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).

1 . A method of treating hypersomnia in a subject, the method comprising administering a therapeutically effective amount of droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, to the subject in need of treatment of the hypersomnia. 
     
     
         2 . The method of  claim 1 , wherein the administration reduces excessive daytime sleepiness in the subject. 
     
     
         3 . The method of  claim 1 , wherein the administration reduces fatigue in the subject. 
     
     
         4 . The method of  claim 1 , wherein the method further comprises administering one or more additional active agents. 
     
     
         5 . The method of  claim 4 , wherein the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, is administered in a pharmaceutical composition and the one or more additional active agents are formulated in the same pharmaceutical composition with the droxidopa. 
     
     
         6 . The method of  claim 4 , wherein the one or more additional active agents are administered separate from the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof. 
     
     
         7 . The method of  claim 4 , wherein the one or more additional active agents comprise 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. 
     
     
         8 . The method of  claim 4 , wherein the one or more additional active agents comprises a DOPA decarboxylase inhibiting compound. 
     
     
         9 . The method of  claim 4 , wherein the one or more additional active agents comprises a DOPA decarboxylase inhibiting compound selected from the group consisting of benserazide, carbidopa, difluoromethyldopa, α-methyldopa, and combinations thereof. 
     
     
         10 . The method of  claim 4 , wherein the one or more additional active agents comprises a catechol-O-methyltransferase inhibiting compound. 
     
     
         11 . The method of  claim 4 , wherein the one or more additional active agents comprises a catechol-O-methyltransferase inhibiting compound selected from the group consisting of entacapone, tolcapone, nitecapone, and combinations thereof. 
     
     
         12 . The method of  claim 4 , wherein the one or more additional active agents comprises a cholinesterase inhibiting compound. 
     
     
         13 . The method of  claim 4 , wherein the one or more additional active agents comprises a cholinesterase inhibiting compound selected from the group consisting of pyridostigmine, donepezil, rivastigmine, galantamine, tacrine, neostigmine, metrifonate, physostigmine, ambenonium, demarcarium, thiaphysovenine, phenserine, edrophonium, cymserine, and combinations thereof. 
     
     
         14 . The method of  claim 4 , wherein the one or more additional active agents comprises a monoamine oxidase inhibiting compound. 
     
     
         15 . The method of  claim 4 , wherein the one or more additional active agents comprises a monoamine oxidase inhibiting compound 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. 
     
     
         16 . The method of  claim 4 , wherein the one or more additional active agents comprises a norepinephrine reuptake inhibiting compound. 
     
     
         17 . The method of  claim 4 , wherein the one or more additional active agents comprises a norepinephrine reuptake inhibiting compound selected from the group consisting of atomoxetine, reboxetine, viloxazine, maprotiline, bupropion, radafaxine, and combinations thereof. 
     
     
         18 . The method of  claim 4 , wherein the one or more additional active agents comprises a selective serotonin reuptake inhibiting compound. 
     
     
         19 . The method of  claim 4 , wherein the one or more additional active agents comprises a selective serotonin reuptake inhibiting compound selected from the group consisting of fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, and combinations thereof. 
     
     
         20 . The method of  claim 4 , wherein the one or more additional active agents comprises a tricyclic antidepressant compound. 
     
     
         21 . The method of  claim 4 , wherein the one or more additional active agents comprises a tricyclic antidepressant compound selected from the group consisting of amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine, and combinations thereof. 
     
     
         22 . The method of  claim 4 , wherein the one or more additional active agents comprises a DOPA decarboxylase inhibiting compound and a third active agent selected from the group consisting of 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. 
     
     
         23 . The method of  claim 4 , wherein the one or more additional active agents comprises a stimulant. 
     
     
         24 . The method of  claim 4 , wherein the one or more additional active agents comprises a stimulant selected from the group consisting of caffeine, methylphenidate, dextroamphetamine, methamphetamine, pemoline, mazindol, modafinil, gamma-hydroxybutyrate, and combinations thereof. 
     
     
         25 . The method of  claim 1 , wherein the method comprises administering a therapeutically effective amount of droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, in combination with one or more compounds selected from the following group of compounds:
 a DOPA decarboxylase inhibiting compound selected from the group consisting of benserazide, carbidopa, difluoromethyldopa, α-methyldopa, and combinations thereof;   a catechol-O-methyltransferase inhibiting compound selected from the group consisting of entacapone, tolcapone, nitecapone, and combinations thereof;   a cholinesterase inhibiting compound selected from the group consisting of pyridostigmine, donepezil, rivastigmine, galantamine, tacrine, neostigmine, metrifonate, physostigmine, ambenonium, demarcarium, thiaphysovenine, phenserine, edrophonium, cymserine, and combinations thereof;   a monoamine oxidase inhibiting compound 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;   a norepinephrine reuptake inhibiting compound selected from the group consisting of atomoxetine, reboxetine, viloxazine, maprotiline, bupropion, radafaxine, and combinations thereof;   a selective serotonin reuptake inhibiting compound selected from the group consisting of fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine, sertraline, and combinations thereof;   a tricyclic antidepressant compound selected from the group consisting of amitriptyline, amoxapine, butriptyline, clomipramine, desipramine, dibenzepin, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine, and combinations thereof; and   a stimulant selected from the group consisting of caffeine, methylphenidate, dextroamphetamine, methamphetamine, pemoline, mazindol, modafinil, gamma-hydroxybutyrate, and combinations thereof.   
     
     
         26 . The method of  claim 1 , wherein the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, is administered in the form of a mixture enantiomerically enriched in the L-threo isomer. 
     
     
         27 . The method of  claim 1 , wherein the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, is administered in a sustained-release composition. 
     
     
         28 . The method of  claim 1 , wherein the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, is administered in a rapid-onset composition. 
     
     
         29 . The method of  claim 1 , wherein the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, is administered once daily. 
     
     
         30 . The method of  claim 1 , wherein the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, is administered twice daily. 
     
     
         31 . The method of  claim 1 , wherein the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, is administered three times daily. 
     
     
         32 . The method of  claim 1 , wherein the droxidopa, or a pharmaceutically acceptable ester, amide, or salt thereof, is administered in a disintegrating tablet composition. 
     
     
         33 . The method of  claim 32 , wherein the tablet is an orally disintegrating tablet. 
     
     
         34 . The method of  claim 1 , wherein the subject in need of treatment of the hypersomnia suffers from Parkinson's disease. 
     
     
         35 . The method of  claim 1 , wherein the subject in need of treatment of the hypersomnia suffers from orthostatic hypotension.