CN107281114A - A kind of injection levo-oxiracetam freeze-dried powder and preparation method thereof - Google Patents
A kind of injection levo-oxiracetam freeze-dried powder and preparation method thereof Download PDFInfo
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- 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
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
A kind of injection levo-oxiracetam freeze-dried powder, it be using levo-oxiracetam, L serines, mannitol, sodium glutamate, Tween 80, methionine, phenmethylol as supplementary material by concentrated compounding, it is dilute match somebody with somebody, be freeze-dried, roll lid etc. step be prepared；The levo-oxiracetam 33% ~ 38% that wherein described supplementary material consumption is weight percentage, L serines 22% ~ 27%, mannitol 28% ~ 33%, sodium glutamate 6% ~ 12%, Tween 80 1% ~ 2%, methionine 2% ~ 7%, phenmethylol 1% ~ 3%;According to levo-oxiracetam freeze-dried powder produced by the present invention, less, the impurity incrementss of impurity increase are only 0.02% in preparation process, product has solid shape, in lyophilized preparation process without spray bottle phenomenon, impurity is few, its total impurities is less than 0.30%, and product clarity is good, less than No. 0.5 standard turbidity solution, stability is good, shelf life is up to 24 months, and pain is lighter in patient injection procedure, good patient compliance.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of injection levo-oxiracetam freeze-dried powder and preparation method thereof.
Background technology
Oxiracetam (S-oxiracetam) is a kind of hydroxy-amino-butyric acid of synthesis (BABOB) cyclic derivatives, in being only used for
Pivot nervous system, is mainly distributed on cerebral cortex, hippocampus, there is activation, protection or the functional rehabilitation for promoting nerve cell, improves
The mnemonic learning function of disturbance of intelligence patient, and medicine is also acted in itself without direct vasoactive without central excitation, it is right
The influence of ability of learning and memory is a kind of lasting facilitation.
The medicine is in 1987 in Italy's listing, and the formulation of listing is tablet, 800mg；Capsule, 800mg；Parenteral solution, 1g/5ml.
It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic modification.Ye Lei etc. is in public affairs
The number of opening is obvious to the promoting wakening gone into a coma caused by alcoholism to mention levo-oxiracetam in the A patents of CN 103735545, and right
Rotation Oxiracetam is not acted on substantially, and the awake effect of above-mentioned rush of levo-oxiracetam is 2 times of racemization Oxiracetam；Left-handed Aura west
The smooth promoting wakening to stupor caused by wound, anesthesia is notable.Peak etc. is opened to drape over one's shoulders in the A of Publication No. CN 103599101 patent
Dew levo-oxiracetam has significantly to traumatic brain injury learning and memory in rats cognition dysfunction caused by hydraulic pressure and freely falling body
Improvement result, its drug effect is far above dextrorotation Oxiracetam.And 200mg/kg levo-oxiracetams and 400mg/kg Oxiracetams
Effect is suitable.Pharmacokinetic study results are shown：Levo-oxiracetam and dextrorotation Oxiracetam are in beasle dog body without obvious hand
Property conversion.Beasle dog single intravenous injection gives after left-handed and 2 multiple doses racemization Oxiracetams levo-oxiracetam in blood plasma
The equal no significant difference of main pharmacokinetic parameters.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level,
Levo-oxiracetam is with Oxiracetam to animal subject or the toxicity no significant difference of cell.Above-mentioned preclinical result of study shows,
Levo-oxiracetam is the main active that drug effect is played in Oxiracetam body, and this product, which is used alone, can reduce Clinical practice dosage,
Reduce potential toxicity.
Existing injection levo-oxiracetam freeze-dried powder its be primarily present in preparation process impurity increase substantially, without solid shape, no
Easily formed in skeleton, freezing dry process and easily spray bottle phenomenon occur, product clarity is unqualified, and stability is poor, and shelf life is short,
And product injection process pain is substantially, the problems such as patient's poor compliance.
The content of the invention
It is an object of the invention to provide a kind of injection levo-oxiracetam freeze-dried powder good with solid form, stability.
Another object of the present invention is to provide the preparation method of above-mentioned injection levo-oxiracetam freeze-dried powder.
The purpose of the present invention is realized by following technical measures：
A kind of injection levo-oxiracetam freeze-dried powder, it is characterised in that it is, using levo-oxiracetam as raw material, to add one
Quantitative additives are made；Wherein described additives are sucrose, trehalose, mannitol, lactose, glucose, maltose, Portugal
Glycan, albumin, polyethylene glycol, glycerine, Serine, vitamin C, sodium thiosulfate, methionine, sodium glutamate,
One or more in alanine, glycine, methyl amimoacetic acid, phosphate, acetate, citrate, Tween 80, phenmethylol.
Inventor has found to select specific supplementary material species and specific supplementary material proportioning to close in research process by many experiments
System, coordinates special processing step, can cause the impurity increase in preparation process of above-mentioned injection levo-oxiracetam freeze-dried powder
It is smaller, product have solid shape, easily form skeleton, be not in that spray bottle phenomenon, product clarity have in freezing dry process
Improved, and product injection process pain has mitigated；Above-mentioned injection levo-oxiracetam freeze-dried powder, it is characterised in that
It is using levo-oxiracetam, Serine, mannitol, sodium glutamate, Tween 80, methionine, phenmethylol as supplementary material
By concentrated compounding, it is dilute match somebody with somebody, be freeze-dried, roll lid etc. step be prepared；The left side that wherein described supplementary material consumption is weight percentage
Revolve Oxiracetam 33%~38%, Serine 22%~27%, mannitol 28%~33%, sodium glutamate 6%~12%, tween
80 1%~2%, methionine 2%~7%, phenmethylol 1%~3%.
Further, a kind of injection levo-oxiracetam freeze-dried powder, it is characterised in that it is the original by following weight percents
Auxiliary material is made：Levo-oxiracetam 33%~36%, Serine 23%~25%, mannitol 29%~31%, sodium glutamate
6%~8%, Tween 80 1%~2%, methionine 3%~6%, phenmethylol 1%~2%；Above-mentioned supplementary material is placed in container,
The sterilized water for injection stirring of 10 times of parts by weight of levo-oxiracetam is added, after dissolving, the pin for adding mass fraction 0.5% is lived
Property charcoal, stir 30min, then with 0.45 micrometer Millipore filter membrane filter, collection filtrate, sterilized water for injection is added into filtrate
To 1000 times of filtrate volume, pH to 5.5 is adjusted with hydrochloric acid or sodium hydroxide, it is then degerming with 0.22 micron of miillpore filter
Filtering, takes filtrate is qualified rear filling to be sub-packed in sterile glass vials.Specific prescription proportioning, coordinates specific pH and specific
Supplementary material process step so that this quality is further improved.
A kind of preparation method of injection levo-oxiracetam freeze-dried powder, it is characterised in that it is obtained as follows：
1. concentrated compounding：The supplementary material of recipe quantity is placed in container, the sterilized water for injection of 10 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, then micro- with 0.45
Rice miillpore filter filtration, collects filtrate, standby；
2. dilute 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 5.5, 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 it is sterile
It is standby in vial；
3. freeze-drying：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, rapidly temperature is refrigerated to
- 40 DEG C, whole process is kept for 180 minutes, then vacuumizes drying, -10 DEG C are warming up to 15 DEG C/h,
- 10 DEG C of constant temperature are kept for 120 minutes；0 DEG C is warming up to 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；With 5 DEG C/
Hour is warming up to 10 DEG C, 10 DEG C of constant temperature 240 minutes, and 30 DEG C, 30 DEG C of constant temperature are warming up to 10 DEG C/h
60 minutes, while preceding case vacuum drop reaches 10Pa/10 timesharing, freeze and terminate；
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：
It is only 0.02% that injection levo-oxiracetam freeze-dried powder of the present invention impurity in preparation process, which increases less, impurity incrementss,
Product has solid shape, in lyophilized preparation process without spray bottle phenomenon, impurity is few, and its total impurities is less than 0.30%, and product is clear
Spend clearly, less than No. 0.5 standard turbidity solution, stability is good, shelf life is up to 24 months, and pain is lighter in patient injection procedure,
Good patient compliance.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be following examples be served only for this
Invention is further described, it is impossible to be interpreted as limiting the scope of the invention, without departing substantially from spirit of the invention and essence
In the case of, 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 injection levo-oxiracetam freeze-dried powder, is made according to the following steps：
Preparation process：
1. concentrated compounding：The supplementary material of recipe quantity is placed in container, the sterilized water for injection of 10 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, then micro- with 0.45
Rice miillpore filter filtration, collects filtrate, standby；
2. dilute 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 5.5, 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 it is sterile
It is standby in vial；
3. freeze-drying：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, rapidly temperature is refrigerated to
- 40 DEG C, whole process is kept for 180 minutes, then vacuumizes drying, -10 DEG C are warming up to 15 DEG C/h,
- 10 DEG C of constant temperature are kept for 120 minutes；0 DEG C is warming up to 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；With 5 DEG C/
Hour is warming up to 10 DEG C, 10 DEG C of constant temperature 240 minutes, and 30 DEG C, 30 DEG C of constant temperature are warming up to 10 DEG C/h
60 minutes, while preceding case vacuum drop reaches 10Pa/10 timesharing, freeze and terminate；
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, the beneficial effect of invention medicine is expanded on further below by way of stability test of the present invention,
Rather than limitation of the present invention.
Experiment one：A kind of injection levo-oxiracetam freeze-dried powder stability experiment of the present invention
Experiment material：
Injection levo-oxiracetam freeze-dried powder sample：It is made for embodiment 1
Acceleration study method：Injection levo-oxiracetam freeze-dried powder made from embodiment 1 is packed by listing, Acceleration study is put
In case, 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, clarity, 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 accelerates real
Test June, quality keeps stable, and this product stability is preferable.
Long-term experiment method：Injection levo-oxiracetam freeze-dried powder made from embodiment 1 is packed by listing, puts and keeps sample for a long time
In 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, clarity, pH, relevant material, content, sterility test
Long term test stability is recorded：
Long term test shows：24 months characters of this product long term test, visible foreign matters, clarity, pH value, relevant material, contain
Amount and sterility test indices meet every relevant regulations of production quality standard draft without significant changes.This product
24 months steady qualities of long term test, therefore minimum 24 months of this product shelf life, long term test is still during continuing to investigate.
Experiment two：Spray bottle phenomenon is counted in injection levo-oxiracetam freeze-dried powder freezing dry process
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 (percentage by weight meter)
| Levo-oxiracetam | 33% |
| Serine | 25% |
| Mannitol | 32% |
| Sodium glutamate | —— |
| Tween 80 | 2% |
| Methionine | 6% |
| Phenmethylol | 2% |
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 | 43 | 100 | 43 |
4. conclusion：Spray bottle phenomenon does not occur in freezing dry process for the sample of embodiment 1, and control sample generation spray bottle phenomenon is
43%, therefore it is believed that the probability that spray bottle occurs for this product can effectively be reduced by adding sodium glutamate.
Experiment three：A kind of injection levo-oxiracetam freeze-dried powder preparation process of the present invention is on the increased influence of impurity
1. experiment material：
Levo-oxiracetam freeze-dried powder sample：Prepared by embodiment 1.
Levo-oxiracetam freeze-dried powder control sample：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, is investigated and prepared
Process is to the influence about material.Meanwhile, the prescription for lacking methionine is taken as control prescription, by the preparation side 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 | 0.16% | 0.33% | 0.17% |
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.
Experiment four：Pain experiment in mouse writhing method observation injection process
Test specimen：A kind of injection levo-oxiracetam freeze-dried powder as made from embodiment 1 does not add the place of phenmethylol as test sample
Side's levo-oxiracetam freeze-dried powder as made from embodiment 1 is used as control sample；
Purpose：Compare the pain degree in two kinds of levo-oxiracetam freeze-dried powder injection process
Method：Experimental white mouse is taken, levo-oxiracetam freeze-dried powder (physiological saline solution is diluted to 10ml) is subcutaneously injected, is observed small
Whether white mouse can occur writhing response, occur the probability of writhing response to judge pain in injection process according to mouse
Power, 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 | 3 | 10.0% |
| Control sample | 30 | 26 | 86.7% |
Conclusion：As seen from the above table, pain is markedly less than control in a kind of injection levo-oxiracetam freeze-dried powder injection process of the invention
Sample.
Embodiment 2
A kind of injection levo-oxiracetam freeze-dried powder, is made according to the following steps：
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
24 months phases steady quality, therefore minimum 24 months of this product term of validity；The sample of embodiment 2 does not spray in freezing dry process
Bottle phenomenon；The influence increased on impurity of the preparation process of embodiment 2 is test result indicates that this product product impurity increase in preparation process
Amount is smaller, meets product requirement；Mouse writhing method observation injection process in pain result of the test show, the sample of embodiment 2
Pain is markedly less than control sample in injection process.
Embodiment 3
A kind of injection levo-oxiracetam freeze-dried powder, is made according to the following steps：
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
24 months phases steady quality, therefore minimum 24 months of this product term of validity；The sample of embodiment 3 does not spray in freezing dry process
Bottle phenomenon；The influence increased on impurity of the preparation process of embodiment 3 is test result indicates that this product product impurity increase in preparation process
Amount is smaller, meets product requirement；Mouse writhing method observation injection process in pain result of the test show, the sample of embodiment 3
Pain is markedly less than control sample in injection process.
Embodiment 4-6：A kind of injection levo-oxiracetam freeze-dried powder, is prepared, preparation method by the supplementary material of following weight
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 that acceleration sample quality in June is steady
It is fixed, long-term 24 months steady qualities, therefore minimum 24 months of this product term of validity；The sample of embodiment 4,5,6 had been freeze-dried
Spray bottle phenomenon does not occur for Cheng Zhongjun.The influence increased on impurity of the preparation process of embodiment 4,5,6 is test result indicates that this product is in system
Product impurity incrementss are smaller during standby, meet product requirement.Pain experiment in mouse writhing method observation injection process
As a result show, pain is markedly less than control sample during the sample injection of embodiment 4,5,6.
Claims (3)
1. a kind of injection levo-oxiracetam freeze-dried powder, characterized in that, it be using levo-oxiracetam, Serine, mannitol, sodium glutamate, Tween 80, methionine, phenmethylol as supplementary material by concentrated compounding, it is dilute match somebody with somebody, be freeze-dried, roll lid etc. step be prepared；The levo-oxiracetam about 33% ~ 38% that wherein described supplementary material consumption is weight percentage, Serine about 22% ~ 27%, mannitol about 28% ~ 33%, sodium glutamate 6% ~ 12%, Tween 80 1% ~ 2%, methionine 2% ~ 7%, phenmethylol 1% ~ 3%.
2. injection levo-oxiracetam freeze-dried powder as claimed in claim 1, it is characterised in that it is made by the supplementary material of following weight percents:Levo-oxiracetam 33% ~ 36%, Serine 23% ~ 25%, mannitol 29% ~ 31%, sodium glutamate 6% ~ 8%, Tween 80 1% ~ 2%, methionine 3% ~ 6%, phenmethylol 1% ~ 2%；Above-mentioned supplementary material is placed in container, add the sterilized water for injection stirring of 10 times of parts by weight of levo-oxiracetam, after dissolving, the needle-use activated carbon of mass fraction 0.5% is added, 30min is stirred, then filtered with 0.45 micrometer Millipore filter membrane, filtrate is collected, sterilized water for injection is added into filtrate to 1000 times of filtrate volume, pH to 5.5 is adjusted with hydrochloric acid or sodium hydroxide, then with 0.22 micron of miillpore filter aseptic filtration, take filtrate is qualified rear filling to be sub-packed in sterile glass vials.
3. a kind of preparation method of injection levo-oxiracetam freeze-dried powder, it is characterised in that it is obtained as follows：
A. concentrated compounding：The supplementary material of recipe quantity is placed in container, the sterilized water for injection stirring of 10 times of parts by weight of levo-oxiracetam is added, after dissolving, adds the needle-use activated carbon of mass fraction 0.5%, stir 30min, then filtered with 0.45 micrometer Millipore filter membrane, 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 to 5.5 is adjusted with hydrochloric acid or sodium hydroxide, 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；
C. it is freeze-dried：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, temperature -40 DEG C are refrigerated to rapidly, whole process is kept for 180 minutes, then vacuumizes drying, -10 DEG C are warming up to 15 DEG C/h, -10 DEG C of constant temperature are 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 are warming up to 5 DEG C/h, 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, is freezed and terminated；
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 |
|---|---|---|---|
| CN201610194253.6A CN107281114A (en) | 2016-03-31 | 2016-03-31 | A kind of injection levo-oxiracetam freeze-dried powder and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610194253.6A CN107281114A (en) | 2016-03-31 | 2016-03-31 | A kind of injection levo-oxiracetam freeze-dried powder and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN107281114A true CN107281114A (en) | 2017-10-24 |
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| CN201610194253.6A Withdrawn CN107281114A (en) | 2016-03-31 | 2016-03-31 | A kind of injection levo-oxiracetam freeze-dried powder and preparation method thereof |
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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 |
| 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 |
-
2016
- 2016-03-31 CN CN201610194253.6A patent/CN107281114A/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 |
| 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 |
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Application publication date: 20171024 |