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WO 2012/173581 Al 20 December 2012 (20.12.2012) P O P C T

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WO 2012/173581 Al 20 December 2012 (20.12.2012) P O P C T (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: THIOCOLCHICOSIDE, ETODOLAC AND FAMOTIDINE 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 muscle relaxant, 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 inflammation 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 colchicine 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 tablet. 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 analgesic 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 acetic acid. 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, carisoprodol + aspirin + codeine, methocarbamol + aspirin and orphenadrine + aspirin + caffeine) 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, bleeding and perforation; especially in case of high dose usage, long-term treatments, history of a gastrointestinal disease 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 Therapies: 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 ibuprofen 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 diclofenac 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 flurbiprofen and an alpha-2 adrenergic receptor agonist or a gamma-aminobutiric acid receptor agonist, particularly tizanidine and thiocolchicoside. International patent application WO201 0084500 Al (Sanofi-Synthelabo) relates to a combination in the form of a solid dosage form containing ketoprofen 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.
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