Therapeutic drug for dyskinesia

Abstract

To provide a therapeutic drug that is useful for levodopa induced dyskinesia in Parkinson's disease.SOLUTION: The present invention provides a composition for treating, improving, suppressing the progression, or preventing motor complications associated with levodopa therapy for Parkinson's disease, especially levodopa induced dyskinesia (PD-LID), comprising tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is parenterally administered.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to a preparation containing tandospirone or a pharma- ceutical acceptable salt or prodrug thereof as an active ingredient, which is useful as a medicine, and which treats levodopa-induced dyskinesia in Parkinson's disease by parenteral administration (e.g., transdermal administration), or a method for treating the same. [Background technology]

[0002] Parkinson's disease is a progressive neurodegenerative disease whose main symptom is abnormalities in extrapyramidal function. Pathologically, dopaminergic neuronal loss and alpha-synuclein deposition are observed in the substantia nigra pars compacta. Clinically, the disease presents with various motor symptoms such as akinesia, resting tremor, muscular rigidity, and loss of postural reflexes.

[0003] The basis of Parkinson's disease treatment is drug therapy aimed at replenishing dopamine in the brain, and drugs containing the dopamine precursor levodopa (L-dopa, levodopa) are used as the first-line treatment for early Parkinson's disease. However, as the disease progresses, almost all patients undergoing levodopa treatment develop motor complications such as Parkinson's disease levodopa-induced dyskinesia (hereinafter referred to as "PD-LID" (Parkinson's Disease Levodopa induced dyskinesia)).

[0004] The incidence of PD-LID is 30-50% 5 years after the start of levodopa treatment, and increases as the disease progresses, reaching 50-100% 10 years after the start of treatment. Peak-dose dyskinesia is known as a typical symptom of PD-LID, and is an involuntary movement that appears in the face, tongue, neck, limbs, trunk, etc. when levodopa blood concentrations are high.

[0005] Patent Document 1 discloses a transdermal absorption formulation of tandospirone. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 11-228414 Summary of the Invention [Means for solving the problem]

[0007] As a result of intensive research, the present inventors have found that parenteral administration (e.g., transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, etc.) of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof has a high effect of improving Parkinson's disease levodopa-induced dyskinesia (PD-LID) and the like, as compared with oral administration, and can provide a useful technology for treating, improving, inhibiting the progression, and preventing the motor complications of Parkinson's disease. According to the present invention, a transdermal pharmaceutical composition containing tandospirone or a pharma- ceutically acceptable salt or prodrug thereof and improving PD-LID, and a method for treating, improving, inhibiting the progression, and preventing the motor complications of Parkinson's disease by parenteral administration containing tandospirone or a pharma- ceutically acceptable salt or prodrug thereof are provided.

[0008] That is, the present invention includes the following.

[0009] [Item 1] A composition for treating, ameliorating, inhibiting the progression of, or preventing motor complications associated with levodopa treatment of Parkinson's disease, comprising tandospirone or a pharma- ceutical acceptable salt or prodrug thereof, wherein the tandospirone or a pharma- ceutical acceptable salt or prodrug thereof is administered parenterally. [Item 2] The composition according to any one of the above items, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, and combinations thereof. [Item 3] The composition according to any one of the above items, wherein the parenteral administration is sustained or administered continuously. [Item 4] The composition according to any one of the above items, wherein the parenteral administration includes transdermal administration. [Item 5] The composition according to any one of the above items, wherein the motor complication includes levodopa-induced dyskinesia (PD-LID). [Item 6] A composition for treating, ameliorating, or preventing motor complications associated with levodopa treatment of Parkinson's disease, comprising tandospirone or a pharma- ceutical acceptable salt or prodrug thereof, the composition being characterized in that it improves levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms, and in that the tandospirone or a pharma-ceutical acceptable salt or prodrug thereof is administered transdermally. [Item 7] The composition according to any one of the above items, wherein the levodopa-induced dyskinesia (PD-LID) includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item 8] The composition according to any one of the above items, wherein the treatment, amelioration, inhibition of progression, or prevention of motor complications includes improvement of symptoms, inhibition of progression, or prevention of levodopa-induced dyskinesia (PD-LID), shortening the time to onset of levodopa-induced dyskinesia (PD-LID), or a combination thereof. [Item 9] A composition for improving, inhibiting the progression of, or preventing levodopa-induced dyskinesia (PD-LID) symptoms, shortening the time to onset of levodopa-induced dyskinesia (PD-LID), or a combination thereof, comprising tandospirone or a pharma- ceutically acceptable salt or prodrug thereof, wherein the composition is administered parenterally. [Item 10] The composition according to any one of the above items, wherein the improvement in symptoms of levodopa-induced dyskinesia (PD-LID) is at least a clinically significant improvement. [Item 11] The composition according to any one of the above items, wherein the improvement in symptoms of levodopa-induced dyskinesia (PD-LID) is at a level sufficient to achieve a clinical effect. [Item 12] The composition according to any one of the above items, wherein the composition is a transdermal preparation. [Item 13] The composition according to any one of the above items, wherein the composition is a patch preparation. [Item 14] The composition according to any one of the above items, wherein the transdermal preparation is a tape / patch. [Item 15] The composition according to any one of the above items, wherein the dosage of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day in terms of the free form of tandospirone. [Item 16] The composition according to any one of the above items, wherein the delivered amount of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is 0.1 to 20 mg per day in terms of the free form of tandospirone. [Item 17] The composition is a transdermal absorption preparation, and the total application area per application is 1 to 100 cm 2 The composition according to any one of the preceding claims, [Item 18] The composition according to any one of the above items, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered for 12 hours or more per day so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL. [Item 19] The composition according to any one of the above items, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL within 8 to 16 hours after administration of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof. [Item 20] The composition according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is an adjunct to levodopa. [Item 21] The composition according to any one of the above items, which is used in combination with levodopa in a fixed-dose formulation or in separate formulations. [Item 22] A pharmaceutical for treating or preventing Parkinson's disease without or with minimal PD-LID, the pharmaceutical comprising a combination of tandospirone or a pharma- ceutical acceptable salt or prodrug thereof with (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, wherein the tandospirone or a pharma-ceutical acceptable salt or prodrug thereof is administered parenterally. [Item 23] A pharmaceutical for treating or preventing Parkinson's disease without or with minimal PD-LID, the pharmaceutical comprising tandospirone or a pharma- ceutical acceptable salt or prodrug thereof, the tandospirone or a pharma- ceutical acceptable salt or prodrug thereof being administered in combination with (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, and the tandospirone or a pharma-ceutical acceptable salt or prodrug thereof being administered parenterally. [Item 24] A pharmaceutical for treating or preventing Parkinson's disease without or with minimal PD-LID, the pharmaceutical comprising (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, the (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor being administered in combination with tandospirone or a pharma- ceutical acceptable salt or prodrug thereof, and the tandospirone or a pharma-ceutical acceptable salt or prodrug thereof being administered parenterally. [Item 25] A composition for improving the deterioration of the quality of response to levodopa treatment in Parkinson's disease patients with dyskinesia, comprising tandospirone or a pharma- ceutically acceptable salt or prodrug thereof, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered parenterally. [Item 26] The pharmaceutical or composition according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is a free form of tandospirone.

[0010] [Item 1A] A method for treating, ameliorating, or preventing motor complications associated with levodopa treatment of Parkinson's disease, comprising a step of parenterally administering to a subject an effective amount of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof. [Item 2A] The method according to any one of the above items, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, and combinations thereof. [Item 3A] The method according to any one of the above items, wherein the parenteral administration is sustained or continuous administration. [Item 4A] The method according to any one of the above items, wherein the parenteral administration includes transdermal administration. [Item 5A] The method according to any one of the above items, wherein the motor complication includes levodopa-induced dyskinesia (PD-LID). [Item 6A] A method for treating, ameliorating, or preventing motor complications associated with levodopa treatment of Parkinson's disease, the method comprising the step of transdermally administering an effective amount of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof to a subject, thereby ameliorating levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms. [Item 7A] The method according to any one of the above items, wherein the levodopa-induced dyskinesia (PD-LID) includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item 8A] The method according to any one of the above items, wherein the treatment, improvement, inhibition of progression, or prevention of motor complications includes improvement of symptoms, inhibition of progression, or prevention of levodopa-induced dyskinesia (PD-LID), shortening the time to onset of levodopa-induced dyskinesia (PD-LID), or a combination thereof. [Item 9A] A method for achieving improvement, inhibition of progression, or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening the time to onset of levodopa-induced dyskinesia (PD-LID), or a combination thereof, the method comprising a step of parenterally administering to a subject an effective amount of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof. [Item 10A] The method according to any one of the above items, wherein the improvement in levodopa-induced dyskinesia (PD-LID) symptoms is at least a clinically significant improvement. [Item 11A] The method according to any one of the above items, wherein the improvement in symptoms of levodopa-induced dyskinesia (PD-LID) is at a level sufficient to achieve a clinical effect. [Item 12A] The method according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is provided as a transdermal preparation. [Item 13A] The method according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is provided as a patch preparation. [Item 14A] The method according to any one of the above items, wherein the transdermal preparation is a tape / patch. [Item 15A] The method according to any one of the above items, wherein the dosage of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day in terms of the free form of tandospirone. [Item 16A] The method according to any one of the above items, wherein the delivered amount of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is 0.1 to 20 mg per day as the free form of tandospirone. [Item 17A] The administration is achieved by a transdermal absorption preparation, and the total application area per administration is 1 to 100 cm 2 The method according to any one of the above claims, [Item 18A] The method according to any one of the above items, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered for 12 hours or more per day so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL. [Item 19A] The method according to any one of the above items, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL within 8 to 16 hours after administration of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof. [Item 20A] The method according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is an adjunct to levodopa. [Item 21A] The method according to any one of the above items, wherein the drug is used in combination with levodopa in the same formulation or in separate formulations. [Item 22A] A method for treating or preventing Parkinson's disease in a subject without or with minimal PD-LID, the method comprising the step of administering to the subject an effective amount of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof and (1) an effective amount of levodopa, or (2) an effective amount of a combination of levodopa and a levodopa-metabolizing enzyme inhibitor, wherein the effective amount of tandospirone or a pharma-ceutically acceptable salt or prodrug thereof is administered parenterally. [Section 23A] The method according to any one of the preceding paragraphs, wherein the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof and the (1) or (2) are administered simultaneously or at different times. [Item 24A] A composition for improving the deterioration of the quality of response to levodopa treatment in Parkinson's disease patients with dyskinesia, comprising tandospirone or a pharma- ceutically acceptable salt or prodrug thereof, characterized in that an effective amount of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered parenterally. [Item 25A] The method according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt thereof is a free form of tandospirone. [Item 1B] Use of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment, amelioration, or prevention of motor complications associated with levodopa treatment of Parkinson's disease, characterized in that the medicament is administered parenterally. [Item 2B] The use according to any one of the above items, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, and combinations thereof. [Item 3B] The use according to any one of the above items, wherein the parenteral administration is sustained or administered continuously. [Item 4B] The use according to any one of the above items, wherein the parenteral administration includes transdermal administration. [Item 5B] The use according to any one of the above items, wherein the motor complication includes levodopa-induced dyskinesia (PD-LID). [Item 6B] Use of tandospirone or a pharma- ceutical acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment, amelioration, or prevention of motor complications associated with levodopa treatment of Parkinson's disease, the use being characterized by improving levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms, and characterized in that the tandospirone or a pharma-ceutical acceptable salt or prodrug thereof is administered transdermally. [Item 7B] The use according to any one of the above items, wherein levodopa-induced dyskinesia (PD-LID) includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item 8B] The use according to any one of the above items, wherein the treatment, improvement, inhibition of progression, or prevention of motor complications includes improvement of symptoms, inhibition of progression, or prevention of levodopa-induced dyskinesia (PD-LID), shortening the time to onset of levodopa-induced dyskinesia (PD-LID), or a combination thereof. [Item 9B] Use of tandospirone or a pharma- ceutical acceptable salt or prodrug thereof in the manufacture of a medicament for improving, inhibiting the progression of, or preventing symptoms of levodopa-induced dyskinesia (PD-LID), shortening the time to onset of levodopa-induced dyskinesia (PD-LID), or a combination thereof, wherein the tandospirone or a pharma-ceutical acceptable salt or prodrug thereof is administered parenterally. [Item 10B] The use according to any one of the above items, wherein the improvement in levodopa-induced dyskinesia (PD-LID) symptoms is at least a clinically meaningful improvement. [Item 11B] The use according to any one of the above items, wherein the improvement in symptoms of levodopa-induced dyskinesia (PD-LID) is at a level sufficient to achieve a clinical effect. [Item 12B] The use according to any one of the above items, wherein the medicament is a transdermal preparation. [Item 13B] The use according to any one of the above items, wherein the pharmaceutical is a patch preparation. [Item 14B] The use according to any one of the above items, wherein the transdermal preparation is a tape / patch. [Item 15B] The use according to any one of the above items, wherein the dosage of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day in terms of the free form of tandospirone. [Item 16B] The use according to any one of the above items, wherein the delivered amount of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is 0.1 to 20 mg per day as the free form of tandospirone. [Item 17B] The medicine is a transdermal absorption preparation, and the total application area per application is 1 to 100 cm 2 The use according to any one of the above claims, [Item 18B] The use according to any one of the above items, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered for 12 hours or more per day so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL. [Item 19B] The use according to any one of the above items, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof. [Item 20B] The use according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is an adjunct to levodopa. [Item 21B] The use according to any one of the above items, wherein the medicament is used in combination with levodopa in the same formulation or in separate formulations. [Item 22B] Use in the manufacture of a medicine for treating or preventing Parkinson's disease without or with minimal PD-LID, the medicine comprising a combination of tandospirone or a pharma- ceutical acceptable salt or prodrug thereof with (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, wherein the tandospirone or a pharma-ceutical acceptable salt or prodrug thereof is administered parenterally. [Item 23B] A use in the manufacture of a medicine for treating or preventing Parkinson's disease without or with minimal PD-LID, the medicine comprising tandospirone or a pharma- ceutical acceptable salt or prodrug thereof, wherein the tandospirone or a pharma- ceutical acceptable salt or prodrug thereof is 、 (1) Use in which tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered parenterally in combination with levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor. [Item 24B] Use in the manufacture of a medicine for treating or preventing Parkinson's disease without or with minimal PD-LID, the medicine comprising (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, the (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor being administered in combination with tandospirone or a pharma- ceutically acceptable salt or prodrug thereof, and the tandospirone or a pharma-ceutically acceptable salt or prodrug thereof being administered parenterally. [Item 25B] Use of tandospirone or a pharma- ceutical acceptable salt or prodrug thereof in the manufacture of a medicament for improving the deterioration of the quality of response to levodopa treatment in a patient with Parkinson's disease accompanied by dyskinesia, characterized in that the tandospirone or a pharma- ceutical acceptable salt or prodrug thereof is administered parenterally. [Item 26B] The use according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt thereof is a free form of tandospirone. [Item 1C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof for the treatment, amelioration, or prevention of motor complications associated with levodopa treatment of Parkinson's disease, characterized in that the tandospirone or a pharma-ceutically acceptable salt or prodrug thereof is administered parenterally. [Item 2C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, and combinations thereof. [Item 3C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, characterized in that the parenteral administration is sustained or administered continuously. [Item 4C] The tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the parenteral administration includes transdermal administration. [Item 5C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the motor complication includes levodopa-induced dyskinesia (PD-LID). [Item 6C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof for the treatment, amelioration, or prevention of motor complications associated with levodopa treatment of Parkinson's disease, characterized in that it improves levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms, and characterized in that the tandospirone or a pharma-ceutically acceptable salt or prodrug thereof is administered transdermally. [Item 7C] Tandospirone or a phasic acceptable salt or prodrug thereof according to any one of the above items, wherein the levodopa-induced dyskinesia (PD-LID) includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item 8C] The tandospirone or a pharmacologic acceptable salt or prodrug thereof according to any one of the above items, wherein the treatment, improvement, inhibition of progression, or prevention of motor complications includes improvement of symptoms, inhibition of progression, or prevention of levodopa-induced dyskinesia (PD-LID), shortening the time to onset of levodopa-induced dyskinesia (PD-LID), or a combination thereof. [Item 9C] Tandospirone or a pharmaceutically acceptable salt or prodrug thereof for achieving improvement, inhibition of progression, or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening the time to onset of levodopa-induced dyskinesia (PD-LID), or a combination thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 10C] Tandospirone or a pharma- ceutical acceptable salt or prodrug thereof according to any one of the above items, wherein the improvement in symptoms of levodopa-induced dyskinesia (PD-LID) is at least a clinically significant improvement. [Item 11C] Tandospirone or a pharma- ceutical acceptable salt or prodrug thereof according to any one of the above items, wherein the improvement in symptoms of levodopa-induced dyskinesia (PD-LID) is at a level sufficient to obtain a clinical effect. [Item 12C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, which is a transdermal preparation. [Item 13C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, which is a patch preparation. [Item 14C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the transdermal preparation is a tape / patch. [Item 15C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the dosage of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day in terms of the free form of tandospirone. [Item 16C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the amount of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof delivered is 0.1 to 20 mg per day as the free form of tandospirone. [Item 17C] The tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is a transdermal preparation, and the total application area per application is 1 to 100 cm2. 2 4. The method of claim 1, wherein the tandospirone is a phenyl or phenyl group, or a phenyl group, [Item 18C] The tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered for 12 hours or more per day so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL. [Item 19C] The tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, characterized in that the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharma-ceutically acceptable salt or prodrug thereof. [Item 20C] The tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is an adjunct to levodopa. [Item 21C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof according to any one of the above items, used in combination with levodopa in the same formulation or in separate formulations. [Item 22C] A combination of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof with (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, for treating or preventing Parkinson's disease without or with minimal PD-LID, characterized in that the tandospirone or a pharma-ceutically acceptable salt or prodrug thereof is administered parenterally. [Item 23C] Tandospirone or a pharma- ceutical acceptable salt or prodrug thereof for treating or preventing Parkinson's disease without or with minimal PD-LID, wherein the tandospirone or a pharma- ceutical acceptable salt or prodrug thereof 、 Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is administered in combination with (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, and the tandospirone or a pharma-ceutically acceptable salt or prodrug thereof is administered parenterally. [Item 24C] A combination of (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor, for treating or preventing Parkinson's disease without or with minimal PD-LID, characterized in that the combination of (1) levodopa, or (2) levodopa and a levodopa metabolic enzyme inhibitor is administered in combination with tandospirone or a pharma- ceutically acceptable salt or prodrug thereof, and the tandospirone or a pharma-ceutically acceptable salt or prodrug thereof is administered parenterally. [Item 25C] Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof for improving the deterioration of the quality of response to levodopa treatment in Parkinson's disease patients with dyskinesia, characterized in that the tandospirone or a pharma-ceutically acceptable salt or prodrug thereof is administered parenterally. [Item 26C] Tandospirone according to any one of the above items, or a pharma- ceutically acceptable salt or prodrug thereof, in the free form.

[0011] In a specific embodiment, the present invention is provided as a patch (also referred to as a tape). By applying the tape of the present invention, dyskinetic symptoms associated with levodopa treatment of Parkinson's disease can be more preferably prevented or ameliorated. Furthermore, by applying the tape of the present invention to more preferably prevent or ameliorate dyskinetic symptoms associated with levodopa treatment of Parkinson's disease, treatment of Parkinson's disease can be performed in actual clinical settings by increasing the dose of levodopa per administration and / or per day compared to before treatment with the tape of the present invention without worsening dyskinesia. In current treatment, Parkinson's disease patients who experience dyskinesias are treated with low and frequent doses of levodopa (Guidelines for the Management of Parkinson's Disease, 2018 Edition (Part III, Q&A on the Management of Parkinson's Disease, Chapter 3, Treatment of Motor Symptoms)). By administering the parenteral preparation of tandospirone provided by the present invention, the onset of dyskinesia can be suppressed and the dosage of the preparation containing levodopa can be adjusted to an optimal dose. In other words, for Parkinson's disease patients who have or are at risk of developing dyskinesia, even if the single dose of levodopa is increased to reduce the number of doses or the daily dose of levodopa is increased, the symptoms of dyskinesia do not worsen, and more preferable treatment of Parkinson's disease symptoms is possible. The tandospirone or a pharma- ceutically acceptable salt or prodrug thereof and the treatment method of the present invention make it possible to treat or prevent reduced levodopa-induced motor complications and levodopa-induced dyskinesias associated with the usual daily dose of levodopa treatment described in the 2018 version of the Guidelines for the Diagnosis and Treatment of Parkinson's Disease published by the Japanese Society of Neurology or corresponding guidelines in the United States and Europe. Furthermore, administration of the parenteral formulation of tandospirone provided by the present invention can provide more favorable effects of improving levodopa-induced dyskinesia (PD-LID) and the like, as compared with oral administration. The present inventors have found for the first time that oral administration of tandospirone in the hope of improving dyskinesias temporarily worsens dyskinesias. In other words, they have found that oral administration of tandospirone is accompanied by the "rebound symptoms" of dyskinesias, and is therefore undesirable as a therapeutic agent for improving dyskinesias. The "rebound symptoms" in the present invention refer to the symptoms described in

[0036] . Furthermore, oral administration of tandospirone causes the "rebound symptoms," and therefore it is also undesirable to increase the dosage of a levodopa-containing preparation. The present inventors have found that the tandospirone parenteral composition of the present invention can improve dyskinesia without the "rebound symptom." The score of dyskinesia can be measured as the "AIMs score" (AIMs is an abbreviation for "abnormal involuntary movements") by the method described in

[0038] . Thus, the present invention may be embodied in the following specific embodiments. (1) (A) parenteral administration of tandospirone; (B) administering levodopa at a dose greater than the conventional dose; The present invention relates to a method for preventing or treating Parkinson's disease, a method for improving dyskinesia, or a method for preventing or treating Parkinson's disease with improved dyskinesia, comprising the steps of: (2) (A) parenteral administration of tandospirone; (B) increasing the dose of levodopa from the conventional dose and adjusting the number of times it is taken per day; The present invention relates to a method for preventing or treating Parkinson's disease, a method for improving dyskinesia, or a method for preventing or treating Parkinson's disease with improved dyskinesia, comprising the steps of: (3) (A) parenteral administration of tandospirone; (B) maintaining or increasing the dose of levodopa; The present invention relates to a method for preventing or treating Parkinson's disease, a method for improving dyskinesia, or a method for preventing or treating Parkinson's disease with improved dyskinesia, in a patient experiencing or at risk of experiencing dyskinesia, the method comprising the steps of: (4) (A) adding parenteral administration of tandospirone to conventional levodopa therapy; (B) increasing the dose of levodopa to a level that does not worsen dyskinesia and administering tandospirone parenterally in combination; The present invention relates to a method for preventing or treating Parkinson's disease, a method for improving dyskinesia, or a method for preventing or treating Parkinson's disease with improved dyskinesia, in a patient experiencing or at risk of experiencing dyskinesia, the method comprising the steps of: (5) (A) maintaining the plasma concentration of tandospirone at 0.05 to 20 ng / mL; (B) administering levodopa; The present invention relates to a method for preventing or treating Parkinson's disease, a method for improving dyskinesia, or a method for preventing or treating Parkinson's disease with improved dyskinesia, comprising the steps of: (6) (A) maintaining the plasma concentration of tandospirone at 0.05 to 20 ng / mL; (B) administering levodopa; The present invention relates to a method for preventing or treating Parkinson's disease, a method for improving dyskinesia, or a method for preventing or treating Parkinson's disease with improved dyskinesia, in a patient experiencing or at risk of experiencing dyskinesia, the method comprising the steps of: The reasons are as follows: · Levodopa has a short half-life and its effect does not last long, so it is usually taken multiple times a day, but when the tandospirone of the present invention is administered as a tape, that is, when one piece is applied per day, the blood concentration of tandospirone is maintained for 24 hours. Therefore, in the case of a transdermal preparation, levodopa is taken in a state where there is exposure to tandospirone, regardless of the timing of administration of levodopa. On the other hand, for example, if Sedir tablets and levodopa are taken three times a day at the same timing (oral administration), levodopa is taken in a state where the tandospirone concentration is reduced. In other words, it can be said that the characteristics are different from those of oral preparations. It is also considered preferable that the blood concentration of tandospirone is maintained when levodopa is administered.

[0012] In a detailed embodiment, the present invention can be used for various applications (indications, efficacy and effects), for example, improvement of dyskinesia (anti-dyskinesia drug) <PD-LID improvement drug>, treatment of dyskinesia (involuntary movements) in Parkinson's disease patients treated with levodopa (with or without combination with other medicines that increase the effects of dopamine in the brain) [Treating dyskinesia (involuntary movements) in Parkinson’s disease patients treated with levodopa therapy, with or without other medicines that increase the effects of dopamine in the brain.], etc. Efficacy and effects, precautions for use, and labels (package inserts) can be attached.

[0013] In the present invention, it is intended that the above one or more features can be provided in further combinations in addition to the explicitly stated combinations. Further embodiments and advantages of the present invention will be recognized by those skilled in the art upon reading the following detailed description as necessary. In this specification, unless otherwise specified, motor complications and dyskinesia mean symptoms associated with levodopa treatment for Parkinson's disease, and do not include symptoms derived from other diseases or symptoms associated with treatments other than levodopa.

Effects of the Invention

[0014] The pharmaceutical composition of the present invention can be expected to be a drug for treating, improving, suppressing the progression or preventing levodopa-induced motor complications (such as levodopa-induced dyskinesia (PD-LID), etc.) in Parkinson's disease. Specifically, it can be expected to be a drug for treating, improving, suppressing the progression or preventing PD-LID without rebound symptoms.

Brief Description of the Drawings

[0015] [Figure 1]Figure 1 shows the change in plasma concentration of tandospirone when the tape was applied to normal rats. In detail, the change in plasma concentration of tandospirone obtained by applying the tape (9 cm2: 31±2 cm2 / kg) to normal rats is shown as the mean±standard deviation. The x-axis shows the time from application, and the y-axis shows the plasma concentration of tandospirone. [Diagram 2] FIG. 2 shows the results of evaluation of dyskinesia-like symptoms when tandospirone tape was applied to PD-LID model rats under administration condition 1. In detail, tandospirone tape was administered transdermally to PD-LID model rats, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms, and the results are shown as mean ± standard error. ** indicates p<0.01, meaning that there is a significant difference compared to the placebo tape group (Wilcoxon rank sum test). In the figure, graph A shows the change in AIMs score over time after levodopa administration. Graph B shows the total AIMs score for 180 minutes. Graph C shows the total AIMs score for 100-180 minutes. [Diagram 3] FIG. 3 shows the results of evaluation of dyskinesia-like symptoms when tandospirone tape was applied to PD-LID model rats under administration condition 2. In detail, tandospirone tape was administered transdermally to PD-LID model rats that had undergone keratin stripping treatment at the tape application site, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms, and the results are shown as mean ± standard error. ** indicates p<0.01, meaning that there is a significant difference compared to the placebo tape application group (Wilcoxon rank sum test). In the figure, graph A shows the change in AIMs score over time after levodopa administration. Graph B shows the total AIMs score for 180 minutes. Graph C shows the total AIMs score for 100-180 minutes. [Figure 4]Figure 4 shows the results of evaluation of dyskinesia-like symptoms when tandospirone was continuously administered subcutaneously to PD-LID model rats. In detail, tandospirone was continuously administered subcutaneously to PD-LID model rats, and levodopa was administered 4 hours later to evaluate dyskinesia-like symptoms, and the results are shown as mean ± standard error. * indicates p<0.05, which means that there is a significant difference compared to the vehicle-administered group (Steel test). In the figure, graph A shows the change in AIMs score over time after levodopa administration. Graph B shows the total AIMs score for 180 minutes. Graph C shows the total AIMs score for 100-180 minutes. [Diagram 5] Figure 5 shows the long-term evaluation results of dyskinesia-like symptoms when tandospirone citrate was continuously administered subcutaneously to PD-LID model rats. In detail, tandospirone citrate was continuously administered subcutaneously to PD-LID model rats, and dyskinesia-like symptoms were evaluated on the first day of administration and the 13th day of administration, and the total AIMs score for 180 minutes was shown as the mean ± standard error. ** indicates p<0.01, which means that there is a significant difference compared to the vehicle-administered group (Wilcoxon rank-sum test). In the figure, graph A shows the results on day 0 after pump implantation, and graph B shows the results on day 13 after pump implantation. [Figure 6] Figure 6 shows the effect of tandospirone citrate on the onset of dyskinesia when it was continuously administered subcutaneously to rats with unilateral intracerebral 6-hydroxydopamine treatment. In detail, levodopa was repeatedly administered to rats with unilateral intracerebral 6-hydroxydopamine treatment, and tandospirone citrate was continuously administered subcutaneously. The effect on the onset of dyskinesia-like symptoms induced by repeated administration of levodopa was evaluated, and the results were shown as mean ± standard error. * indicates p<0.05, ** indicates p<0.01, and indicates a significant difference compared to the vehicle-administered group (Steel test). In the figure, graph A shows the results over time of repeated administration of levodopa, and graph B shows the results on the day after the administration of tandospirone citrate was completed (16th day). [Figure 7]FIG. 7 shows the results of evaluation of dyskinesia-like symptoms when tandospirone citrate was orally administered to PD-LID model rats. In detail, tandospirone citrate (citrate concentration: 10 mg / kg, 30 mg / kg) was orally administered to PD-LID model rats, and levodopa was administered 5 minutes later to evaluate dyskinesia-like symptoms, and the results were shown as mean ± standard error. * indicates p<0.05, which means that there is a significant difference compared to the vehicle-administered group (Steel test). In the figure, graph A shows the change in AIMs score over time after levodopa administration. Graph B shows the total AIMs score for 180 minutes. Graph C shows the total AIMs score for 100-180 minutes. [Figure 8] FIG. 8 shows the evaluation results of dyskinesia-like symptoms when tandospirone citrate was orally administered to PD-LID model rats. In detail, tandospirone citrate (citrate concentration: 30 mg / kg, 100 mg / kg) was orally administered to PD-LID model rats, and levodopa was administered 5 minutes later to evaluate dyskinesia-like symptoms, and the results are shown as mean ± standard error. In the figure, graph A shows the change in AIMs score over time after levodopa administration. Graph B shows the total AIMs score for 180 minutes. Graph C shows the total AIMs score for 100-180 minutes. [Figure 9] FIG. 9 shows the powder X-ray diffraction patterns of tandospirone free form, tandospirone citrate (hydrate) and tandospirone citrate (anhydrous). [Figure 10] FIG. 10 shows the evaluation results of dyskinesia-like symptoms when 1-PP dihydrochloride was administered subcutaneously to PD-LID model rats. In detail, 1-PP dihydrochloride (10 mg / kg, 30 mg / kg) was administered subcutaneously to PD-LID model rats, and levodopa was administered 5 minutes later to evaluate dyskinesia-like symptoms, and the results are shown as mean ± standard error. In the figure, graph A shows the change in AIMs score over time after levodopa administration. Graph B shows the total AIMs score for 180 minutes. Graph C shows the total AIMs score for 100-180 minutes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention will be described below while showing the best mode. Throughout this specification, the expression of the singular form should be understood to include the concept of the plural form, unless otherwise specified. Therefore, the singular article (for example, in the case of English, "a", "an", "the", etc.) should be understood to include the concept of the plural form, unless otherwise specified. In addition, it should be understood that the terms used in this specification are used in the sense commonly used in the field, unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, this specification (including definitions) will take precedence.

[0017] (Definition, etc.) The following provides definitions of terms particularly used in this specification and / or explains basic technical content as appropriate.

[0018] As used herein, "tandospirone [chemical name: (1R,2S,3R,4S)-N-[4-{4-(pyrimidin-2-yl)piperazin-1-yl}butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide] has the following structure: [ka] Sedir tablets, which contain tandospirone citrate as an active ingredient, are used in treatment as a serotonergic anxiolytic (see, for example, Sedir package insert, April 2016, 14th edition, Sumitomo Dainippon Pharma Co., Ltd.; JP 58-126865 A). Tandospirone has a beneficial effect on memory in chronic schizophrenia, and is known to improve cognitive dysfunction by administering tandospirone or a pharma- ceutical acceptable salt thereof while continuing maintenance therapy with a typical antipsychotic such as haloperidol (see JP 2002-20291 A).

[0019] As an active ingredient used in the pharmaceutical composition of the present invention, tandospirone (free form) is preferred, and pharma- ceutically 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.

[0020] A prodrug of tandospirone refers to any component that is structurally different from tandospirone but can be converted by metabolism into tandospirone or an active component based thereon after administration to exert a medicinal effect.

[0021] A prodrug of tandospirone refers to a compound that is converted to tandospirone by a reaction caused by an enzyme or the like under physiological conditions in a living body, i.e., a compound that is converted to tandospirone by enzymatic oxidation, reduction, hydrolysis, etc., or a compound that is converted to tandospirone by hydrolysis with an acid, etc. In addition, a prodrug of tandospirone may be one that is converted to tandospirone under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Shoten in 1990. Tandospirone or a salt thereof or a prodrug thereof of the present invention (hereinafter also referred to as tandospirones) has excellent serotonin 5-HT1A receptor activating activity. Furthermore, the tandospirone of the present invention has low toxicity and is safe.

[0022] Drugs containing "tandospirone citrate" as an active ingredient are used in clinical applications as oral drugs to treat (1) depression and fear in neurosis, and (2) physical symptoms in psychosomatic disorders (autonomic nervous system imbalance, essential hypertension, peptic ulcer), as well as depression, anxiety, restlessness, and sleep disorders. In in vitro receptor binding evaluations of various neurotransmitter receptors, tandospirone has high selectivity for serotonin 1A receptors (hereinafter also referred to as "5-HT1A receptors"), while it has low affinity for dopamine 2 receptors (hereinafter also referred to as "D2 receptors"). For this reason, tandospirone is thought to be effective against neurosis by activating 5-HT1A receptors and selectively acting on serotonin nerves.

[0023] In this specification, "levodopa" (broad sense) includes levodopa in the narrow sense (L-3,4-dihydroxyphenylalanine (IUPAC name is (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid), also known as L-dopa), as well as any other drug that has the same efficacy as L-3,4-dihydroxyphenylalanine. Examples of such other drugs include, but are not limited to, esters of L-3,4-dihydroxyphenylalanine and salts thereof. Examples of esters of L-3,4-dihydroxyphenylalanine include levodopa ethyl ester (LDEE; ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), levodopa propyl ester; levodopa propyl ester (propyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), levodopa methyl ester (methyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), and the like, and the esters of L-3,4-dihydroxyphenylalanine may be salts, including hydrated salts. Salts of levodopa esters may include, but are not limited to, any of octanoate, myristate, succinate, succinate dihydrate, fumarate, fumarate dihydrate, mesylate, tartrate, and hydrochloride. For example, the succinate salt or succinate dihydrate of an ester of L-3,4-dihydroxyphenylalanine can include levodopa ethyl ester succinate (LDEE-S) or levodopa ethyl ester succinate dihydrate (LDEE-S-dihydrate or LDEE-S(d)).

[0024] In this specification, the term "levodopa metabolic enzyme inhibitor" refers to any drug having the effect of inhibiting the metabolism of levodopa in a broad sense so as to enhance the effect of the same, and examples thereof include dopa decarboxylase inhibitors (DCIs) (examples include carbidopa, α-methyldopa, benzerazide (Ro4-4602), α-difluoromethyl-DOPA (DFMD) or salts thereof) that prevent levodopa from being converted to dopamine in the intestines, liver, or blood vessels, catecholamine-O-methyltransferase inhibitors (COMT-Is) (examples include entacapone) that similarly prevent levodopa from being broken down before entering the brain, and monoamine oxidase inhibitors (MAO-Is) (examples include selegiline) that prevent dopamine from being broken down in the brain.

[0025] (Diseases and disorders)

[0026] In this specification, the term "motor complications" refers to any motor symptoms that are observed in patients with advanced Parkinson's disease and that are problematic in treatment, including dyskinesia, an involuntary movement associated with levodopa treatment (levodopa-induced dyskinesia (PD-LID)). Motor complications are believed to be due to the excessive action of levodopa, but the mechanism is not necessarily clear.

[0027] In this specification, "levodopa-induced dyskinesia (involuntary movement) (PD-LID)" refers to an involuntary movement of the limbs or body that is induced by excessive administration of levodopa, such as an involuntary twisting movement of the limbs or body. It is known that dyskinesia is likely to occur when excessively large amounts of levodopa are taken from the early stage of the disease, and that once dyskinesia has appeared, it is very difficult to control it even if the dosage of levodopa is adjusted in various ways. Peak-dose dyskinesia is known as a typical symptom of PD-LID, and symptoms appear in the face, tongue, neck, limbs, trunk, etc. when the blood concentration of levodopa is high.

[0028] Dyskinesia refers to the involuntary movement of a body part that cannot be stopped, lip biting, difficulty in speaking, difficulty in staying still, and difficulty in moving the limbs as desired. It is a movement disorder in which involuntary movements of the limbs and / or orofacial and / or axial parts of the body are observed. Dyskinesia observed in PD patients treated with levodopa is called levodopa-induced dyskinesia (LID) and occurs in more than half of PD patients after 5 to 10 years of levodopa treatment, and the proportion (%) of patients affected by LID is increasing over time (for a review, see e.g. 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).

[0029] Peak-dose dyskinesia is an involuntary movement that occurs when an anti-Parkinson's drug is taken in excess. Diphasic dyskinesia is a type of dyskinesia that occurs in two phases, when the anti-Parkinson's drug begins to work and when it wears off.

[0030] As used herein, the term "pharmaceutically acceptable salt" includes acid and / or base salts formed by inorganic and / or organic acids and bases, and includes acid addition salts and base addition salts.For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, etc., or organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, etc. Examples of base addition salts include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, and aluminum salts, and 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. Examples of "pharmaceutically acceptable salts" include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (1977) 66:1-19.

[0031] Tandospirone or its pharma- ceutically acceptable salt or prodrug or medicament of the present invention may contain a carrier, if necessary. As used herein, the term "carrier" refers to a pharma- ceutically acceptable substance, composition, or excipient, such as a liquid or solid filler, diluent, additive, solvent, base, or skin permeation enhancer, that is involved in or enables the delivery or transport of the subject pharmaceutical compound from one organ, tissue, or part of the body to another organ, tissue, or part of the body. "Pharmaceutically acceptable" means compatible with other ingredients in the formulation and not harmful to the subject.

[0032] Diseases treatable in the present invention include any levodopa-induced motor complications of Parkinson's disease.

[0033] In a specific embodiment, patients treatable in accordance with the present invention include Parkinson's disease patients who have or may develop levodopa-induced motor complications, including levodopa-induced dyskinesias.

[0034] The improving effect of the present invention on levodopa-induced dyskinesia in Parkinson's disease can be clinically confirmed by clinical rating scales such as the Unified Dyskinesia Rating Scale (UDysRS), Clinical Dyskinesia Rating Scale (CDRS), and Abnormal Involuntary Movement Scale (AIMS) and patient diaries. In addition, in a non-clinical PD-LID model rat, the improving effect on dyskinesia can be confirmed by evaluating dyskinesia-like abnormal involuntary movement behavior. By using this method, it is possible to measure the improvement of levodopa-induced dyskinesia (PD-LID) symptoms, inhibition of progression, or prevention, as well as the shortening of the onset time of levodopa-induced dyskinesia (PD-LID).

[0035] In the present invention, whether PD-LID symptoms are aggravated can be confirmed by whether clinical assessment scales for dyskinesia, such as UDysRS, CDRS, AIMS, etc., are significantly worse than before treatment with tandospirone. It can also be confirmed by whether symptoms related to dyskinesia are clearly worsened by a patient diary. In the present specification, whether levodopa-induced dyskinesia symptoms are painful can be confirmed by clinical records such as a patient diary.

[0036] In the present invention, the "rebound symptom" of levodopa-induced dyskinesia (PD-LID) refers to a phenomenon in which a therapeutic drug for improving dyskinesia temporarily worsens the dyskinesia score. The "rebound symptom" is a phenomenon in which dyskinesia worsens during treatment with a dyskinesia improving drug after the peak time (e.g., 1 hour) of the anti-Parkinson's disease effect of levodopa compared to when treatment with the dyskinesia improving drug is not performed, and is assumed to appear 1 to 6 hours after administration of levodopa.

[0037] In the present invention, improving levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms means that dyskinesia does not worsen, even if only temporarily, after administration of levodopa, and the total dyskinesia score improves, compared to when treatment with a dyskinesia improving drug is not performed. "Without worsening dyskinesia" means a state in which dyskinesia is present (AIMs score of 2 or more in the AIMs evaluation system of non-clinical PD-LID model rats) and the dyskinesia score does not significantly worsen, compared to when treatment with a dyskinesia improving drug is not performed.

[0038] In the AIMs evaluation system of non-clinical PD-LID model rats, the rebound symptoms of levodopa-induced dyskinesia (PD-LID) can be evaluated, for example, using clear dyskinesia-like symptoms (AIMs score of 2 or more) observed at 120-140 minutes after levodopa administration and the total AIMs score from 100 to 180 minutes as indicators. Improvement of dyskinesia can be evaluated by the total AIMs score for 180 minutes after levodopa administration. In this AIMs evaluation system of PD-LID model rats, an AIMs score of 2 or more is judged to be dyskinesia, and the higher the number, the more severe the dyskinesia. Also, an AIMs score of less than 2 is judged to be absent of dyskinesia.

[0039] The present inventors have found that oral administration of tandospirone causes rebound symptoms and is therefore not suitable for the treatment of PD-LID. On the other hand, the present invention has found that parenteral administration of tandospirone improves levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms. As a form of treatment, it is preferable to administer tandospirone parenterally continuously or parenterally in the form of a sustained-release preparation, and it is more preferable to administer tandospirone transdermally.

[0040] In this specification, the term "adjunct" refers to a drug other than the drug that has the main action. In the present invention, if levodopa is the main drug, tandospirone and the like can be said to be adjuncts.

[0041] In this specification, the daily dose of levodopa, which is the main agent, is the usual dose of levodopa treatment described in the 2018 version of the Parkinson's Disease Clinical Practice Guidelines or the corresponding guidelines in the United States and Europe. In general, the usual daily dose of levodopa is 50 to 1200 mg / day, preferably 100 mg to 600 mg / day, as a combination or compounding agent with a peripheral dopa decarboxylase inhibitor (DCI). For example, SINEMET (registered trademark) (Carbidopa-Levodopa combination tablet) (New Drug Application (NDA) #017555) approved by the FDA is provided as a 1:4 ratio combination tablet (Carbidopa 25 mg-Levodopa 100 mg) and a 1:10 ratio combination tablet (Carbidopa 10 mg-Levodopa 100 mg, Carbidopa 25 mg-Levodopa 250 mg). The daily maintenance dose of SINEMET® is 70 mg to 100 mg of Carbidopa, up to a maximum daily dose of 200 mg of SINEMET®. Tandospirone or a pharma- ceutically acceptable salt or prodrug thereof or treatment herein allows for the reduced treatment of motor complications or prevention of motor complications associated with the administration of normal doses of levodopa treatment.

[0042] By administering tandospirone or a pharma- ceutically acceptable salt or prodrug thereof of the present invention, the dose of levodopa can be adjusted appropriately, for example, to within the range of single dose and daily dose as defined in the 2018 version of the Guidelines for the Diagnosis and Treatment of Parkinson's Disease published by the Japanese Society of Neurology or the corresponding guidelines in the United States and Europe.

[0043] In the present specification, the term "having sustained action" can be determined by a person skilled in the art, taking into consideration the description in the present specification and utilizing knowledge known in the art. Specifically, when the blood drug concentration is maintained for a long time and the biological half-life extension effect is shown, it can be defined as having sustained action. Examples of compositions having sustained action include various transdermal absorption preparations described in

[0051] , various sustained injections described in

[0089] , and various implants described in

[0090] . In addition, in the present invention, "administered sustainedly" means that the active ingredient in the present invention is administered sustainedly from outside the body to the body. It can be selected from the parenteral administration routes described in

[0048] , and can be achieved by transdermal absorption, injection, infusion, etc.

[0044] In the present specification, the term "clinically significant time" can be determined by a person skilled in the art, taking into consideration the description in the present specification and utilizing knowledge known in the art. Specifically, when a significant effect is shown in the prevention, treatment, or alleviation of motor complications targeted by the present invention, the time can be defined as a clinically significant time. Similarly, in the present specification, when a significant effect is shown in the prevention, treatment, or alleviation of motor complications targeted by the present invention, the condition can be defined as a clinically significant improvement. Such a method of measuring time or improvement is a matter that can be appropriately selected by a person skilled in the art, and for example, any method described in the present specification can be considered, but is not limited thereto, and for example, the 2018 version of the Parkinson's Disease Treatment Guidelines issued by the Japanese Society of Neurology can be used. Alternatively, it has been reported that the clinical evaluation index of dyskinesia (MDS UDysRS Part III) is 2.32 points (Parkinsonism Relat Disord 21:1349, 2015)), and it can be appropriately determined in consideration of such matters as (1) comparison with placebo and (2) before and after treatment for each patient.

[0045] In the present specification, the terms "sufficient time to obtain a clinical effect" and "sufficient level to obtain a clinical effect" can also be determined by a person skilled in the art, taking into account the description in the present specification and utilizing knowledge known in the art. Specifically, if the time or level at which a clinical effect such as prevention, treatment or reduction of motor complications targeted by the present invention can be obtained can be measured, the time or level can be evaluated as being sufficient to obtain a clinical effect. Such a method for measuring the time or level can be appropriately selected by a person skilled in the art, and for example, any method described in the present specification can be considered, but is not limited thereto. For example, the 2018 version of the Parkinson's Disease Clinical Practice Guidelines published by the Japanese Society of Neurology or corresponding guidelines in the United States and Europe can also be used.

[0046] As used herein, "not worsening levodopa-induced dyskinesia (PD-LID) symptoms in Parkinson's disease patients" means not worsening existing dyskinesia symptoms to a clinically significant degree or not significantly worsening them, not extending the time of dyskinesia onset, not significantly worsening even temporarily like rebound symptoms of dyskinesia, and not causing new dyskinesia symptoms. Dyskinesia symptoms can be measured, for example, by UPDRS, UDysRS, CDRS, AIMS, etc., or confirmed by clinical records such as a patient diary.

[0047] As used herein, "worsening of the quality of response to levodopa treatment in a Parkinson's disease patient" refers to any decrease in the patient's responsiveness to levodopa treatment, and such deterioration in the quality of response can be measured from dyskinetic symptoms, etc. Furthermore, "improvement" in "worsening of the quality of response to levodopa treatment in a Parkinson's disease patient" refers to an improvement in the degree of dyskinetic symptoms in levodopa treatment in each patient, and can be confirmed by measurement using UPDRS, UDysRS, CDRS, AIMS, etc., or by clinical records such as a patient diary.

[0048] As used herein, the term "parenteral administration" refers to any administration route other than oral administration, and preferably any administration route in which tandospirone is administered in a form and at a level effective for levodopa-induced motor complications of Parkinson's disease. Examples of parenteral administration include administration by transdermal or transmucosal absorption, including injection or infusion, and combinations thereof. For example, administration by transdermal or transmucosal absorption is effective when a transdermal preparation such as a coating agent, patch, or spray is brought into contact with the skin or mucosa, and the drug in the preparation is transferred into the body through the skin or mucosa. Examples of administration by injection or infusion include intravenous, intradermal, subcutaneous, intramuscular, and enteral (enema) administration, and may be bolus administration and / or continuous infusion. They may be suspensions, solutions, emulsions, or implants in oily or aqueous media, including 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 by percutaneous endoscopic gastrostomy using a tube and a portable infusion pump. In one preferred embodiment, parenteral administration can be performed in the form of continuous administration. Such continuous administration can be achieved by a patch, injection, infusion, or the like.

[0049] In the present invention, tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is preferably administered by a method capable of maintaining the blood drug concentration for a long time, and more preferably by a method capable of suppressing the production of metabolites. Examples of the administration method include transdermal administration and subcutaneous, intradermal, and intramuscular injections. In the case of subcutaneous, intradermal, and intramuscular injections, it is preferable that the administration method is one that maintains the blood concentration. Among them, transdermal administration is the most preferable because it does not require hospital visits and is a less invasive administration method.

[0050] In the present invention, the treatment, improvement, inhibition of progression, or prevention of motor complications associated with levodopa treatment of Parkinson's disease by parenteral administration containing tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is preferable compared to treatments using active ingredients other than those of the present invention and treatments and compositions other than those of the present invention, from the viewpoints of not adversely affecting the duration of levodopa action (ON time), not adversely affecting Parkinson's symptoms (which can be evaluated by UPRDS, etc.), not weakening the effects of the present invention even with repeated administration, and being able to reduce the number of times the levodopa formulation is administered per day by increasing the dose of the levodopa formulation to an optimal dose without worsening the motor complications.

[0051] The "percutaneous absorption preparation" refers to a liniment, a patch, or a spray (aerosol). Specifically, liniment includes a tape (patch), a cataplasm, and a plaster, while liniment includes an ointment, a cream, a lotion, a liniment, a liquid, and a gel. A patch is preferred. A tape (patch) is more preferred. In the present invention, a "tape" is synonymous with a "patch," and therefore may be referred to as a "tape / patch" in the present specification.

[0052] The percutaneous absorption preparation is produced by a known method using pharma- ceutical acceptable additives. In one embodiment, the percutaneous absorption preparation used in the present invention has an adhesive layer provided on a support, and the adhesive layer can be produced by including a thermoplastic elastomer or the like. The "thermoplastic elastomer" is an elastomer that exhibits thermoplasticity, which softens and exhibits fluidity when heated and returns to a rubber-like elastic body when cooled, and includes various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based, and olefin-based elastomers.

[0053] In the case of the percutaneous absorption preparation of the present invention, the adhesive layer may contain a non-volatile hydrocarbon oil. As the non-volatile hydrocarbon oil, a chain saturated hydrocarbon having about 20 to 40 carbon atoms or a chain unsaturated hydrocarbon having about 20 to 40 carbon atoms is preferable, and examples thereof include liquid paraffin, squalene, squalane, pristane, etc. Among them, liquid paraffin is more preferable from the viewpoint of availability. Liquid paraffin is a colorless and odorless liquid mixture of alkanes having 20 or more carbon atoms, and in the present invention, those conforming to the standards specified in the Japanese Pharmacopoeia, the United States Pharmacopoeia, etc. can be preferably used. As the non-volatile hydrocarbon oil, those with high viscosity are preferable, and in particular, it is preferable to use liquid paraffin with high viscosity from the viewpoint of adhesion.

[0054] The adhesive layer may contain a tackifier as necessary. Tackifiers are resins that are generally used in the field of patches to impart skin adhesion, such as rosin resins, polyterpene resins, coumarone-indene resins, petroleum resins, terpene-phenol resins, and alicyclic saturated hydrocarbon resins, and one or more of these may be selected for use.

[0055] When transdermal administration is envisaged, this can also be achieved by applying an ointment to the skin.

[0056] Dosage forms for parenteral administration (e.g., transdermal administration) of tandospirone or a pharma- ceutically acceptable salt or prodrug thereof of the present disclosure other than tapes / patches can include powders, sprays, ointments, pastes, creams, lotions, gels, and solutions.

[0057] The ointments, pastes, creams, and gels can contain, in addition to the tandospirone of the present disclosure or a pharma- ceutically acceptable salt or prodrug thereof, additives such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0058] Powders and sprays can contain, in addition to the pharmaceutical composition of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Furthermore, sprays can contain common propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.

[0059] In addition to ointments, powders, solutions, and the like, so long as they are suitable for parenteral administration, are also intended to be within the scope of the present disclosure.

[0060] Compositions suitable for parenteral administration can comprise at least one pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension, emulsion, implant, or sterile powder that can be reconstituted into a sterile injectable solution or dispersion immediately before use.

[0061] The compositions disclosed herein can be made into suppositories for rectal or vaginal administration, which can be prepared by mixing one or more compounds according to the present disclosure with one or more suitable non-irritating excipients or carriers, including cocoa butter, polyethylene glycol, suppository waxes, or salicylates, 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 present disclosure. Pharmaceutical compositions suitable for vaginal administration can also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known in the art to be appropriate.

[0062] In the present invention, the "drug dose" refers to the amount of drug contained in the composition. In addition, in the present invention, the "drug transfer amount" refers to the amount of drug taken into the body. When the composition is a transdermal preparation, the "drug transfer amount" refers to the amount of drug transferred from the transdermal preparation to the skin, and is a value calculated by the following formula. The "residual drug amount" refers to the amount of drug remaining in the transdermal preparation that has been peeled off after application, and can be quantified by the method described in the Examples (Reference Manufacturing Examples) (

[0098] to

[0101] ), etc. Drug transfer amount (mg / day) = Drug administration amount (mg / day) - Drug remaining amount (mg / day)

[0063] In the present invention, the drug dose, drug transfer amount, remaining drug amount and blood (plasma) tandospirone concentration are amounts converted into free tandospirone unless otherwise specified.

[0064] In the present invention, 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, body weight, renal and hepatic function, etc. For example, the drug dosage per day can be 0.1 to 100 mg, preferably 0.2 to 50 mg, etc., with the upper limit being 100 mg, 80 mg, 50 mg, 30 mg, 15 mg, etc., and the lower limit being 0.1 mg, 0.2 mg, 1 mg, 2 mg, 3 mg, etc., and the preferred range can be any combination of both of these upper and lower limits. The drug transfer amount per day can be 0.1 to 20 mg, preferably 0.2 to 10 mg, with the upper limit being 20 mg, 10 mg, 8 mg, 7 mg, 5 mg, 3 mg, etc., and the lower limit being 0.1 mg, 0.2 mg, 1 mg, 1.5 mg, etc., and the preferred range can be any combination of both of these upper and lower limits. The frequency of administration can be adjusted appropriately depending on the characteristics of the composition. When the composition is a transdermal preparation, it can be, for example, once every 12 hours to once every 7 days, and any frequency between these can be used, for example, once every 2 days, once every 3 days, once every 4 days, etc. When the composition is an injectable preparation, it can be, for example, once every day to once every 3 months, and any frequency between these can be used, for example, once a week, once every 2 weeks, once every 4 weeks, once every 3 months, etc. In addition, it is possible to administer the drug continuously for 24 hours using a pump-type automatic injection device, or to administer the drug only when awake, and to adjust the administration time according to the symptoms. The drug can also be mixed with a preparation containing levodopa and administered continuously.

[0065] In the present invention, tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is preferably administered so that the concentration of tandospirone in human blood (plasma) is 0.05 to 20 ng / mL in terms of the free form during the period during which levodopa is desired to act, specifically, for 12 hours or more, preferably 16 hours or more per day.

[0066] The concentration of tandospirone in human blood (plasma) can be 0.05 to 20 ng / mL, etc., in terms of the free form, with the upper limit being 20 ng / mL, 15 ng / mL, 10 ng / mL, 8 ng / mL, 5 ng / mL, etc., and the lower limit being 0.05 ng / mL, 0.1 ng / mL, 0.2 ng / mL, 0.5 ng / mL, 1 ng / mL, etc. Preferred ranges can include any combination of these upper and lower limits. The above-mentioned concentration of tandospirone in human blood (plasma) can be achieved by a single administration, or can be achieved as a maintenance concentration by repeated administration.

[0067] In the present invention, the maximum concentration (Cmax) of tandospirone in human blood (plasma) can be 0.1 to 20 ng / mL, calculated as the free form, with the upper limit being 20 ng / mL, 15 ng / mL, 10 ng / mL, 8 ng / mL, 5 ng / mL, etc., and the lower limit being 0.1 ng / mL, 0.2 ng / mL, 0.5 ng / mL, 1 ng / mL, etc. Preferred ranges can include any combination of these upper and lower limits.

[0068] In the present invention, the area under the tandospirone concentration-time curve (AUC) in human blood (plasma) can be, in terms of the free form, 3 to 700 ng·h / mL, etc., with the upper limit being 700 ng·h / mL, 600 ng·h / mL, 400 ng·h / mL, 300 ng·h / mL, 200 ng·h / mL, etc., and the lower limit being 3 ng·h / mL, 5 ng·h / mL, 10 ng·h / mL, 30 ng·h / mL, etc. Preferred ranges can be any combination of these upper and lower limits.

[0069] In the present invention, a composition containing tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is characterized in that it is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 8 to 16 hours after administration of the tandospirone or a pharma- ceutically acceptable salt or prodrug thereof.

[0070] In the present invention, when the composition containing tandospirone or a pharma- ceutically acceptable salt or prodrug thereof is a percutaneous absorption preparation, the application area of ​​the preparation can usually be adjusted appropriately, but preferably, the total application area per application is 1 to 100 cm. 2 The upper limit is 100 cm. 2 , 50cm 2 , 40cm 2 , 30cm 2 , 20cm 2 The lower limit is 1 cm. 2 , 2cm 2 , 4cm 2 , 9cm 2 As a preferred range, any combination of these upper and lower limits can be used, providing a favorable therapeutic effect.

[0071] The tandospirone or pharma- ceutically acceptable salt or prodrug thereof of the present invention exceeds the lower limit of human blood (plasma) tandospirone concentration within 8 hours, preferably within 6 hours, and more preferably within 4 hours after a single administration, and maintains the human blood (plasma) tandospirone concentration within the upper and lower limits for up to 16 hours, preferably up to 18 hours, and more preferably up to 20 hours after a single administration.

[0072] In the present invention, the tandospirone transdermal preparation is used in combination with a levodopa-containing preparation to treat Parkinson's disease. The tandospirone transdermal preparation of the present invention is more effective when the levodopa-containing preparation is administered 6 hours or more, preferably 8 hours or more, and more preferably 12 hours or more after application of the tandospirone transdermal preparation. In addition, by repeatedly administering the tandospirone transdermal preparation by replacing it at a predetermined time, a stable therapeutic effect can be obtained regardless of the administration timing of the levodopa-containing preparation.

[0073] The process for producing the percutaneously absorbable preparation of the present invention will be explained below, but the present invention is not limited to this process.

[0074] The percutaneous absorption preparation of the present invention can be produced by a generally known method. The tape preparation of the present invention can be produced, for example, by the following Production Example 1.

[0075] (Production Example 1) A general method for producing the tape preparation will be described. The tape preparation (patch preparation) of the present invention can be produced by a conventional method. For example, it can be produced according to the section on the production of plaster preparations described in "Transdermal Application Preparation Development Manual" edited by Matsumoto Mitsuo (1985). It can also be produced by, for example, the apparatus and method described in "Development of a Patch Manufacturing Apparatus for Transdermal Therapeutic Systems (Membrane, 32(2), 116-119(2007))".

[0076] Specifically, in the production of the tape preparation of the present invention, a typical method for producing a pressure-sensitive adhesive tape can be applied to form the pressure-sensitive adhesive layer, a typical example of which is a solvent coating method, but other methods such as a hot melt coating method and an electron beam curing emulsion coating method can also be used.

[0077] To form the adhesive layer by the solvent coating method, for example, a mixture containing tandospirone and an adhesive, and formulation components such as a permeation enhancer and a curing agent are mixed with an organic solvent to prepare an adhesive layer mixture, the mixture is applied to one side of a support or a release liner, dried to remove the organic solvent, and the release liner or support is attached either before or after drying, thereby producing the adhesive layer. The thickness of the adhesive layer of the tape preparation is not particularly limited, and is preferably about 10 μm to about 400 μm, more preferably about 20 μm to about 200 μm, even more preferably about 50 μm to about 180 μm, and particularly preferably about 70 μm to about 150 μm.

[0078] (Production Example 2) Preparation of other parenteral dosage forms

[0079] Ointments can be produced by commonly known methods. In order to produce an oleaginous ointment, an oleaginous base such as fats and oils, waxes, and hydrocarbons such as paraffin is usually heated to melt, an active ingredient is added, mixed to dissolve or disperse, and the whole is mixed and kneaded until it becomes homogeneous. In order to produce a water-soluble ointment, a water-soluble base such as macrogol is usually heated to melt, an active ingredient is added, and the whole is mixed and kneaded until it becomes homogeneous.

[0080] For example, tandospirone can be prepared by blending higher alcohols such as cetanol and stearyl alcohol, higher fatty acids such as myristic acid, lauric acid, palmitic acid, stearic acid, and linoleic acid or their esters, waxes such as purified lanolin and spermaceti, surfactants such as sorbitan fatty acid esters and sucrose fatty acid esters, and hydrocarbons such as hydrophilic petrolatum, liquid paraffin, and plastibase. The formulation of this ointment is, for example, 0.5-10% by weight of tandospirone, 0.1-5% by weight of higher alcohol, 1-15% by weight of higher fatty acid or its ester, 1-10% by weight of surfactant, 4-10% by weight of wax, and 50-80% by weight of hydrocarbon. For example, the preparation method is to add tandospirone and the above-mentioned additive components, mix them under heating, and keep them at 50-100°C. After all the components become a transparent solution, they are mixed uniformly with a homomixer. Then, the ointment can be obtained by cooling and stirring while leaving it to cool.

[0081] Injections for subcutaneous, intradermal, and intramuscular administration can be prepared by generally known methods, typically by the following method. (i) The active ingredient, either as is or with the addition of additives, is dissolved, suspended or emulsified in water for injection, other aqueous solvents or non-aqueous solvents to make a homogeneous solution, which is then filled into a container for injection, sealed, and sterilized. (ii) The active ingredient, either as is or with the addition of additives, is dissolved, suspended or emulsified in water for injection, other aqueous solvents or non-aqueous solvents to obtain a homogeneous solution, which is then subjected to sterile filtration, or a homogeneous solution prepared aseptically is filled into a container for injection and sealed.

[0082] The above-mentioned injections may be prepared as lyophilized or powdered injections in order to prevent the active ingredients from being decomposed or inactivated in solution.

[0083] Freeze-dried injections can usually be produced by dissolving the active ingredient as is, or the active ingredient and additives such as excipients, in water for injection, sterilizing and filtering, filling into a container for injections, and then freeze-drying, or by freeze-drying in a dedicated container and then filling into a direct container.

[0084] Powdered injections can usually be prepared by treating with sterile filtration, followed by adding a sterilized additive to a powder obtained by crystallization or to the powder, and then filling the resulting mixture into a container for injections.

[0085] For example, tandospirone is dissolved together with a surfactant in water, an organic solvent, or a mixed solvent of an organic solvent and water to prepare an active ingredient solution. The obtained solution can be sterilized by filtration using a sterilizing filter to prepare a sterile active ingredient solution. The solvent used for dissolution here (water, an organic solvent, or a mixed solvent of an organic solvent and water) is preferably an organic solvent, or a mixed solvent of an organic solvent and water, more preferably a mixed solvent of an organic solvent and water. The sterilizing filter is effective not only for sterilization by filtration, but also for removing foreign matter derived from raw materials or exogenous foreign matter mixed in during the manufacturing process.

[0086] Examples of the surfactant include polysorbate 80, polysorbate 20, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkonium chloride, sodium lauryl sulfate, etc., and two or more of these may be used. Polysorbate 80 is preferable. The surfactant is preferably used at about 0.005% (w / v) to about 10% (w / v). The water used may be purified water, water of the same or higher grade as purified water, or water for injection. Examples of the organic solvent include alcohol solvents (e.g., methanol, ethanol, etc.), aprotic solvents (e.g., acetone, dimethyl sulfoxide, N,N-dimethylacetamide, etc.), etc., and two or more kinds of solvents may be used. Preferred are 1-propanol, methanol, ethanol, 2-propanol, acetone, dimethyl sulfoxide, and N,N-dimethylacetamide.

[0087] The injection of the present invention can be administered intramuscularly or subcutaneously after attaching an injection needle to a prefilled syringe filled with the formulation. In addition, the formulation can be aspirated from a container such as a vial filled with the formulation into an injection syringe through an injection needle, and then discharged intramuscularly or subcutaneously for injection. Furthermore, the formulation can be freeze-dried by filling the formulation into a container such as a vial and then freeze-drying it to obtain a freeze-dried formulation, or the active ingredient crystals in the formulation can be isolated and then dried to obtain dry powder crystals, which can be powder-filled into a container such as a vial to obtain a powder-filled formulation. In the freeze-dried formulation and the powder-filled formulation, a suspension prepared by suspending the active ingredient in a suspension liquid in a container at the time of use can be aspirated from the container into an injection syringe through an injection needle and then administered intramuscularly or subcutaneously. The injection of the present invention can also be administered intramuscularly or subcutaneously after placing a container filled with the formulation in a needleless syringe (a syringe device having a mechanism for discharging a drug solution filled in the container by utilizing pressure generated by a gas, an explosive, a spring, etc. incorporated in the syringe device, and a form that can be administered without using an injection needle.)

[0088] Example of continuous infusion pump adjustment The injection of the present invention can be continuously administered using a commercially available continuous subcutaneous infusion pump. The continuous subcutaneous infusion pump is a device having a drug storage section and a pump for continuously injecting a drug, and for continuously injecting the drug subcutaneously into a patient through an infusion tube. This device usually has a built-in clock and a program that can change the amount of injection at regular intervals. The drug storage section is a sealed container filled with a drug solution adjusted to a drug concentration required for the drug effect, and is equipped with a drug solution inlet and outlet for connection to the pump. The pump is a pump that can continuously inject this drug solution with precision, and is a device that can inject a small amount of liquid, from 0.1 mL / day to 10 mL / hour. The drug storage section is filled with and stored with a tandospirone solution that is guaranteed to be sterile.

[0089] Long-acting injections are injections that are applied subcutaneously, intradermally, intramuscularly, etc., for the purpose of releasing the active ingredient over a long period of time. Long-acting injections can be produced by commonly known methods. Typically, they can be produced by dissolving or suspending the active ingredient in vegetable oil or the like, or by forming a suspension of microspheres using a biodegradable polymer compound.

[0090] The implant is a solid or gel-like injection that is applied subcutaneously, intramuscularly, etc., using an implantation device or by surgery, with the aim of releasing the active ingredient over a long period of time. The implant can be produced by a commonly known method. In general, it can be obtained by forming a pellet, microsphere, or gel-like preparation using a biodegradable polymer compound.

[0091] (Concomitant medications) The percutaneous absorption preparation of the present invention can be used in combination with existing Parkinson's disease treatment drugs other than levodopa. Examples of such existing Parkinson's disease treatment drugs include, but are not limited to, dopamine agonists (e.g., bromocriptine, pergolide, talipexole, cabergoline, pramipexole, ropinirole, rotigotine, etc.), monoamine oxidase B (MAOB) inhibitors (e.g., selegiline, rasagiline, safinamide), catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone), amantadine, apomorphine, istradefylline, anticholinergic drugs (e.g., biperiden, trihexyphenidyl, profenamine, mazaticol), tiapride, droxidopa, carbidopa, zonisamide, etc.

[0092] The present invention will be described in more detail below with reference to examples, examples and test examples, but the present invention is not limited thereto. The compound names shown in the following reference examples and examples do not necessarily conform to the IUPAC nomenclature. EXAMPLES

[0093] Examples are described below.

[0094] The specific reagents used were those described in the Examples, but equivalent products from other manufacturers (Sigma-Aldrich, Wako Pure Chemical Industries, Nacalai Tesque, R&D Systems, USCN Life Science INC, etc.) can also be used.

[0095] (Production example) Reference Manufacturing Example 1: Manufacturing of Tandospirone Tandospirone ((1R,2S,3R,4S)-N-[4-[4-(pyrimidin-2-yl)piperazin-1-yl]butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide) has the chemical formula shown below, and its production method, etc. are described in JP-A-58-126865, the disclosure of which is incorporated herein by reference. [ka]

[0096] (Reference manufacturing example: manufacturing of tandospirone tape) (Manufacturing of tandospirone tape) Acrylic adhesive (MAS683, Cosmedi Pharmaceutical Co., Ltd., solid content 35.6 wt%, 12.5068 g), ethyl acetate (1.5 mL), and polyoxyethylene lauryl ether (0.2530 g) were mixed. A solution of tandospirone (0.32512 g) in ethyl acetate (5.5 mL) was prepared and added to the adhesive mixture and thoroughly stirred. The resulting mixture was spread on a support and dried at room temperature for one day. A release liner was then attached to produce a tandospirone tape. (Placebo tape manufacturing) An acrylic adhesive (MAS683, manufactured by Cosmedi Pharmaceutical Co., Ltd., solid content 35.6 wt%, 18.6962 g), ethyl acetate (5.5 mL), and polyoxyethylene lauryl ether (0.3520 g) were mixed and thoroughly stirred. The resulting mixture was spread on a support and dried at room temperature for one day. A release liner was then attached to produce a placebo tape.

[0097] The support used was a 50.8 μm polyethylene terephthalate and / or ethylene vinyl acetate copolymer laminate film (Scotchpak #9732) manufactured by 3M Healthcare Co., Ltd. The release liner used was Binasheet 64S-018B manufactured by Fujimori Kogyo Co., Ltd. [Table 1]

[0098] Measurement of the amount of drug in the tape (drug dose) and the amount of drug remaining Examples of conditions for measuring the drug dose and remaining drug amount are described below, but these may be substituted with other measurement methods that have been verified to be capable of measuring the drug dose or remaining drug amount of tandospirone. <Example of measurement conditions> Preparation of standard solutions Prepare tandospirone solutions (approximately 4, 20, 100 μg / mL). Preparation of formulation solutions (1) Place the tape in a container, add 10 mL of acetone, and irradiate with ultrasound for approximately 30 minutes. (2) Add 1 mL of methanol to 1 mL of the extract from (1) and mix. (3) Filter through a filter (Millipore: Millex-FH (0.45 μm, PTFE)).

[0099] High performance liquid chromatogram (HPLC) conditions Column: YMC-Pack ODS-AM 250 x 4.6mm (particle size 5μm) Column oven: 40℃ Detector: Ultraviolet spectrophotometer (measurement wavelength: 240 nm) Flow rate: 0.9mL / min Injection volume: 10μL Mobile phase: 10 mM phosphate buffer (pH 6.8) / acetonitrile mixture (35:65)

[0100] ( Plasma concentration evaluation) 1. Test Method 1.1. Pretreatment procedure 50μL of rat plasma sample was taken into a polypropylene microtube, 50μL of methanol (50μL of standard solution for calibration curve sample) and 200μL of internal standard solution (Bezafibrate methanol solution: 200nmol / L, 200μL of methanol for blank sample) were added, and the mixture was stirred for about 10 seconds in a mixer. After centrifuging (4℃, 4500rpm, 10min), the supernatant was suction filtered through a filtration filter (FastRemover MF 0.2μm). 70μL of the obtained filtrate was added with 70μL of 10mmol / L ammonium acetate aqueous solution, and the mixture was stirred for about 10 seconds in a mixer to prepare the measurement sample. Tandospirone concentrations are measured by liquid chromatography-mass spectrometry.

[0101] 1.2. Measurement conditions Column: XSELECT CSH C18, 3.5μm, 100×3.0mm ID Column temperature: 50℃ Mobile phase A: 10mmol / L ammonium acetate aqueous solution Mobile phase B: Methanol Flow rate: 0.6mL / min Gradient conditions: [Table 2] Ionization method: Electrospray ionization Detection method: multiple reaction monitoring, positive ion detection mode Monitor ions: 384.2 / 122.1 (Tandospirone Q1 / Q3, m / z), 362.02 / 138.9 (Bezafibrate Q1 / Q3, m / z)

[0102] (Example 1: Evaluation of plasma concentration transition when tandospirone tape was applied to normal rats) (Test Method) Male Wistar rats (14 weeks old, Japan SLC) were used. The hair on the rat's abdomen was shaved before the tape preparation was evaluated, and the tape preparation of Formulation 1 was applied to the abdomen on the evaluation day (size: 9 cm 2 Blood samples were taken at 2, 4, 6, and 24 hours after patch administration, and the plasma tandospirone concentration was analyzed. The results are shown as the mean ± standard deviation.

[0103] (result) Tandospirone tape application (9cm 2 :31±2cm 2 The change in plasma tandospirone concentration over time due to the administration of 100 mg / kg of tandospirone is shown in Figure 1. It was confirmed that the tape formulation smoothed and sustained the blood concentration of tandospirone.

[0104] (Example 2: Evaluation of the effect of tandospirone tape in improving dyskinesia) A representative experimental model for PD-LID is the rat striatal dopamine nerve destruction model by local administration of 6-hydroxydopamine (hereinafter sometimes referred to as "6-OHDA") to one side of the brain (6-OHDA unilaterally treated rats (6-OHDA lesioned rats)). In this model, repeated administration of levodopa causes dyskinesia-like abnormal involuntary movements (AIMs) (Lundblad et al., European Journal of Neuroscience, 2002, 15:120-132, Winkler et al., Neurobiology of Disease, 2002, 10:165-186).

[0105] (Test Method) Male Wistar rats (12 weeks old, Japan SLC) were used to prepare the model animals. Desipramine hydrochloride (25 mg / kg; Wako Pure Chemical Industries, Ltd.) was administered intraperitoneally, and 30 minutes after administration, anesthesia with isoflurane was administered by inhalation using a general anesthesia machine for experimental animals. Under isoflurane anesthesia, the rat was fixed in a brain stereotaxic apparatus, the skin of the head was incised with a scalpel to expose the skull, and the coordinates of the bregma, which was the origin (AP: 0, ML: 0, DV: 0), were confirmed, and the coordinates of the right medial forebrain bundle (AP: -4.4 mm, ML: 1.5 mm, DV: 7.8 mm from bregma) were measured. After inserting an injection tube for administration at the measurement coordinates, 6-OHDA (9 μg / 4 μL; Sigma-Aldrich), which has a dopamine neurodegenerative effect, was locally injected. Two weeks after surgery, apomorphine hydrochloride 0.5-hydrate (0.5 mg / kg; Wako Pure Chemical Industries, Ltd.) was administered subcutaneously, and rotational movement toward the contralateral side to the 6-OHDA injection site was observed. Rats that made more than seven rotations per minute were used as 6-OHDA unilaterally treated rats.

[0106] To prepare the PD-LID model, a mixture of levodopa methyl ester hydrochloride (6 mg / kg; Sigma-Aldrich) and benserazide hydrochloride (15 mg / kg; Sigma-Aldrich) dissolved in saline (hereinafter referred to as "levodopa combination solution") was intraperitoneally administered once a day to 6-OHDA-lesioned rats. The levodopa combination solution was repeatedly administered for more than three weeks, and behavioral observation evaluation was performed. The behavioral observation evaluation was performed in a transparent acrylic cage for 1 minute every 20 minutes, starting 20 minutes after intraperitoneal administration of the levodopa combination solution, until 3 hours after administration. Behavioral observations were classified into limb AIMs (involuntary bending and straightening of the forelimb on the side opposite to the lesion, opening and closing of the palm, moving the wrist up and down, chorea-like tremors, and dystonia-like rigidity), axial AIMs (twisting the upper body and neck toward the side opposite to the lesion, losing balance and falling, or continuing to maintain the unstable posture), orolingual AIMs (jaw shaking or violently protruding the tongue forward), and locomotive behavior (rotation behavior toward the side opposite to the lesion), and were scored from 0 to 4 (0; not at all, 1; occurring for less than 30 seconds, 2; occurring for more than 30 seconds, 3; always occurring but stopped by sound or other stimuli, 4; always occurring and not stopped by sound or other stimuli). The sum of the scores for limb AIMs, axial AIMs, and orolingual AIMs over 3 hours was taken as the total AIMs score. Individuals with a total AIMs score of less than 10 were excluded from the study as they were considered to have no dyskinesia-like symptoms. Behavioral observation evaluation was performed before the drug evaluation day, and the rats were assigned to each treatment group based on the 3-hour AIMs score, locomotive behavior score, and body weight, and used for drug evaluation.

[0107] (Transdermal administration (condition 1)) When evaluating the tape preparation, the hair on the rat's abdomen was shaved before the evaluation day. On the evaluation day, the tape preparation of Formulation 2 was applied at a thickness of 60 cm. 2 The tape was applied to the abdomen of rats at a dose of 37 mg / kg (37 mg / kg), and 4 hours after application, a levodopa combination solution was administered intraperitoneally and behavioral observation evaluation was performed. Animals in which more than 50% of the tape peeled off during the test were excluded from the analysis. After the behavioral observation evaluation, plasma was collected and the plasma concentration of tandospirone was analyzed.

[0108] (Transdermal administration (condition 2)) When evaluating the tape preparation under keratin stripping conditions (high tandospirone exposure conditions), strip the abdomen of rats 10 times using Transpore Surgical Tape (3M) on the day of evaluation, and then apply the tape preparation of Formulation 3 60 cm 2 The tape was applied to the rats at a dose of 45 mg / kg (45 mg / kg), and 4 hours after application, a levodopa combination solution was administered intraperitoneally, followed by a behavioral observation evaluation. Animals in which more than 50% of the tape had come off during the test were excluded from the analysis. After the behavioral observation evaluation, plasma was collected and the plasma concentration of tandospirone was analyzed.

[0109] In the evaluation of dyskinesia-like symptoms, the AIMs score was calculated as the sum of the limb AIMs, axial AIMs, and orolingual AIMs at each evaluation point. Statistical analysis of the test results was performed using the Wilcoxon rank sum test with the total AIMs score, calculated by adding up the AIMs scores for the 3 hours, and the total AIMs score for the 100-180 minutes as indicators. ** indicates p<0.01, which means there is a significant difference compared to the placebo tape group. The results in the figure are shown as mean ± standard error.

[0110] (result) When tandospirone was absorbed through the skin by applying tandospirone tape (preparation 2: drug dose 37 mg / kg) via transdermal administration (condition 1), the total AIMs score was 12.6. The total AIMs score was 17.7 lower than when a placebo tape not containing tandospirone was applied, and a significant improvement in dyskinesia-like symptoms was observed (Figures 2A and 2B). In addition, at 120-140 minutes after levodopa administration, no clear dyskinesia-like symptoms (mean AIMs score of 2 or more) were observed in either the placebo tape group or the tandospirone tape group, and no significant difference was observed in the total AIMs score from 100 to 180 minutes between the two groups (Figure 2C). The mean plasma tandospirone concentration measured after the behavioral observation evaluation was 71.8 ng / mL.

[0111] When tandospirone tape (formulation 3: drug dose 45 mg / kg) was applied under keratin stripping conditions, the total AIMs score was 5.8. The total AIMs score was 27.1 lower than when a placebo tape not containing tandospirone was applied, and a significant improvement in dyskinesia-like symptoms was observed. Under administration condition 2, a greater improvement effect was observed than under administration condition 1 (Figures 3-A and 3-B). In addition, at 120-140 minutes after levodopa administration under keratin stripping conditions, no clear dyskinesia-like symptoms (mean AIMs score of 2 or more) were observed in either the placebo tape group or the tandospirone tape group, and no significant difference was observed in the total AIMs score from 100 to 180 minutes between the two groups (Figure 3-C). The mean plasma tandospirone concentration measured after the behavioral observation evaluation was 269 ng / mL. The mean plasma tandospirone concentration under administration condition 2 was more than three times higher than that under administration condition 1.

[0112] These results suggest that transdermal tandospirone improved PD-LID symptoms without causing rebound symptoms. In addition, in non-clinical models, it was found that the anxiolytic effect of tandospirone and its effect on PD-LID were expressed at the same dose. The anxiolytic effect was evaluated using the rat Vogel conflict tests model, and the effect on PD-LID was evaluated using 6-OHDA-lesioned rats. Therefore, it is considered that the therapeutic effect of the present invention is expressed at the same blood concentration as that of tandospirone citrate tablets (Sedir tablets), which are commercially available as an anxiolytic drug.

[0113] Example 3: Evaluation of the effect of continuous subcutaneous administration of tandospirone on improving dyskinesia The efficacy of tandospirone against dyskinesia-like symptoms was evaluated by continuous subcutaneous administration of tandospirone to PD-LID model rats.

[0114] (Test Method) As in Example 2, levodopa compound solution was repeatedly administered to 6-OHDA-lesioned rats for more than 3 weeks, and behavioral observation evaluation was performed. Behavioral observation evaluation was performed before the drug evaluation day, and the rats were assigned to each administration group based on the 3-hour AIMs score, locomotive behavior score, and body weight, and used for drug evaluation. However, individuals with a total AIMs score of less than 10 were excluded from the test because they did not show dyskinesia-like symptoms. In addition, individuals with a body weight that deviated by 10% or more from the average were also excluded from the test in order to suppress the variation in the dosage for each individual.

[0115] Tandospirone (free form) was dissolved in 1 M hydrochloric acid (Nacalai Tesque) and diluted with physiological saline to prepare 0.05, 0.25, and 1.25 mg / kg / hour. The prepared solution was injected into an ALZET (registered trademark) Osmotic Pump MODEL2ML1 (9.68 μL / hour; DURECT) for use.

[0116] Osmotic pumps infused with tandospirone or vehicle were implanted subcutaneously in rats (n=6 per group), and 4 hours later, a levodopa combination solution was administered and behavioral observations were performed. After behavioral observations, blood was collected from the rats in the tandospirone group and the plasma tandospirone concentration was analyzed.

[0117] The results in the figure are shown as mean ± standard error. The test results were statistically analyzed by comparing the 3-hour total AIMs score and the 100-180-minute total AIMs score with the vehicle-administered group using the Steel test. * indicates p<0.05, which means there is a significant difference.

[0118] (result) Continuous subcutaneous administration of tandospirone improved dyskinesia-like symptoms in a dose-dependent manner, with a significant improvement observed at 1.25 mg / kg / h (Figure 4-A, B). In addition, at 120-140 min after levodopa administration, no clear dyskinesia-like symptoms (mean AIMs score of 2 or more) were observed in either the vehicle or tandospirone groups. Furthermore, in the total AIMs score at 100-180 min, continuous subcutaneous administration of tandospirone reduced the total AIMs score in a dose-dependent manner, with a significant improvement observed at 1.25 mg / kg / h (Figure 4-C). The mean plasma tandospirone concentrations measured after the behavioral observation evaluation were 23.5 ng / mL at 0.05 mg / kg / h, 119 ng / mL at 0.25 mg / kg / h, and 541 ng / mL at 1.25 mg / kg / h.

[0119] These results suggest that continuous subcutaneous administration of tandospirone improved dyskinetic symptoms in a dose-dependent manner, without causing rebound symptoms at any dose.

[0120] Example 4: Evaluation of the long-term effect of continuous subcutaneous administration of tandospirone on improving dyskinesia Tandospirone was administered subcutaneously to PD-LID model rats for 2 weeks to evaluate the sustained efficacy of tandospirone against dyskinesia-like symptoms.

[0121] (Test Method) As in Example 2, levodopa compound solution was repeatedly administered to 6-OHDA-lesioned rats for more than 3 weeks, and behavioral observation evaluation was performed. Individuals with a total AIMs score of less than 15 were excluded from the study because they were considered not to have developed dyskinesia-like symptoms. Behavioral observation evaluation was performed before the drug evaluation day, and the rats were assigned to each administration group based on the 3-hour AIMs score, locomotive behavior score, and body weight of the rats, and used for drug evaluation.

[0122] Tandospirone citrate was dissolved in 1 M hydrochloric acid (Nacalai Tesque) and diluted with saline to prepare a concentration of 60 mg / mL (citrate concentration). The prepared solution was injected into an ALZET (registered trademark) Osmotic Pump MODEL2ML2 (4.53 μL / hour; DURECT), which releases the drug solution at a stable rate for two weeks.

[0123] Osmotic pumps infused with tandospirone citrate or vehicle were implanted subcutaneously in rats (n=8 per group), and 4 hours later, a levodopa combination solution was administered and behavioral observations were performed (day 0 after pump implantation). Thereafter, repeated administration of the levodopa combination solution was continued once a day, and behavioral observations were performed again on day 13 after pump implantation. After each behavioral observation, blood was collected from half of the rats (n=4) in the tandospirone administration group, and the plasma tandospirone concentration was analyzed.

[0124] The results in the figure are shown as the mean value of the total AIMs score over 3 hours ± standard error. Statistical analysis of the test results was performed using the Wilcoxon rank sum test with the total AIMs score as an index. Compared to the vehicle administration group, ** indicates p<0.01, which means there is a significant difference.

[0125] (result) Continuous subcutaneous administration of tandospirone citrate (60 mg / mL as tandospirone citrate: average 0.78 mg / kg / hour) significantly improved dyskinetic symptoms compared to the vehicle group on day 0 after pump implantation (Figure 5-A). The mean plasma tandospirone concentration (free form equivalent) measured after behavioral observation was 281 ng / mL. Furthermore, a significant improvement in dyskinetic symptoms was observed on day 13 after pump implantation compared to the vehicle group (Figure 5-B). The mean plasma tandospirone concentration (free form equivalent) measured after behavioral observation was 143 ng / mL.

[0126] These results suggest that the improvement in PD-LID symptoms was sustained even after continuous subcutaneous administration of tandospirone for 13 days.

[0127] (Example 5: Evaluation of the preventive and suppressive effect of continuous subcutaneous administration of tandospirone on the onset of dyskinesia) Repeated administration of levodopa in 6-OHDA-lesioned rats induces dyskinesia-like abnormal involuntary movements. We therefore evaluated the preventive effect of tandospirone on the appearance of dyskinesia-like symptoms by continuously administering tandospirone subcutaneously immediately after the start of repeated levodopa administration.

[0128] (Test Method) Tandospirone citrate was dissolved in 1 M hydrochloric acid (Nacalai Tesque) and diluted with physiological saline to prepare a concentration of 60 mg / mL or 30 mg / mL. The prepared solution was injected into an ALZET (registered trademark) Osmotic Pump MODEL2ML2 (4.53 μL / hour; DURECT) for use.

[0129] The rats were assigned to each administration group based on the number of rotations induced by apomorphine hydrochloride 0.5 hydrate and the body weight in 6-OHDA-lesioned rats. On the day after the start of repeated administration of levodopa compound solution with the same composition as in Example 2, osmotic pumps injected with tandospirone citrate or a solvent were subcutaneously implanted in the rats. On the 3rd, 5th, 9th, and 15th days after the start of repeated administration of levodopa, behavioral observation evaluation was performed using the same method as in Example 2. After the behavioral observation evaluation on the 15th day, the subcutaneously implanted osmotic pump was removed, and behavioral observation evaluation was performed the next day (16th day of repeated administration of levodopa).

[0130] The results in the figure are shown as the mean value ± standard error of the total AIMs score over 3 hours. The total AIMs score on the 16th day of repeated levodopa administration was used as an index, and statistical analysis of the test results was performed by comparing with the vehicle-administered group using the Steel test. Compared with the vehicle-administered group, * indicates p<0.05 and ** indicates p<0.01, indicating a significant difference.

[0131] (result) Continuous subcutaneous administration of tandospirone citrate (30 mg / mL: mean 0.41 mg / kg / hour or 60 mg / mL: mean 0.83 mg / kg / hour) inhibited the increase in total AIMs score associated with repeated administration of levodopa compared to the vehicle group (Figure 6-A). Furthermore, even on the day after administration of tandospirone citrate was terminated, the total AIMs score was significantly lower in the group administered tandospirone citrate compared to the vehicle group (Figure 6-B). These results suggest that continuous subcutaneous administration of tandospirone prevented the development of PD-LID, and this effect continued even after the day after the final administration of tandospirone.

[0132] (Comparative Example 1: Evaluation of oral administration of tandospirone on dyskinesia symptoms)

[0133] (Test Method) Behavioral observation evaluation was performed using the same method as in Example 2. Tandospirone citrate was suspended in 0.5% methylcellulose solution and orally administered to rats, and 5 minutes later, levodopa combination solution was administered intraperitoneally to perform 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 AIMs score for 3 hours and the total AIMs score for 100-180 minutes with the vehicle-administered group using Steel's test as indicators. * indicates p<0.05, meaning there is a significant difference.

[0134] (result) (1) Dyskinetic symptoms In the oral administration groups of tandospirone citrate (citrate concentration 10, 30, 100 mg / kg), no significant change in total AIMs score was observed compared to the vehicle administration group (Figures 7, 8-A, B). This result suggests that oral administration of tandospirone formulations cannot improve PD-LID.

[0135] At 120-140 minutes after levodopa administration, dyskinesia-like symptoms subsided in the vehicle group, but clear dyskinesia-like symptoms (mean AIMs score of 2 or more) were observed in the oral tandospirone citrate group (30, 100 mg / kg). Furthermore, when the vehicle group and the oral tandospirone citrate group were compared using the total AIMs score from 100 to 180 minutes as an index, a significant increase in the total AIMs score was observed in the oral tandospirone citrate group (30, 100 mg / kg) compared with the vehicle group (Figs. 7 and 8-C). These results suggest that the oral tandospirone formulation may cause delayed appearance and exacerbation of dyskinesia-like symptoms (rebound dyskinesia).

[0136] As described above, no improvement in dyskinesia symptoms was observed in the PD-LID model rats in the oral tandospirone group (Table 3-(i)). Furthermore, rebound dyskinesia symptoms were observed in the high oral dose group (Table 3-(ii)). These results suggest that oral tandospirone is insufficiently effective in improving dyskinesia, and there is a concern about the occurrence of rebound symptoms, so that combination therapy with levodopa preparations may not be appropriate.

[0137] [Table 3] The dose was recorded as a value converted to tandospirone free body. The difference in the total AIMs score over 3 hours (#1) was recorded as an index of the improvement of dyskinesia symptoms, and the difference in the total AIMs score over 100-180 minutes (#2) was recorded as an index of dyskinesia rebound symptoms. (#1) Difference in total AIMS score over 3 hours = (total AIMs score of placebo tape or vehicle group) - (total AIMs score of tandospirone group) (#2) Difference in total AIMs score for 100-180 minutes = (total AIMs score for 100-180 minutes in the placebo tape or vehicle group) - (total AIMs score for 100-180 minutes in the tandospirone group) **: Significant difference (p<0.01), *: Significant difference (p<0.05)

[0138] As shown in Table 3, in improving levodopa-induced dyskinesia symptoms, no significant difference was observed with oral administration, whereas a significant improvement was observed with transdermal administration. In addition, it was newly discovered that oral administration of tandospirone caused rebound symptoms of dyskinesia, indicating that oral administration of tandospirone is not a desirable treatment, whereas transdermal administration did not cause rebound symptoms of dyskinesia. In conclusion, the therapeutic effect of oral tandospirone on levodopa-induced dyskinesia is limited, suggesting that transdermal administration of tandospirone is preferable.

[0139] (Comparative Example 2: Evaluation of tandospirone metabolites on dyskinesia symptoms)

[0140] The effect of 1-(2-pyrimidyl)piperazine (hereinafter sometimes referred to as "1-PP"), a metabolite of tandospirone, on dyskinesia-like symptoms was evaluated.

[0141] (Test Method) Behavioral observation evaluation was performed using the same method as in Example 2. 1-PP dihydrochloride (Tokyo Chemical Industry) was dissolved in physiological saline and administered subcutaneously to rats, and 5 minutes later, a levodopa combination solution was administered intraperitoneally to perform 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 AIMs score for 3 hours and the total AIMs score for 100-180 minutes with the vehicle-administered group using the Steel test as indicators.

[0142] (result) In the groups administered 1-PP dihydrochloride (10, 30 mg / kg) subcutaneously, no significant change in the total AIMs score was observed compared to the vehicle-administered group (FIGS. 10A and 10B).

[0143] At 120-140 minutes after levodopa administration, the 1-PP dihydrochloride subcutaneous administration group (10, 30 mg / kg) showed clear dyskinesia-like symptoms (mean AIMs score of 2 or more). Furthermore, when the vehicle administration group and the 1-PP dihydrochloride administration group were compared using the total AIMs score from 100 to 180 minutes as an index, the 1-PP dihydrochloride administration group showed a tendency toward an increase in the total AIMs score, although not significant, compared to the vehicle administration group (Figure 10-C). This result suggests that 1-PP, a metabolite of tandospirone, may cause rebound symptoms of dyskinesia.

[0144] These results suggest that rebound dyskinesia may occur under administration conditions that produce the metabolite 1-PP of tandospirone. In other words, administration methods that suppress the production of 1-PP for tandospirone are preferable because they have less effect on rebound dyskinesia.

[0145] Example 6: Demonstration in a clinical protocol As an appropriately designed clinical trial capable of evaluating PD-LID, a clinical trial similar to the method described in the following Reference 1 (Amantadine P3) can be used to confirm the improving effect of the compound of the present invention or the combination drug of the present invention on PD-LID (Reference 1: JAMA Neurology 2017; 74 (8) 941-949; Reference 2: Movement Disorders 2015; 30 (19) 1343-1350).

[0146] More specifically, for example, in patients aged 20 years or older who have been diagnosed with Parkinson's disease, the tandospirone of the present invention or a pharma- ceutically acceptable salt or prodrug thereof, or the concomitant drug of the present invention is administered for a certain administration period (for example, 8 to 12 weeks, but is not limited to this period), and the improvement effect on PD-LID can be confirmed by comparing the scores of UPDRS, UDysRS, CDRS, AIMS, etc. before and after the administration period, as well as the time to onset of dyskinesia based on a patient diary, etc.

[0147] In the above tests, the conditions such as the subject patient, administration period, drug dosage, and evaluation method can be appropriately changed.

[0148] (Note) Although the present invention has been illustrated by using the preferred embodiment of the present invention, it is understood that the scope of the present invention should be interpreted only by the claims. This application claims priority to U.S. Patent Application No. 16 / 395,531, the entire contents of which are incorporated herein by reference. It is understood that the patents, patent applications and other documents cited in this specification are incorporated herein by reference in their entirety as if the contents themselves were specifically set forth herein. [Industrial Applicability]

[0149] The parenteral formulation of tandospirone is useful as a therapeutic agent for improving PD-LID.

Claims

[Claim 1] The invention described in this specification.

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