STABLE LYOPHILIZED COMPOSITIONS OF CARFILZOMIB
Background of the invention
Carfllzomib is an anti-cancer drug acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. The chemical name for Carfllzomib is (2S)-N-((S)-l-((S)-4-methyl-l-((R)-2-methyloxiran-2-yl)-l-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide. Carfllzomib has molecular weight of 719.9 and molecular formula is C40H57N5O7. Carfllzomib is practically insoluble in water, and very slightly soluble in acidic conditions. Carfllzomib has the following structure:
u 6
The U.S. Food and Drug Administration approved Carfllzomib injection in July 2012 under the brand name Kyprolis®. Kyprolis® is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy.
U.S Patent Nos. 7,417,042; 7,491,704; 8,207,125; 8,207,126; 8,207,127 and 8,207,297 to Mark et al., disclose Carfllzomib or a pharmaceutically acceptable salt thereof and a method of treating cancer. The method of synthesizing the compound is also disclosed in the patents.
U.S Patent Application Nos. 2013/303465 and 2013/303482 to Evan et al., disclose method for preparing pharmaceutical composition comprising of one or more peptide proteasome inhibitors and a cyclodextrin, or a mixture of cyclodextrins, to increase the solubility and stability of proteasome inhibitors and facilitate both their manufacture
nnr\ aHmini i 6 ND 499
diol isomer-1
Total Impurity 0.88 5.05 1.00 9.19
*ND: Not detectable
Surprisingly the percentage of impurities observed in the invention formulation is significantly less compared to the reference product, when stored for a period of 1 week at 40°C/75%RH. Carfllzomib diol isomer-1 impurity observed in reference product is around 5%, whereas in invention formulation it is around 1.6%.
A most preferred embodiment of the invention comprises: (i) Carfllzomib
(ii) sulfobutylether-P-cyclodextrin (iii) aspartic acid and (iv) water.
The formulation of the present invention can be prepared using the following manufacturing steps:
(i) Addition of cyclodextrin to the manufacturing vessel containing solvent and stirred till a clear solution is obtained.

(ii) Addition of acidifying agent to the solution.
(iii)The solution is cooled to 5±3°C.
(iv)Addition of Carfilzomib to the solution obtained, while maintaining the
temperature at 5±3°C. (v) Filtering of the solution through 0.22u sterile filters and filling in vials. (vi)Freeze drying the vials.
The following examples further describe certain specific aspects and embodiments of the present invention and demonstrate the practice and advantages thereof.
Example 1: F-l
S.No Ingredients Quantity/ml (nig)
1 Carfilzomib 2.5
2 SBECD 143.35
3 Citric Acid 2.5
4 Water QS to lmL
Manufacturing Process
SBECD was added to the compounding vessel containing water and stirred till a clear solution was obtained. Citric acid was added and stirred. The solution was cooled to 5±3°C. Carfilzomib was added to the solution, while maintaining the temperature at 5±3°C and stirred till a clear homogenous solution was obtained. The solution was filtered and filled into sterilized vials with nitrogen purging, followed by freeze drying.
Example 2:
Quantity/ml (nig)
S.No Ingredients F^2 I ¥-3 I IM
1 Carfilzomib 2^5 2^5 2^5
2 SBECD 143.35 143.35 143.35
3 Maieic acid 3.0
4 Tartaric acid - 2.065
5 Aspartic acid - - 2.5

6 I Water I QS to lmL I QS to lmL I QS to lmL
Manufacturing Process
SBECD was added to the compounding vessel containing water and stirred till a clear solution was obtained. Acidifying agent was added and stirred. The solution was cooled to 5±3°C. Carfilzomib was added to the solution, while maintaining the temperature at 5±3°C and stirred till a clear homogenous solution was obtained. The solution was filtered and filled into sterilized vials with nitrogen purging, followed by freeze drying.
Example 3:
S.No Ingredients Quantity/ml
1 Carfilzomib 2.86
2 SBECD 143.35
3 Aspartic acid 2.86
4 Water QS to lmL
Manufacturing Process
SBECD was added to the compounding vessel containing water and stirred till a clear solution was obtained. Aspartic acid was added and stirred. The solution was cooled to 5±3°C. Carfilzomib was added to the solution, while maintaining the temperature at 5±3°C and stirred till a clear homogenous solution was obtained. The solution was filtered and filled into sterilized vials with nitrogen purging, followed by freeze drying.

We claim
Claim 1: A stable lyophilized parenteral formulation of Carfilzomib, wherein the formulation is free of citric acid.
Claim 2: A stable lyophilized parenteral formulation of Carfilzomib comprising Carfilzomib diol isomer-1 impurity of about 2% or less, when stored at 40°C and 75% relative humidity for 1 week.
Claim 3: A stable lyophilized parenteral formulation of Carfilzomib comprising:
(i) Carfilzomib
(ii) cyclodextrin
(iii) acidifying agent and
(iv) one or more solvents, wherein the formulation is free of citric acid.
Claim 4: The stable lyophilized formulation of claim 3, comprising:
(i) Carfilzomib
(ii) sulfobutylether-P-cyclodextrin (SBECD)
(iii) acidifying agent selected from the group comprising of tartaric acid, aspartic acid, maleic acid, ascorbic acid, succinic acid and
(iv) water, wherein the formulation is free of citric acid.