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Treatment of Pulmonary Hypertension with Carbonic Anhydrase Inhibitors in Combination with a Sympathomimetic Amine

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Treatment of Pulmonary Hypertension with Carbonic Anhydrase Inhibitors in Combination with a Sympathomimetic Amine (19) TZZ _Z9B_T (11) EP 2 167 099 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/7048 (2006.01) A61K 31/137 (2006.01) 17.10.2012 Bulletin 2012/42 A61K 31/423 (2006.01) A61K 31/433 (2006.01) A61K 45/06 (2006.01) A61P 9/12 (2006.01) (2006.01) (21) Application number: 08767969.2 A61P 11/00 (22) Date of filing: 30.05.2008 (86) International application number: PCT/US2008/006850 (87) International publication number: WO 2008/156550 (24.12.2008 Gazette 2008/52) (54) TREATMENT OF PULMONARY HYPERTENSION WITH CARBONIC ANHYDRASE INHIBITORS IN COMBINATION WITH A SYMPATHOMIMETIC AMINE BEHANLDUNG VON PULMONALER HYPERTONIE MIT CARBONSÄUREANHYDRASE- INHIBITOREN IN KOMBINATION MIT EINEM SYMPATHOMIMETISCHEN AMIN TRAITEMENT DE L’HYPERTENSION PULMONAIRE AVEC DES INHIBITEURS DE L’ANHYDRASE CARBONIQUE (84) Designated Contracting States: •TAM,Peter AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Redwood City, CA 94061 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • WILSON, Leland RO SE SI SK TR Menlo Park, CA 94025 (US) • PETERSON, Craig (30) Priority: 13.06.2007 US 818306 Mountain View, CA 94040 (US) (43) Date of publication of application: (74) Representative: Finnie, Isobel Lara et al 31.03.2010 Bulletin 2010/13 Mintz Levin Cohn Ferris Glovsky and Popeo Intellectual Property LLP (60) Divisional application: Alder Castle 12172276.3 / 2 500 024 10 Noble Street London (73) Proprietor: Vivus, Inc. EC2V 7JX (GB) Mountain View, CA 94040 (US) (56) References cited: (72) Inventors: WO-A-00/76493 WO-A-2006/063078 • NAJARIAN, Thomas WO-A-2007/084290 WO-A-2008/060963 Los Osos, CA 93402 (US) 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 2 167 099 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 167 099 B1 Description TECHNICAL FIELD 5 [0001] This disclosure relates generally to methods and pharmaceutical compositions useful in treating pulmonary hypertension. The disclosure finds utility in the fields of medicine and pharmacology. BACKGROUND 10 [0002] Pulmonary hypertension (PH), also known as pulmonary arterial hypertension (PAH), is a disorder characterized by high blood pressure in the arteries that supply the lungs. Pulmonary hypertension is often classified as either secondary pulmonary hypertension (SPH), in which the cause of the elevated blood pressure is known, or primary pulmonary hypertension (PPH), in which the cause is unknown. Examples of pre-existing conditions that may cause SPH include chronic obstructive pulmonary disease (COPD), sleep apnea, emphysema, bronchitis, sclerodema, CREST syndrome, 15 systemic lupus erythematosus, chronic pulmonary thromboembolism, HIV infection, liver disease, and certain congenital heart diseases. Certain diet drugs such as fenfluramine and dexfenfluramine may also cause SPH. [0003] In addition to high arterial blood pressure, PH may also be characterized by: narrowing and/or stiffening of the pulmonary arteries as the muscles within the walls of the arteries tighten or thicken; the formation of scar tissue in the walls of the pulmonary arteries; and the formation of blood clots within the smaller pulmonary arteries. 20 [0004] Symptoms of pulmonary hypertension include shortness of breath with minimal exertion, fatigue, chest pain, dizzy spells, low blood pressure, and fainting. The blood pressure in the pulmonary arteries of a patient suffering from PH may be twice as high or higher than the pulmonary blood pressure in a normal, healthy individual. [0005] Although PPH is extremely rare, occurring in about two persons per million population per year, SPH is far more common and represents a significant medical concern for the population as a whole. Pulmonary hypertension is 25 frequently misdiagnosed and progresses to late stage before it is accurately diagnosed. [0006] There is no known cure for PH; current methods of treatment focus on prolonging patient lifespan and enhancing patient quality of life. Current methods of treatment of PH include administration of: vasodilators such as prostacyclin, epoprostenol, and sildenafil; endothelin receptor antagonists such as bosentan; calcium channel blockers such as amlodipine, diltiazem, and nifedipine; anticoagulants such as warfarin; and diuretics. Treatment of PH has also been 30 carried out using oxygen therapy; and lung and/or heart transplantation. Each of these methods, however, suffers from one or multiple drawbacks which may include lack of effectiveness, serious side effects, low patient compliance, and high cost. WO 00/76493 describes a therapy for effecting weight loss and treating Syndrome X consisting of a sym- pathomimetic agent (e.g., phentermine or a phentermine-like drug) in combination with an anticonvulsant sulfamate derivative (e.g., topiramate). WO 2006/063078 describes a controlled- release pharmaceutical formulation which contains 35 therapeutic amounts of topiramate for treating various types of seizures. WO 2008/060963 describes layered pharma- ceutical formulations including pharmaceutical compositions useful for effecting weight loss, suppressing appetite and/or treating obesity-related conditions. [0007] An ideal method of treatment would eliminate or significantly reduce the symptoms of PH, would lower pulmonary pressures, would be substantially more effective and easy to administer, and would have minimal or no side effects. 40 The present disclosure is directed at providing one or more of these characteristics in a chemotherapeutic method for treating PH. SUMMARY OF THE DISCLOSURE 45 [0008] The present disclosure describes compositions and methods for treating pulmonary hypertension. [0009] In one embodiment, then, the present disclosure describes a combination of a carbonic anhydrase inhibitor and a sympathomimetic amine for use in treating pulmonary hypertension in a patient, comprising administering a therapeutically effective dose to the patient, wherein the sympathomimetic amine is bupropion and wherein the carbonic anhydrase inhibitor is topiramate. 50 [0010] In another embodiment, the present disclosure describes a combination of a carbonic anhydrase inhibitor and a sympathomimetic amine for use in treating pulmonary hypertension in a patient, comprising administering to the subject a daily dose of a carbonic anhydrase inhibitor that is gradually increased, over an extended time period, from an initial daily dosage up to a final daily dosage suitable for continued maintenance therapy, wherein the final daily dosage is in the range of about 10 mg to 400 mg, wherein the sympathomimetic amine is bupropion and wherein the carbonic 55 anhydrase inhibitor is topiramate, wherein the weight ratio of topiramate administered to the bupropion administered is in the range of about 1:4 to about 2: 1. [0011] In another embodiment, the present disclosure describes a combination of a carbonic anhydrase inhibitor and a sympathomimetic amine for use in treating pulmonary hypertension in a patient comprising administering a therapeu- 2 EP 2 167 099 B1 tically effective dose to the patient, wherein the sympathomimetic amine is bupropion and wherein the carbonic anhydrase inhibitor is a selective cyclooxygenase-2 inhibitor. DETAILED DESCRIPTION OF THE INVENTION 5 DEFINITIONS AND NOMENCLATURE: [0012] Before describing the present invention in detail, it is to be understood that unless otherwise indicated, this invention is not limited to particular formulations, active and inactive agents, modes of administration, or methods of 10 treatment or use, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. [0013] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "an active agent" refers not only to a single active agent but also to a combination of two or more different active agents, "a dosage form" refers 15 to a combination of dosage forms as well as to a single dosage form, and the like. Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein may be useful in the practice or testing of the present invention, preferred methods and materials are described below. Specific termi- nology of particular importance to the description of the present invention is defined below. 20 [0014] When referring to an active agent, applicants intend the term "active agent" to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds. [0015] The terms "treating" and "treatment" as used herein refer to reduction in severity and/or frequency of symptoms, 25 elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms
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