DESC:BACKGROUND OF THE INVENTION

Carfilzomib is a tetrapeptide epoxy ketone and an active ingredient of USFDA approved formulation, Kyprolis® (Onyx Pharma). Like bortezomib, carfilzomib is also a selective proteosome inhibitor and binds irreversibly to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib is indicated as single agent and in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies.
The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido) 4-phenylbutanamido)-4-methylpentanamide. It has following structure;

Epoxy ketones, like carfilzomib, display very low solubility in water and therefore throws challenge in formulating such compounds. Kyprolis® is lyophilized injectable composition containing beta-cyclodextrin and citric acid. The solubility of carfilzomib is enhanced by formation of inclusion complex with beta-cyclodextrin. Apart from that stability of reconstituted formulation is very limited i.e. 24hr if refrigerated and 4 hrs at room temperature.
US publication no. 2014/0073583 provides lyophilized formulations of carfilzomib with polyethylene glycol and lactobionic acid. PCT publication no. WO 2015/092813 provides lyophilized formulations of carfilzomib with isomalt. US publication no. 2014/0220110 provides liposomal formulations of carfilzomib. PCT publication no. WO 2016/116882 discloses lyophilized composition of Carfilzomib for parenteral administration that is free of cyclodextrins. However, considering water insolubility and stability of carfilzomib, there is a need to develop improved and stable formulations of carfilzomib. These types of formulations will allow multiple dosing for patients with multiple myeloma. Further, ready to use formulation will avoid reconstitution steps and hence dosing errors in the treatment.
Inventors of the present invention have found pharmaceutical compositions of comprising carfilzomib or salt thereof, an adsorbent and pharmaceutically acceptable excipients, which can be used effectively for the treatment of multiple myeloma.
SUMMARY OF THE INVENTION

In general aspect of this invention there is provided a pharmaceutical composition of comprising: (a) carfilzomib or salt thereof, (b) an adsorbent, and (c) a pharmaceutically acceptable excipient.

In one aspect of this invention, there is provided a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6.

In one embodiment of this aspect, the carfilzomib or salt thereof is present in the amount of about 2 mg/ml. In another embodiment of this aspect, the adsorbent comprises sugar or its derivatives selected from lactose, sorbitol, xylitol, erythritol, sucrose, mannitol or mixture thereof. In another embodiment of this aspect, the adsorbent is lactose present in about 25% w/v of the composition.
In another embodiment of this aspect, the pharmaceutically acceptable excipient comprises a solvent, a buffer, a pH adjusting agent, a preservative, an antioxidant, a diluent or mixture thereof. In another embodiment of this aspect, the composition has the pH from about 3 to about 5.

In another embodiment of this aspect, the composition is a ready to use solution and is diluted with water for injection or 5% dextrose or 0.9% sodium chloride solution before administering to a patient in need thereof.

In another embodiment of this aspect, the composition is a lyophilized powder to be reconstituted and further diluted with water for injection or 5% dextrose or 0.9% sodium chloride solution before administering to a patient in need thereof.

In another embodiment of this aspect, there is provided a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml carfilzomib or salt thereof, (b) about 25% w/v of lactose, and (c) about 0.1% w/v of citric acid; wherein the composition has a pH of about 3.5.

In another aspect of this invention, there is provided a method of treating multiple myeloma, wherein said method comprises of administering to a patient in need thereof a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6.

In another aspect of this invention, there is provided a kit comprising: (A) a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6, and (B) a diluent selected from water for injection or 5% dextrose or 0.9% sodium chloride solution.
In another aspect of this invention, there is provided a process of preparing a pharmaceutical composition of carfilzomib for parenteral administration, wherein the composition has a pH of about 3.5, and wherein said process comprises steps of:
(i) preparing a mixture of the lactose and citric acid,
(ii) adding an ethanolic solution of carfilzomib or salt thereof to the mixture of step (i) with mixing to obtain a slurry,
(iii) spraying the slurry into vertical spray drier through a rotary atomizer to obtain a powder,
(iv) reconstituting the powder of step (iii) to make desired concentration of the carfilzomib and adjusting a pH to about 3.5 with pH adjusting agent to obtain a solution, and
(v) aseptic filtering the solution of step (iv) and filling into vials to obtain a ready to use solution for parenteral administration,
(vi) optionally, lyophilising the solution of step (v) to obtain the pharmaceutical composition in the form of lyophilized powder.

In another aspect of this invention, there is provided a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof, (b) an inclusion-complexing agent, (c) a surfactant, and (d) a pharmaceutically acceptable excipient.

In another embodiment of this aspect, there is provided a process of preparing a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof, (b) an inclusion-complexing agent, (c) a surfactant, and (d) a pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF THE INVENTION
In general aspect of this invention there is provided a pharmaceutical composition of comprising: (a) carfilzomib or salt thereof, (b) an adsorbent, and (c) a pharmaceutically acceptable excipient.
Unless otherwise indicated, this disclosure uses the following definitions.
“Pharmaceutical composition” refers to the combination of one or more drug substances and one or more excipients.
The term “Carfilzomib” refers to (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido) 4-phenylbutanamido)-4-methylpentanamide.
The term “salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art and includes any pharmaceutically acceptable salt soluble in water to form an aqueous solution.
The term “Pharmaceutically acceptable excipient” refers to non-active pharmaceutical ingredient substances which are within the scope of sound medical judgment suitable for use in formulating pharmaceutical products.
The term “adsorbent” refers to materials that have an ability of adsorption and/or chemical reaction or ion exchange.
The term “buffer” refers to a pharmaceutically acceptable excipient, which stabilizes the pH of a pharmaceutical preparation.
The term “inclusion-complexing agent” refers to substance which forms a cavity and incorporates active ingredient wherein the complex has higher solubility than active ingredient alone.
The term “solubilising agent” refers to a substance that increases the solubility in water of another material that is only partially water soluble.
The term “surfactant” refers to a substance that contains a lipophilic segment and a hydrophilic segment, which when added to water or solvents, reduces the surface tension of the system.
In one aspect of this invention, there is provided a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6.

The active ingredient of the invention compositions provided here in is carfilzomib, (2S) - N- ((S) -1 - ((S) – 4 - methyl-1- ((R) - 2 – methyloxiran 2 - yl) -1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido) 4-phenylbutanamido)-4-methylpentanamide or pharmaceutically acceptable salt thereof.
According to the invention, the salt of carfilzomib comprises, but not limited to, salts with hydrohalic acid such as hydrochloride, hydrobromide and the like; salts with inorganic acid such as sulfate, nitrate, phosphate and the like; salts with organic acid such as acetate, propionate, hydroxyacetate, 2-hydroxypropionate, pyruvate, malonate, succinate, maleate, fumarate, dihydroxyfumarate, oxalate, benzoate, cinnamate, salicylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, 4-aminosalicylate and the like. In one embodiment the concentration of carfilzomib or salt thereof is about 0.01 mg/ml to about 4 mg/ml, or about 1 mg/ml to about 3 mg/ml. In one embodiment, the carfilzomib or salt thereof is present in the amount of about 2 mg/ml.
In another embodiment of this aspect, the adsorbent comprises sugar or its derivatives selected from lactose, sorbitol, xylitol, erythritol, sucrose, mannitol or mixture thereof. Each of the adsorbent constitutes an alternate embodiment of the invention. In another embodiment of this aspect, the adsorbent is lactose. In another embodiment, the adsorbent (e.g., Lactose) is present in about 5% w/v to about 35% w/v of the composition. Alternatively, the adsorbent (e.g., Lactose) is present in about 10% w/v, or about 15% w/v, or about 20% w/v, or about 25% w/v, or about 30% w/v. The preferred concentration of the adsorbent (e.g., Lactose) is about 25% w/v of the composition.
In another embodiment, the weight ratio of carfilzomib or salt and adsorbent is from about 1: 110 to 1: 150. Alternatively, the weight ratio of carfilzomib or salt and adsorbent is about 1: 116, or about 1:141, or about 1:133, or about 1:125. Each of the weight ratios of carfilzomib or salt and adsorbent constitutes an alternate embodiment of the invention.
In another embodiment of this aspect, the pharmaceutically acceptable excipient comprises a solvent, a buffer, a pH adjusting agent, a preservative, an antioxidant, a diluent or mixture thereof.
Examples of pharmaceutically acceptable buffers comprise, but are not limited to, acetic acid, citric acid, sodium acetate, citrate and phosphate, potassium phosphate, dibasic sodium phosphate heptahydrate. Preferably, the composition comprises citric acid. The molar concentration of the buffer typically ranges between about 5 millimolar and about 150 millimolar, and is most preferably about 10 millimolar. The composition comprises buffer in concentration from about 0.01% w/v to about 10% w/v. Alternatively, composition comprises buffer in concentration of about 0.05% w/v, or about 0.1% w/v, or about 0.5% w/v, or about 1 % w/v, or about 2% w/v, or about 3% w/v, or about 6% w/v, or about 8% w/v. Preferred concentration in some embodiment is about 0.1% w/v and about 1.6% w/v. It will be recognized by those of skill in the art that determination of the preferred solubility range of a peptide epoxy ketone around a pH of 3.5 using any of the aforementioned buffers can be performed using known techniques.
Suitable examples of preservative comprise, but not limited to, phenol, thimerosal, chlorobutanol, benzyl alcohol, m-cresol, phenoxyethanol, methylparaben and propylparaben. Most preferred is benzyl alcohol. In some embodiments the concentration of benzyl alcohol is from about 0.001% w/v to about 5% w/v. Preferred 0.1% w/v to about 3% w/v and most preferred is about 1.5% w/v.
Suitable examples antioxidant comprise but not limited to, hydrophobic anti-oxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate and a.-tocopherol, DL-tocopherol, a-tocopherol acetate, a-tocopherol tocopherol polyethylene glycol succinate (Vitamin E TPGS), L-cysteine, or hydrophilic anti-oxidants, including sodium EDTA and thioglycerol. Most preferred is sodium EDTA. In one embodiment concentration of antioxidant is from about 0.005% w/v to about 5% w/v. Most preferred is 0.05% w/v.
Diluents are used for reconstitution of lyophilised powder and for dilution of composition before administering to patient in a need thereof. Suitable examples of diluents comprise water for injection, 5% dextrose, 0.9% sodium chloride and like.
In another embodiment, pH of composition can be adjusted at a value of about 2 to about 9.0 and preferably about 2 to about 6 and still preferably about 3 to about 5 and most preferably about 3.5 with the pH adjusting agent, an acid or a base as known in the art, e.g. hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide. In another embodiment of this aspect, the composition has the pH from about 3 to about 5.
In another embodiment, the composition comprises a buffer, a pH adjusting agent, a preservative, an antioxidant, a diluent or mixture thereof.
In another embodiment, the compositions for parenteral administration and are formulated as ready to use solution or lyophilized powders known to ordinary person skilled in the art. The solution compositions will be administered after dilution with one or more pharmaceutically acceptable diluents. The lyophilized compositions will be administered after reconstitution and dilution with one or more pharmaceutically acceptable diluents. In another embodiment of this aspect, the composition is a ready to use solution and is diluted with water for injection or 5% dextrose or 0.9% sodium chloride solution before administering to a patient in need thereof.
In another embodiment of this aspect, the composition is a lyophilized powder to be reconstituted and further diluted with water for injection or 5% dextrose or 0.9% sodium chloride solution before administering to a patient in need thereof.
In an embodiment, the compositions for parenteral administration are given by intravenously (infusion or injection), intramuscularly, subcutaneously and other parenteral route known to ordinary person skilled in the art.
In another embodiment of this aspect, there is provided a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml carfilzomib or salt thereof, (b) about 25% w/v of lactose, and (c) about 0.1% w/v of citric acid; wherein the composition has a pH of about 3.5.
In another aspect of this invention, there is provided a method of treating multiple myeloma, wherein said method comprises of administering to a patient in need thereof a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6.
In another aspect of this invention, there is provided a method of treating multiple myeloma, wherein said method comprises of administering to a patient in need thereof a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml carfilzomib or salt thereof, (b) about 25% w/v of lactose, and (c) about 0.1% w/v of citric acid; wherein the composition has a pH of about 3.5.
In another aspect of this invention, there is provided a kit comprising: (A) a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6, and (B) a diluent selected from water for injection or 5% dextrose or 0.9% sodium chloride solution.

In another aspect of this invention, there is provided a kit comprising: (A) a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml carfilzomib or salt thereof, (b) about 25% w/v of lactose, and (c) about 0.1% w/v of citric acid; wherein the composition has a pH of about 3.5, and (B) a diluent selected from water for injection or 5% dextrose or 0.9% sodium chloride solution.

In another aspect of this invention, there is provided a kit comprising: (A) a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml carfilzomib or salt thereof, (b) about 25% w/v of lactose, and (c) about 0.1% w/v of citric acid; wherein the composition is in the form of lyophilised powder, and (B) a diluent selected from water for injection or 5% dextrose or 0.9% sodium chloride solution.

In another aspect of this invention, there is provided a process of preparing a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6, and wherein said process comprises steps of:
(i) preparing a mixture of the lactose and citric acid,
(ii) adding an ethanolic solution of carfilzomib or salt thereof to the mixture of step (i) with mixing to obtain a slurry,
(iii) spraying the slurry into vertical spray drier through a rotary atomizer to obtain a powder,
(iv) reconstituting the powder of step (iii) to make desired concentration of the carfilzomib and adjusting a pH to about 2 to about 6 with pH adjusting agent to obtain a solution, and
(v) aseptic filtering the solution of step (iv) and filling into vials to obtain a ready to use solution for parenteral administration,
(vi) optionally, lyophilising the solution of step (v) to obtain the pharmaceutical composition in the form of lyophilized powder.
In another aspect of this invention, there is provided a process of preparing a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml carfilzomib or salt thereof, (b) about 25% w/v of lactose, and (c) about 0.1% w/v of citric acid; wherein the composition has a pH of about 3.5, wherein the composition has a pH of about 3.5, and wherein said process comprises steps of:
(i) preparing a mixture of the lactose and citric acid,
(ii) adding an ethanolic solution of carfilzomib or salt thereof to the mixture of step (i) with mixing to obtain a slurry,
(iii) spraying the slurry into vertical spray drier through a rotary atomizer to obtain a powder,
(iv) reconstituting the powder of step (iii) to make desired concentration of the carfilzomib and adjusting a pH to about 3.5 with pH adjusting agent to obtain a solution, and
(v) aseptic filtering the solution of step (iv) and filling into vials to obtain a ready to use solution for parenteral administration,
(vi) optionally, lyophilising the solution of step (v) to obtain the pharmaceutical composition in the form of lyophilized powder.

In alternate embodiments of this invention, a pharmaceutical composition for parenteral administration of carfilzomib or salt thereof can also be prepared by using inclusion-complexing agent and/or surfactant.

In another aspect of the invention, there is provided a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof, (b) an inclusion-complexing agent, and (c) a pharmaceutically acceptable excipient.

In another aspect of the invention, there is provided a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof, (b) an inclusion-complexing agent, (c) a surfactant, and (d) a pharmaceutically acceptable excipient.
Suitable examples of inclusion-complexing agents are, but not limited to, alpha-, beta- and gamma-cyclodextrin. In one embodiment, the cyclodextrin is gamma-cyclodextrin, present, for example, in about 1% w/v to about 10% w/v. In a certain embodiment, the preferred amount of a cyclodextrin is about 4% w/v.
Categories of surfactants include ionic, non-ionic and cationic surfactants. Suitable examples of surfactants are, but not limited to, alkyl ether sulfates and carboxylic acids, in particular in form of their alkali salts, as well as protein fatty acid condensates, fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates alkyl polyglycosides, mixtures thereof, and the like. Certain preferred nonionic surfactants include polyoxyethylene derivatives of polyol esters, alkyl quaternaries (mono, di, or tri), benzyl quaternaries, ester quaternaries, ethoxylated quaternaries, alkyl amines, and mixtures thereof. Most preferred is polyoxyethylene derivative of polyol esters, polysorbate 80. In some embodiment the concentration of surfactant is from about 2% w/v to about 15% w/v. In some embodiment the most preferred concentration is about 4% w/v or about 10% w/v.
In one embodiment, there is provided a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 0.1% w/v (10mM) of citric acid, and (d) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 2 to about 6.
In one embodiment, there is provided a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 10% w/v of polysorbate 80, (d) about 0.1% w/v (10mM) of citric acid, and (e) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 2 to about 6.
In one embodiment, there is provided a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 0.1% w/v (10mM) of citric acid, and (d) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 3.5.
In one embodiment, there is provided a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 10% w/v of polysorbate 80, (d) about 0.1% w/v (10mM) of citric acid, and (e) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 3.5.
In another aspect of this invention, there is provided a method of treating multiple myeloma, wherein said method comprises of administering to a patient in need thereof a composition comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 10% w/v of polysorbate 80, (d) about 0.1% w/v (10mM) of citric acid, and (e) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 2 to about 6.
In another aspect of this invention, there is provided a method of treating multiple myeloma, wherein said method comprises of administering to a patient in need thereof a composition comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 10% w/v of polysorbate 80, (d) about 0.1% w/v (10mM) of citric acid, and (e) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 3.5.
In another aspect of this invention, there is provided a kit comprising: (A) a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 10% w/v of polysorbate 80, (d) about 0.1% w/v (10mM) of citric acid, and (e) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 2 to about 6, and (B) a diluent selected from water for injection or 5% dextrose or 0.9% sodium chloride solution.

In another aspect of this invention, there is provided a kit comprising: (A) a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 10% w/v of polysorbate 80, (d) about 0.1% w/v (10mM) of citric acid, and (e) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 3.5, and (B) a diluent selected from water for injection or 5% dextrose or 0.9% sodium chloride solution.
In another embodiment of this aspect, there is provided a process of preparing a pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof, (b) an inclusion-complexing agent, (c) a surfactant, and (d) a pharmaceutically acceptable excipient, and wherein said process comprises steps of:
(i) preparing a mixture of the inclusion-complexing agent and surfactant,
(ii) adding an ethanolic solution of carfilzomib or salt thereof to the mixture of step (i) with mixing to obtain a solution,
(iii) diluting the solution of step (ii) to make desired concentration of the carfilzomib or salt thereof and adjusting a pH to about 2 about 6 with pH adjusting agent to obtain a solution, and
(v) aseptic filtering the solution of step (iv) and filling into vials to obtain a ready to use solution for parenteral administration,
(vi) optionally, lyophilising the solution of step (v) to obtain the pharmaceutical composition in the form of lyophilized powder.

In another embodiment of this aspect, there is provided a process of preparing a pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml of carfilzomib or pharmaceutically acceptable salt thereof, (b) about 4% w/v of gamma-cyclodextrin, (c) about 10% w/v of polysorbate 80, (d) about 0.1% w/v (10mM) of citric acid, and (e) a pharmaceutically acceptable excipient, and wherein the composition has pH of about 3.5, and wherein said process comprises steps of:
(i) preparing a mixture of the gamma-cyclodextrin and polysorbate 80,
(ii) adding an ethanolic solution of carfilzomib or salt thereof to the mixture of step (i) with mixing to obtain a solution,
(iii) diluting the solution of step (ii) to make desired concentration of the carfilzomib or salt thereof and adjusting a pH to about 3.5 with pH adjusting agent to obtain a solution, and
(v) aseptic filtering the solution of step (iv) and filling into vials to obtain a ready to use solution for parenteral administration,
(vi) optionally, lyophilising the solution of step (v) to obtain the pharmaceutical composition in the form of lyophilized powder.

While the invention has been described in term of its specific embodiments, certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

EXAMPLES
EXAMPLE 1: Compositions of carfilzomib with Lactose

Table 1

Ingredients
Compositions
Amount

a b c d
Carfilzomib 60 mg 60 mg 60 mg 60 mg
Lactose 7000 mg 8000 mg 8500 mg 7500 mg
Ethanol 5% 2% 7% 6%
Citric acid 57.7 mg 57 mg 55 mg 60 mg
Hydrochloric acid q.s q.s q.s q.s
pH 3.5 3.5 3.5 3.5
Water for injection q.s. up to 30 ml

Manufacturing Process:
A. Solution formulation:
Compositions were prepared by forming a mixture containing lactose and citric acid in water in a stainless steel jacketed tank equipped with a turbine agitator. To this, an ethanolic solution of carfilzomib was added with agitation to obtain slurry. The slurry was sprayed into a four foot diameter vertical spray drier through a rotary atomizer at 20,000 to 23,000 revolutions per minute to obtain a powder. The resulting powder was further reconstituted with water for injection to make desired concentration of the carfilzomib and the pH was adjusted by hydrochloric acid to about 3.5 to obtain a solution. The solution was aseptic filtered and filled into vials to obtain the pharmaceutical composition of carfilzomib for parenteral administration.
B. Lyophilized powder formulation:
Compositions were prepared by forming a mixture containing lactose and citric acid in water in a stainless steel jacketed tank equipped with a turbine agitator. To this, an ethanolic solution of carfilzomib was added with agitation to obtain slurry. The slurry was sprayed into a four foot diameter vertical spray drier through a rotary atomizer at 20,000 to 23,000 revolutions per minute to obtain a powder. The resulting powder was further reconstituted with water for injection to make desired concentration of the carfilzomib and the pH was adjusted by hydrochloric acid to about 3.5 to obtain a solution. The solution was aseptic filtered and filled into vials. This composition was lyophilised to yield final formulation.

EXAMPLE 2: Composition of carfilzomib with inclusion-complexing agent (?-cyclodextrin)

Table 2

Ingredient Composition
Amount

a b c d
Carfilzomib 60 mg 60 mg 60 mg 60 mg
Gamma-Cyclodextrin 1200 mg 1000 mg 1500 mg 1300 mg
Citric acid 57.7 mg 57 mg 55 mg 50 mg
Hydrochloric acid q.s q.s q.s q.s
pH 3.5 3.5 3.5 3.5
Water for injection q.s. up to 30 ml

Manufacturing process:

A. Solution formulation:

Accurately weighed amount of gamma-cyclodextrin and citric acid were added to appropriate volume of water for injection and stirred well to ensure complete dissolution of gamma-cyclodextrin and citric acid. To this mixture was added carfilzomib with mixing until it gets completely dissolved. The resultant solution was diluted with water for injection to make desired concentration of peptide (e.g. 2 mg/ml). The pH was adjusted of this mixture by slow addition of hydrochloric acid to 3.5. Aseptic filter this solution to yield the final formulation.
B. Lyophilized powder formulation:
Accurately weighed amount of gamma-cyclodextrin and citric acid were added to appropriate volume of water for injection and stirred well to ensure complete dissolution of gamma-cyclodextrin and citric acid. To this mixture was added carfilzomib with mixing until it gets completely dissolved. The resultant solution was diluted with water for injection to make desired concentration of peptide (e.g. 2 mg/ml). The pH was adjusted of this mixture by slow addition of hydrochloric acid to 3.5. Aseptic filter this solution and filled into vials. This composition was lyophilised to yield final formulation.

EXAMPLE 3: Composition of carfilzomib with inclusion-complexing agent and surfactant (?-cyclodextrine and Polysorbates)

Table 3

Ingredient Composition
Amount
a b c d
Carfilzomib 60 mg 60 mg 60 mg 60 mg
Gamma-Cyclodextrin 1200 mg 1000 mg 1500 mg 1300 mg
Polysorbate 80 3000 mg 2500 mg 2700 mg 2200 mg
Citric acid 57.7 mg 57 mg 55 mg 50 mg
Hydrochloric acid q.s q.s q.s q.s
pH 3.5 3.5 3.5 3.5
Water for injection q.s. up to 30 ml

Manufacturing Process:

A. Solution formulation:

Accurately weighed amount of gamma-cyclodextrin, polysorbate 80and citric acid were added to appropriate volume of water for injection and stirred well to ensure complete dissolution of gamma-cyclodextrin and citric acid. To this mixture was added carfilzomib with mixing until it gets completely dissolved. The resultant solution was diluted with water for injection to make desired concentration of peptide (e.g. 2 mg/ml). The pH was adjusted of this mixture by slow addition of hydrochloric acid to 3.5. Aseptic filter this solution to yield the final formulation.
B. Lyophilized powder formulation:
Accurately weighed amount of gamma-cyclodextrin, polysorbate 80 and citric acid were added to appropriate volume of water for injection and stirred well to ensure complete dissolution of gamma-cyclodextrin and citric acid. To this mixture was added carfilzomib with mixing until it gets completely dissolved. The resultant solution was diluted with water for injection to make desired concentration of peptide (e.g. 2 mg/ml). The pH was adjusted of this mixture by slow addition of hydrochloric acid to 3.5. Aseptic filter this solution and filled into vials. This composition was lyophilised to yield final formulation.
,CLAIMS:1. A pharmaceutical composition for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6.
2. The pharmaceutical composition of claim 1, wherein the carfilzomib or salt thereof is present in the amount of about 2 mg/ml.
3. The pharmaceutical composition of claim 1, wherein the adsorbent comprises sugar or its derivatives selected from lactose, sorbitol, xylitol, erythritol, sucrose, mannitol or mixture thereof.
4. The pharmaceutical composition of claim 3, wherein the adsorbent is lactose present in about 25% w/v of the composition.
5. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient comprises a buffer, a pH adjusting agent, a preservative, an antioxidant, a diluent or mixture thereof.
6. The pharmaceutical composition of claim 1, wherein the composition has the pH from about 3 to about 5.
7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is a ready to use solution and is diluted with water for injection or 5% dextrose or 0.9% sodium chloride solution before administering to a patient in need thereof.
8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the composition is a lyophilized powder to be reconstituted and further diluted with water for injection or 5% dextrose or 0.9% sodium chloride solution before administering to a patient in need thereof.

9. A pharmaceutical composition for parenteral administration comprising: (a) about 2 mg/ml carfilzomib or salt thereof, (b) about 25% w/v of lactose, and (c) about 0.1% w/v of citric acid; wherein the composition has a pH of about 3.5.
10. A process of preparing a pharmaceutical composition for parenteral administration for parenteral administration comprising: (a) carfilzomib or salt thereof present in an amount of about 0.1 mg/ml to about 4 mg/ml, (b) an adsorbent present in about 5% w/v to about 35% w/v of the composition, and (c) a pharmaceutically acceptable excipient; wherein the composition has a pH from about 2 to about 6, and wherein said process comprises steps of:
(i) preparing a mixture of the lactose and citric acid,
(ii) adding an ethanolic solution of carfilzomib or salt thereof to the mixture of step (i) with mixing to obtain a slurry,
(iii) spraying the slurry into vertical spray drier through a rotary atomizer to obtain a powder,
(iv) reconstituting the powder of step (iii) to make desired concentration of the carfilzomib and adjusting a pH to about 3.5 with pH adjusting agent to obtain a solution, and
(v) aseptic filtering the solution of step (iv) and filling into vials to obtain a ready to use solution for parenteral administration,
(vi) optionally, lyophilising the solution of step (v) to obtain the pharmaceutical composition in the form of lyophilized powder.