CN107468644A - A kind of levo-oxiracetam injection and preparation method thereof - Google Patents
A kind of levo-oxiracetam injection and preparation method thereof Download PDFInfo
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- CN107468644A CN107468644A CN201610408051.7A CN201610408051A CN107468644A CN 107468644 A CN107468644 A CN 107468644A CN 201610408051 A CN201610408051 A CN 201610408051A CN 107468644 A CN107468644 A CN 107468644A
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- oxiracetam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
A kind of levo-oxiracetam injection, the water for injection comprising levo-oxiracetam, cysteine, calcio-disodium edetate, thimerosal and as parenteral solution solvent；With reference to the calcio-disodium edetate, cysteine and thimerosal of specific dosage, the pH of levo-oxiracetam solution is strictly controlled by citric acid sodiocitrate, acted synergistically by each raw material, it not only avoid glycine anhydride content increase in injection, so as to avoid the situation for the influence injection quality such as discoloration, relevant material be exceeded occur, terminal sterilization technique can also be resistant to, stability is good, is effectively guaranteed the validity and security of medicine.
Description
Technical field
The present invention relates to levo-oxiracetam, and in particular to a kind of levo-oxiracetam injection and its system
Preparation Method.
Background technology
Levo-oxiracetam (S-Oxiracetam), chemical name are the oxo -1- of (S) -4- hydroxyls -2
Pyrrolidine acetamide, the synthesis of Phosphorylcholine and phosphatidyl ethanolamine can be promoted, promote brain metabolism, pass through
Blood-brain barrier has stimulation to specific nervous centralis road, and the neurological functional recovery of patient is acted on
Substantially, to light moderate vascular dementia, senile dementia and various cerebrovascular diseases, brain damage, cranium
The curative effect of disease such as interior infection are definite, and security is good.Its structure is as follows：
It is well known that dementia and intelligence for the symptoms such as cough of easily being choked with coma, dysphagia, feed
Power impaired patients should not be by the way of being administered orally, particularly with cerebrovascular disease, the acute disease of brain damage
The patient of shape, clinically use the administering modes of drip-feed, drug effect is rapid, reliable effect more.
CN101766597A discloses a kind of preparation method of levo-oxiracetam injection, and it prepares work
Skill is to take partial syringe water, adds levo-oxiracetam stirring and dissolving, and PH is adjusted with PH conditioning agents,
Appropriate needle-use activated carbon is added, by medicine liquid heating to 50-70 DEG C, is stirred, after filtering decarbonization, filling is penetrated
With water to total amount, then using 0.22 μm of miillpore filter refined filtration, filling in ampoule bottle, sterilizing.
CN 102670497A disclose a kind of preparation method of levo-oxiracetam injection, and its preparation technology is
After taking S-oxiracetam to be dissolved in water, the dissolving of EDETATE SODIUM calcium is added, is adjusted with sodium hydroxide/hydrochloric acid
PH value of solution, after charcoal absorption, filtering decarbonization, it is sealed in ampoule bottle.These methods not only walk
It is rapid long, and lower step process of being allowed for access after the completion of often walking, seriously limit speed of production, cause energy consumption and
The loss of manpower, production cost is had a strong impact on, while charcoal absorption also be present and remove thermal source step, it is living
Property charcoal be filtered to remove in process of production, it is known that activated carbon in filter process often exist lets out
, potential security risk be present in leakage and residual.Therefore it is still necessary to providing a kind of preparation method, technique
Simply, steady quality.In present Chinese market, the poisoning of parenteral solution occurs repeatedly, majority be because
For do not accomplish it is sterile cause, therefore nonterminal sterilization process cannot be guaranteed levo-oxiracetam parenteral solution
Clinical safety.Therefore it is still necessary to proposing a kind of composition of stabilization, note levo-oxiracetam
Penetrate liquid energy and meet terminal sterilization technique.
The content of the invention
The defects of in order to overcome prior art, according to the first aspect of the invention, the purpose of the present invention, exist
In providing a kind of levo-oxiracetam injection, the injection simple production process, it is resistant to terminal and goes out
Bacterium technique, steady quality.
Unless otherwise specified, percentage of the present invention is mass percent.
The object of the present invention is achieved like this：
A kind of levo-oxiracetam injection, includes levo-oxiracetam, cysteine, ethylenediamine tetraacetic
Calcium acetate sodium, thimerosal and the water for injection as parenteral solution solvent；Wherein per in 1000mL parenteral solutions
Contain levo-oxiracetam 80-240g, calcio-disodium edetate 0.2-0.4g, cysteine
0.1-0.3g, thimerosal 0.1-0.3g；The levo-oxiracetam injection citric acid-sodium citrate
It is 4.5-6.8 that buffer salt, which adjusts pH,.
According to one embodiment of the invention, the concentration of above-mentioned citric acid-sodium citrate buffer salt, with
Citric acid radical ionometer in the parenteral solution, is advisable with 10~50mmol/L, preferably 15~
30mmol/L.When calculating the citric acid-sodium citrate buffer salinity, with citric acid radical ion concentration
Meter, the citric acid radical ion include the citric acid radical ion added in a variety of manners, such as including with work
The citric acid added for pH adjusting agent and the sodium citrate added with buffer salt.In the present invention, lead to
The value for calculating the citric acid radical ion added and controlling parenteral solution is crossed, can readily determine that prescription group
Into the amount without especially removing " citric acid-sodium citrate buffer salt " in determination prescription.
Levo-oxiracetam is directly dissolved in aqueous solution pH made of water for injection less than 4, is not suitable as
Injection directly uses, it is therefore desirable to adjusts the pH of solution；But as pH increase, inventor exist
Found in research, glycine anhydride content increase in levo-oxiracetam injection, so as to occur changing colour,
About the exceeded situation for waiting influence injection quality of material.The present invention combines the ethylenediamine tetraacetic of specific dosage
Calcium acetate sodium, cysteine and thimerosal, strictly controlled by citric acid-sodium citrate buffer salt left-handed
The pH of Oxiracetam solution, each raw material synergy, it not only avoid injection discoloration, relevant thing
The exceeded situation of matter, additionally it is possible to be resistant to terminal sterilization technique, be effectively guaranteed the validity of medicine
With security.
According to the second aspect of the invention, the present invention provides one kind and prepares above-mentioned levo-oxiracetam injection
The method of agent, this method is simple to operate, is adapted to industrialized production.
Inventor has found that when the bacterial endotoxin in control supplementary material well, making
During standby and activated carbon need not be added carry out adsorbing depyrogenation step, produce left-handed Aura west
The bacterial endotoxin of smooth injection is still what is conformed to quality requirements.Levo-oxiracetam bulk drug of the present invention
Bacterial endotoxin≤0.1Eu/mg, auxiliary material cysteine of the present invention, calcio-disodium edetate, sulphur
Bacterial endotoxin≤5Eu/g of willow mercury and citric acid-sodium citrate buffer salt.
Persistently stirred under the conditions of 60 DEG C or higher temperature because charcoal absorption depyrogenation generally requires
Mix, parenteral solution is typically unstable under the high temperature conditions, easily decomposes.Therefore levo-oxiracetam is being prepared
The step of reducing charcoal absorption depyrogenation during injection, not only it is only capable of reducing in production process
Processing step, improve production efficiency, and levo-oxiracetam injection can be avoided in high temperature bar
Degraded under part, be advantageous to improve the stability of product.Charcoal absorption is added except thermal source is introduced into newly
Insoluble composition activated carbon, often increase a processing step in production process and pass through filtering
Activated carbon is removed, but activated carbon filters off and occurs during removing and can not remove completely, while at present again
Lack effective detection means to be monitored the activated carbon in solution after filtering, therefore will certainly exist
Security risk.
A kind of preparation method of levo-oxiracetam injection, using following steps：
1st, concentrated compounding：With recipe quantity 50%-70% sterilized water for injection by calcio-disodium edetate, half
Cystine and thimerosal dissolving, then add levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-liquor sodii citratis, adjusts pH to 4.5-6.8,
Stirring, mix, add sterilized water for injection to recipe quantity；
3rd, embedding：It is filling with 0.22 μm of filtering with microporous membrane, sealing；
4th, sterilize：Canned peace is cutd open and is sent into steam sterilization pan sterilizing, 121 DEG C of sterilizings
15min-30min, sterilizing are completed, leak detection；
5th, examine：The sample for hunting leak qualified is checked into visible foreign matters, qualified sample will be examined to carry out outer
Bag, full inspection, storage, produce.
It is well known that it was found from the mathematical modeling of microorganism killing, in the case of initial contamination identical,
Sterilize F0Value is bigger, and sterility assurance level is higher.It is, therefore, apparent that to reduce product residue microorganism
Risk, high F is selected as far as possible0Value is natural.The decision tree selected with reference to European Union's sterilization process,
Because of preferred F0Sterilization process more than 12.Levo-oxiracetam parenteral solution prepared in accordance with the present invention can be with
121 degree of 15min sterilization process is resistant to, the current existing most stringent of sterilization process of regulation can be met
Condition.
F0It is worth the parameter as checking sterilizing reliability, it is 10 DEG C to refer in certain sterilising temp (T), Z values
It is suitable that caused sterilization effect and 121 DEG C, Z values are sterilization effect caused by 10 DEG C when identical
Time (min).
According to the preparation method of levo-oxiracetam parenteral solution of the present invention, it is characterised in that prepare
During the buffer solution system that uses for citric acid-sodium citrate liquid.The present inventor is in research process point
Do not examine and be not added with buffer salt system, sodium acetate-glacial acetic acid buffer salt system, citric acid-sodium citrate
System, sodium dihydrogen phosphate-dibastic sodium phosphate buffer salt system, by gained sample be individually positioned in 60 DEG C and
Under illumination condition, the stability of gained finished product parenteral solution is investigated, the results showed that using citric acid-citric acid
Sodium group sample solution is most stable.
According to one embodiment of the invention, above-mentioned miillpore filter is selected from the miillpore filter of following material：
Cellulose acetate membrane material matter, makrolon membrane material, nitrocellulose membrane material or poly tetrafluoroethylene
Material.
According to one embodiment of the invention, above-mentioned miillpore filter is selected from makrolon membrane material.
It is unexpectedly during above-mentioned levo-oxiracetam injection is prepared, to use makrolon
The filtering with microporous membrane of membrane material, it can effectively reduce the glycine anhydride impurity in bulk drug；Make us eating
It is frightened, other materials such as cellulose acetate membrane material matter, nitrocellulose membrane material or polytetrafluoroethylene (PTFE)
The effect of membrane material in this respect and unobvious.
According to one embodiment of the invention, a kind of preparation method of levo-oxiracetam injection,
It is characterized in that：The injection includes levo-oxiracetam, cysteine, Ca-EDTA
Sodium, thimerosal and the water for injection as parenteral solution solvent；Contain a left side in wherein per 1000mL parenteral solutions
Oxiracetam 80-240g, calcio-disodium edetate 0.2-0.4g, cysteine 0.1-0.3g are revolved,
Thimerosal 0.1-0.3g；Preparation technology uses following steps：
1st, concentrated compounding：With recipe quantity 50%-70% sterilized water for injection by calcio-disodium edetate, half
Cystine and thimerosal dissolving, then add levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-liquor sodii citratis, adjusts pH to 5.2-6.0,
Stirring, mix, add sterilized water for injection to recipe quantity；
3rd, embedding：It is filling with 0.22 μm of makrolon membrane material filtering with microporous membrane, sealing；
4th, sterilize：Canned peace is cutd open and is sent into steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min, is gone out
Bacterium program：10 DEG C/min, 121 DEG C are risen to, 15min is kept at 121 DEG C；3~5 DEG C of compressed air air blast
/ min cools, and 8~12min is cooled to 70~80 DEG C, and 2~3 DEG C/min of cooling water cools, 15~18min
30 DEG C are cooled to, sterilizing is completed, and is hunted leak by rated condition；
5th, examine：The sample for hunting leak qualified is checked into visible foreign matters, qualified sample will be examined to carry out outer
Bag, full inspection, storage, produce.
In the present invention, its adding in parenteral solution of phrase " water for injection as parenteral solution solvent "
Entering amount need not particularly limit, and those skilled in the art are generally with " being settled to full dose ", " balance
To full dose ", the similar statement such as " adding to prescription full dose " determine, such as when other in 5ml parenteral solutions
Solid material determine and add after when, because they have a bulk effect, therefore water for injection can be with
Similar to " mode for adding to 5ml " or " adding to full dose " or " adding to prescription full dose " is recorded.
Beneficial effect：
The present invention provides a kind of levo-oxiracetam injection, with reference to the ethylenediamine tetra-acetic acid of specific dosage
Calcium sodium, cysteine and thimerosal, levo-oxiracetam is strictly controlled by citric acid-sodiocitrate
The pH of solution, acted synergistically by each raw material, not only avoid glycine anhydride content in injection and increase
Add, so as to avoid the situation for the influence injection quality such as discoloration, relevant material be exceeded occur, moreover it is possible to
Terminal sterilization technique can be enough resistant to, stability is good, is effectively guaranteed the validity and peace of medicine
Quan Xing.
Preparation method of the present invention in preparation process and need not add activated carbon carry out adsorb depyrogenation step
Suddenly, the bacterial endotoxin for producing levo-oxiracetam injection is still to conform to quality requirements, so as to
Potential security risk caused by avoiding activated carbon leakage or residual.Simple production process of the present invention, production
Quality is stable, is adapted to commercially produce.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be following
Embodiment is served only for that the present invention is further described, it is impossible to is interpreted as to the scope of the present invention
Limitation, person skilled in art can make some non-according to the invention described above content to the present invention
The modifications and adaptations of matter.All raw materials of the present invention and reagent are commercially available prod.
Embodiment 1
Levo-oxiracetam injection, is made according to the following steps：
1st, concentrated compounding：With recipe quantity 50%-70% sterilized water for injection by calcio-disodium edetate, half
Cystine and thimerosal dissolving, then add levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-liquor sodii citratis (citric acid radical ion concentration
For 30mmol/L), pH to 5.4 is adjusted, is stirred, mixes, adds sterilized water for injection to recipe quantity；
3rd, embedding：It is filling with 0.22 μm of makrolon membrane material filtering with microporous membrane, sealing；
4th, sterilize：Canned peace is cutd open and is sent into steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min, is gone out
Bacterium program：10 DEG C/min, 121 DEG C are risen to, 15min is kept at 121 DEG C；3~5 DEG C of compressed air air blast
/ min cools, and 8~12min is cooled to 70~80 DEG C, and 2~3 DEG C/min of cooling water cools, 15~18min
30 DEG C are cooled to, sterilizing is completed, and is hunted leak by rated condition；
5th, examine：The sample for hunting leak qualified is checked into visible foreign matters, qualified sample will be examined to carry out outer
Bag, full inspection, storage, produce.
Embodiment 2
Levo-oxiracetam injection, is made according to the following steps：
| Composition | Dosage |
| Levo-oxiracetam | 80g |
| Calcio-disodium edetate | 0.2g |
| Cysteine | 0.1g |
| Thimerosal | 0.1g |
| Sterilized water for injection | Add to 1000ml |
Preparation process：
1st, concentrated compounding：With recipe quantity 50%-70% sterilized water for injection by calcio-disodium edetate, half
Cystine and thimerosal dissolving, then add levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-liquor sodii citratis (citric acid radical ion concentration
For 15mmol/L), pH to 5.4 is adjusted, is stirred, mixes, adds sterilized water for injection to recipe quantity；
3rd, embedding：It is filling with 0.22 μm of makrolon membrane material filtering with microporous membrane, sealing；
4th, sterilize：Canned peace is cutd open and is sent into steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min, is gone out
Bacterium program：10 DEG C/min, 121 DEG C are risen to, 15min is kept at 121 DEG C；3~5 DEG C of compressed air air blast
/ min cools, and 8~12min is cooled to 70~80 DEG C, and 2~3 DEG C/min of cooling water cools, 15~18min
30 DEG C are cooled to, sterilizing is completed, and is hunted leak by rated condition；
5th, examine：The sample for hunting leak qualified is checked into visible foreign matters, qualified sample will be examined to carry out outer
Bag, full inspection, storage, produce.
Embodiment 3
Levo-oxiracetam injection, is made according to the following steps：
| Composition | Dosage |
| Levo-oxiracetam | 240g |
| Calcio-disodium edetate | 0.4g |
| Cysteine | 0.3g |
| Thimerosal | 0.3g |
| Sterilized water for injection | Add to 1000ml |
Preparation process：
1st, concentrated compounding：With recipe quantity 50%-70% sterilized water for injection by calcio-disodium edetate, half
Cystine and thimerosal dissolving, then add levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-liquor sodii citratis (citric acid radical ion concentration
For 50mmol/L), pH to 6.8 is adjusted, is stirred, mixes, adds sterilized water for injection to recipe quantity；
3rd, embedding：It is filling with 0.22 μm of makrolon membrane material filtering with microporous membrane, sealing；
4th, sterilize：Canned peace is cutd open and is sent into steam sterilization pan sterilizing, 121 DEG C of sterilizings
18min-20min, sterilizing are completed, leak detection；
5th, examine：The sample for hunting leak qualified is checked into visible foreign matters, qualified sample will be examined to carry out outer
Bag, full inspection, storage, produce.
With reference to embodiment 1, run according to following parameter, prepare embodiment 4-14.
In above-mentioned table, calcio-disodium edetate is referred to as：EDTA-CaNa2；Ethylenediamine tetra-acetic acid two
Sodium is referred to as：EDTA-2Na.Embodiment 8-14 is comparative example, as different from Example 7, real
Apply example 8 and be not used thimerosal, embodiment 9 is not used cysteine, embodiment 10 be not used metal from
Sub- chelating agent, the metal ion chelation agent that embodiment 11 uses are disodium ethylene diamine tetraacetate.Embodiment
12 are not used buffer salt regulation pH, and the buffer salt of embodiment 13 is sodium dihydrogen phosphate buffer salt, is implemented
The buffer salt of example 14 is acetate buffer salt.
Embodiment 15
Levo-oxiracetam injection bacterial endotoxin and clarity checking experiment
Levo-oxiracetam bulk drug bacterial endotoxin≤0.1Eu/mg that the present invention uses, auxiliary material half
The bacterium endogenous toxic material of cystine, calcio-disodium edetate, thimerosal and citric acid-sodium citrate buffer salt
Plain equal≤5Eu/g, embodiment 1-7 levo-oxiracetam parenteral solution, the traditional Chinese medicines with reference in are prepared
Allusion quotation (2015 editions) annex XI E detection of bacterial endotoxin methods, detection embodiment 1-7 left-handed Aura west
Smooth parenteral solution, result are feminine gender.As a result show：When in the bacterium for controlling bulk drug and auxiliary material
When malicious, in formulation and technology and activated carbon need not be added carry out adsorbing depyrogenation step, gained finished product is left
It is still qualified to revolve the bacterial endotoxin of oxiracetam injection.
With reference to version pharmacopeia annex IXB clarity inspection techniques in 2015, detection embodiment 1-7 left-handed Austria
La Xitan parenteral solutions, the results showed that the sample clarity produced is less than No. 0.5 standard turbidity solution, this product
Clarity is good.
Embodiment 16
Levo-oxiracetam injection stability experiment
Experiment material：
The Oxiracetam sample of injection：It is made for embodiment 1.
Acceleration study method：The Oxiracetam of injection made from embodiment 1 is packed by listing, put
In Acceleration study case, certain time sampling, investigation project is tested.
Acceleration study temperature：40±2℃
Humidity：RH75% ± 5%
Investigate the time：0th, 1,2,3, June
Inspection target：Character, visible foreign matters, clarity, pH, (impurity A is sweet ammonia to relevant material
Acid anhydrides), content, sterility test
Accelerated test stability records：
Acceleration study result shows：Acceleration sample in June is suitable with 0 month sample items Testing index quality,
Show this product Acceleration study June, quality keeps stable, and this product stability is preferable.
Long-term experiment method：Levo-oxiracetam injection made from embodiment 1 is packed by listing,
Put in the long-term case that keeps sample, certain time sampling, investigation project is tested.
Acceleration study temperature：25±2℃
Humidity：RH60% ± 10%
Investigate the time：0th, 3,6,9,12,18 months
Inspection target：Character, visible foreign matters, clarity, pH, (impurity A is sweet ammonia to relevant material
Acid anhydrides), content, sterility test
Long term test stability records：
Long term test shows：18 months characters of this product long term test, visible foreign matters, clarity, pH
Value, relevant material, content and sterility test indices without significant changes, meet production and used
Every relevant regulations of quality standard draft.18 months steady qualities of this product long term test, therefore this product has
Minimum 18 months of effect phase, long term test is still during investigation is continued.
The levo-oxiracetam injection that embodiment 2-7 is prepared is entered with reference to the method for embodiment 16
Row stability test, the levo-oxiracetam injection that embodiment 2-7 is prepared, long-time stability
Test 18 months steady qualities, total impurities content is less than 0.5%, therefore minimum 18 months of this product term of validity.
Long-term stable experiment 18 months：Injection total impurities content prepared by embodiment 8/9 is less than
0.5%, but clarity is higher than 0.5 standard turbidity solution；Injection total impurities prepared by embodiment 10 contains
Amount is less than 0.5%, but metal ion content is exceeded；Injection total impurities prepared by embodiment 11 contains
Amount is less than 0.5%, because natrium adetate can cause subtracting for calcium with calcium binding into solvable complex compound
It is few, natrium adetate is used in intravenous formulations, patient's long-term use can cause blood calcium to decline.Embodiment
The 12 injection total impurities contents prepared are more than 1%, and pH is less than 4, is not suitable as injection；
12 months total impurities contents of injection prepared by embodiment 13 are less than 0.5%, wherein Impurity A content
0.3% or so；18 months total impurities contents 0.7% or so, wherein Impurity A content 0.5% or so；It is real
The 12 months total impurities contents of injection for applying the preparation of example 14 are less than 0.5%, wherein Impurity A content 0.35%
Left and right；18 months total impurities contents 0.8% or so, wherein Impurity A content 0.5% or so.
Claims (7)
1. a kind of levo-oxiracetam injection, the water for injection comprising levo-oxiracetam, cysteine, calcio-disodium edetate, thimerosal and as parenteral solution solvent；Contain levo-oxiracetam 80-240g, calcio-disodium edetate 0.2-0.4g, cysteine 0.1-0.3g, thimerosal 0.1-0.3g in wherein per 1000mL parenteral solutions；It is 4.5-6.8 that the levo-oxiracetam injection adjusts pH with citric acid-sodium citrate buffer salt.
2. injection as claimed in claim 1, it is characterised in that：The concentration of the citric acid-sodium citrate buffer salt, it is 10~50mmol/L with the citric acid radical ionometer in the parenteral solution.
3. injection as claimed in claim 2, it is characterised in that：The citric acid radical ion concentration is 15~30mmol/L.
4. the preparation method of levo-oxiracetam injection as described in claim any one of 1-3, using following steps：
1st, concentrated compounding：Calcio-disodium edetate, cysteine and thimerosal are dissolved with recipe quantity 50%-70% sterilized water for injection, then add levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-liquor sodii citratis, adjusts pH to 4.5-6.8, is stirred, mixes, adds sterilized water for injection to recipe quantity；
3rd, embedding：It is filling with 0.22 μm of filtering with microporous membrane, sealing；
4th, sterilize：Canned peace is cutd open and is sent into steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min-30min, sterilizing is completed, leak detection；
5th, examine：The sample for hunting leak qualified is checked into visible foreign matters, qualified sample will be examined to carry out outsourcing, full inspection, storage, produced.
5. method as claimed in claim 4, it is characterised in that：The miillpore filter is selected from the miillpore filter of following material：Cellulose acetate membrane material matter, makrolon membrane material, nitrocellulose membrane material or polytetrafluoroethylene (PTFE) membrane material.
6. method as claimed in claim 5, it is characterised in that：The miillpore filter is selected from makrolon membrane material.
A kind of 7. preparation method of levo-oxiracetam injection, it is characterised in that：The injection includes levo-oxiracetam, cysteine, calcio-disodium edetate, thimerosal and the water for injection as parenteral solution solvent；Contain levo-oxiracetam 80-240g, calcio-disodium edetate 0.2-0.4g, cysteine 0.1-0.3g, thimerosal 0.1-0.3g in wherein per 1000mL parenteral solutions；Preparation technology uses following steps：
1st, concentrated compounding：Calcio-disodium edetate, cysteine and thimerosal are dissolved with recipe quantity 50%-70% sterilized water for injection, then add levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-liquor sodii citratis, adjusts pH to 5.2-6.0, is stirred, mixes, adds sterilized water for injection to recipe quantity；
3rd, embedding：It is filling with 0.22 μm of makrolon membrane material filtering with microporous membrane, sealing；
4th, sterilize：Canned peace is cutd open and is sent into 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 cools, 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；
5th, examine：The sample for hunting leak qualified is checked into visible foreign matters, qualified sample will be examined to carry out outsourcing, full inspection, storage, produced.
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| CN201610408051.7A CN107468644A (en) | 2016-06-08 | 2016-06-08 | A kind of levo-oxiracetam injection and preparation method thereof |
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Cited By (1)
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| CN116350581A (en) * | 2023-03-16 | 2023-06-30 | 石家庄四药有限公司 | Acetylcysteine injection and preparation method thereof |
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| US20040067986A1 (en) * | 2002-10-04 | 2004-04-08 | Nathan Sassover | Neuro-degenerative inhibitor, neuro-endocrine modulator, and neuro-cerebral metabolism enhancer |
| CN102512363A (en) * | 2011-12-23 | 2012-06-27 | 重庆药友制药有限责任公司 | Oxiracetam injection and preparation method thereof |
| CN105434373A (en) * | 2016-01-11 | 2016-03-30 | 青岛辰达生物科技有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
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2016
- 2016-06-08 CN CN201610408051.7A patent/CN107468644A/en not_active Withdrawn
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| US20040067986A1 (en) * | 2002-10-04 | 2004-04-08 | Nathan Sassover | Neuro-degenerative inhibitor, neuro-endocrine modulator, and neuro-cerebral metabolism enhancer |
| CN102512363A (en) * | 2011-12-23 | 2012-06-27 | 重庆药友制药有限责任公司 | Oxiracetam injection and preparation method thereof |
| CN105434373A (en) * | 2016-01-11 | 2016-03-30 | 青岛辰达生物科技有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
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| CN116350581A (en) * | 2023-03-16 | 2023-06-30 | 石家庄四药有限公司 | Acetylcysteine injection and preparation method thereof |
| CN116350581B (en) * | 2023-03-16 | 2023-11-21 | 石家庄四药有限公司 | Preparation method of acetylcysteine injection |
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