CN105326784B - A kind of sodium vedproate parenteral solution - Google Patents
A kind of sodium vedproate parenteral solution Download PDFInfo
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- CN105326784B CN105326784B CN201410390030.8A CN201410390030A CN105326784B CN 105326784 B CN105326784 B CN 105326784B CN 201410390030 A CN201410390030 A CN 201410390030A CN 105326784 B CN105326784 B CN 105326784B
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- parenteral solution
- sodium
- sodium vedproate
- vedproate
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Abstract
The present invention provides a kind of sodium vedproate parenteral solutions, it contains sodium vedproate, stabilizer, pH adjusting agent and parenteral solution water, and the stabilizer is calcium disodium chelate.The present invention is using calcium disodium chelate (EDTA 2NaCa) as stabilizer, so that stability of the sodium vedproate parenteral solution in preparation and storage process will be substantially better than the sodium vedproate parenteral solution using other stabilizers, product is embodied in prepare and pH value variation range smaller in storage process, related content of material, which increases less and active component content, to be reduced less, this explanation can further improve the safety of sodium vedproate parenteral solution using EDTA 2NaCa as stabilizer.
Description
Technical field
The present invention relates to a kind of sodium vedproate parenteral solutions and preparation method thereof.
Background technology
The entitled valproate of sodium vedproate chemistry, molecular formula：C8H15NaO2, molecular weight 166.2 is white odorless
Crystalline powder soluble easily in water has extremely strong hygroscopicity, suitable for a plurality of types of epileptic attacks, such as petit mal, focal
Property breaking-out, psychomotor attack, Combination breaking-out, the prevention of personality behavior disorder caused by status epilepticus and epilepsy
And treatment.
The mechanism of action of sodium vedproate is related with inhibiting Voltage Sensitive Na+ Channels.It is by inhibiting gamma-amino fourth
Acid metabolic, increase intracerebral γ-aminobutyric acid build up, reach inhibit lesion neuron over-discharge and paradoxical discharge diffusion
Effect.
At present, the sodium vedproate of listing is mainly oral solid formulation and injection.Such as there is ordinary tablet, sustained release tablets, delay
Particle, oral administration solution, syrup and injection are released, but the prevention for average of operation periods epilepsy, status epilepticus or epilepsy are acute
The emergency treatment of breaking-out, is merely able to give patient and is administered in a manner of injecting, therefore injection type plays irreplaceable work
With.
The kind of sodium vedproate injection type is mostly freeze-dried powder in the market, although it is conducive to keep sodium vedproate system
Stability of the agent in preparation and storage process, but its preparation process requires very strict, high energy consumption, period length, production cost
Height, and parenteral solution with its preparation process is simple, manufacture cost is relatively low, face the used time without redissolve preparation again the characteristics of in clinical practice
In have its unique advantage.
For injection, since its first pass effect without liver is just directly entered blood circulation, for it
The substances such as impurity content and endotoxin must be controlled strictly.And for sodium vedproate, stability should give spy
It does not pay close attention to.This is because sodium vedproate easy to absorb moisture during storage and transport, causes main ingredient to be degraded, impurity increases.
And for injection articles for use for, impurity content needs strictly to control, and otherwise can not only influence drug effect, can also give patient with
Carry out dangerous, initiation malpractice.
Domestic market there is no sodium vedproate parenteral solution to supply, also not about the document report of sodium vedproate parenteral solution
Road.
Invention content
The purpose of the present invention is to provide a kind of sodium vedproate parenteral solutions having good stability and preparation method thereof.
Specifically, the present invention provides a kind of sodium vedproate parenteral solution, it contains sodium vedproate, stabilizer, pH adjusting agent
With parenteral solution water, the stabilizer is calcium disodium chelate.Experiment is found, adds in the sodium vedproate of EDTA-2NaCa
The stability of parenteral solution will be substantially better than the commercially available sodium vedproate parenteral solution using other stabilizers.
Wherein, the mass ratio of calcium disodium chelate and sodium vedproate is 1:100~4000.
Further, the mass ratio of calcium disodium chelate and sodium vedproate is 1：287.5~3285.7, such as 1:
287.5~2875.
Further, the mass ratio of calcium disodium chelate and sodium vedproate is 1:1437.5~3285.7, such as
1:1916.7~2875.
Calcium disodium chelate is a kind of potent complexing of metal ion agent, it is contemplated that it may be to gold micro in body fluid
Belong to the influence of element, so in the case where playing similary stabilization, it can be with the less ethylenediamine tetra-acetic acid two of preferred content
Stabilizer of the sodium calcium as parenteral solution of the present invention.
Further, a concentration of 10~600 mg/ml of sodium vedproate in parenteral solution.
Further, a concentration of 11.5~460mg/ml of sodium vedproate in parenteral solution.
Preferably, a concentration of 11.5~115mg/ml of sodium vedproate in parenteral solution.Although in the present invention in terms of sodium vedproate
Parenteral solution active ingredient concentration is calculated, if however, sodium vedproate concentration conversion can also be realized the present invention into valproic acid concentration.
Further, parenteral solution pH is 4.0~9.0.
Further, parenteral solution pH is 4.8~8.2, can be in neutrality, faintly acid and alkalescent.
PH adjusting agent used in the present invention is known in field of pharmaceutical preparations and common pH adjusting agent, present invention injection
The stability of liquid is unrelated with pH adjusting agent type used, and related with the whole pH value of sodium vedproate system.For example, pH adjusting agent
It can use in hydrochloric acid, phosphoric acid, maleic acid, citric acid, tartaric acid, acetic acid, methanesulfonic acid, sodium hydroxide, sodium citrate, sodium carbonate
One or more kinds of combinations.
The present invention also provides the preparation methods of above-mentioned sodium vedproate parenteral solution, it includes following operating procedure：
Calcium disodium chelate and sodium vedproate are added in water for injection, stirring makes to be completely dissolved, and adjusts solution
PH value, then with water for injection constant volume；Then needle-use activated carbon is added in, with 0.22 μm of membrane filtration, gained liquid is dispensed, hot pressing
Sterilizing to get.
The present invention is in order to improve the safety of sodium vedproate parenteral solution, using calcium disodium chelate (EDTA-
2NaCa) as stabilizer, the influence being injected intravenously after sodium vedproate to internal blood calcium is not only eliminated, it has been unexpectedly discovered that plus
Enter the sodium vedproate parenteral solution of EDTA-2NaCa prepare and storage process in stability to be substantially better than and use other stabilizations
The sodium vedproate parenteral solution of agent shows as product and is preparing and pH value variation range smaller in storage process, related content of material
Increasing less and active component content reduces less, this explanation can be further improved using EDTA-2NaCa as stabilizer
The safety of sodium vedproate parenteral solution.
Below by way of specific embodiment, the present invention is described in further detail, but is not intended to limit the present invention, ability
Field technique personnel are variously modified and replace according to the present invention, without departing from the spirit of the present invention, should all belong to the present invention
Scope of the appended claims.
Specific embodiment
Related substance-measuring method
Using gas chromatography, chromatographic condition：With the capillary chromatographic column that polyethylene glycol (PEG-20M) is fixer；It rises
Beginning temperature is 130 DEG C, is maintained 20 minutes, then is warming up to 200 DEG C with 5 DEG C per minute of rate, is maintained 15 minutes；Injector temperature
It is 220 DEG C；Detector temperature is 220 DEG C.
Sample solution：It takes parenteral solution appropriate, is dissolved and diluted with dichloromethane after being evaporated and be made the 5mg/ml's containing valproic acid
Solution.
2 phenylethyl alcohol 20mg is taken, is put in 25ml measuring bottles, adds sample solution 1ml, scale is diluted to dichloromethane, shakes up,
As system suitability solution.
1 μ l of system suitability solution are taken, inject gas chromatograph, detection sensitivity is adjusted, makes principal component chromatographic peak
Peak height be full scale 20%；Sample solution is injected into gas chromatograph, record chromatogram to the 3 of principal component peak retention time
Times, calculate impurity peak area percentage.
Content assaying method
With high performance liquid chromatography, chromatographic condition：Chromatographic column is octyl group silane group unmodified packed column (C8,4.6*
150mm,5μm)；Detection wavelength：215nm；Flow velocity：1ml/min；Sample size：20μl；
Solution is prepared：
Buffer solution：3.5g/L sodium dihydrogen phosphates are 3.5 with phosphoric acid tune pH；
Mobile phase：Acetonitrile：Buffer solution (45:55)；
Dilution：Acetonitrile：Water (45:55)；
System suitability solution：With diluted be made the 0.5mg/ml of reference substance containing valproic acid with valproic acid related substance
The solution of B reference substances 0.05mg/ml；
Standard solution：The solution of the 0.5mg/ml of reference substance containing valproic acid is made of diluted；
Sample solution：It takes parenteral solution appropriate, the solution that the 0.5mg/ml containing valproic acid is made is diluted with water.
System suitability：It is accurate respectively to measure 20 μ l sample introductions of system suitability solution and standard solution, record chromatogram.System
It unites in adaptability solution chromatogram, related separating degree between substance B and valproic acid peak is not less than 2.0 (in relation to substance B and the third penta
The relative retention time of acid is respectively 0.90 and 1.0).In standard solution chromatogram, valproic acid peak tailing factor is not greater than
1.5, valproic acid peak area RSD is not greater than 1.0% in continuous 6 needle standard solution.
Measuring method：Precision measures blank, standard solution and each 20 μ l of sample solution, injects liquid chromatograph, records chromatography
Figure, by external standard method with calculated by peak area to get.Calculation formula is as follows：
As a result=(rU/rS)×(CS/CU)×100
In formula, rUValproic acid peak area in=sample solution；
rSValproic acid peak area in=standard solution；
CSValproic acid reference substance concentration in=standard solution；
CUValproic acid concentration in=sample solution.
Embodiment 1
Prescription：
Adjust pH to 4.8；
Preparation method：
The EDTA-2NaCa of recipe quantity and sodium vedproate are added in water for injection, stirring makes to be completely dissolved, and adjusts solution
PH value is to 7.6, then is settled to water for injection and enough is configured to required concentration；Then needle-use activated carbon is added in stir 30 minutes,
With 0.22 μm of membrane filtration, gained liquid is dispensed, pressure sterilizing to get.
Embodiment 2
Prescription：
Adjust pH to 8.2；
Preparation method：With embodiment 1.
Embodiment 3
Prescription：
Adjust pH to 7.6；
Preparation method：With embodiment 1.
Embodiment 4
Adjust pH to 7.2；
Preparation method：With embodiment 1.
Embodiment 5
Prescription：
Adjust pH to 7.4；
Preparation method：With embodiment 1.
Embodiment 6
Prescription：
Adjust pH to 4.8；
Preparation method：With embodiment 1.
Embodiment 7
Prescription：
Adjust pH to 6.8；
Preparation method：With embodiment 1.
Embodiment 8
Prescription：
Adjust pH to 7.8；
Preparation method：With embodiment 1.
Embodiment 9
Prescription：
Adjust pH to 7.2；
Preparation method：With embodiment 1.
Embodiment 10
Prescription：
Adjust pH to 7.4；
Preparation method：With embodiment 1.
Illustrate beneficial effects of the present invention below by way of specific stability test.
Comparative example 1
Prescription：
Adjust pH to 7.6；
Preparation method：With embodiment 1.
Comparative example 2
Prescription：
Adjust pH to 7.4；
Preparation method：With embodiment 1.
Comparative example 3
Prescription：
Adjust pH to 7.2；
Preparation method：With embodiment 1.
1 accelerated stability test of test example
Take sodium vedproate parenteral solution and foreign countries in the embodiment of the present invention 1~10, comparative example 1~3 commercially availableNote
Liquid is penetrated, in 40 DEG C ± 2 DEG C of temperature, is placed 6 months under conditions of relative humidity 75% ± 5%, respectively at 0,1,2,3 and 6 months
Sampling, checks its appearance, pH value, the situation of change in relation to substance and content, is as a result listed in table 1.
1 accelerated test result of table
It can be seen that during accelerating to place 6 months from accelerated stability test result, the valproic acid of Examples 1 to 10
Sodium injection appearance is without significant change, pH value is almost unchanged, related substance does not increase or is slightly increased, content is also without under significantly
Drop；On the contrary, the sodium vedproate parenteral solution of comparative example 1~3 and external commercial productParenteral solution, during placement,
PH value change clearly, the increase of related substance it is more, but content is but decreased obviously, this brings safety to parenteral solution use
Hidden danger.
Test example 2, long-term stable experiment
Take sodium vedproate parenteral solution and foreign countries in the embodiment of the present invention 1~10, comparative example 1~3 commercially availableNote
Liquid is penetrated, in 25 DEG C ± 2 DEG C of temperature, is placed 12 months under conditions of relative humidity 60% ± 10%, respectively at 0,3,6,9 and 12
Moon sampling, checks its appearance, pH value, the situation of change in relation to substance and content, is as a result listed in table 2.
2 long-term test results of table
It can be seen that during normal place 12 months from long-term stable experiment result, the valproic acid of Examples 1 to 10
Sodium injection appearance does not increase or is slightly increased without significant change, almost unchanged, the related substance of pH value, content is almost kept not
Become；On the contrary, the sodium vedproate parenteral solution of comparative example 1~3 and external commercial productParenteral solution, during placement,
PH value variation clearly, in relation to substance significantly increases, but content is but decreased obviously.So as to prove the sodium vedproate of the present invention
Parenteral solution stability is more excellent, the safety brought therewith and validity also higher.
Claims (9)
1. a kind of sodium vedproate parenteral solution, it contains sodium vedproate, stabilizer, pH adjusting agent and parenteral solution water, feature and exists
In：The stabilizer is calcium disodium chelate；The mass ratio 1 of the calcium disodium chelate and sodium vedproate:
287.5~3285.7.
2. sodium vedproate parenteral solution according to claim 1, it is characterised in that：Calcium disodium chelate and valproic acid
The mass ratio of sodium is 1:1437.5~3285.7.
3. sodium vedproate parenteral solution according to claim 1 or 2, it is characterised in that：Sodium vedproate is a concentration of in parenteral solution
10~600mg/ml.
4. sodium vedproate parenteral solution according to claim 3, it is characterised in that：Sodium vedproate a concentration of 11.5 in parenteral solution
~460mg/ml.
5. sodium vedproate parenteral solution according to claim 4, it is characterised in that：Sodium vedproate a concentration of 11.5 in parenteral solution
~115mg/ml.
6. sodium vedproate parenteral solution according to claim 1, it is characterised in that：Parenteral solution pH is 4.0~9.0.
7. sodium vedproate parenteral solution according to claim 6, it is characterised in that：Parenteral solution pH is 4.8~8.2.
8. sodium vedproate parenteral solution according to claim 1, it is characterised in that：The pH adjusting agent be selected from hydrochloric acid, phosphoric acid,
One or more of maleic acid, citric acid, tartaric acid, acetic acid, methanesulfonic acid, sodium hydroxide, sodium citrate, sodium carbonate
Combination.
9. the preparation method of sodium vedproate parenteral solution described in claim 1~8 any one, it is characterised in that：It includes as follows
Operating procedure：
Calcium disodium chelate and sodium vedproate are added in water for injection, stirring makes to be completely dissolved, and adjusts pH value of solution
Value, then with water for injection constant volume；Then needle-use activated carbon is added in, with 0.22 μm of membrane filtration, gained liquid is dispensed, hot pressing is gone out
Bacterium to get.
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| CN109580831B (en) * | 2018-12-28 | 2022-05-13 | 四川健能制药有限公司 | Method for measuring related substances of sodium valproate oral solution |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101524345A (en) * | 2009-03-13 | 2009-09-09 | 天津南开允公医药科技有限公司 | Medicine composition without any excipients and preparation process thereof |
| CN101637447A (en) * | 2009-08-31 | 2010-02-03 | 武汉武药科技有限公司 | Sitafloxacin hydrate injection and preparation method thereof |
| CN102784098A (en) * | 2011-05-20 | 2012-11-21 | 湖南省湘中制药有限公司 | Magnesium valproate injection and preparation method thereof |
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| WO2014108808A2 (en) * | 2013-01-09 | 2014-07-17 | Henry James Lorne | Pharmaceutical formulations for the treatment and prevention of trauma-induced neuropathology and neurodegeneration |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101524345A (en) * | 2009-03-13 | 2009-09-09 | 天津南开允公医药科技有限公司 | Medicine composition without any excipients and preparation process thereof |
| CN101637447A (en) * | 2009-08-31 | 2010-02-03 | 武汉武药科技有限公司 | Sitafloxacin hydrate injection and preparation method thereof |
| CN102784098A (en) * | 2011-05-20 | 2012-11-21 | 湖南省湘中制药有限公司 | Magnesium valproate injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| Depacon Injection;无;《道客巴巴网页，网址：http://www.doc88.com/p-472334769211.html》;20120726;文档第2页description部分 * |
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Address after: 646000 national high tech Zone, Sichuan, Luzhou Province Pharmaceutical Industrial Park Applicant after: Sichuan Keruide pharmaceutical Limited by Share Ltd Address before: 646000 Luxian County City, Sichuan province Fu Town Industrial Park Applicant before: Keruide Pharmaceutical Co., Ltd., Sichuan |
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