CN106692074A - Good-stability freeze-dried powder injection of L-oxiracetam and preparation method thereof - Google Patents
Good-stability freeze-dried powder injection of L-oxiracetam and preparation method thereof Download PDFInfo
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- CN106692074A CN106692074A CN201510458361.5A CN201510458361A CN106692074A CN 106692074 A CN106692074 A CN 106692074A CN 201510458361 A CN201510458361 A CN 201510458361A CN 106692074 A CN106692074 A CN 106692074A
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- oxiracetam
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Abstract
The invention provides a good-stability freeze-dried powder injection of L-oxiracetam. The good-stability freeze-dried powder injection of L-oxiracetam is characterized by being prepared from L-oxiracetam, L-serine, mannitol, polyethylene glycol, Tween and phenol through concentrated-solution preparation, dilute-solution preparation, freeze drying, capping and the like. The freeze-dried powder injection of L-oxiracetam prepared in the invention has a fixed shape, is free of drying shrinkage and bubbling and low in purity content, with total purity content less than 0.22%, enables safety in medication to be improved, and reduces adverse reaction; the prepared freeze-dried powder injection of L-oxiracetam has good clarity, lower than the clarity of the standard turbidity solution No. 5; and the freeze-dried powder injection of L-oxiracetam meets sterility test requirements and has good stability and long shelf life of 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of levo-oxiracetam of good stability is freezed
Powder pin and preparation method thereof.
Background technology
Oxiracetam (S-oxiracetam) is that a kind of hydroxy-amino-butyric acid of synthesis (BABOB) ring-type derives
Thing, is only used for central nervous system, is mainly distributed on cerebral cortex, hippocampus, has activation, protection or promotes god
Through the functional rehabilitation of cell, improve the mnemonic learning function of disturbance of intelligence patient, and medicine is in itself without direct
Vasoactive, also acts on without central excitation, and the influence to ability of learning and memory is a kind of lasting facilitation.
The medicine was listed in 1987 in Italy, and the formulation of listing is tablet, 800mg；Capsule, 800mg；
Parenteral solution, 1g/5ml.Domestic at present only have oxiracetam capsule and parenteral solution listing, and chief active used into
Divide and be racemic modification.Ye Lei etc. mentions levo-oxiracetam in the A patents of Publication No. CN 103735545
Promoting wakening to being gone into a coma caused by alcoholism is obvious, and dextrorotation Oxiracetam is not acted on substantially, left-handed Aura
The awake effect of western smooth above-mentioned rush is 2 times of racemization Oxiracetam；Levo-oxiracetam is to wound, anesthesia institute stunning
The promoting wakening of fan is notable.Open peak etc. and left-handed Austria is disclosed in the patent of the A of Publication No. CN 103599101
La Xitan has bright to traumatic brain injury learning and memory in rats cognition dysfunction caused by hydraulic pressure and freely falling body
Aobvious improvement result, its drug effect is far above dextrorotation Oxiracetam.And 200mg/kg levo-oxiracetams with
The effect of 400mg/kg Oxiracetams is suitable.Pharmacokinetic study results show：Levo-oxiracetam and the right side
Rotation Oxiracetam is in beasle dog body without obvious chiral inversion.Beasle dog single intravenous injection gives left-handed and 2
After the racemization Oxiracetam of multiple dose in blood plasma levo-oxiracetam the equal no significant difference of main pharmacokinetic parameters.
The result of the tests such as safe pharmacology, anxious poison malicious, long show, under isodose level, levo-oxiracetam with it is difficult to understand
La Xitan is to animal subject or the toxicity no significant difference of cell.Above-mentioned preclinical result of study shows, left-handed
Oxiracetam is the main active that drug effect is played in Oxiracetam body, and exclusive use this product can reduce clinic to be made
With dosage, potential toxicity is reduced.
Existing levo-oxiracetam freeze-dried powder its be primarily present without solid shape, be difficult to be formed skeleton, easily occur
Drying shrinkage and bubbling phenomenon, product clarity are unqualified, and stability is poor, and shelf life is short, and steriling test is unqualified etc.
Problem.
The content of the invention
It is an object of the invention to provide a kind of levo-oxiracetam freeze-dried powder with solid form, good stability
Pin.
Preparation another object of the present invention is to provide the good levo-oxiracetam freeze-dried powder of aforementioned stable
Method.
The purpose of the present invention is realized by following technical measures：
The levo-oxiracetam freeze-dried powder of a kind of good stability, it is characterised in that it is with levo-oxiracetam
It is raw material, adds a certain amount of excipient and be obtained；Wherein described excipient be sucrose, trehalose, mannitol,
Lactose, glucose, maltose, glucan, albumin, polyethylene glycol, glycerine, Serine, glutamic acid
One kind in sodium, alanine, glycine, methyl amimoacetic acid, phosphate, acetate, citrate, Tween 80
Or it is various.
Researcher had found in research process, and a certain proportion of Serine, sweet is selected in above component
Dew alcohol, polyethylene glycol 2000, Tween 80 composition Composite excipient, are coordinating a certain amount of phenol, according to spy
Determining levo-oxiracetam freeze-dried powder obtained in preparation technology has solid shape, easily forms skeleton, is less prone to
Drying shrinkage and bubbling phenomenon, shelf life extension, clarity are improved and reach sterility requirements；Aforementioned stable is good
Levo-oxiracetam freeze-dried powder, it is characterised in that it is with levo-oxiracetam, Serine, sweet dew
Alcohol, polyethylene glycol, Tween 80, phenol be supplementary material, according to concentrated compounding, it is dilute match somebody with somebody, freeze-drying, roll lid etc.
Step is obtained；Wherein described concentrated compounding step is that the supplementary material of recipe quantity is placed in container, adds left-handed Aura west
The sterilized water for injection stirring of smooth 10 times of weight portions, after dissolving, adds the needle-use activated carbon of mass fraction 0.5%,
Stirring 30min, is then filtered with 0.45 micrometer Millipore filter membrane, collects filtrate；It is described it is dilute be to filtrate with step
Middle addition sterilized water for injection adjusts pH to 5.5, then with 0.22 to recipe quantity with hydrochloric acid or NaOH
The miillpore filter aseptic filtration of micron, takes that filtrate is qualified rear filling to be sub-packed in sterile glass vials.
The levo-oxiracetam freeze-dried powder of most preferred a kind of good stability, it is characterised in that it is by following
The supplementary material of percentage by weight is obtained：Levo-oxiracetam 50%~54%, Serine 17%~21%, sweet dew
Alcohol 25%~27%, polyethylene glycol 2000 3%~6%, Tween 80 0.5%~1%, phenol 0.1%~0.5%；Will
The supplementary material of recipe quantity is placed in container, adds the sterilized water for injection of 10 times of weight portions of levo-oxiracetam to stir
Mix, after dissolving, add the needle-use activated carbon of mass fraction 0.1%, 30min is stirred, then with 0.45 micron
Miillpore filter is filtered, and collects filtrate, to sterilized water for injection is added in filtrate to recipe quantity, with hydrochloric acid or hydrogen-oxygen
Change sodium regulation pH to 5.5, then with 0.22 micron of miillpore filter aseptic filtration, take filtrate after the assay was approved
It is filling 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 by such as
Obtained in lower step：
1. concentrated compounding：The supplementary material of recipe quantity is placed in container, 10 times of weight portions of levo-oxiracetam are added
Sterilized water for injection is stirred, and after dissolving, adds the needle-use activated carbon of mass fraction 0.5%, is 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 with hydrochloric acid or NaOH
To 5.5, then with 0.22 micron of miillpore filter aseptic filtration, filtrate is taken qualified rear filling
It is sub-packed in sterile glass vials, it is standby；
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/h are warming up to -10 DEG C, and -10 DEG C of constant temperature are kept for 120 minutes；With 5 DEG C/h
It is warming up to 0 DEG C, 0 DEG C of constant temperature 320 minutes；10 DEG C, 10 DEG C are warming up to 5 DEG C/h
Constant temperature 240 minutes, 30 DEG C are warming up to 10 DEG C/h, 30 DEG C of constant temperature 60 minutes,
Case vacuum drop reaches 10Pa/10 timesharing before simultaneously, freezes and terminates；
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, was prepared lyophilized
Phenomenon without drying shrinkage and bubbling in journey, impurity is few, and its total impurities is less than 0.22%, is conducive to raising medicine to use
Security, reduce adverse drug reaction, product clarity is good, less than No. 0.5 standard turbidity solution, meets nothing
Bacterium examination requirements, good stability, 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 following examples
It is served only for being further described the present invention, it is impossible to be interpreted as limiting the scope of the invention, is not carrying on the back
In the case of spirit of the invention and 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 | 36g |
| Mannitol | 51g |
| Polyethylene glycol 2000 | 10g |
| Tween 80 | 2g |
| Phenol | 1g |
It is made 1000 bottles
Preparation process：
1. concentrated compounding：The supplementary material of recipe quantity is placed in container, 10 times of weight portions of levo-oxiracetam are added
Sterilized water for injection is stirred, and after dissolving, adds the needle-use activated carbon of mass fraction 0.5%, is 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 with hydrochloric acid or NaOH
To 5.5, then with 0.22 micron of miillpore filter aseptic filtration, filtrate is taken qualified rear filling
It is sub-packed in sterile glass vials, it is standby；
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/h are warming up to -10 DEG C, and -10 DEG C of constant temperature are kept for 120 minutes；With 5 DEG C/h
It is warming up to 0 DEG C, 0 DEG C of constant temperature 320 minutes；10 DEG C, 10 DEG C are warming up to 5 DEG C/h
Constant temperature 240 minutes, 30 DEG C are warming up to 10 DEG C/h, 30 DEG C of constant temperature 60 minutes,
Case vacuum drop reaches 10Pa/10 timesharing before simultaneously, 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 | 32g |
| Mannitol | 47g |
| Polyethylene glycol 2000 | 6g |
| Tween 80 | 1g |
| Phenol | 0.5g |
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 | 33g |
| Mannitol | 49g |
| Polyethylene glycol 2000 | 7g |
| Tween 80 | 1g |
| Phenol | 0.8g |
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 of following weight
It is prepared, preparation method is with embodiment 1：
| Embodiment | Levo-oxiracetam | Serine | Mannitol | Polyethylene glycol 2000 | Tween 80 | Phenol |
| 4 | 100g | 35g | 50g | 9g | 1g | 1g |
| 5 | 100g | 37g | 52g | 8g | 2g | 0.8g |
| 6 | 100g 195.9 | 36g | 51g | 7g | 1g | 0.9g |
In order to be better understood from the present invention, 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 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：The levo-oxiracetam freeze-dried powder of injection obtained in embodiment 1 is wrapped by listing
Dress, is put in Acceleration study case, and 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, clarity, 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
This product Acceleration study 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, length is put
Phase keeps sample in case, certain hour sampling, and investigation project is tested.
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, clarity, 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, clarity, pH value, have
Material, content and sterility test indices are closed without significant changes, meets production quality standard draft
Every relevant regulations.24 months steady qualities of this product 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 freeze-dried powder.
2. test method：Sample obtained by Example 1 (is obtained) with control sample by the preparation method of embodiment 1
Each 20 bottles, 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, shines
Version Chinese Pharmacopoeia in 2010 carries out Sterility testing, and sample preparation prescription see the table below：
| Prescription title | Levo-oxiracetam | Serine | Mannitol | Polyethylene glycol 2000 | Tween 80 | Phenol |
| Control sample | 100g | 35g | 52g | 10g | 2g | - |
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, Tween 80, phenol as supplementary material, according to 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 0.5%, stirring 30min, is then filtered with 0.45 micrometer Millipore filter membrane, collects filtrate；It is described it is dilute be, to adding sterilized water for injection to recipe quantity in filtrate, pH to 5.5 being adjusted with hydrochloric acid or NaOH, then with 0.22 micron of miillpore filter aseptic filtration, to take that filtrate is qualified rear filling 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 50% ~ 54%, Serine 17% ~ 21%, mannitol 25% ~ 27%, polyethylene glycol 2000 3% ~ 6%, Tween 80 0.5% ~ 1%, 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 5.5 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 injection levo-oxiracetam freeze-dried powder as claimed in claim 1 or 2, 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 weight portions of levo-oxiracetam is added, after dissolving, the needle-use activated carbon of mass fraction 0.5% is added, 30min is stirred, is then filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, 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 5.5 is adjusted with hydrochloric acid or NaOH, 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. 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 |
|---|---|---|---|
| CN201510458361.5A CN106692074A (en) | 2015-07-30 | 2015-07-30 | Good-stability freeze-dried powder injection of L-oxiracetam and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510458361.5A CN106692074A (en) | 2015-07-30 | 2015-07-30 | Good-stability freeze-dried powder injection of L-oxiracetam and preparation method thereof |
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| Publication Number | Publication Date |
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| CN106692074A true CN106692074A (en) | 2017-05-24 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510458361.5A Pending CN106692074A (en) | 2015-07-30 | 2015-07-30 | Good-stability freeze-dried powder injection of L-oxiracetam and preparation method thereof |
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| Country | Link |
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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
- 2015-07-30 CN CN201510458361.5A patent/CN106692074A/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: 20170823 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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