Stable pharmaceutical composition of 5-aza-2′-deoxycitidine

Abstract

Described herein are ready to use, non-aqueous pharmaceutical compositions comprising 5-aza-2-deoxycitidine and at least one aprotic solvent. The pharmaceutical compositions may further comprise at least one protic solvent. Also described are processes for preparing the pharmaceutical compositions and their use for the treatment of patients suffering from myelodysplastic syndromes.

Claims

1. A ready to use pharmaceutical composition comprising unmicronized 5-aza-2-deoxycitidine, at least one protic solvent, and at least one aprotic solvent, wherein the composition is non-aqueous, the at least one protic solvent is ethanol, the at least one aprotic solvent is dimethylacetamide, and the protic solvent and the aprotic solvent are present in a ratio of 10:90 to 50:50 (protic:aprotic).

2. The composition according to claim 1, wherein the 5-aza-2-deoxycitidine is present in a concentration of 5 mg/ml.

3. The composition according to claim 1, wherein the protic and aprotic solvents are present in a protic:aprotic ratio of 30:70 to 40:60.

4. The composition according to claim 1, wherein the composition is a solution of 5-aza-2-deoxycitidine.

5. A method of treating a patient suffering from a myelodysplastic syndrome, the method comprising administering to the patient a composition according to claim 1.

6. A container comprising the composition according to claim 1.

7. A ready to use pharmaceutical composition comprising 5 mg/ml unmicronized 5-aza-2-deoxycitidine and a non-aqueous solvent system comprising ethanol and dimethylacetamide in a ratio of 30:70 to 40:60 (ethanol:dimethylacetamide) by volume.

8. The composition according to claim 7, wherein the ethanol:dimethylacetamide ratio is 30:70 by volume.

9. A container comprising the composition according to claim 8.

10. The composition according to claim 7, wherein the ethanol:dimethylacetamide ratio is 40:60 by volume.

11. A container comprising the composition according to claim 10.

12. A method of preparing a pharmaceutical composition comprising unmicronized 5-aza-2-deoxycitidine, the method comprising the steps of: a) dissolving at least one protic solvent in a suitable quantity of at least one aprotic solvent, wherein the protic solvent is ethanol and the aprotic solvent is dimethylacetamide; b) purging nitrogen into the solution obtained in step a) until the oxygen content is below 7 mg/L; c) dissolving the 5-aza-2-deoxycitidine in about 80% of a predetermined volume of the solution obtained in step b); d) making the volume up to 100% with solution obtained in step b) to form a drug solution; e) filtering the drug solution and filling it into vials; f) blanketing the headspace of the vials with nitrogen to achieve a headspace oxygen content of less than 10%; and g) stoppering and sealing the vials, wherein the protic solvent and the aprotic solvent are present in a ratio of 10:90 to 50:50 (protic:aprotic).

13. The method according to claim 12, wherein the oxygen content in step b) is below 3 mg/L.

14. The method according to claim 12, wherein the oxygen content in step f) is less than 5%.

15. The method according to claim 12, wherein the oxygen content in step f) is less than 2%.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) In one aspect the present invention relates to ready to use, non aqueous pharmaceutical compositions comprising 5-aza-2-deoxycitidine and at least one aprotic solvent. The pharmaceutical compositions may further comprise at least one protic solvent.

(2) In another embodiment of the present invention the oxygen content is controlled by using antioxidants or an inert gas such as nitrogen.

(3) In a preferred embodiment the formulations are presented as a single vial presentation comprising 5-aza-2-deoxycitidine in a concentration of 5 mg/ml.

(4) The pharmaceutical compositions of the present invention are suitable for parenteral administration. These pharmaceutical compositions are then administered via intravenous infusion to treat patients suffering from myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate2, and high-risk International Prognostic Scoring System groups.

(5) In one embodiment of the present invention, the 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, or mixtures thereof. Dimethylacetamide, dimethyl sulfoxide, or mixtures thereof are preferred. Dimethylacetamide is especially preferred.

(6) In another embodiment of the present invention, the protic solvent is selected from the group consisting of alcohols, amides, or mixtures thereof. Alcohols, for example ethanol, are especially preferred.

(7) In yet another embodiment of the present invention, the oxygen content is controlled by using antioxidants or inert gas such as nitrogen. 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. Purging can be expected to reduce the oxygen level in the sealable container to a level of from about 0.5% to about 10%, typically about 5% or lower, depending on the efficiency of flushing and how quickly the container is sealed after flushing. The gas used for purging the sealable container may be any appropriate inert gas known to those in the art, the most commonly used gases being argon, helium or nitrogen, or mixtures thereof. However the most preferred inert gas is nitrogen.

(8) In yet another embodiment of the present invention decitabine is not micronized. It has surprisingly been found that the micronization step is not necessary when preparing the compositions according to the present invention. Hence, these are more cost efficient and economical.

(9) The invention is further illustrated by the following examples, which are not construed to be limiting the scope of the invention.

EXAMPLES

Example 1

(10) The composition of the present invention contains decitabine in a concentration of 5 mg/mL in a solvent system comprising dimethylacetamide and ethanol in the ratio of 70:30. The details of the composition are shown in Table 1.

(11) TABLE-US-00001 TABLE 1 Composition according to example 1 containing dimethylacetamide and ethanol in the ratio of 70:30 Quantity Sr. No. Ingredients (mg/mL) 1 Decitabine 5 mg 2 Dimethylacetamide 0.7 mL 3 Ethanol qs to 1 mL 4 Nitrogen* qs *Nitrogen is used for purging in bulk solution and blanketing in vial headspace

(12) The pharmaceutical composition according to example 1 was prepared by the following process:

(13) A suitable quantity of dimethylacetamide was fed into a manufacturing vessel and subsequently the required quantity of alcohol was added. The two components were then mixed. Nitrogen was then purged into the solution obtained in the previous step until the oxygen content was below 7 mg/L, preferably below 3 mg/L. Decitabine was added and stirred in about 80% of the solution obtained in the previous step and dissolved. The volume was then made up to 100% with the solution obtained in step 2. The resulting Decitabine solution was then filtered through a suitable sterilizing grade filter and filled into vials. The vial headspace was then blanketed with nitrogen to achieve a headspace oxygen content of less than 10%, preferably less than 5%, more preferably less than 2%. Finally the vials were stoppered and sealed.

(14) The stability profile of the formulation according example 1 was analysed and is presented in Table 2. The amount of Decitabine in the composition was measured before and after storage. The term assay as used in table 2 refers to the quantitative determination of decitabine via HPLC. Also, the impurity profile of the composition was analyzed before and after storage at various temperature and humidity conditions.

(15) TABLE-US-00002 TABLE 2 Stability data of the composition according to example 1 Related Substances Stability (% w/w) Conditions Assay (%) Water by KF Total impurity Initial 102.8 0.42 0.15 40 C./75% RH 100.9 0.34 0.44 (7 days) Accelerated 102.9 0.24 0.85 stability condition 25 C./60% RH (3 M) Accelerated 102.1 0.26 0.90 stability condition 25 C./60% RH (6 M) Real time 103.4 0.23 0.36 stability condition 2-8 C. (3 M) Real time 102.9 0.28 0.27 stability condition 2-8 C. (6 M)

Example 2

(16) The composition of the present invention contains Decitabine in a concentration of 5 mg/mL in a solvent system comprising dimethylacetamide and ethanol in the ratio of 60:40.

(17) The details of the composition are given in table 3.

(18) TABLE-US-00003 TABLE 3 Composition according to example 2 containing dimethylacetamide and ethanol in the ratio of 60:40 Quantity Sr. No. Ingredients (mg/mL) 1 Decitabine 5 mg 2 Dimethylacetamide 0.6 mL 3 Ethanol qs to 1 mL 4 Nitrogen* qs *Nitrogen is used for purging in bulk solution and blanketing in vial headspace

(19) The pharmaceutical composition according to example 2 was prepared by the following process:

(20) A suitable quantity of dimethylacetamide was fed into a manufacturing vessel and subsequently the required quantity of alcohol was added. The two components were then mixed. Nitrogen was then purged into the solution obtained in the previous step until the oxygen content was below 7 mg/L, preferably below 3 mg/L. Decitabine was added and stirred in about 80% of the solution obtained in the previous step and dissolved. The volume was then made up to 100% with solution obtained in step 2. The drug solution was then filtered through a suitable sterilizing grade filter and filled into vials. The vial headspace was then blanketed with nitrogen to achieve a headspace oxygen content of less than 10%, preferably less than 5%, more preferably less than 2%. Finally the vials were stoppered and sealed.

(21) The stability profile of the formulation according to example 2 was analyzed by subjecting the samples to various conditions and is presented in table 4. The amount of Decitabine in the composition was measured before and after storage. (The term assay as used in table 2 refers to the quantitative determination of decitabine via HPLC.) Also, the impurity profile of the formulation was analyzed before and after storage at various conditions.

(22) TABLE-US-00004 TABLE 4 Stability Data of Representative Formulation (Example-2) Related Substances (% w/w) Stability Conditions Assay (%) Water by KF Total impurity Initial 100.0 0.41 0.13 40 C./75% RH 100.2 0.43 0.49 (7 days) 40 C./75% RH 102.9 0.31 1.09 (1 month) Accelerated stability 100.4 0.46 0.83 condition 25 C./60% RH (3 M) Accelerated stability 98.9 0.48 1.08 condition 25 C./60% RH (6 M) Real time stability 101.1 0.47 0.28 condition 2-8 C. (3 M) Real time stability 100.3 0.47 0.20 condition 2-8 C. (6 M)

(23) From the stability data provided in the tables above it is apparent that the pharmaceutical compositions according to the present invention are stable under various storage conditions (both real time and accelerated stability conditions).

(24) Also, the impurity profile is better than that of the reference formulation, the commercially available lyophilized product Dacogen, under accelerated storage conditions.