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WO2023030471A1 - 一种两亲嵌段共聚物的纯化方法 - Google Patents

一种两亲嵌段共聚物的纯化方法 Download PDF

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WO2023030471A1
WO2023030471A1 PCT/CN2022/116659 CN2022116659W WO2023030471A1 WO 2023030471 A1 WO2023030471 A1 WO 2023030471A1 CN 2022116659 W CN2022116659 W CN 2022116659W WO 2023030471 A1 WO2023030471 A1 WO 2023030471A1
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block copolymer
amphiphilic block
copolymer
polyethylene glycol
monomethyl ether
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PCT/CN2022/116659
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English (en)
French (fr)
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史瑞文
卞祥
刘永东
鲍雪竹
任晋生
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先声药业有限公司
江苏先声药业有限公司
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Priority to CN202280053107.5A priority Critical patent/CN117813338A/zh
Publication of WO2023030471A1 publication Critical patent/WO2023030471A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/85—Germanium, tin, lead, arsenic, antimony, bismuth, titanium, zirconium, hafnium, vanadium, niobium, tantalum, or compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/88—Post-polymerisation treatment
    • C08G63/90—Purification; Drying

Definitions

  • the present disclosure relates to the field of polymer materials, in particular, to a method for purifying an amphiphilic block copolymer, and to the purified amphiphilic block copolymer, and a pharmaceutical composition comprising the amphiphilic block copolymer .
  • Polymer micelles are self-assembled by amphiphilic polymer compounds in aqueous solution, and are nanoscale microspheres with a core-shell structure of a hydrophilic shell and a hydrophobic core. Polymer micelles can encapsulate poorly soluble drugs in the inner core to solubilize them. Compared with commonly used solubilizers, the polymer micelles drug delivery system uses biocompatible and degradable materials, which have higher safety.
  • Polyethylene glycol monomethyl ether-polylactic acid amphiphilic block copolymer is a biodegradable material with good biocompatibility, which can be degraded into lactic acid and polyethylene glycol in vivo, which can be directly excreted from the body and can be used as paclitaxel
  • the carrier material for preparing micellar preparations from similar compounds is generally obtained by ring-opening polymerization of polyethylene glycol monomethyl ether and lactide, using stannous isooctanoate as a catalyst.
  • this polymerization method tends to produce polymers containing metal tin ion impurities, and the residual stannous octoate catalyst may accelerate the hydrolysis of the copolymer, resulting in a decrease in the molecular weight and pH value of the block copolymer, which affects the micellar effect.
  • CN201410030294.2 discloses a refining process of polyethylene glycol monomethyl ether-poly(D, L) lactide block copolymer, the prepared polyethylene glycol monomethyl ether-poly(D, L) The white solid of lactide block copolymer is dissolved in water, and the obtained polymer aqueous solution is exchanged by cation exchange column, eluted with water, and freeze-dried to obtain polyethylene glycol monomethyl ether-poly(D, L) lactide block Segmented copolymers having a metal ion tin content of less than 100 ppm. The content of tin ions after purification is at most 85% lower than that before purification, and both are above 20ppm.
  • the purpose of the present disclosure is to provide a method for purifying an amphiphilic block copolymer, which can significantly reduce the content of metal tin ions in the copolymer.
  • Another object of the present disclosure is to provide a purified amphiphilic block copolymer.
  • Another object of the present disclosure is to provide a pharmaceutical composition comprising the purified amphiphilic block copolymer.
  • a method for purifying an amphiphilic block copolymer comprising:
  • the amphiphilic block copolymer has a hydrophilic polyalkylene glycol A block component and a hydrophobic polymer B block component; wherein the polyalkylene glycol is selected from: polyethylene Diol, polyethylene glycol monomethyl ether or monoacyloxy polyethylene glycol; the hydrophobic polymer B block component is selected from: polylactic acid, polyglycolide, polycaprolactone, polylactic acid- Glycolide copolymer or polylactic acid-caprolactone copolymer.
  • the amphiphilic block copolymer is selected from AB diblock, ABA triblock or BAB triblock copolymer, preferably, the amphiphilic block copolymer is selected from AB diblock copolymer.
  • the polyalkylene glycol is selected from polyethylene glycol or polyethylene glycol monomethyl ether
  • the hydrophobic polymer B block component is selected from polylactic acid or polyglycolide
  • the amphiphilic block copolymer is selected from polyethylene glycol monomethyl ether-polylactic acid block copolymers.
  • the polyethylene glycol monomethyl ether-polylactic acid block copolymer is prepared by reacting polyethylene glycol monomethyl ether and D,L-lactide in the presence of a tin-containing catalyst.
  • the tin-containing catalyst is stannous isooctanoate.
  • the mass of stannous isooctanoate accounts for 0.05-0.5 wt%, preferably 0.15-0.3 wt%, of the total mass of D,L-lactide and polyethylene glycol monomethyl ether.
  • the molecular weight of the polyalkylene glycol is 1000-20000, preferably 1000-5000, more preferably 1800-2200, and even more preferably 2000.
  • the organic solvent is selected from dichloromethane, chloroform, ethyl acetate, isopropyl acetate, butyl acetate, butanone, toluene, acetone, acetonitrile, dimethyl One or more of methyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, and short-chain fatty alcohols, preferably dichloromethane, chloroform, methanol, ethanol, and isopropanol One or more, more preferably dichloromethane.
  • the amount of the organic solvent accounts for 0.05 to 50 times the volume (L/kg) of the copolymer mass, preferably 0.1 to 25 times the volume (L/kg), more preferably 0.25 to 10 times the volume (L/kg ).
  • the amount of activated carbon accounts for 1-500 wt%, preferably 5-200 wt%, more preferably 5-75 wt%, further preferably 20-50 wt%, of the mass of the copolymer.
  • Another aspect of the present disclosure provides the amphiphilic block copolymer purified by the method described above.
  • the content of metal tin ions is less than 10 ppm based on the total weight of the amphiphilic block copolymer, preferably less than 1 ppm, more preferably less than 0.1 ppm.
  • a pharmaceutical composition comprising the aforementioned amphiphilic block copolymer.
  • the purification method provided by the disclosure is simple to operate, has low production cost, and is suitable for industrial production.
  • the metal tin ion content of the prepared copolymer is significantly reduced, and an unexpected technical effect is achieved.
  • Metallic tin ions refer to stannous ions or tin ions, or a mixture of both.
  • Short-chain fatty alcohols refer to fatty alcohols with 1 to 6 carbon atoms, which can be monohydric alcohols, dihydric alcohols or polyhydric alcohols, including but not limited to: methanol, ethanol, isopropanol, n-propanol, n-butanol, Isobutanol, n-pentanol, isoamyl alcohol, n-hexanol, isohexanol, 1,2-propanediol, glycerol, or 1,3-butanediol. Preference is given to methanol, ethanol or isopropanol.
  • the quality of the copolymer can be calculated according to the total feeding quality of the A block component and the B block component.
  • Figure 1 is the 1 HNMR spectrum of polyethylene glycol monomethyl ether-polylactic acid block copolymer.
  • Examples of the present disclosure use the following methods to investigate the molecular weight and distribution of polyethylene glycol monomethyl ether-polylactic acid block copolymers:
  • 1 HNMR takes 10%-20% (g/mL) deuterated chloroform of 1% tetramethylsilane 0.5-1.0mL of this product solution, scans from 0ppm to 10ppm, and quantifies it by direct comparison method.
  • the specific method is: at 3.6ppm It is the peak of CH in polylactic acid, and the peak of CH in polyethylene glycol monomethyl ether is at 5.1ppm.
  • L is the integrated area of the composite peak at 5.1ppm, representing the methine group of polylactide
  • G is the integrated area of the composite peak at 3.6ppm, representing the methylene group of polyoxyethylene
  • m is the degree of polymerization of oxyethylene in the copolymer structural formula
  • n is the degree of polymerization of D,L-lactide in the copolymer structure formula.
  • GPC was determined according to high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Four General Rules ⁇ 0512>).
  • the chromatographic conditions adopt gel chromatographic column; differential refraction detection; tetrahydrofuran as mobile phase; flow rate 1.0mL/min, column temperature 40°C.
  • Determination method Take an appropriate amount of this product, add tetrahydrofuran to prepare a 1% solution, draw 20 ⁇ L, inject it into a liquid chromatograph, use polystyrene standard substance as a standard sample, and use GPC software to process the data.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Polyesters Or Polycarbonates (AREA)

Abstract

两亲嵌段共聚物的纯化方法，纯化的两亲嵌段共聚物，以及包含所述两亲嵌段共聚物的药物组合物。两亲嵌段共聚物的纯化方法包括：(1)提供包含在有机溶剂中的两亲嵌段共聚物的溶液；(2)将活性炭添加到步骤(1)的溶液中；(3)过滤以除去活性炭，得到两亲嵌段共聚物。提供的方法能够有效去除两亲嵌段共聚物中金属锡离子的含量。

Description

一种两亲嵌段共聚物的纯化方法
本公开要求2021年09月03日向中国国家知识产权局提交的，专利申请号为202111032910.4，发明名称为“一种两亲嵌段共聚物的纯化方法”的中国专利申请的优先权。上述在先申请的全文通过引用的方式结合于本公开中。
技术领域
本公开涉及高分子材料领域，具体而言，涉及一种两亲嵌段共聚物的纯化方法，还涉及纯化后的两亲嵌段共聚物、包含所述两亲嵌段共聚物的药物组合物。
背景技术
聚合物胶束是由两亲性高分子化合物在水溶液中自发组装，具有亲水外壳和疏水内核的壳核结构的纳米级微球。聚合物胶束可以将难溶性药物包裹于内核部分达到对其增溶，与常用的增溶剂相比，聚合物胶束载药系统选用生物相容性可降解材料，其安全性较高。
聚乙二醇单甲醚-聚乳酸两亲嵌段共聚物是一种生物相容性好的生物降解材料，体内降解为乳酸和聚乙二醇，二者可直接排出体外，可以用作紫杉醇类化合物制备胶束制剂的载体材料，一般以异辛酸亚锡为催化剂，由聚乙二醇单甲醚与丙交酯通过开环聚合反应而得。然而这种聚合方法倾向于产生含金属锡离子杂质的聚合物，残留的辛酸亚锡催化剂可能加速共聚物的水解，导致嵌段共聚物的分子量降低和pH值的下降，影响胶束效果。
CN201410030294.2公开了一种聚乙二醇单甲醚-聚(D，L)丙交酯嵌段共聚物的精制工艺，将制备得到的聚乙二醇单甲醚-聚(D，L)丙交酯嵌段共聚物白色固体加水溶解，得到的聚合物水溶液经阳离子交换柱交换、水洗脱后，经冷冻干燥得聚乙二醇单甲醚-聚(D，L)丙交酯嵌段共聚物，其金属离子锡含量小于100ppm。其纯化后的锡离子含量相较于纯化前至多下降85％，且均在20ppm以上。
发明内容
本公开的目的是提供一种两亲嵌段共聚物的纯化方法，该方法能够显著降低共聚物中金属锡离子含量。
本公开的另一个目的是提供一种纯化后的两亲嵌段共聚物。
本公开的另一个目的是提供一种包含纯化后的两亲嵌段共聚物的药物组合物。
为实现上述目的，本公开提供以下技术方案：
一种两亲嵌段共聚物的纯化方法，包括：
(1)提供包含在有机溶剂中的两亲嵌段共聚物的溶液；
(2)将活性炭添加到步骤(1)的溶液中；
(3)过滤以除去活性炭，得到两亲嵌段共聚物，
其中，所述两亲嵌段共聚物具有亲水性聚亚烷基二醇A嵌段组分和疏水性聚合物B嵌段组分；其中所述聚亚烷基二醇选自：聚乙二醇、聚乙二醇单甲醚或单酰氧基聚乙二醇；所述疏水性聚合物B嵌段组分选自：聚乳酸、聚乙交酯、聚己内酯、聚乳酸-乙交酯共聚物或聚乳酸-己内酯共聚物。
在一些实施方案中，所述两亲嵌段共聚物选自AB二嵌段、ABA三嵌段或者BAB三嵌段共聚物，优选地，所述两亲嵌段共聚物选自AB二嵌段共聚物。
在一些实施方案中，所述聚亚烷基二醇选自聚乙二醇或聚乙二醇单甲醚，所述疏水性聚合物B嵌段组分选自聚乳酸或聚乙交酯。
在一些实施方案中，所述两亲嵌段共聚物选自聚乙二醇单甲醚-聚乳酸嵌段共聚物。
在一些实施方案中，所述聚乙二醇单甲醚-聚乳酸嵌段共聚物由聚乙二醇单甲醚和D,L-丙交酯在含锡催化剂存在下反应制得。
在一些实施方案中，所述含锡催化剂为异辛酸亚锡。
在一些实施方案中，所述异辛酸亚锡的质量占D,L-丙交酯和聚乙二醇单甲醚总质量的0.05～0.5wt％，优选0.15～0.3wt％。
在一些实施方案中，所述聚亚烷基二醇的分子量为1000～20000，优选为1000～5000，更优选为1800～2200，进一步优选2000。
在一些实施方案中，步骤(1)中，所述有机溶剂选自二氯甲烷、三氯甲烷、乙酸乙酯、乙酸异丙酯、乙酸丁酯、丁酮、甲苯、丙酮、乙腈、二甲基甲酰胺、二甲亚砜、四氢呋喃、1,4-二氧六环、短链脂肪醇中的一种或多种，优选二氯甲烷、三氯甲烷、甲醇、乙醇、异丙醇中的一种或多种，更优选二氯甲烷。
在一些实施方案中，所述有机溶剂的用量占共聚物质量0.05～50倍体积(L/kg)，优选0.1～25倍体积(L/kg)，更优选0.25～10倍体积(L/kg)。
在一些实施方案中，步骤(2)中，所述活性炭的用量占共聚物质量的1～500wt％，优选5～200wt％，更优选5～75wt％，进一步优选20～50wt％。
本公开另一方面提供由上述方法纯化的两亲嵌段共聚物。
在一些实施方案中，金属锡离子的含量是基于所述两亲嵌段共聚物总重量的10ppm以下，优选1ppm以下，更优选0.1ppm以下。
药物组合物，其包含上述两亲嵌段共聚物。
本公开提供的纯化方法操作简便、生产成本较低，适于工业化生产。制备得到的共聚物金属锡离子含量显著降低，取得了预料不到的技术效果。
术语定义和说明
除非本公开另外定义，与本公开相关的科学和技术术语应具有本领域普通技术人员所理解的含义。
金属锡离子是指亚锡离子或者锡离子，或者两者的混合。
短链脂肪醇是指碳原子数是1～6的脂肪醇，可以是一元醇、二元醇或多元醇，包括但不限于：甲醇、乙醇、异丙醇、正丙醇、正丁醇、异丁醇、正戊醇、异戊醇、正己醇、异己醇、1，2-丙二醇、丙三醇、或1，3-丁二醇。优选是甲醇、乙醇或异丙醇。
共聚物质量可按照A嵌段组分和B嵌段组分总投料质量计算。
附图说明
图1为聚乙二醇单甲醚-聚乳酸嵌段共聚物的 1HNMR图谱。
具体实施方式
下面结合具体实施例来进一步描述本公开，本公开的优点和特点将会随着描述而更为清楚。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
本公开实施例仅是范例性的，并不对本公开的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本公开的精神和范围下可以对本公开技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本公开的保护范围内。
本公开实施例使用以下方法考察聚乙二醇单甲醚-聚乳酸嵌段共聚物的分子量和分布：
1HNMR取1％四甲基硅烷的氘代氯仿10％～20％(g/mL)本品溶液0.5～1.0mL，从0ppm扫描到10ppm，以直接比较法定量，具体方法为：3.6ppm处为聚乳酸中CH的峰，5.1ppm处为聚乙二醇单甲醚中CH2的峰，峰面积与氢的数目存在以下关系：聚乙二醇单甲醚分子量2000，L/G＝2m/4n，m＝2000/44＝45.5，则可求出共聚物的组成及分子量。
Figure PCTCN2022116659-appb-000001
共聚物的分子量＝(1+PDLLA/MPEG的重量比)×2000
式中：L为5.1ppm处复合峰的积分面积，代表聚丙交酯的次甲基；
G为3.6ppm处复合峰的积分面积，代表聚氧乙烯的亚甲基；
m为共聚物结构式中氧乙烯的聚合度；
n为共聚物结构式中D,L-丙交酯的聚合度。
GPC照高效液相色谱法(中国药典2020年版四部通则＜0512＞)测定。
色谱条件采用凝胶色谱柱；示差折光检测；四氢呋喃为流动相；流速1.0mL/min，柱温40℃。
测定法取本品适量，加四氢呋喃制备成1％的溶液，吸取20μL，注入液相色谱仪，用聚苯乙烯标准物质作为标样，数据采用GPC软件处理。
对比例1：
氮气保护下向反应瓶内加入150g聚乙二醇单甲醚(2000)，充氮气、抽真空，使反应瓶中保持真空，加热至120℃，待全部熔融，继续加热并保持真空，干燥2h后用氮气置换。在氮气保护下加入称量好的165g D,L-丙交酯，充氮气、抽真空，使反应瓶中保持真空；搅拌均匀后氮气置换。升温至135℃，氮气保护条件下，加入0.6g异辛酸亚锡，氮气置换，氮气保护，加热至140℃反应5h。反应结束后，产物降温至40℃，加入150ml二氯甲烷溶解，搅拌下加入3000ml的冷无水乙醚，搅拌30min后，静置，过滤，滤饼按上述操作过程再精制两次，真空干燥，得到聚乙二醇单甲醚-聚乳酸嵌段共聚物224g。电感耦合等离子体质谱法ICPMS检测金属锡离子含量，结果：金属锡离子含量为350ppm。
对比例2：
取对比例1制得的聚乙二醇单甲醚-聚乳酸嵌段共聚物20g(金属锡离子含量350ppm)， 加入200ml二氯甲烷溶解，加入10g柱层析硅胶，室温打浆30min，过滤除去硅胶，滤液浓缩干，加入10ml二氯甲烷溶解澄清，加入200ml冷乙醚沉降4h，过滤，固体真空干燥得到白色固体15g，检测锡含量，金属锡离子含量为330ppm。
实施例1：
氮气保护下向反应瓶内加入20g聚乙二醇单甲醚(2000)，充氮气、抽真空，使反应瓶中保持真空，加热至120℃，待全部熔融，继续加热并保持真空，干燥2h后用氮气置换。在氮气保护下加入称量好的22g D,L-丙交酯，充氮气、抽真空，使反应瓶中保持真空；搅拌均匀后氮气置换。升温至135℃，氮气保护条件下，加入0.08g异辛酸亚锡，氮气置换，氮气保护，加热至140℃反应5h。反应结束后，产物降温至40℃，加入160ml二氯甲烷和10g活性炭，搅拌1h，过滤。滤液减压浓缩至干。用20ml二氯甲烷将旋转蒸发仪中的物料转移至反应瓶中，搅拌下加入400ml的冷无水乙醚，搅拌30min后，静置，过滤。滤饼按上述操作过程再精制两次，真空干燥，得到聚乙二醇单甲醚-聚乳酸嵌段共聚物成品32g。电感耦合等离子体质谱法ICPMS检测金属锡离子含量，结果：金属锡离子含量为0.042ppm。
实施例2：
氮气保护下向反应瓶内加入20g聚乙二醇单甲醚(2000)，充氮气、抽真空，使反应瓶中保持真空，加热至120℃，待全部熔融，继续加热并保持真空，干燥2h后用氮气置换。在氮气保护下加入称量好的22g D,L-丙交酯，充氮气、抽真空，使反应瓶中保持真空；搅拌均匀后氮气置换。升温至135℃，氮气保护条件下，加入0.08g异辛酸亚锡，加热至140℃反应5h。反应结束后，产物降温至40℃，加入160ml二氯甲烷和20g活性炭，搅拌1h，过滤。滤液减压浓缩至干。用20ml二氯甲烷将旋转蒸发仪中的物料转移至反应瓶中，搅拌下加入400ml的冷无水乙醚，搅拌30min后，静置，过滤。滤饼按上述操作过程再精制两次，真空干燥，得到聚乙二醇单甲醚-聚乳酸嵌段共聚物成品32g。电感耦合等离子体质谱法ICPMS检测金属锡离子含量，检测结果：金属锡离子含量为0.06ppm。
实施例3
氮气保护下向反应釜中加入4.50kg聚乙二醇单甲醚(2000)，充氮气、抽真空，加热至120℃，待全部熔融，继续加热并保持真空，干燥2h后用氮气置换，在氮气保护下加入4.95kg D,L-丙交酯，充氮气、抽真空，使反应釜中保持真空；搅拌均匀后氮气置换。升温至140℃，氮气保护下，加入18.000g异辛酸亚锡，氮气置换，氮气保护加热至140±5℃反应5h。反应结束后，产物降温至40℃，加入36L二氯甲烷和4.50kg活性炭，搅拌脱色1h，过滤，滤液减压浓缩至干。
加入4.5L二氯甲烷，搅拌下加入90L冷无水乙醚，搅拌30min后静置，过滤，滤饼按上述操作过程再精制两次，真空干燥得到聚乙二醇单甲醚-聚乳酸嵌段共聚物成品6.204kg。得到的共聚物用核磁共振进行表征，结果如图1所示。分子量为3647，GPC分析结果：多分散系数PD＝1.2。

Claims (10)

  1. 一种两亲嵌段共聚物的纯化方法，包括：
    (1)提供包含在有机溶剂中的两亲嵌段共聚物的溶液；
    (2)将活性炭添加到步骤(1)的溶液中；
    (3)过滤以除去活性炭，得到两亲嵌段共聚物，
    其中，所述两亲嵌段共聚物具有亲水性聚亚烷基二醇A嵌段组分和疏水性聚合物B嵌段组分；其中所述聚亚烷基二醇选自：聚乙二醇、聚乙二醇单甲醚或单酰氧基聚乙二醇；所述疏水性聚合物B嵌段组分选自：聚乳酸、聚乙交酯、聚己内酯、聚乳酸-乙交酯共聚物或聚乳酸-己内酯共聚物。
  2. 根据权利要求1所述的方法，其中，所述两亲嵌段共聚物选自AB二嵌段、ABA三嵌段或者BAB三嵌段共聚物，优选地，所述两亲嵌段共聚物选自AB二嵌段共聚物。
  3. 根据权利要求1所述的方法，其中，所述聚亚烷基二醇选自聚乙二醇或聚乙二醇单甲醚，所述疏水性聚合物B嵌段组分选自聚乳酸或聚乙交酯。
  4. 根据权利要求1所述的方法，其中，所述两亲嵌段共聚物是聚乙二醇单甲醚-聚乳酸嵌段共聚物；优选地，所述聚乙二醇单甲醚-聚乳酸嵌段共聚物由聚乙二醇单甲醚和D,L-丙交酯在含锡催化剂存在下反应制得；更优选地，所述含锡催化剂为异辛酸亚锡。
  5. 根据权利要求1所述的方法，其中，所述聚亚烷基二醇的分子量为1000～20000，优选为1000～5000，更优选为1800～2200，进一步优选2000。
  6. 根据权利要求1所述的方法，其中，步骤(1)中，所述有机溶剂是二氯甲烷、三氯甲烷、乙酸乙酯、乙酸异丙酯、乙酸丁酯、丁酮、甲苯、丙酮、乙腈、二甲基甲酰胺、二甲亚砜、四氢呋喃、1,4-二氧六环、短链脂肪醇中的一种或多种，优选二氯甲烷、三氯甲烷、甲醇、乙醇、异丙醇中的一种或多种，更优选二氯甲烷。
  7. 根据权利要求1所述的方法，其中，所述有机溶剂的用量占共聚物总质量0.05～50倍体积(L/kg)，优选0.1～25倍体积(L/kg)，更优选0.25～10倍体积(L/kg)。
  8. 根据权利要求1所述的方法，其中，步骤(2)中，所述活性炭的用量占共聚物质量的1～500wt％，优选5～200wt％，更优选5～75wt％，进一步优选20～50wt％。
  9. 权利要求1～8任一项所述方法制备得到的两亲嵌段共聚物，其中，金属锡离子的含量是基于所述共聚物总重量的10ppm以下，优选1ppm以下，更优选0.1ppm以下。
  10. 药物组合物，其包含权利要求1-9任一项所述的两亲嵌段共聚物。
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