PHARMACEUTICAL COMPOSITIONS OF BORTEZOMIB

Abstract

The present invention relates to a sterile, ready-to-use, aqueous composition of bortezomib that is stable over its shelf life.

Claims

1. A sterile, ready-to-use, aqueous composition comprising 1 to 2.5 mg/ml of bortezomib, sufficient tonicity adjusting agent to provide an osmolality of from about 280 mosm/kg to about 360 mosm/kg, a solvent, a cosolvent and a pH of from about 4.5 to about 6.5, wherein the tonicity adjusting agent is mannitol, the solvent is ethanol, the cosolvent is propylene glycol, and wherein upon storage at 25° C. and 60% relative humidity for six months, the bortezomib content in the composition is not less than 90%, and the amount of impurities is as follows— a. Impurity B not more than 0.5% w/v, b. Impurity C not more than 0.5% w/v, c. Impurity I not more than 0.5% w/v, d. Impurity J not more than 0.5% w/v, and e. Total impurities not more than 3.5% w/v.

2. The sterile, ready-to-use, aqueous composition of claim 1 wherein the composition is free of preservatives.

3. (canceled)

4. The sterile, ready-to-use, aqueous composition of claim 3 wherein the amount of mannitol used ranges from about 1% w/v to about 5% w/v.

5. The sterile, ready-to-use, aqueous composition of claim 1 wherein the solvent and cosolvent are together present in an amount ranging from about 0.05% w/v to about 5% w/v.

6. (canceled)

7. The sterile, ready-to-use, aqueous composition of claim 1, wherein the composition further comprises a stabilizer and wherein the stabilizer is present in an amount ranging from about 0.01% w/v to about 2% w/v.

8. The sterile, ready-to-use, aqueous composition of claim 7 wherein the stabilizer is selected from the group consisting of arginine, alanine, glycine, methionine, lysine or proline, or a derivative or salt thereof, and mixtures thereof.

9. The sterile, ready-to-use, aqueous composition of claim 1 further comprising a chelating agent.

10. The sterile, ready-to-use, aqueous composition of claim 9 wherein the chelating agent is selected from DOTA (1, 4, 7, 10 tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid), EDTA (Ethylenediaminetetraacetic acid), ODDA (1, 4, 10, 13-tetraoxa-7, 16-diazacyclooctadecane-7), EGTA (ethylene glycol-bis (β-aminoethyl ether)-tetraacetic acid).

11. The sterile, ready-to-use, aqueous composition of claim 10 wherein the chelating agent is present in an amount of at least 0.005% w/v.

Description

DESCRIPTION

[0019] The present invention relates to a stable aqueous pharmaceutical composition of bortezomib for parenteral administration comprising [0020] a. bortezomib or its pharmaceutically acceptable salt [0021] b. one or more solvent(s) [0022] c. one or more cosolvent(s) [0023] d. one or more isotonicity agent(s) [0024] e. optionally one or more stabilizer(s) [0025] f. optionally a chelating agent

[0026] wherein the composition is a liquid that is ready-to-use and/or is ready-to-dilute for administration to a patient in need thereof, and is free of preservatives, antioxidants and buffers.

[0027] The present invention also provides stable aqueous pharmaceutical composition of bortezomib for parenteral administration comprising [0028] a. bortezomib or its pharmaceutically acceptable salt [0029] b. one or more solvent(s) [0030] c. one or more cosolvent(s) [0031] d. one or more isotonicity agent(s) [0032] e. optionally one or more stabilizer(s) [0033] f. optionally a chelating agent [0034] g. optionally one or more preservative(s)

[0035] wherein the composition is provided in the form of a multidose vial and is ready-to-use or ready-to-dilute.

[0036] According to the present invention, the bortezomib is present in the said composition in an amount ranging from about 0.05% w/v to about 0.5% w/v. The amount of bortezomib used in the liquid composition of the present invention ranges from about 0.5 mg/ml to about 5 mg/ml. In preferred embodiments, the amount of bortezomib in the composition is 2.5 mg/ml. In some other embodiments, the amount of bortezomib in the composition is 1 mg/ml.

[0037] The present invention comprises liquid compositions of bortezomib or its pharmaceutically acceptable salt in an aqueous solvent system comprising one or more solvents and cosolvents. These may be selected from, but are not limited to, glycerine, ethanol, propylene glycol, water and mixtures thereof. Preferred solvents are ethanol, propylene glycol, water and mixtures thereof. The aqueous liquid compositions of the present invention are concentrates comprising bortezomib or its pharmaceutically acceptable salt that are either (1) ready-to-dilute, i.e. can be diluted and administered intravenously, or (2) ready-to-use, i.e. can be administered subcutaneously without any further dilution. As such, the term “ready-to-use” covers use of the compositions of the present invention that can be administered without further dilution, as well as those that need dilution for intravenous administration.

[0038] The stable aqueous compositions of the present invention may further comprise cosolvents in suitable amounts. The compositions of the present invention may include solvents and cosolvents, or mixtures thereof, in amount ranging from about 0.05% w/v to about 5% w/v.

[0039] According to the present invention, the composition may comprise tonicity adjusting agents. Tonicity adjusting agents decrease the hemolysis of blood cells and reduce pain and irritation at the injection site. The stable aqueous compositions of the present invention have osmolality ranging between about 280 mosm/kg and about 360 mosm/kg. Tonicity adjusting agents that can be included in the compositions of the present invention may be selected from mannitol, lactose, dextrose, glycerol and mixtures thereof, to provide the desired osmolality. A preferred tonicity adjusting agent is mannitol. The amount of the tonicity adjusting agent used is such that the desired osmolality is obtained. According to the present invention, the amount of tonicity adjusting agent may range from about 1% w/v to about 5% w/v.

[0040] According to the present invention, the pharmaceutical composition may comprise one or more stabilizers. A stabilizer, when present, may be selected from the group comprising arginine, alanine, glycine, methionine, lysine or proline, or a derivative or salt thereof, and mixtures thereof, in a concentration of from about 0.01% w/v to about 2% w/v. A preferred stabilizer may be arginine.

[0041] According to the present invention, the pharmaceutical composition may comprise a chelating agent. The chelating agent may be selected from DOTA (1, 4, 7, 10 tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid), EDTA (Ethylenediaminetetraacetic acid), ODDA (1, 4, 10, 13-tetraoxa-7, 16-diazacyclooctadecane-7), EGTA (ethylene glycol-bis(β-aminoethyl ether)-tetraacetic acid). The amount of chelating agent, when present, may be at least about 0.005% w/v.

[0042] According to the present invention, the composition may be provided in single dose vials or multidose vials that are free from preservatives, antioxidants and buffers, or may be provided in the form of multidose vials containing preservative, but which are free of antioxidants and buffers. The amount and type of preservative(s), when present, is selected from those conventionally used in parenteral compositions and well-known in the pharmaceutical art.

[0043] The fill volume for the vials containing the bortezomib compositions of the present invention may vary from about 1 ml to about 10 ml. Typically, a single dose of bortezomib is included in a volume of about 1.4 ml, while multidose vials are available in a volume of 5 ml. The stable, ready-to-use aqueous compositions of the present invention are typically filled in USP Type-I clear glass vials and are stoppered with inert rubber stoppers that are typically used in the pharmaceutical arts.

[0044] According to the present invention, the pH of the composition is in the range of about 4.5 to about 6.5. The pH is critical to the stability of the compositions of the present invention, and help in providing liquid compositions that are stable over the shelf life.

[0045] The present invention also provides a process for the preparation of sterile stable aqueous injectable compositions of bortezomib or its pharmaceutically acceptable salt. The processes are detailed in the examples included herein below. The compositions of the present invention are prepared under aseptic manufacturing conditions and filled in suitable vials, i.e. either in single dose vials or multidose vials. The headspace of the vials is then charged with nitrogen, thereby providing a nitrogen blanket above the aqueous composition of the invention, and ensuring that the dissolved oxygen in the aqueous compositions is not more than 2 ppm.

[0046] The compositions of the present invention can be administered parenterally via an intravenous or a subcutaneous route. For administration by a subcutaneous route, the composition can be administered as is, and may not require further dilution. Typically, subcutaneous administration involves use at a concentration of 2.5 mg/ml of bortezomib. For administration by an intravenous route, the composition will need to be diluted prior to administration. Typically, intravenous administration involves use at a concentration of 1 mg/ml.

[0047] The sterile, ready-to-use, aqueous compositions of the present invention may be packaged in clear glass vials, followed by light resistant secondary packaging. The material of construction of the vials is such that stability and sterility of the bortezomib composition is not compromised over its shelf-life. The composition can be stored at a temperature of about 2° C. to about 8° C. As previously described, the pharmaceutical compositions of the present invention are preconcentrates that are ready-to-dilute for intravenous administration, and are ready-to-use for subcutaneous administration. The preconcentrate or ready-to-dilute compositions of the present invention may be diluted with conventional diluents used for intravenous administration in the pharmaceutical art, such as dextrose, normal saline and the like. Upon dilution and/or the first opening of the vial, the composition is stable for about 28 days, when stored at a temperature of about 2° C. to about 8° C. when protected from light, and is stable for up to 7 days when stored in the original vial at about 25 degrees Celsius in normal indoor lighting conditions.

[0048] The pharmaceutical composition of the present invention is stable such that the bortezomib content after storage at (i) a temperature of about 2° C. to about 8° C., and/or (ii) under accelerated storage conditions of 25° C. and 60% relative humidity for six months, is not less than 90%. Preferably, the bortezomib content ranges between 90% and about 110%. Under the above described storage conditions, the maximum unspecified impurities in the pharmaceutical composition are not more than about 0.5% by weight of the composition. Further, the total impurities in the pharmaceutical composition, under the storage conditions described above, are not more than about 3.5% by weight of the composition.

[0049] The preferred specification for the sterile, ready-to-use, aqueous composition of the present invention, when stored at about 2° C. to about 8° C., is as seen in Table 1 below. Such a composition has a shelf life of at least 12 months.

TABLE-US-00001 TABLE 1 Parameter Specification pH 4.5-6.5 Osmolality 280-360 mosm/kg Assay (%) NLT 90.0% to NMT 105.0% Impurity C NMT 0.5% Impurity B NMT 0.5% Impurity I NMT 0.5% Impurity J NMT 0.5% Maximum unspecified/unknown impurities NMT 0.5% Total impurities NMT 3.5%

[0050] The names and structures of the known impurities are provided below—

##STR00002##

Impurity C: (2S)-3-Phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanamide; or N-(1-Amino-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide

[0051] ##STR00003##

Impurity B: (2S)-3-Phenyl-2-[(pyrazin-2-ylcarbonyl) amino] propanoic acid; or N-(2-Pyrazinyl carbonyl)-L-phenylalanine; (S)-3-Phenyl-2-(pyrazine-2-carboxamido) propanoic acid

[0052] ##STR00004##

Impurity I: N—[(S)-1-{[(S)-1-Hydroxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide

[0053] ##STR00005##

Impurity J: N—[(S)-1-{[(R)-1-Hydroxy-3-methylbutyl]amino}-1-oxo-3-phenylpropan-2-yl]pyrazine-2-carboxamide

[0054] The term “shelf life”, as used herein, refers to the amount of time the pharmaceutical composition may be stored without loss of potency and/or performance profile, i.e. compositions that stay within the specification defined in Table 1 above, upon storage at about 2° C. to about 8° C., and/or at about 25° C. and 60% relative humidity. The stable compositions provided herein are designed to have shelf life of at least 12 months, 24 months or 36 months. Preferred embodiments of the present invention have a shelf life of about 24 months.

Definitions

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0056] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination.

[0057] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.

[0058] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety for all purposes.

[0059] As used herein, “a,” “an,” or “the” can mean one or more than one.

[0060] Also, as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0061] As used herein, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±10% of the specified amount.

[0062] “Ready to dilute” when used in connection with a bortezomib composition refers to a composition that includes bortezomib in dissolved or solubilized form, and may be used as such, or upon further dilution with intravenous diluents. The terms “composition” and “solution” may be used interchangeably.

[0063] As used herein, and unless otherwise specified, the term “stable” refers to physical and chemical stability of the composition.

[0064] The present invention is further illustrated by reference to the following examples which is for illustrative purposes only, and does not limit the scope of the invention in any manner.

TABLE-US-00002 Example 1 Ingredients Quantity per mL Quantity in % Bortezomib 2.5 mg 0.25 Ethanol 30 mg 3 Mannitol 25 mg 2.5 Water for Injection qs to 1 mL qs to 100 pH 5.3

[0065] Bortezomib was dispensed and transferred to a vessel containing ethanol, and mixed and heated to 50-55° C. until dissolved completely. Water for Injection was purged with nitrogen to obtain less than 2 ppm of dissolved oxygen. About 90% of the purged water for injection was added into a container and heated to 50° C.-60° C. Mannitol was added and mixed until dissolved completely. The bortezomib solution was added slowly to the mannitol solution by continuous stirring at 50° C.-60° C. It was then cooled to room temperature and the volume was made up to batch size with water for injection previously purged with nitrogen.

[0066] The composition was subjected to stability studies, the results of which are recorded in Table 2 below—

TABLE-US-00003 TABLE 2 40° C. ± 2° C./ Condition 2-8° C. 25° C. ± 2° C./60 ± 5% RH 75 ± 5% RH 60° C. Parameter Initial 45 days 12 days 45 days 60 days 10 days 1 day Description CCS CCS CCS CCS CCS CCS CCS pH 5.79 NT NT NT NT NT NT Assay (%) 100.83  100.01  101.9   99.06  97.68  99.36  97.25  Related % w/w substances by HPLC Unknown ND ND ND ND 0.03 ND ND Impurity @ RRT 0.20 Impurity C 0.01 0.01 0.01 0.04 0.08 0.12 Impurity B 0.03 0.10 0.12 0.47 0.68 0.63 0.22 Unknown ND 0.04 0.07 0.09 0.19 0.27 0.19 Impurity @ RRT 1.24 Unknown 0.12 0.12 0.20 0.15 0.19 0.17 0.15 Impurity @ RRT 1.50 Unknown 0.03 0.06 0.11 0.16 0.22 0.15 0.07 Impurity @ RRT 1.91 Total Impurities 0.43 0.48 0.63 1.14 1.55 1.40 0.84 Note: NT: Not tested; W: Week; CCS: Clear Colourless solution; RRT: Relative Retention Time

[0067] The composition of Example 1 was subjected to further stability testing, the results of which are recorded in Tables 3 and 4 below.

TABLE-US-00004 TABLE 3 40° C. ± 2° C./ Condition 2-8° C. 25° C. ± 2° C./60 ± 5% RH 75 ± 5% RH Parameter Initial 1 M 2 M 3 M 6 M 1 M 2 M 3 M 6 M 1 W 2 W Description CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS CCS pH 5.24 5.33 5.55 5.60 5.66 5.54 5.54 5.63 5.70 NT NT Assay (%) 102.7   102.1   102.1   101.4   102.8   100.8   100.9   100.7   100.0   102.8 100.1

TABLE-US-00005 TABLE 4 Related substances by HPLC (% w/w) 40° C. ± 2° C./ 2-8° C. 25° C. ± 2° C./60 ± 5% RH 75 ± 5% RH Initial 1 M 2 M 3 M 6 M 1 M 2 M 3 M 6 M 1 W 2 W Unknown 0.01 ND ND 0.00 ND 0.00 ND 0.02 0.09 0.01 0.01 Impurity @ RRT 0.24 Impurity C 0.01 0.01 0.01 0.01 0.02 0.03 0.05 0.07 0.13 0.06 0.12 Impurity B 0.04 0.05 0.06 0.11 0.14 0.32 0.60 0.87 1.68 0.48 1.02 Unknown 0.08 0.06 0.06 0.07 0.07 0.14 0.19 0.25 0.39 0.13 0.21 Impurity @ RRT 1.24 Impurity I 0.12 0.08 0.10 0.07 0.08 0.06 0.06 0.07 0.09 0.08 0.07 Impurity J 0.05 0.04 0.06 0.07 0.09 0.07 0.08 0.11 0.15 0.08 0.11 Maximum 0.03 0.04 0.03 0.4  0.04 0.03 0.04 0.04 0.06 0.04 0.03 unspecified impurities Total Impurities 0.46 0.41 0.43 0.50 0.55 0.74 1.16 1.61 2.79 1.02 1.74

Example 2

[0068]

TABLE-US-00006 Ingredients Quantity per mL Quantity in % Bortezomib 2.5 mg 0.25 Ethanol 30 mg 3 Mannitol 25 mg 2.5 Arginine 0.23 mg 0.023 Water for Injection Qs to 1 mL QS to 100 pH 6.6

[0069] The composition was obtained by process similar to that in Example 1 above. The results of the stability testing conducted for the composition are recorded in Table 5 below—

TABLE-US-00007 TABLE 5 25° C. ± 2° C./ 40° C. ± 2° C./ Condition 2-8° C. 2-8° C. 60 ± 5% RH 75 ± 5% RH 60° C. Parameter Initial 2 W 1 M 2 W 1 M 2 W 1 D Description CCS CCS CCS CCS CCS CCS CCS pH 6.61 NT NT NT NT NT NT Osmolality NT 715    NT 704    NT 705    NT Assay (%) 100.8   98.3  99.5  100.1   97.5  94.66  100.5   Related % w/w substances by HPLC Unknown ND 0.01 0.06 0.44 0.81 0.39 ND Impurity @ RRT 0.18 Impurity C @ 0.01 0.04 0.12 0.10 0.3  0.88 0.13 RRT 0.4 Impurity B @ 0.03 0.20 0.39 0.08 0.88 2.51 0.43 RRT 0.69 Unknown 0.08 0.16 0.25 0.30 0.52 1.97 0.42 Impurity @ RRT 1.24 Unknown 0.08 0.11 0.11 0.24 0.33 0.18 0.13 Impurity @ RRT 1.50 Unknown 0.01 0.03 0.03 0.07 0.12 0.08 0.03 Impurity @ RRT 1.91 Total Impurities 0.31 0.69 1.13 1.39 2.42 6.25 1.28 Note: NT - Not tested; CCS: Clear Colourless solution; RRT: Relative Retention Time

[0070] The composition of Example 2 was subjected to further stability testing, the results of which are recorded in Tables 6 and 7 below—

TABLE-US-00008 TABLE 6 Condition 2-8° C. Parameter Initial 1 M 2 M 3 M 6 M Description CCS CCS CCS CCS CCS pH 6.61 NT NT 6.43 6.47 Osmolality NT NT NT 651 709 Assay (%) 100.8   99.5 99.5 98.9 100.0

TABLE-US-00009 TABLE 7 Related substances by HPLC (% w/w) 2-8° C. Initial 1 M 2 M 3 M 6 M Unknown Impurity @ RRT 0.24 ND 0.06 ND ND ND Impurity C 0.01 0.12 0.04 0.04 0.07 Impurity B 0.03 0.39 0.23 0.25 0.39 Unknown Impurity @ RRT 1.24 0.08 0.25 0.14 0.22 0.31 Impurity I 0.08 0.11 0.12 0.11 0.12 Impurity J 0.01 0.03 0.03 0.03 0.04 Maximum unspecified impurities 0.06 0.04 0.05 0.04 0.06 Total Impurities 0.31 1.13 0.73 0.79 1.17

Example 3

[0071]

TABLE-US-00010 Ingredients Quantity per mL Quantity in % Bortezomib 2.5 mg 0.25 Ethanol 30 mg 3 Mannitol 25 mg 2.5 Arginine 0.23 mg 0.023 DOTA 0.2 mg 0.02 Water for Injection qs to 1 mL qs to 100 pH 5.77

[0072] Bortezomib was dispensed and transferred to a vessel containing ethanol, and the same was mixed and heated to 50-55° C., until completely dissolved. Water for Injection was purged with nitrogen to obtain less than 2 ppm of dissolved oxygen, and heated to 50° C.-60° C. Mannitol was added to the water for injection and mixed until dissolved completely. The bortezomib solution was added slowly to the mannitol solution by continuous stirring at 50° C.-60° C. Arginine and DOTA were added to the above mixture, and stirred for another 60 mins at 50° C.-60° C., until a solution was obtained. The solution was then cooled to room temperature and the volume was made up with water for injection previously purged with nitrogen.

[0073] The testing results for composition of Example 3 are shown in Table 8 below—

TABLE-US-00011 TABLE 8 Condition 60° C. Parameter Initial 1 day Description CCS CCS pH 5.77 NT Assay (%) 99.34  95.93  Related substances by HPLC (% w/w) Unknown Impurity @ RRT 0.24 ND 0.05 Impurity C 0.01 0.12 Impurity B 0.01 0.47 Unknown Impurity @ RRT 1.24 0.04 0.31 Impurity I 0.06 0.15 Impurity J 0.02 0.01 Maximum unspecified impurities 0.05 0.04 Total Impurities 0.27 1.41

Example 4

[0074]

TABLE-US-00012 Quantity Quantity Quantity Ingredients per mL per vial (% w/v) Bortezomib 2.5 mg 3.5 mg 0.25% Ethanol 1.0 mg 1.4 mg 0.1% Propylene glycol 9.0 mg 12.6 mg 0.9% Mannitol 25 mg 35 mg 2.5% Water for Injection qs to 1 mL qs to 1.4 mL qs to 100%

[0075] Ethanol and propylene glycol were dispensed and transferred to a manufacturing vessel-1 and stirred to obtain a uniform solution. The solution was heated to 40-60° C. The required quantity of bortezomib was added into the above manufacturing vessel-1 and stirred until a clear solution was obtained by maintaining the temperature at 40-60° C. Water for injection was transferred to manufacturing vessel-2. Mannitol was added to vessel-2 and stirred until a clear solution was obtained. The solution was heated to 40-60° C. The bortezomib solution from compounding vessel-1 was slowly added to compounding vessel-2 and stirred until a clear solution was obtained by maintaining the temperature at 40-60° C. Finally the volume was made up to 100% using the remaining water for injection. The solution was then cooled to room temperature (20-25° C.) and filtered using a 0.2 micron sterilizing grade filter. The solution was then filled in vials (Fill Volume: 1.4 mL), stoppered and sealed. The final product was stored under refrigerated conditions.

Example 5

[0076] The composition of Example 4 above was subjected to stability studies, the results of which are shown in Table 9 and Table 10 below—

TABLE-US-00013 TABLE 9 25° C. ± 2° C./ 40° C. ± 2° C./ Condition 2-8° C. 60 ± 5% RH 75 ± 5% RH 60° C. Parameter Initial 1 W 2 W 1 W 2 W 1 W 2 W 1 day Description CCS CCS CCS CCS CCS CCS CCS CCS pH 5.20 NT NT NT NT NT NT NT Osmolality 302 287 NT 286 NT 287 NT NT Assay (%) 98.11 96.7 97.64 96.5 96.5 95.7 95.9 104

TABLE-US-00014 TABLE 10 Related substances by HPLC (% w/w) 25° C. ± 2° C./ 40° C. ± 2° C./ 2-8° C. 60 ± 5% RH 75 ± 5% RH 60° C. Initial 1 W 2 W 1 W 2 W 1 W 2 W 1 day Unknown ND 0.04 0.03 0.25 0.09 0.13 0.06 BDL Impurity @ RRT 0.20 Impurity C @ 0.08 0.09 0.08 0.10 0.09 0.14 0.18 0.07 0.4 Impurity B @ 0.33 0.39 0.36 0.28 0.45 0.80 1.27 0.44 0.69 Unknown 0.06 0.14 0.10 0.12 0.12 0.23 0.24 0.20 Impurity @ RRT 1.24 Unknown 0.10 0.10 0.1 0.10 0.1  0.10 0.08 0.06 Impurity @ RRT 1.50 Unknown 0.14 0.15 0.15 0.15 0.16 0.16 0.14 0.09 Impurity @ RRT 1.91 Total Impurities 0.83 1.05 0.99 1.14 1.18 1.7  2.14 1.03 Note- W: Week; ND: Not detected; NT: Not tested; RRT: Relative Retention Time; BDL: below detection limit

Example 6

[0077] The composition of Example 4 above was subjected to additional stability testing, the results of which are shown in Table 11 and Table 12 below—

TABLE-US-00015 TABLE 11 Condition 2-8° C. 25° C./60% relative humidity Parameter Initial 1 M 2 M 3 M 6 M 1 M 2 M 3 M 6 M Description CCS CCS CCS CCS CCS CCS CCS CCS CCS pH 5.20 NT 5.36 5.58 5.41 NT 5.38 5.40 5.22 Osmolality 302 NT 296 293 290 NT 301 309 285 Assay (%) 98.1 96.4 96.0 96.3 95.3 96.2 95.2 95.8 94.1 Note- M: Month; NT: Not tested; RRT: Relative Retention Time

TABLE-US-00016 TABLE 12 Related substances by HPLC (% w/w) 2-8° C. 25° C./60% relative humidity Initial 1 M 2 M 3 M 6 M 1 M 2 M 3 M 6 M Unknown ND 0.04 0.03 0.02 0.03 0.61 0.67 1.01 1.55 Impurity @ RRT 0.24 Impurity C 0.08 0.09 0.07 0.08 0.08 0.11 0.11 0.13 0.14 Impurity B 0.33 0.37 0.32 0.37 0.42 0.22 0.20 0.14 0.33 Impurity I 0.10 0.1  0.08 0.10 0.09 0.10 0.08 0.08 0.06 Impurity J 0.14 0.16 0.12 0.14 0.15 0.17 0.13 0.13 0.12 Maximum 0.06 0.05 0.09 0.11 0.10 0.08 0.13 0.26 0.28 unspecified impurities Total Impurities 0.83 0.94 0.88 0.99 1.07 1.44 1.39 2.07 2.85 Note- M: Month; ND: Not detected; RRT: Relative Retention Time

Example 7

[0078]

TABLE-US-00017 Quantity Quantity Quantity Ingredients per mL per vial (% w/v) Bortezomib 2.5 mg 12.5 mg 0.25% Ethanol 1.0 mg 5 mg 0.1% Propylene glycol 9.0 mg 45 mg 0.9% Mannitol 25 mg 125 mg 2.5% Water for Injection qs to 1 mL qs to 5 mL qs to 100%

[0079] The composition was obtained by a process similar to that in the examples above. 5 ml of the composition was filled in 10 ml USP Type I glass vials with rubber stoppers, each containing about 5 doses of bortezomib.

[0080] The stability testing conducted for the composition is recorded in Table 13 below—

TABLE-US-00018 TABLE 13 40° C. ± 2° C./ Condition 60° C. 75 ± 5% RH Parameter Initial 1 day 1 W Description CCS CCS CCS pH 5.60 5.83 5.64 Osmolality mosm/kg 336    303    301    Assay (%) 93.7  92.8  92.9  Related substances by HPLC (% w/w) Unknown Impurity @ RRT ND 0.01 0.02 0.24 Impurity C 0.01 0.09 0.06 Impurity B 0.03 0.56 0.44 Unknown Impurity @ RRT 0.05 0.21 0.12 1.24 Impurity I 0.08 0.06 0.18 Impurity J 0.04 0.11 0.17 Maximum unspecified 0.05 0.05 0.05 impurities Total Impurities 0.35 1.26 1.19