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(12) United States Patent (10) Patent N0.: US 8,557,851 B2 Szelenyi Et A1

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(12) United States Patent (10) Patent N0.: US 8,557,851 B2 Szelenyi Et A1 US008557851B2 (12) United States Patent (10) Patent N0.: US 8,557,851 B2 Szelenyi et a1. (45) Date of Patent: Oct. 15, 2013 (54) COMBINATIONS OF FLUPIRTINE AND FOREIGN PATENT DOCUMENTS SODIUM CHANNEL INHIBITING SUBSTANCES FOR TREATING PAINS CA 2542434 5/2005 DE 3604575 A1 8/1986 DE 103 49 729.3 10/2003 (75) Inventors: Istvan Szelenyi, SchWaig (DE); Kay DE 103 49 729 .3 10/2003 Brune, Marloffstein (DE); Robert DE 103 59 335 5/2005 Hermann, Hanau (DE); Mathia Locher, EP 189788 A1 8/1986 EP 1813285 A1 8/2007 Ronneburg (DE) JP 2000-143510 A 5/2000 RU 2006117525 12/2005 (73) Assignee: MEDA Pharma GmbH & Co. KG, Bad W0 WO 00/59487 A2 10/2000 Homburg (DE) W0 WO 00/59508 A1 10/2000 W0 WO 01/01970 A2 1/2001 W0 WO 01/22953 A2 4/2001 ( * ) Notice: Subject to any disclaimer, the term of this W0 WO 2005/039576 5/2005 patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 236 days. PratZel et al., Pain, 1996, vol. 67, pp. 417-425.* (21) Appl.No.: 12/403,213 Balano KB. Anti-in?ammatory drugs and myorelaxants. Pharmacol ogy and clinical use in musculoskeletal disease. Prim Care. Jun. 1996;23(2):329-34. (22) Filed: Mar. 12, 2009 Richards BL, Whittle SL, Buchbinder R. Muscle relaxants for pain management in rheumatoid arthritis. Cochrane Database Syst Rev. (65) Prior Publication Data Jan. 18, 2012;11CD008922. pp 1-11. Argoff CE. Pharmacologic management of chronic pain. J Am Osteo US 2009/0176814 A1 Jul. 9, 2009 path Assoc. Sep. 2002;102(9 Suppl 3):S21-7. Kvien TK, Viktil K. Pharmacotherapy for regional musculoskeletal pain. Best Pract Res Clin Rheumatol. Feb. 2003;17(1): 137-50. Quasthoff S, Mockel C, Zieglgansberger W, Schreibmayer W. Related US. Application Data Tolperisone: a typical representative of a class of centrally acting (63) Continuation of application No. 10/727,658, ?led on muscle relaxants With less sedative side effects. CNS Neurosci Ther. 2008 Summer;14(2):107-19. Dec. 5, 2003, noW abandoned. Smith HS, Barton AE. TiZanidine in the management of spasticity and musculo skeletal complaints in the palliative care population. Am (30) Foreign Application Priority Data J Hosp Palliat Care. Jan-Feb. 2000;17(1):50-8). Solaro C, Messmer Uccelli M. Pharmacological management of pain Oct. 20, 2003 (DE) ................................ .. 103 49 729 in patients with multiple sclerosis. Drugs. Jul. 9, 2010;70(10):1245 54. Fuh JL, Chang DB, Wang SJ, Ju TH, Liu HC. Painful tonic spasms: (51) Int. Cl. an interesting phenomenon in cerebral ischemia. Acta Neurol Scand. A61K 31/44 (2006.01) Dec. 1991;84(6):534-6. A61K 31/4453 (2006.01) ZakrZeWska JM, Linskey ME. Trigeminal neuralgia. Clin Evid (52) US. Cl. (Online). Mar. 12, 2009;2009. pii: 1207. Krafft RM. Trigeminal neuralgia. Am Fam Physician. May 1, USPC .......................... .. 514/352; 514/317; 514/906 2008;77(9): 1291-6. (58) Field of Classi?cation Search Stanko JR. Review of oral skeletal muscle relaxants for the None craniomandibular disorder (CMD) practitioner. Cranio. Jul. See application ?le for complete search history. 1990;8(3):234-43. Hersh EV, Balasubramaniam R, Pinto A. Pharmacologic manage (56) References Cited ment of temporomandibular disorders. Oral Maxillofac Surg Clin North Am. May 2008;20(2): 197-210, vi. U.S. PATENT DOCUMENTS Gore M, Tai KS, Sadosky A, Leslie D, Stacey BR. Use and Costs of Prescription Medications and Alternative Treatments in Patients With 4,442,084 A 4/1984 Romer Osteoarthritis and Chronic Low Back Pain in Community-Based 4,668,684 A 5/1987 Tibes et a1. Settings. Pain Pract. Feb. 5, 2012. doi: 10.1111/j.1533-2500.2012. 4,778,799 A 10/1988 Tibes et a1. 00532.X. [Epub ahead of print]. 5,162,346 A 11/1992 Lobisch et a1. Rollings HE. Cari soprodol in osteoarthritis. Clin Med (North?eld II). 5,284,861 A 2/1994 Lobisch et a1. Aug. 1964;71:1378-80. 5,384,330 A 1/1995 Dieter et a1. 5,760,007 A 6/1998 Shank et a1. (Continued) 5,849,789 A 12/1998 Rostocket al. 5,852,053 A 12/1998 Rostocket al. Primary Examiner * Savitha Rao 5,925,634 A 7/1999 Olney Assistant Examiner * Gregg Polansky 6,117,900 A 9/2000 Rundfeldt et a1. (74) Attorney, Agent, or Firm * CroWell & Moring LLP 6,211,171 B1 4/2001 Sawynoketal. 6,281,211 B1 8/2001 Caietal. (57) ABSTRACT 6,348,486 B1 2/2002 Argentieriet al. 6,451,857 B1 9/2002 Hurtt et a1. The invention relates to pharmaceutical combinations of 6,472,165 B1 10/2002 Rundfeldt et a1. potassium channel openers and sodium channel inhibitors, 6,500,455 B1 12/2002 Frantsits for treating pains Which are accompanied by an increase in 6,537,991 B1 3/2003 Shaw etal. muscle tone. RE38,115 E 5/2003 Smith etal. 7,419,981 B2 9/2008 Fieldetal. 9 Claims, No Drawings US 8,557,851 B2 Page 2 (56) References Cited Ha AD, Jankovic J. Pain in Parkinson’s disease. Mov Disord. Apr. 20l2;27(4):485-9l. OTHER PUBLICATIONS Chung EJ, Kim SJ. Tonic spasms in acute transverse myelitis. J Clin Tarpley EL. Evaluation of diaZepam (Valium) in the symptomatic Neurosci. Jan. 2009;l6(l):l65-6. treatment of rheumatic disorders. A controlled comparative study. J Smith PF, Darlington CL. Recent developments in drug therapy for Chronic Dis. Jan. 1965;18:99-106. multiple sclerosis. Mult Scler. Apr. l999;5(2):ll0-20. Bhatia R, Dureja GP, Tripathi M, Bhattacharjee M, Bijlani RL, What Are Muscle Relaxants and When Are They Used to Treat Pain? Mathur R. Role of temporalis muscle over activity in chronic tension type headache: effect of yoga based management. Indian J Physiol (http ://abcnews . go .com/Health/TreatingPain/story?id:40476 l 7), Pharmacol. Oct.-Dec. 2007;5l(4):333-44. Christo,P., download May 30, 2012. Freitag FG. 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Brugman F, Scheffer H, Wokke JH, Nillesen WM, de Visser M, Properties and Clinical Use, CNS Drugs, 2010; 24 (10) Adis Data Aronica E, Veldink JH, van den Berg LH. Paraplegin mutations in Information BV (http://medi .ru/doc/ 140346 .htrn). sporadic adult-onset upper motor neuron syndromes. Neurology. Spastic Paraplegia Foundation, Inc., Pain Management and Treat Nov. 4, 2008;7l(l9):l500-5. ment (http :/ / www. sp-foundation. org/ content/ c ommunity/ pain -treat R0 5 ulescu E, Stanoiu C, Buteica E, Stanoiu B, Burada F, Zavaleanu ment.html), Redden,R., Feb. 26, 2011, 5 pages. M. Hereditary spastic paraplegia. Rom J Morphol Embryol. Cerebral Palsy Source, Quadriplegia and Cerebral Palsy (http:// 2009;50(2):299-303. cerebralpalsysource.com/TypesiofiCP/Quadriplegiaicp/index. Contino G, Novelli G. Hereditary spastic paraplegia: clinical genom htrnl), copyright 2005, downloaded May 30, 2012. ics and pharmacogenetic perspectives. Expert Opin Pharmacother. Kuo et al., Inhibition of Na+ Current by Diphenhydramine and Other Oct. 2006;7(l4):l849-56. Diphenyl Compounds . , Molecular Pharmacology, 2000, Gormley ME Jr, Krach LE, Piccini L. Spasticity management in the 57(l):l35-l43. child with spastic quadriplegia. Eur J Neurol. Nov. 200l;8 Suppl Beck et al., KreuZschmerZen in der Gynaekologischen Praxis, 5:127-35. Gynaekologe, Springer Verlag, Berlin Germany, 2002, 35(5):490 Wasner G, Deuschl G. Pains in Parkinson disease-many syndromes 494. under one umbrella. Nat Rev Neurol. Apr. 17, 2012. doi: 10.1038/ nrneurol.20l2.54. [Epub ahead of print]. * cited by examiner US 8,557,851 B2 1 2 COMBINATIONS OF FLUPIRTINE AND perisone-like compounds. Tolperisone suppresses transmis SODIUM CHANNEL INHIBITING sion of the spinal segment re?ex and effectively reduces C SUBSTANCES FOR TREATING PAINS ?ber-induced transmission in the afferent nerves both in vivo and in vitro (Farkas et al., Neurobiology 1997; 5:57-58). As This application is a continuation of US. application Ser. compared With lidocaine, a local anesthetic, the sub stance has No. 10/727,658, ?led Dec. 5, 2003, Which claims priority less of a blocking effect on transmission in the A ?bers. It under 35 U.S.C. §119 to German application no. DE characteristic effect is that of strongly inhibiting the mono 10349729.3, ?led Oct. 23, 2003, each of Which the entire synaptic and polysynaptic spinal re?exes (Farkas et al. Neu contents are incorporated herein by reference. robiology 1997; 5:57-58, Kocsis et al., Acta Pharrn Hung The invention relates to pharmaceutical combinations of 2002; 72(1):49.-61, Okada et al., Jpn. J Pharmacol 2001; 86: 134-136). In rats, Ono et al. (J Pharrnacobio Dynam 1984; potassium channel openers and sodium channel inhibitors for 7: 171 -178) shoWed that tolperisone exhibits an effect like that treating pains Which are accompanied by an increase in of a local anesthetic (“membrane-stabiliZing”) both in motor muscle tone.
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