CN101152204A - Vein drug administration preparations of clofarabine and method for preparing the same - Google Patents
Vein drug administration preparations of clofarabine and method for preparing the same Download PDFInfo
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- CN101152204A CN101152204A CN 200610113476 CN200610113476A CN101152204A CN 101152204 A CN101152204 A CN 101152204A CN 200610113476 CN200610113476 CN 200610113476 CN 200610113476 A CN200610113476 A CN 200610113476A CN 101152204 A CN101152204 A CN 101152204A
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- clofarabine
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Abstract
The invention provides a clofarabine intravenous injection or clofarabine medicine salt intravenous injection and the preparation method. The excipient of the injection formula is mainly sodium chloride or glucose. The injection has high thermal stability and is used to treat child refractory and recurrent acute lymphoblastic leukemia.
Description
Technical field
The present invention relates to the intravenous administration formulation and the formulation method thereof of clofarabine (clofarabine), particularly clofarabine infusion preparation and injection.
Background technology
Clofarabine is the DNA synthetic inhibitor that Britain Genzyme Corporation company develops, reduce triphosphate deoxy-nucleotide content in the cell by the activity that suppresses ribonucleotide reductase, stop the DNA chain elongation, and emulative inhibition archaeal dna polymerase and suppress DNA and repair.Its trade name is CLOLAR
TM, specification is 1mg/ml, is used for the treatment of the intractable and recurrent acute lymphoblastic leukemia of child clinically.Clofarabine (clofarabine) chemical structural formula is:
Chemical name is (2-chloro-9-(2-deoxidation-2-fluoro-beta-D-furyl glycosyl)-9H-purine-6-amino), and clofarabine is white or off-white color crystalline powder, and odorless, tasteless is molten in the water part omitted.The clofarabine injection is a colourless clear liquid.
WO9220347 discloses clofarabine, its preparation method and therapeutic use.WO9939732 discloses the treatment that PEG-ASNase and ribonucleotide reductase inhibitor coupling are used for HIV.WO2004028463 discloses the application of clofarabine in the treatment lupus erythematosus.
Britain Genzyme Corporation company develops CLOLAR
TMInjection, solvent is a water for injection, do not contain other adjuvant, and we develop adding sodium chloride or glucose in the clofarabine injection, the unexpected discovery, adding sodium chloride or glucose not only help to improve the dissolution velocity of medicine, even under situation about not heating, the fast fast dissolving of medicine energy, and can significantly reduce the absorption of active carbon to medicine, reduce the principal agent dosage, improve injection stability simultaneously.And we do not have hemolytic, blood vessel irritation and anaphylaxis by the pharmacological testing proof according to this prepared injection of filling a prescription.
Summary of the invention
The invention provides the intravenous fluid of a kind of chloride farad shore or its officinal salt, comprise infusion preparation and injection, especially a kind of stable clofarabine injection, the concentration of clofarabine is 0.01mg/ml～10mg/ml in this injection, preferred 1mg/ml.
Its additives of clofarabine injection of the present invention comprise sodium chloride or glucose.
Clofarabine injection pH scope of the present invention is 4.5～7.5, preferred 5.0～6.0.
Another object of the present invention provides the preparation method of stable clofarabine injection: in this preparation method clofarabine, sodium chloride for injection or glucose are dissolved in the proper amount of water for injection, add the injection water to aequum, regulate between pH value to 5.0～6.0 with hydrochloric acid/sodium hydroxide, add active carbon, take off the charcoal coarse filtration, again through the microporous filter membrane fine straining, embedding, sterilize finished product.
Prepare the solution of chloride farad shore and injection additives, adopting hydrochloric acid/sodium hydrate regulator solution pH value is 5.0,5.5,6.0, adds active carbon, takes off the charcoal coarse filtration, fine straining, and embedding, sterilization gets product.The injection liquid samples of prepared different pH value is carried out stability test, and the result shows clofarabine injection equal can retention properties the stablizing under high temperature (40 ℃, 60 ℃), high humidity (75%RH, 92%RH), high light condition between pH5.0～6.0.Therefore, we with the pH regulator of injection liquid samples in pH5.0～6.0.Britain GenzymeCorporation company develops CLOLAR
TMInjection pH value scope is 4.5～7.5, does not add the pH regulator agent, and the fact shows that as not adding the pH regulator agent, pH value of solution changes greatly, is unfavorable for control of product quality.
The medication of clofarabine injection is intravenous injection, therefore needs to regulate the injection osmotic pressure and equates with blood plasma.We adopt sodium chloride or glucose as osmotic pressure regulator, have improved the osmotic pressure of solution, with the CLOLAR that does not add osmotic pressure regulator
TMInjection is compared, and more can increase compliance of patients.
Needle-use activated carbon has strong adsorption to clofarabine, the content that causes adding clofarabine in the solution behind the charcoal descends significantly, therefore, the aqueous solution of clofarabine is effectively removed pyrogen because of adding active carbon, if but in solution, added sodium chloride or glucose, then active carbon would reduce greatly to the adsorption of medicine, therefore, adding sodium chloride or glucose not only help to reduce the absorption of active carbon to medicine in solution, can also effectively remove pyrogen.
Clofarabine dissolution velocity in aqueous solution is slower, usually will be at heating in water bath more than 60 ℃ about 30 minutes, could guarantee that medicine dissolution is complete, and clofarabine dissolution velocity in sodium chloride or glucose solution is very fast, usually in the sodium chloride or glucose solution of room temperature, stirred 10 minutes, clofarabine can dissolve fully, not only raise the efficiency, and cut down the consumption of energy.
Injection liquid samples adopted 115 ℃ of flowing steam sterilizations 30 minutes, and the gained finished product is qualified through the inspection of pharmacology health examination bacterium, and related substance is not seen significant change.
The specific embodiment
Further illustrate the present invention by the following examples, but be not limited to embodiment.
Embodiment 1
Prescription is formed:
Clofarabine 20g
Sodium chloride 180g
Water for injection adds to 20L
Make 1000
The clofarabine of recipe quantity is dissolved in 0.9% sodium chloride solution of full dose, gained clofarabine concentration is 1mg/ml, add hydrochloric acid/sodium hydroxide and regulate pH value to 5.0～6.0, add an amount of needle-use activated carbon, stir filtering decarbonization, through the microporous filter membrane fine straining, every ampoule embedding 20ml fine straining liquid, 115 ℃ of sterilizations of flowing steam 30 minutes get product.
Embodiment 2 (comparative example)
Prescription is formed:
Clofarabine 20g
Sodium chloride 180g
Water for injection adds to 20L
Make 1000
Clofarabine is soluble in water, do not regulate pH value, operate by the method for stating, prepare a batch sample.
Embodiment 3
To the method for preparing sample of embodiment 1 and embodiment 2, investigate its dissolution velocity, activated carbon adsorption amount, the result shows, adopts the sample of the present invention's preparation, and medicine dissolution speed is fast, and the activated carbon adsorption amount is few.
Table 1 clofarabine dissolution velocity, activated carbon adsorption amount are investigated the result
| Embodiment 1 | Embodiment 2 | |
| Medicine dissolution speed activated carbon adsorption amount (%) | Dissolving complete 2.34 in 7 minutes | 60 ℃ of water-baths dissolving complete 15.78 in 30 minutes |
Embodiment 4
To the sample that embodiment 1 and embodiment 2 obtain, investigate its stability, it is little that the result shows that sample pH value of the present invention changes, and helps control of product quality, and concrete data see Table 2.
Table 2 clofarabine injection study on the stability result
| Outward appearance | PH value | |||
| Embodiment 1 sample embodiment 2 samples | 0 day achromaticity and clarification liquid achromaticity and clarification liquid | 10 days achromaticity and clarification liquid achromaticity and clarification liquid | 0 day 5.17 4.68 | 10 days 5.28 6.34 |
Claims (8)
1. a stable clofarabine injection is characterized in that containing clofarabine or its water solublity officinal salt, also contains sodium chloride or glucose simultaneously.
2. injection according to claim 1, the concentration that it is characterized in that clofarabine is 0.01mg/ml～10mg/ml.
3. injection according to claim 2, the concentration that it is characterized in that clofarabine is 0.5mg/ml～5mg/ml.
4. injection according to claim 2, the concentration that it is characterized in that clofarabine is 1mg/ml.
5. injection according to claim 1, the concentration that it is characterized in that sodium chloride is 7.5mg/ml～10.5mg/ml, preferred 8.5mg/ml～9.5mg/ml.
6. injection according to claim 1, the concentration that it is characterized in that glucose is 40mg/ml～100mg/ml, preferred 50mg/ml～60mg/ml.
7. injection according to claim 1 is characterized in that the pH scope is 4.5～7.5, preferred 5.0～6.0.
8. according to the preparation method of each described injection of claim 1-7, it is characterized in that may further comprise the steps:
A) clofarabine, sodium chloride for injection or glucose are dissolved in the proper amount of water for injection, add the injection water to aequum;
B) with hydrochloric acid/sodium hydrate regulator solution pH value 5.0～6.0;
C) add needle-use activated carbon and stir evenly, the titanium rod takes off charcoal, again through the microporous filter membrane fine straining;
D) embedding;
E) circulation steam sterilization or pressure sterilizing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610113476 CN101152204A (en) | 2006-09-29 | 2006-09-29 | Vein drug administration preparations of clofarabine and method for preparing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610113476 CN101152204A (en) | 2006-09-29 | 2006-09-29 | Vein drug administration preparations of clofarabine and method for preparing the same |
Publications (1)
| Publication Number | Publication Date |
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| CN101152204A true CN101152204A (en) | 2008-04-02 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200610113476 Pending CN101152204A (en) | 2006-09-29 | 2006-09-29 | Vein drug administration preparations of clofarabine and method for preparing the same |
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Cited By (2)
| 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 |
| CN102697710A (en) * | 2012-05-23 | 2012-10-03 | 南京臣功制药股份有限公司 | Clofarabine injection and preparation method thereof |
-
2006
- 2006-09-29 CN CN 200610113476 patent/CN101152204A/en active Pending
Cited By (3)
| 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 |
| CN102697710A (en) * | 2012-05-23 | 2012-10-03 | 南京臣功制药股份有限公司 | Clofarabine injection and preparation method thereof |
| CN102697710B (en) * | 2012-05-23 | 2014-07-16 | 南京臣功制药股份有限公司 | Clofarabine injection and preparation method thereof |
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Open date: 20080402 |