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WO2020147421A1 - 一种舒更葡糖的分离纯化方法 - Google Patents

一种舒更葡糖的分离纯化方法 Download PDF

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WO2020147421A1
WO2020147421A1 PCT/CN2019/120176 CN2019120176W WO2020147421A1 WO 2020147421 A1 WO2020147421 A1 WO 2020147421A1 CN 2019120176 W CN2019120176 W CN 2019120176W WO 2020147421 A1 WO2020147421 A1 WO 2020147421A1
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sugammadex
phase
separating
solution
purifying
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PCT/CN2019/120176
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French (fr)
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江必旺
王希
李易
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苏州纳微科技股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass

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  • the invention relates to the field of medicine purification, in particular to a method for efficiently separating and purifying sugammadex.
  • Sugammadex is a selective antagonist of steroidal muscle relaxants, which is used to quickly reverse the neuromuscular blockade caused by the anesthetics rocuronium and vecuronium during surgery in adult patients.
  • Shu Glucose is a synthetic modified ⁇ -cyclodextrin composed of a lipophilic core and a hydrophilic outer end.
  • the administration of sugammadex via intravenous injection can significantly improve the recovery of muscle relaxation after surgery.
  • the rapid reversal of the neuromuscular blockade of steroidal muscle relaxants in a short time is of positive significance for improving the safety of general anesthesia.
  • CN201810153493.0 provides a method for separating and purifying sugammadex, which describes the separation and purification using C18 reversed-phase column chromatography, and the mobile phase is ultrapure water and acetonitrile.
  • the method uses a solvent as an organic reagent, which is harmful. Therefore, it is necessary to do further research on the separation, purification and preparation of sugammadex.
  • the purpose of the present invention is to provide a method for efficiently separating and purifying sugammadex. It only needs one step of chromatographic purification to meet the requirements of sugammadex purity greater than 99.0% and single impurities less than 0.1%, and the purification yield is high and stable. At the same time, the invention uses a pure water phase, no organic solvent, low cost, environmental protection and green, and is suitable for industrial separation and purification.
  • the technical scheme of the present invention is as follows: a method for separating and purifying sugammadex, including the following steps: dissolving and filtering the crude sugammadex extract; and removing the filtered sugammadex solution Load the sample to a weak anion exchange resin chromatography column for chromatography; use a salt solution as the mobile phase to elute the sugammadex solution; collect the target peak sugammadex solution in sections to determine the components that meet the requirements The solution was collected to obtain purified sugammadex.
  • the microsphere model of the weak anion exchange resin is UniDEAE.
  • the weak anion exchange resin chromatography column is equilibrated, first with 40%-50% phase B for impurity removal, and then with 100% phase A for equilibrium.
  • the gradient elution process is to wash with phase A first, and then perform gradient elution with A and B relative to the main peak.
  • the elution gradient concentration ranges from 0% to 32%.
  • the gradient elution process is as follows: in the first stage, wash with phase A; in the second stage, use A and B phase gradient to elute the main peak, wherein the concentration of phase B is increased from 0% to 4%; and third In the fourth stage, the concentration of phase B is increased from 8% to 20%; in the fifth stage, the concentration of phase B is increased from 20% to 32%.
  • the purity of the crude sugammadex extract is 90%-95%.
  • the purity of the purified sugammadex is above 99.0%.
  • the yield of the purified sugammadex is above 59.0%.
  • UniDEAE is a weak anion exchange chromatography medium. Its matrix is monodisperse polyacrylate, and the surface of the matrix is also bonded with tertiary amine functional groups.
  • the polyacrylate matrix has very weak hydrophobicity and can separate and purify sugammadex in the pure water phase. At the same time, it has the characteristics of a polymer matrix and has good alkali resistance and can be used in relatively high alkaline conditions.
  • Activated chromatographic media under flushing has more excellent impact resistance, alkali resistance and aging resistance, far better than traditional silica gel matrix reversed-phase chromatography packing, so it has a long service life.
  • UniDEAE chromatography media has strictly controlled particle size and pore structure (particle size is 36 ⁇ m, pore size , As shown in Figure 1, the microscopic scanning electron microscope image of the chromatographic medium).
  • Sugammadex is a synthetic modified ⁇ -cyclodextrin, composed of a lipophilic core and a hydrophilic outer end.
  • the functional groups and matrix properties of UniDEAE can bind and separate Sugammadex well and can be used as Sugammadex.
  • the chromatographic medium for sugar separation and purification has a good pertinence.
  • the invention uses sodium acetate aqueous solution and sodium chloride aqueous solution as mobile phases, and can complete the elution of the main peak of sugammadex with 20-22 column volumes without using organic solvents, so the mobile phase used in the method of the invention is safe and pollution-free And the cost is lower.
  • the invention adopts UniDEAE-30S as a stationary phase, through gradient elution, the purity of sugammadex is higher than 99.0%, the single impurities are less than 0.1%, and the yield can reach 59.0%, which is suitable for the deep purification of sugammadex.
  • the method of the present invention separates and purifies sugammadex, not only has high purity, high yield and stability, but also has simple and convenient operation, the used stationary phase can be reused, the used mobile phase is environmentally friendly and harmless, and the cost is greatly reduced.
  • Figure 1 is a scanning electron micrograph of UniDEAE microspheres used in Example 1.
  • Fig. 2 shows the HPLC analysis of the crude sugammadex extract before purification in Example 1.
  • Figure 3 shows the high performance liquid chromatography analysis of sugammadex purified in Example 1.
  • a method for the separation and purification of sugammadex comprising the following steps: dissolving and filtering the crude sugammadex extract; loading the filtered sugammadex solution to a weak anion exchange resin chromatography column. Chromatography; using a salt solution as the mobile phase for elution to the sugammadex solution; collect the target peak sugammadex solution in sections, and summarize the components that meet the requirements to obtain purified sugammadex.
  • the microsphere model of the weak anion exchange resin is UniDEAE.
  • the weak anion exchange resin chromatography column is equilibrated, first with 40%-50% phase B for impurity removal, and then with 100% phase A for equilibrium.
  • the gradient elution process is to wash with phase A first, and then perform gradient elution with A and B relative to the main peak.
  • the elution gradient concentration ranges from 0% to 32%.
  • the gradient elution process is as follows: in the first stage, wash with phase A; in the second stage, use A and B phase gradient to elute the main peak, wherein the concentration of phase B is increased from 0% to 4%; and third In the fourth stage, the concentration of phase B is increased from 8% to 20%; in the fifth stage, the concentration of phase B is increased from 20% to 32%.
  • the microsphere model of the weak anion exchange resin is UniDEAE-30S.
  • the purity of the crude sugammadex extract is 90%-95%.
  • the purity of the purified sugammadex is above 99.0%.
  • the yield of the purified sugammadex is above 59.0%.
  • FIG. 2 shows the HPLC analysis of the crude extract of Shugenglucose before purification, and it can be seen that there are certain impurities.
  • Figure 3 shows the purified Shugenglucose HPLC analysis. It can be seen that there are very few impurities and very small peaks.
  • the flow rate is controlled at 0.4ml/min.
  • the gradient elution process is as follows: first rinse with 100% phase A for 15 minutes, then increase the concentration gradient from 0% B to 4% B within 15-20 minutes, and increase the concentration gradient from 4% B to 8% within 20-40 minutes B, the concentration gradient increases from 8% B to 20% B within 40-120 minutes, and the concentration gradient increases from 20% B to 32% B within 120-200 minutes.
  • the solution of the target peak is collected in sections, and the components that meet the requirements are summarized. After high performance liquid chromatography analysis, the purity of sugammadex in the eluent is 99.2%, the single impurities are less than 0.1%, and the yield is 23.3%.
  • the gradient elution process is that 10% B is increased to 40% B and eluted 20 column volumes. Collect the solution of the target peak in sections, and summarize the components that meet the requirements. After high performance liquid chromatography analysis, the purity of the sugammadex in the eluent is 98.310%, and the single impurity content exceeds 0.1%, which is not qualified. section.
  • the invention is used for the deep purification of sugammadex, only one step of chromatographic purification can meet the requirement of sugammadex with a single impurities of less than 0.1%, and the purification yield is high and stable.
  • the invention uses sodium acetate aqueous solution and sodium chloride aqueous solution as mobile phases, does not use organic solvents, and the mobile phases used are safe, pollution-free and low in cost.
  • the separation method of the invention is simple and convenient, can be used for large-scale production, and greatly reduces production costs.

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Abstract

提供了一种高效分离纯化舒更葡糖的方法，包括以下步骤，将舒更葡糖粗提取物进行溶解、过滤；将上述过滤后的溶液上样到装有弱阴离子交换树脂中进行层析；采用盐溶液作为流动相对目标产物进行洗脱；分段收集目的峰值的溶液，对符合要求的组份液进行汇总。该方法用于舒更葡糖的深度精纯，仅需一步层析纯化即可满足舒更葡糖纯度大于99.0％，单杂小于0.1％的要求，纯化收率高而稳定；采用醋酸钠水溶液和氯化钠水溶液作为流动相，不采用有机溶剂，所用流动相安全、无污染且成本较低；分离方法简单方便，可用于规模化生产，大大降低生产成本。

Description

一种舒更葡糖的分离纯化方法 技术领域
本发明涉及药物纯化领域，特别是一种高效分离纯化舒更葡糖的方法。
背景技术
舒更葡糖(Sugammadex)属于甾体类肌松药的选择性拮抗剂，用于快速逆转成年患者手术中麻醉剂罗库溴铵、维库溴铵引起的神经肌肉阻断。舒更葡糖是人工合成改良γ-环糊精，由亲脂核心和亲水外端组成。舒更葡糖经由静脉注射给药，可以显著改善手术后肌松的恢复，短时间内迅速逆转甾体类肌松药的神经肌肉阻滞作用对于提高全身麻醉的安全性具有积极的意义。
结构式如下：
Figure PCTCN2019120176-appb-000001
目前国内外专利、文献等对舒更葡糖的报道多为合成方法和临床方面的专利，分离纯化方法鲜有报道。CN201810153493.0提供了一种舒更葡糖的分离纯化方法，其中描述了采用C18反相柱色谱分离纯化，流动相为超纯水和乙腈，该方法使用溶剂为有机试剂，有一定危害。因此有必要对舒更葡糖的分离、纯化和制备做更进一步的研究。
发明内容
本发明的目的在于提供一种高效分离纯化舒更葡糖的方法，仅需一步层析纯化即可满足舒更葡糖纯度大于99.0％，单杂小于0.1％的要求，纯化收率高而稳定，同时本发明使用纯水相，无有机溶剂， 成本低，环保绿色，适合工业化分离纯化。
为达到上述目的，本发明的技术方案如下：一种舒更葡糖的分离纯化方法，包括以下步骤：将舒更葡糖粗提取物进行溶解、过滤；将上述过滤后的舒更葡糖溶液上样到弱阴离子交换树脂层析柱中进行层析；采用盐溶液作为流动相对所述舒更葡糖溶液进行洗脱；分段收集目的峰值的舒更葡糖溶液，对符合要求的组份液进行汇总，得到纯化的舒更葡糖。
优选的，所述流动相为：A相：pH＝5.5的20mM醋酸钠；B相：pH＝5.5的20mM醋酸钠+1MNaCl。
优选的，所述弱阴离子交换树脂的微球型号是UniDEAE。
优选的，上样前，对所述弱阴离子交换树脂层析柱进行平衡，先用40％-50％B相进行除杂，后用100％A相进行平衡。
优选的，所述梯度洗脱过程为，先用A相冲洗，再用A、B相对主峰进行梯度洗脱。
优选的，所述B相溶液中，洗脱梯度浓度范围为0％-32％。
优选的，所述梯度洗脱过程为，第一阶段，用A相冲洗；第二阶段，用A、B相梯度洗脱主峰，其中，B相的浓度由0％提高至4％；第三阶段，B相的浓度由4％提高至8％；第四阶段，B相的 浓度由8％提高至20％；第五阶段，B相的浓度由20％提高至32％。
优选的，所述舒更葡糖粗提取物的纯度为90％-95％。
优选的，所述纯化的舒更葡糖的纯度在99.0％以上。
优选的，所述纯化的舒更葡糖的收率在59.0％以上。
UniDEAE是一种弱阴离子交换层析介质，其基质为单分散的聚丙烯酸酯，基质表面还键合了叔胺基功能基团。该聚丙烯酸酯基质疏水性很弱，可以在纯水相中分离纯化舒更葡糖，同时它具有高分子聚合物基质的特点，具有很好的耐碱性，可以在比较高的碱性条件下冲洗活化层析介质，具有更优异的耐冲击性、耐碱性及耐老化性，远远优于传统硅胶基质的反相色谱填料，因此具有很长的使用寿命。
同时UniDEAE层析介质具有严格控制的粒径大小和孔径结构(粒径为36μm，孔径
Figure PCTCN2019120176-appb-000002
，如图1，该层析介质的微观扫描电镜图)。舒更葡糖是人工合成改良γ-环糊精，由亲脂核心和亲水外端组成，UniDEAE的功能基团和基质性质可以很好地结合和分离舒更葡糖，用作舒更葡糖分离纯化的层析介质时具有很好的针对性。
本发明采用醋酸钠水溶液和氯化钠水溶液作为流动相，用20-22个柱体积就可完成舒更葡糖主峰的洗脱，不采用有机溶剂，因此本 发明方法所用流动相安全、无污染且成本较低。
本发明采用UniDEAE-30S作为固定相，通过梯度洗脱可使舒更葡糖纯度高于99.0％，单杂小于0.1％，收率可达59.0％，适用于舒更葡糖的深度提纯。
因此，本发明方法分离纯化舒更葡糖，不仅纯度高、收率高且稳定，而且操作简单方便，所用固定相可重复利用，所用流动相环保无危害，大大降低成本。
附图说明
图1为实施例1使用的UniDEAE微球的的扫描电镜照片。
图2为实施例1提纯前的舒更葡糖粗提取物的高效液相色谱分析。
图3为实施例1纯化后的舒更葡糖的高效液相色谱分析。
具体实施方式
下面结合具体实施例对本发明的技术方案作进一步的描述，但本发明并不限于这些实施例。
一种舒更葡糖的分离纯化方法，包括以下步骤：将舒更葡糖粗提取物进行溶解、过滤；将上述过滤后的舒更葡糖溶液上样到弱阴 离子交换树脂层析柱中进行层析；采用盐溶液作为流动相对所述舒更葡糖溶液进行洗脱；分段收集目的峰值的舒更葡糖溶液，对符合要求的组份液进行汇总，得到纯化的舒更葡糖。
优选的，所述流动相为：A相：pH＝5.5的20mM醋酸钠；B相：pH＝5.5的20mM醋酸钠+1MNaCl。
优选的，所述弱阴离子交换树脂的微球型号是UniDEAE。
优选的，上样前，对所述弱阴离子交换树脂层析柱进行平衡，先用40％-50％B相进行除杂，后用100％A相进行平衡。
优选的，所述梯度洗脱过程为，先用A相冲洗，再用A、B相对主峰进行梯度洗脱。
优选的，所述B相溶液中，洗脱梯度浓度范围为0％-32％。
优选的，所述梯度洗脱过程为，第一阶段，用A相冲洗；第二阶段，用A、B相梯度洗脱主峰，其中，B相的浓度由0％提高至4％；第三阶段，B相的浓度由4％提高至8％；第四阶段，B相的浓度由8％提高至20％；第五阶段，B相的浓度由20％提高至32％。
优选的，所述弱阴离子交换树脂的微球型号是UniDEAE-30S。
优选的，所述舒更葡糖粗提取物的纯度为90％-95％。
优选的，所述纯化的舒更葡糖的纯度在99.0％以上。
优选的，所述纯化的舒更葡糖的收率在59.0％以上。
实施例1
取纯度为93.11％的舒更葡糖粗提取物，加水溶解，溶液中舒更葡糖含量为50mg/mL。待溶液澄清后，用孔径为0.45μm滤膜过滤，收集滤液待用。采用4.6×250mm的色谱柱，UniDEAE-30S微球(苏州纳微科技有限公司生产)作为层析柱填料，装柱体积为4.2ml。以20mM醋酸钠溶液(A相)和20mM醋酸钠+1MNaCl(B相)作为流动相进行梯度洗脱。对层析柱进行柱前预处理，先用50％B相进行除杂，后用100％A相进行平衡。流速控制在0.4ml/min。梯度洗脱过程为，先用100％A相冲洗15分钟，后在15-20分钟内洗脱浓度梯度由0％B提高至4％B，20-40分钟内浓度梯度由4％B提高至8％B，40-120分钟内浓度梯度由8％B提高至20％B，120-200分钟内浓度梯度由20％B提高至32％B。分段收集目的峰值的溶液，对符合要求的组份液进行汇总，经高效液相色谱分析，洗脱液中舒更葡糖的纯度99.658％，单杂小于0.1％，收率59.5％。
图2是提纯前的舒更葡糖粗提取物的高效液相色谱分析，可见有一定的杂质。图3是提纯后的舒更葡糖高效液相色谱分析，可见杂质非常少，杂峰非常小。
实施例2
取纯度为92.55％的舒更葡糖粗提取物，加水溶解，溶液中舒更葡糖含量为50mg/mL。待溶液澄清后，用孔径为0.45μm滤膜过滤，收集滤液待用。采用4.6×250mm的色谱柱，UniQ-30S微球作为层析柱填料，装柱体积为4.2ml。以20mM醋酸钠溶液(A相)和20mM醋酸钠+1MNaCl(B相)作为流动相进行梯度洗脱，对层析柱进行柱前预处理，先用50％B相进行除杂，后用100％A相进行平衡。流速控制在0.4ml/min。梯度洗脱过程为，先用100％A相冲洗15分钟，后在15-20分钟内浓度梯度由0％B提高至4％B，20-40分钟内浓度梯度由4％B提高至8％B，40-120分钟内浓度梯度由8％B提高至20％B，120-200分钟内浓度梯度由20％B提高至32％B。分段收集目的峰值的溶液，对符合要求的组份液进行汇总，经高效液相色谱分析，洗脱液中舒更葡糖的纯度99.2％，单杂小于0.1％，收率23.3％。
实施例3
取纯度为92.55％的舒更葡糖粗提取物，加水溶解，溶液中舒更葡糖含量为50mg/mL。待溶液澄清后，用孔径为0.45μm滤膜过滤，收集滤液待用。采用4.6×250mm的色谱柱，UniDEAE-30S微球作为层析柱填料，装柱体积为4.2ml。以20mM醋酸钠溶液(A相)和 20mM醋酸钠+1MNaCl(B相)作为流动相进行梯度洗脱，对层析柱进行柱前预处理，先用50％B相进行除杂，后用100％A相进行平衡。流速控制在0.4ml/min。梯度洗脱过程为，10％B提高至40％B洗脱20个柱体积。分段收集目的峰值的溶液，对符合要求的组份液进行汇总，经高效液相色谱分析，洗脱液中舒更葡糖的纯度98.310％，有部分单杂含量超出0.1％，未有合格部分。
本发明用于舒更葡糖的深度精纯，仅需一步层析纯化即可满足舒更葡糖单杂小于0.1％的要求，纯化收率高而稳定。本发明采用醋酸钠水溶液和氯化钠水溶液作为流动相，不采用有机溶剂，所用流动相安全、无污染且成本较低。同时本发明分离方法简单方便，可用于规模化生产，大大降低生产成本。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。

Claims (10)

  1. 一种舒更葡糖的分离纯化方法，其特征在于，包括以下步骤：将舒更葡糖粗提取物进行溶解、过滤；将上述过滤后的舒更葡糖溶液上样到弱阴离子交换树脂中进行层析；采用盐溶液作为流动相对所述舒更葡糖溶液进行梯度洗脱；分段收集目的峰值的舒更葡糖溶液，对符合要求的组份液进行汇总，得到纯化的舒更葡糖。
  2. 如权利要求1所述的舒更葡糖的分离纯化方法，其特征在于，所述流动相为：A相：pH＝5.5的20mM醋酸钠；B相：pH＝5.5的20mM醋酸钠+1MNaCl。
  3. 如权利要求1所述的舒更葡糖的分离纯化方法，其特征在于，所述弱阴离子交换树脂的产品型号是UniDEAE。
  4. 如权利要求1所述的舒更葡糖的分离纯化方法，其特征在于，上样前，对所述弱阴离子交换树脂层析柱进行平衡，先用40％-50％B相进行除杂，后用100％A相进行平衡。
  5. 如权利要求1所述的舒更葡糖的分离纯化方法，其特征在于，所述梯度洗脱过程为，先用A相冲洗，再用A、B相对主峰进行梯度洗脱。
  6. 如权利要求5所述的舒更葡糖的分离纯化方法，其特征在于， 所述B相溶液中，洗脱梯度浓度范围为0％-32％。
  7. 如权利要求5所述的舒更葡糖的分离纯化方法，其特征在于，所述梯度洗脱过程为，第一阶段，用A相冲洗；第二阶段，用A、B相梯度洗脱主峰，其中，B相的浓度由0％提高至4％；第三阶段，B相的浓度由4％提高至8％；第四阶段，B相的浓度由8％提高至20％；第五阶段，B相的浓度由20％提高至32％。
  8. 如权利要求1～7任一所述的舒更葡糖的分离纯化方法，其特征在于，所述舒更葡糖粗提取物的纯度为90％-95％。
  9. 如权利要求1～7任一所述的舒更葡糖的分离纯化方法，其特征在于，所述纯化的舒更葡糖的纯度在99.0％以上。
  10. 如权利要求1～7任一所述的舒更葡糖的分离纯化方法，其特征在于，所述纯化的舒更葡糖的收率在59.0％以上。
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