DESC:Field of Invention
The present invention relates to an aqueous injectable composition comprising about 75 mg/ml of Diclofenac or its pharmaceutically acceptable salt. In particular, the present invention provides an aqueous injectable composition comprising about 75 mg/ml of Diclofenac or its pharmaceutically acceptable salt along with glycine. The composition is a stable composition and is safer for parenteral administration.
Background of Invention
Diclofenac Sodium (2-[(2,6 - Dichlorophenyl) amino] benzene acetic acid sodium salt) is a phenyl acetic acid derivative. Both salts of Diclofenac i.e., Diclofenac Sodium and Diclofenac Potassium and alike salts share almost the same physicochemical properties except their molecular weights. It can be also employed and used as diethylamine salt or diethanolamine or beta-dimethyl aminoethanol salt.

Fig. 1 Diclofenac Sodium
Diclofenac Sodium, a non-selective reversible and competitive inhibitor of cyclooxygenase (COX), is the most widely used Nonsteroidal Anti-inflammatory Drug (NSAIDs). It possesses analgesic, antipyretic and anti-inflammatory activity. It prevents the conversion of arachidonic acid into prostaglandin precursors, inhibits formation of prostaglandins that are involved in pain, inflammation and fever (PubChem). As prostaglandins sensitize pain receptors, inhibition of their synthesis is responsible for the analgesic effects of Diclofenac.
Diclofenac is useful in management of mild to moderate pain, acute and chronic symptomatic treatment of arthritic (rheumatic) diseases viz. rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis Reiter's syndrome, osteoarthritis, dysmenorrhea. Diclofenac is used mainly as the sodium salt for the relief of pain and inflammation in various conditions: musculoskeletal and joint disorders such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis; peri-articular disorders such as bursitis and tendinitis; soft-tissue disorders such as sprains and strains; and other painful conditions such as renal colic, acute gout, dysmenorrhoea, migraine and after some surgical procedures and in actinic keratoses and fever.
Diclofenac is a faintly yellow-white to light-beige, slightly hygroscopic crystalline powder. It is a weak acid, freely soluble in Methanol and poorly soluble in water. Its sodium salt is BCS II drug which belongs to low soluble and high permeable drug. The drug is highly protein bound.
Although Diclofenac given orally is almost completely absorbed, it is subject to first-pass metabolism so that about 50% of the drug reaches the systemic circulation in the unchanged form. The terminal plasma half-life is about 1 to 2 hours. Diclofenac is metabolized to 4'-hydroxy Diclofenac, 5-hydroxy Diclofenac, 3'-hydroxy Diclofenac and 4',5-dihydroxy Diclofenac. It is then excreted in the form of glucuronide and sulfate conjugates, mainly in the urine (about 60%) but also in the bile (about 35%); less than 1% is excreted as unchanged Diclofenac (Martindale, 36th edition, 2009).Therefore Diclofenac needs to be administered orally in multiple doses in order to maintain the desired drug plasma level.
Generally Diclofenac is required to be administered in higher dosages due to immediate release and less absorption. In the United States of America, for the relief of osteoarthritis the recommended dosage is 100-150 mg/day as two (75 mg) or three (50 mg) divided doses. For the relief of rheumatoid arthritis the recommended dosage is 150-200 mg/day as three or four divided dose of 50 mg or two divided dose of 75 mg. For the relief of ankylosing spondylitis the recommended dosage is 100-125 mg/day as four divided dose of 25 mg and if required extra dose of 25 mg at bedtime. In U.K, The recommended maximum daily dose of Diclofenac Sodium is 150 mg/day. In Japan by PMDA, the daily adult dose is recommended as 37.5 mg/dose of Diclofenac Sodium twice a day after meal. This is a known fact that a drug requiring repeated administration has an additional limitation of reduced patient compliance.
Although injectable compositions of Diclofenac Sodium are available in the market, there are several drawbacks associated with these injectable compositions. Low solubility of Diclofenac Sodium poses the main problem and hence its volume is always more. Having more volume for injection composition is an undesirable feature.
While solubilizing Diclofenac sodium in lesser volumes, viscosity is often compromised. Viscous injectable compositions cause lot of pain. Although, prior art describes various Diclofenac compositions most of them have one or more drawbacks.
Indian patent application no. 1382/MUM/2008 discloses injectable formulation of high concentration Diclofenac comprising Polyoxyl 35 Castor Oil, synonymously called as Cremophor EL®. Its’ use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy (Gelderblom H. et al, European Journal of Cancer, 37; 2001; 1590–1598). Even High viscosity of Cremophor EL® (almost more than 600 cps) results into viscous formulations painful to the patients at the site of administration.
Indian patent application no. 3449/DEL/2011 discloses pharmaceutical composition comprising one or more of ethyl acetate; triacetin; Dimethyl isosorbide; N;N Dimethyl acetamide; Dimethyl sulphoxide; Polyethylene glycol; Polyvinyl pyrrolidone; Polyvinyl alcohol; Polysorbate 80; Dichloromethane; Benzyl alcohol; acetone or a combination thereof and it is manufactured by process of obtaining microspheres and lyophilization which gives controlled release pharmaceutical composition. The composition upon administration has immediate burst release followed by sustained release of at least 18 to 24 hrs.
Indian patent application no. 201721010402 discloses an aqueous injectable solution comprising Diclofenac about 10 mg/ml to 100mg/ml and Polyvinylpyrrolidone about 160 mg/ml.
US patent 8679544B2 provides disclosure to a unit dose of a pharmaceutical composition containing 35 mg of Diclofenac acid and comprising lactose monohydrate and sodium lauryl sulfate wherein the particles of Diclofenac acid have a median particle size on a volume average basis of less than 500 nm and greater than 25 nm. The process to produce the composition and the composition is very tedious, time consuming and cost intensive. Particle size of Diclofenac, lactose and SLS are essential elements of the costly process and the composition taught by the patent.
US patent 8735450 teaches a method for producing a composition comprising nanoparticles of Diclofenac acid, comprising: dry milling a composition comprising Diclofenac acid, lactose and sodium lauryl sulfate in a mill containing a plurality of milling bodies for a time period sufficient to produce a composition comprising nanoparticles of Diclofenac acid having a median particle size on a particle volume basis between 1,000 nm and 25 nm. The said form is tested in USP apparatus I (Basket) method. This process has inherent drawbacks as listed in the preceding paragraph. The composition is in solid dosage form. In the description there is reference of use of 0.3% Glycine to produce these solid dosage forms. One of the limitations of the invention is it does not dissolve more than 35 mg of Diclofenac. It is also silent on volume of solvent and the final volume of composition in which 35mg of Diclofenac is dissolved.
Indian patent application no. 201728018691 describes a unit dosage form of a pharmaceutical composition containing 18mg or 35mg of Diclofenac, wherein the median particle size of the Diclofenac determined on a particle volume basis, or the average particle size determined on a particle number basis, is less than or equal to 5000nm. It has the same drawbacks as described in the paragraph herein before.
CN107126418 discloses Diclofenac sodium drug composition for injection and preparation method of Diclofenac sodium drug composition. The document discloses the pharmaceutical composition which is reconstituted with water to a concentration of Diclofenac sodium reconstitution solution 37.5mg/mL of the stabilizer the pH range of the reconstituted solution is controlled to 7-10, preferably 8.0-9.0.
WO1993000873 discloses composition and method for transdermal delivery of Diclofenac. The document discloses a topical anti-inflammatory composition comprising a therapeutically effective amount of Diclofenac sodium, thickening agents, a medium containing a lower molecular weight alcohol, a glycol, an ether alcohol, a fatty alcohol ester and water; and an agent capable of neutralizing the composition. The document discloses concentration range of Diclofenac between approximately 0.1% to 2.5% with a preferred concentration of approximately 1%.
US patent 4711906 discloses an aqueous, stable, relatively concentrated solution of Diclofenac, which contain a mixture of propylene glycol and polyethylene glycol in defined quantitative proportions. The solutions preferably contain a local anesthetic such as lidocaine and a reducing agent as stabilizer. However, use of propylene glycol makes the injection painful and lignocaine is added to alleviate such painful administration. There is a need to provide a formulation which is free from local anesthetic.
US patent 5283067 relates to a dry formulation, in particular a dry formulation of 25-150 mg of a sterile, lyophilized formulation of micronized Diclofenac sodium obtainable by lyophilisation, which is suitable for the preparation of a stable, aqueous suspension for the parenteral administration of a Diclofenac salt. The dry formulation contains a pharmaceutically acceptable and micronized salt of Diclofenac and optional pharmaceutically acceptable adjuvants. Additional step of lyophilisation is time consuming and raises the cost.
US patent 5554650 discloses an antiphlogistic, analgesic, antipyretic parenteral preparation comprising Diclofenac, its salt or both, a surfactant, co-surfactant, water, having a pH of 3-10 and optionally it comprises an oily component that can exhibit sustained therapeutic levels of Diclofenac in plasma. In the parenteral preparation surfactant is one or more compounds of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylene alkyl esters and polyoxyethylene alkyl ethers. Use of castor oil has unfavorable safety profile. Also some other excipients like fatty acid esters may have safety concern. Therefore there is a need to develop safe stable aqueous composition. US patent 7648711 B2 discloses a sustained release formulation by using Dimethicone as the dispersion medium, which includes active ingredient (e.g., drugs against parasites, insecticides, NSAIDs, antibiotics, sex hormone like agents or oily soluble Vitamins) and Dimethicone as the medium. Suitable solubilizer, antioxidant, local analgesics and material for sustained release may be added. The formulation is bio-compatible, stable and injectable. It comprises 10% of micronized powder form of Diclofenac. Use of micronized powder form of Diclofenac requires the micronization procedure which consumes more time and increases the cost. As discussed above, this document provides that the use of processed active drug Dimethicone is viscous. The present invention does not employ Dimethicone or complexes Diclofenac with PVP to provide aqueous composition.
WO2013/005226A1 is related to a synergistic pharmaceutical composition which contains more than one active ingredient which are Diclofenac, Glycofurol and Drotaverine with pharmaceutically accepted excipients. The combined composition shows enhanced efficacy and synergistic effect to provide protection from Dysmenorrhea, Gastrointestinal colic, Biliary colic, Renal colic, Dysmenorrheal and Abdominal pain associated with irritable bowel syndrome, pre and post lithotripsy, post-surgical smooth muscle spasm, post-MTP (Medical Termination of Pregnancy) and D&C (dilatation and curettage) thereof. Excipient Glycofurol is not recommended as safe to use. It is highly viscous and hence it may act as irritant upon parenteral administration.
Dynapar AQ, Diclofenac Sodium injection product of Troikaa also contains possibly toxic solvent Glycofurol. Glycofurol is not included in inactive ingredient database of USFDA. Secondly there is no DMF filed. It raises question to its safety. Glycofurol is not a pharmaceutically acceptableexcipient. It is also known in the field of art that there are 2 homologues N1 and N2 used in injections but question of presence of homologue more than 2 are not acceptable features of pharmaceutically acceptable excipients (Rowe RC et al, Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press, 2009). Therefore it is reiterated that Glycofurol is not advisable for use in an intravenous administration.
US patent application 20050238674A1 discloses the Diclofenac formulation with cyclodextrin. Currently marketed products of Diclofenac Sodium have limitations or demerits. Dyloject injection (by Hospira/Shimoda Biotech/Javelin Pharmaceuticals) is available as single use vial containing 37.5 mg/mL Dyloject. As low dose injection it is needed to be administered in multiple doses for 4 times a day. In the past there were complaints for development of particulate matter during the storage when marketed in Europe and which was withdrawn from market.
US patent application 20050282776A1 discloses composition of Diclofenac along with hydroxypropyl beta cyclodextrin which is currently available in market by brand name Akis®. More dosage can lead to accumulation of BCDs which is excreted very slowly, it is excreted through kidney and because of its high molecular weight may be toxic (PubChem).
US patent application 20140187635A1 discloses stable injectable formulation of Diclofenac Sodium with Transcutol as solvent. However, there is still a need of development of aqueous formulation.
WO2014060857 discloses pharmaceutical compositions of Diclofenac or salts thereof. The document provides an improved pharmaceutical composition of Diclofenac or pharmaceutically acceptable salt and pharmaceutically acceptable excipients, wherein the composition is substantially free of solubilizing agents. The salt of Diclofenac is disclosed to be Diclofenac potassium in 25mg/ml concentration.
WO2016170401 A1 disclosed injectable preparations containing 75 mg to 100 mg of water soluble salts of Diclofenac and use of hydroxypropyl beta cyclodextrin.
US patent 20180228903 discloses compositions with permeation enhancers for drug delivery which makes the use of polysaccharides. This document discloses use of at least two polymers. Polysaccharides as high molecular weight may affect the viscosity of the formulation and hence it may be painful at the site of administration.
US patent 20170119660 discloses pharmaceutical compositions for transmucosal delivery. The invention makes use of polymers viz. vinyl acetate-vinyl pyrrolidone copolymers, polymethacrylic acid copolymers etc. which are not approved by IID FDA. Vinyl acetate is reported as carcinogenic to humans since it is rapidly transformed into Acetaldehyde in human blood and animal tissues. Vinyl acetate and Acetaldehyde both are reported as genotoxic in human cells in-vitro.
US patent application 20150080353A1 discloses pharmaceutical compositions for the delivery of substantially water-insoluble drugs. The document has cited use of multiple organic solvents includes alcohols, such as, Methanol, Ethanol, n-Propanol, 2-Propanol, n-Butanol, 2-Butanol, C1-C4 linear or branched alcohol; aromatic hydrocarbon, such as, benzene, toluene and xylene, substituted toluenes, substituted xylenes; halogenated hydrocarbons, such as, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, dichloropropane, chloroform, carbon tetrachloride; ethers, such as, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran; ketones, such as, acetone, methyl ethyl ketone, methyl isobutyl ketone; alkyl acetate, such as, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate; alkyl nitriles, such as, acetonitrile, propionitrile; amides, such as, N,N-dimethyl formamide; dimethyl sulfoxide. Many of solvents used in the invention are not included in IID FDA and hence are unsafe. Use of multiple organic solvents may cause tissue irritation while injecting the formulation.
US patent 20130274297 discloses pharmaceutical composites of poorly water soluble drugs and polymers. The patent document provides use of polymeric carrier and not chemically cross linked polymer. The invention has cited the use of vinyl acetate-vinyl pyrrolidone copolymers which is not included in IID FDA. Vinyl acetate is carcinogenic substance. US patent application 20090238763A1 discloses high penetration compositions and uses thereof. The document has cited examples of aqueous and non-aqueous carriers for parenteral administration include water, Ethanol, polyols (e.g., such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils, such as olive oil and injectable organic esters, such as ethyl oleate. The patent document further provides that proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The formulation disclosed by the document involves additional steps to maintain the fluidity which is time consuming and costly. Additionally it makes the use of multiple ingredients and hence parenteral administration is painful. As discussed above the currently marketed products of Diclofenac injection are associated with several drawbacks. Most of the Diclofenac injection compositions where more than 25 mg is dissolved, the volume is more than 1 ml. Poor solubility of Diclofenac Sodium in water by conventional pharmaceutically acceptable ingredients forced researchers to resort to excipients or specialty chemicals which are generally not acceptable for formulation of pharmaceutical composition. These ingredients are often associated with variety of risks and do not possess established safety profile.
In view of above drawbacks of available and known injectable compositions of Diclofenac or its pharmaceutically acceptable salt thereof, there still exists a strong need to provide an alternate stable, safe and effective aqueous injectable Diclofenac Sodium composition. There is a need to provide a Diclofenac composition which has relatively higher concentration of Diclofenac per ml of the composition yet has less viscosity and is easy to syringe, aspire and inject in tissues without much efforts to health workers.
Objects of the Invention
It is an object of the invention to provide a stable aqueous injectable composition comprising about 75mg Diclofenac or its pharmaceutically acceptable salt thereof per ml of the composition.
It is another object of the invention to provide a less viscous, easily syringeable and easily aspiratable composition of Diclofenac.
It is yet another object of the invention to provide aqueous injectable composition of Diclofenac which are patient compliant and non-irritating.
A still another object of the invention is to provide an aqueous injectable stable composition comprising higher concentrations of Diclofenac for treatment and/or relief of mild to moderate pain.
Summary of the Invention
The present invention provides aqueous injectable composition comprising about 75 mg/ml of Diclofenac or its pharmaceutically acceptable salt thereof. The aqueous injectable composition is safe and stable. The composition is easily syringeable and easily aspiratable.
In one embodiment of the invention, a stable aqueous injectable composition comprising about 75 mg/ml of Diclofenac or pharmaceutically acceptable salts thereof and Glycine along with pharmaceutically acceptable excipients, is provided. In a particular embodiment, the Glycine is present in an amount from 0.1%w/v to 2%w/v.
In another embodiment of the invention, the composition comprises the pharmaceutically acceptable excipients are selected from solvents or co-solvents, complexing agents, antimicrobial preservatives, chelating agents, antioxidants, buffering agents, pH adjusting agents and combination thereof, is provided.
In one embodiment of the invention, the composition comprises solvents or co-solvents in an amount of from 0.1% to 50%. In one particular embodiment, the solvents or co-solvents are selected from Polyethylene Glycol 300, Polyethylene Glycol 400, PVP K-12, Benzyl Benzoate, Benzyl Alcohol, Ethanol, Castor oil, Dimethylacetamide, Glycerin, Sesame oil, Soybean oil and derivatives thereof, is provided.
In another embodiment of the invention, the composition comprises complexing agents in an amount up to 33.33% w/v, and more preferably up to 20% w/v. In one particular embodiment, the complexing agents are selected from Hydroxypropyl Beta-Cyclodextrin and Sulfobutyl Ether ?-Cyclodextrin is provided.
In yet another embodiment of the invention, the composition comprises the antimicrobial preservatives in an amount from 0.01% to 7%. The antimicrobial preservatives are selected from Benzethonium Chloride, Benzyl Alcohol, Benzalkonium Chloride, Chlorobutanol, m-Cresol, methyl paraben, propyl paraben, phenol, 2-PhenoxyEthanol, Phenyl Mercuric Nitrate, Thimerosal and derivatives thereof, is provided.
In even another embodiment of the invention, the composition comprises chelating agents in an amount from 0.1% to 4%. The chelating agents are selected from disodium EDTA, sodium EDTA, Calcium disodium EDTA, Versetamide, Calteridol Calcium, Diethylenetriaminepenta Acetic Acid and derivatives thereof, is provided.
In still another embodiment of the invention, the surfactants are present in an amount of about 12% and are selected from Polysorbate 80, Polysorbate 20, Lecithin, Polyoxyethylene-Polyoxypropylene copolymers and derivatives thereof, is provided.
In even still another embodiment of the invention, the composition comprises antioxidants in an amount from 0.01% to 2%. The antioxidants are selected from Sodium Sulfite, Sodium Bisulfite, Sodium Metabisulfite, Butylated Hydroxy Toluene, Cysteine Hydrochloride, Potassium Metabisulfite, Methionine, Monothioglycerol, Acetone Ascorbyl Palmitate, Ascorbate, Dithionite Sodium, Genticic Acid, Genticic Acid Ethanolamine, Propyl Gallate, Alpha Tocopherol, Sodium Thioglycolate, Glutathione Formaldehyde Sulfoxylate Sodium and derivatives thereof.
In even still yet another embodiment of the invention, the composition comprises buffering agents selected from Sodium hydroxide, Potassium Hydroxide, Sodium Citrate, monosodium phosphate salt, disodium phosphate salt, mono Potassium Phosphate salt, di Potassium Phosphate salt, Tris Buffer, Sodium Acetate, Glycine, Lysine, Meglumine, Methanesulfonic Acid, Maleic acid, Sodium Carbonate, Sodium Bicarbonate, Citric Acid, Sodium Citrate, Disodium Citrate, Trisodium Citrate, Ammonium Sulfate, Ammonium Hydroxide, Arginine, Aspartic Acid, Benzene Sulfonic Acid, Monoethanolamine, Sodium Succcinate, Disodium Succcinate, Sodium Tartarate and derivatives thereof. The buffenting agents are provided in an amount to maintain the pH of composition between 7.5 to 9.0.
In an embodiment, the composition has a viscosity between 2-5 cps at 250C to 400C.
In even still yet another embodiment of the invention, the composition comprises a further pharmaceutically active agent selected from Paracetamol, Drotaverine, Dicyclomine, antispasmodic, anti-inflammatory agents and combination thereof, is provided.
In another embodiment of the invention, a method of preparation of aqueous injectable composition comprising about 75 mg/ml of Diclofenac or pharmaceutically acceptable salts thereof is provided. The method comprises
a) preparing aqueous solution of glycine at about 25 °C and continuously stirring under Nitrogen atmosphere till a clear homogenous solution is obtained;
b) adding Diclofenac Sodium or other pharmaceutically acceptable salt thereof in homogenous solution obtained in step (b) with continuous stirring under nitrogen atmosphere and adding buffering agents to said solution to have a pH between 7.5-9.0.
In yet another embodiment of the invention, the method comprises that the glycine in step (a) is present in an amount of about 0.1%w/v to 2%w/v and Diclofenac sodium in step (b) is added in an amount of about 75 mg, is provided.
In still yet another embodiment of the invention, the method comprises addition of pharmaceutically acceptable excipients before step (b) with continuous stirring under nitrogen atmosphere.
Detailed Description of the Invention
The present invention provides safe and stable aqueous injectable composition comprising Diclofenac or pharmaceutically acceptable salts thereof, Glycine along with pharmaceutically acceptable excipients. The composition comprises about 75mg/ml of Diclofenac. The composition comprises Glycine in an amount from 0.1%w/v to 2%w/v. The composition further comprises pharmaceutically acceptable excipients acceptable and defined in regulatory databases like IID FDA. The composition of the present invention is suitable for administration by multiple routes preferably injectable route.
Conventionally formulated Diclofenac Sodium injections are limited to intramuscular administration. This limitation has arisen, not as a consequence of the intravenous safety profile, but principally due to the physico-chemical properties of the drug. Poor aqueous solubility of the Sodium salt of Diclofenac has a particularly high tendency to crystallize from aqueous and organic solutions. The present invention provides therapeutically effective amount of Diclofenac or salts thereof in an aqueous composition suitable to be administered by multiple routes.
Glycine is 2-aminoacetic acid a white, odorless, crystalline sweet tasting powder and is used as buffering agent for parenteral preparations in up to 1.5%, bulking agent, dietary supplement, freeze-drying agent, tablet disintegrant and wetting agent.

Fig. 2 Glycine
It was surprisingly found that in presence of Glycine 0.1 to 2%, Diclofenac Sodium about 75 mg can be dissolved in just 1 ml to provide a safe and stable aqueous composition that can be administered through several routes. Currently there is no Diclofenac Sodium composition wherein about 75 mg of Diclofenac Sodium is dissolved in 1 ml in presence of Glycine, to provide a stable, aqueous, safe composition for parenteral use. The present invention provides that presence of Glycine enable dissolution of about 75 mg of Diclofenac Sodium to provide stable and safe aqueous composition that would be fit for parenteral and other routes of administration.
Composition described in the present invention provides that about 75 mg of Diclofenac Sodium is dissolved in 1 ml of final composition. It gives economic benefit, technical and administrative convenience for the service of patients and health workers. The present invention does not employ any non-acceptable pharmaceutical excipient to solubilize the drug. The surprising finding of the invention is incorporation of pharmaceutically acceptable excipients for dissolution of Diclofenac Sodium in about 75 mg; whereas other compositions have failed to do so and therefore have to use some non-pharmaceutically acceptable excipients to dissolve about 75 mg of Diclofenac Sodium in 1 ml of a composition. The composition of present invention exhibits low viscosity and provides a stable, aqueous and effective composition convenient for use.

The preferred pharmaceutically acceptable excipients used are the of Parenteral grade and acceptable Glycols like polyethylene glycols, propylene glycol etc., antioxidant like Monothioglycerol, Polysorbates viz. Polysorbate 20, Polysorbate 80, etc., Povidones, Sodium Hydroxide solution, Magnesium Chloride, Di sodium EDTA and excipients alike.
A-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl (Rowe RC et. al, Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press, 2009) is Polyethylene Glycol (Macrogol, PEG). PEG of various molecular weights is a pharmaceutically acceptable excipient for pharmaceutical composition. General monograph describing macrogol 300, 400, 600, 1000, 1500, 3000, 3350, 4000, 6000, 8000, 20000 and 35000. Macrogol 300, 400 and 600 are clear, viscous, colorless or almost colorless, hygroscopic liquids, miscible with water; very soluble in alcohol, in acetone and in dichloromethane, practically insoluble in fatty oils and in mineral oils.

Fig. 3 Polyethylene Glycol
In concentrations ranging from 1% to 30% w/v, PEG 300 and PEG 400 have been used as the vehicle for parenteral dosage forms (Rowe RC et al, Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press, 2009).
Polysorbate 80, a lemon to amber colored oily liquid, with a faint characteristic odor is an oleate ester of sorbitol and its anhydrides copolymerized with about 20 mole of ethylene oxide for each mole of sorbitol and its anhydrides. It is soluble in water, producing an odorless and practically colorless solution; soluble in alcohol and in ethyl acetate; insoluble in liquid paraffin (Martindale, 36th edition, 2009).

Fig. 4 Polysorbate 80
They are used as solubilizing agents for a variety of substances including essential oils and oil-soluble Vitamins and as wetting agents in the formulation of oral and parenteral suspensions. (Rowe RC et al, Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press, 2009).
Monothioglycerol also known as a-Monothioglycerol, Monotioglicerol, Thioglycerol or 3-Mercaptopropane- 1,2-diol and 3-sulfanylpropane-1,2-diol IUPAC name is colorless or pale yellow, viscous, hygroscopic liquid with a slight odor of sulfide, freely soluble in water, miscible with alcohol and insoluble in ether (Martindale, 36th edition, 2009).

Fig. 5 Monothioglycerol
Monothioglycerol is used as an antioxidant in Pharmaceutical formulations, mainly in parenteral preparations. It has some antimicrobial activity. Monothioglycerol is a relatively nontoxic and nonirritant material at the concentrations used as a pharmaceutical excipient. It is Included in the FDA Inactive Ingredients Database (IM, IV and other injections 1%). It is Included in the Canadian List of Acceptable Non-medicinal Ingredients.
Benzethonium Chloride occurs as a white crystalline material with a mild odor and very bitter taste and chemically it is N,N-Dimethyl-N-[2-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethoxy]ethyl]benzene- methanaminium chloride, a quaternary ammonium compound and can also be used as preservative.
Phosphate buffer may be used as single or in combination with other ingredients like Povidone, PEG 300/400, Polysorbates, and Glycine etc.
The invention provides composition comprising Diclofenac Sodium in a concentration of about 75 mg/ml for parenteral administration through IM/IV route and for use in ocular, dermal, otic, oral and for other preparations.
Stability of actives in presence of different excipients is unpredictable. Further it is more difficult to stabilize actives in higher concentrations which are less soluble or sparingly soluble or poorly soluble in solvent, in presence of various excipients.
It was surprisingly noticed that composition of the present invention in which Glycine is present are stable under stability testing conditions. Compositions prepared with Glycine did not produce unwarranted impurities. Assay of active content was well within the limit. Appearance and description conformed to standard Appearance or description. The stability was satisfactory under various stability testing conditions such as 40 0C + 2 0C; 75+ 5%RH, 30 0C + 2 0C; 75+ 5%RH; 30 0C + 2 0C; 65+ 5%RH, 25 0C + 2 0C; 60+ 5%RH.
In another aspect, the present invention also provides stable aqueous pharmaceutical composition comprising therapeutically effective amount of Diclofenac Sodium in combination with drugs like Paracetamol, Drotaverine and Dicyclomine which further comprises said excipients.
Diclofenac Sodium in the composition may be used in its original form, powder form, spray dried form, nano-sized form or Diclofenac Sodium. Ultimately Diclofenac Sodium dissolves.
In one embodiment viscosity of current invention is maintained ranging from about 1.0 to 5.0 cps. In another aspect viscosity of current invention is maintained ranging from about 1.0 to 4.0 cps. In another aspect viscosity of current invention is maintained ranging from about 2.0 to 5.0 cps. The prepared Diclofenac injection composition is easily syringeable and offers less pressure when administered intramuscularly. It can be administered with ease by health professional while administering in to the tissues by the health workers, thereby causing less pressure.
The composition comprises solvents/co-solvents incorporated in an amount ranging from 0.1% to 50%. The solvents/co-solvents may be selected from but not limited to Polyethylene Glycol 300 up to 50%, Polyethylene Glycol 400 up to 20.3%, Povidones like PVP K-12 up to 0.9%, Benzyl Benzoate up to 50%, Benzyl Alcohol up to 4%, Ethanol as and when required, Castor oil up to 29%, Dimethylacetamide up to 33%, Glycerin up to 15% etc. The composition may also comprise Sesame oil, Soybean oil and solvents alike which are of pharmacopoeial grade available in the market. It may also comprise Propylene Glycol in allowable quantity known to be used parentally for use in intramuscular and intravenous route.
The composition optionally may comprise complexing agents selected from but not limited to cyclodextrins like Hydroxypropyl Beta-Cyclodextrin and Sulfobutyl Ether ?-Cyclodextrin.
The composition comprises antimicrobial preservatives incorporated in an amount ranging from 0.01% to 7%. Antimicrobial preservatives may be selected from but not limited to Benzethonium Chloride up to 0.01%, Benzyl Alcohol up to 2%, Benzalkonium Chloride about 0.02%, Chlorobutanol about 2.5% to 5%, m-Cresol about 0.1% to 0.3% Parabens like methyl paraben, propyl paraben up to 1%, phenol up to 0.45%. Some more excipients like 2-PhenoxyEthanol, Phenyl Mercuric Nitrate, Thimerosal and excipients alike may be used in the formulation. Benzyl Alcohol about 2% is used as preservative and if it is used at about 4%, it may work as solvent.
In another embodiment, composition may comprise chelating agents in an amount ranging from 0.1% to 4%. The chelating agents may be selected from but not limited to disodium EDTA, sodium EDTA, Calcium disodium EDTA about 0.2%, Versetamide about 2.54%, Calteridol Calcium about 0.023%, also Diethylenetriaminepenta Acetic Acid and ingredients alike.
The composition may comprise surfactants in an amount of about 12% of the composition. The surfactants may be selected from but not limited to Polysorbates like Polysorbate 80 up to 12%, Polysorbate 20 up to 12%, Lecithin, Polyoxyethylene-Polyoxypropylene copolymers and surfactants alike.
The composition comprises antioxidants incorporated in an amount ranging from 0.01% to 2%. The antioxidants may be selected from but not limited to Sodium Sulfite up to 0.2%, Sodium Bisulfite about 0.1% to 1.6%, Sodium Metabisulfite about 0.15% to 1.1%, Butylated Hydroxy Toluene about 0.002% to 0.03%, Cysteine Hydrochloride about 0.1%, Potassium Metabisulfite about 0.1%, Methionine about 0.01% to 0.3% and Monothioglycerol up to 1%. Antioxidants used in the formulation may be also selected from group of Acetone Ascorbyl Palmitate, Ascorbate, Dithionite Sodium, Genticic Acid, Genticic Acid Ethanolamine, Propyl Gallate, Alpha Tocopherol, Sodium Thioglycolate, Glutathione Formaldehyde Sulfoxylate Sodium and antioxidants alike.
The pH is critical for maintaining stability of the Diclofenac injection and is maintained from about 7.5 to 9.0, preferably about 8.0 to 9.0 using suitable buffering agents and alkalizers. The buffering agents may be selected from, but not limited to alkali metal hydroxides like Sodium hydroxide, Potassium Hydroxide, Sodium Citrate, Sodium Phosphate salts like monosodium phosphate salt or disodium phosphate salt, Potassium Phosphate salts like mono or di Potassium Phosphate salt, Tris Buffer, Sodium Acetate, Glycine, Lysine, Meglumine, Methanesulfonic Acid etc.
In preferred embodiment the Glycine is used in range of about 0.1 to 2% w/v, more preferably it may comprise about 1.0 to 1.5% w/v of Glycine. In another aspect the formulation may comprise buffering agents and pH adjusting agents which are Maleic acid, Sodium Carbonate, Sodium Bicarbonate, Citric Acid, Sodium Citrate, Disodium Citrate, Trisodium Citrate, Ammonium Sulfate, Ammonium Hydroxide, Arginine, Aspartic Acid, Benzene Sulfonic Acid, Monoethanolamine, Sodium Succcinate, Disodium Succcinate, Sodium Tartarate and excipients alike.
In another embodiment Monothioglycerol act as antioxidant as well as preservative. Methionine in the invention also plays a role of pH adjusting agent. All excipients/additives used in the formulation are present in IIG database.
Water in the formulation used as quantity sufficient to make different volumes for different strengths, preferably 0.5 ml or 1 ml solution.
In another aspect of the invention, composition may be available with or without Polysorbate 80, with or without Monothioglycerol, with or and without Glycine, with or without PEG 300 and or PEG 400, with or without PVP.
In another aspect pharmaceutical composition comprises said solvents or other parentally useful solvents to achieve about 75 mg/ml concentration.
In another embodiment, the injectable composition may be filled in ampoule and vials or PFS or special syringes available with like BDS with specific volume and placed in pouch or filled in smaller canisters, filled in containers for use as spray for spray for musculoskeletal disorders, nasal drops, otic drops, throat spray, delivered in devices used for brain drug delivery after aseptic filtration and flushed under nitrogen blanket or terminally sterilized. The composition may be available as single use vials or glass ampoules or glass ampoules with black ring or with non-reactive glass ampoules or filled in bags for LVP using diluents and buffers or ready to infuse kit such as bags and glass or plastic bottles preferably of single compartment which may be composed of low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene (PP) or mixtures of polyethylene and polypropylene. Glass bottles in packaging of said composition are composed of mixture of crystalline oxides and carbonates. Preferably used glass material is as cited in USP such as type I glass (borosilicate glass) and type II glass (soda lime glass with chemical surface treatment). In another embodiment, the said composition may be provided in volume of equal or greater than 1 ml to 500 ml of single compartment or ready-to-use injection which can be diluted according to physiological use. The kit said herein may be also of flexible bags.
In another embodiment, closures used may include sealing or rubber stoppers, closures or disc seals, screw-caps or cap-stopper combination seals closures may be used as a component of packaging.
The composition is prepared and filled in article and is sterilized by aseptic filtration or by electron beam irradiation, ?-irradiation, natural light, microwave heat viz. moist heat sterilization or terminal sterilization or suitable method..
Injections so formed are stable and may diluted further in infusion liquid to obtain the desired strength of drug or without diluting further by intramuscular and as slow bolus intravenous or suitably adding to infusion liquid as per physician need.
Normally non-pharmaceutically acceptable excipients are resorted to when pharmaceutically acceptable excipients fail to serve the purpose. Non- pharmaceutically acceptable excipients or specialty chemicals are often costlier than conventional pharmaceutically acceptable excipients. Safety and Toxicity profiles of Non- pharmaceutically acceptable excipients or specialty chemicals may be disputable. Inventors across the globe resorted to the use of unsafe, non- pharmaceutically acceptable excipients because they failed to dissolve about 75 mg of Diclofenac in just 1 ml of water using available pharmaceutically acceptable excipients, to provide safe, stable aqueous composition that is fit for administration by parenteral and other routes of administration. The composition of present invention employs only pharmaceutically acceptable excipients or regulatory approved ingredients.
The present invention provides that by employing safe pharmaceutically acceptable excipients, stable composition of Diclofenac or pharmaceutically acceptable salts thereof with lower comparable viscosity are obtained. By modulating the quantity of PEG 400 or other ingredients, compositions with desirable viscosity are produced.
The above and other objects, features and advantages of the present invention will now be described in detail with reference to certain exemplary embodiments thereof illustrated in the accompanying examples which are given herein below but are not limitative of the present invention. While the invention will be described in conjunction with exemplary embodiments, it will be understood that present description is not intended to limit the invention to those exemplary embodiments. On the contrary, the invention is intended to cover not only the exemplary embodiments, but also various alternatives, modifications, equivalents and other embodiments, which may be included within the spirit and scope of the invention as defined by the appended claims. Thus composition wherein an additional active ingredient is present along with claimed % of Diclofenac and Glycine would fall within the purview of the present invention.
Examples
The stable aqueous injectable composition of Diclofenac or pharmaceutically acceptable salts thereof along with various pharmaceutically acceptable excipients is prepared and tested for desired properties as per the Examples herein below:

Example 1:
An exemplary aqueous injectable composition of Diclofenac Sodium as per the present invention was prepared by employing various pharmaceutically acceptable ingredients or excipients in following quantities shown in Table 1:
Item Name Standard Quantity / Batch UOM&
Diclofenac Sodium IP (Injectable grade) 1.875 * Kg
Glycine USP-NF 0.313@ Kg
Polysorbate 80 EP (Montanox 80 PPI) 0.250 Kg
Polyethylene glycol 400 USP-NF(Super refined) 5.000 Kg
Monothioglycerol USP 0.125 Kg
Sodium Hydroxide IP 20.000# g
Water For Injection IP/IH q.s. to 25 L
Table 1: Exemplary Diclofenac composition of present invention
*Calculation: Compensation based on potency (Assay) of active ingredient.
# For preparing 1M sodium hydroxide solution in water for injection IP/IH, used required quantity and destroyed the balance quantity.
@ Glycine quantity should be dispensed 312.5 g
& Unit of Measurement
Example 2:
Preparation of stable aqueous Diclofenac composition as per present invention:
1. In Stainless steel (SS) vessel WFI (Water for Injection) was taken and cooled to about 25 °C. Dispensed quantity of Glycine, as indicated in Table 1 depicted in Example 1, was added in jacketed manufacturing tank with continuous stirring and Nitrogen purging till a clear solution was obtained. The clarity of the solution was subsequently checked and the solution was further stirred for about 5 minutes;
2. Dispensed quantity of Polyethylene glycol 400, as indicated in Table 1 depicted in Example 1, in separate SS container was taken and Polysorbate 80 and Monothioglycerol were added in dispensed quantities, as indicated in Table 1 depicted in Example 1, with continuous stirring in step wise manner. The solution was stirred, followed by adding nitrogen purging for about 2 minutes to form homogeneous mixture;
3. Diclofenac Sodium or other pharmaceutically acceptable salt thereof was added in dispensed quantity in above SS container with continuous stirring until the drug was completely wet and dispersed in above solution. Addition of drug is further followed by stirring for about 10 minutes with continuous nitrogen purging to obtain clear solution;
4. Homogeneous mixture of drug was added into jacketed manufacturing tank under continuous stirring and followed by rinsing the container twice with water for injection IP/IH and added in above jacketed manufacturing tank with continuous stirring to get a clear solution;
5. pH of the drug product solution was adjusted with Sodium Hydroxide solution and final volume was adjusted with required quantity of WFI;
6. Prepared solution was filled and sealed in 1 mL SFC Blue OPC dot Ampoule USP type I and subjected to stability studies at room temperature, 25/60, 30/65, 30/75 and 40/75 respectively at its proposed stability time points. It passed sterility and bacterial endotoxin tests.

Example 3: Stability of the Composition
The prepared drug solution or aqueous composition of Diclofenac of Example 1 was subjected to various stability tests at room temperature of 30 to 40 °C and at relative humidity (RH) of about 75.
Table 2: 6 months stability data of composition of Example 1 at 40 0C + 2 0C; 75+ 5% RH.
6 months
1. Description (Visual) A clear, colourless to yellowish liquid. Complies
2. pH (at 25°C) 8.1 to 9.0 8.38
3. Assay of Diclofenac Sodium (By HPLC) Each mL contains:
NLT 71.25 mg to NMT 78.75 mg (NLT 95.0% to NMT 105.0%) 101.06%
4. Related substances (BY HPLC)
4.1 Impurity A NMT 0.5% 0.251%
4.2 Impurity F NMT 0.5% 0.00 %
4.3 Any maximum unspecified Impurity NMT 0.5% 0.00 %
4.4 Total Impurities NMT 2.0% 0.251%
HPLC: High Performance Liquid Chromatography
Table 3: 9 months stability data of composition of Example 1 at 30 0C + 2 0C; 75+ 5% RH.
Specification 9 months
1. Description (Visual) A clear, colourless to yellowish liquid. Complies
2. pH (at 25°C) 8.1 to 9.0 8.48
3. Assay of Diclofenac Sodium (By HPLC) Each mL contains:
NLT 71.25 mg to NMT 78.75 mg (NLT 95.0% to NMT 105.0%) 101.3%
4. Related substances (BY HPLC)
4.1 Impurity A NMT 0.5% 0.00 %
4.2 Impurity F NMT 0.5% 0.00 %
4.3 Any maximum unspecified Impurity NMT 0.5% 0.00 %
4.4 Total Impurities NMT 2.0% 0.00 %

NLT = Not less than. NMT = Not more than
Example 4
2 more batches DIF-902 and DIF-903 (Internal batch code numbers) were manufactured and subjected to stability testing. The stability data obtained at the end of 9 months for 30 0C + 2 0C; 75+ 5% RH is herein below reproduced:
Table 4: 9 months stability data of composition DIF- 902 and DIF-903 at 30 0C + 2 0C; 75+ 5% RH
Specification DIF-902 DIF-903
1. Description (Visual) A clear, colourless to yellowish liquid. Complies Complies
2. pH (at 25°C) 8.1 to 9.0 8.44 8.42
3. Assay of Diclofenac Sodium (By HPLC) Each mL contains:
NLT 71.25 mg to NMT 78.75 mg (NLT 95.0% to NMT 105.0%) 101.63% 100.77%
4. Related substances (BY HPLC)
4.1 Impurity A NMT 0.5% 0.00 % 0.00 %
4.2 Impurity F NMT 0.5% 0.00 % 0.00%
4.3 Any maximum unspecified Impurity NMT 0.5% 0.00 % 0.00 %
4.4 Total Impurities NMT 2.0% 0.00 % 0.00 %

Viscosity of the compositions so produced was found to be between 2 to 5 cps at 250C to 400C measured as per British Pharmacopoeia.

,CLAIMS:We claim:
1. A stable aqueous injectable composition comprising about 75 mg/ml of Diclofenac or pharmaceutically acceptable salts thereof and from 0.1%w/v to 2%w/v Glycine along with pharmaceutically acceptable excipients.
2. The composition as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from solvents or co-solvents, complexing agents, antimicrobial preservatives, chelating agents, antioxidants, buffering agents, pH adjusting agents and combination thereof.
3. The composition as claimed in claim 2 wherein the solvents or co-solvents are present in an amount of from 0.1% to 50% and are selected from Polyethylene Glycol 300, Polyethylene Glycol 400, PVP K-12, Benzyl Benzoate, Benzyl Alcohol, Ethanol, Castor oil, Dimethylacetamide, Glycerin, Sesame oil, Soybean oil and derivatives thereof.
4. The composition as claimed in claim 2, wherein the complexing agents are present in an amount of up to 33.33%w/v and are selected from Hydroxypropyl Beta-Cyclodextrin and Sulfobutyl Ether ?-Cyclodextrin.
5. The composition as claimed in claim 2 wherein the antimicrobial preservatives present in an amount from 0.01% to 7% and are selected from Benzethonium Chloride, Benzyl Alcohol, Benzalkonium Chloride, Chlorobutanol, m-Cresol, methyl paraben, propyl paraben, phenol, 2-PhenoxyEthanol, Phenyl Mercuric Nitrate, Thimerosal and derivatives thereof.
6. The composition as claimed in claim 2 wherein the chelating agents are present in an amount from 0.1% to 4% and are selected from disodium EDTA, sodium EDTA, Calcium disodium EDTA, Versetamide, Calteridol Calcium, Diethylenetriaminepenta Acetic Acid and derivatives thereof.
7. The composition as claimed in claim 2 wherein the surfactants present in an amount of about 12% and are selected from Polysorbate 80, Polysorbate 20, Lecithin, Polyoxyethylene-Polyoxypropylene copolymers and derivatives thereof.
8. The composition as claimed in claim 2 wherein the antioxidants present in an amount from 0.01% to 2% and are selected from Sodium Sulfite, Sodium Bisulfite, Sodium Metabisulfite, Butylated Hydroxy Toluene, Cysteine Hydrochloride, Potassium Metabisulfite, Methionine, Monothioglycerol, Acetone Ascorbyl Palmitate, Ascorbate, Dithionite Sodium, Genticic Acid, Genticic Acid Ethanolamine, Propyl Gallate, Alpha Tocopherol, Sodium Thioglycolate, Glutathione Formaldehyde Sulfoxylate Sodium and derivatives thereof.
9. The composition as claimed in claim 2 wherein the buffering agents are selected from Sodium hydroxide, Potassium Hydroxide, Sodium Citrate, monosodium phosphate salt, disodium phosphate salt, mono Potassium Phosphate salt, di Potassium Phosphate salt, Tris Buffer, Sodium Acetate, Glycine, Lysine, Meglumine, Methanesulfonic Acid, Maleic acid, Sodium Carbonate, Sodium Bicarbonate, Citric Acid, Sodium Citrate, Disodium Citrate, Trisodium Citrate, Ammonium Sulfate, Ammonium Hydroxide, Arginine, Aspartic Acid, Benzene Sulfonic Acid, Monoethanolamine, Sodium Succcinate, Disodium Succcinate, Sodium Tartarate and derivatives thereof in in an amount to maintain the pH of composition between 7.5 to 9.0.
10. The composition as claimed in any of preceding claims, wherein the composition has a viscosity between 2- 5 cps at 250C to 400C.
11. The composition as claimed in any of preceding claims, wherein the composition has a pH between 7.5 to 9.0.
12. The composition as claimed in any of preceding claims, wherein said composition comprises a further pharmaceutically active agent selected from Paracetamol, Drotaverine, Dicyclomine, antispasmodic, anti-inflammatory agents and combination thereof.
13. A method of preparation of aqueous injectable composition as claimed in any of the preceding claim, said method comprises:
a) preparing aqueous solution of glycine at about 25 °C and continuously stirring under Nitrogen atmosphere till a clear homogenous solution is obtained;
b) adding Diclofenac Sodium or other pharmaceutically acceptable salt thereof in homogenous solution obtained in step (b) with continuous stirring under nitrogen atmosphere and adding buffering agents to said solution to have a pH between 7.5-9.0.
14. The method as claimed in claim 13, wherein the glycine in step (a) is present in an amount of about 0.1%w/v to 2%w/v and diclofenac sodium in step (b) is added in an amount of about 75 mg.
15. The method as claimed in claim 1 wherein pharmaceutically acceptable excipients are added before step (b) with continuous stirring under nitrogen atmosphere.

Dated this the 24th day of February 2020.

ASHISH KUMAR SHARMA
[IN/PA-858]
of SUBRAMANIAM & ASSOCIATES
Attorney for the applicants