CN103251554A - Stable edaravone injection and preparation method thereof - Google Patents
Stable edaravone injection and preparation method thereof Download PDFInfo
- Publication number
- CN103251554A CN103251554A CN2013102224591A CN201310222459A CN103251554A CN 103251554 A CN103251554 A CN 103251554A CN 2013102224591 A CN2013102224591 A CN 2013102224591A CN 201310222459 A CN201310222459 A CN 201310222459A CN 103251554 A CN103251554 A CN 103251554A
- Authority
- CN
- China
- Prior art keywords
- sodium
- preparation
- edaravone
- injection
- regulator
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention mainly relates to a stable edaravone injection and a preparation method thereof. The edaravone injection comprises an osmotic pressure adjustor comprising sodium chloride, phosphoric acid, phosphoric acid, citric acid monohydrate and sodium hydrogen sulfite, a pH adjustor, a dissolving adjuvant and an antioxygen, wherein sodium hydroxide is not only used as the pH adjustor, but also has the effect of the dissolving adjuvant, so that the dissolving time of main medicines is greatly shortened. The medicine is not dissolved at higher temperature to the benefit of stability of the product. Compared with L-cysteine hydrochloride and sodium hydrogen sulfite as the antioxygen, citric acid monohydrate and sodium hydrogen sulfite are used as the antioxygen of the edaravone injection, so that the stability of the product is greatly improved. Compared acceleration and long-term test show that related substances generated are less, and the product quality is relatively stable and safe.
Description
One, technical field
The present invention relates to technical field of medicine, especially relate to Edaravone Injection of a kind of good stability and preparation method thereof.
Two, technical background
Apoplexy is commonly encountered diseases, the frequently-occurring disease of middle-aged and elderly people, is one of three big diseases that human mortality rate is the highest now, also is disease kinds with fastest developing speed in the three big diseases, that recovery is the slowest, death is maximum.Apoplexy can be divided into Ischemic Stroke and hemorrhagic apoplexy according to pathogenesis, and comprises cerebral thrombosis and cerebral embolism in Ischemic Stroke, and both are referred to as cerebral infarction clinically the back.Chinese annual apoplexy neopathy 2,500,000 examples have 1,500,000 people approximately and die from apoplexy every year at present, and 3/4 deformity that leaves is in various degree arranged among the survivor.Therefore reduce the sequela of cerebral infarction, reduction improves the nervous symptoms due to the cerebral infarction, recovers self care ability, reduces disability rate, is the key of cerebral infarction therapy.
Edaravone (edaravone) by Mitsubishi Tokyo drugmaker (Mitsubishi-Tokyo Pharmaceuticals Inc.) exploitation is a kind of cranial nerve protective agent; its chemical name is 3-methyl isophthalic acid-phenyl-2-pyrazoline-5-ketone, and Fig. 1 seen in its chemical structural formula.
Edaravone is first cerebral protective agent in the world, and namely free radical scavenger can effectively be removed oxygen-derived free radicals, suppresses lipid peroxidation, improves the function of brain cell (vascular endothelial cell, neurocyte).Edaravone acts on cerebral infarction in earlier stage; suppress cerebral edema, dwindle the cerebral infarction district, alleviate the outbreak of neural syndrome, the death of the tardy property neurocyte of inhibition and appearance and the progress (namely worsening) of ischemic cerebral vascular obstacle, the 26S Proteasome Structure and Function of protection cerebral tissue.Edaravone can effectively alleviate nervous symptoms and the dysfunction that brain tissue impairment causes behind the cerebral infarction.
Edaravone Injection (the trade name: Radicut of Mitsubishi Denki K.K.'s development of Japan in 2001
) listing, specification is 20ml:30mg, is the achromatism and clarity injection.Listing at home in 2003, dosage form is injection, and specification is 5ml:10mg, 20ml:30mg, and indication is to improving nervous symptoms, daily life active ability and the dysfunction due to the acute cerebral infarction.Because dissolubility is very little in the Edaravone aqueous solution, in the process for preparation of water type injection, be difficult to reach effective drug level, preparation and the sterilization process of while at injection need carry out under heated condition, makes the Edaravone degraded easily and produces more objectionable impurities.Therefore conventional Edaravone pharmaceutical composition and preparation technology are difficult to prepare that steady quality, effect duration are long, the Edaravone Injection of clinical drug safety.
In addition, Edaravone is oxidation very easily, easily forms insoluble matter Edaravone dimer, brings certain potential safety hazard to clinical application.In preparation injection process, need dosing temperature, pH, sterilising temp and whether inflated with nitrogen carries out a large amount of experimentation work just can prepare steady quality, the higher injection of safety.
We are in order to improve the stability of medicine, and a kind of stable Edaravone Injection and preparation method thereof has been invented in research.It is characterized in that in medicine dissolution, for accelerate its dissolving plain and guarantee that medicine is stable, after wherein adding an amount of assist in dissolving agent, the Edaravone that adds recipe quantity again, treat principal agent dissolving fully after, add osmotic pressure regulator and antioxidant successively, what wherein antioxidant adopted is monohydrate potassium and sodium sulfite, after being stirred to dissolving fully, to adding medicinal carbon, absorption is stirred; Sucking filtration; With phosphorus acid for adjusting pH value 3.0-4.5; Fine straining; Fill; Sterilization, and omnidistance nitrogen filled protection.
Three, summary of the invention
The object of the present invention is to provide a kind of stable Edaravone Injection and preparation method thereof, this injection good stability, can better application in clinical, have more obvious advantage.
By relatively monohydrate potassium and sodium sulfite as antioxidant and L-cysteine hydrochloride and sodium sulfite as antioxidant, find that the Edaravone Injection that the former obtains is more stable, accelerate and long term test in the generation of related substance less.
Purpose of the present invention can be achieved through the following technical solutions.
Edaravone Injection among the present invention is characterized in that comprising dissolving adjuvant, osmotic pressure regulator, pH regulator and antioxidant.Preparation method is: after adding the dissolving fully of dissolving adjuvant in an amount of water for injection, add Edaravone, osmotic pressure regulator, the antioxidant of recipe quantity, be stirred to dissolving fully after, add medicinal carbon, stir; Sucking filtration; Regulate the pH value, stir; Fine straining; Fill; Sterilization; Lamp inspection; Packing; Warehouse-in.
The antioxidant of the Edaravone Injection among the present invention is selected from one or more of monohydrate potassium, sodium pyrosulfite, sodium sulfite and L-cysteine hydrochloride, preferably unites and uses monohydrate potassium and sodium sulfite.
The dissolving adjuvant of the Edaravone Injection among the present invention is selected from sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide, sodium phosphate, the sodium hydrogen phosphate one or more, preferred sodium hydroxide.
Edaravone Injection among the present invention osmotic pressure regulator be selected from mannitol, sodium chloride, sorbitol, the glucose one or more, preferred sodium chloride.
Acidity regulator is selected from one or more in dilute hydrochloric acid, L-arginine, citric acid, boric acid, spirit of vinegar and the phosphoric acid, preferably phosphoric acid in the pH regulator agent of the Edaravone Injection among the present invention; Alkalinity regulator is selected from sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide, sodium phosphate, the sodium hydrogen phosphate one or more, preferred sodium hydroxide.
The pH regulator scope of the Edaravone Injection among the present invention is 3.0-4.5; Preferred 3.5.-4.0.
The consumption of the medicinal carbon of the Edaravone Injection among the present invention is 0.05-0.5%, preferred 0.05-0.20%, more preferably 0.10%; Medicinal carbon absorption mixing time is 5-20 minute, preferred 10 minutes.
What the sterilization of the Edaravone Injection among the present invention was adopted is excessively to kill, 121 ℃ pressure sterilizing 15-30 minute, preferred 15 minutes.
The noble gas that the embedding process of the Edaravone Injection among the present invention need charge into is protected, and the noble gas that charges into is selected from a kind of in nitrogen, carbon dioxide and the helium; Be preferably nitrogen or carbon dioxide; Nitrogen more preferably.
Four, Figure of description
The structural formula of Fig. 1 Edaravone;
Fig. 2 temperature is to the influence of principal agent Edaravone dissolution time and stability;
Fig. 3 dissolves adjuvant to the influence of Edaravone dissolution time and stability;
Influence factor's test of Fig. 4 embodiment 1 and embodiment 2;
The accelerated test of Fig. 5 embodiment 1 and embodiment 2;
The long term test of Fig. 6 embodiment 1 and embodiment 2 (12 months);
Five, the specific embodiment:
Embodiment 1:
Edaravone 30g
Sodium sulfite 20g
L-cysteine hydrochloride monohydrate 10g
Sodium chloride 135g
Sodium hydroxide is an amount of
Phosphoric acid is an amount of
Make 2L
Preparation method:
The Edaravone, sodium chloride, the antioxidant that add recipe quantity in about 70 ℃ water for injection, be stirred to dissolving fully after, add medicinal carbon, stir; Sucking filtration; Regulate the pH value to 3.0-4.5, stir; Fine straining; Fill; 121 ℃ of sterilization 15min; Lamp inspection; Packing; Warehouse-in.
Embodiment 2:
Edaravone 30g
Sodium sulfite 20g
Monohydrate potassium 50g
Sodium chloride 150g
Sodium hydroxide 16g
Phosphoric acid is an amount of
Make 2L
Preparation method:
The water for injection of 0.2mol/mL of preparation 500mL, to the Edaravone that wherein adds recipe quantity, sodium chloride, sodium sulfite and monohydrate potassium, be stirred to dissolving fully after, add medicinal carbon, stir; Sucking filtration; Phosphoric acid is regulated the pH value in right amount to 3.0-4.5, stirs; Fine straining; Fill; 121 ℃ of sterilization 15min; Lamp inspection; Packing; Warehouse-in.
Embodiment 3:
The principal agent Edaravone is dissolved in the injection water of different temperatures, investigates temperature to the influence of principal agent Edaravone dissolution time and stability, analysis result is seen Fig. 2.
The result shows that the too high then Edaravone of temperature is easily degraded, so select temperature unsuitable too high, it is longer that it's the time of hanging down then principal agent Edaravone dissolving is past temperature, so temperature is chosen as 60-70 ℃.
Embodiment 4:
Add the dissolving adjuvant (sodium hydroxide) of variable concentrations to the injection water of room temperature, investigate the dissolving adjuvant to the influence of Edaravone dissolution time and stability, divide to the results are shown in Figure 3.
The result shows, even under room temperature (20-30 ℃) condition, adds the dissolving adjuvant, and the dissolution time of principal agent Edaravone is shorter, and stability better, and suitable dissolving adjuvant (sodium hydroxide) concentration is 0.2mol/mL.
Embodiment 5:
120301)-embodiment 2 (lot number: 120401) carry out influence factor test (60 ℃ ± 2 ℃ of high temperature get embodiment 1 (lot number:, high light 4500lx ± 500lx) placed 10 days under the condition, detect respectively at sampling in 0,5 and 10 day, investigate appearance luster, related substance, content, analysis result is seen accompanying drawing 4.
The influence factor of high temperature and high light tests discovery, embodiment 2 is better than embodiment 1 aspect related substance, embodiment 1 and embodiment 2 are not all having significant change aspect character and the content, illustrate that adopting monohydrate potassium and sodium sulfite is that the embodiment 2 of antioxidant is that embodiment 1 (listing packing) product quality under this experimental condition of antioxidant is more stable than adopting L-cysteine hydrochlorides and sodium sulfite.
Embodiment 6:
120301)-embodiment 2 (lot number: 120401) listing packing get embodiment 1 (lot number:, 40 ℃ ± 2 ℃ of temperature, placed 6 months under the condition of relative humidity 75% ± 5%, respectively at 0,1,2,3 and sampling in 6 months detect, investigate appearance luster, related substance, content, analysis result is seen accompanying drawing 5.
Stability test is found through 25 ℃ ± 2 ℃, 60% ± 10% accelerated test 6 months, embodiment 2 is better than embodiment 1 aspect related substance, embodiment 1 and embodiment 2 are not all having significant change aspect appearance luster and the content, illustrate that adopting monohydrate potassium and sodium sulfite is that the embodiment 2 of antioxidant is that embodiment 1 (listing packing) product quality under this experimental condition of antioxidant is more stable than adopting L-cysteine hydrochlorides and sodium sulfite.
Embodiment 7:
120301)-embodiment 2 (lot number: 120401) listing packing get embodiment 1 (lot number:, 25 ℃ ± 2 ℃ of temperature, placed 12 months under the condition of relative humidity 60% ± 10%, respectively at 0,3,6,9 and sampling in 12 months detect, investigate appearance luster, related substance, content, analysis result is seen accompanying drawing 6.
Stability test is found through 25 ℃ ± 2 ℃, 60% ± 10% long term test 12 months, embodiment 2 is better than embodiment 1 aspect related substance, embodiment 1 and embodiment 2 are not all having significant change aspect appearance luster and the content, illustrate that adopting monohydrate potassium and sodium sulfite is that the embodiment 2 of antioxidant is that embodiment 1 (listing packing) product quality under this experimental condition of antioxidant is more stable than adopting L-cysteine hydrochlorides and sodium sulfite.
Claims (6)
1. stable Edaravone Injection and preparation method thereof is characterized in that comprising dissolving adjuvant, osmotic pressure regulator, pH regulator and antioxidant; Preparation technology is: after adding the dissolving fully of dissolving adjuvant in an amount of water for injection, add Edaravone, osmotic pressure regulator, the antioxidant of recipe quantity, be stirred to dissolving fully after, add medicinal carbon, stir; Sucking filtration; Regulate the pH value, stir; Fine straining; Fill; Sterilization; Lamp inspection; Packing; Warehouse-in.
2. according to described Edaravone Injection of claim 1 and preparation method thereof, it is characterized in that, described antioxidant is selected from one or more of monohydrate potassium, sodium pyrosulfite, sodium sulfite and L-cysteine hydrochloride, preferably unites and uses monohydrate potassium and sodium sulfite.
3. according to described Edaravone Injection of claim 1 and preparation method thereof, it is characterized in that, described dissolving adjuvant is selected from sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide, sodium phosphate, the sodium hydrogen phosphate one or more, preferred sodium hydroxide.
4. according to described Edaravone Injection of claim 1 and preparation method thereof, it is characterized in that described osmotic pressure regulator is selected from one or more in mannitol, sodium chloride, sorbitol, the glucose, preferred sodium chloride.
5. according to described Edaravone Injection of claim 1 and preparation method thereof, it is characterized in that acidity regulator is selected from one or more in dilute hydrochloric acid, L-arginine, citric acid, boric acid, spirit of vinegar and the phosphoric acid, preferably phosphoric acid in the described pH regulator agent; Alkalinity regulator is selected from sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide, sodium phosphate, the sodium hydrogen phosphate one or more, preferred sodium hydroxide.
6. according to described Edaravone Injection of claim 1 and preparation method thereof, it is characterized in that described pH regulator scope is 3.0-4.5; Preferred 3.5.-4.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102224591A CN103251554A (en) | 2013-06-06 | 2013-06-06 | Stable edaravone injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102224591A CN103251554A (en) | 2013-06-06 | 2013-06-06 | Stable edaravone injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103251554A true CN103251554A (en) | 2013-08-21 |
Family
ID=48955998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013102224591A Pending CN103251554A (en) | 2013-06-06 | 2013-06-06 | Stable edaravone injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103251554A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103393595A (en) * | 2013-08-28 | 2013-11-20 | 芦红代 | Pharmaceutical composition of edaravone |
| CN104784111A (en) * | 2015-03-28 | 2015-07-22 | 河北仁合益康药业有限公司 | Edaravone injection composition and preparation method thereof |
| CN106963768A (en) * | 2017-04-01 | 2017-07-21 | 南京中瑞药业有限公司 | A kind of pharmaceutical composition and purposes |
| WO2018133957A1 (en) | 2017-01-17 | 2018-07-26 | Treeway Tw001 B.V. | Medical treatment comprising enteral administration of edaravone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101732247A (en) * | 2010-01-06 | 2010-06-16 | 长沙易睿医药科技有限公司 | Edaravone-containing injection |
| CN101934037A (en) * | 2010-08-26 | 2011-01-05 | 南京先声东元制药有限公司 | Edaravone injection and preparation process thereof |
| CN102091028A (en) * | 2009-12-15 | 2011-06-15 | 南京长澳医药科技有限公司 | Edaravone injection and preparation method thereof |
-
2013
- 2013-06-06 CN CN2013102224591A patent/CN103251554A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102091028A (en) * | 2009-12-15 | 2011-06-15 | 南京长澳医药科技有限公司 | Edaravone injection and preparation method thereof |
| CN101732247A (en) * | 2010-01-06 | 2010-06-16 | 长沙易睿医药科技有限公司 | Edaravone-containing injection |
| CN101934037A (en) * | 2010-08-26 | 2011-01-05 | 南京先声东元制药有限公司 | Edaravone injection and preparation process thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103393595A (en) * | 2013-08-28 | 2013-11-20 | 芦红代 | Pharmaceutical composition of edaravone |
| CN103393595B (en) * | 2013-08-28 | 2014-07-23 | 芦红代 | Pharmaceutical composition of edaravone |
| CN104784111A (en) * | 2015-03-28 | 2015-07-22 | 河北仁合益康药业有限公司 | Edaravone injection composition and preparation method thereof |
| WO2018133957A1 (en) | 2017-01-17 | 2018-07-26 | Treeway Tw001 B.V. | Medical treatment comprising enteral administration of edaravone |
| US10966960B2 (en) | 2017-01-17 | 2021-04-06 | Treeway Tw001 B.V. | Medical treatment comprising enteral administration of edaravone |
| CN106963768A (en) * | 2017-04-01 | 2017-07-21 | 南京中瑞药业有限公司 | A kind of pharmaceutical composition and purposes |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2011153403A (en) | STABILIZED COMPOSITION CONTAINING AT LEAST ONE ADRENERGIC COMPOUND | |
| CN103251554A (en) | Stable edaravone injection and preparation method thereof | |
| JP2013529654A (en) | Pharmaceutical composition comprising levocarnitine and dobesylate | |
| CN104224829A (en) | Injection containing sodium, potassium, magnesium, calcium and glucose injection and preparation method of injection | |
| CN104622855A (en) | Oral solution containing ambroxol hydrochloride and salbutamol sulfate | |
| CN104055766A (en) | Pharmaceutical composition of compound amino acid injection 18AA and application thereof | |
| CN102091028A (en) | Edaravone injection and preparation method thereof | |
| US20160058724A1 (en) | Baclofen formulations and methods for making same | |
| RU2014114512A (en) | WATER COMPOSITIONS CONTAINING ARBECACIN | |
| CN108324683A (en) | A kind of big infusion Edaravone Injection and its preparation process of stabilization | |
| US6048540A (en) | Acetamenophen composition with reduced liver toxicity | |
| US20140147519A1 (en) | Migraine Treatment | |
| CN103191054A (en) | Heparin sodium tube sealing injection and preparation method thereof | |
| RU2006114834A (en) | INFUSION DRUG CONTAINING (2R) -2-PROPYLOCTANIC ACID AS AN ACTIVE INGREDIENT | |
| RU2013148799A (en) | DIHYDROPYRIDINES (KLEVIDIPIN) SHORT-TERM ACTION FOR USE IN RECOVERY AFTER A STROKE | |
| US9044418B2 (en) | Treatment for depression and other mental conditions with synthetic isotope-modified lithium | |
| CN104840417A (en) | Ambroxol hydrochloride injection and preparation method thereof | |
| CN103751104A (en) | Edaravone injection and preparation method thereof | |
| CN104622800A (en) | Bendazac lysine eye drop and preparation method thereof | |
| CN101947253B (en) | External compound preparation for curing tinea corporis as well as preparation method and content measuring method thereof | |
| CN111249227A (en) | Preparation method of fondaparinux sodium injection | |
| RU2014148062A (en) | INJECTION PHARMACEUTICAL COMPOSITION OF DEXKETOPROFEN AND TRAMADOL | |
| CN102198092A (en) | Breviscapine injection and preparation method thereof | |
| JP5992293B2 (en) | Ophthalmic agent | |
| RU2013121820A (en) | COMBINED MEDICINE FOR THE ELIMINATION OF SYMPTOMS AND TREATMENT OF ACUTE RESPIRATORY VIRAL INFECTIONS AND INFLUENZA |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130821 |