CN107115290B - (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity and preparation method thereof - Google Patents
(S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
An injection of (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide with good clarity is prepared from (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, propylene glycol, lecithin and benzyl alcohol as raw and auxiliary materials by the steps of concentrated preparation, diluted preparation, filling and sealing, sterilization, inspection and packaging; the (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection prepared by the invention has almost no change in solution pH before and after sterilization, good product clarity which is lower than No. 0.5 standard turbidity solution, good stability, no crystallization in the storage process, long effective period which can reach more than 18 months, less product impurities in the effective period, less total impurities which are lower than 0.37 percent, reduced 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 (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection with good clarity and a preparation method thereof.
Background
Oxiracetam (oxiracetam, CAS No.: 62613-82-5) has the chemical name of 4-hydroxy-2-oxo-1-pyrrolidine acetamide, is an anti-hypoxia nootropic drug (the compound is disclosed in US4118396) which is synthesized for the first time in 1974 by ISFS. P.A. company of Italy, is a cyclic GABOB derivative, can promote the synthesis of phosphorylcholine and phosphorylethanolamine, promote brain metabolism, penetrate blood brain barrier, has stimulation effect on specific central nervous pathways, can improve intelligence and memory, has better curative effect on cerebrovascular diseases, brain trauma, brain tumor, intracranial infection, brain degeneration diseases and the like, and has extremely low toxicity, no mutagenic effect, carcinogenic effect and reproductive toxicity. The chemical structure and preparation of oxiracetam is disclosed in US4118396 by Giorgio et al, and the pharmaceutical efficacy of oxiracetam in the S configuration (levo) is shown in the clinical results in WO9306826A by Chiodini et al, which is stronger than that in the R configuration (dextro), with oxiracetam and levooxiracetam structures shown below.
The existing (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection mainly has the problems of large solution pH change in the sterilization process, poor product stability, easy crystallization in the storage process, poor clarity, obvious pain of patients in the injection process, poor compliance and the like.
Disclosure of Invention
The invention aims to provide the (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection with good stability and clarity.
The invention also aims to provide a preparation method of the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection.
The aim of the invention is realized by the following technical measures:
the (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection with good clarity is characterized in that the injection is prepared by taking (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide as a raw material and adding a certain amount of additive; wherein the additive is one or more of glucose, sodium chloride, mannitol, glycerol, L-serine, sodium glutamate, alanine, glycine, lecithin, propylene glycol, benzyl alcohol, chlorobutanol, sodium sulfite, sodium bisulfite, sodium pyrosulfite, vitamin C, and ethylenediamine tetraacetic acid.
The inventor finds that the compound additive consisting of propylene glycol, lecithin and benzyl alcohol in a certain proportion is selected, matched with a specific pH regulator and a specific pH value of the solution, and matched with a specific preparation process, the pH value of the solution before and after sterilization of the product is basically unchanged, the product stability is good, crystallization is avoided in the storage process, the clarity of the product is remarkably improved, the pain of a patient is reduced in the injection use process, and the compliance of the patient is good; the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity is characterized in that: the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, propylene glycol, lecithin and benzyl alcohol are used as raw and auxiliary materials and are prepared by the steps of concentrated preparation, diluted preparation, encapsulation, sterilization, inspection and packaging; wherein the raw materials and auxiliary materials comprise (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide 50-70 wt%, propylene glycol 15-35 wt%, lecithin 12-30 wt%, and benzyl alcohol 1-5 wt%; the concentration step is that the raw and auxiliary materials are added into a mixing tank, and then 2/3 of the prescription amount of sterilized water for injection is added, stirred and dissolved to obtain concentrated solution; the dilute preparation step comprises the steps of taking a concentrated preparation solution, adding a sodium phosphate buffer solution (65.697 g of disodium hydrogen phosphate and 2.346g of sodium dihydrogen phosphate are precisely weighed and placed in a 1000ml volumetric flask, adding purified water for dissolving, diluting and fixing the volume to a scale, and obtaining the product), adjusting the pH value to 6.5-7.0, adding chitosan with the total volume of 0.2-0.6% (g/ml) into the solution, stirring, uniformly mixing, standing for 30-50 min, filtering by using a 0.8 mu m filter membrane, adding active carbon with the total volume of 0.1-0.3% (g/ml), adsorbing and decoloring, filtering by using a 0.45 mu m filter membrane, collecting the filtrate, adding sterilized water for injection to the prescription amount, and passing the inspection by intermediate products.
Most preferably, the (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection is characterized by being prepared from the following raw and auxiliary materials in percentage by weight: 55-60% of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide, 18-25% of propylene glycol, 15-20% of lecithin and 2-5% of benzyl alcohol; the concentration step is that the raw and auxiliary materials are added into a mixing tank, and then 2/3 of the prescription amount of sterilized water for injection is added, stirred and dissolved to obtain concentrated solution; the dilute preparation step comprises the steps of taking a concentrated preparation solution, adding a sodium phosphate buffer solution (65.697 g of disodium hydrogen phosphate and 2.346g of sodium dihydrogen phosphate are precisely weighed and placed in a 1000ml volumetric flask, adding purified water for dissolving, diluting and fixing the volume to a scale, and obtaining the product), adjusting the pH value to 6.8, adding chitosan with the total volume of 0.2-0.6% (g/ml) into the solution, stirring, uniformly mixing, standing for 30-50 min, filtering by using a 0.8 mu m filter membrane, adding active carbon with the total volume of 0.1-0.3% (g/ml), adsorbing and decoloring, filtering by using a 0.45 mu m filter membrane, collecting the filtrate, adding sterilized water for injection to the prescription amount, and passing the inspection by intermediate products.
A preparation method of (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection with good clarity is characterized by comprising the following steps:
1. concentration and preparation: adding the raw and auxiliary materials into a mixing tank, immediately adding 2/3 of the formula amount of sterilized water for injection, stirring and dissolving to obtain a concentrated solution;
2. diluting and preparing: taking the concentrated preparation solution, adding a sodium phosphate buffer solution (65.697 g of disodium hydrogen phosphate and 2.346g of sodium dihydrogen phosphate are precisely weighed and placed in a 1000ml volumetric flask, adding purified water for dissolving, diluting and fixing the volume to a scale, thus obtaining the product), adjusting the pH value to 6.8, adding chitosan with the total volume of 0.2-0.6% (g/ml) into the solution, stirring, uniformly mixing, standing for 30-50 min, filtering with a 0.8 mu m filter membrane, adding active carbon with the total volume of 0.1-0.3% (g/ml), adsorbing and decolorizing, filtering with a 0.45 mu m filter membrane, collecting the filtrate, adding sterilized injection water to the prescribed amount, and passing the intermediate product inspection;
3. encapsulating: filtering the intermediate with a 0.22 μm filter after the intermediate is qualified, checking visible foreign matters, filling in a production line after the bacterial endotoxin is qualified, and sealing;
4. and (3) sterilization: and (3) feeding the filled Ancui cut semi-finished product into a steam sterilization pot for sterilization, and sterilizing for 15min at 121 ℃, wherein the sterilization procedure comprises the following steps: heating to 121 deg.C at 10 deg.C/min, and maintaining at 121 deg.C for 15 min; cooling by blowing compressed air at 3-5 ℃/min for 8-12 min to 70-80 ℃, cooling by cooling water at 2-3 ℃/min to 30 ℃ for 15-18 min, completing sterilization, and detecting leakage according to specified conditions;
5. and (4) checking: and (4) inspecting the sterilized sample for visible foreign matters, packaging the qualified sample, fully inspecting and warehousing.
The invention has the following beneficial effects:
the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity has almost no change in the pH value of the solution before and after sterilization, the product has good clarity which is lower than that of No. 0.5 standard turbidity solution, good stability, no crystallization in the storage process, long validity period which can reach more than 18 months, less product impurities in the validity period, less total impurities than 0.37 percent, reduced pain of patients in the injection process and good compliance of the patients.
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 (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity is prepared by the following steps:
| composition (I) | Dosage of |
| (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide | 100g |
| Propylene glycol | 45g |
| Lecithin | 31g |
| Benzyl alcohol | 5g |
| Sterilized water for injection | Adding to 2000ml |
Make 1000 pieces
The preparation process comprises the following steps:
1. concentration and preparation: adding the raw and auxiliary materials into a mixing tank, immediately adding 2/3 of the formula amount of sterilized water for injection, stirring and dissolving to obtain a concentrated solution;
2. diluting and preparing: taking the concentrated preparation solution, adding a sodium phosphate buffer solution (65.697 g of disodium hydrogen phosphate and 2.346g of sodium dihydrogen phosphate are precisely weighed and placed in a 1000ml volumetric flask, adding purified water for dissolving, diluting and fixing the volume to a scale, thus obtaining the product), adjusting the pH value to 6.8, adding chitosan with the total volume of 0.2-0.6% (g/ml) into the solution, stirring, uniformly mixing, standing for 30-50 min, filtering with a 0.8 mu m filter membrane, adding active carbon with the total volume of 0.1-0.3% (g/ml), adsorbing and decolorizing, filtering with a 0.45 mu m filter membrane, collecting the filtrate, adding sterilized injection water to the prescribed amount, and passing the intermediate product inspection;
3. encapsulating: filtering the intermediate with a 0.22 μm filter after the intermediate is qualified, checking visible foreign matters, filling in a production line after the bacterial endotoxin is qualified, and sealing;
4. and (3) sterilization: and (3) feeding the filled Ancui cut semi-finished product into a steam sterilization pot for sterilization, and sterilizing for 15min at 121 ℃, wherein the sterilization procedure comprises the following steps: heating to 121 deg.C at 10 deg.C/min, and maintaining at 121 deg.C for 15 min; cooling by blowing compressed air at 3-5 ℃/min for 8-12 min to 70-80 ℃, cooling by cooling water at 2-3 ℃/min to 30 ℃ for 15-18 min, completing sterilization, and detecting leakage according to specified conditions;
5. and (4) checking: and (4) inspecting the sterilized sample for visible foreign matters, packaging the qualified sample, fully inspecting and warehousing.
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: the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity is used for stability experiment
Experimental materials:
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection samples: prepared for example 1
The accelerated test method comprises the following steps: the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection prepared in example 1 is packaged on the market, put in an accelerated experiment box, sampled for a certain time and examined for items.
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, sterility test accelerated test stability record:
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 (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection prepared in example 1 is packaged on the market, placed in a long-term sample-retaining box, sampled for a certain time and examined for items.
Accelerated test temperature: 25 +/-2 DEG C
Humidity: RH 60% +/-10%
Investigation time: 0. months 3, 6, 9, 12 and 18
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 18 months, and all the indexes meet the relevant regulations of production quality standard draft. The product has stable quality for 18 months in long-term test, so the product has a minimum effective period of 18 months, and the long-term test is still in the process of continuous investigation.
Experiment two: the invention relates to a research on clarity contrast test of (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with less impurities
1. Experimental materials:
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection samples: prepared for example 1
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection control samples: (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide for injection, prepared as described in example 1, was used as a control sample after changing pH adjusting agent, pH value and not adding chitosan, respectively, one factor.
2. The experimental method comprises the following steps: the examination was carried out according to the examination method of the clarity in the pharmacopoeia appendix IXB, 2010 edition.
3. The results of the experiment are shown in the following table:
| test sample | Results |
| Example 1 sample | Turbidity of not more than 0.5 |
| Control sample 1: sample prepared with sodium bicarbonate as pH regulator | Standard turbidity solution with clarity not less than 1.0 and not more than 0.5 |
| Control sample 2: adjusting the pH to 7.5 | Standard turbidity solution with clarity not less than 1.0 and not more than 0.5 |
| Control sample 3: adjusting the pH to 6.0 | Standard turbidity solution with clarity not less than 1.0 and not more than 0.5 |
| Control sample 4: samples not treated with chitosan | ≥1.0 |
4. And (4) experimental conclusion: the clarity of the samples produced in example 1 was better than that of the control samples.
Experiment three: test for observing pain feeling during injection by mouse writhing method
Test samples: (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection prepared in example 1 was used as a test sample, and (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection prepared in example 1 was used as a control sample without adding benzyl alcohol;
the purpose is as follows: comparing the degree of pain during injection of two (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injections
The method comprises the following steps: injecting (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection into mice subcutaneously, observing whether the mice generate writhing reaction, judging the pain intensity in the injection process according to the probability of the mice generating writhing reaction, and repeating the test for 30 times for the test sample and the 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 | 7 are | 23.3％ |
| Control sample | 30 pieces of | 26 are | 86.7％ |
And (4) conclusion: as can be seen from the above table, the pain during injection of the (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection of the present invention was significantly less than that of the control sample.
Experiment four: effect of different pH regulators on the pH of solutions before and after product sterilization
1. Experimental materials:
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection samples: prepared for example 1
(S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection sample control samples: the (S) -4-hydroxy-2 oxo-1-pyrrolidineacetamide injection sample prepared according to the preparation method of example 1 with sodium bicarbonate, sodium hydroxide, disodium hydrogen phosphate as pH adjusting agents was used as a control sample.
2. The experimental method comprises the following steps: the pH of the solution before and after product sterilization is tested according to a VIIG pH value measurement method in the first step of the first appendix of the 2010 version of Chinese pharmacopoeia, and the influence of different pH regulators on the pH before and after product sterilization is examined.
3. The results of the experiment are shown in the following table:
4. and (4) experimental conclusion: the pH of the solution was substantially unchanged before and after sterilization of the samples prepared in example 1.
Example 2
The (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity is prepared by the following steps:
| composition (I) | Dosage of |
| (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide | 100g |
| Propylene glycol | 32g |
| Lecithin | 27g |
| Benzyl alcohol | 8g |
| Sterilized water for injection | Adding to 2000ml |
Make 1000 pieces
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, stability test investigation, clarity contrast test, pain test in the injection process of mouse writhing observation and the influence test of pH regulator on the pH of the solution before and after sterilization of the product are respectively carried out, and the sample stability test result of the example 2 shows that the sample quality is stable in 6 months and is stable in 18 months for a long time, so that the product has the minimum effective period of 18 months. The clarity contrast test result shows that the clarity of the sample produced in example 2 is less than that of No. 0.5 standard turbidity solution, and the product has good clarity. The test result of the pain feeling in the injection process observed by the mouse writhing method shows that the pain feeling in the left injection process of the sample in the example 2 is obviously weaker than that of the control sample. Experiments on the influence of different pH regulators on the pH of the solution before and after sterilization of the product showed that the pH of the solution before and after sterilization of the sample prepared in example 2 was substantially unchanged.
Example 3
The (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity is prepared by the following steps:
make 1000 pieces
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, stability test investigation, clarity contrast test, pain test in the injection process of mouse writhing observation and the influence test of pH regulator on the pH of the solution before and after sterilization of the product are respectively carried out, and the sample stability test result of the example 3 shows that the sample quality is stable in 6 months and is stable in 18 months for a long time, so that the product has the minimum effective period of 18 months. The clarity contrast test result shows that the clarity of the sample produced in example 3 is less than that of No. 0.5 standard turbidity solution, and the product has good clarity. The test result of the pain feeling in the injection process observed by the mouse writhing method shows that the pain feeling in the left injection process of the sample in the example 3 is obviously weaker than that of the control sample. Experiments on the effect of different pH modifiers on the pH of the solutions before and after sterilization of the products showed that the pH of the solutions before and after sterilization of the samples prepared in example 3 was essentially unchanged.
Examples 4 to 6: the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity is prepared from the following raw and auxiliary materials by weight, and the preparation method is the same as that in example 1:
according to the test method of the example 1, stability test investigation, clarity contrast test, pain test in the injection process of mouse writhing observation and the influence test of pH regulator on the pH of the solution before and after sterilization of the product are respectively carried out, and the test results of the stability of the samples of the examples 4, 5 and 6 show that the quality of the samples is stable in 6 months at the accelerated speed, the quality is stable in 18 months for a long time, and therefore, the effective period of the product is at least 18 months. The clarity contrast test result shows that the clarity of the samples produced by the examples 4, 5 and 6 is less than that of No. 0.5 standard turbidity liquid, and the clarity of the product is good. The test results of the pain sensation during the injection process observed by the mouse writhing method show that the pain sensation during the left injection process of the samples of examples 4, 5 and 6 is obviously weaker than that of the control sample. Experiments on the influence of different pH regulators on the pH of the solutions before and after sterilization of the products show that the pH of the solutions before and after sterilization of the samples prepared in examples 4, 5 and 6 is not substantially changed.
Claims (3)
1. The (S) -4-hydroxy-2 oxo-1-pyrrolidine acetamide injection with good clarity is characterized in that: the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, propylene glycol, lecithin and benzyl alcohol are used as raw and auxiliary materials and are prepared by the steps of concentrated preparation, diluted preparation, encapsulation, sterilization, inspection and packaging; wherein the raw and auxiliary materials comprise (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide 50-70 wt%, propylene glycol 15-35 wt%, lecithin 12-30 wt%, and benzyl alcohol 1-5 wt%;
the preparation method comprises the following steps:
A. concentration and preparation: adding the raw and auxiliary materials into a mixing tank, immediately adding 2/3 of the formula amount of sterilized water for injection, stirring and dissolving to obtain a concentrated solution;
B. diluting and preparing: taking the concentrated preparation solution, adding a sodium phosphate buffer solution to adjust the pH value to 6.5-7.0, adding chitosan with the total volume of 0.2-0.6% (g/ml) into the solution, stirring, uniformly mixing, standing for 30-50 min, filtering with a 0.8 mu m filter membrane, adding active carbon with the total volume of 0.1-0.3% (g/ml), adsorbing and decoloring, filtering with a 0.45 mu m filter membrane, collecting filtrate, adding sterile water for injection to the prescription amount, and inspecting and qualifying through an intermediate product; the preparation method of the sodium phosphate buffer solution comprises the steps of precisely weighing 65.697g of disodium hydrogen phosphate and 2.346g of sodium dihydrogen phosphate, placing the weighed materials into a 1000ml volumetric flask, adding purified water to dissolve, diluting and fixing the volume to a scale, and thus obtaining the sodium phosphate buffer solution;
C. encapsulating: filtering the intermediate with a 0.22 μm filter after the intermediate is qualified, checking visible foreign matters, filling in a production line after the bacterial endotoxin is qualified, and sealing;
D. and (3) sterilization: and (3) sterilizing the filled ampoule semi-finished product in a steam sterilization pot at 121 ℃ for 15min, wherein the sterilization procedure is as follows: heating to 121 deg.C at 10 deg.C/min, and maintaining at 121 deg.C for 15 min; cooling by blowing compressed air at 3-5 ℃/min for 8-12 min to 70-80 ℃, cooling by cooling water at 2-3 ℃/min to 30 ℃ for 15-18 min, completing sterilization, and detecting leakage according to specified conditions;
E. and (4) checking: and (4) inspecting the sterilized sample for visible foreign matters, packaging the qualified sample, fully inspecting and warehousing.
2. The (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection of claim 1, which is prepared from the following raw materials by weight: 55-60% of (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, 18-25% of propylene glycol, 15-20% of lecithin and 2-5% of benzyl alcohol;
the preparation method comprises the following steps:
A. concentration and preparation: adding the raw and auxiliary materials into a mixing tank, immediately adding 2/3 of the formula amount of sterilized water for injection, stirring and dissolving to obtain a concentrated solution;
B. diluting and preparing: adding a sodium phosphate buffer solution into the concentrated solution to adjust the pH value to 6.8, adding chitosan with the total volume of 0.2-0.6% (g/ml) into the solution, stirring, uniformly mixing, standing for 30-50 min, filtering with a 0.8-micron filter membrane, adding activated carbon with the total volume of 0.1-0.3% (g/ml), adsorbing and decoloring, filtering with a 0.45-micron filter membrane, collecting filtrate, adding sterilized water for injection to the prescription amount, and inspecting and qualifying through an intermediate product;
the preparation method of the sodium phosphate buffer solution comprises the steps of precisely weighing 65.697g of disodium hydrogen phosphate and 2.346g of sodium dihydrogen phosphate, placing the weighed materials into a 1000ml volumetric flask, adding purified water to dissolve, diluting and fixing the volume to a scale, and thus obtaining the sodium phosphate buffer solution;
C. encapsulating: filtering the intermediate with a 0.22 μm filter after the intermediate is qualified, checking visible foreign matters, filling in a production line after the bacterial endotoxin is qualified, and sealing;
D. and (3) sterilization: and (3) sterilizing the filled ampoule semi-finished product in a steam sterilization pot at 121 ℃ for 15min, wherein the sterilization procedure is as follows: heating to 121 deg.C at 10 deg.C/min, and maintaining at 121 deg.C for 15 min; cooling by blowing compressed air at 3-5 ℃/min for 8-12 min to 70-80 ℃, cooling by cooling water at 2-3 ℃/min to 30 ℃ for 15-18 min, completing sterilization, and detecting leakage according to specified conditions;
E. and (4) checking: and (4) inspecting the sterilized sample for visible foreign matters, packaging the qualified sample, fully inspecting and warehousing.
3. The method for preparing (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide injection according to claim 2, comprising the steps of:
A. concentration and preparation: adding the raw and auxiliary materials into a mixing tank, immediately adding 2/3 of the formula amount of sterilized water for injection, stirring and dissolving to obtain a concentrated solution;
B. diluting and preparing: adding a sodium phosphate buffer solution into the concentrated solution to adjust the pH value to 6.8, adding chitosan with the total volume of 0.2-0.6% (g/ml) into the solution, stirring, uniformly mixing, standing for 30-50 min, filtering with a 0.8-micron filter membrane, adding activated carbon with the total volume of 0.1-0.3% (g/ml), adsorbing and decoloring, filtering with a 0.45-micron filter membrane, collecting filtrate, adding sterilized water for injection to the prescription amount, and inspecting and qualifying through an intermediate product;
the preparation method of the sodium phosphate buffer solution comprises the steps of precisely weighing 65.697g of disodium hydrogen phosphate and 2.346g of sodium dihydrogen phosphate, placing the weighed materials into a 1000ml volumetric flask, adding purified water to dissolve, diluting and fixing the volume to a scale, and thus obtaining the sodium phosphate buffer solution;
C. encapsulating: filtering the intermediate with a 0.22 μm filter after the intermediate is qualified, checking visible foreign matters, filling in a production line after the bacterial endotoxin is qualified, and sealing;
D. and (3) sterilization: and (3) sterilizing the filled ampoule semi-finished product in a steam sterilization pot at 121 ℃ for 15min, wherein the sterilization procedure is as follows: heating to 121 deg.C at 10 deg.C/min, and maintaining at 121 deg.C for 15 min; cooling by blowing compressed air at 3-5 ℃/min for 8-12 min to 70-80 ℃, cooling by cooling water at 2-3 ℃/min to 30 ℃ for 15-18 min, completing sterilization, and detecting leakage according to specified conditions;
E. and (4) checking: and (4) inspecting the sterilized sample for visible foreign matters, packaging the qualified sample, fully inspecting and warehousing.
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| CN201610105739.8A CN107115290B (en) | 2016-02-25 | 2016-02-25 | (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity and preparation method thereof |
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| CN201610105739.8A CN107115290B (en) | 2016-02-25 | 2016-02-25 | (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide injection with good clarity and preparation method thereof |
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| CN107115290B true CN107115290B (en) | 2020-09-29 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102512363A (en) * | 2011-12-23 | 2012-06-27 | 重庆药友制药有限责任公司 | Oxiracetam injection and preparation method thereof |
| CN102670497A (en) * | 2012-05-31 | 2012-09-19 | 北京阜康仁生物制药科技有限公司 | Stable S-oxiracetam preparation for injection and preparation method of same |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223328B1 (en) * | 1985-07-26 | 1992-01-29 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102512363A (en) * | 2011-12-23 | 2012-06-27 | 重庆药友制药有限责任公司 | Oxiracetam injection and preparation method thereof |
| CN102670497A (en) * | 2012-05-31 | 2012-09-19 | 北京阜康仁生物制药科技有限公司 | Stable S-oxiracetam preparation for injection and preparation method of same |
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