CN106692040A - (S)-4-hydroxyl-dioxo-1-pyrrolidone acetamide injection with good stability and preparation method thereof - Google Patents
(S)-4-hydroxyl-dioxo-1-pyrrolidone acetamide injection with good stability and preparation method thereof Download PDFInfo
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- CN106692040A CN106692040A CN201510510354.5A CN201510510354A CN106692040A CN 106692040 A CN106692040 A CN 106692040A CN 201510510354 A CN201510510354 A CN 201510510354A CN 106692040 A CN106692040 A CN 106692040A
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- pyrrolidine ethanamide
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Abstract
A (S)-4-hydroxyl-dioxo-1-pyrrolidone acetamide injection with good stability is characterized in that the injection is prepared from the following raw materials by weight percentage: 60%-80% of (S)-4-hydroxyl dioxo-1-pyrrolidone acetamide, 10%-30% of propylene glycol, 5%-20% of lecithin and 1%-5% of benzyl alcohol. The prepared (S)-4-hydroxyl-dioxo-1-pyrrolidone acetamide injection with the good stability has good stability, does not generate crystals in a storage process, has a long expiration date that can reach 18 months or above, and has few product impurities in the expiration date; the total impurity content of the injection is less than 0.35%; the pain feeling of a patient is reduced; and the patient compliance is good.
Description
Technical field
The invention mainly relates to pharmaceutical technology field, and in particular to a kind of oxo -1- of (S) -4- hydroxyls -2 of good stability
Pyrrolidine acetamide injection and preparation method thereof.
Background technology
Oxiracetam (S-oxiracetam) is a kind of hydroxy-amino-butyric acid of synthesis (BABOB) cyclic derivatives, only
For central nervous system, cerebral cortex, hippocampus are mainly distributed on, have activation, protection or promote the function of nerve cell
Recover, improve the mnemonic learning function of disturbance of intelligence patient, and medicine in itself without direct vasoactive, also without in
Pivot excitation, the influence to ability of learning and memory is a kind of lasting facilitation.
The medicine was listed in 1987 in Italy, and the formulation of listing is tablet, 800mg；Capsule, 800mg；Parenteral solution,
1g/5ml.It is domestic at present there was only oxiracetam capsule and parenteral solution listing, and main active used is racemic modification.
The rush that Ye Lei etc. goes into a coma caused by mentioning levo-oxiracetam in the A patents of Publication No. CN 103735545 to alcoholism
Effect of waking up is obvious, and dextrorotation Oxiracetam is not acted on substantially, and the above-mentioned rush of levo-oxiracetam wakes up effect for racemization Aura
Western smooth 2 times；Levo-oxiracetam is notable to the promoting wakening of stupor caused by wound, anesthesia.Peak etc. is opened in publication number
It is big to traumatic brain injury caused by hydraulic pressure and freely falling body to disclose levo-oxiracetam in the patent of the A of CN 103599101
Mouse learning and memory cognition dysfunction improves significantly, and its drug effect is far above dextrorotation Oxiracetam.And
200mg/kg levo-oxiracetams are suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results show：
Levo-oxiracetam and dextrorotation Oxiracetam are in beasle dog body without obvious chiral inversion.Beasle dog single intravenous injection gives
The main pharmacokinetic parameters of levo-oxiracetam nothing is substantially poor in blood plasma after left-handed and 2 multiple doses racemization Oxiracetam
It is different.The result of the tests such as safe pharmacology, anxious poison malicious, long show, under isodose level, levo-oxiracetam and Aura
It is western smooth to animal subject or the toxicity no significant difference of cell.Above-mentioned preclinical result of study shows, levo-oxiracetam
It is the main active that drug effect is played in Oxiracetam body, this product is used alone can reduce Clinical practice dosage, reduces latent
Toxicity.
The existing oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 its be primarily present that stability is poor, storage process is held
Easily crystallization, injection process pain substantially, the problems such as patient's poor compliance.
The content of the invention
It is an object of the invention to provide a kind of good stability, the oxo -1- pyrroles of (S) -4- hydroxyls -2 of good patient compliance
Alkyl acetamide injection.
Preparation another object of the present invention is to provide the above-mentioned oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2
Method.
The purpose of the present invention is realized by following technical measures：
A kind of (S) -4- hydroxyls -2 oxo-1-pyrrolidine ethanamide injection of good stability, 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
One kind or many in fat, propane diols, phenmethylol, anesin, sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite
Kind.
Inventor has found to select a certain proportion of propane diols, lecithin and phenmethylol group in composition described above by many experiments
Into compound additives, coordinate the specific oxo-1-pyrrolidine ethanamide concentration of (S) -4- hydroxyls -2 again, may be such that above-mentioned
(S) the oxo-1-pyrrolidine ethanamide injection good stability of -4- hydroxyls -2, will not form crystallization during storage, injection
Process patient pain sense mitigates, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 of above-mentioned injection, it is characterised in that
It is obtained by the supplementary material of following weight percents：(S) oxo-1-pyrrolidine ethanamide 60%~80% of -4- hydroxyls -2,
Propane diols 10%~30%, lecithin 5%~20%, phenmethylol 1%~5%.
Most preferably, the good oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 of aforementioned stable, its feature exists
In it is obtained by the supplementary material of following significant percentage：(S) oxo-1-pyrrolidine ethanamide 65%~75% of -4- hydroxyls -2,
Propane diols 13%~20%, lecithin 10%~15%, phenmethylol 1%~3%.
A kind of preparation method of the oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 of good stability, its feature exists
In it is obtained as follows：
1. concentrated compounding：By in above-mentioned 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, pH to 6.5~7.0 is adjusted with hydrochloric acid or sodium bicarbonate solution, add cumulative volume 0.1%~0.3%
(g/ml) activated carbon, adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate, plus go out
Bacterium water for injection tests qualified to recipe quantity 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, bacterial endotoxin
After 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 drops
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, sterilizing is completed, and is hunted leak by rated condition；
5. check：Sample checks visible foreign matters after sterilizing, and qualified sample will be checked to carry out outsourcing, full inspection, storage,
Obtain final product.
The present invention has following beneficial effect：
A kind of oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 of good stability of the present invention has good stability,
Crystallization will not be produced during storage, the term of validity is long, can reach more than 18 months, product impurity is few in the term of validity, its
Total impurities is less than 0.35%, pain reduction, good patient compliance in patient injection procedure.
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 oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 of good stability, is obtained according to the following steps：
| Composition | Consumption |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 100g |
| Propane diols | 30g |
| Lecithin | 21g |
| Phenmethylol | 2g |
| Sterilized water for injection | Add to 2000ml |
It is made 1000
Preparation process：
1. concentrated compounding：By in above-mentioned 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, pH to 6.5~7.0 is adjusted with hydrochloric acid or sodium bicarbonate solution, add cumulative volume 0.1%~0.3%
(g/ml) activated carbon, adsorption bleaching is filtered with 0.45 μm of filter membrane, collects filtrate, plus go out
Bacterium water for injection tests qualified to recipe quantity 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, bacterial endotoxin
After 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 drops
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, sterilizing is completed, and is hunted leak by rated condition；
5. check：Sample checks visible foreign matters after sterilizing, and qualified sample will be checked to carry out outsourcing, full inspection, storage,
Obtain final product.
The present invention actually is better understood from, having for 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 oxo-1-pyrrolidine ethanamide injection stability experiment of (S) -4- hydroxyls -2 of good stability of the present invention
Experiment material：
(S) the oxo-1-pyrrolidine ethanamide injection sample of -4- hydroxyls -2：For embodiment 1 is obtained
Acceleration study method：By the oxo-1-pyrrolidine ethanamide injection 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, 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 injection 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, 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, pH value, relevant material, content with
And sterility test indices meet every relevant regulations of production quality standard draft without significant changes.This product
18 months steady qualities of long term test, therefore minimum 18 months of this product term of validity, long term test is still during continuing to investigate.
Experiment two：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 | 6 | 20.0% |
| Control sample | 30 | 22 | 73.3% |
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 oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 of good stability, is obtained according to the following steps：
| Composition | Consumption |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 100g |
| Propane diols | 18g |
| Lecithin | 14g |
| Phenmethylol | 2g |
| Sterilized water for injection | Add to 2000ml |
It is made 1000
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, stability test knot respectively
Fruit shows to accelerate June sample quality stabilization, long-term 18 months steady qualities, therefore minimum 18 months of this product term of validity.It is small
Pain result of the test in mouse writhing method observation injection process shows that pain is obvious during the sample injection of embodiment 2
It is weaker than control sample.
Embodiment 3
A kind of oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 of good stability, is obtained according to the following steps：
| Composition | Consumption |
| (S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2 | 100g |
| Propane diols | 22g |
| Lecithin | 18g |
| Phenmethylol | 3g |
| Sterilized water for injection | Add to 2000ml |
It is made 1000
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, stability test knot respectively
Fruit shows to accelerate June sample quality stabilization, long-term 18 months steady qualities, therefore minimum 18 months of this product term of validity.It is small
Pain result of the test in mouse writhing method observation injection process shows that pain is obvious during the sample injection of embodiment 3
It is weaker than control sample.
Embodiment 4-6：The oxo-1-pyrrolidine ethanamide injection of (S) -4- hydroxyls -2 of a kind of good stability, by following
The supplementary material of weight is prepared, and preparation method is with embodiment 1：
By the test method of embodiment 1, embodiment 4,5,6 is carried out into stability test investigation, stability test respectively
Result shows to accelerate June sample quality stabilization, long-term 18 months steady qualities, therefore minimum 18 months of this product term of validity.
Pain result of the test in mouse writhing method observation injection process shows, aches during the sample injection of embodiment 4,5,6
Pain is markedly less than control sample.
Claims (3)
1. a kind of good stability（S）The oxo-1-pyrrolidine ethanamide injection 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 60% ~ 80% of -4- hydroxyls -2, propane diols 10% ~ 30%, lecithin 5% ~ 20%, phenmethylol 1% ~ 5%.
2. as claimed in claim 1（S）The oxo-1-pyrrolidine ethanamide injection of -4- hydroxyls -2, it is characterised in that it is obtained by the supplementary material of following significant percentage：（S）The oxo-1-pyrrolidine ethanamide 65% ~ 75% of -4- hydroxyls -2, propane diols 13% ~ 20%, lecithin 10% ~ 15%, phenmethylol 1% ~ 3%.
3. as claimed in claim 1 or 2（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：By in above-mentioned 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, pH to 6.5 ~ 7.0 is adjusted with hydrochloric acid or sodium bicarbonate solution, add the activated carbon of the mass volume ratio of cumulative volume 0.1% ~ 0.3%, adsorption bleaching, is filtered with 0.45 μm of filter membrane, collects filtrate, plus sterilized water for injection tests qualified to recipe quantity 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 carry out outsourcing, and full inspection, storage is obtained final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510510354.5A CN106692040A (en) | 2015-08-19 | 2015-08-19 | (S)-4-hydroxyl-dioxo-1-pyrrolidone acetamide injection with good stability and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510510354.5A CN106692040A (en) | 2015-08-19 | 2015-08-19 | (S)-4-hydroxyl-dioxo-1-pyrrolidone acetamide injection with good stability and preparation method thereof |
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| Publication Number | Publication Date |
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| CN106692040A true CN106692040A (en) | 2017-05-24 |
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|---|---|---|---|
| CN201510510354.5A Pending CN106692040A (en) | 2015-08-19 | 2015-08-19 | (S)-4-hydroxyl-dioxo-1-pyrrolidone acetamide injection with good stability and preparation method thereof |
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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
- 2015-08-19 CN CN201510510354.5A patent/CN106692040A/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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Application publication date: 20170524 |