Carfilzomib-containing pharmaceutical composition

Abstract

To provide a novel pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof, enabling solubilization and stabilization in water of carfilzomib or the pharmaceutically acceptable salt thereof.SOLUTION: According to the present invention, there is provided a carfilzomib-containing pharmaceutical composition, comprising carfilzomib or a pharmaceutically acceptable salt thereof, a cyclodextrin, and an acid, wherein the acid is one or more selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or is an acid in an amount of 3.7 molar equivalents or more based on 1 molar equivalent of carfilzomib or the pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention belongs to the technical field of pharmaceutical preparations. The present invention relates to a carfilzomib-containing pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof in the technical field, and more particularly to a carfilzomib-containing pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof as an active ingredient, mainly comprising carfilzomib or a pharmaceutically acceptable salt thereof, cyclodextrins, and a certain acid. [Background technology]

[0002] Carfilzomib, whose chemical name is N-[(2S)-2-[(morpholin-4-ylacetyl)amino]-4-phenylbutanoyl]-L-leucyl-L-phenylalanine-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amide, is a compound having the structure shown in (1) below. Carfilzomib is a peptide proteasome inhibitor that is manufactured, sold, and used as Kyprolis® Intravenous Infusion 10 mg to 40 mg for the treatment of relapsed or refractory multiple myeloma.

[0003] [ka]

[0004] Carfilzomib is a compound that is practically insoluble in water, making it difficult to formulate into intravenous or injectable formulations. It is known that carfilzomib's aqueous solubility increases with decreasing pH (solubility at pH 5: 0.002 mg / mL, at pH 3: 0.02 mg / mL, at pH 1: 1.8 mg / mL). However, carfilzomib is prone to hydrolysis into peptide fragments at lower pH levels, and the relatively unstable epoxy ring is prone to cleavage at lower pH levels. Therefore, formulation strategies to both solubilize carfilzomib in water and stabilize it are necessary.

[0005] In Patent Document 1, a suspension of carfilzomib and cyclodextrin, particularly a substituted cyclodextrin, is prepared, and a specific acid, specifically an aqueous solution of citric acid, is added to the suspension to form a complex between carfilzomib and cyclodextrin, thereby solubilizing and stabilizing carfilzomib in water. In Patent Document 2, cyclodextrin is not used, and carfilzomib is solubilized and stabilized in water using a certain injectable organic solvent or the like.

[0006] The commercially available carfilzomib formulation is a lyophilized formulation for intravenous infusion, with each vial containing 10 mg (actual fill amount: 10.7 mg) or 40 mg (actual fill amount: 42.6 mg) of carfilzomib, and for each dose, 533 mg or 2130 mg of sulfobutyl ether β-cyclodextrin sodium, 10.2 mg or 40.9 mg of anhydrous citric acid, and an appropriate amount of pH adjuster. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 6410264 (Special Publication No. 2015-516430) [Patent Document 2] Special Publication No. 2023-509518 Summary of the Invention [Problem to be solved by the invention]

[0008] A primary object of the present invention is to provide a novel pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof, which is solubilized and stabilized in water by a formulation technique different from that of the invention of Patent Document 1, while using cyclodextrin, as in the invention of Patent Document 1. [Means for solving the problem]

[0009] As a result of extensive research, the present inventors have found that the above problems can be solved by adjusting the type and amount of acid, and have thus completed the present invention.

[0010] The present invention can include, for example, the following aspects. [1] A pharmaceutical composition comprising carfilzomib or a pharmaceutically acceptable salt thereof, a cyclodextrin, and an acid, wherein the acid is one or more selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or the acid is present in an amount of 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof. [2] The carfilzomib-containing pharmaceutical composition according to [1] above, wherein the acid is an acid in an amount within the range of 3.7 to 15 molar equivalents per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof. [3] The carfilzomib-containing pharmaceutical composition according to [1] or [2] above, wherein the acid has a pKa1 in water of 4.8 or less. [4] The carfilzomib-containing pharmaceutical composition according to [1] or [2] above, wherein the cyclodextrins are β-cyclodextrins. [5] The carfilzomib-containing pharmaceutical composition according to [4] above, wherein the β-cyclodextrin is sulfobutyl ether β-cyclodextrin or a pharmaceutically acceptable salt thereof. [6] The carfilzomib-containing pharmaceutical composition according to [1] or [2] above, which contains 30 to 80 parts by weight of the cyclodextrin per 1 part by weight of carfilzomib or a pharmaceutically acceptable salt thereof. [7] The carfilzomib-containing pharmaceutical composition according to [1] or [2] above, which is in the form of a lyophilized formulation or a lyophilized cake thereof. [8] The carfilzomib-containing pharmaceutical composition according to [7] above, which can be dissolved within 2 minutes and 30 seconds when a lyophilized formulation or a lyophilized cake thereof is added with water in an amount equivalent to 5 mL per 10 mg of carfilzomib or a pharmaceutically acceptable salt thereof.

[0011] [9] A method for producing a pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof, comprising the step of preparing an aqueous solution in which carfilzomib or a pharmaceutically acceptable salt thereof, a cyclodextrin, and an acid are dissolved, wherein the acid in this step is one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or an acid in an amount of 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

[10] A method for producing the carfilzomib-containing pharmaceutical composition according to [9] above, further comprising the steps of adjusting the pH of the aqueous solution to within the range of 3.0 to 4.0 with a base, lyophilizing the aqueous solution whose pH has been adjusted with a base, and / or sterilizing the aqueous solution before lyophilization.

[11] The method for producing a carfilzomib-containing pharmaceutical composition according to [9] or

[10] above, wherein the acid has a pKa1 in water of 4.8 or less.

[12] The method for producing a carfilzomib-containing pharmaceutical composition according to [9] or

[10] above, wherein the cyclodextrins are β-cyclodextrins.

[13] The method for producing a carfilzomib-containing pharmaceutical composition according to

[12] above, wherein the β-cyclodextrin is sulfobutyl ether β-cyclodextrin or a pharmaceutically acceptable salt thereof.

[14] The method for producing a carfilzomib-containing pharmaceutical composition according to [9] or

[10] above, wherein the cyclodextrin is blended in an amount of 30 to 80 parts by weight per part by weight of carfilzomib or a pharmaceutically acceptable salt thereof.

[0012]

[15] A method for improving the solubility in water of a pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof, the method comprising the step of preparing an aqueous solution in which carfilzomib or a pharmaceutically acceptable salt thereof and a cyclodextrin are dissolved, using one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or 3.7 molar equivalents or more of an acid per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

[16] The method according to

[15] above, further comprising the steps of adjusting the pH of the aqueous solution to within the range of 3.0 to 4.0 with a base, freeze-drying the aqueous solution whose pH has been adjusted with a base, and / or sterilizing the aqueous solution before freeze-drying.

[0013]

[17] A method for improving the solubility of carfilzomib or a pharmaceutically acceptable salt thereof in water, the method comprising using one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or an acid in an amount of 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, and a cyclodextrin when dissolving carfilzomib or a pharmaceutically acceptable salt thereof in water. [Effects of the Invention]

[0014] According to the present invention, a new method can be used to solubilize and stabilize carfilzomib or a pharmaceutically acceptable salt thereof in water, thereby enabling the production of a novel pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof. Furthermore, depending on the embodiment of the present invention, the object of the present invention can be achieved with a relatively small amount of acid. [Brief explanation of the drawings]

[0015] [Figure 1]This shows a freeze-dried cake of the carfilzomib-containing pharmaceutical composition of the present invention (top row), the reconstitution time (minutes / seconds) with water for injection (middle row), and the state of the reconstituted solution when diluted with 5% glucose solution (bottom row). [Figure 2] This shows a freeze-dried cake of the carfilzomib-containing pharmaceutical composition of the present invention (top row), the reconstitution time (minutes / seconds) with water for injection (middle row), and the state of the reconstituted solution when diluted with 5% glucose solution (bottom row). DETAILED DESCRIPTION OF THE INVENTION

[0016] 1. Carfilzomib-containing pharmaceutical composition according to the present invention The pharmaceutical composition of the present invention containing carfilzomib or a pharmaceutically acceptable salt thereof (hereinafter referred to as the "composition of the present invention") is a pharmaceutical composition comprising carfilzomib or a pharmaceutically acceptable salt thereof, a cyclodextrin, and an acid, wherein the acid is one or more selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or the acid is present in an amount of 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

[0017] 1.1 About Carfilzomib The composition of the present invention comprises carfilzomib or a pharmaceutically acceptable salt thereof. Carfilzomib is the active ingredient in the composition of the present invention and is an active ingredient for treating diseases such as multiple myeloma. Carfilzomib is a known organic compound having the structure of the structural formula (I) with the chemical name above. Carfilzomib is already known, and its molecular weight is 719.91 and its pKa1 is 5.14. It is also a compound that is almost insoluble in water for injection. Its production method and other aspects are also known, and it is easily available to those skilled in the art.

[0018] The salt of carfilzomib is not particularly limited as long as it is a pharmaceutically acceptable acid addition salt, and examples thereof include salts with inorganic acids and salts with organic acids. Specific examples of the acid addition salt include salts with inorganic acids such as hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, and nitrate; and salts with organic acids such as acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, amino acid salts, and besylate.

[0019] A salt of carfilzomib can be obtained, for example, by reacting the free form of carfilzomib with a desired inorganic acid or organic acid in an appropriate solvent by a conventional method, and isolating and purifying the resulting salt.

[0020] The content of carfilzomib or a pharmaceutically acceptable salt thereof in the composition of the present invention varies depending on the type and amount of the desired cyclodextrin and acid, but is suitably, for example, in the range of 0.1 to 50% by mass. The amount is preferably in the range of 1 to 20% by mass, more preferably in the range of 1 to 5% by mass, and even more preferably in the range of 1.0 to 3.5% by mass. If the content of carfilzomib or a pharmaceutically acceptable salt thereof is less than 0.1% by mass, a large amount of the composition of the present invention may need to be administered to the subject to exert its efficacy. If the content is more than 50% by mass, carfilzomib or a pharmaceutically acceptable salt thereof may not be sufficiently solubilized in water.

[0021] 1.2 Cyclodextrins The composition of the present invention contains cyclodextrins (CDs), which can increase the solubility of the active ingredient carfilzomib or a pharmaceutically acceptable salt thereof in water.

[0022] The cyclodextrins are not particularly limited as long as they do not impair the objects or effects of the present invention, and examples thereof include α-cyclodextrins typified by α-cyclodextrin with 6 glucose residues, β-cyclodextrins typified by β-cyclodextrin with 7 glucose residues, and γ-cyclodextrins typified by γ-cyclodextrin with 8 glucose residues. Of these, β-cyclodextrins are preferred in the present invention.

[0023] Cyclodextrins include chemically modified cyclodextrins that have increased water solubility and reduced toxicity, and the use of such chemically modified cyclodextrins is suitable for the present invention. Among these, chemically modified β-cyclodextrins with increased water solubility are preferred. Specific examples of such chemically modified groups include monosaccharides (e.g., glucosyl, maltosyl), carboxyalkyls (e.g., carboxymethyl, carboxyethyl), hydroxyalkyls (e.g., hydroxyethyl, 2-hydroxypropyl), alkyls (e.g., methyl), and sulfoalkyls (e.g., sulfoethyl, sulfobutyl). More specifically, examples of the chemically modified cyclodextrins include 2-hydroxypropyl β-cyclodextrin (HPβCD, degree of substitution: 0.6 to 0.9 units / glucose), 2-hydroxypropyl γ-cyclodextrin (HPγCD, degree of substitution: 0.5 to 0.7 units / glucose), sulfobutyl ether β-cyclodextrin (SBEβCD, degree of substitution: 0.8 to 1 unit / glucose), and pharmaceutically acceptable salts thereof, particularly alkali metal salts (e.g., lithium salt, potassium salt, sodium salt), methyl β-cyclodextrin (degree of substitution: 1.7 to 1.9 units / glucose), and monoacetyl β-cyclodextrin (degree of substitution: 0.8 to 1.2 units / glucose). Among these, SBEβCD or its sodium salt is preferred. The salt may be one type or any two or more types in combination.

[0024] The content of cyclodextrins in the composition of the present invention varies depending on the type of cyclodextrin, but is suitably within the range of 5 to 100 parts by mass, preferably 10 to 80 parts by mass, and more preferably 30 to 60 parts by mass, per part by mass of the contained carfilzomib or a pharmaceutically acceptable salt thereof. If the amount is less than 5 parts by mass per part by mass of the contained carfilzomib or a pharmaceutically acceptable salt thereof, complex formation may not proceed or carfilzomib or a pharmaceutically acceptable salt thereof may not be sufficiently dissolved in water such as water for injection. If the amount is more than 100 parts by mass per part by mass of the contained carfilzomib or a pharmaceutically acceptable salt thereof, the composition may become bulky or the cyclodextrin may not be soluble in water such as water for injection.

[0025] 1.3 Acids The composition of the present invention contains a certain acid. Specifically, the acid is one or more selected from the group consisting of lactic acid (pKa 1:3.86), ascorbic acid (pKa 1:4.2), phosphoric acid (pKa 1:1.97), tartaric acid (pKa 1:2.99), L-aspartic acid (pKa 1:2.09), maleic acid (pKa 1:1.93), acetic acid (pKa 1:4.76), and succinic acid (pKa 1:4.19). Alternatively, the acid is present in an amount of 3.7 molar equivalents or more, or in a range of 3.7 to 15 molar equivalents, or in a range of 5.0 to 15 molar equivalents, relative to 1 molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof. These acids can increase the solubility of the active ingredient, carfilzomib or a pharmaceutically acceptable salt thereof, in water and can provide a preferred composition with excellent pharmaceutical stability.

[0026] Among these acids, lactic acid, ascorbic acid, and phosphoric acid are preferred, as well as acids with a pKa1 of 4.8 or less and at 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, or acids with a pKa1 of 4.8 or less and at 3.7 to 5.0-15 molar equivalents per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof. In particular, lactic acid and phosphoric acid are more preferred. The acid may be used alone or in combination of any two or more kinds.

[0027] The contents of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid in the composition of the present invention vary depending on the type of acid, but are all 2 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, preferably within the range of 3.5 to 15 molar equivalents per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof. The amounts of other acids are 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, preferably within the range of 5.0 to 15 molar equivalents per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

[0028] 1.4 Other ingredients The pH of the aqueous solution of the composition of the present invention is suitably within the range of pH 1.5 to 4, preferably within the range of pH 2 to 3.8, more preferably within the range of pH 3 to 3.6, and particularly preferably pH 3.5. To adjust the pH of the aqueous solution of the composition of the present invention to such a pH, an appropriate basic pH adjuster can be added. The pH adjuster can be any pharmaceutically acceptable inorganic or organic base. Specific examples of inorganic bases include sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, and carbonates or bicarbonates of sodium, potassium, or ammonium. Specific examples of organic bases include organic bases with a pKb of approximately -6 to +10 or pKb 1, such as pyridine, methylamine, triethylamine, imidazole, benzimidazole, histidine, and phosphazene bases. Among these, sodium hydroxide is preferred. The pH adjuster may be used alone or in combination of any two or more kinds.

[0029] In one embodiment of the composition of the present invention, the composition of the present invention may contain water. Such water is essentially a medium and a carrier in the composition of the present invention. Examples of such water include purified water, distilled water, physiological saline, water for injection, and RO water.

[0030] The composition of the present invention may contain, as necessary, pharmaceutically acceptable additives, such as isotonicity agents, excipients, solubilizers, antioxidants, stabilizers, surfactants, soothing agents, and preservatives, provided that the additives do not impair the object or effect of the present invention.

[0031] Examples of isotonic agents or excipients include salts such as sodium chloride, sodium acetate, sodium lactate, sodium tartrate, sodium citrate, sodium salicylate, sodium benzoate, and sodium caprylate; and sugars or sugar alcohols such as mannitol, lactose, sucrose, maltose, trehalose, xylitol, sorbitol, inositol, glucose, fructose, gluconic acid or a salt thereof, meglumine, sucrose, and dextran.

[0032] Examples of solubilizing agents include polyols such as glycerin, thioglycerin, and propylene glycol; polyether compounds such as polysorbate, polyethylene glycol, polypropylene glycol, and polyoxyethylene castor oil; and lecithins such as purified soybean lecithin.

[0033] Antioxidants can include, for example, propyl gallate, ascorbic acid, tocopherol polyethylene glycol succinate, L-cysteine, acetone, potassium metabisulfite, potassium sulfite, ascorbyl palmitate, citric acid, butylated hydroxyanisole, dibutylhydroxytoluene, hypophosphorous acid, monothioglycerol, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, sodium edetate or hydrate thereof, pentetate, and sodium metabisulfite.

[0034] Examples of stabilizers include sodium pyrophosphate, sodium thiosulfate, sodium metasulfobenzoate, sodium ethylenediamine gluconate, potassium L-glutamate, L-lysine-L-glutamate, sodium chondroitin sulfate, albumin, and L-aspartic acid.

[0035] Examples of surfactants include sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene polyoxypropylene glycol, polysorbate, and sodium lauryl sulfate.

[0036] Soothing agents include, for example, lidocaine, procaine, meprylcaine, and benzyl alcohol.

[0037] Examples of preservatives include cresol, phenol, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, benzalkonium chloride, and benzethonium chloride.

[0038] Other additives include, for example, amino acids such as glycine, L-alanine, L-phenylalanine, L-valine, L-leucine, L-isoleucine, taurine, DL-methionine, L-threonine, L-glutamine, sodium L-glutamate, acetyltryptophan, and L-histidine.

[0039] 2. Method of production, reconstitution, and use of the composition of the present invention 2.1 Manufacturing method The composition of the present invention can be produced by a conventional method depending on the embodiment. One embodiment of the present invention is a method for producing a pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof (hereinafter referred to as the "production method of the present invention"), which comprises the step of preparing an aqueous solution in which carfilzomib or a pharmaceutically acceptable salt thereof, a cyclodextrin, and an acid are dissolved, wherein the acid used in this step is one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or an acid in an amount of 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

[0040] The production method of the present invention can further include, for example, a step of adjusting the pH of the aqueous solution to within the range of 3.0 to 4.0 with a base, a step of freeze-drying the aqueous solution whose pH has been adjusted with a base, and / or a step of sterilizing the aqueous solution before freeze-drying. The process of the present invention is particularly useful for producing the composition of the present invention in the form of a freeze-dried preparation or an injection.

[0041] Freeze-drying and sterilization of aqueous solutions can be carried out by conventional methods. Specifically, freeze-drying involves placing the object to be frozen in a freeze-dryer and completely freezing it, followed by primary drying, usually under a vacuum of 0.03 Torr to 0.8 Torr. Secondary drying is carried out at a higher temperature and lower pressure than in the primary drying. After secondary drying is complete, the pressure can be restored to atmospheric pressure or a slightly negative pressure using an inert gas such as nitrogen or dry air. Specific examples of sterilization of aqueous solutions include using a sterile filtration membrane (0.22 μm filter).

[0042] Specifically, one embodiment of the composition of the present invention as a lyophilized preparation can be produced, for example, by a method including the following steps 1 to 5.

[0043] 1: An aqueous solution is prepared in which the desired cyclodextrin and one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or 3.7 molar equivalents or more of an acid per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, are dissolved in water such as water for injection. 2: Subsequently, the desired carfilzomib or a pharmaceutically acceptable salt thereof is dissolved in the aqueous solution obtained in 1 above, and the solution is adjusted to, for example, pH 3.5 with a base such as 1N sodium hydroxide to prepare an aqueous solution in which carfilzomib or a pharmaceutically acceptable salt thereof is dissolved. 3: The aqueous solution obtained in step 2 above is sterilized using a sterile filtration membrane (0.22 μm filter) or the like, and an appropriate amount is filled into vials or the like. 4: The vials are placed in a freeze dryer and completely frozen at a shelf temperature of -45°C, then the shelf temperature is raised to -18°C for primary drying, and then the shelf temperature is raised to 30°C for secondary drying. 5: After secondary drying is complete, restore pressure with nitrogen and seal the vial.

[0044] 2.2 Reconfiguration The composition of the present invention as a lyophilized preparation is usually used by dissolving the dried cake of the lyophilized preparation in an appropriate solvent and reconstituting it. Examples of solvents used for such reconstitution include water for injection (distilled water for injection); electrolyte solutions (e.g., physiological saline, Ringer's solution), nutritional infusions (sugar solutions (e.g., glucose solutions such as 5% (w / v) glucose solution), protein amino acid injections, vitamin injections, etc.), blood substitutes combining electrolyte solutions and nutritional infusions (sugar solutions, etc.), and fat emulsions containing emulsified fat. These solvents may be used alone or in combination with any two or more of them. If necessary, a pH adjuster (e.g., an acidic substance, a weakly basic substance) may be added to the solvent. The composition of the present invention may also be reconstituted by dissolving it in an organic solvent such as ethanol, propylene glycol, or polyethylene glycol. After dissolving it in an organic solvent, it can also be further diluted with the above-mentioned solvents.

[0045] The "electrolyte solution" is a solution in which an electrolyte is dissolved in water for injection, and examples thereof include solutions containing one or more of sodium chloride, potassium chloride, calcium chloride, sodium lactate, sodium dihydrogen phosphate, magnesium carbonate, etc., lactated Ringer's solution, acetated Ringer's solution, etc. A preferred electrolyte solution is a solution containing sodium chloride, and particularly preferred is physiological saline [0.9% (w / v) sodium chloride solution].

[0046] The "sugar solution" is a solution in which a sugar is dissolved in water for injection, and examples thereof include solutions containing one or more of glucose, fructose, sorbitol, mannitol, dextran, etc. Preferred sugar solutions are 5 to 70% (w / v) glucose solutions, and particularly preferred are 5% (w / v) glucose solutions and 10% (w / v) glucose solutions.

[0047] The above-mentioned "protein amino acid injection" is a solution in which an amino acid is dissolved in water for injection, and examples thereof include a solution containing one or more of glycine, aspartic acid, lysine, etc.

[0048] The "vitamin injection" is a solution in which vitamins are dissolved in water for injection, and examples thereof include a solution containing one or more vitamins such as vitamin B1 and vitamin C.

[0049] Preferred solvents used for reconstitution include water for injection, physiological saline, and glucose solution (for example, 5% (w / v) glucose solution).

[0050] 2.3 Purpose (How to use) The composition of the present invention can be used in the treatment of relapsed or refractory multiple myeloma in the same manner and dosage as Kyprolis® for intravenous infusion, but can also be used to treat the following diseases, in the following methods of use, and for the following subjects:

[0051] (1) Treatment for the following diseases: The composition of the present invention can be used, for example, to treat or prevent the following diseases. Proliferative diseases, neurotoxic / degenerative diseases, Alzheimer's disease, ischemic conditions, inflammation, autoimmune diseases, HIV, cancer, organ transplant rejection, septic shock, inhibition of antigen presentation, reduction of viral gene expression, parasitic infections, acidosis-related conditions, macular degeneration, lung diseases, muscle wasting disorders, fibrotic disorders, bone and hair growth disorders.

[0052] The cancers include, for example, diseases of the blood, bone, organs, skin tissue, and vascular system, including cancers of the bladder, blood, bone, brain, breast, chest, colon, esophagus, eye, head, kidney, liver, lung, lymph node, mouth, neck, ovary, pancreas, prostate, rectum, skin, stomach, testicles, throat, and uterus, and specifically, leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell leukemia), mature B-cell neoplasms (small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (e.g., Waldenstrom University Hospital), and other cancers. globulinemia), splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, monoclonal immunoglobulin deposition disease, heavy chain disease, extranodal marginal zone B-cell lymphoma (MALT lymphoma, nodal marginal zone B-cell lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, diffuse B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma and Burkitt's lymphoma / leukemia), mature T-cell and natural killer (NK) cell neoplasms (T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, advanced NK-cell leukemia, adult T-cell neoplasm Follicular leukemia / lymphoma, extranodal NK / T-cell lymphoma, enteropathic T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK-cell lymphoma, mycosis fungoides (Sezary syndrome), primary cutaneous dysplastic large cell lymphoma, lymphomatoid papulosis, angioimmunoblastic T-cell lymphoma, unspecified peripheral T-cell lymphoma and dysplastic large cell lymphoma), Hodgkin lymphoma (nodular sclerosis, mixed cellular solid, lymphocyte-rich, lymphocyte-depleted or non-depleted, nodular lymphocyte-predominant), myeloma (multiple myeloma, indolent myeloma, smoldering myeloma), chronic myeloproliferative disorders, myelodysplasia / Myeloproliferative disorders, myelodysplastic syndromes, immunodeficiency-associated lymphoproliferative disorders, histiocytic and dendritic cell neoplasms, mastocytosis, chondrosarcoma, Ewing's sarcoma, fibrosarcoma, malignant large cell tumor, myeloma bone disease, osteosarcoma, breast cancer (hormone-dependent and hormone-independent), gynecological cancers (cervix, endometrium, fallopian tube, pregnancy-associated disorders, ovary, peritoneal cavity, uterus, vagina and vulva), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, astrocytoma, pilocytic astrocytoma, embryonal teratoma neuroepithelial tumor, oligodendroglioma, ependymoma,Glioblastoma multiforme, mixed glioma, oligoastrocytoma, medulloblastoma, retinoblastoma, neuroblastoma, germinoma, teratoma, malignant mesothelioma (peritoneal mesothelioma, pericardial mesothelioma, pleural mesothelioma), gastric-entero-pancreatic or gastroenteropancreatic duct transneuroendocrine tumor (GEP-NET), carcinoid, pancreatic endocrine tumor (PET), colorectal adenocarcinoma, colorectal carcinoma, advanced neuroendocrine tumor, leiomyosarcoma-mucinous adenocarcinoma, signet ring cell adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hemangioma, hepatic adenoma, focal nodular hyperplasia These include cystic fibrosis (nodular regenerative hyperplasia, hamartoma), non-small cell lung cancer (NSCLC) (squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma), small cell lung carcinoma, thyroid carcinoma, prostate cancer (hormone-refractory, androgen-independent, androgen-dependent, hormone-insensitive), and soft tissue sarcomas (fibrosarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma, liposarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor / neurofibrosarcoma, extraskeletal osteoblastic sarcoma).

[0053] In the present invention, "treatment" refers to directly or indirectly improving, alleviating, curing, or preventing the worsening of a target disease, symptom, or associated symptoms. Specifically, it refers to inhibiting the growth of tumor tissue, reducing its size, inhibiting metastasis, reducing tumor markers, improving the patient's systemic symptoms, extending survival time, etc. "Prevention" refers to treating a patient who is likely to contract a target disease, or exhibit its symptoms, or develop associated symptoms, in order to prevent, delay, or reduce the risk of such development.

[0054] (2) Combination with the composition of the present invention The compositions of the present invention can be used in combination with one or more other proteasome inhibitors, such as the drugs listed below.

[0055] A chemotherapy agent For example, natural products such as vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine); taxanes (e.g., docetaxel, paclitaxel); epidipodophyllotoxins (e.g., teniposide); antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), minomycin; enzymes (e.g., L-asparaginase); antiplatelet agents; antiproliferative / antimitotic agents Alkylating agents, such as nitrogen mustards (e.g., mechlorethamine, ifosfamide, cyclophosphamide and analogs, melphalan, chlorambucil), ethylenimines, methylmelamines (e.g., hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, streptozocin), trazene-dacarbazine (DTIC); antiproliferative / antimitotic antimetabolites, such as folic acid analogs (e.g., methotrexate), Pyrimidine analogues (e.g., fluorouracil, floxuridine, cytarabine), purine analogues and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, 2-chlorodeoxyadenosine); aromatase inhibitors (e.g., anastrozole), exemestane, letrozole); platinum coordination complexes (e.g., cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; DNE-binding / cytotoxic agents (e.g., xalipsis); histone deacetylase (HDA) inhibitors C) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, vorinostat (SAHA), trichostatin A, depsipeptide, apicidin, A-161906, scriptaid, PXD-101, CHAP, butyric acid, depudecin, oxamflatin, phenylbutyrate, valproic acid, panobinostat); hormones (e.g., estrogen), hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, triptorelin).

[0056] b. steroids For example, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednor, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fluclonide, flumethasone, flunisolide, flucinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, Examples include fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexonolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and / or derivatives thereof.

[0057] c. immunotherapeutic agents Examples include MDR modulators (e.g., verapamil, valspolder, bilicordar, taliquidar, laniquidar), cyclosporine, pomalidomide, thalidomide, CC-4047 (Actimid), lenalidomide (Revlimid), and monoclonal antibodies.

[0058] d.Other Examples of such inhibitors include topoisomerase inhibitors (e.g., irinotecan, topotecan, camptothecin, lamellarin D, etoposide), m-TOR inhibitors (e.g., CCI-779, AP23573, RAD-001), protein kinase inhibitors (e.g., sorafenib, imatinib, dasatinib, sunitinib, pazopanib, nilotinib), CDK inhibitors (e.g., dinaciclib), KSP (Eg5) inhibitors (e.g., Array 520), PI13δ inhibitors (e.g., GS-1101PI3K), PI3Kδ·γ inhibitors (e.g., CAL-130), multi-kinase inhibitors (e.g., TG02), and PI3Kδ inhibitors (e.g., TGR-1202).

[0059] (3) Administration route The compositions of the present invention, either as is or in a reconstituted form, can be injected and infused (infused) for example, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, subarachnoidally, intraspinally, and intrasternally.

[0060] (4) Subjects The composition of the present invention can be administered to humans or non-human mammals, including, for example, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, and monkeys.

[0061] (5) Dosage The composition of the present invention varies depending on the target disease or symptom, the subject of administration, the administration method, etc., but for example, the dose of carfilzomib for an adult is usually 1 to 1000 mg / m 2 (body surface area), preferably 10 to 200 mg / m 2 (body surface area), more preferably 20 to 70 mg / m 2 (body surface area). In some cases, it can be administered within 1 mg / m 2 (body surface area) or 1000 mg / m 2 It can be administered in an amount greater than the body surface area. The frequency of administration is usually up to 1 to 4 times a day.

[0062] 3. Method for improving the water solubility of carfilzomib-containing pharmaceutical composition or carfilzomib or a pharmaceutically acceptable salt thereof One aspect of the present invention is a method for improving the water solubility of a carfilzomib-containing pharmaceutical composition (hereinafter referred to as "Solubility Improvement Method A of the Present Invention"), which comprises the steps of preparing an aqueous solution in which carfilzomib or a pharmaceutically acceptable salt thereof and cyclodextrins are dissolved, using one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or using 3.7 molar equivalents or more of an acid per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, and freeze-drying the solution. An example of a method for improving the solubility of carfilzomib or a pharmaceutically acceptable salt thereof in water is a method for improving the solubility of carfilzomib or a pharmaceutically acceptable salt thereof in water (hereinafter referred to as "solubility-improving method B of the present invention" and collectively referred to as "solubility-improving method of the present invention"), which is characterized by using one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or 3.7 molar equivalents or more of an acid per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, and a cyclodextrin when dissolving carfilzomib or a pharmaceutically acceptable salt thereof in water.

[0063] The solubility improving method of the present invention may further include, as necessary, a step of adjusting the pH of an aqueous solution containing carfilzomib or a pharmaceutically acceptable salt thereof with a base to within the range of 3.0 to 4.0, a step of lyophilizing the aqueous solution whose pH has been adjusted with a base, and / or a step of sterilizing the aqueous solution before lyophilization.

[0064] In the solubility improving method of the present invention, the concepts of "carfilzomib," "a pharmaceutically acceptable salt thereof," "cyclodextrins," "3.7 molar equivalents or more of acid per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof," "water," "lyophilization," "sterilization of aqueous solution," and matters related to each component are as defined above.

[0065] Specifically, the solubility improving method A of the present invention can be carried out, for example, by a method including the following steps 1 to 4.

[0066] 1: An aqueous solution is prepared in which the desired cyclodextrin and one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or 3.7 molar equivalents or more of an acid per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, are dissolved in water such as water for injection. 2: Subsequently, the desired carfilzomib or a pharmaceutically acceptable salt thereof is dissolved in the aqueous solution obtained in 1 above, and if necessary, the solution is adjusted to, for example, pH 3.5 with a base such as 1N sodium hydroxide to prepare an aqueous solution in which carfilzomib or a pharmaceutically acceptable salt thereof is dissolved. 3: If necessary, sterilize the aqueous solution obtained in step 2 above using a sterile filtration membrane (0.22 μm filter) or the like, and fill an appropriate amount into vials or the like. 4: Place the above vial in a freeze-dryer and freeze-dry as described above.

[0067] According to the solubility-improving method A of the present invention, the solubility in water (reconstitution liquid) of a pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof can be improved. Alternatively, a pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof with improved solubility in water (reconstitution liquid) can be obtained. Specifically, when an appropriate amount of water (reconstitution liquid) is added to the pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof obtained by the solubility-improving method A of the present invention, the composition of the present invention can be dissolved in water (reconstitution liquid) within 2 minutes 30 seconds or within 1 to 2 minutes.

[0068] Specifically, solubility improving method B of the present invention can be carried out, for example, by dissolving carfilzomib or a pharmaceutically acceptable salt thereof in water using an aqueous solution in which a desired cyclodextrin and one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid are dissolved in water such as water for injection, or an acid in an amount of 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

[0069] According to solubility-improving method B of the present invention, the solubility of carfilzomib or a pharmaceutically acceptable salt thereof in water can be improved. [Example]

[0070] The present invention will be explained below with reference to examples and test examples, but the present invention is not limited to these examples in any way.

[0071] [Examples 1 to 5 and Comparative Example 1] Preparation of carfilzomib-containing pharmaceutical composition Each carfilzomib-containing pharmaceutical composition was prepared according to the formulation in Table 1 below. 5,000 mg of sulfobutyl ether beta-cyclodextrin sodium (SBEβCD) and 500 μmol of acid were dissolved in water for injection. Next, 100 mg of the active compound carfilzomib was dissolved, and the pH was adjusted to 3.5 with 1N sodium hydroxide solution. Water for injection was added to bring the total volume to 20 mL. The resulting solution was sterilized by filtration using a sterile filtration membrane (0.22 μm filter) and filled into vials in 2 mL portions.

[0072] The vial was placed in a freeze-dryer, and the contents were completely frozen with a shelf temperature set to -45°C. The shelf temperature was then raised to -18°C to carry out primary drying. The shelf temperature was then raised to 30°C to complete secondary drying. After drying was complete, the pressure was restored using nitrogen, and the vial was sealed to obtain a freeze-dried formulation (carfilzomib-containing pharmaceutical composition).

[0073] [Table 1]

[0074] [Examples 6 and 7 and Comparative Example 1] Each carfilzomib-containing pharmaceutical composition was prepared according to the formulation in Table 2 below. 5,000 mg of sulfobutyl ether beta-cyclodextrin sodium (SBEβCD) and a predetermined amount of acid were dissolved in water for injection. 100 mg of carfilzomib was then dissolved, and the pH was adjusted to 3.5 with 1N sodium hydroxide solution. Water for injection was added to bring the total volume to 20 mL. The resulting solution was sterilized by filtration using a sterile filtration membrane (0.22 μm filter) and filled into vials in 2 mL portions.

[0075] The vial was placed in a freeze-dryer, and the contents were completely frozen with a shelf temperature set to -45°C. The shelf temperature was then raised to -18°C to carry out primary drying. The shelf temperature was then raised to 30°C to complete secondary drying. After drying was complete, the pressure was restored using nitrogen, and the vial was sealed to obtain a freeze-dried formulation (carfilzomib-containing pharmaceutical composition).

[0076] [Table 2]

[0077] [Test example] Reconstitution test 5 mL of water for injection was added to the freeze-dried preparation prepared in the above Examples or Comparative Examples. The mixture was gently shaken to avoid foaming, and the time until the powder of the freeze-dried preparation was completely dissolved was measured. The dissolution time here corresponds to the reconstitution time of the freeze-dried preparation. The reconstituted aqueous solution was diluted with 50 mL of 5% glucose injection solution, and the dissolution state was confirmed.

[0078] The results are shown in Figures 1 and 2. All freeze-dried formulations dissolved in 5 mL of water for injection within 2 minutes and 30 seconds, and the active ingredient, carfilzomib, was also completely dissolved.

[0079] Although Comparative Example 1 is a known carfilzomib-containing pharmaceutical composition (lyophilized formulation), the present invention is able to solubilize and stabilize carfilzomib in water even with a smaller amount of acid (excluding ascorbic acid) than the amount of acid (citric acid) used in the known carfilzomib-containing pharmaceutical composition, and is also able to provide a carfilzomib-containing lyophilized formulation equivalent to the known lyophilized formulation. [Industrial Applicability]

[0080] The pharmaceutical product of the present invention can be a substitute for the pharmaceutical product manufactured and sold under the trademark Kyprolis (registered trademark), and is therefore useful in the pharmaceutical industry.

Claims

1. A pharmaceutical composition comprising carfilzomib or a pharmaceutically acceptable salt thereof, a cyclodextrin, and an acid, wherein the acid is one or more selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or the acid is present in an amount of 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

2. 2. The carfilzomib-containing pharmaceutical composition according to claim 1, wherein the content of the acid is within the range of 3.7 to 15 molar equivalents per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

3. The acid has a pKa in water of １ The carfilzomib-containing pharmaceutical composition according to claim 1 or 2, wherein the β-glucan is 4.8 or less.

4. 3. The carfilzomib-containing pharmaceutical composition according to claim 1, wherein the cyclodextrin is a β-cyclodextrin.

5. 5. The carfilzomib-containing pharmaceutical composition according to claim 4, wherein the β-cyclodextrin is sulfobutyl ether β-cyclodextrin or a pharmaceutically acceptable salt thereof.

6. 3. The carfilzomib-containing pharmaceutical composition according to claim 1, wherein the cyclodextrin is contained in an amount of 30 to 80 parts by weight per part by weight of carfilzomib or a pharmaceutically acceptable salt thereof.

7. The carfilzomib-containing pharmaceutical composition according to claim 1 or 2, which is in the form of a lyophilized formulation or a lyophilized cake thereof.

8. 8. The carfilzomib-containing pharmaceutical composition according to claim 7, wherein the carfilzomib-containing pharmaceutical composition can be dissolved within 2 minutes and 30 seconds when a lyophilized formulation or a lyophilized cake thereof is added with water in an amount equivalent to 5 mL per 10 mg of carfilzomib or a pharmaceutically acceptable salt thereof.

9. A method for producing a pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof, the method comprising the step of preparing an aqueous solution in which carfilzomib or a pharmaceutically acceptable salt thereof, a cyclodextrin, and an acid are dissolved, wherein the acid in this step is one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or an acid in an amount of 3.7 molar equivalents or more per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

10. The method for producing the carfilzomib-containing pharmaceutical composition according to claim 9, further comprising the steps of adjusting the pH of the aqueous solution to within the range of 3.0 to 4.0 with a base, lyophilizing the aqueous solution whose pH has been adjusted with a base, and / or sterilizing the aqueous solution before lyophilization.

11. The acid has a pKa in water of １ The method for producing a carfilzomib-containing pharmaceutical composition according to claim 9 or 10, wherein the β-amino acid residue is 4.8 or less.

12. The method for producing a carfilzomib-containing pharmaceutical composition according to claim 9 or 10, wherein the cyclodextrins are β-cyclodextrins.

13. The method for producing a carfilzomib-containing pharmaceutical composition according to claim 12, wherein the β-cyclodextrin is sulfobutyl ether β-cyclodextrin or a pharmaceutically acceptable salt thereof.

14. The method for producing a carfilzomib-containing pharmaceutical composition according to claim 9 or 10, wherein the cyclodextrin is blended in an amount of 30 to 80 parts by weight per part by weight of carfilzomib or a pharmaceutically acceptable salt thereof.

15. A method for improving the solubility in water of a pharmaceutical composition containing carfilzomib or a pharmaceutically acceptable salt thereof, the method comprising the step of preparing an aqueous solution in which carfilzomib or a pharmaceutically acceptable salt thereof and a cyclodextrin are dissolved, using one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or 3.7 molar equivalents or more of an acid per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof.

16. 16. The method of claim 15, further comprising the steps of adjusting the pH of the aqueous solution to within the range of 3.0 to 4.0 with a base, lyophilizing the aqueous solution whose pH has been adjusted with a base, and / or sterilizing the aqueous solution before lyophilization.

17. A method for improving the solubility of carfilzomib or a pharmaceutically acceptable salt thereof in water, the method comprising using one or more acids selected from the group consisting of lactic acid, ascorbic acid, phosphoric acid, tartaric acid, L-aspartic acid, maleic acid, acetic acid, and succinic acid, or 3.7 molar equivalents or more of an acid per molar equivalent of carfilzomib or a pharmaceutically acceptable salt thereof, and a cyclodextrin when dissolving carfilzomib or a pharmaceutically acceptable salt thereof in water.

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