CN104771369B - A kind of Fludarabine phosphate freeze-dried powder injection - Google Patents
A kind of Fludarabine phosphate freeze-dried powder injection Download PDFInfo
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- CN104771369B CN104771369B CN201410010241.4A CN201410010241A CN104771369B CN 104771369 B CN104771369 B CN 104771369B CN 201410010241 A CN201410010241 A CN 201410010241A CN 104771369 B CN104771369 B CN 104771369B
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- fludarabine phosphate
- freeze
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- injection
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Abstract
The present invention relates to a kind of Fludarabine phosphate freeze-dried powder injections, are made of fludarabine phosphate as sole component.Preferably, water for injection is added in 75~100 μm of fludarabine phosphate powder, is made into the solution that fludarabine phosphate concentration is 5~20%, freeze-drying is got product.Fludarabine phosphate freeze-dried powder injection of the present invention, preparation process simple possible are conducive to operation, are suitble to the needs of industrialized production.
Description
Technical field
The present invention relates to a kind of Fludarabine phosphate freeze-dried powder injections, belong to technical field of medicine.
Background technique
Fludarabine phosphate is a kind of fluorination purine nucleoside analogs of antimetabolic, it has the selection of height to lymphocyte
Property, it is able to suppress the reparation in stationary phase cells DNA and the synthesis in division cells DNA, and has and promote this
The effect of a little Apoptosis, widely is applied to treat various diseases in the blood system, especially chronic bone-marrow-derived lymphocyte is white at present
Blood disease.Fludarabine phosphate is to improve the remission rate of disease by promoting apoptosis of tumor cells.Its mode for promoting apoptosis is main
To be reached by adjusting following several approach: death receptor pathway *, mitochondria pathway, P53, ceramide, BCl-2 family and
Some apoptosis promote son and Apoptosis inhibitor.
Fludarabine phosphate (Fludarabine phosphate) system is developed by Germany, since its stability is poor, is faced
Bed uses the form of freeze-dried powder.At the past 10 years, fludarabine phosphate was to the curative effect for improving B- cell malignant disease
Important function has been played, it is lesser for chronic lymphocytic leukemia (chronic lymphocyte eukaemia, CLL)
Dosage can reach satisfactory curative effect, and adverse reaction is less.In international CLL drug market, fludarabine phosphate is current
It maintains the leading position, is worth clinical application.
In the prior art, patent CN101947208A give a kind of injection fludarabine phosphate composition and its
Formulation method, but lyophilized technique design is complicated in this method, requires harshness, especially pre-freeze first stage, control temperature to condition
Degree -11 DEG C~-13 DEG C, keep 60~90 minutes, which is not easy accurately to control, and be easy to appear in this stage or
Pre-freeze liquid freezeout is had already appeared, the effect is not achieved.
Patent 200710202969.7 discloses a kind of fludarabine sustained-release implantation agent for treating entity tumor, which plants
Enter agent and contains fludarabine, slow-release auxiliary material and a certain amount of release modifying agents.Patent CN102091046B discloses a kind of phosphoric acid
Fludarabine freeze drying powder injection and preparation method thereof, the Fludarabine phosphate freeze-dried powder injection is by fludarabine phosphate and mannitol
Composition, the mass ratio of the two are 1: 0.6~1.2.A kind of pharmaceutical composition of fludarabine phosphate of patent 103040855A, institute
It states and contains fludarabine phosphate, sodium chloride and excipient in pharmaceutical composition, wherein fludarabine phosphate: sodium chloride: excipient
Weight ratio be 10:1~5:6~12, preferably 10:1~3:6~10.Adjunct ingredient is more in these inventions, not only increases auxiliary
The type and content for expecting bring impurity, also increase auxiliary material to risk brought by human body.
Patent CN102552175A discloses a kind of injection fludarabine phosphate lyophilized preparation and preparation method thereof, the phosphorus
Sour fludarabine lyophilized preparation is mainly prepared by active constituent fludarabine phosphate and excipient, fludarabine phosphate and tax
The mass ratio of shape agent are as follows: 1: 0.5~2.0.It is -20 DEG C that its primary drying, which requires temperature, and the used time is longer, 30 DEG C of redrying, at
Product moisture is difficult to ensure.
Summary of the invention
In view of the deficiencies in the prior art, the purpose of the present invention is to provide a kind of Fludarabine phosphate freeze-dried powder injections, should
Fludarabine phosphate freeze-dried powder injection good forming ability, solution appearance clarification before freezing, dried frozen aquatic products solubility is good, clear and bright after redissolution
It spends, impurity content is low, and moisture content is low, and stability is good, quality controllable.Freeze drying powder injection of the invention is stored and is added for a long time
Speed experiments have shown that, stable product quality.
Specific technical solution of the present invention is as follows:
A kind of Fludarabine phosphate freeze-dried powder injection is made of fludarabine phosphate as sole component.
The preparation method of the powder-injection includes the following steps: 75~100 μm of fludarabine phosphate powder note is added
It penetrates and is made into the solution that fludarabine phosphate concentration is 5~20% using sodium hydroxide adjusting pH value to 7.2~8.2 with water, freeze
Dry, tamponade is rolled lid, is packed to obtain the final product.
Preferably, the freeze-drying process specifically includes the following steps:
1) the quick-frozen stage: before fludarabine phosphate solution is put into, plate layer cools to -40 DEG C~-50 DEG C, and product is put into jelly
Dry machine keeps the temperature 1h~4h；
2) the pre-freeze stage: after the quick-frozen stage, plate layer is warming up to -2 DEG C -10 DEG C, keeps the temperature 1h~3h；Then plate layer is dropped
Temperature keeps the temperature 2h~4h to -40 DEG C~-50 DEG C；
3) lyophilization: after the pre-freeze stage, plate layer is gradually warmed up to 15 DEG C~25 DEG C in 8~12h；
4) parsing-desiccation: after lyophilization, plate layer is warming up to 30 DEG C~40 DEG C, keeps the temperature 6h~10h.
It is further preferred that the freeze-drying process specifically includes the following steps:
1) the quick-frozen stage: before fludarabine phosphate solution is put into, plate layer cools to -45 DEG C, and product is put into freeze dryer, protects
Warm 2h；
2) the pre-freeze stage: after the quick-frozen stage, plate layer is warming up to -8 DEG C, keeps the temperature 2h；Then plate layer is cooled to -40
DEG C, keep the temperature 3h；
3) lyophilization: after the pre-freeze stage, plate layer is gradually warmed up to 20 DEG C in 8~12h；
4) parsing-desiccation: after lyophilization, plate layer is warming up to 35 DEG C, keeps the temperature 8h.
Compared with prior art, fludarabine phosphate powder-injection of the present invention have the following advantages that and significantly into
Step: (1) preparation stability is high.Find out from the table 1 of specific embodiment, Fludarabine phosphate freeze-dried powder injection prepared by the present invention
Stability it is good, better than the prior art report preparation.(2) prior art prejudice is overcome.The prior art, which generally believes, to be made
It needs that freeze-drying proppant is added when standby Fludarabine phosphate freeze-dried powder injection, however through overtesting it was unexpectedly observed that the present inventor
Fludarabine phosphate solution without any additives is directly lyophilized, available good appearance, quality stabilization, safety are more
High fludarabine phosphate freeze-dried powder.It is demonstrated experimentally that Fludarabine phosphate freeze-dried powder injection of the present invention and existing skill
The freeze-dried powder effect that art obtains is suitable and safer.(3) preparation process simple possible is conducive to operation, is suitble to industrialization big raw
The needs of production.
Specific embodiment
The following is specific embodiments of the present invention, is described further to technical solution of the present invention, but of the invention
Protection scope is not limited to these examples.
Embodiment 1
Fludarabine phosphate 5g
Water for injection 100ml
75~100 μm of the fludarabine phosphate powder 5g that micronization obtains is weighed, water for injection 100ml is added, uses
Sodium hydroxide adjusts pH value to 7.2~8.2, and stirring makes it completely dissolved, and every 1ml is filling in 10ml cillin bottle.Freeze dryer
Plate layer cools to -45 DEG C, and cillin bottle is put into freeze dryer after filling, keeps the temperature 2h.Plate layer temperature is warming up to -8 DEG C, heat preservation
Plate layer is cooled to -45 DEG C after 2h, continues to keep the temperature 3h.Plate layer is warming up to 20 DEG C in 8~12h；After 35 DEG C of heat preservation 8h, punching
Enter nitrogen tamponade, taking-up is rolled lid pack and both obtained.
Embodiment 2
Fludarabine phosphate 5g
Water for injection 100ml
75~100 μm of the fludarabine phosphate powder 5g that micronization obtains is weighed, water for injection 100ml is added, uses
Sodium hydroxide adjusts pH value to 7.2~8.2, and stirring makes it completely dissolved, and every 1ml is filling in 10ml cillin bottle.Freeze dryer
Plate layer cools to -45 DEG C, and cillin bottle is put into freeze dryer after filling, keeps the temperature 4h.Plate layer temperature is warming up to -8 DEG C, heat preservation
Plate layer is cooled to -40 DEG C after 2h, continues to keep the temperature 3h.Plate layer is warming up to 15 DEG C in 8~12h；After 40 DEG C of heat preservation 10h,
Nitrogen tamponade is poured, taking-up is rolled lid pack and both obtained.
Embodiment 3
Fludarabine phosphate 5g
Water for injection 100ml
75~100 μm of the fludarabine phosphate powder 5g that micronization obtains is weighed, water for injection 100ml is added, uses
Sodium hydroxide adjusts pH value to 7.2~8.2, and stirring makes it completely dissolved, and every 1ml is filling in 10ml cillin bottle.Freeze dryer
Plate layer cools to -50 DEG C, and cillin bottle is put into freeze dryer after filling, keeps the temperature 1h.Plate layer temperature is warming up to -8 DEG C, heat preservation
Plate layer is cooled to -40 DEG C after 2h, continues to keep the temperature 3h.Plate layer is warming up to 25 DEG C in 8~12h；After 30 DEG C of heat preservation 10h,
Nitrogen tamponade is poured, taking-up is rolled lid pack and both obtained.
Comparative example 1
According to the method that patent CN102091046B embodiment 1 provides, supplementary material preparation in above-mentioned prescription is taken both to obtain.
Comparative example 2
Fludarabine phosphate 50g
Lactose 50g
Water for injection 2000ml
According to the method that patent CN102552175 Examples 1 to 4 provides, supplementary material preparation in above-mentioned prescription is taken both to obtain.
Verify embodiment
Fludarabine phosphate stability study
[character] this product is that loose block or powder is lyophilized in white.
Basicity takes 1 bottle of this product, and water 2ml is added to dissolve, and measures (two annex VI H of Chinese Pharmacopoeia version in 2010) in accordance with the law, pH value
It should be 7.2~8.2.
The clarity and color of solution take this product, add water that the solution in every 1ml containing 5.0mg is made respectively by labelled amount, according to
Method inspection, solution answer clear, colorless；Such as aobvious muddiness, compares with No. 1 turbidity standard (two Ⅸ B of annex of Chinese Pharmacopoeia version in 2010)
Compared with must not be denseer；It, must not be more with No. 1 standard color solution of yellow (two Ⅸ A of annex of Chinese Pharmacopoeia version in 2010) such as colour developing
It is deep.
Related substance is measured according to high performance liquid chromatography (two V D of annex of Chinese Pharmacopoeia version in 2010).
Condition A-- elutes impurity early period
Chromatographic condition and system suitability are filler with octadecylsilane chemically bonded silica；With methanol-
0.01mol/L potassium dihydrogen phosphate (6:94) is mobile phase；Detection wavelength is 260nm.It is tested by chromatographic condition, takes spirit
Sensitivity test injects liquid chromatograph with 20 μ l of solution, adjusts detection sensitivity, makes the ratio of principal component peak height and baseline noise not
It obtains less than 10；Take 20 μ l liquid chromatograph of system suitability solution, (relative retention time is about at arabinose isoguanine riboside phosphate peak
0.26) should be not less than 2(note with the separating degree of isoguanine peak (relative retention time is about 0.34): changing Detection wavelength is
The peak height of 292nm, impurity arabinose isoguanine riboside phosphate and isoguanine can obviously increase, it may be determined that arabinose isoguanine riboside phosphate with
Isoguanine peak)；Reference substance solution separately is taken, continuous sample introduction 5 times, the relative standard deviation of peak area measurement value should be not greater than
2.0%。
System suitability solution takes fludarabine phosphate 10mg, accurately weighed, sets in 10ml measuring bottle, adds 0.1mol/ml salt
Acid solution makes to dissolve and be diluted to scale in right amount, 80 DEG C heating water bath 15 minutes, shake up, as system suitability solution.
Reference substance solution takes fludarabine phosphate reference substance appropriate, accurately weighed, adds flowing phased soln and quantifies dilution system
At, containing about the solution of 20 μ g, shaken up in every 1ml to get.
Sensitivity test measures reference substance solution 5ml with solution precision, sets in 200ml measuring bottle, is diluted to quarter with mobile phase
Degree, shake up to get.
Test solution, which takes 5 bottles of this product, every bottle plus water 2ml, to be made to dissolve, and moves to and (swung with mobile phase and wash bottle) same 250ml
In measuring bottle, it is diluted to scale with mobile phase, is shaken up, as test solution.
Measuring method precision measures 20 μ l of test solution, injects liquid chromatograph, and record chromatogram to principal component peak retains
4.5 times of time.The percentage of elution fludarabine phosphate early period impurity is calculated with following formula:
100F1(Ru/Rs)
F1For the relative coefficient for each impurity listed in table, other impurity are 1.0；
RuRefer to the peak value of single impurity in test solution；
RsRefer to the peak value of the fludarabine phosphate in test solution.
In addition to the single impurity provided in table, other single impurity must not be higher than 0.2% before fludarabine phosphate peak.
| Relative retention time | Relative coefficient (F1) | Relative coefficient (F2) | Impurity | Limit |
| 0.26 | 4.0 | - | Arabinose isoguanine riboside phosphate | 1.0 |
| 0.34 | 2.5 | - | Isoguanine | 0.2 |
| 1.5 | - | 0.5 | 2- fluoroadenine | 0.2 |
| 1.9 | - | 0.6 | The fluoro- arabinosy ladenosine of 2- (fludarabine) | 0.2 |
Condition B-later period elutes impurity
Chromatographic condition and system suitability are filler with octadecylsilane chemically bonded silica；With methanol-
0.01mol/L potassium dihydrogen phosphate (20:80) is mobile phase；Detection wavelength is 260nm.It is tested, is taken by chromatographic condition
Sensitivity test injects liquid chromatograph with 20 μ l of solution, adjusts detection sensitivity, makes the ratio of principal component peak height and baseline noise
It cannot be less than 10；Reference substance solution separately is taken, continuous sample introduction 5 times, the relative standard deviation of peak area measurement value should be not greater than
2.0%, tailing factor should be not greater than 2.0.
Reference substance solution takes fludarabine phosphate reference substance appropriate, accurately weighed, adds flowing phased soln and quantifies dilution system
At, containing about the solution of 20 μ g, shaken up in every 1ml to get.
Sensitivity test measures reference substance solution 5ml with solution precision, sets in 200ml measuring bottle, is diluted to quarter with mobile phase
Degree, shake up to get.
Test solution, which takes 5 bottles of this product, every bottle plus water 2ml, to be made to dissolve, and moves to and (swung with mobile phase and wash bottle) same 250ml
In measuring bottle, it is diluted to scale with mobile phase, is shaken up, as test solution.
Measuring method precision measures 20 μ l of test solution, injects liquid chromatograph, and record chromatogram to principal component peak retains
8 times of time.The percentage of fludarabine phosphate later period elution impurity is calculated with following formula:
100F2(ru/rs)
F2For the relative coefficient for each impurity listed in table, other impurity are 1.0；
Ru refers to the peak value of single impurity in test solution；
Rs refers to the peak value of the fludarabine phosphate in test solution.
In addition to the single impurity provided in table, other single impurity must not be higher than 0.2% behind fludarabine phosphate peak.
All impurity of condition A and condition B elution flow phase system detection must not cross 2.0%.
Moisture takes this product, and according to aquametry (two annex of Chinese Pharmacopoeia version in 2010, VIII the first method A of M), moisture content is not
Obtained 5.0%.
[assay] is measured according to high performance liquid chromatography (two V D of annex of Chinese Pharmacopoeia version in 2010).
Chromatographic condition and system suitability are filler with octadecylsilane chemically bonded silica；With methanol-
0.01mol/L potassium dihydrogen phosphate (6:94) is mobile phase；Detection wavelength is 260nm；Number of theoretical plate presses fludarabine phosphate
Peak, which calculates, should be not less than 2500.
Measuring method, which takes 5 bottles of this product, every bottle plus water 2ml, to be made to dissolve, and moves to and (swung with mobile phase and wash bottle) same 250ml measuring bottle
In, it is diluted to scale with mobile phase, is shaken up, precision measures 2ml, and 100ml measuring bottle is set, scale is diluted to mobile phase, shakes up, essence
20 μ l of close measurement inject liquid chromatograph, record chromatogram；It is appropriate that another precision weighs fludarabine phosphate reference substance, with flowing
Phased soln is made in every 1ml containing about the solution of 20 μ g, is measured in the same method, by external standard method with calculated by peak area to get.
Embodiment 1 and comparative example 1,2 gained samples are placed in 40 DEG C, accelerated test is carried out in the environment of RH75%, point
Not in the 0th, 1,2,3,6 month sampling investigated, inspection target include in relation to substance, content, moisture, solution clarity with
The indexs such as color and moisture, concrete outcome see the table below 1.
1 fludarabine phosphate freeze-dried powder study on the stability result of table
By upper table 1 as can be seen that the indexs such as the related substance of sample, moisture for preparing through the invention are better than existing skill
Art, and auxiliary material is not added in the present invention, improves the safety of injection fludarabine phosphate clinical application, and changes existing
There is the prejudice of technology.
Claims (1)
1. a kind of Fludarabine phosphate freeze-dried powder injection, which is characterized in that be made, wrapped as sole component by fludarabine phosphate
Include following steps: water for injection be added in 75~100 μm of fludarabine phosphate powder, using sodium hydroxide adjust pH value to
7.2~8.2, it is made into the solution that fludarabine phosphate concentration is 5%, freeze-drying, tamponade is rolled lid, packed to obtain the final product, the freeze-drying process
Specifically includes the following steps:
1) the quick-frozen stage: before fludarabine phosphate solution is put into, plate layer cools to -45 DEG C, and product is put into freeze dryer, heat preservation
2h；
2) the pre-freeze stage: after the quick-frozen stage, plate layer is warming up to -8 DEG C, keeps the temperature 2h；Then plate layer is cooled to -45 DEG C, protected
Warm 3h；
3) lyophilization: after the pre-freeze stage, plate layer is gradually warmed up to 20 DEG C in 8~12h；
4) parsing-desiccation: after lyophilization, plate layer is warming up to 35 DEG C, keeps the temperature 8h.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410010241.4A CN104771369B (en) | 2014-01-09 | 2014-01-09 | A kind of Fludarabine phosphate freeze-dried powder injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410010241.4A CN104771369B (en) | 2014-01-09 | 2014-01-09 | A kind of Fludarabine phosphate freeze-dried powder injection |
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| CN104771369A CN104771369A (en) | 2015-07-15 |
| CN104771369B true CN104771369B (en) | 2019-03-26 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110974789B (en) * | 2019-12-27 | 2020-08-25 | 瀚晖制药有限公司 | Fludarabine phosphate freeze-drying agent and preparation method thereof |
| CN113398079B (en) * | 2020-03-16 | 2024-01-19 | 鲁南制药集团股份有限公司 | Fludarabine freeze-dried powder for injection |
| CN113995723A (en) | 2020-07-27 | 2022-02-01 | 浙江普洛家园药业有限公司 | Preparation method of Sofadil freeze-dried powder injection, product and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8158152B2 (en) * | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
| WO2010046917A2 (en) * | 2008-10-13 | 2010-04-29 | Intas Pharmaceuticals Limited | Fludarabine phosphate composition |
| CN101947208B (en) * | 2010-10-09 | 2012-05-23 | 江苏奥赛康药业股份有限公司 | Fludarabine phosphate composition for injection and preparation method thereof |
| CN102133201B (en) * | 2011-03-23 | 2013-01-16 | 山东新时代药业有限公司 | Faropenem sodium freeze-dried powder injection |
| CN102552175B (en) * | 2011-12-28 | 2017-07-07 | 辰欣药业股份有限公司 | A kind of injection fludarabine phosphate lyophilized formulations and preparation method thereof |
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