Title of Invention

PHARMACEUTICAL COMPOSITION CONSISTING OF COX-II INHIBITOR AND MUSCLE RELAXANT

Abstract

Disclosed herein is pharmaceutical composition comprising of a COX-II inhibitor and a muscle relaxant in combination which is useful in the treatment of management of pain and pain related disorders and symptoms. Particularly the present invention discloses pharmaceutical composition comprising etoricoxib and tizanidine in combination in oral solid dosage form. Further the present invention discloses process for manufacture of the same.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule13) 1. TITLE OF THE INVENTION: "Pharmaceutical composition consisting of Cox-II inhibitor and muscle relaxant" 2. APPLICANT (a) NAME: LYKA LABS LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 7?, Nehru Road, Vile Parle(East), Mumbai - 400 099, Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical field: The present invention relates to a pharmaceutical composition comprising a COX-II inhibitor and a muscle relaxant in combination which is useful in the treatment of management of pain and pain related disorders and symptoms. Particularly the present invention relates to pharmaceutical composition comprising etoricoxib and tizanidine in combination in oral solid dosage form. Further the present invention relates to a process for manufacture of the same. Background and prior art: Pain and inflammation are conditions wherein quick relief is most desirable. Nonsteroidal anti-inflammatory drugs (NSAIDS) are the main drugs used for treatment of painful inflammatory joint conditions such as osteo arthritis (OA), rheumatoid arthritis, peri-arthritis, tennis elbow, frozen shoulder, etc. These conditions are characterized by pain, stiffness, restricted mobility of the affected joints etc. COX II inhibitors are a relatively new family of nonsteroidal anti-inflammatory drugs (NSAIDS). Though not necessarily more effective at reducing inflammation and pain than older, traditional nonsteroidal anti-inflammatory drugs, they are believed to cause less stomach irritation as compared to the older drugs. However, they are still classified as NSAIDS. NSAIDS are responsible for the anti-inflammatory and analgesic effects due to specific Cox- 2 inhibition. Etoricoxib is chemically known as 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'-bipyridine. The structural formula is given below. 2 Etoricoxib, a novel, highly selective cox-2 inhibitor has been recently approved for the treatment of osteo arthritis, rheumatoid arthritis and pain and the signs of inflammation associated with acute gouty arthritis. Tizanidine is used in multiple sclerosis to treat the increased muscle tone associated with spasticity. Even though, it does not provide a cure for the problem, it is designed to relieve the spasms, cramping and tightness of the muscle. Tizanidine is chemically known as 5-chloro-4-(2-imidazolin-2-ylamino)-2, 1,3-benzothiodiazole. US4515802 describes a process for the production of analgesic preparation comprising paracetamol and tizanidine in the form of tablets and suppositories. Transdermal systemic administration of pharmaceutical preparation comprising tizanidine is disclosed in EPO155229. Pharmaceutical compositions and dosage forms comprising tizanidine used for sublingual and buccal administration disclosed in US2004122065. WO2004058163 discloses pharmaceutical compositions comprising Cox-II inhibitor, with or without concomitant use of one or more anti Parkinson drugs for treating and methods of treating Parkinson's disease. Pharmaceutical composition and dosage form containing in combination a COX-II and a muscle relaxant is useful for the treatment of pain and pain related disorders and symptoms. EP1362585 discloses pharmaceutical compositions 3 containing Cox-II inhibitor selected from rofecoxib and celecoxib and a muscle relaxant such as prindinol. Etoricoxib is a potent Cox-II inhibitor and is commercially available in the market as oral dosage forms for the management of osteoarthritis, rheumatoid arthritis and acute gouty arthritis. Tizanidine hydrochloride is available in the market as oral dosage form for the treatment of musculoskeletal disorders. The present invention describes a pharmaceutical formulation comprising a combination of etoricoxib, a potential Cox-II inhibitor and tizanidine, a centrally acting muscle relaxant as an oral solid dosage form. This effective combination of a Cox-II and a muscle relaxant is to combat pain as well as to relax the muscle spasm. Objectives of the invention: The objective is to develop oral dosage form comprising in combination a COX-II inhibitor as etoricoxib and a muscle relaxant as tizanidine hydrochloride which is useful for the treatment of pain and pain related disorders and symptoms. Another objective is to develop bilayer tablets comprising of etoricoxib conventional release and sustained release tizanidine hydrochloride thus ensuring patient compliance to prescribed dosage regimen. Summary of the invention: The present invention discloses a pharmaceutical composition comprising Cox II Inhibitor as Etoricoxib, which is in the range of 60 to 120 mg, and muscle relaxant is Tizanidine hydrochloride equivalent to Tizanidine which is in the range of 2 to 6 mg with pharmaceutically acceptable excipients such as binders, diluents, lubricants, disintegrants, sustained release agents, glidant and colorants. 4 The binder is selected from Maize Starch, Povidone and the like. The concentration of binders is in the range of 1-8% total weight of the tablet. The lubricant is selected from the Magnesium Stearate, Colloidal Silicon Dioxide, and the like. The concentration of lubricant is in the range of 0.5 - 5% of the total weight of the tablet. The diluent is selected from the Lactose, Microcrystalline Cellulose, Maize Starch and the like. The concentration of said diluents is in the range of 10 -90 % of the total weight of the tablet. The glidant is selected from Talc, Colloidal Silicon Dioxide and the like. The concentration of glidant is in the range of 0.5 - 6% of the total weight of the tablet. The disintigrating agent is Croscarmellose Sodium. The concentration of disintegrating agent is in the range of 5- 25% of the total weight of the tablet. The Sustained Releasing Agent is selected from group of Hydroxy propyl Methyl Cellulose, (90SH 4000), (90SH 15000), Hydroxy Propyl Cellulose. The concentration of Sustained Releasing agent is in the range of 5% - 25%_of the total weight of the tablet. The concentraiton of colorant is in the range of 0.05 - 2% of the total weight of the tablet. The dosage form of the present composition is film coated tablet, bilayertablet, sustained relase bilayer tablet, capsules or pellets filled in capsules. Detailed description: The present invention provides a pharmaceutical formulation comprising of etoricoxib, a potential Cox-II inhibitor and tizanidine, a centrally acting muscle relaxant to combat the pain as well as to relieve muscle spasm. 5 An embodiment of the present invention provides a pharmaceutical composition comprising etoricoxib and tizanidine hydrochloride (120mg + 2mg) as film coated tablets which was prepared by wet granulation method. The said composition comprises etoricoxib and tizanidine hydrochloride along with pharmaceutically acceptable excipients selected from glidants, lubricants, diluents, binders, disintegrating agents and colourants. The process for the manufacture of the said film coated tablets comprises passing Etoricoxib and Tizanidine Hydrochloride through a suitable mesh sieve to obtain mixture A; passing Lactose, Microcrystalline cellulose and Croscarmellose sodium through a suitable mesh sieve to obtain mixture B; blending the said mixture A and mixture B; preparing starch- povidone paste by using Maize starch, Povidone K-30 and purified water; granulating the said blend by using starch povidone paste till wet mass of suitable consistency obtained; passing the said wet mass obtained through a suitable mesh sieve to obtain wet granules; drying the said granules in dryer at a suitable temperature for suitable period of time; passing the said dried granules through a suitable mesh sieve; passing Magnesium stearate, Talc, Colloidal Silicon Dioxide and Croscarmellose Sodium through a suitable mesh sieve and mixing with said dried granules to obtain lubricated granules; compressing the said Lubricated granules to obtain tablets and coating tablets with a non-aqueous coating formula to obtain orange coloured film coated tablets. Similarly following tablets can be prepared: Etoricoxib + Tizanidine (90mg + 2mg) Etoricoxib + Tizanidine (60mg + 2mg) Another embodiment of the invention provides pharmaceutical composition comprising of etoricoxib and tizanidine hydrochloride (120mg + 3mg) as bilayer tablet. The said composition comprises etoricoxib and tizanidine hydrochloride along with pharmaceutically acceptable excipients selected from glidants, lubricants, diluents binders, disintegrating agents and Colouring agents. 6 A process for manufacture of the above said bilayer tablet comprises following steps i) Preparing Etoricoxib granules in which Etoricoxib and Lactose was passed through suitable mesh sieve to obtain mixture A; Croscarmellose Sodium was passed through a suitable mesh sieve to obtain mixture B; Ingredients of mixture A and mixture B were blended together; Starch - povidone paste was prepared by using Maize Starch, Povidone K-30 and purified water; the said blend was granulated by using starch povidone paste till wet mass of suitable consistency is obtained; the said wet mass was passed through a suitable mesh sieve to obtain wet granules, the granules were dried in dryer at a suitable temperature for suitable period of time and the dried granules were passed through a suitable mesh sieve. Magnesium Stearate, Colloidal Silicon Dioxide, Talc and Croscarmellose Sodium were passed through a suitable mesh sieve and mixed with the said dried granules to obtain lubricated granules; ii) Preparing tizanidine granules^ Tizanidine Hydrochloride was passed through a suitable mesh sieve. Lactose, Microcrystalline cellulose and Croscarmellose sodium were passed through a suitable mesh sieve; Sunset yellow lake was passed through a suitable mesh sieve. Sifted tizanidine; lactose, Microcrystalline cellulose, Croscarmellose sodium and Sunset yellow lake were blended together; Starch - povidone paste was prepared by using Maize Starch, Povidone K-30 and purified water; The said blend was granulated by using starch-povidone paste till wet mass of suitable consistency was obtained; The said wet mass was passed through a suitable mesh sieve. The granules were dried in dryer at a suitable temperature for suitable period of time and the dried granules were passed through a suitable mesh sieve. Magnesium Stearate, Colloidal Silicon Dioxide, Talc and Croscarmellose Sodium were passed through a suitable mesh sieve and mixed with dried granules to obtain lubricated granules; 7 iii) Compressing the said lubricated granules of Etoricoxib and Tizanidine on a double rotary machine suitable for bilayer tablets to obtain bilayer tablets of which one layer comprises of Etoricoxib and other layer of Tizanidine. Similarly following bilayer tablets can be prepared: Etoricoxib + Tizanidine (90mg + 3mg) Etoricoxib + Tizanidine (60mg + 3mg) Another embodiment of the invention provides pharmaceutical composition comprising of etoricoxib conventional release and sustained release tizanidine hydrochloride (120mg + 6mg SR) as bilayer tablets. The said composition comprises etoricoxib and tizanidine hydrochloride along with pharmaceutically acceptable excipients selected from glidants, lubricants, diluents, binders, sustained release agent, colouring agents and disintegrating agents. The process for the manufacture of the said sustained release bilayer tablet comprises following steps: i) Preparing Tizanidine sustained release granules in which Tizanidine Hydrochloride was passed through a suitable mesh sieve; Lactose, Hydroxypropyl Methyl Cellulose (HPMC 90SH 4000) and Colloidal silicon dioxide were passed through a suitable mesh sieve; Erythrosine Lake was passed through a suitable mesh sieve; The sifted ingredients were mixed together to obtain uniform blend; Povidone solution was prepared in mixture of purified water and Isopropyl alcohol (2 : 1); the said blend was granulated by using povidone solution till wet mass of suitable consistency was obtained; the said wet mass obtained was passed through a suitable mesh sieve; the granules were dried in dryer at a suitable temperature for suitable period of time and the said dried granules were passed through a suitable mesh sieve; Magnesium stearate and colloidal Silicon Dioxide were passed through a suitable mesh sieve; the sifted lubricants were mixed with the said dried granules to obtain lubricated granules; 8 ii) Preparing Etoricoxib granules in which Etoricoxib and Lactose was passed through suitable mesh sieve; Croscarmellose Sodium was passed through a suitable mesh sieve; The sifted ingredients were mixed together to obtain uniform blend; Starch - povidone paste was prepared by using Maize Starch, Povidone K-30 and purified water; the said blend was granulated by using starch povidone paste till wet mass of suitable consistency was obtained; the said wet mass was passed through a suitable mesh sieve to get wet granules which were dried in dryer at a suitable temperature for suitable period of time and the said dried granules were passed through a suitable mesh sieve; Magnesium Stearate, Colloidal Silicon Dioxide, Talc and Croscarmellose Sodium were passed through a suitable mesh sieve and mixed with dried granules to obtain lubricated granules; iii) Compressing the said lubricated granules of Etoricoxib and Tizanidine on a double rotary machine suitable for bilayer tablets to obtain capsule shaped bilayer tablets of which one layer comprises of Etoricoxib and other layer of Tizanidine sustained release. Tizanidine sustained release Tablets showed satisfactory dissolution release profile for a period of 12 hours. Similarly the following bilayer tablets can be prepared: Etoricoxib and Tizanidine (120mg + 4mg SR) bilayer Tablets Etoricoxib and Tizanidine (90mg + 4mg SR) bilayer Tablets Etoricoxib and Tizanidine (60mg + 4mg SR) bilayer Tablets Similarly following bilayer tablets can be prepared by using a combination of HPMC K4M and HPMC K15M in which Tizanidine Sustained Release Tablets showed satisfactory dissolution release profile for a period of 24 hours. Etoricoxib and Tizanidine (120mg + 4mg SR) bilayer Tablets Etoricoxib and Tizanidine (90mg + 4mg SR) bilayer Tablets Etoricoxib and Tizanidine (60mg + 4mg SR) bilayer Tablets 9 Another embodiment of the invention provides Pharmaceutical composition comprising of Etoricoxib and Tizanidine hydrochloride granules filled in a hard gelatin capsules. The said composition comprises of Etoricoxib and Tizanidine Hydrochloride along with pharmaceutically acceptable excipients selected from glidants, lubricants diluents, binders and disintegrating agents. The process for the manufacture of the said capsules comprises of passing Etoricoxib and Tizanidine Hydrochloride through a suitable mesh sieve to obtain mixture A, passing Lactose and Crosscarmellose Sodium through a suitable mesh sieve to obtain mixture B, Blending the said mixture A and mixture B, preparing povidone paste by using Povidone K-30 and water; granulating the said blend by using povidone paste till wet mass of suitable consistency is obtained, passing the said wet mass through a suitable mesh sieve to obtain wet granules, drying the said granules in dryer at a suitable temperature for suitable period of time; passing the said dried granules through a suitable mesh sieve, passing Magnesium Stearate, Colloidal Silicon Dioxide and Croscarmellose Sodium through a suitable mesh sieve and mixing with dried granules to obtain lubricated granules, filling the lubricated granules in hard gelatin capsules. Yet another embodiment of the invention provides pharmaceutical composition comprising etoricoxib and tizanidine hydrochloride pellets filled in a hard gelatin capsules. The said composition comprises etoricoxib and tizanidine hydrochloride along with pharmaceutically acceptable excipients selected from glidants, lubricants, diluents and binders and disintegrating agents. The process for the manufacture of the said capsules comprises of passing Etoricoxib and Tizanidine Hydrochloride through a suitable mesh sieve to obtain mixture A, passing Lactose, Microcrystalline cellulose and Croscarmellose Sodium through a suitable mesh sieve to obtain mixture B, blending Mixture A and Mixture B; preparing povidone solution by using Povidone K-30 and purified 10 water granulating the said blend by using Povidone solution, till wet mass of suitable consistency is obtained passing the said wet mass through a extruder to obtain Extrudate which is then spherodized in a spherodizer to convert it into pellets. The said pellets are then dried and filled into hard gelatin capsules. The excipients used in all above embodiments are selected from binders, diluents, lubricants, sustained release agents, glidants and colorants. The said binders are selected from the group of Maize Starch, Povidone. The said lubricants are selected from the group of Magnesium Stearate, Colloidal Silicon Dioxide. The said diluents are selected from the group of Lactose, Microcrystalline Cellulose, Maize Starch. The said glidants are selected from Talc, Colloidal Silicon Dioxide. The said disintegrating agents is Croscarmellose Sodium. The said Sustained Releasing Agents are selected from Hydroxy propyl Methyl Cellulose (90SH 4000), Hydroxy propyl Methyl Cellulose (90SH 15000), Hydroxy Propyl Cellulose etc. The concentration of Etoricoxib is 60 - 120 mg tablet. The concentration of Tizanidine in terms of Tizanidine hydrochloride is 2-6 mg tablet. The concentration of the binders are 1-8% range of the total weight of the tablet. The concentration of the lubricants are 0.5 - 5% range of the total weight of the tablet. The concentration of the diluents are 10 -90 % range of the total weight of the tablet. The concentration of the colorants are in the range of 0.05 - 2% of the total weight of the tablet. The concentration of the glidants are in the range of 0.5 - 6% of the total weight of the tablet. The concentration of disintegrating agents is 5-25%. The concentration of Sustained Releasing agent is 5% - 25% The present invention is described herein with the following examples. 11 Example 1 ETORICOXIB 120mg AND TIZAMDINE 2mg FILM COATED TABLETS Sr.No. Ingredients Qty.(in mg/tablet) 1) Etoricoxib 120.000 mg 2) Tizanidine Hydrochloride equivalent to 2 mg of Tizanidine 2.288 mg 3) Lactose 31.712 mg 4) Microcrystalline cellulose 79.800 mg 5) Maize starch 8.000 mg 6) Povidone K-30 3.200 mg 7) Magnesium Stearate 3.000 mg 8) Talc 5.000 mg 9) Colloidal silicon dioxide 2.000 mg 10) Croscarmellose sodium 25.000 mg 11) Purified water q.s. PROCEDURE: STEP 1 Etoricoxib and Tizanidine Hydrochloride are Passed through a suitable mesh sieve. STEP 2 Lactose, Microcrystalline cellulose and Croscarmellose sodium are passed through a suitable mesh sieve. STEP 3 Ingredients of step 1 and step 2 are mixed together. STEP 4 Starch- povidone paste is prepared by using Maize starch, Povidone K-30 and purified water. STEP 5 12 The blend of step 3 is granulated by using starch povidone paste till wet mass of suitable consistency is obtained. STEP 6 The wet mass obtained in step 5 is passed through a suitable mesh sieve. STEP 7 The granules are dried in dryer at a suitable temperature for suitable period of time and the dried granules are passed through a suitable mesh sieve. STEP 8 Magnesium stearate, Talc, Colloidal Silicon Dioxide and Croscarmellose Sodium are passed through a suitable mesh sieve and mixed with dried granules of step 7 to obtain lubricated granules. STEP 9 The Lubricated granules are compressed to obtain tablets. STEP 10 The core tablets are then coated with a non-aqueous coating formula given below to obtain Orange coloured, film coated tablets. S.No. Ingredients % w/w 1. Hydroxy Propyl Methyl Cellulose 3.0 2. Diethyl Phthalate 0.45 3. PEG 4000 0.45 4. Talc 0.70 5. Titanium Dioxide 1.10 6. Methanol 46.0 7. Methylene Chloride 47.75 8. Sunset yellow Lake 0.55 Example 2 ETORICOXIB 120mg AND TIZANIDINE 3mg BILAYER TABLETS 13 ETORICOXIB GRANULES Sr.No. Ingredients Qty.(in mg/tablet) 1) Etoricoxib 120.00 mg 2) Lactose 21.56 mg 3) Croscarmellose sodium 30.00 mg 4) Maize Starch 4.60 mg 5) Povidone K-30 1.84 mg 6) Talc 4.00 mg 7) Magnesium Stearate 2.00 mg 8) Colloidal Silicon Dioxide 1.00 mg 9) Purified water q.s. TIZANIDINE GRANULES : Sr.No. Ingredients Qty.(in mg/tablet) 1) Tizanidine Hydrochloride equivalent to 3 mg of Tizanidine 3.432 mg 2) Lactose 29.000 mg 3) Microcrystalline Cellulose 75.218 mg 4) Croscarmellose sodium 10.000 mg 5) Sunset Yellow Lake 0.150 mg 6) Maize starch 3.000 mg 7) Povidone K-30 1.200 mg 8) Colloidal silicon dioxide 1.000 mg 9) Magnesium Stearate 1.000 mg 10) Talc 1.000 mg 11) Purified water q.s. PROCEDURE: I) ETORICOXIB GRANULES : STEP 1 Etoricoxib and Lactose is passed through suitable mesh sieve. 14 STEP 2 Croscarmellose Sodium is passed through a suitable mesh sieve. STEP 3 Ingredients of step 1 and step 2 are mixed together. STEP 4 Starch - povidone paste is prepared by using Maize Starch, Povidone K-30 and purified water. STEP 5 The blend of step 3 is granulated by using starch povidone paste till wet mass of suitable consistency is obtained. STEP 6 The wet mass obtained in step 5 is passed through a suitable mesh sieve. STEP 7 The granules are dried in dryer at a suitable temperature for suitable period of time and the dried granules are passed through a suitable mesh sieve. STEP 8 Magnesium Stearate, Colloidal Silicon Dioxide, Talc and Croscarmellose Sodium are passed through a suitable mesh sieve and mixed with dried granules of step 7 to obtain lubricated granules. II) TIZANIDINE GRANULES : STEP1 Tizanidine Hydrochloride is passed through a suitable mesh sieve. STEP 2 Lactose, Microcrystalline cellulose and Croscarmellose sodium are passed through a a suitable mesh sieve. STEP 3 Sunset yellow lake is passed through a suitable mesh sieve. STEP 4 Ingredients of step 1, step 2 and step 3 are mixed together. STEP 5 15 Starch - povidone paste is prepared by using Maize Starch, Povidone K-30 and purified water. STEP 6 The blend of step 4 is granulated by using starch- povidone paste till wet mass of suitable consistency is obtained. STEP 7 The wet mass obtained in step 6 is passed through a suitable mesh sieve. STEP 8 The granules are dried in dryer at a suitable temperature for suitable period of time and the dried granules are passed through a suitable mesh sieve. STEP 9 Magnesium Stearate, Colloidal Silicon Dioxide, Talc and Croscarmellose Sodium are passed through a suitable mesh sieve and mixed with dried granules of step 8 to obtain lubricated granules. Ill) COMPRESSION STEP1 The lubricated granules of Etoricoxib and Tizanidine granules are compressed on a double rotary machine suitable for bilayer tablets to obtain bilayer tablets of which one layer comprises of Etoricoxib and other layer of Tizanidine. Example 3 ETORICOXIB 120mg AND 6mg SR TIZANIDINE BILAYER TABLETS ETORICOXIB GRANULES Sr.No. Ingredients Qty.(in mg/tablet) 16 1) Etoricoxib 120.00 mg 2) Lactose 21.56 mg 3) Croscarmellose sodium 30.00 mg 4) Maize Starch 4.60 mg 5) Povidone K-30 1.84 mg 6) Talc 4.00 mg 7) Magnesium Stearate 2.00 mg 8) Colloidal Silicon Dioxide 1.00 mg 9) Purified water q.s. TIZANIDINE EXTENDED RELEASE GRANULES: Sr.No. Ingredients Qty.(in mg/tablet) 1) Tizanidine Hydrochloride equivalent to 6 mg of Tizanidine 6.864 mg 2) Lactose 74.986 mg 3) Colloidal Silicon Dioxide 1.500 mg 4) Hydroxypropyl Methyl Cellulose (HPMC 90SH 4000) 40.000 mg 5) Erythrosine Lake 0.150 mg 6) Povidone K-30 0.500 mg 7) Magnesium Stearate 1.000 mg 8) Isopropyl Alcohol q.s. 9) Purified water q.s. PROCEDURE: I) TIZANIDINE SUSTAINED RELEASE GRANULES : STEP 1 Tizanidine Hydrochloride is passed through a suitable mesh sieve. STEP 2 17 Lactose, Hydroxypropyl Methyl Cellulose (HPMC 90SH 4000) and Colloidal silicon dioxide are passed through a suitable mesh sieve. STEP 3 Erythrosine Lake is passed through a suitable mesh sieve. STEP 4 Ingredients of step 1, step 2 and step 3 are mixed together. STEP 5 Povidone solution is prepared in mixture of purified water and Isopropyl alcohol (2 : 1) STEP 6 The blend of step 4 is granulated by using povidone solution till wet mass of suitable consistency is obtained. STEP 7 The wet mass obtained in step 6 is passed through a suitable mesh sieve. STEP 8 The granules are dried in dryer at a suitable temperature for suitable period of time and the dried granales are passed through a suitable mesh sieve. STEP 9 Magnesium stearate and colloidal Silicon Dioxide are passed through a suitable mesh sieve. STEP 10 The sifted ingredients of step 9 are mixed with dried granules of step 8 to obtain lubricated granules. II) ETORICOXIB GRANULES ; 18 STEP 1 Etoricoxib and Lactose is passed through suitable mesh sieve. STEP 2 Croscarmellose Sodium is passed through a suitable mesh sieve. STEP 3 Ingredients of step 1 and step 2 are mixed together. STEP 4 Starch - povidone paste is prepared by using Maize Starch, Povidone K-30 and purified water. STEP 5 The blend of step 3 is granulated by using starch povidone paste till wet mass of suitable consistency is obtained. STEP 6 The wet mass obtained in step 5 is passed through a suitable mesh sieve. STEP 7 The granules are dried in dryer at a suitable temperature for suitable period of time and the dried granules are passed through a suitable mesh sieve. STEP 8 Magnesium Stearate, Colloidal Silicon Dioxide, Talc and Croscarmellose Sodium are passed through a suitable mesh sieve and mixed with dried granules of step 7 to obtain lubricated granules. Ill) COMPRESSION The lubricated granules of Etoricoxib and Tizanidine granules are compressed on a double rotary machine suitable for bilayer tablets to obtain capsule shaped bilayer tablets of which one layer comprises of Etoricoxib and other layer of Tizanidine sustained release. Tizanidine sustained release Tablets showed satisfactory dissolution release profile for a period of 12 hours. 19 Example 4 ETORICOXIB 120mg AND TIZANIDINE 2mg CAPSULES Sr.No. Ingredients Qty.(in mg/tablet) 1) Etoricoxib 120.000 mg 2) Tizanidine Hydrochloride equivalent to 2mg of Tizanidine 2.288mg 3) Lactose 63.712mg 4) Croscarmellose sodium 25.000mg 5) Povidone K-30 4.000 mg 6) Magnesium Stearate 3.000mg 7) Colloidal Silicon Dioxide 2.000 mg 8) Purified water q.s. Procedure : Etoricoxib and Tizanidine Hydrochloride were passed through a suitable mesh sieve to obtain mixture A. Lactose and Croscarmellose Sodium were passed through a suitable mesh sieve to obtain mixture B. Mixture A and Mixture B were blended. Povidione solution was prepared by using Povidone K-30 and purified water. The said blend was granulated using Povidone solution till wet mass of suitable consistency is obtained. The said wet mass is passed through a suitable mesh sieve to obtain wet granules. The granules were dried in dryer at a suitable temperature for suitable period of time. The dried granules were passed through a suitable mesh sieve. Magnesium Stearate and Colloidal Silicon Dioxide were passed through a suitable mesh sieve and mixed with said dried granules to obtain lubricated granules. The lubricated granules were filled in hard gelatin capsules. 20 Example 5 ETORICOXIB 120mg AND TIZANIDINE 2mg PELLETS IN CAPSULES Sr.No. Ingredients Qty.(in mg/tablet) 1) Etoricoxib 120.000 mg 2) Tizanidine Hydrochloride equivalent to 2mg of Tizanidine 2.288mg 3) Lactose 23.712mg 4) Microcrystalline cellulose 40.000mg 5) Croscarmellose sodium 25.000mg 6) Povidone K-30 4.000 mg 7) Purified water q.s. Procedure : Etoricoxib and Tizanidine Hydrochloride were passed through a suitable mesh sieve to obtain mixture A. Lactose and Croscarmellose Sodium were passed through a suitable mesh sieve to obtain mixture B. Mixture A and Mixture B were blended. Povidione solution was prepared by using Povidone K-30 and purified water. The said blend was granulated using Povidone solution till wet mass of suitable consistency is obtained. The said wet mass is passed through a extruder to obtain extrudate which is then spherodized in a spherodizer to convert then into pellets. The said pellets are then dried and filled into hard gelatin capsules. 21 claim: 1. A pharmaceutical composition comprising Cox II Inhibitor and muscle relaxant with pharmaceutically acceptable excipients such as binders, diluents, lubricants, disintegrating agent, sustained release agents, glidant and colorants. 2. The composition as claimed in claim 1, wherein said Cox II inhibitor is Etoricoxib used in the concentration range of 60-120mg. 3. The composition as claimed in claim 1, wherein said muscle relaxant is Tizanidine hydrochloride equivalent to Tizanidine used in the concentration range of 2 to 6mg. 4. The composition as claimed in claim 1, wherein said binders are selected from Maize Starch, Povidone and the like used in the range of 1-8% total weight of the tablet. 5. The composition as claimed in claim 1, wherein said lubricants are selected from the Magnesium Stearate, Colloidal Silicon Dioxide, and the like used in the range of 0.5 - 5% of the total weight of the tablet. 6. The composition as claimed in claiml, wherein said diluents are selected from the Lactose, Microcrystalline Cellulose, Maize Starch and the like used in the range of 10 -90 % of the total weight of the tablet.. 7. The composition as claimed in claim 1, wherein said glidant is selected from Talc, Colloidal Silicon Dioxide and the like used in the range of 0.5 - 6% of the total weight of the tablet.. 8. The composition as claimed in claiml, wherein said disintigrating agent is Croscarmellose Sodium used in the range of 5- 25% of the total weight of the tablet. 9. The composition as claimed in claim 1, wherein said Sustained Releasing Agent is selected from group of Hydroxy propyl Methyl Cellulose, (90SH 4000), (90SH 15000), Hydroxy Propyl Cellulose etc used in the range of 5% - 25% of the total weight of the tablet. 10. The composition as claimed in claim 1, wherein concentraiton of said colorant is in the range of 0.05 - 2% of the total weight of the tablet. 22 11. The composition as claimed in claim 1 ,wherein the dosage form is film coated tablet, bilayertablet, sustained relase bilayer tablet , capsules or pellets filled in capsules. 12. A pharmaceutical composition comprising Cox II Inhibitor and muscle relaxant as substantially described herein with reference to foregoing examples 1 to 5. Dated this 7th day of April 2005 23 ABSTRACT : Disclosed herein is pharmaceutical composition comprising of a COX-II inhibitor and a muscle relaxant in combination which is useful in the treatment of management of pain and pain related disorders and symptoms. Particularly the present invention discloses pharmaceutical composition comprising etoricoxib and tizanidine in combination in oral solid dosage form. Further the present invention discloses process for manufacture of the same. 24

Documents:

446-MUM-2005-ABSTRACT(3-11-2008).pdf

446-MUM-2005-ABSTRACT(7-4-2005).pdf

446-mum-2005-abstract(granted)-(29-5-2009).pdf

446-mum-2005-abstract.doc

446-mum-2005-abstract.pdf

446-MUM-2005-CLAIMS(3-11-2008).pdf

446-MUM-2005-CLAIMS(7-4-2005).pdf

446-mum-2005-claims(granted)-(29-5-2009).pdf

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446-MUM-2005-CORRESPONDENCE(3-11-2008).pdf

446-MUM-2005-CORRESPONDENCE(4-12-2006).pdf

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446-mum-2005-correspondence-received-05052005.pdf

446-mum-2005-correspondence-received-07042005.pdf

446-mum-2005-description (complete).pdf

446-MUM-2005-DESCRIPTION(COMPLETE)-(3-11-2008).pdf

446-MUM-2005-DESCRIPTION(COMPLETE)-(7-4-2005).pdf

446-mum-2005-description(granted)-(29-5-2009).pdf

446-MUM-2005-FORM 1(5-5-2005).pdf

446-MUM-2005-FORM 1(7-4-2005).pdf

446-MUM-2005-FORM 18(5-12-2006).pdf

446-mum-2005-form 2(3-11-2008).pdf

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446-mum-2005-form 2(granted)-(29-5-2009).pdf

446-MUM-2005-FORM 2(TITLE PAGE)-(3-11-2008).pdf

446-MUM-2005-FORM 2(TITLE PAGE)-(7-4-2005).pdf

446-mum-2005-form 2(title page)-(granted)-(29-5-2009).pdf

446-MUM-2005-FORM 3(3-11-2008).pdf

446-MUM-2005-FORM 3(7-4-2005).pdf

446-mum-2005-form-1.pdf

446-mum-2005-form-2.doc

446-mum-2005-form-2.pdf

446-mum-2005-form-26.pdf

446-mum-2005-form-3.pdf