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Home , Metaxalone, Zaltoprofen

(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 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, 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. 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] , , and pharmaceutical composition comprising zaltoprofen or a 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 -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 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 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 anti-inflammatory tilayer tablet or a capsule. drugs other than , acetaminophen and phenace- 55 [0026] Novel pharmaceutical composition in the form tin, in combination with at least one skeletal muscle re- of a tablet or a capsule administrated orally may provide laxant, and optionally xanthine or a xanthine derivative, a significant advance in the available treatments. Such such as caffeine, and to methods of using said compo- combination therapy may also provide for therapeutic im-

3 5 EP 2 977 045 A1 6 provements owing to the potential synergistic effect pro- ingredients and the excipients used; and (b) to insure the vided by the combination. therapeutical compatibility between the two active ingre- [0027] Muscle relaxants suitable for use in the compo- dients regarding their pharmacokinetic and/or pharma- sition of the present invention are selected from the group ceutical properties in order that the posology of the com- comprising thiocolchicoside, carisoprodol, tizanidine, 5 bined composition allowsto obtainsafe and efficient plas- dantrolene, flavoxate, , , diaza- ma levels of both pharmacological agents. pem, metaxalone, , iodide, [0037] According to these main challenges above, the succinylcholine, , , . pharmaceutical composition comprising zaltoprofen in Muscle relaxants used in the composition of this present combination with muscle relaxants in particular tizani- invention isan antispasmodic drugor an antispastic drug. 10 dine, thiocolchicoside, dantrolene or carisopradol have [0028] In one embodiment, antispasmodic drugs are an additive analgesic effect in relief of postoperative pain selected from the group comprising, thiocolchicoside, and provide greater analgesia with the results in a lower carisoprodol, flavoxate, cyclobenzaprine, metaxalone, incidence of side effects according to priori. These phar- metocurine iodide, orphenadrine or chlorzoxazone. Pref- maceutical combinations are administrated orally, erably they are thiocolchicoside or carisoprodol or phar- 15 parenteraly, intramuscularly or topicaly. maceutically acceptable salts thereof. More preferably [0038] The pharmaceutical compositions of the inven- the antispasmodic drug is thiocolchicoside. tion include tablets, bilayer tablet, multilayer tablet, cap- [0029] In one embodiment, antispastic drugs are se- sules, injectables, suspensions, syrups, sachets, oint- lected from the group comprising, tizanidine, dantrolene, ments, creams or gels can be made in accordance with baclofen, diazapem, methocarbamol, succinylcholine, 20 methods that are standard in the art. Examples of oral quinine. Preferably they are tizanidine or dantrolene or dosage forms include tablets (including compressed, pharmaceutically acceptable salts thereof. More prefer- coated or uncoated), capsules, hard or soft gelatin cap- ably the antispastic drug is tizanidine. sules, pellets, pills, powders, granules, elixirs, tinctures, [0030] According to one embodiment, zaltoprofen or a colloidal dispersions, dispersions, effervescent compo- pharmaceutically acceptable salt thereof is present in an 25 sitions, films, sterile solutions or suspensions, syrups or amount of between 10 - 90%, preferably 15 - 50% and emulsions more preferably 25 - 35% by weight of total composition. [0039] According to one embodiment, the combination [0031] According to one embodiment, thiocolchicoside of a zaltoprofen with tizanidine, thiocolchicoside, dantro- or a pharmaceutically acceptable salt thereof is present lene or carisoprodol is in the form of a tablet or a capsul. in an amount of between 1 - 10%, preferably 2 - 8%, more 30 Moreover, it may be granulated by methods such as, dry preferably 2 - 4% by weight of total composition. granulation, low- or high-shear granulation, wet granula- [0032] According to one embodiment, tizanidine or a tion or fluidized-bed granulation. Low-shear granulation, pharmaceutically acceptable salt thereof is present in an high-shear granulation, wet granulation and fluidized- amount of between 0.5 - 10%, preferably 0.5 - 8%, more bed granulation generally produce harder, less friable preferably 0.5 - 4% weight of total composition. 35 tablets. [0033] According to one embodiment, dantrolene or a [0040] In one embodiment, pharmaceutical composi- pharmaceutically acceptable salt thereof is present in an tion of this present invention further comprises at least amount of between 2 - 90%, preferably 3 - 50%, more one pharmaceuticlly acceptable excipient. According to preferably 5 - 30% weight of total composition. this embodiment, at least one pharmaceuticlly accepta- [0034] According to one embodiment, carisoprodol or 40 ble excipient is selected from a group comprising binders, a pharmaceutically acceptable salt thereof is present in diluents, disintegrants, lubricants and glidants or mix- an amount of between 2 - 90%, preferably 10 - 80%, tures thereof. more preferably 30 - 50% weight of total composition. [0041] According to this embodiment, binders used in [0035] Further embodiment of the present invention the present composition are selected from the group provides a pharmaceutical composition comprising zal- 45 comprising hydroxypropyl cellulose, hydroxyethylmethyl toprofen in combination with muscle relaxants in partic- cellulose, povidone, carbomers, carboxymethylcellulose ular tizanidine, thiocolchicoside, dantrolene or carisopra- sodium, cellulose acetate phthalate, chitosan, copovi- dol in the treatment of painful muscle spasms associated done, corn starch, pregelatinized starch, dextrates, dex- with static and functional disorders of vertebra or oc- trin, dextrose, ethylcellulose, gelatin, glyceryl behenate, curred in post-operations of osteoarthritis, pain and in- 50 guar gum, hydrogenated vegetable oil type I, hydroxye- flammatory symptoms associated with tissue trauma, de- thyl cellulose, hydroxypropyl starch, hypromellose, liquid generative vertebra diseases as torticollis, dorsalgy, lom- glucose, magnesium aluminum silicate, maltodextrin, balgy, disk hernia, neurologic and traumatic disorders maltose, methylcellulose, pectin, poloxamer, polycar- associated with spasticity. bophil, polydextrose, polyethylene oxide, polymethacr- [0036] The main challenges when combining two or 55 ylates, sodium alginate, stearic acid, sucrose or mixtures more molecules in the same pharmaceutical form are (a) thereof. Preferably, binder is hydroxypropyl cellulose. to guarantee the chemico-physical compatibility between [0042] In a further embodiment, hydroxypropyl cellu- the different active ingredients and/or between the active lose (HPC) is used as a binder in the composition of the

4 7 EP 2 977 045 A1 8 present invention to improve tabletting characteristics. dyes and iron oxide and talc or mixtures thereof. Zaltoprofen and muscle relaxants used in the composi- [0048] In this present invention, zaltoprofen and mus- tion have different flowability, solubility and viscosity cle relaxant compositions have been designed, compris- characteristics. It makes the granulation more difficult. ing of the following: Moreover, zaltoprofen and muscle relaxants used in the 5 composition are moisture sensitive. In this invention, to - 10 - 90% by weight of zaltoprofen or pharmaceuti- overcome these problems, HPC is used and it has been cally acceptable salt thereof, suprisingly found that HPC provides both better tableting - 1 - 10% by weight of thiocolchicoside or pharmaceu- characteristics and stability of the composition. tically acceptable salt thereof, [0043] According to one embodiment, diluents used in 10 - 1 - 60 % by weight of lactose, the present composition are selected from the group - 5 - 80 % by weight of microcrystalline celluose, comprising lactose, mannitol, microcrystalline cellulose, - 0.5 - 5 % by weight of croscarmellose sodium starch, sodium carbonate, sodium bicarbonate, calcium - 0.1 - 50 % by weight of hydroxypropyl cellulose carbonate, sucrose and mixtures thereof. Preferably, - 0.01 - 5 % by weight of colloidal silicon dioxide, diluent is lactose. 15 - 0.1 - 5 % by weight of magnesium stearate, [0044] According to one embodiment, disintegrants - water and, used in the present composition are selected from the - optionally, coating. group comprising microcristalline cellulose, croscarmel- lose sodium, sodium starch glycollate, crospovidone, - 10 - 90% by weight of zaltoprofen or pharmaceuti- starch and their mixtures thereof. Preferably, disintegrant 20 cally acceptable salt thereof, is microcristalline cellulose, croscarmellose sodium or - 0.5 - 10% by weight of tizanidin or pharmaceutically mixtures thereof. acceptable salt thereof, [0045] According to one embodiment, lubricants used - 1 - 60 % by weight of lactose, in the present composition are selected from the group - 5 - 80 % by weight of microcrystalline celluose, comprising of magnesium stearate, stearic acid, colloidal 25 - 0.1 - 50 % by weight of hydroxypropyl cellulose silicon dixode, collodial anhydrous silica, talc, sodium - 0.01 - 5 % by weight of colloidal silicon dioxide, stearil fumarate and mixtures thereof. Preferably, lubri- - 0.1 - 5 % by weight of stearic acid, cant is magnesium stearate or stearic acid. - water and, [0046] According to one embodiment, glidants used in - optionally, coating. the present composition are selected from the group30 comprising of colloidal silicon dioxide, talc, aluminium sil- - 10 - 90% by weight of zaltoprofen or pharmaceuti- icate or mixtures thereof; preferably glidant is colloidal cally acceptable salt thereof, silicon dioxide. - 2 - 90% by weight of dantrolene or pharmaceutically [0047] Coating agents may include but not limited Opa- acceptable salt thereof, dryTM derivatives (such as opadry yellow (20A22418) 35 - 1 - 60 % by weight of lactose, and opadry II), aminoalkyl metacrylate, carboxymethyl- - 5 - 80 % by weight of microcrystalline celluose, cellulose calcium, carboxymethylcellulose sodium, car- - 0.1 - 50 % by weight of hydroxypropyl cellulose nauba wax, cellulose acetate, cellulose acetate phtha- - 0.01 - 5 % by weight of colloidal silicon dioxide, late, ceresin, cetyl , chitosan, ethylcellulose, fruc- - 0.1 - 5 % by weight of stearic acid, tose, gelatin, glycerin, glyceryl behenate, glyceryl palmi- 40 - water and, tostearate, hydroxyethyl cellulose, hydroxyethylmethyl - optionally, coating. cellulose, hydroxypropyl cellulose, hypromellose, hy- promellose phthalate, isomalt, liquid glucose, maltitol, and maltodextrin, methylcellulose, microcrystalline wax, par- affin, poloxamer, polydextrose, polyethylene oxide, poly- 45 - 10 - 90 % by weight of zaltoprofen or pharmaceuti- DL-(lactic acid), polyvinyl acetate phthalate, potassium cally acceptable salt thereof, chloride, shellac, shellac with stearic acid, sucrose, sur- - 2 - 90% by weight of carisoprodol or pharmaceuti- face color agents, titanium oxide, tributyl citrate, triethyl cally acceptable salt thereof, citrate, vanillin, white wax, xylitol, yellow wax, zein, - 1 - 60 % by weight of lactose, dimethylaminoethyl methacrylate, butyl methacrylate50 - 5 - 80 % by weight of microcrystalline celluose, and methyl methacrylate (Eudragit E 100) (Poly(butyl - 0.5 - 5 % by weight of croscarmellose sodium methacrylate-co-(2- demethylaminoeethyl)methacr- - 0.1 - 50 % by weight of hydroxypropyl cellulose ylate-co-methyl methacrylate)) or mixture of polyethyl- - 0.01 - 5 % by weight of colloidal silicon dioxide, ene glycol and polyvinyl alcohol (Kollicoat IR) and their - 0.1 - 5 % by weight of magnesium stearate, copolymers, hydroxypropyl methyl cellulose (HPMC), 55 - water and, polyethyleneglycol (PEG), polivinylpyrrolidon (PVP), pol- - optionally, coating. yvinyl alcohol (PVA), vinylpyrrolidone-vinyl acetate co- polymer (PVP- PVAc) and pigments, titanium dioxide,

5 9 EP 2 977 045 A1 10

Example 1 andcolloidal silicon dioxide are sieved and a ddedto gran- ules then mixed again. Total mixture is pressed into tab- [0049] lets. Tablets are coated with Opadry II.

Ingredient (%) amount 5 Example 3

zaltoprofen 25.0 - 35.0 [0053] thiocolchicoside 2.0 - 4.0 lactose 5.0 - 50.0 Ingredient (%) amount 10 microcrystalline celluose PH 101 5.0 - 50.0 zaltoprofen 25.0 - 35.0 croscarmellose sodium 2.0 - 3.0 dantrolene 5.0 - 30.0 hydroxypropyl cellulose LF 0.5 - 20.0 lactose 5.0 - 50.0 colloidal silicon dioxide 0.05 - 2.0 15 microcrystalline celluose PH 101 5.0 - 50.0 magnesium stearate 0.1 - 5.0 hydroxypropyl cellulose LF 0.5 - 20.0 coating 0.01 - 3.0 colloidal silicon dioxide 0.05 - 2.0 stearic acid 0.1 - 5.0 water q.s. 20 coating 0.01 - 3.0 [0050] The process of the composition is carried out water q.s. as follows: Zaltorprofen, thiocolchicoside, lactose, cro- scarmellose sodium and microcrystalline celluose (PH [0054] The process of the composition is carried out 101) are taken into fluid bed dryer and mixed. Solution 25 as follows: Zaltoprofen, lactose, hydroxypropyl cellulose of hydroxypropylcellulose LF is prepared and granulation LF and microcrystalline celluose (PH 101) are sieved and is performed by spraying this solution on the mixture. mixed. Wet granulation is performed. Then granules are Granules are dried and sieved. Collodial silicon dioxide dried and sieved. Dantrolene, stearic acid and colloidal is added to granules and mixed. Magnesium stearate is silicon dioxide are sieved and mixed with granules. Total added to this mixture and mixed again. Total mixture is 30 powder pressed into tablets. Tablets are coated with pressed into the tablets. Tablets are coated with Opadry Opadry II. yellow (20A22418).

Example 4 Example 2 35 [0055] [0051]

Ingredient (%) amount Ingredient (%) amount zaltoprofen 25.0 - 35.0 zaltoprofen 25.0 - 35.0 40 carisoprodol 30.0 - 50.0 tizanidin hydrochloride 0.5 - 4.0 lactose 5.0 - 50.0 lactose 5.0 - 50.0 microcrystalline celluose PH 101 5.0 - 50.0 microcrystalline celluose PH 101 5.0 - 50.0 45 croscarmellose sodium 2.0 - 3.0 hydroxypropyl cellulose LF 0.5 - 20.0 hydroxypropyl cellulose LF 0.5 - 20.0 colloidal silicon dioxide 0.05 - 2.0 colloidal silicon dioxide 0.05 - 2.0 stearic acid 0.1 - 5.0 magnesium stearate 0.1 - 5.0 coating 0.01 - 3.0 50 coating 0.01 - 3.0 water q.s. water q.s.

[0052] The process of the composition is carried out as follows: zaltoprofen, lactose, hydroxypropyl cellulose 55 [0056] The process of the composition is carried out and microcrystalline cellulose (PH 101) are sieved and as follows: Zaltorprofen, carisoprodol, lactose, croscar- mixed. Wet granulation is performed. Then, granules are mellose sodium and microcrystalline celluose (PH 101) dried and sieved. Tizanidin hydrochloride, stearic acid are taken into fluid bed dryer and mixed. Solution of hy-

6 11 EP 2 977 045 A1 12 droxypropyl cellulose LF is prepared and granulation is 10. The pharmaceutical composition of claim 1 or 3, performed by spraying this solution on the mixture. Gran- wherein carisoprodol or a pharmaceutically accept- ules are dried and sieved. Collodial silicon dioxide is add- able salt thereof is present in an amount of between ed to granules and mixed. magnesium stearate is added 2 - 90%, preferably 10 - 80%, more preferably 30 - to this mixture and mixed again. Total mixture is pressed 5 50% weight of total composition. into the tablets. Tablets are coated with Opadry yellow (20A22418). 11. The pharmaceutical composition of claim 1 or 4, wherein dantrolene or a pharmaceutically accepta- ble salt thereof is present in an amount of between Claims 10 2 - 90%, preferably 3 - 50%, more preferably 5 - 30% weight of total composition. 1. A pharmaceutical composition comprising zaltopro- fen or a pharmaceutically acceptable salt thereof in 12. The pharmaceutical composition according to any combination with muscle relaxant drugs. preceding claims, further comprising at least one 15 pharmaceuticlly acceptable excipient. 2. The pharmaceutical composition according to claim 1, wherein the muscle relaxant drug is an antispas- 13. Thepharmaceutical composition accordingto claims modic drug or an antispastic drug. 12, wherein at least one pharmaceuticlly acceptable excipient is selected from a group comprising bind- 3. The pharmaceutical composition according to claim 20 ers, diluents, disintegrants, lubricants and glidants 2, wherein antispasmodic drugs are selected from or mixtures thereof. the group comprising thiocolchicoside, carisoprodol, flavoxate, cyclobenzaprine, metaxalone, meto- 14. The pharmaceutical composition according to claim curine iodide, orphenadrine or chlorzoxazone. Pref- 13, wherein binders are selected from the group erably, they are thiocolchicoside or carisoprodol or 25 comprising hydroxypropyl cellulose, hydroxyethyl- pharmaceutically acceptable salts thereof. methyl cellulose, povidone, carbomers, car- boxymethylcellulose sodium, cellulose acetate 4. The pharmaceutical composition according to claim phthalate, chitosan, copovidone, corn starch, prege- 2, wherein antispastic drugs are selected from the latinized starch, dextrates, dextrin, dextrose, ethyl- group comprising tizanidine, dantrolene, baclofen, 30 cellulose, gelatin, glyceryl behenate, guar gum, hy- diazapem, methocarbamol, succinylcholine, qui- drogenated vegetable oil type I, hydroxyethyl cellu- nine. Preferably, they are tizanidine or dantrolene or lose, hydroxypropyl starch, hypromellose, liquid glu- pharmaceutically acceptable salts thereof. cose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, poly- 5. The pharmaceutical composition according to claim 35 carbophil, polydextrose, polyethylene oxide, 1, 2 or 3, antispasmodic drug is thiocolchicoside. polymethacrylates, sodium alginate, stearic acid, su- crose or mixtures thereof, preferably, binder is hy- 6. The pharmaceutical composition according to claim droxypropyl cellulose (HPC). 1, 2 or 4, antispastic drug is tizanidine. 40 15. The pharmaceutical composition of any preceding 7. The pharmaceutical composition of claim 1, wherein claims, wherein said pharmaceutical composition is zaltoprofen or a pharmaceutically acceptable salt administrated orally, parenteraly, intramuscularly or thereof is present in an amount of between 10 - 90%, topicaly. preferably 15 - 50% and more preferably 25 - 35% by weight of total composition. 45 16. The pharmaceutical composition of any preceding claims, wherein said pharmaceutical composition is 8. The pharmaceutical composition of claim 5, wherein in the form of a tablet, bilayer tablet, multilayer tablet, thiocolchicoside or a pharmaceutically acceptable capsule, injectable preparat, suspension, syrup, sa- salt thereof is present in an amount of between 1 - chet, ointment, cream or a gel. 10%, preferably 2 - 8%, more preferably 2 - 4% by 50 weight of total composition.

9. The pharmaceutical composition of claim 6, wherein tizanidine or a pharmaceutically acceptable salt thereof is present in an amount of between 0.5 - 10%, 55 preferably 0.5 - 8%, more preferably 0.5 - 4% weight of total composition.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 8603681 A1 [0018] • GB 2197198 A1 [0019]

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