Drug for treating dyskinesia

Abstract

The present invention provides a therapeutic agent useful for treating levodopa-induced dyskinesia in Parkinson's disease. In particular, the present invention provides a composition and method for treating, ameliorating, inhibiting the progression of, or preventing motor complications associated with levodopa treatment of Parkinson's disease, particularly levodopa-induced dyskinesia (PD-LID), which contains tandospirone or a pharmaceutically acceptable salt or prodrug thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally.

Description

Technical Field

[0001] The present invention relates to a preparation containing tandospirone useful as a medicine, and a pharmaceutically acceptable salt or prodrug thereof as an active ingredient, and treating levodopa-induced dyskinesia in Parkinson's disease by parenteral administration (for example, transdermal administration), or a treatment method thereof.

Background Art

[0002] Parkinson's disease is one of the progressive neurodegenerative diseases mainly characterized by abnormal extrapyramidal function. Pathologically, dopaminergic neuron loss and deposition of Alpha-synuclein are observed in the substantia nigra pars compacta. Clinically, it presents various motor symptoms such as akinesia, tremor at rest, rigidity, and loss of postural reflexes.

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

[0004] The onset frequency of PD-LID 5 years after the start of levodopa treatment is 30 - 50%, and it increases with the progression of the disease state, reaching 50 - 100% 10 years after the start of treatment. As a typical symptom of PD-LID, peak-dose dyskinesia is known, which is involuntary movement that appears in the face, tongue, neck, limbs, trunk, etc. during the period when the levodopa blood concentration is high.

[0005] Patent Document 1 discloses a transdermal absorbent of tandospirone.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0007] As a result of intensive research, the present inventors have found that by parenterally administering tandospirone or a pharmaceutically acceptable salt or prodrug thereof (for example, transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration, etc.), compared with oral administration, a useful treatment, improvement, progression suppression, and prevention technique with a high improvement effect on levodopa-induced dyskinesia (PD-LID) of Parkinson's disease can be provided. According to the present invention, a transdermal absorbent pharmaceutical composition for improving PD-LID, which contains tandospirone or a pharmaceutically acceptable salt or prodrug thereof, and a method for treating, improving, suppressing the progression, and preventing motor complications of Parkinson's disease by parenteral administration containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof are provided.

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

[0009] [Item 1] A composition for treating, improving, suppressing the progression, or preventing motor complications associated with levodopa treatment of Parkinson's disease, which contains tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the tandospirone or a pharmaceutically 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 characterized by having persistence or being 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 the treatment, improvement or prevention of motor complications associated with levodopa treatment of Parkinson's disease, which contains tandospirone or a pharmaceutically acceptable salt or prodrug thereof, and is characterized by improving levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms, and the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered transdermally. [Item 7] The composition according to any one of the above items, wherein levodopa-induced dyskinesia (PD-LID) includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item 8] The treatment, improvement, progression suppression or prevention of the motor complication includes improvement, progression suppression or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or combinations thereof, and the composition according to any one of the above items. [Item 9] A composition for achieving improvement, progression suppression or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or combinations thereof, which contains tandospirone or a pharmaceutically acceptable salt or prodrug thereof, and is characterized in that the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 10] The composition according to any one of the above items, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is at least a clinically significant improvement. [Item 11] The composition according to any one of the above items, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is at a level sufficient to obtain a clinical effect. [Item 12] The composition according to any one of the above items, wherein the composition is a transdermal absorption 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 absorption preparation is a tape / patch. [Item 15] The composition according to any one of the above items, wherein the drug dosage of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day as the free form of tandospirone. [Item 16] The composition according to any one of the above items, wherein the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 20 mg per day as the free form of tandospirone. [Item 17] The composition according to any one of the above items, wherein the composition is a transdermal absorption preparation, and the total area of the sticking surface per application is 1 to 100 cm 2 The composition according to any one of the above items. [Item 18] The composition according to any one of the above items, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered such that the concentration of tandospirone in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. [Item 19] The composition according to any one of the above items, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered such that the concentration of tandospirone in human blood (plasma) is 0.05 to 20 ng / mL between 8 and 16 hours after the administration of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof. [Item 20] The composition according to any one of the above items, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is an adjunct of 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 medicament for treating or preventing Parkinson's disease without or minimizing PD-LID, the medicament comprising tandospirone or a pharmaceutically acceptable salt or prodrug thereof in combination with (1) levodopa, or (2) levodopa and a metabolic enzyme inhibitor of levodopa, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 23] A medicament for treating or preventing Parkinson's disease without or minimizing PD-LID, the medicament comprising tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered in combination with (1) levodopa, or (2) levodopa and a metabolic enzyme inhibitor of levodopa, and the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 24] A medicament for treating or preventing Parkinson's disease without or minimizing PD-LID, the medicament comprising (1) levodopa, or (2) levodopa and a metabolic enzyme inhibitor of levodopa, wherein the (1) levodopa, or (2) levodopa and a metabolic enzyme inhibitor of levodopa are administered in combination with tandospirone or a pharmaceutically acceptable salt or prodrug thereof, and tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 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 pharmaceutically acceptable salt or prodrug thereof, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 26] The medicament or composition according to any one of the above items, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is the 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 the step of parenterally administering to a subject an effective amount of tandospirone or a pharmaceutically 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 complications include 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 improving levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms by transdermally administering to a subject an effective amount of tandospirone or a pharmaceutically acceptable salt or prodrug thereof. [Item 7A] The method according to any one of the above items, wherein levodopa-induced dyskinesia (PD-LID) includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item 8A] The treatment, amelioration, progression inhibition or prevention of the motor complications includes improvement, progression inhibition or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or combinations thereof, according to any one of the above items. [Item 9A] A method for achieving improvement, progression inhibition, or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, the method comprising the step of parenterally administering to a subject an effective amount of tandospirone or a pharmaceutically acceptable salt or prodrug thereof. [Item 10A] The method according to any one of the above items, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is above a clinically significant improvement. [Item 11A] The method according to any one of the above items, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is at a level sufficient to obtain a clinical effect. [Item 12A] The method according to any one of the above items, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as a transdermal absorption preparation. [Item 13A] The method according to any one of the above items, wherein the tandospirone or a pharmaceutically 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 absorption preparation is a tape / patch. [Item 15A] The method according to any one of the above items, wherein the drug dosage of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day as the free form of tandospirone. [Item 16A] The method according to any one of the above items, wherein the drug transfer amount of the tandospirone or a pharmaceutically 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 sticking area per application is 1 to 100 cm 2 The method according to any one of the above items. [Item 18A] The method according to any one of the above items, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered so that the concentration of tandospirone in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. [Item 19A] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered such that the concentration of tandospirone in human blood (plasma) becomes 0.05 to 20 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof, according to the method of any one of the above items. [Item 20A] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof is an adjunct to levodopa, according to the method of any one of the above items. [Item 21A] It is used in combination with levodopa in the same formulation or separate formulations, according to the method of any one of the above items. [Item 22A] A method for treating or preventing Parkinson's disease in a subject without or minimizing PD-LID, the method comprising administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt or prodrug thereof and an effective amount of (1) levodopa, or (2) a combination of levodopa and a levodopa metabolism enzyme inhibitor, wherein the effective amount of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally, the method. [Item 23A] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof and the (1) or (2) are administered simultaneously or at different times, according to the method of any one of the above items. [Item 24A] A composition for improving the deterioration of the quality of response to levodopa treatment in a Parkinson's disease patient with dyskinesia, containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the effective amount of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally, the composition. [Item 25A] The tandospirone or a pharmaceutically acceptable salt thereof is the free form of tandospirone, according to the method of any one of the above items. [Use in the manufacture of a medicament for the treatment, amelioration or prevention of motor complications associated with levodopa treatment of Parkinson's disease with tandospirone or a pharmaceutically acceptable salt or prodrug thereof, characterized in that the medicament is administered parenterally.] [Use according to any one of the preceding paragraphs, wherein the parenteral administration is selected from transdermal administration, intradermal administration, subcutaneous administration, intramuscular administration and combinations thereof.] [Use according to any one of the preceding paragraphs, wherein the parenteral administration is characterized by being sustained or administered continuously.] [Use according to any one of the preceding paragraphs, wherein the parenteral administration includes transdermal administration.] [Use according to any one of the preceding paragraphs, wherein the motor complications include levodopa-induced dyskinesia (PD-LID).] [Use in the manufacture of a medicament for the treatment, amelioration or prevention of motor complications associated with levodopa treatment of Parkinson's disease with tandospirone or a pharmaceutically acceptable salt or prodrug thereof, characterized by ameliorating levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms, and wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered transdermally.] [Use according to any one of the preceding paragraphs, wherein the levodopa-induced dyskinesia (PD-LID) includes peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof.] [Use according to any one of the preceding paragraphs, wherein the treatment, amelioration, progression inhibition or prevention of the motor complications includes amelioration, progression inhibition or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or combinations thereof.] [Item 9B] Use in the manufacture of a medicament for achieving improvement, progression suppression, or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or a combination thereof, which contains tandospirone or a pharmaceutically acceptable salt or prodrug thereof, characterized in that the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 10B] The use according to any one of the above items, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is more than a clinically significant improvement. [Item 11B] The use according to any one of the above items, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is at a level sufficient to obtain a clinical effect. [Item 12B] The use according to any one of the above items, wherein the medicament is a transdermal absorption preparation. [Item 13B] The use according to any one of the above items, wherein the medicament is a patch preparation. [Item 14B] The use according to any one of the above items, wherein the transdermal absorption preparation is a tape / patch. [Item 15B] The use according to any one of the above items, wherein the drug dosage of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day as the free form of tandospirone. [Item 16B] The use according to any one of the above items, wherein the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 20 mg per day as the free form of tandospirone. [Item 17B] The use according to any one of the above items, wherein the medicament is a transdermal absorption preparation, and the total area of the sticking surface per application is 1 to 100 cm 2 is. [Item 18B] The use according to any one of the above items, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered so that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. [Item 19B] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered such that the concentration of tandospirone in human blood (plasma) becomes 0.05 to 20 ng / mL between 8 and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof, and the use according to any one of the above items is characterized thereby. [Item 20B] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof is an adjunct of levodopa, and the use according to any one of the above items is characterized thereby. [Item 21B] The medicament is used in combination with levodopa in the same formulation or in separate formulations, and the use according to any one of the above items is characterized thereby. [Item 22B] Use in the manufacture of a medicament for treating or preventing Parkinson's disease, with no or minimal PD-LID, the medicament comprising a combination of tandospirone or a pharmaceutically acceptable salt or prodrug thereof with (1) levodopa, or (2) levodopa and an inhibitor of a metabolic enzyme of levodopa, and characterized in that the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 23B] Use in the manufacture of a medicament for treating or preventing Parkinson's disease, with no or minimal PD-LID, the medicament comprising tandospirone or a pharmaceutically acceptable salt or prodrug thereof, 、 administered in combination with (1) levodopa, or (2) levodopa and an inhibitor of a metabolic enzyme of levodopa, and characterized in that the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Use in the manufacture of a medicament for treating or preventing Parkinson's disease without or with minimal PD-LID, wherein the medicament comprises (1) levodopa, or (2) levodopa and an inhibitor of the metabolic enzyme of levodopa, and the (1) levodopa, or (2) levodopa and the inhibitor of the metabolic enzyme of levodopa are administered in combination with tandospirone or a pharmaceutically acceptable salt or prodrug thereof, and tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally.] [Use in the manufacture of a medicament for improving the deterioration of the quality of response to levodopa treatment in Parkinson's disease patients with dyskinesia, which comprises tandospirone or a pharmaceutically acceptable salt or prodrug thereof, and tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally.] [The use according to any one of the above items, wherein the tandospirone or a pharmaceutically acceptable salt thereof is the free form of tandospirone.] [Tandospirone or a pharmaceutically acceptable salt or prodrug thereof for treating, improving or preventing motor complications associated with levodopa treatment of Parkinson's disease, wherein tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally.] [The tandospirone or a pharmaceutically 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.] [The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the parenteral administration is characterized by having persistence or being administered continuously.] [The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the parenteral administration includes transdermal administration.] [Item 5C] The motor complication is tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, including levodopa-induced dyskinesia (PD-LID). [Item 6C] Tandospirone or a pharmaceutically acceptable salt or prodrug thereof for the treatment, improvement or prevention of motor complications associated with levodopa treatment of Parkinson's disease, which is characterized by improving levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms, and the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered transdermally. [Item 7C] Levodopa-induced dyskinesia (PD-LID) is tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, including peak-dose dyskinesia, diphasic dyskinesia, and combinations thereof. [Item 8C] The treatment, improvement, progression inhibition or prevention of the motor complication includes improvement, progression inhibition or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or combinations thereof, and is tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items. [Item 9C] Tandospirone or a pharmaceutically acceptable salt or prodrug thereof for achieving improvement, progression inhibition or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or combinations thereof, and the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 10C] The improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is above clinically significant improvement, and is tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items. [Item 11C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is at a level sufficient to obtain a clinical effect. [Item 12C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, which is a transdermal absorption preparation. [Item 13C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, which is a patch preparation. [Item 14C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the transdermal absorption preparation is a tape / patch preparation. [Item 15C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the drug dosage of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day as the free form of tandospirone. [Item 16C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, wherein the drug transfer amount of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 20 mg per day as the free form of tandospirone. [Item 17C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, which is a transdermal absorption preparation, and the total sticking area per application is 1 to 100 cm 2 as described in any one of the above items. [Item 18C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, which is characterized in that it is administered so that the concentration of tandospirone in human blood (plasma) is 0.05 to 20 ng / mL for 12 hours or more per day. [Item 19C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered such that the concentration of tandospirone in human blood (plasma) becomes 0.05 to 20 ng / mL between 8 hours and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof, the tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items. [Item 20C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof is an adjunct of levodopa, the tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items. [Item 21C] The tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items is used in combination with levodopa in the same formulation or in separate formulations. [Item 22C] A combination of a tandospirone or a pharmaceutically acceptable salt or prodrug thereof for treating or preventing Parkinson's disease without or minimizing PD-LID and (1) levodopa, or (2) levodopa and a metabolic enzyme inhibitor of levodopa, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. [Item 23C] A tandospirone or a pharmaceutically acceptable salt or prodrug thereof for treating or preventing Parkinson's disease without or minimizing PD-LID, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof 、 is administered in combination with (1) levodopa, or (2) levodopa and a metabolic enzyme inhibitor of levodopa, and the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally, the tandospirone or a pharmaceutically acceptable salt or prodrug thereof. [Item 24C] (1) Levodopa, or (2) a combination of levodopa and an inhibitor of levodopa-metabolizing enzyme, for treating or preventing Parkinson's disease without or with minimal PD-LID, wherein the (1) levodopa, or (2) the combination of levodopa and an inhibitor of levodopa-metabolizing enzyme is administered in combination with tandospirone or a pharmaceutically acceptable salt or prodrug thereof, and tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. A combination of (1) levodopa, or (2) levodopa and an inhibitor of levodopa-metabolizing enzyme. [Item 25C] Tandospirone or a pharmaceutically acceptable salt or prodrug thereof for improving the deterioration of the quality of response to levodopa treatment in patients with Parkinson's disease accompanied by dyskinesia, wherein tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered parenterally. Tandospirone or a pharmaceutically acceptable salt or prodrug thereof. [Item 26C] Tandospirone or a pharmaceutically acceptable salt or prodrug thereof according to any one of the above items, which is a free form.

[0011] In a specific embodiment, the present invention is provided as a patch (also referred to as a tape). When the tape of the present invention is applied, dyskinesia symptoms associated with levodopa treatment for Parkinson's disease can be more preferably prevented or improved. Further, when the tape of the present invention is applied and dyskinesia symptoms associated with levodopa treatment for Parkinson's disease are more preferably prevented or improved, the treatment of Parkinson's disease can be carried out in a real clinical setting, such that the dose per administration and / or the dose per day of levodopa is increased without exacerbating dyskinesia as compared to before the treatment using the tape of the present invention. In current treatment, for Parkinson's disease patients with dyskinesia, treatment with levodopa at low doses and frequent doses has been attempted (Parkinson's Disease Clinical Practice Guidelines 2018 version (Chapter III Q&A on Parkinson's Disease Clinical Practice, 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 levodopa-containing preparation can be adjusted to an optimal dosage. That is, for Parkinson's disease patients who have developed dyskinesia or are at risk of developing it, even if the single dose of levodopa is increased to reduce the number of administrations or the daily dosage of levodopa is increased, the dyskinesia symptoms will not worsen, and more favorable treatment of Parkinson's disease symptoms becomes possible. By the tandospirone of the present invention or a pharmaceutically acceptable salt or prodrug thereof and a treatment method, treatment or prevention can be achieved in which levodopa-induced movement complications and levodopa-induced dyskinesia associated with the usual daily dosage of levodopa treatment described in the Parkinson's Disease Treatment Guidelines 2018 version published by the Japanese Society of Neurology or corresponding guidelines in the United States and Europe are reduced. In addition, by administering the parenteral preparation of tandospirone provided by the present invention, a more favorable improvement effect such as levodopa-induced dyskinesia (PD-LID) can be provided as compared with oral administration. The inventors of the present invention have first found that when tandospirone is orally administered in anticipation of an improvement effect on dyskinesia, the dyskinesia temporarily worsens. That is, it has been found that oral administration of tandospirone is not preferable as a therapeutic agent for improving dyskinesia because it is accompanied by the "rebound symptom" of dyskinesia. In addition, the "rebound symptom" in the present invention is the symptom described in

[0036] . In addition, oral administration of tandospirone is not preferable for increasing the dosage of the levodopa-containing preparation because the "rebound symptom" occurs. The inventors of the present invention have found that the parenteral composition of tandospirone of the present invention can improve dyskinesia without accompanying the "rebound symptom". In addition, 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] . Therefore, the present invention can be implemented in the following specific embodiments. (1) (A) tandospirone parenteral administration step, and (B) a step of administering levodopa in an increased dose compared to the conventional dose 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, which includes the above steps. (2) (A) tandospirone parenteral administration step, and (B) a step of increasing the dose of levodopa from the conventional single-dose and adjusting the number of daily administrations 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, which includes the above steps. (3) (A) tandospirone parenteral administration step, and (B) a step of administering levodopa while maintaining or increasing the dose 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 patients with existing or potential dyskinesia, which includes the above steps. (4) (A) a step of adding parenteral administration of tandospirone to conventional levodopa treatment, and (B) a step of increasing the dose of levodopa within the range where dyskinesia does not worsen and combining with parenteral administration of tandospirone 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 patients with existing or potential dyskinesia, which includes the above steps. (5) (A) a step of maintaining the plasma concentration of tandospirone at 0.05 - 20 ng / mL, and (B) a step of administering levodopa 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, which comprises (6) (A) A step of maintaining the plasma concentration of tandospirone at 0.05 to 20 ng / mL; (B) A step of administering levodopa 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 with existing or potential dyskinesia, which comprises The basis is as follows · Levodopa has a short half-life and its effect does not last, so it is usually taken multiple times a day. However, when the tandospirone of the present invention is administered as a patch, that is, when one patch is applied per day, the blood concentration of tandospirone is maintained for 24 hours. Therefore, in the case of a transdermal absorption preparation, no matter at what timing levodopa is administered, levodopa will be taken in a state where there is exposure to tandospirone. On the other hand, for example, when Sediel tablets and levodopa are taken (orally administered) three times a day at the same timing, levodopa will be taken in a state where the tandospirone concentration has decreased. That is to say, it can be said that this is a feature different from oral preparations. Also, it is considered preferable that the blood concentration of tandospirone is maintained during levodopa administration.

[0012] In a detailed embodiment, the present invention can be used for various applications (indications and efficacy effects). For example, it can be used for improving dyskinesia (anti-dyskinesia drug) <PD-LID improvement drug>, treating 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.]. It is possible to attach efficacy effects, precautions for use, and labels (package inserts).

[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 refer to 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]

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Mode for Carrying Out the Invention

[0016] Hereinafter, the present invention will be described while showing the best mode. Throughout this specification, it should be understood that the singular expressions include the concepts of their plurals unless otherwise specified. Therefore, it should be understood that the singular articles (for example, "a", "an", "the", etc. in English) include the concepts of their plurals unless otherwise specified. Also, the terms used in this specification should be understood to be used in the ordinary meanings used in the relevant field unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meanings as generally understood by those skilled in the art to which the present invention pertains. In case of contradiction, this specification (including the definitions) shall prevail.

[0017] (Definitions, etc.) Hereinafter, the definitions of the terms particularly used in this specification and / or the basic technical contents will be appropriately explained.

[0018] In this specification, "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. [Chemical formula] Sediel tablets containing the citrate of tandospirone as an active ingredient are used for treatment as a serotoninergic anxiolytic (for example, refer to the Sediel package insert, revised in April 2016, 14th edition; Sumitomo Dainippon Pharma Co., Ltd.; Japanese Patent Laid-Open No. 58-126865). Regarding tandospirone, it has a beneficial effect on the memory of chronic schizophrenia, and it is known that cognitive dysfunction can be improved by administering tandospirone or a pharmaceutically acceptable salt thereof while continuing maintenance therapy with a typical antipsychotic such as haloperidol (refer to Japanese Patent Laid-Open No. 2002-20291).

[0019] As the active ingredient used in the pharmaceutical composition of the present invention, tandospirone (free form) is preferred, and pharmaceutically acceptable salts of tandospirone and prodrugs of tandospirone can also be used in the same manner as tandospirone. Pharmaceutically acceptable salts or prodrugs of tandospirone include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate, and salts with organic acids such as acetate, butyrate, tartrate, citrate, maleate, and fumarate.

[0020] The prodrug of tandospirone refers to any component that has a structure different from that of tandospirone but can be converted into tandospirone or an active ingredient based on it by metabolism after administration to exert a medicinal effect.

[0021] The prodrug of tandospirone refers to a compound that is converted into tandospirone by a reaction with an enzyme or the like under physiological conditions in vivo, that is, a compound that undergoes enzymatic oxidation, reduction, hydrolysis, etc. to change into tandospirone, or a compound that undergoes hydrolysis, etc. by an acid or the like to change into tandospirone. Also, the prodrug of tandospirone may be one that changes into tandospirone under physiological conditions as described on pages 163 to 198 of Volume 7, Molecular Design, "Development of Pharmaceuticals", published by Hirokawa Shoten in 1990. The tandospirone, its salt, or its prodrug (hereinafter also referred to as tandospirones) of the present invention has an excellent serotonin 5-HT1A receptor activation effect. In addition, the tandospirone of the present invention has low toxicity and is safe.

[0022] Drugs containing " tandospirone citrate " as the active ingredient are clinically applied orally as therapeutic agents for (1) depression, fear in neurosis, and (2) physical symptoms in psychosomatic diseases (autonomic nervous system disorders, essential hypertension, peptic ulcer) and for depression, anxiety, restlessness, and sleep disorders. Tandospirone has high selectivity for the serotonin 1A receptor (hereinafter also referred to as the "5-HT1A receptor") in in vitro receptor binding evaluations for various neurotransmitter receptors, while having low affinity for the dopamine 2 receptor (also referred to as the "D2 receptor"). From this, it is considered that tandospirone activates the 5-HT1A receptor and selectively acts on serotonergic nerves to be effective in neurosis and the like.

[0023] As used herein, "levodopa" (in the broad sense) includes, in addition to levodopa in the narrow sense (L-3,4-dihydroxyphenylalanine (IUPAC name: (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid), also known as L-DOPA), any other agent having the same medicinal effect as L-3,4-dihydroxyphenylalanine. Such other agents include, but are not limited to, for example, esters of L-3,4-dihydroxyphenylalanine and salts thereof. 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), etc. Esters of L-3,4-dihydroxyphenylalanine can be salts containing, for example, hydrated salts. Salts of levodopa esters can include, but are not limited to, any of octanoate, myristate, succinate, succinate dihydrate, fumarate, fumarate dihydrate, mesylate, tartrate, and hydrochloride. For example, succinate 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] As used herein, the "levodopa metabolism inhibitor" refers to any drug that has the effect of inhibiting the metabolism of levodopa so as to enhance its effect in a broad sense, including dopa decarboxylase (decarboxylase) inhibitors (DCI) (e.g., carbidopa, α-methyldopa, benzidazide (Ro4-4602), α-difluoromethyl-DOPA (DFMD) or their salts, etc.) that prevent levodopa from being converted into dopamine in the intestine, liver, and blood vessels, catecholamine-O-methyltransferase inhibitors (COMT-I) (e.g., entacapone) that prevent levodopa from being decomposed before entering the brain, and monoamine oxidase inhibitors (MAO-I) (e.g., selegiline) that prevent dopamine from being decomposed in the brain.

[0025] (Disease / Disorder)

[0026] As used herein, "motor complications" refers to any motor symptoms that are problematic in the treatment of patients with advanced Parkinson's disease, including dyskinesia, an involuntary movement associated with levodopa treatment (levodopa-induced dyskinesia (PD-LID)). Motor complications are interpreted as being based on the excessive action of levodopa, but their mechanism has not been fully elucidated.

[0027] As used herein, "levodopa-induced dyskinesia <involuntary movement> (PD-LID)" refers to involuntary movements such as the limbs and body twitching uncontrollably, induced by excessive administration of levodopa. It is known that dyskinesia is likely to appear when levodopa is taken in excessive amounts continuously from the early stage of the disease, and once it appears, it is very difficult to control even if the dosage of levodopa is adjusted. The typical symptom of PD-LID is peak-dose dyskinesia, which appears in the face, tongue, neck, limbs, trunk, etc. when the blood concentration of levodopa is high.

[0028] Involuntary movement (dyskinesia) refers to a situation where a part of the body moves spontaneously and cannot stop, chews the lips, has difficulty speaking, cannot stay still, and has difficulty moving the limbs as intended. It is a movement disorder in which involuntary movements can be observed in the limbs and / or oro-facial region and / or axial part of the body. Dyskinesia observed in PD patients receiving treatment with levodopa is called levodopa-induced dyskinesia (LID), and it occurs in more than half of PD patients who have been treated with levodopa for 5 to 10 years. The percentage of patients affected by LID increases over time (for a review, see, for example, Encarnacion and Hauser, (2008), "Levodopa-induced dyskinesias in Parkinson’s disease: etiology, impact on quality of life, and treatments.", Eur Neurol, 60(2), pp. 57-66).

[0029] Peak-dose dyskinesia is an involuntary movement that occurs when the anti-Parkinson's disease medication is excessive. Diphasic dyskinesia is a dyskinesia that occurs in two phases: at the onset and waning of the effect of the anti-Parkinson's disease medication.

[0030] As used herein, the "pharmaceutically acceptable salts" include acid and / or base salts formed by inorganic and / or organic acids and bases, and include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, 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. Base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, aluminum salt, etc., or organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylamine, etc. Further, the "pharmaceutically acceptable salts" also include amino acid salts with basic amino acids or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid. Pharmaceutically acceptable salts are well known in the prior art. For example, Berge et al. have described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.

[0031] The tandospirone of the present invention or its pharmaceutically acceptable salt or prodrug and medicine may optionally contain a carrier. As used herein, the term "carrier" refers to a pharmaceutically acceptable substance, composition, or excipient such as a liquid or solid bulking agent, diluent, additive, solvent, base, or skin penetration enhancer, etc., related to or enabling the transport or conveyance 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 being compatible with other raw materials in the formulation and not being harmful to the subject.

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

[0033] In a specific embodiment, the patients treatable in the present invention include Parkinson's disease patients with levodopa-induced movement complications or those who may develop levodopa-induced movement complications. Levodopa-induced movement complications include levodopa-induced dyskinesia.

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

[0035] In the present invention, whether the PD-LID symptoms are deteriorating can be confirmed by whether the clinical evaluation scales of dyskinesia such as UDysRS, CDRS, AIMS, etc. are significantly deteriorated compared to before treatment with tandospirone. Also, it can be confirmed by whether there is an obvious deterioration of the symptoms related to dyskinesia in the patient diary. Whether the levodopa-induced dyskinesia symptoms are accompanied by pain in this specification can be confirmed by clinical records such as patient diaries.

[0036] In the present invention, the "rebound symptom" of levodopa-induced dyskinesia (PD-LID) means a phenomenon in which the dyskinesia score temporarily deteriorates due to a therapeutic agent for improving dyskinesia. The "rebound symptom" is a phenomenon in which dyskinesia deteriorates after the peak time (for example, 1 hour) of the antiparkinsonian action of levodopa during treatment with a dyskinesia-improving agent, compared with the case where treatment with the dyskinesia-improving agent is not performed, and is assumed to appear 1 to 6 hours after levodopa administration.

[0037] In the present invention, improving levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms means that, compared with the case where treatment with a dyskinesia-improving agent is not performed after levodopa administration, the total score of dyskinesia is improved without the primary dyskinesia deteriorating. "Without the dyskinesia deteriorating" means a state in which there is dyskinesia (in the AIMs evaluation system of non-clinical PD-LID model rats, the AIMs score is 2 or more), and the dyskinesia score does not significantly deteriorate compared with the case where treatment with a dyskinesia-improving agent is not performed.

[0038] In the AIMs evaluation system of non-clinical PD-LID model rats, the rebound symptom of levodopa-induced dyskinesia (PD-LID) can be evaluated using, for example, clear dyskinesia-like symptoms (AIMs score of 2 or more) observed at 120 to 140 minutes after levodopa administration or the total AIMs score from 100 to 180 minutes as an index. Improvement of dyskinesia can be evaluated by the total AIMs score for 180 minutes after levodopa administration. In the AIMs evaluation system of this PD-LID model rat, when the AIMs score is 2 or more, it is determined that there is dyskinesia, which means that the higher the number, the more severe the dyskinesia. Also, when the AIMs score is less than 2, it is determined that there is no dyskinesia.

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

[0040] As used herein, "adjunct" refers to a drug other than the drug having the main action. In the present invention, assuming that levodopa is the main drug, tandospirone and the like can be said to be adjuncts.

[0041] In this specification, the daily dose of levodopa as the main drug is the normal dose of levodopa treatment described in the Parkinson's Disease Treatment Guidelines 2018 version or the corresponding guidelines in the United States and Europe. Generally, the normal daily dose of levodopa is 50 to 1200 mg / day, preferably 100 mg to 600 mg / day, as a combination or formulation with a peripheral dopa decarboxylase inhibitor (DCI). For example, SINEMET (registered trademark) (Carbidopa-Levodopa combination tablets) (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 is such that SINEMET (registered trademark) is administered so that Carbidopa is 70 mg to 100 mg, and the maximum daily dose is such that SINEMET (registered trademark) is administered up to 200 mg as Carbidopa. The tandospirone, pharmaceutically acceptable salt, prodrug, or treatment method described in this specification enables the reduction of movement complications associated with the administration of the normal dose of levodopa treatment or the prevention of movement complications.

[0042] By administering the tandospirone of the present invention or its pharmaceutically acceptable salt or prodrug, the levodopa dosage can be appropriately adjusted. For example, it can be increased within the range of the single-dose and daily-dose defined in the Parkinson's Disease Treatment Guidelines 2018 version issued by the Japanese Society of Neurology or the corresponding guidelines in the United States and Europe.

[0043] In this specification, "having persistence" can be determined by those skilled in the art considering the description in this specification and utilizing the knowledge known in the art. Specifically, when the blood drug concentration is maintained for a long time and an effect of prolonging the biological half-life is shown, it can be defined as having persistence. Examples of compositions having persistence include various transdermal absorption preparations described in

[0051] , various sustained-release injections described in

[0089] , various implants described in

[0090] , etc. Also, in the present invention, "administered continuously" means continuously administering the active ingredient in the present invention from outside the body into the body. It can be selected from the parenteral administration routes described in

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

[0044] In this specification, the "clinically significant time" can be determined by those skilled in the art by considering the descriptions in this specification and utilizing the knowledge known in the art. Specifically, when the present invention shows a significant effect on the prevention, treatment, or alleviation of exercise complications, etc., that time can be defined as the clinically significant time. Similarly, in this specification, "clinically significant improvement" can be defined as such a state when the present invention shows a significant effect on the prevention, treatment, or alleviation of exercise complications, etc. The measurement methods for such time and improvement are matters that can be appropriately selected by those skilled in the art. For example, any method described in this specification can be considered, but it is not limited thereto. For example, the Parkinson's Disease Treatment Guidelines 2018 version issued by the Japanese Society of Neurology can also be used. Alternatively, there is a report on the clinical evaluation index of dyskinesia (MDS UDysRS Part III) of 2.32 points (Parkinsonism Relat Disord 21:1349, 2015)), and it can be appropriately determined by considering matters such as (1) comparison with placebo and (2) before and after treatment of each patient.

[0045] In this specification, the "time sufficient to obtain a clinical effect" and the "level sufficient to obtain a clinical effect" can also be determined by those skilled in the art by considering the descriptions in this specification and utilizing the knowledge known in the art. Specifically, if the time and level for obtaining the clinical effect such as the prevention, treatment, or alleviation of exercise complications targeted by the present invention can be measured, then that time and level can be evaluated as the time sufficient to obtain a clinical effect. The measurement methods for such time and level are matters that can be appropriately selected by those skilled in the art. For example, any method described in this specification can be considered, but it is not limited thereto. For example, the Parkinson's Disease Treatment Guidelines 2018 version issued by the Japanese Society of Neurology or the corresponding guidelines in the United States and Europe can also be used.

[0046] As used herein, "not exacerbating the symptoms of levodopa-induced dyskinesia (PD-LID) in Parkinson's disease patients" means not clinically significantly exacerbating or significantly exacerbating the already developed dyskinesia symptoms, not prolonging the onset time of dyskinesia, not significantly exacerbating even primary symptoms such as the rebound symptoms of dyskinesia, and not newly developing dyskinesia symptoms. The dyskinesia symptoms can be measured, for example, by UPDRS, UDysRS, CDRS, AIMS, etc., or confirmed by clinical records such as patient diaries.

[0047] As used herein, "deterioration in the quality of response to levodopa treatment in Parkinson's disease patients" refers to any decrease in the responsiveness of patients to levodopa treatment, and such deterioration in the quality of response can be measured from dyskinesia symptoms and the like. Also, "improvement in the deterioration in the quality of response to levodopa treatment in Parkinson's disease patients" means that the degree of dyskinesia symptoms in each patient's levodopa treatment is improved, which can be measured by UPDRS, UDysRS, CDRS, AIMS, etc., or confirmed by clinical records such as patient diaries.

[0048] As used herein, "parenteral administration" refers to any route of administration other than oral administration, preferably any form and level of administration in which tandospirone is effective for levodopa-induced motor complications in Parkinson's disease. As means of parenteral administration, administration by transdermal absorption or transmucosal absorption may be mentioned, including injection or infusion, and combinations thereof. For example, as administration by transdermal absorption or transmucosal absorption, a transdermal absorption preparation such as an ointment, a patch, a spray, etc. is brought into contact with the skin or mucosa, and the drug in the preparation migrates into the body through the skin or mucosa to exert an effect. As administration by injection or infusion, intravenous, intradermal, subcutaneous, intramuscular, enteral (enema) administration may be mentioned, and bolus administration and / or continuous infusion may be performed. These may use a suspension, a solution, an emulsion, an implant in an oily or aqueous medium containing other pharmaceutical substances such as a suspending agent, a stabilizer and / or a dispersing agent. As enteral (enema) administration, it can be continuously delivered to the proximal small intestine using a tube and a portable infusion pump by percutaneous endoscopic gastrostomy. In one preferred embodiment, parenteral administration can be carried out in the form of sustained administration. Such sustained administration can be achieved with a patch, an injection or an infusion, etc.

[0049] In the present invention, tandospirone or a pharmaceutically acceptable salt or prodrug thereof is preferably administered in a manner capable of maintaining the blood drug concentration for a long time, and more preferably administered in a manner capable of suppressing the generation of metabolites. Examples of the administration method include transdermal administration and injection administration such as subcutaneous, intradermal and intramuscular injections. In the case of injection administration such as subcutaneous, intradermal and intramuscular injections, it is preferably an administration method in which the blood concentration is sustained. Among them, transdermal administration is most preferred because it does not require a hospital visit and has less invasiveness.

[0050] In the present invention, treatment, improvement, suppression of progression or prevention of motor complications associated with levodopa treatment for Parkinson's disease by parenteral administration containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof is preferred as compared with treatment with active ingredients other than those of the present invention, other treatment methods and compositions, from the viewpoints such as not adversely affecting the levodopa action time (ON time), not adversely affecting Parkinson's symptoms (evaluable by UPRDS etc.), the effects of the present invention not being attenuated even in repeated administration, and being able to reduce the number of administrations of levodopa preparations per day by increasing the levodopa preparation to the optimal dose without exacerbating motor complications.

[0051] The "transdermal absorption preparation" refers to a preparation such as a coating agent, a patch, or a spray (aerosol). Specifically, examples of the patch include a tape (patch), a poultice, and a plaster, and examples of the coating agent include an ointment, a cream, a lotion, a liniment, a liquid, and a gel. A patch is preferred. More preferably, it is a tape (patch). In the present invention, since the "tape" is synonymous with the "patch", it may be referred to as "tape / patch" in this specification.

[0052] The transdermal absorption preparation is produced by a known method using pharmaceutically acceptable additives. In one embodiment, the transdermal 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 shows fluidity by softening when heated and returns to a rubbery elastic body when cooled, and various thermoplastic elastomers such as urethane-based, acrylic-based, styrene-based, and olefin-based thermoplastic elastomers can be mentioned.

[0053] In the case of the transdermal preparation of the present invention, the pressure-sensitive 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, but in the present invention, those conforming to the standards specified in the Japanese Pharmacopoeia, the United States Pharmacopoeia, etc. can be preferably used. The non-volatile hydrocarbon oil is preferably one having a high viscosity, and particularly preferably using a highly viscous liquid paraffin from the viewpoint of adhesiveness.

[0054] In addition, the pressure-sensitive adhesive layer may contain a tackifier as necessary. A tackifier is a resin generally used for imparting skin adhesiveness in the field of patches, and examples thereof include rosin-based resins, polyterpene resins, coumarone-indene resins, petroleum-based resins, terpene-phenol resins, alicyclic saturated hydrocarbon resins, etc., and one or more of these can be selected and used.

[0055] In addition, when transdermal administration is assumed, it can also be realized by applying an ointment to the skin.

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

[0057] Ointments, pastes, creams, and gels can contain additives such as animal and plant fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof, in addition to the tandospirone of the present disclosure or a pharmaceutically acceptable salt or prodrug thereof.

[0058] In addition to the pharmaceutical compositions of the present disclosure, powders and sprays can include additives such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Further, sprays can include common high-pressure gases such as chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.

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

[0060] Compositions suitable for parenteral administration can include at least one pharmaceutically 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, and one or more compounds according to the present disclosure can be mixed with one or more suitable non-irritating additives or carriers including cocoa butter, polyethylene glycol, suppository wax, or salicylate, etc. and prepared. They are solid at room temperature but liquid at body temperature, and thus melt in the rectal 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 to be suitable in the prior art.

[0062] In the present invention, the "drug dosage" refers to the amount of drug contained in the composition. Also, in the present invention, the "drug transfer amount" refers to the amount of drug taken into the body. When the composition is a transdermal absorption preparation, the "drug transfer amount" refers to the amount of drug transferred from the transdermal absorption preparation to the skin and is a value calculated by the following formula. The "drug residual amount" refers to the amount of drug remaining in the transdermal absorption preparation peeled off after application and can be quantified by the methods described in the examples (reference production examples) (

[0098] to

[0101] ). Drug migration amount (mg / day) = Drug administration amount (mg / day) - Drug residual amount (mg / day)

[0063] In the present invention, when there is no particular description, the drug administration amount, drug migration amount, drug residual amount, and tandospirone concentration in blood (plasma) are amounts converted to the free form of tandospirone.

[0064] In the present invention, the drug administration amount and drug migration amount of tandospirone or its salt can be appropriately adjusted according to the type of compound, the symptoms, age, weight, renal and hepatic functions, etc. of the patient. For example, the drug administration amount per day can be 0.1 to 100 mg, preferably 0.2 to 50 mg, etc. The upper limits can include 100 mg, 80 mg, 50 mg, 30 mg, 15 mg, etc., and the lower limits can include 0.1 mg, 0.2 mg, 1 mg, 2 mg, 3 mg, etc. The preferred ranges can include any combination of these upper and lower limits. The drug migration amount per day can be 0.1 to 20 mg, preferably 0.2 to 10 mg. The upper limits can include 20 mg, 10 mg, 8 mg, 7 mg, 5 mg, 3 mg, etc., and the lower limits can include 0.1 mg, 0.2 mg, 1 mg, 1.5 mg, etc. The preferred ranges can include any combination of these upper and lower limits. The administration frequency can be appropriately adjusted according to the characteristics of the composition. When the composition is a transdermal absorption preparation, for example, it is once every 12 hours to once every 7 days, and any frequency between these is also possible, such as once every 2 days, once every 3 days, once every 4 days, etc. When the composition is an injection preparation, for example, it is once every day to once every 3 months, and any frequency between these is also possible, such as once a week, once every 2 weeks, once every 4 weeks, once every 3 months, etc. Also, it is possible to administer continuously for 24 hours, administer only during waking hours, or adjust the administration time according to symptoms using a pump-type automatic infusion device. This agent can also be mixed with a preparation containing levodopa and administered continuously.

[0065] In the present invention, tandospirone or a pharmaceutically acceptable salt or prodrug thereof is preferably administered such that the tandospirone concentration in human blood (plasma) is 0.05 to 20 ng / mL in terms of the free form amount for the period of time when it is desired to act on levodopa. Specifically, it is 12 hours or more, preferably 16 hours or more per day.

[0066] The tandospirone concentration in human blood (plasma) can be, for example, 0.05 to 20 ng / mL in terms of the free form amount. Examples of the upper limit include 20 ng / mL, 15 ng / mL, 10 ng / mL, 8 ng / mL, 5 ng / mL, etc., and examples of the lower limit include 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 tandospirone concentration in human blood (plasma) may be achieved by single administration or as a maintenance concentration by repeated administration.

[0067] In the present invention, the maximum value (Cmax) of the tandospirone concentration in human blood (plasma) can be, for example, 0.1 to 20 ng / mL in terms of the free form amount. Examples of the upper limit include 20 ng / mL, 15 ng / mL, 10 ng / mL, 8 ng / mL, 5 ng / mL, etc., and examples of the lower limit include 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 human blood (plasma) tandospirone concentration-time curve (AUC) can be, for example, 3 to 700 ng·h / mL in terms of the free form conversion amount. As the upper limit, 700 ng·h / mL, 600 ng·h / mL, 400 ng·h / mL, 300 ng·h / mL, 200 ng·h / mL, etc. can be mentioned, and as the lower limit, 3 ng·h / mL, 5 ng·h / mL, 10 ng·h / mL, 30 ng·h / mL, etc. can be mentioned. As the preferable range, any combination of both the upper limit and the lower limit can be mentioned.

[0069] In the present invention, a composition containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof is a composition characterized in that the tandospirone concentration in human blood (plasma) becomes 0.05 to 20 ng / mL between 8 hours and 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof.

[0070] In the present invention, when the composition containing tandospirone or a pharmaceutically acceptable salt or prodrug thereof is a transdermal absorption preparation, the application area of the preparation can usually be adjusted as appropriate, but preferably, the total sticking area per application is 1 to 100 cm 2 is. As the upper limit, 100 cm 2 , 50 cm 2 , 40 cm 2 , 30 cm 2 , 20 cm 2 etc. can be mentioned. As the lower limit, 1 cm 2 , 2 cm 2 , 4 cm 2 , 9 cm 2 etc. can be mentioned. As the preferable range, any combination of both the upper limit and the lower limit can obtain a preferable therapeutic effect.

[0071] The tandospirone of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, exceeds the lower limit value of the tandospirone concentration in human blood (plasma) within 8 hours, preferably within 6 hours, more preferably within 4 hours after a single administration, and the tandospirone concentration in human blood (plasma) is maintained within the range of the upper limit and the lower limit until 16 hours, preferably until 18 hours, more preferably until 20 hours after a single administration.

[0072] In the present invention, the tandospirone transdermal absorption preparation is used in combination with a levodopa-containing preparation for the treatment of Parkinson's disease. For the tandospirone transdermal absorption preparation in the present invention, more preferable effects can be expected when a levodopa-containing preparation is administered 6 hours or more, preferably 8 hours or more, more preferably 12 hours or more after the tandospirone transdermal absorption preparation is applied. Further, by repeatedly administering the tandospirone transdermal absorption preparation by replacing it at predetermined intervals, a stable therapeutic effect can be obtained regardless of the administration timing of the levodopa-containing preparation.

[0073] The method for manufacturing the transdermal absorption preparation of the present invention will be described below, but the present invention is not limited thereto.

[0074] The transdermal absorption preparation of the present invention can be manufactured by a generally known method. The tape preparation of the present invention can be manufactured, for example, according to Production Example 1 below.

[0075] (Production Example 1) Describe a general method for manufacturing a tape preparation. The tape preparation (patch) of the present invention can be manufactured by a usual method. For example, it can be manufactured according to the section on the manufacture of plaster preparations described in "Manual for the Development of Transdermal Application Preparations" supervised by Mitsuo Matsumoto (1985). Also, for example, it can be manufactured by the devices, methods, etc. 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, in forming the adhesive layer, the production method of ordinary adhesive tapes can be applied. A typical example thereof is the solvent coating method, but in addition to this, a hot melt coating method, an electron beam-curing emulsion coating method, etc. can also be used.

[0077] To form the adhesive layer by the solvent coating method, for example, tandospirone, a mixed solution containing an adhesive, and pharmaceutical components such as a permeation enhancer and a curing agent are mixed with an organic solvent to prepare an adhesive layer mixed solution. The mixed solution is applied to one side of a support or a release liner, dried to remove the organic solvent, and the release liner or the support is laminated at any timing before or after drying, whereby it can be manufactured. The thickness of the adhesive layer of the tape preparation is not particularly limited, preferably about 10 μm to about 400 μm, more preferably about 20 μm to about 200 μm, still 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 Preparations

[0079] Ointments can be produced by generally known methods. To produce an oily ointment, usually, an oily base such as fats and oils, waxes, and hydrocarbons such as paraffin is heated and melted, an active ingredient is added, mixed, dissolved or dispersed, and kneaded until the whole becomes homogeneous. To produce a water-soluble ointment, usually, a water-soluble base such as macrogol is heated and melted, an active ingredient is added, and kneaded until the whole becomes homogeneous.

[0080] For example, tandospirone can be manufactured by blending it with higher alcohols such as cetanol and stearyl alcohol, higher fatty acids such as myristic acid, lauric acid, palmitic acid, stearic acid, linoleic acid or their esters, purified lanolin, waxes such as 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 to 10% by weight of tandospirone, 0.1 to 5% of higher alcohol, 1 to 15% by weight of higher fatty acid or its ester, 1 to 10% by weight of surfactant, 4 to 10% by weight of waxes, and 50 to 80% by weight of hydrocarbons. As a manufacturing method, for example, tandospirone and the above-mentioned additive components are added, mixed under heating, maintained at 50 to 100 °C, and after all components become a transparent solution, they are uniformly mixed with a homomixer. Then, an ointment can be obtained by cooling and stirring while allowing it to cool naturally.

[0081] Injections for subcutaneous, intradermal, and intramuscular administration can be manufactured by generally known methods. Usually, they can be manufactured by the following methods. (i) The active ingredient as it is, or the active ingredient with additives added, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents, etc., to make it homogeneous, filled into a container for injection, sealed, and sterilized. (ii) The active ingredient as it is, or the active ingredient with additives added, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents, etc., to make it homogeneous, and then aseptically filtered, or prepared aseptically to make it homogeneous, and filled into a container for injection and sealed.

[0082] In order to prevent the active ingredient from decomposing or deactivating in the solution, the above-mentioned injection can also be manufactured as a freeze-dried injection or a powder injection.

[0083] A freeze-dried injection can usually be manufactured by dissolving the active ingredient as it is, or the active ingredient and additives such as excipients in water for injection, aseptically filtering, filling into a container for injection, and then freeze-drying, or freeze-drying in a dedicated container and then directly filling into a container.

[0084] Powder injections are usually prepared by treating them by sterile filtration, adding a powder obtained by crystallization or a sterilized additive to the powder, and filling them 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. As the solvent used for dissolution (water, an organic solvent, or a mixed solvent of an organic solvent and water), an organic solvent or a mixed solvent of an organic solvent and water is preferable, and a mixed solvent of an organic solvent and water is more preferable. The sterilizing filter is effective for removing foreign substances derived from raw materials or foreign substances mixed during the manufacturing process in addition to sterilizing filtration.

[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, and sodium lauryl sulfate, etc., and two or more of these may be used. Preferably, it is polysorbate 80. The surfactant is preferably used at about 0.005% (w / v) to about 10% (w / v). As the water, purified water, water of a grade equal to or higher than purified water, or water for injection is used. 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 solvents may be used. Preferably, they are 1-propanol, methanol, ethanol, 2-propanol, acetone, dimethyl sulfoxide, or 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 preparation. Also, after sucking the present preparation into an injection syringe through an injection needle from a container such as a vial filled with the preparation, it can be discharged intramuscularly or subcutaneously for injection administration. Furthermore, the preparation can be a lyophilized preparation obtained by lyophilizing after filling the preparation into a container such as a vial, and it is also possible to make a powder-filled preparation by powder-filling a dried powder crystal obtained by drying after isolating the active ingredient crystals in the present preparation into a container such as a vial. In the lyophilized preparation and the powder-filled preparation, a suspension prepared by suspending in situ in a container with a suspending liquid can be sucked into an injection syringe through an injection needle from the container and then injected intramuscularly or subcutaneously for administration. The injection of the present invention can also be administered intramuscularly or subcutaneously after installing a container filled with the preparation in a needleless syringe (a form that utilizes the pressure generated by gas, an initiator, a spring, etc. incorporated in a syringe device to discharge the chemical solution filled in the container and can be administered without using an injection needle).

[0088] Example of adjustment of continuous infusion pump The injection of the present invention can be administered continuously using a commercially available continuous subcutaneous infusion pump. A continuous subcutaneous infusion pump is a device that has a drug storage part and a pump for continuously injecting a drug, and continuously injects the drug subcutaneously into a patient through an injection tube. This device usually incorporates a clock and a program that can change the injection amount at regular intervals. The drug storage part is a sealed container filled with a chemical solution adjusted to the drug concentration required for the drug effect, which is provided with a chemical solution inlet and outlet for connection to the pump. The pump is a pump that can inject this chemical solution in a very small and precise continuous manner, and is a device that can inject a very small liquid volume of about 0.1 mL / day to 10 mL / hour. The drug storage part is filled and stored with an aseptically guaranteed tandospirone solution.

[0089] A sustained-release injection is an injection applied subcutaneously, intradermally, intramuscularly, etc. for the purpose of releasing an active ingredient over a long period. The sustained-release injection can be manufactured by generally known methods. Usually, it can be manufactured by dissolving or suspending the active ingredient in a vegetable oil or the like, or by making it a suspension of microspheres using a biodegradable polymer compound.

[0090] An implant is a solid or gel-like injection applied subcutaneously, intramuscularly, etc. using an implantation device or by surgery for the purpose of releasing an active ingredient over a long period. The implant can be manufactured by generally known methods. Usually, it can be obtained by using a biodegradable polymer compound to form a pellet, microsphere or gel-like preparation.

[0091] (Combined drug) The transdermal absorption preparation of the present invention can be used in combination with existing Parkinson's disease therapeutic drugs other than levodopa. Such existing Parkinson's disease therapeutic drugs include, for example, 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., but are not limited thereto.

[0092] The present invention will be described more specifically below with reference examples, examples and test examples, but the present invention is of course not limited thereto. In addition, the compound names shown in the following reference examples, examples, etc. do not necessarily follow the IUPAC nomenclature.

Example

[0093] Examples are described below.

[0094] Specifically, the products described in the examples were used for the reagents, but equivalent products of other manufacturers (such as Sigma-Aldrich, Wako Pure Chemical Industries, Ltd., Nacalai Tesque, R&D Systems, USCN Life Science INC, etc.) can also be substituted.

[0095] (Production Example) Reference Production Example 1: Production 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, and this description is incorporated herein by reference.

Chemical formula

[0096] (Reference Production Example: Production of tandospirone tape agent) (Production of tandospirone tape agent) An acrylic adhesive (MAS683, manufactured by Cosmed Pharmaceutical Co., Ltd., solid content 35.6% by weight, 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 mixed adhesive solution, and the mixture was stirred well. The obtained mixed solution was spread on a support and dried at room temperature for 1 day. Then, a release liner was laminated to produce a tandospirone tape agent. (Production of placebo tape agent) An acrylic adhesive (MAS683, manufactured by Cosmed Pharmaceutical Co., Ltd., solid content 35.6% by weight, 18.6962 g), ethyl acetate (5.5 mL), and polyoxyethylene lauryl ether (0.3520 g) were mixed and stirred well. The resulting mixture was spread on a support and dried at room temperature for 1 day. Then, a release liner was laminated to produce a placebo tape agent.

[0097] As the support, 50.8 μm polyethylene terephthalate manufactured by 3M Health Care Co., Ltd., and / or ethylene vinyl acetate copolymer laminate film (Scotchpak #9732) were used. As the release liner, Binasyte 64S-018B manufactured by Fujimori Kogyo Co., Ltd. was used.

Table 1

[0098] Measurement of the amount of drug (drug dosage) and remaining amount of drug in the tape agent Examples of the measurement conditions for the drug dosage and the remaining amount of drug are described below, but it is possible to substitute other measurement methods that have been verified to be able to measure the drug dosage or the remaining amount of tandospirone. <Examples of measurement conditions> Preparation of standard solution Prepare tandospirone solutions (approximately 4, 20, 100 μg / mL). Preparation of formulation solution (1) Put the tape agent in a container, add 10 mL of acetone, and irradiate with ultrasonic waves for about 30 minutes. (2) Add 1 mL of methanol to 1 mL of the extract from (1) and mix. (3) Filter with a filter (Millipore: Millex-FH (0.45 um, PTFE)).

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

[0100] ( (Plasma concentration evaluation) 1. Test method 1.1. Pretreatment operation method Aliquot 50 μL of rat plasma sample into a polypropylene microtube, add 50 μL of methanol (50 μL of standard solution for calibration curve sample), 200 μL of internal standard solution (Bezafibrate methanol solution: 200 nmol / L, 200 μL of methanol for blank sample), and stir with a mixer for about 10 seconds. After centrifuging this (4 °C, 4500 rpm, 10 minutes), filter the supernatant by suction through a filtration filter (FastRemover MF 0.2 μm). Add 70 μL of 10 mmol / L ammonium acetate aqueous solution to 70 μL of the obtained filtrate and stir with a mixer for about 10 seconds to obtain a sample for measurement. Measure the tandospirone concentration by liquid chromatography - mass spectrometry.

[0101] 1.2. Measurement conditions Column: XSELECT CSH C18, 3.5 μm, 100×3.0 mm I.D. Column temperature: 50 °C Mobile phase A: 10 mmol / L ammonium acetate aqueous solution Mobile phase B: Methanol Flow rate: 0.6 mL / min Gradient conditions:

Table 2

[0102] (Example 1: Evaluation of the Plasma Concentration Profile When a Tandospirone Tape Preparation was Applied to Normal Rats) (Test Method) Wistar male rats (14 weeks old, Japan SLC) were used. Before the evaluation date of the tape preparation, the hair on the abdomen of the rats was shaved, and on the evaluation date, the tape preparation of Formulation 1 was applied to the abdomen (size: 9 cm 2 ). Blood was collected over time 2, 4, 6, and 24 hours after the topical administration, and the concentration analysis of tandospirone in the plasma was performed. The results were shown as the mean ± standard deviation.

[0103] (Results) The application of the tandospirone tape preparation (9 cm 2 : 31 ± 2 cm 2 / kg) resulted in the plasma tandospirone concentration profile as shown in Figure 1. It was confirmed that the tape preparation smoothed and sustained the blood concentration of tandospirone.

[0104] (Example 2: Evaluation of the Dyskinesia Improvement Effect of a Tandospirone Tape Preparation) As a typical experimental model for PD-LID, a rat striatal dopamine neuron destruction model by local administration of 6-hydroxydopamine (hereinafter sometimes referred to as "6-OHDA") into one side of the brain is known (6-OHDA unilateral treatment rats (6-OHDA-lesioned rats)). In this model, dyskinesia-like abnormal involuntary movements (AIMs) appear by repeated administration of levodopa (Lundblad et al., European Journal of Neuroscience, 2002, 15: 120 - 132, Winkler et al., Neurobiology of Disease, 2002, 10: 165 - 186).

[0105] (Test Method) For the production of model animals, Wistar male rats (12 weeks old, Japan SLC) were used. Desipramine hydrochloride (25 mg / kg; Wako Pure Chemical Industries, Ltd.) was administered intraperitoneally. Thirty minutes after administration, isoflurane inhalation anesthesia was performed using a general anesthesia apparatus for experimental animals. Under isoflurane anesthesia, the rats were fixed to a stereotaxic apparatus, and the skull was exposed by incising the skin of the head with a surgical scalpel. The coordinates of bregma, which served as 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 measured coordinates, 6-OHDA (9 μg / 4 μL; Sigma-Aldrich), which has a dopaminergic neurodegenerative effect, was locally injected. Two weeks after the surgery, apomorphine hydrochloride hemihydrate (0.5 mg / kg; Wako Pure Chemical Industries, Ltd.) was administered subcutaneously, and rotational movement to the contralateral side of the site where 6-OHDA was injected was observed. Rats that rotated more than 7 times per minute were used as 6-OHDA unilateral-treated rats.

[0106] To prepare the PD-LID model, a mixed solution of levodopa methyl ester hydrochloride (6 mg / kg; Sigma-Aldrich) and benserazide hydrochloride (15 mg / kg; Sigma-Aldrich) dissolved in physiological saline (hereinafter sometimes referred to as the "levodopa mixture") was intraperitoneally administered to 6-OHDA-lesioned rats once a day. Repeated administration of the levodopa mixture was carried out for 3 weeks or more, and behavioral observation and evaluation were performed. The behavioral observation and evaluation were carried out in a transparent acrylic cage for 1 minute every 20 minutes starting 20 minutes after the intraperitoneal administration of the levodopa mixture until 3 hours after administration. Behavioral observations were classified into Limb AIMs (involuntary flexion and extension of the forelimb on the side opposite the lesion, opening and closing of the palm, up and down movement of the wrist, choreiform tremors, dystonia-like rigidity), Axial AIMs (twisting of the upper body and neck to the side opposite the lesion, loss of balance and falling, or maintaining that unstable posture), Orolingual AIMs (chattering of the jaw or violently protruding the tongue forward), and Locomotive behavior (rotational behavior to the side opposite the lesion), and scored from 0 to 4 (0; none, 1; less than 30 seconds of manifestation, 2; 30 seconds or more of manifestation, 3; always present but stopped by stimuli such as sound, 4; always present and not stopped by stimuli such as sound). The sum of the scores of Limb AIMs, Axial AIMs, and Orolingual AIMs at 3 hours was defined as the total AIMs score. Individuals with a total AIMs score of less than 10 were excluded from the study as they did not show dyskinesia-like symptoms. Behavioral observation and evaluation were performed before the drug evaluation day, and rats were assigned to each administration group based on the 3-hour AIMs score, Locomotive behavior score, and rat body weight, and used for drug evaluation.

[0107] (Transdermal administration (Condition 1)) When evaluating the patch, hair on the rat abdomen was shaved before the evaluation day. On the evaluation day, the patch of Formulation 2 was applied to the rat abdomen at 60 cm 2 / kg (37 mg / kg), and the levodopa mixture was intraperitoneally administered 4 hours after application, followed by behavioral observation and evaluation. Individuals in which more than 50% of the patch peeled off during the test were excluded from the analysis. Plasma was collected after the behavioral observation and evaluation, and the concentration of tandospirone in the plasma was analyzed.

[0108] (Transdermal administration (Condition 2)) When evaluating the tape formulation under the keratin stripping condition (high tandospirone exposure condition), on the evaluation day, after performing 10 times of stripping on the rat abdomen using Transpore surgical tape (3M), the tape formulation of Formulation 3 was applied at 60 cm 2 / kg (45 mg / kg), and after 4 hours of application, levodopa mixture was intraperitoneally administered to conduct behavioral observation evaluation. Individuals in which more than 50% of the tape formulation peeled off during the test were excluded from the analysis. After the completion of the behavioral observation evaluation, plasma was collected and the concentration of tandospirone in the plasma was analyzed.

[0109] In the evaluation of dyskinesia-like symptoms, the sum of Limb AIMs, Axial AIMs, and Orolingual AIMs at each evaluation time point was used as the AIMs score. The statistical analysis of the test results was performed by the Wilcoxon rank sum test using the total AIMs score obtained by summing the AIMs scores for 3 hours and the total AIMs score for 100 - 180 minutes as indices. ** indicates p < 0.01, meaning that there is a significant difference compared to the placebo tape formulation application group. The results in the figure are shown as the mean value ± standard error.

[0110] (Results) When the tandospirone tape formulation (Formulation 2: drug dosage 37 mg / kg) was applied by transdermal administration (Condition 1) to absorb tandospirone transdermally, the total AIMs score was 12.6. Compared with the case of applying a placebo tape formulation containing no tandospirone, the total AIMs score decreased by 17.7, and a significant improvement in dyskinesia-like symptoms was observed (Figure 2 - A, B). Also, at the time point of 120 - 140 minutes after levodopa administration, clear dyskinesia-like symptoms (average AIMs score of 2 or more) were not observed in either the placebo tape formulation application group or the tandospirone tape formulation application group, and no significant difference was observed between the two groups in the total AIMs score for 100 - 180 minutes (Figure 2 - C). In addition, the average value of the tandospirone concentration in the plasma measured after the completion of the behavioral observation evaluation was 71.8 ng / mL.

[0111] Under transdermal administration (Condition 2), a tandospirone tape formulation (Formulation 3: drug dosage 45 mg / kg) was applied under keratin stripping conditions to allow transdermal absorption of highly exposed tandospirone. The total AIMs score was 5.8. The total AIMs score decreased by 27.1 compared to the case where a placebo tape formulation without tandospirone was applied, and a significant improvement in dyskinesia-like symptoms was observed. Under Administration Condition 2, a higher improvement effect was observed compared to Administration Condition 1 (Figs. 3-A, B). Also, at the time point of 120 - 140 minutes after levodopa administration under keratin stripping conditions, no clear dyskinesia-like symptoms (average AIMs score of 2 or more) were observed in either the placebo tape formulation application group or the tandospirone tape formulation application group, and no significant difference was observed between the two groups in the total AIMs score for 100 - 180 minutes (Fig. 3-C). In addition, the average value of the plasma tandospirone concentration measured after the end of the behavioral observation evaluation was 269 ng / mL. The average value of the plasma tandospirone concentration under Administration Condition 2 was more than three times higher than that under Administration Condition 1.

[0112] From the above results, the tandospirone transdermal administration formulation improved PD-LID symptoms without causing rebound symptoms. Also, in a non-clinical model, it was found that the anxiolytic effect of tandospirone and its effect on PD-LID were manifested at the same dosage. The anxiolytic effect was evaluated in a rat Vogel conflict tests model, and the effect on PD-LID was evaluated in 6-OHDA-lesioned rats. Therefore, it is considered that the therapeutic effect in the present invention is manifested at a blood concentration equivalent to that of commercially available tandospirone citrate tablets (Sediel tablets) as an anxiolytic drug.

[0113] (Example 3: Evaluation of the dyskinesia improvement effect of subcutaneous sustained administration of tandospirone) The drug efficacy of tandospirone against dyskinesia-like symptoms was evaluated by subcutaneously and continuously administering tandospirone to PD-LID model rats.

[0114] (Test method) Similar to Example 2, repeated administration of the levodopa formulation solution was performed on 6-OHDA-lesioned rats for 3 weeks or more, and behavioral observation and evaluation were carried out. Behavioral observation and evaluation were performed before the drug evaluation date, and the assignment to each administration group was made based on the 3-hour AIMs score, Locomotive behavior score, and the body weight of the rats, and these were used for the drug evaluation. However, individuals with a total AIMs score of less than 10 were excluded from the study as they did not show dyskinesia-like symptoms. Also, in order to suppress the variation in the administered dose for each individual, individuals whose body weight deviated by more than 10% from the average body weight were also excluded from the study.

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

[0116] The osmotic pumps injected with tandospirone or the solvent were implanted subcutaneously in rats (n = 6 per group). Four hours later, the levodopa formulation solution was administered, and behavioral observation and evaluation were carried out. Also, after the behavioral observation and evaluation, blood was collected from the rats in the tandospirone administration group, and the concentration of tandospirone in the plasma was analyzed.

[0117] The results in the figures are shown as mean ± standard error. Statistical analysis of the test results was performed by the Steel test, comparing with the solvent administration group using the 3-hour total AIMs score and the total AIMs score from 100 - 180 minutes as indices. * indicates p < 0.05, meaning there is a significant difference.

[0118] (Results) Subcutaneous continuous administration of tandospirone dose-dependently improved dyskinesia-like symptoms, and significant improvement was observed at 1.25 mg / kg / hour (Figs. 4-A, B). Also, at the time point of 120 - 140 minutes after levodopa administration, no clear dyskinesia-like symptoms (mean AIMs score of 2 or more) were observed in either the solvent administration group or the tandospirone administration group. Furthermore, in the total AIMs score for 100 - 180 minutes, subcutaneous continuous administration of tandospirone dose-dependently decreased the total AIMs score, and significant improvement was observed at 1.25 mg / kg / hour (Fig. 4-C). The average value of the plasma tandospirone concentration measured after the behavioral observation evaluation was 23.5 ng / mL at 0.05 mg / kg / hour, 119 ng / mL at 0.25 mg / kg / hour, and 541 ng / mL at 1.25 mg / kg / hour.

[0119] From the above results, subcutaneous continuous administration of tandospirone dose-dependently improved dyskinesia-like symptoms. Also, no rebound symptoms occurred at any of the administered doses.

[0120] (Example 4: Evaluation of the long-term dyskinesia improvement effect of subcutaneous continuous administration of tandospirone) The efficacy persistence of tandospirone against dyskinesia-like symptoms was evaluated by continuously administering tandospirone subcutaneously to PD-LID model rats for 2 weeks.

[0121] (Test method) Similar to Example 2, 6-OHDA-lesioned rats were repeatedly administered a levodopa formulation for 3 weeks or more, and behavioral observation evaluations were performed. Individuals with a total AIMs score of less than 15 were excluded from the test as they did not show dyskinesia-like symptoms. Behavioral observation evaluations were performed before the drug evaluation day, and rats were assigned to each administration group using the 3-hour AIMs score, Locomotive behavior score, and the body weight of the rats as indices, and these were used for the drug evaluation.

[0122] Tandospirone citrate was dissolved in 1 M hydrochloric acid (Nacalai Tesque) and diluted with physiological saline to a concentration of 60 mg / mL (concentration of citrate). The prepared solution was injected into an ALZET (registered trademark) Osmotic Pump MODEL2ML2 (4.53 μL / hour; DURECT) that released the drug solution at a stable rate for 2 weeks and used.

[0123] Osmotic pumps injected with tandospirone citrate or the solvent were implanted subcutaneously in rats, with n = 8 in each group. Four hours later, a levodopa formulation was administered, and behavioral observation and evaluation were performed (day 0 of pump implantation). Thereafter, the repeated administration of the levodopa formulation was continued once a day, and behavioral observation and evaluation were also performed on day 13 of pump implantation. In addition, after each behavioral observation and evaluation, blood was collected from half of the rats (n = 4) in the tandospirone administration group, and the concentration of tandospirone in plasma was analyzed.

[0124] The results in the figure are shown as the mean ± standard error of the total AIMs score over 3 hours. Using the total AIMs score as an index, statistical analysis of the test results was performed by the Wilcoxon rank sum test. Compared with the solvent administration group, ** indicates p < 0.01, meaning there is a significant difference.

[0125] (Results) Continuous subcutaneous administration of tandospirone citrate (60 mg / mL as tandospirone citrate: average 0.78 mg / kg / hour) resulted in a significant improvement in dyskinesia-like symptoms compared with the solvent group on day 0 of pump implantation (Figure 5-A). The average value of the plasma tandospirone concentration (free form conversion value) measured after the completion of the behavioral observation and evaluation was 281 ng / mL. Furthermore, on day 13 of pump implantation, a significant improvement in dyskinesia-like symptoms was also observed compared with the solvent group (Figure 5-B). The average value of the plasma tandospirone concentration (free form conversion value) measured after the completion of the behavioral observation and evaluation was 143 ng / mL.

[0126] From the above results, the improvement effect on PD-LID symptoms persisted even after 13 days of continuous subcutaneous administration of tandospirone.

[0127] (Example 5: Evaluation of the preventive and inhibitory effects of tandospirone on the development of dyskinesia with subcutaneous sustained administration) When levodopa is repeatedly administered to 6-OHDA-lesioned rats, dyskinesia-like abnormal involuntary movements appear. Therefore, the preventive effect of tandospirone on the appearance of dyskinesia-like symptoms was evaluated by subcutaneously and continuously administering tandospirone immediately after the start of repeated levodopa administration.

[0128] (Test method) Tandospirone citrate was dissolved in 1M hydrochloric acid (Nacalai Tesque) and diluted with physiological saline to 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) and used.

[0129] In 6-OHDA-lesioned rats, assignment to each administration group was carried out using the number of rotations induced by apomorphine hydrochloride hemihydrate and body weight as indices. On the day after the start of repeated administration of the levodopa formulation with the same composition as in Example 2, an osmotic pump injected with tandospirone citrate or a solvent was implanted subcutaneously in the rats. On the 3rd, 5th, 9th, and 15th days after the start of repeated levodopa administration, behavioral observation evaluations were carried out using the same method as in Example 2. Also, after the behavioral observation evaluation on the 15th day, the osmotic pump implanted subcutaneously was removed, and a behavioral observation evaluation was also carried out on the next day (the 16th day of repeated levodopa administration).

[0130] The results in the figure are shown as the mean value ± standard error of the total AIMs score for 3 hours. Using the total AIMs score on the 16th day of repeated levodopa administration as an index, statistical analysis of the test results was carried out by comparison with the solvent administration group using the Steel test. Compared with the solvent administration group, * indicates p < 0.05 and ** indicates p < 0.01, meaning that there is a significant difference.

[0131] (Results) Subcutaneous sustained administration of tandospirone citrate (30 mg / mL: average 0.41 mg / kg / hour or 60 mg / mL: average 0.83 mg / kg / hour) suppressed the increase in the total AIMs score associated with repeated levodopa administration compared with the vehicle group (Figure 6-A). Furthermore, even on the day after the termination of tandospirone citrate administration, the total AIMs score was significantly decreased in the group administered tandospirone citrate compared with the vehicle group (Figure 6-B). From the above results, subcutaneous sustained administration of tandospirone prevented the onset of PD-LID, and the effect persisted even on the day after the last administration of tandospirone.

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

[0133] (Test method) Behavioral observation evaluation was performed using the same method as in Example 2. Tandospirone citrate was suspended in a 0.5% methylcellulose solution and orally administered to rats, and 5 minutes later, a levodopa formulation was intraperitoneally administered to perform behavioral observation evaluation. The results in the figures are shown as mean ± standard error. Statistical analysis of the test results was performed by the Steel test by comparing with the vehicle administration group using the total AIMs score for 3 hours and the total AIMs score for 100 - 180 minutes as indices. * indicates p < 0.05, meaning there is a significant difference.

[0134] (Results) (1) Dyskinesia-like symptoms In the oral administration groups of tandospirone citrate (citrate concentrations of 10, 30, 100 mg / kg), no significant change in the total AIMs score was observed compared with the vehicle administration group (Figures 7, 8-A, B). From this result, it was suggested that PD-LID cannot be improved with an oral administration preparation of tandospirone.

[0135] At the time point of 120 - 140 minutes after levodopa administration, dyskinesia-like symptoms subsided in the solvent administration group, but clear dyskinesia-like symptoms (average AIMs score of 2 or more) were observed in the oral administration groups of tandospirone citrate (30, 100 mg / kg). Furthermore, when comparing the solvent administration group with the oral administration groups of tandospirone citrate using the total AIMs score from 100 - 180 minutes as an index, a significant increase in the total AIMs score was observed in the oral administration groups of tandospirone citrate (30, 100 mg / kg) compared to the solvent administration group (Figures 7, 8-C). From the above results, it was suggested that in the oral dosage form of tandospirone, there is a possibility of the appearance of a phenomenon in which dyskinesia-like symptoms appear late and worsen (rebound symptoms of dyskinesia).

[0136] As described above, in the oral tandospirone administration group, no improvement in dyskinesia symptoms was observed in the PD-LID model rats (Table 3-(i)). In addition, rebound symptoms of dyskinesia were observed in the high-dose oral administration group (Table 3-(ii)). From these results, oral administration of tandospirone has an insufficient effect in improving dyskinesia, and there is a concern about the occurrence of rebound symptoms. Therefore, a treatment method combined with a levodopa preparation may not be appropriate.

[0137]

Table 3

[0138] As shown in Table 3, in the improvement of levodopa-induced dyskinesia symptoms, no significant difference was observed in oral administration, while significant improvement was observed in transdermal administration. In addition, it was newly found that there is a rebound symptom of dyskinesia in the case of oral administration, and it was found that treatment with oral tandospirone is not preferable. On the other hand, no rebound symptom of dyskinesia was observed in the case of transdermal administration. As described above, it was suggested that the therapeutic effect of oral tandospirone on levodopa-induced dyskinesia symptoms is limited, and transdermal administration of tandospirone is preferable.

[0139] (Comparative Example 2: Evaluation of the effect 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 carried out using the same method as in Example 2. 1-PP dihydrochloride (Tokyo Chemical Industry) was dissolved in physiological saline and subcutaneously administered to rats, and 5 minutes later, a levodopa mixture was intraperitoneally administered to carry out behavioral observation evaluation. The results in the figure are shown as the mean value ± standard error. Statistical analysis of the test results was carried out by comparing with the solvent administration group using the Steel test, with the total AIMs score for 3 hours and the total AIMs score for 100 - 180 minutes as indicators.

[0142] (Results) In the subcutaneous administration group of 1-PP dihydrochloride (10, 30 mg / kg), no significant change in the total AIMs score was observed compared with the solvent administration group (Figure 10 - A, B).

[0143] At the time point of 120 - 140 minutes after levodopa administration, distinct dyskinesia-like symptoms (average AIMs score of 2 or more) were observed in the subcutaneous administration groups (10, 30 mg / kg) of 1-PP dihydrochloride. Furthermore, when the solvent administration group was compared with the 1-PP dihydrochloride administration group using the total AIMs score from 100 - 180 minutes as an index, an increasing trend in the total AIMs score, although not significant, was observed in the 1-PP dihydrochloride administration group compared with the solvent administration group (Figure 10-C). From these results, it was suggested that the metabolite 1-PP of tandospirone might cause rebound symptoms of dyskinesia.

[0144] From the above results, it was suggested that rebound symptoms of dyskinesia might occur under the administration conditions that produce the metabolite 1-PP of tandospirone. That is, for tandospirone, an administration method that can suppress the production of 1-PP is more preferable as it has less impact on the rebound symptoms of dyskinesia.

[0145] (Example 6: Demonstration in Clinical Protocol) As a clinical trial with an appropriate design for evaluating PD-LID, the improvement effect regarding PD-LID can be confirmed for the compound of the present invention or the combined drug of the present invention by a clinical trial according to the method described in the following Reference 1 (Amantadine P3) (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 diagnosed with Parkinson's disease aged 20 years or older, after administering the tandospirone of the present invention or a pharmaceutically acceptable salt or prodrug thereof, or the combined drug of the present invention for a certain administration period (for example, 8 - 12 weeks, but not limited thereto), the improvement effect regarding PD-LID can be confirmed by comparing the scores of UPDRS, UDysRS, CDRS, AIMS, etc. and the dyskinesia onset time based on the patient diary before and after the administration period.

[0147] In the above-mentioned test, conditions such as the target patient, administration period, dosage of the drug, evaluation method, etc. can be appropriately changed.

[0148] (Note) As described above, the present invention has been exemplified using preferred embodiments of the present invention. However, it is understood that the scope of the present invention should be construed only by the claims. This application claims the priority of US Patent Application No. 16 / 395,531, the entire content of which is incorporated herein by reference. It is understood that patents, patent applications, and other documents cited in this specification should be incorporated herein by reference as if the content itself were specifically described herein.

Industrial Applicability

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

Claims

1. A composition for treating, ameliorating, suppressing the progression of, or preventing levodopa-induced dyskinesia (PD-LID) without causing rebound symptoms, comprising tandospirone or a pharmaceutically acceptable salt thereof, wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered transdermally.

2. The composition according to claim 1, wherein the transdermal administration is sustained or administered continuously.

3. The composition according to claim 1 or 2, wherein the levodopa-induced dyskinesia (PD-LID) includes peak-dose dyskinesia, biphasic dyskinesia, and combinations thereof.

4. The treatment, amelioration, suppression of the progression of, or prevention of the levodopa-induced dyskinesia (PD-LID) according to any one of claims 1 to 3 includes improvement, suppression of the progression of, or prevention of levodopa-induced dyskinesia (PD-LID) symptoms, shortening of the onset time of levodopa-induced dyskinesia (PD-LID), or combinations thereof.

5. The composition according to claim 4, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is at least a clinically significant improvement.

6. The composition according to claim 4 or 5, wherein the improvement of the levodopa-induced dyskinesia (PD-LID) symptoms is at a level sufficient to obtain a clinical effect.

7. The composition according to any one of claims 1 to 6, wherein the composition is a transdermal absorption preparation.

8. The composition according to any one of claims 1 to 7, wherein the composition is a patch preparation.

9. The composition according to any one of claims 1 to 8, wherein the transdermal absorption preparation is a tape / patch.

10. The composition according to any one of claims 1 to 9, wherein the drug dosage of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 100 mg per day as the free form of tandospirone.

11. The composition according to any one of claims 1 to 10, wherein the amount of drug transferred of tandospirone or a pharmaceutically acceptable salt thereof is 0.1 to 20 mg per day as the free form of tandospirone.

12. The composition according to any one of claims 1 to 11, wherein the composition is a transdermal absorption preparation, and the total area of the sticking surface per application is 1 to 100 cm ２ The composition according to any one of claims 1 to 11, wherein the composition is a transdermal absorption preparation, and the total area of the sticking surface per application is 1 to 100 cm

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

14. The composition according to any one of claims 1 to 13, wherein tandospirone or a pharmaceutically acceptable salt thereof is administered such that the concentration of tandospirone in human blood (plasma) is 0.05 to 20 ng / mL between 8 and 16 hours after administration of tandospirone or a pharmaceutically acceptable salt thereof.

15. The composition according to any one of claims 1 to 14, wherein tandospirone or a pharmaceutically acceptable salt thereof is an adjuvant for levodopa.

16. The composition according to any one of claims 1 to 15, which is used in combination with levodopa in a fixed-dose formulation or separate formulations.

17. The composition according to any one of claims 1 to 16, wherein tandospirone or a pharmaceutically acceptable salt thereof is the free form of tandospirone.

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