CN105326784A - Sodium valproate injection - Google Patents
Sodium valproate injection Download PDFInfo
- Publication number
- CN105326784A CN105326784A CN201410390030.8A CN201410390030A CN105326784A CN 105326784 A CN105326784 A CN 105326784A CN 201410390030 A CN201410390030 A CN 201410390030A CN 105326784 A CN105326784 A CN 105326784A
- Authority
- CN
- China
- Prior art keywords
- injection
- sodium valproate
- sodium
- acid
- valproate
- 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.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a sodium valproate injection. The sodium valproate injection is composed of sodium valproate, a stabilizing agent, a pH regulating agent and water for injection, wherein EDTA (ethylene diamine tetraacetic acid)-2NaCa serves as the stabilizing agent. By adoption of the EDTA-2NaCa serving as the stabilizing agent, stability of the sodium valproate injection in preparation and storage is evidently superior to that of sodium valproate injections adopting other stabilizing agents, to be more specific, the sodium valproate injection in preparation and storage is small in pH value variation range, related substances are less increased, and active ingredients are less reduced. Therefore, safety of the sodium valproate injection can be further improved by adoption of the EDTA-2NaCa serving as the stabilizing agent.
Description
Technical field
The present invention relates to a kind of sodium valproate injection and preparation method thereof.
Background technology
Sodium valproate chemistry valproate by name, molecular formula: C
8h
15naO
2molecular weight is 166.2, for the crystalline powder that white odorless is soluble in water, there is extremely strong hygroscopicity, be applicable to polytype epilepsy, as the prevention and therapy of the personality behavior disorder that petit mal, focal attack, psychomotor attack, Combination outbreak, status epilepticus and epilepsy cause.
The mechanism of action of sodium valproate is relevant with suppression Voltage Sensitive Na+ Channels.It is by suppressing γ-aminobutyric acid metabolism, and the γ-aminobutyric acid increased in brain is built up, and reaches the effect suppressing focus neuron over-discharge and paradoxical discharge diffusion.
At present, the sodium valproate of listing is mainly oral solid formulation and injection.Such as there are ordinary tablet, slow releasing tablet, slow-releasing granules, oral administration solution, syrup and injection, but for the emergency treatment of the prevention of average of operation periods epilepsy, status epilepticus or epileptic episodes, be merely able to give patient with the mode administration of injection, therefore injection type plays irreplaceable effect.
On market, the kind of sodium valproate injection type is mostly freeze-dried powder, although it is conducive to keeping the stability of sodium valproate preparation in preparation and storage process, but its preparation technology require very strict, energy consumption is high, the cycle is long, production cost is high, and injection so that its preparation technology is simple, manufacturing cost is lower, face the used time, without the need to redissolving the feature of preparation again, there is in clinical practice the advantage of its uniqueness.
For injection, because its first pass effect without liver just directly enters blood circulation, therefore must strictly control for its material such as impurity content and endotoxin.And for sodium valproate, its stability should give to pay close attention to especially.This is that cause principal agent to be degraded, impurity increases due to sodium valproate very easily moisture absorption in the process of storage and transport.And for injection articles for use, its impurity content needs strict control, otherwise not only can affect drug effect, also can bring danger to patient, cause malpractice.
Domestic market there is no the supply of sodium valproate injection, also not about the bibliographical information of sodium valproate injection.
Summary of the invention
The object of the present invention is to provide a kind of sodium valproate injection had good stability and preparation method thereof.
Concrete, the invention provides a kind of sodium valproate injection, it contains sodium valproate, stabilizing agent, pH adjusting agent and injection water, and described stabilizing agent is calcium disodium chelate.Test finds, the stability adding the sodium valproate injection of EDTA-2NaCa obviously will be better than the sodium valproate injection of commercially available other stabilizing agents of use.
Wherein, the mass ratio of calcium disodium chelate and sodium valproate is 1:100 ~ 4000.
Further, the mass ratio of calcium disodium chelate and sodium valproate is 1:287.5 ~ 3285.7, as 1:287.5 ~ 2875.
Further, the mass ratio of calcium disodium chelate and sodium valproate is 1:1437.5 ~ 3285.7, as 1:1916.7 ~ 2875.
Calcium disodium chelate is a kind of potent complexing of metal ion agent, consider that it may on the impact of minor metallic element in body fluid, so when playing same Stabilization, can the less calcium disodium chelate of preferred content as the stabilizing agent of injection of the present invention.
Further, in injection, sodium valproate concentration is 10 ~ 600mg/ml.
Further, in injection, sodium valproate concentration is 11.5 ~ 460mg/ml.
Preferably, in injection, sodium valproate concentration is 11.5 ~ 115mg/ml.Although calculate injection effective ingredient concentration with sodium valproate in the present invention, but, if sodium valproate concentration conversion is become valproic acid concentration, also can the present invention be realized.
Further, injection pH is 4.0 ~ 9.0.
Further, injection pH is 4.8 ~ 8.2, can in neutrality, faintly acid and alkalescence.
PH adjusting agent used in the present invention is the known and conventional pH adjusting agent of field of pharmaceutical preparations, and stability and the pH adjusting agent kind used of injection of the present invention have nothing to do, and relevant with the overall pH value of sodium valproate system.Such as, pH adjusting agent can use one or more the combination in hydrochloric acid, phosphoric acid, maleic acid, citric acid, tartaric acid, acetic acid, methanesulfonic acid, sodium hydroxide, sodium citrate, sodium carbonate.
Present invention also offers the preparation method of above-mentioned sodium valproate injection, it comprises following operating procedure:
Calcium disodium chelate and sodium valproate are added in water for injection, stirs, make to dissolve completely, regulate solution ph, then use water for injection standardize solution; Then add needle-use activated carbon, with 0.22 μm of membrane filtration, by gained medicinal liquid subpackage, pressure sterilizing, to obtain final product.
The present invention is in order to improve the safety of sodium valproate injection, adopt calcium disodium chelate (EDTA-2NaCa) as stabilizing agent, not only eliminate the impact on blood calcium in body after intravenous injection sodium valproate, also be surprised to find that the stability of sodium valproate injection in preparation and storage process adding EDTA-2NaCa obviously will be better than using the sodium valproate injection of other stabilizing agents, show as product pH value excursion in preparation and storage process less, its related substances increases less and active component content reduction is less, this illustrates the safety adopting EDTA-2NaCa can improve sodium valproate injection further as stabilizing agent.
Below by way of detailed description of the invention, the present invention is described in further detail, but do not limit the present invention, those skilled in the art make various change and replacement according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Detailed description of the invention
Determination of related substances method
Adopt gas chromatography, chromatographic condition: the capillary chromatographic column being fixative with Polyethylene Glycol (PEG-20M); Initial temperature is 130 DEG C, maintains 20 minutes, then with the ramp to 200 DEG C of 5 DEG C per minute, maintains 15 minutes; Injector temperature is 220 DEG C; Detector temperature is 220 DEG C.
Sample solution: get injection appropriate, dissolve with dichloromethane after evaporate to dryness and dilute the solution made containing valproic acid 5mg/ml.
Get 2 phenylethyl alcohol 20mg, put in 25ml measuring bottle, add sample solution 1ml, with dchloromethane to scale, shake up, as system suitability solution.
Get system suitability solution 1 μ l, inject gas chromatograph, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be 20% of full scale; By sample solution inject gas chromatograph, record chromatogram, to 3 times of main constituent peak retention time, calculates impurity peak area percentage ratio.
Content assaying method
By high performance liquid chromatography, chromatographic condition: chromatographic column is octyl group silane group unmodified packed column (C
8, 4.6*150mm, 5 μm); Determined wavelength: 215nm; Flow velocity: 1ml/min; Sample size: 20 μ l;
Solution preparation:
Buffer: 3.5g/L sodium dihydrogen phosphate, adjusts pH to be 3.5 with phosphoric acid;
Mobile phase: acetonitrile: buffer (45:55);
Diluent: acetonitrile: water (45:55);
System suitability solution: make the solution containing valproic acid reference substance 0.5mg/ml and valproic acid related substance B reference substance 0.05mg/ml by diluted;
Standard solution: make the solution containing valproic acid reference substance 0.5mg/ml by diluted;
Sample solution: get injection appropriate, dilute with water makes the solution containing valproic acid 0.5mg/ml.
System suitability: precision measures system suitability solution and standard solution 20 μ l sample introduction respectively, record chromatogram.In system suitability solution chromatogram, related substance B and the peak-to-peak separating degree of valproic acid are not less than 2.0 (relative retention time of related substance B and valproic acid is respectively 0.90 and 1.0).In standard solution chromatogram, valproic acid peak tailing factor must not be greater than 1.5, and in continuous 6 pin standard solution, valproic acid peak area RSD must not be greater than 1.0%.
Algoscopy: precision measures each 20 μ l of blank, standard solution and sample solution, injection liquid chromatography, record chromatogram, by external standard method with calculated by peak area, to obtain final product.Computing formula is as follows:
Result=(r
u/ r
s) × (C
s/ C
u) × 100
In formula, r
uvalproic acid peak area in=sample solution;
R
svalproic acid peak area in=standard solution;
C
svalproic acid reference substance concentration in=standard solution;
C
uvalproic acid concentration in=sample solution.
Embodiment 1
Prescription:
Regulate pH to 4.8;
Preparation method:
The EDTA-2NaCa of recipe quantity and sodium valproate are added in water for injection, stirs, make to dissolve completely, regulate solution ph to 7.6, then be settled to water for injection and be enoughly mixed with desired concn; Then add needle-use activated carbon and stir 30 minutes, with 0.22 μm of membrane filtration, by gained medicinal liquid subpackage, pressure sterilizing, to obtain final product.
Embodiment 2
Prescription:
Regulate pH to 8.2;
Preparation method: with embodiment 1.
Embodiment 3
Prescription:
Regulate pH to 7.6;
Preparation method: with embodiment 1.
Embodiment 4
Regulate pH to 7.2;
Preparation method: with embodiment 1.
Embodiment 5
Prescription:
Regulate pH to 7.4;
Preparation method: with embodiment 1.
Embodiment 6
Prescription:
Regulate pH to 4.8;
Preparation method: with embodiment 1.
Embodiment 7
Prescription:
Regulate pH to 6.8;
Preparation method: with embodiment 1.
Embodiment 8
Prescription:
Regulate pH to 7.8;
Preparation method: with embodiment 1.
Embodiment 9
Prescription:
Regulate pH to 7.2;
Preparation method: with embodiment 1.
Embodiment 10
Prescription:
Regulate pH to 7.4;
Preparation method: with embodiment 1.
Below by way of concrete stability test, beneficial effect of the present invention is described.
Comparative example 1
Prescription:
Regulate pH to 7.6;
Preparation method: with embodiment 1.
Comparative example 2
Prescription:
Regulate pH to 7.4;
Preparation method: with embodiment 1.
Comparative example 3
Prescription:
Regulate pH to 7.2;
Preparation method: with embodiment 1.
Test example 1 accelerated stability test
To get in the embodiment of the present invention 1 ~ 10, comparative example 1 ~ 3 sodium valproate injection and commercially available abroad
injection, temperature 40 DEG C ± 2 DEG C, places 6 months under the condition of relative humidity 75% ± 5%, respectively at 0,1,2,3 and sampling in 6 months, checks the situation of change of its outward appearance, pH value, related substance and content, the results are shown in table 1.
Table 1 accelerated test result
As can be seen from accelerated stability test result, in acceleration placement 6 months period, almost constant, related substance does not increase or slightly increases, content is also without obviously decline without significant change, pH value for the sodium valproate injection outward appearance of embodiment 1 ~ 10; On the contrary, the sodium valproate injection of comparative example 1 ~ 3 and external commercially available prod
injection, between resting period, pH value changes clearly, related substance increases more, but content but obviously declines, and this uses to injection and brings potential safety hazard.
Test example 2, long-term stable experiment
To get in the embodiment of the present invention 1 ~ 10, comparative example 1 ~ 3 sodium valproate injection and commercially available abroad
injection, temperature 25 DEG C ± 2 DEG C, places 12 months under the condition of relative humidity 60% ± 10%, respectively at 0,3,6,9 and sampling in 12 months, checks the situation of change of its outward appearance, pH value, related substance and content, the results are shown in table 2.
Table 2 long-term test results
As can be seen from long-term stable experiment result, place 12 months periods normal, almost constant, related substance does not increase or slightly increases, content almost remains unchanged without significant change, pH value for the sodium valproate injection outward appearance of embodiment 1 ~ 10; On the contrary, the sodium valproate injection of comparative example 1 ~ 3 and external commercially available prod
injection, between resting period, pH value changes clearly, related substance obviously increases, but content but obviously declines.Thus proving that sodium valproate injection stability of the present invention is more excellent, the safety thereupon brought and effectiveness are also higher.
Claims (10)
1. a sodium valproate injection, it contains sodium valproate, stabilizing agent, pH adjusting agent and injection water, it is characterized in that: described stabilizing agent is calcium disodium chelate.
2. sodium valproate injection according to claim 1, is characterized in that: the mass ratio of calcium disodium chelate and sodium valproate is 1:100 ~ 4000.
3. sodium valproate injection according to claim 2, is characterized in that: mass ratio 1:287.5 ~ 3285.7 of calcium disodium chelate and sodium valproate.
4. sodium valproate injection according to claim 3, is characterized in that: the mass ratio of calcium disodium chelate and sodium valproate is 1:1437.5 ~ 3285.7.
5. the sodium valproate injection according to Claims 1 to 4 any one, is characterized in that: in injection, sodium valproate concentration is 10 ~ 600mg/ml.
6. sodium valproate injection according to claim 5, is characterized in that: in injection, sodium valproate concentration is 11.5 ~ 460mg/ml.
7. sodium valproate injection according to claim 6, is characterized in that: in injection, sodium valproate concentration is 11.5 ~ 115mg/ml.
8. the sodium valproate injection according to claim 1 ~ 7 any one, is characterized in that: injection pH is 4.0 ~ 9.0; Preferably, injection pH is 4.8 ~ 8.2.
9. sodium valproate injection according to claim 1, is characterized in that: described pH adjusting agent is selected from one or more the combination in hydrochloric acid, phosphoric acid, maleic acid, citric acid, tartaric acid, acetic acid, methanesulfonic acid, sodium hydroxide, sodium citrate, sodium carbonate.
10. the preparation method of sodium valproate injection described in claim 1 ~ 9 any one, is characterized in that: it comprises following operating procedure:
Calcium disodium chelate and sodium valproate are added in water for injection, stirs, make to dissolve completely, regulate solution ph, then use water for injection standardize solution; Then add needle-use activated carbon, with 0.22 μm of membrane filtration, by gained medicinal liquid subpackage, pressure sterilizing, to obtain final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410390030.8A CN105326784B (en) | 2014-08-08 | 2014-08-08 | A kind of sodium vedproate parenteral solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410390030.8A CN105326784B (en) | 2014-08-08 | 2014-08-08 | A kind of sodium vedproate parenteral solution |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105326784A true CN105326784A (en) | 2016-02-17 |
| CN105326784B CN105326784B (en) | 2018-06-26 |
Family
ID=55277693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410390030.8A Active CN105326784B (en) | 2014-08-08 | 2014-08-08 | A kind of sodium vedproate parenteral solution |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105326784B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109580831A (en) * | 2018-12-28 | 2019-04-05 | 四川健能制药有限公司 | Method for measuring related substances of sodium valproate oral solution |
Citations (4)
| 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 |
| WO2014108808A2 (en) * | 2013-01-09 | 2014-07-17 | Henry James Lorne | Pharmaceutical formulations for the treatment and prevention of trauma-induced neuropathology and neurodegeneration |
-
2014
- 2014-08-08 CN CN201410390030.8A patent/CN105326784B/en active Active
Patent Citations (4)
| 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 |
| WO2014108808A2 (en) * | 2013-01-09 | 2014-07-17 | Henry James Lorne | Pharmaceutical formulations for the treatment and prevention of trauma-induced neuropathology and neurodegeneration |
Non-Patent Citations (2)
| Title |
|---|
| 无: "Depacon Injection", 《道客巴巴网页，网址：HTTP://WWW.DOC88.COM/P-472334769211.HTML》 * |
| 罗明生，等主编: "《中国药用辅料》", 30 April 2006 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109580831A (en) * | 2018-12-28 | 2019-04-05 | 四川健能制药有限公司 | Method for measuring related substances of sodium valproate oral solution |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105326784B (en) | 2018-06-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102138892B (en) | Choline alfoscerate injection preparation as well as preparation method and detection method thereof | |
| WO2018107975A1 (en) | Dexrazoxane analysis method | |
| CN103690975B (en) | A kind of water solution of levocarnitine produces method and the application thereof of trace 2 (5H)-furanones | |
| CN101929985A (en) | Method for measuring atorvastatin calcium associated matters by high performance liquid chromatography | |
| CN101199477A (en) | Ratification of highly purified tranexamic acid injection and quality standard thereof | |
| CN105326784A (en) | Sodium valproate injection | |
| CN109946398B (en) | Method for detecting dalbavancin and impurities thereof | |
| CN106474048A (en) | A kind of more stable desonide gel preparation of quality | |
| CN102895200B (en) | Mecobalamine freeze-drying composition and preparation method thereof | |
| CN105640873A (en) | Sodium valproate injection, preparation method and applications thereof | |
| KR102668112B1 (en) | Method of removing acetaldehyde from radioactive pharmaceuticals | |
| CN110441421A (en) | A kind of method of high effective liquid chromatography for measuring Entacapone tablet dissolution | |
| CN105168224A (en) | Fasudil hydrochloride injection and preparing method thereof | |
| CN103638018B (en) | Compound amino acid injection 18AA-VII pharmaceutical composition and preparation method thereof | |
| CN103405384B (en) | Pharmaceutical composition of tranexamic acid | |
| CN113081958B (en) | Desloratadine oral solution and preparation method thereof | |
| CN103860461B (en) | A kind of pharmaceutical composition containing active ingredient hydrochloric acid ambroxol | |
| CN105974000B (en) | Purposes of the 7- benzoyl -1,3- Indolin-2-ones in nepafenac stability quality control | |
| CN102269737B (en) | HPLC (high performance liquid chromatography) detection method of arginine ketoglutarate | |
| CN113740464A (en) | Method for detecting oxaloacetate content in malic acid solution | |
| CN103159710B (en) | Antiviral decalin derivate | |
| CN107356690B (en) | Separation and detection method of related substances in ophthalmic gel | |
| CN105267160B (en) | A kind of injection vinpocetine lyophilized preparation composition and preparation method thereof | |
| CN102973556A (en) | Compound amino acid injection (18AA-IV) composition | |
| CN112057417B (en) | Carprostenol tromethamine injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
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 |
|
| COR | Change of bibliographic data | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |