WO2016202212A2 - 一种采用粒子过程晶体产品分子组装与形态优化技术制备的奥美拉唑钠化合物及其制剂 - Google Patents

一种采用粒子过程晶体产品分子组装与形态优化技术制备的奥美拉唑钠化合物及其制剂 Download PDF

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WO2016202212A2
WO2016202212A2 PCT/CN2016/085299 CN2016085299W WO2016202212A2 WO 2016202212 A2 WO2016202212 A2 WO 2016202212A2 CN 2016085299 W CN2016085299 W CN 2016085299W WO 2016202212 A2 WO2016202212 A2 WO 2016202212A2
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omeprazole
omeprazole sodium
hours
temperature
compound
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WO2016202212A3 (zh
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陶灵刚
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Tianjin University
Hainan Lingkang Pharmaceutical Co Ltd
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Tianjin University
Hainan Lingkang Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • A61K9/14—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

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to an omeprazole sodium compound prepared by using molecular assembly and shape optimization technology of a particle process crystal product and a preparation thereof.
  • Omeprazole sodium chemical name: 5-methoxy-2- ⁇ [(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl]-sulfinyl ⁇ -1H - Benzimidazole sodium, having the formula C 17 H 18 N 3 NaO 3 S, molecular weight: 367.41.
  • Omeprazole sodium was the first proton pump inhibitor to be marketed and was successfully developed by Astra Pharmaceuticals of Sweden. It was first marketed in Switzerland in 1988 under the trade name “Antra”. In 1989, he entered the US market for the treatment of duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome under the trade name "Losec”. Its principle of action is that omeprazole is a weakly alkaline substance that is concentrated and converted into an active form in the acidic environment of parietal cells to inhibit H + and K + -ATPase.
  • omeprazole sodium there is no adverse reaction after administration of omeprazole sodium, and it has no effect on liver and kidney function. Therefore, the drug has the characteristics of high cure rate, less side effects, convenient medication, etc. It is the best drug for treating peptic ulcer at home and abroad, and is also the most promising anti-ulcer drug.
  • CN 102827147 is obtained by dissolving sodium omeprazole in water, adding a mixed solution of acetone and isopropyl alcohol, and separating and separating.
  • CN 102351846 is obtained by dissolving sodium omeprazole in water, adding isopropanol crystals and separating.
  • isopropanol and sodium hydroxide are added to an aqueous solution of omeprazole, and B-type omeprazole sodium salt is added thereto to induce crystallization and separation.
  • omeprazole sodium In the preparation of omeprazole sodium, omeprazole sodium has different crystal forms, and temperature, solvent, external force, additives and other factors will affect the formation and purity of crystals to varying degrees.
  • the different crystal forms prepared in the above patents are all omeprazole sodium monohydrate, either improved in stability or improved in terms of wettability, but their performance is improved unilaterally. limitation.
  • an omegaprazole sodium anhydrous compound is obtained by using molecular assembly and morphology optimization technology of a particle process crystal product, and the compound has the characteristics of high purity, good fluidity, low hygroscopicity and good stability.
  • the omeprazole sodium pharmaceutical composition is prepared by using the omeprazole sodium compound as a raw material. The preparation of the preparation does not require any excipients and has better stability than the prior art, thereby completing the present invention.
  • a first object of the present invention is to provide a omeprazole sodium compound prepared by molecular assembly and morphology optimization technology of a particle process crystal product, which has high purity, good fluidity, low hygroscopicity and stability. Good characteristics are easy to handle during the production of APIs and preparation of preparations. In addition, the compound is easy to filter and dry, has high purity, and is suitable as a drug substance.
  • the omeprazole sodium compound can be as pure as 99.8%.
  • the preparation of the omeprazole sodium compound of the present invention comprises the following steps:
  • Omeprazole is added to methanol to stir and dissolve completely, and it is added to a certain amount of sodium hydroxide aqueous solution, and stirred and dissolved by stirring to obtain a omeprazole sodium salt solution.
  • the stirring temperature is 30 to 40 ° C for 2 to 3 hours.
  • the organic solvent is an ester solvent (such as ethyl acetate), an ether solvent (such as diethyl ether, tetrahydrofuran), a halogenated hydrocarbon solvent (such as dichloromethane, chloroform), and a nitro group.
  • an ester solvent such as ethyl acetate
  • an ether solvent such as diethyl ether, tetrahydrofuran
  • a halogenated hydrocarbon solvent such as dichloromethane, chloroform
  • a nitro group such as a hydrocarbon solvent (nitromethane, nitroethane) alkane solvent (such as methanol, isoamyl alcohol) and a ketone solvent (such as acetone). More preferably, any two of acetone, nitromethane, and isoamyl alcohol are combined.
  • the volume ratio of the two solvents is 1:3 to 1:8.
  • the temperature at which the organic solvent is added to the aqueous solution of omeprazole is 20 to 30 ° C, and the stirring speed is 40 to 50 rpm.
  • the volume ratio of the omeprazole salt solution to the organic solvent is 1:1 to 1:5.
  • the crystal formation process is controlled to be stirred at 10 to 20 ° C for 2.0 hours, then at 5 to 10 ° C for 2.5 hours, and then allowed to stand for 5 hours.
  • the detergent is an oxygen-containing aliphatic hydrocarbon derivative or a mixture thereof or an alkane or an ether. It mainly includes fatty acids, fatty alcohols or ketones and a mixture of two or more solvents.
  • the fatty acid is formic acid or acetic acid;
  • the fatty alcohol is methanol, ethanol, propanol, isopropanol, n-butanol or isobutanol;
  • the ketone is acetone, isobutyl ketone or methyl ethyl ketone;
  • the ether is diethyl ether. More preferably, any one or a combination of two of propanol, methanol, and diethyl ether is used.
  • the washed product is dried under vacuum, and the drying time is 3 to 8 hours, and the drying temperature is 30 to 40 °C.
  • the omeprazole sodium compound is prepared by molecular assembly and morphological optimization techniques of a particle process crystal product.
  • the specific step is to add omeprazole to methanol, stir and dissolve completely, and add it to a certain amount of sodium hydroxide solution.
  • the mixture is stirred and dissolved at 30 to 40 ° C for 2 to 3 hours to obtain a omeprazole sodium salt solution, and the organic solvent 1 is slowly added thereto at a temperature of 20 to 30 ° C and a rotation speed of 40 to 50 rpm.
  • Stir 10 to 20 ° C for 2.0 hours. It was further stirred at 5 to 10 ° C for 2.5 hours and then allowed to stand for 5 hours.
  • the mixture is filtered, washed with an organic solvent 2, dried under vacuum, dried for 3 to 8 hours, and dried at a temperature of 30 to 40 ° C to obtain a omeprazole sodium compound.
  • a second object of the present invention is to provide a process for preparing a pharmaceutical composition of omeprazole sodium containing the omeprazole sodium compound of the present invention, which has the following characteristics: the preparation process is simple and does not require any shaping It has better stability than previous products.
  • the preparation method of the omeprazole sodium pharmaceutical composition of the invention comprises the following steps:
  • the metal ion complexing agent is weighed and dissolved in water for injection, stirred and dissolved. Control the water temperature below 35 ° C, add omeprazole sodium, stir at room temperature to dissolve, adjust the pH to 10 ⁇ 12 with pH adjuster, add water for injection to the full amount, stir well, add activated carbon, stir at room temperature for 20 minutes .
  • the charcoal was filtered using a 0.5 ⁇ m or 0.65 ⁇ m titanium rod. 0.45 ⁇ m and 0.22 ⁇ m microporous membranes were connected in series, finely filtered, and dispensed.
  • the sample is placed in a lyophilization box that has been cooled to -40 ° C, and the sample is cooled rapidly by cooling.
  • the sample temperature drops to -40 ° C, it is kept for 3 to 5 hours, the condenser is cooled, vacuum is applied, and the temperature of the condenser is to be
  • the shelf is heated, the sample is slowly heated, and the temperature is raised to 0 ° C at a rate of 3 ° C / h.
  • the temperature is rapidly raised to 30 ° C and maintained for 3 to 6 hours.
  • the entire lyophilization process was carried out for about 30 hours to prepare a lyophilized powder of omeprazole sodium.
  • the omeprazole sodium pharmaceutical composition of the present invention comprises the omeprazole sodium compound of the present invention and a common injection adjuvant comprising a metal ion complexing agent and a pH adjusting agent.
  • the metal ion complexing agent is sodium edetate, ethylenediaminetetraacetic acid, monosodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate or the like, but is not limited thereto.
  • the pH adjuster is sodium citrate, anhydrous sodium carbonate, sodium hydroxide or the like, but is not limited thereto.
  • the pharmaceutical composition is a lyophilized powder prepared by freeze-drying a omeprazole sodium compound and a pharmaceutically acceptable adjuvant.
  • the omeprazole sodium pharmaceutical composition comprises 20 to 60 parts by weight of omeprazole sodium (based on omeprazole) by weight.
  • the omeprazole sodium pharmaceutical composition comprises 1 to 2 parts by weight of the metal ion complexing agent in parts by weight.
  • the pH adjusting agent is in a pharmaceutical grade and after the addition, the pH of the solution before filling according to the invention is in the range of 10 to 12, and the solution is diluted to ensure a pH value in the range of 10.0 to 11.5. Just inside.
  • the sample is placed in a lyophilization box that has been cooled to -40 ° C, and the sample is cooled rapidly by cooling.
  • the sample temperature drops to -40 ° C, it is kept for 4 hours, the condenser is cooled, evacuated, and the temperature and vacuum of the condenser are to be
  • the shelf was heated, the sample was slowly warmed, and the temperature was raised to 0 ° C at a rate of 3 ° C / h. After the sample was drained, the temperature was rapidly raised to 30 ° C and held for 5 hours.
  • the entire lyophilization process was carried out for about 32 hours to prepare a lyophilized powder of omeprazole sodium.
  • the sample is placed in a lyophilization box that has been cooled to -40 ° C, and the sample is cooled rapidly by cooling.
  • the sample temperature drops to -40 ° C, it is kept for 3 hours, the condenser is cooled, evacuated, and the temperature and vacuum of the condenser are to be
  • the shelf was heated, the sample was slowly warmed, and the temperature was raised to 0 ° C at a rate of 3 ° C / h. After the sample was drained, the temperature was rapidly raised to 30 ° C and held for 5 hours.
  • the entire lyophilization process was carried out for about 30 hours to prepare a lyophilized powder of omeprazole sodium.
  • the sample is placed in a lyophilization box that has been cooled to -40 ° C, and the sample is cooled rapidly by cooling.
  • the sample temperature drops to -40 ° C, it is kept for 4 hours, the condenser is cooled, evacuated, and the temperature and vacuum of the condenser are to be
  • the shelf was heated, the sample was slowly warmed, and the temperature was raised to 0 ° C at a rate of 3 ° C / h. After the sample was drained, the temperature was rapidly raised to 30 ° C and held for 5 hours.
  • the entire lyophilization process was carried out for about 32 hours to prepare a lyophilized powder of omeprazole sodium.
  • omeprazole sodium compound was prepared according to the method described in CN1261362A.
  • omeprazole 120 g was dissolved in 26.7 g of water, 480 ml of isopropanol and 13.2 g of sodium hydroxide were added thereto, and stirred at room temperature for 40 minutes, and the resulting solution was filtered, and the filtrate was filtered with isopropanol. washing. The isopropanol wash was combined with the previous isopropanol solution. 6 g of B-type omeprazole sodium was dissolved in 25 ml of isopropanol for seeding, added to the above combined solution, stirring was continued for 25 hours, and the product was filtered and dried at 40 ° C to obtain omeprazole sodium compound. .
  • omeprazole sodium compound was prepared according to the method described in CN102827147A.
  • omeprazole sodium was dissolved in 200 ml of water to obtain 0.21 g/ml of an aqueous solution of omeprazole sodium, which was filtered.
  • the filtrate was added to a mixed solution of 4.1 L of acetone and isopropanol (1:3.5 by volume). After the addition of the filtrate, the temperature was lowered to 3 ° C, and the crystals were stirred for 10 minutes. After filtration, the filter cake was washed with water and spray dried. To obtain the omeprazole sodium compound.
  • the omeprazole sodium pharmaceutical composition was prepared using the sodium omeprazole sodium compound prepared in Comparative Example 2 according to the method described in CN102827147A.
  • the present inventors studied the hygroscopicity of the omeprazole sodium compound prepared in Example 1 of the present invention and Comparative Example 1-4.
  • the conditions of investigation were a relative humidity of 75% (RH) and a relative humidity of 92.5% (RH), and a temperature of 40 ° C, and the index was the water content in the omeprazole sodium compound.
  • the omeprazole sodium compound prepared by the present invention has significantly lower hygroscopicity than the omeprazole sodium compound prepared by the prior art.
  • the omeprazole sodium compound of the present invention has good stability and is suitable for the manufacture and long-term storage of pharmaceutical preparations.
  • the present inventors studied the fluidity of omeprazole sodium prepared in Examples 1 and 2 and Comparative Examples 1-4 of the present invention.
  • Example Height H Radius r Angle of repose ⁇ Example 1 30mm 59.0mm 27.0°
  • Example 2 30mm 58.5mm 27.1° Comparative example 1 30mm 44.6mm 33.9° Comparative example 2 30mm 43.6mm 34.5° Comparative example 3
  • 30mm 40.9mm 36.2° Comparative example 4 30mm 41.7mm 35.7°
  • the present inventors investigated the influencing factors of the omeprazole sodium compound prepared in Example 1 and Comparative Example 1-4 of the present invention.
  • the conditions of investigation were high temperature (60 ⁇ 2°C), illumination (4500 ⁇ 500Lx), high humidity (92.5%, RH), and the indicators were related to the content and related substances.
  • omeprazole sodium compound prepared by the present invention was basically unchanged at high temperature (60 ⁇ 2 °C), light (4500 ⁇ 500Lx) and high humidity (92.5%, RH).
  • the content of the meprazole sodium compound and related substances showed a certain degree of change, indicating that the omeprazole compound of the present invention has good stability.
  • the present inventors conducted an accelerated stability study on the pharmaceutical composition of omeprazole sodium prepared in Examples 3-5 and Comparative Example 5 of the present invention.
  • the conditions of investigation were temperature 40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%. After 6 months of storage, samples were taken at the end of 0, 1, 2, 3, and 6 months, respectively.
  • the indicators are traits, alkalinity, visible foreign matter, insoluble particles, content and related substances.
  • the omeprazole sodium pharmaceutical composition of the invention has simple prescription and reasonable process, and can meet the demand of large production. Tests by various indicators and accelerated tests show that the stability is good and the quality is reliable.

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Abstract

本发明公开了一种奥美拉唑钠化合物，所述奥美拉唑钠化合物采用粒子过程晶体产品分子组装与形态优化技术制备而成。本化合物为奥美拉唑钠无水化合物，具有纯度高、流动性好、吸湿性低、稳定性好的特点。同时，本发明还公开了一种奥美拉唑钠药物组合物，所述药物组合物包括以下重量份的组分：奥美拉唑钠(以奥美拉唑计)20～60份、金属离子络合剂1～2份和pH调节剂适量。本发明所述奥美拉唑钠药物组合物，制备过程操作简单，不需任何赋形剂，较以往产品具有更好的稳定性。

Description

一种采用粒子过程晶体产品分子组装与形态优化技术制备的奥美拉唑钠化合物及其制剂 技术领域
本发明属于医药技术领域，具体涉及一种采用粒子过程晶体产品分子组装与形态优化技术制备的奥美拉唑钠化合物及其制剂。
背景技术
奥美拉唑钠，化学名称：5-甲氧基-2-{[(4-甲氧基-3,5-二甲基-2-吡啶基)-甲基]-亚磺酰基}-1H-苯并咪唑钠，分子式为C17H18N3NaO3S，分子量：367.41。奥美拉唑钠是首个上市的质子泵抑制剂，由瑞典阿斯特拉制药公司研发成功，于1988年在瑞士首先上市，商品名为“Antra”。1989年进入美国市场，用于治疗十二指肠溃疡、胃溃疡、反流性食管炎及Zollinger-Ellison综合征，商品名为“洛赛克”。其作用原理为奥美拉唑是一种弱碱性物质，在壁细胞的酸性环境中浓集并转化为活性形式，抑制H+、K+-ATP酶。
据相关资料证明，奥美拉唑钠用药后无任何不良反应，对肝、肾功能也无影响。故此药具有治愈率高，副作用少，服药方便等特点，是目前国内外治疗消化性溃疡的最佳药物，也是最有前途的抗溃疡药物。
在现有技术中已经提供了奥美拉唑钠化合物的几种制备方法。CN 102827147是将奥美拉唑钠溶于水，加入丙酮和异丙醇混合溶液结晶并分离而得到的。CN 102351846是将奥美拉唑钠溶于水中，加入异丙醇结晶并分离而得到的。CN1261362A中是将异丙醇和氢氧化钠加入奥美拉唑水溶液中，向其中加入B型奥美拉唑钠盐诱导结晶并分离而得到的。在奥美拉唑钠的制备过程中，奥美拉唑钠存在不同的晶型，温度、溶剂、外力、添加剂等因素均会不同程度的影响晶体的形成及纯度。上述专利中所制备的不同晶型均为奥美拉唑钠一水化合物，或是在稳定性方面有所提升，或是在引湿性方面有所提升，但其性能的提升都存在单方面的局限性。
本发明中通过采用粒子过程晶体产品分子组装与形态优化技术获得了一种奥美拉唑钠无水化合物，该化合物具有纯度高、流动性好、吸湿性低、稳定性好的特点。以此奥美拉唑钠化合物为原料，制备奥美拉唑钠药物组合物。该制剂制备过程不需任何赋形剂，较以往产品具有更好的稳定性，从而完成了本发明。
发明内容
本发明的第一目的在于提供一种奥美拉唑钠化合物，该化合物采用粒子过程晶体产品分子组装与形态优化技术制备而来，具有纯度高、流动性好、吸湿性低、稳定性 好的特点，在原料药的生产和制剂制备过程中容易处理。此外，所述化合物容易过滤和干燥，纯度高，适合做原料药。
所述奥美拉唑钠化合物纯度可高达99.8％。
本发明所述的奥美拉唑钠化合物制备包括下列步骤：
(1)将奥美拉唑加入甲醇中搅拌溶解完全，将其加入到一定量的氢氧化钠水溶液中，保温搅拌溶解，得到奥美拉唑钠盐溶液。
(2)在一定的温度及转速条件下，向其中缓慢加入有机溶剂。
(3)在不同的温度梯度条件下搅拌，然后静置。
(4)过滤，洗涤，干燥，得奥美拉唑钠化合物。
优选地，上述制备方法中，奥美拉唑钠盐溶液形成过程中，搅拌温度为30～40℃，时间为2～3小时。
优选地，上述制备方法中，所述有机溶剂为酯类溶剂(如乙酸乙酯)、醚类溶剂(如二乙醚，四氢呋喃)、卤代烃类溶剂(如二氯甲烷，氯仿)、硝基烃类溶剂(硝基甲烷、硝基乙烷)烷烃类溶剂(如甲醇、异戊醇)、酮类溶剂(如丙酮)中的任意两种组合。更优选地，丙酮、硝基甲烷、异戊醇中的任意两种组合。
优选地，上述混合溶剂中，所述两种溶剂的体积比1:3～1:8。
优选地，上述制备方法中，所述奥美拉唑钠水溶液中加入有机溶剂时的温度20～30℃，搅拌转速40～50转/分。
优选地，上述制备方法中，所述奥美拉唑盐溶液和有机溶剂的体积比1:1～1:5。
优选地，上述制备方法中，所述晶体形成过程控制在10～20℃下搅拌2.0小时，再在5～10℃下搅拌2.5小时，然后静置5小时。
优选地，上述制备方法中，所述洗涤剂是含氧脂肪烃衍生物或其混合物或烷烃或醚类。主要包括脂肪酸、脂肪醇或酮类以及两种或多种溶剂的混合物。脂肪酸为甲酸或乙酸等；脂肪醇为甲醇、乙醇、丙醇、异丙醇、正丁醇或异丁醇；酮类为丙酮、异丁酮或甲基乙基酮；醚类为乙醚。更优选地，丙醇、甲醇、乙醚中的任意一种或两种组合。
优选地，上述制备方法中，所述洗涤产品在真空条件下干燥，干燥时间为3～8小时，干燥温度30～40℃。
综上所述的奥美拉唑钠化合物采用粒子过程晶体产品分子组装与形态优化技术制备,具体步骤为将奥美拉唑加入甲醇中搅拌溶解完全，将其加入到一定量的氢氧化钠水溶液中，30～40℃搅拌溶解2～3小时，得到奥美拉唑钠盐溶液，在温度为20～30℃及转速为40～50转/分条件下，向其中缓慢加入有机溶剂1，在10～20℃下搅拌2.0小时， 再在5～10℃下搅拌2.5小时，然后静置5小时。过滤，采用有机溶剂2洗涤，在真空条件下干燥，干燥时间为3～8小时，干燥温度为30～40℃，得奥美拉唑钠化合物。
本发明第二目的在于提供一种包含本发明所述奥美拉唑钠化合物的奥美拉唑钠药物组合物的制备工艺，该制备工艺具有如下特点：制备过程操作简单，不需任何赋形剂，较以往产品具有更好的稳定性。
本发明所述的奥美拉唑钠药物组合物的制备方法，包括如下步骤：
1.配料
称取金属离子络合剂溶于注射用水中，搅拌，溶解。控制水温在35℃以下，加入奥美拉唑钠，室温搅拌使溶解，用pH调节剂调pH值至10～12，补加注射用水至全量，搅匀后，加入活性炭，室温搅拌吸附20分钟。采用0.5μm或0.65μm钛棒过滤脱炭。将0.45μm和0.22μm微孔滤膜串联，进行精滤，分装。
2.冻干
将样品放入已降温至-40℃的冻干箱中，制冷使样品快速降温，当样品温度降至-40℃时，保持3～5小时，冷凝器制冷，抽真空，待冷凝器温度及真空度稳定后，搁板加热，使样品缓慢升温，以3℃/h的速度升至0℃，观察样品水分抽干后，快速升温至30℃，并保持3～6小时。整个冻干过程约30小时，制得奥美拉唑钠冻干粉。
本发明的奥美拉唑钠药物组合物包括本发明所述的奥美拉唑钠化合物及常用注射剂辅料包括金属离子络合剂、pH调节剂组成。
优选地，上述制备方法中，金属离子络合剂为依地酸钙钠、乙二胺四乙酸、乙二胺四乙酸一钠、乙二胺四乙酸二钠等，但不局限于此。
优选地，上述制备方法中，pH调节剂为枸橼酸钠、无水碳酸钠、氢氧化钠等，但不限于此。
优选地，上述制备方法中，所述的药物组合物为由奥美拉唑钠化合物和药用辅料经冷冻干燥制成的冻干粉。
优选地，上述制备方法中，所述奥美拉唑钠药物组合物按重量份数计包含奥美拉唑钠(以奥美拉唑计)的重量份为20～60份。
优选地，上述制备方法中，所述奥美拉唑钠药物组合物按重量份数计包含金属离子络合剂的重量份为1～2份。
优选地，上述制备方法中，所述pH调节剂只要是药用级别且加入后使本发明灌装前溶液的pH值在10～12范围内，该溶液稀释后保证pH值在10.0～11.5范围内即可。
具体实施方式
以下实施例是对本发明的进一步说明，但绝不是对本发明范围的限制。下面参照 实施例进一步详细阐述本发明，但是本领域技术人员应当理解，本发明并不限于这些实施例以及使用的制备方法。而且，本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰，但这些都将包括在本发明的范围内。
实施例1：奥美拉唑钠化合物的制备
1)将奥美拉唑1kg加至1L甲醇中溶解。另将250g氢氧化钠溶于1.25L纯化水中。
2)在温度35℃条件下，将奥美拉唑甲醇溶液缓慢加入到氢氧化钠水溶液中，搅拌2小时，得到奥美拉唑钠盐溶液，作为溶液1。
3)在温度为25℃、转速为50转/分条件下，向溶液1中缓慢加入6L体积比为1:4的丙酮和硝基甲烷的混合溶液，得到溶液2。
3)将溶液2在13℃下搅拌2.0小时，再在8℃下搅拌2.5小时，然后静置5小时，过滤，用乙醚洗涤，保持温度为35℃，真空干燥6小时，得奥美拉唑钠化合物。
实施例2：奥美拉唑钠化合物的制备
1)将奥美拉唑1.02kg加至1L甲醇中溶解。另将250g氢氧化钠溶于1.25L纯化水中。
2)在温度30℃条件下，将奥美拉唑甲醇溶液缓慢加入到氢氧化钠水溶液中，搅拌2.5小时，得到奥美拉唑钠盐溶液，作为溶液1。
2)在温度为25℃、转速为40转/分条件下，向溶液1中缓慢加入6L体积比为1:6的丙酮和异戊醇的混合溶液，得到溶液2。
3)将溶液2在17℃下搅拌2.0小时，再在5℃下搅拌2.5小时，然后静置5小时，过滤，用丙醇洗涤，保持温度为40℃，真空干燥5小时，得奥美拉唑钠化合物。
实施例3：奥美拉唑钠药物组合物的制备
处方：
Figure PCTCN2016085299-appb-000001
制备工艺：
1.配料
称取处方量的依地酸钙钠溶于注射用水中，搅拌，溶解。控制水温在30℃，加入实施例1获得的奥美拉唑钠，室温搅拌使溶解，用氢氧化钠调pH值至11.2，补加注 射用水至全量，搅匀后，加入活性炭，室温搅拌吸附20分钟。采用0.5μm钛棒过滤脱炭。将0.45μm和0.22μm微孔滤膜串联，进行精滤，分装。
2.冻干
将样品放入已降温至-40℃的冻干箱中，制冷使样品快速降温，当样品温度降至-40℃时，保持4小时，冷凝器制冷，抽真空，待冷凝器温度及真空度稳定后，搁板加热，使样品缓慢升温，以3℃/h的速度升至0℃，观察样品水分抽干后，快速升温至30℃，并保持5小时。整个冻干过程约32小时，制得奥美拉唑钠冻干粉。
3.检验
检测上述无菌粉末：含量、澄明度、碱度。
4.加塞、轧盖。
5.包装、全检、入库。
实施例4：奥美拉唑钠药物组合物的制备
处方：
Figure PCTCN2016085299-appb-000002
制备工艺：
1.配料
称取处方量的依地酸钙钠溶于注射用水中，搅拌，溶解。控制水温在32℃，加入实施例2获得奥美拉唑钠，室温搅拌使溶解，用氢氧化钠调pH值至11.0，补加注射用水至全量，搅匀后，加入活性炭，室温搅拌吸附20分钟。采用0.5μm钛棒过滤脱炭。将0.45μm和0.22μm微孔滤膜串联，进行精滤，分装。
2.冻干
将样品放入已降温至-40℃的冻干箱中，制冷使样品快速降温，当样品温度降至-40℃时，保持3小时，冷凝器制冷，抽真空，待冷凝器温度及真空度稳定后，搁板加热，使样品缓慢升温，以3℃/h的速度升至0℃，观察样品水分抽干后，快速升温至30℃，并保持5小时。整个冻干过程约30小时，制得奥美拉唑钠冻干粉。
3.检验
检测上述无菌粉末：含量、澄明度、碱度。
4.加塞、轧盖。
5.包装、全检、入库。
实施例5：奥美拉唑钠药物组合物的制备
处方：
Figure PCTCN2016085299-appb-000003
制备工艺：
1.配料
称取处方量的依地酸钙钠溶于注射用水中，搅拌，溶解。控制水温在30℃，加入实施例1获得的奥美拉唑钠，室温搅拌使溶解，用氢氧化钠调pH值至11.0，补加注射用水至全量，搅匀后，加入活性炭，室温搅拌吸附20分钟。采用0.5μm钛棒过滤脱炭。将0.45μm和0.22μm微孔滤膜串联，进行精滤，分装。
2.冻干
将样品放入已降温至-40℃的冻干箱中，制冷使样品快速降温，当样品温度降至-40℃时，保持4小时，冷凝器制冷，抽真空，待冷凝器温度及真空度稳定后，搁板加热，使样品缓慢升温，以3℃/h的速度升至0℃，观察样品水分抽干后，快速升温至30℃，并保持5小时。整个冻干过程约32小时，制得奥美拉唑钠冻干粉。
3.检验
检测上述无菌粉末：含量、澄明度、碱度。
4.加塞、轧盖。
5.包装、全检、入库。
对比例1
按照CN1261362A中所述的方法制备奥美拉唑钠化合物。
制备工艺：将120克奥美拉唑溶于26.7克水中，向其中加入480ml异丙醇和13.2克氢氧化钠，在室温条件下搅拌40分钟，将所得的溶液滤过，过滤物用异丙醇洗涤。将异丙醇洗涤液与前面的异丙醇溶液合并。将6克B型的奥美拉唑钠溶于25ml异丙醇中做晶种，加入上述合并液中，继续搅拌25小时，将产物过滤并在40℃下干燥，得奥美拉唑钠化合物。
对比例2
按照CN102827147A中所述的方法制备奥美拉唑钠化合物。
制备工艺：将奥美拉唑钠42g溶于200ml水中，得到0.21g/ml的奥美拉唑钠水溶液，过滤。将滤液加入到4.1L丙酮和异丙醇(体积比为1:3.5)的混合溶液中，滤液加完后降温至3℃，得到晶体后继续搅拌10分钟；过滤，滤饼用水洗涤，喷雾干燥，得到奥美拉唑钠化合物。
对比例3：奥美拉唑钠化合物的制备
1)将奥美拉唑1kg加至1L甲醇中溶解。另将250g氢氧化钠溶于1.25L纯化水中。
2)在温度40℃条件下，将奥美拉唑甲醇溶液缓慢加入到氢氧化钠水溶液中，搅拌3小时，得到奥美拉唑钠盐溶液，作为溶液1。
2)在温度为30℃、转速为45转/分条件下，向溶液1中缓慢加入7L体积比为1:5的2-丁酮和异戊醇的混合溶液，得到溶液2。
3)将溶液2在15℃下搅拌2.0小时，再在10℃下搅拌2.5小时，然后静置5小时，过滤，用乙醚和甲醇(体积比为1:1)洗涤，保持温度为30℃，真空干燥5小时，得奥美拉唑钠化合物。
对比例4：奥美拉唑钠化合物的制备
1)将奥美拉唑1kg加至1L甲醇中溶解。另将250g氢氧化钠溶于1.25L纯化水中。
2)在温度40℃条件下，将奥美拉唑甲醇溶液缓慢加入到氢氧化钠水溶液中，搅拌3小时，得到奥美拉唑钠盐溶液，作为溶液1。
2)在温度为30℃、转速为45转/分条件下，向溶液1中缓慢加入7L丙酮的混合溶液，得到溶液2。
3)将溶液2在15℃下搅拌2.0小时，再在10℃下搅拌2.5小时，然后静置5小时，过滤，用乙醚和甲醇(体积比为1:1)洗涤，保持温度为30℃，真空干燥5小时，得奥美拉唑钠化合物。
对比例5
按照CN102827147A中所述的方法，使用对比例2中制备奥美拉唑钠化合物制备奥美拉唑钠药物组合物。
1、制备工艺：将奥美拉唑钠化合物22.31克与甘露醇50克加入至配液缸中，加入800ml注射用水搅拌至全部溶解，用0.15mol/L柠檬酸钠溶液调测pH10.0～11.0，加入注射用水至1000ml；加入溶液总量0.05％的针用活性炭，搅拌15分钟，过滤脱炭；将药液用0.22μm除菌微孔滤膜精滤，测定pH值、含量、半加塞；冷冻干燥：-40℃预冻2小时，-40～10℃，减压真空干燥25小时，置35℃温度下干燥7小时；压塞、 轧盖，制得奥美拉唑钠冻干粉。
2、检测上述无菌粉末：含量、碱度、有关物质。
试验例1
本发明人对本发明实施例1和对比例1-4所制备奥美拉唑钠化合物吸湿性进行了研究。考察条件为相对湿度75％(RH)与相对湿度92.5％(RH)，温度为40℃，考察指标为奥美拉唑钠化合物中的含水量。
含水量检测结果：
Figure PCTCN2016085299-appb-000004
结果：本发明制备的奥美拉唑钠化合物吸湿性明显低于现有技术制备的奥美拉唑钠化合物。说明本发明所述的奥美拉唑钠化合物稳定性良好，适合药物制剂的制造及长期储存。
试验例2
本发明人对本发明实施例1和2及对比例1-4所制备奥美拉唑钠的流动性进行了研究。休止角检测方法为将颗粒置于固定的漏斗中，使其自由落至水平面上，形成一底部半径为r的圆盘形堆积体，测定堆积体的高度为H，根据公式tanθ＝H/r计算。
休止角检测结果:
实施例 高度H 半径r 休止角θ
实施例1 30mm 59.0mm 27.0°
实施例2 30mm 58.5mm 27.1°
对比例1 30mm 44.6mm 33.9°
对比例2 30mm 43.6mm 34.5°
对比例3 30mm 40.9mm 36.2°
对比例4 30mm 41.7mm 35.7°
结果：本发明制备的奥美拉唑钠化合物的流动性明显高于现有技术的奥美拉唑钠化合物，在制剂的制备过程中，可以满足制备方式的需要。
试验例3
本发明人对本发明实施例1和对比例1-4所制备奥美拉唑钠化合物进行了影响因素考察。考察条件为高温(60±2℃)、光照(4500±500Lx)，高湿(92.5％，RH)，考察指标为含量和有关物质。
影响因素考察结果：
Figure PCTCN2016085299-appb-000005
结果：本发明制备的奥美拉唑钠化合物在高温(60±2℃)、光照(4500±500Lx)和高湿(92.5％，RH)条件下含量和有关物质基本无变化，对比例中奥美拉唑钠化合物含量和有关物质均出现一定程度的变化，说明本发明中的奥美拉唑化合物稳定性好。
试验例4
本发明人对本发明实施例3-5和对比例5所制备奥美拉唑钠药物组合物进行了加速稳定性考察。考察条件为温度40℃±2℃、相对湿度75％±5％。放置6个月，分别于0、1、2、3、6月末取样。考察指标为性状、碱度、可见异物、不溶性微粒、含量及有关物质。
加速试验考察结果：
Figure PCTCN2016085299-appb-000006
Figure PCTCN2016085299-appb-000007
结果：实施例与对比例产品在上述试验条件下放置6个月，本发明实施例3～5样品含量和有关物质及其他各项指标均未出现明显变化，质量稳定。对比例5样品含量和pH明显下降，有关物质明显升高，质量差。
本发明的奥美拉唑钠药物组合物处方简单，工艺合理，可满足大生产的需求。经各项指标检验和加速试验考察表明稳定性好，质量可靠。

Claims (8)

  1. 一种奥美拉唑钠化合物，其特征在于，化合物的结构式为：
    Figure PCTCN2016085299-appb-100001
    所述的奥美拉唑钠化合物采用以下方法制备而成：将奥美拉唑加入甲醇中搅拌溶解完全，将其加入到一定量的氢氧化钠水溶液中，在温度为30～40℃的条件下，搅拌溶解2～3小时，得到奥美拉唑钠盐溶液，在温度为20～30℃及转速为40～50转/分条件下，向其中缓慢加入有机溶剂1，在温度为10～20℃条件下搅拌2.0小时，再在温度为5～10℃条件下搅拌2.5小时，然后静置5小时，过滤，采用有机溶剂2洗涤，在真空条件下干燥，干燥时间为3～8小时，干燥温度为30～40℃，得奥美拉唑钠化合物。
  2. 如权利要求1所述的有机溶剂1为丙酮、硝基甲烷、异戊醇中的任意两种组合。
  3. 如权利要求2所述的有机溶剂1中两种溶剂的体积比1:3～1:8。
  4. 如权利要求1所述的奥美拉唑盐溶液和有机溶剂1的体积比1:1～1:5。
  5. 如权利要求1所述的有机溶剂2为丙醇、甲醇、乙醚中的任意一种或两种组合。
  6. 一种奥美拉唑钠药物组合物，其特征在于，所述的药物组合物含有权利要求1所述的奥美拉唑钠化合物或权利要求2～5任意一项所述的制备方法制得的奥美拉唑钠化合物。
  7. 如权利要求6所述的药物组合物，其特征在于，所述的药物组合物为由本发明中所述的奥美拉唑钠化合物和药用辅料溶于注射用水，使用pH调节剂调节pH值后经冷冻干燥制成的冻干粉。
  8. 如权利要求7所述的药物组合物，其特征在于按重量份数计包括以下重量份的组分：奥美拉唑钠20～60份、金属离子络合剂1～2份和pH调节剂适量，pH调节剂用量为保证加入后使本发明灌装前溶液的pH值在10～12范围内，该溶液稀释后pH值在10.0～11.5范围内即可。
PCT/CN2016/085299 2015-06-17 2016-06-08 一种采用粒子过程晶体产品分子组装与形态优化技术制备的奥美拉唑钠化合物及其制剂 Ceased WO2016202212A2 (zh)

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CN113893223A (zh) * 2021-09-29 2022-01-07 北京悦康科创医药科技股份有限公司 一种注射用艾司奥美拉唑钠冻干制剂及其制备方法

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CN113893223A (zh) * 2021-09-29 2022-01-07 北京悦康科创医药科技股份有限公司 一种注射用艾司奥美拉唑钠冻干制剂及其制备方法

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