Title of Invention	A NOVEL FORMULATION OF N-(4-NITRO-2-PHENOXYPHENYL) METHANESULFONAMIDE
Abstract	A pharmaceutical composition, especially suitable for application intravenously or intramuscularly or topically, comprising: N-(4-Nitro-2-Phenoxyphenyl)methanesulfonamide and 2,5-di-O-methyl-1,4:3,6-dianhydro-D-glucitol.

Full Text

FORM 3A The Patents Act 1970 COMPLETE SPECIFICATION SECTION 10 TITLE A NOVEL FORMULATION OF N-(4-Nitro-2-Phenoxyphenyl) methauesulfonamide ) APPLICANT DR. DINESH SHANTILAL PATEL, an Indian national, Of 11/12 Udyognagar, S.V. Road, Goregaon (West), Mumbai - 400 104, State of Maharashtra, and SHASHIKANT PRABHUDAS KURANI, an Indian national, of 11/12 Udyognagar, S.V. Road, Goregaon (West), Mumbai - 400 104, State of Maharashtra. GRANTED 31 MAY 1999 18-10-2007 The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed : Field of invention The present invention relates to a novel therapeutic composition. More particularly the composition comprises N-(4-Nitro-2-Phenoxyphenyl)methanesulfonamide (Nimesuhde) with 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol,which is in the form of injectables both intravenous and intramuscular, as well as in the form of oral liquid composition and liquid preparation for topical applications and to a process for preparing such compositions. Nimesuhde which has the chemical name N-(4-Nitro-2-Phenoxyphenyl)methane-sulfonamide (Nimesuhde) has the following chemical formula: Background of the invention Nimesuhde preparations are used for analgesic applications in the form of tablet, suspension, ointment and intramuscular preparations. The poor solubility of Nimesuhde in aqueous media, restricts the use of the substance in analgesic compositions through the injectable format or for preparation of compositions with various ingredients in oral preparations or its use for local applications. The preparation of such formulations in oil base leads to various problems eg., injectables are difficult to filter; when administered intramuscularly because it results in pain and depot formation and therefore unsuitable for intravenous use. The various castor oil derivatives when used internally may give anaphylactic reactions and defy the object of quick relief. US Patent no. 5,688,829 describes the preparation of Nimesulide for therapeutic use in the form of intramuscular injectables. The patent describes the use of a number of vehicles like dimethyl acetamide, benzyl benzoate, benzyl alcohol and ethyl oleate in various proportions thus involving more than one ingredient, which in turn requires substantial quality checks for individual ingredients and stabilizers. The use of such solutions for intravenous purposes is limited due to certain characteristics of the product. The salt of Nimesulide is not frequently used as such since such solution, in the aqueous phase, gives very high alkaline pH, not homeostatically proper for injectable preparations. WO 95/34533 describes the injectable preparation of Nimesulide as complex formed with L-lysine. This also has limitations in terms of use eg., to achieve high therapeutic efficacy, higher quantities of the formulation is to be administered or a dose given intramuscularly would be of sub-therapeutic level if given through normal intramuscular route. The inherent drawbacks of Nimesulide makes it unsuitable for use in intravenous as well as in the form of clear transparent preparations of syrups and drops. Therefore there is still a need for a stable, dose-flexible analgesic / anti-inflammatory / anti-pyretic formulation / solution which can be conveniently filtered, sterilized and free from all limitations of oil based formulation and its ingredients. Summary of the invention A pharmaceutical composition, especially suitable for application intravenously or intramuscularly or topically, comprising: N-(4-Nitro-2-Phenoxyphenyl)methanesulfonamide and 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol. The applicants have now found that a formulation in the form of injectables, oral liquids viz., syrups & drops, lotions, creams and ointments can be provided when N-(4-Nitro-2-Phenoxyphenyl)methanesulfonamide (Nimesulide) is dissolved in 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol. This solution, in its injectable form, can be conveniently administered intravenously with flexibility of dose as per the need of the patient It is a clear, limpid solution which is stable, safe and as effective as the present marketed formulation. The applicants have also found a suitable process for the preparation of the new formulation whereby the formulation may be prepared at a cheaper cost. The process of the invention is also simple. Alternatively the formulation can be prepared by / solving \ N-(4-Nitro-2- Phenoxyphenyl)methanesulfonamide (Nimesulide) in 2,5-di-0-methyl-l,4:3,6-dianhydro- D-glucitol- water mixture. Alternatively the compositions may also contain vehicles and adjuvants such as diluting agents, sweetners, buffering agents, flavouring agents, stabilizers and the like. The invention also relates to a process for the preparation of the said therapeutic composition which comprises - mixing of N-(4-Nitro-2-Phenoxyphenyl)methanesulfonamide (Nimesulide) with 2,5-di- 0-methyl-l,4:3,6-dianhydro-D-itolunde istirring and heating; cooling the mixture and recovering the solution. Detailed Description The solutions of Nimesulide may be administered either through intravenous or intramuscular manner. The analgesic efficacy is maximum when the drug level is sufficiently distributed to reach therapeutic levels after absorption and the use of the composition of the invention achieves this when administered intravenously or intramuscularly. The dosage can be flexible in various concentrations from 25 mg/ml to 100 mg/ml and the same is non-toxic. This may be provided in the form of single dose or multiple dose as per the requirement of physicians. The composition according to the invention is also suitable for various oral formulations and for topical application. The solvent used in the formulation is easily water soluble, versatile and non-toxic at the level of applicable use. It thus reduces cost, with improved efficacy over the presently available oral preparations. Moreover the side effects like gastric irritation, shown by oral preparations, can be reduced if the formulation of the present invention is administered in either injectable form or as paediatric drops or as oral liquid form by incorporating necessary diluents of formulation. The composition may be prepared as an injection with a solvent which is ready to be used in a single / multi dose vial, therapeutically usable specifically for debiliated Geriatric and Paediatric patients. However this does not limit its use to only the above category of patients and can be used in various other categories too where, instantaneous, quick effects with high therapeutic index, without the limitations of oral / suppository route, are required. The oral dose in humans is 100 mg given twice or 5 mg/kg/day in 2-3 divided doses with onset of action within 30-60 minutes and this action lasts for 8-10 hours. For topical application of the compostion, gel may be prepared using carbopol and 1% alcohol. In the present invention, solution formulations of 25 mg/ml and 100 mg/ml - prepared with or without antioxidant - have been made, which can be administered intramuscularly / intravenously or for formulating oral liquids which give a maximum peak threshold level for reducing pain thus having best analgesic, anti-pyretic and anti-inflammatory effect. The advantage is 'rapid onset of action' as time is the critical factor for 'relief from conditions like pain, temperature, etc. The examples are illustrative and non-limiting and using the teachings of the invention, derivatives of Nimesulide can also be prepared in this versatile and elegant solvent. The solvent is readily miscible in water. The dose up to 100 mg/ml of Nimesulide and its analogues can be prepared in 2,5-di-0-methyl-l,4.3,6-dianhydro-D-glucitol. The same solvent may be used for preparation of 1% gel. This invention will now be illustrated in the Examples to follow illustrating the preparation of Nimesulide in carrier solvent 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol and a mix of 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol / water which gives safe, effective, economic, easy to prepare solution either used as injectables for intramuscular / intravenous route and for oral preparations as drops and syrups. EXAMPLES Example I: 8.10872 mmol of Nimesulide is taken in a round bottom flask containing 50 ml. of 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol. With arrangement of stirring and heating, the temperature of vessel is maintained at 40°C with continuous stirring continued up to 1 hour under Nitrogen. Reaction mixture is brought to 25°C and volume of preparation is made to 100 ml. with 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol. This solution is filtered aseptically using a 0.2 micron filter, filled and sealed in amber vials for the preparation of injectables. The clear liquid can be utilized for the preparation of oral liquids and paediatric drops by incorporating diluting agents, sweeteners, buffering agents, flavouring agents and stabilizers. Example II: 32.43 mmol Nimesulide is taken in a round bottom flask containing 50 ml. 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol with an arrangement of stirring and nitrogen flushing. The mixture is stirred at 40°C for 45 mins. The mixture is cooled to 25°C and volume of the resultant solution is made to 100 ml. The solution is filtered through Millipore 0.2 micron filter and then filled and sealed in amber vials for injections and some can be used for preparing drops and oral liquids by incorporating necessary vehicles and adjuvants like diluents, sweeteners, flavouring agents and stabilizers. EXAMPLE - III: 8.1072 mmol of Nimesulide is taken in a 100 ml. round bottom flask with 50 ml. of 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol. The solution is maintained at 60°C. With continuous stirring, 15 ml. of injection grade double distilled water is added and further stirring is carried out. 0.7 mmol chlorocresol is added with continuous stirring to dissolve and solution is brought to room temperature. The volume of final solution is made to 100 ml with 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol. The pH of solution is measured potentiometrically using glass calomel electrode and is about 6. The solution is filtered through millipore filter 0.2 micron aseptically and then filled and sealed under nitrogen in amber vials. Omitting the addition of chlorocresol and by incorporating necessary diluents like sugar, buffering agents and flavouring agents, paediatric drops and oral liquids can be prepared. EXAMPLE - IV; 16.21 mmol of Nimesulide is taken in a flask containing 50 ml of 2,5-di-O-methyl-1,4.3,6-dianhydro-D-glucitol appended with stirring mechanism. Stirred for 45 mins. at 60°C and then to the solution, 15 ml. of double distilled water is added. With continuous stirring, 0.7mmol chlorocresol is added, allowed to dissolve and after its solubilization, the mixture is brought to room temperature and made to 100 ml. with 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol. The solution is filtered through 0.2micron filter aseptically and then filled and sealed in amber vials. Omitting the addition of chlorocresol and by incorporating necessary diluents like sugar, buffering agents and flavouring agents, paediatric drops and oral liquids can be prepared. ** ** The solution of Nimesulide in 2,5-di-0-methyl-l,4:3,6-dianhydro-D-glucitol was also tested by stability indicating method for the assay contents and was found to be stable at RT and accelerated temperature of 40°C up to 6 months. PERIODICAL STABILITY STUDD2S Name of the product: NimesuUde Storage Conditions : 25° ± 2° C / 60% ± 5% RH EXAMPLE 1: LIMITS 6 months 9 months SR NO. TEST Initial 3 months 12 months] 1. Assay C13HI2N205S 95%-105% 101.0% 100.8% 100.3% 99.6% 98.9% EXAMPLE 2 : LIMITS Initial 3 months 6 months SR NO. TEST 9 months 12 months 1. Assay C13H12N205S 95% -105% 100.8% 100.6% 100.0% 6 months 99.7% 99.2% EXAM [PLE 3: LIMITS Initial 3 months SR NO. TEST 9 months 12 months 1. EXAM SR NO. Assay C13H12N2O5S [PLE 4: TEST 95% - 105% 101.8% Initial 101.4% 3 months 101.0% 6 months 100.3% 9 months 100.0% 12 months LIMITS 1. Assay Cl3H,2N205S 95% -105% 101.0% 100.65% 100.45% 100.25% 99.90% ACCELERATED STABIUTY STUDIES Name of the product: Nimesulide Storage Conditions : 40° ± 2° C / 75% ± 5% RH EXAMPLE 1: SR. NO. TEST LIMITS INITIAL 2 months 4 months 6 months 1. Assay C13H12N205S 95% - 105% 101.0% 100.6% 100.0% 99.4% EXAMPLE 2 : SR. NO. TEST LIMITS INITIAL 2 months 4 months 6 months 1 1. Assay C13Hl2N205S 95%-105% 100.8% 100.3% 99.8% 99.4% I EXAMPLE 3: TEST EXAMPLE 4 SR. NO. TEST LIMITS INITIAL 2 months 4 months 6 months I 1. Assay C13H12N205S 95% -105% 101.0% 100.3% 100.0% 99.3% Thus it is seen that the prepared solutions, in the various strengths of 25 mg/ml., 50 mg/ml and 100 mg/ml, which can be given either in single dose or multi-dose as injections or solution used for preparation of oral liquids are very stable. Various diluents like water up to 15% V/v may be used. Formulations are stable when tested by stability indicating Spectro method. The efficacy of the solution preparation, as an anti-inflammatory agent in animal models was studied and it was found to be more quickly effective than the oral Nimesulide preparations. WE CLAIM : 1. A pharmaceutical composition, especially suitable for application intravenously or intramuscularly or topically, comprising: N-(4-Nitro-2-Phenoxyphenyl)methanesulfonamide and 2,5-di-O-methyl-1,4:3,6-dianhydro-D-glucitol. 2. A composition as claimed in Claim 1, additionally comprising water. 3. A composition as claimed in anyone of Claims 1 or 2 wherein the concentration of N-(4-Nitro-2-Phenoxyphenyl)methanesulfonamide is 25 to 100 mg /ml of composition in an injectable form. 4. A composition as claimed in anyone of Claims 2 or 3 wherein the amount of water is up to 15% by volume of said composition. 5. A composition as claimed in anyone of the preceding claims which is in a single or multi-dose form filled in sterile vials or ampoules or bottles for use as injectables or for the preparation of oral liquids. 6. A composition as claimed in anyone of the preceding claims optionally comprising vehicles and adjuvants selected from diluents, sweeteners, flavouring agents and stabilizers. 7. A composition as claimed in anyone of claims 1 to 6 optionally comprising antioxidants. 8. A composition as claimed in anyone of the preceding claims which is in the form of lotions, creams, ointments for topical application. 9. A pharmaceutical composition comprising N-(4-Nitro-2-phenoxyphenyl) methanesusfonamide (Nimesulide) and 2,5-di-0-methyl-1l4:3,6-dianhydro-D-gludtol substantially as hereindescribed and illustrated with reference to the examples. Dated this 28th day of May, 1999. ANJAN SEN Of S.MAJUMDAR & CO. Applicants' Agent.

Documents:

406-bom-1999-cancelled pages(18-10-2007).pdf

406-bom-1999-claims(granted)-(18-10-2007).doc

406-bom-1999-claims(granted)-(18-10-2007).pdf

406-bom-1999-correspondence(18-10-2007).pdf

406-bom-1999-correspondence(ipo)-(20-06-2007).pdf

406-bom-1999-form 1(31-05-1999).pdf

406-bom-1999-form 13(08-01-2001).pdf

406-bom-1999-form 19(04-08-2003).pdf

406-bom-1999-form 2(3a)-(granted)-(18-10-2007).pdf

406-bom-1999-form 3a(2 granted)-(18-10-2007).doc

406-bom-1999-form 4(23-11-2000).pdf

406-bom-1999-form 4(31-05-1999).pdf

406-bom-1999-form-pct-ipea-409(31-05-1999).pdf

406-bom-1999-form-pct-isa-210(02-07-2007).pdf

406-bom-1999-petition under rule 123(25-10-2000).pdf

406-bom-1999-power of attorney(18-10-2007).pdf