STABLE SOLUTIONS OF 2-CHLORO-2'-DEOXYADENOSINE FORMULATIONS

SOLUTIONS STABLES DE FORMULATIONS DE 2-CHLORO-2'-DESOXYADENOSINE

English Abstract

Shelf stable formulations of 2-CdA in water are disclosed which contain benzyl
alcohol, m-cresol, a buffer and sodium chloride or a
solubilizing agent such as propylene glycol or polyethylene glycol.

French Abstract

L'invention concerne des formulations aqueuses de 2-chloro-2'-desoxyadénosine stables à la conservation et contenant de l'alcool de benzyle, du m-crésol, un tampon et du chlorure de sodium ou un agent solubilisant, tel que le propylène glycol ou le polyéthylène glycol.

Claims

8
WHAT IS CLAIMED IS:
1. A solution of 2-CdA in water comprising:
a) from about 1 to about 8 mg/mL 2-CdA;
b) from about 50 to about 400 mg/mL of solubilizing agent selected
from the group consisting of propylene glycol and polyethylene glycol;
c) from about 5 to about 50 mg/mL of benzyl alcohol;
d) from 0 to about 3 mg/mL of m-cresol; and
e) an effective amount of a pharmaceutically acceptable buffer to
stabilize the pH at between about 5.5 and about 8.5.
2. The solution of claim 1 comprising from about 3 to about 7 mg/mL of 2-
CdA, from 75 to about 200 mg/mL of solubilizing agent, from about 8 to
about 20 mg/mL of benzyl alcohol and from about 1.5 to about 2.5
mg/mL of m-cresol.
3. The solution of claim 1 wherein the buffer is selected from the group
consisiting of phosphate, citrate, acetate, borate and tris buffers.
4. The solution of claim 1 wherein the buffer is an effective amount of
phospate buffer comprising sodium phosphate monobasic,
monohydrate, and sodium phosphate dibasic, heptahydrate, to stabilize
the pH at between about 6.0 and about 7Ø
5. The solution of claim 1 comprising:
a) from about 4 to about 6 mg/mL 2-CdA;
b) from about 100 to about 150 mg/mL of solubilizing agent selected
from the group consisting of propylene glycol and polyethylene glycol;
c) from about 10 to about 15 mg/mL of benzyl alcohol;

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d) about 2 mg/mL of m-cresol; and
e) about 1.816 mg/mL sodium phosphate monobasic, monohydrate,
and about 0.941 mg/mL sodium phosphate dibasic, heptahydrate.
6. The solution of claim 1 wherein the solubilizing agent is propylene glycol.
7. A solution of 2-CdA in water comprising:
a) from about 1 to about 5 mg/mL 2-CdA;
b) from about 2 to about 10 mg/mL of sodium chloride;
c) from about 5 to about 50 mg/mL of benzyl alcohol;
d) from about 0 to about 3 mg/mL of m-cresol; and
e) an effective amount of a pharmaceutically acceptable buffer to
stabilize the pH at between about 5.5 and about 8.5.
8. The solution of claim 7 comprising from about 2 to about 4 mg/mL of 2-
CdA, from 3 to about 8 mg/mL of sodium chloride, from about 8 to about
20 mg/mL of benzyl alcohol and from about 1.5 to about 2.5 mg/mL of
m-cresol.
9. The solution of claim 7 wherein the buffer is selected from the group
consisiting of phosphate, citrate, acetate, borate and tris buffers.
10. The solution of claim 7 wherein the buffer is an effective amount of
phospate buffer comprising sodium phosphate monobasic,
monohydrate, and sodium phosphate dibasic, heptahydrate, to stabilize
the pH at between about 6.0 and about 7Ø

11. The solution of claim 7 comprising:
a) about 3 mg/mL 2-CdA;
b) about 4 mg/mL of sodium chloride;
c) about 10 to about 15 mg/mL of benzyl alcohol;
d) about 2 mg/mL of m-cresol; and
e) about 1.555 mg/mL sodium phosphate monobasic, monohydrate,
and about 1.446 mg/mL sodium phosphate dibasic, heptahydrate.

Description

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STABLE SOLUTIONS OF 2-CHLORO-2'-DEOXYADENOSINE FORMULATIONS
This invention relates to pharmaceutically useful and stable
formulations of 2-chloro-2'-deoxyadenosine (2-CdA) in water. More
particularly, this invention relates to stable formulations of 2-CdA in water
with
certain preservatives, buffers and solubilizers which are injectable in humans
and have a improved shelf-life.
BACKGROUND OF THE INVENTION
The compound 2-CdA has the following formula:
NH2
Z~
N N
N
CI
O
HO "OH
2-CdA is known as an antileukemic agent, i.e., in treating leukemias, such as,
hairy cell leukemia and L 1210 leukemia, and as an immunosuppressive
agent (D. A. Carson, D. Bruce Wasson, and Ernst Beutler, Proc. Soc. Acad.
Sci. USA, Vol. 81, pp 2232- 2236, 1984). More recently, 2-CdA has been has
been disclosed as effective in the treatment of rheumatoid arthritis and
multiple sclerosis, U.S. Pat. No. 5,310,732.
To date, 2-CdA has been administered by intravenous injection of
saline solutions presenting two problems for subcutaneous or intramuscular
injection. First, 2-CdA is slightly soluble in water which requires a large
volume of matrial to be injected subcutaneously or intramuscularly to achieve
the required dose. Secondly, 2-CdA has limited stability in simple saline
= solutions. Longer shelf-life is beneficial for extended storage at
refrigerated or
room temperature conditions.

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U.S. Pat. No. 5,310,732, col. 8, teaches a 0.1 mg/mL isotonic saline
solution of 2-CdA. There has been marketed a non-buffered solution
containing 1.0 mg/mL of 2-CdA in 9.0 mg/mL sodium chloride injection, USP.
SUMMARY OF THE INVENTION
There is provided by the present invention a first improved shelf stable
solution of 2-CdA in water comprising:
a) from about 1 to about 8 mg/mL 2-CdA;
b) from about 50 to about 400 mg/mL of solubilizing agent selected
from the group consisting of propylene glycol and polyethylene glycol;
c) from about 5 to about 50 mg/mL of benzyl alcohol;
d) from 0 to about 3 mg/mL of m-cresol; and
e) an effective amount of a pharmaceutically acceptable buffer to
stabilize the pH at between about 5.5 and about 8.5.
There is provided by the present invention a second improved shelf
stable solution of 2-CdA in water comprising:
a) from about 1 to about 5 mg/mL 2-CdA;
b) from about 2 to about 10 mg/mL of sodium chloride;
c) from about 5 to about 50 mg/mL of benzyl alcohol;
d) from about 0 to about 3 mg/mL of m-cresol; and
e) an effective amount of a pharmaceutically acceptable buffer to
stabilize the pH at between about 5.5 and about 8.5.

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DETAILED DESCRIPTION OF THE INVENTION
Processes for preparing 2-CdA are known. European Patent
Application No. 173,059 A2 and Robins et al., J. Am. Chem. Soc., 106, 6379
(1984) disclose the preparation or 2-CdA. The preparation consists of the
glycosilation of 2,6-dichloropurine with 1-chloro-2'-deoxy-3',5'-di-O-p-
toluoyl-b-
D-erythropentofuranose to yield the N-9 glycosilated purine, 2,6-dichloro-9-(2-
deoxy-3,5-di-O-p-toluoyl-b-D-erythropentofuranosyl)-purine, which is
subsequently reacted with ammonia to yield 2-CdA. An attemative method to
manufacture 2-CdA is taught in U.S. Pat. No. 5,208,327 by Robert H. K.
Chen.
Preferably, the first shelf stable solution contains from about 3 to about
7 mg/mL and most preferably from about 4 to about 6 mg/mL of 2-CdA. The
second shelf stable solution preferably contains from about 2 to about 4
mg/mL of 2-CdA.
Propylene glycol and polyethylene glycol are known solubilizing agents
for a variety of pharmaceuticals. Suitable polyethylene glycols are
exemplified by polyethylene glycol 300 or polyethylene glycol 400. Preferably
in the first shelf stable solution there is from about 75 to about 200 mg/mL
of
propylene glycol or polyethylene glycol and most preferrably from about 100
to about 150 mg/mL.
The second shelf stable solution is isotonic and should contain
sufficient sodium chloride to render it so. Preferrably this solution should
contain from about 3 to about 8 mg/mL sodium chloride and most preferrably
3 to 6 mg/mL.
Benzyl alcohol is known generally as a preservative in pharmaceutical
formulations based on its antibacterial action and as a solubilizing agent for
certain pharmaceutical compounds. Preferably, in both the first and second
shelf stable solutions there is present from about 8 to about 20 mg/mL benzyl
alcohol and most preferrably from about 10 to about 15 mg/mL.

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The m-cresol is known generally as a preservative in pharmaceutical
formulations based on its antibacterial action. Preferably, in both the first
and
second shelf stable solutions there is present from about 1.5 to about 2.5
mg/mL of m-cresol and most preferrably about 2 mg/mL. Use of m-cresol 5 may be
eliminated provided that sufficient other preservative is used to render
a suitably preserved formulation.
Suitable buffers are any of those available for pharmaceutical
application and which are capable of stabilizing the pH between 5.5 and 8.5.
Such buffers include but are not limited to phosphate, citrate, acetate,
borate
and tris. The preferred buffer for use herein is a sodium phosphate buffer
system. A preferred pH range for the shelf stable solutions herein is between
about 6.0 and about 7Ø The ratio of the sodium phophate monobasic,
NaH2PO4=H2O, and the sodium phosphate dibasic, Na2HPO4=7H20, are
adjusted to achieve the pH desired. This buffer is generally useful to achieve
a pH in the range of from 4.5 to 8.5. Of course, sufficient buffer-should be
employed not only to obtain the desired pH but to stabilize the pH at that
value. For the first shelf stable solution, there should be employed about a 2
to 1 weight ratio of the sodium phosphate monobasic to the sodium
phosphate dibasic. For the second shelf stable solution, there should be
employed about a 1 to 1 weight ratio of the sodium phosphate monobasic to
the sodium phosphate dibasic.
2-CdA may be administered to a patient in need of the same in a daily
dose of 0.05 to 0.15 mg/Kg. A more desirable daily dose would be from 0.07
to 0.1 mg/Kg.
The invention is illustrated, but in no way limited, by the following
examples.
EXAMPLE
The following formulations were prepared. Solutions containing a
phospate buffer were adjusted to pH 6.5. All figures shown are in mg/mL.
The following abbreviations were employed: polyethylene glycol, NF, (PEG),
propylene glycol, USP, (PG), benzyl alcohol, NF, (BA), m-cresol, (MC),
sodium phosphate monobasic, monohydrate, USP, (SPMM) and sodium

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phosphate dibasic, heptahydrate, USP, (SPDH). Water for injection, USP,
was added to make the final volume of 1.0 mL.
5 TABLE 1
Formulation 1 2 ~ Control
2-CdA 5.0 5.0 3.0 1.0
NaCi 4.0 9.0
PEG 300 100.0
PG 100.0
BA 10.0 10.0 10.0
MC 2.0 2.0 2.0
SPMM 1.816 1.816 1.555
SPDH 0.941 0.941 1.446
The formulations of Table 1 were tested for stability after being stored
for various times at various temperatures. The formulations were tested for 2-
CdA content, 2-CAD content (hydrolysis product of 2-CdA), benzyl alcohol
content and m-cresol content. The reported figure is in % of initial with the
%
of 2-CAD expressed in % initial of 2-CdA.
TABLE 2
Formulation 1 g ~ Control
Initial, % label
2-CdA 98.8 99.1 104.9 102.3
2-CAD ND ND ND ND
BA 109 108.7 111.4 N/A
MC 99.6 99.9 101.5 N/A

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TABLE 2 - Cont'd.
Formulation 1 2 Control
50 C/4 wk
2-CdA 99.4 99.1 93.2 82.9
2-CAD 2.8 2.7 3.6 6.0
BA 95.1 95.3 91.9 N/A
MC 98.8 99.2 94.6 N/A
50 C/8 wk
2-CdA 96.6 95.8 89.8 81.2
2-CAD 3.7 3.6 3.0 5.7
BA 90.9 90.2 86.8 N/A
MC 98.2 96.3 92.6 N/A
40 C/4 wk
2-CdA 101.8 101.8 96.3 96.2
2-CAD 0.7 0.7 0.9 1.3
BA 95.4 95.8 92.4 N/A
MC 99.5 100.0 95.9 N/A
40 C/8 wk
2-CdA 102.3 100.2 96.3 94.8
2-CAD 1.0 0.9 1.2 2.9
BA 90.8 90.5 87.1 N/A
MC 96.5 98.0 94.4 N/A
25 C/12 wk 35 2-CdA 103.7 97.6 98.3
2-CAD 0.21 0.25 0.36
BA 92.8 88.1 N/A
MC 99.6 96.4 N/A

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TABLE 2 - Cont'd.
Formulation Control
5 C/8 wk
2-CdA 103.4 104.5 97.9 100.7
2-CAD 0.0 0.0 0.1 0.1
BA 92.5 93.4 89.9 N/A
MC 99.0 100.2 97.0 N/A
It is evident from the data above, that the formulations of the present
invention are exceptionally shelf stable as compared to the control, which is
the presently marketed formulation. Nowhere are such stable formulations of
2-CdA taught or suggested in the prior art. In addition, the data show that
significantly less 2-CAD hydrolysis degradation product is formed in
formulations 1, 2 and 3 compared to the control.