WO2017162103A1 - 一种注射用阿扎胞苷的制备方法 - Google Patents

一种注射用阿扎胞苷的制备方法 Download PDF

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WO2017162103A1
WO2017162103A1 PCT/CN2017/077026 CN2017077026W WO2017162103A1 WO 2017162103 A1 WO2017162103 A1 WO 2017162103A1 CN 2017077026 W CN2017077026 W CN 2017077026W WO 2017162103 A1 WO2017162103 A1 WO 2017162103A1
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azacitidine
temperature
injection
preparation
controlled
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PCT/CN2017/077026
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English (en)
French (fr)
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施祥杰
刘洁凝
王新石
胡李斌
陈浩
王志云
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浙江华海药业股份有限公司
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Priority to US16/086,592 priority Critical patent/US10617649B2/en
Publication of WO2017162103A1 publication Critical patent/WO2017162103A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/26—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F26—DRYING
    • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
    • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
    • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
    • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a preparation method of azacitidine for injection.
  • Myelodysplastic syndrome is a group of diseases characterized by clonal abnormalities in hematopoietic stem cells that cause hematopoietic failure and a high risk of progression to acute myeloid leukemia (AML).
  • the disease is divided into five types, namely, refractory anemia (RA), ring-shaped iron granulocyte anemia, refractory anemia with blast-producing (REAB), refractory anemia with blasts-transformation (RAEB).
  • RA refractory anemia
  • RAB refractory anemia with blast-producing
  • RAEB refractory anemia with blasts-transformation
  • CMML chronic granulocyte-monocytic leukemia
  • myelodysplastic syndrome In Europe and the United States, the incidence of myelodysplastic syndrome is 4 per 100,000 per year, which is twice the incidence of acute myeloid leukemia. In the elderly population over 70 years old, the incidence can reach 100,000. twenty. In China, the incidence of the disease has increased due to the extension of the average life expectancy and the aging of the population. In general, patients with low-risk myelodysplastic syndrome use supportive therapy to control the progression of the disease, while for high-risk patients, due to poor prognosis, effective drugs or therapies are needed for treatment.
  • Azacitidine is a DNA methyltransferase inhibitor that causes DNA hypomethylation and has direct cytotoxicity. It is developed by Pharmion Pharmaceuticals. In May 2004, the US FDA approved the drug Vidaza for the treatment of all subtypes of myelodysplastic syndrome. Since the active ingredient of the drug, azacitidine, is rapidly hydrolyzed in water, it is difficult to control the substance related to the lyophilized preparation, and the product stability during storage is poor, which has a potential impact on the safety and effectiveness of the clinical drug.
  • Patent CN103251564A discloses an azacitidine for injection and a preparation method thereof, which mainly controls the pH value of aqueous solution of azacitidine by using hydrochloric acid or sodium hydroxide, and reduces the yield after lyophilization.
  • Related substances of the product In the preparation process of the invention, it is necessary to add activated carbon to the 80 ° C water bath for 20 minutes, and then filter the charcoal. It is well known that activated carbon tends to leak and remain in the filtration process, posing a potential safety risk. Therefore, it is still necessary to provide a method with simple process and stable quality.
  • Patent CN101632643A discloses an azacitidine for injection and a preparation method thereof, which are intended to increase the stability of the product in an aqueous solution by using vitamin C as a stabilizer.
  • activated carbon still needs to be added during the preparation process, and leakage and residue problems of the activated carbon during the filtration process cannot be avoided.
  • vitamin C is a component that is not contained in the original product, and introduction of a new component may cause unnecessary safety problems for the injection.
  • Patent US20110042247 discloses a preparation method of azacitidine for injection, 1) cooling 95% sterile water to -1 to -3 ° C; 2) adding mannitol, stirring and dissolving; 3) meeting quality requirements The cytidine was added and the mixture was stirred to form a solution; 4) the final temperature was controlled at -3 ° C, stirred for 5 minutes until the solution was clear; 5) the solution was filtered through a 0.2 ⁇ m sterile filter; 6) bottled and lyophilized. It is well known that circulating condensed water is commonly used in production at present, and water is easily crystallized at -1 to -3 ° C, and cannot be cooled by circulation. Therefore, it is often necessary to replace a cooling solvent such as absolute ethanol, and the anhydrous ethanol is flammable and explosive, which tends to bring danger to production and increase production cost.
  • a cooling solvent such as absolute ethanol
  • the inventors have found through research that when the bacterial endotoxin in the raw materials is well controlled, it is not necessary to add activated carbon to adsorb the depyrogen during the preparation process, and the bacterial endotoxin produced by the injection of azacitidine is still Meet the quality requirements.
  • the step of reducing the adsorption of activated carbon in the process of preparing azacitidine for injection can not only reduce the process steps in the production process, but also improve the production efficiency.
  • Activated carbon adsorption in addition to pyrogens generally requires continuous stirring at 60 ° C or higher, while the solution of azacitidine is strictly controlled at 2-6 ° C, so the solution after removal of the pyrogen is passed through the dosing tank clamp
  • the raw material drug azacitidine can be added after the condensed water in the sleeve is lowered to 2-6 °C.
  • azacitidine has good stability when the temperature of the solution of azacitidine is controlled at 2-6 °C.
  • the temperature of the azacitidine solution is higher than 6 ° C, the content of azacitidine can be significantly decreased, and the related substances are significantly increased, resulting in a decline in product quality.
  • the inventors have found through research that when the temperature of the preparation of the azacitidine solution is controlled at 4-6 ° C, the azacitidine has the same stability with respect to the temperature control at 2-3 ° C, and has 4-6 ° C at the same time. Conducive to improving production efficiency and reducing energy consumption.
  • the temperature of the solution is mainly controlled by first using the condensed water to lower the temperature of the water for injection into the target range, and then controlling the heat preservation through the condensed water circulating in the liquid distribution tank.
  • the minimum temperature of the condensed water is close to 0 ° C.
  • the condensed water is in a state of solid-liquid coexistence, and the flow circulation heat preservation cannot be performed.
  • the temperature of the condensed water is often controlled at 1-3 ° C. Controlling the temperature of the solution to 2-4 °C with 1-3 °C condensed water often requires a longer cooling time, and the ambient temperature in the production interval is controlled at 18-26 ° C. The lower the solution temperature, the more energy is consumed. Insulation is carried out to increase the production cost, so the temperature of the preparation of the azacitidine solution is controlled at 4-6 ° C, the production efficiency is higher, the cost is lower, and the product quality is more stable.
  • the invention provides a preparation method of azacitidine for injection, which comprises 100 mg of azacitidine and 100 mg of mannitol per azacitidine for injection, wherein the preparation method comprises the following steps:
  • the invention provides a preparation method of azacitidine for injection, which is characterized in that the preparation process does not contain an activated carbon adsorption step.
  • the invention provides a preparation method of azacitidine for injection, which is characterized in that the raw material medicine
  • the bacterial endotoxin of cytidine is ⁇ 0.6Eu/mg.
  • the invention provides a preparation method of azacitidine for injection, which is characterized in that the bacterial endotoxin of the auxiliary mannitol is ⁇ 2.5Eu/g.
  • the invention provides a preparation method of azacitidine for injection, which is characterized in that the prepared bacterial endotoxin of azacitidine for injection is ⁇ 1.2Eu/mg.
  • the present invention provides a method for preparing azacitidine for injection, and the dosing temperature is more preferably controlled at 4-6 °C.
  • the invention provides a preparation method of azacitidine for injection, characterized in that the freeze-drying process is:
  • Pre-freezing After the temperature of the laminar layer drops to -35 ⁇ 5°C, the sample is placed and kept for 2 hours;
  • Sublimation drying reduce the vacuum to 50-150 ⁇ bar, the shelf temperature is raised to -10 ° C at 15 ° C / h, and kept for 15 hours;
  • freeze-drying process cycle of the invention is greatly shortened, which is beneficial to improving production efficiency and reducing energy consumption.
  • the prepared azacitidine for injection has the advantages of simple production process, low energy consumption, stable product quality and more suitable for commercial production.
  • the preparation method comprises the following steps: measuring 80% water for injection, the temperature is controlled at 2 ° C; adding mannitol, stirring Mix until completely dissolved, the temperature is controlled at 2 ° C; add azacitidine, stir until completely dissolved, the temperature is controlled at 2 ° C; after filtration, carry out the partial packing, half-plug; the above-mentioned filled half-plugged vials are sent to the frozen In the dry box, pre-freeze -35 ° C, heat preservation 2h; shelf temperature is raised to -10 ° C at 15 ° C / h, heat preservation 15h; 20 ° C / h to 30 ° C, heat preservation 18h; after nitrogen filling, rolling, pressure Plug, the package is available.
  • the preparation method comprises the following steps: measuring 80% water for injection, the temperature is controlled at 4° C.; adding mannitol, stirring until completely dissolved, and controlling the temperature at 4° C.; adding azacitidine, stirring until completely dissolved, and controlling the temperature at 4° C.; After the sub-packaging, semi-plugging; the above-mentioned filled semi-plugged vials are sent to the freeze-drying box, pre-frozen -35 ° C, heat preservation 2h; shelf temperature is raised to -10 ° C at 15 ° C / h, heat preservation 15h The temperature is raised to 30 ° C at 20 ° C / h, and kept for 18 hours; after nitrogen filling, the lid is rolled, the plug is pressed, and the package is obtained.
  • the mannitol bacterial endotoxin is 2.5 EU/g, and the azacitidine bacterial endotoxin is 0.6 EU/mg.
  • the preparation method comprises the following steps: measuring 80% water for injection, the temperature is controlled at 6 ° C; adding mannitol, stirring until completely dissolved, the temperature is controlled at 6 ° C; adding azacitidine, stirring until completely dissolved, the temperature is controlled at 6 ° C; After the sub-packaging, semi-plugging; the above-mentioned filled semi-plugged vials are sent to the freeze-drying box, pre-frozen -35 ° C, heat preservation 2h; shelf temperature is raised to -10 ° C at 15 ° C / h, heat preservation 15h The temperature is raised to 30 ° C at 20 ° C / h, and kept for 18 hours; after nitrogen filling, the lid is rolled, the plug is pressed, and the package is obtained.
  • Example 1 The traits, contents and related substances at 6 days and 40 °C for 6 months were examined in Example 1, Example 2 and Example 3, respectively. The results are shown in the following table:
  • the azacitidine for injection has the same stability when the dosing temperature is 2 ° C, 4 ° C and 6 ° C, respectively.
  • the result of the test of the finished bacterial endotoxin of Example 3 was less than 1.2 EU/mg.
  • the preparation method comprises the following steps: measuring 80% water for injection, the temperature is controlled at 6 ° C; adding mannitol, stirring until completely dissolved, the temperature is controlled at 6 ° C; adding azacitidine, stirring until completely dissolved, the temperature is controlled at 6 ° C; After the sub-packaging, semi-plugging; the above-mentioned filled semi-plugged vials were sent to the freeze-drying box, pre-frozen -40 ° C, and kept for 2 h; the shelf temperature was raised to -10 ° C at 15 ° C / h, and kept for 15 h. The temperature is raised to 30 ° C at 20 ° C / h, and kept for 18 hours; after nitrogen filling, the lid is rolled, the plug is pressed, and the package is obtained.
  • the preparation method comprises the following steps: measuring 80% water for injection, the temperature is controlled at 2 ° C; adding mannitol, stirring until completely dissolved, the temperature is controlled at 2 ° C; adding azacitidine, stirring until completely dissolved, the temperature is controlled at 2 ° C; After the sub-packaging, semi-plugging; the above-mentioned filled semi-plugged vials are sent to the freeze-drying box, pre-frozen at -30 ° C, and kept for 2 h; the shelf temperature is raised to -10 ° C at 15 ° C / h, and kept for 15 h. The temperature is raised to 30 ° C at 20 ° C / h, and kept for 18 hours; after nitrogen filling, the lid is rolled, the plug is pressed, and the package is obtained.

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Abstract

一种注射用阿扎胞苷的制备方法，每支注射用阿扎胞苷中含有阿扎胞苷100mg和甘露醇100mg，制备方法包括以下步骤：量取80％注射用水，温度控制在2-6℃；加入甘露醇，搅拌至完全溶解，温度控制在2-6℃；加入阿扎胞苷，搅拌至完全溶解，温度控制在2-6℃；过滤后进行分装，23ml/瓶；按预设温度进行冷冻干燥；充氮后压塞、轧盖和包装。该制备方法工艺简单，能耗低，生产效率高，产品质量稳定。

Description

一种注射用阿扎胞苷的制备方法
本申请要求于2016年3月24日提交中国专利局、申请号为201610172614.7、发明名称为“一种注射用阿扎胞苷的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于医药技术领域，具体的涉及到一种注射用阿扎胞苷的制备方法。
背景技术
骨髓增生异常综合症(MDS)是一组以造血干细胞克隆性异常为特征的疾病，会导致造血功能衰竭，并有进展为急性髓细胞白血病(AML)的高危险性。该病分为5种类型，即难治性贫血(RA)、环形铁粒幼细胞性贫血、难治性贫血伴原始细胞增多(REAB)、难治性贫血伴原始细胞增多-转变型(RAEB-T)及慢性粒-单核细胞白血病(CMML)。
在欧美、骨髓增生异常综合症的发病率每年为十万分之四，为急性髓细胞样白血病发病率的2倍，在70岁以上的老年人群中，则该发病率可达到十万分之二十。而在我国，由于平均寿命的延长以及人口的老龄化，该疾病的发病率有增长的趋势。通常，对低危骨髓增生异常综合症患者使用支持疗法控制疾病的进程，而对于高危患者来说，由于预后不良，因此需要使用有效的药物或疗法进行治疗。
阿扎胞苷(Azacitidine)为DNA甲基转移酶抑制剂，可引起DNA低甲基化，并具有直接细胞毒作用，由美国Pharmion制药公司研发开发。2004年5月美国FDA批准该药物Vidaza上市，用于对骨髓增生异常综合症的所有亚型的治疗。由于该药物活性成分阿扎胞苷在水中迅速水解，使得冻干制剂有关物质很难控制，储存期间产品稳定性差，因而对于临床用药安全和有效性造成了潜在的影响。
专利CN103251564A公开了一种注射用阿扎胞苷及其制备方法，主要通过使用盐酸或氢氧化钠控制阿扎胞苷水溶液的pH值，降低冻干后产 品的有关物质。但该发明制备过程中需要加入活性炭进行80℃水浴保温20分钟后，过滤除炭。众所周知活性炭在过滤过程中往往会存在泄漏和残留，存在潜在的安全风险。因此仍有必要提供一种方法，工艺简单，质量稳定。
专利CN101632643A公开了一种注射用阿扎胞苷及其制备方法，通过使用维生素C作为稳定剂，试图增加本品在水溶液中的稳定性。但制备过程中仍需加入活性炭，无法避免活性炭在过滤过程中存在的泄漏和残留问题。另外维生素C作为原研产品中不含的组分，对于注射液来说，新组分引入可能带来不必要的安全问题。
专利US20110042247公开了一种注射用阿扎胞苷的制备方法，1)将95％无菌水冷却至-1～-3℃；2)加入甘露醇，搅拌溶解；3)将质量符合要求的阿扎胞苷加入，混合物搅拌，形成溶液；4)最后温度控制在-3℃，搅拌5分钟，直至溶液澄清；5)溶液用0.2μm无菌过滤器过滤；6)瓶装，冷冻干燥。众所周知，目前生产上普遍使用的为循环冷凝水进行冷却，在-1～-3℃时，水易结晶，无法进行循环冷却。因此往往需要更换冷却溶剂如无水乙醇，而无水乙醇易燃易爆，往往会给生产带来危险和生产成本的提高。
因此目前仍有必要提供一种新的解决方案来克服以上缺点，使得注射用阿扎胞苷工艺简单，质量合格，有利于商业化生产。
发明内容
发明人经过研究发现，当很好的控制原辅料中的细菌内毒素时，在制备过程中并不需要加入活性炭进行吸附除热原，生产出来的注射用阿扎胞苷的细菌内毒素仍是符合质量要求的。
在制备注射用阿扎胞苷的过程中减少活性炭吸附步骤，不仅能减少生产过程中的工艺步骤，提高生产效率。活性炭吸附除热原一般需要在60℃或者更高温度条件下持续搅拌，而加入阿扎胞苷的溶液需严格控制温度在2-6℃，因此需要将除热原后溶液通过配液罐夹套中的冷凝水降至2-6℃后才能加入原料药阿扎胞苷。理论上冷凝水的最低温度为接近0℃，通 过冷凝水(0℃)将除热原后溶液从高温降至2-6℃往往需要较长的时间，不仅造成能耗的增加，同时影响生产效率。
本发明人经过研究发现，当配制阿扎胞苷溶液的温度控制在2-6℃时，阿扎胞苷具有良好的稳定性。而当阿扎胞苷溶液的温度高于6℃时，可以发现阿扎胞苷的含量出现显著下降，有关物质明显上升，导致产品质量下降。
本发明人经过研究发现，当配制阿扎胞苷溶液的温度控制在4-6℃时，相对于温度控制在2-3℃，阿扎胞苷具有相同的稳定性，同时4-6℃有利于提高生产效率，减少能耗。目前溶液温度的控制主要通过先用冷凝水将加入注射用水温度降至目标范围，然后通过配液罐中循环的冷凝水进行保温控制。而冷凝水最低温度为接近0℃，当接近0℃时，冷凝水为固液共存状态，无法进行流动循环保温，因此为保持循环状态，冷凝水的温度往往控制在1-3℃。用1-3℃冷凝水将溶液温度控制在2-4℃，往往需要更长的降温时间，并且生产区间的环境温度控制在18-26℃，溶液温度更低往往需要消耗更多的能耗进行保温，增加生产成本，因此配制阿扎胞苷溶液的温度控制在4-6℃时生产效率更高，成本更低，产品质量更稳定。
本发明提供了一种注射用阿扎胞苷的制备方法，包括每支注射用阿扎胞苷中含有阿扎胞苷100mg和甘露醇100mg，其特征在于制备方法包括以下步骤：
a.量取80％注射用水，温度控制在2-6℃；
b.加入甘露醇，搅拌至完全溶解，温度控制在2-6℃；
c.加入阿扎胞苷，搅拌至完全溶解，温度控制在2-6℃；
d.过滤后进行分装，23ml/瓶；
e.按预设温度进行冷冻干燥；
f.充氮后压塞、轧盖、包装。
本发明提供了一种注射用阿扎胞苷的制备方法，其特征在于制备过程中不含活性炭吸附步骤。
本发明提供了一种注射用阿扎胞苷的制备方法，其特征在于原料药阿 扎胞苷的细菌内毒素≤0.6Eu/mg。
本发明提供了一种注射用阿扎胞苷的制备方法，其特征在于辅料甘露醇的细菌内毒素≤2.5Eu/g。
本发明提供了一种注射用阿扎胞苷的制备方法，其特征在于所制备的注射用阿扎胞苷成品细菌内毒素≤1.2Eu/mg。
本发明提供了一种注射用阿扎胞苷的制备方法，配液温度更优选为控制在4-6℃。
本发明提供了一种注射用阿扎胞苷的制备方法，其特征在于冷冻干燥过程为：
a.预冻：板层温度降至-35±5℃后放入样品，保温2小时；
b.一次升华干燥：降低真空度至50-150μbar，搁板温度以15℃/h升温至-10℃，保温15小时；
c.二次升华干燥：维持真空度至50-150μbar，搁板温度以20℃/h升温至30℃，保温18小时，充氮后压塞，出箱。
与现有技术相比，本发明冷冻干燥过程周期大大缩短，有利于提高生产效率，减少能耗。
根据本发明，制备的注射用阿扎胞苷具有生产工艺简单，能耗低，产品质量稳定，更适合商业化生产。
具体实施方式
为了更充分理解本发明，特给出以下具体实施例，但本发明不限定于以下实施例。
实施例1：
Figure PCTCN2017077026-appb-000001
制备方法为：量取80％注射用水，温度控制在2℃；加入甘露醇，搅 拌至完全溶解，温度控制在2℃；加入阿扎胞苷，搅拌至完全溶解，温度控制在2℃；过滤后进行分装，半加塞；将上述灌装好半加塞的西林瓶送入冻干箱中，预冻-35℃，保温2h；搁板温度以15℃/h升温至-10℃，保温15h；以20℃/h升温至30℃，保温18h；充氮后轧盖，压塞，包装即得。
实施例2：
Figure PCTCN2017077026-appb-000002
制备方法为：量取80％注射用水，温度控制在4℃；加入甘露醇，搅拌至完全溶解，温度控制在4℃；加入阿扎胞苷，搅拌至完全溶解，温度控制在4℃；过滤后进行分装，半加塞；将上述灌装好半加塞的西林瓶送入冻干箱中，预冻-35℃，保温2h；搁板温度以15℃/h升温至-10℃，保温15h；以20℃/h升温至30℃，保温18h；充氮后轧盖，压塞，包装即得。
实施例3：
Figure PCTCN2017077026-appb-000003
备注：甘露醇细菌内毒素为2.5EU/g，阿扎胞苷细菌内毒素为0.6EU/mg。
制备方法为：量取80％注射用水，温度控制在6℃；加入甘露醇，搅拌至完全溶解，温度控制在6℃；加入阿扎胞苷，搅拌至完全溶解，温度控制在6℃；过滤后进行分装，半加塞；将上述灌装好半加塞的西林瓶送入冻干箱中，预冻-35℃，保温2h；搁板温度以15℃/h升温至-10℃，保温15h；以20℃/h升温至30℃，保温18h；充氮后轧盖，压塞，包装即得。
将实施例1、实施例2、实施例3分别考察0天和40℃条件下6个月的性状、含量以及有关物质，结果见下表：
Figure PCTCN2017077026-appb-000004
由上表可见，配液温度分别为2℃、4℃和6℃时，注射用阿扎胞苷具有相同的稳定性。
实施例3成品细菌内毒素检测结果为小于1.2EU/mg。
实施例4：
Figure PCTCN2017077026-appb-000005
制备方法为：量取80％注射用水，温度控制在6℃；加入甘露醇，搅拌至完全溶解，温度控制在6℃；加入阿扎胞苷，搅拌至完全溶解，温度控制在6℃；过滤后进行分装，半加塞；将上述灌装好半加塞的西林瓶送入冻干箱中，预冻-40℃，保温2h；搁板温度以15℃/h升温至-10℃，保温15h；以20℃/h升温至30℃，保温18h；充氮后轧盖，压塞，包装即得。
实施例5：
Figure PCTCN2017077026-appb-000006
Figure PCTCN2017077026-appb-000007
制备方法为：量取80％注射用水，温度控制在2℃；加入甘露醇，搅拌至完全溶解，温度控制在2℃；加入阿扎胞苷，搅拌至完全溶解，温度控制在2℃；过滤后进行分装，半加塞；将上述灌装好半加塞的西林瓶送入冻干箱中，预冻-30℃，保温2h；搁板温度以15℃/h升温至-10℃，保温15h；以20℃/h升温至30℃，保温18h；充氮后轧盖，压塞，包装即得。

Claims (7)

  1. 一种注射用阿扎胞苷的制备方法，每支注射用阿扎胞苷中含有阿扎胞苷100mg和甘露醇100mg，其特征在于制备方法包括以下步骤：
    a.量取80％注射用水，温度控制在2-6℃；
    b.加入甘露醇，搅拌至完全溶解，温度控制在2-6℃；
    c.加入阿扎胞苷，搅拌至完全溶解，温度控制在2-6℃；
    d.过滤后进行分装，23ml/瓶；
    e.按预设温度进行冷冻干燥；
    f.充氮后压塞、轧盖、包装。
  2. 根据权利要求1所述的注射用阿扎胞苷的制备方法，其特征在于制备过程中不含活性炭吸附步骤。
  3. 根据权利要求1所述的注射用阿扎胞苷的制备方法，其特征在于原料药阿扎胞苷的细菌内毒素≤0.6Eu/mg。
  4. 根据权利要求1所述的注射用阿扎胞苷的制备方法，其特征在于辅料甘露醇的细菌内毒素≤2.5Eu/g。
  5. 根据权利要求1所述的注射用阿扎胞苷的制备方法，其特征在于所制备的注射用阿扎胞苷成品细菌内毒素≤1.2Eu/mg。
  6. 根据权利要求1所述的注射用阿扎胞苷的制备方法，其特征在于所述的配液温度控制在4-6℃。
  7. 根据权利要求1所述的注射用阿扎胞苷的制备方法，其特征在于冷冻干燥过程为：
    a.预冻：板层温度降至-35±5℃后放入样品，保温2小时；
    b.一次升华干燥：降低真空度至50-150μbar，搁板温度以15℃/h升温至-10℃，保温15小时；
    c.二次升华干燥：维持真空度至50-150μbar，搁板温度以20℃/h升温至30℃，保温18小时，充氮后压塞，出箱。
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