CN107115291A - Oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2 and preparation method thereof - Google Patents
Oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2 and preparation method thereof Download PDFInfo
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- CN107115291A CN107115291A CN201610105752.3A CN201610105752A CN107115291A CN 107115291 A CN107115291 A CN 107115291A CN 201610105752 A CN201610105752 A CN 201610105752A CN 107115291 A CN107115291 A CN 107115291A
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
It is a kind of（S）The oxo-1-pyrrolidine ethanamide injection of -4- hydroxyls -2, it is characterised in that：It is with（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, propane diols, lecithin, vitamin C, ethylenediamine tetra-acetic acid be supplementary material, by concentrated compounding, it is dilute match somebody with somebody, embedding, sterilizing, test package step be made；According to produced by the present invention（S）PH value of solution is substantially unchanged in the oxo-1-pyrrolidine ethanamide injection sterilization process of -4- hydroxyls -2, sterilization process impurity incrementss are only 0.05%, finished product has the advantages that will not to crystallize during storage, is difficult to be oxidized, stability is good, shelf life is up to more than 18 months, product impurity is few in shelf life, its total impurities is less than 0.28%, preparation technology simple possible, is worth marketing.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to the OXo-1-pyrrolidine of one kind (S) -4- hydroxyls -2
Acetamide injection and preparation method thereof.
Background technology
Levo-oxiracetam chemical name is：S- (-) -4- hydroxyl -2- oxo-pyrrolidine-N- acetamides, are white
Color crystallite sprills, 135~136 DEG C of fusing point, -36 ° of optical activity (C=1.00in water), levo-oxiracetam
Dissolubility be substantially better than raceme.Chemical structural formula is as follows：
The medicine is in 1987 in Italy's listing, and the formulation of listing is tablet, 800mg；Capsule, 800mg；
Parenteral solution, 1g/5ml.Domestic at present only have oxiracetam capsule and parenteral solution listing, and chief active used into
It is racemic modification to divide.Ye Lei etc. mentions levo-oxiracetam in the A patents of Publication No. CN 103735545
To the promoting wakening gone into a coma caused by alcoholism substantially, and dextrorotation Oxiracetam is not acted on substantially, left-handed Aura
The awake effect of western smooth above-mentioned rush is 2 times of racemization Oxiracetam；Levo-oxiracetam is to wound, anesthesia institute stunning
The promoting wakening of fan is notable.Open peak etc. and left-handed Austria is disclosed in the A of Publication No. CN 103599101 patent
La Xitan has bright to traumatic brain injury learning and memory in rats cognition dysfunction caused by hydraulic pressure and freely falling body
Aobvious improvement result, its drug effect is far above dextrorotation Oxiracetam.And 200mg/kg levo-oxiracetams with
The effect of 400mg/kg Oxiracetams is suitable.Pharmacokinetic study results are shown：Levo-oxiracetam and the right side
Oxiracetam is revolved in beasle dog body without obvious chiral inversion.Beasle dog single intravenous injection is given left-handed and 2
After the racemization Oxiracetam of multiple dose in blood plasma levo-oxiracetam the equal no significant difference of main pharmacokinetic parameters.
The result of the tests such as safe pharmacology, anxious malicious, long poison show, under isodose level, levo-oxiracetam and Austria
La Xitan is to animal subject or the toxicity no significant difference of cell.Above-mentioned preclinical result of study shows, left-handed
Oxiracetam is the main active that drug effect is played in Oxiracetam body, and exclusive use this product, which can reduce clinic, to be made
With dosage, potential toxicity is reduced.
The existing oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 its be primarily present solution in sterilization process
PH is changed greatly, sterilization process easily cause impurity increase, product stability it is bad it is oxidizable, storage during
The problems such as easily crystallizing.
The content of the invention
It is an object of the invention to provide the oxo of (S) -4- hydroxyls -2 that a kind of stability is good, product is not oxidizable
- 1- pyrrolidine acetamide injections.
Another object of the present invention is to provide the above-mentioned oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2
Preparation method.
The purpose of the present invention is realized by following technical measures：
The oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2, it is characterised in that it is with (S)
The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 is raw material, adds a certain amount of additives and is made；It is wherein described
Additives are glucose, sodium chloride, mannitol, glycerine, Serine, sodium glutamate, alanine, sweet ammonia
Acid, lecithin, propane diols, phenmethylol, anesin, sodium sulfite, sodium hydrogensulfite, pyrosulfurous acid
Sodium, vitamin C, the one or more of ethylenediamine tetra-acetic acid.
Inventor has found in research process, selects suitable additives species, specific supplementary material consumption proportion
Specific pH adjusting agent and the specific pH value of solution, the specific sterilizing work of cooperation in relation, preparation process
Skill step, may be such that total miscellaneous in the above-mentioned oxo-1-pyrrolidine ethanamide injection sterilization process of (S) -4- hydroxyls -2
Matter increase is smaller, solution ph change is smaller, and finished product has good stability, will not be crystallized during storage,
Product is difficult to be oxidized during storage, the above-mentioned oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2,
It is characterized in that：It is with the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, propane diols, lecithin, dimension
Raw element C, ethylenediamine tetra-acetic acid are supplementary material, by concentrated compounding, it is dilute match somebody with somebody, embedding, sterilizing, test package step
It is made；The OXo-1-pyrrolidine acetyl of (S) -4- hydroxyls -2 that the consumption of wherein described supplementary material is weight percentage
Amine 62%~72%, propane diols 13%~22%, lecithin 9%~15%, vitamin C 3%~6%, ethylenediamine
Tetraacethyl 2%~5%；The concentrated compounding step is the sterilized water for injection that 2/3 recipe quantity is added into material-compound tank,
The supplementary material of recipe quantity is added, is stirred, dissolving obtains concentrated wiring liquid；Dilute step of matching somebody with somebody is takes concentrated wiring liquid, addition
(precision weighs disodium hydrogen phosphate 65.697g to sodium phosphate buffer and sodium dihydrogen phosphate 2.346g is placed in 1000ml
In volumetric flask, add purified water dissolving, dilution and be settled to scale, produce) regulation pH to 6.5~7.0, add
Mass fraction is 0.1%~0.3% activated carbon, and adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate,
Sterilized water for injection is added to prescription, tests qualified through middle product examine, you can；The sterilization steps are will be canned
Peace cut open semi-finished product feeding steam sterilization pan sterilizing, 121 DEG C 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, 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.
Further, in order that obtaining the above-mentioned oxo-1-pyrrolidine ethanamide injection stability of (S) -4- hydroxyls -2
More preferably, impurity increase is further in sterilization process reduces, the OXo-1-pyrrolidine acetyl of one kind (S) -4- hydroxyls -2
Amine injection, it is characterised in that it is made by the supplementary material of following significant percentage：(S) -4- hydroxyls -2
Oxo-1-pyrrolidine ethanamide 65%~68%, propane diols 15%~18%, lecithin 10%~13%, vitamin
C 3%~6%, ethylenediamine tetra-acetic acid 3%~5%；Above-mentioned supplementary material is placed in material-compound tank, 2/3 prescription is added
The sterilized water for injection of amount, is stirred, and dissolving obtains concentrated wiring liquid；Concentrated wiring liquid is taken, sodium phosphate buffer (essence is added
It is close to weigh disodium hydrogen phosphate 65.697g and sodium dihydrogen phosphate 2.346g is placed in 1000ml volumetric flasks, add pure
Change water dissolving, dilution and be settled to scale, produce) regulation pH to 6.8, it is 0.1%~0.3% to add mass fraction
Activated carbon, adsorption bleaching filters with 0.45 μm of filter membrane, collects filtrate, add sterilized water for injection extremely
Recipe quantity, is filtered with 0.22 μm of filter, checked in visible foreign matters, bacterium after the assay was approved through middle product
After toxin is qualified, upper streamline progress is filling, and pouring process need to be filled with the nitrogen of purity 99.99% so that in tank
Oxygen content in water for injection is no more than 0.01%, is sealed after inflated with nitrogen；Canned peace is cutd open into semi-finished product to send
Enter steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min, sterilizing program：10 DEG C/min, 121 DEG C are risen to,
121 DEG C of holding 15min；3~5 DEG C/min of compressed air air blast cools, and 8~12min is cooled to 70~80 DEG C, cold
But 2~3 DEG C/min of water cools, and 15~18min is cooled to 30 DEG C, and sterilizing is completed, and is hunted leak by rated condition.
The preparation method of the oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2, it is characterised in that
It is obtained as follows：
1. concentrated compounding：The sterilized water for injection of 2/3 recipe quantity is added into material-compound tank, the former auxiliary of recipe quantity is added
Material, is stirred, and dissolving obtains concentrated wiring liquid；
2. dilute match somebody with somebody：Concentrated wiring liquid is taken, adding sodium phosphate buffer, (precision weighs disodium hydrogen phosphate 65.697g
It is placed in sodium dihydrogen phosphate 2.346g in 1000ml volumetric flasks, adds purified water dissolving, dilution and be settled to
Scale, is produced) regulation pH to 6.8, the activated carbon that mass fraction is 0.1%~0.3% is added, absorption is de-
Color, is filtered with 0.45 μm of filter membrane, collects filtrate, sterilized water for injection is added to prescription, through centre
Product examine is tested qualified, you can；
3. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters,
After bacterial endotoxin is qualified, upper streamline progress is filling, and pouring process need to be filled with the nitrogen of purity 99.99%
So that the oxygen content in tank in water for injection is no more than 0.01%, sealed after inflated with nitrogen；
4. sterilizing：Canned peace is cutd open into semi-finished product feeding steam sterilization pan to sterilize, 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 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 coolings, 15~18min is cold
But to 30 DEG C, sterilizing is completed, and is hunted leak by rated condition；
5. examine：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to be packed, entirely
Inspection, storage.
The present invention has following beneficial effect：
PH value of solution is basic in the oxo-1-pyrrolidine ethanamide injection sterilization process of the present invention (S) -4- hydroxyls -2
Unchanged, sterilization process impurity incrementss are only 0.05%, and finished product will not be crystallized during having storage, is difficult
Be oxidized, the advantages of stability is good, shelf life is up to more than 18 months, and product impurity is few in shelf life,
Its total impurities is less than 0.28%, and preparation technology simple possible is worth marketing.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be following examples
It is served only for that the present invention is further described, it is impossible to be interpreted as limiting the scope of the invention, is not carrying on the back
In the case of spirit of the invention and essence, the modifications or substitutions made to the inventive method, step or condition,
Belong to the scope of the present invention.
Embodiment 1
The oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：
1. concentrated compounding：The sterilized water for injection of 2/3 recipe quantity is added into material-compound tank, the former auxiliary of recipe quantity is added
Material, is stirred, and dissolving obtains concentrated wiring liquid；
2. dilute match somebody with somebody：Concentrated wiring liquid is taken, adding sodium phosphate buffer, (precision weighs disodium hydrogen phosphate 65.697g
It is placed in sodium dihydrogen phosphate 2.346g in 1000ml volumetric flasks, adds purified water dissolving, dilution and be settled to
Scale, is produced) regulation pH to 6.8, the activated carbon that mass fraction is 0.1%~0.3% is added, absorption is de-
Color, is filtered with 0.45 μm of filter membrane, collects filtrate, sterilized water for injection is added to prescription, through centre
Product examine is tested qualified, you can；
3. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters,
After bacterial endotoxin is qualified, upper streamline progress is filling, and pouring process need to be filled with the nitrogen of purity 99.99%
So that the oxygen content in tank in water for injection is no more than 0.01%, sealed after inflated with nitrogen；
4. sterilizing：Canned peace is cutd open into semi-finished product feeding steam sterilization pan to sterilize, 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 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 coolings, 15~18min is cold
But to 30 DEG C, sterilizing is completed, and is hunted leak by rated condition；
5. examine：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to be packed, entirely
Inspection, storage.
In order to be better understood from the present invention, invention medicine is expanded on further below by way of stability test of the present invention
Beneficial effect, rather than limitation of the present invention.
Experiment one：The oxo-1-pyrrolidine ethanamide injection stability experiment of present invention one kind (S) -4- hydroxyls -2
Experiment material：
(S) the oxo-1-pyrrolidine ethanamide injection liquid samples of -4- hydroxyls -2：It is made for embodiment 1
Acceleration study method：The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 made from embodiment 1 is injected
Liquid is packed by listing, is put in Acceleration study case, certain time sampling, 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, pH, relevant material, content, sterility test
Accelerated test stability is recorded：
Acceleration study result shows：Acceleration sample in June is suitable with the every Testing index quality of 0 month sample, shows
This product Acceleration study June, quality keeps stable, and this product stability is preferable.
Long-term experiment method：The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 made from embodiment 1 is injected
Liquid is packed by listing, is put in the long-term case that keeps sample, and certain time 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：Character, visible foreign matters, pH, relevant material, content, sterility test
Long term test stability is recorded：
Long term test shows：18 months characters of this product long term test, visible foreign matters, 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 during continuing to investigate.
Experiment two：The oxo-1-pyrrolidine ethanamide parenteral solution sterilization process of present invention one kind (S) -4- hydroxyls -2 is to impurity
Increased influence
1. experiment material：
(S) the oxo-1-pyrrolidine ethanamide injection liquid samples of -4- hydroxyls -2：Prepared by embodiment 1.
(S) the oxo-1-pyrrolidine ethanamide parenteral solution control sample 1 of -4- hydroxyls -2：For lack vitamin C and
The sample of ethylenediamine tetra-acetic acid, its preparation technology be the same as Example 1.
(S) the oxo-1-pyrrolidine ethanamide parenteral solution control sample 2 of -4- hydroxyls -2：For the prescription of embodiment 1,
Sterilising temp is 115 DEG C, and sterilization time is 32 minutes, obtained product.
2. experimental method：In the preparation process of embodiment 1, sample afterwards before sterilization respectively, detect it about material,
Investigate sterilizing front and rear to the influence about material.Meanwhile, take the place for lacking vitamin C and ethylenediamine tetra-acetic acid
Fang Zuowei compares prescription, is prepared by the preparation method of embodiment 1, and equally sampling detects that its is relevant afterwards before sterilization
Material, investigates sterilization process to the influence about material.Meanwhile, the prescription of Example 1, according to sterilizing temperature
Degree is changed to 115 DEG C, and sterilization time is prepares sample for 32 minutes, and sampling detects relevant thing afterwards before sterilization respectively
Matter, investigates sterilization process to the influence about material.
3. experimental result see the table below：
4. experiment conclusion：The prescription of embodiment 1, coordinates specific sterilization process, relevant material increase is only 0.05%,
It is substantially better than other two control samples.
Experiment three：The influence of pH value of solution before and after different pH adjusting agents sterilize to product
1. experiment material：
(S) the oxo-1-pyrrolidine ethanamide injection liquid samples of -4- hydroxyls -2：It is made for embodiment 1
(S) the oxo-1-pyrrolidine ethanamide injection liquid samples control sample of -4- hydroxyls -2：Respectively with sodium acid carbonate,
Sodium hydroxide, disodium hydrogen phosphate are as pH adjusting agent, (the S) -4- as made from the preparation method of embodiment 1
The oxo-1-pyrrolidine ethanamide injection liquid samples of hydroxyl -2 are used as control sample.
2. experimental method：Product is gone out according to the G pH value determination methods of version Chinese Pharmacopoeia first step annex VII in 2010
PH value of solution before and after bacterium is tested, and investigates the influence of pH before and after different pH adjusting agents sterilize to product.
3. experimental result see the table below：
4. experiment conclusion：PH value of solution is substantially unchanged before and after sample sterilizing obtained by embodiment 1.
Embodiment 2
The oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, progress stability test investigation, sterilization process are increased to impurity respectively
The influence of pH value of solution is tested before and after influence experiment and pH adjusting agent sterilize to product, stability test result
Show to accelerate June sample quality stable, long-term 18 months steady qualities, therefore minimum 18 months of this product term of validity.
Sterilization process influence result of the test increased on impurity shows the prescription of embodiment 2, coordinates specific sterilization process,
Relevant material increase is substantially better than its control sample.PH value of solution before and after different pH adjusting agents sterilize to product
Influence experiment shows that the front and rear pH value of solution of sample sterilizing obtained by embodiment 2 is substantially unchanged.
Embodiment 3
The oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2, is made according to the following steps：
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, progress stability test investigation, sterilization process are increased to impurity respectively
The influence of pH value of solution is tested before and after influence experiment and pH adjusting agent sterilize to product, stability test result
Show to accelerate June sample quality stable, long-term 18 months steady qualities, therefore minimum 18 months of this product term of validity.
Sterilization process influence result of the test increased on impurity shows the prescription of embodiment 3, coordinates specific sterilization process,
Relevant material increase is substantially better than its control sample.PH value of solution before and after different pH adjusting agents sterilize to product
Influence experiment shows that the front and rear pH value of solution of sample sterilizing obtained by embodiment 3 is substantially unchanged.
Embodiment 4-6：The oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2, by following weight
Supplementary material be prepared, preparation method be the same as Example 1：
By the test method of embodiment 1, stability test investigation, sterilization process are carried out respectively on the increased influence of impurity
The influence of pH value of solution is tested before and after experiment and pH adjusting agent sterilize to product, the sample of embodiment 4,5,6
Stability test result shows to accelerate sample quality stabilization in June, long-term 18 months steady qualities, therefore this product has
Minimum 18 months of effect phase.Sterilization process influence result of the test increased on impurity shows embodiment 4,5,6
Prescription, coordinates specific sterilization process, and relevant material increase is substantially better than its control sample.Different pH regulations
The influence experiment of pH value of solution shows before the sample sterilizing obtained by embodiment 4,5,6 before and after agent sterilizes to product
PH value of solution is substantially unchanged afterwards.
Claims (3)
1. it is a kind of（S）The oxo-1-pyrrolidine ethanamide injection of -4- hydroxyls -2, it is characterised in that：It is with（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, propane diols, lecithin, vitamin C, ethylenediamine tetra-acetic acid be supplementary material, by concentrated compounding, it is dilute match somebody with somebody, embedding, sterilizing, test package step be made；What the consumption of wherein described supplementary material was weight percentage（S）The oxo-1-pyrrolidine ethanamide 62% ~ 72% of -4- hydroxyls -2, propane diols 13% ~ 22%, lecithin 9% ~ 15%, vitamin C 3% ~ 6%, ethylenediamine tetra-acetic acid 2% ~ 5%；The concentrated compounding step is the sterilized water for injection that 2/3 recipe quantity is added into material-compound tank, adds the supplementary material of recipe quantity, is stirred, and dissolving obtains concentrated wiring liquid；Dilute step of matching somebody with somebody is to take concentrated wiring liquid, adds sodium phosphate buffer（Precision weighs disodium hydrogen phosphate 65.697g and sodium dihydrogen phosphate 2.346g is placed in 1000ml volumetric flasks, adds purified water dissolving, dilution and is settled to scale, produces）PH to 6.5 ~ 7.0 is adjusted, the activated carbon that mass fraction is 0.1% ~ 0.3% is added, adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate, is added sterilized water for injection to prescription, is tested qualified through middle product examine, you can；The sterilization steps are that 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 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.
2. it is as claimed in claim 1（S）The oxo-1-pyrrolidine ethanamide injection of -4- hydroxyls -2, it is characterised in that it is made by the supplementary material of following significant percentage：（S）The oxo-1-pyrrolidine ethanamide 65% ~ 68% of -4- hydroxyls -2, propane diols 15% ~ 18%, lecithin 10% ~ 13%, vitamin C 3% ~ 6%, ethylenediamine tetra-acetic acid 3% ~ 5%；Above-mentioned supplementary material is placed in material-compound tank, the sterilized water for injection of 2/3 recipe quantity is added, stirred, dissolving obtains concentrated wiring liquid；Concentrated wiring liquid is taken, sodium phosphate buffer is added（Precision weighs disodium hydrogen phosphate 65.697g and sodium dihydrogen phosphate 2.346g is placed in 1000ml volumetric flasks, adds purified water dissolving, dilution and is settled to scale, produces）Adjust pH to 6.8, the activated carbon that mass fraction is 0.1% ~ 0.3% is added, adsorption bleaching is filtered with 0.45 μm of filter membrane, collect filtrate, sterilized water for injection is added to recipe quantity, is filtered after the assay was approved with 0.22 μm of filter through middle product, checks visible foreign matters, after bacterial endotoxin is qualified, upper streamline progress is filling, and pouring process need to be filled with the nitrogen of purity 99.99% so that the oxygen content in tank in water for injection is sealed no more than 0.01% after inflated with nitrogen；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 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.
3. it is as claimed in claim 1 or 2 a kind of（S）The preparation method of the oxo-1-pyrrolidine ethanamide injection of -4- hydroxyls -2, it is characterised in that it is obtained as follows：
A. concentrated compounding：The sterilized water for injection of 2/3 recipe quantity is added into material-compound tank, the supplementary material of recipe quantity is added, stirred, dissolving obtains concentrated wiring liquid；
B. it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, sodium phosphate buffer is added（Precision weighs disodium hydrogen phosphate 65.697g and sodium dihydrogen phosphate 2.346g is placed in 1000ml volumetric flasks, adds purified water dissolving, dilution and is settled to scale, produces）PH to 6.8 is adjusted, the activated carbon that mass fraction is 0.1% ~ 0.3% is added, adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate, is added sterilized water for injection to prescription, is tested qualified through middle product examine, you can；
C. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, visible foreign matters are checked, after bacterial endotoxin is qualified, upper streamline carries out filling, pouring process need to be filled with the nitrogen of purity 99.99% so that the oxygen content in tank in water for injection is sealed no more than 0.01% after inflated with nitrogen；
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 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；
E. examine：Sample checks visible foreign matters after sterilizing, and qualified sample will be examined to be packed, full inspection, storage.
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| CN201610105752.3A CN107115291A (en) | 2016-02-25 | 2016-02-25 | Oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2 and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610105752.3A CN107115291A (en) | 2016-02-25 | 2016-02-25 | Oxo-1-pyrrolidine ethanamide injection of one kind (S) -4- hydroxyls -2 and preparation method thereof |
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| CN107115291A true CN107115291A (en) | 2017-09-01 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116251057A (en) * | 2022-12-29 | 2023-06-13 | 平光制药股份有限公司 | Isosorbide dinitrate injection and preparation method thereof |
Citations (3)
| 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 |
| 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 |
| CN102670497A (en) * | 2012-05-31 | 2012-09-19 | 北京阜康仁生物制药科技有限公司 | Stable S-oxiracetam preparation for injection and preparation method of same |
-
2016
- 2016-02-25 CN CN201610105752.3A patent/CN107115291A/en not_active Withdrawn
Patent Citations (3)
| 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 |
| 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 |
| CN102670497A (en) * | 2012-05-31 | 2012-09-19 | 北京阜康仁生物制药科技有限公司 | Stable S-oxiracetam preparation for injection and preparation method of same |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116251057A (en) * | 2022-12-29 | 2023-06-13 | 平光制药股份有限公司 | Isosorbide dinitrate injection and preparation method thereof |
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Application publication date: 20170901 |