Treatment for motor complications of Parkinson's disease

Abstract

The present disclosure provides a therapeutic agent useful for the treatment of motor fluctuations (e.g., wearing-off) in Parkinson's disease. In particular, the present disclosure provides: a composition characterized by containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof for treating, ameliorating, inhibiting the progression of, or preventing motor complications, particularly, motor fluctuations, of Parkinson's disease; and a method characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is parenterally administered.

Description

[Technical Field]

[0001] This disclosure relates to a formulation containing tandospirone, which is useful as a pharmaceutical, and a pharmaceutically acceptable salt or prodrug thereof, as an active ingredient, for the treatment or prevention of motor complications of Parkinson's disease, such as diurnal motor fluctuations, by parenteral administration (e.g., transdermal administration), or to a treatment thereof. [Background technology]

[0002] Parkinson's disease is a progressive neurodegenerative disease characterized primarily by abnormalities in extrapyramidal function. Pathologically, it involves the loss of dopamine neurons and deposition of alpha-synuclein in the substantia nigra pars compacta. Clinically, it presents with various motor symptoms, including akinesia, resting tremor, rigidity, and loss of postural reflexes.

[0003] The basis of Parkinson's disease treatment is drug therapy aimed at replacing dopamine in the brain, and drugs containing levodopa (L-dopa, levodopa), a dopamine precursor, are used as the first-line treatment for early-stage Parkinson's disease. However, as the disease progresses, motor complications such as diurnal fluctuations in Parkinson's symptoms (motor fluctuations), levodopa-induced dyskinesia in Parkinson's disease (hereinafter sometimes referred to as "PD-LID" (Parkinson's disease levodopa-induced dyskinesia)), and dystonia appear in almost all patients receiving levodopa treatment.

[0004] As typical symptoms of diurnal fluctuation, wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon and the like are known. Among these, wearing-off is, as described above, a symptom that occurs when the dopamine retaining capacity in the synaptic cleft decreases with the progression of the pathological condition, the intracerebral dopamine concentration fluctuates according to the blood concentration of levodopa, and as a result, the duration of effect of levodopa whose blood concentration falls below the safe therapeutic range is shortened.

[0005] PD-LID has an onset frequency of 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, which is an involuntary movement that appears in the face, tongue, neck, limbs, trunk and the like when the blood concentration of levodopa is high.

[0006] Patent Document 1 discloses a transdermal absorption preparation of tandospirone. [Background Art] [Patent Documents]

[0007] [Patent Document 1] Japanese Unexamined Patent Publication No. 11-228414 [Summary of the Invention] [Means for Solving the Problem]

[0008] As a result of diligent research, the inventors have discovered that tandospirone or a pharmaceutically acceptable salt thereof possesses both the effect of suppressing the rapid increase in dopamine levels in the synaptic cleft of the striatum and the effect of delaying the decrease over time in various situations, such as when levodopa is administered to patients with Parkinson's disease. They have found that this provides a desirable technique for the treatment, improvement, progression inhibition (delay or suppression), and prevention of motor complications such as those seen in levodopa treatment for Parkinson's disease. Furthermore, they have found that parenteral administration of tandospirone (e.g., transdermal, intradermal, subcutaneous, intramuscular administration, etc.) provides a useful technique for the treatment, improvement, progression inhibition, and prevention of motor complications such as those seen in Parkinson's disease, with a higher improvement effect compared to oral administration. These motor complications that can be improved include motor fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena, as well as dyskinesia in Parkinson's disease, such as levodopa-induced dyskinesia (PD-LID). While this disclosure primarily focuses on explanations related to levodopa treatment, it is understood that this disclosure also applies to other causes. In the treatment of Parkinson's disease and other conditions, controlling non-motor symptoms is also important. Compared to other therapeutic agents for the motor symptoms of Parkinson's disease (e.g., amantadine extended-release formulations), the composition of this disclosure has the advantage of not adversely affecting non-motor symptoms when treating motor complications such as dyskinesia. In some patients, improvement in non-motor symptoms can be expected in addition to improvement in motor complications such as dyskinesia and diurnal variation. The non-motor symptoms mentioned above include psychiatric symptoms, sleep disorders, sensory disturbances, pain, olfactory disorders, and autonomic nervous system symptoms. Psychiatric symptoms include depression, anxiety, apathy, agitation, irritability, hallucinations, delusions, and cognitive impairment. Sleep disorders include daytime hypersomnia, insomnia, restless legs syndrome, and REM sleep behavior disorder. Autonomic nervous system symptoms include constipation, urinary dysfunction, and orthostatic hypotension. The composition disclosed herein is expected to not worsen depression, anxiety, irritability, restless legs syndrome, REM sleep behavior disorder, or hallucinations, in particular, compared to other therapeutic agents for the motor symptoms of Parkinson's disease (e.g., amantadine extended-release formulations, etc.), and is expected to have an effect in improving depression, anxiety, irritability, restless legs syndrome, or REM sleep behavior disorder.

[0009] In other words, this disclosure includes the following: [Item H1] A composition for the treatment, improvement or prevention of motor complications, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H1B] A composition for the treatment, improvement or prevention of dyskinesia, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H1C] A composition for the treatment, improvement or prevention of dyskinesia in a subject, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy for Parkinson's disease. [Item H1D] A composition for the treatment, improvement or prevention of dyskinesia in a subject, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy. [Item H1E-1] A composition for reducing OFF time in a subject who is a Parkinson's disease patient, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy. [Item H1E] A composition for reducing OFF time in a subject who is a Parkinson's disease patient, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy. [Item H1F] A composition for reducing OFF time and increasing ON time in a subject who is a Parkinson's disease patient, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy. [Item H1G] A composition for reducing the time of inactivity (off time) and increasing the ON time without troublesome dyskinesia in a patient with Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy. [Item H1H] A composition for reducing the off-time and increasing the on-time of an antiparkinsonian disease effect without troublesome dyskinesia in a patient with Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy. [Item H2] A composition for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H3] A composition for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy for Parkinson's disease. [Item H4] A composition for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally, and the subject is receiving pharmacotherapy selected from the group consisting of levodopa-containing preparations, levodopa metabolic enzyme inhibitors, dopamine receptor agonists, and other pharmacotherapy for Parkinson's disease, and adjuncts for Parkinson's disease. [Item H5] A composition for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving dopamine replacement therapy for Parkinson's disease. [Item H6] A composition for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy for Parkinson's disease. [Item H7] A composition for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that an effective amount of the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally to a subject, thereby maintaining a sustained level of dopamine in the synaptic cleft of the striatum, suppressing rapid fluctuations in dopamine levels, and / or suppressing intermittent dopamine receptor stimulation. [Clause H8] The composition according to any one of the preceding clauses, characterized in that it is administered to the subject in a manner that does not cause rebound symptoms. [Clause H9] The motor complication is the composition according to any one of the preceding clauses, wherein the motor complication includes motor fluctuations. [Item H10] The parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof, and is the composition according to any one of the preceding items. [Item H11] The composition according to any one of the preceding items, characterized in that the parenteral administration is sustained or administered continuously. [Item H12] The parenteral administration includes transdermal administration, the composition according to any one of the preceding items. [Item H13] The composition according to any one of the preceding items, characterized in that the treatment, improvement, or prevention improves motor complications in Parkinson's disease without worsening dyskinesia symptoms. [Item H14] The composition according to any one of the preceding items, characterized in that the treatment, improvement, or prevention improves motor complications without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Item H15] The composition according to any one of the preceding items, characterized in that the treatment, improvement or prevention improves motor fluctuations without worsening dyskinesia symptoms in Parkinson's disease. [Item H16] The composition according to any one of the preceding items, characterized in that the treatment, improvement, or prevention improves motor fluctuations without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Item H17] The composition according to any one of the preceding items, characterized in that the treatment, improvement or prevention improves motor complications or motor fluctuations in Parkinson's disease without worsening dyskinesia symptoms. [Item H18] The composition according to any one of the preceding items, characterized in that the treatment, improvement, or prevention improves motor complications or motor fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). [Item H19] The composition according to any one of the preceding items, wherein the motor fluctuations include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof. [Item H20] The composition according to any one of the preceding items, wherein the treatment, improvement, or prevention of the motor fluctuations includes extending the on-time of the antiparkinson's disease effect, shortening the off-time, or a combination thereof. [Item H21] The composition according to any one of the preceding items, wherein the motor complications further include dyskinesia symptoms in Parkinson's disease. [Item H22] The composition according to any one of the preceding items, further comprising levodopa-induced dyskinesia (PD-LID) as the exercise complication. [Item H23] A composition according to any one of the preceding items, wherein the dyskinesiological symptoms in Parkinson's disease include peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item H24] Levodopa-induced dyskinesia (PD-LID) is a composition according to any one of the preceding items, comprising peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item H25] The composition according to any one of the preceding items, characterized in that the treatment, improvement, or prevention improves motor fluctuations without being accompanied by dyskinesia symptoms. [Item H26] The composition according to any one of the preceding items, characterized in that the treatment, improvement or prevention improves motor fluctuations without causing painful dyskinesia symptoms. [Item H27] A composition for achieving improvement or prevention of dyskinesia symptoms in patients with Parkinson's disease, reduction of the duration of dyskinesia in patients with Parkinson's disease, or a combination thereof, wherein the composition does not exacerbate diurnal variation, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H28] The composition according to any one of the preceding items, for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of levodopa-induced dyskinesia (PD-LID) onset time, or a combination thereof. [Item H29] A composition containing tandospirone or a pharmaceutically acceptable salt thereof for achieving improvement or prevention of dyskinesia symptoms in patients with Parkinson's disease, reduction of the duration of dyskinesia onset in patients with Parkinson's disease, or a combination thereof, characterized in that the composition does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or does not extend the time of no response (off time) beyond a clinically significant time, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H30] The composition is for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, characterized in that the composition does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or does not extend the time of no response (off time) beyond a clinically significant time, as described in any one of the preceding items. [Item H31] The composition according to any one of the preceding items, wherein the reduction in the time of inaction (off-time) is greater than or equal to a clinically significant time. [Clause H32] The composition according to any one of the preceding clauses, wherein the reduction in the time of inaction (off-time) is sufficient to obtain a clinical effect. [Item H33] A composition containing tandospirone or a pharmaceutically acceptable salt thereof for achieving an extension of the on-time, a reduction in the off-time, improvement or prevention of dyskinesia symptoms, a reduction in the onset time of dyskinesia, or a combination thereof in Parkinson's disease, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H34] A composition containing tandospirone or a pharmaceutically acceptable salt thereof for achieving an extension of the on-time, a reduction in the off-time, improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, a reduction in the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H35] The composition according to any one of the preceding items, wherein the improvement in the motor fluctuations is clinically significant or greater. [Item H36] The composition according to any one of the preceding items, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item H37] A composition according to any one of the preceding items, which is a transdermal absorption preparation. [Item H38] A composition according to any one of the preceding items, provided as a transdermal patch. [Item H39] The composition according to any one of the preceding items, wherein the transdermal absorption preparation is a tape / patch. [Item H40] The composition according to any one of the preceding items, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg per day as the free form of tandospirone. [Item H41] The composition according to any one of the preceding items, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 3 to 250 mg per day as the free form of tandospirone. [Item H42] The composition according to any one of the preceding items, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 100 mg per day as the free form of tandospirone. [Item H43] The composition according to any one of the preceding items, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 1 to 60 mg per day as the free form of tandospirone. [Item H44] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The composition described in any one of the preceding items. [Item H45] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 9 to 60 cm². 2 The composition described in any one of the preceding items. [Item H46] The composition according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for 12 hours or more per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Item H47] The composition according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for 12 hours or more per day so that the human blood (plasma) tandospirone concentration is 0.5 to 15 ng / mL. [Item H48] The composition according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 12 to 30 hours after a single dose of the tandospirone or a pharmaceutically acceptable salt thereof. [Item H49] The composition according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause H50] The composition according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.1 to 15 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Item H51] The composition according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 10 to 100% of the maximum blood concentration after administration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Item H52] The composition according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the human blood (plasma) tandospirone concentration to the maximum blood concentration after administration (with the minimum concentration being 100%) is 10 to 95%, wherein the maximum blood concentration after administration is 1 to 15 ng / mL. [Item H53] The composition according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, for a period of 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the human blood (plasma) tandospirone concentration to the minimum concentration, with the maximum blood concentration after administration being 100%, is 10 to 95%. [Item H54] The composition according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the maximum blood concentration of human blood (plasma) tandospirone at steady state is 1 to 15 ng / mL, and the ratio of the minimum concentration to the maximum human blood (plasma) tandospirone concentration is 30 to 95%. [Item H55] The tandospirone or a pharmaceutically acceptable salt thereof is used to measure the striatum before levodopa administration and 1 hour after administration of the tandospirone or a pharmaceutically acceptable salt thereof. 11 The composition according to any one of the preceding items, characterized in that it is administered such that the change in raclopride receptor binding (change B / 1h) is less than 10%. [Item H56] A composition according to any one of the preceding items, provided as an adjunct to levodopa. [Item H57] A composition according to any one of the preceding items, used in combination with levodopa, either in the same formulation or in separate formulations. [Item H58] A pharmaceutical product for treating or preventing Parkinson's disease with or without motor complications, wherein the pharmaceutical product comprises a combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H59] The exercise complication is a pharmacopoeia as described in any one of the preceding items, including diurnal fluctuations. [Item H60] The pharmacopoeia according to any one of the preceding items, wherein the motor complication further includes dyskinesia. [Item H61] The pharmacopoeia according to any one of the preceding items, wherein the exercise complication further includes drug-induced dyskinesia. [Item H62] The exercise complication further includes levodopa-induced dyskinesia (PD-LID), as described in any one of the preceding items. [Item H63] The medicament described in any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item H64] A pharmaceutical product for treating or preventing Parkinson's disease with or without motor complications, wherein the pharmaceutical product comprises (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa, wherein the (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item H65] The exercise complication is the pharmacopoeia described in any one of the preceding items, including dyskinesia. [Item H66] The exercise complication is a drug-induced dyskinesia, as described in any one of the preceding items. [Item H67] The exercise complication is the pharmacopoeia described in any one of the preceding items, including levodopa-induced dyskinesia (PD-LID). [Item H68] The medicament described in any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item H69] A composition for improving the deterioration of the quality of response to levodopa treatment in patients with Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause H70] The composition according to any one of the preceding clauses, wherein the improvement includes improvement of motor fluctuations. [Item H71] The composition according to any one of the preceding items, wherein the improvement includes an improvement in dyskinesia. [Item H72] The composition according to any one of the preceding items, wherein the improvement includes improvement of drug-induced dyskinesia. [Item H73] The composition according to any one of the preceding items, wherein the improvement includes improvement of levodopa-induced dyskinesia (PD-LID). [Item J1] Use for the manufacture of a medicament for the treatment, improvement or prevention of motor complications, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item J1B] Use for the manufacture of a medicament for the treatment, improvement or prevention of dyskinesia, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item J1C] Use for the manufacture of a medicament for the treatment, improvement or prevention of dyskinesia in a subject, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving pharmacotherapy for Parkinson's disease. [Item J1D] Use for the manufacture of a medicament for the treatment, improvement or prevention of dyskinesia in a subject, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy. [Item J1E-1] Use for the manufacture of a pharmacopoeia for reducing OFF time in a subject who is a patient with Parkinson's disease, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving pharmacotherapy. [Item J1E] Use for the manufacture of a pharmacopoeia for reducing OFF time in a subject who is a patient with Parkinson's disease, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving pharmacotherapy. [Item J1F] Use for the manufacture of a pharmacopoeia containing tandospirone or a pharmaceutically acceptable salt thereof for reducing OFF time and increasing ON time in a subject who is a patient with Parkinson's disease, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving pharmacotherapy. [Item J1G] Use for the manufacture of a medicament comprising tandospirone or a pharmaceutically acceptable salt thereof for reducing the time of inactivity (off time) and increasing the ON time without troublesome dyskinesia in patients with Parkinson's disease, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving pharmacotherapy. [Item J1H] Use for the manufacture of a medicament comprising tandospirone or a pharmaceutically acceptable salt thereof for reducing the off-time and increasing the on-time of troublesome dyskinesia-free antiparkinsonian action in a patient with Parkinson's disease, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy. [Item J2] Use for the manufacture of a medicament for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item J3] A use for the manufacture of a medicament for the treatment, improvement or prevention of motor complications of Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally, and the subject is receiving pharmacotherapy for Parkinson's disease. [Item J4] Use for the manufacture of a medicament for the treatment, improvement or prevention of motor complications of Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally, and the subject is receiving pharmacotherapy selected from the group consisting of levodopa-containing preparations, levodopa metabolic enzyme inhibitors, dopamine receptor agonists, and other pharmacotherapy for Parkinson's disease, and adjuncts for Parkinson's disease. [Item J5] Use for the manufacture of a medicament for the treatment, improvement or prevention of motor complications of Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving dopamine replacement therapy for Parkinson's disease. [Item J6] A use for the manufacture of a medicament for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy for Parkinson's disease. [Item J7] Use for the manufacture of a medicament for the treatment, improvement or prevention of motor complications of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, wherein an effective amount of the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally to sustainably maintain the amount of dopamine in the synaptic cleft of the striatum, suppress rapid fluctuations in dopamine levels and / or suppress intermittent dopamine receptor stimulation in a subject. [Clause J8] The use described in any one of the preceding clauses, characterized in that the subject is administered in a manner that does not cause rebound symptoms. [Section J9] The motor complications include motor fluctuations, as described in any one of the preceding sections. [Clause J10] The parenteral administration is the use described in any one of the preceding clauses, selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, and combinations thereof. [Clause J11] The use described in any one of the preceding clauses, characterized in that the parenteral administration is sustained or administered continuously. [Section J12] The parenteral administration is the use described in any one of the preceding sections, including transdermal administration. [Clause J13] The use described in any one of the preceding clauses, characterized in that the treatment, improvement, or prevention improves motor complications without worsening dyskinesia symptoms in Parkinson's disease. [Clause J14] The use described in any one of the preceding clauses, characterized in that the treatment, improvement, or prevention improves motor complications without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Clause J15] The use described in any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without worsening dyskinesia symptoms in Parkinson's disease. [Clause J16] The use described in any one of the preceding clauses, characterized in that the treatment, improvement, or prevention improves motor fluctuations without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Clause J17] The use described in any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor complications or motor fluctuations without worsening dyskinesia symptoms in Parkinson's disease. [Clause J18] The use described in any one of the preceding clauses, characterized in that the treatment, improvement, or prevention improves motor complications or motor fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). [Section J19] The motor fluctuations described above include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, as described in any of the preceding sections. [Section J20] Treatment, improvement, or prevention of the motor fluctuations is the use described in any one of the preceding paragraphs, including prolongation of the on-time of the antiparkinsonian effect, reduction of the off-time, or a combination thereof. [Section J21] The use described in any one of the preceding paragraphs, wherein the motor complications further include dyskinesia symptoms in Parkinson's disease. [Section J22] The use described in any one of the preceding sections, wherein the exercise complication further includes levodopa-induced dyskinesia (PD-LID). [Section J23] Dyskinesia in Parkinson's disease includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof, as described in any one of the preceding sections. [Section J24] Levodopa-induced dyskinesia (PD-LID) is the use described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause J25] The use described in any one of the preceding clauses, characterized in that the treatment, improvement, or prevention improves motor fluctuations without being accompanied by dyskinesia symptoms. [Clause J26] The use described in any one of the preceding clauses, characterized in that the treatment, improvement, or prevention improves motor fluctuations without distressing dyskinesia symptoms. [Item J27] Use for the manufacture of a medicament containing tandospirone or a pharmaceutically acceptable salt thereof to improve or prevent dyskinesia symptoms in patients with Parkinson's disease, shorten the duration of dyskinesia in patients with Parkinson's disease, or a combination thereof, characterized in that the use does not exacerbate diurnal variation, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section J28] The use described above is the use described in any one of the preceding sections for the purpose of improving or preventing symptoms of levodopa-induced dyskinesia (PD-LID), shortening the duration of levodopa-induced dyskinesia (PD-LID), or a combination thereof. [Item J29] Use for the manufacture of a medicament containing tandospirone or a pharmaceutically acceptable salt thereof to achieve improvement or prevention of dyskinesia symptoms in patients with Parkinson's disease, reduction of the duration of dyskinesia onset in patients with Parkinson's disease, or a combination thereof, characterized in that the use does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or does not extend the time of no response (off time) beyond a clinically significant time, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section J30] The use described above is for the purpose of improving or preventing levodopa-induced dyskinesia (PD-LID) symptoms, shortening the duration of levodopa-induced dyskinesia (PD-LID) onset, or a combination thereof, characterized in that the use does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or extend the time of no response (off time) beyond a clinically significant time, as described in any one of the preceding paragraphs. [Item J31] Use as described in any one of the preceding items, wherein the reduction in the time of no response (off-time) is greater than or equal to a clinically significant time. [Section J32] The reduction in the time of no response (off-time) is sufficient to produce a clinical effect, as described in any one of the preceding sections. [Item J33] Use for the manufacture of a medicament containing tandospirone or a pharmaceutically acceptable salt thereof to achieve an extension of the on-time, a reduction in the off-time, improvement or prevention of dyskinesia symptoms, a reduction in the onset time of dyskinesia, or a combination thereof, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item J34] Use for the manufacture of a medicament containing tandospirone or a pharmaceutically acceptable salt thereof to achieve an extension of the on-time, a reduction in the off-time, improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, a reduction in the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item J35] Use as described in any one of the preceding items, provided that the improvement in the motor fluctuations is clinically significant or greater. [Section J36] Use as described in any one of the preceding sections, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item J37] Use as described in any one of the preceding items, for a transdermal absorption preparation. [Section J38] The use described in any one of the preceding sections, provided as a transdermal patch. [Item J39] The use described in any one of the preceding items, wherein the transdermal preparation is a tape / patch. [Section J40] The use described in any one of the preceding sections, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg per day as the free form of tandospirone. [Section J41] The use described in any one of the preceding paragraphs, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 3 to 250 mg per day as the free form of tandospirone. [Section J42] The use described in any one of the preceding sections, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 100 mg per day as the free form of tandospirone. [Section J43] The use described in any one of the preceding sections, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 1 to 60 mg per day as the free form of tandospirone. [Item J44] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The use described in any one of the preceding clauses. [Item J45] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, with a total application area of ​​9 to 60 cm² per application. 2 The use described in any one of the preceding clauses. [Clause J46] The use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses, characterized in that it is administered for at least 12 hours per day to achieve a human blood (plasma) tandospirone concentration of 0.05 to 20 ng / mL. [Clause J47] The use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses, characterized in that it is administered for at least 12 hours per day to achieve a human blood (plasma) tandospirone concentration of 0.5 to 15 ng / mL. [Clause J48] The use described in any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 12 to 30 hours after a single dose of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause J49] The use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses, characterized in that the tandospirone is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause J50] The use of tandospirone or a pharmaceutically acceptable salt thereof, characterized in that it is administered such that the human blood (plasma) tandospirone concentration is 0.1 to 15 ng / mL for 8 to 16 hours after administration of tandospirone or a pharmaceutically acceptable salt thereof. [Clause J51] The use according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 10-100% of the maximum blood concentration after administration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause J52] The use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses, characterized in that, for 8 to 16 hours after administration of tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the human blood (plasma) tandospirone concentration to the maximum blood concentration after administration (with the minimum concentration being 100%) is 10 to 95%, wherein the maximum blood concentration after administration is 1 to 15 ng / mL. [Item J53] The use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding items, characterized in that the human blood (plasma) tandospirone concentration is administered such that, for 8 to 16 hours after administration of tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the minimum concentration to the maximum blood concentration after administration (with the maximum blood concentration after administration being 100%) is 10 to 95%. [Item J54] The use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding items, characterized in that, after administration of tandospirone or a pharmaceutically acceptable salt thereof, the maximum blood concentration of human blood (plasma) tandospirone at steady state is 1 to 15 ng / mL, and the ratio of the minimum concentration to the maximum human blood (plasma) tandospirone concentration is 30 to 95%, with the maximum concentration being 100%. [Item J55] The tandospirone or a pharmaceutically acceptable salt thereof is used to measure the striatum before and 1 hour after administration of levodopa after administration of the tandospirone or a pharmaceutically acceptable salt thereof. 11 The use described in any one of the preceding paragraphs, characterized in that the drug is administered such that the change in raclopride receptor binding (change B / 1h) is less than 10%. [Section J56] The use described in any one of the preceding sections, provided as an adjunct to levodopa. [Item J57] The use described in any one of the preceding items, in combination with the same or different formulations of levodopa. [Item J58] Use of a combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, for the manufacture of a medicament for the treatment or prevention of Parkinson's disease with or without motor complications, wherein the use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section J59] The motor complications described above include motor fluctuations, as described in any one of the preceding sections. [Section J60] The use described in any one of the preceding paragraphs, wherein the exercise complication further includes dyskinesia. [Section J61] The use described in any one of the preceding paragraphs, wherein the exercise complication further includes drug-induced dyskinesia. [Section J62] The use described in any one of the preceding sections, wherein the exercise complication further includes levodopa-induced dyskinesia (PD-LID). [Section J63] The use of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) as described in any one of the preceding sections, administered simultaneously or at different times. [Item J64] Use for the manufacture of a medicament for treating or preventing Parkinson's disease with or without motor complications, wherein the medicament comprises (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa, wherein the (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section J65] The use described in any one of the preceding paragraphs, including the exercise complication dyskinesia. [Section J66] The exercise complication is drug-induced dyskinesia, as described in any one of the preceding sections. [Section J67] The exercise complication is the use described in any one of the preceding sections, including levodopa-induced dyskinesia (PD-LID). [Section J68] The use of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) as described in any one of the preceding sections, administered simultaneously or at different times. [Item J69] Use of 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 use is characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section J70] The improvement is the use described in any one of the preceding sections, including the improvement of motor fluctuations. [Section J71] The improvement is the use described in any one of the preceding sections, including the improvement of dyskinesia. [Section J72] The improvement is the use described in any one of the preceding sections, including the improvement of drug-induced dyskinesia. [Section J73] The improvement is the use described in any one of the preceding sections, including the improvement of levodopa-induced dyskinesia (PD-LID). [Item K1] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor complications, characterized in that the tandospirone or pharmaceutically acceptable salt thereof is administered parenterally. [Item K1B] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of dyskinesia, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Item K1C] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of dyskinesia in a subject, characterized in that the tandospirone or pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving pharmacotherapy for Parkinson's disease. [Item K1D] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of dyskinesia in a subject, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy. [Item K1E-1] Tandospirone or a pharmaceutically acceptable salt thereof for reducing OFF time in a subject who is a Parkinson's disease patient, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy. [Item K1E] Tandospirone or a pharmaceutically acceptable salt thereof for reducing OFF time in a subject who is a Parkinson's disease patient, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving pharmacotherapy. [Item K1F] Tandospirone or a pharmaceutically acceptable salt thereof for reducing OFF time and increasing ON time in a subject who is a Parkinson's disease patient, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy. [Item K1G] Tandospirone or a pharmaceutically acceptable salt thereof for reducing the time of inactivity (off time) and increasing the ON time without troublesome dyskinesia in patients with Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving pharmacotherapy. [Item K1H] Tandospirone or a pharmaceutically acceptable salt thereof for reducing the time of no response (off-time) and increasing the duration of anti-Parkinson's disease action (on-time) without troublesome dyskinesia in patients with Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy. [Item K2] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor complications of Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Item K3] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor complications of Parkinson's disease, characterized in that the tandospirone or pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving drug therapy for Parkinson's disease. [Item K4] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor complications of Parkinson's disease, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally, and the subject is receiving pharmacotherapy selected from the group consisting of levodopa-containing preparations, levodopa metabolic enzyme inhibitors, dopamine receptor agonists, and other pharmacotherapy for Parkinson's disease, and adjuncts for Parkinson's disease. [Item K5] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor complications of Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving dopamine replacement therapy for Parkinson's disease. [Item K6] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor complications of Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally and the subject is receiving levodopa therapy for Parkinson's disease. [Item K7] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor complications of Parkinson's disease, characterized in that an effective amount of the tandospirone or pharmaceutically acceptable salt thereof is administered parenterally to a subject, thereby maintaining a sustained level of dopamine in the synaptic cleft of the striatum, suppressing rapid fluctuations in dopamine levels, and / or suppressing intermittent dopamine receptor stimulation. [Clause K8] Tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses, characterized in that it is administered to the subject in a manner that does not cause rebound symptoms. [Section K9] The motor complications include motor fluctuations, and are tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K10] The parenteral administration is tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections, selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, and combinations thereof. [Clause K11] The parenteral administration is characterized by being sustained or administered continuously, as described in any one of the preceding clauses, tandospirone or a pharmaceutically acceptable salt thereof. [Section K12] The parenteral administration includes transdermal administration, tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K13] The treatment, improvement or prevention described herein is characterized by improving motor complications without worsening dyskinesia symptoms in Parkinson's disease, and is characterized by the use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K14] The treatment, improvement or prevention described herein is characterized by improving motor complications without worsening levodopa-induced dyskinesia (PD-LID) symptoms, and is characterized by the use of tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections. [Section K15] The treatment, improvement or prevention described herein is characterized by improving motor fluctuations without worsening dyskinesia symptoms in Parkinson's disease, and is characterized by the use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K16] The treatment, improvement or prevention described herein is characterized by improving motor fluctuations without worsening levodopa-induced dyskinesia (PD-LID) symptoms, and is characterized by the use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K17] The treatment, improvement or prevention described herein is characterized by improving motor complications or motor fluctuations without worsening dyskinesia symptoms in Parkinson's disease, and is tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding paragraphs. [Section K18] The treatment, improvement or prevention described herein is characterized by improving motor complications or motor fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID), and is characterized by the use of tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections. [Section K19] The motor fluctuations described herein include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, as described in any one of the preceding sections, tandospirone or a pharmaceutically acceptable salt thereof. [Section K20] Treatment, improvement, or prevention of the motor fluctuations described herein, including prolongation of the on-time, reduction of the off-time, or a combination thereof, as described in any of the preceding paragraphs, of tandospirone or a pharmaceutically acceptable salt thereof. [Section K21] The motor complications further include dyskinesia in Parkinson's disease, as described in any one of the preceding sections, tandospirone or a pharmaceutically acceptable salt thereof. [Section K22] The exercise complication further comprises levodopa-induced dyskinesia (PD-LID), tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K23] Dyskinesia in Parkinson's disease includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof, as described in any one of the preceding sections, tandospirone or a pharmaceutically acceptable salt thereof. [Section K24] Levodopa-induced dyskinesia (PD-LID) is defined as tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Section K25] The treatment, improvement or prevention described herein is characterized by improving motor fluctuations without dyskinesia symptoms, and is tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K26] The treatment, improvement or prevention described herein is characterized by improving motor fluctuations without distressing dyskinesia symptoms, and is tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections. [Item K27] Tandospirone or a pharmaceutically acceptable salt thereof for achieving improvement or prevention of dyskinesia symptoms in patients with Parkinson's disease, reduction of the duration of dyskinesia in patients with Parkinson's disease, or a combination thereof, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof does not worsen diurnal variation and the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Section K28] The tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections, for the purpose of improving or preventing symptoms of levodopa-induced dyskinesia (PD-LID), shortening the duration of levodopa-induced dyskinesia (PD-LID), or a combination thereof. [Item K29] Tandospirone or a pharmaceutically acceptable salt thereof for achieving improvement or prevention of dyskinesia symptoms in patients with Parkinson's disease, reduction of the duration of dyskinesia in patients with Parkinson's disease, or a combination thereof, wherein the tandospirone or the pharmaceutically acceptable salt thereof does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or does not extend the time of no response (off time) beyond a clinically significant time, and the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Clause K30] Tandospirone or a pharmaceutically acceptable salt thereof, for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of levodopa-induced dyskinesia (PD-LID) onset time, or a combination thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or does not extend the time of no response (off time) beyond a clinically significant time, as described in any one of the preceding clauses. [Section K31] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections, wherein the reduction in the time of no response (off-time) is greater than or equal to a clinically significant time. [Section K32] The reduction in the time of no response (off-time) is sufficient to obtain a clinical effect, as described in any one of the preceding sections, for tandospirone or a pharmaceutically acceptable salt thereof. [Item K33] Tandospirone or a pharmaceutically acceptable salt thereof for achieving prolongation of the duration of antiparkinsonian disease effect (on time), shortening of the time of no response (off time), improvement or prevention of dyskinesia symptoms, shortening of the time of dyskinesia onset, or a combination thereof, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Item K34] Tandospirone or a pharmaceutically acceptable salt thereof for achieving the extension of the duration of anti-Parkinson's disease effect (on time), the reduction of the time of no response (off time), the improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, the reduction of the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Item K35] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding items, wherein the improvement in the motor fluctuations is clinically significant or greater. [Section K36] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item K37] A transdermal formulation of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding items. [Section K38] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections, provided as a transdermal patch. [Item K39] The transdermal preparation is a tape / patch, and the tandospirone or pharmaceutically acceptable salt thereof as described in any of the preceding items. [Clause K40] The pharmacopoeia of tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg per day as the free form of tandospirone. [Section K41] The drug dose of tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding sections, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 3 to 250 mg per day as the free form of tandospirone. [Clause K42] The tandospirone or pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 100 mg per day as the free form of tandospirone. [Item K43] The tandospirone or pharmaceutically acceptable salt thereof according to any one of the preceding items, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 1 to 60 mg per day as the free form of tandospirone. [Item K44] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding paragraphs. [Section K45] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, with a total application area of ​​9-60 cm² per application. 2 The tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding paragraphs. [Clause K46] The tandospirone or pharmaceutically acceptable salt thereof described in any one of the preceding clauses, characterized in that the tandospirone or pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Clause K47] The tandospirone or pharmaceutically acceptable salt thereof described in any one of the preceding clauses, characterized in that the tandospirone or pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.5 to 15 ng / mL. [Clause K48] The tandospirone or pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 12 to 30 hours after a single dose of the tandospirone or pharmaceutically acceptable salt thereof. [Clause K49] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause K50] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.1 to 15 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause K51] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 10-100% of the maximum blood concentration after administration during a period of 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Item K52] The tandospirone or a pharmaceutically acceptable salt thereof is administered such that, between 8 hours and 16 hours after administration of said tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the minimum tandospirone concentration in human blood (plasma), when the maximum blood concentration after administration is defined as 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 according to any one of the preceding items. [Item K53] The tandospirone or a pharmaceutically acceptable salt thereof is characterized in that, between 8 hours and 16 hours after administration of said tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the minimum tandospirone concentration in human blood (plasma), when the maximum blood concentration after administration is defined as 100%, is 10% to 95%, the tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items. [Item K54] The tandospirone or a pharmaceutically acceptable salt thereof is characterized in that, after administration of said tandospirone or a pharmaceutically acceptable salt thereof, the maximum concentration of tandospirone in human blood (plasma) at steady state is 1 to 15 ng / mL, and the ratio of the minimum concentration of tandospirone in human blood (plasma), when the maximum concentration is defined as 100%, is 30% to 95%, the tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items. [Item K55] The tandospirone or a pharmaceutically acceptable salt thereof is characterized in that, after administration of said tandospirone or a pharmaceutically acceptable salt thereof and before levodopa administration, in the striatum one hour after administration 11 C] the amount of change in raclopride receptor binding (amount of change B / 1h) is less than 10%, the tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items. [Item K56] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items, which is provided as an adjunct to levodopa. [Item K57] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding items, which is used in combination as the same formulation as levodopa or in separate formulations. [Item K58] A combination of tandospirone or a pharmaceutically acceptable salt thereof for treating or preventing Parkinson's disease with or without motor complications, wherein the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Section K59] The motor complications include motor fluctuations, and are tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K60] The exercise complication further comprises dyskinesia, tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K61] The exercise complication further comprises drug-induced dyskinesia, tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K62] The exercise complication further comprises levodopa-induced dyskinesia (PD-LID), tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Section K63] The tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times, as described in any one of the preceding sections. [Item K64] (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors for treating or preventing Parkinson's disease with or without motor complications, wherein the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section K65] The exercise complication is dyskinesia, and is (1) levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors as described in any one of the preceding sections. [Section K66] The exercise complication is drug-induced dyskinesia, and is one of the drugs described in any of the preceding sections: (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors. [Section K67] The exercise complication is levodopa-induced dyskinesia (PD-LID), and is one of the following: (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors. [Section K68] Tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times, and are (1) levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors as described in any one of the preceding sections. [Item K69] Tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response to levodopa therapy in patients with Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Section K70] The improvement includes improvement of motor fluctuations, as described in any one of the preceding sections, tandospirone or a pharmaceutically acceptable salt thereof. [Section K71] The improvement is the tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections, including the improvement of dyskinesia. [Section K72] The improvement includes improvement of drug-induced dyskinesia, as described in any one of the preceding sections, tandospirone or a pharmaceutically acceptable salt thereof. [Section K73] The improvement includes improvement of levodopa-induced dyskinesia (PD-LID), as described in any one of the preceding sections, tandospirone or a pharmaceutically acceptable salt thereof. [Item L1] A method for treating, improving or preventing motor complications in a subject, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to the subject parenterally. [Item L1B] A method for treating, improving or preventing dyskinesia in a subject, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to the subject parenterally. [Item L1C] A method for treating, improving or preventing dyskinesia in a subject, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof parenterally to the subject, characterized in that the subject is receiving pharmacotherapy for Parkinson's disease. [Item L1D] A method for treating, improving or preventing dyskinesia in a subject, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof parenterally to the subject, characterized in that the subject is receiving levodopa therapy. [Item L1E-1] A method for reducing OFF time in a subject who is a patient with Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof parenterally to the subject, characterized in that the subject is receiving pharmacotherapy. [Item L1E] A method for reducing OFF time in a subject who is a patient with Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof parenterally to the subject, characterized in that the subject is receiving pharmacotherapy. [Item L1F] A method for reducing OFF time and increasing ON time in a subject who is a patient with Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof parenterally to the subject, characterized in that the subject is receiving pharmacotherapy. [Item L1G] A method for reducing the time of inaction (off time) and increasing the time of troublesome dyskinesia-free ON time in a patient with Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof parenterally to a subject, characterized in that the subject is receiving pharmacotherapy. [Item L1H] A method for reducing the off-time and increasing the on-time of troublesome dyskinesia-free antiparkinsonian effect in a Parkinson's disease patient, comprising administering an effective dose of tandospirone or a pharmaceutically acceptable salt thereof parenterally to a subject, characterized in that the subject is receiving levodopa therapy. [Item L2] A method for treating, improving or preventing motor complications of Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject parenterally. [Item L3] A method for treating, improving or preventing motor complications of Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject parenterally, characterized in that the subject is receiving pharmacotherapy for Parkinson's disease. [Item L4] A method for treating, improving or preventing motor complications of Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject parenterally, characterized in that the subject is receiving pharmacotherapy selected from the group consisting of levodopa-containing preparations, levodopa metabolic enzyme inhibitors, dopamine receptor agonists, and adjuncts for Parkinson's disease. [Item L5] A method for treating, improving or preventing motor complications of Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject parenterally, characterized in that the subject is receiving dopamine replacement therapy for Parkinson's disease. [Item L6] A method for treating, improving or preventing motor complications of Parkinson's disease, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject parenterally, characterized in that the subject is receiving levodopa therapy for Parkinson's disease. [Item L7] A method for treating, improving or preventing motor complications of Parkinson's disease, comprising parenterally administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject, characterized in that the subject maintains a sustained level of dopamine in the synaptic cleft of the striatum, suppresses rapid fluctuations in dopamine levels, and / or suppresses intermittent dopamine receptor stimulation. [Clause L8] The method according to any one of the preceding clauses, characterized in that it is administered to the subject in a manner that does not cause rebound symptoms. [Clause L9] The motor complications are those described in any one of the preceding clauses, including motor fluctuations. [Clause L10] The parenteral administration is the method described in any one of the preceding clauses, selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof. [Clause L11] The method according to any one of the preceding clauses, characterized in that the parenteral administration is sustained or administered continuously. [Clause L12] The parenteral administration is the method described in any one of the preceding clauses, including transdermal administration. [Clause L13] The method according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor complications without worsening dyskinesia symptoms in Parkinson's disease. [Clause L14] The method according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor complications without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Clause L15] The method according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without worsening dyskinesia symptoms in Parkinson's disease. [Clause L16] The method according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Clause L17] The method according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor complications or motor fluctuations in Parkinson's disease without worsening dyskinesia symptoms. [Clause L18] The method according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor complications or motor fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). [Clause L19] The motor fluctuations described herein include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, as described in any one of the preceding clauses. [Clause L20] Treatment, improvement or prevention of the motor fluctuations as described in any one of the preceding clauses, including extending the on-time of the antiparkinsonian effect, shortening the off-time, or a combination thereof. [Clause L21] The method according to any one of the preceding clauses, wherein the motor complications further include dyskinesia symptoms in Parkinson's disease. [Clause L22] The method according to any one of the preceding clauses, further comprising levodopa-induced dyskinesia (PD-LID) as the exercise complication. [Item L23] Dyskinesia in Parkinson's disease is the method described in any one of the preceding items, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause L24] Levodopa-induced dyskinesia (PD-LID) is the method described in any one of the preceding clauses, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause L25] The method according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without being accompanied by dyskinesia symptoms. [Clause L26] The method according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without distressing dyskinesia symptoms. [Item L27] A method for improving or preventing dyskinesia symptoms in a patient with Parkinson's disease, shortening the duration of dyskinesia in a patient with Parkinson's disease, or a combination thereof, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof parenterally to a subject, characterized in that the method does not exacerbate diurnal variation. [Clause L28] The method described in any one of the preceding clauses for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of the duration of levodopa-induced dyskinesia (PD-LID) onset, or a combination thereof. [Item L29] A method for achieving improvement or prevention of dyskinesia symptoms in a patient with Parkinson's disease, reduction of the duration of dyskinesia in a patient with Parkinson's disease, or a combination thereof, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof parenterally to a subject, characterized in that the method does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or extend the time of no response (off time) beyond a clinically significant time. [Clause L30] The method according to any one of the preceding clauses, for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the duration of levodopa-induced dyskinesia (PD-LID) onset, or a combination thereof, characterized in that the method does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or does not extend the time of no response (off time) beyond a clinically significant time. [Item L31] The method according to any one of the preceding items, wherein the reduction in the time of no response (off-time) is greater than or equal to a clinically significant time. [Clause L32] The method according to any one of the preceding clauses, wherein the reduction in the time of no response (off-time) is sufficient to obtain a clinical effect. [Item L33] A method for achieving, parenterally administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof, an extension of the on-time, reduction of the off-time, improvement or prevention of dyskinesia symptoms, reduction of the onset time of dyskinesia, or a combination thereof, in Parkinson's disease. [Item L34] A method for achieving, parenterally administering to a subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof, an extension of the on-time, reduction of the off-time, improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, associated with levodopa treatment for Parkinson's disease. [Item L35] The method according to any one of the preceding items, wherein the improvement in the motor fluctuations is clinically significant or greater. [Item L36] The method according to any one of the preceding items, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item L37] The method according to any one of the preceding items, wherein the preparation is a transdermal absorption preparation. [Clause L38] The method according to any one of the preceding clauses, provided as a transdermal patch. [Clause L39] The method according to any one of the preceding clauses, wherein the transdermal preparation is a tape / patch. [Clause L40] The method according to any one of the preceding claims, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg per day as the free form of tandospirone. [Clause L41] The method according to any one of the preceding claims, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 3 to 250 mg per day as the free form of tandospirone. [Clause L42] The method according to any one of the preceding claims, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 100 mg per day as the free form of tandospirone. [Clause L43] The method according to any one of the preceding claims, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof delivered is 1 to 60 mg per day as the free form of tandospirone. [Item L44] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The method described in any one of the preceding terms. [Item L45] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, with a total application area of ​​9-60 cm² per application. 2 The method described in any one of the preceding terms. [Clause L46] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Clause L47] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.5 to 15 ng / mL. [Clause L48] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 12 to 30 hours after a single dose of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause L49] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL during a period of 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause L50] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.1 to 15 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause L51] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 10-100% of the maximum blood concentration after administration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause L52] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the human blood (plasma) tandospirone concentration to the maximum blood concentration after administration (with the minimum concentration being 100%) is 10 to 95%, wherein the maximum blood concentration after administration is 1 to 15 ng / mL. [Clause L53] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, for a period of 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the human blood (plasma) tandospirone concentration to the minimum concentration, with the maximum blood concentration after administration being 100%, is 10 to 95%. [Clause L54] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the maximum blood concentration of human blood (plasma) tandospirone at steady state is 1 to 15 ng / mL, and the ratio of the minimum concentration to the maximum human blood (plasma) tandospirone concentration, with the maximum concentration being 100%, is 30 to 95%. [Item L55] The tandospirone or a pharmaceutically acceptable salt thereof is used to measure the striatum before levodopa administration and 1 hour after administration of the tandospirone or a pharmaceutically acceptable salt thereof. 11 The method according to any one of the preceding items, characterized in that it is administered such that the change in raclopride receptor binding (change B / 1h) is less than 10%. [Item L56] The method described in any one of the preceding items, provided as an adjunct to levodopa. [Item L57] The method described in any one of the preceding items, used in combination with levodopa, either in the same formulation or in separate formulations. [Item L58] A method for treating or preventing Parkinson's disease with or without motor complications, the method comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof in combination with (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section L59] The motor complications described herein include motor fluctuations, as described in any one of the preceding sections. [Clause L60] The method according to any one of the preceding clauses, wherein the motor complication further includes dyskinesia. [Clause L61] The method according to any one of the preceding clauses, wherein the exercise complication further includes drug-induced dyskinesia. [Clause L62] The method according to any one of the preceding clauses, wherein the exercise complication further comprises levodopa-induced dyskinesia (PD-LID). [Clause L63] The method according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item L64] A method for treating or preventing Parkinson's disease with or without motor complications, the method comprising administering (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa, wherein the (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section L65] The exercise complication is the method described in any one of the preceding sections, including dyskinesia. [Clause L66] The exercise complication is the method described in any one of the preceding clauses, including drug-induced dyskinesia. [Clause L67] The exercise complication is the method described in any one of the preceding clauses, including levodopa-induced dyskinesia (PD-LID). [Section L68] The method according to any one of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item L69] A method for improving the quality of response to levodopa therapy in patients with Parkinson's disease, comprising administering an effective dose of tandospirone or a pharmaceutically acceptable salt thereof parenterally to the patient. [Clause L70] The improvement is the method described in any one of the preceding clauses, including an improvement in motor fluctuations. [Clause L71] The improvement is the method described in any one of the preceding clauses, including the improvement of dyskinesia. [Clause L72] The improvement is the method described in any one of the preceding clauses, including the improvement of drug-induced dyskinesia. [Clause L73] The improvement described herein is the method described in any one of the preceding clauses, including the improvement of levodopa-induced dyskinesia (PD-LID).

[0010] [Item 1] A composition for the treatment, improvement or prevention of motor complications associated with levodopa treatment for Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item 2] The composition according to Item 1, wherein the motor complications include motor fluctuations. [Item 3] The parenteral administration is selected from transdermal, intradermal, subcutaneous, intramuscular, and combinations thereof, of the composition according to item 1 or 2. [Clause 4] The composition according to any one of the preceding clauses, characterized in that the parenteral administration is sustained or administered continuously. [Clause 5] The parenteral administration includes transdermal administration, the composition according to any one of the preceding clauses. [Clause 6] The composition according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor complications without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Clause 7] The composition according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Clause 8] A composition according to any one of the preceding claims, characterized in that it improves motor complications or motor fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). [Clause 9] The composition according to any one of the preceding claims, wherein the motor fluctuations include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof. [Clause 10] The composition according to any one of the preceding clauses, wherein the treatment, improvement, or prevention of the motor fluctuations includes extending the on-time of the antiparkinson's disease effect, shortening the off-time, or a combination thereof. [Clause 11] The composition according to any one of the preceding clauses, further comprising levodopa-induced dyskinesia (PD-LID) as the exercise complication. [Clause 12] Levodopa-induced dyskinesia (PD-LID) is a composition according to any one of the preceding clauses, comprising peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause 13] The composition according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without causing dyskinesia symptoms. [Clause 14] The composition according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without distressing dyskinesia symptoms. [Item 15] A composition for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of levodopa-induced dyskinesia (PD-LID) onset time, or a combination thereof, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the composition does not exacerbate diurnal variation and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item 16] A composition for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of the duration of levodopa-induced dyskinesia (PD-LID) onset, or a combination thereof, wherein the composition does not shorten the duration of antiparkinsonian disease action (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or does not extend the time of no response (off time) beyond a clinically significant time, and wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause 17] The composition according to any one of the preceding clauses, wherein the reduction in the time of inaction (off-time) is greater than or equal to a clinically significant time. [Clause 18] The composition according to any one of the preceding clauses, wherein the reduction in the time of inaction (off-time) is sufficient to obtain a clinical effect. [Item 19] A composition comprising tandospirone or a pharmaceutically acceptable salt thereof for achieving an extension of the on-time, a reduction in the off-time, improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, a reduction in the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause 20] The composition according to any one of the preceding clauses, wherein the improvement in motor fluctuations is clinically significant or greater. [Clause 21] The composition according to any one of the preceding clauses, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item 22] A composition according to any one of the preceding items, which is a transdermal absorption preparation. [Clause 23] The composition according to any one of the preceding clauses, provided as a transdermal patch. [Clause 24] The composition according to any one of the preceding clauses, wherein the transdermal formulation is a tape / patch. [Clause 25] The composition according to any one of the preceding claims, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause 26] The composition according to any one of the preceding claims, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item 27] ​​The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The composition described in any one of the preceding items. [Clause 28] The composition according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day to a human blood (plasma) tandospirone concentration of 0.05 to 20 ng / mL. [Clause 29] The composition according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause 30] A composition according to any one of the preceding clauses, provided as an adjunct to levodopa. [Item 31] The composition described in any one of the preceding items, which is used in combination with levodopa, either in the same formulation or in separate formulations. [Clause 32] A pharmaceutical agent for treating or preventing Parkinson's disease with or without motor complications, wherein the pharmaceutical agent comprises a combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause 33] The motor complications described herein include motor fluctuations, as described in any one of the preceding paragraphs. [Clause 34] The exercise complication further comprises levodopa-induced dyskinesia (PD-LID), as described in any one of the preceding clauses. [Clause 35] The medicament described in any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item 36] A pharmaceutical product for treating or preventing Parkinson's disease with or without motor complications, comprising (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa, wherein (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause 37] The exercise complication further comprises levodopa-induced dyskinesia (PD-LID), as described in any one of the preceding paragraphs. [Clause 38] The medicament described in any one of the preceding paragraphs, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item 39] A composition for improving the deterioration of the quality of response to levodopa treatment in patients with Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause 40] The composition according to any one of the preceding clauses, wherein the improvement includes an improvement in motor fluctuations. [Clause 41] The composition according to any one of the preceding clauses, wherein the improvement includes improvement of levodopa-induced dyskinesia (PD-LID). [Clause 42] The pharmaceutical or composition according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone. [Item 1A] A composition comprising tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor fluctuations associated with levodopa treatment for Parkinson's disease, characterized in that the composition is administered by parenteral administration. [Item 2A] The composition according to Item 1A, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof. [Clause 3A] The composition according to either Clause 1A or 2A, characterized in that the parenteral administration is sustained or administered continuously. [Clause 4A] The composition according to any one of the preceding clauses, characterized in that the parenteral administration results in little variation in blood concentration. [Clause 5A] The parenteral administration includes transdermal administration, the composition according to any one of the preceding clauses. [Clause 6A] The composition according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without worsening dyskinesia. [Section 7A] The motor fluctuations of Parkinson's symptoms described above include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, as described in any of the preceding paragraphs. The composition of. [Clause 8A] The composition according to any one of the preceding clauses, wherein the treatment, improvement, or prevention of the motor fluctuations includes extending the on-time of the antiparkinson's disease effect, shortening the off-time, or a combination thereof. [Clause 9A] The composition according to any one of the preceding clauses, wherein the reduction in the off-time is greater than or equal to a clinically significant time. [Clause 10A] The composition according to any one of the preceding clauses, wherein the reduction in the off-time is sufficient to produce a clinical effect. [Clause 11A] The composition according to any one of the preceding clauses, wherein the improvement in the motor fluctuations is clinically significant or greater. [Clause 12A] The composition according to any one of the preceding clauses, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item 13A] A composition according to any one of the preceding items, which is a transdermal absorption preparation. [Clause 14A] A composition according to any one of the preceding clauses, provided as a transdermal patch. [Clause 15A] The composition according to any one of the preceding clauses, wherein the transdermal formulation is a tape / patch. [Clause 16A] The composition according to any one of the preceding clauses, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause 17A] The composition according to any one of the preceding clauses, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item 18A] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The composition described in any one of the preceding items. [Clause 19A] The composition according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day to a human blood (plasma) tandospirone concentration of 0.05 to 20 ng / mL. [Clause 20A] A composition according to any one of the preceding clauses, further used to treat, improve or prevent levodopa-induced dyskinesia (PD-LID). [Clause 21A] Levodopa-induced dyskinesia (PD-LID) is a composition according to any one of the preceding clauses, comprising peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause 22A] The composition according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Item 23A] A composition according to any one of the preceding items, provided as an adjunct to levodopa. [Item 24A] A composition according to any one of the preceding items, used in combination with levodopa, either in the same formulation or in separate formulations. [Item 25A] A pharmaceutical product for treating or preventing Parkinson's disease with or without motor fluctuations, wherein the pharmaceutical product comprises a combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism. [Clause 26A] The medicament described in any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item 27A] A pharmaceutical product for treating or preventing Parkinson's disease with or without motor fluctuations, wherein the pharmaceutical product comprises (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa, and the (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof. [Clause 28A] The medicament described in any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (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 to levodopa therapy in patients with Parkinson's disease, wherein the improvement includes improvement of motor fluctuations. [Clause 30A] The pharmaceutical or composition according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone. [Item A1] A method for treating, improving, or preventing motor complications associated with levodopa treatment for Parkinson's disease, comprising the step of administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to a subject parenterally. [Item A2] The method according to Item A1, wherein the motor complications include motor fluctuations. [Item A3] The parenteral administration is the method according to item A1 or A2, selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof. [Item A4] The parenteral administration is sustained or administered continuously, as described in any one of the preceding items. [Clause A5] The parenteral administration is the method described in any one of the preceding clauses, including transdermal administration. [Clause A6] The treatment, improvement or prevention described herein is the method described in any one of the preceding clauses, which improves motor complications without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Clause A7] The treatment, improvement or prevention described herein is the method described in any one of the preceding clauses, which improves motor fluctuations without worsening symptoms of levodopa-induced dyskinesia (PD-LID). [Item A8] The method described in any one of the preceding items for improving motor complications or motor fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). [Clause A9] The motor fluctuations described herein include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, as described in any one of the preceding clauses. [Clause A10] Treatment, improvement or prevention of the motor fluctuations described above, including the method described in any one of the preceding clauses, which includes extending the on-time of the antiparkinsonian effect, shortening the off-time, or a combination thereof. [Clause A11] The method according to any one of the preceding clauses, further comprising levodopa-induced dyskinesia (PD-LID) as the exercise complication. [Clause A12] Levodopa-induced dyskinesia (PD-LID) is the method described in any one of the preceding clauses, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause A13] The treatment, improvement or prevention described herein is the method described in any one of the preceding clauses, which improves motor fluctuations without the presence of dyskinesia symptoms. [Section A14] The treatment, improvement or prevention described herein is the method described in any one of the preceding sections, which improves motor fluctuations without distressing dyskinesia symptoms. [Item A15] A method for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of levodopa-induced dyskinesia (PD-LID) onset time, or a combination thereof, comprising parenterally administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof, wherein the method does not exacerbate diurnal variation. [Item A16] A method for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of the duration of levodopa-induced dyskinesia (PD-LID) onset, or a combination thereof, comprising parenterally administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof, wherein the method does not shorten the duration of antiparkinsonian effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or extend the duration of no response (off time) beyond a clinically significant time. [Item A17] The method according to any one of the preceding items, wherein the reduction in the time of no response (off-time) is greater than or equal to a clinically significant time. [Item A18] The method according to any one of the preceding items, wherein the reduction in the time of no response (off-time) is sufficient to obtain a clinical effect. [Item A19] A method for achieving, parenterally administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof, an extension of the on-time, a reduction in the off-time, improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, a reduction in the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, associated with levodopa treatment for Parkinson's disease. [Item A20] The method according to any one of the preceding items, wherein the improvement in the motor fluctuations is clinically significant or greater. [Item A21] The method according to any one of the preceding items, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Clause A22] The method according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation. [Clause A23] The method according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal patch. [Item A24] The method according to any one of the preceding items, wherein the transdermal preparation is a tape / patch. [Clause A25] The method according to any one of the preceding claims, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause A26] The method according to any one of the preceding claims, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as free tandospirone. [Item A27] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The method described in any one of the preceding terms. [Clause A28] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Clause A29] The method according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Section A30] The method according to any one of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as an adjunct to levodopa. [Item A31] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used in combination with levodopa, either in the same formulation or in a separate formulation. [Section A32] A method for treating or preventing Parkinson's disease with or without motor complications, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof and an effective amount of (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section A33] The method according to any one of the preceding sections, wherein the motor complications include motor fluctuations. [Clause A34] The method according to any one of the preceding clauses, further comprising levodopa-induced dyskinesia (PD-LID) as the exercise complication. [Item A35] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item A36] A method for treating or preventing Parkinson's disease with or without motor complications, comprising administering an effective amount of (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, in combination with tandospirone or a pharmaceutically acceptable salt thereof, wherein tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause A37] The method according to any one of the preceding clauses, further comprising levodopa-induced dyskinesia (PD-LID) as the exercise complication. [Item A38] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item A39] A method for improving the quality of response to levodopa therapy in patients with Parkinson's disease, comprising parenteral administration of an effective amount of tandospirone or a pharmaceutically acceptable salt thereof. [Clause A40] The improvement described herein is the method described in any one of the preceding clauses, including an improvement in motor fluctuations. [Section A41] The improvement described herein is the method described in any one of the preceding sections, including the improvement of levodopa-induced dyskinesia (PD-LID). [Item A42] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone. [Item A1A] A method for treating, improving, or preventing motor fluctuations associated with levodopa treatment of Parkinson's disease in a subject, comprising administering an effective dose of tandospirone or a pharmaceutically acceptable salt thereof parenterally to the subject. [Item A2A] The method according to Item A1A, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof. [Clause A3A] The method according to either Clause A1A or A2A, characterized in that the parenteral administration is sustained or administered continuously. [Item A4A] The method according to any one of the preceding items, characterized in that the parenteral administration results in little variation in blood concentration. [Section A5A] The parenteral administration is the method described in any one of the preceding sections, including transdermal administration. [Section A6A] The treatment, improvement or prevention described herein is the method described in any one of the preceding sections, which improves motor fluctuations without worsening dyskinesia. [Section A7A] The motor fluctuations of Parkinson's symptoms described above include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, as described in any of the preceding sections. Method of loading. [Section A8A] Treatment, improvement or prevention of the motor fluctuations described above, including the method described in any one of the preceding sections, which includes extending the on-time of the antiparkinsonian effect, shortening the off-time, or a combination thereof. [Item A9A] The method according to any one of the preceding items, wherein the reduction in the off-time is greater than or equal to a clinically significant amount of time. [Item A10A] The method according to any one of the preceding items, wherein the reduction in the off-time is sufficient to produce a clinical effect. [Item A11A] The method according to any one of the preceding items, wherein the improvement in the motor fluctuations is clinically significant or greater. [Item A12A] The method according to any one of the preceding items, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Section A13A] The method according to any one of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation. [Section A14A] The method according to any one of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal patch. [Item A15A] The method according to any one of the preceding items, wherein the transdermal preparation is a tape / patch. [Clause A16A] The method according to any one of the preceding claims, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause A17A] The method according to any one of the preceding claims, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item A18A] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The method described in any one of the preceding terms. [Item A19A] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day to a human blood (plasma) tandospirone concentration of 0.05 to 20 ng / mL. [Section A20A] The method described in any one of the preceding sections, further used to treat, improve or prevent levodopa-induced dyskinesia (PD-LID). [Clause A21A] Levodopa-induced dyskinesia (PD-LID) is the method described in any one of the preceding clauses, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Section A22A] The method according to any one of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Section A23A] The method according to any one of the preceding sections, provided as an adjunct to levodopa. [Item A24A] The method described in any one of the preceding items, used in combination with levodopa, either in the same formulation or in a separate formulation. [Item A25A] A method for treating or preventing Parkinson's disease in a subject with little to no motor fluctuations, comprising administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt thereof in combination with (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism. [Section A26A] The method according to any one of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item A27A] A method for treating or preventing Parkinson's disease with or without motor fluctuations, comprising administering an effective amount of (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, wherein the (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, in combination with tandospirone or a pharmaceutically acceptable salt thereof. [Section A28A] The method according to any one of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (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 patients with Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, wherein the improvement includes improvement of motor fluctuations. [Item A30A] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone. [Item B1] Use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment, improvement or prevention of motor complications associated with levodopa treatment for Parkinson's disease, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section B2] The motor complications include motor fluctuations, as described in Section B1. [Item B3] The parenteral administration is the use described in Item B1 or B2, selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, and combinations thereof. [Item B4] The use described in any one of the preceding items, characterized in that the parenteral administration is sustained or administered continuously. [Item B5] The parenteral administration is the use described in any one of the preceding items, including transdermal administration. [Item B6] The use described in any one of the preceding items, characterized in that the treatment, improvement or prevention improves motor complications without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Clause B7] The use described in any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without worsening levodopa-induced dyskinesia (PD-LID) symptoms. [Item B8] The use described in any one of the preceding items, characterized by improving motor complications or motor fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). [Section B9] The motor fluctuations described above include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, as described in any of the preceding sections. [Section B10] Treatment, improvement, or prevention of the motor fluctuations is the use described in any one of the preceding paragraphs, including extending the on-time of the antiparkinsonian effect, shortening the off-time, or a combination thereof. [Section B11] The use described in any one of the preceding paragraphs, wherein the exercise complication further includes levodopa-induced dyskinesia (PD-LID). [Section B12] Levodopa-induced dyskinesia (PD-LID) is the use described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause B13] The use described in any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without being accompanied by dyskinesia symptoms. [Clause B14] The use described in any one of the preceding paragraphs, characterized in that the treatment, improvement or prevention improves motor fluctuations without distressing dyskinesia symptoms. [Item B15] Use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to improve or prevent symptoms of levodopa-induced dyskinesia (PD-LID), shorten the duration of levodopa-induced dyskinesia (PD-LID), or a combination thereof, characterized in that the medicament does not exacerbate diurnal variation and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item B16] Use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to improve or prevent symptoms of levodopa-induced dyskinesia (PD-LID), shorten the duration of levodopa-induced dyskinesia (PD-LID) onset, or a combination thereof, characterized in that the medicament does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or extend the time of no response (off time) beyond a clinically significant time. [Item B17] Use as described in any one of the preceding items, wherein the reduction in the time of no response (off-time) is greater than or equal to a clinically significant time. [Item B18] The reduction in the time of no response (off-time) is sufficient to produce a clinical effect, as described in any one of the preceding items. [Item B19] Use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to achieve the extension of the on-time, reduction of the off-time, improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item B20] Use as described in any one of the preceding items, wherein the improvement in the motor fluctuations is clinically significant or greater. [Item B21] The use described in any one of the preceding items, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item B22] The use described in any one of the preceding items, wherein the pharmaceutical product is provided as a transdermal formulation. [Item B23] The use described in any one of the preceding items, wherein the pharmaceutical product is provided as a transdermal patch. [Item B24] The use described in any one of the preceding items, wherein the transdermal preparation is a tape / patch. [Item B25] The use described in any one of the preceding items, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Item B26] The use described in any one of the preceding items, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item B27] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The use described in any one of the preceding clauses. [Item B28] The use described in any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Item B29] The use according to any one of the preceding items, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Section B30] The use of the pharmacopoeia as described in any one of the preceding paragraphs, provided as an adjunct to levodopa. [Item B31] The use described in any one of the preceding items, wherein the pharmaceutical product is used in combination with levodopa, either as the same formulation or as a separate formulation. [Item B32] A pharmaceutical product for the manufacture of a combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, for the treatment or prevention of Parkinson's disease with or without motor complications, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Item B33] The exercise complication is a pharmacopoeia as described in any one of the preceding items, including motor fluctuations. [Item B34] The exercise complication is further comprising levodopa-induced dyskinesia (PD-LID), as described in any one of the preceding items. [Item B35] The medicament described in any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item B36] Use of (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors, for the manufacture of a medicament for the treatment or prevention of Parkinson's disease with or without motor complications, characterized in that the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section B37] The use described in any one of the preceding paragraphs, wherein the exercise complication further includes levodopa-induced dyskinesia (PD-LID). [Item B38] The use of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) as described in any one of the preceding items, administered simultaneously or at different times. [Item B39] Use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving the deterioration of the quality of response to levodopa therapy in patients with Parkinson's disease, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Section B40] The improvement is the use described in any one of the preceding sections, including the improvement of motor fluctuations. [Section B41] The improvement is the use described in any one of the preceding sections, including the improvement of levodopa-induced dyskinesia (PD-LID). [Section B42] The use described in any of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof is the free form of tandospirone. [Item B1A] Use for the manufacture of a medicament for the treatment, improvement or prevention of motor fluctuations associated with levodopa treatment for Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the use is administered by parenteral administration. [Item B2A] The parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof, as described in Item B1A. [Item B3A] The use described in either item B1A or B2A, wherein the parenteral administration is characterized by being sustained or administered continuously. [Item B4A] The parenteral administration is characterized by minimal fluctuation in blood concentration, as described in any one of the preceding items. [Section B5A] The parenteral administration is the use described in any one of the preceding sections, including transdermal administration. [Clause B6A] The use according to any one of the preceding clauses, characterized in that the treatment, improvement or prevention improves motor fluctuations without worsening dyskinesia. [Section B7A] The use described in any one of the preceding paragraphs, wherein the motor fluctuations of the Parkinson's symptoms include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof. [Section B8A] Treatment, improvement, or prevention of the motor fluctuations is the use described in any one of the preceding paragraphs, including extending the on-time of the antiparkinsonian effect, shortening the off-time, or a combination thereof. [Section B9A] The reduction in the off-time is greater than or equal to a clinically significant amount of time, as described in any of the preceding sections. [Item B10A] The use described in any one of the preceding items, wherein the reduction in the off-time is sufficient to produce a clinical effect. [Item B11A] Use as described in any one of the preceding items, wherein the improvement in the motor fluctuations is clinically significant or greater. [Item B12A] Use as described in any one of the preceding items, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Section B13A] The use described in any one of the preceding paragraphs, wherein the pharmaceutical product is provided as a transdermal formulation. [Section B14A] The use described in any one of the preceding paragraphs, wherein the pharmaceutical product is provided as a transdermal patch. [Item B15A] The use described in any one of the preceding items, wherein the transdermal preparation is a tape / patch. [Item B16A] The use described in any one of the preceding items, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Item B17A] The use described in any one of the preceding items, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item B18A] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The use described in any one of the preceding clauses. [Item B19A] The use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding items, characterized in that it is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Section B20A] Furthermore, the use described in any one of the preceding sections for the treatment, improvement or prevention of levodopa-induced dyskinesia (PD-LID). [Section B21A] Levodopa-induced dyskinesia (PD-LID) is the use described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item B22A] The use of tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Section B23A] The use of the pharmacopoeia as described in any one of the preceding paragraphs, provided as an adjunct to levodopa. [Item B24A] The use described in any one of the preceding items, wherein the pharmaceutical product is used in combination with levodopa, either as the same formulation or as a separate formulation. [Item B25A] Use of tandospirone or a pharmaceutically acceptable salt thereof in combination with (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, for the manufacture of a medicament for the treatment or prevention of Parkinson's disease with or without motor fluctuations. [Section B26A] The use of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) as described in any one of the preceding sections, administered simultaneously or at different times. [Item B27A] Use for the manufacture of a medicament for the treatment or prevention of Parkinson's disease, characterized in that the combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof. [Section B28A] The use of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) as described in any one of the preceding sections, administered simultaneously or at different times. [Item B29A] Use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to improve the quality of response to levodopa therapy in patients with Parkinson's disease, wherein the improvement includes improvement of motor fluctuations. [Section B30A] The use described in any of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof is the free form of tandospirone. [Item C1] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor complications associated with levodopa treatment for Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Clause C2] The motor complications include motor fluctuations, and are tandospirone or a pharmaceutically acceptable salt thereof as described in Clause C1. [Clause C3] The parenteral administration is selected from transdermal, intradermal, subcutaneous, intramuscular, and combinations thereof, and is a pharmaceutically acceptable salt of tandospirone or any pharmaceutically acceptable salt thereof as described in Clause C1 or C2. [Clause C4] The parenteral administration is characterized by being sustained or administered continuously, as described in any one of the preceding clauses, and is a pharmaceutically acceptable salt thereof. [Clause C5] The parenteral administration includes transdermal administration, tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C6] The treatment, improvement or prevention described herein is characterized by improving motor complications without worsening levodopa-induced dyskinesia (PD-LID) symptoms, and is a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C7] The treatment, improvement or prevention described herein is characterized by improving motor fluctuations without worsening levodopa-induced dyskinesia (PD-LID) symptoms, and is a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses. [Clause C8] Tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses, characterized by improving motor complications or motor fluctuations without causing rebound symptoms of levodopa-induced dyskinesia (PD-LID). [Clause C9] The motor fluctuations described in any of the preceding clauses include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, and tandospirone or a pharmaceutically acceptable salt thereof. [Clause C10] Treatment, improvement or prevention of the motor fluctuations, including prolongation of the on-time, reduction of the off-time, or a combination thereof, of tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C11] The exercise complication further comprises levodopa-induced dyskinesia (PD-LID), tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses. [Clause C12] Levodopa-induced dyskinesia (PD-LID) is defined as tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause C13] The treatment, improvement or prevention described herein is characterized by improving motor fluctuations without the presence of dyskinesia symptoms, and is a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C14] The treatment, improvement or prevention described herein is characterized by improving motor fluctuations without distressing dyskinesia symptoms, and is a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Item C15] Tandospirone or a pharmaceutically acceptable salt thereof for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of levodopa-induced dyskinesia (PD-LID) onset time, or a combination thereof, characterized in that the tandospirone or pharmaceutically acceptable salt thereof does not exacerbate diurnal variation, and the tandospirone or pharmaceutically acceptable salt thereof is administered parenterally. [Item C16] Tandospirone or a pharmaceutically acceptable salt thereof for achieving improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of the duration of levodopa-induced dyskinesia (PD-LID) onset, or a combination thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof does not shorten the duration of anti-Parkinson's disease effect (on time) associated with levodopa treatment for Parkinson's disease beyond a clinically significant time, and / or does not extend the time of no response (off time) beyond a clinically significant time, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause C17] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein the reduction in the time of no response (off-time) is greater than or equal to a clinically significant time. [Clause C18] The reduction in the time of no response (off-time) is sufficient to produce a clinical effect, as described in any of the preceding clauses, for tandospirone or a pharmaceutically acceptable salt thereof. [Item C19] Tandospirone or a pharmaceutically acceptable salt thereof, comprising tandospirone or a pharmaceutically acceptable salt thereof, for achieving extension of the on-time, reduction of the off-time, improvement or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, reduction of the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Clause C20] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein the improvement in motor fluctuations is clinically significant or greater. [Clause C21] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item C22] A transdermal formulation of tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding items. [Clause C23] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, provided as a transdermal patch. [Clause C24] The transdermal preparation is a tape / patch, wherein the tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C25] The pharmacopoeia of tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause C26] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item C27] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The tandospirone or any pharmaceutically acceptable salt thereof as described in any one of the preceding paragraphs. [Clause C28] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Clause C29] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause C30] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, provided as an adjunct to levodopa. [Item C31] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding items, used in combination with levodopa, either in the same formulation or in separate formulations. [Item C32] A combination of tandospirone or a pharmaceutically acceptable salt thereof for treating or preventing Parkinson's disease with or without motor complications, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause C33] The motor complications are any combination of the preceding clauses, including motor fluctuations. [Clause C34] The exercise complication is any combination of the preceding clauses, further comprising levodopa-induced dyskinesia (PD-LID). [Clause C35] The combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) described in any one of the preceding clauses, administered simultaneously or at different times. [Item C36] (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors for treating or preventing Parkinson's disease with or without motor complications, wherein the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof, and the tandospirone or a pharmaceutically acceptable salt thereof is administered parenterally. [Clause C37] The exercise complication further includes levodopa-induced dyskinesia (PD-LID), and is one of the (1) levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors as described in any one of the preceding clauses. [Clause C38] Tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times, and are (1) levodopa or (2) levodopa and levodopa metabolic enzyme inhibitors as described in any one of the preceding clauses. [Item C39] Tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response to levodopa therapy in patients with Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered parenterally. [Clause C40] The improvement includes improvement of motor fluctuations, wherein the improvement is tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C41] The improvement includes improvement of levodopa-induced dyskinesia (PD-LID), the tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses. [Clause C42] The tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone, the medicament described in any one of the preceding clauses, or tandospirone or a pharmaceutically acceptable salt thereof, combination, or (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism. [Item C1A] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of motor fluctuations associated with levodopa treatment for Parkinson's disease, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered by parenteral administration. [Clause C2A] The parenteral administration is selected from transdermal, intradermal, subcutaneous, intramuscular, and combinations thereof, and is a pharmaceutically acceptable salt thereof as described in Clause C1A. [Clause C3A] The parenteral administration is characterized by being sustained or administered continuously, as described in either Clause C1A or C2A, and is a pharmaceutically acceptable salt thereof. [Clause C4A] The parenteral administration is characterized by minimal variation in blood concentration, and is a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses. [Clause C5A] The parenteral administration includes transdermal administration, and is a pharmaceutically acceptable salt of tandospirone or any pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C6A] The treatment, improvement or prevention described herein is characterized by improving motor fluctuations without worsening dyskinesia, and is a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses. [Clause C7A] The motor fluctuations of Parkinson's symptoms include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof, as described in any one of the preceding clauses, tandospirone or a pharmaceutically acceptable salt thereof. [Clause C8A] Treatment, improvement or prevention of the motor fluctuations, including prolongation of the on-time, reduction of the off-time, or a combination thereof, of tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C9A] The reduction in the off-time is greater than or equal to a clinically significant amount of time, as described in any of the preceding clauses, for tandospirone or any pharmaceutically acceptable salt thereof. [Clause C10A] The reduction in the off-time is sufficient to produce a clinical effect, as described in any one of the preceding clauses, for tandospirone or a pharmaceutically acceptable salt thereof. [Clause C11A] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein the improvement in motor fluctuations is clinically significant or greater. [Clause C12A] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein the improvement in motor fluctuations is at a level sufficient to produce a clinical effect. [Item C13A] A transdermal formulation of tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding items. [Clause C14A] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, provided as a transdermal patch. [Clause C15A] The transdermal formulation is a tape / patch, wherein the tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause C16A] The pharmacokinetic dose of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause C17A] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item C18A] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The tandospirone or any pharmaceutically acceptable salt thereof as described in any one of the preceding paragraphs. [Clause C19A] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Section C20A] Furthermore, tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections, used to treat, improve or prevent levodopa-induced dyskinesia (PD-LID). [Clause C21A] Levodopa-induced dyskinesia (PD-LID) is defined as tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause C22A] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Section C23A] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections, provided as an adjunct to levodopa. [Item C24A] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding items, used in combination with levodopa, either in the same formulation or in a separate formulation. [Item C25A] A combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, for the treatment or prevention of Parkinson's disease with minimal or no motor fluctuations. [Clause C26A] The combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) described in any one of the preceding clauses, administered simultaneously or at different times. [Item C27A] (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors, for treating or preventing Parkinson's disease with or without motor fluctuations, wherein the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof. [Clause C28A] Tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times, and are (1) levodopa or (2) levodopa and a levodopa metabolic enzyme inhibitor as described in any one of the preceding clauses. [Item C29A] Tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response to levodopa therapy in patients with Parkinson's disease, wherein the improvement includes improvement of motor fluctuations. [Clause C30A] The tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone, the medicament described in any of the preceding clauses, or tandospirone or a pharmaceutically acceptable salt thereof, a combination thereof, or (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism. [Item 1D] A composition for the treatment, improvement or prevention of levodopa-induced dyskinesia (PD-LID) of Parkinson's disease, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the composition is administered parenterally. [Clause 2D] The composition according to Clause 1D, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof. [Clause 3D] The composition according to Clause 1D or 2D, characterized in that the parenteral administration is sustained or administered continuously. [Clause 4D] The composition according to any one of the preceding clauses, characterized in that the parenteral administration results in little variation in blood concentration. [Clause 5D] The parenteral administration includes transdermal administration, the composition according to any one of the preceding clauses. [Clause 6D] The composition according to any one of the preceding clauses, characterized in that the treatment or improvement of PD-LID improves PD-LID without causing rebound symptoms. [Clause 7D] The composition according to any one of the preceding clauses, wherein the PD-LID comprises peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause 8D] The composition according to any one of the preceding clauses, wherein the treatment, improvement, or prevention of PD-LID includes the treatment, improvement, or prevention of PD-LID symptoms, a reduction in the duration of PD-LID onset, or a combination thereof. [Clause 9D] The composition according to any one of the preceding clauses, wherein the treatment or improvement of the PD-LID is for a clinically significant duration or longer. [Clause 10D] The composition according to any one of the preceding clauses, wherein the treatment or improvement of PD-LID is for a sufficient amount of time to obtain a clinical effect. [Clause 11D] The composition according to any one of the preceding clauses, wherein the treatment or improvement of PD-LID is a clinically significant improvement or better. [Clause 12D] The composition according to any one of the preceding clauses, wherein the treatment or improvement of PD-LID is at a level sufficient to produce a clinical effect. [Item 13D] A composition according to any one of the preceding items, which is a transdermal absorption preparation. [Clause 14D] A composition according to any one of the preceding clauses, provided as a transdermal patch. [Clause 15D] The composition according to any one of the preceding clauses, wherein the transdermal formulation is a tape / patch. [Clause 16D] The composition according to any one of the preceding claims, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause 17D] The composition according to any one of the preceding clauses, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item 18D] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, with a total application area of ​​1 to 100 cm² per application. 2 The composition described in any one of the preceding items. [Clause 19D] The composition according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day to a human blood (plasma) tandospirone concentration of 0.05 to 20 ng / mL. [Clause 20D] The composition according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause 21D] A composition according to any one of the preceding clauses, provided as an adjunct to levodopa. [Item 22D] A composition according to any one of the preceding items, used in combination with levodopa, either in the same formulation or in separate formulations. [Item 23D] A pharmaceutical agent for treating or preventing Parkinson's disease with or without levodopa-induced dyskinesia (PD-LID), wherein the pharmaceutical agent comprises a combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism. [Clause 24D] The medicament described in any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item 25D] A pharmaceutical product for treating or preventing Parkinson's disease without or with minimal levodopa-induced dyskinesia (PD-LID), wherein the pharmaceutical product comprises (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, wherein the (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof. [Clause 26D] The medicament described in any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item 27D] A composition comprising tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response to levodopa therapy in patients with Parkinson's disease, wherein the improvement includes improvement of levodopa-induced dyskinesia (PD-LID). [Clause 28D] The tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone, as described in any of the preceding clauses, a tandospirone or a pharmaceutically acceptable salt thereof, a composition, or a pharmaceutical. [Item D1D] A method for treating, improving, or preventing levodopa-induced dyskinesia (PD-LID) in a subject, comprising parenterally administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to the subject. [Item D2D] The parenteral administration method according to Item D1D, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof. [Item D3D] The parenteral administration is sustained or administered continuously, according to the method of item D1D or D2D. [Item D4D] The parenteral administration is the method described in any one of the preceding items, wherein the blood concentration fluctuates less. [Item D5D] The parenteral administration is the method described in any one of the preceding items, including transdermal administration. [Clause D6D] The treatment or improvement of PD-LID as described in any one of the preceding clauses, which improves PD-LID without causing rebound symptoms. [Clause D7D] The method according to any one of the preceding clauses, wherein the PD-LID includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Clause D8D] The treatment, improvement, or prevention of PD-LID is the method described in any one of the preceding clauses, including treatment, improvement, or prevention of PD-LID symptoms, reduction of PD-LID duration, or a combination thereof. [Item D9D] The treatment or improvement of PD-LID as described in any one of the preceding items, wherein the treatment is for a clinically significant duration or longer. [Item D10D] The method according to any one of the preceding items, wherein the treatment or improvement of PD-LID is for a sufficient amount of time to obtain a clinical effect. [Item D11D] The treatment or improvement of PD-LID as described in any one of the preceding items. [Item D12D] The method according to any one of the preceding items, wherein the treatment or improvement of PD-LID is at a level sufficient to produce a clinical effect. [Clause D13D] The method according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered as a transdermal formulation. [Clause D14D] The method according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered as a transdermal patch. [Item D15D] The method according to any one of the preceding items, wherein the transdermal preparation is a tape / patch. [Clause D16D] The method according to any one of the preceding claims, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause D17D] The method according to any one of the preceding claims, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item D18D] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The method described in any one of the preceding terms. [Clause D19D] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Clause D20D] The method according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL during the period of 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Clause D21D] The method according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as an adjunct to levodopa. [Item D22D] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof is used in combination with levodopa, either in the same formulation or in a separate formulation. [Item D23D] A method for treating or preventing Parkinson's disease in a subject, without or with minimal levodopa-induced dyskinesia (PD-LID), 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 an enzyme inhibitor of levodopa metabolism. [Item D24D] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item D25D] A method for treating or preventing Parkinson's disease without or with minimal levodopa-induced dyskinesia (PD-LID), comprising 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 an enzyme inhibitor of levodopa metabolism. [Item D26D] The method according to any one of the preceding items, wherein the tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times. [Item D27D] A method for improving the quality of response to levodopa therapy in a Parkinson's disease patient, comprising administering an effective amount of tandospirone or a pharmaceutically acceptable salt thereof to the patient, wherein the improvement includes improvement of levodopa-induced dyskinesia (PD-LID). [Item D28D] The method according to any one of the preceding items, 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 medicament for the treatment, improvement or prevention of levodopa-induced dyskinesia (PD-LID) of Parkinson's disease, characterized in that such use is administered by parenteral administration. [Section E2D] The parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof, as described in Section E1D. [Clause E3D] The use according to Clause E1D or E2D, characterized in that the parenteral administration is sustained or administered continuously. [Item E4D] The parenteral administration is characterized by minimal fluctuation in blood concentration, as described in any one of the preceding items. [Section E5D] The parenteral administration is the use described in any one of the preceding sections, including transdermal administration. [Clause E6D] The use according to any one of the preceding clauses, characterized in that the treatment or improvement of PD-LID improves PD-LID without causing rebound symptoms. [Section E7D] The use of the PD-LID as described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Section E8D] The treatment, improvement, or prevention of PD-LID is the use described in any one of the preceding sections, including the treatment, improvement, or prevention of PD-LID symptoms, reduction of PD-LID duration, or a combination thereof. [Section E9D] The treatment or improvement of PD-LID is the use described in any one of the preceding sections, for a duration of clinical significance or longer. [Section E10D] The use described in any one of the preceding sections, wherein the treatment or improvement of PD-LID is for a sufficient period of time to obtain a clinical effect. [Section E11D] The treatment or improvement of PD-LID is a clinically significant improvement or better, as described in any one of the preceding sections. [Section E12D] The use described in any one of the preceding sections, wherein the treatment or improvement of PD-LID is at a level sufficient to produce a clinical effect. [Clause E13D] The use of the pharmaceutical product as described in any one of the preceding clauses, wherein the pharmaceutical product is provided as a transdermal formulation. [Clause E14D] The use of the pharmaceutical product as described in any one of the preceding paragraphs, wherein the pharmaceutical product is provided as a transdermal patch. [Clause E15D] The use according to any one of the preceding clauses, wherein the transdermal preparation is a tape / patch. [Clause E16D] The use described in any one of the preceding clauses, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause E17D] The use described in any one of the preceding clauses, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item E18D] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2The use described in any one of the preceding clauses. [Clause E19D] The use of tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding clauses, characterized in that it is administered for at least 12 hours per day to achieve a human blood (plasma) tandospirone concentration of 0.05 to 20 ng / mL. [Clause E20D] The use of tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Section E21D] The use of the pharmacopoeia as described in any one of the preceding paragraphs, wherein the pharmacopoeia is provided as an adjunct to levodopa. [Clause E22D] The use described in any one of the preceding paragraphs, wherein the pharmaceutical product is used in combination with levodopa, either as the same formulation or as a separate formulation. [Item E23D] Use of tandospirone or a pharmaceutically acceptable salt thereof in combination with (1) levodopa, or (2) levodopa and an enzyme inhibitor of levodopa metabolism, for the manufacture of a medicament for the treatment or prevention of Parkinson's disease, without or with minimal levodopa-induced dyskinesia (PD-LID). [Section E24D] The use of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) as described in any one of the preceding sections, administered simultaneously or at different times. [Item E25D] Use for the manufacture of a medicament for the treatment or prevention of Parkinson's disease, wherein (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors, is administered in combination with tandospirone or a pharmaceutically acceptable salt thereof. [Section E26D] The use of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) as described in any one of the preceding sections, administered simultaneously or at different times. [Item E27D] Use of tandospirone or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for improving the quality of response to levodopa therapy in patients with Parkinson's disease, wherein the improvement includes improvement of levodopa-induced dyskinesia (PD-LID). [Section E28D] The use described in any of the preceding sections, wherein the tandospirone or a pharmaceutically acceptable salt thereof is the free form of tandospirone. [Item F1D] Tandospirone or a pharmaceutically acceptable salt thereof for the treatment, improvement or prevention of levodopa-induced dyskinesia (PD-LID) of Parkinson's disease, characterized in that the tandospirone or the pharmaceutically acceptable salt thereof is administered by parenteral administration. [Item F2D] The parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, and combinations thereof, and is tandospirone or a pharmaceutically acceptable salt thereof as described in Item F1D. [Item F3D] The parenteral administration is characterized by being sustained or administered continuously, as described in Item F1D or F2D, tandospirone or a pharmaceutically acceptable salt thereof. [Item F4D] The parenteral administration is characterized by minimal fluctuation in blood concentration, and is tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding items. [Section F5D] The parenteral administration includes transdermal administration, tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections. [Clause F6D] The treatment or improvement of PD-LID is characterized by improving PD-LID without causing rebound symptoms, as described in any one of the preceding clauses, tandospirone or a pharmaceutically acceptable salt thereof. [Section F7D] The PD-LID is tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding sections, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Section F8D] The treatment, improvement, or prevention of PD-LID includes treatment, improvement, or prevention of PD-LID symptoms, reduction of PD-LID onset time, or a combination thereof, as described in any one of the preceding sections, tandospirone or a pharmaceutically acceptable salt thereof. [Section F9D] The treatment or improvement of the PD-LID is for a clinically significant duration or longer, using tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections. [Section F10D] The treatment or improvement of PD-LID is for a period of time sufficient to obtain a clinical effect, and is tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding sections. [Item F11D] The treatment or improvement of PD-LID is a clinically significant improvement or better, provided that the treatment or improvement is tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding items. [Section F12D] The treatment or improvement of PD-LID is at a level sufficient to produce a clinical effect, as described in any one of the preceding sections, tandospirone or a pharmaceutically acceptable salt thereof. [Clause F13D] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation. [Clause F14D] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal patch. [Clause F15D] The transdermal preparation is a tape / patch, and the tandospirone or pharmaceutically acceptable salt thereof as described in any of the preceding clauses. [Clause F16D] The drug dose of tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 180 mg per day as the free form of tandospirone. [Clause F17D] The tandospirone or pharmaceutically acceptable salt thereof according to any one of the preceding clauses, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 20 mg per day as the free form of tandospirone. [Item F18D] The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, and the total area of ​​application per application is 1 to 100 cm². 2 The tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding paragraphs. [Clause F19D] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for at least 12 hours per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL. [Clause F20D] The tandospirone or a pharmaceutically acceptable salt thereof according to any one of the preceding clauses, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof. [Item F21D] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding items, provided as an adjunct to levodopa. [Item F22D] Tandospirone or a pharmaceutically acceptable salt thereof as described in any of the preceding items, used in combination with levodopa, either in the same formulation or in a separate formulation. [Item F23D] (1) levodopa, or (2) levodopa in combination with an enzyme inhibitor of levodopa metabolism, for the treatment or prevention of Parkinson's disease with or without levodopa-induced dyskinesia (PD-LID). [Item F24D] The combination of tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) described in any one of the preceding items, administered simultaneously or at different times. [Item F25D] (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors for treating or preventing Parkinson's disease without or with minimal levodopa-induced dyskinesia (PD-LID), characterized in that the (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors are administered in combination with tandospirone or a pharmaceutically acceptable salt thereof. [Item F26D] Tandospirone or a pharmaceutically acceptable salt thereof and (1) or (2) are administered simultaneously or at different times, and are (1) levodopa or (2) levodopa and a levodopa metabolic enzyme inhibitor as described in any one of the preceding items. [Item F27D] Tandospirone or a pharmaceutically acceptable salt thereof for improving the deterioration of the quality of response to levodopa therapy in patients with Parkinson's disease, wherein the improvement includes improvement of levodopa-induced dyskinesia (PD-LID). [Item F28D] The tandospirone or a pharmaceutically acceptable salt thereof is a free form of tandospirone, the tandospirone or a pharmaceutically acceptable salt thereof as described in any one of the preceding items, tandospirone or a pharmaceutically acceptable salt thereof, a combination thereof, or (1) levodopa, or (2) levodopa and levodopa metabolic enzyme inhibitors.

[0011] In specific embodiments, the present disclosure can be provided as a transdermal patch (also known as a tape). When the tape of the present disclosure is applied, it is possible to more favorably treat, improve or prevent motor fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena, and / or motor complications such as dyskinesia, including levodopa-induced dyskinesia (PD-LID), that accompany drug treatment for Parkinson's disease (e.g., levodopa treatment), or to treat, improve or prevent motor fluctuations without worsening dyskinesia symptoms. Thus, when the tape of the present disclosure is applied, it is possible to more favorably treat, improve or prevent motor complications in Parkinson's disease, and to treat, improve or prevent motor fluctuations without worsening dyskinesia symptoms.

[0012] Furthermore, by applying the transdermal patch of this disclosure, motor complications associated with drug treatment for Parkinson's disease (e.g., levodopa treatment) can be more favorably treated, improved, or prevented. In clinical practice, this allows for an increase in the single dose and / or daily dose of drugs such as levodopa compared to before treatment with the transdermal patch of this disclosure, without worsening dyskinesia symptoms. In current treatment, Parkinson's disease patients exhibiting dyskinesia are being treated with low-dose, frequent doses of levodopa (Parkinson's Disease Treatment Guidelines 2018 Version (Part III Q&A on Parkinson's Disease Treatment, Chapter 3 Treatment of Motor Symptoms)), but this disclosure may also apply in other cases.

[0013] By administering the parenteral formulation of tandospirone provided in this disclosure, the occurrence of motor complications such as motor fluctuations including wearing-off, on-off, no-on, and delayed-on phenomena, as well as drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), can be suppressed, and the levodopa-containing formulation can be adjusted to the optimal dose. In other words, for Parkinson's disease patients who are experiencing or at risk of experiencing motor complications such as dyskinesia, including diurnal fluctuations (motor fluctuations) like wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), increasing the single dose of levodopa to reduce the number of administrations or increasing the daily dose of levodopa does not improve these motor complications. This allows for better treatment of Parkinson's disease symptoms without worsening complications.

[0014] The tandospirone or its pharmaceutically acceptable salts or prodrugs and therapies disclosed herein enable the treatment, improvement, or prevention of levodopa-induced motor complications associated with the usual daily dose of levodopa therapy as described in the 2018 version of the Parkinson's Disease Treatment Guidelines published by the Japanese Society of Neurology or corresponding guidelines in the United States and Europe. These complications include motor fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena, as well as drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), and other motor complications seen in Parkinson's disease.

[0015] While existing drugs that improve diurnal variation, such as entacapone, are known to carry a risk of causing dyskinesia (dyskinesia, a dopaminergic side effect), the composition disclosed herein has been found for the first time to extend the on-time (the duration of anti-Parkinson's disease effect associated with drug therapy such as levodopa treatment for Parkinson's disease) without dyskinesia.

[0016] The inventors of the present invention have discovered for the first time that when tandospirone is orally administered with the expectation of improving motor complications such as dyskinesia, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), the motor complications such as dyskinesia, including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), temporarily worsen. In other words, oral administration of tandospirone is associated with "rebound symptoms" of dyskinesia, and it has been found that it is undesirable as a treatment for motor complications such as dyskinesia seen in Parkinson's disease, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID). In this disclosure, "rebound symptoms" refers to the symptoms described in

[0052] . Furthermore, because oral administration of tandospirone causes "rebound symptoms," it is also undesirable to increase the dosage of levodopa-containing preparations. In this disclosure, "without worsening dyskinesia" refers to the state described in

[0041] . This disclosure suggests that diurnal motor fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena can be improved without exacerbating dyskinesia.

[0017] The present inventors have found that the parenteral tandospirone composition of this disclosure can improve motor complications such as dyskinesia, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), without causing a "rebound symptom" of dyskinesia. Furthermore, motor complications such as motor fluctuations (including wearing-off, on-off, no-on, and delayed-on phenomena) and drug-induced dyskinesia (including levodopa-induced dyskinesia (PD-LID)) seen in Parkinson's disease can be measured as the "AIMs score" (AIMs being an abbreviation for "abnormal involuntary movements") using the method described in

[0140] .

[0018] The inventors have found that the compositions of this disclosure can be expected to have therapeutic, ameliorative, or preventive effects against both diurnal variation and drug-induced dyskinesia, such as levodopa-induced dyskinesia (PD-LID), as seen in Parkinson's disease. This means that they are excellent as therapeutic agents for motor complications. There are no approved drugs that are effective against both diurnal variation and drug-induced dyskinesia, such as levodopa-induced dyskinesia (PD-LID), as seen in Parkinson's disease.

[0019] Therefore, this disclosure may be implemented, in some examples, in the following specific embodiments. (1) (A) Parenteral administration step of tandospirone, (B) The step of administering levodopa at a dose higher than the conventional dose. A method for treating, improving or preventing Parkinson's disease, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), as seen in Parkinson's disease, or a method for treating, improving or preventing Parkinson's disease in which diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), as seen in Parkinson's disease, have been improved. (2) (A) Parenteral administration step of tandospirone, (B) A method for treating, improving or preventing Parkinson's disease, comprising the step of increasing the dose of levodopa from the conventional single dose and adjusting the number of doses per day, a method for treating, improving or preventing motor complications such as dyskinesia seen in Parkinson's disease, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), or a method for treating, improving or preventing motor complications such as dyskinesia seen in Parkinson's disease, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID) A method for treating, improving, or preventing Parkinson's disease with improved complications. (3) (A) Parenteral administration step of tandospirone, (B) The step of maintaining or increasing the levodopa dose This includes motor fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena, as well as motor complications such as dyskinesia seen in Parkinson's disease, including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID). This describes methods for treating, improving, or preventing Parkinson's disease in patients who are experiencing or at risk of experiencing these conditions. Methods for treating, improving, or preventing complications, or methods for treating, improving, or preventing Parkinson's disease in which diurnal fluctuations (motor fluctuations) such as wearing-off, on-off phenomenon, no-on phenomenon, delayed-on phenomenon, etc., and motor complications (motor complications) such as levodopa-induced dyskinesia (PD-LID) have been improved. (4) (A) A step of adding parenteral administration of tandospirone to conventional levodopa treatment, (B) The levodopa dose is increased within a range that does not worsen motor complications such as motor fluctuations (wearing-off, on-off, no-on, delayed-on) and drug-induced dyskinesia (PD-LID), including dyskinesia, as seen in Parkinson's disease, and parenteral administration of tandospirone is also included in the step of increasing the dose within a range that does not worsen motor complications such as motor fluctuations (wearing-off, on-off, no-on, delayed-on) and drug-induced dyskinesia (PD-LID), as seen in Parkinson's disease, Methods for treating, improving, or preventing Parkinson's disease in patients who have or are at risk of developing complications; methods for treating, improving, or preventing motor complications such as dyskinesia seen in Parkinson's disease, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off phenomenon, no-on phenomenon, and delayed-on phenomenon, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID); or methods for treating, improving, or preventing Parkinson's disease in which motor complications such as dyskinesia seen in Parkinson's disease, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off phenomenon, no-on phenomenon, and delayed-on phenomenon, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), have been improved. (5) (A) The step of maintaining the plasma concentration of tandospirone at 0.05 to 20 ng / mL, (B) The step of administering levodopa and A method for treating, improving or preventing Parkinson's disease, a method for improving dyskinesia, or a method for treating, improving or preventing Parkinson's disease in which motor complications such as dyskinesia, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), are improved. (6) (A) The step of maintaining the plasma concentration of tandospirone at 0.05 to 20 ng / mL, (B) The step of administering levodopa and This includes motor fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena, as well as motor complications such as dyskinesia seen in Parkinson's disease, including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID). This describes methods for treating, improving, or preventing Parkinson's disease in patients who are experiencing or at risk of experiencing these conditions. Methods for treating, improving, or preventing complications, or methods for treating, improving, or preventing Parkinson's disease in which motor complications such as dyskinesia, including diurnal fluctuations (motor fluctuations) such as wearing-off, on-off, no-on, and delayed-on phenomena, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), have been improved.

[0020] The basis for the effectiveness of this disclosure in treating exercise-related complications such as diurnal variation is as follows, although we do not intend to be bound by theory. · Since levodopa has a short half-life and does not provide sustained effects, it is usually administered multiple times per day. In contrast, when tandospirone of the present disclosure is administered as a patch, i.e., when one patch is applied per day, the blood concentration of tandospirone is maintained for 24 hours. Therefore, in the case of a transdermally absorbable preparation, regardless of the timing of levodopa administration, levodopa is taken while tandospirone exposure is maintained. On the other hand, for example, when Sedil tablets and levodopa are administered (orally) three times a day at the same timing, levodopa is taken when the tandospirone concentration has decreased. In other words, it can be said that this feature distinguishes the preparation from oral formulations. Furthermore, it is considered preferable to maintain a constant blood concentration of tandospirone during levodopa administration.

[0021] In another aspect, the present disclosure provides a composition for treating, improving or preventing motor fluctuations associated with levodopa therapy for Parkinson's disease, which comprises tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the composition is administered parenterally.

[0022] In a detailed embodiment, the present disclosure can be used for various uses (indications / therapeutic effects), for example, for improving motor complications such as dyskinesia as seen in Parkinson's disease, including motor fluctuations such as wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID); indications and therapeutic effects including the treatment (with or without combination with a medicament that increases the effect of dopamine in the brain) of motor complications such as dyskinesia as seen in Parkinson's disease, including motor fluctuations such as wearing-off, on-off phenomenon, no-on phenomenon, delayed on phenomenon, and drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID) in Parkinson's disease patients treated with levodopa, notes on use, and labels (package inserts) may be attached.

[0023] In the present disclosure, it is intended that the one or more features described above may be provided in further combinations in addition to the explicitly stated combinations. Those skilled in the art will recognize further embodiments and advantages of the present disclosure upon reading and understanding the following detailed description as necessary.

[0024] In this specification, unless otherwise specified, motor complications such as diurnal variation and dyskinesia mean symptoms associated with drug treatment for Parkinson's disease, such as levodopa treatment, or equivalent circumstances. Symptoms originating from other diseases and associated with treatments other than levodopa or equivalent circumstances for Parkinson's disease are not included. Here, "symptoms originating from other diseases and associated with treatments other than levodopa or equivalent circumstances for Parkinson's disease" means symptoms originating solely from conditions other than Parkinson's disease. Therefore, if diurnal variation, dyskinesia, or other motor complications include those originating from Parkinson's disease (coexisting), they are understood to be included within the scope of this disclosure. Furthermore, it is understood that diurnal variation, dyskinesia, and other motor complications do not need to be proven to have a causal relationship with drugs such as levodopa, and are included as long as they occur when taking antiparkinson's disease drugs such as levodopa or during a period when their effects are thought to persist (for example, methods for treating dyskinesia occurring in patients receiving levodopa treatment are included). It also includes motor complications associated with Parkinson's disease-like neurodegenerative diseases resulting from striatal dopamine deficiency. Examples include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and Lewy body dementia. [Effects of the Invention]

[0025] The pharmaceutical compositions disclosed herein are expected to be effective in treating, improving, or preventing drug-induced motor complications of Parkinson's disease, such as levodopa-induced dyskinesia (PD-LID). These complications include diurnal fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena, as well as dyskinesia and other motor complications seen in Parkinson's disease, including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID). The disclosure is also expected to be effective in treating, improving, or preventing diurnal fluctuations without worsening dyskinesia symptoms. This disclosure is also expected to shorten the wearing-off time without dyskinesia symptoms and / or lengthen the on time without dyskinesia symptoms. This disclosure is also expected to be a treatment, improvement, or preventive agent for motor complications such as dyskinesia seen in Parkinson's disease, including drug-induced dyskinesia such as levodopa-induced dyskinesia (PD-LID), without worsening diurnal variation. [Brief explanation of the drawing]

[0026] [Figure 1] Figure 1 shows the results of measuring ON time (the duration of the anti-Parkinson's disease effect associated with levodopa treatment in Parkinson's disease model rats (6-OHDA-lesioned rats) by measuring rotational behavior (total rotations in 5 minutes) for 180 minutes after levodopa administration, following oral administration of tandospirone. ON time was defined as the time at which the rotational speed reached 20% or more of the peak value of the total rotations in 5 minutes after levodopa administration. Oral administration of tandospirone citrate (30 mg / kg, 100 mg / kg) resulted in an extension of the ON time from 120 to 180 minutes after levodopa administration compared to the solvent administration group (Figure 1A), and a significant extension of the total ON time over 180 minutes was observed (Figure 1B). [Figure 2] Figure 2 shows the results of measuring ON time in Parkinson's disease model rats (6-OHDA-lesioned rats) after transdermal administration of tandospirone by measuring rotational behavior (total rotations in 5 minutes) for 180 minutes after levodopa administration. ON time was defined as the time at which the rotational rate was 20% or more of the peak value of the total rotations in 5 minutes after levodopa administration. Compared to the solvent administration group, application of tandospirone patch (60 cm2 / kg (containing 6.5% W / V tandospirone-free)) resulted in an extension of ON time from 120 to 180 minutes after levodopa administration (Figure 2A), and a significant extension of the total ON time over 180 minutes was observed (Figure 2B). [Figure 3-1]Figure 3 shows the results of measuring dyskinesia-like symptoms and rotational behavior (ON score) in PD-LID model rats administered levodopa via oral tandospirone, with measurements taken every 20 minutes for 180 minutes. Behavioral observation was performed in a transparent acrylic cage for 1 minute every 20 minutes, starting 20 minutes after intraperitoneal administration of levodopa, and continued until 3 hours after administration. Behavioral observations were classified into Limb AIMs (involuntary bending and straightening of the forelimb opposite the injury, opening and closing of the palm, up and down movement of the wrist, chorea-like tremors, dystonia-like rigidity), Axial AIMs (twisting the upper body and neck to the opposite side of the injury, losing balance and falling, or maintaining that unstable posture), Orolingual AIMs (jaw jerking or violently thrusting the tongue forward), and Locomotive behavior (rotational behavior toward the opposite side of the injury), and were scored from 0 to 4 (0: none, 1: occurring for less than 30 seconds, 2: occurring for 30 seconds or more, 3: constant but stopped by stimuli such as sound, 4: constantly occurring and not stopped by stimuli such as sound). The sum of the scores for Limb AIMs, Axial AIMs, and Orolingual AIMs over 3 hours was used as the total dyskinesia-like symptoms (AIMs) score. PD-LID model rats were orally administered tandospirone citrate (at citrate concentrations of 30 and 100 mg / kg), followed by levodopa administration 5 minutes later. Dyskinesia-like symptoms (Figure 3A) and spinning behavior (Figure 3B) were scored, and the results are shown as mean ± standard error. Oral administration of tandospirone citrate (100 mg / kg) resulted in an increase in the total ON score (Figure 3C) and a significant extension of 180 minutes of dyskinesia-free ON time (Locomotive behavior ≥ 1, AIMs score = 0) (Figure 3D). [Figure 3-2]Figure 3 shows the results of measuring dyskinesia-like symptoms and rotational behavior (ON score) in PD-LID model rats administered levodopa via oral tandospirone, with measurements taken every 20 minutes for 180 minutes. Behavioral observation was performed in a transparent acrylic cage for 1 minute every 20 minutes, starting 20 minutes after intraperitoneal administration of levodopa, and continued until 3 hours after administration. Behavioral observations were classified into Limb AIMs (involuntary bending and straightening of the forelimb opposite the injury, opening and closing of the palm, up and down movement of the wrist, chorea-like tremors, dystonia-like rigidity), Axial AIMs (twisting the upper body and neck to the opposite side of the injury, losing balance and falling, or maintaining that unstable posture), Orolingual AIMs (jaw jerking or violently thrusting the tongue forward), and Locomotive behavior (rotational behavior toward the opposite side of the injury), and were scored from 0 to 4 (0: none, 1: occurring for less than 30 seconds, 2: occurring for 30 seconds or more, 3: constant but stopped by stimuli such as sound, 4: constantly occurring and not stopped by stimuli such as sound). The sum of the scores for Limb AIMs, Axial AIMs, and Orolingual AIMs over 3 hours was used as the total dyskinesia-like symptoms (AIMs) score. PD-LID model rats were orally administered tandospirone citrate (at citrate concentrations of 30 and 100 mg / kg), followed by levodopa administration 5 minutes later. Dyskinesia-like symptoms (Figure 3A) and spinning behavior (Figure 3B) were scored, and the results are shown as mean ± standard error. Oral administration of tandospirone citrate (100 mg / kg) resulted in an increase in the total ON score (Figure 3C) and a significant extension of 180 minutes of dyskinesia-free ON time (Locomotive behavior ≥ 1, AIMs score = 0) (Figure 3D). [Figure 4-1]Figure 4 shows the results of measuring dyskinesia-like symptoms and rotational behavior (ON score) in PD-LID model rats administered levodopa after transdermal administration of tandospirone (without stripping), with measurements taken every 20 minutes for 180 minutes. Specifically, PD-LID model rats were administered tandospirone transdermally, followed by levodopa administration 4 hours later, and dyskinesia-like symptoms (Figure 4A) and rotational behavior (Figure 4B) were evaluated. The results are shown as mean ± standard error. Application of the tandospirone transderm was associated with an increase in the total ON score (Figure 4C) and a significant extension of the 180-minute dyskinesia-free ON time (Locomotive behavior ≥ 1, AIMs score = 0) (Figure 4D). [Figure 4-2] Figure 4 shows the results of measuring dyskinesia-like symptoms and rotational behavior (ON score) in PD-LID model rats administered levodopa after transdermal administration of tandospirone (without stripping), with measurements taken every 20 minutes for 180 minutes. Specifically, PD-LID model rats were administered tandospirone transdermally, followed by levodopa administration 4 hours later, and dyskinesia-like symptoms (Figure 4A) and rotational behavior (Figure 4B) were evaluated. The results are shown as mean ± standard error. Application of the tandospirone transderm was associated with an increase in the total ON score (Figure 4C) and a significant extension of the 180-minute dyskinesia-free ON time (Locomotive behavior ≥ 1, AIMs score = 0) (Figure 4D). [Figure 5-1]Figure 5 shows the results of measuring dyskinesia-like symptoms and rotational behavior (ON score) in PD-LID model rats administered levodopa after transdermal administration of tandospirone (with stripping), measured every 20 minutes for 180 minutes. Specifically, PD-LID model rats that underwent keratin stripping at the application site of the tape were administered tandospirone tape transdermally, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms (Figure 5A) and rotational behavior (Figure 5B). The results are shown as mean ± standard error. Application of tandospirone tape after keratin stripping resulted in an increase in the total ON score (Figure 5C) and a significant extension of dyskinesia-free ON time (Locomotive behavior ≥ 1, AIMs score = 0) over 180 minutes (Figure 5D). [Figure 5-2] Figure 5 shows the results of measuring dyskinesia-like symptoms and rotational behavior (ON score) in PD-LID model rats administered levodopa after transdermal administration of tandospirone (with stripping), measured every 20 minutes for 180 minutes. Specifically, PD-LID model rats that underwent keratin stripping at the application site of the tape were administered tandospirone tape transdermally, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms (Figure 5A) and rotational behavior (Figure 5B). The results are shown as mean ± standard error. Application of tandospirone tape after keratin stripping resulted in an increase in the total ON score (Figure 5C) and a significant extension of dyskinesia-free ON time (Locomotive behavior ≥ 1, AIMs score = 0) over 180 minutes (Figure 5D). [Figure 6-1] Figure 6A shows the results of measuring the time-dependent changes in dopamine in the striatum using microdialysis after intraperitoneal administration of levodopa to PD-LID model rats. [Figure 6-2] Figure 6B shows the results of calculating the time at which a change in dopamine release of 0.2 pg or more was observed. Compared to the placebo group, application of the tandospirone patch showed an extension of the striatal dopamine release time. Figure 6C shows the results of total dopamine release after levodopa administration. No difference was observed in total dopamine release. [Figure 7] Figure 7 shows the evaluation of the plasma concentration profile when the tandospirone patch of Example 4 was applied to normal rats. Specifically, the changes in plasma tandospirone concentration obtained by applying the tandospirone patch to normal rats (9 cm²: 31 ± 2 cm² / kg) are shown as mean ± standard deviation. The x-axis represents time from application, and the y-axis represents the tandospirone plasma concentration. [Figure 8] Figure 8 shows the results for administration condition 1 in Example 5. When tandospirone was administered transdermally (condition 1) by applying a tandospirone patch (formulation 2: drug dose 37 mg / kg) and absorbed transdermally, the total dyskinesia-like symptoms (AIMs) score was 12.6. Compared to when a placebo patch without tandospirone was applied, the total AIMs score decreased by 17.7, indicating a significant improvement in dyskinesia-like symptoms. In detail, PD-LID model rats were administered tandospirone patch transdermally, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms. The results are shown as mean ± standard error. ** indicates p<0.01, meaning there is a significant difference compared to the placebo patch group (Wilcoxon rank-sum test). In the figure, Graph A shows the total AIMs score over 180 minutes. Graph B shows the total AIMs score from 100 to 180 minutes. [Figure 9] Figure 9 shows the results for administration condition 2 in Example 5. Under keratin stripping conditions, when tandospirone tape (formulation 3: drug dose 45 mg / kg) was applied and high exposure to tandospirone was absorbed transdermally, the total dyskinesia-like symptoms (AIMs) score was 5.8. In detail, PD-LID model rats that underwent keratin stripping treatment at the tape application site were administered tandospirone tape transdermally, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms. The results are shown as mean ± standard error. ** indicates p<0.01, meaning there is a significant difference compared to the placebo tape application group (Wilcoxon rank-sum test). Figure 9-A shows the total AIMs score over 180 minutes. Figure 9-B shows the total AIMs score from 100 to 180 minutes. [Figure 10-1]Figure 10 shows the evaluation of the improvement of dyskinesia-like symptoms with continuous subcutaneous administration of tandospirone in Example 6. Specifically, PD-LID model rats were continuously subcutaneously administered tandospirone, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms. The results are shown as mean ± standard error. * indicates p<0.05, meaning there is a significant difference compared to the solvent administration group (Steel test). Continuous subcutaneous administration of tandospirone improved dyskinesia-like symptoms in a dose-dependent manner, with a significant improvement observed at 1.25 mg / kg / hour (Figure 10-A, B). Furthermore, in total dyskinesia-like symptoms over 100-180 minutes, continuous subcutaneous administration of tandospirone reduced the total dyskinesia-like symptoms (AIMs) score in a dose-dependent manner, with a significant improvement observed at 1.25 mg / kg / hour (Figure 10-C). [Figure 10-2] Figure 10 shows the evaluation of the improvement of dyskinesia-like symptoms with continuous subcutaneous administration of tandospirone in Example 6. Specifically, PD-LID model rats were continuously subcutaneously administered tandospirone, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms. The results are shown as mean ± standard error. * indicates p<0.05, meaning there is a significant difference compared to the solvent administration group (Steel test). Continuous subcutaneous administration of tandospirone improved dyskinesia-like symptoms in a dose-dependent manner, with a significant improvement observed at 1.25 mg / kg / hour (Figure 10-A, B). Furthermore, in total dyskinesia-like symptoms over 100-180 minutes, continuous subcutaneous administration of tandospirone reduced the total dyskinesia-like symptoms (AIMs) score in a dose-dependent manner, with a significant improvement observed at 1.25 mg / kg / hour (Figure 10-C). [Figure 11]Figure 11 shows the evaluation of long-term improvement in dyskinesia-like symptoms with continuous subcutaneous administration of tandospirone in Example 7. Osmotic pumps injected with tandospirone citrate or a solvent were implanted subcutaneously in rats in each group (n=8), and levodopa-based solution was administered 4 hours later. Behavioral observation evaluations were conducted (Day 0 after pump implantation) (Figure 11-A). Repeated administration of levodopa-based solution was continued once daily thereafter, and behavioral observation evaluations were conducted again on Day 13 after pump implantation (Figure 11-B). The mean ± standard error of the total dyskinesia-like symptoms (AIMs) score over 3 hours is shown. Statistical analysis of the test results was performed using the Wilcoxon rank-sum test with the total AIMs score as the index. Compared with the solvent-administered group, ** indicates a p<0.01, meaning a statistically significant difference. In addition, after each behavioral observation evaluation, blood was collected from half of the rats in the tandospirone-administered group (n=4), and the concentration of tandospirone in the plasma was analyzed. [Figure 12] Figure 12 shows the evaluation of the preventive and suppressive effect of continuous subcutaneous administration of tandospirone on dyskinesia-like symptoms in Example 8. Rats with 6-OHDA injury were randomized to each administration group based on apomorphine hydrochloride 0.5 hydrate-induced turnover rate and body weight. An osmotic pump injected with tandospirone citrate or a solvent was implanted subcutaneously in the rats the day after the start of repeated administration of a levodopa solution with the same composition as in Example 2. Behavioral observation evaluations were conducted on days 3, 5, 9, and 15 of repeated levodopa administration using the same method as in Example 2. After the behavioral observation evaluation on day 15, the subcutaneously implanted osmotic pump was removed, and another behavioral observation evaluation was conducted the following day (day 16 of repeated levodopa administration). The results are shown as the mean ± standard error of the 3-hour total dyskinesia-like symptoms (AIMs) score. Figure 12-A shows the results over time for repeated levodopa administration, and Figure 12-B shows the results on the day after discontinuation of tandospirone citrate administration (day 16). Statistical analysis of the test results was performed by comparing the total AIMs score on day 16 of repeated levodopa administration with the solvent administration group using Steel's test. Compared with the solvent administration group, * indicates p<0.05 and ** indicates p<0.01, meaning there is a statistically significant difference. [Figure 13]Figure 13 shows the evaluation of dyskinesia symptoms after oral administration of tandospirone in Comparative Example 1. Behavioral observation evaluation was performed using the same method as in Example 2. Tandospirone citrate was suspended in a 0.5% methylcellulose solution and orally administered to rats (citrate concentrations of 10 and 30 mg / kg), and after 5 minutes, a levodopa-containing solution was administered intraperitoneally, followed by behavioral observation evaluation. The results in the figure are shown as mean ± standard error. Statistical analysis of the test results was performed by comparing the total dyskinesia-like symptoms (AIMs) score at 3 hours (Figure 13-A) and the total dyskinesia-like symptoms score at 100-180 minutes (Figure 13-B) with the solvent administration group using Steel's test. * indicates p<0.05, meaning there is a statistically significant difference. [Figure 14] Figure 14 shows the evaluation of dyskinesia symptoms after oral administration of tandospirone in Comparative Example 1. Behavioral observation evaluation was performed using the same method as in Example 2. Tandospirone citrate was suspended in a 0.5% methylcellulose solution and orally administered to rats (citrate concentrations of 30 and 100 mg / kg), and after 5 minutes, a levodopa-containing solution was administered intraperitoneally, followed by behavioral observation evaluation. The results in the figure are shown as mean ± standard error. Statistical analysis of the test results was performed by comparing the total dyskinesia-like symptoms (AIMs) score at 3 hours (Figure 14-A) and the total dyskinesia-like symptoms score at 100-180 minutes (Figure 14-B) with the solvent administration group using Steel's test. * indicates p<0.05, meaning there is a statistically significant difference. [Figure 15-1] Figure 15 shows the evaluation of dyskinesia symptoms of the tandospirone metabolite in Comparative Example 2. Behavioral observation evaluation was performed using the same method as in Example 2. 1-PP dihydrochloride (Tokyo Chemical Industries) was dissolved in physiological saline and administered subcutaneously to rats (10, 30 mg / kg), and levodopa-containing solution was administered intraperitoneally 5 minutes later, followed by behavioral observation evaluation (Figure 15-A). The results in the figure are shown as mean ± standard error. Statistical analysis of the test results was performed by comparing the total dyskinesia-like symptoms (AIMs) score at 3 hours (Figure 15-B) and the total dyskinesia-like symptoms score at 100-180 minutes (Figure 15-C) with the solvent administration group using Steel's test. [Figure 15-2]Figure 15 shows the evaluation of the tandospirone metabolite of Comparative Example 2 against dyskinesia symptoms. Behavioral observation evaluation was carried out using the same method as in Example 2. 1-PP dihydrochloride (Tokyo Chemical Industry) was dissolved in physiological saline and subcutaneously administered to rats (10, 30 mg / kg), and 5 minutes later, a levodopa combination solution was intraperitoneally administered, and behavioral observation evaluation was carried out (Figure 15-A). The results in the figure are shown as mean ± standard error. Using the total 3-hour dyskinesia-like symptoms (AIMs) score (Figure 15-B) and the total 100-180 minute dyskinesia-like symptoms score (Figure 15-C) as indicators, statistical analysis of the test results was carried out by comparison with the vehicle-administered group via Steel's test. [Figure 16] Figure 16 is a diagram showing the powder X-ray diffraction patterns of tandospirone free base, tandospirone citrate (hydrate) and tandospirone citrate (anhydride). [Figure 17] Figure 17 shows the results in Example 9. It shows the predicted plasma concentration profile (mean value) of tandospirone free base when a single transdermal administration of tandospirone tape preparation is carried out for 24 hours. Panel B of Figure 17 shows the value obtained by predictive analysis based on the actually measured value for 17.6 mg. [Figure 18] Figure 18 also shows the results in Example 9. It shows the predicted plasma tandospirone concentration profile when repeated transdermal administration of a tandospirone tape preparation is carried out once a day. [Figure 19] Figure 19 also shows the results in Example 9. It shows the predicted plasma tandospirone concentration profile at steady state when repeated transdermal administration of a tandospirone tape preparation is carried out once a day. [Figure 20]Figure 20 shows the results from Example 10. In a rhesus monkey model of MPTP-induced Parkinson's disease levodopa-induced dyskinesia (PD-LID), levodopa / Benserazide (levodopa 22 mg / kg, Benserazide 1 / 4 the weight of levodopa) was orally administered, and dyskinesia symptoms were evaluated every 30 minutes from 5 minutes after administration to 150 minutes. The model monkeys were administered transdermally either an ointment containing tandospirone or a placebo ointment without tandospirone. The backs of the rhesus monkeys were shaved, and the ointment was applied to a 4 cm x 10 cm area 19 hours before the test, covered with tape and a clean cloth, and then the monkeys were fitted with a jacket. Dyskinesia was evaluated by analyzing videos of the model monkeys and scoring by evaluators skilled in behavioral assessment. Dyskinesia scores were assessed based on the Revised non-human primate dyskinesia rating scale (J Neurosci 2001;21:6853-6861). A score of 0 was assigned if no dyskinesia was observed. A score of 1 was assigned if dyskinesia was observed for less than 30% of the assessment time, which was considered mild dyskinesia. A score of 2 was assigned if dyskinesia was observed for 30% or more of the assessment time but normal behavior was not impaired, which was considered moderate dyskinesia. A score of 3 was assigned if dyskinesia was observed for 30% to 70% of the assessment time and normal behavior was impaired, which was considered significant dyskinesia. A score of 4 was assigned if dyskinesia was observed for 70% or more of the assessment time and normal behavior was impaired, which was considered severe dyskinesia. In addition, systemic dyskinesia was evaluated as a particularly severe form of dyskinesia. Based on the UDysRS, a clinical assessment scale that incorporates assessment of site-specific dyskinesia, generalized dyskinesia was defined as the presence of dyskinesia in four or more of the six areas: face, right arm, left arm, trunk, right leg, and left leg. A score of 1 was assigned if generalized dyskinesia occurred for 30% or more of the assessment time, and a score of 2 was assigned if generalized dyskinesia occurred for 70% or more of the assessment time. [Modes for carrying out the invention]

[0027] The present disclosure is described below in best form. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0028] (definition, etc.) The following provides definitions of terms used specifically in this specification and / or basic technical concepts as appropriate.

[0029] In this specification, "tandospirone [chemical name: (1R,2S,3R,4S)-N-[4-{4-(pyrimidine-2-yl)piperazine-1-yl}butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide]" has the following structure. [ka] Sediel tablets, which contain tandospirone citrate as the active ingredient, are used in treatment as a serotonergic anxiolytic (see, for example, Sediel package insert, revised April 2016, 14th edition, Dainippon Sumitomo Pharma Co., Ltd.; Japanese Patent Publication No. 58-126865). Tandospirone has beneficial effects on memory in chronic schizophrenia, and it is known that cognitive impairment can be improved by administering tandospirone or a pharmaceutically acceptable salt thereof while continuing maintenance therapy with typical antipsychotics such as haloperidol (see Japanese Patent Publication No. 2002-20291; powder X-ray diffraction pattern is shown in Figure 16).

[0030] The active ingredient used in the pharmaceutical compositions of this disclosure is preferably tandospirone (free form), and pharmaceutically acceptable salts of tandospirone and prodrugs 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 hydrochloride, hydrobromide, sulfate, and phosphate, and salts with organic acids such as acetate, butyrate, tartrate, citrate, maleate, and fumarate.

[0031] A tandospirone prodrug is any component that has a different structure from tandospirone but can be metabolized after administration to tandospirone or a tandospirone-based active ingredient to exert its therapeutic effect.

[0032] A tandospirone prodrug is a compound that is converted to tandospirone by enzymes or other reactions under physiological conditions in the body; that is, a compound that changes to tandospirone through enzymatic oxidation, reduction, hydrolysis, etc., or a compound that changes to tandospirone through hydrolysis, etc., by acids, etc. Furthermore, a tandospirone prodrug may also be one that changes to tandospirone under physiological conditions, as described on pages 163 to 198 of Volume 7, Molecular Design, of "Pharmaceutical Development," published by Hirokawa Shoten in 1990. The tandospirone or its salts or prodrugs (hereinafter also referred to as tandospirones) of this disclosure have excellent serotonin 5-HT1A receptor activating activity. Furthermore, the tandospirones disclosed herein are low in toxicity and safe.

[0033] Drugs containing "tandospirone citrate" as the active ingredient are clinically applied as oral medications for the treatment of (1) depression and phobias in neuroses, and (2) physical symptoms, depression, anxiety, restlessness, and sleep disorders in psychosomatic disorders (autonomic nervous system dysfunction, essential hypertension, peptic ulcers). In in vitro receptor binding evaluations of various neurotransmitter receptors, tandospirone shows high selectivity for serotonin 1A receptors (hereinafter also referred to as "5-HT1A receptors"), while showing low affinity for dopamine 2 receptors (also referred to as "D2 receptors"). Therefore, it is thought that tandospirone is effective in treating neuroses and other conditions by activating 5-HT1A receptors and selectively acting on serotonergic neurons. In this specification, "pharmacotherapy for Parkinson's disease" means receiving treatment with medications for Parkinson's disease. Drug therapies for Parkinson's disease include dopamine replacement therapy (levodopa therapy, levodopa metabolic enzyme inhibitors, dopamine receptor agonists, etc.) and adjunctive medications for Parkinson's disease. A typical example of dopamine replacement therapy is levodopa therapy, which includes levodopa therapy in the narrow sense (also called treatment with levodopa-containing preparations) and drug therapy with levodopa metabolic enzyme inhibitors. The pharmaceutical compositions disclosed herein are expected to be effective in treating, improving, or preventing motor complications in patients receiving drug therapy for Parkinson's disease. In particular, patients receiving levodopa therapy are known to be prone to developing motor complications, and the pharmaceutical compositions disclosed herein are useful for these patients.

[0034] In this specification, "levodopa" (in the broad sense) includes not only levodopa in the narrow sense (L-3,4-dihydroxyphenylalanine (IUPAC name: (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid), also known as L-dopa), but also any other drugs that exhibit equivalent pharmacological effects to L-3,4-dihydroxyphenylalanine. Such other drugs include, but are not limited to, esters and salts of L-3,4-dihydroxyphenylalanine. Examples of esters of L-3,4-dihydroxyphenylalanine include levodopaethyl ester (LDEE; ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), levodopapropyl ester (propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), levodopamethyl ester (methyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), and others. Esters of L-3,4-dihydroxyphenylalanine may include salts containing hydrated salts, for example. Salts of levodopa esters may include, but are not limited to, octanoate, myristate, succinate, succinate dihydrate, fumarate, fumarate dihydrate, mesylate, tartrate, and hydrochloride. For example, succinate salts or succinate dihydrates of L-3,4-dihydroxyphenylalanine esters include levodopaethyl ester succinate (LDEE-S) or levodopaethyl ester succinate dihydrate (LDEE-S-dihydrate or LDEE-S(d)).

[0035] In this specification, "levodopa metabolic enzyme inhibitors" refers to any drug that inhibits the metabolism of levodopa in a broad sense, thereby enhancing its effects. Examples include dopa decarboxylase inhibitors (DCIs) that prevent levodopa from being converted to dopamine in the intestines, liver, and blood vessels (e.g., carbidopa, α-methyldopa, benzerazide (Ro4-4602), α-difluoromethyl-DOPA (DFMD), or their salts); catecholamine-O-methyltransferase inhibitors (COMT-Is) that prevent levodopa from being broken down before it enters the brain (e.g., entacapone); and monoamine oxidase inhibitors (MAO-Is) that prevent dopamine from being broken down in the brain (e.g., selegiline).

[0036] (Diseases / Disorders) In this specification, "motor complications" refers to any motor symptoms that pose therapeutic problems in patients with advanced Parkinson's disease. Examples include dyskinesia (levodopa-induced dyskinesia (PD-LID)), which is an involuntary movement associated with levodopa treatment, and motor fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena. On / off is a phenomenon in which symptoms fluctuate rapidly, like switching a switch on and off. While wearing-off is predictable, on / off is unpredictable. Motor complications are interpreted as being based on either an overdose or deficiency of levodopa, but the mechanism is not necessarily clear (Parkinson's Disease Treatment Guidelines 2018 Version (Part III Q&A on Parkinson's Disease Treatment Chapter 3 Treatment of Motor Symptoms)).

[0037] Dyskinesia (involuntary movement) is a type of motor complication that appears in patients with Parkinson's disease and other neurodegenerative diseases, referring to involuntary movements of the limbs or body, such as uncontrolled wriggling. Similar to Parkinson's disease, it includes dyskinesia in patients with neurodegenerative diseases accompanied by a deficiency of dopamine in the striatum. Dyskinesia is believed to be caused by various factors, including those induced by various drugs (e.g., levodopa) and dyskinesia that occurs during drug administration. In this specification, "levodopa-induced dyskinesia (PD-LID)" refers to involuntary movements of the limbs and body, such as uncontrolled wriggling, induced by an overdose of levodopa. It is known that dyskinesia is more likely to appear if excessive amounts of levodopa are taken from the early stages of the disease, and that once dyskinesia appears, it is very difficult to control even with various adjustments to the levodopa dosage. Peak-dose dyskinesia is a representative symptom of PD-LID, in which symptoms appear in the face, tongue, neck, limbs, trunk, etc., during periods of high levodopa blood concentration.

[0038] In this specification, "circadian rhythm" and "kinetic rhythm" are interchangeable. Circadian rhythm refers to a shortening of the drug's duration of action, with the effect disappearing before the next dose. This is attributed to a decrease in dopamine-retaining nerve endings as Parkinson's disease progresses. Typical circadian rhythms include the wearing-off phenomenon. In this specification, "not worsening" of circadian rhythm means, for example, that the wearing-off, on-off, no-on, and delayed-on phenomena do not worsen, and that the ON time does not shorten or the OFF time does not lengthen.

[0039] In this specification, “progression inhibition” includes delaying, halting, or improving (including perception) the progression of motor complications in Parkinson’s disease compared to no treatment. In the case of motor complications in Parkinson’s disease, this can be determined by, but is not limited to, confirming an extension of ON time without dyskinesia. The treatment, prevention, or improvement of various diseases, disorders, or symptoms of this disclosure may include inhibition of the progression of motor complications in Parkinson’s disease.

[0040] In this specification, the "wearing-off phenomenon" refers to the phenomenon caused by a shortening of the duration of action of levodopa, resulting in a period during which the effects of levodopa wear off. The period during which levodopa is effective is called the "on period," and the period during which the effects of levodopa have disappeared is called the "off period." The on-off phenomenon refers to a sudden improvement (on) or worsening (off) of symptoms regardless of the timing of levodopa administration. The no-on phenomenon refers to a situation where no effect is observed even after taking levodopa, and the delayed-on phenomenon refers to a situation where it takes time for the effects of levodopa to appear. The "on time," which is the duration of anti-Parkinson's disease action, refers to the total time during which the effects of levodopa are observed. In nonclinical studies, it is defined as the time during which levodopa-induced rotational behavior is observed in 6-OHDA-treated rats. Rotational behavior is indicated by the duration of rotational movement in the opposite direction of destruction or the total number of rotational movements, and reflects striatal dopamine hyperactivity.

[0041] Involuntary movements (dyskinesia) refer to movements of parts of the body that are uncontrollable, such as biting the lip, difficulty speaking, inability to sit still, and difficulty controlling the limbs. It is a motor disorder characterized by involuntary movements of the limbs and / or oral and facial regions and / or the axial parts of the body. Dyskinesia observed in Parkinson's disease (PD) patients receiving levodopa treatment is called levodopa-induced dyskinesia (LID), and occurs in more than half of PD patients 5 to 10 years after starting levodopa treatment. The proportion of patients affected by LID increases over time (see, for example, Encarnacion and Hauser, (2008), "Levodopa-induced dyskinesias in Parkinson's disease: etiology, impact on quality of life, and treatments," Eur Neurol, 60(2), pp. 57-66). As used herein, "not exacerbating dyskinesia symptoms" means, for example, a state in which, compared to before the initiation of the treatment disclosed herein or in a state in which the therapeutic agent disclosed herein is not administered, no new dyskinesia symptoms appear, no exacerbation of dyskinesia symptoms occurs, or no rebound dyskinesia symptoms occur.

[0042] Peak-dose dyskinesia is involuntary movement that occurs when antiparkinson's disease medication is administered in excess. Diphasic dyskinesia is dyskinesia that occurs in two phases: before the onset of the effect of the antiparkinson's disease medication and during the withdrawal of that effect.

[0043] In the phrases "without dyskinesia," "without exacerbating dyskinesia," and "without rebound symptoms of dyskinesia" in this disclosure, when "dyskinesia" refers to levodopa-induced peak-dose dyskinesia, this can be confirmed by evaluating the effect of the therapeutic agent / treatment method of the present invention during the time period when the pharmacological effect of the antiparkinson's disease drug is high. For example, when it is levodopa-induced peak-dose dyskinesia, this can be confirmed by evaluating the time from 1 to 6 hours after levodopa administration.

[0044] ON time without dyskinesia refers to the total time during which dyskinesia does not occur within the "ON time," which is the duration of antiparkinsonian disease action. In nonclinical settings, it can be defined, for example, as the time during which the dyskinesia symptom (AIMs) score is 0 and the locomotive behavior score is 1 or higher at each evaluation point after levodopa administration in PD-LID model animals. However, if a similar model exists, it can also be used for evaluation.

[0045] As used herein, "pharmaceutically acceptable salts" include acid and / or base salts formed by inorganic and / or organic acids and bases, and include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, or organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. Furthermore, examples of base addition salts include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, and aluminum salts, or organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. In addition, "pharmaceutically acceptable salts" include amino acid salts with basic amino acids or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid. Pharmaceutically acceptable salts are well known in the prior art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.

[0046] A pharmaceutical product comprising tandospirone or a pharmaceutically acceptable salt or prodrug thereof as disclosed herein may optionally include a carrier. As used herein, the term “carrier” means a pharmaceutically acceptable substance, composition, or excipient, such as a liquid or solid extender, diluent, additive, solvent, base, or skin penetration enhancer, relating to or enabling the transport or delivery of the pharmaceutical compound of interest from one organ, tissue, or part of the body to another organ, tissue, or part of the body. “Pharmacologically acceptable” means that it is compatible with other ingredients in the formulation and is not harmful to the subject.

[0047] The diseases treatable in this invention include any motor complications of Parkinson's disease.

[0048] In this disclosure, treatable diseases include any levodopa-induced motor complications of Parkinson's disease and associated diurnal variations.

[0049] In specific embodiments, patients treatable in this disclosure include Parkinson's disease patients who have or are likely to develop levodopa-induced motor complications. Levodopa-induced motor complications include levodopa-induced dyskinesia.

[0050] The improvement effect of the present invention on dyskinesia in Parkinson's disease, such as levodopa-induced dyskinesia, can be clinically confirmed by clinical evaluation scales such as the Unified Dyskinesia Rating Scale (UDysRS), Clinical Dyskinesia Rating Scale (CDRS), The Rush Dyskinesia Rating Scale (Rush DRS), 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 Questionnaire-39), Clinical Global Impressions (CGI), and Patient Global Impression (PGI), as well as scales calculated from movement information acquired by wearable devices such as patient diaries, accelerometers, and / or gyroscopes. Furthermore, in nonclinical PD-LID model rats, the improvement in dyskinesia can be confirmed by evaluating dyskinesia-like abnormal involuntary motor behaviors. Using this method, it is possible to measure the improvement, suppression or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, as well as the reduction in the duration of levodopa-induced dyskinesia (PD-LID) episodes.

[0051] In this disclosure, the duration of action (ON time) and the downtime (OFF time) of antiparkinson's disease drugs such as levodopa can be clinically confirmed using, for example, clinical evaluation scales such as the Unified Parkinson's Disease Rating Scale (UPDRS), MDS-UPDRS, EQ-5D-5L, PDQ-39, CGI, and PGI, as well as scales calculated from locomotion information obtained from patient diaries and wearable devices such as accelerometers and / or gyroscopes. Furthermore, in the nonclinical model 6-OHDA unilaterally treated rat, the therapeutic effect on ON time can be confirmed by the extension of levodopa-induced rotational behavior time.

[0052] In this disclosure, "rebound symptoms" of dyskinesia in patients with Parkinson's disease, etc., refer to a phenomenon in which dyskinesia worsens compared to when treatment with a dyskinesia-improving drug was not performed, after the peak time of the anti-Parkinson's disease effect of levodopa (e.g., 1 hour), and is assumed to appear 1 to 6 hours after levodopa administration. Here, levodopa-induced dyskinesia (PD-LID) is given as an example of dyskinesia in patients with Parkinson's disease, etc. In this disclosure, improving dyskinesia in patients with Parkinson's disease or other conditions (e.g., levodopa-induced dyskinesia (PD-LID)) without causing rebound symptoms can be confirmed by evaluating the effect of the therapeutic agent / treatment method of the present invention during the time period when the pharmacological effect of the anti-Parkinson's disease drug is high. For example, in the case of PD-LID or in patients receiving levodopa therapy, this can be evaluated by checking that the total dyskinesia score improves without worsening of dyskinesia at one, preferably multiple, evaluation points 1 to 6 hours after levodopa administration. For example, in the AIMs evaluation system of a nonclinical PD-LID model rat, rebound symptoms of levodopa-induced dyskinesia (PD-LID) can be evaluated using indicators such as clear dyskinesia-like symptoms (AIMs score of 2 or higher) observed 120-140 minutes after levodopa administration or the total dyskinesia-like symptom score at 100-180 minutes. Improvement in dyskinesia can be assessed using the total AIMs score 180 minutes after levodopa administration.

[0053] In this disclosure, whether the ON time of an antiparkinson's disease drug (e.g., levodopa) is extended without worsening dyskinesia (e.g., PD-LID symptoms) in patients with Parkinson's disease or the like can be clinically confirmed using clinical evaluation scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, and PGI, or scales calculated from ON time, OFF time recorded in the patient's diary, and locomotion information acquired by wearable devices such as accelerometers and / or gyroscopes. In addition, for example, in a nonclinical model PD-LID rat, this can be confirmed by evaluating dyskinesia and rotational behavior time.

[0054] Whether the ON time without dyskinesia is prolonged in this disclosure can be clinically confirmed using clinical assessment scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, and PGI, or scales calculated from ON time, OFF time, and movement information obtained from wearable devices such as accelerometers and / or gyroscopes, as recorded in the patient's diary. For example, UDysRS and the patient's diary can be used for evaluation. In addition, for example, in the nonclinical model PD-LID rat, it can be confirmed by evaluating the rotational behavior time without dyskinesia.

[0055] In this disclosure, whether the on-time without troublesome dyskinesia is prolonged can be clinically confirmed using clinical assessment scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, and PGI recorded in patient diaries, as well as scales calculated from on-time, off-time, and motion information obtained from wearable devices such as accelerometers and / or gyroscopes. For example, UDysRS and patient diaries can be combined for evaluation.

[0056] Whether the ON time is prolonged without the rebound symptoms of dyskinesia described in this disclosure can be confirmed, for example, by comparing it with the case where the therapeutic agent described in this disclosure was not administered. Clinically, this can be confirmed by clinical evaluation scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, and PGI recorded in the patient's diary, as well as by scales calculated from ON time, OFF time, and movement information acquired by wearable devices such as accelerometers and / or gyroscopes, as recorded in the patient's diary. In addition, for example, in the nonclinical model PD-LID rat, it can be confirmed by evaluating dyskinesia and rotational behavior time. For example, UDysRS and the patient's diary can be used in combination for evaluation.

[0057] In this disclosure, diurnal variation in motor symptoms (motor complications) can be clinically confirmed using clinical assessment scales such as UPDRS, MDS-UPDRS, EQ-5D-5L, PDQ-39, CGI, and PGI recorded in patient diaries, as well as scales calculated from ON time, OFF time, and movement information acquired by wearable devices such as accelerometers and / or gyroscopes recorded in patient diaries. Diurnal variation can be considered to have improved when improvement in the clinical assessment scale or a reduction in OFF time is confirmed in the patient diary. Clinical assessment scales can be evaluated using methods known in the relevant field.

[0058] In this disclosure, improving diurnal variation (motor complications) without causing rebound symptoms of dyskinesia means that, compared to cases where treatment with a drug that improves diurnal variation (motor complications) is not performed after levodopa administration, diurnal variation (motor complications) improves without worsening of dyskinesia, even temporarily.

[0059] The inventors have found that tandospirone improves diurnal variation (motor complications), preferably without worsening dyskinesia. Improvement without worsening dyskinesia includes improvement without the emergence of new dyskinesia symptoms, worsening of clinical dyskinesia scores, or occurrence of dyskinesia rebound symptoms. Furthermore, the inventors have found that parenteral administration of tandospirone improves diurnal variation (motor complications) better than oral administration, specifically demonstrating superior extension of dyskinesia-free ON time. In other words, parenteral administration (transdermal administration) showed an extension of dyskinesia-free ON time regardless of the dose, but oral administration did not show extension of dyskinesia-free ON time at the usual dose (10, 30 mg / kg in rats). Only when the dose was increased to a dose where central nervous system side effects were a concern (100 mg / kg in rats) did the dyskinesia-free ON time become extended. Those skilled in the art can calculate appropriate human doses in light of these doses. (See, for example, the Sediel Tablets Drug Interview Form, 10th Edition, December 2017, Dainippon Sumitomo Pharma Co., Ltd.). Therefore, while tandospirone can be administered orally, parenteral administration is preferred, continuous parenteral administration or parenteral administration of a sustained-release formulation is even more preferred, and transdermal administration of tandospirone is most preferred.

[0060] In this specification, levodopa-induced "dystonia," also known as dystonia, is a general term for motor disorders involving involuntary and sustained muscle contractions caused by central nervous system damage associated with levodopa administration. It refers to symptoms such as postural abnormalities, twisting, rigidity, and spasms of the whole body or parts of the body. Levodopa-induced dystonia can be clinically evaluated using the MDS-UPDRS (Part IV), UDysRS, etc.

[0061] In this specification, "adjunct" refers to any agent other than the main agent. In this disclosure, for example, if levodopa is the main agent, then tandospirone and the like can be considered adjuncts.

[0062] In this specification, the daily dose of antiparkinson's disease drugs is the usual dose of antiparkinson's disease drugs as described in the 2018 version of the Parkinson's Disease Treatment Guidelines or the corresponding guidelines in the United States and Europe. In this specification, the daily dose of levodopa, the active ingredient, provided as an example, is the usual dose of levodopa treatment as described in the 2018 version of the Parkinson's Disease Treatment Guidelines or the corresponding guidelines in the United States and Europe. Generally, the usual daily dose of levodopa, when used in combination with or in combination with a peripheral dopa decarboxylase inhibitor (DCI), is 50 to 1200 mg / day, preferably 100 to 600 mg / day. For example, SINEMET® (Carbidopa-Levodopa combination tablets) (New Drug Application (NDA) #017555), approved by the FDA, is available as 1:4 ratio combination tablets (Carbidopa 25 mg - Levodopa 100 mg) and 1:10 ratio combination tablets (Carbidopa 10 mg - Levodopa 100 mg, Carbidopa 25 mg - Levodopa 250 mg). The daily maintenance dose is administered with SINEMET® to provide 70 mg to 100 mg of Carbidopa, and the daily maximum dose is administered with SINEMET® up to 200 mg of Carbidopa.

[0063] The tandospirone or its pharmaceutically acceptable salts or prodrugs or therapies described herein enable the reduced treatment or prevention of motor complications associated with the administration of standard doses of levodopa.

[0064] By administering tandospirone or a pharmaceutically acceptable salt or prodrug thereof as disclosed herein, the levodopa dosage can be appropriately adjusted. For example, it can be increased within the range of single doses and daily doses specified in the 2018 version of the Parkinson's Disease Treatment Guidelines published by the Japanese Society of Neurology or the corresponding guidelines in the United States and Europe.

[0065] By administering tandospirone or a pharmaceutically acceptable salt or prodrug thereof as disclosed herein, it is possible to improve diurnal variability (motor complications) without increasing the levodopa dose above the usual dose.

[0066] In this specification, “having sustained release” can be determined by a person skilled in the art, taking into consideration the descriptions herein and utilizing the knowledge known in the art. Specifically, it can be defined as having sustained release if it maintains a blood drug concentration for a long period of time and exhibits an effect of extending the biological half-life. Examples of sustained-release compositions include the various transdermal formulations described in

[0076] , the various sustained-release injectable formulations described in

[0117] , and the various implantable formulations described in

[0118] . Furthermore, in this disclosure, “administered continuously” means continuously administering the active ingredient in this disclosure into the body from outside the body. This can be selected from the parenteral administration routes described in

[0071] and can be achieved by transdermal absorption, injection, or infusion. Alternatively, “having sustained release” may mean that there is little fluctuation in the blood concentration of tandospirone. In this specification, "low blood concentration variability" means that the ratio of the maximum (Cmax) to the minimum (Cmin) tandospirone concentration at the final dose after reaching a steady state falls within a certain range. This certain range can be appropriately determined by a person skilled in the art by referring to the disclosure herein, depending on the objective to be achieved (for example, suppression of exercise complications (e.g., suppression of diurnal variation)), for example, the ratio of the maximum (Cmax) to the minimum (Cmin) tandospirone concentration at the final dose after reaching a steady state being 1.0 to 3.0, 1.0 to 2.0, 1.0 to 1.8, or 1.0 to 1.7.

[0067] In this specification, “clinically significant time” can be determined by a person skilled in the art, taking into consideration the descriptions herein and utilizing the knowledge known in the art. Specifically, if a significant effect is shown in the prevention, treatment, or reduction of the motor complications covered by this disclosure, that time can be defined as clinically significant time. Similarly, in this specification, “clinically significant improvement” can be defined as a clinically significant improvement if a significant effect is shown in the prevention, treatment, or reduction of the motor complications covered by this disclosure. The method for measuring such time or improvement can be appropriately selected by a person skilled in the art, and for example, any method described herein can be considered, but is not limited thereto, and for example, the 2018 version of the Parkinson's Disease Treatment Guidelines published by the Japanese Society of Neurology can be used. Alternatively, there is a report of a clinical evaluation index for dyskinesia (MDS UDysRS Part III) of 2.32 points (Parkinsonism Relat Disord 21:1349, 2015), and can be appropriately determined by considering (1) comparison with placebo, and (2) before and after treatment for each patient. In this specification, "maintaining a sustained level of dopamine in the synaptic cleft of the striatum" means that the level of dopamine in the synaptic cleft of the striatum is maintained above a certain concentration. For example, this can be confirmed in this specification by PET tests under the conditions described in the aforementioned references, and the striatum [ 11 [C] The change in raclopride receptor binding amount over 1h / 4h is less than 5%, and / or the striatum [ 11 In this specification, the effect of the pharmaceutical composition can be confirmed by the fact that the percentage change in the amount of raclopride receptor binding over 1h / 4h is 90% or less, preferably 80% or less, and more preferably 70% or less. Here, in this specification, the striatum before administration of levodopa and 1 hour after administration of levodopa [ 11 The change in C]raclopride receptor binding is referred to as the change amount B / 1h. In this specification, "suppressing rapid fluctuations in dopamine levels 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. For example, this can be confirmed by PET scans under the conditions described in the aforementioned references, and the striatum [ 11 The effectiveness of the pharmaceutical composition of the present invention can be confirmed by the fact that the change in the amount of raclopride receptor binding B / 1h is less than 10%, and / or the rate of change B / 1h is 90% or less, preferably 80% or less, and more preferably 70% or less. In this specification, "suppressing intermittent dopamine receptor stimulation" means suppressing the time-dependent increase or decrease in dopamine levels in the synaptic cleft of the striatum. For example, this can be confirmed by PET scans under the conditions described in the aforementioned references, and the striatum [ 11 The effectiveness of the pharmaceutical composition of the present invention can be confirmed by whether or not the difference between the change in raclopride receptor binding amount B / 1h and the change in B / 4h is reduced.

[0068] In this specification, “a sufficient time to obtain a clinical effect” and “a sufficient level to obtain a clinical effect” can also be determined by a person skilled in the art, taking into consideration the descriptions herein and utilizing the knowledge known in the art. Specifically, if it is possible to measure the time or level at which a clinical effect such as the prevention, treatment, or reduction of motor complications covered by this disclosure can be obtained, then that time or level can be evaluated as a sufficient time to obtain a clinical effect. The method for measuring such time or level can be appropriately selected by a person skilled in the art, and may include, for example, any method described herein, or, for example, the 2018 version of the Parkinson's Disease Treatment Guidelines published by the Japanese Society of Neurology or corresponding guidelines in the United States or Europe.

[0069] In this specification, "not exacerbating dyskinesia symptoms (e.g., levodopa-induced dyskinesia (PD-LID) symptoms) in patients with Parkinson's disease" means not exacerbating already present dyskinesia symptoms to a clinically significant degree or significantly, not prolonging the duration of dyskinesia, not significantly exacerbating symptoms even temporarily like dyskinesia rebound symptoms, not causing new dyskinesia symptoms, and not significantly increasing the frequency of dyskinesia side effects compared to cases where the composition of the present invention is not administered. Dyskinesia symptoms can be confirmed, for example, by clinical evaluation scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, PGI, etc., or by scales calculated from ON time, OFF time, and movement information obtained by wearable devices such as accelerometers and / or gyroscopes recorded in the patient's diary.

[0070] In this specification, "deterioration of the quality of response to levodopa treatment in Parkinson's disease patients" refers to any decline in a patient's responsiveness to levodopa treatment, and such deterioration in the quality of response can be measured from diurnal variation and dyskinesia symptoms. Furthermore, "improvement" of "deterioration of the quality of response to levodopa treatment in Parkinson's disease patients" refers to an improvement in the degree of diurnal variation and dyskinesia symptoms in each patient's response to levodopa treatment, and can be confirmed by clinical evaluation scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, PGI, etc., or by scales calculated from ON time, OFF time recorded in the patient's diary, and motion information acquired by wearable devices such as accelerometers and / or gyroscopes.

[0071] In this specification, "parenteral administration" refers to any form of administration other than oral administration, preferably any form in which tandospirone is administered in a form and level effective for levodopa-induced motor complications of Parkinson's disease. Means of parenteral administration include transdermal or transmucosal absorption, and include injection, infusion, or combination thereof. For example, transdermal or transmucosal absorption involves applying a transdermal formulation such as a topical application, patch, or spray to the skin or mucous membrane, and the drug in the formulation is absorbed into the body through the skin or mucous membrane to exert its effect. Administration by injection or infusion includes intravenous, intradermal, subcutaneous, intramuscular, and enteral (enema) administration, and may be bolus administration and / or continuous infusion. These may be suspensions, solutions, emulsions, or implants in an oily or aqueous medium containing other formulation substances such as suspending agents, stabilizers, and / or dispersants. For enteral (enema) administration, the drug can be continuously delivered to the proximal small intestine using a tube and portable infusion pump via percutaneous endoscopic gastrostomy. In one preferred embodiment, parenteral administration may be carried out in the form of continuous administration. Such continuous administration can be achieved by patch, injection, or infusion.

[0072] In this disclosure, tandospirone or a pharmaceutically acceptable salt or prodrug thereof is preferably administered in a manner that can maintain a blood drug concentration for a long period of time, and more preferably in a manner that can suppress the production of metabolites. Methods of administration include transdermal administration and subcutaneous, intradermal, and intramuscular injection. In the case of subcutaneous, intradermal, and intramuscular injection, a method of administration that sustains blood concentration is preferred. Among these, transdermal administration is the most preferred because it does not require hospital visits and is less invasive.

[0073] In this disclosure, the treatment, improvement, or prevention of motor complications associated with levodopa treatment for Parkinson's disease by parenteral administration of tandospirone or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical or composition containing the same, is preferable to treatment with active ingredients other than those disclosed, or to treatments and compositions other than those disclosed, from the viewpoint that it does not adversely affect the duration of action (ON time) of levodopa, does not adversely affect Parkinson's symptoms (which can be evaluated by UPDRS, etc.), the effect of this disclosure is not diminished even with repeated administration, and the number of daily administrations of levodopa preparations can be reduced by increasing the levodopa preparation to the optimal dose without worsening motor complications.

[0074] This disclosure provides compositions, pharmaceuticals, methods for treatment or prevention of motor fluctuations in Parkinson's disease, etc., containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof. Motor fluctuations in Parkinson's disease have become a problem, and such fluctuations can occur in conjunction with drug therapies for Parkinson's disease, such as levodopa therapy, though this is not intended to be an limitation. In this disclosure, the inventors have unexpectedly found that tandospirone or a pharmaceutically acceptable salt or prodrug thereof can suppress or eliminate motor fluctuations in Parkinson's disease. Furthermore, they have found that parenteral administration has the effect of extending ON time without dyskinesia, and that it has a clinically significant and more favorable effect in improving motor complications. Thus, the fact that parenteral administration of tandospirone exerted the effect of extending ON time without dyskinesia was not predictable from conventional knowledge. In other words, drugs that suppress or eliminate diurnal motor fluctuations are typically thought to have a pharmacological effect that increases dopamine levels, which is therefore expected to be accompanied by an exacerbation of dyskinesia.

[0075] This disclosure also finds that it can treat, improve, or prevent motor fluctuations such as wearing-off, on-off, no-on, and delayed-on phenomena, as well as treat, improve, or prevent dyskinesia in Parkinson's disease, such as levodopa-induced dyskinesia (PD-LID). PD-LID, a typical example of dyskinesia, is induced by levodopa overdose, so suppressing brain dopamine concentration is considered effective. On the other hand, increasing brain dopamine concentration is considered effective in suppressing motor fluctuations by extending on time or shortening off time. Therefore, it was not possible from conventional knowledge that the composition of this disclosure could treat, improve, or prevent motor fluctuations while simultaneously treating, improving, or preventing motor fluctuations in Parkinson's disease, such as levodopa-induced dyskinesia (PD-LID).

[0076] "Transdermal absorption preparations" refer to topical preparations, patches, and sprays (aerosols). Specifically, examples of patches include tapes, poultices, and plasters, while examples of topical preparations include ointments, creams, lotions, liniments, liquids, and gels. Patches are preferred. Tapes are even more preferred. In this disclosure, "tape" is synonymous with "patch," and therefore may also be referred to as "tape / patch" in this specification.

[0077] Transdermal formulations are manufactured by known methods using pharmaceutically acceptable additives. In one embodiment, the transdermal formulation used in this disclosure has an adhesive layer provided on a support, and the adhesive layer can be manufactured by including a thermoplastic elastomer or the like. A "thermoplastic elastomer" is an elastomer that exhibits thermoplasticity, softening and becoming fluid when heated and returning to a rubbery elastic body when cooled, and includes various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based, and olefin-based elastomers.

[0078] In the transdermal formulations of this disclosure, the adhesive layer may contain a non-volatile hydrocarbon oil. The non-volatile hydrocarbon oil is preferably a chain-type saturated hydrocarbon or a chain-type unsaturated hydrocarbon with approximately 20 to 40 carbon atoms, such as liquid paraffin, squalene, squalane, or pristane. Liquid paraffin is more preferred from the viewpoint of availability. Liquid paraffin is a colorless, odorless liquid mixture of alkanes with 20 or more carbon atoms, and in this 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 is preferably of high viscosity, and particularly high viscosity liquid paraffin is preferred from the viewpoint of adhesiveness.

[0079] Furthermore, the adhesive layer may contain a tackifier as needed. The tackifier is a resin commonly used in the field of adhesive patches to impart skin adhesion, and examples include rosin resins, polyterpene resins, coumarone-indene resins, petroleum resins, terpene-phenol resins, and alicyclic saturated hydrocarbon resins. One or more of these can be selected and used.

[0080] Furthermore, if transdermal administration is intended, it can also be achieved by applying ointment to the skin.

[0081] Dosage forms for parenteral administration (e.g., transdermal administration) of tandospirone or a pharmaceutically acceptable salt or prodrug thereof of the present disclosure, other than tapes / patches, may include powders, sprays, ointments, pastes, creams, lotions, gels, and solutions.

[0082] Ointments, pastes, creams, and gels may contain additives such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof, in addition to tandospirone or its pharmaceutically acceptable salts or prodrugs as disclosed herein.

[0083] The powders and sprays may, in addition to the pharmaceutical compositions of this disclosure, contain additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Furthermore, the sprays may contain common high-pressure gases such as chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.

[0084] In addition to ointments, powders, solutions, and other materials are also considered to be within the scope of this disclosure, as long as they are suitable for parenteral administration.

[0085] Compositions suitable for parenteral administration may include at least one pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solution, dispersion, suspension, emulsion, embedding agent, or sterile powder that can be reconstituted into a sterile injection solution or dispersion immediately before use.

[0086] The compositions disclosed herein can be made into suppositories for rectal or vaginal administration and can be prepared by mixing one or more compounds of the herein with one or more suitable non-irritating additives or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and thus melt in the rectum or vaginal cavity to release the compounds of the herein. 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.

[0087] In this disclosure, "drug dosage" refers to the amount of drug contained in the composition. On the label (package insert), it is stated as the content of the active ingredient. In this disclosure, "drug transfer amount" refers to the amount of drug taken into the body. If the composition is a transdermal formulation, "drug transfer amount" refers to the amount of drug transferred from the transdermal formulation to the skin, and is a value calculated by the following formula. The drug transfer amount is related to the efficacy of the drug. In clinical formulation results, the transfer amount is often 40-50% of the administered dose, but is not limited to this. "Remaining drug amount" refers to the amount of drug remaining on the transdermal formulation after it has been removed from the patch, and can be quantified by the method described in the Examples (Reference Manufacturing Examples) (

[0127] ), etc. Drug transfer amount (mg / day) = Drug dose (mg / day) - Remaining drug amount (mg / day) In addition, for formulations other than transdermal formulations, such as oral formulations and injectable formulations, the entire formulation is administered to the body, so the amount of drug administered and the amount of drug transferred are usually considered to be substantially the same. Therefore, for example, in the case of oral formulations, "being taken into the body" means being delivered into the gastrointestinal tract. If the amount of drug administered and the amount of drug transferred differ in transdermal laminated wood, for example in the case of a tape formulation, this can be identified by measuring the amount remaining in the tape after removal.

[0088] In this disclosure, drug dosage, drug transfer amount, residual drug amount, and blood (plasma) tandospirone concentration are expressed in terms of tandospirone-free form unless otherwise specified.

[0089] In this disclosure, the drug dosage and drug transfer amount of tandospirone or its salt can be appropriately adjusted depending on the type of compound, the patient's symptoms, age, weight, renal and hepatic function, etc. For example, the daily drug dose can be 0.1-500 mg, 0.1-400 mg, 0.1-250 mg, 0.1-220 mg, 0.1-180 mg, 0.1-100 mg, preferably 0.2-50 mg, 1-50 mg, 4-180 mg, 1-250 mg, 3-250 mg, etc. The upper limit can be 1000 mg, 800 mg, 500 mg, 400 mg, 250 mg, 220 mg, 180 mg, 150 mg, 100 mg, 80 mg, 50 mg, 30 mg, 15 mg, etc. The lower limit can be 0.1 mg, 0.2 mg, 1 mg, 2 mg, 3 mg, 4 mg, 10 mg, 15 mg, etc. Any combination of both the upper and lower limits can be considered a preferred range. The daily drug delivery amount can be 0.1-100 mg, 0.1-80 mg, 0.1-60 mg, 0.1-20 mg, preferably 0.2-10 mg or 1-60 mg. The upper limit can be 100 mg, 80 mg, 60 mg, 40 mg, 30 mg, 20 mg, 10 mg, 8 mg, 7 mg, 5 mg, or 3 mg, while the lower limit can be 0.1 mg, 0.2 mg, 1 mg, 1.5 mg, or 3 mg. A preferred range can be any combination of both the upper and lower limits. The administration frequency can be adjusted as appropriate depending on the characteristics of the composition. If the composition is a transdermal formulation, for example, it can be once every 12 hours to once every 7 days, and any frequency in between is also possible, for example, once a day, once every two days, once every three days, or once every four days. Preferably, it is once a day. If the composition is an injectable formulation, the administration frequency can be, for example, once daily to once every three months, or any frequency in between, such as once a week, once every two weeks, once every four weeks, or once every three months. Furthermore, it is possible to administer the drug continuously for 24 hours, only when awake, or adjust the administration time according to the symptoms using a pump-type automatic infusion device. In a preferred example, this drug can also be mixed with a formulation containing levodopa for continuous administration.

[0090] In this disclosure, tandospirone or a pharmaceutically acceptable salt or prodrug thereof is preferably administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL in free form during the time for which levodopa is to be effective. Specifically, this is 12 hours or more per day, preferably 16 hours or more.

[0091] Human blood (plasma) tandospirone concentrations, when converted to free form, can be categorized as follows: 0.05-20 ng / mL, 0.1-10 ng / mL, 0.5-15 ng / mL, 0.5-12 ng / mL, 0.1-15 ng / mL, 1-15 ng / mL, 1-12 ng / mL, 2-10 ng / mL, etc. The upper limits can be 20 ng / mL, 15 ng / 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 limits can be 0.01 ng / mL, 0.02 ng / mL, 0.05 ng / mL, 0.1 ng / mL, 0.2 ng / mL, 0.5 ng / mL, 1 ng / mL, 2 ng / mL, etc. Any combination of these upper and lower limits can be considered a preferred range. The above human blood (plasma) tandospirone concentrations may be achieved with a single dose or as a maintenance concentration through repeated administration.

[0092] In this disclosure, the maximum human blood (plasma) tandospirone concentration (Cmax) can be expressed as free-form equivalent values ​​of 0.1-20 ng / mL, 0.2-15 ng / mL, 0.3-12 ng / mL, 0.3-10 ng / mL, 1-15 ng / mL, 1-12 ng / mL, 1-10 ng / mL, 2-10 ng / mL, etc., with upper limits of 20 ng / mL, 15 ng / 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., and lower limits of 0.1 ng / mL, 0.2 ng / mL, 0.5 ng / mL, 1 ng / mL, 2 ng / mL, etc. A preferred range can be any combination of both these upper and lower limits.

[0093] In this disclosure, the area under the human blood (plasma) tandospirone concentration-time curve (AUC) can be expressed as 3-700 ng·h / mL, 3-500 ng·h / mL, 3-300 ng·h / mL, 3-250 ng·h / mL, 3-200 ng·h / mL, etc., on a free-form basis, with upper limits being 700 ng·h / mL, 600 ng·h / mL, 500 ng·h / mL, 4 Possible values ​​include 00 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, etc. Lower limits include 3 ng·h / mL, 5 ng·h / mL, 10 ng·h / mL, 20 ng·h / mL, 30 ng·h / mL, etc. Preferred ranges include any combination of both these upper and lower limits. The area under the tandospirone concentration-time curve (AUC) can be calculated using pharmacokinetic analysis methods. For example, values ​​can be calculated for 0-48 hours, 0-72 hours, from 0 hours to the final measurement point, or extrapolated to infinite time.

[0094] In this disclosure, a composition containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered such that, for a period of 8 to 16 hours, more preferably 8 to 20 hours, or for 12 hours or more per day, preferably 16 hours or more, and more preferably 18 hours or more, the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL, 0.1 to 15 ng / mL, 0.1 to 10 ng / mL, 0.5 to 15 ng / mL, 0.5 to 12 ng / mL, 1 to 15 ng / mL, 1 to 12 ng / mL, 2 to 10 ng / mL, etc., as described above. The above human blood (plasma) tandospirone concentration may be achieved by a single dose or as a maintenance concentration (which can also be called a steady state) by repeated doses. Steady-state blood concentrations may be calculated using the superposition method of single-dose concentrations. In the case of maintenance concentrations (steady state) achieved through repeated administration, the time after administration refers to the time since the last dose. In this specification, tandospirone or a pharmaceutically acceptable salt thereof is administered such that, after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the maximum steady-state human blood (plasma) tandospirone concentration is 1 to 15 ng / mL, and the ratio of the minimum concentration to the maximum human blood (plasma) tandospirone concentration (with the maximum concentration being 100%) is 30 to 95%, preferably 35 to 85%.

[0095] In this disclosure, when a composition containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof is a transdermal formulation, the application area of ​​the formulation can usually be adjusted as appropriate, but preferably the total application area per application is 1 to 200 cm². 2 , 1-100cm 2 , 2-80cm 2 , 9-60cm 2 The upper limit is 200cm. 2 , 160cm 2 , 130cm 2 , 100cm 2 , 80cm 2, 60cm 2 , 50cm 2 , 40cm 2 , 30cm 2 , 20cm 2 Examples include the following. The lower limit is 1 cm. 2 , 2cm 2 , 4cm 2 , 9cm 2 These are some examples. A preferred range is any combination of both the upper and lower limits, which can yield a desirable therapeutic effect.

[0096] The tandospirone of this disclosure or a pharmaceutically acceptable salt or prodrug thereof will cause the human blood (plasma) tandospirone concentration to exceed the lower limit within 12 hours, 8 hours, preferably 6 hours, and more preferably 4 hours after a single dose, and will maintain the human blood (plasma) tandospirone concentration within the upper and lower limits up to 16 hours, preferably 18 hours, more preferably 20 hours, and 24 hours after a single dose.

[0097] The tandospirone or its pharmaceutically acceptable salts or prodrugs of this disclosure are preferably pharmacokinetic profiles that reach peak blood concentration (Cmax) more slowly and are eliminated more slowly compared to oral administration. The average time to reach peak blood concentration (Cmax) is, for example, between 16 and 36 hours after a single dose, and between 20 and 32 hours. The average lower limit of the time to reach peak blood concentration (Cmax) is 16, 20, and 24 hours, while the average upper limit is 36 and 32 hours. The average half-life is, for example, between 3 and 20 hours. The average lower limit of the half-life is 3, 4, 5, and 6 hours, while the average upper limit is 20, 18, 16, and 14 hours.

[0098] As one appropriate clinical evaluation to confirm the efficacy of the pharmaceutical composition of the present invention against dyskinesia in Parkinson's disease, the protocol described in the following reference (J Clin Invest. (2014) 124(3):1340-1349.) can be used as a reference. Specifically, for patients with dyskinesia symptoms, brain functional imaging analysis using positron emission tomography (PET) of striatal dopamine D2 receptors can be performed and used to estimate the progression of the disease, the effective concentration of the drug, and to evaluate the treatment effect. For example, [ 11 C] raclopride can be used. 11 C] raclopride PET, striatum from baseline (OFF state) after administration of levodopa or in combination with administration of the pharmaceutical composition of the present invention and levodopa [ 11 By measuring the change in [C]raclopride binding, it is possible to evaluate the change in dopamine release in the striatum. Striatum in Parkinson's disease [ 11 Changes in raclopride receptor binding have been reported to be associated with the progression of Parkinson's disease, diurnal variation, and dyskinesia (Reference: Brain. (2004) 127:2747-2754). Based on the conditions of the PET scans described in the aforementioned references, the results of evaluating the dopamine levels in the striatum can be considered as follows. For example, in Parkinson's disease patients with diurnal variation or dyskinesia, compared to Parkinson's disease patients without diurnal variation or dyskinesia, the striatum before and 1 hour after levodopa administration is [ 11It is known that the change in raclopride receptor binding (sometimes abbreviated as change B / 1h) is large, for example, 10% or more, or 15% or more. When the change B / 1h decreases with drug treatment, it means that there is a therapeutic effect on motor complications such as dyskinesia. The pharmaceutical composition of the present invention is expected to reduce the change B / 1h, and in particular, it is expected to reduce the change B / 1h and have a therapeutic effect on motor complications such as dyskinesia in Parkinson's disease patients whose change B / 1h is significantly larger than in Parkinson's disease patients without diurnal variation or dyskinesia. When treated with the pharmaceutical composition of the present invention, for example, it is expected that the change B / 1h can be reduced to less than 10%. For example, in Parkinson's disease patients with diurnal variation or dyskinesia, compared to Parkinson's disease patients without diurnal variation or dyskinesia, the striatum [ 1 hour and 4 hours after levodopa administration ] 11 It is known that the absolute value of the change in C]raclopride receptor binding (sometimes abbreviated as change in 1h / 4h) is large, for example, 5% or more. When the change in B / 1h decreases with drug treatment, it means that there is a therapeutic effect on motor complications such as diurnal variation. The pharmaceutical composition of the present invention is expected to reduce the change in B / 1h, and in particular, it is expected to reduce the change in 1h / 4h and have a therapeutic effect on motor complications such as diurnal variation in Parkinson's disease patients with diurnal variation and dyskinesia, whose change in B / 1h is significantly larger than in Parkinson's disease patients without diurnal variation and dyskinesia. When treated with the pharmaceutical composition of the present invention, for example, it is expected that the change in 1h / 4h can be reduced to less than 5%. For example, "The striatum before and 1 hour after administration of levodopa before treatment with the composition of the present invention [ 11 When the change in raclopride receptor binding (sometimes abbreviated as change before treatment B / 1h) is taken as 100%, the striatum before and 1 hour after levodopa administration following therapeutic intervention with the pharmaceutical composition of the present invention [ 11A decrease in the percentage of change in raclopride receptor binding (sometimes abbreviated as change amount B / 1h after treatment) (sometimes abbreviated as change rate B / 1h) indicates a therapeutic effect on motor complications such as dyskinesia. The pharmaceutical composition of the present invention is expected to reduce the change rate B / 1h, and when a PET test is performed under the conditions reported in the literature, for example, the change rate B / 1h can be reduced to 90% or less, preferably 80% or less, and more preferably 70% or less. For example, in Parkinson's disease patients with diurnal variation and dyskinesia, "the striatum was observed 1 hour and 4 hours after administration of levodopa prior to treatment with the composition of the present invention." 11 [C] The change in raclopride receptor binding (sometimes abbreviated as the change before treatment at 1h / 4h) is greater than the change in the striatum at 1 hour and 4 hours after administration of levodopa following therapeutic intervention with the pharmaceutical composition of the present invention. 11 A decrease in the percentage of change in raclopride receptor binding (sometimes abbreviated as change amount 1h / 4h after treatment) (sometimes abbreviated as change rate 1h / 4h) indicates a therapeutic effect on exercise complications such as diurnal variation. The pharmaceutical composition of the present invention is expected to reduce the change rate 1h / 4h, and when a PET test is performed under the conditions reported in the literature, for example, the change rate 1h / 4h can be reduced to 90% or less, preferably 80% or less, and more preferably 70% or less. Furthermore, the measurement point before levodopa administration should be measured after sufficient time has elapsed since levodopa administration, when the effects of levodopa are no longer noticeable. The measurement point one hour after administration can be measured at a fixed time 1 to 2 hours after levodopa administration. The measurement point 4 hours after administration can be measured at a fixed time between 4 and 8 hours after levodopa administration. [ 11 [C] raclopride receptor binding amount Change B / 1h (%) = (Receptor binding amount before levodopa administration - Receptor binding amount 1 hour after levodopa administration) ÷ Receptor binding amount before levodopa administration × 100 Change B / 4h (%) = (Receptor binding amount before levodopa administration - Receptor binding amount 4 hours after levodopa administration) ÷ Receptor binding amount before levodopa administration × 100 Change in 1h / 4h (%) = |Receptor binding amount 1 hour after levodopa administration - Receptor binding amount 4 hours after levodopa administration| ÷ Receptor binding amount 1 hour after levodopa administration × 100 [ 11 [C] raclopride receptor binding amount Change rate B / 1h (%) = Change after treatment with the composition of the present invention B / 1h ÷ Change before treatment with the composition of the present invention B / 1h × 100 Percentage change 1h / 4h (%) = Change after treatment with the composition of the present invention 1h / 4h ÷ Change before treatment with the composition of the present invention 1h / 4h × 100 The therapeutic effect of the pharmaceutical composition of the present invention on diurnal variation, dyskinesia and other motor complications is [ 11 Dyskinesia onset time, ON time, OFF time, plasma drug concentration (levodopa, drug), etc., based on changes in raclopride receptor binding, clinical evaluation scales such as UPDRS, MDS-UPDRS, UDysRS, CDRS, Rush DRS, AIMS, EQ-5D-5L, PDQ-39, CGI, PGI, etc., recorded in patient diaries, ON time, OFF time, and scales calculated from movement information obtained by wearable devices such as accelerometers and / or gyroscopes, can be confirmed by comparing the placebo-treated patient group and the drug-treated patient group. In the above-mentioned trials, the target patients, duration of administration, drug dosage, evaluation methods, and other protocols can be modified as appropriate. (These experiments can be appropriately conducted by those skilled in the art, referring to J Clin Invest (2014) 124 (3) 1340-1349 and Mov Disord. (2017) 32(2):235-240., etc.) In this disclosure, the tandospirone transdermal formulation can be used in combination with a Parkinson's disease treatment agent such as a levodopa-containing formulation to treat Parkinson's disease. In this disclosure, a more favorable effect can be expected when the levodopa-containing formulation is administered 6 hours or more, preferably 8 hours or more, and more preferably 12 hours or more, after the application of the tandospirone transdermal formulation. Furthermore, by repeatedly administering the tandospirone transdermal formulation by replacing it at predetermined intervals, a stable therapeutic effect can be obtained regardless of the timing of administration of the levodopa-containing formulation.

[0099] The manufacturing method for the transdermal formulations described herein is described below, but this disclosure is not limited to these methods.

[0100] The transdermal formulations of this disclosure can be manufactured by generally known methods. The transdermal formulations of this disclosure can be manufactured, for example, by Manufacturing Example 1 below.

[0101] (Manufacturing Example 1) This document describes the general manufacturing method for adhesive tapes. The tape (patch) formulation described herein can be manufactured by conventional methods. For example, it can be manufactured according to the section on the manufacture of plaster formulations described in "Manual for the Development of Transdermal Formulations," supervised by Mitsuo Matsumoto (1985). Alternatively, it can be manufactured using the apparatus and methods described in, for example, "Development of a Manufacturing Apparatus for Transdermal Therapy Systems (Membrane, 32(2), 116-119 (2007))."

[0102] Specifically, in the manufacture of the tape material of this disclosure, the conventional method for manufacturing adhesive tapes can be applied to form the adhesive layer. A typical example is the solvent coating method, but other methods such as the hot melt coating method and the electron beam curing emulsion coating method can also be used.

[0103] To form the adhesive layer using a solvent coating method, for example, a mixture containing tandospirone and an adhesive, and formulation components such as a permeation accelerator and a curing agent, are mixed with an organic solvent to prepare an adhesive layer mixture. This mixture is then applied to one side of a support or release liner, dried to remove the organic solvent, and the release liner or support is bonded together either before or after drying. The thickness of the adhesive layer of the tape is not particularly limited, but is approximately 10 μm to approximately 600 μm. Preferably, it is approximately 10 μm to approximately 400 μm, more preferably approximately 20 μm to approximately 200 μm, even more preferably approximately 50 μm to approximately 180 μm, and particularly preferably approximately 70 μm to approximately 150 μm.

[0104] (Manufacturing example 2) Preparation of other parenteral formulations

[0105] Ointments can be manufactured by generally known methods. To prepare oily ointments, an oily base such as oils, waxes, or hydrocarbons like paraffin is typically heated and melted, an active ingredient is added, mixed and dissolved or dispersed, and then mixed and kneaded until the mixture is homogeneous. To prepare water-soluble ointments, a water-soluble base such as macrogol is typically heated and melted, an active ingredient is added, and then mixed and kneaded until the mixture is homogeneous.

[0106] For example, tandospirone can be manufactured by compounding it with higher alcohols such as cetanol and stearyl alcohol, higher fatty acids or their esters such as myristic acid, lauric acid, palmitic acid, stearic acid, and linoleic acid, waxes such as refined lanolin and whale wax, surfactants such as sorbitan fatty acid esters and sucrose fatty acid esters, hydrophilic petrolatum, liquid paraffin, and hydrocarbons such as Plastibase. A formulation of this ointment may be, for example, 0.5-10% by weight of tandospirone, 0.1-5% of higher alcohols, 1-15% by weight of higher fatty acids or their esters, 1-10% by weight of surfactants, 4-10% by weight of waxes, and 50-80% by weight of hydrocarbons. As for the manufacturing method, for example, tandospirone and the above-mentioned additive components are added, mixed under heating, maintained at 50-100°C, and after all components have become a clear solvent, uniformly mixed with a homomixer. Then, the ointment can be obtained by stirring while cooling and letting it cool.

[0107] Injectable preparations for subcutaneous, intradermal, and intramuscular administration can be manufactured by commonly known methods. Typically, they can be manufactured by the following methods: (i) The active ingredient, either as is or with add...

Claims

1. A composition for treating or improving motor fluctuations in dyskinesia symptoms in Parkinson's disease without exacerbating them, comprising tandospirone or a pharmaceutically acceptable salt thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered transdermally to a subject in the form of a transdermal formulation, wherein the exacerbation of dyskinesia symptoms in Parkinson's disease is a rebound symptom of levodopa-induced dyskinesia (PD-LID).

2. The composition according to claim 1, characterized in that the subject is receiving a drug therapy selected from the group consisting of levodopa-containing preparations, levodopa metabolic enzyme inhibitors, dopamine receptor agonists, and other drug therapies for Parkinson's disease, and adjuncts for Parkinson's disease.

3. The composition according to claim 1, characterized in that it sustainably maintains the amount of dopamine in the synaptic cleft of the striatum in the subject, suppresses rapid fluctuations in the amount of dopamine, and / or suppresses intermittent dopamine receptor stimulation.

4. The composition according to any one of claims 1 to 3, wherein the motor fluctuations include wearing-off phenomena, on-off phenomena, no-on phenomena, delayed-on phenomena, and combinations thereof.

5. The composition according to any one of claims 1 to 4, wherein the treatment or improvement of the aforementioned motor fluctuations includes extending the duration of the anti-Parkinson's disease effect (on time), shortening the time of inaction (off time), or a combination thereof.

6. The composition according to any one of claims 1 to 5, characterized in that the treatment or improvement improves motor fluctuations without causing painful dyskinesia symptoms.

7. The composition according to claim 1, provided as a transdermal patch.

8. The composition according to claim 1, wherein the transdermal absorption preparation is a tape / patch.

9. The composition according to any one of claims 1 to 8, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg per day as the free form of tandospirone.

10. The composition according to any one of claims 1 to 8, wherein the drug dose of tandospirone or a pharmaceutically acceptable salt thereof is 3 to 250 mg per day as the free form of tandospirone.

11. The composition according to any one of claims 1 to 8, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 0.1 to 100 mg per day as the free form of tandospirone.

12. The composition according to any one of claims 1 to 8, wherein the amount of tandospirone or a pharmaceutically acceptable salt thereof transferred is 1 to 60 mg per day as the free form of tandospirone.

13. The tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, with a total application area of ​​1 to 100 cm² per application. ２ The composition according to any one of claims 1 to 12.

14. The aforementioned tandospirone or a pharmaceutically acceptable salt thereof is provided as a transdermal formulation, with a total application area of ​​9 to 60 cm² per application. ２ The composition according to any one of claims 1 to 12.

15. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for 12 hours or more per day so that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL.

16. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered for 12 hours or more per day so that the human blood (plasma) tandospirone concentration is 0.5 to 15 ng / mL.

17. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 12 to 30 hours after a single dose of the tandospirone or a pharmaceutically acceptable salt thereof.

18. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.

19. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 0.1 to 15 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.

20. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that the human blood (plasma) tandospirone concentration is 10 to 100% of the maximum blood concentration after administration for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof.

21. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the minimum concentration to the maximum post-administration blood concentration (in plasma) is 10 to 95%, wherein the maximum post-administration blood concentration is 1 to 15 ng / mL.

22. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, for a period of 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the ratio of the human blood (plasma) tandospirone concentration to the minimum concentration, with the maximum blood concentration after administration being 100%, is 10 to 95%.

23. The composition according to any one of claims 1 to 14, characterized in that the tandospirone or a pharmaceutically acceptable salt thereof is administered such that, after administration of the tandospirone or a pharmaceutically acceptable salt thereof, the maximum blood concentration of human blood (plasma) tandospirone at steady state is 1 to 15 ng / mL, and the ratio of the minimum concentration to the maximum human blood (plasma) tandospirone concentration is 30 to 95%, with the maximum concentration being 100%.

24. The tandospirone or a pharmaceutically acceptable salt thereof was administered to the striatum before and one hour after levodopa administration. 11 The composition according to any one of claims 1 to 14, characterized in that it is administered such that the change in raclopride receptor binding (change B / 1h) is less than 10%.

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