Title of Invention

AN ANTISPASMODIC ANALGESIC SYNERGISTIC FORMULATION FOR THE RELIEF OF PAIN IN AN ORAL SYRUP FORM

Abstract

An antispasmodic analgesic synergistic oral syrup formulation comprising (a) 5 to 30 mg of camylofin dihydrochloride per 5 ml of the formulation; (b) 50 to 250 mg of paracetamol per 5 ml of the formulation; (c) 20 to 60 wt % of adjuvant solvents used alone or in combination based on the total mass of the formulation; (d) 40 to 60 wt % of a syrup base based on the total mass of the formulation; (e) 0.1 to 5 wt % of a flavoring agent used alone or in combinations based on the total mass of the formulation; (f) 0.1 to 4 wt % of a buffering agent based on the total mass of the formulation; (g) 0.001 to 3 wt % of a buffering agent used alone or in combination based on the total mass of the formulation; (h) 0.001 to 2 wt % of F&D approved colors used alone or in combination based on the total mass of the formulation; (i) 0.01 to 3 wt % of an buffering agent (optional) used alone or in combination based on the total mass of the formulation; (j) 0.01 to 3 wt % of a surfactant (optional) used alone or in combination based on the total mass of the formulation.

Full Text

FORM - 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE (See section 10 and rule 13) AN ANTISPASMODIC ANALGESIC SYNERGISTIC FORMULATION FOR THE RELIEF OF PAIN IN AN ORAL SYRUP FORM SANJEEV KHANDELWAL an Indian National of Prem Nivas, 13, Altamount Road, Mumbai 400026, Maharashtra, India, 2-2-2007 THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. DETAILED DESCRIPTION OF THE INVENTION This invention relates to an antispasmodic analgesic synergistic formulation for the relief of pain in an oral syrup form. The main feature of this invention is the use of both camylofin dihydrochloride and paracetamol as the active ingredients in an oral syrup formulation. This formulation can effectively provide the short-term relief from the colic or gastro intestinal spasm by acting both systemically and locally. The method for treating a patient comprises an orally administering a pharmaceutical formulation comprising of (a) Active ingredients camylofin dihydrochloride and paracetamol (b) Pharmaceutically acceptable inert excipients such as adjuvant solvents, syrupy base, buffering agents, preservatives, antioxidants, coloring agents and other inert excipients. According to this invention thereof, there provided an antispasmodic analgesic synergistic oral syrup formulation comprising (a) 5 to 30 mg of camylofin dihydrochloride per 5 ml of the formulation; (b) 50 to 250 mg of paracetamol per 5 ml of the formulation; (c) 20 to 60 wt % of adjuvant solvents used alone or in combination based on the total mass of the formulation; (d) 40 to 60 wt % of a syrup base based on the total mass of the formulation; (e) 0.1 to 5 wt % of a flavoring agent used alone or in combinations based on the total mass of the formulation; (f) 0.1 to 4 wt % of a buffering agent based on the total mass of the formulation; (g) 0.001 to 3 wt % of a preservative used alone or in combination based on the total mass of the formulation; (h) 0.001 to 2 wt % of F&D approved colors used alone or in combination based on the total mass of the formulation; (i) 0.01 to 3 wt % of an antioxidant (optional) used alone or in combination based on the total mass of the formulation; (j) 0.01 to 3 wt % of a surfactant (optional) used alone or in combination based on the total mass of the formulation. In accordance with the formulation preferred aspect of the invention includes at least one adjuvant solvent that may be any pharmaceutically acceptable inert material selected from the group of glycols such as propylene glycols, polyethylene glycols, others includes glycerin, sorbitol. The adjuvant solvents are used to make the formulation stable through out the shelf life of the product by preventing any occurrence of precipitations and loss of potency. The formulation preferably includes at least one set of the buffering agents such as citric acid & sodium citrate, ammonium acetate & acetic acid, sodium acetate & acetic acid. The buffers used to maintain a constant pH of the formulation and there by make the formulation suitable for oral administration. The preservative used in the formulation is mainly to prevent the microbial growth thereby inhibit the deterioration of the product. The preservative used in the formulation is at least one of the pharmaceutically acceptable materials that may be benzyl alcohol, sodium benzoate, methylparaben, propylparaben. The coloring agent used in the formulation is mainly to increase the appealing or elegance of the formulation comprises at least one selected from the approved food and drug colors such as color carminosine, color sunset yellow, color indigo caramine etc. The sweeteners and flavors used in the formulation to mask the bitter taste and organoleptic character of the drug. The sweeteners includes Parma grade sugars (sucrose), aspartame stevia. The flavor includes at least one acceptable approved synthetic flavor such as bitter taste masking flavors, honey flavors, banana flavors, mixed fruit flavors, black current flavor etc. The anti oxidant is at least one compound selected from a group of compounds consisting of Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), sodium metabisulfite, sodium sulfite, sodium bisulfite and propyl gallate. The major solvent used for the preparation of the formulation is purified water. That is used to make the sugar solution during the process of manufacturing. The surfactant is at least one compound selected from a group consisting of: sodium lauryl sulfate, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, hydrogenated or non-hydrogenated glycerolipids, ethoxylated or non-ethoxylated, linear or branched, saturated or mono- or polyunsaturated C.sub.6 to C.sub.30 fatty acids in the form of the acid or an alkali metal or its salt, cyclodextrin, sodium lauryl sulfate, alkaline earth metal or amine salt, ethoxylated or non-ethoxylated esters of sucrose, sorbitol, sorbitan monooleate, mannitol, glycerol or polyglycerol containing from 2 to 20 glycerol units, or glycol with said fattyacids, mono-, di- or triglycerides or mixtures of glycerides of said fatty acids, ethoxylated or non-ethoxlylated, linear or branched, saturated or mono- or polyunsaturated (C.sub.6 to C.sub.30 fatty alcohols, cholesterol and derivatives thereof, other derivatives with a sterol skeleton, ethoxylated or non-ethoxylated ethers of sucrose, sorbitol, mannitol, glycerol or polyglycerol containing from 2 to 20 glycerol units, or glycol with said fatty alcohols, hydrogenated or non-hydrogenated, polyethoxylated vegetable oils, polyoxyethylene/ polyoxypropylene block polymers (poloxamers), polyethylene glycol hydroxystearate, sphingolipids and sphingosine derivatives, polyalkyl glucosides, ceramides, polyethylene glycol/alkyl glycol copolymers, and polyethylene glycol/polyalkylene glycol ether di-block or tri-block copolymers, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octoxinols, tyloxapol, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sucrose esters. MANUFACTURING METHODS According to one aspect of this invention there is provided a process for making an antispasmodic analgesic synergistic oral syrup formulation as claimed in any one of the preceding claims, comprising the following steps: (a) Transferring purified water to a s.s tank and heating it to 90 °C; (b) stirring the purified water mechanically and adding dispensed quantity of preservative and dissolving it completely; (c) dissolving the sweetening agent completely with stirring and then adding sugar to the above solution and heating to dissolve it completely; (d) transfer the solution in step (c) to another s.s tank with filtration and allowing it to cool; (e) dissolving buffering agent in purified water and add to the solution in step (d) with stirring; (f) transfer dispensed quantity of adjuvant solvent to another s.s tank and dissolving dispensed quantity of Paracetamol in the adjuvant solvent with constant stirring; (g) adding solution in step (f) to the solution in step (e) with constant stirring; (h) adding camylofin dihydrochloride to purified water and making a solution; (i) adding antioxidant solution [optionally] to the camylofin solution in step (h) (j) and adding solution in step (i) to the solution in step (g). (k) adding other excipients like surfactants, flavors, color solution in water to the solution in step (j) with stirring.; adjusting the pH of the solution in step (k) in the range 3.5 to 6.0 with the buffering agent and finally adjust the volume. 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 5 ml of the oral drop contains Camylofin Dihydrochloride 12.5 mg Paracetamol 125 mg Flavored syrupy Base q.s Manufacturing Process for Batch size 1000 liters: PART A : Syrup Preparation 1. Transfer 200 lits. of Purified Water in 1000 lits. capacity s.s. tank (No. 1). Heat it to 90°C. 2. Start stirring Purified Water mechanically and add 0.5 kg Methyl paraben and 0.05 kg Propyl Paraben I.P. Dissolve completely. 3. Add 0.200 kg Citric Acid to the above solution. Dissolve completely. 4. Add 10.0 kg of Aspartame to above solution. Dissolve completely. 5. Add 500 kgs of Sugar (General) to above solution and heat upto 90°C to dissolve it under stirring. 6. Transfer the above solution to 2000 lits. capacity s.s. tank (No. 2) after filtering through nylon filter cloth. PART B 7. Dissolve Sodium Citrate 2 kgs in 10 lits. Purified Water and transfer to tank No. 2 with stirring. 8. Add Propylene Glycol 300 kgs in a s.s tank through filter cloth under continuous stirring. Add 25 kg of Paracetamol to this solution with constant stirring till to get a clear solution. PART C 9. Transfer 20 lits. Purified Water in 250 lits. s.s. Tank (No. 3). Start stirring and add 2.5 kgs of Camylofin Dihydrochloride Dissolve 2.0 kg of sodium metabisulfite in water completely and transfer it into tank No. 2 under stirring. 10. Add 2.0 lits BTM, 2.0 lits Pineapple flavour ,0.500 lits Black current flavour to tank No. 2 under continuous stirring. Dissolve 0.03 kg of color carminosine in purified water and add it to the above solution with stirring. 11. Stir the mixture of tank No. 2 continuously for 1 hour. Adjust pH if necessary with (10% w/v) Citric Acid solution or (20% w/v) Sodium Citrate solution. Record the pH that was 4.78. 12. Make up the volume to 1000 lits with Purified Water. 14. Filter Syrup through polypropylene filter pad assembly and collect filtered syrup in 2000 lits. s.s. tank with ball valve or in storage tank in case of continuous batches. Inform Q.C. Dept. for in-process checking. EXAMPLE - 2 Each 5 ml of the oral drop contains Camylofin Dihydrochloride 12.5 mg Paracetamol 125 mg Flavored syrupy Base q.s Manufacturing Process for Batch size 1000 liters: PART A : Syrup Preparation 1. Transfer 200 lits. of Purified Water in 1000 lits. capacity s.s. tank (No. 1). Heat it to 90°C. 2. Add 0.200 kg Citric Acid to the above solution. Dissolve completely. 3. Add 10.0 kg of Aspartame to above solution. Dissolve completely. 4. Add 500 kgs of Sugar (General) to above solution and heat upto 90°C to dissolve it under stirring. Add 10 lits sorbitol, 1 lits of the potassium sorbate to this solution with constant stirring till to get a clear solution. 5. Transfer the above solution to 2000 lits. capacity s.s. tank (No. 2) after filtering through nylon filter cloth. PART B 6. Dissolve Sodium Citrate 2 kgs in 10 lits. Purified Water and transfer to tank No. 2 with stirring. 7. Add Propylene Glycol 300 kgs in a s.s tank through filter cloth under continuous stirring. Add 25 kg of Paracetamol to this solution with constant stirring till to get a clear solution. PART C 8. Transfer 20 lits. Purified Water in 250 lits. s.s. Tank (No. 3). Start stirring and add 2.5 kgs of Camylofin Dihydrochloride Dissolve 2.0 kg of sodium metabisulfite in water completely and transfer it into tank No. 2 under stirring. 9. Add 2.0 lits BTM, 2.0 lits rusbery flavour, 0.500 lits Black current flavour to tank No. 2 under continuous stirring. Dissolve 0.03 kg of color erythrosine in purified water and add it to the above solution with stirring. 10. Stir the mixture of tank No. 2 continuously for 1 hour. Adjust pH if necessary with (10% w/v) Citric Acid Solution or (20% w/v) Sodium Citrate solution. Record the pH that was 4.6. 11. Make up the volume to 1000 lits with Purified Water. 13. Filter the Syrup through polypropylene filter pad assembly and collect filtered syrup in 2000 lits. s.s. tank with ball valve or in storage tank in case of continuous batches. EXAMPLE - 3 Each 5 ml of the oral drop contains Camylofin Dihydrochloride 12.5 mg Paracetamol 75 mg Flavored syrupy Base q.s Manufacturing Process for Batch size 1000 liters: PART A : Syrup Preparation 1. Transfer 200 lits. of Purified Water in 1000 lits. capacity s.s. tank (No. 1). Heat it to 90°C. 2. Add 0.200 kg Citric Acid to the above solution. Dissolve completely. 3. Add 10.0 kg of Aspartame to above solution. Dissolve completely. 4. Add 500 kgs of Sugar (General) to above solution and heat upto 90°C to dissolve it under stirring. Add 10 lits sorbitol, 1 lits of the potassium sorbate to this solution with constant stirring till to get a clear solution. 5. Transfer the above solution to 2000 lits. capacity s.s. tank (No. 2) after filtering through nylon filter cloth. PART B 6. Dissolve Sodium Citrate 2 kgs in 10 lits. Purified Water and transfer to tank No. 2 with stirring. 7. Add Propylene Glycol 300 kgs in a s.s tank through filter cloth under continuous stirring. Add 15 kg of Paracetamol to this solution with constant stirring till to get a clear solution. PART C 8. Transfer 20 lits. Purified Water in 250 lits. s.s. Tank (No. 3). Start stirring and add 2.5 kgs of Camylofin Dihydrochloride Dissolve 2.0 kg of sodium metabisulfite in water completely and transfer it into tank No. 2 under stirring. 9. Add 2.0 lits BTM, 2.0 lits rusbery flavour, 0.500 lits Black currant flavour to tank No. 2 under continuous stirring. Dissolve 0.03 kg of color erythrosine in purified water and add it to the above solution with stirring. 10. Stir the mixture of tank No. 2 continuously for 1 hour. Adjust pH if necessary with (10% w/v) Citric Acid solution or (20% w/v) Sodium Citrate solution. Record the pH that was 4.56. 11. Make up the volume to 1000 lits with Purified Water. 12. Filter Syrup through polypropylene filter pad assembly and collect filtered syrup in 2000 lits. s.s. tank with ball valve or in storage tank in case of continuous batches. EXAMPLE - 4 Each 5 ml of the oral drop contains Camylofin Dihydrochloride 12.5 mg Paracetamol 75 mg Flavored syrupy Base q.s Manufacturing Process for Batch size 1000 liters: PART A : Syrup Preparation 1. Transfer 200 lits. of Purified Water in 1000 lits. capacity s.s. tank (No. 1). Heat it to 90°C. 2. Start stirring Purified Water mechanically and add 0.5 kg Methyl paraben and 0.05 kg Propyl Paraben I.P. Dissolve completely. 3. Add 0.200 kg Citric Acid to the above solution. Dissolve completely. 4. Add 10.0 kg of Aspartame to above solution. Dissolve completely. 5. Add 500 kgs of Sugar (General) to above solution and heat upto 90°C to dissolve it under stirring. 6. Transfer the above solution to 2000 lits. capacity s.s. tank (No. 2) after filtering through nylon filter cloth. PART B 7. Dissolve Sodium Citrate 2 kgs in 10 lits. Purified Water and transfer to tank No. 2 with stirring. 8. Add Propylene Glycol 300 kgs in a s.s tank through filter cloth under continuous stirring. Add 15 kg of Paracetamol to this solution with constant stirring till to get a clear solution. PART C 9. Transfer 20 lits. Purified Water in 250 lits. s.s. Tank (No. 3). Start stirring and add 2.5 kgs of Camylofin Dihydrochloride Dissolve 2.0 kg of sodium metabisulfite in water completely and transfer it into tank No. 2 under stirring. 10. Add 2.0 lits BTM, 2.0 lits Pineapple flavour ,0.500 lits Black current flavour to tank No. 2 under continuous stirring. Dissolve 0.03 kg of color carminosine in purified water and add it to the above solution with stirring. 11. Stir the mixture of tank No. 2 continuously for 1 hour. Adjust pH if necessary with (10% w/v) Citric Acid solution or (20% w/v) Sodium Citrate solution. Record the pH that was 4.78. 12. Make up the volume to 1000 lits with Purified Water. 13. Filter Syrup through polypropylene filter pad assembly and collect filtered syrup in 2000 lits. s.s. tank with ball valve or in storage tank in case of continuous batches. I Claim: [1]An antispasmodic analgesic synergistic oral syrup formulation comprising (a) 5 to 30 mg of camylofin dihydrochloride per 5 ml of the formulation; (b) 50 to 250 mg of paracetamol per 5 ml of the formulation; (c) 20 to 60 wt % of adjuvant solvents used alone or in combination based on the total mass of the formulation; (d) 40 to 60 wt % of a syrup base based on the total mass of the formulation; (e) 0.1 to 5 wt % of a flavoring agent used alone or in combinations based on the total mass of the formulation; (f) 0.1 to 4 wt % of a buffering agent based on the total mass of the formulation; (g) 0.001 to 3 wt % of a buffering agent used alone or in combination based on the total mass of the formulation; (h) 0.001 to 2 wt % of F&D approved colors used alone or in combination based on the total mass of the formulation; (i) 0.01 to 3 wt % of an buffering agent (optional) used alone or in combination based on the total mass of the formulation; (j) 0.01 to 3 wt % of a surfactant (optional) used alone or in combination based on the total mass of the formulation. [2] An antispasmodic analgesic synergistic oral syrup formulation as claimed in claim 1, in which the adjuvant solvent is at least one compound selected from a group of compounds consisting of the group of glycols such as propylene glycols, polyethylene glycols, others includes glycerin, sorbitol together with purified water. [3] An antispasmodic analgesic synergistic oral syrup formulation as claimed in claim 1, in which the syrup base is at least one compound selected from a group of compounds consisting of Pharma grade sugars (sucrose), aspartame stevia blended with at least one acceptable approved synthetic flavor such as bitter taste masking flavors, honey flavors, banana flavors, mixed fruit flavors, black currant flavor . [4] An antispasmodic analgesic synergistic oral syrup formulation as claimed in claim 1, in which the preservative is at least one compound selected from a group of compounds consisting of benzyl alcohol, sodium benzoate, methylparaben, propylparaben. [5] An antispasmodic analgesic synergistic oral syrup formulation as claimed in claim 1, in which the buffering agent is at least one compound selected from a group of compounds consisting of citric acid & sodium citrate, ammonium acetate & acetic acid, sodium acetate & acetic acid. [6] An antispasmodic analgesic synergistic oral syrup formulation as claimed in claim 1, in which the anti oxidant is at least one compound selected from a group of compounds consisting of Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), sodium metabisulfite, sodium sulfite, sodium bisulfite and propyl gallate. [7] An antispasmodic analgesic synergistic oral syrup formulation as claimed in claim 1, in which the surfactant in which the surfactant is at least one compound selected from a group consisting of: sodium lauryl sulfate, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, hydrogenated or non-hydrogenated glycerolipids, ethoxylated or non-ethoxylated, linear or branched, saturated or mono- or polyunsaturated C.sub.6 to C.sub.30 fatty acids in the form of the acid or an alkali metal or its salt, cyclodextrin, sodium lauryl sulfate, alkaline earth metal or amine salt, ethoxylated or non-ethoxylated esters of sucrose, sorbitol, sorbitan monooleate, mannitol, glycerol or polyglycerol containing from 2 to 20 glycerol units, or glycol with said fattyacids, mono-, di- or triglycerides or mixtures of glycerides of said fatty acids, ethoxylated or non-ethoxlylated, linear or branched, saturated or mono- or polyunsaturated (C.sub.6 to C.sub.30 fatty alcohols, cholesterol and derivatives thereof, other derivatives with a sterol skeleton, ethoxylated or non-ethoxylated ethers of sucrose, sorbitol, mannitol, glycerol or polyglycerol containing from 2 to 20 glycerol units, or glycol with said fatty alcohols, hydrogenated or non-hydrogenated, polyethoxylated vegetable oils, polyoxyethylene/ polyoxypropylene block polymers (poloxamers), polyethylene glycol hydroxystearate, sphingolipids and sphingosine derivatives, polyalkyl glucosides, ceramides, polyethylene glycol/alkyl glycol copolymers, and polyethylene glycol/polyalkylene glycol ether di-block or tri-block copolymers, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octoxinols, tyloxapol, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sucrose esters. [8] A process for making an antispasmodic analgesic synergistic oral syrup formulation as claimed in any one of the preceding claims, comprising the following steps: (a) Transferring purified water to a s.s tank and heating it to 90 °C; (b) stirring the purified water mechanically and adding dispensed quantity of preservative and dissolving it completely; (c) dissolving the sweetening agent completely with stirring and then adding sugar to the above solution and heating to dissolve it completely; (d) transfer the solution in step (c) to another s.s tank with filtration and allowing it to cool; (e) dissolving buffering agent in purified water and add to the solution in step (d) with stirring; (f) transfer dispensed quantity of adjuvant solvent to another s.s tank and dissolving dispensed quantity of Paracetamol in the adjuvant solvent with constant stirring; (g) adding solution in step (f) to the solution in step (e) with constant stirring; (h) adding camylofin dihydrochloride to purified water and making a solution; (i) adding antioxidant solution [optionally] to the camylofin solution in step (h) (j) and adding solution in step (i) to the solution in step (g). (k) adding other excipients like surfactants, flavors, color solution in water to the solution in step Q) with stirring.; (I) adjusting the pH of the solution in step (k) in the range 3.5 to 6.0 with the buffering agent and finally adjusting the volume and filtering. Dated this 4th day of April, 2005.

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