CN108403626A - A kind of injection of Levetiracetam and preparation method thereof - Google Patents
A kind of injection of Levetiracetam and preparation method thereof Download PDFInfo
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Abstract
The present invention provides a kind of injections of Levetiracetam and preparation method thereof, belong to pharmaceutical field.The injection includes：A concentration of 2~8mg/mL of Levetiracetam in injection, pH value are 5.0~6.0.Preparation method includes：The pharmaceutically acceptable auxiliary material of formula ratio is dissolved with water for injection, auxiliary material solution is obtained, then dissolves the Levetiracetam of formula ratio with auxiliary material solution, obtains injection mother liquor, the pH value of a concentration of 2~8mg/mL of Levetiracetam in injection mother liquor, injection mother liquor are 5.0~6.0；And it is 0.4~0.5 μm and 0.20~0.25 μm of membrane filtration injection mother liquor to use aperture successively.The content of Levetiracetam is low in this injection and stability is high, and clinically can directly instil use, improve the safety of clinical application.
Description
Technical field
The present invention relates to pharmaceutical fields, in particular to a kind of injection of Levetiracetam and preparation method thereof.
Background technology
Levetiracetam is a kind of pyrrolidinone derivatives, chemical constitution and existing antiepileptic non-correlation.
The precise mechanism of Levetiracetam antiepileptic action is unclear.Levetiracetam is had evaluated in a variety of animal epileptic models
Antiepileptic action is found：Levetiracetam is to electric current or a variety of simple epileptic attack unrestraints for causing to shy agent maximal stimulation induction
Effect, and only show Weak activity in sub- maximal stimulation and Test of threshold；But it induces pilocarpinum and kainic acid
The secondary generalized seizures of focal attack there is protective effect.Both chemistry of pilocarpinum and kainic acid cause to faint from fear
Agent can imitate some characteristics with the complex partial seizures of secondary generalized seizure.Meanwhile Levetiracetam is to complexity
The ignition procedures of the rat kindling model of partial seizures and the state of lighting all have inhibiting effect, these animal models are to human body
The predictive value of specific type epilepsy is still not clear.In addition, external, in vivo studies shows that Levetiracetam can inhibit hippocampus
Epileptic burst electric discharge, and prompt Levetiracetam that may selectively inhibit epilepsy without influence normal neurons excitability
The propagation of the supersynchronous property and epileptic attack of sample burst electric discharge.
Currently, it is antiepileptic that left second, which draws western composite injection, for being grown up (16 years old or more) when oral left second is drawn
When western smooth treatment is temporarily infeasible and with the patient of Types Below epilepsy：
(1) partial seizures：Auxiliary of the Levetiracetam sodium chloride injection for adult partial seizure epileptic is controlled
It treats.
(2) lafora's disease of juvenile myoclonic epilepsy patient：Levetiracetam sodium chloride injection be used at
The auxiliary treatment of the myoclonic seizures of people juvenile myoclonic epilepsy patient.
(3) primary generalized tonic-clonic breaking-out (Primary generalized tonic-clonic
seizures)：Levetiracetam sodium chloride injection is used for adult idiopathic systemic epilepsy (diopathic
Generalized epilepsy) patient primary generalized tonic-clonic breaking-out auxiliary treatment.
However, since the stability of levetiracetam injection under low concentration is poor, and the Levetiracetam of high concentration is injected
Liquid is stronger to the irritation of blood vessel, is susceptible to a variety of side effects, therefore needs to dilute during Clinical practice.Currently on the market
Levetiracetam composition injection be big specification preparation (i.e. the wherein Levetiracetam containing high concentration), such as it is external
The levetiracetam injection (KEPPRA injection) of listing, wherein contain 100mg/mL Levetiracetams, every bottle of 5mL's
Levetiracetam containing 500mg in injection.The levetiracetam composition injection formulation of this kind of big specification makes in clinic
With preceding, need to instil again after diluting it with diluent, that is, need the dilution that the liquid of 100mg/mL is diluted to 5-15mg/mL
Solution, and require dilute solution to store at room temperature and be not to be exceeded 4 hours, and to inject and finish in 15min medium sized veins, it can
Ensure drug safety.It can be seen that the levetiracetam injection of this high concentration in dilution, easily draws existing hand over
Fork pollutes and causes the generation of impurity Levetiracetam acid, influences the safety of its Clinical practice.
Invention content
The first object of the present invention is to provide a kind of injection of Levetiracetam, Levetiracetam in this injection
Content it is low and stability is high, clinically can directly instil use, improve the safety of clinical application.
The second object of the present invention is to provide a kind of preparation method of the injection of above-mentioned Levetiracetam, party's legal system
It is standby simple for process, and be avoided that and introduce other impurity, increase the stability of drug.
In order to realize that the above-mentioned purpose of the present invention, spy use following technical scheme：
A kind of injection of Levetiracetam, a concentration of 2~8mg/mL of Levetiracetam, pH value 5.0 in injection
~6.0.
A kind of preparation method of the injection of above-mentioned Levetiracetam comprising：
The pharmaceutically acceptable auxiliary material that formula ratio is dissolved with water for injection, obtains auxiliary material solution, then molten with auxiliary material solution
The Levetiracetam for solving formula ratio, obtains injection mother liquor, a concentration of 2~8mg/mL of Levetiracetam in injection mother liquor,
The pH value of injection mother liquor is 5.0~6.0；And
It is 0.4~0.5 μm and 0.20~0.25 μm of membrane filtration injection mother liquor to use aperture successively.
Compared with prior art, beneficial effects of the present invention for example including：
The levetiracetam injection of low concentration will produce that Levetiracetam is sour and total miscellaneous increasing under the influence of the substances such as oxygen
Add, it is poor so as to cause the stability of levetiracetam injection；And the levetiracetam injection of high concentration is in use
It is strong to the irritation of patient vessel, it needs to be diluted during Clinical practice to avoid.Left second currently on the market draws west
Smooth injection is the Levetiracetam solution of high concentration, in its dilution, easily draws existing cross contamination and causes miscellaneous
The generation of matter Levetiracetam acid, influences the safety of its Clinical practice.
And the injection of this Levetiracetam provided by the invention, the content of wherein Levetiracetam are low, and stability
By force, it disclosure satisfy that clinical normal use, that is, be not necessarily to dilute the use that can directly instil.Thus Clinical practice compatibility process can be reduced
In the cross contamination that is likely to occur, and the left second of impurity caused by introducing the oxidizing substances such as oxygen can effectively be avoided to draw west
The generation of smooth acid, to improve the safety of clinical application.
Meanwhile in the preparation method of the injection of this Levetiracetam provided by the invention, miillpore filter is directly used
Injection mother liquor is filtered, rather than coarse filtration is carried out to injection mother liquor using activated carbon (injection), is conducive to avoid
Levetiracetam is tightly held by activated carbon and leads to the reduction of its content, and is avoided that introducing other impurities, enhances the stabilization of injection
Property.In addition, the injection of the Levetiracetam prepared in this way, by acceleration and long-term stable experiment, bacterium
The preparation that endotoxin is detected and filtered using activated carbon, testing result is identical, meets regulation.
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Present embodiment provides the injection of Levetiracetam, a concentration of 2~8mg/ of Levetiracetam in the injection
ML is either that 3~7mg/mL is either 4~6mg/mL or is 5mg/mL.The injection of the Levetiracetam of this small dimension
Liquid can directly instil during Clinical practice, avoid the introducing of the cross contamination and impurity when dilution, drug safety
It is high；The compliance of patient can also be improved simultaneously.
The pH value of the injection of the Levetiracetam is 5.0~6.0, and inventor is the study found that the pH value when injection is
When 5.0~6.0, injection still has preferable stability at low concentrations, can long-term preservation.It is more preferred, the injection
The pH value of liquid is 5.3~5.7, or is 5.4~5.6.
Further, the formula number meter of injection includes：
1.6~11 parts of 0.8~1.2 part of Levetiracetam and pharmaceutically acceptable auxiliary material.
Wherein, pharmaceutically acceptable auxiliary material includes at least one of inorganic salts and organic salt of metal, inorganic salts packet
Any one of sodium chloride, potassium chloride and calcium chloride are included, organic salt includes sodium acetate and/or sodium lactate.
Further, in the preferred embodiment, the formula of injection is：
It counts in parts by weight, 0.8~1.2 part of Levetiracetam, 0.8~4.0 part of sodium chloride, 0.02~1.2 part of sodium acetate.
Or be to count in parts by weight, 0.8~1.2 part of Levetiracetam, 0.8~1.2 part of sodium chloride, sodium acetate 0.8
~1.2 parts.
Or be to count in parts by weight, 0.8~1.2 part of Levetiracetam, 3.5~4 parts of sodium chloride, sodium acetate 0.01
~0.03 part.
Or be to count in parts by weight, 0.8~1.2 part of Levetiracetam, 1.6~1.7 parts of sodium chloride, sodium acetate 0.3
~0.4 part.
Or be to count in parts by weight, 0.8~1.2 part of Levetiracetam, 1.6~1.7 parts of sodium chloride, sodium acetate 0.8
~1.2 parts.
Or be to count in parts by weight, 0.8~1.2 part of Levetiracetam, 1.6~1.7 parts of sodium chloride, sodium acetate
0.01~0.03 part.
Or be to count in parts by weight, 0.8~1.2 part of Levetiracetam, 1.0~1.4 parts of sodium chloride, sodium lactate 0.6
~0.7 part, 0.05~0.07 part or 0.03~0.05 part of potassium chloride.
Further, in another embodiment, the formula of injection is：
It counts in parts by weight, 0.8~1.2 part of Levetiracetam, 9~11 parts of glucose.
The preparation method of the injection of this Levetiracetam includes：
Step S1：The pharmaceutically acceptable auxiliary material that formula ratio is dissolved with water for injection, obtains auxiliary material solution, then use auxiliary material
Solution dissolves the Levetiracetam of formula ratio, obtains injection mother liquor, and a concentration of the 2 of Levetiracetam in injection mother liquor~
The pH value of 8mg/mL, injection mother liquor are 5.0~6.0；
Further, auxiliary material include sodium chloride, potassium chloride, calcium chloride, sodium acetate, sodium lactate, glacial acetic acid and glucose and
Any one in a combination thereof.
Further, auxiliary material includes sodium acetate, glacial acetic acid and sodium chloride.The step includes：First with 80% formula ratio
Water for injection dissolve formula ratio sodium acetate and glacial acetic acid, then in acquired solution dispensing formulations amount sodium chloride, obtain auxiliary material
Solution；Then, with the Levetiracetam for dissolving formula ratio with auxiliary material solution；The water for injection of remaining 20% formula ratio is finally used again
Complement to formula full dose.
Step S2：It is 0.4~0.5 μm and 0.20~0.25 μm of filtering injection mother liquor to use aperture successively.
It is more preferred, use aperture to carry out the coarse filtration and refined filtration of injection mother liquor for 0.45 μm and 0.22 μm of filter membrane, more
Further, the material of filter membrane is polyether sulfone.It is filtered using filter membrane, helps avoid introducing other impurities, enhancing gained
The stability of injection.
Further, further include：The filtered fluid obtained after filtering is sealed in nitrogen environment and is carried out at sterilizing
Reason.It is stored in nitrogen environment, helps avoid in prolonged storage, Levetiracetam is oxidized to by the oxygen in air
Levetiracetam acid, causes the impurity content of injection to become larger.
Preferably, sterilization treatment includes 3~15min that filtered fluid sterilizes at 115~130 DEG C；Or it is by filtered fluid
Sterilize 8~15min at 120~125 DEG C；Or for filtered fluid is sterilized 10~12min at 121~124 DEG C.This sterilizing
Method, sterilization time is short, helps avoid Levetiracetam and decomposes or occur chemical reaction generation impurity at high temperature, to carry
The drug safety of high injection.
The preparation method does not have to activated carbon mistake by controlling the pH value of liquid, and the nitrogen charging gas shielded in filling overall process
The modes such as filter reduce the influence to it such as oxygen and metal ion, to control the quality of the injection before the deadline.
The feature and performance of the present invention are described in further detail with reference to embodiments：
Embodiment 1
The present embodiment provides a kind of levetiracetam composition injection, formula composition is as shown in table 1：
The formula composition of injection in 1. embodiment 1 of table
Preparation method includes：
A. the preparation of glacial acetic acid solution：1ml glacial acetic acid is taken to be diluted to 100mL with water for injection, it is spare；
B. water for injection 1120ml is taken, the sodium acetate, sodium chloride, Levetiracetam stirring and dissolving of recipe quantity are sequentially added；
C. pH value is adjusted respectively with glacial acetic acid solution to 5.3；
D. it is settled to total amount with remaining water for injection, stirred evenly；
E. it is filtered successively with 0.45 μm and 0.22 μm of filter membrane, in 100ml inner packings, inflated with nitrogen simultaneously seals quantitative filling；
F. the filtrate being sealed is sterilized at 121 DEG C 10min to get.
Embodiment 2
The present embodiment provides a kind of levetiracetam composition injection, formula composition is as shown in table 2：
The formula composition of injection in 2. embodiment 2 of table
Preparation method includes：
A. the preparation of glacial acetic acid solution：1mL glacial acetic acid is taken to be diluted to 100mL with water for injection, it is spare；
B. water for injection 1120ml is taken, the sodium acetate, sodium chloride, Levetiracetam stirring and dissolving of recipe quantity are sequentially added；
C. pH value is adjusted respectively with glacial acetic acid solution to 5.0；
D. it is settled to total amount with remaining water for injection, stirred evenly；
E. it is filtered successively with 0.4 μm and 0.25 μm of filter membrane, in 100mL inner packings, inflated with nitrogen simultaneously seals quantitative filling；
F. the filtrate being sealed is sterilized at 115 DEG C 15min to get.
Embodiment 3
The present embodiment provides a kind of levetiracetam composition injection, formula composition is as shown in table 3：
The formula composition of injection in 3. embodiment 3 of table
Preparation method includes：
A. the preparation of glacial acetic acid solution：1mL glacial acetic acid is taken to be diluted to 100mL with water for injection, it is spare；
B. water for injection 1120ml is taken, the sodium acetate, sodium chloride, Levetiracetam stirring and dissolving of recipe quantity are sequentially added；
C. pH value is adjusted respectively with glacial acetic acid solution to 6.0；
D. it is settled to total amount with remaining water for injection, stirred evenly；
E. it is filtered successively with 0.50 μm and 0.20 μm of filter membrane, in 100mL inner packings, inflated with nitrogen simultaneously seals quantitative filling；
F. the filtrate being sealed is sterilized at 130 DEG C 3min to get.
Embodiment 4
The present embodiment provides a kind of levetiracetam composition injection, formula composition is as shown in table 4：
The formula composition of injection in 4. embodiment 4 of table
Preparation method includes：
A. the preparation of glacial acetic acid solution：1mL glacial acetic acid is taken to be diluted to 100mL with water for injection, it is spare；
B. water for injection 1120ml is taken, the sodium acetate, sodium chloride, Levetiracetam stirring and dissolving of recipe quantity are sequentially added；
C. pH value is adjusted respectively with glacial acetic acid solution to 5.2；
D. it is settled to total amount with remaining water for injection, stirred evenly；
E. it is filtered successively with 0.45 μm and 0.22 μm of filter membrane, in 100mL inner packings, inflated with nitrogen simultaneously seals quantitative filling；
F. the filtrate being sealed is sterilized at 125 DEG C 8min to get.
Embodiment 5
The present embodiment provides a kind of levetiracetam composition injection, formula composition is as shown in table 5：
The formula composition of injection in 5. embodiment 5 of table
Preparation method includes：
A. the preparation of glacial acetic acid solution：1mL glacial acetic acid is taken to be diluted to 100mL with water for injection, it is spare；
B. water for injection 1120ml is taken, the sodium acetate, sodium chloride, Levetiracetam stirring and dissolving of recipe quantity are sequentially added；
C. pH value is adjusted respectively with glacial acetic acid solution to 5.7；
D. it is settled to total amount with remaining water for injection, stirred evenly；
E. it is filtered successively with 0.45 μm and 0.22 μm of filter membrane, in 100mL inner packings, inflated with nitrogen simultaneously seals quantitative filling；
F. the filtrate being sealed is sterilized at 118 DEG C 12min to get.
Embodiment 6
The present embodiment provides a kind of levetiracetam composition injection, formula composition is as shown in table 6：
The formula composition of injection in 6. embodiment 6 of table
Preparation method includes：
A. the preparation of glacial acetic acid solution：1mL glacial acetic acid is taken to be diluted to 100mL with water for injection, it is spare；
B. water for injection 1120ml is taken, sodium lactate, sodium chloride, potassium chloride, calcium chloride and the left second of recipe quantity are sequentially added
La Xitan stirring and dissolvings；
C. pH value is adjusted respectively with glacial acetic acid solution to 5.5；
D. it is settled to total amount with remaining water for injection, stirred evenly；
E. it is filtered successively with 0.45 μm and 0.22 μm of filter membrane, in 100mL inner packings, inflated with nitrogen simultaneously seals quantitative filling；
F. the filtrate being sealed is sterilized at 121 DEG C 15min to get.
Embodiment 7
The present embodiment provides a kind of levetiracetam composition injection, formula composition is as shown in table 7：
The formula composition of injection in 7. embodiment 7 of table
Preparation method includes：
A. the preparation of glacial acetic acid solution：1mL glacial acetic acid is taken to be diluted to 100mL with water for injection, it is spare；
B. water for injection 1120ml is taken, the glucose and Levetiracetam stirring and dissolving of recipe quantity are sequentially added；
C. pH value is adjusted respectively with glacial acetic acid solution to 5.4；
D. it is settled to total amount with remaining water for injection, stirred evenly；
E. it is filtered successively with 0.45 μm and 0.22 μm of filter membrane, in 100mL inner packings, inflated with nitrogen simultaneously seals quantitative filling；
F. the filtrate being sealed is sterilized at 124 DEG C 12min to get.
Comparative example 1
This comparative example provides a kind of levetiracetam composition injection, and injection formula of liquid is consistent with embodiment 1, different
Place is that preparation method includes：
A. the preparation of glacial acetic acid solution：1ml glacial acetic acid is taken to be diluted to 100mL with water for injection, it is spare；
B. water for injection 1120ml is taken, the sodium acetate, sodium chloride, Levetiracetam stirring and dissolving of recipe quantity are sequentially added；
C. pH value is adjusted respectively with glacial acetic acid solution to 5.3；
D. it is settled to total amount with remaining water for injection, stirred evenly；
E. solution 0.5% activated carbon adsorption 30 minutes, after quiet worry, quantitative filling is in 100ml inner packings, and inflated with nitrogen is simultaneously
Sealing；
F. the filtrate being sealed is sterilized at 121 DEG C 10min to get.
First experimental example
Investigate influence of the levetiracetam composition injection filter type to its stability
1. the prescription and technique according to embodiment 1 and comparative example 1 prepare pilot sample, it is respectively placed in 40 DEG C, 60 DEG C, illumination
10 days under the conditions of (4500Lx ± 500Lx), and its character is observed respectively at sampling in 0,5,10 day, measures pH value, related substance.
(1) strong illumination experimental method：This product number branch is taken, is placed under the illumination that luminous intensity is 4500Lx ± 500Lx and carries out
Strong illumination is tested, and is sampled respectively at 0,5,10 day, detection.
(2) high temperature experimental method：This product number branch is taken, 40 DEG C is respectively placed in, is tested in 60 DEG C of insulating boxs, and respectively at
It samples within 0,5,10 day, detection.
Testing result is shown in Table 8：
Influence of the different filter types of table 8. to injection stability
2. preparing pilot sample according to the prescription and technique of embodiment 1 and comparative example 1, carry out stability test.
It is placed 6 months under the conditions of accelerated test (40 DEG C, RH25%), observes its character respectively at 0,3, sampling in June, carefully
Bacterium endotoxin, related substance.
It is placed 24 months under the conditions of long term test (25 DEG C, RH40%), respectively at sampling observation in 0,6,12,18,24 month
Its character, bacterial endotoxin, related substance.
Testing result is shown in Table 9：
Influence of the different filter types of table 9. to bacterial endotoxin in injection
Above-mentioned test result shows：By the filtering of activated carbon, active constituent Levetiracetam is tightly held by activated carbon, and is caused
Content reduces, and there is also relative increases for Levetiracetam acid.The preparation for not carrying out activated carbon filtering, by accelerating and steadily in the long term
Property experiment, detection of bacterial endotoxin with using activated carbon filtering preparation, testing result is identical, meets regulation.
Second experimental example
Investigate influence of the different pH value to injection stability：
Prepare injection according to the prescription and technique of embodiment 1, in the preparation method of each experimental group the difference is that：With
Glacial acetic acid solution adjust injection mother liquor pH value be respectively：4.5、5.0、5.2、5.4、5.5、5.6、5.8、6.0、6.5.
The injection of the different pH value of above-mentioned preparation is respectively placed in 40 DEG C, 60 DEG C, illumination (4500Lx ± 500Lx) condition
Lower 10 days, and its character is observed respectively at sampling in 0,5,10 day, and measure pH value, related substance.
(1) strong illumination experimental method：This product number branch is taken, is placed under the illumination that luminous intensity is 4500Lx ± 500Lx and carries out
Strong illumination is tested, and is sampled respectively at 0,5,10 day, detection.
(2) high temperature experimental method：This product number branch is taken, 40 DEG C is respectively placed in, is tested in 60 DEG C of insulating boxs, and respectively at
It samples within 0,5,10 day, detection.
Testing result is shown in Table 10：
Influence of the different pH value of table 10. to levetiracetam injection stability
As shown in Table 10：
(1) under the conditions of illumination, high temperature (40 DEG C, 60 DEG C), pH value, the character of all pH value samples have no significant change.
(2) in pH value screening experiment, for the sample of all pH value 10 days under illumination condition, the variation of Levetiracetam acid is unknown
It is aobvious, and total impurities change without conspicuousness；10 days at 40 DEG C of high temperature, Levetiracetam acid is increased slightly, and total impurities are without apparent
Variation.
(3) for the sample that pH value is 4.5 and 6.5 under the conditions of 60 DEG C of high temperature, the variation of Levetiracetam acid is apparent, and total impurities increase
Add and obviously illustrates that the Levetiracetam sodium chloride injection that pH value is 4.5 and 6.5 is more sensitive to high temperature.
It is above-mentioned the experimental results showed that：Sample of the pH value between 5.0 to 6.0, character, pH value, related substance are without apparent
Variation.Further, it is that strictly control product quality, optimal ph range should control between 5.3-5.7.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from the present invention's
Many other change and modification can be made in the case of spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of injection of Levetiracetam, which is characterized in that a concentration of 2 of Levetiracetam described in the injection~
8mg/mL, pH value are 5.0~6.0.
2. the injection of Levetiracetam according to claim 1, which is characterized in that the formula of the injection is by weight
Number meter includes：
1.6~11 parts of 0.8~1.2 part of Levetiracetam and pharmaceutically acceptable auxiliary material.
3. the injection of Levetiracetam according to claim 2, which is characterized in that the auxiliary material includes the inorganic of metal
At least one of salt and organic salt, the inorganic salts include any one of sodium chloride, potassium chloride and calcium chloride, described organic
Salt includes sodium acetate and/or sodium lactate.
4. the injection of Levetiracetam according to claim 3, which is characterized in that the formula of the injection is：
It counts in parts by weight, 0.8~1.2 part of Levetiracetam, 0.8~4.0 part of sodium chloride, 0.02~1.2 part of sodium acetate.
5. the injection of Levetiracetam according to claim 3, which is characterized in that the formula of the injection is：
It counts in parts by weight, 0.8~1.2 part of Levetiracetam, 1~1.4 part of sodium chloride, 0.6~0.7 part of sodium lactate, potassium chloride
0.05~0.07 part and 0.03~0.05 part of calcium chloride.
6. the injection of Levetiracetam according to claim 2, which is characterized in that the auxiliary material is 9~11 parts by weight
Glucose.
7. a kind of preparation method of such as injection of claim 1~6 any one of them Levetiracetam, which is characterized in that
It includes：
The pharmaceutically acceptable auxiliary material that formula ratio is dissolved with water for injection obtains auxiliary material solution, then is matched with the dissolving of auxiliary material solution
The Levetiracetam just measured obtains injection mother liquor, and a concentration of the 2 of Levetiracetam described in the injection mother liquor~
The pH value of 8mg/mL, the injection mother liquor are 5.0~6.0；And
Injection mother liquor described in the membrane filtration that aperture is 0.4~0.5 μm and 0.20~0.25 μm is used successively.
8. the preparation method of the injection of Levetiracetam according to claim 7, which is characterized in that further include：Incited somebody to action
The filtered fluid obtained after filter is sealed in nitrogen environment and carries out sterilization treatment.
9. the preparation method of the injection of Levetiracetam according to claim 8, which is characterized in that the sterilization treatment
Including the filtered fluid is sterilized 3~15min at 115~130 DEG C.
10. the preparation method of the injection of Levetiracetam according to claim 6, which is characterized in that the accessory package
Include any one in sodium chloride, potassium chloride, calcium chloride, sodium acetate, sodium lactate, glacial acetic acid and glucose and combinations thereof.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021028838A1 (en) * | 2019-08-14 | 2021-02-18 | Sintetica S.A. | Intrathecal administration of levetiracetam |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525900A (en) * | 2012-01-19 | 2012-07-04 | 南京恒道医药科技有限公司 | Levetiracetam injection and preparation method thereof |
| CN103550143A (en) * | 2013-10-19 | 2014-02-05 | 浙江华海药业股份有限公司 | Preparation method of levetiracetam injection |
| CN105412007A (en) * | 2015-12-15 | 2016-03-23 | 河北仁合益康药业有限公司 | Levetiracetam-sodium chloride injection compound and preparation method thereof |
-
2018
- 2018-04-13 CN CN201810332283.8A patent/CN108403626A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525900A (en) * | 2012-01-19 | 2012-07-04 | 南京恒道医药科技有限公司 | Levetiracetam injection and preparation method thereof |
| CN103550143A (en) * | 2013-10-19 | 2014-02-05 | 浙江华海药业股份有限公司 | Preparation method of levetiracetam injection |
| CN105412007A (en) * | 2015-12-15 | 2016-03-23 | 河北仁合益康药业有限公司 | Levetiracetam-sodium chloride injection compound and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021028838A1 (en) * | 2019-08-14 | 2021-02-18 | Sintetica S.A. | Intrathecal administration of levetiracetam |
| CN114630654A (en) * | 2019-08-14 | 2022-06-14 | 辛苔蒂加股份有限公司 | Intrathecal administration of levetiracetam |
| US11590105B2 (en) | 2019-08-14 | 2023-02-28 | Sintetica S.A. | Intrathecal administration of levetiracetam |
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Application publication date: 20180817 |