CN102552175B - An injection with fludarabine phosphate lyophilized formulation and preparation method - Google Patents

An injection with fludarabine phosphate lyophilized formulation and preparation method Download PDF

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CN102552175B
CN102552175B CN 201110447906 CN201110447906A CN102552175B CN 102552175 B CN102552175 B CN 102552175B CN 201110447906 CN201110447906 CN 201110447906 CN 201110447906 A CN201110447906 A CN 201110447906A CN 102552175 B CN102552175 B CN 102552175B
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fludarabine phosphate
fludarabine
pre
temperature
hours
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CN102552175A (en )
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李明丽
于清路
王子熙
盛照志
随顺安
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辰欣药业股份有限公司
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Abstract

本发明公开了一种注射用磷酸氟达拉滨冻干制剂及其制备方法,属于医药技术领域,该磷酸氟达拉滨冻干制剂主要由活性成分磷酸氟达拉滨和赋形剂制备而成,磷酸氟达拉滨和赋形剂的质量比为:1∶0.5~2.0。 The present invention discloses a method for injection fludarabine phosphate fluoro lyophilized preparation and preparation method, belonging to the field of medical technology, the fludarabine phosphate lyophilized formulation prepared mainly fludarabine phosphate of the active ingredient and excipients by fluorine to, fludarabine phosphate, and a mass ratio of excipient: 0.5 to 2.0. 本发明的一种注射用磷酸氟达拉滨冻干制剂和现有技术相比,该制剂产品质地疏松,加水后迅速溶解复溶性好;在真空中进行升华干燥,含水量低,稳定性好,有利于产品长期贮存和临床使用;另外,该制剂的制备方法简单、运输方便、有效的降低了生产成本。 An injection according to the present invention, as compared with fludarabine phosphate lyophilized formulation and the prior art, the loose texture of the product formulation, a rapidly dissolving add water-insoluble complex is good; and dried in vacuum sublimation, low water content and good stability is conducive to long-term storage and clinical use of the product; further, a simple method for preparing the formulation, to facilitate transportation, effectively reducing the production cost.

Description

一种注射用磷酸氟达拉滨冻干制剂及其制备方法 An injection with fludarabine phosphate lyophilized formulation and preparation method

技术领域 FIELD

[0001] 本发明涉及医药技术领域,具体地说是一种注射用磷酸氟达拉滨冻干制剂及其制备方法。 [0001] The present invention relates to the field of medical technology, in particular an injection with phosphate lyophilized formulation and preparation method fludarabine.

背景技术 Background technique

[0002] 氟达拉滨是一种抗代谢的氟化嘌呤核苷类似物,它对淋巴细胞有高度的选择性, 它能够抑制处于静止期细胞DNA的修复及处于分裂期细胞DNA的合成,并且具有促进这些细胞凋亡的作用,已显示出良好疗效果,目前被广泛的运用于治疗各种血液系统疾病,尤其是慢性B淋巴细胞白血病。 [0002] Fludarabine is a fluorinated antimetabolite purine nucleoside analogs, it is highly selective lymphocyte, it inhibits DNA repair in resting cells and in DNA synthesis of dividing cells, and has an effect of promoting apoptosis in these cells, it has shown good efficacy results, currently widely used in the treatment of various hematological disorders, especially chronic lymphocytic leukemia B.

[0003] 磷酸氟达拉滨(Fludarabine phosphate)系由德国开发研制,由于其稳定性差,因此,在研究、临床应用、保存及其运输过程中都需要格外注意,临床应用采用冻干粉针制剂的形式较好。 [0003] fludarabine phosphate (Fludarabine phosphate) system developed by the German developed due to poor stability, therefore, require special attention in the research, and clinical application of the process, transport storage, freeze-dried powder preparation clinical applications the form is good. 现有技术中,专利CN 101947208 A给出了一种供注射用的磷酸氟达拉滨组合物及其制剂方法,但该方法中冻干工艺设计复杂,对条件要求苛刻,尤其是预冻第一阶段, 控制温度-irC〜_13°C,保持60〜90分钟,该工艺不容易精确控制,并且在这一阶段容易出现或者已经出现预冻液冻结现象,达不到所述效果。 In the prior art, Patent CN 101947208 A fluorophosphate fludarabine given composition and method of preparation for injection, but this method lyophilized complex process design for demanding conditions, in particular, pre-freezing of a stage, controlling the temperature -irC~_13 ° C, held 60~90 minutes, it is not easy to accurately control the process, and prone to occur at this stage or pre-freezing solution has a freezing point, reach the effect.

发明内容 SUMMARY

[0004] 本发明的技术任务是提供一种注射用磷酸氟达拉滨冻干制剂及其制备方法。 [0004] The technical task of the present invention is to provide fludarabine lyophilized formulation and preparation method fluoro injection with phosphate.

[0005] 本发明的技术任务是按以下方式实现的,该磷酸氟达拉滨冻干制剂主要由活性成分磷酸氟达拉滨和赋形剂制备而成,磷酸氟达拉滨和赋形剂的质量比为:1: 〇. 5〜2.0; [0005] The technical task of the present invention are achieved in the following manner, the lyophilized preparation of fludarabine phosphate, mainly the active ingredient and excipients fludarabine phosphate prepared by, fludarabine phosphate and excipients mass ratio: 1: 5~2.0 square;.

[0006] 所述的赋形剂为乳糖、甘露醇、葡萄糖、氯化钠和甘氨酸中的一种或多种的混合物。 [0006] The excipients are lactose An mannitol, glucose, sodium chloride, and glycine or more thereof.

[0007] 注射用磷酸氟达拉滨冻干制剂的制备方法步骤如下:将赋形剂溶解到注射用水中形成溶液,然后向溶液中加入活性炭,吸附后脱炭过滤;然后加入活性成分磷酸氟达拉滨, 搅拌溶解,再向溶液中加入PH调节剂调节pH值在7.0〜8.5范围内,所得溶液经过微孔滤膜两次过滤,分装后冷冻干燥,即得磷酸氟达拉滨冻干制剂; [0007] Injection fludarabine phosphate fluoro method step lyophilized formulation prepared as follows: dissolving in water for injection vehicle to form a solution, and then adding activated carbon to the solution, the carbon was filtered off after adsorption; fluoro-phosphate was then added the active ingredient fludarabine, stirring and dissolving again pH adjusting agent was added to adjust the pH within the range of 7.0~8.5, the resulting solution was filtered twice through a microporous membrane, aliquots and freeze-dried to obtain the fluorophosphate frozen fludarabine dry formulation;

[0008] 所述的赋形剂为乳糖、甘露醇、葡萄糖、氯化钠和甘氨酸中的一种或多种的混合物; [0008] The excipients are lactose, mannitol, glucose, sodium chloride, and one kind or more of glycine mixture;

[0009] 所述的pH调节剂为0. lmol/L的磷酸或氢氧化钠溶液。 pH adjusting agent [0009] is the 0. lmol / L of phosphoric acid or sodium hydroxide solution.

[0010] 所述的冷冻干燥分以下三个阶段进行: [0010] The freeze-drying the following three stages:

[0011] 1)预冻阶段:将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在0.5〜1.0小时内达到预冻温度,预冻温度范围为-35°C〜-45 °C之间,达到预冻温度后保温2小时后,即可进行升华干燥; [0011] 1) pre-freezing stage: The semifinished product filling and capping half pre-freezing is placed on a lyophilizer separator tank, and semi pre-freezing temperature reached within 0.5~1.0 hours, pre-freezing temperature range between -35 ° C~-45 ° C, incubated for 2 hours after reaching the pre-freezing temperature, it can be dried by sublimation;

[0012] 2)升华干燥阶段:干燥箱内的真空度达到13Pa〜HPa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度范围为_45°C〜_55°C之间,隔板温度不高于-20°C,升华干燥时间在8〜12小时; [0012] 2) primary drying stage: 13Pa~HPa reached degree of vacuum in the dry box, switch off the cooling tank, the cooling open cold trap, the cold trap and the temperature maintained in the range of between _45 ° C~_55 ° C, separated plate temperature of not higher than -20 ° C, sublimation drying time of 8~12 hours;

[0013] 3)再干燥阶段:再干燥阶段温度不高于30°C,再干燥时间为8〜12小时,即得磷酸氟达拉滨冻干制剂。 [0013] 3) further drying stage: stage then drying temperature not higher than 30 ° C, and then drying time of 8~12 hours to obtain the lyophilized preparation of fludarabine phosphate.

[0014] 所述的微孔滤膜两次过滤中,第一次的微孔滤膜的孔径为0.45μπι,第二次的微孔滤膜的孔径为〇.22μπι。 [0014] The microporous membrane filter twice, the first microporous membrane pore size is 0.45μπι, the microporous membrane is 〇.22μπι second aperture.

[0015] 本发明的一种注射用磷酸氟达拉滨冻干制剂和现有技术相比,该制剂产品质地疏松,加水后迅速溶解复溶性好;在真空中进行升华干燥,含水量低,稳定性好,有利于产品长期贮存和临床使用;另外,该制剂的制备方法简单、运输方便、有效的降低了生产成本。 [0015] An injection according to the present invention, fludarabine phosphate lyophilized formulation than the prior art, the loose texture of the product formulation, a rapidly dissolving add water-insoluble complex is good; and dried in vacuum sublimation, low water content, good stability, long term storage and facilitate clinical use of the product; further, a simple method for preparing the formulation, to facilitate transportation, effectively reducing the production cost.

具体实施方式 detailed description

[0016] 实施例1〜4: 磷酸氟达拉滨50g 「 1 &、乳糖50g [0016] Example embodiments 1 ~ 4: fluoro fludarabine phosphate 50g '1 & amp ;, 50g Lactose

[0017] 处万注射用水_加至2000ml 共制成1000支 At [0017] Wan 2000ml water for injection was added to the co-made _ 1000

[0018] 制法:称取处方量乳糖,加入1200ml注射用水,搅拌使全溶,按照0.5 %、1.0 %、 1 · 5 %、2 · 0 % (g/L)加入活性炭,分别于20 °C、25 °C、30 °C、35 °C 下搅拌吸附IOmin、15min、 20min、25min,加入磷酸氟达拉滨,用0. lmol/L的氢氧化钠溶液或0. lmol/L磷酸溶液调节溶液pH值为7.0、7.5、8.0、8.5后继续搅拌使全部溶解并混合均匀,所得溶液依次经0.45μπι、 0.22μπι微孔滤膜过滤,对所得半成品滤液进行检验合格后进行灌装,将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在〇.5、0.7、0.8、1.0小时内达到预冻温度,预冻温度为-35 °C、-37 °C、-42 °C、-45 °C,达到预冻温度后保温2小时,干燥箱内的真空度达到13Pa、13Pa、13.5Pa、HPa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度为-45 cC、-48 cC、-52 cC、-55 cC之间,隔板温度-20 cC、-22 cC、-25 cC、-30 [0018] Method: Weigh formulation amounts of lactose, was added 1200ml water for injection, stirring the whole solution, in accordance with the 0.5%, 1.0%, 1 · 5%, 2 · 0% (g / L) was added activated charcoal, respectively, in 20 ° C, 25 ° C, 30 ° C, stirred at 35 ° C adsorption IOmin, 15min, 20min, 25min, fludarabine phosphate was added with 0. lmol / L sodium hydroxide solution or 0. lmol / L phosphate solution pH of the solution was adjusted for filling 7.0,7.5,8.0,8.5 is kept stirred all dissolved and mixed uniformly, the resulting solution was sequentially 0.45μπι, 0.22μπι filter membrane resulting semi filtrate after passing inspection, the filling and capping semifinished product placed on the half-separator tank lyophilizer pre-frozen, pre-freezing temperature is reached and semi-finished products in 〇.5,0.7,0.8,1.0 hours, pre-freezing temperature of -35 ° C , -37 ° C, -42 ° C, -45 ° C, after reaching the pre-freezing temperature for 2 hours, the degree of vacuum in the oven was allowed reach 13Pa, 13Pa, 13.5Pa, HPa time, switch off the cooling tank, the cold trap is opened cooling and maintaining the temperature of the cold trap was -45 cC, between -48 cC, -52 cC, -55 cC, shelf temperature -20 cC, -22 cC, -25 cC, -30 cC,升华干燥时间在8、10、 11、12小时;之后进行再干燥,再干燥阶段温度20°C、25°C、28°C、30°C,再干燥时间8、10、11、 12小时后,进行无菌密封、乳盖、经质检合格后包装,即得注射用磷酸氟达拉滨。 cC, sublimation drying time of 8, 10, 11 and 12 hours; followed by re-drying, and then drying stage temperature of 20 ° C, 25 ° C, 28 ° C, 30 ° C, and then drying time 8,10,11, 12 after hours, aseptic sealing, milk cap, the quality inspection after packaging, i.e. injectable fludarabine phosphate.

[0019] 实施例5〜8: 磷酸氟达拉滨50g 「 I ^、乳糖25g [0019] Example 5 ~ 8: fludarabine phosphate, 50g "I ^, lactose 25g

[0020] 处万注射用水_加至2000ml 共制成1000支 At [0020] Wan 2000ml water for injection was added to the co-made _ 1000

[0021] 制法:称取处方量乳糖,加入1200ml注射用水,搅拌使全溶,按照0.5 %、1.0 %、 1 · 5 %、2 · 0 % (g/L)加入活性炭,分别于20 °C、25 °C、30 °C、35 °C 下搅拌吸附IOmin、15min、 20min、25min,加入磷酸氟达拉滨,用0. lmol/L的氢氧化钠溶液或0. lmol/L磷酸溶液调节溶液pH值为7.0、7.5、8.0、8.5后继续搅拌使全部溶解并混合均匀,所得溶液依次经0.45μπι、 0.22μπι微孔滤膜过滤,对所得半成品滤液进行检验合格后进行灌装,将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在〇.5、0.7、0.8、1.0小时内达到预冻温度,预冻温度为-35 °C、-37 °C、-42 °C、-45 °C,达到预冻温度后保温2小时,干燥箱内的真空度达到13Pa、13Pa、13.5Pa、14Pa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度为-45 cC、-48 cC、-52 cC、-55 cC之间,隔板温度-20 cC、-22 cC、-25 cC、-3 [0021] Method: Weigh formulation amounts of lactose, was added 1200ml water for injection, stirring the whole solution, in accordance with the 0.5%, 1.0%, 1 · 5%, 2 · 0% (g / L) was added activated charcoal, respectively, in 20 ° C, 25 ° C, 30 ° C, stirred at 35 ° C adsorption IOmin, 15min, 20min, 25min, fludarabine phosphate was added with 0. lmol / L sodium hydroxide solution or 0. lmol / L phosphate solution pH of the solution was adjusted for filling 7.0,7.5,8.0,8.5 is kept stirred all dissolved and mixed uniformly, the resulting solution was sequentially 0.45μπι, 0.22μπι filter membrane resulting semi filtrate after passing inspection, the filling and capping semifinished product placed on the half-separator tank lyophilizer pre-frozen, pre-freezing temperature is reached and semi-finished products in 〇.5,0.7,0.8,1.0 hours, pre-freezing temperature of -35 ° C , -37 ° C, -42 ° C, -45 ° C, after reaching the pre-freezing temperature for 2 hours, the degree of vacuum in the oven was allowed reach 13Pa, 13Pa, 13.5Pa, when 14Pa, switch off the cooling tank, the cold trap is opened cooling and maintaining the temperature of the cold trap was -45 cC, between -48 cC, -52 cC, -55 cC, shelf temperature -20 cC, -22 cC, -25 cC, -3 0 cC,升华干燥时间在8、10、 11、12小时;之后进行再干燥,再干燥阶段温度20°C、25°C、28°C、30°C,再干燥时间8、10、11、 12小时后,进行无菌密封、乳盖、经质检合格后包装,即得注射用磷酸氟达拉滨。 0 cC, sublimation drying time of 8, 10, 11 and 12 hours; followed by re-drying, and then drying stage temperature of 20 ° C, 25 ° C, 28 ° C, 30 ° C, and then drying time 8,10,11, after 12 hours, aseptically sealed, milk cap, the quality inspection after packaging, i.e. injectable fludarabine phosphate.

[0022] 实施例9〜12: 磷酸氟达拉滨50g 「 I ^、乳糖15〇g [0022] Example 9~12: fludarabine phosphate, 50g "I ^, lactose 15〇g

[0023] 处万注射用水_加至2000ml 共制成1000支 [0023] Wan at 2000ml water for injection was added to the co-made _ 1000

[0024] 制法:称取处方量乳糖,加入1200ml注射用水,搅拌使全溶,按照0.5 %、1.0 %、 1 · 5 %、2 · 0 % (g/L)加入活性炭,分别于20 °C、25 °C、30 °C、35 °C 下搅拌吸附IOmin、15min、 20min、25min,加入磷酸氟达拉滨,用0. lmol/L的氢氧化钠溶液或0. lmol/L磷酸溶液调节溶液pH值为7.0、7.5、8.0、8.5后继续搅拌使全部溶解并混合均匀,所得溶液依次经0.45μπι、 0.22μπι微孔滤膜过滤,对所得半成品滤液进行检验合格后进行灌装,将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在〇.5、0.7、0.8、1.0小时内达到预冻温度,预冻温度为-35 °C、-37 °C、-42 °C、-45 °C,达到预冻温度后保温2小时,干燥箱内的真空度达到13Pa、13Pa、13.5Pa、HPa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度为-45 cC、-48 cC、-52 cC、-55 cC,隔板温度-20 cC、-22 cC、-25 cC、-30 cC, [0024] Method: Weigh formulation amounts of lactose, was added 1200ml water for injection, stirring the whole solution, in accordance with the 0.5%, 1.0%, 1 · 5%, 2 · 0% (g / L) was added activated charcoal, respectively, in 20 ° C, 25 ° C, 30 ° C, stirred at 35 ° C adsorption IOmin, 15min, 20min, 25min, fludarabine phosphate was added with 0. lmol / L sodium hydroxide solution or 0. lmol / L phosphate solution pH of the solution was adjusted for filling 7.0,7.5,8.0,8.5 is kept stirred all dissolved and mixed uniformly, the resulting solution was sequentially 0.45μπι, 0.22μπι filter membrane resulting semi filtrate after passing inspection, the filling and capping semifinished product placed on the half-separator tank lyophilizer pre-frozen, pre-freezing temperature is reached and semi-finished products in 〇.5,0.7,0.8,1.0 hours, pre-freezing temperature of -35 ° C , -37 ° C, -42 ° C, -45 ° C, after reaching the pre-freezing temperature for 2 hours, the degree of vacuum in the oven was allowed reach 13Pa, 13Pa, 13.5Pa, HPa time, switch off the cooling tank, the cold trap is opened cooling and maintaining the temperature of the cold trap was -45 cC, -48 cC, -52 cC, -55 cC, shelf temperature -20 cC, -22 cC, -25 cC, -30 cC, 升华干燥时间在8、10、11、12 小时;之后进行再干燥,再干燥阶段温度20°C、25°C、28°C、30°C,再干燥时间8、10、11、12小时后,进行无菌密封、乳盖、经质检合格后包装,即得注射用磷酸氟达拉滨。 After the re-dried, and the drying stage the temperature of 20 ° C, 25 ° C, 28 ° C, 30 ° C, and then drying time hours 8,10,11,12; 8,10,11,12 sublimation drying time in hours , aseptic sealing, milk cap, passing the quality inspection after packaging, to obtain fludarabine phosphate injection with fluorine.

[0025] 实施例13: 磷酸氟达拉滨50g 「 1 &、甘露醇25g [0025] Example 13: 50g-fluoro fludarabine phosphate "1 & amp ;, 25g Mannitol

[0026] 处万注射用水_加至2000ml 共制成1000支 At [0026] Wan 2000ml water for injection was added to the co-made _ 1000

[0027] 制法:称取处方量甘露醇,加入1200ml注射用水,搅拌使全溶,按照1.0% (g/L)加入活性炭,分别于25°C下搅拌吸附15min,加入磷酸氟达拉滨,用0. lmol/L的氢氧化钠溶液或0. lmol/L磷酸溶液调节溶液pH值为7.5后继续搅拌使全部溶解并混合均匀,所得溶液依次经0.45μπι、0.22μπι微孔滤膜过滤,对所得半成品滤液进行检验合格后进行灌装,将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在0.8小时内达到预冻温度,预冻温度为_42°C,达到预冻温度后保温2小时,干燥箱内的真空度达到13.5Pa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度为_52°C,隔板温度_25°C,升华干燥时间10小时;之后进行再干燥,再干燥阶段温度28°C,再干燥时间10小时后,进行无菌密封、乳盖、经质检合格后包装,即得注射用磷酸氟达拉滨。 [0027] Method: Weigh formulated mannitol, was added 1200ml water for injection to make the whole solution was stirred, in accordance with 1.0% (g / L) was added activated charcoal were stirred at 25 ° C for adsorption 15min, added fluorophosphate fludarabine with 0. lmol / L sodium hydroxide solution or 0. lmol / L phosphate solution to adjust pH of the solution was kept stirred to the complete dissolution of 7.5 and uniformly mixed, the resulting solution was sequentially 0.45μπι, 0.22μπι filter membrane after the resulting filtrate was semi inspection for filling, and the filling cover half semifinished product placed on the pre-freezing lyophilizer separator tank, and semi pre-freezing temperature reached 0.8 hours, pre-freezing temperature of _42 ° C, after reaching the pre-freezing incubation temperature for 2 hours, the degree of vacuum in the oven was allowed reach 13.5 Pa, switch off the cooling tank, the cooling open cold trap, the cold trap temperature is maintained and _52 ° C, the separator a temperature of _25 ° C, sublimation drying for 10 hours; followed by re-drying, and then drying phase temperature of 28 ° C, and then dried for 10 hours after, aseptically sealed, milk cap, the quality inspection after packaging, i.e. injectable with fludarabine phosphate.

[0028] 实施例14: 磷酸氟达拉滨50g 葡萄糖37.5g [0028] Example 14: 50g of glucose fludarabine phosphate fluoro 37.5g

[0029] 处方乳糖62.5g 注射用水_加至2000ml 共制成1000支 [0029] Prescription 62.5g lactose was added to 2000ml water for injection were made _ 1000

[0030] 制法:称取处方量葡萄糖、乳糖,加入1200ml注射用水,搅拌使全溶,按照1.0 % (g/ L)加入活性炭,分别于25°C下搅拌吸附15min,加入磷酸氟达拉滨,用0. lmol/L的氢氧化钠溶液或〇. lmol/L磷酸溶液调节溶液pH值为7.5后继续搅拌使全部溶解并混合均匀,所得溶液依次经0.45μπι、0.22μπι微孔滤膜过滤,对所得半成品滤液进行检验合格后进行灌装,将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在0.8小时内达到预冻温度,预冻温度为_42°C,达到预冻温度后保温2小时,干燥箱内的真空度达到13.5Pa时, 关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度为_52°C,隔板温度_25°C,升华干燥时间10小时;之后进行再干燥,再干燥阶段温度28°C,再干燥时间10小时后,进行无菌密封、乳盖、经质检合格后包装,即得注射用磷酸氟达拉滨。 [0030] Method: Weigh prescribed amount of glucose, lactose, added to 1200ml water for injection to make the whole solution was stirred, in accordance with 1.0% (g / L) was added activated charcoal were stirred at 25 ° C for adsorption 15min, added fluorophosphate Dallas Bin with 0. lmol / L sodium hydroxide solution or square. lmol / L phosphoric acid solution was adjusted so that all stirring was continued to dissolve and mix the solution a pH of 7.5, the resulting solution was sequentially 0.45μπι, 0.22μπι microporous membrane was filtered, the filtrate obtained semi-finished product inspection after filling, the filling and capping of the semi-frozen semi-finished product is placed on the pre-separator tank lyophilizer, and semi pre-freezing temperature reached 0.8 hours, the pre- freezing temperature of _42 ° C, after reaching the pre-freezing incubation temperature for 2 hours, the degree of vacuum in the oven was allowed reach 13.5 Pa, switch off the cooling tank, the cooling open cold trap, the cold trap temperature is maintained and _52 ° C, separated plate temperature _25 ° C, sublimation drying for 10 hours; followed by re-drying, and then drying phase temperature of 28 ° C, and then dried for 10 hours after, aseptically sealed, milk cap, the quality inspection after packaging, to obtain injection fludarabine phosphate.

[0031] 实施例15: 磷酸氟达拉滨50g 氯化钠50g [0031] Example 15: sodium fluorophosphate fludarabine 50g 50g

[0032] 处万注射用水_加至2000ml 共制成1000支 At [0032] Wan 2000ml water for injection was added to the co-made _ 1000

[0033] 制法:称取处方量氯化钠,加入1200ml注射用水,搅拌使全溶,按照1.0% (g/L)加入活性炭,分别于25°C下搅拌吸附15min,加入磷酸氟达拉滨,用0. lmol/L的氢氧化钠溶液或0. lmol/L磷酸溶液调节溶液pH值为7.5后继续搅拌使全部溶解并混合均匀,所得溶液依次经0.45μπι、0.22μπι微孔滤膜过滤,对所得半成品滤液进行检验合格后进行灌装,将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在0.8小时内达到预冻温度,预冻温度为_42°C,达到预冻温度后保温2小时,干燥箱内的真空度达到13.5Pa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度为_52°C,隔板温度_25°C,升华干燥时间10小时;之后进行再干燥,再干燥阶段温度28°C,再干燥时间10小时后,进行无菌密封、乳盖、经质检合格后包装,即得注射用磷酸氟达拉滨。 [0033] Method: Weigh prescribed amount of sodium chloride was added 1200ml water for injection to make the whole solution was stirred, in accordance with 1.0% (g / L) was added activated charcoal were stirred at 25 ° C for adsorption 15min, added fluorophosphate Dallas Bin with 0. lmol / L sodium hydroxide solution or 0. lmol / L phosphoric acid solution was adjusted so that all stirring was continued to dissolve and mix the solution a pH of 7.5, the resulting solution was sequentially 0.45μπι, 0.22μπι microporous membrane was filtered, the filtrate obtained semi-finished product inspection after filling, the filling and capping of the semi-frozen semi-finished product is placed on the pre-separator tank lyophilizer, and semi pre-freezing temperature reached 0.8 hours, the pre- freezing temperature of _42 ° C, after reaching the pre-freezing incubation temperature for 2 hours, the degree of vacuum in the oven was allowed reach 13.5 Pa, switch off the cooling tank, the cooling open cold trap, the cold trap temperature is maintained and _52 ° C, separated plate temperature _25 ° C, sublimation drying for 10 hours; followed by re-drying, and then drying phase temperature of 28 ° C, and then dried for 10 hours after, aseptically sealed, milk cap, the quality inspection after packaging, to obtain injection fludarabine phosphate.

[0034] 实施例16: 磷酸氟达拉滨50g F ^ &、甘氨酸62.5g [0034] Example 16: fluorine fludarabine phosphate 50g F ^ & amp ;, 62.5g Glycine

[0035] 处万注射用水_加至2000ml 共制成1000支 At [0035] Wan 2000ml water for injection was added to the co-made _ 1000

[0036] 制法:称取处方量甘氨酸,加入1200ml注射用水,搅拌使全溶,按照1.0% (g/L)加入活性炭,分别于25°C下搅拌吸附15min,加入磷酸氟达拉滨,用0. lmol/L的氢氧化钠溶液或0. lmol/L磷酸溶液调节溶液pH值为7.5后继续搅拌使全部溶解并混合均匀,所得溶液依次经0.45μπι、0.22μπι微孔滤膜过滤,对所得半成品滤液进行检验合格后进行灌装,将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在0.8小时内达到预冻温度,预冻温度为_42°C,达到预冻温度后保温2小时,干燥箱内的真空度达到13.5Pa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度为_52°C,隔板温度_25°C,升华干燥时间10小时;之后进行再干燥,再干燥阶段温度28°C,再干燥时间10小时后,进行无菌密封、乳盖、经质检合格后包装,即得注射用磷酸氟达拉滨。 [0036] Method: Weigh the amount of glycine formulation, was added 1200ml water for injection to make the whole solution was stirred, in accordance with 1.0% (g / L) was added activated charcoal were stirred at 25 ° C for adsorption 15min, fludarabine phosphate was added, adjustment 0. lmol / L sodium hydroxide solution or 0. lmol / L phosphoric acid solution and stirring was continued so that all the solution is uniformly dissolved and mixed a pH of 7.5, the resulting solution was sequentially 0.45μπι, 0.22μπι filter membrane, the resulting semi-finished products after inspection filtrate was filled, and the filling cover half semifinished product placed on the pre-freezing lyophilizer separator tank, and semi pre-freezing temperature reached 0.8 hours, the pre-freezing temperature when _42 ° C, after reaching the pre-freezing temperature for 2 hours, the degree of vacuum in the oven was allowed reach 13.5 Pa, switch off the cooling tank, the cooling open cold trap, the cold trap temperature is maintained and _52 ° C, the temperature of the separator _25 ° C, sublimation drying for 10 hours; followed by re-drying, and then drying phase temperature of 28 ° C, and then dried for 10 hours after, aseptically sealed, milk cap, the quality inspection after packaging, i.e. injectable fludarabine phosphate.

[0037] 对实施例1〜16中所制得的制剂进行外观、复溶性进行考察,发现实施例中所有冻干粉针成型良好,呈疏松状块状物,在加入注射用水后均能较快的溶解,所得溶液的澄清度合格。 [0037] The formulations prepared in Example 1~16 the appearance of the embodiment, the insoluble complex to inspect all embodiments found good freeze-dried powder molding was loose form lumps, after addition of water for injection can more fast dissolution, the resulting solution clarity qualified.

[0038] 实验例: [0038] Experimental Example:

[0039] 对实施例2制得的成品进行稳定性考察。 [0039] Example 2 was the finished product stability monitoring embodiment.

[0040] (1)影响因素试验 [0040] (1) Test factors

[0041] 将本发明实施例2制得的成品制剂置于光强度45001X、60 °C恒温箱、25 °C RH92.5 % 条件下,分别于第5、10天取样,分别考察性状、酸度、溶液澄清度与颜色、有关物质和含量的变化,试验结果见表1、表2。 [0041] Formulation Example 2 was finished the embodiment of the present invention into the optical intensity 45001X, 60 ° C incubator under conditions of 25 ° C RH92.5%, respectively at 5, 10-day sample were investigated traits, acidity , clarity and color of the solution, change in the material and content of the test results shown in table 1, table 2.

[0042] 表1影响因素试验考察结果 [0042] Table 1 Effect factor test results of the examinations

[0043] [0043]

Figure CN102552175BD00071

[0044] 表2影响因素试验考察结果 [0044] Table 2 Influence factor test results of the examinations

[0045] [0045]

Figure CN102552175BD00072

[0046] [0046]

Figure CN102552175BD00081

[0047] (2)加速试验 [0047] (2) acceleration test

[0048] 将本发明实施例2制得的成品制剂置于40°CRH75%恒温恒湿箱中,分别于0、1、2、 3、6月取样,按重点考察检测项目,结果见表3、表4。 [0048] The embodiments of the present invention obtained in Example 2 was placed FPP 40 ° CRH75% constant temperature and humidity tank, respectively 0,1,2, 3, June, sampling, testing items by the emphasis on the results shown in Table 3 ,Table 4.

[0049] 表3加速试验考察结果 [0049] Table 3 Test results of the examinations accelerated

[0050] [0050]

Figure CN102552175BD00082

[0051] 表4加速试验考察结果 [0051] Table 4 Test results of the examinations accelerated

[0052] [0052]

Figure CN102552175BD00083

[0053] 以上结果表明:按照实施例2制得的成品在40°C相对湿度为75%的条件下,经过6 个月的考察,制剂的性状、酸度、溶液澄清度与颜色、有关物质和含量的测定结果与实验前同批制剂样品分析结果基本一致,产品冻形美观、复溶性好、各项指标无明显变化,产品质量稳定,说明了本发明制剂的。 [0053] The above results show: obtained as described in Example 2 finished at 40 ° C relative humidity 75% conditions, after inspection six months, traits formulation acidity, solution clarity and color, related substances and batch sample analysis result with the measurement result with the experimental formulation before contents are basically the same product freeze-shaped appearance, good soluble complex, no significant change in the indicators, product quality and stability, the formulations of the present invention is described.

Claims (2)

  1. 1. 一种注射用磷酸氟达拉滨冻干制剂的制备方法,所述的磷酸氟达拉滨冻干制剂由活性成分磷酸氟达拉滨和赋形剂制备而成,磷酸氟达拉滨和赋形剂的质量比为:1:0.5〜2.0;其特征在于制备步骤如下:将赋形剂溶解到注射用水中形成溶液,然后向溶液中加入活性炭,吸附后脱炭过滤;然后加入活性成分磷酸氟达拉滨,搅拌溶解,再向溶液中加入PH调节剂调节PH值在7.0〜8.5范围内,所得溶液经过微孔滤膜两次过滤,分装后冷冻干燥,即得磷酸氟达拉滨冻干制剂; 所述的赋形剂为乳糖、甘露醇、葡萄糖、氯化钠和甘氨酸中的一种或多种的混合物; 所述的pH调节剂为0. lmol/L的磷酸或氢氧化钠溶液; 所述的冷冻干燥分以下三个阶段进行: 1) 预冻阶段:将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在0.5〜1.0小时内达到预冻温度,预冻温 An injectable preparation of fludarabine phosphate fluoro lyophilized formulations, excipients and fludarabine prepared by the fluorophosphate fludarabine lyophilized formulation of the active ingredient fluoro phosphate, fludarabine and a mass ratio of excipient: 1: 0.5~2.0; wherein the preparation steps of: dissolving in water for injection vehicle to form a solution, and then adding activated carbon to the solution, the carbon was filtered off after adsorption; activity was then added fludarabine phosphate fluorine component, stirring to dissolve, was added again to adjust the PH value PH adjusting agent in the range of 7.0~8.5, the resulting solution was filtered twice through a microporous membrane, aliquots and freeze-dried to obtain the fluorophosphate of Bin pull lyophilized formulation; the excipient is lactose a mannitol, glucose, sodium chloride, and glycine or more thereof; said pH adjusting agent is 0. lmol / L phosphate or sodium hydroxide solution; the lyophilization divided into the following three stages: 1) pre-freezing stage: the semifinished product filling and capping half pre-freezing is placed on a lyophilizer separator tank, and semi-finished products pre-freezing temperature is reached, the pre-freezing temperature 0.5~1.0 hours 范围为-35 °C〜-45°C之间,达到预冻温度后保温2小时后,即可进行升华干燥; 2) 升华干燥阶段:干燥箱内的真空度达到13Pa〜HPa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度范围为-45 °C〜-55 °C之间,隔板温度为-30〜-20°C,升华干燥时间在8〜12小时; 3) 再干燥阶段:再干燥阶段温度为20〜30°C,再干燥时间为8〜12小时,即得磷酸氟达拉滨冻干制剂。 In the range of between -35 ° C~-45 ° C, after 2 hours of incubation reach a pre-freezing temperature, can be dried by sublimation; 2) primary drying stage: when the degree of vacuum in the oven was allowed reach 13Pa~HPa, closed refrigeration switch boxes, open refrigeration cold trap, the cold trap and the temperature range is maintained between -45 ° C~-55 ° C, the temperature of the separator to -30~-20 ° C, sublimation drying time of 8~12 hours; 3) and then drying stage: further drying stage temperature 20~30 ° C, and then drying time of 8~12 hours to obtain the fluorophosphate fludarabine lyophilized formulation.
  2. 2. 根据权利要求1所述的注射用磷酸氟达拉滨冻干制剂的制备方法,其特征在于所述的微孔滤膜两次过滤中,第一次的微孔滤膜的孔径为〇.45μπι,第二次的微孔滤膜的孔径为0.22ym〇 2. Injection fludarabine phosphate method of preparing a lyophilized formulation according to claim wherein said microporous membrane filter twice, the first pore size microporous membrane is square .45μπι, the second microporous membrane pore size is 0.22ym〇
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US20040006041A1 (en) * 2002-05-24 2004-01-08 Dorla Mirejovsky Aqueous fludarabine phosphate composition
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