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Pharmaceutical Compositions Comprising Droxidopa

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Pharmaceutical Compositions Comprising Droxidopa (19) & (11) EP 2 363 123 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 07.09.2011 Bulletin 2011/36 A61K 31/198 (2006.01) A61P 9/02 (2006.01) A61K 31/275 (2006.01) A61K 31/27 (2006.01) (2006.01) (21) Application number: 11165690.6 A61K 31/15 (22) Date of filing: 28.06.2007 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Roberts, Michael, J. HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE CHARLOTTE, NC 28277 (US) SI SK TR • Pedder, Simon Designated Extension States: FORT MILL, SC 29715 (US) AL BA HR MK RS (74) Representative: Noel, Chantal Odile et al (30) Priority: 28.06.2006 US 806036 P Cabinet Orès 36, rue de St Pétersbourg (62) Document number(s) of the earlier application(s) in 75008 Paris (FR) accordance with Art. 76 EPC: 07784556.8 / 1 948 155 Remarks: This application was filed on 11-05-2011 as a (71) Applicant: Chelsea Therapeutics, Inc. divisional application to the application mentioned Charlotte, NC 28277 (US) under INID code 62. (54) Pharmaceutical compositions comprising droxidopa (57) The present invention provides combinations of monoamine oxidase inhibiting compounds. The inven- droxidopa and one or more further pharmaceutically ac- tion further provides methods of treating conditions, such tive compounds, said further compounds preferentially as orthostatic hypotension, comprising administering the being selected from the group of COMT inhibiting com- combinations. pounds, cholinesterase inhibiting compounds, and EP 2 363 123 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 363 123 A1 Description FIELD OF THE INVENTION 5 [0001] The present invention is directed to combinations of droxidopa with one or more pharmaceutically active com- pounds. More particularly, the invention is directed to combinations of droxidopa with one or more catechol-O-methyl- transferase inhibitors, one or more cholinesterase inhibitors, or one or more monoamine oxidase inhibitors. BACKGROUND 10 [0002] Droxidopa is a known synthetic amino acid precursor of norepinephrine that is converted directly to norepine- phrine via the action of aromatic L-amino acid decarboxylase, also known as dopa decarboxylase (DDC). Droxidopa is an artificial amino acid that has been used to supplement noradrenaline in neurodegenerative disorders, such as Par- kinson’s disease; however, multiple pharmacological activities have been observed with droxidopa, including the follow- 15 ing: (1) it is directly converted to 1-norepinephrine by the action of the aromatic L-amino acid decarboxylase which is widely distributed in a living body, and thus has an effect of replenishing norepinephrine; (2) it passes through the blood- brain barrier into the brain; (3) it specifically recovers norepinephrine activated nerve functions which have decreased in the central and peripheral nervous system; and (4) it shows various actions via the adrenergic receptors in various tissues. Droxidopa has particularly been indicated as being useful for treatment of peripheral orthostatic hypotension 20 (see U.S. Patent No. 4,330,558, which is incorporated herein by reference in its entirety). [0003] Orthostatic hypotension is not a disease, but is rather a physical finding that is a manifestation of abnormal blood pressure regulation due to various causes. The American Autonomic Society (AAS) and the American Academy of Neurology (AAN) define orthostatic hypotension as a systolic blood pressure decrease of at least 20 mm Hg or a diastolic blood pressure decrease of at least 10 mm Hg within three minutes of standing up from a non- standing position. 25 [0004] While orthostatic hypotension has been observed in all age groups, it occurs more frequently in the elderly population, particularly in frail or sick individuals or those with Parkinson’s disease. The condition can be associated with multiple diagnoses, conditions, and symptoms, such as lightheadedness associated with standing, susceptibility to falling, and a history of myocardial infarction or transient ischemic attack. Further, the condition may actually be a predictor of ischemic stroke. 30 [0005] The etiology and pathophysiology of orthostatic hypotension is rather complex, involving multiple body systems and physical responses. The gravitational stress of sudden standing normally causes pooling of blood in the venous capacitance vessels of the legs and trunk (on the order of 300 to 800 mL of blood). Accordingly, maintenance of blood pressure during positional changes, particularly standing, requires coordinated and rapid cardiac, vascular, neurologic, muscular, and neurohumoral responses. Abnormalities in any of these responses can cause a reduction in blood pressure 35 and organ perfusion, particularly cerebral perfusion. [0006] The autonomic nervous system particularly plays an important role in maintaining blood pressure upon positional change. The sympathetic nervous system adjusts the tone in arteries, veins, and the heart. Baroreceptors, which are located primarily in the carotid arteries and aorta, are highly sensitive to changes in blood pressure (such as upon standing from a seated or lying position) and activate autonomic reflexes that rapidly normalize blood pressure by causing 40 a transient tachycardia. These changes reflect primarily the sympathetic mediated increase in catecholamine levels, which augments vasomotor tone of the capacitance vessels, increases heart rate and myocardial contractility, and thereby enhances cardiac output. Arterial and venous vasoconstriction are also mediated by similar mechanisms. Other physiologic mechanisms may also be involved, including low-pressure receptors in the heart and lungs, the renin- angiotensin-aldosterone system, vasopressin, and the systemic release of norepinephrine. Generally, all parts of the 45 cardiovascular and nervous systems must work together to maintain blood pressure upon positional change. If there is inadequate intravascular volume, impairment of the autonomic nervous system, reduction of venous return, or inability of the heart to beat more rapidly or with greater power, orthostatic hypotension may result. [0007] Orthostatic hypotension can be classified as neurogenic, non-neurogenic, or iatrogenic ( e.g., caused by med- ication). Neurogenic etiologies include the following: spinal cord problems (such as related to Shy-Drager syndrome, 50 syringomyelia, tabes dorsalis, transverse myelitis, or tumors); peripheral nervous system problems (such as related to HIV/AIDS, alcoholic polyneuropathy, amyloidosis, diabetes mellitus, dopamine beta-hydroxylase deficiency, Guillain- Barré syndrome, paraneoplastic syndrome, renal failure, or vitamin 12B deficiency); and other neurogenic etiologies (such as related to brain-stem lesions, brain tumors, carotid sinus hypersensitivity, cerebral vascular accidents, dysau- tonomias, multiple sclerosis, neurocardiogenic syncope, Parkinson’s disease, pure autonomic failure, or Sepsis Syrin- 55 gobulbia). Non-neurogenic etiologies include the following: cardiac pump failure (such as related to aortic stenosis, bradyarrhythmia, myocardial infarction, myocarditis, pericarditis, or tachyarrhythmia); reduced intravascular volume (such as related to adrenal insufficiency, bums, dehydration, diabetes insipidus, diarrhea, hemorrhage, salt-losing neu- ropathy, straining with heavy lifting, urination, or defecation, or vomiting); and venous pooling (such as related to alcohol 2 EP 2 363 123 A1 consumption, fever, heat, postprandial dilation of splanchnic vessel beds, prolonged recumbency or standing, sepsis, or vigorous exercise with dilation of skeletal vessel beds). Drugs known to cause orthostatic hypotension include: alpha and beta blockers; antihypertensives; bromocriptine (PARLODEL®); dopamine agonists; diuretics; insulin; MAO inhibi- tors; marijuana; minor tranquilizers; narcotics/ sedatives; nitrates; phenothiazines; sildenafil (VIAGRA ®); sympatholytics; 5 sympathomimetics (with prolonged use); tricyclic antidepressants; vasodilators; and vincristine (Oncovin). [0008] Given the broad array of underlying causes, treatment for orthostatic hypotension can vary. The first steps in treatment of orthostatic hypotension are diagnosis and management of the underlying cause. When the causative disease cannot be identified or improved, management is typically designed to produce peripheral vasoconstriction and/or in- crease cardiac output. Aldosterone analogs, such as the mineralocorticoid fludrocortisone (FLORINEF®), have been 10 used in some patients to expand intravascular volume; however the efficacy of these drugs is often unpredictable, and such treatment carries the risk of volume overload, as well as possible development of hypokalemia or hypomagnesemia. Midodrine (PROAMITINE®), a vasoconstrictor, may be used in patients with severe orthostatic unresponsive to other drugs, but this also has undesirable side effects, papillary dilation, piloerection, parasthesias, pruritus, and supine hy- pertension and is capable of inducing hypertensive crisis. 15 [0009] In addition to the above, orthostatic hypotension can also be classified as "central" type or "peripheral" type. Central type orthostatic hypotension is so classified as arising from, or being directly related to, the central nervous system, particularly the sympathetic nerves. Peripheral type orthostatic hypotension broadly includes non- central types, such as non-neurogenic and iatrogenic orthostatic hypotension, as well as neurogenic orthostatic hypotension related to the peripheral nervous system.
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