramuscular injection administration, it is preferable to use an administration method in which the blood concentration is sustained. Of these, transdermal administration is most preferable because it does not require hospital visits and is less invasive.
  • treatment of motor complications associated with the treatment of levodopa in Parkinson's disease by parenteral administration of tandospirone or a pharmaceutically acceptable salt or prodrug thereof or a drug or composition containing the same.
  • Improvement or prevention does not adversely affect the levodopa action time (ON time), does not adversely affect Parkinson's disease (which can be evaluated by UPDRS, etc.), does not diminish the effect of the present disclosure even after repeated administration, and exercise complications.
  • Treatment with active ingredients other than the present disclosure and treatment methods other than the present disclosure from the viewpoint that the number of administrations of the levodopa preparation per day can be reduced by increasing the amount of the levodopa preparation to the maximum applicable amount without aggravating the disease.
  • the composition which is preferable.
  • Methods etc. are provided.
  • Chronotypes of Parkinson's disease have become a problem, and such chronotypes are not intended to be limited, but may occur with drug therapy for Parkinson's disease such as levodopa treatment.
  • the inventors have unexpectedly found that tandospirone or a pharmaceutically acceptable salt or prodrug thereof can suppress or eliminate the chronotypes of Parkinson's disease. ..
  • the present disclosure also treats motor fluxuations such as wearing-off, on-off, no-on, delayed on, etc. , And found that it is possible to treat, improve or prevent Parkinson's disease dyskinesia such as levodopa-induced dyskinesia (PD-LID). Since PD-LID, which is a typical example of dyskinesia, is induced by overdose of levodopa, it is considered effective to suppress the dopamine concentration in the brain, but on the other hand, by extending the on-time or shortening the off-time, etc. In order to suppress chronotype, it is considered effective to increase the dopamine concentration in the brain.
  • Parkinson's disease dyskinesia such as levodopa-induced dyskinesia (PD-LID). Since PD-LID, which is a typical example of dyskinesia, is induced by overdose of levodopa, it is considered effective to suppress the dopamine concentration in the brain, but on the other hand,
  • composition of the present disclosure treats, improves or prevents dyskinesias of Parkinson's disease such as levodopa-induced dyskinesias (PD-LID), and treats, improves or prevents diurnal fluctuations (motor fluxuations) at the same time. What can be done is something that could not be predicted from conventional findings.
  • Parkinson's disease such as levodopa-induced dyskinesias (PD-LID)
  • PD-LID levodopa-induced dyskinesias
  • the "transdermal pharmaceutical product” refers to a coating agent, a patch, or a spray agent (aerosol agent).
  • the patch include a tape (patch), a pap, a plaster, and the like, and examples of the coating include an ointment, a cream, a lotion, a liniment, a liquid, and a gel. It is preferably a patch. More preferably, it is a tape agent (patch agent).
  • tape agent is synonymous with “patch agent”, and thus may be referred to as “tape / patch” in the present specification.
  • the transdermal preparation is manufactured by a known method using a pharmaceutically acceptable additive.
  • the transdermal pharmaceutical product used in the present disclosure has a pressure-sensitive adhesive layer provided on a support, and the pressure-sensitive adhesive layer can be produced by including a thermoplastic elastomer or the like. ..
  • Thermoplastic elastomer is an elastomer that softens when heat is applied and exhibits fluidity, and returns to a rubber-like elastic body when cooled, and is various types such as urethane-based, acrylic-based, styrene-based, and olefin-based. Thermoplastic elastomers can be mentioned.
  • the pressure-sensitive adhesive layer may contain a non-volatile hydrocarbon oil.
  • the non-volatile hydrocarbon oil is preferably a chain-type saturated hydrocarbon having about 20 to 40 carbon atoms or a chain-type unsaturated hydrocarbon having about 20 to 40 carbon atoms, and examples thereof include liquid paraffin, squalene, squalene, and pristane. Can be mentioned. Of these, liquid paraffin is more preferable from the viewpoint of availability.
  • the liquid paraffin is a colorless, odorless, liquid mixture of alkanes having 20 or more carbon atoms, and in the present disclosure, those conforming to the standards specified in the Japanese Pharmacopoeia, the United States Pharmacopeia, etc. can be preferably used.
  • the non-volatile hydrocarbon oil preferably has a high viscosity, and it is particularly preferable to use liquid paraffin having a high viscosity from the viewpoint of adhesiveness.
  • the pressure-sensitive adhesive layer may contain a pressure-sensitive adhesive, if necessary.
  • the tackifier is a resin that is generally used in the field of adhesives to impart skin tackiness, and is, for example, a rosin-based resin, a polyterpene resin, a kumaron-inden resin, a petroleum-based resin, a terpene-phenol resin, and the like. Examples thereof include alicyclic saturated hydrocarbon resins, and one or more of them can be selected and used.
  • transdermal administration When transdermal administration is assumed, it can also be realized by applying an ointment to the skin.
  • Dosage forms for parenteral administration include powders, sprays, ointments, pastes, Can include creams, lotions, gels, and solutions.
  • Ointments, pastes, creams, and gels include animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, in addition to tandospirone or pharmaceutically acceptable salts or prodrugs thereof of the present disclosure. , Silicone, bentonite, silicic acid, starch, and additives such as zinc oxide, or mixtures thereof.
  • the powder and spray can contain additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances, in addition to the pharmaceutical compositions of the present disclosure.
  • the spray can contain common high pressure gases such as chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.
  • a composition suitable for parenteral administration may be a sterile isotonic or non-aqueous solution, a dispersion, a suspension, an emulsion, an implant, or a sterile injectable solution immediately before use, which is acceptable as at least one pharmaceutical product.
  • the dispersion can contain sterile powders that can be reconstituted.
  • compositions disclosed herein can be suppositories for rectal or vaginal administration and include one or more compounds according to the present disclosure, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate. It can be prepared by mixing with more than a variety of suitable non-irritating additives or carriers and is solid at room temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity to release the compounds of the present disclosure.
  • Pharmaceutical compositions suitable for vaginal administration may also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the prior art.
  • the "drug dose” is the amount of drug contained in the composition.
  • the label (package insert) states the content of the active ingredient.
  • the “drug transfer amount” is the amount of drug taken into the body.
  • the “drug transfer amount” is the amount of the drug transferred from the transdermal preparation to the skin, and is a value calculated by the following formula.
  • the amount of drug transfer is related to drug efficacy. According to the results of the clinical product, the transfer amount is often 40-50% when the dose is 100%, but the transfer amount is not limited to 40-50%.
  • the “residual drug amount” is the amount of the drug remaining in the transdermal pharmaceutical product peeled off after application, and can be quantified by the method described in Example (Reference Production Example) ([0127]).
  • Drug transfer amount (mg / day) drug dose (mg / day) -drug residual amount (mg / day)
  • drug dose and the drug transfer amount are substantially the same amount. It is interpreted. Therefore, for example, in an oral preparation, "taken into the body” means that it is provided in the gastrointestinal tract.
  • the drug dose and the drug transfer amount are different in the transdermal old laminated lumber, for example, in the case of a tape agent, it can be specified by measuring the residual amount in the tape after peeling.
  • the drug dose, drug transfer amount, drug residual amount and blood (plasma) tandospirone concentration are amounts converted into tandospirone-free form unless otherwise specified.
  • the drug dose and drug transfer amount of tandospirone or a salt thereof can be appropriately adjusted according to the type of compound, the patient's symptoms, age, body weight, renal liver function, and the like.
  • the daily drug dose is 0.1 to 500 mg, 0.1 to 400 mg, 0.1 to 250 mg, 0.1 to 220 mg, 0.1 to 180 mg, 0.1 to 100 mg, preferably 0. .2 to 50 mg, 1 to 50 mg, 4 to 180 mg, 1 to 250 mg, 3 to 250 mg, etc., and the upper limit thereof are 1000 mg, 800 mg, 500 mg, 400 mg, 250 mg, 220 mg, 180 mg, 150 mg, 100 mg, etc.
  • the daily drug transfer amount can be 0.1 to 100 mg, 0.1 to 80 mg, 0.1 to 60 mg, 0.1 to 20 mg, preferably 0.2 to 10 mg, 1 to 60 mg.
  • the upper limit may be 100 mg, 80 mg, 60 mg, 40 mg, 30 mg, 20 mg, 10 mg, 8 mg, 7 mg, 5 mg, 3 mg, etc.
  • the lower limit may be 0.1 mg, 0.2 mg, 1 mg, 1.5 mg.
  • the administration frequency can be appropriately adjusted depending on the characteristics of the composition.
  • the composition is a transdermal pharmaceutical product, for example, once every 12 hours to once every 7 days, any frequency between these is possible, for example, once a day, every two days. It is possible to use once, once every three days, once every four days, and the like. It is preferably once a day.
  • the composition is an injectable formulation, for example, once a day to once every three months, any frequency between them is possible, for example, once a week, once every two weeks. It is possible to use once, once every four weeks, once every three months, and so on.
  • a pump-type automatic injection device can be used for continuous administration for 24 hours, administration only during awakening, or adjustment of the administration time according to symptoms.
  • this drug can be mixed with a preparation containing levodopa and administered continuously.
  • tandospirone or a pharmaceutically acceptable salt or prodrug thereof has a tandospirone concentration in human blood (plasma) of 0.05 to 20 ng / g / 20 ng / as a free form during the period in which levodopa is desired to act. It is preferably administered in mL. Specifically, it is 12 hours or more, preferably 16 hours or more per day.
  • the concentration of tandospirone in human blood (in plasma) is 0.05 to 20 ng / mL, 0.1 to 10 ng / mL, 0.5 to 15 ng / mL, 0.5 to 12 ng / mL, 0. 1 to 15 ng / mL, 1 to 15 ng / mL, 1 to 12 ng / mL, 2 to 10 ng / mL, etc. can be mentioned, and the upper limit thereof is 20 ng / mL, 15 ng / mL, 12 ng / mL, 10 ng / mL.
  • the above human blood (plasma) tandospirone concentration may be achieved with a single dose or as a maintenance concentration with repeated doses.
  • the maximum value (Cmax) of human blood (plasma) tandospirone concentration is 0.1 to 20 ng / mL, 0.2 to 15 ng / mL, 0.3 to 12 ng / mL in terms of free form. , 0.3 to 10 ng / mL, 1 to 15 ng / mL, 1 to 12 ng / mL, 1 to 10 ng / mL, 2 to 10 ng / mL, etc., and the upper limit thereof is 20 ng / mL, 15 ng / mL.
  • mL 12 ng / mL, 10 ng / mL, 8 ng / mL, 5 ng / mL, 4 ng / mL, 3 ng / mL, 2 ng / mL, 1 ng / mL, etc.
  • the lower limit is 0.1 ng / mL.
  • 0.2 ng / mL, 0.5 ng / mL, 1 ng / mL, 2 ng / mL and the like can be mentioned.
  • Preferred ranges may include any combination of both the upper and lower limits.
  • the area under the human blood (plasma) tandospirone concentration-time curve is 3 to 700 ng ⁇ h / mL, 3 to 500 ng ⁇ h / mL, 3 to 300 ng ⁇ h as a free form equivalent amount.
  • / ML, 3-250 ng ⁇ h / mL, 3-200 ng ⁇ h / mL, etc. can be mentioned, and the upper limit thereof is 700 ng ⁇ h / mL, 600 ng ⁇ h / mL, 500 ng ⁇ h / mL, 400 ng ⁇ .
  • h / mL 300 ng ⁇ h / mL, 200 ng ⁇ h / mL, 150 ng ⁇ h / mL, 50 ng ⁇ h / mL, 100 ng ⁇ h / mL, 80 ng ⁇ h / mL, 50 ng ⁇ h / mL, 40 ng ⁇ h / mL and the like can be mentioned, and as the lower limit, 3 ng ⁇ h / mL, 5 ng ⁇ h / mL, 10 ng ⁇ h / mL, 20 ng ⁇ h / mL, 30 ng ⁇ h / mL and the like can be mentioned.
  • the area under the tandospirone concentration-time curve can be calculated by an analysis method of pharmacokinetics. For example, the value from 0 to 48 hours, 0 to 72 hours, from 0 hour to the final measurement point, or the value extrapolated to infinite time is calculated.
  • a composition containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof is used for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof.
  • concentration of tandospirone in human blood (in plasma) is 0.05 to 20 ng / mL, 0, preferably between 8 and 20 hours, or 12 hours or more per day, preferably 16 hours or more, more preferably 18 hours or more.
  • composition is characterized in that it is administered so as to have the concentration described as the above-mentioned human blood (plasma) tandospirone concentration.
  • the above-mentioned human blood (plasma) tandospirone concentration may be achieved by a single administration or as a maintenance concentration (which can also be called a steady state) by repeated administration.
  • Steady-state blood levels may be calculated by a single-dose superposition method.
  • the time after administration means the time after the last administration.
  • tandospirone or a pharmaceutically acceptable salt thereof is the maximum blood concentration of tandospirone in human blood (in plasma) in a steady state after administration of the tandospirone or a pharmaceutically acceptable salt thereof. It is 1 to 15 ng / mL, and is administered so that the ratio of the minimum concentration when the maximum concentration of human blood (plasma) tandospirone is 100% is 30 to 95%, preferably 35 to 85%. ..
  • the applicable area of the pharmaceutical product can usually be appropriately adjusted, but preferably per dose.
  • the total sticking area is 1 to 200 cm 2 , 1 to 100 cm 2 , 2 to 80 cm 2 , and 9 to 60 cm 2 .
  • the upper limit thereof include 200 cm 2 , 160 cm 2 , 130 cm 2 , 100 cm 2 , 80 cm 2 , 60 cm 2 , 50 cm 2 , 40 cm 2 , 30 cm 2 , 20 cm 2 , and the like.
  • the lower limit 1 cm 2 , 2 cm 2 , 4 cm 2 , 9 cm 2 , etc. can be mentioned.
  • any combination of both the upper limit and the lower limit thereof, a preferable therapeutic effect can be obtained.
  • the tandospirone of the present disclosure or a pharmaceutically acceptable salt or prodrug thereof is contained in human blood (plasma) within 12 hours, 8 hours, preferably 6 hours, more preferably 4 hours after a single dose.
  • human blood (plasma) tandospirone concentration is in the upper and lower limits for up to 16 hours, preferably up to 18 hours, more preferably up to 20 hours, up to 24 hours after a single dose. Be maintained.
  • the tandospirone of the present disclosure or a pharmaceutically acceptable salt or prodrug thereof is preferably a pharmacokinetic profile that slowly reaches the maximum blood concentration (Cmax) and slowly disappears as compared with oral administration. ..
  • the time (mean value) to reach the maximum blood concentration (Cmax) is, for example, between 16 hours and 36 hours after a single administration, and between 20 hours and 32 hours.
  • the lower limit (mean value) of the time to reach the maximum blood concentration (Cmax) is 16 hours, 20 hours, and 24 hours, and the upper limit (mean value) is 36 hours and 32 hours.
  • the half-life (mean value) is, for example, between 3 and 20 hours.
  • the lower limit (average value) of the half-life is 3 hours, 4 hours, 5 hours, 6 hours and the like, and the upper limit (average value) is 20 hours, 18 hours, 16 hours, 14 hours and the like.
  • Striatal [ 11 C] raclopride receptor binding changes in Parkinson's disease have been reported to be associated with pathological progression, chronotype, and dyskinesia in Parkinson's disease (Reference: Brain. (2004) 127: 2747-2754). .).
  • the results of evaluating the amount of dopamine in the striatum based on the PET test conditions of the above-mentioned references can be considered as follows.
  • the pharmaceutical composition of the present invention can be expected to reduce the amount of change B / 1h, especially for Parkinson's disease patients whose change amount B / 1h is significantly larger than that of Parkinson's disease patients without diurnal variation or dyskinesia. It reduces the amount of change B / 1h and can be expected to have a therapeutic effect on motor complications such as dyskinesia. Treatment with the pharmaceutical composition of the present invention can be expected to reduce, for example, the amount of change B / 1h to less than 10%.
  • the pharmaceutical composition of the present invention can be expected to reduce the amount of change B / 1h, and in particular, Parkinson with diurnal variation and dyskinesia in which the amount of change B / 1h is significantly larger than that of a Parkinson's disease patient without diurnal variation and dyskinesia.
  • the amount of change is reduced by 1h / 4h, and a therapeutic effect on motor complications such as diurnal variation can be expected.
  • Treatment with the pharmaceutical composition of the present invention can be expected to reduce, for example, the amount of change 1h / 4h to less than 5%.
  • the amount of change in [ 11 C] raclopride receptor binding in the striatum before and 1 hour after administration of levodopa before treatment with the composition of the present invention may be abbreviated as the amount of change B / 1h before treatment.
  • the amount of change in striatal [ 11 C] raclopride receptor binding (change after treatment B /) before and 1 hour after administration of levodopa after intervention with the pharmaceutical composition of the present invention Decreasing the rate of (sometimes omitted as 1h) (sometimes omitted as change rate B / 1h) means that there is a therapeutic effect on motor complications such as dyskinesia.
  • the pharmaceutical composition of the present invention can be expected to reduce the rate of change B / 1h, and when the PET test is performed under the conditions reported in the literature, for example, the rate of change B / 1h is 90% or less, preferably 80% or less. , More preferably, it can be reduced to 70% or less.
  • the pharmaceutical composition of the present invention can be expected to reduce the rate of change of 1h / 4h, and when the PET test is performed under the conditions reported in the literature, for example, the rate of change of 1h / 4h is 90% or less, preferably 80% or less. , More preferably, it can be reduced to 70% or less.
  • the measurement point before the administration of levodopa is measured at a time when a sufficient time has passed after the administration of levodopa and the effect of levodopa is not recognized.
  • the measurement point 1 hour after administration can be measured at a fixed time 1 to 2 hours after administration of levodopa.
  • the measurement point 4 hours after administration can be measured at a fixed time between 4 to 8 hours after administration of levodopa.
  • [ 11 C] raclopride receptor binding rate of striatum B / 1h (%) change after treatment with the composition of
  • the tandospirone transdermal preparation can be used for the treatment of Parkinson's disease in combination with a therapeutic agent for Parkinson's disease such as a levodopa-containing preparation.
  • a therapeutic agent for Parkinson's disease such as a levodopa-containing preparation.
  • a more preferable effect can be expected by administering the levodopa-containing preparation 6 hours or more, preferably 8 hours or more, and more preferably 12 hours or more after the tandospirone transdermal absorption preparation is applied.
  • a stable therapeutic effect can be obtained regardless of the administration timing of the levodopa-containing preparation.
  • the transdermal preparation of the present disclosure can be produced by a generally known method.
  • the tape agent of the present disclosure can be produced, for example, according to Production Example 1 below.
  • the tape agent (patch agent) of the present disclosure can be produced by a usual method.
  • it can be manufactured in accordance with the section relating to the manufacture of plaster agents described in "Manufacturing Manual for Transdermal Application Formula” supervised by Mitsuo Matsumoto (1985). Further, for example, it can be manufactured by the device, method or the like described in "Development of patch manufacturing apparatus for transdermal treatment system (membrane, 32 (2), 116-119 (2007))".
  • a normal method for producing an adhesive tape can be applied to form an adhesive layer.
  • a typical example thereof is the solvent coating method, but other than this, a hot melt coating method, an electron beam curing emulsion coating method, or the like can be used.
  • a mixture of tandospirone, a mixture containing a pressure-sensitive adhesive, and a formulation component such as a permeation accelerator and a curing agent are mixed with an organic solvent to form a pressure-sensitive adhesive layer mixture.
  • the mixed solution is applied to one side of the support or the release liner, dried to remove the organic solvent, and the release liner or the support is bonded at any timing before or after drying. Can be done.
  • the thickness of the pressure-sensitive adhesive layer of the tape agent is not particularly limited, and is about 10 ⁇ m to about 600 ⁇ m. It is preferably about 10 ⁇ m to about 400 ⁇ m, more preferably about 20 ⁇ m to about 200 ⁇ m, still more preferably about 50 ⁇ m to about 180 ⁇ m, and particularly preferably about 70 ⁇ m to about 150 ⁇ m.
  • the ointment can be produced by a generally known method.
  • oily bases such as oils and fats, waxes and hydrocarbons such as paraffin are usually heated and melted, the active ingredient is added, and the mixture is mixed to dissolve or disperse.
  • a water-soluble ointment can usually be produced by heating and melting a water-soluble base such as macrogol, adding the active ingredient, mixing and kneading until the whole is homogeneous. ..
  • tandospirone contains higher alcohols such as cetanol and stearyl alcohol, higher fatty acids such as myristic acid, lauric acid, palmitic acid, stearic acid, and linoleic acid or esters thereof, waxes such as purified lanolin and whale wax, and sorbitan fatty acid esters. It can be produced by blending a surfactant such as sucrose fatty acid ester, hydrophilic vaseline, liquid paraffin, and hydrocarbons such as plastibase.
  • a surfactant such as sucrose fatty acid ester, hydrophilic vaseline, liquid paraffin, and hydrocarbons such as plastibase.
  • the formulation of this ointment is, for example, tandospirone 0.5 to 10% by weight, higher alcohol 0.1 to 5%, higher fatty acid or ester thereof 1 to 15% by weight, surfactant 1 to 10% by weight, waxes. It is 4 to 10% by weight and 50 to 80% by weight of hydrocarbon.
  • tandospirone and the above-mentioned additive component are added, mixed under heating, kept at 50 to 100 ° C., all the components become a transparent solution, and then uniformly mixed with a homomixer. Then, the ointment can be obtained by stirring while cooling and allowing to cool.
  • Injections for subcutaneous, intradermal and intramuscular administration can be produced by commonly known methods. Usually, it can be manufactured by the following method.
  • a container for injection which is obtained by dissolving, suspending or emulsifying the active ingredient as it is or the active ingredient with an additive added to water for injection, another aqueous solvent or a non-aqueous solvent, and the like. Fill, seal and sterilize.
  • the active ingredient as it is, or the active ingredient with an additive added is dissolved in water for injection, another aqueous solvent or a non-aqueous solvent, suspended or emulsified, and homogenized by sterile filtration. Aseptically prepared and homogenized, the mixture is filled in a container for injection and sealed.
  • the above-mentioned injection may be produced as a lyophilized injection or a powder injection in order to prevent the active ingredient from being decomposed or inactivated in the solution.
  • Freeze-dried injections are usually lyophilized as is, or by dissolving the active ingredient and additives such as excipients in water for injection, filtering sterile, filling in a container for injection and then lyophilizing. It can be manufactured by freeze-drying in a special container and then filling it directly in a container.
  • Powder injections can usually be produced by treating with aseptic filtration, then adding sterilized additives to the powder obtained by crystallization or the powder thereof, and filling it in a container for injections.
  • tandospirone is dissolved in water, an organic solvent, or a mixed solvent of an organic solvent and water together with a surfactant to prepare an active ingredient solution.
  • the obtained solution can be sterilized by filtration through a sterilization filter to prepare a sterile active ingredient solution.
  • a sterilization filter As the solvent used for dissolution (water, an organic solvent, or a mixed solvent of an organic solvent and water), an organic solvent or a mixed solvent of an organic solvent and water is preferable, and a mixed solvent of an organic solvent and water is more preferable.
  • the sterilization filter is effective for removing foreign substances derived from raw materials or foreign foreign substances mixed in during the manufacturing process, in addition to filtration sterilization.
  • the surfactant examples include polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyxyethylene castor oil, benzalkonium chloride, sodium lauryl sulfate and the like. Two or more of these may be used. Preferably, it is polysorbate 80. It is preferable to use about 0.005% (w / v) to about 10% (w / v) of the surfactant.
  • purified water water of the same grade as purified water or higher, or water for injection is used.
  • organic solvent examples include alcohol solvents (eg, methanol, ethanol, etc.), aprotic solvents (eg, acetone, dimethyl sulfoxide, N, N-dimethylacetamide, etc.), and even if two or more kinds of solvents are used. good. Preferred are 1-propanol, methanol, ethanol, 2-propanol, acetone, dimethyl sulfoxide, or N, N-dimethylacetamide.
  • alcohol solvents eg, methanol, ethanol, etc.
  • aprotic solvents eg, acetone, dimethyl sulfoxide, N, N-dimethylacetamide, etc.
  • the injection of the present disclosure can be injected intramuscularly or subcutaneously after attaching an injection needle to a prefilled syringe filled with the preparation.
  • the pharmaceutical product can be sucked into an injection syringe from a container such as a vial filled with the pharmaceutical product through an injection needle, and then discharged intramuscularly or subcutaneously for injection administration.
  • the pharmaceutical product should be a freeze-dried product obtained by lyophilizing after filling the product in a container such as a vial, and a dry powder crystal obtained by drying after isolating the active ingredient crystal in the product.
  • the suspension prepared by suspending it in a container with a suspension solution at the time of use is aspirated from the container into an injection syringe via an injection needle and then injected intramuscularly or subcutaneously.
  • the injectable agent of the present disclosure is a mechanism for discharging a drug solution filled in a container using a needleless syringe (pressure generated by a gas, a detonator, a spring, etc. incorporated in a syringe device, etc.) in a container filled with the pharmaceutical product. It can also be injected intramuscularly or subcutaneously after being placed in a form that can be administered without using an injection needle.
  • the injections of the present disclosure can be continuously administered using a commercially available continuous subcutaneous infusion pump.
  • the continuous subcutaneous injection pump is a device having a drug storage unit and a pump for continuously injecting a drug, and continuously injecting the drug subcutaneously of a patient through an injection tube.
  • This device usually contains a clock and a program that can change the injection amount at regular intervals.
  • the drug storage unit is a closed container provided with a drug solution inlet / outlet for connecting to a pump and filled with a drug solution adjusted to the drug concentration required for the drug effect.
  • a pump is a pump capable of continuously injecting this chemical solution with a small amount of precision, and is a device capable of injecting a small amount of liquid in an amount of about 0.1 mL / day to 10 mL / hour.
  • the drug storage is filled with and stored aseptically guaranteed tandospirone solution.
  • a continuous injection is an injection that is applied subcutaneously, intradermally, intramuscularly, etc. for the purpose of releasing the active ingredient for a long period of time.
  • Persistent injections can be produced by commonly known methods. It can usually be produced by dissolving or suspending the active ingredient in vegetable oil or the like, or by making a suspension of microspheres using a biodegradable polymer compound.
  • the implant is a solid or gel-like injection that is applied subcutaneously, intramuscularly, or by surgery for the purpose of releasing the active ingredient for a long period of time.
  • the implant can be produced by a commonly known method. It can usually be obtained by using a biodegradable polymer compound as a pellet, microsphere or gel-like preparation.
  • the transdermal preparation of the present disclosure can be used in combination with existing Parkinson's disease therapeutic agents other than levodopa.
  • existing Parkinson's disease therapeutic agents include, for example, dopamine agonists (eg, bromocryptin, pergolide, talipexol, cabergolin, pramipexol, ropinilol, rotigotine, etc.), monoamine oxidase B (MAOB) inhibitors (eg, eg).
  • dopamine agonists eg, bromocryptin, pergolide, talipexol, cabergolin, pramipexol, ropinilol, rotigotine, etc.
  • MAOB monoamine oxidase B
  • Selegiline Selegiline, rasagiline, safinamide), catechol-O-methyltransferase (COMT) inhibitors (eg, entacapone), amantadine, apomorphine, istradefylline, anticholinergic drugs (eg, viperidene, trihexy) Phenidil, profenamine, mazaticol), thiaprid, droxydopa, carvidopa, zonisamide and the like, but are not limited thereto.
  • catechol-O-methyltransferase (COMT) inhibitors eg, entacapone
  • amantadine eg, apomorphine
  • istradefylline eg, anticholinergic drugs (eg, viperidene, trihexy) Phenidil, profenamine, mazaticol), thiaprid, droxydopa, carvidopa, zonisamide and the like,
  • reagents described in the examples were used, but equivalent products from other manufacturers (Sigma-Aldrich, Wako Pure Chemical Industries, Nacalai Tesque, R & D Systems, USCN Life Science INC, etc.) can be used instead. ..
  • Tandospirone ((1R, 2S, 3R, 4S) -N- [4- [4- (pyrimidine-2-yl) piperazine-1-yl] butyl] -2,3-bicyclo [ 2.2.1] Heptane dicarboxyimide) has the following chemical formula, and its production method and the like are described in JP-A No. 58-126865, and this description is referred to in the present specification. It is used as.
  • Acrylic adhesive (MAS683, manufactured by Cosmed Pharmaceutical Co., Ltd., solid content 35.6% by weight, 18.6962 g), ethyl acetate (5.5 mL), and polyoxyethylene lauryl ether (0.3520 g) are mixed sufficiently.
  • ethyl acetate 5.5 mL
  • polyoxyethylene lauryl ether 0.3520 g
  • polyethylene terephthalate and / or ethylene vinyl acetate copolymer laminated film (Scotchpac # 9732) manufactured by 3M Healthcare Ltd. was used.
  • peeling liner Bina Sheet 64S-018B manufactured by Fujimori Kogyo Co., Ltd. was used.
  • Measurement of residual drug amount in tape Although examples of measurement conditions for residual drug amount are described below, it is possible to substitute for other verified measurement methods. ⁇ Example of measurement conditions> Preparation of standard solution Prepare a tandospirone solution (approximately 4,20,100 ⁇ g / mL). Preparation of pharmaceutical solution (1) Put the tape in a container, add 10 mL of acetone, and irradiate with ultrasonic waves for about 30 minutes. (2) Add 1 mL of methanol to 1 mL of the extract of (1) and mix. (3) Filter with a filter (Millipore Co., Ltd .: Millex-FH (0.45 um, PTFE)).
  • HPLC High Performance Liquid Chromatogram
  • Column YMC-Pack ODS-AM 250 x 4.6 mm (particle diameter 5 ⁇ m) Column oven: 40 ° C.
  • Detector Ultraviolet absorptiometer (measurement wavelength: 240 nm) Flow rate: 0.9 mL / min Injection volume: 10 ⁇ L
  • Mobile phase 10 mM phosphate buffer (pH 6.8) / acetonitrile mixture (35:65)
  • Test method 1.1 Pretreatment operation method 50 ⁇ L of rat plasma sample is dispensed into a polypropylene microtube, 50 ⁇ L of methanol (50 ⁇ L of standard solution for calibration line sample), 200 ⁇ L of internal standard solution (Bezafibrate methanol solution: 200 nmol / L, 200 ⁇ L of methanol for blank sample). ) Is added, and the mixture is stirred with a mixer for about 10 seconds. After centrifuging this (4 ° C., 4500 rpm, 10 min), the supernatant is suction-filtered with a filtration filter (FastRemover MF 0.2 ⁇ m).
  • Example 1 Evaluation of the effect of prolonging the ON time of levodopa of tandospirone in a Parkinson's disease model animal
  • the anti-Parkinson's disease action time or "ON time" of tandospirone levodopa was evaluated using various routes of administration.
  • rat striatal dopamine nerve destruction by topical administration of 6-hydroxydopamine (hereinafter referred to as "6-OHDA") to one side of the brain.
  • 6-OHDA 6-hydroxydopamine
  • Models are known (6-OHDA one-sided treated rats (6-OHDA injured rats)).
  • Parkinson's disease therapeutic agents that activate the dopaminergic system in the brain such as levodopa and dopamine receptor agonists, show a rotational behavior to the opposite side to the site where 6-OHDA was injected.
  • the usefulness of a drug for treating Parkinson's disease can be evaluated using the rotation behavior as an index.
  • the coordinates were confirmed, and the coordinates of the right medial forebrain bundle (AP: -4.4 mm, ML: 1.5 mm, DV: 7.8 mm from bregma) were measured.
  • 6-OHDA (9 ⁇ g / 4 ⁇ L; Sigma-Aldrich) having a dopamine neurodegenerative effect was locally injected.
  • apomorphine hydrochloride 0.5 hydrate (0.5 mg / kg; Wako Pure Chemical Industries, Ltd.) was subcutaneously administered, and the rotational movement to the opposite side of the injection site of 6-OHDA was observed. Rats with 7 or more revolutions per minute were used as 6-OHDA one-sided treated rats.
  • Tandospiron citrate (suspended in 0.5% methylcellulose solution) or solvent (0.5% methylcellulose solution) was orally administered to 6-OHDA one-sided treated rats 5 minutes before observation of rotational behavior, in terms of free body concentration.
  • Levodopa methyl ester hydrochloride (5 mg / kg in levodopa-free form) containing 1/4 of the amount of levodopa was intraperitoneally administered.
  • Benserazide is a drug known to suppress peripheral metabolism of levodopa, increase blood levodopa concentration, and enhance levodopa intracerebral transfer.
  • tandospirone showed the same ON time prolonging effect by different administration methods of oral administration and transdermal administration.
  • Example 2 Evaluation of ON time prolonging effect in PD-LID model animals
  • the anti-Parkinson's disease action time that is, the ON time of tandospirone levodopa was evaluated in PD-LID model animals.
  • the behavioral observation evaluation was performed from 20 minutes after the intraperitoneal administration of the levodopa compound solution to 1 minute every 20 minutes in a transparent acrylic cage until 3 hours after the administration.
  • Behavioral observations include Limb AIMs (involuntary bending and stretching of the forelimbs on the opposite side of the disorder, opening and closing of the palm, up and down wrists, chorea-like shaking, dystonia-like rigidity), and Axial AIMs (upper body and neck on the opposite side of the disorder).
  • AIMs total dyskinesia-like symptom
  • the total of Limb AIMs, Axial AIMs, and Orlingual AIMs at the time of each evaluation was used as the AIMs score.
  • the rotation behavior (ON score) was based on the Locomotive behavior at each evaluation time, and the total ON score was the total ON score for 3 hours.
  • ON time with out dyskinesia ON time without dyskinesia
  • the time when the AIMs score at each evaluation time was 0 and the Locomotive behavior was 1 or more was totaled.
  • the duration of action of dyskinesia without dyskinesia is the total time of the "ON time", which is the anti-Parkinson's disease action time, during which dyskinesia does not occur, and administration of dyskinesia. It was defined as the time when the dyskinesia symptom (AIMs) score was 0 and the Locomotive behavior score was 1 or more at each of the subsequent evaluation points.
  • AIMs dyskinesia symptom
  • Tandospirone citrate (citrate concentration: 30, 100 mg / kg) was suspended in a 0.5% methylcellulose solution and orally administered to rats, and 5 minutes later, a levodopa combination solution was intraperitoneally administered for behavioral observation and evaluation. Carried out. The results in the figure are shown by mean ⁇ standard error. Statistical analysis of test results was performed by comparing with the solvent-administered group by Steel test using the total ON score for 3 hours or ON time without dyskinesia as an index. ** indicates p ⁇ 0.01, which means that there is a significant difference.
  • test results were compared with the placebo tape-administered group by the Wilcoxon rank sum test using the total ON score for 3 hours or the ON time with out dyskinesia as an index. * Indicates p ⁇ 0.05 and ** indicates p ⁇ 0.05, which means that there is a significant difference from the oral solvent administration group or the placebo tape administration group.
  • tandospirone showed an ON time-prolonging effect in PD-LID model rats, and in particular, in the case of transdermal administration of tandospirone, the ON time without dyskinesia (ON time without dyskinesia) increased, but oral administration was performed. In this case, an extension of the ON time without dyskinesia was observed only at the dose (100 mg / kg) where side effects were a concern. It suggests that oral treatment is not preferable. Rather, it is unexpected that transdermal administration was able to exert a therapeutic effect comparable to oral administration.
  • Example 3 Evaluation of striatal dopamine-releasing action in PD-LID model animals
  • Test method To measure striatal dopamine release, guide cannula implantation into the striatum of PD-LID model rats and by the method described in reference (Pharmacol Res Perspect. 2015 Jun; 3 (3): e00142.) Chromatography was performed. On the day of the test, a dialysis probe was inserted into the striatum along the guide cannula. The tape was applied to the abdomen of the rat so as to be 60 cm 2 / kg (containing 6.5% W / V tandospirone-free body).
  • the levodopa compound solution was intraperitoneally administered, and the dialysate was collected in a sample vial every 10 minutes.
  • the amount of dopamine in the recovered dialysate was measured using an HPLC-ECD system (Acom Co., Ltd.). The results in the figure are shown as mean ⁇ standard error. Individuals whose tapes were peeled off by 50% or more during the test were excluded from the analysis.
  • Statistical analysis of test results was performed by comparing with the placebo tape-administered group by t-test. * Indicates p ⁇ 0.05, which means that there is a significant difference from the placebo tape-administered group.
  • the amount of change in dopamine (pg) was measured at each sampling point (every 10 minutes), calculated as the amount of change from the baseline (mean value of 4 samples before administration of levodopa formulation), and after administration of levodopa formulation. It was measured up to 420 minutes.
  • the tandospirone tape reduced the amount of dopamine released in the striatum between 30 and 150 minutes after administration of levodopa, and increased the amount of dopamine released after 150 minutes. (Fig. 6A).
  • the tandospirone tape agent showed a sustained release action of striatal dopamine in PD-LID. That is, it was found that PD-LID has an effect of suppressing excessive secretion of dopamine immediately after administration of levodopa and slowly releasing dopamine to keep the amount of dopamine in the synaptic cleft of the striatum constant for a long period of time. ..
  • the motor complications associated with the treatment of levodopa in Parkinson's disease are thought to be influenced by the rapid increase or decrease in the amount of levodopa in the striatal synaptic cleft.
  • the drug By suppressing the increase or decrease, the diurnal variation associated with the treatment of levodopa in Parkinson's disease and the effect of improving PD-LID are expected, and it has been found that the drug has an ideal pharmacological action capable of comprehensively treating exercise complications.
  • Example 4 Evaluation of plasma concentration transition when tandospirone tape is applied to normal rats
  • Test method Wistar male rats (14 weeks old, Japan SLC) were used. The abdomen of the rat was shaved before the evaluation day of the tape preparation, and the tape preparation of the pharmaceutical product 1 was attached to the abdomen on the evaluation day (size 9 cm 2 ). Blood was collected over time 2, 4, 6 and 24 hours after patch administration, and plasma tandospirone concentration analysis was performed. The results are shown as mean ⁇ standard deviation.
  • Example 5 Evaluation of motor complications of tandospirone tape
  • Transdermal administration (Condition 1)
  • the abdomen of the rat was shaved before the evaluation day.
  • the tape of the pharmaceutical product 2 was applied to the abdomen of the rat so as to be 60 cm 2 / kg (37 mg / kg), and 4 hours after the application, the levodopa compound solution was intraperitoneally administered to perform behavioral observation evaluation. Individuals whose tapes were peeled off by 50% or more during the test were excluded from the analysis. Plasma was collected after the behavioral observation and evaluation, and the concentration of tandospirone in the plasma was analyzed.
  • the total of Limb AIMs, Axial AIMs, and Orlingual AIMs at the time of each evaluation was used as the AIMs score.
  • Statistical analysis of the test results was performed by the Wilcoxon rank sum test using the total dyskinesia-like symptom (AIMs) score, which is the sum of the AIMs scores for 3 hours, and the total dyskinesia-like symptom score, which is 100 to 180 minutes, as indicators. ** indicates p ⁇ 0.01, which means that there is a significant difference compared to the placebo tape application group. The results in the figure are shown by mean ⁇ standard error.
  • tandospirone tape (formulation 3: drug dose 45 mg / kg) is applied by transdermal administration (condition 2) under keratin stripping conditions and highly exposed tandospirone is percutaneously absorbed, the total AIMs score is It was 5.8. The total AIMs score decreased by 27.1 as compared with the placebo tape containing no tandospirone, and a significant improvement in dyskinesia-like symptoms was observed. Under administration condition 2, a higher improvement effect was observed than with administration condition 1 (FIG. 9-A).
  • the transdermal tandospirone preparation improved the diurnal fluctuation symptoms without causing rebound symptoms of dyskinesia.
  • Example 6 Evaluation of motor complications of continuous subcutaneous administration of tandospirone
  • Test method Similar to Example 2, 6-OHDA injured rats were repeatedly administered with the levodopa combination solution for 3 weeks or longer, and behavioral observation evaluation was performed. Behavioral observation evaluation was performed before the drug evaluation day, and allocation was performed to each administration group using the 3-hour dyskinesia-like symptom (AIMs) score, Locomotive behavior score, and rat weight as indicators, and used for drug evaluation. However, individuals with a total AIMs score of less than 10 were excluded from the study because they did not develop dyskinesia-like symptoms. In addition, in order to suppress variability in dosage among individuals, individuals who deviated from the average body weight by 10% or more were also excluded from the study.
  • AIMs 3-hour dyskinesia-like symptom
  • Tandospirone (free form) was dissolved in 1M hydrochloric acid (Nacalai Tesque) and diluted with physiological saline to prepare 0.05, 0.25, 1.25 mg / kg / hour.
  • the prepared solution was injected into ALZET (registered trademark) Osmotic Pump MODEL2ML1 (9.68 ⁇ L / hour; DUREC) and used.
  • Fig. 10 The results in Fig. 10 are shown by mean ⁇ standard error. Statistical analysis of test results was performed by comparing with the solvent-administered group by Steel test using the total dyskinesia-like symptom (AIMs) score for 3 hours and the total dyskinesia-like symptom score for 100-180 minutes as indicators. * Indicates p ⁇ 0.05, which means that there is a significant difference.
  • Example 7 Evaluation of long-term motor complications of continuous subcutaneous administration of tandospirone
  • the long-lasting efficacy of tandospirone for dyskinesia-like symptoms was evaluated by continuous subcutaneous administration of tandospirone to PD-LID model rats for 2 weeks.
  • Example 5 6-OHDA injured rats were repeatedly administered with the levodopa combination solution for 3 weeks or longer, and behavioral observation evaluation was performed. Individuals with a total AIMs score of less than 15 were excluded from the study as having no dyskinesia-like symptoms. Behavioral observation evaluation was performed before the drug evaluation day, and allocation was performed to each administration group using the 3-hour dyskinesia-like symptom (AIMs) score, Locomotive behavior score, and rat weight as indicators, and used for drug evaluation.
  • AIMs 3-hour dyskinesia-like symptom
  • Tandospirone citrate was dissolved in 1M hydrochloric acid (Nakalitesk) and diluted with physiological saline to prepare a concentration of 60 mg / mL (citrate concentration).
  • the prepared solution was injected into ALZET (registered trademark) Osmotic Pump MODEL2ML2 (4.53 ⁇ L / hour; DUREC), which releases the drug solution at a stable rate for 2 weeks, and used.
  • ALZET registered trademark Osmotic Pump MODEL2ML2 (4.53 ⁇ L / hour; DUREC
  • results in FIG. 11 are shown as mean ⁇ standard error of total dyskinesia-like symptom (AIMs) scores for 3 hours. Using the total AIMs score as an index, statistical analysis of the test results was performed by the Whitney rank sum test. Compared with the solvent-administered group, ** indicates p ⁇ 0.01, which means that there is a significant difference.
  • AIMs total dyskinesia-like symptom
  • Tandospirone citrate was dissolved in 1M hydrochloric acid (Nakalitesk) and diluted with physiological saline to prepare a concentration of 60 mg / mL or 30 mg / mL. The prepared solution was injected into ALZET® Osmotic Pump MODEL2ML2 (4.53 ⁇ L / hour; DUREC) and used.
  • results in FIG. 12 are shown as the mean ⁇ standard error of the total dyskinesia-like symptom (AIMs) score for 3 hours.
  • Statistical analysis of test results was performed by comparing with the solvent-administered group by Steel test using the total AIMs score on the 16th day of repeated administration of levodopa as an index. Compared with the solvent-administered group, * indicates p ⁇ 0.05 and ** indicates p ⁇ 0.01, which means that there is a significant difference.
  • dyskinesia-like symptoms subsided in the solvent-administered group, but clear dyskinesia-like symptoms (mean AIMs score) in the oral tandospirone citrate group (30, 100 mg / kg). 2 or more) was recognized. Furthermore, when the solvent-administered group and the tandospirone citrate oral-administered group were compared using the total dyskinesia-like symptom score of 100-180 minutes as an index, the tandospirone citrate oral-administered group (30,) was compared with the solvent-administered group.
  • Total dyskinesia-like symptom (AIMs) score for 3 hours (total dyskinesia-like symptom (AIMs) score in the placebotape or solvent-administered group)-(total dyskinesia-like symptom (AIMs) score in the tandospirone-administered group)
  • 100-180 minutes total dyskinesia-like symptom score (100-180 minutes total dyskinesia-like symptom score in the placebotape or solvent-administered group)-(100-180 minutes total dyskinesia-like symptom in the tandospirone-administered group) Score)
  • Rotational action time without dyskinesia Rotational action time without dyskinesia-like symptoms
  • Test method Behavioral observation evaluation was performed using the same method as in Example 2.
  • 1-PP dihydrochloride (Tokyo Chemical Industry) was dissolved in physiological saline and subcutaneously administered to rats, and 5 minutes later, levodopa compound solution was intraperitoneally administered and behavioral observation evaluation was performed. The results in the figure are shown as mean ⁇ standard error.
  • Statistical analysis of test results was performed by comparing with the solvent-administered group by Steel test using the total dyskinesia-like symptom (AIMs) score for 3 hours and the total dyskinesia-like symptom score for 100-180 minutes as indicators.
  • AIMs total dyskinesia-like symptom
  • dyskinesia rebound symptoms may occur under the administration conditions in which the tandospirone metabolite 1-PP is produced. That is, the administration method of tandospirone capable of suppressing the production of 1-PP is preferable because it has less influence on the rebound symptom of dyskinesia.
  • Example 9 Clinical trial of pharmacokinetics of tandospirone tape
  • pharmacokinetics such as blood concentration of tandospirone was tested and analyzed in clinical trials.
  • plasma tandospirone concentration was measured and predictive analysis was performed based on the following method.
  • Tandospirone tape (free body content: 4.4 mg, 8.8 mg and 17.6 mg) was administered transdermally to the chest in a single transdermal administration for 24 hours to 9 healthy Japanese adult males, and plasma was administered. Medium tandospirone concentration was measured.
  • Second, the plasma tandospirone concentration was predicted based on the result of 17.6 mg.
  • Phoenix® WinNonlin® (Certara) was used to predict plasma tandospirone concentrations in steady state.
  • the tandospirone tape agent has a sheet-like structure consisting of a support, an adhesive layer, and a release film (liner), and contains an acrylic adhesive tape agent containing tandospirone (free body) as an active ingredient.
  • the drug transfer amount at the time of application for 24 hours was about 1/3 to 1/2 of the tandospirone-free body content (drug dose) in the tape preparation.
  • drug dose drug dose
  • any tape preparation can be used in plasma at the same level as in this example. It is understood that tandospirone levels are achieved.
  • FIG. 17 shows the transition of plasma tandospirone concentration ((mean value)) when the tandospirone tape used in this example was transdermally administered once for 24 hours; the plasma tandospirone concentration is the concentration as a tandospirone-free form. There is.) Is shown.
  • FIG. 17A the plasma tandospirone concentrations of 4.4 mg, 8.8 mg and 17.6 mg are actually measured values based on the preliminary analysis results.
  • B of FIG. 17 the value predicted and analyzed from the measured value of 17.6 mg is shown.
  • FIG. 18 shows the predicted value of the change in plasma tandospirone concentration when the tandospirone patch of this example is repeatedly transdermally administered once a day.
  • the results shown in A of FIG. 18 show predicted values based on the plasma tandospirone concentrations of 4.4 mg, 8.8 mg, and 17.6 mg after a single 24-hour administration.
  • the results shown in B of FIG. 18 show predicted values based on the plasma tandospirone concentration after a single administration of 17.6 mg for 24 hours.
  • FIG. 19 shows the predicted value of the plasma tandospirone concentration transition in the steady state when the tandospirone tape agent of this example is repeatedly transdermally administered once a day.
  • a in FIG. 19 is a prediction based on the plasma tandospirone concentration after a single 24-hour administration of 4.4 mg, 8.8 mg, and 17.6 mg.
  • B in FIG. 19 is a prediction based on the plasma tandospirone concentration at the time of a single administration of 17.6 mg for 24 hours.
  • chronotype can be suppressed by using a daily dose (drug dose per day) of 4 mg to 180 mg of the active ingredient.
  • Example 10 Verification in MPTP-induced PD-LID model rhesus monkey
  • tandospirone is passed through a PD-LID model rhesus monkey induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) used to generate an animal model for Parkinson's disease.
  • MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • MPTP-induced Parkinson's disease levodopa-induced dyskinesia (PD-LID) model rhesus monkeys were generated as follows. Using male rhesus monkeys (Hamley Co., Ltd.), MPTP 0.4 or 0.6 mg / kg was administered once or twice a week and continued until Parkinson's disease symptoms were stably developed. Then, levodopa (20 or 30 mg / kg) was administered once or twice a week and continued until dyskinesia was stably expressed to prepare a PD-LID model rhesus monkey.
  • Levodopa / Benserazide 22 mg / kg for levodopa, 1/4 weight of levodopa for Benserazide was orally administered to PD-LID model rhesus monkeys, and dyskinesia symptoms were evaluated every 30 minutes from 5 minutes to 150 minutes after administration. ..
  • Model monkeys were transdermally administered a tandospirone-containing ointment or a tandospirone-free placebo ointment. The back of the rhesus monkey was shaved, an ointment was applied to an area of 4 cm x 10 cm 19 hours before the test, covered with tape and a clean cloth, and then the jacket was worn.
  • dyskinesia (dyskinesia score) was performed by analyzing a video of a model monkey and scoring it by an evaluator who is skilled in behavioral evaluation.
  • the dyskinesia score was evaluated based on the Revised non-human primate dyskinesia ratting scale (J Neuroscience 2001; 21: 6853-6861.). If no dyskinesia is found, the score is 0, and if less than 30% of the evaluation time is observed, the score is considered to be mild dyskinesia, and the score is 1, and it is normal even if 30% or more of the evaluation time is seen.
  • the behavior is not inhibited, it is regarded as moderate dyskinesia and the score is 2, and if less than 70% of the evaluation time and 30% or more of the dyskinesia is observed and the normal behavior is inhibited, it is marked as remarkable dyskinesia.
  • the deemed score was set to 3, and if dyskinesia was observed in 70% or more of the evaluation time and normal behavior was impaired, the deemed score was set to 4 as severe dyskinesia.
  • systemic dyskinesia was evaluated as a particularly severe dyskinesia.
  • dyskinesia occurs in 4 or more of the 6 locations of the face, right arm, left arm, trunk, right leg, and left leg.
  • the case was defined as systemic dyskinesia, and the score was 1 if systemic dyskinesia occurred in 30% or more of the evaluation time, and 2 if systemic dyskinesia occurred in 70% or more of the evaluation time.
  • PD-LID model benserazide was orally administered with levodopa / Benserazide (22 mg / kg for levodopa, 1/4 weight of levodopa for Benserazide), and dyskinesia symptoms every 30 minutes from 5 minutes after administration of levodopa / Benserazide to 155 minutes. (Dyskinesia score) was evaluated.
  • the placebo ointment showed a dyskinesia score of 4 between 65 and 155 minutes after the administration of levodopa / Benserazide, but the ointment containing tandospirone showed a sustained suppression of the dyskinesia score.
  • Fig. 20A The total dyskinesia score for 155 minutes after administration of levodopa / Benserazide was suppressed by 76.5%.
  • Fig. 20B The total dyskinesia score for 155 minutes after administration of levodopa / Benserazide was suppressed by 76.5%.
  • Example 11 Demonstration in clinical protocol
  • the compound of the present invention or the concomitant drug of the present disclosure was subjected to PD- by a clinical trial according to the method described in Reference 1 (Amantadine P3) below.
  • the improvement effect can be confirmed for LID (Reference 1: JAMA Neurology 2017; 74 (8) 941-949; Reference 2: Movement Disorderers 2015; 30 (19) 1343-1350).
  • the tandospirone of the present invention or a tandospirone of the present invention may be administered.
  • the pharmaceutically acceptable salt or prodrug, or the concomitant drug of the present disclosure is administered, and UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39 before and after the administration period. , CGI, PGI, etc., and ON time, OFF time, accelerometer and / or scale calculated from mobile motion information acquired by wearable devices such as angular velocimeter, etc. described in the patient's diary. Therefore, the improvement effect can be confirmed for exercise complications such as PD-LID and diurnal variation.
  • conditions such as target patient, administration period, drug dose, evaluation method, etc. can be changed as appropriate.
  • the tandospirone preparation of the present disclosure is useful as a therapeutic agent for improving motor complications such as chronotype in Parkinson's disease.

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CN202180053119.3A CN116113402A (zh) 2020-08-31 2021-08-30 帕金森病的运动并发症治疗药
EP21861757.9A EP4218764A4 (en) 2020-08-31 2021-08-30 THERAPEUTIC AGENT FOR MOTOR COMPLICATIONS OF PARKINSON'S DISEASE
MX2023002422A MX2023002422A (es) 2020-08-31 2021-08-30 Farmaco terapeutico para complicaciones motoras en enfermedad de parkinson.
CA3189670A CA3189670A1 (en) 2020-08-31 2021-08-30 Therapeutic drug for motor complications in parkinson's disease
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