READY TO USE DANTROLENE COMPOSITIONS

FIELD OF THE INVENTION

The present invention relates to a stable, multidose, ready to use, non- aqueous compositions comprising (i) dantrolene or pharmaceutically acceptable salts thereof; (ii) non-aqueous solvent system suitable for injection, wherein dantrolene was substantially dissolved in the non-aqueous solvent system; wherein non-aqueous solvent system is free of polar aprotic solvents.

BACKGROUND OF THE INVENTION

Dantrolene, 1 -[(E)-[5-(4-nitrophenyl) furan-2-yl] methylideneamino] imidazolidine-2,4-dione, is a direct-acting skeletal muscle relaxant. It is the rescue agent of choice in the treatment of malignant hyperthermia, therefore widely available in most locations where anesthetics are delivered.

Dantrolene is structurally represented as

The commercial formulation Ryanodex ^® for injectable suspension is a sterile lyophilized powder comprising mannitol, polysorbate 80, povidone K12 and sodium hydroxide or hydrochloric acid for pH adjustment. Reconstituted RYANODEX ^® was administered by intravenous push at a minimum dose of 1 mg/kg for the treatment of malignant hyperthermia, whereas the

recommended prophylactic dose of RYANODEX is 2.5 mg/kg administered intravenously over a period of at least 1 minute, starting approximately 75 minutes prior to surgery.

Another commercial formulation Dantrium ^® is a sterile, non-pyrogenic, lyophilized formulation of dantrolene sodium for injection comprising 3000 mg mannitol, and sufficient sodium hydroxide. Dantrium ^® intravenous should be administered by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached.

Upon reconstitution of Dantrium ^® with 60 ml sterile water, a final concentration of 0.33 mg/ml of dantrolene and 50 mg/ml mannitol is achieved, i which exhibits a number of undesirable properties like cumbersome, imprecise preparation, significant time and elevated temperatures

to prepare a solution, large volume of solution to deliver an efficacious dose and large loading of mannitol can cause CNS complications.

U.S. Pat. No. 5,091 ,188 discloses, water-insoluble drugs injectable formulations as aqueous suspensions of phospholipid-coated microcrystals. Example 14 illustrates the lecithin-coated microcrystals of dantrolene.

U.S. Pat. No. 7,758,890 discloses low volume, safe for injection, colloidal dispersion of dantrolene sodium, water soluble polysorbate, dispersing agents like sorbitol and mannitol and water as a liquid carrier. Examples 1 -3 illustrates dantrolene colloidal suspension formulations and their preparation process.

U.S. Patent Application No 2003/0045587 discloses a pharmaceutical composition comprising dantrolene sodium and a solvent system comprising polar organic material comprising a sugar having at least two hydroxyl groups or an alcohol of two or three carbons having at least two hydroxyl groups or both and a second polar organic material comprising an amide group or an ammonium group or both. In a preferred embodiment polar solvent system comprising glycerol and N, N-dimethylacetamide (DMA).

The‘587 application aimed at developing formulations of dantrolene in a mixture of N, N-dimethylacetamide and glycerol (illustrated in examples 1 -5 preferably contain) are not recommended/suitable for injection because of DMA toxicity profile.

U.S. Pat. No. 9,433,608 discloses an emulsion prepared by mixing a component comprising val-dantrolene in glycerine or Vitamin E with another component comprising dantrolene in polyethylene glycol/propylene glycol/pluronic acid.

U.S. Patent Application No. 2004/0242646 discloses low volume safe for injection aqueous composition comprising dantrolene sodium and liquid carriers selected from group consisting of water, a water miscible solvent, glycerol, propylene glycol, dimethylacetamide, ethanol, polyethylene glycol, triethyl citrate, triacetin, monothioglycerol, or mixtures thereof.

In‘646 application, examples 1 -3 illustrates dantrolene colloidal suspension formulations and their preparation process. There has been no disclosure on the use of liquid carrier in preparing liquid compositions and their stability.

Although the use of non-aqueous solvents or solvent systems for the preparation of dantrolene compositions has been disclosed in the scientific and patent literatures (see for example U.S. 2003/0045587), there has been no disclosure of non-aqueous ready to use dantrolene compositions comprising high concentration of dantrolene.

Though the prior arts disclose dantrolene was dissolved in the solvents or solvent systems, they didn’t disclose the compositions comprising high concentration of dantrolene and their stability and the solvent systems disclosed in the prior arts preferably contain dimethyl acetamide which is not a preferred solvent for this type of drugs.

Surprisingly, inventors of the present application developed stable, ready-to-use, compositions comprising dantrolene and non-aqueous solvent systems. The compositions of the present invention, wherein dantrolene was substantially dissolved in the non-aqueous solvent system and the non- aqueous solvent system is free of polar aprotic solvents. The compositions of the present invention are stable for commercially significant time and also suitable for direct or instant administration.

SUMMARY OF THE INVENTION

The present invention relates to a stable, multidose, ready to use, non- aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection which is free from polar aprotic solvents.

The object of the invention is to prepare a stable, multidose, ready to use, non-aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection; wherein dantrolene was substantially dissolved in the non-aqueous solvent system.

In another aspect of the present invention provides dantrolene compositions in non-aqueous solvent systems which are free from polar aprotic solvents provides a stable, multidose, ready to use compositions. In another aspect a stable, multidose, ready to use, non-aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein

compositions comprising from about 50 mg/mL to about 150 mg/mL of dantrolene or pharmaceutically acceptable salts thereof.

The present invention relates to a stable, multidose, ready to use, non- aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein non- aqueous solvent system selected from the group comprising glycerol, propylene glycol, ethanol, polyethylene glycol, methanol, 1 -Butanol, 2-butanol, tertiary butanol, isopropanol, 1 -propanol and mixtures thereof.

In another aspect a stable, multidose, ready to use, non-aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein non- aqueous solvent system preferably comprising propylene glycol, polyethylene glycol, ethanol and combinations thereof.

In another aspect, stability of high concentrations (at least about 5%, w/v) of compound has been provided by the formulations of the present invention.

The present invention relates to a stable, multidose, ready to use, non- aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein the compositions further comprises at least one pharmaceutically acceptable excipients selected form the group of solubilizers, stabilizers, buffering agents, tonicity contributing agents, pH adjusting agents.

The present invention relates to a stable, multidose, ready to use, non- aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein the compositions is having a pH ranging from about 5.0 to about 1 1.

It is an object of this invention to provide a method for treating malignant hyperthermia and other conditions including but not limited to heat stroke, psychostimulant drug-induced toxicity (PDIT), pumphead, and other neurological, cognitive and motor dysfunction incident to iatrogenically or trauma induced situations, by the use of stable, multidose, ready to use, non- aqueous compositions comprising dantrolene or its pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stable, multidose, ready to use, non- aqueous compositions comprising (i) dantrolene or pharmaceutically acceptable salts thereof, (ii) non-aqueous solvent system suitable for injection; wherein dantrolene was substantially dissolved in the non-aqueous solvent system; wherein non-aqueous solvent system is free of polar aprotic solvents.

The present invention drawn to unexpected discovery of stable, ready to use, compositions of dantrolene in non-aqueous solvent system free from polar aprotic solvents.

The term“dantrolene” includes the compound dantrolene,

pharmaceutically acceptable salts thereof, isomers, solvates, prodrugs, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.

The term“pharmaceutically acceptable salts” includes

pharmaceutically acceptable salts, solvates, hydrates, anhydrates,

enantiomers, esters, isomers, polymorphs, tautomers, complexes and thereof.

The term“ready-to-use” refers to a liquid for parenteral administration that is not obtained by reconstituting a lyophilized product.

The terms“composition” and“formulation” refer to preparations comprising dantrolene or pharmaceutically acceptable salts thereof; in a form suitable for administration to a mammal.

The term“substantially dissolved" relates to 0.1 % to 99% of total dantrolene is dissolved in the compositions.

The term "stable" or "stability" as used herein includes both physical and chemical stability. Stability parameters include but not limited to potency, stable pH value and other physico-chemical parameters.

The term "physical stability" refers to compositions free from particles and that do not significantly change during storage.

The term "chemical stability" relates to a limited formation of impurities, limited decrease in potency and the like. The term“polar aprotic solvents” relates to a polar solvent that lack an acidic hydrogen and do not participate in hydrogen bonding (lack of O-H or N- H bonds), for example N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), hexamethyl phosphorotriamide (HMPT), dichloromethane, hydro furans (e.g. tetrahydrofuran), hydro pyrans, ethyl acetate, acetone, acetonitrile, propylene carbonate, N-methyl-2-pyrrolidone, and the like.

In one embodiment stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection.

In another embodiment stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein dantrolene was substantially dissolved in the non-aqueous solvent system.

In another embodiment stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein dantrolene was substantially dissolved in the non-aqueous solvent system; wherein non- aqueous solvent system is free of polar aprotic solvents.

In one embodiments, the stable, multidose, ready to use, non-aqueous composition comprising from about 10 mg/mL to about 200 mg/mL or from about 25 mg/ml to about 175 mg/ml or from about 50 mg/ml to about 150 mg/ml of dantrolene or pharmaceutically acceptable salts thereof.

In another embodiment, the composition comprising combination of dantrolene with other agents within the scope of the invention for example azumolene, NMDA blocker, benzodiazepine derivatives and the like, combinations thereof.

In one embodiment, the non-aqueous solvent system comprises non- aqueous solvents and their mixture thereof.

In another embodiment the non-aqueous solvent system is free from polar aprotic solvents.

In one embodiment of the invention, the composition comprising less than 5% by weight of residual water content. This residual water content may have contributed from the non-aqueous solvents used in the composition. In another embodiment of the invention, the composition comprising less than 2.5% by weight of residual water content.

In one embodiment suitable non-aqueous solvents comprise, polar protic solvents and mixtures thereof. The polar protic solvents are known in the art and include alkyl alcohols, for example ethanol, methanol, 1 -butanol, 2-butanol, 1 -propanol, isopropanol, tertiary butanol; alkyl glycols for example, ethylene glycol, propylene glycol and butylene glycol; glycerin; polyalkylene glycols, such as polyethylene glycol, polypropylene glycol, and polybutylene glycol.

In one embodiment non-aqueous solvents selected from the group comprising glycerol, propylene glycol, ethanol, polyethylene glycol, methanol, acetone, acetonitrile, 1 -Butanol, 2-butanol, tertiary butanol, isopropanol, 1 - propanol, and mixtures thereof.

In another embodiment non-aqueous solvent system preferably comprising propylene glycol, polyethylene glycol, ethanol and/or combinations thereof.

In one embodiment the stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof; non-aqueous solvent system suitable for injection, wherein non- aqueous solvent system comprises of polyethylene glycol.

In another embodiment the stable, multidose, ready to use, non- aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof; non-aqueous solvent system suitable for injection, wherein non- aqueous solvent system comprises the mixture of polyethylene glycol and propylene glycol.

In another embodiment the stable, multidose, ready to use, non- aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof; non-aqueous solvent system suitable for injection, wherein non- aqueous solvent system comprises the mixture of polyethylene glycol and ethanol.

In one embodiment the stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof; non-aqueous solvent system suitable for injection, wherein non- aqueous solvent system comprises of propylene glycol. In another embodiment the stable, multidose, ready to use, non- aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof; non-aqueous solvent system suitable for injection, wherein non- aqueous solvent system comprises the mixture of propylene glycol and ethanol.

In one embodiment the stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof; non-aqueous solvent system suitable for injection, wherein non- aqueous solvent system comprises the mixture of polyethylene glycol, propylene glycol and ethanol.

In one embodiment, the PEG has a molecular weight ranging from about 100 g/mol to about 2,500 g/mol.

In another embodiment, the PEG has a molecular weight ranging from between about 300 g/mol to about 1000 g/mol.

In another embodiment, the PEG has an average molecular weight ranging from between about 400 g/mol to about 800 g/mol.

In one embodiment, exemplary PEG’S include PEG-300, PEG-400, PEG-600 and PEG-800.

In another embodiment, polypropylene glycol (PPG) may have a molecular weight ranging from about 200 g/mol to about 2500 g/mol.

In a preferred embodiment, exemplary poly propylene glycols include PPG-250, PPG-425, and PPG-700.

In one embodiment, the composition comprising propylene glycol in a range from about 30% to about 90% by weight of the composition;

alternatively, composition comprising propylene glycol in a range from about 10% to about 90% by weight of the composition.

In another embodiment, the composition comprising polyethylene glycol in a range from about 30% to about 90% by weight of the composition.

In another embodiment, the composition comprising ethanol in a range from about 5% to about 50% by weight of the composition.

In one embodiment, the stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection and at least one pharmaceutically acceptable excipient selected form the group of solubilizers, stabilizers, buffering agents, tonicity contributing agents, pH adjusting agents.

In one embodiment the stable, multidose, ready to use, non-aqueous composition comprising tonicity contributors including one or more of sodium chloride, potassium chloride, and alkaline substances including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and meglumine and salts.

The term“solubilizer” refers to any substance which enhances the solubility of the dantrolene in the solvents.

Suitable solubilizer comprises, but not limited to, carboxylic acid, sugar and tromethamine.

Suitable carboxylic acid comprises, but not limited to, citric acid, malic acid, tartaric acid, succinic acid, acetic acid and the like.

Suitable sugar comprises, but not limited to, monosaccharide, disaccharide and reduced sugars that are suitable for administration by subcutaneous and intravenous routes. Some examples of sugar include, but not limited to, sucrose, fructose, trehalose, xylitol, mannitol, sorbitol and the like.

In one embodiment stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein the composition is having a pH ranging from about 5.0 to about 11.

In one embodiment stable, multidose, ready to use, non-aqueous composition comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection, wherein the composition is having a pH ranging from about 7.0 to about 11.

The term“stabilizer” refers to an agent which improves the composition stability.

In one embodiment suitable stabilizers includes surfactants,

antioxidants, chelating agents, proteins, polymers and combinations thereof.

In another embodiment stabilizers include antioxidants selected from the group, but not limited to butylated hydroxyanisole (BHA), butylated hydroxyl toluene (BHT), ascorbic acid and their esters, lactic acid, benzoic acid, tocopherol (Vitamin E) and its derivatives, sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium bisulfate, sodium thiosulfate, sodium acetate trihydrate, sodium formaldehyde sulfoxylate, monothioglycerol, L-cysteine, parabens, benzyl alcohol, thiourea, propyl gallate, methionine, thioglycolic acid, tartaric acid, phosphoric acid, gluconic acid, thiodipropionic acid, acetonic dicarboxylic acid, amino acids such as histidine, tryptophan, tyrosine;

Chelating agents include, but are not limited to, edetate salts, for example, edetate disodium and citric acid, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N’,N’-tetraacetic acid (EGTA) and 8-Amino-2-[(2-amino-5- methylphenoxy)methyl]-6-methoxyquinoline-N,N,N’N’-tetraa cetic acid, tetrapotassium salt (QUIN-2) and the like combinations thereof.

In another embodiment proteins as stabilizers include albumin, casein, and salts of casein; Polymers include polyvinylpyrrolidone (PVP), acacia (gum arabic), carmellose sodium, dextran, collagen, gelatin, gelatin hydrosylate, sodium starch glycolate, inulin, and xanthan; suitable surfactants or block copolymer components (or mixtures thereof) include cationic surfactants, anionic surfactants, non-ionic surfactants, zwitterionic surfactants, PEGylated surfactants, block copolymer and mixtures thereof.

In another embodiment surfactants include but not limited to

polysorbates, sodium oleate, sodium dodecyl sulfate, sodium diethyl hexyl sulfosuccinate, sodium dimethyl hexyl sulfosuccinate, sodium di-2-ethyl acetate, sodium 2-ethylhexyl sulfate, sodium undecane-3-sulfate, sodium ethyl phenyl undecanoate, dimethylammonium and trimethylammonium

Surfactants, myristyl-gammapicolinium chloride, dodecyl dimethyl

ammoniopropane- 1 -sulfate, dodecyl dimethyl ammoniobutyrate,

Dodecyl trimethylene di(ammonium chloride); decyl methyl sulfonediimine; dimethyl eicosyl ammoniohexanoate, Poloxamer 188 (Pluronic

F-68), Pluronic F- 127, polyoxyl castor oil and related PEGylated

castor oil derivatives such as Cremaphore EL, Arlatone G, sorbitan

monopalmitate, Pluronic 123, and sodium 2-ethylhexanoic

acid, polyoxyethylene fatty acid esters and mixtures thereof.

In one embodiment, the dantrolene compositions of the present invention can be packaged in any suitable sterile vial or container fit for the sterile storage of a pharmaceutical such as dantrolene for extended periods of time. Suitable containers can be glass vials, i.e. treated vials, molded glass vials, and CZ resin vials, polypropylene or polyethylene vials or other special purpose containers.

In one embodiment, the dantrolene compositions of the present invention can be loaded into an auto injectors/pen injector, prefilled syringes, plastic RTU bags, IV bags and the like.

Containers are of a size sufficient to hold one or more doses of dantrolene.

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof

(ii) non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol and propylene glycol;

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents.

where in composition comprising from about 50 mg/mL to about 150 mg/mL of dantrolene or pharmaceutically acceptable salts thereof.

In another embodiment the non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol from about 30% to about 90% and propylene glycol from about 10% to about 90%.

In another embodiment the non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol from about 30% to about 90% and propylene glycol from about 30% to about 90%.

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof

(ii) non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol and ethanol;

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents; where in composition comprising from about 50 mg/mL to about 150 mg/mL of dantrolene or pharmaceutically acceptable salts thereof.

In another embodiment the non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol from about 30% to about 90% and propylene glycol from about 10% to about 90%.

In another embodiment the non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol from about 30% to about 90% and propylene glycol from about 5% to about 50%.

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof

(ii) non-aqueous solvent system suitable for injection comprises mixture of propylene glycol and ethanol;

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents;

where in composition comprising from about 50 mg/mL to about 150 mg/mL of dantrolene or pharmaceutically acceptable salts thereof.

In another embodiment the non-aqueous solvent system suitable for injection comprises mixture of propylene glycol from about 10% to about 90% and ethanol from about 5% to about 50%.

In another embodiment the non-aqueous solvent system suitable for injection comprises mixture of propylene glycol from about 30% to about 90% and ethanol from about 5% to about 50%.

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof

(ii) non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol, propylene glycol and ethanol;

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents; where in composition comprising from about 50 mg/mL to about 150 mg/mL of dantrolene or pharmaceutically acceptable salts thereof.

In another embodiment the non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol from about 30% to about 90%, propylene glycol from about 10% to about 90% and ethanol from about 5% to about 50%.

In another embodiment the non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol from about 30% to about 90%, propylene glycol from about 30% to about 90% and ethanol from about 5% to about 50%.

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof

(ii) non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol, propylene glycol and ethanol;

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents;

where in composition comprising from about 50 mg/mL to about 150 mg/mL of dantrolene or pharmaceutically acceptable salts thereof.

wherein the composition is having a pH ranging from about 5.0 to about

1 1 .

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof

(ii) non-aqueous solvent system suitable for injection;

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents;

where in composition optionally further comprising a stabilizer.

In another embodiment a stable, multidose, ready to use, non-aqueous composition comprising (i) dantrolene or pharmaceutically acceptable salts thereof

(ii) non-aqueous solvent system suitable for injection;

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents;

where in composition optionally further comprising an antioxidant.

In another embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof

(ii) non-aqueous solvent system suitable for injection;

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents;

where in composition optionally further comprising an antioxidant and/or surfactant.

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof;

(ii) non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol, propylene glycol and ethanol;

(iii) polysorbate 80 and

(iv) monothioglycerol

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents.

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof;

(ii) non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol, propylene glycol and ethanol;

(iii) polysorbate 80 and (iv) alpha-tocopherol

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents.

In one embodiment a stable, multidose, ready to use, non-aqueous composition comprising

(i) dantrolene or pharmaceutically acceptable salts thereof;

(ii) non-aqueous solvent system suitable for injection comprises mixture of polyethylene glycol, propylene glycol and ethanol;

(iii) polysorbate 80 and

(iv) butylated hydroxyanisole

wherein dantrolene was substantially dissolved in the non-aqueous solvent system;

where in non-aqueous solvent system is free from polar aprotic solvents.

The compositions of the invention upon reconstitution with sterile water for injection forms a uniform colloidal suspension.

In one embodiment of the invention, the mean particle size of dantrolene in the colloidal suspension was less than 1 micron.

In another embodiment of the invention, the mean particle size of dantrolene in the colloidal suspension was less than 0.5 micron.

In another aspect, the compositions of the present invention may be prepared by measuring required quantities of propylene glycol in a container. Add suitable stabilizers to above container and stirred for 10-15 mins followed by addition of oth 1. Dispense all the required quantity of materials.

2. Required quantity of propylene glycol was weighed and to this measured quantity of antioxidant (MTG or Alpha-Tocopherol or BHA) was added and stirred for 15 mins.

3. To the above solution, PEG-300 was added and stirred to obtain a uniform solution.

4. Weighed quantity of dantrolene sodium was added to above step mixture and stirred to obtain a clear solution. 5. To the above solution, polysorbate 80 was added and stirred, further measured quantity of ethanol was added to obtain a solution.

6. The above composition was filtered through 0.22 pm filter and filled to suitable containers er solvent PEG 300 and stirred to dissolve it completely. Further, weighed quantity of dantrolene was added and stirred to dissolve it completely. Further surfactant was added to the above composition and to this ethanol was added and stirred to obtain a solution. This solution was filtered through 0.22pm filter and filled to suitable containers.

In one embodiment stable, multidose, ready to use, non-aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection used for the treatment of malignant hyperthermia and other related diseases or disorders.

In one embodiment stable, multidose, ready to use, non-aqueous compositions comprising dantrolene or pharmaceutically acceptable salts thereof, non-aqueous solvent system suitable for injection used for the treatment of dantrolene sensitive diseases or disorders include malignant hyperthermia, heat stroke, psychostimulant drug-induced toxicity (PDIT), pumphead, and other neurological, cognitive and motor dysfunction incident to iatrogenically or trauma induced situations.

In another embodiment, the compositions are also effective in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication.

In one embodiment of the invention, the compositions effective for the treatment or protecting from at least one cardiac arrest-related dysfunction including cardiac arrhythmia, premature ventricular contraction (PVC) induced left ventricular dysfunction, atrial fibrillation induced left ventricular

dysfunction, ventricular arrhythmia, and a combination thereof.

In one embodiment of the invention, the compositions comprising dantrolene or pharmaceutically acceptable salts alone or in combination with NMDA blocker or benzodiazepine derivatives or combinations thereof used for the treatment of neuronal reperfusion injury with ischemic neuropathy. Example 1 :

Formulations of dantrolene were prepared and evaluated chemical stability.

Table 1 : Non-aqueous compositions of Dantrolene

Manufacturing Process:

1. Dispense all the required quantity of materials.

2. Required quantity of propylene glycol was weighed and to this

measured quantity of monothioglycerol (MTG) was added and stirred for 15 mins.

3. To the above solution, PEG-300 was added and stirred to obtain a uniform solution.

4. Weighed quantity of dantrolene sodium was added to above step mixture and stirred to obtain a clear solution.

5. To the above solution, polysorbate 80 was added and stirred,

further measured quantity of ethanol was added to obtain a solution.

6. The above composition was filtered through 0.22 pm filter and filled to suitable containers.

Table 2: Stability data for the formulations of Example 1

Conclusion: Formulation trials with the higher strength of up to 100 mg/mL were carried out and it was found that formulations with strength of 70 mg/mL and above were physically unstable due to solubility as the solubility was near to saturation solubility. Though, all the formulations were chemically stable, formulations with PEG 300 or PEG 300 and Propylene Glycol were too viscous to proceed further in terms of manufacturing and administration.

Formulation with polysorbate 80 formed smooth suspension during administration making it one of the necessary excipients. Based on the formulation trials and the data, it can be concluded that formulation with 50 mg/ mL strength containing co solvents in the said proportion along with polysorbate 80 and ethanol is necessary for formulation of non-aqueous Dantrolene compositions.

Example 2:

Table 3: Non-aqueous compositions of Dantrolene

Manufacturing Process:

1. Dispense all the required quantity of materials.

2. Required quantity of propylene glycol was weighed and to this

measured quantity of antioxidant (MTG or Alpha-Tocopherol or BHA) was added and stirred for 15 mins.

3. To the above solution, PEG-300 was added and stirred to obtain a uniform solution.

4. Weighed quantity of dantrolene sodium was added to above step mixture and stirred to obtain a clear solution. 5. To the above solution, polysorbate 80 was added and stirred, further measured quantity of ethanol was added to obtain a solution.

6. The above composition was filtered through 0.22 pm filter and filled to suitable containers.

Table 4: Stability data for the formulations of Example 2

TBA: To be analysed

Conclusion: Based on the antioxidant screening trials, it can be concluded that anti-oxidant BHA is more feasible in terms of manufacturability and also provides promising stability to the multi-dose formulation.

Example 3:

The composition F9, upon reconstituted with sterile water for injection forms a uniform colloidal suspension and the particle size of dantrolene was measured. The dantrolene particle size of test product was compared with a reference composition which is similar to RYANODEX (inhouse preparation).