This patent application claims the benefit of Indian Patent Application No.
1143/DEL/2015, filed April24, 2015, which is incorporated by reference herein in its
entirety.
FIELD OF THE INVENTION
The present invention relates to a stable ready to use pharmaceutical composition
comprising proteasome inhibitor carfilzomib that has better safety, solubility and
stability.
BACKGROUND OF THE INVENTION
The compound (2S)-N-{ (1 S)-1-Benzyl-2-[((1 S)-3-methyl-1-{[(2R)-2-methyloxiran-
2-yl]carbonyl} butyl)amino ]-2-oxoethyl} -4-methyl-2-( { (2S)-2-[(morpholin-4-
ylacetyl)amino ]-4-phenylbutanoyl }amino) pentanamide, also known as carfilzomib,
is represented by the Formula (1):
Formula (I)
Carfilzomib is an analog of epoxomicin. It was approved by the U.S. Food and Drug
Administration (FDA) on 20 July 2012 for use in patients with multiple myeloma
who have received at least two prior therapies, including treatment with bortezomib
and an immunomodulatory therapy and have demonstrated disease progression on or
within 60 days of completion of the last therapy. It was first disclosed in
W005105827.
2
Carfilzomib is marketed by Onyx Pharmaceuticals, Inc. under the tradename
Kyprolis®. Proteasome inhibitor like carfilzomib is difficult to formulate for the
reason that it has low aqueous solubility and stability. There have been few attempts
to formulate carfilzomib in the past.
Carfilzomib for injection is a sterile, white to off-white lyophilized powder supplied
in a single use vial. The disadvantage of lyophilized drugs is that they have to be
reconstituted, usually by injecting diluents through the septum into the vial. The drug
is drawn up into a new syringe, the needle changed before finally being injected into
the patient. The multiple steps make it inconvenient for use and increase the risk of
injuries for the nursing staff.
As per product pack insert of Kyprolis®, it should be aseptically reconstituted with 29
mL of Sterile Water for Injection (USP); upon reconstitution, each mL contains
approximately 2.0 mg of Carfilzomib. Immediately after reconstitution, the solution
should be further diluted into 50 mL 5% Dextrose Injection. Stability of reconstituted
and diluted Kyprolis is 4 hours at room temperature (15°C-30°C) and 24 hours at
2°C-8°C. Total time from reconstitution to administration should not exceed 24
hours. It is thus apparent that reconstituted carfilzomib for Injection is unstable in the
liquid state and hence there is a need for a stable ready to use formulation of
carfilzomib.
US Patent No. US 7737112 discloses pharmaceutical compositions of practically
insoluble proteasome inhibitors. The compositions disclosed in this patent utilize
cyclodextrin, water and organic solvents in order to increase the solubility and
stability of the practically insoluble proteasome inhibitors. There exist two limitations
with the compositions disclosed in this patent. Firstly, as already pointed above, the
lyophilized product has to be reconstituted and diluted before administration to the
patient and secondly, the liquid composition according to the patent is aqueous in
nature and susceptible to hydrolytic degradation.
3
US Patent Application No. US 14/023,247 discloses pharmaceutical compositions of
peptide epoxy ketone carfilzomib comprising non volatile sugar acid, water miscible
organic solvents and water. Compositions as per the invention contain polysorbate 80
as a solubilizer. Polysorbate 80 is known to cause anaphylactic reactions and require
premedication with steroids. Hence, polysorbate 80 is not a preferred excipient for
injectables. It is also apparent that the compositions disclosed in this application are
not stable.
As discussed above, it is well known fact that proteasome inhibitor has limited
aqueous solubility and stability. None ofthe above cited references disclose long term
stable ready to use compositions of proteasome inhibitor that are substantially free of
water. Hence, safety, solubility and stability of the compositions still remain a major
concern. Thus, there remains a need to formulate ready to use pharmaceutical
compositions of proteasome inhibitor like carfilzomib which are stable, convenient to
use, substantially free of water and devoid of any disadvantages associated with
excipients used in preparing such compositions. In the context of this invention,
substantially free of water is defined as compositions containing less than 2.5 percent
w/w. The advantages of the compositions according to the current invention would
be apparent from experiments and results illustrated underneath.
Surprisingly, it has been found by the inventors that safe and stable ready to use
compositions of proteasome inhibitor like carfilzomib can be prepared using organic
solvents, wherein, said organic solvent is selected from at least one protic solvent, at
least one aprotic solvent or mixtures thereof.
SUMMARY OF INVENTION
The present invention relates to long term stable ready to use pharmaceutical
compositions of proteasome inhibitor. The proteasome inhibitor is carfilzomib or a
pharmaceutically acceptable salt thereof.
4
In one embodiment, the invention provides compositions in liquid form which are
ready to use and has a water content less than 2.5 percent w/w. The compositions thus
prepared can be administered to patients without further reconstitution.
In another embodiment, the invention provides compositions which are convenient to
use and requires minimal steps before it can be administered to patients.
In another embodiment, the compositions apart from active ingredient, comprises one
or more pharmaceutically acceptable excipients like organic solvents, buffers,
solubilizers, pH modifiers, preservatives, antioxidants, isotonicity adjusters and
combinations thereof.
In another embodiment, the compositions according to present invention are purged
with inert gas in order to reduce oxygen content in the vial.
In another embodiment, the invention provides a process for preparing stable, ready
to use pharmaceutical compositions of Carfilzomib.
In another embodiment, the compositions of present invention can be packed in
suitable containers like vials, ampoules and prefilled syringes.
In another embodiment, pharmaceutical compositions of present invention can be
used for the treatment of multiple myeloma.
In yet another embodiment, compositions according to the present invention can be
administered parenterally.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical compositions of proteasome inhibitor
like carfilzomib of formula (1). Also provided herein are stable, ready to use
5
pharmaceutical compositions which are safe and convenient to use. The present
invention also provides process for preparing such compositions.
The pharmaceutical compositions as developed by the inventors of the present
application are suitable for parenteral administration. These compositions are
presented in a vial, ampoules or pre filled syringe. The pharmaceutical compositions
are then administered via intravenous infusion to treat patients suffering from
multiple myeloma.
In one embodiment, the amount of carfilzomib in the pharmaceutical compositions
ranges from 100 to 1000 mg, preferably in the range of 300 to 600 mg per 100 ml.
In another embodiment, the compositions of the present invention comprise organic
solvents, buffers, solubilizers, pH modifiers, preservatives, antioxidants, isotonicity
adjusters and combinations thereof.
The stable, ready to use pharmaceutical compositions of carfilzomib according to the
present invention are solvated in at least one organic solvent, wherein, said organic
solvent is selected from at least one protic solvent, at least one aprotic solvent or
mixtures thereof. In some embodiments, the organic solvent comprises two or more
protic solvents, e.g., three protic solvents, four protic solvents, or five protic solvents.
In other embodiments, the organic solvent comprises two or more aprotic solvents,
e.g., three aprotic solvents, four aprotic solvents, or five aprotic solvents. In certain
embodiments, the organic solvent comprises two or more protic solvents and one
aprotic solvent. In other embodiments, the organic solvent comprises one protic
solvent and two or more aprotic solvents.
The amount of protic and/or aprotic solvent in the compositions of present invention
per 100 ml ranges from about 1-100 ml in any suitable ratio. In some embodiments
the organic solvent comprises a first protic solvent and a second protic solvent
present in a ratio ranging from l :0.05 to I :20 by volume (v/v), e.g., l :0.1 to I: 10 v/v,
6
1:0.4 to 1:2 v/v, 1:0.8 to 1:5 v/v, or 1: 1 to 1:4 v/v. In certain embodiments, the
organic solvent comprises a first protic solvent and a second protic solvent in a ratio
of about 1: I v/v. In other embodiments, the organic solvent comprises a first protic
solvent and a second pro tic solvent in a ratio of about I: 1.4 v/v.
In another embodiment of the present invention, at least one aprotic solvent is
selected from 1-methyl-2-pyrrolidone, 1 ,3-dimethyl-2-imidazolidinone,
dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, I ,4-dioxane,
acetonitrile, dimethyl formamide, propylene carbonate, and mixtures thereof.
In another embodiment of the present invention, at least one protic solvent is selected
from alkyl alcohol selected from methanol, ethanol, ethylene glycol, propylene
glycol, butylene glycol, glycerin; a polyalkylene glycol selected from polyethylene
glycol, polypropylene glycol, polybutylene glycol, and mixtures thereof.
In some embodiments, the pharmaceutical composition contains one or more
components that regulate the pH of the composition, such as a pH modifier and/or a
buffer. In certain embodiments, the pH modifier and/or buffer are present in amounts
sufficient to provide a pH in the range of 2 to 6, e.g., 3 to 5, 2.5 to 4.5, 3.5 to 4.5, 4.5
to 6 or 4 to 5.5. Examples of suitable buffers include citric acid, acetic acid, maleic
acid, phosphoric acid, tartaric acid, succinic acid and counter ions salts thereof. In
some embodiments, the pharmaceutical composition comprises citric acid in an
amount of about I: l relative to the amount of carfilzomib by weight.
The ready to use compositions according to present invention typically include at
least one solubilizer. In some embodiments, the solubilizer is alpha, beta or gamma
cyclodextrin, which can be a substituted or an unsubstituted cyclodextrin. In certain
embodiments, the Cyclodextrin is beta cyclodextrin which is selected from
Hydroxypropyl beta-cyclodextrin (HPBCD), sulfobutylether beta-cyclodextrin
(SBECD), and mixtures thereof.
7
In some embodiments, the solubilizer is present in the ready to use pharmaceutical
composition in an amount of about 0.1 mg/mL or greater, e.g., 1 mg/mL or greater, 5
mg/mL or greater, 10 mg/mL or greater, 50 mg/mL or greater, 80 mg/L or greater, or
100 mg/mL or greater. In other embodiments, the solubilizer is present in the ready
to use pharmaceutical composition in an amount of about 500 mg/mL or less, e.g.,
400 mg/mL or less, 300 mg/mL or less, 250 mg/mL or less, 200 mg/mL or less, 150
mg/mL, or 120 mg/mL or less. In yet other embodiments, the solubilizer is present in
the ready to use pharmaceutical composition in an amount bounded by any of the
foregoing values, e.g., 0.1 mg/mL to 200 mg/mL, 5 mg/mL to 250 mg/mL, 10 mg/mL
to 400 mg/mL, or 40 mg/mL to 300 mg/mL. In certain embodiments, the solubilizer
is present in an amount ranging from about 40 to 200 mg/mL.
In some embodiments, the solubilizer is HPBCD, and the ratio of HPBCD to
carfilzomib is about 100:1 by weight (w/w), e.g., about 60:1 w/w, about 40:1 w/w,
about 20:1 w/w, about 10:1 w/w, about 5:1 w/w, about 2:1 w/w, or any range therein.
In certain embodiments, the ratio of HPBCD to carfilzomib is about 16.6:1 w/w.
In another embodiment, the oxygen content can be controlled by using antioxidants
or alternatively by limiting the oxygen content of drug solution and in vial headspace
with the use of inert gas such as helium, argon and nitrogen or mixtures thereof. This
may be aided by, for example, purging the sealable container with a gas which is
substantially oxygen-free, or substantially moisture free, or substantially oxygen and
moisture free anytime during the process of preparing the compositions.
In certain embodiments, the pharmaceutical composition is sterile. Sterilization of
the pharmaceutical composition can be achieved by any suitable method, including
but not limited to by applying heat, chemicals, irradiation, high pressure, filtration, or
combinations thereof. In certain embodiments, the pharmaceutical composition is
sterilized by passing the composition through one or more filters having a pore
diameter of0.2 1-lm.
8
The pharmaceutical composition according to the invention is stable over a wide
range of storage conditions. The terms "stable" and "stability" as used herein with
respect to a composition is meant to encompass any characteristic of a composition
which may be affected by storage conditions including, without limitation, any
individual impurity associated with carfilzomib or an excipient, total impurities,
carfilzomib or excipient degradation products, water content, appearance, sterility,
and color. Methods for determining the stability of a composition of the invention
with respect to a given parameter are well-known to those of skill in the art. For
example, impurities can be assessed by high-performance liquid chromatography
(HPLC) or thin layer chromatography (TLC). Unless otherwise indicated to the
contrary, a percentage amount of an impurity reported herein is relative to the amount
of carfilzomib present in the composition as determined by an HPLC method.
In some embodiments, following storage of a composition of the invention at 25±2
oc or 40±2 oc for predetermined time period, the amount of any individual impurity
present in the composition is not more than 3%. In other embodiments, following
storage of a composition of the invention at 25±2 oc or 40±2 oc for predetermined
time period, the amount of any individual impurity present in the composition is not
more than 2.5%, e.g., not more than 2.0%, not more than 1.8%, not more than 1.5%,
not more than 1.2%, not more than 1.0%, not more than 0.9%, not more than 0.8%,
not more than 0.7%, not more than 0.6%, not more than 0.5%, not more than 0.4%,
not more than 0.3%, not more than 0.25%, not more than 0.2%, not more than 0.1 %,
or any range therein. For example, in certain embodiments, following storage of a
composition of the invention at 25±2 oc or 40±2 oc for predetermined time period,
the amount of any individual impurity present in the composition is 0.2%-2.0%,
0.5%-3.0%, 0.5%-2.5%, 0.6%-1.8%, 0.9%-2.0%, 0.5%-1.5%, or 0.8%-1.2%. The
predetermined time period can be any duration, e.g., 1 week, 2 weeks, I month, 2
months, 3 months, 6 months, I 2 months, I 8 months, 24 months, or 36 months.
9
The pharmaceutical composition of the invention is ready to use and suitable for
administration to a subject in need of therapy with a proteasome inhibitor, such as
carfilzomib. Thus, the invention also provides a method of treating a subject in need
of therapy with a proteasome inhibitor by administering a therapeutically effective
amount of a pharmaceutical composition of the invention to the subject. The subject
can be any mammal, including a rodent, a non-human primate, or a human. In some
embodiments, the subject is a human cancer patient, such as a patient with multiple
myeloma.
The invention is further illustrated by way of the following examples, which in no
way should be construed as limiting the scope of the invention.
Examplel: Composition I
S.No. Ingredients Quantity /vial
1 Carfilzomib 60mg
2 Anhydrous Citric acid 57.7 mg
3 Hydroxypropyl beta-cyclodextrin Igm
4 Propylene Glycol lOmL
5 Ethanol q.s. to 20 mL
* Nitrogen is used for purging in bulk solution and blanketmg m vtal headspace
Example 2: Composition II
S.No. Ingredients Quantity /vial
1 Carfilzomib 60mg
2 Anhydrous Citric acid 57.7 mg
10
3 Hydroxypropyl beta-cyclodextrin lgm
4 Propylene Glycol 5 mL
5 Ethanol q.s. to 12 mL
* Nttrogen ts used for purgmg m bulk solution and blanketmg m vtal headspace
The compositions were prepared by below mentioned process:
Suitable quantity of propylene glycol was taken in a manufacturing vessel and
subsequently required quantity of hydroxypropyl beta Cyclodextrin was added to it.
The two components were stirred and mixed. Nitrogen was purged into the solution
obtained in the previous step. Required quantity of absolute alcohol was taken in a
manufacturing vessel separately and required quantity of Carfilzomib was added and
mixed with the help of stirrer. Required quantity of citric acid anhydrous was added
to the solution of previous step and mixed using a stirrer to get a clear solution. This
solution was then added to the first solution with continuous stirring and stirring was
continued for 30 minutes. The volume of the solution was made 100 percent using
absolute alcohol. The drug solution was then filtered into vials. The headspace ofthe
vials was blanketed with nitrogen and vials were sealed.
Stability data comparison of the compositions of the present invention with
compositions disclosed in prior art:
The compositions of the present invention were then tested for stability at various
conditions including long term storage (25°C±2/60% RH) and stress condition
(40°C±2/75% RH) and compared with the aqueous liquid composition of the prior art
as disclosed in Example 2 ofUS7737112. The samples collected were tested on High
Performance Liquid Chromatography (HPLC). The HPLC apparatus used was
Agilent having a stationary phase YMC Pack PRO RS C-18 (150x4.6mm) 3j.tm,
mobile phase as buffer and acetonitrile 50:50v/v. The buffer was prepared by
11
dissolving about l.36g of potassium dihydrogen phosphate into IL water. 2ml
triethylamine was then added, mixed and pH was adjusted to 3.0±0.03 with
orthophosphoric acid. The samples were detected at 21 Onm on ultraviolet detector.
The gradient used for elution is tabulated below:
Table 01: Gradient used for elution:
Time Mobile Phase A % Mobile Phase B %
0 77 23
40 38 62
50 30 70
51 77 23
60 77 23
wherein, the related substances were measured in minutes between injection of the
sample on the column and elusion of the particular component through the detector,
known as retention time (RT). This time period varies based upon the condition of the
instrument and many other factors. To mitigate the effect that such variations have
upon accurate identification of an impurity, relative retention time (RRT) is used to
identify impurities. The RRT of an impurity is its retention time divided by the
retention time of a reference marker.
The stability results as obtained are summarized below:
Table 02: Stability data comparison of compositions of present invention and prior
art aqueous composition
12
RRT Condition Com position- Composition- Aq,ueous liquid
I n composition of
prior artns
disclosed in
E~ample2 of
US1112
Initial ND ND 0.05
40°C±2/75% 0.07 0.05 4.35
RH
I week
25°C±2/60% 0.09 0.06 3.10
0.21
RH
I month
25°C±2/60% 0.26 0.14 7.14
RH
3 month
Initial ND ND ND
40°C±2/75% 0.05 ND 0.82
RH
I week
0.27 25°C±2/60% ND ND 0.54
RH
1 month
25°C±2/60% 0.04 ND 1.31
RH
3 month
13
Initial ND 0.05 ND
40°C±2/75% 0.07 0.05 1.27
RH
1 week
25°C±2/60% 0.07 0.06 0.80
0.28
RH
1 month
25°C±2/60% 0.21 0.10 1.99
RH
3 month
Initial ND ND ND
40°C±2/75% 0.04 ND 0.50
RH
1 week
0.31 25°C±2/60% 0.04 ND 0.39
RH
1 month
25°C±2/60% 0.16 0.12 1.84
RH
3 month
Initial 0.04 ND ND
40°C±2/75% 0.07 ND 0.39
0.47
RH
1 week
14
25°C±2/60%
RH
1 month
25°C±2/60%
RH
3 month
Initial
40°C±2/75%
RH
1 week
0.56 25°C±2/60%
RH
1 month
25°C±2/60%
RH
3 month
RRT- Relative RetentiOn Ttme
ND - Not Detected
Example 3: Composition III
S.No. Ingredients
1 Carfilzomib
0.07
0.23
0.17
0.19
0.19
0.28
2 Hydroxypropyl beta-cyclodextrin
3 Anhydrous Citric acid
15
0.05 0.33
0.17 0.82
0.14 0.58
0.16 17.60
0.16 16.66
0.18 39.34
Quantity/vial
60mg
2.0 g
30mg
4 Propylene Glycol 2mL
5 Dimethylacetamide 0.6ml
6 Ethanol q.s. to 6 mL
The compositions were prepared by below mentioned process:
Suitable quantity of ethanol was taken in a manufacturing vessel and subsequently
required quantity of anhydrous citric acid was added to it. The two components were
mixed using a mechanical stirrer. Required quantity of dimethylacetamide,
Carfilzomib, Propylene glycol and hydroxypropyl beta cyclodextrin were added into
the solution obtained in the previous step. The solution was then mixed using a
mechanical stirrer. Nitrogen was purged into the solution. The volume of the solution
was made 100% with ethanol. The drug solution was then filtered through a suitable
sterilizing grade filter and filled into the vials. The headspace of the vials was
blanketed with nitrogen followed by sealing of vials. The order of addition of
carfilzomib and excipients in preparation of the composition may vary.
The compositions according to example III were then tested for stability at conditions
like 25°C±2/60% RH, one month and 40°C±2/75% RH, one week. The HPLC
apparatus used was Agilent having a stationary phase Orosil C-18, (250mm x
4.6mm), 3jlm, mobile phase as buffer and acetonitrile. The buffer was prepared by
dissolving about l.36g of potassium dihydrogen phosphate into 1 L water. 2ml
triethylamine was then added, mixed and pH was adjusted to 3.3 ± 0.05 with
orthophosphoric acid. The total related substances was found to be 1.4 7 at
25°C±2/60% RH (1 month) and 1.71 at 40°C±2/75% RH, (1 week).
16
It is apparent from the results that the ready to use compositions of the present
invention are appreciably stable when compared to aqueous liquid composition of
prior art in long term storage as well as stress conditions.
17

We Claim:
I. A pharmaceutical composition comprising:
1. carfilzomib or a pharmaceutically acceptable salt thereof,
u. at least one organic solvent, and
iii. a solubilizer
wherein said composition has a water content of less than 2.5 percent w/w.
2. The pharmaceutical composition according to claim I, wherein the
concentration ofthe carfilzomib ranges from 100 to 1000 mg per IOO mi.
3. The pharmaceutical composition according to claim I, wherein said organic
solvent is selected from at least one protic solvent, at least one aprotic solvent,
and mixtures thereof.
4. The pharmaceutical composition according to claim 3, comprising a mixture
of a first pro tic solvent and a second protic solvent.
5. The pharmaceutical composition according to claim 4, wherein the ratio of the
first protic solvent to the second protic solvent ranges from I :0.1-I :5 v/v.
6. The pharmaceutical composition according to claim 3, comprising a mixture
of protic solvents and an aprotic solvent.
7. The pharmaceutical composition according to claim 6, wherein the ratio of the
protic solvents to the aprotic solvent ranges from I :O.I-1 :5 v/v
8. The pharmaceutical composition according to claim 3, wherein the at least
one protic solvent is selected from the group consisting of methanol, ethanol,
18
ethylene glycol, propylene glycol, butylene glycol, glycerin, a polyalkylene
glycol selected from polyethylene glycol, polypropylene glycol, polybutylene
glycol, and mixtures thereof.
9. The pharmaceutical composition according to claim 3, wherein the at least
one aprotic solvent is selected from the group consisting of 1-methyl-2-
pyrrolidone, 1 ,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl
sulfoxide, acetone, tetrahydrofuran, 1 ,4-dioxane, acetonitrile, dimethyl
formamide, propylene carbonate, and mixtures thereof.
10. The pharmaceutical composition according to claim 1, wherein the solubilizer
is a beta cyclodextrin.
11. The pharmaceutical composition according to claim 10, wherein the beta
cyclodextrin is selected from hydroxypropyl beta-cyclodextrin (HPBCD),
sulfobutylether beta-cyclodextrin (SBECD), and mixtures thereof.
12. The pharmaceutical composition according to claim 1, wherein (a) the organic
solvent comprises propylene glycol and ethanol, (b) the solubilizer is HPBCD,
and (c) the composition further comprises citric acid.
13. The pharmaceutical composition according to claim 1, wherein (a) the organic
solvent comprises dimethylacetamide, propylene glycol and ethanol, (b) the
solubilizer is HPBCD, and (c) the composition further comprises citric acid.
14. The pharmaceutical composition according to claim 12 comprising:
a) carfilzomib in an amount of 60 mg,
b) anhydrous citric acid in an amount of 58 mg,
19
c) propylene glycol and ethanol in an amount of 12 mL, and
d) HPBCD in an amount of 1000 mg.
15. The pharmaceutical composition according to claim 12 comprising:
a) carfilzomib in an amount of 60 mg,
b) anhydrous citric acid in an amount of 58 mg,
c) propylene glycol and ethanol in an amount of20 mL, and
d) HPBCD in an amount of 1000 mg
16. The pharmaceutical composition according to claim 13 comprising:
a) carfilzomib in an amount of 60 mg,
b) anhydrous citric acid in an amount of 30 mg,
c) dimethylacetamide in an amount of 0.6 mL
d) propylene glycol and ethanol in an amount of 6 mL, and
e) HPBCD in an amount of 2000 mg
17. The pharmaceutical composition according to claim 12, wherein the weight
ratio of citric acid to carfilzomib is about 1: 1 and the weight ratio of HPBCD
to carfilzomib is about 16.6:1.
18. A method of preparing the pharmaceutical composition according to claim
1, comprising the steps of:
(a) dissolving 1-100 ml of a first organic solvent with about 8500 mg of
cyclodextrin to form a first solution,
(b) dissolving about 500 mg of carfilzomib in a second organic solvent in
a separate vessel,
(c) dissolving about 485 mg of citric acid into the solution of step b to
form a second solution
20
(d) mixing the first and second solutions to form a third solution,
(e) making the volume of the third solution up to 100 mi.
19. The method according to claim 18, wherein the organic solvents are
independently selected from at least one protic solvent, at least one aprotic
solvent, and mixtures thereof.
20. A container comprising the pharmaceutical composition according to any of
claims 1-17, wherein the container is a vial, ampule, or syringe, and wherein
the composition is sterile.
21. A pharmaceutical composition according to any of claims 1-17 for use in the
treatment of multiple myeloma.
22. A method of treating multiple myeloma in a subject in need thereof,
comprising administering a therapeutically effective amount of the
composition according to any of claims 1-17 to the subject.
23. The composition of any of claims 1-17, wherein following storage of the
composition at 25 oc for a predetermined time period, the amount of any
individual impurity present in the composition is not more than 0.5% relative
to the amount of carfilzomib.
24. The composition of claim 23, wherein the predetermined time period is one
month or three months.
25.The composition of any of claims 1-17, wherein following storage of the
composition at 40 oc for a predetermined time period, the amount of any
21
individual impurity present in the composition is not more than 0.25% relative
to the amount of carfilzomib.
26. The composition of claim 25, wherein the predetermined time period is one
week.