CN105412007B - A kind of Levetiracetam sodium chloride injection composition and preparation method thereof - Google Patents
A kind of Levetiracetam sodium chloride injection composition and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of Levetiracetam sodium chloride injection compositions.The Levetiracetam sodium chloride injection of the present invention is made of Levetiracetam, sodium chloride and water for injection, and wherein the ratio between weight content of Levetiracetam and sodium chloride is 1:4.5~3:1.The Levetiracetam sodium chloride injection of the present invention has many advantages, such as that prescription is simple, stability is high, safe, suitable industrialized production.
Description
Technical field
The present invention relates to technical field of medicine, and in particular to a kind of Levetiracetam sodium chloride injection composition and
Its preparation method.
Background technology
Levetiracetam (Levetiracetam) is a kind of new antiepileptic, entitled (S)-α-ethyl of chemistry-
2- oxo-1-pyrrolidine ethanamides, molecular formula C8H14N2O2, structural formula is as follows：
Levetiracetam has the characteristics that therapeutic index is high, security is good, side effect is slight, is the unique tool reported at present
There is the wide spectrum antiepileptic of prevention effect.As a kind of innovative efficient antiepileptic, the knot with other antiepileptics
Structure is different, has brand-new anti-epileptic mechanism.The definite anti-epileptic mechanism of Levetiracetam is still unknown, but and conventional antiepileptic drugs
Object acts on ion channel or excitability, inhibitory neurotransmitter system are different.Levetiracetam almost possesses preferable anti-
All pharmacokinetics features of epilepsy drugs, the development of antiepileptic is concentrated mainly on efficient, low-risk on international market at present
In low side effect.But the stability of Levetiracetam is poor, for parenteral solution after pressure sterilizing, degradable generation is miscellaneous
Matter --- Levetiracetam acid.
2011, U.S. FDA had approved the Levetiracetam sodium chloride injection of three specifications, but it is in relation to content of material
Higher, stability is poor, and prescription is as follows：
| 500mg:100ml | 1000mg:100ml | 1500mg:100ml | |
| Levetiracetam | 500mg | 1000mg | 1500mg |
| Sodium chloride | 820mg | 750mg | 540mg |
| Sodium acetate trihydrate | 164mg | 164mg | 164mg |
| Glacial acetic acid | 5.5mg | 6.5mg | 7.5mg |
Chinese patent CN200910086292.4, CN201110002308.6, CN201210016087.2,
CN201310416616.2 and CN201310416619.6 etc. studies the injection of Levetiracetam, and exists
The shortcomings of prescription and preparation process are complicated, stability is poor, content in relation to substance is higher.For example, CN201210016087.2
The levetiracetam injection containing sodium acetate, acetic acid is disclosed, mainly has studied office of the parenteral solution to rabbit auricular vein
Portion's stimulate the reaction.Above-mentioned patent another disadvantage is that the parenteral solution is injection with small volume, when use, need to match somebody with somebody temporarily
System, makes troubles for clinical practice, and secondary pollution easily occurs.
Therefore, in order to improve the quality and stability of Levetiracetam sodium chloride injection, for the ease of clinical practice, system
Standby a kind of prescription is simple, stability is high, drug safety is high, the Levetiracetam sodium chloride injection of suitable industrialized production is
The technical issues of those skilled in the art is needed to put forth effort to solve.
The content of the invention
For the content in relation to substance existing for Levetiracetam sodium chloride injection is higher, stability is poor etc., technologies are asked
Topic, on the basis of long-term, numerous studies, applicant has found unexpectedly：The content of Levetiracetam and sodium chloride is tieed up
It holds in certain proportion, particularly controls the weight content ratio of the two 1:4.5~3:1, and the pH value control of parenteral solution is existed
Between 4.0-6.0, it is excellent that Levetiracetam sodium chloride injection obtained can obtain that the content in relation to substance is low, stability is high
Different in nature energy, and the pharmaceutic adjuvants such as Sodium acetate trihydrate need not be added, production cost is not only reduced, but also improves drug safety.
Based on above-mentioned discovery, following Levetiracetam sodium chloride injection composition is applicant provided：
A kind of Levetiracetam sodium chloride injection composition, wherein the pH value of the parenteral solution is 4.0-6.0, the left side
The ratio between weight content of etiracetam and sodium chloride is 1:4.5~3:1, composition is as follows：
Levetiracetam 0.5-1.5g,
Sodium chloride 0.5-2.25g,
Water for injection adds to 100-250ml.
As optimal technical scheme, above-mentioned Levetiracetam sodium chloride injection composition forms as follows：
Levetiracetam 0.5-1.5g,
Sodium chloride 0.9-2.25g,
Water for injection adds to 100-250ml.
Wherein, the parenteral solution pH value is preferably 4.0-5.5, more preferably 4.0-5.0.
Specifically, the present invention provides following several Levetiracetam sodium chloride injection compositions
1) a kind of Levetiracetam sodium chloride injection composition, wherein the pH value of the parenteral solution is 4.0-6.0, group
Into as follows：
Levetiracetam 0.5g,
Sodium chloride 0.9g,
Water for injection adds to 100ml.
2) a kind of Levetiracetam sodium chloride injection composition, wherein the pH value of the parenteral solution is 4.0-6.0, group
Into as follows：
Levetiracetam 1.0g,
Sodium chloride 0.8g,
Water for injection adds to 100ml.
3) a kind of Levetiracetam sodium chloride injection composition, wherein the pH value of the parenteral solution is 4.0-6.0, group
Into as follows：
Levetiracetam 1.5g,
Sodium chloride 0.5g,
Water for injection adds to 100ml.
4) a kind of Levetiracetam sodium chloride injection composition, wherein the pH value of the parenteral solution is 4.0-6.0, group
Into as follows：
Levetiracetam 0.5g,
Sodium chloride 2.25g,
Water for injection adds to 250ml.
5) a kind of Levetiracetam sodium chloride injection composition, wherein the pH value of the parenteral solution is 4.0-6.0, group
Into as follows：
Levetiracetam 1.5g,
Sodium chloride 2.25g,
Water for injection adds to 250ml.
In addition, the invention further relates to the preparation method of above-mentioned Levetiracetam sodium chloride injection composition, including as follows
Step：
The water for injection of recipe quantity 50-80% is taken, adds in Levetiracetam, sodium chloride, stirring and dissolving, with acetic acid, phosphoric acid
Or salt acid for adjusting pH value, to 4.0-6.0 (being preferably adjusted to 4.0-5.0), activated carbon adsorption is filtered, added to the full amount of water for injection,
Filling through 0.22 μm of filtering with microporous membrane, 121 DEG C sterilize 15 minutes.
The dosage of the Levetiracetam sodium chloride injection of the present invention can sentencing according to clinician
Depending on disconnected.
Research shows compared with the prior art (Chinese patent application CN201210016087.2 and commercialized product), this hair
The better quality of bright Levetiracetam sodium chloride injection, stability higher, drug safety higher, are mainly reflected in：
1) in terms of related substance, the content of the related substance of prior art parenteral solution is higher, and as storage time is prolonged
It is long and the content in relation to substance substantially increases, and the content pole of Levetiracetam Sodium Chloride Injections Related Substances of the invention
It is low, and the only slight increase during two-year investigation.
2) in terms of pH value, during two-year storage, the pH of Levetiracetam sodium chloride injection of the invention
Value does not almost change.
3) prescription of the invention is extremely simple, without adding the auxiliary materials such as Sodium acetate trihydrate, has both saved production cost, has simplified
Preparation process, and drug safety is improved, it is suitble to industrialized production.
Therefore, Levetiracetam sodium chloride injection composition of the invention has that prescription is simple, of low cost, stability
High, drug safety height is suitble to many advantages, such as industrialized production.Compared with commercial product, Levetiracetam chlorination of the present invention
The prescription component of sodium injection composition is few, drug safety is high, stability is high, achieves unexpected technique effect.
Specific embodiment
Specific embodiment is only that the present invention is further explained and described, and is not necessarily to be construed as any limit to the present invention
System.
Supplementary material used is purchased in market in embodiment.
The Levetiracetam sodium chloride injection of 1 present invention of embodiment
Prescription：
Levetiracetam 5g,
Sodium chloride 9g,
Water for injection adds to 1000ml.
Preparation method：
The water for injection of recipe quantity 50-80% is taken, adds in Levetiracetam, sodium chloride, stirring and dissolving, with acetic acid, phosphoric acid
Or hydrochloric acid adjusts pH4.0, with activated carbon adsorption 15-30 minute of 0.02%-0.1% (w/v), filtering carbon removal adds water for injection
Filling through 0.22 μm of filtering with microporous membrane to full dose, 121 DEG C sterilize 15 minutes.
The Levetiracetam sodium chloride injection of 2 present invention of embodiment
Prescription：
Levetiracetam 10g,
Sodium chloride 8g,
Water for injection adds to 1000ml.
Preparation method：PH value is adjusted to 4.5, remaining is the same as embodiment 1.
The Levetiracetam sodium chloride injection of 3 present invention of embodiment
Prescription：
Levetiracetam 15g,
Sodium chloride 5g,
Water for injection adds to 1000ml.
Preparation method：PH value is adjusted to 5.0, remaining is the same as embodiment 1.
The Levetiracetam sodium chloride injection of 4 present invention of embodiment
Prescription：
Levetiracetam 5g,
Sodium chloride 22.5g,
Water for injection adds to 2500ml.
Preparation method：PH value is adjusted to 5.5, remaining is the same as embodiment 1.
The Levetiracetam sodium chloride injection of 5 present invention of embodiment
Prescription：
Levetiracetam 15g,
Sodium chloride 22.5g,
Water for injection adds to 2500ml.
Preparation method：PH value is adjusted to 6.0, remaining is the same as embodiment 1.
1 Chinese patent application CN201210016087.2 embodiments 1 of reference examples
Prescription：
Preparation method：
1) Levetiracetam is weighed into Agitation Tank by regulation.
2) water for injection for adding in recipe quantity 75% by regulation is mixed into above-mentioned Agitation Tank to being completely dissolved.
3) sodium acetate is weighed by regulation to be mixed into Agitation Tank to being completely dissolved.
4) acetic acid is weighed by regulation to be mixed into Agitation Tank to being completely dissolved.
5) sodium chloride is weighed by regulation to be mixed into Agitation Tank to being completely dissolved.
6) recipe quantity is injected water to, is mixed.
7) needle-use activated carbon of 0.05% (w/v) is added in into solution, is stirred 15 minutes, pressurization makes liquid by using wrapping up in outside
1 μm of neutral filter paper and 0.45 μm of stud filter, filter out activated carbon into dilute preparing tank.
8) pH value of solution is checked, pH value should be in right amount adjusted in the range of 5.0-6.0, if do not existed using acetic acid.
9) solution is first with 0.45 μm of filter membrane coarse filtration, then with 0.22 μm of filter membrane refined filtration.
10) filtrate sampling carries out quality testing.
11) solution is filled into the cillin bottle of 5ml under nitrogen stream protection, then gland seals.
12) cillin bottle is taken to be placed on 121 DEG C, is sterilized under the conditions of 15 minutes terminal sterilizations, rear take out is put to room temperature.
The quality and stability study of experimental example Levetiracetam sodium chloride injection
Levetiracetam sodium chloride injection and commercially available Levetiracetam chlorination prepared by Example 1-5, reference examples 1
Sodium injection product (reference examples 2).Under 15-30 DEG C of experimental condition, use《United States Pharmacopeia》The 35th edition left second recorded is drawn
It is western it is smooth in related substance detecting method detect the content of above-mentioned three kinds of parenteral solutions in related substance in two years, and measure pH
Value is as a result as follows：
As it can be seen that during the storage of 2 years, the pH value of Levetiracetam sodium chloride injection of the present invention is substantially not
It changes, related substance when great stability is also maintained in terms of the content in relation to substance, and being stored 2 years
Content is even lower than the content for listing related substance when storing 1 year.
Claims (10)
1. a kind of Levetiracetam sodium chloride injection composition, wherein the pH value of the parenteral solution is 4.0-6.0, the left second
The ratio between weight content of La Xitan and sodium chloride is 1:4.5~3:1, composition is as follows：
Levetiracetam 0.5-1.5g,
Sodium chloride 0.5-2.25g,
Water for injection adds to 100-250ml.
2. Levetiracetam sodium chloride injection composition according to claim 1, wherein the pH value of the parenteral solution is
4.0-5.0。
3. Levetiracetam sodium chloride injection composition according to claim 1 or 2, composition is as follows：
Levetiracetam 0.5-1.5g,
Sodium chloride 0.9-2.25g,
Water for injection adds to 100-250ml.
4. Levetiracetam sodium chloride injection composition according to claim 1 or 2, composition is as follows：
Levetiracetam 0.5g,
Sodium chloride 0.9g,
Water for injection adds to 100ml.
5. Levetiracetam sodium chloride injection composition according to claim 1 or 2, composition is as follows：
Levetiracetam 1.0g,
Sodium chloride 0.8g,
Water for injection adds to 100ml.
6. Levetiracetam sodium chloride injection composition according to claim 1 or 2, composition is as follows：
Levetiracetam 1.5g,
Sodium chloride 0.5g,
Water for injection adds to 100ml.
7. Levetiracetam sodium chloride injection composition according to claim 1 or 2, composition is as follows：
Levetiracetam 0.5g,
Sodium chloride 2.25g,
Water for injection adds to 250ml.
8. Levetiracetam sodium chloride injection composition according to claim 1 or 2, composition is as follows：
Levetiracetam 1.5g,
Sodium chloride 2.25g,
Water for injection adds to 250ml.
9. the preparation method of any Levetiracetam sodium chloride injection compositions of claim 1-8, including walking as follows
Suddenly：
The water for injection of recipe quantity 50-80% is taken, adds in Levetiracetam, sodium chloride, stirring and dissolving adjusts pH value to 4.0-
6.0, activated carbon adsorption filters carbon removal, adds to the full amount of water for injection, filling through 0.22 μm of filtering with microporous membrane, 121 DEG C of sterilizings
15 minutes.
10. the preparation method of Levetiracetam sodium chloride injection composition according to claim 9, wherein the pH
It is adjusted to 4.0-5.0.
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| CN107913247A (en) * | 2016-10-10 | 2018-04-17 | 北京阜康仁生物制药科技有限公司 | A kind of Levetiracetam injection preparation and preparation method thereof |
| CN108403626A (en) * | 2018-04-13 | 2018-08-17 | 黑龙江珍宝岛药业股份有限公司 | A kind of injection of Levetiracetam and preparation method thereof |
| TW202114655A (en) | 2019-08-14 | 2021-04-16 | 瑞士商辛鐵堤卡公司 | Intrathecal administration of levetiracetam |
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