Title of Invention	AN ANTISPASMODIC, NSAID AND ANTINFLAMMATORY ORAL TABLET AND MTHOD OF MAKING THE SAME
Abstract	A synergistic formulation for the relief of spasmodic pain comprising (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 50 mg to 200 mg of nimesulide (c) 10 mg to 75 mg of Diclofenac (d) Pharmaceutical^ acceptable inert excipients, and (e) pharmaceutical acceptable carriers.

Full Text

FORM - 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE Specification (See section 10 and rule 13) AN ANTISPASMODIC AND AN ANALGESIC ANTIPYRETIC WITH AN ANTI-INFLAMMATORY AND ANALGESIC COMBINATION AND TO A METHOD OF MAKING THE SAME SANJEEV KHANDELWAL An Indian National of Prem Nivas, 13, Altamount Road, Mumbai 400 026, Maharashtra, India, 2 4 MAY 2005 THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE ANNER IN WHICH IT IS TO BE PERFORMED:- FIELD OF INVENTION This invention relates to an antispasmodic and an analgesic antipyretic with an anti-inflammatory and analgesic combination and to a method of making the same. WHAT IS THE INVENTION INVISAGES This invention envisages a composition containing Camylofin dihydrochloride combining therewith two active pharmaceutical ingredients Diclofenac and Nimesulide to obtain a synergistaic formulation for the quick and effectice relief of spasmodic pain, fever and inflammation. The fixed dose combinatin of Camylofin dihydrochloride, combining with two active pharmaceutical ingredients including Diclofenac and Nimesulide produce a synergistic response in the effective relief of spasm. In particular this invention envisages a film coated tablet formulation for oral composition containing Camylofin dihydrochloride, combined with Diclofenac and Nimesulide. Therapeutic effective amount of Camylofin used in the formulation preferably as camylofin dihydrochloride or any pharmaceutically acceptable salt form it that may be such as camylofin hydrochloride, camylofin citrate, camylofin sodium or any other steriochemical pure form of it. Therapeutic effective amount of Diclofenac used in the formulation is preferably any pharmaceutically acceptable salt form that may be such as Diclofenac sodium, Diclofenac Potassium or any other pure form of it. The process wherein the diclofenac sodium used in the formulation is an enteric-coated granules form. Therapeutic effective amount of nimesulide used in the formulation is preferably nimesulide in its pure form or any pharmaceutically acceptable form. 2 The active materials in the formulation can be formulated within a dosage form wherein the active materials are mixed along with excipients to form an uniform blend and thereafter bound with suitable binder to form granules of the mixed active blend or at least one of the active drug can be coated with a suitable polymer for obtaining two different granular mass of each drug. DETAILED DESCRIPTION OF THE INVENTION The main feature of this invention is the use of active ingredients for making the oral dosage form of the formulation Camylofin dihydrochloride, along with the other active ingredients being an analgesic and anti-inflammatory agent in a single dosage form. The method for treating a patient comprises orally administering a pharmaceutical formulation comprising a combination of (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 50 mg to 200 mg of nimesulide (c) 10 mg to 75 mg of Diclofenac (d) Pharmaceutically acceptable inert excipients (e) A pharmaceutical acceptable carrier. According to this invention therefore there is provided a synergistic antispasmodic, analgesic, antipyretic formulation comprising a core consisting of pharmaceutical acceptable inert excipients consisting of at least one diluent 10% to 80% of the total mass of the formulation, at least one binder being 0.1% to 4% of the total mass of the formulation, at least one glidant from 0.01% to 3% of the total mass of the formulation, at least one lubricant being from 0.6% to 5% of the total mass of the formulation, optionally a surfactant being from 0.01% to 5% of the total mass of the formulation and at least one disintegrant being 0.6% to 8% of the total mass of the formulation and at least one film coat on the core consisting of at least one film forming polymer and a plasticizer 2 to 4 wt % based on the weight of the core composition. 3 The diluent may be any pharmaceutically acceptable inert material selected from the group consisting of micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures of these. The disintegrating agent in the formulation which will accelerate the dispersion of the active particles.is at least one compound selected from a group of compounds consisting of cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, polarcrin potassium resins, cellulose gum and mixtures of these. The binders in the formulation increases the bulk density of the active particles and make it easier to formulate in a compressed form, It is at least one compound selected from a group of compounds consisting of pregelatinized starch, starches, gelatin, vinyl chloride, povidone, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethuyl cellulose, waxes and mixture of these. The polymer for barrier coating granules includes, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethuyl cellulose phthalate, acrylate polymers and other suitable moisture protective and enteric coating polymers. The formulation preferably includes optionally one surfactant selected from the group consisting of sodium lauryl sulfate, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, hydrogenated or non-hydrogenated glycerolipids, ethoxylated or non-ethoxylated, linear or branched, saturated or mono- or polyunsaturated C.sub.6 to C.sub.30 fatty acids in the form of the acid or an alkali metal or its salt, cyclodextrin, sodium lauryl sulfate, alkaline earth metal or amine salt, ethoxylated or non-ethoxylated esters of sucrose, sorbitol, sorbitan monooleate, mannitol, glycerol or polyglycerol containing from 2 to 20 glycerol units, or glycol with said fattyacids, mono-, di- or triglycerides or mixtures of glycerides of said fatty acids, ethoxylated or non-ethoxlylated, linear or branched, saturated or mono- or polyunsafurafed (C.sub.6 to C.sub.30 fatty afcohofs, 4 cholesterol and derivatives thereof, other derivatives with a sterol skeleton, ethoxylated or non-ethoxylated ethers of sucrose, sorbitol, mannitol, glycerol or polyglycerol containing from 2 to 20 glycerol units, or glycol with said fatty alcohols, hydrogenated or non-hydrogenated, polyethoxylated vegetable oils, polyoxyethylene/ polyoxypropylene block polymers (poloxamers), polyethylene glycol hydroxystearate, sphingolipids and sphingosine derivatives, polyalkyl glucosides, ceramides, polyethylene glycol/alkyl glycol copolymers, and polyethylene glycol/polyalkylene glycol ether di-block or tri-block copolymers, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octoxinols, tyloxapol, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sucrose esters. The glidants in the formulation accelerate the flow of the granules at the time of tabletting or filling, is at least one compound selected from a group of compounds consisting of corn starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures of these. The formulation includes a lubricant, which reduces adhesion and ease release of the product, is at least one compound selected from a group of compounds includes magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, surfactants, talc, waxes and zinc stearate. 5 The coating layer of the formulation is preferably used to form a protective layer that will protect the formulation from moisture which includes film forming cellulose polymers such as Ethyl Cellulose and/ or hydroxypropylmethylcellulose, hydroxy propyl cellulose, plasticizers such as propylene glycol, surfactants, coloring agents that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brillant blue etc, solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and opacifier includes titanium dioxide. The weight of the film coating layer preferably 2 to 4 wt % based on the weight of the core composition may be employed. According to one aspect of this invention there is provided a process for making a synergistic antispasmodic, analgesic antipyretic formulation comprising the steps of [a] dissolving a dispensed quantity of binder in a solvent in a S.S. Container to form a first binder solution; [b] transferring dispensed quantities of sifted Camylofin Dihydrochloride and diluents, disintegrates in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing the Camylofin Dihydrochloride and diluents for 15 to 30 minutes at an ambient temperature below 25 degrees Celsius and relative humidity below 60%. to obtain a first uniform mass. [c] transferring the first binder solution slowly to the contents of planetary mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a first uniform dough is formed. [d] passing the first dough to a multimill fitted with sieves of diameter ranging from 10 mm to 14 mm at medium speed to produce wet granules of camylofin dihydrochloride; [e] transferring the wet camylofin dihydrochloride granules to a drier for drying at 50° C to 55° C [f] passing the dried camylofin dihydrochloride granules to 16-mesh sieve through vibrosifter and pass retained granules through multimill using 1.5mm screen at a 6 speed of 10 to 20 rpm to obtain dried uniformly sized granules of camylofin dihydrochloride; [g] dissolving a dispensed quantity of a second binder/ barrier coating polymer in second solvent in a S.S. container to form a second binder solution. [h] transferring dispensed quantities of sifted other active ingredients and excipients in a similar way as described above. [i] lubricating the granules by passing the uniformly sized dried active granules to a double cone blender to gether with dispensed quantities of sifted lubricants, glidants, and disintegrating agents and mixing for 10 to 20 minutes to obtain lubricated granules [j] compressing the lubricated granules at a compression pressure of 2 to 6 kg/sq cm . at Temperature between 20°C to 30°C and relative Humidity : Below 60% to form cores; [k] film coating the cores with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer. The weight of the total coating layer should be between 2.0 to 3.5 % of the total weight of the core. Following are few examples sited in accordance to the said formulation. But it is not intended that the scope of this invention is limited to these. EXAMPLE -1 Each tablet contains: Camylofin Dihydrochloride 25 mg Diclofenac Potassium 50 mg Nimesulide 100 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step -1: Making the camylofin granules 2.5 Kg of Camylofin dihydrochloride, 5.0 kg of microcrystalline cellulose, and 0.1 kg of colloidal silicondioxide were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 7 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted. 200 gms of methyl cellulose was mixed with 5 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.2%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the diclofenac potassium granules 5.0 Kg of diclofenac potassium, 4.0 kg of dibasic calcium phosphate were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. 200 gms of ethyl cellulose and 300 gms of cellulose acetate phthalate was mixed with 6 Kg of isopropyl alcohol and 3.0 kg of acetone in a stainless steel [s.s.] tank under continuous stirring until a clear solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. 8 The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.8%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step 3: making the nimesulide granules 10.0 Kg of nimesulide, 2.0 kg of microcrystalline cellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. The starch paste was prepared with 2.0 kgs of starch and purified water. The paste was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.6%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 4: Lubrication 1.2 kg sodium starch glycollate, 4.0 kg of microcrystalline cellulose, 0.100 kg of colloidal silicon dioxide and 0.6 kg of magnesium stearate were sifted through 40 # sieve. Sifted mass (except magnesium stearate) along with all dried granules were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of magnesium stearate; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass. 9 Step - 5: Compression This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: circular, Standard curvature, with diameter 11.0 ± 0.1 mm Average weight of core 372 mg ± 3 %. Step - 6: film - coating The cores were coated with a film coating. Pre-coating solution: A pre-coating solution is prepared by dispersing 0.250 kg of ethyl cellulose and 0.100 kg of hydroxymethyl cellulose in 3.50 kg of isopropyl alcohol followed by addition of 5.0 kg methylene chloride and 100 ml of propylene glycol with constant stirring till to obtain a uniform slurry. Seal-coating solution: A seal-coating suspension was prepared by mixing 0.6 kg of hydroxypropyl cellulose and mixed together with 7kg of isdpropyl alcohol and 12 kg of Methylene chloride; 0.01 kg of diethyl phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron oxide yellow, and stirred for five minutes using overhead stirrer until smooth slurry was obtained. The freshly prepared coating solution was sieved through 80-mesh sieve and sprayed one after another by following the usual method. The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: Dimension: circular, standard curvature, with 11.1 ±0.1 mm diameter Average weight of core 380 mg ± 3 %. EXAMPLE - 2 10 Each tablet contains: Camylofin Dihydrochloride 25 mg Diclofenac sodium 50 mg Nimesulide 100 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step -1: Making the camylofin granules 2.5 Kg of Camylofin dihydrochloride, 5.0 kg of microcrystalline cellulose, and 0.1 kg of colloidal silicondioxide were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted. 200 gms of ethyl cellulose was mixed with 5 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.6%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the diclofenac sodium granules 5.0 Kg of diclofenac sodium, 2.0 kg of dibasic calcium phosphate, 2.0 kg of microcrystalline cellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 11 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. 600 gms of cellulose acetate phthalate was mixed with 3 Kg of isopropyl alcohol and 6.0 kg of acetone in a stainless steel tank under continuous stirring until a clear solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.8%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step 3: making the nimesulide granules 10.0 Kg of nimesulide, 4.0 kg of microcrystalline cellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. The starch paste was prepared with 2.0 kgs of starch and purified water. The paste was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: 12 The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.6%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 4: Lubrication 1.1 kg of croscarmellose sodium, 4.0 kg of microcrystalline cellulose, 0.100 kg of colloidal silicon dioxide and 0.6 kg of magnesium stearate were sifted through 40 # sieve. Sifted mass (except magnesium stearate) along with all dried granules were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of magnesium stearate; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass. Step - 5: Compression This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: circular, Standard curvature, with diameter 11.0 ± 0.1 mm Average weight of core 392 mg ± 3 %. Step - 6: film - coating The cores were coated with a film coating. Pre-coating solution: A pre-coating solution is prepared by dispersing 0.250 kg of ethyl cellulose and 0.100 kg of hydroxymethyl cellulose in 3.50 kg of isopropyl alcohol followed by addition of 5.0 kg methylene chloride and 100 ml of propylene glycol with constant stirring till to obtain a uniform slurry. Seal-coating solution: A seal-coating suspension was prepared by mixing 0.3 kg of ethyl cellulose and 0.6 kg of hydroxypropyl cellulose and mixed together with 7kg of isopropyl alcohol and 12 kg of Methylene chloride; 0.01 kg of diethyl phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron oxide yellow, and stirred for five minutes using overhead stirrer until smooth slurry was obtained. 13 The freshly prepared coating solution was sieved through 80-mesh sieve and sprayed one after another by following the usual method. The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: Dimension: circular, standard curvature, with 11.1 ±0.1 mm diameter Average weight of core 402 mg + 3 %. EXAMPLE - 3 Each tablet contains: Camylofin Dihydrochloride 50 mg Diclofenac Potassium 25 mg Nimesulide 100 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step -1: Making the camylofin granules 5.0 Kg of Camylofin dihydrochloride, 6.0 kg of microcrystalline cellulose, 4.0 kg dibasic calcium phosphate and 0.1 kg of colloidal silicon dioxide were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 20 minutes at 20 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted. 300 gms of methyl cellulose was mixed with 6 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. 14 The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.2%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the diclofenac potassium granules 2.5 Kg of diclofenac potassium, 5.0 kg of dibasic calcium phosphate were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. 500 gms of cellulose acetate phthalate was mixed with 6 Kg of isopropyl alcohol and 3.0 kg of acetone in a stainless steel [s.s.] tank under continuous stirring until a clear solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.2%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step 3: making the nimesulide granules 10.0 Kg of nimesulide, 3.0 kg of microcrystalline cellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was 15 maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. The starch paste was prepared with 2.0 kgs of starch and purified water. The paste was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.5%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 4: Lubrication 0.9 kg croscarmellose sodium, 0.100 kg of colloidal silicon dioxide, 0.400 kg of talcum and 0.2 kg of hydrogenated castor oil were sifted through 40 # sieve. Sifted mass (except the blend of talcum and hydrogenated castor oil) along with all dried granules were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. The blend of talcum and hydrogenated castor oil was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass. Step - 5: Compression This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: circular, Standard curvature, with diameter 11.0 ± 0.1 mm Average weight of core 400 mg ± 3 %. Step - 6: film - coating The cores were coated with a film coating. Pre-coating solution: 16 A pre-coating solution is prepared by dispersing 0.150 kg of ethyl cellulose and 0.100 kg of hydroxymethyl cellulose in 3.50 kg of isopropyl alcohol followed by addition of 5.0 kg methylene chloride and 50 ml of polysorbate 80 with constant stirring till to obtain a uniform slurry. Seal-coating solution: A seal-coating suspension was prepared by mixing 0.1 kg of ethyl cellulose and 0.6 kg of hydroxypropyl cellulose and mixed together with 7kg of isopropyl alcohol and 12 kg of Methylene chloride; 50 ml of triethyl citrate, 0.05 kg of titanium dioxide in a s.s. Container, 0.01 kg of color tetrazine, and stirred for five minutes using overhead stirrer until smooth slurry was obtained. The freshly prepared coating solution was sieved through 80-mesh sieve and sprayed one after another by following the usual method. The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: Dimension: circular, standard curvature, with 11.1 ±0.1 mm diameter Average weight of core 410 mg ± 3 %. EXAMPLE - 4 Each tablet contains: Camylofin Dihydrochloride 50 mg Diclofenac sodium 50 mg Nimesulide 50 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step -1: Making the camylofin granules 5.0 Kg of Camylofin dihydrochloride, 4.0 kg of maize starch, 3.0 kg of dibasic calcium phosphate and 0.1 kg of fume silica were passed through a 40-mesh sieve 17 and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted. 100 gms of carnuba wax, 200 gms of polyvinyl pyrrolidone, 100 gms of ethyl cellulose were mixed with 5 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a rriultimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.2%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the diclofenac sodium granules 5.0 Kg of diclofenac sodium, 3.0 kg of dibasic calcium phosphate, 3.0 kg of microcrystalline cellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. 600 gms of cellulose acetate phthalate was mixed with 3 Kg of isopropyl alcohol and 6.0 kg of acetone in a stainless steel tank under continuous stirring until a clear solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mass. 18 Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.4%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step 3: making the nimesulide granules 5.0 Kg of nimesulide, 5.0 kg of microcrystalline cellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. The binder solution was prepared by adding 200 gms of polyvinyl pyrrolidone to 4.00 kg of purified water. This binder solution was then add to the planetary mixer with mixing. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.8 %. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 4: Lubrication 1.0 kg sodium starch glycollate, 3.0 kg of microcrystalline cellulose, 0.100 kg of colloidal silicon dioxide and 0.6 kg of zinc stearate were sifted through 40 # sieve. Sifted mass (except zinc stearate) along with all dried granules were transferred to 19 a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of magnesium stearate; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass. Step - 5: Compression This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: circular, Standard curvature, with diameter 11.0 ± 0.1 mm Average weight of core 400 mg ± 3 %. Step - 6: film - coating The cores were coated with a film coating. Pre-coating solution: A pre-coating solution is prepared by dispersing 0.200 kg of ethyl cellulose and 0.100 kg of hydroxymethyl cellulose in 4.00 kg of isopropyl alcohol followed by addition of 6.0 kg methylene chloride and 100 ml of tri ethyl citrate with constant stirring till to obtain a uniform slurry. Seal-coating solution: A seal-coating suspension was prepared by mixing 0.1 kg of ethyl cellulose and 0.4 kg of hydroxypropyl cellulose and mixed together with 7kg of isopropyl alcohol and 12 kg of Methylene chloride; 0.01 kg of diethyl phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron oxide yellow, and stirred for five minutes using overhead stirrer until smooth slurry was obtained. The freshly prepared coating solution was sieved through 80-mesh sieve and sprayed one after another by following the usual method. The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: 20 Dimension: circular, standard curvature, with 11.1 ±0.1 mm diameter Average weight of core 410 mg ± 3 %. EXAMPLE - 5 (MEDICAL TRIALS) Trials were conducted by administering the tablets of the above examples to patients suffering from spasmodic pain with slight fever and headache. Patients were divided into groups. One group of patients were administered nimesulide and diclofenac separately and another group was given tablets of the above said formulation in accordance with this invention having the above indications. Significant results were obtained for the formulation of this invention over separate dose of nimesulide or diclofenac in different patients. Unexpectedly, the relief was obtained significantly earlier [perceived to be at least 20 to 30 minutes earlier] and was more satisfactory [perceived to be at least 20% better]. In addition the single \dosage form of the two active ingredients improved patient compliance [25% Improvement} as well as the cost of manufacture [15% less]. A ^, , -,;:, 4; 21 I Claim: [1] A synergistic formulation for the relief of spasmodic pain comprising (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 50 mg to 200 mg of nimesulide (c) 10 mg to 75 mg of Diclofenac (d) Pharmaceutical^ acceptable inert excipients, and (e) pharmaceutical acceptable carriers. [2] A synergistic formulation for the relief of spasmodic pain, as claimed in claim 1, comprising (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 50 mg to 200 mg of nimesulide (c) 10 mg to 75 mg of Diclofenac (d) pharmaceutical acceptable inert excipients and carriers consisting of at least one diluent 10% to 80% of the total mass of the formulation, at least one binder being 0.1% to 4% of the total mass of the formulation, at least one glidant from 0.01% to 3% of the total mass of the formulation, at least one lubricant being from 0.6% to 5% of the total mass of the formulation, optionally a surfactant being from 0.01% to 5% of the total mass of the formulation and at least one disintegrant being 0.6% to 8% of the total mass of the formulation and (e) at least one film coat on the core consisting of at least one film forming polymer and a plasticizer 2 to 4 wt % based on the weight of the core composition. [3] A synergistic formulation for the relief of spasmodic pain, as claimed in claim 2, in which the diluent is at least one diluent selected from a group of diluents comprising micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures of these. 22 [4] A synergistic formulation for the relief of spasmodic pain, as claimed in claim 2, in which the binder is at least one binder selected from a group of binders comprising pregelatinized starch, starches, gelatin, vinyl chloride, povidone, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethuyl cellulose, waxes and mixture of these. [5] A synergistic formulation for the relief of spasmodic pain, as claimed in claim 2, in which the disintegrant is at least one disintegrant selected from a group of disintegfants comprising cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, polarcrin potassium resins, cellulose gum and mixtures of these. [6] A synergistic formulation for the relief of spasmodic pain, as claimed in claim 2, in which the glidant is at least one glidant selected from a group of glidants comprising corn starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures of these. [7] A synergistic formulation for the relief of spasmodic pain, as claimed in claim 2, in which the lubricant is at least one lubricant selected from a group of lubricants comprising magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, surfactants, talc, waxes and zinc stearate. [8] A synergistic formulation for the relief of spasmodic pain, as claimed in claim 2, in which the surfactant is at least one surfactant selected from a group of surfactants comprising sodium lauryl sulfate, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, hydrogenated or non-hydrogenated glycerolipids, ethoxylated or non-ethoxylated, linear or branched, saturated or mono- or polyunsaturated C.sub.6 to C.sub.30 fatty acids in the form of the acid or 23 an alkali metal or its salt, cyclodextrin, sodium lauryl sulfate, alkaline earth metal or amine salt, ethoxylated or non-ethoxylated esters of sucrose, sorbitol, sorbitan monooleate, mannitol, glycerol or polyglycerol containing from 2 to 20 glycerol units, or glycol with said fattyacids, mono-, di- or triglycerides or mixtures of glycerides of said fatty acids, ethoxylated or non-ethoxlylated, linear or branched, saturated or mono- or polyunsaturated (C.sub.6 to C.sub.30 fatty alcohols, cholesterol and derivatives thereof, other derivatives with a sterol skeleton, ethoxylated or non-ethoxylated ethers of sucrose, sorbitol, mannitol, glycerol or polyglycerol containing from 2 to 20 glycerol units, or glycol with said fatty alcohols, hydrogefiated or non-hydrogenated, polyethoxylated vegetable oils, polyoxyethylene/ polyoxypropylene block polymers (poloxamers), polyethylene glycol hydroxystearate, sphingolipids and sphingosine derivatives, polyalkyl glucosides, ceramides, polyethylene glycol/alkyl glycol copolymers, and polyethylene glycol/polyalkylene glycol ether di-block or tri-block copolymers, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octoxinols, tyloxapol, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sucrose esters. [9] A synergistic formulation for the relief of spasmodic pain, as claimed in claim 2, in which the film coat is composed of a film forming cellulosic polymer which is at least one polymer selected from a group of polymers comprising Ethyl Cellulose and/ or hydroxypropylmethylcellulose, hydroxy propyl cellulose, together with a plasticizer such as propylene glycol, surfactants, and optionally coloring agents that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brilliant-blue etc, and solvents such as purified water, 24 isopropyl alcohol, acetone, methylene chloride and an opacifier such as titanium dioxide. [10] A process for making a synergistic formulation as claimed in any one of the preceding claims comprising the steps of [a] dissolving a dispensed quantity of binder in a solvent to form a first binder solution; [b] transferring dispensed quantities of sifted Camylofin Dihydrochloride and diluents, disintegrants in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing the Camylofin Dihydrochloride and diluents for 15 to 30 minutes at an ambient temperature below 25 degrees Celsius and relative humidity below 60%. to obtain a first uniform mass; [c] transferring the first binder solution slowly to the first uniform mass and rotating the planetary mixer at slow speed for 10 to 20 minutes till a first uniform dough is formed; [d] passing the first uniform dough to a multimill fitted with sieves of diameter ranging from 10 mm to 14 mm at medium speed to produce wet granules of camylofin dihydrochloride; [e] transferring the wet camylofin dihydrochloride granules to a drier for drying at 50° C to 55° C [f] passing the dried camylofin dihydrochloride granules to 16-mesh sieve through vibrosifter and pass retained granules through multimill using 1.5mm screen at a speed of 10 to 20 rpm to obtain dried uniformly sized granules of camylofin dihydrochloride; [g] dissolving a dispensed quantity of a second binder/ barrier coating polymer in second solvent in a S.S. container to form a second and third binder solution. [h] transferring dispensed quantities of sifted other diclofenac salt and nimesulide and excipients in a similar way as in steps [b] to [g] to obtain uniformly sized granules of diclofenac salt and nimesulide respectively;, [i] lubricating the granules by passing the uniformly sized dried granules to a double cone blender together with dispensed quantities of sifted lubricants, 25 glidants, and disintegrating agents and mixing for 10 to 20 minutes to obtain lubricated granules 0] compressing the lubricated granules at a compression pressure of 2 to 6 kg/sq cm . at Temperature between 20°C to 30°C and relative Humidity : Below 60% to form cores; [k] film coating the cores with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer to obtain the formulation. Dated this 24th day of May, 2005. MOHAN DEWAN OF R.K.DEWAN & COMPANY APPLICANT'S PATENT ATTORNEY 26

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