CN106943361A - It is a kind of（S）Oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2 and preparation method thereof - Google Patents
It is a kind of（S）Oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2 and preparation method thereof Download PDFInfo
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- 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
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- 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
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Abstract
It is a kind of（S）The pyrrolidine acetamide aseptic powdery of 4 hydroxyl, 2 oxo 1, it is made by the supplementary material of following weight percents：（S）The pyrrolidine acetamide 35% ~ 45% of 4 hydroxyl, 2 oxo 1, L serines 20% ~ 28%, mannitol 25% ~ 38%, sodium glutamate 3% ~ 9%, methionine 2% ~ 10%;According to produced by the present invention（S）It is only 0.02% that impurity, which increases less, impurity incrementss, in the pyrrolidine acetamide aseptic powdery preparation process of 4 hydroxyl, 2 oxo 1, product has solid shape, in lyophilized preparation process without spray bottle phenomenon, and this product impurity is few, its total impurities is less than 0.26%, product stability is good, and shelf life is up to 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to the OXo-1-pyrrolidine second of one kind note (S) -4- hydroxyls -2
Acid amides aseptic powdery and preparation method thereof.
Background technology
It is a kind of promotion study that cereboactive drug, which is also known as cereboactive drug, strengthens the new medicine for central nervous system of memory.
Nootropics requires selection index system in cerebral cortex, with selection activation, protection and promotion damaged nerve cell functional rehabilitation
Feature.Different from other neurologic agents be a little their above-mentioned effect not by network or olfactory bulb, but directly
Act on cortex.Behavior is neither influenceed, also without calm excitation, therefore such medicine has caused the extensive concern of people and emerging
Interest, the demand to such medicine is also growing day by day.
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, promote 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.
The existing oxo-1-pyrrolidine ethanamide aseptic powdery of (S) -4- hydroxyls -2 its be primarily present preparation process impurity increase
Substantially, without solid shape, be difficult to form skeleton, easily there is spray bottle phenomenon in freeze-drying process in product, and stability is poor, and shelf life is short
The problems such as.
The content of the invention
It is an object of the invention to provide it is a kind of with solid form, good stability, shelf life length (S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide aseptic powdery.
Another object of the present invention is to provide the above-mentioned oxo-1-pyrrolidine ethanamide aseptic powdery of (S) -4- hydroxyls -2
Preparation method.
The purpose of the present invention is realized by following technical measures：
The oxo-1-pyrrolidine ethanamide aseptic powdery of one kind (S) -4- hydroxyls -2, it is characterised in that it is by following weight
The supplementary material of percentage is made：(S) oxo-1-pyrrolidine ethanamide 30%~50% of -4- hydroxyls -2, additives 50%~
70%, wherein the additives are sucrose, trehalose, mannitol, lactose, glucose, maltose, glucan, albumin, poly- second
Glycol, glycerine, Serine, vitamin C, sodium thiosulfate, methionine, sodium glutamate, alanine, glycine, methyl amimoacetic acid,
One or more in phosphate, acetate, citrate.
Inventor has found in research process, selects specific additives species, coordinates specific supplementary material consumption proportion
Relation, may be such that the oxo-1-pyrrolidine ethanamide aseptic powdery of above-mentioned injection (S) -4- hydroxyls -2 in preparation process impurity level
Increasing smaller, product has solid shape, easily forms skeleton, is not in spray bottle phenomenon in freezing dry process, and can
Extend shelf life；The above-mentioned oxo-1-pyrrolidine ethanamide aseptic powdery of (S) -4- hydroxyls -2, it is characterised in that it is
It is made by the supplementary material of following weight percents：(S) oxo-1-pyrrolidine ethanamide 35%~45% of -4- hydroxyls -2, L- ammonia
Acid 20%~28%, mannitol 25%~38%, sodium glutamate 3%~9%, methionine 2%~10%.
In order to which further such that product impurity incrementss in preparation process are smaller, shelf life is longer, above-mentioned (S) -4- hydroxyls
The oxo-1-pyrrolidine ethanamide aseptic powdery of base -2, it is characterised in that it is made by the supplementary material of following weight percents：
(S) oxo-1-pyrrolidine ethanamide 38%~42% of -4- hydroxyls -2, Serine 22%~25%, mannitol 28%~
33%, sodium glutamate 4%~7%, methionine 3%~6%.
Supplementary material needed for above-mentioned, is well known to those skilled in the art, in the market is commercially available.
The preparation method of the oxo-1-pyrrolidine ethanamide aseptic powdery of one kind (S) -4- hydroxyls -2, it is characterised in that it is
It is obtained as follows：
1. concentrated compounding：The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 of recipe quantity, additives are placed in container, plus
Enter the sterilized water for injection stirring of (S) -4- hydroxyls 10 times of parts by weight of -2 oxo-1-pyrrolidine ethanamide, after dissolving, add quality
The needle-use activated carbon of fraction 0.1%, stirs 30min, is then filtered with 0.45 micrometer Millipore filter membrane, 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 NaOH
PH to 7.0 is saved, then with 0.22 micron of miillpore filter aseptic filtration, takes that filtrate is qualified rear filling to be sub-packed in sterile glass vials
In, it is standby；
3. freeze-drying：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, it is rapidly that temperature is cold
Freeze to -40 DEG C, whole process is kept for 180 minutes, then vacuumizes drying, -10 DEG C, -10 DEG C of constant temperature are warming up to 15 DEG C/h
Kept for 120 minutes；0 DEG C is warming up to 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；10 DEG C, 10 DEG C of constant temperature are warming up to 5 DEG C/h
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, freezes
Dry and hard beam；
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：
In the oxo-1-pyrrolidine ethanamide aseptic powdery preparation process of the present invention (S) -4- hydroxyls -2 impurity increase it is less,
Impurity incrementss are only 0.02%, product has solid shape, in lyophilized preparation process without spray bottle phenomenon, and this product impurity
Few, its total impurities is less than 0.26%, and product stability is good, and shelf life is up to 24 months.
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 modification or replacement made to the inventive method, step or condition belong to the scope of the present invention.
Embodiment 1
The oxo-1-pyrrolidine ethanamide aseptic powdery of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：
1. concentrated compounding：The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 of recipe quantity, additives are placed in container, plus
Enter the sterilized water for injection stirring of (S) -4- hydroxyls 10 times of parts by weight of -2 oxo-1-pyrrolidine ethanamide, after dissolving, add quality
The needle-use activated carbon of fraction 0.1%, stirs 30min, is then filtered with 0.45 micrometer Millipore filter membrane, 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 NaOH
PH to 7.0 is saved, then with 0.22 micron of miillpore filter aseptic filtration, takes that filtrate is filling after the assay was approved to be sub-packed in sterile glass
It is standby in bottle；
3. freeze-drying：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, it is rapidly that temperature is cold
Freeze to -40 DEG C, whole process is kept for 180 minutes, then vacuumizes drying, -10 DEG C, -10 DEG C of constant temperature are warming up to 15 DEG C/h
Kept for 120 minutes；0 DEG C is warming up to 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；10 DEG C, 10 DEG C of constant temperature are warming up to 5 DEG C/h
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, freezes
Dry and hard beam；
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：The oxo-1-pyrrolidine ethanamide aseptic powdery stability experiment of present invention one kind (S) -4- hydroxyls -2
Experiment material：
The Oxiracetam aseptic powdery sample of injection：It is made for embodiment 1
Acceleration study method：Oxiracetam aseptic powdery made from embodiment 1 is packed by listing, Acceleration study case is put
In, 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：Oxiracetam aseptic powdery made from embodiment 1 is packed by listing, the long-term case that keeps sample is put
In, 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：(S) spray bottle phenomenon in the oxo-1-pyrrolidine ethanamide aseptic powdery freezing dry process of -4- hydroxyls -2
Statistics
1. test objective：Examine the spray bottle phenomenon for wiping different prescriptions in freezing dry process.
2. test method：With control sample the percentage of spray bottle phenomenon occurs in preparation process for the sample of Statistics Implementation example 1,
Control sample prescription see the table below：
Control sample prescription (% by weight percentage)
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 38% |
| Serine | 24% |
| Mannitol | 30% |
| Sodium glutamate | —— |
| Methionine | 5% |
3. result of the test：
| Numbering | Generation spray bottle bottle number | Total inspection bottle number | Spray bottle percentage % |
| Embodiment 1 | 0 | 100 | 0 |
| Control sample | 36 | 100 | 36 |
4. conclusion：Spray bottle phenomenon does not occur in freezing dry process for the sample of embodiment 1, and control sample occurs spray bottle and showed
As for 36%, therefore it is believed that the probability that spray bottle occurs for this product can effectively be reduced by adding sodium glutamate.
Experiment three：The oxo-1-pyrrolidine ethanamide aseptic powdery preparation process of present invention one kind (S) -4- hydroxyls -2 is to miscellaneous
The increased influence of matter
1. experiment material：
(S) the oxo-1-pyrrolidine ethanamide aseptic powdery sample of -4- hydroxyls -2：Prepared by embodiment 1.
(S) the oxo-1-pyrrolidine ethanamide aseptic powdery control sample of -4- hydroxyls -2：To lack the sample of methionine,
Its preparation technology be the same as Example 1.
2. experimental method：In the preparation process of embodiment 1, sampled respectively before and after preparing, detect that it, about material, investigates system
Standby process is to the influence about material.Meanwhile, the prescription for lacking methionine is taken as control prescription, by the preparation of embodiment 1
Prepared by method, sampling detects it about material equally before and after preparing, and investigates preparation process to the influence about material.
3. experimental result see the table below：
| Test sample | Relevant material % before preparing | Relevant material % after preparation | The relevant material incrementss % of preparation process |
| Embodiment 1 | 0.16% | 0.18% | 0.02% |
| Control sample 1 | 0.17% | 0.38% | 0.21% |
4. experiment conclusion：The prescription of embodiment 1, the relevant material increase of preparation process is only 0.02%, hence it is evident that better than control
Sample.
Embodiment 2
The oxo-1-pyrrolidine ethanamide aseptic powdery of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, spray bottle phenomenon statistical experiment in stability test, freezing dry process is carried out respectively
And preparation process influence increased on impurity is tested, the sample stability result of the test of embodiment 2 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；The sample of embodiment 2 in freezing dry process not
Generation spray bottle phenomenon.The influence increased on impurity of the preparation process of embodiment 2 is test result indicate that this product product in preparation process
Impurity incrementss are smaller, meet product requirement.
Embodiment 3
The oxo-1-pyrrolidine ethanamide aseptic powdery of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, spray bottle phenomenon statistical experiment in stability test, freezing dry process is carried out respectively
And preparation process influence increased on impurity is tested, the sample stability result of the test of embodiment 3 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；The sample of embodiment 3 in freezing dry process not
Generation spray bottle phenomenon.The influence increased on impurity of the preparation process of embodiment 3 is test result indicate that this product product in preparation process
Impurity incrementss are smaller, meet product requirement.
Embodiment 4-6：The oxo-1-pyrrolidine ethanamide aseptic powdery of one kind (S) -4- hydroxyls -2, by the original of following weight
Auxiliary material is prepared, preparation method be the same as Example 1：
By the test method of embodiment 1, the sample obtained by embodiment 4,5,6 carries out stability test, freezing and done respectively
Spray bottle phenomenon statistical experiment and preparation process influence experiment increased on impurity during dry, the sample of embodiment 4,5,6 are stable
Property result of the test show to accelerate June sample quality stable, long-term 24 months steady qualities, therefore minimum 24 months of this product term of validity；
Spray bottle phenomenon does not occur in freezing dry process for the sample of embodiment 4,5,6.The preparation process of embodiment 4,5,6 is to impurity increase
Influence test result indicate that this product product impurity incrementss in preparation process are smaller, meet product requirement.
Claims (3)
1. it is a kind of（S）The oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2, it is characterised in that it is by following weight hundred
The supplementary material of ratio is divided to be made：（S）The oxo-1-pyrrolidine ethanamide 35% ~ 45% of -4- hydroxyls -2, Serine 20% ~ 28%, sweet dew
Alcohol 25% ~ 38%, sodium glutamate 3% ~ 9%, methionine 2% ~ 10%.
2. it is as claimed in claim 1（S）The oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2, it is characterised in that it
It is to be made by the supplementary material of following weight percents：（S）The oxo-1-pyrrolidine ethanamide 38% ~ 42% of -4- hydroxyls -2, L- ammonia
Acid 22% ~ 25%, mannitol 28% ~ 33%, sodium glutamate 4% ~ 7%, methionine 3% ~ 6%.
3. it is as claimed in claim 1 or 2 a kind of（S）The preparation side of the oxo-1-pyrrolidine ethanamide aseptic powdery of -4- hydroxyls -2
Method, it is characterised in that it is obtained as follows：
A. concentrated compounding：By recipe quantity（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, additives are placed in container, are added
（S）The sterilized water for injection stirring of -4- hydroxyls 10 times of parts by weight of -2 oxo-1-pyrrolidine ethanamide, after dissolving, adds quality point
The needle-use activated carbon of number 0.1%, stirs 30min, is then filtered with 0.45 micrometer Millipore filter membrane, collects filtrate, 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 NaOH
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：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, be rapidly refrigerated to temperature-
40 DEG C, whole process is kept for 180 minutes, then vacuumizes drying, is warming up to -10 DEG C with 15 DEG C/h, -10 DEG C of constant temperature are kept
120 minutes；0 DEG C is warming up to 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；10 DEG C, 10 DEG C of 240 points of constant temperature are warming up to 5 DEG C/h
Clock, 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 knot
Beam；
D. lid is rolled：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, produces.
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| CN102872011A (en) * | 2012-05-31 | 2013-01-16 | 北京阜康仁生物制药科技有限公司 | Pharmaceutical composition comprising (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| CN103446067A (en) * | 2013-09-16 | 2013-12-18 | 石药集团欧意药业有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
| CN105434373A (en) * | 2016-01-11 | 2016-03-30 | 青岛辰达生物科技有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
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Application publication date: 20170714 |