Therapeutic drug for dyskinesia

Abstract

The present invention provides a therapeutic drug that is useful for levodopa induced dyskinesia in Parkinson's disease. In particular, the present invention provides a composition and method for treating, improving, delaying the progression, or preventing motor complications associated with levodopa therapy for Parkinson's disease, especially levodopa induced dyskinesia (PD-LID), comprising tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is parenterally administered.

What is claimed is: 
     
         1 . A method for treating, improving, delaying the progression, or preventing dyskinesia in a subject, comprising parenterally administering to the subject an effective amount of tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is administered so that a human blood (plasma) tandospirone concentration is 0.1 to 15 ng/mL for 12 hours or longer per day; and/or 0.1 to 15 ng/mL for 8 to 16 hours after administration of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         2 . The method according to  claim 1 , wherein the patient is suffered from Parkinson's disease. 
     
     
         3 . The method according to  claim 1 , wherein the subject is subject to a drug therapy of Parkinson's disease. 
     
     
         4 . The method according to  claim 1 , wherein the subject is subject to a drug therapy of Parkinson's disease, wherein the drug therapy is at least one selected from the group consisting of Parkinson's disease drug therapy such as levodopa therapy, a therapy with levodopa metabolism enzyme inhibitor and Dopamine receptor agonist; and Parkinson's disease adjunct. 
     
     
         5 . The method according to  claim 1 , wherein the subject is subject to a drug therapy of Parkinson's disease, wherein the drug therapy is at least one selected from the group consisting of dopamine replacement therapies such as levodopa therapy, a therapy with levodopa metabolism enzyme inhibitor and a dopamine receptor agonist. 
     
     
         6 . The method according to  claim 1 , wherein the subject is subject to a drug therapy of Parkinson's disease, wherein the drug therapy is at least one selected from the group consisting of levodopa therapies such as therapy with levodopa containing formulation, and a therapy with levodopa metabolism enzyme inhibitor and a dopamine receptor agonist. 
     
     
         7 . The method according to  claim 1 , wherein dopamine amount in striatal synaptic cleft of the subject is sustainably maintained and/or suppressing rapid changes. 
     
     
         8 . The method according to  claim 1 , wherein the administration is performed without inducing rebound symptoms in the subject. 
     
     
         9 . The method according to  claim 1 , wherein a levodopa-evoked synaptic dopamine fluxes in the striatum of the subject using  11 C-raclopride Positron Emission Tomography (PET) test is sustainably maintained, and/or suppressing rapid changes and/or intermittent domain receptor stimulation is suppressed. 
     
     
         10 . The method of  claim 1 , wherein the parenteral administration comprises transdermal administration. 
     
     
         11 . The method of  claim 1 , wherein the treatment, improvement, delay of progression, or prevention improves dyskinesia without a rebound symptom. 
     
     
         12 . The method of  claim 1 , wherein the dyskinesia comprises at least one of the group consisting of peak-dose dyskinesia, diphasic dyskinesia, and a combination thereof. 
     
     
         13 . The method of  claim 1 , wherein the treatment, improvement, delay of progression, or prevention of dyskinesia comprises improvement, delay of progression, or prevention of a dyskinesia symptom, reduction of a period of PD-LID manifestation, or a combination thereof. 
     
     
         14 . The method of  claim 13 , wherein the improvement of a dyskinesia symptom is a clinically significant improvement or greater. 
     
     
         15 . The method of  claim 13 , wherein the improvement of a dyskinesia symptom is to a sufficient level to attain a clinical effect. 
     
     
         16 . The method of  claim 1 , wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as a transdermally administered formulation. 
     
     
         17 . The method of  claim 1 , wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as an adhesive formulation. 
     
     
         18 . The method of  claim 10 , wherein the transdermally administered formulation is a tape/patch. 
     
     
         19 . The method of  claim 1 , wherein a drug dosage of the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 100 mg per day as a free form of tandospirone. 
     
     
         20 . The method of  claim 1 , wherein an amount of drug penetration for the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is 0.1 to 20 mg per day as a free form of tandospirone. 
     
     
         21 . The method of  claim 1 , wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is provided as a transdermally administered formulation, and a total applied area per dose is 1 to 100 cm 2 . 
     
     
         22 . The method of  claim 1 , wherein the human blood (plasma) tandospirone concentration is 1 to 12 ng/mL 
     
     
         23 . The method of  claim 1 , wherein the human blood (plasma) tandospirone concentration is 2 to 10 ng/mL. 
     
     
         24 . The method of  claim 1 , wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is an adjunct of levodopa. 
     
     
         25 . The method of  claim 1 , wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is used with levodopa as the fixed-dose combination or concomitantly as separate formulations. 
     
     
         26 . The method according to  claim 1 , wherein the method further improves motor fluctuations in the subject. 
     
     
         27 . The method according to  claim 26 , wherein the motor fluctuations comprise at least one of the group consisting of a wearing-off phenomenon, an on-off phenomenon, a no-on phenomenon, a delayed on phenomenon, and a combination thereof. 
     
     
         28 . The method according to  claim 26 , wherein treatment, improvement, or prevention of the motor fluctuations comprises prolongation of an antiparkinsonian action effective time (ON-time), a reduction of a non-response time (OFF-time), or a combination thereof. 
     
     
         29 . The method of  claim 1 , wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered so that a maximum blood concentration of human blood (plasma) tandospirone in a steady state is 1 to 15 ng/mL, and a ratio of a minimum concentration, with respect to the maximum concentration of human blood (plasma) tandospirone concentration as 100%, is 30 to 95% after administration of the tandospirone or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The method of  claim 1 , wherein the tandospirone or a pharmaceutically acceptable salt thereof is administered so that a maximum blood concentration of human blood (plasma) tandospirone in a steady state is 2 to 12 ng/mL, and a ratio of a minimum concentration, with respect to the maximum concentration of human blood (plasma) tandospirone concentration as 100%, is 30 to 95% after administration of the tandospirone or a pharmaceutically acceptable salt thereof.