CN106692044A - (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity and preparation method thereof - Google Patents
(S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity and preparation method thereof Download PDFInfo
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- CN106692044A CN106692044A CN201510511535.XA CN201510511535A CN106692044A CN 106692044 A CN106692044 A CN 106692044A CN 201510511535 A CN201510511535 A CN 201510511535A CN 106692044 A CN106692044 A CN 106692044A
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Abstract
The invention provides an (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity. The injection is characterized by being prepared from, by weight, 58 to 78% of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide, 10 to 25% of propylene glycol, 10 to 30% of lecithin and 1 to 3% of benzyl alcohol through concentrated-solution preparation, dilute-solution preparation, filling, sterilization, inspection and packaging. The (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide injection prepared in the invention has the following advantages: the injection has good clarity, which is lower than the clarity of the standard turbidity solution No. 0.5; the injection has good stability and produces no crystal during storage; the injection has a long period of validity, as long as 18 months or more; he injection has low impurity content in the period of validity, wherein the amount of total impurities in the period of validity is lower than 0.36%; and pain is reduced during injection of the injection, so good patient compliance is obtained.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of good oxo -1- of (S) -4- hydroxyls -2 of clarity
Pyrrolidine acetamide parenteral solution and preparation method thereof.
Background technology
Oxiracetam (oxiracetam, CAS No.：62613-82-5) chemical entitled 4- hydroxyls -2- OXo-1-pyrrolidine second
Acid amides, is that (compound is disclosed in the anti anoxia class cereboactive drug that synthesized first in 1974 of Italian ISFS.P.A companies
US4118396), it is ring GABOB derivatives, Phosphorylcholine and phosphatidyl ethanolamine can be promoted to synthesize, promotes brain metabolism,
Through blood-brain barrier, have stimulation to specific nervous centralis road, intelligence and memory can be improved, to cerebrovascular disease,
Brain trauma, brain tumor, intracranial infection, brain degenerative disease etc. also have preferable curative effect, and the drug toxicity is extremely low, nothing
Mutagenesis and carcinogenesis and genotoxicity.Giorgio et al. discloses the chemistry knot of Oxiracetam in US4118396
Structure and preparation method, Chiodini et al. are disclosed in WO9306826A, and clinical effectiveness proves S's configurations (left-handed)
The drug effect of Oxiracetam is better than R configurations (dextrorotation), and Oxiracetam and levo-oxiracetam structure are as follows.
The existing oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 its to be primarily present stability bad, store process
In easily crystallize, clarity is bad, patient injection procedure's pain substantially, the problems such as poor compliance.
The content of the invention
It is an object of the invention to provide the good OXo-1-pyrrolidine second of (S) -4- hydroxyls -2 of a kind of good stability, clarity
Acid amides parenteral solution.
Preparation another object of the present invention is to provide the above-mentioned oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2
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 be with
(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 is raw material, adds a certain amount of additives and is obtained；It is wherein described attached
Plus agent is glucose, sodium chloride, mannitol, glycerine, Serine, sodium glutamate, alanine, glycine, lecithin
In fat, propane diols, phenmethylol, anesin, sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, vitamin C,
One or more of ethylenediamine tetra-acetic acid.
Inventor has found that it is compound attached that a certain proportion of propane diols of selection, lecithin and phenmethylol are constituted in research process
Plus agent, then coordinate specific preparation technology, and may be such that product stability is good, will not be crystallized during storage, product clarification
With significantly improving, pain is reduced degree during patient's injection use, good patient compliance；Above-mentioned clarity good (S)
The oxo-1-pyrrolidine ethanamide parenteral solution of -4- hydroxyls -2, it is characterised in that：It is with the oxo -1- pyrroles of (S) -4- hydroxyls -2
Alkyl acetamide, propane diols, lecithin, phenmethylol are coughed up for supplementary material, by concentrated compounding, it is dilute match somebody with somebody, embedding, sterilizing, inspection
Packaging step is obtained；The OXo-1-pyrrolidine second of (S) -4- hydroxyls -2 that the consumption of wherein described supplementary material is weight percentage
Acid amides 58%~78%, propane diols 10%~25%, lecithin 10%~30%, phenmethylol 1%~3%；The concentrated compounding step
It is, by supplementary material addition material-compound tank, sterilized water for injection to be added immediately, stirs, dissolving obtains concentrated wiring liquid；It is described dilute to match somebody with somebody
Step adds 0.1mol/L~0.5mol/L sodium hydroxide solutions to take concentrated wiring liquid, pH to 6.5~7.0 is adjusted, to above-mentioned
The shitosan of cumulative volume 0.2%~0.6% (g/ml) is added in solution, stirring is mixed, and 30~50min is stood, with 0.8
μm filter membrane filtration, add cumulative volume 0.1%~0.3% (g/ml) activated carbon, adsorption bleaching, with 0.45 μm
Filter membrane is filtered, and collects filtrate, adds sterilized water for injection to recipe quantity, tests 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 be by
The supplementary material of following significant percentage is obtained：(S) oxo-1-pyrrolidine ethanamide 65%~72% of -4- hydroxyls -2, propane diols
15%~20%, lecithin 12%~18%, phenmethylol 1%~3%, by above-mentioned supplementary material addition material-compound tank, is added immediately
The sterilized water for injection of 1/3 recipe quantity, stirring, dissolving obtains concentrated wiring liquid；Concentrated wiring liquid is taken, 0.1mol/L hydroxides are added
Sodium solution, adjusts pH to 6.5~7.0, to the shitosan that cumulative volume 0.2%~0.6% (g/ml) is added in above-mentioned solution,
Stirring, mixes, and stands 30~50min, is filtered with 0.8 μm of filter membrane, adds cumulative volume 0.1%~0.3% (g/ml)
Activated carbon, adsorption bleaching filters 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.
A kind of preparation method of the good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity, its feature exists
In it is obtained as follows：
1. concentrated compounding：By in supplementary material addition material-compound tank, the sterilized water for injection of 1/3 recipe quantity is added immediately, stir,
Dissolving, obtains concentrated wiring liquid；
2. it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, 0.1mol/L sodium hydroxide solutions are added, pH to 6.5~7.0 is adjusted, to above-mentioned
The shitosan of the mass volume ratio of cumulative volume 0.2%~0.6% is added in solution, stirring is mixed, and stands 30~50min,
Filtered with 0.8 μm of filter membrane, add the activated carbon of the mass volume ratio of cumulative volume 0.1%~0.3%, adsorption bleaching to use
0.45 μm of filter membrane filtration, collects filtrate, adds sterilized water for injection to recipe quantity, tests qualified through middle product examine,
；
3. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters, bacterium endogenous toxic material
After element is qualified, upper streamline carries out filling, sealing；
4. 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 lowers the temperature,
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, has sterilized
Into by rated condition leak detection.
5. check：Sample checks visible foreign matters after sterilizing, and qualified sample will be checked to be packed, full inspection, storage.
The present invention has following beneficial effect：
A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity of the present invention has clarity good,
Clarity is less than No. 0.5 standard turbidity solution, and good stability will not produce crystallization during storage, the term of validity is long, reachable
By more than 18 months, product impurity was few in the term of validity, and its total impurities is less than 0.36%, pain drop in patient injection procedure
It is low, good patient compliance.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be that following examples are served only for
The present invention is further described, it is impossible to be interpreted as limiting the scope of the invention, without departing substantially from spirit of the invention
In the case of essence, the modification or replacement 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, is obtained according to the following steps：
Preparation process：
1. concentrated compounding：By in supplementary material addition material-compound tank, the sterilized water for injection of 1/3 recipe quantity is added immediately, stir,
Dissolving, obtains concentrated wiring liquid；
2. it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, 0.1mol/L sodium hydroxide solutions are added, pH to 6.5~7.0 is adjusted, to above-mentioned
The shitosan of the mass volume ratio of cumulative volume 0.2%~0.6% is added in solution, stirring is mixed, and stands 30~50min,
Filtered with 0.8 μm of filter membrane, add the activated carbon of the mass volume ratio of cumulative volume 0.1%~0.3%, adsorption bleaching to use
0.45 μm of filter membrane filtration, collects filtrate, adds sterilized water for injection to recipe quantity, tests qualified through middle product examine,
；
3. embedding：Intermediate is filtered with 0.22 μm of filter after the assay was approved, checks visible foreign matters, bacterium endogenous toxic material
After element is qualified, upper streamline carries out filling, sealing；
4. 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 lowers the temperature,
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, has sterilized
Into by rated condition leak detection；
5. check：Sample checks visible foreign matters after sterilizing, and qualified sample will be checked to be packed, full inspection, storage.
In order to be better understood from the present invention, the beneficial of invention medicine is expanded on further below by way of stability test of the present invention
Effect, rather than limitation of the present invention.
Experiment one：A kind of good oxo-1-pyrrolidine ethanamide parenteral solution stability experiment of (S) -4- hydroxyls -2 of clarity of the present invention
Experiment material：
(S) the oxo-1-pyrrolidine ethanamide injection liquid samples of -4- hydroxyls -2：For embodiment 1 is obtained
Acceleration study method：By the oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 obtained in embodiment 1 by upper
City is packed, and puts in Acceleration study case, and certain hour sampling is tested to investigation project.
Acceleration study temperature：40±2℃
Humidity：RH75% ± 5%
The investigation time：0th, 1,2,3, June
Inspection target：Proterties, visible foreign matters, clarity, pH, relevant material, content, sterility test
Accelerated test stability is recorded：
Acceleration study result shows：Accelerate June sample suitable with 0 month sample items Testing index quality, show that this product adds
Speed experiment June, quality keeps stabilization, and this product stability is preferable.
Long-term experiment method：By the oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 obtained in embodiment 1 by upper
City is packed, and puts in the long-term case that keeps sample, and certain hour 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：Proterties, visible foreign matters, clarity, pH, relevant material, content, sterility test
Long term test stability is recorded：
Long term test shows：18 months proterties of this product long term test, visible foreign matters, clarity, pH value, relevant material,
Content and sterility test indices without significant changes, meet the related rule of items of production quality standard draft
It is fixed.18 months steady qualities of this product long term test, therefore minimum 18 months of this product term of validity, long term test still is continuing to examine
During examining.
Experiment two：A kind of few oxo-1-pyrrolidine ethanamide clarity of injection of (S) -4- hydroxyls -2 of impurity of the present invention is to having a competition
Test research
1. experiment material：
(S) the oxo-1-pyrrolidine ethanamide injection liquid samples of -4- hydroxyls -2：For embodiment 1 is obtained
(S) the oxo-1-pyrrolidine ethanamide parenteral solution control sample of -4- hydroxyls -2：The change pH regulations of single factor test respectively
Agent, pH value and after being not added with the factors such as shitosan, the oxo -1- of (S) -4- hydroxyls -2 of injection as obtained in embodiment 1
Pyrrolidine acetamide sample is used as control sample.
2. experimental technique：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 | 0.5 standard turbidity solution≤clarity≤1.0 standard turbidity solution |
| Control sample 2：PH is adjusted to 7.5~8.0 | 0.5 standard turbidity solution≤clarity≤1.0 standard turbidity solution |
| Control sample 3：PH is adjusted to 6.0~6.5 | 0.5 standard turbidity solution≤clarity≤1.0 standard turbidity solution |
| Control sample 4：The sample of non-shell adding glycan treatment | ≥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 obtained in embodiment 1-2 as test sample,
Not plus phenmethylol the oxo-1-pyrrolidine ethanamide of prescription (S) -4- as obtained in embodiment 1 hydroxyls -2 note
Agent is penetrated as control sample；
Purpose：Compare the pain degree in two kinds of oxo-1-pyrrolidine ethanamide injection injection process of (S) -4- hydroxyls -2
Method：Small white mouse, the oxo-1-pyrrolidine ethanamide injection of hypodermic injection (S) -4- hydroxyls -2 are taken, observation small white mouse is
It is no that writhing response can occur, there is the probability of writhing response according to mouse to judge the strong of pain in injection process
Weak, 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 | 8 | 26.7% |
| Control sample | 30 | 25 | 83.3% |
Conclusion：As seen from the above table, ache in the oxo-1-pyrrolidine ethanamide injection injection process of the present invention (S) -4- hydroxyls -2
Pain is markedly less than control sample.
Embodiment 2
A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity, is obtained according to the following steps：
Preparation process：Preparation technology according to embodiment 1 is obtained.
By the test method of embodiment 1, the sample of embodiment 2 is carried out into stability test investigation, clarity to having a competition respectively
Test, stability test result shows to accelerate June sample quality stabilization, long-term 18 months steady qualities, therefore this product is effective
Minimum 18 months of phase.Clarity contrast test result of the test shows that the sample clarity that embodiment 2 is produced is less than 0.5
Number standard turbidity solution, this product clarity is good.Pain result of the test in mouse writhing method observation injection process shows, real
Pain is markedly less than control sample in applying the left injection process of sample of example 2.
Embodiment 3
A kind of good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of clarity, is obtained according to the following steps：
Preparation process：Preparation technology according to embodiment 1 is obtained.
By the test method of embodiment 1, the sample of embodiment 3 is carried out into stability test investigation, clarity to having a competition respectively
Test, stability test result shows to accelerate June sample quality stabilization, long-term 18 months steady qualities, therefore this product is effective
Minimum 18 months of phase.Clarity contrast test result of the test shows that the sample clarity that embodiment 3 is produced is less than 0.5
Number standard turbidity solution, this product clarity is good.Pain result of the test in mouse writhing method observation injection process shows, real
Pain is markedly less than control sample in applying the left injection process of sample of example 3.
Embodiment 4-6：The good oxo-1-pyrrolidine ethanamide parenteral solution of (S) -4- hydroxyls -2 of a kind of clarity, by following
The supplementary material of weight is prepared, and preparation method is with embodiment 1：
By the test method of embodiment 1, the sample of embodiment 4,5,6 is carried out into stability test investigation, clarity respectively
Contrast test, stability test result shows to accelerate June sample quality stable, long-term 18 months steady qualities, therefore this
Minimum 18 months of the product term of validity.Clarity contrast test result of the test shows that the sample that embodiment 4,5,6 is produced is clear
Clear degree is less than No. 0.5 standard turbidity solution, and this product clarity is good.Pain experiment in mouse writhing method observation injection process
Result shows that pain is markedly less than control sample in the left injection process of sample of 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 obtained；What the consumption of wherein described supplementary material was weight percentage（S）The oxo-1-pyrrolidine ethanamide 58% ~ 78% of -4- hydroxyls -2, propane diols 10% ~ 25%, lecithin 10% ~ 30%, phenmethylol 1% ~ 3%；The concentrated compounding step is, by supplementary material addition material-compound tank, sterilized water for injection to be added immediately, is stirred, and dissolving obtains concentrated wiring liquid；It is described it is dilute with step to take concentrated wiring liquid, add 0.1mol/L ~ 0.5mol/L sodium hydroxide solutions, pH to 6.5 ~ 7.0 is adjusted, to adding cumulative volume 0.2% ~ 0.6% in above-mentioned solution（g/ml）Shitosan, stirring mixes, and stands 30 ~ 50min, is filtered with 0.8 μm of filter membrane, adds cumulative volume 0.1% ~ 0.3%（g/ml）Activated carbon, adsorption bleaching filters with 0.45 μm of filter membrane, collects filtrate, adds sterilized water for injection to recipe quantity, tests qualified through middle product examine, you can.
2. as claimed in claim 1（S）The oxo-1-pyrrolidine ethanamide parenteral solution of -4- hydroxyls -2, it is characterised in that it is obtained by the supplementary material of following weight percents：（S）The oxo-1-pyrrolidine ethanamide 65% ~ 72% of -4- hydroxyls -2, propane diols 15% ~ 20%, lecithin 12% ~ 18%, phenmethylol 1% ~ 3%, by above-mentioned supplementary material addition material-compound tank, adds the sterilized water for injection of 1/3 recipe quantity immediately, stirs, and dissolving obtains concentrated wiring liquid；Concentrated wiring liquid is taken, 0.1mol/L sodium hydroxide solutions are added, pH to 6.5 ~ 7.0 is adjusted, to addition cumulative volume 0.2% ~ 0.6% in above-mentioned solution（g/ml）Shitosan, stirring mixes, and stands 30 ~ 50min, is filtered with 0.8 μm of filter membrane, adds cumulative volume 0.1% ~ 0.3%（g/ml）Activated carbon, adsorption bleaching filters with 0.45 μm of filter membrane, collects filtrate, adds sterilized water for injection to recipe quantity, tests qualified through middle product examine, you can.
3. as described 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：By in supplementary material addition material-compound tank, the sterilized water for injection of 1/3 recipe quantity being added immediately, being stirred, dissolving obtains concentrated wiring liquid；
B. it is dilute to match somebody with somebody：Concentrated wiring liquid is taken, 0.1mol/L sodium hydroxide solutions are added, pH to 6.5 ~ 7.0 is adjusted, to the shitosan that the mass volume ratio of cumulative volume 0.2% ~ 0.6% is added in above-mentioned solution, stirring is mixed, 30 ~ 50min is stood, is filtered with 0.8 μm of filter membrane, add the activated carbon of the mass volume ratio of cumulative volume 0.1% ~ 0.3%, adsorption bleaching, filtered with 0.45 μm of filter membrane, collect 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, and after bacterial endotoxin is qualified, 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 lowers the temperature, 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. check：Sample checks visible foreign matters after sterilizing, and qualified sample will be checked to be packed, full inspection, storage.
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Citations (1)
| 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 |
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- 2015-08-19 CN CN201510511535.XA patent/CN106692044A/en active Pending
Patent Citations (1)
| 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 |
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Effective date of registration: 20170823 Address after: 400042 Chongqing city Yubei District Qinye Road No. 9 Applicant after: Chongqing Runze Pharmaceutical Co., Ltd. Address before: 400030 Chongqing city Shapingba District Yubei Road No. 50 of No. 13-15-6A Applicant before: DONGZE PHARMACEUTICAL SCIENCE AND TECHNOLOGY CO., LTD. |
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