DESC:FIELD OF THE INVENTION
The present invention relates to the liquid compositions of amyotrophic lateral sclerosis drug. More particularly, the present invention relates to the oral suspensions of edaravone or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION
Edaravone, which is a member of the substituted 2-pyrazolin-5-one class and chemically known as [3-methyl-1-phenyl-2-pyrazolin-5-one], is a therapeutic agent having medical use in treating amyotrophic lateral sclerosis (ALS; United States Patent Number 6,933,310, incorporated herein by reference in its entirety) in addition to being a brain function normalizing agent.

ALS as one type of motor neuron disease is an intractable disease that leads to respiratory failure from initial symptoms such as weakness in hands, movement disorders with fingers and fascicular contraction in upper limbs, through symptoms such as amyotrophia and/or muscular weakness, bulbar paralysis and fascicular contraction in muscles. ALS is divided into upper limb, bulbar, lower limb and mixed types, depending on a site of onset. In all of these types, as symptoms progress, a systemic muscle group is affected. Causal factors of ALS have not yet been sufficiently elucidated. The following hypotheses have been proposed as main causal factors of ALS: (1) autoimmune theory (appearance of an autoantibody against a Ca channel); (2) excessive excitatory amino acid and/or toxication theory (an increase in extracellular glutamic acid and transport disorders of glutamic acid); (3) oxidative stress disorder theory (Cu/Zn superoxide dismutase (SOD) genetic abnormality and nerve cell damage caused by free radicals); (4) cytoskeleton disorder theory (accumulation of neurofilament in motor nerve cells and appearance of inclusion bodies); and (5) deficiency of neurotrophic factors.

Edaravone is a white crystalline powder with a melting point of 129.7°C. It is freely soluble in acetic acid, methanol, or ethanol and slightly soluble in water or diethyl ether. The molecular formula of edaravone is C10H10N2O and its molecular weight is 174.20. The structural formula of edaravone is shown in figure 1.

Figure 1
Edaravone was approved by the United States Food and Drug Administration (USFDA) in the form of intravenous solution in May 2017 (RADICAVA®). RADICAVA® intravenous solution is available in two strengths: 30mg/100mL (0.3mg/mL) & 60mg/100mL (0.6mg/mL). The higher strength of RADICAVA® intravenous solution (0.6mg/mL) was approved by the USFDA in November 2018.

Then, recently in May 2022, the USFDA also approved RADICAVA ORS (edaravone). RADICAVA ORS is an oral suspension of edaravone which is a white to off-white color, opaque, homogenous suspension containing 105 mg of edaravone per 5 mL of suspension (21mg/mL). RADICAVA ORS contains L-cysteine hydrochloride hydrate, polyvinyl alcohol, simethicone emulsion, sodium bisulfite, sorbitol, and xanthan gum as inactive ingredients. Phosphoric acid and sodium hydroxide are added to adjust to pH 4. RADICAVA ORS is supplied in a multi-dose amber glass bottle.

The recommended dosage of RADICAVA ORS is 105mg (5mL) taken orally or via feeding tube in the morning after overnight fasting. RADICAVA ORS is administered according to the following schedule:
• An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period.
• Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug free periods.
The pharmacy storage and handling conditions of RADICAVA ORS include, storage at refrigerated conditions, i.e. between 2°C to 8°C while protected from light. RADICAVA ORS should not be frozen and it should be stored upright. While, the patient storage and handling conditions of RADICAVA ORS include, storage upright at room temperature between 20°C to 25°C while protected from light. RADICAVA ORS should be discarded after 15 days of opening bottle or if unopened, after 30 days from the date of shipment indicated on the carton pharmacy label.

Edaravone oral suspensions:
The United States Patent Number 10,987,341 (Hayama et al., Mitsubishi Tanabe Pharma Corp, incorporated herein by reference in its entirety) discloses & teaches edaravone suspension for oral administration which comprises: water; edaravone particles comprising edaravone dispersed in the water; and a dispersant dispersing the edaravone particles in water such that the dispersant maintains the edaravone particles in a solid particle state in the water, wherein a blending amount of the edaravone particles is in a range of 0.5% (w/v) to 36% (w/v), and the dispersant is at least one dispersant selected from the group consisting of polyvinyl alcohol, methylcellulose, hypromellose, sucrose fatty acid ester and polysorbate.

According to the specification of the US’341 patent, any dispersant that allows the edaravone particles to be well dispersed in water without causing the edaravone particles to form secondary agglomerates may be used. However, the US’341 patent prefers those dispersants exhibiting a transmission scattering light intensity of 1% or more. Here, “1% or more” means a range of 1%-100% (the US’341 patent at col 3, lines 64-67; col 4, lines 1-2). Examples of such dispersants include polyvinyl alcohol, sucrose fatty acid ester, polysorbate, methylcellulose, and hypromellose (the US’341 patent at col 4, lines 27-30).

Further, according to the specification of the US’341 patent, a dispersant exhibiting a contact angle of 80 degrees or less can also be suitably used. Here, “80 degrees or less” means a range of 0-80 degrees (the US’341 patent at col 4, lines 31-33). Examples of a dispersant exhibiting a contact angle of 80 degrees or less include polyvinyl alcohol, sucrose fatty acid ester, polysorbate, hypromellose, and the like (the US’341 patent at col 4, lines 52-54).

Per the specification of the US’341 patent, specific examples of a preferred dispersant are one or more selected from a group of polyvinyl alcohol, sucrose fatty acid ester, polysorbate, methylcellulose and hypromellose. Particularly preferably, the dispersant is one or two selected from a group of polyvinyl alcohol and methylcellulose, and most preferably, the dispersant is polyvinyl alcohol (the US’341 patent at col 4, lines 55-61).

The specification of the US’341 patent further teaches that, in order for the edaravone particles to maintain a well dispersed state for a long period of time, a thickening agent may be blended. By containing a thickening agent, an effect is achieved that the suspension is easily swallowed without a risk of aspiration even for patients with dysphagia and, when being administered to humans, variation in drug concentration in blood among patients is greatly reduced, and a more stable drug effect can be expected (the US’341 patent at col 5, lines 15-22). As the thickening agent, a pharmaceutically known thickening agent can be used. Specifically, for example, carmellose sodium, dextrin, tragacanth powder, xanthan gum, and the like can be used. From a perspective of storage stability of edaravone, tragacanth powder and xanthan gum are preferable, and xanthan gum is most preferable (the US’341 patent at col 5, lines 23-28). Thus, the specification of the US’341 patent separately teaches use of dispersing agent such as polyvinyl alcohol, sucrose fatty acid ester, polysorbate, methylcellulose & hypromellose and thickening agent such as tragacanth powder & xanthan gum.

Further, the inventors of the US’341 patent in Test Example-1, tested various dispersants such as Gum Arabic Powder, Bentonite, Polyvinyl Alcohol, Sodium Alginate, Xanthan Gum, Sucrose Fatty Acid Ester, Tragacanth Powder, Methylcellulose, Hypromellose and Carmellose Sodium. However, amongst these, the inventors of the US’341 patent found that only polyvinyl alcohol, methylcellulose, sucrose fatty acid ester, and hypromellose can suitably disperse edaravone particles in water.

Further, in Test Example-2, the inventors of the US’341 patent carried out transmission scattering light intensity test of Polyvinyl Alcohol, Methylcellulose, Sucrose Fatty Acid Ester, Hypromellose, Gum Arabic Powder, Bentonite, Tragacanth Powder, Sodium Alginate, Xanthan Gum, Carmellose Sodium, MACROGOL 6000, D-sorbitol, & Polysorbate 80 and found out that only Polyvinyl alcohol, Methylcellulose, Sucrose fatty acid ester, Hypromellose and Polysorbate 80 has a transmission scattering light intensity ?T % of 1% or more whereas Gum Arabic Powder, Bentonite, Tragacanth Powder, Sodium Alginate, Xanthan Gum, Carmellose Sodium, MACROGOL 6000, & D-sorbitol did not have transmission scattering light intensity ?T % of 1% or more and therefore they are not useful.

Furthermore, in Test Example-3, the inventors of the US’341 patent carried out contact angle test and found out that amongst Polyvinyl Alcohol, Sucrose Fatty Acid Ester, Hypromellose, Gum Arabic Powder, Bentonite, Tragacanth Powder, Sodium Alginate, Xanthan Gum, Carmellose Sodium, D-sorbitol and Polysorbate 80, only Polyvinyl Alcohol, Sucrose Fatty Acid Ester, Hypromellose and Polydorbate 80 exhibits a contact angle of 80 degrees or less.

Hence, from the disclosure & teachings of the specification of the US’341 patent it can be said that only Polyvinyl alcohol, Methylcellulose, Sucrose fatty acid ester, Hypromellose and Polysorbate 80 can disperse edaravone particles in water and other additives such as Gum Arabic Powder, Bentonite, Tragacanth Powder, Sodium Alginate, Xanthan Gum, Carmellose Sodium, MACROGOL 6000, & D-sorbitol cannot disperse edaravone particles in water and therefore are not useful.

Another United States Patent Number 11,241,416 (Hayama et al., Mitsubishi Tanabe Pharma Corp, incorporated herein by reference in its entirety) discloses & teaches edaravone suspension for oral administration. The US’416 patent is a continuation of the U.S. Patent No. 10,987,341 and therefore its disclosure & teachings are same as the disclosure & teachings of the US’341 patent.

The United States Patent Application Publication Number 2021/0251965 (Hayama et al., Mitsubishi Tanabe Pharma Corp, incorporated herein by reference in its entirety) also teaches edaravone suspension for oral administration. The US’965 publication is a continuation in-part of the U.S. Patent No. 11,241,416 and therefore its disclosure & teachings are similar to the disclosure & teachings of the US’416 patent.

Another United States Patent Application Publication Number 2022/0110915 (Hayama et al., Mitsubishi Tanabe Pharma Corp, incorporated herein by reference in its entirety) discloses & teaches a method of treating amyotrophic lateral sclerosis comprising orally administering, an oral formulation comprising edaravone, wherein the oral formulation is an edaravone suspension comprising water, the edaravone comprising edaravone particles dispersed in water, and a dispersant dispersing the edaravone particles in the water such that the dispersant maintains the edaravone particles in a solid particle state in the water. The US’915 publication is a continuation of the U.S. Patent No. 11,241,416 and therefore have disclosure & teachings similar to the US’416 patent.

Another United States Patent Application Publication Number 2022/0142982 (Shimizu et al., Mitsubishi Tanabe Pharma Corp, incorporated herein by reference in its entirety) discloses & teaches a method of administering a pharmaceutical composition comprising edaravone, comprising: orally or intragastrically administering, to a subject in need thereof, a pharmaceutical composition comprising edaravone with a first time interval from a consumption of a meal by the subject in need thereof to an administration of the pharmaceutical composition to the subject in need thereof, wherein the first time interval is 8 hours or longer after the consumption of a high-fat meal, the first time interval is 4 hours or longer after the consumption of a standard meal, or the first time interval is 2 hours or longer after the consumption of a light meal.

The pharmaceutical composition used in the studies provided in the US’982 publication comprises edaravone, polyvinyl alcohol, xanthan gum, sodium hydrogen sulfite, L-cysteine hydrochloride hydrate, sodium hydroxide, phosphoric acid, simethicone emulsion, D-sorbitol, and purified water which is similar to the qualitative composition of RADICAVA ORS.

The International Publication Number WO 2021/009775 (Shah et al., BDR Pharmaceuticals International Private Limited, incorporated herein by reference in its entirety) discloses & teaches oral suspensions of edaravone. The WO’775 publication on page 06 and in lines 21-23 states that “the prime objective of the present invention is that the pharmaceutical composition establishes a dual release pattern owing to kind of solubilizes used in the formulation and thereby producing an immediate burst absorption followed by delayed absorption”. Further, the WO’775 publication teaches nano-suspension of edaravone wherein particle size D100 of edaravone is less than 8 microns (WO’775 publication at page 14, lines 26-27 & page 15, lines 1-2; Figures 1 & 2).

The WO’775 publication further teaches that the edaravone suspensions disclosed therein contain hydroxypropyl methylcellulose (HPMC E15 premium) to entrap some of the drug molecules in order to maintain maintenance release just after burst release. Further, it can be seen that the WO’775 publication essentially teaches use of polysorbate 80 (Examples 1, 2, 6, 7, 8, 11 & 12) and hydroxypropyl methylcellulose (Examples 1, 2, 3, 4, 5, 10, 11 & 12).

Thus, looking at the published prior art documents, it can be said that the formulation scientists either have essentially used polyvinyl alcohol, methylcellulose, sucrose fatty acid ester, polysorbate 80 or hypromellose as the only preferred dispersants to disperse edaravone particles in water (Hayama et al.) or have prepared nano-suspensions of edaravone with essential use of polysorbate 80 and/or hydroxypropyl methylcellulose (Shah et al.).

Further, other prior art documents also exist which disclose & teach different formulations of edaravone. For example, the United States Patent Number 11,020,375 (Zhou et al., Suzhou Auzone Biological Technology Co Ltd., incorporated herein by reference in its entirety) discloses lipid based drug delivery system comprising edaravone or its salt and a lipid (Edaravone formulation 1). According to the US’375 patent, the lipid-based drug delivery system is selected from a lipid solution, a lipid suspension, surfactant or polymer-lipid mixed micelles, a self-microemulsifying drug delivery system (SMEDDS) and a nano-emulsion formulation.

The US’375 patent also discloses solid phase dispersion formulation comprising edaravone or its salt and a polymer carrier (Edaravone formulation 2). According to the US’375 patent, the solid phase dispersion formulation may be formulated into a tablet, a ring, a patch, a capsule, a pellet, granules, fine granules or powders. The US’375 patent also discloses a micelle-based formulation (Edaravone formulation 3), comprising edaravone or its salt, a polymer carrier and water/a buffering agent. An effective amount of edaravone is included in the micelle.

The US’375 patent also discloses a co-solvent-based formulation (Edaravone formulation 4), comprising edaravone or its salt, and 1-99% (v/v) of a water-soluble organic solvent and/or a surfactant or co-surfactant. According to the US’375 patent, the above edaravone formulations 1-3 may be formulated as a solid dosage form, selected from a tablet, a capsule, powders or strips (strip), by oral, parenteral, inhalation, topical or transdermal, intranasal, ocular, ear, rectal, vaginal route. The above edaravone formulations 1-4 may be formulated as a liquid dosage form, selected from a solution, a suspension, an emulsion, a co-solvent-based system, an aerosol, by oral, parenteral, inhalation, topical or transdermal, intranasal, intraocular, ear, rectal, vaginal route. And the above edaravone formulations 1-4 may be formulated as a semi-solid dosage form, selected from an ointment, a cream, a gel, a paste, by topical or transdermal route, for a topical or systemic administration purpose.

Journal of Pharmaceutical Sciences 103:730-742, 2014, International Journal of Pharmaceutics 515 (2016) 490-500, and Drug Delivery, 24:1, 962-978 describe CMC-Na suspensions of edaravone. However, it is described that when these suspensions were administered to animals, all of them had low bioavailability. The entire contents of these publications are incorporated herein by reference.

Japanese Patent Application Publication Number 2004/91441 describes an edaravone solution for oral administration using an aqueous solution of tragacanth gum, and it is described that a sufficient concentration in blood was obtained in rats. However, the concentration in blood is lower than a result of the CMC-Na suspension described in Journal of Pharmaceutical Sciences 103:730-742, 2014, International Journal of Pharmaceutics 515 (2016) 490-500, and Drug Delivery, 24:1, 962-978, and a drug product described in the document does not have bioavailability comparable to that of an injection either. The entire contents of these publications are incorporated herein by reference.
Edaravone oral solutions:
Japanese Patent Application Publication Number 2004/91441 describes an edaravone solution for oral administration using an aqueous solution of tragacanth gum, and it is described that a sufficient concentration in blood was obtained in rats. However, the concentration in blood is lower than a result of the CMC-Na suspension described in Journal of Pharmaceutical Sciences 103:730-742, 2014, International Journal of Pharmaceutics 515 (2016) 490-500, and Drug Delivery, 24:1, 962-978, and a drug product described in the document does not have bioavailability comparable to that of an injection either. The entire contents of these publications are incorporated herein by reference.

Sato et al. (Pharmacology 85:88-94, 2010) teaches novel administration route of edaravone, i.e. mucosal absorption of edaravone from edaravone/hydroxypropyl-beta-cyclodextrin complex solution including L-cysteine and sodium bisulfite. However, this publication does not talk about preparation of edaravone oral suspensions.

To overcome low bioavailability in suspensions, the International Publication Number WO 2018/134243 (Moolenaar et al., Treeway TW001 B.V.) describes an edaravone solution having excellent absorbability. However, due to low solubility of edaravone in water, a dose of this solution becomes as high as 100 mL and thus is not preferable from a perspective of medication adherence of patients. The entire contents of these publications are incorporated herein by reference.

Similarly, the International Publication Number WO 2019/008144 (Van Der Geest et al., Treeway TW001 B.V.) also describes an edaravone solution. However, here also, due to low solubility of edaravone in water, a dose of this solution becomes as high as 100 mL and thus is not preferable from a perspective of medication adherence of patients. The entire contents of these publications are incorporated herein by reference.
Other edaravone oral compositions:
The International Publication Number WO 2012/019381 (Nanjing Normal University & Nanjing Baite Biological Engineering Co. Ltd.) oral pharmaceutical composition containing inclusion of edaravone and cyclodextrin and preparation method thereof. The entire contents of these publications are incorporated herein by reference.

The United States Patent Number 11,135,199 (Simcere Pharmaceutical Co., Ltd.) discloses sublingual tablet composition of edaravone. However, said composition also comprises (+)-2-borneol.

The United States Patent Application Number 2021/0128529 (Nobelpharma Co. Ltd.) discloses a medicament comprising edaravone, a glutathione analogue and an aqueous solvent, which is free of sodium bisulfite. Though, the US’529 publication states that the administration route of the medicament of the present invention is not particularly limited and can be administered orally or parenterally, the edaravone compositions prepared in the US’529 publication are aqueous solutions of edaravone and are injections.

Hence, in view of the above paragraphs, it can be said that, oral suspensions of edaravone are not much explored and the earlier disclosed edaravone suspensions either require specific dispersants (US Patent 10,987,341 & its family patents/applications) or require preparation of nano-suspension which principally contains polysorbate 80 and/or hydroxypropyl methylcellulose (WO 2021/009775). Therefore, the need still exists in the art for the preparation of the edaravone oral suspensions which eliminate abovementioned specific requirements/limitations and can simply be prepared using commonly available excipients in an economic way.

The inventors of the present invention have therefore attempted to prepare aqueous edaravone oral suspensions which contain the same concentration of edaravone as present in the marketed edaravone oral suspension, RADICAVA ORS and do not contain any of the dispersant specifically required by the US Patent 10,987,341 (viz. polyvinyl alcohol, sucrose fatty acid ester, polysorbate 80, methylcellulose and hypromellose). Since, amyotrophic lateral sclerosis is a long term treatment, these suspensions contain excipients which are known to be safe for patients, if taken for longer period of time making them more patients compliant.

Further, as opposed to the prior art documents, the aqueous edaravone oral suspensions of the present invention also do not contain one or more of chelating agents, complexing agents, solubility enhancing agents, glidants, or diluents.
OBJECTS OF THE INVENTION
Thus, it is an object of the present invention to provide aqueous edaravone oral suspensions which do not include any of the dispersants preferred by the prior art document(s), viz. polyvinyl alcohol, sucrose fatty acid ester, polysorbate 80, methylcellulose and hypromellose.

Another object of the present invention is to provide aqueous edaravone oral suspensions which do not show secondary aggregation of the edaravone particles and/or floating of the edaravone particles on liquid surface during appearance observations of the dispersibility test.

A further object of the present invention is to provide aqueous edaravone oral suspensions having the same edaravone concentration as the marketed edaravone oral suspension, RADICAVA ORS. A yet another object of the present invention is to provide aqueous edaravone oral suspensions which contain only one release mechanism, i.e. immediate release mechanism.

It is documented that aqueous solutions of edaravone are very unstable because it is present as edaravone anion, which is capable of transferring an electron to free radicals including oxygen, and becomes edaravone radical. Hence, the present invention also provides non-aqueous edaravone oral suspensions.

A yet another object of the present invention is to provide process for preparation of the edaravone oral suspensions of the present invention.

A yet another object of the present invention is to provide use of the edaravone oral suspension for treating amyotrophic lateral sclerosis (ALS). A yet another object of the present invention is to provide use of the edaravone oral suspension for the management of diseases and abnormal conditions which are mitigated by the administration of edaravone.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides edaravone oral suspensions. The edaravone oral suspensions of the present invention include both aqueous as well as non-aqueous suspensions.
Aqueous edaravone oral suspensions:
The aqueous edaravone oral suspensions of the present invention do not include any of the dispersants preferred by the US Patent 10,987,341 viz. polyvinyl alcohol, sucrose fatty acid ester, hypromellose, methylcellulose and polysorbate 80. On the contrary, the aqueous edaravone oral suspensions of the present invention include those additives/excipients which specifically have not been preferred by the US Patent 10,987,341 and in spite being that fact, the suspensions do not show secondary aggregation of the edaravone particles and/or floating of the edaravone particles on liquid surface during appearance observations of the dispersibility test. Further, no sedimentation was observed when the suspensions were kept under storage conditions for prolonged time.

Further, as opposed to the prior art documents, the aqueous edaravone oral suspensions of the present invention also do not contain one or more of chelating agents, complexing agents, solubility enhancing agents, glidants, or diluents.

The aqueous edaravone oral suspensions of the present invention contain edaravone concentration same as the marketed edaravone oral suspension RADICAVA ORS (i.e. 21mg/mL). Further, the aqueous edaravone oral suspensions of the present invention does not contain dual release mechanism and shows only immediate release mechanism.

The aqueous edaravone oral suspensions of the present invention comprise edaravone and a pharmaceutically acceptable excipient selected from the group consisting of preservatives, antioxidants/stabilizing agents, wetting agents, suspending agents/thickening agents, antifoaming agents, pH adjusting agents/buffers, anticaking agents, dispersing agents and combinations thereof. Water is the preferred vehicle for aqueous edaravone oral suspensions. However, organic solvents may also be used along with the water.

Microbiological contamination presents a significant health hazard in liquid formulations. Therefore, the use of preservatives or disinfectants become inevitable to prevent the growth of microorganisms during the product’s manufacture and shelf life, although it may be most desirable to develop a “preservative-free” formulation to address the increasing concerns about the biological activity of these compounds. Most formulations require some kind of preservative to ensure no microbial growth. Non-limiting examples of preservatives when used in the formulations of the present invention include alcohol, ethanol, chlorobutanol, phenoxyethanol, potassium benzoate, benzyl alcohol, benzoic acid, potassium sorbate, sorbic acid, quaternary amine (such as benzalkonium chloride), benzethonium chloride, cetrimonium bromide, cetylpyridinium chloride, bronopol, chlorbutol, chlorocresol, cresol, parahydroxybenzoates (or parabens), phenol, thymol, phenylethanol, sodium benzoate, antimicrobial solvents like propylene glycol, glycerin, chloroform and the like.

The parahydroxybenzoate preservative(s) if incorporated in the present compositions is/are selected from the group comprising methyl p-hydroxybenzoate (methyl paraben), ethyl p-hydroxybenzoate (ethyl paraben), propyl p-hydroxybenzoate (propyl paraben), butyl p-hydroxybenzoate (butyl paraben), isobutyl p-hydroxybenzoate (isobutyl paraben), isopropyl p-hydroxybenzoate (isopropyl paraben), benzyl p-hydroxybenzoate (benzyl paraben) and the like and mixtures thereof.

Antioxidants are the compounds that can reduce a drug that has been oxidized, or compounds that are more readily oxidized than the agents they are to protect (oxygen scavengers) and therefore also known as stabilizing agents. Non-limiting examples of antioxidants/stabilizing agents include amino acids, butylated hydroxytoluene, butylated hydroxyanisole, tert-butyl-hydroquinone, 4-hydroxymethyl-2, 6-di-tert-butylphenol, 2, 4, 5- trihydroxybutyrophenone, alkylgallates, propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gallic acid, nordihydroguaiaretic acid, glycine, ascorbic acid, fatty acid esters of ascorbic acid such as ascorbyl palmitate and ascorbyl stearate, and salts of ascorbic acid such as sodium, calcium, or potassium ascorbate; erythorbic acid, L-carnitine, monothioglycerol, acetyl L-carnitine, thioglycolic acid, N-acetyl cysteine, cysteines, glutathione, methionines, tartaric acid, citric acid, fumaric acid, glycolic acid, oxalic acid, succinic acid, ellagic acid, malic acid, maleic acid, tocopherols such as, but not limited to, delta tocopherol, alpha tocopherol; lipoic acid, thiolated polymers such as, but not limited to, polymethacrylic-SH, carboxymethylcellulose-cysteine, polycarbophil-cysteine, beta-carotene, carotenoids, flavonoids, flavones, isoflavones, flavanones, catechins, anthocyanidins, chalcones, sulfites, bisulfites, pyrosulfites, polyoxyethylene polyoxypropylene glycol, EDTA or a combination thereof may be employed.

Examples of sulphites include sodium sulfite, potassium sulfite, and calcium sulfite. Examples of bisulfites include sodium bisulfite, potassium bisulfite, and ammonium bisulfite. Examples of pyrosulfites include sodium pyrosulfite and potassium pyrosulfite. Further, examples of cysteines include L-cysteine, DL-cysteine, N-acetylcysteine, hydrochlorides thereof, and the like.

Wetting agents as used herein are routinely used in the pharmaceutical formulations, especially in liquid dosage forms to create a homogeneous dispersion of solid particles in a liquid vehicle. For an aqueous vehicle, alcohol, glycerin, and propylene glycol are frequently used wetting agents. Whereas for a non-aqueous liquid vehicle, mineral oil is commonly used as a wetting agent. Non-limiting examples of wetting agents are Alcohols, Benzalkonium chloride, Benzethonium chloride, Cetylpyridinium chloride, Docusate sodium, Mineral oil, Nonoxynol 9, Octoxynol, Poloxamer, Poloxamer 124, Poloxamer 188, 237, 338, 407, Polyoxyl 35 castor oil, Polyoxyl 40 hydrogenated castor oil, Polyoxyl 10 oleyl ether, Polyoxyl 20 cetylstearyl ether, Polyoxyl 40 stearate, Propylene glycol, Sodium lauryl sulfate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan monostearate, Glycerin, Tyloxapol and the like or combinations thereof.

Suspending agents/thickening agents can be classified into cellulose derivatives, clays, natural gums, and synthetic gums. In many cases, these excipients are used in combination. There are many water soluble hydrocolloids that can act as suspending agents in the formulation of pharmaceutical suspensions. They can be of natural, semi-synthetic or synthetic origin. Non-limiting examples of suspending agents are Acacia, Agar, Alginic acid, Carbomer, Dextrin, Gelatin, Gellan gum, Sodium alginate, Hydroxyethyl cellulose, Hydroxypropyl cellulose, Hydroxypropyl starch, Maltodextrin, Modified starch, Pectin, Polycarbophil, Polyethylene glycol, Polyvinyl acetate, Potassium alginate, Polyvinyl pyrrolidone, Pregelatinized starch, Propylene glycol alginate, Sodium alginate, Colloidal silicon dioxide, Carboxymethyl cellulose or an alkali metal salt thereof, gum Arabic, Karaya gum, Sterculia gum, Tragacanth, Xanthan gum, Bentonite, Carrageenan, Guar gum, and the like or combinations thereof.

Anti-foaming agents may be used in the preparation of the liquid pharmaceutical compositions of the present invention to lower the surface tension and cohesive binding of liquid phase. Non-limiting examples of anti-foaming agents are simethicone, dimethicone, organic phosphates, alcohols, paraffin oils, stearates, glycols and the like.
It is necessary and advantageous if the edaravone particles in the suspension of the present invention are in a well dispersed state, and even when the edaravone particles have settled after a long period of time of storage, the edaravone particles can be quickly redispersed by shaking (for example, manual or mechanical shaking). A behavior of redispersion can be confirmed visually or using a spectroscopic method (for example, using a laser diffraction particle size distribution device). It may therefore be beneficial to include dispersing in the suspensions of the present invention. Non-limiting examples of dispersing agents include veegum (magnesium aluminum silicate), microcrystalline cellulose, and the like.

Upon storage of the liquid suspensions, particles may settle down at the bottom of the container and forms a hard cake which creates hurdles in re-dispersion of the suspension. It may therefore be suitable to use anti-caking agents in the suspensions. Anti-caking agents if used in the suspensions of the present invention, without limitation, include one or more from colloidal silicon dioxide, tribasic calcium phosphate, magnesium trisilicate, starch and the like.

Organic solvents if used in the suspensions of the present invention, without limitation include dichloromethane, acetonitrile, ethyl acetate, acetone, propylene carbonate, glycerin, coconut fatty acid diethanolamide, medium and/or long chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soyabean oil, peanut oil, corn oil, corn oil monoglycerides, corn oil diglycerides, corn oil triglycerides, polyethylene glycol, caprylocaproylmacroglycerides, caproyl 90, propylene glycol, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone and any combination thereof.

Since, oxidation of edaravone is accelerated at a pH of 2.5 or lower and at a pH of 6.0 or higher, a pH adjusting agent and/or a buffer is preferably added in a suspension according to an embodiment of the present invention. The pH adjusting agent and/or a buffer can be used in an amount such that the pH of the suspension is adjusted/maintained to a range of 2.5-6.0, and preferably to a range 3.0-4.5. Suitable pH adjusting agents typically include at least an acid or a salt thereof, and/or a base or a salt thereof. Acids and bases can be added on an as needed basis in order to achieve the desired pH. For example, if the pH is greater than the desired pH, an acid can be used to lower the pH to the desired pH. Acids suitable for use in formulations include, but are not limited to, hydrochloric acid, phosphoric acid, citric acid, ascorbic acid, acetic acid, sulphuric acid, carbonic acid, nitric acid and the like. By way of another example, if the pH is less than the desired pH, a base can be used to adjust the pH to the desired pH. Bases suitable for use in formulations include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium citrate, sodium acetate, magnesium hydroxide and the like.
The buffering agent if used in the suspensions of the present invention may be any pharmaceutically acceptable agent, known to a person skilled in the art. The buffering agent may be selected from a group consisting of organic acids and its salts, mineral acids, alkali metal phosphates, carbonates, borates, hydroxides, base and the like and mixtures thereof. Preferably selected from a group consisting of lactic acid, citric acid, tartaric acid, phosphoric acid, acetic acid, hydrochloric acid, nitric acid, sodium or potassium metaphosphate, sodium or potassium phosphate, sodium or potassium acetate, ammonia, sodium carbonate, sodium or potassium hydroxide, dibasic sodium phosphate, sodium borate, and the like and mixtures thereof.

Sweeteners, flavors & coloring agents are responsible for the organoleptic properties of the oral suspensions and their presence makes the product more patient compliant and acceptable. Hence, the aqueous edaravone oral suspensions optionally comprises one or more of the sweeteners, flavoring agents, and coloring agents.

Non-limiting examples of sweetening agents include Glucose, Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose, Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol, Xylitol, Saccharine or the corresponding sodium, potassium or calcium salt, Cyclamate or the corresponding sodium or calcium salt, Aspartame, or Acesulfame or the potassium salt thereof, Dulcin or Ammonium glycyrrhizinate, Alitame, Inulin, Isomalt, Neohesperidin dihydrochalcone, Thaumatin, Stevia extract and the like. These sweeteners may each be independently used, or two or more of these sweeteners may be used in combination.

Non-limiting examples of flavoring agents are synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants leaves, flowers, fruits, and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and so forth. Solid forms, such as spray dried forms of flavoring agents, may also be useful in the liquid dosage forms disclosed herein.

Coloring agents may also be used in the preparation of the suspensions of the present invention. Pharmaceutical colors come in two types; soluble dyes and insoluble pigments. For pharmaceutical suspensions intended for oral use, soluble dyes are often used; however, pigments may also be used and would be part of the disperse phase. Soluble dyes have the potential to interact with other components of the formulation.
Non-aqueous edaravone oral suspensions:
In another aspects, the present invention also provides non-aqueous edaravone oral suspensions. These suspensions do not contain any added water and are therefore known as non-aqueous oral suspensions.

The non-aqueous edaravone oral suspensions of the present invention comprise edaravone and a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient is selected from the group consisting of antioxidants, surfactants, suspending agents, and combinations thereof. The non-aqueous suspensions comprise non-aqueous solvent as the vehicle.

Further, the non-aqueous edaravone suspensions of the present invention may further comprise one or more of the sweeteners, flavoring agents and coloring agents. Buffering agents and/or pH adjusting agents may not be required to be added in the non-aqueous edaravone oral suspensions of the present invention.

The non-limiting examples of antioxidants, suspending agents, sweeteners, flavoring agents and coloring agents have already mentioned in the paragraphs above. Therefore, any of these agents can also be used for preparing non-aqueous edaravone oral suspensions of the present invention.

So far surfactants to be used in the non-aqueous edaravone oral suspensions of the present invention are concerned, surfactant is a general name for materials that possess surface activity; in solution they tend to orient at the surface of the liquid. There are several general classes of surfactants: anionic, cationic, amphoteric and non-ionic. Surfactants are amphiphilic molecules, i.e. part of the molecule is hydrophilic, and part is lipophilic. This combination of the two opposite affinities in the same molecule causes them to orient to the interface and thereby reduce the interfacial tension between the continuous and disperse phases, such as in emulsions and suspensions. Ionic surfactants work primarily through electrostatic forces, whereas non-ionic surfactants work primarily through steric forces. Non-limiting examples of surfactants are Sodium lauryl sulfate, Docusate sodium, Cocamidopropyl amino betaine, Polyoxyethylene sorbitan fatty acid esters (Polysorbate, Tween®), Polyoxyethylene 15 hydroxystearate (Macrogol 15 hydroxystearate, Solutol HS15®), Polyoxyethylene castor oil derivatives (Cremophor® EL, ELP, RH 40), Polyoxyethylene stearates (Myrj®), Sorbitan fatty acid esters (Span®), Polyoxyethylene alkyl ethers (Brij®), Polyoxyethylene nonylphenol ether (Nonoxynol®), polyoxylglycerides (PEG-8 Caprylic/Capric glycerides; Labrasol®) and the like.

The non-aqueous solvent to be used in the preparation of the non-aqueous edaravone oral suspensions of the present invention, without limitation include, dichloromethane, acetonitrile, ethyl acetate, acetone, propylene carbonate, glycerin, coconut fatty acid diethanolamide, medium and/or long chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soyabean oil, peanut oil, corn oil, corn oil monoglycerides, corn oil diglycerides, corn oil triglycerides, polyethylene glycol, caprylocaproylmacroglycerides, caproyl 90, propylene glycol, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone and any combination thereof.

Embodiments of the preferred composition combinations in the suspension of the present invention are illustrated below, but are not limited thereto.
1. Edaravone, methyl paraben or its salt (preservative), propyl paraben or its salt (preservative), L-cysteine or its salt (antioxidant/stabilizer), sodium bisulfite (antioxidant/stabilizer), glycerin (wetting agent), carrageenan or acacia or tragacanth or guar gum (suspending agent/thickening agent), 30% simethicone emulsion (antifoaming agent), colloidal silicon dioxide (anticaking agent), citric acid monohydrate (buffer/pH adjuster), trisodium citrate dihydrate (buffer/pH adjuster), sweetener, flavor, and water.
2. Edaravone, methyl paraben or its salt (preservative), propyl paraben or its salt (preservative), L-cysteine or its salt (antioxidant/stabilizer), sodium bisulfite (antioxidant/stabilizer), glycerin (wetting agent), polyoxyl 35 castor oil (wetting agent), carrageenan or acacia or tragacanth or guar gum (suspending agent/thickening agent), 30% simethicone emulsion (antifoaming agent), colloidal silicon dioxide (anticaking agent), citric acid monohydrate (buffer/pH adjuster), trisodium citrate dihydrate (buffer/pH adjuster), sweetener, flavor, and water.
3. Edaravone, methyl paraben or its salt (preservative), propyl paraben or its salt (preservative), L-cysteine or its salt (antioxidant/stabilizer), sodium bisulfite (antioxidant/stabilizer), glycerin (wetting agent), carboxymethylcellulose or its salt (suspending agent/thickening agent), 30% simethicone emulsion (antifoaming agent), microcrystalline cellulose (dispersing agent), citric acid monohydrate (buffer/pH adjuster), trisodium citrate dihydrate (buffer/pH adjuster), sweetener, flavor, and water.
4. Edaravone, methyl paraben or its salt (preservative), propyl paraben or its salt (preservative), L-cysteine or its salt (antioxidant/stabilizer), sodium bisulfite (antioxidant/stabilizer), polyoxyl 35 castor oil (wetting agent), veegum (magnesium aluminum silicate, dispersing agent), 30% simethicone emulsion (antifoaming agent), carboxymethylcellulose or its salt (thickening agent), citric acid monohydrate (buffer/pH adjuster), trisodium citrate dihydrate (buffer/pH adjuster), sweetener, flavor, and water.
5. Edaravone, methyl paraben or its salt (preservative), propyl paraben or its salt (preservative), L-cysteine or its salt (antioxidant/stabilizer), sodium bisulfite (antioxidant/stabilizer), glycerin (wetting agent), carrageenan or acacia or tragacanth or guar gum (suspending agent/thickening agent), veegum (magnesium aluminum silicate, dispersing agent), 30% simethicone emulsion (antifoaming agent), citric acid monohydrate (buffer/pH adjuster), trisodium citrate dihydrate (buffer/pH adjuster), sweetener, flavor, and water.
6. Edaravone, methyl paraben or its salt (preservative), butylated hydroxyanisole or butylated hydroxytoluene or propyl gallate (antioxidant), polysorbate 80 (surfactant), colloidal silicon dioxide (suspending agent), sweetener, flavor, and medium chain triglycerides.
7. Edaravone, methyl paraben or its salt (preservative), butylated hydroxyanisole or butylated hydroxytoluene or propyl gallate (antioxidant), Labrasol (surfactant), colloidal silicon dioxide (suspending agent), sweetener, flavor, and medium chain triglycerides.
8. Edaravone, methyl paraben or its salt (preservative), propyl paraben or its salt (preservative), L-cysteine or its salt (antioxidant/stabilizer), sodium bisulfite (antioxidant/stabilizer), polyoxyl 35 castor oil (wetting agent), glycerin (wetting agent), carrageenan or acacia or tragacanth or guar gum (suspending agent/thickening agent), 30% simethicone emulsion (antifoaming agent), microcrystalline cellulose (dispersing agent), citric acid monohydrate (buffer/pH adjuster), trisodium citrate dihydrate (buffer/pH adjuster), sweetener, flavor, and water.

In above mentioned compositions, one or more excipients may be optional and can be used on the need basis, such as preservatives.

For a suspension according to an embodiment of the present invention, after the components are mixed, a homogeneous suspension can be prepared using a mixing method such as stirring, shaking, and ultrasonic irradiation.

In an embodiment, the present invention also provides method of treating amyotrophic lateral sclerosis which comprises administration of the edaravone suspension of the present invention.

Further, in addition to ALS, a suspension according to an embodiment of the present invention can also be used for diseases that have been reported to involve oxidative stress, for example, neurodegenerative diseases with motor dysfunction such as Parkinson's disease and spinocerebellar degeneration; muscle diseases such as muscular dystrophy; intracranial neurodegenerative diseases with cognitive impairment such as Alzheimer's disease; vascular disorders such as cerebral infarction; systemic inflammatory diseases such as multiple sclerosis and systemic scleroderma; and local inflammatory diseases such as stomatitis. The edaravone suspensions of the present invention can be administered in the same dosage and in the same manner, RADICAVA ORS is being administered.
Definitions:
Unless otherwise indicated, the term edaravone also includes pharmaceutically acceptable salt of edaravone. Edaravone may be in a crystalline state or an amorphous state. Particle sizes of the edaravone particles in the suspension are not particularly limited. However, from perspectives such as maintaining a stable dispersed state in the suspension, rapid in-body absorption and a smooth feeling when the suspension is taken, preferably, a D50 particle size (volume-based cumulative 50% particle size) is in a range of 10 µm-100 µm, and a D90 particle size (volume-based cumulative 90% particle size) is in a range of 50 µm-300 µm; and, more preferably, the D50 particle size is in a range of 20 µm-80 µm, and the D90 particle size is in a range of 100 µm-250 µm. In the present invention, the cumulative 50% particle size and the cumulative 90% particle size are volume-based particle sizes.

A “buffering agent” or a “pH adjusting agent” as used herein is a system which is used for the purposes and is capable of maintaining the desired/required pH of the formulations throughout desired/required time period, e.g. stability studies and/or shelf life of the drug product. The desired pH of the formulations according to the present invention is between about 3.0 and about 4.5.

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

As used herein, “optional” or “optionally” means that the subsequently described event or circumstance does or does not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, an optionally substituted group means that the group is un-substituted or is substituted.
All percentages mentioned herein, unless otherwise indicated, are on a w/v basis, i.e. percentage ingredient (active/inactive) present by weight in the total volume of the composition.

Best mode of carrying out the Invention
Examples
The invention will now be explained in more detail by reference to the following non-limiting examples.
Examples-1-5: Aqueous edaravone oral suspensions
Ingredient Ex-1
mg/mL Ex-2
mg/mL Ex-3
mg/mL Ex-4
mg/mL Ex-5
mg/mL
Edaravone 21.0 21.0 21.0 21.0 21.0
Methyl paraben or its salt 0.5-2.0 0.5-2.0 0.5-2.0 0.5-2.0 0.5-2.0
Propyl paraben or its salt 0.05-0.5 0.05-0.5 0.05-0.5 0.05-0.5 0.05-0.5
L-cysteine or its salt 0.05-10.0 0.05-10.0 0.05-10.0 0.05-10.0 0.05-10.0
Sodium bisulfite 0.05-10.0 0.05-10.0 0.05-10.0 0.05-10.0 0.05-10.0
Glycerin 100.0-500.0 100.0-500.0 - - 100.0-500.0
Carrageenan gum or
Acacia or Guar gum or
Tragacanth 1.0-10.0 1.0-10.0 - - 1.0-10.0
Veegum (Magnesium aluminum silicate) - - - 10.0-25.0 10.0-25.0
Polyoxyl 35 castor oil - 0.5-5.0 - 0.5-5.0 -
Carboxymethylcellulose or its salt - - 1.0-10.0 10.0-50.0 -
Microcrystalline cellulose - - 5.0-50.0 - -
Sweetener 0.05-2.0# 0.05-2.0# 0.05-2.0# 0.05-2.0# 0.05-2.0#
Simethicone/Dimethicone 1.0-10.0 1.0-10.0 1.0-10.0 1.0-10.0 1.0-10.0
Colloidal silicon dioxide 2.0-10.0 2.0-10.0 - - -
Citric acid monohydrate 0.5-25.0 0.5-25.0 0.5-25.0 0.5-25.0 0.5-25.0
Trisodium citrate dihydrate 0.5-25.0 0.5-25.0 0.5-25.0 0.5-25.0 0.5-25.0
Flavor 0.05-3.0# 0.05-3.0# 0.05-3.0# 0.05-3.0# 0.05-3.0#
Purified water q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL
#or in a quantity sufficient to make palatable formulation; q.s. = quantity sufficient

Process of preparation for Example-1:
1. Purified water (45% of the total batch size) was taken. Nitrogen was purged into purified water to get dissolve oxygen less than 2 ppm. 30% of glycerin was added under stirring with nitrogen purging. Solution was heated up to 70-80°C.
2. Required quantities of methylparaben or its salt and propylparaben or its salt were dissolved into the solution of step 1.
3. Solution of step 2 was allowed to cool down to 20-30°C with stirring and continuous nitrogen purging.
4. Required quantities of citric acid monohydrate and trisodium citrate dihydrate were dissolved under nitrogen purging & stirring into the solution of step 3.
5. Required quantities of L-cysteine or its salt and sodium bisulfite were dissolved under nitrogen purging and stirring into the solution of step 4.
6. Required quantity of 30% simethicone emulsion was added & dispersed under nitrogen purging into step 5.
7. 2% glycerin was taken into separate vessel and 25% of total required carrageenan gum or acacia gum or tragacanth or guar gum was added into it and stirred well to get smooth lump-free dispersion of the gum.
8. Carrageenan gum or acacia gum or tragacanth or guar gum dispersion of step 7 was added into step 6 and was stirred until completely swelled in aqueous dispersion of step 6 to get uniform and lump-free dispersion. At this step, nitrogen was purged in the headspace of the dispersion instead of purging into dispersion to avoid excessive bubbles formation. (N2 Blanketing)
9. Required quantity of colloidal silicone dioxide was added into step 8 and was stirred until completely dispersed. (N2 Blanketing)
10. Required quantity of edaravone was added into step 9 and was stirred until completely dispersed to form smooth lump-free suspension. (N2 Blanketing)
11. Remaining 3% of glycerin was taken into separate vessel and remaining amount of carrageenan gum or acacia gum or tragacanth or guar gum was added into it and stirred well to get smooth lump-free dispersion of the gum. (N2 Blanketing)
12. Carrageenan gum or acacia gum or tragacanth or guar gum dispersion of step 11 was added into step 10 and was stirred until completely swelled in aqueous dispersion of step 10 to get uniform and lump-free dispersion. (N2 Blanketing)
13. Required quantity of the sweetener was added into step 12 and was stirred until completely dissolved. (N2 Blanketing)
14. Required quantity of the flavor was added into step 13 and was stirred until completely mixed. (N2 Blanketing)
15. The final volume of the suspension was made up with the remaining amount of the purified water and thusly prepared suspension was homogenized for 15 minutes using homogenizer. (N2 Blanketing)
Physical observations:
• Wetting of edaravone was easily achieved with the used gum and glycerin.
• Lumps/aggregates free white to off-white smooth suspension was formed.
• No sedimentation and aggregates observed even after 24 hours.
Examples 2-5 can be prepared in the same manner as Example 1 using suitable excipients as shown above.
Examples 6-7: Non-aqueous edaravone oral suspensions
Ingredient Ex-6 Ex-7
Edaravone 21.0 mg 21.0 mg
Methyl paraben or its salt 0.2-2.0 mg 0.2-2.0 mg
Butylated hydroxyanisole (BHA)
or
Butylated hydroxytoluene (BHT)
or
Propyl gallate
or combination thereof 0.01-2.0 mg 0.01-2.0 mg
Polysorbate 80 - 10.0-30.0 mg
Labrasol 10.0-30.0 mg -
Sweetener 0.01-2.0 mg# 0.01-2.0 mg#
Colloidal silicon dioxide 10.0-20.0 mg 10.0-20.0 mg
Flavor 0.05-3.0 mg# 0.05-3.0 mg#
Medium chain triglyceride q.s. to 1 mL q.s. to 1 mL
#or in a quantity sufficient to make palatable formulation
q.s. = quantity sufficient

Process of preparation for Example 6:
1. Medium chain triglyceride (80% of the total batch size) was taken (N2 Purging) and was heated to 80°C.
2. Required quantity of methylparaben or its salt was added into step 1 and was stirred until dissolved completely.
3. Required quantity of sweetener was added into step 2 and was stirred until dissolved completely.
4. Required quantities of BHT & BHA were added one by one into step 3 and were stirred until dissolved completely.
5. The solution of step 4 was allowed to cool down to 20-30°C. (N2 Purging)
6. Required quantity of Labrasol was added into step 5 and was stirred & mixed well. (N2 Purging)
7. Required quantity of edaravone was added into step 6 and was stirred until dispersed completely to get lump-free dispersion. (N2 Purging)
8. Required quantity of colloidal silicon dioxide was added into step 7 and was stirred until dispersed completely. (N2 Blanketing)
9. The dispersion of step 8 was homogenized using homogenizer.
10. Required quantity of the flavor was added into step 9 and was stirred until mixed completely. (N2 Blanketing)
11. The remaining amount of medium chain triglycerides was added into step 10 to make up the final volume.
Physical observations:
• Lumps/aggregates free off-white suspension was formed.
• No sedimentation and aggregates observed even after 24 hours.
Example 7 can be prepared in the same manner as Example 6 using suitable excipients as shown above.
Examples-8-10: Aqueous edaravone oral suspensions
Ingredient Ex-8
mg/mL Ex-9
mg/mL Ex-10
mg/mL
Edaravone 21.0 21.0 21.0
L-cysteine or its salt 0.05-10.0 0.05-10.0 0.05-10.0
Carboxymethylcellulose or its salt 1.0-10.0 - -
Hydroxypropyl cellulose - 1.0-10.0 1.0-10.0
Sweetener 0.05-2.0# 0.05-2.0# 0.05-2.0#
Simethicone/Dimethicone 0.5-10.0 - 1.0-10.0
Colloidal silicon dioxide - - 1.0-10.0
Orthophosphoric acid Q.S. to pH 4.0 Q.S. to pH 4.0 Q.S. to pH 4.0
Sodium hydroxide Q.S. to pH 4.0 Q.S. to pH 4.0 Q.S. to pH 4.0
Flavor 0.05-3.0# 0.05-3.0# 0.05-3.0#
Purified water q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL

Examples 8-10 can be prepared in the same manner as Example 1 using suitable excipients as shown above.
Example-11: Stability study results of aqueous edaravone suspensions
Examples Stability Time point Appearance pH %Assay of Edaravone Related substances (% w/w) Total impurities (% w/w)
Edaravone N-oxide dimer 2-methyl-4-hydroxy-quinoline Bispyrazolone
Ex-3 60°C-15 days Off white suspension 6.631 147.7 0.2 - 0.11 3.4
30°C-10M Off white suspension 4.029 80.9 0.04 - 0.09 5.22
40°C-10M Off white suspension - 68.8 0.07 - 0.28 6.09
Ex-8 25°C-15 days Off white suspension 5.671 100.9 - - 0.76
25°C-2M Off white suspension 5.778 99.7 0.07 - 0.69
60°C-15 days Off white suspension 5.369 105.6 - - 0.08 1.07
40°C-2M Off white suspension 5.492 98.2 0.08 - 0.87
Ex-9 25°C-15 days Off white suspension 3.972 78.4 0.04 - 0.72
25°C-2M Off white suspension 4.100 80.7 0.04 - 0.69
60°C-15 days Light yellow suspension 4.098 71.2 0.02 - 0.13 1.18
40°C-2M Light yellow suspension 4.111 39.4 0.09 - 0.7
Ex-10 60°C-30 days Off white suspension 4.118 - ND - 0.1 0.98

Example-12: Stability study results of non-aqueous edaravone suspensions
Examples Stability Time point Appearance pH %Assay of Edaravone Related substances (% w/w) Total impurities (% w/w)
Edaravone N-oxide dimer 2-methyl-4-hydroxy-quinoline Bispyrazolone
Ex-2 60°C-15 days Off white suspension 6.852 95.0 0.67 - - 6.63
Ex-3 60°C-15 days Off white suspension 6.573 94.7 0.78 - - 4.14
25°C-10M Yellow color suspension 5.229 98.3 0.33 - - 3.71
30°C-10M Yellow color suspension 4.663 100.1 0.1 - - 3.90
40°C-10M Yellow color suspension 4.469 92.5 0.08 - - 4.82

The United States Patent Number 10,987,341, in Test Example-1, teaches that there is secondary aggregation and floating of the edaravone particles on liquid surface during appearance observation while testing dispersibility of the edaravone particles with respect to Sodium alginate, Xanthan gum, and Carmellose sodium (carboxymethyl cellulose sodium). Whereas, there is some secondary aggregation and floating of the edaravone particles on liquid surface with respect to Gum Arabic powder, Bentonite, and Tragacanth powder.

However, to the surprise of the inventors and contrary to the findings of the US’341 patent, the inventors did not find any secondary aggregation and/or floating of the edaravone particles on liquid surface during appearance observations of the dispersibility test when the edaravone suspensions of the present invention were stored under storage conditions for prolonged time. Further, the inventors of the present invention also did not observe any sedimentation or cake formation in the suspensions of the present invention.

It can therefore be said that even in the absence of the dispersants preferred by the US’341 patent, physically & chemically stable edaravone suspensions can be prepared which represents the inventive merit of the present invention.

It should be understood that various changes and modifications to the embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the subject matter of the present invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered within the scope of the present invention and appended claims. ,CLAIMS:WE CLAIM,
1. An edravone aqueous oral suspension comprising edaravone, a suspending agent, and an antioxidant wherein said suspension lacks a dispersant selected from the group consisting of polyvinyl alcohol, methylcellulose, hypromellose, sucrose fatty acid ester and polysorbate; and wherein said suspension is not a nano-suspension.
2. An edaravone non-aqueous oral suspension comprising edaravone, a surfactant, an antioxidant, a suspending agent and a vehicle.
3. The edaravone suspension as claimed in claim 1, wherein said suspension further comprises one or more excipients selected from the group consisting of a buffering agent, a pH adjusting agent, antifoaming agent, and a combination thereof.
4. The edaravone suspension as claimed in claim 1 or claim 2, wherein said suspension optionally comprises a preservative, a sweetener and a flavor.
5. The edaravone suspension as claimed in claim 1 or claim 2, wherein the suspending agent is selected from the group consisting of Acacia, Agar, Alginic acid, Carbomer, Dextrin, Gelatin, Gellan gum, Sodium alginate, Hydroxyethyl cellulose, Hydroxypropyl cellulose, Hydroxypropyl starch, Maltodextrin, Modified starch, Pectin, Polycarbophil, Polyethylene glycol, Polyvinyl acetate, Potassium alginate, Polyvinyl pyrrolidone, Pregelatinized starch, Propylene glycol alginate, Sodium alginate, Colloidal silicon dioxide, Carboxymethyl cellulose or an alkali metal salt thereof, gum Arabic, Karaya gum, Sterculia gum, veegum, microcrystalline cellulose, Tragacanth, Bentonite, Carrageenan, Guar gum, or combinations thereof.
6. The edaravone suspension as claimed in claim 1 or claim 2, wherein the antioxidant is selected from the group consisting of amino acids, butylated hydroxytoluene, butylated hydroxyanisole, tert-butyl-hydroquinone, 4-hydroxymethyl-2, 6-di-tert-butylphenol, 2, 4, 5- trihydroxybutyrophenone, alkylgallates, propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, gallic acid, nordihydroguaiaretic acid, glycine, ascorbic acid, fatty acid esters of ascorbic acid such as ascorbyl palmitate and ascorbyl stearate, and salts of ascorbic acid such as sodium, calcium, or potassium ascorbate; erythorbic acid, L-carnitine, monothioglycerol, acetyl L-carnitine, thioglycolic acid, N-acetyl cysteine (incuding L-cysteine, DL-cysteine, N-acetylcysteine, hydrochlorides thereof), cysteines, glutathione, methionines, tartaric acid, citric acid, fumaric acid, glycolic acid, oxalic acid, succinic acid, ellagic acid, malic acid, maleic acid, tocopherols such as delta tocopherol, alpha tocopherol; lipoic acid, thiolated polymers such as polymethacrylic-SH, carboxymethylcellulose-cysteine, polycarbophil-cysteine, beta-carotene, carotenoids, flavonoids, flavones, isoflavones, flavanones, catechins, anthocyanidins, chalcones, sulfites such as sodium sulfite, potassium sulfite, and calcium sulfite, bisulfites such as sodium bisulfite, potassium bisulfite, and ammonium bisulfite, pyrosulfites such as sodium pyrosulfite and potassium pyrosulfite, polyoxyethylene polyoxypropylene glycol, EDTA or a combination thereof.
7. The edaravone suspension as claimed in claim 2, wherein the surfactant is selected from the group consisting of Sodium lauryl sulfate, Docusate sodium, Cocamidopropyl amino betaine, Polyoxyethylene sorbitan fatty acid esters (Polysorbate, Tween®), Polyoxyethylene 15 hydroxystearate (Macrogol 15 hydroxystearate, Solutol HS15®), Polyoxyethylene castor oil derivatives (Cremophor® EL, ELP, RH 40), Polyoxyethylene stearates (Myrj®), Sorbitan fatty acid esters (Span®), Polyoxyethylene alkyl ethers (Brij®), Polyoxyethylene nonylphenol ether (Nonoxynol®), polyoxylglycerides (PEG-8 Caprylic/Capric glycerides; Labrasol®) and a combination thereof.
8. The edaravone suspension as claimed in claim 2, wherein the vehicle is selected from the group consisting of dichloromethane, acetonitrile, ethyl acetate, acetone, propylene carbonate, glycerin, coconut fatty acid diethanolamide, medium and/or long chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soyabean oil, peanut oil, corn oil, corn oil monoglycerides, corn oil diglycerides, corn oil triglycerides, polyethylene glycol, caprylocaproylmacroglycerides, caproyl 90, propylene glycol, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone and any combination thereof.
9. The edaravone suspension as claimed in claim 4, wherein the preservative is selected from the group consisting of alcohol, ethanol, chlorobutanol, phenoxyethanol, potassium benzoate, benzyl alcohol, benzoic acid, potassium sorbate, sorbic acid, quaternary amine (such as benzalkonium chloride), benzethonium chloride, cetrimonium bromide, cetylpyridinium chloride, bronopol, chlorbutol, chlorocresol, cresol, parahydroxybenzoates (or parabens), phenol, thymol, phenylethanol, sodium benzoate, antimicrobial solvents like propylene glycol, glycerin, chloroform and combinations thereof.