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(12) Patent Application Publication (10) Pub. No.: US 2009/0023705 A1 Roberts Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0023705 A1 Roberts Et Al US 20090023705A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0023705 A1 Roberts et al. (43) Pub. Date: Jan. 22, 2009 (54) DROXIDOPA AND PHARMACEUTICAL Publication Classification COMPOSITION THEREOF FOR THE (51) Int. Cl. TREATMENT OF MOOD DISORDERS, SLEEP A 6LX 3/553 (2006.01) DSORDERS ORATTENTION DEFICT A 6LX 3L/95 (2006.01) DSORDERS A 6LX 3L/275 (2006.01) A6II 3/12 (2006.01) A6II 3/445 (2006.01) A6IP 25/20 (2006.01) A6IP 25/24 (2006.01) (75) Inventors: Michael J. Roberts, Charlotte, NC A6IP 25/22 (2006.01) (US); Simon Pedder, Fort Mill, SC A63L/35 (2006.01) (US) A6II 3/44 (2006.01) A 6LX 3/5.375 (2006.01) A63/37 (2006.01) (52) U.S. Cl. .................... 514/211.13: 514/567; 514/565; Correspondence Address: 514/619; 514/676; 514/319; 514/354; 514/239.2: ALSTON & BRD LLP 514/651: 514/646 BANK OF AMERICA PLAZA, 101 SOUTH TRYON STREET, SUITE 4000 (57) ABSTRACT CHARLOTTE, NC 28280-4000 (US) The present invention provides pharmaceutical compositions comprising droxidopa alone, or in combination with one or more further active ingredients, for the treatment of condi tions, such as mood disorders, sleep disorders, or attention deficit disorders. In certain embodiments, the compositions (73) Assignee: Chelsea Therapeutics, Inc. useful in the methods of the invention comprise droxidopa and a compound selected from the group consisting of DOPA decarboxylase inhibiting compounds, catechol-O-methyl (21) Appl. No.: 12/116,560 transferase inhibiting compounds, cholinesterase inhibiting compounds, monoamine oxidase inhibiting compounds, norepinephrine reuptake inhibiting compounds, selective serotonin reuptake inhibiting compounds, tricyclic antide (22) Filed: May 7, 2008 pressant compounds, serotonin norepinephrine reuptake inhibiting compounds, norepinephrine dopamine reuptake inhibiting compound, noradrenergic and specific serotoner Related U.S. Application Data gic antidepressants, and combinations thereof. The inventive compositions are particularly useful in the treatment of (60) Provisional application No. 60/916,497, filed on May depression, narcolepsy, insomnia, and Attention Deficit/Hy 7, 2007. peractivity Disorder (AD/HD). Patent Application Publication Jan. 22, 2009 Sheet 1 of 2 US 2009/0023705 A1 250 - 200 150 100 50 Patent Application Publication Jan. 22, 2009 Sheet 2 of 2 US 2009/0023705 A1 O 50 100 150 200 250 300 350 Vehicle Despiramine Entacapone Fluoxetine Wenlafaxine Amitriptyline Droxidopa -- Carbidopa Droxidopa + Carbidopa it Entacapone Droxidopa + Carbidopa -- Fluoxetine Droxidopa + Carbidopa + Venlafaxine Droxidopa + Carbidopa + Amitriptyline FIG. 2 US 2009/0023705 A1 Jan. 22, 2009 DROXDOPA AND PHARMACEUTICAL decisions; Suicidal thoughts or attempts; frequent physical COMPOSITION THEREOF FOR THE complaints (i.e., headache, stomach ache, fatigue); running TREATMENT OF MOOD DISORDERS, SLEEP away or threats of running away from home; hypersensitivity DISORDERS ORATTENTON DEFCIT to failure or rejection; and irritability, hostility, or aggression. DISORDERS In mood disorders, these feelings appear more intense than what a person may normally feel from time to time, and these CROSS-REFERENCE TO RELATED feelings tend to continue over a period of time or interfere APPLICATIONS with an individual’s interest in family, friends, community, or work. 0001. The present application claims priority to U.S. Pro 0006 Various treatments are currently available for mood visional Patent Application No. 60/916,497, filed May 7, disorders. Examples of current treatments include antidepres 2007, which is incorporated herein by reference in its entirety. sant medications, psychotherapy, and family therapy. Three major types of medication are typically used to treat depres FIELD OF THE INVENTION sion: tricyclics, selective serotonin re-uptake inhibitors (SS 0002 The present application is directed to methods of RIs), and monoamine oxidase inhibitors (MAO inhibitors). treatment of various conditions. In particular, the application All three classes of medications are known to have varying is directed to the use of droxidopa, alone or in combination degrees of effectiveness from patient to patient. Moreover, all with one or more additional components, for the treatment of three classes of medications are known to cause varying, various conditions, such as mood disorders, sleep disorders, undesirable side effects. It is estimated that approximately 44 or attention deficit disorders. million Americans experience a mental disorder each year, and mental illnesses are among the most common conditions BACKGROUND affecting health today. Accordingly, there remains a need in 0003 Droxidopa is a known synthetic amino acid precur the art for further pharmaceutical compositions useful in the sor of norepinephrine that is converted directly to norepi treatment of mood disorders, particularly depression. nephrine via the action of dopa decarboxylase (DDC). Droxi 0007 Sleep disorder encompasses a broad range of con dopa is generally used to treat orthostatic hypotension (OH) ditions, including sleep apnea (brief periods while sleeping and can be categorized as an antiparkinsonian agent; how during which breathing stops), insomnia (which includes dif ever, multiple pharmacological activities have been observed ficulty falling asleep or staying asleep, waking too early, or with droxidopa, including the following: (1) it is directly Sleep State Misperception), narcolepsy (an irresistible need converted to 1-norepinephrine by the action of the aromatic to sleep, where sleep attacks lasting from about 30 seconds to L-amino acid decarboxylase which is widely distributed in a about 30 minutes occur during waking hours), and restless leg living body, and thus has an effect of replenishing norepi syndrome (a discomfort in the legs, often sensed while trying nephrine; (2) it has limited permeability through the blood to sleep, which can include crawling, tingling, or prickling brain barrier into the brain; (3) it specifically recovers nore sensation, that can be relieved by moving or stimulating the pinephrine activated nerve functions which have decreased in legs). Sleep disorders are often comorbid with other condi the central and peripheral nervous system; and (4) it shows tions, such as depression, fibromyalgia, and chronic fatigue various actions, as norepinephrine, via the adrenaline recep syndrome. tors in various tissues. 0008 Narcolepsy, in particular, is known to adversely 0004 Mood disorders form a category of mental health affect an individual’s ability to function in daily life. This problems that include all types of depression and are some condition may be classified under the broader term of hyper times called affective disorders. The most common types of Somnia, which encompasses additional sleep attack condi mood disorders include: major depressive disorder, which is tions, such as idiopathic hypersomnia, recurrent hyperSom defined as an at least two-week period of a depressed or nia, and hypersomnia resulting from a medical condition. The irritable mood or a noticeable decrease in interest or pleasure 'sleep attacks' common with narcolepsy can occur at any in usual activities, along with other signs of a mood disorder; time. Such as while working, carrying on a conversation, or dysthymia (dysthymic disorder), which is defined as a even driving a car. The four classic symptoms of narcolepsy chronic, low-grade, depressed or irritable mood for at least are excessive daytime sleepiness; cataplexy (Sudden, brief one year, manic depression (bipolar disorder), which is episodes of muscle weakness or paralysis brought on by defined as at least one episode of a depressed or irritable mood strong emotions such as laughter, anger, Surprise, or antici and at least one period of a manic (persistently elevated) pation); sleep paralysis (paralysis upon falling asleep or wak mood; mood disorder due to a general medical condition ing up); and hypnagogic hallucinations (vivid dreamlike (such as cancer, injuries, infections, and chronic medical images that occur at sleep onset). Disturbed nighttime sleep, illnesses), which can trigger symptoms of depression; and including tossing and turning in bed, leg jerks, nightmares, Substance induced mood disorder, wherein symptoms of and frequent awakenings, may also occur. depression are present due to the effects of medication, drug 0009. There is no known cure for narcolepsy, but some abuse, exposure to toxins, or other forms of treatment. evidence Suggests the condition may be linked to abnormali 0005 Depending upon age and the type of mood disorder ties in cerebral perfusion. See Joo et al., Neuroimage (2005), present, a person may exhibit different symptoms of depres 28(2): p. 410-416, which is incorporated herein by reference. Sion. The following are the most common symptoms of a Excessive daytime sleepiness is typically treated with stimu mood disorder; however, each individual may experience lant drugs, such as methylphenidate (e.g., RITALINR), dex symptoms differently. Symptoms may include: persistent troamphetamine (e.g., DEXTROSTATCR) O feelings of sadness; feeling hopeless or helpless; having low DEXEDRINE(R), methamphetamine (DESOXYNR), pemo self-esteem; feeling inadequate; excessive guilt; feelings of line (CYLERTR), mazindol (SANOREX(R), as well as the wanting to die; loss of interest in usual activities or activities “non-stimulant stimulant modafinil (PROVIGIL(R). Cata once enjoyed; difficulty with relationships; sleep distur plexy and other REM-sleep symptoms are often
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