Novel compositions

Abstract

There is provided inter alia a storage stable liquid solution composition comprising carfilzomib or a pharmaceutically acceptable salt thereof and a solvent consisting of (a) an organic solvent component comprising propylene glycol optionally together with polyethylene glycol (PEG), present at a total concentration of at least about 65% (v / v based on the total volume of the composition) and (b) water at a concentration of no more than about 15% (v / v based on the total volume of the composition); and a neutral amino acid, wherein the pH of the storage stable liquid solution composition is in the range 2.5 to 4.0.

Description

[0001] NOVEL COMPOSITIONS

[0002] Field

[0003] The present invention relates to liquid solution compositions comprising carfilzomib, in particular storage stable i.e. ready-to-dilute storage stable liquid solution compositions which have improved stability and handling.

[0004] Background

[0005] Carfilzomib is a targeted therapy drug used to treat relapsed or refractory multiple myeloma, in combination with dexamethasone and / or lenalidomide and / or anti-CD38 antibodies such as daratumumab, in adult patients who have received one or more prior therapies. Carfilzomib is a modified tetrapeptidyl epoxide, which in solid form is isolated as the crystalline free base, which works as a proteasome inhibitor. Carfilzomib irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib has been shown to have antiproliferative and proapoptotic activities in vitro in solid and hematologic tumour cells. The compound has also been shown to inhibit proteasome activity in blood and tissue and delay tumour growth in models of multiple myeloma, hematologic, and solid tumours.

[0006] Carfilzomib has proven difficult to formulate due to its low aqueous solubility. Indeed, carfilzomib is practically insoluble in water and very slightly soluble in acidic conditions. Thus compositions comprising carfilzomib are typically formulated with a carrier system such as a cyclodextrin e.g. sulfobutylether beta-cyclodextrin (as in the approved Kyprolis® formulation). The drug forms an inclusion complex with the cyclodextrin carrier molecule which is lyophilized before storage and reconstituted prior to use.

[0007] Kyprolis® is currently the only marketed product containing carfilzomib. Kyprolis® is a sterile, white to off-white lyophilized powder and is available as a single-dose 10 mg, 30 mg or 60 mg vial. The lyophilized product is reconstituted aseptically with sterile water for injection. The reconstituted solution contains carfilzomib at a concentration of 2 mg / mL and sulfobutylether beta-cyclodextrin at a concentration of 100 mg / mL. The solution is then diluted into 50 mL or 100 mL intravenous bags containing 5% dextrose solution. The diluted composition is administered by intravenous infusion. Lyophilized products, such as Kyprolis®, require multiple steps and calculations for reconstitution and administration. The present invention addresses the need for a liquid carfilzomib product that does not require reconstitution. Ideally, such a storage stable ready- to-dilute (RTD) liquid product comprises 2-8 mg / mL carfilzomib and is suitable for dilution (either into 5% dextrose or 0.9% saline or another suitable diluent), to be subsequently administered by intravenous infusion.

[0008] Summary of the invention

[0009] The present invention provides, inter alia, a storage stable liquid solution composition comprising:

[0010] (i) carfilzomib or a pharmaceutically acceptable salt thereof;

[0011] (ii) a solvent consisting essentially of (or consisting of) (a) an organic solvent component comprising propylene glycol optionally together with polyethylene glycol (PEG) wherein the propylene glycol optionally together with polyethylene glycol (PEG) is present at a total concentration of at least about 65% (v / v based on the total volume of the composition) and (b) water at a concentration of no more than about 15% (v / v based on the total volume of the composition); and

[0012] (iii) a neutral amino acid; wherein the pH of the composition is in the range 2.5 to 4.0

[0013] (referred to herein as “storage stable compositions of the invention”).

[0014] Detailed description of the invention

[0015] In the storage stable compositions of the invention carfilzomib may be present in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include acid addition salts such as hydrochloride, citrate, formate, acetate, tartrate, sulphate, tosylate, nitrate, mesylate, napsylate, besylate, oxalate, maleate, phosphate, pamoate, fumarate, hippurate, succinate and carbonate salts. Suitably the carfilzomib is present in neutral form i.e. not in any salt form.

[0016] The storage stable compositions of the present invention are “ready-to-dilute” compositions (and may also be described as a “composition concentrate”) unless stated otherwise, containing carfilzomib at a concentration which is higher than that required for administration (typically intravenous administration). The storage stable i.e. ready-to-dilute composition of the invention is therefore typically diluted to the required concentration shortly before the administration. Prior to use, the composition is typically stored in a suitable container such as a sealed vial. In one embodiment, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-10 mg / mL, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg / mL. In one embodiment, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL or about 2 mg / mL. In an alternative embodiment, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL. In particular, the concentration of carfilzomib of a pharmaceutically acceptable salt thereof is about 4 mg / mL, about 6 mg / mL or about 8 mg / mL. In one particular embodiment, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-3 mg / mL, for example about 2 mg / mL. For example, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 2 mg / mL. In another particular embodiment, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, about 6 mg / mL, or about 8 mg / mL. For example, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4 mg / mL. For example, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 6 mg / mL. For example, the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 8 mg / mL.

[0017] Suitably, the concentration of carfilzomib or a pharmaceutically acceptable salt thereof is less than about 10 mg / mL and / or more than about 1 mg / mL, for example and / or more than about 2 mg / mL, for example and / or more than about 3 mg / mL, for example and / or about 4 mg / mL or more than about 4 mg / mL.

[0018] All references to carfilzomib concentration in mg / mL herein are based on weight of carfilzomib as such without accounting for any possible salt counter ion, if present.

[0019] The storage stable compositions of the invention comprise a solvent consisting essentially of (or consisting of) an organic solvent component comprising propylene glycol optionally together with polyethylene glycol, wherein propylene glycol optionally together with polyethylene glycol is present at a total concentration of at least about 65% (v / v), and water at a concentration of no more than about 15% (v / v). The term “v / v” means “volume per volume” and is used to express the concentration of a liquid substance in the composition on a volume per volume basis relative to the total volume of the composition. The term “solvent” as used herein refers to the organic solvent component together with water. As used herein, the terms ‘organic solvent component’ and ‘solvent’ refer to the liquid solvent elements of the composition only. Accordingly, reference to an ‘organic solvent component’ or ‘solvent’ consisting essentially of (or consisting of) specific liquid solvent elements does not exclude said ‘organic solvent component’ or ‘solvent’ further comprising dissolved non-liquid elements which do not act as solvents.

[0020] In one embodiment, storage stable compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol optionally together with polyethylene glycol, wherein propylene glycol optionally together with polyethylene glycol is present at a total concentration of at least about 70% (v / v), for example of at least about 75% (v / v), for example of at least about 80% (v / v), for example of at least about 85% (v / v), for example of at least about 90% (v / v), wherein “v / v” is based on the total volume of the composition.

[0021] In one embodiment, storage stable compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol optionally together with polyethylene glycol, wherein propylene glycol optionally together with polyethylene glycol is present at a total concentration of about 75-99.5% (v / v), for example about 75-96% (v / v), for example about 80-96% (v / v), for example about 85-96% (v / v), for example about 90-96% (v / v), or about 95% (v / v), wherein “v / v” is based on the total volume of the composition.

[0022] In one embodiment, storage stable compositions of the invention comprise the organic solvent component, including propylene glycol optionally together with polyethylene glycol and any additional organic solvent, at a total concentration of at least about 75% (v / v), for example of at least about 80% (v / v), for example of at least about 85% (v / v), for example of at least about 90% (v / v), wherein “v / v” is based on the total volume of the composition.

[0023] In one embodiment, storage stable compositions of the invention comprise the organic solvent component, including propylene glycol optionally together with polyethylene glycol and any additional organic solvent, at a total concentration of about 85-99.5% (v / v), for example about 85-96% (v / v), for example about 90-96% (v / v) or about 95% (v / v), wherein “v / v” is based on the total volume of the composition.

[0024] In one embodiment, storage stable compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol optionally together with polyethylene glycol and / or optionally together an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. In a suitable embodiment, compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol. In an alternative embodiment, compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol and polyethylene glycol. In another embodiment, compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. In particular, compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol and ethanol. In a further embodiment, compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol, polyethylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. In particular, compositions of the invention comprise a solvent comprising an organic solvent component, comprising propylene glycol, polyethylene glycol, and ethanol.

[0025] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the storage stable compositions of the invention comprise an organic solvent component consisting essentially of (or consisting of) propylene glycol.

[0026] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the storage stable compositions of the invention comprise an organic solvent component consisting essentially of (or consisting of) propylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. Suitably the additional organic solvent is ethanol.

[0027] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the storage stable compositions of the invention comprise an organic solvent component consisting essentially of (or consisting of) propylene glycol and polyethylene glycol and an optional additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the storage stable compositions of the invention comprise an organic solvent component consisting essentially of (or consisting of) propylene glycol and polyethylene glycol. In an alternative embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the storage stable compositions of the invention comprise an organic solvent component consisting essentially of (or consisting of) propylene glycol, polyethylene glycol, and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. In a particular embodiment, suitably wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the storage stable compositions of the invention comprise an organic solvent component consisting essentially of (or consisting of) propylene glycol, polyethylene glycol, and ethanol.

[0028] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the storage stable compositions of the invention comprise an organic solvent component consisting essentially of (or consisting of) propylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

[0029] In one preferred embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol and ethanol.

[0030] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, suitably wherein propylene glycol is present in the composition at a concentration of about 85-99.5% (v / v), for example about 85-96% (v / v), for example about 90-96% (v / v) or about 95% (v / v), wherein “v / v” is based on the total volume of the composition.

[0031] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof, suitably wherein propylene glycol is present in the composition at a concentration of 75-99% (v / v), for example 80-99% (v / v), 80-95% (v / v), 80-90% (v / v), or about 85% (v / v), and wherein the additional organic solvent is present in the composition at a concentration of 0.5-24.5% (v / v), for example 0.5-19.5% (v / v), 4.5- 19.5% (v / v), 4.5-15.5% (v / v), or about 10% (v / v), wherein “v / v” is based on the total volume of the composition.

[0032] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL the organic solvent component consists essentially of (or consists of) propylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof, in particular ethanol, suitably wherein the ratio of the amount of propylene glycol to the amount of additional organic solvent, in particular ethanol, for example wherein each is measured in (v / v based on the total volume of the composition), is between about 200:1 and about 2:1 , for example between about 200:1 and about 3:1 , for example between about 200:1 and about 4:1 , for example between about 20:1 and about 4:1, for example between about 20:1 and about 5:1, for example between about 15:1 and about 6:1.

[0033] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol and polyethylene glycol (PEG), suitably wherein propylene glycol is present in the composition at a concentration of 20-85% (v / v), for example 25-80% (v / v), 30-75% (v / v), or 30-70% (v / v), and wherein polyethylene glycol (PEG) is present at a concentration of 10-75% (v / v), for example 15-70% (v / v), 20-65% (v / v), or 25-65% (v / v), wherein “v / v” is based on the total volume of the composition.

[0034] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG) and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N- methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof, suitably wherein propylene glycol is present in the composition at a concentration of 20-80% (v / v), for example 25-75% (v / v), 30-75% (v / v), or 30-70% (v / v), wherein polyethylene glycol (PEG) is present in the composition at a concentration of 10-50% (v / v), 15-50% (v / v), or 15-45% (v / v), and wherein the additional organic solvent is present in the composition at a concentration of 0.5-30% (v / v), for example 5-30% (v / v), 5-25% (v / v), 10-20% (v / v), for example about 10% (v / v) or about 20% (v / v), wherein “v / v” is based on the total volume of the composition.

[0035] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG) and ethanol, suitably wherein propylene glycol is present in the composition at a concentration of 20-80% (v / v), for example 25-75% (v / v), 30-75% (v / v), or 30-70% (v / v), wherein polyethylene glycol (PEG) is present in the composition at a concentration of 10-50% (v / v), 15-50% (v / v), or 15-45% (v / v), and wherein ethanol is present in the composition at a concentration of 0.5-30% (v / v), for example 5-30% (v / v), 5-25% (v / v), 10-20% (v / v), for example about 10% (v / v) or about 20% (v / v), wherein “v / v” is based on the total volume of the composition.

[0036] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG) and ethanol, suitably wherein propylene glycol is present in the composition at a concentration of about 25-75% (v / v), for example about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% (v / v), wherein polyethylene glycol (PEG) is present in the composition at a concentration of about 15-50% (v / v), for example about 20%, 25%, 30%, 35%, 40%, or 45% (v / v), and wherein ethanol is present on the composition at a concentration of about 5-30% (v / v), for example about 10%, 15%, 20%, or 25% (v / v), wherein “v / v” is based on the total volume of the composition. In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol and polyethylene glycol (PEG), suitably wherein the ratio of the amount of propylene glycol to polyethylene glycol (PEG), for example wherein each is measured in (v / v based on the total volume of the composition), is between about 9:1 and about 1:4, for example between about 8:1 and about 1 :3, for example between about 5:1 and about 2:5, for example between about 4: 1 and about 2:5, for example about 3: 1.

[0037] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), and ethanol, suitably wherein the ratio of the amount of propylene glycol to polyethylene glycol (PEG), for example wherein each is measured in (v / v based on the total volume of the composition), is between about 8:1 and about 1 :3, for example between about 5:1 and about 1 :2, for example between about 5: 1 and about 2:3, for example about 3: 1 , and suitably wherein the ratio of the amount of polyethylene glycol (PEG) to ethanol, for example wherein each is measured in (v / v based on the total volume of the composition), is between about 100:1 and about 1:3, for example between about 10:1 and about 1 :3, for example between about 10:1 and about 1:2, for example between about 10:1 and about 3:5, for example between about 9:1 and about 3:4, for example between 9:2 and about 3:4.

[0038] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N- methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof, suitably wherein propylene glycol is present in the composition at a concentration of 75-99% (v / v), for example 80-99% (v / v), 80-95% (v / v), 80-90% (v / v), or about 85% (v / v), and wherein the additional organic solvent is present in the composition at a concentration of 0.5-24.5% (v / v), for example 0.5-19.5% (v / v), 4.5-19.5% (v / v), 4.5-15.5% (v / v), or about 10% (v / v), wherein “v / v” is based on the total volume of the composition. In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N- methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof, in particular ethanol, suitably wherein the ratio of the amount of propylene glycol to the amount of additional organic solvent, in particular ethanol, for example wherein each is measured in (v / v based on the total volume of the composition), is between about 200:1 and about 2:1, for example between about 200:1 and about 3:1 , for example between about 200:1 and about 4:1, for example between about 20:1 and about 4:1, for example between about 20:1 and about 5:1, for example between about 15:1 and about 6:1.

[0039] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG) and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof, suitably wherein propylene glycol is present in the composition at a concentration of 20-80% (v / v), for example 25-75% (v / v), 30-75% (v / v), or 30-70% (v / v), wherein polyethylene glycol (PEG) is present in the composition at a concentration of 10-50% (v / v), 15-50% (v / v), or 15-45% (v / v), and wherein the additional organic solvent is present in the composition at a concentration of 0.5-30% (v / v), for example 5-30% (v / v), 5-25% (v / v), 10-20% (v / v), for example about 10% (v / v) or about 20% (v / v), wherein “v / v” is based on the total volume of the composition.

[0040] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG) and ethanol, suitably wherein propylene glycol is present in the composition at a concentration of 20-80% (v / v), for example 25-75% (v / v), 30-75% (v / v), or 30-70% (v / v), wherein polyethylene glycol (PEG) is present in the composition at a concentration of 10-50% (v / v), 15-50% (v / v), or 15-45% (v / v), and wherein ethanol is present in the composition at a concentration of 0.5- 30% (v / v), for example 5-30% (v / v), 5-25% (v / v), 10-20% (v / v), for example about 10% (v / v) or about 20% (v / v), wherein “v / v” is based on the total volume of the composition. In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG) and ethanol, suitably wherein propylene glycol is present in the composition at a concentration of about 25-75% (v / v), for example about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% (v / v), wherein polyethylene glycol (PEG) is present in the composition at a concentration of about 15-50% (v / v), for example about 20%, 25%, 30%, 35%, 40%, or 45% (v / v), and wherein ethanol is present on the composition at a concentration of about 5-30% (v / v), for example about 10%, 15%, 20%, or 25% (v / v), wherein “v / v” is based on the total volume of the composition.

[0041] In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, or about 6 mg / mL, propylene glycol is present in the composition at a concentration of about 65% (v / v), polyethylene glycol (PEG) is present in the composition at a concentration of about 20% (v / v), and ethanol is present in the composition at a concentration of about 10% (v / v), wherein “v / v” is based on the total volume of the composition.

[0042] In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, or about 6 mg / mL, propylene glycol is present in the composition at a concentration of about 60% (v / v), polyethylene glycol (PEG) is present in the composition at a concentration of about 20% (v / v), and ethanol is present in the composition at a concentration of about 15% (v / v), wherein “v / v” is based on the total volume of the composition.

[0043] In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, or about 6 mg / mL, propylene glycol is present in the composition at a concentration of about 35% (v / v), polyethylene glycol (PEG) is present in the composition at a concentration of about 40% (v / v), and ethanol is present in the composition at a concentration of about 20% (v / v), wherein “v / v” is based on the total volume of the composition.

[0044] In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, or about 6 mg / mL, propylene glycol is present in the composition at a concentration of about 55% (v / v), polyethylene glycol (PEG) is present in the composition at a concentration of about 30% (v / v), and ethanol is present in the composition at a concentration of about 10% (v / v), wherein “v / v” is based on the total volume of the composition.

[0045] In one embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), and ethanol, suitably wherein the ratio of the amount of propylene glycol to polyethylene glycol (PEG), for example wherein each is measured in (v / v based on the total volume of the composition), is between about 8:1 and about 1 :3, for example between about 5:1 and about 1 :2, for example between about 5:1 and about 2:3, for example about 3:1 , and suitably wherein the ratio of the amount of polyethylene glycol (PEG) to ethanol, for example wherein each is measured in (v / v based on the total volume of the composition), is between about 100:1 and about 1 :3, for example between about 10:1 and about 1 :3, for example between about 10:1 and about 1 :2, for example between about 10:1 and about 3:5, for example between about 9:1 and about 3:4, for example between 9:2 and about 3:4.

[0046] Suitably, the polyethylene glycol (PEG) referred to herein comprises one or more e.g. two, three or four, different polyethylene glycol (PEG) polymers. Said polyethylene glycol (PEG) polymers typically have an average molecular weight in the range 150-650 Da. For example, polyethylene glycol (PEG) comprises one or more polyethylene glycol (PEG) polymers selected from the group consisting of PEG200, PEG300, PEG400 and PEG600. In a particular embodiment, polyethylene glycol (PEG) used herein comprises PEG300. In a suitable embodiment, polyethylene glycol (PEG) used herein consists essentially of (or consists of) one polyethylene glycol (PEG) polymer, in particular wherein said polyethylene glycol (PEG) polymer is selected from the group consisting of PEG200, PEG300, PEG400 and PEG600. In a particular embodiment, polyethylene glycol (PEG) used herein consists essentially of (or consists of) PEG300.

[0047] In one embodiment, the storage stable compositions of the invention comprise water at a concentration of no more than about 15% (v / v), for example no more than about 12% (v / v), for example no more than about 10% (v / v), wherein “v / v” is based on the total volume of the composition. Suitably the water is sterile water for injection or bacteriostatic water for injection.

[0048] In a particular embodiment, the storage stable compositions of the invention comprise water at a concentration of 0.5-15% (v / v), for example 0.5-12% (v / v), 2-12% (v / v), 4-15% (v / v), 4- 12% (v / v), 4-10% (v / v) or about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0049] In one embodiment, the storage stable compositions of the invention, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, comprise a solvent which consists essentially of (or consists of) propylene glycol and water, suitably wherein propylene glycol is present at a concentration of 90-96% (v / v), and wherein water is present at a concentration of 4-10% (v / v), wherein “v / v” is based on the total volume of the composition. For example, propylene glycol is present at a concentration of about 95% (v / v) and water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0050] In one embodiment, the storage stable compositions of the invention, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, comprise a solvent which consists essentially of (or consists of) propylene glycol, ethanol, and water, suitably wherein propylene glycol is present at a concentration of 80-90% (v / v), wherein ethanol is present at a concentration of 5-15% (v / v), and wherein water is present at a concentration of 4-10% (v / v), wherein “v / v” is based on the total volume of the composition. For example, propylene glycol is present at a concentration of about 85% (v / v), ethanol is present at a concentration of about 10% (v / v), and water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0051] In one embodiment, the storage stable compositions of the invention, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, comprise a solvent which consists essentially of (or consists of) propylene glycol, polyethylene glycol, and water, suitably wherein propylene glycol is present at a concentration of 20-85% (v / v), wherein polyethylene glycol is present at a concentration of 10-75% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition. For example, propylene glycol is present at a concentration of about 65% (v / v), polyethylene glycol is present at a concentration of about 30% (v / v), and water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0052] Alternatively, in one embodiment, the storage stable compositions of the invention, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL, comprise a solvent which consists essentially of (or consists of) propylene glycol, polyethylene glycol, ethanol and water, suitably wherein propylene glycol is present at a concentration of 20-80% (v / v), wherein polyethylene glycol is present at a concentration of 10-50% (v / v), wherein ethanol is present at a concentration of 0.5-30% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition. For example, propylene glycol is present at a concentration of about 65% (v / v), polyethylene glycol is present at a concentration of about 20% (v / v), ethanol is present at a concentration of about 10% (v / v), and water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0053] In one embodiment, the storage stable compositions of the invention, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, comprise a solvent which consists essentially of (or consists of) propylene glycol, ethanol, and water, suitably wherein propylene glycol is present at a concentration of 80-90% (v / v), wherein ethanol is present at a concentration of 5-15% (v / v), and wherein water is present at a concentration of 4-10% (v / v), wherein “v / v” is based on the total volume of the composition. For example, propylene glycol is present at a concentration of about 85% (v / v), ethanol is present at a concentration of about 10% (v / v), and water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0054] In one embodiment, the storage stable compositions of the invention, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL, comprise a solvent which consists essentially of (or consists of) propylene glycol, polyethylene glycol, ethanol and water, suitably wherein propylene glycol is present at a concentration of 20-80% (v / v), wherein polyethylene glycol is present at a concentration of 10-50% (v / v), wherein ethanol is present at a concentration of 0.5-30% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition. For example, propylene glycol is present at a concentration of about 65% (v / v), polyethylene glycol is present at a concentration of about 20% (v / v), ethanol is present at a concentration of about 10% (v / v), and water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0055] In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, or about 6 mg / mL, propylene glycol is present in the composition at a concentration of about 65% (v / v), polyethylene glycol (PEG) is present in the composition at a concentration of about 20% (v / v), ethanol is present in the composition at a concentration of about 10% (v / v), and water is present in the composition at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0056] In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, or about 6 mg / mL, propylene glycol is present in the composition at a concentration of about 60% (v / v), polyethylene glycol (PEG) is present in the composition at a concentration of about 20% (v / v), ethanol is present in the composition at a concentration of about 15% (v / v), and water is present in the composition at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0057] In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, or about 6 mg / mL, propylene glycol is present in the composition at a concentration of about 35% (v / v), polyethylene glycol (PEG) is present in the composition at a concentration of about 40% (v / v), ethanol is present in the composition at a concentration of about 20% (v / v), and water is present in the composition at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0058] In a particular embodiment, in particular wherein the concentration of carfilzomib or pharmaceutically acceptable salt thereof is about 4-8 mg / mL, for example about 4 mg / mL, or about 6 mg / mL, propylene glycol is present in the composition at a concentration of about 55% (v / v), polyethylene glycol (PEG) is present in the composition at a concentration of about 30% (v / v), ethanol is present in the composition at a concentration of about 10% (v / v), and water is present in the composition at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition.

[0059] The storage stable compositions of the invention comprise a neutral amino acid. As described in the examples infra, the inclusion of a neutral amino acid led to physical stability improvements. As used herein, a “neutral amino acid” is an amino acid having essentially zero net charge at pH 7.4. Such neutral amino acids have a side chain (particularly an a position sidechain) which is essentially not charged at pH 7.4. A neutral amino acid may be provided in the form of a salt (e.g. under acid conditions an acid additional salt formed e.g. with a mineral acid such as an HCI salt). Indeed, at the acidic pH of the storage stable compositions of the invention, the neutral amino acid is expected to have a net positive charge. The neutral amino acid may for example be a natural amino acid (i.e. selected from the 20 proteinogenic amino acids). In one embodiment, the storage stable compositions of the invention comprise a neutral amino acid selected from the group consisting of alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In a particular embodiment, the neutral amino acid is selected from the group consisting of alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, proline, serine, threonine, and valine. In a preferred embodiment, the neutral amino acid is selected from the group consisting of glycine, methionine, and proline, for example the neutral amino acid is glycine.

[0060] In another embodiment, the storage stable compositions of the invention comprise a neutral amino acid that is a non-natural amino acid such as a non-natural a amino acid e.g. hydroxyproline, norleucine, 3-nitrotyrosine, naphthylalanine, methionine sulfoxide or methionine sulfone.

[0061] Neutral amino acids having a chiral centre may be employed as the D- or L- enantiomeric forms or any mixture thereof including racemic mixtures. Suitably neutral amino acids having a chiral centre are employed as a racemic mixture or as the L enantiomeric form.

[0062] In one embodiment, the storage stable compositions of the invention comprise the neutral amino acid at a concentration of no more than about 125 mM, for example no more than about 120 mM, no more than about 110 mM or no more than about 100 mM.

[0063] In one embodiment, the neutral amino acid is present at a concentration of more than about 10 mM. In a particular embodiment the neutral amino acid is present at a concentration of about 10-100 mM, for example 25-75 mM, for example about 50 mM.

[0064] The effect of pH on the stability of carfilzomib is shown in Examples 4 and 5. Thus, in one embodiment the pH of the storage stable compositions of the invention is in the range 2.5 to 4.0. In a particular embodiment the pH of the storage stable compositions of the invention is in the range 2.5 to 3.5, for example 2.6 to 3.4, for example about 2.8-3.2., for example about 3.0 In one embodiment the carfilzomib concentration is about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL and the pH is 3.0. In one embodiment the carfilzomib concentration is 4 mg / mL and the pH is 3.0. In one embodiment the carfilzomib concentration is 6 mg / mL and the pH is 3.0. In one embodiment the carfilzomib concentration is 8 mg / mL and the pH is 3.0. It should be noted that all references herein to “pH” refer to the pH of a composition evaluated at 21 °C. All references to “pKa” refer to the pKaof an ionisable group evaluated at 25 °C (see CRC Handbook of Chemistry and Physics, 79thEdition, 1998, D. R. Lide).

[0065] In one embodiment, the storage stable composition of the invention further comprises an antioxidant which is not a neutral amino acid, which is suitably selected from the group consisting of monothioglycerol, butylated hydroxyanisole, butylated hydroxytoluene and glutathione (reduced). When included, the antioxidant is typically present in the composition at a concentration of 1-100 mM, e.g. 10-50 mM or 25-50 mM (such as for monothioglycerol or glutathione) or 1-10 mM or 1-2 mM (such as for butylated hydroxyanisole or butylated hydroxytoluene).

[0066] In one embodiment, the storage stable composition of the invention is substantially free of e.g. free of cyclodextrin.

[0067] In one embodiment, the storage stable composition of the invention is substantially free of e.g. free of sugars. Examples of such sugars include but are not limited to mannitol, glucose (e.g. a-D-glucose i.e. dextrose), sucrose, lactose, trehalose, maltose, sorbitol, dextran and raffinose and mixtures thereof.

[0068] In one embodiment, the storage stable composition of the invention is substantially free of e.g. free of organic acids and / or organic acidifying agents (i.e. acids or acidifying agents containing at least one carbon atom). Examples of such organic acids or organic acidifying agents include but are not limited to tartaric acid, citric acid, aspartic acid, maleic acid, ascorbic acid, succinic acid, glutaric acid, malic acid, carbonic acid, acetic acid, aconitic acid, lactic acid, fumaric acid and propionic acid and mixtures thereof. In a particular embodiment, the storage stable composition of the invention is substantially free of e.g. free of acids and / or acidifying agents which are sugar acids. Examples of such sugar acids include but are not limited to N- acetylneuraminic acid, N-acetyltalosaminuronic acid, aldaric acid, aldonic acid, 3-deoxy-D- manno-oct-2-ulosonic acid, galaturonic acid, D-galacturonic acid, glucaric acid, gluconic acid, glucuronic acid, glucono-y-lactone, glyceric acid, N-glycolylneuraminlc acid, iduronic acid, isosaccharinic acid, lactobionic acid, mucic acid, muramic acid, neuraminic acid, pangamic acid, saccharic acid, sialic acid, threonic acid, ulosonic acid, uronic acid, X-Gluc, xylonic acid and ascorbic acid and mixtures thereof. In this application, the neutral amino acid e.g. glycine is not counted as an organic acid or an organic acidifying agent. For the purposes of preparing the storage stable composition of the invention at the desired acidic pH, suitably a mineral acid i.e. an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, particularly hydrochloric acid is used.

[0069] The storage stable compositions of the invention may be considered to be “substantially free of” a substance if the concentration of said substance in the composition is less than about 0.1 mM, such as less than about 0.05 mM, such as less than about 0.04 mM or less than about 0.01 mM.

[0070] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0071] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0072] - a solvent consisting essentially of (or consisting of) propylene glycol and water, wherein propylene glycol is present at a concentration of 85-99.5% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), wherein “v / v” is based on the total volume of the composition;

[0073] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0074] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0075] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0076] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG) and water, wherein propylene glycol is present at a concentration of 20-85% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 10-75% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0077] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0078] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0079] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0080] - a solvent consisting essentially of (or consisting of) propylene glycol and water, wherein propylene glycol is present at a concentration of 85-96% (v / v), in particular 90-96% (v / v), for example about 95% (v / v), and wherein water is present at a concentration of 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0081] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0082] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0083] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0084] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG) and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 25-65% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0085] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0086] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0087] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0088] - a solvent consisting essentially of (or consisting of) propylene glycol and water, wherein propylene glycol is present at a concentration of 85-96% (v / v), in particular 90-96% (v / v), for example about 95% (v / v), and wherein water is present at a concentration of 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0089] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0090] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0091] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0092] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL; - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG) and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 25-65% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0093] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0094] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0095] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0096] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0097] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 75-99% (v / v), wherein ethanol is present at a concentration of 0.5-24.5% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), wherein “v / v” is based on the total volume of the composition;

[0098] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0099] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0100] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0101] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 20-80% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v), wherein ethanol is present at a concentration of 0.5-30% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0102] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0103] In one embodiment, there is provided a storage stable liquid solution composition comprising: - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL; - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 80-95% (v / v), in particular 80-90% (v / v), for example about 85% (v / v), wherein ethanol is present at a concentration of 4.5-19.5% (v / v), in particular 4.5-15.5% (v / v), for example about 10% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), such as 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0104] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0105] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0106] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0107] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 5-25% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0108] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0109] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0110] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0111] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 80-95% (v / v), in particular 80-90% (v / v), for example about 85% (v / v), wherein ethanol is present at a concentration of 4.5-19.5% (v / v), in particular 4.5-15.5% (v / v), for example about 10% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), such as 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0112] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0113] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2. In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0114] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0115] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 5-25% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0116] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0117] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0118] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0119] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL;

[0120] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 75-99% (v / v), wherein ethanol is present at a concentration of 0.5-24.5% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), wherein “v / v” is based on the total volume of the composition;

[0121] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0122] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0123] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL;

[0124] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 20-80% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v), wherein ethanol is present at a concentration of 0.5-30% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ; - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0125] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0126] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL;

[0127] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 80-95% (v / v), in particular 80-90% (v / v), for example about 85% (v / v), wherein ethanol is present at a concentration of 4.5-19.5% (v / v), for example about 10% (v / v), in particular 4.5-15.5% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), such as 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0128] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0129] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0130] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL;

[0131] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 5-25% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0132] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0133] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0134] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL;

[0135] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 80-95% (v / v), in particular 80-90% (v / v), for example about 85% (v / v), wherein ethanol is present at a concentration of 4.5-19.5% (v / v), in particular 4.5-15.5% (v / v), for example about 10% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), such as 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0136] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0137] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0138] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0139] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL;

[0140] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 5-25% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0141] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0142] - optionally an antioxidant wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0143] In one embodiment, there is provided a storage stable liquid solution composition comprising:

[0144] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-8 mg / mL, for example about 4 mg / mL, about 6 mg / mL, or about 8 mg / mL;

[0145] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 10-20% (v / v), for example about 10% (v / v) or about 20% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0146] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2. In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0147] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-8 mg / mL, for example about 4 mg / mL, about 6 mg / mL, or about 8 mg / mL;

[0148] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 10-20% (v / v), for example about 10% (v / v) or about 20% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0149] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0150] - optionally an antioxidant wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0151] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0152] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4 mg / mL;

[0153] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 65% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 20% (v / v), wherein ethanol is present at a concentration of about 10% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0154] - glycine, at a concentration of about 50 mM;

[0155] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0156] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0157] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4 mg / mL;

[0158] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 55% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 30% (v / v), wherein ethanol is present at a concentration of about 10% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0159] - glycine, at a concentration of about 50 mM;

[0160] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0161] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0162] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 6 mg / mL;

[0163] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 65% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of about 20% (v / v), wherein ethanol is present at a concentration of about 10% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0164] - glycine, at a concentration of about 50 mM;

[0165] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0166] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of:

[0167] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 6 mg / mL;

[0168] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 60% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of about 20% (v / v), wherein ethanol is present at a concentration of about 15% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0169] - glycine, at a concentration of about 50 mM;

[0170] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0171] In one embodiment, there is provided a storage stable liquid solution composition consisting essentially of, or consisting of: - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 6 mg / mL;

[0172] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 35% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of about 40% (v / v), wherein ethanol is present at a concentration of about 20% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0173] - glycine, at a concentration of about 50 mM;

[0174] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0175] Suitably the storage stable compositions of the invention are chemically stable i.e. are at least 90% pure e.g. at least 95% pure following storage at 2-8 °C for an extended period of time, such as at least 6 months, at least 12 months, at least 18 months or at least 24 months. Moreover, suitably the storage stable composition of the invention is physically stable i.e. is free of particles following storage at 2-8 °C for an extended period of time, such as at least 6 months, at least 12 months, at least 18 months or at least 24 months. Suitably the storage stable compositions of the invention are clear (no opalescence and free or virtually free of particles) e.g. as determined by the Visual Assessment Method. Suitably the storage stable compositions of the invention are clear (no opalescence and free or virtually free of particles) e.g. as determined by the Visual Assessment Method following storage at 2-8 °C for an extended period of time, such as at least 6 months, at least 12 months, at least 18 months or at least 24 months.

[0176] The storage stable compositions of the invention should suitably be protected from light during storage.

[0177] The storage stable compositions of the invention are suitably diluted prior to administration. Once diluted, the resulting composition (i.e. ready-to-administer composition) is usually administered by intravenous infusion. A typical method for administration of a diluted composition of the invention involves transferring a volume of composition concentrate to a container which contains a diluent suitable for intravenous (IV administration and which is suitably an IV bag or a bottle, where the required volume of ready-to-dilute composition is calculated according to the required dose and the volume of the container. Following thorough mixing of the diluted solution, the contents of the container can be administered via intravenous infusion to the patient. When the container is an IV solution bag, it is suitably constructed from plastic such as PVC, polyolefin, polypropylene, a blend of PO and PP (polyolefin blend), polyurethane, or a material that is substantially free of e.g. free of PVC, plasticizers, adhesives and latex, such as DEHP (di(2- ethylhexyl) phthalate). When the container is a bottle, it can be made from plastic (as described above for the IV solution bag) or can be made from glass, e.g. it is a type 1 glass bottle. In one embodiment, the volume of the IV solution bag or bottle is 50 mL to 500 mL, e.g. 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL or 500 mL.

[0178] As such, in one embodiment there is provided a process for the preparation of a ready-to- administer carfilzomib composition comprising the step of diluting a storage stable (i.e. ready- to-dilute) composition of the invention with a diluent suitable for intravenous administration. The diluent is suitably selected from saline e.g. 0.9% (w / v) saline, dextrose in water e.g. 5% (w / v) dextrose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection) and most suitably is 5% (w / v) dextrose in water. In one embodiment, the process provides a ready-to-administer composition wherein the concentration of carfilzomib or the pharmaceutically acceptable salt thereof after dilution, is 0.1-1.5 mg / mL, for example 0.2-1.3 mg / mL.

[0179] When diluting the storage stable (i.e. ready-to-dilute) composition of the invention, the composition is typically first equilibrated to room temperature and subsequently diluted in a suitable diluent by addition of the calculated volume of the composition, based on patient body weight and dosing regimen, via a syringe and needle to appropriate volume of the diluent. A 21-gauge or a larger gauge needle is typically used for the dilution process.

[0180] Furthermore, in one embodiment, there is provided a ready-to-administer carfilzomib composition comprising a storage stable (i.e. ready-to-dilute) composition of the invention diluted with a diluent suitable for intravenous administration. The diluent is suitably selected from 0.9% saline, 5% dextrose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection). In one embodiment, the concentration of carfilzomib or the pharmaceutically acceptable salt thereof in the ready-to-administer composition of the invention is 0.1 -1.5 mg / mL, for example 0.2-1.3 mg / mL. Another possible range is 0.1 -1.2 mg / mL.

[0181] Suitably the diluted form i.e. the ready-to-administer composition of the invention is free of visible particles, i.e. it is clear and not opalescent as measured according to the procedures described in chapters 2.2.1 , 2.2.2, and 2.9.20 of the European Pharmacopoeia. In one embodiment, the diluted form of the composition is isotonic. In another embodiment, the diluted form of the composition is hypertonic. Typically, the diluted form of the composition is hypertonic. Suitably the diluted form of the composition has an osmolarity of greater than or equal to 300 mOsm / L, for example, 300-5000 mOsm / L e,g, 300-3000 mOsm / L such as 500-2000 mOsm / L.

[0182] Suitably the storage stable (i.e. ready-to-dilute) compositions of the invention are stable for at least 12 weeks e.g. at least 6 months or at least 12 months at 2-8 °C. For example, the storage stable (i.e. ready-to-dilute) compositions of the invention suffer degradation as determined in the RP-HPLC Method described in General Methods of no more than 3% e.g. no more than 2% e.g. no more than 1 % after storage at 2-8 °C for 12 weeks, 6 months or 12 months (e.g. no more than 3% after storage at 2-8 °C for 12 months). This percentage is a chromatographic purity based on the said RP-HPLC Method which approximates to w / w but there may be some discrepancy due to differences in extinction coefficients of impurities and carfilzomib at the wavelength used.

[0183] Suitably, once prepared the diluted form of the composition (i.e. the ready-to-administer composition) is stable for at least 24 hours at 2-8 °C and at least 4 hours at 15-30 °C.

[0184] In one embodiment, the various compositions of the invention (storage stable i.e. ready-to- dilute and diluted i.e. ready-to-administer) are compositions for use in therapy. In one embodiment, the compositions of the invention (storage stable i.e. ready-to-dilute and diluted i.e. ready-to-administer) are pharmaceutical compositions.

[0185] Carfilzomib is indicated inter alia for the treatment of cancer, in particular for the treatment of multiple myeloma. It may be administered in combination with dexamethasone and / or lenalidomide and / or an anti-CD38 antibody such as daratumumab. It is indicated for patients who have received one or more prior therapies, including treatment with bortezomib and an immunomodulatory therapy, such as lenalidomide, and have demonstrated disease progression on or within 60 days of completion of the last therapy.

[0186] Accordingly, in one embodiment there is provided a composition as described hereinabove (storage stable i.e. ready-to-dilute or diluted i.e. ready-to-administer) for use in treating cancer, in particular multiple myeloma. When the composition of the invention for use is a storage stable i.e. ready-to-dilute composition, the storage stable i.e. ready-to-dilute composition is typically diluted before use. In one embodiment is provided a method of treating cancer, in particular multiple myeloma, which comprises administering to a patient, particularly a human patient, in need thereof a therapeutically effective amount of a composition as described hereinabove (storage stable i.e. ready-to-dilute or diluted i.e. ready-to-administer). In one embodiment, there is provided use of a composition as described hereinabove (storage stable i.e. ready-to-dilute or diluted i.e. ready-to-administer) in the manufacture of a medicament for the treatment of cancer, in particular multiple myeloma.

[0187] The compositions of the invention (storage stable i.e. ready-to-dilute or diluted i.e. ready-to- administer) can be used as a sole therapy, or in combination with one or more other therapeutic agents.

[0188] There is also provided a container, containing a dose or a plurality of doses of the composition as described hereinabove (storage stable i.e. ready-to-dilute or diluted i.e. ready-to- administer). The container is suitably a vial e.g. a vial made of plastics or glass. The container e.g. vial is suitably provided with an airtight seal until use. Suitably a glass vial is a type 1 glass vial e.g. containing 80% silica and 10% boric oxide, with a small amount of sodium oxide and aluminium oxide. In one embodiment is provided a multiple-dose vial, in particular a glass vial, containing the composition as described hereinabove. In one embodiment, the fill volume of the vial is 1.5 mL to 50 mL e.g. 1.66 mL, 2.5 mL, 5 mL, 7.5 mL,10 mL, 15 mL, 20 mL, 30 mL, 40 mL or 50 mL. Typically, a vial with a larger fill volume is preferred to enable use of fewest number of vials for preparation of a dose.

[0189] The invention is further defined by the following clauses:

[0190] Clause 1. A storage stable liquid solution composition comprising:

[0191] (i) carfilzomib or a pharmaceutically acceptable salt thereof;

[0192] (ii) a solvent consisting essentially of (or consisting of) (a) an organic solvent component comprising propylene glycol optionally together with polyethylene glycol (PEG) wherein the propylene glycol optionally together with polyethylene glycol (PEG) is present at a total concentration of at least about 65% (v / v based on the total volume of the composition) and (b) water at a concentration of no more than about 15% (v / v based on the total volume of the composition); and

[0193] (iii) a neutral amino acid; wherein the pH of the composition is in the range 2.5 to 4.0. Clause 2. The storage stable liquid solution composition according to clause 1 , wherein carfilzomib is present in neutral (i.e. unsalted) form.

[0194] Clause 3. The storage stable liquid solution composition according to clause 1 or clause 2, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is 1-10 mg / mL, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg / mL (based on weight of carfilzomib).

[0195] Clause 4. The storage stable liquid solution composition according to clause 3, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 1-4 mg / mL, for example about 1-3 mg / mL (based on weight of carfilzomib).

[0196] Clause 5. The storage stable liquid solution composition according to clause 4, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 2 mg / mL (based on weight of carfilzomib).

[0197] Clause 6. The storage stable liquid solution composition according to clause 3, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 4-10 mg / mL, for example about 4-8 mg / mL (based on weight of carfilzomib).

[0198] Clause 7. The storage stable liquid solution composition according to clause 6, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 4-6 mg / mL or about 6-8 mg / mL.

[0199] Clause 8. The storage stable liquid solution composition according to clause 6, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 4 mg / mL, about 6 mg / mL, or about 8 mg / mL (based on weight of carfilzomib).

[0200] Clause 9. The storage stable liquid solution composition according to clause 7, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 4 mg / mL (based on weight of carfilzomib). Clause 10. The storage stable liquid solution composition according to clause 7, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 6 mg / mL (based on weight of carfilzomib).

[0201] Clause 11. The storage stable liquid solution composition according to clause 7, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 8 mg / mL (based on weight of carfilzomib).

[0202] Clause 12. The storage stable liquid solution composition according to any one of clauses 1 to 11 , wherein the organic solvent component comprises propylene glycol optionally together with polyethylene glycol at a total concentration of at least about 70% (v / v based on the total volume of the composition), for example of at least about 75% (v / v based on the total volume of the composition).

[0203] Clause 13. The storage stable liquid solution composition according to any one of clauses 1 to 12, wherein the organic solvent component is present in the composition at a total concentration of 85-99.5% (v / v based on the total volume of the composition), for example 85-96% (v / v based on the total volume of the composition), for example 90-96% (v / v based on the total volume of the composition) or about 95% (v / v based on the total volume of the composition).

[0204] Clause 14. The storage stable liquid solution composition according to any one of clauses 1 to 5, wherein the organic solvent component consists essentially of (or consists of) propylene glycol and polyethylene glycol, and an optional additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

[0205] Clause 15. The storage stable liquid solution composition according to clause 14, wherein the organic solvent component consists essentially of (or consists of) propylene glycol and polyethylene glycol (PEG).

[0206] Clause 16. The storage stable liquid solution composition according to clause 14, wherein the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. Clause 17. The storage stable liquid solution composition according to clause 16, wherein the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), and ethanol.

[0207] Clause 18. The storage stable liquid solution composition according to any one of clauses 1 to 5, wherein the organic solvent component consists essentially of (or consists of) propylene glycol and an optional additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

[0208] Clause 19. The storage stable liquid solution composition according to clause 18, wherein the organic solvent component consists essentially of (or consists of) propylene glycol, and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

[0209] Clause 20. The storage stable liquid solution composition according to clause 19, wherein the organic solvent component consists essentially of (or consists of) propylene glycol and ethanol.

[0210] Clause 21. The storage stable liquid solution composition according to any one of clauses 1 to 3 and 6 to 11 , wherein the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N- methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

[0211] Clause 22. The storage stable liquid solution composition according to clause 21 , wherein the organic solvent component consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), and ethanol.

[0212] Clause 23. The storage stable liquid solution composition according to any one of clauses 1 to 3 and 6 to 11 , wherein the organic solvent component consists essentially of (or consists of) propylene glycol, and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof. Clause 24. The storage stable liquid solution composition according to clause 23, wherein the organic solvent component consists essentially of (or consists of) propylene glycol, and ethanol.

[0213] Clause 25. The storage stable liquid solution composition according to clause 15, wherein propylene glycol is present at a concentration of 20-85% (v / v based on the total volume of the composition), for example 25-80% (v / v based on the total volume of the composition), for example 30-75% (v / v based on the total volume of the composition), and wherein polyethylene glycol (PEG) is present at a concentration of 10-75% (v / v based on the total volume of the composition), for example 15-70% (v / v based on the total volume of the composition), for example 20-65% (v / v based on the total volume of the composition).

[0214] Clause 26. The storage stable liquid solution composition according to clause 25, wherein propylene glycol is present at a concentration of 30-70% (v / v based on the total volume of the composition), and wherein polyethylene glycol (PEG) is present at a concentration of 25-65% (v / v based on the total volume of the composition).

[0215] Clause 27. The storage stable liquid solution composition according to clause 25 or clause 26, wherein the ratio of the amount of propylene glycol to polyethylene glycol (PEG), for example wherein each is measured in (v / v based on the total volume of the composition), is between about 9:1 and about 1:4, for example between about 8:1 and about 1:3, for example between about 5:1 and about 2:5, for example between about 4:1 and about 2:5, for example about 3: 1.

[0216] Clause 28. The storage stable liquid solution composition according to clause 16, wherein propylene glycol is present at a concentration of 20-80% (v / v based on the total volume of the composition), for example 25-75% (v / v based on the total volume of the composition), for example 30-75% (v / v based on the total volume of the composition), and wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v based on the total volume of the composition), for example 15-50% (v / v based on the total volume of the composition), and wherein the additional organic solvent is present at a concentration of 0.5- 30% (v / v based on the total volume of the composition), for example 5-30% (v / v based on the total volume of the composition).

[0217] Clause 29. The storage stable liquid solution composition according to clause 28, wherein propylene glycol is present at a concentration of 30-70% (v / v based on the total volume of the composition), and wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v based on the total volume of the composition), and wherein the additional organic solvent is present at a concentration of 5-25% (v / v based on the total volume of the composition), for example 10-20% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition) or about 20% (v / v based on the total volume of the composition).

[0218] Clause 30. The storage stable liquid solution composition according to clause 21 , wherein propylene glycol is present at a concentration of 20-80% (v / v based on the total volume of the composition), for example 25-75% (v / v based on the total volume of the composition), for example 30-75% (v / v based on the total volume of the composition), and wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v based on the total volume of the composition), for example 15-50% (v / v based on the total volume of the composition), and wherein the additional organic solvent is present at a concentration of 0.5- 30% (v / v based on the total volume of the composition), for example 5-30% (v / v based on the total volume of the composition).

[0219] Clause 31. The storage stable liquid solution composition according to clause 30, wherein propylene glycol is present at a concentration of 30-70% (v / v based on the total volume of the composition), and wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v based on the total volume of the composition), and wherein the additional organic solvent is present at a concentration of 5-25% (v / v based on the total volume of the composition), for example 10-20% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition) or about 20% (v / v based on the total volume of the composition).

[0220] Clause 32. The storage stable liquid solution composition according to clause 17, wherein propylene glycol is present at a concentration of 20-80% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 0.5-30% (v / v based on the total volume of the composition).

[0221] Clause 33. The storage stable liquid solution composition according to clause 32, wherein propylene glycol is present at a concentration of 25-75% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of 15-50% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 5-30% (v / v based on the total volume of the composition). Clause 34. The storage stable liquid solution composition according to clause 33, wherein propylene glycol is present at a concentration of about 25-75% (v / v based on the total volume of the composition), for example about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of about 15-50% (v / v based on the total volume of the composition), for example about 20%, 25%, 30%, 35%, 40%, or 45% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of about 5- 30% (v / v based on the total volume of the composition), for example about 10%, 15%, 20%, or 25% (v / v based on the total volume of the composition).

[0222] Clause 35. The storage stable liquid solution composition according to clause 33, wherein propylene glycol is present at a concentration of 30-70% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 5-25% (v / v based on the total volume of the composition), for example 10-20% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition) or about 20% (v / v based on the total volume of the composition).

[0223] Clause 36. The storage stable liquid solution composition according to any one of clauses 32 to 35, wherein the ratio of the amount of propylene glycol to polyethylene glycol (PEG), for example wherein each is measured in (v / v based on the total volume of the composition), is between about 8:1 and about 1 :3, for example between about 5:1 and about 1 :2, for example between about 5: 1 and about 2:3, for example about 3: 1.

[0224] Clause 37. The storage stable liquid solution composition according to any one of clauses 32 to 36, wherein the ratio of the amount of polyethylene glycol (PEG) to ethanol, for example wherein each is measured in (v / v based on the total volume of the composition), is between about 100:1 and about 1:3, for example between about 10:1 and about 1 :3, for example between about 10:1 and about 1:2, for example between about 10:1 and about 3:5, for example between about 9:1 and about 3:4, for example between 9:2 and about 3:4.

[0225] Clause 38. The storage stable liquid solution composition according to clause 22, wherein propylene glycol is present at a concentration of 20-80% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 0.5-30% (v / v based on the total volume of the composition). Clause 39. The storage stable liquid solution composition according to clause 38, wherein propylene glycol is present at a concentration of 25-75% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of 15-50% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 5-30% (v / v based on the total volume of the composition).

[0226] Clause 40. The storage stable liquid solution composition according to clause 39, wherein propylene glycol is present at a concentration of about 25-75% (v / v based on the total volume of the composition), for example about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of about 15-50% (v / v based on the total volume of the composition), for example about 20%, 25%, 30%, 35%, 40%, or 45% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of about 5- 30% (v / v based on the total volume of the composition), for example about 10%, 15%, 20%, or 25% (v / v based on the total volume of the composition).

[0227] Clause 41. The storage stable liquid solution composition according to clause 39, wherein propylene glycol is present at a concentration of 30-70% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 5-25% (v / v based on the total volume of the composition), for example 10-20% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition) or about 20% (v / v based on the total volume of the composition).

[0228] Clause 42. The storage stable liquid solution composition according to any one of clauses 38 to 41, wherein the ratio of the amount of propylene glycol to polyethylene glycol (PEG), for example wherein each is measured in (v / v based on the total volume of the composition), is between about 8:1 and about 1 :3, for example between about 5:1 and about 1 :2, for example between about 5: 1 and about 2:3, for example about 3: 1.

[0229] Clause 43. The storage stable liquid solution composition according to any one of clauses 38 to 42, wherein the ratio of the amount of polyethylene glycol (PEG) to ethanol, for example wherein each is measured in (v / v based on the total volume of the composition), is between about 100:1 and about 1:3, for example between about 10:1 and about 1 :3, for example between about 10:1 and about 1:2, for example between about 10:1 and about 3:5, for example between about 9:1 and about 3:4, for example between 9:2 and about 3:4.

[0230] Clause 44. The storage stable liquid solution composition according to clause 19 or clause 23, wherein propylene glycol is present at a concentration of 75-99% (v / v based on the total volume of the composition), for example 80-99% (v / v based on the total volume of the composition), and wherein the additional organic solvent is present at a concentration of 0.5-24.5% (v / v based on the total volume of the composition), for example 0.5-19.5% (v / v based on the total volume of the composition).

[0231] Clause 45. The storage stable liquid solution composition according to clause 44, wherein propylene glycol is present at a concentration of 80-90% (v / v based on the total volume of the composition), for example about 85% (v / v based on the total volume of the composition), and wherein the additional organic solvent is present at a concentration of 4.5- 15.5% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition).

[0232] Clause 46. The storage stable liquid solution composition according to clause 44 or clause 45, wherein the ratio of the amount of propylene glycol to the additional organic solvent, for example wherein each is measured in (v / v based on the total volume of the composition), is between about 200:1 and about 2:1, for example between about 200:1 and about 3:1, for example between about 200:1 and about 4:1, for example between about 20:1 and about 4:1, for example between about 20:1 and about 5:1, for example between about 15:1 and about 6:1.

[0233] Clause 47. The storage stable liquid solution composition according to clause 20 or clause 24, wherein propylene glycol is present at a concentration of 75-99% (v / v based on the total volume of the composition), for example 80-99% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 0.5-24.5% (v / v based on the total volume of the composition), for example 0.5-19.5% (v / v based on the total volume of the composition).

[0234] Clause 48. The storage stable liquid solution composition according to clause 47, wherein propylene glycol is present at a concentration of 80-90% (v / v based on the total volume of the composition), for example about 85% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 4.5-15.5% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition).

[0235] Clause 49. The storage stable liquid solution composition according to clause 47 or clause 48, wherein the ratio of the amount of propylene glycol to the additional organic solvent, for example wherein each is measured in (v / v based on the total volume of the composition), is between about 200:1 and about 2:1, for example between about 200:1 and about 3:1, for example between about 200:1 and about 4:1, for example between about 20:1 and about 4:1, for example between about 20:1 and about 5:1, for example between about 15:1 and about 6:1.

[0236] Clause 50. The storage stable liquid solution composition according to any one of clauses 1 to 49, wherein polyethylene glycol (PEG) comprises one or more polyethylene glycol (PEG) polymers selected from the group consisting of PEG200, PEG300, PEG400 and PEG600.

[0237] Clause 51. The storage stable liquid solution composition according to clause 50, wherein polyethylene glycol (PEG) comprises PEG300.

[0238] Clause 52. The storage stable liquid solution composition according to clause 50, wherein polyethylene glycol (PEG) consists essentially of (or consists of) one polyethylene glycol (PEG) polymer selected from the group consisting of PEG200, PEG300, PEG400 and PEG600.

[0239] Clause 53. The storage stable liquid solution composition according to clause 52, wherein polyethylene glycol (PEG) consists essentially of (or consists of) PEG300.

[0240] Clause 54. The storage stable liquid solution composition according to any one of clauses 1 to 53, wherein water is present at a concentration of no more than about 15% (v / v based on the total volume of the composition), for example no more than about 12% (v / v based on the total volume of the composition), for example no more than about 10% (v / v based on the total volume of the composition).

[0241] Clause 55. The storage stable liquid solution composition according to clause 54 wherein water is present at a concentration of no more than about 10% (v / v based on the total volume of the composition). Clause 56. The storage stable liquid solution composition according to clause 54 wherein water is present at a concentration of 0.5-15% (v / v based on the total volume of the composition), for example 0.5-12% (v / v based on the total volume of the composition), for example 2-12% (v / v based on the total volume of the composition), for example 4-12% (v / v based on the total volume of the composition), for example 4-10% (v / v based on the total volume of the composition) for example about 5% (v / v based on the total volume of the composition).

[0242] Clause 57. The storage stable liquid solution composition according to clause 56 wherein water is present at a concentration of 4-10% (v / v based on the total volume of the composition), for example about 5% (v / v based on the total volume of the composition).

[0243] Clause 58. The storage stable liquid solution composition according to any one of clauses 1 to 5, wherein the solvent consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), and water.

[0244] Clause 59. The storage stable liquid solution composition according to clause 58 wherein propylene glycol is present at a concentration of 20-85% (v / v), wherein polyethylene glycol is present at a concentration of 10-75% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v).

[0245] Clause 60. The storage stable liquid solution composition according to any one of clauses 1 to 5, wherein the solvent consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), ethanol and water.

[0246] Clause 61 . The storage stable liquid solution composition according to clause 60 wherein propylene glycol is present at a concentration of 20-80% (v / v), wherein polyethylene glycol is present at a concentration of 10-50% (v / v), wherein ethanol is present at a concentration of 0.5-30% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v).

[0247] Clause 62. The storage stable liquid solution composition according to any one of clauses 1 to 3 and 6 to 11 , wherein the solvent consists essentially of (or consists of) propylene glycol, polyethylene glycol (PEG), ethanol and water.

[0248] Clause 63. The storage stable liquid solution composition according to clause 62 wherein propylene glycol is present at a concentration of 20-80% (v / v), wherein polyethylene glycol is present at a concentration of 10-50% (v / v), wherein ethanol is present at a concentration of 0.5-30% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v).

[0249] Clause 64. The storage stable liquid solution composition according to any one of clauses 1 to 5, wherein the solvent consists essentially of (or consists of) propylene glycol and water.

[0250] Clause 65. The storage stable liquid solution composition according to clause 64, wherein propylene glycol is present at a concentration of 85-96% (v / v based on the total volume of the composition), in particular 90-96% (v / v based on the total volume of the composition), for example about 95% (v / v based on the total volume of the composition) and wherein water is present at a concentration of 4-15% (v / v based on the total volume of the composition), in particular 4-10% (v / v based on the total volume of the composition), for example about 5% (v / v based on the total weight of the composition).

[0251] Clause 66. The storage stable liquid solution composition according to any one of clauses 1 to 5, wherein the solvent consists essentially of (or consists of) propylene glycol, ethanol, and water.

[0252] Clause 67. The storage stable liquid solution composition according to clause 66, wherein propylene glycol is present at a concentration of 80-90% (v / v based on the total volume of the composition), for example about 85% (v / v based on the total volume of the composition), ethanol is present at a concentration of 4.5-14.5% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition) and wherein water is present at a concentration of 4-10% (v / v based on the total volume of the composition), for example about 5% (v / v based on the total weight of the composition).

[0253] Clause 68. The storage stable liquid solution composition according to any one of clauses 1 to 3 and 6 to 11 , wherein the solvent consists essentially of (or consists of) propylene glycol, ethanol, and water.

[0254] Clause 69. The storage stable liquid solution composition according to clause 68, wherein propylene glycol is present at a concentration of 80-90% (v / v based on the total volume of the composition), for example about 85% (v / v based on the total volume of the composition), ethanol is present at a concentration of 4.5-14.5% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition) and wherein water is present at a concentration of 4-10% (v / v based on the total volume of the composition), for example about 5% (v / v based on the total weight of the composition).

[0255] Clause 70. The storage stable liquid solution composition according to any one of clauses 1 to 69, wherein the neutral amino acid is a natural amino acid e.g. selected from the group consisting of alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

[0256] Clause 71. The storage stable liquid solution composition according to clause 70, wherein the neutral amino acid is selected from the group consisting of alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, proline, serine, threonine, and valine.

[0257] Clause 72. The storage stable liquid solution composition according to clause 71 , wherein the neutral amino acid is selected from the group consisting of glycine, methionine, and proline.

[0258] Clause 73. The storage stable liquid solution composition according to clause 72, wherein the neutral amino acid is glycine.

[0259] Clause 74. The storage stable liquid solution composition according to any one of clauses 1 to 69, wherein the neutral amino acid is a non-natural amino acid.

[0260] Clause 75. The storage stable liquid solution composition according to any one of clauses 1 to 74, wherein the neutral amino acid is present at a concentration of no more than about 125 mM, for example no more than about 120 mM, no more than about 110 mM or no more than about 100 mM.

[0261] Clause 76. The storage stable liquid solution composition according to clause 75, wherein the neutral amino acid is present at a concentration of more than about 10 mM for example 10-100 mM.

[0262] Clause 77. The storage stable liquid solution composition according to clause 76, wherein the neutral amino acid is present at a concentration of about 25-75 mM, for example about 50 mM. Clause 78. The storage stable liquid solution composition according to any one of clauses 1 to 77, wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.6 to 3.4, for example about 2.8 to 3.2, or about 3.0.

[0263] Clause 79. The storage stable liquid solution composition according to any one of clauses 1 to 78, further comprising an antioxidant which is not a neutral amino acid.

[0264] Clause 80. The storage stable liquid solution composition according to clause 79, wherein the antioxidant is selected from the group consisting of monothioglycerol, butylated hydroxyanisole, butylated hydroxytoluene and glutathione (reduced).

[0265] Clause 81. The storage stable liquid solution composition according to clause 79 or clause 80, wherein the antioxidant is present at a concentration of 1-100 mM, for example 10-50 mM or 25-50 mM.

[0266] Clause 82. The storage stable liquid solution composition according to any one of clauses 1 to 81 , wherein the composition is substantially free of e.g. free of cyclodextrin.

[0267] Clause 83. The storage stable liquid solution composition according to any one of clauses 1 to 82, wherein the composition is substantially free of e.g. free of mannitol, glucose (e.g. a-D-glucose i.e. dextrose), sucrose, lactose, trehalose, maltose, sorbitol, dextran and raffinose and mixtures thereof.

[0268] Clause 84. The storage stable liquid solution composition according to any one of clauses 1 to 83, wherein the composition is substantially free of e.g. free of sugars.

[0269] Clause 85. The storage stable liquid solution composition according to any one of clauses 1 to 84, wherein the composition is substantially free of e.g. free of tartaric acid, citric acid, aspartic acid, maleic acid, ascorbic acid, succinic acid, glutaric acid, malic acid, carbonic acid, acetic acid, aconitic acid, lactic acid, hydrochloric acid, sulfuric acid, fumaric acid and propionic acid and mixtures thereof.

[0270] Clause 86. The storage stable liquid solution composition according to any one of clauses 1 to 85, wherein the composition is substantially free of e.g. free of to N- acetylneuraminic acid, N-acetyltalosaminuronic acid, aldaric acid, aldonic acid, 3-deoxy-D- manno-oct-2-ulosonic acid, galaturonic acid, D-galacturonic acid, glucaric acid, gluconic acid, glucuronic acid, glucono-y-lactone, glyceric acid, N-glycolylneuraminlc acid, iduronic acid, isosaccharinic acid, lactobionic acid, mucic acid, muramic acid, neuraminic acid, pangamic acid, saccharic acid, sialic acid, threonic acid, ulosonic acid, uronic acid, X-Gluc, xylonic acid and ascorbic acid and mixtures thereof.

[0271] Clause 87. The storage stable liquid solution composition according to any one of clauses 1 to 86, wherein the composition is substantially free of e.g. free of sugar acids.

[0272] Clause 88. The storage stable liquid solution composition according to any one of clauses 1 to 87, wherein the composition is substantially free of e.g. free of organic acids and / or organic acidifying agents.

[0273] Clause 89. The storage stable liquid solution composition according to clause 1 comprising:

[0274] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL (based on weight of carfilzomib);

[0275] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG) and water, wherein propylene glycol is present at a concentration of 20-85% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 10-75% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0276] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0277] Clause 90. The storage stable liquid solution composition according to clause 1 consisting essentially of, or consisting of:

[0278] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL (based on weight of carfilzomib);

[0279] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG) and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 25-65% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0280] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM; - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0281] Clause 91. The storage stable liquid solution composition according to clause 1 comprising:

[0282] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL (based on weight of carfilzomib);

[0283] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 20-80% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v), wherein ethanol is present at a concentration of 0.5-30% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0284] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0285] Clause 92. The storage stable liquid solution composition according to clause 1 consisting essentially of, or consisting of:

[0286] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL (based on weight of carfilzomib);

[0287] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 5-25% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0288] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0289] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0290] Clause 93. The storage stable liquid solution composition according to clause 1 comprising: - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0291] - a solvent consisting essentially of (or consisting of) propylene glycol and water, wherein propylene glycol is present at a concentration of 85-99.5% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), wherein “v / v” is based on the total volume of the composition;

[0292] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0293] Clause 94. The storage stable liquid solution composition according to clause 1 consisting essentially of, or consisting of:

[0294] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0295] - a solvent consisting essentially of (or consisting of) propylene glycol and water, wherein propylene glycol is present at a concentration of 85-96% (v / v), in particular 90-96% (v / v), for example about 95% (v / v), and wherein water is present at a concentration of 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0296] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0297] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2

[0298] Clause 95. The storage stable liquid solution composition according to clause 1 comprising:

[0299] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0300] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 75-99% (v / v), wherein ethanol is present at a concentration of 0.5-24.5% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), wherein “v / v” is based on the total volume of the composition;

[0301] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2. Clause 96. The storage stable liquid solution composition according to clause 1 consisting essentially of, or consisting of:

[0302] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 1-4 mg / mL, for example about 1-3 mg / mL, for example about 2 mg / mL;

[0303] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 80-95% (v / v), in particular 80-90% (v / v), for example about 85% (v / v), wherein ethanol is present at a concentration of 4.5-19.5% (v / v), in particular 4.5-15.5% (v / v), for example about 10% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), such as 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0304] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0305] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0306] Clause 97. The storage stable liquid solution composition according to claim 1 comprising:

[0307] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL (based on weight of carfilzomib);

[0308] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 20-80% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v), wherein ethanol is present at a concentration of 0.5-30% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0309] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0310] Clause 98. The storage stable liquid solution composition according to claim 1 consisting essentially of, or consisting of:

[0311] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL (based on weight of carfilzomib);

[0312] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 5-25% (v / v) and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0313] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0314] - optionally an antioxidant wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0315] Clause 99. The storage stable liquid solution composition according to claim 1 consisting essentially of, or consisting of:

[0316] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-8 mg / mL, for example about 4 mg / mL, about 6 mg / mL, or about 8 mg / mL (based on weight of carfilzomib);

[0317] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of 30-70% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 15-45% (v / v), wherein ethanol is present at a concentration of 10-20% (v / v), for example about 10% (v / v) or about 20% (v / v), and wherein water is present at a concentration of 4-10% (v / v), in particular about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0318] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0319] - optionally an antioxidant wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0320] Clause 100. The storage stable liquid solution composition according to claim 1 consisting essentially of, or consisting of:

[0321] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4 mg / mL (based on weight of carfilzomib);

[0322] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 65% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 20% (v / v), wherein ethanol is present at a concentration of about 10% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0323] - glycine, at a concentration of about 50 mM;

[0324] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0. Clause 101. The storage stable liquid solution composition according to claim 1 consisting essentially of, or consisting of:

[0325] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4 mg / mL (based on weight of carfilzomib);

[0326] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 55% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 30% (v / v), wherein ethanol is present at a concentration of about 10% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0327] - glycine, at a concentration of about 50 mM;

[0328] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0329] Clause 102. The storage stable liquid solution composition according to claim 1 consisting essentially of, or consisting of:

[0330] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 6 mg / mL (based on weight of carfilzomib);

[0331] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 65% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 20% (v / v), wherein ethanol is present at a concentration of about 10% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0332] - glycine, at a concentration of about 50 mM;

[0333] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0334] Clause 103. The storage stable liquid solution composition according to claim 1 consisting essentially of, or consisting of:

[0335] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 6 mg / mL (based on weight of carfilzomib);

[0336] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 60% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of about 20% (v / v), wherein ethanol is present at a concentration of about 15% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0337] - glycine, at a concentration of about 50 mM;

[0338] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0339] Clause 104. The storage stable liquid solution composition according to claim 1 consisting essentially of, or consisting of:

[0340] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 6 mg / mL (based on weight of carfilzomib);

[0341] - a solvent consisting essentially of (or consisting of) propylene glycol, polyethylene glycol (PEG), ethanol, and water, wherein propylene glycol is present at a concentration of about 35% (v / v), wherein polyethylene glycol (PEG) is present at a concentration of 40% (v / v), wherein ethanol is present at a concentration of about 20% (v / v), and wherein water is present at a concentration of about 5% (v / v), wherein “v / v” is based on the total volume of the composition ;

[0342] - glycine, at a concentration of about 50 mM;

[0343] - optionally an antioxidant wherein the pH of the composition is in the range 2.8-3.2, for example about 3.0.

[0344] Clause 105. The storage stable liquid solution composition according to claim 1 comprising:

[0345] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL;

[0346] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 75-99% (v / v), wherein ethanol is present at a concentration of 0.5-24.5% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), wherein “v / v” is based on the total volume of the composition;

[0347] - a neutral amino acid, for example glycine, at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0348] Clause 106. The storage stable liquid solution composition according to claim 1 consisting essentially of, or consisting of:

[0349] - carfilzomib or a pharmaceutically acceptable salt thereof, at a concentration of about 4-10 mg / mL, for example about 4-8 mg / mL, for example about 4-6 mg / mL or about 6-8 mg / mL;

[0350] - a solvent consisting essentially of (or consisting of) propylene glycol, ethanol, and water, wherein propylene glycol is present at a concentration of 80-95% (v / v), in particular 80-90% (v / v), for example about 85% (v / v), wherein ethanol is present at a concentration of 4.5-19.5% (v / v), in particular 4.5-15.5% (v / v), for example about 10% (v / v), and wherein water is present at a concentration of 0.5-15% (v / v), such as 4-15% (v / v), in particular 4-10% (v / v), for example about 5% (v / v), wherein “v / v” is based on the total volume of the composition;

[0351] - a neutral amino acid, for example glycine, at a concentration of 25-75 mM, for example about 50 mM;

[0352] - optionally an antioxidant; wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.8-3.2.

[0353] Clause 107. The storage stable liquid solution composition according to any one of clauses 1 to 106 which suffers degradation as determined in the RP-HPLC Method described in General Methods of no more than 3% e.g. no more than 2% e.g. no more than 1 % after storage at 2-8 °C for 12 weeks, 6 months or 12 months (e.g. no more than 3% after storage at 2-8 °C for 12 months).

[0354] Clause 108. A process for the preparation of a ready-to-administer carfilzomib composition comprising the step of diluting a storage stable liquid solution composition according to any one of clauses 1 to 107 with a diluent suitable for intravenous administration.

[0355] Clause 109. The process according to clause 108 wherein the diluent is selected from 0.9% saline, 5% dextrose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection).

[0356] Clause 110. The process according to clause 108 or clause 109 wherein the concentration of carfilzomib or the pharmaceutically acceptable salt thereof after dilution is 0.1 -1.5 mg / mL, for example 0.2-1.3 mg / mL (based on weight of carfilzomib).

[0357] Clause 111. A ready-to-administer carfilzomib composition comprising a storage stable liquid solution composition according to any one of clauses 1 to 107 diluted with a diluent suitable for intravenous administration.

[0358] Clause 112. The ready-to-administer carfilzomib composition according to clause 111 wherein the diluent is selected from 0.9% saline, 5% dextrose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection).

[0359] Clause 113. The ready-to-administer carfilzomib composition according to clause 111 or clause 112, wherein the concentration of carfilzomib or the pharmaceutically acceptable salt thereof in the composition is 0.1-1.5 mg / mL, for example 0.2-1.3 mg / mL (based on weight of carfilzomib).

[0360] Clause 114. The storage stable liquid solution composition according to any one of clauses 1 to 107, or the ready-to-administer carfilzomib composition according to any one of clauses 111 to 113, which is a pharmaceutical composition.

[0361] Clause 115. The storage stable liquid solution composition according to any one of clauses 1 to 107, the ready-to-administer carfilzomib composition according to any one of clauses 111 to 113, or the pharmaceutical composition according to clause 114, for use in therapy.

[0362] Clause 116. The storage stable liquid solution composition for use, the ready-to-administer carfilzomib composition for use, or the pharmaceutical composition for use according to clause

[0363] 115, for use in treating cancer, for example multiple myeloma.

[0364] Clause 117. The storage stable liquid solution composition for use, the ready-to-administer carfilzomib composition for use, or the pharmaceutical composition for use according to clause

[0365] 116, for use in treating multiple myeloma.

[0366] Clause 118. A method of treating cancer, for example multiple myeloma, which comprises administering to a patient in need thereof a therapeutically effective amount of a storage stable liquid solution composition according to any one of clauses 1 to 107, a ready-to-administer carfilzomib composition according to any one of clauses 111 to 113, or a pharmaceutical composition according to clause 114.

[0367] Clause 119. Use of a storage stable liquid solution composition according to any one of clauses 1 to 107, a ready-to-administer carfilzomib composition according to any one of clauses 111 to 113, or a pharmaceutical composition according to clause 114, for the manufacture of a medicament for use in the treatment of cancer, for example multiple myeloma.

[0368] Clause 120. The storage stable liquid solution composition for use, the ready-to-administer carfilzomib composition for use, the pharmaceutical composition for use, method, or use according to any one of clauses 115 to 119, for use in combination with one or more further therapeutic agent(s). Clause 121. The storage stable liquid solution composition for use, the ready-to-administer carfilzomib composition for use, the pharmaceutical composition for use, method, or use according to clause 120, wherein the one or more further therapeutic agent(s) is / are selected from the group consisting of dexamethasone, lenalidomide and anti-CD38 antibodies such as daratumumab.

[0369] Clause 122. A vial which is suitably a glass vial containing the storage stable liquid solution composition according to any one of clauses 1 to 107.

[0370] Clause 123. The vial according to clause 122, which is a multiple dose vial.

[0371] Examples

[0372] General Methods

[0373] Reversed-Phase Chromatography Method (RP-HPLC)

[0374] High performance reverse phase chromatography is performed using the Thermo-Scientific Ultimate 3000 HPLC with variable wavelength detector (VWD3400) with a Zorbax Stable Bond C18 250 mm by 4.6 mm, 3.5 pm particle size and 80 A pore size. Mobile Phase A is 0.1% Trifluoroacetic acid (TFA) in water. Mobile Phase B is 0.1% TFA in acetonitrile. The sample comprising carfilzomib (or pharmaceutically acceptable salt thereof) is bound in a ratio of Mobile Phase A 70% and mobile phase B 30% (using online mixing in the HPLC) and eluted using a gradient consisting of increasing proportions of Mobile Phase B in the range of 50- 90%. The sample volume is 10 pL, the flow rate is 2.0 mL / min, with 210 nm UV detection. All analyses are performed at 25 °C.

[0375] Visual Assessment Method

[0376] Visual assessment (appearance) is performed essentially following the 2.9.20. European Pharmacopoeia Monograph (Particulate Contamination: Visible Particles). The apparatus required consists of a viewing station comprising:

[0377] • a matt black panel of appropriate size held in a vertical position

[0378] • a non-glare white panel of appropriate size held in a vertical position next to the black panel

[0379] • an adjustable lampholder fitted with a suitable, shaded, white-light source and with a suitable light diffuser (a viewing illuminator containing two 13 W fluorescent tubes, each 525 mm in length, is suitable). The intensity of illumination at the viewing point is maintained between 2000 lux and 3750 lux.

[0380] Any adherent labels are removed from the container and the outside washed and dried. The container is gently swirled or inverted, ensuring that air bubbles are not introduced, and observed for about 5 s in front of the white panel. The procedure is repeated in front of the black panel. The presence of any particles and opalescence is recorded. The visual scores are ranked as follows in the experiments reported here:

[0381] Visual score: Clear (no opalescence and free or virtually free of particles)

[0382] Visual score: Slightly opalescent

[0383] Visual score: Opalescent

[0384] Example 1 : Solubility of carfilzomib in aqueous environments and organic solvents

[0385] The solubility of carfilzomib, at a target concentration of 2 mg / mL, in selected solvents and mixtures of solvents is shown in Table 1. Carfilzomib was confirmed to be insoluble in water at this concentration. Presence of a non-ionic surfactant (polysorbate 80) did not appear to improve solubility in water. Carfilzomib was shown to be soluble in several organic solvents, including propylene glycol, PEG200, PEG400 and DMSO. Some of the organic solvents tested did not appear to enable solubilization of carfilzomib, e.g., glycerol and ethylene glycol.

[0386] Table 1 : Solubility of carfilzomib (2 mg / mL) in selected solvents

[0387] Example 2: Impact on solubility of carfilzomib, in solutions in propylene glycol, of the presence of water Addition of water to carfilzomib solutions prepared in organic solvents enables inclusion of ionic excipients in the composition, that would otherwise be insoluble in organic solvents. Table 2 shows that addition of up to 10% (v / v based on the total volume of the composition) of water to compositions based on propylene glycol is possible. The dissolution process was slower in the presence of water, but the final compositions were clear. Moreover, Table 2 shows that the presence of 50% (v / v based on the total volume of the composition) water was not found to facilitate solubilization of carfilzomib (2 mg / mL).

[0388] Table 2: Solubility of carfilzomib (2 mg / mL) in propylene glycol and mixtures of propylene glycol and water

[0389] (v / v based on the total volume of the composition)

[0390] Example 3: The effect of water on the stability of carfilzomib solutions prepared in propylene glycol

[0391] The stability of the following propylene glycol-based carfilzomib compositions (2 mg / mL) (pH not measured but ca 3.0) was assessed by RP-HPLC following storage at 40°C for 7 days (see Table 3). The presence of 2% (v / v) water did not appear to impact the chemical stability of carfilzomib. Furthermore, only a slight (between 1 % and 2%) decrease in chemical stability was observed in the presence of 5% (v / v) and 10% (v / v) water.

[0392] Table 3: Solvent systems of formulations used to investigate the effect of water on the stability of carfilzomib Example 4: The effect of pH on the stability of carfilzomib solutions

[0393] Carfilzomib compositions (2 mg / mL) comprising propylene glycol (95% v / v based on the total volume of the composition), water (5% v / v based on the total volume of the composition) and citrate buffer (5 mM) were produced at pH 3.0, 4.0, 5.0, 6.0 and 7.0. The chemical stability (assessed by RP-HPLC purity method) of the compositions was assessed prior to, and following, storage at 40°C for 2 weeks. Table 3 shows that compositions with pH 3.0-5.0 were found to have optimal stability, that is they experienced the smallest decrease in purity. The stability of carfilzomib compositions at pH 6.0 and at pH 7.0 was significantly reduced.

[0394] Table 4: The effect of pH on the chemical stability of carfilzomib compositions

[0395] Example 5: Assessment of the stability of carfilzomib in different solvents and with different excipients following dilution of ready-to-dilute compositions

[0396] Ready-to-dilute carfilzomib compositions must be diluted into a suitable solvent, such as 5% dextrose prior to administration, for example by intravenous infusion. In the present experiment, carfilzomib (2 mg / mL) compositions based on selected solvent components (see Table 5) were diluted into an aqueous 5% dextrose solution to produce a ready-to-administer composition comprising 0.1 or 1 .2 mg / mL carfilzomib. The appearance of the dextrose solution following dilution was recorded using the Visual Assessment Method (see General Methods). Opalescence is an indication of carfilzomib insolubility and such a ready-to-administer composition, and the ready-to-dilute composition from which it is derived, would be unsuitable for use. Table 4 shows that many carfilzomib compositions based on various organic solvents, with or without water, produced unacceptable opalescence following dilution and as such said compositions would be unsuitable for a ready-to-dilute product.

[0397] Table 5: Appearance of the 5% dextrose solution following addition of carfilzomib (2 mg / mL) in selected solvents to achieve 0.1 mg / mL and 1.2 mg / mL final carfilzomib concentrations.

[0398] (v / v based on the total volume of the composition)

[0399] It was subsequently investigated whether addition of water and an acid or an amino acid can overcome the opalescence recorded in Table 5. In particular, ready-to-dilute compositions comprising carfilzomib (2 mg / mL), propylene glycol, and water (5% v / v based on the total volume of the composition, save for the control) were prepared containing acids or the amino acid glycine at two different concentrations (25 mM or 50 mM). Said compositions were then diluted into an aqueous 5% dextrose solution to produce a ready-to-administer composition comprising 0.1 , 0.5, or 1.2 mg / mL carfilzomib. The pH of a concentrated stock solution of amino acid in water was adjusted to 3.0 with hydrochloric acid before the appropriate volume of stock solution was added to the propylene glycol component and mixed. Carfilzomib was subsequently added and dissolved. Table 6 shows that ready-to-dilute compositions comprising 5% (v / v based on the total volume of the composition) water and glycine produced ready-to-administer compositions which were clear according to the Visual Assessment Method (see General Methods). The preferred concentration of glycine in the ready-to-dilute composition is 25-50 mM. Excipients tested as alternatives to glycine (e.g. citric acid, acetic acid, ascorbic acid, gluconic acid) improved the visual appearance but none of them resulted in clear solutions across the whole concentration range (0.1 , 0.5 and 1.2 mg / mL carfilzomib).

[0400] Table 6: Appearance of the 5% dextrose solution following addition of carfilzomib (2 mg / mL) in selected solvents to achieve 0.1 mg / mL, 0.5 mg / mL and 1.2 mg / mL final carfilzomib concentrations. Compositions contained propylene glycol (PG) plus the additional components stated in the table.

[0401] (v / v based on the total volume of the composition)

[0402] Glycine is a neutral amino acid. Without being limited by theory, the beneficial effect on physical stability of inclusion of a neutral amino acid is rationalised by the inventors as follows: The reported pKa of carfilzomib is 5.1 and consequently carfilzomib is positively charged at a pH between 2.5 and 4.0. It is believed that the positive net charge of the neutral amino acid causes repulsion of carfilzomib molecules in solution and makes them less likely to aggregate, leading to opalescence. The neutral amino acid is also expected to provide a favourable buffering effect. By contrast, amino acids and other organic molecules with a net negative charge can lead to formation of ionic bridge between the carfilzomib molecules in solution and thus increase the likelihood of aggregation. Example 6: Effect of pH on appearance of carfilzomib compositions containing glycine following dilution

[0403] The effect of pH on the appearance of ready-to-dilute compositions after dilution with 5% dextrose solution was investigated. Compositions comprising carfilzomib (2 mg / mL), 95% (v / v based on the total volume of the composition) propylene glycol, 5% (v / v based on the total volume of the composition) water and 50 mM glycine were diluted into an agueous 5% dextrose solution to produce a ready-to-administer composition comprising 0.1, 0.5, or 1.2 mg / mL carfilzomib. The pH of a concentrated stock solution of amino acid in water was adjusted to 3.0, 4.0, 5.0, 6.0 or 7.0 with hydrochloric acid (as reguired) before the appropriate volume of stock solution was added to the propylene glycol component and mixed. Carfilzomib was subseguently added and dissolved. Table 7 shows that compositions at pH 3.0 resulted in clear solutions upon addition to 5% dextrose. Mild opalescence was observed when using ready-to-dilute compositions at pH 4.0. Significant opalescence was observed when using ready-to-dilute compositions at pH 5.0, 6.0 and 7.0.

[0404] Table 7: The effect of pH on the appearance of 5% dextrose solution following addition of carfilzomib (2 mg / mL) in a composition comprising 95% (v / v based on the total volume of the composition) propylene glycol, 5% (v / v based on the total volume of the composition) water and 50 mM glycine to achieve 0.1 mg / mL, 0.5 mg / mL and 1.2 mg / mL final carfilzomib concentrations. Subsequent experiments investigated whether the opalescence observed upon dilution of ready-to-dilute compositions in 5% dextrose can be minimised by adding ethanol to the ready-to-dilute composition. Compositions comprising carfilzomib (2 mg / mL), propylene glycol (variable % based on the total volume of the composition), water (5% v / v based on the total volume of the composition), and citric acid (25 mM or 50 mM) or glycine (25 mM), had different quantities (5%, 10% or 20% v / v based on the total volume of the composition) of ethanol added. Said compositions were diluted into an aqueous 5% dextrose solution to produce a ready-to-administer composition comprising 0.1 , 0.5, or 1.2 mg / mL carfilzomib. All compositions were prepared at pH 3.0 as described above. Table 8 shows that addition of ethanol to compositions containing 25 mM glycine improves the appearance of the ready-to- administer composition. The optimal concentration of ethanol appears to be around 10% (v / v based on the total volume of the composition). In contrast, ethanol was shown to not improve the visual appearance of compositions containing citrate (25 mM or 50 mM) instead of glycine.

[0405] Table 8: Appearance of the 5% dextrose solution following addition of carfilzomib (2 mg / mL) in selected solvent systems to achieve 0.1 mg / mL, 0.5 mg / mL and 1.2 mg / mL final carfilzomib concentrations. Compositions contained propylene glycol plus additional components stated in the table.

[0406]

[0407] (v / v based on the total volume of the composition)

[0408] Example 7: Preparation of 4 mq / mL carfilzomib compositions

[0409] The following example formulation was prepared: carfilzomib (4 mg / mL), 95% (v / v based on the total volume of the composition) propylene glycol, 5% (v / v based on the total volume of the composition) water and 50 mM glycine. Upon dilution into 5% dextrose there was no development of opalescence. The carfilzomib concentration in this ready-to-dilute composition is potentially beneficial as, relative to compositions comprising 2 mg / mL, the ready-to-administer compositions produced after dilution will contain about half the quantity of excipients delivered to the patient in a given dose.

[0410] Example 8: Stability of ready-to-dilute carfilzomib compositions at 2-8°C

[0411] The following compositions were prepared:

[0412] Composition A: carfilzomib (2 mg / mL), 85% (v / v based on the total volume of the composition) propylene glycol, 10% (v / v based on the total volume of the composition) ethanol, 5% (v / v based on the total volume of the composition) water and 50 mM glycine, pH 3.0

[0413] Composition B: carfilzomib (4 mg / mL), 85% (v / v based on the total volume of the composition) propylene glycol, 10% (v / v based on the total volume of the composition) ethanol, 5% (v / v based on the total volume of the composition) water and 50 mM glycine, pH 2.8. The stability of Composition A and Composition B was assessed by the Visual Assessment Method and by RP-HPLC (see General Methods) following storage at 2-8°C for 12 weeks. Both compositions remained clear by visual assessment following storage at 2-8°C for 12 weeks. The RP-HPLC results are shown in Table 9. Only a small loss in carfilzomib purity (i.e. % intact carfilzomib, approximately 1%) was observed in both compositions following storage at 2-8°C for 12 weeks. This percentage is a chromatographic purity based on the RP-HPLC Method (see General Methods). It approximates to w / w but there may be some discrepancy due to differences in extinction coefficients of impurities and carfilzomib at the wavelength used.

[0414] Table 9: Purity (i.e. % intact carfilzomib) of Composition A and Composition B assessed by RP-HPLC.

[0415] Example 9: Assessment of solubility of carfilzomib in 4 mg / mL carfilzomib compositions and assessment of stability of said compositions following dilution

[0416] As noted above, it is advantageous to develop a ready-to-dilute composition comprising carfilzomib at a concentration of greater than 2 mg / mL, for example at 4 mg / mL, 6 mg / mL, or even 8 mg / mL, since the ready-to-administer compositions produced after dilution will contain about a much lower guantity of pharmaceutical excipients which will then be delivered to the patient in a given dose. This is associated with a number of benefits including improved regulatory acceptability, reduced risk to patients and conseguently improved patient compliance.

[0417] The solubility of carfilzomib, at a target concentration of 4 mg / mL, in selected organic solvent systems comprising propylene glycol, ethanol and, optionally, PEG300 is shown in Table 10. All compositions comprised carfilzomib (4 mg / mL), water (5% v / v based on the total volume of the composition), and glycine (50 mM), in view of the above Examples 1 to 8 which demonstrated the utility of these excipients in carfilzomib compositions. All compositions were prepared at pH 3.0. In particular, it was shown that propylene glycol can be replaced by PEG300 up to a concentration of 50% (v / v based on the total volume of the composition) in a formulation comprising 10% (v / v based on the total volume of the composition) ethanol. This is advantageous since it facilitates a reduction in the concentration of propylene glycol in the carfilzomib composition and therefore a reduction in the amount of propylene glycol delivered to a patient.

[0418] Table 10: Solubility of carfilzomib (4 mg / mL) in organic solvents comprising propylene glycol, ethanol and, optionally, PEG300

[0419] Subsequent experiments investigated whether formulations comprising 4 mg / mL carfilzomib and the above organic solvent systems comprising propylene glycol, ethanol and, optionally, PEG300, are stable upon dilution of said ready-to-dilute compositions. In particular, the above compositions were diluted into an aqueous 5% dextrose solution to produce a ready-to- administer composition comprising 0.1 , 0.5, or 1.2 mg / mL carfilzomib. The ready-to-administer compositions were then assessed by the Visual Assessment Method (see General Methods) in order to detect any opalescence, which is an indicator of carfilzomib insolubility and instability. Table 11 shows that compositions comprising 4 mg / mL carfilzomib remain stable upon replacement of propylene glycol with PEG300, up to a concentration of 50% (v / v based on the total volume of the composition), in particular in the context of a formulation further comprising 10% (v / v based on the total volume of the composition) ethanol, 5% (v / v based on the total volume of the composition) water, and 50 mM glycine.

[0420] Table 11 : Appearance of the 5% dextrose solution following addition of carfilzomib (4 mg / mL) in selected solvent systems to achieve 0.1 mg / mL, 0.5 mg / mL and 1.2 mg / mL final carfilzomib concentrations.

[0421] Example 10: Assessment of solubility of carfilzomib in 6 mg / mL carfilzomib compositions and assessment of stability of said compositions following dilution

[0422] As discussed above, it is desirable to develop ready-to-dilute compositions comprising carfilzomib at a high concentration of for example 4 mg / mL, 6 mg / mL, or 8 mg / mL.

[0423] The solubility of carfilzomib, at a target concentration of 6 mg / mL, in organic solvent systems comprising propylene glycol and ethanol only is shown in Table 12. All compositions comprised carfilzomib (6 mg / mL), water (5% v / v based on the total volume of the composition), and glycine (50 mM), and were prepared at pH 3.0. In particular, formulations comprising propylene glycol and ethanol only as organic solvents did not appear to enable solubilization of carfilzomib at the higher concentration of 6 mg / mL, despite the suitability of such solvent systems at the lower carfilzomib concentrations of 2 mg / mL and 4 mg / mL (see, for example, Examples 7 and 9).

[0424] Table 12: Solubility of carfilzomib (6 mg / mL) in organic solvents comprising propylene glycol and ethanol

[0425] Further experiments investigated whether further organic solvent systems comprising propylene glycol, ethanol, and a further organic solvent, such as PEG300, PEG400 or glycerol, could facilitate solubilization of 6 mg / mL carfilzomib, the results of which are shown in Table 13. All compositions comprised carfilzomib (6 mg / mL), water (5% v / v based on the total volume of the composition), and glycine (50 mM), and were prepared at pH 3.0.

[0426] Specifically, formulations comprising propylene glycol, ethanol, and PEG300 as the organic solvent appeared to facilitate solubilization of 6 mg / mL carfilzomib, although the relative amounts of these organic solvents could be varied (e.g. 35% to 65% (v / v) propylene glycol, 5% to 20% (v / v) ethanol, and 15% to 40% (v / v) PEG 300, wherein “v / v” is based on the total volume of the composition) whilst retaining suitability of the solvent system. Whilst the addition of PEG300 to the propylene glycol and ethanol solvent system had a positive impact on the solubility of 6 mg / mL carfilzomib, PEG400 and glycerol fail to have the same positive impact on said solubility since their inclusion (at the same concentration as PEG300) fails to enable solubilization of 6 mg / mL carfilzomib.

[0427] Table 13: Solubility of carfilzomib (6 mg / mL) in organic solvents comprising propylene glycol, ethanol, and a further organic solvent selected from PEG300, PEG400 and glycerol

[0428] Subsequent experiments investigated whether formulations comprising 6 mg / mL carfilzomib and the above organic solvent systems which facilitated the required solubilization of 6 mg / mL carfilzomib (i.e. comprising propylene glycol, ethanol, and PEG300), are stable upon dilution of the ready-to-dilute compositions. In particular, the compositions were diluted into an aqueous 5% dextrose solution to produce a ready-to-administer composition comprising 0.1 , 0.5, or 1.2 mg / mL carfilzomib. The ready-to-administer compositions were then assessed by the Visual Assessment Method (see General Methods) in order to detect any opalescence, which is an indicator of carfilzomib insolubility and instability. Table 14 shows that compositions comprising 6 mg / mL carfilzomib and an organic solvent component consisting of propylene glycol, ethanol and PEG300 at different concentrations remain stable upon dilution, in particular in the context of a formulation of pH 3.0 further comprising 5% (v / v based on the total volume of the composition) water, and 50 mM glycine.

[0429] Table 14: Appearance of the 5% dextrose solution following addition of carfilzomib (6 mg / mL) in selected solvent systems to achieve 0.1 mg / mL, 0.5 mg / mL and 1.2 mg / mL final carfilzomib concentrations.

[0430] Miscellaneous

[0431] All patents, patent applications and references mentioned throughout the specification of the present invention are herein incorporated in their entirety by reference.

[0432] Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.

[0433] As used herein when referring to the composition of the invention, the term “consists of” means that no further components are included in the composition other than those listed. As used herein when referring to the composition of the invention, the term “consists essentially of” means that further components can be present but said components do not materially affect the essential characteristics of the composition, and are typically present in a de minimis amount.

[0434] The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

[0435] The invention embraces all combinations of preferred and more preferred groups and suitable and more suitable groups and embodiments of groups recited above.

Claims

Claims1. A storage stable liquid solution composition comprising:(i) carfilzomib or a pharmaceutically acceptable salt thereof;(ii) a solvent consisting of (a) an organic solvent component comprising propylene glycol optionally together with polyethylene glycol (PEG) wherein the propylene glycol optionally together with polyethylene glycol (PEG) is present at a total concentration of at least about 65% (v / v based on the total volume of the composition) and (b) water at a concentration of no more than about 15% (v / v based on the total volume of the composition); and(iii) a neutral amino acid; wherein the pH of the composition is in the range 2.5 to 4.0.

2. The storage stable liquid solution composition according to claim 1, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is 1-10 mg / mL, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg / mL (based on weight of carfilzomib).

3. The storage stable liquid solution composition according to claim 2, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 1-4 mg / mL, for example about 1-3 mg / mL (based on weight of carfilzomib).

4. The storage stable liquid solution composition according to claim 3, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 2 mg / mL (based on weight of carfilzomib).

5. The storage stable liquid solution composition according to claim 2, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 4-10 mg / mL, for example about 4-8 mg / mL (based on weight of carfilzomib).

6. The storage stable liquid solution composition according to claim 5, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 4 mg / mL, about 6 mg / mL, or about 8 mg / mL (based on weight of carfilzomib)..

7. The storage stable liquid solution composition according to claim 6, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 4 mg / mL (based on weight of carfilzomib).

8. The storage stable liquid solution composition according to claim 6, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 6 mg / mL (based on weight of carfilzomib).

9. The storage stable liquid solution composition according to claim 6, wherein the concentration of carfilzomib or a pharmaceutically acceptable salt thereof in the composition is about 8 mg / mL (based on weight of carfilzomib).

10. The storage stable liquid solution composition according to any one of claims 1 to 9, wherein the organic solvent component is present in the composition at a total concentration of about 85-99.5% (v / v based on the total volume of the composition), for example about 85- 96% (v / v based on the total volume of the composition), for example about 90-96% (v / v based on the total volume of the composition) or about 95% (v / v based on the total volume of the composition).

11. The storage stable liquid solution composition according to any one of claims 1 to 4, wherein the organic solvent component consists of propylene glycol and polyethylene glycol (PEG) and an optional additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

12. The storage stable liquid solution composition according to claim 11, wherein the organic solvent component consists of propylene glycol and polyethylene glycol (PEG).

13. The storage stable liquid solution composition according to claim 11 , wherein the organic solvent component consists of propylene glycol, polyethylene glycol (PEG) and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

14. The storage stable liquid solution composition according to claim 13, wherein the organic solvent component consists of propylene glycol, polyethylene glycol (PEG), and ethanol.

15. The storage stable liquid solution composition according to any one of claims 1, 2, and 5 to 10, wherein the organic solvent component consists of propylene glycol and polyethylene glycol (PEG) and an additional organic solvent selected from the groupconsisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

16. The storage stable liquid solution composition according to claim 15, wherein the organic solvent component consists of propylene glycol, polyethylene glycol (PEG), and ethanol.

17. The storage stable liquid solution composition according to claim 12, wherein propylene glycol is present at a concentration of 20-85% (v / v based on the total volume of the composition), for example 25-80% (v / v based on the total volume of the composition), for example 30-75% (v / v based on the total volume of the composition), for example 30-70% (v / v based on the total volume of the composition), and wherein polyethylene glycol (PEG) is present at a concentration of 10-75% (v / v based on the total volume of the composition), for example 15-70% (v / v based on the total volume of the composition), for example 20-65% (v / v based on the total volume of the composition), for example 25-65% (v / v based on the total volume of the composition).

18. The storage stable liquid solution composition according to any one of claims 13 to 16, wherein propylene glycol is present at a concentration of 20-80% (v / v based on the total volume of the composition), for example 25-75% (v / v based on the total volume of the composition), for example 30-75% (v / v based on the total volume of the composition), for example 30-70% (v / v based on the total volume of the composition), and wherein polyethylene glycol (PEG) is present at a concentration of at a concentration of 10-50% (v / v based on the total volume of the composition), for example 15-50% (v / v based on the total volume of the composition), for example 15-45% (v / v based on the total volume of the composition), and wherein the additional organic solvent is present at a concentration of 0.5- 30% (v / v based on the total volume of the composition), for example 5-30% (v / v based on the total volume of the composition), for example 5-25% (v / v based on the total volume of the composition), for example 10-20% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition) or about 20% (v / v based on the total volume of the composition).

19. The storage stable liquid solution composition according to any one of claims 13 to 16, and 18, wherein propylene glycol is present at a concentration of 20-80% (v / v based on the total volume of the composition), for example 25-75% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of 10-50% (v / v based on the total volume of the composition), for example 15-50% (v / v based on thetotal volume of the composition), and wherein ethanol is present at a concentration of 0.5- 30% (v / v based on the total volume of the composition), for example 5-30% (v / v based on the total volume of the composition).

20. The storage stable liquid solution composition according to any one of claims 13 to 16, 18, and 19, wherein propylene glycol is present at a concentration of about 25-75% (v / v based on the total volume of the composition), for example about 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65%, or 70% (v / v based on the total volume of the composition), wherein polyethylene glycol (PEG) is present at a concentration of about 15-50% (v / v based on the total volume of the composition), for example about 20%, 25%, 30%, 35%, 40%, or 45% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of about 5-30% (v / v based on the total volume of the composition), for example about 10%, 15%, 20%, or 25% (v / v based on the total volume of the composition).

21. The storage stable liquid solution composition according to any one of claims 1 to 10, wherein the organic solvent component consists of propylene glycol and an additional organic solvent selected from the group consisting of ethanol, glycerol, dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide (DMSO) and mixtures thereof.

22. The storage stable liquid solution composition according to claim 21, wherein the organic solvent component consists of propylene glycol and ethanol.

23. The storage stable liquid solution composition according to claim 21 or claim 22, wherein propylene glycol is present at a concentration of 80-90% (v / v based on the total volume of the composition), for example about 85% (v / v based on the total volume of the composition), and wherein the additional organic solvent is present at a concentration of 4.5- 15.5% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition).

24. The storage stable liquid solution composition according to any one of claims 21 to 23, wherein propylene glycol is present at a concentration of 80-90% (v / v based on the total volume of the composition), for example about 85% (v / v based on the total volume of the composition), and wherein ethanol is present at a concentration of 4.5-15.5% (v / v based on the total volume of the composition), for example about 10% (v / v based on the total volume of the composition).

25. The storage stable liquid solution composition according to any one of claims 1 to 24, wherein polyethylene glycol (PEG) comprises one or more polyethylene glycol (PEG) polymers selected from the group consisting of PEG200, PEG300, PEG400 and PEG600.

26. The storage stable liquid solution composition according to claim 25, wherein polyethylene glycol (PEG) comprises PEG300.

27. The storage stable liquid solution composition according to claim 26, wherein polyethylene glycol (PEG) consists of PEG300.

28. The storage stable liquid solution composition according to any one of claims 1 to 27, wherein water is present at a concentration of 0.5-15% (v / v based on the total volume of the composition), for example 0.5-12% (v / v based on the total volume of the composition), for example 2-12% (v / v based on the total volume of the composition), for example 4-12% (v / v based on the total volume of the composition), for example 4-10% (v / v based on the total volume of the composition).

29. The storage stable liquid solution composition according to claim 28, wherein water is present at a concentration of 4-10% (v / v based on the total volume of the composition), for example about 5% (v / v based on the total volume of the composition).

30. The storage stable liquid solution composition according to any one of claims 1 to 29, wherein the neutral amino acid is selected from the group consisting of alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

31. The storage stable liquid solution composition according to claim 30, wherein the neutral amino acid is selected from the group consisting of alanine, asparagine, glutamine, glycine, isoleucine, leucine, methionine, proline, serine, threonine, and valine.

32. The storage stable liquid solution composition according to claim 31, wherein the neutral amino acid is selected from the group consisting of glycine, methionine, and proline.

33. The storage stable liquid solution composition according to claim 32, wherein the neutral amino acid is glycine.

34. The storage stable liquid solution composition according to any one of claims 1 to 33, wherein the neutral amino acid is present at a concentration of 10-100 mM, for example 25- 75 mM, for example about 50 mM.

35. The storage stable liquid solution composition according to any one of claims 1 to 34, wherein the pH of the composition is in the range 2.5 to 3.5, for example about 2.6 to 3.4, 2.8 to 3.2, or about 3.0.

36. The storage stable liquid solution composition according to any one of claims 1 to 35, further comprising an antioxidant which is not a neutral amino acid.

37. The storage stable liquid solution composition according to claim 36, wherein the antioxidant is selected from the group consisting of monothioglycerol, butylated hydroxyanisole, butylated hydroxytoluene and glutathione (reduced).

38. The storage stable liquid solution composition according to any one of claims 1 to 37, wherein the composition is substantially free of cyclodextrin, sugars, organic acids, organic acidifying agents and sugar acids.

39. A process for the preparation of a ready-to-administer carfilzomib composition comprising the step of diluting a storage stable liquid solution composition according to any one of claims 1 to 38 with a diluent suitable for intravenous administration.

40. The process according to claim 39 wherein the concentration of carfilzomib or the pharmaceutically acceptable salt thereof after dilution is 0.1 -1.5 mg / mL, for example 0.2-1.3 mg / mL (based on weight of carfilzomib).

41. A ready-to-administer carfilzomib composition comprising a storage stable liquid solution composition according to any one of claims 1 to 38 diluted with a diluent suitable for intravenous administration.

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