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Ep 1448205 B1 (19) & (11) EP 1 448 205 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/56 (2006.01) A61K 31/519 (2006.01) 23.03.2011 Bulletin 2011/12 A61P 1/04 (2006.01) A61P 29/00 (2006.01) (21) Application number: 02800923.1 (86) International application number: PCT/US2002/031866 (22) Date of filing: 04.10.2002 (87) International publication number: WO 2003/030823 (17.04.2003 Gazette 2003/16) (54) COMBINATIONS FOR THE TREATMENT OF IMMUNOINFLAMMATORY DISORDERS KOMBINATIONEN FÜR DIE BEHANDLUNG VON IMMUN-ENTZÜNDLICHEN ERKRANKUNGEN COMBINAISONS PERMETTANT LE TRAITEMENT DES TROUBLES IMMUNOINFLAMMATOIRES (84) Designated Contracting States: (74) Representative: Bösl, Raphael Konrad et al AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Isenbruck Bösl Hörschler LLP IE IT LI LU MC NL PT SE SK TR Patentanwälte Designated Extension States: Prinzregentenstrasse 68 AL LT LV MK RO SI 81675 München (DE) (30) Priority: 05.10.2001 US 327674 P (56) References cited: WO-A-01/47572 WO-A-01/68056 (43) Date of publication of application: WO-A-92/16226 WO-A2-00/12497 25.08.2004 Bulletin 2004/35 GB-A- 2 292 079 US-A- 3 934 036 US-A- 4 554 271 US-A- 5 242 921 (60) Divisional application: US-A- 5 314 688 US-A- 5 468 729 10013063.2 / 2 279 742 US-A- 6 071 514 US-A1- 2001 016 604 (73) Proprietor: Zalicus Inc. • NICOLAUS B.J.R.: ’"SYMBIOTIC APPROACH TO Cambridge, MA 02142 (US) DRUG DESIGN"’ DECISION MAKING IN DRUG RESEARCH 1983, (72) Inventors: • BERGER: "Long-term toxicology effects..." • KEITH, Curtis SEMINARS IN ONCOLOGY, 13,1,1,1988,, 2019, Boston, MA 02116 (US) pages 8-13, • BORISY, Alexis • BERGER: "comparative carcinogenic..." ARCH. Boston, MA 02114 (US) GESCHWULSTFORSCH., 1985, • ZIMMERMANN, Grant • RYEFELDT: "Liver tumors..." TOXICOLOGIC Somerville, MA 02144 (US) PATHOLOGY, 1992, •JOST-PRICE, Edward, Roydon • CONWAY: "inhibition of cartilage..." J. EXP. West Roxbury, MA 02132 (US) MED., 1995, • MANIVASAKAM, Palaniyandi • BADGER: "disease-modifying activity of..." Brighton, MA 02135 (US) ARTHRITIS AND RHEUMATISM, 2000, • HURST, Nicole • FELDMANN: "anti-TNFalpha therapy of Boston, MA 02132 (US) trheumatoid arthritis..." ANNUA. REV. • FOLEY, Michael, A. IMMUNOL., 2001, Chestnut Hill, MA 02467 (US) • INTERNETCITATION, [Online] Retrieved from the Internet: <URL:en.wikipedia.org/wiki/ prednisone> • INTERNETCITATION, [Online] Retrieved from the Internet: <URL:en.wikipedia/wiki/prednisolone> 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 1 448 205 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 448 205 B1 Remarks: Thefile contains technical information submitted after the application was filed and not included in this specification 2 EP 1 448 205 B1 Description Field of the Invention 5 [0001] The invention relates to the treatment of immunoinflammatory disorders. Background of the Invention [0002] Immunoinflammatory disorders (e.g., rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn’s disease, stroke- 10 induced brain cell death, ankylosing spondylitis, fibromyalgia, and inflammatory dermatoses, asthma, multiple sclerosis, type I diabetes, systemic lupus erythematosus, scleroderma, systemic sclerosis, and Sjögren’s syndrome) are charac- terized by dysregulation of the immune system and inappropriate activation of body’s defenses resulting in damage to healthy tissue. [0003] One percent of humans world- wide are afflicted with rheumatoid arthritis (RA), a relentless, progressive disease 15 causing severe swelling, pain, and eventual deformity and destruction of joints. According to the Arthritis Foundation, rheumatoid arthritis currently affects over two million Americans, of which women are three times more likely to be afflicted. Rheumatoid arthritis is characterized by inflammation of the lining of the joints and/or other internal organs, and the presence of elevated numbers of lymphocytes and high levels of proinflammatory cytokines. [0004] Diagnosis of RA generally includes: (i) morning stiffness in joints lasting at least one hour before improvement, 20 (ii) arthritis of three or more joint areas having simultaneously soft tissue swelling or fluid; (iii) arthritis of at least one hand joint; (iv) symmetric arthritis, i.e., simultaneous involvement of the same joint area on both sides of the body; (v) rheumatoid nodules; (vi) abnormal serum rheumatoid factor; and (vii) radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints. Patients are classified as having RA if at least four of these seven criteria, 25 and (i) through (iv) must have been present for at least six weeks. (American College of Rheumatology, 1987 Criteria for the Classification of Acute Arthritis of Rheumatoid Arthritis, based on Arnett FC et al., Arthritis Rheum. 1988; 31: 315-324). Pain per se is not required for the diagnosis of RA. [0005] Treatment of RA generally includes anti-inflammatory strategies directed at suppressing the clinical manifes- tations of joint inflammation, including synovial thickening, joint tenderness, and joint stiffness. Drugs used to address 30 these signs and symptoms generally include (i) non-steroidal anti-inflammatory drugs (NSAIDs; e.g., detoprofen, di- clofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenameate, mefenam- ic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, rofecoxib, aspirin, choline salicylate, salsalte, and sodium and magnesium salicylate)--these drugs may be adequate for mild RA, but do not appear to alter the longterm course of the disease; and (ii) steroids (e.g., cortisone, dexamethasone, hydrocortisone, 35 methylprednisolone, prednisolone, prednisone, triamcinolone). [0006] Treatment for RA may also include strategies directed at limiting the long term joint damage and deformity caused by the inflammation in the joints. Such treatments are generally described as DMARDs, i.e., disease modifying antirheumatic drugs (e.g., cyclosporine, azathioprine, methotrexate, leflunomide, cyclophosphamide, hydroxychloro- quine, sulfasalazine, D-penicillamine, minocycline, gold, etanercept (soluble TNF receptor) and infliximab (a chimeric 40 monoclonal anti-TNF antibody)). [0007] There is a need to develop new compositions for the treatment of immunoinflammatory disorders. Summary of the Invention 45 [0008] We have discovered that the combination of dipyridamole (also known as 2,6- bis(diethanolamino)-4,8-dipipe- ridinopyrimido(5,4-d)pyrimidine), and corticosteroids, such as fludrocortisone (as known as 9-alpha-fluoro-11-beta, 17- alpha, 21-trihydroxy-4-pregnene-3,20-dione acetate) or prednisolone (also known as 1-dehydrocortisol; 1-dehydrohy- drocortisone; 1,4-pregnadiene-11 beta,17alpha,21-triol-3,20-dione; and 11beta,17alpha,21-trihydroxy-1,4-pregna- diene-3,20-dione), brings about substantial suppression of TNFα levels induced in peripheral blood mononuclear cells 50 (PBMCs). [0009] Accordingly, the invention features a composition for treating a patient having, or at risk for developing, an immunoinflammatory disorder. The method includes administering (i) a corticosteroid; and (ii) dipyridamole. The two compounds are each to be administered in an amount that, when combined is sufficient to treat or prevent the immu- noinflammatory disorder. 55 [0010] Dipyridamole and the corticosteroid may be present in pharmaceutical compositions that contain a pharma- ceutically acceptable carrier, diluent, or excipient, and are administered at dosages and frequencies sufficient to suppress TNFα levels enough to produce a therapeutic benefit to the patient. Dipyridamole and the corticosteroid can be admin- istered within 14 days of each other (e.g., within 10 days, within five days, twenty-four hours, or one hour of each other, 3 EP 1 448 205 B1 or even simultaneously). Administration of each compound can occur, e.g. 1 to 5 times each day, or as necessary to alleviate symptoms. [0011] Accordingly, this invention also features pharmaceutical compositions, pharmaceutical packs, and kits con- taining dipyridamole and one or more corticosteroid. Compositions (pharmaceutical compositions and pharmaceutical 5 packs) of the invention may feature higher order combinations of dipyridamole and corticosteroids. Specifically, dipyri- damole may be combined with one, two, three, or more corticosteroids. In preferred embodiments, the dipyridomole , the corticosteroid, or both are approved by the United States Food and Drug Administration (USFDA) for administration to a human. [0012] The invention described herein has been exemplified using the corticosteroids fludrocortisone (as known as 10 9-alpha-fluoro-11-beta, 17-alpha, 21-trihydroxy-4-pregnene-3,20-dione acetate) and prednisolone (also known as 1- dehydrocortisol; 1-dehydrohydrocortisone; 1,4-pregnadiene-11beta, 17alpha, 21-triol-3,20-dione; and 11beta, 17alpha, 21-trihydroxy-1,4-pregnadiene-3,20-dione); however, a skilled artisan will recognize that structural and functional analogs of these corticosteroids
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