Title of Invention

"NOVEL THERAPEUTIC ANTI-INFLAMMATORY AND ANALGESIC COMPOSITION FOR TOPICAL AND/OR TRANSDERMAL USE"

Abstract

Novel therapeutic anti-inflammatory and analgesic pharmaceutical composition for topical and/or transdermal use is provided. The composition comprises nimesulide from 0 1% to 10% w/w, percutaneous enhancer from 0.5% to 30% w/w, surfactant from 0 5% to 12% w/w, gelling agent/thickening agent from 0 2% to 50% w/w, neutralizing agent/pH adjusting agent from 0 0% to 2.;0% w/w, and one or more vehicles/bases from 5% to 60% w/w.

Full Text

This present invention relates to a novel therapeutic anti-inflammatory and analgesic composition containing Nimesulide which is N-(4 nitro, 2 phenoxyphenyl methane sulphonamide) for topical use. Transdermal route for administration of anti-inflammatory agents offers various advantages over the oral route such as lower dosage, less toxicity/side effects, no G.I irritation, no dose dumping in the body and it is more site specific (Chien YW; Novel Drug Delivery System, Marcel Dekker, New York, 1982). For a drug to be absorbed transdermal^, it has to travel across different layers of skin before reaching the site of action. These skin layers differ widely in nature; some are predominantly hydrophilic whereas others are lipophilic (Montagna W. Parrakhal PF: The structure and Function of the skin, 3rd ed. Academic press, New York, 1974). Due to this, the drug is required to have absorption. Highly hydrophobic drugs like Nimesulide or highly or highly hydrophilic drugs are considered poor candidates for transdermal drug delivery. When applied to the skin, such drugs are either not absorbed or absorbed in very minute amounts, not suitable therapeutic use. The Literature and the market surveys show that at present, there exists no properly effective percutaneous formulations of Nimesulide. In the patent for Nimesulide drug molecule (US Patent No. 3,840,597) the use of Nimesulide as an anti-inflammatory agent in the dose range of 1 mg to 500 mg per kg body weight in the form of cream, gel, tapes and the like has been cited. According to our studies, it was observed that the drug either precipitated out in the conventional formulation or precipitated on application to human skin when applied as a conventional gel or cream in the above stated dosage and practically no percutaneous absorption occurred. An over-riding difficulty is the inherent insolubility of the Nimesulide in aqueous media and hence the provision of a dosage form which can contain Nimesulide in sufficiently high concentration to permit convenient use and yet meet the required criteria in terms of bioavailability e.g. enabling effective absorption from the skin. According to the present invention, it has been found that it is possible to solubilise and deliver a highly hydrophobic drug like Nimesulide to the site of action through transdermal route. The present invention involves the process of incorporation of Nimesulide in a formulation which can be solubilize the drug and transport it through the skin barriers, in intact condition, to the site of action. It is an object of the present invention to provide a novel therapeutic composition containing Nimesulide in combination with other compounds which alter the physico-chemical property of Nimesulide, thus making it possible for the said composition to be used for direct application on the skin for the treatment of inflammation through transdermal absorption, at dose levels much lower than the dose levels according to the known art. STATEMENT OF INVENTION: Accordingly the present invention provides a novel therapeutic anti-inflammatory and analgesic composition for topical use, which comprises: 1. Nimesulide 2. Percutaneous enhancer as herein described 3. Surfactant as herein described 4. Gelling/thickening agent as herein described 5. Neutralising agent/pH adjusting agent as herein described 0.0% to 2.0% w/w 6. One or more vehicle/base as herein described 0.1% to 10% w/w 0.5% to 30% w/w 0.5% to 12% w/w 0.2% to 50% w/w 5 % to 60% w/w According to a preferred embodiment of the present invention, the said novel antiinflammatory and analgesic composition for topical use comprises: 1. Nimesulide 2. Percutaneous enhancer as herein described 3. Surfactant as herein described 4. Gelling/thickening agent as herein described 5. Neutralising/pH adjusting agent as herein described 6. One or more vehicles/base as herein described 1.0% w/w 6% to 15% w/w 0.5% to 12% w/w 0.5% to 20% w/w 0.0% to 2.0% w/w 5 % to 45% w/w The novel therapeutic anti-inflammatory and analgesic composition, according to the -3- present invention, is prepared by the process which comprises the following steps : (a) 0.5% to 30% w/w of a Percutaneous enhancer, as herein described, is mixed with 2.5% to 30% w/w of one or more Vehicle or base, as herein described, in a container by stirring and to the mixture obtained 0.1% to 10% w/w of Nimesulide is added and stirred till completely dissolved. (b) 0.5% to 12 % w/w of a Surfactant, as herein described, 0.2% to 50% w/w of a Gelling agent/thickening agent, as herein described, and 2.5% to 30% w/w of one or more Vehicle/base, as herein described, are mixed in a homogenizer to obtain a homogenized mixture. (c) The mixture obtained in step (a) is added to the homogenized mixture obtained in step (b) under stirring without vortex formation to avoid aeration. The mixture is neutralized or its pH adjusted by addition of 0.0% to 2.0% of a neutralizing agent or a pH adjusting agent, as herein described, with slow stirring resulting in the preparation of the desired anti-inflammatory and analgesic composition. As Percutaneous enhancer, any known Percutaneous enhancer may be used preferably a C12-24 mono or poly-unsaturated fatty acids such as vaccenic, cis-vaccenic, linoleic, linolenic, elaidic, oleic, pretroselinic, erucic or nervonic acid or any of their corresponding alcohols, especially oleic acid or oleyl alcohol or 1-dodecylazacycloheptan-2-one also known as azone; sulfoxides like dimethyl sulfoxide, n-decyl methyl sulfoxide; Amides like dimethylacetamide, dimethylformamide and N, N-diethyl-toluamide; Pyrrolidones like 2-pyrrolidone and N-methyl-2-Pyrrolidone. As surfactant, any pharmaceutically acceptable hydrophilic or lipophilic surfactant or mixture thereof may be used, especially suitable for this purpose are the reaction products of natural or hydrogenated vegetable oils and ethylene glycol i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils, e.g. polyoxyethylene glycolated natural or hydrogenated castor oils; especially various tensides available under the trade name CREMOPHOR® particularly CREMOPHOR® RH40 and CREMOPHOR® EL. Also suitable for use are the various surfactants available under the trade name NIKKOL® e.g. NIKKOL® HCO-60. Polyoxyethylene -Sorbitan fatty acid esters e.g. mono and trilauryl, palmityl, stearyl and oleyl esters e.g. those available under the trade name TWEEN® preferably TWEEN® 40 and TWEEN® 80. Polyoxyethylene-polyoxypropylene block copolymers e.g. especially those available under the trade name POLOXAMER® preferably POLOXAMER® 188. Polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters, commercially available under the trade name MYRJ® as well as polyoxyethylene fatty acid esters commercially available under the trade name CETIOL® HE. Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol, isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate. Examples of suitable lipophilic surfactants include transestenfication products of natural vegetable oil triglycerides and polyalkylene polyols. Preferred are products obtained by transestenfication of 2 molar parts of natural vegetable oil triglycerides with one molar parts of polyethylene glycol (e.g. having an average molecular weight of from 200 to 800). Various forms of such transestenfication product are commercially available under the trade name LABRAFIL®, preferably LABRAFIL® M 1944 CS. Sorbitan fatty acid esters commercially available under the trade name SPAN including Sorbitan monolauryl, monopalmityl, -monostearyl, -tristearyl -monooleyl and -trioeyl esters. Monoglycerides e.g. Glycerol monooleate, glycerol monopalmitate and glycerol monostearate commercially available under the trade names MYVATEX®, MYVAPLEX® and MYVEROL® As gelling Agent/Thickening agent, any known such pharmaceutically acceptable agent may be used including synthetic or semi-synthetic polymeric materials, polyacrylate and polyacrylate co-polymeric resins e.g. polyacrylic acid and polyacrylic acid/methacrylic acid resins, commercially available under the trade name CARBOPOL®, particularly CARBOPOL® 934, 940 and 941 and EUDRAGIT®, particularly EUDRAGIT® E, L, S, RL and RS; Cellulose and cellulose derivatives including alkyl celluloses e.g. methyl-, ethyl-, and propyl-celluloses; hydroxyalkyl-celluloses e.g. hydroxypropyl cellulose, hydroxypropyl alkylcellulose such as hydroxypropyl methylcellulose, acylated celluloses e.g. cellulose-acetates, cellulose acetate phthalates and salts thereof such as sodium carboxymethyl cellulose. Polyvinyl resins including polyvinyl acetates and alcohols as well as other polymeric materials including alginates e.g. alginic acid and salts thereof e.g. sodium alginate and propylene glycol alginate. As Neutralising/pH adjusting agent any such conventional such agent may be used including sodium bicarbonate, sodium hydroxide, potassium hydroxide, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate. Preferably polar organic amines like diethylamine, diisopropanolamine, trithylamine and triethanolamine may be used. As vehicles/base, the following may be used: Pharmaceutically acceptable lower (having C1-5) alkanols, particularly ethanol; water soluble macrogols like polyethylene glycol having an average molecular weight from 200 to 600: 1, 2-propylene carbonate, propane-1, 2-diol and 1, 2-propylene glycol; glycerol triacetate or (1,2,3)-triacetin; lower ketones, particularly acetone and 1,2,3 -propanetriol may be incorporated. Water in varying concentration may be added to provide the requisite hydrophilic nature to the composition. Pharmaceutically acceptable C1-5 alkyl or tetra hydrofurfuryl; di or partial ether of a low molecular weight mono or polyoxy-alkanediol particularly those available under the trade names TRANSCUTOL® and GLYCOFUROL® As the base having lipophilic phase for the preparation of emulsions, may be used fatty acid triglycerides, preferably medium chain fatty acid triglycerides; vegetable oils like coconut oils, olive oil, castor oil and their derivatives; and ethyl oleate. As base, for the preparation of the said therapeutic composition in the form of an ointment, may be used fatty acids, fats, oils and waxes of animal origin like bees wax, spermacetii, wool fat, waxes of vegetable origin or mineral origin like hard, soft and liquid paraffin. The topical dosage forms are formulated suitably such that the resultant product is easy to apply and is non-staining. For the said therapeutic composition in form of aerosol formulation for topical applications, as pharmaceutically acceptable propellents may be used chlorofluoro carbons e.g. the Propellant 11, Propellant 12, Propellant 114; Hydrocarbon propellants like n-butane, isobutane and propane; compressed gas propellants e.g. Nitrous oxide, carbon dioxide, and nitrogen. The novel therapeutic composition according to the present invention may be used in the following forms: 1. Topical aqueous gel 2. Oil-in-water or water-in-oil emulsion or micro-emulsion or cream. 3. Solution for topical applications, 4. Ointment 5. Aerosol formulation for topical applications. 6. Medicated plaster or transdermal patch When the therapeutic composition is used as medicated plaster or transdermal patch, it is secured on backing membrane, which serves as a drug reservoir or drug-rate controlling membrane, by means of an adhesive. Such backing membrane may comprise materials like regenerated cellulose, cellulose nitrate acetate, cellulose triacetate, polypropylene, polycarbonate and polytetrafluoroethylene. The therapeutic composition according to the present invention may be applied on the skin by utilizing a physical form of energy like electrical energy or ultrasonic energy to effect better percutaneous absorption of the drug. The invention will now be described with reference to the foregoing examples : EXAMPLE 1 Preparation of topical gel dosage form SI. No. Component Quantity 1. Nimesulide 2.0 g 2. Dimethylacetamide 22.0 g 3. Ethyl Alcohol 40.0 g 4. Acetone 10.0 g 5. Cremophor RH 40 4.0 g 6. Propylene glycol 38.0 g 7. Polyethylene glycol 400 48.8 g 8. Carbopol 934 4.0 g 9. Water 30.0 g 10. Diethylamine 1.2 g Total 200.0 g Step (a) Dimethylacetamide is mixed with ethyl alcohol and acetone at 30°C in a container with stirring. To the mixture obtained Nimesulide is added and stirred till completely dissolved. Step (b) Propylene glycol, polyethylene glycol 400 and water are mixed in homogenizer. To the homogenized mixture obtained, 1.5 % w/w of carbopol 934 is added in small amount at a time at room temperature and the speed of the homogenizer is kept at approximately 1500 - 2000 rpm. Step (c) The mixture obtained in step (a) is added to the mixture obtained in step (b) under stirring without vortex formation to avoid aeration preferably under vacuum (25 mm of Hg). The mixture obtained is neutralised by slow addition of diethylamine with slow stirring at a temperature of 25° - 30°C and under vacuum (25 mm of Hg) of affect gel formation. EXAMPLE 2 Preparation of emulsion type topical dosage form SI.No. Component Quantity 1 Nimesulide 1.0 g 2. Transcutol 35.0 g 3. Water 10.0 g 4. Disodium Hydrogen 0.1 g Phosphate 5. Cremophor RH 40 5.0 g 6. LabrafilM 1944 CS 10.0 g 7. Glyceryl monostearate 8.0 g 8. Stearic acid 13.0 g 9. Ethyl oleate 2.9 g 10. Diethyl sulphoxide 15.0 g Total 100.0 g Dissolve Nimesulide in a mixture of (6), (7), (8), (9) and (10) with warming. Separately mix (2), (3), (4) and (5) and slowly add the Nimesulide mixture to it with stirring. EXAMPLE 3 Preparation of solution type dosage form for topical application SI.No. Component Quantity 1. Nimesulide 1.0 g 2. Dimethyl formamide 10.0 g 3. Poloxamer 188 2.0 g 4. Ethyl alcohol 20.0 g 5. Propylene glycol 25.0 g 6. Polyethylene glycol 400 43.0 g 7. Hydroxypropyl methylcellulose 1.0 g 8. Triethanolamine 0.2 g Total 100.0 g Nimesulide is dissolved in (2) with stirring and (3), (4), (5), (6), (7) and (8) are added to obtain a clear solution with stirring. Preparation of ointment type? dosage form topical application SI.No. Component Quantity 1. Nimesulide 2.0 g 2. Dimethyl sulfoxide 21.0 g 3. Glyceryl monostearate 16.0 g 4. Mineral oil 62.0 g 5. White Petrolatum 99.0 g Total 200.0 g Warm (3), (4) and (5) and add with stirring a solution of Nimesulide in dimethyl sulphoxide. EXAMPLE 5 Preparation of an aerosol dosage form for topical use SI.No. Component Quantity 1. Nimesulide 1.0 g 2. Dimethylacetamide 10.0 g 3. Ethyl alcohol 10.0 g 4. Cremophor RH 40 10.0 g 5. Propellant 114 30.0 g 6. Propellant 12 39.0 g Total 100.0 g The therapeutic composition prepared according to the present invention is not a mere admixture but has properties different from the sum total of the properties of its ingredients. The dose levels of the novel anti-inflammatory and analgesic composition, according to the present invention, are comparatively much lower than the dose levels of the conventional Nimesulide formulation for equally effective results. The various forms of the therapeutic composition prepared according to the present invention were subjected to in-vitro drug release studies using modified USP dissolution apparatus attached with enhancer cell (Pharm Tech. Jan. 1995, 52-58). The dissolution media used was phosphate buffer pH 7.4. The results indicated that the cumulative drug release and permeation flux were proportional to the drug load. The said compositions were also subjected to standard pharmacological test methods to measure anti-inflammatory activity such as rat paw oedema and guinea pig erythema. These tests showed significant activity when compared to placebo. The said therapeutic compositions were also tested on sixty healthy human volunteers for irritation or other undue side effect. No incidence of irritation/side effects was reported. Since many apparently different embodiments of the present invention could be made without departing from the spirit and scope thereof, it is intended that the description of the invention herein be interpreted as being illustrative only and not limiting in any manner whatsoever. We claim: 0.1%to10%w/w 0.5% to 30% w/w 0.5%to12%w/w 0.2% to 50% w/w 5% to 60% w/w and 0.0% to 2.0% w/w 1. A novel therapeutic anti-inflammatory and analgesic composition for topical and/or transdermal use characterized in that: Nimesulide Percutaneous enhancer Surfactant Gelling agent/thickening agent comprising One or more vehicle/base optionally comprising Neutralizing agent/pH adjusting agent 1.0% w/w 6% to 15% w/w 0.5% to 12% w/w 0.5% to 20% w/w 0.0% to 2.0% w/w 5% to 45% w/w 2. The therapeutic composition as claimed in claim 1, which comprises Nimesulide Percutaneous enhancer Surfactant Gelling agent/thickening agent Neutralizing agent/pH adjusting agent One or more vehicle/base 3. A composition as claimed in claim 1, wherein the percutaneous enhancer is selected from the group comprising C12-24 mono or poly-unsaturated fatty acids or any of their corresponding alcohols, sulfoxides, amides or pyrrolidones. 4. A composition as claimed in claim 1, wherein the surfactant is a pharmaceutically acceptable hydrophilic or lipophilic surfactant or mixture thereof. 5. A composition as claimed in claim 4, wherein the surfactant is selected from the group comprising polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene fatty acids esters, propylene glycol mono-and di-fatty acid esters; lipophilic surfactant selected from the group comprising sorbitan fatty acid esters, monoglycerides, transesterification products of natural vegetable oil triglycerides and alkylene polyols. A composition as claimed in claim 1, wherein said gelling agent/thickening agent is selected from the group comprising natural, synthetic or semi-synthetic polymeric materials selected from group comprising polyacrylate and polyacrylate co-polymeric resins, cellulose and cellulose derivatives and polyvinyl resins. A composition as claimed in claim 1, wherein the neutralizing agent/pH adjusting agent is selected from the group comprising polar organic amines, acidifying agents, sodium bicarbonate, sodium hydroxide, potassium hydroxide, borax, disodium hydrogen phosphate, and sodium dihydrogen phosphate. A composition as claimed in claim 7, wherein the polar organic amine is diethylamine, diisopropanolamine, trithylamine ortriethanolamine. A composition as claimed in claim 1, wherein the vehicle/base is selected from the group comprising pharmaceutically acceptable lower (C1-5) alkanols; water soluble macrogols; 1,2-propylene carbonate, polypropylene glycol, 1,2-propylene glycol, glycerol triacetate, lower ketones, chlorofluorocarbons, hydrofluorocarbons and water. The therapeutic composition as claimed in claims 1 to 9, which is in the form of a topical aqueous gel, oil-in-water or water-in-oil emulsion or micro-emulsion or cream, solution, ointment, aerosol formulation, medicated plaster or a transgel patch. The novel therapeutic anti-inflammatory and analgesic composition for topical and/or transdermal use substantially as herein described and illustrated in the examples.

Documents:

2046-del-1995-abstract.pdf

2046-del-1995-claims.pdf

2046-del-1995-complete specification (granted).pdf

2046-del-1995-correspondence-others.pdf

2046-del-1995-correspondence-po.pdf

2046-del-1995-description (complete).pdf

2046-del-1995-form-1.pdf

2046-del-1995-form-13.pdf

2046-del-1995-form-19.pdf

2046-del-1995-form-2.pdf

2046-del-1995-form-29.pdf

2046-del-1995-form-3.pdf

2046-del-1995-form-60.pdf

2046-del-1995-form-61.pdf

2046-del-1995-gpa.pdf

2046-del-1995-pa.pdf

2046-del-1995-petition-138.pdf