CN106692073A - Levo-oxiracetam sterile powder and preparation method thereof - Google Patents

Levo-oxiracetam sterile powder and preparation method thereof Download PDF

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CN106692073A
CN106692073A CN 201510458344 CN201510458344A CN106692073A CN 106692073 A CN106692073 A CN 106692073A CN 201510458344 CN201510458344 CN 201510458344 CN 201510458344 A CN201510458344 A CN 201510458344A CN 106692073 A CN106692073 A CN 106692073A
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oxiracetam
sterile
minutes
prepared
levo
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CN 201510458344
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叶雷
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重庆东泽医药科技发展有限公司
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Abstract

A levo-oxiracetam sterile powder is characterized by being prepared from the following raw and auxiliary materials by the weight percentage: 35%-60% of levo-oxiracetam, and 40%-65% of an excipient, wherein the excipient is a composition of L-serine, mannitol and sodium glutamate. The levo-oxiracetam sterile powder for injection prepared by the preparation method has a fixed shape and has no bottle spraying phenomenon in a freeze-drying preparation process; the product has fewer impurities, has the total impurity content less than 0.22%, is conducive to improvement of the safety of drug use, reduces drug adverse reactions, has good product stability, and has the shelf life as long as 24 months.

Description

一种左旋奥拉西坦无菌粉末及其制备方法 One kind of sterile powders -oxiracetam and preparation method

技术领域 FIELD

[0001] 本发明主要涉及制药技术领域,具体涉及一种注左旋奥拉西坦无菌粉末及其制备方法。 [0001] The present invention generally relates to the field of pharmaceutical technology, in particular to a sterile powders -oxiracetam injection and its preparation method.

背景技术 Background technique

[0002] 促智药又称大脑激活素是一种促进学习,增强记忆力的新型中枢神经系统药物。 [0002] nootropics, also known as brain activation is a prime facilitate learning and enhance the memory of the new central nervous system drugs. 促智药物要求选择作用于大脑皮层,具有选择激活、保护和促进受损神经细胞功能恢复的特征。 Nootropic drugs asked to choose the role of the cerebral cortex, has selected activation, protect and promote the features of the damaged nerve cell function recovery. 与其他神经药物不同的一点是它们的上述作用并不通过网状系统或嗅球,而是直接作用于皮层。 And other neurological drugs so that they are different from the action of the olfactory bulb or the system does not pass through the mesh, but directly act on the skin. 既不影响行为,也无镇静兴奋作用,因此该类药物已引起人们的广泛关注和兴趣,对该类药物的需求量也与日倶增。 Neither affect behavior, and no sedative stimulant, so these drugs has caused widespread concern and interest, the demand for drugs is also increasing with the Japanese Ju.

[0003] 奥拉西坦(oxiracetam,CAS No. :62613-82-5)化学名为4-羟基-2-氧代-1-吡咯烷乙酰胺,为意大利ISFS. P. A公司于1974年首次合成的抗缺氧类促智药(化合物披露于US4118396),是环GABOB衍生物,可促进磷酰胆碱和磷酰乙醇胺合成,促进脑代谢,透过血脑屏障,对特异性中枢神经道路有刺激作用,可以改善智力和记忆,对脑血管病、脑外伤、 脑瘤、颅内感染、脑变性疾病等也具有较好的疗效,并且该药物毒性极低,无致突变和致癌作用及生殖毒性。 [0003] -oxiracetam (oxiracetam, CAS No.: 62613-82-5) the chemical name 4-hydroxy-2-oxo-1-pyrrolidine acetamide, ISFS P. A company in Italy in 1974. synthesis of the first anti-anoxia nootropics (compound disclosed in US4118396), is a cyclic derivative GABOB, phosphorylcholine and may facilitate phosphoryl ethanolamine synthesis, promoting brain metabolism, brain barrier, specific for the central nervous system road stimulation can improve intelligence and memory, cerebrovascular disease, traumatic brain injury, brain tumors, intracranial infection, cerebral degenerative disorders, also having a good effect, and the extremely low toxicity, no mutagenic and carcinogenic effects and reproductive toxicity. Giorgio等人在US4118396中披露了奥拉西坦的化学结构和制备方法, Chiodini等人在W09306826A中披露,临床结果证明S构型(左旋)的奥拉西坦的药效强于R构型(右旋),奥拉西坦和左旋奥拉西坦结构如下所示。 Giorgio et al in US4118396 disclose a method of preparation and chemical structures oxiracetam, Chiodini et al. Disclose in W09306826A, the clinical results demonstrate that the S configuration (L) is stronger than the efficacy oxiracetam R configuration ( dextrose), and FIG -oxiracetam -oxiracetam structured as follows.

Figure CN106692073AD00031

[0005] 现有左旋奥拉西坦无菌粉末其主要存在无固定形状、不易形成骨架,产品在冻干过程中易出现喷瓶现象,稳定性差,货架期短等问题。 [0005] Existing -oxiracetam sterile powders which mainly no fixed shape easily form the skeleton, the product prone spray bottle phenomenon during lyophilization, poor stability and short shelf life problems.

发明内容 SUMMARY

[0006] 本发明的目的在于提供一种具有固定形态、稳定性好、货架期长的左旋奥拉西坦无菌粉末。 [0006] The object of the present invention is to provide a fixed form, good stability, long shelf life of sterile powders -oxiracetam.

[0007] 本发明的另一目的在于提供上述左旋奥拉西坦无菌粉末的制备方法。 [0007] Another object of the present invention to provide a method for preparing the above-described -oxiracetam sterile powders.

[0008] 本发明的目的是通过如下技术措施实现的: [0008] The object of the present invention are achieved by the following technical measures:

[0009] —种左旋奥拉西坦无菌粉末,其特征在于,它是由下列重量百分比的原辅料制得: 左旋奥拉西坦35%〜60%、赋形剂40%〜65%,其中所述赋形剂为蔗糖、海藻糖、甘露醇、 乳糖、葡萄糖、麦芽糖、葡聚糖、白蛋白、聚乙二醇、甘油、L-丝氨酸、谷氨酸钠、丙氨酸、甘氨酸、肌氨酸、磷酸盐、醋酸盐、柠檬酸盐中的一种或多种。 [0009] - species -oxiracetam sterile powders, characterized in that it is the percentage by weight of raw materials following was prepared: -oxiracetam 35% ~ 60%, 40% ~ 65% excipient, wherein the excipient is sucrose, trehalose, mannitol, lactose, glucose, maltose, dextran, albumin, polyethylene glycol, glycerol, L- serine, sodium glutamic acid, alanine, glycine, sarcosine, phosphate, acetate, citrate, one or more.

[0010] 发明人通过大量实验发现在以上组成中选择一定比例的L-丝氨酸、甘露醇和谷氨酸钠组成的复合赋形剂、再配合特定的左旋奥拉西坦浓度,可使得上述注射用左旋奥拉西坦无菌粉末具有固定形状、易形成骨架,产品在冷冻干燥过程中不会出现喷瓶现象,并且可使产品货架期延长;上述左旋奥拉西坦无菌粉末,其特征在于,它是由下列重量百分比的原辅料制得:左旋奥拉西坦42 %〜52 %,L-丝氨酸22 %〜28 %,甘露醇18 %〜32 %,谷氨酸钠4%〜12%。 [0010] The inventors found by experiment to select a certain percentage of L- serine in the above composition, the composite excipient mannitol and sodium glutamic acid, and then with the specific -oxiracetam concentration, so that the injection can be used -oxiracetam sterile powders having a fixed shape, is easy to form the skeleton, the product will not squirt bottle phenomenon during lyophilization, and the product can extend the shelf life; -oxiracetam above sterile powders, wherein it is the percentage by weight of raw materials following was prepared: -oxiracetam 42% ~52%, L- serine 22% ~28% mannitol 18% ~ 32%, ~ 12% 4% sodium glutamate .

[0011] 最优选地,上述左旋奥拉西坦无菌粉末,其特征在于,它是由下列重要百分比的原辅料制得:左旋奥拉西坦45 %〜50 %,L-丝氨酸22 %〜26 %,甘露醇20 %〜26 %、谷氨酸钠5%〜8%〇 [0011] Most preferably, sterile powders -oxiracetam above, characterized in that it is made from the following raw materials made significant percentage: -oxiracetam 45% ~50%, L- serine ~ 22% 26%, 20% ~26% mannitol, sodium glutamate 5% ~ 8% billion

[0012] —种左旋奥拉西坦无菌粉末的制备方法,其特征在于,它是按如下步骤制得的: [0012] - preparation of seed -oxiracetam sterile powders, characterized in that it is prepared as follows:

[0013] 1.浓配:将处方量的左旋奥拉西坦、赋形剂置于容器中,加入左旋奥拉西坦10倍重量份的灭菌注射用水搅拌,溶解后,加入质量分数〇. 1 %的针用活性炭,搅拌30min,随后用0. 45微米微孔滤膜滤过,收集滤液,备用; [0013] 1 with concentrated: the formulation amounts of -oxiracetam, excipients are placed in the vessel, was added 10 parts by -oxiracetam times the weight of sterile water for injection was stirred and dissolved, mass fraction . 1% of the square pin with charcoal, stirred for 30min, followed by 0.45 micron microporous membrane filtration, the filtrate was collected and set aside;

[0014] 2.稀配:向滤液中加入灭菌注射用水至处方量,用盐酸或氢氧化钠调节pH至7. 0, 随后用0. 22微米的微孔滤膜除菌过滤,取滤液合格后灌装分装于无菌玻璃瓶中,备用; [0014] 2. Dilute with: the filtrate was added to sterile water for injection prescriptions, with hydrochloric acid or sodium hydroxide to adjust the pH to 7.0, followed by sterilization by filtration with a microporous membrane of 0.22 microns, the filtrate after passing the filling dispensed in sterile glass vials for later use;

[0015] 3.冷冻干燥:将上述分装于无菌玻璃瓶中的药液置冷冻干燥机中,迅速将温度冷冻至-40°C,整个过程保持180分钟,然后抽真空干燥,以15°C /小时升温至-KTC,-KTC 恒温保持120分钟;以5°C /小时升温至(TC,(TC恒温320分钟;以5°C /小时升温至KTC, KTC恒温240分钟,以KTC /小时升温至30°C,30°C恒温60分钟,同时前箱真空降达到10Pa/10分时,冻干结束; [0015] 3. The freeze-dried: The above dispensed into sterile glass vials of liquid placed in a freeze dryer, the temperature was quickly frozen to -40 ° C, throughout the process kept for 180 minutes and then vacuum dried at 15 ° C / hr to warm to -KTC, -KTC temperature for 120 min; to 5 ° C / hr to warm to (TC, (TC thermostat 320 minutes; at 5 ° C / hr to warm to KTC, KTC thermostat 240 minutes KTC / h warmed to 30 ° C, 30 ° C thermostat for 60 minutes while vacuum drop reaches the headbox 10Pa / 10 min, ending lyophilized;

[0016] 4.乳盖:铝塑组合盖需经清洗后灭菌、干燥,然后进行乳盖,即得。 [0016] 4. milk cap: cap for an aluminum composition after cleaning and sterilizing, drying, and then cover the milk, that is, too.

[0017] 本发明具有如下的有益效果: [0017] The present invention has the following advantages:

[0018] 本发明左旋奥拉西坦无菌粉末具有固定形状、在冻干制备过程中无喷瓶现象,并且本品杂质少,其总杂质低于〇. 22%,有利于提高药物使用的安全性,减少药物不良反应, 产品稳定性好,货架期长达24月。 [0018] The present invention -oxiracetam sterile powders having a fixed shape, the lyophilized preparation process without spray bottle phenomenon, and the product less impurities, the total impurity is less than square. 22%, help to improve the use of drugs safety, reduce adverse drug reactions, product stability, shelf life of up to 24 months.

具体实施方式 detailed description

[0019] 下面通过实施例对本发明进行具体的描述,有必要在此指出的是以下实施例只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限制,在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。 [0019] Next, by the present invention will be specifically described embodiments, it is necessary to point out that the following examples are only for the present invention is further illustrated not to be construed as limiting the scope of the present invention, without departing from the spirit of the invention and substantial case, the method of the present invention, modified or replaced, or step made in conditions, are within the scope of the present invention. [0020] 实施例1 [0020] Example 1

[0021] —种左旋奥拉西坦无菌粉末,按以下步骤制得: [0021] - species -oxiracetam sterile powders, prepared according to the following steps:

Figure CN106692073AD00041

[0023] 制成1000 瓶 [0023] 1000 bottles made

Figure CN106692073AD00051

[0024] 制剂工艺: [0024] The preparation process:

[0025] 1.浓配:将处方量的左旋奥拉西坦、赋形剂置于容器中,加入左旋奥拉西坦10倍重量份的灭菌注射用水搅拌,溶解后,加入质量分数〇. 1 %的针用活性炭,搅拌30min,随后用0. 45微米微孔滤膜滤过,收集滤液,备用; [0025] 1 with concentrated: the formulation amounts of -oxiracetam, excipients are placed in the vessel, was added 10 parts by -oxiracetam times the weight of sterile water for injection was stirred and dissolved, mass fraction . 1% of the square pin with charcoal, stirred for 30min, followed by 0.45 micron microporous membrane filtration, the filtrate was collected and set aside;

[0026] 2.稀配:向滤液中加入灭菌注射用水至处方量,用盐酸或氢氧化钠调节pH至7. 0, 随后用0. 22微米的微孔滤膜除菌过滤,取滤液检验合格后灌装分装于无菌玻璃瓶中,备用; [0026] 2. Dilute with: the filtrate was added to sterile water for injection prescriptions, with hydrochloric acid or sodium hydroxide to adjust the pH to 7.0, followed by sterilization by filtration with a microporous membrane of 0.22 microns, the filtrate after inspection glass bottles filled in sterile packaging, a spare;

[0027] 3.冷冻干燥:将上述分装于无菌玻璃瓶中的药液置冷冻干燥机中,迅速将温度冷冻至-40°C,整个过程保持180分钟,然后抽真空干燥,以15°C /小时升温至-KTC,-KTC 恒温保持120分钟;以5°C /小时升温至(TC,(TC恒温320分钟;以5°C /小时升温至KTC, KTC恒温240分钟,以KTC /小时升温至30°C,30°C恒温60分钟,同时前箱真空降达到10Pa/10分时,冻干结束; [0027] 3. The freeze-dried: The above dispensed into sterile glass vials of liquid placed in a freeze dryer, the temperature was quickly frozen to -40 ° C, throughout the process kept for 180 minutes and then vacuum dried at 15 ° C / hr to warm to -KTC, -KTC temperature for 120 min; to 5 ° C / hr to warm to (TC, (TC thermostat 320 minutes; at 5 ° C / hr to warm to KTC, KTC thermostat 240 minutes KTC / h warmed to 30 ° C, 30 ° C thermostat for 60 minutes while vacuum drop reaches the headbox 10Pa / 10 min, ending lyophilized;

[0028] 4.乳盖:错塑组合盖需经清洗后灭菌、干燥,然后进行乳盖,即得。 [0028] 4. milk cover: plastic closure assembly for an error after cleaning and sterilizing, drying, and then cover the milk, that is, too.

[0029] 实施例2 [0029] Example 2

[0030] —种左旋奥拉西坦无菌粉末,按以下步骤制得: [0030] - species -oxiracetam sterile powders, prepared according to the following steps:

Figure CN106692073AD00052

[0032] 制成1000 瓶 [0032] 1000 bottles made

[0033] 制剂工艺:照实施例1的制备工艺制得。 [0033] The preparation process: prepared according to Preparation Example 1 to obtain the embodiment.

[0034] 实施例3 [0034] Example 3

[0035] —种左旋奥拉西坦无菌粉末,按以下步骤制得: [0035] - species -oxiracetam sterile powders, prepared according to the following steps:

Figure CN106692073AD00053

[0037] 制成1000 瓶 [0037] 1000 bottles made

Figure CN106692073AD00061

[0038] 制剂工艺:照实施例1的制备工艺制得。 [0038] The preparation process: prepared according to Preparation Example 1 to obtain the embodiment.

[0039] 实施例4-6 :—种左旋奥拉西坦无菌粉末,按以下重量的原辅料制备而得,制备方法同实施例1 : [0039] Examples 4-6: - Species -oxiracetam sterile powders, was prepared to give the following raw materials by weight, the same method of Preparation Example 1:

Figure CN106692073AD00062

[0041] 为了更好的理解本发明,以下通过本发明稳定性试验来进一步阐述发明药物的有益效果,而非对本发明的限制。 [0041] For a better understanding of the invention, the following stability tests by the present invention is further illustrated beneficial effects of the invention the drug, not to limit the present invention.

[0042] 实验一:本发明一种左旋奥拉西坦无菌粉末稳定性实验 [0042] Experiment 1: -oxiracetam present invention provides a sterile powders stability test

[0043] 实验材料: [0043] Experimental materials:

[0044] 注射用的奥拉西坦无菌粉末样品:为实施例1制得 [0044] -oxiracetam sterile powders for injection of the sample: is prepared as described in Example 1

[0045] 加速实验方法:将实施例1制得的奥拉西坦无菌粉末按上市包装,置加速实验箱中,一定时间取样,对考察项目进行检验。 [0045] The accelerated test method: Example 1 was sterile powders -oxiracetam the embodiment according to commercial packaging, box set acceleration test, a certain time sampling inspection of inspection items.

[0046] 加速实验温度:40±2°C [0046] The accelerated test temperature: 40 ± 2 ° C

[0047] 湿度:RH75%±5% [0047] Humidity: RH75% ± 5%

[0048] 考察时间:0、1、2、3、6 月 [0048] study time: 0,1,2,3,6 month

[0049] 考察指标:性状、可见异物、pH、有关物质、含量、无菌检查 [0049] the indexes: traits, visible foreign matter, pH, related substance content, sterility test

[0050] 加速试验稳定性记录: [0050] The accelerated stability test record:

[0051] [0051]

Figure CN106692073AD00071

[0052] 加速实验结果表明:加速6月样品与0月样品各项检测指标质量相当,表明本品加速实验6月,质M保持稳定,本品稳定性$父好。 [0052] The results show that the acceleration: the acceleration detection index sample mass June October sample equivalent accelerated test indicates that the product June, M quality stability, good stability of the product $ parent.

[0053] 长期实验方法:将实施例1制得的奥拉西坦无菌粉末按上市包装,置长期留样箱中,一定时间取样,对考察项目进行检验。 [0053] Long-term experimental procedure: Example 1 was -oxiracetam sterile packaged powder Listing embodiment, the sample is set to stay long box, a certain sampling time of inspection items tested.

[0054] 加速实验温度:25 ± 2 °C [0054] The accelerated test temperature: 25 ± 2 ° C

[0055] 湿度:RH60%±10% [0055] Humidity: RH60% ± 10%

[0056] 考察时间:0、3、6、9、12、18、24 月 [0056] study time: 0,3,6,9,12,18,24 month

[0057] 考察指标:性状、可见异物、pH、有关物质、含量、无菌检查 [0057] the indexes: traits, visible foreign matter, pH, related substance content, sterility test

[0058] 长期试验稳定性记录: [0058] Long-term stability test record:

[0059] [0059]

Figure CN106692073AD00072

[0060] 长期试验表明:本品长期试验24个月性状、可见异物、pH值、有关物质、含量以及无菌检查各项指标均无显著变化,均符合生产用质量标准草案的各项相关规定。 [0060] Long-term tests show: This 24-month long trial traits, visible foreign matter, pH, and related substances, content and sterility test of the indicators did not change significantly, it is in line with the relevant provisions of the draft production quality standards . 本品长期试验24个月质量稳定,故本品货架期最少24个月,长期试验仍在继续考察过程中。 This product is stable for 24 months, long-term trial quality, so this product shelf life of at least 24 months, long-term trials are continuing the process of inspection.

[0061] 实验二:左旋奥拉西坦无菌粉末冷冻干燥过程中喷瓶现象统计 [0061] Experiment II: -oxiracetam sterile powders freeze-drying process statistical phenomenon spray bottle

[0062] 1.试验目的:考擦不同处方在冷冻干燥过程中的喷瓶现象。 [0062] 1. Test Objective: rub test different prescriptions phenomenon spray bottle in a freeze drying process.

[0063] 2.试验方法:统计实施例1样品与对照样品在制备过程中发生喷瓶现象的百分率,对照样品处方见下表: [0063] Test Method 2: Percentage spray bottle phenomenon and control samples in Example 1 occurred during the preparation of statistical embodiments, the control sample formulation in the table below:

Figure CN106692073AD00081

[0068] 4.结论:实施例1样品在冷冻干燥过程中未发生喷瓶现象,而对照样品发生喷瓶现象为27%,故可认为加入谷氨酸钠可有效降低本品发生喷瓶的概率。 [0068] 4. Conclusion: Example 1 samples were not squirt bottle phenomenon occurs in a freeze-drying process, the spray bottle phenomenon occurs the control sample was 27%, it can be considered effective in reducing sodium glutamate spray bottle of the product occurred probability.

Claims (4)

  1. 1. 一种左旋奥拉西坦无菌粉末,其特征在于,它是由下列重量百分比的原辅料制得: 左旋奥拉西坦35%~60%、赋形剂40%~65%,其中所述赋形剂L-丝氨酸、甘露醇、谷氨酸钠的组合物。 A -oxiracetam sterile powders, characterized in that it is the percentage by weight of raw materials following was prepared: -oxiracetam 35% to 60%, 40% to 65% excipient, wherein the excipient L- serine, mannitol, sodium glutamate composition.
  2. 2. 如权利要求1所述的一种左旋奥拉西坦无菌粉末,其特征在于,它是由下列重量百分比的原辅料制得:左旋奥拉西坦42%~52%,L-丝氨酸22%~28%,甘露醇18%~32%,谷氨酸钠4%~12%〇 L- serine -oxiracetam of 42% to 52%: 2. The one -oxiracetam sterile powders according to claim 1, characterized in that it is composed of the following percentages by weight of raw materials prepared 22% ~ 28%, 18% to 32% mannitol, sodium glutamate, 4% to 12% square
  3. 3. 如权利要求1或2所述的左旋奥拉西坦无菌粉末的制备方法,其特征在于,它是按如下步骤制得的: A. 浓配:将处方量的左旋奥拉西坦、赋形剂置于容器中,加入左旋奥拉西坦10倍重量份的灭菌注射用水搅拌,溶解后,加入质量分数0. 1%的针用活性炭,搅拌30min,随后用 3. The method as recited in 12 or -oxiracetam sterile powders claim, characterized in that it is prepared as follows: A. concentrated with: the formulation amounts of -oxiracetam , excipients are placed in the vessel, was added 10 parts by -oxiracetam times the weight of sterile water for injection with stirring and dissolved, and 0.1% (mass fraction) of a needle with charcoal, stirred for 30min, followed by
  4. 0. 45微米微孔滤膜滤过,收集滤液,备用; B. 稀配:向滤液中加入灭菌注射用水至处方量,用盐酸或氢氧化钠调节pH至7. 0,随后用0. 22微米的微孔滤膜除菌过滤,取滤液合格后灌装分装于无菌玻璃瓶中,备用; C. 冷冻干燥:将上述分装于无菌玻璃瓶中的药液置冷冻干燥机中,迅速将温度冷冻至-40°C,整个过程保持180分钟,然后抽真空干燥,以15°C /小时升温至-KTC,-KTC恒温保持120分钟;以5°C /小时升温至(TC,(TC恒温320分钟;以5°C /小时升温至10°C,10°C 恒温240分钟,以10°C /小时升温至30°C,30°C恒温60分钟,同时前箱真空降达到10Pa/10 分时,冻干结束; D. 乳盖:铝塑组合盖需经清洗后灭菌、干燥,然后进行乳盖,即得。 0.45 m microporous membrane filtration, the filtrate was collected, standby; B. Dilute with: To the filtrate was added to sterile water for injection prescriptions, with hydrochloric acid or sodium hydroxide to adjust the pH to 7.0, followed by 0. 22 micron microporous membrane sterilization by filtration, the filtrate after passing the filling dispensed in sterile glass vials, standby; C. freeze drying: the above dispensed into sterile glass vials in the freeze drier is set liquid , the temperature quickly frozen to -40 ° C, throughout the process kept for 180 minutes and then vacuum dried at 15 ° C / hr to warm to -KTC, -KTC temperature for 120 min; to 5 ° C / hr warmed to ( TC, (TC thermostat 320 minutes; at 5 ° C / hr to warm to 10 ° C, 10 ° C thermostat for 240 minutes at 10 ° C / h warmed to 30 ° C, 30 ° C thermostat for 60 minutes while headbox vacuo drop reaches 10Pa / 10 min, ending lyophilized; D. L. cap: cap for an aluminum composition after cleaning and sterilizing, drying, and then cover the milk, that is, too.
CN 201510458344 2015-07-30 2015-07-30 Levo-oxiracetam sterile powder and preparation method thereof CN106692073A (en)

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