DESC:FORM 2

THE PATENTS ACT 1970

(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION

(SECTION 10)

AQUEOUS INJECTABLE PREPARATIONS OF DICLOFENAC AND ITS

PHARMACEUTICALLY ACCEPTABLE SALTS

We, HETERO HEALTHCARE LIMITED

a company incorporated under the companies act, 1956 having address at Sy. No. 80-84, Melange Towers, 4th Floor, C-wing, Patrikanagar, Madhapur, Hyderabad-500081, Telangana State, India

The following specification particularly describes the invention and the manner in

which it is to be performed.

FIELD OF INVENTION
The present invention relates to aqueous injectable preparations of diclofenac. The invention specifically relates to the stable aqueous injectable formulation comprising diclofenac or pharmaceutically acceptable salts thereof.
In particular, this invention provides a composition for the parenteral administration through intramuscular, intravenous, subcutaneous, intra-articular delivery, which causes significantly less pain at the site of injection.
BACKGROUND OF INVENTION
Diclofenac is a non-steroidal anti-inflammatory drug (“NSAID”) with analgesic, anti-inflammatory and anti-pyretic activity, most commonly used for treatment of acute and chronic pain and inflammation such as Musculoskeletal and joint disorders such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, management of post-operative pain, in both parenteral and oral dosage forms. It has also been used for the fever management. It is also used for the prevention of intra-operative miosis occurred during cataract extraction, for the treatment of inflammation after surgery or accidental trauma, and for the relief of ocular signs and symptoms of seasonal allergic conjunctivitis.
Diclofenac is mainly used in form of sodium or potassium salts and act by the inhibition of arachidonic acid cyclooxygenase system, lipooxygenase pathway, arachidonic acid release resulting in decreased production of prostaglandins and thromboxanes, leukotrienes and reduction of arachidonic acid, respectively (Martindale, 2002). When given by oral route, dose is 100-200 mg/day, while by parenteral route, dose range from 75-150 mg/day given by either infusion or in divided doses. Toxicity of parenteral and oral forms are well established, includes gastro-intestinal haemorrhagic, hepatic, renal, cardiovascular and allergic adverse events.
Conventional formulations of Diclofenac Sodium injection are limited to intramuscular administration which causes substantial pain at the site. This limitation has been arising primarily due to the physicochemical properties of drug.

Due to poor aqueous solubility of the Sodium salt of Diclofenac, it has a high tendency to crystallize from aqueous and organic solutions. Potent solubilizing co solvents, such as Macrogols and Benzyl alcohol have been used to achieve physically stable solutions containing at least 75 mg/3ml of Diclofenac Sodium which would allow intra-muscular (IM) administration of the desired dose. However, these co-solvents have an unfavourable intravenous safety profile and are associated with venous sequelae, high haemolytic and sensitizing (Reed, K. W. et al, J. Par. Sci. Technol. 39 (2) (1985) 64-68). Low solubility of Diclofenac salts has limited the parenteral use to IM and/or slow intravenous (IV) administration of diluted (100-500 ml diluent) product.
Further, these conventional formulations of diclofenac sodium contain high amounts of propylene glycol, which is known to cause irritation at injection site. It has been reported that the aqueous solution of 2% propylene glycol is isosmotic with serum causes 100% haemolysis of erythrocytes in 45 min. (Martindale, the Extra Pharmacopoeia 28th Edition). Also, high pH is required for solubilisation of Diclofenac Sodium and along with the hyper-osmolar nature of the formulation it contributes to the discomfort at the site of the injection when administered intramuscularly. Currently marketed formulations have osmolality more than 840 mOsm/kg which is mainly responsible for the discomfort at the site of the injection.
However, many attempts have been made to eliminate propylene glycol from the formulation to minimize pain at the site of the injection and improve the solubility of Diclofenac Sodium and then administer for treatment of various pathological conditions.
Due to low solubility, the commercial products are formulated as 75 mg/3mL of diclofenac sodium. The recommended dosage for Diclofenac sodium is 75mg and therefore the product is given as a 3 mL intramuscular injection. This is above the recommended volume of 2 mL for intramuscular injection accepted by the United States Food and Drug Administration.
US 4,711,906 disclose an aqueous concentrated solution of Diclofenac, which contain a mixture of propylene glycol and polyethylene glycol. The solutions also contain a local anaesthetic such as lidocaine and a reducing agent as stabilizer. Propylene glycol in composition makes the injection painful and lidocaine is added to reduce such painful administration.
US 2012/0142779 A1 disclose an injectable composition comprising Diclofenac or a pharmaceutically acceptable Diclofenac salt and a cyclodextrin suitable for intramuscular and intravenous administration. The solutions also contain an antioxidant as Monothioglycerol, or a combination of ethylene diamine tetra-acetic acid and N-acetyl-cysteine. However, it is observed that elimination of cyclodextrin is a problem in renal compromised patient.
US 5,389,681 disclose an invention relates to a composition in the form or a sterilizable parenteral solution containing a Diclofenac or a pharmaceutically acceptable Diclofenac salt and stabilizers, such as ethyl lactate combined with glutathione or N-acetylcysteine. Glutathione is amino acids derivative and being very costly thereby increases the basic cost of the injection.
US 2011/0275717 A1 disclose a formulation containing salt of Diclofenac, at least one polyoxyalkylene ester of a hydroxyl fatty acid, water, and a co-solvent. This composition contains fatty acid derivative and they require special carriers.
US 5,679,660 disclose veterinary composition contains either Diclofenac or a salt thereof and 2-hydroxypropyl beta-cyclodextrin, or an inclusion complex of Diclofenac or a salt thereof and 2-hydroxypropyl beta-cyclodextrin at concentration of Diclofenac of 25 mg/ml. Again, administration of 75 mg/3 ml Diclofenac which can be painful as IM dosage.
US 8,809,393 disclose an injectable formulation of water-soluble salts of diclofenac in Glycofurol and benzyl alcohol and claimed that intramuscular administration causes significantly less pain at the site of injection. However, Glycofurol is known as a tissue irritant while Benzyl alcohol causes thrombophlebitis.
US 2014/0187635 A1 disclose a composition comprising a combination of water-soluble salts of Diclofenac in Transcutol and Benzyl alcohol. However, Transcutol is known as a tissue irritant while Benzyl alcohol causes thrombophlebitis.
US 8,580,954 disclose a pharmaceutical composition containing a unit dose of a diclofenac compound and a beta-cyclodextrin compound; wherein the dose of the diclofenac compound is less than 10 mg. The use of beta cyclodextrin has also toxicity problem which is always questioned for IV administration.
WO 96/03121 A1 disclose a antiphlogistic, analgesic, antipyretic parenteral preparation comprising diclofenac, its salt, or both, a surfactant, co-surfactant, Benzyl alcohol, water, at pH of 3-10, that can exhibit sustained therapeutic levels of diclofenac in plasma and which does not cause pain at site of injection. Formulation uses Benzyl alcohol which causes thrombophlebitis
The present invention attempts to provide a stable aqueous preparation of water soluble salts of diclofenac and low content of co-solvents/solubilizers and other excipients with low osmolality as compare to commercial formulations resulting in the minimization of side effects and pain at site of injection. Also, this invention attempts to provide a parenteral dosage form of diclofenac which addresses the limitations associated with conventional formulation and which may be used for both intramuscular and intravenous administration.
OBJECTIVE OF INVENTION
The objective of the present invention is to provide a stable aqueous injectable composition comprising Diclofenac or salts thereof, which cause significantly less pain at the site of injection.
Another objective of the present invention is to provide a stable aqueous injectable composition comprising Diclofenac or salt thereof which is substantially free of oily components, cyclodextrins and benzoyl alcohol.
Another objective of the present invention is to provide a stable aqueous injectable composition Diclofenac or salt thereof, further comprising co-solvents/solubilizers, a polar aprotic solvent, alkalizer, water and optionally other excipients.
Another objective of the present invention is to provide a stable composition comprising Diclofenac or salts thereof, which is suitable to be given through multiple routes i.e. intramuscular, intravenous, subcutaneous, intra-articular delivery.
Yet another objective of the present invention is to provide a stable aqueous composition of Diclofenac or salts thereof which is not irritating or painful and does not cause haemolysis.
Yet another objective of the present invention is to provide a stable aqueous composition comprising Diclofenac or salts thereof with less toxicity and more bioavailability.
SUMMARY OF INVENTION
The present invention provides a stable aqueous injectable composition of a therapeutically effective amount of diclofenac and/or pharmaceutically acceptable salts thereof, which is substantially free of oily components, cyclodextrins and benzoyl alcohol.
Another embodiment of the present invention provides a stable aqueous injectable composition of a therapeutically effective amount of diclofenac, and/or pharmaceutically acceptable salt thereof, which is substantially free of oily components, cyclodextrins and benzoyl alcohol further comprises co-solvents/solubilizers, a polar aprotic solvent, alkalizer, water and optionally other excipients.
Another embodiment of the present invention provides a stable aqueous injectable composition comprising of Diclofenac or salt thereof, 4% to 12% % w/v of co-solvents/solubilizers, 0.5% to 30 % w/v of a polar aprotic solvents, 0.5% to 10 % w/v of alkalizers, water and optionally other excipients, wherein the composition having a pH of 8.1-9.
Another embodiment of the present invention provides a stable aqueous injectable composition comprising of Diclofenac or salt thereof, 4% to 12% % w/v of co-solvents, 0.1% to 0.6% w/v of solubilizers, 0.5% to 30 % w/v of a polar aprotic solvent, 0.5% to 10 % w/v of alkalizer, water and optionally other excipients, wherein the composition having a pH of 8.1-9.
Another embodiment of the present invention provides a stable aqueous injectable composition comprising Diclofenac or salt thereof, 4% to 12% % w/v of Polysorbate 80, 0.5% to 30 % w/v of Dimethyl acetamide, 0.5% to 10 % w/v of triethanolamine, water and optionally other excipients.
Another embodiment of the present invention provides a stable aqueous injectable composition comprising Diclofenac or salt thereof, 4% to 12% % w/v of Polysorbate 80, 0.1% to 0.6% w/v of Poloxamer 188, 0.5% to 30 % w/v of Dimethyl acetamide, 0.5% to 10 % w/v of triethanolamine, water and optionally other excipients.
Another embodiment of the present invention provides a method for preparing a composition of Diclofenac or a salt thereof which is substantially free of oily components, cyclodextrins and benzoyl alcohol.
Another embodiment of the present invention provides a method for preparing a composition comprising Diclofenac or a salt thereof, co-solvents/solubilizers, a polar aprotic solvent, alkalizer, water and optionally other excipients.
Another embodiment of the present invention provides a method for preparing a stable aqueous injectable composition comprising Diclofenac or salt thereof, wherein the composition is free of oily components, cyclodextrins and benzoyl alcohol, said method comprising;
a) preparing an aqueous solution by adding 4-12% w/v of co-solvent/solubilizer, 0.5-10 % w/v of alkalizer, 0.1-1 % w/v of antioxidant, and 0.01-0.05% w/v of Chelating agent to 50% w/v of water followed by addition of solution of 0.0005-0.002 % w/v of Butylhydroxytoluene and or 0.0005-0.0015% w/v ButylhydroxyAnisole added in 0.5-30 % w/v of a polar aprotic solvents,
b) adding Diclofenac or a salt thereof in said aqueous solution with constant stirring under a nitrogen atmosphere,
c) adjusting the pH of said solution in a range of 8.1-9.0,
d) optionally, Diluting said solution to achieve a desired concentration of Diclofenac in said solution, and
e) finally, sterilized either by sterile filtration or by autoclaving and filled in ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering.
Another embodiment of the present invention provides a method for preparing a stable aqueous injectable composition comprising Diclofenac or salt thereof, wherein the composition is free of oily components, cyclodextrins and benzoyl alcohol, said method comprising;
a) preparing an aqueous solution by adding 4-12% w/v of Polysorbate 80, 0.5-10 % w/v of Triethanolamine, 0.1-1 % w/v of monothioglycerol and 0.01-0.05% w/v of Disodium EDTA to 50% w/v of water followed by addition of solution of 0.0005-0.002 % w/v of Butylhydroxytoluene and or 0.0005-0.0015 % w/v of Butylhydroxyanisole in 0.5-30 % w/v of N, N-Dimethylacetamide,
b) adding Diclofenac or a salt thereof in said aqueous solution with constant stirring under a nitrogen atmosphere,
c) adjusting the pH of said solution in a range of 8.1-9.0,
d) optionally, Diluting said solution to achieve a desired concentration of Diclofenac in said solution,
e) finally sterilized either by sterile filtration or by autoclaving and filled in ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering, and
f) resulted formulation has osmolality below 470 mOsm/kg, more preferably between 270- 370 mOsm/kg.
Another embodiment of the present invention provides a method for preparing a stable aqueous injectable composition comprising Diclofenac or salt thereof, wherein the composition is free of oily components, cyclodextrins and benzoyl alcohol, said method comprising;
a) preparing an aqueous solution by adding 4-12% w/v of Polysorbate 80, 0.1- 0.6% w/v of Poloxamer 188, 0.5-10 % w/v of Triethanolamine, 0.1-1 % w/v of monothioglycerol and 0.01-0.05% w/v of Disodium EDTA to 50% w/v of water followed by addition of solution of 0.0005-0.002 % w/v of Butylhydroxytoluene and or 0.0005-0.0015 % w/v of Butylhydroxyanisole in 0.5-30 % w/v of N, N-Dimethylacetamide,
g) adding Diclofenac or a salt thereof in said aqueous solution with constant stirring under a nitrogen atmosphere,
h) adjusting the pH of said solution in a range of 8.1-9.0,
i) optionally, Diluting said solution to achieve a desired concentration of Diclofenac in said solution,
j) finally sterilized either by sterile filtration or by autoclaving and filled in ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering, and
k) resulted formulation has osmolality below 470 mOsm/kg, more preferably between 270- 370 mOsm/kg.

DETAILED DESCRIPTION OF THE INVENTION
The invention provides a stable aqueous composition comprising Diclofenac or salt thereof. Diclofenac salt includes Diclofenac sodium, Diclofenac potassium, Diclofenac diethanolamine, Diclofenac diethylamine, or Diclofenac beta-dimethyl aminoethanol.
Conventional formulations of Diclofenac Sodium injections are restricted to intramuscular use and causes pain at injection site due to the physico-chemical properties of the drug. Poor aqueous solubility of the Sodium salt of Diclofenac has a high tendency to crystallize from aqueous and organic solutions. This invention provides therapeutically effective amount of Diclofenac or salts thereof in an aqueous composition suitable to be administered by multiple routes such as i.e. intramuscular, intravenous, subcutaneous, intra-articular delivery.
The invention provides a composition comprising Diclofenac Sodium in a concentration of 18.75-75 mg for parenteral through intramuscular, intravenous, subcutaneous, intra-articular route. The composition comprises Diclofenac Sodium and non-ionic surfactants.
The amount of Diclofenac Sodium varies between 18.75-37.5 mg in 0.5 to 1 ml solutions, and more preferably 1 ml solutions.
The Polar aprotic solvents used in the present invention selected from the group consisting of 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate or combination thereof, particularly preferred polar aprotic solvent includes N, N-Dimethylacetamide.
Polar aprotic solvents such as N, N-dimethylacetamide, when used as sole solvent may be incorporated in the range of about 0.5 % to 30 % w/v. However, when used as solvent in combination with other co-solvent/solubilizer, the amount is up to about 0.5 % to 20 % w/v, preferably reduced to about 0.5 % to 10 %, most preferably 0.5% to 5 % w/v.
The most important component of the diluent is parenterally acceptable co-solvents/solubilizers. Co-solvents/solubilizers generally have chosen from nonionic hydrophilic compounds whose hydrophilic/lipophilic balance (HLB) value which reflects the proportion of hydrophilic groups and of lipophilic groups in the molecule is between 13 and 29; preferably between 13 and 17.
The co-solvent/solubilizer as used herein and not limited to the group consisting of an ethylene oxide/propylene oxide copolymer such as Pluronic® P 94 and Pluronic® F 68 (Poloxamer 188), a polyethoxylated castor oil such as Cremophor® EL, an ethoxylated polysorbate such as polysorbate 80 or alternatively a polyethylene hydroxystearate such as polyethylene hydroxystearate -660 or combination thereof. Particularly, desirable co-solvent/solubilizer is polysorbate 80, alternatively, suitable co-solvent/solubilizer selected from among salts of bile acids (taurocholate, glycocholate, cholate, deoxycholate, etc.) which are optionally combined with lecithin or vitamin E tocopherol propylene glycol succinate (Vitamin E TPGS).
The amount of an ethoxylated polysorbate such as polysorbate 80 when used as the sole co-solvent/solubilizer may be incorporated in the range of about 4% to 12% w/v.
However, when used as co-solvent/solubilizer in combination with other solubilizers like Pluronic® P 68 the amount of polysorbate 80 is up to about 10% w/v, preferably about 8% w/v.
The amount of an ethylene oxide/propylene oxide copolymer such as Pluronic® P 68 (Poloxamer 188) when used as the sole solubilizer may be incorporated in the range of about 0.1% to 0.6% w/v, preferably about 0.6% w/v.
It has also been discovered that stable formulations of Diclofenac or salts thereof can be obtained by mixing a polar aprotic solvent, or a mixture of polar aprotic solvents, with a pharmaceutically acceptable non-ionic surfactant such as polysorbates e.g. Polysorbate 80 and poloxamers e.g. Poloxamer 188.
The alkalizer as used herein and not limited to the group consisting of meglumine, sodium carbonate, potassium carbonate, calcium carbonate, magnesium oxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, diethanolamine, potassium bicarbonate, potassium citrate, sodium borate, sodium citrate and triethanolamine.
The amount of alkalizer such as Triethanolamine, when used as sole co-solvent/solubilizer is in the range of about 0.5 % to 10 % w/v. However, when used as co-solvent/solubilizer in combination with other co-solvent/solubilizer, the amount is up to around 0.5% to 5 % w/v, preferably 0.5 % to 2 % w/v.
The composition of the present invention may further comprising one or more additional excipients such as antioxidants and chelating agents.
The antioxidants used in the compositions of the present invention include, but are not limited to, butylated hydroxytoluene, butylated hydroxyanisole, tert-butyl-hydroquinone, 4-hydroxymethy1-2,6-di-tert-butylphenol, 2,4,5-trihydroxybutyrophenone, alkylgallates, propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gallic acid, nordihydroguaiaretic acid, glycine, ascorbic acid, fatty acid esters of ascorbic acid such as ascorbyl palmitate and ascorbyl stearate, and salts of ascorbic acid such as sodium, calcium, or potassium ascorbate; erythorbic acid, L-carnitine, monothioglycerol, acetyl L-carnitine, thioglycolic acid, N-acetyl cysteine, cysteine, glutathione, methionine, tartaric acid, citric acid, fumaric acid, glycolic acid, oxalic acid, succinic acid, ellagic acid, malic acid, maleic acid, tocopherols such as, but not limited to, delta tocopherol, alpha tocopherol; lipoic acid, thiolated polymers such as, but not limited to, polymethacrylic-SH, carboxy methylcellulose-cysteine, polycarbophil-cysteine, beta-carotene, carotenoids, flavonoids, flavones, isoflavones, flavanones, catechins, anthocyanidins, chalcones, sulfites, including but not limited to potassium sulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate and sodium bisulfite or a combination thereof may be employed.
Chelating agents used in the compositions of the present invention include, but are not limited to, ethylene diaminetetraacetic acid (EDTA), deferoxannine, desferrioxannine B, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), dihydroethylglycine, bis(anninoethyl)glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, poly(aspartic acid), citric acid, tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, oxalic acid, malic acid, lecithin or any salt thereof, and the like or a combination thereof may be employed. In addition, the compositions of the present invention may comprise one or more additional ingredients, particularly a stabilizers or protective agent such as an antioxidant. The use of an antioxidant in the form of monothioglycerol (0.1 % to 1.0% w/v) or in combinations with other antioxidants or a combination of ethylene diamine tetra-acetic acid (EDTA) has been found effectively stabilizes the solution preventing the formation of particulate matter at elevated temperature in pre-fillable syringes, ampoules and vials.
The composition of the present invention is prepared by process comprising, 50% of water is mixed with 5 to 12% of Polysorbate 80 most appropriately in 10% concentration and 0.1 to 0.6 % of Poloxamer 188 most appropriately in 0.6% concentration. 3.75% of Diclofenac Sodium is then added into this solution with proper stirring. After dissolving Diclofenac Sodium, this solution is admixture with variable concentration of monothioglycerol in 0.1 to 1% respectively. EDTA about 0.01% to 0.05% is added optionally as chelating agent to prevent metallic ion impurity into the solution and to make the solution stable for longer storage. 0.0005-0.002 % of Butylhydroxytoluene and or 0.0005-0.0015 % of Butylhydroxyanisole dissolved in 0.5 % to 30% of N, N-Dimethylacetamide and added to above solution, followed by addition of Triethanolamine in range of 0.5% to 10% as a alkalizer to adjust the pH of solution in the range of 8.1 to 9.0. Then solution is further diluted with remaining amount of water in sufficient amount to get a stable solution under inert environment. If required, 1M sodium hydroxide solution or acids such as Diluted Acetic acid or diluted hydrochloric acid also added to adjust the required pH ranging between 6.5 to 9.5, preferably range between 7.5 to 9.0 and more preferably 8.1 to 9.0. Resulted formulation has osmolality below 470 mOsm/kg, more preferably between 270- 370 mOsm/kg.
The process is carried under the constant nitrogen flushing to replace the level to minimum amount of the oxygen. The final composition is filtered aseptically using 0.22-micron filter and sterilized by autoclaving to prevent endotoxins growth and removing oxygen under the constant flush of nitrogen gas followed by filling into ampoules, vials, and Prefilled syringes flushed with inert gas prior to sealing or stoppering. Solution prepared is clear and stable. The resultant liquid solution consist 37.5 mg/ml of Diclofenac Sodium may and may be used as injection solution for administration through intramuscular, intravenous, subcutaneous, intra-articular route. The above batches were found to be stable when kept for stability study according ICH guidelines. Test for assay and relative impurity test were performed. The satisfactory results were obtained for the prepared batches and final composition is selected based on best result obtained from the prepared batches.
The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.
EXAMPLES:
Example 1:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.2% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, monothioglycerol, Disodium EDTA in water with constant stirring, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 2:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.8% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, monothioglycerol, Disodium EDTA in water with constant stirring. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 3:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.2% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, Disodium EDTA in water with constant stirring, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 400 mOsm/kg.
Example 4:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.8% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, Disodium EDTA in water with constant stirring. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 400 mOsm/kg.
Example 5:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 0.6 % w/v of Poloxamer 188, about 1.3% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Poloxamer 188, Dimethyl acetamide, Disodium EDTA in water with constant stirring. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 330 mOsm/kg.
Example 6:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 0.6 % w/v of Poloxamer 188, about 1% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Poloxamer 188, Dimethyl acetamide, Disodium EDTA in water with constant stirring. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 300 mOsm/kg.
Example 7:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 0.6 % w/v of Poloxamer 188, about 1.6 % w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Poloxamer 188, Dimethyl acetamide, Disodium EDTA in water with constant stirring. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 400 mOsm/kg.
Example 8:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.2% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, monothioglycerol, Disodium EDTA in water with constant stirring. Butylhydroxytoluene dissolved in Dimethyl acetamide and added to above solution, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 9:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.2% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, monothioglycerol, Disodium EDTA in water with constant stirring. Butylhydroxyanisole dissolved in Dimethyl acetamide and added to above solution, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg
Example 10:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.8% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, monothioglycerol, Disodium EDTA in water with constant stirring. Butylhydroxytoluene dissolved in Dimethyl acetamide and added to above solution. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 11:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.8% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, monothioglycerol, Disodium EDTA in water with constant stirring. Butylhydroxyanisole dissolved in Dimethyl acetamide and added to above solution. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 12:
A parenteral preparation containing diclofenac sodium 3.75%, about 12% w/v of Polysorbate 80, about 1.17% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, Disodium EDTA in water with constant stirring, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 13:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.17% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, Disodium EDTA in water with constant stirring, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 14:
A parenteral preparation containing diclofenac sodium 3.75%, about 8% w/v of Polysorbate 80, about 1.17% w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, Disodium EDTA in water with constant stirring, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 15:
A parenteral preparation containing diclofenac sodium 3.75%, about 12% w/v of Polysorbate 80 is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Disodium EDTA in water with constant stirring, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 16:
A parenteral preparation containing diclofenac sodium 3.75%, about 10% w/v of Polysorbate 80, about 1.8 % w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, monothioglycerol, Disodium EDTA in water with constant stirring, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 17:
A parenteral preparation containing diclofenac sodium 3.75%, about 10 % w/v of Polysorbate 80, about 2 % w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, monothioglycerol, Disodium EDTA in water with constant stirring. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/L. Resulted formulation has osmolality below 470 mOsm/kg.
Example 18:
A parenteral preparation containing diclofenac sodium 3.75%, about 8 % w/v of Polysorbate 80, about 2.2 % w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, monothioglycerol, Disodium EDTA in water with constant stirring, followed by addition of triethanolamine and pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Example 19:
A parenteral preparation containing diclofenac sodium 3.75%, about 8 % w/v of Polysorbate 80, about 2.4 % w/v of Dimethyl acetamide is prepared in an inert gas environment by suspending the diclofenac sodium in a mixture of requisite quantities of Polysorbate 80, Dimethyl acetamide, monothioglycerol, Disodium EDTA in water with constant stirring. pH adjusted to 8.1-9 using sodium hydroxide or hydrochloric acid or acetic acid. The solution is diluted with sterile water to achieve the required concentration of 37.5 mg in 1 ml. The entire process is carried out under inert gas environment. The ingredients may be mixed in any order. The resultant solution is sterilized either by sterile filtration or by autoclaving and filled in 2 ml ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering. Resulted formulation has osmolality below 470 mOsm/kg.
Finished product was stored at different stability conditions as per ICH guideline. The initial sample of ready to use solution and samples stored at stored at different stability conditions were analyzed for assay, related substance (%), pH, and osmolality. Results are given below tables.
The Diclofenac Sodium formulation of the present invention has less than or no more than 0.5 % total impurities, more preferably no more than about 0.4%, more preferably no more than about 0.3%, and most preferably no more than about 0.2 % at the time of release.
The Diclofenac Sodium formulation of the present invention after a certain period of shelf life have less than or no more than 2.0 % total impurities, more preferably no more than about 1.75%, more preferably no more than about 1.5%, more preferably no more than about 1.25%, more preferably no more than about 1.0%, more preferably no more than about 0.75%, and most preferably no more than about 0.5 %.
The present invention provides a composition that may have a low level of 1-(2,6 – dicholorophenyl) -1,3-dihydro-2 H – indol-2-one (Impurity A), 2-[(2,6- dicholorophenyl)amino]benzaldehyde (Impurity B), 2-[(2,6-dicholorophenyl)amino]phenyl] methanol (Impurity C), 2-[2-[(2-bromo-6-chlorophenyl)amino]phenyl] acetic acid (Impurity D), 1,3-dihydro-2H-indol-2- one (Impurity E) and N-(4-chlorophenyl)-2-(2,6-dicholorophenyl) acetamide (Impurity F). In some embodiments, the concentration of Impurity A/ Impurity B/ Impurity C, Impurity D/ Impurity E/ Impurity F in the composition after a certain period of shelf life may be no more than about 0.2%, preferably no more than about 0.18%, more preferably no more than about 0.15%, more preferably no more than about 0.13%, more preferably no more than about 0.10%, more preferably no more than about 0.09%, more preferably no more than about 0.08%, more preferably no more than about 0.07%, and most preferably no more than about 0.06%.
The Diclofenac Sodium formulation of the present invention has less than or no more than 0.5 % total impurities over a shelf-life of at least 12 months, including no more than 0.06 % of known impurities i.e. Impurity A, Impurity B, Impurity C, Impurity D, Impurity E and Impurity F.
Table 1: Stability results of Diclofenac Sodium Injection (Example 1)

Conations/Tests Description Assay of Diclofenac Sodium Related substances pH
Osmolality
Individual impurity level Highest unknown Imp Total Imp
Initial Limits A Clear colourless to yellowish solution NLT 95.0 % and NMT 105.0 % NMT 0.2 %
NMT 0.5 % NMT 2.0 % Between 8.1 to 9.0 270- 470 mOsm/kg
Initial A Clear colourless solution 103.5 Complies 0.02 0.08 8.56 441
40°C± 2°C /75% ±5% RH
1M A Clear colourless solution 102.4 Complies 0.02 0.17 8.50 424
2M A Clear colourless solution 103.3 Complies 0.08 0.29 8.50 410
3M A Clear colourless solution 102.6 Complies 0.16 0.51 8.46 426
6M A pale yellow colour solution 101.5 Complies 0.24 0.83 8.48 430
25°C± 2°C /60% ±5% RH
3M A Clear colourless solution 104.2 Complies 0.01 0.11 8.52 429
6M A Clear colourless solution 102.6 Complies 0.01 0.14 8.30 439
NLT: Not Less Than, NMT: Not More Than.

Table 2: Stability results of Diclofenac Sodium Injection (Example 2)

Conations/Tests Description Assay of Diclofenac Sodium Related substances pH
Osmolality
Individual impurity level Highest unknown Imp Total Imp
Initial Limits A Clear colourless to yellowish solution NLT 95.0 % and NMT 105.0 % NMT 0.2 % NMT 0.5 % NMT 2.0 % Between 8.1 to 9.0 270- 470 mOsm/kg
Initial A Clear colourless solution 104.3 Complies 0.01 0.09 8.67 462
40°C± 2°C /75% ±5% RH
1M A Clear colourless solution 104.2 Complies 0.02 0.17 8.46 452
2M A Clear colourless solution 103.1 Complies 0.04 0.22 8.37 440
3M A Clear colourless solution 104.8 Complies 0.07 0.41 8.34 448
6M A pale yellow colour solution 104.1 Complies 0.11 0.64 8.19 393
25°C± 2°C /60% ±5% RH
3M A Clear colourless solution 103.7 Complies 0.02 0.13 8.60 446
6M A Clear colourless solution 103.5 Complies 0.01 0.14 8.42 449
NLT: Not Less Than, NMT: Not More Than.

Table 3: Stability results of Diclofenac Sodium Injection (Example 3)

Conations/Tests Description Assay of Diclofenac Sodium Related substances pH
Osmolality
Individual impurity level Highest unknown Imp Total Imp
Initial Limits A Clear colourless to yellowish solution NLT 95.0 % and NMT 105.0 % NMT 0.2 % NMT 0.5 % NMT 2.0 % Between 8.1 to 9.0 270- 470 mOsm/kg
Initial A Clear colourless solution 99.4 Complies 0.01 0.09 8.66 379
40°C± 2°C /75% ±5% RH
1M A pale yellow colour solution 100.4 Complies 0.05 0.2 8.53 395
2M A yellow colour solution 103.4 Complies 0.09 0.26 8.58 384
3M A pale yellow colour solution 103.4 Complies 0.19 0.45 8.32 393
6M A yellowish colour solution 102.1 Complies 0.63 1.17 8.23 402
25°C± 2°C /60% ±5% RH
3M A pale yellow colour solution 104.2 Complies 0.02 0.14 8.62 392
6M A pale yellow colour solution 101.4 Complies 0.02 0.13 8.52 396
NLT: Not Less Than, NMT: Not More Than. ,CLAIMS:We Claim:
1. A stable aqueous injectable composition of a therapeutically effective amount of diclofenac and/or pharmaceutically acceptable salts thereof, which is substantially free of oily components, cyclodextrins and benzoyl alcohol.
2. The composition as claimed in claim 1, which further comprising co-solvents/solubilizers, a polar aprotic solvent, alkalizer, water and optionally other excipients.
3. The composition as claimed in claim 1, which comprises 4% to 12% % w/v of co-solvents/solubilizers, 0.5% to 30 % w/v of a polar aprotic solvents, 0.5% to 10 % w/v of alkalizers, water and optionally other excipients, wherein the composition having a pH of 8.1-9.
4. The composition as claimed in claim 1, wherein said Diclofenac salt is selected from the group consisiting of Diclofenac sodium, Diclofenac potassium, Diclofenac diethylamine, Diclofenac diethanolamine and Diclofenac beta-dimethyl aminoethanol.
5. The composition as claimed in claim 1, wherein the composition comprises 37.5 mg of Diclofenac or a salt thereof.
6. The composition as claimed in claim 2, wherein the co-solvent/solubilizer as used herein and not limited to the group consisting of an ethylene oxide/propylene oxide copolymer such as Pluronic® P 94 and Pluronic® F 68 (Poloxamer 188), a polyethoxylated castor oil such as Cremophor® EL, an ethoxylated polysorbate such as polysorbate 80 or alternatively a polyethylene hydroxystearate such as polyethylene hydroxystearate -660 or combination thereof.
7. The composition as claimed in claim 2, wherein the Polar aprotic solvents used in the present invention selected from the group consisting of 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate or combination thereof, particularly preferred polar aprotic solvent includes N, N-Dimethylacetamide.
8. The composition as claimed in claim 2, wherein the alkalizer is selected from meglumine, sodium carbonate, potassium carbonate, calcium carbonate, magnesium oxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, diethanolamine, potassium bicarbonate, potassium citrate, sodium borate, sodium citrate and triethanolamine.
9. The composition as claimed in claim 6, wherein said ethoxylated polysorbate is Polysorbate 80 when used as sole co-solvent/solubilizer for diclofenac sodium or its therapeutically equivalent salts is incorporated at 4% to 12% % w/v.
10. The composition as claimed in claim 6, wherein said ethylene oxide/propylene oxide copolymer is Poloxamer 188 when used as the sole solubilizer may be incorporated in the range of about 0.1% to 0.6% w/v, preferably about 0.6% w/v.
11. The composition as claimed in claim 1, wherein the composition further comprises an antioxidant and chelating agent.
12. The composition as claimed in claim 11, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole, tert-butyl-hydroquinone, 4-hydroxymethy1-2,6-di-tert-butylphenol, 2,4,5-trihydroxybutyrophenone, alkylgallates, propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gallic acid, nordihydroguaiaretic acid, glycine, ascorbic acid, fatty acid esters of ascorbic acid such as ascorbyl palmitate and ascorbyl stearate, and salts of ascorbic acid such as sodium, calcium, or potassium ascorbate; erythorbic acid, L-carnitine, thioglycerol, monothioglycerol, acetyl L-carnitine, thioglycolic acid, N-acetyl cysteine, cysteine, glutathione, methionine, tartaric acid, citric acid, fumaric acid, glycolic acid, oxalic acid, succinic acid, ellagic acid, malic acid, maleic acid, tocopherols such as, but not limited to, delta tocopherol, alpha tocopherol; lipoic acid, thiolated polymers such as, but not limited to, polymethacrylic-SH, carboxy methylcellulose-cysteine, polycarbophil-cysteine, beta-carotene, carotenoids, flavonoids, flavones, isoflavones, flavanones, catechins, anthocyanidins, chalcones, sulfites, including but not limited to potassium sulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate and sodium bisulfite or a combination thereof.
13. The composition as claimed in claim 11, wherein said chelating agent is selected from the group consisting of ethylene diaminetetraacetic acid (EDTA), deferoxannine, desferrioxannine B, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), dihydroethylglycine, bis(anninoethyl)glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, poly(aspartic acid), citric acid, tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, oxalic acid, malic acid, lecithin or any salt thereof, and the like or a combination thereof.
13. The composition as claimed in claim 1, wherein the pH of said composition is between 8.1-9.0.
14. The composition as claimed in claim 1, wherein the composition is free of oily components, cyclodextrins and Benzoyl alcohol.
15. A method for preparing a stable aqueous injectable composition comprising Diclofenac or salt thereof, said method comprising;
a) preparing an aqueous solution by adding 4-12% w/v of co-solvent/solubilizer, 0.5-10 % w/v of alkalizer, 0.1-1 % w/v of antioxidant, and 0.01-0.05% w/v of Chelating agent to 50% w/v of water followed by addition of solution of 0.0005-0.002 % w/v of Butylhydroxytoluene and or 0.0005-0.0015% w/v ButylhydroxyAnisole added in 0.5-30 % w/v of a polar aprotic solvents,
b) adding Diclofenac or a salt thereof in said aqueous solution with constant stirring under a nitrogen atmosphere,
c) adjusting the pH of said solution in a range of 8.1-9.0,
d) optionally, Diluting said solution to achieve a desired concentration of Diclofenac in said solution, and
e) finally, sterilized either by sterile filtration or by autoclaving and filled in ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering.
16. A method for preparing a stable aqueous injectable composition comprising Diclofenac or salt thereof, said method comprising;
a) preparing an aqueous solution by adding 4-12% w/v of Polysorbate 80, 0.5-10 % w/v of Triethanolamine, 0.1-1 % w/v of monothioglycerol and 0.01-0.05% w/v of Disodium EDTA to 50% w/v of water followed by addition of solution of 0.0005-0.002 % w/v of Butylhydroxytoluene and or 0.0005-0.0015 % w/v of Butylhydroxyanisole in 0.5-30 % w/v of N, N-Dimethylacetamide,
b) adding Diclofenac or a salt thereof in said aqueous solution with constant stirring under a nitrogen atmosphere,
c) adjusting the pH of said solution in a range of 8.1-9.0,
d) optionally, Diluting said solution to achieve a desired concentration of Diclofenac in said solution,
e) finally sterilized either by sterile filtration or by autoclaving and filled in ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering, and
f) resulted formulation has osmolality below 470 mOsm/kg, more preferably between 270- 370 mOsm/kg.
17. A method for preparing a stable aqueous injectable composition comprising Diclofenac or salt thereof, said method comprising;
a) preparing an aqueous solution by adding 4-12% w/v of Polysorbate 80, 0.1- 0.6% w/v of Poloxamer 188, 0.5-10 % w/v of Triethanolamine, 0.1-1 % w/v of monothioglycerol and 0.01-0.05% w/v of Disodium EDTA to 50% w/v of water followed by addition of solution of 0.0005-0.002 % w/v of Butylhydroxytoluene and or 0.0005-0.0015 % w/v of Butylhydroxyanisole in 0.5-30 % w/v of N, N-Dimethylacetamide,
b) adding Diclofenac or a salt thereof in said aqueous solution with constant stirring under a nitrogen atmosphere,
c) adjusting the pH of said solution in a range of 8.1-9.0,
d) optionally, Diluting said solution to achieve a desired concentration of Diclofenac in said solution,
e) finally sterilized either by sterile filtration or by autoclaving and filled in ampoules, vials or prefilled syringes flushed with inert gas prior to sealing or stoppering, and
f) resulted formulation has osmolality below 470 mOsm/kg, more preferably between 270- 370 mOsm/kg.
18. The composition as claimed in claim 1, wherein the formulation having no more than 0.2 % total impurities at release, including no more than 0.1 % of known impurities i.e. Impurity A, Impurity B, Impurity C, Impurity D, Impurity F. The composition as claimed in claim 1, wherein the formulation having no more than 0.5 % total impurities over a shelf-life of at least 12 months, including no more than 0.06 % of known impurities i.e. Impurity A, Impurity B, Impurity C, Impurity D, Impurity F; said liquid pharmaceutical formulation stored in a container with an inert gas prior to use.
Dated this First (01st) day of February, 2018.

__________________________________

Dr. S. Padmaja
Agent for the Applicant
IN/PA/883