CN107468642A - A kind of method for preparing levo-oxiracetam injection - Google Patents
A kind of method for preparing levo-oxiracetam injection Download PDFInfo
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- CN107468642A CN107468642A CN201610405415.6A CN201610405415A CN107468642A CN 107468642 A CN107468642 A CN 107468642A CN 201610405415 A CN201610405415 A CN 201610405415A CN 107468642 A CN107468642 A CN 107468642A
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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
- A61K47/02—Inorganic compounds
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
A kind of preparation method of levo-oxiracetam injection, it is specially：By levo-oxiracetam, calcio-disodium edetate, sodium hydrogensulfite, methyl hydroxybenzoate are dissolved with water for injection, and the pH of solution is adjusted into 4.5 6.5 with pH buffer systems；Contain the 200g of levo-oxiracetam 50 in wherein per 1000mL parenteral solutions, the 0.4g of calcio-disodium edetate 0.2, the 0.4g of sodium hydrogensulfite 0.2, the 0.5g of methyl hydroxybenzoate 0.2, surplus is water for injection；Prepared levo-oxiracetam injection steady quality, clarity is good, and preparation technology is simple, is adapted to industrialized production.
Description
Technical field
The present invention relates to levo-oxiracetam, and in particular to a kind of preparation method of levo-oxiracetam injection.
Background technology
Levo-oxiracetam (S-Oxiracetam), chemical name are the OXo-1-pyrrolidine acetyl of (S) -4- hydroxyls -2
Amine.Research shows that levo-oxiracetam can promote the synthesis of Phosphorylcholine and phosphatidyl ethanolamine, promotes brain metabolism, passes through
Blood-brain barrier has stimulation to specific nervous centralis road, the neurological functional recovery of patient is acted on substantially, in light
It is definite to spend the curative effect of disease such as vascular dementia, senile dementia and various cerebrovascular diseases, brain damage, intracranial infection, peace
Good perfection.
It is well known that for coma, dysphagia, feed easily choke the symptoms such as cough dementia and dysnoesia patient not
It is clinically more using quiet particularly with cerebrovascular disease, the patient of brain damage acute symptom preferably by the way of being administered orally
The administering mode that arteries and veins instils, drug effect is rapid, reliable effect.
In levo-oxiracetam synthesis technique, process intermediates S-4 hydroxyl -2- OXo-1-pyrrolidines acetic acid can introduce end
In product；In order to ensure the quality of medicine, Drug safety is improved as far as possible, when preparing injection, effectively
It is very necessary to control the process intermediates impurity.
The content of the invention
The defects of in order to overcome prior art, it is an object of the invention to provide a kind of preparation side of levo-oxiracetam injection
Method.
Unless otherwise specified, percentage of the present invention is mass percent.
The object of the present invention is achieved like this：
A kind of preparation method of levo-oxiracetam injection, it is characterised in that：By levo-oxiracetam, ethylenediamine tetrem
Sour calcium sodium, sodium hydrogensulfite, methyl hydroxybenzoate are dissolved with water for injection, are adjusted to the pH of solution with pH buffer salts
4.8-6.3；Contain levo-oxiracetam 50-200g, calcio-disodium edetate in wherein per 1000mL parenteral solutions
0.2-0.4g, sodium hydrogensulfite 0.2-0.4g, methyl hydroxybenzoate 0.2-0.5g, surplus are water for injection.
Above-mentioned pH buffer salts are citric acid-citrate buffer solution, acetic acid-acetate buffer, phosphate buffer
In one or more combination.
Levo-oxiracetam is directly dissolved in aqueous solution pH made of water for injection less than 4, and it is direct to be not suitable as injection
Use, it is therefore desirable to adjust the pH of solution；But as pH increase, inventor have found under study for action, left-handed Aura
S-4 hydroxyls -2- OXo-1-pyrrolidines acetic acid content increase in western smooth injection, it is exceeded so as to discoloration, relevant material occur
Deng the situation for influenceing injection quality.The present invention combines calcio-disodium edetate, sodium hydrogensulfite and the Buddhist nun of specific dosage
Tortoise beetle ester is moored, the strict pH for controlling levo-oxiracetam solution, is effectively controlled S-4 hydroxyls -2- oxos -1- in system
The content of pyrrolidine acetic acid, it ensure that the validity and security of medicine.
In preparation process, inventor it has furthermore been found that pH buffer salts species with regulation pH to levo-oxiracetam
Solution has considerable influence, except being embodied on the hydrolysis S-4 hydroxyl -2- OXo-1-pyrrolidine acetic acid of acetylamino, goes back body
Present levo-oxiracetam racemization, with the increase of racemization degree, not only lose the work of levo-oxiracetam pharmacology
The advantage of property, also introduces new impurity, adds toxic side effect.
In order to reduce levo-oxiracetam racemization, the preparation method of above-mentioned levo-oxiracetam injection, it is characterised in that：
By levo-oxiracetam, calcio-disodium edetate, sodium hydrogensulfite, methyl hydroxybenzoate are dissolved with water for injection, then
PH to 5.0-6.0 is adjusted with citric acid-citrate buffer solution；Contain left-handed Aura west in wherein per 1000mL parenteral solutions
Smooth 80-180g, calcio-disodium edetate 0.2-0.4g, sodium hydrogensulfite 0.2-0.4g, methyl hydroxybenzoate 0.2-0.5g,
Surplus is water for injection.
The concentration of above-mentioned citric acid-citrate buffer solution, with the citrate ion densimeter in the injection, it is
15-40mmol/L。
In order to further control the racemization of levo-oxiracetam, the preparation method of above-mentioned levo-oxiracetam injection, adopt
Use following steps：
1st, concentrated compounding：With recipe quantity 50%-70% sterilized water for injection by calcio-disodium edetate, sodium hydrogensulfite with
And methyl hydroxybenzoate 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-sodium citrate buffer, adjusts pH to 5.2-5.8, is stirred,
Mix, add sterilized water for injection to recipe quantity；
3rd, embedding：It is dilute match somebody with somebody add activated carbon in liquid, adsorption bleaching, filtered with 0.45 μm of filter membrane, collect filtrate,
Then with 0.22 μm of filtering with microporous membrane, visible foreign matters are checked, after bacterial endotoxin is qualified, carry out filling, sealing；
4th, sterilize：Canned peace is cutd open and is sent into steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min-30min, has been sterilized
Into 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, is produced.
In order to further increase the stability of levo-oxiracetam solution, the preparation side of above-mentioned levo-oxiracetam injection
Method, using following steps：
1st, concentrated compounding：With recipe quantity 50%-70% water for injection by calcio-disodium edetate, sodium hydrogensulfite and Buddhist nun
The dissolving of tortoise beetle ester is moored, then adds levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-sodium citrate buffer, adjusts pH to 5.2-5.5, is stirred,
Mix, add sterilized water for injection to recipe quantity；
3rd, embedding：In dilute activated carbon for matching somebody with somebody addition cumulative volume 0.1%-0.2% mass ratioes in liquid, adsorption bleaching, constantly stir
15-30min is mixed, is filtered with 0.45 μm of filter membrane, collects filtrate, then with 0.22 μm of filtering with microporous membrane,
Visible foreign matters are checked, after bacterial endotoxin is qualified, carry out filling, 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℃
/ 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, 8~12min coolings
To 70~80 DEG C, 2~3 DEG C/min of cooling water coolings, 15~18min is cooled to 30 DEG C, and sterilizing is completed, by rated condition
Leak detection；
5th, examine：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to carry out outsourcing, full inspection, be put in storage,
Produce.
Inventor it has unexpectedly been discovered that, in the preparation process of above-mentioned levo-oxiracetam injection, in charcoal absorption
During add a certain amount of paper pulp, the content of impurity in injection can be effectively reduced, ensure the clarity of injection.
The amount of filter paper is added, in terms of dry filter paper, concentration in the solution is 0.1%-0.3% (w/v).Those skilled in the art are public
Know the occupation mode of the paper pulp when preparing injection, such as in the following manner can be shone and prepare paper pulp：Common big filter paper is taken to be torn into broken
Piece, soaked with appropriate water for injection, be then broken into atherosclerotic with bruisher.The concentration of paper pulp can be according to using need
It was determined that for example generally can be the wide in range interior of 10%-30%.
In order to further increase the stability of levo-oxiracetam solution, the preparation side of above-mentioned levo-oxiracetam injection
Method, using following steps：
1st, concentrated compounding：With recipe quantity 50%-70% water for injection by calcio-disodium edetate, sodium hydrogensulfite and Buddhist nun
The dissolving of tortoise beetle ester is moored, then adds levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-sodium citrate buffer, adjusts pH to 5.3-5.5, is stirred,
Mix, add sterilized water for injection to recipe quantity；
3rd, embedding：In dilute activated carbon for matching somebody with somebody addition cumulative volume 0.1%-0.2% mass ratioes in liquid, adsorption bleaching, add
0.1%-0.3% paper pulp (paper pulp added in i.e. per 100mL decoctions is calculated as 0.1-0.3g with dry filter paper), is stirred continuously
15-30min, filtering, to remove activated carbon and paper pulp；Then filtered successively with 0.45 μm of filter membrane, collect filtrate,
With 0.22 μm of filtering with microporous membrane, visible foreign matters are checked, after bacterial endotoxin is qualified, carry out filling, 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℃
/ 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, 8~12min coolings
To 70~80 DEG C, 2~3 DEG C/min of cooling water coolings, 15~18min is cooled to 30 DEG C, and sterilizing is completed, by rated condition
Leak detection；
5th, examine：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to carry out outsourcing, full inspection, be put in storage,
Produce.
The filter paper aperture of above-mentioned removing activated carbon and paper pulp is advisable with 80~100 μm.
Beneficial effect：
1. levo-oxiracetam injection of the present invention, it is 4.5-6.5 to adjust pH using pH buffer salts, and is aided with specific
The calcio-disodium edetate of content, sodium hydrogensulfite and methyl hydroxybenzoate so that levo-oxiracetam racemization
Degree is low, and S-4 hydroxyls -2- OXo-1-pyrrolidine acetic acid contents are few in injection, injection steady quality.
2. the present invention uses the pH of particular types pH buffer salts (citric acid-citrate buffer solution) regulation solution
To 4.8-5.7, and combine the calcio-disodium edetate of certain content, sodium hydrogensulfite and methyl hydroxybenzoate etc.
Levo-oxiracetam injection prepared by material, after preserving 18 months, total impurities content is less than 0.5%, impurity
S-4 hydroxyl -2- OXo-1-pyrrolidines acetic acid content is less than 0.2%, the oxo -1- pyrroles of impurity (R) -4- hydroxyls -2
Alkyl acetamide content is not more than 0.3%, is effectively guaranteed the quality of injection.
3. the present invention adds a certain amount of paper pulp in charcoal adsorption process, further can reduce in injection
The content of impurity so that the maximum single miscellaneous content of injection is less than 0.25%, and clarity is less than No. 0.5 standard turbidity solution.
4. preparation technology of the present invention is simple, it is adapted to industrialized production.
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, person skilled in art can
So that some nonessential modifications and adaptations are made to the present invention according to the invention described above content.
Embodiment 1
Levo-oxiracetam injection, is made according to the following steps：
| Composition | Dosage |
| Levo-oxiracetam | 100g |
| Calcio-disodium edetate | 0.3g |
| Sodium hydrogensulfite | 0.3g |
| Methyl hydroxybenzoate | 0.4g |
| Sterilized water for injection | Add to 1000ml |
Preparation process：
1st, concentrated compounding：With the water for injection of recipe quantity 60% by calcio-disodium edetate, sodium hydrogensulfite and nipalgin
Methyl esters dissolves, and then adds levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, adds citric acid-sodium citrate solution (citrate ion concentration is 25mmol/L),
PH to 5.2 is adjusted, is stirred, mixes, adds sterilized water for injection to recipe quantity；
3rd, embedding：In dilute activated carbon for matching somebody with somebody the addition mass ratio of cumulative volume 0.2% in liquid, adsorption bleaching, 0.3% is added
Paper pulp (the paper pulp 0.3g in terms of dry filter paper added in i.e. per 100mL decoctions), 25min is stirred continuously, with 100 μ
M filter paper filtering, to remove activated carbon and paper pulp；Then filtered successively with 0.45 μm of filter membrane, collect filtrate, used
0.22 μm of filtering with microporous membrane, visible foreign matters are checked, after bacterial endotoxin is qualified, carry out filling, 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℃
/ 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, 8~12min coolings
To 70~80 DEG C, 2~3 DEG C/min of cooling water coolings, 15~18min is cooled to 30 DEG C, and sterilizing is completed, by rated condition
Leak detection；
5th, examine：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to carry out outsourcing, full inspection, be put in storage,
Produce.
Embodiment 2
Levo-oxiracetam injection, is made according to the following steps：
| Composition | Dosage |
| Levo-oxiracetam | 50g |
| Calcio-disodium edetate | 0.2g |
| Sodium hydrogensulfite | 0.2g |
| Methyl hydroxybenzoate | 0.2g |
| Sterilized water for injection | Add to 1000ml |
Preparation process：
1st, concentrated compounding：With the water for injection of recipe quantity 50% by calcio-disodium edetate, sodium hydrogensulfite and nipalgin
Methyl esters dissolves, and then adds levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Take concentrated wiring liquid, adding citric acid-sodium citrate buffer, (citrate ion concentration is
15mmol/L), pH to 4.8 is adjusted, is stirred, mixes, adds sterilized water for injection to recipe quantity；
3rd, embedding：In dilute activated carbon for matching somebody with somebody the addition mass ratio of cumulative volume 0.1% in liquid, adsorption bleaching, 0.1% is added
Paper pulp (the paper pulp 0.1g in terms of dry filter paper added in i.e. per 100mL decoctions), 15min is stirred continuously, with 80 μm
Filter paper filtering, to remove activated carbon and paper pulp；Then filtered successively with 0.45 μm of filter membrane, collect filtrate, used
0.22 μm of filtering with microporous membrane, visible foreign matters are checked, after bacterial endotoxin is qualified, carry out filling, 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℃
/ 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, 8~12min coolings
To 70~80 DEG C, 2~3 DEG C/min of cooling water coolings, 15~18min is cooled to 30 DEG C, and sterilizing is completed, by rated condition
Leak detection；
5th, examine：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to carry out outsourcing, full inspection, be put in storage,
Produce.
Embodiment 3
Levo-oxiracetam injection, is made according to the following steps：
| Composition | Dosage |
| Levo-oxiracetam | 200g |
| Calcio-disodium edetate | 0.4g |
| Sodium hydrogensulfite | 0.4g |
| Methyl hydroxybenzoate | 0.5g |
| Sterilized water for injection | Add to 1000ml |
Preparation process：
1st, concentrated compounding：With the water for injection of recipe quantity 70% by calcio-disodium edetate, sodium hydrogensulfite and nipalgin
Methyl esters dissolves, and then adds levo-oxiracetam, stirring and dissolving；
2nd, it is dilute to match somebody with somebody：Take concentrated wiring liquid, adding citric acid-sodium citrate buffer, (citrate ion concentration is
40mmol/L), pH to 6.5 is adjusted, is stirred, mixes, adds sterilized water for injection to recipe quantity；
3rd, embedding：In dilute activated carbon for matching somebody with somebody the addition mass ratio of cumulative volume 0.2% in liquid, adsorption bleaching, 0.3% is added
Paper pulp (the paper pulp 0.3g in terms of dry filter paper added in i.e. per 100mL decoctions), 30min is stirred continuously, with 90 μm
Filter paper filtering, to remove activated carbon and paper pulp；Then filtered successively with 0.45 μm of filter membrane, collect filtrate, used
0.22 μm of filtering with microporous membrane, visible foreign matters are checked, after bacterial endotoxin is qualified, carry out filling, 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℃
/ 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, 8~12min coolings
To 70~80 DEG C, 2~3 DEG C/min of cooling water coolings, 15~18min is cooled to 30 DEG C, and sterilizing is completed, by rated condition
Leak detection；
5th, examine：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to carry out outsourcing, full inspection, be put in storage,
Produce.
Embodiment 4
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 is sampled, and 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 S-4 hydroxyl -2- oxos to relevant material
- 1- pyrrolidine acetic acids, impurity B are the oxo-1-pyrrolidine ethanamide of (R) -4- hydroxyls -2), 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, shows that this product adds
Speed is tested June, and quality keeps stable, and this product stability is preferable.
Long-term experiment method：Levo-oxiracetam injection made from embodiment 1 is packed by listing, puts the long-term case that keeps sample
In, 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 S-4 hydroxyl -2- oxos to relevant material
- 1- pyrrolidine acetic acids, impurity B are the oxo-1-pyrrolidine ethanamide of (R) -4- hydroxyls -2), 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,
Without significant changes, the items correlation for meeting production quality standard draft is advised for content and sterility test indices
It is fixed.18 months steady qualities of this product long term test, therefore minimum 18 months of this product term of validity, long term test still is continuing to examine
During examining.
A kind of levo-oxiracetam injection clarity comparative experimental research of the present invention
1. experiment material：
Levo-oxiracetam injection sample：It is made for embodiment 1
Levo-oxiracetam injection control sample：After single factor test changes the factor such as pH adjusting agent and pH value respectively, press
Levo-oxiracetam injection sample is as control sample made from embodiment 1.
2. experimental method：Tested according to version pharmacopeia annex IXB clarity inspection techniques in 2015.
3. experimental result see the table below：
Experiment conclusion：Sample clarity obtained by embodiment 1 is better than each control sample.
With reference to embodiment 1, run according to following parameter, prepare embodiment 5-15.
In above-mentioned table, calcio-disodium edetate is referred to as：EDTA-CaNa2；Disodium ethylene diamine tetraacetate is referred to as：
EDTA-2Na.Embodiment 9-15 is comparative example, and as different from Example 8, pH regulations are not used in embodiment 9
Agent adjusts pH, and it is 4.2 that embodiment 10, which adjusts pH, and it is 4.5 that embodiment 11, which adjusts pH, and embodiment 12 is not added with Buddhist nun
Tortoise beetle ester is moored, embodiment 13 is not added with sodium hydrogensulfite, and metal ion chelation agent, embodiment is not used in embodiment 14
15 metal ion chelation agents used are disodium ethylene diamine tetraacetate.
The levo-oxiracetam injection that embodiment 2,3,5-15 are prepared with reference to the method for embodiment 4 carries out steady
Qualitative test and clarity experiment investigation.
The levo-oxiracetam injection that embodiment 2,3,5-8 are prepared, 18 months quality of long-term stable experiment
Stable, total impurities content is less than 0.5%, therefore minimum 18 months of this product term of validity；Clarity contrast test result of the test table
Bright produced sample clarity is less than No. 0.5 standard turbidity solution, and this product clarity is good.
Long-term stable experiment 18 months：Injection total impurities content prepared by embodiment 9 is more than 1%, and pH is less than
4, it is not suitable as injection；More than 0.8%, wherein impurity A contains injection total impurities content prepared by embodiment 10
Amount is higher than 0.4%；Injection total impurities content prepared by embodiment 11 is less than 0.5%, and wherein impurity B content is 0.28%；
Injection total impurities content prepared by embodiment 12/13 is less than 0.5%, but clarity is higher than 0.5 standard turbidity solution；It is real
The injection total impurities content for applying the preparation of example 14 is less than 0.5%, but metal ion content is exceeded；It is prepared by embodiment 15
Injection total impurities content be 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.
Claims (7)
- A kind of 1. preparation method of levo-oxiracetam injection, it is characterised in that：By levo-oxiracetam, calcio-disodium edetate, sodium hydrogensulfite, methyl hydroxybenzoate are dissolved with water for injection, and the pH of solution is adjusted into 4.5-6.5 with pH buffer salts；Contain levo-oxiracetam 50-200g in wherein per 1000mL parenteral solutions, calcio-disodium edetate 0.2-0.4g, sodium hydrogensulfite 0.2-0.4g, methyl hydroxybenzoate 0.2-0.5g, surplus is water for injection.
- 2. preparation method as claimed in claim 1, it is characterised in that：The pH buffer salts are the one or more combination in citric acid-citrate buffer, acetic acid-acetate buffer, phosphate buffer.
- 3. preparation method as claimed in claim 1 or 2, it is characterised in that：By levo-oxiracetam, calcio-disodium edetate, sodium hydrogensulfite, methyl hydroxybenzoate are dissolved with water for injection, then adjust pH to 4.8-5.7 with citric acid-citrate buffer；Contain levo-oxiracetam 80-180g in wherein per 1000mL parenteral solutions, calcio-disodium edetate 0.2-0.4g, sodium hydrogensulfite 0.2-0.4g, methyl hydroxybenzoate 0.2-0.5g, surplus is water for injection.
- 4. preparation method as claimed in claim 3, it is characterised in that：The concentration of the citric acid-citrate buffering, is 15-40mmol/L with the citrate ion densimeter in the injection.
- 5. the preparation method as described in claim 3 or 4, it is characterised in that using following steps：1st, concentrated compounding：Calcio-disodium edetate, sodium hydrogensulfite and methyl hydroxybenzoate 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-sodium citrate buffer, adjusts pH to 4.8-5.7, is stirred, mixes, adds sterilized water for injection to recipe quantity；3rd, embedding：It is dilute match somebody with somebody add activated carbon in liquid, adsorption bleaching, filtered with 0.45 μm of filter membrane, collect filtrate, then with 0.22 μm of filtering with microporous membrane, check visible foreign matters, after bacterial endotoxin is qualified, carry out filling, 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.
- 6. preparation method as claimed in claim 5, it is characterised in that using following steps：1st, concentrated compounding：Calcio-disodium edetate, sodium hydrogensulfite and methyl hydroxybenzoate are dissolved with recipe quantity 50%-70% 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-sodium citrate buffer, adjusts pH to 4.8-5.5, is stirred, mixes, adds sterilized water for injection to recipe quantity；3rd, embedding：In dilute activated carbon for matching somebody with somebody addition cumulative volume 0.1%-0.2% mass ratioes in liquid, adsorption bleaching, 15-30min is stirred continuously, is filtered with 0.45 μm of filter membrane, filtrate is collected, then with 0.22 μm of filtering with microporous membrane, checks visible foreign matters, after bacterial endotoxin is qualified, filling, sealing is carried out；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：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to carry out outsourcing, full inspection, storage, produced.
- A kind of 7. preparation method of levo-oxiracetam parenteral solution, using following steps：1st, concentrated compounding：Calcio-disodium edetate, sodium hydrogensulfite and methyl hydroxybenzoate are dissolved with recipe quantity 50%-70% 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-sodium citrate buffer, adjusts pH to 5.1-5.5, is stirred, mixes, adds sterilized water for injection to recipe quantity；3rd, embedding：In dilute activated carbon for matching somebody with somebody addition cumulative volume 0.1%-0.2% mass ratioes in liquid, adsorption bleaching, 0.1%-0.3% paper pulp is added, is stirred continuously 15-30min, filtered, to remove activated carbon and paper pulp；Then filtered successively with 0.45 μm of filter membrane, collect filtrate, with 0.22 μm of filtering with microporous membrane, check visible foreign matters, after bacterial endotoxin is qualified, carry out filling, 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：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to carry out outsourcing, full inspection, storage, produced.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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