WO2011014541A1

WO2011014541A1 - Stable formulations of azacitidine

Info

Publication number: WO2011014541A1
Application number: PCT/US2010/043503
Authority: WO
Inventors: Nagesh R. Palepu; Philip Christopher Buxton; Bulusu Bhanu Teja
Original assignee: Eagle Pharmaceuticals, Inc.
Priority date: 2009-07-30
Filing date: 2010-07-28
Publication date: 2011-02-03

Abstract

Compositions including azacitidine and a pharmacologically suitable fluid are disclosed. The pharmacologically suitable fluid is preferably non-aqueous and includes propylene glycol, polyethylene glycol, or mixtures thereof; and a surfactant.

Description

STABLE FORMULATIONS OF AZACITIDINE Cross-reference to Related Applications This application claims the benefit of priority from U.S. Provisional Patent Application No. 61/229,832, filed July 30, 2009, entitled "STABLE

FORMULATIONS OF AZACITIDINE," the contents of which are incorporated herein by reference. Background of the Invention

Azacitidine is a pyrimidine nucleoside analog. The structure of azacitidine is

Azatftiάne

Azacitidine is used in the treatment of myelodysplastic syndrome subtypes:

refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. It is believed that azacitidine causes hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in bone marrow. Azacitidine (ACD) use is not widespread due to limitations of the formulation, specifically the chemical stability of the reconstituted lyophile is very short. A simple solution in water loses around 30% of its drug content over a period of 16 hours and at least 9% over the first 2 hours.

Azacitidine is commercially available as Vidaza™ for intravenous or subcutaneous treatment of acute forms of leukemia. Vidaza™ which is formulated at a pH of about 6.5, contains a small quantity of sodium hydroxide and delivers lOOmg of azacitidine in 10ml of water when the lyophile is reconstituted. This concentrate is further diluted with normal saline or Ringer's Lactate to yield a finally

administered concentration of 1 mg/ml. The presence of sodium hydroxide in Vidaza™ also results in limited stability.

Degradation Mechanism of Azacitidine

I II III Azacitidine, in common with other nitrogen-containing hetero cycles, is prone to hydration across the 5,6 carbon-nitrogen bond yielding the transient intermediate (II) which immediately collapses by ring opening to the formamide derivative (HT) which appears as the main hydrolysis product at Relative Retention Time (RRT) 0.66. If the reaction is forced further by extended reaction times or by the use of more extreme conditions, III hydrolyses to give guanidino or urea based derivatives. Prevention or retardation of this process is necessary to provide a product with a viable shelf life and sufficient in-use stability to allow

administration to take place.

The reconstituted azacitidine product is stable only for about 1 hour under ambient conditions and about 8 hours at 5 ⁰C. A hospital environment requires a minimum of about 8 hours of reconstitution stability under ambient conditions. Thus, there is a need for azacitidine formulations with increased stability after reconstitution, especially at ambient conditions.

Summary of the Invention

The invention is generally directed to azacitidine-containing compositions that are stable for at least about 24 hours at room temperature, i.e. temperatures of less than or equal to about 25 ⁰C. In several aspects of the invention, the inventive compositions contain azacitidine or a pharmaceutically acceptable salt thereof and a pharmacologically suitable fluid which includes (i) propylene glycol (PG), polyethylene glycol (PEG), or mixtures thereof and (ii) an ef⁴^⁴""* ^amount _of _a surfactant which, in many preferred embodiments, is at least //w). In some aspects of the invention, the fluid can be about 99.5% propylene glycol or PEG and about 0.5% of a surfactant such as polysorbate 80. Still further aspects include fluids with about equal portions of PG and PEG, with about 0.5% surfactant. In most embodiments, the amount of surfactant included is at least about 0.5% and less than about 10% with amounts of less than or equal to 2.5% being preferred.

In an alternative embodiment, there are provided kits containing an amount of azacitidine or a pharmaceutically acceptable salt thereof, preferably in lyophilized form, in a first vial or container and a pharmacologically suitable fluid which contains at least one of PG or PEG, or mixtures thereof and an effective amount of a surfactant, i.e. at least about 0.5%, in a second vial or container.

The inventive compositions can also include dispersions of a lyophilized azacitidine in the pharmacologically suitable fluids, forming homogenous suspensions. The inventive compositions are substantially free of hydrolysis products, including formamide, guanidine and urea based derivatives for periods of at least about 24 hours or more. In accordance with some particularly preferred embodiments, stable compositions according to the invention include those in which the formulation is substantially free of, i.e. less than about 2% but preferably less than about 0.2-0.5%, hydrolysis products, including formamide, guanidine and urea based derivatives for a period of at least about 24 hours at temperatures of less than or equal to about 25°C, hereinafter "room temperature".

Thus, most formulations in accordance with the present invention will have less than about 0.5% total hydrolysis products after about 24 hours when stored at temperatures of less than or equal to 25°C. Surprisingly, it h^ rmw been discovered that the stability of azacitidine as measured at lea t by the absence of substantially all hydrolysis products, is much improved by dispersing azacitidine (preferably lyophilized) in the pharmacologically suitable fluids described herein. Moreover, it has also been surprisingly found that the dispersibility of azacitidine is markedly increased in the aforementioned pharmacologically suitable fluids. As a result, when appropriate storage conditions are employed, i.e. room temperature or under refrigerated conditions, a shelf-life of at least 24 hours for reconstituted azacitidine is attained.

Still further aspects of the invention include methods for making azacitidine formulations suitable for parenteral administration. The methods include dispersing a lyophilized azacitidine such as that described herein into a pharmacologically suitable, non-aqueous fluid as defined herein and forming a dispersion that is suitable for intramuscular, subcutaneous or subdermal injection and an extended shelf life. Detailed Description of the Invention

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs, hi the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

As used herein, stable refers to azacitidine-containing compositions in which there is not more than about 2% hydrolysis products after a period of at least about 24 hours at a temperature of less than or equal 25°C.

As used herein, pharmaceutically suitable fluid is a solvent suitable for

pharmaceutical use and, if desired, as part of a parenteral formulation.

As used herein, azacitidine also includes pharmaceutically acceυtable salts thereof or derivatives of the compound, including esters, enol ethers ήds, bases, solvates, hydrates or prodrugs thereof. Such salts and derivatives may be readily prepared by those of skill in the art using known methods. The salts and derivatives produced may be administered to animals or humans without substantial toxic effects and are either pharmaceutically active or are prodrugs.

In some aspects of the invention, the azacitidine can be prepared and lyophilized in conventional methods known in the art, such as that described in the package insert for Vidaza™, the contents of which are incorporated herein by reference. In another aspect of the invention, the azacitidine is obtained from commercial sources, hi either case, the azacitidine is understood by those of ordinary skill to be suitable for inclusion in the formulations described herein. In accordance with one aspect of the invention, there are provided azacitidine- containing compositions which have improved stability and dispersibility. In one embodiment, the invention includes azacitidine-containing compositions, including:

a) azacitidine or a pharmaceutically acceptable salt thereof; and

b) a pharmacologically suitable fluid which contains

i) one of propylene glycol or polyethylene glycol, or a mixture thereof; and

ii) an effective amount, i.e. preferably at least about 0.5%, of a surfactant (w/w).

For purposes of the present invention, "effective amount" shall be understood to be an amount which is sufficient, when combined with the propylene glycol or polyethylene glycol to confer not only suitable dispersability upon the azacitidine included in the inventive formulations, but will also sufficient to impart the unexpected increase in stability thereon. While in many preferred aspects, the amount of surfactant is at least about 0.5%, it will be appreciated that some surfaciants, when included in amounts below 0.5% will none^+1if>1(iQ<i ^f sufficient to impart the desired qualities upon the formulation.

Preferably, the surfactant is apoloxamer of the general formula (I),

polyoxyethylene sorbitan fatty acid ester surfactants of general formula (II), polyoxyethylene sorbitan fatty acid ester surfactants of general formula (III), or mixtures thereof. See below. Formula (I)

Formula (II)

Formula (III)

wherein:

R = fatty acid;

w + x + y + z = 20; 5; or 4.

Preferably, the surfactant is selected from the non-limiting list of materials which includes polysorbate 80, poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 85, polysorbate 81, polysorbate 21, polysorbate 61 and Cremophor EL™. In some other preferred aspects of the invention, the pharmacologically suitable fluid includes polysorbate 80 as the surfactant. In other preferred aspects of the invention, the pharmacologically suitable fluid includes poloxamer 188 as the surfactant.

The pharmaceutically suitable fluids used herein are preferably non-aqueous or substantially non-aqueous. The fact that the surfactant or other ingredients included therein may include a small amount of water, the non- aqueous nature of the fluids herein is not altered.

The PG and PEG used in the fluids will be pharmaceutically acceptable (as such term is understood by those of ordinary skill in the art) and meet all necessary pharmacopeial (USP, JP, PhEur, etc.) standards.

Preferably, the molecular weight of polyethylene glycol is from about 190 to about 9,000 or higher, as known to be used by those of ordinary skill in the art. More preferably, the polyethylene glycol is PEG 400. This invention is not limited to the aforementioned fluids and can optionally also include all pharmacologically acceptable organic solvents that are miscible in water such as ethanol, benzyl alcohol, etc. The surfactants described herein allow the azacitidine to be more readily dispersed in the preferably non-aqueous fluids.

In some preferred aspects of the invention, the pharmacologically suitable fluid includes a combination of propylene glycol and a surfactant. The ratio of propylene glycol to surfactant can be from about 99.6/0.4 to about 90/10 (w/w). Preferably, the ratio of propylene glycol to surfactant is from about 99.5/0.5 to about 97.5/2.5 (w/w) or, more preferably, from about 99.5/0.5 to about 98.5/1.5

(w/w). One particularly preferred fluid useful herein includes 99.5% PG and 0.5% surfactant.

In one embodiment of the invention, the azacitidine-containing composition includes azacitidine or a pharmaceutically acceptable salt thereof; a

pharmacologically suitable fluid including propylene glycol, and polysorbate 80; wherein the ratio of propylene glycol to polysorbate 80 is about 99.5/0.5 (w/w). One particularly preferred fluid useful herein includes 99.5% PG and 0.5% surfactant. Other preferred aspects of the invention are those in which the pharmacologically suitable fluid includes a combination of polyethylene glycol and surfactant. The ratio of polyethylene glycol to surfactant can be from about 99.6/0.4 to about 90/10 (w/w). Preferably, the ratio of polyethylene glycol to surfactant is from about 99.5/0.5 to about 97.5/2.5 (w/w) or from about 99.5/0.5 to about 98.5/1.5 (w/w). One particularly preferred fluid useful herein includes 99.5% PEG and 0.5% surfactant.

pharmacologically suitable fluid including polyethylene glycol, and polysorbate 80; wherein the ratio of polyethylene glycol to polysorbate 80 is about 99.5/0.5

(w/w).

In another alternative embodiment, the pharmacologically sv^hl^p fluid includes a mixture of propylene glycol and polyethylene glycol. The r< ae glycol to polyethylene glycol is from about 1/99 to about 99/1 (w/w). Preferably, the ratio of propylene glycol to polyethylene glycol is about 50/50 (w/w). After inclusion of the surfactant, the fluid will include PG:PEG:surfactant in a ratio of about 49.25:49.25:0.5.

In one embodiment of the invention, the azacitidine concentration is from about 0.5 mg/ml to about 120 mg/mL. In another embodiment of the invention, the azacitidine concentration is from about 1 mg/ml to about 34 mg/ml. Preferably, the azacitidine concentration is from about 20 mg/ml to about 31 mg/ml. More preferably, the azacitidine concentration is from about 25 to about 30 mg/ml. In alternative embodiments, there are provided formulations in accordance with the invention where the azacitidine concentration is about 100 mg/ml.

Still further aspects of the invention include methods for making azacitidine formulations suitable for parenteral administration. The methods include dispersing azacitidine as described herein, i.e. lyophilized or not, into a

pharmacologically suitable fluid as defined herein and forming a dispersion that is suitable for intramuscular, subcutaneous or subdermal injection and an extended shelf life. The steps are carried out under pharmaceutically acceptable conditions for sterility and manufacturing. In another aspect of the invention, the dispersion can be transferred into an IV container or bag containing infusion fluid such as normal saline, dissolved and administered as IV infusion. The dosage form of azacitidine can be packaged with the Add-vantage™ system for dispersion and administration by IV. The principle indications and uses and amounts

administered will be apparent to those of ordinary skill in the art without undue experimentation. A further aspect of the invention includes a reconstituted dispersion that is ready to administer.

Another embodiment of the invention includes methods of tπ^™^ " "'""itidine sensitive disease in mammals, including administering an efi of an azacitidine-containing composition as described herein, i.e. including azacitidine or a pharmaceutically acceptable salt thereof; and a pharmacologically suitable fluid including propylene glycol, polyethylene glycol, or mixtures thereof; and an effective amount of a surfactant, to a mammal in need thereof. In some

embodiments, the azacitidine sensitive disease is, but not limited to,

myelodysplastic syndrome, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Another embodiment of the Invention provides a kit including:

(a) a first container including an amount of lyophilized azacitidine or a pharmaceutically acceptable salt thereof; and

b) a second container which includes a pharmacologically suitable fluid including

i) propylene glycol, polyethylene glycol, or mixtures thereof; and ii) an effective amount of a surfactant, which, in most cases, is at least about 0.5%.

The kit may also include instructions for use in/administration of the drug and/or ancillary materials useful in the administration of the drug to a patient in need thereof. The amount of azacitidine included in the container will vary, depending upon need but generally is an amount suffient for one or more therapeutic doses to a patient. Examples

The following examples serve to provide further appreciation of the invention but are not meant in any way to restrict the effective scope of the invention.

Comparative Example 1

100% water was added to vials containing lyophilized azacitidine (ACD) obtained from commercial sources. The final ACD concentration was 0.5mg/ml. The vials were sealed and stored at room temperature (25 ⁰C) for 16 hours. The samples were tested via HPLC, and the relative retention time (RRT) is reported in Table 1 below. RRT is calculated by dividing the retention time of the peak of interest by the retention time of the main peak, 10 minutes for azacitidine. Any peak with an RRT <1 elutes before the main peak, and any peak with an RRT >1 elutes after the main peak. Table 1 shows that azacitidine in water loses about 30% of its drug content over a period of 16 hours, and at least 9% over the first two hours. Thus, azacitidine exhibits poor stability in water. Table 1 : Stability of ACD (0.5mg/ml) in Water (Ambient Laboratory Temperature, about 25 ⁰C)

Analysis by validated HPLC method, ND- Not Detected

Comparative Example 2

Normal saline and lactated Ringers Solution were added to vials containing Vidaza™, which contains lyophilized azacitidine and sodium hydroxide. The final concentration of azacitidine was lmg/ml and the pH was 6.5 Te sealed and stored at room temperature (25 ⁰C) for 2 hours. 1 ,..„ ;re tested via HPLC, and the relative retention time (RRT) is reported in Table 2 below. Table 2 shows that azacitidine plus sodium hydroxide is stable only for about 1 hour at room temperature in saline and in lactated Ringers Solution, and thus, exhibits poor stability. Table 2: Stability of Vidaza™ (1 mg/ml) in Normal Saline and Lactated Ringers

Solution

(25 ⁰C and pH 6.5)

Note: % Imp is the sum total of all other recorded impurities

% HP is the area normalized percentage of the hydrolysis product at RRT

0.67

¹ Comparative Example 3 Normal saline and lactated Ringers Solution were added to A ^' \

Vidaza™, which contains lyophilized azacitidine and sodiur „ The final concentration of azacitidine was lmg/ml and the pH was 6.5. The vials were sealed and stored at 5 ⁰C for over 13 hours. The samples were tested via HPLC, and the relative retention time (RRT) is reported in Table 3 below. Table 3 shows that azacitidine plus sodium hydroxide is stable only for about 8 hours at 5 ⁰C in saline and in lactated Ringers Solution, and thus, exhibits poor stability. Table 3: Stability of Vidaza™ (lmg/ml) in Normal Saline and Lactated Ringers

Solutions

(5 ⁰C and pH 6.5)

Note: Times recorded for Ringer's lactate after initial were 10 minutes longer than indicated

% Imp is the sum total of all other recorded impurities

% HP is the area normalized percentage of the hydrolysis product at RRT 0.66

Example 4

100% propylene glycol was added to vials containing lyophilized ACD. The resulting ACD concentration was 21.6 mg/mL. The vials were sealed and stored at room temperature for 24 hours. The samples were tested via HPLC, and the relative retention time (RRT) is reported in Table 4 below. Although the samples do not show substantial degradation, the reconstitαtion time to disperse the azacitidine in the samples was long and required vigorous mixing. Table 4; 24 hour stability of ACD lyophile reconstituted with 100% Propylene glycol

ND: None detected

Example 5

A mixture of 90% propylene glycol and 10% water (w/w), instead of 100% propylene glycol of Example 4, was added to vials containing lyophilized ACD to obtain an ACD concentration of 31.5 mg/mL. The amount of degradation over a 24 hour period at room temperature is reported in Table 5 below. The addition of 10% water provided excellent reconstitution and stability.

Table 5: 24 hour stability of ACD lyophile reconstituted with 90% Propylene

Glycol/ 10% Water (w/w)

Example 6

The ACD-containing preparation of Example 4 was made by adding a mixture of 80% propylene glycol and 20% water (w/w) instead of 100% propylene glycol and the lyophilized ACD was reconstituted at a concentration of 27.3 mg/mL. The amount of degradation over a 24 hour period at room temperature is reported in Table 6 below. The addition of 20% water provided excellent reconstitution and stability.

Table 6: 24 hour stability of ACD lyophile reconstituted with 80% Propylene Glycol/ 20% Water (w/w)

Example 7

The ACD-containing preparation of Example 4 was made by adding a mixture of 70% propylene glycol and 30% water (w/w) instead of 100% propylene glycol and the lyophilized ACD was reconstituted at a concentration of 29.1 mg/mL. The amount of degradation over a 24 hour period at room temperature is reported in Table 7 below. The addition of 30% water provided excellent reconstitution and stability. Table 7: 24 hour stability of ACD lyophile reconstituted with 70% Propylene

Glycol/ 30% Water (w/w)

Examples 5-7 demonstrate that alternative embodiments in which some water is included can provide useful formulations.

Example 8

100% polyethylene glycol 400 was added to vials containing lyophilized ACD. The lyophilized ACD was reconstituted at a concentration of 30.9 mg/mJL. The vials were sealed and stored at room temperature for 24 hours. The samples were tested via HPLC, and the relative retention time (RRT) is reported in Table 8 below. Although the samples do not show substantial degradation, the

reconstitution time to disperse the azacitidine in the samples required vigorous mixing.

Table 8: 24 hour stability of ACE) lyophile. reconstituted with 100% PEG 400

Example 9

A mixture containing 50% propylene glycol and 50% PEG 400 was added to vials containing lyophilized ACD. The lyophilized ACD was reconstituted at a concentration of 29.4 mg/mL. The vials were sealed and stored at room temperature for 24 hours. The samples were tested via HPLC, and the relative retention time (RRT) is reported in Table 9 below. Although the samples do not show substantial degradation, the reconstitution time to disperse the azacitidine in the samples was long and required vigorous mixing.

Table 9: 24 hour stability of ACD lyophile reconstituted with PEG/ Propylene

Glycol 50/50 (w/w)

Example 10

99.5% propylene glycol and 0.5% polysorbate 80 (w/v) were added to vials containing lyophilized ACD. The lyophilized ACD was reconstituted at a concentration of 31.2 mg/mL. The vials were sealed and stored at room temperature for one week. The samples were tested via HPLC, and the relative retention time (RRT) is reported in Table 10 below. The data shows that the presence of small amount of polysorbate 80 improved the reconstitution time as well as dispersibility of the lyophile.

Table 10: One week stability of ACD lyophile reconstituted with 99.5% Propylene

Glycol containing 0.5% polysorbate 80 (w/v)

Example 11

The ACD-containing preparation of Example 10 was made with 98.5% propylene glycol and 1.5% polysorbate 80 (w/v) instead of 99.5% prop ^{' ' *} id 0.5% polysorbate 80 (w/v), and the lyophilized ACD was reconstii

concentration of 31.8 mg/niL. The amount of degradation over a one week period at room temperature is reported in Table 11 below. The data shows that the presence of small amount of polysorbate 80 improved the reconstitution time as well as dispersibility of the lyophile without negatively affecting long-term stability. Table 11: One week stability of ACD lyophile reconstituted with 98,5% Propylene Glycol containing 1.5% polysorbate 80 (w/v)

Example 12

The ACD-contarnrng preparation of Example 10 was made with a mixture of 97.5% propylene glycol and 2.5% polysorbate 80 (w/v) instead of 99.5% propylene glycol and 0.5% polysorbate 80 (w/v), and the ly_C ^~t--¹---'^{< Λ} ^^ was reconstituted at a concentration of 31.2 mg/mL. The amoun n over a one week period at room temperature is reported in Table 12 below. The data shows that the presence of small amount of polysorbate 80 improved the reconstitution time as well as dispersibility of the lyophile without negatively affecting long-term stability. Table 12: One week stability of ACD lyophile reconstituted with 97.5% Propylene Glycol containing 2.5% polysorbate 80 (w/v)

When water is not present in the formulation, the reconstituted dispersion may be stable for 18 months either under ambient storage conditions or under refrigerated conditions.

Examples 13-17 The procedures above were repeated using additional inventive formulations in accordance with the invention. In each case, it can be seen that the inventive formulations have sufficient long term stability so that the a) )lysis products after 24 hours at a temperature of = 25⁰C is less than about ΛU%.

Table 13

BDL: Below Detectable Levels

Table 14

Claims

We claim:

1. An azacitidine-containing composition, comprising:

a) azacitidine or a pharmaceutically acceptable salt thereof; and

b) a pharmacologically suitable fluid comprising

i) propylene glycol, polyethylene glycol or mixtures thereof; and ii) an effective amount of a surfactant .

2. The azacitidine-containing composition of claim 1, wherein the

pharmacologically suitable fluid comprises propylene glycol and the surfactant is polysorbate 80.

3. The azacitidine-containing composition of claim 1, wherein the

pharmacologically suitable fluid comprises polyethylene glycol and the surfactant is polysorbate 80.

4. The azacitidine-containing composition of claim 1, wherein the molecular weight of the polyethylene glycol is 400.

5. The azacitidine-containing composition of claim 1, w actant is selected from the group consisting of polysorbate 80, poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 85, polysorbate 81, polysorbate 21, polysorbate 61 and Cremophor EL™ and mixtures thereof.

6. The azacitidine-containing composition of claim 1, wherein said fluid includes propylene glycol and a surfactant in a ratio of about 99.5 to about 0.5 (w/w).

7. The azacitidine-containing composition of claim 1, wherein said fluid includes propylene glycol and a surfactant in a ratio of from about 99.5/0.5 to about 97.5/2.5 (w/w).

8. The azacitidine-containing composition of claim 7, wherein said fluid includes propylene with one of when one of what one of one of one withglycol and a surfactant in a ratio of from about 99.5/0.5 to about 98.5/1.5 (w/w).

9. The azacitidine-containing composition of claim 1, wherein said fluid includes propylene glycol arid polyethylene glycol.

10. The azacitidine-containing composition of claim 9, wherein said fluid further comprises up to about 2.5% (w/w) of a surfactant.

11. The azacitidine-containing composition of claim 10, wherein the fluid comprises about 0.5% (w/w) of a surfactant.

12. The azacitidine-containing composition of claim 1, wherein the azacitidine concentration is from about 0.5 mg/ml to about 120 mg/ml.

13. The azacitidine-containing composition of claim 12, wherein the azacitidine concentration is from about 20 mg/ml to about 31 mg/ml.

14. The azacitidine-containing composition of claim 13, wherein the azacitidine concentration is from about 25 to about 30 mg/ml.

15. An azacitidine-containing composition according to claim 1, comprising: a) azacitidine or a pharmaceutically acceptable salt thereof;

b) a pharmacologically suitable fluid consisting essentially of

i) propylene glycol, and ii) a surfactant; wherein

the ratio of propylene glycol to surfactant is about 99.5 to about 0.5 (w/w).

16. An azacitidine-containing composition according to claim 1, comprising: a) azacitidine or a pharmaceutically acceptable salt thereof;

b) a pharmacologically suitable fluid consisting essentially of

i) polyethylene glycol, and

ii) a surfactant; wherein

the ratio of polyethylene glycol to surfactant is about 99.5 to about 0.5 (w/w).

17. An azacitidine-containing composition according to claim 1, comprising: a) azacitidine or a pharmaceutically acceptable salt thereof;

b) a pharmacologically suitable fluid consisting essentially of

i) propylene glycol,

ii) polyethylene glycol, and

ii) a surfactant; wherein

the ratio of PG:PEG:surfactant is 49.25:49.25:0.5.

18. A method of treating of an azacitidine sensitive dise< s, comprising administering an effective amount of an azacitidine-containing composition of claim 1 to a mammal in need thereof.

19. A kit comprising :

(a) a first container including lyophilized azacitidine or a pharmaceutically acceptable salt thereof; and

b) a second container including a pharmacologically suitable fluid comprising

i) propylene glycol, polyethylene glycol, or mixtures thereof; and ii) at least about 0.5% surfactant (w/w).

20. An azacitidine- containing composition according to claim 1 wherein the amount of hydrolysis products after 24 hours at a temperature of = 25⁰C is less than about 2.0%.