FIELD OF THE INVENTION
The present invention relates to novel and highly stable injectable pharmaceutical compositions comprising at least one cyclooxygenase-II enzyme (COX-II) inhibitor or non-steroidal antiinflammatory drug (NSAID) or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs or salts thereof as active ingredient suitable for parenteral administration preferably by intramuscular (IM) or intravenous (IV) route, process of preparing such compositions and therapeutic methods of using such compositions
The analgesic and anti-inflammatory injectable compositions of the present invention are very useful in mammals particularly in humans for the treatment of acute painful conditions like one or more of post-operative trauma, pain associated with cancer, sports injuries, migraine headache, neurological pain and pain associated with sciatica and spondylitis, and the like, and/or chronic painful conditions, and/or other associated disorders such as inflammation, fever, allergy, or the like
BACKGROUND OF THE INVENTION
Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-II enzyme (COX-II) inhibitors are in general highly hydrophobic compounds and readily precipitate even in the presence of minor amounts of water Hence it is very difficult to formulate such compounds into injectable compositions for intramuscular or intravenous use
NSAIDs such as mmesulide, ketorolac, diclofenac, ibuprofen and naproxen, and COX-II inhibitors in parenteral form capable of instant therapeutic action are extremely desirable In order to prepare parenteral formulations of these classes of compounds, a suitable, safe and nontoxic carrier/vehicle is required in which these drugs are soluble Due to the physico-chemical properties of these groups of compounds, the NSAIDs or the COX-II inhibitors are poorly soluble in water hence presenting a difficulty in formulating these drugs in the parenteral form Attempts to provide NSAIDs and COX-II inhibitory drugs or their analogs in parenteral form using various solvents such as alcohols, dimethyl sulphoxide, propylene glycol and glycerin were found to be unsuccessful either due to problems of solubility or that when these drugs dissolve in solvents like isopropenol acid mixture, dimethyl sulphoxide and propylene glycol, the desired concentration range for the therapeutic administration of the above drugs particularly through intramuscular route does not permit the above solvent usage as they are found to be toxic Due to
such problems, it has been extremely difficult to develop stable injectable formulation of such drugs
Several efforts have been made in the past to make injectable compositions comprising of NSAIDs such as nimesulide An injectable formulation of nimesulide has been reported in PCT Patent No WO 95/34533 that discloses the utilization of a salt form of nimesulide with L-lysine which is in turn further complexed with cyclodextrins that may be dissolved in water to give an injectable preparation The maximum solubility achieved by this injectable composition was reported to be 2 4 mg/ml, which is not sufficient for intramuscular administration, as it would require very large volumes to administer therapeutic doses Moreover, making a salt form of nimesulide and then combining with cyclodextnns not only makes the process cumbersome but also increases the cost of the formulations Another reference (Daffonchio, L et al, Inflammatory Research, 45, 259-264, 1995), wherein nimesulide is dissolved in saline for intravenous administration for experimental studies in animals, also describes only very dilute solutions which cannot deliver therapeutic doses of nimesulide in humans
Nimesulide is a potent non-steroidal anti-inflammatory (NSAID) drug, presently used in the treatment of painful inflammatory conditions due to rheumatoid arthritis, which also possesses antipyretic activity Compared to other NSAIDs, nimesulide has a better therapeutic ratio, low gastrotoxicity and generally good tolerability Nimesulide is a strongly hydrophobic substance that is practically insoluble in water (solubility in water at room temperature being 0 01 mg/ml) Since nimesulide is insoluble in water and in a large number of non-toxic solvents specifically those which are approved for parenteral use, it becomes highly difficult to formulate it into solutions suitable for parenteral administration via intramuscular or intravenous route Other NSAIDs such as diclofenac, lbuprofen, lndomethacin, and naproxen also offer a lot of difficulty in making them into injectable compositions using approved excipients and the permissible concentrations in which they are approved for parenteral use Parenteral compositions particularly comprising cyclooxygenase-II inhibitors such as rofecoxib or valdecoxib are highly unstable upon storage due to the tendency of such drugs to precipitate out, and hence it becomes difficult to obtain a homogeneous solution for parenteral administration during the shelf life of such products It is known and well accepted that parenteral administration of drugs for the treatment of painful inflammatory conditions, is more effective than other routes of administration, since the drug enters the circulation directly and promptly manifests its therapeutic effect
Seedher, Neelam et al (Indian Journal of Pharmaceutical Sciences, 65(1), 58-61, 2003) had described the solubility of nimesulide in various solvents and solvent-cosolvent mixtures in relation to the development of parenteral formulations The said publication showed that the solubilization of nimesulide increased in semi-polar solvents such as polyethylene glycols (PEGs) and non-ionic surfactants such as Tween® 80 and Bry® 30 However, the concentration of PEGs used to achieve the desired solubility is too high i e 90% which is not recommended for parenteral use specifically meant for IV administration US Patent Nos 4,056,635 and 4,452,817 disclose compositions containing propofol suitable for parenteral administration to produce anesthesia in warm-blooded animals as mixtures of propofol with surfactants such as Cremophor® RH40, Cremophor® EL, and Tween® 80 in an aqueous medium that may also contain ethanol or other pharmaceutically acceptable ingredients US Patent No 4,794,117 claims a process for solubilizing indomethacin in water consisting essentially of dissolving an anti-inflammatory amount of indomethacin in a solubilizing amount of at least one polyethylene glycol having a molecular weight of 300 to 700 and dissolving the resulting solution in a solubilizing amount of an aqueous medium buffered in a pH range of 4 5 to 8 especially intended for the external use US Patent No 4,798,846 discloses sterile propofol compositions containing 1% to 2% propofol alone or dissolved in oil such as arachis oil or ethyl oleate These formulations are stabilized with surfactants US Patent No 5,858,999 discloses a sterile aqueous pharmaceutical composition for parenteral administration which comprises about 0 9 to about 90 mg/ml of a lazaroid or a pharmaceutically acceptable salt thereof, about 0 002 to about 2 0M citrate, upto about 80% of a cosolvent selected from the group consisting of propylene glycol, polyethylene glycol, glycerol, ethanol, dimethylsulfoxide, dimethylacetamide, dimethyl isosorbide, N-methyl-2-pyrrohdone and water at a pH of about 2 4 to about 3 5 These compositions use very high concentrations of cosolvents
US Patent No 5,688,829 assigned to the applicant of the present invention discloses a therapeutic injectable analgesic pharmaceutical composition for intra-muscular administration comprising essentially nimesulide in a parenteral absorption enhancing base comprising dimethylacetamide, benzyl benzoate and ethyl oleate The said composition uses lipophilic solvents that are oily in nature to solubilize nimesulide, which does not allow administration of the injectable via the intravenous route Another US Patent No 6,451,302 assigned to the same applicant describes an injectable water-miscible composition comprising nimesulide, benzyl alcohol, a substance selected from the group consisting of dimethylacetamide, dimethylformamide, dimethylsulphoxide, and N-methyl pyrrohdone, and a glycol selected from
the group consisting of polyethylene glycol (PEG 200 to 600), propylene glycol, hexylene glycol, butylene glycol, and polyethylene glycol 660 hydroxy stearate The said patent necessitates the use of alkyl amides/alkyl sulphoxides or pyrrohdones to solubilize nimesuhde
US Patent No 6,589,973 pertains to a clear, stable novel pharmaceutical preparation of selective COX-II inhibitors in the parenteral form for the treatment of pain and inflammatory conditions arising because of cyclooxygenase-II activity In particular, the pharmaceutical preparation of COX-II inhibitors comprise of selective COX-II inhibitors such as celecoxib, rofecoxib and their analogs dissolved in a selective isosorbide type solvent EP Patent No 1228757 relates to stable pharmaceutical solutions suitable for parenteral administration of nimesuhde consisting of 80% glycerol formal, 15% ethanol and 5% water and/or 75% glycerol formal, 10% ethanol, 10% propylene glycol and 5% water However the solvents and the concentrations in which they are used are not approved for parenteral administration PCT Publication No WO 2000072884 describes a novel pharmaceutical composition of nimesuhde and 2,5-di-0-methyl-l,4 3,6-dianhydro-D-glucitol with or without water, optionally containing one or more diluents which can be used for IV/IM administration or oral or topical formulations US Publication No 20030078266 specifically relates to a pharmaceutical composition comprising in powder form, at least one water-soluble therapeutic agent selected from selective COX-2 inhibitory drugs and prodrugs and salts thereof, in a therapeutically effective total amount constituting about 30% to about 90% by weight, a parenterally acceptable buffering agent in an amount of about 5% to about 60% by weight, and other parenterally acceptable excipient ingredients in a total amount of zero to about 10% by weight, of the composition, said composition being reconstitutable in a parenterally acceptable solvent liquid to form an injectable solution
The solvents used to formulate compositions intended for parenteral use should be non-toxic and should be preferably present in low concentrations Most of the existing patent and literature references describe parenteral compositions, which comprise very high concentrations of solvents that are primarily not approved for parenteral use and also are unstable during storage
Hence, there still exists an unmet need for developing effective non-toxic parenteral compositions comprising COX-II inhibitors or NSAIDs in which the latter are substantially soluble, and compositions those are devoid of such aforementioned problems and which could remain stable throughout the shelf life of the product
The inventors of the present invention have done extensive research and conducted several experiments using different non-toxic solvents and discovered that their combination in various concentrations along with suitable buffers and alkalizing agents results in a highly solubihzed system suitable for parenteral administration in which the COX-II inhibitors and/or NSAIDs are soluble and which are also stable during the storage of the product thus demonstrating a significant advancement over the prior art
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient and a solvent system comprising a mixture of glycols, optionally with other pharmaceutically acceptable excipients
It is an objective of the present invention to provide novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient, a solvent system comprising a mixture of glycols, at least one alkalizing agent, optionally with other pharmaceutically acceptable excipients
It is an objective of the present invention to provide novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient, a solvent system comprising a mixture of glycols, at least one alkalizing agent, at least one buffering agent, optionally with other pharmaceutically acceptable excipients
It is also an objective of the present invention to provide novel injectable pharmaceutical compositions comprising a NSAID preferably nimesulide as active ingredient, a solvent system comprising a mixture of glycols, at least one alkalizing agent, at least one buffering agent, optionally with other pharmaceutically acceptable excipients
It is another objective of the present invention to provide novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as active
ingredient and a solvent system comprising a mixture of glycols, optionally with other pharmaceutically acceptable excipients, additionally comprising one or more other pharmaceutically acceptable active mgredient(s)
It is another objective of the present invention to provide highly stable injectable pharmaceutical compositions suitable for intramuscular (IM) or intravenous (IV) administration
It is yet another objective of the present invention to provide a process for the preparation of such novel injectable compositions
It is yet another objective of the present invention to provide a process for preparation of a novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient and a solvent system comprising a mixture of glycols, optionally with other pharmaceutically acceptable excipients, which comprises of the following steps
I) adding the active mgredient(s) to the mixture of glycols followed by mixing,
II) optionally adding other pharmaceutically acceptable excipients and mixing to produce the injectable composition
It is a still further objective of the present invention to provide a process for preparation of a
novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or
NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs,
solvates, prodrugs, or salts thereof as active ingredient and a solvent system comprising a
mixture of glycols, optionally with other pharmaceutically acceptable excipients, additionally
comprising one or more buffering agent(s) and/or alkalizing agent(s), which comprises of the
following steps
1) adding one or more buffering agent(s) to the mixture of glycols and mixing to obtain a
homogeneous mixture, n) adding the active mgredient(s) to the mixture followed by mixing,
III) adding alkalizing agent(s) followed by mixing,
IV) adding the buffering agent(s) with mixing to obtain a homogeneous mixture, v) optionally adjusting the pH of the mixture to an alkaline pH by adding alkalizing agent(s) to produce the injectable composition
It is yet another objective of the present invention to provide a method of using such composition which comprises administering to a patient in need thereof an effective amount of the composition
The compositions of the present invention are particularly useful for the treatment of one or more acute painful conditions such as post-operative trauma, pain associated with cancer, sports injuries, migraine headache, neurological pain and pain associated with sciatica and spondylitis, or chronic painful conditions, and/or other associated disorders
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient Preferably the active ingredient is a NSAID, more preferably nimesulide The compositions of the present invention additionally comprise a solvent system comprising a mixture of glycols, optionally with other pharmaceutically acceptable excipients
In an embodiment, the novel injectable pharmaceutical compositions of the present invention comprise additionally at least one alkalizing agent(s) and/or at least one buffering agent(s)
In an embodiment, the novel injectable pharmaceutical composition comprises at least one COX-II inhibitor or NSAID or COX/LOX inhibitor or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts or thereof as active ingredient from about 0 1% to about 80% w/v of the composition and a solvent system comprising a mixture of glycols from about 1% to about 80% v/v of the composition, optionally with other pharmaceutically acceptable excipients In another embodiment, the composition of the present invention additionally comprise at least one alkalizing agent from about 0 2% to about 60% v/v of the composition and/or at least one buffering agent from about 2% to about 80% v/v of the composition
In an embodiment, the present invention provides novel injectable pharmaceutical compositions comprising nimesulide as active ingredient, a solvent system comprising a mixture of glycols, at least one alkalizing agent, at least one buffering agent, optionally with other pharmaceutically acceptable excipients
According to an embodiment of the present invention, the injectable compositions comprising COX-II inhibitor or NSAID or COX/LOX inhibitor can be prepared using a mixture of different non-toxic solvents in various concentrations along with suitable buffers and alkalizing agents These compositions are clear, odorless, highly stable, non-toxic and homogeneous and are therefore suitable for parenteral administration In an embodiment of the present invention, the injectable compositions are suitable particularly for administration by intravenous (IV) or intramuscular (IM) route
In the present invention, the solubilization techniques used to solubilize the poorly soluble COX-II inhibitors or NSAIDs or COX/LOX inhibitor are based on cosolvation and/or pH modification techniques Particularly, the compositions of the present invention are highly stable, preferably in the pH range of about 7 5 to 11 5, more preferably in the pH range of about 9 0 to 11 0
The active ingredient useful in the present invention are preferably NSAIDs selected from but not limited to a group comprising nimesulide, nabumetone, tapoxalin, diclofenac, flosuhde lbuprofen, indomethacin, naproxen, and the like, their tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof or COX-II inhibitors selected from but not limited to a group comprising celecoxib, rofecoxib, valdecoxib, etoncoxib, parecoxib, itacoxib, deracoxib and the like or their tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs or salts thereof In an embodiment, the active ingredient of the present invention belongs to the category of COX/LOX (cyclooxygenase/hpooxygenase) inhibitor such as hcofelone In an embodiment of the present invention, the active ingredient is present in the micromzed form
In an embodiment of the present invention, the novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient and a solvent system comprising a mixture of glycols, optionally with other pharmaceutically acceptable excipients, additionally comprises one or more other pharmaceutically acceptable active mgredient(s) Other pharmaceutically acceptable active mgredient(s) useful in the present invention is any active agent, which can be combined with a COX-II inhibitor or a NSAID or COX/LOX inhibitor, known in the art such as acetaminophen, serratiopeptidase, antibacterial agents, CNS agents, CVS agents, or the like
In an embodiment of the present invention, the mixture of glycols used to make the solvent system is polyethylene glycol (PEG) selected from but not limited to a group comprising PEG 200, PEG 300, PEG 400, PEG 600 and PEG 700, or mixtures thereof, and propylene glycol In a preferred embodiment, the solvent system comprises a mixture of PEG 400 and propylene glycol
In an embodiment of the present invention, the alkalizing agent used is an inorganic base or an organic base or a combination of both In an embodiment of the present invention, the alkalizing agent used is selected from but not limited to a group comprising inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate, magnesium carbonate, magnesium oxide, and the like, or mixtures thereof, and/or organic bases such as meglumine, triethanolamine, diethanolamine and the like, or mixtures thereof In a preferred embodiment, the alkalizing agent is an inorganic base such as sodium hydroxide or potassium hydroxide The alkalizing agent is preferably used as an aqueous (water) solution, prepared by dissolving the said agent in water The quantity of the said agent and volume of water in which the agent is dissolved is used so as to obtain desired concentration of the agent
The buffering agent used in the present invention is preferably an alkaline buffering agent selected from but not limited to a group comprising glycine buffer, lysine buffer, phosphate buffer, acetate buffer, and the like, or mixtures thereof, preferably having a pH range of about 7 2 to about 12 5 In a preferred embodiment, glycine buffer is used as the buffering agent in the compositions of the present invention In a still preferred embodiment, glycine buffer having pH of about 8 3 to about 11 3 is used as the buffering agent The buffering agent is preferably used as an aqueous (water) solution, prepared by dissolving the desired compound(s) in water The quantity of the desired compound(s) and volume of water in which the desired compound(s) is dissolved is used so as to obtain desired concentration and pH of the agent
Pharmaceutically acceptable excipients used in the composition of the present invention are selected from but not limited to the group of excipients generally known to persons skilled in the art e g vehicles, bulking agents, stabilizers, preservatives, surfactants, hydrophihc polymers, solubility enhancing agents such as glycerine, various grades of polyethylene oxides, beta-cyclodextrins like sulfobutylether-beta-cyclodextnn, transcutol and glycofurol, tonicity adjusting agents, local anesthetics, pH adjusting agents, antioxidants, osmotic agents, chelating agents, viscosifying agents, wetting agents, emulsifying agents, acids, sugar alcohol, reducing sugars,
non-reducing sugars and the like, or mixtures thereof In an embodiment, the Pharmaceutical ly acceptable excipient(s) is used in an amount of about 0 1% to about 70% w/v or v/v of the composition
The vehicles suitable useful in the present invention can be selected from but not limited to a group comprising dimethylacetamide, dimethylformamide, dimethylsulphoxide, N-methyl pyrrolidone, benzyl benzoate, benzyl alcohol, ethyl oleate, polyoxyethylene glycolated castor oils (Cremophor® EL), polyethylene glycol such as those having molecular weight of about 200 to 6000, propylene glycol, hexylene glycols, butylene glycols and glycol derivatives such as polyethylene glycol 660 hydroxy stearate (Solutrol® HS15) and the like, or mixtures thereof
In another embodiment of the present invention, the compositions additionally comprises an antimicrobial preservative such as benzyl alcohol preferably at a concentration of about 0 001% to about 5 0% w/w of the composition
In yet another embodiment of the present invention, the composition additionally comprises a conventionally known antioxidant selected from but not limited to a group comprising ascorbyl palmitate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate, α-tocopherol and the like, or mixtures thereof
The compositions of the present invention are highly stable In an embodiment, the novel compositions of the present invention may be diluted with suitable diluting fluids known to the art to prepare a solution or dispersion or infusion before administration The novel compositions of the present invention are highly stable and compatible with different diluting fluids such as deminerahzed (DM) water, dextrose 5% w/v, sodium chloride 0 9% w/v or mixtures thereof These fluids can be employed during the manufacture of the composition or can be used for diluting the composition before administration For example, the composition is stable for 5 hrs upto 1 150 dilution and for 48 hrs up to 1 5 dilution with DM water, for 2 hrs upto 1 150 dilution and for 4 hrs upto 1 3 dilution with dextrose 5 0% solution, and for 24 hrs upto 1 150 dilution and for 48 hrs upto 1 100 dilution with 0 9% NaCl solution, particularly at room temperature
The compositions of the present invention are preferably filled into ampoules Compatibility study on mmesulide injection (content of one ampoule) with different infusion solutions were performed to study the physical stability (during intravenous infusion) of the injection after
diluting with infusion solutions Most of the infusion solutions possess pH in acidic range (e g Normal saline, about 6 2, Ringer lactate solution, about 6 5 and Dextrose 5% w/v, about 5 5) Admixing with infusion solution for known injections comprising a COX-II inhibitor or NSAID or COX/LOX inhibitor results into saturation and thus crystallization This is not desirable for a solution if diluted as such since such solution is meant for parenteral administration Thus, particularly in case of nimesulide as the active ingredient, it is required to maintain the pH of final solution at alkaline side to stabilize the nimesulide in infusion solution Hence, compatibility studies were performed on the Nimesulide in infusion solutions already buffered with sodium bicarbonate to impart the alkalinity to the final solution and thus prevent recrystallization The study showed that the injectable composition was highly stable and compatible with different infusion solutions
In a further embodiment, ethanol and/or dimethylacetamide (DMA) can also be added to the compositions of the present invention to further enhance the solubility of the active mgredient(s)
Stability study was conducted on the composition stated in Example-1 herein Long term (at controlled room temperature l e 25°C), intermediate (at 30°C and 70% RH), accelerated (at 40°C and 75% RH), and stress (at 60°C) stability studies were performed on the product and samples were analyzed including the controlled samples kept at freezing conditions (at 2-8°C) The product was found to be stable for more than six months at each of the above conditions and it did not show any stability issues relating to physical changes like particulate matter, crystallization and color change or chemical changes such as change in potency or presence of any degradation product Furthermore, in order to assess the product stability, 'freeze-thaw cycle' study was also conducted and the product was found to be stable physically and chemically even after four freeze-thaw cycles (l e refrigeration of the product followed by keeping the product at 40°C and 75% RH for one day each)
In the present invention, the nimesulide injection is formulated preferably as an aqueous injection meant for dilution with infusion solutions particularly in case of IV administration Nimesulide possess pH dependent solubility le nimesulide is soluble at alkaline pH and practically insoluble at acidic pH Thus, preferably a solvent system comprising a mixture of solvents (particularly glycols) optionally along with a pH adjusting system has been adopted to prepare a stable formulation in the present invention
Pharmacological Study
Acute toxicity study of nimesulide IV injection was carried in female Swiss mice weighing between 20-25 g (n = 6 per group) The samples used for the study were Nimesulide IV injection (Label claim Each 3 ml contains 100 mg of nimesulide) and Placebo injection 0 1 ml of injection equivalent to doses of 41 6, 50, 54 17, 58 3 and 83 3 mg of nimesulide per kg body weight were administered by IV route for 14 days Mice injected with 0 1 ml of injection equivalent to a dose of 50 0 mg/kg, 54 17 mg/kg, and 83 3 mg/kg showed toxic symptoms of decreased locomotor activity, stupor, and tremors Mice injected at dose level of 41 6 mg/kg and 5 ml/kg placebo did not show any toxic symptom The mortality rate of 16 6 %, 50 %, and 100% was observed at dose levels of 54 17 mg/kg, 58 3 mg/kg, and 83 3 mg/kg respectively The LD50 of the nimesulide injection (IV) was found to be 57 54 mg/kg
Acute toxicity study of nimesulide IM injection was carried out in female Swiss mice weighing between 20-25 g (n = 5 per group) The samples used for the study were Nimesulide IM injection (Label claim Each 3 ml contains 100 mg of nimesulide) and Placebo injection The dose given was 1 25, 2 5, 5, 6 25, and 7 5 ml/kg of Nimesulide IM injection equivalent to 41 6, 83 3, 166 67, 208 33, and 250 mg of nimesulide per kg body weight respectively by IM route for 14 days No toxicity symptoms were observed at dose level of 41 6 mg/kg of nimesulide injection and with 2 5 ml/kg placebo injection in mice Mice injected with a dose of 83 3, 166 67, 208 33 or 250 mg/kg showed toxicity symptoms The mortality rates of 40%, 80%, and 100% were observed at dose level of 166 67 mg/kg, 208 33 mg/kg, and 250 mg/kg respectively The LD50 of the nimesulide injection when administered intramuscularly was found to be 173 78 mg/kg
A study was conducted to compare the hemolytic potential of Nimesulide IV injection 100 mg/ml of the present invention with that of commercially available IV/IM injections on Rat whole blood (citrated) and Rat packed red blood cells (citrated) The commercially available IV/IM injections used for the study were Diazepam injection 5 mg/ml (CALMPOSE®), Diclofenac sodium injection 25 mg/ml (VOVERAN®), Frusemide injection 10 mg/ml (LASIX®), Nimesulide injection 10% w/v (NIMOVET®), and Pentazocin lactate injection 30 mg/ml (FORTWIN®) The study showed that Nimesulide IV injection of the present invention when tested (at blood to test sample ratio of 1 10) on Rat packed red blood cells (citrated) showed comparative fractions of healthy cells as compared to CALMPOSE®, FORTWIN®, NIMOVET® and VOVERAN® Nimesulide IV injection when tested (at blood to test sample
ratio of 13 1) on Rat whole blood (citrated) showed comparative fractions of healthy cells as compared to CALMPOSE®, FORTWIN®, and LASIX®
The perivenous tolerance following a single intravenous administration of Nimesulide IV injection 100 mg/3 ml of the present invention against a placebo composition was studied in rabbits The study showed that the animals injected intravenously with Nimesulide IV injection of the present invention or the placebo did not show any signs of local irritation at the site of injection in the right ears
Pharmacokinetic study of Nimesulide IV injection of the present invention was carried out in rabbits Albino rabbits (1 9-2 1 kg) of either sex (n=4 rabbits) were selected for the study Nimesulide IV injection, each 2 ml ampoule containing 75 mg nimesulide, was used A dose of 3 75 mg/kg body weight of rabbit equivalent to human dose of 75 mg/60kg were administered by IV route via marginal ear vein of rabbits and blood sampling was done at 0, 0 25, 0 5, 1, 1 5, 2, 2 5, 3, 4, 6, 8, 10, 12, and 24 hour intervals, and the plasma samples were analyzed for nimesulide by LC-MS/MS The pharmacokinetic profile of Nimesulide injection in rabbits is presented below
Table-1 Pharmacokinetic profile of Nimesulide injection in rabbits

(Table Removed)
In a further embodiment of the present invention, a process for the preparation of such novel injectable compositions is provided
In an embodiment, the process for preparation of a novel injectable pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient and a solvent system comprising a mixture of glycols, optionally with other pharmaceutically acceptable excipients, which comprises of the following steps I) adding the active mgredient(s) to the mixture of glycols followed by mixing, n) optionally adding other pharmaceutically acceptable excipients and mixing to produce the injectable composition
In another embodiment, the process for preparation of a novel injectable pharmaceutical
compositions comprising at least one COX-II inhibitor and/or NSAID or COX/LOX inhibitor, or
its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof as
active ingredient and a solvent system comprising a mixture of glycols, optionally with other
pharmaceutically acceptable excipients, additionally comprising one or more buffering agent(s)
and/or alkalizing agent(s), which comprises of the following steps
l) adding one or more buffering agent(s) to the mixture of glycols and mixing to obtain a
homogeneous mixture, n) adding the active mgredient(s) to the mixture followed by mixing, in) adding alkalizing agent(s) followed by mixing,
IV) adding the buffering agent(s) with mixing to obtain a homogeneous mixture, v) optionally adjusting the pH of the mixture to an alkaline pH by adding alkalizing agent(s)
to produce the injectable composition
In another embodiment, the process as described herein comprises the active ingredient selected from a group comprising of at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof, optionally with one or more additional active mgredient(s) that can be combined with a COX-II
inhibitor or NSAID known to art Preferably the NSAID is nimesuhde or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof
In yet another embodiment of the present invention, therapeutic methods of use of such compositions are provided The analgesic and anti-inflammatory injectable compositions of the present invention are useful for the treatment of acute painful conditions like post-operative trauma, pain associated with cancer, sports injuries, migraine headache, neurological pain and pain associated with sciatica and spondylitis, and the like, in mammals particularly in humans and animals, more particularly in humans
In a further embodiment, the present invention provides a method of using the novel injectable pharmaceutical composition, which comprises administering to a patient in need thereof an effective amount of the composition
In a further embodiment, the present invention provides a method of using the injectable pharmaceutical composition preferably for the treatment of acute and/or chronic painful conditions in mammals particularly mammals, including a variety of painful and inflammatory conditions like postoperative pain, primary dysmenorrhea and painful osteoarthritisand/or other associated disorders such as inflammation, fever, allergy, or the like
In a further embodiment, the present invention provides a method of using the injectable pharmaceutical composition particularly for the treatment of acute painful conditions, wherein such condition is one or more of post-operative trauma, pain associated with cancer, sports injuries, migraine headache, neurological pain and pain associated with sciatica and spondylitis
In a further embodiment is provided the use of the compositions of the present invention for the preparation of medicament for the treatment of acute painful conditions, wherein such condition is one or more of post-operative trauma, pain associated with cancer, sports injuries, migraine headache, neurological pain and pain associated with sciatica and spondylitis, and/or chronic painful conditions, and/or painful and inflammatory conditions like postoperative pain, primary dysmenorrhea and painful osteoarthritis and/or other associated disorders such as inflammation, fever, allergy, or the like
Some typical examples illustrating embodiments of the present invention are provided However, it should also be understood that the particular compositions, processes and methods illustrating the present invention are exemplary only and should not be regarded as limitations of the present invention
EXAMPLES
Example-1 Nimesuhde Injection (100 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-400) 30 00 ml
2 Propylene Glycol 20 00 ml
3 Glycine Buffer pH 11 3 36 00 ml
4 Nimesuhde 3 34 gm
5 Sodium hydroxide (NaOH) solution 4 0% w/v 11 20 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
n) Add Propylene glycol (20 00 ml) to step (l) with continuous stirring using mechanical
rf* stirrer in) Add about 30 0 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture IV) Add weighed amount of Nimesuhde (3 34 gm) passed through #60 mesh to the step (m)
with continuous stirring v) Add specified quantity (11 20 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vn) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml via) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 10 0 by adding NaOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-2 Diclofenac Injection (75 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-300) 30 00 ml
2 Propylene Glycol 20 00 ml
3 Glycine Buffer pH 12 0 30 00 ml
4 Diclofenac 2 50 gm
5 Sodium hydroxide (NaOH) solution 4 0% w/v 10 00 ml Procedure
I) Take specified quantity (30 00 ml) of PEG-300 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (I) with continuous stirring using mechanical
stirrer iii) Add about 25 0 ml of the Glycine Buffer pH 12 0 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Diclofenac (2 50 gm) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (10 00 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer to step (vi) vii) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 7 5 by adding NaOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-3 Indomethacin Injection (25 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-400) 30 00 ml
2 Propylene Glycol 20 00 ml
3 Lysine Buffer pH 10 42 00 ml
4 Indomethacin 0 84 gm
5 Sodium hydroxide (NaOH) solution 4 0% w/v 11 20 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (I) with continuous stirring using mechanical
stirrer iii) Add about 36 0 ml of the Lysine Buffer to the step (n) with continuous stirring to form a
homogeneous mixture iv) Add weighed amount of Indomethacin (0 84 gm) passed through #60 mesh to the step
(in) with continuous stirring
v) Add specified quantity (1120 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution
vi) Mix the solution for about 30 minutes by continuous stirring
vii) Add remaining quantity of Lysine Buffer to step (vi)
viii) Mix the solution for about 10 minutes by continuous stirring
IX) Adjust final pH to 11 5 by adding NaOH 4 0% w/v solution
x) Mix the solution for about 10 minutes by continuous stirring
Example-4 Rofecoxib Injection (25 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-400) 20 00 ml
2 Propylene Glycol 20 00 ml
3 Dimethylacetamide 10 00 ml
4 Glycine Buffer pH 11 3 36 00 ml
5 Rofecoxib 0 84 gm
6 Sodium hydroxide (NaOH) solution 4 0% w/v 12 00 ml Procedure
i) Take specified quantity (20 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (l) with continuous stirring using mechanical
stirrer Add 10 00 ml of Dimethylacetamide and mix iii) Add about 30 0 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Rofecoxib (0 84 gm) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (12 00 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring ix) Adjust final pH to 11 0 by adding NaOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-5 Licofelone Injection (100 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-400) 30 00 ml
2 Propylene Glycol 20 00 ml
3 Glycine Buffer pH 11 3 36 00 ml
4 Licofelone 3 34 gm
5 Sodium hydroxide (NaOH) solution 3 0% w/v 14 40 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (I) with continuous stirring using mechanical
stirrer iii) Add about 30 0 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of licofelone (3 34 gm) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (14 40 ml) of NaOH 3 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 10 0 by adding NaOH 3 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-6 Nimesuhde Injection (100 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-400) 30 00 ml
2 Propylene Glycol 20 00 ml
3 Glycine Buffer pH 11 3 36 00 ml
4 Nimesuhde micronized 3 34 gm
5 Sodium hydroxide (NaOH) solution 5 0% w/v 11 00 ml Procedure
i) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (l) with continuous stirring using mechanical stirrer
iii) Add about 30 0 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Nimesulide micronized (3 34 gm) passed through #60 mesh to
the step (m) with continuous stirring v) Add specified quantity (1100 ml) of NaOH 5 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 10 0 by adding NaOH 5 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-7 Nimesulide Injection (100 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-400) 30 00 ml
2 Propylene Glycol 20 00 ml
3 Glycine Buffer pH 11 3 36 00 ml
4 Nimesulide 3 34 gm
5 Potassium hydroxide (KOH) solution 5 6 % w/v 11 00 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (l) with continuous stirring using mechanical
stirrer iii) Add about 30 0 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Nimesulide (3 34 gm) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (11 00 ml) of KOH 5 6% solution to the step (iv) with continuous
stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring ix) Adjust final pH to 11 0 by adding KOH 5 6% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-8 Nimesulide Injection (100 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-400) 30 00 ml
2 Propylene Glycol 10 00 ml
3 Glycine Buffer pH 11 3 46 00 ml
4 Nimesulide 3 34 gm
5 Potassium hydroxide (KOH) solution 4 0 % w/v 13 80 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (10 00 ml) to step (l) with continuous stirring using mechanical
stirrer iii) Add about 40 0 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Nimesulide (3 34 gm) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (13 80 ml) of KOH 4 0% solution to the step (iv) with continuous
stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring ix) Adjust final pH to 11 0 by adding KOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-9 Nimesulide Injection (100 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Polyethylene glycol (PEG-600) 20 00 ml
2 Propylene Glycol 10 00 ml
3 Phosphate Buffer pH 7 2 56 00 ml
4 Nimesulide 3 34 gm
5 Potassium hydroxide (KOH) solution 5 6 % w/v 11 20 ml Procedure
I) Take specified quantity (20 00 ml) of PEG-600 into a vessel
ii) Add Propylene glycol (10 00 ml) to step (1) with continuous stirring using mechanical
stirrer iii) Add about 50 0 ml of the Phosphate Buffer pH 7 2 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Nimesulide (3 34 gm) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (11 20 ml) of KOH 4 0% solution to the step (iv) with continuous
stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring
vii) Add remaining quantity of Phosphate Buffer pH 7 2 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 11 0 by adding KOH 5 6% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-10 Nimesulide Injection (100 mg/3 ml)
S No Ingredients Quantity/100 ml
1 Polyethylene glycol (PEG-300) 30 00 ml
2 Glycine Buffer pH 11 3 56 00 ml
3 Nimesulide micromzed 3 34 gm
4 Potassium hydroxide (KOH) solution 6 5 % w/v 9 50 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-300 into a vessel
ii) Add about 40 0 ml of the Glycine Buffer pH 11 3 to the step (l) with continuous stirring
to form a homogeneous mixture iii) Add weighed amount of Nimesulide micromzed (3 34 gm) passed through #60 mesh to
the step (n) with continuous stirring iv) Add specified quantity (9 50 ml) of KOH 6 5% solution to the step (in) with continuous
stirring to form a homogeneous solution v) Mix the solution for about 30 minutes by continuous stirring vi) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml vii) Mix the solution for about 10 minutes by continuous stirring viii) Adjust final pH to 9 5 by adding KOH 6 5% w/v solution ix) Mix the solution for about 10 minutes by continuous stirring
Example-11 Nimesulide injection (75mg/2ml)
S No Ingredients Quantity/ 100 ml
1 Nimesulide micromzed 3 77 gm
2 Polyethylene Glycol (PEG 400) 30 00 ml
3 Propylene Glycol 20 00 ml
4 Glycine Buffer pH 11 3 35 00 ml
5 NaOH solution 4 0% 13 00 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (l) with continuous stirring using mechanical
stirrer iii) Add about 30 00 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Nimesulide (3 75 g) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (13 00 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 10 0 by adding NaOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-12 Licofelone injection (100 mg/3 ml)
S No Ingredients Quantity/ 100 ml
1 Licofelone 3 34 g
2 Polyethylene Glycol (PEG-400) 30 00 ml
3 Propylene Glycol 20 00 ml
4 Glycine Buffer pH 11 3 30 00 ml
5 NaOH solution 4 0% 15 00 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (l) with continuous stirring using mechanical stirrer
iii) Add about 28 00 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Licofelone (3 34 g) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (15 00 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 10 0 by adding NaOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-13 Parecoxib injection (50 mg/2 ml)
S No Ingredients Quantity/ 100 ml
1 Parecoxib 2 50 g
2 Polyethylene Glycol (PEG-400) 30 00 ml
3 Propylene Glycol 20 00 ml
4 Glycine Buffer pH 11 3 34 00 ml
5 NaOH solution 4 0% 14 00 ml Procedure
I) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (l) with continuous stirring using mechanical
stirrer iii) Add about 30 00 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture iv) Add weighed amount of Parecoxib (2 50 g) passed through #60 mesh to the step (in) with
continuous stirring v) Add specified quantity (14 00 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring ix) Adjust final pH to 10 0 by adding NaOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-14 Diclofenac Sodium injection (75 mg/2 ml)
S No Ingredients Quantity/100 ml
1 Diclofenac Sodium 3 77 g
2 Polyethylene Glycol (PEG-400) 30 00 ml
3 Propylene Glycol 20 00 ml
4 Glycine Buffer pH 11 3 35 00 ml
5 NaOH solution 4 0% 13 00 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (l) with continuous stirring using mechanical
stirrer iii) Add about 30 00 ml of the Glycine Buffer pH 11 3 to the step (a) with continuous stirring
to form a homogeneous mixture IV) Add weighed amount of Diclofenac sodium (3 77 g) passed through #60 mesh to the step
(in) with continuous stirring v) Add specified quantity (13 00 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 10 0 by adding NaOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring
Example-15 Ibuprofen injection (200 mg/2 ml)
S No Ingredients Quantity/100 ml
1 Ibuprofen 10 g
2 Polyethylene Glycol (PEG-400) 30 00 ml
3 Propylene Glycol 20 00 ml
4 Glycine Buffer pH 11 3 25 00 ml
5 NaOH solution 4 0% 18 00 ml Procedure
l) Take specified quantity (30 00 ml) of PEG-400 into a vessel
ii) Add Propylene glycol (20 00 ml) to step (1) with continuous stirring using mechanical
stirrer iii) Add about 22 00 ml of the Glycine Buffer pH 11 3 to the step (n) with continuous stirring
to form a homogeneous mixture IV) Add weighed amount of Ibuprofen (10 00 g) passed through #60 mesh to the step (in)
with continuous stirring v) Add specified quantity (18 00 ml) of NaOH 4 0% solution to the step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution for about 30 minutes by continuous stirring vii) Add remaining quantity of Glycine Buffer pH 11 3 to make up the volume to 100 ml viii) Mix the solution for about 10 minutes by continuous stirring IX) Adjust final pH to 10 0 by adding NaOH 4 0% w/v solution x) Mix the solution for about 10 minutes by continuous stirring

We Claims
1. A novel injectable pharmaceutical composition comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts or thereof as active ingredient from 0.1% to 80% w/v and a solvent system comprising a mixture of glycols from 1% to 80% v/v; optionally with other pharmaceutically acceptable excipients.
2. A composition according to claim 1, wherein the said composition additionally comprises at least one alkalizing agent from 0.2% to 60% v/v.
3. A composition according to claims 1 or 2, wherein the said composition additionally comprises at least one buffering agent from 2% to 80% v/v.
4. A composition according to claims 1 to 3, wherein the COX-II inhibitor is selected from a group comprising celecoxib, rofecoxib, valdecoxib, etoricoxib, parecoxib, itacoxib, deracoxib or their tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs or salts thereof.
5. A composition according to claims 1 to 3, wherein the NSAID is selected from a group comprising nimesulide, nabumetone, tapoxalin, diclofenac, flosulide, ibuprofen, indomethacin, naproxen or their tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts thereof.
6. A composition according to claims 1 to 3, wherein the COX/LOX inhibitor is licofelone.
7. A composition according to claim 1, wherein the solvent system comprises a mixture of polyethylene glycol and propylene glycol.
8. A composition according to claim 2, wherein the alkalizing agent is an inorganic base selected from a group comprising sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate, magnesium carbonate and magnesium oxide, or mixtures thereof, and/or an organic base selected from a group comprising meglumine, triethanolamine and diethanolamine, or mixtures thereof.
9. A composition according to claim 3, wherein the buffering agent is an alkaline buffering agent selected from a group comprising glycine buffer, lysine buffer, phosphate buffer and acetate buffer, or mixtures thereof, having a pH of about 7.2 to about 12.5.
10. A composition according to claim 1, wherein the pharmaceutical excipients are selected from a group comprising vehicles, bulking agents, stabilizers, preservatives, surfactants, hydrophilic polymers, solubility enhancing agents, tonicity adjusting agents, local anesthetics, pH adjusting agents, antioxidants, osmotic agents, chelating agents, viscosifying agents, wetting agents, emulsifying agents, acids, sugar alcohol, reducing sugars and non-reducing sugars, either alone or in combination thereof, and used in an amount of about 0.1% to about 70% w/v or v/v of the composition.
11. A process for preparation of a novel injectable pharmaceutical composition according to claim 1, which comprises of the following steps:
i) adding the active ingredient(s) to the mixture of glycols followed by mixing,
ii) optionally adding other pharmaceutically acceptable excipients and mixing to produce the injectable composition.
12. The pharmaceutical compositions and processes thereof substantially as herein described
in the specification and illustrated by the examples.