CN107281136A - Good levo-oxiracetam aseptic powdery of a kind of stability and preparation method thereof - Google Patents
Good levo-oxiracetam aseptic powdery of a kind of stability and preparation method thereof Download PDFInfo
- Publication number
- CN107281136A CN107281136A CN201610195354.5A CN201610195354A CN107281136A CN 107281136 A CN107281136 A CN 107281136A CN 201610195354 A CN201610195354 A CN 201610195354A CN 107281136 A CN107281136 A CN 107281136A
- Authority
- CN
- China
- Prior art keywords
- minutes
- constant temperature
- oxiracetam
- warming
- levo
- 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.)
- Withdrawn
Links
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of good levo-oxiracetam aseptic powdery of stability, it is that phenol, phenmethylol is supplementary material by levo-oxiracetam, L serines, mannitol, polyethylene glycol, with concentrated compounding, dilute match somebody with somebody, is freeze-dried, rolls lid step and be prepared；The levo-oxiracetam 52% ~ 60% that wherein described supplementary material consumption is weight percentage, L serines 15% ~ 23%, mannitol 20% ~ 27%, polyethylene glycol 2000 1% ~ 5%, phenol 1% ~ 2%, phenmethylol 1% ~ 3%;There is solid shape, the phenomenon without drying shrinkage and bubbling in lyophilized preparation process according to levo-oxiracetam aseptic powdery produced by the present invention, product homogeneity is good, levels character is consistent, steriling test meets the requirements, and this product impurity is few, and its total impurities is less than 0.26%, product stability is good, shelf life is up to 24 months, and patient pain feels lighter, good patient compliance in injection process.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of good levo-oxiracetam aseptic powdery of stability
And preparation method thereof.
Background technology
Oxiracetam (S-oxiracetam) is a kind of hydroxy-amino-butyric acid of synthesis (BABOB) cyclic derivatives, is only used
In central nervous system, cerebral cortex, hippocampus are mainly distributed on, has activation, protection or the functional rehabilitation for promoting nerve cell, changes
The mnemonic learning function of kind disturbance of intelligence patient, and medicine is also acted in itself without direct vasoactive without central excitation,
Influence to ability of learning and memory is a kind of lasting facilitation.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled 4- hydroxyls -2- OXo-1-pyrrolidines
Acetamide, is that (compound is disclosed in the anti anoxia class cereboactive drug that was synthesized first in 1974 of Italian ISFS.P.A companies
US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine can be promoted to synthesize, promotes brain metabolism, through blood brain
Barrier, has stimulation to specific nervous centralis road, can improve intelligence and memory, to cerebrovascular disease, brain trauma, brain
Knurl, intracranial infection, brain degenerative disease etc. also have preferable curative effect, and the drug toxicity is extremely low, no mutagenesis and carcinogenic work
With and genotoxicity.Giorgio et al. discloses the chemical constitution and preparation method of Oxiracetam in US4118396,
Chiodini et al. is disclosed in WO9306826A, and clinical effectiveness proves that the drug effect of the Oxiracetam of S configurations (left-handed) is better than R structures
Type (dextrorotation), Oxiracetam and levo-oxiracetam structure are as follows.
Existing levo-oxiracetam aseptic powdery its be primarily present no solid shape, be difficult to form skeleton, drying shrinkage easily occur
With bubbling phenomenon, product homogeneity is bad, and levels character is inconsistent, and stability is poor, and shelf life is short, and steriling test is unqualified,
Injection process pain substantially, the problems such as patient's poor compliance.
The content of the invention
Have that solid form, stability is good, shelf life length levo-oxiracetam it is an object of the invention to provide a kind of
Aseptic powdery.
Another object of the present invention is to provide the preparation method of the good levo-oxiracetam aseptic powdery of aforementioned stable.
The purpose of the present invention is realized by following technical measures：
The good levo-oxiracetam aseptic powdery of a kind of stability, it is characterised in that it is using levo-oxiracetam as original
Material, adds a certain amount of additives and is made；Wherein described additives are sucrose, trehalose, mannitol, lactose, glucose, wheat
Bud sugar, glucan, albumin, polyethylene glycol, glycerine, Serine, sodium glutamate, alanine, glycine, methyl amimoacetic acid, phosphoric acid
One or more in salt, acetate, citrate, phenmethylol.
Inventor has found that specific additives species coordinates specific supplementary material to use in research process by many experiments
Proportion relation is measured, then coordinates specific preparation method, can make above-mentioned levo-oxiracetam aseptic powdery that there is solid shape, easy shape
Into skeleton, drying shrinkage and bubbling phenomenon are less prone to, homogeneity is good, product levels character is consistent, sterile to meet the requirements, shelf life
Extension, and product patient pain's sense decline, good patient compliance in use can be made；Good left-handed of aforementioned stable
Oxiracetam aseptic powdery, it is characterised in that it be by levo-oxiracetam, Serine, mannitol, polyethylene glycol, phenol,
Phenmethylol is supplementary material, with concentrated compounding, dilute match somebody with somebody, is freeze-dried, rolls lid step and be prepared；Wherein described supplementary material consumption is weight
The levo-oxiracetam 52%~60% of percentage, Serine 15%~23%, mannitol 20%~27%, polyethylene glycol
20001%~5%, phenol 1%~2%, phenmethylol 1%~3%；The concentrated compounding step is that the supplementary material of recipe quantity is placed in into appearance
In device, the sterilized water for injection stirring of 5 times of parts by weight of levo-oxiracetam is added, after dissolving, the pin of mass fraction 0.1% is added
With activated carbon, 30min is stirred, is then filtered with 0.45 micrometer Millipore filter membrane, filtrate is collected；Dilute is to be added into filtrate with step
Sterilized water for injection adjusts pH to 7.0 to 1000 times of filtrate volume with hydrochloric acid or sodium hydroxide, then micro- with 0.22 micron
Hole filter membrane aseptic filtration, takes filtrate is filling to be after the assay was approved sub-packed in sterile glass vials；Freeze-drying step is that will quickly lead
Hot oil temperature is refrigerated to -40 DEG C, keeps constant temperature 60 minutes, and -10 DEG C are warming up to 5 DEG C/h, keeps constant temperature 80 minutes, fast
Speed is cooled to -40 DEG C, cryostat 120 minutes；Then drying is vacuumized, is warming up to 10 DEG C/h, -10 DEG C of 150 points of constant temperature
Clock；0 DEG C is warming up to 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；10 DEG C are warming up to 5 DEG C/h, 10 DEG C of constant temperature 240 minutes, with
10 DEG C/h are warming up to 30 DEG C, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum drop reaches 10Pa/10 timesharing, freeze and terminate.
The good levo-oxiracetam aseptic powdery of most preferred aforementioned stable, it is characterised in that it is by following weight
The supplementary material of percentage is made：Levo-oxiracetam 54%~57%, Serine 17%~20%, mannitol 22%~
25%, polyethylene glycol 2000 2%~3%, phenol 1%~2%, phenmethylol 1%~2%；The supplementary material of recipe quantity is placed in appearance
In device, the sterilized water for injection stirring of 5 times of parts by weight of levo-oxiracetam is added, after dissolving, the pin of mass fraction 0.1% is added
With activated carbon, 30min is stirred, is then filtered with 0.45 micrometer Millipore filter membrane, filtrate is collected, sterile injection is added into filtrate and is used
Water adjusts pH to 7.0 to 1000 times of filtrate volume with hydrochloric acid or sodium hydroxide, then degerming with 0.22 micron of miillpore filter
Filtering, takes filtrate is filling to be after the assay was approved sub-packed in sterile glass vials, standby；Heat conduction oil temperature is quickly refrigerated to -40 DEG C,
Keep constant temperature 60 minutes, -10 DEG C are warming up to 5 DEG C/h, keep constant temperature 80 minutes, be quickly cooled to -40 DEG C, constant temperature is cold
Freeze 120 minutes.Then drying is vacuumized, is warming up to 10 DEG C/h, -10 DEG C of constant temperature 150 minutes；0 is warming up to 4 DEG C/h
DEG C, 0 DEG C of constant temperature 300 minutes；10 DEG C are warming up to 5 DEG C/h, and 10 DEG C of constant temperature 240 minutes is warming up to 30 DEG C with 10 DEG C/h,
30 DEG C of constant temperature 60 minutes, while preceding case vacuum drop reaches 10Pa/10 timesharing, freezes and terminates.
A kind of preparation method of the good levo-oxiracetam aseptic powdery of stability is worthy of careful study, it is characterised in that it be by
Made from following steps：
1. concentrated compounding：The supplementary material of recipe quantity is placed in container, the sterile injection of 5 times of parts by weight of levo-oxiracetam is added
Blunge, after dissolving, add the needle-use activated carbon of mass fraction 0.5%, stir 30min, then filtered with 0.45 micrometer Millipore
Membrane filtration mistake, collects filtrate, standby；
2. dilute match somebody with somebody：Sterilized water for injection is added into filtrate to 1000 times of filtrate volume, is adjusted with hydrochloric acid or sodium hydroxide
PH to 7.0 is saved, then with 0.22 micron of miillpore filter aseptic filtration, takes filtrate is qualified rear filling to be sub-packed in sterile glass vials
In, it is standby；
3. freeze-drying：It is quick that heat conduction oil temperature is refrigerated to -40 DEG C, constant temperature is kept 60 minutes, with 5 DEG C/h of heatings
To -10 DEG C, constant temperature is kept 80 minutes, be quickly cooled to -40 DEG C, cryostat 120 minutes.Then drying is vacuumized, with 10
DEG C/h it is warming up to, -10 DEG C of constant temperature 150 minutes；0 DEG C is warming up to 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；With 5 DEG C/h
It is warming up to 10 DEG C, 10 DEG C of constant temperature 240 minutes is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum
Drop reaches 10Pa/10 timesharing, freezes and terminates；
4. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, produces.
The present invention has following beneficial effect：
The good levo-oxiracetam aseptic powdery of stability of the present invention has solid shape, nothing is dry in lyophilized preparation process
Contracting and the phenomenon of bubbling, product homogeneity are good, and levels character is consistent, and steriling test meets the requirements, and this product impurity is few, its
Total impurities is less than 0.26%, and product stability is good, and shelf life is up to 24 months, and patient pain feels lighter, Huan Zheshun in injection process
Answering property is good.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be that following examples are only used
It is further described in the present invention, it is impossible to be interpreted as limiting the scope of the invention, without departing substantially from spirit of the invention
In the case of essence, the modifications or substitutions made to the inventive method, step or condition belong to the scope of the present invention.
Embodiment 1
A kind of good levo-oxiracetam aseptic powdery of stability, is made according to the following steps：
| Composition | Consumption (percentage by weight %) |
| Levo-oxiracetam | 54 |
| Serine | 18 |
| Mannitol | 23 |
| Polyethylene glycol 2000 | 3 |
| Phenol | 1 |
| Phenmethylol | 1 |
It is made 1000 bottles
Preparation process：
1. concentrated compounding：The supplementary material of recipe quantity is placed in container, the sterile injection of 5 times of parts by weight of levo-oxiracetam is added
Blunge, after dissolving, add the needle-use activated carbon of mass fraction 0.5%, stir 30min, then filtered with 0.45 micrometer Millipore
Membrane filtration mistake, collects filtrate, standby；
2. dilute match somebody with somebody：Sterilized water for injection is added into filtrate to 1000 times of filtrate volume, is adjusted with hydrochloric acid or sodium hydroxide
PH to 7.0 is saved, then with 0.22 micron of miillpore filter aseptic filtration, takes filtrate is qualified rear filling to be sub-packed in sterile glass vials
In, it is standby；
3. freeze-drying：It is quick that heat conduction oil temperature is refrigerated to -40 DEG C, constant temperature is kept 60 minutes, with 5 DEG C/h of heatings
To -10 DEG C, constant temperature is kept 80 minutes, be quickly cooled to -40 DEG C, cryostat 120 minutes.Then drying is vacuumized, with 10
DEG C/h it is warming up to, -10 DEG C of constant temperature 150 minutes；0 DEG C is warming up to 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；With 5 DEG C/h
It is warming up to 10 DEG C, 10 DEG C of constant temperature 240 minutes is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum
Drop reaches 10Pa/10 timesharing, freezes and terminates.
4. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, produces.
In order to be better understood from the present invention, having for invention medicine is expanded on further below by way of stability test of the present invention
Beneficial effect, rather than limitation of the present invention.
Experiment one：A kind of good levo-oxiracetam aseptic powdery stability experiment of stability of the present invention
Experiment material：
The Oxiracetam aseptic powdery sample of injection：It is made for embodiment 1
Acceleration study method：The Oxiracetam aseptic powdery of injection made from embodiment 1 is packed by listing, acceleration is put
In experimental box, certain time sampling is tested to investigation project.
Acceleration study temperature：40±2℃
Humidity：RH75% ± 5%
The investigation time：0th, 1,2,3, June
Inspection target：Character, visible foreign matters, pH, relevant material, content, sterility test
Accelerated test stability is recorded：
Acceleration study result shows：Acceleration sample in June is suitable with the every Testing index quality of 0 month sample, shows that this product adds
Speed is tested June, and quality keeps stable, and this product stability is preferable.
Long-term experiment method：Injection Oxiracetam aseptic powdery made from embodiment 1 is packed by listing, puts and stays for a long time
In sample case, certain time sampling is tested to investigation project.
Acceleration study temperature：25±2℃
Humidity：RH60% ± 10%
The investigation time：0th, 3,6,9,12,18,24 months
Inspection target：Character, visible foreign matters, pH, relevant material, content, sterility test
Long term test stability is recorded：
Long term test shows：This product long term test 24 months characters, visible foreign matters, pH value, relevant material, content and nothings
Bacterium checks that indices, without significant changes, meet every relevant regulations of production quality standard draft.This product is tried for a long time
Test 24 months steady qualities, therefore minimum 24 months of this product shelf life, long term test is still during continuing to investigate.
Experiment two：A kind of good levo-oxiracetam aseptic powdery antibacterial ability experiment of stability of the present invention
1. test objective：Investigate the antibacterial ability of levo-oxiracetam aseptic powdery.
2. test method：Sample and control sample (being made by the preparation method of embodiment 1) each 20 obtained by Example 1
(temperature 25 DEG C ± 5 DEG C, relative humidity 70% ± 10%) place 15 day, respectively at 0 are placed under natural conditions after bottle, open bottle cover
My god, sample within 5 days, 10 days, 15 days, each time point takes 5 bottles, and Sterility testing, sample preparation are carried out according to version Chinese Pharmacopoeia in 2010
Prescription see the table below：
3. result of the test：
4. conclusion：The antibacterial ability of the sample of embodiment 1 is better than control sample.
Experiment three：Pain experiment in mouse writhing method observation injection process
Test specimen：A kind of good levo-oxiracetam aseptic powdery of stability as made from embodiment 1 as test sample,
Not plus prescription levo-oxiracetam aseptic powdery as made from embodiment 1 of phenmethylol is used as control sample；
Purpose：Compare the pain degree in two kinds of levo-oxiracetam aseptic powdery injection process
Method：Experimental white mouse is taken, levo-oxiracetam aseptic powdery is subcutaneously injected, and (physiological saline solution is diluted to
10ml), whether observation small white mouse can occur writhing response, occur the probability of writhing response to judge in injection process according to mouse
The power of pain, test sample respectively repeats 30 experiments with control sample；
Result of the test：Result of the test see the table below：
| Name of product | Experiment sample (mouse) | Generation writhing response number of individuals | Writhing response incidence % |
| Test sample | 30 | 7 | 23.3% |
| Control sample | 30 | 22 | 73.3% |
Conclusion：As seen from the above table, ache in a kind of good levo-oxiracetam aseptic powdery injection process of stability of the invention
Pain is markedly less than control sample.
Embodiment 2
A kind of good levo-oxiracetam aseptic powdery of stability, is made according to the following steps：
| Composition | Consumption (percentage by weight %) |
| Levo-oxiracetam | 57 |
| Serine | 17 |
| Mannitol | 22 |
| Polyethylene glycol 2000 | 2 |
| Phenol | 1 |
| Phenmethylol | 1 |
It is made 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, the sample stability result of the test of embodiment 2 shows to accelerate sample quality stabilization in June,
Long-term 24 months steady qualities, therefore minimum 24 months of this product term of validity.Antibacterial ability test result indicates that the sample of embodiment 2 it is anti-
Bacterium ability is better than control sample.Pain result of the test in mouse writhing method observation injection process shows that the sample of embodiment 2 is noted
Pain is markedly less than control sample during penetrating.
Embodiment 3
A kind of good levo-oxiracetam aseptic powdery of stability, is made according to the following steps：
| Composition | Consumption (percentage by weight %) |
| Levo-oxiracetam | 55 |
| Serine | 18 |
| Mannitol | 22 |
| Polyethylene glycol 2000 | 3 |
| Phenol | 1 |
| Phenmethylol | 1 |
It is made 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, the sample stability result of the test of embodiment 3 shows to accelerate sample quality stabilization in June,
Long-term 24 months steady qualities, therefore minimum 24 months of this product term of validity.Antibacterial ability test result indicates that the sample of embodiment 3 it is anti-
Bacterium ability is better than control sample.Pain result of the test in mouse writhing method observation injection process shows that the sample of embodiment 3 is noted
Pain is markedly less than control sample during penetrating.
Embodiment 4-6：The good levo-oxiracetam aseptic powdery of a kind of stability, by the supplementary material preparation of following weight
, preparation method be the same as Example 1：
By the test method of embodiment 1, the sample stability result of the test of embodiment 4,5,6 shows to accelerate sample quality in June
It is stable, long-term 24 months steady qualities, therefore minimum 24 months of this product term of validity.Antibacterial ability test result indicates that embodiment 4,5,
The antibacterial ability of 6 samples is better than control sample.Pain result of the test in mouse writhing method observation injection process shows, implements
Pain is markedly less than control sample during the sample injection of example 4,5,6.
Claims (3)
1. the good levo-oxiracetam aseptic powdery of a kind of stability, it is characterised in that it is by levo-oxiracetam, L- ammonia
Acid, mannitol, polyethylene glycol, phenol, phenmethylol is supplementary material, with concentrated compounding, dilute match somebody with somebody, is freeze-dried, rolls lid step and be prepared；
The levo-oxiracetam 52% ~ 60% or so that wherein described supplementary material consumption is weight percentage, Serine 15% ~ 23% or so,
Mannitol 20% ~ 27% or so, polyethylene glycol 2000 1% ~ 5%, phenol 1% ~ 2%, phenmethylol 1% ~ 3%;The concentrated compounding step is will place
The supplementary material of side's amount is placed in container, adds the sterilized water for injection stirring of 5 times of parts by weight of levo-oxiracetam, after dissolving, plus
Enter the needle-use activated carbon of mass fraction 0.1%, stir 30min, then filtered with 0.45 micrometer Millipore filter membrane, collect filtrate；It is dilute to match somebody with somebody
Step adjusts pH to 7.0 to add sterilized water for injection into filtrate to 1000 times of filtrate volume with hydrochloric acid or sodium hydroxide,
Then with 0.22 micron of miillpore filter aseptic filtration, take filtrate is filling to be after the assay was approved sub-packed in sterile glass vials；Freezing
Heat conduction oil temperature is refrigerated to -40 DEG C by drying steps to be quick, keeps constant temperature 60 minutes, and -10 DEG C, guarantor are warming up to 5 DEG C/h
Hold constant temperature 80 minutes, be quickly cooled to -40 DEG C, cryostat 120 minutes；Then drying is vacuumized, with 10 DEG C/h of heatings
Extremely, -10 DEG C of constant temperature 150 minutes；0 DEG C is warming up to 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；10 DEG C are warming up to 5 DEG C/h,
10 DEG C of constant temperature 240 minutes, 30 DEG C are warming up to 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum drop reaches 10Pa/
10 timesharing, freeze and terminate.
2. the good levo-oxiracetam aseptic powdery of stability as claimed in claim 1, it is characterised in that it is by following heavy
The supplementary material for measuring percentage is made：Levo-oxiracetam 54% ~ 57%, Serine 17% ~ 20%, mannitol 22% ~ 25%, poly- second two
Alcohol 2,000 2% ~ 3%, phenol 1% ~ 2%, phenmethylol 1% ~ 2%;The supplementary material of recipe quantity is placed in container, left-handed Aura west is added
The sterilized water for injection stirring of smooth 5 times of parts by weight, after dissolving, adds the needle-use activated carbon of mass fraction 0.1%, stirs 30min,
Then filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, sterilized water for injection is added into filtrate to the 1000 of filtrate volume
Times, pH to 7.0 is adjusted with hydrochloric acid or sodium hydroxide, then with 0.22 micron of miillpore filter aseptic filtration, takes filtrate to examine conjunction
It is filling after lattice to be sub-packed in sterile glass vials, it is standby；It is quick that heat conduction oil temperature is refrigerated to -40 DEG C, keep constant temperature 60 minutes, with
5 DEG C/h are warming up to -10 DEG C, keep constant temperature 80 minutes, are being quickly cooled to -40 DEG C, then cryostat 120 minutes takes out true
Sky is dried, and is warming up to 10 DEG C/h, -10 DEG C of constant temperature 150 minutes；0 DEG C is warming up to 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；
10 DEG C are warming up to 5 DEG C/h, and 10 DEG C of constant temperature 240 minutes is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, together
When before case vacuum drop reach 10Pa/10 timesharing, freeze terminate.
3. a kind of preparation method of the good levo-oxiracetam aseptic powdery of stability as claimed in claim 1 or 2, its feature
It is, it is obtained as follows：
A. concentrated compounding：The supplementary material of recipe quantity is placed in container, the sterilized water for injection of 5 times of parts by weight of levo-oxiracetam is added
Stirring, after dissolving, adds the needle-use activated carbon of mass fraction 0.5%, stirs 30min, is then filtered with 0.45 micrometer Millipore filter membrane
Cross, collect filtrate, it is standby；
B. it is dilute to match somebody with somebody：Sterilized water for injection is added into filtrate to 1000 times of filtrate volume, pH is adjusted with hydrochloric acid or sodium hydroxide
To 7.0, then with 0.22 micron of miillpore filter aseptic filtration, take filtrate it is qualified it is rear it is filling be sub-packed in sterile glass vials, it is standby
With；
C. it is freeze-dried：It is quick that heat conduction oil temperature is refrigerated to -40 DEG C, keep constant temperature 60 minutes, -10 are warming up to 5 DEG C/h
DEG C, keep constant temperature 80 minutes, be quickly cooled to -40 DEG C, then cryostat 120 minutes vacuumizes drying, with 10 DEG C/it is small
When be warming up to, -10 DEG C of constant temperature 150 minutes；0 DEG C is warming up to 4 DEG C/h, 0 DEG C of constant temperature 300 minutes；It is warming up to 5 DEG C/h
10 DEG C, 10 DEG C of constant temperature 240 minutes is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum drop reaches
10Pa/10 timesharing, freezes and terminates；
D. lid is rolled：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, produces.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610195354.5A CN107281136A (en) | 2016-03-31 | 2016-03-31 | Good levo-oxiracetam aseptic powdery of a kind of stability and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610195354.5A CN107281136A (en) | 2016-03-31 | 2016-03-31 | Good levo-oxiracetam aseptic powdery of a kind of stability and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107281136A true CN107281136A (en) | 2017-10-24 |
Family
ID=60087670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610195354.5A Withdrawn CN107281136A (en) | 2016-03-31 | 2016-03-31 | Good levo-oxiracetam aseptic powdery of a kind of stability and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107281136A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766597A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Injection preparation with levo-oxiracetam as active component |
| CN102670527A (en) * | 2012-05-28 | 2012-09-19 | 南京优科生物医药研究有限公司 | Freeze-dried powder injection of L-oxiracetam and process for preparing freeze-dried powder injection |
-
2016
- 2016-03-31 CN CN201610195354.5A patent/CN107281136A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766597A (en) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | Injection preparation with levo-oxiracetam as active component |
| CN102670527A (en) * | 2012-05-28 | 2012-09-19 | 南京优科生物医药研究有限公司 | Freeze-dried powder injection of L-oxiracetam and process for preparing freeze-dried powder injection |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103446067B (en) | Oxiracetam freeze-drying preparation for injection and preparation method thereof | |
| CN107281136A (en) | Good levo-oxiracetam aseptic powdery of a kind of stability and preparation method thereof | |
| CN107281134A (en) | Good levo-oxiracetam aseptic powdery of a kind of stability and preparation method thereof | |
| CN106943360A (en) | A kind of levo-oxiracetam aseptic powdery and preparation method thereof | |
| CN107281117A (en) | Good levo-oxiracetam freeze-dried powder of a kind of stability and preparation method thereof | |
| CN107281122A (en) | A kind of levo-oxiracetam freeze-dried powder and preparation method thereof | |
| CN107281138A (en) | A kind of (S) -4- hydroxyls -2 oxo-1-pyrrolidine ethanamide aseptic powdery of injection and preparation method thereof | |
| CN107281135A (en) | A kind of injection levo-oxiracetam freeze-dried powder and preparation method thereof | |
| CN107281127A (en) | It is a kind of（S）Oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2 and preparation method thereof | |
| CN107281129A (en) | A kind of levo-oxiracetam aseptic powdery of injection and preparation method thereof | |
| CN107281126B (en) | (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide freeze-dried powder injection with good stability and preparation method thereof | |
| CN107281125A (en) | A kind of stability is good（S）Oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2 and preparation method thereof | |
| CN107281115A (en) | Good levo-oxiracetam freeze-dried powder of a kind of stability and preparation method thereof | |
| CN107281118A (en) | Good levo-oxiracetam freeze-dried powder of a kind of stability and preparation method thereof | |
| CN106692072A (en) | L-oxiracetam sterile powder with good stability and preparation method thereof | |
| CN107281131A (en) | A kind of stability is good（S）Oxo-1-pyrrolidine ethanamide freeze-dried powder of -4- hydroxyls -2 and preparation method thereof | |
| CN107397725A (en) | Injection levo-oxiracetam freeze-dried composition and preparation method thereof | |
| CN107281132A (en) | A kind of impurity is few（S）Oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2 and preparation method thereof | |
| CN106943361A (en) | It is a kind of（S）Oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2 and preparation method thereof | |
| CN107281128A (en) | Few levo-oxiracetam aseptic powdery of a kind of impurity and preparation method thereof | |
| CN107281130A (en) | A kind of levo-oxiracetam aseptic powdery injection and preparation method thereof | |
| CN106692076A (en) | (S)-oxiracetam lyophilized injection powder with good stability and preparation method of (S)-oxiracetam lyophilized injection powder | |
| CN106955272A (en) | A kind of levo-oxiracetam aseptic powdery of injection and preparation method thereof | |
| CN107281116A (en) | It is a kind of（S）Oxo-1-pyrrolidine ethanamide aseptic powdery injection of -4- hydroxyls -2 and preparation method thereof | |
| CN107281124A (en) | It is a kind of（S）Oxo-1-pyrrolidine ethanamide freeze-dried powder of -4- hydroxyls -2 and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20171024 |