CN106692043A - Good-stability levo oxiracetam injection and preparation method thereof - Google Patents
Good-stability levo oxiracetam injection and preparation method thereof Download PDFInfo
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- CN106692043A CN106692043A CN201510511525.6A CN201510511525A CN106692043A CN 106692043 A CN106692043 A CN 106692043A CN 201510511525 A CN201510511525 A CN 201510511525A CN 106692043 A CN106692043 A CN 106692043A
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- levo
- oxiracetam
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Abstract
A good-stability levo oxiracetam injection is characterized by comprising the following raw materials by weight: 50%-70% of levo oxiracetam, 15%-30% of glycerol, 5%-25% of glycine and 1%-5% of benzyl alcohol; the good-stability levo oxiracetam injection has good stability. The effective period is long, and can reach more than 18 months, product impurities are less in validity period, the total impurity is less than 0.37%, product main drug solubility is good, insoluble particles are less than 25 mu m, and in the process of injection, pain feeling of patients is reduced, and patient compliance is good.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of levo-oxiracetam injection of good stability and its
Preparation method.
Background technology
Oxiracetam (S-oxiracetam) is a kind of hydroxy-amino-butyric acid of synthesis (BABOB) cyclic derivatives, only
For central nervous system, cerebral cortex, hippocampus are mainly distributed on, have activation, protection or promote the function of nerve cell
Recover, improve the mnemonic learning function of disturbance of intelligence patient, and medicine in itself without direct vasoactive, also without in
Pivot excitation, 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.It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic modification.
The rush that Ye Lei etc. goes into a coma caused by mentioning levo-oxiracetam in the A patents of Publication No. CN 103735545 to alcoholism
Effect of waking up is obvious, and dextrorotation Oxiracetam is not acted on substantially, and the above-mentioned rush of levo-oxiracetam wakes up effect for racemization Aura
Western smooth 2 times；Levo-oxiracetam is notable to the promoting wakening of stupor caused by wound, anesthesia.Peak etc. is opened in publication number
It is big to traumatic brain injury caused by hydraulic pressure and freely falling body to disclose levo-oxiracetam in the patent of the A of CN 103599101
Mouse learning and memory cognition dysfunction improves significantly, and its drug effect is far above dextrorotation Oxiracetam.And
200mg/kg levo-oxiracetams are suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results show：
Levo-oxiracetam and dextrorotation Oxiracetam are in beasle dog body without obvious chiral inversion.Beasle dog single intravenous injection gives
The main pharmacokinetic parameters of levo-oxiracetam nothing is substantially poor in blood plasma after left-handed and 2 multiple doses racemization Oxiracetam
It is different.The result of the tests such as safe pharmacology, anxious poison malicious, long show, under isodose level, levo-oxiracetam and Aura
It is western smooth to animal subject or the toxicity no significant difference of cell.Above-mentioned preclinical result of study shows, levo-oxiracetam
It is the main active that drug effect is played in Oxiracetam body, this product is used alone can reduce Clinical practice dosage, reduces latent
Toxicity.
Existing levo-oxiracetam injection its be primarily present that stability is poor, product main ingredient dissolubility is bad, injection process pain
Bitterly substantially, the problems such as patient's poor compliance.
The content of the invention
It is an object of the invention to provide a kind of good stability, the levo-oxiracetam injection of good patient compliance.
Preparation method another object of the present invention is to provide above-mentioned levo-oxiracetam injection.
The purpose of the present invention is realized by following technical measures：
A kind of levo-oxiracetam injection of good stability, it is characterised in that it be with levo-oxiracetam as raw material,
A certain amount of additives are added to be obtained；Wherein described additives be glucose, sodium chloride, mannitol, glycerine, L-
Propylhomoserin, sodium glutamate, alanine, glycine, lecithin, propane diols, phenmethylol, anesin, sodium sulfite,
One or more in sodium hydrogensulfite, sodium pyrosulfite.
Inventor has found to select a certain proportion of glycerine, glycine and phenmethylol to constitute in composition described above by many experiments
Compound additives, coordinate specific levo-oxiracetam concentration again, may be such that above-mentioned levo-oxiracetam injection stabilization
Property it is good, product main ingredient dissolubility is good, injection process patient pain sense mitigate, the levo-oxiracetam of above-mentioned injection, its
It is characterised by, it is obtained by the supplementary material of following weight percents：Levo-oxiracetam 50%~70%, glycerine
15%~30%, glycine 5%~25%, phenmethylol 1%~5%.
Most preferably, the good levo-oxiracetam injection of aforementioned stable, it is characterised in that it is by following important hundred
The supplementary material of ratio is divided to be obtained：Levo-oxiracetam 60%~65%, glycerine 20%~25%, glycine 10%~15%, benzene
Methyl alcohol 1%~3%.
The preparation method of the levo-oxiracetam injection of a kind of good stability, it is characterised in that it is to make as follows
：
1. concentrated compounding：By in above-mentioned supplementary material addition material-compound tank, sterilized water for injection being added immediately, being stirred, dissolving obtains dense
With liquid；
2. it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, pH to 6.5~7.0 is adjusted with hydrochloric acid or sodium bicarbonate solution, add cumulative volume 0.1%~0.3%
(g/ml) activated carbon, adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate, plus go out
Bacterium water for injection tests qualified to recipe quantity through middle product examine, you can；
3. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters, bacterial endotoxin
After qualified, upper streamline carries out filling, sealing；
4. sterilize：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min, sterilizing program：
10 DEG C/min, 121 DEG C are risen to, 15min is kept at 121 DEG C；3~5 DEG C/min of compressed air air blast drops
Temperature, 8~12min is cooled to 70~80 DEG C, and 2~3 DEG C/min of cooling water coolings, 15~18min is cooled to
30 DEG C, sterilizing is completed, and is hunted leak by rated condition；
5. check：Sample checks visible foreign matters after sterilizing, and qualified sample will be checked to carry out outsourcing, full inspection, storage,
Obtain final product.
The present invention has following beneficial effect：
A kind of levo-oxiracetam injection of good stability of the present invention has good stability, and the term of validity is long, can reach 18
More than individual month, product impurity was few in the term of validity, and its total impurities is less than 0.37%, and product main ingredient dissolubility is good, insoluble micro-
Grain is respectively less than 25 μm, pain reduction, good patient compliance in patient injection procedure.
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 injection of good stability, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Glycerine | 41g |
| Glycine | 23g |
| Phenmethylol | 2g |
| Sterilized water for injection | Add to 1000ml |
It is made 500
Preparation process：
1. concentrated compounding：By in above-mentioned supplementary material addition material-compound tank, the sterilized water for injection of 1/3 recipe quantity is added immediately, stir,
Dissolving, obtains concentrated wiring liquid；
2. it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, pH to 6.5~7.0 is adjusted with hydrochloric acid or sodium bicarbonate solution, add cumulative volume 0.1%~0.3%
(g/ml) activated carbon, adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate, plus go out
Bacterium water for injection tests qualified to recipe quantity through middle product examine, you can；
3. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters, bacterial endotoxin
After qualified, upper streamline carries out filling, sealing；
4. sterilize：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min, sterilizing program：
10 DEG C/min, 121 DEG C are risen to, 15min is kept at 121 DEG C；3~5 DEG C/min of compressed air air blast drops
Temperature, 8~12min is cooled to 70~80 DEG C, and 2~3 DEG C/min of cooling water coolings, 15~18min is cooled to
30 DEG C, sterilizing is completed, and is hunted leak by rated condition；
5. check：Sample checks visible foreign matters after sterilizing, and qualified sample will be checked to carry out outsourcing, full inspection, storage,
Obtain final product.
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 injection stability experiment of good stability of the present invention
Experiment material：
Levo-oxiracetam injection sample：For embodiment 1 is obtained
Acceleration study method：Levo-oxiracetam injection obtained in embodiment 1 is packed by listing, Acceleration study case is put
In, 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, particulate matter, 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 injection obtained in embodiment 1 is packed by listing, the long-term case that keeps sample is put
In, 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 months
Inspection target：Proterties, visible foreign matters, particulate matter, pH, relevant material, content, sterility test
Long term test stability is recorded：
Long term test shows：It is 18 months proterties of this product long term test, visible foreign matters, particulate matter, pH value, relevant
Material, content and sterility test indices without significant changes, meet every phase of production quality standard draft
Close regulation.18 months steady qualities of this product long term test, therefore minimum 18 months of this product term of validity, long term test still after
During continuous investigation.
Experiment two：Pain experiment in mouse writhing method observation injection process
Test specimen：Levo-oxiracetam injection does not add the prescription of phenmethylol by real as test sample as obtained in embodiment 1
Levo-oxiracetam injection obtained in example 1 is applied as control sample；
Purpose：Compare the pain degree in two kinds of levo-oxiracetam injection injection process
Method：Small white mouse is taken, whether hypodermic injection levo-oxiracetam injection, observation small white mouse can occur writhing response, root
The power of pain in injection process, test sample and control sample are judged according to the probability of mouse generation writhing response
It is each to repeat 30 experiments；
Result of the test：Result of the test see the table below：
| Name of product | Experiment sample (mouse) | Generation writhing response number of individuals | Writhing response incidence % |
| Test sample | 30 | 8 | 26.7% |
| Control sample | 30 | 21 | 70.0% |
Conclusion：As seen from the above table, pain is markedly less than control sample in levo-oxiracetam injection injection process of the present invention.
Embodiment 2
A kind of levo-oxiracetam injection of good stability, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Glycerine | 34g |
| Glycine | 16g |
| Phenmethylol | 3g |
| Sterilized water for injection | Add to 1000ml |
It is made 500
Preparation process：Preparation technology according to embodiment 1 is obtained.
By the test method of embodiment 1, the sample of embodiment 2 is carried out into stability test investigation, stability test knot respectively
Fruit shows to accelerate June sample quality stabilization, long-term 18 months steady qualities, therefore minimum 18 months of this product term of validity.It is small
Pain result of the test in mouse writhing method observation injection process shows that pain is obvious during the sample injection of embodiment 2
It is weaker than control sample.
Embodiment 3
A kind of levo-oxiracetam injection of good stability, is obtained according to the following steps：
| Composition | Consumption |
| Levo-oxiracetam | 100g |
| Glycerine | 33g |
| Glycine | 21g |
| Phenmethylol | 4g |
| Sterilized water for injection | Add to 1000ml |
It is made 500
Preparation process：Preparation technology according to embodiment 1 is obtained.
By the test method of embodiment 1, the sample of embodiment 3 is carried out into stability test investigation, stability test knot respectively
Fruit shows to accelerate June sample quality stabilization, long-term 18 months steady qualities, therefore minimum 18 months of this product term of validity.It is small
Pain result of the test in mouse writhing method observation injection process shows that pain is obvious during the sample injection of embodiment 3
It is weaker than control sample.
Embodiment 4-6：A kind of levo-oxiracetam injection of good stability, is prepared by the supplementary material of following weight,
Preparation method is with embodiment 1：
| Embodiment | Levo-oxiracetam | Glycerine | Glycine | Phenmethylol | Sterilized water for injection |
| 4 | 100g | 35g | 17g | 3g | Add water to 1000ml |
| 5 | 100g | 35g | 18g | 3g | Add water to 1000ml |
| 6 | 100g | 35g | 19g | 4g | Add water to 1000ml |
By the test method of embodiment 1, embodiment 4,5,6 is carried out into stability test investigation, stability test respectively
Result shows to accelerate June sample quality stabilization, long-term 18 months steady qualities, therefore minimum 18 months of this product term of validity.
Pain result of the test in mouse writhing method observation injection process shows, aches during the sample injection of embodiment 4,5,6
Pain is markedly less than control sample.
Claims (3)
1. the injection levo-oxiracetam of a kind of good stability, it is characterised in that it is obtained by the supplementary material of following weight percents：Levo-oxiracetam 50% ~ 70%, glycerine 15% ~ 30%, glycine 5% ~ 25%, phenmethylol 1% ~ 5%.
2. levo-oxiracetam injection as claimed in claim 1, it is characterised in that it is obtained by the supplementary material of following significant percentage：Levo-oxiracetam 60% ~ 65%, glycerine 20% ~ 25%, glycine 10% ~ 15%, phenmethylol 1% ~ 3%.
3. the preparation method of levo-oxiracetam injection as claimed in claim 1 or 2, it is characterised in that it is obtained as follows：
A. concentrated compounding：By in above-mentioned supplementary material addition material-compound tank, sterilized water for injection being added immediately, being stirred, dissolving obtains concentrated wiring liquid；
B. it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, pH to 6.5 ~ 7.0 is adjusted with hydrochloric acid or sodium bicarbonate solution, add cumulative volume 0.1% ~ 0.3%（g/ml）Activated carbon, adsorption bleaching filters with 0.45 μm of filter membrane, collects filtrate, plus sterilized water for injection tests qualified to recipe quantity through middle product examine, you can；
C. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters, and after bacterial endotoxin is qualified, upper streamline carries out filling, sealing；
D. sterilize：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min, sterilizing program：10 DEG C/min, 121 DEG C are risen to, 15min is kept at 121 DEG C；3 ~ 5 DEG C/min of compressed air air blast lowers the temperature, and 8 ~ 12min is cooled to 70 ~ 80 DEG C, and 2 ~ 3 DEG C/min of cooling water coolings, 15 ~ 18min is cooled to 30 DEG C, and sterilizing is completed, and is hunted leak by rated condition；
E. check：Sample checks visible foreign matters after sterilizing, and qualified sample will be checked to carry out outsourcing, and full inspection, storage is obtained final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510511525.6A CN106692043A (en) | 2015-08-19 | 2015-08-19 | Good-stability levo oxiracetam injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510511525.6A CN106692043A (en) | 2015-08-19 | 2015-08-19 | Good-stability levo oxiracetam injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106692043A true CN106692043A (en) | 2017-05-24 |
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ID=58918607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510511525.6A Pending CN106692043A (en) | 2015-08-19 | 2015-08-19 | Good-stability levo oxiracetam injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106692043A (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
- 2015-08-19 CN CN201510511525.6A patent/CN106692043A/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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| PB01 | Publication | ||
| PB01 | Publication | ||
| 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: 20170824 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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| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170524 |