Field of the invention

The present invention relates to stable aqueous parenteral solutions comprising nonsteroidal anti-inflammatory drugs (NSAIDs) and polyvinylpyrrolidone. It also relates to processes for preparing such parenteral solutions. It also relates to a method of treating migraine and various kinds of body pain comprising administering such parenteral solution through a parenteral route.

Background of the invention

Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class used to treat pain and inflammation in rheumatic diseases and osteoarthritis, through oral route (taken by mouth). It is recommended that it be used for as short a period as possible and at a low dose. Common side effects of meloxicam include abdominal pain, dizziness, swelling, headache, and a rash. Metacam ^® (meloxicam) solution for Injection was approved by the USFDA for use in the dogs for the control of pain and inflammation associated with osteoarthritis. Each mL of Metacam ^® product contains meloxicam 5 mg, alcohol 15%, glycofurol 10%, poloxamer 188 5%, sodium chloride 0.6%, glycine 0.5% and meglumine 0.3%, in water for injection, pH adjusted with sodium hydroxide and hydrochloric acid.

Loxicom ^® (meloxicam) solution for Injection was approved by the USFDA for use in the cats for the control of postoperative pain and inflammation associated with orthopedic surgery, ovariohysterectomy and castration when administered prior to surgery. Each mL of Loxicom ^® product contains meloxicam 5 mg, alcohol 15%, glycofurol 10%, poloxamer 188 5%, sodium chloride 0.6%, glycine 0.5% and meglumine 0.3%, in water for injection, pH adjusted with sodium hydroxide and hydrochloric acid. U. S. Publication No. 2010/0137292 A1 (“the US’292 Al”) discloses a solution of meloxicam in combination with meglumine for administration by oral or parenteral route, comprising one or more pharmaceutically acceptable excipients, characterized in that the solution is comprising N,N dimethylacetamide and propylene glycol. It discloses preferred solubilizers as propylene glycol and N,N- dimethylacetamide. It discloses preparation of meloxicam solution using meglumine and co-solvents, viz., N,N dimethyl acetamide and propylene glycol. It also discloses the usage of meglumine and high concentration of co-solvent to prepare the meloxicam solution, wherein the high concentration is more than 20 % w/v. The formulations according to the US’292 Al are suitable for treating animals.

U. S. Publication No. 2003/0119825 Al (“the US’825 Al”) discloses aqueous solution containing meloxicam, meglumine, polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer (poloxamer), ethanol, glycine and disodium EDTA, wherein the content of dissolved meloxicam salt is from 35 to 100 mg/ml. The formulations according to the US’825 Al are suitable for treating animals, particularly domestic pets, working animals or farm animals.

U. S. Publication No. 2014/0336163 Al discloses composition of meloxicam containing hydroxypropyl-P-cyclodextrin, preservative (cresol etc.) and ethanol.

U. S. Publication No. 2005/0288280 Al discloses use of meloxicam in veterinary medicine. It discloses meloxicam solution containing meglumine, macrogol (polyethylene glycol), poloxamer, ethanol and glycine. It also discloses meloxicam oily suspension.

U. S. Publication No. 2005/0245510 Al discloses use of meloxicam formulations in veterinary medicine. It discloses meloxicam solution containing meglumine, glycofurol, poloxamer, ethanol and glycine. It also discloses meloxicam oily suspension. U. S. Publication No. 2013/0178467 A1 discloses highly concentrated stable meloxicam solutions suitable for treating animals, preferably farm animals, and more particularly large farm animals. International (PCT) Publication No. WO 2001/097813 (WO’813) discloses meloxicam solutions. It discloses meloxicam solution having concentration 15 mg/mL or above, containing meglumine, polyethylene glycol, poloxamer, ethanol, glycine and disodium EDTA. The formulation according to WO’813 is suitable for treating animals, farm animals or large farm animals.

International (PCT) Publication No. WO 2008/062274 discloses solution of meloxicam containing ethyl alcohol and 2-Pyrollidone/N-m ethyl 2-Pyrollidone.

International (PCT) Publication No. WO 2019/037757 discloses injectable pharmaceutical compositions comprising meloxicam nanoparticles, a surface stabilizer and a sedimentation inhibitor. The stabilizers disclosed are polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylmethylcellulose, Tween 80, poloxamer, polyethylene glycol stearate, lecithin, sodium deoxycholate, sodium cholate, sodium dodecyl sulfate or sodium lauryl sulfate. The sedimentation inhibitors disclosed are glycerin, propylene glycol, polyethylene glycol, albumin, hydroxyethyl starch, sodium carboxymethyl cellulose or hydroxypropyl-P-cyclodextrin. It also discloses an injectable pharmaceutical composition comprising meloxicam nanoparticles, polyvinylpyrrolidone, sodium deoxycholate, sedimentation inhibitor, and water, wherein the meloxicam nanoparticles have an average particle size of less than 500 nm, preferably less than 200 nm.

SunYing-hua et al.; Journal of Shenyang Pharmaceutical University; 2004-02, discloses utilization of 2-hydroxpropy-P-cyclodextrin as the solubilizer for meloxicam. Chinese Publication No. 1493292 A discloses a liquid preparation of meloxicam prepared from meloxicam or its medical salt and water soluble cyclodextrin derivative HP-beta-CD used as a solubilizer and a stabilizer. ZhaoJun et a/. ; Journal of China Pharmaceutical University, “Study on the solubilization of meloxicam in meglumine aqueous solution”, 2003, Vol. 34, No.

5, abstract, discloses that meloxicam is a hydrophobic drug and difficult to dissolve in aqueous solution. Meglumine can increase the solubility of meloxicam in aqueous solution.

U. S. Patent No. 7,030,162 discloses pharmaceutical compositions containing metoclopramide and one or more Non-Steroidal Anti-Inflammatory Agents (NSAIDs) useful in the treatment of migraine. U. S. Patent No. 10,583,144 discloses compositions comprising an NSAID such as meloxicam and/or rizatriptan in combination with cyclodextrin and/or a carbonate or a bicarbonate. It also discloses that these compositions may be orally administered, for example, to improve the bioavailability or pharmacokinetics of the NSAID for the treatment of pain such as migraine, arthritis, and other conditions.

Currently, there is no USFDA approved therapy available for the treatment of migraine using meloxicam as a sole drug or as an adjunctive therapy with other drug(s). There exists a need for a storage stable parenteral solution comprising meloxicam for administration through subcutaneous, intravenous or intramuscular route which may provide a treatment option for the treatment of migraine and various kinds of body pain.

Summary of the invention

In one general aspect, the present invention provides a stable aqueous parenteral solution comprising a nonsteroidal anti-inflammatory drug, polyvinylpyrrolidone (PVP) and one or more pharmaceutically acceptable excipients. In one general aspect, the present invention provides a stable aqueous parenteral solution comprising meloxicam, polyvinylpyrrolidone and one or more pharmaceutically acceptable excipients.

Embodiments of the aqueous parenteral solution may include one or more of the following features. For example, the pharmaceutically acceptable excipients may include one or more solvents, solubilizers, stabilizers, preservatives, anti-oxidants, surfactants, buffering agents, nucleation inhibitors, pH adjusting agents and isotonicity adjusting agents.

In another general aspect, the present invention provides a process for preparing the parenteral solution comprising meloxicam and polyvinylpyrrolidone.

In another general aspect, the present invention provides a pre-filled syringe (PFS), wherein the PFS contains meloxicam parenteral solution of the present invention in a therapeutically effective dose.

In another general aspect, the present invention provides an auto-injector which contains a PFS (a PFS assembled/placed in an auto-injector), wherein the PFS contains meloxicam parenteral solution of the present invention in a therapeutically effective dose.

In another general aspect, the present invention provides a kit comprising an auto injector and a PFS, wherein the PFS contains meloxicam parenteral solution of the present invention in a therapeutically effective dose.

In another general aspect, the present invention provides a method of treating migraine comprising administering, to a human being in need thereof, the parenteral solution of the present invention.

In another general aspect, the present invention provides a method of treating migraine comprising administering to a human being in need thereof, the parenteral solution of the present invention comprising meloxicam in a therapeutically effective dose to a patient in need thereof through a subcutaneous route. 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 invention have found that when meloxicam is dissolved in water for injection in presence of polyvinylpyrrolidone, a concentrated aqueous parenteral solution of meloxicam having improved solubility and stability can be obtained. The inventors of the invention have also found that when such aqueous parenteral solution of meloxicam is administered through a parenteral route to a patient in need thereof in a therapeutically effective dose, it may treat migraine, arthritis and/or pain.

The term, “therapeutically effective dose”, as used herein, means a quantity of a drug taken at a particular time that is effective in therapy, or sufficient to provide a therapeutic effect.

In one embodiment, present invention provides a stable composition comprising one or more nonsteroidal anti-inflammatory drugs and one or more pharmaceutically acceptable excipients. The stable composition may be an aqueous parenteral solution.

The term “stable”, as used herein for (aqueous) parenteral solution, means such a parenteral solution, when evaluated just after completion of manufacturing of parenteral solution (also known as initial time point T ₀ ), possesses value of all physico-chemical parameters as required by the regulatory authorities within allowable limits (also known as specifications), to render the solution suitable for administering to a human being in need thereof through a parenteral route. Suitable drug for the composition of the invention may have low water solubility or may be water insoluble. Examples of suitable nonsteroidal anti-inflammatory drugs may include one or more of meloxicam, ampiroxicam, piroxicam, tenoxicam, droxicam, lomoxicam, isoxicam, etc.

The term “meloxicam”, as used herein, means meloxicam base, pharmaceutically acceptable salts, hydrate and solvate forms thereof. The salt forms may include, but not limited to, meloxicam sodium, meloxicam potassium, and meloxicam ethanolamine.

In one embodiment, the present invention provides a stable parenteral solution comprising meloxicam, polyvinylpyrrolidone and water.

The aqueous parenteral solution may be in the form of a clear solution comprising meloxicam and polyvinylpyrrolidone.

The term “clear solution”, as used herein, means a solution which does not contain any visible particulate matter, solid particles, liposomes, or nanoparticles. The clear solution provides % transmittance, when measured at 650 nm, not less than 97%, for example, 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%.

In another embodiment, the present invention provides a stable aqueous parenteral solution comprising meloxicam and polyvinylpyrrolidone. Polyvinylpyrrolidone present in the aqueous parenteral solution comprising meloxicam of the present invention is solubilizer, stabilizer and/or nucleation inhibitor. In one embodiment, polyvinylpyrrolidone may be PVP K12, PVP K17, PVP K25, PVP K30, PVP K40, or PVP K90.

In one embodiment, the present invention provides a stable aqueous parenteral solution comprising meloxicam in a concentration of from about 1 mg/mL to about 60 mg/mL, for example, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, or about 55 mg/mL.

The term “about”, as used herein, means in reasonable vicinity of the stated numerical value, for example, plus or minus 10% or 5%.

The stable aqueous parenteral solution may comprise polyvinylpyrrolidone in a concentration of from about 5 mg/mL to about 300 mg/mL, for example, about 10 mg/mL, about 30 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 125 mg/mL, about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, or about 275 mg/mL.

In another embodiment, the stable aqueous parenteral solution may comprise meloxicam in a concentration of about 10 mg/mL, about 15 mg/mL or about 30 mg/mL, wherein the solution does not require any dilution step before administration, and remains clear (free of any crystals) after storage for 24 hours at 2-8°C or after storage for at least 6 months, for example, 12 months, 18 months, or 24 months, at controlled room temperature. The solution is ready to use for administration through intravenous, subcutaneous or intramuscular route.

The term “controlled room temperature”, as used herein, means a temperature of from about 20°C to about 25°C.

In another embodiment, the invention provides a parenteral solution comprising meloxicam, polyvinylpyrrolidone and water, wherein the solution remains clear after storage for 6 months at 25±2°C and 60±5%RH.

In another embodiment, the invention provides a parenteral solution comprising meloxicam, polyvinylpyrrolidone, polysorbate and water, wherein the solution remains clear after storage for 6 months at 25±2°C and 60±5%RH.

In another embodiment, the invention provides a parenteral solution comprising meloxicam, polyvinylpyrrolidone and water, wherein the solution remains clear after storage for at least 6 months, for example, 12 months, 18 months, or 24 months, at 25±2°C and 60±5%RH.

In another embodiment, the present invention provides a stable aqueous parenteral solution comprising meloxicam and polyvinylpyrrolidone. The stable meloxicam aqueous parenteral solution may further comprise one or more pharmaceutically acceptable solvents, solubilizers, stabilizers, preservatives, anti-oxidants, surfactants, buffering agents, nucleation inhibitors, pH adjusting agents and isotonicity adjusting agents.

Examples of suitable solvents may include, but not limited to, water for injection, and the like.

Examples of suitable solubilizers may include, but not limited to benzyl benzoate, N, N- dimethylacetamide, dehydrated ethanol, glycerol, N-methyl-2- pyrrolidone, diethanolamine, L-arginine, or any combination thereof.

Examples of suitable stabilizers may include may include, but not limited to polysorbate 80, aminoethyl sulfonic acid, L-arginine, butylhydroxyanisol, L- cysteine, cysteine hydrochloride, diethanolamine, diethylenetriaminepentaacetic acid, ferric chloride, inositol, D,L-methionine, 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, cetylpyridinium chloride, benzyl bromide, benzyl alcohol, phenylmercury nitrate, phenylmercury acetate, thiomersal, merthiolate, chlorhexidine, phenylethyl alcohol, quaternary ammonium chloride, sodium benzoate, sodium propionate, or any combination thereof. Examples of suitable anti-oxidants may include, but not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, monothioglycerol, ascorbic acid, sodium ascorbate, erythorbic acid, potassium metabi sulfite, 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 surfactants may include, but not limited to, amphoteric, non ionic, cationic or anionic molecules. Suitable surfactants may include, but not limited to, polysorbate 80, poloxamer (e.g., poloxamer 188), sodium lauryl sulfate, lauryl dimethyl amine oxide, docusate sodium, cetyltrimethyl ammonium bromide (CTAB), polyvinyl alcohol, polyethoxylated alcohols, polyoxyethylenesorbitan, octoxynol, polyoxyl lauryl ether, Brij ^® surfactants (e.g., polyoxyethylene vegetable-based fatty ethers derived from lauryl, cetyl, stearyl and oleyl alcohols), bile salts (e.g., sodium deoxycholate and sodium cholate), polyoxyl castor oil, nonylphenolethoxylate, lecithin, polyoxyethylenesurfactants, 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, sorbitanmonolaurate and stearate, Solutol ^® (ethylene oxide/12-hydroxy stearic acid), tyloxapol, or any combination thereof.

The stable aqueous parenteral solution of the present invention may comprise polysorbate 80 in a concentration of from about 1 mg/mL to about 100 mg/mL, for example, about 2 mg/mL, about 5 mg/mL, about 7 mg/mL, about 10 mg/mL, about 20 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, or about 80 mg/mL.

Examples of suitable buffering agents may include, but not limited to, acetate (e.g. sodium acetate etc.), citrate (e.g. citric acid/sodium citrate etc.), phosphate (e.g. monobasic sodium phosphate, dibasic sodium phosphate etc.), carbonate, glycine, borate (boric acid/potassium chloride), or any combination thereof. The stable aqueous parenteral solution of the present invention may comprise glycine in a concentration of from about 1 mg/mL to about 10 mg/mL, for example, about 2 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, or about 8 mg/mL. Examples of suitable nucleation inhibitors may include, but not limited to, crospovidone, hydroxypropylmethyl cellulose (HPMC), poloxamers, polysorbate, phospholipids such as dimyristoylphosphatidyl glycerol (DMPG), disteroylphosphatidylethanolamine (DSPE), 1,2-Distearoyl- phosphatidylethanolamine-methyl -polyethyleneglycol conjugate (DSPE-mPEG), or any combination thereof.

Examples of suitable pH adjusting agents may include, but not limited to, sodium hydroxide, hydrochloric acid, boric acid, citric 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 stable aqueous parenteral solution may comprise one or more pH adjusting agents in an amount to provide pH of the solution from about 8 to about 9, for example, about 8.5.

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.

The stable aqueous parenteral solution of the present invention may comprise sodium chloride in a concentration of, if present, from about 1 mg/mL to about 10 mg/mL, for example, about 3 mg/mL, about 5 mg/mL, or about 7 mg/mL. In one embodiment, the parenteral meloxicam solution of the present invention may not require any isotonicity adjusting agent.

In another embodiment, the stable parenteral solution may comprise about 10 mg/mL of meloxicam, about 45 mg/mL of polyvinylpyrrolidone, about 15 mg/mL of polysorbate 80, one or more pH adjusting agents, for example, sodium hydroxide (NaOH) and/or hydrochloric acid (HC1) in a quantity sufficient to adjust pH of the solution about 8.5 and quantity sufficient water.

In another embodiment, the stable parenteral solution may comprise about 10 mg/mL of meloxicam, about 100 mg/mL of polyvinylpyrrolidone, one or more pH adjusting agents, for example, NaOH and/or HC1 in a quantity sufficient to adjust pH of the solution about 8.5 and quantity sufficient water.

In another embodiment, the stable parenteral solution may comprise about 15 mg/mL of meloxicam, about 150 mg/mL of polyvinylpyrrolidone, about 20 mg/mL of polysorbate 80, about 5 mg/mL of monothioglycerol, one or more pH adjusting agents, for example, NaOH and/or HC1 in a quantity sufficient to adjust pH of the solution about 8.5 and quantity sufficient water.

In another embodiment, the stable parenteral solution may comprise about 15 mg/mL of meloxicam, about 200 mg/mL of polyvinylpyrrolidone, one or more pH adjusting agents, for example, NaOH and/or HC1 in a quantity sufficient to adjust pH of the solution about 8.5 and quantity sufficient water.

In one embodiment, the stable meloxicam aqueous parenteral solution of the present invention has improved meloxicam solubility and improved physico chemical stability compared to the meloxicam parenteral solution compositions disclosed in the prior arts.

The term “storage stable”, as used herein for (aqueous) parenteral solution, means parenteral solution which remains stable after storage for at least 6 months, for example, 12 months, 18 months or 24 months, at desired storage conditions, for example, at controlled room temperature or at 2-8°C. The storage stable aqueous parenteral solution may be administered through parenteral routes, to a human being in need thereof, for example, through intramuscular routes (e.g. intradeltoid or intragluteal), subcutaneous route, or intravenous route (as infusion or as bolus). The aqueous parenteral solution of the present invention, after such administration through any of the parenteral routes, may provide minimal or no injection site reactions including pain, tenderness erythema/redness, and induration/swelling.

In one embodiment, the present invention provides a storage stable aqueous parenteral solution comprising meloxicam and one or more pharmaceutically acceptable excipients, wherein the solution retains at least 95% of the meloxicam (% assay as measured by HPLC).

The storage stable aqueous parenteral solution may retain at least 95% of the meloxicam (% assay as measured by HPLC) after storage for at least 1 month, for example, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months at controlled room temperature (CRT).

The storage stable aqueous parenteral solution may retain at least 95% of the meloxicam (% assay as measured by HPLC) after storage for at least 1 month, for example, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months at 25°C temperature and 60% relative humidity (%RH).

The storage stable aqueous parenteral solution may retain at least 95% of the meloxicam (% assay as measured by HPLC) after storage for at least 1 month, for example, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months at 40°C temperature and 75%RH.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam is clear (free of any crystals) by visual inspection. The solution may provide the value of % transmittance not less than 90%, for example, not less than 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. In another embodiment, the stable aqueous parenteral solution comprising meloxicam does not contain 4-Hydroxy-2-methyl-2H-l ,2- benzothiazine-3- carboxylic acid ethyl ester 1, 1 -dioxide (Impurity A) more than 0.5%, for example, 0.3%, 0.4%, 0.2%, 0.1%, or 0.05%, by weight of meloxicam, as measured by HPLC.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam does not contain 2-Amino-5-methyl-thiazole (Impurity B) more than 0.5%, for example, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05%, by weight of meloxicam, after storage for 6 months at 25±2°C and 60±5%RH, as measured by HPLC.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam does not contain N-(3,5-dimethylthiazol-2(3H)-ylidene)-4-hydroxy-2- m ethyl -2H-benzo[e][l,2]thiazine-3 -carboxamide 1,1 -dioxide (Impurity E) more than 0.5%, for example, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05%, by weight of meloxicam, as measured by HPLC.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam does not contain N-(3-Ethyl-5-methylthiazol-2(3H)-ylidene)-4- hydroxy-2-methyl-2H-benzo[e][l,2]thiazine-3 -carboxamide 1,1 -dioxide (Ethyl meloxicam impurity) more than 0.5%, for example, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05%, by weight of meloxicam, as measured by HPLC.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam does not contain Methyl4-hydroxy-2-methyl-2H- l,2-benzothiazine-3- carboxylate 1, 1-Dioxide (Impurity-D) more than 0.5%, for example, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05%, by weight of meloxicam, as measured by HPLC.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam does not contain 5-N-methylthiazol-2-yl oxalic acid impurity more than 0.5%, for example, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05%, by weight of meloxicam, as measured by HPLC. In another embodiment, the stable aqueous injectable solution comprising meloxicam does not contain 2-(diazenylsulfonyl)-N-methylaniline oxide (Meloxicam diazenylsulfonyl) Impurity more than 0.5%, for example, 0.4%, 0.3%, 0.2%, 0.1% or 0.05%, by weight of meloxicam, after storage for 6 months at 25±2°C and 60±5%RH, as measured by HPLC.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam does not contain total impurities more than 3%, for example, 2%, 1%, 0.5%, or 0.2%, by weight of meloxicam, after storage for 6 months at 25±2°C and 60±5%RH, as measured by HPLC.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam may have a viscosity value of from about 1 cP to about 5 cP, for example, 1.5 cP, 2 cP, 2.5 cP, 3 cP, 3.5 cP, 4 cP, or 4.5 cP.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam may have an osmolality value of from about 200 mOsm/kg to about 600 mOsm/kg, for example, about 250 mOsm/kg, about 300 mOsm/kg, about 350 mOsm/kg, about 400 mOsm/kg, about 450 mOsm/kg, about 500 mOsm/kg, or about 550 mOsm/kg.

In another embodiment, the stable aqueous parenteral solution comprising meloxicam has a pH of from about 7 to about 10, for example, about 7.5, about 8, about 8.5, about 9, or about 9.5.

In another embodiment, the present invention provides a stable parenteral solution comprising meloxicam and water, wherein the solution does not contain any co solvent, for example, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethyl acetamide, benzyl alcohol, N-methyl pyrrolidone, or glycerol formal, ethanol, transcutol, glycerol, cremophor (polyethoxylated castor oil), glycofurol, propylene glycol, or polyethylene glycol.

In one embodiment, the present invention provides a stable parenteral solution comprising meloxicam, polyvinylpyrrolidone, polysorbate 80 and water, wherein the solution is substantially free of co-solvent(s), for example, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethyl acetamide, benzyl alcohol, N-methyl pyrrolidone or glycerol formal, ethanol, transcutol, glycerol, cremophor (polyethoxylated castor oil), glycofurol, propylene glycol orolyethylene glycol. The term “substantially free of’ as used herein, unless and otherwise specifically mentioned, means total amount of co-solvent(s) (organic and/or inorganic), if present in the solution, is less than 5 % v/v of the solution, for example, less than 3 % v/v, less than 1 % v/v, or less than 0.5 % v/v of the solution. The solution may be free of any co-solvent.

In another embodiment, the present invention provides a stable parenteral solution comprising meloxicam and water, wherein meloxicam may be the only active ingredient present in the solution.

In another embodiment, the present invention provides a stable parenteral solution comprising meloxicam and water, wherein the solution does not contain rizatriptan or metoclopramide.

In another embodiment, the stable aqueous parenteral solution does not contain any local anesthetic, for example, lidocaine, prilocaine, tetracaine, bupivacaine, mepivacaine and/or xylocaine.

In another embodiment, the present invention provides a stable parenteral solution comprising meloxicam and water, wherein the solution is not for any other route of administration except for the parenteral route of administration, for example, solution is not for the administration through ophthalmic route, otic route, topical route (application on skin) or oral route. The stable parenteral solution comprising meloxicam and water is not an eye drop solution and/or ear drop solution.

The stable aqueous parenteral solution of the present invention does not contain any toxic and/or irritant ingredient, for example, any cyclodextrin derivative like beta-cyclodextrin and its derivatives (HRbOϋ (hydroxypropyl beta cyclodextrin), SBECD (sulfobutylether-P-cyclodextrin) etc.), transcutol, cremophor (polyethoxylated castor oil), glycofurol, propylene glycol and/or polyethylene glycol. The stable aqueous parenteral solution of the present invention does not contain meglumine.

In another embodiment, the present invention provides a parenteral solution comprising meloxicam, polyvinylpyrrolidone and water, wherein the solution does not contain any cyclodextrin derivative or meglumine. In one embodiment, the present invention provides stable aqueous parenteral solution comprising meloxicam and polyvinylpyrrolidone, wherein the solution is not for the preparation of solid dispersion for oral administration.

In one embodiment, the physical and chemical stability (physico-chemical stability) of the parenteral solution of the present invention was studied at 25°C temperature and 60% relative humidity (%RH) as well as at 40°C temperature and 75%RH.

In another embodiment, the present invention provides a process for preparing a stable parenteral solution comprising meloxicam, polyvinylpyrrolidone, polysorbate 80 and water. The process includes steps: (a) adding polyvinylpyrrolidone and polysorbate 80 into water to form a clear solution, (b) adding meloxicam into the solution prepared in step (a), and (c) adding pH adjusting agent like NaOH/HCl to have a pH of the solution of from about 8 to about 9. Additionally, the process may include adding an appropriate amount of NaCl at the step (a). The prepared solution may be subjected to a terminal sterilization process. The stable meloxicam parenteral solution of the present invention may be suitable to undergo a sterilization process to provide a sterile meloxicam parenteral solution.

In one embodiment, the stable meloxicam aqueous parenteral solution of the present invention is supplied / provided in a suitable packaging material, for example, in a glass vial, in a glass ampoule, in a glass bottle, in a plastic bottle, in a PFS, in an auto-injector which contains a PFS or in a kit comprising a PFS and an auto-injector.

In one embodiment, the present invention provides a PFS containing a stable meloxicam aqueous parenteral solution of the present invention, wherein the PFS may contain various constituent parts, for example, a sterile clear glass syringe barrel, a hypodermic needle fitted with rigid needle shield and a laminated bromobutyl plunger stopper. In one embodiment, the present invention provides a pre-filled syringe (PFS) containing a stable meloxicam aqueous parenteral solution of the present invention, wherein the stable meloxicam aqueous parenteral solution may comprise, from about 7.5 mg to about 60 mg of meloxicam, from about 30 mg to about 300 mg of polyvinylpyrrolidone, from about 7.5 mg to about 60 mg of polysorbate 80, one or more pH adjusting agents in an amount sufficient to provide pH of the solution from about 8 to about 9 and water.

In another embodiment, the present invention provides an auto-injector which contains a PFS (a PFS assembled/placed in the auto-injector), wherein the PFS contains a stable meloxicam aqueous parenteral solution of the present invention. The auto-injector may provide convenience to the patient for self-administration.

In another embodiment, the present invention provides a kit comprising (a) a PFS containing a stable meloxicam aqueous parenteral solution of the present invention and (b) an auto-injector device.

In another embodiment, the present invention provides a single-dose PFS containing a stable meloxicam aqueous parenteral solution of the present invention with an auto-injector, wherein the PFS with an auto-injector is suitable to administer the therapeutically effective dose of meloxicam through a subcutaneous route. The single dose PFS may comprise the dose of meloxicam from about 7.5 mg to about 60 mg, for example, 10 mg, 15 mg, 30 mg, 40 mg, 45 mg, or 50 mg. In another embodiment, the present invention provides a single-dose vial or ampoule containing a stable meloxicam aqueous parenteral solution of the present invention, wherein the content of vial or ampoule is suitable to administer the therapeutically effective dose of meloxicam through an intravenous route. The single dose vial or ampoule may comprise the dose of meloxicam from about 7.5 mg to about 60 mg, for example, 10 mg, 15 mg, 30 mg, 40 mg, 45 mg, or 50 mg.

The auto-injector 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.

In another embodiment, the present invention provides a single-dose pre-filled syringe with an auto-injector, wherein the pre-filled syringe contains solution comprising meloxicam, polyvinylpyrrolidone and water, wherein the pre-filled syringe with an auto-injector is suitable to administer the therapeutically effective dose of meloxicam through a subcutaneous route for the acute treatment of pain.

In another embodiment, the present invention provides a single-dose pre-filled syringe with an auto-injector, wherein the pre-filled syringe contains solution comprising meloxicam, polyvinylpyrrolidone and water, wherein the pre-filled syringe with an auto-injector is suitable to administer the therapeutically effective dose of meloxicam through a subcutaneous route for the treatment of migraine.

In another embodiment, the present invention provides a method of treating migraine, acute pain, osteoarthritis, rheumatoid arthritis and juvenile rheumatoid arthritis pauciarticular and polyarticular course comprising administering, to a human being in need thereof, the parenteral meloxicam solution of the present invention through a parenteral route. The parenteral dose of meloxicam may range from about 7.5 mg to about 60 mg, for example, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 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 recommended dose of meloxicam is 30 mg once daily, administered as intravenous bolus injection over 15 seconds. The bolus injection administration time may range between about 5 seconds and about 60 seconds.

In another embodiment, the recommended dose of meloxicam is 30 mg once every alternate day, administered as intravenous bolus injection over 15 seconds.

The recommended dose of meloxicam is 30 mg once daily, administered as subcutaneous injection. The recommended dose may range between about 7.5 mg and about 60 mg.

In another embodiment, the recommended dose of meloxicam is 30 mg once every alternate day, administered as subcutaneous injection.

In one embodiment, the present invention provides a method of treating migraine comprising administering, to a human being in need thereof, a composition comprising meloxicam. The method may use meloxicam as a sole drug for treating migraine. The method may not use meloxicam in combination rizatriptan for treating migraine.

In another embodiment, the present invention provides a method of treating migraine comprising administering, to a human being in need thereof, a solution comprising meloxicam. The method may use meloxicam as a sole drug for treating migraine.

In another embodiment, the present invention provides a method of treating acute pain comprising administering, to a human being in need thereof, the parenteral meloxicam solution of the present invention through an intravenous route, for example, as intravenous bolus injection. In another embodiment, the present invention provides a method of treating migraine, osteoarthritis, rheumatoid arthritis and juvenile rheumatoid arthritis comprising administering, to a human being in need thereof, the parenteral meloxicam solution of the present invention through a subcutaneous route.

In another embodiment, the present invention may provide a method of treating various types of migraine and various types of primary headache and secondary headache comprising administering, to a human being in need thereof, the parenteral meloxicam solution of the present invention through a subcutaneous route. The types of migraine may include, but not limited to, acute migraine, chronic migraine, migraine without aura (common migraine) and migraine with aura (classic migraine). The types of primary headache may include, but not limited to, cluster headache, migraine headache, tension-type headache and trigeminal autonomic cephalalgias. The types of secondary headache may include, but not limited to, headache attributed to trauma or injury to the head and/or neck, headache attributed to cranial and/or cervical vascular disorder, headache attributed to non-vascular intracranial disorder, headache attributed to a substance or its withdrawal, headache attributed to infection, headache attributed to disorder of homoeostasis, headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structure and headache attributed to psychiatric disorder.

The solution comprising therapeutically effective dose of meloxicam of the invention may provide value of T _max less than 5 hours, for example, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, less than 20 minutes, less than 10 minutes, less than 5 minutes, less than 3 minutes, or less than 1 minute, when the solution is administered through a subcutaneous route, to a human being in need thereof, at a meloxicam dose from about 7.5 mg to about 60 mg. The solution comprising therapeutically effective dose of meloxicam of the invention provides immediate availability of the entire dose of meloxicam in the blood when the solution is administered through an intravenous route, to a human being in need thereof. The solution comprising therapeutically effective dose of meloxicam of the invention may provide value of T _max less than 5 hours, for example, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, less than 20 minutes, less than 10 minutes, less than 5 minutes, less than 3 minutes, or less than 1 minute, when the solution is administered through an intramuscular route, to a human being in need thereof, at a meloxicam dose from about 7.5 mg to about 60 mg.

The solution comprising therapeutically effective dose of meloxicam, when administered through a subcutaneous route, to a human being in need thereof, at a meloxicam dose from about 7.5 mg to about 60 mg, for example 30 mg, provides minimum effective concentration of meloxicam in less than 1 hour, for example, less than 30 minutes, less than 15 minutes, less than 10 minutes, less than 5 minutes, less than 2 minutes, or less than 1 minute. The term “minimum effective concentration of meloxicam” as used herein means a concentration of meloxicam in plasma that is required to produce the desired pharmacologic response (for example: at least 1250 ng/mL).

The term “T _max ”, as used herein, unless and otherwise specifically mentioned, means time to achieve maximum concentration of the drug in plasma, achieved after administration of the product (unit for example: minutes).

The solution comprising meloxicam of the invention may provide value of C _max more than 400 ng/mL, for example, more than 500 ng/mL, more than 1000 ng/mL, more than 2500 ng/mL, more than 5000 ng/mL, more than 7500 ng/mL, more than 10,000 ng/mL, or more than 12,000 ng/mL, when the solution is administered through a subcutaneous route, to a human being in need thereof, at a meloxicam dose of from about 7.5 mg to about 60 mg, as measured by LCMS/MS (Liquid Chromatography coupled to tandem Mass Spectrometry / Mass Spectrometry).

The solution comprising meloxicam of the invention may provide value of C _max more than 1000 ng/mL, for example, more than 2500 ng/mL, more than 5000 ng/mL, more than 7500 ng/mL, more than 10,000 ng/mL, more than 12,000 ng/mL, more than 14,000 ng/mL, more than 16,000 ng/mL, or more than 18,000 ng/mL, when the solution is administered through an intravenous route, to a human being in need thereof, at a meloxicam dose of from about 7.5 mg to about 60 mg, as measured by LCMS/MS (Liquid Chromatography coupled to tandem

Mass Spectrometry / Mass Spectrometry).

The term “C _max ”, as used herein, unless and otherwise specifically mentioned, means maximum concentration of drug in plasma, achieved after administration of the product (unit for example: ng/mL).

The solution comprising meloxicam of the invention may provide value of AUC average more than 5,000 ng*h/mL (nanogram*hour/milliliter), more than 7,500 ng*h/mL, more than 10,000 ng*h/mL, more than 50,000 ng*h/mL, more than 1,00,000 ng*h/mL, more than 2,00,000 ng*h/mL, more than 2,50,000 ng*h/mL, or more than 3,00,000 ng*h/mL, when the solution is administered through a subcutaneous route, to a human being in need thereof, at a meloxicam of dose from about 7.5 mg to about 60 mg, as measured by LCMS/MS (Liquid Chromatography coupled to tandem Mass Spectrometry / Mass Spectrometry).

The solution comprising meloxicam of the invention may provide value of AUC _average more than 5,000 ng*h/mL, more than 7,500 ng*h/mL, more than 10,000 ng*h/mL, more than 50,000 ng*h/mL, more than 1,00,000 ng*h/mL, more than 2,00,000 ng*h/mL, more than 2,50,000 ng*h/mL, or more than 3,00,000 ng*h/mL, when the solution is administered through an intravenous route, to a human being in need thereof, at a meloxicam of dose from about 7.5 mg to about 60 mg, as measured by LCMS/MS (Liquid Chromatography coupled to tandem Mass Spectrometry / Mass Spectrometry). The term “AUC”, as used herein, unless and otherwise specifically mentioned, means area under the curve for a plot of concentration of drug in plasma vs. time (unit for example: ng*h/mL). The solution comprising of meloxicam, when administered through a subcutaneous route for the treatment of migraine, may provide one or more benefits from faster onset of pain relief, consistent pain relief, and less or no recurrence of pain during the same day of administration.

The solution comprising a therapeutically effective dose of meloxicam, when administered through a subcutaneous route for the treatment of migraine, to a human being in need thereof, may provide a state having no headache pain at 2 hours after dose administration. The administration may also demonstrate effect on the most bothersome migraine-associated symptoms, viz., nausea, photophobia, phonophobia, at 2 hours after dose.

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:

Examples 1 - 3:-

Table 1: Process for Example 1:

1. Water for injection was kept under nitrogen sparging until dissolved oxygen less than 2 mg/L.

2. Accurately weighed polyvinylpyrrolidone K12, polysorbate 80, sodium chloride and glycine was added into 80 mL of water for injection, stirred and dissolved completely at controlled room temperature.

3. Meloxicam was added to the above prepared solution with moderate stirring at controlled room temperature.

4. Then pH of the solution was adjusted to 8.5 using 5% w/v NaOH and/or IN HC1 and the volume was made up to 100 mL using water for injection.

5. The solution was filtered through a 0.22m filter and filled into a glass vial.

Process for Examples 2-3:

1. Water for injection was kept under nitrogen sparging until dissolved oxygen less than 2 mg/L.

2. Accurately weighed polyvinylpyrrolidone K12, polysorbate 80, monothioglycerol and glycine was added into 80 mL of water for injection, stirred and dissolved completely at controlled room temperature.

3. Meloxicam was added to the above prepared solution with moderate stirring at controlled room temperature.

4. Then pH of the solution was adjusted to 8.5 using 5% w/v NaOH and/or IN HC1 and the volume was made up to 100 mL using water for injection.

5. The solution was filtered through a 0.22m filter and filled into a glass vial.

Stability data for Example 1

The meloxicam solution obtained at Example 1 was tested for its physical and chemical stability, at initial time point as well as after twelve months stability testing for 25±2°C, 60 ± 5%RH and six months stability testing for 40±2°C, 75 ± 5%RH, and results are reported in Table 2 below. Table 2:

Stability data for Example 2 The meloxicam solution obtained at Example 2 was tested for its physical and chemical stability, at initial time point as well as after six months stability testing, and results are reported in Table 3 below.

Table 3: Stability data for Example 3

The meloxicam solution obtained at Example 3 was tested for its physical and chemical stability, at initial time point, and six months results are reported in Table 4 below.

Table 4:

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.