Dopamine-agonist combination therapy for improving sleep quality

Abstract

The present invention generally relates to pharmaceutical compositions comprising a dopamine agonist and sedative agent. In a preferred embodiment, the dopamine agonist is optically pure (S)-didesmethylsibutramine. In a preferred embodiment, the sedative agent is optically pure (S)-zopiclone or optically pure (S)-N-desmethylzopiclone. In a preferred embodiment, the dopamine agonist is optically pure (S)-didesmethylsibutramine; and the sedative agent is optically pure (S)-zopiclone or optically pure (S)-N-desmethylzopiclone. The pharmaceutical compositions of the invention are useful in the treatment of restless-leg syndrome and periodic-limb-movement disorder, as well as various sleep disorders. In addition, the present invention relates to a method of treating a patient suffering from restless-leg syndrome, periodic-limb-movement disorder, a sleep abnormality, or insomnia, comprising coadministering a therapeutically effective amount of a dopamine agonist and a therapeutically effective amount of a sedative agent. In a preferred embodiment, the dopamine agonist is optically pure (S)-didesmethylsibutramine. In a preferred embodiment, the sedative agent is optically pure (S)-zopiclone or optically pure (S)-N-desmethylzopiclone. In a preferred embodiment, the dopamine agonist is optically pure (S)-didesmethylsibutramine; and the sedative agent is optically pure (S)-zopiclone or optically pure (S)-N-desmethylzopiclone.

1 . A pharmaceutical composition, comprising a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is selected from the group consisting of racemic zopiclone, optically pure (S)-zopiclone, optically pure (S)-N-desmethylzopiclone, indiplon, zolpidem, zaleplon, and gaboxadol or a pharmaceutically acceptable salt, solvate, or hydrate of any of them; and said dopamine-receptor agonist is selected from the group consisting of amantadine, apomorphine, bromocriptine, cabergoline, carmoxirole, optically pure (S)-didesmethylsibutramine, dopexamine, fenoldopam, ibopamine, lergotrile, lisuride, memantine, mesulergine, pergolide, piribedil, pramipexole, quinagolide, ropinirole, roxindole, and talipexole or a pharmaceutically acceptable salt, solvate, or hydrate of any of them.  
   
   
       2 . The pharmaceutical composition of  claim 1 , wherein said sedative agent is selected from the group consisting of optically pure (S)-zopiclone and optically pure (S)-N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, or hydrate of either of them.  
   
   
       3 . The pharmaceutical composition of  claim 1 , wherein said sedative agent is optically pure (S)-zopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       4 . The pharmaceutical composition of  claim 1 , wherein said dopamine-receptor agonist is selected from the group consisting of apomorphine, bromocriptine, cabergoline, optically pure (S)-didesmethylsibutramine, lisuride, pergolide, pramipexole, and ropinirole or a pharmaceutically acceptable salt, solvate, or hydrate of any of them.  
   
   
       5 . The pharmaceutical composition of  claim 1 , wherein said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       6 . A pharmaceutical composition, comprising a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is optically pure (S)-zopiclone or optically pure (S)-N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       7 . A pharmaceutical composition, comprising a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is optically pure (S)-zopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       8 . The pharmaceutical composition of any one of claims  1 - 7 , wherein said pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.  
   
   
       9 . A pharmaceutical composition consisting essentially of a sedative agent, a dopamine-receptor agonist, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is selected from the group consisting of racemic zopiclone, optically pure (S)-zopiclone, optically pure (S)-N-desmethylzopiclone, indiplon, zolpidem, zaleplon, and gaboxadol or a pharmaceutically acceptable salt, solvate, or hydrate of any of them; and said dopamine-receptor agonist is selected from the group consisting of amantadine, apomorphine, bromocriptine, cabergoline, carmoxirole, optically pure (S)-didesmethylsibutramine, dopexamine, fenoldopam, ibopamine, lergotrile, lisuride, memantine, mesulergine, pergolide, piribedil, pramipexole, quinagolide, ropinirole, roxindole, and talipexole or a pharmaceutically acceptable salt, solvate, or hydrate of any of them.  
   
   
       10 . The pharmaceutical composition of  claim 9 , wherein said sedative agent is selected from the group consisting of optically pure (S)-zopiclone and optically pure (S)-N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, or hydrate of either of them.  
   
   
       11 . The pharmaceutical composition of  claim 9 , wherein said sedative agent is optically pure (S)-zopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       12 . The pharmaceutical composition of  claim 9 , wherein said dopamine-receptor agonist is selected from the group consisting of apomorphine, bromocriptine, cabergoline, optically pure optically pure (S)-didesmethylsibutramine, lisuride, pergolide, pramipexole, and ropinirole or a pharmaceutically acceptable salt, solvate, or hydrate of any of them.  
   
   
       13 . The pharmaceutical composition of  claim 9 , wherein said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       14 . A pharmaceutical composition consisting essentially of a sedative agent, a dopamine-receptor agonist, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is optically pure (S)-zopiclone and optically pure (S)-N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       15 . A pharmaceutical composition consisting essentially of a sedative agent, a dopamine-receptor agonist, and at least one pharmaceutically acceptable carrier; wherein said sedative agent is optically pure (S)-zopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       16 . A method of treating a patient suffering from restless-leg syndrome or periodic-limb-movement disorder, comprising the step of: 
 co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is selected from the group consisting of racemic zopiclone, optically pure (S)-zopiclone, optically pure (S)-N-desmethylzopiclone, indiplon, zolpidem, zaleplon, and gaboxadol or a pharmaceutically acceptable salt, solvate, or hydrate of any of them; and said dopamine-receptor agonist is selected from the group consisting of amantadine, apomorphine, bromocriptine, cabergoline, carmoxirole, optically pure (S)-didesmethylsibutramine, dopexamine, fenoldopam, ibopamine, lergotrile, lisuride, memantine, mesulergine, pergolide, piribedil, pramipexole, quinagolide, ropinirole, roxindole, and talipexole or a pharmaceutically acceptable salt, solvate, or hydrate of any of them.    
   
   
       17 . The method of  claim 16 , wherein said sedative agent is selected from the group consisting of optically pure (S)-zopiclone and optically pure (S)-N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, or hydrate of either of them.  
   
   
       18 . The method of  claim 16 , wherein said sedative agent is optically pure (S)-zopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       19 . The method of  claim 16 , wherein said dopamine-receptor agonist is selected from the group consisting of apomorphine, bromocriptine, cabergoline, optically pure (S)-didesmethylsibutramine, lisuride, pergolide, pramipexole, and ropinirole or a pharmaceutically acceptable salt, solvate, or hydrate of any of them.  
   
   
       20 . The method of  claim 16 , wherein said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       21 . A method of treating a patient suffering from restless-leg syndrome or periodic-limb-movement disorder, comprising the step of: 
 co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is optically pure (S)-zopiclone or optically pure (S)-N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.    
   
   
       22 . A method of treating a patient suffering from restless-leg syndrome or periodic-limb-movement disorder, comprising the step of: 
 co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is optically pure (S)-zopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.    
   
   
       23 . A method of treating a patient suffering from a sleep abnormality, comprising the step of: 
 co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is selected from the group consisting of racemic zopiclone, optically pure (S)-zopiclone, optically pure (S)-N-desmethylzopiclone, indiplon, zolpidem, zaleplon, and gaboxadol or a pharmaceutically acceptable salt, solvate, or hydrate of any of them; and said dopamine-receptor agonist is selected from the group consisting of amantadine, apomorphine, bromocriptine, cabergoline, carmoxirole, optically pure (S)-didesmethylsibutramine, dopexamine, fenoldopam, ibopamine, lergotrile, lisuride, memantine, mesulergine, pergolide, piribedil, pramipexole, quinagolide, ropinirole, roxindole, and talipexole or a pharmaceutically acceptable salt, solvate, or hydrate of any of them.    
   
   
       24 . The method of  claim 23 , wherein said sedative agent is selected from the group consisting of optically pure (S)-zopiclone and optically pure (S)-N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, or hydrate of either of them.  
   
   
       25 . The method of  claim 23 , wherein said sedative agent is optically pure (S)-zopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       26 . The method of  claim 23 , wherein said dopamine-receptor agonist is selected from the group consisting of apomorphine, bromocriptine, cabergoline, optically pure (S)-didesmethylsibutramine, lisuride, pergolide, pramipexole, and ropinirole or a pharmaceutically acceptable salt, solvate, or hydrate of any of them.  
   
   
       27 . The method of  claim 23 , wherein said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.  
   
   
       28 . A method of treating a patient suffering from a sleep abnormality, comprising the step of: 
 co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is optically pure (S)-zopiclone or optically pure (S)-N-desmethylzopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.    
   
   
       29 . A method of treating a patient suffering from a sleep abnormality, comprising the step of: 
 co-administering to a patient in need thereof a therapeutically effective amount of a sedative agent and a dopamine-receptor agonist; wherein said sedative agent is optically pure (S)-zopiclone or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and said dopamine-receptor agonist is optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.    
   
   
       30 . The method of any one of claims  23 - 29 , wherein said sleep abnormality is difficulty falling asleep, difficulty staying awake, or waking up too early.