Pharmaceutical compositions comprising an antipsychotic drug and a vmat2 inhibitor and uses thereof

Abstract

New methods of treating schizophrenia and schizoaffective disorder by administration of pharmaceutical compositions comprising an antipsychotic compound and a VMAT2 inhibitor to a subject in need thereof are provided.

1 . A method for treating a neuropsychiatric disorder in a subject comprising administering to the subject (a) an antipsychotic drug and (b) a VMAT2 inhibitor, wherein the therapeutically effective amount of the antipsychotic drug administered to the subject is less than the therapeutically effective amount of the antipsychotic drug when administered in the absence of the VMAT2 inhibitor. 
     
     
         2 - 17 . (canceled) 
     
     
         18 . A pharmaceutical preparation for use in treating a neuropsychiatric disorder, said preparation comprising an antipsychotic drug and a VMAT2 inhibitor, wherein the preparation comprises an amount of the antipsychotic drug that is a subtherapeutic amount if used in the absence of the VMAT2 inhibitor. 
     
     
         19 - 32 . (canceled) 
     
     
         33 . A method for enhancing efficacy of an antipsychotic drug comprising administering to a subject a combination of (a) the antipsychotic drug, and (b) a VMAT2 inhibitor. 
     
     
         34 - 46 . (canceled) 
     
     
         47 . A pharmaceutical preparation comprising an antipsychotic drug and a VMAT2 inhibitor, wherein the preparation is effective for treating a neuropsychiatric disorder, and wherein the amount of the antipsychotic drug is subtherapeutic compared with the therapeutic amount of the antipsychotic drug when used alone for treating the neuropsychiatric disorder in the absence of the VMAT2 inhibitor. 
     
     
         48 . A pharmaceutical preparation comprising synergistically effective amounts of an antipsychotic drug and a VMAT2 inhibitor. 
     
     
         49 - 60 . (canceled) 
     
     
         61 . A vesicular monoamine transport 2 (VMAT2) inhibitor that is [(2R,3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol,
 wherein the VMAT2 inhibitor is for the treatment of tardive dyskinesia in a subject in need thereof who is receiving an antipsychotic drug for the treatment of a neuropsychiatric disorder.   
     
     
         62 . A vesicular monoamine transport 2 (VMAT2) inhibitor that is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester,
 wherein the VMAT2 inhibitor is for the treatment of tardive dyskinesia in a subject in need thereof who is receiving an antipsychotic drug for the treatment of a neuropsychiatric disorder.   
     
     
         63 . A vesicular monoamine transport 2 (VMAT2) inhibitor that is a toluenesulfonate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester,
 wherein the VMAT2 inhibitor is for the treatment of tardive dyskinesia in a subject in need thereof who is receiving an antipsychotic drug for the treatment of a neuropsychiatric disorder.   
     
     
         64 . A first pharmaceutical preparation for the treatment of tardive dyskinesia, said first pharmaceutical preparation comprising a vesicular monoamine transport 2 (VMAT2) inhibitor that is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester,
 wherein the first pharmaceutical preparation is to be used in combination with a second pharmaceutical preparation for the treatment of a neuropsychiatric disorder, and   wherein the second pharmaceutical preparation comprises an antipsychotic drug.   
     
     
         65 . A first pharmaceutical preparation for the treatment of tardive dyskinesia, said first pharmaceutical preparation comprising a vesicular monoamine transport 2 (VMAT2) inhibitor that is a toluenesulfonate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester,
 wherein the first pharmaceutical preparation is to be used in combination with a second pharmaceutical preparation for the treatment of a neuropsychiatric disorder, and   wherein the second pharmaceutical preparation comprises an antipsychotic drug.   
     
     
         66 . A method for treating a neuropsychiatric disorder in a subject in need thereof, comprising:
 administering to the subject an antipsychotic drug for the treatment of a neuropsychiatric disorder and a vesicular monoamine transport 2 (VMAT2) inhibitor that is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester.   
     
     
         67 . A method for treating a neuropsychiatric disorder in a subject in need thereof, comprising:
 administering to the subject an antipsychotic drug for the treatment of a neuropsychiatric disorder and a vesicular monoamine transport 2 (VMAT2) inhibitor that is a toluenesulfonate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester.   
     
     
         68 . A method of treating tardive dyskinesia in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester,   wherein the subject is also being administered an antipsychotic drug for the treatment of a neuropsychiatric disorder.   
     
     
         69 . A method of treating tardive dyskinesia in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is a toluenesulfonate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester,   wherein the subject is also being administered an antipsychotic drug for the treatment of a neuropsychiatric disorder.   
     
     
         70 . A method of treating tardive dyskinesia in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester,   wherein the subject has schizophrenia, schizoaffective disorder, bipolar disorder, or major depressive disorder.   
     
     
         71 . A method of treating tardive dyskinesia in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is a toluenesulfonate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester, wherein the subject has schizophrenia, schizoaffective disorder, bipolar disorder, or major depressive disorder.   
     
     
         72 . A method of reducing the frequency of occurrence of tardive dyskinesia associated with administration of an antipsychotic drug in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester.   
     
     
         73 . A method of reducing the frequency of occurrence of tardive dyskinesia associated with administration of an antipsychotic drug in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is a toluenesulfonate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester.   
     
     
         74 . A method of reducing the severity or intensity of a movement disorder associated with administration of an antipsychotic drug in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester.   
     
     
         75 . A method of reducing the severity or intensity of a movement disorder associated with administration of an antipsychotic drug in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is a toluenesulfonate salt of (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester.   
     
     
         76 . A method of treating tardive dyskinesia by inhibiting vesicular monoamine transport 2 (VMAT2) in a subject in need thereof, comprising:
 contacting the VMAT2 with a therapeutically effective amount of a VMAT2 inhibitor that is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ),   wherein the subject is being administered an atypical antipsychotic drug for the treatment of a neuropsychiatric disorder.   
     
     
         77 . The method of  claim 76 , wherein the R,R,R DHTBZ results from administration to the subject of a precursor of R,R,R, DHTBZ wherein the precursor is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester. 
     
     
         78 . A method of treating tardive dyskinesia by inhibiting vesicular monoamine transport 2 (VMAT2) in a subject in need thereof, comprising:
 contacting the VMAT2 with a therapeutically effective amount of a VMAT2 inhibitor that is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ),   wherein the subject has schizophrenia, schizoaffective disorder, bipolar disorder, or major depressive disorder.   
     
     
         79 . The method of  claim 78 , wherein the R,R,R DHTBZ results from administration to the subject of a precursor of R,R,R, DHTBZ wherein the precursor is (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2yl ester. 
     
     
         80 . A method of treating tardive dyskinesia in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ),   wherein the subject is also being administered an atypical antipsychotic drug for the treatment of a neuropsychiatric disorder.   
     
     
         81 . A method of treating tardive dyskinesia in a subject in need thereof, comprising:
 administering to the subject a vesicular monoamine transport 2 (VMAT2) inhibitor that is (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol (R,R,R DHTBZ),   wherein the subject has schizophrenia, schizoaffective disorder, bipolar disorder, or major depressive disorder.