Injectable compositions of apixaban

Abstract

The present invention relates to an injectable pharmaceutical composition comprising apixaban. The invention particularly relates to a ready to dilute injectable composition comprising apixaban, and pharmaceutically acceptable excipients. The present invention also relates to a ready to use injectable composition comprising apixaban, and pharmaceutically acceptable excipients The invention also particularly relates to a process of preparing the composition.

Description

[0001] INJECTABLE COMPOSITIONS OF APIXABAN

[0002] FIELD OF INVENTION

[0003] The present invention relates to an injectable pharmaceutical composition comprising apixaban. The invention particularly relates to a ready to dilute injectable composition comprising apixaban, and pharmaceutically acceptable excipients. The present invention also relates to a ready to use injectable composition comprising apixaban, and pharmaceutically acceptable excipients The invention also particularly relates to a process of preparing the composition.

[0004] BACKGROUND OF INVENTION

[0005] Apixaban is a poorly aqueous soluble drug that has poor bioavailability and low absorption. Solubility and stability are long identified factors hindering the development of therapeutic agents. Conventional delivery systems for very insoluble drugs typically use a combination of specialized excipients like cyclodextrins, extreme pH conditions, all of which are detrimental and toxic, when ingested in large amounts.

[0006] Apixaban is marketed as an oral immediate release tablet under the trademark Eliquis™ in the United States. Such oral dosage forms cannot be administered in patients who are not conscious and have difficulty in swallowing (dysphagia). Hence there remains a need in the art for an injectable dosage form of apixaban, which can overcome the poor and erratic absorption and bioavailability issues observed with oral formulations. Further, it would be convenient to administer such injectable dosage forms to patients who are not conscious and who have difficulty in swallowing.

[0007] Apixaban has limited solubility in aqueous solutions and formulation of an injectable composition is very complex. It is challenging to formulate an injectable composition of apixaban wherein the apixaban is in dissolved state and precipitation is prevented throughout the shelf of the product. Further, such injectable composition needs to be diluted in compatible admixture diluents before administration. Owing to the low aqueous solubility of apixaban, there is a high chance of precipitation of apixaban when diluted with compatible admixture diluents. It is of utmost challenge to prevent precipitation of apixaban at this stage, and this makes the formulation further challenging.

[0008] There have been some prior attempts on formulation of apixaban in an injectable composition, however, there is limited data on stability of such injectable composition. Thus, there exists a need in the art to develop a ready to use as well as a ready to dilute composition comprising apixaban.

[0009] OBJECT OF THE INVENTION

[0010] An object of the invention is to provide an injectable composition comprising apixaban.

[0011] Another object of the invention is to provide an injectable composition comprising (a) apixaban, (b) at least one solubilizer, (c) a pharmaceutically acceptable vehicle, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

[0012] One another object of the present invention is to provide a ready to dilute injectable composition comprising apixaban.

[0013] One more object of the present invention is to provide a ready to use injectable composition comprising apixaban.

[0014] SUMMARY OF THE INVENTION

[0015] The present invention relates to injectable pharmaceutical composition comprising apixaban. The invention particularly relates to a ready to dilute composition comprising apixaban, and pharmaceutically acceptable excipients, process of preparing the composition. The invention also relates to a ready to use composition comprising apixaban, and pharmaceutically acceptable excipients, process of preparing the composition.

[0016] The present invention relates to an injectable composition of the present invention comprising (a) apixaban, (b) at least one solubilizer, (c) a pharmaceutically acceptable vehicle, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

[0017] In one embodiment, the injectable composition of the present invention is a ready to use composition.

[0018] In another embodiment, the injectable composition of the present invention is a ready to dilute composition.

[0019] In one more embodiment, the injectable composition of the present invention comprises apixaban in an amount of about 0.1 mg to about 20 mg.

[0020] In a further embodiment, the injectable composition of the present invention comprises apixaban in an amount of about 0.1 mg to about 10 mg.

[0021] In one embodiment, the injectable composition of the present invention may comprise about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about Img, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8mg, about 1.9 mg, about 2mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg or about 10 mg apixaban.

[0022] In one embodiment, the present invention relates to an injectable composition comprising apixaban wherein the composition is a ready to use composition. In a further embodiment, the injectable composition of the present invention comprises solubilizer in an amount of about 1 mg / ml to about 200 mg / ml.

[0023] In another embodiment, the present invention relates to an injectable composition comprising apixaban wherein the composition is a ready to dilute composition. In one embodiment, the injectable composition of the present invention comprises solubilizer in an amount of about 1 mg / ml to about 1000 mg / ml.

[0024] In an embodiment, the injectable composition of the present invention comprises atleast one buffering agent in an amount of about 0.01 mg / ml to about 10 mg / ml.

[0025] In an embodiment, the injectable composition of the present invention comprises atleast one tonicity adjusting agent in an amount of Img / ml to about 100 mg / ml.

[0026] The present invention relates to an injectable composition comprising apixaban wherein the composition is a ready to use composition.

[0027] In one embodiment, the present invention relates to an injectable composition of the present invention comprising (a) apixaban, (b) at least one solubilizer, (c) a pharmaceutically acceptable vehicle, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

[0028] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) water for injection, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

[0029] In a further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (d) water for injection.

[0030] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent and (d) water for injection.

[0031] In one more embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent, (d) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (e) water for injection.

[0032] The present invention relates to an injectable composition comprising apixaban wherein the composition is a ready to dilute composition.

[0033] In one embodiment, the present invention relates to an injectable composition of the present invention comprising (a) apixaban, (b) at least one solubilizer, (c) a pharmaceutically acceptable vehicle, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent. In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) water for injection, (d) optionally containing atleast one tonicity adjusting agent and (d) optionally containing atleast one buffering agent.

[0034] In a further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (d) water for injection.

[0035] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent and (d) water for injection.

[0036] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent, (d) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (e) water for injection.

[0037] In an embodiment, the injectable composition of the present invention is an aqueous composition.

[0038] In one embodiment, the injectable composition of the present invention is an injectable solution.

[0039] Other objects, features and advantages of the present invention will be apparent to those of ordinary skill in the art in view of the following detailed description of the invention and accompanying drawings. DETAILED DESCRIPTION OF THE INVENTION

[0040] The present invention relates to an injectable pharmaceutical composition comprising apixaban. The invention particularly relates to a ready to dilute injectable composition comprising apixaban, and pharmaceutically acceptable excipients. The present invention also relates to a ready to use injectable composition comprising apixaban, and pharmaceutically acceptable excipients The invention also particularly relates to a process of preparing the composition.

[0041] Apixaban is designated chemically as l-(4- methoxyphenyl)-7-oxo-6-[4-(2- oxopiperidin-l-yl)phenyl]- 4, 5,6,7- tetrahydro- lH-pyrazolo[3,4 c]pyridine-3- carboxamide and a molecular weight of 459.5. The chemical structure is:

[0042] Apixaban has limited solubility in aqueous solutions and formulation of an injectable composition is complex. Apixaban is available as an oral dosage form viz. immediate release tablet, which is reported to have poor absorption and low bioavailability. There remains a need in the art for an injectable dosage form of apixaban, which can overcome the variable and poor absorption and low bioavailability issues observed with oral formulations. Further, it would be convenient to administer such injectable dosage forms to patients who are not conscious and who have difficulty in swallowing.

[0043] Owing to the limited aqueous solubility, it is challenging to formulate an injectable composition of apixaban wherein the apixaban is in a dissolved state and precipitation is prevented throughout the shelf life of the product. Further, such injectable composition is typically diluted in compatible admixture diluents before administration. Owing to the low aqueous solubility of apixaban, there is a high chance of precipitation of apixaban when diluted with compatible admixture diluents. It is of utmost challenge to prevent precipitation of apixaban at this stage, and this makes the formulation further challenging. Thus, there exists a need in the art to develop a ready to dilute composition as well as ready to use composition comprising apixaban.

[0044] The present invention addresses this unmet need and provides an injectable composition of apixaban, which can be administered to a patient in need thereof. The injectable composition of the present invention also exhibits sufficient stability and prevents precipitation of apixaban even after dilution with compatible admixture diluents.

[0045] The injectable composition of the present invention comprises apixaban, along with pharmaceutically acceptable excipients. The particle size is a critical attribute for improving the solubilization of apixaban. The particle size of apixaban as per the present invention may have a D90 about 10 pm to about 200 pm, preferably from about 15 pm to about 100 pm. In some embodiments, the particle size of apixaban may have a D90 of at least about 10 pm 20 pm., 30 pm, 40 pm, 50 pm, 60 pm. In some embodiments, the composition contains at least about 0.01 mg to about 20 mg apixaban, preferably about 0.1 mg to about 20 mg apixaban, preferably about 0.1 mg to about 10 mg.

[0046] In one embodiment, the injectable composition of the present invention comprises apixaban in an amount of about 0.1 mg to about 20 mg.

[0047] In a further embodiment, the injectable composition of the present invention comprises apixaban in an amount of about 0.1 mg to about 10 mg.

[0048] In one embodiment, the injectable composition of the present invention may comprise about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about Img, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8mg, about 1.9 mg, about 2mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about

[0049] 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about

[0050] 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about

[0051] 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about

[0052] 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about

[0053] 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about

[0054] 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg or about 10 mg apixaban.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] The injectable composition of the present invention comprises (a) apixaban, (b) at least one solubilizer, (c) a pharmaceutically acceptable vehicle, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent. In another embodiment, the injectable composition of the present invention is aqueous.

[0059] The injectable composition of the present invention comprises at least one solubilizer. Non-limiting examples of solubilizer are ethanol, benzyl alcohol, pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, 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-methyl pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, dichloromethane, chloroform, carbon tetrachloride, 1,2-di chlorobenzene, 1,2-dichloroethane, tetrachloroethylene and 1 -chlorobutane, tetrahydrofuran, 1,4-di oxane; glycerin / glycerol, Polyethylene glycol (PEG) e.g.: PEG 400 and Polypropylene glycol (PPG), e.g. PPG 400, PPG 1200 and PPG 2000, D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), PEG 35 Castor oil, polysorbate or polyethoxylated castor oil, Polyoxyl 20 stearate, Polyoxyl 35 castor oil, pol oxamer, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate, Polyoxyl 40 Hydrogenated castor oil, Polysorbate, Polysorbate 20, Polysorbate 40, Polyoxyl 60 stearate, Polysorbate 85, Polysorbate 60, poloxamer 331, polyoxyethylene fatty acid esters, Polyoxyl 40 castor oil, poloxamer 188, polyoxyethylene polyoxypropylene 1800, oleic acid, Sodium desoxy cholate, Sodium lauryl sulfate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan trioleate, N-Carbamoyl methoxypolyethylene glycol 2000-1,2-distearol, myristic acid, Steareth, Stearic acid, Polyoxyl 40 stearate, Sucrose stearate, Tocopherol, polyoxyl castor oil, Triglyceride synthetic, Trimyristin, Tristearin, magnesium stearate, lecithin, lauryl sulfate, Vitamin E, egg yolk phosphatides, docusate sodium, Polysorbate 80, dimyristoyl phosphatidylglycerol, dimyristoyl lecithin, Capryol 90 (propylene glycol monocaprylate), Capryol PGMC (propylene glycol monocaprylate), deoxycholate, cholesterol, Cremophor EL, Propylene glycol alginate, Croval A- 10 (PEG 60 almond glycerides), Labrafil 1944 (oleoyl macrogol-6 glycerides), Labrafil 2125 (linoleoyl macrogol-6 glycerides), Labrasol (caprylocaproyl macrogol-8 glycerides), Lauroglycol 90 (propylene glycol monolaurate), Lauroglycol FCC (propylene glycol laurate), calcium stearate, Lecithin Centromix E, Lecithin Centrophase 152, Lecithin Centrol 3F21B, POE 26 glycerin, Olepal isosteariques (PEG-6 isostearate), Plurol diisostearique (polyglycerol-3-diisostearate), Plurol Oleique CC, POE 20 Sorbitan trioleate, Tagat TO (polyoxyethylene glycerol trioleate), or Solutol (macrogol-15 hydroxystearate).

[0060] The present invention relates to an injectable composition comprising apixaban wherein the composition is a ready to use composition. In one embodiment, the injectable composition of the present invention comprises solubilizer in an amount of about 1 mg / ml to about 200 mg / ml.

[0061] The present invention relates to an injectable composition comprising apixaban wherein the composition is a ready to dilute composition. In one embodiment, the injectable composition of the present invention comprises solubilizer in an amount of about 1 mg / ml to about 1000 mg / ml. The injectable composition of the present invention may optionally contain atleast one buffering agent. Suitable buffering agent, include, but are not limited to, phosphate, citrate, tartrate, or acetate buffer. In a preferred embodiment, the buffer is selected from citric acid anhydrous, sodium citrate dihydrate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate or sodium hydrogen phosphate, monobasic sodium phosphate, dibasic sodium phosphate and combination thereof.

[0062] In another embodiment, the injectable composition of the present invention comprises atleast one buffering agent in an amount of about 0.01 mg / ml to about 10 mg / ml.

[0063] The injectable composition of the present invention may optionally contain atleast one tonicity adjusting agent. Suitable examples include, but are not limited to sodium chloride, dextrose, lactose, sorbitol, sucrose, mannitol, trehalose, raffinose and the like. The injectable composition of the present invention comprises atleast one tonicity adjusting agent in an amount of about 1 mg / ml to about 100 mg / ml.

[0064] The injectable composition of the present invention may also contain a pharmaceutically acceptable vehicle, which allows for solubilization of the active and excipients and also aids in stabilization of the composition. In one embodiment, the pharmaceutically acceptable vehicle can be a non-aqueous vehicle and can be selected from the list as given under solubilizers. In an embodiment, the injectable composition of the present invention contains water as a pharmaceutically acceptable vehicle.

[0065] Ready to use injectable compositions

[0066] The present invention relates to an injectable composition comprising apixaban wherein the composition is a ready to use composition. In one embodiment, the present invention relates to an injectable composition of the present invention comprising (a) apixaban, (b) at least one solubilizer, (c) a pharmaceutically acceptable vehicle, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

[0067] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) water for injection, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

[0068] In a further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (d) water for injection.

[0069] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent and (d) water for injection.

[0070] In one more embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent, (d) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (e) water for injection.

[0071] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 29.4 mg / ml PEG 35 castor oil, (c) about 28.0 mg / ml propylene glycol, (d) about 0.02 mg / ml citric acid anhydrous, (e) about 0.8 mg / ml sodium citrate dihydrate, and (f) water for injection. In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 29.4 mg / ml PEG 35 castor oil, (c) about 28.0 mg / ml propylene glycol, (d) about 0.02 mg / ml citric acid anhydrous, (e) about 0.8 mg / ml sodium citrate dihydrate, (f) about 6.0mg / ml sodium chloride, and (g) water for injection.

[0072] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 5.0 mg / ml PEG 35 castor oil, (c) about 20.0 mg / ml propylene glycol, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride, and (g) water for injection.

[0073] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 5.0 mg / ml PEG 35 castor oil, (c) about 10.0 mg / ml propylene glycol, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride, and (g) water for injection.

[0074] In one more embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 5.0 mg / ml PEG 35 castor oil, (c) about 5.0 mg / ml propylene glycol, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride, and (g) water for injection.

[0075] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 20.0 mg / ml PEG 35 castor oil, (c) about 20.0 mg / ml propylene glycol, (d) about 6.5 mg / ml sodium chloride, and (e) water for injection.

[0076] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 20.0 mg / ml PEG 35 castor oil, (c) about 20.0 mg / ml propylene glycol, (d) about 0.15 mg / ml citric acid anhydrous, (e) about 1.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride, and (g) water for injection.

[0077] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 14.0 mg / ml PEG 35 castor oil, (c) about 20.0 mg / ml propylene glycol, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride, and (g) water for injection.

[0078] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 28.0 mg / ml PEG 35 castor oil, (c) about 20.0 mg / ml propylene glycol, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride, and (g) water for injection.

[0079] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 40.0 mg / ml propylene glycol, (c) about 0.60 mg / ml citric acid anhydrous, (d) about 4.0 mg / ml sodium citrate dihydrate and (e) water for injection.

[0080] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 40.0 mg / ml propylene glycol, (c) about 0.6 mg / ml citric acid anhydrous, (d) about 4.0 mg / ml sodium citrate dihydrate, (e) about 6.0mg / ml sodium chloride and (f) water for injection.

[0081] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 20.0 mg / ml propylene glycol, (c) about 0.3 mg / ml citric acid anhydrous, (d) about 2.0 mg / ml sodium citrate dihydrate, (e) about 6.0 mg / ml sodium chloride and (f) water for injection. In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 29.4 mg / ml polysorbate 80, (c) about 28.0 mg / ml propylene glycol, (d) about 0.02 mg / ml citric acid anhydrous, (e) about 0.01 mg / ml sodium citrate dihydrate, and (f) water for injection.

[0082] In one more embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 15.0 mg / ml polysorbate 80, (c) about 8.0 mg / ml propylene glycol, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride and (g) water for injection.

[0083] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 21.0 mg / ml polysorbate 80, (c) about 10.0 mg / ml propylene glycol, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride and (g) water for injection.

[0084] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 5.5 mg / ml polysorbate 80, (c) about 10.0 mg / ml propylene glycol, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride and (g) water for injection.

[0085] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 2.3 mg / ml PEG 35 castor oil, (c) about 2.3 mg / ml benzyl alcohol, and (d) water for injection.

[0086] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 3.0 mg / ml PEG 35 castor oil, (c) about 3.0 mg / ml benzyl alcohol, (d) about 8.0 mg / ml sodium chloride and (e) water for injection. In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 20.0 mg / ml PEG 400, (c) about 0.3 mg / ml citric acid anhydrous, (d) about 2.0 mg / ml sodium citrate dihydrate, (e) about 5.5 mg / ml sodium chloride and (f) water for injection.

[0087] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 50.0 mg / ml PEG 400, (c) about 0.3 mg / ml citric acid anhydrous, (d) about 2.0 mg / ml sodium citrate dihydrate, (e) about 5.5 mg / ml sodium chloride and (f) water for injection.

[0088] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 20.0 mg / ml PEG 400, (c) about 20.0 mg / ml PEG 35 castor oil, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride and (g) water for injection.

[0089] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 40.0 mg / ml N, N dimethyl acetamide, (c) about 0.3 mg / ml citric acid anhydrous, (d) about 2.0 mg / ml sodium citrate dihydrate, (e) about 5.5 mg / ml sodium chloride and (f) water for injection.

[0090] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 40.0 mg / ml N, N dimethyl acetamide, (c) about 10.0 mg / ml PEG 35 castor oil, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride and (g) water for injection.

[0091] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 20.0 mg / ml N, N dimethyl acetamide, (c) about 10.0 mg / ml PEG 35 castor oil, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 6.0 mg / ml sodium chloride and (g) water for injection.

[0092] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 40.0 mg / ml N methyl pyrrolidone (c) about 0.3 mg / ml citric acid anhydrous, (d) about 2.0 mg / ml sodium citrate dihydrate, (e) about 5.5 mg / ml sodium chloride and (f) water for injection.

[0093] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 40.0 mg / ml N methyl pyrrolidone, (c) about 10.0 mg / ml PEG 35 castor oil, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 5.5 mg / ml sodium chloride and (g) water for injection.

[0094] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 20.0 mg / ml N methyl pyrrolidone, (c) about 10.0 mg / ml PEG 35 castor oil, (d) about 0.3 mg / ml citric acid anhydrous, (e) about 2.0 mg / ml sodium citrate dihydrate, (f) about 6.0 mg / ml sodium chloride and (g) water for injection.

[0095] In an embodiment, the ready to use injectable composition has a volume of about 25 ml to about 500 ml. In another embodiment, the ready to use injectable composition has a volume of about 25 ml, about 50 ml, about 100 ml, about 200 ml, about 250 ml or about 500 ml. In a preferred embodiment, the ready to use injectable composition has a volume of about 50 ml. In another preferred embodiment, the ready to use injectable composition has a volume of about 100 ml. Ready to dilute injectable compositions

[0096] The present invention relates to an injectable composition comprising apixaban wherein the composition is a ready to dilute composition. In one embodiment, the present invention relates to an injectable composition of the present invention comprising (a) apixaban, (b) at least one solubilizer, (c) a pharmaceutically acceptable vehicle, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

[0097] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) water for injection, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

[0098] In a further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (d) water for injection.

[0099] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent and (d) water for injection.

[0100] In one more embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent, (d) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (e) water for injection.

[0101] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 400.0 mg / ml propylene glycol, (c) about 5.5 mg / ml sodium chloride and (d) water for injection. In one more embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 200.0 mg / ml propylene glycol, (c) about 5.5 mg / ml sodium chloride and (d) water for injection.

[0102] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 400.0 mg / ml propylene glycol, and (c) water for injection.

[0103] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 25.0 mg / ml PEG 35 castor oil, (c) about 25.0 mg / ml benzyl alcohol, (d) about 6.0 mg / ml sodium chloride and (e) water for injection.

[0104] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 30.0 mg / ml PEG 35 castor oil, (c) about 30.0 mg / ml benzyl alcohol, (d) about 6.0 mg / ml sodium chloride and (e) water for injection.

[0105] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 25.0 mg / ml PEG 35 castor oil, (c) about 25.0 mg / ml benzyl alcohol, and (d) water for injection.

[0106] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 500.0 mg / ml PEG 400, (c) about 5.5 mg / ml sodium chloride, and (d) water for injection.

[0107] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 300.0 mg / ml PEG 400, (c) about 5.5 mg / ml sodium chloride, and (d) water for injection. In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 500.0 mg / ml PEG 400, and (c) water for injection.

[0108] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 500.0 mg / ml PEG 35 castor oil, (c) about 8.0 mg / ml sodium chloride, and (d) water for injection.

[0109] In one more embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 200.0 mg / ml PEG 35 castor oil, (c) about 8.0 mg / ml sodium chloride, and (d) water for injection.

[0110] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 350.0 mg / ml PEG 35 castor oil, (c) about 9.0 mg / ml sodium chloride, and (d) water for injection.

[0111] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 500.0 mg / ml PEG 35 castor oil, and (c) water for injection.

[0112] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 400.0 mg / ml N, N- dimethylacetamide, (c) about 6.0 mg / ml sodium chloride, and (d) water for injection.

[0113] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 200.0 mg / ml N, N- dimethylacetamide, (c) about 6.0 mg / ml sodium chloride, and (d) water for injection. In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 500.0 mg / ml N, N- dimethylacetamide, (c) about 6.0 mg / ml sodium chloride, and (d) water for injection.

[0114] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 400.0 mg / ml N, N- dimethylacetamide, and (c) water for injection.

[0115] In an embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 400.0 mg / ml N methyl pyrrolidone, (c) about 6.0 mg / ml sodium chloride, and (d) water for injection.

[0116] In another embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 200.0 mg / ml N methyl pyrrolidone, (c) about 6.0 mg / ml sodium chloride, and (d) water for injection.

[0117] In further embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 500.0 mg / ml N methyl pyrrolidone, (c) about 6.0 mg / ml sodium chloride, and (d) water for injection.

[0118] In one embodiment, the injectable composition of the present invention comprises (a) about 0.1 mg to about 20 mg apixaban, (b) about 400.0 mg / ml N methyl pyrrolidone, and (c) water for injection.

[0119] In an embodiment, the ready to dilute injectable composition has a volume of about 1 ml to about 20 ml. In one embodiment, the ready to dilute injectable composition has a volume of about 5 ml. In an embodiment, the ready to dilute injectable composition has a volume of about 10 ml.

[0120] In an embodiment, the injectable composition of the present invention is aqueous. In an embodiment, the injectable composition of the present invention is an injectable solution.

[0121] The injectable composition of the present invention may be diluted with compatible admixture diluents well known in the art before administering to a subject in need thereof.

[0122] The pH of the injectable composition of the present invention may be between about 4.5 to about 8.

[0123] The injectable composition of the present invention may demonstrate an osmolality between about 300 to about 350 osmol / kg upon dilution with compatible admixture diluents.

[0124] The term "stable" refers to an injection composition of 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, 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. The term “stable” also refers to an injectable composition as per the present invention which exhibits physical stability for a sufficiently long time to allow for infusion of the product upon dilution with compatible admixture diluent such as sterile water for injection, saline or dextrose. The injectable compositions of the present invention remain stable after dilution with a compatible admixture diluent for a sufficient time to allow for infusion to be completed. Suitably, the injectable composition of apixaban of present invention remains physically stable, with no precipitation or crystallization or color change upon storage and the shelf life period of 18-24 months when stored at 2-8° C. Suitably, the injectable composition of apixaban remains chemically stable when stored at 2-8° C., wherein various parameters such as the drug content (assay of apixaban) 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 injectable composition of the present invention remains stable for at least 1 hour after dilution with a compatible admixture diluent.

[0125] The 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 apixaban containing 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) after a period of about 18 months at a temperature of from about 2° C. to about 8° C. The amount of impurities is further calculated as being based upon the original amount of apixaban being present in the composition. Preferably, the said injectable compositions of apixaban prevent degradation of apixaban such that not more than 2 %, not more than 1%, not more than 0.4%, not more than 0.2% of apixaban impurity or impurities are formed over the storage period. In yet another preferred embodiment the value of assay of apixaban remains within the specified limit of 90-110% by weight of the label claim.

[0126] The ICH storage stability studies were performed on the 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, 30°C, and 40°C. The necessary parameters viz., assay, related substances, particle size distribution, pH, and osmolality were tested and found to be within specification at both stability conditions. The stability data suggested long term stability at 2-8°C. 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 when stored at 2-8°C. The addition of the components for the preparation of stable injectable composition can be achieved by methods known in the art.

[0127] The injectable composition can be sterilized by process known in the art. In one embodiment, the injectable composition of the present invention can be sterilized using terminal sterilization techniques such as autoclaving. In another embodiment, the injectable composition of the present invention can be sterilized by aseptic processes such as filtration sterilization.

[0128] The injectable compositions of the present invention can be packaged in any suitable sterile vial or prefilled syringe or container fit for the sterile storage of pharmaceuticals. The stable 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, i.e., Schott treated vials, molded glass vials, CZ resin vials, polypropylene or polyethylene vials or other special purpose containers. Suitable containers can be prefilled syringes such as glass prefilled syringes, plastic prefilled syringes. Containers are of a size sufficient to hold one or more doses of apixaban. 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 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 injectable composition of the present invention may be filtered by using an in-line filter before administration.

[0129] 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.

[0130] The below examples represent ready to use injectable compositions

[0131] Example 1-9

[0132] Manufacturing process:

[0133] 1. Apixaban was dissolved in a mixture of propylene glycol and PEG 35 castor oil.

[0134] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection. 3. Citric acid anhydrous, sodium citrate dihydrate, and sodium chloride were added to the solution of step 2 under stirring.

[0135] 4. Volume was made up with sterile water for injection

[0136] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation.

[0137] The stability data for Example 7 above is given in the below table:

[0138] Example 10-12

[0139] Manufacturing process:

[0140] 1. Apixaban was dissolved in propylene glycol. 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0141] 3. Citric acid anhydrous, sodium citrate dihydrate, and sodium chloride were added to the solution of step 2 under stirring.

[0142] 4. Volume was made up with sterile water for injection

[0143] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation.

[0144] Example 13-16

[0145] Manufacturing process:

[0146] 1. Apixaban was dissolved in a mixture of propylene glycol and polysorbate 80.

[0147] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0148] 3. Citric acid anhydrous, sodium citrate dihydrate, and sodium chloride were added to the solution of step 2 under stirring.

[0149] 4. Volume was made up with sterile water for injection

[0150] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation. Example 17-18

[0151] Manufacturing process:

[0152] 1. Apixaban was dissolved in a mixture of benzyl alcohol and PEG 35 castor oil.

[0153] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0154] 3. Citric acid anhydrous, sodium citrate dihydrate, and sodium chloride were added to the solution of step 2 under stirring.

[0155] 4. Volume was made up with sterile water for injection

[0156] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation

[0157] Example 19-21

[0158] Manufacturing process:

[0159] 1. Apixaban was dissolved in a mixture of polyethylene glycol 400 and PEG 35 castor oil.

[0160] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0161] 3. Citric acid anhydrous, sodium citrate dihydrate, and sodium chloride were added to the solution of step 2 under stirring.

[0162] 4. Volume was made up with sterile water for injection

[0163] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation.

[0164] Examples 22-24

[0165] Manufacturing process: 1. Apixaban was dissolved in a mixture of NN dimethyl acetamide and PEG 35 castor oil.

[0166] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0167] 3. Citric acid anhydrous, sodium citrate dihydrate, and sodium chloride were added to the solution of step 2 under stirring.

[0168] 4. Volume was made up with sterile water for injection

[0169] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation.

[0170] Examples 25-27

[0171] Manufacturing process:

[0172] 1. Apixaban was dissolved in a mixture of N Methyl pyrrolidone and PEG 35 castor oil.

[0173] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0174] 3. Citric acid anhydrous, sodium citrate dihydrate, and sodium chloride were added to the solution of step 2 under stirring. 4. Volume was made up with sterile water for injection

[0175] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation.

[0176] The below examples represent ready to dilute injectable compositions

[0177] Example 28-30

[0178] Manufacturing process:

[0179] 1. Apixaban was dissolved in propylene glycol.

[0180] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0181] 3. Sodium chloride were added to the solution of step 2 under stirring.

[0182] 4. Volume was made up with sterile water for injection

[0183] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation.

[0184] Example 31-33

[0185] Manufacturing process:

[0186] 1. Apixaban was dissolved in a mixture of benzyl alcohol and PEG 35 castor oil.

[0187] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0188] 3. Sodium chloride were added to the solution of step 2 under stirring.

[0189] 4. Volume was made up with sterile water for injection

[0190] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation

[0191] Examples 34-36

[0192] Manufacturing process:

[0193] 1. Apixaban was dissolved in polyethylene glycol 400.

[0194] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0195] 3. Sodium chloride were added to the solution of step 2 under stirring.

[0196] 4. Volume was made up with sterile water for injection

[0197] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation

[0198] Examples 37-40

[0199]

[0200] Manufacturing process:

[0201] 1. Apixaban was dissolved in PEG 35 castor oil.

[0202] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0203] 3. Sodium chloride were added to the solution of step 2 under stirring.

[0204] 4. Volume was made up with sterile water for injection

[0205] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation

[0206] Examples 41-44

[0207] Manufacturing process:

[0208] 1. Apixaban was dissolved in NN Dimethyl acetamide.

[0209] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0210] 3. Sodium chloride were added to the solution of step 2 under stirring.

[0211] 4. Volume was made up with sterile water for injection 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation

[0212] Examples 45-48

[0213] Manufacturing process:

[0214] 1. Apixaban was dissolved in N Methyl pyrrolidone.

[0215] 2. The mixture of step 1 was heated till a clear solution was obtained and was then diluted to 90% of the final batch volume using sterile water for injection.

[0216] 3. Sodium chloride were added to the solution of step 2 under stirring.

[0217] 4. Volume was made up with sterile water for injection

[0218] 5. The solution of step 5 was then subjected to an appropriate sterilization method to yield a sterile injection formulation

[0219] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

Claims

We claim:

1. An injectable composition comprising (a) apixaban, (b) at least one solubilizer, (c) a pharmaceutically acceptable vehicle, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

2. The injectable composition of claim 1, wherein said composition is a ready to use composition.

3. The injectable composition of claim 1, wherein said composition is a ready to dilute composition.

4. The injectable composition of claim 1, wherein said composition comprises about 0.1 mg to about 20 mg apixaban.

5. The injectable composition of claim 1, wherein said composition comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about Img, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8mg, about 1.9 mg, about 2mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg,about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg or about 10 mg apixaban.

6. The injectable composition of claim 2, wherein said composition comprises solubilizer in an amount of about 1 mg / ml to about 200 mg / ml.

7. The injectable composition of claim 3, wherein said composition comprises solubilizer in an amount of about 1 mg / ml to about 1000 mg / ml.

8. The injectable composition of claim 1, wherein said composition comprises atleast one buffering agent in an amount of about 0.01 mg / ml to about 10 mg / ml.

9. The injectable composition of claim 1, wherein said composition comprises atleast one tonicity adjusting agent in an amount of Img / ml to about 100 mg / ml.

10. The injectable composition of claim 1, wherein said pharmaceutically acceptable vehicle is water for injection.

11. The injectable composition of claim 2, wherein said composition comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) water for injection, (d) optionally containing atleast one tonicity adjusting agent and (e) optionally containing atleast one buffering agent.

12. The injectable composition of claim 2, wherein said composition comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (d) water for injection.

13. The injectable composition of claim 2, wherein said composition comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent and (d) water for injection.

14. The injectable composition of claim 2, wherein said composition comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 200 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent, (d) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (e) water for injection.

15. The injectable composition of claim 3, wherein said composition comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) water for injection, (d) optionally containing atleast one tonicity adjusting agent and (d) optionally containing atleast one buffering agent.

16. The injectable composition of claim 3, wherein said composition comprises (a) about 0.01 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (d) water for injection.

17. The injectable composition of claim 3, wherein said composition comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent and (d) water for injection.

18. The injectable composition of claim 3, wherein said composition comprises (a) about 0.1 mg to about 20 mg of apixaban, (b) about 1 mg / ml to about 1000 mg / ml of at least one solubilizer, (c) about 1 mg / ml to about 100 mg / ml of atleast one tonicity adjusting agent, (d) about 0.01 mg / ml to about 10 mg / ml of atleast one buffering agent and (e) water for injection.

19. The injectable composition of claim 1, wherein said composition is sterilized using terminal sterilization.

20. The injectable composition of claim 1, having a purity, such that the total impurities is less than 1%.

21. The injectable composition of claim 1, packaged in a vial, bag, or prefilled syringe.

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