Edaravone oral preparation and improved preparation method thereof

Abstract

The present invention relates to a powder for an edaravone oral suspension dosage form. The invention also relates to providing patient compliant, economical and technically advanced dosage forms over existing dosage forms. In addition, compared with the prior art, the patient compliance edaravone preparation prepared according to the invention is proved to be higher in solubility and stability. In addition, the present invention also provides a powder composition for oral suspension prepared by an improved method that is relatively simple, easy for commercial production, and replicable in function.

Description

Field of the Invention:

[0001] The present invention relates to an edaravone powder for oral suspension. In addition, the present invention relates to providing a dosage form that is economical and technologically advanced over existing dosage forms. The present invention provides an edaravone oral suspension powder for oral administration having excellent physical properties and bioavailability. It is expected that the burden on ALS patients and caregivers can be reduced as a result. Background of the invention:

[0003] Edaravone (CAS: 89-25-8) is a member of the substituted 2-pyrazolin-5-one chemical molecule. Edaravone is chemically known as [3-methyl-1-phenyl-2-pyrazolin-5-one], and its structure is shown below:

[0004]

[0005] The active ingredient in RADICAVA and RADICAVA ORS is edaravone, a member of the class of substituted 2-pyrazolin-5-ones. 10 H 10 N2O, molecular weight is 174.20. Edaravone is a white crystalline powder with a melting point of 129.7°C. It is easily soluble in acetic acid, methanol or ethanol, and slightly soluble in water or ether.

[0006] Edaravone was disclosed in DE473214 as early as 1925. The German patent discloses a method for preparing 1-phenyl-3-methylpyrazolone by oxidizing 1-phenyl-3-methylpyrazolone in aqueous hydrochloric acid solution and in the presence of an oxygen-transfer metal salt, characterized in that oxygen or an oxygen-containing metal salt gas is used as an oxidant.

[0007] Edaravone is currently marketed in the United States under the trade name "RADICAVA". This intravenous infusion is indicated for the treatment of amyotrophic lateral sclerosis (ALS). The recommended dose of edaravone is 60 mg administered as an intravenous infusion over 60 minutes. Prior to the U.S. approval, Mitsubishi Tanabe Pharm Co., Ltd. (Osaka, Japan) launched edaravone in Japan under the brand name "RADICUT" as the world's first neurovascular protective drug. RADICUT oral suspension is administered once daily using an oral dosing syringe.

[0008] The recommended dose of edaravone is 60 mg, which should be administered over 60 minutes as two consecutive infusion bags containing 60 mg of edaravone, i.e., 30 mg in each infusion bag. Each 100 mL RADICAVA infusion bag contains edaravone, L-cysteine ​​hydrochloride hydrate, and sodium bisulfate. The pH of the formulation is adjusted with phosphoric acid and sodium hydroxide, and isotonicity is maintained by the addition of sodium chloride. The dosing regimen for edaravone consists of 2 cycles. Cycle 1 consists of an initial treatment cycle of daily dosing for 14 days; followed by a 14-day drug-free period. Subsequent treatment cycles (Cycles 2-6) are dosed daily for 10 of the 14 days; followed by a 14-day drug-free period.

[0009] Currently, edaravone is used as an ALS therapeutic agent. However, edaravone as an ALS therapeutic agent is only provided by injection or using an oral dosage syringe. Therefore, it is desired that an orally administered pharmaceutical product is less burdensome to patients and caregivers and is preferred from the perspective of quality of life (QOL).

[0010] However, unlike injections that are administered directly into the blood, for drugs administered orally, various factors such as absorption from the gastrointestinal tract and the first-pass effect affect bioavailability, making it difficult to obtain drugs that are biologically equivalent to injections. As oral drug products, solid drug products such as tablets and capsules are common. However, when these forms of drug products are taken directly, it is difficult for ALS patients who are expected to have reduced swallowing ability to take these drug products. For these patients, oral administration forms such as liquids and oral suspensions are ideal.

[0011] US6933310 claims a method for treating motor neuron disease, amyotrophic lateral sclerosis (ALS), which mainly comprises administering an effective amount of edaravone or a physiologically acceptable salt thereof to a patient.

[0012] CN1241565C discloses a freeze-dried pharmaceutical composition of Edaravone that is convenient for storage and transportation. According to the Chinese patent, Edaravone powder is suspended in water for injection and an alkaline substance, and then other scaffolding agents are added to prepare a freeze-dried dosage form. However, from the perspective of patient compliance, the invention is not friendly to long-term treatment. Therefore, a patient-compliant invention is needed. WO2009 / 067343 discloses an emulsion formulation in which alcohol, chelating agents and reducing agents are not present. In addition, the emulsifier is selected from egg yolk phospholipids or soybean phospholipids. However, during long-term storage, the poor stability of this liquid emulsion formulation is an obstacle, and a new stable formulation is needed.

[0013] WO2012 / 019381 discloses a fusion-type oral pharmaceutical composition containing edaravone and cyclodextrin. The patent includes mixing edaravone and cyclodextrin into water for 1 to 2 hours. More contact time with water forces edaravone to hydrolyze. The present invention does increase the solubility of edaravone; however, it fails to reduce the inherent oxidation of edaravone. Therefore, a new invention is needed to produce better solubility and significant stability of edaravone in oral dosage forms.

[0014] WO2017 / 157350 discloses a lipid-based drug delivery system comprising edaravone or a pharmaceutically acceptable salt. A solid dispersion comprising edaravone and a polymer carrier. However, the preparation of a solid dispersion of edaravone requires reducing the particle size of the API, and the reduction in particle size increases the surface area of ​​edaravone. Therefore, due to the larger surface area of ​​the particles, the probability of oxidation is higher. Therefore, the invention also fails to minimize the oxidation of edaravone.

[0015] WO2018 / 133957 claims a water-dispersible solid pharmaceutical composition comprising dispersing the pharmaceutical composition into an aqueous liquid to produce an enterally administrable liquid containing at least 0.5 g of the pharmaceutical composition and at least 0.3 g / ml of edaravone, which is then administered to a human patient to provide a dose of 30-300 mg of edaravone. The pharmaceutical composition comprises 2-50% by weight of edaravone and 3-50% by weight of a water-soluble alkalizing agent.

[0016] WO2018 / 134243 discloses a liquid pharmaceutical composition comprising at least 75% by weight of water and 0.2-9 mg / ml of edaravone, wherein the treatment comprises orally or intragastricly administering 10-250 ml of the liquid pharmaceutical composition to provide 30-300 mg of edaravone.

[0017] Toshiki Sato et al. (Pharmacology 2010(85); pp. 88–94) described the pharmacokinetics of edaravone using an edaravone / hydroxypropyl-β-cyclodextrin complex solution including l-cysteine ​​(L-Cys) and sodium bisulfite (SHS). This study demonstrated that L-Cys and SHS are useful for oral mucosal and rectal administration of edaravone.

[0018] Parikh et al. (International Journal of Pharmaceutics, 2016(515); pp. 490-500) discussed the development of an oral delivery system for edaravone. The novel oral delivery system (NODS) for edaravone consisted of a mixture of caprylic acid capric acid macrogol glyceride Labrasol and an acidic water system and was optimized based on solubility and stability studies. The oral bioavailability of the NODS delivery system was found to be 5.7 times higher than that of an edaravone suspension containing 30 mg / mL of edaravone and 0.5% sodium carboxymethylcellulose.

[0019] Parikh et al. (Drug Delivery 2017; 24(1); pp. 962-978) describe a study aimed at enabling oral administration of edaravone by developing a lipid-based nanosystem (LNS). The components of LNS include oil, surfactant, and co-surfactant, selected based on their potential to maximize solubilization in gastrointestinal fluids, reduce its glucuronidation, and improve transmembrane permeability. Liquid LNS (L-LNS) was prepared in the form of a microemulsion, which contained propylene glycol monocaprylate (oil), polyoxyethylene castor oil RH40:caprylic acid capric acid macrogol glyceride:TPGS1000 (1:0.8:0.2) (surfactant) and diethylene glycol monoethyl ether (co-surfactant). The oral bioavailability of L-LNS was found to be almost 11 times higher than that of an edaravone suspension containing 30 mg / ml edaravone and 0.5% sodium carboxymethylcellulose.

[0020] It is worth noting that since Edaravone was used for stroke treatment, its efficacy has achieved undisputed success. Edaravone itself has a wide range of applicability and has the potential to be used for more therapeutic indications. In the case of increased use of this product, the injectable dosage form is a limiting factor. Importantly, the development of an oral dosage form of Edaravone is a challenging process because of its low solubility and permeability (Biopharmaceutics Classification System IV product). In addition, injectable dosage forms have inherent difficulties in use after hospitalization. In addition to this, Edaravone is also very sensitive to hydrolysis and oxidation, making oral preparations even more difficult. The inventors of the present invention noticed during the development process that Edaravone was difficult to stabilize. Compared with the powder form, Edaravone is easily oxidized and decomposed in aqueous solution. The inventors of the present invention have very effectively discovered the above limitations, and therefore developed a stable and effective powder dosage form for oral suspension to meet the needs that are not realized in the prior art.

[0021] The present invention discloses a drug delivery system of edaravone in the form of a powder for oral suspension, which does not use complex technology and is economically affordable compared to oral liquid dosage forms based on parenteral and syringes. In addition, when compared with other edaravone preparations, the formulated powder for oral suspension dosage form prepared according to the present invention provides greater stability. In addition, the oral route is the preferred route of administration for patients with chronic neurodegenerative diseases. In addition, due to the advantages of overcoming hydrolysis and oxidation, easy administration, increasing patient compliance, reducing hospital stay or assisting / monitoring edaravone administration, medical practitioners also prefer powder dosage forms for oral suspension rather than oral liquid dosage forms based on injection and syringes.

[0022] Powders for oral suspension are a heterogeneous mixture containing solid particles large enough to settle. Suspended particles can be seen by the naked eye, which are usually larger than 1 micron and / or 1 nanometer. Generally, the solid portion is dispersed by mechanical agitation using a suspending agent. The present invention overcomes the problems of precipitation and filter cake formation.

[0023] The present invention combines edaravone with a stabilizer that reduces oxidation of edaravone. In addition, the smaller particle size suspension increases the solubility of edaravone by providing a better dissolution profile. In addition, the present invention achieves higher stability of edaravone compared to other existing dosage forms. In addition, the solubility and stability of the patient-compliant edaravone formulation prepared according to the present invention are shown to be higher than the prior art inventions.

[0024] Furthermore, the present invention provides a powder for oral suspension which is prepared by a relatively simple, commercially amenable and functionally reproducible process. In addition, the suspension composition of the present invention can also incorporate two or more active ingredients.

[0025] Purpose of the invention:

[0026] The main object of the present invention is to provide an oral dosage form comprising edaravone and one or more pharmaceutically acceptable excipients, wherein the oral dosage form includes powders for oral suspension and other oral dosage forms.

[0027] The primary object of the present invention is to provide an improved oral pharmaceutical formulation of Edaravone and its pharmaceutically acceptable salts in the form of powder in unit dose sachets for oral suspension.

[0028] Another object of the present invention is to provide an edaravone composition, an economical and advanced dosage form that is superior to existing dosage forms.

[0029] Another general object of the present invention is to provide a method that solves the problems of existing dosage forms.

[0030] Another object of the present invention is to provide an oral dosage form in the form of a powder for oral suspension having an improved taste and thus high patient compliance.

[0031] Another object of the present invention is to provide a composition for use as a medicine and a method for preparing the same. Summary of the invention:

[0033] Despite the extensive research on edaravone reported in prior art publications, powders for oral compositions of edaravone are not available worldwide. Therefore, there remains an unmet need to develop oral compositions of edaravone with good stability and patient compliance.

[0034] Therefore, the present invention provides an oral composition of edaravone containing a pharmaceutically acceptable excipient and a preparation method thereof, wherein the composition is preferably a powder for oral suspension dosage form.

[0035] In a general aspect, the pharmaceutical composition according to the present invention is in the form of a powder for oral preparation, which, when reconstituted in water in a serving cup, is shaken for 1 minute to obtain a suitable suspension for oral administration, and the powder does not adhere to the walls and bottom of the mixing cap.

[0036] In another aspect, the stable pharmaceutical composition of the present invention comprises edaravone and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of an oral powder suspension.

[0037] In one aspect of the present invention, the edaravone particles in the suspension of the present invention are solid particles comprising edaravone, and may be formed by edaravone alone or may comprise other components. Edaravone may also be in a crystalline or amorphous form.

[0038] In another aspect of the present invention, wherein the active ingredient in the pharmaceutical composition comprises a particle size D90 in the range of 1 to 100 microns, preferably D90 in the range of 2 to 80 microns.

[0039] In another aspect of the present invention, the pharmaceutical composition prepared therein has a particle size ranging from nanometers to micrometers, thereby having a good in vitro dissolution curve.

[0040] According to another aspect of the present invention, the product prepared is an oral dosage suspension which is a powder for oral suspension, thereby giving a good in vitro dissolution profile.

[0041] According to an additional aspect of the present invention, the formulation manufactured therein has a particle size in the nanometer to micrometer range, which results in good bioabsorption.

[0042] Another aspect of the present invention, wherein the pharmaceutical composition is manufactured by multiple stages in the manufacturing process including granulation, homogenization, sonication, mixing and / or evaporation by flash mixer granulator and / or spray drying.

[0043] According to another aspect of the present invention, the formulated product is a stable powder in the form of a unit dose sachet for oral suspension.

[0044] In another aspect of the present invention, wherein the pH value of the pharmaceutical composition is in the range of 2-6.

[0045] One aspect of the present invention may include a pharmaceutical composition comprising about 0.1 mg to 2000 mg of edaravone and a pharmaceutically acceptable excipient.

[0046] Another aspect of the pharmaceutical composition may include edaravone as an active ingredient, and one or more selected from pharmaceutically acceptable excipients, such as fillers or diluents, solubilizers, wetting agents or surfactants, solvents, pH adjusters, antioxidants, stabilizers, flavoring agents, sweeteners, etc.

[0047] Another aspect is a kit comprising one or more unit dose sachets of edaravone powder, a syringe and a supply cup, and optionally a drinking cup. The edaravone powder is dispensed in the supply cap, drinking water is added via a syringe, and after mixing, the patient drinks from the drinking cup.

[0048] In another aspect of the present invention, the pharmaceutical composition is in the form of a powder for oral suspension comprising:

[0049] a) Place all materials in separate containers.

[0050] b) converting the raw API to edaravone and converting one or more pharmaceutically acceptable diluents to Part A;

[0051] c) co-converting part A into part B with one or more pharmaceutically acceptable diluents;

[0052] d) one or more pharmaceutically acceptable pH adjusters, antioxidants, stabilizers, flavoring agents and sweeteners are separately used as part C;

[0053] e) adding a sufficient amount of one or more pharmaceutically acceptable solubilizers and surfactants to the solvent as part D;

[0054] f) mixing part B with the solution of part D to form part E;

[0055] g) drying Part E and transferring the dried particles as Part F;

[0056] h) mixing part C with part F as part G;

[0057] i) Pack the powder of Part G in suitable sachets.

[0058] The details of one or more embodiments of the present invention are set forth in the description below. Other features of the present invention will become apparent through the description. Detailed description of the invention:

[0060] The invention will now be disclosed by describing certain preferred and alternative embodiments to facilitate its various aspects.

[0061] Edaravone, chemically known as 3-methyl-1-phenyl-2-pyrazolin-5-one, is a small lipophilic molecule with a molecular weight of 174.203 g / mol and a solubility of 25 μg / mL. Edaravone is considered a Biopharmaceutics Classification System (BCS) Class IV drug because of its poor solubility in water and low lipid permeability. The mean terminal elimination half-life of edaravone is 4.5 to 6 hours.

[0062] References to "a certain," "one," or "various" embodiments in this disclosure do not necessarily refer to the same embodiment, and such references encompass more than one embodiment. Therefore, the following detailed description should not be taken in a limiting sense, and the scope is limited only by the appended claims and the full scope of legal equivalents to which such claims are entitled.

[0063] The term "drug" or "active ingredient" or "active pharmaceutical ingredient (API)" herein refers to edaravone or a pharmaceutically acceptable salt thereof.

[0064] According to the present invention, the pharmaceutical composition of Edaravone comprises Edaravone as an active ingredient and a pharmaceutically acceptable excipient. According to the present invention, the term "Edaravone" used herein includes Edaravone in the form of a free base, a pharmaceutically acceptable salt, amorphous, crystalline, any isomer, derivative, hydrate, solvate or prodrug thereof or a combination thereof.

[0065] The term "pharmaceutical composition" includes oral dosage forms such as, but not limited to, tablets, soft gelatin capsules, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, pellets, mini-tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, sprinkles microspheres and multi-particulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, pellets, mini-tablet units, multiple unit pellet systems, disintegrating tablets, dispersible tablets, granules, sprinkles microspheres and multi-particulates) and sprinkles. The term "oral dosage form" may include one or more of syrups, oral solutions, oral suspensions, oral drops, oral emulsions, mixtures, elixirs, elixirs, and the like.

[0066] The term "pharmaceutically acceptable excipient" as used herein refers to an excipient conventionally used in a pharmaceutical composition. Pharmaceutically acceptable excipients may include fillers or diluents, solubilizers, wetting agents or surfactants, solvents, pH adjusters, antioxidants, stabilizers, flavoring agents, sweeteners, and combinations thereof.

[0067] Suitable fillers or diluents may include one or more sugars, such as lactose, sucrose glucose, fructose, glucose, galactose, starch; cellulose derivatives, such as microcrystalline cellulose; carbonates, such as calcium carbonate; sugar alcohols, such as mannitol, sorbitol, erythritol; magnesium carbonate, calcium phosphate, kaolin, magnesium oxide, magnesium hydroxide; and cellulose derivatives such as Avicel CL-611 (microcrystalline cellulose and sodium carboxymethyl cellulose), etc.

[0068] Suitable solubilizers may include one or more substances selected from surfactants, such as (1) nonionic, such as polyoxyethylene sorbitan fatty acid esters, sorbitan esters, polyoxyethylene ethers, etc. (2) anionic, such as sodium lauryl sulfate, sodium laurate, dialkyl sodium sulfosuccinate, especially bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate and sodium oleate, etc. (3) cationic, such as benzalkonium chloride and bis-2-hydroxyethyl oleylamine, etc. (4) Zwitterionic / amphoteric surfactants; fatty alcohols, such as lauryl alcohol, cetyl alcohol and stearyl alcohol; glycerides, such as naturally occurring monoglycerides, diglycerides and triglycerides; fatty acid esters of fatty alcohols and other alcohols, such as propylene glycol and polyethylene glycol; sucrose; polymers, such as poloxamer, polyvinyl pyrrolidone; glycerides, such as triacetin, glyceryl monocaprylate, glyceryl monooleate, glyceryl monostearate; diethylene glycol monoethyl ether, oleic acid polyethylene glycol glyceride M1944CS, etc.

[0069] Suitable wetting agents or surfactants may include, but are not limited to, one or more selected from the following: sodium lauryl sulfate, heptadecylmethylenetrimethylammonium bromide, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers, such as poloxamer; Pluronic F68; polyglycerol fatty acid esters, such as decaglycerol monolaurate and decaglycerol monomyristate; sorbitan fatty acid esters, such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene monooleate; polyethylene glycol fatty acid esters, such as polyoxyethylene monostearate; polyoxyethylene alkyl ethers, such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, oleic acid macrogol glyceride M1944CS, and the like.

[0070] Polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers, such as poloxamer; Pluronic F68, polyglycerol fatty acid esters, such as decaglycerol monolaurate and decaglycerol monomyristate; sorbitan fatty acid esters, such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid esters, such as polyoxyethylene monostearate; polyoxyethylene alkyl ethers, such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, Sepitrap 80, polysorbate 80 (Tween 80, polyoxyethylene sorbitan monooleate), PEG 6000, PEG 400, etc.

[0071] Solvents play a key role in designing drug delivery systems (DDSs). Specifically, organic solvents are commonly used as reaction media in the pharmaceutical industry. Solvents can safely and effectively dissolve drugs into these drug formulations. In addition, organic solvents suitable for preparing binding solutions may include one or more of water, organic solvents such as ethanol, isopropyl alcohol (IPA), acetone, propylene glycol, glycerol, etc.

[0072] The pH adjuster may include one or more of acetic acid, aminoethylethanolamine, barium carbonate, caustic potash, caustic soda, anhydrous citric acid, citric acid (industrial grade), citric acid, aqueous solution (food grade), ammonium bicarbonate, calcium acid pyrophosphate, gluconic acid, lactic acid, magnesium carbonate, sodium bisulfite, and the like.

[0073] Suitable antioxidants may include one or more of citric acid, butylated hydroxytoluene, butylated hydroxyanisole, sodium bisulfite, ascorbic acid, magnesium bisulfite, sodium metabisulfite, tocopherol, ubiquinol, β-carotene, uric acid, lipoic acid, propyl gallate, thiourea, glutathione, and the like.

[0074] Suitable stabilizers may include one or more of citric acid, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, L-cysteine ​​hydrochloride, magnesium bisulfite, sodium metabisulfite, tocopherol, ubiquinol, β-carotene, uric acid, lipoic acid, propyl gallate, thiourea, glutathione, and the like.

[0075] Suitable flavoring agents may include one or more selected from mint, grapefruit, orange, lime, lemon, tangerine, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, black currant, red currant, gooseberry, willowberry, cumin, thyme, basil, Camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bagamo, sage, aloe balm, spearmint, piperine, eucalyptus, etc.

[0076] Sweeteners are used in oral suspension dosage forms for oral administration to increase the palatability of the therapeutic agent. In addition, suitable sweeteners may include one or more neohesperidin DC / neotame, sucralose, aspartame, neotame, saccharin sodium, sucrose, glycyrrhizin, acesulfame potassium, sorbitol, mannitol, xylitol, high fructose corn syrup.

[0077] Suitable suspending agents or thickening agents may include one or more of sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, xanthan gum, gum arabic, tragacanth gum, bentonite, carbomer, carrageenan, gelatin, and the like.

[0078] One embodiment of the present invention may include a pharmaceutical composition comprising about 0.1 mg to 2000 mg of edaravone and a pharmaceutically acceptable excipient.

[0079] Another embodiment of the present invention includes a pharmaceutical composition comprising edaravone and a pharmaceutically acceptable excipient and a pH adjuster.

[0080] In one embodiment of the present invention, the active ingredient incorporated into the pharmaceutical composition comprises D90 particles with a particle size ranging from 1 to 100 microns, preferably, the D90 particle size ranges from 2 to 80 microns.

[0081] In one embodiment, the pharmaceutical composition prepared according to the present invention is a powder for oral suspension.

[0082] In yet another embodiment of the present invention, wherein the pharmaceutical composition prepared is an oral dosage suspension, which results in a good in vitro dissolution profile.

[0083] According to another embodiment of the present invention, wherein the formulated product prepared is an oral dosage suspension, it is a powder for oral suspension, which results in a good in vitro dissolution profile.

[0084] According to a further embodiment of the present invention, the formulation manufactured therein is a powder for oral suspension, which results in good bioabsorption.

[0085] In another embodiment of the present invention, wherein the pharmaceutical composition is manufactured by multiple stages in the manufacturing process including homogenization, granulation, sonication, mixing and / or evaporation by flash mixer granulator and / or spray drying.

[0086] According to another embodiment of the present invention, the formulated product is a very stable powder for oral suspension.

[0087] In another embodiment of the present invention, the pH value of the pharmaceutical composition is in the range of 2-6.

[0088] In another embodiment, the method includes the step of providing edaravone, wherein the edaravone comprises part A, which can be prepared by mixing edaravone with one or more pharmaceutically acceptable diluents.

[0089] In another embodiment, the method comprises the step of co-sieving Part A with one or more pharmaceutically acceptable diluents and treating it as Part B.

[0090] In another embodiment, the method comprises the steps of transferring one or more pharmaceutically acceptable pH adjusters, antioxidants, stabilizers, flavoring agents and sweeteners separately and considered as Part C.

[0091] In another embodiment, the method includes the step of adding a sufficient amount of one or more pharmaceutically acceptable solubility enhancers and surfactants to the solvent and is considered as part D.

[0092] In one embodiment, the method includes the step of granulating part B with the solution of part D, which is considered to be the yield part E. In another embodiment, the method includes the step of drying part E and transferring the dried granules, which is considered to be the yield part F. In yet another embodiment, the method includes mixing part C with part F, which is considered to be the yield part G.

[0093] In another embodiment, the method comprises the step of packaging the powder of Part G in a suitable sachet.

[0094] Another embodiment is a kit comprising one or more unit dose sachets of Edaravone powder, a syringe and a supply cup and optionally a drinking cup for drinking the medicine. The Edaravone powder is dispensed in the supply cap, drinking water is added through the syringe, mixed and then drunk by the patient in the drinking cup.

[0095] In another embodiment, the method comprises the step of providing the above-described formulation, wherein the formulation is a powder for oral suspension, which can be prepared by a step comprising the steps of:

[0096] In another aspect of the present invention, the pharmaceutical composition is in the form of a powder for oral suspension comprising:

[0097] a) Place all materials in separate containers.

[0098] b) converting the raw API to edaravone and converting one or more pharmaceutically acceptable diluents to Part A;

[0099] c) co-converting part A into part B with one or more pharmaceutically acceptable diluents;

[0100] d) one or more pharmaceutically acceptable pH adjusters, antioxidants, stabilizers, flavoring agents and sweeteners are separately used as part C;

[0101] e) adding a sufficient amount of one or more pharmaceutically acceptable solubilizers and surfactants to the solvent as part D;

[0102] f) mixing part B with the solution of part D to form part E;

[0103] g) drying part E and forming the dried granules as part F;

[0104] h) mixing part C with part F as part G;

[0105] i) Pack the powder of Part G in suitable sachets.

[0106] The present invention will be further described with reference to the following examples; however, the scope of the present invention is not limited thereto. Unless otherwise indicated, all percentages described in this specification are weight percentages. Although the present invention has been described according to its specific embodiments, certain modifications and equivalents are obvious to those skilled in the art and are intended to be included within the scope of the present invention.

[0107] Example 1:

[0108] Table 1

[0109]

[0110] Manufacturing process:

[0111] A.Pack all materials in different containers according to the required quantities.

[0112] B. Pass sorbitol powder through a No. 60 sieve.

[0113] C. Pass edaravone and sorbitol together through a No. 60 sieve.

[0114] D. Co-sieve the mixture from step C above with xanthan gum.

[0115] E. Sieve anhydrous citric acid, sodium bisulfite, L-cysteine ​​hydrochloride, strawberry flavor and sucralose through a No. 60 sieve respectively and store aside.

[0116] F. Add sufficient isopropanol to a stainless steel container. Start slow stirring. Add polysorbate 80, oleyl macrogolglyceride M1944CS and polyethylene glycol 400 under a stirrer. Stir to form a clear solution.

[0117] G. Transfer the materials from step D to a rapid mixing granulator and dry blend.

[0118] H. Granulation of step G using the solution of step F

[0119] I. Transfer the wet granules from step H to a fluid bed dryer. Set the parameters to achieve the desired product temperature and continue the process until the desired drying effect is achieved.

[0120] J. Sieve the granules from step I through a No. 60 sieve.

[0121] K. Transfer the sieved powder from step J to a blender.

[0122] L. Transfer the sieved material from step E to a blender.

[0123] M. Stir for 10 minutes.

[0124] N. Pack the final mixture of step M in double polyethylene bags, place silica bags in between the polyethylene bags and the same polyethylene bag in an aluminum bag and seal appropriately.

[0125] O. Store it in an airtight container.

[0126] P. Final packaging materials should be kept under appropriate storage conditions.

[0127] Q. Carry out filling and sealing of sachets.

[0128] R. Store the sachets under appropriate conditions.

[0129] Example 2:

[0130] Table 2

[0131]

[0132] Manufacturing process:

[0133] A.Pack all materials in different containers according to the required quantities.

[0134] B. Pass sorbitol powder through a No. 60 sieve.

[0135] C. Pass edaravone and sorbitol together through a No. 60 sieve.

[0136] D. Co-sieve the mixture from step C above with sodium carboxymethyl cellulose.

[0137] E. Sieve anhydrous citric acid, sodium bisulfite, L-cysteine ​​hydrochloride, strawberry flavor and sucralose through a No. 60 sieve respectively and store aside.

[0138] F. Add sufficient isopropanol to a stainless steel container. Start slow stirring. Add polysorbate 80, oleyl macrogolglyceride M1944CS and polyethylene glycol 400 under a stirrer. Stir to form a clear solution.

[0139] G. Transfer the materials from step D to a rapid mixing granulator and dry blend.

[0140] H. Granulation of step G using the solution of step f

[0141] I. Transfer the wet granules from step H to a fluid bed dryer. Set the parameters to achieve the desired product temperature and continue the process until the desired drying effect is achieved.

[0142] J. Sieve the granules from step I through a No. 60 sieve.

[0143] K. Transfer the sieved powder from step J to a blender.

[0144] L. Transfer the sieved material from step E to a blender.

[0145] M. Stir for 10 minutes.

[0146] N. Pack the final mixture of step M in double polyethylene bags, place silica bags in between the polyethylene bags and the same polyethylene bag in an aluminum bag and seal appropriately.

[0147] O. Store it in an airtight container.

[0148] P. Final packaging materials should be kept under appropriate storage conditions.

[0149] Q. Carry out filling and sealing of sachets.

[0150] R. Store the sachets under appropriate conditions.

[0151] Example 3:

[0152]

[0153]

[0154] Manufacturing process:

[0155] A.Pack all materials in different containers according to the required quantities.

[0156] B. Pass sorbitol powder through a No. 60 sieve.

[0157] C. Pass edaravone and sorbitol together through a No. 60 sieve.

[0158] D. Co-sieve the mixture from step C above with xanthan gum.

[0159] E. Sieve anhydrous citric acid, sodium bisulfite, L-cysteine ​​hydrochloride, strawberry flavor and sucralose through a No. 60 sieve respectively and store aside.

[0160] F. Add sufficient isopropanol to a stainless steel container. Start slow stirring. Add polysorbate 80, oleyl macrogolglyceride M1944CS and PEG400 under a stirrer. Stir to form a clear solution.

[0161] G. Transfer the materials from step D to a rapid mixing granulator and dry blend.

[0162] H. Granulation of step G using the solution of step F

[0163] I. Transfer the wet granules from step H to a fluid bed dryer. Set the parameters to achieve the desired product temperature and continue the process until the desired drying effect is achieved.

[0164] J. Sieve the granules from step I through a No. 60 sieve.

[0165] K. Transfer the sieved powder from step J to a blender.

[0166] L. Transfer the sieved material from step E to a blender.

[0167] M. Stir for 10 minutes.

[0168] N. Pack the final mixture of step M in double polyethylene bags, place silica bags in between the polyethylene bags and the same polyethylene bag in an aluminum bag and seal appropriately.

[0169] O. Store it in an airtight container.

[0170] P. Final packaging materials should be kept under appropriate storage conditions.

[0171] Q. Carry out filling and sealing of sachets.

[0172] R. Store the sachets under appropriate conditions.

[0173] observe:

[0174] The main challenges during development were achieving the required powder reconstitution time and non-stickiness, as the formulation is in powder form and is administered as a suspension after reconstitution. Any loss of powder due to sticking to the surface of the sachet, mixing cap or supply container could result in inappropriate administration of the drug, resulting in failure to achieve the appropriate therapeutic dose.

[0175] During reconstitution of the powder into suspension, the powder did not adhere to the walls and bottom of the mixing cap and a suitable suspension was obtained. An ideal reconstitution time was observed, i.e. within 1 minute.

[0176] Assay and Dissolution of Edaravone Oral Suspension:

[0177] The content determination and dissolution profile study were performed at different times. The dissolution profile study was observed in a medium defined by the US Food and Drug Administration, which had 30 rpm in 900 ml of 0.1N hydrochloric acid. For this stability study, the oral suspension composition prepared according to Example 3 was observed.

[0178]

[0179]

[0180] The present invention is long-term storage stable. The composition is stable at 30°C / 75% RH and 40°C / 75% RH, and there is no change in color and / or taste.

[0181] The invention described herein includes various objects as described above and descriptions thereof on features, compositions and methods adopted. Although these aspects are emphasized in the present invention, any changes of the above invention are not considered to depart from the spirit and scope of the present invention.

[0182] The above embodiments are for illustrative purposes only and are not intended to limit the present invention.

Claims

1. A pharmaceutical composition in the form of a reconstitutable powder for oral suspension comprising edaravone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

2. The composition of claim 1, comprising edaravone or a pharmaceutically acceptable salt thereof in the form of solid particles having a particle size distribution wherein D90 is in the range of 1 to 100 microns.

3. The composition of claim 1, comprising about 0.005% to 95% mass / volume of edaravone and one or more pharmaceutically acceptable excipients.

4. The composition according to claim 1, comprising a pharmaceutically acceptable excipient selected from fillers or diluents, solubilizers, wetting agents or surfactants, solvents, pH regulators, antioxidants, stabilizers, flavoring agents, sweeteners.

5. The composition of claim 1, comprising (a) 0.005% to 95% mass / volume edaravone (b) 2% to 99% by mass / volume of fillers or diluents (c) 0.05% to 65% mass / volume solubilizer (d) 0.05% to 55% W / V of a wetting agent or surfactant (e) 0.0025% to 25% mass / volume pH adjuster (f) 0.001% to 15% by mass / volume of an antioxidant (g) 0.001% to 15% by mass / volume of a stabilizer (h) 0.005% to 50% by mass / volume of flavoring agent (i) 0.001% to 10% mass / volume sweetener.

6. The composition of claim 1, comprising: (a) edaravone at a concentration of about 0.005 weight percent to about 95 weight percent of the composition; (b) a filler or diluent component at a concentration of about 2% to about 99% by weight of the composition, the filler or diluent component comprising one or more pharmaceutically acceptable filler or diluent components selected from sugars such as lactose, sucrose glucose, fructose, glucose, galactose, starch; cellulose derivatives such as microcrystalline cellulose; carbonates such as calcium carbonate; sugar alcohols such as mannitol, sorbitol, erythritol; magnesium carbonate, calcium phosphate, kaolin, magnesium oxide, magnesium hydroxide; and cellulose derivatives such as Avicel CL-611 (microcrystalline cellulose and sodium carboxymethylcellulose); (c) a solubilizer component at a concentration of about 0.05% to about 65% by weight of the composition, the solubilizer component comprising one or more pharmaceutically acceptable solubilizer components selected from (1) nonionic, such as polyoxyethylene sorbitan fatty acid esters, sorbitan esters, polyoxyethylene ethers, etc. (2) anionic, such as sodium lauryl sulfate, sodium laurate, dialkyl sodium sulfosuccinate, especially sodium bis-(2-ethylhexyl) sulfosuccinate, sodium stearate, potassium stearate and sodium oleate, etc. (3) cationic, such as benzalkonium chloride and bis-2-hydroxyethyl oleylamine, etc. (4) zwitterionic / amphoteric surfactants; fatty alcohols such as lauryl alcohol, cetyl alcohol and stearyl alcohol; glycerides such as naturally occurring mono-, di- and triglycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol; sucrose; polymers such as poloxamers, polyvinyl pyrrolidone; glycerides such as triacetin, glyceryl monocaprylate, glyceryl monooleate, glyceryl monostearate; diethylene glycol monoethyl ether, oleic acid macrogol glyceride M1944CS; (d) a wetting agent or surfactant component at a concentration of about 0.05% to about 55% by weight of the composition, the wetting agent or surfactant component comprising at least one pharmaceutically acceptable wetting agent or surfactant selected from the group consisting of sodium lauryl sulfate, cetyltrimethylammonium bromide, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers such as poloxamer, Pluronic F68, polyglycerol fatty acid esters such as decaglycerol monolaurate and decaglycerol monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, Sepitrap 80, polysorbate 80 (Tween 80, polyoxyethylene sorbitan monooleate), oleic acid macrogolglyceride M1944CS; (e) a pH adjuster component at a concentration of about 0.0025% to about 25% by weight of the composition, the pH adjuster component comprising at least one pharmaceutically acceptable pH adjuster selected from acetic acid, aminoethylethanolamine, barium carbonate, caustic potash, caustic soda, anhydrous citric acid, citric acid (technical grade), citric acid, aqueous solution (food grade), ammonium bicarbonate, calcium acid pyrophosphate, gluconic acid, lactic acid, magnesium carbonate, sodium bisulfite; (f) an antioxidant component at a concentration of about 0.001% to about 15% by weight of the composition, the antioxidant component comprising at least one pharmaceutically acceptable antioxidant selected from the group consisting of citric acid, butylated hydroxytoluene, butylated hydroxyanisole, sodium bisulfite, ascorbic acid, magnesium bisulfite, sodium metabisulfite, tocopherol, ubiquinol, beta-carotene, uric acid, lipoic acid, propyl gallate, thiourea, and glutathione; (g) a stabilizer component at a concentration of about 0.001% to about 15% by weight of the composition, the stabilizer component comprising at least one pharmaceutically acceptable stabilizer selected from citric acid, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, L-cysteine ​​hydrochloride, magnesium bisulfite, sodium metabisulfite, tocopherol, ubiquinol, beta-carotene, uric acid, lipoic acid, propyl gallate, thiourea, and glutathione; (h) a flavor component at a concentration of about 0.005% to about 50% by weight of the composition, the flavor component comprising at least one pharmaceutically acceptable flavoring agent. (i) a sweetener component comprising at least one pharmaceutically acceptable sweetener at a concentration of about 0.001% to about 10% by weight of the composition.

7. The composition according to claim 1, comprising a pharmaceutical composition manufactured by the following steps: (a) All materials should be packed in different containers; (b) converting the raw API to edaravone and converting one or more pharmaceutically acceptable diluents to Part A; (c) co-converting part A into part B with one or more pharmaceutically acceptable diluents; (d) one or more pharmaceutically acceptable pH adjusters, antioxidants, stabilizers, flavoring agents and sweeteners are separately included as part C; (e) adding a sufficient amount of one or more pharmaceutically acceptable solubilizers and surfactants to the solvent as part D; (f) mixing part B with the solution of part D to form part E; (g) drying Part E and forming the dried granules as Part F; (h) mixing part C with part F as part G; (i) Pack the powder of Part G in suitable sachets.

8. The composition according to claim 1, wherein the pH value of the pharmaceutical composition is in the range of 2-6.

9. A composition according to any one of claims 1 to 9 in the form of an oral suspension in a unit dose sachet reconstituted in water.

10. A kit for administering a pharmaceutically active substance, the kit comprising: (a) one or more unit dose packages of edaravone powder; (b) a syringe; (c) Supply cup and (d) Optionally, a drinking cup for drinking the medicine.

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