CN1148192C - 细胞保护剂氨磷汀制剂及其制备方法 - Google Patents

细胞保护剂氨磷汀制剂及其制备方法 Download PDF

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CN1148192C
CN1148192C CNB001190385A CN00119038A CN1148192C CN 1148192 C CN1148192 C CN 1148192C CN B001190385 A CNB001190385 A CN B001190385A CN 00119038 A CN00119038 A CN 00119038A CN 1148192 C CN1148192 C CN 1148192C
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amifostine
preparation
ethyol
present
freezing
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CN1291475A (zh
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程培元
程光
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Nanjing Luye Pharmaceutical Co Ltd
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NANJING ZHENZHONG BIOLOGICAL ENGINEERING Co Ltd
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Priority to RU2003114443/15A priority patent/RU2264808C2/ru
Priority to PCT/CN2001/000310 priority patent/WO2002032401A1/zh
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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Abstract

本发明公开了稳定性改进的细胞保护剂氨磷汀粉针剂及其制备方法，本方法无需冻干，在无菌条件下通过调节pH，冷冻，得到晶型大小合适的单一成份的固体，过筛后可直接分装成粉针剂，其稳定性优于目前国外上市产品。

Description

细胞保护剂氨磷汀制剂及其制备方法
技术领域
本发明涉及稳定性改进的氨磷汀(即硫代磷酸二氢S-2(3-氨丙氨基)乙酯、amifostine)无菌粉针剂及其制备方法。
背景技术
氨磷汀为一种广谱细胞保护剂。以前作为军用抗辐射剂，现用作放射治疗和化学治疗的保护药。在减少抗癌药物如环磷酰胺、氯氨铂、阿霉素和抗HIV药物如3-叠氮基-3-脱氧胸苷的副作用方面疗效显著，并且不影响抗癌药或抗HIV药物的疗效。目前市售氨磷汀产品由美国生命科学有限公司独家生产，商品名为ETHYOL。该产品只有冻干粉针剂，但通过低压冻干法生产的这种非晶形式是热不稳定的。这种冻干的制剂必须保持在约-20℃的温度下和在约-70℃至-20℃的温度下运输，才可避免该配制的产品降解，这不但不方便，而且需要特殊的包装和大量的运费。美国生命科学有限公司认为：“氨磷汀非冻干型粉针剂‘干装’或‘粉装’方法，在包装散装的固体氨磷汀时涉及大量的实际问题。这类问题包括：粉末的人工操作法中的困难，需要将粉末磨至可接受的颗粒尺寸和流动性，保持无粉尘、无菌条件中的困难，和将精确剂量的固体氨磷汀装入每个小瓶中的困难。”(参见CN93117436.8)
发明内容
本发明的目的在于提供一种稳定的非冻干型的氨磷汀无菌粉针剂，该粉针由长度大小适中的氨磷汀结晶组成。本发明的目的还在于提供一种制备稳定的非冻干型氨磷汀无菌粉针剂的工业化方法，所得结晶长度大小适中，无需磨即具有良好流动性，可精确装瓶。
本发明的技术方案是：一种氨磷汀粉针剂，其特征在于由氨磷汀单一成分的结晶组成。所述的氨磷汀粉针剂，其特征在于氨磷汀的结晶中含三分子的结晶水，结晶颗粒长度为300～700μm。本发明的还提供一种氨磷汀粉针剂的制备方法，其特征在于将氨磷汀原料药溶于注射用水中，用碱液调pH至6.6～7.4后，加入乙醇，冷冻，析出结晶。所述氨磷汀粉针剂的制备方法，用碱液调节pH至6.8～7.2较好，用碱液调节pH至7.0～7.2亦好，加入乙醇，冷冻析出结晶，所用碱液可以是氢氧化钠、氢氧化钾、碳酸氢钠、碳酸钠溶液或氨液，析出颗粒长度为300～700μm的氨磷汀结晶。
所述氨磷汀粉针剂的制备方法，其特征在于，结晶时温度可以是-16～-23℃。
氨磷汀是以无水物计算的。在化疗、放疗药物使用前半小时内静脉注射，按体表面积计算，化疗时每平方米800mg，放疗时每平方米200mg，具体病例应遵医嘱。
本发明的有益效果在于产品的稳定性增加，无需冷藏，可于室温下保存二年。将本发明产品(下称南京振中氨磷汀非冻干粉针剂)与常规冻干剂及美国氨磷汀专利处方制品进行稳定性比较实验，表明本发明产品的稳定性优于这两种产品。参见表1。
   表1  常规冻干剂、美国专利冻干处方与南京振中非冻干粉针剂的
                           稳定性比较
注：所采用的条件(40℃、RH75％、90天)是美国FDA规定的加速试验方法，在此种条件下如果药物能耐受不变质，预测药物在室温条件下可贮存二年。含量测定采用经典的碘量法。
将本发明产品与国内外注射用氨磷汀进行药效比较，证明本产品总体疗效略优于目前国外产品。见表2。
   表2  国内外注射用氨磷汀药效比较表
项目分类   Z200+CY   Z100+CY   Z50+CY   E200+CY   CY   对照
原始红细胞早幼红细胞中幼红细胞晚幼红细胞   00.25±0.282.05±0.61**8.45 ±2.73**   01.15±0.783.67±1.41**6.80±3.93*   00.48±0.391.92±1.61*4.56±3.20   001.25±0.84*2.57±3.45*   000.20±0.201.73±0.38   02.00±1.896.05±2.66**12.60±4.90**
原始粒细胞早幼粒细胞中性中幼粒细胞中性晚幼粒细胞中性杆状核细胞中性分叶核细胞   0.75±0.903.55±3.1719.45±7.14**32.45±6.01**28.50±10.691.90±1.67   3.40±2.002.67±2.6622.53±6.90**30.13±3.71*24.93±1.941.67±1.23   3.68±2.172.56±1.4225.04±3.24**37.12±3.31**17.04±4.840.80±0.25   7.40±5.336.00±4.4126.40±9.70**35.33±5.70**14.80±10.880.65±0.53   10.53±7.245.80±2.1148.80 ±7.6416.20±11.477.47±4.210.47±0.59   0.40±0.490.85±0.7524.45±4.03**18.40±5.8013.95±7.281.10±0.77
成熟淋巴细胞   2.55±1.37   2.60±1.91   6.80±4.02   4.90±2.97   7.80±4.44   17.60±6.69
巨核细胞   9.25±1.85   10.67±7.43   8.20±5.19   14.00±9.94   12.33±7.41   23.00±13.35
注：(1)Z为注射用氨磷汀，CY为化疗药环磷酰胺，E为国外注射用氨磷汀；与CY组比较*P＜0.05    **P＜0.01；
(2)Z200+CY组表示使用南京振中氨磷汀产品200mg/kg效果；
(3)Z100+CY组表示使用南京振中氨磷汀产品100mg/kg效果；
(4)Z50+CY组表示使用南京振中氨磷汀产品50mg/kg效果；
(5)E200+CY组表示使用国外氨磷汀产品200mg/kg效果；
(6)CY组表示不使用氨磷汀效果；
(7)对照组表示正常值。
本发明的氨磷汀粉针剂制备方法中不加赋形剂，不经过冷冻干燥而采用真空干燥，避免了冻干粉针剂因反复冻溶(即反复降温升温)过程可能导致的制剂不稳定。制备过程中通过调pH获得大小合适的结晶，氨磷汀结晶的颗粒长度为300～700μm，这种大小的结晶可过30目筛直接装瓶。从而克服了“粉末人工操作中的困难”，无需“将粉末磨至可接受的颗粒尺寸和流动性”，克服了“保持无粉尘无菌条件中的困难和将精确剂量的固体装入每个小瓶中的困难”。
具体实施方式
实施例1：按文献方法制备氨磷汀原料，参见童增寿等药学学报1981，16(4)，302。在无菌条件下(通过国家GMP论证的车间)，室温18～22℃时，将50克氨磷汀原料药搅拌溶解在250毫升水中，滴加碳酸氢钠饱和溶液数滴，溶解完全，测溶液pH值在7.0～7.2，缓慢加入乙醇125毫升，放入冰柜中6～8小时，使其析出白色结晶性粉末，结晶颗粒长度为300～700μm，抽滤后，减压真空干燥，测水份后，过30目筛，分装于小瓶中。
实施例2：在无菌条件下(通过国家GMP论证的车间)，室温(同上)，取100克氨磷汀原料药，溶解于500毫升水中，滴加碳酸氢钠饱和溶液数滴，调溶液pH值在6.8～7.0，加无水乙醇250毫升，析晶(同上)，结晶颗粒长度为300～700μm，抽滤后，置五氧化二磷真空干燥器中干燥，测水份后，过30目筛，分装于小瓶。

Claims (6)

1.一种细胞保护剂氨磷汀粉针剂的制备方法，其特征在于将氨磷汀原料药溶于注射用水中，用碱液调pH至6.6～7.4后，加入乙醇，冷冻结晶。
2.根据权利要求1所述氨磷汀粉针剂的制备方法，其特征在于将氨磷汀原料药溶于注射用水中，用碱液调pH至6.8～7.2后，加入乙醇，冷冻，结晶。
3.根据权利要求2所述氨磷汀粉针剂的制备方法，其特征在于将氨磷汀原料药溶于注射用水中，用碱液调pH至7.0～7.2后，加入乙醇，冷冻，结晶。
4.根据权利要求2所述氨磷汀粉针剂的制备方法，其特征在于所用碱液是氢氧化钠、氢氧化钾、碳酸氢钠、碳酸钠溶液或氨液。
5.根据权利要求2所述氨磷汀粉针剂的制备方法，其特征在于冷冻结晶时温度是-16～-23℃。
6.根据权利要求2所述氨磷汀粉针剂的制备方法，其特征在于冷冻结晶的时间为6-8小时。
CNB001190385A 2000-10-19 2000-10-19 细胞保护剂氨磷汀制剂及其制备方法 Expired - Lifetime CN1148192C (zh)

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CNB001190385A CN1148192C (zh) 2000-10-19 2000-10-19 细胞保护剂氨磷汀制剂及其制备方法
AU2001248229A AU2001248229A1 (en) 2000-10-19 2001-02-28 Amifostine powder injection and its method of process
RU2003114443/15A RU2264808C2 (ru) 2000-10-19 2001-02-28 Амифостин в виде порошка для инъекций и способ его получения
PCT/CN2001/000310 WO2002032401A1 (fr) 2000-10-19 2001-02-28 Produit a injecter sous forme de poudre a base d'amifostine et son procede de preparation

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WO2007096901A1 (en) * 2006-02-24 2007-08-30 Natco Pharma Limited Novel dihydrate form of amifostine and process for its preparation
CN101347412B (zh) * 2008-09-02 2011-07-27 大连美罗药业股份有限公司 三水合氨磷汀结晶冻干制剂及其制备方法
CN102286019B (zh) * 2011-07-11 2014-02-05 大连美罗大药厂 二水合3-氨基丙基胺乙基硫代磷酸的制备方法
CN109694386B (zh) * 2019-01-23 2021-03-23 美罗药业股份有限公司 氨磷汀三水合物的制备方法

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US5167947A (en) * 1989-10-26 1992-12-01 Southwest Research Institute Enhancement of absorption of radioprotective drugs
SG47101A1 (en) * 1992-07-31 1998-03-20 Us Bioscience Crystalline amifostine compositions and methods for the preparation and use of same

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Address before: 210061 Nanjing hi tech Industrial Development Zone, Jiangsu

Patentee before: Kanghai Pharmaceutical Co.,Ltd. Nanjing

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Address after: High road 210061 Jiangsu city of Nanjing province high tech Industrial Development Zone No. 28

Patentee after: NANJING LUYE PHARMACEUTICAL Co.,Ltd.

Address before: High road 210061 Jiangsu city of Nanjing province high tech Industrial Development Zone No. 28

Patentee before: NANJING LVYE PHARMACEUTICAL CO.,LTD.

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Granted publication date: 20040505

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