CN114191410A - 一种诊疗一体化双亲微球缓释微球的制备方法 - Google Patents

一种诊疗一体化双亲微球缓释微球的制备方法 Download PDF

Info

Publication number
CN114191410A
CN114191410A CN202111349778.XA CN202111349778A CN114191410A CN 114191410 A CN114191410 A CN 114191410A CN 202111349778 A CN202111349778 A CN 202111349778A CN 114191410 A CN114191410 A CN 114191410A
Authority
CN
China
Prior art keywords
microsphere
diagnosis
amphiphilic
release microspheres
release
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202111349778.XA
Other languages
English (en)
Inventor
周钢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Beihang Emerging Industrial Technology Research Institute
Original Assignee
Shenzhen Beihang Emerging Industrial Technology Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Beihang Emerging Industrial Technology Research Institute filed Critical Shenzhen Beihang Emerging Industrial Technology Research Institute
Priority to CN202111349778.XA priority Critical patent/CN114191410A/zh
Publication of CN114191410A publication Critical patent/CN114191410A/zh
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/605—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the macromolecule containing phosphorus in the main chain, e.g. poly-phosphazene
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明公开了一种用于诊疗一体化双亲微球缓释微球的研究领域的制备技术，具体地说，是以壳聚糖为原料，通过微流控方法制成具有诊疗一体化双亲微球缓释微球。该方法特征在于，以PEOz‑CS嵌段共聚物为基本骨架构建微球缓释体基材。再利用微流控方式，盐析、透析法精制缓释微球。整个制备过程中，缓释微球损失少、变性小、得率高。

Description

一种诊疗一体化双亲微球缓释微球的制备方法
技术领域
本发明涉及一种用于诊疗一体化双亲微球缓释微球的研究领域的制备技术，具体地说，是以壳聚糖为原料，通过微流控方法制成具有诊疗一体化双亲微球缓释微球。
背景技术
近年来我国癌症发病形势严峻，发病率与死亡率呈持续上升趋势。近期，国家癌症中心发布了2017中国城市癌症数据最新报告，该报告汇总了全国347家癌症登记点的数据。数据显示，全国每天约1万人确诊癌症，肺癌为发病率、死亡率双率第一。
本申请项目的研究针对淋巴管畸形微环境，集中于逆转肿瘤耐药作用的微球缓释体系的构建，核心目标是实现药物的靶向治疗和可控释放行为；以及在近红外光作用下实现成像/治疗的双重目的。实现这些目标的关键是设计和筛选对于肿瘤细胞器和细胞内环境具有特异性和响应性给药能力的高分子复合体系。设计合成一系列结构明确、功能可预期，在肿瘤组织微环境中具有响应递药性能的两亲性高分子，获得具有抑制跨膜转运蛋白外排功能的微球缓释体系。因此，我们以壳聚糖为原料，通过微流控方法制成具有诊疗一体化双亲微球缓释微球。其具有广阔的市场前景。
发明内容
本发明的目的是克服现有缓释微球的不足，采用微流控方法获取具有诊疗一体化双亲微球缓释微球。这种制备方法可以癌症治疗需要。
本发明首先是以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材。基于针对肿瘤细胞器酸性环境作出响应的目标，将具有促内涵体逃逸功能的PBAE引入聚合物主链，预期可降低抗肿瘤药物在溶酶体中的代谢。通过选择不同的PBAE主链和侧链，考察不同结构的高分子载体对内涵体的逃逸能力和对亚细胞环境进行响应性传递药物的性能。为提高细胞毒药物治疗肿瘤的效果和特异性，将肿瘤靶向基元叶酸等分子结合到聚合物上。
设计结合有淋巴管畸形细胞靶向信号分子的聚膦腈两亲高分子，其主链由氮磷双键构成，侧链分别为可在酸性环境下质子化的DPA、EAB等和亲水性的PEG，PEG末端修饰靶向性基元。利用该高分子制备的胶束共装载抗肿瘤药物，微球胶束在进入细胞内涵体后由于聚合物侧基DPA和/或EAB的质子化得以逃逸，载药胶束在淋巴管畸形细胞靶向信号介导下定位于淋巴管细胞内部，释放出的细胞毒药物以不同作用机制诱导细胞凋亡，实现联合治疗肿瘤的目的。
具体实施方式
本发明通过以下实例作进一步阐述，但并不限制本发明的范围。这种制造技术的生产工艺对于本专业的人员来说是容易实施的。
例1本发明首先是以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材。在pH2的酸性环境下质子化的0.5mol/LDPA和亲水性的1.5mol/L PEG。通过微流控模板，按每次1.5分钟。按溶胀比为1:15-30加入0.5mol/L的乙酸溶液，从而获得改性后的缓释微球。将粗提液和NaCl溶液按重量配比混合，以3500-5500r/min转速离心5-30min，弃去上清液，沉淀用10倍体积的0.5mol/L的乙酸溶解，以3500-5500r/min转速离心5-30min。重复此步3次左右。将透析过后的微球溶液用真空冷冻干燥机进行干燥，即可得诊疗一体化双亲微球缓释微球。
例2本发明首先是以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材。在pH2的酸性环境下质子化的0.5mol/L EAB和亲水性的1.5mol/L PEG。通过微流控模板，按每次1.5分钟。按溶胀比为1:15-30加入0.5mol/L的乙酸溶液，从而获得改性后的缓释微球。将粗提液和NaCl溶液按重量配比混合，以3500-5500r/min转速离心5-30min，弃去上清液，沉淀用10倍体积的0.5mol/L的乙酸溶解，以3500-5500r/min转速离心5-30min。重复此步3次左右。将几次盐析过后得到的上清液透析三天，每半天换一次蒸馏水。透析袋孔径为7000。将透析过后的微球溶液用真空冷冻干燥机进行干燥，即可得诊疗一体化双亲微球缓释微球。

Claims (3)

1.一种用于诊疗一体化双亲微球缓释微球的研究领域的制备技术，具体地说，是以壳聚糖为原料，通过微流控方法制成具有诊疗一体化双亲微球缓释微球。
2.一种用于诊疗一体化双亲微球缓释微球的方法，其特征在于：该方法特征在于，以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材。再利用微流控方式，盐析、透析法精制缓释微球。整个制备过程中，缓释微球损失少、变性小、得率高。
3.一种用于诊疗一体化双亲微球缓释微球的方法，其特征在于包含如下步骤：包括以下工艺步骤：
(1)本发明首先是以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材；
(2)在pH2的酸性环境下质子化的0.5mol/LDPA和亲水性的1.5mol/LPEG；
(3)通过微流控模板，按每次1.5分钟，备用；
(4)按溶胀比为1:15-30加入0.5mol/L的乙酸溶液，从而获得改性后的缓释微球；
(5)将粗提液和NaCl溶液按重量配比混合，以3500-5500r/min转速离心5-30min，弃去上清液，沉淀用10倍体积的0.5mol/L的乙酸溶解，以3500-5500r/min转速离心5-30min。重复此步3次左右；
(6)干燥样品：将透析过后的微球溶液用真空冷冻干燥机进行干燥，即诊疗一体化双亲微球缓释微球。
CN202111349778.XA 2021-11-15 2021-11-15 一种诊疗一体化双亲微球缓释微球的制备方法 Pending CN114191410A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111349778.XA CN114191410A (zh) 2021-11-15 2021-11-15 一种诊疗一体化双亲微球缓释微球的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111349778.XA CN114191410A (zh) 2021-11-15 2021-11-15 一种诊疗一体化双亲微球缓释微球的制备方法

Publications (1)

Publication Number Publication Date
CN114191410A true CN114191410A (zh) 2022-03-18

Family

ID=80647602

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111349778.XA Pending CN114191410A (zh) 2021-11-15 2021-11-15 一种诊疗一体化双亲微球缓释微球的制备方法

Country Status (1)

Country Link
CN (1) CN114191410A (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10273447A (ja) * 1997-01-29 1998-10-13 Takeda Chem Ind Ltd 徐放性マイクロスフィア、その製造法および用途
WO2010062678A2 (en) * 2008-10-30 2010-06-03 David Liu Micro-spherical porous biocompatible scaffolds and methods and apparatus for fabricating same
CN103371974A (zh) * 2012-04-25 2013-10-30 中国科学院大连化学物理研究所 一种基于微流控技术制备的药物缓释聚合物微球及应用
WO2018028058A1 (zh) * 2016-08-08 2018-02-15 江南大学 一种表面功能化可载药洗脱微球的制备方法
US20180221503A1 (en) * 2015-07-31 2018-08-09 Tarveda Therapeutics, Inc. Compositions and methods for immuno-oncology therapies
US20190117799A1 (en) * 2016-04-01 2019-04-25 The Brigham And Women's Hospital, Inc. Stimuli-responsive nanoparticles for biomedical applications

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10273447A (ja) * 1997-01-29 1998-10-13 Takeda Chem Ind Ltd 徐放性マイクロスフィア、その製造法および用途
WO2010062678A2 (en) * 2008-10-30 2010-06-03 David Liu Micro-spherical porous biocompatible scaffolds and methods and apparatus for fabricating same
CN103371974A (zh) * 2012-04-25 2013-10-30 中国科学院大连化学物理研究所 一种基于微流控技术制备的药物缓释聚合物微球及应用
US20180221503A1 (en) * 2015-07-31 2018-08-09 Tarveda Therapeutics, Inc. Compositions and methods for immuno-oncology therapies
US20190117799A1 (en) * 2016-04-01 2019-04-25 The Brigham And Women's Hospital, Inc. Stimuli-responsive nanoparticles for biomedical applications
WO2018028058A1 (zh) * 2016-08-08 2018-02-15 江南大学 一种表面功能化可载药洗脱微球的制备方法

Similar Documents

Publication Publication Date Title
Wang et al. Core–shell tecto dendrimers formed via host–guest supramolecular assembly as pH-responsive intelligent carriers for enhanced anticancer drug delivery
Zan et al. Dual pH-triggered multistage drug delivery systems based on host–guest interaction-associated polymeric nanogels
CN102920649B (zh) 载药纳米胶束及其制备方法和应用
Li et al. Drug binding rate regulates the properties of polysaccharide prodrugs
CN103333301B (zh) 一种两亲性pH响应4/6杂臂星型共聚物及其制备方法
Ilbasmis-Tamer et al. Stimuli-responsive lipid nanotubes in gel formulations for the delivery of doxorubicin
CN108310395B (zh) 一种表面电荷可转换的聚合物纳米药物载体及制备方法和应用
CN104162169A (zh) 一种药物组合物及其制备方法和用途
Wang et al. A novel preparation method of paclitaxcel-loaded folate-modified chitosan microparticles and in vitro evaluation
CN109988314B (zh) 一种超支化聚壳多糖及其制备方法和应用
CN104162166A (zh) pH敏感性多糖纳米载药胶束及其制备方法
CN101708335A (zh) pH敏感树枝状聚合物药物载体
Yi et al. A novel pH-responsive charge reversal nanospheres based on acetylated histidine-modified lignin for drug delivery
CN102408560A (zh) 一种环境响应型星形共聚物的制备方法
CN108794709A (zh) 一种超高pH刺激响应的两亲性星形嵌段聚合物制备方法
CN104721831A (zh) 一种透明质酸共价连接靶向性穿膜肽和活性药物的水溶性前药及其制备方法
CN109303768B (zh) 一种负载漆酚的pH响应性两亲共聚物胶束的制备方法
CN104031270A (zh) 可完全解离型聚乙二醇-聚(L-谷氨酸-γ-苄酯)-聚乙烯亚胺共聚物及其合成方法和应用
CN105646861B (zh) 基于聚姜黄素的两亲性嵌段共聚物及其应用
CN114191410A (zh) 一种诊疗一体化双亲微球缓释微球的制备方法
Saraei et al. Co‐delivery of methotrexate and doxorubicin via nanocarriers of star‐like poly (DMAEMA‐block‐HEMA‐block‐AAc) terpolymers
CN104434792A (zh) 聚合物胶束及其制备方法和抗肿瘤药物组合物、制剂及其制备方法
CN111249473B (zh) 一种聚合氯喹芴甲基羰基纳米凝胶递送系统及其制备方法
CN109432051B (zh) 一种具有抗卵巢癌活性的靶向纳米粒及制备和应用
Wu et al. Preparation of pH-sensitive zwitterionic nano micelles and drug controlled release for enhancing cellular uptake

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20220318

WD01 Invention patent application deemed withdrawn after publication