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Home , Ebrotidine, Etodolac, Famotidine, Fenamic acid, Lafutidine, Licofelone

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2012/173581 Al 20 December 2012 (20.12.2012) P O P C T

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/407 (2006.01) A61P 19/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/426 (2006.01) A61P 21/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/704 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) Number: International Application HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/TR20 12/000053 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 2 1 March 2012 (21 .03.2012) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: glish ( ) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 201 1/02628 2 1 March 201 1 (21.03.201 1) TR GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, (71) Applicant (for all designated States except US) : AK TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, KIMYA ITHALAT-IHRACAT VE SANAYII A.S. DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, [TR/TR]; Pak Is Merkezi Prof. Dr. Bulent Tarcan Sk. LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, No:5/l, Gayrettepe / Istanbul 34349 (TR). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/Applicants (for US only): PISAK, Ibrahim Published: Mustafa Iskender [TR/TR]; Pak Is Merkezi Prof. Dr. Bu — with international search report (Art. 21(3)) lent Tarcan Sk. No:5/l, Gayrettepe / Istanbul 34349 (TR). SELAMOGLU , Mehmet Levent [TR/TR]; Pak Is — before the expiration of the time limit for amending the Merkezi Prof. Dr. Bulent Tarcan Sk. No: 5/1, Gayrettepe / claims and to be republished in the event of receipt of Istanbul 34349 (TR). BINGOL, Semra [TR/TR]; Pak Is amendments (Rule 48.2(h)) Merkezi Prof. Dr. Bulent Tarcan Sk. No: 5/1, Gayrettepe / Istanbul 34349 (TR).

(54) Title: , AND COMBINATIONS

(57) Abstract: The present invention relates to the unit dosage forms comprising a. thiocolchicoside or a pharmaceutically accept able salt thereof or any therapeutically active optically pure stereoisomer thereof as a , b. etodolac or a pharmaceutic - ally acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as an NSAID, and c. famotidine or a pharmaceutically acceptable salt thereof as a gastroprotectant. DESCRIPTION

THIOCOLCHICOSIDE, ETODOLAC AND FAMOTIDINE COMBINATIONS

Field of the invention

The present invention relates to the pharmaceutical compositions in unit dosage form comprising thiocolchicoside as a muscle relaxant, etodolac as a non-steroidal anti¬ inflammatory drug and famotidine as a gastroprotectant; and to the preparation methods thereof. Pharmaceutical compositions of the invention are used in the treatment of muscular and skeletal system diseases as well as and pain; and are safe due to the reduced gastrointestinal side effects.

Background of the invention

The present invention relates to the unit dosage forms comprising a. a muscle relaxant, b. a non-steroidal anti-inflammatory drug (an NSAID), and c. a gastroprotectant.

Unit dosage forms of the invention comprises a. thiocolchicoside or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as a muscle relaxant, b. etodolac or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as an NSAID, and c. famotidine or a pharmaceutically acceptable salt thereof as a gastroprotectant:

Unit dosage forms of the invention comprise thiocolchicoside as a muscle relaxant in an amount of from 4 to 16 mg, preferably in an amount of 8 mg; etodolac as an NSAID in an amount of from 200 to 1200 mg, preferably in an amount of 400 mg; and famotidine as a gastroprotectant in an amount of from 5 to 200 mg, preferably in an amount of 20 mg.

Pharmaceutical combinations of the invention used in the treatment of muscular and skeletal system diseases as well as inflammation and pain can reduce the gastrointestinal side effects induced by the NSAID content in the composition due to the presence of the gastroprotectant in said composition. Thiocolchicoside is a glycosulfurated analogue of and is a well known centrally acting muscle relaxant used in the treatment of muscular and skeletal system diseases. Its chemical structure is shown in Formula 1.

Formula 1

The chemical name of thiocolchicoside is N-[3-( -D-glucopyranosyloxy)-l,2-dimethoxy-10- (methylthio)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide.

The usual initial dose is 16 mg daily by oral administration in the form of capsule or . It is also used for intramuscular administration in doses up to 8 mg per day or for topical application as cream, ointment, gel or aerosol.

Etodolac is an NSAID used in the treatment of inflammation and pain. It possesses and antipyretic properties as well as anti-inflammatory activity. Its chemical structure is shown in Formula 2.

Formula 2

The chemical name of etodolac is l,8-diethyl-l,3,4,9-tetrahydropyrano (3,4-b) indol-l-yl .

The usual initial dose is 200-400 mg daily for acute pain, 800-1200 mg daily for inflammation-related diseases by oral administration in the form of tablet. Famotidine is an H2-reseptor antagonist used in the treatment of gastrointestinal diseases. It protects the gastric mucosa against irritation. Its chemical structure is shown in Formula 3.

Formula 3

The chemical name of famotidine is 3-(2-(diaminomethyleneamino)thiazol-4-yl methylthio)- N-sulfamoyl propionamidine.

The usual initial dose is 40 mg daily by oral administration in the form of tablet or intravenous administration.

Centrally acting skeletal muscle relaxants are generally prescribed either as single agents or as components of combination products. Several commercial combinations of a muscle relaxant and ( + aspirin, carisoprodol + aspirin + , + aspirin and + aspirin + ) have been approved by the U.S. Food and Drug Administration (U.S. FDA) and are marketed in the USA.

Due to the fact that NSAIDs can cause gastrointestinal ulseration, and perforation; especially in case of high dose usage, long-term treatments, history of a or sensitivity to develop disease; additional use of gastroprotectant drugs for reducing gastrointestinal irritation is needed.

In cases where use of more than one medicine is needed, patient compliance is an important factor to be considered. According to the research, 50% of the patients fail to take medicines as prescribed and to fulfill the requirements of the treatment (Sabate, E. "Adherence to Long- Term : Evidence for Action". World Health Organization. Geneva, 2003. 212 pp.). Patients fail to take their medicines prescribed so as to include a complicated treatment regimen requiring use of more than one medicine due to the facts such as forgetfulness, busy lifestyle, different methods of the administration of the medicines, lack of suitable environment for taking medicines, misunderstanding of the disease or treatment, patient's perspective of the disease or treatment, side effects, depression, cognitive disorders and financial problems. In this case, combining the active components in a single dosage form will increase patient compliance to the treatment.

The present invention is directed to the pharmaceutical compositions in unit dosage form wherein the patient compliance is increased, the composition is used for the treatment of muscular and skeletal system diseases as well as inflammation and pain, and gastrointestinal side effects are reduced.

Pharmaceutical compositions of the invention comprise thiocolchicoside as muscle relaxant, etodolac as NSAID and famotidine as gastroprotectant in a single dosage form.

Binary combinations of thiocolchicoside as muscle relaxant and NSAIDs as well as NSAIDs and gastroprotectants have been disclosed in the prior art. But, any information relating to the combinations of the invention comprising all active components (thiocolchicoside, etodolac and famotidine) combined in unit dosage form has not been disclosed.

French patent FR 2725134 Bl (Laboratoire Lederle) relates to a new combination comprising or a pharmaceutically acceptable salt thereof and thiocolchicoside or a pharmaceutically acceptable salt thereof in a weight ratio of between about 1:50 and about 1:200 for oral administration in the form of a capsule, tablet or granule.

European patent EP 0837684 Bl (Sanofi-Synthelabo) relates to a new combination comprising a salt and thiocolchicoside with at least one pharmaceutically acceptable excipient, wherein said combination is in solid form which is stable over time.

European patent application EP 1992333 A l (Sanovel) relates to a combination comprising and an alpha-2 adrenergic or a gamma-aminobutiric acid receptor agonist, particularly and thiocolchicoside.

International patent application WO201 0084500 Al (Sanofi-Synthelabo) relates to a combination in the form of a solid dosage form containing and thiocolchicoside, wherein the active ingredients are present in the free form or in the form of a salt and not being intimately mixed in the composition.

Above-mentioned patents relate to the combined use of thiocolchicoside and specific NSAIDs (ibuprofen, diclofenac, flurbiprofen and ketoprofen, respectively). But, said patents do not include even the binary combinations of etodolac and thiocolchicoside which are comprised in the triple combinations of the invention.

European patent EP 141 1900 Bl (Pozen) relates to a multi-layer tablet suitable for oral administration comprising an outer layer of an acid inhibitor (H2-, preferably famotidine, or proton pump inhibitor), an inner core of an NSAID (preferably aspirin or ) and a barrier coating surrounding the inner core of said NSAID.

American patent application US 20070237820 Al (Andrx) relates to a solid oral dosage form comprising a first portion comprising an NSAID (preferably diclofenac); and a coating comprising an antiulcerative compound (preferably ); said coating at least partially surrounding said first NSAID portion.

American patent application US 20090233970 Al relates to a pharmaceutical composition for the treatment of pain and inflammation with reduced gastrointestinal irritation, the composition comprising at least one NSAID (preferably naproxen or ibuprofen); and at least one acid blocking agent (preferably ).

Above-mentioned patents relate to the combined use of NSAIDs (preferably aspirin, naproxen, diclofenac or ibuprofen) and gastroprotectants (preferably famotidine, proton pump inhibitors, misoprostol or ranitidine). But, said patents do not clearly include even the binary combinations of etodolac and famotidine which are comprised in the triple combinations of the invention.

As a result, the present invention discloses novel and stable unit dosage forms comprising thiocolchicoside as muscle relaxant, etodolac as NSAID and famotidine as gastroprotectant.

Summary of the invention

The present invention relates to a pharmaceutical composition for use in the treatment of muscular and skeletal system diseases, inflammation and pain in mammalian organism and adapted for unit administration, wherein the pharmaceutical composition comprises a) thiocolchicoside or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as muscle relaxant; b) etodolac or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as NSAID; c) famotidine or a pharmaceutically acceptable salt thereof as gastroprotectant; and d) at least one pharmaceutically acceptable non-toxic carrier.

Detailed description of the invention

The present invention encompasses unit dosage forms comprising a muscle relaxant, a non¬ steroidal anti-inflammatory drug (NSAID) and a gastroprotectant.

The muscle relaxant of the invention is preferably thiocolchicoside or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof.

The NSAID of the invention may preferably be selected from an acetic acid derivative, a derivative, an enolic acid derivative, a derivative, a COX-2 inhibitor, a salicylate and other NSAI drugs.

The acetic acid derivative of the invention may be selected from, but is not limited to, etodolac, , diclofenac, indomethacin, and nabumeton; and is preferably etodolac. Etodolac may be in the form of a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof.

The propionic acid derivative of the invention may be selected from, but is not limited to, ibuprofen, naproxen, , ketoprofen, flurbiprofen, and .

The enolic acid derivative of the invention may be selected from, but is not limited to, , , , , and .

The fenamic acid derivative of the invention may be selected from, but is not limited to, , , and .

The COX-2 inhibitor of the invention may be selected from, but is not limited to, , , , , and .

The salicylate of the invention may be selected from, but is not limited to, acetylsalicylic acid, and . The other NSAI drugs of the invention may be selected from, but are not limited to, and .

The gastroprotectant of the invention may preferably be selected from an H2-receptor antagonist, a proton pump inhibitor, an antiacid or a .

The H2-receptor antagonist of the invention may be selected from, but is not limited to, famotidine, , ranitidine, , pabutidine, , loxtidine, , roxatidine, tiotidine, and ; and is preferably famotidine. Famotidine may be in free form or in the form of a pharmaceutically acceptable salt thereof.

The proton pump inhibitor of the invention may be selected from, but is not limited to, , , , , , and leminoprazole.

The antiacid of the invention may be selected from, but is not limited to, CaC0 3, MgC0 3,

Mg(OH)2, Al(OH) 3, NaHC0 3 and KHC0 3.

The prostaglandin of the invention may be selected from, but is not limited to, misoprostol and .

The present invention relates to a combination of thiocolchicoside or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as muscle relaxant; etodolac or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as NSAID; famotidine or a pharmaceutically acceptable salt thereof as gastroprotectant and at least one pharmaceutically acceptable non¬ toxic carrier, wherein said combination is developed for unit dose application.

Combinations of the invention comprise thiocolchicoside as a muscle relaxant in an amount of from 4 to 16 mg, preferably in an amount of 8 mg; etodolac as an NSAID in an amount of from 200 to 1200 mg, preferably in an amount of 400 mg; and famotidine as a gastroprotectant in an amount of from 5 to 200 mg, preferably in an amount of 20 mg.

The addition of thiocolchicoside to a standard NSAID treatment has shown more effective results for the treatment of muscular and skeletal system diseases as well as inflammation and pain than NSAID treatment alone. The addition of a gastroprotectant to said combination has substantially reduced the gastrointestinal side effects of the NSAID.

Combinations of the invention may be used for oral, buccal, ocular, otic, rectal, topical, implantal, mucosal, parenteral, sublingal, nasal or pulmonary administration in the form of gel, cream, ointment, tablet, capsule, drop, pellet, granule, solution, suspension, syrup, powder, injectable suspension, injectable powder and injectable solution; and are preferably in oral dosage form; more preferably in tablet form. Dosage forms of the invention may be administered once or twice a day. Therapeutically effective amount of thiocolchicoside included in the dosage forms of the invention is between 4 mg and 16 g, preferably 8 mg. Therapeutically effective amount of etodolac included in the dosage forms of the invention is between 200 mg and 1200 mg, preferably 400 mg. Therapeutically effective amount of famotidine included in the dosage forms of the invention is between 5 mg and 200 mg, preferably 20 mg.

Oral dosage forms of the invention preferably in tablet form may comprise a pharmaceutically acceptable non-toxic inert carrier such as lactose, microcrystalline cellulose, starch, pre- gelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose and the like. Oral dosage forms of the invention may optionally comprise suitable binders, lubricants, disintegrating agents, flavoring agents, sweetening agents, coloring agents and coating agents. Suitable binders of the invention may be selected from starches, natural sugars, corn sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, PVP, polyethylene glycols, waxes, sodium alginate, alcohols, water and the like. Suitable lubricants of the invention may be selected from metallic stearates, metallic lauryl sulfates, fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable oils, polyethylene glycols, boric acid, sodium benzoate, sodium acetate, sodium chloride, talk and the like. Suitable disintegrating agents of the invention may be selected from starches, cellulose derivatives, PVP, crospovidone, clays, ion-exchange resins, , sodium alginate and the like. Suitable coating agents of the invention may be selected from hydroxypropylmethylcellulose as a film coating agent, PEG 400 as a plasticizer, titanium dioxide and iron oxide as coloring agents.

The present invention may comprise an injectable unit dosage form for intravenous, intramuscular or subcutaneous administration formulated as aqueous or non-aqueous solution or suspension, or as powder for injection, with suitable pharmaceutically acceptable non-toxic excipients.

The present invention may also comprise extended, modified or controlled release (controlled, prolonged, sustained, immediate, timed, slow or fast release) tablet or capsule to provide the control of the release of the active components, preferably thiocolchicoside and/or etodolac and/or famotidine in order to optimize the therapeutic effects and minimize the undesirable side effects.

Pharmaceutical compositions of the inventions are used in the treatment of muscular and skeletal system diseases as well as inflammation and pain; and have reduced gastrointestinal side effects. Pharmaceutical compositions of the inventions may be administered once or twice a day in unit doses.

Examples

Pharmaceutical compositions of the inventions

Table 1: Film tablet Preparation methods of thepharmaceutical compositions of the inventions

1. Preparation method wherein the active components are not directly mixed

At the first stage, a certain amount of PVP (K-30) is dissolved in purified water. Etodolac, remaining amount of PVP (K-30), lactose, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide are mixed together. The obtained mixture is wet-granulated with the PVP (K-30) solution. Granules so-obtained are dried and pass through the dry granulator.

At the second stage, thiocolchicoside and famotidine are added to the granules obtained in the first stage. Suitable mixing is applied. Final mixture is obtained by the addition of magnesium stearate to the mixture. After the tablets are pressed, they are film-coated.

2. Preparation method wherein the active components are directly mixed

A certain amount of PVP (K-30) is dissolved in purified water. Etodolac, thiocolchicoside, famotidine, remaining amount of PVP (K-30), lactose, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide are mixed together. The obtained mixture is wet- granulated with the PVP (K-30) solution. Granules so-obtained are dried and pass through the dry granulator. Final mixture is obtained by the addition of magnesium stearate to the mixture. After the tablets are pressed, they are film-coated.

Tablets prepared by the processes of the invention have not met any stability problems during long term stability studies performed at 25 ± 2 °C and 60 ± 5 % RH across a 0-, 3- and 6- month follow-up period; and accelerated stability studies performed at 40 ± 2 °C and

75 ± 5 % RH across a 0-, 3- and 6-month follow-up period.

The extent of the invention should not be limited by the examples. The examples above are only given to illustrate the invention. CLAIMS

1. A pharmaceutical composition for use in the treatment of muscular and skeletal system diseases, inflammation and pain in mammalian organism and adapted for unit administration, wherein the pharmaceutical composition comprises a) a muscle relaxant; b) an NSAID; c) a gastroprotectant; and d) at least one pharmaceutically acceptable non-toxic carrier.

2. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises thiocolchicoside or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as muscle relaxant.

3. Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a drug selected from an acetic acid derivative, a propionic acid derivative, an enolic acid derivative, a fenamic acid derivative, a COX-2 inhibitor, a salicylate and other NSAI drugs as NSAID. 4. Pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises a drug selected from etodolac, ketorolac, diclofenac, indomethacin, sulindac and nabumeton as acetic acid derivative. 5. Pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises etodolac or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as acetic acid derivative. 6. Pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises a drug selected from ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and loxoprofen as propionic acid derivative. 7. Pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises a drug selected from piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam as enolic acid derivative. 8. Pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises a drug selected from mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid as fenamic acid derivative. 9. Pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises a drug selected from celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib and etoricoxib as COX-2 inhibitor. 10. Pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises a drug selected from acetylsalicylic acid, salsalate and diflunisal as salicylate. 1. Pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises a drug selected from nimesulide and licofelone as other NSAI drugs.

1 . Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a drug selected from an H2-receptor antagonist, a proton pump inhibitor, an antiacid or a prostaglandin as gastroprotectant. 13. Pharmaceutical composition according to claim 12, wherein the pharmaceutical composition comprises a drug selected from famotidine, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine as H2-receptor antagonist. 14. Pharmaceutical composition according to claim 13, wherein the pharmaceutical composition comprises famotidine or a pharmaceutically acceptable salt thereof as H2-receptor antagonist. 15. Pharmaceutical composition according to claim 12, wherein the pharmaceutical composition comprises a drug selected from omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole and leminoprazole as proton pump inhibitor. 16. Pharmaceutical composition according to claim 12, wherein the pharmaceutical

composition comprises a drug selected from CaC0 3, MgC0 3, Mg(OH)2, Al(OH)3,

NaHC0 3 and KHC0 3 as antiacid. 17. Pharmaceutical composition according to claim 12, wherein the pharmaceutical composition comprises a drug selected from misoprostol and enprostil as prostaglandin. 18. A pharmaceutical composition for use in the treatment of muscular and skeletal system diseases, inflammation and pain in mammalian organism and adapted for unit administration, wherein the pharmaceutical composition comprises a) thiocolchicoside or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as muscle relaxant; b) etodolac or a pharmaceutically acceptable salt thereof or any therapeutically active optically pure stereoisomer thereof as NSAID; c) famotidine or a pharmaceutically acceptable salt thereof as gastroprotectant; and d) at least one pharmaceutically acceptable non-toxic carrier. 19. Pharmaceutical composition according to claim 1 or 18, wherein the pharmaceutical composition comprises thiocolchicoside in an amount of from 4 to 16 mg, etodolac in an amount of from 200 to 1200 mg and famotidine in an amount of from 5 to 200 mg. 20. Pharmaceutical composition according to claim 1 or 18, wherein the pharmaceutical composition comprises thiocolchicoside in an amount of 8 mg, etodolac in an amount of 400 mg and famotidine in an amount of 20 mg. 21. Pharmaceutical composition according to claim 1 or 18, wherein the pharmaceutical composition is adapted for oral, buccal, ocular, otic, rectal, topical, implantal, mucosal, parenteral, sublingal, nasal and pulmonary administration of the pharmaceutical dosage form. 22. Pharmaceutical composition according to claim 21, wherein the pharmaceutical composition is adapted for oral administration of the pharmaceutical dosage form. 23. Pharmaceutical composition according to claim 1 or 18, wherein the pharmaceutical composition is adapted to be in the form of gel, cream, ointment, tablet, capsule, drop, pellet, granule, solution, suspension, syrup, powder, injectable suspension, injectable powder and injectable solution. 24. Pharmaceutical composition according to claim 23, wherein the pharmaceutical composition is adapted to be in the form of tablet. 25. Pharmaceutical composition according to claim 1 or 18, wherein the pharmaceutical composition is adapted to provide controlled, prolonged, sustained, immediate, timed, slow and fast release of the active components. 26. Pharmaceutical composition according to claim 1 or 18, wherein the pharmaceutical composition is adapted to be administered once and twice a day in unit doses. 27. Preparation process of the pharmaceutical composition according to claim 1 or 18, wherein the process comprises the steps of - at the first stage, dissolving a certain amount of PVP (K-30) in purified water; mixing etodolac, remaining amount of PVP (K-30), lactose, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide together; wet- granulating the obtained mixture with the PVP (K-30) solution; drying the granules so-obtained and passing the granules through the dry granulator; and - at the second stage, adding thiocolchicoside and famotidine to the granules obtained in the first stage; applying suitable mixing; obtaining final mixture by the addition of magnesium stearate to the mixture; pressing and film-coating the tablets. 28. Preparation process of the pharmaceutical composition according to claim 1 or 18, wherein the process comprises the steps of dissolving a certain amount of PVP (K-30) in purified water; mixing etodolac, thiocolchicoside, famotidine, remaining amount of PVP (K-30), lactose, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide together; wet-granulating the obtained mixture with the PVP (K-30) solution; drying the granules so-obtained and passing the granules through the dry granulator; obtaining final mixture by the addition of magnesium stearate to the mixture; pressing and film-coating the tablets. 29. Use of a pharmaceutical composition according to any one of the preceding claims in the treatment of muscular and skeletal system diseases, inflammation and pain in mammalian organism. A . CLASSIFICATION O F SUBJECT MATTER INV. A61K31/407 A61K31/426 A61K31/704 A61P19/00 A61P21/00 ADD.

According to International Patent Classification (IPC) or to both national classification and IPC

B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , BIOSIS, EMBASE, WPI Data, CHEM ABS Data

C . DOCUMENTS CONSIDERED TO B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

FI LALI K ET AL: "The case of a chroni c 1-3 ,6, l ow back pai n treatment" , 12 , 15 , ACTUALITES PHARMACEUTIQUES 2002 FR, 2 1 ,22 no. 413 , 2002 , pages 37-40, XP9163705 , ISSN : 0515-3700 Ordonnance n° 2 1-29

FR 2 735 369 Al (SYNTHELABO [FR] ) 1-4, 20 December 1996 (1996-12-20) 21-26 the whol e document 1-29 page 2 , l i nes 21-25 c l aims 1, 4

W0 2010/120253 Al (MUSTAFA NEVZAT I LAC 1-29 SANAYI I A [TR] ; PISAK IBRAHIM MUSTAFA ISKENDER [TR) 2 1 October 2010 (2010-10-21) the whol e document c l aim 28

-/--

X| Further documents are listed in the continuation of Box C . X I See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance "E" earlier application or patent but published o n or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" documentwhich may throw doubts on priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

17 October 2012 24/10/2012

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Col l ura, Al essandra C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2009/092819 Al (DUO GE [FR] ; LUGRIN 1-29 ANNE-EMMANUELLE [FR] ; GRISCELLI CLAUDE [FR] ; EL GL) 30 July 2009 (2009-07-30) page 12 ; c l aim 20

EP 1 992 333 Al (SANOVEL I LAC SANAYI VE 1-29 TI CARET [TR] ) 19 November 2008 (2008-11-19) c l aims 9 , 12

US 2005/163847 Al (CHENG XIU X [US] ET AL) 1-29 28 July 2005 (2005-07-28) c l aims 1, 5-12

FR 2 725 134 Al ( LEDERLE LAB [FR] ) 1-29 5 Apri l 1996 (1996-04-05) c i ted i n the appl i cati on the whol e document Patent document Publication Patent family Publication cited in search report date member(s) date

FR 2735369 Al 20-12-1996 AT 216246 T 15-05-2002 DE 69620761 Dl 23-05-2002 EP 0837684 Al 29-04-1998 ES 2175104 T3 16-11-2002 FR 2735369 Al 20-12-1996 PT 837684 E 30-09-2002 WO 9641635 Al 27-12-1996

WO 2010120253 Al 21-10-2010 T R 200903036 A2 21-06-2010 WO 2010120253 Al 21-10-2010

WO 2009092819 Al 30-07-2009 AU 2009207580 Al 30-07-2009 CA 2713197 Al 30-07-2009 CN 101969933 A 09-02-2011 EP 2249815 Al 17-11-2010 P 2011510049 A 31-03-2011 RU 2010135514 A 27-02-2012 US 2011027356 Al 03-02-2011 WO 2009092819 Al 30-07-2009

EP 1992333 Al 19-11-2008 EP 1992333 Al 19-11-2008 T R 200703092 Al 22-12-2008 US 2008279933 Al 13-11-2008

US 2005163847 Al 28-07-2005 US 2005163847 Al 28-07-2005 US 2007237820 Al 11-10-2007

FR 2725134 Al 05-04-1996 NONE