AU762821B2 - 'Soluble 2-chloro-2'-deoxyadenosine formulations' - Google Patents

Description

-1-

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicants: Ortho-McNeil Pharmaceutical, Inc.

Actual Inventors: Michael Bornstein and Rosemary Rozman and Kevin Francis Long and George Kaon Wong

S

Address for Service: BALDWIN SHELSTON WATERS MARGARET STREET SYDNEY NSW 2000 Invention Title: 'SOLUBLE 2-CHLORO-2'-DEOXYADENOSINE FORMULATIONS' Details of Original Application No. 44251/96 dated 15 DEC 1995 The following statement is a full description of this invention, including the best method of performing it known to me/us:- File: 26730AUP00 1A SOLUBLE 2-CHLORO-2'-DEOXYADENOSINE FORMULATIONS This invention relates to pharmaceutically useful and soluble formulations of 2-chloro-2'-deoxyadenosine (2-CdA) in water. More particularly, this invention relates to soluble formulations of 2-CdA in water with certain solubilizers and optionally certain preservatives and buffers which are injectable in humans and have a improved shelf-life.

BACKGROUND OF THE INVENTION The compound 2-CdA has the following formula:

NH

2

N

1 OH

HO

15 2-CdA is known as an antileukemic agent, in treating leukemias, such as, hairy cell leukemia and L 1210 leukemia, and as an immunosuppressive agent 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 subtaneous or intramuscular injection. First, 2-CdA is slightly soluble in water which requires a large volume of material to be injected subscutaneously or intramuscularly to achieve the required dose. Dilute solutionsare acceptable for intravenous injection, but may create pain or inflammatory difficulties tor subcutaneous or intramuscular injection. Secondly, 2-CdA has limited stability in simple saline solutions. Longer shelf-life is beneficial for extended storae at refrigerated or room temperature conditions.

-2- 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.

Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the concentration of 2-CdA versus time in water and with 1% benzyl alcohol as a cosolvent.

Figure 2 is the concentration of 2-CdA versus time with 10% propylene glycol as a cosolvent.

Figure 3 is the concentration of 2-CdA versus time with various levels of benzyl alcohol and a single combination of benzyl alcohol and propylene glycol as shown.

SUMMARY OF THE INVENTION There is provided by the present invention a solution of 2-CdA in water comprising: a) from about 2 to about 8 mg/mL of 2-CdA; and b) a solubilizing agent which is from about 5 to about 30 mg/mL of benzyl alcohol.

**oo Unless the context clearly requires otherwise, throughout the description and the 20 claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

500014798 1.DOC/CMW 2a 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 2,6dichloropurine 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-Derythropentofuranosyl)-purine, which is subsequently reacted with ammonia to yield 2- CdA. An alternative method to manufacture 2-CdA is taught in U.S. Pat. No. 5,208,327 by Robert H.K. Chen.

o o• 5000147981 .DOC/CMW Preferably, the solution contains from aoout 2 to about 7 mg/mL of 2- CdA. Most preferably the solution contains from about 3 to about 5 mg/mL of 2-CdA.

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 the solutions of the present invention there is present from about 8 to about 20 mg/mL benzyl alcohol and most preferrably from about 10 to about 15 mg/mL.

Propylene glycol is a known solubilizing agent for a variety of pharmaceuticals. Preferably in the solution of the present invention there is from about 75 to about 200 mg/mL of propylene glycol and most preferrably from about 100 to about 150 mg/mL.

It is preferred that both benzyl alcohol and propylene glycol be present :i within the prescribed ranges to obtain optimum solubility of 2-CdA in water.

Of course, where one of either benzyl alcohol or propylene glycol it is contemplated within the present invention that the other may be present in less that the prescibed minimum amount.

o To provide for useful solutions of 2-CdA which may be injected to ooo achieve the desired pharmaceutical effect, it may be necessary or desirable to include further compounds in the formulation.

In the absence of propylene glycol. sodium chloride might be added to render the solution isotonic. Where employed, it might constitute from about 2 to about 6 mg/mL of the solution.

The m-cresol is known generally as a preservative in pharmaceutical formulations based on its antibacterial action. In preferred solutions herein there might be added from about 1.5 to about 2.5 mg/mL of m-cresol and most preferrably about 2 mg/mL.

Suitable buffers are any of those available for pharn.r-J-ital application and which are capable of stabilizing pH for the instant solutions between 5.5 and 8.5. Such buffers include but are not limited to cr;p chate, citrate, acetate, borate and tris. The preferred buffer for use herein is sodium phosphate buffer. A preferred pH range for the sneif stable solutions herein is between about 6.0 and about 7.0. The ratio of the sodium phophate monobasic. NaH 2

PO

4 .H20. and the sodium phosohate dibasic.

Na 2

HPO

4 -7H 2 0, 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 emoloyed not only to obtain the desired pH but to stabilize the pH at that value. For solutions herein there might be employed a weight ratio from about 2 to 1 to about 1 to 1 of the sodium phosphate monobasic to the sodium phosphate dibasic.

The formulation of Table 1 was prepared and found suitable for use as an injectable and pharmaceutically useful solution. This solution is pH All figures shown are in mg/mL. The following abbreviations are employed in Table 1 and e!k ere herein: propylene glycol. USP, benzyl alcohol, 15 NF, m-cresoi, sodium phosphate monobasic, monohydrate, USP, (SPMM) and sodium phosphate dibasic, heptahydrate, USP, (SPDH). Water :for injection, USP (WFI), was added to 1.0 mL.

TABLE 1 Formulation 1 2-CdA PG 100.0 25 BA 10.0 MC SPMM 1.816 SPDH 0.941 2-CdA may be administered to a patient in need of the same in a daily dose of 0.05 to about 0.15 mg/Kg. A more desirable daily dose would be from 0.07 to about 0.1 mg/Kg.

The invention is illustrated, but in no way limited, by the following examples.

EXAMPLE.

The following Solutions were prepared with water for injection to make a total volume of 1.0 mL. All figures are in mg/mL.

TABLE2 Formulation Control 1 2 3 4 5 6 7 8 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 15.0 20.0 25.0 30.0 10.0 100.0 100.0 The formulations of Table 2 were stored in a darkened container at roOM temperature and tested periodically for the amount of 2-CdA in solution.

The reported figure is 2-OdA in solution in mg/mL.

TABLE 3 Formulation 32. 4 5. 6 7 8.L CQDI! 0 (target) 3 4 6 17 22 24 32 38 10.0 10.0 10.0 10.1 8.29 4.71 9.54 4.66 2.94 4.25 2.61 3.64 10.0 10.0 10.0 10.0 10.0 10.0 7.65 9.97 9.80 10.1 9.99 9.67 '7.30 2.21 2.26 2.09 4.42 6.25 6.85 7 92 /1.71 59 3.63 2.15 74 2.66 102 2.85 111 3.7 2.24 It is evident from the data above, that the solubility of 2-CdA in water is greatly increased by the addition of either propylene glycol or benzyi alcohol.

Nowhere are cc-soivents having such a marked effect on the solubility of 2- CdA taught or suggested in the prior art.

Claims (9)

1. -7- CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: A solution of 2-CdA in water comprising: a) from about 2 to about 8 mg/mL 2-CdA; and\ b) a solubilizing agent which is from about 5 to about 30 mg/mL of benzyl alcohol. 0 0 .00. 000 .00. oo

2. The solution of claim 1 comprising from about 2 to about 7 mg/mL of 2-CdA.

3. The solution of claim 1 or claim 2 comprising from about 3 to about 5 mg/mL of 2-CdA.

4. The solution of any one of the preceding claims wherein the solubilizing agent is from about 8 to about 20 mg/mL of benzyl alcohol.

The solution of any one of claims 1-3 wherein the solubilizing agent selected from the group consisting of from about 10 to about 15 mg/mL of benzyl alcohol.

6. The solution of any one of the preceding claims wherein the solubilizing agent further comprises from about 50 to about 400 mg/mL ofpropylene glycol. 15

7. The solution of any one of the preceding claims wherein the solubilizing agent further comprises from about 75 to about 200 mg/mL ofpropylene glycol.

8. The solution of any one of the preceding claims wherein the solubilizing agent further comprises from about 100 to about 150 mg/mL ofpropylene glycol.

9. A solution of 2-CdA in water, substantially as herein described with reference to the Example. DATED this 2 5 th Day of March 2003 BALDWIN SHELSTON WATERS Attorneys for: ORTHO-MCNEIL PHARMACEUTICAL, INC. 500014798 1.DOC/CMW