CN101934037B - Edaravone injection and preparation process thereof - Google Patents
Edaravone injection and preparation process thereof Download PDFInfo
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Abstract
The invention discloses edaravone injection and a preparation process thereof. The injection contains an active component edaravone and an antioxidant bamboo flavonoid. The stability of the edaravone injection is improved, the valid period of the injection is prolonged, and the edaravone injection is safe and effective clinically.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of stable Edaravone Injection preparation and preparation technology.
Background technology
Edaravone Injection (Edaravone Injection) is the neuroprotection agent that is used for the treatment of Patients with Acute Cerebral Infarction by the development of Mitsubishi Tokyo Pharmaceutical Co., Ltd.Nanjing Xianshengdongyuan Pharmaceutical Co., Ltd at first researches and develops listing in December, 2003 in China, and commodity are by name must be deposited
This medicine is used for new free-radical scavenger and the nerve protection medicine for the treatment of ischemic cerebrovascular, has clear and definite clinical efficacy aspect the treatment cardiovascular and cerebrovascular disease especially acute ischemic stroke.
Edaravone is potent free radical scavenger, can suppress to pour into a large amount of free radicals of causing and the generation of lipid peroxide after cerebral ischemia, anoxia again, thereby the protection cerebral tissue alleviates the cranial nerve symptom, promotes the recovery of function of nervous system.
Edaravone is a kind of antioxidant of hydroxyl radical free radical scavenging action of new development, has shown the remarkable antioxidation to the lipid peroxide that is produced by hydroxyl radical free radical and ion.Its chemical name is: 3-Methyl-1-phenyl-2-pyrazolin-5-one (3-Methyl-1-phenyl-2-pyrazolin-5-one), and its structural formula is:
Molecular formula: C10H10N2O molecular weight: 174.20
Because the Edaravone main ring is pentacyclic ketone, carbonyl and N are adjacent, the N of No. 2 positions unsaturated bond of ining succession, be easy to oxidation, so this molecular structure is very unstable, runs into oxygen and will be oxidized to and do not have activated material, and easily produce macromolecule impurity, human body is damaged.In addition, because there are not the hydrophilic groups such as hydroxyl, carboxyl in the structure,, and methyl and phenyl are insoluble in water, long course of dissolution can aggravate its oxidation and cause unstability.Not a lot of to the research of the antioxidation aspect of Edaravone Injection at present both at home and abroad, there is research to adopt sodium sulfite to make antioxidant, but find only to be difficult to resolve certainly easy oxidation, the unsettled difficult problem of this product with sodium sulfite by our test, sample effect duration of preparation only is 1.5 years.
Summary of the invention
The objective of the invention is in order to solve the problem of Edaravone poor stability, easy oxidation in aqueous solution, by in solution, increasing suitable antioxidant and cosolvent, regulate pH, and the free oxygen in eliminating medicinal liquid and the environment, thereby a kind of Edaravone Injection preparation is provided, and said preparation has guaranteed that medicine is in production process and the stability between the storage life.
Another object of the present invention provides a kind of preparation method of above-mentioned Edaravone Injection.
Purpose of the present invention can reach by following measures:
A kind of Edaravone Injection, this injection contain active component Edaravone and antioxidant Folium Bambosae flavone.
Antioxidant in the adjuvant of Edaravone Injection of the present invention is Folium Bambosae flavone.Folium Bambosae flavone is a kind of novel antioxidant, soluble in water pure with low concentration, water, the heat stability of height are arranged, and molecular weight is little, can be rapidly absorbed, have good resistant activity free radical ability, conclusive SOD is active and significant oxidation resistance, Folium Bambosae flavone energy blocking nitrosamine formation is synthetic simultaneously, energy anti-stress, resisting fatigue, blood fat reducing, control cardiovascular and cerebrovascular disease, enhancing immunity, antitumor, antibiotic, antiviral are all had good effect, and Edaravone also can play synergism.Clinical experiment also shows, Folium Bambosae flavone is safe and effective, be applicable to the metabolism of polytype dyslipidemia, and the control of atherosclerosis, cardiovascular and cerebrovascular disease is had preferably potential applicability in clinical practice.Folium Bambosae flavone is pressed the grade scale of LD50 for actual nontoxic, can participate in body metabolism, and without body accumulation, safety is good.It is similar to the hemoglobin of human body that Folium Bambosae flavone is considered to its structure in Japanese scientific and technological circle, can make injection and directly inject vein.The content of antioxidant Folium Bambosae flavone in injection is preferably 0.1～10mg/ml, and more preferably 0.5～5mg/ml most preferably is 0.5～2mg/ml.
Also can contain cosolvent in the injection, can use the cosolvent that is selected from HYDROXYPROPYL BETA-CYCLODEXTRIN, ethanol, propylene glycol, glycerol, Polyethylene Glycol, polyvidone more than a kind or a kind, the content of cosolvent in injection is preferably 1～200mg/ml, more preferably 1～80mg/ml.Select above cosolvent dissolving Edaravone to make injection, process vascular stimulation test and sample survey, stability experiment, preferred HYDROXYPROPYL BETA-CYCLODEXTRIN and/or propylene glycol.HYDROXYPROPYL BETA-CYCLODEXTRIN is a kind of Novel aid solvent, it is the hydroxyalkylation derivant of a class betacyclodextrin, very easily water-soluble, to study at present the most sufficient novel adjuvant, be widely used in the solubilising of insoluble drug and improve the stability of medicine, and zest is little, hemolytic activity is low, toxic and side effects is little, safe.
The pH of this injection is 2.0～5.0.Acid-alkali accommodation pH of the present invention is to the most stable acidity of Edaravone aqueous solution, available 0.1mol/L hydrochloric acid and/or sodium hydroxide solution are regulated pH, show that through experimental result the pH of sample was stabilized in to 2.0～5.0 o'clock, be conducive to the stability of Edaravone in water.
Injection of the present invention adopts and fills the nitrogen embedding, and oxygen content is lower than 3% in the injection after the encapsulation.In ampoule bottle, fill high pure nitrogen before and after the medicinal liquid embedding, make that oxygen content is lower than 3% in the medicine bottle, thereby better prevent Edaravone oxidation Decomposition in aqueous solution.The sample for preparing respectively different oxygen content, through the low temperature accelerated test, illustrate that filling nitrogen makes oxygen content be lower than the stability that helps to improve Edaravone Injection after 4.5%, and especially be lower than 3% and help to improve the stability of Edaravone Injection to fill behind the nitrogen oxygen content, be lower than 3% so preferably fill nitrogen to oxygen content.
The content of Edaravone can be adjusted according to demand and the national regulation of concrete preparation in the injection, and its content is generally 0.4～10mg/ml.
A kind of preparation technology of Edaravone Injection of the present invention: get Edaravone and adjuvant and be dissolved in the water for injection, add needle-use activated carbon after being stirred to fully dissolving, regulate pH with hydrochloric acid or sodium hydroxide solution after the carbon removal, fill the nitrogen embedding in ampoule, at last at 110～120 ℃ of lower pressure sterilizings.Wherein said adjuvant comprises but not necessarily only limits to above-mentioned antioxidant and cosolvent.Another kind of concrete method is: get Edaravone and cosolvent, antioxidant is dissolved in the water for injection, add needle-use activated carbon after being stirred to fully dissolving, regulate pH with 0.1mol/L hydrochloric acid and/or sodium hydroxide solution after the carbon removal, fill the nitrogen embedding in ampoule, 115 ℃ of pressure sterilizings 30 minutes, and get final product.
Select different antioxidant as: Folium Bambosae flavone, sodium sulfite, vitamin C and cysteine hydrochloride prepare respectively sample, compare experiment: character, pH, content, related substance and clarity qualification rate to sample are tested, under placement under 10 days, 40 ℃ acceleration environments of placement under high temperature (60 ℃) condition 6 months and 25 ℃ of long-term conditions, placed 36 months simultaneously, check character, pH, visible foreign matters, content, related substance, aseptic, pyrogen etc. are carried out study on the stability to determine effect duration.
The different antioxidant of table 1 prepare sample
The long-time stability of table 2R1, R2, R4 sample are investigated data
Conclusion: use sodium sulfite (R2), vitamin C (R3) as the sample of antioxidant respectively 24 months, 18 months the time related substance exceed standard, against regulation, effect duration was respectively 1.5 years, 1 year.Use Folium Bambosae flavone (R1), cysteine hydrochloride (R4) to be 3 years as sample effect duration of antioxidant, and the related substance amount of R1 is also less than the related substance amount of R4, and related substance increases seldom in long term test, embodies better quality; Do not advocate the adjuvant that the cysteine hydrochloride that uses biological product is used as injection in China simultaneously, so the present invention uses Folium Bambosae flavone as antioxidant quality and the stability that improves Edaravone Injection to be had great advantage.
Use Folium Bambosae flavone to pass through vascular stimulation tests, hypersensitive test and hemolytic test as the sample R1 of antioxidant, also prove absolutely the safety and stability of the Edaravone Injection that the present invention prepares.
(1) vascular stimulation tests
3 of healthy new zealand white rabbits are selected in test, and rabbit is from auris dextra auricular vein injection R1, and left ear auricular vein injection equivalent normal saline compares.Every day 1 time, for three days on end, blood vessel and the surrounding tissue of observing intravenous site every day have or not the phenomenons such as erythema, edema.After the last administration 24 hours, get blood vessel 4cm from ear vein to proximal part and carry out pathological examination, observe blood vessel and surrounding tissue and have or not the irritative responses such as hyperemia, edema, distortion, necrosis.
Result of the test is: the rabbit auris dextra to R1 after, congested, edema and the abnormal phenomenas such as downright bad are found significantly in injection site perusal end, obvious irritation is also seen in the end in contrast injection site, left side.Get blood vessel 4cm from the ear vein injection to proximal part and carry out pathological examination, light microscopy checking is found: find to ooze out around obvious cell infiltration, necrosis, intravascular coagulation, the blood vessel and the irritative response such as downright bad for R1 and normal saline end.
The perusal of vascular stimulation tests after the intravenous injection of table 3 Edaravone Injection
Annotate: the negative reference substance group of left ear, auris dextra is trial-production medicine group; "-" expression is without significant change.
Conclusion: give rabbit auricular vein every day injection R1 for three days on end, rabbit ear injection site blood vessel and surrounding tissue are without obvious irritative response.
(2) hypersensitive test
18 of healthy guinea pigs are selected in test, be divided at random three groups, every group 6, male and female half and half, distinguish negative matched group (normal saline group), positive controls (Ovum Gallus domesticus album group), trial-production medicine group (R1 group) for 3 groups, the next day respectively intramuscular injection normal saline, Ovum Gallus domesticus album and R1, continuous 3 times.After first injection the 14th day and 21 days, every group get 3 respectively intraperitoneal injection of saline, Ovum Gallus domesticus album and R1 attack, observe injection after animal have or not anaphylaxiss such as grabbing nose, hard hair, dyspnea, spasm, shock even death.Judge its order of reaction by the judgment criteria in the table 4, all orders of reaction reach when (comprising 2 grades) more than 2 grades, can think that this is subjected to the reagent hypersensitive test defective.Such as tested medicine animal anaphylaxis is arranged, should get not 2 of sensitized guinea pigs of health, intravenous injection is subjected to reagent 2ml, observes the similar symptoms of allergic that has or not drug effect to cause, judges for the result.
Table 4 Cavia porcellus anaphylaxis progression
| The order of reaction | Reaction symptom |
| 0 | Without significant reaction |
| 1 | Only have and slightly grab nose, tremble or erect hair |
| 2 | Several coughs are arranged, grab nose, tremble or perpendicular hair |
| 3 | Repeatedly or continuously cough, with dyspnea or spasm, tic |
| 4 | Spasm, tic, gatism, shock death |
Result of the test is: the Ovum Gallus domesticus album group allergic symptoms such as obvious spasm, tic, gatism all occur in the attack of the 14th day and 21 days, and animal is shock death in the 30min after attack generally, and obvious anaphylaxis does not all appear in R1 group and normal saline group.
The systemic anaphylaxis test of table 5R1
Conclusion: after injection gave R1, Cavia porcellus was there are no systemic anaphylaxis.
(3) external hemolytic test
Test is got blood 20ml with rabbit heart, put in the triangular flask, stir the removal fibrin with Glass rod, then blood is moved in the graduated centrifuge tube, added behind the normal saline mixing centrifugal (2500r/min) 5 minutes, and removed supernatant, add again behind the normal saline mixing centrifugal, cyclic washing 3～4 times is water white transparency to supernatant and can be used for test.The gained erythrocyte is pressed volume, become 2% suspension with normal saline dilution.Get 7 of clean tube, press table 6 and add various solution, the 6th pipe does not add need testing solution, as the blank pipe; The 7th pipe does not still add need testing solution, and replaces normal saline with distilled water, as the positive control of haemolysis.Each pipe is shaken up gently, in 37 ℃ of calorstats, be incubated.Begin every 15min and observe once, per hour observe once Continuous Observation 4h behind the 1h.
Criterion as a result: full haemolysis: solution is clear and bright, redness, and the pipe end, is remaining without erythrocyte.
Part haemolysis: solution is clear and bright, and is red or brown, and the bottom has a small amount of erythrocyte remaining.
Haemolysis not: erythrocyte is all heavy, the supernatant liquid achromatism and clarity.
Cohesion: though red cell agglutination appears in haemolysis not, can not disperse after the vibration.
Result of the test is: haemolysis appears in each pipe and the 6th pipe blank Guan Junwei that add different volumes R1, and obvious haemolysis appears in the 7th pipe positive control pipe.
The external hemolytic test of table 6 R1
| Test tube number | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| R1 | 0.1 | 0.2 | 0.3 | 0.4 | 0.5 | - | - |
| Normal saline (ml) | 2.4 | 2.3 | 2.2 | 2.1 | 2.0 | 2.5 | (2.5 distilled water) |
| 2% red blood cell suspension (ml) | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| The result | - | - | - | - | - | - | + |
Annotate: "+" expression haemolysis and/or aggregation in the table; "-" expression is without haemolysis and aggregation.
Conclusion: R1 is without haemolysis and coacervation.
The present invention has improved the stability of Edaravone Injection, prolongs its effect duration, and it is safe and effective to guarantee that Edaravone Injection uses clinically.Characteristics of the present invention are to adopt the novel antioxidant Folium Bambosae flavone, and by adding suitable cosolvent promotion Edaravone dissolving, with acid-alkali accommodation pH to the most stable acidity of Edaravone aqueous solution, and when the medicinal liquid embedding, in ampoule bottle, fill high pure nitrogen, thereby guarantee that Edaravone is in the environment of a hypoxia all the time.Folium Bambosae flavone is except as the antioxidant, also can anti-stress, resisting fatigue, and blood fat reducing, control cardiovascular and cerebrovascular disease enhancing immunity, antitumor, antibiotic, antiviral are all had good effect, and Edaravone can play synergism.Use Folium Bambosae flavone to be vascular stimulation tests, hypersensitive test and the hemolytic test of the Edaravone Injection of antioxidant, also prove absolutely the safety and stability of the Edaravone Injection that the present invention prepares.
The specific embodiment
The below adopts some specific embodiments to further describe the present invention, but scope of the present invention is not limited in following examples.
Embodiment 1:
Prescription (specification: 5ml:10mg)
| Supplementary material | Consumption | Effect | Specification |
| Edaravone | 10g | Principal agent | Medicinal |
| HYDROXYPROPYL BETA-CYCLODEXTRIN | 40g | Cosolvent | Medicinal |
| Folium Bambosae flavone | 5g | Antioxidant | Medicinal |
| Water for injection adds to | 5000ml | Solvent | Injection |
| Nitrogen is filled in embedding | Remaining oxygen 1.8% | Anti-oxidation | High Purity Nitrogen |
Edaravone, HYDROXYPROPYL BETA-CYCLODEXTRIN, the Folium Bambosae flavone of getting formula ratio add in the water for injection, are stirred to fully dissolving, add needle-use activated carbon, regulate pH with 0.1mol/L hydrochloric acid and/or sodium hydroxide solution after the carbon removal, fill the nitrogen embedding in ampoule, 115 ℃ of pressure sterilizings 30 minutes, and get final product.
Sample afterwards check in 3 years, the equal conformance with standard of every inspection such as shape, pH, visible foreign matters, active constituent content and related substance illustrate that effect duration can reach 3 years.
Embodiment 2:
Prescription (specification: 5ml:10mg)
| Supplementary material | Consumption | Effect | Specification |
| Edaravone | 10g | Principal agent | Medicinal |
| Propylene glycol | 400g | Cosolvent | Medicinal |
| Folium Bambosae flavone | 4g | Antioxidant | Medicinal |
| Water for injection adds to | 5000ml | Solvent | Injection |
| Nitrogen is filled in embedding | Remaining oxygen 1.6% | Anti-oxidation | High Purity Nitrogen |
The Edaravone of getting formula ratio is dissolved in the propylene glycol, be stirred to fully dissolving after, add ascorbic aqueous solution and stir, add needle-use activated carbon, regulate pH with 0.1mol/L hydrochloric acid and/or sodium hydroxide solution after the carbon removal, fill the nitrogen embedding in ampoule, 115 ℃ of pressure sterilizings 30 minutes, and get final product.
Sample afterwards check in 3 years, the equal conformance with standard of every inspection such as shape, pH, visible foreign matters, active constituent content and related substance illustrate that effect duration can reach 3 years.
Embodiment 3:
Prescription (specification: 20ml:30mg)
| Supplementary material | Consumption | Effect | Specification |
| Edaravone | 30g | Principal agent | Medicinal |
| HYDROXYPROPYL BETA-CYCLODEXTRIN | 160g | Cosolvent | Medicinal |
| Folium Bambosae flavone | 24g | Antioxidant | Medicinal |
| Water for injection adds to | 20000ml | Solvent | Injection |
| Nitrogen is filled in embedding | Remaining oxygen 1.5% | Anti-oxidation | High Purity Nitrogen |
Edaravone, HYDROXYPROPYL BETA-CYCLODEXTRIN, the Folium Bambosae flavone of getting formula ratio add in the water for injection, are stirred to fully dissolving, add needle-use activated carbon, regulate pH with 0.1mol/L hydrochloric acid and/or sodium hydroxide solution after the carbon removal, fill the nitrogen embedding in ampoule, 115 ℃ of pressure sterilizings 30 minutes, and get final product.
Sample afterwards check in 3 years, the equal conformance with standard of every inspection such as shape, pH, visible foreign matters, active constituent content and related substance illustrate that effect duration can reach 3 years.
Embodiment 4:
Prescription (specification: 20ml:30mg)
| Supplementary material | Consumption | Effect | Specification |
| Edaravone | 30g | Principal agent | Medicinal |
| Propylene glycol | 1200g | Cosolvent | Medicinal |
| Folium Bambosae flavone | 20g | Antioxidant | Medicinal |
| Water for injection adds to | 20000ml | Solvent | Injection |
| Nitrogen is filled in embedding | Remaining oxygen 2.5% | Anti-oxidation | High Purity Nitrogen |
The Edaravone of getting formula ratio is dissolved in the propylene glycol, be stirred to fully dissolving after, add ascorbic aqueous solution and stir, add needle-use activated carbon, regulate pH with 0.1mol/L hydrochloric acid and/or sodium hydroxide solution after the carbon removal, fill the nitrogen embedding in ampoule, 115 ℃ of pressure sterilizings 30 minutes, and get final product.
Sample afterwards check in 3 years, the equal conformance with standard of every inspection such as shape, pH, visible foreign matters, active constituent content and related substance illustrate that effect duration can reach 3 years.
Claims (4)
1. Edaravone Injection, it is characterized in that: this injection by active component Edaravone, antioxidant Folium Bambosae flavone, cosolvent, water for injection and the hydrochloric acid or the sodium hydroxide that are used for regulating pH value form, the pH of this injection is 2.0～5.0, it adopts and fills the nitrogen embedding, and oxygen content is lower than 3% in the injection after the encapsulation; Described cosolvent is selected from one or more in HYDROXYPROPYL BETA-CYCLODEXTRIN, ethanol, propylene glycol, glycerol, Polyethylene Glycol or the polyvidone, and the content of cosolvent in injection is 1～200mg/ml; The content of described antioxidant Folium Bambosae flavone in injection is 0.1～10mg/ml; The content of Edaravone is 0.4～10mg/ml.
2. Edaravone Injection according to claim 1, it is characterized in that: the content of described antioxidant Folium Bambosae flavone in injection is 0.5～5mg/ml.
3. Edaravone Injection according to claim 1, it is characterized in that: the content of described cosolvent in injection is 1～80mg/ml.
4. the preparation technology of arbitrary described Edaravone Injection in the claim 1～3, it is characterized in that getting Edaravone, antioxidant and cosolvent is dissolved in the water for injection, add needle-use activated carbon after being stirred to fully dissolving, regulate pH with hydrochloric acid or sodium hydroxide solution after the carbon removal, fill the nitrogen embedding in ampoule, at last at 110～120 ℃ of lower pressure sterilizings.
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| CN103251554A (en) * | 2013-06-06 | 2013-08-21 | 南京亿华药业有限公司 | Stable edaravone injection and preparation method thereof |
| CN106727287B (en) * | 2015-11-23 | 2020-01-24 | 江苏先声药业有限公司 | High-concentration injection of edaravone and natural borneol |
| CN109125261B (en) | 2016-03-16 | 2021-11-30 | 苏州澳宗生物科技有限公司 | Edaravone dosage form |
| JP6298206B1 (en) * | 2017-08-08 | 2018-03-20 | 田中 正彦 | Medicine containing pyrazolone derivative |
| CN110090225B (en) * | 2019-04-19 | 2021-07-16 | 济南康和医药科技有限公司 | Edaravone sodium chloride injection and preparation method thereof |
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| CN101732247A (en) * | 2010-01-06 | 2010-06-16 | 长沙易睿医药科技有限公司 | Edaravone-containing injection |
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| CN101732247A (en) * | 2010-01-06 | 2010-06-16 | 长沙易睿医药科技有限公司 | Edaravone-containing injection |
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Address after: No.99, Huakang Road, Jiangbei new district, Nanjing, Jiangsu Province, 210032 Patentee after: SIMCERE PHARMACEUTICAL Group Address before: 211800, No. 8, prosperous road, Pukou Economic Development Zone, Jiangsu, Nanjing Patentee before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. |