CN107281135B - Levo-oxiracetam freeze-dried powder for injection and preparation method thereof - Google Patents
Levo-oxiracetam freeze-dried powder for injection and preparation method thereof Download PDFInfo
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Abstract
A levo-oxiracetam freeze-dried powder for injection is prepared by taking levo-oxiracetam, L-serine, mannitol, sodium glutamate, Tween 80 and benzyl alcohol as raw and auxiliary materials through the steps of concentrated preparation, diluted preparation, freeze drying and capping; the raw materials and auxiliary materials comprise, by weight, 30-38% of levo-oxiracetam, 25-30% of L-serine, 28-35% of mannitol, 5-12% of sodium glutamate, 801-2% of tween and 1-2% of benzyl alcohol; the levo-oxiracetam freeze-dried powder prepared according to the invention has a fixed shape, has no bottle spraying phenomenon in the freeze-drying preparation process, has less impurities, has less than 0.27 percent of total impurities, good product clarity which is less than 0.5 standard turbidity solution, good stability, long shelf life of 24 months, less pain of patients in the injection process and good patient compliance.
Description
Technical Field
The invention mainly relates to the technical field of pharmacy, and in particular relates to levo-oxiracetam freeze-dried powder for injection and a preparation method thereof.
Background
Oxiracetam (S-oxiracetam) is a synthetic hydroxy aminobutyric acid (BABOB) cyclic derivative, is only used for a central nervous system, is mainly distributed in cerebral cortex and hippocampus, has the functions of activating, protecting or promoting the recovery of nerve cells and improving the memory and learning functions of patients with intellectual disabilities, and has no direct vascular activity and central excitation effect on medicaments, so that the oxiracetam has a lasting promoting effect on the learning and memory capacity.
The drug is marketed in Italy in 1987 in the form of tablets, 800 mg; capsule, 800 mg; injection, 1g/5 ml. At present, only oxiracetam capsules and injection are sold on the market at home, and the main active ingredients are racemes. Lei et al in patent publication No. CN 103735545A mention that levo-oxiracetam has obvious effect of promoting awakening of coma caused by alcoholism, while dextro-oxiracetam has no effect basically, and the awakening effect of levo-oxiracetam is 2 times of that of racemic oxiracetam; the levo-oxiracetam has obvious awakening effect on coma caused by trauma and anesthesia. Zhang Feng et al in the patent publication No. CN 103599101A discloses that levo-oxiracetam has obvious improvement effect on learning, memory and cognition dysfunction of rats with traumatic brain injury caused by hydraulic pressure and free fall, and the drug effect of the levo-oxiracetam is far higher than that of dextro-oxiracetam. And the levo-oxiracetam with the dose of 200mg/kg has the equivalent effect with the oxiracetam with the dose of 400 mg/kg. The results of the pharmacokinetic study showed that: levo-oxiracetam and dextro-oxiracetam have no obvious chiral conversion in beagle dogs. There was no significant difference in the major pharmacokinetic parameters of levo-oxiracetam in plasma after single i.v. administration of levo and 2 times the dose of racemic oxiracetam to beagle dogs. The test results of safe pharmacology, acute toxicity, long toxicity and the like show that the toxicity of the levo-oxiracetam and oxiracetam to tested animals or cells is not obviously different under the same dosage level. The research results before clinical application show that the levo-oxiracetam is a main active ingredient for the oxiracetam to exert the drug effect in vivo, and the product can be used alone to reduce the clinical application dose and reduce the potential toxic and side effects.
The existing levo-oxiracetam freeze-dried powder for injection mainly has the problems of no fixed shape, difficult formation of a skeleton, easy occurrence of bottle spraying phenomenon in a freeze-drying process, unqualified product clarity, poor stability, short shelf life, obvious pain in the injection process, poor patient compliance and the like.
Disclosure of Invention
The invention aims to provide the levo-oxiracetam freeze-dried powder for injection, which has a fixed form and good stability.
The invention also aims to provide a preparation method of the levo-oxiracetam freeze-dried powder for injection.
The aim of the invention is realized by the following technical measures:
the levo-oxiracetam freeze-dried powder for injection is characterized by being prepared by taking levo-oxiracetam as a raw material and adding a certain amount of additives; wherein the additive is one or more of sucrose, trehalose, mannitol, lactose, glucose, maltose, dextran, albumin, polyethylene glycol, glycerol, L-serine, sodium glutamate, alanine, glycine, sarcosine, phosphate, acetate, citrate, tween 80 and benzyl alcohol.
The inventor discovers through a large number of experiments in the research process that a proper additive is selected to match with a specific raw material and auxiliary material dosage proportion relation, and then matches with a specific process step, so that the levo-oxiracetam freeze-dried powder for injection has a fixed shape, is easy to form a framework, does not have a bottle spraying phenomenon in the freeze drying process, improves the clarity of the product, reduces the pain of a patient in the use process of the product, and has good patient compliance; the levo-oxiracetam freeze-dried powder for injection is characterized by being prepared by taking levo-oxiracetam, L-serine, mannitol, sodium glutamate, Tween 80 and benzyl alcohol as raw and auxiliary materials through the steps of concentrated preparation, diluted preparation, freeze drying and capping; wherein the dosage of the raw materials and auxiliary materials is 30-38 percent of levo-oxiracetam, 25-30 percent of L-serine, 28-35 percent of mannitol, 5-12 percent of sodium glutamate, 801-2 percent of tween and 1-2 percent of benzyl alcohol; the concentration step comprises the steps of putting the raw and auxiliary materials in a container according to the prescription amount, adding 10 times of sterilized injection water by weight of the levo-oxiracetam, stirring, adding the activated carbon for injection with the mass fraction of 0.5% after dissolving, stirring for 30min, filtering by using a 0.45-micron microporous membrane, and collecting the filtrate for later use; the diluting step comprises the steps of adding sterile water for injection into the filtrate to 1000 times of the volume of the filtrate, adjusting the pH to 5.5 by using hydrochloric acid or sodium hydroxide, then performing sterile filtration by using a 0.22 micron microporous filter membrane, filling the qualified filtrate into sterile glass bottles, and subpackaging for later use.
Further, the levo-oxiracetam freeze-dried powder for injection is characterized by being prepared from the following raw and auxiliary materials in percentage by weight: 32-35% of levo-oxiracetam, 26-28% of L-serine, 29-33% of mannitol, 6-9% of sodium glutamate, 801-2% of tween and 1-2% of benzyl alcohol; placing the raw materials into a container, adding 10 weight parts of sterilized injection water of levetiracetam, stirring, dissolving, adding 0.5 mass percent of needle activated carbon, stirring for 30min, filtering with a 0.45 micron microporous membrane, collecting filtrate, adding sterilized injection water into the filtrate to 1000 volume times of the filtrate, adjusting pH to 5.5 with hydrochloric acid or sodium hydroxide, sterilizing with a 0.22 micron microporous membrane, filtering, filling the qualified filtrate, and subpackaging in sterile glass bottles. The quality of the product is further improved by matching a specific prescription ratio with a specific pH value and a specific raw and auxiliary material treatment step.
A preparation method of levo-oxiracetam freeze-dried powder for injection is characterized by comprising the following steps:
1. concentration and preparation: placing the raw and auxiliary materials in a container according to the prescription amount, adding 10 weight-times of sterilized water for injection of levetiracetam, stirring, dissolving, adding 0.5 mass percent of injectable activated carbon, stirring for 30min, filtering with a 0.45-micron microporous membrane, and collecting the filtrate for later use;
2. diluting and preparing: adding sterile water for injection into the filtrate to 1000 times of the volume of the filtrate, adjusting pH to 5.5 with hydrochloric acid or sodium hydroxide, sterilizing with 0.22 micrometer microporous membrane, filtering, packaging the qualified filtrate in sterile glass bottle;
3. and (3) freeze drying: placing the liquid medicine subpackaged in the sterile glass bottles in a freeze dryer, quickly freezing to-40 ℃, keeping the temperature for 180 minutes in the whole process, then vacuumizing and drying, heating to-10 ℃ at the speed of 15 ℃/hour, and keeping the constant temperature of-10 ℃ for 120 minutes; heating to 0 ℃ at the speed of 5 ℃/h, and keeping the temperature at 0 ℃ for 320 minutes; heating to 10 ℃ at the speed of 5 ℃/h, keeping the temperature of 10 ℃ constant for 240 minutes, heating to 30 ℃ at the speed of 10 ℃/h, keeping the temperature of 30 ℃ constant for 60 minutes, simultaneously reducing the vacuum of the front box to 10Pa/10 minutes, and finishing the freeze-drying;
4. and (3) rolling a cover: and cleaning the aluminum-plastic combined cover, sterilizing, drying, and rolling to obtain the aluminum-plastic combined cover.
The invention has the following beneficial effects:
the levo-oxiracetam freeze-dried powder for injection has a fixed shape, has no bottle spraying phenomenon in the freeze-drying preparation process, has less impurities, has the total impurities of less than 0.27 percent, good product clarity of less than 0.5 standard turbidity solution, good stability, long shelf life of 24 months, light pain of patients in the injection process and good patient compliance.
Detailed Description
The present invention is described in detail below by way of examples, it being necessary to note that the following examples are provided only for illustrating the present invention and are not to be construed as limiting the scope of the present invention, and modifications or substitutions of the method, steps or conditions of the present invention may be made without departing from the spirit and spirit of the present invention.
Example 1
The levo-oxiracetam freeze-dried powder for injection is prepared by the following steps:
| composition (I) | Dosage (% by weight) |
| Levo-oxiracetam | 32％ |
| L-serine | 27％ |
| Mannitol | 33％ |
| Glutamic acid sodium salt | 6％ |
| Tween 80 | 1％ |
| Benzyl alcohol | 1％ |
Make into 1000 bottles
The preparation process comprises the following steps:
1. concentration and preparation: placing the raw and auxiliary materials in a container according to the prescription amount, adding 10 weight-times of sterilized water for injection of levetiracetam, stirring, dissolving, adding 0.5 mass percent of injectable activated carbon, stirring for 30min, filtering with a 0.45-micron microporous membrane, and collecting the filtrate for later use;
2. diluting and preparing: adding sterile water for injection into the filtrate to 1000 times of the volume of the filtrate, adjusting pH to 5.5 with hydrochloric acid or sodium hydroxide, sterilizing with 0.22 micrometer microporous membrane, filtering, packaging the qualified filtrate in sterile glass bottle;
3. and (3) freeze drying: placing the liquid medicine subpackaged in the sterile glass bottles in a freeze dryer, quickly freezing to-40 ℃, keeping the temperature for 180 minutes in the whole process, then vacuumizing and drying, heating to-10 ℃ at the speed of 15 ℃/hour, and keeping the constant temperature of-10 ℃ for 120 minutes; heating to 0 ℃ at the speed of 5 ℃/h, and keeping the temperature at 0 ℃ for 320 minutes; heating to 10 ℃ at the speed of 5 ℃/h, keeping the temperature of 10 ℃ constant for 240 minutes, heating to 30 ℃ at the speed of 10 ℃/h, keeping the temperature of 30 ℃ constant for 60 minutes, simultaneously reducing the vacuum of the front box to 10Pa/10 minutes, and finishing the freeze-drying;
4. and (3) rolling a cover: and cleaning the aluminum-plastic combined cover, sterilizing, drying, and rolling to obtain the aluminum-plastic combined cover.
For a better understanding of the present invention, the following stability tests are provided to further illustrate the beneficial effects of the inventive agents, but not to limit the present invention.
Experiment one: stability experiment of levo-oxiracetam freeze-dried powder for injection
Experimental materials:
levo-oxiracetam freeze-dried powder for injection sample: prepared for example 1
The accelerated test method comprises the following steps: the levo-oxiracetam freeze-dried powder for injection prepared in example 1 is packaged on the market, placed in an acceleration experiment box, sampled for a certain time, and inspected on an investigation project.
Accelerated test temperature: 40 +/-2 DEG C
Humidity: RH 75% +/-5%
Investigation time: 0. months 1, 2, 3 and 6
And (4) investigation indexes are as follows: character, visible foreign matter, clarity, pH, related substances, content, and sterility test
Recording the stability of the accelerated test:
the results of accelerated experiments show that: the quality of each detection index of the sample in the accelerated 6 months is equivalent to that of the sample in the 0 month, which shows that the product has stable quality and better stability in the accelerated experiment for 6 months.
The long-term experimental method comprises the following steps: the levo-oxiracetam freeze-dried powder for injection prepared in example 1 is packaged on the market, placed in a long-term sample box, sampled for a certain time and inspected on an investigation project.
Accelerated test temperature: 25 +/-2 DEG C
Humidity: RH 60% +/-10%
Investigation time: 0. 3, 6, 9, 12, 18, 24 months
And (4) investigation indexes are as follows: character, visible foreign matter, clarity, pH, related substances, content, and sterility test
Long-term test stability recording:
long-term tests show that: the product has no obvious change in characters, visible foreign matters, clarity, pH value, related substances, content and various indexes of sterility test after long-term test for 24 months, and all the indexes meet various related regulations of production quality standard draft. The product has stable quality for 24 months in long-term test, so the product has a minimum shelf life of 24 months, and the long-term test is still in the process of continuous investigation.
Experiment two: statistics of bottle spraying phenomenon in freeze drying process of levo-oxiracetam freeze-dried powder for injection
1. The purpose of the test is as follows: the bottle spraying phenomenon of different prescriptions in the freeze drying process is considered.
2. The test method comprises the following steps: the percentage of the spray bottle phenomenon occurred during the preparation process was counted for the samples of example 1 and the control samples, which were formulated as follows:
control sample prescription (% by weight)
| Levo-oxiracetam | 32％ |
| L-serine | 29％ |
| Mannitol | 35％ |
| Tween 80 | 2％ |
| Glutamic acid sodium salt | —— |
| Benzyl alcohol | 2％ |
3. And (3) test results:
| numbering | Number of spray bottles | Total number of observation bottles | Percentage of spray bottle% |
| Example 1 | 0 | 100 | 0 |
| Control sample | 32 | 100 | 32 |
4. And (4) conclusion: in example 1, the sample does not generate bottle spraying phenomenon in the freeze drying process, and the bottle spraying phenomenon of the control sample is 32%, so that the probability of bottle spraying of the product can be effectively reduced by adding sodium glutamate.
Experiment three: test for observing pain feeling during injection by mouse writhing method
Test samples: the levo-oxiracetam freeze-dried powder for injection prepared according to the example 1 is used as a test sample, and the levo-oxiracetam freeze-dried powder prepared according to the example 1 is used as a control sample without adding benzyl alcohol;
the purpose is as follows: comparing the pain degree of the two levo-oxiracetam freeze-dried powders in the injection process
The method comprises the following steps: taking a white mouse for experiment, subcutaneously injecting levo-oxiracetam freeze-dried powder (dissolved and diluted to 10ml by normal saline), observing whether the white mouse can generate a writhing reaction, judging the intensity of pain in the injection process according to the probability of the writhing reaction of the mouse, and repeating the test for 30 times on a test sample and a control sample;
and (3) test results: the results of the tests are given in the following table:
| product name | Experimental sample (mouse) | Number of individuals with writhing reaction | The occurrence rate of twisting reaction% |
| Test article | 30 pieces of | 3 pieces of | 10.0％ |
| Control sample | 30 pieces of | 24 are | 80.0％ |
And (4) conclusion: as can be seen from the table above, the pain feeling of the levo-oxiracetam freeze-dried powder for injection is obviously weaker than that of a control sample in the injection process.
Example 2
The levo-oxiracetam freeze-dried powder for injection is prepared by the following steps:
| composition (I) | Dosage (% by weight) |
| Levo-oxiracetam | 35％ |
| L-serine | 26％ |
| Mannitol | 30％ |
| Glutamic acid sodium salt | 7％ |
| Tween 80 | 1％ |
| Benzyl alcohol | 1％ |
Make into 1000 bottles
The preparation process comprises the following steps: prepared according to the preparation process of example 1.
According to the test method of the example 1, the stability test result of the sample of the example 2 shows that the quality of the sample is stable in 6 months at an accelerated speed, and the quality is stable in 24 months for a long time, so that the product has a minimum effective period of 24 months. The statistical result of the bottle spraying phenomenon in the freeze drying process shows that the bottle spraying phenomenon does not occur in the freeze drying process of the sample in the example 2. The test result of the pain feeling in the injection process observed by the mouse writhing method shows that the pain feeling in the injection process of the sample in the embodiment 2 is obviously weaker than that of the control sample.
Example 3
The levo-oxiracetam freeze-dried powder for injection is prepared by the following steps:
| composition (I) | Dosage (% by weight) |
| Levo-oxiracetam | 33％ |
| L-serine | 28％ |
| Mannitol | 31％ |
| Glutamic acid sodium salt | 6％ |
| Tween 80 | 1％ |
| Benzyl alcohol | 1％ |
Make into 1000 bottles
The preparation process comprises the following steps: prepared according to the preparation process of example 1.
According to the test method of the example 1, the stability test result of the sample of the example 3 shows that the quality of the sample is stable in 6 months at an accelerated speed, and the quality is stable in 24 months for a long time, so that the product has a minimum effective period of 24 months. The statistical result of the bottle spraying phenomenon in the freeze drying process shows that the bottle spraying phenomenon does not occur in the freeze drying process of the sample in the example 3. The test result of the pain feeling in the injection process observed by the mouse writhing method shows that the pain feeling in the injection process of the sample in the embodiment 3 is obviously weaker than that of the control sample.
Examples 4 to 6: the levo-oxiracetam freeze-dried powder for injection is prepared from the following raw and auxiliary materials in parts by weight, and the preparation method is the same as that in example 1:
according to the test method of the example 1, the stability test results of the samples of the examples 4, 5 and 6 show that the quality of the sample is stable in 6 months at an accelerated speed, and the quality is stable in 24 months for a long time, so that the product has a minimum effective period of 24 months; the statistical result of the bottle spraying phenomenon in the freeze drying process shows that the bottle spraying phenomenon does not occur in the freeze drying process of the samples of examples 4, 5 and 6; the test results of the pain sensation in the injection process observed by the mouse writhing method show that the pain sensation in the injection process of the samples of examples 4, 5 and 6 is obviously weaker than that of the control sample.
Claims (2)
1. The levo-oxiracetam freeze-dried powder for injection is characterized in that the levo-oxiracetam freeze-dried powder is prepared by taking levo-oxiracetam, L-serine, mannitol, sodium glutamate, Tween 80 and benzyl alcohol as raw and auxiliary materials through the steps of concentrated preparation, diluted preparation, freeze drying and capping; the raw materials and auxiliary materials comprise, by weight, 30-38% of levo-oxiracetam, 25-30% of L-serine, 28-35% of mannitol, 5-12% of sodium glutamate, 801-2% of tween and 1-2% of benzyl alcohol; the concentration step comprises the steps of putting the raw and auxiliary materials in a container according to the prescription amount, adding 10 times of sterilized injection water by weight of the levo-oxiracetam, stirring, adding the activated carbon for injection with the mass fraction of 0.5% after dissolving, stirring for 30min, filtering by using a 0.45-micron microporous membrane, and collecting the filtrate for later use; the diluting step comprises the steps of adding sterile water for injection into the filtrate to 1000 times of the volume of the filtrate, adjusting the pH to 5.5 by using hydrochloric acid or sodium hydroxide, then performing sterile filtration by using a 0.22 micron microporous filter membrane, filling the qualified filtrate into sterile glass bottles, and subpackaging for later use.
2. The levo-oxiracetam freeze-dried powder for injection as claimed in claim 1, which is prepared from the following raw and auxiliary materials, by weight, 32% -35% of levo-oxiracetam, 26% -28% of L-serine, 29% -33% of mannitol, 6% -9% of sodium glutamate, 801% -2% of tween and 1% -2% of benzyl alcohol; placing the raw materials into a container, adding 10 weight parts of sterilized injection water of levetiracetam, stirring, dissolving, adding 0.5 mass percent of needle activated carbon, stirring for 30min, filtering with a 0.45 micron microporous membrane, collecting filtrate, adding sterilized injection water into the filtrate to 1000 volume times of the filtrate, adjusting pH to 5.5 with hydrochloric acid or sodium hydroxide, sterilizing with a 0.22 micron microporous membrane, filtering, filling the qualified filtrate, and subpackaging in sterile glass bottles.
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