Droxidopa and pharmaceutical composition thereof for the treatment of mood disorders, sleep disorders, or attention deficit disorders

Abstract

The present invention provides pharmaceutical compositions comprising droxidopa alone, or in combination with one or more further active ingredients, for the treatment of conditions, such as mood disorders, sleep disorders, or attention deficit disorders. In certain embodiments, the compositions useful in the methods of the invention comprise droxidopa and a compound selected from the group consisting of DOPA decarboxylase inhibiting compounds, catechol-O-methyltransferase inhibiting compounds, cholinesterase inhibiting compounds, monoamine oxidase inhibiting compounds, norepinephrine reuptake inhibiting compounds, selective serotonin reuptake inhibiting compounds, tricyclic antidepressant compounds, serotonin norepinephrine reuptake inhibiting compounds, norepinephrine dopamine reuptake inhibiting compound, noradrenergic and specific serotonergic antidepressants, and combinations thereof. The inventive compositions are particularly useful in the treatment of depression, narcolepsy, insomnia, and Attention Deficit/Hyperactivity Disorder (AD/HD).

That which is claimed: 
     
         1 . A method of treating an Attention Deficit Disorder (ADD), the method comprising administering a first active agent and a second active agent to a subject in need of treatment of the condition, wherein:
 the first active agent is a therapeutically effective amount of droxidopa, or a pharmaceutically acceptable ester, amide, salt, solvate, or prodrug thereof; and   the second active agent is a therapeutically effective amount of a compound selected from the group consisting of DOPA decarboxylase inhibiting compounds, catechol-O-methyltransferase inhibiting compounds, cholinesterase inhibiting compounds, monoamine oxidase inhibiting compounds, norepinephrine reuptake inhibiting compounds, selective serotonin reuptake inhibiting compounds, tricyclic antidepressant compounds, serotonin norepinephrine reuptake inhibiting compounds, norepinephrine dopamine reuptake inhibiting compound, noradrenergic and specific serotonergic antidepressants, and combinations thereof.   
     
     
         2 . The method of  claim 1 , wherein the attention deficit disorder is Attention-Deficit/Hyperactivity Disorder (AD/HD). 
     
     
         3 . The method of  claim 1 , wherein the subject is suffering from at least one symptom of the ADD, and the method comprises eliminating the symptom, reducing the severity of the symptom, or reducing the frequency of occurrence of the symptom. 
     
     
         4 . The method of  claim 1 , wherein the droxidopa is administered in a sustained release form. 
     
     
         5 . The method of  claim 1 , wherein the droxidopa is administered in a controlled release form. 
     
     
         6 . The method of  claim 1 , wherein the droxidopa is administered in the form of a mixture enantiomerically enriched in the L-threo isomer. 
     
     
         7 . The method of  claim 1 , wherein the active agents are administered in a single pharmaceutical composition. 
     
     
         8 . The method of  claim 1 , wherein the active agents are administered in separate pharmaceutical compositions. 
     
     
         9 . The method of  claim 1 , wherein the one or more additional active agents is a catechol-O-methyltransferase inhibiting compound. 
     
     
         10 . The method of  claim 9 , wherein the catechol-O-methyltransferase inhibiting compound is selected from the group consisting of entacapone, tolcapone, nitecapone, and combinations thereof. 
     
     
         11 . The method of  claim 1 , wherein the one or more additional active agents is a cholinesterase inhibiting compound. 
     
     
         12 . The method of  claim 11 , wherein the cholinesterase inhibiting compound is selected from the group consisting of pyridostigmine, donepezil, rivastigmine, galantamine, tacrine, neostigmine, metrifonate, physostigmine, ambenonium, demarcarium, thiaphysovenine, phenserine, edrophonium, cymserine, and combinations thereof. 
     
     
         13 . The method of  claim 1 , wherein the one or more additional active agents is a monoamine oxidase inhibiting compound. 
     
     
         14 . The method of  claim 13 , wherein the monoamine oxidase inhibiting compound is selected from the group consisting of isocarboxazid, moclobemide, phenelzine, tranylcypromine, selegiline, nialamide, iproniazid, iproclozide, toloxatone, harmala, brofaromine, benmoxin, 5-methoxy-N,N-dimethyltryptamine, 5-methoxy-α-methyltryptamine, and combinations thereof. 
     
     
         15 . The method of  claim 1 , wherein the one or more additional active agents is a norepinephrine reuptake inhibiting compound. 
     
     
         16 . The method of  claim 15 , wherein the norepinephrine reuptake inhibiting compound is selected from the group consisting of atomoxetine, reboxetine, viloxazine, maprotiline, bupropion, radafaxine, and combinations thereof. 
     
     
         17 . The method of  claim 1 , wherein the one or more additional active agents is a selective serotonin reuptake inhibiting compound. 
     
     
         18 . The method of  claim 17 , wherein the selective serotonin reuptake inhibiting compound is selected from the group consisting of fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, and combinations thereof. 
     
     
         19 . The method of  claim 1 , wherein the one or more additional active agents is a tricyclic antidepressant compound. 
     
     
         20 . The method of  claim 19 , wherein the tricyclic antidepressant compound is selected from the group consisting of amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine, and combinations thereof. 
     
     
         21 . The method of  claim 1 , wherein the first active agent and the second active agent are the only active agents administered in the method of treating the ADD. 
     
     
         22 . A method of treating an Attention Deficit Disorder (ADD), the method comprising administering a pharmaceutical composition to a subject in need of treatment of the condition, the pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of droxidopa, or a pharmaceutically acceptable ester, amide, salt, solvate, or prodrug thereof, as an active agent; wherein the droxidopa, or a pharmaceutically acceptable ester, amide, salt, solvate, or prodrug thereof is the lone active agent administered in the method of treating the ADD. 
     
     
         23 . The method of  claim 22 , wherein the droxidopa is administered in a sustained release form. 
     
     
         24 . The method of  claim 22 , wherein the droxidopa is administered in a controlled release form. 
     
     
         25 . The method of  claim 22 , wherein the droxidopa is administered in the form of a mixture enantiomerically enriched in the L-threo isomer. 
     
     
         26 . A method of treating an Attention Deficit Disorder (ADD) with a pharmaceutical composition, the method consisting of administering the pharmaceutical composition to a subject in need of treatment of the condition, the pharmaceutical composition consisting of: one or more non-active, pharmaceutically acceptable adjuvants; and a therapeutically effective amount of droxidopa, or a pharmaceutically acceptable ester, amide, salt, solvate, or prodrug thereof as the lone active agent. 
     
     
         27 . The method of  claim 26 , wherein the droxidopa is administered in a sustained release form. 
     
     
         28 . The method of  claim 26 , wherein the droxidopa is administered in a controlled release form. 
     
     
         29 . The method of  claim 26 , wherein the droxidopa is administered in the form of a mixture enantiomerically enriched in the L-threo isomer. 
     
     
         30 . A pharmaceutical composition comprising:
 a) droxidopa, or a pharmaceutically acceptable ester, amide, salt, solvate, or prodrug thereof, and   b) a tricyclic antidepressant compound.   
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the tricyclic antidepressant compound is selected from the group consisting of amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine, and combinations thereof. 
     
     
         32 . The pharmaceutical composition of  claim 30 , further comprising:
 c) a compound selected from the group consisting of DOPA decarboxylase inhibiting compounds, catechol-O-methyltransferase inhibiting compounds, cholinesterase inhibiting compounds, monoamine oxidase inhibiting compounds, norepinephrine reuptake inhibiting compounds, selective serotonin reuptake inhibiting compounds, serotonin norepinephrine reuptake inhibiting compounds, norepinephrine dopamine reuptake inhibiting compound, noradrenergic and specific serotonergic antidepressants, and combinations thereof.   
     
     
         33 . The pharmaceutical composition of  claim 32 , comprising:
 a) droxidopa, or a pharmaceutically acceptable ester, amide, salt, solvate, or prodrug thereof,   b) a tricyclic antidepressant compound selected from the group consisting of amitriptyline, butriptyline, nortriptyline, protriptyline, and combinations thereof, and   c) a DOPA decarboxylase inhibiting compound selected from the group consisting of benserazide, carbidopa, difluoromethyldopa, α-methyldopa, and combinations thereof.