Stable, dilution formulation of carfilzomib

Abstract

This invention provides a room-temperature stable, dilution-free injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof. This invention also provides a method for treating patients with multiple myeloma by administering a room-temperature stable, dilution-free injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof.

Description

Technical Field

[0001] This invention relates to room-temperature stable injectable formulations of carfilzomib or pharmaceutically acceptable derivatives thereof, in the form of ready-to-dilute solutions and concentrates. Furthermore, this invention relates to a method for treating patients with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted ready-to-dilute solution, comprising mixing component 1 and component 2 to form the reconstituted ready-to-dilute solution, wherein component 1 is stored at room temperature for at least one month. Background Technology

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

[0003] Carfilzomi is commercially known by its name Available for sale in single-dose vials containing 10 mg, 30 mg, and 60 mg of the active ingredient. In addition to lyophilized carfilzomib, each vial also contains sodium hydroxide for pH adjustment, citric acid, and sulfobutyl ether β-cyclodextrin.

[0004] One issue associated with commercially available formulations is that the reconstitution of lyophilized products is complex and cumbersome. Because the reconstitution process is complex, it involves aseptically reconstitution of each vial by slowly injecting sterile water for injection through the stopper, guiding the water to the inner wall of the vial to ensure minimal foam formation. If foaming occurs, one must wait for the foam to settle and subside until the solution becomes clear. Furthermore, in reconstituted products, visual inspection of the solution before administration is crucial; if the reconstituted solution appears to have any discoloration or particulate matter, it must be discarded. Additionally, it is known that excessive foaming can lead to loss of efficacy.

[0005] Efforts have been made to obtain improved carfilzomib compositions. For example, substituted cyclodextrin additives have been explored to enhance the solubility of carfilzomib.

[0006] Developing cost-effective, room-temperature stable carfilzomib injections is highly challenging due to its sensitivity to degradation. Improved carfilzomib formulations with enhanced ease of manufacture, route of administration, and stability over time, particularly when stored at room temperature, remain needed. Summary of the Invention

[0007] One object of the present invention is to provide a room-temperature stable, dilution-type injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof.

[0008] Another object of the present invention is to provide a method for treating patients with multiple myeloma by administering a room-temperature stable, i.e., dilute, injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof.

[0009] Furthermore, the object of the present invention is to provide a method for treating patients with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution, and then diluting the reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof; and component 2 is an acidifier.

[0010] In one aspect, 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.

[0011] In one aspect, the present invention provides a carfilzomib formulation that is stable at room temperature and is stable for a period of at least one month when stored at 25°C, wherein the formulation has a total impurity content of no more than 6%, preferably no more than 5%, preferably no more than 4%, preferably no more than 3%, preferably no more than 2%, preferably no more than 1.5%, preferably no more than 1%, preferably no more than 0.5%. Detailed Implementation

[0012] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” used in the specification and appended claims include plural references.

[0013] As used herein, the term “about” means a deviation of ±5% from the stated value.

[0014] As used herein, the terms “optional” or “optionally” mean that the events or circumstances described below may or may not occur.

[0015] The formulations of this invention comprise "carfilzomib" or a pharmaceutically acceptable derivative thereof. The pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, solvates, hydrates, anhydrous forms, enantiomers, isomers, polymorphs, tautomers, or mixtures thereof.

[0016] Pharmaceutically acceptable salts are those that retain the desired biological activity of the parent compound without conferring undesirable toxicological effects. Examples of such salts include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid; salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, methanesulfonic acid, p-toluenesulfonic 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.

[0017] The term "stable formulation" or "stabilized formulation" refers to any formulation of carfilzomib that has sufficient physical and chemical stability to allow it to be stored at a convenient temperature for a reasonable period of time.

[0018] As used in this article, the term "room temperature" refers to a temperature of approximately 15°C to approximately 40°C.

[0019] As used herein, the term "carfilzomib impurity" refers to any compound produced by the chemical degradation of carfilzomib. Exemplary degradation pathways include, but are not limited to, hydrolysis, oxidation, epimerization of amides and / or epoxides, and products resulting from ethylene oxide ring-opening with various nucleophiles.

[0020] As used herein, the term "ready-to-dilute" refers to a formulation that can be directly combined with an infusion medium (e.g., dextran solution, water for injection, Ringer's solution, isotonic sodium chloride solution, a suitable non-aqueous solvent, or any other infusion medium) and then administered to a patient with carfilzomib or a pharmaceutically acceptable derivative thereof. In some embodiments, the ready-to-dilute formulation may be provided in a single vial containing an injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof. Optionally, the ready-to-dilute formulation may be further diluted with other suitable excipients prior to combination with an infusion medium.

[0021] As used herein, the term "component 1" refers to a diluted formulation of carfilzomib or a pharmaceutically acceptable derivative thereof.

[0022] As used herein, the term "component 2" refers to an acidifier that, together with component 1, is reconstituted to form a reconstituted, i.e., diluted formulation, which may optionally be further added to or mixed into the infusion medium. Component 2 is used in the form of a clear solution or powder.

[0023] As used herein, the term "reconstituted ready to dilute" refers to a formulation of carfilzomib or a pharmaceutically acceptable derivative thereof obtained by mixing component 1 and component 2 prior to addition to the infusion medium.

[0024] The term "ready to use" refers to any formulation of carfilzomib or its pharmaceutically acceptable derivatives that can be given directly to a patient without any further dilution or processing.

[0025] The formulations of the present invention are injectable formulations. Injectable formulations of carfilzomib or its pharmaceutically acceptable derivatives according to the present invention can be administered via any route, including intramuscular, intravenous, or subcutaneous. Preferably, the injectable formulations of the present invention can be administered intravenously. Formulations of carfilzomib or its pharmaceutically acceptable derivatives can be in the form of liquid concentrates, i.e., diluted or ready-to-use solutions. Injectable formulations can be packaged in conventional sterile vials or other suitable sterile containers.

[0026] In one embodiment, the room-temperature stable, dilution-type injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof comprises 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 is one having a carfilzomib concentration of about 10 mg / mL or about 60 mg / mL.

[0027] In one embodiment, the present invention provides a room-temperature stable injectable diluent formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof and one or more solvents. In one embodiment, the diluent composition may comprise one or more solvents selected from ethanol, isopropanol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide (DMA), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), diethylene glycol monoethyl ether, caprylocaproyl polyoxyl-8 glycerides, tetrahydrofuran polyethylene glycol ether, or mixtures thereof. In a preferred embodiment, the formulation may comprise ethanol, dimethylacetamide, propylene glycol, polyethylene glycol, or mixtures thereof. In one embodiment, the ratio of the one or more solvents used to carfilzomib or a pharmaceutically acceptable derivative thereof may vary from about 100:1 to 8:1.

[0028] 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.

[0029] 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 oxide, such as PEG 300 or PEG 400. Pharmaceutically acceptable surfactants used in this application include, but are not limited to, polysorbates or polyethoxylated castor oil, polyoxyethylene 20 stearate, polyoxyethylene 35 castor oil, poloxamer, polyoxyethylene sorbitan monoisostearate, and polyethylene glycol 40 sorbitan diisostearate. diisostearate), polyoxyethylene 40 hydrogenated castor oil, polysorbate, polysorbate 20, polysorbate 40, polyoxyethylene 60 stearate, polysorbate 80, polysorbate 60, poloxamer 331, polyoxyethylene fatty acid ester, polyoxyethylene 40 castor oil, poloxamer 188, polyoxyethylene polyoxypropylene 1800, oleic acid, sodium deoxycholate, sodium lauryl sulfate, dehydrated sorbitol monolaurate, dehydrated sorbitol monooleate, dehydrated sorbitol monopalmitate, dehydrated sorbitol trioleate, N-carbamoyl methoxy polyethylene glycol 2000-1,2-Distearol, Myristic Acid, Stearyl Alcohol, Stearic Acid, Polyoxyethylene 40 Stearate, Sucrose Stearate, Tocopherol, Triglyceride Synthesis, Trimyristate, Tristearate, Magnesium Stearate, Lecithin, Lauryl Sulfate, Vitamin E, Vitamin E-TPGS, Egg Yolk Lecithin, Sodium Docusate, Dimyristicophosphatidylglycerin, Dimyristicolecithin, Capryol 90 (Propylene Glycol Monocaprylate), Capryol PGMC (Propylene Glycol Monocaprylate), Deoxycholate, Cholesterol, Polyoxyethylene Castor Oil (Cremophor EL), Propylene Glycol Alginate, Croval A-10 (PEG 60 Almond Glyceryl Ester), Labrafil 1944 (Oleoyl Polyethylene Glycol-6 Glyceryl Ester) Macrogol-6-glyceride), Labrafil 2125 (linoleoyl macrogol-6-glyceride), Labrasol (caprylocaproyl macrogol-8-glyceride), Lauroglycol 90 (propylene glycol monolaurate), Lauroglycol FCC (propylene glycol laurate), calcium stearate, lecithin Centromix E, lecithin Centrophase 152, lecithin Centrol 3F21B, POE 26-glycerol, Olepal isosteariques (PEG-6 isostearate), Plurol diisostearique (polyglycerol-3-diisostearate), Plurol Oleique CC, POE20 sorbitol trioleate, Tagat TO (polyoxyethylene glycerol trioleate) or Solutol (polyethylene glycol-15-hydroxy stearate, macrogol-15-hydroxy stearate). In some embodiments, the surfactant optionally constitutes about 10% to about 90% of the total weight of the diluent formulation, preferably about 20% to about 80% of the total weight of the diluent formulation, and more preferably about 30% to about 60% of the total weight of the diluent formulation.

[0030] The formulation may contain a buffer selected from mixtures of weak acids and alkali metal salts (e.g., sodium, potassium) and conjugate bases of weak acids. Suitable buffers include, for example, those 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, galacturonic acid, lactic acid, lactobionic acid, edetric acid, gentian acid, metaphosphoric acid, nitric acid, pentilic acid, glycolic acid, and their counter-ion salts.

[0031] The formulation may contain one or more antioxidants selected from butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and C.-tocopherol, DL-tocopherol, C.-tocopheryl acetate, C.-tocopherol-tocopheryl polyethylene glycol succinate (vitamin E TPGS), L-cysteine, ascorbyl palmitate thioglycolic acid, sodium metabisulfite (SMBS), ascorbic acid, sodium formaldehyde sulfoxylate, or hydrophilic antioxidants including sodium EDTA and thioglycerol. Most typically, the concentration of the antioxidant is from 0.005% (w / w) to 5% (w / w) of the total composition.

[0032] The formulation may contain a preservative selected from phenol, thimerosal, chlorobutanol, benzyl alcohol, m-cresol, phenoxyethanol, methylparaben, and propylparaben, typically at a concentration of about 0.001% (by weight) to about 5% (by weight) of the total composition, and most typically about 0.003% (by weight) to about 2.0% (by weight) of the total composition.

[0033] The formulation may contain an acidifier 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, galacturonic acid, lactic acid, lactobionic acid, edemaic acid, gentianic acid, metaphosphoric acid, nitric acid, pentimic acid, and glycolic acid. The purpose of using an acidifier in this invention is to maintain an acidic pH, thereby allowing carfilzomib or its pharmaceutically acceptable salts to dissolve in the infusion medium. Additionally, the purpose of using an acidifier in this invention is to prevent drug precipitation in the infusion medium.

[0034] Some compounds have been identified as impurities obtained from carfilzomib degradation, and stability samples have been analyzed, such as [acid impurity] (S)-2-((S)-4-methyl-2-((S)-2-(2-morpholinoacetamyl)-4-phenylbutamido)pentamido)-3-phenylpropionic acid; [diasteremeric impurity] (S)-4-methyl-N-((R)-1-(((S)-4-methyl-1-((R)-2- Methylethylene oxide-2-yl)-1-oxopentane-2-yl)amino)-1-oxo-3-phenylpropane-2-yl)-2-((S)-2-(2-morpholinoacetamyl)-4-phenylbutamido)pentanamide; [phenol impurity] 2,3,4,5,6-pentafluorophenol; [diol impurity] (S)-N-((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxo (Heptane-4-yl)amino)-1-oxo-3-phenylpropane-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamyl)-4-phenylbutamido)pentanamide; [Chlorine impurity](S)-N-((S)-1-(((2S,4S)-1-chloro-2-hydroxy-2,6-dimethyl-3-oxoheptane-4-yl)amino)-1-oxo-3-phenylpropane-2-yl)-4-methyl -2-((S)-2-(2-morpholinoacetamido)-4-phenylbutamido)pentanamide; [N-oxide impurity]4-((4S,7S,10S,13S)-10-benzyl-7-isobutyl-15-methyl-13-((R)-2-methylethylene oxide-2-carbonyl)-2,5,8,11-tetraoxo-4-phenylethyl-3,6,9,12-tetraazahexadecyl)morpholin-4-oxide.

[0035] In one embodiment, the room-temperature stable formulation contains no more than 6% of the total impurities formed during the storage period. In another embodiment, the room-temperature stable formulation contains no more than 5% of the total impurities formed during the storage period. In another embodiment, the room-temperature stable formulation contains no more than 4% of the total impurities formed during the storage period. In another embodiment, the room-temperature stable formulation contains no more than 3% of the total impurities formed during the storage period. In another embodiment, the room-temperature stable formulation contains no more than 2% of the total impurities formed during the storage period. In another embodiment, the room-temperature stable formulation contains no more than 1% of the total impurities formed during the storage period. In another embodiment, the room-temperature stable formulation contains no more than 0.5% of the total impurities formed during the storage period. In one embodiment, the storage period of the formulation of the present invention can be a reasonable period during which the formulation has sufficient chemical and physical stability. The storage period can be selected, for example, at least about one month, at least about three months, at least about six months, at least about one year, or at least about two years.

[0036] In one embodiment, a room-temperature stable formulation refers to any carfilzomib formulation having sufficient stability to allow storage at room temperature, such as from about 15°C to about 40°C; preferably from about 20°C to about 40°C; more preferably from about 25°C to about 40°C; and most preferably from about 20°C to about 25°C. It should be understood that the stability of the carfilzomib formulation within the temperature range of the stated embodiments is always accompanied by an additional parameter of 60% humidity. In a preferred embodiment of the invention, the stability of the room-temperature stable formulation can be evaluated at 25°C and 60% relative humidity after storing the formulation of the invention in a sealed, sterile container.

[0037] In one embodiment, the present invention provides a room-temperature stable carfilzomib formulation that is stable for at least one month when stored at 40°C and 75% relative humidity. In another embodiment, the present invention provides a room-temperature stable carfilzomib formulation that is stable for at least three months when stored at 40°C and 75% relative humidity. In yet another embodiment, the present invention provides a room-temperature stable carfilzomib formulation that is stable for at least six months when stored at 40°C and 75% relative humidity. In yet another embodiment, the present invention provides a room-temperature stable carfilzomib formulation that is stable for at least one year when stored at 40°C and 75% relative humidity.

[0038] In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and remains stable for at least two years when stored at 40°C and 75% relative humidity. The stability of the formulation is measured by the amount of total impurities formed at the end of the stability period. In one embodiment, stability is achieved when the impurities formed during the specified stability period do not exceed 6%, preferably not more than 5%, preferably not more than 4%, preferably not more than 3%, preferably not more than 2%, preferably not more than 1.5%, preferably not more than 1%, preferably not more than 0.5%.

[0039] In one embodiment, after storage at 75% RH and 40°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 6% as determined by HPLC. In another embodiment, after storage at 75% RH and 40°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 5% as determined by HPLC. In yet another embodiment, after storage at 75% RH and 40°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 4% as determined by HPLC. In yet another embodiment, after storage at 75% RH and 40°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 3% as determined by HPLC. In yet another embodiment, after storage at 75% RH and 40°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 2% as determined by HPLC. In yet another embodiment, after storage at 75% RH and 40°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 1.5% as determined by HPLC. In one embodiment, after storage at 75% RH and 40°C for one month, the carfilzomib composition can have a total impurity content of no more than 1% as determined by HPLC. In another embodiment, after storage at 75% RH and 40°C for one month, the carfilzomib composition can have a total impurity content of no more than 0.5% as determined by HPLC.

[0040] In one embodiment, after storage at 75% RH and 40°C for three months, the carfilzomib composition exhibits a total impurity content of no more than 6% as determined by HPLC. In another embodiment, after storage at 75% RH and 40°C for three months, the carfilzomib composition exhibits a total impurity content of no more than 5% as determined by HPLC. In yet another embodiment, after storage at 75% RH and 40°C for three months, the carfilzomib composition exhibits a total impurity content of no more than 4% as determined by HPLC. In yet another embodiment, after storage at 75% RH and 40°C for three months, the carfilzomib composition exhibits a total impurity content of no more than 3% as determined by HPLC. In yet another embodiment, after storage at 75% RH and 40°C for three months, the carfilzomib composition exhibits a total impurity content of no more than 2% as determined by HPLC. In yet another embodiment, after storage at 75% RH and 40°C for three months, the carfilzomib composition exhibits a total impurity content of no more than 1.5% as determined by HPLC. In one embodiment, after storage at 75% RH and 40°C for three months, the carfilzomib composition can have a total impurity content of no more than 1% as determined by HPLC. In another embodiment, after storage at 75% RH and 40°C for three months, the carfilzomib composition can have a total impurity content of no more than 0.5% as determined by HPLC.

[0041] In one embodiment, after storage for six months at 75% RH and 40°C, the carfilzomib composition exhibits a total impurity content of no more than 6% as determined by HPLC. In another embodiment, after storage for six months at 75% RH and 40°C, the carfilzomib composition exhibits a total impurity content of no more than 5% as determined by HPLC. In yet another embodiment, after storage for six months at 75% RH and 40°C, the carfilzomib composition exhibits a total impurity content of no more than 4% as determined by HPLC. In yet another embodiment, after storage for six months at 75% RH and 40°C, the carfilzomib composition exhibits a total impurity content of no more than 3% as determined by HPLC. In yet another embodiment, after storage for six months at 75% RH and 40°C, the carfilzomib composition exhibits a total impurity content of no more than 2% as determined by HPLC. In yet another embodiment, after storage for six months at 75% RH and 40°C, the carfilzomib composition exhibits a total impurity content of no more than 1.5% as determined by HPLC. In one embodiment, after storage for six months at 75% RH and 40°C, the carfilzomib composition can have a total impurity content of no more than 1% as determined by HPLC. In another embodiment, after storage for six months at 75% RH and 40°C, the carfilzomib composition can have a total impurity content of no more than 0.5% as determined by HPLC.

[0042] In one embodiment, the present invention provides a room-temperature stable carfilzomib formulation that is stable for at least one month when stored at 25°C and 60% relative humidity. In another embodiment, the present invention provides a room-temperature stable carfilzomib formulation that is stable for at least three months when stored at 25°C and 60% relative humidity. In yet another embodiment, the present invention provides a room-temperature stable carfilzomib formulation that is stable for at least six months when stored at 25°C and 60% relative humidity. In yet another embodiment, the present invention provides a room-temperature stable carfilzomib formulation that is stable for at least one year when stored at 25°C and 60% relative humidity.

[0043] In one embodiment, the present invention provides a carfilzomib formulation that is stable at room temperature and remains stable for at least two years when stored at 25°C and 60% relative humidity. The stability of the formulation is measured by the amount of total impurities formed at the end of the stability period. In one embodiment, stability is achieved when the impurities formed during the specified stability period do not exceed 6%, preferably not more than 5%, preferably not more than 4%, preferably not more than 3%, preferably not more than 2%, preferably not more than 1.5%, preferably not more than 1%, and preferably not more than 0.5%.

[0044] In one embodiment, after storage at 60% RH and 25°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 6% as determined by HPLC. In another embodiment, after storage at 60% RH and 25°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 5% as determined by HPLC. In another embodiment, after storage at 60% RH and 25°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 4% as determined by HPLC. In another embodiment, after storage at 60% RH and 25°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 3% as determined by HPLC. In another embodiment, after storage at 60% RH and 25°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 2% as determined by HPLC. In yet another embodiment, after storage at 60% RH and 25°C for one month, the carfilzomib composition exhibits a total impurity content of no more than 1.5% as determined by HPLC. In one embodiment, after storage at 60% RH and 25°C for one month, the carfilzomib composition can have a total impurity content of no more than 1% as determined by HPLC. In another embodiment, after storage at 60% RH and 25°C for one month, the carfilzomib composition can have a total impurity content of no more than 0.5% as determined by HPLC.

[0045] In one embodiment, after storage for three months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 6% as determined by HPLC. In another embodiment, after storage for three months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 5% as determined by HPLC. In yet another embodiment, after storage for three months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 4% as determined by HPLC. In yet another embodiment, after storage for three months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 3% as determined by HPLC. In yet another embodiment, after storage for three months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 2% as determined by HPLC. In yet another embodiment, after storage for three months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 1.5% as determined by HPLC. In one embodiment, after storage for three months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 1% as determined by HPLC. In another embodiment, after storage for three months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 0.5% as determined by HPLC.

[0046] In one embodiment, after storage for six months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 6% as determined by HPLC. In another embodiment, after storage for six months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 5% as determined by HPLC. In yet another embodiment, after storage for six months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 4% as determined by HPLC. In yet another embodiment, after storage for six months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 3% as determined by HPLC. In yet another embodiment, after storage for six months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 2% as determined by HPLC. In yet another embodiment, after storage for six months at 60% RH and 25°C, the carfilzomib composition exhibits a total impurity content of no more than 1.5% as determined by HPLC. In one embodiment, after storage for six months at 60% RH and 25°C, the carfilzomib composition can have a total impurity content of no more than 1% as determined by HPLC. In another embodiment, after storage for six months at 60% RH and 25°C, the carfilzomib composition can have a total impurity content of no more than 0.5% as determined by HPLC.

[0047] 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.

[0048] 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.

[0049] 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 dilution, a ready-to-use formulation, and a liquid concentrate. In a preferred embodiment, the injectable formulation of the present invention comprises a room-temperature stable dilution solution.

[0050] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents.

[0051] In one embodiment, the present invention provides a room-temperature stable, dilution-compatible 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.

[0052] In one embodiment, the present invention provides a room-temperature stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 6% total impurities after one month of storage.

[0053] In one embodiment, the present invention provides a room-temperature stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 5% total impurities after one month of storage.

[0054] In one embodiment, the present invention provides a room-temperature stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 4% total impurities after one month of storage.

[0055] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 3% total impurities after one month of storage.

[0056] In one embodiment, the present invention provides a room-temperature stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 2% total impurities after one month of storage.

[0057] In one embodiment, the present invention provides a room-temperature stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 1.5% total impurities after one month of storage.

[0058] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 1.0% total impurities after one month of storage.

[0059] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 0.5% total impurities after one month of storage.

[0060] In one embodiment, the present invention provides a stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof and one or more solvents; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 6% total impurities after one month of storage.

[0061] In one embodiment, the present invention provides a stable, dilution-compatible 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 6% total impurities after one month of storage.

[0062] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 5% total impurities after one month of storage.

[0063] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 4% total impurities after one month of storage.

[0064] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 3% total impurities after one month of storage.

[0065] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 2% total impurities after one month of storage.

[0066] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 1.5% total impurities after one month of storage.

[0067] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 1.0% total impurities after one month of storage.

[0068] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 0.5% total impurities after one month of storage.

[0069] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 6% total impurities after three months of storage.

[0070] In one embodiment, the present invention provides a room-temperature stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 5% total impurities after three months of storage.

[0071] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 4% total impurities after three months of storage.

[0072] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 3% total impurities after three months of storage.

[0073] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 2% total impurities after three months of storage.

[0074] In one embodiment, the present invention provides a room-temperature stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 1.5% total impurities after three months of storage.

[0075] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 1.0% total impurities after three months of storage.

[0076] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 0.5% total impurities after three months of storage.

[0077] In one embodiment, the present invention provides a stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof and one or more solvents; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 6% total impurities after three months of storage.

[0078] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 6% total impurities after three months of storage.

[0079] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 5% total impurities after three months of storage.

[0080] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 4% total impurities after three months of storage.

[0081] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 3% total impurities after three months of storage.

[0082] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 2% total impurities after three months of storage.

[0083] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 1.5% total impurities after three months of storage.

[0084] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 1.0% total impurities after three months of storage.

[0085] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 0.5% total impurities after three months of storage.

[0086] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 6% total impurities after six months of storage.

[0087] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 5% total impurities after six months of storage.

[0088] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 4% total impurities after six months of storage.

[0089] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 3% total impurities after six months of storage.

[0090] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 2% total impurities after six months of storage.

[0091] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 1.5% total impurities after six months of storage.

[0092] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 1.0% total impurities after six months of storage.

[0093] In one embodiment, the present invention provides a room-temperature stable, dilution-type injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 0.5% total impurities after six months of storage.

[0094] In one embodiment, the present invention provides a stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable derivative thereof and one or more solvents; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 6% total impurities after six months of storage.

[0095] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 6% total impurities after six months of storage.

[0096] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 5% total impurities after six months of storage.

[0097] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 4% total impurities after six months of storage.

[0098] In one embodiment, the present invention provides a stable, dilution-compatible 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 3% total impurities after six months of storage.

[0099] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 2% total impurities after six months of storage.

[0100] In one embodiment, the present invention provides a stable, dilution-compatible 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 1.5% total impurities after six months of storage.

[0101] In one embodiment, the present invention provides a stable, dilutionable 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 1.0% total impurities after six months of storage.

[0102] In one embodiment, the present invention provides a stable, dilution-compatible 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; wherein, when stored at 25°C and 60% relative humidity, the formulation contains no more than 0.5% total impurities after six months of storage.

[0103] Having stable, room-temperature injectable formulations is always desirable and beneficial, offering commercial and handling advantages compared to formulations stored under stringent conditions (e.g., 2–8°C). However, obtaining injectable formulations that are stable at room temperature and have fewer impurities or impurity levels within the limits acceptable to drug approval authorities is very challenging.

[0104] During stability studies, it was surprisingly found that the instantaneous dilution injectable solution without an acidifier had a significantly better impurity profile than the instantaneous dilution injectable solution with an acidifier. Therefore, compared to the formulation without an acidifier, the acidifier negatively impacts the stability of the formulation at room temperature and generates more impurities during the stable period. The better impurity profile described in this invention includes the difference in total impurities obtained during the stable period when the formulation sample is analyzed by HPLC.

[0105] In one embodiment, the present invention provides a room-temperature stable injectable formulation comprising carfilzomib and its pharmaceutically acceptable salts, which is free of any acidifiers.

[0106] In one embodiment, the present invention provides a room-temperature stable injectable formulation comprising carfilzomib and its pharmaceutically acceptable salts, which does not contain any acidifiers during the stability period of the formulation.

[0107] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib and a pharmaceutically acceptable salt thereof; one or more solvents; and optionally one or more excipients selected from antioxidants, buffers, and surfactants; and which is free of any acidifiers during the stability period of the formulation.

[0108] In one embodiment, the present invention provides a room-temperature stable, dilution-based injectable formulation comprising carfilzomib and a pharmaceutically acceptable salt thereof; one or more solvents; and optionally one or more excipients selected from antioxidants, buffers, and surfactants; and which is free of any acidifiers during the stability period of the formulation.

[0109] In one embodiment, the present invention relates to the delivery of a room-temperature stable injectable, i.e., diluted formulation of carfilzomib, which, once diluted to an appropriate injection (particularly infusion, most particularly intravenous infusion) concentration, can be administered in an appropriate amount for the treatment of carfilzomib-responsive conditions known in the art.

[0110] In one embodiment, the present invention provides a method for treating patients with relapsed or refractory multiple myeloma by administering, in combination with dexamethasone or lenalidomide plus dexamethasone, or by administering alone, a room-temperature stable, dilute, or ready-to-use parenteral formulation of carfilzomib.

[0111] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a room-temperature stable, dilutionable injectable formulation of carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein the formulation contains no more than 6% total impurities after the expiration of its shelf life. In one embodiment, the method for treating a patient with relapsed or refractory multiple myeloma comprises administering a formulation of carfilzomib or a pharmaceutically acceptable salt thereof, the formulation containing no more than 5% total impurities after the expiration of its shelf life. In one embodiment, the method for treating a patient with relapsed or refractory multiple myeloma comprises administering a formulation of carfilzomib or a pharmaceutically acceptable salt thereof, the formulation containing no more than 4% total impurities after the expiration of its shelf life. In one embodiment, the method for treating a patient with relapsed or refractory multiple myeloma comprises administering a formulation of carfilzomib or a pharmaceutically acceptable salt thereof, the formulation containing no more than 3% total impurities after the expiration of its shelf life. In one embodiment, a method of treating a patient with relapsed or refractory multiple myeloma includes administering a formulation of carfilzomib or a pharmaceutically acceptable salt thereof, said formulation containing no more than 2% total impurities after the expiration of its shelf life. In one embodiment, a method of treating a patient with relapsed or refractory multiple myeloma includes administering a formulation of carfilzomib or a pharmaceutically acceptable salt thereof, said formulation containing no more than 1.5% total impurities after the expiration of its shelf life. In one embodiment, a method of treating a patient with relapsed or refractory multiple myeloma includes administering a formulation of carfilzomib or a pharmaceutically acceptable salt thereof, said formulation containing no more than 1% total impurities after the expiration of its shelf life. In one embodiment, a method of treating a patient with relapsed or refractory multiple myeloma includes administering a formulation of carfilzomib or a pharmaceutically acceptable salt thereof, said formulation containing no more than 0.5% total impurities after the expiration of its shelf life.

[0112] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a room-temperature stable, dilutionable injectable formulation of carfilzomib or a pharmaceutically acceptable salt thereof, wherein the dilutionable injectable formulation is stable for one month of storage at 25°C and 60% relative humidity. Preferably, in one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a room-temperature stable, dilutionable injectable formulation of carfilzomib or a pharmaceutically acceptable salt thereof, wherein the dilutionable injectable formulation is stable for three months of storage at 25°C and 60% relative humidity. More preferably, in one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a room-temperature stable, dilutionable injectable formulation of carfilzomib or a pharmaceutically acceptable salt thereof, wherein the dilutionable injectable formulation is stable for six months of storage at 25°C and 60% relative humidity.

[0113] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, i.e., diluted solution, comprising mixing component 1 and component 2 and then diluting with an infusion medium; wherein component 1 comprises a room-temperature stable, i.e., diluted parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier.

[0114] In one embodiment of the invention, component 2 comprises an acidifying agent, which may be selected from citric acid, malic acid, phosphoric acid, orthophosphoric acid (OPA), fumaric acid, or mixtures thereof. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof, based on w / w, is from about 1:50 to about 1:1. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof, based on w / w, is from about 1:40 to about 1:1. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof, based on w / w, is from about 1:30 to about 1:1. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof, based on w / w, is from about 1:20 to about 1:1. In one embodiment, the ratio of the acidifying agent used to carfilzomib or a pharmaceutically acceptable salt thereof, based on w / w, is from about 1:10 to about 1:1.

[0115] Adding component 2 to component 1 allows carfilzomib or a pharmaceutically acceptable salt thereof to readily degrade in an immediate-dilute parenteral solution at room temperature. In one embodiment, when the mixture of components 1 and 2 is stored at room temperature, it should not be used after 4 hours of mixing. In a preferred embodiment, when the mixture of components 1 and 2 is stored at room temperature, it should not be used after 5 hours of mixing. In a preferred embodiment, when the mixture of components 1 and 2 is stored at room temperature, it should not be used after 6 hours of mixing.

[0116] In a preferred embodiment, when the mixture of component 1 and component 2 is stored at 2-8°C, the mixture should not be applied to the infusion medium 24 hours after mixing.

[0117] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture of components 1 and component 2 is stored at room temperature, the mixture should not be used for administration after 4 hours of mixing.

[0118] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture of components 1 and component 2 is stored at room temperature, the mixture should not be used for administration after 5 hours of mixing.

[0119] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture of components 1 and component 2 is stored at room temperature, the mixture should not be used for administration after 6 hours of mixing.

[0120] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture is stored at room temperature, the reconstituted, dilute composition has no more than 2% total impurities for up to 4 hours after mixing.

[0121] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture is stored at room temperature, the reconstituted, dilute composition has no more than 1% total impurities for up to 4 hours after mixing.

[0122] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture is stored at room temperature, the reconstituted, dilute composition has no more than 2% total impurities for up to 5 hours after mixing.

[0123] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture is stored at room temperature, the reconstituted, dilute composition has no more than 1% total impurities for up to 5 hours after mixing.

[0124] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture is stored at room temperature, the reconstituted, dilute composition has no more than 2% total impurities for up to 6 hours after mixing.

[0125] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 is a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein, when the mixture is stored at room temperature, the reconstituted, dilute composition has no more than 1% total impurities for up to 6 hours after mixing.

[0126] In one embodiment, the present invention provides a method for treating a patient with relapsed or refractory multiple myeloma, the method comprising administering a reconstituted, dilute solution, comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier; and wherein when the mixture of components 1 and component 2 is stored at 2-8°C, the mixture is no longer used for administration 24 hours after mixing.

[0127] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral formulation of carfilzomib or a pharmaceutically acceptable salt thereof, and component 2 is an acidifier.

[0128] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and contains no more than 6% total impurities after six months of storage at 25°C and 60% relative humidity; and component 2 is an acidifier.

[0129] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and contains no more than 5% total impurities after six months of storage at 25°C and 60% relative humidity; and component 2 is an acidifier.

[0130] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and contains no more than 4% total impurities after six months of storage at 25°C and 60% relative humidity; and component 2 is an acidifier.

[0131] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and contains no more than 3% total impurities after six months of storage at 25°C and 60% relative humidity; and component 2 is an acidifier.

[0132] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and contains no more than 2% total impurities after six months of storage at 25°C and 60% relative humidity; and component 2 is an acidifier.

[0133] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and contains no more than 1.5% total impurities after six months of storage at 25°C and 60% relative humidity; and component 2 is an acidifier.

[0134] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and contains no more than 1% total impurities after six months of storage at 25°C and 60% relative humidity; and component 2 is an acidifier.

[0135] In one embodiment, the present invention provides a method for administering a reconstituted, dilute solution, the method comprising mixing component 1 and component 2 to form a reconstituted, dilute solution with an infusion medium; wherein component 1 comprises a room-temperature stable, dilute, parenteral preparation of carfilzomib or a pharmaceutically acceptable salt thereof, and contains no more than 0.5% total impurities after six months of storage at 25°C and 60% relative humidity; and component 2 is an acidifier.

[0136] The following embodiments are provided for the purpose of illustrating the present invention and should not be considered as limiting the scope of the present invention.

[0137] Example 1: Preparation of Carfilzomib Formulation

[0138] Ingredients (batch number) APPL-006 / 01 / 068 Carfilzomi 30mg orthophosphoric acid 10μL dimethylacetamide 500μL Dehydrated alcohol (ethanol) 500μL

[0139] process:

[0140] 1. Place a portion of dimethylacetamide in a container, add weighed carfilzomib, and mix under nitrogen purging and sodium vapor lamp with continuous stirring;

[0141] 2. Add the dehydrated alcohol to the above solvent system and mix until a clear solution is obtained;

[0142] 3. Add the weighed phosphoric acid while continuously stirring, and mix thoroughly;

[0143] 4. Make up the final volume with dimethylacetamide and mix thoroughly to form a homogeneous solution;

[0144] 5. The product was filtered through a 0.22μ filter and filled into vials.

[0145] Example 2: Preparation of Carfilzomib Formulation

[0146] Ingredients (batch number) APPL-006 / 01 / 033 Carfilzomi 10mg Propylene glycol 425μL Polysorbate 80 300μL α-Tocopherol 0.2mg lactic acid qs to pH 3-4 DMA 200μL

[0147] process:

[0148] 1. Mix propylene glycol and polysorbate 80 at 2-8℃ for 10 minutes;

[0149] 2. Add α-tocopherol to the above mixture;

[0150] 3. Adjust the pH of the solution to 3-4 (3.5) using lactic acid;

[0151] 4. Add the mixture of carfilzomib and dimethylacetamide to step 3 and mix until a clear solution is obtained;

[0152] 5. Nitrogen purging and photoprotection were performed at 2-8℃ throughout the entire batch preparation process;

[0153] 6. Filter the product through a 0.22 μL filter, fill the vial, and seal.

[0154] Example 2A: Preparation of Carfilzomib Formulation

[0155] Example 2A was prepared in a similar manner to that shown in Example 2.

[0156] Ingredients (batch number) APPL-006 / 01 / 035 Carfilzomi 10mg Propylene glycol Qs to 1mL Polysorbate 80 300μL α-Tocopherol 0.2mg lactic acid qs to pH 3-4 dimethylacetamide 200μL Water for Injection 30mg

[0157] Example 2B: Preparation of Carfilzomib Formulation

[0158] Example 2B was prepared in a similar manner to that shown in Example 2.

[0159] Ingredients (batch number) APPL-006 / 01 / 036 Carfilzomi 10mg Propylene glycol Qs to 1mL Polysorbate 80 300μL lactic acid qs to pH 3-4 dimethylacetamide 200μL Butylated hydroxytoluene 0.02mg

[0160] Example 2C: Preparation of Carfilzomib Formulation

[0161] Example 2C was prepared in a similar manner to that shown in Example 2.

[0162] Ingredients (batch number) APPL-006 / 01 / 037 Carfilzomi 10mg Propylene glycol Qs to 1mL Polysorbate 80 300μL lactic acid qs to pH 3-4 dimethylacetamide 200μL Water for Injection 30mg Butylated hydroxytoluene 0.02mg

[0163] Example 3: Preparation of Carfilzomib Formulation

[0164] Ingredients (batch number) APPL-006 / 01 / 069 Carfilzomi 30mg dimethylacetamide 500μL Dehydrated alcohol (ethanol) 500μL

[0165] process:

[0166] 1. Mix dimethylacetamide and dehydrated alcohol thoroughly at room temperature under nitrogen purging and sodium vapor lamp;

[0167] 2. Add carfilzomib to the above solvent system and mix until completely dissolved;

[0168] 3. The product was filtered through a 0.22μ filter and filled into vials.

[0169] Example 4: Preparation of Carfilzomib Formulation

[0170] Formulations T1 to T4 were prepared using a process similar to that described in Example 3.

[0171] Element T1 T2 T3 T4 Carfilzomi 10 mg 30mg 60mg 100mg dimethylacetamide -- -- 1000μL 1000μL Dehydrated alcohol (ethanol) 1000μL 1000μL --- ---

[0172] Example 5: Preparation of Carfilzomib Formulation

[0173] Ingredients (batch number) APPL-006 / 01 / 062 Carfilzomi 10mg Propylene glycol 440μL Polysorbate 80 300μL α-Tocopherol 0.2mg dimethylacetamide 250μL Water for Injection 30μL

[0174] process:

[0175] 1. Place dimethylacetamide in a suitable container and maintain the temperature at 2-8℃;

[0176] 2. Add α-tocopherol in step 1;

[0177] 3. Add carfilzomib to the DMA and tocopherol mixture from step 2 and mix thoroughly until completely dissolved;

[0178] 4. Add water for injection and polysorbate 80 to step 3 above, and mix thoroughly until a homogeneous solution is obtained;

[0179] 5. Make up the volume with propylene glycol and mix until a homogeneous solution is obtained;

[0180] 6. The entire process was completed under nitrogen purging and sodium vapor lamp conditions;

[0181] 7. The product was filtered through a 0.22μ filter and filled into vials.

[0182] Example 5A:

[0183] Example 5A was prepared in a similar manner to that shown in Example 5.

[0184] Ingredients (batch number) APPL-006 / 01 / 058 Carfilzomi 30mg Polysorbate 80 300μL α-Tocopherol 0.2mg lactic acid Qs to pH 3-4 dimethylacetamide 250μL Water for Injection 30mg Super Refined PG Qs to 1mL

[0185] Example 5B:

[0186] Example 5B was prepared in a similar manner to that shown in Example 5.

[0187] Ingredients (batch number) APPL-006 / 01 / 059 Carfilzomi 10mg Polysorbate 80 300μL α-Tocopherol 0.2mg HCL Qs to pH 3-4 DMA 250μL Water for Injection 30mg Super Refined PG Qs to 1mL

[0188] Table 1: Stability of the formulations prepared in Examples 5A and 5B

[0189]

[0190]

[0191] Example 6: Preparation of Carfilzomib Formulation

[0192] The formulation in this embodiment was prepared using a process similar to that described in Example 5.

[0193] Ingredients (batch number) APPL-006 / 01 / 070 Carfilzomi 15mg Propylene glycol 220μL Polysorbate 80 210μL α-Tocopherol 0.2mg dimethylacetamide 275μL Dehydrated alcohol (ethanol) 275μL

[0194] Example 6A: Preparation of Carfilzomib Formulation

[0195] Ingredients (batch number) APPL-006 / 01 / 078 Carfilzomi 30mg α-Tocopherol 0.5mg Dehydrated alcohol (ethanol) Qs to 1mL

[0196] 1. Place sufficient ethanol in the manufacturing container;

[0197] 2. Add the weighed α-tocopherol while continuously stirring until a homogeneous solution is obtained, and record the description.

[0198] 3. Add the weighed carfilzomib while stirring continuously until a homogeneous solution is obtained, and record the description.

[0199] 4. Make up the final volume with ethanol and stir until a homogeneous solution is obtained;

[0200] 5. Filter the bulk through a 0.22μPTFE filter and fill it into vials.

[0201] Example 6B: Preparation of Carfilzomib Formulation

[0202] Ingredients (batch number) APPL-006 / 01 / 087 Carfilzomi 30mg α-Tocopherol 0.5mg dimethylacetamide 200μL Dehydrated alcohol (ethanol) Qs to 1mL

[0203] 1. Place sufficient N,N-dimethylacetamide in a manufacturing container;

[0204] 2. Add the weighed α-tocopherol while stirring continuously until a homogeneous solution is obtained, and record the description.

[0205] 3. Add the weighed carfilzomib while stirring continuously until a homogeneous solution is obtained, and record the description.

[0206] 4. Make up the final volume with ethanol and stir until a homogeneous solution is obtained;

[0207] 5. Filter the bulk material through a 0.22μPTFE filter and fill it into a vial.

[0208] Example 7:

[0209] Table 2: Comparison of the stability of the formulations prepared in Examples 1, 2, 3 and 5

[0210]

[0211] *RT indicates room temperature (stability test parameters: temperature 25℃ and relative humidity 60%), *ND indicates not detected, and *NMT indicates not exceeding.

[0212] Example 8: Preparation and stability data of injectable compositions with acidifiers.

[0213] Element Qty / ml Carfilzomi 30mg α-Tocopherol 0.5mg orthophosphoric acid 15μL Deethanol qs to 1mL

[0214] process:

[0215] 1. Place 80% of the required amount of dehydrated ethanol in a clean container;

[0216] 2. Add the required amount of carfilzomib to the solvent from step 1 at 2-8℃ and dissolve it with a mechanical stirrer until a clear solution is observed;

[0217] 3. At 2-8℃, add the required amount of α-tocopherol while stirring as in step 2, until a clear solution is observed;

[0218] 4. At 2-8℃, add the required amount of phosphoric acid while stirring as in step 3, until a clear solution is observed;

[0219] 5. Prepare the final batch size with the required amount of dimethylacetamide and mix it thoroughly at 2-8℃;

[0220] 6. Filter the bulk solution using a 0.2μPTFE filter;

[0221] 7. Fill the amber vial, then cover it with nitrogen and seal it properly with a rubber stopper;

[0222] 8. The vials maintain thermal stability at 25°C and 60% RH and 2-8°C.

[0223] Table 3: Stability data of injectable compositions containing acidifiers

[0224]

[0225] Example 9: Preparation of injectable compositions and stability data before and after mixing with acidifiers

[0226] Element Qty / ml Carfilzomi 30mg dimethylacetamide 500μL Dehydrated alcohol (ethanol) 500μL

[0227] process:

[0228] 1. Place 80% of the required amount of dimethylacetamide in a clean container;

[0229] 2. At 2-8°C, add the required amount of carfilzomib from step 1 and dissolve it with a mechanical stirrer until a clear solution is observed;

[0230] 3. At 2-8℃, add the required amount of dehydrated ethanol while stirring as in step 2, until a clear solution is observed;

[0231] 4. Prepare the final batch size with the required amount of dimethylacetamide and mix it thoroughly at 2-8℃;

[0232] 5. Filter the bulk solution using a 0.2 μPTFE filter;

[0233] 6. Fill the amber vial, then cover it with nitrogen and seal it properly with a rubber stopper;

[0234] 7. The vials maintain thermal stability at 25°C / 60%RH and 2-8°C.

[0235] Table 4: Stability data of injectable compositions before mixing with acidifier

[0236]

[0237] *NP = Not performed

[0238] Table 5: The process of mixing the acidifier into the dilution composition:

[0239]

[0240] 1. Aseptically mix vials 1 and 2 according to Table 3 above;

[0241] 2. Gently rotate and / or slowly invert the bottle for about 1 minute;

[0242] 3. Visually inspect for particulate matter and discoloration before mixing; the diluted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, the product should not be mixed.

[0243] 4. Dilute the mixed product solution from step 3 with sterile water for injection to concentrations of 0.5 mg / mL and 1.5 mg / mL, and test the solution stability at 25°C and 2-8°C.

[0244] Table 6: Stability data of injectable compositions after mixing with acidifiers (concentrations of 0.5 mg / mL and 1.5 mg / mL)

[0245]

[0246] Example 10: Preparation of injectable compositions and stability data before and after mixing with acidifiers

[0247] Element Qty / ml Carfilzomi 60mg dimethylacetamide 1000μL

[0248] process:

[0249] 1. Place 80% of the required amount of dimethylacetamide in a clean container;

[0250] 2. At 2-8°C, add the required amount of carfilzomib from step 1 and dissolve it using a mechanical stirrer;

[0251] 3. Prepare the final batch size with the required amount of dimethylacetamide and mix thoroughly at 2-8°C;

[0252] 4. Filter the bulk solution using a 0.2μPTFE filter;

[0253] 5. Fill the amber vial, then cover it with nitrogen and seal it properly with a rubber stopper;

[0254] 6. The vials maintain thermal stability at 25°C / 60%RH, 2-8°C and 40°C / 75%RH.

[0255] Table 7: Stability data of injectable compositions before mixing with acidifier

[0256]

[0257] *ND = Not detected

[0258] Table 8: Process of incorporating acidifiers into dilutable compositions

[0259]

[0260] 1. Aseptically mix vials 1 and 2 according to the table above;

[0261] 2. Gently rotate and / or slowly invert the bottle for about 1 minute;

[0262] 3. Visually inspect for particulate matter and discoloration before mixing; the diluted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, it should not be mixed with the infusion solution.

[0263] 4. Dilute the mixed product solution with sterile water for injection to concentrations of 0.5 mg / mL and 1.5 mg / mL, and test the solution stability at 25°C and 2-8°C.

[0264] Table 9: Stability data for injectable compositions after mixing of acidifiers (concentrations of 0.5 mg / mL and 1.5 mg / mL)

[0265]

[0266] Example 11: Preparation of Carfilzomib Formulation

[0267] Ingredients (batch number) APPL-006 / 01 / 062 Carfilzomi 10mg NN DMA 250mg Polysorbate 80 300μL α-Tocopherol 0.2mg Water for Injection 30mg Ultra-refined propylene glycol Qs to 1mL

[0268] process:

[0269] 1. Place a standard amount of N,N-dimethylacetamide in a manufacturing container at a temperature of 2-8℃;

[0270] 2. Add the weighed batch amount of α-tocopherol while continuously stirring until a homogeneous solution is obtained;

[0271] 3. Add the weighed batch amount of carfilzomib while stirring continuously until completely dissolved;

[0272] 4. Add the weighed batch amount of water for injection while continuously stirring until a homogeneous solution is obtained;

[0273] 5. Add the weighed batch amount of polysorbate 80 while continuously stirring until a homogeneous solution is obtained;

[0274] 6. Make up the final volume with ultra-refined PG and stir until a homogeneous solution is obtained;

[0275] 7. Filter the bulk material through a 0.22μPTFE filter and fill it into a vial.

[0276] Example 12: Preparation of Carfilzomib Formulation

[0277] Ingredients (batch number) APPL-006 / 01 / 063 Carfilzomi 10mg Polysorbate 80 300μL α-Tocopherol 0.2mg Ethanol (dehydrated alcohol) 500mg Water for Injection 30mg Ultra-refined propylene glycol Qs to 1mL

[0278] process:

[0279] 1. Place a standard amount of ethanol in a manufacturing container at a temperature of 2-8℃;

[0280] 2. Add the weighed batch amount of α-tocopherol while continuously stirring until a homogeneous solution is obtained;

[0281] 3. Add the weighed batch amount of carfilzomib while stirring continuously until completely dissolved;

[0282] 4. Add the weighed batch amount of water for injection while continuously stirring until a homogeneous solution is obtained;

[0283] 5. Add the weighed batch amount of polysorbate 80 while continuously stirring until a homogeneous solution is obtained;

[0284] 6. Make up the final volume with ultra-refined PG and stir until a homogeneous solution is obtained;

[0285] 7. Filter the bulk material through a 0.22μPTFE filter and fill it into a vial.

[0286] Example 13: Preparation of Carfilzomib Formulation

[0287] Ingredients (batch number) APPL-006 / 01 / 066C Carfilzomi 10mg Polysorbate 80 300mg α-Tocopherol 0.2mg Orthophosphoric acid (OPA) QS to pH 5-6 dimethylacetamide 250mg Water for Injection 30mg Ultra-refined propylene glycol QS to 1mL

[0288] process:

[0289] 1. Place a standard amount of dimethylacetamide in a manufacturing container at a temperature of 2-8℃;

[0290] 2. Add the weighed batch amount of α-tocopherol while continuously stirring until a homogeneous solution is obtained;

[0291] 3. Add the weighed batch amount of polysorbate 80 while stirring continuously until completely dissolved;

[0292] 4. Add the weighed batch amount of water for injection while continuously stirring until a homogeneous solution is obtained;

[0293] 5. Add the weighed batch amount of ultrapure PG while continuously stirring until a homogeneous solution is obtained;

[0294] 6. Add the weighed batch amount of carfilzomib while continuously stirring until a homogeneous solution is obtained;

[0295] 7. Make up the final volume with ultra-refined PG and stir until a homogeneous solution is obtained;

[0296] 8. Filter the bulk material through a 0.22μPTFE filter and fill it into a vial.

[0297] Example 14: Preparation of Carfilzomib Formulation

[0298] Ingredients (batch number) APPL-006 / 01 / 067 Carfilzomi 10mg Polysorbate 80 300mg α-Tocopherol 0.2mg Orthophosphoric acid (OPA) QS to pH 5-6 Water for Injection 30mg Ultra-refined propylene glycol QS to 1mL ethanol 400mg

[0299] process:

[0300] 1. Place a standard amount of ethanol in a manufacturing container at a temperature of 2-8℃;

[0301] 2. Add the weighed batch amount of α-tocopherol while continuously stirring until a homogeneous solution is obtained;

[0302] 3. Add the weighed batch amount of polysorbate 80 while stirring continuously until completely dissolved;

[0303] 4. Add the weighed batch amount of water for injection while continuously stirring until a homogeneous solution is obtained;

[0304] 5. Add the weighed batch amount of ultrapure PG while continuously stirring until a homogeneous solution is obtained;

[0305] 6. Add the weighed batch amount of carfilzomib while continuously stirring until a homogeneous solution is obtained;

[0306] 7. Make up the final volume with ultra-refined PG and stir until a homogeneous solution is obtained;

[0307] 8. Filter the bulk material through a 0.22μPTFE filter and fill it into a vial.

[0308] Example 15: Preparation of Carfilzomib Formulation

[0309] Ingredients (batch number) APPL-006 / 01 / 102 Carfilzomi 60mg N,N-DMA QS to 1mL

[0310] process:

[0311] 1. Place 90% N,N-dimethylacetamide in a manufacturing container at a temperature of 2-8℃;

[0312] 2. Add the weighed batch amount of carfilzomib while continuously stirring until a homogeneous solution is obtained;

[0313] 3. Make up the final volume with N,N-dimethylacetamide and stir until a homogeneous solution is obtained;

[0314] 4. Filter the bulk material through a 0.22μPTFE filter and fill it into vials.

[0315] Example 16: Preparation of Carfilzomib Formulation

[0316] Ingredients (batch number) APPL-006 / 01 / 103 Carfilzomi 30mg N,N DMA 500μL ethanol QS to 1mL

[0317] process:

[0318] 1. Place the weighed batch amount of N,N-dimethylacetamide into the manufacturing container at a temperature of 2-8℃;

[0319] 2. Add the weighed batch amount of carfilzomib while continuously stirring until a homogeneous solution is obtained;

[0320] 3. Make up the final volume with ethanol and stir until a homogeneous solution is obtained;

[0321] 4. Filter the bulk material through a 0.22μPTFE filter and fill it into vials.

[0322] Example 17: Preparation of Carfilzomib Formulation

[0323] Batch specifications: 50mL batch number APPL-006 / 01 / 105 Element Quantitative (mg / mL) Carfilzomi 60.0 N,N-Dimethylacetamide QS to mL

[0324] process:

[0325] 1. Place 80% N,N-dimethylacetamide in a manufacturing container at a temperature of 2-8℃;

[0326] 2. Add the weighed batch amount of carfilzomib while continuously stirring until a homogeneous solution is obtained;

[0327] 3. Make up the final volume with N,N-dimethylacetamide and stir until a homogeneous solution is obtained;

[0328] 4. Filter the bulk material through a 0.22μPTFE filter and fill it into vials.

[0329] Table 10: Thermal stability and analysis results of APPL-006 / 01 / 105

[0330]

[0331] NMT: Not exceeding, ND - Not detected

[0332] Example 18: Preparation of Carfilzomib Formulation

[0333] Batch specifications: 50mL batch number APPL-006 / 01 / 106 Element Quantitative (mg / mL) Carfilzomi 30.0 N,N-Dimethylacetamide QS to mL ethanol 500.0μL

[0334] process:

[0335] 1. Place the weighed batch amount of N,N-dimethylacetamide into the manufacturing container at a temperature of 2-8℃;

[0336] 2. Add the weighed batch amount of carfilzomib while continuously stirring until a homogeneous solution is obtained;

[0337] 3. Make up the final volume with ethanol and stir until a homogeneous solution is obtained;

[0338] 4. Filter the bulk material through a 0.22μPTFE filter and fill it into vials.

[0339] Table 11: Thermal stability and analysis results of APPL-006 / 01 / 106

[0340]

[0341] NMT: Not exceeding, ND - Not detected

Claims

1. A room-temperature stable, dilution-compatible injectable formulation comprising carfilzomib or a pharmaceutically acceptable salt thereof and one or more solvents; wherein, The formulation contains no more than 3% total impurities when stored at 25°C and 60% relative humidity for three months; wherein the formulation does not contain any acidifying agents during the stable period, and the solvent is selected from dimethylacetamide, or a combination of dimethylacetamide with ethanol or propylene glycol.

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

3. The room-temperature stable, dilution-type injectable formulation according to claim 2, wherein, The concentration of carfilzomib or its pharmaceutically acceptable salt is in the range of 10 mg / mL to 60 mg / mL.

4. The room-temperature stable, dilution-type injectable formulation of claim 1, further comprising one or more pharmaceutically acceptable excipients selected from antioxidants, buffers, preservatives, and surfactants.

5. The room-temperature stable, dilution-type injectable formulation according to claim 1, wherein, The formulation contains no more than 3% total impurities when stored for at least six months.

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

1.

7. The room-temperature stable, dilution-type injectable formulation according to claim 4, wherein, The antioxidant is selected from hydrophilic antioxidants.

8. The room-temperature stable, dilution-type injectable formulation according to claim 4, wherein, The antioxidants are selected from butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, 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, sodium EDTA, and thioglycerol.

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

10. The room-temperature stable, dilution-type injectable formulation according to claim 1, wherein, The formulation contains no more than 2% total impurities after the expiration of its storage period.

11. The room-temperature stable, dilution-type injectable formulation according to claim 1, wherein, The formulation contains no more than 1.5% total impurities after the expiration of its storage period.

12. The room-temperature stable, dilution-type injectable formulation according to claim 1, wherein, The formulation contains no more than 1% total impurities after the expiration of its storage period.

13. The room-temperature stable, dilution-type injectable formulation according to claim 1, wherein, The formulation contains no more than 0.5% total impurities after the expiration of its storage period.

14. Use in the preparation of a medicament for the treatment of patients with relapsed or refractory multiple myeloma in one or more solvents, carfilzomib, or a pharmaceutically acceptable salt thereof, at room temperature, as a dilution-resistant injectable formulation; wherein, The formulation contains no more than 3% total impurities when stored at 25°C and 60% relative humidity for at least three months; wherein the formulation does not contain any acidifiers during the stability period, and the solvent is selected from dimethylacetamide, or a combination of dimethylacetamide with ethanol or propylene glycol.

15. Use of the formulation according to claim 14, wherein, The dilutable injectable formulation is stable for up to six months when stored at 25°C and 60% relative humidity.

16. The use of reconstituted, i.e., diluted formulations in the preparation of medicaments for the treatment of patients with relapsed or refractory multiple myeloma, wherein, Component 1 and Component 2 are mixed to form a reconstituted, dilutable formulation, which is then diluted with an infusion medium. Component 1 comprises a room-temperature stable, dilutable formulation of one or more solvents, carfilzomib, or a pharmaceutically acceptable salt thereof, and contains no more than 3% total impurities after three months of storage at 25°C and 60% relative humidity. Component 1 is free of any acidifiers during its stability period. Component 2 is an acidifier, and the solvent is selected from dimethylacetamide, or a combination of dimethylacetamide with ethanol or propylene glycol.

17. Use of the reconstituted, i.e., diluted formulation according to claim 16, wherein, The concentration of carfilzomib or its pharmaceutically acceptable salts contained is in the range of 10 mg / mL to 60 mg / mL.

18. Use of the reconstituted, i.e., diluted formulation according to claim 16, wherein, The ratio (w / w) of the acidifier in component 2 to carfilzomib or a pharmaceutically acceptable salt thereof in component 1 is selected from 1:50 to 1:

1.

19. The use of the reconstituted, i.e., diluted formulation according to claim 16, wherein, Component 1 comprises a room-temperature stable, i.e., diluted parenteral preparation of one or more solvents, carfilzomib, or a pharmaceutically acceptable salt thereof, and contains no more than 3% total impurities after six months of storage when stored at 25°C and 60% relative humidity, wherein the solvent is selected from dimethylacetamide, or a combination of dimethylacetamide with ethanol or propylene glycol.

20. Use of the reconstituted, i.e., diluted formulation according to claim 16, wherein the formulation comprises component 1, which, when stored at 25°C and 60% relative humidity, contains no more than 2% total impurities after a storage period of six months.

21. Use of the reconstituted, i.e., diluted formulation according to claim 16, wherein the formulation comprises component 1, which, when stored at 25°C and 60% relative humidity, contains no more than 1.5% total impurities after a storage period of six months.

22. Use of the reconstituted, i.e., diluted formulation according to claim 16, wherein the formulation comprises component 1, which, when stored at 25°C and 60% relative humidity, contains no more than 1% total impurities after a storage period of six months.

23. Use of the reconstituted, i.e., diluted formulation according to claim 16, wherein the formulation comprises component 1, which, when stored at 25°C and 60% relative humidity, contains no more than 0.5% total impurities after a storage period of six months.

24. The use of the reconstituted, i.e., diluted formulation according to claim 16, wherein the formulation comprises component 2 as an acidifying agent, wherein, The acidifying agent is 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, galacturonic acid, lactic acid, lacturonic acid, edetic acid, gentian acid, metaphosphoric acid, nitric acid, penti acid, glycolic acid, or mixtures thereof.

25. Use of the reconstituted, dilutable formulation in the preparation of a medicament for treating patients with relapsed or refractory multiple myeloma, comprising mixing component 1 and component 2 to form the reconstituted, dilutable formulation with an infusion medium; wherein, Component 1 is a room-temperature stable, dilute parenteral preparation of one or more solvents, carfilzomib, or a pharmaceutically acceptable salt thereof, containing no more than 3% total impurities when stored at 25°C and 60% relative humidity for three months, wherein component 1 does not contain any acidifiers during the stability period; component 2 is an acidifier, and wherein, when the mixture is stored at room temperature, the reconstituted dilute composition contains no more than 2% total impurities for up to 6 hours after mixing, wherein the solvent is selected from dimethylacetamide, or a combination of dimethylacetamide with ethanol or propylene glycol.

26. Use of the reconstituted, i.e., diluted formulation according to claim 25, wherein, When the mixture is stored at room temperature, the reconstituted, diluted composition contains no more than 1% total impurities for up to 6 hours after mixing.

27. Use of the reconstituted, i.e., diluted formulation according to claim 25, wherein, When the mixture is stored at room temperature, the reconstituted, diluted composition contains no more than 2% total impurities for up to 5 hours after mixing.

28. Use of the reconstituted, i.e., diluted formulation according to claim 25, wherein, When the mixture is stored at room temperature, the reconstituted, diluted composition contains no more than 1% total impurities for up to 5 hours after mixing.

29. Use of the reconstituted, i.e., diluted formulation according to claim 25, wherein, When the mixture is stored at room temperature, the reconstituted, diluted composition contains no more than 2% total impurities for up to 4 hours after mixing.

30. Use of the reconstituted, i.e., diluted formulation according to claim 25, wherein, When the mixture is stored at room temperature, the reconstituted, diluted composition contains no more than 1% total impurities for up to 4 hours after mixing.

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