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Droxidopa and Pharmaceutical

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Droxidopa and Pharmaceutical (19) & (11) EP 2 142 185 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/15 (2006.01) A61K 31/198 (2006.01) 15.08.2012 Bulletin 2012/33 A61K 31/275 (2006.01) A61K 31/407 (2006.01) A61P 9/02 (2006.01) (21) Application number: 08732012.3 (86) International application number: (22) Date of filing: 12.03.2008 PCT/US2008/056675 (87) International publication number: WO 2008/112773 (18.09.2008 Gazette 2008/38) (54) DROXIDOPA AND PHARMACEUTICAL COMPOSITION THEREOF FOR THE TREATMENT OF NEURALLY MEDIATED HYPOTENSION DROXIDOPAUND PHARMAZEUTISCHE ZUSAMMENSETZUNG DAVON ZUR BEHANDLUNG VON NEURAL VERMITTELTER HYPERTONIE DROXIDOPA ET COMPOSITION PHARMACEUTIQUE DE CELLE-CI POUR LE TRAITEMENT DE L’HYPOTENSION VÉHICULÉE PAR VOIE NEURALE (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-2008/003028 HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR • MATHIAS C J ET AL: "L-threo- Designated Extension States: dihydroxyphenylserine (L-threo-DOPS; AL BA MK RS droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi- (30) Priority: 12.03.2007 US 894354 P center, dose-ranging study in multiple system atrophy and pure autonomic failure." CLINICAL (43) Date of publication of application: AUTONOMIC RESEARCH : OFFICIAL JOURNAL 13.01.2010 Bulletin 2010/02 OF THE CLINICAL AUTONOMIC RESEARCH SOCIETY AUG 2001, vol. 11, no. 4, August 2001 (73) Proprietor: Chelsea Therapeutics, Inc. (2001-08), pages 235-242, XP002500633 ISSN: Charlotte, NC 28277 (US) 0959-9851 • GOLDSTEIN DAVID S: "L- dihydroxyphenylserine (72) Inventors: (L-DOPS): A norepinephrine prodrug" • ROBERTS, Michael, J. CARDIOVASCULAR DRUG REVIEWS, NEVA Charlotte, NC 28277 (US) PRESS, BRANFORD, CT, US, vol. 24, no. 3-4, 1 • PEDDER, Simon October 2006 (2006-10-01), pages 189-203, Fort Mill, SC 29715 (US) XP009107442 ISSN: 0897-5957 • KATO T ET AL: "STUDIES ON THE ACTIVITY OF (74) Representative: Noel, Chantal Odile et al L-THREO-3 4 DIHYDROXYPHENYLSERINE L Cabinet Orès DOPS AS A CATECHOLAMINE PRECURSOR IN 36, rue de St Pétersbourg THE BRAIN COMPARISON WITH THAT OF L 75008 Paris (FR) DOPA" BIOCHEMICAL PHARMACOLOGY, PERGAMON, OXFORD, GB, vol. 36, no. 18, 1 January 1987 (1987-01-01), pages 3051-3058, XP002459988 ISSN: 0006-2952 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 142 185 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 142 185 B1 Description FIELD OF THE INVENTION 5 [0001] The present specification is directed to droxidopa, alone or in combination with one or more additional compo- nents, for use in the treatment of neurally mediated hypotension. BACKGROUND 10 [0002] Droxidopa is a known synthetic amino acid precursor of norepinephrine that is converted directly to norepine- phrine via the action of dopa decarboxylase (DDC). Droxidopa is generally used to treat orthostatic hypotension (OH), as is reported by Mathias et al. (2001) C/in. Auton. Res. 11: 235-242 and Goldstein (2006) Cardiovascular Drug Review 24:189-203, and can be categorized as an antiparkinsonian agent; however, multiple pharmacological activities have been observed with droxidopa, including the following: (1) it is directly converted to 1-norepinephrine by the action of 15 the aromatic L- amino acid decarboxylase which is widely distributed in a living body, and thus has an effect of replenishing norepinephrine; (2) it has limited permeability 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, as norepinephrine, via the adrenaline receptors in various tissues. Kawabata et al. (1994) Br. J. Pharmacol. 111:503-508 further report that droxidopa exhibits antinociceptive activity via central α-adrenoreceptors 20 in the mouse. [0003] Neurally mediated hypotension (NMH) can be linked to fibromyalgia and chronic fatigue syndrome. In many individuals, however, NMH is a "stand- alone" condition (i.e., presents without comorbidities). NMH is also known by the terms "the fainting reflex", neurocardiogenic syncope, vasodepressor syncope, the vaso-vagal reflex, and autonomic dysfunction, and the condition arises from an abnormal reflex interaction between the heart and the brain, both of which 25 are usually structurally normal. This miscommunication typically results in a failure to maintain appropriate increases in heart rate and leads to dizziness and fainting after standing for prolonged periods. While it is not uncommon for prolonged standing to cause fluctuations in blood pressure, the body typically compensates for such fluctuations by increasing heart rate appropriately. For individuals with NMH, however, instead of increasing, the heart rate may remain constant, or actually drop, which prevents the necessary amount of blood from being circulated within the body, and particularly 30 to the brain. [0004] Individuals susceptible to NMH can experience the condition in a variety of situations. For example, NMH can occur in the following settings: after prolonged periods of quiet upright posture (such as standing in line, standing in a shower, or even sitting up for long periods); after being in a warm environment (such as in hot summer weather, a hot crowded room, or a hot shower or bath); immediately after exercise; and after emotionally stressful events (such as 35 seeing blood or gory scenes, being scared, or being anxious). Some individuals also experience symptoms soon after eating, when blood flow has shifted to the intestinal circulation during the process of digestion. All humans are susceptible to activation of the vaso- vagal reflex that results in a lowered blood pressure (NMH); however, each person’s susceptibility is affected by his or her genetic make-up, dietary factors, psychological make-up, and acute triggers such as infection and allergy. Thus, all humans do not suffer from NMH. Rather, the clinical problem of NMH occurs when there is sufficiently 40 early triggering of this reflex to cause symptoms. [0005] Neurally mediated hypotension is typically treated with a combination of increased salt and water intake in conjunction with drugs that regulate blood pressure. Some drugs work by allowing the kidneys to retain sodium and others block the body’s response to adrenaline, which can kick- start the blood pressure abnormality. Known treatments for NMH generally require persistence, commitment, and the willingness to try several possible drugs and combinations 45 over an extended period of time. Treatment often requires careful physician monitoring because there is a risk of serious side effects with some of the known treatments, such as elevated blood pressure, elevated sodium levels, lowered potassium levels, or depression. Examples of drugs that have been used to treat patients with NMH include fludrocor- tisone, beta-blockers, disopyramide, fluoxetine, sertraline, ephedrine, pseudoephedrine, theophylline, methylphenidate, and midodrine. All of these drugs can cause undesirable side effects and may not be effective to sufficiently treat NMH. 50 Thus, there remains a need in the art for effective drug treatment of NMH. SUMMARY OF THE INVENTION [0006] The present invention provides pharmaceutical compositions comprising droxidopa alone or in combination 55 with one or more further pharmaceutically active compounds for use in the treatment of neurally mediated hypotension in accordance wiith claim 1-16. [0007] In one embodiment, the invention comprises administering to a subject suffering from neurally mediated hy- potension a pharmaceutical composition comprising a therapeutically effective amount of droxidopa. 2 EP 2 142 185 B1 [0008] In certain embodiments, treatment can be indicated in a subject that is suffering from neurally mediated hypo- tension and exhibiting a symptom known to be indicative of neurally mediated hypotension, such as dizziness, fainting, lightheadedness, fatigue, muscle aches, headaches, confusion, or nausea. In such embodiments, the method of treat- ment can comprise reducing or eliminating the symptom. 5 [0009] In further embodiments, treatment can be indicated in a subject that is suffering from neurally mediated hypo- tension and is known to have previously exhibited a symptom known to be indicative of neurally mediated hypotension, such as dizziness, fainting, lightheadedness, fatigue, muscle aches, headaches, confusion, or nausea. In such embod- iments, the method of treatment can comprise preventing re-occurrence of the symptom. [0010] In certain embodiments, the one or more further pharmaceutically active compounds comprise compounds 10 useful for treatment or prevention of symptoms associated with neurally mediated hypotension. For example, such further pharmaceutically active compounds can comprise antidepressants (such as selective serotonin reuptake inhibitors, tricyclics, serotonin norepinephrine, reuptake inhibitors, norepinephrine reuptake inhibitors, and norepinephrine and dopamine reuptake inhibitors), corticosteroids, beta-blockers, serotonin receptor antagonists, serotonin receptor
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