(19) TZZ ¥ ZZ_T (11) EP 2 320 740 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61P 9/12 (2006.01) A61K 31/519 (2006.01) 26.03.2014 Bulletin 2014/13 A61K 9/10 (2006.01) (21) Application number: 09803550.4 (86) International application number: PCT/US2009/052127 (22) Date of filing: 29.07.2009 (87) International publication number: WO 2010/014727 (04.02.2010 Gazette 2010/05) (54) PHARMACEUTICAL COMPOSITIONS OF CLEVIDIPINE AND METHODS FOR PRODUCING LOW IMPURITY CONCENTRATIONS OF THE SAME PHARMAZEUTISCHE ZUSAMMENSETZUNGEN VON CLIVIDIPINE UND VERFAHREN ZUR HERSTELLUNG VON KONZENTRATIONEN DARAUS MIT GERINGEM VERUNREINIGUNGSGRAD COMPOSITIONS PHARMACEUTIQUES, COMPRENANT CLIVIDIPINE ET PROCÉDÉS POUR PRODUIRE DE FAIBLES CONCENTRATIONS D’IMPURETÉ DE CELLES-CI (84) Designated Contracting States: • FLOOD Keith AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Cary, NC 27518 (US) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • RAMAKRISHNA Kornepati PT RO SE SI SK SM TR Cary, NC 27513 (US) (30) Priority: 03.09.2008 US 93772 P (74) Representative: Wallace, Sheila Jane et al 01.08.2008 US 85597 P Marks & Clerk LLP 90 Long Acre (43) Date of publication of application: London 18.05.2011 Bulletin 2011/20 WC2E 9RA (GB) (60) Divisional application: (56) References cited: 14150954.7 WO-A1-00/31035 WO-A1-2006/118210 US-A1- 2003 119 883 US-A1- 2005 272 763 (73) Proprietors: US-A1- 2005 276 824 US-A1- 2006 047 125 • The Medicines Company US-A1- 2007 196 465 US-A1- 2008 019 978 Parsippany, NJ 07054 (US) • Hospira, Inc. • NORDLANDER ET AL.: ’Pharmacodynamic, Lake Forest, Illinois 60045 (US) Pharmacokinetic and Clinical Effects of Clevidipine, an Ultrashort-acting Calcium (72) Inventors: Antagonist for Rapid Blood Pressure Control.’ • MOTHERAM, Rajeshwar CARDIVASCULAR DRUG REVIEWS, [Online] vol. Dayton 22, no. 3, 2004, pages 227 - 250, XP008142879 NJ 08810 (US) Retrieved from the Internet: <URL:http:/ • KRISHNA, Gopal lwww.edictforpressurecontrol.com /pdf/ Randolph NorlanderCardiovascDrugRev.pdf> NJ 07869 (US) • GYLLENHALL ET AL.: ’Packed-column • DING, Min supercritical fluid chromatography for the purity Tarrytown analysis of clevidipine, a new dihyrdopyridine NY 10591 (US) drug.’ JOURNAL OF CHROMATOGRAPHY A vol. 862, no. ISS 1, 1999, pages 95 - 104, XP009150407 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 2 320 740 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 320 740 B1 Description Field of the Invention 5 [0001] The instant invention relates to pharmaceutical compositions, and in particular to compositions of clevidipine having a reduced level of impurities, and a method of maintaining the stability of such pharmaceutical compositions. Background of the Invention 10 [0002] Clevidipine, which is also known as Cleviprex™, is a short-acting, vascular selective calcium antagonist that has been shown to reduce arterial blood pressure with a fast termination of effect due to metabolism by blood and tissue esterases. As an arterial-selective vasodilator, clevidipine reduces peripheral vascular resistance directly, without dilating the venous capacitance bed. [0003] The chemical name of clevidipine is butyroxymethyl methyl 4-(2’,3’-dichlorophenyl)-1,4-dihydro-2,6-dimethyl- 15 3,5-pyridinedicarboxylate (C21H23Cl2NO6). Its structure is as follows: 20 25 [0004] Clevidipine is typically formulated as a liquid emulsion suitable for intravenous administration. Lipid emulsions are widely used in parenteral nutrition use for approximately 30 years and in the recent past have been used as drug carriers for insoluble drugs such as propofol (Diprivan®), and diazepam. Apart from their ab ility to deliver insoluble drugs, 30 emulsionsare also suitable dosage formsfor drugs like clevidipinethat aresusceptible to hydrolytic breakdown. Emulsions have also been reported to prevent drugs from adhering to plastic administration sets used during intravenous injection, and reduce local toxicity on infusion. [0005] As a pharmaceutical composition, it is essential that clevidipine maintains its stability. Over the past several years, various impurities have been identified in compositions containing clevidipine as an active ingredient. For example, 35 some impurities arise from the process used in making clevidipine, while others are due to gradual degradation of the active ingredient. As a pharmaceutical composition, it is essential to maintain stability and minimize the amount of impurities regardless of their source or the mechanism of degradation. Therefore, a need exists for compositions of clevidipine having acceptable stability profiles with respect to their ultimate potency and impurity levels. There is also a need for methods for maintaining the stability of compositions having clevidipine as an active ingredient. 40 Summary of the Invention [0006] There is herein disclosed a number of impurities which may be derived from clevidipine through a hydrolysis, decarboxylation and condensation reaction. The structure of these impurities and methods of detecting and analyzing 45 these impurities is also disclosed. [0007] An aspect of the present invention describes methods of reducing the amount of such impurities in pharma- ceutical compositions having clevidipine as an active ingredient, as defined in Claims 8 to 12. [0008] A further aspect of the present invention describes pharmaceutical compositions prepared or stored using the methods described herein wherein the level of certain impurities is minimized or reduced, as defined in Claims 1 to 6. 50 [0009] In particular, the present invention describes pharmaceutical composition having clevidipine as an active in- gredient, and having a reduced level of one or more impurities selected from a group consisting of Substance 23, Substance 24, Substance 25 and H168/79, as defined by Claims 1 to 6. [0010] There is herein disclosed a pharmaceutical composition having clevidipine as an active ingredient, wherein the compositions contains equal or no more than 0.2% of an impurity on a weight-to-weight of impurity to clevidipine and 55 the impurity is selected from a group consisting of Substance 23, 24 and 25. [0011] There is also disclosed a pharmaceutical composition having clevidipine or any of its pharmaceutically accept- able salt forms, as the active ingredient, wherein the composition contains equal or no more than 0.2% on a weight-to- weight of impurity to clevidipine for each of the impurities, Substance 23, 24 and 25. 2 EP 2 320 740 B1 [0012] The present invention includes compositions having clevidipine, as an active ingredient, wherein the composition contain a reduced level of an amount of the impurity H168/79 that is no greater than about 1.5% weight-to-weight of impurity to clevidipine basis, or where the ratio of the area under the chromatographic curve between clevidipine and H168/79 is equal or greater than 60 to 0.9, as defined in Claims 1 to 6. 5 [0013] The present invention also includes compositions having clevidipine or any of its pharmaceutical acceptable salt forms, as an active ingredient, wherein the compositions contain a reduced level of an amount of the impurities H168/79, Substance 23, Substance 24, and Substance 25 that the level of H168/79 is no greater than about 1.5% on a weight-to-weight of impurity to clevidipine or where the ratio of the area under the chromatographic curve between clevidipine and each of Substance 23, Substance 24, and/or Substance 25 is equal or greater than 500 to 1, and the 10 ratio the area under the chromatographic curve between clevidipine and H168/79 is equal or greater than 60 to 0.9, as defined in Claim 6. [0014] The present invention also describes a method of manufacturing compositions having clevidipine as an active ingredient, and an amount of the impurity H168/79 that is no greater than about 1.0% weight-to-weight of impurity to clevidipine, or where the ratio between clevidipine and H168/79 is equal or greater than 100 to 1, as defined in Claim 9. 15 [0015] There is further disclosed a use of a composition as described herein in a method of treating or alleviating a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition having clevidipine or any of its pharmaceutical acceptable salt forms as the active ingredient, wherein the level of impurities is reduced or minimized to no more than 0.2% weight-to-weight of impurity to clevidipine for any of Substance 23, Substance 24, and Substance 25, and no more than 1.5% for H168/79 based on a weight-to- 20 weight of impurity to clevidipine. As used herein the disease or condition refers to any disease or condition which may be treated using a selective calcium channel block, such as clevidipine. Examples of such disease or condition include, without limitation, hypertension, such as primary hypertension, secondary hypertension, acute hypertension, chronic hypertension, high blood pressure, chest pain (angina), migraine, brain aneurysm complications, irregular heartbeats (arrhythmia) and Raynaud’s disease. 25 [0016] A further aspect of the invention relates to the use of a composition as described herein in treating