WO2023102877A1 - 吲哚菁绿脂质体及其大规模制备方法和应用 - Google Patents

吲哚菁绿脂质体及其大规模制备方法和应用 Download PDF

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WO2023102877A1
WO2023102877A1 PCT/CN2021/136998 CN2021136998W WO2023102877A1 WO 2023102877 A1 WO2023102877 A1 WO 2023102877A1 CN 2021136998 W CN2021136998 W CN 2021136998W WO 2023102877 A1 WO2023102877 A1 WO 2023102877A1
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indocyanine green
lipid
liposome
scale preparation
icg
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盛宗海
郑海荣
胡德红
高笃阳
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深圳先进技术研究院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes

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  • the invention belongs to the technical field of compound materials, and in particular relates to indocyanine green liposomes and a large-scale preparation method and application thereof.
  • ICG Indocyanine green
  • FDA US Food and Drug Administration
  • indocyanine green since ICG is very unstable in aqueous solution, it is easy to be quickly cleared in blood circulation, and ICG is easy to aggregate in aqueous solution, resulting in fluorescence quenching, which affects its optical properties. And although indocyanine green has been approved for clinical use, its side effects are also obvious, which may cause nausea, fever, shock and other reactions, so it is necessary to reduce the dosage of indocyanine green. At present, indocyanine green is mostly applied in small doses (0.5mg/kg) in hepatobiliary surgery, gynecology, gastrointestinal surgery, thoracic surgery and other disciplines. Indocyanine green near-infrared fluorescence imaging technology is in the leading position in the world.
  • the object of the present invention is to design and provide indocyanine green liposomes and large-scale preparation methods and applications thereof.
  • the method of the invention has high efficiency, good liposome particle size uniformity, and consistent basic conditions for liposome production, thereby improving the clinical safety and effectiveness of the liposome.
  • indocyanine green liposome it is characterized in that described indocyanine green liposome is through the method of film hydration-freeze-thaw-high pressure homogenizer combination, utilizes indocyanine green and lipid small molecule Hydrophobic interactions of indocyanine green were synthesized and embedded in lipid bilayers.
  • a kind of indocyanine green liposome is characterized in that the thickness of the lipid bilayer is 1-20nm.
  • step (4) the lipid indocyanine green solution that above-mentioned step (4) obtains is placed in hot water and heated, puts into liquid nitrogen and rapidly cools;
  • step (8) Repeat the above step (7) several times to obtain indocyanine green liposomes.
  • the large-scale preparation method is characterized in that the ratio of the amount of DOPC to DSPE-PEG2000 in the step (1) is 50-1:1.
  • the large-scale preparation method is characterized in that the mass volume ratio of ICG to DMSO in the step (2) is 0.01-10 mg/mL, and the amount of methanol added is 0.1-20 mL.
  • the large-scale preparation method is characterized in that the ultrasonic treatment time in the step (3) is 1-2min.
  • the large-scale preparation method is characterized in that the vacuum drying time in the step (4) is 2-4 hours, and the amount of the PBS buffer added is 1-100mL.
  • the large-scale preparation method is characterized in that the temperature of the hot water in the step (5) is 20-100°C, and the heating time is 1-30min.
  • the large-scale preparation method is characterized in that the pressure in the step (7) is 5-150 psi.
  • the present invention has the following beneficial effects:
  • the invention provides a method for preparing indocyanine green liposomes by combining film hydration-freezing-thawing-high pressure homogenizer.
  • the method utilizes the hydrophobic interaction between indocyanine green and small lipid molecules to synthesize indole
  • the cyanine green is embedded in the liposome of the lipid bilayer, and the indocyanine green avoids the self-quenching caused by the interaction with water, significantly increases the fluorescence intensity, and reduces the dosage of the indocyanine green.
  • the method of the invention has high efficiency, good liposome particle size uniformity, and consistent basic conditions for liposome production, thereby improving the clinical safety and effectiveness of the liposome.
  • the production process of the invention requires less equipment input, is simple and convenient to operate, and has low production cost, and is very suitable for large-scale industrial production.
  • the invention helps to promote the further clinical application of indocyanine green, so that the clinical injection dosage can be greatly reduced.
  • Fig. 1 is the frozen transmission electron micrograph of indocyanine green liposome
  • Fig. 2 is the near-infrared one region spectrogram of indocyanine green liposome
  • Fig. 3 is the near-infrared second region spectrogram of indocyanine green liposome.
  • DOPC:DSPE-PEG2000 95:5mol/mol
  • the lipid indocyanine green solution was heated in hot water at 65°C for 3 minutes, and then cooled rapidly in liquid nitrogen. This process was repeated 5 times.
  • the large-scale preparation method of indocyanine green liposome comprises the following steps:
  • DOPC and DSPE-PEG2000 dissolve in chloroform and disperse evenly to obtain lipid solution, the ratio of DOPC to DSPE-PEG2000 is 45:1;
  • the large-scale preparation method of indocyanine green liposome comprises the following steps:
  • DOPC and DSPE-PEG2000 dissolve in chloroform and disperse evenly to obtain lipid solution, the ratio of DOPC to DSPE-PEG2000 is 5:1;

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Abstract

提供一种吲哚菁绿脂质体，通过薄膜水化-冻融-高压均质机联用的方法，利用吲哚菁绿与脂质小分子的疏水相互作用，合成吲哚菁绿并嵌入到脂质双分子层后得到的。该方法效率高，脂质体粒径均一性好，脂质体产生的基础条件一致，从而提高了该脂质体用于临床的安全性和有效性。同时投入设备少，操作简便，生产成本低，非常适合于工业化大生产。

Description

吲哚菁绿脂质体及其大规模制备方法和应用 技术领域
本发明属于化合物材料技术领域，具体涉及吲哚菁绿脂质体及其大规模制备方法和应用。
背景技术
吲哚菁绿(ICG)是目前为数不多的被美国食品药品监督管理局(FDA)批准用于临床的近红外荧光造影剂。它不仅可以用来检查肝脏功能和肝有效血流量，而且可以用在术中疾病的实时诊断中。
然而，由于ICG在水溶液中很不稳定、在血液循环中容易被快速清除，并且ICG在水溶液中容易聚集导致荧光淬灭，从而影响其光学性质。并且吲哚菁绿虽然被批准用于临床，但是其副作用也是很明显的，可能引起恶心、发烧、休克等反应，因此需要降低吲哚菁绿的用量。现阶段，吲哚菁绿在肝胆外科、妇科、胃肠外科、胸外科等学科领域的应用多数为小剂量应用(0.5mg/kg)，吲哚菁绿近红外荧光成像技术在世界范围内处于探索和起步阶段，北京市海淀医院胸外科团队自2015年将吲哚菁绿近红外荧光技术应用于胸外科手术中(术前24小时外周静脉滴注5mg/kg)，实现了精准定位下交感神经的切断。
现有技术中公布号为CN110960694B和CN103690486A两个专利中公开了吲哚菁绿脂质体的合成方法，但由于操作繁琐而不能进行工业化生产。虽然上述研究清楚地确认使用脂质体包裹吲哚菁绿的可能性，但是商业上还没有获得吲哚菁绿脂质体制剂。例如，这些制剂很多由于与稳定性、包载率、规模化生产的可能性以及使用的脂质成本相关的问题而具有可疑的制药潜能。
发明内容
针对上述现有技术中存在的问题，本发明的目的在于设计提供吲哚菁绿脂质体及其大规模制备方法和应用。本发明方法效率高，脂质体粒径均一性好，脂质体产生的基础条件一致，从而提高了该脂质体用于临床的安全性和有效性。
为了实现上述目的，本发明采用以下技术方案：
一种吲哚菁绿脂质体，其特征在于所述吲哚菁绿脂质体是通过薄膜水化-冻融-高压均质机联用的方法，利用吲哚菁绿与脂质小分子的疏水相互作用，合成吲哚菁绿并嵌入到脂质双分子层后得到的。
所述的一种吲哚菁绿脂质体，其特征在于所述脂质双分子层的厚度为1-20nm。
所述的吲哚菁绿脂质体的大规模制备方法，其特征在于包括以下步骤：
(1)称取DOPC和DSPE-PEG2000，溶解于三氯甲烷中分散均匀，得到脂质溶液；
(2)称取ICG溶解于DMSO中，加入甲醇，均匀分散得到ICG溶液；
(3)将上述步骤(1)得到的脂质溶液与上述步骤(2)得到的ICG溶液混合，进行超声处理后旋转蒸发去除有机溶剂，形成薄膜；
(4)将上述步骤(3)得到的薄膜进行真空干燥，完成后加入PBS缓冲液，震荡，得到脂质吲哚菁绿溶液；
(5)将上述步骤(4)得到的脂质吲哚菁绿溶液置于热水中加热，放入液氮中迅速冷却；
(6)重复上述步骤(5)1-100次后得到样品；
(7)打开高压均质机气泵，设置压力，打开均质阀，安装装有上述步骤(6)得到样品的注射器，收集均质后的样品；控制均质阀手柄至充压状态，充压完成后安装装有样品的注射器，调节控制手柄，等待样品完全进入均质机；调节均质阀，控制手柄，用注射器收集均质好样品；均质操作重复若干次，得到最终吲哚菁绿脂质体。
(8)重复上述步骤(7)若干次，得到吲哚菁绿脂质体。
所述的大规模制备方法，其特征在于所述步骤(1)中DOPC与DSPE-PEG2000的物质的量之比为50-1:1。
所述的大规模制备方法，其特征在于所述步骤(2)中ICG与DMSO的质量体积比为0.01-10mg/mL，所述甲醇的加入量为0.1-20mL。
所述的大规模制备方法，其特征在于所述步骤(3)中超声处理的时间为1-2min。
所述的大规模制备方法，其特征在于所述步骤(4)中真空干燥的时间为2-4h，所述PBS缓冲液的加入量为1-100mL。
所述的大规模制备方法，其特征在于所述步骤(5)中热水的温度为20-100℃，所述加热时间为1-30min。
所述的大规模制备方法，其特征在于所述步骤(7)中压力为5-150psi。
任一所述的大规模制备方法在工业上大规模制备吲哚菁绿脂质体的应用。
与现有技术相比，本发明具有以下有益效果：
本发明提供了一种薄膜水化-冻融-高压均质机联用制备吲哚菁绿脂质体的方法，该方法利用吲哚菁绿与脂质小分子的疏水相互作用，合成吲哚菁绿被嵌入脂质双分子层的脂质体，吲哚菁绿避免了与水相互作用导致的自淬灭，显著提高荧光强度，降低吲哚菁绿的使用计量。
本发明方法效率高，脂质体粒径均一性好，脂质体产生的基础条件一致，从而提高了该脂质体用于临床的安全性和有效性。本发明生产工艺投入设备少，操作简便，生产成本低，非常适合于工业化大生产。本发明有助于推动吲哚菁绿在临床上面的进一步应用，使临床的 注射计量能够大大降低。
附图说明
图1为吲哚菁绿脂质体的冷冻透射电子显微镜图；
图2为吲哚菁绿脂质体的近红外一区光谱图；
图3为吲哚菁绿脂质体的近红外二区光谱图。
具体实施方式
以下将通过附图和实施例对本发明作进一步说明。
实施例1：
1.称量适量DOPC及DSPE-PEG2000(DOPC：DSPE-PEG2000＝95:5mol/mol)溶解于三氯甲烷中，分散均匀得到脂质溶液。
2.称量一定量ICG溶于20-100μLDMSO，然后加入2mL甲醇，均匀分散得到ICG溶液。
3.将脂质溶液与ICG溶液混合，超声1-2min。
4.通过旋转蒸发去除有机溶剂，形成薄膜。
5.真空干燥2-4小时。
6.加入适量PBS缓冲液，震荡将脂质吲哚菁绿薄膜完全溶解。
7.脂质吲哚菁绿溶液在65℃热水中加热3min，然后放入液氮中迅速冷却，此过程重复5次。
8.打开高压均质机气泵，设置至合适压力，打开均质阀填充压力；安装装有样品的注射器，收集均质好样品；均质操作重复若干次，得到吲哚菁绿脂质体。如图1所示为制备得到的吲哚菁绿脂质体的冷冻透射电子显微镜图，表征了该吲哚菁绿脂质体的结构。
设置泵体气压至40psi，调节均质阀至打开状态。
控制均质阀手柄至充压状态，充压完成后安装装有样品的注射器，调节控制手柄，等待样品完全进入均质机。调节均质阀，控制手柄，用注射器收集均质好样品；均质操作重复若干次，得到最终吲哚菁绿脂质体。
如图2所示，与ICG相比，吲哚菁绿脂质体的荧光强度增强了，而且荧光峰发生了红移。如图3所示，与ICG相比，吲哚菁绿脂质体的荧光强度增强了。
实施例2：
吲哚菁绿脂质体的大规模制备方法，包括以下步骤：
1.称取DOPC和DSPE-PEG2000，溶解于三氯甲烷中分散均匀，得到脂质溶液，DOPC与DSPE-PEG2000的物质的量之比为45:1；
2.称取ICG溶解于DMSO中，ICG与DMSO的质量体积比为0.01mg/mL，加入0.5mL甲醇， 均匀分散得到ICG溶液；
3.将上述步骤1得到的脂质溶液与上述步骤2得到的ICG溶液混合，进行超声处理2min后旋转蒸发去除有机溶剂，形成薄膜；
4.将上述步骤3得到的薄膜进行真空干燥4h，完成后加入PBS缓冲液3mL，震荡，得到脂质吲哚菁绿溶液；
5.将上述步骤4得到的脂质吲哚菁绿溶液置于30℃热水中加热30min，放入液氮中迅速冷却；6.重复上述步骤5，15次后得到样品；
7.打开高压均质机气泵，设置压力10psi，打开均质阀，安装装有上述步骤6得到样品的注射器，收集均质后的样品；
8.重复上述步骤7若干次，得到吲哚菁绿脂质体。
实施例3：
吲哚菁绿脂质体的大规模制备方法，包括以下步骤：
1.称取DOPC和DSPE-PEG2000，溶解于三氯甲烷中分散均匀，得到脂质溶液，DOPC与DSPE-PEG2000的物质的量之比为5:1；
2.称取ICG溶解于DMSO中，ICG与DMSO的质量体积比为10mg/mL，加入20mL甲醇，均匀分散得到ICG溶液；
3.将上述步骤1得到的脂质溶液与上述步骤2得到的ICG溶液混合，进行超声处理2min后旋转蒸发去除有机溶剂，形成薄膜；
4.将上述步骤3得到的薄膜进行真空干燥2h，完成后加入PBS缓冲液100mL，震荡，得到脂质吲哚菁绿溶液；
5.将上述步骤4得到的脂质吲哚菁绿溶液置于90℃热水中加热10min，放入液氮中迅速冷却；
6.重复上述步骤5，10次后得到样品；
7.打开高压均质机气泵，设置压力100psi，打开均质阀，安装装有上述步骤6得到样品的注射器，收集均质后的样品；
8.重复上述步骤7若干次，得到吲哚菁绿脂质体。

Claims (10)

  1. 一种吲哚菁绿脂质体，其特征在于所述吲哚菁绿脂质体是通过薄膜水化-冻融-高压均质机联用的方法，利用吲哚菁绿与脂质小分子的疏水相互作用，合成吲哚菁绿并嵌入到脂质双分子层后得到的。
  2. 如权利要求1所述的一种吲哚菁绿脂质体，其特征在于所述脂质双分子层的厚度为1-20nm。
  3. 如权利要求1或2所述的吲哚菁绿脂质体的大规模制备方法，其特征在于包括以下步骤：
    (1)称取DOPC和DSPE-PEG2000，溶解于三氯甲烷中分散均匀，得到脂质溶液；
    (2)称取ICG溶解于DMSO中，加入甲醇，均匀分散得到ICG溶液；
    (3)将上述步骤(1)得到的脂质溶液与上述步骤(2)得到的ICG溶液混合，进行超声处理后旋转蒸发去除有机溶剂，形成薄膜；
    (4)将上述步骤(3)得到的薄膜进行真空干燥，完成后加入PBS缓冲液，震荡，得到脂质吲哚菁绿溶液；
    (5)将上述步骤(4)得到的脂质吲哚菁绿溶液置于热水中加热，放入液氮中迅速冷却；
    (6)重复上述步骤(5)1-100次后得到样品；
    (7)打开高压均质机气泵，设置压力，打开均质阀，安装装有上述步骤(6)得到样品的注射器，收集均质后的样品；
    (8)重复上述步骤(7)若干次，得到吲哚菁绿脂质体。
  4. 如权利要求3所述的大规模制备方法，其特征在于所述步骤(1)中DOPC与DSPE-PEG2000的物质的量之比为50-1:1。
  5. 如权利要求3所述的大规模制备方法，其特征在于所述步骤(2)中ICG与DMSO的质量体积比为0.01-10mg/mL，所述甲醇的加入量为0.1-20mL。
  6. 如权利要求3所述的大规模制备方法，其特征在于所述步骤(3)中超声处理的时间为1-2min。
  7. 如权利要求3所述的大规模制备方法，其特征在于所述步骤(4)中真空干燥的时间为2-4h，所述PBS缓冲液的加入量为1-100mL。
  8. 如权利要求3所述的大规模制备方法，其特征在于所述步骤(5)中热水的温度为20-100℃，所述加热时间为1-30min。
  9. 如权利要求3所述的大规模制备方法，其特征在于所述步骤(7)中压力为5-150psi。
  10. 如权利要求3-9任一所述的大规模制备方法在工业上大规模制备吲哚菁绿脂质体的应用。
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