CN101830970B - 一种高纯度达托霉素(Daptomycin)的纯化制备方法 - Google Patents
一种高纯度达托霉素(Daptomycin)的纯化制备方法 Download PDFInfo
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- DOAKLVKFURWEDJ-OFNKPWESSA-N daptomycin Chemical compound C([C@H]1C(=O)OC(C)C(C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)C(C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-OFNKPWESSA-N 0.000 description 1
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Abstract
本发明公开了一种高纯度达托霉素的纯化制备方法，该方法采用缓冲溶液和达托霉素粗品配成样品溶液，上复合型YT-01反相硅胶材料柱吸附，用强极性溶剂的水溶液作解析剂进行梯度洗脱或恒定浓度洗脱，其色谱纯度大于98％。
Description
技术领域
本发明涉及高纯度达托霉素(Daptomycin)的纯化制备方法。
背景技术
达托霉素(Daptomycin)是自玫瑰孢链霉菌(Streptomyces roseosporus)发酵液中提取得到的一个环酯肽类物质，达托霉素的化学式为C72H101N17O26，分子量为1620.67，其结构式如下：
同目前临床上使用的能够治疗多药耐药性革兰氏阳性病原菌所致危及生命的严重感染的药物——万古霉素、利奈唑胺、共杀菌素等相比，达托霉素具有如下特点：首先，它的作用机制与现已上市的各类抗菌药物都不相同，具有在多个方面破坏细菌细胞膜、细胞壁功能，从而迅速杀死病原菌，使耐药菌产生的几率大大降低。自2003年首次上市至今，尚未发现耐药现象；其次，达托霉素的抗菌活性强，对临床上最重要的多重耐药革兰氏阳性球菌(包括耐甲氧西林金黄色葡萄球菌、耐万古霉素粪肠球菌、耐利奈唑胺菌等)均具有强力活性；此外，达托霉素还具有抗菌谱广、毒副作用小、不良反应轻——能够用于治疗不能耐受其它抗生素治疗患者、用药次数少(每日1次)、治疗成本低等特点。
在国外，达托霉素目前已被批准用于治疗革兰氏阳性体外敏感菌所致并发性皮肤及皮肤结构感染——包括MRSA、酿脓链球菌(Streptococcus pyogenes)、无乳链球菌(Streptococcus agalactiae)、停乳链球菌亚种(Streptococcusdysgalactiae)、似马链球菌(Streptococcus equi)和VRE感染以及用于治疗由MRSA引起的心脏感染和菌血症(即血液感染和败血症)。
目前，关于达托霉素的制备方法报道很多，但大都集中在提取部分，对于高纯度达托霉素的制备报道不多，其中，美国卡比斯特制药公司申请的中国专利CN1404487报道比较全面、详细。该专利在制备高纯度达托霉素的方法方面主要阐述了：1、交替使用阴离子交换色谱、疏水相互作用色谱和阴离子交换色谱进行反复纯化，最后制得色谱纯度大于98％的达托霉素。2、阴离子交换色谱方法的缓冲体系。该专利方法反复交替使用阴离子交换色谱、疏水相互作用色谱法，操作极其复杂，产品损失很大，很难实现规模化制备。此外，目前所有关于高纯度达托霉素制备的文献报道中，均未报道其制备规模和收率情况。
发明内容
本发明的目的是为了提供一种高效、适用于规模化生产的高纯度达托霉素的纯化制备方法。
本发明所指纯化制备方法，采用了复合型YT-01反相硅胶材料进行上柱，该复合型反相硅胶材料将反相疏水相互作用和阴离子交换作用原理有机结合起来，显著提高了纯化效果，大大提高了纯化制备收率，最大限度简化了生产操作，使其更加符合实际生产情况。
本发明所指复合型YT-01反相硅胶材料是阴离子和C4反相硅胶的复合物，其粒径为150～200目。
本发明所述纯化制备方法，其复合型YT-01反相硅胶材料的用量为上样量的80～120倍体积(例如，样品量为X公斤，则反相硅胶材料的用量为80X～120X升)。
本发明所述纯化制备方法，其缓冲溶液采用醋酸铵缓冲液，缓冲液的浓度为5％～10％，缓冲液的pH值为6～8。
本发明所述纯化制备方法，其样品溶液用缓冲液配制，样品浓度为2％～8％。
本发明所述纯化制备方法，其解析方式为梯度洗脱或恒定浓度洗脱。
本发明所述纯化制备方法，其解析剂为一定浓度的强极性溶剂的水溶液，该强极性溶剂包括甲醇、乙腈，解析剂的浓度为10～40％。
除非另有说明，本说明书中所谓的样品纯度，其HPLC检测方法为：C18色谱柱；以0.1％三氟乙酸溶液/乙腈(7∶3)为流动相，检测波长220nm。
具体实施方式
下面结合实施例对本发明进行更进一步详细说明，但不是对本发明的限定。
实施例1
缓冲液：5％醋酸铵溶液，pH6.0
将达托霉素粗品100g(纯度89.22％)，用缓冲液配制成浓度为10％的溶液，过滤，得样品溶液。
装YT-01反相硅胶柱8L(粒径为150～200目)，将样品溶液上柱，先用3个柱体积的缓冲液冲洗，然后在同一缓冲液中，加入10％的乙腈解析1个柱体积，再用20％的乙腈解析2个柱体积，再用30％的乙腈解析2个柱体积，最后用40％的乙腈解析1个柱体积，大约在40％的乙腈缓冲液时，从反相硅胶上洗脱纯化的达托霉素。用HPLC方法测定，达托霉素的纯度为98.63％，收率为54.8％。
实施例2
缓冲液：8％醋酸铵溶液，醋酸调pH7.0
将达托霉素粗品100g(纯度89.22％)，用缓冲液配制成浓度为8％的样品溶液。
YT-01反相硅胶(粒径150～200目)：10L
洗脱条件：10～40％乙腈梯度洗脱
纯化后达托霉素的HPLC纯度为98.91％，收率为53.2％。
实施例3
缓冲液：10％醋酸铵溶液，醋酸调pH8.0
将达托霉素粗品100g(纯度89.22％)，用缓冲液配制成浓度为5％的样品溶液。
YT-01反相硅胶(粒径150～200目)：12L
洗脱条件：10～40％乙腈梯度洗脱
纯化后达托霉素的HPLC纯度为99.21％，收率为52.9％。
实施例4
缓冲液：8％醋酸铵溶液，醋酸调pH7.0
将达托霉素粗品100g(纯度89.22％)，用缓冲液配制成浓度为8％的样品溶液。
YT-01反相硅胶(粒径150～200目)：10L
洗脱条件：20％乙腈洗脱
纯化后达托霉素的HPLC纯度为98.89％，收率为53.1％。
实施例5
缓冲液：5％醋酸铵溶液，醋酸调pH6
将达托霉素粗品100g(纯度89.22％)，用缓冲液配制成浓度为10％的样品溶液。
YT-01反相硅胶(粒径150～200目)：8L
洗脱条件：10～40％甲醇梯度洗脱
纯化后达托霉素的HPLC纯度为98.57％，收率为53.7％。
实施例6
缓冲液：8％醋酸铵溶液，醋酸调pH7.0
将达托霉素粗品100g(纯度89.22％)，用缓冲液配制成浓度为8％的样品溶液。
YT-01反相硅胶(粒径150～200目)：10L
洗脱条件：10～40％甲醇梯度洗脱
纯化后达托霉素的HPLC纯度为98.97％，收率为53.4％。
实施例7
缓冲液：10％醋酸铵溶液，醋酸调pH8.0
将达托霉素粗品100g(纯度89.22％)，用缓冲液配制成浓度为5％的样品溶液。
YT-01反相硅胶(粒径150～200目)：12L
洗脱条件：10～40％甲醇梯度洗脱
纯化后达托霉素的HPLC纯度为99.17％，收率为52.8％。
实施倒8
缓冲液：8％醋酸铵溶液，醋酸调pH7.0
将达托霉素粗品100g(纯度89.22％)，用缓冲液配制成浓度为8％的样品溶液。
YT-01反相硅胶(粒径150～200目)：10L
洗脱条件：20％甲醇洗脱
纯化后达托霉素的HPLC纯度为99.03％，收率为53.5％。
Claims (4)
1.一种高纯度达托霉素的纯化制备方法，其特征在于采用缓冲溶液和达托霉素粗品配成样品溶液，上复合型YT-01反相硅胶材料柱吸附，用强极性溶剂的水溶液作解析剂进行梯度洗脱或恒定浓度洗脱；所述复合型YT-01反相硅胶材料是阴离子和C4反相硅胶的复合物，其粒径为150～200目；所述的缓冲溶液为醋酸铵缓冲液；醋酸铵缓冲液的浓度为5％～10％，pH值为6～8；所述的解析剂的浓度为10～40％，强极性溶剂为甲醇或乙腈。
2.如权利要求1所述的纯化制备方法，其特征在于所述复合型YT-01反相硅胶材料的用量为达托霉素粗品重量的80～120倍体积。
3.如权利要求1所述纯化制备方法，其特征在于所述采用缓冲溶液和达托霉素粗品配成的样品溶液的浓度为2％～8％。
4.如权利要求1所述纯化制备方法，其特征在于解析方式为梯度解析或恒定浓度解析。
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|---|---|---|---|---|
| CN102965304B (zh) * | 2011-10-27 | 2014-03-26 | 四川大学 | 达托霉素高产菌株及制备方法 |
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| CN104511011A (zh) * | 2013-09-29 | 2015-04-15 | 山东新时代药业有限公司 | 一种达托霉素无菌粉末及其制备方法 |
| CN105001305A (zh) * | 2015-04-29 | 2015-10-28 | 利穗科技(苏州)有限公司 | 利用层析技术提取高纯度达托霉素的方法 |
| CN104877010B (zh) * | 2015-06-15 | 2018-05-29 | 华北制药集团新药研究开发有限责任公司 | 一种普那霉素ia单组分的制备方法 |
| CN105481950B (zh) * | 2016-01-28 | 2019-01-04 | 丽珠集团福州福兴医药有限公司 | 一种达托霉素提取方法 |
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