CN106692073A - Levo-oxiracetam sterile powder and preparation method thereof - Google Patents
Levo-oxiracetam sterile powder and preparation method thereof Download PDFInfo
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- CN106692073A CN106692073A CN201510458344.1A CN201510458344A CN106692073A CN 106692073 A CN106692073 A CN 106692073A CN 201510458344 A CN201510458344 A CN 201510458344A CN 106692073 A CN106692073 A CN 106692073A
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- oxiracetam
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Abstract
A levo-oxiracetam sterile powder is characterized by being prepared from the following raw and auxiliary materials by the weight percentage: 35%-60% of levo-oxiracetam, and 40%-65% of an excipient, wherein the excipient is a composition of L-serine, mannitol and sodium glutamate. The levo-oxiracetam sterile powder for injection prepared by the preparation method has a fixed shape and has no bottle spraying phenomenon in a freeze-drying preparation process; the product has fewer impurities, has the total impurity content less than 0.22%, is conducive to improvement of the safety of drug use, reduces drug adverse reactions, has good product stability, and has the shelf life as long as 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to one kind note levo-oxiracetam aseptic powdery and its preparation side
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.
It is primarily present without solid shape, is difficult to form skeleton existing levo-oxiracetam aseptic powdery, and product was being freezed
Easily there is spray bottle phenomenon in journey, stability is poor, the problems such as shelf life is short.
The content of the invention
It is an object of the invention to provide a kind of levo-oxiracetam long with solid form, good stability, shelf life without
Bacterium powder end.
Preparation method another object of the present invention is to provide above-mentioned levo-oxiracetam aseptic powdery.
The purpose of the present invention is realized by following technical measures：
A kind of levo-oxiracetam aseptic powdery, it is characterised in that it is obtained by the supplementary material of following weight percents：
Levo-oxiracetam 35%~60%, excipient 40%~65%, wherein the excipient be sucrose, trehalose, mannitol,
Lactose, glucose, maltose, glucan, albumin, polyethylene glycol, glycerine, Serine, sodium glutamate, third
One or more in propylhomoserin, glycine, methyl amimoacetic acid, phosphate, acetate, citrate.
Inventor has found to select a certain proportion of Serine, mannitol and glutamic acid in composition described above by many experiments
The Composite excipient of sodium composition, coordinate specific levo-oxiracetam concentration again, may be such that above-mentioned injection left-handed Aura west
Smooth aseptic powdery has solid shape, easily forms skeleton, and product is not in spray bottle phenomenon in freezing dry process, and
And can extend shelf life；Above-mentioned levo-oxiracetam aseptic powdery, it is characterised in that it is by following weight hundred
The supplementary material of ratio is divided to be obtained：Levo-oxiracetam 42%~52%, Serine 22%~28%, mannitol 18%~32%,
Sodium glutamate 4%~12%.
Most preferably, above-mentioned levo-oxiracetam aseptic powdery, it is characterised in that it is by the original of following significant percentage
Auxiliary material is obtained：Levo-oxiracetam 45%~50%, Serine 22%~26%, mannitol 20%~26%, glutamic acid
Sodium 5%~8%.
A kind of preparation method of levo-oxiracetam aseptic powdery, it is characterised in that it is obtained as follows：
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 that filtrate is qualified rear filling to be sub-packed in sterile glass
It is standby in bottle；
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：
Levo-oxiracetam aseptic powdery of the present invention has solid shape, in lyophilized preparation process without spray bottle phenomenon, and
This product impurity is few, and its total impurities is less than 0.22%, is conducive to improving the security that medicine is used, and reduces adverse drug reaction,
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 aseptic powdery, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 55g |
| Mannitol | 52g |
| Sodium glutamate | 15g |
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 aseptic powdery, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 44g |
| Mannitol | 40g |
| Sodium glutamate | 16g |
It is made 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 3
A kind of levo-oxiracetam aseptic powdery, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Serine | 52g |
| Mannitol | 45g |
| Sodium glutamate | 11g |
It is made 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 4-6：A kind of levo-oxiracetam aseptic powdery, is prepared, preparation side by the supplementary material of following weight
Method is with embodiment 1：
| Embodiment | Levo-oxiracetam | Serine | Mannitol | Sodium glutamate |
| 4 | 100g | 50g | 45g | 12g |
| 5 | 100g | 51g | 47g | 13g |
| 6 | 100g | 50g | 43g | 15g |
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 aseptic powdery stability experiment of the present invention
Experiment material：
The Oxiracetam aseptic powdery sample of injection：For embodiment 1 is obtained
Acceleration study method：Oxiracetam aseptic powdery obtained in embodiment 1 is packed by listing, in putting Acceleration study case,
Certain hour is sampled, 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 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：Oxiracetam aseptic powdery obtained in embodiment 1 is packed by listing, in putting the long-term case that keeps sample,
Certain hour is sampled, 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 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：Spray bottle phenomenon statistics in levo-oxiracetam aseptic powdery freezing dry process
1. test objective：Examine the spray bottle phenomenon for wiping different prescriptions in freezing dry process.
2. test method：There is the percentage of spray bottle phenomenon in preparation process with control sample in the sample of Statistics Implementation example 1
Rate, control sample prescription see the table below：
Control sample prescription
| Levo-oxiracetam | 100g |
| Serine | 57g |
| Mannitol | 51g |
| Sodium glutamate | —— |
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 | 27 | 100 | 27 |
4. conclusion：There is no spray bottle phenomenon in the sample of embodiment 1, and control sample occurs spray bottle and shows in freezing dry process
As being 27%, therefore it is believed that the probability for adding sodium glutamate effectively to reduce this product generation spray bottle.
Claims (3)
1. a kind of levo-oxiracetam aseptic powdery, it is characterised in that it is obtained by the supplementary material of following weight percents:Levo-oxiracetam 35% ~ 60%, excipient 40% ~ 65%, wherein the excipient Serine, mannitol, the composition of sodium glutamate.
2. a kind of levo-oxiracetam aseptic powdery as claimed in claim 1, it is characterised in that it is obtained by the supplementary material of following weight percents：Levo-oxiracetam 42% ~ 52%, Serine 22% ~ 28%, mannitol 18% ~ 32%, sodium glutamate 4% ~ 12%.
3. the preparation method of levo-oxiracetam aseptic powdery 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 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 |
|---|---|---|---|
| CN201510458344.1A CN106692073A (en) | 2015-07-30 | 2015-07-30 | Levo-oxiracetam sterile powder and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510458344.1A CN106692073A (en) | 2015-07-30 | 2015-07-30 | Levo-oxiracetam sterile powder and preparation method thereof |
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| CN106692073A true CN106692073A (en) | 2017-05-24 |
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| CN201510458344.1A Pending CN106692073A (en) | 2015-07-30 | 2015-07-30 | Levo-oxiracetam sterile powder and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050250704A1 (en) * | 2004-05-10 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powder comprising new compositions of oligosaccharides and methods for their preparation |
| 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 |
| CN103239397A (en) * | 2013-05-30 | 2013-08-14 | 石家庄开发区博欣医药科技开发有限公司 | Oxiracetam injection composition and preparation method thereof |
| 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 |
| CN104072400A (en) * | 2014-07-04 | 2014-10-01 | 朗天药业(湖北)有限公司 | Oxiracetam compound and pharmaceutical composition thereof |
-
2015
- 2015-07-30 CN CN201510458344.1A patent/CN106692073A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050250704A1 (en) * | 2004-05-10 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powder comprising new compositions of oligosaccharides and methods for their preparation |
| 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 |
| CN103239397A (en) * | 2013-05-30 | 2013-08-14 | 石家庄开发区博欣医药科技开发有限公司 | Oxiracetam injection composition and preparation method thereof |
| 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 |
| CN104072400A (en) * | 2014-07-04 | 2014-10-01 | 朗天药业(湖北)有限公司 | Oxiracetam compound and pharmaceutical composition thereof |
Non-Patent Citations (1)
| Title |
|---|
| 刘嘉，刘汉清: "冻干技术及其在中药冻干制剂中应用的研究进展", 《中国医药技术经济与管理》 * |
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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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Application publication date: 20170524 |