CN106692076A - (S)-oxiracetam lyophilized injection powder with good stability and preparation method of (S)-oxiracetam lyophilized injection powder - Google Patents
(S)-oxiracetam lyophilized injection powder with good stability and preparation method of (S)-oxiracetam lyophilized injection powder Download PDFInfo
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- CN106692076A CN106692076A CN201510458499.5A CN201510458499A CN106692076A CN 106692076 A CN106692076 A CN 106692076A CN 201510458499 A CN201510458499 A CN 201510458499A CN 106692076 A CN106692076 A CN 106692076A
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Abstract
The invention provides an (S)-oxiracetam lyophilized injection powder with good stability. The (S)-oxiracetam lyophilized injection powder is characterized by being prepared from (S)-oxiracetam, L-serine, mannitol, polyethylene glycol 2000 and phenol as raw and auxiliary materials through steps of concentration, dilution, freeze-drying, capping and the like. The (S)-oxiracetam lyophilized injection sterile powder prepared with the preparation method has a fixed shape, is free of shrinkage and bubbling during freeze-drying preparation process and meets requirements of sterile tests; besides, the product contains fewer impurities, the total impurity content is smaller than 0.22%, the medicine use safety is improved, adverse medicine reactions are reduced, the product stability is good, and the shelf life is as long as 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of levo-oxiracetam freeze-dried powder of good stability and
Its preparation method.
Background technology
Cereboactive drug is a kind of new medicine for central nervous system for promoting study, strengthening memory also known as cereboactive drug.Promote
Intelligence medicine requirement selection index system activates, protects and promotes damaged nerve cell functional rehabilitation in cerebral cortex with selection
Feature.Different from other neurologic agents be a little their above-mentioned effect not by network or olfactory bulb, but directly
Connect and act on cortex.Behavior is neither influenceed, also without calm excitation, therefore such medicine has caused the extensive pass of people
Note and interest, the demand to such medicine are also growing day by day.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled 4- hydroxyls -2- OXo-1-pyrrolidine second
Acid amides, is that (compound is disclosed in the anti anoxia class cereboactive drug that 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, have stimulation to specific nervous centralis road, intelligence and memory can be improved, to cerebrovascular disease,
Brain trauma, brain tumor, intracranial infection, brain degenerative disease etc. also have preferable curative effect, and the drug toxicity is extremely low, nothing
Mutagenesis and carcinogenesis and genotoxicity.Giorgio et al. discloses the chemistry knot of Oxiracetam in US4118396
Structure and preparation method, Chiodini et al. are disclosed in WO9306826A, and clinical effectiveness proves S's configurations (left-handed)
The drug effect of Oxiracetam is better than R configurations (dextrorotation), and Oxiracetam and levo-oxiracetam structure are as follows.
Existing levo-oxiracetam freeze-dried powder its be primarily present without solid shape, be difficult to be formed skeleton, easily there is drying shrinkage and
Bubbling phenomenon, product stability is poor, and shelf life is short, the problems such as steriling test is unqualified.
The content of the invention
It is an object of the invention to provide a kind of levo-oxiracetam jelly long with solid form, good stability, shelf life
Dry powder pin.
Preparation method another object of the present invention is to provide above-mentioned levo-oxiracetam freeze-dried powder.
The purpose of the present invention is realized by following technical measures：
A kind of levo-oxiracetam freeze-dried powder of good stability, it is characterised in that it be with levo-oxiracetam as raw material,
A certain amount of excipient is added to be obtained；Wherein described excipient be sucrose, trehalose, mannitol, lactose, glucose,
Maltose, glucan, albumin, polyethylene glycol, glycerine, Serine, sodium glutamate, alanine, glycine,
One or more in methyl amimoacetic acid, phosphate, acetate, citrate.
Inventor has found that selection Serine, mannitol and polyethylene glycol 2000 are added as Composite excipient
A certain amount of phenol, then coordinate specific processing step, may be such that levo-oxiracetam freeze-dried powder have solid shape,
Skeleton, product is easily formed to be less prone to drying shrinkage and bubbling phenomenon, meet sterility requirements and shelf life extension；One
The levo-oxiracetam freeze-dried powder of kind of good stability, it is characterised in that it be with levo-oxiracetam, Serine,
Mannitol, polyethylene glycol 2000, phenol be supplementary material, by concentrated compounding, it is dilute match somebody with somebody, freeze-drying, roll lid etc. step be obtained；
Wherein described concentrated compounding step is that the supplementary material of recipe quantity is placed in container, adds 10 times of weight portions of levo-oxiracetam
Sterilized water for injection is stirred, and after dissolving, adds the needle-use activated carbon of mass fraction 0.1%, stirs 30min, is then used
0.45 micrometer Millipore filter membrane is filtered, and collects filtrate；It is dilute with step be in filtrate add sterilized water for injection to recipe quantity,
PH to 7.0 is adjusted with hydrochloric acid or NaOH, then with 0.22 micron of miillpore filter aseptic filtration, filtrate inspection is taken
It is qualified rear filling to be sub-packed in sterile glass vials.
Most preferred above-mentioned levo-oxiracetam freeze-dried powder, it is characterised in that it is by the former auxiliary of following weight percents
Material is obtained：Levo-oxiracetam 59%~61%, Serine 17%~18%, mannitol 19%~21%, polyethylene glycol
20002%~4%, phenol 0.1%~0.5%；The supplementary material of recipe quantity is placed in container, levo-oxiracetam 10 is added
The sterilized water for injection stirring of times weight portion, 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, to adding sterilized water for injection to recipe quantity in filtrate, use salt
Acid or NaOH regulation pH to 7.0, then with 0.22 micron of miillpore filter aseptic filtration, take filtrate inspection qualified
It is filling afterwards to be sub-packed in sterile glass vials.
The preparation method of the levo-oxiracetam freeze-dried powder of a kind of good stability, it is characterised in that it is as follows
It is obtained：
1. concentrated compounding：The levo-oxiracetam of recipe quantity, excipient are placed in container, 10 times of weights of levo-oxiracetam are added
The sterilized water for injection stirring of part is measured, after dissolving, the needle-use activated carbon of mass fraction 0.1% is added, stirred
30min is mixed, is then filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, it is standby；
2. it is dilute to match somebody with somebody：To sterilized water for injection to recipe quantity is added in filtrate, pH is adjusted to 7.0 with hydrochloric acid or NaOH,
Then with 0.22 micron of miillpore filter aseptic filtration, take filtrate after the assay was approved it is filling be sub-packed in it is aseptic
It is standby in vial；
3. freeze-drying：During the above-mentioned liquid being sub-packed in sterile glass vials put into freeze drier, temperature is freezed rapidly
To -40 DEG C, whole process is kept for 180 minutes, then vacuumizes drying, is risen with 15 DEG C/h
To -10 DEG C, -10 DEG C of constant temperature are kept for 120 minutes temperature；0 DEG C, 0 DEG C of perseverance are warming up to 5 DEG C/h
Temperature 320 minutes；Be warming up to 10 DEG C with 5 DEG C/h, 10 DEG C of constant temperature 240 minutes, with 10 DEG C/
Hour is warming up to 30 DEG C, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum drop reaches 10Pa/10 points
When, freeze and terminate；
4. lid is rolled：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, obtains final product.
The present invention has following beneficial effect：
A kind of levo-oxiracetam freeze-dried powder of good stability of the present invention has solid shape, the nothing in lyophilized preparation process
The phenomenon of drying shrinkage and bubbling, steriling test meets the requirements, and this product impurity is few, and its total impurities is less than 0.22%, favorably
In the security that medicine is used is improved, adverse drug reaction is reduced, product stability is good, and shelf life is up to 24 months.
Specific 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 served only for
The present 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
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
A kind of levo-oxiracetam freeze-dried powder of good stability, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 30g |
| Mannitol | 33g |
| Polyethylene glycol 2000 | 4g |
| Phenol | 0.5g |
It is made 1000 bottles
Preparation process：
1. concentrated compounding：The levo-oxiracetam of recipe quantity, excipient are placed in container, 10 times of weights of levo-oxiracetam are added
The sterilized water for injection stirring of part is measured, after dissolving, the needle-use activated carbon of mass fraction 0.1% is added, stirred
30min is mixed, is then filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, it is standby；
2. it is dilute to match somebody with somebody：To sterilized water for injection to recipe quantity is added in filtrate, pH is adjusted to 7.0 with hydrochloric acid or NaOH,
Then with 0.22 micron of miillpore filter aseptic filtration, take filtrate after the assay was approved it is filling be sub-packed in it is aseptic
It is standby in vial；
3. freeze-drying：During the above-mentioned liquid being sub-packed in sterile glass vials put into freeze drier, rapidly by temperature
Degree is refrigerated to -40 DEG C, and whole process is kept for 180 minutes, then vacuumizes drying, with 15 DEG C/
Hour is warming up to -10 DEG C, and -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, 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, freezes and terminates；
4. lid is rolled：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, obtains final product.
Embodiment 2
A kind of levo-oxiracetam freeze-dried powder of good stability, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 29g |
| Mannitol | 32g |
| Polyethylene glycol 2000 | 4g |
| Phenol | 0.7g |
It is made 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 3
A kind of levo-oxiracetam freeze-dried powder of good stability, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 30g |
| Mannitol | 32g |
| Polyethylene glycol 2000 | 5g |
| Phenol | 0.5g |
It is made 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 4-6：The levo-oxiracetam freeze-dried powder of a kind of good stability, by the supplementary material preparation of following weight
, preparation method is with embodiment 1：
| Embodiment | Levo-oxiracetam | Serine | Mannitol | Polyethylene glycol 2000 | Phenol |
| 4 | 100g | 30g | 32g | 5g | 0.5g |
| 5 | 100g | 31g | 35g | 4g | 0.6g |
| 6 | 100g | 29g | 31g | 5g | 0.6g |
In order to be better understood from the present invention, the beneficial of invention medicine is expanded on further below by way of stability test of the present invention
Effect, rather than limitation of the present invention.
Experiment one：A kind of levo-oxiracetam freeze-dried powder stability experiment of good stability of the present invention
Experiment material：
Levo-oxiracetam freeze-dried powder sample：For embodiment 1 is obtained
Acceleration study method：Levo-oxiracetam freeze-dried powder obtained in embodiment 1 is packed by listing, Acceleration study is put
In case, certain hour sampling is tested to investigation project.
Acceleration study temperature：40±2℃
Humidity：RH75% ± 5%
The investigation time：0th, 1,2,3, June
Inspection target：Proterties, visible foreign matters, pH, relevant material, content, sterility test
Accelerated test stability is recorded：
Acceleration study result shows：Accelerate June sample suitable with 0 month sample items Testing index quality, show that this product adds
Speed experiment June, quality keeps stabilization, and this product stability is preferable.
Long-term experiment method：Levo-oxiracetam freeze-dried powder obtained in embodiment 1 is packed by listing, is put and is kept sample for a long time
In case, certain hour 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：Proterties, visible foreign matters, pH, relevant material, content, sterility test
Long term test stability is recorded：
Long term test shows：24 months proterties of this product long term test, visible foreign matters, pH value, relevant material, content with
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：A kind of levo-oxiracetam freeze-dried powder antibacterial ability experiment of good 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 obtained by the preparation method of embodiment 1) each 20 obtained by Example 1
Bottle, be placed under natural conditions after open bottle cover (25 DEG C ± 5 DEG C of temperature, relative humidity 70% ± 10%) place 15 days,
Sampled respectively at 0 day, 5 days, 10 days, 15 days, each time point takes 5 bottles, enters according to version Chinese Pharmacopoeia in 2010
Row Sterility testing, sample preparation prescription see the table below：
| Prescription title | Levo-oxiracetam | Serine | Mannitol | Polyethylene glycol 2000 | Phenol |
| Control sample | 100g | 32g | 35g | 5g | - |
3. result of the test：
4. conclusion：The antibacterial ability of the sample of embodiment 1 is better than control sample.
Claims (3)
1. the levo-oxiracetam freeze-dried powder of a kind of good stability, it is characterised in that it is, with levo-oxiracetam, Serine, mannitol, polyethylene glycol 2000, phenol as supplementary material, by concentrated compounding, dilute to match somebody with somebody, freeze-drying, roll the steps such as lid and be obtained；Wherein described concentrated compounding step is that the supplementary material of recipe quantity is placed in container, the sterilized water for injection stirring of 10 times of weight portions of levo-oxiracetam is added, after dissolving, add the needle-use activated carbon of mass fraction 0.1%, stirring 30min, is then filtered with 0.45 micrometer Millipore filter membrane, collects filtrate；Dilute is, to adding sterilized water for injection to recipe quantity in filtrate, pH to 7.0 being adjusted with hydrochloric acid or NaOH, then with 0.22 micron of miillpore filter aseptic filtration, to take that filtrate is filling after the assay was approved to be sub-packed in sterile glass vials with step.
2. the levo-oxiracetam freeze-dried powder of a kind of good stability as claimed in claim 1, it is characterised in that it is obtained by the supplementary material of following weight percents：Levo-oxiracetam 59% ~ 61%, Serine 17% ~ 18%, mannitol 19% ~ 21%, polyethylene glycol 2000 2% ~ 4%, phenol 0.1% ~ 0.5%；The supplementary material of recipe quantity is placed in container, add the sterilized water for injection stirring of 10 times of weight portions of levo-oxiracetam, after dissolving, the needle-use activated carbon of mass fraction 0.1% is added, stir 30min, then filtered with 0.45 micrometer Millipore filter membrane, filtrate is collected, to sterilized water for injection to recipe quantity is added in filtrate, pH to 7.0 is adjusted with hydrochloric acid or NaOH, then with 0.22 micron of miillpore filter aseptic filtration, take that filtrate is filling after the assay was approved to be sub-packed in sterile glass vials.
3. the preparation method of the levo-oxiracetam freeze-dried powder of a kind of good stability as claimed in claim 1 or 2, it is characterised in that it is obtained as follows：
A. concentrated compounding：The levo-oxiracetam of recipe quantity, excipient are placed in container, the sterilized water for injection stirring of 10 times of weight portions of levo-oxiracetam are added, after dissolving, the needle-use activated carbon of mass fraction 0.1% is added, 30min is stirred, is then filtered with 0.45 micrometer Millipore filter membrane, filtrate is collected, it is standby；
B. it is dilute to match somebody with somebody：To adding sterilized water for injection to recipe quantity in filtrate, pH to 7.0 is adjusted with hydrochloric acid or NaOH, then with 0.22 micron of miillpore filter aseptic filtration, take that filtrate is filling after the assay was approved to be sub-packed in sterile glass vials, it is standby；
C. freeze-drying：During the above-mentioned liquid being sub-packed in sterile glass vials put into freeze drier, temperature is refrigerated to -40 DEG C 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, obtains final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510458499.5A CN106692076A (en) | 2015-07-30 | 2015-07-30 | (S)-oxiracetam lyophilized injection powder with good stability and preparation method of (S)-oxiracetam lyophilized injection powder |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510458499.5A CN106692076A (en) | 2015-07-30 | 2015-07-30 | (S)-oxiracetam lyophilized injection powder with good stability and preparation method of (S)-oxiracetam lyophilized injection powder |
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| CN106692076A true CN106692076A (en) | 2017-05-24 |
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| CN201510458499.5A Pending CN106692076A (en) | 2015-07-30 | 2015-07-30 | (S)-oxiracetam lyophilized injection powder with good stability and preparation method of (S)-oxiracetam lyophilized injection powder |
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Citations (1)
| 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 |
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- 2015-07-30 CN CN201510458499.5A patent/CN106692076A/en active Pending
Patent Citations (1)
| 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 |
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Effective date of registration: 20170825 Address after: 400042 Chongqing city Yubei District Qinye Road No. 9 Applicant after: Chongqing Runze Pharmaceutical Co., Ltd. Address before: 400030 Chongqing city Shapingba District Yubei Road No. 50 of No. 13-15-6A Applicant before: DONGZE PHARMACEUTICAL SCIENCE AND TECHNOLOGY CO., LTD. |
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Application publication date: 20170524 |