Title of Invention	A TOPICAL ANALGESIC AND RUBAFACIENT
Abstract	A pharmaceutical synergistic formulation for topical application comprising a combination of (a) 0.75 %w/w to 2.0 %w/w of diclofenac diethylammonium (b) 5 %w/w to 15 %w/w of methyl salicylate (c) 2 %w/w to 8 %w/w of menthol (d) 0.01 %w/w to 0.05 % w/w of capsaicin (e) 0.05 %w/w to 5.0 %w/w of oleum lini (f) pharmaceutical acceptable inert excipients, and (g) a Semisolid gel base.

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FORM-2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE Specification (See section 10 and rule 13) A PHARMACEUTICAL SYNERGISTIC FORMULATION FOR TOPICAL APPLICATION CONTAINING DICLOFENAC DIETHYLAMMONIUM SANJEEV KHANDELWAL an Indian National of Prem Nivas, 13, Altamount Road, Mumbai 400026, Maharashtra, India, GRANTED 19-4-2005 THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED. 11 SEP 2006 This invention relates to a pharmaceutical synergistic formulation for topical application. FIELD OF INVENTION This invention relates to a synergistic formulation related to a nonsteroidal analgesic and anti-inflammatory and rubafacient in the form of a topical gel form and to a method of making the same. WHAT THE INVENTION ENVISAGES This invention envisages a synergistic formulation composition containing diclofenac diethylammonium, methyl salicylate, menthol, oleum lini, and capsaicin in a topical gel form. PHARMACOLOGY Diclofenac Diethylammonium is systemically absorbed through the skin, it inhibits the enzyme cyclo-oxygenase, thus reducing the formation of PGE2. Moreover, it also increases the uptake of Arachidonic acid into the cellullar pool. Menthol on topical application, dilates the blood vessels causing a sensation of coldness followed by an analgesic effect. Menthol also acts as a penetration enhancer. It increases the penetration of drugs when applied on the skin to give a faster onset of action. Menthol functions as a penetration enhancer either due to its vasodilatation property or since menthol readily penetrates the skin, it may reversibly change barrier-structures in the stratum corneum without affecting blood circulation at the site of application. Methyl Salicylate is used topically as a counter-irritant. On topical application, it is absorbed through the skin and is applied for the relief of pain in rheumatic conditions and painful muscle or joints. One of the most popular over-the counter group of topical agents is the salicylate-containing anti-inflammatory formulation, recommended for use in wide range of painful or inflammatory conditions in muscles and joints. It has been shown that first-pass metabolism exists in the skin with esterases rapidly hydrolyzing salicylate esters to release the active salicylate in both the epidermis and dermis. Oleum Lini contains predominantly Essential Fatty Acids i.e. Linolenic acid. On percutaneous absorbtion, - Linolenic acid gets converted to Elcosapentanoic acid(EPA). EPA is acted upon by cycjo-oxygahase enzyme to produce prostaglandin E3 which is a weak inflammatory agent. Presence of EPA prevents the action of cyclo-oxygenase on Archidonic acid which reduces its coversion to PGE2(a highly inflammatory agent). Presence of PGE3 itself modulates the inflammatory response through a feedback machanism. Capsaicin inhibits substance P in the peripheral neurons. Thus inhibits the transmission of pain sensation to bpaiii as well as inhibits the release of further mediators of inflammation. Capsaicin, the substance that makes chile peppers so hot, has been found to reduce pain in arthritis patients when topically applied as a cream repeatedly over several weeks. It has been used to treat nerve pain inside the mouth, for patients with painful sores from cancer therapy. Recently Capsaicin has been used to treat atypical facial pain, especially when a specific pain "trigger point" (a place, if touched, causes or exacerbates facial pain) is involved. Capsaicin is applied directly to this "trigger point" several times a day. If the trigger point is inside the mouth, a plastic dental splint is used to apply the capsaicin cream. If the trigger point is on the face, it is topically applied. In some cases, pain reduction only occurs after several weeks of application. There is anecdotal evidence that a course of capsaicin treatment can result in long-term pain remission for some patients with atypical facial pain. RATIONALE OF FORMULATION: Diclofenac is systemically absorbed through the skin, it inhibits the enzyme cyclo-oxygenase, thus reducing the formation of PGE2. Moreover, it also increases the uptake of Arachidonic acid into the cellullar pool. Oleum lini contains predominantly alpha linolenic acid that converts to EPA (Eicosapentaenoic acid). EPA prevents the action of cyclo-oxygenase on arachidonic acid, which on conversion gives rise to PGE2 (a highly inflammatory agent). EPA is acted upon by cyclo-oxygenase enzyme to produce PGE3, which is a weak inflammatory agent. Methyl-salicylate is used locally as a counter irritant. Menthol desensitizes the capsaicin irritation and probably acts as a local anesthetic. Hence the components of this multi component preparation complement each other's action. INDICATIONS: The said formulation is indicated for the quick relief from pain, swelling and inflammation due to musculo-skelital disorders such as sprains, strains, tendonitis, bursitis, hand, ^ neck and shoulder pain, sciatica, muscle stiffness, joint pain, back-ache and lumbago. DETAILED DESCRIPTION OF THE INVENTION The main feature of this invention is the use of combination of active ingredients for making the topical semisolid dosage form (gel) of the formulation comprising diclofenac diethylammonium, methyl salicylate, menthol, oleum lini, and capsaicin. The method for treating a patient comprises topically applying the pharmaceutical formulation comprising a combination of (a) 0.75 %w/w to 2.0 %w/w of diclofenac diethylammonium (b) 5 %w/w to 15 %w/w of methyl salicylate (c) 2 %w/w to 8 %w/w of menthol (d) 0.01 %w/w to 0.05 % w/w of capsaicin (e) 0.05 %w/w to 5.0 %w/w of oleum lini (f) Pharmaceutical acceptable inert excipients, and (g) A Semisolid gel base. The said formulation may contain one or more pharmaceutical acceptable inert excipients comprising of binders, preservatives, antioxidants, surfactants and pH adjusting agents. The binders used in the formulation may be selected from polyvinyl pyrrolidone, natural binders such as alginates, traganth. The preferable concentration of the binder used in the formulation is 0.05 %w/w to 3 %w/w. The use of the binder also depends on the concentration of viscosity modifying agent in the formulation as the later may also have the binding properties. The preservative in the formulation is essential as the viscosity enhancer polymer it self act as a suitable medium for the microbial growth. However the use of the glycol solvents in high concentration in the formulation reduce the occurrence of such microbial growth. Additional support to prevent this microbial growth may be achieved by the use of other preservatives such as chlorocresol, methyl paraben, propyl paraben, thiomarsal, sorbic acid, potassium sorbate and benzyl alcohol. The preferable concentration of these preservatives may be 0.001 %w/w to 2 %w/w. The antioxidants are optionally used in the formulation may includes Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), sodium metabisulfite, sodium sulfite, sodium bisulfite and propyl gallate. The surfactants used in the formulation mainly to improve the penetration of the active ingredients to the skin by increasing the solublization of the active in the lipophilic membrane. These may include polysorbate 80, polysorbate 20, sorbitan groups (spans). The concentration of surfactant in the formulation may include 0.1 %w/w to 3.0% w/w. The pH-adjusting agents used in the formulation may include diethanolamine, triethanolamine, sodium hydroxide, citric acid and monobasic sodium phosphate. Semisolid base in the formulation mainly comprising of the adjuvant solvents, viscosity enhancer (jelling) agents and solvent such as isopropyl alcohol and purified water. The adjuvant solvent in the formulation includes glycols that may be selected from the Propylene glycol, polyethylene glycols [PEG-300, PEG-400, etc], and other substituted glycols such as different grade of cremaphors. The viscosity increasing agents may include the synthetic polymers such as carbomors [cross linked polymers of acrylic acid], cellulosic polymers such as hydroxypropyl methylcellulose, methylcellulose, sodium carboxy methylcellulose, and hydroxypropyl cellulose. The different grades of the cabomers available for the topical gel formulation, those are carbopol 910, carbopol 934P. carbopol 940, carbopol 941, carbopol 1342. These are used in concentration of 0.5 %w/w to 2.0 %w/w for the purpose. When cellulosic polymers used in the formulation high concentrations is preferred [3 %w/w to 20 %w/w for the same purpose. MANUFACTURING PROCEDURE [A] Preparation of slurry of the viscosity enhancing agent: Take weighed quantity of purified water and add in a suitable S.S. jacketted vessel of 500 litre capacities. Heat it to 65 °C and keep stirring to create a vortex. Add viscosity-increasing agent in Small parts to the hot water taking care that it disperse easily without forming lumps. Add propylene glycol. Continue stirring for 1 hour. Transfer the slurry to PLM 600 Itrs. Stir for 5 minutes at fast speed then mix under vacuum for 30 minutes under slow speed. Attach funnel to PLM. Add Triethanolamine through funnel to PLM with slow speed. Complete additional mix for 10 minutes at fast speed and 20 minutes at slow speed under vacuum. Check pH (6.7 to 6.8 pH). [B] Preparation Of Diclofenac Diethylamine Solution: Take Propylene Glycol in a S.S. vessel and heated to 50 °C. Add antioxidant and Diclofenac Diethylamine. Cool to room temperature. Filter into suitable tank. [C] Preparation of Menthol and Capsaicin Solution Take Isopropyl alcohol in a suitable tank. Dissolve with stirring slowly with propeller and Add labeled quantity of Menthol, antioxidants, Capsaicin and preservatives. [D] Preparation of Oleum Lini & Methyl Salicylate Solution In a suitable S.S. vessel, take surfactants, adjuvant solvents, Oleumlini and Methyl Salicylate. Mix for 10 minutes with a slow speed stirring. Add stage 'B' to stage 'C Mix for 10 minutes and then add to PLM at slow speed. Mix for 30 minutes. Then add the stage D to PLM with fast speed mixing for 15 minutes and then 45 minutes slow speed. Adjust pH 6.5 to 7.5 using 50% solution of pH adjusting agent in distilled water. Add sufficient quantity of water with continuous stirring to make final weight of gel. 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 gram of the gel contains Diclofenac diethylammonium 1.16 %w/w Methyl Salicylate 10.0 %w/w Menthol 5.0 %w/w Oleum lini 1.0 %w/w Capsaicin 0.025 %w/w MANUFACTURING PROCEDURE [Batch Size: 500 kg] A Preparation of Carbopol slurry : Take weighed quantity of purified water and add in a suitable S.S. jacketted vessel of 600-litre capacity. Heat it to 65°C and keep stirring to create a vortex. Add Carbapol 940 in small parts to the hot water taking care that it disperses easily without forming lumps. Add propylene glycol. Continue stirring for 1 hour. Propylene Glycol - 1.650 kgs Distilled water - 243.750 kgs Carbopol 940 B.P. - 7.500 kgs Transfer carbopol slurry to PLM 600 Itrs. Stir for 5 minutes at fast speed then mix under vacuum for 30 minutes under slow speed. Attach funnel to PLM. Add Triethanolamine through funnel to PLM with slow speed. Complete additional mix for 10 minutes at fast speed and 20 minutes at slow speed under vacuum. Check pH (6.7 to 6.8 pH). B. Preparation Of Diclofenac Diethylamine Solution Take Propylene Glycol in a S.S. vessel heated to 50°C. Add BHA and Diclofenac Diethylamine. Cool to room temperature. Filter into suitable tank. Propylene Glycol - 73.350 kgs B.H.A. - 0.005 kgs Diclofenac Diethyl amine - 5.800 kgs C. Preparation of Menthol and Capsaicin Solution Take 25 kgs Isopropyl alcohol in a suitable tank. Dissolve with stirring slowly with propeller. Add : Menthol - 26.250 kgs BHT - 0.005 kgs Capsaicin - 0.131 kgs Benzyl Alcohol - 5.000 kgs 25.000 kgs 5.000 kgs 5.250 kgs 52.500 kgs D. Preparation of Oleum Lini & Methyl Salicylate Solution In a suitable S.S. vessel, take following ingredients: Cremaphore RH 40 Tween 60 Oleumlini Methyl Salicylate Mix for 10 minutes with a slow speed stirring. Add stage 'B' to stage 'C. Mix for 10 minutes and then add to PLM at slow speed. Mix for 30 minutes. Then add the stage D to PLM with fast speed mixing for 15 minutes and then 45 minutes slow speed. Adjust pH: 7 - 7.5 using 50% solution 0.200 kg or q.s. Triethanolamine in distilled water. Add sufficient quantity of water with continuous stirring to make 500 kgs weight of gel EXAMPLE - 2: Each gram of the gel contains Diclofenac diethylammonium 1.16 %w/w Methyl Salicylate Menthol Oleum lini Capsaicin 10.0 %w/w 5.0 %w/w 1.0 %w/w 0.025 %w/w MANUFACTURING PROCEDURE [B^tch Size: 500 kg] A. Preparation of Hydroxypropylmethylcellulose slurry: Take weighed quantity of purified water and add in a suitable S.S. jacketted vessel of 600-litre capacity. Heat it to 65°C and keep stirring to create a vortex. Add Hydroxypropylmethylcellulose in small parts to the hot water taking care that it disperses easily without forming lumps. Add propylene glycol. Continue stirring for 1 hour. Propylene Glycol -1.600 kgs Distilled water - 150.000 kgs Hydroxypropylmethylcellulose - 50.00 kgs Transfer Hydroxypropylmethylcellulose slurry to PLM 600 Itrs. Stir for 5 minutes at fast speed then mix under vacuum for 30 minutes under slow speed. Attach funnel to PLM. Complete additional mix for 10 minutes at fast speed and 20 minutes at slow speed under vacuum. B. Preparation Of Diclofenac Diethylamide Solution Take Propylene Glycol in a S.S. vessel heated to 50°C. Add BHA and Diclofenac Diethylamine. Cool to room temperature. Filter into suitable tank. Propylene Glycol - 70.000 kgs B.H.A. - 0.005 kgs Diclofenac Diethyl amine - 5.800 kgs C. Preparation of Menthol and Capsaicin Solution Take 25 kgs Isopropyl alcohol in a suitable tank. Dissolve with stirring slowly with propeller. Add : Menthol - 26.250 kgs BHT - 0.005 kgs Capsaicin - 0.131 kgs Benzyl Alcohol - 5.000 kgs D. Preparation of Oleum Lini & Methyl Salicylate Solution In a suitable S.S. vessel, take following ingredients: Cremaphore RH 40 Tween 60 Oleumlini Methyl Salicylate Mix for 10 minutes with a slow speed stirring. 30.000 kgs 5.000 kgs 5.250 kgs 52.500 kgs Add stage 'B' to stage XC\ Mix for 10 minutes and then add to PLM at slow speed. Mix for 30 minutes. Then add the stage D to PLM with fast speed mixing for 15 minutes and then 45 minutes slow speed. Adjust pH: 7 - 7.5 using 50% solution 0.200 kg or q.s. sodium hydroxide in distilled water. Add sufficient quantity of water with continuous stirring to make 500 kgs weight of gel EXAMPLE - 3: Each gram of the gel contains Diclofenac diethylammonium 1.16 %w/w Methyl Salicylate 10.0 %w/w Menthol 5.0 %w/w Oleum lini Capsaicin 1.0%w/w 0.025 %w/w MANUFACTURING PROCEDURE [Batch Size: 500 kg] A. Preparation of Sodium carboxymethylcellulose slurry: Take weighed quantity of purified water and add in a suitable S.S. jacketted vessel of 600-litre capacity. Heat it to 65°C and keep stirring to create a vortex. Add Sodium carboxymethylcellulose slurry in small parts to the hot water taking care that it disperses easily without forming lumps. Add propylene glycol. Continue stirring for 1 hour. Propylene Glycol -1.600 kgs Distilled water - 150.000 kgs Sodium carboxymethylcellulose - 75.00 kgs Transfer Sodium carboxymethylcellulose slurry to PLM 600 Itrs. Stir for 5 minutes at fast speed then mix under vacuum for 30 minutes under slow speed. Attach funnel to PLM. Complete additional mixing for 10 minutes at fast speed and 20 minutes at slow speed under vacuum. B. Preparation Of Diclofenac Diethylamine Solution Take Propylene Glycol in a S.S. vessel heated to 50°C. Add BHA and Diclofenac Diethylamine. Cool to room temperature. Filter into suitable tank. Propylene Glycol - 70.000 kgs B.H.A. - 0.005 kgs Diclofenac Diethyl amine - 5.800 kgs C. Preparation of Menthol and Capsaicin Solution Take 25 kgs Isopropyl alcohol in a suitable tank. Dissolve with stirring slowly with propeller. Add : Menthol - 26.250 kgs BHT - 0.005 kgs Capsaicin - 0.131 kgs Benzyl Alcohol - 5.000 kgs D. Preparation of Oleum Lini & Methyl Salicylate Solution In a suitable S.S. vessel, take following ingredients: Cremaphore RH 40 - 30.000 kgs Tween60 - 5.000 kgs Oleumlini - 5.250 kgs Methyl Salicylate - 52.500 kgs Mix for 10 minutes with a slow speed stirring. Add stage 'B' to stage 'C Mix for 10 minutes and then add to PLM at slow speed. Mix for 30 minutes. Then add the stage D to PLM with fast speed mixing for 15 minutes and then 45 minutes slow speed. Adjust pH: 7 - 7.5 using 50% solution 0.200 kg or q.s. sodium hydroxide in distilled water. Add sufficient quantity of water with continuous stirring to make 500 kgs weight of gel I Claim: [1] A pharmaceutical synergistic formulation for topical application comprising a combination of (a) 0.75 %w/w to 2.0 %w/w of diclofenac diethylammonium (b) 5 %w/w to 15 %w/w of methyl salicylate (c) 2 %w/w to 8 %w/w of menthol (d) 0.01 %w/w to 0.05 % w/w of capsaicin (e) 0.05 %w/w to 5.0 %w/w of oleum lini (f) pharmaceutical acceptable inert excipients, and (g) a Semisolid gel base. [2] A pharmaceutical synergistic formulation for topical application as claimed in claim 1, in which the excipients comprise binders, preservatives, antioxidants, surfactants and pH adjusting agents. [3] A pharmaceutical synergistic formulation for topical application as claimed in claim 2, in which the binder is a at least on binder selected from a group of binders comprising polyvinyl pyrrolidone, and natural binders such as alginates, traganth in a typical concentration of 0.05 %w/w to 3 %w/w. [4] A pharmaceutical synergistic formulation for topical application as claimed in claim 2, in which the preservative is a at least on preservative selected from a group of preservative comprising glycol solvents chlorocresol, methyl paraben, propyl paraben, thiomarsal, sorbic acid, potassium sorbate and benzyl alcohol in a typical concentration of 0.001 %w/w to 2 %w/w. [5] A pharmaceutical synergistic formulation for topical application as claimed in claim 2, in which the anti oxidant is a at least on anti oxidant selected from a group of anti oxidants comprising Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), sodium metabisulfite, sodium sulfite, sodium bisulfite and propyl gallate . [6] A pharmaceutical synergistic formulation for topical application as claimed in claim 2, in which the surfactant is a at least on surfactant selected from a group of surfactants comprising polysorbate 80, polysorbate 20, sorbitan groups (spans) in a typical concentration of 1 %w/w to 3.0 % w/w. [7] A pharmaceutical synergistic formulation for topical application as claimed in claim 2, in which the pH adjusting agent is a at least on agent selected from a group of pH adjusting agents comprising diethanolamine, triethanolamine, sodium hydroxide, citric acid and monobasic sodium phosphate. [8] A pharmaceutical synergistic formulation for topical application as claimed in claim 1, in which the semi solid gel base comprises an intimate mixture of adjuvant solvents selected from a group consisting of glycols including Propylene glycol, polyethylene glycols [PEG-300, PEG-400], substituted glycols such as different grades of cremaphors, viscosity enhancer (Jelling) agents selected from a group consisting of carbomers in concentration of 0.5 %w/w to 2.0 %w/w [cross linked polymers of acrylic acid], cellulosic polymers such as hydroxypropyl methylcellulose, methylcellulose, sodium carboxy methylcellulose, and hydroxypropyl cellulose, in a concentration 3%w/w to 20 %w/w and solvent such as isopropyl alcohol and purified water. [9] A process for making a synergistic formulation as claimed in claim 1, which comprises the steps of (a) preparing a slurry of a viscosity enhancing agent by adding weighed quantity of purified water in a suitable Stainless Steel jacketted vessel ; heating the water to 60 to 70 °C while stirring to create a vortex; adding viscosity-increasing agent in small parts to the voretex forming hot water and dispersing the same in the water without forming lumps; adding an adjuvant solvent and continuing to stir for at least 1 hour at slow speed and for at least 5 minutes at fast speed and then mix under vacuum for 30 minutes under slow speed; adding a pH asjusting agent via a funnel at slow speed to adjust pH between 6.7 to 6.8 pH and mixing for 10 minutes at fast speed and 20 minutes at slow speed under vacuum; (b) preparing Diclofenac Diethylamine Solution: by placing Propylene Glycol in a S.S. vessel and heating to about 50°C; adding antioxidant and Diclofenac Diethylamine to the solution and cooling the solution to room temperature and filtering; (c) preparing a Menthol and Capsaicin Solution; by placing Isopropyl alcohol in a suitable tank and dissolving with stirring slowly with propeller dispensed quantities of Menthol, antioxidants, Capsaicin and preservatives; (d) preparing a solution of Oleum Lini & Methyl Salicylate by placing In a suitable S.S. vessel, surfactants, adjuvant solvent, Oleumlini and Methyl Salicylate and mixing the same for about 10 minutes at a slow speed; and (el adding the diclofenac diethylamine solution to the menthol and capsacaim solution; mixing the resultant solution for 10 minutes and then adding the resultant solution to the viscosity enhancing agent slurry at slow speed, mixing the solution so formed for about 30 minutes and then adding the solution of oleum lini and methyl salicylate to the formed solution and fast speed mixing for 15 minutes and then 45 minutes slow speed to obtain the final un adjusted solution and adjusting the pH to between 6.5 to 7.5 using 50% solution of pH adjusting agent in distilled water and adding sufficient quantity of water with continuous stirring to obtain the synergistic formulation of this invention. Dated this 19th day of April 2005.

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