CN106389350A - L-oxiracetam aseptic powder for injection and preparation method of L-oxiracetam aseptic powder - Google Patents
L-oxiracetam aseptic powder for injection and preparation method of L-oxiracetam aseptic powder Download PDFInfo
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- CN106389350A CN106389350A CN201510460328.6A CN201510460328A CN106389350A CN 106389350 A CN106389350 A CN 106389350A CN 201510460328 A CN201510460328 A CN 201510460328A CN 106389350 A CN106389350 A CN 106389350A
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Abstract
L-oxiracetam aseptic powder for injection is characterized by being prepared from the following raw and auxiliary materials, by weight percentage, 50-75% of L-oxiracetam and 25-50% of an excipient, wherein the excipient is a composition of L-serine and mannitol. The prepared L-oxiracetam aseptic powder for injection has a fixed shape, the phenomena of dry shrinkage and bubbling doesn't happen in a freeze-drying preparation process, and the prepared L-oxiracetam aseptic powder is less in impurities, wherein the amount of impurities is less than 0.23%. The use safety of the medicine improved, the adverse drug reaction of the medicine is reduced, and the medicine is good in quality. The shelf life of the medicine can reach 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field and in particular to a kind of levo-oxiracetam aseptic powdery of injection and its
Preparation method.
Background technology
Cereboactive drug is a kind of new medicine for central nervous system promoting study, strengthening memory also known as cereboactive drug.Promote
Intelligence medicine requires selection index system in cerebral cortex, has and selects activation, protection and promote 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
Connect and act on cortex.Neither affect behavior, also no calm excitation, therefore such medicine has caused the extensive pass of people
Note and interest, also grow with each passing day to the demand of such medicine.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled 4- hydroxyl -2- OXo-1-pyrrolidine second
Acid amides, (compound is disclosed in the anti anoxia class cereboactive drug synthesizing first in 1974 for Italian ISFS.P.A company
US4118396), it is ring GABOB derivative, Phosphorylcholine and phosphatidyl ethanolamine synthesis can be promoted, promote 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 this drug toxicity is extremely low, no
Mutagenesis and carcinogenesis and genotoxicity.Giorgio et al. discloses the chemistry knot of Oxiracetam in US4118396
Structure and preparation method, Chiodini et al. discloses in WO9306826A, and clinical effectiveness proves S configuration (left-handed)
The drug effect of Oxiracetam is better than R configuration (dextrorotation), and Oxiracetam and levo-oxiracetam structure are as follows.
Existing injection levo-oxiracetam aseptic powdery its be primarily present no solid shape, be difficult to form skeleton, easily occur
Drying shrinkage and bubbling phenomenon, and product stability is poor, the problems such as shelf life is short.
Content of the invention
It is an object of the invention to provide a kind of left-handed Aura of injection with solid form, good stability, shelf life length
Western smooth aseptic powdery.
Another object of the present invention is to providing the preparation method of above-mentioned injection levo-oxiracetam aseptic powdery.
The purpose of the present invention is realized by following technical measures：
A kind of levo-oxiracetam aseptic powdery of injection is it is characterised in that it is former auxiliary by following weight percents
Material is obtained：Levo-oxiracetam 50%～75%, excipient 25%～50%, wherein said excipient be sucrose, trehalose,
Mannitol, lactose, glucose, maltose, glucan, albumin, polyethylene glycol, glycerine, Serine, paddy ammonia
One or more of sour sodium, alanine, glycine, methyl amimoacetic acid, phosphate, acetate, citrate.
Inventor finds to select a certain proportion of Serine and mannitol composition in composition described above by many experiments
Composite excipient, coordinate specific levo-oxiracetam concentration again, above-mentioned injection levo-oxiracetam aseptic powder can be made
End has solid shape, easily forms skeleton, and above-mentioned injection levo-oxiracetam aseptic powdery is it is characterised in that it is
It is obtained by the supplementary material of following weight percents：Levo-oxiracetam 58%～65%, Serine 20%～25%, sweet dew
Alcohol 10%～17%.
Inventor finds in research process, adds a certain amount of polyethylene glycol 2000, product can be made to be less prone to drying shrinkage
With bubbling phenomenon, and can make shelf life extend, above-mentioned injection levo-oxiracetam aseptic powdery, its feature exists
In it is to be obtained by the supplementary material of following weight percents：Levo-oxiracetam 58%～65%, Serine 20%～25%,
Mannitol 10%～17%, polyethylene glycol 2000 5%～7%.
Most preferably, above-mentioned injection levo-oxiracetam aseptic powdery is it is characterised in that it is by following important percentage
The supplementary material of ratio is obtained：Levo-oxiracetam 59%～62%, Serine 22%～23%, mannitol 11%～13%,
Polyethylene glycol 2000 5%～7%.
A kind of preparation method of the levo-oxiracetam aseptic powdery of injection is it is characterised in that it is to make as follows
?：
1. dense join：The levo-oxiracetam of recipe quantity, excipient are placed in container, add 10 times of weights of levo-oxiracetam
The sterilized water for injection stirring of amount part, after dissolving, adds the needle-use activated carbon of mass fraction 0.1%, stirs
Mix 30min, subsequently filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, standby；
2. dilute join：Add sterilized water for injection to recipe quantity in filtrate, adjust pH to 7.0 with hydrochloric acid or NaOH,
Subsequently use 0.22 micron of miillpore filter aseptic filtration, take that filtrate is qualified filling to be afterwards sub-packed in sterile glass
In bottle, standby；
3. freeze-drying：The above-mentioned liquid being sub-packed in sterile glass vials is put in freeze drier, rapidly temperature is freezed
To -40 DEG C, whole process keeps 180 minutes, then vacuumizes drying, is risen with 15 DEG C/h
To -10 DEG C, -10 DEG C of constant temperature keep 120 minutes temperature；It is warming up to 0 DEG C with 5 DEG C/h, 0 DEG C of perseverance
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 be warming up to 30 DEG C, 30 DEG C of constant temperature 60 minutes, simultaneously front case vacuum fall reach 10Pa/10 and divide
When, it is lyophilized and terminate；
4. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, obtains final product.
The present invention has following beneficial effect：
Injection levo-oxiracetam aseptic powdery of the present invention have solid shape, in lyophilized preparation process no drying shrinkage and drum
The phenomenon of bubble, and this product impurity is few, and its total impurities is less than 0.23%, is conducive to improving the security that medicine uses, subtracts
Few adverse drug reaction, product stability is good, and shelf life is up to 24 months.
Specific embodiment
Below by embodiment, the present invention is specifically described 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 present invention spirit
In the case of essence, the modification that the inventive method, step or condition are made or replacement, belong to the scope of the present invention.
Embodiment 1
A kind of injection levo-oxiracetam aseptic powdery, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 38g |
| Mannitol | 20g |
| Polyethylene glycol 2000 | 11g |
Make 1000 bottles
Preparation process：
1. dense join：The levo-oxiracetam of recipe quantity, excipient are placed in container, add 10 times of weights of levo-oxiracetam
The sterilized water for injection stirring of amount part, after dissolving, adds the needle-use activated carbon of mass fraction 0.1%, stirs
Mix 30min, subsequently filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, standby；
2. dilute join：Add sterilized water for injection to recipe quantity in filtrate, adjust pH to 7.0 with hydrochloric acid or NaOH,
Subsequently with 0.22 micron of miillpore filter aseptic filtration, take filtrate after the assay was approved filling be sub-packed in aseptic
In vial, standby；
3. freeze-drying：The above-mentioned liquid being sub-packed in sterile glass vials is put in freeze drier, rapidly by temperature
Degree is refrigerated to -40 DEG C, and whole process keeps 180 minutes, then vacuumizes drying, with
15 DEG C/h are warming up to -10 DEG C, and -10 DEG C of constant temperature keep 120 minutes；With 5 DEG C/h
It is warming up to 0 DEG C, 0 DEG C of constant temperature 320 minutes；It is warming up to 1O DEG C with 5 DEG C/h, 10 DEG C
Constant temperature 240 minutes, is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes,
Front case vacuum fall reaches 1OPa/10 timesharing simultaneously, is lyophilized and terminates；
4. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, obtains final product.
Embodiment 2
A kind of injection levo-oxiracetam aseptic powdery, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 36g |
| Mannitol | 17g |
| Polyethylene glycol 2000 | 9g |
Make 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 3
A kind of injection levo-oxiracetam aseptic powdery, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 37g |
| Mannitol | 19g |
| Polyethylene glycol 2000 | 9g |
Make 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 4-6：A kind of injection levo-oxiracetam aseptic powdery, is prepared by the supplementary material of following weight,
Preparation method is with embodiment 1：
| Embodiment | Levo-oxiracetam | Serine | Mannitol | Polyethylene glycol 2000 |
| 4 | 100g | 37g | 21g | 10g |
| 5 | 100g | 38g | 20g | 11g |
| 6 | 100g | 36g | 19g | 11g |
In order to be better understood from the present invention, invention medicine beneficial 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 aseptic powdery stability experiment of injection of the present invention
Experiment material：
The Oxiracetam aseptic powdery sample of injection：It is obtained for embodiment 1
Acceleration study method：The Oxiracetam aseptic powdery of the injection that embodiment 1 is obtained presses listing packaging, puts acceleration
In experimental box, certain time samples, and investigation project is tested.
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 record：
Acceleration study result shows：Accelerate June sample suitable with 0 month sample items Testing index quality, show that this product adds
In speed experiment June, quality keeps stable, and this product stability is preferable.
Long-term experiment method：The injection Oxiracetam aseptic powdery that embodiment 1 is obtained presses listing packaging, puts and stays for a long time
In sample case, certain time samples, 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, pH, relevant material, content, sterility test
Long term test stability record：
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 all no significant changes, all meet every relevant regulations of production quality standard draft.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.
Claims (4)
1. a kind of levo-oxiracetam aseptic powdery of injection is it is characterised in that it is to be obtained by the supplementary material of following weight percents:Levo-oxiracetam 50% ~ 75%, excipient 25% ~ 50%；Wherein said excipient is the composition of Serine and mannitol.
2. levo-oxiracetam aseptic powdery as claimed in claim 1 is it is characterised in that it is to be obtained by the supplementary material of following weight percents：Levo-oxiracetam 58% ~ 65%, Serine 20% ~ 25%, mannitol 10% ~ 17%.
3. a kind of levo-oxiracetam aseptic powdery of injection is it is characterised in that it is to be obtained by the supplementary material of following weight percents：Levo-oxiracetam 58% ~ 65%, Serine 20% ~ 25%, mannitol 10% ~ 17%, polyethylene glycol 2000 5% ~ 7%.
4. if the preparation method of any one of the claim 1 ~ 3 levo-oxiracetam aseptic powdery of described injection is it is characterised in that it is obtained as follows：
A. dense join：The levo-oxiracetam of recipe quantity, excipient are placed in container, add the sterilized water for injection stirring of 10 times of weight portions of levo-oxiracetam, after dissolving, add the needle-use activated carbon of mass fraction 0.1%, stir 30min, subsequently filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, standby；
B. dilute join：Add sterilized water for injection to recipe quantity in filtrate, adjust pH to 7.0 with hydrochloric acid or NaOH, subsequently use 0.22 micron of miillpore filter aseptic filtration, take filtrate qualified filling afterwards be sub-packed in sterile glass vials, standby；
C. freeze-drying：The above-mentioned liquid being sub-packed in sterile glass vials is put in freeze drier, rapidly temperature is refrigerated to -40 DEG C, whole process keeps 180 minutes, then vacuumizes drying, is warming up to -10 DEG C with 15 DEG C/h, -10 DEG C of constant temperature keep 120 minutes；It is warming up to 0 DEG C with 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；Be warming up to 10 DEG C with 5 DEG C/h, 10 DEG C of constant temperature 240 minutes, be warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, simultaneously front case vacuum fall reach 10Pa/10 timesharing, be lyophilized and terminate；
D. roll lid：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 |
|---|---|---|---|
| CN201510460328.6A CN106389350A (en) | 2015-07-30 | 2015-07-30 | L-oxiracetam aseptic powder for injection and preparation method of L-oxiracetam aseptic powder |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510460328.6A CN106389350A (en) | 2015-07-30 | 2015-07-30 | L-oxiracetam aseptic powder for injection and preparation method of L-oxiracetam aseptic powder |
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| CN106389350A true CN106389350A (en) | 2017-02-15 |
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|---|---|---|---|
| CN201510460328.6A Pending CN106389350A (en) | 2015-07-30 | 2015-07-30 | L-oxiracetam aseptic powder for injection and preparation method of L-oxiracetam aseptic powder |
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| US20090291076A1 (en) * | 2005-12-28 | 2009-11-26 | Chugai Seiyaku Kabushiki Kaisha | Stabilized antibody-containing formulations |
| CN101234102A (en) * | 2007-01-31 | 2008-08-06 | 广州市众为生物技术有限公司 | Peperphentonamine hydrochloride freeze-dried injection and preparation and application thereof |
| 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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| TA01 | Transfer of patent application right |
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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