Carfilzomib preparation for stable dilution

Abstract

Stable, Dilutable Carfilzomib Formulations: The present invention provides room temperature stable injectable formulations for dilution comprising carfilzomib or a pharmaceutically acceptable derivative thereof. The present invention further provides methods of treating patients with multiple myeloma by administering room temperature stable injectable formulations for dilution comprising carfilzomib or a pharmaceutically acceptable derivative thereof.

Description

Technical Field

[0001] The present invention provides a stable injection preparation for dilution at room temperature, containing carfilzomib or a pharmaceutically acceptable derivative thereof. Further, the present invention relates to a method for treating patients with relapsed or refractory multiple myeloma, including forming a dilution solution reconstituted by mixing Component 1 and Component 2, where Component 1 is stored at room temperature for at least one month, regarding the method.

Background Art

[0002] Carfilzomib is a selective proteasome inhibitor used for the treatment of multiple myeloma. Carfilzomib is a tetrapeptide-type epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active site of the 20S proteasome, which is the proteolytic core particle within the 26S proteasome.

[0003] Carfilzomib is commercially available under the name Kyprolis (registered trademark) in single-dose vials containing 10 mg, 30 mg, and 60 mg of the active ingredient. Each vial contains lyophilized carfilzomib, and sulfobutylether β-cyclodextrin, citric acid, and sodium hydroxide for pH adjustment.

[0004] The problem with commercially available preparations is that the reconstitution of the lyophilized product is complex and cumbersome. The reconstitution process is complex, and each vial needs to be aseptically reconstituted by slowly injecting sterile water for injection from the stopper, and it is necessary to direct the water against the inner wall of the vial to ensure a reduction in foam generation. If foam occurs, it must be waited until the foam settles and the solution becomes clear. Also, in the reconstituted product, it is very important to visually inspect the solution before administration, and any reconstituted solution suspected of containing discoloration or particulate matter must be discarded. Additionally, the presence of excessive foam is known to lead to a decrease in potency. Efforts have been made to obtain improved carfilzomib compositions. For example, substituted cyclodextrin additives have been studied to increase the solubility of carfilzomib. [Overview of the project] [Problems that the invention aims to solve]

[0005] Because carfilzomib is sensitive to degradation, developing a cost-effective, room-temperature stable injectable formulation of carfilzomib is extremely difficult. Especially when stored at room temperature, there is still a need for improved carfilzomib formulations with enhanced ease of manufacture, administration methods, and long-term stability. [Means for solving the problem]

[0006] The object of the present invention is to provide a room-temperature stable, dilutable injectable formulation containing carfilzomib or a pharmaceutically acceptable derivative thereof. Another object of the present invention is to provide a method for treating patients with multiple myeloma by administering a room-temperature stable, dilutable injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof. Furthermore, an object of the present invention is to provide a method for treating patients with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, then diluting the reconstituted diluent in an injection medium and administering the reconstituted diluent, wherein the method comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent. One aspect of the present invention is to provide a carfilzomib formulation that is stable at room temperature and stable for at least one month when stored at 25°C. One aspect of the present invention provides a carfilzomib formulation that is stable at room temperature and stable for at least one month when stored at 25°C, wherein the total impurities do not exceed 6%, preferably 5% or less, preferably 4% or less, preferably 3% or less, preferably 2% or less, preferably 1.5% or less, preferably 1% or less, and preferably 0.5% or less. [Modes for carrying out the invention]

[0007] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context explicitly indicates otherwise. The term "about" as used herein means a deviation of +5% from the given value. As used herein, the terms "in some cases" or "in certain circumstances" mean whether the events or situations described below may occur.

[0008] The formulation of the present invention comprises "carfilzomib" or a pharmaceutically acceptable derivative a thereof. Examples of pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, solvates, hydrates, anhydrides, enantiomers, isomers, polymorphs, tautomers, or mixtures thereof. A pharmaceutically acceptable salt is one that retains the desirable biological activity of the parent compound without conferring undesirable toxic effects. Examples of such salts include, for example, acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid; salts formed from organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, methanesulfonic acid, plutenesulfonic acid, naphthalenesulfonic acid, and polygalacturonic acid; salts formed from elemental anions such as chlorides, bromides, and iodides; salts formed from metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates such as sodium sulfate and potassium sulfate; and salts formed from metal nitrates such as sodium nitrate and potassium nitrate.

[0009] "Stabilized formulation" or "stabilized formulation" refers to a formulation of carfilzomib that has sufficient physical and chemical stability to be stored at an appropriate temperature for a reasonable period of time. As used herein, the term "room temperature" refers to a temperature between approximately 15°C and approximately 40°C. As used herein, the term "impurities of carfilzomib" refers to any compounds resulting from the chemical degradation of carfilzomib. Typical degradation pathways include, but are not limited to, products resulting from the hydrolysis, oxidation, epimerization, and ring-opening of the oxirane ring by various nucleophiles of amides and / or epoxides.

[0010] As used herein, the term “dilution” refers to a dilution formulation for injection containing carfilzomib or a pharmaceutically acceptable derivative thereof that can be administered to a patient after being directly combined with an injectable medium (e.g., glucose solution, sterile water for injection, Ringer's solution, isotonic sodium chloride solution, a suitable non-aqueous solvent, or any other injectable medium). In some embodiments, the dilution formulation may be provided as a single vial containing the injectable formulation containing carfilzomib or a pharmaceutically acceptable derivative thereof. In some cases, the dilution formulation may be further diluted with other suitable excipients before being combined with an injectable medium.

[0011] As used herein, the term "component 1" refers to a diluted injectable preparation comprising carfilzomib or a pharmaceutically acceptable derivative thereof. As used herein, "component 2" refers to an acidifying agent that, when reconstituted with component 1, forms a reconstituted diluent formulation, and which may be further added to or mixed into the injection medium. Component 2 is used in the form of a clear solution or powder.

[0012] As used herein, the term “reconstituted dilution (formulation)” refers to a formulation of carfilzomib or a pharmaceutically acceptable derivative thereof, obtained by mixing component 1 and component 2 before adding them to the infusion medium. As used herein, the term "dilution (formulation)" refers to a formulation of carfilzomib or a pharmaceutically acceptable derivative thereof that can be administered directly to a patient without further dilution or processing.

[0013] The formulation of the present invention is an injectable formulation. The injectable formulation of carfilzomib or its pharmaceutically acceptable derivative according to the present invention can be administered by any route, including intramuscular, intravenous, or subcutaneous. Intravenous administration is preferred for the injectable formulation of the present invention. The formulation of carfilzomib or its pharmaceutically acceptable derivative may be in the form of a liquid concentrate that can be diluted. The injectable formulation may be packaged in a standard sterile vial or other suitable sterile container.

[0014] In one embodiment, a room-temperature stable, dilutable injectable formulation containing carfilzomib or a pharmaceutically acceptable derivative thereof contains carfilzomib at a concentration of about 5 mg / mL to about 350 mg / mL. In one embodiment, the concentration of carfilzomib is in the range of about 10 mg / mL to about 100 mg / mL, or about 15 mg / mL to about 60 mg / mL, or about 10 mg / mL to about 60 mg / mL. In a preferred embodiment, the injectable formulation contains carfilzomib at a concentration of about 10 mg / mL or about 60 mg / mL.

[0015] In one embodiment, the present invention provides a room-temperature stable diluent for injection comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents. In one embodiment, the diluent composition may contain one or more solvents selected from ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide (DMA), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), diethylene glycol monoethyl ether, caprylocaproyl polyoxyl-8 glyceride, glycoflor, or mixtures thereof. In a preferred embodiment, the formulation may contain ethanol, dimethylacetamide, propylene glycol, polyethylene glycol, or mixtures thereof. In one embodiment, the ratio of the amount of one or more solvents used to the amount of carfilzomib or a pharmaceutically acceptable derivative thereof can vary from about 100:1 to 8:1.

[0016] In one embodiment, the room-temperature stable injectable formulation of the present invention may optionally contain one or more pharmaceutically acceptable excipients, such as buffers, surfactants, antioxidants, and preservatives. The formulation may contain one or more pharmaceutically acceptable surfactants. Suitable surfactants include anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants. Exemplary nonionic surfactants include polyethylene oxides such as PEG300 or PEG400. Pharmaceutically acceptable surfactants for this application include polysorbate or polyethoxylated castor oil, polyoxyl 20 stearate, polyoxyl 35 castor oil, poloxamer, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate, polyoxyl 40 hydrogenated castor oil, polysorbate, polysorbate 20, polysorbate 40, polyoxyl 60 stearate, polysorbate 80, and polysorbate 60, Poloxamer 331, Polyoxyethylene fatty acid ester, Polyoxyl 40 castor oil, Poloxamer 188, Polyoxyethylene polyoxypropylene 1800, Oleic acid, Sodium deoxycholate, 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, synthetic triglycerides, trimiristin, tristearin, magnesium stearate, lecithin, lauryl sulfate, vitamin E, vitamin E-TPGS, egg yolk phospholipid, sodium doxate, dimyristoyl phosphatidylglycerol, dimyristoyl lecithin, capriol 20 (propylene glycol monocaprylate), capriol PGMC (monocaprylate) Propylene glycol propylene sulfate, deoxycholic acid, cholesterol, Cremofor EL, propylene glycol alginate, Croval A-10 (PEG-40 almond glyceride), Labrafil 1944 (oleoyl macrogol-6 glyceride), Labrafil 2125 (linoleoyl macrogol-6 glyceride), Labrasol (caprylocaproyl macrogol-8 glyceride), Lauroglycol 90 (propylene glycol monolaurate),Examples include lauroglycol FCC (propylene glycol laurate), calcium stearate, lecithincentromix E, lecithincentrophase 152, lecithincentrol 3F21B, POE26 glycerin, olepal isostealik (PEG-6 isostearate), plurol diisostealik (polyglycerol-3-diisostealik), plurol oleic CC, POE20 sorbitan trioleate, tagat TO (polyoxyethylene glycerol trioleate), or solutol (macrogol 15 hydroxystearate). In some embodiments, the surfactant may be present in an amount of about 10% to about 90%, preferably about 20% to about 80%, and preferably about 30% to about 60% of the total mass of the diluent formulation.

[0017] The formulation may include a buffer selected from a mixture of a weak acid and an alkali metal salt (e.g., sodium, potassium), and a conjugate base of the weak acid. Suitable buffers include, for example, buffers selected from the group consisting of citric acid, acetic acid, maleic acid, phosphoric acid, succinic acid, tartaric acid, ascorbic acid, benzenesulfonic acid, oxalic acid, fumaric acid, gluconic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, lacturonic acid, lactic acid, lactobionic acid, edetic acid, gentisic acid, metaphosphoric acid, nitric acid, pentetic acid, glycolic acid, and their counterion salts.

[0018] The formulation contains butyl transformation Hydroxytoluene, butyl transformation It may include hydroxyanisole, propyl gallate, and one or more antioxidants selected from hydrophilic antioxidants including C-tocopherol, DL-tocopherol, C-tocopherol acetate, C-tocopherol polyethylene glycol succinate (vitamin E TPGS), L-cysteine ​​ascorbyl palmitate thioglycolic acid, sodium metabisulfite (SMBS), ascorbic acid, sodium formaldehyde sulfoxylate, or sodium EDTA or thioglycerol. Most typically, antiThe concentration of the oxidizing agent is 0.005% to 5% by mass of the total composition.

[0019] The formulation may typically contain preservatives selected from phenol, thimerosal, chlorobutanol, benzyl alcohol, m-cresol, phenoxyethanol, methylparaben, and propylparaben at concentrations ranging from 0.001% to approximately 5% by mass of the total composition, most typically from approximately 0.003% to approximately 2.0% by mass of the total composition.

[0020] The formulation may include an acidifying agent selected from citric acid, acetic acid, maleic acid, phosphoric acid, succinic acid, tartaric acid, ascorbic acid, benzenesulfonic acid, oxalic acid, fumaric acid, gluconic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, lacturonic acid, lactic acid, lactobionic acid, edetic acid, gentisic acid, metaphosphoric acid, nitric acid, pentetic acid, and glycolic acid. The purpose of using the acidifying agent of the present invention is to solubilize carfilzomib or a pharmaceutically acceptable salt thereof in the infusion medium by maintaining an acidic pH. Furthermore, the purpose of using the acidifying agent of the present invention is to avoid drug precipitation in the infusion medium.

[0021] Certain compounds have been identified as impurities obtained by the decomposition of carfilzomib, [acid impurity] (S)-2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentaamido)-3-phenylpropanoic acid; [diastereomeric impurity] (S)-4-methyl-N-((R)-1-((S)-4-methyl-1-((R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido); [phenol impurity] 2,3,4,5,6-pentafluorophenol; [diol impurity] (S)-N-((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentaamide; [chloro impurity] (S)-N-((S)-1-(((2S,4S)-1-chloro-2-hydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentaamide; [N-oxide impurity] 4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methyloxirane-2-carbonyl)-2,5,8,11-tetraoxo-4-phenethyl-3,6,9,12-tetraazadecyl)morpholine-4-oxide and other stability samples have been analyzed.

[0022] In one embodiment, it is a formulation that is stable at room temperature and in which the total impurities contained during the storage period are 6% or less. In one embodiment, it is a formulation that is stable at room temperature and in which the total impurities contained during the storage period are 5% or less. In one embodiment, it is a formulation that is stable at room temperature and in which the total impurities contained during the storage period are 4% or less. In one embodiment, it is a formulation that is stable at room temperature and in which the total impurities contained during the storage period are 3% or less. In one embodiment, it is a formulation that is stable at room temperature and in which the total impurities contained during the storage period are 2% or less. In one embodiment, it is a formulation that is stable at room temperature and in which the total impurities contained during the storage period are 1% or less. In one embodiment, it is a formulation that is stable at room temperature and in which the total impurities contained during the storage period are 0.5% or less. In one embodiment, the storage period of the formulation of the invention can be a reasonable period during which the formulation has sufficient chemical and physical stability. The storage period can be selected to be at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years.

[0023] In one embodiment, a formulation that is stable at room temperature refers to any formulation of carfilzomib that has sufficient stability to be stored at room temperature, such as about 15°C to about 40°C. A temperature of about 20°C to about 40°C is desirable; more preferably, it is a temperature of about °C to about 40°C, and most preferably, it is a temperature of about 20°C to about 25°C. Here, it should be understood that the stability of the formulation of carfilzomib in the temperature range of each embodiment always involves an additional parameter of 60% humidity. In a preferred embodiment of the present invention, the stability of a formulation that is stable at room temperature can be evaluated after storing the formulation of the present invention in a sealed sterile container at a relative humidity of 60% and a temperature of 25°C.

[0024] In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for at least one month when stored at 40°C and 75% relative humidity. In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for at least three months when stored at 40°C and 75% relative humidity. In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for at least six months when stored at 40°C and 75% relative humidity. In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for at least one year when stored at 40°C and 75% relative humidity.

[0025] In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature, and which is stable for at least two years when stored at 40°C and 75% relative humidity. The stability of the formulation of the present invention is measured by the amount of total impurities formed at the end of the stability period. In one embodiment, stability is achieved when the amount of impurities formed during a specified stability period is 6% or less, preferably 5% or less, preferably 4% or less, preferably 3% or less, preferably 2% or less, preferably 1.5% or less, preferably 1% or less, and preferably 0.5% or less.

[0026] In one embodiment, after storage at 75% RH and 40°C for one month, the total impurities of the carfilzomib composition may be 6% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for one month, the total impurities of the carfilzomib composition may be 5% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for one month, the total impurities of the carfilzomib composition may be 4% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for one month, the total impurities of the carfilzomib composition may be 3% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for one month, the total impurities of the carfilzomib composition may be 2% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for one month, the total impurities of the carfilzomib composition may be 1.5% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for one month, the total impurities of the carfilzomib composition may be 1% or less by HPLC. In another embodiment, after storage at 75% RH and 40°C for one month, the total impurities of the carfilzomib composition may be 0.5% or less by HPLC.

[0027] In one embodiment, after storage at 75% RH and 40°C for 3 months, the total impurities of the carfilzomib composition may be 6% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 3 months, the total impurities of the carfilzomib composition may be 5% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 3 months, the total impurities of the carfilzomib composition may be 4% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 3 months, the total impurities of the carfilzomib composition may be 3% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 3 months, the total impurities of the carfilzomib composition may be 2% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 3 months, the total impurities of the carfilzomib composition may be 1.5% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 3 months, the total impurities of the carfilzomib composition may be 1% or less by HPLC. In another embodiment, after storage at 75% RH and 40°C for 3 months, the total impurities of the carfilzomib composition may be 0.5% or less by HPLC.

[0028] In one embodiment, after storage at 75% RH and 40°C for 6 months, the total impurities of the carfilzomib composition may be 6% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 6 months, the total impurities of the carfilzomib composition may be 5% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 6 months, the total impurities of the carfilzomib composition may be 4% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 6 months, the total impurities of the carfilzomib composition may be 3% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 6 months, the total impurities of the carfilzomib composition may be 2% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 6 months, the total impurities of the carfilzomib composition may be 1.5% or less by HPLC. In one embodiment, after storage at 75% RH and 40°C for 6 months, the total impurities of the carfilzomib composition may be 1% or less by HPLC. In another embodiment, after storage at 75% RH and 40°C for 6 months, the total impurities of the carfilzomib composition may be 0.5% or less by HPLC.

[0029] In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for at least one month when stored at 25°C and 60% relative humidity. In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for at least three months when stored at 25°C and 60% relative humidity. In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for at least six months when stored at 25°C and 60% relative humidity. In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for at least one year when stored at 25°C and 60% relative humidity.

[0030] In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature, and which is stable for at least two years when stored at 25°C and 60% relative humidity. This stability of the formulation of the present invention is measured by the amount of total impurities formed at the end of the stability period. In one embodiment, stability is achieved when the amount of impurities formed during a specified stability period is 6% or less, preferably 5% or less, preferably 4% or less, preferably 3% or less, preferably 2% or less, preferably 1.5% or less, preferably 1% or less, and preferably 0.5% or less.

[0031] In one embodiment, after storage at 60% RH and 25°C for one month, the total impurities of the carfilzomib composition may be 6% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for one month, the total impurities of the carfilzomib composition may be 5% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for one month, the total impurities of the carfilzomib composition may be 4% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for one month, the total impurities of the carfilzomib composition may be 3% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for one month, the total impurities of the carfilzomib composition may be 2% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for one month, the total impurities of the carfilzomib composition may be 1.5% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for one month, the total impurities of the carfilzomib composition may be 1% or less by HPLC. In another embodiment, after storage at 60% RH and 25°C for one month, the total impurities of the carfilzomib composition may be 0.5% or less by HPLC.

[0032] In one embodiment, after storage at 60% RH and 25°C for 3 months, the total impurities of the carfilzomib composition may be 6% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 3 months, the total impurities of the carfilzomib composition may be 5% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 3 months, the total impurities of the carfilzomib composition may be 4% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 3 months, the total impurities of the carfilzomib composition may be 3% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 3 months, the total impurities of the carfilzomib composition may be 2% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 3 months, the total impurities of the carfilzomib composition may be 1.5% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 3 months, the total impurities of the carfilzomib composition may be 1% or less by HPLC. In another embodiment, after storage at 60% RH and 25°C for 3 months, the total impurities of the carfilzomib composition may be 0.5% or less by HPLC.

[0033] In one embodiment, after storage at 60% RH and 25°C for 6 months, the total impurities of the carfilzomib composition may be 6% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 6 months, the total impurities of the carfilzomib composition may be 5% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 6 months, the total impurities of the carfilzomib composition may be 4% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 6 months, the total impurities of the carfilzomib composition may be 3% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 6 months, the total impurities of the carfilzomib composition may be 2% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 6 months, the total impurities of the carfilzomib composition may be 1.5% or less by HPLC. In one embodiment, after storage at 60% RH and 25°C for 6 months, the total impurities of the carfilzomib composition may be 1% or less by HPLC. In another embodiment, after storage at 60% RH and 25°C for 6 months, the total impurities of the carfilzomib composition may be 0.5% or less by HPLC.

[0034] In one embodiment, the present invention provides a room-temperature stable injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents. In one embodiment, the present invention provides a room-temperature stable injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants. In one embodiment, the present invention provides a room-temperature stable injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the injectable formulation includes a diluent formulation, a ready-to-use formulation and a liquid concentrate formulation. In a preferred embodiment, the injectable formulation of the present invention is a room-temperature stable diluent solution. In one embodiment, the present invention provides a room-temperature stable injectable dilution formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants.

[0035] In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a one-month storage period are 6% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a one-month storage period are 5% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a one-month storage period are 4% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a one-month storage period are 3% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a one-month storage period are 2% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a one-month storage period are 1.5% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a one-month storage period are 1% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a one-month storage period are 0.5% or less.

[0036] In one embodiment, the present invention provides a room-temperature stable dilution for injection, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 6% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 6% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 5% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 4% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 3% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 2% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 1.5% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 1% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for one month are 0.5% or less.

[0037] In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 3-month storage period are 6% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 3-month storage period are 5% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 3-month storage period are 4% or less. In one embodiment, a room-temperature stable dilution for injection is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 3-month storage period are 3% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 3-month storage period are 2% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 3-month storage period are 1.5% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 3-month storage period are 1% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 3-month storage period are 0.5% or less.

[0038] In one embodiment, the present invention provides a room-temperature stable dilution for injection, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during storage at 25°C and 60% relative humidity for 3 months are 6% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for three months are 6% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for three months are 5% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 3 months are 4% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 3 months are 3% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 3 months are 2% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for three months are 1.5% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for three months are 1% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 3 months are 0.5% or less.

[0039] In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 6-month storage period are 6% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 6-month storage period are 5% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 6-month storage period are 4% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 6-month storage period are 3% or less. In one embodiment, a room-temperature stable dilution for injection is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 6-month storage period are 2% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 6-month storage period are 1.5% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 6-month storage period are 1% or less. In one embodiment, a room-temperature stable injectable dilution formulation is provided, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total impurities present during a 6-month storage period are 0.5% or less.

[0040] In one embodiment, the present invention provides a room-temperature stable dilution for injection comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 6% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 6% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 5% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 4% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 3% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 2% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 1.5% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 1% or less. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally, one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants, wherein the total impurities present during storage at 25°C and 60% relative humidity for 6 months are 0.5% or less.

[0041] Obtaining injectable formulations that are stable at room temperature is always desirable and beneficial because it offers commercial and handling advantages compared to formulations stored under harsh conditions such as 2–8°C. However, obtaining injectable formulations that are stable at room temperature and have low levels of impurities, or impurity levels within the acceptable range for drug regulatory authorities, is extremely difficult.

[0042] During the stability study period, surprisingly, the dilution injection solution without an acidifying agent was found to have a significantly better impurity profile than the dilution injection solution with an acidifying agent. Therefore, the acidifying agent negatively affects the stability of the formulation at room temperature, and more impurities are generated during the stability period compared to formulations without an acidifying agent. The better impurity profile according to the present invention includes the difference in total impurities obtained during the stability period in the analysis of formulation samples by HPLC.

[0043] In one embodiment, the present invention provides a room-temperature stable injectable formulation containing carfilzomib or a pharmaceutically acceptable salt thereof that does not contain any acidifying agent. In one embodiment, the present invention provides a room-temperature stable injectable formulation containing carfilzomib and a pharmaceutically acceptable salt thereof, which contains no acidifying agent during the formulation's stabilization period. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, and surfactants, but free from acidifying agents during the formulation's stabilization period. In one embodiment, the present invention provides a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof, one or more solvents; and optionally one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, and surfactants, but free from acidifying agents during the formulation's stabilization period.

[0044] One embodiment of the present invention relates to the delivery of a carfilzomib dilution injection formulation that is stable at room temperature, which can be diluted to an appropriate injection (particularly by infusion, particularly by intravenous injection) concentration and then administered in an appropriate amount to treat carfilzomib-responsive conditions known in the industry.

[0045] One embodiment of the present invention provides a parenteral formulation for diluting carfilzomib that is stable at room temperature, or of A method is provided for treating patients with relapsed or refractory multiple myeloma by administering the preparation, which can be used as is, alone or in combination with dexamethasone or lenalidomide + dexamethasone.

[0046] One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable injectable diluent formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities during storage is 6% or less. Another embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable injectable diluent formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities during storage is 5% or less. Another embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable injectable diluent formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities during storage is 4% or less. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable injectable diluent formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities during storage is 3% or less. Another embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable injectable diluent formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities during storage is 2% or less. Another embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable injectable diluent formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities during storage is 1.5% or less. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable dilution for injection formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities during storage is 1% or less.One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable injectable dilution formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities during storage is 0.5% or less.

[0047] One embodiment of the present invention provides a method for treating patients with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable dilution for injection containing carfilzomib or a pharmaceutically acceptable salt thereof, which is stable for one month when stored at 25°C and 60% relative humidity. Another embodiment of the present invention provides a method for treating patients with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable dilution for injection containing carfilzomib or a pharmaceutically acceptable salt thereof, which is stable for three months when stored at 25°C and 60% relative humidity. Another embodiment of the present invention provides a method for treating patients with relapsed or refractory multiple myeloma, comprising administering a room-temperature stable dilution for injection containing carfilzomib or a pharmaceutically acceptable salt thereof, which is stable for six months when stored at 25°C and 60% relative humidity.

[0048] One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent.

[0049] In one embodiment, component 2 comprises an acidifying agent that can be selected from citric acid, malic acid, phosphoric acid, orthophosphoric acid (OPA), fumaric acid, or a mixture thereof. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof is about 1:50 to about 1:1 on a w / w basis. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof is about 1:40 to about 1:1 on a w / w basis. In one embodiment, the ratio of the acidifying agent used compared to carfilzomib or a pharmaceutically acceptable salt thereof is about 1:30 to about 1:1 on a w / w basis. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof is about 1:20 to about 1:1 on a w / w basis. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof is approximately 1:10 to approximately 1:1 on a w / w basis.

[0050] Carfilzomib or its pharmaceutically acceptable salts become more readily biodegradable at room temperature in a diluted parenteral solution when component 2 is added to component 1. In one embodiment, a mixture containing component 1 and component 2 should not be used 4 hours after mixing if the mixture is stored at room temperature. In a preferred embodiment, a mixture containing component 1 and component 2 should not be used 5 hours after mixing if the mixture is stored at room temperature. In a preferred embodiment, a mixture containing component 1 and component 2 should not be used 6 hours after mixing if the mixture is stored at room temperature. In a preferred embodiment, when the mixture is stored at 2-8°C, the mixture of component 1 and component 2 should not be used for administration to an injection medium 24 hours after mixing.

[0051] One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 is not used within 4 hours of mixing if the mixture is stored at room temperature. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 is not used 5 hours after mixing if the mixture is stored at room temperature. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 is not used 6 hours after mixing if the mixture is stored at room temperature.

[0052] One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 has a total impurity content of 2% or less from mixing to 4 hours after mixing when the mixture is stored at room temperature. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 has a total impurity content of 1% or less from mixing to 4 hours after mixing when the mixture is stored at room temperature. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 has a total impurity content of 2% or less from mixing to 5 hours after mixing when the mixture is stored at room temperature. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 has a total impurity content of 1% or less from mixing to 5 hours after mixing when the mixture is stored at room temperature. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 has a total impurity content of 2% or less from mixing to 6 hours after mixing when the mixture is stored at room temperature. One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture comprising component 1 and component 2 has a total impurity content of 1% or less from mixing to 6 hours after mixing when the mixture is stored at room temperature.

[0053] One embodiment of the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form a reconstituted diluent solution, and then diluting the reconstituted diluent solution with an infusion medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent, and the mixture containing component 1 and component 2 is not used for administration 24 hours after mixing when stored at 2-8°C.

[0054] One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifying agent.

[0055] One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and the total impurities present during storage at 25°C, 60% relative humidity, and for 6 months are 6% or less, and component 2 is an acidifying agent. One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and the total impurities present during storage at 25°C, 60% relative humidity, and for 6 months are 5% or less, and component 2 is an acidifying agent. One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and the total impurities present during storage at 25°C, 60% relative humidity, and for 6 months are 4% or less, and component 2 is an acidifying agent. One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and the total impurities present during storage at 25°C, 60% relative humidity, and for 6 months are 3% or less, and component 2 is an acidifying agent. One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and the total impurities present during storage at 25°C, 60% relative humidity, and for 6 months are 2% or less, and component 2 is an acidifying agent. One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and the total impurities present during storage at 25°C, 60% relative humidity, and for 6 months are 1.5% or less, and component 2 is an acidifying agent. One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and the total impurities present during storage at 25°C, 60% relative humidity, and for 6 months are 1% or less, and component 2 is an acidifying agent. One embodiment of the present invention provides a method for administering a reconstituted diluent, comprising mixing component 1 and component 2 to form a reconstituted diluent, and then diluting the reconstituted diluent with an injection medium, wherein component 1 comprises a room-temperature stable parenteral diluent formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and the total impurities present during storage at 25°C, 60% relative humidity, and for 6 months are 0.5% or less, and component 2 is an acidifying agent. The following examples are provided for illustrative purposes only and should not be considered as limiting the scope of the present invention. [Examples]

[0056] Formulation of carfilzomib

[0057] [Table 1] procedure: 1. A portion of dimethylacetamide was placed in a container, to which carfilzomib was weighed and added. The mixture was then mixed under continuous stirring with nitrogen purging and a sodium vapor lamp. 2. Dehydrated alcohol was added to the above solvent system and mixed until a clear solution was obtained. 3. While continuously stirring, weigh out and add orthophosphate, and mix well. 4. Dimethylacetamide was used to prepare the final volume, and the mixture was thoroughly mixed until a homogeneous solution was obtained. 5. The product was filtered through a 0.22μ filter and filled into vials. [Examples]

[0058] Formulation of carfilzomib

[0059] [Table 2] procedure: 1. Propylene glycol and polysorbate 80 were mixed at 2-8°C for 10 minutes. 2. Alpha-tocopherol was added to the above mixture. 3. The pH of the solution was adjusted to 3-4 (3.5) using lactic acid. 4.3 was mixed with a mixture of carfilzomib and dimethylacetamide until it became a clear solution. 5. Nitrogen purging and light protection were carried out throughout the batch preparation at 2–8°C. 6. The product was filtered through a 0.22 μm filter, filled into vials, and sealed.

[0060] [Example 2A: Preparation of carfilzomib formulation] Example 2A was prepared using the same method as in Example 2.

[0061] [Table 3] [Example 2B: Preparation of carfilzomib formulation] Example 2B was prepared using the same method as in Example 2.

[0062] [Table 4] [Example 2C: Preparation of carfilzomib formulation] Example 2C was prepared using the same method as in Example 2.

[0063] [Table 5] [Examples]

[0064] Formulation of carfilzomib

[0065] [Table 6] procedure: 1. Dimethylacetamide and dehydrated alcohol were homogeneously mixed at room temperature under nitrogen purging and a sodium vapor lamp. 2. Add carfilzomib to the above solvent system and mix until completely solubilized. 3. The product was filtered through a 0.22μ filter and filled into vials. [Examples]

[0066] Formulation of carfilzomib Formulations T1 to T4 were prepared using the same procedure as in Example 3.

[0067] [Table 7] [Examples]

[0068] Formulation of carfilzomib

[0069] [Table 8] procedure: 1. Dimethylacetamide was placed in a suitable container and the temperature was maintained at 2-8°C. 2. Alpha-tocopherol was added to step 1. 3. Add carfilzomib to the mixture of DMA and tocopherol from step 2 and mix thoroughly until completely solubilized. 4. Add sterile water for injection and polysorbate 80 to the above-mentioned 3 and mix well until uniformly dissolved. 5. The volume was adjusted using propylene glycol, and the mixture was stirred until a homogeneous solution was obtained. 6. The entire process was carried out under nitrogen purging and sodium vapor lamps. 7. The product was filtered through a 0.22μ filter and filled into vials.

[0070] [Example 5A: Preparation of carfilzomib formulation] Example 5A was prepared using the same method as in Example 5.

[0071] [Table 9] [Example 5B: Preparation of carfilzomib formulation] Example 5B was prepared in the same manner as in Example 5.

[0072] [Table 10] Table 1: Stability of the prepared formulations in Examples 5A and 5B

[0073] [Table 11] [Examples]

[0074] Formulation of carfilzomib The formulation in this example was prepared using the procedure described in Example 5.

[0075] [Table 12] [Example 6A: Preparation of carfilzomib formulation]

[0076] [Table 13] procedure 1. A sufficient amount of ethanol was collected in the preparation container. 2. While continuously stirring until a homogeneous solution was obtained, α-tocopherol by mass was added. The details were recorded. 3. While continuously stirring until a homogeneous solution was obtained, the mass of carfilzomib was added. The details were recorded. 4. Ethanol was added to prepare the final volume, and the mixture was stirred until a homogeneous solution was obtained. 5. The bulk material was filtered through a 0.22 μT PTFE filter and packed into vials.

[0077] [Example 6B: Preparation of carfilzomib formulation]

[0078] [Table 14] procedure 1. A sufficient amount of N,N-dimethylacetamide was collected in the preparation container. 2. While continuously stirring until a homogeneous solution was obtained, the required amount of α-tocopherol was added. The details were recorded. 3. While continuously stirring until a homogeneous solution was obtained, the required amount of carfilzomib was added. The details were recorded. 4. Ethanol was added to prepare the final volume, and the mixture was stirred until a homogeneous solution was obtained. 5. The bulk material was filtered through a 0.22 μT PTFE filter and packed into vials. [Examples]

[0079] Table 2: Stability comparison of the preparations from Examples 1, 2, 3, and 5

[0080] [Table 15] *RT Room temperature (stability test parameters: temperature 25°C, relative humidity 60%), *ND: Not detected, *NMT: Not detected. [Examples]

[0081] Preparation and stability data of acidifying agent-containing injectable formulation compositions

[0082] [Table 16] procedure: The required amount of 1.80% dehydrated alcohol was collected in a clean container. 2. Add the required amount of carfilzomib to the solvent from step 1 at 2-8°C and dissolve it using a mechanical stirrer until a clear solution is observed. 3. In step 2, the required amount of alpha-tocopherol was added while stirring at 2-8°C until a clear solution was observed. 4. In step 3, the required amount of o-phosphate was added while stirring at 2-8°C until a clear solution was observed. 5. Prepare the final batch size with the required amount of dimethylacetamide and mix thoroughly at 2-8°C. The bulk solution was filtered using a 6.0.2 micron PTFE filter. 7. After filling the amber-colored vials, cover them with a nitrogen blanket and seal them appropriately with rubber stoppers. 8. The vials maintained thermal stability at 25°C, 60% RH, and 2–8°C.

[0083] Table 3. Stability data of injectable formulations containing acidifying agents.

[0084] [Table 17] [Examples]

[0085] Preparation and stability data of injectable formulation compositions before and after mixing with acidifying agents.

[0086] [Table 18] procedure: The required amount of 1.80% dehydrated alcohol was collected in a clean container. 2. In step 1, the required amount of carfilzomib was added at 2-8°C and dissolved using a mechanical stirrer until a clear solution was observed. 3. In step 2, the required amount of anhydrous ethanol was added while stirring at 2-8°C until a clear solution was observed. 4. Prepare the final batch size with the required amount of dimethylacetamide and mix thoroughly at 2-8°C. 5.0. The bulk solution was filtered using a PTFE filter. 6. After filling the amber-colored vials, a nitrogen blanket was placed over them and they were properly sealed with rubber stoppers. 7. The vials maintained thermal stability at 25°C, 60% RH, and 2–8°C.

[0087] Table 4. Stability data of injectable formulations before mixing with acidifying agents.

[0088] [Table 19] *NP = Not executed Table 5: Procedure for mixing the acidifying agent into the dilution composition

[0089] [Table 20] procedure: 1. Mix vial 1 and vial 2 aseptically as shown in Table 3 above. 2. Slowly rotate or invert the vial for 1 minute. 3. Before mixing, visually inspect for particulate matter and discoloration. The diluted solution should be colorless and transparent. Do not mix if discoloration or particulate matter is observed. 4. The mixed product solution from step 3 was diluted with sterile water for injection to concentrations of 0.5 mg / ml and 1.5 mg / ml, and the solution was stabilized at 25°C and 2-8°C.

[0090] Table 6. Stability data of injectable formulations after mixing with acidifying agents at concentrations of 0.5 mg / ml and 1.5 mg / ml.

[0091] [Table 21] [Examples]

[0092] Preparation and stability data of injectable formulation compositions before and after mixing with acidifying agents

[0093] [Table 22] procedure: A 1.80% concentration of the required amount of dimethylacetamide was collected in a clean, sterile container. 2. In step 1, the required amount of carfilzomib was added at 2-8°C and dissolved using a mechanical stirrer. 3. Prepare the final batch size with the required amount of dimethylacetamide and mix thoroughly at 2-8°C. 4.0. The bulk solution was filtered using a PTFE filter. 5. After filling the amber-colored vials, a nitrogen blanket was placed over them and they were properly sealed with rubber stoppers. 6. The vials maintained thermal stability at 25°C, 60%RH, 2-8°C, and 40°C / 75%RH.

[0094] Table 7 Stability data of injectable formulation compositions before mixing with acidifying agents

[0095] [Table 23] *ND = Not detected Table 8 Procedure for mixing the acidifying agent into the dilution composition

[0096] [Table 24] procedure: 1) Mix vial 1 and vial 2 aseptically as shown in the table above. 2) Slowly rotate or invert the vial for 1 minute. 3) Visually inspect for particulate matter and discoloration before mixing. The diluted solution should be colorless and transparent. If discoloration or particulate matter is observed, do not mix it with the injection medium. 4) The mixed product solution was diluted with sterile water for injection to concentrations of 0.5 mg / ml and 1.5 mg / ml, and the solution stability was observed at 25°C and 2-8°C.

[0097] Table 9. Stability data of injectable formulations after mixing acidifying agents at 0.5 mg / ml and 1.5 mg / ml concentrations.

[0098] [Table 25] [Examples]

[0099] Formulation of carfilzomib

[0100] [Table 26] procedure: 1. A standard amount of N,N-dimethylacetamide was collected in a preparation container at a temperature of 2-8°C. 2. While continuously stirring until a homogeneous solution was obtained, a batch amount of alpha-tocopherol was weighed and added. 3. Subsequently, while continuously stirring until completely dissolved, the batch amount of carfilzomib was weighed and added. 4. While continuously stirring until a homogeneous solution was obtained, the batch amount of water for injection was added. 5. While continuously stirring until a homogeneous solution was obtained, the batch amount of polysorbate 80 was added. 6. Add ultra-purified PG to reach the final volume and stir until a homogeneous solution is obtained. 7. The bulk material was filtered through a 0.22 μT PTFE filter and filled into vials. [Examples]

[0101] Formulation of carfilzomib

[0102] [Table 27] procedure: 1. A standard amount of ethanol was collected in a preparation container at a temperature of 2-8°C. 2. While continuously stirring until a homogeneous solution was obtained, a batch amount of alpha-tocopherol was weighed and added. 3. Subsequently, while continuously stirring until completely dissolved, the batch amount of carfilzomib was weighed and added. 4. While continuously stirring until a homogeneous solution was obtained, the batch amount of water for injection was added. 5. While continuously stirring until a homogeneous solution was obtained, the batch amount of polysorbate 80 was added. 6. Add ultra-purified PG to reach the final volume and stir until a homogeneous solution is obtained. 7. The bulk material was filtered through a 0.22 μT PTFE filter and filled into vials. [Examples]

[0103] Formulation of carfilzomib

[0104] [Table 28] procedure: 1. A standard amount of dimethylacetamide was collected in a preparation container at a temperature of 2-8°C. 2. While continuously stirring until a homogeneous solution was obtained, a batch amount of alpha-tocopherol was weighed and added. 3. Add the batch amount of polysorbate 80 while continuously stirring until completely dissolved. 4. While continuously stirring until a homogeneous solution was obtained, the batch amount of water for injection was added. 5. Batch-sized amounts of ultra-purified PG were added while continuously stirring until a homogeneous solution was obtained. 6. While continuously stirring until a homogeneous solution was obtained, the batch amount of carfilzomib was weighed and added. 7. Add ultra-purified PG to reach the final volume and stir until a homogeneous solution is obtained. 8. The bulk material was filtered through a 0.22 μT PTFE filter and filled into vials. [Examples]

[0105] Formulation of carfilzomib

[0106] [Table 29] procedure: 1. A standard amount of dimethylacetamide was collected in a preparation container at a temperature of 2-8°C. 2. While continuously stirring until a homogeneous solution was obtained, a batch amount of alpha-tocopherol was weighed and added. 3. Add the batch amount of polysorbate 80 while continuously stirring until completely dissolved. 4. While continuously stirring until a homogeneous solution was obtained, the batch amount of water for injection was added. 5. Batch-sized amounts of ultra-purified PG were added while continuously stirring until a homogeneous solution was obtained. 6. While continuously stirring until a homogeneous solution was obtained, the batch amount of carfilzomib was weighed and added. 7. Add ultra-purified PG to reach the final volume and stir until a homogeneous solution is obtained. 8. The bulk material was filtered through a 0.22 μT PTFE filter and filled into vials. [Examples]

[0107] Formulation of carfilzomib

[0108] [Table 30] procedure: A 1.90% N,N-dimethylacetamide solution was collected in a preparation container at a temperature of 2-8°C. 2. While continuously stirring until a homogeneous solution was obtained, the batch amount of carfilzomib was weighed and added. 3. Add N,N-dimethylacetamide to reach the final volume and stir until a homogeneous solution is obtained. 4. The bulk material was filtered through a 0.22 μT PTFE filter and filled into vials. [Examples]

[0109] Formulation of carfilzomib

[0110] [Table 31] procedure: 1. Batch quantities of N,N-dimethylacetamide were collected in a preparation container at a temperature of 2-8°C. 2. While continuously stirring until a homogeneous solution was obtained, the batch amount of carfilzomib was weighed and added. 3. Add ethanol to reach the final volume and stir until a homogeneous solution is obtained. 4. The bulk material was filtered through a 0.22 μT PTFE filter and filled into vials. [Examples]

[0111] Formulation of carfilzomib

[0112] [Table 32] procedure: A 1.80% N,N-dimethylacetamide solution was collected in a preparation container at a temperature of 2-8°C. 2. While continuously stirring until a homogeneous solution was obtained, the batch amount of carfilzomib was weighed and added. 3. Add N,N-dimethylacetamide to reach the final volume and stir until a homogeneous solution is obtained. 4. The bulk material was filtered through a 0.22 μT PTFE filter and filled into vials.

[0113] Table 10 Thermal stability and analysis results of APPL-006 / 01 / 105

[0114] [Table 33] NMT: Maximum ND - Not Detected [Examples]

[0115] Formulation of carfilzomib

[0116] [Table 34] procedure: 1. Batch quantities of N,N-dimethylacetamide were collected in a preparation container at a temperature of 2-8°C. 2. While continuously stirring until a homogeneous solution was obtained, the batch amount of carfilzomib was weighed and added. 3. Ethanol was added to prepare the final volume, and the mixture was stirred until a homogeneous solution was obtained. 4. The bulk material was filtered through a 0.22 μT PTFE filter and filled into vials.

[0117] Table 11: Thermal stability and analysis results of APPL-006 / 01 / 106

[0118] [Table 35] NMT: Maximum ND - Not detected

Claims

1. A ready-to-dilute injectable formulation stable at room temperature, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, wherein the total amount of impurities after storage at 25°C and 60% relative humidity for at least three months is 6% or less, and no acidifying agents are included during the stable period.

2. The room-temperature stable injectable formulation for dilution according to claim 1, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof is in the range of 10 mg / mL to 100 mg / mL.

3. The room-temperature stable injectable formulation for dilution according to claim 1, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof is in the range of 10 mg / mL to 60 mg / mL.

4. Furthermore, the room-temperature stable, dilutable injectable formulation according to claim 1 comprises one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants.

5. A room-temperature stable injectable preparation for dilution according to claim 1, wherein the total amount of impurities after storage for at least six months is 6% or less.

6. A room-temperature stable injectable formulation for dilution according to claim 1, comprising one or more solvents selected from ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide (DMSO), diethylene glycol monoethyl ether, caprylocaproyl polyoxyl-8 glyceride, glycoflor, or a mixture thereof.

7. The room-temperature stable injectable dilution formulation according to claim 1, wherein the ratio of one or more solvents to carfilzomib or a pharmaceutically acceptable salt thereof is 100:1 to 8:

1.

8. The room-temperature stable injectable formulation for dilution according to claim 4, wherein the antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and one or more hydrophilic antioxidants including C-tocopherol, DL-tocopherol, C-tocopherol acetate, C-tocopherol polyethylene glycol succinate (vitamin E TPGS), L-cysteine ​​ascorbyl palmitate thioglycolic acid, sodium metabisulfite (SMBS), ascorbic acid, sodium formaldehyde sulfoxylate, or sodium EDTA or thioglycerol.

9. The room-temperature stable injectable formulation for dilution according to claim 8, wherein the antioxidant is present at a concentration of 0.005% to 5% by mass of the entire composition.

10. A room-temperature stable injectable dilution formulation according to claim 1, comprising carfilzomib or a pharmaceutically acceptable salt thereof, and one or more solvents, and stored at 25°C and 60% relative humidity.

11. The room-temperature stable injectable formulation for dilution according to claim 1, wherein the total amount of impurities contained during the storage period is 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, or 0.5% or less.

12. A ready-to-dilute formulation for use in the treatment of patients with relapsed or refractory multiple myeloma, comprising a carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, wherein the total amount of impurities after storage at 25°C and 60% relative humidity for at least three months is 6% or less, and the formulation does not contain acidifying agents during the stable period.

13. The injectable preparation is stable when stored at 25°C and 60% relative humidity for 6 months, as described in claim 12.

14. A preparation for use in the treatment of patients with relapsed or refractory multiple myeloma, which can be used immediately by diluting a diluent preparation, constituted by mixing components 1 and 2, with an infusion medium, wherein The aforementioned component 1 is a room-temperature stable diluent formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, and the total amount of impurities is 6% or less when stored at 25°C and 60% relative humidity for at least 3 months, wherein the aforementioned component 1 contains no acidifying agents during its stable period, and The aforementioned component 2 is an acidifying agent, and the formulation is ready for immediate use.

15. The ready-to-use formulation according to claim 14, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof is in the range of 10 mg / mL to 60 mg / mL.

16. The ready-to-use formulation according to claim 14, wherein the ratio of the amount (w / w) of the acidifying agent of component 2 to the amount (w / w) of carfilzomib or a pharmaceutically acceptable salt thereof in component 1 is about 1:50 to about 1:

1.

17. The ready-to-use formulation according to claim 14, wherein component 1 comprises a room-temperature stable parenteral dilution formulation of carfilzomib or a pharmaceutically acceptable salt thereof, the total amount of impurities being 6% or less when stored at 25°C and 60% relative humidity for 6 months, and component 2 is an acidifying agent.

18. The ready-to-use formulation according to claim 14, wherein component 1 is stored at 25°C and 60% relative humidity or 40°C and 75% relative humidity for a period of at least 3 months.

19. The ready-to-use formulation according to claim 14, wherein when stored at 25°C and 60% relative humidity for 6 months, the total amount of impurities contained in component 1 is 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, or 0.5% or less.

20. The ready-to-use formulation according to claim 14, comprising, as an acidifying agent, component 2 selected from citric acid, acetic acid, maleic acid, phosphoric acid, succinic acid, tartaric acid, ascorbic acid, benzenesulfonic acid, oxalic acid, fumaric acid, orthophosphoric acid, gluconic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, lacturonic acid, lactic acid, lactobionic acid, edetic acid, gentisic acid, metaphosphoric acid, nitric acid, pentetic acid, glycolic acid, or a mixture thereof.

21. A preparation for use in the treatment of patients with relapsed or refractory multiple myeloma, which can be used immediately by diluting a diluent preparation, constituted by mixing components 1 and 2, with an infusion medium, wherein The aforementioned component 1 is a room-temperature stable diluent formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents, and the total amount of impurities after storage at 25°C and 60% relative humidity for at least three months is 3% or less, wherein the aforementioned component 1 contains no acidifying agents during the stable period. Furthermore, component 2 is an acidifying agent, and the reconstituted dilution formulation is a ready-to-use formulation in which the total impurities within 6 hours after mixing component 1 and component 2 and storing at room temperature are 2% or less.

22. The ready-to-use formulation according to claim 21, wherein the total impurities of the reconstituted diluent formulation are 1% or less up to 6 hours after mixing, 2% or less up to 5 hours, 1% or less up to 5 hours, 2% or less up to 4 hours, or 1% or less up to 4 hours after mixing components 1 and 2 and storing at room temperature.

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