CN105326784A - Sodium valproate injection - Google Patents
Sodium valproate injection Download PDFInfo
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- 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
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- Prior art keywords
- injection
- sodium valproate
- sodium
- acid
- valproate
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- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 238000002347 injection Methods 0.000 title claims abstract description 68
- 239000007924 injection Substances 0.000 title claims abstract description 68
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 title claims abstract description 67
- 229940084026 sodium valproate Drugs 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 239000003381 stabilizer Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008215 water for injection Substances 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 16
- RXDLGFMMQFNVLI-UHFFFAOYSA-N [Na].[Na].[Ca] Chemical group [Na].[Na].[Ca] RXDLGFMMQFNVLI-UHFFFAOYSA-N 0.000 claims description 13
- 239000013522 chelant Substances 0.000 claims description 13
- 239000003002 pH adjusting agent Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000005374 membrane filtration Methods 0.000 claims description 3
- 230000001954 sterilising effect Effects 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 238000011017 operating method Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 9
- 238000003860 storage Methods 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 229960001484 edetic acid Drugs 0.000 abstract 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 229960000604 valproic acid Drugs 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 7
- 239000012488 sample solution Substances 0.000 description 7
- 239000012086 standard solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 208000005809 status epilepticus Diseases 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010034759 Petit mal epilepsy Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000000803 paradoxical effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (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 |
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| 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 |
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