STABLE PARENTERAL DOSAGE FORM OF PYRAZOLONE DERIVATIVE

Abstract

Edaravone, in the United States, is approved in the form of ready-to-use intravenous solution for infusion, RADICAVA. RADICAVA injection is supplied in a polypropylene bag overwrapped with polyvinyl alcohol (PVA) secondary packaging. Edaravone is susceptible to oxidation and the overwrapped package also contains an oxygen absorber and oxygen indicator to minimize oxidation. Various efforts have been put in the art for packaging edaravone drug solution in different types of packaging materials, for example, plastic containers and glass bottles to prevent edaravone from oxidation and other degradation. The present invention involves use of simple and economic container-closure system for packaging edaravone drug solution while maintaining its stability during storage, transportation and use which includes glass bottles or vials and closures made of elastic polymer or rubber (for example elastomer, isoprene rubber or butyl rubber and the like).

Claims

1. A bottle or vial filled with a parenteral dosage form of edaravone in the form of an intravenous solution for infusion or drip comprising edaravone or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof, the bottle or vial, closed with a lid or cap or stopper, wherein the lid or cap or stopper is not coated with an anti-adhesive coating.

2. The bottle or vial filled with a parenteral dosage form of edaravone as claimed in claim 1, wherein the bottle or vial is made of borosilicate glass.

3. The bottle or vial filled with a parenteral dosage form of edaravone as claimed in claim 1, wherein the lid or cap or stopper is made of a material based on an elastic polymer or rubber.

4. The bottle or vial filled with a parenteral dosage form of edaravone as claimed in claim 3, wherein the rubber is natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, or chloroprene rubber and the like.

5. The bottle or vial filled with a parenteral dosage form of edaravone as claimed in claim 1, wherein said parenteral dosage form is stable at 25° C. at least for 6 months or more or 12 months or more.

6. A method for obtaining a parenteral dosage form of edaravone in the form of an intravenous solution for infusion or drip, said method comprises: (a) preparing a solution comprising edaravone or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof; (b) packaging the edaravone dosage form in a glass bottle or vial, that is optionally pre-sterilized, with a lid or cap or stopper covered on said glass bottle or vial, wherein said lid or cap or stopper is without an anti-adhesive coating; and (c) closing the bottle or vial with a lid or cap or stopper covered on said bottle or vial and optionally sterilizing said bottle or vial containing said edaravone solution.

7. The method for obtaining a parenteral dosage form of edaravone as claimed in claim 6, wherein the glass bottle or vial is made of borosilicate glass.

8. The method for obtaining a parenteral dosage form of edaravone as claimed in claim 6, wherein the lid or cap or stopper is made of rubber selected from natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, or chloroprene rubber and the like.

9. A packaging method for a parenteral dosage form of edaravone in the form of an intravenous solution for infusion or drip, said method comprises: (a) optionally sterilization of a glass bottle or vial with a lid or cap or stopper over it; (b) filling a solution comprising edaravone or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof into said optionally pre-sterilized glass bottle or vial; (c) closing (sealing) the bottle or vial containing edaravone solution with a lid or cap or stopper covered on it; and (d) optionally sterilizing the closed bottle or vial, wherein said lid or cap or stopper is not coated with an anti-adhesive coating.

10. The packaging method for a parenteral dosage form of edaravone as claimed in claim 9, wherein the glass bottle or vial is made of borosilicate glass and the lid or cap or stopper is made of rubber selected from natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, or chloroprene rubber and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0026] The invention relates to the field of pharmaceutical formulation technology, in particular to a method for producing a drug product comprising a pyrazolone derivative 3-methyl-1-phenyl-2-pyrazoline-5-one, i.e. edaravone. The drug product of the present invention is stable during storage (stability and/or shelf life), transportation and use.

[0027] Edaravone has the ability to scavenge free radicals and this is why it is used as a scavenger of free radicals in cerebral infarction. Edaravone is administered by intravenous infusion or drip.

[0028] However, there is a significant problem when using edaravone, in particular, its instability in solution, adhesion of the molecules of the drug substance on the surface of the bottle cap. In addition, when using packaging with insufficient tightness, the concentration of edaravone in the solution increases due to the evaporation of the liquid.

[0029] In the prior art, the abovementioned problem has been tried to overcome by packing edaravone drug solution in glass ampoules to ensure hermetic storage of a solution with a constant concentration.

[0030] In order to get rid of residual oxygen in the space above the edaravone solution and to ensure the stability of the drug, nitrogen is added before sealing the ampoules with edaravone solution.

[0031] However, ampoule packaging has also numbers of disadvantages, including a small-fixed volume of the drug, which does not allow the solution to be used continuously in the required volume (for example, when the drug is used in infusion or drip). There is also a risk of small glass particles getting into the infusion solution when opening the ampoule. If proper precaution and care is not taken the opener or the health care professional opening the ampoule may also get injured.

[0032] An attempt has therefore been also made to solve above problem existing in the prior art by replacing the glass ampoule with a plastic container. However, such packaging usually has a complex structure. The plastic container is formed by an outer polypropylene layer, an intermediate polypropylene layer and an inner cyclic polyolefin layer.

[0033] A bottle, bag, or syringe pre-filled with the edaravone solution is also used. These packages are at least partially made of plastic, in particular of a cyclic polyolefin resin. A rubber stopper made of elastomer, isoprene rubber or butyl rubber is provided in the said plastic container, and the surface that contacts the edaravone solution is coated with a fluorine or parylene resin having anti-adhesive properties.

[0034] However, when using plastic, the problem of the tightness arises, namely, oxygen from the air enters into the edaravone solution. Due to the high affinity, when edaravone combines with atmospheric oxygen, the properties of the drug change. In order to overcome this problem, antioxidants and double packaging are used to stabilize the edaravone in the solution, which complicates the process of obtaining a stable finished dosage form. So, the container is made of polypropylene, polyethylene or other flexible plastic; it has a rubber stopper made of elastomer coated with a fluorine-based coating. The container is packaged in another container that has a reduced oxygen permeability and is made of a film based on alumina or silica or other similar material.

[0035] Although this package provides stability to the drug into the solution, it is not convenient for use, because after opening or damaging the seal of the outer container, it loses its protective property. In addition, such packaging does not provide containers of different sizes (volumes), which can lead to irrational use of the drug.

[0036] From the prior art documents, edaravone or its pharmaceutically acceptable salt in liquid form which is ready-to-use packaged in different packaging materials is known. Packaging in the form of ampoules is hermetically sealed, however, the disadvantage of this form of preparation is the impossibility of multiple use of one ampoule and the high probability of glass particles getting into the infusion solution. Also, the drug is produced in large volume plastic packaging, which, however, is not tight enough and, as a result, allows oxygen to pass from the environment, which negatively affects the quality of the drug.

[0037] A multilayer plastic container performs its function of ensuring the stability of the drug during storage and transportation only until it is opened. After opening the container, the drug must be used immediately, since the tightness is broken and the degradation of edaravone starts occurring. As a result, the drug increases the permissible level of impurities/degradants that can cause undesirable side effects and/or less therapeutic effect when used in patients. In addition, this form of packaging is complex both for the production of the drug itself (the plastic must withstand double high heat treatment with the drug), and for the production of packaging as such (a double container is made of a triple layer of plastic).

[0038] Thus, there is a problem of obtaining the edaravone in the solution packaged in such a package which would allow maintaining its stability during storage, transportation, and use.

[0039] Accordingly, the object of the present invention is to provide a ready-to-use, stable (during storage-stability/shelf life), easy and convenient to transport and use edaravone parenteral dosage form. The edaravone finished dosage form according to the present invention is in the form of intravenous solution for infusion or drip.

[0040] Accordingly, the present invention provides a method for obtaining a parenteral dosage form of edaravone in the form of intravenous solution for infusion or drip, that is stable during storage, transportation and convenient in use. The method comprises: [0041] (a) preparing a solution containing edaravone or its pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof; [0042] (b) packaging the edaravone dosage form in a glass bottle or vial, preferably pre-sterilized, with a lid covered on said glass bottle or vial, wherein said lid is without an anti-adhesive coating; and [0043] (c) closing the bottle or vial with a lid covered on said bottle or vial and sterilizing said bottle or vial containing edaravone solution.

[0044] In an alternative embodiment, the present invention provides a method for obtaining a parenteral dosage form of edaravone in the form of intravenous solution for infusion or drip. The method comprises: [0045] (a) preparing a solution containing edaravone or its pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof; [0046] (b) packaging the edaravone dosage form in a glass bottle or vial, that is optionally pre-sterilized, with a lid covered on said glass bottle or vial, wherein said lid is without an anti-adhesive coating; and [0047] (c) closing the bottle or vial with a lid covered on said bottle or vial and optionally sterilizing said bottle or vial containing edaravone solution.

[0048] In the above method, the glass bottle or vial is made of borosilicate glass and the lid or cap or stopper is made of an elastic polymer or rubber (which, for example, without limitation include natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, chloroprene rubber and the like) which is uncoated, i.e. without anti-adhesive coating.

[0049] The present invention also provides a packaging method for a parenteral dosage form of edaravone in the form of intravenous solution for infusion or drip, that is stable during storage, transportation and convenient in use. The method comprises: [0050] (a) sterilization of a glass bottle or vial with a lid or cap over it; [0051] (b) filling a solution containing edaravone or its pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof into said pre-sterilized glass bottle or vial; [0052] (c) closing (sealing) the bottle or vial containing edaravone solution with a lid or cap covered on it; and [0053] (d) sterilizing the closed bottle or vial.

[0054] In an alternative embodiment, the present invention provides a packaging method for a parenteral dosage form of edaravone in the form of intravenous solution for infusion or drip. The method comprises: [0055] (a) optionally sterilization of a glass bottle or vial with a lid or cap over it; [0056] (b) filling a solution containing edaravone or its pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof into said optionally pre-sterilized glass bottle or vial; [0057] (c) closing (sealing) the bottle or vial containing edaravone solution with a lid or cap covered on it; and [0058] (d) optionally sterilizing the closed bottle or vial.

[0059] In the above method, the glass bottle or vial is made of borosilicate glass and the lid or cap or stopper is made of an elastic polymer or rubber (which, for example, without limitation include natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, chloroprene rubber and the like) which is uncoated, i.e. without anti-adhesive coating.

[0060] The present invention further provides a bottle or vial filled with a parenteral dosage form of edaravone in the form of intravenous solution for infusion or drip, containing edaravone or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable excipient selected from an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof, the bottle or vial made of glass, closed with a lid or cap or stopper made of a material based on an elastic polymer, rubber (which, for example, without limitation include natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, chloroprene rubber and the like) the lid or cap is not coated with an anti-adhesive coating.

[0061] According to the present invention, the bottle or vial is made of borosilicate glass, the lid or cap or stopper is made of a derivative of rubber or thermoplastic polymer and on the inside or is completely uncoated with a release coating known in the art. When packing, an aluminum cap may also be used, which crimps the bottle cap in order to seal the container with the solution containing edaravone.

A Pharmaceutically Acceptable Excipient:

[0062] The edaravone formulation as described in the present invention comprises a pharmaceutically acceptable excipient, which comprises an antioxidant, a stabilizer, a pH adjusting agent, a tonicity modifying agent, a vehicle and a combination thereof. Non-limiting embodiments on the pharmaceutically acceptable excipients which may be used in the present invention are described below.

[0063] Antioxidants can be compounds that can reduce a drug that has been oxidized, or compounds that are more readily oxidized than the agents they are to protect (oxygen scavengers). Mixtures of chelating agents and antioxidants are often used because there appears to be a synergistic effect. This occurs because many of the agents act at differing steps in the oxidative process. The antioxidants when used in the compositions of the present invention include, but are not limited to, butylated hydroxytoluene, butylated hydroxyanisole, tert-butyl-hydroquinone, 4-hydroxymethyl-2, 6-di-tert-butylphenol, 2, 4, 5-trihydroxybutyrophenone, alkylgallates, propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gallic acid, nordihydroguaiaretic acid, glycine, ascorbic acid, fatty acid esters of ascorbic acid such as ascorbyl palmitate and ascorbyl stearate, and salts of ascorbic acid such as sodium, calcium, or potassium ascorbate; erythorbic acid, L-carnitine, monothioglycerol, acetyl L-carnitine, thioglycolic acid, N-acetyl cysteine, cysteine, glutathione, methionine, tartaric acid, citric acid, fumaric acid, glycolic acid, oxalic acid, succinic acid, ellagic acid, malic acid, maleic acid, tocopherols such as, but not limited to, delta tocopherol, alpha tocopherol; lipoic acid, thiolated polymers such as, but not limited to, polymethacrylic-SH, carboxy methylcellulose-cysteine, polycarbophil-cysteine, beta-carotene, carotenoids, flavonoids, flavones, isoflavones, flavanones, catechins, anthocyanidins, chalcones, sulfites, including but not limited to potassium sulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate and sodium bisulfite or a combination thereof may be employed. The use of an antioxidant in the form of sodium bisulfite (about 0.005 mg/mL to about 1.0 mg/mL) has been found effectively prevents oxidation of edaravone in the solution at elevated temperature in pre-fillable syringes, ampoules and bottles/vials.

[0064] Typically, tonicity adjusting agents are used to adjust the osmolality of the pharmaceutical compositions to bring it closer to the osmotic pressure of body fluids, such as blood or plasma. In some embodiments the tonicity of the formulation can be modified by adjusting the concentration of buffer and/or other components present in the formulation.

[0065] Provided that the compositions are physiologically compatible, the compositions do not require any particular osmolality. Thus, the compositions can be hypotonic, isotonic or hypertonic. Typically, the pharmaceutical compositions have a tonicity between about 250 to about 350 mOsm/kg. In some of the alternative embodiments, the formulations of the present invention are isotonic, i.e., in the range of 260-320 mOsm/kg. In some of the alternative embodiments, the formulations of the present invention are isotonic, i.e., in the range of 270-328 mOsm/kg. However, the formulations may have a tonicity in the range of 250-350 mOsm/kg. Therefore, the formulations may be either slightly hypotonic, 250-269 mOsm/kg, or slightly hypertonic, 329-350 mOsm/kg.

[0066] Suitable tonicity adjusting agents for use in the pharmaceutical compositions include, but are not limited to, anhydrous or hydrous forms of sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride and other inorganic salts. The quantity of the tonicity adjusting agent in the formulation can be expressed in mg/ml or in g/L. In typical embodiments, the tonicity adjusting agent(s) is present from about 1 mg/ml to about 90 mg/ml. Thus, the pharmaceutical compositions can comprise one or more tonicity adjusting agents at about 1-5 mg/ml, at about 5-10 mg/ml, at about 10-15 mg/ml, at about 15-25 mg/ml, at about 25-50 mg/ml, at about 50-60 mg/ml, at about 60-70 mg/ml, at about 70-80 mg/ml, and at about 80 to 90 mg/ml, as well as combinations of the above ranges.

[0067] Alternatively, the tonicity adjusting agent concentration is measured in weight/volume percent. In typical embodiments, the tonicity adjusting agent(s) is present from about 0.1% to about 10%. For example, suitable tonicity adjusting agent concentrations include, but are not limited to, from about 0.1% to about 0.2%, from about 0.2% to about 0.3%, from about 0.3% to about 0.4%, from about 0.4% to about 0.5%, from about 0.5% to about 0.6%, from about 0.6% to about 0.7%, from about 0.7% to about 0.8%, from about 0.8% to about 0.9%, from about 0.9% to about 1%, from about 1% to about 2%, from about 2% to about 3%, from about 3% to about 4%, from about 4% to about 5%, from about 5% to about 6%, from about 6% to about 7%, from about 7% to about 8%, from about 8% to about 9%, and from about 9% to about 10%, as well as combinations of the above ranges.

[0068] In some embodiments, the tonicity adjusting agent is sodium chloride. Typically, the concentration of sodium chloride suitable for use in the pharmaceutical compositions is between about 0.1% (w/v) to about 1.8%. By way of example, suitable sodium chloride concentrations include, but are not limited to, from about 0.1% to about 0.2%, from about 0.2% to about 0.3%, from about 0.3% to about 0.4%, from about 0.4% to about 0.5%, from about 0.5% to about 0.6%, from about 0.6% to about 0.7%, from about 0.7% to about 0.8% (which is equivalent to 8 mg/ml), from out 0.8% to about 0.9% (which is equivalent to 9 mg/ml), from about 0.9% to about 1.0%, from about 1% to about 1.2%, from 1.2% (which is equivalent to 12 mg/ml) to about 1.4%, from about 1.4% to about 1.6%, and from about 1.6% to about 1.8%.

[0069] In some embodiments, the pharmaceutical composition comprises two, three, or more tonicity adjusting agents. In these embodiments, the concentration of each tonicity adjusting agent is typically less than the concentration that is used when only a single agent is present in the formulation.

[0070] Buffers/Buffering agent(s) if and when used in the formulation of the present invention include, but are not limited to, pharmaceutically acceptable salts and acids of acetate, glutamate, citrate, tartrate, benzoate, lactate, histidine or other amino acids such as arginine, alanine, glycine and lysine, gluconate, phosphate, malate, succinate, formate, propionate, and carbonate. “Pharmaceutically acceptable” is used herein in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Accordingly, the term “pharmaceutically acceptable salt” references salt forms of the active compounds which are prepared with counter ions which are non-toxic under the conditions of use and are compatible with a stable formulation. Buffers suitable for use in the formulations of the present invention also include, but are not limited to tris (hydroxymethyl)aminomethane (TRIS), triethanolamine, trolamine, diethanolamine, meglumine etc.

[0071] The concentration of the buffer/buffering agent in the formulation can be expressed in mg/ml, g/1 or as a molar concentration. Typically, from about 0.0001 mg/ml to about 100 mg/ml of a suitable buffer is present in the formulations of the present invention. Thus, the formulations can comprise from about 0.0001 to about 0.001 mg/ml of a suitable buffer, from about 0.001 to about 0.01 mg/ml of a suitable buffer, from about 0.01 to about 0.1 mg/ml of a suitable buffer, from about 0.1 to 1 mg/ml of a suitable buffer, from about 1 to about 5 mg/ml of a suitable buffer, from about 5 to about 10 mg/ml of a suitable buffer, from about 10 to about 15 mg/ml of a suitable buffer, from about 15 to about 20 mg/ml of a suitable buffer, from about 20 to about 25 mg/ml of a suitable buffer, from about 25 to about 50 mg/ml of a suitable buffer, from about 50 to about 75 mg/ml of a suitable buffer, and from about 75 to about 100 mg/ml of a suitable buffer.

[0072] Alternatively, the buffer concentration can be expressed as molar concentrations. In typical embodiments, from about 0.1 to 100 mM of a suitable buffer is present in the pharmaceutical compositions. Thus, the pharmaceutical compositions can comprise a suitable buffer having a concentration from about 0.1 to about 100 mM, from about 0.1 to about 0.5 mM, from about 0.5 to about 1.0 mM, from about 1.0 to about 5 mM, from about 5 to about 10 mM, from about 10 to about 15 mM, from about 15 to about 25 mM, from about 25 to about 50 mM, from about 50 to about 75 mM, and from about 75 to about 100 mM.

[0073] In some embodiments, the formulation of the present invention comprises a pH adjusting agent. Suitable pH adjusting agents typically include at least an acid or a salt thereof, and/or a base or a salt thereof. Acids and bases can be added on an as needed basis in order to achieve the desired pH. For example, if the pH is greater than the desired pH, an acid can be used to lower the pH to the desired pH. Acids suitable for use in formulations include, but are not limited to, hydrochloric acid, phosphoric acid, citric acid, ascorbic acid, acetic acid, sulphuric acid, carbonic acid, nitric acid and the like. By way of another example, if the pH is less than the desired pH, a base can be used to adjust the pH to the desired pH. Bases suitable for use in formulations include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium citrate, sodium acetate, magnesium hydroxide and the like.

[0074] A “Buffer/Buffering agent” or a “pH adjusting agent” as used herein is a system which is used for the purposes and is capable of maintaining the desired/required pH of the formulations throughout desired/required time period, e.g. stability studies and/or shelf life of the drug product. The desired pH of the formulation according to the present invention is about 4.0.

[0075] In some of the embodiments of the invention, both buffering agent and pH adjusting agent is used. In some of the embodiments of the invention, only a buffering agent is used. In some of the embodiments of the invention, only a pH adjusting agent is used.

[0076] In some of the preferred embodiments, phosphoric acid and/or sodium hydroxide are used as pH adjusting agent(s) which adjusts and/or maintains the desired/required pH, i.e. about 4.0.

[0077] However, in the non-limiting embodiments of the present invention, the pH of the edaravone formulation is between about 3.0 and about 5.0. In some of the non-limiting embodiments, the pH of the edaravone solution of the present invention is about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, and about 5.0. In some of the further non-limiting embodiments, the pH of the edaravone solution of the present invention is any value between the ranges about 3.0 to about 5.0.

[0078] Stabilizing agents when used in the formulation of the present invention without limitation include ethylene diamine tetraacetic acid (EDTA) or salts thereof, ascorbic acid, cysteine or salt thereof, L-cysteine or salt thereof, sorbitol, sorbitol solution, glycols such as propylene glycol and the like and a combination thereof. The use of a stabilizing agent in the form of L-cysteine hydrochloride hydrate (about 0.005 mg/mL to about 1.0 mg/mL) has been found effectively stabilizes edaravone in the solution at elevated temperature in pre-fillable syringes, ampoules and bottles/vials.

[0079] Since, the edarvone formulation of the present invention is in the form of aqueous solution, water or water for injection is used as a vehicle.

[0080] Further, during the packaging of the drug product of the present invention and also during its preparation, the drug product may have to undergo sterilization process for multiple times, for example, twice. Therefore, the materials from which the container which contains ready-to-use edaravone injection solution is made, must have appropriate characteristics.

[0081] If above mentioned conditions are fulfilled then prolonged stability of the drug (i.e. edaravone) may be ensured during its storage under various conditions and may make the edaravone solution prepared according to the present invention safer for use, storage for prolonged time and even during transport.

[0082] The packaging material according to the present invention, which should ensure the stability of the drug into the solution without changing pH, density, heat resistance and other characteristics, is borosilicate glass, which can easily withstand temperatures above 200° C. and does not change the chemical composition of the edaravone. Thus, it is advantageous to fill or store the edaravone solution in a borosilicate glass container.

[0083] The closure of the glass bottle or vial with the edaravone drug product must be carried out in such a way that the lid or cap or stopper, firstly, seals the vial hermetically, and secondly, the lid or cap or stopper must be heat-resistant, and thirdly, made of a material that prevents the adhesion of the active substance on its surface.

[0084] According to the present invention, the lid or cap or stopper is made of an elastic polymer based on a rubber or thermoplastic derivative, which has high impermeable properties, high heat resistance, strength and at the same time good flexible properties, which prevents the lid from breaking. Other similar materials may also be used which meet the specified characteristics, for example, in the class of unnatural synthetic elastomers. It is pertinent to note that the lid or cap or stopper used in the present invention are uncoated and does not contain anti-adhesive coating.

[0085] It is also not required that at least that part of the surface of the lid or cap or stopper, partially or completely, which is in contact with the drug solution, be covered with a layer of a substance with anti-adhesive properties. The lid or cap or stopper should not affect the chemical composition of the mixture and it should be heat-resistant.

[0086] During transportation and storage, additional stability of the drug in the package of the present invention is due to the use of an aluminum cap, which crimps the bottle or vial cap to seal the container containing edaravone solution.

[0087] As primary packaging materials, the present invention uses glass vials, rubber closures and aluminum tear off seals. The glass vials used in the present invention are USP/EP Type-I clear 100 mL ISO-Molded glass vials (manufactured by SGD Pharma India Ltd.). However, other glass vials of similar quality and having different size (capacity) may also be used for the purposes of the present invention. Similarly, Type II and Type III glass containers may also be used if found suitable for parenteral use. The glass vials of the present invention are made of borosilicate glass. However, vials made of other glass material (which, for example, without limitation include lime soda glass, neutral glass, lead free glass sulphured containers, silicone treated containers and the like) may also be used if found suitable for parenteral use. The lids or caps or stoppers used in the present invention to close the vials containing edaravone solution are 20 mm chlorobutyl rubber stoppers (S-127 4432/50/Grey Westar RS SIL 1; manufactured by West Pharmaceutical Services Singapore Pte. Ltd.). However, 20 mm-35 mm size rubber closures which, for example, without limitation include natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, chloroprene rubber or any other suitable closures made of suitable material and the like may also be used for the purposes of the present invention. The formulation of the rubber closures used in the present invention complies with the chemical requirements in the corresponding monograph 3.2.9 for “rubber closures” Type 1 in the valid version of the European Pharmacopoeia. The formulation also complies with the physicochemical tests, as described in the current USP General Chapter [381] “Elastomeric Closures for Injections”. The rubber closures used in the present invention are uncoated which means they do not contain any anti-adhesive coatings. The present invention also uses 20 mm size Aluminum tear off seal to pack the vial containing edaravone solution. These Aluminum seal crimps the vial cap to seal the containers. However, Aluminum seals of any suitable size may also be used depending upon the size of the stopper used.

[0088] As secondary packaging materials, the present invention uses white folded cartoon. However, any packaging material made of suitable material which fulfills the requirements of the present invention (i.e. stability during storage and transportation, easy and convenient use etc.) may also be used.

Definitions

[0089] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0090] As used herein, the term “about” is synonymous with “approximately” and is used to provide flexibility to a numerical value or range endpoint by providing that a given value may be “a little above” or “a little below” the value stated. “About” can mean, for example, within 3 or more than 3 standard deviations. “About” can mean within a percentage range of a given value. For example, the range can be ±1%, ±5%, ±10%, ±20%, ±30%, ±40% or ±50% of a given value. “About” can mean with an order of magnitude of a given value, for example, within 2-fold, 3-fold, 4-fold or 5-fold of a value. However, it is to be understood that even when a numerical value is accompanied by the term “about” in this specification, that express support shall be provided at least for the exact numerical value as well as though the term “about” were not present.

[0091] As used herein, the terms “stable” or “stability” encompass any characteristic of the formulations which may be affected by storage conditions including, without limitation, potency, total impurities, degradation products, specific optical rotation, optical purity, water content, appearance, viscosity, sterility, and colour and clarity. The storage conditions which may affect stability include, for example, duration of storage, temperature, humidity, and/or light exposure.

[0092] The term “degradant”, “impurity”, “degradation impurity” and “related substance” as used herein represents the same meaning and can be used interchangeably.

[0093] In some embodiments, the formulations of the present invention are stable for prolonged time when stored under storage conditions. The term “storage conditions” as used herein without limitation include typical storage conditions such as 2° C.-8° C. The compositions of the present invention may also be stored at 40° C.±2° C./75±5% RH, 30° C.±2° C./65±5% RH, 25° C.±2° C./40±5% RH, 25° C.±2° C./60±5% RH, 40° C.±2° C./NMT 25% RH (NMT=not more than) and accelerated conditions such as 40° C.±2° C./75±5% RH. The term “prolonged time” as used herein indicates that the formulations of the present invention are stable for at least 1 month or more, at least 3 months or more, at least 6 months or more or at least 12 months or more when stored under storage conditions.

[0094] In some of the embodiments of the present invention, “stable” or “storage stable”, or “stability” when used with reference to the formulations of the present invention or when used “stable or storage stable formulations” or “stability of the formulations” all these terms/phrases refer to formulations of the present invention which retain at least about 90%, or at least about 95%, or at least about 96%, or at least about 98%, of the labelled concentration of edaravone or salt thereof contained in the said formulation after storage under typical and/or accelerated conditions. In further embodiments, stable formulations or stability of the formulations refer to less than about 15% (area percent), or less than about 10% (area percent), or less than about 7% (area percent), or less than about 5% (area percent), or less than about 2% (area percent) of edaravone-related impurities are present after storage under typical and/or accelerated conditions.

[0095] In some of the embodiments, formulations of the present invention contain no more than about 15% (area percent), or no more than about 10% (area percent), or no more than about 7% (area percent), or no more than about 5% (area percent), or no more than about 2% (area percent), or no more than about 1% (area percent), or no more than about 0.5% (area percent), or no more than about 0.2% (area percent), or no more than about 0.1% (area percent) any known or unknown single edaravone-related impurity or other impurity after storage under typical and/or accelerated conditions.

[0096] In some of the embodiments, formulations of the present invention contain no more than about 15% (area percent), or no more than about 10% (area percent), or no more than about 7% (area percent), or no more than about 5% (area percent), or no more than about 2% (area percent), or no more than about 1% (area percent), or no more than about 0.5% (area percent), or no more than about 0.2% (area percent), or no more than about 0.1% (area percent) total edaravone-related impurities or other impurities after storage under typical and/or accelerated conditions.

[0097] Methods for determining the stability of the formulations of the present invention with respect to a given parameter are well-known to those of skill in the art. For example, individual impurities and total impurities can be assessed by high-performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Unless otherwise indicated to the contrary, a percentage amount of any individual impurities (known/unknown), or total impurities reported herein in the formulations are determined by a peak area percent method using HPLC.

[0098] The term “compatible” as used herein refers to those added excipients or ingredients or additives those are not substantially antagonistic to the other excipients or ingredients or additives or pharmaceutically active ingredients.

[0099] As used herein an “effective amount” of a compound or composition for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce symptoms to achieve the desired physiological effect. Such amount can be administered as a single dosage or can be administered according to a regimen, whereby it is effective. The effective amount is readily determined by one of skill in the art following routine procedures.

[0100] As used herein, “optional” or “optionally” means that the subsequently described event or circumstance does or does not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, an optionally substituted group means that the group is un-substituted or is substituted.

[0101] As used herein, “comprises”, “comprising”, “containing” and “having” and the like can have the meaning ascribed to them in patent law and can mean “includes”, “including” and the like, and are generally interpreted to be open ended terms. The terms “consisting of” or “consists of” are closed terms, and include only the components, structures, steps, or the like specifically listed in conjunction with such terms, as well as that which is in accordance with patent law. “Consisting essentially of” or “consists essentially of” have the meaning generally ascribed to them by patent law. In particular, such terms are generally closed terms, with the exception of allowing inclusion of additional items, materials, components, steps, or elements, that do not materially affect the basic and novel characteristics or function of the item(s) used in connection therewith. For example, trace elements present in a composition, but not affecting the composition's nature or characteristics would be permissible if present under the “consisting essentially of” language, even though not expressly recited in a list of items following such terminology. When using an open ended term, like “comprising” or “including” it is understood that direct support should be afforded also to “consisting essentially of” language as well as “consisting of” language as if stated explicitly and vice versa. In essence, use of one of these terms in the specification provides support for all of the others. The term “comprise/comprises/comprising” as used herein mean that other ingredients, steps, etc. are optionally present. When reference is made herein to a method comprising two or more defined steps, the steps can be carried in any order or simultaneously (except where the context excludes that possibility), and the method can include one or more steps which are carried out before any of the defined steps, between two of the defined steps, or after all of the defined steps (except where the context excludes that possibility).

[0102] As used herein, “rubber” without limitation includes natural rubber (latex), synthetic rubber, isoprene rubber (a chemical copy of natural rubber), styrene-butadiene rubber, neoprene (poly-(2-chloro-1,3-butadiene), styrol-butadine rubber, ethylene propylene dyes monomers, silicone (polysiloxane) rubber, butyl or halogenized butyl rubber such as bromobutyl, chlorobutyl and the like, nitrile rubber, and chloroprene rubber. Thus, the rubber stoppers include all stoppers made of above mentioned rubbers.

[0103] As used herein, “glass vials” or “glass bottles” without limitation include vials or bottles made of borosilicate glass, lime-soda glass, neutral glass, lead free glass, sulphured treated glass, and silicone treated glass. The glass vials according to the present invention without limitation include tubing glass vials and molded glass vials.

[0104] The term “easy and convenient to transport and use”, as used herein, means that the bottles or vials containing edaravone formulation of the present invention when packaged as described in the present invention are not adversely affected or damaged during transportation from one place to another and even during use, e.g., use by pharmacies, healthcare providers etc. In other words, the transportation and use of the edaravone formulation of the present invention when packaged as described in the present invention does not require any special handling techniques and/or care.

[0105] Further, as used herein, the term “stable during storage, transportation and convenient in use” means that the bottles or vials containing edaravone formulation of the present invention when packaged as described in the present invention, the quality of the product is not adversely affected or diminished during storage period or during transportation during one place to another and also during shelf life and that it is convenient to use by the healthcare providers or in pharmacies that no special handling techniques or care is required.

[0106] As used herein, “USP” is an abbreviated form of United States Pharmacopeia and “EP” is an abbreviated form of European Pharmacopeia.

[0107] All percentages mentioned herein, unless otherwise indicated, are on a w/v basis, i.e. percentage ingredient (active/inactive) present by weight in the total volume of the composition.

BEST MODE OF CARRYING OUT THE INVENTION

Example(s)

[0108] The edaravone parenteral dosage form of the present invention is prepared as ready-to-use intravenous solution for infusion. Said edaravone dosage form contains edaravone or its pharmaceutically acceptable salt as active ingredient and an antioxidant, a stabilizer, a pH adjusting agent and a tonicity modifying agent as inactive ingredients. The edaravone dosage form of the present invention is in the form of aqueous solution having pH about 4.0.

TABLE-US-00001 TABLE 1 Edaravone aqueous solution of the present invention Name of Role of Strength(s) Sr ingredient ingredient 0.3 mg/mL 0.6 mg/mL 1 Edaravone Active 30 mg/100 mL 60 mg/100 mL 2 L-cysteine Stabilizer 10 mg/100 mL 20 mg/100 mL hydrochloride hydrate 3 Sodium bisulfite Antioxidant 20 mg/100 mL 40 mg/100 mL 4 Sodium chloride Tonicity 860 mg/100 mL 855 mg/100 mL modifying agent 5 Phosphoric pH Q.S. to Q.S. to acid/sodium adjusting adjust/maintain adjust/maintain hydroxide agent(s) pH about 4.0 pH about 4.0 6 Water for Vehicle Q.S. to 100 Q.S. to 100 mL injection mL Q.S. = quantity sufficient

[0109] The edaravone solution of the present invention, in the qualitative and quantitative composition as mentioned above, was prepared by dissolving required quantity of L-cysteine hydrochloride in the required quantity of the water for injection (having dissolved oxygen below 1 ppm). Required quantity of edaravone was dissolved in above solution. The mixture was heated, if required. Required quantity of sodium chloride was dissolved in the above drug solution. The pH was adjusted to about 4.0 using suitable pH adjusting agent (phosphoric acid/sodium hydroxide). For example, if pH of the solution is higher than 4.0 then pH is adjusted using phosphoric acid and if pH of the solution is lower than 4.0 then pH is adjusted using sodium hydroxide. Finally, required quantity of sodium bisulfite is dissolved in above pH adjusted drug solution. The pH of the final drug solution is checked and adjusted to about 4.0, if required, as mentioned above. The above method of preparation is for illustrative purpose only and the edaravone solution of the present invention can be prepared by following alternative methods also where the order of addition of drug and excipients is altered. The edaravone solution can also be prepared in two or more parts preparation process where some excipients with or without drug are dissolved in one part and some excipients with or without drug is dissolved in another part followed by mixing of both the parts to finally prepare edaravone solution. It should be noted that the order to addition of drug and excipients and the two-part preparation does not negatively affect the quality of the product.

[0110] The fact that sodium chloride used in the edaravone formulations of the present invention is 8.6 mg/mL (for 0.3 mg/mL strength) and 8.55 mg/mL (for 0.6 mg/mL strength) does not necessarily mean it can only be used in the edaravone formulations in these amounts only. Sodium chloride can be used in any quantity that is sufficient to bring the osmolality of the solution between about 260 mOsmol/kg and about 320 mOsmol/kg, e.g., sodium chloride may be used from 710 mg/100 mL to 860 mg/100 mL for both the strengths.

[0111] The edaravone drug formulation obtained by above method is filled in USP/EP Type-I clear 100 mL ISO-Molded glass vial (manufactured by SGD Pharma India Ltd.). The glass vial was closed using 20 mm chlorobutyl uncoated rubber stopper (S-127 4432/50/Grey Westar RS SIL 1; manufactured by West Pharmaceutical Services Singapore Pte. Ltd.). The glass vial closed with above said rubber stopper was finally clogged with 20 mm Aluminum tear off seal to pack the vial. The Aluminum seal crimps the vial cap to seal the container. The sealed vial was finally packed in white folded cartoon.

[0112] The stability of the edaravone in the solution using above mentioned primary and secondary packaging was tested at various temperatures and under different humidity conditions at various end points (for example after 1 month, 2 months, 3 months, 6 months, 9 months etc.). The results of these stability studies show that the edaravone was not susceptible to oxidation and other degradation even after using above mentioned simple and economic packaging materials. The concentration of edaravone in the solution was not increased due to evaporation of the liquid of the solution. Also, the concentration of edaravone was not decreased due to adhesion of the drug molecule with the rubber closure used even after using uncoated rubber stopper (rubber stopper without anti-adhesive coating). These surprising findings are not envisaged from the disclosure of any of the prior art documents, then, when the prior art documents specifically teaches advantages of the coated stoppers/lids with anti-adhesive polymers.

Thermal Stability Study Results of Edaravone Injection 30 mg/100 mL:

TABLE-US-00002 40° C./75% RH 30° C./65% RH 25° C./60% RH 1 M 3 M 6 M 1 M 3 M 6 M 12 M 1 M 3 M 6 M 12 M Test parameters Initial I I I I I I I I I I I Description C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. pH 4.25 4.21 3.93 3.68 4.30 4.09 3.64 3.63 4.02 4.02 3.67 3.65 Osmolality 280 283 287 282 280 288 280 282 284 288 281 283 Assay of Edaravone 100.1 99.7 98.7 98.0 99.8 99.3 98.8 99.3 99.9 100.1 99.4 100.2 (in %) Content of L- 103.6 97.6 82.9 83.6 97.8 84.9 78.9 70.2 101.0 90.4 80.1 67.2 Cysteine HCl Mono-hydrate (in %) Content of Sodium 89.1 82.4 73.6 66.9 84.8 77.4 70.0 64.8 86.9 81.2 70.3 65.7 Bisulfite (in %) Head Space Oxygen 2.73 2.09 1.49 1.11 2.43 1.53 0.95 1.66 1.88 1.45 2.01 1.11 (in % v/v) Single maximum 0.02 0.03 0.07 0.13 0.02 0.02 0.05 0.09 0.02 0.02 0.03 0.05 unspecified impurity Total impurities 0.06 0.12 0.23 0.44 0.07 0.07 0.17 0.38 0.06 0.06 0.12 0.20 C.S. = colorless solution; NMT = not more than; NLT = not less than; RH = relative humidity; M = month(s); I = inverted
Thermal Stability Study Results of Edaravone Injection 60 mg/100 mL:

TABLE-US-00003 40° C./75% RH 30° C./65% RH 25° C./60% RH 1 M 3 M 6 M 1 M 3 M 6 M 1 M 3 M 6 M Test parameters Initial I I I I I I I I I Description C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. C.S. pH 4.24 3.59 3.78 3.54 3.85 3.59 3.57 3.95 3.67 3.60 Osmolality 286 287 293 289 287 293 288 288 292 288 Assay of Edaravone 99.8 99.2 99.1 97.9 99.5 99.6 98.9 99.6 99.8 99.0 (in %) Content of L-Cysteine 102.3 96.3 88.0 81.5 98.3 77.9 82.7 101.1 83.3 83.5 HCl Monohydrate (in %) Content of Sodium 80.9 76.6 68.9 64.9 78.7 64.5 67.2 80.5 66.8 68.4 Bisulfite (in %) Head space Oxygen 3.59 1.54 0.89 3.66 2.07 1.34 NP 2.01 1.7 NP (in % v/v) Single maximum 0.02 0.04 0.07 0.14 0.03 0.04 0.07 0.03 0.05 0.03 unspecified impurity Total impurities 0.04 0.11 0.18 0.38 0.07 0.11 0.17 0.07 0.11 0.09 C.S. = colorless solution; NMT = not more than; NLT = not less than; RH = relative humidity; M = month(s); NP = not performed; I = inverted

[0113] From above data it can be concluded that the edaravone formulation of the present invention when packaged in the packaging materials described herein is stable at 25° C. temperature and 60% relative humidity. Further, based on the above data it can be concluded that the shelf life of the edaravone solution when packaged in the packaging materials of the present invention can be at least 2 years (or 24 months) at 25° C.

[0114] It is pertinent to note that, the quality and stability of the drug product is not affected even after using uncoated stoppers/caps (that does not contain anti-adhesive coatings/polymers as described in the prior art). In other words, all the test parameters were within the specification even after using the uncoated stoppers/vials and keeping the containers containing edaravone solution in inverted position for above said time periods and stability conditions. These studies suggest that for packaging edaravone solution expensive packaging system (coated stoppers/caps having anti-adhesive polymers) is not required and the edaravone solution can be packaged in less expensive and easily available packaging materials which makes the drug product more economically viable and affordable by the patients.

[0115] The compositions and the packaging materials in which they are packaged as described in the present invention are suitable for use in the industry.

[0116] It should be understood that various changes and modifications to the embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the subject matter of the present invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered within the scope of the present invention.