Stable pharmaceutical composition of edaravone

Abstract

The present invention relates to a liquid pharmaceutical composition of edaravone. More specifically, a stable solution of edaravone for enteral administration is provided, and the composition is stable for a long period of time. The present invention further relates to the stable solution of edaravone, its administration method, its manufacturing process, and the use of these compositions for the treatment of diseases treatable with edaravone.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Indian Provisional Application No. 202341010407, filed on February 16, 2023, the entire contents of which are incorporated herein.

[0002] FIELD OF THE INVENTION The present invention relates to stable liquid pharmaceutical compositions of edaravone, methods of administering the same, processes for preparing the same, and uses of these compositions for treating diseases treatable with edaravone. [Background technology]

[0003] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive, fatal degenerative disease that affects the motor neurons connecting the brain and spinal cord, ultimately leading to paralysis and death. Edaravone is an antioxidant that acts by preventing motor neuron death due to oxidative stress. It also inhibits the nitration of tyrosine residues in the cerebrospinal fluid, thereby improving motor function. Therefore, edaravone is indicated as a neuroprotective agent for the treatment of ALS. Chemically, this compound is described as 3-methyl-1-phenyl-2-pyrazolin-5-one and is represented by the structural formula (1).

[0004] Edaravone is currently sold in the United States under the brand names Radicava™ (intravenous edaravone injection; 0.3 mg / mL and 0.6 mg / mL) and RadicavaORS™ (oral edaravone suspension; 105 mg / 5 mL). The recommended dose of Radicava™ is 60 mg administered as an intravenous infusion over 60 minutes, while 105 mg (5 mL) of RadicavaORS™ is taken orally or via a feeding tube in the morning after an overnight fast.

[0005] Intravenous (IV) administration is recognized for its precise and comprehensive drug delivery. However, it is also considered a less desirable administration route because it places additional burdens on patients, their families, and healthcare professionals. This is primarily due to the need for frequent injections and the need for repeated hospital visits and caregiver assistance, which can be burdensome. Edaravone in the form of intravenous infusion also poses similar challenges during administration. Therefore, to facilitate self-administration and improve patient compliance, the oral route is the most convenient method of administering edaravone for the treatment of ALS.

[0006] Dysphagia (difficulty swallowing) is a symptom of ALS. In addition to adversely affecting nutritional intake, swallowing disorders can also severely impact the administration of beneficial medications. For example, the solid dosage form of edaravone is not user-friendly for individuals with this condition. As a result, such patients may delay or completely skip medication doses, which often prompts clinicians to seek alternative dosage forms. Furthermore, with advanced dysphagia, oral intake becomes more difficult due to impaired tongue movement. In such cases, enteral and parenteral routes become essential for delivering both nutrients and medications. Therefore, dosage forms that allow medication administration to ALS patients, even via enteral feeding tubes, should be considered. Liquid formulations, such as solutions and suspensions, readily serve this purpose.

[0007] Solubility and stability are two important factors to consider when developing a robust liquid formulation. Edaravone is a lipophilic molecule with low oral bioavailability (Fabs = 5.23%). This low oral bioavailability is due to several factors, including low solubility, poor permeability across the gastrointestinal (GI) tract, and extensive glucuronidation during phase II metabolism. These properties classify edaravone as a BCS Class II molecule. A major obstacle in developing aqueous liquid formulations of edaravone is its low water solubility, measured at 1.85 mg / mL. Edaravone has also been reported to exhibit instability in aqueous solutions due to rapid degradation. In water, edaravone exists as an "enol form" and an "edaravone anion." The edaravone anion becomes an edaravone radical when the anion donates an electron to oxygen. Therefore, electron reduction by the edaravone anion is the primary step in edaravone degradation.

[0008] As mentioned above, Radicava ORS™ is a liquid dosage form of edaravone approved and commercially available in the form of an oral suspension. Drugs are formulated as suspensions for many different reasons, the most common being poor solubility of the drug and unpleasant taste caused by the drug dissolved in the solution. However, problems associated with suspension dosage forms include sedimentation, caking, poor redispersibility, or particle growth (Ostwald ripening), which can raise concerns about drug uniformity and ultimately result in under- or over-dosing of the drug. Therefore, there is a need to develop a robust and stable liquid composition of edaravone suitable for enteral administration, in which edaravone remains solubilized for extended periods under appropriate storage conditions.

[0009] U.S. Patent No. 10,966,960 ("Treeway") discloses a solid, water-dispersible pharmaceutical composition of edaravone combined with a water-soluble alkalizing agent. This composition allows for the preparation of an edaravone solution by simply dispersing it in an aqueous liquid at the time of administration. Because the disclosed formulation is in the form of a solid composition, it offers the advantage of having longer room temperature stability than commercially available edaravone oral suspensions. There remains a need to develop a stable, ready-to-use edaravone formulation, such as an oral solution, that exhibits better patient compliance compared to the disclosed and commercially available edaravone formulations.

[0010] International Publication No. WO2023006565A1 ("Medichem SA") discloses a process for preparing a heat-sterilized aqueous formulation containing edaravone and bisulfite anions, with an oxygen content of less than 1 ppm. In the case of edaravone, minimizing the use of techniques such as heat sterilization (121°C) is always desirable because it tends to cause instability issues, decompose edaravone, and produce more undesirable impurities. Furthermore, the presence of bisulfite ions can trigger allergic-type reactions, including anaphylactoid symptoms and life-threatening or relatively mild asthma attacks, in people with certain allergic sensitivities. According to Sec. 201.22 of Title 21 of the Code of Federal Regulations, prescription drugs containing sulfites must carry a "warning" statement in the labeling section. There is also a need to develop a more stable and robust edaravone oral solution that minimizes or completely eliminates the use of excipients containing sulfite ions without compromising the solubility and stability of the final formulation.

[0011] It is desirable to develop a novel, stable, easy-to-drink, ready-to-use edaravone solution suitable for oral administration to humans that exhibits solubility and stability at room temperature over an extended period without significant loss of efficacy. The present invention fulfills such a need by developing a stable edaravone solution that increases patient compliance and thus helps achieve improved standards of patient care. Summary of the Invention

[0012] The present invention relates to a stable liquid pharmaceutical composition of edaravone or a pharmaceutically acceptable salt thereof, for treating diseases treatable with edaravone. The edaravone composition of the present invention is advantageously stable, ready-to-use (RTU), and suitable for enteral administration.

[0013] The present invention encompasses various methods of enteral administration, including, but not limited to, oral administration and intragastric administration, which can be achieved through the use of a tube inserted through the nasal passages (nasogastric tube) or placed through the abdomen directly into the stomach (percutaneous endoscopic gastrostomy tube; PEG tube).

[0014] One aspect of the present invention relates to a stable solution of edaravone suitable for enteral administration, comprising at least one pharmaceutically acceptable solvent and one or more pharmaceutically acceptable excipients selected from the group consisting of solubility enhancers, antioxidants, crystallization inhibitors, stabilizers, preservatives, flavoring agents, sweeteners, thickeners, and mixtures thereof.

[0015] Yet another embodiment of the present invention relates to a stable solution of edaravone suitable for enteral administration, wherein edaravone is present in a concentration of about 0.05 mg / mL to about 50 mg / mL.

[0016] The stable solution of edaravone of the present invention exhibits a pH of about 2.0 to about 7.0, preferably about 2.5 to about 6.0.

[0017] In another aspect, there is provided a process for preparing a stable solution of edaravone suitable for enteral administration, the process comprising solubilizing edaravone in a solvent together with other pharmaceutically acceptable excipients to obtain a stable solution.

[0018] In one embodiment, a stable solution comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients is provided, wherein the solution is stable for at least 3 months at 25°C / 60% RH.

[0019] In one embodiment, a pharmaceutical composition is provided that includes (i) edaravone in an amount ranging from about 0.05 mg / mL to about 50 mg / mL, (ii) water in an amount of up to about 50% (W / W), (iii) a non-aqueous solvent in an amount ranging from about 10% (W / W) to about 90% (W / W), (iv) a crystallization inhibitor in an amount ranging from about 0.5% (W / W) to about 50% (W / W), and (v) an antioxidant in an amount ranging from about 0.05% (W / W) to about 5.0% (W / W). The composition is in the form of an oral solution, and is stable for at least 3 months when stored at 25°C / 60% RH, 40°C / 75% RH, or 40°C / 25% RH.

[0020] In another embodiment, there is provided a pharmaceutical composition comprising: (i) edaravone in an amount ranging from about 0.05 mg / mL to about 50 mg / mL; (ii) water in an amount of up to about 50% (W / W); (iii) alcohol in an amount ranging from about 10% (W / W) to about 90% (W / W); (iv) a crystallization inhibitor in an amount ranging from about 0.5% (W / W) to about 50% (W / W); and (v) an antioxidant in an amount ranging from about 0.05% (W / W) to about 5.0% (W / W). The composition is in the form of an oral solution and is stable for at least 3 months when stored at 25°C / 60% RH, 40°C / 75% RH, or 40°C / 25% RH.

[0021] Another aspect of the present invention relates to a solution of edaravone having extended stability. In one aspect, the present invention relates to a stable solution of edaravone suitable for enteral administration, which is stable for at least 6 months when stored under conditions of 40°C / 75% RH, 40°C / 25% RH, 25°C / 60% RH, or 2-8°C.

[0022] Another aspect relates to a method for treating amyotrophic lateral sclerosis by enterally administering an effective amount of a stable edaravone solution.

[0023] By way of non-limiting example, exemplary combinations applicable to the embodiments described herein can include any combination of one or more of the elements described above. [Brief explanation of the drawings]

[0024] [Figure 1] Preparation of API phase.

[0025] [Figure 2] Preparation of the non-API phase.

[0026] [Figure 3] Preparation of the final bulk solution. Detailed Description of the Invention

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly known to those skilled in the art.If there is any discrepancy, the definitions provided herein shall prevail.Unless otherwise specified, all percentages, portions and ratios in the present invention are by weight.

[0028] The term "about" used in conjunction with a numerical variable generally refers to the value of the variable and all values ​​of the variable within measurement or experimental error (e.g., a 95% confidence interval for the mean), or within a wider range of the specified value (e.g., ±10%).

[0029] The term "pharmaceutically acceptable" means a substance that, according to common medical judgment, is suitable for contact with the tissues of a patient without undue toxicity, irritation, or allergic reaction, and has a reasonable balance of advantages and disadvantages that allows it to be effectively applied for its intended use.

[0030] The term "pharmaceutically acceptable salt" refers to a salt of edaravone formed with an inorganic or organic acid.

[0031] As used throughout the description and claims, the meaning of "a," "an," and "the" includes plural references unless the context clearly dictates otherwise. Also, as used herein, the word "in" encompasses "in" and "on" unless the context clearly dictates otherwise.

[0032] As used herein, the term "ready to use" or "RTU" refers to a formulation that does not require constitution or dilution with a predetermined amount of diluent, such as water or other suitable diluent, prior to use by a designated route.

[0033] As used herein, the term "ready to dilute" or "RTD" refers to a formulation that is diluted with a suitable diluent for enteral administration.

[0034] As used herein, the term "ready to administer" or "RTA" refers to a formulation that can be administered orally directly to a patient without the need for any procedures, handling, or manipulation prior to administration.

[0035] As used herein, the term "dosage," "dosage unit," or "dose" refers to the amount of a pharmaceutical composition containing a therapeutically active ingredient administered at one time.

[0036] "Effective amount" or "therapeutically effective amount" means an amount of a drug sufficient to treat, prevent, or ameliorate a condition in a subject or patient. The effective amount of edaravone or a pharmaceutically acceptable salt thereof can be determined and adjusted by those skilled in the art to provide an appropriate amount and dosage regimen depending on the method of administration, the age, weight, sex, and / or general health condition of the patient.

[0037] In the context of the present invention, the term "solution" refers to a mixture of one or more substances uniformly dissolved in a liquid medium or vehicle or solvent. The solution is preferably homogeneous, in the sense that the active pharmaceutical ingredient (API) is essentially uniformly dissolved and distributed throughout the solution.

[0038] The term "alcohol" as used herein refers to "ethanol" according to the United States Food and Drug Administration's (USFDA) Inactive Ingredients Database (IID).

[0039] The term "subject" refers to a human or non-human. The terms "patient" and "subject" can be used interchangeably herein.

[0040] The terms "stable" and "stability" mean that changes in a product over time and / or under specific environmental conditions (i.e., temperature, humidity, etc.) do not significantly affect its quality, safety, and / or effectiveness for a given period of time. This can be measured by the formation of degradation products (impurities), pH fluctuations, appearance (precipitation), microbial growth, and / or color. The term "stable" can refer to physical stability and / or chemical stability.

[0041] The term "physically stable" refers to a solution of edaravone in which no visible crystals of edaravone are present and which does not tend to precipitate when stored under specified conditions, such as 2-8°C, room temperature, 25°C / 60%RH, 40°C / 25%RH, or 40°C / 75%RH, for a specified period of at least 1 week, 2 weeks, 1 month, 2 months, 6 months, 1 year, or 2 years.

[0042] The term "chemically stable" means that the loss of edaravone is about 10% or less under typical commercial storage conditions. Preferably, the formulation of the present invention loses about 8% or less, more preferably about 5% or less, and even more preferably about 3% or less of edaravone under specific conditions, such as at 2-8°C, room temperature, 25°C / 60% RH, 40°C / 25% RH, or 40°C / 75% RH, for at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, at least 24 months, at least 30 months, and at least 36 months.

[0043] In one embodiment, the stable solutions of the present invention are stable over a wide temperature range, for example, from -20°C to 40°C. The stable solutions of the present invention can be stored at about 5°C to about 25°C.

[0044] The term "storage" as used herein refers to the retention of a composition under controlled or uncontrolled conditions for a period of time ranging from a few minutes to several months or longer. Controllable storage conditions include, for example, temperature, humidity, and light level. In many cases, pharmaceutical preparations are stored under industry-accepted standards and / or standards mandated by regulatory authorities such as the USFDA.

[0045] As used herein, the term "degradation product" refers to unwanted chemicals or impurities (including, but not limited to, known or unknown related substances) that may arise during the manufacturing, transportation, and / or storage of a pharmaceutical product, which may affect the efficacy of the pharmaceutical product. They may form in response to changes in light, temperature, pH, and humidity, or due to inherent properties of the active ingredient, such as reaction with excipients or contact with packaging.

[0046] As used herein, "extended period" refers to maintaining the composition under controlled or uncontrolled conditions for a period of 30 days or more.

[0047] As used herein, "significant loss of potency" means a loss of 10% or more of edaravone under typical commercial storage conditions.

[0048] As used herein, "treating a condition" or "treatment of a condition" refers to an approach to obtaining beneficial or desired results, e.g., clinical results. Beneficial or desired results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; reduction in the severity of a disease, disorder, or condition; a stable (i.e., not worsening) state of a disease, disorder, or condition; preventing the spread of a disease, disorder, or condition; slowing or slowing the progression of a disease, disorder, or condition; improvement or palliation of a disease, disorder, or condition; and remission (partial or total), whether detectable or not.

[0049] The terms "bioequivalence" and "bioequivalence" are technical terms and are intended to be defined in accordance with "Approved Drug Products with Therapeutic Equivalence Evaluations, 41st Edition," published by the U.S. Department of Health and Human Services and commonly known as the "Orange Book." Generally, bioequivalence can be defined as the absence of significant differences in the rate and extent to which the active ingredient or moiety in a drug equivalent or drug substitute becomes available at the site of drug action when administered at the same molar dose under similar conditions in well-designed studies. Bioequivalence of different formulations of the same drug substance includes equivalence with respect to the rate and extent of drug absorption. Pharmacokinetic characteristics of the concentration-time curve, such as the maximum observed plasma concentration (Cmax), the time to reach Cmax, and the area under the plasma concentration versus time curve (AUC), are examined using statistical procedures well established in the field of pharmacokinetics. Two formulations whose rate and extent of absorption differ by no more than -20% / +25% are generally considered bioequivalent.

[0050] The innovative pharmaceutical compositions described herein are provided in the form of a solution. Enteral administration modes that can be employed in the present invention include, but are not limited to, oral and intragastric administration. Enterally acceptable diluents used for oral or intragastric administration can include water, water for injection, normal saline, half-normal saline, dextrose solution (5%), alcohol, glycerin, polyols (e.g., propylene glycol, polyethylene glycol, etc.), dimethylacetamide, N-methyl-pyrrolidone, dimethyl sulfoxide, Ringer's solution, isotonic sodium chloride solution, or suitable mixtures thereof. According to the present invention, the compositions can be provided in kit form with an enterally acceptable diluent. The pharmaceutical compositions of the present invention can be formulated according to conventional pharmaceutical practice and administered by any conventional method. Those skilled in the art will readily understand how to administer the compositions of the present invention to human subjects.

[0051] In one embodiment, the pharmaceutical composition of the present invention comprises edaravone, and the concentration of edaravone ranges from about 0.05 mg / mL to about 50 mg / mL. The present application relates to a stable solution of edaravone, in which edaravone is present at a concentration of about 5 mg / mL or more.

[0052] In a preferred embodiment, the concentration of edaravone in the composition of the present invention is about 0.05 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 3 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, 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 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL.

[0053] Preferably, the liquid pharmaceutical composition is provided in a form suitable for enteral administration, including, but not limited to, a solution, a suspension, a syrup, or an elixir. The pharmaceutical composition can be formulated according to conventional pharmaceutical practice.

[0054] The term "edaravone" as used herein refers to edaravone free base or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In principle, any crystalline or amorphous form of edaravone can be used to prepare the innovative pharmaceutical composition of the present invention.

[0055] In one embodiment, the present invention provides a stable liquid pharmaceutical composition suitable for enteral administration comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients.

[0056] In one embodiment, the present invention provides a stable liquid pharmaceutical composition suitable for enteral administration, comprising (i) edaravone, (ii) at least one pharmaceutically acceptable non-aqueous solvent, and (iii) one or more pharmaceutically acceptable excipients.

[0057] In one embodiment, the present invention provides a method for treating amyotrophic lateral sclerosis by enterally administering to a subject a stable solution containing about 0.5 mg / mL to about 50 mg / mL of edaravone, wherein the solution comprises (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients.

[0058] In one embodiment, the present invention provides a stable pharmaceutical composition suitable for enteral administration, comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients, and in the form of a solution.

[0059] In one embodiment, the present invention provides a stable pharmaceutical composition suitable for enteral administration comprising (i) edaravone, and (ii) one or more pharmaceutically acceptable excipients, wherein the composition is not in the form of a powder or granules.

[0060] In a further embodiment, the present invention provides a stable pharmaceutical composition suitable for enteral administration comprising (i) edaravone, and (ii) one or more pharmaceutically acceptable excipients, wherein the composition is not in the form of a powder for solution.

[0061] In a further embodiment, the present invention provides a stable pharmaceutical composition suitable for oral administration comprising (i) edaravone, and (ii) one or more pharmaceutically acceptable excipients, wherein the composition is not in the form of a powder for oral solution.

[0062] In a further embodiment, the present invention provides a stable pharmaceutical composition suitable for oral administration comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients, wherein the composition is not in the form of an oral suspension.

[0063] In a further embodiment, the present invention provides a stable pharmaceutical composition suitable for oral administration comprising (i) edaravone, and (ii) one or more pharmaceutically acceptable excipients, wherein the composition is not in the form of a powder for oral suspension.

[0064] In a further embodiment, the present invention provides a stable pharmaceutical composition suitable for oral administration comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients, wherein the composition is an easy-to-swallow oral solution.

[0065] As used herein, the term "solvent" or "pharmaceutically acceptable solvent" or "vehicle" or "pharmaceutically acceptable vehicle" refers to any liquid medium used to dilute or dissolve enteral formulations, such as water, aqueous organic solvents, non-aqueous organic solvents, and other liquids described herein or used in the pharmaceutical and / or food industries. The solvent of the present invention is selected from water, alcohol, propylene glycol, polyethylene glycol, glycerin, dimethylacetamide, N-methyl-pyrrolidone, dimethyl sulfoxide, or a mixture thereof. The solvent of the present invention is selected from water, alcohol, propylene glycol, polyethylene glycol, glycerin, dimethylacetamide, N-methyl-pyrrolidone, dimethyl sulfoxide, or a mixture thereof. Preferably, water, purified water, alcohol, glycerin, and propylene glycol are used as liquid media. The non-aqueous solvent can include alcohol, glycerin, propylene glycol, polyethylene glycol, N-methyl-pyrrolidone, dimethyl sulfoxide, or a mixture thereof. In a preferred embodiment, the concentration of these pharmaceutically acceptable solvents in the compositions of the present invention ranges from about 5% to about 90%, preferably from about 10% to about 70%, and more preferably from about 15% to about 60%, based on the total weight of the composition.

[0066] In one embodiment, the present invention provides a stable solution suitable for enteral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients selected from the group consisting of solubility enhancers, cosolvents, antioxidants, crystallization inhibitors, pH adjusters, buffers, stabilizers, preservatives, flavoring agents, sweeteners, and mixtures thereof.

[0067] In one embodiment, the present invention provides a stable solution suitable for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients selected from the group consisting of solubility enhancers, cosolvents, antioxidants, crystallization inhibitors, pH adjusters, buffers, stabilizers, preservatives, flavoring agents, sweeteners, and mixtures thereof.

[0068] In one embodiment, the present invention provides a stable solution suitable for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients selected from the group consisting of solubility enhancers, cosolvents, antioxidants, crystallization inhibitors, pH adjusters, buffers, stabilizers, preservatives, flavoring agents, sweeteners, and mixtures thereof.

[0069] In one embodiment, the present invention provides a stable solution suitable for oral administration, comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable non-aqueous solvent; and (iii) one or more pharmaceutically acceptable excipients selected from the group consisting of solubility enhancers, cosolvents, antioxidants, crystallization inhibitors, pH adjusters, buffers, stabilizers, preservatives, flavoring agents, sweeteners, and mixtures thereof.

[0070] In a further embodiment, the present invention provides a stable solution suitable for intragastric administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients selected from the group consisting of solubility enhancers, co-solvents, antioxidants, crystallization inhibitors, pH adjusters, buffers, stabilizers, preservatives, flavoring agents, sweeteners, and mixtures thereof.

[0071] In a further embodiment, the present invention provides a stable solution suitable for enteral administration consisting essentially of (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients selected from the group consisting of solubility enhancers, co-solvents, antioxidants, crystallization inhibitors, pH adjusters, buffers, stabilizers, preservatives, flavoring agents, sweeteners, and mixtures thereof.

[0072] In one embodiment, the present invention provides a stable solution suitable for enteral administration, comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients selected from the group consisting of solubility enhancers, cosolvents, antioxidants, crystallization inhibitors, pH adjusters, buffers, stabilizers, preservatives, flavoring agents, sweeteners, and mixtures thereof.

[0073] In a further embodiment, the present invention provides a stable solution comprising: (i) edaravone; (ii) alcohol; (iii) water; and (iv) one or more pharmaceutically acceptable excipients, wherein the amount of water in the solution is up to about 50% W / V, based on the total weight of the solution. In a further embodiment, the present invention provides a stable solution comprising: (i) edaravone; (ii) alcohol; (iii) water; and (iv) one or more pharmaceutically acceptable excipients, wherein the amount of water in the solution is up to about 1% w / v, up to about 5% w / v, up to about 10% w / v, up to about 15% w / v, up to about 20% w / v, up to about 25% w / v, up to about 30% w / v, up to about 35% w / v, up to about 40% w / v, up to about 45% w / v, up to about 50% w / v, up to about 55% w / v, up to about 60% w / v, up to about 65% w / v, up to about 70% w / v, up to about 75% w / v, or up to about 80% w / v, based on the total weight of the solution.

[0074] In one embodiment, the present invention provides a stable solution comprising: (i) edaravone; (ii) a non-aqueous solvent; (iii) purified water; and (iv) one or more pharmaceutically acceptable excipients, wherein the amount of the non-aqueous solvent in the solution ranges from about 10% W / V to about 90% W / V, based on the total weight of the solution.

[0075] In one embodiment, the present invention provides a stable solution comprising (i) edaravone; (ii) alcohol; (iii) purified water; and (iv) one or more pharmaceutically acceptable excipients, wherein the amount of alcohol in the solution ranges from about 10% W / V to about 90% W / V, based on the total weight of the solution.

[0076] In a further embodiment, the present invention provides a stable solution comprising (i) edaravone; (ii) alcohol; (iii) purified water, and (iv) one or more pharmaceutically acceptable excipients, wherein the amount of alcohol in the solution is at least about 10% W / V, at least about 15% W / V, at least about 20% W / V, at least about 25% W / V, at least about 30% W / V, at least about 35% W / V, at least about 40% W / V, at least about 45% W / V, at least about 50% W / V, at least about 55% W / V, at least about 60% W / V, at least about 65% W / V, at least about 70% W / V, at least about 75% W / V, at least about 80% W / V, at least about 85% W / V, or at least about 90% W / V, based on the total weight of the solution.

[0077] In one embodiment, the present invention provides a stable solution comprising (i) edaravone, (ii) alcohol, (iii) purified water, and (iv) one or more pharmaceutically acceptable excipients, wherein the alcohol:water ratio (wt%:wt%) in the solution ranges from about 90:10 to about 10:90. In yet other embodiments, the alcohol:water ratio (wt%:wt%) ranges from about 90:10 to about 10:90, about 80:20 to about 20:80, about 70:30 to about 30:70, about 60:40 to about 40:60, or about 50:50.

[0078] The compositions of the present invention may further include acidifying agents, alkalizing agents, bulking agents, complexing agents, cryoprotectants, chelating agents, density modifiers, electrolytes, plasticizers, volatility modifiers, viscosity modifiers, antifoaming agents, colorants, and other excipients used in pharmaceutical compositions known to those skilled in the art.

[0079] Edaravone is a compound with low water solubility. The solubility enhancer is a compound that improves the solubility of edaravone. Suitable solubility enhancers include one or more solvents, oils, surfactants, hydrophilic polymers, polyhydric alcohols, cyclodextrins, or mixtures thereof. In a preferred embodiment, the concentration of the solubility enhancer ranges from about 0.1% to about 90% based on the total weight of the composition.

[0080] The innovative compositions described herein may include certain solvents as solubility enhancers. Such solvents are used to dissolve active ingredients or pharmaceutical excipients other than the active ingredient. Non-aqueous solvents may include alcohol, glycerin, propylene glycol, polyethylene glycol, N-methyl-pyrrolidone, dimethyl sulfoxide, or mixtures thereof. In preferred embodiments, the concentration of these solvents ranges from about 1% to about 80% based on the total weight of the composition.

[0081] The term "oil" as used herein can function as a non-aqueous solvent or a solubility enhancer, and the function of the oil depends particularly on the amount of oil used in the innovative compositions described herein. More specifically, oils include, but are not limited to, medium-chain fatty acids, medium-chain fatty acid esters of glycerol (e.g., mono-, di-, or triglycerides), medium-chain fatty acid esters of polyethylene glycol, medium-chain fatty acid esters of propylene glycol, long-chain fatty acids, long-chain fatty acid esters of glycerol (e.g., mono-, di-, or triglycerides), long-chain fatty acid esters of polyethylene glycol, long-chain fatty acid esters of propylene glycol, or combinations thereof. In a preferred embodiment, the concentration of the oil ranges from about 1% to about 80% based on the total weight of the composition.

[0082] Suitable surfactants for use in the present invention can be ionic or nonionic surfactants. Suitable ionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include sodium, potassium, and ammonium salts of long-chain alkyl sulfonates and alkylaryl sulfonates, such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinates, such as sodium bis-(2-ethylthiol)-sulfosuccinate; alkyl sulfates, such as sodium lauryl sulfate; quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, and stearyldimethylbenzylammonium chloride; and polyoxyethylene. In a preferred embodiment, the concentration of the ionic surfactant ranges from about 0.05% to about 50% by weight of the total composition.

[0083] Suitable nonionic surfactants that can be used in the present invention include, but are not limited to, glycol stearates such as ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, polyethylene glycol dilaurate, polyethylene glycol monolaurate, polysorbate, polyoxyethylene octylphenyl ether, polyethylene glycol cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, stearoyl monoisopropanolamide, polyoxyethylene hydrogenated tallowamide, polyoxyethylated castor oil (Cremophor™), polyoxyethylene ester of 12-hydroxystearic acid (Solutol™), and PEGylated glycerides (Labrasol™). In a preferred embodiment, the concentration of the nonionic surfactant is from about 0.05% to about 50% by weight of the total composition.

[0084] The hydrophilic polymer referred to herein is a compound derived by adding a large number of smaller units and has a strong affinity for water.Suitable hydrophilic polymer can be selected from the group consisting of povidone, copovidone, hydroxypropyl cellulose or hydroxypropyl methylcellulose.In a preferred embodiment, the concentration of hydrophilic polymer is in the range of about 0.5% to about 50% based on the total weight of the composition.

[0085] The polyhydric alcohol referred to herein is a compound having two or more hydroxyl groups. Non-limiting examples of polyhydric alcohols that can be used include glycerin, propylene glycol, and mannitol. In a preferred embodiment, the concentration of polyhydric alcohol is in the range of about 5% to about 80% based on the total weight of the composition.

[0086] The cyclodextrin can be selected from the group consisting of α-cyclodextrin, β-cyclodextrin, δ-cyclodextrin, γ-cyclodextrin, or derivatives thereof. In a preferred embodiment, the concentration of the cyclodextrin ranges from about 5% to about 80% by weight of the total composition.

[0087] The table below shows the best solubilizers for use in the present invention. [Table 1]

[0088] The present invention involves the use of a solubility enhancer to solubilize the active ingredient (i.e., edaravone). However, edaravone may crystallize over time, losing its desirable properties and shortening its shelf life. The present invention uses a "crystallization inhibitor" or "crystal growth inhibitor" or "crystal inhibitor" to promote the physical stability of edaravone in a liquid formulation. As used herein, the term "crystallization inhibitor" or "crystal growth inhibitor" or "crystal inhibitor" refers to inhibiting the crystallization of the active ingredient, thereby making the formulation physically stable for a longer period of time. Highly disperse silicon dioxide or polymeric substances are suitable as crystallization inhibitors. Examples of polymeric substances include polyvinylpyrrolidone (Kollidon™), polyvinyl alcohol, glycerin, gelatin, starch (derivatives), dextrin and dextran, such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin, dimethyl-β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin, acacia, alginate bentonite, carbomer, calcium carboxymethylcellulose or sodium carboxymethylcellulose, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin gum, hydroxyethylcellulose (HEC), hydroxypropyl Examples of suitable crystallization inhibitors include cellulose (HPC), hydroxypropyl methylcellulose (HPMC), maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum, and any combination thereof; sterols (such as cholesterol) or bile acids (such as cholic acid or lithocholic acid), sugar alcohols selected from erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, polyglycitol, or combinations thereof. In a preferred embodiment, the concentration of the crystallization inhibitor ranges from about 0.5% to about 50% by weight of the total composition.

[0089] In one embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; (iii) a crystallization inhibitor, and (iv) one or more pharmaceutically acceptable excipients.

[0090] In one embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable non-aqueous solvent; (iii) a crystallization inhibitor, and (iv) one or more pharmaceutically acceptable excipients.

[0091] In another embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) alcohol; (iii) purified water; (iv) sorbitol, and (v) one or more pharmaceutically acceptable excipients.

[0092] In yet another embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) alcohol; (iii) purified water; (iv) xylitol, and (v) one or more pharmaceutically acceptable excipients.

[0093] The pharmaceutical composition of the present invention may further comprise a "stability enhancer" or "stabilizer." As used herein, the term "stability enhancer" or "stabilizer" refers to an agent that inhibits, prevents, slows down, or reduces the decomposition of edaravone. More specifically, stability enhancers include amino acids such as glycine, alanine, glutamic acid, sodium glutamate, L-arginine, lysine, L-cysteine, or methionine; sodium chloride or sodium sulfate; ethylenediaminetetraacetic acid (EDTA), metal ions such as zinc, magnesium, and calcium, or mixtures thereof; natural or synthetic gums such as acacia, alginate bentonite, gelatinous argum, alginates, sodium alginate, tragacanth starch, and xanthan gum, and any combination thereof; cellulose derivatives such as carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and polyanionic cellulose; cyclodextrin; sugars; sugar alcohols; monosaccharides, disaccharides, or polysaccharides, or combinations thereof. The concentration of the stabilizer ranges from about 0.001% to about 50% based on the total weight of the composition.

[0094] The pharmaceutical compositions of the present invention can additionally contain an antioxidant. As used herein, the term "antioxidant" refers to an agent used to inhibit oxidation and thus prevent the deterioration of formulations due to the oxidative process. Examples of such compounds include, but are not limited to, sodium bisulfite, ascorbic acid, ascorbyl palmitate, glycine, L-cysteine ​​hydrochloride, L-methionine, butylated hydroxyanisole, butylated hydroxytoluene, hydrophosphorous acid, monothioglycerol, propyl gallate, glutathione, sodium ascorbate, anhydrous sodium citrate, sodium citrate dihydrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite, alpha-tocopherol, and others known to those skilled in the art. The concentration of the antioxidant in the present invention ranges from about 0.001% to about 10%, preferably from about 0.01% to about 5.0%, and more preferably from about 0.05% to about 1.0%, based on the total weight of the composition.

[0095] In one embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; (iii) one or more antioxidants, and (iv) one or more pharmaceutically acceptable excipients.

[0096] In one embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients, wherein the solution does not contain an antioxidant.

[0097] In one embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; (iii) one or more antioxidants, and (iv) one or more pharmaceutically acceptable excipients, wherein the solution does not contain L-cysteine ​​as the antioxidant.

[0098] In another embodiment, the present invention provides a stable solution for oral administration, wherein the solution is sulfite-free, comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; (iii) one or more antioxidants, and (iv) one or more pharmaceutically acceptable excipients.

[0099] The pH of the compositions of the present invention ranges from about 2 to about 7. In some embodiments, the pH of the compositions is preferably between about 2.5 and about 6.0, more preferably between about 3.0 and about 5.5. The pharmaceutical compositions of the present invention can contain a buffer to resist changes in pH due to dilution or the addition of acid or alkali. Non-limiting examples of such compounds include sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, citric acid, ascorbic acid, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, disodium hydrogen phosphate dodecahydrate, lactic acid, Tris buffer, tartaric acid, potassium metaphosphate, potassium phosphate, sodium acetate monobasic, sodium bicarbonate, sodium ascorbate anhydrous, sodium ascorbate monohydrate, sodium tartrate, and others known to those skilled in the art. The concentration of the buffer in the present invention is about 0.001% to about 10% based on the total weight of the composition.

[0100] The pH of the composition can be adjusted with any combination of acidic and / or basic pH adjusters known in the art. Acidic substances include organic and inorganic acids, particularly monocarboxylic, dicarboxylic, and tricarboxylic acids, such as acetic acid, citric acid, tartaric acid, alpha-hydroxy acids, beta-hydroxy acids, salicylic acid, lactic acid, malic acid, glycolic acid, amino acids, and natural fruit acids, or inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, sulfamic acid, phosphoric acid, and combinations thereof. Basic substances include inorganic and organic bases, and combinations thereof. Examples of inorganic bases include, but are not limited to, alkali metal hydroxides (especially sodium, potassium, and ammonium), and alkali metal salts such as sodium borate (borax), sodium phosphate, sodium pyrophosphate, and mixtures thereof. Examples of organic bases include triethanolamine (TEA), diisopropanolamine, triisopropanolamine, aminomethylpropanol, dodecylamine, cocamine, oleamine, morpholine, triamylamine, triethylamine, tetrakis(hydroxypropyl)ethylenediamine, L-arginine, aminomethylpropanol, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol), and PEG-15 cocamine. Such pH adjusters can be present in a concentration ranging from about 0.001% to about 20% based on the total weight of the composition.

[0101] In one embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; (iii) one or more pH adjusting agents, and (iv) one or more pharmaceutically acceptable excipients.

[0102] In one embodiment, the present invention provides a stable solution for oral administration comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, (iii) one or more pH adjusting agents, and (iv) one or more pharmaceutically acceptable excipients, wherein the pH of the solution is in the range of about 2.0 to about 7.0, preferably about 3.0 to about 6.0.

[0103] In one embodiment, the present invention provides a stable solution comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients, wherein the solution does not contain a pH adjuster or buffering agent.

[0104] In addition to stabilizing pharmaceutical formulations against chemical and physical deterioration, liquid formulations, especially multi-dose formulations, must usually be protected from microbial contamination. In one embodiment of the present invention, the pharmaceutical composition may contain a preservative selected from the group consisting of benzoic acid and its sodium or potassium salts, isopropanol, butyl alcohol, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, ethylparaben sodium, methylparaben, methylparaben sodium, phenol, phenylethyl alcohol, phenylethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium, butylparaben, sodium dehydroacetate, sodium propionate, sodium benzoate, sorbic acid, thimerosal, thymol, or a combination thereof. The concentration of the preservative ranges from about 0.001% to about 10% based on the total weight of the composition.

[0105] The pharmaceutical compositions of the present invention may be preservative-free compositions. The term "preservative-free" means that the present compositions and methods do not use preservatives.

[0106] The term "sweetener" refers to both bulk (caloric) and intense (non-caloric) sweeteners that impart sweetness to the formulation. Examples of sweeteners include acesulfame, alitame, aspartame, cyclamate, saccharin, sucralose, acesulfame potassium or sodium cyclamate, sorbitol, xylitol, Magna Sweet 110, and mixtures thereof. The concentration of the sweetener ranges from about 0.001% to about 10% by weight of the total composition.

[0107] The term "flavoring agent" as used herein refers to an agent or mixture of agents that adds flavor to a mixture. The flavoring agent is selected from the group consisting of natural flavoring agents, artificial flavoring agents, and mixtures thereof. Flavoring agents include, but are not limited to, mint, peppermint, cola, apple, vanilla, grape, orange, menthol, peach, apricot, raspberry, cherry, honey, lemon, coconut, pineapple, strawberry banana, mixed berry, mixed red fruit, Magna Sweet 110, and cream flavor, and mixtures thereof. The concentration of the flavoring agent ranges from about 0.001% to about 10% by weight of the total composition.

[0108] Furthermore, it is desirable to have a solution of edaravone that is convenient to administer to patients who cannot ingest solid or liquid dosage forms. Therefore, in such cases, the edaravone solution of the present invention is desirably administered via an indwelling tube, such as a nasogastric tube or other similar tube.

[0109] In a preferred embodiment, the present invention provides a stable solution for oral administration comprising (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients, which can be administered through an indwelling tube, such as a nasogastric tube or other feeding tube (including for the small intestine or duodenum), without causing obstruction, for example, a small-bore needle catheter feeding tube.

[0110] In one embodiment, the present invention provides a stable solution comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients, wherein the composition exhibits bioequivalence to the marketed reference formulation, i.e., Radicava ORS™, upon enteral administration, and the bioequivalence is established by at least one of the following: (i) a confidence interval for mean AUC0-t in the range of about 80% to about 125%, (ii) a confidence interval for mean AUC0-∞ in the range of about 80% to about 125%, (iii) a confidence interval for mean Cmax in the range of about 80% to about 125%, or a combination thereof.

[0111] In one embodiment, the present invention provides a process for preparing a stable solution of edaravone for enteral administration, the process comprising solubilizing edaravone together with other pharmaceutically acceptable excipients in a solvent to obtain a stable solution.

[0112] In one embodiment, the pharmaceutical composition of the present invention is filled into a suitable pharmaceutically acceptable container selected from the group consisting of a bottle, a bag, and a vial.

[0113] In one embodiment, the pharmaceutically acceptable container is a bottle, wherein the bottle is selected from the group consisting of a glass bottle or a plastic bottle, wherein the glass bottle is selected from the group consisting of Type I, II, and III borosilicate glass bottles, and wherein the glass bottle can be an amber glass bottle or a clear glass bottle.

[0114] In another embodiment, the pharmaceutically acceptable container is a bottle, and the bottle is selected from the group consisting of a high density polyethylene (HDPE) bottle, a polyethylene terephthalate (PET), and a polypropylene (PP), and the plastic bottle can be an amber, white opaque, or translucent plastic bottle.

[0115] In preferred embodiments, glass and HDPE bottles are available in fill volumes of about 30 mL, about 50 mL, about 60 mL, about 100 mL, about 120 mL, about 150 mL, about 250 mL, or about 500 mL.

[0116] In one embodiment, the pharmaceutical composition of the present application is packaged in a kit including a bottle with a child-resistant cap, an administration syringe, an adapter, and an administration syringe.

[0117] A pharmaceutically inert gas selected from nitrogen or carbon dioxide can be bubbled through the solution to displace oxygen. Preferably, the solution was kept under a nitrogen or carbon dioxide sparge until the dissolved oxygen in the final solution was less than about 1 ppm.

[0118] According to another embodiment, the pharmaceutical composition of the present invention is packaged in a suitable container and covered with an overpouch or overwrap, preferably a light and oxygen protective overpouch that protects the formulation from the effects of light and the ingress of oxygen, and further provides other moisture and / or gas barriers such as aluminum foil or polypropylene film.

[0119] In one embodiment, an oxygen absorber or scavenger, such as an absorbent material, is disposed between the inner or primary container and the overwrap or overpouch, and in yet another embodiment, an oxygen indicator is disposed to indicate whether oxygen has permeated the overpouch.

[0120] In a preferred embodiment, the present invention provides a stable solution for oral administration comprising: (i) edaravone; (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients, wherein the total oxygen content of the solution is about 10 ppm or less, about 8 ppm or less, about 6 ppm or less, about 5 ppm or less, about 4 ppm or less, about 3 ppm or less, about 2 ppm or less, about 1 ppm or less, or preferably about 0.5 ppm or less.

[0121] stability The term "stable" can refer to physical stability and / or chemical stability. The term "physically stable" refers to a solution of edaravone that is free of visible edaravone crystals and does not tend to precipitate when stored under specific conditions, such as 2-8°C, room temperature, 25°C / 60%RH, 40°C / 25%RH, or 40°C / 75%RH, for a specific period of at least 1 week, 2 weeks, 1 month, 2 months, 6 months, 1 year, or 2 years. The term "chemically stable" refers to a loss of edaravone of about 10% or less under typical commercial storage conditions. Preferably, the formulations of the present invention will have about 8% or less edaravone loss, more preferably about 5% or less edaravone loss, and even more preferably about 3% or less edaravone loss for at least 2 months, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, at least 24 months, at least 30 months, and at least 36 months at 2-8°C, or room temperature, or 25°C / 60% RH, 40°C / 25% RH, or 40°C / 75% RH. In yet another embodiment, the level of total impurities in the compositions of the present invention is less than about 5% w / w, less than about 3% w / w, less than about 2% w / w, less than about 1% w / w, or less than about 0.5% w / w under normal commercial storage conditions. The composition retains at least about 90% of the potency of edaravone as measured by HPLC after storage at 40°C / 75% RH, 40°C / 25% RH, 25°C / 60% RH, or room temperature for at least 6 months. In one embodiment, the composition retains at least about 95% of the potency of edaravone as measured by HPLC after storage at 2-8°C for at least 12 months.

[0122] In one embodiment, the present invention provides a stable solution comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients, wherein the solution is stable when stored under room temperature conditions for an extended period of time without significant loss of potency.

[0123] In one embodiment, the present invention provides a stable solution comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients, wherein the solution is stable for at least 15 days, at least 1 month, at least 2 months, or at least 3 months, or at least 3 months, or at least 6 months, or at least 9 months, or at least 12 months, or at least 24 months when stored at 25°C / 60% RH or 25°C / 40% RH.

[0124] In one embodiment, the present invention provides a stable solution comprising (i) edaravone, (ii) at least one pharmaceutically acceptable liquid solvent, and (iii) one or more pharmaceutically acceptable excipients, wherein the solution is stable for at least 15 days, at least 1 month, at least 2 months, or at least 3 months, or at least 3 months, or at least 6 months, or at least 9 months, or at least 12 months, or at least 24 months when stored at 40°C / 75% RH or 40°C / 25% RH.

[0125] In one embodiment, the present invention provides a stable solution comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients, wherein the solution is stable for at least 1 month, at least 3 months, or at least 6 months, or at least 12 months, or at least 18 months, or at least 24 months, or at least 36 months when stored at 2-8°C.

[0126] In one embodiment, the present invention provides a stable solution comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients, wherein the solution is stable after storage at 2-8°C for at least 18 months and after storage at 25°C or room temperature for at least 30 days.

[0127] Edaravone has known and unknown impurities. In particular, known impurities such as oxidation impurities, phenylhydrazine impurities, dimer impurities, trimer impurities, and amine impurities are observed. The following table shows the potential impurities of Edaravone: [Table 2] JPEG2026505473000004.jpg98141

[0128] In one embodiment, the present invention provides a stable solution intended for enteral administration, wherein the total impurity level in the composition is less than about 5% w / w, less than about 3% w / w, less than about 2% w / w, less than about 1% w / w, or less than about 0.5% w / w as determined by HPLC.

[0129] In another embodiment, the level of unknown impurities in the compositions of the present invention resulting from degradation of edaravone is less than about 2% (W / W), less than about 1.5% (W / W), less than about 1% (W / W), less than about 0.5% (W / W), less than about 0.4% (W / W), less than about 0.3% (W / W), less than about 0.2% (W / W), less than about 0.15% (W / W), and less than about 0.1% (W / W) as determined by HPLC.

[0130] In yet another embodiment, the level of known impurities in the compositions of the present invention resulting from degradation of edaravone is less than about 2% (W / W), less than about 1.5% (W / W), less than about 1% (W / W), less than about 0.5% (W / W), less than about 0.4% (W / W), less than about 0.3% (W / W), less than about 0.2% (W / W), less than about 0.15% (W / W), and less than about 0.1% (W / W) as determined by HPLC.

[0131] In one embodiment, there is provided a stable solution comprising (i) edaravone, (ii) at least one pharmaceutically acceptable solvent; and (iii) one or more pharmaceutically acceptable excipients, wherein the solution is stable at 25°C / 60% RH for at least 3 months.

[0132] In one embodiment, a pharmaceutical composition comprising: (i) edaravone in an amount ranging from about 0.05 mg / mL to about 50 mg / mL; (ii) water in an amount of up to about 50% (W / W); (iii) a non-aqueous solvent in an amount ranging from about 10% (W / W) to about 90% (W / W); (iv) a crystallization inhibitor in an amount ranging from about 0.5% (W / W) to about 50% (W / W); and (v) an antioxidant in an amount ranging from about 0.05% (W / W) to 5.0% (W / W), wherein the pharmaceutical composition is in the form of an oral solution and is stable for at least 3 months when stored at 25°C / 60% RH, 40°C / 75% RH, or 40°C / 25% RH.

[0133] In yet another embodiment, a pharmaceutical composition comprising: (i) edaravone in an amount ranging from about 0.05 mg / mL to about 50 mg / mL; (ii) water in an amount of up to about 50% (W / W); (iii) alcohol in an amount ranging from about 10% (W / W) to about 90% (W / W); (iv) a crystallization inhibitor in an amount ranging from about 0.5% (W / W) to about 50% (W / W); and (v) an antioxidant in an amount ranging from about 0.05% (W / W) to about 5.0% (w / w), wherein the pharmaceutical composition is in the form of an oral solution and is stable for at least 3 months when stored at 25°C / 60% RH, 40°C / 75% RH, or 40°C / 25% RH. [Example]

[0134] The following examples are illustrative and not intended to be limiting. The above disclosure provides many different embodiments for carrying out the features of the present invention, and the following examples describe specific embodiments. Those skilled in the art will understand that other modifications and methods can be applied to the following experimental procedures without departing from the scope of the present invention. Example 1:

[0135] The details of the edaravone composition are shown in Table 3 below. [Table 3]

[0136] A brief manufacturing process flow chart is provided in FIGS.

[0137] Freeze-Thaw Cycle (FTC) Study: The above compositions were subjected to FTC study, where three cycles of FTC were performed at -20°C and room temperature for 24 hours each. [Table 4] [Table 5]

[0138] Example 2: The role of antioxidants [Table 6]

[0139] A brief manufacturing process flow chart is provided in FIGS. [Table 7] [Table 8] [Table 9]

[0140] Example 3: Role of crystallization inhibitors [Table 10]

[0141] A brief manufacturing process flow chart is provided in FIGS. [Table 11] [Table 12] [Table 13] [Table 14]

[0142] Example 4: Edaravone composition [Table 15]

[0143] A brief manufacturing process flow chart is provided in FIGS. [Table 16]

[0144] Example 4: pH Study on Composition J pH studies were performed on composition J and the pH of the final solutions was adjusted to 3.0, 3.5, 4.0, 4.5, and 5.0. Analytical data are as follows: [Table 17] [Table 18]

Claims

1. (i) edaravone, (ii) at least one pharmaceutically acceptable solvent, and (iii) one or more pharmaceutically acceptable excipients wherein the solution is stable for at least 3 months at 25°C / 60%RH.

2. 10. The solution of claim 1, wherein the pharmaceutically acceptable solvent is selected from water, alcohol, glycerin, propylene glycol, glycerin, dimethylacetamide, N-methyl-pyrrolidone, or mixtures thereof.

3. 10. The solution of claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of solubility enhancers, cosolvents, antioxidants, crystallization inhibitors, pH adjusters, buffers, stabilizers, preservatives, flavoring agents, sweeteners, and mixtures thereof.

4. 10. The solution of claim 1, wherein the solution has less than about 0.5% (W / W) oxidative impurities when stored at 2-8°C or 25°C / 60% RH or 40°C / 75% RH for at least 3 months, as measured by HPLC.

5. 10. The solution of claim 1, wherein the solution has been stored for at least 3 months at 2-8°C or 25°C / 60% RH or 40°C / 75% RH and has less than about 0.5% (W / W) dimer impurity as measured by HPLC.

6. 10. The solution of claim 1, wherein the solution has been stored for at least 3 months at 2-8°C or 25°C / 60% RH or 40°C / 75% RH and has less than about 0.5% (W / W) trimer F impurity as measured by HPLC.

7. 10. The solution of claim 1, wherein the solution has a pH in the range of about 2.5 to about 7.

0.

8. 10. The solution of claim 1, wherein the solution is preservative-free.

9. 10. The solution of claim 1, wherein the solution is free of pH adjusters and buffers.

10. 2. The solution according to claim 1, wherein the concentration of edaravone is from about 5 mg / mL to about 50 mg / mL.

11. 2. The solution according to claim 1, wherein the concentration of edaravone is about 21 mg / mL.

12. 10. The solution of claim 1, which is a ready-to-use solution.

13. 10. The solution of claim 1, which is a ready-to-dilute solution.

14. (a) edaravone in an amount ranging from about 0.05 mg / mL to about 50 mg / mL; (b) water in an amount of up to about 50% (w / w); (c) a non-aqueous solvent in an amount ranging from about 10% (w / w) to about 90% (w / w); (d) a crystallization inhibitor in an amount ranging from about 0.5% (w / w) to about 50% (w / w); and (e) an antioxidant in an amount ranging from about 0.05% (W / W) to 5.0% (W / W); A pharmaceutical composition comprising: the composition is in the form of an oral solution; A pharmaceutical composition that is stable for at least 3 months when stored at 25°C / 60% RH or 40°C / 75% RH or 40°C / 25% RH.

15. 15. The composition of claim 14, wherein the non-aqueous solvent is selected from the group consisting of alcohol, glycerin, propylene glycol, polyethylene glycol, N-methyl-pyrrolidone, dimethyl sulfoxide, and mixtures thereof.

16. 15. The composition of claim 14, wherein the crystallization inhibitor is selected from the group consisting of highly dispersed silicon dioxide; polyvinylpyrrolidone; polyvinyl alcohol; hydroxypropyl cellulose; gelatin, glycerin; starch; starch derivatives; dextrin; dextran; sterols; bile acids; sugar alcohols selected from erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, polyglycitol, and combinations thereof; cellulose polymers and non-cellulose polymers; cetostearyl alcohol; methylcellulose; ethylcellulose; gelatin gum; hydroxyethyl cellulose (HEC); hydroxypropyl cellulose (HPC); hydroxypropyl methylcellulose (HPMC); maltodextrin; polyvinyl alcohol; povidone; propylene carbonate; propylene glycol alginate; sodium alginate; sodium starch glycolate; starch tragacanth; xanthan gum; and combinations thereof.

17. 15. The composition of claim 14, wherein the antioxidant is selected from the group consisting of sodium bisulfite, ascorbic acid, ascorbyl palmitate, glycine, L-cysteine ​​hydrochloride, L-methionine, butylated hydroxyanisole, butylated hydroxytoluene, hydrophosphorous acid, monothioglycerol, propyl gallate, glutathione, sodium ascorbate, sodium citrate anhydrous, sodium citrate dihydrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite, alpha-tocopherol, and combinations thereof.

18. 15. The composition of claim 14, further comprising an excipient selected from an antioxidant, a preservative, a buffer, a sweetener, a flavoring agent, a solubility enhancer, and a stability enhancer.

19. 19. The composition of claim 18, wherein the antioxidant is present in an amount ranging from about 0.05% (W / W) to about 5.0% (W / W), the preservative is present in an amount ranging from about 0.1% (W / W) to about 90% (W / W), the buffering agent is present in an amount ranging from about 0.001% (W / W) to about 10% (W / W), the sweetening agent is present in an amount ranging from about 0.001% (W / W) to about 10% (W / W), the flavoring agent is present in an amount ranging from about 0.001% (W / W) to about 10% (W / W), the solubility enhancer is present in an amount ranging from about 0.1% (W / W) to about 90% (W / W), and the stability enhancer is present in an amount ranging from about 0.001% (W / W) to about 50% (W / W). (W / W) of the composition.

20. 19. The composition of claim 18, the preservative is selected from the group consisting of benzoic acid and its sodium or potassium salts, isopropanol, butyl alcohol, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, sodium ethylparaben, methylparaben, sodium methylparaben, phenol, phenylethyl alcohol, phenylethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, sodium propylparaben, butylparaben, sodium dehydroacetate, sodium propionate, sodium benzoate, sorbic acid, thimerosal, thymol, and combinations thereof; the buffering agent is selected from the group consisting of sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, citric acid, ascorbic acid, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, sodium citrate, sodium phosphate monobasic, sodium phosphate dibasic, disodium hydrogen phosphate dodecahydrate, lactic acid, Tris buffer, tartaric acid, potassium metaphosphate, potassium phosphate, sodium acetate monobasic, sodium bicarbonate, sodium ascorbate anhydrous, sodium ascorbate monohydrate, sodium tartrate, and combinations thereof; and the sweetening agent is acesulfame, alitame, aspartame, cyclamate, saccharin, sucralose, acesulfame carbonate, sorbitol ... the flavoring agent is selected from the group consisting of natural flavoring agents, artificial flavoring agents, and mixtures thereof; the solubility enhancer is selected from the group consisting of oils, surfactants, hydrophilic polymers, polyhydric alcohols, cyclodextrins, and mixtures thereof; and the stability enhancer is selected from the group consisting of amino acids; sodium chloride; sodium sulfate; ethylenediaminetetraacetic acid (EDTA), metal ions; natural or synthetic gums; cellulose derivatives; cyclodextrins; sugars; sugar alcohols; monosaccharides; disaccharides; polysaccharides; and combinations thereof.

21. 15. The composition of claim 14, wherein the pH ranges from about 2.5 to about 6.0.

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