CN105412007A - Levetiracetam-sodium chloride injection compound and preparation method thereof - Google Patents
Levetiracetam-sodium chloride injection compound and preparation method thereof Download PDFInfo
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- CN105412007A CN105412007A CN201510929585.XA CN201510929585A CN105412007A CN 105412007 A CN105412007 A CN 105412007A CN 201510929585 A CN201510929585 A CN 201510929585A CN 105412007 A CN105412007 A CN 105412007A
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- levetiracetam
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Abstract
The invention provides a levetiracetam-sodium chloride injection compound which comprises levetiracetam, sodium chloride and water for injection, wherein the weight content ratio of levetiracetam to sodium chloride is (1-3):(4.5-1). The levetiracetam-sodium chloride injection compound has the advantages of being simple in prescription, high in stability and safety, suitable for industrialized production, and the like.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to a kind of levetiracetam sodium chloride injection composition and preparation method thereof.
Background technology
Levetiracetam (Levetiracetam) is a kind of novel antiepileptic, and its chemistry (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide by name, molecular formula is C
8h
14n
2o
2, structural formula is as follows:
Levetiracetam has the features such as therapeutic index is high, safety good, side effect is slight, is the wide spectrum antiepileptic uniquely with preventive effect of report at present.As the innovative Effective Anti AED of one, different from the structure of other antiepileptics, there is brand-new epilepsy mechanism.The definite epilepsy mechanism of levetiracetam is still not clear, but act on ion channel or irritability from Antiepileptic drugs, inhibitory neurotransmitter system is different.Levetiracetam has almost possessed all pharmacokinetics features of good antiepileptic, and on current international market, the development of antiepileptic mainly concentrates on efficiently, in low-risk and low side effect.But, the less stable of levetiracetam, its injection is after pressure sterilizing, and easily degraded generates impurity---levetiracetam acid.
2011, U.S. FDA have approved the levetiracetam sodium chloride injection of three specifications, but its its related substances is higher, less stable, and its 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. are studied the injection of levetiracetam, and there is the shortcoming such as content is higher of prescription and complicated process of preparation, less stable, related substance.Such as, CN201210016087.2 discloses the levetiracetam injection containing sodium acetate, acetic acid, mainly have studied this injection and reacts the local excitation of rabbit auricular vein.Another shortcoming of above-mentioned patent is that described injection is injection with small volume, needs Extemporaneous, for clinical practice is made troubles, and easily secondary pollution occurs during use.
Therefore, in order to improve quality and the stability of levetiracetam sodium chloride injection, for the ease of clinical practice, preparing that a kind of prescription is simple, stability is high, drug safety is high, being applicable to the levetiracetam sodium chloride injection of suitability for industrialized production is the technical problem that needs those skilled in the art put forth effort to solve.
Summary of the invention
Content for the related substance of levetiracetam sodium chloride injection existence is higher, the technical problems such as less stable, for a long time, on the basis of large quantity research, applicant finds unexpectedly: the content of levetiracetam and sodium chloride is maintained certain proportion, particularly the weight content ratio of the two is controlled at 1:4.5 ~ 3:1, and the pH value of injection is controlled between 4.0-6.0, the content that obtained levetiracetam sodium chloride injection can obtain related substance is low, the excellent properties that stability is high, again without the need to adding the pharmaceutic adjuvants such as Sodium acetate trihydrate, both production cost was reduced, turn improve drug safety.
Based on above-mentioned discovery, applicant provide following levetiracetam sodium chloride injection composition:
A kind of levetiracetam sodium chloride injection composition, the pH value of wherein said injection is 4.0-6.0, and described levetiracetam is 1:4.5 ~ 3:1 with the ratio of the weight content of sodium chloride, and it is composed 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, it is composed as follows:
Levetiracetam 0.5-1.5g,
Sodium chloride 0.9-2.25g,
Water for injection adds to 100-250ml.
Wherein, described injection pH value is preferably 4.0-5.5, is more preferably 4.0-5.0.
Particularly, the invention provides following several levetiracetam sodium chloride injection composition
1) a levetiracetam sodium chloride injection composition, the pH value of wherein said injection is 4.0-6.0, and it is composed as follows:
Levetiracetam 0.5g,
Sodium chloride 0.9g,
Water for injection adds to 100ml.
2) a levetiracetam sodium chloride injection composition, the pH value of wherein said injection is 4.0-6.0, and it is composed as follows:
Levetiracetam 1.0g,
Sodium chloride 0.8g,
Water for injection adds to 100ml.
3) a levetiracetam sodium chloride injection composition, the pH value of wherein said injection is 4.0-6.0, and it is composed as follows:
Levetiracetam 1.5g,
Sodium chloride 0.5g,
Water for injection adds to 100ml.
4) a levetiracetam sodium chloride injection composition, the pH value of wherein said injection is 4.0-6.0, and it is composed as follows:
Levetiracetam 0.5g,
Sodium chloride 2.25g,
Water for injection adds to 250ml.
5) a levetiracetam sodium chloride injection composition, the pH value of wherein said injection is 4.0-6.0, and it is composed as follows:
Levetiracetam 1.5g,
Sodium chloride 2.25g,
Water for injection adds to 250ml.
In addition, the invention still further relates to the preparation method of above-mentioned levetiracetam sodium chloride injection composition, comprise the steps:
Get the water for injection of recipe quantity 50-80%, add 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, filters, add to the full amount of water for injection, through 0.22 μm of filtering with microporous membrane, fill, 121 DEG C of sterilizings 15 minutes.
The using dosage of the described levetiracetam sodium chloride injection that the present invention relates to can be determined according to the judgement of clinician.
Research shows, compares with prior art (Chinese patent application CN201210016087.2 and commercialized product), and the better quality of levetiracetam sodium chloride injection of the present invention, stability is higher, drug safety is higher, is mainly reflected in:
1) in related substance, the content of the related substance of prior art injection is higher, and along with storage time prolongation, the content of related substance obviously increases, and the content of levetiracetam Sodium Chloride Injections Related Substances of the present invention is extremely low, and only there is slight increase between two-year probation.
2) in pH value, between the two-year storage life, the pH value of levetiracetam sodium chloride injection of the present invention does not almost change.
3) prescription of the present invention is very simple, without the need to adding the adjuvants such as Sodium acetate trihydrate, both having saved production cost, and having simplified preparation technology, and having turn improved drug safety, is applicable to industrialized great production.
Therefore, levetiracetam sodium chloride injection composition of the present invention has the plurality of advantages such as prescription is simple, with low cost, stability is high, drug safety is high, applicable suitability for industrialized production.Compared with commercially available prod, the prescription component of levetiracetam sodium chloride injection composition of the present invention is few, drug safety is high, stability is high, achieves unforeseeable technique effect.
Detailed description of the invention
Detailed description of the invention is only and further explains and describes the present invention, should not be interpreted as any limitation of the invention.
In embodiment, supplementary material used is commercial.
Embodiment 1 levetiracetam sodium chloride injection of the present invention
Prescription:
Levetiracetam 5g,
Sodium chloride 9g,
Water for injection adds to 1000ml.
Preparation method:
Get the water for injection of recipe quantity 50-80%, add levetiracetam, sodium chloride, stirring and dissolving, regulate pH4.0 with acetic acid, phosphoric acid or hydrochloric acid, with the activated carbon adsorption 15-30 minute of 0.02%-0.1% (w/v), filter carbon removal, add to the full amount of water for injection, through 0.22 μm of filtering with microporous membrane, fill, 121 DEG C of sterilizings 15 minutes.
Embodiment 2 levetiracetam sodium chloride injection of the present invention
Prescription:
Levetiracetam 10g,
Sodium chloride 8g,
Water for injection adds to 1000ml.
Preparation method: adjust ph to 4.5, all the other are with embodiment 1.
Embodiment 3 levetiracetam sodium chloride injection of the present invention
Prescription:
Levetiracetam 15g,
Sodium chloride 5g,
Water for injection adds to 1000ml.
Preparation method: adjust ph to 5.0, all the other are with embodiment 1.
Embodiment 4 levetiracetam sodium chloride injection of the present invention
Prescription:
Levetiracetam 5g,
Sodium chloride 22.5g,
Water for injection adds to 2500ml.
Preparation method: adjust ph to 5.5, all the other are with embodiment 1.
Embodiment 5 levetiracetam sodium chloride injection of the present invention
Prescription:
Levetiracetam 15g,
Sodium chloride 22.5g,
Water for injection adds to 2500ml.
Preparation method: adjust ph to 6.0, all the other are with embodiment 1.
Reference examples 1 Chinese patent application CN201210016087.2 embodiment 1
Prescription:
Preparation method:
1) levetiracetam is taken in Agitation Tank by regulation.
2) add the water for injection of recipe quantity 75% in above-mentioned Agitation Tank by regulation, be mixed to and dissolve completely.
3) take in sodium acetate to Agitation Tank to be mixed to by regulation and dissolve completely.
4) take in acetic acid to Agitation Tank to be mixed to by regulation and dissolve completely.
5) take in sodium chloride to Agitation Tank to be mixed to by regulation and dissolve completely.
6) recipe quantity is injected water to, mixing.
7) in solution, add the needle-use activated carbon of 0.05% (w/v), stir 15 minutes, pressurization makes medicinal liquid pass through to use 1 μm and 0.45 μm of titanium rod filter wrapping up in neutral filter paper outward, and filtering active carbon is in dilute preparing tank.
8) check the pH value of solution, pH value should, within the scope of 5.0-6.0, if do not existed, use acetic acid to regulate in right amount.
9) solution first uses 0.45 μm of filter membrane coarse filtration, then uses 0.22 μm of filter membrane fine straining.
10) quality testing is carried out in filtrate sampling.
11) under nitrogen current protection, filled with solution is entered in the cillin bottle of 5ml, then gland seal.
12) get cillin bottle and be placed on 121 DEG C, sterilizing under 15 minutes terminal sterilization conditions, rear taking-up is put to room temperature.
The quality of experimental example levetiracetam sodium chloride injection and stability study
The levetiracetam sodium chloride injection of Example 1-5, reference examples 1 preparation and commercially available levetiracetam chloride injection liquid product (reference examples 2).Under the experimental condition of 15-30 DEG C, adopt the related substance detection method in " American Pharmacopeia " the 35th edition levetiracetam recorded to detect the content of above-mentioned three kinds of injection at related substance in two years, and measure pH value, result is as follows:
Visible, reaching in the storage process of 2 years, the pH value of levetiracetam sodium chloride injection of the present invention does not change substantially, in the content of related substance, also maintain great stability, and the content of related substance when storing 2 years is even lower than the content of related substance during listing storage 1 year.
Claims (10)
1. a levetiracetam sodium chloride injection composition, the pH value of wherein said injection is 4.0-6.0, and described levetiracetam is 1:4.5 ~ 3:1 with the ratio of the weight content of sodium chloride, and it is composed 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, the pH value of wherein said injection is 4.0-5.0.
3. levetiracetam sodium chloride injection composition according to claim 1 and 2, it is composed 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 and 2, it is composed 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 and 2, it is composed 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 and 2, it is composed 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 and 2, it is composed 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 and 2, it is composed as follows:
Levetiracetam 1.5g,
Sodium chloride 2.25g,
Water for injection adds to 250ml.
9. the preparation method of the arbitrary described levetiracetam sodium chloride injection composition of claim 1-8, comprises the steps:
Get the water for injection of recipe quantity 50-80%, add levetiracetam, sodium chloride, stirring and dissolving, adjust ph is to 4.0-6.0, and activated carbon adsorption, filters carbon removal, add to the full amount of water for injection, through 0.22 μm of filtering with microporous membrane, and fill, 121 DEG C of sterilizings 15 minutes.
10. the preparation method of levetiracetam sodium chloride injection composition according to claim 9, wherein said pH regulator is 4.0-5.0.
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Cited By (3)
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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 |
| US11590105B2 (en) | 2019-08-14 | 2023-02-28 | Sintetica S.A. | Intrathecal administration of levetiracetam |
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| US11590105B2 (en) | 2019-08-14 | 2023-02-28 | Sintetica S.A. | Intrathecal administration of levetiracetam |
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| CN105412007B (en) | 2018-05-25 |
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