FIELD OF THE INVENTION: The present invention relates to oral formulation of Edaravone as a tablet. Further, the present invention discloses preferably sublingual tablet composition of Edaravone and pharmaceutically acceptable salt thereof using one or more excipients. Furthermore, the invention relates to providing an economical and technically advanced dosage form over existing parenteral dosage form.

BACKGROUND OF THE INVENTION:

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

EDARAVONE ®

Edaravone, a very old molecule, is disclosed earlier during 1925 in DE473214. The said German patent discloses a process for the preparation of 1 -phenyl-3- methylpyrazolone by the oxidation of 1 -phenyl-3-methylpyrazolidone in aqueous hydrochloric acid solution and in the presence of oxygen-transferring metal salts, characterized by the use of oxygen or oxygen-containing metal salts gases as oxidizing agents.

Edaravone is marketed presently under the brand name “RADICAVA ^® ” in United States. This intravenous infusion is indicated for the treatment of amyotrophic lateral sclerosis (ALS). The recommended dosage of Edaravone is 60 mg administered as an intravenous infusion over 60 minutes. Prior to US approval, Mitsubishi Tanabe Pharm Corp. (Osaka, Japan) launched Edaravone under the brand name “RADICUT ^® ” in Japan as world's first neurovascular protection drug. The recommended dose of Edaravone is 60 mg, which should be administered in the form of two consecutive infusion bags containing 60 mg of Edaravone, i.e. 30 mg per each infusion bag over a period of 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 the isotonicity is maintained by adding sodium chloride. The dosing regimen of Edaravone consist of 2 cycles. Cycle 1 includes an initial treatment cycle with daily dosing for 14 days; followed by a 14-day drug-free period. Subsequent treatment cycles (cycles 2 to 6) are provided with daily dosing for 10 days out of 14-day periods; followed by 14-day drug-free periods.

Edaravone is prone to oxidation from environmental oxygen. Therefore, Edaravone is supplied in single-dose polypropylene bags, each overwrapped with polyvinyl alcohol (PVA). Further, secondary packaging contains an oxygen absorber with oxygen indicator, which should be pink to reflect appropriate oxygen levels. The oxygen indicator will turn blue or purple if the oxygen has exceeded acceptable levels.

US6933310 discloses a method for treating motor neuron diseases, amyotrophic lateral sclerosis (ALS), consisting essentially of administering an effective amount of Edaravone or a physiologically acceptable salt thereof to a patient.

CN1241565 discloses freeze-dried pharmaceutical composition of Edaravone to facilitate storage and transport. As per this Chinese patent, Edaravone powder is suspended in water for injection and alkaline material followed by addition of other scaffolds agent to prepare lyophilized dosage form. However, the said invention is not considered as friendly for long-term treatment from the patient compliance point of view. Therefore, there is a need for a patient compliant invention.

W02009/067343 discloses Edaravone emulsion formulation wherein alcohol, chelating agent and reducing agents are absent. Further, the emulsifier is chosen from egg-yolk phospholipid or soyabean phospholipid. However, during long-term storage, poor stability of this liquid dosage form is a hurdle and requires a novel stable dosage form.

WO201 2/019381 discloses an oral pharmaceutical composition containing inclusion complex of Edaravone and cyclodextrin. This patent comprises mixing Edaravone with cyclodextrin into water for 1 to 2 h. More contact time with water forces Edaravone to oxidize. This invention does improve solubility of Edaravone, however, fails to reduce inherent oxidation of Edaravone. Therefore, there is requirement of a novel invention that yields better solubility with significant stability of Edaravone in the oral dosage form. WO201 7/157350 discloses a lipid-based drug delivery system comprising Edaravone or a pharmaceutically acceptable salt thereof. A solid dispersion is prepared for formulation comprises Edaravone and a polymeric carrier. However, preparing solid dispersion of Edaravone needs reduction in particle size of API and reduction in particle size yield larger surface area to Edaravone. Thereby, producing higher chance of oxidation to Edaravone due to larger surface area of particles. Therefore, this invention also fails to minimize oxidative effect on Edaravone.

WO201 8/040989 discloses sublingual pharmaceutical compositions of Edaravone and (+)-2-Borneol. The sublingual preparation is directly absorbed by sublingual mucosa that has large surface area and strong permeation ability. However, Edaravone is classified under BCS class-IV, i.e., it has low solubility as well as low permeability. Therefore, poor permeability of Edaravone leads poor bioavailability of sublingual dosage form if not prepared a robust one. Further, this patent application has reported stability data for 90 days and hence, one cannot predict whether the product is stable afterward or not. Therefore, there is requirement of a novel sublingual invention of Edaravone.

At present, market availability of only injectable Edaravone formulation need an additional Edaravone dosage form. From patient's compliance point of view, parenteral formulation is not suitable for long-term therapy. Therefore, the inventors of the present invention have developed an oral dosage form of Edaravone.

The present invention discloses the administration of Edaravone in an oral tablet form that does not use sophisticated techniques and is economically affordable compared to parenteral dosage form. Further, the formulated tablet dosage form prepared as per the present invention provides greater stability when compared with marketed Edaravone liquid formulation. Moreover, the oral route is the preferred one for administration in patients with chronic neurodegenerative diseases. In addition, medical practitioners also prefer oral dosage form over injectable dosage forms due to advantages like ease of administration, increased patient compliance, reduced the need for the hospital stay.

The present invention incorporates Edaravone-HPMC complex that reduce oxidation the drug. This complex also increases solubility of Edaravone by providing better dissolution profile and thereby reducing usage of hazardous organic solvents during preparation of tablet. Moreover, the present invention resulted in achieving higher stability of Edaravone as comparing to marketed parenteral dosage form. Moreover, as per the present invention, solubility and stability of this patient compliant Edaravone formulation is proven higher when compared to prior art inventions. Hence, the inventors of the present invention felt that still, there is an unmet need to develop a dosage form of Edaravone, which overcome the drawbacks of prior available formulations and has good physical stability, cost effective, can be produced by simple manufacturing techniques and can maximize the permeability of Edaravone from such dosage form and thereby improve its bioavailability with patient compliance.

OBJECTIVES OF THE INVENTION:

The principal object of the present invention is to provide novel sublingual pharmaceutical formulations of Edaravone and pharmaceutically acceptable salt thereof in the form of tablet which is to be placed under the tongue. The sublingual tablet provides better patient compliance; however, none of prior-arts teaches about sublingual formulations for Edaravone.

Another prime objective of the present invention is to provide dose reduction of Edaravone with the sublingual route by avoiding or reducing drug degradation in the gastric pH and Gl tract metabolism.

Another prime objective of the present invention is to provide dose reduction of Edaravone with the sublingual route through bypassing first pass metabolism, and thereby reducing excessive metabolism of Edaravone.

Further, another aspect is to avoid food effect on the Gl tract absorption of Edaravone thereby reducing plasma concentration variation.

Furthermore, another object of the present invention is to achieve a rapid onset of action through sublingual administration because of the high permeability and the rich blood supply to the sub lingual mucosa i.e., under the tongue.

Moreover, another aspect is reduction in the total dose administered through sub lingual route compare to conventional oral route by avoiding the loss of drug dose due to pre-systemic metabolism.

Yet another object of the present invention is to provide synergistic formulations of Edaravone or pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients which are essential for synergistic effect.

Another object of the present invention is to provide technically advanced patient- compliant dosage forms over existing dosage form and prior-arts.

The other object of the present invention is to provide reduced dose Edaravone formulations and thereby reducing the cost of final formulations by providing an economic significant dosage form over existing dosage form and prior-arts. Yet another objective of the present invention is to provide sublingual oral formulations of Edaravone and one or more pharmaceutically acceptable excipients, excluding (+)-2-borneol with good physical stability over the prior art.

SUMMARY OF THE INVENTION

Notwithstanding of wide research on Edaravone as reported in prior-art publications, there is an unmet need to develop a patient compliant oral sublingual composition for Edaravone with technical advancement which provide fast dissolution for immediate action as well as good stability for at least more than two- year storage. This dosage form also increases patient compliance because patient feels difficulty in taking conventional tablet or dispersible tablets when he or she is outdoor; whereas sublingual tablet does not require even water. Thus, the present invention has solved the problem that is present in the prior-arts as well as in the existing marketed formulations.

In one general aspect, a pharmaceutical composition comprising Edaravone and one or more pharmaceutically acceptable excipients wherein the composition is in the form of a capsule or a tablet.

In another general aspect, a pharmaceutical composition as per the present invention may be in the form of tablet, capsule, caplet, pellets, beads, granules or powder.

Accordingly, the present invention provides novel oral compositions of Edaravone preferably as a sublingual tablet dosage form with pharmaceutically acceptable excipients and method of preparation thereof.

The present invention establishes a very fast release of the pharmaceutical composition during initial dissolution owing to kind of excipients used in the formulation and thereby producing an immediate burst release which in turn immediate absorption of the drug into the blood stream. This action will help to increase bioavailability of Edaravone and pharmaceutically acceptable salt thereof in very short time.

In another general aspect, above-mentioned pharmaceutical composition is optionally provided with barrier coating.

In another general aspect, a pharmaceutical composition as per the present invention comprises Edaravone or pharmaceutically acceptable salt thereof. In yet another general aspect, pharmaceutical composition as per the present invention is substantially free of excipients such as pH modifying agents and isotonicity agents.

In another embodiment of the present invention, a synergistic pharmaceutical composition as per the present invention comprises several advantages including dose reduction, higher dose dependent side-effects and bypassing first pass metabolism of Edaravone on the particular target in human body.

Embodiments of the pharmaceutical composition may include Edaravone as an active ingredient with one or more selected from pharmaceutically acceptable excipients like diluents, disintegrants, binders, lubricants, vehicles / solubility enhancing agents, stabilizers / anti-oxidants, suspending agents, permeability enhancers, preservatives, glidants, active carriers, anti-caking agents, wetting agents, preservatives, buffering agents, flavouring agent and the like.

In another general embodiment of the present invention, a pharmaceutical composition as per the present invention comprises Edaravone or pharmaceutically acceptable salt thereof. Preferably, Edaravone is present in the form of free base, a pharmaceutically acceptable salt thereof, amorphous Edaravone, crystalline Edaravone, any isomer, derivative, hydrate, solvate or prodrug or a combination thereof.

In another embodiment, pharmaceutical composition as per the present invention is in the form of a tablet comprising: a) Edaravone with one or more pharmaceutically acceptable excipients; b) granulating the mixture obtained in a granulator; c) drying the granules followed by blending, lubrication and compression.

In yet another general aspect, pharmaceutical composition as per the present invention is in the form of a capsule comprising: a) Edaravone with diluents, binders, disintegrants and other suitable pharmaceutical excipients followed by lubrication; b) filling of above prepared granules to suitable size of capsule.

In yet another general aspect, pharmaceutical composition as per the present invention is in the form of a capsule comprising: a) Edaravone with diluents, binders, disintegrants and other suitable pharmaceutical excipients followed by lubrication and compression; b) filling of above prepared mini-tablets to suitable size of capsule. In another embodiment of the present invention, the pharmaceutical composition is in the form of sublingual tablets is/are prepared by wet granulation process comprises a step for providing Edaravone, wherein the Edaravone is contained in a sublingual tablet that may be prepared by the steps comprising: (a) dispensing of all raw material, (b) sifting one or more pharmaceutically acceptable excipients, (c) binder solution preparation by using binders and anti-oxidants in solvent and surfactant, (d) granulating by the rapid mixer granulator and/or the top spray granulating, (e) drying and sieving the wet mass to obtain granules, (e) blending the granules of step (d) with extra granular excipients if any, followed by lubrication and (f) compressing the lubricated blend of step (g) preparing tablets or filled into capsules.

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:

The following detailed description of the present subject matter the various embodiments. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized and structural, logical, and electrical changes may be made without departing from the scope of the present subject matter.

Further, the present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.

References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.

Edaravone, chemically known as, 3-methyl-1 -phenyl-2-pyrazolin-5-one, is a small lipophilic molecule with molecular weight 174.203 g/mol with a solubility of 25pg/ml. Edaravone is considered a Bio-pharmaceutics Classification System (BCS) Class IV drug substance due to its poor solubility in water and lower lipid permeability. The mean terminal elimination half-life of Edaravone is 4.5 to 6 h.

In accordance with the present invention, a pharmaceutical composition of Edaravone comprising of Edaravone as an active ingredient with pharmaceutically acceptable excipients like carriers, diluents, binders, polymers, chelating agents, anti-oxidants, disintegrating agents, gliding agents, lubricants and the like. The term "drug" or “active ingredient” or “active pharmaceutical ingredient (API)” herein refers to Edaravone or a pharmaceutically acceptable salt thereof.

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

The term "drug solution" as used herein according to the present invention includes solution obtained by dissolving Edaravone or its pharmaceutically acceptable salt thereof in solvent and (or) mixture of solvents.

The term "granulation" as used herein according to the present invention includes, wet-granulation, dry-granulation or direct compression.

At the time of preparation of the dosage form, the excipients of tablet are mainly divided into three parts according to their uses in the manufacturing process (A) intra-granular excipients, (B) excipients used in binder solution, and (C) extra- granular ingredients. The list of excipients used are listed in tables below however it is not limited to the said pharmaceutically acceptable excipients.

The term "pharmaceutically acceptable excipients" as used herein, refers to excipients those are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise of diluents, disintegrants, binders, lubricants, vehicles / solubility enhancing agents, stabilizers / anti oxidants, suspending agents, permeability enhancers, preservatives, glidants, active carriers, anti-caking agents, wetting agents, preservatives, buffering agents, Flavouring agents and combinations thereof. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the health of the patient.

Suitable fillers or diluents may include one or more of sugars such as lactose, sucrose glucose, fructose, dextrose, galactose, starch; cellulose derivatives such as microcrystalline cellulose; carbonates like calcium carbonate; sugar alcohols such as mannitol, sorbitol, erythritol; magnesium carbonate, calcium phosphates kaolin, magnesium oxide, and combination thereof.

Suitable binders or polymers may include one or more of hydroxyl ethyl cellulose (HEC), hydroxyl propyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinylpyrrolidone, pre-gelatinized starch, sodium alginate, gums, synthetic resins, silicic acid, hydrophilic polymers and the like. The term "hydrophilic polymer" comprises polymers with polar groups such as hydroxy, amino, carboxy, carbonyl, ethers, esters and sulfonates. Examples of suitable hydrophilic polymers are cellulose derivatives, in particular hydrophilic derivatives of the cellulose (e.g. HPMC, HPC, carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose), polyvinylpyrrolidone, copolymers of PVP, preferably co-polymers comprising vinylpyrrolidone, vinyl acetate, poly(oxyethylene) alkyl ether, polyethylene glycol, co-block polymers of ethylene oxide, propylene oxide (poloxamer, Pluronic), derivatives of polymethacrylates, polyvinyl alcohol and derivatives thereof, polyethylene glycol and derivatives thereof.

Suitable organic solvents for preparing binding solution may include one or more of water, organic solvents such as ethanol, isopropyl alcohol, acetone and the like.

Suitable complexing agent or chelating agent may include one or more of cyclodextrins and derivatives thereof; HPMC (Hypromellose) and derivatives thereof; group consisting of ethylenediamine, calcium disodium edetate, disodium edetate and the like.

Suitable amino acids may include one or more of cysteine, glycine, arginine, glutamine and derivatives thereof.

Suitable anti-oxidants may include one or more of sulfites such as sodium bisulfite, magnesium bisulfite; ascorbic acid, metabisulfite, tocopherol, BHT (Butylated hydroxy toluene), BHA, ubiquinol, carotenes, uric acid, lipoic acid, glutathione and the like.

Suitable surfactants or co-surfactants may include one or more of anionic, cationic, non-ionic or amphoteric surfactants. Non-limiting examples of surfactants include polyoxyethylene-polyoxypropylene co-polymers and block co-polymers, ethoxylated cholesterins, vitamin derivatives, e.g., vitamin E derivatives such as tocopherol polyethylene glycol succinate (TPGS), sodium dodecyl sulfate or sodium lauryl sulfate; a bile acid or salt thereof, for example cholic acid, glycolic acid or a salt; and the like.

Suitable permeability enhancers may include one or more of Propylene glycol monocaprylate; Oleoyl polyoxyl-6 glycerides; Caprylocaproyl polyoxyl-8 glycerides; Propylene glycol monolaurate; diethylene glycol monoethyl ether; pyrrolidones such as N-methylpyrrilidone; cyclodextrins and derivatives thereof; Sulfoxides such as Dimethyl sulfoxide, decylmethalsulfoxide and the like.

Suitable disintegrating agents may include one or more of crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and the like. Suitable gliding agents and lubricating agents may include one or more of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and the like.

In accordance with the present invention, it provides a wet granulation process for preparing stable sublingual compositions of Edaravone comprising the steps of: (a) sifting one or more pharmaceutically acceptable excipients, (b) preparing drug solution by dissolving Edaravone and anti-oxidants in a organic solvent and/or surfactant, (c) granulating the dry mix of step (a) with the drug solution of step (b) to obtain wet mass, (d) drying and sieving the wet mass to obtain granules, (e) blending the granules of step (d) with extra granular excipients if any, followed by lubrication and (f) compressing the lubricated blend of step (e) preparing tablets or filled into capsules.

One embodiment of the present invention may include a pharmaceutical composition comprising about 1 .0% w/w to 40.0% w/w of Edaravone, preferably 3.00% w/w to 34.00% w/w with pharmaceutically acceptable excipients.

Suitable stabilizers or anti-oxidants may include but are not limited to one or more from butylated hydroxytoluene (BHT), Butylated hydroxy anisole (BHA), tocopherols (Vitamin E), scorbic acid (Vitamin C) or its derivatives, propyl gallate, sodium bisulphite, L-cysteine, magnesium bisulfite, sodium metabisulfite, ubiquinol, b-carotenes, uric acid, lipoic acid, thiourea, glutathione, Pluronic F68 (Poloxamer 188) and fumaric acid and the like. The inventors of the present invention surprisingly found that BHT provided better stability than other anti oxidants. The present invention comprises about 0.10% w/w to 5.00% w/w of stabilizer or anti-oxidants of the total composition, preferably in the range of 0.10%w/w to 3.00% w/w of stabilizer or anti-oxidants of the total composition.

Suitable diluents, fillers, or bulking agents may include but are not limited to one or more from lactose, microcrystalline cellulose, reduced sugars such as monosaccharides like galactose, glucose, glyceraldehyde, fructose, ribose, and xylose; sugar alcohol such as mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol and hydrogenated starch hydrolysates; dibasic calcium phosphate, calcium phosphate, powdered cellulose, calcium carbonate, magnesium carbonate, starch, pre gelatinized starch and the like.

The inventors of the present invention used different diluents like Mannitol (Pearlitol 25C), Mannitol (Pearlitol 100 SD), F-Melt Type M, Prosolv Easytab SP, Prosolv Easytab SP - LM, PROSOLV ODT G2, Pharmaburst 500, Dexrates (Emdex -Non- GMO), lactose, Dextrose, microcrystalline cellulose, ludipress, pharmaburst, Ultaburst, PEARLITOL flash.

The inventors of the present invention surprisingly observed at the time of development of sub-lingual tablet that the diluent impacts disintegration (DT) time, tablet properties and impurity. The inventors of the present invention observed problems of Tablet DT and Tablet surface roughness and moisture uptake on storage.

Suitable binders may include but are not limited to one or more from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (povidone), gum arabic and sugars such as sucrose, glucose, dextrose, lactose, polyvinyl alcohol and the like.

Suitable disintegrants may include but are not limited to one or more from crospovidone, croscarmellose sodium, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and the like. The present invention comprises about 1% w/w to 25% w/w of disintegrants of the total composition, preferably in the range of 3%w/w to 20% w/w of disintegrants of the total composition.

The inventors of the present invention observed that disintegration time of Sodium starch glycolate was not achieved at different levels. Surprisingly, disintegration time of crospovidone was achieved with different grades and levels but the tablet surface was very rough. In addition, tablets made with crospovidone absorbed moisture and swelled. The inventors of the present invention noted that roughness on the tablet surface was observed due to the moisture absorption by crospovidone.

Surprisingly, when the inventors of the present invention combined Prosolv Easytab SP - LM in optimum concentration in combination with croscarmellose sodium, the rough surface tablet problem was solved and optimum disintegration time was also achieved. Thus, synergistic effect was observed by the inventors of the present invention by combining these two inactive ingredients. In addition, this excipient combination also provided rapid dissolution which is prime requirement of sub-lingual route. Furthermore, this combination of excipients also improved mouthfeel than other excipients which is also the requirement for the sub-lingual route.

Suitable wetting agents or surfactants or solubilizers may include but are not limited to one or more from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof. Suitable examples of wetting agents are sodium lauryl sulphate, cetrimide, polyethylene glycols, polyoxyethylene- polyoxypropylene block copolymers such as poloxamers, 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 and the like. The present invention comprises about 0.10%w/w to 20%w/w of solubilizers of the total composition, preferably in the range of 0.10%w/w to 15%w/w of solubilizers of the total composition.

The inventors of the present invention surprisingly found that Sodium Lauryl Sulfate [SLS] (brand: Kolliphor SLS Fine, Kolliphor P188) improved dissolution in different dissolution media. Hence, it shows that the final formulation is showing the same dissolution nature in any pH of the dissolution media and hence, is more stable in releasing profile.

SEPITRAP 80 is a micro-encapsulated solubilizer in powder form designed to simplify the manufacturing of solid oral form drugs. It is manufactured by adsorption of the solubilizer in liquid form on a porous support. It contains Polysorbate 80 adsorbed on Magnesium Alumino metasilicate. The inventors of the present invention found Sepitrap 80 as beneficial because it helped to provide a better dissolution profile.

Suitable lubricants may include but are not limited to one or more from fatty acids, fatty acid salts, and fatty acid esters such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, colloidal silicon dioxide and mixtures thereof. The present invention comprises about 1 -15% w/w of lubricants of the total composition, preferably in the range of 1 -8% w/w of lubricants of the total composition.

The inventors of the present invention surprisingly found that being water-soluble lubricant, Sodium stearyl fumarate provided better dissolution profile than water insoluble lubricants like Magnesium stearate. In addition, the inventors of the present invention observed that colloidal silicon dioxide improved wet granulation process. Hence, the combination of these inactive ingredients provided a synergistic effect.

Suitable permeability enhancers may include but are not limited to one or more from the group comprising alcohols, Polyols, short-chain glycerides, amines, amides, cyclodextrins, fatty acids, pyrrolidines, azones, sulfoxides, surfactants, terpenes and the like.

Suitable chelating or complexing agents may include but are not limited to one or more from the group comprising cyclodextrin, ethylenediamine tetra acetic acid or derivatives/salts thereof, e.g., disodium edetate, dihydroxyethyl glycine, glucamine, citric acid, tartaric acid, gluconic acid, phosphoric acid and the like.

Suitable coloring and flavoring agents may include but are not limited to one or more from sucralose, maltose, orange flavor, vanilla flavor and the like. Being zero- calorie artificial flavoring agent, Sucralose and orange flavour were used in the formulation. Hence, the patients with diabetes can also take this medicine and thus, the present invention provided better patient compliance. The present invention comprises about less than 3%w/w of flavoring agents of the total composition, preferably less than 1%w/w of flavoring agents of the total composition.

The inventors of the present invention also optimized the hardness of the tablet and disintegration time of the tablet by the selection of suitable punch tolling.

The prime aspect of the present invention is that the pharmaceutical composition establishes a fast release pattern owing to the kind of excipients used in the formulation and thereby producing an immediate release that will in turn increase in bioavailability at initial release.

In another aspect of the present invention, a synergistic pharmaceutical composition as per the present invention comprises several advantages including dose reduction, reduction in dose dependent side-effects and bypassing first pass metabolism of Edaravone on the particular target in human body.

One aspect of the present invention may include a pharmaceutical composition comprising about 1%w/w to 40%w/w of Edaravone with pharmaceutically acceptable excipients.

In yet another aspect of the present invention, wherein the pharmaceutical composition manufactured is sublingual tablet, which results in to enhanced dissolution profile.

Another aspect according to the present invention, wherein the formulated product manufactured is homogenous dispersions, which results in to enhanced dissolution profile and stability profile.

In yet another aspect of the present invention, wherein the pharmaceutical composition manufactured by number of stages in manufacturing process including mixing, wet-granulation and compression.

Additional aspect according to the present invention is that the formulated product is a stabilized sublingual tablet.

In one aspect process for preparation of an oral pharmaceutical composition as per the present invention comprising following steps: 1 . Co-milling of Mannitol, crospovidone and colloidal silicon dioxide through #40 sieve;

Binder solution preparation:

1. Mixing of ethanol and purified water, Isopropyl alcohol, ethanol and Dichloromethane were followed by addition of BFIT, Pulronic F68 (Poloxamer 188) and orange flavour;

2. Dissolving Edaravone in to the solution obtained in step-2 to prepare the binder solution;

Granulation:

3. Geometrically mixing of dry mix blend obtained in step-1 in slow manner to the binder solution obtained in step-3;

4. Drying and sifting of wet-granules obtained in stape-4;

Lubrication:

5. Adding and mixing of Crospovidone, sucralose, Sepitrap 80 to the dried and sized granules obtained in step-5;

6. Lubricating the blend obtained in step-6 with magnesium stearate or calcium stearate or sodium stearyl fumarate.

Compression:

7. Compressing the lubricated blend obtained in step-7 to form tablets.

The pharmaceutical formulations as described herein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet granulation, dry granulation or hot melt granulation.

The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. All percentages stated in this specification are by weight, unless otherwise specified. While the present invention has been described in terms of its specific embodiments, 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.

EXAMPLES:

Following section now will describe various formulation example as well as test examples by which the formulation example were evaluated. Further, results of the present invention were compared with the marketed formulation as well as nearest prior-arts. EXAMPLE-1 & 2:

Table-1

Process for preparation: Step-1 : Preparation of binding solution:

Edaravone, Hypromellose, L-cysteine, Sodium Bisulfite are mixed to prepare binding solution using purified water with ethanol (Example-1) OR isopropyl alcohol (Example-2). Step-2: Preparation of granules:

Binding solution prepared as per step-1 is admixed with premixed excipients lactose and crospovidone to prepare granules in a granulator. The granules are dried and sized. Step-3: Lubrication:

The dried and sized granules prepared as per step-2 are lubricated with magnesium stearate and Crospovidone.

Step-4a: Compression: The lubricated granules prepared as per step-3 is subjected to compression to form a tablet.

OR

Step-4b: Capsule filling: The lubricated granules prepared as per step-3 are filled in appropriate size of capsule.

Step-5: Coating (Optional):

The tablet prepared as per step-4a is optionally coated with pharmaceutically acceptable coating agents.

EXAMPLE-3 & 4:

Table-2 Process for preparation:

Step-1 : Preparation of binding solution: Edaravone, Hypromellose, L-cysteine, Sodium Bisulfite are mixed to prepare binding solution using purified water with ethanol (Example-3) OR isopropyl alcohol (Example-4).

Step-2: Preparation of granules:

Binding solution prepared as per step-1 is admixed with premixed excipients lactose and crospovidone to prepare granules in a granulator. The granules are dried and sized.

Step-3: Lubrication:

The dried and sized granules prepared as per step-2 are lubricated with magnesium stearate and Crospovidone.

Step-4a: Compression:

The lubricated granules prepared as per step-3 is subjected to compression to form a tablet.

OR

Step-4b: Capsule filling:

The lubricated granules prepared as per step-3 are filled in appropriate size of capsule.

Step-5: Coating (Optional):

The tablet prepared as per step-4a is optionally coated with pharmaceutically acceptable coating agents.

EXAMPLE- 5:

Table-3

Process for preparation:

Step-1 : Preparation of binding solution:

Edaravone, Pluronic F68 (Poloxamer 188), Butylated Hydroxy Toluene with orange flavour are mixed to prepare binding solution using ethanol with Dichloromethane (Example-5).

Step-2: Preparation of granules:

Binding solution prepared as per step-1 is admixed with premixed excipients mannitol, crospovidone and colloidal silicone dioxide to prepare granules in a granulator. The granules are dried and sized.

Step-3: Lubrication:

The dried and sized granules prepared as per step-2 are lubricated with magnesium stearate or calcium stearate, Sucralose, Sepitrap 80 (Polysorbate 80 and Magnesium Aluminometasilicate) and Crospovidone.

Step-4a: Compression:

The lubricated granules prepared as per step-3 is subjected to compression to form a tablet.

OR

Step-4b: Capsule filling:

The lubricated granules prepared as per step-3 are filled in appropriate size of capsule.

Step-5: Coating (Optional):

The tablet prepared as per step-4a is optionally coated with pharmaceutically acceptable coating agents. EXAMPLE- 6:

Table-4

Process for preparation: Step-1 : Preparation of binding solution:

Edaravone, Pluronic F68 (Poloxamer 188), Butylated Hydroxy Toluene (BHT) with orange flavour are mixed to prepare binding solution using ethanol with Dichloromethane (Example-6). Step-2: Preparation of granules:

Binding solution prepared as per step-1 is admixed with premixed excipients Prosolv Easytab SP - LM /Prosolv Easytab SP / F melt , Sodium lauryl Sulfate and Colloidal silicone dioxide to prepare granules in a granulator. The granules are dried and sized.

Step-3: Lubrication:

The dried and sized granules prepared as per step-2 are lubricated with Sodium Stearyl Fumarate. Step-4a: Compression:

The lubricated granules prepared as per step-3 is subjected to compression to form a tablet. OR Step-4b: Capsule filling:

The lubricated granules prepared as per step-3 are filled in appropriate size of capsule.

Step-5: Coating (Optional):

The tablet prepared as per step-4a is optionally coated with pharmaceutically acceptable coating agents. EXAMPLE- 7:

Table-5

Process for preparation:

Step-1 : Preparation of binding solution:

Edaravone, Hydroxypropyl methylcellulose (HPMC), Povidone, Polyvinyl alcohol, Butylated Hydroxy Toluene with Orange Flavour are mixed to prepare binding solution using ethanol with Dichloromethane (Example-7). Step-2: Preparation of granules:

Binding solution prepared as per step-1 is admixed with premixed excipients Mannitol or Lactose or Dextrose or microcrystalline cellulose or Ludipress or Pharmaburst or Ultraburst or What is Ludiflash or PEARLITOL Flash, L- cysteine, Croscarmellose Sodium or Sodium Starch glycolate or Starch and Colloidal silicone dioxide to prepare granules in a granulator. The granules are dried and sized.

Step-3: Lubrication:

The dried and sized granules prepared as per step-2 are lubricated with magnesium stearate.

Step-4a: Compression:

The lubricated granules prepared as per step-3 is subjected to compression to form a tablet.

OR

Step-4b: Capsule filling:

The lubricated granules prepared as per step-3 are filled in appropriate size of capsule.

Step-5: Coating (Optional):

The tablet prepared as per step-4a is optionally coated with pharmaceutically acceptable coating agents.

The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.

The following examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.