(19) TZZ __T (11) EP 2 429 291 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: B82Y 5/00 (2011.01) A61K 47/00 (2006.01) 06.07.2016 Bulletin 2016/27 (86) International application number: (21) Application number: 10775566.2 PCT/US2010/034800 (22) Date of filing: 13.05.2010 (87) International publication number: WO 2010/132711 (18.11.2010 Gazette 2010/46) (54) PHARMACEUTICAL COMPOSITIONS COMPRISING PRASUGREL AND CYCLODEXTRIN DERIVATIVES AND METHODS OF MAKING AND USING THE SAME PHARMAZEUTISCHE ZUSAMMENSETZUNGEN MIT PRASUGREL- UND CYCLODEXTRINDERIVATEN SOWIE VERFAHREN ZU IHRER HERSTELLUNG UND VERWENDUNG COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES DÉRIVÉS DE PRASUGREL ET DE CYCLODEXTRINE, LEURS PROCÉDÉS DE PRÉPARATION ET MÉTHODES D’UTILISATION (84) Designated Contracting States: • MACHATHA, Stephen, G. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Overland, KS 66212 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • CUSHING, Daniel, J. PL PT RO SE SI SK SM TR Phoenixville, PA 19460 (US) (30) Priority: 13.05.2009 US 177718 P (74) Representative: Harris, Jennifer Lucy et al Kilburn & Strode LLP (43) Date of publication of application: 20 Red Lion Street 21.03.2012 Bulletin 2012/12 London WC1R 4PJ (GB) (73) Proprietor: Cydex Pharmaceuticals, Inc. (56) References cited: La Jolla, CA 92037 (US) US-A- 5 989 578 US-A1- 2008 108 589 (72) Inventors: Remarks: • MOSHER, Gerold Thefile contains technical information submitted after Kansas City, MO 64145 (US) the application was filed and not included in this specification 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 2 429 291 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 429 291 B1 Description BACKGROUND OF THE INVENTION 5 Field of the Invention [0001] The present invention relates to pharmaceutical compositions comprising prasugrel and a cyclodextrin deriv- ative, and methods of making and using the same, for example, to treat disorders and diseases that are therapeutically responsive to prasugrel. 10 Background of the Invention [0002] Platelets play a central role in the pathogenesis of atherothrombosis and in the formation of thrombi following coronary angioplasty, with and without stent implantation. Platelets initially adhere at sites of vascular injury, atheroscle- 15 rotic plaque rupture, balloon angioplasty, and stenting. Platelet activation following these interactions results in the release of adenosine diphosphate ("ADP"), thromboxane A2, and other mediators. Released ADP promotes platelet activation via the G-protein linked P2Y 1 and P2Y 12 purinergic receptors leading to further platelet activation, aggregation, and other platelet functions, such as platelet shape change, secretion, and the development of pro-coagulant and pro- inflammatory activities. Activated platelets are recruited to sites of coronary plaque rupture and intra-arterial stenting, 20 thereby forming aggregates that may lead to platelet-rich thrombi, vascular occlusion, tissue ischemia, and myocardial necrosis in what is collectively known as Acute Coronary Syndrome ("ACS"). The term ACS is a pathophysiological continuum progressing from ischemic chest pain with sudden onset and worsening, to ischemia severe enough to cause irreversible myocardial damage detected with cardiac biomarkers without persistent ST-segment elevation, to total occlusionof the culprit coronary artery with persistentST-segment elevation,resulting in myocardial necrosis andelevated 25 biomarkers. ACS occurs in a diverse global population and has a significant socioeconomic impact as subjects require hospitalization, rehabilitation, and often suffer subsequent ischemic events. [0003] Options for the initial management of ACS include pharmacotherapy alone or an early invasive strategy with percutaneous coronary intervention ("PCI," with or without coronary stenting) or coronary artery bypass grafting (CABG) as guided by the results of coronary angiography. The current American College of Cardiology/American Heart Asso- 30 ciation and European Society of Cardiology guidelines recommend an early invasive strategy for ACS subjects with intermediate to high-risk features. Pharmacotherapy includes both anticoagulant and anti-platelet drugs. The current standard of care for subjects with ACS includes dual anti-platelet therapy with aspirin and thienopyridine in both the acute and chronic phases of treatment. This therapy improves outcome in subjects with ACS and those undergoing PCI; the high risk of early stent-associated thrombosis is substantially reduced by dual antiplatelet therapy. Ticlopidine and 35 clopidogrel are the two currently approved thienopyridines. Due to its once-daily dosing regimen, clopidogrel is the predominantly prescribed therapeutic agent to treat subjects suffering from ACS. [0004] Several potential limitations of clopidogrel therapy have been identified despite the loading dose of clopidogrel. This includes marked inter-individual variability in platelet inhibition and relatively slow onset of action. An association between thrombotic complications following PCI and poor antiplatelet response to the approved standard clopidogrel 40 dosing regimen (loading dose ("LD") 300 mg and maintenance dose ("MD") 75 mg) has been suggested. Further, it has been shown that "nonresponsiveness" to a clopidogrel 600 mg LD is a strong predictor of stent thrombosis in subjects receiving drug-eluting stents, and in addition, that residual platelet aggregation above the median is associated with a 6.7-fold increased risk of major adverse cardiac events (death, myocardial infarction and target vessel revascularisation) at 1 month follow-up in subjects undergoing elective PCI. These observations suggest the possibility that higher and 45 more consistent levels of platelet inhibition may improve clinical outcome in subjects with ACS undergoing PCI. [0005] Prasugrel is a thienopyridine ADP receptor antagonist that can be orally or parenterally administered, and has the chemical name 5-[(1 RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl ac- etate (chemical formula: C20H20FNO3S; molecular weight 373.44 g/mol). Clinical testing of prasugrel has utilized a racemic mixture of the hydrochloride salt, which is a white to light brown crystalline solid that is slightly hygroscopic. 50 Prasugrel hydrochloride is soluble to slightly soluble at pH 1-4, very slightly soluble at pH 5 and practically insoluble at pH 6-7. The pKa value of prasugrel hydrochloride is 5.1. Prasugrel is also known to demonstrate polymorphism. [0006] Prasugrel undergoes in vivo metabolism via hydrolysis by carboxylesterases and then multiple cytochrome P450 enzymes to form an active metabolite that irreversibly inhibits platelet activation and aggregation mediated by the P2Y12-receptor. Once bound, a platelet is inhibited for its remaining lifespan. After prasugrel dosing is stopped, a return 55 to baseline levels of platelet aggregation will occur as new platelets are formed, a process that typically occurs over about 7-10 days after treatment is stopped. [0007] Non-clinical studies indicate that, with respect to inhibiting ex vivo platelet aggregation and in vivo thrombus formation, prasugrel was approximately 10-fold to 100-fold more potent than clopidogrel and ticlopidine, respectively. 2 EP 2 429 291 B1 Prasugrel compositions, dosage forms, and methods of treatment using the same are known.See, e.g., U.S. Patent Nos. 5,288,726, 5,436,242 and 6,693,115, U.S. Patent Pub. Nos. 2008/0108589 and 2008/0176893, and WO 2004/098713, WO 2006/138317 and WO 2008/073759. Clinical data in healthy subjects has confirmed the greater platelet inhibition and more consistent response to prasugrel compared to clopidogrel. While the active metabolites of 5 prasugrel and clopidogrel resulted in similar levels of platelet inhibition in vitro, the amount of each active metabolite generated in vivo differs significantly: a prasugrel loading dose of 60 mg results in approximately a 50-fold greater exposure, on a per milligram basis, to its active metabolite compared to a clopidogrel loading dose of 300 mg. [0008] Compositions comprising clopidogrel and a cyclodextrin derivative are known.See, e.g., U.S. Patent No. 5,989,578, U.S. 2008/108589, WO 2008/072836, WO 2008/ 134600 and WO 2008/134601. 10 [0009] Prasugrel has completed at least one clinical trial relating to treating subjects suffering from acute coronary syndromes who have undergone a percutaneous coronary intervention or for whom a percutaneous coronary intervention is planned. See, e.g., Wiviott, S.D. et al., N. Engl. J. Med. 357:2001 (2007). Acute coronary syndrome includes heart attacks and unstable angina (chest pain). Prasugrel has demonstrated a reduction in the combined rate of death from cardiovascular causes and nonfatal myocardial infarction, as well as nonfatal stroke compared to clopidogrel. However, 15 subjects administered prasugrel have also exhibited an increased rate of serious bleeding events. In the clinical trial, three subgroups had less efficacy and greater absolute levels of bleeding than the overall treatment group, resulting in a reduced net clinical