(19) TZZ Z_T (11) EP 2 977 045 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 27.01.2016 Bulletin 2016/04 A61K 31/135 (2006.01) A61K 31/27 (2006.01) A61K 31/38 (2006.01) A61K 31/421 (2006.01) (2006.01) (2006.01) (21) Application number: 15177490.8 A61K 31/445 A61K 31/704 A61K 31/138 (2006.01) A61K 31/197 (2006.01) (2006.01) (2006.01) (22) Date of filing: 20.07.2015 A61K 31/4178 A61K 31/423 A61K 31/433 (2006.01) A61K 31/49 (2006.01) A61K 31/5513 (2006.01) A61P 21/02 (2006.01) (84) Designated Contracting States: • TÜRKYILMAZ, Ali AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 34460 Istanbul (TR) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • ILDES ERDEM, Ayse PL PT RO RS SE SI SK SM TR 34460 Istanbul (TR) Designated Extension States: • YILDIRIM, Ediz BA ME 34460 Istanbul (TR) Designated Validation States: • KARABULUT, Tutku Ceren MA 34460 Istanbul (TR) (30) Priority: 21.07.2014 TR 201408575 (74) Representative: Sevinç, Erkan Istanbul Patent A.S. (71) Applicant: Sanovel Ilac Sanayi ve Ticaret A.S. Plaza-33, Büyükdere Cad. No: 33/16 34460 Istanbul (TR) Sisli 34381 Istanbul (TR) (72) Inventors: • CIFTER, Ümit 34460 Istanbul (TR) (54) ZALTOPROFEN AND MUSCLE RELAXANT COMBINATIONS (57) The present invention relates to a novel pharmaceutical composition comprising zaltoprofen or a pharmaceu- tically acceptable salt thereof in combination with muscle relaxants with anti-inflammatory, analgesic and myorelaxant activity. EP 2 977 045 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 977 045 A1 2 Description or spasticity occurring in musculoskeletal and neuromus- cular disorders. Spasms are sudden alternating contrac- Technical Aspect tionsand relaxationsor sustainedcontractions of muscle. Antispasmodic drugs are used to treat musculoskeletal [0001] The present invention relates to a novel phar- 5 conditions or inflamation, which includes back pain. maceutical composition comprising zaltoprofen or a Spasticity is defined as an upper motor neuron disorder, pharmaceutically acceptable salt thereof in combination possibly caused by a conduction interruption in the nerve with muscle relaxant drugs with anti-inflammatory, anal- pathway. Antispastic drugs are primarily used to treat gesic and myorelaxant activity. neurological disorders, such as cerebral palsy. [0002] More specifically, this invention relates to a10 [0007] Tizanidine, dantrolene, thiocolchicoside and pharmaceutical composition comprising zaltoprofen or a carisoprodol are known muscle relaxant agents used in pharmaceutically acceptable salt thereof in combination the treatment of painful muscle spasms and spasticity with muscle relaxants with anti-inflammatory, analgesic occurring in musculoskeletal and neuromuscular disor- and myorelaxant activity administrated orally, parenter- ders and for treating contractures and inflammatory con- aly, intramuscularly or topicaly in the form of a tablet, 15 ditions that affect the muscular system. bilayer tablet, multilayer tablet, capsule, injectable pre- [0008] Tizanidine is an example for antispastic drugs. parat, suspension, syrup, sachet, ointment, cream or a Its chemical structure is shown in Formula II. gel form. Background of the Invention 20 [0003] Zaltoprofen is a propionic acid derivative, is a known NSAID (non-steroidal anti-inflammatory drug) with analgesic and anti-inflammatory activity. Its chemi- cal structure is shown in the Formula I. 25 30 [0009] Tizanidine is a α2-adrenergic agonist and acts mainly at spinal and supraspinal levels to inhibit excita- tory interneurones. It is used for the symptomatic relief of spasticity associated with multiple sclerosis or with spi- nal cord injury or disease. The recommended dose of 35 tizanidin is 2 mg, 4mg or 6 mg. [0010] Dantrolene is also an antispastic drug indicated in controlling the manifestations of clinical spasticity re- [0004] The chemical name of zaltoprofen is 2-(10-oxo- sulting from upper motor neuron disorders (e.g., spinal 10,11-dihydrodibenzo[b,f]thiepin-2-yl)propanoic acid. It cord injury, stroke, cerebral palsy, or multiple sclerosis). is a preferential COX-2 inhibitor. It selectively inhibits 40 Its chemical structure is shown in Formula III. PGE2 (Prostaglandin E2) that mediates the pain path- way. It inhibits bradykinin-induced pain responses with- out interfering with the bradykinin receptors. It is used in musculoskeletal and joint disorders such as osteoarthri- tis and rheumatoid arthritis and other chronic inflamma- 45 tory pain conditions or the treatment of lumbar pain, fro- zen shoulder, musculoskeletal pain, dental pain, post- operative pain, cervicobrachial syndrome, other pain and inflammatory conditions. It has also effect on post-sur- gery or post trauma chronic inflammation. 50 [0005] Muscle relaxants are used alone or in combi- nation with analgesics in the management of muscu- loskeletal and neuromuscular disorders. There are two [0011] The recommended dose of dantrolene is 25 mg main types; centrally acting relaxants and directly acting to 100 mg four times a day and at bedtime. relaxants. 55 [0012] Thiocolchicoside is an antispasmodic drug that [0006] Centrally acting relaxants generally have a se- is a gamma-aminobutiric acid receptor agonist. Its chem- lective action on the central nervous system (CNS) and ical structure is shown in Formula IV. are principally used for relieving painful muscle spasms 2 3 EP 2 977 045 A1 4 sitions in the treatment o a variety of skeletal muscle dis- orders including skeletal muscle spasm, certain ortho- pedic conditions, disk syndromes and low back pain. [0019] United Kingdom patent application GB 2 197 5 198 A1 (Sandoz Ltd.) 03.11.1986, describes to novel pharmaceutical preparations comprising ibuprofen and tizanidine with analgesic and myotonolytic activity as well as to methods of inducing analgesia and of treating con- ditions associated with increased muscle tone. 10 [0020] It is well known that drugs used in the same therapeutic area or even for treating the same indication cannot always be combined a priori with the expectation of at least additive therapeutic effects. The scientific lit- erature is full of examples wherein compounds of differ- 15 ent classes, which are used to treat the same indications, [0013] It has recently been shown that thiocoichico- cannot be combined into safe and efficacious dosage side’s activity can be ascribed to its ability of interacting forms thereby resulting in incompatible drug combina- withthe strychnine-sensitive glycinereceptors and there- tions. The reasons for this unexpected lack of compati- fore that compounds endowed with glycino-mimetic ac- bility are varied; however, it is often found that the incom- tivity can be used in the rheumatologic-orthopedic field 20 patibledrug combinations result in increasedside effects, for their muscle relaxant properties. unwanted drug interactions or additional side effects. [0014] The maximum recommended oral dose of Thi- More specifically, in the area of analgesia there are drug ocolchicoside is 8 mg every 12 hours; treatment duration combinations that are contraindicated for some or all of should be no more than 7 consecutive days. When given these very same reasons. intramuscularly, the maximum dose should be 4 mg eve- 25 [0021] Conventional analgesic and myorelaxant ther- ry 12 hours, for up to 5 days. apy generally involves administration of a pharmaceuti- [0015] In addition, Carisoprodol is an antispasmodic cal composition containing one or more different analge- drug indicated for the relief of discomfort associated with sic and muscle relaxant drugs. However, not all combi- acute, painful musculoskeletal conditions. Its chemical nations of analgesic drugs and muscle relaxant drugs structure is shown in Formula V. 30 are more suitable, in terms of safety or efficacy, than the administration of a single product. [0022] Thus, there is a need in the art for a pharma- ceutical composition or a dosage form comprising a com- bination of a zaltoprofen and a muscle relaxant, in par- 35 ticular tizanidine, thiocolchicoside, dantrolene or cariso- pradol. Detailed description of the invention 40 [0023] The present invention relates to a pharmaceu- [0016] The recommended dose of Carisoprodol is 250 tical composition comprising zaltoprofen or a pharma- mg to 350 mg three times a day and at bedtime. The ceutically acceptable salt thereof in combination with recommended maximum duration of Carisoprodol use is muscle relaxant drugs. up to two or three weeks. [0024] In one embodiment, pharmaceutical composi- [0017] Muscle relaxants have been evaluated alone or 45 tion comprising zaltoprofen or a pharmaceutically ac- in combination with conventional analgesics for the treat- ceptable salt thereof in combination with muscle relax- ment of pain. Mixed and unpredictable results have been ants with anti-inflammatory, analgesic and myorelaxant obtained in a pharmaceutical composition. But zaltopro- activity administrated orally, parenteraly, intramuscularly fen has not previously been combined with muscle re- or topicaly in the form of a tablet, bilayer tablet, multilayer laxantsin apharmaceutical compositionfor thetreatment 50 tablet, capsule, injectable preparat, suspension, syrup, of inflammatory, pain and musculoskeletal diseases. sachet, ointment, cream or a gel. [0018] PCT application WO 86/03681 A1 , relates gen- [0025] According to one embodiment, the present erally to novel pharmaceutical compositions of matter composition is in the form of a tablet, bilayer tablet, mul- comprising one or more non-steroidal