CN1463969A - 紫杉醇纳米微粒的制备方法 - Google Patents

紫杉醇纳米微粒的制备方法 Download PDF

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CN1463969A
CN1463969A CN 02133333 CN02133333A CN1463969A CN 1463969 A CN1463969 A CN 1463969A CN 02133333 CN02133333 CN 02133333 CN 02133333 A CN02133333 A CN 02133333A CN 1463969 A CN1463969 A CN 1463969A
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taxol
paclitaxel
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mother liquor
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CN1255394C (zh
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朱斌
朱颉安
章丽云
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CHENGDU SIMO NANOMETER TECHN Co Ltd
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Abstract

本发明是一种紫杉醇纳米微粒的制备方法，是在紫杉醇的醇溶液中添加0.05－5％的表面活性剂，在高速搅拌和超声震动条件下，将母液滴加到5－500倍纯净水中，并经一定时间存放后即成为纳米紫杉醇悬浮液，经冷冻干燥等方法，即可获得紫杉醇纳米微粒。本发明的方法可靠，操作简便，所需能耗很低，不产生环境污染，所制得的纳米紫杉醇具有更高的生物活性，可以充分发挥紫杉醇的治疗效果。

Description

紫杉醇纳米微粒的制备方法
本发明属于制药领域，具体是将醇溶性的紫杉醇制成紫杉醇的纳米微粒的方法。
紫杉醇(Paclitaxel)是从红豆杉或短叶紫杉中提取分离的双萜烯成分。紫杉醇是1994年7月由美国FDA批准进入市场的一种新型抗微管药物，是一种广谱抗癌药物。现已作为卵巢癌和乳腺癌的一线药物，对铂类等已有抗药性的顽固性卵巢癌亦有效，紫杉醇为具有重大突破的新一代肿瘤化疗药物。但是紫杉醇也具有显著的毒副作用，主要为骨髓抑制和神经毒性，关节痛、肌肉痛常于用药后2～3天出现，GPT升高占33％，脱发见于所有病人，常发生于治后第12～21天。另外，由于紫杉醇在红豆杉树皮中含量仅为万分之二至五，在叶、茎中含量仅为十万分之五左右，提取工艺复杂，不仅造成紫杉醇价格昂贵，而且将大量破坏现已不多的红豆杉等植物资源。为此，研制具有更高生物利用度的紫杉醇纳米微粒，大幅降低其毒副作用，减少紫杉醇使用剂量，不仅具有重大经济价值还可以减少治疗费用，对保护生态环境也有重大贡献。
本发明的目的是制备紫杉醇纳米颗粒，提高紫杉醇的生物利用度，大幅降低其毒副作用，减少紫杉醇的使用剂量，以达到降低治疗费用，充分利用红豆杉等植物资源。
本发明的目的是通过下述技术方案来实现的：
1.紫杉醇的醇溶液制备
根据需要可制成浓度为1～10％的紫杉醇的醇溶液。将离子型和非离子型表面活性剂单独或复合添加到紫杉醇的醇溶液中，制成滴加母液。表面活性剂的浓度为0.05～5％。如选用无水乙醇为醇溶剂，选用吐温-80为表面活性剂。
2.在搅拌和超声振动条件下，将含有表面活性剂的紫杉醇的醇溶液缓慢滴加到纯净水中，经一定时间存放即形成纳米紫杉醇悬浮液。纯净水的用量可为母液的5～500倍。
3.采用减压蒸发法去除紫杉醇-水悬浮液中的溶剂醇。
4.为了进一步提高紫杉醇纳米微粒的生物利用度和克服某种生物屏障，可对紫杉醇的纳米颗粒进行表面修饰。
5.如需获得纳米紫杉醇粉末，可采用真空干燥或冷冻干燥等方法。
采用本发明方法所制备的纳米紫杉醇悬浮液经激光粒度仪测定，其平均粒径为202纳米，经同济医科大学体外杀灭癌细胞试验，结果表明在低浓度的条件下，纳米紫杉醇悬浮液仍然呈现出显著的杀灭癌细胞作用(附测试结果)。附：测试结果
紫杉醇及纳米紫杉醇对三种肿瘤细胞的杀伤实验一、采用方法：乳酸脱氢酶法
将三种处于对数生长细胞K562、A549、HL-60分别调成5×104/ml接种于96孔培养板，每孔100ul，分别加入不同浓度紫杉醇或纳米紫杉醇，每种浓度平行3孔，并设立空白对照。给予10％牛血清1640培养液，每孔加100ul，最大释放孔加100ul 1％NP40，培养48小时后。吸取上清部分，每孔100ul，加乳酸脱氢酶的底物，每孔100ul，室温放置20分钟后，加1M柠檬酸(30ul/孔)终止反应。二、计算公式：杀伤活性＝OD(试验孔-自然孔)/OD(最大释放孔-自然孔)×100％三、结果见表1、表2、表3
表1不同浓度紫杉醇对K562细胞的作用(杀伤％)
    紫杉醇浓度(ug/ml)     0#     1#     2#
    100     10.7     43.8     78.3
    50     8.3     19.2     42.2
    20     6.3     13.5     22.8
    10     4.2     10.3     22.5
    5     4     7.8     17.7
    2.5     2.2     6.3     15
    1.25     1.8     6.3     14.8
    0.625     /     /     13.8
表2不同浓度紫杉醇对A549细胞的杀伤作用(杀伤％)
    紫杉醇浓度(ug/ml)     0#     1#     2#
    100     12.2     45.7     78
    50     10     28.4     57
    20     9.5     1 6.7     28
    10     7.6     10.7     22.2
    5     5.7     9.7     20.5
    2.5     1.5     7.8     18.3
    1.25     0     7.2     17.4
    0.625     /     /     15
表3不同浓度紫杉醇对HL-60细胞的杀伤作用(杀伤％)
    紫杉醇浓度(ug/ml)     0#     1#     2#
    100     11.3     40.6     80.6
    50     9.8     22.8     51.7
    20     8.4     16.8     29.8
    10     5.7     12.7     25.3
    5     3.3     11.3     23
    2.5     3.3     11     19.3
    1.25     3.1     10.5     17.7
    0.625     /     /     17.7
说明：0#为紫杉醇水溶液；1#为纳米紫杉醇悬浮液(粒度316nm)；
  2#为纳米紫杉醇悬浮液(粒度202nm)
乳酸脱氢酶底物配制：硝基氯化四氮唑(NBT)3.2mg加氧化型辅酶I(NAD+)8mg、吩嗪二甲酯硫酸盐(PMS)0.8mg，再加双蒸水至1.6ml，加乳酸钠0.4ml，加0.1M PH7.4 PBS至10ml。

Claims (4)

1.紫杉醇纳米微粒的制备方法，其特征在于将紫杉醇溶于醇中，形成紫杉醇的醇溶液；将离子型表面活性剂和非离子型表面活性剂单独或复合添加到紫杉醇的醇溶液中，制成滴加母液；然后在搅拌和超声复合条件下，将母液滴加到纯净水中，经一定时间存放后即可得到纳米紫杉醇悬浮液，若需获得紫杉醇纳米粉末，采用真空干燥或冷冻干燥等方法即可。
2.根据权利要求1所述的纳米紫杉醇微粒的制备方法，其特征在于表面活性剂的浓度为0.05-5％；纯净水的用量为母液的5-500倍。
3.根据权利要求1或2所述的纳米紫杉醇微粒的制备方法，其特征在于在搅拌的条件下，同时使用超声振动分散措施，减小紫杉醇颗粒粒径。
4.根据权利要求1、2、3所述的纳米紫杉醇微粒的制备方法，其特征在于还可对制成的纳米紫杉醇颗粒进行各种表面修饰，可进一步提高纳米紫杉醇的生物利用度或赋予某种靶向性能。
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Cited By (9)

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CN101829061A (zh) * 2010-05-14 2010-09-15 无锡纳生生物科技有限公司 一种紫杉醇纳米颗粒组合物及其制备方法
CN101973967A (zh) * 2010-10-12 2011-02-16 东北林业大学 一种水溶性纳米化紫杉醇粉体的负压反溶剂制备方法
CN105055341A (zh) * 2015-08-13 2015-11-18 黑龙江泰华源生物技术有限责任公司 一种紫杉醇白蛋白结合型冻干制剂及其制备方法
CN106974896A (zh) * 2016-05-10 2017-07-25 北京德立福瑞医药科技有限公司 一种含有疏水性化疗药物纳米颗粒和纤维蛋白胶的抗肿瘤剂
WO2017176628A1 (en) * 2016-04-04 2017-10-12 Crititech, Inc. Methods for solid tumor treatment
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CN101829061A (zh) * 2010-05-14 2010-09-15 无锡纳生生物科技有限公司 一种紫杉醇纳米颗粒组合物及其制备方法
CN101973967A (zh) * 2010-10-12 2011-02-16 东北林业大学 一种水溶性纳米化紫杉醇粉体的负压反溶剂制备方法
CN101973967B (zh) * 2010-10-12 2012-09-05 东北林业大学 一种水溶性纳米化紫杉醇粉体的负压反溶剂制备方法
US10507195B2 (en) 2015-06-04 2019-12-17 Crititech, Inc. Taxane particles and their use
US11123322B2 (en) 2015-06-04 2021-09-21 Crititech, Inc. Taxane particles and their use
US10993927B2 (en) 2015-06-04 2021-05-04 Crititech, Inc. Taxane particles and their use
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CN105055341A (zh) * 2015-08-13 2015-11-18 黑龙江泰华源生物技术有限责任公司 一种紫杉醇白蛋白结合型冻干制剂及其制备方法
CN109475492A (zh) * 2016-04-04 2019-03-15 克里蒂泰克公司 实体肿瘤治疗方法
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WO2017176628A1 (en) * 2016-04-04 2017-10-12 Crititech, Inc. Methods for solid tumor treatment
US11033542B2 (en) 2016-04-04 2021-06-15 Crititech, Inc. Methods for solid tumor treatment
AU2017246316B2 (en) * 2016-04-04 2022-09-29 Crititech, Inc. Methods for solid tumor treatment
CN109475492B (zh) * 2016-04-04 2022-04-29 克里蒂泰克公司 实体肿瘤治疗方法
CN106974896A (zh) * 2016-05-10 2017-07-25 北京德立福瑞医药科技有限公司 一种含有疏水性化疗药物纳米颗粒和纤维蛋白胶的抗肿瘤剂
US11523983B2 (en) 2017-06-09 2022-12-13 Crititech, Inc. Treatment of epithelial cysts by intracystic injection of antineoplastic particles
US11737972B2 (en) 2017-06-09 2023-08-29 Crititech, Inc. Treatment of epithelial cysts by intracystic injection of antineoplastic particles
US11160754B2 (en) 2017-06-14 2021-11-02 Crititech, Inc. Methods for treating lung disorders
US10507181B2 (en) 2017-06-14 2019-12-17 Crititech, Inc. Methods for treating lung disorders
US10398646B2 (en) 2017-06-14 2019-09-03 Crititech, Inc. Methods for treating lung disorders
US11058639B2 (en) 2017-10-03 2021-07-13 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
US11583499B2 (en) 2017-10-03 2023-02-21 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
US11918691B2 (en) 2017-10-03 2024-03-05 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer

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