Title of Invention	ANTISPASMODIC AND ANALGESIC COMBINATION AND A METHOD OF MAKING THE SAME
Abstract	A synergistic antispasmodic, analgesic antipyretic formulation comprising a core consisting of (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 100 mg to 600 mg of paracetamol (c) pharmaceutical acceptable inert excipients consisting of at least one diluent 10% to 60% of the total mass of the formulation, at least one binder being 0.3% to 4% of the total mass of the formulation, at least one glidant from 0.2% 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, and at least one disintegrant being 0.6% to 5% of the total mass of the formulation and at least one film coat on the core consisting of at least one film forming polymer such as ethyl Cellulose and/ or Vhydroxypropylmethylcellulose and a plasticizer such as propylene glycol, said film coat being 2 to 4 wt % based on the weight of the core composition

Title of Invention

ANTISPASMODIC AND ANALGESIC COMBINATION AND A METHOD OF MAKING THE SAME

Abstract

A synergistic antispasmodic, analgesic antipyretic formulation comprising a core consisting of (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 100 mg to 600 mg of paracetamol (c) pharmaceutical acceptable inert excipients consisting of at least one diluent 10% to 60% of the total mass of the formulation, at least one binder being 0.3% to 4% of the total mass of the formulation, at least one glidant from 0.2% 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, and at least one disintegrant being 0.6% to 5% of the total mass of the formulation and at least one film coat on the core consisting of at least one film forming polymer such as ethyl Cellulose and/ or Vhydroxypropylmethylcellulose and a plasticizer such as propylene glycol, said film coat being 2 to 4 wt % based on the weight of the core composition

Full Text	FORM-2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE Specification (See section 10 and rule 13) A SYNERGISTIC ANTISPASMODIC AND ANALGESIC FORMULATION AND TO A METHOD OF MAKING THE SAME SANJEEV KHANDELWAL, an Indian National of Prem Nivas, 13, Altamount Road, Mumbai 400 026, '2 8 JAM 2005 THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:- FIELD OF INVENTION This invention relates to a synergistic_antispasmodic and analgesic formulatiqn and to a method of making the same. WHAT THE INVENTION ENVISAGES This invention envisages a synergistic formulation composition containing Camvlofin dihydrochloride and Paracetamol. The fixed dose combination of paracetamol and camylofin produce a synergistic response in the effective relief of spasm. In particular this invention envisages a film coated tablet formulation for oral administration Camylofin dihydrochloride and Paracetamol. Therapeutic effective amount of Camylofin used in the formulation is preferably as camylofin dihydrochloride or any pharmaceutically acceptable salt form such as camylofin 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. The two active materials in the formulation can be formulated within a dosage form wherein the two active materials are mixed along with excipients to form a 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. CAMYLOFIN Camylofm dihydrochloride chemically it is isopentyl 2-[2-diethylaminoethylamino] -2-phenyl ^acetate dihydroghloride of molecular weight 393.4, Molecular Formula C19H32N202 2HC1. Camylofin is a pale yellow oil. Camylofm Dihydrochloride is a white crystalline powder melting point 170 °C and 180 °C, soluble in water. Brock et a] studied the chemical structure and pharmacological properties of camylofin dihydrochloride in detail. Camylofm has a direct papaverine like spasmolytic action on the smooth muscle and a mild atropine like anticholinergic action, making it one of the most potent antispasmodics. It inhibits the enzyme phosphodiesterase, which in turn causes increase in concentration of cyclic AMP and smooth muscle relaxation. Due to its phosphodiesterase enzyme-IV isoenzyme selectivity, this drug does not interfere with uterine contractility. LD 50 in mice 760 mg/kg orally; 1.35 gmJ kg s.c; 49.2 mg/kg i.v. Camylofin dihydrochloride primarily acts on smooth muscles (intestine, ureter, cervix) whereas its influence on glands, eyes, heart and circulation is slight and of no clinical significance. It has very mild anticholinergic side effects like dryness of mouth, dilatation of pupils, paralysis of accommodation and palpitations. It has a wide margin of safety. The ratio of the effective therapeutic dose to the toxicity dose in animal studies varies from 1:40 to 1:150.5 PARACETAMOL Paracetamol is 4-acetamidophenol and may be represented by the following formula In some publications, it is described as 4-hydroxyacetanilide or N-acetyl-p-aminophenol and in the US Pharmacopoeia it is known as acetaminophen. Paracetamol is a white, odourless crystalline powder with a bitter taste, soluble in 70 parts of water (1 in 20 boiling water), 7 parts of alcohol (95%), 13 parts of acetone, 40 parts of glycerol, 9 parts of propylene glycol, 50 parts of chloroform, or 10 parts of methyl alcohol. It is also soluble in solutions of alkali hydroxides. It is insoluble in benzene and ether. A saturated aqueous solution has a pH of about 6 and is stable (half-life over 20 years) but stability decreases in acid or alkaline conditions, paracetamol being slowly broken down into acetic acid and p-aminophenol. Paracetamol is a peripherally acting analgesic and is well absorbed orally. Paracetamol produces analgesia by elevation of the pain threshold and antipyresis through action on the hypothalamic heat-regulating center. Paracetamol is equal to aspirin in analgesic and antipyretic effectiveness. The production of prostaglandins is part of the body's inflammatory response to injury, and inhibition of prostaglandin production around the body by blocking the cyclooxygenase enzymes known as COX-1 and COX-2 has long been known to be the mechanism of action of aspirin and other non-steroidal anti¬inflammatory drugs (NSAIDs) such as ibuprofen. However, their action in blocking COX-1 is known to be responsible for also causing the unwanted gastrointestinal side effects associated with these drugs. Paracetamol has no significant action on COX-1 and COX-2, which left its mode of action a mystery but did explain its lack of anti-inflammatory action and also, more importantly, its freedom from gastrointestinal side effects typical of NSAIDs. Early work had suggested that the fever reducing action of paracetamol was due to activity in the brain while its lack of any clinically useful anti-inflammatory action was consistent with a lack of prostaglandin inhibition peripherally in the body. » Now, recent research has shown the presence of a new, previously unknown cyclooxygenase enzyme COX-3, found in the brain and spinal cord, which is selectively inhibited by paracetamol, and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX-2. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the effectiveness of paracetamol in relieving pain and reducing fever without having unwanted gastrointestinal side effects. Paracetamol is one of the most widely used analgesics and is regarded to offer highest degree of safety and tolerability in the recommended dose. Although its mode of action is not fully understood, Paracetamol is believed to inhibit cyclo- oxygenase (COX) in the central nervous system, besides exerting action on the peripheral pain chemoreceptors (Bradykinin). Paracetamol provides temporary relief of minor aches and pains with heartburn or acid indigestion and upset stomach associated with these symptoms. Acetaminophen chewable tablets, elixir, drops, suspension liquid and suspension drops are designed for treatment of infants and children with conditions requiring temporary relief of fever and discomfort due to colds and "flu," and of simple pain and discomfort due to teething, immunizations and tonsillectomy. Paracetamol at recommended doses is a safe and effective medicine for the relief of mild pain and fever. It is generally available as 500 mg tablets, but is also available in soluble form (also generally 500 mg tablets), and in a variety of combinations. Liquid preparations are also available for young children. The plasma elimination half-life ranges from 1 to 4 hours for Paracetamol. Paracetamol is distributed throughout most fluids of the body, and is metabolized primarily in the liver. Little unchanged drug is excreted in the urine, but most metabolic products appear in the urine within 24 hours Paracetamol is rapidly absorbed, the soluble form being absorbed faster than the solid tablet form. The peak blood level for both forms is similar and is usually less than 20 mg/litre following a 1000 mg dose. Peak serum levels usually occur 30 minutes to 2 hours after ingestion. Elimination from the body is rapid with a half-life of about two hours. Paracetamol is primarily metabolised by the liver. Most of it is combined with glucuronide and sulphate, which account for about 90% of the dose excreted. About 5% of the dose is excreted unchanged and a further 5% is oxidised to a benzoquinoneimine, which is then combined with glutathione and metabolised on to cysteine and mercapturate compounds, which are safely excreted. Paracetamol and its two primary metabolites are remarkably safe compounds, and the hepatotoxicity of paracetamol arises only through the 5% that is oxidised. The immediate oxidation metabolite, benzoquinoneimine, is a highly reactive substance that normally combines with glutathione. As the dose of paracetamol increases, the quantity of benzoquinoneimine produced increases too. There then comes a point where the glutathione stores in the liver have been completely used up and the rate of production of new glutathione cannot keep up with the rate of production of the benzoquinoneimine. It is at this point that the benzoquinoneimine attaches to liver protein and causes liver injury. The time required for the liver to become depleted of glutathione, and for the benzoquinoneimine to build up and cause fatal liver damage, is three to four days. During the early stages of this process, there may be few overt symptoms, and it is important that in cases of suspected overdose the patient does not wait for symptoms to appear before seeking medical help. It is estimated that liver injury may begin to occur at a single dose of paracetamol of 15g (30 standard tablets) or over. New research suggests that paracetamol may help to protect from changes leading to hardening of the arteries, a condition that contributes to many deaths per year from stroke, heart attacks and other forms of cardiovascular disease. The research indicates that use of paracetamol at recommended doses inhibits the oxidation of certain low-density lipoproteins which carry the 'bad' form of cholesterol, preventing one of the main processes involved in the formation of arterial plaque and hardening of the arteries. Research is continuing into these properties of paracetamol and how it may protect against cardiovascular disease. Early studies have shown a significant protective association between paracetamol use and ovarian cancer. The effect was apparent after use of paracetamol weekly for a period of six months but was most apparent for women who used paracetamol on a daily basis and who had been using it for more than ten years. There was no similar significant effect from the use of other pain relievers that are available over the counter. Further research is continuing before any kind of public health recommendations can be made for this apparent protective effect of paracetamol. DETAILED DESCRIPTION OF THE INVENTION The main feature of this invention is the use of both active ingredients for making the oral dosage form of the formulation Camylofin dihydrochloride and Paracetamol 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 which is called first active ingredients (b) 100 mg to 600 mg of paracetamol which is called the second active ingredients (c) pharmaceutical acceptable inert excipients (d) a pharmaceutical acceptable carrier. According to this invention therefore there is provided a synergistic antispasmodic, analgesic antipyretic formulation comprising a core consisting of (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 100 mg to 600 mg of paracetamol (c) pharmaceutical acceptable inert excipients consisting of at least one diluent 10% to 60% of the total mass of the formulation , at least one binder being 0.3% to 4% of the total mass of the formulation, at least one glidant from 0.2% 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, and at least one disintegrant being 0.6% to 5% 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. In accordance with a preferred aspect of the invention, the formulation includes a surfactant being from 0.2% to 5% of the total mass of the formulation. 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 and mixture of these. 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 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. 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, plasticizers such as propylene glycoll , surfactants, coloring agents that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brillant blue etc, solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and opacifier includes titanium dioxide. The weight of the film coating layer preferably 2 to 4 wt % based on the weight of the core composition may be employed. According to one aspect of this invention there is provided a process for making a synergistic antispasmodic, analgesic antipyretic formulation comprising the steps of [a] dissolving a dispensed quantity of binder in a solvent in a S.S. Container to form a first binder solution; [b] transferring dispensed quantities of sifted Camylofm Dihydrochloride and diluents, disintegrants in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing the Camylofm 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 camylofm 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 in a second solvent in a S.S. Container to form a second binder solution. [h] transferring dispensed quantities of sifted paracetamol and second diluents in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing the paracetamol and second diluents for 15 to 30 minutes at an ambient temperature below 25 degrees Celsius and relative humidity below 60%. to obtain a second uniform mass. [i] transferring the second binder solution slowly to the contents of planetary mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a second uniform dough is formed. [j] passing the second dough to a multimill fitted with sieves of diameter ranging from 10 mm to 14 mm at a speed of 10 to 20 rpm to produce wet paracetamol granules; [k] transferring the wet paracetamol granules to a drier for drying at 50° C to 55° C to obtain dried paracetamol [1] passing the dried paracetamol granules to al2 to 20-mesh sieve through vibrosifter and pass retained granules through multimill using 2 mm screen at a speed of 10 to 20 rpm to obtain uniformly sized dried paracetamol granules; [m] lubricating the granules by passing the uniformly sized dried paracetamol granules and dried uniformly sized granules of camylofin dihydrochloride 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 [n] 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; [o] film coating the cores with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer. According to another aspect of this invention there is provided an alternative process for making a synergistic antispasmodic, analgesic antipyretic formulation comprising the steps of [a] transferring dispensed quantities of sieved Camylofin dihydrochloride and paracetamol, diluents and glidants to a mixer at an ambient temperature below 25 degrees Celsius and relative humidity below 60% and obtaining a homogenous mixture of the particles of paracetamol, camylofin and the diluents and glidants . [b] forming a solution of a dispended quantity of binder and its solvent and added the binder solution to the mixer containing the homogenous mixture of the particles of paracetamol and camylofin dihydrochloride . [c] wet mixing the the binder solution to the mixer containing the homogenous mixture of the particles of paracetamol and camylofin dihydrochloride to obtain a wet homogenous mixture mass; [d] milling the wet homogenous mixture mass in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm; [e] subjecting the wet granules to ambient drying: [f] subjecting the ambient dried granules to hea drying at a temperature of 50 to 60 degrees Celsius to obtain dry active ingredient granules [g] sifting the said dry granules in an 18-mesh vibrosifter to obtain uniform sized dry granules. [h] transferring the said dry granules to a blender and adding dispensed quantities of lubricant and glidant and blending to obtain lubricated granules; [i] 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 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 tableting process easier by increasing the bulk density of the active materials as well as the inert materials used. The granulation procedure performed by either of the aforesaid two methods that may be by preparing the granules of the two active products separately using two different 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 granulation are manufactured by following methods Camvlofin Dihydrochloride Granulation Dissolve dispensed quantity of binders in the solvent in a S.S. Container. Transfer the sifted Camylofin Dihydrochloride 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. Rake 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% 2. Paracetamol Granulation : Dissolve dispensed quantity of Polyvinyl Pyrollidone (K-30) in Isopropyl Alcohol in a S.S. Container. Transfer paracetamol and colloidal silicon dioxide ( M-FILA ) and starch in the planetary mixer and mix at slow speed . Transfer polyvinyl pyrrolidone solution in IPA slowly to the contents of planetary mixer 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 on F.B.D bowl and dry at 50-55 deg Celsius . 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 % Paracetamol granulation Similar method is followed for the granulation of the paracetamol part. Lubrication: The granules are mixed in double cone blender. And the sifted lubricants, glidants, surfactants, disintegrating agents and mix for 10 to 20 minutes. Lubricated granules obtained are ready for compression. Compression: Environmental conditions: Temperature : Between 22°C to 25°C Relative Humidity : Below 60% A rotary compression machine is set up with suitable punches and dies and compression is started after complying with necessary parameters. Film-Coating Process: The film coating can comprise of either two layers or one layers of coating. 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% 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 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 de-dusted 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. 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, plasticizer 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 contains: Camylofin Dihydrochloride 25 mg Paracetamol 325 mg MANUFACTURING PROCESS Step-1: Making the camylofin granules 2.5 Kg of Camylofin dihydrochloride, 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 Camylofin and microcrystalline cellulose resulted. 190 gms of ethyl cellulose, 10 ml of propylene glycol was mixed with 6 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until a clear solution was 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 Camylofin and microcrystalline cellulose. 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 paracetamol granules 32.5 Kg of paracetamol, 3.6 kg of microcrystalline cellulose, 3.0 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 paracetamol and the diluents resulted. 500 gms of povidone was mixed with 10 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 mixture of the particles of paracetamol and microcrystalline cellulose. 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 sized paracetamol granules. Step - 3 : Lubrication Through a vibro sifter of mesh size 40 mesh the following materials were passed: 2.0 kg sodium starch glycollate, 0.2 kg of colloidal silicon dioxide; 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 and paracetamol 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. 0.5 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: Length-14.0 ±0.2 mm Width-9.0 ±0.2 mm Thickness - 5.2 ± 0.3 mm Avg weight of core 490 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. A coating suspension was prepared by mixing 0.5 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 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 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- 14.1 ± 0.2 mm Width-9.1+0.2 mm Thickness - 5.3 + 0.3 mm Avg weight of film coated tablet 500 mg ± 3 %. EXAMPLE - 2 Each tablet contained: Camylofm Dihydrochloride 10 mg Paracetamol 125 mg Step - 1: Granulation 1 kg of Camylofm, 12.5 Kg of paracetamol, 8 kg of microcrystallihe cellulose, 5.0 kg of starch 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 paracetamol, camylofm and the diluents resulted. 400 gms of povidone was mixed with 5 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 mixture of the particles of paracetamol and microcrystalline cellulose. 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 sized granules. Step - 2 : Lubrication Mix granules in double cone blender. Add pre-sifted talcum, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate to double cone blender and mix till uniformly lubricated granules ready for compression is obtained. Step - 3 : Compression Environmental conditions: Temperature : Between 23°C to 30°C Relative Humidity : Below 60% This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm . 1,00,000 Cores were obtained : Dimension: Diameter: 10.3 ± 0.1 mm Thickness - 5.2 ± 0.3 mm Avg weight of core 490 mg ± 3 %. Step - 4: Film Coating Pre Coating Process Environmental Conditions: Temperature : Between 20°C to 30°C Relative Humidity : Below 60% 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 Cellulose, diethyl phthalate and 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 attained 45°C, it was ready for spray coating. The exhaust was started and spraying was continued and the bed was allowed to dry completely.. After the last coat of ethyl cellulose solution was applied, the drying of the tablet was continued for 15 - 20 minutes. Then proceeded for final coating. Preparation of the seal coating solution: The seal coating solution was 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 one coloring agent such as titanium dioxide, iron oxide red and the coating was continued as above. EXAMPLES: 3 25 mg 500 mg Each tablet contained: Camylofm Dihydrochloride Paracetamol MANUFACTURING PROCESS Step-1: Making the camylofin granules 2.5 Kg of Camylofin dihydrochloride, 2.0 kg of microcrystalline cellulose, and 0.1 kgs 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 24 r.p.m. so that a homogenous mixture of the particles of Camylofin and the microcrystalline cellulose resulted. 200 gms of cellulose acetate phthalate, 10 ml of polysorbate 80 was mixed with 2.0 kg of acetone and 6 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until a clear solution was 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 Camylofin and microcrystalline cellulose. Wet mixing was then commenced for 18 minutes at 18 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 2 hrs. 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 paracetamol granules 50 Kg of paracetamol, 2 kg of microcrystalline cellulose, 2 kg of starch, 1 kg of dibasic calcium phosphate were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 25 r.p.m. so that a homogenous mixture of the particles of paracetamol and the diluents resulted. 2 kg of starch paste was mixed with 1 Kg of purified water in a stainless steel [s.s.] tank under continuous stirring to form a slurry. Then 5 kg of purified water was heated in steam-jacketed container. The hot water was drained in the starch slurry with fast stirring until a uniform translucent paste was formed. The paste was then added to the planetary mixer containing the homogenous mixture of the particles of paracetamol and diluents. 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 sized paracetamol granules. Step - 3 : Lubrication Through a vibro sifter of mesh size 40 mesh the following materials were passed: 1.6 kg sodium starch glycollate, 0.2 kg of colloidal silicon dioxide; 0.8 kg of talcum, and 0.6 kg of calcium stearate. This sifted mass (except magnesium stearate) along with the dried granules of Camylofin, paracetamol were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 28 r.p.m. for 15 minutes. 0.6 kg of calcium stearate; was then added to the blender and further blending was done for 3 minutes resulting in the lubricated core mass. 4. Compression Environmental conditions: Temperature : Between 23°C to 30°C Relative Humidity : Below 60% This core mass was fed to the 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 Thickness - 5.0 ± 0.3 mm Avg weight of core 650 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. A coating suspension was prepared by mixing 0.5 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 the inching process using hot air blower. The initial temperature was set at 40 °C. Once the tablet bed attained 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 Thickness - 5.1 ± 0.3 mm Avg weight of film coated tablet 665 mg ± 3 %. EXAMPLES: 4 Each tablet contained: Camylofm Dihydrochloride 50 mg Paracetamol 500 mg MANUFACTURING PROCESS Step - 1: Making the camylofm granules 5 Kg of Camylofm dihydrochloride, 3.0 kg of microcrystalline cellulose, and 0.1 kgs 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 Camylofm and the microcrystalline cellulose resulted. 200 gms of ethyl 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 mixture of the particles of Camylofm and microcrystalline cellulose. Wet mixing was then commenced for 20 minutes at 18 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 2 hrs. The Loss on drying was 1.6%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofm granules. Step 2: making the paracetamol granules 50 Kg of paracetamol, 3 kg of microcrystalline cellulose, 3 kg of starch, 2 kg of lactose 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 paracetamol and the diluents resulted. 0.5 kg of hydroxy propyl cellulose was mixed with 6 Kg of purified water in a stainless steel [s.s.] tank under continuous stirring to form a paste. The paste was then added to the planetary mixer containing the homogenous mixture of the particles of paracetamol and diluents. 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 paracetamol granules. Step - 3 : Lubrication Through a vibro sifter of mesh size 40 mesh the following materials were passed: 1.4 kg dried starch, 0.1 kg of colloidal silicon dioxide; 1 kg of pregelatinized starch, and 0.7 kg of purified stearic acid. This sifted mass (except stearic acid) along with the dried granules of Camylofin, paracetamol were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 28 r.p.m. for 15 minutes. 0.7 kg of stearic acid was then added to the blender and further blending was done for 3 minutes resulting in the lubricated core mass. 4. Compression Environmental conditions: Temperature : Between 23°C to 30°C Relative Humidity : Below 60% This core mass was fed to the 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 Thickness - 5.6 ± 0.3 mm Avg weight of core 700 mg ± 3 %. Step - 4: film - coating The cores were coated with a film coating that consists of a single coating . A pre-coating suspension was pre prepared by mixing together 0.5 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 attained 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 Thickness - 5.8 ± 0.3 mm Avg weight of film coated tablet 720 mg ± 3 %. Trials were conducted by administering the tablets of the above examples to patients suffering from spasmodic pain. Patients were also administered paracetamol alone and separate tablets of paracetamol and camylofin. Significant results were obtained for the formulation of this invention over both paracetamol alone and the active ingredients administered separately. Unexpectedly, the relief was obtained significantly earlier [ perceived to be at least 15 to 30 minutes earlier] but 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 antispasmodic, analgesic antipyretic formulation comprising a core consisting of (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 100 mg to 600 mg of paracetamol (c) pharmaceutical acceptable inert excipients consisting of at least one diluent 10% to 60% of the total mass of the formulation, at least one binder being 0.3% to 4% of the total mass of the formulation, at least one glidant from 0.2% 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, and at least one disintegrant being 0.6% to 5% of the total mass of the formulation and at least one film coat on the core consisting of at least one film forming polymer such as ethyl Cellulose and/ or Vhydroxypropylmethylcellulose and a plasticizer such as propylene glycol, said film coat being 2 to 4 wt % based on the weight of the core composition. [2] A synergistic antispasmodic, analgdsic antipyretic formulation as claimed in s claim 1, which includes a surfactant being from 0.2% to 5% of the total mass of the formulation. [3] A synergistic antispasmodic, analgesic antipyretic formulation as claimed in claim 1 or claim 2, in which the diluent is a pharmaceutically acceptable inert material selected from the group consisting of micorcrystalline cellulose, starches, lactose, mamiitol, calcium phosphate, dibasic calcium phosphate and mixtures of these. [4] A synergistic antispasmodic, analgesic antipyretic formulation as claimed in any one of the preceding claims, in which the disintegrating agent in the formulation 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. [5] A synergistic antispasmodic, analgesic antipyretic formulation as claimed in any one of the preceding claims, in which the binders in the formulation 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 and mixture of these. [6] A synergistic antispasmodic, analgesic antipyretic formulation as claimed in any one of claims [2] to [5,] in which the surfactant is 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 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, [b] transferrirjg_dijiipenaed-"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 bindej^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 mrultimill 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_wetxarnylofin 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 in a second solvent in a S.S. Container to form a second binder solution. [h] transferring dispensed quantities of sifted paracetamol and second diluents in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing the paracetamol and second diluents for 15 to 30 minutes at an ambient temperature below 25 degrees Celsius and relative humidity below 60%. to obtain a second uniform mass. [i] trans^ferrm£jhe_je£ojid,„binder solution slowly to the contents of planetary mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a second uniform dough is formed. [j] passing the second dough to a multimill fitted with sieves of diameter ranging from 10 mm to 14 mm at a speed of 10 to 20 rpm to produce wet paracetamol granules; [k] transferring the wet paracetamol granules to a drier for drying at 50° C to 55° C to obtain dried paracetamol [1] passing the dried paracetamol granules to al2 to 20-mesh sieve through vibrosifter and pass retained granules through multimill using 2 mm screen at a speed of 10 to 20 rpm to obtain uniformly sized dried paracetamol granules; [m] lubricating the granules by posing the uniformly sized dried paracetamol granules and dried uniformly sized granules of camylofin dihydrochloride 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 [n] 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; [o] film coating the cores by spraying with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer. [T] A process for making a synergistic antispasmodic, analgesic antipyretic^ formulation as claimed in.anyone.ofjhe claims 1 to 9, comprising the steps of [a] transferring dispensed quantities of sieved Camylofin dihydrochloride and paracetamol, diluents and glidants to a mixer at an ambient temperature below 25 degrees Celsius and relative humidity below 60% and obtaining a homogenous mixture of the particles of paracetamol, camylofin and the diluents and glidants . [b] forming a solution of a dispended quantity of binder and its solvent and added the binder solution to the mixer containing the homogenous mixture of the particles of paracetamol and camylofin dihydrochloride . [c] wet mixing the the binder solution to the mixer containing the homogenous mixture of the particles of paracetamol and camylofin dihydrochloride to obtain a wet homogenous mixture masg;. [d] milling the wet homogenous mixture mass in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm; [e] subjecting the wet granules to ambient drying: [f] subjecting the ambient dried granules to heat drying at a temperature of 50 to 60 degrees Celsius to obtain dry active ingredient granules [g] sifting the said dry granules in an 18-mesh vibrosifter to obtain uniform sized dry granules. [h] transferring the said dry granules to a blender and adding dispensed quantities of lubricant and glidant and blending to obtain lubricated granules; [i] 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 by spraying the cores with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer to obtain tablets of the formulation. [12] A process for making a synergistic antispasmodic, analgesic antipyretic formulation as claimed in claims 10 or 11 whjchjn,cludesLthe steps [A] of preparing a pre coating solution using dispensed quantities of film forming polyrrier and plasticizer; [b] spraying the pre coating solution on the cores after the cores are heated to / around 45 degrees Celsius to pre coat the cores; [c] drying the pre coated cores; [d]preparing a sealing solution using dispensed quantities of film forming polymer , plasticizer and a coloring agent; [e] spraying the pre coated cores with the sealing solution to obtain the formulation in tablet form.

Full Text

FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE
Specification
(See section 10 and rule 13)

A SYNERGISTIC ANTISPASMODIC AND ANALGESIC FORMULATION AND TO A METHOD OF MAKING THE SAME
SANJEEV KHANDELWAL,
an Indian National of Prem Nivas, 13, Altamount Road, Mumbai 400 026,

'2 8 JAM 2005
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:-

FIELD OF INVENTION
This invention relates to a synergistic_antispasmodic and analgesic formulatiqn and to a method of making the same.
WHAT THE INVENTION ENVISAGES
This invention envisages a synergistic formulation composition containing Camvlofin dihydrochloride and Paracetamol.
The fixed dose combination of paracetamol and camylofin produce a synergistic response in the effective relief of spasm.
In particular this invention envisages a film coated tablet formulation for oral administration Camylofin dihydrochloride and Paracetamol.
Therapeutic effective amount of Camylofin used in the formulation is preferably as camylofin dihydrochloride or any pharmaceutically acceptable salt form such as camylofin 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.
The two active materials in the formulation can be formulated within a dosage form wherein the two active materials are mixed along with excipients to form a 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.

CAMYLOFIN
Camylofm dihydrochloride chemically it is isopentyl 2-[2-diethylaminoethylamino] -2-phenyl ^acetate dihydroghloride of molecular weight 393.4, Molecular Formula C19H32N202 2HC1. Camylofin is a pale yellow oil. Camylofm Dihydrochloride is a white crystalline powder melting point 170 °C and 180 °C, soluble in water.
Brock et a] studied the chemical structure and pharmacological properties of camylofin dihydrochloride in detail. Camylofm has a direct papaverine like spasmolytic action on the smooth muscle and a mild atropine like anticholinergic action, making it one of the most potent antispasmodics. It inhibits the enzyme phosphodiesterase, which in turn causes increase in concentration of cyclic AMP and smooth muscle relaxation. Due to its phosphodiesterase enzyme-IV isoenzyme selectivity, this drug does not interfere with uterine contractility. LD 50 in mice 760 mg/kg orally; 1.35 gmJ kg s.c; 49.2 mg/kg i.v.
Camylofin dihydrochloride primarily acts on smooth muscles (intestine, ureter, cervix) whereas its influence on glands, eyes, heart and circulation is slight and of no clinical significance. It has very mild anticholinergic side effects like dryness of mouth, dilatation of pupils, paralysis of accommodation and palpitations. It has a wide margin of safety. The ratio of the effective therapeutic dose to the toxicity dose in animal studies varies from 1:40 to 1:150.5
PARACETAMOL
Paracetamol is 4-acetamidophenol and may be represented by the following formula

In some publications, it is described as 4-hydroxyacetanilide or N-acetyl-p-aminophenol and in the US Pharmacopoeia it is known as acetaminophen.
Paracetamol is a white, odourless crystalline powder with a bitter taste, soluble in 70 parts of water (1 in 20 boiling water), 7 parts of alcohol (95%), 13 parts of acetone, 40 parts of glycerol, 9 parts of propylene glycol, 50 parts of chloroform, or 10 parts of methyl alcohol. It is also soluble in solutions of alkali hydroxides. It is insoluble in benzene and ether. A saturated aqueous solution has a pH of about 6 and is stable (half-life over 20 years) but stability decreases in acid or alkaline conditions, paracetamol being slowly broken down into acetic acid and p-aminophenol.
Paracetamol is a peripherally acting analgesic and is well absorbed orally. Paracetamol produces analgesia by elevation of the pain threshold and antipyresis through action on the hypothalamic heat-regulating center. Paracetamol is equal to aspirin in analgesic and antipyretic effectiveness. The production of prostaglandins is part of the body's inflammatory response to injury, and inhibition of prostaglandin production around the body by blocking the cyclooxygenase enzymes known as COX-1 and COX-2 has long been known to be the mechanism of action of aspirin and other non-steroidal anti¬inflammatory drugs (NSAIDs) such as ibuprofen. However, their action in blocking COX-1 is known to be responsible for also causing the unwanted gastrointestinal side effects associated with these drugs.
Paracetamol has no significant action on COX-1 and COX-2, which left its mode of action a mystery but did explain its lack of anti-inflammatory action and also, more importantly, its freedom from gastrointestinal side effects typical of NSAIDs.
Early work had suggested that the fever reducing action of paracetamol was due to
activity in the brain while its lack of any clinically useful anti-inflammatory action was
consistent with a lack of prostaglandin inhibition peripherally in the body.
» Now, recent research has shown the presence of a new, previously unknown
cyclooxygenase enzyme COX-3, found in the brain and spinal cord, which is
selectively inhibited by paracetamol, and is distinct from the two already known

cyclooxygenase enzymes COX-1 and COX-2. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the effectiveness of paracetamol in relieving pain and reducing fever without having unwanted gastrointestinal side effects.
Paracetamol is one of the most widely used analgesics and is regarded to offer highest degree of safety and tolerability in the recommended dose. Although its mode of action is not fully understood, Paracetamol is believed to inhibit cyclo- oxygenase (COX) in the central nervous system, besides exerting action on the peripheral pain chemoreceptors (Bradykinin).
Paracetamol provides temporary relief of minor aches and pains with heartburn or acid indigestion and upset stomach associated with these symptoms. Acetaminophen chewable tablets, elixir, drops, suspension liquid and suspension drops are designed for treatment of infants and children with conditions requiring temporary relief of fever and discomfort due to colds and "flu," and of simple pain and discomfort due to teething, immunizations and tonsillectomy.
Paracetamol at recommended doses is a safe and effective medicine for the relief of mild pain and fever. It is generally available as 500 mg tablets, but is also available in soluble form (also generally 500 mg tablets), and in a variety of combinations. Liquid preparations are also available for young children.
The plasma elimination half-life ranges from 1 to 4 hours for Paracetamol. Paracetamol is distributed throughout most fluids of the body, and is metabolized primarily in the liver. Little unchanged drug is excreted in the urine, but most metabolic products appear in the urine within 24 hours
Paracetamol is rapidly absorbed, the soluble form being absorbed faster than the solid tablet form. The peak blood level for both forms is similar and is usually less than 20 mg/litre following a 1000 mg dose. Peak serum levels usually occur 30 minutes to 2 hours after ingestion. Elimination from the body is rapid with a half-life of about two hours.

Paracetamol is primarily metabolised by the liver. Most of it is combined with glucuronide and sulphate, which account for about 90% of the dose excreted. About 5% of the dose is excreted unchanged and a further 5% is oxidised to a benzoquinoneimine, which is then combined with glutathione and metabolised on to cysteine and mercapturate compounds, which are safely excreted.
Paracetamol and its two primary metabolites are remarkably safe compounds, and the hepatotoxicity of paracetamol arises only through the 5% that is oxidised. The immediate oxidation metabolite, benzoquinoneimine, is a highly reactive substance that normally combines with glutathione. As the dose of paracetamol increases, the quantity of benzoquinoneimine produced increases too. There then comes a point where the glutathione stores in the liver have been completely used up and the rate of production of new glutathione cannot keep up with the rate of production of the benzoquinoneimine. It is at this point that the benzoquinoneimine attaches to liver protein and causes liver injury.
The time required for the liver to become depleted of glutathione, and for the benzoquinoneimine to build up and cause fatal liver damage, is three to four days. During the early stages of this process, there may be few overt symptoms, and it is important that in cases of suspected overdose the patient does not wait for symptoms to appear before seeking medical help. It is estimated that liver injury may begin to occur at a single dose of paracetamol of 15g (30 standard tablets) or over.
New research suggests that paracetamol may help to protect from changes leading to hardening of the arteries, a condition that contributes to many deaths per year from stroke, heart attacks and other forms of cardiovascular disease.
The research indicates that use of paracetamol at recommended doses inhibits the oxidation of certain low-density lipoproteins which carry the 'bad' form of cholesterol, preventing one of the main processes involved in the formation of arterial plaque and hardening of the arteries.

Research is continuing into these properties of paracetamol and how it may protect against cardiovascular disease.
Early studies have shown a significant protective association between paracetamol use and ovarian cancer. The effect was apparent after use of paracetamol weekly for a period of six months but was most apparent for women who used paracetamol on a daily basis and who had been using it for more than ten years. There was no similar significant effect from the use of other pain relievers that are available over the counter.
Further research is continuing before any kind of public health recommendations can be made for this apparent protective effect of paracetamol.
DETAILED DESCRIPTION OF THE INVENTION
The main feature of this invention is the use of both active ingredients for making the oral dosage form of the formulation Camylofin dihydrochloride and Paracetamol 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 which is called first active ingredients (b) 100 mg to 600 mg of paracetamol which is called the second active ingredients (c) pharmaceutical acceptable inert excipients (d) a pharmaceutical acceptable carrier.
According to this invention therefore there is provided a synergistic antispasmodic, analgesic antipyretic formulation comprising a core consisting of (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 100 mg to 600 mg of paracetamol (c) pharmaceutical acceptable inert excipients consisting of at least one diluent 10% to 60% of the total mass of the formulation , at least one binder being 0.3% to 4% of the total mass of the formulation, at least one glidant from 0.2% 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, and at least one disintegrant being 0.6% to 5% 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.
In accordance with a preferred aspect of the invention, the formulation includes a surfactant being from 0.2% to 5% of the total mass of the formulation.
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 and mixture of these.
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 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.
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, plasticizers such as propylene glycoll , surfactants, coloring agents that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brillant blue etc, solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and opacifier includes titanium dioxide. The weight of the film coating layer preferably 2 to 4 wt % based on the weight of the core composition may be employed.
According to one aspect of this invention there is provided a process for making a synergistic antispasmodic, analgesic antipyretic formulation comprising the steps of
[a] dissolving a dispensed quantity of binder in a solvent in a S.S. Container to form a first binder solution;
[b] transferring dispensed quantities of sifted Camylofm Dihydrochloride and diluents, disintegrants in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing the Camylofm 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 camylofm 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 in a second solvent in a
S.S. Container to form a second binder solution.
[h] transferring dispensed quantities of sifted paracetamol and second diluents
in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing
the paracetamol and second diluents for 15 to 30 minutes at an ambient
temperature below 25 degrees Celsius and relative humidity below 60%. to
obtain a second uniform mass.
[i] transferring the second binder solution slowly to the contents of planetary
mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a
second uniform dough is formed.
[j] passing the second dough to a multimill fitted with sieves of diameter
ranging from 10 mm to 14 mm at a speed of 10 to 20 rpm to produce wet
paracetamol granules;
[k] transferring the wet paracetamol granules to a drier for drying at 50° C to 55°
C to obtain dried paracetamol
[1] passing the dried paracetamol granules to al2 to 20-mesh sieve through
vibrosifter and pass retained granules through multimill using 2 mm screen at a
speed of 10 to 20 rpm to obtain uniformly sized dried paracetamol granules;
[m] lubricating the granules by passing the uniformly sized dried paracetamol
granules and dried uniformly sized granules of camylofin dihydrochloride 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

[n] 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;
[o] film coating the cores with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer.
According to another aspect of this invention there is provided an alternative process for making a synergistic antispasmodic, analgesic antipyretic formulation comprising the steps of
[a] transferring dispensed quantities of sieved Camylofin dihydrochloride and paracetamol, diluents and glidants to a mixer at an ambient temperature below 25 degrees Celsius and relative humidity below 60% and obtaining a homogenous mixture of the particles of paracetamol, camylofin and the diluents and glidants .
[b] forming a solution of a dispended quantity of binder and its solvent and added the binder solution to the mixer containing the homogenous mixture of the particles of paracetamol and camylofin dihydrochloride .
[c] wet mixing the the binder solution to the mixer containing the homogenous mixture of the particles of paracetamol and camylofin dihydrochloride to obtain a wet homogenous mixture mass;
[d] milling the wet homogenous mixture mass in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm;
[e] subjecting the wet granules to ambient drying:
[f] subjecting the ambient dried granules to hea drying at a temperature of 50 to 60 degrees Celsius to obtain dry active ingredient granules
[g] sifting the said dry granules in an 18-mesh vibrosifter to obtain uniform sized dry granules.
[h] transferring the said dry granules to a blender and adding dispensed quantities of lubricant and glidant and blending to obtain lubricated granules;

[i] 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 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 tableting process easier by increasing the bulk density of the active materials as well as the inert materials used. The granulation procedure performed by either of the aforesaid two methods that may be by preparing the granules of the two active products separately using two different 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 granulation are manufactured by following methods Camvlofin Dihydrochloride Granulation
Dissolve dispensed quantity of binders in the solvent in a S.S. Container. Transfer the sifted Camylofin Dihydrochloride 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. Rake 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%
2. Paracetamol Granulation :
Dissolve dispensed quantity of Polyvinyl Pyrollidone (K-30) in Isopropyl
Alcohol in a S.S. Container. Transfer paracetamol and colloidal silicon
dioxide ( M-FILA ) and starch in the planetary mixer and mix at slow speed .
Transfer polyvinyl pyrrolidone solution in IPA slowly to the contents of
planetary mixer 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 on F.B.D bowl and dry at 50-55 deg Celsius . 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 %
Paracetamol granulation
Similar method is followed for the granulation of the paracetamol part.
Lubrication:
The granules are mixed in double cone blender. And the sifted lubricants,
glidants, surfactants, disintegrating agents and mix for 10 to 20 minutes.
Lubricated granules obtained are ready for compression.
Compression:
Environmental conditions:
Temperature : Between 22°C to 25°C
Relative Humidity : Below 60%
A rotary compression machine is set up with suitable punches and dies and
compression is started after complying with necessary parameters.
Film-Coating Process:
The film coating can comprise of either two layers or one layers of coating. 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%
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 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 de-dusted 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. 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, plasticizer 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 contains:

Camylofin Dihydrochloride 25 mg
Paracetamol 325 mg
MANUFACTURING PROCESS
Step-1: Making the camylofin granules
2.5 Kg of Camylofin dihydrochloride, 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 Camylofin and microcrystalline cellulose resulted. 190 gms of ethyl cellulose, 10 ml of propylene glycol was mixed with 6 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until a clear solution was 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 Camylofin and microcrystalline cellulose.
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 paracetamol granules

32.5 Kg of paracetamol, 3.6 kg of microcrystalline cellulose, 3.0 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 paracetamol and the diluents resulted.
500 gms of povidone was mixed with 10 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 mixture of the particles of paracetamol and microcrystalline cellulose.
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 sized
paracetamol granules.
Step - 3 : Lubrication
Through a vibro sifter of mesh size 40 mesh the following materials were passed:
2.0 kg sodium starch glycollate, 0.2 kg of colloidal silicon dioxide; 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 and paracetamol 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.
0.5 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:
Length-14.0 ±0.2 mm
Width-9.0 ±0.2 mm
Thickness - 5.2 ± 0.3 mm
Avg weight of core 490 mg ± 3 %.
Step - 5: film - coating
The cores were coated with a film coating.
A coating suspension was prepared by mixing 0.5 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 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 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- 14.1 ± 0.2 mm
Width-9.1+0.2 mm
Thickness - 5.3 + 0.3 mm
Avg weight of film coated tablet 500 mg ± 3 %.
EXAMPLE - 2
Each tablet contained:
Camylofm Dihydrochloride 10 mg
Paracetamol 125 mg
Step - 1: Granulation
1 kg of Camylofm, 12.5 Kg of paracetamol, 8 kg of microcrystallihe cellulose, 5.0 kg of starch 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 paracetamol, camylofm and the diluents resulted.
400 gms of povidone was mixed with 5 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 mixture of the particles of
paracetamol and microcrystalline cellulose.
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 sized
granules.
Step - 2 : Lubrication
Mix granules in double cone blender. Add pre-sifted talcum, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate to double cone blender and mix till uniformly lubricated granules ready for compression is obtained.
Step - 3 : Compression
Environmental conditions:
Temperature : Between 23°C to 30°C
Relative Humidity : Below 60%
This core mass was fed to hopper of a single rotary compression machine and the
compression pressure was set at 3 kg/sq cm .
1,00,000 Cores were obtained :
Dimension:
Diameter: 10.3 ± 0.1 mm
Thickness - 5.2 ± 0.3 mm
Avg weight of core 490 mg ± 3 %.
Step - 4: Film Coating Pre Coating Process
Environmental Conditions:
Temperature : Between 20°C to 30°C
Relative Humidity : Below 60%
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 Cellulose, diethyl phthalate and 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 attained 45°C, it was ready for spray coating. The exhaust was started and spraying was continued and the bed was allowed to dry completely.. After the last coat of ethyl cellulose solution was applied, the drying of the tablet was continued for 15 - 20 minutes. Then proceeded for final coating.
Preparation of the seal coating solution:
The seal coating solution was 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 one coloring agent such as titanium dioxide, iron oxide red and the coating was continued as above.
EXAMPLES: 3
25 mg 500 mg
Each tablet contained:
Camylofm Dihydrochloride Paracetamol
MANUFACTURING PROCESS
Step-1: Making the camylofin granules
2.5 Kg of Camylofin dihydrochloride, 2.0 kg of microcrystalline cellulose, and 0.1 kgs 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 24 r.p.m. so that a homogenous mixture of the particles of Camylofin and the microcrystalline cellulose resulted.
200 gms of cellulose acetate phthalate, 10 ml of polysorbate 80 was mixed with 2.0 kg of acetone and 6 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until a clear solution was 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 Camylofin and microcrystalline cellulose.
Wet mixing was then commenced for 18 minutes at 18 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 2 hrs. 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 paracetamol granules
50 Kg of paracetamol, 2 kg of microcrystalline cellulose, 2 kg of starch, 1 kg of
dibasic calcium phosphate were passed through a 40-mesh sieve and placed in a
planetary mixer. The ambient temperature was maintained below 25 degrees
Celsius and the relative humidity below 60%. The mixer was run for 25 minutes
at 25 r.p.m. so that a homogenous mixture of the particles of paracetamol and the
diluents resulted.
2 kg of starch paste was mixed with 1 Kg of purified water in a stainless steel
[s.s.] tank under continuous stirring to form a slurry. Then 5 kg of purified water
was heated in steam-jacketed container. The hot water was drained in the starch

slurry with fast stirring until a uniform translucent paste was formed. The paste was then added to the planetary mixer containing the homogenous mixture of the particles of paracetamol and diluents.
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 sized paracetamol granules.
Step - 3 : Lubrication
Through a vibro sifter of mesh size 40 mesh the following materials were passed:
1.6 kg sodium starch glycollate, 0.2 kg of colloidal silicon dioxide; 0.8 kg of
talcum, and 0.6 kg of calcium stearate.
This sifted mass (except magnesium stearate) along with the dried granules of
Camylofin, paracetamol were transferred to a double cone blender at temperature
of 22 degrees Celsius and the mass was blended at speed of 28 r.p.m. for 15
minutes.
0.6 kg of calcium stearate; was then added to the blender and further blending
was done for 3 minutes resulting in the lubricated core mass.
4. Compression
Environmental conditions:
Temperature : Between 23°C to 30°C
Relative Humidity : Below 60%
This core mass was fed to the 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
Thickness - 5.0 ± 0.3 mm
Avg weight of core 650 mg ± 3 %.
Step - 5: film - coating
The cores were coated with a film coating.
A coating suspension was prepared by mixing 0.5 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 the inching process using hot air blower. The initial temperature was set at 40 °C. Once the tablet bed attained 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
Thickness - 5.1 ± 0.3 mm
Avg weight of film coated tablet 665 mg ± 3 %.

EXAMPLES: 4
Each tablet contained:
Camylofm Dihydrochloride 50 mg
Paracetamol 500 mg
MANUFACTURING PROCESS
Step - 1: Making the camylofm granules
5 Kg of Camylofm dihydrochloride, 3.0 kg of microcrystalline cellulose, and 0.1 kgs 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 Camylofm and the microcrystalline cellulose resulted.
200 gms of ethyl 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 mixture of the particles
of Camylofm and microcrystalline cellulose.
Wet mixing was then commenced for 20 minutes at 18 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 2 hrs. The Loss on drying was 1.6%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized
camylofm granules.
Step 2: making the paracetamol granules

50 Kg of paracetamol, 3 kg of microcrystalline cellulose, 3 kg of starch, 2 kg of lactose 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 paracetamol and the diluents resulted.
0.5 kg of hydroxy propyl cellulose was mixed with 6 Kg of purified water in a stainless steel [s.s.] tank under continuous stirring to form a paste. The paste was then added to the planetary mixer containing the homogenous mixture of the particles of paracetamol and diluents.
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 paracetamol granules.
Step - 3 : Lubrication
Through a vibro sifter of mesh size 40 mesh the following materials were passed:
1.4 kg dried starch, 0.1 kg of colloidal silicon dioxide; 1 kg of pregelatinized
starch, and 0.7 kg of purified stearic acid.
This sifted mass (except stearic acid) along with the dried granules of Camylofin,
paracetamol were transferred to a double cone blender at temperature of 22
degrees Celsius and the mass was blended at speed of 28 r.p.m. for 15 minutes.
0.7 kg of stearic acid was then added to the blender and further blending was
done for 3 minutes resulting in the lubricated core mass.

4. Compression
Environmental conditions:
Temperature : Between 23°C to 30°C
Relative Humidity : Below 60%
This core mass was fed to the 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
Thickness - 5.6 ± 0.3 mm
Avg weight of core 700 mg ± 3 %.
Step - 4: film - coating
The cores were coated with a film coating that consists of a single coating . A pre-coating suspension was pre prepared by mixing together 0.5 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 attained 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
Thickness - 5.8 ± 0.3 mm
Avg weight of film coated tablet 720 mg ± 3 %.
Trials were conducted by administering the tablets of the above examples to patients suffering from spasmodic pain. Patients were also administered paracetamol alone and separate tablets of paracetamol and camylofin. Significant results were obtained for the formulation of this invention over both paracetamol alone and the active ingredients administered separately. Unexpectedly, the relief was obtained significantly earlier [ perceived to be at least 15 to 30 minutes earlier] but 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 antispasmodic, analgesic antipyretic formulation comprising a core consisting of (a) 10 mg to 100 mg of camylofin dihydrochloride (b) 100 mg to 600 mg of paracetamol (c) pharmaceutical acceptable inert excipients consisting of at least one diluent 10% to 60% of the total mass of the formulation, at least one binder being 0.3% to 4% of the total mass of the formulation, at least one glidant from 0.2% 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, and at least one disintegrant being 0.6% to 5% of the total mass of the formulation and at least one film coat on the core consisting of at least one film forming polymer such as ethyl Cellulose and/ or Vhydroxypropylmethylcellulose and a plasticizer such as propylene glycol, said film coat being 2 to 4 wt % based on the weight of the core composition.
[2] A synergistic antispasmodic, analgdsic antipyretic formulation as claimed in
s
claim 1, which includes a surfactant being from 0.2% to 5% of the total mass of the formulation.
[3] A synergistic antispasmodic, analgesic antipyretic formulation as claimed in claim 1 or claim 2, in which the diluent is a pharmaceutically acceptable inert material selected from the group consisting of micorcrystalline cellulose, starches, lactose, mamiitol, calcium phosphate, dibasic calcium phosphate and mixtures of these.
[4] A synergistic antispasmodic, analgesic antipyretic formulation as claimed in any one of the preceding claims, in which the disintegrating agent in the formulation 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.

[5] A synergistic antispasmodic, analgesic antipyretic formulation as claimed in any one of the preceding claims, in which the binders in the formulation 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 and mixture of these.
[6] A synergistic antispasmodic, analgesic antipyretic formulation as claimed in any one of claims [2] to [5,] in which the surfactant is 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 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,

[b] transferrirjg_dijiipenaed-"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 bindej^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 mrultimill 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_wetxarnylofin 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 in a second solvent in a
S.S. Container to form a second binder solution.
[h] transferring dispensed quantities of sifted paracetamol and second diluents
in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing
the paracetamol and second diluents for 15 to 30 minutes at an ambient
temperature below 25 degrees Celsius and relative humidity below 60%. to
obtain a second uniform mass.
[i] trans^ferrm£jhe_je£ojid,„binder solution slowly to the contents of planetary
mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a
second uniform dough is formed.
[j] passing the second dough to a multimill fitted with sieves of diameter
ranging from 10 mm to 14 mm at a speed of 10 to 20 rpm to produce wet
paracetamol granules;

[k] transferring the wet paracetamol granules to a drier for drying at 50° C to 55°
C to obtain dried paracetamol
[1] passing the dried paracetamol granules to al2 to 20-mesh sieve through
vibrosifter and pass retained granules through multimill using 2 mm screen at a
speed of 10 to 20 rpm to obtain uniformly sized dried paracetamol granules;
[m] lubricating the granules by posing the uniformly sized dried paracetamol
granules and dried uniformly sized granules of camylofin dihydrochloride 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
[n] 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;
[o] film coating the cores by spraying with at least one film coat comprising
dispensed quantities of film forming polymer and plasticizer.
[T] A
process for making a synergistic antispasmodic, analgesic antipyretic^ formulation as claimed in.anyone.ofjhe claims 1 to 9, comprising the steps of
[a] transferring dispensed quantities of sieved Camylofin dihydrochloride and paracetamol, diluents and glidants to a mixer at an ambient temperature below 25 degrees Celsius and relative humidity below 60% and obtaining a homogenous mixture of the particles of paracetamol, camylofin and the diluents and glidants .
[b] forming a solution of a dispended quantity of binder and its solvent and added the binder solution to the mixer containing the homogenous mixture of the particles of paracetamol and camylofin dihydrochloride .
[c] wet mixing the the binder solution to the mixer containing the homogenous mixture of the particles of paracetamol and camylofin dihydrochloride to obtain a wet homogenous mixture masg;.
[d] milling the wet homogenous mixture mass in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm;

[e] subjecting the wet granules to ambient drying:
[f] subjecting the ambient dried granules to heat drying at a temperature of 50 to 60 degrees Celsius to obtain dry active ingredient granules
[g] sifting the said dry granules in an 18-mesh vibrosifter to obtain uniform sized dry granules.
[h] transferring the said dry granules to a blender and adding dispensed quantities
of lubricant and glidant and blending to obtain lubricated granules;
[i] 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 by spraying the cores with at least one film coat comprising
dispensed quantities of film forming polymer and plasticizer to obtain tablets of
the formulation.
[12] A process for making a synergistic antispasmodic, analgesic antipyretic
formulation as claimed in claims 10 or 11 whjchjn,cludesLthe steps
[A] of preparing a pre coating solution using dispensed quantities of film forming
polyrrier and plasticizer;
[b] spraying the pre coating solution on the cores after the cores are heated to
/ around 45 degrees Celsius to pre coat the cores;
[c] drying the pre coated cores; [d]preparing a sealing solution using dispensed quantities of film forming
polymer , plasticizer and a coloring agent;
[e] spraying the pre coated cores with the sealing solution to obtain the
formulation in tablet form.

Documents:

208-mum-2004-claims(granted)-(28-1-2005).doc

208-mum-2004-claims(granted)-(28-1-2005).pdf

208-mum-2004-correspondence(28-1-2005).pdf

208-mum-2004-correspondence(ipo)-(29-6-2007).pdf

208-mum-2004-form 1(23-2-2004).pdf

208-mum-2004-form 18(2-6-2005).pdf

208-mum-2004-form 2(granted)-(28-1-2005).doc

208-mum-2004-form 2(granted)-(28-1-2005).pdf

208-mum-2004-form 3(23-2-2004).pdf

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

208-mum-2004-form 5(28-1-2005).pdf

208-mum-2004-form 9(28-1-2005).pdf

208-mum-2004-power of attorney(23-2-2004).pdf

« Previous Patent

Next Patent »

Patent Number

207877

Indian Patent Application Number

208/MUM/2004

PG Journal Number

42/2008

Publication Date

17-Oct-2008

Grant Date

29-Jun-2007

Date of Filing

23-Feb-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

A61P 1/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA