WO2014127496A1 - Pantoprazole sodium freeze-dry preparation and preparing method thereof - Google Patents
Pantoprazole sodium freeze-dry preparation and preparing method thereof Download PDFInfo
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- WO2014127496A1 WO2014127496A1 PCT/CN2013/000434 CN2013000434W WO2014127496A1 WO 2014127496 A1 WO2014127496 A1 WO 2014127496A1 CN 2013000434 W CN2013000434 W CN 2013000434W WO 2014127496 A1 WO2014127496 A1 WO 2014127496A1
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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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Definitions
- the present invention relates to a pantoprazole sodium lyophilized preparation and a process for the preparation thereof.
- Pantoprazole is the third proton pump inhibitor listed worldwide after omeprazole and lansoprazole. The drug has high selectivity and bioavailability and is highly recognized by doctors and patients for its high safety in clinical treatment. Pantoprazole was first launched in South Africa in October 1994 by the German big drug factory Byk Gulden. Pantoprazole is a dialkylpyridylbenzimidazole compound clinically used for duodenal ulcer, gastric ulcer, Zhuo's syndrome, and moderate to severe reflux esophagitis. Its advantage lies in the cure rate. High, fast healing.
- Pantoprazole sodium is a selective proton pump inhibitor that can be accumulated in the tubular membrane of gastric mucosal cells and converted into an active metabolite - sulfin Amide.
- the active substance can inhibit the secretion of gastric acid H+ K+-ATPase by gastric parietal cells, and exerts an acid suppression effect.
- Pantoprazole sodium can reduce the basic level of gastric acid and reduce the secretion of gastric acid after meals.
- CN1235018 discloses a pantoprazole sodium lyophilized powder injection and a preparation method thereof, wherein the injection is a lyophilized powder injection containing no crystal water, and the pH value is between 9 and 12.5, and the composition comprises pantoprazole sodium.
- lyophilized powder support agent, metal ion complexing agent and pH adjuster parts by weight of pantoprazole sodium 1 part; lyophilized powder support agent 1 ⁇ 5 parts; metal ion complexing agent 0.05 ⁇ 2 parts.
- the above formula is filtered to remove charcoal, sterilize and fill; first pre-freeze to -55 ⁇ -35 °C, keep warm for 1 ⁇ 4 hours, start vacuuming, raise the temperature to 10 ⁇ 50 °C within 15 ⁇ 30 hours , continue to maintain the vacuum for 3 to 10 hours; nitrogen storage, that is, get a freeze-dried powder injection.
- CN101011397 discloses a pantoprazole sodium freeze-dried powder injection and a preparation method thereof, and the pantoprazole sodium jelly Dry powder injection, pH value 9.5-11.5, the formula includes the following parts by weight ratio: pantoprazole sodium 1 part, support agent 0.5-1 part, weak acid strong base salt 0-0.06 parts, inorganic base amount .
- the preparation method comprises the following steps: 1) according to the following parts by weight ratio: 0.5-1 parts of support agent, 0-0.06 parts of weak acid strong base salt, 1 part of pantoprazole sodium; 2) support agent and The weak acid and alkali salt are dissolved in water for injection, the pH value is adjusted to 9.5-11.5 with an inorganic base, pantoprazole sodium is added, and the pH is adjusted to 9.5-11.5 with an inorganic base after dissolution; 3) filtration; 4) lyophilization, Pantoprazole sodium lyophilized powder injection.
- the powder needle is suitable for diseases such as peptic ulcer bleeding, acute gastric mucosal damage caused by non-body anti-inflammatory drugs, and ulcer bleeding under stress.
- CN1679563 discloses a pantoprazole sodium lyophilized powder injection, which comprises, in parts by weight, 1 part of pantoprazole sodium, 0-0.125 parts of a bismuth agent, and 0.075-0.125 parts of a weak acid strong base salt. Disodium edetate 0.025-0.0375 parts, an appropriate amount of inorganic base. However, if the above-mentioned powder needle is added to the auxiliary material too much, it may cause unknown side effects, and there is a big safety hazard.
- pantoprazole sodium is a white or off-white crystalline powder of pantoprazole sodium, which is pH-dependent for the stability of its aqueous solution of the racemate, and the degradation rate is accelerated with the decrease of pH.
- Pantoprazole sodium is an alkaline drug that is unstable under acidic or neutral conditions. The API is very susceptible to oxidation or degradation, which causes the substance to rise.
- pantoprazole sodium lyophilized preparation which is safe and stable.
- Another object of the present invention is to provide a method for preparing a pantoprazole sodium lyophilized preparation which is simple in preparation process and has less material related to the finished product.
- pantoprazole sodium lyophilized preparation which is prepared by dissolving pantoprazole sodium raw material in water for injection It is prepared by a freeze-drying process after adjusting the pH value to 9.5 to 11.5 with a pH adjuster.
- the pantoprazole sodium lyophilized preparation comprises a metal chelating agent, and the weight ratio of pantoprazole sodium to the metal chelating agent is 1:0.5 to 1.5.
- the metal chelating agent is one or a mixture of mannitol and sodium citrate.
- the pH adjusting agent is a mixture of one or more of tromethamine, meglumine, and sodium phosphate.
- the present invention also discloses a preparation method of pantoprazole sodium lyophilized preparation comprising the following steps -
- the water for injection is cooled to 10 ⁇ 15 Torr, then filled with nitrogen, fully filled with nitrogen, then added with a metal chelating agent, and then added with a cerium adjusting agent to adjust the enthalpy to 9.5 ⁇ 11.5;
- pantoprazole sodium is a basic drug, it is unstable under acidic or neutral conditions, and the API is very susceptible to oxidation or degradation, resulting in an increase in related substances.
- the water for injection is firstly cooled, and then the metal chelating agent is added after fully nitrogen filling, and the pH value is adjusted, and then the raw material pantoprazole sodium is added to ensure that the pantoprazole sodium is not oxidized during the preparation process.
- Degradation greatly improves the stability of pantoprazole sodium lyophilized preparation and reduces the content of related substances.
- Example 1 Preparation of 100 bottles of pantoprazole sodium frozen powder injection using the following materials.
- Pantoprazole sodium 4000mg (based on pantoprazole)
- Preparation method (1) First, the water for injection is cooled to 10 ° C, and then filled with nitrogen, fully filled with nitrogen, then added to the metal chelating agent mannitol, and then added pH regulator sodium phosphate to adjust the pH to 10.5; (2) Weighing the raw material pantoprazole sodium, adding it to the above-mentioned water for injection, and stirring evenly;
- filter membrane diameter of the filter is 0.22um
- Tg - 5 degrees or so.
- pantoprazole sodium lyophilized preparation prepared in the present embodiment is subjected to nitrogen filling and pH adjustment during the preparation process, thereby effectively preventing oxidative degradation of the raw material during the preparation process and improving the stability of the preparation.
- Example 2 Preparation 100 bottles of pantoprazole sodium lyophilized preparation, using the following materials:
- Pantoprazole sodium 4000mg (based on pantoprazole)
- the preparation method was the same as in Example 1.
- the preparation method was the same as in Example 1.
- Example 4 Preparation 100 bottles of pantoprazole sodium lyophilized preparation using the following materials: pantoprazole sodium 4000 mg (based on pantoprazole)
- Meglumine pH adjuster adjusted to ⁇ .5-10.8
- Example 5 Preparation of 100 bottles of pantoprazole sodium frozen powder injection, using the following materials - pantoprazole sodium 4000mg (based on pantoprazole)
- the preparation method of 100 bottles was the same as that of Example 1.
- Test 1 High temperature (60 ° C) stability test.
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Abstract
A pantoprazole sodium freeze-dry preparation and a preparing method thereof. The freeze-dry preparation is prepared by dissolving pantoprazole sodium in water for injection, adjusting the PH value to be 9.5 to 11.5 by using a PH regulator, and performing a freeze-dry process. During the preparing process, the water for injection is first cooled, sufficient nitrogen is filled in and a metal chelator is added, then the PH value is regulated, and pantoprazole sodium is added, which fully ensures that the pantoprazole sodium may not be oxidized or degraded during the preparing process and improves temperature stability of the pantoprazole sodium freeze-dry preparation.
Description
泮托拉唑钠冻干制剂及其制备方法 Pantoprazole sodium lyophilized preparation and preparation method thereof
技术领域 Technical field
[0001] 本发明涉及泮托拉唑钠冻干制剂及其制备方法。 [0001] The present invention relates to a pantoprazole sodium lyophilized preparation and a process for the preparation thereof.
背景技术 Background technique
[0002] 泮托拉唑（Pantoprazole)是继奥美拉唑、 兰索拉唑之后在全球第 3个上市的质子泵抑 制剂。 该药具有较高的选择性和生物利用度， 在临床治疗中以高度的安全性受到医生和患者 的认可。 泮托拉唑于 1994年 10月由德国百克顿 （Byk Gulden) 大药厂在南非首次上市。 泮 托拉唑是一种二烷基吡啶基苯并咪唑化合物， 临床用于十二指肠溃疡、 胃溃疡、 卓艾氏综合 征以及缓解中至重度反流性食管炎， 其优势在于治愈率高、 治愈速度快。 泮托拉唑钠药理作 用机理与特点： 泮托拉唑钠是选择性的质子泵抑 制剂， 服用后可在胃粘膜壁细胞的小管膜中 聚集， 并转换成有活性的代 谢产物 -亚磺酰胺。 该活性物质可抑制刺激胃壁细胞分泌胃酸的 H+ K+-ATP酶， 而发挥抑酸的作用。 泮托拉唑钠即可降低胃酸的基础水平， 又可减少饭后胃 酸的分泌。 夜间及 24hr胃酸分泌， 使 H+减少 90%以上， 24hr保持胃内 pH 4， 泮托拉唑钠 在弱酸环境下比奥美拉唑和兰索拉唑更为稳定， 其生物利用度比奥美拉唑提高 7倍。 对胃的 壁细胞的选择性更专一。 [0002] Pantoprazole is the third proton pump inhibitor listed worldwide after omeprazole and lansoprazole. The drug has high selectivity and bioavailability and is highly recognized by doctors and patients for its high safety in clinical treatment. Pantoprazole was first launched in South Africa in October 1994 by the German big drug factory Byk Gulden. Pantoprazole is a dialkylpyridylbenzimidazole compound clinically used for duodenal ulcer, gastric ulcer, Zhuo's syndrome, and moderate to severe reflux esophagitis. Its advantage lies in the cure rate. High, fast healing. Mechanism and characteristics of pantoprazole sodium pharmacological action: Pantoprazole sodium is a selective proton pump inhibitor that can be accumulated in the tubular membrane of gastric mucosal cells and converted into an active metabolite - sulfin Amide. The active substance can inhibit the secretion of gastric acid H+ K+-ATPase by gastric parietal cells, and exerts an acid suppression effect. Pantoprazole sodium can reduce the basic level of gastric acid and reduce the secretion of gastric acid after meals. Nighttime and 24hr gastric acid secretion, reducing H+ by more than 90%, maintaining intragastric pH 4 at 24hr, pantoprazole sodium is more stable than omeprazole and lansoprazole in a weak acid environment, and its bioavailability is higher than Ogilvy. The carbazole is increased by 7 times. The selectivity to the parietal cells of the stomach is more specific.
[0003] 在现有技术的泮托拉唑钠冻干制剂， 与本发明相关的专利如下： [0003] In the prior art pantoprazole sodium lyophilized preparation, the patents related to the present invention are as follows:
CN1235018公开了一种泮托拉唑钠冻干粉针剂及其制备方法， 所述的针剂为不含结晶水的冻 干粉针剂， pH值在 9〜12.5之间， 组成包括泮托拉唑钠、 冻干粉支持剂、 金属离子络合剂和 pH调节剂， 重量份数为泮托拉唑钠 1份； 冻干粉支持剂 1〜5份； 金属离子络合剂 0.05〜2 份。 上述配方过滤除炭， 除菌， 灌装； 首先预冻至 -55〜- 35°C， 保温 1〜4小时， 开始抽真空， 在 15〜30 小时内， 将温度升至 10〜50°C， 继续保持真空 3〜10小时； 充氮保藏， 即得到冻 干粉针剂。 CN1235018 discloses a pantoprazole sodium lyophilized powder injection and a preparation method thereof, wherein the injection is a lyophilized powder injection containing no crystal water, and the pH value is between 9 and 12.5, and the composition comprises pantoprazole sodium. , lyophilized powder support agent, metal ion complexing agent and pH adjuster, parts by weight of pantoprazole sodium 1 part; lyophilized powder support agent 1~5 parts; metal ion complexing agent 0.05~2 parts. The above formula is filtered to remove charcoal, sterilize and fill; first pre-freeze to -55~-35 °C, keep warm for 1~4 hours, start vacuuming, raise the temperature to 10~50 °C within 15~30 hours , continue to maintain the vacuum for 3 to 10 hours; nitrogen storage, that is, get a freeze-dried powder injection.
[0004] CN101011397公幵了一种泮托拉唑钠冻干粉针剂及其制备方法， 所述的泮托拉唑钠冻
干粉针剂， pH值为 9.5-11.5， 其配方包括下述重量份数比的组分： 泮托拉唑钠 1份， 支持剂 0.5-1份， 弱酸强碱盐 0-0.06份， 无机碱适量。 其制备方法包括以下步骤： 1)按下述重量份数 配比取料： 支持剂 0.5-1份， 弱酸强碱盐 0-0.06份， 泮托拉唑钠 1份； 2)将支持剂和弱酸强碱 盐用注射用水溶解， 用无机碱调 pH值至 9.5-11.5， 加入泮托拉唑钠， 溶解后用无机碱调 pH 值至 9.5-11.5; 3)过滤； 4)冻干， 得到泮托拉唑钠冻干粉针剂。 所述粉针适用于消化性溃疡出 血、非 体类抗炎药引起的急性胃黏膜损伤和应激状态下溃疡大出血等疾病。 CN1679563 公开了一种泮托拉唑钠冻干粉针剂， 按重量份数计， 其组成包括： 泮托拉唑钠 1份， 陚形剂 0-0.125份， 弱酸强碱盐 0.075-0.125份， 依地酸二钠 0.025-0.0375份， 无机碱适量。 但 是， 上述粉针加入辅料过多， 有可能引起未知副作用， 存在较大的安全隐患。 而且泮托拉唑 钠是一种泮托拉唑钠为白色或类白色结晶性粉末， 为其外消旋体水溶液稳定性呈 pH依赖性， 降解速率随 pH 的减小而加快。 泮托拉唑钠为碱性药物， 在酸性或中性条件下不稳定， API 非常容易发生氧化或降解， 导致有关物质会上升。 [0004] CN101011397 discloses a pantoprazole sodium freeze-dried powder injection and a preparation method thereof, and the pantoprazole sodium jelly Dry powder injection, pH value 9.5-11.5, the formula includes the following parts by weight ratio: pantoprazole sodium 1 part, support agent 0.5-1 part, weak acid strong base salt 0-0.06 parts, inorganic base amount . The preparation method comprises the following steps: 1) according to the following parts by weight ratio: 0.5-1 parts of support agent, 0-0.06 parts of weak acid strong base salt, 1 part of pantoprazole sodium; 2) support agent and The weak acid and alkali salt are dissolved in water for injection, the pH value is adjusted to 9.5-11.5 with an inorganic base, pantoprazole sodium is added, and the pH is adjusted to 9.5-11.5 with an inorganic base after dissolution; 3) filtration; 4) lyophilization, Pantoprazole sodium lyophilized powder injection. The powder needle is suitable for diseases such as peptic ulcer bleeding, acute gastric mucosal damage caused by non-body anti-inflammatory drugs, and ulcer bleeding under stress. CN1679563 discloses a pantoprazole sodium lyophilized powder injection, which comprises, in parts by weight, 1 part of pantoprazole sodium, 0-0.125 parts of a bismuth agent, and 0.075-0.125 parts of a weak acid strong base salt. Disodium edetate 0.025-0.0375 parts, an appropriate amount of inorganic base. However, if the above-mentioned powder needle is added to the auxiliary material too much, it may cause unknown side effects, and there is a big safety hazard. Moreover, pantoprazole sodium is a white or off-white crystalline powder of pantoprazole sodium, which is pH-dependent for the stability of its aqueous solution of the racemate, and the degradation rate is accelerated with the decrease of pH. Pantoprazole sodium is an alkaline drug that is unstable under acidic or neutral conditions. The API is very susceptible to oxidation or degradation, which causes the substance to rise.
发明内容 Summary of the invention
[0005] 本发明的目的在于提供一种安全性好、 稳定性好的泮托拉唑钠冻干制剂。 [0005] It is an object of the present invention to provide a pantoprazole sodium lyophilized preparation which is safe and stable.
[0006] 本发明的另一目的在于提供一种制备过程简单， 成品有关物质少的泮托拉唑钠冻干制 剂的制备方法。 Another object of the present invention is to provide a method for preparing a pantoprazole sodium lyophilized preparation which is simple in preparation process and has less material related to the finished product.
[0007] 为了解决背景技术中存在的问题， 实现上述发明目的， 本发明采用了如下技术方案： 泮托拉唑钠冻干制剂， 该冻干制剂由泮托拉唑钠原料溶于注射用水后， 用 PH值调节剂调节 PH值为 9.5~11.5后经冻干工艺制备得到。 [0007] In order to solve the problems in the prior art, to achieve the above object, the present invention adopts the following technical solution: a pantoprazole sodium lyophilized preparation, which is prepared by dissolving pantoprazole sodium raw material in water for injection It is prepared by a freeze-drying process after adjusting the pH value to 9.5 to 11.5 with a pH adjuster.
[0008] 所述的泮托拉唑钠冻干制剂， 包括金属螯合剂， 且泮托拉唑钠和金属螯合剂的重量比 为 1 :0.5〜1.5。 [0008] The pantoprazole sodium lyophilized preparation comprises a metal chelating agent, and the weight ratio of pantoprazole sodium to the metal chelating agent is 1:0.5 to 1.5.
[0009] 所述的金属螯合剂为甘露醇、 柠檬酸钠中的一种或两种混合。 [0009] The metal chelating agent is one or a mixture of mannitol and sodium citrate.
[0010] 所述的 PH调节剂为氨丁三醇、 葡甲胺、 磷酸钠中的一种或多种混合。
[0011] 本发明还公开了泮托拉唑钠冻干制剂的制备方法包括如下步骤-[0010] The pH adjusting agent is a mixture of one or more of tromethamine, meglumine, and sodium phosphate. [0011] The present invention also discloses a preparation method of pantoprazole sodium lyophilized preparation comprising the following steps -
( 1 ) 首先将注射用水冷却至 10~15Ό， 再充入氮气， 充分充氮气后加入金属螯合剂， 再加入 ΡΗ调节剂调节 ΡΗ值至 9.5~11.5； (1) First, the water for injection is cooled to 10~15 Torr, then filled with nitrogen, fully filled with nitrogen, then added with a metal chelating agent, and then added with a cerium adjusting agent to adjust the enthalpy to 9.5~11.5;
(2 ) 称取原料泮托拉唑钠， 加入到上述注射用水中， 搅拌均匀； (2) Weighing the raw material pantoprazole sodium, adding it to the above-mentioned water for injection, and stirring evenly;
(3 ) 过滤除菌； (3) filtration sterilization;
(4) 分装在西林瓶中， 置于冷冻干燥设备中冷冻干燥即得。 (4) Dispense in a vial and freeze-dry in a freeze-drying equipment.
(0012】 步骤 （3 ) 过滤除菌的滤膜孔径为 0.22um。 (0012) Step (3) The filtration membrane diameter of the filter was 0.22 um.
[0013] 由于泮托拉唑钠为碱性药物， 在酸性或中性条件下不稳定， API非常容易发生氧化或 降解， 导致有关物质会上升。 本发明在制备过程中首先将注射用水冷却， 然后充分充氮后加 入金属螯合剂， 调节 PH值后再加入原料泮托拉唑钠， 充分保障泮托拉唑钠在制备过程中不 被氧化或降解， 极大地提高了泮托拉唑钠冻干制剂的稳定性， 降低有关物质的含量。 [0013] Since pantoprazole sodium is a basic drug, it is unstable under acidic or neutral conditions, and the API is very susceptible to oxidation or degradation, resulting in an increase in related substances. In the preparation process, the water for injection is firstly cooled, and then the metal chelating agent is added after fully nitrogen filling, and the pH value is adjusted, and then the raw material pantoprazole sodium is added to ensure that the pantoprazole sodium is not oxidized during the preparation process. Degradation greatly improves the stability of pantoprazole sodium lyophilized preparation and reduces the content of related substances.
具体实施方式 detailed description
[0014] 下面通过具体实施例对本发明做进一步的说明， 但本发明的保护范围并不为实施例所 限。 The invention is further illustrated by the following specific examples, but the scope of the invention is not limited by the embodiments.
[0015] 实施例 1 : 制备 100瓶泮托拉唑钠冻千粉针剂， 采用如下物料。 [0015] Example 1: Preparation of 100 bottles of pantoprazole sodium frozen powder injection using the following materials.
[0016] 泮托拉唑钠 4000mg (以泮托拉唑计） [0016] Pantoprazole sodium 4000mg (based on pantoprazole)
甘露醇 4000mg Mannitol 4000mg
磷酸钠 pH调节剂， 调到 ρΗΙΟ.5-10.8 Sodium phosphate pH adjuster, adjusted to ρΗΙΟ.5-10.8
注射用水 100ml 氮气 适量 Water for injection 100ml nitrogen
制成 100瓶 Made into 100 bottles
制备方法： （1 ) 首先将注射用水冷却至 10°C， 再充入氮气， 充分充氮气后加入金属螯合剂甘 露醇， 再加入 PH调节剂磷酸钠调节 PH值至 10.5;
(2 ) 称取原料泮托拉唑钠， 加入到上述注射用水中， 搅拌均匀； Preparation method: (1) First, the water for injection is cooled to 10 ° C, and then filled with nitrogen, fully filled with nitrogen, then added to the metal chelating agent mannitol, and then added pH regulator sodium phosphate to adjust the pH to 10.5; (2) Weighing the raw material pantoprazole sodium, adding it to the above-mentioned water for injection, and stirring evenly;
(3 ) 过滤除菌， 过滤除菌的滤膜孔径为 0.22um; (3) filtration sterilization, filter membrane diameter of the filter is 0.22um;
(4) 分装在西林瓶中， 置于冷冻干燥设备中冷冻干燥即得； (4) Packed in a vial and placed in a freeze-drying device for freeze-drying;
注射用泮托拉唑钠冻干工艺参数表 Process parameters of pantoprazole sodium freeze-dried for injection
Tg:- 5度左右。 Tg: - 5 degrees or so.
[0017] 本实施例制备得到的泮托拉唑钠冻干制剂， 在制备过程中对注射用水进行了充氮、 调 节 PH值， 有效地防止在制备过程中原料被氧化降解， 提高制剂的稳定性， 降低有关物质的 [0017] The pantoprazole sodium lyophilized preparation prepared in the present embodiment is subjected to nitrogen filling and pH adjustment during the preparation process, thereby effectively preventing oxidative degradation of the raw material during the preparation process and improving the stability of the preparation. Sexuality
[0018] 实施例 2: 制备 100瓶泮托拉唑钠冻干制剂， 采用如下物料： Example 2: Preparation 100 bottles of pantoprazole sodium lyophilized preparation, using the following materials:
泮托拉唑钠 4000mg (以泮托拉唑计） Pantoprazole sodium 4000mg (based on pantoprazole)
甘露醇 4000mg
葡甲胺 pH调节剂， 调到 ρΗΙΟ.5-10.8 Mannitol 4000mg Meglumine pH adjuster, adjusted to ρΗΙΟ.5-10.8
注射用水 100ml Water for injection 100ml
氮气 适量 Nitrogen
制成 100瓶 Made into 100 bottles
制备方法和实施例 1相同。 The preparation method was the same as in Example 1.
[0019] 实施例 3: 制备 100瓶泮托拉唑钠冻千制剂， 采用如下物料： 泮托拉唑钠 4000mg (以泮托拉唑计） Example 3: Preparation 100 bottles of pantoprazole sodium frozen preparations were prepared using the following materials: pantoprazole sodium 4000 mg (based on pantoprazole)
甘露醇 2000mg Mannitol 2000mg
柠檬酸钠 2000mg Sodium citrate 2000mg
磷酸钠 pH调节剂， 调到 ρΗΙΟ.5-10.8 Sodium phosphate pH adjuster, adjusted to ρΗΙΟ.5-10.8
注射用水 100ml Water for injection 100ml
氮气 适量 Nitrogen
制成 100瓶 Made into 100 bottles
制备方法和实施例 1相同。 The preparation method was the same as in Example 1.
[0020] 实施例 4: 制备 100瓶泮托拉唑钠冻干制剂， 采用如下物料： 泮托拉唑钠 4000mg (以泮托拉唑计） Example 4: Preparation 100 bottles of pantoprazole sodium lyophilized preparation using the following materials: pantoprazole sodium 4000 mg (based on pantoprazole)
甘露醇 2000mg Mannitol 2000mg
柠檬酸钠 2000mg Sodium citrate 2000mg
葡甲胺 pH调节剂， 调到 ρΗΙΟ.5-10.8 Meglumine pH adjuster, adjusted to ρΗΙΟ.5-10.8
注射用水 100ml Water for injection 100ml
氮气 适量 Nitrogen
制成 100瓶 Made into 100 bottles
制备方法和实施例 1相同。
[0021] 实施例 5: 制备 100瓶泮托拉唑钠冻千粉针剂， 采用如下物料- 泮托拉唑钠 4000mg (以泮托拉唑计） The preparation method was the same as in Example 1. Example 5: Preparation of 100 bottles of pantoprazole sodium frozen powder injection, using the following materials - pantoprazole sodium 4000mg (based on pantoprazole)
磷酸钠 pH调节剂， 调到 ρΗΙΟ.5-10.8 注射用水 100ml Sodium phosphate pH adjuster, adjusted to ρΗΙΟ.5-10.8 water for injection 100ml
氮气 适量 Nitrogen
制成 100瓶 制备方法和实施例 1相同。 The preparation method of 100 bottles was the same as that of Example 1.
[0022] [0022]
试验 1 : 高温 （60°C ) 稳定性试验。 Test 1: High temperature (60 ° C) stability test.
[0023] 取实施例 1~4的注射用泮托拉唑钠各 1批样品， 分别置 60°C的电热恒温鼓风干燥箱 放置 10天， 于第 5天和第 10天取样， 按稳定性重点考察项目进行检测。 同时取 RLD进行对 照试验。 [0023] Take one batch of each sample of pantoprazole sodium for injection in Examples 1 to 4, and place them in an electric heating constant temperature blast oven at 60 ° C for 10 days, and sample on the 5th and 10th days, according to the stability. Sexual focus on the project for testing. At the same time, the RLD was taken for the control test.
[0024]
[0024]
mm 有纖 16 (%) 含簠 驄 Mm with fiber 16 (%) with 簠 骢
性状 PH c D-t ε 未知 Character PH c D-t ε unknown
幽 ( %) A B Quiet (%) A B
1%) 1%)
NO ND ND ND 032 NO ND ND ND 032
0天 9 60 2.5 006 006 98.0 0 days 9 60 2.5 006 006 98.0
魏例 NO NO NO D 0.48 Wei case NO NO NO D 0.48
5天 9.58 2,7 0 06 006 97,5 5 days 9.58 2,7 0 06 006 97,5
1 m 1 m
ND 0.21 NO 0,05 ND 0.21 NO 0,05
10天 9.55 2,8 0.10 0,05 97.3 10 days 9.55 2,8 0.10 0,05 97.3
0天 9.53 1,7 0.05 0,05 NO ND NO NO o.to 99.3 0 days 9.53 1,7 0.05 0,05 NO ND NO NO o.to 99.3
m m
5夭 9.57 1.9 0.07 005 NO NO NO 00Θ 058 99.0 5夭 9.57 1.9 0.07 005 NO NO NO 00Θ 058 99.0
10天 9.49 2,0 ND 0.16 ND 0,14 0.75 98.5 10 days 9.49 2,0 ND 0.16 ND 0,14 0.75 98.5
0.10 006 0.10 006
0天 9.67 1 9 NO ND ND NO 0 11 97.6 0 days 9.67 1 9 NO ND ND NO 0 11 97.6
0 06 0,06 0 06 0,06
5天 9.64 2,0 0.12 0.10 ND ND ND NO 036 97.2 5 days 9.64 2,0 0.12 0.10 ND ND ND NO 036 97.2
3 3
1(]夭 鎩舰 9.64 2.2 0.16 0 12 ND NO NO ND 058 97.0 1(]夭 铩 9.64 2.2 0.16 0 12 ND NO NO ND 058 97.0
HD NO NO NO 0 12 98.9 HD NO NO NO 0 12 98.9
0天 9.6f 2,1 0.06 006 0 days 9.6f 2,1 0.06 006
m ND ND NO 0.11 98.6 m ND ND NO 0.11 98.6
5天 m& 955 2,0 0.12 0,10 5 days m& 955 2,0 0.12 0,10
4 4
I碰 ND 0.13 ND 0 15 0.94 984 I touch ND 0.13 ND 0 15 0.94 984
10夭 9 58 2.3 0.16 0 15 10夭 9 58 2.3 0.16 0 15
NO 0.32 ND NO 033 95.4 NO 0.32 ND NO 033 95.4
0夭 9.61 2J 0.03 NO 0夭 9.61 2J 0.03 NO
LD LD
ND 1.23 ND 1.22 256 94.3 ND 1.23 ND 1.22 256 94.3
10天 9,58 2.3 0.10 NO 备注： ND表示未检出 高温稳定性试验结果表明： 本发明实施例所得药品在 60Ό高温稳定性考察合格。 [0025] 试验 2: 加速稳定性考察试验。 10 days 9,58 2.3 0.10 NO Remarks: ND means not detected. The results of the high temperature stability test show that: the obtained medicines of the examples of the present invention have passed the high temperature stability test at 60 。. [0025] Test 2: Accelerated stability test.
[0026] 取上述实施例 1~4处方的注射用泮托拉唑钠各 1批样品，分别置恒温恒湿箱 (温度 40'C ±2°C， 相对湿度 75%±5%) 内， 放置 3个月。 于第 1、 2、 3、 3个月取样进行检测。 [0027]
处雄 樣 [0026] Take one batch of each sample of pantoprazole sodium for injection prepared in the above Examples 1 to 4, and respectively set them in a constant temperature and humidity chamber (temperature 40'C ± 2 ° C, relative humidity: 75% ± 5%). Place for 3 months. Samples were taken for testing at 1, 2, 3, and 3 months. [0027] Male
性棱 OH C E 細 MM mm C%> A B Sexual edge OH C E fine MM mm C%> A B
{%) {%)
ND ND ND ND 0.11 o天 3,60 25 0,06 0,06 98.0 ND ND ND ND 0.11 o days 3,60 25 0,06 0,06 98.0
NO NO NO ND 0.28 NO NO NO ND 0.28
1 958 26 0.06 0.05 98.2 m 1 958 26 0.06 0.05 98.2 m
1 NO 0.11 ND ND 040 1 NO 0.11 ND ND 040
2月 2,6 0.06 0,06 97,6 February 2,6 0.06 0,06 97,6
ND 0,28 NO ND 0.78 ND 0,28 NO ND 0.78
3月 9,64 2 7 o.oe 0.06 97.5 March 9,64 2 7 o.oe 0.06 97.5
S 53 1 ? 0.05 0.05 NO MO NO ND 0-10 99.3S 53 1 ? 0.05 0.05 NO MO NO ND 0-10 99.3
0天 0 days
9,55 1.9 0.06 0.05 ND ND NO ND 035 99,2 9,55 1.9 0.06 0.05 ND ND NO ND 035 99,2
1 1
m m
2 9.61 1 8 0.05 0,06 NO 0.14 NO 0.03 0J61 99.4 2 9.61 1 8 0.05 0,06 NO 0.14 NO 0.03 0J61 99.4
2月 February
贜繊 9.52 2,0 0 07 0 5 ND 0.26 ND O OS OS? 99.0 贜繊 9.52 2,0 0 07 0 5 ND 0.26 ND O OS OS? 99.0
3 i 3 i
3,6? 1.9 ND MO NO NO 97.6 3,6? 1.9 ND MO NO NO 97.6
0天 006 O.OS 0 days 006 O.OS
1 9 ND NO NO ND 048 97,5 月 0.0? 0,09 1 9 ND NO NO ND 048 97, May 0.0? 0,09
3 9.64 2,1 NO 0,08 ND NO om 97.2 3 9.64 2,1 NO 0,08 ND NO om 97.2
2月 0.09 0.08 龃條 9.68 0J2 0.10 ND 0,20 NO NO OSS 97.9February 0.09 0.08 9. 9.68 0J2 0.10 ND 0,20 NO NO OSS 97.9
3月 i 1 >t i¾h 2 2 March i 1 >t i3⁄4h 2 2
ND NO NO ND 012 98.9 ND NO NO ND 012 98.9
0天 9,61 2,1 0.06 0.06 0 days 9,61 2,1 0.06 0.06
ND NO ND 003 045 98,5 月 9,60 2.2 0,08 0.08 ND NO ND 003 045 98, May 9,60 2.2 0,08 0.08
mm Mm
4 ND 0.21 NO 0.05 cm 98.4 4 ND 0.21 NO 0.05 cm 98.4
2月 0J3 2,2 0.12 0,09 龃繊 NO 0,31 ND 0,10 036 98,1 February 0J3 2,2 0.12 0,09 龃繊 NO 0,31 ND 0,10 036 98,1
3 M 959 2.3 0.15 0.12 备注： ND表示未检出 从实验结果来看， 本发明实施例所得样品在 3个月加速稳定性考察中合格。
3 M 959 2.3 0.15 0.12 Remarks: ND indicates no detection From the experimental results, the samples obtained in the examples of the present invention passed the 3-month accelerated stability test.
Claims
1. 泮托拉唑钠冻干制剂， 其特征在于该冻干制剂由泮托拉唑钠原料溶于注射用水后， 用 PH 值调节剂调节 PH值为 9.5~11.5后经冻干工艺制备得到。 A pantoprazole sodium lyophilized preparation, characterized in that the lyophilized preparation is prepared by dissolving a pantoprazole sodium raw material in water for injection, adjusting a pH value of 9.5 to 11.5 with a pH adjuster, and preparing by a freeze-drying process. .
2. 根据权利要求 1所述的泮托拉唑钠冻干制剂， 其特征在于包括金属螯合剂， 且泮托拉唑钠 和金属螯合剂的重量比为 1 :0.5~1.5。 The pantoprazole sodium lyophilized preparation according to claim 1, which comprises a metal chelating agent, and the weight ratio of pantoprazole sodium to the metal chelating agent is 1:0.5 to 1.5.
3. 根据权利要求 2所述的泮托拉唑钠冻干制剂， 其特征在于所述的金属螯合剂为甘露醇、 柠 檬酸钠中的一种或两种混合。 The pantoprazole sodium lyophilized preparation according to claim 2, wherein the metal chelating agent is one or a mixture of mannitol and sodium citrate.
4. 根据权利要求 1所述的泮托拉唑钠冻干制剂， 其特征在于所述的 PH调节剂为氨丁三醇、 葡甲胺、 磷酸钠中的一种或多种混合。 The pantoprazole sodium lyophilized preparation according to claim 1, wherein the pH adjusting agent is one or more of a mixture of tromethamine, meglumine, and sodium phosphate.
5. 根据权利要求 1〜4任何一项所述的泮托拉唑钠冻干制剂的制备方法， 其特征在于包括如下 歩骤： The method for preparing a pantoprazole sodium lyophilized preparation according to any one of claims 1 to 4, which comprises the following steps:
( 1 ) 首先将注射用水冷却至 10~15'C， 再充入氮气， 充分充氮气后加入金属螯合剂， 再加入 PH调节剂调节 PH值至 9.5~11.5; (1) First, the water for injection is cooled to 10~15'C, and then filled with nitrogen. After fully filling with nitrogen, the metal chelating agent is added, and then the pH adjuster is added to adjust the pH to 9.5~11.5 ;
(2 ) 称取原料泮托拉唑钠， 加入到上述注射用水中， 搅拌均匀； (2) Weighing the raw material pantoprazole sodium, adding it to the above-mentioned water for injection, and stirring evenly;
( 3 ) 过滤除菌； (3) Filtration sterilization;
(4 ) 分装在西林瓶中， 置于冷冻干燥设备中冷冻干燥即得。 (4) Dispense in a vial and freeze-dry in a freeze-drying equipment.
6. 根据权利要求 5所述的泮托拉唑钠冻干制剂的制备方法， 其特征在于步骤 （3 ) 过滤除菌 的滤膜孔径为 0.22um。
The method for preparing a pantoprazole sodium lyophilized preparation according to claim 5, wherein the step (3) filter-filtering membrane pore size is 0.22 um.
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| CN105193745A (en) * | 2015-09-18 | 2015-12-30 | 康普药业股份有限公司 | Pantoprazole sodium freeze-drying medicine composition for injection and preparation method thereof |
| CN113041226A (en) * | 2021-03-29 | 2021-06-29 | 海南锦瑞制药有限公司 | Preparation process of pantoprazole sodium for injection |
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| CN111202715A (en) * | 2018-11-19 | 2020-05-29 | 浙江长典医药有限公司 | Preparation method of pantoprazole sodium for injection |
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| CN1235018A (en) * | 1999-04-22 | 1999-11-17 | 沈阳东宇药业有限公司 | Preparation of freeze-dried pantoprazole injection and preparing method thereof |
| CN1476335A (en) * | 2000-11-22 | 2004-02-18 | ��̹��ҽҩ��˾ | Freeze-dried pantoprazole preparation and pantoprazole injection |
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| CN1235018A (en) * | 1999-04-22 | 1999-11-17 | 沈阳东宇药业有限公司 | Preparation of freeze-dried pantoprazole injection and preparing method thereof |
| CN1476335A (en) * | 2000-11-22 | 2004-02-18 | ��̹��ҽҩ��˾ | Freeze-dried pantoprazole preparation and pantoprazole injection |
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| CN105193745A (en) * | 2015-09-18 | 2015-12-30 | 康普药业股份有限公司 | Pantoprazole sodium freeze-drying medicine composition for injection and preparation method thereof |
| CN113041226A (en) * | 2021-03-29 | 2021-06-29 | 海南锦瑞制药有限公司 | Preparation process of pantoprazole sodium for injection |
| CN113041226B (en) * | 2021-03-29 | 2022-10-14 | 海南锦瑞制药有限公司 | Preparation process of pantoprazole sodium for injection |
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