Title of Invention

A PROCESS FOR PREPARATION OF A PHARMACEUTICAL COMPOSITION CONTAINING NONSTEROIDAL ANTI-INFLAMMATORY SUBSTANCE

Abstract

A PROCESS FOR PREPARATION OF A PHARMACEUTICAL COMPOSITION CONTAINING NONSTEROIDAL ANTI-INFLAMMATORY SUBSTANCE AND A CYCLODEXTRIN The present invention relates to a preparation of a pharmaceutical composition containing nonsteroidal anti-inflammatory substance and a cyclodextrin such as valdecoxib and a cyclodextrin. The cyclodextrin may be substituted or unsubstituted cyclodextrin in the ratio of 1: 0.5 to 1 : 100 equivalence of drug : cyclodextrin. The premixed drug - cyclodextrin blend may be ball milled and further added to fillers and other additives to formulate a stable pharmaceutical composition

Full Text

The Patents Act 1970 Complete Specifications Section 10 A PROCESS FOR PREPARATION OF A PHARMACEUTICAL COMPOSITION CONTAINING NONSTEROIDAL ANTI-INFLAMMATORY SUBSTANCE- Inventor: DR. SHRUTI UMESH BHAT , an Indian national C/o Unichem laboratories Ltd., Unichem Bhavan, Prabhat Estate, S.V.Road, Jogeshwari West, Mumbai 400102, India and residing at Shreyas , B-6 113 J.P.Road, Andheri (West), Mumbai 400058, India Applicant: Untchem laboratories Ltd, an Indian company, having office at Unichem Bhavan, Prabhat Estate, S.V.Road, Jogeshwari West, Mumbai 400102, India The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed: - Back ground of invention : The present invention relates to the process of preparation of pharmaceutical formulation containing a cyclo oxygenase inhibitor and cyclodextrin. The term "cycio oxygenase inhibitor" or " Cox inhibitor" interchangeably refers to a therapeutic compound, which inhibits the enzyme cycio- oxygenase. Phanmaceutically effective cycio- oxygenase inhibitors include for example Cox- inhibitor non-steroidal anti-inflammatory drug substances (NSAIDS). A "pharmaceuticady effective" amount of Cox inhibitor is an amount sufficient to provide the intended treatment in the body being treated (for e.g. to treat or prevent inflammation in a mammal). Cox enzyme has two isoforms: Cox 1 and Cox 2 enzyme. Cox- 2 enzyme is inducible by inflammation where as on the other hand inhibitor of Cox -2 enzyme accounts for the therapeutic benefits. The ability of Cox-2 inhibitors to selectively block formation of pro-inflammatory prostaglandins while sparing those that guard the gastro- intestinal tract makes them an attractive choice for long term use, such as in rheumatoid arthritis or osteo-arthritis. Several patents disclose different types of dosage forms of Cox-2 inhibitors and several routes of administration such as oral, parenteral, topical, rectal and intranasal have been described for the same. Also several delivery systems and technologies for development of Celecoxib, Meloxicam, Rofecoxib dosage forms have been disclosed in the prior art [WO 0038716, WO 0037107, WO 0205815, WO 0178724, WO 005319, WO 0051685, US 5633272, US 5643933, WO 9641626, US 5700816, WO 9641645, WO 9729775, WO 9729776, WO 9806708, WO 9816227, WO 9847509, WO 9922720, WO 9959635, WO 0012093, WO 9738986, WP 0927555, WO 03049720, WO 03051878, WO 03029230, WO 03032961, WO 03033001, WO 03035080, WO 03035081, WO 03039542, WO 03039599, US 2003119895, WO 03066030, US 2003130334, WO 03070233, WO 03065988, WO 03059347, US 2003114416, WO 03015797, WO 03015608, WO 03013655, WO 03013473, WO 02096435, WO 02083177, WO 02080912, EP 1051994, EP 1064964, US 2002119193, WO 03057166, WO 03059294 ] Cox inhibitors as well as cyclodextrins in pharmaceutical formulations are well cited in literature. [Chemical Abstract 116(16); 15871 p (1992); Int. J. Pharmaceutics 79; 289-299 (1992); J. Pharm. Pharmacology 46 (6); 470-80; Pharmaceutical Research vol. 10 (5); p 682-86 (1993); US patent 6485706, 6482830, 6479467, 64724486, 6469989, 6468521, 6465012, 6465425, 6462237, 6458383, 6455533, 6451339, ,6436442, 6423344, 6423342, 6407079, 6403110, 6383471, 6376550, 6379697, 6372402, 6368629, 6358530, 6358469, Chemical Abstract vol. 137 (5) 2002; 574434,y, Chemical Abstract Vol. 137 (12) 2002; 163184, WO 0215884, WO 0215885, WO 0215886, WO 0217923, WO 0205815, WO 0205799, WO 0141761, WO 0145698, WO 0145706, WO 0053149, WO 0051685, WO 09729776, WO 0972775, WO 96625, WO 9641626, WO 9625405]. Compositions disclosed in the priort art employ large quantities of chlorinated or other aliphatic organic solvents during film -coating of granules or tablets which hazardous during industrial scale processing. Another important NSAID cox-inhibitor is Valdecoxib or a pharmaceutically acceptable salt or derivative or a prodrug thereof. Valdecoxib has poor water solubility, extremely bitter and unpleasant taste and is sensitive to light. Commercially available Valdecoxib tablet compositions are therefore film coated either with cellulose or methacrylic or the like polymers . Use of cyclodextrin for forming complexes with cox-inhibitors such as those disclosed in present invention to impart photo-stability is hither to not reported. Moreover, taste-masking techniques as well as film coating techniques described in the prior art have one or more limitations such as: 1. Known processes are time consuming and present low yields of final product, thereby increasing production costs when produced on commercial scale. 2. Some of the processes employ large quantities of organic solvents such as methylene chloride, methanol, acetone which are hazardous and also less preferred for use in a pharmaceutical facility. 3. Some of the processes employed makes use of large quantities of polymers, cellulose derivatives or other coating aids for the purpose of taste masking there by increasing production run times and product cost. There is therefore, need to formulate pharmaceutical compositions of cox-inhibitors NSAID using cyclodextrins that would be novel, easy to process on industrial scale at an affordable cost to patient and do not employ large amounts of any hazardous organic solvents in the process of manufacture, avoid film-coating of drug granules or tablets or powder or crystals and give compositions with desired photo-stability and masked taste . Scope of the invention :- The objective of the present invention is to develop process to obtain a pharmaceutical composition containing a COX-inhibitor or a pharmaceutically acceptable salt or derivative or prodrug thereof and a complexing agent such as cyclodextrin. The further objection of the present invention is to develop process to obtain a pharmaceutical composition containing COX-inhibitor or a pharmaceutically acceptable salt or derivative or prodrug thereof and a complexing agent such as cyclodextrin where in the bitter taste of the drug is masked. The further objective of the present invention is to develop process to obtain a pharmaceutical composition of COX-inhibitor or a pharmaceutically acceptable salt or derivative or prodrug thereof and a complexing agent such as cyclodextrin, which is safe and efficacious. The further objective of the present invention is to develop process to obtain a pharmaceutical composition of a COX-inhibitor or a pharmaceutically acceptable salt or derivative or prodrug thereof and a complexing agent such as cyclodextrin as a drug delivery system that is accurate in dosing as well as stable. The further objective of the present invention is to develop a process to obtain a pharmaceutical composition containing COX-inhibitor or a pharmaceutically acceptable salt or derivative or prodrug thereof and a complexing agent such as cyclodextrin that can be manufactured at an industrial scale and may not employ use of large amounts of any hazardous organic solvents during process of manufacture. The further objective of the present invention is to develop process to obtain a pharmaceutical composition of a COX-inhibitor or a pharmaceutically acceptable salt or derivative or prodrug thereof and a complexing agent such as cyclodextrin as a drug delivery system that is stable to light and therefore eliminates use of film-coating operation of drug granules or tablets or powder or crystals. Detailed description of the invention : Cox- inhibitor compounds disclosed in the present invention may be used in their native forms or as salts. In cases, where forming a stable non-toxic acid or base salt is desired, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acid that form a physiological acceptable anion for example tosyiate, methane, sulfonate, acetate citrate, maionate, tartarate, succinate, benezene sulfonate, benzoates, ascorbate, etoglutarate and glycerophosphate. Suitable in organic salts including hydrochloride, hydro bromide, sulfate, nitrate, bicarbonate and carbonate may also be formed insitu. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art for example reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. The term 'prodrug' refers to a chemical compound that can be converted into a therapeutic compound by metabolic or simple chemical process within the body of the subject. It will be appreciated by those skilled in the art that the compounds disclosed in the present application may have a chiral center and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. Cox-inhibitor drug substances present in the pharmaceutical composition disclosed in the present invention encompass any racemic, optically active, polymorphic, tautomeric or stereoisomeric form or mixture thereof of the substance or its derivative or salt or prodrug that possesses the useful properties described therein. It is well known in the art how to prepare optically active forms (for e.g. by resolution of the racemic forms through recrystallization techniques by synthesis from optically active starting materials by chiral synthesis or by chromatographic separation using a chiral stationery phase) and how to determine anti-inflammatory activity using standard tests or other tests that are well-known in the art. The process disclosed in the present invention involves use of the NSAID substance or its derivative or salt or prodrug with cyclodextrin as a complex along with binder, disintegrating agents, lubricants, levigating agent and other additives. The composition may or may not contain at least one further active ingredient. An inclusion complex for use in the process of preparation of pharmaceutical composition of the present invention disclosed in the application may be prepared as follows: 1. Pre-mixture of the required ratios of pre-screened cox-2 inhibitor and cyclodextrin. containing water content below 18 %w/w but preferably below 8 % w/w more preferably between 3.5 -4.0 % w/w. 2. Transfer to a ball-mill containing balls made either or porcelain or stainless steel. Ball milling the blend for a definite period of time for e.g. 1 -14 hours preferably 2-6 hours with occasional scraping of the blend from the sides of the mill until a uniform soild complex is formed. 3. Screening the complex solid through 60 mesh. 4. Adding formulation additives such as binders, bulking agents levigating agents, surfactants, etc. and granulating the mass to form a dough. Wet screening of the above dough of step (4) through 8 mesh and drying the granules obtained at 60°C in a fluidized bed drier for 1-4 hours or in a tray drier for up to 12 hours until granules with moisture content between 2.5-3.0% w/w are obtained. 6. Blending the dried granules of step (5) with suitable excipients such as lubricants, disintegrants and glidants to form a suitable oral dosage form such as tablets or capsules. 7. The dough from step (4) may also be extruded through an extruder to form rods, which may be then spheronized through a marumerizer to form beads or pellets. 8. The beads or pellets from step (7) may be then either encapsulated into a hard gelatin capsule or compressed into tablets after incorporating suitable excipients scuh as lubricants, disintegrants and glidants. 9. The solid complex powder from step 3 may also be sterilized and filled aseptically in vials along with other ingredients such as pH modifiers, stabilizers, osmolality and tonicity adjusters to be administered as an ophthalmic preparation. 10. The solid complex powder from step 3 may also be sterilized and filled aseptically in vials along with other ingredients such as pH modifiers, stabilizers, osmolality and tonicity adjusters to be administered as an parenteral preparation. 11. The solid complex powder from step 3 may also be added along with other ingredients such as pH modifiers, stabilizers, gel base to be administered as an topical preparation The preferred active component of the pharmaceutical composition of the invention is an inclusion complex of Valdecoxib or a pharmaceutically acceptable salt or a derivative or prodrug thereof and an un-substituted or substituted beta- or gamma cyclodextrin or atoricoxib or parecoxib or a pharmaceutically accepted salt or or a derivative or prodrug thereof and an unsubstituted or substituted beta-or gamma-cyclodextrin. The cox-2 inhibitor NSAID substance or its derivative or salt or prodrug and cyclodextrin may be premixed at ratios between 1:0.5 upto 1:100, but preferably at a ratio of 1:10, more preferably at 1:6. the cyclodextrin being incorporated may be either substituted or unsubstituted gamma or beta-cyclodextrin but preferably an unsubstituted beta or gamma cyclodextrin more preferably unsubstituted betacyclodextrin. The NSAID and cyclodextrin may be complexed with techniques well known such as by simple addition, phase coeservation, trituration, kneading or ball milling using stainless steel or porcelain balls, but preferably by ball milling technique followed by aqueous dispersion and spray or tray drying. The complex is evaluated using DSC (Differential scanning colorimetry) and IR (infra red) techniques to investigate complexation procedure. Several formulation additives viz. binders for example acacia, cellulose, chitosan, gellan, saccharides, polyvinyl pyrrolidone, gelatin, pre-gelatinised starch, liquid glucose, sorbitol, maltol etc. may be used; but preferably polyvinyl pyrollidone may be used. Bulking agents for example calcium carbonate, diclacium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, mannitol hydroxypropyl ceitufose, \actose} starch, magnesium carbonate, magnesium oxide, sugars etc., may be incorporated but preferably microcrystalline cellulose and lactose may be used. Levigating agents such as water, isopropyl, alcohol, water-isopropanol mixture, ethyl alcohol etc. may be used, but preferably water may be used. Surfactants such as sodium lauryl sulfate, polysorbate 80, polyethylene glycol (PEG) 6000, chremophore RH, poloxamer, hydrogenated castor waxes etc. may be incorporated into the formulation, but polysorbate 80 and PEG 6000 may be used. Disintegrants amongst crospovidone, microcrystalline cellulose, colloidal silicon dioxide, starch, cros-iinked sodium carboxymethyl cellulose, sodium starch glycollate, partially pre-gelainised starch etc., may be used but preferably crospovidone and colloidal silicon dioxide are used. The NSAID substance such as valdecoxib or its derivative or salt or prodrug as a cyclodextrin complex after addition of suitable fillers and or processing may be compressed into either a conventional, effervescent, chewable or a dispersible tablet or encapsulated into a hard gelatin capsule or filled as dry powder into bottle to be reconstituted with water prior to use. Suitable chemical and microbial preservatives such as sodium benzoate, parahydroxy benzoates and soluble salts thereof, butylated hydroxy anisole, butylated hydroxy toluene, ascorbic acid, tocopherol, edetates, sodium chloride, propyl gallate, sodium ascorbate, sodium metabisulfite, sorbic acid, tartaric acid, citric acid, triacetin, bronopol, sodium bicarbonate etc. in effective concentration may be incorporated into the formulation. Several ratios of 1:0 to 1:25 of flavouring agents such as cherry, butterscotch, mango, pineapple, orange, peppermint, mixed fruit, caramel, blackcurrent, raspberry, vanilla, spearmint etc., shall be added to the formulation. In addition, soluble or lake colours such as sunset yellow, caramel, quionoline yellow, tartrazine yellow, ponceau red, erythrosine pink, iron oxides etc., wherever necessary may be incorporated into the formulation. The pharmaceutical composition of cyclodextrin with COX-2 inhibitor NSAID substance such as Valdecoxib or its derivative or salt or prodrug has been evaluated in-vitro for its disintegration time, uniformity of dispersion, assay, dissolution in surrogate biological fluids and photo-sensivity to natural and UV light. Studies for drug availability for absorption with respect to time using in the-vitro dissolution rate test the formulation containing complex disclosed in the present invention showed superior drug solubility measured as amount of drug dissolved in simulated gastric or simulated intestinal fluid versus time in comparison with commercially available Valdecoxib tablets used as reference products. Due to enhanced dissolution, oral formulations according to the invention containing Valdecoxib propose to exhibit increased drug availability than that observed with reference products. Also, the impurity profile of Valdecoxib complex complies acceptance criteria when compared with plain drug . The pharmaceutical composition so developed by the process of the present invention has been evaluated for stability at several combinations of temperature and relative humidity viz 25 deg. C -60% RH, 30 deg. C - 70% RH, 40 deg. C. Ambient room temperature - RH 60 deg. C, 90% RH as well as under ultraviolet and fluorescence light etc., for a period between 1-36 months. The pharmaceutical composition so developed by the process of the present invention has been analyzed by chromatographic techniques viz.HPLC and was found to be stable and the quantity of the medicament as well as impurities / related substances well within specified limits. Since complexation of NSAID substance, valdecoxib such as those disclosed in the present invention with "cyclodextrin" prevented degradation of the drug as well as taste-masked the bitter drug, therefore film coating of valdecoxib tablet or granules or powder or crystals for formulation of the pharmaceutical composition could therefore be omitted. The pharmaceutical composition so developed by the process of the present invention was found to be safe, stable, and efficacious accurate in dosing. It could be employed on the industrial scale for the purpose of commercialization as was indicated by the encouraging results of the pilot scale-up batches. As film-coating operation has been omitted in the process of the present invention, the process therefore does not employ any organic solvent and hence saves cost use of expensive film coating materials in the final product. The above specified specification can be better understood with the help of examples However, these examples do not in any way restrict the broad scope of the invention. Example 1: Tablets Conventional tablets: Vaidecoxib with beta-cyclodextrin complex may be admixed with additives such as microcrystalline cellulose or lactose, granulated with a binder solution containing povidone or starch in solvent such as water or isopropyl alcohol of methylene chloride containing polysorbate 80. The granules may be dried using a fluidized bed or tray drier and admixed with materials such as colloidal silicon dioxide, talcum, disintegrating agents viz. ac-di-sol or Crospovidone and lubricated using magnesium stearate or stearic acid and compressed into a tablet. Suitable flavouring, colouring and sweetening agents may be added to the formula to compress the blend as a dispersible, chewable or effervescent tablet. Cherry, butterscotch, mango, pineapple, orange, peppermint, mixed fruit, caramel, blackcurrant, raspberry, vanilla, spearmint etc., may be added to the formulation. In addition, soluble or lake colours such as sunset yellow, caramel, quionoline yellow, tartrazine yellow, ponceau red, erythrosine pink, iron oxides etc., wherever necessary may be incorporated into the formulation. However. It is not intended that the scope of the invention be limited by these examples. Example 2: Capsule dosage forms: Vaidecoxib with beta-cyclodextrin complex may be admixed with additives such as microcrystalline cellulose or lactose, granulated with a binder solution containing povidone or starch in solvent such as water or isopropyl alcohol of methylene chloride containing polysorbate 80. The granules may be dried using a fluidized bed or tray drier and admixed with materials such as colloidal silicon dioxide, talcum, disintegrating agents viz. ac-di-sol or Crospovidone and lubricated using magnesium stearate or stearic acid and filled into hard or soft gelatin or saccharide capsules Example 3: Liquid dosage forms The Valdecoxib + betacyclodextrin complex powder is admixed with lactose or mannitol or sucrose. Flavouring, colouring agents, viscosity builders, buffering agents, stabilizers etc., may be added. Cherry, butterscotch, mango, pineapple, orange, peppermint, mixed fruit, caramel, blackcurrent, raspberry, vanilla, spearmint etc., may be added to the formulation. In addition, soluble or lake colours such as sunset yellow, caramel, quionoline yellow, tartrazine yellow, ponceau red, erythrosine pink, iron oxides etc., wherever necessary may be incorporated into the formulation. However. It is not intended that the scope of the invention be limited by these examples. The product is reconstituted using water prior to use. The powder containing the Valdecoxib + betacyclodextrin complex is admixed into a syrup base. Sweeteners, flavours, colouring stabilizing agents, viscosity builders etc., may be added to the liquid dosage form. Following sweeteners such as sucrose, mannitol, sorbitol, xylitol, aspartame, saccharin, saccharin sodium, glycyrrhizin, sodium monoamino glutamate etc. may be added to the tablet or liquid composition. However. It is not intended that the scope of the invention be limited by these examples. Following flavours such as orange, peppermint, pineapple, mango, raspberry, strawberry, tutti-frutti, colour etc., may be added to the tablet or liquid compositions. However, it is intended that the scope of this invention may not be limited by these examples The cyclodextrin used in the present invention may be dried at a temperature of not more than 100 deg.C before use The particle size of the NSAID drug substance may be between 1- 200 microns but preferably below 100 microns more preferably below 50 microns. The above specified specification can be better understood with the help of following formulae. However, these formulae do not in any way restrict the broad scope of the invention Formula 1(a): Valdecoxib and betacyciodextrin in 1:6 ratio dried to contain water content of approximately 3.5 % to 4.0 % w/w were screened through 60 mesh and mixed in a blender. The mixture was transferred to a ball mill containing porcelain balls (1 inch radius) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added lactose , crospovidone, polyvinyl pyrollidone and polysorbate 80. The mixture was granulated using water. The wet mass was screened through 8 mm screen and dried in a fluidized bed drier at 60 deg.C for 2 hours. The loss on drying for these granules was checked to be between 2.5 - 3.0 % w/w. The dried granules were rasped through 20 mesh. Lactose, crospovidone , colloidal silica, talc and magnesium stearate were added to this dried granules and the lubricated granules were compressed into tabiets.Color, flavour, aspartame, citric acid , sodium bicarbonate may also be added to the lubricated blend and compress the blend as effervescent tablets. The tablets had an average weight of 107.5 mg for tablets containing 10 mg of Valdecoxib; 215 mg and 350 mg tablets contain 20 mg and 40 mg Valdecoxib respectively. Formula 1 (b): Valdecoxib and betacyciodextrin in 1:6 ratio dried to contain water content of approximately 3.5 % to 4.0 % w/w were screened through 60 mesh and mixed in a blender. The mixture was transferred to a bafl mill containing porcelain balls (1 inch radius) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added lactose , crospovidone, polyvinyl pyrollidone and polysorbate 80. The mixture was granulated using water. The wet mass was screened through 8 mm screen and dried in a fluidized bed drier at 60 deg.C for 2 hours. The loss on drying for these granules was checked to be between 2.5 - 3.0 % w/w. The dried granules were rasped through 20 mesh. Lactose, crospovidone , colloioal silica, talc and magnesium stearate were added to this dried granules and the lubricated granules were filled into hard gelatin capsules to contain valdecoxib 10, 20 and 40 mg per capsule. Formula 2 : Valdecoxib and betacyciodextrin in 1:6 ratio dried to contain water content of approximately 3.5 % to 4.0 % w/w were screened through 60 mesh and mixed in a blender. The mixture was transferred to a ball mill containing porcelain balls (1 inch radius) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. To this complex was added aspartame, color, flavour, methyl paraben and propyl paraben at effective concentration and sucrose. The blend was screened through 40 mesh and filled into glass or HDPE or PET bottles. On reconstitution with water the product would administer valdecoxib 10,20 and 40 mg per 5 ml of the reconstituted suspension. Formula 3 : Valdecoxib and betacyciodextrin in 1:6 ratio dried to contain water content of approximately 3.5 % to 4.0 % w/w were screened through 60 mesh and mixed in a blender. The mixture was transferred to a ball mill containing porcelain balls (1 inch radius) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. The complex was added under stirring to a syrupy base containing microcrystalline cellulose, polysorbate 80, polyethylene glycol 6000, glycerine, sorbitol, paraben at effective concentrations, disodium edetate, potassium sorbate and colloidal silicon dioxide. The syrup obtained contained valdecoxib 10 and 20 mg per 5 ml. The syrup was filled into glass or HOPE or PET bottles. Formula 4 : Valdecoxib and cyclodextrin in 1:1 ratio dried to contain water content of approximately 3.5 % to 4.0 % w/w were screened through 60 mesh and mixed in a blender. The mixture was transferred to a ball mill containing porcelain balls (1 inch radius) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh. The complex was added to a gel base containing carbomer, disodium edetate,citric acid, benzyl alcohol, triethylamine and purified water. The gel to contain 1- 3 % w/w of valdecoxib. Also methyl salicylate, capsacin and menthol may be incorporated in therapeutically effective concentrations to this gel Formula 5 : Valdecoxib and gamma cyclodextrin in 1:6 ratio dried to contain water content of approximately 3.5 % to 4.0 % w/w were screened through 60 mesh and mixed in a blender. The mixture was transferred to a ball mill containing stain steel balls (1 inch radius) and milled for 7 hours to form a complex. The complex was then screened through 40 mesh and sterilized in a dry heat sterilizer. Pre-sterilized meglumine, citric acid, sodium phospate or bicarbonate or chloride or edetate and water may be added to the complex and filled aseptically into sterile vials and sealed to give parenteral valdecoxib composition. We Claim, 1) A process for manufacture of a pharmaceutical composition containing Cox-2 inhibitor non - steroidal anti-inflammatory agent or a pharmacologically acceptable salt there of and cyclodextrin comprising of:- a) Pre-mixture of the required ratios of the pre-screened Cox-2 inhibitor and cyclodextrin containing water content below 18% w/w, b) Transfer to a ball mill containing balls made either of porcelain or stainless steel . Ball milling the blend for 1-14 hours, preferably for 6 hours with occasional scraping of the blend from sides of the mill until a uniform solid complex is formed , c) Screening the solid complex through 60 mesh , d) Adding formulation additives such as binders, bulking agents, levigating agents, surfactants and granulating the mass to form a dough , e) Wet screening of the above dough of step (d) and drying the granules obtained in a drying device, until granules with moisture content between 2.5 - 3.0% w/w are obtained , f) Blending the dried granules of step (e) with suitable excipients such as lubricants, disintegrant and glidants as presented in the invention to form a suitable pharmaceutical composition for oral use such as powder or tablet or capsule or liquid preparation. 2) A process as claimed in Claim 1 to make a stable pharmaceutical composition wherein the non-steroidal anti-inflammatory agent or a pharmaceutically acceptable salt thereof is for example valdecoxib, or parecoxib or etoricoxib or lumirocoxib alone or in combinations thereof 3) A process as described in Claims 1- 2 to provide a stable pharmaceutical composition comprising of a non-steroidal anti-inflammatory agent or its pharmaceutically acceptable salt and cyclodextnn incorporated with physiologically accepted excipients selected in nature and quantities to formulate a solid or liquid oral composition such as powder or tablet or ready suspension or powder for reconstitution wherein the bitter taste of the solid drug or its pharmaceutically accepted salt is masked. 4) A process as claimed in Claims 1-3, to provide a stable pharmaceutical composition for oral use wherein the cyclodextrin is alfa, beta, gamma or substituted cyclodextrin but preferably beta cyclodextrin. . 5) A process as claimed in Claims 1-4, to provide a stable pharmceutical composition for oral use wherein the ratio of non- steroidal anti-inflammatory agent or a pharmaceutically accepted salt thereof to cyclodextrin is in the ratio of 1:100 to but preferably is 1: 6 as drugs or its pharmaceutically active salt : cyclodextrin. 6) A process as claimed in Claims 1-5, wherein the water content of cyclodextrin used for complexation technique is below 10% w/w but preferably below 5% w/w more preferably below 3.5% w/w. 7) A process as claimed in Claims 1-6, wherein the non-steroid anti-inflammatory agent or its pharmaceutically acceptable salt has particle size between 1-200 microns preferably below 100 microns more preferably below 50 microns. 8) A process as claimed in Claims 1-7, where in the amount of non-steroidal anti¬inflammatory agent or a pharmaceutically acceptable salt thereof complexed to the cyclodextrin salt there of complexed to the cyclodextrin in the pharmaceutical compositions is in the range of about 5% to 95% by weight of drug or its pharmaceutically acceptable salt - cyclodextrin complex. 9) A process as claimed in Claims 1-8, wherein the physiologically acceptable excipients such as saccharides, cellulose, salts of alkaline earth metals, povidone, starch derivates, glycols, talc, stearic acid and its salts, sodium citrate, sodium acetate, polysorbates, sodium lauryl sulphate, glycerine, colloidal silicon dioxide, gums, vegetable oil, almond oil, waxes, carbopol, sodium metabisulfite, salts of methyl, ethyl, propyl paraben, sodium benzoate, poloxamer, copolymer of methacrylic acid and methacrylate , aspartame, saccharine, colours and flavours are added suitable for preparation for liquid suspension or dispersion or chewable tablets or dispersible tablet or effervescent tablet or powder for reconstitution or modified release tablet or mouth dissolve tablet or a conventional release tablet or capsule 10) A process as claimed in Claims 1-9, wherein the non-steroid anti-inflammatory agent is Valdecoxib or a pharmaceutically acceptable salt thereof. 11) A process as claimed in Claims 1-9, wherein the non-steroidal anti-inflammatory agent is Parecoxib or a pharmaceutically acceptable salt thereof. 12) A process as claimed in Claims 1-9, wherein the non-steroid anti-inflammatory agent is Etoricoxib or a pharmaceutically acceptable salt thereof. 13) A process as claimed in Claims 1-9, wherein the non-steroid anti-inflammatory agent is Lumirocoxib or a pharmaceuticaily acceptable salt thereof. 14) A process for preparation of a pharmaceutical composition for oral use containing a non-steroidal anti-inflammatory agent or a pharmaceuticaily acceptable salt thereof and a cyclodextrin as claimed in Claims 1-13, substantially as described herein before with reference to Formulae 1-5. Dated this 18 th day of October 2003

Documents:

1097-mum-2003-abstract.doc

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1097-mum-2003-cancelled pages(15-03-2004).pdf

1097-mum-2003-claims.doc

1097-mum-2003-claims.pdf

1097-mum-2003-correspondence(ipo).pdf

1097-mum-2003-correspondence.pdf

1097-mum-2003-description(granted).doc

1097-mum-2003-description(granted).pdf

1097-mum-2003-form 1.pdf

1097-mum-2003-form 19.pdf

1097-mum-2003-form 2(granted).doc

1097-mum-2003-form 2(granted).pdf

1097-mum-2003-form 2(title page).pdf

1097-mum-2003-form 3.pdf

1097-mum-2003-form 5.pdf

1097-mum-2003-form 8.pdf