Oral formulation of edaravone and improved method for producing same

Abstract

The present invention relates to a powder for oral suspension formulation of edaravone. The present invention also relates to providing an economically and technologically advanced dosage form that is more patient-friendly than existing dosage forms. Furthermore, the solubility and stability of the patient-friendly edaravone formulation prepared according to the present invention have been proven to be higher when compared with prior art inventions. Furthermore, the present invention also provides a powder for oral suspension composition prepared by an improved method that is relatively simple, easy to commercially manufacture, and functionally reproducible.

Description

[Technical Field]

[0001] The present invention relates to edaravone powder for oral suspension. Furthermore, the present invention relates to providing a dosage form that is economically and technologically advanced over existing dosage forms. The present invention provides edaravone powder for oral suspension for oral administration that has excellent physical properties and bioavailability. This is expected to reduce the burden on ALS patients and their caregivers. [Background technology]

[0002] Edaravone (CAS: 89-25-8) is a member of the substituted 2-pyrazolin-5-one chemical moiety. Edaravone is chemically known as [3-methyl-1-phenyl-2-pyrazolin-5-one] and is structurally represented as follows: [ka]

[0003] The active ingredient in RADICAVA and RADICAVA ORS is edaravone, a member of the substituted 2-pyrazolin-5-one class. Its molecular formula is C 10 H 10 Edaravone is a white crystalline powder with a melting point of 129.7°C and a molecular weight of 174.20. It is easily soluble in acetic acid, methanol, and ethanol, but slightly soluble in water or diethyl ether.

[0004] Edaravone was disclosed in Patent Document 1 in 1925. The German patent discloses a process for the preparation of 1-phenyl-3-methylpyrazolone by oxidation of 1-phenyl-3-methylpyrazolidone in aqueous hydrochloric acid and in the presence of an oxygen-transfer metal salt, characterized by using oxygen or an oxygen-containing metal salt gas as an oxidizing agent.

[0005] 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 its approval in the United States, Mitsubishi Tanabe Pharm Corp. (Osaka, Japan) marketed edaravone in Japan under the trade name "RADICUT®" as the world's first neurovascular protective drug. RADICUT oral suspension is administered once daily using an oral administration syringe.

[0006] The recommended dose of edaravone is 60 mg, administered in two continuous infusion bags containing 60 mg of edaravone, i.e., 30 mg per infusion bag over 60 minutes. Each 100 ml infusion bag of RADICAVA® 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 adding sodium chloride. The edaravone dosing regimen consists of two cycles. Cycle 1 includes an initial treatment cycle of daily administration for 14 days, followed by a 14-day drug-free period. Subsequent treatment cycles (cycles 2-6) include daily administration for 10 of the 14 days, followed by a 14-day drug-free period.

[0007] Currently, edaravone is used as a therapeutic agent for ALS. However, edaravone as a therapeutic agent for ALS is provided only as an injection or by using an oral administration syringe. Thus, there is a need for an orally administered medical product that reduces the burden on patients and caregivers and is preferable from the perspective of QOL.

[0008] However, unlike injectable drugs that are administered directly into the bloodstream, various factors such as absorption from the gastrointestinal tract and the first-pass effect affect the bioavailability of orally administered pharmaceutical products, making it difficult to obtain pharmaceutical products that are bioequivalent to injectable drugs.

[0009] Orally administered medications are generally solid medications such as tablets and capsules. However, these forms of medications can be difficult for ALS patients who are expected to have impaired swallowing ability. For these patients, oral dosage forms such as liquids and oral suspensions are preferred.

[0010] Patent document 2 claims a method for treating amyotrophic lateral sclerosis (ALS), a motor neuron disease, consisting essentially of administering to a patient an effective amount of edaravone or a physiologically acceptable salt thereof.

[0011] Patent Document 3 discloses a freeze-dried pharmaceutical composition of edaravone for easy storage and transportation. According to this Chinese patent, edaravone powder is suspended in water for injection and alkaline substance, and then other scaffolding agents are added to prepare a freeze-dried dosage form. However, the invention is not considered to be friendly for long-term treatment in terms of patient compliance. Therefore, a patient-friendly invention is needed.

[0012] Patent Document 4 discloses an emulsion formulation that does not contain alcohol, chelating agents, and reducing agents. In addition, the emulsifier is selected from egg yolk phospholipids or soybean phospholipids. However, the poor stability of this liquid emulsion formulation during long-term storage is an obstacle, and a new stable formulation is needed.

[0013] Patent Document 5 discloses an oral pharmaceutical composition containing an inclusion complex of edaravone and cyclodextrin. This patent involves mixing edaravone with cyclodextrin in water for 1 to 2 hours. Prolonged contact with water causes edaravone to hydrolyze. This invention improves the solubility of edaravone; however, it fails to reduce the inherent oxidation of edaravone. Therefore, there is a need for a new invention that provides better solubility along with significant stability of edaravone in oral dosage forms.

[0014] Patent Document 6 discloses a lipid-based drug delivery system containing edaravone or its pharmaceutically acceptable salt. The solid dispersion contains edaravone and a polymer carrier. However, to prepare a solid dispersion of edaravone, the particle size of the API must be reduced to obtain a larger surface area than edaravone. This increases the particle surface area, making oxidation to edaravone more likely. Therefore, this invention also fails to minimize the oxidation effect on edaravone.

[0015] Patent Document 7 claims a solid water-dispersible pharmaceutical composition comprising dispersing a pharmaceutical composition in an aqueous liquid to produce an enterally administrable liquid containing at least 0.5 grams of the pharmaceutical composition and at least 0.3 g / ml of edaravone, and subsequently enterally administering the liquid to a human patient in an amount to provide a dose of 30 to 300 mg of edaravone. The pharmaceutical composition contains 2 to 50 wt.% edaravone and 3 to 50 wt.% water-soluble alkalizing agent.

[0016] Patent Document 8 discloses a liquid pharmaceutical composition which is a single-phase aqueous solution of uncomplexed edaravone containing at least 75 wt.% water and 0.2-9 mg / ml edaravone, wherein treatment comprises oral or intragastric administration of 10-250 ml of the liquid pharmaceutical composition to provide 30-300 mg of edaravone.

[0017] Non-Patent Document 1 describes the pharmacokinetics of edaravone using an edaravone / hydroxypropyl-β-cyclodextrin complex solution containing L-cysteine ​​(L-Cys) and sodium bisulfite (SHS). This study suggested that L-Cys and SHS are useful for oral mucosal and rectal administration of edaravone.

[0018] Non-Patent Document 2 discusses the development of an oral delivery system for edaravone. The novel oral delivery system (NODS) for edaravone is composed of a mixture of Labrasol and an acidic aqueous system 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 edaravone and 0.5% sodium carboxymethylcellulose.

[0019] Non-Patent Document 3 describes a study aimed at enabling oral use of edaravone by developing a lipid-based nanosystem (LNS). The components of the LNS, including oil, surfactant, and co-surfactant, were selected based on their potential to maximize solubilization in gastrointestinal (GI) fluids, reduce its glucuronidation, and improve transmembrane permeability. A liquid LNS (L-LNS) in the form of a microemulsion containing Capryol™ PGMC (oil), Cremophor® RH40:Labrasol®:TPGS 1000 (1:0.8:0.2) (surfactant), and Transcutol® P (co-surfactant), was prepared. The oral bioavailability of L-LNS was found to be approximately 11-fold higher than that of an edaravone suspension containing 30 mg / mL edaravone and 0.5% sodium carboxymethylcellulose.

[0020] It should be noted that the effectiveness of edaravone has been an undeniable success since its launch in the treatment category of stroke management. Edaravone itself has broad applicability and the potential to be used in more therapeutic indications. The injectable dosage form has been a limiting factor in the increased use of this product. Importantly, developing an oral dosage form of edaravone is a difficult process due to its low solubility and low permeability (BCS Class IV product). Furthermore, injectable dosage forms pose inherent challenges regarding their use after hospitalization. Apart from all of this, edaravone is also highly susceptible to hydrolysis and oxidation, thereby making oral formulation more challenging. During development, the inventors realized that stabilizing edaravone was difficult. Edaravone is prone to oxidative degradation in aqueous solution compared to powder form. The above limitations were very effectively identified by the inventors of the present invention, and thus, a stable and effective powder for oral suspension dosage form was developed to fulfill the unmet needs in the prior art.

[0021] The present invention discloses the administration of edaravone in a powder for oral suspension formulation, which does not require sophisticated technology and is economically more affordable than parenteral and syringe-based oral liquid dosage forms. Furthermore, the powder formulated for oral suspension formulation prepared according to the present invention provides greater stability compared to other edaravone formulations. Furthermore, the oral route is the preferred route for administration in patients with chronic neurodegenerative diseases. Furthermore, medical professionals also prefer powder for oral suspension formulation to injection and syringe-based oral liquid dosage forms due to advantages such as overcoming hydrolysis and oxidation, ease of administration, increased patient compliance, and reduced need for hospitalization or assisted / monitored administration of edaravone.

[0022] Oral suspension powders are heterogeneous mixtures containing solid particles large enough to settle. The suspended particles, usually larger than 1 micrometer and / or 1 nanometer, are visible to the naked eye. The solids are generally dispersed by mechanical agitation using a suspending agent. The present invention overcomes the problems of settling and cake formation.

[0023] The present invention incorporates edaravone with a stabilizer that reduces the oxidation of edaravone. Furthermore, the smaller particle size of the suspension increases the solubility of edaravone by providing a better dissolution profile. Furthermore, the present invention achieves higher stability of edaravone compared to other existing dosage forms. Furthermore, the solubility and stability of the patient-compatible edaravone formulation prepared in accordance with the present invention have been proven to be higher than those of prior art inventions.

[0024] Furthermore, the present invention provides powders for oral suspension prepared by a relatively simple, commercially easy, and functionally reproducible method. Additionally, the suspension compositions of the present invention can incorporate two or more active ingredients. [Prior art documents] [Patent documents]

[0025] [Patent Document 1] German Patent No. 473214 [Patent Document 2] U.S. Patent No. 6,933,310 [Patent Document 3] Chinese Patent No. 1241565 [Patent Document 4] International Publication No. 2009 / 067343 [Patent Document 5] International Publication No. 2012 / 019381 [Patent Document 6] International Publication No. 2017 / 157350 [Patent Document 7] International Publication No. 2018 / 133957 [Patent Document 8] International Publication No. 2018 / 134243 [Non-patent literature]

[0026] [Non-Patent Document 1] Toshiaki Sato et.al.(Pharmacology 2010(85);p.88-94) [Non-patent document 2] Parikh et al.(International Journal of Pharmaceutics,2016(515);p.490-500) [Non-patent document 3] Parikh et al.(Drug Delivery 2017;24(1);p.962-978) Summary of the Invention [Problem to be solved by the invention]

[0027] A primary object of the present invention is to provide oral dosage forms comprising edaravone and one or more pharmaceutically acceptable excipients, including powders for oral suspension and other oral dosage forms.

[0028] The main 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.

[0029] Another object of the present invention is to provide a composition of edaravone in a dosage form that is more economical and advanced than existing dosage forms.

[0030] Yet another general object of the present invention is to provide a problem-solving approach to existing dosage forms.

[0031] It is yet another object of the present invention to provide an oral dosage form in the form of a powder for oral suspension that has improved taste, thereby increasing patient compliance.

[0032] It is yet another object of the present invention to provide compositions for use as medicaments and methods for preparation. [Means for solving the problem]

[0033] Despite extensive research on edaravone reported in prior art publications, powder for oral compositions of edaravone is not commercially available worldwide. Thus, there is an unmet need to develop a patient-compatible oral composition for edaravone with good stability.

[0034] Accordingly, the present invention provides an oral composition of edaravone comprising pharmaceutically acceptable excipients, preferably an oral composition of edaravone as a powder for oral suspension dosage form, and a method for preparing the same.

[0035] In one general aspect, the pharmaceutical composition according to the invention is in the form of a powder for oral formulation which, when reconstituted in water held in a supply cup, provides a suitable suspension for oral administration within one minute of shaking and the powder does not adhere to the walls and bottom of the mixing cap.

[0036] In yet another embodiment, a stable pharmaceutical composition according to 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 embodiment of the present invention, the edaravone particles contained in the suspension of the present invention are solid particles containing edaravone, and may be formed of edaravone alone or may contain other components. Edaravone may be in a crystalline state or an amorphous state.

[0038] The active ingredient incorporated into the pharmaceutical composition is D of particle size in the range of 1 to 100 microns. 90 , preferably in the range of 2 to 80 microns 90 Another aspect of the invention includes:

[0039] In yet another aspect of the present invention, the pharmaceutical composition manufactured has particle sizes in the nanometer to micrometer range, resulting in good in vitro dissolution profiles.

[0040] Another embodiment according to the present invention, wherein the formulated product produced is an oral dosage suspension, which is a powder for oral suspension that provides a good in vitro dissolution profile.

[0041] An additional embodiment according to the present invention, wherein the formulation produced has particle sizes in the nanometer to micrometer range, resulting in good bioabsorption.

[0042] In yet another aspect of the present invention, a pharmaceutical composition produced by several stages of a manufacturing process including granulation by rapid mixer granulator and / or spray drying, homogenization, sonication, mixing and / or evaporation.

[0043] An additional aspect according to the present invention is that the formulated product is a stabilized powder in the form of a unit dose sachet for oral suspension.

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

[0045] One embodiment of the present invention may include a pharmaceutical composition comprising approximately 0.1 mg to 2000 mg of edaravone together with a pharmaceutically acceptable excipient.

[0046] Yet another embodiment of the pharmaceutical composition may contain edaravone as an active ingredient together with one or more selected from pharmaceutically acceptable excipients such as fillers or diluents, solubility enhancers, wetting agents or surfactants, solvents, pH adjusters, antioxidants, stabilizers, flavoring agents, and sweeteners.

[0047] 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 ingestion. The edaravone powder is dispensed into the supply cap, and drinking water is added by the syringe, mixed, and consumed by the patient in the drinking cup.

[0048] In another embodiment of the invention, the pharmaceutical composition comprises: a) Distribute all ingredients into separate containers; b) shifting the material API as edaravone together with one or more pharmaceutically acceptable diluents as part-A; c) co-shifting part-A together with one or more pharmaceutically acceptable diluents as part-B; d) separately shifting one or more pharmaceutically acceptable pH adjusters, antioxidants, stabilizers, flavoring agents and sweeteners as part-C; e) adding a sufficient amount of one or more pharmaceutically acceptable solubility enhancers and surfactants into the solvent as part-D; f) granulating Part-B with the solution of Part-D as Part-E; g) Drying part-E and shifting the dried granules as part-F; h) blending Part-C with Part-F as Part-G; i) Packaging the powder of Part-G in suitable sachets It is in the form of a powder for oral suspension comprising:

[0049] The details of one or more embodiments of the invention are set forth in the description below. Other features of the invention will be apparent from the description. DETAILED DESCRIPTION OF THE INVENTION

[0050] Detailed Description of the Invention The present invention will now be disclosed by describing certain preferred and optional embodiments in order to facilitate its various aspects.

[0051] 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. Due to its low aqueous solubility and poor lipid permeability, edaravone is considered a Biopharmaceutics Classification System (BCS) Class IV drug substance. The mean terminal elimination half-life of edaravone is 4.5 to 6 hours.

[0052] References to "an," "one," or "various" embodiments in this disclosure do not necessarily refer to the same embodiment, and such references contemplate more than one embodiment. Therefore, the following detailed description is not to be taken in a limiting sense, and the scope is defined solely by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.

[0053] The term "drug" or "active ingredient" or "active pharmaceutical ingredient (API)" as used herein refers to edaravone or a pharmaceutically acceptable salt thereof.

[0054] According to the present invention, a pharmaceutical composition of edaravone comprising edaravone as an active ingredient together with a pharmaceutically acceptable excipient.

[0055] The term "edaravone" according to the present invention, as used herein, includes edaravone in the form of a free base, a pharmaceutically acceptable salt thereof, amorphous, crystalline, any isomer, derivative, hydrate, solvate or prodrug thereof, or a combination thereof.

[0056] The term "pharmaceutical composition" includes oral dosage forms such as, but not limited to, tablets, soft gelatin capsules, capsules (powder, powder for reconstitution, pellets, beads, minitablets, pills, micropellets, minitablet units, multi-unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, dispersible microspheres and multiparticulates), sachets (filled with powder, pellets, beads, minitablets, pills, micropellets, minitablet units, MUPS, disintegrating tablets, dispersible tablets, granules, dispersible microspheres and multiparticulates) and sprinkles.

[0057] The term "oral dosage form" may include one or more of the following forms: syrup, oral solution, oral suspension, oral drops, oral emulsion, mixture, linktos, elixir, and the like.

[0058] The term "pharmaceutically acceptable excipient" as used herein refers to an excipient that is routinely used in pharmaceutical compositions. Pharmaceutically acceptable excipients can include fillers or diluents, solubility enhancers, wetting agents or surfactants, solvents, pH adjusters, antioxidants, stabilizers, flavoring agents, sweeteners, and combinations thereof.

[0059] Suitable fillers or diluents may include one or more of sugars such as lactose, sucrose, glucose, fructose, dextrose, galactose, starch, and the like; cellulose derivatives such as microcrystalline cellulose; carbonates such as calcium carbonate; sugar alcohols such as mannitol, sorbitol, erythritol, and the like; magnesium carbonate, calcium phosphate, kaolin, magnesium oxide, magnesium hydroxide; and cellulose derivatives such as Avicel CL-611 (microcrystalline cellulose and sodium carboxymethylcellulose).

[0060] Suitable solubility enhancers include 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, sodium dialkyl sulfosuccinates, particularly sodium bis-(2-ethylhexyl) sulfosuccinate, sodium stearate, potassium stearate, and sodium oleate, etc.; (3) cationic, such as benzalkonium chloride and bis-2-hydroxyethyloleylamine, etc.; and (4) zwitterionic surfactants. Ionic / amphoteric surfactants; fatty alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol; glyceryl esters, e.g., naturally occurring mono-, di-, and triglycerides; fatty acid esters of fatty alcohols and other alcohols, such as propylene glycol, polyethylene glycol; sucrose; polymers, e.g., poloxamer, polyvinylpyrrolidone; glycerides, e.g., triacetin, glyceryl monocaprylate, glyceryl monooleate, glyceryl monostearate; diethylene glycol monoethyl ether, Labrafil M 1944 CS; etc. may include one or more from the group comprising:

[0061] Suitable wetting agents or surfactants include, but are not limited to, sodium lauryl sulfate, cetrimide, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers such as poloxamer, Pluronic F68, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl 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), Labrafil M 1944 CS, and the like.

[0062] One or more of the following may be mentioned: polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers such as poloxamer, Pluronic F68, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl 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.

[0063] Solvents play an important role in the design of drug delivery systems (DDS). Specifically, organic solvents are commonly used in the pharmaceutical industry as reaction media. Solvents are uniquely capable of safely and effectively dissolving drugs in these pharmaceutical formulations. Furthermore, suitable organic solvents for preparing the binding solution may include one or more of the following organic solvents: water, ethanol, isopropyl alcohol (IPA), acetone, propylene glycol, glycerin, etc.

[0064] The pH adjuster may include one or more of 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 pyrophosphate, gluconic acid, lactic acid, magnesium carbonate, sodium bisulfite, and the like.

[0065] 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.

[0066] Suitable stabilizers may include one or more of citric acid, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, L-cysteine ​​HCl, magnesium bisulfite, sodium metabisulfite, tocopherol, ubiquinol, β-carotene, uric acid, lipoic acid, propyl gallate, thiourea, glutathione, and the like.

[0067] Suitable flavoring agents may include one or more from the group consisting of peppermint, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, blackcurrant, redcurrant, gooseberry, lingonberry, cumin, thyme, basil, camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bergamot, salvia, aloe vera balsam, spearmint, piperine, eucalyptus, and the like.

[0068] Sweeteners are used in oral suspension pharmaceutical dosage forms, particularly those intended for oral administration, to enhance the palatability of the therapeutic agent. Suitable sweeteners include neohesperidin DC / neotame, sucralose, aspartame, neotame, sodium saccharin, sucrose, Glycyrrhiza glabra, acesulfame potassium, sorbitol, mannitol, xylitol, and high fructose corn syrup. Suitable suspending or thickening agents may include one or more of sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, xanthan gum, acacia, tragacanth, bentonite, carbomer, carrageen, gelatin, and the like.

[0069] One embodiment of the present invention may include a pharmaceutical composition comprising about 0.1 mg to 2000 mg of edaravone together with a pharmaceutically acceptable excipient.

[0070] Another embodiment of the present invention includes a pharmaceutical composition comprising edaravone together with a pharmaceutically acceptable excipient, which comprises a pH adjusting agent.

[0071] In one embodiment of the present invention, the active ingredient incorporated into the pharmaceutical composition is a D 90, preferably in the range of 2 to 80 microns 90 Includes:

[0072] In one embodiment, the pharmaceutical composition prepared in accordance with the present invention is a powder for oral suspension.

[0073] In yet another embodiment of the present invention, the pharmaceutical composition manufactured is an oral dosage suspension that provides a good in vitro dissolution profile.

[0074] Another embodiment according to the present invention, wherein the formulated product produced is an oral dosage suspension, which is a powder for oral suspension that provides a good in vitro dissolution profile.

[0075] An additional embodiment according to the present invention, wherein the formulation produced is a powder for oral suspension which provides good bioabsorption.

[0076] In yet another embodiment of the present invention, a pharmaceutical composition produced by several stages of a manufacturing process including homogenization, granulation, sonication, mixing and / or evaporation by rapid mixer granulator and / or spray drying.

[0077] An additional embodiment according to the present invention is that the formulated product is a highly stabilized powder for oral suspension.

[0078] In yet another embodiment of the present invention, the pH of the pharmaceutical composition is in the range of 2-6.

[0079] In another embodiment, the method comprises a step for providing edaravone, wherein the edaravone is contained in part-A, which can be prepared by mixing edaravone with one or more pharmaceutically acceptable diluents.

[0080] In another embodiment, the method includes co-staining Part-A with one or more pharmaceutically acceptable diluents to form Part-B.

[0081] In another embodiment, the method includes separately shifting one or more pharmaceutically acceptable pH adjusters, antioxidants, stabilizers, flavoring agents and sweeteners, designated as Part-C.

[0082] In yet another embodiment, the method comprises adding a sufficient amount of one or more pharmaceutically acceptable solubility enhancers and surfactants to the solvent to form part-D.

[0083] In one embodiment, the process comprises granulating Part-B with the solution of Part-D to give Part-E.

[0084] In another embodiment, the method comprises drying Part-E and shifting the dried granules to form Part-F.

[0085] In yet another embodiment, the method comprises blending Part-C with Part-F to form Part-G.

[0086] In another embodiment, the method comprises packaging the powder of Part-G in a suitable sachet.

[0087] 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 ingestion, wherein the edaravone powder is dispensed into the supply cap, and drinking water is added by the syringe, mixed, and consumed by the patient in the drinking cup.

[0088] In another embodiment, the method comprises the steps of providing the formulation described above, wherein the formulation comprises: a) distributing all ingredients into separate containers; b) shifting the material API as edaravone together with one or more pharmaceutically acceptable diluents as part-A; c) co-shifting Part-A with one or more pharmaceutically acceptable diluents to form Part-B; d) separately shifting one or more pharmaceutically acceptable pH adjusters, antioxidants, stabilizers, flavoring agents and sweeteners as part-C; e) adding a sufficient amount of one or more pharmaceutically acceptable solubility enhancers and surfactants into the solvent as part-D; f) granulating Part-B with the solution of Part-D as Part-E; g) drying Part-E and shifting the dried granules as Part-F; h) blending Part-C with Part-F as Part-G; i) packaging the powder of Part-G into suitable sachets and (c) preparing a powder for oral suspension by a process comprising:

[0089] The present invention will be further described with reference to the following examples, which do not limit the scope of the present invention. All percentages set forth herein are by weight unless otherwise specified. Although the present invention has been described with reference to specific embodiments thereof, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Example 1: [Table 1]

[0090] Manufacturing Procedure: A. Distribute all ingredients into separate containers according to the amount required. B. Sift the sorbitol powder through a 60# sieve. C. Co-sieve edaravone and sorbitol through a 60# sieve. D. Co-shift onto the mixture of step C and xanthan gum. E. Shift anhydrous citric acid, sodium bisulfite, L-cysteine ​​HCl, strawberry flavor and sucralose separately through a 60# sieve and keep aside. F. Add a sufficient amount of isopropyl alcohol to a SS vessel. Start stirring at low speed. Add Polysorbate 80, Labrafil M 1944 CS, and Polyethylene Glycol 400 therein under stirring. Stir to form a clear solution. G. Transfer the materials from step D to a Rapid Mixer Granulator and dry mix. H. Granulation in step G is carried out using the solution in step F. I. Transfer the wet granules from Step H to a fluid bed dryer. Set parameters to achieve the required product temperature and continue the process until the desired dryness is achieved. J. Shift the granules from step I through 60#. K. Transfer the shifted powder from step J into a blender. L. Transfer the shifted material from step E into a blender. M. Blend for 10 minutes. N. The final blend of step M is packaged in a double lined polyethylene bag with a silica bag sandwiched between two polyethylene bags and the same polyethylene bag is placed in an aluminium bag and properly sealed. O. Store it in an airtight container. P. Final packaged materials should be kept under appropriate storage conditions. Q. Fill and seal the sachets. R. Store the sachets under appropriate conditions. Example 2:

[0091] [Table 2]

[0092] Manufacturing Procedure: A. Distribute all ingredients into separate containers according to the amount required. B. Sift the sorbitol powder through a 60# sieve. C. Co-sieve edaravone and sorbitol through a 60# sieve. D. The above mixture of step C is co-shifted with sodium carboxymethylcellulose. E. Shift anhydrous citric acid, sodium bisulfite, L-cysteine ​​HCl, strawberry flavor and sucralose separately through a 60# sieve and keep aside. F. Take a sufficient amount of isopropyl alcohol into a SS vessel. Start stirring at low speed. Add Polysorbate 80, Labrafil M 1944 CS and Polyethylene Glycol 400 therein under stirring. Stir to form a clear solution. G. Transfer the materials from step D to a Rapid Mixer Granulator and dry mix. H. Granulation in step G is carried out using the solution in step F. I. Transfer the wet granules from Step H to a fluid bed dryer. Set parameters to achieve the required product temperature and continue the process until the desired dryness is achieved. J. Shift the granules from step I through 60#. K. Transfer the shifted powder from step J into a blender. L. Transfer the shifted material from step E into a blender. M. Blend for 10 minutes. N. The final blend of step M is packaged in a double lined polyethylene bag with a silica bag sandwiched between two polyethylene bags and the same polyethylene bag is placed in an aluminium bag and properly sealed. O. Store it in an airtight container. P. Final packaged materials should be kept under appropriate storage conditions. Q. Fill and seal the sachets. R. Store the sachets under appropriate conditions. Example 3:

[0093] [Table 3]

[0094] Manufacturing Procedure: A. Distribute all ingredients into separate containers according to the amount required. B. Sift the sorbitol powder through a 60# sieve. C. Co-sieve edaravone and sorbitol through a 60# sieve. D. Co-shift onto the mixture of step C and xanthan gum. E. Shift anhydrous citric acid, sodium bisulfite, L-cysteine ​​HCl, strawberry flavor and sucralose separately through a 60# sieve and keep aside. F. Take a sufficient amount of isopropyl alcohol into a SS vessel. Start stirring at low speed. Add Polysorbate 80, Labrafil M 1944 CS and PEG 400 therein under stirring. Stir to form a clear solution. G. Transfer the materials from step D to a Rapid Mixer Granulator and dry mix. H. Granulation in step G is carried out using the solution in step F. I. Transfer the wet granules from Step H to a fluid bed dryer. Set parameters to achieve the required product temperature and continue the process until the desired dryness is achieved. J. Shift the granules from step I through 60#. K. Transfer the shifted powder from step J into a blender. L. Transfer the shifted material from step E into a blender. M. Blend for 10 minutes. N. The final blend of step M is packaged in a double lined polyethylene bag with a silica bag sandwiched between two polyethylene bags and the same polyethylene bag is placed in an aluminium bag and properly sealed. O. Store it in an airtight container. P. Final packaged materials should be kept under appropriate storage conditions. Q. Fill and seal the sachets. R. Store the sachets under appropriate conditions. observation:

[0095] Because the formulation is in powder form and administered after reconstitution in suspension form, the main challenges during development were achieving the desired reconstitution time and non-stickiness of the powder. Any loss of powder due to adhesion to the surfaces of the sachet, mixing cap or supply container can lead to inadequate administration of the drug, and therefore failure to achieve the appropriate therapeutic dose.

[0096] During reconstitution of the powder into suspension, the powder does not stick to the walls and bottom of the mixing cap and a proper suspension is obtained. The desired reconstitution time observed, i.e., within 1 minute. Assay and dissolution of edaravone oral suspension:

[0097] Assays and dissolution profile studies were conducted at various time periods. The dissolution profile study was conducted in a USFDA-defined medium with 900 mL of 0.1 N hydrochloric acid at 30 rpm. For this stability study, the oral suspension composition prepared according to Example 3 was monitored.

[0098] [Table 4]

[0099] The present invention is storage stable over long periods of time. The composition is stable at 30° C. / 75% RH and 40° C. / 75% RH with no change in color and / or taste.

[0100] The invention described herein includes various objectives as set forth above, as well as descriptions thereof with respect to the properties, compositions, and processes employed. While these aspects are emphasized in the present invention, any variation of the invention described above should not be considered a departure from the spirit and scope of the invention as described.

[0101] The above examples are provided for illustrative purposes only and are not intended to limit the invention in any way.

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. 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 with D90 in the range of 1 to 100 microns.

3. 10. The composition as claimed in claim 1, comprising about 0.005% to 95% W / V edaravone together with one or more pharmaceutically acceptable excipients.

4. 10. The composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of fillers or diluents, solubility enhancers, wetting agents or surfactants, solvents, pH adjusters, antioxidants, stabilizers, flavoring agents, and sweeteners.

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

6. (a) edaravone in a concentration of about 0.005% to about 95% by weight of the composition; (b) a filler or diluent component at a concentration of about 2% to about 99% by weight of the composition, said filler or diluent component comprising one or more pharmaceutically acceptable filler or diluent components selected from the group consisting of sugars such as lactose, sucrose glucose, fructose, dextrose, galactose, starch, etc.; 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 (microcrystalline cellulose and sodium carboxymethylcellulose) such as Avicel CL-611; (c) a solubility enhancer component at a concentration of about 0.05% to about 65% by weight of the composition, said solubility enhancer component comprising one or more pharmaceutically acceptable solubility enhancer components, said solubility enhancer component being (1) non-ionic, e.g., polyoxyethylene sorbitan fatty acid esters, sorbitan esters, polyoxyethylene ethers, and the like; (2) Anionic, such as sodium lauryl sulfate, sodium laurate, sodium dialkyl sulfosuccinate, particularly sodium bis-(2-ethylhexyl) sulfosuccinate, sodium stearate, potassium stearate, and sodium oleate. (3) Cationic, such as benzalkonium chloride and bis-2-hydroxyethyloleylamine. (4) Zwitterionic / Amphoteric surfactants; fatty alcohols such as lauryl alcohol, cetyl alcohol, and stearyl alcohol; glyceryl esters such as naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol; sucrose; polymers such as poloxamer, polyvinylpyrrolidone, glycerides such as triacetin, glyceryl monocaprylate, glyceryl monooleate, glyceryl monostearate; diethylene glycol monoethyl ether, Labrafil M 1944 CS a solubility enhancer component selected from the group consisting of: (d) a wetting agent or surfactant component at a concentration of about 0.05% to about 55% by weight of the composition, comprising at least one pharmaceutically acceptable wetting agent or surfactant selected from the group consisting of sodium lauryl sulfate, cetrimide, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers such as poloxamer, Pluronic F68, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl 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), Labrafil M 1944 CS; (e) a pH adjuster component at a concentration of about 0.0025% to about 25% by weight of the composition, comprising at least one pharmaceutically acceptable pH adjuster selected from the group consisting of 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 pyrophosphate, gluconic acid, lactic acid, magnesium carbonate, and sodium bisulfite; (f) an antioxidant component at a concentration of about 0.001% to about 15% by weight of the composition, 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, β-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, comprising at least one pharmaceutically acceptable stabilizer selected from the group consisting of citric acid, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, L-cysteine ​​HCl, magnesium bisulfite, sodium metabisulfite, tocopherol, ubiquinol, β-carotene, uric acid, lipoic acid, propyl gallate, thiourea, and glutathione; (h) a flavoring component at a concentration of about 0.005% to about 50% by weight of said composition, said flavoring component comprising at least one pharmaceutically acceptable flavoring agent. (i) a sweetener component at a concentration of about 0.001% to about 10% by weight of the composition, the sweetener component comprising at least one pharmaceutically acceptable sweetener. The composition of claim 1 comprising:

7. The following steps: (a) distributing all ingredients into separate containers; (b) shifting the material API as edaravone together with one or more pharmaceutically acceptable diluents as part-A; (c) co-shifting Part-A with one or more pharmaceutically acceptable diluents as Part-B; (d) separately shifting one or more pharmaceutically acceptable pH adjusters, antioxidants, stabilizers, flavoring agents and sweeteners as part-C; (e) adding a sufficient amount of one or more pharmaceutically acceptable solubility enhancers and surfactants into the solvent as Part-D; (f) granulating Part-B with the solution of Part-D as Part-E; (g) drying Part-E and shifting the dried granules as Part-F; (h) blending Part-C with Part-F as Part-G; (i) packaging the powder of Part-G into suitable sachets; 10. The composition of claim 1, comprising a pharmaceutical composition manufactured by

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

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

10. 1. A kit for administering a pharmaceutically active substance, comprising: (a) one or more unit dose sachets of edaravone powder; (b) a syringe; (c) a serving cup; and (d) optionally, a drinking cup for consumption; Includes a kit.

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