AU4425196A - Soluble 2-chloro-2'-deoxyadenosine formulations - Google Patents
Soluble 2-chloro-2'-deoxyadenosine formulationsInfo
- Publication number
- AU4425196A AU4425196A AU44251/96A AU4425196A AU4425196A AU 4425196 A AU4425196 A AU 4425196A AU 44251/96 A AU44251/96 A AU 44251/96A AU 4425196 A AU4425196 A AU 4425196A AU 4425196 A AU4425196 A AU 4425196A
- Authority
- AU
- Australia
- Prior art keywords
- cda
- solution
- benzyl alcohol
- propylene glycol
- formulations
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 title claims description 7
- 239000000203 mixture Substances 0.000 title description 10
- 238000009472 formulation Methods 0.000 title description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 42
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 39
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 description 21
- 239000000872 buffer Substances 0.000 description 7
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229910000397 disodium phosphate Inorganic materials 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 235000019800 disodium phosphate Nutrition 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- -1 USP Chemical compound 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000000063 antileukemic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
SOLURL F g-CHLORO-2'-DEOXYADENOSINE FORMULATIONS
This invention relates to pharmaceutically useful and soluble formulations of 2-chloro-2'-deoxyadenosιne (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:
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 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 solutions are 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 storaqe at refrigerated or room temperature conditions.
U.S. Pat. No. 5.310,732. col. 8. teacnes 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.
BRIFF 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 fo 2-CdA versus time with various levels of benzyl alcohol and a single combination of benzyl alcohol and propylene gylcol as shown.
SUMMARY OF THE INVENTION
There is provided by the present invention a solution of 2-CdA in water comprising:
a) from about 1 to about 8 mg/mL of 2-CdA; and
b) a solubilizmg agent selected from the group consisting of from about 5 to about 30 mg/mL of benzyl alcohol and from about 50 to about 400 mg/mL of propylene glycol.
DETAILED DESCRIPTION OF THF 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-dιchloropunne with 1 -chloro-2'-deoxy-3\5'-dι-0-p-toluoyl-b- D-erythropentofuranose to yield the N-9 glycosilated puπne, 2,6-dιchloro-9-(2- deoxy-3,5-di-0-p-toluoyl-b-D-erythropentofuranosyl)-puπne, which is subsequently reacted with ammonia to yield 2-CdA. n alternative method to manufacture 2-CdA is taught in U.S. Pat. No. 5,208,327 by Robert H. K. Chen.
Preferably, the solution contains from aσout 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 solubilizmg 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 solubilizmg 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 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 presαbed minimum amount.
To provide for useful solutions of 2-CdA which may be injected to 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 antibactenal 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 phaτp£?r?jτ-;al application and which are capable of stabilizing pH for the instant solutions between 5.5 and 8.5. Such buffers include but are not 'im " - *o c.r-o_Dhate, citrate, acetate, borate and tns. The preferred buffer for LS ? ^÷re n is sodium
pnospnate buffer. A preferred pH range for the snelf stable solutions herein is between about 6.0 and about 7.0. The ratio of the sodium phophate monobasic. NaH Pθ4-H20. and the sodium phosphate dibasic, Na2HP04*7H 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 employed 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 6.5. All figures shown are in mg/mL. The following abbreviations are employed in Table 1 and elsewhere herein: propylene glycol, USP, (PG), benzyl alcohol, NF, (BA), m-cresol, (MC), 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 5.0
PG 100.0
BA 10.0
MC 2.0
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
TAPLE 2
Formulation 2-CdA fiA P£
Control 10.0
1 10.0 100.0
2 10.0 5.0
3 10.0 10.0
4 10.0 15.0
5 1 100..00 20.0
6 10.0 25.0
7 10.0 30.0
8 10.0 10.0 100.0
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-CdA in solution in mg/mL.
TAB E 3
Da s Formulation
Control
0 (target) 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 3 10.1 7.65
4 8.29 9.97 9.80 10.1 9.99 9.67
6 4.71
10 9.54 7.30
17 4.66 2.21 22 2.94
24 4.25 2.26
32 2.61 4.42 6.25 6.85 7 92 4 71
38 3.64 2.09
9 3.63 2.15 4 2.66
102 2.85
11 1 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 benzyl alcohol. Nowhere are co-solvents having such a marked effect on the solubility of 2- CdA taught or suggested in the prior art.
Claims (7)
1. A solution of 2-CdA in water comprising: '
a) from about 1 to aDOut 8 mg/mL 2-CdA: and
b) a solubilizing agent selected from the group consisting of from about 5 to about 30 mg/mL of benzyl alcohol and from about 50 to about 400 mg/mL of propylene glycol.
2. The solution of claim 1 comprising from about 2 to about 7 mg/mL of 2- CdA.
3. The solution of claim 1 compπsing from about 3 to about 5 mg/mL of 2- CdA.
4. The solution of claim 1 wherein the solubilizing agent is propylene glycol.
5. The solution of claim 1 wherein the solubilizing agent is benzyl alcohol.
6. The solution of claim 1 wherein the solubilizing agent selected from the group consisting of from about 8 to about 20 mg/mL of benzyl alcohol and from about 75 to about 200 mg/mL of propylene glycol.
7. The solution of claim 1 wherein the solubilizing agent selected from the group consisting of from about 10 to about 15 mg/mL of benzyl alcohol and from about 100 to about 150 nmg/mL of propylene glycol.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU44251/96A AU4425196A (en) | 1994-12-22 | 1995-12-15 | Soluble 2-chloro-2'-deoxyadenosine formulations |
| AU11345/00A AU762821B2 (en) | 1994-12-22 | 2000-01-14 | 'Soluble 2-chloro-2'-deoxyadenosine formulations' |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36208394A | 1994-12-22 | 1994-12-22 | |
| US362083 | 1994-12-22 | ||
| PCT/US1995/016418 WO1996019230A1 (en) | 1994-12-22 | 1995-12-15 | Soluble 2-chloro-2'-deoxyadenosine formulations |
| AU44251/96A AU4425196A (en) | 1994-12-22 | 1995-12-15 | Soluble 2-chloro-2'-deoxyadenosine formulations |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU11345/00A Division AU762821B2 (en) | 1994-12-22 | 2000-01-14 | 'Soluble 2-chloro-2'-deoxyadenosine formulations' |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU4425196A true AU4425196A (en) | 1996-07-10 |
Family
ID=25626643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU44251/96A Abandoned AU4425196A (en) | 1994-12-22 | 1995-12-15 | Soluble 2-chloro-2'-deoxyadenosine formulations |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU4425196A (en) |
-
1995
- 1995-12-15 AU AU44251/96A patent/AU4425196A/en not_active Abandoned
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| TC | Change of applicant's name (sec. 104) |
Free format text: ORTHO-MCNEIL PHARMACEUTICAL, INC. |
|
| MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |