CN106377512A - S-oxiracetam freeze-dried powder for injection and preparation method thereof - Google Patents
S-oxiracetam freeze-dried powder for injection and preparation method thereof Download PDFInfo
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- CN106377512A CN106377512A CN201510460107.9A CN201510460107A CN106377512A CN 106377512 A CN106377512 A CN 106377512A CN 201510460107 A CN201510460107 A CN 201510460107A CN 106377512 A CN106377512 A CN 106377512A
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- oxiracetam
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Abstract
An S-oxiracetam freeze-dried powder for injection is characterized in that the S-oxiracetam freeze-dried powder for injection is prepared with S-oxiracetam, L-serine, mannitol, polyethylene glycol 2000 and Tween-80 as raw and auxiliary materials and through the steps of concentrated preparation, dilute preparation, freeze-drying and capping; the S-oxiracetam sterile freeze-dried powder for injection prepared according to the preparation method has a fixed shape, has no dry shrinkage or bubbling phenomena in the freeze drying preparation process, has fewer impurities, has the total impurities of less than 0.23%, is conducive to improvement of the safety of drug use, reduces adverse drug reactions, has good product clarity which is lower than that of a No.0.5 standard turbidity solution, has good stability and has the shelf life as long as 24 months.
Description
Technical field
The invention mainly relates to pharmaceutical technology field is and in particular to a kind of levo-oxiracetam freeze-dried powder and its preparation side
Method.
Background technology
Oxiracetam (S-oxiracetam) is a kind of hydroxy-amino-butyric acid of synthesis (BABOB) cyclic derivatives, only
For central nervous system, it is mainly distributed on cerebral cortex, Hippocampus, have activation, protection or the function of promoting neurocyte
Recover, improve the mnemonic learning function of disturbance of intelligence patient, and medicine does not have direct vasoactive in itself, in not having yet
Pivot excitation, the impact to ability of learning and memory is a kind of lasting facilitation.
In 1987 in Italy's listing, the dosage form of listing is tablet to this medicine, 800mg；Capsule, 800mg；Injection,
1g/5ml.Domestic at present only oxiracetam capsule and injection listing, and main active used is racemic modification.
Ye Lei etc. mention in Publication No. CN 103735545 A patent levo-oxiracetam to alcoholism caused by stupor rush
Wake up effect substantially, and dextrorotation oxiracetam does not act on substantially, the above-mentioned rush of levo-oxiracetam wakes up effect for racemization Aura
Western smooth 2 times；Levo-oxiracetam is all notable to the promoting wakening of stupor caused by wound, anesthesia.Zhang Feng etc. is in publication number
Big to traumatic brain injury caused by hydraulic pressure and freely falling body for disclosing levo-oxiracetam in the patent of CN 103599101 A
Mus learning and memory cognitive dysfunction all improves significantly, and its drug effect is far above dextrorotation oxiracetam.And
200mg/kg levo-oxiracetam is suitable with the effect of 400mg/kg oxiracetam.Pharmacokinetic study results show：
Levo-oxiracetam and dextrorotation oxiracetam no obvious chiral inversion in beasle dog body.Beasle dog single intravenous injection gives
In blood plasma after the left-handed and racemization oxiracetam of 2 multiple doses, the main pharmacokinetic parameters of levo-oxiracetam are all no substantially poor
Different.The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level, levo-oxiracetam and Aura
The western smooth toxicity no significant difference to animal subject or cell.Above-mentioned preclinical result of study shows, levo-oxiracetam
It is the main active playing drug effect in oxiracetam body, is used alone this product and can reduce Clinical practice dosage, reduce latent
Toxicity.
A kind of existing levo-oxiracetam freeze-dried powder its be primarily present no solid shape, be difficult to be formed skeleton, easily occur dry
Contracting and bubbling phenomenon, product clarity is unqualified, and 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 levo-oxiracetam freeze-dried powder with solid form, good stability.
Another object of the present invention is to providing the preparation method of 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, it is characterised in that it is with levo-oxiracetam as raw material, adds one
Quantitative excipient is obtained；Wherein said excipient be sucrose, trehalose, Mannitol, Lactose, glucose, maltose,
Glucosan, albumin, Polyethylene Glycol, glycerol, L-Serine, sodium glutamate, alanine, glycine, sarcosine,
One or more of phosphate, acetate, citrate, Tween 80.
Inventor finds in research process, selects L-Serine, Mannitol, Macrogol 2000 and Tween 80 conduct
Excipient, coordinating specific preparation technology, can make above-mentioned levo-oxiracetam freeze-dried powder have solid shape, easily
Form skeleton, product is less prone to drying shrinkage and bubbling phenomenon, shelf life extend and product clarity can be made to improve；
Above-mentioned levo-oxiracetam freeze-dried powder it is characterised in that it be with levo-oxiracetam, L-Serine, Mannitol,
Macrogol 2000, Tween 80 be supplementary material, join through overrich, dilute join, lyophilization, roll lid step be obtained；Wherein
Described dense step of joining is that supplementary material is placed in container, adds the sterilized water for injection of 10 times of weight portions of levo-oxiracetam
Stirring, after dissolving, adds the needle-use activated carbon of mass fraction 0.5%, stirs 30min, subsequently uses 0.45 micrometer Millipore
Filter membrane filters, and collects filtrate；Described dilute step of joining is to add sterilized water for injection in filtrate to recipe quantity, with hydrochloric acid or
Sodium hydroxide adjusts pH to 5.5, subsequently with 0.22 micron of microporous filter membrane aseptic filtration, takes the qualified rear fill of filtrate to divide
It is loaded in sterile glass vials.
Most preferably, above-mentioned levo-oxiracetam freeze-dried powder, it is to be obtained by the supplementary material of following significant percentage：Left
Rotation oxiracetam 54%～56%, L-Serine 16%～18%, Mannitol 25%～27%, Macrogol 2000 1%～2%,
Tween 80 0.5%～1%, above-mentioned supplementary material is placed in container, adds the sterilizing note of 10 times of weight portions of levo-oxiracetam
Penetrate and blunge, after dissolving, add the needle-use activated carbon of mass fraction 0.5%, stir 30min, subsequently with 0.45 micro-
Rice microporous filter membrane filtration, collects filtrate, adds sterilized water for injection to recipe quantity, with hydrochloric acid or sodium hydroxide in filtrate
Adjust pH to 5.5, subsequently with 0.22 micron of microporous filter membrane aseptic filtration, take the qualified rear fill of filtrate to be sub-packed in aseptic
In vial.Specific prescription proportioning, coordinates specific preparation technology and specific pH so that this quality enters one
Step improves.
A kind of preparation method of levo-oxiracetam freeze-dried powder is it is characterised in that it is obtained as follows：
1. dense join：The supplementary material of recipe quantity is placed in container, adds the sterile injection of 10 times of weight portions of levo-oxiracetam
Blunge, after dissolving, add the needle-use activated carbon of mass fraction 0.5%, stir 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 5.5 with hydrochloric acid or sodium hydroxide,
Subsequently with 0.22 micron of microporous filter membrane aseptic filtration, the qualified rear fill of filtrate is taken to be sub-packed in sterile glass
In bottle, standby；
3. lyophilization：The above-mentioned medicinal liquid being sub-packed in sterile glass vials is put in freezer dryer, rapidly temperature is freezed
To -40 DEG C, whole process keeps 180 minutes, and then evacuation 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, lyophilizing terminates；
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：
A kind of present invention levo-oxiracetam freeze-dried powder have solid shape, in lyophilizing preparation process no drying shrinkage and bubbling
Phenomenon, impurity is few, and its total impurities is less than 0.23%, is conducive to improving the safety that medicine uses, reduces adverse drug
Reaction, product clarity is good, and less than No. 0.5 standard turbidity solution, good stability, 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 levo-oxiracetam freeze-dried powder, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| L-Serine | 30g |
| Mannitol | 49g |
| Macrogol 2000 | 3g |
| Tween 80 | 1g |
Make 1000 bottles
Preparation process：
1. dense join：The supplementary material of recipe quantity is placed in container, adds the sterile injection of 10 times of weight portions of levo-oxiracetam
Blunge, after dissolving, add the needle-use activated carbon of mass fraction 0.5%, stir 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 5.5 with hydrochloric acid or sodium hydroxide,
Subsequently with 0.22 micron of microporous filter membrane aseptic filtration, the qualified rear fill of filtrate is taken to be sub-packed in sterile glass
In bottle, standby；
3. freeze-drying curve：The above-mentioned medicinal liquid being sub-packed in sterile glass vials is put in freezer dryer, rapidly temperature is freezed
To -40 DEG C, whole process keeps 180 minutes, and then evacuation 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, lyophilizing 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 levo-oxiracetam freeze-dried powder, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| L-Serine | 32g |
| Mannitol | 45g |
| Macrogol 2000 | 2g |
| Tween 80 | 1g |
Make 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 3
A kind of levo-oxiracetam freeze-dried powder, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| L-Serine | 31g |
| Mannitol | 48g |
| Macrogol 2000 | 3g |
| Tween 80 | 1g |
Make 1000 bottles
Preparation process：Preparation technology according to embodiment 1 is obtained.
Embodiment 4-6：A kind of levo-oxiracetam freeze-dried powder, is prepared by the supplementary material of following weight, preparation side
Method is with embodiment 1：
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 present invention levo-oxiracetam freeze-dried powder stability experiment
Experiment material：
The oxiracetam sterilized powder sample of injection：It is obtained for embodiment 1
Acceleration study method：The levo-oxiracetam freeze-dried powder that embodiment 1 is obtained presses listing packaging, puts Acceleration study
In case, 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：Character, visible foreign matters, clarity, 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 levo-oxiracetam freeze-dried powder that embodiment 1 is obtained presses listing packaging, puts and keeps sample for a long time
In 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：Character, visible foreign matters, clarity, pH, relevant material, content, sterility test
Long term test stability record：
Long term test shows：24 months character of this product long term test, visible foreign matters, clarity, pH, relevant material,
Content and sterility test indices all no significant changes, all meet the every related rule of production quality standard draft
Fixed.24 months steady qualities of this product long term test, therefore minimum 24 months of this product shelf life, long term test still is continuing to examine
During examining.
Claims (3)
1. a kind of levo-oxiracetam freeze-dried powder is it is characterised in that it is with levo-oxiracetam, L-Serine, Mannitol, Macrogol 2000, Tween 80 as supplementary material, joins through overrich, dilute join, lyophilization, rolls lid step and be obtained；Wherein said dense step of joining is that supplementary material is placed in container, adds 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 0.5%, stirring 30min, is subsequently filtered with 0.45 micrometer Millipore filter membrane, collects filtrate；Described dilute step of joining is to add sterilized water for injection to recipe quantity in filtrate, adjusts pH to 5.5 with hydrochloric acid or sodium hydroxide, subsequently with 0.22 micron of microporous filter membrane aseptic filtration, takes the qualified rear fill of filtrate to be sub-packed in sterile glass vials.
2. levo-oxiracetam freeze-dried powder as claimed in claim 1 is it is characterised in that it is to be obtained by the supplementary material of following significant percentage：Levo-oxiracetam 54% ~ 56%, L-Serine 16% ~ 18%, Mannitol 25% ~ 27%, Macrogol 2000 1% ~ 2%, Tween 80 0.5% ~ 1%, above-mentioned supplementary material is 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 0.5%, stirring 30min, subsequently filtered with 0.45 micrometer Millipore filter membrane, collect filtrate, add sterilized water for injection to recipe quantity in filtrate, adjust pH to 5.5 with hydrochloric acid or sodium hydroxide, subsequently with 0.22 micron of microporous filter membrane aseptic filtration, the qualified rear fill of filtrate is taken to be sub-packed in sterile glass vials.
3. the preparation method of levo-oxiracetam freeze-dried powder as claimed in claim 1 or 2 is it is characterised in that it is obtained as follows：
A. dense join：The supplementary material of recipe quantity is placed in container, adds 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 0.5%, 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 5.5 with hydrochloric acid or sodium hydroxide, subsequently with 0.22 micron of microporous filter membrane aseptic filtration, take the qualified rear fill of filtrate to be sub-packed in sterile glass vials, standby；
C. lyophilization：The above-mentioned medicinal liquid being sub-packed in sterile glass vials is put in freezer dryer, rapidly temperature is refrigerated to -40 DEG C, whole process keeps 180 minutes, and then evacuation 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, lyophilizing terminates；
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 |
|---|---|---|---|
| CN201510460107.9A CN106377512A (en) | 2015-07-30 | 2015-07-30 | S-oxiracetam freeze-dried powder for injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510460107.9A CN106377512A (en) | 2015-07-30 | 2015-07-30 | S-oxiracetam freeze-dried powder for injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106377512A true CN106377512A (en) | 2017-02-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510460107.9A Pending CN106377512A (en) | 2015-07-30 | 2015-07-30 | S-oxiracetam freeze-dried powder for injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106377512A (en) |
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 |
-
2015
- 2015-07-30 CN CN201510460107.9A patent/CN106377512A/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 |
Non-Patent Citations (2)
| Title |
|---|
| 罗明生，等: "《药剂辅料大全》", 31 January 2006, 四川科学技术出版社 * |
| 董捷: "《无公害蜂产品加工技术》", 31 January 2003, 中国农业出版社 * |
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| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
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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Application publication date: 20170208 |