CN107823128A - A kind of preparation method of Edaravone Injection - Google Patents
A kind of preparation method of Edaravone Injection Download PDFInfo
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- CN107823128A CN107823128A CN201711171654.0A CN201711171654A CN107823128A CN 107823128 A CN107823128 A CN 107823128A CN 201711171654 A CN201711171654 A CN 201711171654A CN 107823128 A CN107823128 A CN 107823128A
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- China
- Prior art keywords
- injection
- preparation
- solution
- edaravone
- water
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- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 title claims abstract description 109
- 229950009041 edaravone Drugs 0.000 title claims abstract description 109
- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- 238000002347 injection Methods 0.000 title claims abstract description 62
- 239000007924 injection Substances 0.000 title claims abstract description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 124
- 239000000243 solution Substances 0.000 claims abstract description 105
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 62
- 230000001954 sterilising effect Effects 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000002253 acid Substances 0.000 claims abstract description 27
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 230000008569 process Effects 0.000 claims abstract description 25
- 239000007788 liquid Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 85
- 239000008215 water for injection Substances 0.000 claims description 69
- 238000006392 deoxygenation reaction Methods 0.000 claims description 52
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 27
- 238000013329 compounding Methods 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 26
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical group [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 17
- 229940079827 sodium hydrogen sulfite Drugs 0.000 claims description 17
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 17
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 15
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 15
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 239000003963 antioxidant agent Substances 0.000 claims description 10
- 230000003078 antioxidant effect Effects 0.000 claims description 10
- 239000011521 glass Substances 0.000 claims description 10
- 239000007951 isotonicity adjuster Substances 0.000 claims description 10
- 239000003610 charcoal Substances 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000003643 water by type Substances 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims 1
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 5
- 230000006872 improvement Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 20
- 238000011049 filling Methods 0.000 description 16
- 238000011068 loading method Methods 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 9
- 238000004886 process control Methods 0.000 description 9
- 238000012546 transfer Methods 0.000 description 9
- 230000008859 change Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 208000006011 Stroke Diseases 0.000 description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000002490 cerebral effect Effects 0.000 description 4
- 238000002845 discoloration Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000003182 parenteral nutrition solution Substances 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 description 3
- -1 Edaravone Free radical Chemical class 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910000831 Steel Inorganic materials 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 229960002433 cysteine Drugs 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 206010008092 Cerebral artery thrombosis Diseases 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 206010019468 Hemiplegia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000009760 functional impairment Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000007731 hot pressing Methods 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229910021655 trace metal ion Inorganic materials 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to drug field, specifically, is related to a kind of preparation method of Edaravone Injection.The step of preparation method of the present invention is comprised at least with liquid, embedding and sterilizing, the process with liquid and embedding is carried out under nitrogen protection.In process for preparation, CYSTEAMINE HCL acid solution is first prepared, then Edaravone is added in CYSTEAMINE HCL acid solution.Improvement of the invention by the preparation method to Edaravone Injection and the accurate control to condition, the original for not only needing not changing Edaravone Injection grind prescription, moreover it is possible to further improve the stability of Edaravone Injection.
Description
Technical field
The present invention relates to drug field, specifically, is related to a kind of preparation method of Edaravone Injection.
Background technology
Cerebral arterial thrombosis (Ischemic cerebral stroke) is cerebral infarction, account for whole palsys 70%~
80%, brain blood caused by referring to a variety of causes supplies obstacle, causes brain tissue ischemia, Hypoxic necrosis, corresponding god occurs
Through functional impairment symptom.In China, cerebral apoplexy has become urban and urual areas of whole country's resident's primary cause of death, and the world's second largest is dead
Die reason.Cerebral apoplexy has the characteristics that high incidence, high disability rate, high case fatality rate and high concurrent disease incidence, seriously endangers people
Class health.In the patient of survival, only 10% or so can recover normal function completely, and most patients leave hemiplegia, lost
The sequelae such as language, serious burden is caused to society and family.
Edaravone (Edaravone) chemical name：3-methyl-1-phenyl-2-pyrazolin-5-one, structural formula are as follows：
Edaravone is a kind of cerebral protective agent (free radical scavenger), and N- acetyl L-aminobutanedioic acid (NAA) is prompted in clinical research
It is the mark of specific viable neuronal cell, cerebral infarction early stage content is drastically reduced.Acute period of cerebral infarction patient gives
Edaravone, the reduction of periinfarct local cerebral blood flow can be suppressed, make after morbidity in the 28th day brain NAA contents compared with glycerol control
Group is significantly raised.Preclinical study is prompted, and rat vein after ischemia-reperfusion gives Edaravone, can prevent encephaledema and brain
The progress of infraction, and alleviate adjoint nervous symptoms, suppress delayed neuronal death.Study mechanism is prompted, Edaravone
Free radical, anti-lipid peroxidation, so as to suppress the oxidative damage of brain cell, vascular endothelial cell, nerve cell can be removed.From
And the effect of with preferably treatment cerebral apoplexy.Also, Edaravone Injection can be additionally used in ALS (ALS)
Treatment.
The patent of Application No. 201010216022.3 discloses a kind of Edaravone Injection, makees phosphoric acid in parenteral solution
For cosolvent, to expect in the dissolubility that Edaravone is improved using phosphoric acid solution so as to improve the stabilization of Edaravone Injection
Property.However, needing to add substantial amounts of phosphoric acid in the preparation of the patent, then pH value is adjusted by alkaline matter, generate a large amount of phosphorus
Hydrochlorate accessory substance, its security is both needed to further verify with curative effect, and the stability of Edaravone Injection still has much room for improvement.
The patent of Application No. 201110086709.4 disclose a kind of pharmaceutical composition containing edaravone compound and
Its preparation method, by the way that first Edaravone is dissolved in appropriate ethanol, and finally it will contain whole main ingredients and auxiliary material with hydrochloric acid
The pH value of solution adjust to 3.7, to expect in the stability for improving Edaravone Injection.However, only disclosed in the patent
Using appropriate ethanol dissolving Edaravone, the dosage of ethanol is not controlled, therefore is prepared using the patented method
Obtained preparation has certain potential safety hazard, and is not suitable for clinical practice.
In consideration of it, special propose the present invention.
The content of the invention
The present invention goal of the invention be to propose a kind of preparation method of Edaravone Injection, do not change Yi Dala not only
The original for giving parenteral solution grinds prescription, and further improves the stability of Edaravone Injection.
In order to complete the purpose of the present invention, the technical scheme that uses for：
The present invention proposes a kind of preparation method of Edaravone Injection, and the preparation method is comprised at least with liquid, embedding
It is the step of with sterilizing, described to be carried out under nitrogen protection with liquid and the process of the embedding, it is described to be injected with liquid using deoxygenation
Prepared with water；
It is described with liquid include concentrated compounding and it is dilute match somebody with somebody two steps, the concentrated compounding comprises at least following steps：
(1) 90 DEG C~100 DEG C of deoxygenation water for injection is being added with container 1, after being cooled to 50 DEG C~80 DEG C at addition
The isotonic agent just measured；By the cysteine hydrochloride of recipe quantity with 50 DEG C~80 DEG C of the deoxygenation injection in container 2
Water dissolves, and obtains CYSTEAMINE HCL acid solution, the Edaravone of recipe quantity then is added into the CYSTEAMINE HCL acid solution
In, obtain solution I；
(2) by solution I be added to it is described match somebody with somebody in container 1, stir 10min~60min；
(3) it is the antioxidant addition of recipe quantity is described with container 1, obtain solution II；
(4) activated carbon is added to solution II, stirring, takes off charcoal.
Optionally, the pressure of nitrogen is not less than 0.02Mpa during the concentrated compounding, it is described it is dilute match somebody with somebody during nitrogen
Pressure is not less than 0.01Mpa and is not more than 0.02Mpa, and the pressure of nitrogen is not less than 0.2Mpa during the embedding.
Optionally, after the deoxygenation water for injection dissolving is respectively adopted in the isotonic agent and the antioxidant, add
Match somebody with somebody to described in container 1；
Preferably, the preparation method of the deoxygenation water for injection is：90 DEG C~100 DEG C waters for injection are placed in container,
Vacuumize while stirring, then pass to nitrogen, produce；It is furthermore preferred that the pressure of nitrogen is not less than 0.02Mpa.
Optionally, in step (1), the concentration of the CYSTEAMINE HCL acid solution is 24mg/ml~36mg/ml, preferably
For 28mg/ml~32mg/ml；
Preferably, described with container 2 is glass container.
Optionally, in step (1), water for injection recipe quantity is being accounted for the deoxygenation water for injection that container 1 adds
60%~80%.
Optionally, in step (4), the ratio of 0.005g~0.05g activated carbons is added according to every 100ml solution, to
Activated carbon is added in the solution II, is stirred under the conditions of 30 DEG C~50 DEG C, is filtered after being incubated 15min~60min；
Preferably, after activated carbon is first soaked using deoxygenation water for injection, it is then added in the solution II.
Optionally, it is described dilute with comprising at least：The deoxygenation water for injection is added to recipe quantity, obtains solution III；By institute
State solution III and be cooled to 24 DEG C~36 DEG C, preferably 28 DEG C~32 DEG C；The pH value for adjusting the solution III is 4.0~4.6；
Preferably, it is described dilute to fit over being carried out in container 3.
Optionally, the cooling is completed in 10min~30min, is 10%~20% hydrogen-oxygen with mass percent concentration
Change the pH value that sodium solution or mass percent concentration adjust the solution III for 10%~20% phosphoric acid solution.
Optionally, the condition of the sterilizing is that 15min~18min is incubated under the conditions of 121.0 DEG C, in 15min~30min
It is interior to complete heating, and cooling is completed in 15min~30min.
Optionally, the isotonic agent is selected from sodium chloride, and the antioxidant is selected from sodium hydrogensulfite；
Preferably, the recipe quantity of each raw material is in the Edaravone Injection：Edaravone 15mg~30.0mg, chlorination
Sodium 67.5mg~135mg, sodium hydrogensulfite 10mg~20mg, cysteine hydrochloride 5mg~10mg, water for injection 10ml~20ml
And sodium hydroxide and appropriate phosphoric acid；
It is furthermore preferred that the recipe quantity of each raw material is in the Edaravone Injection：Edaravone 30.0mg, sodium chloride
135mg, sodium hydrogensulfite 20mg, cysteine hydrochloride 10mg, 10~20ml of water for injection and sodium hydroxide and appropriate phosphoric acid.
Technique effect that technical scheme can reach at least that：
The present invention is not only needed by the improvement of the preparation method to Edaravone Injection and the accurate control of condition
The original for not changing Edaravone Injection grinds prescription, moreover it is possible to further improves the stability of Edaravone Injection.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.
The embodiment of the present invention proposes a kind of preparation method of Edaravone Injection, does not change Edaravone Injection not only
Original grind prescription, and further improve the stability of Edaravone Injection.
At present, many research is expanded for Edaravone preparation, such as develops novel form, such as lyophilized formulations, fat
Matter drug delivery system etc.；Or optimization formulation, it is mainly reflected in optimize adjustment on the basis of the prescription of former triturate, such as
Change dosage of sodium hydrogensulfite and L-cysteine hydrochloride etc., and directly change the composition species of prescription.However, mostly
The preparation technology of novel formulation is complex, and big manufacturing feasibility is relatively low, and difficulty is larger, and therapeutic effect needs further
Checking.Also, change prescription may make the physical and chemical quality of medicine obtain appropriate improvement, but relative to the original place used for a long time
For square preparation, also it is both needed to further verify with curative effect in the presence of certain potential safety hazard, its security.However, due to Yi Dala
It is bad and be easy to aoxidize to give dissolubility, the stability for the Edaravone Injection that existing preparation method is prepared is bad.
The present invention researchs and develops a kind of preparation method of brand-new Edaravone Injection, need not only changed by studying with keen determination
The original for becoming Edaravone Injection grinds prescription, can also further improve the stability of Edaravone Injection.
It is described in detail below by the Edaravone Injection for the embodiment of the present invention.
The recipe quantity that the original of Edaravone Injection grinds each raw material in prescription is：
Edaravone 15mg~30.0mg, isotonic agent 67.5mg~135mg, antioxidant 10mg~20mg, the Guang of hydrochloric acid half
Propylhomoserin 5mg~10mg, water for injection 10ml~20ml and sodium hydroxide and appropriate phosphoric acid；Wherein, isotonic agent is selected from sodium chloride,
Antioxidant is selected from sodium hydrogensulfite.
Further alternative, the recipe quantity that the original of Edaravone Injection grinds each raw material in prescription is as shown in table 1：
Table 1
It should be noted that the preparation method of the Edaravone Injection of the embodiment of the present invention is directed to not adding other
Additive (such as cosolvent, antioxidant and stabilizer etc.) changes composition (increase cysteine hydrochloride dosage, increasing
Phosphorate sour dosage etc.) on the basis of further improve the stability of Edaravone Injection, but the Edaravone of other prescriptions
Parenteral solution can use the preparation method of the present invention to be prepared.
The step of preparation method of the embodiment of the present application is comprised at least with liquid, embedding and sterilizing, wherein, with liquid and embedding
Process is carried out under nitrogen protection.Because edaravone raw material medicine is oxidizable, so being filled in preparation and pouring process whole process
Nitrogen protection is lower to be carried out.
Further alternative, nitrogen pressure is not less than 0.02Mpa during concentrated compounding, it is dilute match somebody with somebody during nitrogen pressure not
Less than 0.01Mpa and it is not more than 0.02Mpa, nitrogen pressure is not less than 0.2Mpa during embedding.In order to ensure the steady of equipment
Qualitative, 0.5Mpa is not to be exceeded in nitrogen pressure maximum.The present invention it has been investigated that, in the pressure of different technical process inflated with nitrogen
Carry out the control of differentiation, can more efficiently improve the stability of preparation, for example, it is dilute with Stress control be not less than
0.01Mpa and it is not more than 0.02Mpa, it is ensured that the amount of sodium hydrogensulfite, preferable antioxygen is played in placement process and is turned into
With so as to ensure that the long term quality of sample is stable.This is due to that sodium hydrogensulfite can be decomposed into sulfur dioxide in the solution, if nitrogen
It is excessive that pressure is swept in air-blowing, sulfur dioxide can be caused to lose, so as to cause sodium hydrogensulfite further to decompose, thus caused in solution
The content of sodium hydrogensulfite is reduced.
The embodiment of the present invention with liquid process using concentrated compounding and it is dilute match somebody with somebody two steps and prepared, this is because, in concentrated compounding
During carry out activated carbon absorption, to reduce the loss of Edaravone.
Concentrated compounding refers to first be completely dissolved active material and auxiliary material using a part for water for injection recipe quantity, Ran Houzai
It is dilute match somebody with somebody during supply whole recipe quantities of water for injection.The embodiment of the present invention uses deoxygenation water for injection with liquid process,
The purpose is to reduce the oxygen entered in preparation system, the oxidation of Edaravone is further avoided.Specifically, deoxygenation water for injection
Preparation method be：Water for injection is placed in container, vacuumized while stirring, then passes to nitrogen, is produced.Wherein, nitrogen
Pressure is nor less than 0.02Mpa.
Still more preferably, before isotonic agent and antioxidant are then added to preparation system, respectively injected using deoxygenation
After being dissolved with water, it is then added in preparation system.So as to avoid during medicament powder is added, by micro oxygen
It is incorporated into preparation system.
Specifically, match somebody with somebody container 1 used by concentrated compounding to be provided with vacuum extractor and being passed through the concentrated compounding of nitrogen device
Tank, concentrated compounding comprise at least following steps：
(1) 90 DEG C~100 DEG C of deoxygenation water for injection is added in dense preparing tank, wherein, it can be directly added into by deoxygenation
The water for injection of reason, normal injection can be also added with carrying out deoxygenation processing after water directly in dense preparing tank again；Be cooled to 50 DEG C~
The isotonic agent of recipe quantity, i.e. sodium chloride are added after 80 DEG C, obtains sodium chloride solution；
The cysteine hydrochloride of recipe quantity is dissolved with 50 DEG C~80 DEG C of deoxygenation water for injection in container 2, obtained
To CYSTEAMINE HCL acid solution, then the Edaravone of recipe quantity is added in CYSTEAMINE HCL acid solution, obtains solution I；
Edaravone now soaks in solution I, can not be completely dissolved, the purpose is to using have simultaneously tool help solubilization and
The CYSTEAMINE HCL acid solution of antioxidation protects Edaravone, not only avoid Edaravone in process for preparation
Be oxidized, the dissolving of Edaravone can also be promoted, accelerate the dissolution velocity of Edaravone, further avoid Edaravone with
It is oxidized during system.Also, the embodiment of the present invention finds that 50 DEG C~80 DEG C of CYSTEAMINE HCL acid solution is not only by research
Solution efficacy can be significantly improved, can also prevent temperature is too high to increase impurity phenylhydrazine, so as to can at least make Edaravone
It is completely dissolved in 60min.
(2) solution I is added to in container 1, stirs 10min~60min, be completely dissolved Edaravone, significantly
The dissolution time of Edaravone is shortened, makes Edaravone is not oxidized in course of dissolution to add a guarantee.
(3) sodium hydrogensulfite of recipe quantity is added and matched somebody with somebody in container 1, obtain solution II；
(4) activated carbon is added to solution II, stirring, takes off charcoal.
Match somebody with somebody accurate control of the liquid mode to dissolving order, temperature, time and pressure by above-mentioned in the embodiment of the present invention, it is complete
Oxidation of the Edaravone in course of dissolution is avoided entirely, the dissolution time of Edaravone is significantly shorten, so as to significantly reduce
The content of impurity in Edaravone Injection, improve the quality of preparation.
One kind as preparation method of the embodiment of the present invention is improved, in step (1), the concentration of CYSTEAMINE HCL acid solution
For 24mg/ml~36mg/ml, preferably 28mg/ml~32mg/ml, most preferably 30mg/ml.Under the concentration conditions, most have
Beneficial to the protection formed to Edaravone.
One kind as preparation method of the embodiment of the present invention changes, and is glass container with container 2 in step (1).It is actual
The container of the conventional stainless steel of production, such as stainless steel cask or stainless cylinder of steel, Edaravone is dissolved, but the present invention is in research process
Pleasantly surprised discovery, using glass material compounding high concentration Edaravone is used, the impurity in parenteral solution can be reduced.This be probably by
In the reason for the Edaravone of high concentration is contacted with stainless steel wall, reacted with the trace metal ion of stainless steel.
One kind as preparation method of the embodiment of the present invention is improved, in step (1), in the deoxygenation added with container 1
Water for injection accounts for the 60%~80% of water for injection recipe quantity, even if being carried out with 60%~80% water for injection of recipe quantity dense
Match somebody with somebody.The present invention has found that, if the ratio of water for injection is too small during concentrated compounding, one is detrimental to the dissolving of Edaravone under study for action；
Second, the concentration for the solution II being prepared is excessive, and when carrying out charcoal absorption, the amount increase of charcoal absorption Edaravone.
One kind as preparation method of the embodiment of the present invention is improved, and in step (4), is added according to every 100ml solution
The ratio of 0.005g~0.05g activated carbons, activated carbon is added into the solution II, stirred under the conditions of 30 DEG C~50 DEG C, protected
Filtered after warm 15min~60min.The present invention has found under study for action, if temperature is too high, the amount of charcoal absorption Edaravone increases
Add, so temperature when controlling absorption is 30 DEG C~50 DEG C.
One kind as preparation method of the embodiment of the present invention is improved, dilute to fit over container 3, i.e., dilute with being carried out in filling, and is walked
Suddenly comprise at least：Mend first and inject water to recipe quantity, obtain solution III；Solution III is cooled to 24 DEG C~36 DEG C, it is excellent
Elect 28 DEG C~32 DEG C, most preferably 30 DEG C as；The pH value for adjusting solution III is 4.0~4.6.The present invention is carried out again after cooling
PH value is adjusted, advantageously with accurate control ph.Also, because sterilization process can bring trickle change to the pH value of preparation
Change, in order that the pH value of preparation is more accurate, the embodiment of the present invention before sterilization by the pH value control of solution III 4.0~
4.6, it is ensured that the pH value of the preparation after sterilizing is between 3.8~4.5, under the pH value condition, Edaravone Injection matter
Amount is more stable.
Still more preferably, in order to be further ensured that the stability of Edaravone, control cooling of the embodiment of the present invention exists
Completed in 10min~30min.
The pH value regulator of the embodiment of the present invention uses phosphoric acid solution or sodium hydroxide solution, further alternative, hydrogen-oxygen
The mass percent concentration for changing sodium solution is 10%~20%, and the mass percent concentration of phosphoric acid solution is 10%~20%.
One kind as preparation method of the embodiment of the present invention is improved, and the condition of sterilizing is to be incubated under the conditions of 121.0 DEG C
15min~18min.If high temperature hold time is longer, impurity phenylhydrazine can be made, such as dimer increases, therefore, the present invention
Above-mentioned sterilising conditions are selected.Also, in order to be further ensured that the stability of Edaravone, the strict control liter in sterilization process
Temperature fall time, temperature-rise period control are completed in 15min~30min, and temperature-fall period is also controlled and completed in 15min~30min.
To sum up, the embodiment of the present invention passes through the improvement of the preparation method to Edaravone Injection and the accurate control of condition
System, the original for not only needing not changing Edaravone Injection grind prescription, moreover it is possible to further improve the stabilization of Edaravone Injection
Property.
Embodiment 1
Original according to the Edaravone Injection in above-mentioned table 1 grinds prescription and prepares Edaravone Injection.Preparation method is：
1st, concentrated compounding
1.1 prepare deoxygenation water for injection：90 DEG C~100 DEG C of water for injection is placed in container, vacuumized while stirring,
Nitrogen is then passed to, the pressure of nitrogen is 0.02Mpa.
90 DEG C~100 DEG C of deoxygenation water for injection is added in dense preparing tank, the amount for adding deoxygenation water for injection is prescription
The 80% of amount；By deoxygenation water for injection greenhouse cooling to 60 DEG C, the sodium chloride being pre-dissolved using deoxygenation water for injection is added；In glass
The cysteine hydrochloride of recipe quantity is pre-dissolved with 60 DEG C of deoxygenation water for injection in container, the concentration of CYSTEAMINE HCL acid solution is
30mg/ml；The Edaravone of recipe quantity is added in CYSTEAMINE HCL acid solution again, is soaked, obtains solution I.
1.2 are added to solution I in dense preparing tank, stir 60min, are completely dissolved Edaravone.
1.3 add the sodium hydrogensulfite for the recipe quantity being pre-dissolved in dense preparing tank, obtain solution II.
1.4 add the ratio of 0.01g activated carbons according to every 100ml solution, and activated carbon is added into the solution II,
Stir under the conditions of 40 DEG C, filtered after being incubated 40min.
During whole concentrated compounding, it is 0.02Mpa that whole process, which maintains the pressure of nitrogen,.
2nd, it is dilute to match somebody with somebody
Dilute preparing tank vacuumizes, more than nitrogen charging 5min, and the pressure for maintaining nitrogen is 0.01Mpa, treats that concentrated compounding decoction all shifts
After into dilute dispensing container, wash dense preparing tank with injection pond and transfer to dilute preparing tank, mend and inject water in dilute dispensing container
Full dose, open agitator stirring and be cooled to 30 DEG C；Cooling is completed in 30min；With 20% sodium hydroxide solution or 20% phosphoric acid
Solution adjusts pH value to 4.0~4.6.
3rd, embedding
Filling head is eluted with the water for injection filtered through 0.2 μm of filter, to visible foreign matters are detected, is stopped after qualified, regulation
Bottle placer loading amount, it is 20.60 ± 0.20ml branch to make loading amount.After head washing water visible foreign matters detection to be filled is qualified, lead to nitrogen exhaust 5
More than minute, transfer decoction is to filling.Front and rear nitrogen charging gas shielded when filling.Nitrogen pressure is not less than 0.2Mpa.
4th, sterilize
The good ampoule sabot of embedding is sent to sterilization process, sterilising conditions：121.0℃、15.0min.Final sterilization FO
Value should be greater than 12, and sterilization time process control needs 15min, decoction should be without discolorations.The whole sterilization process control heating-up time with
Temperature fall time, heating-up time control are completed in 30min, and temperature fall time control is completed in 30min.
Embodiment 2
Original according to the Edaravone Injection in above-mentioned table 1 grinds prescription and prepares Edaravone Injection.Preparation method is：
1st, concentrated compounding
1.1 prepare deoxygenation water for injection：90 DEG C~100 DEG C of water for injection is placed in container, vacuumized while stirring,
Nitrogen is then passed to, the pressure of nitrogen is 0.02Mpa.
90 DEG C~100 DEG C of deoxygenation water for injection is added in dense preparing tank, the amount for adding deoxygenation water for injection is prescription
The 70% of amount；By deoxygenation water for injection greenhouse cooling to 80 DEG C, the sodium chloride being pre-dissolved using deoxygenation water for injection is added；In glass
The cysteine hydrochloride of recipe quantity is pre-dissolved with 80 DEG C of deoxygenation water for injection in container, the concentration of CYSTEAMINE HCL acid solution is
32mg/ml；The Edaravone of recipe quantity is added in CYSTEAMINE HCL acid solution again, is soaked, obtains solution I.
1.2 are added to solution I in dense preparing tank, stir 50min, are completely dissolved Edaravone.
1.3 add the sodium hydrogensulfite for the recipe quantity being pre-dissolved in dense preparing tank, obtain solution II.
1.4 add the ratio of 0.02g activated carbons according to every 100ml solution, and activated carbon is added into the solution II,
Stir under the conditions of 50 DEG C, filtered after being incubated 30min.
During whole concentrated compounding, it is 0.02Mpa that whole process, which maintains the pressure of nitrogen,.
2nd, it is dilute to match somebody with somebody
Dilute preparing tank vacuumizes, more than nitrogen charging 5min, and the pressure for maintaining nitrogen is 0.01Mpa, treats that concentrated compounding decoction all shifts
After into dilute dispensing container, wash dense preparing tank with injection pond and transfer to dilute preparing tank, mend and inject water in dilute dispensing container
Full dose, open agitator stirring and be cooled to 28 DEG C；Cooling is completed in 30min；With 20% sodium hydroxide solution or 20% phosphoric acid
Solution adjusts pH value to 4.0~4.6.
3rd, embedding
Filling head is eluted with the water for injection filtered through 0.2 μm of filter, to visible foreign matters are detected, is stopped after qualified, regulation
Bottle placer loading amount, it is 20.60 ± 0.20ml branch to make loading amount.After head washing water visible foreign matters detection to be filled is qualified, lead to nitrogen exhaust 5
More than minute, transfer decoction is to filling.Front and rear nitrogen charging gas shielded when filling.Nitrogen pressure is not less than 0.2Mpa.
4th, sterilize
The good ampoule sabot of embedding is sent to sterilization process, sterilising conditions：121.0℃、15.0min.Final sterilization F0
Value should be greater than 12, and sterilization time process control needs 15min, decoction should be without discolorations.The whole sterilization process control heating-up time with
Temperature fall time, heating-up time control are completed in 30min, and temperature fall time control is completed in 25min.
Embodiment 3
Original according to the Edaravone Injection in above-mentioned table 1 grinds prescription and prepares Edaravone Injection.Preparation method is：
1st, concentrated compounding
1.1 prepare deoxygenation water for injection：90 DEG C~100 DEG C of water for injection is placed in container, vacuumized while stirring,
Nitrogen is then passed to, the pressure of nitrogen is 0.02Mpa.
90 DEG C~100 DEG C of deoxygenation water for injection is added in dense preparing tank, the amount for adding deoxygenation water for injection is prescription
The 60% of amount；By deoxygenation water for injection greenhouse cooling to 50 DEG C, the sodium chloride being pre-dissolved using deoxygenation water for injection is added；In glass
The cysteine hydrochloride of recipe quantity is pre-dissolved with 50 DEG C of deoxygenation water for injection in container, the concentration of CYSTEAMINE HCL acid solution is
25mg/ml；The Edaravone of recipe quantity is added in CYSTEAMINE HCL acid solution again, is soaked, obtains solution I.
1.2 are added to solution I in dense preparing tank, stir 60min, are completely dissolved Edaravone.
1.3 add the sodium hydrogensulfite for the recipe quantity being pre-dissolved in dense preparing tank, obtain solution II.
1.4 add the ratio of 0.01g activated carbons according to every 100ml solution, and activated carbon is added into the solution II,
Stir under the conditions of 50 DEG C, filtered after being incubated 30min.
During whole concentrated compounding, it is 0.02Mpa that whole process, which maintains the pressure of nitrogen,.
2nd, it is dilute to match somebody with somebody
Dilute preparing tank vacuumizes, more than nitrogen charging 5min, and the pressure for maintaining nitrogen is 0.01Mpa, treats that concentrated compounding decoction all shifts
After into dilute dispensing container, wash dense preparing tank with injection pond and transfer to dilute preparing tank, mend and inject water in dilute dispensing container
Full dose, open agitator stirring and be cooled to 32 DEG C；Cooling is completed in 20min；With 20% sodium hydroxide solution or 20% phosphoric acid
Solution adjusts pH value to 4.0~4.6.
3rd, embedding
Filling head is eluted with the water for injection filtered through 0.2 μm of filter, to visible foreign matters are detected, is stopped after qualified, regulation
Bottle placer loading amount, it is 20.60 ± 0.20ml branch to make loading amount.After head washing water visible foreign matters detection to be filled is qualified, lead to nitrogen exhaust 5
More than minute, transfer decoction is to filling.Front and rear nitrogen charging gas shielded when filling.Nitrogen pressure is not less than 0.2Mpa.
4th, sterilize
The good ampoule sabot of embedding is sent to sterilization process, sterilising conditions：121.0℃、15.0min.Final sterilization F0
Value should be greater than 12, and sterilization time process control needs 15min, decoction should be without discolorations.The whole sterilization process control heating-up time with
Temperature fall time, heating-up time control are completed in 20min, and temperature fall time control is completed in 25min.
Embodiment 4
Original according to the Edaravone Injection in above-mentioned table 1 grinds prescription and prepares Edaravone Injection.Preparation method is：
1st, concentrated compounding
1.1 prepare deoxygenation water for injection：90 DEG C~100 DEG C of water for injection is placed in container, vacuumized while stirring,
Nitrogen is then passed to, the pressure of nitrogen is 0.02Mpa.
90 DEG C~100 DEG C of deoxygenation water for injection is added in dense preparing tank, the amount for adding deoxygenation water for injection is prescription
The 75% of amount；By deoxygenation water for injection greenhouse cooling to 70 DEG C, the sodium chloride being pre-dissolved using deoxygenation water for injection is added；In glass
The cysteine hydrochloride of recipe quantity is pre-dissolved with 70 DEG C of deoxygenation water for injection in container, the concentration of CYSTEAMINE HCL acid solution is
30mg/ml；The Edaravone of recipe quantity is added in CYSTEAMINE HCL acid solution again, is soaked, obtains solution I.
1.2 are added to solution I in dense preparing tank, stir 30min, are completely dissolved Edaravone.
1.3 add the sodium hydrogensulfite for the recipe quantity being pre-dissolved in dense preparing tank, obtain solution II.
1.4 add the ratio of 0.01g activated carbons according to every 100ml solution, and activated carbon is added into the solution II,
Stir under the conditions of 40 DEG C, filtered after being incubated 30min.
During whole concentrated compounding, it is 0.02Mpa that whole process, which maintains the pressure of nitrogen,.
2nd, it is dilute to match somebody with somebody
Dilute preparing tank vacuumizes, more than nitrogen charging 5min, and the pressure for maintaining nitrogen is 0.01Mpa, treats that concentrated compounding decoction all shifts
After into dilute dispensing container, wash dense preparing tank with injection pond and transfer to dilute preparing tank, mend and inject water in dilute dispensing container
Full dose, open agitator stirring and be cooled to 30 acid solutions regulation pH value to 4.0~4.6.
3rd, embedding
Filling head is eluted with the water for injection filtered through 0.2 μm of filter, to visible foreign matters are detected, is stopped after qualified, regulation
Bottle placer loading amount, it is 20.60 ± 0.20ml branch to make loading amount.After head washing water visible foreign matters detection to be filled is qualified, lead to nitrogen exhaust 5
More than minute, transfer decoction is to filling.Front and rear nitrogen charging gas shielded when filling.Nitrogen pressure is not less than 0.2Mpa.
4th, sterilize
The good ampoule sabot of embedding is sent to sterilization process, sterilising conditions：121.0℃、15.0min.Final sterilization F0
Value should be greater than 12, and sterilization time process control needs 15min, decoction should be without discolorations.The whole sterilization process control heating-up time with
Temperature fall time, heating-up time control are completed in 30min, and temperature fall time control is completed in 20min.
Experimental example
1st, accelerated test
Three batches of Edaravone Injections that method according to the embodiment of the present invention 1 is prepared, simulation listing packaging,
Placed 6 months under the conditions of (40 ± 2) DEG C, RH (75 ± 5) % accelerated tests, respectively at the 0th, January, 2 months, March, June the end of month
Sampling is investigated.It the results are shown in Table shown in 2~table 4.
Table 2
Table 3
Table 4
2nd, long term test
Three batches of Edaravone Injections that method according to the embodiment of the present invention 1 is prepared, simulation listing packaging,
Place 9 months under the conditions of (25 ± 2) DEG C, RH (50 ± 5) % long term tests, investigated respectively at the 0th, 3,6,9 the end of month sampling.Knot
Fruit is shown in Table shown in 5~table 7.
Table 5
Table 6
Table 7
It can be seen from the experimental data of 2~table of table 7, the Edaravone Injection of the embodiment of the present invention is superior in quality, through length
Phase with accelerating after placing, every Testing index detects qualified, steady quality.The stability experiment knot of other embodiments of the invention
Fruit is similar to Example 1, repeats no more.
Comparative example
The preparation method of comparative example 1 is：
1st, with liquid：Appropriate room temperature water for injection is added in metal Agitation Tank, adds Edaravone, the hydrochloric acid half of recipe quantity
Cystine, sodium hydrogensulfite and sodium chloride, stirring make whole dissolvings；Whole-process control is carried out under nitrogen protection, maintains nitrogen
Pressure is 0.02Mpa.It is 3.0~4.5 with the pH value with identical of embodiment of the present invention pH value regulator regulation solution, constant volume；
Proper amount of active carbon is added, stirring, takes off charcoal, filtering；
2nd, embedding：Filling head is eluted with the water for injection filtered through 0.2 μm of filter, to visible foreign matters are detected, is stopped after qualified
Only, bottle placer loading amount is adjusted, it is 20.60 ± 0.20ml branch to make loading amount.After head washing water visible foreign matters detection to be filled is qualified, lead to
Nitrogen is vented more than 5 minutes, and transfer decoction is to filling.Front and rear nitrogen charging gas shielded when filling.Nitrogen pressure is not less than 0.2Mpa.
3rd, sterilize：Sterilising conditions are 115 DEG C of sterilizing 30min of flowing steam hot pressing, and room temperature is cooled in 30 minutes after sterilizing.
The preparation method of comparative example 2 is substantially same as Example 1, is differed only in：
2-1：The cysteine hydrochloride of recipe quantity is dissolved with 40 DEG C of deoxygenation water for injection in glass container, obtains salt
Sour cysteine solution, then the Edaravone of recipe quantity is added in the CYSTEAMINE HCL acid solution；
2-2：The cysteine hydrochloride of recipe quantity is dissolved with 90 DEG C of deoxygenation water for injection in glass container, obtains salt
Sour cysteine solution, then the Edaravone of recipe quantity is added in the CYSTEAMINE HCL acid solution；
2-3：The cysteine hydrochloride of recipe quantity is dissolved with 60 DEG C of deoxygenation water for injection in rustless steel container, obtained
CYSTEAMINE HCL acid solution, then the Edaravone of recipe quantity is added in the CYSTEAMINE HCL acid solution.
The preparation method of comparative example 3 is substantially same as Example 1, is differed only in：It is dilute match somebody with somebody during nitrogen pressure
For 0.02Mpa.
The preparation method of comparative example 4 is substantially same as Example 1, is differed only in：Without using deoxygenation during with liquid
Water for injection, directly prepared using water for injection.
The preparation method of comparative example 5 is substantially same as Example 1, and the concentration of CYSTEAMINE HCL acid solution is 20mg/ml.
The preparation method of comparative example 6 is substantially same as Example 1, is differed only in：The temperature of charcoal absorption is 55 DEG C.
The preparation method of comparative example 7 is substantially same as Example 1, is differed only in：In sterilization process, 45min~
Heating is completed in 60min, and cooling is completed in 45min~60min.
The Edaravone Injection that above-mentioned comparative example is prepared is added under the same conditions in experimental example of the present invention
Speed experiment, obtained experimental result are as shown in table 8.
Table 8
It can be seen from the experimental data of table 8, the Edaravone for not using the method for the embodiment of the present invention to be prepared is injected
The stability of liquid declines.
It is not for limiting claim, any this area skill although the present invention is disclosed as above with preferred embodiment
Art personnel without departing from the inventive concept of the premise, can make some possible variations and modification, therefore the present invention
Protection domain should be accurate with scope that the claims in the present invention are defined.
Claims (10)
1. a kind of preparation method of Edaravone Injection, the preparation method comprises at least the step of matching somebody with somebody liquid, embedding and sterilizing,
Characterized in that, described carried out under nitrogen protection with liquid and the process of the embedding, it is described to use deoxygenation injection with liquid
Water is prepared；
It is described with liquid include concentrated compounding and it is dilute match somebody with somebody two steps, the concentrated compounding comprises at least following steps：
(1) 90 DEG C~100 DEG C of deoxygenation water for injection is being added with container 1, recipe quantity is added after being cooled to 50 DEG C~80 DEG C
Isotonic agent；It is in container 2 that the cysteine hydrochloride of recipe quantity is water-soluble with 50 DEG C~80 DEG C of the deoxygenation injection
Solution, obtains CYSTEAMINE HCL acid solution, then the Edaravone of recipe quantity is added in the CYSTEAMINE HCL acid solution, obtained
To solution I；
(2) by solution I be added to it is described match somebody with somebody in container 1, stir 10min~60min；
(3) it is the antioxidant addition of recipe quantity is described with container 1, obtain solution II；
(4) activated carbon is added to solution II, stirring, takes off charcoal.
2. preparation method according to claim 1, it is characterised in that the pressure of nitrogen is not less than during the concentrated compounding
0.02Mpa, it is described it is dilute match somebody with somebody during the pressure of nitrogen not less than 0.01Mpa and be not more than 0.02Mpa, the process of the embedding
The pressure of middle nitrogen is not less than 0.2Mpa.
3. preparation method according to claim 1, it is characterised in that the isotonic agent and the antioxidant are respectively adopted
After the deoxygenation water for injection dissolving, described match somebody with somebody in container 1 is then added to；
Preferably, the preparation method of the deoxygenation water for injection is：90 DEG C~100 DEG C waters for injection are placed in container, while stirring
Mix side to vacuumize, then pass to nitrogen, produce；It is furthermore preferred that the pressure of nitrogen is not less than 0.02Mpa.
4. preparation method according to claim 1, it is characterised in that in step (1), the CYSTEAMINE HCL acid solution
Concentration be 24mg/ml~36mg/ml, preferably 28mg/ml~32mg/ml；
Preferably, described with container 2 is glass container.
5. preparation method according to claim 1, it is characterised in that in step (1), in the institute added with container 1
State deoxygenation water for injection accounts for water for injection recipe quantity 60%~80%.
6. preparation method according to claim 1, it is characterised in that in step (4), add according to every 100ml solution
Enter the ratio of 0.005g~0.05g activated carbons, activated carbon added into the solution II, stirred under the conditions of 30 DEG C~50 DEG C,
Filtered after insulation 15min~60min；
Preferably, after activated carbon is first soaked using deoxygenation water for injection, it is then added in the solution II.
7. preparation method according to claim 1, it is characterised in that described dilute with comprising at least：Add the deoxygenation note
Penetrate with water to recipe quantity, obtain solution III；The solution III is cooled to 24 DEG C~36 DEG C, preferably 28 DEG C~32 DEG C；Adjust
The pH value for saving the solution III is 4.0~4.6；
Preferably, it is described dilute to fit over being carried out in container 3.
8. preparation method according to claim 7, it is characterised in that the cooling is completed in 10min~30min, is used
Mass percent concentration is 10%~20% sodium hydroxide solution or mass percent concentration is that 10%~20% phosphoric acid solution is adjusted
Save the pH value of the solution III.
9. preparation method according to claim 1, it is characterised in that the condition of the sterilizing is under the conditions of 121.0 DEG C
15min~18min is incubated, heating is completed in 15min~30min, and cooling is completed in 15min~30min.
10. according to the preparation method described in any one of claim 1~9, it is characterised in that the isotonic agent is selected from sodium chloride,
The antioxidant is selected from sodium hydrogensulfite；
Preferably, the recipe quantity of each raw material is in the Edaravone Injection：Edaravone 15mg~30mg, sodium chloride
67.5mg~135mg, sodium hydrogensulfite 10mg~20mg, cysteine hydrochloride 5mg~10mg, water for injection 10ml~20ml with
And sodium hydroxide and appropriate phosphoric acid；
It is furthermore preferred that the recipe quantity of each raw material is in the Edaravone Injection：Edaravone 30mg, sodium chloride 135mg, Asia
Niter cake 20mg, cysteine hydrochloride 10mg, 10~20ml of water for injection and sodium hydroxide and appropriate phosphoric acid.
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Cited By (3)
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| CN110090225A (en) * | 2019-04-19 | 2019-08-06 | 济南康和医药科技有限公司 | A kind of Edaravone sodium chloride injection and preparation method thereof |
| CN113384525A (en) * | 2021-07-08 | 2021-09-14 | 扬子江药业集团上海海尼药业有限公司 | Preparation method and application of edaravone sodium chloride injection |
| CN114191388A (en) * | 2021-12-27 | 2022-03-18 | 苏州天马医药集团天吉生物制药有限公司 | Preparation method of carbetocin preparation |
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| CN110090225A (en) * | 2019-04-19 | 2019-08-06 | 济南康和医药科技有限公司 | A kind of Edaravone sodium chloride injection and preparation method thereof |
| CN113384525A (en) * | 2021-07-08 | 2021-09-14 | 扬子江药业集团上海海尼药业有限公司 | Preparation method and application of edaravone sodium chloride injection |
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Denomination of invention: A preparation method for edaravone injection Effective date of registration: 20231010 Granted publication date: 20181109 Pledgee: China Everbright Bank Co.,Ltd. Shanghai Branch Pledgor: YANGZIJIANG PHARMACEUTICAL GROUP SHANGHAI HAINI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023310000638 |