CN107281129A - A kind of levo-oxiracetam aseptic powdery of injection and preparation method thereof - Google Patents
A kind of levo-oxiracetam aseptic powdery of injection and preparation method thereof Download PDFInfo
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- CN107281129A CN107281129A CN201610194928.7A CN201610194928A CN107281129A CN 107281129 A CN107281129 A CN 107281129A CN 201610194928 A CN201610194928 A CN 201610194928A CN 107281129 A CN107281129 A CN 107281129A
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- levo
- oxiracetam
- injection
- aseptic powdery
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
Abstract
A kind of injection levo-oxiracetam aseptic powdery, it is made by the supplementary material of following weight percents：Levo-oxiracetam 62% ~ 68%, L serines 12% ~ 18%, mannitol 8% ~ 13%, polyethylene glycol 2000 2% ~ 7%, methionine 2% ~ 6%, phenmethylol 1% ~ 2%；It is smaller according to impurity level increase in injection levo-oxiracetam aseptic powdery preparation process produced by the present invention, whole preparation process impurity only increases phenomenon of the 0.04%, product without drying shrinkage and bubbling, finished product has solid shape, stability is good, impurity is less than 0.27% in shelf life, shelf life is up to 24 months, and pain is lighter in patient injection procedure, good patient compliance.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to levo-oxiracetam aseptic powdery of a kind of injection and preparation method thereof.
Background technology
It is a kind of promotion study that cereboactive drug, which is also known as cereboactive drug, strengthens the new medicine for central nervous system of memory.Nootropics requires selection index system in cerebral cortex, with selection activation, protection and the feature for promoting damaged nerve cell functional rehabilitation.Different from other neurologic agents be a little their above-mentioned effect not by network or olfactory bulb, but directly act on cortex.Behavior is neither influenceed, also without calm excitation, therefore such medicine has caused the extensive concern and interest of people, and the demand to such medicine is also growing day by day.
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled Esomeprazole, the anti anoxia class cereboactive drug synthesized first in 1974 for Italian ISFS.P.A companies (compound is disclosed in US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine can be promoted to synthesize, promote brain metabolism, through blood-brain barrier, there is stimulation to specific nervous centralis road, intelligence and memory can be improved, to cerebrovascular disease, brain trauma, brain tumor, intracranial infection, brain degenerative diseases etc. also have preferable curative effect, and the drug toxicity is extremely low, without mutagenesis and carcinogenesis and genotoxicity.Giorgio et al. discloses the chemical constitution and preparation method of Oxiracetam in US4118396, Chiodini et al. is disclosed in W09306826A, clinical effectiveness proves that the drug effect of the Oxiracetam of S configurations (left-handed) is better than R configurations (dextrorotation), and Oxiracetam and levo-oxiracetam structure are as follows.
Existing injection levo-oxiracetam aseptic powdery its be primarily present in preparation process impurity increase substantially, be difficult to form skeleton, easily drying shrinkage and bubbling phenomenon occur, finished product is without solid shape, stability is poor, shelf life is short, and product injection process pain is substantially, the problems such as patient's poor compliance.
The content of the invention
Have that solid form, stability is good, shelf life length injection levo-oxiracetam aseptic powdery it is an object of the invention to provide a kind of.
Another object of the present invention is to provide the preparation method of above-mentioned injection levo-oxiracetam aseptic powdery.
The purpose of the present invention is realized by following technical measures：
The levo-oxiracetam aseptic powdery of a kind of injection, it is characterised in that it is made by the supplementary material of following weight percents：Levo-oxiracetam 60%~70%, additives 30%~40%, wherein described additives are sucrose, trehalose, mannitol, lactose, glucose, maltose, glucan, albumin, polyethylene glycol, glycerine, Serine, vitamin C, sodium thiosulfate, one or more in methionine, sodium glutamate, alanine, glycine, methyl amimoacetic acid, phosphate, acetate, citrate, phenmethylol.
Inventor has found in research process, select specific additives species, coordinate specific supplementary material consumption proportion relation, it may be such that the impurity level increase in preparation process of above-mentioned injection levo-oxiracetam aseptic powdery is smaller, it is less prone to drying shrinkage and bubbling phenomenon, finished product has solid shape, easily forms skeleton, shelf life extends, and product injection process pain has mitigated, above-mentioned injection levo-oxiracetam aseptic powdery, characterized in that, it is made by the supplementary material of following weight percents：Levo-oxiracetam 62%~68%, Serine 12%~18%, mannitol 8%~13%, polyethylene glycol 2000 2%~7%, methionine 2%~6%, phenmethylol 1%~2%.
Most preferably, above-mentioned injection levo-oxiracetam aseptic powdery, it is characterised in that it is made by the supplementary material of following weight percents：Levo-oxiracetam 63%~66%, Serine 13%~16%, mannitol 10%~12%, polyethylene glycol 2000 3%~6%, methionine 3%~5%, phenmethylol 1%~2%.
Supplementary material needed for above-mentioned, is well known to those skilled in the art, in the market is commercially available.
The preparation method of the levo-oxiracetam aseptic powdery of a kind of injection, it is characterised in that it is obtained as follows：
1. concentrated compounding：The levo-oxiracetam of recipe quantity, additives are placed in container, the sterilized water for injection stirring of 10 times of parts by weight of levo-oxiracetam are added, after dissolving, the needle-use activated carbon of mass fraction 0.1% is added, 30min is stirred, is then filtered with 0.45 micrometer Millipore filter membrane, filtrate is collected, it is standby；
2. dilute match somebody with somebody：Sterilized water for injection is added into filtrate to 1000 times of filtrate volume, pH to 7.0 is adjusted with hydrochloric acid or sodium hydroxide, then with 0.22 micron of miillpore filter aseptic filtration, take filtrate it is qualified it is rear it is filling be sub-packed in sterile glass vials, it is standby；
3. freeze-drying：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, temperature -40 DEG C are refrigerated to rapidly, whole process is kept for 180 minutes, then vacuumizes drying, -10 DEG C are warming up to 15 DEG C/h, -10 DEG C of constant temperature are kept for 120 minutes；0 DEG C is warming up to 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；10 DEG C are warming up to 5 DEG C/h, 10 DEG C of constant temperature 240 minutes is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum drop reaches 10Pa/10 timesharing, is freezed and terminated；
4. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, produces.
The present invention has following beneficial effect：
Impurity level increase is smaller in injection levo-oxiracetam aseptic powdery preparation process of the present invention, whole preparation process impurity only increases phenomenon of the 0.04%, product without drying shrinkage and bubbling, finished product has solid shape, stability is good, impurity is less than 0.27% in shelf life, shelf life is up to 24 months, and pain is lighter in patient injection procedure, good patient compliance.
Embodiment
The present invention is specifically described below by embodiment; it is necessarily pointed out that following examples are served only for that the present invention is further described; it is not intended that limiting the scope of the invention; without departing from the spirit and substance of the case in the present invention; 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 injection levo-oxiracetam aseptic powdery, is made according to the following steps：
Preparation process：
1. concentrated compounding：The levo-oxiracetam of recipe quantity, additives are placed in container, the sterilized water for injection stirring of 10 times of parts by weight of levo-oxiracetam are added, after dissolving, the needle-use activated carbon of mass fraction 0.1% is added, 30min is stirred, is then filtered with 0.45 micrometer Millipore filter membrane, filtrate is collected, it is standby；
2. dilute match somebody with somebody：Sterilized water for injection is added into filtrate to 1000 times of filtrate volume, pH to 7.0 is adjusted with hydrochloric acid or sodium hydroxide, then with 0.22 micron of miillpore filter aseptic filtration, takes filtrate is filling to be after the assay was approved sub-packed in sterile glass vials, it is standby；
3. freeze-drying：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, temperature -40 DEG C are refrigerated to rapidly, whole process is kept for 180 minutes, then vacuumizes drying, -10 DEG C are warming up to 15 DEG C/h, -10 DEG C of constant temperature are kept for 120 minutes；0 DEG C is warming up to 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；10 DEG C are warming up to 5 DEG C/h, 10 DEG C of constant temperature 240 minutes is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum drop reaches 10Pa/10 timesharing, is freezed and terminated；
4. roll lid：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, produces.
In order to be better understood from the present invention, the beneficial effect of invention medicine, rather than limitation of the present invention are expanded on further below by way of stability test of the present invention.
Experiment one：A kind of levo-oxiracetam aseptic powdery stability experiment of injection of the present invention
Experiment material：
The Oxiracetam aseptic powdery sample of injection：It is made for embodiment 1
Acceleration study method：The Oxiracetam aseptic powdery of injection made from embodiment 1 is packed by listing, put in Acceleration study case, certain time sampling is tested to investigation project.
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：Accelerate June sample suitable with the every Testing index quality of 0 month sample, show this product Acceleration study June, stably, this product stability is preferable for quality holding.
Long-term experiment method：Injection Oxiracetam aseptic powdery made from embodiment 1 is packed by listing, put in the long-term case that keeps sample, certain time sampling is tested to investigation project.
Acceleration study temperature：25±2℃
Humidity：RH60% ± 10%
The investigation time：0th, 3,6,9,12,18,24 months
Inspection target：Character, visible foreign matters, pH, relevant material, content, sterility test
Long term test stability is recorded：
Long term test shows：This product long term test 24 months characters, visible foreign matters, pH value, relevant material, content and sterility test indices meet every relevant regulations of production quality standard draft without significant changes.24 months steady qualities of this product long term test, therefore minimum 24 months of this product shelf life, long term test is still during continuing to investigate.
Experiment two：A kind of levo-oxiracetam aseptic powdery preparation process of injection of the present invention is on the increased influence of impurity
1. experiment material：
The levo-oxiracetam aseptic powdery sample of injection：Prepared by embodiment 1.
The levo-oxiracetam aseptic powdery control sample of injection：To lack the sample of methionine, its preparation technology be the same as Example 1.
2. experimental method：In the preparation process of embodiment 1, sampled respectively before and after preparing, detect it about material, investigate preparation process to the influence about material.Meanwhile, take the prescription for lacking methionine as prescription is compareed, prepared by the preparation method of embodiment 1, sampling detects it about material equally before and after preparing, and investigates preparation process to the influence about material.
3. experimental result see the table below：
| Test sample | Relevant material % before preparing | Relevant material % after preparation | The relevant material incrementss % of preparation process |
| Embodiment 1 | 0.14% | 0.18% | 0.04% |
| Control sample 1 | 0.15% | 0.33% | 0.18% |
4. experiment conclusion：The prescription of embodiment 1, the relevant material increase of preparation process is only 0.04%, hence it is evident that better than control sample.
Experiment three：Pain experiment in mouse writhing method observation injection process
Test specimen：A kind of injection levo-oxiracetam aseptic powdery as made from embodiment 1 does not add prescription injection levo-oxiracetam aseptic powdery as made from embodiment 1 of phenmethylol to be used as control sample as test sample；
Purpose：Compare the pain degree in the levo-oxiracetam aseptic powdery injection process of two kinds of injections
Method：Take experimental white mouse, levo-oxiracetam aseptic powdery is subcutaneously injected (physiological saline solution is diluted to 10ml), whether observation small white mouse can occur writhing response, the probability of writhing response occurs according to mouse to judge the power of pain in injection process, 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 | 3 | 10.0% |
| Control sample | 30 | 27 | 90.0% |
Conclusion：As seen from the above table, pain is markedly less than control sample in a kind of injection levo-oxiracetam aseptic powdery injection process of the invention.
Embodiment 2
A kind of injection levo-oxiracetam aseptic powdery, is made according to the following steps：
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, the sample stability result of the test of embodiment 2 shows to accelerate June sample quality stable, long-term 24 months steady qualities, therefore minimum 24 months of this product term of validity.The influence increased on impurity of the preparation process of embodiment 2 meets product requirement test result indicates that this product product impurity incrementss in preparation process are smaller.Pain result of the test in mouse writhing method observation injection process shows that pain is markedly less than control sample during the sample injection of embodiment 2.
Embodiment 3
A kind of injection levo-oxiracetam aseptic powdery, is made according to the following steps：
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, the sample stability result of the test of embodiment 3 shows to accelerate June sample quality stable, long-term 24 months steady qualities, therefore minimum 24 months of this product term of validity.The influence increased on impurity of the preparation process of embodiment 3 meets product requirement test result indicates that this product product impurity incrementss in preparation process are smaller.Pain result of the test in mouse writhing method observation injection process shows that pain is markedly less than control sample during the sample injection of embodiment 3.
Embodiment 4-6：A kind of injection levo-oxiracetam aseptic powdery, is prepared by the supplementary material of following weight, preparation method be the same as Example 1：
Preparation process：Preparation technology according to embodiment 1 is made.
By the test method of embodiment 1, the sample stability result of the test of embodiment 4,5,6 shows to accelerate June sample quality stable, long-term 24 months steady qualities, therefore minimum 24 months of this product term of validity.The influence increased on impurity of the preparation process of embodiment 4,5,6 meets product requirement test result indicates that this product product impurity incrementss in preparation process are smaller.Pain result of the test in mouse writhing method observation injection process shows that pain is markedly less than control sample during the sample injection of embodiment 4,5,6.
Claims (3)
1. a kind of injection levo-oxiracetam aseptic powdery, it is characterised in that it is made by the supplementary material of following weight percents：Levo-oxiracetam about 62% ~ 68%, Serine about 12% ~ 18%, mannitol about 8% ~ 13%, polyethylene glycol 2000 about 2% ~ 7%, methionine about 2% ~ 6%, phenmethylol about 1% ~ 2%.
2. injection levo-oxiracetam aseptic powdery as claimed in claim 1, it is characterised in that it is made by the supplementary material of following weight percents：Levo-oxiracetam 63% ~ 66%, Serine 13% ~ 16%, mannitol 10% ~ 12%, polyethylene glycol 2000 3% ~ 6%, methionine 3% ~ 5%, phenmethylol 1% ~ 2%.
3. the preparation method of the levo-oxiracetam aseptic powdery of a kind of injection as claimed in claim 1 or 2, it is characterised in that it is obtained as follows：
A. concentrated compounding：The levo-oxiracetam of recipe quantity, additives are placed in container, the sterilized water for injection stirring of 10 times of parts by weight of levo-oxiracetam are added, after dissolving, the needle-use activated carbon of mass fraction 0.1% is added, 30min is stirred, is then filtered with 0.45 micrometer Millipore filter membrane, filtrate is collected, it is standby；
B. it is dilute to match somebody with somebody：Sterilized water for injection is added into filtrate to 1000 times of filtrate volume, pH to 7.0 is adjusted with hydrochloric acid or sodium hydroxide, then with 0.22 micron of miillpore filter aseptic filtration, take filtrate it is qualified it is rear it is filling be sub-packed in sterile glass vials, it is standby；
C. it is freeze-dried：The above-mentioned decoction being sub-packed in sterile glass vials is put in freeze drier, temperature -40 DEG C are refrigerated to rapidly, whole process is kept for 180 minutes, then vacuumizes drying, -10 DEG C are warming up to 15 DEG C/h, -10 DEG C of constant temperature are kept for 120 minutes；0 DEG C is warming up to 5 DEG C/h, 0 DEG C of constant temperature 320 minutes；10 DEG C are warming up to 5 DEG C/h, 10 DEG C of constant temperature 240 minutes is warming up to 30 DEG C with 10 DEG C/h, 30 DEG C of constant temperature 60 minutes, while preceding case vacuum drop reaches 10Pa/10 timesharing, is freezed and terminated；
D. lid is rolled：Aluminium-plastic combined cover needs once purged sterilizing, drying, then carries out rolling lid, produces.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610194928.7A CN107281129A (en) | 2016-03-31 | 2016-03-31 | A kind of levo-oxiracetam aseptic powdery of injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610194928.7A CN107281129A (en) | 2016-03-31 | 2016-03-31 | A kind of levo-oxiracetam aseptic powdery of injection and preparation method thereof |
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| CN107281129A true CN107281129A (en) | 2017-10-24 |
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Citations (2)
| 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 |
| CN102872011A (en) * | 2012-05-31 | 2013-01-16 | 北京阜康仁生物制药科技有限公司 | Pharmaceutical composition comprising (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide |
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2016
- 2016-03-31 CN CN201610194928.7A patent/CN107281129A/en not_active Withdrawn
Patent Citations (2)
| 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 |
| CN102872011A (en) * | 2012-05-31 | 2013-01-16 | 北京阜康仁生物制药科技有限公司 | Pharmaceutical composition comprising (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide |
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Application publication date: 20171024 |