Title of Invention	SYNERGISTIC FORMULATION OF AN ANTISPASMODIC AND AN ANALGESIC, ANTIPYRETIC AND ANTI-INFLAMMATORY AGENT IN TABLET FORM
Abstract	Synergistic formulation of an antispasmodic and an analgesic, antipyretic and anti-inflammatory agent in tablet form. Methods and composition are provided for effective relief of spasm. The composition comprises a synergistic formulation comprising an antispasmodic and one analgesic, antipyretic and antiinflammitive agent in a tablet dosage form. Methods of making the same are also disclosed. The composition contains Camylofin Dihydrochloride as the antispasmodic agent and aspirin the non-steroidal anti-inflammatory drugs [NSAID] agents. The formulation mainly contains the combination of camylofin with one nonsteroidal anti-inflammatory drugs [NSAIDs] aspirin and the method of making the same is disclosed.

Title of Invention

SYNERGISTIC FORMULATION OF AN ANTISPASMODIC AND AN ANALGESIC, ANTIPYRETIC AND ANTI-INFLAMMATORY AGENT IN TABLET FORM

Abstract

Synergistic formulation of an antispasmodic and an analgesic, antipyretic and anti-inflammatory agent in tablet form. Methods and composition are provided for effective relief of spasm. The composition comprises a synergistic formulation comprising an antispasmodic and one analgesic, antipyretic and antiinflammitive agent in a tablet dosage form. Methods of making the same are also disclosed. The composition contains Camylofin Dihydrochloride as the antispasmodic agent and aspirin the non-steroidal anti-inflammatory drugs [NSAID] agents. The formulation mainly contains the combination of camylofin with one nonsteroidal anti-inflammatory drugs [NSAIDs] aspirin and the method of making the same is disclosed.

Full Text	FORM - 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE Specification (See section 10 and rule 13) SYNERGISTIC FORMULATION OF AN ANTISPASMODIC AND AN ANALGESIC, ANTIPYRETIC AND ANTI-INFLAMMATORY AGENT IN TABLET FORM SANJEEV KHANDELWAL an Indian National of Prem Nivas, 13, Altamount Road, Mumbai 400026, Maharashtra, India, THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. TITLE Synergistic formulation of an antispasmodic and an analgesic, antipyretic and anti-inflammatory agent in tablet form. FIELD OF INVENTION This invention relates to a synergistic combination of an antispasmodic and an analgesic, antipyretic and anti-inflammatory formulation in a tablet dosage form and to a method of making the same. The synergistic tablet dosage form comprising Camylofin (antispasmodic) and aspirin (analgesic, antipyretic and anti-inflammatory) in their pharmaceutically acceptable form BACKGROUND OF THE INVENTION CAMYLOFIN Camylofin dihydrochloride chemically it is isopentyl 2-[2-diethylaminoethylamino]-2-phenyl acetate dihydrochloride of molecular weight 393.4, Molecular Formula C19H32N202 2HCI. Camylofin is a pale yellow oil. Camylofin Dihydrochloride is a white crystalline powder melting point 170 °C and 180 °C, soluble in water. Brock et al studied the chemical structure and pharmacological properties of camylofin dihydrochloride in detail. Camylofin 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 gm/ 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 2 the effective therapeutic dose to the toxicity dose in animal studies varies from 1:40 to 1:150.5. ASPIRIN: Appearance Chemical name Chemical formula Molecular mass Density Melting point Boiling point Stability : Odorless, Colourless or a white crystalline powder 2-(acetyloxy)benzoic acid C6H4(OCOCH3)COOH 180.57 g/mol 1.40 g/cm3 136°C (277°F) with decomposition 140°C (284°F) Stable in dry air (hydrolyzes in moist air, decomposes in hot water) Aspirin or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory. It has also an anticoagulant (blood thinning) effect and is used in long-term low-doses to prevent heart attacks. Low-dose long-term aspirin irreversibly blocks formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation, and this blood thinning property makes it useful for reducing the incidence of heart attacks. Aspirin produced for this purpose often comes in 75 or 81 mg dispersible tablets and is sometimes called "baby aspirin." High doses of aspirin are also given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may therefore produce a second and different anticoagulant effect. Several hundred fatal overdoses of aspirin occur annually, but the vast majority of its uses are beneficial. Its primary undesirable side effects, especially in stronger doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side effect, due to its anticoagulant properties, is increased bleeding in menstruating women. 3 Because there appears to be a connection between aspirin and Reye's syndrome, aspirin is no longer used to control flu-like symptoms in minors. Aspirin was the first discovered member of the class of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs), not all of which are salicylates, though they all have similar effects and a similar action mechanism. More recent work has shown that there are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin inhibits both of them. Newer NSAID drugs called COX-2 selective inhibitors have been developed that only inhibit COX-2, with the hope that this would reduce the gastrointestinal side effects. However, several of the new COX-2 selective inhibitors have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the arteries in the body express COX-2, and by selectively inhibiting COX-2, prostaglandins (specifically PGF2) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGF2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, rendering them "useless": an important difference with reversible inhibitors. Additionally, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and antiinflammitive properties : • It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria. • It induces the formation of NO-radicals in the body that enable the white bloodcells (leucocyts) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005. 4 Also recently aspirin has been proven to prevent carcinoma of the colon, if given in low doses over years. Aspirin has analgesic, antipyretic and anti-inflammatory actions. Aspirin is indicated for short-term use in the relief of mild to moderate pain (headache, toothache, menstrual cramps, neuralgia, muscular pain, pain associated with colds) and fever. Aspirin, as with many older drugs, has proven to be useful in many conditions, and despite its well-known toxicity, it is widely used, since physicians are familiar with its properties. Indications for its use include: • Fever • Pain (especially useful for conditions involving osteoid osteoma, arthritis and chronic pain) • Migraine • Myocardial infarction prophylaxis (low dose) • Rheumatic fever (drug of choice) Aspirin is a moisture sensitive drug and can hydrolyze into acetic and salicylic acids. Hydrophilic excipients can have adverse effects on aspirin under accelerated stability conditions. SUMMARY OF INVENTION This invention relates to a synergistic combination of an antispasmodic and an analgesic, antipyretic and anti-inflammatory formulation in a tablet form and to a method of making the same particularly for the treatment of colicky pain/ spasm and pain related inflammatory condition. Colicky abdominal pain may be caused by spasm of smooth muscles of various internal abdominal organs such as intestinal colic, biliary colic, renal colic and dysmenorrhoea. 5 DETAILED DESCRIPTION OF THE INVENTION The present invention describes a pharmaceutical composition comprising an antispasmodic is camylofin and an analgesic, antipyretic and antiinflammatory agent aspirin in a tablet dosage form. Therapeutic effective amount of Camylofin used in the formulation preferably as camylofin dihydrochloride or any pharmaceutically acceptable salt form or any other steriochemical pure form of it. Therapeutic effective amount of aspirin used in the formulation preferably in its pure form or any pharmaceutically acceptable salt form or any other steriochemical pure form of it. The main feature of this invention is the use of active ingredients for making the oral dosage form of the formulation Camylofin dihydrochloride and an analgesic, antipyretic and anti-inflammatory agent aspirin 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) 75 to 500 mg of aspirin (second active ingredient) (c) Pharmaceutically 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 pharmaceutical acceptable inert excipients consisting of at least one diluent 20% to 80% of the total mass of the formulation, at least one binder being 0.1% to 2 % of the total mass of the formulation, at least one glidant from 0.1% to 2 % of the total mass of the formulation, at least one lubricant being from 1 % to 4 % of the total mass of the formulation, optionally a surfactant being from 0.01% to 5% of the total mass of the formulation and at least one disintegrant being 1 % to 10 % of the total mass of the formulation and at least one film coat on the core consisting of at least 6 one film forming polymer and a plasticizer. The total film-coating layer is comprises 2 to 4 wt % based on the weight of the core composition. The diluent may be any pharmaceutically acceptable inert material selected from the group consisting of micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures thereof. 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, Croscarmellose sodium, polarcrin potassium resins, cellulose gum and mixtures thereof. The binders in the formulation increases the bulk density of the active particles and make it easier to formulate in a compressed form, It is at least one compound selected from a group of compounds consisting of pregelatinized starch, starches, gelatin, vinyl chloride, povidone, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethuyl cellulose, waxes and mixture thereof. The polymer for barrier coating granules includes, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethuyl cellulose phthalate, acrylate polymers and other suitable moisture protective and enteric coating polymers. The formulation includes optionally one surfactant selected from the group consisting of sodium lauryl sulfate, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, hydrogenated or non-hydrogenated glycerolipids, ethoxylated or non-ethoxylated, linear or branched, saturated or mono- or polyunsaturated C.sub.6 to C.sub.30 fatty acids in the form of the acid or an alkali metal or its salt, cyclodextrin, sodium lauryl sulfate, alkaline earth metal or amine salt, ethoxylated or non-ethoxylated esters' of sucrose, 7 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 thereof. 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 8 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, hydroxy propyl cellulose, plasticizers such as propylene glycol, surfactants, coloring agents that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brillant blue etc, solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and opacifier includes titanium dioxide. The weight of the film coating layer preferably 2 to 4 wt % based on the weight of the core composition may be employed. According to one aspect of this invention there is provided a process for making a synergistic antispasmodic, analgesic antipyretic formulation comprising the steps of [a] dissolving a dispensed quantity of binder in a solvent in a S.S. Container to form a first binder solution; [b] transferring dispensed quantities of sifted Camylofin Dihydrochloride and diluents, disintegrants in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing the Camylofin Dihydrochloride and diluents for 15 to 30 minutes at an ambient temperature below 25 degrees Celsius and relative humidity below 60%. to obtain a first uniform mass. [c] transferring the first binder solution slowly to the contents of planetary mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a first uniform dough is formed. [d] passing the first dough to a multimill fitted with sieves of diameter ranging from 10 mm to 14 mm at medium speed to produce wet granules of camylofin dihydrochloride; [e] transferring the wet camylofin dihydrochloride granules to a drier for drying at 50° C to 55° C [f] passing the dried camylofin dihydrochloride granules to 16-mesh sieve through vibrosifter and pass retained granules through multimill using 1.5mm 9 screen at a speed of 10 to 20 rpm to obtain dried uniformly sized granules of camylofin dihydrochloride; [g] dissolving a dispensed quantity of a second binder/ barrier coating polymer in second solvent in a S.S. container to form a second binder solution. [h] transferring dispensed quantities of sifted aspirin and excipients in a similar way as described above. [i] lubricating the granules by passing the uniformly sized dried active granules to a double cone blender together with dispensed quantities of sifted lubricants, glidants, and disintegrating agents and mixing for 10 to 20 minutes to obtain lubricated granules 0] compressing the lubricated granules at a compression pressure of 2 to 6 kg/sq cm . at Temperature between 20°C to 30°C and relative Humidity : Below 60% to form cores; [k] film coating the cores with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer. The weight of the total coating layer should be between 2.0 to 4 % of the total weight of the core. Following are few examples sited in accordance to the said formulation. But it is not intended that the scope of this invention is limited to these. EXAMPLE -1 Each tablet contains: Camylofin Dihydrochloride 50 mg Aspirin 325 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step - 1: Making the camylofin granules 5.0 Kg of Camylofin dihydrochloride, 8.0 kg of microcrystalline cellulose, 5.0 kg of dibasic calcium phosphate anhydrous and 0.1 kg of colloidal silicon dioxide were passed through a 40-mesh sieve and placed in' a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 10 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted. 300 gms of ethyl cellulose was mixed with 5 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.2%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the aspirin granules 32.5 kg of aspirin, 8.0 kg of microcrystalline cellulose, 3.0 kg of mannitol and 0.2 kg of colloidal silicon dioxide were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. 300 gms of hydroxypropyl methyl cellulose was mixed with 2 Kg of isopropyl alcohol and 3.0 kg of methylene chloride in a stainless steel [s.s.] tank under continuous stirring until a clear solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. 11 The wet granules were subjected to drying: The granules were subjected to drying at room temperature without heating in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 2%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 3: Lubrication Through a vibro sifter of mesh size 40 meshes the following materials were passed: 2.0 kg sodium starch glycolate, , 0.8 kg of talcum, and 0.6 kg of magnesium stearate. This sifted mass (except magnesium stearate) along with the dried granules of Camylofin and other actives were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of magnesium stearate; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass. Step - 4: Compression This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: capsule shaped, Standard curvature, with following dimension Length: 19.0 ±0.1 mm Width: 8.0 ±0.1 mm Average weight of core 658 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. Pre-coating solution: A pre-coating solution is prepared by dispersing 0.400 kg of ethyl cellulose and 0.200 kg of hydroxymethyl cellulose in 4.00 kg of isopropyl alcohol followed by addition of 6.0 kg methylene chloride and 100 ml of propylene glycol with constant stirring till to obtain a uniform slurry. Seal-coating solution: 12 A seal-coating suspension was prepared by mixing 0.6 kg of ethyl cellulose and 0.10 kg of hydroxypropyl cellulose and mixed together with 9 kg of isopropyl alcohol and 15 kg of Methylene chloride; 0.01 kg of diethyl phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron oxide yellow, and stirred for five minutes using overhead stirrer until smooth slurry was obtained. The freshly prepared coating solution was sieved through 80-mesh sieve and sprayed one after another by following the usual method. The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: Dimension: capsule shaped, Standard curvature, with following dimension Length: 19.2 ±0.1 mm Width: 8.2 ±0.1 mm Average weight of film coated tablet 574 mg ± 3 %. EXAMPLE - 2 Each tablet contains: Camylofin Dihydrochloride 50 mg Aspirin 250 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step -1: Making the camylofin granules 5.0 Kg of Camylofin dihydrochloride, 2.0 kg of lactose anhydrous, 5.0 kg of microcrystalline cellulose and 5.0 kg of dibasic calcium phosphate anhydrous were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted. 13 400 gms of cellulose acetate phthalate was mixed with 5 Kg of acetone in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.6%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step - 2: Lubrication 25.0 kg of aspirin, 12.0 kg of microcrystalline cellulose direct compressible grade (PH 112), 0.300 kg of colloidal silicon dioxide were sifted through 20 #. 0.8 kg of talcum and 0.8 kg of magnesium stearate were sifted through 40 # sieve. Sifted mass (except magnesium stearate) along with all dried granules of camylofin was transferred to a double cone blender at temperature of 22 degrees Celsius and! the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of magnesium stearate; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass. Step - 3: Compression This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: circular, standard curvature, with following dimension with 12.7 mm ±0.1 mm diameter Average weight of core 555 mg ± 3 %. 14 Step - 4: film - coating The cores were coated with a film coating. Film-coating solution: A film-coating suspension was prepared by mixing 0.4 kg of ethyl cellulose and 0.8 kg of hydroxypropyl cellulose and mixed together with 8 kg of isopropyl alcohol and 14 kg of Methylene chloride; 0.01 kg of diethyl phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron oxide yellow, 0.02 kg of red iron oxide and stirred for five minutes using overhead stirrer until smooth slurry was obtained. The freshly prepared coating solution was sieved through 80-mesh sieve and sprayed one after another by following the usual method. The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: Dimension: circular, standard curvature, with diameter 12.8 ±0.1 mm Average weight of film coated tablet 565 mg ± 3 %. EXAMPLE -3 Each tablet contains: Camylofin Dihydrochloride 50 mg Aspirin 300 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step -1: Making the camylofin granules 5.0 Kg of Camylofin dihydrochloride, 8.0 kg of microcrystalline cellulose, 5.0 kg of Starch and 0.1 kg of fume silica were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted. 15 200 gms of ethyl cellulose was mixed with 3 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. Separately dissolve 200 gms of cellulose acetate phthalate in acetone. Mix both the solution with slow stirring. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients. Wet mixing was then commenced for 22 minutes at 12 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to heat drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.8%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the aspirin granules 30.0 Kg of aspirin, 8.0 kg of microcrystalline cellulose were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. 300 gms of hydroxy propyl cellulose was mixed with 3 Kg of isopropyl alcohol and 3.0 kg of the methylene chloride in a stainless steel [s.s.] tank under continuous stirring until a clear solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: 16 The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 2.2 %. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 3: Lubrication Through a vibro sifter of mesh size 40 meshes the following materials were passed: 1.2 kg polarcrin potassium, 0.8 kg of talcum, and 0.6 kg of stearic acid. This sifted mass (except stearic acid and talcum) along with the dried granules of Camylofin and other active granules were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. The remaining blend of stearic acid and talcum; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass. Step - 4: Compression This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: circular, standard curvature, with 12.7 ± 0.1 mm diameter Average weight of core 594 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. Film-coating suspension: A film-coating suspension was prepared by mixing 0.6 kg of ethyl cellulose and 0.80 kg of hydroxypropyl cellulose and mixed together with 9 kg of isopropyl alcohol and 15 kg of Methylene chloride; 0.01 kg of triethyl citrate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron oxide yellow, and stirred for five minutes using overhead stirrer until smooth slurry was obtained. The freshly prepared coating solution was sieved through 80-mesh sieve and sprayed one after another by following the usual method. 17 The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: Dimension: circular, standard curvature, with diameter 12.8 ±0.1 mm Average weight of the film coated tablet 604 mg ± 3 %. EXAMPLE - 4 Each tablet contains: Camylofin Dihydrochloride 25 mg Aspirin 200 mg MANUFACTURING PROCESS (Batch Size: 1 lakh tablets) Step - 1: Making the camylofin granules 2.5 Kg of Camylofin dihydrochloride, 2.0 kg of dibasic calcium phosphate, 5.0 kg of microcrystalline cellulose, and 0.1 kg of colloidal silicon dioxide were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted. 300 gms of ethyl cellulose was mixed with 5 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: 18 The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.6%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules. Step 2: making the aspirin granules 20.0 Kg of aspirin, 5.0 kg of microcrystalline cellulose, 0.100 kg of colloidal silicon dioxide were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of actives and the diluents resulted. 200 gms of cellulose acetate phthalate was mixed with 5.0 kg of acetone in a stainless steel tank under continuous stirring until a clear solution is formed and the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mass. Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass. The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain granules of mesh size 8 to 12 mm. The wet granules were subjected to drying: The granules were subjected to drying at a room temperature without heating in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 1.8%. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size. Step - 3: Lubrication 1.0 kg croscarmellose sodium, 1.0 kg of sodium starch glycolate, 0.100 kg of colloidal silicon dioxide, 0.6 kg of talcum and 0.6 kg of calcium stearate were sifted through 40 # sieve. Sifted mass (except calcium stearate) along with all dried granules were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of calcium stearate; was then added to the blender and 19 further blending was done for 5 minutes resulting in the lubricated core mass. Step - 4: Compression This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: oval shaped, Standard curvature, with following dimension Length: 14.2 ±0.1 mm Width: 7.2 ±0.1 mm Average weight of core 385 mg ± 3 %. Step - 5: film - coating The cores were coated with a film coating. Film-coating solution: A film-coating suspension was prepared by mixing 0.4 kg of ethyl cellulose and 0.8 kg of hydroxypropyl cellulose and mixed together with 10.0 kg of isopropyl alcohol and 16.0 kg of Methylene chloride; 0.05 kg of diethyl phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron oxide yellow, 0.02 kg of red iron oxide and stirred for five minutes using overhead stirrer until smooth slurry was obtained. The freshly prepared coating solution was sieved through 80-mesh sieve and sprayed one after another by following the usual method. The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: Dimension: oval shaped, Standard curvature, with following dimension Length: 14.3 ±0.1 mm Width: 7.3 ±0.1 mm Average weight of film coated tablet 393 mg ± 3 %. 20 EXAMPLE - 5 RATIONALE / SYNERGY OF THE FORMULATION Camylofin is a synthetic fast acting anti-spasmodic indicated for the spasmodic conditions of the abdominal hollow organs. Additionally, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and antiinflammitive properties. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria. It induces the formation of NO-radicals in the body that enable the white bloodcells (leucocyts) to fight infections more effectively. The combination of aspirin and Camylofin has a classic with dual mechanism of action (viz. myotropic and neurotropic) ensuring fast relief from smooth muscle spasm and pain. The said formulation combination is indicated for intestinal colic, renal colic, biliary colic, spasmodic dysmenorrhoea. Trials were conducted by administering the tablets of the above examples to patients suffering from spasmodic pain v/ith slight fever and headache. The abstract of the trials is reported below in the section medical trials. Some patients were administered aspirin and camylofin separately and tablets of the above said formulation were given to some patients having the above indications. Significant results were obtained for the formulation of this invention over separate dose of camylofin or aspirin in different patients. Unexpectedly, the relief was obtained significantly earlier [perceived to be at least 10 to 15 minutes earlier] but was more satisfactory [perceived to be at least 16 % better]. In addition the single dosage form of the two active ingredients improved patient compliance as well as the cost of manufacture. MEDICAL TRIAL Four groups of each 20 patients of either sex are selected for Trial having symptoms (Coliky pain due to intestines, gall bladder, kidneys, ureters, urinary bladder and uterus pylorospasm). The observations of the trials are tabulated bellow. 21 TABLE-1 : GROUP-1 Age group - 21 to 30 yrs, Total number of patients - 20 (12 male and 8 female) PRODUCT SEX (NOS) OBSERVATION Male Female Aspirin 500 mg tablet 4 2 Spasm in the gastrointestinal tract persists even after 60 minutes. Headache like symptoms are relieved. There is a presentation of mild acidity in 3 cases (2 male & 1 female). Camylofin 50 mg tablet 4 3 Symptoms related to spasms are relieved completely after 40 to 45 minutes of dosing. No case of acidity was reported. Aspirin 325 mg + Camylofin 50 mg (Example-1) 4 3 Both spasmodic symptoms and pain symptoms are relieved completely between 20 to 25 minutes of dosing. No case of acidity reported. TABLE - 2 : GROUP - 2 Age group - 31 to 40 yrs, Total number of patients - 20 (10 male and 10 female) PRODUCT SEX (NOS) OBSERVATION Male Female Aspirin 500 mg tablet 3 3 Spasm in the gastrointestinal tract persisted even after 60 minutes. Headache like symptoms were relieved. There is a sign of mild acidity in 4 cases (2 male & 2 female). Camylofin 50 mg tablet 3 3 Symptoms related to spasms relieved completely after 44 to 52 minutes of dosing. No case of acidity was reported. Aspirin 325 mg + Camylofin 50 mg (Example-1) 4 4 Both spasmodic symptoms and pain symptoms relieved completely between 25 to 32 minutes of dosing. No case of acidity reported. 22 TABLE-3: GROUP-3 Age group : 41 to 50 yrs Total number of patients - 20 (8 male and 12 female) PRODUCT SEX (NOS) OBSERVATION Male Female Aspirin 500 mg tablet 2 4 Spasm in the gastrointestinal tract persisted even after 60 minutes. Headache like symptoms relieved. There was a sign of mild acidity in 2 female pateints. Camylofin 50 mg tablet 3 4 Symptoms related to spasms relieved completely after 38 to 45 minutes of dosing. No case of acidity was reported. Aspirin 325 mg + Camylofin 50 mg (Example-1) 3 4 Both spasmodic symptoms and pain symptoms are relives completely between 22 to 28 minutes of dosing. No case of acidity reported. TABLE -4: GROUP-4 Age group - 51 to 60 yrs Total number of patients - 20 (13 male and 7 female) PRODUCT SEX (NOS) OBSERVATION Male Female Aspirin 500 mg tablet 4 2 Spasm in the gastrointestinal tract persisted after 60 minutes. Headache like symptoms relieved. There was a sign of mild acidity in 2 cases (2 male). Camylofin 50 mg tablet 4 2 Symptoms related to spasms relieved completely after 45 to 54 minutes of dosing. No case of acidity was reported. Aspirin 325 mg + Camylofin 50 mg (Example-1) 5 3 Both spasmodic symptoms and pains symptoms are relieved completely between 25 to 30 minutes of dosing. No case of acidity reported. Therefore, significant results were obtained for the formulation of this invention over both Aspirin and Camylofin tablet administered separately. Unexpectedly, the relief was obtained significantly earlier and was more satisfactory. In addition the single dosage form of the two active ingredients improved patient compliance as well as the cost of manufacture. Thus it was concluded that combination of the above said active ingredients in an injection form have the synergistic effect with respect to the efficacy. 23 I Claim: 1. A synergistic pharmaceutical composition, comprising Camylofin and aspirin in tablet dosage form, comprising, i) 2 to 20 wt % of composition of camylofin dihydrochloride, ii) 20 to 50 wt % composition of of aspirin, iii) 20 wt % to 80 wt % composition of filler or diluent, iv) 0.1% to 2.0 wt % of composition of binder, v) 1 % to 10 wt % of composition of disintegrant, vi) 1 % to 4.0 wt % of composition of lubricant, vii) 0.1 % to 2.0 wt % composition of the flow promoter or glidant, viii) 2.0 % to 4.0 wt% of the film-coating layer, based on the total weight of the formulation, ix) pharmaceutical solvents. 2. The pharmaceutical composition according to claim 1, in which the diluent is at least one diluent selected from a group consisting of of micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures thereof. 3. The pharmaceutical composition according to claim 1, in which the binder 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, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethuyl cellulose phthalate, acrylate polymers, waxes and mixture thereof. 4. The pharmaceutical composition according to claim 1, 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, Croscarmellose sodium, natural starch, microcrystalline cellulose, polarcrin potassium resins, cellulose gum and mixtures thereof. 24 5. The pharmaceutical composition according to claim 1, in which the glidant is at least one compound selected from a group of compounds consisting of corn starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures thereof. 6. The pharmaceutical composition according to claim 1, in which the lubricant, is at least one compound selected from a group of compounds consisting of 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. 7. The pharmaceutical composition according to claim 1, in which the coating layer is selected form a group of compounds which consists of flm forming cellulose polymers such as Ethyl Cellulose and/ or hydroxypropylmethylcellulose, hydroxy propyl cellulose, plasticizers such as propylene glycol, surfactants, coloring agents that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brillant blue etc, solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and opacifier includes titanium dioxide. 8. A process for making a synergistic antispasmodic and analgesic, antipyretic and antiinflammitive formulation comprising the steps of [a] dissolving a dispensed quantity of binder in a solvent in a S.S. Container to form a first binder solution; [b] transferring dispensed quantities of sifted Camylofin Dihydrochloride and diluents, 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; 25 [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 rnultimill fitted with sieves of diameter ranging from 10 mm to 14 mm at medium speed to produce wet granules of camylofin dihydrochloride; [e] transferring the wet camylofin dihydrochloride granules to a drier for drying at 50° C to 55° C; [f] passing the dried camylofin dihydrochloride granules- to 16-mesh sieve through vibrosifter and pass retained granules through rnultimill using 1.5mm screen at a speed of 10 to 20 rpm to obtain dried uniformly sized granules of camylofin dihydrochloride; [g] dissolving a dispensed quantity of a second binder/ barrier coating polymer in second solvent in a S. S. container to form a second binder solution; h] transferring dispensed quantities of sifted aspirin and excipients in a similar way as described above or transfer directly to the planetary mixer directly without wet granulation; [i] lubricating the granules by passing the uniformly sized dried active granules to a double cone blender together with dispensed quantities of sifted lubricants, glidants, and disintegrating agents and mixing for 10 to 20 minutes to obtain lubricated granules; [j] compressing the lubricated granules at a compression pressure of 2 to 6 kg/sq cm . at Temperature between 20°C to 30°C and relative Humidity : Below 60% to form cores; [k] film coating the cores with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer. The weight of the total coating layer should be between 2.0 to 4 % of the total weight of the core.

Full Text

FORM - 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE
Specification
(See section 10 and rule 13)
SYNERGISTIC FORMULATION OF AN ANTISPASMODIC AND AN ANALGESIC, ANTIPYRETIC AND ANTI-INFLAMMATORY
AGENT IN TABLET FORM

SANJEEV KHANDELWAL
an Indian National
of Prem Nivas, 13, Altamount Road, Mumbai 400026, Maharashtra, India,

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

TITLE
Synergistic formulation of an antispasmodic and an analgesic, antipyretic and anti-inflammatory agent in tablet form.
FIELD OF INVENTION
This invention relates to a synergistic combination of an antispasmodic and an analgesic, antipyretic and anti-inflammatory formulation in a tablet dosage form and to a method of making the same. The synergistic tablet dosage form comprising Camylofin (antispasmodic) and aspirin (analgesic, antipyretic and anti-inflammatory) in their pharmaceutically acceptable form
BACKGROUND OF THE INVENTION
CAMYLOFIN
Camylofin dihydrochloride chemically it is isopentyl 2-[2-diethylaminoethylamino]-2-phenyl acetate dihydrochloride of molecular weight 393.4, Molecular Formula C19H32N202 2HCI. Camylofin is a pale yellow oil. Camylofin Dihydrochloride is a white crystalline powder melting point 170 °C and 180 °C, soluble in water.
Brock et al studied the chemical structure and pharmacological properties of camylofin dihydrochloride in detail. Camylofin 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 gm/ 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
2

the effective therapeutic dose to the toxicity dose in animal studies varies from 1:40 to 1:150.5.
ASPIRIN:

Appearance
Chemical name Chemical formula Molecular mass Density Melting point Boiling point Stability

: Odorless, Colourless or a white crystalline
powder
2-(acetyloxy)benzoic acid
C6H4(OCOCH3)COOH
180.57 g/mol
1.40 g/cm3
136°C (277°F) with decomposition
140°C (284°F)
Stable in dry air (hydrolyzes in moist air,
decomposes in hot water)

Aspirin or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory. It has also an anticoagulant (blood thinning) effect and is used in long-term low-doses to prevent heart attacks.
Low-dose long-term aspirin irreversibly blocks formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation, and this blood thinning property makes it useful for reducing the incidence of heart attacks. Aspirin produced for this purpose often comes in 75 or 81 mg dispersible tablets and is sometimes called "baby aspirin." High doses of aspirin are also given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may therefore produce a second and different anticoagulant effect.
Several hundred fatal overdoses of aspirin occur annually, but the vast majority of its uses are beneficial. Its primary undesirable side effects, especially in stronger doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side effect, due to its anticoagulant properties, is increased bleeding in menstruating women.
3
Because there appears to be a connection between aspirin and Reye's syndrome, aspirin is no longer used to control flu-like symptoms in minors.
Aspirin was the first discovered member of the class of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs), not all of which are salicylates, though they all have similar effects and a similar action mechanism.
More recent work has shown that there are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin inhibits both of them. Newer NSAID drugs called COX-2 selective inhibitors have been developed that only inhibit COX-2, with the hope that this would reduce the gastrointestinal side effects.
However, several of the new COX-2 selective inhibitors have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the arteries in the body express COX-2, and by selectively inhibiting COX-2, prostaglandins (specifically PGF2) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGF2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, rendering them "useless": an important difference with reversible inhibitors.
Additionally, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and antiinflammitive properties :
• It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria.
• It induces the formation of NO-radicals in the body that enable the white bloodcells (leucocyts) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005.
4

Also recently aspirin has been proven to prevent carcinoma of the colon, if given in low doses over years.
Aspirin has analgesic, antipyretic and anti-inflammatory actions.
Aspirin is indicated for short-term use in the relief of mild to moderate pain (headache, toothache, menstrual cramps, neuralgia, muscular pain, pain associated with colds) and fever.
Aspirin, as with many older drugs, has proven to be useful in many conditions, and despite its well-known toxicity, it is widely used, since physicians are familiar with its properties. Indications for its use include:
• Fever
• Pain (especially useful for conditions involving osteoid osteoma,
arthritis and chronic pain)
• Migraine
• Myocardial infarction prophylaxis (low dose)
• Rheumatic fever (drug of choice)
Aspirin is a moisture sensitive drug and can hydrolyze into acetic and salicylic acids. Hydrophilic excipients can have adverse effects on aspirin under accelerated stability conditions.
SUMMARY OF INVENTION
This invention relates to a synergistic combination of an antispasmodic and an analgesic, antipyretic and anti-inflammatory formulation in a tablet form and to a method of making the same particularly for the treatment of colicky pain/ spasm and pain related inflammatory condition.
Colicky abdominal pain may be caused by spasm of smooth muscles of various internal abdominal organs such as intestinal colic, biliary colic, renal colic and dysmenorrhoea.
5

DETAILED DESCRIPTION OF THE INVENTION
The present invention describes a pharmaceutical composition comprising an antispasmodic is camylofin and an analgesic, antipyretic and antiinflammatory agent aspirin in a tablet dosage form.
Therapeutic effective amount of Camylofin used in the formulation preferably as camylofin dihydrochloride or any pharmaceutically acceptable salt form or any other steriochemical pure form of it.
Therapeutic effective amount of aspirin used in the formulation preferably in its pure form or any pharmaceutically acceptable salt form or any other steriochemical pure form of it.
The main feature of this invention is the use of active ingredients for making the oral dosage form of the formulation Camylofin dihydrochloride and an analgesic, antipyretic and anti-inflammatory agent aspirin 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) 75 to 500 mg of aspirin (second active ingredient)
(c) Pharmaceutically 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 pharmaceutical acceptable inert excipients consisting of at least one diluent 20% to 80% of the total mass of the formulation, at least one binder being 0.1% to 2 % of the total mass of the formulation, at least one glidant from 0.1% to 2 % of the total mass of the formulation, at least one lubricant being from 1 % to 4 % of the total mass of the formulation, optionally a surfactant being from 0.01% to 5% of the total mass of the formulation and at least one disintegrant being 1 % to 10 % of the total mass of the formulation and at least one film coat on the core consisting of at least
6

one film forming polymer and a plasticizer. The total film-coating layer is comprises 2 to 4 wt % based on the weight of the core composition.
The diluent may be any pharmaceutically acceptable inert material selected from the group consisting of micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures thereof.
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, Croscarmellose sodium, polarcrin potassium resins, cellulose gum and mixtures thereof.
The binders in the formulation increases the bulk density of the active particles and make it easier to formulate in a compressed form, It is at least one compound selected from a group of compounds consisting of pregelatinized starch, starches, gelatin, vinyl chloride, povidone, hydroxypropyl cellulose, ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethuyl cellulose, waxes and mixture thereof.
The polymer for barrier coating granules includes, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethuyl cellulose phthalate, acrylate polymers and other suitable moisture protective and enteric coating polymers.
The formulation includes optionally one surfactant selected from the group consisting of sodium lauryl sulfate, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, hydrogenated or non-hydrogenated glycerolipids, ethoxylated or non-ethoxylated, linear or branched, saturated or mono- or polyunsaturated C.sub.6 to C.sub.30 fatty acids in the form of the acid or an alkali metal or its salt, cyclodextrin, sodium lauryl sulfate, alkaline earth metal or amine salt, ethoxylated or non-ethoxylated esters' of sucrose,
7

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 thereof.
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
8

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, hydroxy propyl cellulose, plasticizers such as propylene glycol, surfactants, coloring agents that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brillant blue etc, solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and opacifier includes titanium dioxide. The weight of the film coating layer preferably 2 to 4 wt % based on the weight of the core composition may be employed.
According to one aspect of this invention there is provided a process for making a synergistic antispasmodic, analgesic antipyretic formulation comprising the steps of
[a] dissolving a dispensed quantity of binder in a solvent in a S.S. Container to form a first binder solution;
[b] transferring dispensed quantities of sifted Camylofin Dihydrochloride and diluents, disintegrants in a planetary mixer with variable speed ranges from 12 to 40 rpm and mixing the Camylofin Dihydrochloride and diluents for 15 to 30 minutes at an ambient temperature below 25 degrees Celsius and relative humidity below 60%. to obtain a first uniform mass.
[c] transferring the first binder solution slowly to the contents of planetary mixer and rotating the planetary mixer at slow speed for 10 to 20 minutes till a first uniform dough is formed.

[d] passing the first dough to a multimill fitted with sieves of diameter ranging from 10 mm to 14 mm at medium speed to produce wet granules of camylofin dihydrochloride;
[e] transferring the wet camylofin dihydrochloride granules to a drier for drying at 50° C to 55° C
[f] passing the dried camylofin dihydrochloride granules to 16-mesh sieve
through vibrosifter and pass retained granules through multimill using 1.5mm
9

screen at a speed of 10 to 20 rpm to obtain dried uniformly sized granules of
camylofin dihydrochloride;
[g] dissolving a dispensed quantity of a second binder/ barrier coating
polymer in second solvent in a S.S. container to form a second binder
solution.
[h] transferring dispensed quantities of sifted aspirin and excipients in a
similar way as described above.
[i] lubricating the granules by passing the uniformly sized dried active
granules to a double cone blender together with dispensed quantities of
sifted lubricants, glidants, and disintegrating agents and mixing for 10 to 20
minutes to obtain lubricated granules
0] compressing the lubricated granules at a compression pressure of 2 to 6
kg/sq cm . at Temperature between 20°C to 30°C and relative Humidity :
Below 60% to form cores;
[k] film coating the cores with at least one film coat comprising dispensed
quantities of film forming polymer and plasticizer. The weight of the total
coating layer should be between 2.0 to 4 % of the total weight of the core.
Following are few examples sited in accordance to the said formulation. But it is not intended that the scope of this invention is limited to these.
EXAMPLE -1
Each tablet contains:
Camylofin Dihydrochloride 50 mg
Aspirin 325 mg
MANUFACTURING PROCESS (Batch Size: 1 lakh tablets)
Step - 1: Making the camylofin granules
5.0 Kg of Camylofin dihydrochloride, 8.0 kg of microcrystalline cellulose, 5.0 kg of dibasic calcium phosphate anhydrous and 0.1 kg of colloidal silicon dioxide were passed through a 40-mesh sieve and placed in' a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30
10

r.p.m. so that a homogenous mixture of the particles of Camylofin and the
above said inert excipients resulted.
300 gms of ethyl cellulose was mixed with 5 Kg of isopropyl alcohol in a
stainless steel [s.s.] tank under continuous stirring until the binder was
completely dissolved in the solvent. The solution was then added to the
planetary mixer containing the homogenous mixture of the particles of
Camylofin with the excipients.
Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet
homogenous mixture mass.
The wet homogenous mixture mass was milled, in a multimill fitted with 12
mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm.
The wet granules were subjected to drying:
The granules were subjected to heated drying at a temperature of 50 to 60
degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during
the process. The Loss on drying was 1.2%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform
sized camylofin granules.
Step 2: making the aspirin granules
32.5 kg of aspirin, 8.0 kg of microcrystalline cellulose, 3.0 kg of mannitol and
0.2 kg of colloidal silicon dioxide were passed through a 40-mesh sieve and
placed in a planetary mixer. The ambient temperature was maintained below
25 degrees Celsius and the relative humidity below 60%. The mixer was run
for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of
actives and the diluents resulted.
300 gms of hydroxypropyl methyl cellulose was mixed with 2 Kg of isopropyl
alcohol and 3.0 kg of methylene chloride in a stainless steel [s.s.] tank under
continuous stirring until a clear solution is formed and the binder was
completely dissolved in the solvent. The solution was then added to the
planetary mixer containing the homogenous mass.
Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet
homogenous mixture mass.
The wet homogenous mixture mass was milled, in a multimill fitted with 12
mm perforated sieve to obtain granules of mesh size 8 to 12 mm.
11

The wet granules were subjected to drying:
The granules were subjected to drying at room temperature without heating
in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the
process. The Loss on drying was 2%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size.
Step - 3: Lubrication
Through a vibro sifter of mesh size 40 meshes the following materials were passed:
2.0 kg sodium starch glycolate, , 0.8 kg of talcum, and 0.6 kg of magnesium stearate. This sifted mass (except magnesium stearate) along with the dried granules of Camylofin and other actives were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of magnesium stearate; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass.
Step - 4: Compression
This core mass was fed to hopper of a single rotary compression machine
and the compression pressure was set at 3 kg/sq cm.
Dimension: capsule shaped, Standard curvature, with following dimension
Length: 19.0 ±0.1 mm
Width: 8.0 ±0.1 mm
Average weight of core 658 mg ± 3 %.
Step - 5: film - coating
The cores were coated with a film coating.
Pre-coating solution:
A pre-coating solution is prepared by dispersing 0.400 kg of ethyl cellulose
and 0.200 kg of hydroxymethyl cellulose in 4.00 kg of isopropyl alcohol
followed by addition of 6.0 kg methylene chloride and 100 ml of propylene
glycol with constant stirring till to obtain a uniform slurry.
Seal-coating solution:
12

A seal-coating suspension was prepared by mixing 0.6 kg of ethyl cellulose
and 0.10 kg of hydroxypropyl cellulose and mixed together with 9 kg of
isopropyl alcohol and 15 kg of Methylene chloride; 0.01 kg of diethyl
phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron
oxide yellow, and stirred for five minutes using overhead stirrer until smooth
slurry was obtained.
The freshly prepared coating solution was sieved through 80-mesh sieve
and sprayed one after another by following the usual method.
The de-dusted cores were transferred into a coating pan and the tablet bed
was heated by inching process using hot air blower. The initial temperature
was set at 40°C. Once the tablet bed attains 45°C it was ready for spray
coating with the coating suspension. The cores were coated with the
coating suspension. The relative humidity was maintained below 60 %
throughout. The coated tablets were polished with talc.
Final dimensions of the tablets were as follows:
Dimension: capsule shaped, Standard curvature, with following dimension
Length: 19.2 ±0.1 mm
Width: 8.2 ±0.1 mm
Average weight of film coated tablet 574 mg ± 3 %.
EXAMPLE - 2
Each tablet contains:
Camylofin Dihydrochloride 50 mg
Aspirin 250 mg
MANUFACTURING PROCESS (Batch Size: 1 lakh tablets)
Step -1: Making the camylofin granules
5.0 Kg of Camylofin dihydrochloride, 2.0 kg of lactose anhydrous, 5.0 kg of microcrystalline cellulose and 5.0 kg of dibasic calcium phosphate anhydrous were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted.
13

400 gms of cellulose acetate phthalate was mixed with 5 Kg of acetone in a
stainless steel [s.s.] tank under continuous stirring until the binder was
completely dissolved in the solvent. The solution was then added to the
planetary mixer containing the homogenous mixture of the particles of
Camylofin with the excipients.
Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet
homogenous mixture mass.
The wet homogenous mixture mass was milled, in a multimill fitted with 12
mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm.
The wet granules were subjected to drying:
The granules were subjected to heated drying at a temperature of 50 to 60
degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during
the process. The Loss on drying was 1.6%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform
sized camylofin granules.
Step - 2: Lubrication
25.0 kg of aspirin, 12.0 kg of microcrystalline cellulose direct compressible grade (PH 112), 0.300 kg of colloidal silicon dioxide were sifted through 20 #. 0.8 kg of talcum and 0.8 kg of magnesium stearate were sifted through 40 # sieve. Sifted mass (except magnesium stearate) along with all dried granules of camylofin was transferred to a double cone blender at temperature of 22 degrees Celsius and! the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of magnesium stearate; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass.
Step - 3: Compression
This core mass was fed to hopper of a single rotary compression machine
and the compression pressure was set at 3 kg/sq cm.
Dimension: circular, standard curvature, with following dimension with 12.7
mm ±0.1 mm diameter
Average weight of core 555 mg ± 3 %.
14

Step - 4: film - coating
The cores were coated with a film coating.
Film-coating solution:
A film-coating suspension was prepared by mixing 0.4 kg of ethyl cellulose
and 0.8 kg of hydroxypropyl cellulose and mixed together with 8 kg of
isopropyl alcohol and 14 kg of Methylene chloride; 0.01 kg of diethyl
phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron
oxide yellow, 0.02 kg of red iron oxide and stirred for five minutes using
overhead stirrer until smooth slurry was obtained.
The freshly prepared coating solution was sieved through 80-mesh sieve
and sprayed one after another by following the usual method.
The de-dusted cores were transferred into a coating pan and the tablet bed
was heated by inching process using hot air blower. The initial temperature
was set at 40°C. Once the tablet bed attains 45°C it was ready for spray
coating with the coating suspension. The cores were coated with the
coating suspension. The relative humidity was maintained below 60 %
throughout. The coated tablets were polished with talc.
Final dimensions of the tablets were as follows:
Dimension: circular, standard curvature, with diameter 12.8 ±0.1 mm
Average weight of film coated tablet 565 mg ± 3 %.
EXAMPLE -3
Each tablet contains:
Camylofin Dihydrochloride 50 mg
Aspirin 300 mg
MANUFACTURING PROCESS (Batch Size: 1 lakh tablets)
Step -1: Making the camylofin granules
5.0 Kg of Camylofin dihydrochloride, 8.0 kg of microcrystalline cellulose, 5.0 kg of Starch and 0.1 kg of fume silica were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted.
15

200 gms of ethyl cellulose was mixed with 3 Kg of isopropyl alcohol in a
stainless steel [s.s.] tank under continuous stirring until the binder was
completely dissolved in the solvent. Separately dissolve 200 gms of
cellulose acetate phthalate in acetone. Mix both the solution with slow
stirring. The solution was then added to the planetary mixer containing the
homogenous mixture of the particles of Camylofin with the excipients.
Wet mixing was then commenced for 22 minutes at 12 r.p.m. to obtain a wet
homogenous mixture mass.
The wet homogenous mixture mass was milled, in a multimill fitted with 12
mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm.
The wet granules were subjected to drying:
The granules were subjected to heat drying at a temperature of 50 to 60
degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during
the process. The Loss on drying was 1.8%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform
sized camylofin granules.
Step 2: making the aspirin granules
30.0 Kg of aspirin, 8.0 kg of microcrystalline cellulose were passed through a
40-mesh sieve and placed in a planetary mixer. The ambient temperature
was maintained below 25 degrees Celsius and the relative humidity below
60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous
mixture of the particles of actives and the diluents resulted.
300 gms of hydroxy propyl cellulose was mixed with 3 Kg of isopropyl
alcohol and 3.0 kg of the methylene chloride in a stainless steel [s.s.] tank
under continuous stirring until a clear solution is formed and the binder was
completely dissolved in the solvent. The solution was then added to the
planetary mixer containing the homogenous mass.
Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet
homogenous mixture mass.
The wet homogenous mixture mass was milled, in a multimill fitted with 12
mm perforated sieve to obtain granules of mesh size 8 to 12 mm.
The wet granules were subjected to drying:
16

The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a fluidized bed dryer for 1.5 hrs. The drying mass was raked during the process. The Loss on drying was 2.2 %. The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size.
Step - 3: Lubrication
Through a vibro sifter of mesh size 40 meshes the following materials were passed:
1.2 kg polarcrin potassium, 0.8 kg of talcum, and 0.6 kg of stearic acid. This sifted mass (except stearic acid and talcum) along with the dried granules of Camylofin and other active granules were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. The remaining blend of stearic acid and talcum; was then added to the blender and further blending was done for 5 minutes resulting in the lubricated core mass.
Step - 4: Compression
This core mass was fed to hopper of a single rotary compression machine and the compression pressure was set at 3 kg/sq cm. Dimension: circular, standard curvature, with 12.7 ± 0.1 mm diameter Average weight of core 594 mg ± 3 %.
Step - 5: film - coating
The cores were coated with a film coating.
Film-coating suspension:
A film-coating suspension was prepared by mixing 0.6 kg of ethyl cellulose
and 0.80 kg of hydroxypropyl cellulose and mixed together with 9 kg of
isopropyl alcohol and 15 kg of Methylene chloride; 0.01 kg of triethyl citrate,
0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron oxide yellow,
and stirred for five minutes using overhead stirrer until smooth slurry was
obtained.
The freshly prepared coating solution was sieved through 80-mesh sieve
and sprayed one after another by following the usual method.
17

The de-dusted cores were transferred into a coating pan and the tablet bed was heated by inching process using hot air blower. The initial temperature was set at 40°C. Once the tablet bed attains 45°C it was ready for spray coating with the coating suspension. The cores were coated with the coating suspension. The relative humidity was maintained below 60 % throughout. The coated tablets were polished with talc. Final dimensions of the tablets were as follows: Dimension: circular, standard curvature, with diameter 12.8 ±0.1 mm Average weight of the film coated tablet 604 mg ± 3 %.
EXAMPLE - 4
Each tablet contains:
Camylofin Dihydrochloride 25 mg
Aspirin 200 mg
MANUFACTURING PROCESS (Batch Size: 1 lakh tablets)
Step - 1: Making the camylofin granules
2.5 Kg of Camylofin dihydrochloride, 2.0 kg of dibasic calcium phosphate, 5.0 kg of microcrystalline cellulose, and 0.1 kg of colloidal silicon dioxide were passed through a 40-mesh sieve and placed in a planetary mixer. The ambient temperature was maintained below 25 degrees Celsius and the relative humidity below 60%. The mixer was run for 25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of Camylofin and the above said inert excipients resulted.
300 gms of ethyl cellulose was mixed with 5 Kg of isopropyl alcohol in a stainless steel [s.s.] tank under continuous stirring until the binder was completely dissolved in the solvent. The solution was then added to the planetary mixer containing the homogenous mixture of the particles of Camylofin with the excipients.
Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet homogenous mixture mass.
The wet homogenous mixture mass was milled, in a multimill fitted with 12 mm perforated sieve to obtain camylofin granules of mesh size 8 to 12 mm. The wet granules were subjected to drying:
18

The granules were subjected to heated drying at a temperature of 50 to 60 degrees Celsius in a tray drier for 6 hrs. The drying mass was raked during the process. The Loss on drying was 1.6%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform sized camylofin granules.
Step 2: making the aspirin granules
20.0 Kg of aspirin, 5.0 kg of microcrystalline cellulose, 0.100 kg of colloidal
silicon dioxide were passed through a 40-mesh sieve and placed in a
planetary mixer. The ambient temperature was maintained below 25
degrees Celsius and the relative humidity below 60%. The mixer was run for
25 minutes at 30 r.p.m. so that a homogenous mixture of the particles of
actives and the diluents resulted.
200 gms of cellulose acetate phthalate was mixed with 5.0 kg of acetone in a
stainless steel tank under continuous stirring until a clear solution is formed
and the binder was completely dissolved in the solvent. The solution was
then added to the planetary mixer containing the homogenous mass.
Wet mixing was then commenced for 20 minutes at 15 r.p.m. to obtain a wet
homogenous mixture mass.
The wet homogenous mixture mass was milled, in a multimill fitted with 12
mm perforated sieve to obtain granules of mesh size 8 to 12 mm.
The wet granules were subjected to drying:
The granules were subjected to drying at a room temperature without
heating in a fluidized bed dryer for 1.5 hrs. The drying mass was raked
during the process. The Loss on drying was 1.8%.
The dry granules were sifted in an 18-mesh vibrosifter to obtain uniform size.
Step - 3: Lubrication
1.0 kg croscarmellose sodium, 1.0 kg of sodium starch glycolate, 0.100 kg of colloidal silicon dioxide, 0.6 kg of talcum and 0.6 kg of calcium stearate were sifted through 40 # sieve. Sifted mass (except calcium stearate) along with all dried granules were transferred to a double cone blender at temperature of 22 degrees Celsius and the mass was blended at speed of 30 r.p.m. for 25 minutes. 0.6 kg of calcium stearate; was then added to the blender and
19

further blending was done for 5 minutes resulting in the lubricated core mass.
Step - 4: Compression
This core mass was fed to hopper of a single rotary compression machine
and the compression pressure was set at 3 kg/sq cm.
Dimension: oval shaped, Standard curvature, with following dimension
Length: 14.2 ±0.1 mm
Width: 7.2 ±0.1 mm
Average weight of core 385 mg ± 3 %.
Step - 5: film - coating
The cores were coated with a film coating.
Film-coating solution:
A film-coating suspension was prepared by mixing 0.4 kg of ethyl cellulose
and 0.8 kg of hydroxypropyl cellulose and mixed together with 10.0 kg of
isopropyl alcohol and 16.0 kg of Methylene chloride; 0.05 kg of diethyl
phthalate, 0.05 kg of titanium dioxide in a s.s. Container, 0.02 kg of iron
oxide yellow, 0.02 kg of red iron oxide and stirred for five minutes using
overhead stirrer until smooth slurry was obtained.
The freshly prepared coating solution was sieved through 80-mesh sieve
and sprayed one after another by following the usual method.
The de-dusted cores were transferred into a coating pan and the tablet bed
was heated by inching process using hot air blower. The initial temperature
was set at 40°C. Once the tablet bed attains 45°C it was ready for spray
coating with the coating suspension. The cores were coated with the
coating suspension. The relative humidity was maintained below 60 %
throughout. The coated tablets were polished with talc.
Final dimensions of the tablets were as follows:
Dimension: oval shaped, Standard curvature, with following dimension
Length: 14.3 ±0.1 mm
Width: 7.3 ±0.1 mm
Average weight of film coated tablet 393 mg ± 3 %.
20

EXAMPLE - 5
RATIONALE / SYNERGY OF THE FORMULATION
Camylofin is a synthetic fast acting anti-spasmodic indicated for the spasmodic conditions of the abdominal hollow organs. Additionally, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and antiinflammitive properties. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria. It induces the formation of NO-radicals in the body that enable the white bloodcells (leucocyts) to fight infections more effectively. The combination of aspirin and Camylofin has a classic with dual mechanism of action (viz. myotropic and neurotropic) ensuring fast relief from smooth muscle spasm and pain. The said formulation combination is indicated for intestinal colic, renal colic, biliary colic, spasmodic dysmenorrhoea.
Trials were conducted by administering the tablets of the above examples to patients suffering from spasmodic pain v/ith slight fever and headache. The abstract of the trials is reported below in the section medical trials. Some patients were administered aspirin and camylofin separately and tablets of the above said formulation were given to some patients having the above indications. Significant results were obtained for the formulation of this invention over separate dose of camylofin or aspirin in different patients. Unexpectedly, the relief was obtained significantly earlier [perceived to be at least 10 to 15 minutes earlier] but was more satisfactory [perceived to be at least 16 % better]. In addition the single dosage form of the two active ingredients improved patient compliance as well as the cost of manufacture.
MEDICAL TRIAL
Four groups of each 20 patients of either sex are selected for Trial having symptoms (Coliky pain due to intestines, gall bladder, kidneys, ureters, urinary bladder and uterus pylorospasm). The observations of the trials are tabulated bellow.
21

TABLE-1 : GROUP-1
Age group - 21 to 30 yrs, Total number of patients - 20 (12 male and 8 female)

PRODUCT SEX (NOS) OBSERVATION
Male Female
Aspirin 500 mg tablet 4 2 Spasm in the gastrointestinal tract persists even after 60 minutes. Headache like symptoms are relieved. There is a presentation of mild acidity in 3 cases (2 male & 1 female).
Camylofin 50 mg tablet 4 3 Symptoms related to spasms are relieved completely after 40 to 45 minutes of dosing. No case of acidity was reported.
Aspirin 325 mg + Camylofin 50 mg (Example-1) 4 3 Both spasmodic symptoms and pain symptoms are relieved completely between 20 to 25 minutes of dosing. No case of acidity reported.
TABLE - 2 : GROUP - 2
Age group - 31 to 40 yrs, Total number of patients - 20 (10 male and 10 female)

PRODUCT SEX (NOS) OBSERVATION
Male Female
Aspirin 500 mg tablet 3 3 Spasm in the gastrointestinal tract persisted even after 60 minutes. Headache like symptoms were relieved. There is a sign of mild acidity in 4 cases (2 male & 2 female).
Camylofin 50 mg tablet 3 3 Symptoms related to spasms relieved completely after 44 to 52 minutes of dosing. No case of acidity was reported.
Aspirin 325 mg + Camylofin 50 mg (Example-1) 4 4 Both spasmodic symptoms and pain symptoms relieved completely between 25 to 32 minutes of dosing. No case of acidity reported.
22

TABLE-3: GROUP-3
Age group : 41 to 50 yrs
Total number of patients - 20 (8 male and 12 female)

PRODUCT SEX (NOS) OBSERVATION
Male Female
Aspirin 500 mg tablet 2 4 Spasm in the gastrointestinal tract persisted even after 60 minutes. Headache like symptoms relieved. There was a sign of mild acidity in 2 female pateints.
Camylofin 50 mg tablet 3 4 Symptoms related to spasms relieved completely after 38 to 45 minutes of dosing. No case of acidity was reported.
Aspirin 325 mg + Camylofin 50 mg (Example-1) 3 4 Both spasmodic symptoms and pain symptoms are relives completely between 22 to 28 minutes of dosing. No case of acidity reported.
TABLE -4: GROUP-4
Age group - 51 to 60 yrs
Total number of patients - 20 (13 male and 7 female)

PRODUCT SEX (NOS) OBSERVATION
Male Female
Aspirin 500 mg tablet 4 2 Spasm in the gastrointestinal tract persisted after 60 minutes. Headache like symptoms relieved. There was a sign of mild acidity in 2 cases (2 male).
Camylofin 50 mg tablet 4 2 Symptoms related to spasms relieved completely after 45 to 54 minutes of dosing. No case of acidity was reported.
Aspirin 325 mg + Camylofin 50 mg (Example-1) 5 3 Both spasmodic symptoms and pains symptoms are relieved completely between 25 to 30 minutes of dosing. No case of acidity reported.
Therefore, significant results were obtained for the formulation of this invention over both Aspirin and Camylofin tablet administered separately. Unexpectedly, the relief was obtained significantly earlier and was more satisfactory. In addition the single dosage form of the two active ingredients improved patient compliance as well as the cost of manufacture.
Thus it was concluded that combination of the above said active ingredients in an injection form have the synergistic effect with respect to the efficacy.
23

I Claim:
1. A synergistic pharmaceutical composition, comprising Camylofin and
aspirin in tablet dosage form, comprising,
i) 2 to 20 wt % of composition of camylofin dihydrochloride,
ii) 20 to 50 wt % composition of of aspirin,
iii) 20 wt % to 80 wt % composition of filler or diluent,
iv) 0.1% to 2.0 wt % of composition of binder,
v) 1 % to 10 wt % of composition of disintegrant,
vi) 1 % to 4.0 wt % of composition of lubricant,
vii) 0.1 % to 2.0 wt % composition of the flow promoter or glidant,
viii) 2.0 % to 4.0 wt% of the film-coating layer, based on the total
weight of the formulation,
ix) pharmaceutical solvents.
2. The pharmaceutical composition according to claim 1, in which the diluent is at least one diluent selected from a group consisting of of micorcrystalline cellulose, starches, lactose, mannitol, calcium phosphate, dibasic calcium phosphate and mixtures thereof.
3. The pharmaceutical composition according to claim 1, in which the binder 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, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethuyl cellulose phthalate, acrylate polymers, waxes and mixture thereof.
4. The pharmaceutical composition according to claim 1, 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, Croscarmellose sodium, natural starch, microcrystalline cellulose, polarcrin potassium resins, cellulose gum and mixtures thereof.
24

5. The pharmaceutical composition according to claim 1, in which the glidant is at least one compound selected from a group of compounds consisting of corn starch, talcum, colloidal silicon dioxide, silicon dioxide and mixtures thereof.
6. The pharmaceutical composition according to claim 1, in which the lubricant, is at least one compound selected from a group of compounds consisting of 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.
7. The pharmaceutical composition according to claim 1, in which the coating layer is selected form a group of compounds which consists of flm forming cellulose polymers such as Ethyl Cellulose and/ or hydroxypropylmethylcellulose, hydroxy propyl cellulose, plasticizers such as propylene glycol, surfactants, coloring agents that may comprises at least one of the approved food and drug colors such as yellow iron oxides, tetrazine, brillant blue etc, solvents such as purified water, isopropyl alcohol, acetone, methylene chloride and opacifier includes titanium dioxide.
8. A process for making a synergistic antispasmodic and analgesic, antipyretic and antiinflammitive formulation comprising the steps of
[a] dissolving a dispensed quantity of binder in a solvent in a S.S.
Container to form a first binder solution;
[b] transferring dispensed quantities of sifted Camylofin
Dihydrochloride and diluents, 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;
25

[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 rnultimill fitted with sieves of diameter ranging from 10 mm to 14 mm at medium speed to produce wet granules of camylofin dihydrochloride;
[e] transferring the wet camylofin dihydrochloride granules to a drier for drying at 50° C to 55° C;
[f] passing the dried camylofin dihydrochloride granules- to 16-mesh sieve through vibrosifter and pass retained granules through rnultimill using 1.5mm screen at a speed of 10 to 20 rpm to obtain dried uniformly sized granules of camylofin dihydrochloride;
[g] dissolving a dispensed quantity of a second binder/ barrier coating polymer in second solvent in a S. S. container to form a second binder solution;
h] transferring dispensed quantities of sifted aspirin and excipients in a similar way as described above or transfer directly to the planetary mixer directly without wet granulation;
[i] lubricating the granules by passing the uniformly sized dried active granules to a double cone blender together with dispensed quantities of sifted lubricants, glidants, and disintegrating agents and mixing for 10 to 20 minutes to obtain lubricated granules;
[j] compressing the lubricated granules at a compression pressure of
2 to 6 kg/sq cm . at Temperature between 20°C to 30°C and relative
Humidity : Below 60% to form cores;
[k] film coating the cores with at least one film coat comprising dispensed quantities of film forming polymer and plasticizer. The weight of the total coating layer should be between 2.0 to 4 % of the total weight of the core.

Documents:

192-mum-2005-abstract (complete).doc

192-mum-2005-abstract (complete).pdf

192-mum-2005-abstract(21-05-2007).doc

192-mum-2005-abstract(21-05-2007).pdf

192-mum-2005-cancelled pages(21-05-2007).pdf

192-mum-2005-claims (complete).doc

192-mum-2005-claims (complete).pdf

192-mum-2005-claims(granted)-(21-05-2007).doc

192-mum-2005-claims(granted)-(21-05-2007).pdf

192-mum-2005-correspondence(21-05-2008).pdf

192-mum-2005-correspondence(ipo)-(11-11-2008).pdf

192-mum-2005-correspondence-received.pdf

192-mum-2005-declaration(21-02-2005).pdf

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

192-mum-2005-description (provisional).pdf

192-mum-2005-form 1(22-02-2005).pdf

192-mum-2005-form 18(10-11-2006).pdf

192-mum-2005-form 2(granted)-(21-05-2007).doc

192-mum-2005-form 2(granted)-(21-05-2007).pdf

192-mum-2005-form 3(22-02-2005).pdf

192-mum-2005-form 5(17-02-2006).pdf

192-mum-2005-form-1.pdf

192-mum-2005-form-2 (complete).pdf

192-mum-2005-form-2 (provisional).doc

192-mum-2005-form-2 (provisional).pdf

192-mum-2005-form-26.pdf

192-mum-2005-form-3.pdf

192-mum-2005-form-5.pdf

192-mum-2005-power of attorney(22-02-2005).pdf

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Patent Number

225372

Indian Patent Application Number

192/MUM/2005

PG Journal Number

07/2009

Publication Date

13-Feb-2009

Grant Date

11-Nov-2008

Date of Filing

22-Feb-2005

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.
2	PRATIBHA OMRAY	501, REDWOODS, VASANT GARDEN, MULUND(W) MUMBAI- 400 080, MAHARASHTRA,INDIA.

PCT International Classification Number

A61K31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA