CN107115290A - Good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of a kind of clarity and preparation method thereof - Google Patents
Good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of a kind of clarity and preparation method thereof Download PDFInfo
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- CN107115290A CN107115290A CN201610105739.8A CN201610105739A CN107115290A CN 107115290 A CN107115290 A CN 107115290A CN 201610105739 A CN201610105739 A CN 201610105739A CN 107115290 A CN107115290 A CN 107115290A
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- pyrrolidine ethanamide
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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
A kind of clarity is good（S）The oxo-1-pyrrolidine ethanamide parenteral solution of -4- hydroxyls -2, it be with（S）The oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, propane diols, lecithin, phenmethylol 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 almost unchanged before and after the sterilizing of the oxo-1-pyrrolidine ethanamide parenteral solution of -4- hydroxyls -2, product clarity is good, less than No. 0.5 standard turbidity solution of clarity, stability is good, and crystallization will not be produced during storage, the term of validity is long, it can reach more than 18 months, product impurity is few in the term of validity, its total impurities is less than 0.37%, pain is reduced in patient injection procedure, good patient compliance.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of good oxygen of (S) -4- hydroxyls -2 of clarity
Generation -1- pyrrolidine acetamide parenteral solutions and preparation method thereof.
Background technology
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled 4- hydroxyls -2- oxo -1- pyrroles
Alkyl acetamide is coughed up, is that the anti anoxia class cereboactive drug that Italian ISFS.P.A companies synthesized first in 1974 (is changed
Compound is disclosed in US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine can be promoted
Synthesis, promotes brain metabolism, through blood-brain barrier, has stimulation, Ke Yigai to specific nervous centralis road
Kind intelligence and memory, also have to cerebrovascular disease, brain trauma, brain tumor, intracranial infection, brain degenerative disease etc. compared with
Good curative effect, and the drug toxicity is extremely low, no mutagenesis and carcinogenesis and genotoxicity.Giorgio etc.
People discloses the chemical constitution and preparation method of Oxiracetam in US4118396, and Chiodini et al. exists
Disclosed in WO9306826A, clinical effectiveness proves that the drug effect of the Oxiracetam of S configurations (left-handed) is better than R
Configuration (dextrorotation), Oxiracetam and levo-oxiracetam structure are as follows.
The existing oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 its be primarily present solution in sterilization process
PH is changed greatly, and product stability is bad, is easily crystallized during storage, and clarity is bad, patient's injection
Process pain substantially, the problems such as poor compliance.
The content of the invention
It is an object of the invention to provide the oxo -1- of (S) -4- hydroxyls -2 that a kind of stability is good, clarity is good
Pyrrolidine acetamide parenteral solution.
Another object of the present invention is to provide the above-mentioned oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2
Preparation method.
The purpose of the present invention is realized by following technical measures：
A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity, it is characterised in that
It is, using the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 as raw material, to add a certain amount of additives and be made；
Wherein described additives are glucose, sodium chloride, mannitol, glycerine, Serine, sodium glutamate, the third ammonia
Acid, glycine, lecithin, propane diols, phenmethylol, anesin, sodium sulfite, sodium hydrogensulfite,
In sodium pyrosulfite, the one or more of vitamin C, ethylenediamine tetra-acetic acid.
Inventor has found in research process, selects a certain proportion of propane diols, lecithin and phenmethylol composition
Compound additives, coordinate specific pH adjusting agent and the specific pH value of solution, then coordinate specific preparation
Technique, pH value of solution is substantially unchanged before and after may be such that product sterilizing, and product stability is good, during storage not
It can crystallize, product clarity, which has, to be significantly improved, pain is reduced during patient's injection use, and patient complies with
Property is good；The good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of above-mentioned clarity, it is characterised in that：
It is using the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2, propane diols, lecithin, phenmethylol as supplementary material,
By concentrated compounding, it is dilute match somebody with somebody, embedding, sterilizing, test package step be made；The consumption of wherein described supplementary material is attached most importance to
The oxo-1-pyrrolidine ethanamide 50%~70% of (S) -4- hydroxyls -2 of amount percentage, propane diols 15%~35%,
Lecithin 12%~30%, phenmethylol 1%~5%；The concentrated compounding step is to add supplementary material in material-compound tank, with
The sterilized water for injection of 2/3 recipe quantity is added, is stirred, dissolving obtains concentrated wiring liquid；Dilute step of matching somebody with somebody is to take
Concentrated wiring liquid, adding sodium phosphate buffer, (precision weighs disodium hydrogen phosphate 65.697g and sodium dihydrogen phosphate 2.346g
Be placed in 1000ml volumetric flasks, add purified water dissolving, dilution be settled to scale, produce) regulation pH to
6.5~7.0, the chitosan of cumulative volume 0.2%~0.6% (g/ml) is added into above-mentioned solution, is stirred, is mixed,
30~50min is stood, is filtered with 0.8 μm of filter membrane, the activity of cumulative volume 0.1%~0.3% (g/ml) is added
Charcoal, adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate, adds sterilized water for injection to recipe quantity,
Test qualified through middle product examine, you can.
Most preferably, the above-mentioned oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2, it is characterised in that
It is made by the supplementary material of following significant percentage：(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2
55%~60%, propane diols 18%~25%, lecithin 15%~20%, phenmethylol 2%~5%；The concentrated compounding step
Rapid is to add supplementary material in material-compound tank, and the sterilized water for injection of 2/3 recipe quantity is added immediately, is stirred, dissolving,
Obtain concentrated wiring liquid；Dilute step of matching somebody with somebody is to take concentrated wiring liquid, and adding sodium phosphate buffer, (precision weighs phosphoric acid hydrogen two
Sodium 65.697g and sodium dihydrogen phosphate 2.346g are placed in 1000ml volumetric flasks, add purified water dissolving, dilution
Scale is settled to, is produced) regulation pH to 6.8, cumulative volume 0.2%~0.6% (g/ml) is added into above-mentioned solution
Chitosan, stir, mix, stand 30~50min, filtered with 0.8 μm of filter membrane, add cumulative volume
0.1%~0.3% (g/ml) activated carbon, adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate,
Sterilized water for injection is added to recipe quantity, tests qualified through middle product examine, you can.
A kind of preparation method of the good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity, its
It is characterised by, it is obtained as follows：
1. concentrated compounding：Supplementary material is added in material-compound tank, the sterilized water for injection of 2/3 recipe quantity is added immediately,
Stirring, 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, cumulative volume 0.2%~0.6% (g/ml) is added into above-mentioned solution
Chitosan, stir, mix, stand 30~50min, filtered with 0.8 μm of filter membrane, added overall
0.1%~0.3% (g/ml) of product activated carbon, adsorption bleaching is filtered with 0.45 μm of filter membrane, is collected
Filtrate, adds sterilized water for injection to recipe quantity, tests qualified through middle product examine, you can；
3. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters,
After bacterial endotoxin is qualified, upper streamline carries out filling, sealing；
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：
Before and after a kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 sterilizing of clarity of the present invention
PH value of solution is almost unchanged, and product clarity is good, and less than No. 0.5 standard turbidity solution of clarity, stability is good,
Crystallization will not be produced during storage, the term of validity is long, can reach more than 18 months, product impurity in the term of validity
Few, its total impurities, which is less than pain in 0.37%, patient injection procedure, to be reduced, good patient compliance.
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
A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity, makes according to the following steps
：
| Composition | Consumption |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 100g |
| Propane diols | 45g |
| Lecithin | 31g |
| Phenmethylol | 5g |
| Sterilized water for injection | Add to 2000ml |
It is made 1000
Preparation process：
1. concentrated compounding：Supplementary material is added in material-compound tank, the sterilized water for injection of 2/3 recipe quantity is added immediately,
Stirring, 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, cumulative volume 0.2%~0.6% (g/ml) is added into above-mentioned solution
Chitosan, stir, mix, stand 30~50min, filtered with 0.8 μm of filter membrane, added overall
0.1%~0.3% (g/ml) of product activated carbon, adsorption bleaching is filtered with 0.45 μm of filter membrane, is collected
Filtrate, adds sterilized water for injection to recipe quantity, tests qualified through middle product examine, you can；
3. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters,
After bacterial endotoxin is qualified, upper streamline carries out filling, sealing；
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：A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity of the present invention is stable
Property experiment
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, clarity, 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, clarity, 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, clarity, pH value, have
Material, content and sterility test indices are closed without significant changes, meet production quality standard draft
Every relevant regulations.18 months steady qualities of this product long term test, therefore minimum 18 months of this product term of validity,
Long term test is still during continuing to investigate.
Experiment two：A kind of few oxo-1-pyrrolidine ethanamide clarity of injection of (S) -4- hydroxyls -2 of impurity of the present invention
Comparative experimental research
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 parenteral solution control sample of -4- hydroxyls -2：The change pH of difference single factor test
Conditioning agent, pH value and it is not added with after the factors such as chitosan, (S) -4- hydroxyls of the injection as made from embodiment 1
The oxo-1-pyrrolidine ethanamide sample of base -2 is used as control sample.
2. experimental method：Tested according to version pharmacopeia annex IXB clarity inspection techniques in 2010.
3. experimental result see the table below：
| Sample survey | As a result |
| The sample of embodiment 1 | ≤ 0.5 standard turbidity solution |
| Control sample 1：Using sample obtained by sodium acid carbonate as pH adjusting agent | The standard turbidity solution of 0.5 standard turbidity solution≤clarity≤1.0 |
| Control sample 2：PH is adjusted to 7.5 | The standard turbidity solution of 0.5 standard turbidity solution≤clarity≤1.0 |
| Control sample 3：PH is adjusted to 6.0 | The standard turbidity solution of 0.5 standard turbidity solution≤clarity≤1.0 |
| Control sample 4：The sample of non-shell adding glycan processing | ≥1.0 |
4. experiment conclusion：Sample clarity obtained by embodiment 1 is better than each control sample.
Experiment three：Pain experiment in mouse writhing method observation injection process
Test specimen：The oxo-1-pyrrolidine ethanamide injection of the hydroxyls of (the S)-4- as made from embodiment 1-2 is used as confession
Test product, the oxo -1- of prescription (S) -4- as made from embodiment 1 hydroxyls -2 of phenmethylol is not added
Pyrrolidine acetamide injection is used as control sample；
Purpose：Compare the pain journey in two kinds of oxo-1-pyrrolidine ethanamide injection injection process of (S) -4- hydroxyls -2
Degree
Method：Small white mouse is taken, the oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 is subcutaneously injected, observes small
Whether white mouse can occur writhing response, occur the probability of writhing response to judge injection process according to mouse
The power of middle pain, test sample respectively repeats 30 experiments with control sample；
Result of the test：Result of the test see the table below：
| Name of product | Experiment sample (mouse) | Generation writhing response number of individuals | Writhing response incidence % |
| Test sample | 30 | 7 | 23.3% |
| Control sample | 30 | 26 | 86.7% |
Conclusion：As seen from the above table, the oxo-1-pyrrolidine ethanamide injection of the present invention (S) -4- hydroxyls -2 was injected
Pain is markedly less than control sample in journey.
Experiment four：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 sterilized according to version Chinese Pharmacopoeia first step annex VIIG pH value determination method in 2010
Front and rear pH value of solution 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
A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity, makes according to the following steps
：
| Composition | Consumption |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 100g |
| Propane diols | 32g |
| Lecithin | 27g |
| Phenmethylol | 8g |
| Sterilized water for injection | Add to 2000ml |
It is made 1000
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, stability test investigation, clarity contrast test, mouse are carried out respectively
PH value of solution before and after pain experiment and pH adjusting agent in writhing method observation injection process sterilize to product
Influence experiment, the sample stability result of the test of embodiment 2 shows to accelerate sample quality stabilization in June, long-term by 18
Individual month steady quality, therefore minimum 18 months of this product term of validity.Clarity comparative test result shows embodiment 2
The sample clarity produced is less than No. 0.5 standard turbidity solution, and this product clarity is good.Mouse writhing method observation note
Pain result of the test during penetrating shows, pain is markedly less than pair in the left injection process of the sample of embodiment 2
Product in the same old way.The influence experiment of pH value of solution shows that embodiment 2 is made before and after different pH adjusting agents sterilize to product
PH value of solution is substantially unchanged before and after the sample sterilizing obtained.
Embodiment 3
A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity, makes according to the following steps
：
It is made 1000
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, stability test investigation, clarity contrast test, mouse are carried out respectively
PH value of solution before and after pain experiment and pH adjusting agent in writhing method observation injection process sterilize to product
Influence experiment, the sample stability result of the test of embodiment 3 shows to accelerate sample quality stabilization in June, long-term by 18
Individual month steady quality, therefore minimum 18 months of this product term of validity.Clarity comparative test result shows embodiment 3
The sample clarity produced is less than No. 0.5 standard turbidity solution, and this product clarity is good.Mouse writhing method observation note
Pain result of the test during penetrating shows, pain is markedly less than pair in the left injection process of the sample of embodiment 3
Product in the same old way.The influence experiment of pH value of solution shows that embodiment 3 is made before and after different pH adjusting agents sterilize to product
PH value of solution is substantially unchanged before and after the sample sterilizing obtained.
Embodiment 4-6：A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity,
It is prepared by the supplementary material of following weight, preparation method be the same as Example 1：
By the test method of embodiment 1, stability test investigation, clarity contrast test, mouse are carried out respectively
PH value of solution before and after pain experiment and pH adjusting agent in writhing method observation injection process sterilize to product
Influence experiment, the sample stability result of the test of embodiment 4,5,6 shows to accelerate sample quality stabilization in June, long
18 months phases steady quality, therefore minimum 18 months of this product term of validity.Clarity comparative test result shows to implement
The sample clarity that example 4,5,6 is produced is less than No. 0.5 standard turbidity solution, and this product clarity is good.Mouse is turned round
Pain result of the test in body method observation injection process shows, in the left injection process of sample of embodiment 4,5,6
Pain is markedly less than control sample.The influence of pH value of solution is tested before and after different pH adjusting agents sterilize to product
PH value of solution is substantially unchanged before and after showing the sample sterilizing obtained by embodiment 4,5,6.
Claims (3)
1. a kind of clarity is good（S）The oxo-1-pyrrolidine ethanamide parenteral solution 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, phenmethylol 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 50% ~ 70% or so of -4- hydroxyls -2, propane diols 15% ~ 35% or so, lecithin 12% ~ 30% or so, phenmethylol 1% ~ 5% or so；The concentrated compounding step is to add supplementary material in material-compound tank, and the sterilized water for injection of 2/3 recipe quantity is added immediately, 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, cumulative volume 0.2% ~ 0.6% is added into above-mentioned solution（g/ml）Chitosan, stir, mix, stand 30 ~ 50min, filtered with 0.8 μm of filter membrane, add cumulative volume 0.1% ~ 0.3%（g/ml）Activated carbon, adsorption bleaching filters with 0.45 μm of filter membrane, collects filtrate, add sterilized water for injection to recipe quantity, test qualified through middle product examine, you can.
2. it is as claimed in claim 1（S）The oxo-1-pyrrolidine ethanamide parenteral solution 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 55% ~ 60% or so of -4- hydroxyls -2, propane diols 18% ~ 25% or so, lecithin 15% ~ 20% or so, phenmethylol 2% ~ 5% or so；The concentrated compounding step is to add supplementary material in material-compound tank, and the sterilized water for injection of 2/3 recipe quantity is added immediately, 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 6.8 is adjusted, cumulative volume 0.2% ~ 0.6% is added into above-mentioned solution（g/ml）Chitosan, stir, mix, stand 30 ~ 50min, filtered with 0.8 μm of filter membrane, add cumulative volume 0.1% ~ 0.3%（g/ml）Activated carbon, adsorption bleaching filters with 0.45 μm of filter membrane, collects filtrate, add sterilized water for injection to recipe quantity, test qualified through middle product examine, you can.
3. it is as claimed in claim 1 or 2（S）The preparation method of the oxo-1-pyrrolidine ethanamide parenteral solution of -4- hydroxyls -2, it is characterised in that it is obtained as follows：
A. concentrated compounding：Supplementary material is added in material-compound tank, the sterilized water for injection of 2/3 recipe quantity is added immediately, is 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, cumulative volume 0.2% ~ 0.6% is added into above-mentioned solution（g/ml）Chitosan, stir, mix, stand 30 ~ 50min, filtered with 0.8 μm of filter membrane, add cumulative volume 0.1% ~ 0.3%（g/ml）Activated carbon, adsorption bleaching filters with 0.45 μm of filter membrane, collects filtrate, add sterilized water for injection to recipe quantity, test qualified through middle product examine, you can；
C. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters, after bacterial endotoxin is qualified, and upper streamline carries out filling, sealing；
D. sterilize：Canned peace is cutd open into semi-finished product feeding steam sterilization pan sterilizing, 121 DEG C of sterilizing 15min, sterilizing program：10 DEG C/min, 121 DEG C are risen to, 15min is kept at 121 DEG C；3 ~ 5 DEG C/min of compressed air air blast 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4686296A (en) * | 1985-07-26 | 1987-08-11 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| 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 |
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2016
- 2016-02-25 CN CN201610105739.8A patent/CN107115290B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4686296A (en) * | 1985-07-26 | 1987-08-11 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| 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 |
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