Title of Invention

AN ANTISPASMODIC AND AN ANALGESIC COMBINATION AND TO A METHOD OF MAKING THE SAME

Abstract

[1] A once a day synergistic formulation comprising an antispasmodic and an analgesic having (1) a core comprising (a) 50 mg to 200 mg of camylofin dihydrochloride in granule form in a sustained release polymer matrix, mass of the polymer matrix being 40 to 150 per cent of the mass of camylofin dihydrochloride (b) 100 to 400 mg of nimesulide in granule form in a sustained release polymer matrix mass of the polymer matrix being 40 to 150 per cent of the mass of nimesulide; (c) at least one diluent from 10% to 80% of the total mass of the formulation (d) at least one binder from 0.3% to 4% of the total mass of the formulation. (e)at least one lubricant from 0.6% to 5% of the total mass of the formulation. (f) at least one disintegrating agent from 0.2% to 3% of the total mass of the formulation. (g) optionally at least one surfactant from 0.2% to 5% of the total mass of the formulation. (2) a film coating on the said core, the mass of the film coating layer being 2 to 4 wt % based on the mass of the core. [2] A once a day synergistic formulation as claimed in claim 1, in which the diluents are a pharmaceutically acceptable inert material selected from a group of diluents comprising micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures of these.

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 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, THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:- 11-10-2005 FIELD OF INVENTION This invention relates to an antispasmodic and an analgesic combination and to a method of making the same. In particular, this invention relates to a formulation which is a synergistic combination of an antispasmodic and an analgesic in a once a day dosage form. WHAT IS THE INVENTION INVISAGES This invention envisages to a composition containing Camylofin dihydrochloride and Nimesulide to be taken as once a day wherein, the drug release is controlled/sustained and uniform throughout the day by using suitable pharmaceutical excipients. The fixed dose combination of nimesulide and camylofin produce a synergistic response in the effective relief of spasm and further once a day formulation improve the patient compliance and eliminate the chances of miss of dose problem. In particular this invention envisages a film coated tablet formulation for oral composition containing Camylofin dihydrochloride 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 Nimesulide used in the formulation is in its pure form. The two active materials in the formulation are formulated in accordance with this invention within a dosage form wherein the two active materials are mixed along with specific excipients to form an uniform blend and thereafter are bind with a specific 2 binder to form discrete granules with a suitable sustained release polymer for obtaining two different granular mass of the respective drugs. According to this invention there is provided a once a day synergistic formulation comprising an antispasmodic and an analgesic having (1) a core comprising (a) 50 mg to 200 mg of camylofin dihydrochloride in granule form in a sustained release polymer matrix, mass of the polymer matrix being 40 to 150 per cent of the mass of camylofin dihydrochloride (b) 100 to 400 mg of nimesulide in granule form in a sustained release polymer matrix mass of the polymer matrix being 40 to 150 per cent of the mass of nimesulide; (c ) at least one diluent from 10% to 80% of the total mass of the formulation (d) at least one binder from 0.3% to 4% of the total mass of the formulation. (e)at least one lubricant from 0.6% to 5% of the total mass of the formulation. (f) at least one disintegrating agent from 0.2% to 3% of the total mass of the formulation. (g) optionally at least one surfactant from 0.2% to 5% of the total mass of the formulation. (2) a film coating on the said core, the mass of the film coating layer being 2 to 4 wt % based on the mass of the core. DETAILED DESCRIPTION OF THE INVENTION The active ingredients for making the oral dosage form of the composition of this invention are Camylofin dihydrochloride and Nimesulide. 3 The method for treating a patient comprising orally administering a pharmaceutical composition comprising a combination of (a) 50 mg to 200 mg of camylofin dihydrochloride - the first active ingredient in a sustained release granule form (b) 100 mg to 400 mg of nimesulide - the second active ingredient in a sustained release granule form and (c) pharmaceutical acceptable excipients. The specific excipients include at least one diluent, one binder, one glidant, one lubricant, one disintegrant, one surfactant, film forming polymers, one plastizer, one coloring agent, one surfactant and at least one sustained release matrix forming polymer. The diluents can be any pharmaceutically acceptable inert material selected from the groups of micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures of these. A preferred content of diluents is from 10% to 80% of the total mass of the formulation. The binders in the formulation is at least one compound selected from a group of compounds in accordance with this invention which will increase the bulk density of the active particles and make it easier to formulate in a compressed form. Examples of binders according to the invention include pregelatiniged starch, starches, gelatin, vinyl chloride, povidone, hydroxypropyl cellulose, ethyl cellulose, methylcellulose, cellulose acetate, hydroxypropylmethuyl cellulose and combinations thereof. A preferred content of binder is from 0.3% to 4% of the total mass of the formulation. The glidants in the formulation is at least one compound selected from a group of compounds in accordance with this invention which will accelerate the flow of the granules at the time of tebletting or filling. Examples of glidants according to the invention are corn starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures of these. A preferred content of disintegrating agent is from 0.2% to 3% of the total mass of the formulation. 4 The formulation includes a lubricant which is at least one compound selected from a group of compounds added to the composition to reduce adhesion and ease release of the product. Lubricants include, but are not limited to, 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, talc, waxes and zinc stearate. A preferred content of lubricant is from 0.6% to 5% of the total mass of the formulation. The disintegrating agent in the formulation is one compound selected from a group of compounds in accordance with this invention which will accelerate the dispersion and washout of the active particles of the polymers. Examples of disintegrating agents according to the invention include cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, polarcrin potassium resins, cellulose gum and mixtures of these. A preferred content of disintegrating agent is from 0.2% to 3% of the total mass of the formulation. The formulation preferably includes at least 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 5 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. A preferred content of surfactant is from 0.2% to 5% of the total mass of the formulation. The sustained release polymer in the formulation preferably used to prevent the instant release of the drug and to maintain the drug release for an extended period of time so that the drug action will be throughout the full day. The polymers used for this purpose may be at least one or in combinations selected from hydroxy propyl methyl cellulose, polyvinyl acetate, poly-acrylate copolymers, carbapols, carboxy methyl cellulose, waxes, methyl cellulose, ethyl cellulose and other polymers. The amount of polymer is dependent on the quantity of the active ingredient used and may vary from 40 to 150 percent of the active ingredient. The same polymer may be used for making both the granules or different polymers may be used The film coating layer of the formulation provides a protective layer that will protect the formulation from moisture which includes film forming cellulose polymers, plasticizers, 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. 6 The process of making the composition in accordance with this invention is as follows. The process involve the making core by 1. GRANULATION The granulation procedure is preferably followed to make the tabletting process easier by increasing the bulk density of the active materials as well the inert materials used. The granulation procedure performed by either of the two methods that may be by preparing the granules of the two active products separately using two differ binding systems so as to obtain the two different active granules or by making the granules in a single entity using a single binder system. The two different granules are manufactured by following methods Camvlofin Dihvdrochloride Granulation Dissolve dispensed quantity of binders in the solvent in a S.S. Container. Transfer the sifted Camylofin Dihydrochloride, matrix forming agents and diluents in a planetary mixer with variable speed ranges from 12 to 40 rpm and mix for 15 to 30 minutes so as to obtain a uniform mass. Transfer the binder solution slowly to the contents of planetary mixer and rotate the planetary mixer at slow speed for 10 to 20 minutes till the uniform dough is formed. Check the consistency and binding, if necessary additional wetting can be imparted with solvent. Pass this dough on multimill fitted with sieves of diameter ranges from 10 mm to 14 mm at medium speed. Transfer wet granules on F.B.D. bowl for drying at 50 °C to 55 °C for about 90 minutes. OR Transfer the wet granules on a tray drier for drying at 50° C for 6-10 hrs. Reck the granules occasionally while drying in a tray drier. Pass dried granules to 16-mesh sieve through vibrosifter and pass retained granules through multimill using 1.5mm screen at medium speed In-process Controls: LOD at 105° C (IR Moisture Balance): 2% +/- 0.5% Nimesulide Granulation : Dissolve dispensed quantity of binders in solvent. Transfer the binder solution slowly to the contents of planetary mixer [the sifted mix of nimesulid, control release polymer and diluents] and rotate the mixer at slow speed till uniform dough is formed. Pass this dough through multimill fitted with 10 mm sieve at medium speed.Transfer wet granules 7 on F.B.D bowl and dry at 50-55 deg celcius. Pass dried granules through 12 to 20-mesh sieve through vibrosifter and retained granules through multimill using 2.0 mm screen at medium speed. In-process Controls: LOD at 105 °C (IR Moisture Balance) : NMT 2.5 % Nimesulide granulation Smilar method is followed for the granulation of the nimesulide part. 2. LUBRICATION: Mix granules in double cone blender. Add the sifted in lubricants, glidents, surfactants, disintegrating agents and mix for 10 to 20 minutes. Lubricated granules obtained are ready for compression. 3. COMPRESSION: Environmental conditions: Temperature : Between 22°C to 25°C Relative Humidity : Below 60% Set up the single rotary compression machine with suitable punches and dies and start compression with complying necessary parameter. 4. FILM-COATING PROCESS: The film coating can be comprises of either two layers or one layers. The double layer coating includes pre-coating and seal-coating. Pre Coating Process Environmental Conditions: Temperature : Between 20°C to 30°C Relative Humidity : Below 60% All the switches and electrical appliances inside the coating room should be flame proof. Preparation of Pre-coating Solution: Prepare the coating solution using solvents Methylene Chloride and Isopropyl Alcohol into a s.s. container and stir for five minutes using overhead stirrer. Slowly transfer Ethyl 8 Cellulose and/ or hydroxypropylmethylcellulose into the same container under fast stirring till the smooth and uniform slurry is formed. Stir them continuously for 25 minutes, just prior the actual use, pass the suspension through 80 # sieve. Transfer the dedusted tablets (cores) into the coating pan and heat the tablet bed by inching process using hot air blower. The initial temperature should not exceed 45°C - 50°C. Once the tablet bed attains 45°C, it is ready for spray coating. Start the exhaust. Continue spraying the tablet bed as per the parameter attached herewith. Discontinue temporarily spraying of the solution. If the tablet bed is formed to be slightly over wet, allow the bed to dry completely and then continue with spraying. After the last coat of ethyl cellulose solution is applied continue drying of the tablet for 15 - 20 minutes. Then proceed for final coating. Preparation of the seal coating solution: The seal coating solution is prepared by the same method as described above by using the coating material composition containing coating polymer such as ethyl cellulose, hydroxypropylmethylcellulose, plastizer such as propylene glycol, diethyl phthalate and at least coloring agent such as titanium dioxide, iron oxide red. 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 contained: Camylofin Dihydrochloride 100 mg Nimesulide 200 mg MANUFACTURING PROCESS [Batch Size: 1.0 lakh tablet] Step - 1: Making the camylofin granules 10 Kg of Camylofin dihydrochloride, 5.0 kg of microcrystalline cellulose, 7.0 kg of polyacrylate polymer, 1.0 kg of polyvinyl acetate were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature is maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes 9 at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the excipient resulted. 600 gms of cellulose acetate, 10 gm of vinyl acetate, 100 gms of carnuba wax (melted) was mixed with 10 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until a solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the content of planetary mixer. 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 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 granules 20 Kg of nimesulide, 10 kg of lactose, 10.0 kg of hydroxypropylmethylcellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature is 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 nimesulide and the excipients resulted. 600 gms of povidone was mixed with 10 Kg of purified water 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 mixture of the particles of nimesulide and 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 granules of mesh size 8 to 12 mm. 10 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 sized nimesulide granules. Step - 3 : Lubrication Through a vibro sifter of mesh size 40 mesh the following materials were passed: 1.0 kg sodium lauryl sulfate, 1.0 kg of talcum, and 1.0 kg of magnesium stearate. This sifted mass* (except magnesium stearate) along with the dried granules of Camylofin, nimesulide 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. 1.0 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 5 kg/sq cm . 1,00,000 Cores were obtained : Dimension: Length-19.0 ±0.2 mm Width - 8.0 ± 0.2 mm Avg weight of core 674 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. A coating suspension was pre prepared by mixing together 0.4 kg of ethyl cellulose; and 0.8 kg of hydroxypropyl cellulose and mixed together with 10 kg of isopropyl alcohol and 16 kg of Methylene chloride; 0.01 kg of diethyl phthalate , 0.05 kg of titanium dioxide in a s.s. container, 0.01 kg of black iron oxide yellow, 0.02 kg of brilliant blue, 0.015 kg of 11 iron oxide yellow and stirred for five minutes using overhead stirrer until a smooth slurry was obtained. The coating solution was sieved through 80 mesh sieve. 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: Length-19.1 +0.2 mm Width-8.1 ±0.2 mm Avg weight of film coated tablet 684 mg + 3 %. EXAMPLE - 2 Each tablet contained: Camylofin Dihydrochloride 100 mg Nimesulide 200 mg Step - 1: Making the camylofin granules 10 Kg of Camylofin dihydrochloride, 5.0 kg of microcrystalline cellulose, 11.0 kg of cabopol polymer, were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature is 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 excipient resulted. 300 Gms of povidone, 300 Gms of ethyl cellulose were mixed with 10 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until a solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the content of planetary mixer. 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. 12 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 1.4%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the nimesulide granules 20 Kg of nimesulide, 7 kg of lactose, 5.0 kg of microcrystallinecellulose, 8.0 kg of polyacrylate polymer were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature is 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 nimesulide and the excipients resulted. 400 gms of povidone was mixed with 10 Kg of purified water 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 mixture of the particles of nimesulide and 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 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 sized nimesulide granules. Step - 3 : Lubrication Through a vibro sifter of mesh size 40 mesh the following materials were passed: 13 0.7 kg of croscarmellose sodium, 1.0 kg of talcum, and 0.3 kg of hydrogenated vegetable oil. This sifted mass (except talcum and hydrogenated vegetable oil) along with the dried granules of Camylofin, nimesulide were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 24 r.p.m. for 30 minutes. Remaining quantity of lubricants were 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 5 kg/sq cm . 1,00,000 Cores were obtained : Dimension: Length-19.0 ±0.2 mm Width - 8.0 ± 0.2 mm Avg weight of core 670 mg + 3 %. Step - 5: film - coating The cores were coated with a film coating. A coating suspension was pre prepared by mixing together 0.4 kg of ethyl cellulose; and 0.7 kg of hydroxypropyl cellulose and mixed together with 6 kg of isopropyl alcohol and 11 kg of Methylene chloride; 0.01 kg of propylene glycol , 0.05 kg of titanium dioxide in a s.s. container, 0.01 kg of black iron oxide yellow, 0.02 kg of brilliant blue, 0.015 kg of iron oxide yellow and stirred for five minutes using overhead stirrer until a smooth slurry was obtained. The coating solution was sieved through 80 mesh sieve. 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. 14 Final dimensions of the tablets were as follows: Dimension: Length-19.1 ±0.2 mm Width-8.1 ±0.2 mm Avg weight of film coated tablet 682 mg ± 3 %. EXAMPLES: 3 Each tablet contained: Camylofin Dihydrochloride 50 mg Nimesulide 100 mg MANUFACTURING PROCESS Step - 1: Making the camylofin granules 0.5 Kg of Camylofin dihydrochloride, 2.0 kg of microcrystalline cellulose, 4.0 kg of polyacrylate polymer, 0.5 kg of polyvinyl acetate were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature is maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 28 r.p.m. so that a homogenous mixture of the particles of Camylofin and the excipient resulted. 300 gms of cellulose acetate, 5 gm of vinyl acetate, 50 gms of carnuba wax (melted) was mixed with 5 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until a solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the content of planetary mixer. Wet mixing was then commenced for 20 minutes at 22 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 tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.4%. 15 The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the nimesulide granules 10 Kg of nimesulide, 5 kg of lactose, 5.0 kg of hydroxypropylmethylcellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature is maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 22 r.p.m. so that a homogenous mixture of the particles of nimesulide and the excipients resulted. 200 gms of povidone was mixed with 5.0 Kg of purified water 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 mixture of the particles of nimesulide and excipients. Wet mixing was then commenced for 20 minutes at 20 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 sized nimesulide granules. Step - 3 : Lubrication Through a vibro sifter of mesh size 40 mesh the following materials were passed: 0.5 kg sodium lauryl sulfate, 0.5 kg of talcum, and 0.5 kg of magnesium stearate. This sifted mass (except magnesium stearate) along with the dried granules of Camylofin, nimesulide 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. 16 0.5 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 5 kg/sq cm . 1,00,000 Cores were obtained : Dimension: Circular, standard curvature with diameter 10.3 ± 0.2 mm Avg weight of core 338 mg + 3 %. Step - 5: film - coating The cores were coated with a film coating. A coating suspension was pre prepared by mixing together 0.2 kg of ethyl cellulose; and 0.4 kg of hydroxypropyl cellulose and mixed together with 5 kg of isopropyl alcohol and 8 kg of Methylene chloride; 0.005 kg of diethyl phthalate , 0.03 kg of titanium dioxide in a s.s. container, 0.015 kg of iron oxide yellow and stirred for five minutes using overhead stirrer until a smooth slurry was obtained. The coating solution was sieved through 80 mesh sieve. 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 film coated tablet with diameter 10.4 + 0.2 mm Avg weight of film coated tablet 346 mg ± 3 %. 17 EXAMPLE - 4 Each tablet contained: Camylofin Dihydrochloride 50 mg Nimesulide 100 mg Step -1: Making the camylofin granules 5 Kg of Camylofin dihydrochloride, 2.0 kg of microcrystalline cellulose, 6.0 kg of cabopol polymer, were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature is 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 excipient resulted. 200 Gms of povidone, 100 Gms of ethyl cellulose were mixed with 5 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until a solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the content of planetary mixer. Wet mixing was then commenced for 20 minutes at 20r.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 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 granules 10 Kg of nimesulide, 3 kg of lactose, 3.0 kg of microcrystallinecellulose, 4.0 kg of polyacrylate polymer were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature is maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 22 r.p.m. so that a homogenous mixture of the particles of nimesulide and the excipients resulted. 18 200 gms of povidone was mixed with 5 Kg of purified water 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 mixture of the particles of nimesulide and 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 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 sized nimesulide granules. Step - 3 : Lubrication Through a vibro sifter of mesh size 40 mesh the following materials were passed: 0.4 kg of croscarmellose sodium, 0.60 kg of talcum, and 0.1 kg of hydrogenated vegetable oil. This sifted mass (except talcum and hydrogenated vegetable oil) along with the dried granules of Camylofin, nimesulide were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 24 r.p.m. for 30 minutes. Remaining quantity of lubricants were 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 5 kg/sq cm. 1,00,000 Cores were obtained: Dimension: circular, standard curvature with punch diameter 10.3 ± 0.2 mm 19 Avg weight of core 336 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. A coating suspension was prepared by mixing together 0.2 kg of ethyl cellulose; and 0.4 kg of hydroxypropyl cellulose and mixed together with 6 kg of isopropyl alcohol and 11 kg of Methylene chloride; 0.01 kg of propylene glycol , 0.05 kg of titanium dioxide in a s.s. container, 0.01 kg of black iron oxide yellow, 0.02 kg of brilliant blue, 0.015 kg of iron oxide yellow and stirred for five minutes using overhead stirrer until a smooth slurry was obtained. The coating solution was sieved through 80 mesh sieve. 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 punch diameter 10.4 ± 0.2 mm Avg weight of film coated tablet 442 mg ± 3 %. 20 I Claim: [1] A once a day synergistic formulation comprising an antispasmodic and an analgesic having (1) a core comprising (a) 50 mg to 200 mg of camylofin dihydrochloride in granule form in a sustained release polymer matrix, mass of the polymer matrix being 40 to 150 per cent of the mass of camylofin dihydrochloride (b) 100 to 400 mg of nimesulide in granule form in a sustained release polymer matrix mass of the polymer matrix being 40 to 150 per cent of the mass of nimesulide; (c) at least one diluent from 10% to 80% of the total mass of the formulation (d) at least one binder from 0.3% to 4% of the total mass of the formulation. (e)at least one lubricant from 0.6% to 5% of the total mass of the formulation. (f) at least one disintegrating agent from 0.2% to 3% of the total mass of the formulation. (g) optionally at least one surfactant from 0.2% to 5% of the total mass of the formulation. (2) a film coating on the said core, the mass of the film coating layer being 2 to 4 wt % based on the mass of the core. [2] A once a day synergistic formulation as claimed in claim 1, in which the diluents are a pharmaceutically acceptable inert material selected from a group of diluents comprising micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures of these. 21 [3] A once a day synergistic formulation as claimed in claim 1, in which the binder is at least one compound selected from a group of compounds comprising pregelatiniged starch, starches, gelatin, vinyl chloride, povidone, hydroxypropyl cellulose, ethyl cellulose, methylcellulose, cellulose acetate, hydroxypropylmethuyl cellulose and combinations thereof. [41A once a day synergistic formulation as claimed in claim 1., in which the glidant is at least one compound selected from a group of compounds comprising corn starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures of these. [5] A once a day synergistic formulation as claimed in claim 1, in which the lubricant is at least one compound selected from a group of compounds 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, talc, waxes and zinc stearate. [6] A once a day synergistic formulation as claimed in claim 1, in which the disintegrating agent is at least one compound selected from a group of compounds comprising cross-linked polyvinylpyrrolidone, carboxymethyl starch, natural starch, microcrystalline cellulose, poiarcrin potassium resins, cellulose gum and mixtures of these. [7] A once a day synergistic formulation as claimed in claim 1, in which the surfactant is a compound selected from a 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 aarv-ethoxylated esters of sucrose, sorbitol, sorbitaa 22 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. [8] A once a day synergistic formulation as claimed in claim 1, in which the sustained release polymer is at least one polymer selected from a group of polymers comprising hydroxy propyl methyl cellulose, polyvinyl acetate, poly-acrylate copolymers, carbapols, carboxy methyl cellulose, waxes, methyl cellulose, ethyl cellulose and other polymers. [9] A once a day synergistic formulation as claimed in claim 1, in which the the film coating layer comprises at least one film forming cellulosic polymers, together with a piasticizer, a surfactant, and a coloring agent that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brillant blue 23 and solvents comprising at least one solvent purified water, isopropyl alcohol, acetone, methylene chloride and an opacifier which includes titanium dioxide. [10] A method of making a once a day synergistic formulation as claimed in claim 1, comprising the following steps [a] making granules of Camylofin Dihydrochloride, by (i) dissolving dispensed quantity of a binder in a solvent to form a binder solution; (ii) sifting dispensed quantities of Camylofin Dihydrochloride sustained release matrix forming polymer; and diluents in a planetary mixer and mixing at variable speed ranging from 12 to 40 rpm for 15 to 30 minutes so as to obtain a uniform mass, (iii) transferring the binder solution slowly to the contents of planetary mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a uniform dough is formed; (iv) passing the dough through a multimill fitted with sieves of diameter ranging from 10 mm to 14 mm at medium speed to obtain wet granules; (v) drying the wet granules at temperatures between 50 °C to 55 °C in a fluidized bed drier to a tray drier for drying at 50° C (vi) passing the dried granules through a sieve through a vibrosifter and pass retained granules through multimill using 1.5mm screen at medium speed to obtain uniform size granules of camylofin dihydrochloride; [b] making granules of nimesulide by (vii) dissolving dispensed quantity of a binder in a solvent to form a binder solution; (viii) sifting dispensed quantities of nimesulide sustained release matrix forming polymer; and diluents in a planetary mixer and mixing at variable speed ranging from 12 to 40 rpm for 15 to 30 minutes so as to obtain a uniform mass. 24 (ix) transferring the binder solution slowly to the contents of planetary mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a uniform dough is formed; (x) passing the dough through a multimill fitted with sieves of diameter ranging from 10 mm to 14 mm at medium speed to obtain wet granules; (xi) drying the wet granules at temperatures between 50 °C to 55 °C in a fluidized bed drier to a tray drier for drying at 50° C (xii) passing the dried granules through a sieve through a vibrosifter and pass retained granules through multimill using 1.5mm screen at medium speed to obtain uniform size granules of nimesulide; [c] mixing granules of camylofin dihydrochloride and nimesulide in a double cone blender along with dispensed quantities of lubricants, glidants surfactants, and disintegrating agents for 10 to 20 minutes to obtain lubricated granules.; [d] compressing the lubricated granules at Temperature : Between 22°C to 25°C and Relative Humidity : Below 60%, to obtain compressed cores; and [e] providing at least one film coat, preferably two coats on the cores by applying a slurring comprising a film forming polymer in a solvent along with a plasticizer and a colouring agent in a coating pan and heating the pan by the inching process to obtain the formulation of this invention. . Dated this 16th day of May, 2005. MOHAN DEWAN OF R.K.DEWAN & COMPANY APPLICANT'S PATENT ATTORNEY 25

Documents:

175-mum-2004-cancelled pages(11-10-2005).pdf

175-mum-2004-claims(granted)-(11-10-2005).doc

175-mum-2004-claims(granted)-(11-10-2005).pdf

175-mum-2004-correspondence(4-10-2006).pdf

175-mum-2004-correspondence(ipo)-(21-2-2006).pdf

175-mum-2004-form 1(16-2-2004).pdf

175-mum-2004-form 18(29-8-2005).pdf

175-mum-2004-form 2(granted)-(11-10-2005).doc

175-mum-2004-form 2(granted)-(11-10-2005).pdf

175-mum-2004-form 3(16-2-2004).pdf

175-mum-2004-form 4(29-3-2006).pdf

175-mum-2004-form 4(30-12-2004).pdf

175-mum-2004-form 5(16-5-2005).pdf

175-mum-2004-form 9(20-5-2005).pdf

175-mum-2004-power of attorney(16-2-2004).pdf