CN1803143A - Injectable clofarabine composition - Google Patents
Injectable clofarabine composition Download PDFInfo
- Publication number
- CN1803143A CN1803143A CN 200610038023 CN200610038023A CN1803143A CN 1803143 A CN1803143 A CN 1803143A CN 200610038023 CN200610038023 CN 200610038023 CN 200610038023 A CN200610038023 A CN 200610038023A CN 1803143 A CN1803143 A CN 1803143A
- Authority
- CN
- China
- Prior art keywords
- acid
- clofarabine
- compositions
- injection
- solution
- 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.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparation, more specifically, the invention relates to a clofarabine composition for injection, which contains clofarabine and pharmaceutically acceptable acids. The composition has good water-solubility, and can be prepared into liquid preparation or freeze-dried preparation.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of injectable clofarabine composition.
Background technology
Clofarabine English name: Clofarabine; Chemical name: 2-chloro-2 '-fluoro-deoxidation-9-β-D-arabinofuranosyl adenosine.
Its structural formula:
Clofarabine has proposed the chemical compound patent application in 1988 by HOFFMANN LA ROCHE company development and in Europe, and publication number is EP314011, after transfer U.S. Genayme company and Bioenvision company.And obtaining the drugs approved by FDA listing in December, 2004, commodity are called Clolar.
Clofarabine is a purine nucleosides acid-like substance of new generation, is to be ratified the medicine that first is exclusively used in the leukemia of children treatment by FDA up to now.
Because the dissolubility of clofarabine in water is very little, only is 0.02% (g/ml).Its concentration of clofarabine injection of U.S.'s listing only is 0.1% (g/ml), and specification is 20ml:20mg.Because the clofarabine dissolubility is little, therefore its ejection preparation that is prepared into high concentration there is certain difficulty, also increased cost to suitability for industrialized production.
Summary of the invention
The invention discloses the compositions of a kind of chloride farad shore, the compositions good water solubility can be prepared into liquid preparation or lyophilized formulations, can be than the liquid preparation of prior art high 40 times and solution is still clarified stable of clofarabine composition Chinese medicine content of the present invention.
The inventor is through discovering, acid has solubilization-aid effect to clofarabine, can improve its dissolubility in water.But the difference of the addition of acid is also different to the solubilization-aid effect of clofarabine, when the ratio of acid and the molal quantity of clofarabine less than 1 the time, acid is not obvious to the solubilization-aid effect of clofarabine; Even if be mixed with solution, easily separate out precipitation in the storage process.When the ratio of acid and the molal quantity of clofarabine greater than 2 the time, the clofarabine dissolubility does not have obvious raising again, and too much acid has increased the zest of injection.When the ratio of acid and the molal quantity of clofarabine is 1～2, more preferably 1.1～1.5 o'clock, clofarabine showed extraordinary solubility property in water, and the solution clarification is fit to be prepared into ejection preparation.And the pH value of this liquid preparation is less than 6, and preferred pH value is that 2.5～5.5 o'clock preparation stabilities are better.
Described acid is pharmaceutically acceptable mineral acid, organic acid.Mineral acid can be hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid or hydrobromic acid; Organic acid as sour cosolvent can be lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, reaches a kind of or any mixture more than two kinds in the aminoacid such as aspartic acid, arginine, alanine, lysine, phenylalanine.
Preferred sour cosolvent is phosphoric acid, lactic acid, citric acid.
In the mineral acid of selecting for use, the most remarkable with phosphoric acid to the raising of clofarabine dissolubility, can reach 0.4% (g/ml).
In the organic acid of selecting for use, the overwhelming majority all can make the dissolubility of clofarabine be increased to more than 1% (g/ml), is best especially with the citric acid, can make the dissolubility of clofarabine increase to 12% (g/ml).
Thereby for the injection and the lyophilized formulations that clofarabine are prepared into variable concentrations have been created essential condition.
The present invention can be prepared into injection with the clofarabine of indissoluble by using sour hydrotropy.If be mixed with injection, preferred 0.02～4.0% (g/ml) of the concentration of clofarabine then.Injection generally includes little pin and transfusion, selects different concentration for use according to the dosage form difference.The concentration of acid cosolvent has very big difference because of the difference of acid, but the mol ratio of acid and clofarabine must be greater than 1, preferably 1.1～1.5.In addition, the pH value of solution is 2.0～6.0, and is preferably better 2.5～5.5 o'clock stability of formulation.
When being prepared into the clofarabine injection, can also add isotonic agent, select isotonic agent such as glucose or sodium chloride etc. pharmaceutically commonly used for use.
The compound method of clofarabine injection of the present invention is: earlier sour cosolvent is added to make in a certain amount of water for injection molten, again clofarabine is added to make and moltenly (as be prepared into transfusion, need isotonic agent is mixed with concentrated solution, slowly be added in the clofarabine solution, mixing), add the injection water to capacity, add on a small quantity with a kind of acid in case of necessity, make pH value transfer to above-mentioned scope.
Owing to add the water solublity that sour cosolvent has increased clofarabine, therefore the clofarabine of slightly solubility can be prepared into lyophilized formulations, when being prepared into lyophilized formulations, in the preceding solution of lyophilizing, preferred 0.1～4.0% (g/ml) of the concentration of clofarabine, more preferably concentration is 0.4～2.0% (g/ml).The mol ratio of acid and clofarabine also must be greater than 1, preferably 1.1～1.5; In the solution, the concentration of acid is generally 0.03～8.0% (g/ml) before the lyophilizing, and the pH value of solution is controlled at 2～6, and preferred pH value is 2.5～5.5.Clofarabine can be added the directly lyophilizing of acid back, also can add lyophilizing behind the excipient again.Excipient can be an excipient pharmaceutically commonly used, as one or two or more kinds the mixture in mannitol, glucose, lactose, sodium chloride, the gelatin hydrolysate etc.The amount of excipient is decided as required, and usually, in the solution, the concentration of excipient is 0.5～10.0% (g/ml) before the lyophilizing.
The preparation method of lyophilized formulations is: add sour cosolvent in water for injection, add clofarabine again, heating makes molten, adds excipient at last and makes moltenly, add in case of necessity on a small quantity with a kind of acid, and adjust pH to 2～6, preferred pH value is 2.5～5.5.Aseptic filtration, quantitative filling is in cillin bottle or glass tube vial, through lyophilization promptly.
Find after deliberation, clofarabine is prepared into lyophilized formulations after, more stable than pharmaceutical solutions.
Lyophilized formulations of the present invention, during with water for injection or 0.9% sodium chloride injection or 1～2 milliliter of redissolution of 5% glucose injection, lyophilized products dissolves rapidly, and the solution clarity is good.
The specific embodiment
Embodiment 1
Clofarabine sodium chloride injection [the chloride farad of 100ml shore 20mg, promptly concentration is 0.02% (g/ml)]
Prescription:
Clofarabine 0.2g
Lactic acid 0.4ml
Sodium chloride 9.0g
Water for injection is to 1000ml
Preparation technology: add medicinal lactic acid 0.4ml in the 100ml water for injection, mixing, stirring down, the adding clofarabine makes molten; Activated carbon decolorizing filters carbon removal; Be diluted to 850ml with water for injection.
Add sodium chloride in the 100ml water for injection, heating makes molten; Activated carbon decolorizing filters carbon removal.
Under stirring sodium chloride solution slowly is added in the clofarabine diluent, the lactic acid adjust pH to 4 with 1 → 10 adds water for injection to aequum.With 0.45 μ m membrane filtration, in infusion bottle, 105 ℃, sterilized in 30 minutes by every bottle of 100ml fill.
Embodiment 2
Clofarabine injection [the chloride farad of 2ml shore 20mg, promptly concentration is 1% (g/ml)]
Prescription:
Clofarabine 10g
Citric acid 7g
Water for injection is to 1000ml
Preparation technology: add citric acid among the water for injection 950ml, stirring makes molten; Add clofarabine, be heated to 40 ℃, stirring makes molten, adds water for injection to 1000ml (this moment, the pH value of solution was about 4.0).Filter, fill is in 2ml peace bottle.Melt envelope, sterilization.
Need instil with 5% glucose injection or 0.9% sodium chloride injection dilution posterior vein during the clinical use of this injection.
Embodiment 3
Injection clofarabine (every bottle of chloride farad shore 20mg)
Prescription:
Clofarabine 20g
Lactic acid 8.0ml
Mannitol 80g
Water for injection is to 2000ml
Prepare 1000 bottles
Preparation technology: add medicinal lactic acid 8.0ml among the water for injection 1900ml, mixing adds clofarabine, is heated to 45 ℃, and stirring makes molten, adds mannitol again, and stirring makes molten; Add the injection water to 2000ml, use the lactic acid adjust pH 4.5.Aseptic filtration, filtrate are pressed 2ml/ bottle quantitative filling in the 7ml cillin bottle, are prepared into freeze dried powder through freeze drying process.
Redissolve under the test room temperature condition, 1 bottle of freeze dried powder adds 1ml water for injection, or the 1ml0.9% sodium chloride injection, or the 1ml5% glucose injection, slight jolting, and kind can be dissolved into settled solution in about 5 seconds.
Stability test with freeze dried powder and lyophilizing before solution (2ml/ bottle) compare test.
Storage requirement: (A) in 4500LX illumination 10 days; (B) in 60 ℃ of insulations 10 days.
Investigate index: (1) sample color and luster.Method of testing: solution example is directly tested, and every bottle of freeze dried powder is with water for injection 2ml dissolving, makes that the concentration of its chloride farad shore is consistent with solution example (to be 1%, g/ml).Measure absorption value A at the 450nm place with spectrophotometer.The results are shown in Table 1.(2) catabolite.The amount high performance liquid chromatography of catabolite---normalization method is measured.Measurement result sees Table 2.The result shows that the stability of freeze dried powder more is better than solution.
The different storage requirements of table 1 are to the influence (A value) of sample (clofarabine-lactic acid) color and luster
| The sample name | Before the storage | Storage requirement | |
| 4500LX, 10 days | 60 ℃, 10 days | ||
| Solution before the lyophilizing | 0.11 | 0.14 | 0.15 |
| Freeze dried powder | 0.10 | 0.11 | 0.11 |
The different storage requirements of table 2 are to the influence of sample (clofarabine-lactic acid) catabolite
(HPLC---normalization method, %)
| The sample name | Before the storage | Storage requirement | |
| 4500LX, 10 days | 60 ℃, 10 days | ||
| Solution before the lyophilizing | 0.30 | 0.33 | 0.34 |
| Freeze dried powder | 0.30 | 0.31 | 0.31 |
Need instil with 0.9% sodium chloride injection or the dissolving of 5% glucose injection and dilution posterior vein during the clinical use of this freeze-dried powder.
Embodiment 4
Injection clofarabine (every bottle of chloride farad shore 20mg)
Prescription:
Clofarabine 20g
Citric acid 14g
Mannitol 40g
Water for injection is to 1000ml
Prepare 1000 bottles
Preparation technology: add citric acid among the water for injection 900ml, stirring makes molten; Add clofarabine, be heated to 50 ℃, stirring makes molten, adds mannitol again, and stirring makes molten; Add the injection water to 1000ml, mixing (at this moment, the pH value of solution is 4).Aseptic filtration, solution are pressed 1ml/ bottle quantitative filling in the 3ml glass tube vial, are prepared into freeze dried powder through freeze drying process.
Redissolve under the test room temperature condition, 1 bottle of freeze dried powder adds 1ml water for injection, or the 1ml0.9% sodium chloride injection, or the glucose injection of 1ml5%, slight jolting, and kind can be dissolved into settled solution in about 3 seconds.
Stability test with freeze dried powder and lyophilizing before solution (1ml/ bottle) compare test.Storage requirement and investigation index are all with embodiment 3, and the solution of only measuring color and luster is 1% (g/ml) with water for injection dissolving (or dilution) to chloride farad shore concentration all.Measurement result sees Table 3～4.The result shows that the good stability of freeze dried powder is in solution.
The different storage requirements of table 3 are to the influence (A value) of sample (clofarabine-citric acid) color and luster
| The sample name | Before the storage | Storage requirement | |
| 4500LX, 10 days | 60 ℃, 10 days | ||
| Solution before the lyophilizing | 0.10 | 0.13 | 0.14 |
| Freeze dried powder | 0.10 | 0.11 | 0.11 |
The different storage requirements of table 4 are to the influence of sample (clofarabine-citric acid) catabolite
(HPLC---normalization method, %)
| The sample name | Before the storage | Storage requirement | |
| 4500LX, 10 days | 60 ℃, 10 days | ||
| Solution before the lyophilizing | 0.28 | 0.31 | 0.32 |
| Freeze dried powder | 0.27 | 0.28 | 0.28 |
Need instil with 0.9% sodium chloride injection or the dissolving of 5% glucose injection and dilution posterior vein during the clinical use of this freeze-dried powder.
Claims (10)
1, a kind of compositions that contains agent clofarabine is characterized in that containing clofarabine and pharmaceutically acceptable acid.
2, the compositions of claim 1, wherein pharmaceutically acceptable acid is selected from hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, reaches in aspartic acid, arginine, alanine, lysine, the phenylalanine one or more.
3, the compositions of claim 2, wherein pharmaceutically acceptable acid is phosphoric acid, lactic acid or citric acid.
4, the compositions of claim 1, the mole ratio of wherein pharmaceutically acceptable acid and clofarabine is 1～2: 1.
5, the compositions of claim 4, the mole ratio of wherein pharmaceutically acceptable acid and clofarabine is 1.1～1.5: 1.
6, each compositions in the claim 1 to 5, it is an aqueous solution preparation, and wherein the concentration of clofarabine is 0.02～4.0%g/ml, and the pH value of solution is 2.0～6.0.
7, the compositions of claim 6 also contains isotonic agent, and isotonic agent is glucose or sodium chloride.
8, each compositions in the claim 1 to 5, it is a lyophilized formulations, the concentration of clofarabine is 0.1～4.0%g/ml in the preceding solution of lyophilizing.
9, the compositions of claim 8, wherein the concentration of clofarabine is 0.4～2.0%g/ml in the preceding solution of lyophilizing.
10, the compositions of claim 8 also contains excipient, and excipient is selected from one or more in mannitol, glucose, lactose, sodium chloride, the gelatin hydrolysate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610038023 CN1803143A (en) | 2006-01-25 | 2006-01-25 | Injectable clofarabine composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610038023 CN1803143A (en) | 2006-01-25 | 2006-01-25 | Injectable clofarabine composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1803143A true CN1803143A (en) | 2006-07-19 |
Family
ID=36865377
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610038023 Pending CN1803143A (en) | 2006-01-25 | 2006-01-25 | Injectable clofarabine composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1803143A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102138896A (en) * | 2011-04-06 | 2011-08-03 | 山东新时代药业有限公司 | Clofarabine injection and preparation method thereof |
-
2006
- 2006-01-25 CN CN 200610038023 patent/CN1803143A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102138896A (en) * | 2011-04-06 | 2011-08-03 | 山东新时代药业有限公司 | Clofarabine injection and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210138024A1 (en) | Manufacture of degarelix | |
| CN1748705A (en) | New injectable formulations containing progesterone | |
| CN108938654A (en) | A kind of injection preparation of anemoside B4 | |
| CN103222963A (en) | Somatostatin freeze-dried powder injection | |
| CN104414977A (en) | Artesunate and L-arginine composition for injection and preparation method thereof | |
| CN1310029C (en) | Method for preparing liangfuwan and method for controlling quality | |
| CN1803143A (en) | Injectable clofarabine composition | |
| CN102038680B (en) | Medical composition | |
| CN1259041C (en) | Bromhexine Hydrochloride aseptic freeze-drying formulation for injection and its preparation method | |
| CN1572296A (en) | Freeze dried vinpocetine powder injection and its preparation process | |
| CN101254174B (en) | Freeze-dried injection containing carbazochrome sodium sulfonate and method of preparing the same | |
| CN1493283A (en) | Edalavon powder for ampoul injection having good stability and its preparation method | |
| CN1732934A (en) | Freeze dry betahistine hydrochloride injection and method for preparing the same | |
| CN1899296A (en) | Breviscapine B injection preparation and its preparing method | |
| CN100386079C (en) | Injection use-powder ampoule for inhibiting thrombocyte agglutination and its preparation method | |
| CN103816126B (en) | A kind of pharmaceutical composition containing scopolamine butylbromide | |
| CN102895178A (en) | Strong solution-type moxifloxacin hydrochloride injection and preparation method thereof | |
| CN101703466A (en) | Borneol injection and preparation method thereof | |
| RU2471484C2 (en) | Method for preparing composition for injections containing sodium cevtriaxone and sodium tazobactam | |
| CN1231223C (en) | Breviscapine infusion preparation and its preparing method | |
| CN101015539A (en) | Preparation of nedaplatin freeze-dried powder injection | |
| CN104888207A (en) | Injection bivalirudin preparation process | |
| CN1290511C (en) | Doxorubicin liposome hydrochloride preparation and its preparing method | |
| CN102526042B (en) | Stable liquid medicinal composition | |
| CN1271996C (en) | Medicinal powder injection for respiratory system and preparing method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |