CN107536810B - (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide sterile powder for injection - Google Patents
(S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide sterile powder for injection Download PDFInfo
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Abstract
The invention discloses (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide sterile powder for injection; the sterile powder contains (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, methionine, lactose, triethanolamine and sodium bisulfite in a mass ratio of 1: 0.4-0.6: 0.5-0.9: 0.2-0.4: 0.1-0.2; the invention utilizes specific excipient combination and freeze-drying curve, which can not only improve the sublimation temperature in the secondary drying stage and shorten the production period of the preparation, but also can not generate powder scattering phenomenon, and all indexes such as the content and the like of the preparation meet the regulations; and the product has good stability, and after the product is dissolved into glucose injection or sodium chloride injection to prepare intravenous drip solution, the insoluble particles are obviously reduced, thereby being beneficial to improving the safety of the use of the medicine and reducing the adverse reaction of the medicine.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide sterile powder for injection.
Background
The chemical name of the levo-oxiracetam is as follows: the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide is white microcrystalline powder, has the melting point of 135-136 ℃, the optical rotation of-36 degrees (C is 1.00in water), and the solubility of the levo-oxiracetam is obviously superior to that of racemate. The chemical structural formula is as follows:
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.
However, in the existing preparation process of the (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide sterile powder for injection, the inventor finds that the sublimation temperature is lower in the secondary drying stage, and the temperature cannot be higher than 20 ℃, so that the production period of the preparation is greatly prolonged, and if the temperature in the secondary drying stage is increased, the powder scattering phenomenon occurs in the preparation, and the content of the powder is remarkably reduced. In addition, when the existing (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide sterile powder for injection is prepared into an intravenous drip solution for use, insoluble particles are increased along with the prolonging of the standing time, which brings great potential safety hazard to clinical use.
Disclosure of Invention
In view of the above, the present invention aims to provide (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide sterile powder for injection, which can increase sublimation temperature in the secondary drying stage, shorten the production period of the preparation, avoid powder scattering phenomenon, has a qualified content and good product stability, and reduces insoluble particles after being prepared into an intravenous drip solution.
In order to achieve the purpose, the invention provides the following technical scheme:
an (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide sterile powder for injection, which comprises (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, methionine, lactose, triethanolamine and sodium bisulfite in a mass ratio of 1: 0.4-0.6: 0.5-0.9: 0.2-0.4: 0.1-0.2; the preparation method of the sterile powder comprises the following steps: dissolving (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, methionine, lactose, triethanolamine and sodium bisulfite in water for injection, adjusting the pH value to 3.2-3.6 by hydrochloric acid solution, and then freeze-drying according to the following steps:
(1) a pre-freezing stage: freezing to-14 to-18 ℃ within 5-15 min; then heating to-10 to-8 ℃, wherein the heating time is 30-60 min; freezing to-32 to-36 ℃ within 5-15 min; then heating to-20-26 ℃ for 90-120 min; finally, freezing the mixture to-42 to-46 ℃ within 5 to 15min, and keeping the temperature for 120 to 180 min;
(2) a sublimation drying stage: when the vacuum degree in the drying box reaches 800 mTorr-600 mTorr, the drying temperature is increased to-12 to-10 ℃, the time is 60-90 min, and the heat preservation time is 360-480 min;
(3) and a re-drying stage: raising the re-drying temperature to 35-45 ℃, and taking 90-150 min; and pumping the vacuum degree in the drying box to 5 mTorr-0 mTorr, and keeping the temperature for 240-300 min to obtain sterile powder.
Further, the sterile powder contains (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, methionine, lactose, triethanolamine and sodium bisulfite in a mass ratio of 1: 0.5: 0.7: 0.3: 0.15.
The invention has the beneficial effects that:
the invention utilizes specific excipient combination and freeze-drying curve, which can not only improve the sublimation temperature in the secondary drying stage and shorten the production period of the preparation, but also can not generate powder scattering phenomenon, and all indexes such as the content and the like of the preparation meet the regulations; and the product has good stability, and after the product is dissolved into glucose injection or sodium chloride injection to prepare intravenous drip solution, the insoluble particles are obviously reduced, thereby being beneficial to improving the safety of the use of the medicine and reducing the adverse reaction of the medicine.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, preferred embodiments of the present invention will be described in detail below.
Example 1
The formulation of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide sterile powder for injection of example 1 is shown in the following Table:
| prescription | Weight percent of |
| (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide | 50g |
| Methionine | 25g |
| Lactose | 35g |
| Triethanolamine | 15g |
| Sodium bisulfite | 7.5g |
| Water for injection | Adding to 250mL |
The preparation method of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide for injection sterile powder of example 1, comprising the steps of:
the prescribed amounts of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide, methionine, lactose, triethanolamine and sodium bisulfite were dissolved in water for injection, adjusted to pH 3.5 with 0.1mol/L hydrochloric acid solution, and then lyophilized according to the following procedure:
(1) a pre-freezing stage: freezing to-15 deg.C within 10 min; then heating to-10 ℃ for 40 min; freezing again to-35 deg.C within 10 min; then heating to-25 ℃ for 100 min; finally, the temperature is frozen to-45 ℃ within 10min again, and the temperature is kept for 150 min;
(2) a sublimation drying stage: when the vacuum degree in the drying oven reaches 700mTorr, the drying temperature is increased to-11 ℃, the time is 80min, and the heat preservation time is 400 min;
(3) and a re-drying stage: raising the re-drying temperature to 40 deg.C, and taking for 120 min; and pumping the vacuum degree in the drying box to 3mTorr, and keeping the temperature for 280min to obtain sterile powder.
Example 2
The formulation of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide sterile powder for injection of example 2 is shown in the following Table:
| prescription | Weight percent of |
| (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide | 50g |
| Methionine | 20g |
| Lactose | 25g |
| Triethanolamine | 10g |
| Sodium bisulfite | 5g |
| Water for injection | Adding to 250mL |
The preparation method of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide for injection sterile powder of example 2, comprising the steps of:
the prescribed amounts of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide, methionine, lactose, triethanolamine and sodium bisulfite were dissolved in water for injection, adjusted to pH 3.3 with 0.1mol/L hydrochloric acid solution, and then lyophilized according to the following procedure:
(1) a pre-freezing stage: freezing to-15 deg.C within 5 min; then heating to-9 ℃ for 30 min; freezing again to-32 deg.C within 5 min; then heating to-20 ℃ for 90 min; finally, the temperature is frozen to-42 ℃ within 5min again, and the temperature is kept for 120 min;
(2) a sublimation drying stage: when the vacuum degree in the drying oven reaches 800mTorr, the drying temperature is raised to-12 ℃, the use time is 60min, and the heat preservation time is 360 min;
(3) and a re-drying stage: raising the re-drying temperature to 35 deg.C, and taking for 90 min; and pumping the vacuum degree in the drying oven to 5mTorr, and keeping the temperature for 240min to obtain sterile powder.
Example 3
The formulation of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide sterile powder for injection of example 3 is shown in the following Table:
| prescription | Weight percent of |
| (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide | 50g |
| Methionine | 30g |
| Lactose | 45g |
| Triethanolamine | 20g |
| Sodium bisulfite | 10g |
| Water for injection | Adding to 250mL |
The preparation method of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide for injection sterile powder of example 3, comprising the steps of:
the prescribed amounts of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide, methionine, lactose, triethanolamine and sodium bisulfite were dissolved in water for injection, adjusted to pH 3.5 with 0.1mol/L hydrochloric acid solution, and then lyophilized according to the following procedure:
(1) a pre-freezing stage: freezing to-18 deg.C within 15 min; then heating to-8 ℃ for 60 min; freezing again to-36 deg.C within 15 min; then heating to-26 ℃ for 120 min; finally, the temperature is frozen to-46 ℃ within 15min again, and the temperature is kept for 180 min;
(2) a sublimation drying stage: when the vacuum degree in the drying box reaches 600mTorr, the drying temperature is increased to-10 ℃, the time is taken for 90min, and the heat preservation time is 480 min;
(3) and a re-drying stage: raising the re-drying temperature to 45 deg.C, and taking 150 min; and pumping the vacuum degree in the drying oven to 0mTorr, and keeping the temperature for 300min to obtain sterile powder.
Comparative example 1
The (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide for injection sterile powder of comparative example 1 was prepared without adding sodium bisulfite, and the remaining components and preparation method were the same as in example 1.
The finished preparations of examples 1-3 were placed in a constant temperature and humidity chamber at 25 deg.C, and sampled at 0, 12 and 24 months to examine the changes of appearance, moisture, reconstitution time, related substances and contents, and the test results are shown in Table 1.
TABLE 1 Long-term test investigation results of the finished formulations of examples 1-3
From the above examination results, it can be seen that the indexes of appearance, moisture, reconstitution time, related substances and contents of the finished preparations of examples 1 to 3 are all in accordance with the specifications, and it is proved that the present invention can increase the sublimation temperature (35 to 45 ℃) in the secondary drying stage, shorten the production cycle of the preparation, and prevent the powder scattering phenomenon, and the indexes of the contents are all in accordance with the specifications.
The sterile powder of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide for injection prepared in example 1 and comparative example 1 was diluted with 250ml of 0.9% sodium chloride injection and 5% glucose injection, respectively, to prepare an intravenous drip solution, and insoluble microparticles were measured at 0, 4, 8, and 12 hours according to the first method of insoluble microparticle inspection method (photoresist method) of the fourth part of the chinese pharmacopoeia 2015 year edition, and the number of insoluble microparticles per labeled amount was calculated, and the test results are shown in table 2.
Table 2 investigation results of insoluble particles of finished formulations of example 1 and comparative example 1
From the insoluble microparticle examination results, the stability of the finished product preparation of example 1 is obviously better than that of comparative example 1, after the preparation of the preparation into an intravenous drip solution by dissolving into glucose injection or sodium chloride injection, the insoluble microparticles of example 1 are obviously less than that of comparative example 1, the insoluble microparticles of example 1 are hardly increased along with the prolonging of the standing time, and the insoluble microparticles of comparative example 1 are obviously increased.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (2)
1. A sterile powder of (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide for injection, characterized in that: the sterile powder contains (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, methionine, lactose, triethanolamine and sodium bisulfite in a mass ratio of 1: 0.4-0.6: 0.5-0.9: 0.2-0.4: 0.1-0.2; the preparation method of the sterile powder comprises the following steps: dissolving (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, methionine, lactose, triethanolamine and sodium bisulfite in water for injection, adjusting the pH value to 3.2-3.6 by hydrochloric acid solution, and then freeze-drying according to the following steps:
(1) a pre-freezing stage: freezing to-14 to-18 ℃ within 5-15 min; then heating to-10 to-8 ℃, wherein the heating time is 30-60 min; freezing to-32 to-36 ℃ within 5-15 min; then heating to-20-26 ℃ for 90-120 min; finally, freezing the mixture to-42 to-46 ℃ within 5 to 15min, and keeping the temperature for 120 to 180 min;
(2) a sublimation drying stage: when the vacuum degree in the drying box reaches 800 mTorr-600 mTorr, the drying temperature is increased to-12 to-10 ℃, the time is 60-90 min, and the heat preservation time is 360-480 min;
(3) and a re-drying stage: raising the re-drying temperature to 35-45 ℃, and taking 90-150 min; and pumping the vacuum degree in the drying box to 5 mTorr-0 mTorr, and keeping the temperature for 240-300 min to obtain sterile powder.
2. The (S) -4-hydroxy-2-oxo-1-pyrrolidineacetamide sterile powder for injection according to claim 1, characterized in that: the sterile powder contains (S) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, methionine, lactose, triethanolamine and sodium bisulfite in a mass ratio of 1: 0.5: 0.7: 0.3: 0.15.
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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 |
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- 2016-06-28 CN CN201610485336.0A patent/CN107536810B/en active Active
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 |
|---|
| 奥拉西坦注射液的研制;颜素华 等;《中国现代医学杂志》;20100531;第20卷(第10期);1541-1545、1550 * |
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