WO2022084967A1 - Parenteral solutions of selective cyclooxygenase-2 (cox-2) inhibitor and use therof for treating pain / arthritis - Google Patents

Parenteral solutions of selective cyclooxygenase-2 (cox-2) inhibitor and use therof for treating pain / arthritis Download PDF

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Publication number
WO2022084967A1
WO2022084967A1 PCT/IB2021/059795 IB2021059795W WO2022084967A1 WO 2022084967 A1 WO2022084967 A1 WO 2022084967A1 IB 2021059795 W IB2021059795 W IB 2021059795W WO 2022084967 A1 WO2022084967 A1 WO 2022084967A1
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solution
parenteral
etoricoxib
parenteral solution
acid
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PCT/IB2021/059795
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French (fr)
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Kannan Essakimuthu MUTHAIYYAN
Debjani Manoj Singh
Nirav Ishwarlal KHATRI
Amol Mukund KULKARNI
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Cadila Healthcare Limited
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Publication of WO2022084967A1 publication Critical patent/WO2022084967A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to parenteral solutions comprising selective cyclooxygenase-2 (COX-2) inhibitor.
  • the present invention also relates to processes for preparing such parenteral solutions.
  • the present invention also relates to a method of treating pain or arthritis comprising administering such parenteral solution to a human being in need thereof through a parenteral route, viz., intravenous route, subcutaneous route or intramuscular route.
  • Selective COX-2 inhibitors are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly targets cyclooxygenase-2, COX-2, an enzyme responsible for inflammation and pain.
  • NSAID nonsteroidal anti-inflammatory drug
  • Etoricoxib selectively inhibits COX- 2 enzyme.
  • WO 2014/178065 discloses parenteral composition comprising etoricoxib and diethylene glycol monoethyl ether (transcutol).
  • WO 2004/014431 discloses parenteral pharmaceutical dosage form comprising selective COX-2 inhibitor, nonaqueous protic solvent (polyethylene glycol, polyvinylpyrrolidone, propylene glycol and glycerol) and co-solvents (ethyl alcohol and water). It discloses celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib and parecoxib as examples of selective COX-2 inhibitors.
  • Indian Patent No. 234470 discloses lyophilized powder comprising etoricoxib for parenteral use.
  • U. S. Patent No. 6,589,973 discloses injectable formulations comprising COX-2 inhibitor and isosorbide type solvent.
  • Indian Publication No. 929/MUM/2004 discloses parenteral solution comprising etoricoxib and an acidifying agent, wherein pH of the solution is about 2.3.
  • a parenteral solution comprising etoricoxib suitable for administration through intravenous route, subcutaneous route or intramuscular route which enables safe and efficacious treatment for pain I arthritis.
  • a parenteral solution comprising etoricoxib which remains in solution form after dilution using appropriate aqueous diluent vehicle (saline solution or 5% dextrose solution), for the intravenous administration.
  • a parenteral solution comprising etoricoxib which does not cause irritation at the site of injection after the parenteral administration.
  • a parenteral solution comprising etoricoxib which does not cause adverse systemic reaction after the parenteral administration.
  • the present invention provides a parenteral solution comprising a selective COX-2 inhibitor and water.
  • the present invention provides a parenteral solution comprising etoricoxib and water. In another aspect, the present invention provides a parenteral solution comprising etoricoxib and water, wherein the etoricoxib is present in a concentration of 90 mg/mL.
  • the present invention provides a parenteral solution comprising etoricoxib and water, wherein the solution has a pH from about 3 to about 4.5.
  • the present invention provides a parenteral solution comprising etoricoxib and citric acid, wherein weight ratio of etoricoxib to citric acid is 1 :1 or more.
  • Embodiments of the parenteral solution may include one or more of the following features.
  • the solution may further comprise one or more stabilizers, solubilizers, surfactants, isotonicity adjusting agents and optionally comprise pH adjusting agents, buffering agents, preservatives, and antioxidants.
  • the parenteral solution is free of pH adjusting agents, buffering agents, preservatives, and antioxidants.
  • the present invention provides a process for preparing the parenteral solution comprising a selective COX-2 inhibitor and water.
  • the present invention provides a method for treatment of pain or arthritis comprising administering the parenteral solution comprising a selective COX-2 inhibitor of the present invention to a human being in need thereof.
  • the inventors of the present invention have found that when etoricoxib is dissolved in water in presence of citric acid and solubilizer(s) and if pH is kept from about 3 to about 4.5, a stable parenteral solution comprising etoricoxib in a concentration of 90 mg/mL can be obtained.
  • the parenteral solution comprising etoricoxib of the present invention provides benefit of dilution stability.
  • the parenteral solution comprising etoricoxib may provide benefit of less / no irritation at the site of injection after administration.
  • the parenteral solution comprising etoricoxib may provide benefit of less I no adverse systemic reactions after administration.
  • stable refers to any composition comprising a drug having sufficient physical and chemical stability at the time of manufacturing of the composition.
  • the present invention provides a parenteral solution comprising a selective COX-2 inhibitor drug and water.
  • the solution is sterile.
  • suitable selective COX-2 inhibitor drugs may include etoricoxib, celecoxib, valdecoxib, rofecoxib, deracoxib, parecoxib, etc.
  • the present invention provides a parenteral solution comprising etoricoxib and one or more pharmaceutically acceptable excipients, for example, stabilizers, solvents/solubilizers, surfactants, isotonicity adjusting agents and optionally, preservatives, antioxidants, buffering agents, pH adjusting agents.
  • the parenteral solution is free of pH adjusting agents, buffering agents, preservatives, and antioxidants.
  • Suitable stabilizers may include, but not limited to citric acid, tartaric acid, fumaric acid, acetic acid, lactic acid, maleic acid, ascorbic acid, phosphoric acid, methane sulfonic acid, benzene sulfonic acid, or salts thereof, sodium benzoate, sodium bicarbonate, sodium carbonate, sodium citrate, diethanolamine, glycine, hydrochloric acid, hydrogen bromide, monobasic sodium phosphate, dibasic sodium phosphate, lecithin, sodium acetate, polysorbates, for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (polyoxyethylene sorbitan monooleate), or any combination thereof.
  • the citric acid may be present in the form of citric acid monohydrate, anhydrous citric acid, monosodium citrate, disodium citrate, disodium citrate sesquihydrate, glyceryl monocitrate, trisodium citrate, tripotassium citrate, potassium citrate, calcium citrate, dicalcium citrate, tricalcium citrate tetrahydrate, magnesium citrate or triethyl citrate.
  • the parenteral solution of the present invention may comprise citric acid, wherein the citric acid is present in a concentration from about 10 mg/mL to about 100 mg/mL, for example, about 25 mg/mL, about 50 mg/mL or about 75 mg/mL.
  • the parenteral solution of the present invention may comprise polysorbate, wherein the polysorbate is present in a concentration from about 30 mg/mL to about 300 mg/mL, for example, about 50 mg/mL, about 75 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 250 mg/mL or about 275 mg/mL.
  • solvents/solubilizers may include, but not limited to water, benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, benzyl benzoate, castor oil, cottonseed oil, N, N- dimethyl acetamide, glycerol, N-methyl-2- pyrrolidone, diethanolamine, L-arginine, peanut oil, poppyseed oil, safflower oil, sesame oil, soybean oil, vegetable oil, or any combination thereof.
  • the parenteral solution of the present invention may comprise benzyl alcohol, wherein the benzyl alcohol is present in a concentration from about 0.05 mL/mL to about 0.20 mL/mL, for example, about 0.09 mL/mL, about 0.10 mL/mL, or about 0.15 mL/mL.
  • the parenteral solution of the present invention may comprise ethanol (dehydrated alcohol), wherein the ethanol is present in a concentration from about 0.03 mL/mL to about 0.30 mL/mL, for example, about 0.05 mL/mL, about 0.10 mL/mL, about 0.15 mL/mL, about 0.16 mL/mL or about 0.20 mL/mL.
  • the parenteral solution of the present invention may comprise propylene glycol, wherein the propylene glycol is present in a concentration from about 0.2 mL/mL to about 0.8 mL/mL, for example, about 0.3 mL/mL, about 0.4 mL/mL, about 0.5 mL/mL, about 0.6 mL/mL or about 0.7 mL/mL.
  • surfactants may include, but not limited to, poloxamer (poloxamer 188), sodium lauryl sulfate, lauryl dimethyl amine oxide, docusate sodium, cetyl trimethyl ammonium bromide (CTAB), polyvinyl alcohol, polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, polyoxyl lauryl ether, Brij® surfactants (polyoxyethylene vegetable-based fatty ethers derived from lauryl, cetyl, stearyl and oleyl alcohols), bile salts (such as sodium deoxycholate and sodium cholate), polyoxyl castor oil, nonylphenol ethoxylate, lecithin, polyoxyethylene surfactants, phospholipids such as dimyristoylphosphatidyl glycerol (DMPG), disteroylphosphatidylethanolamine (DSPE), 1 ,2-Distearoyl- phosphatidyl
  • Suitable isotonicity adjusting agents may include, but not limited to, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glucose, sucrose, dextrose, mannitol, glycerol, or any combination thereof.
  • Suitable preservatives may include, but not limited to, chlorobutanol, benzalkonium chloride, methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, thiomersal, merthiolate, chlorhexidine, phenylethyl alcohol, quaternary ammonium chloride, sodium benzoate, sodium propionate, or any combination thereof.
  • antioxidants may include, but not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, monothioglycerol, ascorbic acid, sodium ascorbate, erythorbic acid, potassium metabisulfite, sodium metabisulfite, propionic acid, sodium formaldehyde sulphoxylate, reduced glutathione, thiourea, cysteine, n- acetylcysteine, methionine, sodium sulfite, sodium bisulfate, alkyl gallate, including propyl gallate, vitamin E, or other tocopherol analogs, including tocopherol acetate or TPGS, or any combination thereof.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • buffering agents may include, but not limited to, acetate (e.g. sodium acetate etc.), phosphate (e.g. monobasic sodium phosphate, dibasic sodium phosphate etc.), carbonate, glycine, borate (boric acid/potassium chloride), tris, tromethamine or any combination thereof.
  • acetate e.g. sodium acetate etc.
  • phosphate e.g. monobasic sodium phosphate, dibasic sodium phosphate etc.
  • carbonate glycine
  • borate borate (boric acid/potassium chloride), tris, tromethamine or any combination thereof.
  • pH adjusting agents may include, but not limited to, sodium hydroxide, hydrochloric acid, boric acid, acetic acid, phosphoric acid, succinic acid, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, or any combination thereof.
  • the parenteral solution may comprise one or more pH adjusting agents in an amount to provide pH of the solution from about 3 to about 4.5, for example 3.5 or 4.
  • the parenteral solution of the present invention comprises of about 90 mg/mL of etoricoxib is free of any pH adjusting agent.
  • the present invention provides a parenteral solution comprising about 90 mg/mL of etoricoxib, water and one or more of citric acid, benzyl alcohol, ethanol, polysorbate and propylene glycol, wherein the solution has a pH from about 3 to about 4.5.
  • the parenteral solution of the present invention comprises of about 90 mg/mL of etoricoxib, about 50 mg/mL of citric acid, about 0.09 mL/mL of benzyl alcohol, from about 0.10 mL/mL to about 0.16 mL/mL of ethanol, from about 150 mg/mL to about 200 mg/mL of polysorbate, about 0.15 mL/mL of water and propylene glycol, wherein the solution has a pH from about 3 to about 4.5.
  • the present invention provides a parenteral solution comprising about etoricoxib and citric acid (anhydrous), wherein weight ratio of etoricoxib to citric acid is 1 :1 or more, for example, 1.1 :1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1 , 1.7:1, 1.8:1, 1.9:1, 2:1 , 2.5:1 , 3:1 , 3.5:1, or 4:1.
  • the term “clear solution” means a solution which does not contain any visible particulate matter, solid particle, liposome or nanoparticles.
  • the clear solution provides % transmittance, when measured at 650 nm, not less than 95%, for example, not less than 96%, not less than 97%, not less than 98%, not less than 99%, not less than 99.5%, not less than 99.6%, not less than 99.7% or not less than 99.8%.
  • the parenteral solution of the present invention is suitable for administration through parenteral route, for example, intramuscular route (intradeltoid or intragluteal), subcutaneous route or intravenous route.
  • parenteral route for example, intramuscular route (intradeltoid or intragluteal), subcutaneous route or intravenous route.
  • the present invention provides a parenteral solution comprising etoricoxib in a concentration from about 15 mg/mL to about 150 mg/mL, for example, about 30 mg/mL, about 60 mg/mL, about 90 mg/mL or about 120 mg/mL.
  • the parenteral solution is suitable for administration through intramuscular or subcutaneous route, wherein solution does not require any dilution step before administration, i.e., it is ready to administer.
  • the present invention provides a ready to dilute parenteral solution comprising etoricoxib in a concentration of 90 mg/mL and water, wherein the solution has a pH from about 3 to about 4.5.
  • the ready to dilute solution provides ready to use parenteral solution upon mixing of ready to dilute solution with one or more suitable aqueous diluent vehicles.
  • the suitable aqueous diluent vehicles may include, but not limited to, 0.9% NaCI solution, 5% dextrose, or any combination thereof.
  • the ready to use etoricoxib parenteral solution may contain etoricoxib in a concentration from about 0.18 mg/mL to about 0.90 mg/mL.
  • the ready to dilute parenteral solution of the present invention may remain as a clear solution (free of any crystals/precipitate) after storage at controlled room temperature for more than 6 months, for example, 12 months, 18 months, or 24 months.
  • the ready to use etoricoxib parenteral solution of the present invention may remain clear (free of any crystals/precipitate) after storage at controlled room temperature for more than 6 hours, for example, 12 hours, 18 hours, or 24 hours.
  • the ready to use etoricoxib parenteral solution is ready for administration (ready to use) through intravenous, subcutaneous or intramuscular route.
  • controlled room temperature refers to the temperature from 20°C to 25°C.
  • the parenteral solution of the present invention may retain at least 95 % of the etoricoxib (% assay), as determined by HPLC, after storage for more than 1 month, for example, 3 months, 6 months, 12 months, 18 months, or 24 months, at controlled room temperature.
  • the parenteral solution comprising etoricoxib is clear (free of any crystals/precipitates) by visual inspection.
  • the solution may provide the value of absorbance not more than 1 , for example, not more then 0.75, 0.5, 0.4, 0.3, 0.2, 0.1 or 0.05.
  • the solution comprising etoricoxib remains clear after 6 months, 12 months, 18 months, or 24 months of storage at 25°C.
  • the solution may provide the value of APHA (American Public Health Association) color scale of between about 100 units and about 500 units, for example, between about 150 units and about 450 units, between about 200 units and about 450 units, between about 250 unit and about 400 unit, between about 300 unit and about 400 unit, or about 350 units.
  • APHA American Public Health Association
  • the solution comprising etoricoxib remains clear and maintains its initial/original color after 6 months, 12 months, 18 months, or 24 months of storage at 25°C.
  • the scale for APHA color goes from 0 to 500 in units of parts per million of platinum cobalt to water.
  • the parenteral solution comprising etoricoxib may contain total impurities less than 3 %, for example, less than 2 %, less than 1 % or less than 0.5 %, by weight of etoricoxib, as measured by HPLC, after 6 months, 12 months, 18 months, or 24 months of storage at 25°C.
  • the parenteral solution comprising etoricoxib has a viscosity value between of about 25 cP (centipoise) and about 35 cP, for example, about 26 cP, about 27 cP, about 28 cP, about 29 cP, about 30 cP, about 31 cP, about 32 cP, about 33 cP, or about 34 cP.
  • the parenteral solution comprising etoricoxib may have a pH from about 3 to about 4.5, for example, 3.5 or 4.
  • the present invention provides a parenteral solution comprising etoricoxib and water, wherein the solution is only for administration through parenteral route, for example, solution is not for the administration through ophthalmic route, otic route, topical route (application on skin) or oral route.
  • the parenteral solution comprising etoricoxib and water is not an eye drop solution and/or ear drop solution.
  • the parenteral solution does not contain cyclodextrin derivatives like betacyclodextrin and its derivatives (HPBCD (hydroxypropyl beta cyclodextrin), SBECD (sulfobutylether-
  • cyclodextrin derivatives like betacyclodextrin and its derivatives (HPBCD (hydroxypropyl beta cyclodextrin), SBECD (sulfobutylether-
  • gamma-cyclodextrin transcutol (2-(2-ethoxyethoxy) ethanol), cremophor (polyethoxylated castor oil), glycofurol, isosorbide
  • the present invention provides a process for preparing a parenteral solution comprising etoricoxib, benzyl alcohol, ethanol (dehydrated alcohol), propylene glycol, polysorbate, citric acid and water.
  • the process includes steps of: (a) adding benzyl alcohol into a manufacturing vessel, (b) adding ethanol and partial quantity of propylene glycol into the vessel of step (a), (c) adding etoricoxib into the vessel of step (b) and dissolving with optional heat application, (d) adding polysorbate, citric acid and water into the vessel of step (c), (e) making up the volume to the batch size using remaining quantity of propylene glycol and (f) filtering the solution through 0.22p filter and filling into a suitable container.
  • the etoricoxib parenteral solution of the present invention may be suitable to undergo a sterilization process to provide a sterile etoricoxib parenteral solution.
  • suitable sterilization process may include, but not limited to, terminal sterilization involving heat exposure, aseptic membrane filtration sterilization, etc.
  • the present invention provides a stable parenteral solution comprising etoricoxib, wherein the solution is supplied/provided in a suitable packaging material, for example, in a glass vial, in a glass ampoule, in a pre-filled syringe (PFS), in a glass bottle, in a plastic bottle, in a plastic bag, etc.
  • a suitable packaging material for example, in a glass vial, in a glass ampoule, in a pre-filled syringe (PFS), in a glass bottle, in a plastic bottle, in a plastic bag, etc.
  • PFS pre-filled syringe
  • the pre-filled syringe contains various constituent parts, for example, a sterile USP Type-1 siliconized glass syringe barrel (1 mL, cut flange with a gauge (29 size), hypodermic needle (14 inch) fitted with rigid needle shield and laminated bromobutyl plunger stopper for the barrel.
  • the packaging materials like vial, ampoule, or PFS are for single use administration.
  • the vial, ampoule, or PFS contains the solution comprising etoncoxib, wherein the etoncoxib is present in a therapeutically effective dose amount, for example, from about 30 mg to about 120 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 110 mg.
  • the present invention provides a pre-filled syringe (PFS) containing parenteral solution comprising etoricoxib, wherein the PFS is suitable for administration of solution through intramuscular route for the treatment of pain or arthritis.
  • PFS pre-filled syringe
  • the pre-filled syringe contains etoricoxib in a therapeutically effective dose amount of about 90 mg, for single dose administration.
  • the present invention provides an auto-injector which contains a pre-filled syringe (a pre-filled syringe assembled/placed in the auto-injector), wherein the pre-filled syringe contains a solution comprising etoricoxib.
  • the present invention provides a kit comprising (a) a pre-filled syringe containing a solution comprising etoricoxib and (b) an auto-injector device.
  • the kit is suitable to administer the solution through subcutaneous route.
  • the autoinjector may be integrated with a needle stick protection feature and holds a pre-filled syringe containing a single dose, whereby the entire deliverable volume is expelled.
  • the PFS and/or auto-injector provides convenience to the patient or care giver ease of self-administration / administration.
  • the present invention provides a method of treating pain (shoulder pain, knee pain, acute injury pain, bone fracture pain, dental pain, chronic back pain, post-operative pain, pain due to muscular spasm or torn ligament, etc.), arthritis, osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis or acute gout comprising administering the parenteral etoricoxib solution of the present invention to a human being in need thereof through parenteral route.
  • pain shoulder pain, knee pain, acute injury pain, bone fracture pain, dental pain, chronic back pain, post-operative pain, pain due to muscular spasm or torn ligament, etc.
  • arthritis osteoarthritis
  • rheumatoid arthritis juvenile rheumatoid arthritis
  • ankylosing spondylitis or acute gout comprising administering the parenteral etoricoxib solution of the present invention to a human being in need thereof through parenteral route.
  • the parenteral dose of etoricoxib in a day may range from about 30 mg to about 120 mg, for example, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg or about 110 mg.
  • the treatment of osteoarthritis, rheumatoid arthritis and juvenile rheumatoid arthritis involves relief of the signs and symptoms.
  • the treatment of juvenile rheumatoid arthritis involves relief of the signs and symptoms of pauciarticular or polyarticular course juvenile rheumatoid arthritis in patients 2 years of age and older.
  • the method comprises administration of etoricoxib dose of about 90 mg one time in a day (once daily).
  • the present invention provides a method of treating pain comprising administering the parenteral etoricoxib solution of the present invention to a human being in need thereof through intravenous route, for example, intravenous infusion.
  • the solution comprising etoricoxib of the invention when administered through parenteral route for the treatment of pain, may provide one or more benefits such as faster onset of pain relief, consistent pain relief, and less or no recurrence of pain during the same day of administration.
  • step (f) The solution of step (e) and was filtered and filled into a glass vial.
  • the etoricoxib solution obtained at Example 1 , at step (f), was diluted using 0.9% Sodium Chloride Injection, 1 in 250 mL.
  • the diluted solution was a clear colorless solution and has a pH value 3.65. was diluted tested for its physical and chemical parameters, and results are reported in the table below. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

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Abstract

The present invention relates to parenteral solutions comprising selective cyclooxygenase-2 (COX-2) inhibitor. The present invention also relates to processes for preparing such parenteral solutions. The present invention also relates to a method of treating pain or arthritis comprising administering such parenteral solution to a human being in need thereof through a parenteral route, viz., intravenous route, subcutaneous route or intramuscular route.

Description

PARENTERAL SOLUTIONS OF SELECTIVE CYCLOOXYGENASE-2 (COX-2) INHIBITOR AND USE THEROF FOR TREATING PAIN / ARTHRITIS
Field of the invention
The present invention relates to parenteral solutions comprising selective cyclooxygenase-2 (COX-2) inhibitor. The present invention also relates to processes for preparing such parenteral solutions. The present invention also relates to a method of treating pain or arthritis comprising administering such parenteral solution to a human being in need thereof through a parenteral route, viz., intravenous route, subcutaneous route or intramuscular route.
Background of the invention
Selective COX-2 inhibitors are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly targets cyclooxygenase-2, COX-2, an enzyme responsible for inflammation and pain. Etoricoxib selectively inhibits COX- 2 enzyme.
International (PCT) Publication No. WO 2014/178065 discloses parenteral composition comprising etoricoxib and diethylene glycol monoethyl ether (transcutol).
International (PCT) Publication No. WO 2004/014431 discloses parenteral pharmaceutical dosage form comprising selective COX-2 inhibitor, nonaqueous protic solvent (polyethylene glycol, polyvinylpyrrolidone, propylene glycol and glycerol) and co-solvents (ethyl alcohol and water). It discloses celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib and parecoxib as examples of selective COX-2 inhibitors. Indian Patent No. 234470 discloses lyophilized powder comprising etoricoxib for parenteral use.
U. S. Patent No. 6,589,973 discloses injectable formulations comprising COX-2 inhibitor and isosorbide type solvent.
Indian Publication No. 929/MUM/2004 discloses parenteral solution comprising etoricoxib and an acidifying agent, wherein pH of the solution is about 2.3.
There exists a need for a parenteral solution comprising etoricoxib suitable for administration through intravenous route, subcutaneous route or intramuscular route which enables safe and efficacious treatment for pain I arthritis. There also exists a need for a parenteral solution comprising etoricoxib which remains in solution form after dilution using appropriate aqueous diluent vehicle (saline solution or 5% dextrose solution), for the intravenous administration. There also exists a need for a parenteral solution comprising etoricoxib which does not cause irritation at the site of injection after the parenteral administration. There also exists a need for a parenteral solution comprising etoricoxib which does not cause adverse systemic reaction after the parenteral administration.
Summary of the invention
In one general aspect, the present invention provides a parenteral solution comprising a selective COX-2 inhibitor and water.
In one general aspect, the present invention provides a parenteral solution comprising etoricoxib and water. In another aspect, the present invention provides a parenteral solution comprising etoricoxib and water, wherein the etoricoxib is present in a concentration of 90 mg/mL.
In another aspect, the present invention provides a parenteral solution comprising etoricoxib and water, wherein the solution has a pH from about 3 to about 4.5.
In another aspect, the present invention provides a parenteral solution comprising etoricoxib and citric acid, wherein weight ratio of etoricoxib to citric acid is 1 :1 or more.
Embodiments of the parenteral solution may include one or more of the following features. For example, the solution may further comprise one or more stabilizers, solubilizers, surfactants, isotonicity adjusting agents and optionally comprise pH adjusting agents, buffering agents, preservatives, and antioxidants. In one aspect, the parenteral solution is free of pH adjusting agents, buffering agents, preservatives, and antioxidants.
In another general aspect, the present invention provides a process for preparing the parenteral solution comprising a selective COX-2 inhibitor and water.
In another general aspect, the present invention provides a method for treatment of pain or arthritis comprising administering the parenteral solution comprising a selective COX-2 inhibitor of the present invention to a human being in need thereof.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description. Detailed description of the invention
The inventors of the present invention have found that when etoricoxib is dissolved in water in presence of citric acid and solubilizer(s) and if pH is kept from about 3 to about 4.5, a stable parenteral solution comprising etoricoxib in a concentration of 90 mg/mL can be obtained. The parenteral solution comprising etoricoxib of the present invention provides benefit of dilution stability. The parenteral solution comprising etoricoxib may provide benefit of less / no irritation at the site of injection after administration. The parenteral solution comprising etoricoxib may provide benefit of less I no adverse systemic reactions after administration.
The term “about” as used herein, refers to encompass ±20%, ±15%, ±10%, or ±5% of the numerical value of the number with which it is being used.
The term "stable" as used herein, refers to any composition comprising a drug having sufficient physical and chemical stability at the time of manufacturing of the composition.
In one embodiment, the present invention provides a parenteral solution comprising a selective COX-2 inhibitor drug and water. The solution is sterile. Examples of suitable selective COX-2 inhibitor drugs may include etoricoxib, celecoxib, valdecoxib, rofecoxib, deracoxib, parecoxib, etc.
In one embodiment, the present invention provides a parenteral solution comprising etoricoxib and one or more pharmaceutically acceptable excipients, for example, stabilizers, solvents/solubilizers, surfactants, isotonicity adjusting agents and optionally, preservatives, antioxidants, buffering agents, pH adjusting agents. In another embodiment, the parenteral solution is free of pH adjusting agents, buffering agents, preservatives, and antioxidants. Examples of suitable stabilizers may include, but not limited to citric acid, tartaric acid, fumaric acid, acetic acid, lactic acid, maleic acid, ascorbic acid, phosphoric acid, methane sulfonic acid, benzene sulfonic acid, or salts thereof, sodium benzoate, sodium bicarbonate, sodium carbonate, sodium citrate, diethanolamine, glycine, hydrochloric acid, hydrogen bromide, monobasic sodium phosphate, dibasic sodium phosphate, lecithin, sodium acetate, polysorbates, for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (polyoxyethylene sorbitan monooleate), or any combination thereof. The citric acid may be present in the form of citric acid monohydrate, anhydrous citric acid, monosodium citrate, disodium citrate, disodium citrate sesquihydrate, glyceryl monocitrate, trisodium citrate, tripotassium citrate, potassium citrate, calcium citrate, dicalcium citrate, tricalcium citrate tetrahydrate, magnesium citrate or triethyl citrate.
The parenteral solution of the present invention may comprise citric acid, wherein the citric acid is present in a concentration from about 10 mg/mL to about 100 mg/mL, for example, about 25 mg/mL, about 50 mg/mL or about 75 mg/mL.
The parenteral solution of the present invention may comprise polysorbate, wherein the polysorbate is present in a concentration from about 30 mg/mL to about 300 mg/mL, for example, about 50 mg/mL, about 75 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 250 mg/mL or about 275 mg/mL.
Examples of suitable solvents/solubilizers may include, but not limited to water, benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, benzyl benzoate, castor oil, cottonseed oil, N, N- dimethyl acetamide, glycerol, N-methyl-2- pyrrolidone, diethanolamine, L-arginine, peanut oil, poppyseed oil, safflower oil, sesame oil, soybean oil, vegetable oil, or any combination thereof.
The parenteral solution of the present invention may comprise benzyl alcohol, wherein the benzyl alcohol is present in a concentration from about 0.05 mL/mL to about 0.20 mL/mL, for example, about 0.09 mL/mL, about 0.10 mL/mL, or about 0.15 mL/mL.
The parenteral solution of the present invention may comprise ethanol (dehydrated alcohol), wherein the ethanol is present in a concentration from about 0.03 mL/mL to about 0.30 mL/mL, for example, about 0.05 mL/mL, about 0.10 mL/mL, about 0.15 mL/mL, about 0.16 mL/mL or about 0.20 mL/mL.
The parenteral solution of the present invention may comprise propylene glycol, wherein the propylene glycol is present in a concentration from about 0.2 mL/mL to about 0.8 mL/mL, for example, about 0.3 mL/mL, about 0.4 mL/mL, about 0.5 mL/mL, about 0.6 mL/mL or about 0.7 mL/mL.
Examples of suitable surfactants may include, but not limited to, poloxamer (poloxamer 188), sodium lauryl sulfate, lauryl dimethyl amine oxide, docusate sodium, cetyl trimethyl ammonium bromide (CTAB), polyvinyl alcohol, polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, polyoxyl lauryl ether, Brij® surfactants (polyoxyethylene vegetable-based fatty ethers derived from lauryl, cetyl, stearyl and oleyl alcohols), bile salts (such as sodium deoxycholate and sodium cholate), polyoxyl castor oil, nonylphenol ethoxylate, lecithin, polyoxyethylene surfactants, phospholipids such as dimyristoylphosphatidyl glycerol (DMPG), disteroylphosphatidylethanolamine (DSPE), 1 ,2-Distearoyl- phosphatidylethanolamine-methyl-polyethyleneglycol conjugate (DSPE- mPEG), monoalkanolamine condensates, polyoxyethylene fatty acid amides, quaternary ammonium salts, polyoxyethylene alkyl and alicyclic amines, polyoxyethylene, sorbitan monolaurate and stearate, Solutol® (ethylene oxide/12-hydroxy stearic acid), tyloxapol, or any combination thereof.
Examples of suitable isotonicity adjusting agents may include, but not limited to, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, glucose, sucrose, dextrose, mannitol, glycerol, or any combination thereof.
Examples of suitable preservatives may include, but not limited to, chlorobutanol, benzalkonium chloride, methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, thiomersal, merthiolate, chlorhexidine, phenylethyl alcohol, quaternary ammonium chloride, sodium benzoate, sodium propionate, or any combination thereof.
Examples of suitable antioxidants may include, but not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, monothioglycerol, ascorbic acid, sodium ascorbate, erythorbic acid, potassium metabisulfite, sodium metabisulfite, propionic acid, sodium formaldehyde sulphoxylate, reduced glutathione, thiourea, cysteine, n- acetylcysteine, methionine, sodium sulfite, sodium bisulfate, alkyl gallate, including propyl gallate, vitamin E, or other tocopherol analogs, including tocopherol acetate or TPGS, or any combination thereof.
Examples of suitable buffering agents may include, but not limited to, acetate (e.g. sodium acetate etc.), phosphate (e.g. monobasic sodium phosphate, dibasic sodium phosphate etc.), carbonate, glycine, borate (boric acid/potassium chloride), tris, tromethamine or any combination thereof.
Examples of suitable pH adjusting agents may include, but not limited to, sodium hydroxide, hydrochloric acid, boric acid, acetic acid, phosphoric acid, succinic acid, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, or any combination thereof. The parenteral solution may comprise one or more pH adjusting agents in an amount to provide pH of the solution from about 3 to about 4.5, for example 3.5 or 4. In an alternate embodiment, the parenteral solution of the present invention comprises of about 90 mg/mL of etoricoxib is free of any pH adjusting agent.
In one embodiment, the present invention provides a parenteral solution comprising about 90 mg/mL of etoricoxib, water and one or more of citric acid, benzyl alcohol, ethanol, polysorbate and propylene glycol, wherein the solution has a pH from about 3 to about 4.5.
In another embodiment, the parenteral solution of the present invention comprises of about 90 mg/mL of etoricoxib, about 50 mg/mL of citric acid, about 0.09 mL/mL of benzyl alcohol, from about 0.10 mL/mL to about 0.16 mL/mL of ethanol, from about 150 mg/mL to about 200 mg/mL of polysorbate, about 0.15 mL/mL of water and propylene glycol, wherein the solution has a pH from about 3 to about 4.5.
In one embodiment, the present invention provides a parenteral solution comprising about etoricoxib and citric acid (anhydrous), wherein weight ratio of etoricoxib to citric acid is 1 :1 or more, for example, 1.1 :1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1 , 1.7:1, 1.8:1, 1.9:1, 2:1 , 2.5:1 , 3:1 , 3.5:1, or 4:1.
As used herein, the term “clear solution” means a solution which does not contain any visible particulate matter, solid particle, liposome or nanoparticles. The clear solution provides % transmittance, when measured at 650 nm, not less than 95%, for example, not less than 96%, not less than 97%, not less than 98%, not less than 99%, not less than 99.5%, not less than 99.6%, not less than 99.7% or not less than 99.8%.
The parenteral solution of the present invention is suitable for administration through parenteral route, for example, intramuscular route (intradeltoid or intragluteal), subcutaneous route or intravenous route.
In one embodiment, the present invention provides a parenteral solution comprising etoricoxib in a concentration from about 15 mg/mL to about 150 mg/mL, for example, about 30 mg/mL, about 60 mg/mL, about 90 mg/mL or about 120 mg/mL. The parenteral solution is suitable for administration through intramuscular or subcutaneous route, wherein solution does not require any dilution step before administration, i.e., it is ready to administer.
In another embodiment, the present invention provides a ready to dilute parenteral solution comprising etoricoxib in a concentration of 90 mg/mL and water, wherein the solution has a pH from about 3 to about 4.5. In another embodiment, the ready to dilute solution provides ready to use parenteral solution upon mixing of ready to dilute solution with one or more suitable aqueous diluent vehicles. The suitable aqueous diluent vehicles may include, but not limited to, 0.9% NaCI solution, 5% dextrose, or any combination thereof. The ready to use etoricoxib parenteral solution may contain etoricoxib in a concentration from about 0.18 mg/mL to about 0.90 mg/mL. The ready to dilute parenteral solution of the present invention may remain as a clear solution (free of any crystals/precipitate) after storage at controlled room temperature for more than 6 months, for example, 12 months, 18 months, or 24 months. The ready to use etoricoxib parenteral solution of the present invention may remain clear (free of any crystals/precipitate) after storage at controlled room temperature for more than 6 hours, for example, 12 hours, 18 hours, or 24 hours. The ready to use etoricoxib parenteral solution is ready for administration (ready to use) through intravenous, subcutaneous or intramuscular route.
The term “controlled room temperature” as used herein, refers to the temperature from 20°C to 25°C.
The parenteral solution of the present invention may retain at least 95 % of the etoricoxib (% assay), as determined by HPLC, after storage for more than 1 month, for example, 3 months, 6 months, 12 months, 18 months, or 24 months, at controlled room temperature.
In another embodiment, the parenteral solution comprising etoricoxib is clear (free of any crystals/precipitates) by visual inspection. The solution may provide the value of absorbance not more than 1 , for example, not more then 0.75, 0.5, 0.4, 0.3, 0.2, 0.1 or 0.05. The solution comprising etoricoxib remains clear after 6 months, 12 months, 18 months, or 24 months of storage at 25°C. The solution may provide the value of APHA (American Public Health Association) color scale of between about 100 units and about 500 units, for example, between about 150 units and about 450 units, between about 200 units and about 450 units, between about 250 unit and about 400 unit, between about 300 unit and about 400 unit, or about 350 units. The solution comprising etoricoxib remains clear and maintains its initial/original color after 6 months, 12 months, 18 months, or 24 months of storage at 25°C. In general, the scale for APHA color goes from 0 to 500 in units of parts per million of platinum cobalt to water.
The term "between" as used herein for the purpose of defining range inclusive of the lower and upper number of the range.
In another embodiment, the parenteral solution comprising etoricoxib may contain total impurities less than 3 %, for example, less than 2 %, less than 1 % or less than 0.5 %, by weight of etoricoxib, as measured by HPLC, after 6 months, 12 months, 18 months, or 24 months of storage at 25°C.
In another embodiment, the parenteral solution comprising etoricoxib has a viscosity value between of about 25 cP (centipoise) and about 35 cP, for example, about 26 cP, about 27 cP, about 28 cP, about 29 cP, about 30 cP, about 31 cP, about 32 cP, about 33 cP, or about 34 cP.
In another embodiment, the parenteral solution comprising etoricoxib may have a pH from about 3 to about 4.5, for example, 3.5 or 4.
In another embodiment, the present invention provides a parenteral solution comprising etoricoxib and water, wherein the solution is only for administration through parenteral route, for example, solution is not for the administration through ophthalmic route, otic route, topical route (application on skin) or oral route. The parenteral solution comprising etoricoxib and water is not an eye drop solution and/or ear drop solution.
The parenteral solution does not contain cyclodextrin derivatives like betacyclodextrin and its derivatives (HPBCD (hydroxypropyl beta cyclodextrin), SBECD (sulfobutylether-|3-cyclodextrin) etc.), gamma-cyclodextrin, transcutol (2-(2-ethoxyethoxy) ethanol), cremophor (polyethoxylated castor oil), glycofurol, isosorbide type solvent etc.
In another embodiment, the present invention provides a process for preparing a parenteral solution comprising etoricoxib, benzyl alcohol, ethanol (dehydrated alcohol), propylene glycol, polysorbate, citric acid and water. The process includes steps of: (a) adding benzyl alcohol into a manufacturing vessel, (b) adding ethanol and partial quantity of propylene glycol into the vessel of step (a), (c) adding etoricoxib into the vessel of step (b) and dissolving with optional heat application, (d) adding polysorbate, citric acid and water into the vessel of step (c), (e) making up the volume to the batch size using remaining quantity of propylene glycol and (f) filtering the solution through 0.22p filter and filling into a suitable container. The etoricoxib parenteral solution of the present invention may be suitable to undergo a sterilization process to provide a sterile etoricoxib parenteral solution. The examples of suitable sterilization process may include, but not limited to, terminal sterilization involving heat exposure, aseptic membrane filtration sterilization, etc.
In another embodiment, the present invention provides a stable parenteral solution comprising etoricoxib, wherein the solution is supplied/provided in a suitable packaging material, for example, in a glass vial, in a glass ampoule, in a pre-filled syringe (PFS), in a glass bottle, in a plastic bottle, in a plastic bag, etc. The pre-filled syringe contains various constituent parts, for example, a sterile USP Type-1 siliconized glass syringe barrel (1 mL, cut flange with a gauge (29 size), hypodermic needle (14 inch) fitted with rigid needle shield and laminated bromobutyl plunger stopper for the barrel.
In another embodiment, the packaging materials like vial, ampoule, or PFS are for single use administration. The vial, ampoule, or PFS contains the solution comprising etoncoxib, wherein the etoncoxib is present in a therapeutically effective dose amount, for example, from about 30 mg to about 120 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 110 mg.
In another embodiment, the present invention provides a pre-filled syringe (PFS) containing parenteral solution comprising etoricoxib, wherein the PFS is suitable for administration of solution through intramuscular route for the treatment of pain or arthritis. The pre-filled syringe contains etoricoxib in a therapeutically effective dose amount of about 90 mg, for single dose administration.
In another embodiment, the present invention provides an auto-injector which contains a pre-filled syringe (a pre-filled syringe assembled/placed in the auto-injector), wherein the pre-filled syringe contains a solution comprising etoricoxib.
In another embodiment, the present invention provides a kit comprising (a) a pre-filled syringe containing a solution comprising etoricoxib and (b) an auto-injector device. The kit is suitable to administer the solution through subcutaneous route.
The autoinjector may be integrated with a needle stick protection feature and holds a pre-filled syringe containing a single dose, whereby the entire deliverable volume is expelled.
The PFS and/or auto-injector provides convenience to the patient or care giver ease of self-administration / administration.
In one embodiment, the present invention provides a method of treating pain (shoulder pain, knee pain, acute injury pain, bone fracture pain, dental pain, chronic back pain, post-operative pain, pain due to muscular spasm or torn ligament, etc.), arthritis, osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis or acute gout comprising administering the parenteral etoricoxib solution of the present invention to a human being in need thereof through parenteral route. The parenteral dose of etoricoxib in a day may range from about 30 mg to about 120 mg, for example, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg or about 110 mg. The treatment of osteoarthritis, rheumatoid arthritis and juvenile rheumatoid arthritis involves relief of the signs and symptoms. The treatment of juvenile rheumatoid arthritis involves relief of the signs and symptoms of pauciarticular or polyarticular course juvenile rheumatoid arthritis in patients 2 years of age and older. The method comprises administration of etoricoxib dose of about 90 mg one time in a day (once daily).
In another embodiment, the present invention provides a method of treating pain comprising administering the parenteral etoricoxib solution of the present invention to a human being in need thereof through intravenous route, for example, intravenous infusion.
The solution comprising etoricoxib of the invention, when administered through parenteral route for the treatment of pain, may provide one or more benefits such as faster onset of pain relief, consistent pain relief, and less or no recurrence of pain during the same day of administration.
The present invention is illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention.
Examples: - Example 1 :
Table 1:
Figure imgf000016_0001
Process:
Batch size: 60 mL
(a) Accurately weighed quantity of benzyl alcohol was added to a manufacturing vessel at controlled room temperature.
(b) Accurately weighed quantity of dehydrated alcohol and 30% of total batch volume of propylene glycol were added into the vessel.
(c) Accurately weighed quantity of etoricoxib was added in the vessel and dissolved at 55°C to 65°C temperature with stirring.
(d) Accurately weighed quantities of polysorbate 80, water for Injection and citric acid were added to the vessel.
(e) Final quantity to the batch size was made up with the remaining quantity of propylene glycol.
(f) The solution of step (e) and was filtered and filled into a glass vial.
Stability data for Example 1
The etoricoxib solution obtained at Example 1 , at step (f), was tested for its physical and chemical parameters, and results are reported in the table below.
Figure imgf000017_0001
NR: Not recorded
The etoricoxib solution obtained at Example 1 , at step (f), was diluted using 0.9% Sodium Chloride Injection, 1 in 250 mL. The diluted solution was a clear colorless solution and has a pH value 3.65. was diluted tested for its physical and chemical parameters, and results are reported in the table below. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

Claims:
1. A parenteral solution comprising etoricoxib in a concentration of about 90 mg/mL and a stabilizer selected from citric acid, tartaric acid, fumaric acid, acetic acid, lactic acid, maleic acid, ascorbic acid, phosphoric acid, methane sulfonic acid, benzene sulfonic acid, or salts thereof.
2. The parenteral solution according to claim 1 , wherein the stabilizer is citric acid.
3. The parenteral solution according to claim 2, wherein weight ratio of etoricoxib to citric acid is 1 :1 or more.
4. The parenteral solution according to claim 1, wherein the solution further comprises ethanol.
5. The parenteral solution according to claim 4, wherein the ethanol is present in a concentration of about 0.16 mL/mL.
6. The parenteral solution according to claim 1, wherein the solution further comprises benzyl alcohol.
7. The parenteral solution according to claim 6, wherein the benzyl alcohol is present in a concentration of about 0.09 mL/mL.
8. The parenteral solution according to claim 1, wherein the solution further comprises polysorbate.
9. The parenteral solution according to claim 8, wherein the polysorbate is present in a concentration of about 150 mg/mL.
10. The parenteral solution according to claim 1, wherein the solution further comprises water.
11. The parenteral solution according to claim 1, wherein the solution further comprises propylene glycol.
12. The parenteral solution according to claim 1, wherein the solution has a pH from about 3 to about 4.5.
13. The parenteral solution according to claim 1, wherein the solution remains clear after 6 months of storage at 25°C. The parenteral solution according to claim 1, wherein the solution contains total impurities less than 1%, by weight of etoricoxib, as measured by HPLC, after 6 months of storage at 25°C. The parenteral solution according to claim 1, wherein the solution is for administration through intramuscular route. A parenteral solution comprising etoricoxib in a concentration of about 90 mg/mL, wherein the solution does not contain transcutol. A method of treating pain or arthritis comprising administering the parenteral solution of claim 1 to a human being in need thereof, wherein the solution is for administration through intramuscular route. The method of treating pain or arthritis according to claim 17, wherein the method comprises administration of 90 mg etoricoxib once daily. A method of treating pain or arthritis comprising administering the parenteral solution of claim 16 to a human being in need thereof, wherein the solution is for administration through intramuscular route. The method of treating pain or arthritis according to claim 19, wherein the method comprises administration of 90 mg etoricoxib once daily.
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