MXPA97004731A - Stable solutions of formulations of 2-cloro-2'-desoxiadenos - Google Patents
Stable solutions of formulations of 2-cloro-2'-desoxiadenosInfo
- Publication number
- MXPA97004731A MXPA97004731A MXPA/A/1997/004731A MX9704731A MXPA97004731A MX PA97004731 A MXPA97004731 A MX PA97004731A MX 9704731 A MX9704731 A MX 9704731A MX PA97004731 A MXPA97004731 A MX PA97004731A
- Authority
- MX
- Mexico
- Prior art keywords
- cda
- phosphate
- solution
- regulator
- sodium
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title description 13
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 37
- 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 claims abstract description 33
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 18
- RLSSMJSEOOYNOY-UHFFFAOYSA-N M-Cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000019445 benzyl alcohol Nutrition 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 19
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 239000010452 phosphate Substances 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229940045641 Monobasic Sodium Phosphate Drugs 0.000 claims description 5
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 5
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 5
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 5
- XVNVFKZODWAQKN-UHFFFAOYSA-N phosphoric acid;heptahydrate Chemical compound O.O.O.O.O.O.O.OP(O)(O)=O XVNVFKZODWAQKN-UHFFFAOYSA-N 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- 239000007983 Tris buffer Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 3
- -1 onohydrate Chemical compound 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 1
- NUEQNKUVHPBNQB-UHFFFAOYSA-M sodium;dihydrogen phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].OP(O)([O-])=O NUEQNKUVHPBNQB-UHFFFAOYSA-M 0.000 claims 1
- 238000009472 formulation Methods 0.000 description 4
- 230000002335 preservative Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 3
- 229940061607 Dibasic Sodium Phosphate Drugs 0.000 description 2
- 206010024324 Leukaemias Diseases 0.000 description 2
- 230000000844 anti-bacterial Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- RMFWVOLULURGJI-UHFFFAOYSA-N 2,6-dichloro-7H-purine Chemical compound ClC1=NC(Cl)=C2NC=NC2=N1 RMFWVOLULURGJI-UHFFFAOYSA-N 0.000 description 1
- 206010003246 Arthritis Diseases 0.000 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229940068918 Polyethylene Glycol 400 Drugs 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000000063 antileukemic agent Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000003899 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 238000003860 storage Methods 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
Abstract
The present invention relates to a solution of 2-CdA in water comprising, a) from about 1 to about 8 mg / ml of 2-CdA, b) from about 50 to about 400 mg / ml of solubilizing agent selected from the group which consists 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 pH regulator for stabilize the pH between about 5.5 and about 8
Description
STABLE SOLUTIONS OF FORMULATIONS OF 2-CHLORINE-2'- DESOXYDENOSINfí
TECHNICAL FIELD
This invention relates to pharmaceutically useful and stable formulations of 2-chloro-2'-deoxyadenosine (2-Cdfi) in water. More particularly, this invention relates to stable formulations of 2-Cdfl in water with certain preservatives, pH regulators and solubilizers, which are injectable in humans and have an improved shelf life.
BACKGROUND OF THE INVENTION
The compound 2-Cdfl has the following formula:
2-Cdfl is known as an antileukemic agent, that is, for the treatment of leukemias, such as hairy cell leukemia and L 1210 leukemia, and co or a immunosuppressive agent. A. Carson, D. Bruce Uasson, and Ernst Beutler, Proc. Soc. Acad. Sci. USA, Vol. 81, p. 2232-2236, 1984). More recently, it has been described that 2-CdA is effective in the treatment of reurnatoid arthritis and mují + multiple sclerosis, Patent of E. U. A. No. 5,310,732. Up to now, 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 material to be injected subcutaneously or intramuscularly to reach the required dose. Second, 2-CoP has limited stability in simple saline solutions. A longer shelf life is beneficial for prolonged storage under refrigerated or room temperature conditions. The Patent of E. U. 0. No. 5,310,732, col. B teaches an isotonic saline solution of 0.1 g / l of 2-CdA. e has commercialized an unregulated solution in its pH that contains 1.0 rng / rnl of 2-CdA in injection of sodium chloride 9.0 mg / ml, USP.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides a first 2-CdA solution in water with improved shelf life comprising: a) from about 1 to about 8 rng / rnl of b) from about 50 to about 400 mg / ml of solubilizing agent selected of 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 pH regulator to stabilize the pH between about 5.5 and about 8.5. The present invention provides a second solution of 2-CdA in water with improved shelf life comprising: a) from about 1 to about 5 mg / ml of 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 0 to about 3 mg / ml of m-cresol; and e) an effective amount of a pharmaceutically acceptable pH regulator to stabilize the pH between about 5.5 and about 8.5.
DETAILED DESCRIPTION OF THE INVENTION
Processes for the preparation of 2-CdA are known. European Patent Application No. 173,059 A2 and Robms et al., 3. Arn. Chem. Soc. 106, 6379 (1984) describe the preparation of 2-CdA. The preparation consists of the glycosylation of 2,6-dichloropurine with 1-chloro-2'-deeoxi-3 ', 5'-di-Op-toluyl-bD-erythropentofuranose to produce the purine N-9-ylicosyldase, 2 , 6-dichloro-9- (2-deoxy-3, 5 -di-0-α-tolu? L ~ t> -D-erythropentofuranosyl) -purine, which is subsequently reacted with ammonia to produce 2- CdA. In U.S. Patent No. 5,208,327, for Robert H. K. Chen teaches an alternative method to manufacture 2-CdA. Preferably, the first shelf stable solution contains from about 3 about 7 rng / rnl and most preferably from about 4 to about 6 rng / l of 2-Cdfl. The second shelf stable solution preferably contains from about 2 to about 4 mg / rnl of 2-CdA. Propylene glycol and polyethylene glycol are known solubilizing agents for a variety of pharmaceutical agents. 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 g / ml of propylene glycol or polyethylene glycol, and most preferably from 100 to about 150 mg /. ml. The second stable solution on the shelf is isotonic and should contain enough sodium chloride to make it so.
Preferably, this solution should contain from about 3 to about 8 mg / ml of sodium chloride and preferably from 3 to 6 mg / ml. Benzyl alcohol is generally known as a preservative in pharmaceutical formulations because of its antibacterial action and as a solubilizing agent for certain pharmaceutical compounds. Preferably, both the first and second shelf stable solutions are present from about 8 to about 20 mg / ml of benzyl alcohol and most preferably from about 10 to about 15 mg / ml. M-cresol is generally known as a preservative in pharmaceutical formulations due to its antibacterial action. Preferably, about 1.5 to about 2.5 mg / ml of m-cresol, and most preferably about 2 mg / ml, is present in both the first and second shelf stable solutions. The use of m-cresol can be eliminated, provided that enough other preservative is used to make a properly preserved formulation. Suitable pH regulators are any which are available for pharmaceutical application and which are capable of stabilizing the pH between 5.5 and 8.5. These pH regulators include, but are not limited to, phosphate, citrate, acetate, borate and tris. The preferred regulator for use herein is a sodium phosphate pH regulator system. A preferred pH scale for the shelf stable solutions herein is between about 6.0 and about 7.0. The ratio of monobasic sodium phosphate, NaH, is adjusted. PO .; • H2O, and dibasic sodium phosphate, 2HPC • 7H2O, to reach the desired pH. Generally this pH regulator is useful to reach a pH in the range of 4.5 to 8.5. Of course, sufficient pH regulator must be used, not only to obtain the desired pH, but also to stabilize the pH at that value. For the first stable shelf-stable solution, a ratio of about 2 to 1 of sodium monobasic phosphate to sodium dibasic phosphate should be employed. For the second stable solution in the rack, a ratio of approximately 1 l of the monobasic sodium phosphate to the dibasic sodium phosphate should be used. 2-CdA can be administered to a patient in need thereof in a daily dose of 0.05 to 0.15 g / g. A very convenient daily dose would be 0.07 to 0.1 mg / kg. The invention is illustrated, but not limited in any way, with the following examples.
EXAMPLE
The following formulations were prepared. Solutions containing a phosphate pH regulator were adjusted to pH 6.5. All figures are shown in rng / rnl. The following abbreviations were used: polyethylene glycol, NF, (PEG), propylene glycol, USP, (PG), benzyl alcohol, NF, (AB), m-cresol, (MC), monobasic sodium phosphate monohydrate, USP, (FMSM) , and sodium dibasic phosphate heptahydrate, USP, (FDSH). Injectable water, USP, was added to make the final volume of 1.0 ml.
TABLE 1 Control Formulation
2-CdA 5.0 5.0 3.0 1.0 NaCl 4.0 9.0 PEG 300 100.0 PG 100.0 AB 10.0 10.0 10.0 MC 2.0 2.0 2.0 FMSIi 1,816 1,816 1,555 FDSH 0.941 0.941 1.446
The stability of the formulations in Table 1 was analyzed after being stored at different times at different temperatures. The formulations were analyzed to determine their 2-CdA content, 2-CAD content (product of 2-CdA hydrolysis), benzyl alcohol content and m-cresol content. The figure reported is in% of the initial quantity, with the X of 2-CAD expressed in the initial% of 2-CdA. TABLE 2 For ulation 1 1 2 3 Control
Initial,% theoretical 2-CdA 98.8 99.1 104.9 102.3
2-CAD ND ND ND ND AB 109 108.7 111.4 N / A laugh 99.6 99.9 101.5 N / A
50 ° C / 4 weeks 2-CdA 99.4 99.1 93.2 82.9
2 - . 2 -CAD 2.8 2.7 3.6 6.0
AB 95.1 95.3 91.9 N / A laugh 98.8 99.2 94.6 N / A
50 ° C / 8 weeks 2-CdA 96.6 95.8 89.8 81.2
2-CAD 3.7 3.6 3.0 5.7
AB 90.9 90.2 86.6 N / A MC 98.2 96.3 92.6 N / A TABLE 2 (CONTINUED) 2 Formulation Control
40 ° C / 4 weeks 2 ~ CdA 101.8 101.8 96.3 96.2
2-CAD 0.7 0.7 0.9 1.-3
AB 95.4 95.8 92.4 N / A
MC 99.5 100.0 95.9 N / A
40 ° C / 8 weeks 2-CdA 102.3 100.2 96.3 94.8
2-CAD 1.0 0.9 1.2 2.9
AB 90.8 90.5 87.1 N / A
MC 96.5 98.0 94.4 N / A
° C / 12 weeks 2-CdA 103.7 97.6 98.3
2-CAD 0.21 0.25 0.36
AB 92.8 88.1 N / A
MC 99.6 96.4 N / A
° C / 8 weeks 2 ~ CdA 103.4 104.5 97.9 100.7
2-CAD 0.0 0.0 0.1 0.1
AB 92.5 93.4 89.9 N / A
MC 99.0 100.2 97.0 N / A From the above data, it is evident that the formulations of the present invention are exceptionally shelf stable, compared to the control, which is the currently marketed formulation. Nowhere in the prior art are such stable formulations of 2-CdA suggested or taught. In addition, the data shows that in formula 1, 2 and 3, significantly less degradation product is formed by hydrolysis of 2-CAD, compared to the control.
Claims (11)
1. - A 2-CdR solution in water comprising, a) from about 1 to about 8 mg / ml of 2-CdA; b) from about 50 to about 400 mg / ml of solubilizing agent selected from the group consisting of propylene glycol and p > olyethylene glycol; c) from about 5 to about 50 rng / rnl of alcohol, benzyl; d) from 0 to about 3 mg / ml of m-cresol; and e) an acceptable amount of a pharmaceutically acceptable pH regulator) to stabilize the pH between about 5.5 and about 8.5. 2.- The solution in accordance with the claim 1, further characterized in that it comprises from about 3 to about 7 g / rnl of 2-CdA, from 75 to about 200 mg / ml of solubilizing agent, from about 8 to about 20 g / l of benzyl alcohol and from about 1.5 to about 2.5 mg / ml m-cresol. 3. The solution according to claim 1, further characterized in that the pH regulator is selected from the group consisting of phosphate, citrate, acetate, borate and tris pH regulators. 4.- The solution in accordance with the claim 1, further characterized in that the pH regulator is an effective amount of phosphate pH regulator comprising sodium monobasic phosphate, onohydrate, and sodium dihydrogen phosphate heptahydrate, to stabilize the pH between about 6.0 and about 7.0. 5.- The solution in accordance with the claim 1, characterized in that it comprises a) from about 4 to about 6 mg / ml of 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 rng / ml of benzyl alcohol; d) about 2 mg / ml of rn-cresol; and e) about 1816 mg / ml of monobasic sodium phosphate rnonohydrate, and about 0.941 mg / ml of sodium dibasic phosphate heptahydrate. 6.- The solution in accordance with the claim 1, further characterized in that the solubilizing agent is propylene glycol. 7. A solution of 2-CdA in water comprising, a) from about 1 to about 5 mg / ml of 2-CdA; b) from about 2 to about 10 mg / ml of sodium chloride; c) from about 5 to about 50 g / rnl of benzyl alcohol; d) from about 0 to about 3 rng / ml of m-cresol; and e) an effective amount of a pharmaceutically acceptable pH regulator to stabilize the pH between about 5.5 and about 8.5. 8. The solution according to claim 7, further characterized in that it comprises 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 g / rnl of benzyl alcohol and approximately 1.5 to 2.5 rng / ml of m-cresol. 9. The solution according to claim 7, further characterized in that the pH regulator is selected from the group consisting of phosphate, citrate, acetate, borate and tris pH regulators. 10.- The solution in accordance with the claim 7, further characterized in that the pH regulator is an effective amount of phosphate pH regulator comprising monobasic phosphate of sodium onohydrate and sodium dibasic phosphate heptahydrate, to stabilize the pH between about 6.0 and about 7.0. 11. The solution according to claim 7, characterized in that it comprises a) about 3 mg / ml of 2-CdA; b) about 4 mg / ml of sodium chloride; c) from about 10 to about 15 mg / ml of benzyl alcohol; d) approximately 2 mg / ml of -reele; and e) about 1555 mg / ml of monobasic sodium phosphate monohydrate and about 1446 mg / ml of sodium dibasic phosphate heptahydrate.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/362,106 US5641757A (en) | 1994-12-21 | 1994-12-21 | Stable 2-chloro-2'-deoxyadenosine formulations |
US08362106 | 1994-12-22 | ||
PCT/US1995/016238 WO1996019229A1 (en) | 1994-12-21 | 1995-12-15 | Stable solutions of 2-chloro-2'-deoxyadenosine formulations |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9704731A MX9704731A (en) | 1997-10-31 |
MXPA97004731A true MXPA97004731A (en) | 1998-07-03 |
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