CN107536815A - The preparation method of injection levo-oxiracetam freeze drying powder injection - Google Patents
The preparation method of injection levo-oxiracetam freeze drying powder injection Download PDFInfo
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- CN107536815A CN107536815A CN201610505153.0A CN201610505153A CN107536815A CN 107536815 A CN107536815 A CN 107536815A CN 201610505153 A CN201610505153 A CN 201610505153A CN 107536815 A CN107536815 A CN 107536815A
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- oxiracetam
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Abstract
The invention discloses a kind of preparation method of injection levo-oxiracetam freeze drying powder injection；Contain the supplementary material of following mass fraction in the freeze drying powder injection：1 part of levo-oxiracetam, 0.4~0.6 part of methionine, 0.5~0.9 part of lactose, 0.2~0.4 part of triethanolamine, 0.01~0.02 part of Tween 80,0.05~0.1 part of phenmethylol；The present invention utilizes specific excipient composition and freeze-drying curve, the sublimation temperature in redrying stage can be improved, shorten the preparation production cycle, powder dispersion phenomenon will not occur again, the indices such as its content meet regulation, and product clarity is good, less than No. 0.5 standard turbidity solution, and pain is lighter in patient injection procedure, good patient compliance, adverse drug reaction is reduced.
Description
Technical field
The invention belongs to pharmaceutical field, and in particular to a kind of preparation side of injection levo-oxiracetam freeze drying powder injection
Method.
Background technology
Levo-oxiracetam chemical name is：(S)-Esomeprazole, it is white micro-crystals shape
Powder, 135~136 DEG C of fusing point, -36 ° of optical activity (C=1.00in water), the dissolubility of levo-oxiracetam is substantially better than
Raceme.Chemical structural formula is as follows：
The medicine 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.Ye Lei
Deng mentioning levo-oxiracetam in the A patents of Publication No. CN 103735545 to the promoting wakening gone into a coma caused by alcoholism
Substantially, and dextrorotation Oxiracetam does not act on substantially, the above-mentioned rush of levo-oxiracetam wake up that effect is racemization Oxiracetam 2
Times；Levo-oxiracetam is notable to the promoting wakening of stupor caused by wound, anesthesia.Peak etc. is opened in Publication No. CN
Levo-oxiracetam is disclosed in 103599101 A patent to the study note of traumatic brain injury rat caused by hydraulic pressure and freely falling body
Recall cognition dysfunction to improve significantly, its drug effect is far above dextrorotation Oxiracetam.And the left-handed Auras of 200mg/kg
It is western smooth suitable with the effect of 400mg/kg Oxiracetams.Pharmacokinetic study results are shown：Levo-oxiracetam and dextrorotation are difficult to understand
La Xitan is in beasle dog body without obvious chiral inversion.It is difficult to understand that beasle dog single intravenous injection gives left-handed and 2 multiple doses racemizations
The equal no significant difference of the main pharmacokinetic parameters of levo-oxiracetam in blood plasma after La Xitan.The examinations such as safe pharmacology, anxious malicious, long poison
Test result to show, under isodose level, levo-oxiracetam is with Oxiracetam to the toxicity of animal subject or cell without bright
Significant difference is different.Above-mentioned preclinical result of study shows that levo-oxiracetam is the chief active that drug effect is played in Oxiracetam body
Composition, this product, which is used alone, can reduce Clinical practice dosage, reduce potential toxicity.
But inventor has found in existing injection levo-oxiracetam freeze drying powder injection preparation process, in redrying
In the stage, its sublimation temperature is relatively low, and its temperature so greatly extends the production cycle of preparation not above 20 DEG C, if carried
The phenomenon of powder dispersion will occur for the temperature in high redrying stage, preparation, and its content is remarkably decreased, and product clarity
It is unqualified.In addition, existing injection levo-oxiracetam freeze drying powder injection is also present, injection process pain is obvious, and patient complies with
The problems such as property difference.
The content of the invention
In view of this, it is an object of the invention to provide a kind of preparation side of injection levo-oxiracetam freeze drying powder injection
Method, the sublimation temperature in redrying stage can be improved, shorten the preparation production cycle, powder dispersion phenomenon will not occur again, its
Content, product clarity are qualified, and pain is lighter in injection process, good patient compliance.
To reach above-mentioned purpose, the present invention provides following technical scheme：
A kind of preparation method of injection levo-oxiracetam freeze drying powder injection, contain following matter in the freeze drying powder injection
Measure the supplementary material of number：1 part of levo-oxiracetam, 0.4~0.6 part of methionine, 0.5~0.9 part of lactose, triethanolamine 0.2
~0.4 part, 0.01~0.02 part of Tween 80,0.05~0.1 part of phenmethylol；
The preparation method of the freeze drying powder injection is：By levo-oxiracetam, methionine, lactose, triethanolamine, tween
80 and phenmethylol be dissolved in water for injection, with hydrochloric acid solution adjust pH value to 5.5, be then freeze-dried according to following steps：
(1) the pre-freeze stage：Temperature is refrigerated to -14~-18 DEG C in 5~15min；- 10~-8 DEG C are then heated to, is risen
The warm time is 30~60min；Temperature is refrigerated to -32~-36 DEG C in 5~15min again；Then heat to -20~-26
DEG C, the heating-up time is 90~120min；Temperature is finally refrigerated to -42~-46 DEG C in 5~15min again, temperature is kept
120~180min；
(2) the lyophilization stage：When vacuum in drying box reaches 800mTorr~600mTorr, by drying temperature liter
To -12~-10 DEG C, 60~90min of used time, 360~480min of soaking time；
(3) the re-dry stage：Re-dry temperature is increased to 35~45 DEG C, 90~150min of used time；By in drying box
Vacuum is evacuated to 5mTorr~0mTorr, 240~300min of soaking time, obtains freeze drying powder injection.
Further, the supplementary material of following mass fraction is contained in the freeze drying powder injection：1 part of levo-oxiracetam, first sulphur
0.5 part of propylhomoserin, 0.7 part of lactose, 0.3 part of triethanolamine, 0.01 part of Tween 80,0.08 part of phenmethylol.
The beneficial effects of the present invention are：
The present invention utilizes specific excipient composition and freeze-drying curve, can improve the sublimation temperature in redrying stage,
Shorten the preparation production cycle, powder dispersion phenomenon will not occur again, the indices such as its content meet regulation, product clarity
It is good, less than No. 0.5 standard turbidity solution, and pain is lighter in patient injection procedure, good patient compliance, reduces adverse drug
Reaction.
Embodiment
In order that the purpose of the present invention, technical scheme and beneficial effect are clearer, below by the preferred reality of the present invention
Example is applied to be described in detail.
Embodiment 1
The prescription of the injection levo-oxiracetam freeze drying powder injection of embodiment 1 is as shown in the table：
| Prescription | Percentage by weight |
| Levo-oxiracetam | 100g |
| Methionine | 50g |
| Lactose | 70g |
| Triethanolamine | 30g |
| Tween 80 | 1g |
| Phenmethylol | 8g |
| Water for injection | Add to 500mL |
The preparation method of the injection levo-oxiracetam freeze drying powder injection of embodiment 1, comprises the following steps：
The levo-oxiracetam of recipe quantity, methionine, lactose, triethanolamine, Tween 80 and phenmethylol are dissolved in note
Penetrate with water, adjust pH value to 5.5 with 0.1mol/L hydrochloric acid solutions, be then freeze-dried according to following steps：
(1) the pre-freeze stage：Temperature is refrigerated to -14 DEG C in 8min；- 10 DEG C are then heated to, the heating-up time is
40min；Temperature is refrigerated to -35 DEG C in 10min again；- 25 DEG C are then heated to, heating-up time 100min；Again finally
Secondary that temperature is refrigerated into -45 DEG C in 10min, temperature keeps 150min；
(2) the lyophilization stage：When vacuum in drying box reaches 700mTorr, drying temperature is risen to -11 DEG C, used
When 80min, soaking time 420min；
(3) the re-dry stage：Re-dry temperature is increased to 40 DEG C, used time 120min；Vacuum in drying box is taken out
To 2mTorr, soaking time 260min, freeze drying powder injection is obtained.
Embodiment 2
The prescription of the injection levo-oxiracetam freeze drying powder injection of embodiment 2 is as shown in the table：
| Prescription | Percentage by weight |
| Levo-oxiracetam | 100g |
| Methionine | 40g |
| Lactose | 50g |
| Triethanolamine | 20g |
| Tween 80 | 1.5g |
| Phenmethylol | 5g |
| Water for injection | Add to 500mL |
The preparation method of the injection levo-oxiracetam freeze drying powder injection of embodiment 2, comprises the following steps：
The levo-oxiracetam of recipe quantity, methionine, lactose, triethanolamine, Tween 80 and phenmethylol are dissolved in note
Penetrate with water, adjust pH value to 5.5 with 0.1mol/L hydrochloric acid solutions, be then freeze-dried according to following steps：
(1) the pre-freeze stage：Temperature is refrigerated to -15 DEG C in 5min；- 9 DEG C are then heated to, heating-up time 30min；
Temperature is refrigerated to -32 DEG C in 5min again；- 20 DEG C are then heated to, heating-up time 90min；Finally again in 5min
Interior that temperature is refrigerated into -42 DEG C, temperature keeps 120min；
(2) the lyophilization stage：When vacuum in drying box reaches 800mTorr, drying temperature is risen to -12 DEG C, used
When 60min, soaking time 360min；
(3) the re-dry stage：Re-dry temperature is increased to 35 DEG C, used time 90min；Vacuum in drying box is evacuated to
5mTorr, soaking time 240min, obtains freeze drying powder injection.
Embodiment 3
The prescription of the injection levo-oxiracetam freeze drying powder injection of embodiment 3 is as shown in the table：
| Prescription | Percentage by weight |
| Levo-oxiracetam | 100g |
| Methionine | 60g |
| Lactose | 90g |
| Triethanolamine | 40g |
| Tween 80 | 2g |
| Phenmethylol | 10g |
| Water for injection | Add to 500mL |
The preparation method of the injection levo-oxiracetam freeze drying powder injection of embodiment 3, comprises the following steps：
The levo-oxiracetam of recipe quantity, methionine, lactose, triethanolamine, Tween 80 and phenmethylol are dissolved in note
Penetrate with water, adjust pH value to 5.5 with 0.1mol/L hydrochloric acid solutions, be then freeze-dried according to following steps：
(1) the pre-freeze stage：Temperature is refrigerated to -17 DEG C in 14min；- 9 DEG C are then heated to, the heating-up time is
60min；Temperature is refrigerated to -36 DEG C in 15min again；- 26 DEG C are then heated to, heating-up time 120min；Again finally
Secondary that temperature is refrigerated into -46 DEG C in 15min, temperature keeps 180min；
(2) the lyophilization stage：When vacuum in drying box reaches 600mTorr, drying temperature is risen to -10 DEG C, used
When 90min, soaking time 480min；
(3) the re-dry stage：Re-dry temperature is increased to 44 DEG C, used time 140min；Vacuum in drying box is taken out
To 1mTorr, soaking time 290min, freeze drying powder injection is obtained.
Comparative example 1
The injection levo-oxiracetam freeze drying powder injection of comparative example 1 does not add phenmethylol, remaining component and preparation side
Method is same as Example 1.
Embodiment 1-3 finished product preparation is placed in 25 DEG C of climatic chambers, investigated respectively at sampling in the 0th, 12,24 month
Appearance character, moisture, time, clarity, the change about material and content are redissolved, result of the test is shown in Table 1.
The embodiment 1-3 of table 1 finished product preparation long term test investigates result
Result, the appearance character of embodiment 1-3 finished product preparation, moisture, redissolution time, clarification are investigated more than
Spend, meet regulation about the indices such as material and content, it was demonstrated that the present invention can improve the distillation temperature in redrying stage
Spend (35~45 DEG C), shorten the preparation production cycle, powder dispersion phenomenon will not occur again, the indices such as its content meet rule
It is fixed, and product clarity is good, less than No. 0.5 standard turbidity solution.
Injection levo-oxiracetam freeze drying powder injection made from embodiment 1 and comparative example 1 is water-soluble with physiology salt respectively
Solution dilution, then takes experimental white mouse, is subcutaneously injected, and whether observation small white mouse can occur writhing response, be occurred according to mouse
The probability of writhing response judges the power of pain in injection process, each to repeat 30 experiments, and result of the test is shown in Table 2.
The finished product preparation injection pain sense result of the test of the embodiment 1 of table 2 and comparative example 1
| Sample | Experiment sample (mouse) | Generation writhing response number of individuals | Writhing response incidence |
| Embodiment 1 | 30 | 5 | 17% |
| Comparative example 1 | 30 | 28 | 93% |
The injection levo-oxiracetam freeze drying powder injection as made from injection pain sense results showed that embodiment 1 is noted
Pain is markedly less than comparative example 1 during penetrating.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
Cross above preferred embodiment the present invention is described in detail, it is to be understood by those skilled in the art that can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (2)
- A kind of 1. preparation method of injection levo-oxiracetam freeze drying powder injection, it is characterised in that：In the freeze drying powder injection Supplementary material containing following mass fraction：1 part of levo-oxiracetam, 0.4~0.6 part of methionine, 0.5~0.9 part of lactose, three 0.2~0.4 part of monoethanolamine, 0.01~0.02 part of Tween 80,0.05~0.1 part of phenmethylol；The preparation method of the freeze drying powder injection is：By levo-oxiracetam, methionine, lactose, triethanolamine, Tween 80 and Phenmethylol is dissolved in water for injection, is adjusted pH value to 5.5 with hydrochloric acid solution, is then freeze-dried according to following steps：（1）The pre-freeze stage：Temperature is refrigerated to -14~-18 DEG C in 5~15min；- 10~-8 DEG C are then heated to, during heating Between be 30~60min；Temperature is refrigerated to -32~-36 DEG C in 5~15min again；- 20~-26 DEG C are then heated to, is risen The warm time is 90~120min；Temperature is finally refrigerated to -42~-46 DEG C in 5~15min again, temperature keeps 120~ 180 min；（3）The lyophilization stage：When vacuum in drying box reaches 800mTorr~600mTorr, drying temperature is risen to- 12~-10 DEG C, 60~90min of used time, 360~480min of soaking time；（3）The re-dry stage：Re-dry temperature is increased to 35~45 DEG C, 90~150min of used time；By the vacuum in drying box Degree is evacuated to 5mTorr~0mTorr, 240~300min of soaking time, obtains freeze drying powder injection.
- 2. the preparation method of injection levo-oxiracetam freeze drying powder injection according to claim 1, it is characterised in that：Institute State the supplementary material for containing following mass fraction in freeze drying powder injection：1 part of levo-oxiracetam, 0.5 part of methionine, lactose 0.7 Part, 0.3 part of triethanolamine, 0.01 part of Tween 80,0.08 part of phenmethylol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610505153.0A CN107536815A (en) | 2016-06-29 | 2016-06-29 | The preparation method of injection levo-oxiracetam freeze drying powder injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610505153.0A CN107536815A (en) | 2016-06-29 | 2016-06-29 | The preparation method of injection levo-oxiracetam freeze drying powder injection |
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| CN107536815A true CN107536815A (en) | 2018-01-05 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008150080A1 (en) * | 2007-06-04 | 2008-12-11 | Dong-A Pharm. Co., Ltd. | Injectable ready to use solutions comprising human chorionic gonadotropin |
| 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 |
| CN103446067A (en) * | 2013-09-16 | 2013-12-18 | 石药集团欧意药业有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
-
2016
- 2016-06-29 CN CN201610505153.0A patent/CN107536815A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008150080A1 (en) * | 2007-06-04 | 2008-12-11 | Dong-A Pharm. Co., Ltd. | Injectable ready to use solutions comprising human chorionic gonadotropin |
| 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 |
| CN103446067A (en) * | 2013-09-16 | 2013-12-18 | 石药集团欧意药业有限公司 | Oxiracetam freeze-drying preparation for injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 颜素华 等: "奥拉西坦注射液的研制", 《中国现代医学杂志》 * |
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