DESC:FIELD OF INVENTION
The present invention relates to a ready to use injectable composition comprising flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle. The invention also covers process of preparing the said composition and its use in the treatment of paroxysmal supraventricular tachycardias and paroxysmal atrial fibrillation/flutter.

BACKGROUND OF THE INVENTION
Atrial fibrillation is an irregular and often very rapid heart rhythm that may cause blood clots in the heart. Atrial fibrillation increases the risk of stroke, heart failure and other heart-related complications. During atrial fibrillation, the atria are irregular and out of rhythm with the ventricles of the heart. This is mostly an asymptomatic phenomenon and may cause fast, pounding heartbeat, palpitations, shortness of breath or weakness. Atrial fibrillations can be intermittent or may be persistent and require proper timely treatment in order to prevent further complications such as stroke.

Treatment for atrial fibrillation may include medications, therapy to reset the heart rhythm and catheter procedures to block erratic heart signals. Atrial flutter is one more complication associated with patients suffering from atrial fibrillation. Although atrial flutter is a different arrhythmia, the treatment is quite similar to atrial fibrillation.

One of the treatment options available for atrial fibrillation and flutter is Flecainide. Flecainide is approved in the United States as an oral dosage form in the form an immediate release tablet under the brand name Tambocor®. It can be seen from the label of Tambocor® that Flecainide is administered under medical supervision and the dose is decided depending on the cardiac parameters of the patients. Thus, there is a need to accurately and precisely administer a dose which is suitable to a subject in need thereof. The inventors of the present invention formulated an injectable dosage form of flecainide which provides the flexibility of administering a dose in an accurate, precise and convenient manner as compared to administering a solid dosage form.

Flecainide is also approved as an injectable dosage form in European countries. However, it was never approved in the United States. The European pack insert mentions that the injection needs to be diluted before administration to a subject in need thereof. The inventors of the present invention have formulated a ready to use injectable composition in order to reduce the time taken for the reconstitution and also reduced efforts in maintaining the sterility while doing this step. Further, the European label mentions that the injectable composition should not be diluted in any chloride containing diluent to avoid precipitation of flecainide. The inventors of the present invention have formulated a ready to use injectable composition of flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle that remains in solution without the formation of precipitate.

OBJECT OF THE INVENTION
One object of the invention relates to a ready to use injectable composition comprising flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle.

One more object of the invention relates to a ready to use injectable composition comprising flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle and optionally containing at least one pharmaceutically acceptable excipient.

A further object of the invention relates to a ready to use injectable composition comprising 150 mg flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle and at least one pharmaceutically acceptable excipient.
Another object of the invention relates to a ready to use injectable composition comprising 150 mg flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle and at least one pharmaceutically acceptable excipient selected from buffers, co-solvents, tonicity adjusting agents or combination thereof.

SUMMARY OF THE INVENTION
The present invention relates to a ready to use injectable composition comprising flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle. The invention also covers process of preparing the said composition and its use in the treatment of paroxysmal supraventricular tachycardias and paroxysmal atrial fibrillation/flutter.

The present invention relates to an aqueous ready to use injectable composition comprising flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle.

In another embodiment, the injectable composition of the present invention is a ready to use injectable composition comprising flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle and optionally containing at least one pharmaceutically acceptable excipient.

In one more embodiment, the injectable composition of the present invention is a ready to use injectable composition comprising 150 mg flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle and at least one pharmaceutically acceptable excipient.

In a further embodiment, the injectable composition of the present invention is a ready to use injectable composition comprising 150 mg flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle and at least one pharmaceutically acceptable excipient selected from buffers, co-solvents, tonicity adjusting agents or combination thereof.

In another embodiment, the injectable composition of the present invention comprises at least one pharmaceutically acceptable excipient selected from buffers, co-solvents, tonicity adjusting agents or combination thereof.

In a further embodiment, the ready to use injectable composition comprises 50–500 mg flecainide or its pharmaceutically acceptable salts thereof.

In an embodiment, the ready to use injectable composition comprises 150 mg flecainide or its pharmaceutically acceptable salts thereof.

In one more embodiment, the ready to use injectable composition comprises a pharmaceutically acceptable excipient comprising at least one co-solvent. In one further embodiment, the at least one co-solvent is selected from ethanol, propylene glycol, polyethylene glycol, pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, ethanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2-methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, pyridine, xylene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t-butyl ether, formaldehyde, glutaraldehyde, acetone, 3-pentanone (diethyl ketone), ethylene glycol, propylene glycol, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, acetic anhydride, piperidine, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, 1,2-dichloroethane, tetrachloroethylene and 1-chlorobutane, tetrahydrofuran,1,4-dioxane; and glycerin/glycerol.

In another embodiment, the ready to use injectable composition comprises a pharmaceutically acceptable excipient comprising at least one buffer. In one further embodiment, the atleast one buffer is selected from ascorbate, lactobionate, gentisate, succinate, a-lipoic acid, maleate, chloroacetate, bicarbonate, tartrate, glycylglycine, formate, benzoate, citrate, lactate, acetate, phosphate, propionate, pyridine, piperazine, pyrophosphate, histidine, 2-(?-morpholine)ethanesulfonic acid ("MES"), cacodylic acid, (bis(2-hydroxyethyl)-imino-tris(hydroxymethyl)-methane) ("bis-TRIS"), bicarbonate, amino acids (glycine, glutamate, aspartate and etc) or a combination of these buffering agents.

In one embodiment, the ready to use injectable composition of the present invention is a buffer free composition.

In one more embodiment, the ready to use injectable composition comprises a pharmaceutically acceptable excipient comprising at least one tonicity adjusting agent. In one further embodiment, the at least one tonicity adjusting agent is selected from mannitol, glycerol, dextrose and mixtures thereof.

In one embodiment, the ready to use injectable composition contains a chloride containing pharmaceutically acceptable vehicle comprising sodium chloride, calcium chloride, potassium chloride, magnesium chloride or combinations thereof.

In an embodiment, the ready to use injectable composition has a fill volume of less than 500 ml.

In a further embodiment, the ready to use injectable composition has a fill volume of about 50 ml to about 500 ml.

In another preferred embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In another embodiment, the ready to use injectable composition has a pH of about 5 to about 9, more preferably about 6 to about 8.
In one other embodiment, the ready to use injectable composition has osmolality of about 200 mOsm to about 500 mOsm.

In another embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 1200 mg sodium chloride and water for injection.

In a further embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 60 mg potassium chloride, about 40.5 mg calcium chloride, about 400 mg sodium lactate and water for injection.

In yet another embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 450 mg ethanol and water for injection.

In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 1350 mg sodium chloride and water for injection.

In one more embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride and water for injection.

In another embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 60 mg potassium chloride, about 40.5 mg calcium chloride, about 480 mg sodium lactate and water for injection.

In one more embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 5250 mg dextrose and water for injection.

In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 300 mg sodium chloride, about 6000 mg dextrose and water for injection.

In a further embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 150 mg sodium chloride, about 6750 mg dextrose and water for injection.

In an embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 1200 mg ethanol and water for injection.

In a further embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 1800 mg propylene glycol and water for injection.

In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 600 mg sodium chloride, about 1500 mg propylene glycol and water for injection.

In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 90 mg sodium chloride, about 1500 mg propylene glycol and water for injection.

In an embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 750 mg sodium chloride, about 3300 mg mannitol and water for injection.
In another embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 8 mg/ml sodium chloride and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In a further embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 6 mg/ml sodium chloride, about 0.4 mg/ml potassium chloride, about 0.27 mg/ml calcium chloride, about 2.66 mg/ml sodium lactate and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In yet another embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 6 mg/ml sodium chloride, about 3 mg/ml ethanol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 9 mg/ml sodium chloride and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one more embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 6 mg/ml sodium chloride and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In another embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 6 mg/ml sodium chloride, about 0.4 mg/ml potassium chloride, about 0.27 mg/ml calcium chloride, about 3.2 mg/ml sodium lactate and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one more embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 3 mg/ml sodium chloride, about 35 mg/ml dextrose and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In an embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 3 mg/ml sodium chloride, about 8 mg/ml ethanol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In a further embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 3 mg/ml sodium chloride, about 12 mg/ml propylene glycol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 4 mg/ml sodium chloride, about 10 mg/ml propylene glycol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In an embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 5 mg/ml sodium chloride, about 22 mg/ml mannitol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

DETAILED DESCRIPTION
The present invention relates to a ready to use injectable composition comprising flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle. The invention also covers process of preparing the said composition and its use in the treatment of paroxysmal supraventricular tachycardias and paroxysmal atrial fibrillation/flutter.

Flecainide or its pharmaceutically acceptable salts thereof is designated chemically as N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide. Flecainide has a molecular formula C17H20F6N2O3 and has the following structure:

Flecainide is approved in the United States as an oral dosage form in the form an immediate release tablet under the brand name Tambocor®. It can be seen from the label of Tambocor® that Flecainide is administered under medical supervision and the dose is decided depending on the cardiac parameters of the patients. Thus, there is a need to accurately and precisely administer a dose which is suitable to a subject in need thereof. The inventors of the present invention formulated an injectable dosage form of flecainide which provides the flexibility of administering a dose in an accurate, precise and convenient manner as compared to administering a solid dosage form.

Flecainide is also approved as an injectable dosage form in European countries. However, it was never approved in the United States. The European pack insert mentions that the injection needs to be diluted before administration to a subject in need thereof. The inventors of the present invention have formulated a ready to use injectable composition in order to reduce the time taken for the reconstitution and also reduced efforts in maintaining the sterility while doing this step. Further, the European label mentions that the injectable composition should not be diluted in any chloride containing diluent to avoid precipitation of flecainide. The inventors of the present invention have formulated a ready to use injectable composition of flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle that remains in solution without the formation of precipitate.

The term “flecainide” as used herein includes flecainide or its pharmaceutically acceptable salts which are well known in the art and also embrace any polymorph, pseudo-polymorph, solvate, hydrate, crystalline or amorphous form of flecainide and any prodrug of flecainide which can be delivered in a vehicle and manner described herein for flecainide. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the pharmaceutically active substance, having a freebase function, with a suitable organic acid or inorganic acid.

The ready to use injectable composition of the present invention may comprise about 50 mg to about 500 mg flecainide or its pharmaceutically acceptable salts thereof. Preferably, the ready to use injectable composition of the present invention may comprise about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg flecainide or its pharmaceutically acceptable salts thereof. In some embodiments, the ready to use injectable composition contains about 50 mg to about 200 mg flecainide or its pharmaceutically acceptable salt thereof, more preferably about 100 mg to about 200 mg. In a specific embodiment, the ready to use injectable composition contains about 150 mg flecainide or a pharmaceutically acceptable salt thereof.

The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

The ready to use injectable composition of the present invention comprise a chloride containing pharmaceutically acceptable vehicle. In one embodiment, the chloride containing pharmaceutically acceptable vehicle comprises sodium chloride, calcium chloride, potassium chloride, magnesium chloride or combination thereof.

The ready to use injectable composition of the present invention may further comprise at least one pharmaceutically acceptable excipient. In one embodiment, the pharmaceutically acceptable excipient comprise at least one co-solvent, at least one buffer, at least one tonicity adjusting agent or combinations thereof.

Suitable examples of co-solvents include, but are not limited to ethanol, propylene glycol, polyethylene glycol, pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, ethanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2-methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, pyridine, xylene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t-butyl ether, formaldehyde, glutaraldehyde, acetone, 3-pentanone (diethyl ketone), ethylene glycol, propylene glycol, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, acetic anhydride, piperidine, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, 1,2-dichloroethane, tetrachloroethylene and 1-chlorobutane, tetrahydrofuran,1,4-dioxane; and glycerin/glycerol.

The ready to use injectable composition of the present invention may comprise about 1 mg to about 3000 mg of at least one co-solvent, preferably about 300 mg to about 2000 mg of at least one co-solvent.

Suitable examples of buffers include, but not limited to ascorbate, lactobionate, gentisate, succinate, a-lipoic acid, maleate, chloroacetate, bicarbonate, tartrate, glycylglycine, formate, benzoate, citrate, lactate, acetate, phosphate, propionate, pyridine, piperazine, pyrophosphate, histidine, 2-(?-morpholine)ethanesulfonic acid ("MES"), cacodylic acid, (bis(2-hydroxyethyl)-imino-tris(hydroxymethyl)-methane) ("bis-TRIS"), bicarbonate, amino acids (glycine, glutamate, aspartate and etc) or a combination of these buffering agent.

In an embodiment, the ready to use injectable composition of the present invention is free of buffer.

The term “free of buffer” as used herein specifically means an injectable composition which is free of a distinct buffering agent. Without being bound by a particular theory, flecainide or its pharmaceutically acceptable salts thereof may provide a self-buffering effect to the compositions of the invention.
Suitable examples of tonicity adjusting agents include, but not limited to mannitol, glycerol, dextrose and mixtures thereof. The ready to use injectable composition of the present invention may comprise about 2000 mg to about 7000 mg of a tonicity adjusting agent, preferably from about 3000 mg to about 6000 mg of a tonicity adjusting agent.

The ready to use injectable composition of the present invention may have a fill volume less than 500 ml, preferably from about 1 ml to about 250 ml, more preferably from about 50 ml to about 200 ml. Alternatively, a preferred embodiment may comprise a ready to use injectable composition having a fill volume of about 150 ml.

The pH of the ready to use injectable composition of the present invention may range from about 5 to about 9, more preferably about 6 to about 8, including all subranges therebetween. Preferably, the ready to use injectable composition of the present invention may have a pH of about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8. The pH may be adjusted with the help of pH adjusting agents well known in the art. In one embodiment, the ready to use injectable composition may not contain any pH adjusting agents.

The ready to use injectable composition of the present invention may be hypotonic, isotonic or hypertonic, preferably isotonic. In one embodiment, the ready to use injectable composition of the present invention has an osmolality of about 200 mOsm to about 500 mOsm.

In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide in a chloride containing pharmaceutically acceptable vehicle.
In one preferred embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 1200 mg sodium chloride and water for injection.

In a preferred embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 60 mg potassium chloride, about 40.5 mg calcium chloride, about 400 mg sodium lactate and water for injection.

In another preferred embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 450 mg ethanol and water for injection.

In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 1350 mg sodium chloride and water for injection.

In one more embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride and water for injection.

In another embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 60 mg potassium chloride, about 40.5 mg calcium chloride, about 480 mg sodium lactate and water for injection.

In one more embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 5250 mg dextrose and water for injection.
In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 300 mg sodium chloride, about 6000 mg dextrose and water for injection.

In a further embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 150 mg sodium chloride, about 6750 mg dextrose and water for injection.

In an embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 1200 mg ethanol and water for injection.

In a further embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 1800 mg propylene glycol and water for injection.

In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 600 mg sodium chloride, about 1500 mg propylene glycol and water for injection.

In one embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 90 mg sodium chloride, about 1500 mg propylene glycol and water for injection.

In an embodiment, the ready to use injectable composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 750 mg sodium chloride, about 3300 mg mannitol and water for injection.

In another embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 8 mg/ml sodium chloride and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In a further embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 6 mg/ml sodium chloride, about 0.4 mg/ml potassium chloride, about 0.27 mg/ml calcium chloride, about 2.66 mg/ml sodium lactate and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In yet another embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 6 mg/ml sodium chloride, about 3 mg/ml ethanol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 9 mg/ml sodium chloride and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one more embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 6 mg/ml sodium chloride and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In another embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 6 mg/ml sodium chloride, about 0.4 mg/ml potassium chloride, about 0.27 mg/ml calcium chloride, about 3.2 mg/ml sodium lactate and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.
In one more embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 3 mg/ml sodium chloride, about 35 mg/ml dextrose and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 2 mg/ml sodium chloride, about 40 mg/ml dextrose and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In a further embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 1 mg/ml sodium chloride, about 45 mg/ml dextrose and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In an embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 3 mg/ml sodium chloride, about 8 mg/ml ethanol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In a further embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 3 mg/ml sodium chloride, about 12 mg/ml propylene glycol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 0.6 mg/ml sodium chloride, about 10 mg/ml propylene glycol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 4 mg/ml sodium chloride, about 10 mg/ml propylene glycol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In an embodiment, the ready to use injectable composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof, about 5 mg/ml sodium chloride, about 22 mg/ml mannitol and water for injection. In an embodiment, the ready to use injectable composition has a fill volume of about 150 ml.

In one embodiment, the ready to use injectable composition of the present invention is stable throughout the shelf life. The term "stable" refers to a ready to use injectable composition of the present invention which is physically as well as chemically stable as demonstrated by compliance to acceptable specification when the composition is stored at convenient temperature, such as between about 0°C and about 60°C, preferably about 25°C to about 40°C for a commercially reasonable period of time, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years. Suitably, the ready to use injectable composition of flecainide of the present invention remains physically stable, with no precipitation or crystallization or color change upon storage and the shelf life period of 18–24 months. Suitably, ready to use injectable composition of flecainide remains chemically stable, wherein various parameters such as the drug content (assay of flecainide) and content of related substances, i.e. known and unknown impurities remains within specified limits such as those specified according to ICH guidelines, upon storage for prolonged period of time such as for at least 12 months, preferably for 18 months, more preferably 24 months or longer.

The ready to use injectable composition of present invention is substantially free of impurities. For purposes of the present invention, "substantially free of impurities” shall be understood to include flecainide containing ready to use injectable compositions in which the amount of total impurities is less than about 5% of the sum of peak areas of all degradants, as calculated on a normalized peak area response ("PAR") basis as determined by high performance liquid chromatograph ("HPLC"). The amount of impurities is further calculated as being based upon the original amount of flecainide being present in the composition. Preferably, the said ready to use injectable compositions of flecainide prevent degradation of flecainide such that not more than 10 %, not more than 5 %, not more than 4 %, not more than 3 %, not more than 2 %, not more than 1%, not more than 0.4%, not more than 0.2% of flecainide impurity or impurities are formed over the storage period. In yet another preferred embodiment the value of assay of flecainide remains within the specified limit of 90–110% by weight of the label claim.

The ICH storage stability studies were performed on the ready to use injectable composition of the present invention packaged in the proposed commercial primary packaging and closure system. The stability study samples were stored at 2–8°C, 25°C ± 2°C/60% RH ± 5% RH, 30°C ± 2°C/65% RH ± 5% RH, 30°C ± 2°C/75% RH ± 5% RH , and 40°C ± 2°C/75% RH ± 5% RH. The necessary parameters viz., assay, related substances, particle size distribution, pH, and osmolality were tested and found to be within specification at stability conditions. In some preferred aspects of the invention, the time for which long term storage are contemplated include periods of at least about 24 months or longer with such that the composition is substantially free of impurities.

Preferably, the process of preparation of the ready to use injectable composition of the present invention is carried out under nitrogen purging or blanketing. The ready to use injectable composition of the present invention may be sterilized under aseptic conditions well known in the art, preferably sterilization by filtration or by terminal sterilization like autoclaving.

The ready to use injectable compositions of the present invention can be packaged in any suitable sterile vial or prefilled syringe or a bag or any container fit for the sterile storage of the composition. The ready to use injectable composition of the present invention can be provided in a kit or package that includes a container enclosing the composition. Suitable containers can be glass vials, e.g., Schott treated vials, molded glass vials, and CZ resin vials, polypropylene or polyethylene vials or other special purpose containers. Suitable containers can be prefilled syringes such as glass prefilled syringes or plastic prefilled syringes. Containers are of a size sufficient to hold one or more doses of flecainide. The container may be part of a syringe or separate from the syringe. The kit or package also includes a needle that can be suitably mounted to the syringe. The size of the needle, in some embodiments, is equal to or smaller than 18G, 19G, 20G, 21G, 22G, 23G, 24G, or 25G. In one embodiment, the needle has a size that is 20G or smaller. In one embodiment, the needle has a size that is 21G or smaller. In one embodiment, the needle has a size that is 22G or smaller. In one embodiment, the needle has a size that is 23G or smaller. In one embodiment, the ready to use injectable composition of the present invention may be administered without the need of an in-line filter during administration, demonstrating the absence of particulate matter throughout its shelf life. In another embodiment, the ready to use injectable composition of the present invention may be filtered by using an in-line filter before administration.

The injectable composition of the present invention may be a ready to use composition. In one embodiment, such composition may comprise about 150 mg flecainide in a chloride containing pharmaceutically acceptable vehicle, and wherein the fill volume of composition is about 150 ml. In one such embodiment, such composition may comprise about 1 mg/ml flecainide in a chloride containing pharmaceutically acceptable vehicle, and wherein the fill volume of composition is about 150 ml. In an embodiment, the ready to use injectable composition of the present invention is free of buffer.

EXAMPLES
The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever.
Example 1
Ingredients Quantity in mg
1A 1B
Flecainide Acetate 150 150
Sodium chloride 900 450
Ethanol 450 1200
Water q.s to 150 mL q.s to 150 mL
Manufacturing process:
1. Sodium chloride and ethanol was dissolved in water for injection
2. Flecainide acetate was added to the solution of step 1 till a clear solution was obtained.
3. Volume of solution of step 2 was made up with water for injection.
4. The bulk solution of step 3 was then aseptically filtered using PES or PVDF filter.
5. The filtered bulk of step 4 then filled in vials or infusion bags. The filled vials or infusion bags were stoppered and sealed.
6. The sealed vials were terminally sterilized using autoclave at 121ºC for 15 min.

Example 2
Ingredients Quantity in mg
2A 2B
Flecainide Acetate 150 150
Sodium chloride 900 900
Potassium chloride 60 60
Calcium chloride 40.5 40.5
Sodium lactate 400 480
Water q.s to 150 mL q.s to 150 mL

Manufacturing process:
1. Sodium chloride, potassium chloride, calcium chloride and sodium lactate were dissolved in water for injection.
2. Flecainide acetate was added to solution of step 1 till a clear solution was obtained.
3. Volume of solution of step 2 was made up with water for injection.
4. The bulk solution of step 3 was then aseptically filtered using PES filter.
5. The filtered bulk of step 4 then filled in vials or infusion bags. The filled vials or infusion bags were stoppered and sealed.
6. The sealed vials were terminally sterilized using autoclave at 121ºC for 15 min.

Condition Time point Description pH Assay
(%) Total impurities (%)
(Aseptic filtration)
Initial Initial Clear colourless solution 6.8 98.5 <0.1
25°C/60%RH 3M Clear colourless solution 6.8 106.0 <0.1
12 M Clear colourless solution 6.9 104.6 <0.1
40°C/75%RH 3M Clear colourless solution 7.2 106.4 0.1
6M Clear colourless solution 7.1 103.5 0.1
(Terminally sterilized)
Initial Initial Clear colourless solution 6.7 103.1
25°C/60%RH 3M Clear colourless solution 6.6 99.0 0.2
6M Clear colourless solution 6.7 98.3 <0.1
12 M Clear colourless solution 7.1 99.3 0.1
40°C/75%RH 3M Clear colourless solution 6.7 99.6 <0.1
6M Clear colourless solution 6.6 97.4 <0.1

The stability data incubated under two different conditions (aseptically filtered and terminally sterilized) are provided in the above table. It was observed that the compositions sterilized by either sterilization method maintained a clear, colorless solution throughout all stages and conditions. The pH of compositions sterilized by either sterilization method remain in the range of 6.5 to 7.5 during all stages and conditions. Assay values seen for composition sterilized by either sterilization method remain acceptable. Total impurities were consistently seen to be low and was unaffected by sterilization methods.

The composition sterilized by both aseptic filtration and autoclaving demonstrated a good stability under various conditions over a period of up to twelve months. This is evidenced by the consistent physical appearance, stable pH levels, assay values within acceptable ranges, and low levels of total impurities.

Example 3
Ingredients Quantity in mg
3A 3B
Flecainide Acetate 150 150
Sodium chloride 1200 1350
Water q.s to 150 mL q.s to 150 mL

Manufacturing process:
1. Sodium chloride was dissolved in water for injection
2. Flecainide was added to the solution of step 1 till a clear solution was obtained.
3. Volume of solution of step 2 was made up with water for injection.

Example 4
Ingredients Quantity in mg
4A 4B 4C
Flecainide Acetate 150 150 150
Sodium chloride 450 300 150
Dextrose 5250 6000 6750
Water q.s to 150 mL q.s to 150 mL q.s to 150 mL

Manufacturing process:
1. Sodium chloride and dextrose were dissolved in water for injection.
2. Flecainide acetate was added to solution of step 1 till a clear solution was obtained.
3. Volume of solution of step 2 was made up with water for injection.
4. The bulk solution of step 3 was then aseptically filtered using PES filter.
5. The filtered bulk of step 4 then filled in vials or infusion bags. The filled vials or infusion bags were stoppered and sealed.
6. The sealed vials or infusion bags were terminally sterilized using autoclave at 121ºC for 15 min.

Condition Time point Description pH Assay
(%) Total impurities (%)
(Aseptic filtration)
Initial Clear colourless solution 5.7 103.2 <0.1
25°C/60%RH 3M Clear colourless solution 5.3 103.0 <0.1
6M Clear colourless solution 5.3 102.7 <0.1
40°C/75%RH 3M Clear colourless solution 5.7 102.0 <0.1
6M Clear colourless solution 5.6 102.0 <0.1
(Terminally sterilized)
Initial Clear colourless solution 5.6 100.4 0.5
25°C/60%RH 3M Clear colourless solution 5.4 101.0 0.3
6M Clear colourless solution 5.8 100.2 0.3
40°C/75%RH 3M Clear colourless solution 5.4 100.4 0.3
6M Clear colourless solution 5.5 100.6 0.3

The compositions sterilized by either autoclaving or by aseptic filtration maintain their physical appearance as a clear, colorless solution throughout stability period. The pH levels remain stable, ranging from 5.3 to 5.7, suggesting chemical stability. Assay values seen for composition sterilized by either sterilization method remain acceptable. Total impurities were consistently seen to be low and was unaffected by sterilization methods. The data suggests that compositions sterilized by either sterilization method was stable in terms of clarity, colorlessness, pH, assay value consistency, and consistent levels of total impurities across all tested conditions over a six-month period.

Example 5
Ingredients Quantity in mg
5A 5B 5C 5D
Flecainide Acetate 150 150 150 150
Sodium chloride 450 600 90 0
Propylene glycol 1800 1500 1500 3000
Water q.s to 150 mL q.s to 150 mL q.s to 150 mL q.s to 150 mL

Manufacturing process:
1. Sodium chloride and propylene glycol were dissolved in mixture of water for injection.
2. Flecainide acetate was added to solution of step 1 till a clear solution was obtained.
3. Volume of solution of step 2 was made up with water for injection.
4. The bulk solution of step 3 was then aseptically filtered using PES filter.
5. The filtered bulk of step 4 then filled in vials or infusion bags. The filled vials or infusion bags were stoppered and sealed.
6. The sealed vials or infusion bags were terminally sterilized using autoclave at 121ºC for 15 min.

Condition Time point Description pH Assay
(%) Total impurities (%)
Initial Initial Clear colourless solution 6.8 101.1 <0.1
25°C/60%RH 3M Clear colourless solution 7.1 101.0 <0.1
6M Clear colourless solution 7.1 100.7 0.1
40°C/75%RH 3M Clear colourless solution 7.1 100.9 0.1
6M Clear colourless solution 7.2 99.7 0.1

The stability data indicates that the clear, colorless solution maintains its chemical integrity across different environmental conditions. Initially, the solution has a pH of 6.8, an assay of 101.1%, and total impurities less than 0.1%. When stored at real time (25°C/60% RH) and accelerated conditions (40°C/75% RH) for 6 months, the solution remained clear and colorless, with no change in pH (range of 6.8 – 7.1), assay (range of 99.7% – 101.1%). Total impurities remain consistently low at less than 0.1%.

The composition demonstrated a robust chemical stability under varying temperature and humidity conditions. The consistent pH values around neutral and no fluctuations in assay percentages, which remain above 99%, indicate that the composition retains its efficacy.

Example 6
Ingredients Quantity in mg
Flecainide Acetate 150
Sodium chloride 750
Mannitol 3300
Water q.s to 150 mL

Manufacturing process:
1. Sodium chloride and mannitol were dissolved in mixture of water for injection.
2. Flecainide was added to solution of step 1 till a clear solution was obtained.
3. Volume of solution of step 2 was made up with water for injection.
4. The bulk solution of step 3 was then aseptically filtered using PES filter.
5. The filtered bulk of step 4 then filled in vials or infusion bags. The filled vials or infusion bags were stoppered and sealed.

While the invention has been described in connection with specific embodiments thereof. it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth.
,CLAIMS:1. A ready to use injectable composition comprising flecainide or its pharmaceutically acceptable salts thereof in a chloride containing pharmaceutically acceptable vehicle.

2. The composition according to claim 1, wherein said composition is aqueous.

3. The composition according to claim 1, wherein chloride containing pharmaceutically acceptable vehicle comprises sodium chloride, calcium chloride, potassium chloride, magnesium chloride or combinations thereof.

4. The composition according to claim 1, wherein said composition comprises about 50 mg to about 500 mg flecainide or its pharmaceutically acceptable salts thereof.

5. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof.

6. The composition according to claim 1, wherein said composition comprises about 1 mg/ml flecainide or its pharmaceutically acceptable salts thereof.

7. The composition according to claim 1, wherein said composition further comprises at least one pharmaceutically acceptable excipient selected from buffers, co-solvents, tonicity adjusting agents or combination thereof.

8. The composition according to claim 1, wherein said composition is free of buffer.

9. The composition according to claim 1, wherein said composition has a fill volume of about 150 ml.
10. The composition according to claim 1, wherein said composition comprises about 1 mg to about 3000 mg of at least one co-solvent.

11. The composition according to claim 1, wherein said composition comprises about 2000 mg to about 7000 mg of a tonicity adjusting agent.

12. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 1200 mg sodium chloride and water for injection.

13. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 60 mg potassium chloride, about 40.5 mg calcium chloride, about 400 mg sodium lactate and water for injection.

14. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 450 mg ethanol and water for injection.

15. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 1350 mg sodium chloride and water for injection.

16. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride and water for injection.

17. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 900 mg sodium chloride, about 60 mg potassium chloride, about 40.5 mg calcium chloride, about 480 mg sodium lactate and water for injection.

18. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 5250 mg dextrose and water for injection.

19. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 300 mg sodium chloride, about 6000 mg dextrose and water for injection.

20. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 150 mg sodium chloride, about 6750 mg dextrose and water for injection.

21. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 1200 mg ethanol and water for injection.

22. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 450 mg sodium chloride, about 1800 mg propylene glycol and water for injection.

23. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 600 mg sodium chloride, about 1500 mg propylene glycol and water for injection.

24. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 90 mg sodium chloride, about 1500 mg propylene glycol and water for injection.

25. The composition according to claim 1, wherein said composition comprises about 150 mg flecainide or its pharmaceutically acceptable salts thereof, about 750 mg sodium chloride, about 3300 mg mannitol and water for injection.