Title of Invention	AN ANTISPASMODIC AND AN ANALGESIC ANTIPYRETIC WITH AN ANTI-INFLAMMATORY AND ANALGESIC COMBINATION AND TO A METHOD OF MAKING THE SAME
Abstract	Methods and composition are provided for effective relief of spasm. The composition comprises a synergistic formulation comprising an antispasmodic and at least one analgesic and antipyretic and one analgesic/ anti-inflamatory agent in an orally administrable dosage form. Methods of making the same are also disclosed. The composition contains Camylofin Dihydrochloride as the antispasmodic agent, Paracetamol as one analgesic and antipyretic and Nimesulide and Diclofenac may be the anti-inflammatory/ analgesic agents. The formulation mainly contains the combination of camylofin and paracetamol with either one of the above-mentioned analgesic/anti-inflammatory drugs [NSAIDs] in an orally administrable form and the method of making the same is disclosed.

Title of Invention

AN ANTISPASMODIC AND AN ANALGESIC ANTIPYRETIC WITH AN ANTI-INFLAMMATORY AND ANALGESIC COMBINATION AND TO A METHOD OF MAKING THE SAME

Abstract

Methods and composition are provided for effective relief of spasm. The composition comprises a synergistic formulation comprising an antispasmodic and at least one analgesic and antipyretic and one analgesic/ anti-inflamatory agent in an orally administrable dosage form. Methods of making the same are also disclosed. The composition contains Camylofin Dihydrochloride as the antispasmodic agent, Paracetamol as one analgesic and antipyretic and Nimesulide and Diclofenac may be the anti-inflammatory/ analgesic agents. The formulation mainly contains the combination of camylofin and paracetamol with either one of the above-mentioned analgesic/anti-inflammatory drugs [NSAIDs] in an orally administrable form and the method of making the same is disclosed.

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 SAN JEEV KHANDELWAL An Indian National of Prem Nivas, 13, Altamount Road, Mumbai 400 026, Maharashtra, India, THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER 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 combined with an anti pyretic Paracetamol and with an analgesic selected from either one of two active pharmaceutical ingredients Diclofenac and Nimesulide. The fixed dose combination of Camylofin dihydrochloride, combinws with either of two analgesics Diclofenac and Nimesulide and an antipyretic Paracetamol, produce a synergistic response in the effective relief of spasm accompanied with fever. In particular this invention envisages a film coated tablet formulation for oral composition containing Camylofin dihydrochloride, combined with paracetamol and either of two of ingredients , 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 canmylofin hydrochloride, camylofin citrate, camylofin sodium or any other steriochemical pure form of it. Therapeutic effective amount of Paracetamol used in the formulation is in its pure form as a white, odorless, crystalline powder. 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 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. 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, paracetamol and one analgesic - 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) 250 to 500 mg of paracetamol (c) 10 mg to 75 mg of Diclofenac or 50 to 200 mg of nimesulide (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. 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 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, 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 65 [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, 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 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 64 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 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 Paracetamol 325 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 1.2%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: Making the nimesulide and paracetamol granules 10.0 Kg of nimesulide, 32.5 kg of paracetamol, 6.0 kg of microcrystalline cellulose and 0.2 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 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. 600 gms of povidone was mixed with 6 Kg of isopropyl alcohol 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 2%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 3: Lubrication Through a vibro sifter of mesh size 40 meshes the following materials were passed: 1.4 kg dried maize starch, 2.0 kg of pregelatinized starch, 0.8 kg of talcum, and 0.6 kg of magnesium stearate. This sifted mass (except magnesium stearate) along with the dried granules of Camylofin and other actives 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 - 4: 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: capsule shaped, Standard curvature, with following dimension Length: 19.0 + 0.1 mm Width: 8.0 ±0.1 mm Average weight of core 719 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. Pre-coating solution: A pre-coating solution is prepared by dispersing 0.400 kg of ethyl cellulose and 0.200 kg of hydroxymethyl cellulose in 4.00 kg of isopropyl alcohol followed by addition of 6.0 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 ethyl cellulose and 0.10 kg of hydroxypropyl cellulose and mixed together with 9 kg of isopropyl alcohol and 15 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: capsule shaped, Standard curvature, with following dimension Length: 19.2 ±0.1 mm Width: 8.2 ±0.1 mm Average weight of core 736 mg + 3 %. EXAMPLE - 2 Each tablet contains: Camylofin Dihydrochloride 25 mg Diclofenac sodium 50 mg Paracetamol 325 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 grartules 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, 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. 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 paracetamol granules 32.50 Kg of paracetamol, 4.0 kg of microcrystalline cellulose, 5.0 kg of starch 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 2.5 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 1.2 kg cross povidone, 1.0 kg of microcrystalline cellulose, 0.100 kg of colloidal silicon dioxide, 0.8 kg of talcum and 0.8 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: capsule shaped, Standard curvature, with following dimension Length; 19.0 ±0.1 mm Width: 8.0 + 0.1 mm Average weight of core 673 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 0.40 kg of ethyl cellulose and 0.200 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, 0.02 kg of red iron oxide 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: capsule shaped, Standard curvature, with following dimension Length: 19.1 ±0.1 mm Width: 8.1 ±0.1 mm Average weight of core 688 mg ± 3 %. EXAMPLE -3 Each tablet contains: Camylofin Dihydrochloride 25 mg Paracetamol 250 mg Nimesulide 50 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step -1: Making the camylofin granules 2.5 Kg of Camylofin dihydrochloride, 6.0 kg of microcrystalline cellulose, 2.0 kg of dibasic calcium phosphate and 0.1 kg of fume silica 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 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 22 minutes at 12 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 heat 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 1.8%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: Mmaking the nimesulide and paracetamol granules 5.0 Kg of nimesulide, 25.0 kg of paracetamol, 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 beiow 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. 300 gms of hydroxy propyl cellulose was mixed with 6 Kg of isopropyl alcohol 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. 4306 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 2.2 %. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 3: Lubrication Through a vibro sifter of mesh size 40 meshes the following materials were passed: 1.2 kg polarcrin potassium, 0.8 kg of talcum, and 0.6 kg of stearic acid. This sifted mass (except stearic acid and talcum) along with the dried granules of Camylofin and other active 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 remaining blend of stearic acid and talcum; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass. Step - 4: 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: capsule shaped, Standard curvature, with following dimension Length: 14.0 ±0.1 mm Width: 6.0 ±0.1 mm Average weight of core 477 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. Pre-coating solution: A pre-coating solution is prepared by dispersing 0.300 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 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 0.2 kg of ethyl cellulose and 0.40 kg of hydroxypropyl cellulose and mixed together with 9 kg of isopropyl alcohol and 15 kg of Methylene chloride; 0.01 kg of triethyl citrate, 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: capsule shaped, Standard curvature, with following dimension Length: 14.2 + 0.1 mm Width: 6.2 ±0.1 mm Average weight of core 476 mg ± 3 %. EXAMPLE - 4 Each tablet contains: Camylofin Dihydrochloride 25 mg Diclofenac potasium 25 mg Paracetamol 250 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 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 1.6%. 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, 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. 400 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 paracetamol granules 25.0 Kg of paracetamol, 3.0 kg of microcrystalline cellulose, 2.5 kg of starch 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 2.5 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. 64 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 1.0 kg croscarmeliose sodium, 0.8 kg of microcrystalline cellulose, 0.100 kg of colloidal silicon dioxide, 0.6 kg of talcum and 0.6 kg of magnesium stearate were sifted through 40 # sieve. Sifted mass (except calcium 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 calcium 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: capsule shaped, Standard curvature, with following dimension Length: 16.0 ±0.1 mm Width: 9.0 ±0.1 mm Average weight of core 528 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 0.30 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 triacine 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 0.5 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, 0.02 kg of red iron oxide 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: capsule shaped, Standard curvature, with following dimension Length: 16.1 ±0.1 mm Width: 9.1 ±0.1 mm Average weight of core 536 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. Some patients were administered paracetamol, nimesulide and diclofenac separately and tablets of the above said formulation were given to some patients having the above indications. Significant results were obtained for the formulation of this invention over separate dose of paracetamol or nimesulide or diclofenac in different patients. Unexpectedly, the relief was obtained significantly earlier [perceived to be at least 15 to 30 minutes earlier] and was more satisfactory [perceived to be at least 15% better]. In addition the single dosage form of the two active ingredients improved patient compliance as well as the cost of manufacture. I Claim: [1] A synergistic formulation for the relief of spasmodic pain accompanied by fever, comprising a combination of (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 250 to 500 mg of paracetamol (c) 10 mg to 75 mg of Diclofenac or 50 to 200 mg of nimesulide (d) Pharmaceutically acceptable inert excipients (e) a pharmaceutical acceptable carrier. [2] A synergistic formulation for the relief of spasmodic pain accompanied by fever, as claimed in claim 1, comprising (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 250 to 500 mg of paracetamol (c) 50 mg to 200 mg of nimesulide or 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 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 accompanied by fever, 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. [4] A synergistic formulation for the relief of spasmodic pain accompanied by fever, 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 accompanied by fever, as claimed in claim 2, in which the disintegrant is at least one disintegrant selected from a group of disintegrants 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 accompanied by fever, as claimed in claim 2, in which the glidant is at least one glidant selected from a group of glidants comprising com starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures of these. [7] A synergistic formulation for the relief of spasmodic pain accompanied by fever, 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 accompanied by fever, 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 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 giycerides 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, 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. [9] A synergistic formulation for the relief of spasmodic pain accompanied by fever, 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, brillant blue etc, and solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and an opacifier such as titanium dioxide. [10] A process for making a synergistic formulation for the relief of spasmodic pain accompanied by fever, 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 diclofenac salt or nimesulide and paracetamol together with excipients in a similar way as in steps [b] to [gj to obtain uniformly sized granules of diclofenac salt or nimesulide and paracetamol respectively;. [i] lubricating all the granules collectively by passing the uniformly sized dried granules to a double cone blender together 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 to obtain the formulation.

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
SAN JEEV KHANDELWAL
An Indian National
of Prem Nivas, 13, Altamount Road, Mumbai 400 026,
Maharashtra, India,

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES

THE INVENTION AND THE MANNER 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 combined with an anti pyretic Paracetamol and with an analgesic selected from either one of two active pharmaceutical ingredients Diclofenac and Nimesulide.
The fixed dose combination of Camylofin dihydrochloride, combinws with either of two analgesics Diclofenac and Nimesulide and an antipyretic Paracetamol, produce a synergistic response in the effective relief of spasm accompanied with fever.
In particular this invention envisages a film coated tablet formulation for oral composition containing Camylofin dihydrochloride, combined with paracetamol and either of two of ingredients , 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 canmylofin hydrochloride, camylofin citrate, camylofin sodium or any other steriochemical pure form of it.
Therapeutic effective amount of Paracetamol used in the formulation is in its pure form as a white, odorless, crystalline powder.
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 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.
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, paracetamol and one analgesic - 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) 250 to 500 mg of paracetamol
(c) 10 mg to 75 mg of Diclofenac or 50 to 200 mg of nimesulide
(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.
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 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, 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
65
[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, 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 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
64

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 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
Paracetamol 325 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 1.2%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized
camylofin granules.
Step 2: Making the nimesulide and paracetamol granules
10.0 Kg of nimesulide, 32.5 kg of paracetamol, 6.0 kg of microcrystalline
cellulose and 0.2 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 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of
actives and the diluents resulted.
600 gms of povidone was mixed with 6 Kg of isopropyl alcohol 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 2%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size.
Step - 3: Lubrication
Through a vibro sifter of mesh size 40 meshes the following materials were
passed:
1.4 kg dried maize starch, 2.0 kg of pregelatinized starch, 0.8 kg of talcum, and
0.6 kg of magnesium stearate. This sifted mass (except magnesium stearate)
along with the dried granules of Camylofin and other actives 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 - 4: 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: capsule shaped, Standard curvature, with following dimension
Length: 19.0 + 0.1 mm
Width: 8.0 ±0.1 mm
Average weight of core 719 mg ± 3 %.
Step - 5: film - coating
The cores were coated with a film coating.
Pre-coating solution:
A pre-coating solution is prepared by dispersing 0.400 kg of ethyl cellulose and
0.200 kg of hydroxymethyl cellulose in 4.00 kg of isopropyl alcohol followed by
addition of 6.0 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 ethyl cellulose and
0.10 kg of hydroxypropyl cellulose and mixed together with 9 kg of isopropyl
alcohol and 15 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: capsule shaped, Standard curvature, with following dimension
Length: 19.2 ±0.1 mm
Width: 8.2 ±0.1 mm
Average weight of core 736 mg + 3 %.
EXAMPLE - 2
Each tablet contains:
Camylofin Dihydrochloride 25 mg
Diclofenac sodium 50 mg
Paracetamol 325 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 grartules 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, 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.

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 paracetamol granules
32.50 Kg of paracetamol, 4.0 kg of microcrystalline cellulose, 5.0 kg of starch
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 2.5 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
1.2 kg cross povidone, 1.0 kg of microcrystalline cellulose, 0.100 kg of colloidal
silicon dioxide, 0.8 kg of talcum and 0.8 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: capsule shaped, Standard curvature, with following dimension
Length; 19.0 ±0.1 mm
Width: 8.0 + 0.1 mm
Average weight of core 673 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 0.40 kg of ethyl cellulose and
0.200 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, 0.02 kg of red
iron oxide 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: capsule shaped, Standard curvature, with following dimension
Length: 19.1 ±0.1 mm
Width: 8.1 ±0.1 mm
Average weight of core 688 mg ± 3 %.
EXAMPLE -3
Each tablet contains:
Camylofin Dihydrochloride 25 mg
Paracetamol 250 mg
Nimesulide 50 mg
MANUFACTURING PROCESS (Batch Size: 1 lakh tablets)
Step -1: Making the camylofin granules
2.5 Kg of Camylofin dihydrochloride, 6.0 kg of microcrystalline cellulose, 2.0 kg of
dibasic calcium phosphate and 0.1 kg of fume silica 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 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 22 minutes at 12 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 heat 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 1.8%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized
camylofin granules.
Step 2: Mmaking the nimesulide and paracetamol granules
5.0 Kg of nimesulide, 25.0 kg of paracetamol, 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 beiow 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.
300 gms of hydroxy propyl cellulose was mixed with 6 Kg of isopropyl alcohol 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.
4306
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 2.2 %.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size.
Step - 3: Lubrication
Through a vibro sifter of mesh size 40 meshes the following materials were
passed:
1.2 kg polarcrin potassium, 0.8 kg of talcum, and 0.6 kg of stearic acid. This
sifted mass (except stearic acid and talcum) along with the dried granules of
Camylofin and other active 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 remaining blend of stearic acid and talcum; was then
added to the blender and further blending was done for 5 minutes resulting in the
lubricated core mass.
Step - 4: 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: capsule shaped, Standard curvature, with following dimension
Length: 14.0 ±0.1 mm
Width: 6.0 ±0.1 mm
Average weight of core 477 mg ± 3 %.
Step - 5: film - coating
The cores were coated with a film coating.
Pre-coating solution:
A pre-coating solution is prepared by dispersing 0.300 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 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 0.2 kg of ethyl cellulose and
0.40 kg of hydroxypropyl cellulose and mixed together with 9 kg of isopropyl
alcohol and 15 kg of Methylene chloride; 0.01 kg of triethyl citrate, 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: capsule shaped, Standard curvature, with following dimension
Length: 14.2 + 0.1 mm
Width: 6.2 ±0.1 mm
Average weight of core 476 mg ± 3 %.
EXAMPLE - 4
Each tablet contains:
Camylofin Dihydrochloride 25 mg
Diclofenac potasium 25 mg
Paracetamol 250 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 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 1.6%.
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, 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.
400 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 paracetamol granules
25.0 Kg of paracetamol, 3.0 kg of microcrystalline cellulose, 2.5 kg of starch 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 2.5 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.
64
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
1.0 kg croscarmeliose sodium, 0.8 kg of microcrystalline cellulose, 0.100 kg of
colloidal silicon dioxide, 0.6 kg of talcum and 0.6 kg of magnesium stearate were
sifted through 40 # sieve. Sifted mass (except calcium 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 calcium 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: capsule shaped, Standard curvature, with following dimension
Length: 16.0 ±0.1 mm
Width: 9.0 ±0.1 mm
Average weight of core 528 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 0.30 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 triacine 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
0.5 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, 0.02 kg of red
iron oxide 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: capsule shaped, Standard curvature, with following dimension
Length: 16.1 ±0.1 mm
Width: 9.1 ±0.1 mm
Average weight of core 536 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. Some
patients were administered paracetamol, nimesulide and diclofenac separately
and tablets of the above said formulation were given to some patients having the

above indications. Significant results were obtained for the formulation of this invention over separate dose of paracetamol or nimesulide or diclofenac in different patients. Unexpectedly, the relief was obtained significantly earlier [perceived to be at least 15 to 30 minutes earlier] and was more satisfactory [perceived to be at least 15% better]. In addition the single dosage form of the two active ingredients improved patient compliance as well as the cost of manufacture.

I Claim:
[1] A synergistic formulation for the relief of spasmodic pain accompanied by fever, comprising a combination of
(a) 10 mg to 100 mg of camylofin dihydrochloride
(b) 250 to 500 mg of paracetamol
(c) 10 mg to 75 mg of Diclofenac or 50 to 200 mg of nimesulide
(d) Pharmaceutically acceptable inert excipients
(e) a pharmaceutical acceptable carrier.
[2] A synergistic formulation for the relief of spasmodic pain accompanied by fever, as claimed in claim 1, comprising
(a) 10 mg to 100 mg of camylofin dihydrochloride
(b) 250 to 500 mg of paracetamol
(c) 50 mg to 200 mg of nimesulide or 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
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 accompanied by fever, 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.
[4] A synergistic formulation for the relief of spasmodic pain accompanied by fever, 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 accompanied by fever, as claimed in claim 2, in which the disintegrant is at least one disintegrant selected from a group of disintegrants 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 accompanied by fever, as claimed in claim 2, in which the glidant is at least one glidant selected from a group of glidants comprising com starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures of these.
[7] A synergistic formulation for the relief of spasmodic pain accompanied by fever, 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 accompanied by fever, 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 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 giycerides 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, 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.
[9] A synergistic formulation for the relief of spasmodic pain accompanied by fever, 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, brillant blue etc, and solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and an opacifier such as titanium dioxide.
[10] A process for making a synergistic formulation for the relief of spasmodic pain accompanied by fever, 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 diclofenac salt or nimesulide and
paracetamol together with excipients in a similar way as in steps [b] to [gj to
obtain uniformly sized granules of diclofenac salt or nimesulide and
paracetamol respectively;.
[i] lubricating all the granules collectively by passing the uniformly sized dried
granules to a double cone blender together 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 to obtain the formulation.

Documents:

« Previous Patent

Next Patent »

Patent Number

206076

Indian Patent Application Number

788/MUM/2004

PG Journal Number

N/A

Publication Date

13-Apr-2007

Grant Date

17-Apr-2007

Date of Filing

23-Jul-2004

Name of Patentee

SANJEEV KHANDELWAL

Applicant Address

PREM NIVAS, 13, ALTAMOUNT ROAD, MUMBAI 400 026, MAHARASHTRA, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SANJEEV KHANDELWAL	PREM NIVAS, 13,ALTAMOUNT ROAD, MUMBAI 400 026, MAHARASHTRA, INDIA.

PCT International Classification Number

A61K 31/47

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA