CN105640873A - Sodium valproate injection, preparation method and applications thereof - Google Patents
Sodium valproate injection, preparation method and applications thereof Download PDFInfo
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- CN105640873A CN105640873A CN201410736518.1A CN201410736518A CN105640873A CN 105640873 A CN105640873 A CN 105640873A CN 201410736518 A CN201410736518 A CN 201410736518A CN 105640873 A CN105640873 A CN 105640873A
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- Prior art keywords
- sodium valproate
- injection
- injection liquid
- sodium
- preparation
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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 99
- 239000007924 injection Substances 0.000 title claims abstract description 81
- 238000002347 injection Methods 0.000 title claims abstract description 81
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 title claims abstract description 77
- 229940084026 sodium valproate Drugs 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 18
- 239000008215 water for injection Substances 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005374 membrane filtration Methods 0.000 claims description 4
- 238000012856 packing Methods 0.000 claims description 4
- 230000001954 sterilising effect Effects 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 229960004249 sodium acetate Drugs 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 239000013589 supplement Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 4
- 230000007774 longterm Effects 0.000 abstract description 4
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- 210000004369 blood Anatomy 0.000 abstract description 2
- 239000008280 blood Substances 0.000 abstract description 2
- 239000003381 stabilizer Substances 0.000 abstract 2
- 230000002421 anti-septic effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 23
- 230000000052 comparative effect Effects 0.000 description 19
- 239000000047 product Substances 0.000 description 17
- 239000003814 drug Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 12
- 229960000604 valproic acid Drugs 0.000 description 12
- 238000012360 testing method Methods 0.000 description 10
- 230000008859 change Effects 0.000 description 8
- 239000012488 sample solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000001133 acceleration Effects 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 230000007794 irritation Effects 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 206010018910 Haemolysis Diseases 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
- 229940079593 drug Drugs 0.000 description 3
- 230000008588 hemolysis Effects 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 229940124277 aminobutyric acid Drugs 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 230000001037 epileptic effect Effects 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
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- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 206010021750 Infantile Spasms Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010034759 Petit mal epilepsy Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 208000003554 absence epilepsy Diseases 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
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- 229940121657 clinical drug Drugs 0.000 description 1
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- 208000013257 developmental and epileptic encephalopathy Diseases 0.000 description 1
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- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000008676 import Effects 0.000 description 1
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- 239000003978 infusion fluid Substances 0.000 description 1
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- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 208000028492 myoclonic seizure Diseases 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000000803 paradoxical effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 150000004965 peroxy acids Chemical class 0.000 description 1
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- 231100000572 poisoning Toxicity 0.000 description 1
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- -1 polyoxyethylene Polymers 0.000 description 1
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- 239000011734 sodium Substances 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
- 238000001228 spectrum Methods 0.000 description 1
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- 229940102566 valproate Drugs 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a sodium valproate injection, which is prepared from sodium valproate (active component), a pH adjuster, and injection water, wherein the pH of the injection is 7.9 to 8.1. The invention also provides a preparation method of the injection. The provided sodium valproate injection does not contain any stabilizer or antiseptic, so the defect that in the prior art, the safety of auxiliary materials is uncontrollable in clinic is overcome, and thus the safety of injection is guaranteed. Moreover, the injection is nonirritant and is insoluble in blood, the clinical safety can be ensured, the manufacturing cost of the sodium valproate injection is low, and the safety is excellent. Compared with sodium valproate injections, which contains or does not contain a stabilizing agent and is in other pH range, the experiment data of six month accelerated stability and twelve month long term stability of prepared sodium valproate injection is better.
Description
Technical field
The present invention relates to a kind of Sodium Valproate injection liquid.
Background technology
Sodium Valproate chemistry valproate by name, molecular formula: C8H15NaO2, molecular weight is 166.2, for white is without smelly pressed powder soluble in water, has extremely strong water absorbability. This product is white crystalline powder or particle, and slightly valproic acid is smelly, has and draws wet property, soluble in water, is soluble in ethanol, is almost insoluble to acetone. This product water absorbability is extremely strong, and after moisture absorption, weight increases. For improving its water absorbability, in Sodium Valproate, usually add a small amount of organic acid, make the two become mixture. PKa is the pH value of 4.6,5% aqueous solution is 7.5��9.0.
On clinical, Sodium Valproate belongs to anti-epileptic class medicine, has anti-epilepsy spectrum widely, can be used for treatment petit mal epilepsy, myoclonic seizure, general outbreak, componental movement outbreak, absence outbreak and infantile spasm etc. Its mechanism of action is relevant with suppression Voltage Sensitive Na Channels, and it increases the ��-aminobutyric acid in brain build up by suppressing ��-aminobutyric acid metabolism, reaches the effect suppressing focus neurone over-discharge can 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 liquid, syrup and injection, but the emergency treatment for the prevention of average of operation periods epilepsy, epileptic state or epileptic episodes, being merely able to give patient administration in the way of injecting, therefore injection type plays irreplaceable effect.
Owing to injection just directly enters blood circulation without the first pass effect of liver, therefore must carry out strictly monitoring for its steadiness, otherwise not only can affect drug effect, also can bring danger to patient, cause malpractice. In the stability study of injection articles for use, its impurity and about substances content to injection articles for use safety play a part most important, the side reaction overwhelming majority of the appearance in medicine is all that other except main medicine contained by it has related substance to cause, therefore quality and the safety of medicine is ensured, it is necessary to carry out strictly controlling to the related substance that has in medicine.
And for Sodium Valproate, due to Sodium Valproate very easily moisture absorption in the process of storage and transport, causing main medicine to be degraded, impurity increases, so the stability problem of its formulation products is particularly outstanding.
Due to the less stable of existing Sodium Valproate injection, therefore in preparation process, prior art all can add all kinds of stablizer to keep the stability of preparation, and the stablizer that prior art uses is mostly the sanitas such as metallo-chelate or sorbyl alcohol, but the introducing of these materials, excipient substance can be increased on the one hand and enter the uncontrollable of security after human body, cause a series of side effects such as blood in human body in calcium minimizing; On the other hand, the stablizer that prior art uses, particularly metallo-chelate class, its price is very expensive, considerably increases the manufacturing cost of preparation, adds medicine valency.
Also just owing to adding the above-mentioned defect of the prescription of stablizer, result in current domestic market still based on tablet, freeze-dried powder, and injection still needs import, the price of its costliness also brings heavy burden to patient, causes very many patients to be treated in time.
Through retrieval, we find that the prescription of existing Sodium Valproate injection all with the addition of stablizer in varying degrees, and only " Shanghai medicine ", 12 phase 21-23 pages " discussion of Sodium Valproate stability of Oral " in 1993 and these two sections of documents of CN102421428A mention that prescription is the sodium valproate solution of Sodium Valproate, water for injection, pH adjusting agent. Wherein first section of document disclosure is oral liquid, and its content being only Sodium Valproate investigated, and the safety and stability for valproic acid injection prescription does not have reference significance; The Sodium Valproate injection liquid mentioned in 2nd section of document only stops at the pharmacological research of animal body, not for human body, does not relate to for stability during human body, safety issue.
Therefore, develop a kind of low cost of manufacture, stability, the satisfactory Sodium Valproate injection liquid of security have very important significance.
Summary of the invention
It is an object of the invention to provide a kind of low cost of manufacture, the satisfactory Sodium Valproate injection liquid of stability and its preparation method.
Concrete, Sodium Valproate injection liquid provided by the invention, it is prepared from by activeconstituents Sodium Valproate, pH adjusting agent and water for injection, wherein pH=7.9��8.1.
Further, it may also be useful to pH adjusting agent be: one or more the combination in hydrochloric acid, lactic acid, sodium hydroxide, sodium-acetate, dipotassium hydrogen phosphate, Sodium phosphate dibasic.
Wherein, in injection liquid of the present invention, Sodium Valproate concentration is 10��600mg/ml.
Further, in injection liquid, Sodium Valproate concentration is 11.5��460mg/ml.
Further, in injection liquid, Sodium Valproate concentration is 11.5��115mg/ml. Although the present invention calculates injection liquid effective constituent concentration with Sodium Valproate, but, if Sodium Valproate concentration conversion is become valproic acid concentration, the present invention also can be realized.
Present invention also offers the preparation method of above-mentioned Sodium Valproate injection liquid, it comprises following operation steps:
PH value regulator water for injection is dissolved, adds Sodium Valproate, dissolve and stir evenly, supplement pH value regulator/water for injection, adjust ph and the injection water yield, add 0.1% needle-use activated carbon, and filtrate is with 0.22 ��m of membrane filtration, by gained liquid packing, pressure sterilizing, to obtain final product.
The inventive method passes through the control of the pH value to injection liquid, when not adding other stablizer, it is also possible to ensure the security of its Clinical practice.
In general, the pH value of injection liquid all controls between 3��10, can not cross alkali or peracid, otherwise can cause perverse sharp pain and the necrosis of local organization, especially for a large amount of intravenous fluid, it is desired to more strict, otherwise has the danger causing soda acid poisoning.
But in the Sodium Valproate injection liquid of existing technique, the unspecial research for injection liquid pH value is reported, find after our a large amount of experiments, when controlling when optional network specific digit by the pH value of Sodium Valproate, do not add the Sodium Valproate injection liquid that other stablizers also can obtain steady quality, safety.
Concrete, the useful effect of the present invention is as follows:
1, the Sodium Valproate injection liquid of the present invention is without the need to adding stablizer or sanitas, overcomes the uncontrollable defect of the clinical drug safety of auxiliary material in prior art, and the Sodium Valproate injection liquid prepared by the inventive method ensure that the security of quality.
2, the Sodium Valproate injection liquid nonirritant of the present invention and hemolytic, ensure that the security of Clinical practice.
3, the Sodium Valproate injection liquid low cost of manufacture of the present invention. The Sodium Valproate injection formula of the present invention forms simple, only activeconstituents Sodium Valproate, water for injection, pH adjusting agent. Therefore, the manufacturing cost of the Sodium Valproate injection liquid become by formula preparation of the present invention is significantly less than prior art, it is possible to significantly reduce medicine valency.
4, the Sodium Valproate injection liquid stability of the present invention, excellent in safety. Although the inventive method does not add stablizer or sanitas in addition, but by the present invention for the control of the pH value of injection formula, and the control of technical process in injection liquid preparation process can prepare the satisfactory Sodium Valproate injection liquid of stability. 6 months accelerated stabilities and 12 months long-term stable experiment data of the Sodium Valproate injection liquid prepared by the inventive method all are better than with the addition of the Sodium Valproate injection liquid of other pH value range that are stable and that do not add stablizer.
Below by way of embodiment, 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, as long as not departing from the spirit of the present invention, all should belong to the scope of claims of the present invention.
Embodiment
Relevant substance-measuring method
Adopt vapor-phase chromatography, chromatographic condition: taking polyoxyethylene glycol (PEG-20M) as the capillary chromatographic column of stationary liquid; Starting temperature is 130 DEG C, maintains 20 minutes, then with every minute ramp to 200 DEG C of 5 DEG C, maintains 15 minutes; Injector temperature is 220 DEG C; Detector temperature is 220 DEG C.
Sample solution: get injection liquid appropriate, dissolves with methylene dichloride after steaming is dry and dilutes the solution made containing valproic acid 5mg/ml.
Get 2 phenylethyl alcohol 20mg, put in 25ml measuring bottle, add sample solution 1ml, be diluted to scale with methylene dichloride, shake even, as system suitability solution.
Getting system suitability solution 1 �� l, inject gas chromatograph, regulate detection sensitivity, the peak height making principal constituent chromatographic peak is the 20% of full range; By sample solution inject gas chromatograph, record color atlas, to 3 times of principal constituent peak retention time, calculates impurity peak area per-cent.
Content assaying method
By high performance liquid chromatography, chromatographic condition: chromatographic column is octyl group silane group unmodified packed column (C8, 4.6*150mm, 5 ��m); Determined wavelength: 215nm; Flow velocity: 1ml/min;Sample size: 20 �� l;
Solution is prepared:
Damping fluid: 3.5g/L sodium dihydrogen phosphate, adjusts pH to be 3.5 with phosphoric acid;
Moving phase: acetonitrile: damping fluid (45:55);
Diluent: acetonitrile: water (45:55);
System suitability solution: make containing solution about substance B reference substance 0.05mg/ml of valproic acid reference substance 0.5mg/ml and valproic acid by diluted;
Standardized solution: make the solution containing valproic acid reference substance 0.5mg/ml by diluted;
Sample solution: get injection liquid appropriate, makes the solution containing valproic acid 0.5mg/ml with water dilution.
System flexibility: precision measures system flexibility solution and standardized solution 20 �� l enters sample respectively, record color atlas. In system flexibility solution color atlas, it is not less than 2.0 (being respectively 0.90 and 1.0 about the relative retention time of substance B and valproic acid) about the resolution between substance B and valproic acid peak. In standardized solution color atlas, valproic acid peak tailing factor must not be greater than 1.5, and in continuous 6 pin standardized solution, valproic acid peak area RSD must not be greater than 1.0%.
Assay method: precision measures each 20 �� l of blank, standardized solution and sample solution, injection liquid chromatography, record color atlas, by external standard method with calculated by peak area, to obtain final product. Calculation formula is as follows:
Result=(rU/rS)��(CS/CU)��100
In formula, rUValproic acid peak area in=sample solution;
rSValproic acid peak area in=standardized solution;
CSValproic acid reference substance concentration in=standardized solution;
CUValproic acid concentration in=sample solution.
Embodiment 1
Prescription:
Regulate pH to 7.9;
Preparation method: pH value regulator water for injection is dissolved, add Sodium Valproate, dissolve and stir evenly, supplementing pH value regulator/water for injection, adjust ph and the injection water yield, add 0.1% needle-use activated carbon, filtrate is again with 0.22 ��m of membrane filtration, by gained liquid packing, pressure sterilizing, to obtain final product.
Embodiment 2
Prescription:
Regulate pH to 8.0;
Preparation method: with embodiment 1.
Embodiment 3
Prescription:
Regulate pH to 8.1;
Preparation method: with embodiment 1.
Embodiment 4
Prescription:
Regulate pH to 8.0;
Preparation method: with embodiment 1.
Embodiment 5
Prescription:
Regulate pH to 7.9;
Preparation method: with embodiment 1.
Embodiment 6
Prescription:
Regulate pH to 8.1;
Preparation method: with embodiment 1.
The useful effect of the present invention is described below by way of concrete stability test.
Comparative example 1
Prescription:
Regulate pH to 7.6;
Preparation method: with embodiment 1.
Comparative example 2
Prescription:
Regulate pH to 7.3;
Preparation method: with embodiment 1.
Comparative example 3
Prescription:
Regulate pH to 7.0;
Preparation method: with embodiment 1.
Comparative example 4
Prescription:
Regulate pH to 7.6;
Preparation method: add in water for injection by the EDTA-2Na of recipe quantity and Sodium Valproate, stirs, makes to dissolve completely, regulates solution ph to 7.6, then is settled to water for injection and enough is mixed with desired concn; Then adding needle-use activated carbon and stir 30 minutes, with 0.22 ��m of membrane filtration, by gained liquid packing, pressure sterilizing, to obtain final product.
Comparative example 5
Prescription:
Regulate pH to 8.3;
Preparation method: with embodiment 1.
Comparative example 6
Prescription:
Regulate pH to 7.2;
Preparation method: with embodiment 1.
Comparative example 7
Prescription:
Regulate pH to 7.8;
Preparation method: with embodiment 1.
Comparative example 8
Prescription:
Regulate pH to 8.5;
Preparation method: with embodiment 1.
Comparative example 9
Prescription:
Regulate pH to 9.0;
Preparation method: with embodiment 1.
Test example 1 accelerated stability is tested
Get in the embodiment of the present invention 1��7, comparative example 1��9 Sodium Valproate injection liquid and commercially available abroadInjection liquid (comparative example 4), temperature 40 DEG C �� 2 DEG C, place 6 months when relative humidity 75% �� 5%, sample respectively at 0,1,2,3 and 6 months, check its outward appearance, pH value, have the changing conditions of related substance and content, the results are shown in table 1.
Table 1 accelerated test result
Above-mentioned Sodium Valproate accelerated stability testing data can be found out, the Sodium Valproate injection liquid prepared by the inventive method is under high temperature, super-humid conditions, its appearance character is all colorless cleared solution, the pH value of solution does not almost change simultaneously, contrary, with the addition of the variation range of the pH value of the comparative example 4 of stablizer and it is greater than product of the present invention, and the pH value change not adding the injection liquid of other pH value range of stablizer is all greater than product of the present invention, on the other hand, Sodium Valproate injection liquid prepared by the inventive method is at high temperature, under super-humid conditions, not only it is extremely low about substances content, single assorted minimum only 0.01%, total assorted minimum only 0.02%, significantly lower than the drug standard for there being the content requirement of related substance (single assorted to be less than 0.1%, total mixing is less than 0.4%), and this product have related substance variable quantity in Acceleration study also very little, contrary, with the addition of the comparative example 4 of stablizer, not only on single assorted and total assorted content, exceed this product, and its variable quantity in Acceleration study is bigger, and the list not adding the injection liquid of other pH value range of stablizer is assorted and total assorted change is all greater than product of the present invention, finally, the Sodium Valproate injection liquid that the inventive method prepares almost does not reduce on effective ingredient content, and the active constituent content of comparative example has occurred comparatively significantly declining under acceleration conditions.
Test example 2, long-term stable experiment
Get in the embodiment of the present invention 1��6, comparative example 1��9 Sodium Valproate injection liquid and commercially available abroadInjection liquid (comparative example 4), temperature 25 DEG C �� 2 DEG C, place 12 months when relative humidity 60% �� 10%, sample respectively at 0,3,6,9 and 12 months, check its outward appearance, pH value, have the changing conditions of related substance and content, the results are shown in table 2.
Table 2 long-term test results
Above-mentioned Sodium Valproate accelerated stability testing data can be found out, the Sodium Valproate injection liquid prepared by the inventive method is under high temperature, super-humid conditions, its appearance character is all colorless cleared solution, the pH value of solution does not almost change simultaneously, contrary, with the addition of the variation range of the pH value of the comparative example 4 of stablizer and it is greater than product of the present invention, and the pH value change not adding the injection liquid of other pH value range of stablizer is all greater than product of the present invention, on the other hand, Sodium Valproate injection liquid prepared by the inventive method is at high temperature, under super-humid conditions, not only it is extremely low about substances content, single assorted minimum only 0.01%, total assorted minimum only 0.02%, significantly lower than the drug standard for there being the content requirement of related substance (single assorted to be less than 0.1%, total mixing is less than 0.4%), and this product have related substance variable quantity in Acceleration study also very little, contrary, with the addition of the comparative example 4 of stablizer, not only on single assorted and total assorted content, exceed this product, and its variable quantity in Acceleration study is bigger, and the list not adding the injection liquid of other pH value range of stablizer is assorted and total assorted change is all greater than product of the present invention,Finally, the Sodium Valproate injection liquid that the inventive method prepares almost does not reduce on effective ingredient content, and the active constituent content of comparative example has occurred comparatively significantly declining under acceleration conditions.
Test example 3, product local irritation and hemolysis in vitro test
Getting this product, according to requirement and the regulation of " drug registration management method ", Sodium Valproate injection liquid of the present invention has carried out local irritation, supersensitivity and hemolytic test, content of the test is as follows:
Local irritation is tested:
By the Sodium Valproate injection liquid of the present invention after rabbit auricular vein drug administration by injection, having no the irritation such as red and swollen, congested through observer's rabbit auricular vein local, pathological examination results is without sex change, necrosis and inflammatory reaction.
Hemolysis in vitro is tested:
The Sodium Valproate injection liquid of the present invention is observed to the hemolytic action of rabbit erythrocyte, result no matter visual inspection or rabbit erythrocyte is had haemolysis or causes agglutination by all non-part of sediments microscope inspection Sodium Valproate injection liquid of the present invention by external test tube method.
By the data of above-mentioned test example it may be seen that the Sodium Valproate injection liquid prepared by the inventive method is not when adding stablizer, also there is very excellent stability, even it is better than the product of existing interpolation stablizer. Owing to product of the present invention is without the need to adding expensive stablizer, it is possible to effectively reduce the production cost of medicine, ensure that the quality of medicine simultaneously.
Claims (6)
1. a Sodium Valproate injection liquid, it is characterised in that: it is prepared from by activeconstituents Sodium Valproate, pH adjusting agent and water for injection, wherein pH=7.9��8.1.
2. Sodium Valproate injection liquid according to claim 1, described pH adjusting agent is one or more the combination in hydrochloric acid, lactic acid, sodium hydroxide, sodium-acetate, dipotassium hydrogen phosphate, Sodium phosphate dibasic.
3. Sodium Valproate injection liquid according to claim 1, it is characterised in that: described Sodium Valproate concentration is 10��600mg/ml.
4. Sodium Valproate injection liquid according to claim 3, it is characterised in that: described Sodium Valproate concentration is 11.5��460mg/ml.
5. Sodium Valproate injection liquid according to claim 4, it is characterised in that: described Sodium Valproate concentration is 11.5��115mg/ml.
6. preparing a method for the Sodium Valproate injection liquid described in claim 1-5 any one, it comprises the steps:
PH value regulator water for injection is dissolved, adds Sodium Valproate, dissolve and stir evenly, supplement pH value regulator/water for injection, adjust ph and the injection water yield, add 0.1% needle-use activated carbon, and filtrate is with 0.22 ��m of membrane filtration, by gained liquid packing, pressure sterilizing, to obtain final product.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106138105A (en) * | 2016-08-09 | 2016-11-23 | 成都佳迪璐莎生物科技有限公司 | A kind of medicinal composition for injections improving Venenum apis drug injection preparation stability |
| CN110090207A (en) * | 2019-06-11 | 2019-08-06 | 苏州大学 | Application and its pharmaceutical composition of the sodium vedproate in the drug that preparation inhibits glial scar to be formed |
| CN110638801A (en) * | 2019-08-23 | 2020-01-03 | 四川科瑞德制药股份有限公司 | Injection medicine and preparation method thereof |
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| CN110090207A (en) * | 2019-06-11 | 2019-08-06 | 苏州大学 | Application and its pharmaceutical composition of the sodium vedproate in the drug that preparation inhibits glial scar to be formed |
| CN110638801A (en) * | 2019-08-23 | 2020-01-03 | 四川科瑞德制药股份有限公司 | Injection medicine and preparation method thereof |
| WO2021035655A1 (en) * | 2019-08-23 | 2021-03-04 | 四川科瑞德制药股份有限公司 | Medicine for injection and preparation method therefor |
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