WO2026028170A1 - Pharmaceutical composition of edaravone - Google Patents

Abstract

The present invention relates to stable composition of edaravone intended for human oral administration in the form of an aqueous suspension. The invention further relates to an economic, easy to prepare and patient compliant edaravone suspension with improved stability.

Description

PHARMACEUTICAL COMPOSITION OF EDARA VONE

FIELD OF THE INVENTION

The present invention relates to pharmaceutical composition of Edaravone. More particularly, the present invention relates to oral suspension composition of Edaravone and process of preparation thereof.

BACKGROUND OF THE INVENTION

Edaravone is a member of substituted 2-pyrazolin-5-one chemical moiety and is chemically known as [3-methyl-l-phenyl-2-pyrazolin-5-one]. EP1405637 describes the use of Edaravone in the treatment of motor neuron diseases, including amyotrophic lateral sclerosis (ALS).

Edaravone is currently marketed in US as intravenous infusion and oral suspension, for the treatment of ALS, under the brand name Radicava® and Radicava ORS® respectively. Prior to US approval, Mitsubishi Tanabe Pharm Corp. (Osaka, Japan) introduced Edaravone as the first neurovascular protective medication in Japan under the brand name "RADICUT®".

JP2018207646 provide an Edaravone suspension for oral administration, that can achieve an ALS therapeutic effect equivalent to that of an injection, comprising of Edaravone particles, dispersant, thickening agent, stabilizers, pH regulators, antifoaming agents, sweetener and water. This invention particularly emphasizes the role of dispersant for preparation of pharmaceutically superior Edaravone suspension for oral administration.

US6933310 claims 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.

CN1241565C discloses a 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 an emulsion formulation of Edaravone wherein alcohol, chelating agent and reducing agents are absent. Further, the emulsifier is chosen from egg-yolk phospholipid or soybean phospholipid. However, during long-term storage, poor stability of this liquid emulsion dosage form is a hurdle and requires a novel stable dosage form.

W02012/019381 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 hydrolyze. 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. This patent has failed to report the stability data and hence, it proves that the prepared solid pharmaceutical composition for Edaravone is not stable.

WO2017/157350 discloses a lipid-based drug delivery system comprising Edaravone or a pharmaceutically acceptable salt thereof. A solid dispersion 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. Absence of stability data in the patent indicates that lipid-based compositions of Edaravone are not stable.

WO2018/134243 discloses a liquid pharmaceutical composition which is a monophasic aqueous solution of non-complexed Edaravone that comprise of at least 75 wt. % water and 0.2-9 mg/ml of Edaravone, wherein the treatment comprises oral or gastric administration of 10-250 ml of the liquid pharmaceutical composition to provide 30-300 mg Edaravone. This patent has failed to report the stability data and hence, it proves that the prepared liquid composition for Edaravone is not stable.

WO2018/133957 claims a solid water-dispersible pharmaceutical composition comprising of dispersing the pharmaceutical composition into an aqueous liquid to produce an enterally administrable liquid containing at least 0.5 grams of the pharmaceutical composition and at least 0.3 g/1 of Edaravone, followed by enterally administering the liquid to a human patient in an amount providing a dose of SO- SOO mg Edaravone. The said pharmaceutical composition comprising 2-50 wt. % of Edaravone and 3-50 wt. % of water-soluble alkalizing agent. This patent has failed to report the stability data and hence, it proves that the prepared solid water dispersible pharmaceutical composition for Edaravone is not stable.

Toshiaki Sato et. al. (Pharmacology 2010(85); p. 88-94) describes pharmacokinetics of Edaravone using Edaravone/hydroxypropyip-cyclodextrin complex solution, including L-cysteine (L-Cys) and sodium hydrogen sulfite (SHS). This study suggested that L-Cys and SHS were useful for the oral mucosal and rectal administration of Edaravone. These types of compositions are already reported in the previous inventions and hence, face similar kind of difficulties of stability as discussed during W02012/019381.

Parikh et al. (International Journal of Pharmaceutics, 2016(515); p. 490-500) discuss the development of an oral delivery system of Edaravone. The Novel Oral Delivery System (NODS) of Edaravone that is made up of a mixture of Labrasol and an acidic aqueous system that was optimized on the basis of a solubility and stability study. It was found that the oral bioavailability of the NODS delivery system was 5.7 times higher than that of an Edaravone suspension containing 25 mg/mL Edaravone and 0.5% of sodium carboxymethyl cellulose. Higher amount of Labrasol in oral formulation increases gastric disturbances in patient and hence, patient compliance is reduced. Hence, the inventors of the present invention have noted that there is a need for the oral pharmaceutical composition of Edaravone which is stable and does not produce side effects like gastric disturbances.

Parikh et al. (Drug Delivery 2017; 24(1); p. 962-978) describe a study that aimed at enabling oral use of Edaravone by developing a lipid-based nanosystem (LNS). The components of LNS including oil, surfactants, and co-surfactants were selected based on their potential to maximize the solubilization in gastrointestinal fluids, reduce its glucuronidation and improve transmembrane permeability. A liquid LNS (L-LNS) in the form of a micro -emulsion was prepared, comprising Capryol™ PGMC (Oil), Cremophor® RH 40: Labrasol®: TPGS 1000 (l:0.8:0.2) (Surfactant) and Transcutol® P (Co-surfactant). It was found that the oral bioavailability of the L-LNS was almost 11 times higher than that of an Edaravone suspension containing 30 mg/mL Edaravone and 0.5% of sodium carboxymethyl cellulose. Due to presence of so many expensive ingredients, final cost of such formulation increases to very high level. Hence, the inventors of the present invention noted that there is an unmet need of oral pharmaceutical composition of Edaravone which is stable as well as cost-effective to the patients and thereby making it affordable and patient compliant.

Also, it may be noted that the efficacy of Edaravone has seen an undisputed success since its inception in the therapeutic category of stroke management. Edaravone per se has wide applicability and has potential to be used for more therapeutic indications. The injectable dosage form has been a limiting factor in case of increased use of this product. Importantly, developing an oral dosage form of Edaravone is a challenging process due to its less soluble and less permeable (BCS Class-IV product) nature. Further, an injectable dosage form has inherent difficulty in terms of its usage post hospitalization. Apart from all these, Edaravone is also quite sensitive to hydrolysis and oxidation and thereby making manufacturing and development of oral formulation more difficult.

Needs still exist for another oral formulation of Edaravone which is patient compliant, stable, easy to commercially manufacture and cost effective.

OBJECTIVES OF INVENTION

The main objective of the present invention is to provide an oral composition of Edaravone preferably as suspension dosage form with pharmaceutically acceptable excipients and a process for preparation thereof. In one general aspect, the pharmaceutical composition as per the present invention is in the form of stable liquid formulation.

In yet another aspect, the pharmaceutical composition as per the present invention is in the form of stable suspension dosage form.

In yet another general aspect, a pharmaceutical composition as per the present invention comprises Edaravone and one or more pharmaceutically acceptable excipients wherein the composition is in the form of suspension dosage form for oral administration.

In another general aspect there is provided stable liquid oral formulation of Edaravone comprising one or more pharmaceutically acceptable excipients selected from viscosity modifiers, sweeteners, anti-foaming agents, vehicle, solvents, cosolvents, buffering agents, solubilizers, chelating agents, flavoring agents, antioxidants, coloring agents, preservatives, pH modifiers and mixtures thereof.

In another general aspect there is provided stable liquid oral formulation of Edaravone comprising one or more pharmaceutically acceptable excipients selected from viscosity modifiers, sweeteners, anti-foaming agents, vehicle, solvents, cosolvents, buffering agents, solubilizers, chelating agents, flavoring agents, antioxidants, coloring agents, preservatives, pH modifiers and mixtures thereof and wherein the formulation does not contain dispersant/dispersing agent.

In another general aspect there is provided a stable oral suspension formulation of Edaravone comprising one or more pharmaceutically acceptable excipients selected from viscosity modifiers, sweeteners, anti-foaming agents, vehicle, solvents, cosolvents, buffering agents, solubilizers, chelating agents, flavoring agents, antioxidants, coloring agents, preservatives, pH modifiers and mixtures thereof and wherein the formulation does not contain dispersant/dispersing agent.

In another general aspect there is provided a process for preparing a pharmaceutical composition of Edaravone. The process comprises the steps of: a) dissolving part sweetener in the vehicle; b) dissolving viscosity modifier in solution obtained from step (a); c) adding part sweetener, anti-oxidant(s), anti-foaming agent under stirring to the solution obtained from step (b); d) adding active pharmaceutical ingredient to the solution obtained from step (c) under stirring; e) adjusting pH to the solution obtained from step (d); f) making up the volume for the solution obtained from step (e); g) purging gas in bulk suspension to the solution obtained from step (0 under stirring; h) filling the solution obtained from step (g) in the bottle.

Another aspect of the invention is to provide pharmaceutical compositions that may be filled into any suitable pharmaceutically acceptable containers. For example, the pharmaceutically acceptable container may be selected from group consisting of bottles and syringes.

Another aspect of the invention is to provide a pharmaceutical composition comprising Edaravone and one or more pharmaceutically acceptable excipients for the management of neurodegenerative diseases.

The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns an oral, stable, pharmaceutical suspension of Edaravone.

The inventors have developed oral, stable, pharmaceutical suspension of Edaravone by careful selection of excipients with their optimum concentrations. The suspension dosage form is capable of masking the taste of the drug and also provides the drug in a suitable form to dissolve thereby providing patient compliance, especially for children and the elderly.

Various embodiments of the invention are now described in detail. As used in the description and throughout the claims, the meaning of "a", "an", and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description and throughout the claims, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise. Additionally, some terms used in this specification are more specifically defined below.

The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. The invention is not limited to the various embodiments given in this specification.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control.

"Around," "about" or "approximately" shall generally mean within 20% of a given value or range. Numerical quantities given are approximate, meaning that the term "around," "about" or "approximately" can be inferred if not expressly stated.

The term "Edaravone" as used is the invention is meant to cover amorphous or crystalline Edaravone in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. Edaravone may be used as a single active agent, or may be combined with other active agents, vitamins, minerals, dietary supplements, etc. The phrase “pharmaceutically acceptable” as used in the invention is meant to refer to those compounds, materials compositions, or other dosage forms that are, within the scope of medical judgment, suitable for use in contact with tissues of human beings and animals and without excessive toxicity, irritation, allergic response, or any other problem or complication.

An "oral" pharmaceutical composition for oral administration means a pharmaceutical composition which is orally administered orally and is absorbed through the intestine or gastrointestinal tract; referring without limitation to the introduction of substances by means of controlled time-release preparations, liquid suspensions, and sublingual administration. Liquid orals are homogeneous liquid preparations, usually consisting of a solution, an emulsion, or a suspension, of one or more active ingredients in a suitable liquid base.

The term “stable” as used in the present invention relates to both chemical (shelflife) and physical stability (suspension uniformity). Improved uniformity results in an improved product because less shaking of the suspension is required before dosing and allows the product to be stored longer (i.e. longer shelf-life) because the drug in the product will not settle and compact.

Further, in the present specification, "%w/v" means mass % with respect to a volume of a suspension unless otherwise specified, and a numerical range indicated using "to" indicates a range including numerical values before and after "to" as minimum and maximum values, respectively.

The present invention provides pharmaceutical composition comprising Edaravone and one or more pharmaceutically acceptable excipients for the management of neurodegenerative diseases.

The term "neurodegenerative diseases" as described herein includes Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease or Spinal muscular atrophy. The term "Amyotrophic lateral sclerosis" as used herein refers to ALS or Lou Gehrig's disease; a condition in which the nerves that control muscle movement slowly die, causing the muscles to shrink and weaken. As per an aspect of the present invention the Edaravone suspension has a dose of a drug product per one oral administration in a range of 1 to 20 mL, and the dose contains Edaravone in a range of 50 to 210 mg.

The pharmaceutical composition according to the present invention comprises Edaravone in the range of about 1.00 % J/N to about 5.00 %'N/N.

For the purposes of the present invention, small particle size of Edaravone is desirable for reasons other than slowing the rate of sedimentation. For drugs that are not very soluble, smaller particles generally dissolve faster due to the increase in the total surface area. Also, smaller drug particles are less likely to cause grittiness, which improves the palatability of the finished product. The present invention provides pharmaceutical composition, wherein the Dio of about 1 pm to 10 pm, D50 ranges from about 10 pm to 50 pm and D90 ranges from about 50 pm to 200 pm. The particle size of the Edaravone particles is measured for the purpose of this invention using light scattering technique (Malvern Master Sizer).

Another important property of the suspension is viscosity which further plays a role in the stability of suspension that is it helps in slowing the sedimentation rate of suspension. It is desired that in the present invention, the viscosity of the suspension should not be so high that pumping and handling would be difficult in industrial practice, but high enough to confer upon the suspension stability to settling of suspended particles for a reasonable period of time. The viscosity of the suspension should be such that it provides a pourable consistency to the suspension. Preferably, the suspension of the present invention has a viscosity in the range of about 10 cps to about 300 cps.

The stable oral suspension of Edaravone according to the present invention has a suspension base with the active ingredient suspended in the suspension base. The pharmaceutically acceptable suspension base may be, for example, an aqueous solvent such as water and comprising one or more pharmaceutically acceptable excipients selected from viscosity modifiers, sweeteners, anti-foaming agents, vehicle, solvents, co-solvents, buffering agents, solubilizers, chelating agents, flavoring agents, anti-oxidants, coloring agents, preservatives, pH modifiers and mixtures thereof. Examples of viscosity modifiers suitable for use in the present invention include but are not limited to gums, sodium alginate, bentonite, tragacanth sodium, carmellose sodium, crosscarmellose sodium, sorbitol, glycerol, polyvinyl pyrrolidone, polyethylene oxide, cellulose derivatives, such as hydroxypropylmethylcellulose, alkyl ether of cellulose, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose, sodium carboxymethylcellulose and mixtures thereof. Preferably the viscosity modifier is selected from xanthan gum, hydroxyethylcellulose, sodium carboxymethylcellulose or Avicel RC 591 (microcrystalline cellulose and carboxymethylcellulose sodium) or mixtures thereof.

The amount of viscosity modifiers present in the pharmaceutical composition of the present invention ranges from about 0.01 % J/N to about 1.00 %'N/N.

Examples of suitable sweeteners include, but are not limited to, both natural and artificial sweeteners such as sorbitol, sucrose, saccharins such as sodium saccharin, cyclamates such as sodium cyclamates, aspartame, sucralose, thaumatin, acesulfam K, monosaccharides, disaccharides and polysaccharides, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, partially hydrolyzed starch or com syrup, and sugar alcohols such as sorbitol, xylitol, mannitol, glycerin, etc. and combination thereof. Presently preferred as a sugar sweetener is sorbitol. Sugar sweeteners may be replaced or augmented by water- soluble artificial sweeteners. The amount of artificial sweetener used in the composition may vary to provide an appropriate amount of sweetness as determinable by one skilled in the art. Mixtures of sweetening and/or flavoring agents are preferably used.

The amount of sweetener in the pharmaceutical composition of the present invention ranges from about 20.00 % J/N to about 70.00 %'N/N.

Edaravone as a pharmaceutical ingredient has a property of being susceptible to oxidation by dissolved oxygen in a liquid, and thus, it is preferable to blend an antioxidant in a suspension according to an embodiment of the present invention.

Examples of such anti-oxidants include sulfites, bisulfites, and pyrosulfites, cysteines, methionines, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, EDTA, and the like. Examples of sulphites include sodium sulfite (Na2SO3), potassium sulfite (K2SO3), and calcium sulfite (CaSO3). Examples of bisulfites include sodium bisulfite (NaHSO3), potassium bisulfite (KHSO3), and ammonium bisulfite (NH4HSO3). Examples of pyrosulfites include sodium pyrosulfite (Na2S2O5) and potassium pyrosulfite (K2S2O5). Further, examples of cysteines include L-cysteine, DL-cysteine, N-acetylcysteine, hydrochlorides thereof, and the like. Most preferably, as an anti-oxidant, sodium bisulfite can be used, and as a cysteine, L-cysteine hydrochloride can be used. The amount of antioxidant in the pharmaceutical composition of the present invention ranges from about 0.01 %w/v to about 0.500 %w/v.

Suitable anti-foaming agents include, but are not limited to, simethicone emulsion, paraffin oils, organic phosphates, and alcohols alone or in combination. The amount of anti-foaming agent present in the pharmaceutical composition of Edaravone ranges from about 0.03 % J/N to about 0.30 %'N/N.

Suitable pH modifiers or pH adjusting agent include, but are not limited to, sodium hydroxide, phosphoric acid, magnesium trisilicate, sodium carbonate and sodium citrate alone or in combination. A pH adjusting agent may be added as desired to adjust the pH to a value of from about 3 to about 9, preferably from about 3 to about 6, most preferably about pH 4.

The present invention provides a stable oral suspension formulation of Edaravone comprising one or more pharmaceutically acceptable excipients and wherein the formulation does not contain dispersant/dispersing agent; preferably polyvinyl alcohol.

The pharmaceutical composition of the present invention has comparable levels of degradation products to the marketed formulation when kept in real-time and one month stability conditions.

The liquid oral pharmaceutical compositions described in various embodiments of the invention are preferably formed by various methods known in the art. Such manufacturing processes includes, but not limited to Direct Incorporation/Dispersion Method, Precipitation method, Controlled flocculation. The present invention provides stable liquid oral formulation of Edaravone and one or more pharmaceutically acceptable excipients, wherein the method for preparation of the suspension comprises steps of: a) dissolving part sweetener in the vehicle; b) dissolving viscosity modifier in solution obtained from step (a); c) adding part sweetener, anti-oxidant(s), anti-foaming agent under stirring to the solution obtained from step (b); d) adding active pharmaceutical ingredient to the solution obtained from step

(c) under stirring; e) adjusting pH to the solution obtained from step (d); f) making up the volume for the solution obtained from step (e); g) purging nitrogen gas in bulk suspension to the solution obtained from step

(f) under stirring; h) filling the to the solution obtained from step (g) in the bottle with nitrogen purging.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. 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

Example 1: Edaravone suspension composition:

Table 1: Qualitative Edaravone suspension compositions Example 2: Redispersibility Test

[Method]

Edaravone suspension composition were prepared according to Examples 5 and 6 presented below.

Each preparation was vortexed for 2 min. 15 mL sample transferred using glass cylinder into flat bottom glass tube (22 x 134 mm) with lid to undergo natural setting (under gravity) for 10 days. Redispersibility checked after 10 days and again kept to undergo natural setting (under gravity) for 10 days.

[Results]

The number of inversions required to redisperse the suspension formulations after 10 and 20 days is presented in Table 2 below.

Table 2:

The redispersibility rate of suspensions prepared with PVA and without PVA was found to be comparable. Gross observation of each re-dispersed suspension showed a uniform dispersion of fine particles.

The above results indicate that in the case of the aqueous suspension according to the present invention, its redispersibility is well maintained and is not affected by the absence of dispersing agent PVA.

Assay of Top, Middle and Bottom Method:

• Before opening the bottle, turn it upside down (invert) and shake vigorously up and down for at least 30 seconds. Look at the liquid medicine to make sure it is mixed well.

• Then sample bottle was opened and kept upright, undisturbed. • Using 5mL syringe, samples were withdrawn from Top, Middle and Bottom of the container and were analyzed as per assay method.

Observation: Results are tabulated below: Table - Top, Middle and Bottom Assay results for redispersibility testing

Conclusion: Based on sedimentation, redispersibility studies and particle size distribution it can be concluded that the formulation can be easily and uniformly distributed upon shaking. This ensures dose to dose uniformity of suspension throughout its use period.

Example 3: Stability data

Table 3: Comparative Stability data

The above results indicate that in the case of the aqueous suspension according to the present invention, the stability is well maintained and is not affected by the absence of dispersing agent PVA.

Example 4: Dissolution test

[Method 1]

The suspension composition prepared according to Example 6 presented below was subjected to dissolution test immediately after formulation (at the start of storage) and after storage at 2 - 8°C for 1 month and 3 months. The dissolution test was accomplished using Type II apparatus as described in United States Pharmacopoeia, at paddle RPM of 50, with 900 mL of 0.1 N hydrochloric acid as dissolution media, for maximum 60 minutes, the drug release was evaluated at different time intervals up to 60 minutes.

[Method 2] The suspension composition prepared according to Example 6 presented below was subjected to dissolution test immediately after formulation (at the start of storage) and after storage at 2 - 8°C for 3 months, 6 months and 12 months. The dissolution test was accomplished using Type II apparatus as described in United States Pharmacopoeia, at paddle RPM of 75, with 900 mL of pH 4.0 Acetate buffer as dissolution media, for maximum 60 minutes, the drug release was evaluated at different time intervals up to 60 minutes.

[Results]

The dissolution data for the suspension is presented in Table 4 below.

Table 4: Dissolution data for Example 6 Example 5 q.s. - Quantity Sufficient; NA- Not Applicable Notes:

# For pH. Adjustment, if required Manufacturing flow chart

Soak Xanthan gum in purified water overnight

Dispersion

Disperse the Edaravone API in soaked Xanthan gum along with water

Addition of other ingredients under stirring in purified water

(D sorbitol + Polyvinyl alcohol + Sodium bisulphite + L-cysteine Hydrochloride Hydrate + Simethicone emulsion + flavour) pH adjustment

Adjust the pH with Sodium hydroxide or phosphoric acid if required

Make up the volume with Purified water under stirring

Bottle filling

Fill the suspension into bottles as per required final volume per strength

1. Take sufficient quantity of Purified Water in a Manufacturing vessel.

2. Soak xanthan gum in above step 1 under stirring, keep the dispersion overnight.

3. Disperse Edaravone in above step 2 of soaked xanthan gum under stirring.

4. Dissolve Polyvinyl alcohol, Sodium bisulphite, L-cysteine Hydrochloride

Hydrate, D sorbitol and simethicone the above step 3 under stirring.

5. Add required quantity of flavor to the above step 4.

6. Finally make up the volume with Purified water. Check the pH if required add the sodium hydroxide/phosphoric acid to get the desired pH.

7. Fill the above suspension in a HDPE /PET container. Example 6 q.s. - Quantity Sufficient; NA- Not Applicable

Notes: # For pH. Adjustment, if required Manufacturing flow chart

Dissolve Part Sorbitol in purified water

Dispersion

Soak Xanthan gum in above solution 4, Addition of other ingredients under stirring

(sorbitol part 2+ Sodium bisulphite + L-cysteine Hydrochloride Hydrate + Simethicone emulsion)

Addition of API under stirring

Edaravone pH adjustment

Adjust the pH with Sodium hydroxide or phosphoric acid if required

Make up the volume with Purified water under stirring.

Nitrogen Purging

Nitrogen gas purging in bulk suspension under stirring.

Bottle filling with nitrogen purging

Fill the suspension into bottles as per required final volume, purge nitrogen and seal immediately.

1. Take sufficient quantity of Purified Water in a Manufacturing vessel.

2. Dissolve part sorbitol in step 1.

3. Soak viscosity modifier in above step 2 under stirring

4. Add Sorbitol part 2, Sodium bisulphite, L-cysteine Hydrochloride Monohydrate, and simethicone to the above step 3 under stirring.

5. Disperse Edaravone in above step 4 under stirring.

6. Check pH, if required add the sodium hydroxide/phosphoric acid to get the desired pH. Finally make up the volume with Purified water. 7. Purge nitrogen gas in bulk suspension under stirring.

8. Fill the above suspension in a Glass /PET container, purge nitrogen in container headspace, and seal immediately. Example 7

Example 8

Example 9

Example 10

Although certain embodiments and examples have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments and examples without departing from the teachings thereof.

Claims

CLAIMS:

Claim 1: An oral pharmaceutical composition comprising edaravone, viscosity modifier and optionally one or more other pharmaceutically acceptable excipients wherein the said composition does not contain polyvinyl alcohol.

Claim 2: The oral pharmaceutical composition as claimed in claim 1 wherein the composition is in the form of stable liquid suspension dosage form.

Claim 3: The oral pharmaceutical composition as claimed in claim 1 wherein the edaravone is present in the composition in the range of about 1.00% w/v to about 5.00% w/v.

Claim 4: The oral pharmaceutical composition as claimed in claim 1 wherein the viscosity modifier is selected from group comprising of xanthan gum, hydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose or Avicel RC 591 (microcrystalline cellulose and carboxymethylcellulose sodium) or mixture thereof.

Claim 5: The oral pharmaceutical composition as claimed in claim 1 wherein one or more other pharmaceutically acceptable excipients are selected from antioxidants), anti-foaming agent(s), sweetner(s) and pH modifier(s).

Claim 6: A process for preparation of stable liquid suspension of edaravone comprises steps of: a) dissolving part sweetener in the vehicle; b) dissolving viscosity modifier in solution obtained from step (a); c) adding part sweetener, anti-oxidant, anti-foaming agent under stirring to the solution obtained from step (b); d) adding edaravone to the solution obtained from step (c) under stirring; e) adjusting pH to the solution obtained from step (d); f) making up the volume for the solution obtained from step (e); g) purging nitrogen gas in bulk suspension to the solution obtained from step (f) under stirring; h) filling the to the solution obtained from step (g) in the bottle with nitrogen purging.

Claim 7: The process as claimed in claim 6 wherein the sweetener in step (a) and (c) is selected from sorbitol, xylitol, mannitol or mixture thereof in the amount ranging from 20.00% w/v to about 70.00% w/v.

Claim 8: The process as claimed in claim 6 wherein the vehicle is purified water.

Claim 9: The process as claimed in claim 6 wherein the viscosity modifier in step

(b) is selected from xanthan gum, hydroxyethylcellulose, sodium carboxymethylcellulose or Avicel RC 591 (microcrystalline cellulose and carboxymethylcellulose sodium) or mixture thereof in an amount ranging from about 0.01% w/v to about 1.00% w/v.

Claim 10: The process as claimed in claim 6 wherein the anti-oxidant in step (c) is selected from anti-oxidants such as sulfites, bisulfites, and pyrosulfites, cysteines, methionines, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, EDTA or mixture thereof in an amount ranging from about 0.01% w/v to about 0.500% w/v.

Claim 11: The process as claimed in claim 6 wherein the anti-foaming agent in step

(c) is selected from simethicone emulsion, paraffin oils, organic phosphates, alcohols or mixture thereof in the amount ranging from about 0.03% w/v to about 0.30% w/v.

Claim 12: The process as claimed in claim 6 wherein the edaravone suspension is prepared by a process comprising mixing the edaravone particles in step (d) having a Dio of about 1 |jm to 10 |am, D50 ranges from about 10 m to 50 pm and D90 ranges from about 50 pm to 200 pun under stirring.

Claim 13: The process as claimed in claim 6 wherein the pH is adjusted in step (e) using sodium hydroxide, phosphoric acid, magnesium trisilicate, sodium carbonate, sodium citrate or mixture thereof.

Claim 14: A stable oral liquid suspension composition comprising of: a) edaravone b) xanthan gum c) L-cysteine hydrochloride d) sodium bisulfite e) simethicone emulsion f) sorbitol g) pH adjusting agent(s) h) purified water and one or more pharmaceutically acceptable excipients, wherein the composition is free of polyvinyl alcohol.

Claim 15. The oral pharmaceutical composition as claimed in claim 1 or claim 14 wherein the composition comprises not more than 1% of total impurities after storage at 25°C/60% RH for 3 months.

Claim 16. The oral pharmaceutical composition as claimed in claim 1 or claim 14 wherein the composition comprises not more than 1% of total impurities after storage at 2-8°C for 12 months.

Claim 17. The oral pharmaceutical composition as claimed in claim 1 or claim 14 wherein the composition shows dissolution profile of not less than 80% in initial 30 minutes.