WO2021218637A1 - Modified sodium alginate self-developing embolism microsphere and preparation method therefor and application thereof - Google Patents

Modified sodium alginate self-developing embolism microsphere and preparation method therefor and application thereof Download PDF

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WO2021218637A1
WO2021218637A1 PCT/CN2021/087264 CN2021087264W WO2021218637A1 WO 2021218637 A1 WO2021218637 A1 WO 2021218637A1 CN 2021087264 W CN2021087264 W CN 2021087264W WO 2021218637 A1 WO2021218637 A1 WO 2021218637A1
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sodium alginate
modification
substitution rate
modified sodium
modified
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French (fr)
Chinese (zh)
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冷鸿飞
徐小雨
谢辉
王华明
田圣涛
陶秀梅
陈鹏
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北京诺康达医药科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • 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
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the invention relates to the technical field of biomedicine, in particular to a modified sodium alginate auto-imaging embolic microsphere, and a preparation method and application thereof.
  • TACE Transcatheter vascular embolization
  • the ideal embolic material should meet the following requirements: non-toxic, non-antigenic, has good biocompatibility, has no residue in the body, and can be completely degraded.
  • Sodium alginate is a polysaccharide sodium salt composed of a mixture of mannose and guolose extracted from natural plant brown algae, which meets the requirements of an ideal embolic material.
  • Chinese patent CN106620829A proposes a developing embolic material and a preparation method thereof. Sodium alginate is blended with tantalum powder and then cross-linked with calcium ions to prepare developing microspheres.
  • Chinese patent CN103432080A uses sodium alginate, nano silver and anti-tumor drugs to blend with calcium ion to prepare developing microspheres.
  • the developer is dispersed in a conventional stirring method, which is prone to disadvantages such as uneven dispersion and agglomeration of the developer.
  • the microspheres cannot be loaded with drugs or only through physical blending, and the long-term effective release of drugs cannot be controlled. It has a great influence on the efficacy of chemotherapy and embolization treatment of tumors.
  • the purpose of the present invention is to provide a modified sodium alginate embolization microsphere that can increase drug loading, shorten drug loading preparation time, have a long sustained release time, controllable degradation time, and has a visualization function.
  • a modified sodium alginate auto-imaging embolic microsphere comprising: modified sodium alginate and a developer;
  • the modified sodium alginate is sodium alginate that has undergone branching modification to introduce multiple hydroxyl groups, and then hydrophobically modified and sulfonated modified sodium alginate, and the branching substitution rate of the branching modification is 22- 81%; the hydrophobic substitution rate of the hydrophobic modification is 5-32%; the sulfonation substitution rate of the sulfonation modification is 57-266%.
  • the side chain groups of the sodium alginate are first modified by branching in a specific ratio, and a plurality of hydroxyl groups that can be used as sulfonation modification and hydrophobic modification sites are appropriately introduced (modification).
  • the sex site is on the hydroxyl group of the side chain of the sodium alginate structure), and then the hydroxyl group on the side chain is further subjected to a specific ratio of hydrophobic modification and sulfonation modification (the order of sulfonation modification and hydrophobic modification is not limited ), so as to introduce appropriately multiple hydrophobic groups and negatively charged sulfonic acid groups, so that when the negatively charged sulfonic acid groups and the positive and negative charges of the positively charged drugs are attracted to each other to achieve drug loading, both It can significantly increase the drug loading and drug loading rate of positively charged drugs, delay drug release time, reduce drug burst release, and improve the therapeutic effect of chemotherapy and embolization.
  • the branch substitution rate refers to the ratio of the number of moles of the grafted branching agent in the sodium alginate to the number of moles of the sodium alginate repeating unit (C 6 H 7 NaO 6 ) before being modified.
  • the hydrophobic substitution rate refers to the ratio of the number of moles of grafted hydrophobic monomers in the sodium alginate after branching modification to the number of moles of the sodium alginate repeating unit before the modification
  • the sulfonation substitution rate refers to the number of moles of the branched modified sodium alginate.
  • the invention is microspherical.
  • the particle size of the microspheres is 100-1000 ⁇ m, so as to facilitate selective embolization of the inner diameter of blood vessels in different parts.
  • the branch substitution rate of the branch modification is 45%-50%
  • the hydrophobic substitution rate of the hydrophobic modification is 18-25%
  • the sulfonation substitution rate of the sulfonation modification is 82- 121%, in order to further improve the drug loading efficiency, and the sustained release effect is better.
  • the ratio of the branching substitution rate, the hydrophobic substitution rate to the sulfonation substitution rate is 1:(0.4-0.5):(2.5-2.7), so as to obtain a better drug-loading efficiency and relaxation. Interpretation effect.
  • the branched modified branch modifier is one or more of glycerol, pentaerythritol, and diglycerol, preferably pentaerythritol;
  • the hydrophobically modified hydrophobic modifier is one or more of oleic acid, octylamine, dodecylamine, and hexadecylamine, preferably oleic acid;
  • the sulfonated modified sulfonating agent is one or more of sulfite derivatives, chlorosulfonic acid, and concentrated sulfuric acid, preferably sulfite derivatives.
  • the sulfite derivative has the following chemical formula:
  • the sulfite derivative is prepared from sodium bisulfite and sodium nitrite.
  • the sulfite derivative is prepared from sodium bisulfite and sodium nitrite.
  • Synthesis, Characterization, and Anticoagulant Activity of Carboxymethyl Starch Sulfates Lihong Fan, Yugui Gong, Mi Cao, Song Gao, Yi Sun, Lingyun Chen, Hua Zheng, Weiguo Xie, J. APPL. POLYM. 2013 DOI: 10.1002/APP.38088).
  • the branching modifier is pentaerythritol
  • the branch substitution rate is 45%-50%
  • the hydrophobic modifier is oleic acid
  • the hydrophobic substitution rate is 18-25%
  • the sulfonating agent is sub Sulfate derivatives
  • the sulfonation substitution rate is 82-121%; more preferably, the ratio of the branching substitution rate, the hydrophobic substitution rate to the sulfonation substitution rate is 1:(0.4-0.5):( 2.5-2.7).
  • the viscosity of the sodium alginate is 55-619mpa ⁇ s, preferably 280-400mpa ⁇ s, so as to ensure the degradation cycle and facilitate the production of small particle size microspheres.
  • the branching modification, hydrophobic modification and sulfonation modification in the present invention can be carried out by the conventional method of modifying sodium alginate in this field.
  • branching modification includes the following steps: adding sodium alginate to the acetone solution of halogenated hydrocarbons, and adjusting the pH of the solution to 8-12, 30-55 React at °C for 3 ⁇ 6h, add branched modified monomer (branched modifier), the molar ratio of branched modified monomer to unmodified sodium alginate repeat unit is (0.3-1): 1. Stir and react at 80-100°C for 8-24 hours, add excess acetone solution, filter with suction, collect the precipitate, wash and dry to obtain branched modified sodium alginate.
  • the skilled person can select specific reaction conditions for each step according to the common knowledge in the field and the reaction method described in the present invention to achieve the expected branching substitution rate, hydrophobic substitution rate and sulfonation substitution rate.
  • the content of the developer in the embolic microspheres is 8-30 wt%, so as to ensure the development effect without affecting the fluidity of the modified sodium alginate solution of the present invention during preparation; preferably, the The imaging agent is an X-ray imaging agent or an MRI imaging agent.
  • the X-ray developer is iohexol, iotroram, ioverol, diatrizoate meglumine, triiodobenzoic acid or other iodine-based developers, or barium sulfate, nano silver, tantalum powder, etc.
  • the MRI developer is Fe 3 O 4 and so on.
  • the embolic microspheres can also be loaded with positively charged drugs, preferably the drugs are anti-tumor drugs; more preferably doxorubicin hydrochloride, irinotecan, topotecan, epirubicin One or more of, epirubicin, bleomycin, cisplatin, carboplatin, oxaliplatin, lobaplatin, fluorouracil, and mitomycin.
  • drugs are anti-tumor drugs; more preferably doxorubicin hydrochloride, irinotecan, topotecan, epirubicin
  • epirubicin One or more of, epirubicin, bleomycin, cisplatin, carboplatin, oxaliplatin, lobaplatin, fluorouracil, and mitomycin.
  • the drug is water-soluble, and the hydrophobicity of the embolic microspheres can prolong the sustained release time of the drug.
  • the present invention also provides a method for preparing the above-mentioned embolic microspheres, which uses a mixed solution of the modified sodium alginate aqueous solution and the developer as a raw material liquid, and is prepared by an electrostatic droplet method.
  • the mass fraction of the aqueous solution of modified sodium alginate is 1% to 15%.
  • the mixing method of the aqueous solution of modified sodium alginate and the developer is: 200-300r/min after stirring for 30-50min, ultrasonic dispersion for 20-30min, and finally 800-1000r/min for high-speed dispersion for 30- 50min; preferably, after stirring at 300r/min for 40min, ultrasonic dispersion for 30min, and finally high-speed shearing at 900r/min for 35min to facilitate uniform dispersion of the developer.
  • the crosslinking agent used in the crosslinking of the modified sodium alginate is selected from one or more of calcium chloride, magnesium chloride, barium chloride, and copper chloride, preferably calcium chloride. Conducive to safety after embolization.
  • the preparation method of the porous microspherical embolic microspheres of the present invention is:
  • the imaging agent in the microspheres prepared by the method of the present invention is uniformly dispersed without aggregation, and can achieve precise imaging effects during and after vascular embolization.
  • the present invention also provides an application of the embolization microspheres or methods described above in the preparation of products for vascular embolization or hemostasis.
  • the present invention significantly increases the drug loading amount and drug loading rate of the embolic microspheres, can prolong the drug slow release time, reduce the drug burst release, relatively reduce the drug side effects and prolong the drug onset time, Effectively improve the effect of chemotherapy and embolization treatment.
  • the modification of the side chain of sodium alginate by the present invention does not affect the degradation performance and biocompatibility of the sodium alginate main chain structure.
  • Fig. 1 is the microscopic observation results of the dispersion liquid of each embodiment of the experimental example 2 of the present invention and the comparative example.
  • modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
  • Branch modification add sodium alginate with a viscosity of 619mpa ⁇ s to the acetone solution of dibromoethane, adjust the pH of the solution to 10, pre-react at 55°C for 3h, add pentaerythritol, pentaerythritol and sodium alginate The molar ratio of the repeating unit is 0.3:1, and the reaction is stirred at 80°C for 24 hours, an excess of acetone solution is added, and the precipitate is collected by suction filtration, washed and dried to obtain branched modified sodium alginate.
  • Hydrophobic modification add oleic acid and branched modified sodium alginate to N, N-dimethylformamide, add dicyclohexylcarbodiimide and 4-dimethylaminopyridine under stirring conditions , React at room temperature for 24h to obtain hydrophobically modified sodium alginate.
  • the molar ratio of oleic acid to the above-mentioned sodium alginate repeating unit is 0.3:1.
  • the sulfonating agent is a sodium bisulfite derivative, and its chemical formula is:
  • steps 2 and 3 are not limited.
  • the modified sodium alginate obtained by the above three-step modification is configured into a 1% aqueous solution of modified sodium alginate, and the modified sodium alginate is fully dissolved in the water by stirring.
  • tantalum powder to the modified sodium alginate aqueous solution so that the content of the tantalum powder is 8wt%, and after stirring at 200r/min for 30min, ultrasonically disperse for 20min, and finally 800r/min high-speed shearing for 30min until the tantalum powder is evenly dispersed. Mixture.
  • the solidified modified sodium alginate auto-imaging plug microspheres were stored in a maintenance solution (a calcium chloride solution with a concentration of 3%) at a ratio of 1 g/5 ml.
  • Example 2-7 modified sodium alginate auto-imaging embolic microspheres were prepared according to the method of Example 1 and further loaded with drugs. The only difference lies in the preparation of raw materials and dosage, reaction conditions, developer mixing method and preparation electric field force. The voltages are not exactly the same. In addition, in Examples 6-7, the order of steps 2 and 3 are interchanged.
  • Example 2-7 the differences between Examples 2-7 and Example 1 in the sodium alginate raw material in step 1, the concentration of the modified sodium alginate aqueous solution in step 4, the content of the developer, and the drug-carrying drug are shown in Table 1. See Table 2 for the difference between the amount of raw materials and reaction conditions during chemical modification and Example 1, and see Table 3 for the difference between the amount of raw materials and reaction conditions during hydrophobic modification and Example 1. In sulfonation modification The difference between the amount of raw materials and the reaction conditions in Example 1 is shown in Table 4, the difference between the developer mixing mode and Example 1 is shown in Table 5. 1 is the same, and examples 4-7 are 11kv.
  • Example Developer mixing method 2 Stir at 200r/min for 50min, ultrasonically disperse for 20min, and finally shear at 800r/min for 30min 3 After stirring at 200r/min for 50min, ultrasonic dispersion for 30min, and finally 800r/min high-speed shearing for 30min 4 After stirring at 260r/min for 50min, ultrasonic dispersion for 25min, and finally 1000r/min high-speed shearing for 50min 5 After stirring at 300r/min for 40min, ultrasonic dispersion for 30min, finally 900r/min high-speed shearing for 35min 6 After stirring at 230r/min for 35min, ultrasonic dispersing for 25min, and finally high-speed shearing at 900r/min for 35min 7 After stirring at 230r/min for 50min, ultrasonic dispersion for 25min, and finally 1000r/min high-speed shearing for 50min
  • modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
  • Branch modification add sodium alginate with a viscosity of 110mpa ⁇ s to the acetone solution of dibromoethane, adjust the pH of the solution to 11, pre-react at 30°C for 4h, add glycerin, glycerin and sodium alginate The molar ratio of the repeating unit is 0.35:1, and the reaction is stirred at 100°C for 8 hours, an excess of acetone solution is added, and the precipitate is collected by suction filtration, washed and dried to obtain branched modified sodium alginate.
  • steps 2 and 3 are not limited.
  • the modified sodium alginate obtained by the above-mentioned three-step modification is configured into a modified sodium alginate aqueous solution with a mass fraction of 5%, and the modified sodium alginate is fully dissolved in the water by stirring.
  • Example 6 Through the electrostatic droplet generating device of Example 1, the above-mentioned mixed liquid was injected into a barium chloride aqueous solution with a mass concentration of 5% for cross-linking and curing for 24 hours to obtain modified sodium alginate auto-imaging embolic microspheres.
  • the specific preparation method is the same as in Example 1, except that the electric field force and voltage are 7.5 kv.
  • Drug loading The drug loading method of this example is the same as that of Example 1, except that the drug is epirubicin.
  • modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
  • Branching modification This embodiment adopts the same branching modification method as that of Example 8, except that the viscosity of sodium alginate is 90mpa ⁇ s, and dipolyglycerol is used instead of glycerin, dipolyglycerol and alginic acid
  • the molar ratio of sodium repeating unit is 0.6:1, and the reaction time is 12h.
  • Hydrophobic modification This embodiment uses the same hydrophobic modification method as that of Example 8, except that: dodecylamine is used instead of octylamine, and the molar ratio of dodecylamine to the above-mentioned sodium alginate repeating unit is 0.4:1.
  • steps 2 and 3 are not limited.
  • the modified sodium alginate obtained by the above three-step modification is configured into a modified sodium alginate aqueous solution with a mass fraction of 2%, and the modified sodium alginate is fully dissolved in the water by stirring.
  • ferroferric oxide added to the modified sodium alginate aqueous solution to make the content of ferroferric oxide 15wt%. After stirring at 240r/min for 38min, ultrasonically disperse for 30min, and finally high-speed shearing at 1000r/min for 55min to four The ferroferric oxide is evenly dispersed to obtain a mixed solution.
  • Example 6 Through the electrostatic droplet generating device of Example 1, the above-mentioned mixed liquid was injected into a copper chloride aqueous solution with a mass concentration of 12% for cross-linking and curing for 24 hours to obtain modified sodium alginate auto-developing embolic microspheres.
  • the specific preparation method is the same as in Example 1, except that the electric field force and voltage are 30kv.
  • modified sodium alginate embolic microspheres were prepared according to the method of Example 5, except that the sulfonation modification was not performed.
  • modified sodium alginate embolic microspheres were prepared according to the method of comparative example 1, except that the hydrophobic modification was not carried out.
  • modified sodium alginate embolization microspheres were prepared according to the method of Example 5. The only difference is that glucose is used as the branching monomer, and the substitution rate of each step is unchanged.
  • modified sodium alginate embolic microspheres were prepared according to the method of Example 5. The only difference is: in the hydrophobic modification step: the molar ratio of oleic acid to the above-mentioned sodium alginate repeating unit is 0.8:1; the hydrophobic substitution rate is 60% , The replacement rate of the remaining two steps remains unchanged.
  • modified sodium alginate embolization microspheres were prepared according to the method of Example 5. The only difference is: in the sulfonation modification step: the molar ratio of the sulfonating agent and the sodium alginate repeating unit is 0.4:1, and the sulfonation The chemical substitution rate is 32%.
  • modified sodium alginate was prepared according to the formula of Example 5.
  • the specific method of adding developer in step 5 is: adding tantalum powder to the modified sodium alginate aqueous solution obtained in step 4 so that the content of tantalum powder is 15wt%, and mixed at 1000r/min for 100min.
  • the particle size test method is: the microscope method specified in Appendix B of YY/T 1574-2017;
  • This experimental example further tests the developer dispersion effect of the products of Examples 1-9 and Comparative Examples 1-6.
  • the specific method is to take 0.5ml of the dispersion liquid (ie the mixed liquid obtained in step 5) after the developer is dispersed. On a glass slide, cover with a cover glass and observe under a microscope with a 20-fold objective lens. The observation result is shown in Figure 1. It can be seen from Figure 1 that the conventional dispersion method (Comparative Example 6) has a significantly lower dispersion effect than the method used in the present invention.
  • the invention provides a modified sodium alginate auto-imaging embolic microsphere, and a preparation method and application thereof.
  • the modified sodium alginate auto-imaging embolic microspheres of the present invention include: modified sodium alginate and a developer; the modified sodium alginate is modified by branching to introduce multiple hydroxyl groups, and then hydrophobically modified And sulfonated modified sodium alginate, the branching substitution rate of the branch modification is 22-81%; the hydrophobic substitution rate of the hydrophobic modification is 5-32%; the sulfonated modified sulfonate The chemical substitution rate is 57-266%.
  • the embolic microspheres of the present invention can not only significantly increase the drug loading and drug loading rate of negatively charged drugs, but also delay drug release time and reduce drug burst release, and have good economic value and application prospects .

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Abstract

A modified sodium alginate self-developing embolism microsphere and a preparation method therefor and an application thereof. The modified sodium alginate self-developing embolism microsphere comprises modified sodium alginate and a developing agent. The preparation method for modified sodium alginate comprises: performing branching modification to introduce a plurality of hydroxyl groups and then performing hydrophobic modification and sulfonation modification, wherein the branching substitution rate is 22-81%, the hydrophobic substitution rate is 5-32%, and the sulfonation substitution rate is 57-266%. When the sodium alginate self-developing embolism microsphere is used as a drug carrier, the drug loading capacity and the drug loading rate of a negatively charged drug can be remarkably improved, the drug release time can be delayed, and the burst release of the drug is reduced.

Description

一种改性海藻酸钠自显影栓塞微球及其制备方法与应用Modified sodium alginate auto-imaging embolic microspheres and preparation method and application thereof
交叉引用cross reference
本申请要求2020年4月28日提交的专利名称为“一种改性海藻酸钠自显影栓塞微球及其制备方法与应用”的第202010352195.1号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。This application claims the priority of the Chinese patent application No. 202010352195.1 filed on April 28, 2020 entitled "A modified sodium alginate auto-imaging embolic microsphere and its preparation method and application", the entire disclosure of which is approved The reference is incorporated into this article in its entirety.
技术领域Technical field
本发明涉及生物医药技术领域，具体地说，涉及一种改性海藻酸钠自显影栓塞微球及其制备方法与应用。The invention relates to the technical field of biomedicine, in particular to a modified sodium alginate auto-imaging embolic microsphere, and a preparation method and application thereof.
背景技术Background technique
动脉栓塞术是一种重要的介入治疗技术，该治疗技术融合了医学影象和临床治疗等多种学科，具有简便、安全、微创以及治疗后并发症少的特点。经导管血管栓塞术(TACE)主要是经动脉或静脉内导管将栓塞剂注入到病变靶器官的供应血管内，使血管发生闭塞，中断血液供应，最终达到治疗目的。Arterial embolization is an important interventional treatment technique, which combines medical imaging and clinical treatment and other disciplines. It is simple, safe, minimally invasive, and features few complications after treatment. Transcatheter vascular embolization (TACE) is mainly used to inject embolic agents into the supply blood vessels of the diseased target organs through arteries or intravenous catheters to occlude the blood vessels, interrupt the blood supply, and ultimately achieve the purpose of treatment.
目前临床应用比较广泛的微球(栓塞材料)均为可载药的栓塞微球，所用材料为聚乙烯醇，但微球不能实现自显影效果，不利于临床治疗效果的监测。中国专利CN107812232A公开了可显影羧基改性聚乙烯醇微球栓塞剂及其制备工艺，但其载药量少，载药时间长、且存在不可降解的缺点。At present, the most widely used microspheres (embolization materials) in clinical applications are all embolization microspheres that can be loaded with drugs. The material used is polyvinyl alcohol, but the microspheres cannot achieve auto-imaging effect, which is not conducive to the monitoring of clinical treatment effects. Chinese patent CN107812232A discloses a developable carboxyl modified polyvinyl alcohol microsphere embolic agent and its preparation process, but its drug loading is small, drug loading time is long, and it has the disadvantages of non-degradability.
理想的栓塞材料应符合以下要求：无毒，无抗原性，具有较好的生物相容性，在体内无残留，可完全降解。海藻酸钠是从天然植物褐藻中提取的甘露糖和古罗糖混合组成的多糖钠盐，符合理想栓塞材料的要求。中国专利CN106620829A提出一种显影栓塞材料及其制备方法，以海藻酸钠共混钽粉后以钙离子交联制备显影微球。中国专利CN103432080A以海藻酸钠、纳米银和抗肿瘤药物共混以钙离子交联制备显影微球。上述技术中显影剂以常规搅拌方式进行分散，易存在显影剂分散不均匀、团聚等缺 点，此外，微球不能实现载药或仅通过物理共混方式载药，无法控制药物的长期有效释放，对肿瘤的化疗和栓塞治疗的疗效有较大影响。The ideal embolic material should meet the following requirements: non-toxic, non-antigenic, has good biocompatibility, has no residue in the body, and can be completely degraded. Sodium alginate is a polysaccharide sodium salt composed of a mixture of mannose and guolose extracted from natural plant brown algae, which meets the requirements of an ideal embolic material. Chinese patent CN106620829A proposes a developing embolic material and a preparation method thereof. Sodium alginate is blended with tantalum powder and then cross-linked with calcium ions to prepare developing microspheres. Chinese patent CN103432080A uses sodium alginate, nano silver and anti-tumor drugs to blend with calcium ion to prepare developing microspheres. In the above-mentioned technology, the developer is dispersed in a conventional stirring method, which is prone to disadvantages such as uneven dispersion and agglomeration of the developer. In addition, the microspheres cannot be loaded with drugs or only through physical blending, and the long-term effective release of drugs cannot be controlled. It has a great influence on the efficacy of chemotherapy and embolization treatment of tumors.
因此，有必要提供一种新的改性海藻酸钠自显影栓塞微球及其制备方法与应用，以解决现有技术中的缺陷。Therefore, it is necessary to provide a new modified sodium alginate auto-imaging embolic microsphere and its preparation method and application to solve the defects in the prior art.
发明内容Summary of the invention
针对现有技术的缺点，本发明的目的是提供一种可提升载药量、缩短载药制备时间、缓释时间长、降解时间可控，具有显影功能的改性海藻酸钠栓塞微球。In view of the shortcomings of the prior art, the purpose of the present invention is to provide a modified sodium alginate embolization microsphere that can increase drug loading, shorten drug loading preparation time, have a long sustained release time, controllable degradation time, and has a visualization function.
为了实现该目的，本发明的技术方案如下：In order to achieve this objective, the technical solution of the present invention is as follows:
一种改性海藻酸钠自显影栓塞微球，包括：改性海藻酸钠和显影剂；A modified sodium alginate auto-imaging embolic microsphere, comprising: modified sodium alginate and a developer;
所述改性海藻酸钠为先经支化改性以引入多个羟基后，再进行疏水改性和磺化改性的海藻酸钠，所述支化改性的支化取代率为22-81％；所述疏水改性的疏水取代率为5-32％；所述磺化改性的磺化取代率为57-266％。The modified sodium alginate is sodium alginate that has undergone branching modification to introduce multiple hydroxyl groups, and then hydrophobically modified and sulfonated modified sodium alginate, and the branching substitution rate of the branching modification is 22- 81%; the hydrophobic substitution rate of the hydrophobic modification is 5-32%; the sulfonation substitution rate of the sulfonation modification is 57-266%.
本发明的改性海藻酸钠，首先通过对海藻酸钠侧链基团进行特定比例的支化改性，适当地引入了多个可作为磺化改性和疏水改性位点的羟基(改性位点在海藻酸钠结构侧链的羟基上)，之后进一步对其侧链上的羟基进行特定比例的疏水改性和磺化改性(磺化改性和疏水改性的先后顺序不限)，从而引入适当地多个疏水基团和带负电的磺酸基团，以在进一步通过带负电的磺酸基团与带正电的药物的正负电荷相互吸引实现载药时，既可显著提高带正电的药物的载药量和载药速率，又可延缓药物释放时间，减少药物突释，进而提高化疗和栓塞的治疗效果。In the modified sodium alginate of the present invention, the side chain groups of the sodium alginate are first modified by branching in a specific ratio, and a plurality of hydroxyl groups that can be used as sulfonation modification and hydrophobic modification sites are appropriately introduced (modification). The sex site is on the hydroxyl group of the side chain of the sodium alginate structure), and then the hydroxyl group on the side chain is further subjected to a specific ratio of hydrophobic modification and sulfonation modification (the order of sulfonation modification and hydrophobic modification is not limited ), so as to introduce appropriately multiple hydrophobic groups and negatively charged sulfonic acid groups, so that when the negatively charged sulfonic acid groups and the positive and negative charges of the positively charged drugs are attracted to each other to achieve drug loading, both It can significantly increase the drug loading and drug loading rate of positively charged drugs, delay drug release time, reduce drug burst release, and improve the therapeutic effect of chemotherapy and embolization.
本发明中，所述支化取代率指海藻酸钠中接枝支化剂的羟基摩尔数与未改性前的海藻酸钠重复单元(C 6H 7NaO 6)摩尔数的比例，所述疏水取代率指支化改性后的海藻酸钠中接枝疏水单体的羟基摩尔数与未改性前的海藻酸钠重复单元摩尔数的比例，所述磺化取代率指支化改性后的海藻酸钠中磺化的羟基摩尔数与未改性前的海藻酸钠重复单元摩尔数的比例。 In the present invention, the branch substitution rate refers to the ratio of the number of moles of the grafted branching agent in the sodium alginate to the number of moles of the sodium alginate repeating unit (C 6 H 7 NaO 6 ) before being modified. The hydrophobic substitution rate refers to the ratio of the number of moles of grafted hydrophobic monomers in the sodium alginate after branching modification to the number of moles of the sodium alginate repeating unit before the modification, and the sulfonation substitution rate refers to the number of moles of the branched modified sodium alginate. The ratio of the number of moles of sulfonated hydroxyl groups in the latter sodium alginate to the number of moles of sodium alginate repeating units before the modification.
本发明中，所述发明物呈微球形。In the present invention, the invention is microspherical.
优选地，所述微球的粒径为100-1000μm，以利于针对不同部位的血管内径进行选择性栓塞。Preferably, the particle size of the microspheres is 100-1000 μm, so as to facilitate selective embolization of the inner diameter of blood vessels in different parts.
优选地，所述支化改性的支化取代率为45％-50％，所述疏水改性的疏水取代率为18-25％，所述磺化改性的磺化取代率为82-121％，以进一步提升载药效率，且缓释效果更好。Preferably, the branch substitution rate of the branch modification is 45%-50%, the hydrophobic substitution rate of the hydrophobic modification is 18-25%, and the sulfonation substitution rate of the sulfonation modification is 82- 121%, in order to further improve the drug loading efficiency, and the sustained release effect is better.
更优选地，所述支化取代率、所述疏水取代率与所述磺化取代率的比值为1:(0.4-0.5):(2.5-2.7)，以获得更优的载药效率和缓释效果。More preferably, the ratio of the branching substitution rate, the hydrophobic substitution rate to the sulfonation substitution rate is 1:(0.4-0.5):(2.5-2.7), so as to obtain a better drug-loading efficiency and relaxation. Interpretation effect.
本发明中，所述支化改性的支化改性剂为甘油、季戊四醇、二聚甘油中的一种或多种，优选为季戊四醇；In the present invention, the branched modified branch modifier is one or more of glycerol, pentaerythritol, and diglycerol, preferably pentaerythritol;
本发明中，所述疏水改性的疏水改性剂为油酸、辛胺、十二胺、十六胺中的一种或多种，优选为油酸；In the present invention, the hydrophobically modified hydrophobic modifier is one or more of oleic acid, octylamine, dodecylamine, and hexadecylamine, preferably oleic acid;
本发明中，所述磺化改性的磺化剂为亚硫酸盐衍生物、氯磺酸、浓硫酸中的一种或多种，优选为亚硫酸盐衍生物。In the present invention, the sulfonated modified sulfonating agent is one or more of sulfite derivatives, chlorosulfonic acid, and concentrated sulfuric acid, preferably sulfite derivatives.
所述亚硫酸盐衍生物具有如下化学式：The sulfite derivative has the following chemical formula:
Figure PCTCN2021087264-appb-000001
Figure PCTCN2021087264-appb-000001
优选地，所述亚硫酸盐衍生物由亚硫酸氢钠和亚硝酸钠制备而成。具体可参见：Synthesis,Characterization,and Anticoagulant Activity of Carboxymethyl Starch Sulfates(Lihong Fan,Yugui Gong,Mi Cao,Song Gao,Yi Sun,Lingyun Chen,Hua Zheng,Weiguo Xie，J.APPL.POLYM.SCI.2013,DOI:10.1002/APP.38088)。Preferably, the sulfite derivative is prepared from sodium bisulfite and sodium nitrite. For details, please refer to: Synthesis, Characterization, and Anticoagulant Activity of Carboxymethyl Starch Sulfates (Lihong Fan, Yugui Gong, Mi Cao, Song Gao, Yi Sun, Lingyun Chen, Hua Zheng, Weiguo Xie, J. APPL. POLYM. 2013 DOI: 10.1002/APP.38088).
作为一个优选方式，本发明中，支化改性剂为季戊四醇，支化取代率为45％-50％，疏水改性剂为油酸，疏水取代率为18-25％，磺化剂为亚硫酸盐衍生物，磺化取代率为82-121％；更优选地，所述支化取代率、所述疏水取代率与所述磺化取代率的比例为1:(0.4-0.5):(2.5-2.7)。以既兼顾载药量与载药效率，并在药物释放时更稳定长效。As a preferred mode, in the present invention, the branching modifier is pentaerythritol, the branch substitution rate is 45%-50%, the hydrophobic modifier is oleic acid, the hydrophobic substitution rate is 18-25%, and the sulfonating agent is sub Sulfate derivatives, the sulfonation substitution rate is 82-121%; more preferably, the ratio of the branching substitution rate, the hydrophobic substitution rate to the sulfonation substitution rate is 1:(0.4-0.5):( 2.5-2.7). In order to take into account both the drug loading amount and drug loading efficiency, it is more stable and long-lasting when the drug is released.
本发明中，所述海藻酸钠的粘度为55-619mpa·s，优选为280-400mpa·s，以既保证降解周期又易于生产小粒径微球。In the present invention, the viscosity of the sodium alginate is 55-619mpa·s, preferably 280-400mpa·s, so as to ensure the degradation cycle and facilitate the production of small particle size microspheres.
本发明中支化改性、疏水改性和磺化改性可采用本领域常规的对海藻酸钠进行改性的方法进行。The branching modification, hydrophobic modification and sulfonation modification in the present invention can be carried out by the conventional method of modifying sodium alginate in this field.
为了实现更好的改性效果，本发明中作为一个优选方式，支化改性包括如下步骤：将海藻酸钠加入到卤代烃的丙酮溶液中，调节溶液pH至8～12，30～55℃条件下反应3～6h，加入支化改性单体(支化改性剂)，支化改性单体与未改性前的海藻酸钠重复单元的摩尔比为(0.3-1)：1，80～100℃下搅拌反应8～24h，加入过量的丙酮溶液，抽滤，收集沉淀，洗涤后干燥，即得支化改性后的海藻酸钠。In order to achieve a better modification effect, as a preferred method in the present invention, branching modification includes the following steps: adding sodium alginate to the acetone solution of halogenated hydrocarbons, and adjusting the pH of the solution to 8-12, 30-55 React at ℃ for 3～6h, add branched modified monomer (branched modifier), the molar ratio of branched modified monomer to unmodified sodium alginate repeat unit is (0.3-1): 1. Stir and react at 80-100°C for 8-24 hours, add excess acetone solution, filter with suction, collect the precipitate, wash and dry to obtain branched modified sodium alginate.
本发明中，技术人员可根据本领域常识和本发明记载的反应方法，选择具体的各步反应条件，以实现预期的支化取代率、疏水取代率和磺化取代率。In the present invention, the skilled person can select specific reaction conditions for each step according to the common knowledge in the field and the reaction method described in the present invention to achieve the expected branching substitution rate, hydrophobic substitution rate and sulfonation substitution rate.
本发明中，所述显影剂在所述栓塞微球中的含量为8-30wt％，以既保证显影效果又不影响制备时本发明改性海藻酸钠溶液的流动性；优选地，所述显影剂为X射线显影剂或MRI显影剂。In the present invention, the content of the developer in the embolic microspheres is 8-30 wt%, so as to ensure the development effect without affecting the fluidity of the modified sodium alginate solution of the present invention during preparation; preferably, the The imaging agent is an X-ray imaging agent or an MRI imaging agent.
更优选地，X射线显影剂为碘海醇、碘曲仑、碘佛醇、泛影葡胺、三碘苯甲酸等碘类显影剂或硫酸钡、纳米银、钽粉等，MRI显影剂为Fe 3O 4等。 More preferably, the X-ray developer is iohexol, iotroram, ioverol, diatrizoate meglumine, triiodobenzoic acid or other iodine-based developers, or barium sulfate, nano silver, tantalum powder, etc., and the MRI developer is Fe 3 O 4 and so on.
本发明中，所述的栓塞微球还可负载带正电的药物，优选所述药物为可抗肿瘤的药物；更优选为盐酸阿霉素、伊立替康、拓扑替康、表柔比星、表阿霉素、博来霉素、顺铂、卡铂、奥沙利铂、洛铂、氟尿嘧啶、丝裂霉素中的一种或多种。In the present invention, the embolic microspheres can also be loaded with positively charged drugs, preferably the drugs are anti-tumor drugs; more preferably doxorubicin hydrochloride, irinotecan, topotecan, epirubicin One or more of, epirubicin, bleomycin, cisplatin, carboplatin, oxaliplatin, lobaplatin, fluorouracil, and mitomycin.
本发明中，所述药物是水溶性的，栓塞微球的疏水性可延长药物缓释时间。In the present invention, the drug is water-soluble, and the hydrophobicity of the embolic microspheres can prolong the sustained release time of the drug.
本发明另提供一种制备上述栓塞微球的方法，其以所述改性海藻酸钠的水溶液与所述显影剂混合后的溶液作为原料液，采用静电液滴法制备。The present invention also provides a method for preparing the above-mentioned embolic microspheres, which uses a mixed solution of the modified sodium alginate aqueous solution and the developer as a raw material liquid, and is prepared by an electrostatic droplet method.
本发明中，所述改性海藻酸钠的水溶液的质量分数为1％～15％。In the present invention, the mass fraction of the aqueous solution of modified sodium alginate is 1% to 15%.
本发明中，所述改性海藻酸钠的水溶液与所述显影剂的混合方式为：200-300r/min搅拌30-50min后，超声分散20-30min，最后800-1000r/min高速分散30-50min；优选为，300r/min搅拌40min后，超声分散30min，最后900r/min高速剪切35min，以利于显影剂均匀分散。In the present invention, the mixing method of the aqueous solution of modified sodium alginate and the developer is: 200-300r/min after stirring for 30-50min, ultrasonic dispersion for 20-30min, and finally 800-1000r/min for high-speed dispersion for 30- 50min; preferably, after stirring at 300r/min for 40min, ultrasonic dispersion for 30min, and finally high-speed shearing at 900r/min for 35min to facilitate uniform dispersion of the developer.
本发明中，所述改性海藻酸钠在交联时所用的交联剂选自氯化钙、氯化镁、氯化钡、氯化铜中的一种或多种，优选为氯化钙，以利于栓塞后的安全性。In the present invention, the crosslinking agent used in the crosslinking of the modified sodium alginate is selected from one or more of calcium chloride, magnesium chloride, barium chloride, and copper chloride, preferably calcium chloride. Conducive to safety after embolization.
作为一个具体方案，本发明的多孔微球形的栓塞微球的制备方法为：As a specific solution, the preparation method of the porous microspherical embolic microspheres of the present invention is:
1)配置质量分数为1％～15％的改性海藻酸钠水溶液，搅拌使改性海藻酸钠充分溶解在水中；1) Configure a modified sodium alginate aqueous solution with a mass fraction of 1% to 15%, and stir to fully dissolve the modified sodium alginate in the water;
2)按比例加入显影剂并200-300r/min搅拌30-50min后，超声分散20-30min，最后800-1000r/min高速剪切30-50min至显影剂分散均匀；2) After adding the developer in proportion and stirring at 200-300r/min for 30-50min, ultrasonic dispersion for 20-30min, and finally 800-1000r/min high-speed shearing for 30-50min until the developer is evenly dispersed;
3)通过静电液滴发生装置将上述改性海藻酸钠水溶液推注到交联剂溶液中交联固化；3) Push the above-mentioned modified sodium alginate aqueous solution into the cross-linking agent solution through the electrostatic droplet generator to cross-link and solidify;
4)收集交联后的微球并保存到交联剂溶液中。4) Collect the cross-linked microspheres and store them in the cross-linking agent solution.
本发明方法制备的微球中显影剂分散均匀，无聚集，可实现血管栓塞术中和术后的精准显影效果。The imaging agent in the microspheres prepared by the method of the present invention is uniformly dispersed without aggregation, and can achieve precise imaging effects during and after vascular embolization.
本发明另提供一种上述栓塞微球或方法在制备用于血管栓塞术或止血的产品中的应用。The present invention also provides an application of the embolization microspheres or methods described above in the preparation of products for vascular embolization or hemostasis.
本发明的有益效果至少在于：The beneficial effects of the present invention are at least:
本发明通过对海藻酸钠的三次改性，显著提高了栓塞微球的载药量和载药速率，可延长药物缓释时间，减少药物突释，相对降低药物副作用和延长药物起效时间，有效提高化疗和栓塞治疗效果。且本发明对海藻酸钠的侧链改性，还不影响海藻酸钠主链结构的降解性能和生物相容性。By modifying the sodium alginate three times, the present invention significantly increases the drug loading amount and drug loading rate of the embolic microspheres, can prolong the drug slow release time, reduce the drug burst release, relatively reduce the drug side effects and prolong the drug onset time, Effectively improve the effect of chemotherapy and embolization treatment. In addition, the modification of the side chain of sodium alginate by the present invention does not affect the degradation performance and biocompatibility of the sodium alginate main chain structure.
附图说明Description of the drawings
图1为本发明实验例2的各实施例与对比例的分散液显微观察结果。Fig. 1 is the microscopic observation results of the dispersion liquid of each embodiment of the experimental example 2 of the present invention and the comparative example.
具体实施方式Detailed ways
下面将结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的，并不是用于对本发明的范围进行限制。本领域的技术人员在不背离本发明的宗旨和精神的情况下，可以对本发明进行各种修改和替换。The preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are given for illustrative purposes only, and are not intended to limit the scope of the present invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from the spirit and spirit of the present invention.
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.
实施例1Example 1
本实施例按照如下方法制备改性海藻酸钠自显影栓塞微球并进一步进行载药：In this example, the modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
1、支化改性：将粘度为619mpa·s的海藻酸钠加入到二溴乙烷的丙酮溶液中，调节溶液pH至10，55℃条件下预反应3h，加入季戊四醇，季戊四醇与海藻酸钠重复单元的摩尔比为0.3：1，80℃下搅拌反应24h，加入过量的丙酮溶液，抽滤，收集沉淀，洗涤后干燥，获得支化改性后的海藻酸钠。1. Branch modification: add sodium alginate with a viscosity of 619mpa·s to the acetone solution of dibromoethane, adjust the pH of the solution to 10, pre-react at 55℃ for 3h, add pentaerythritol, pentaerythritol and sodium alginate The molar ratio of the repeating unit is 0.3:1, and the reaction is stirred at 80°C for 24 hours, an excess of acetone solution is added, and the precipitate is collected by suction filtration, washed and dried to obtain branched modified sodium alginate.
2、疏水改性：将油酸与支化改性后的海藻酸钠加入到N、N-二甲基甲酰胺中，搅拌条件下加入二环己基碳二亚胺和4-二甲氨基吡啶，室温反应24h得疏水改性的海藻酸钠。油酸与上述海藻酸钠重复单元的摩尔比0.3：1。2. Hydrophobic modification: add oleic acid and branched modified sodium alginate to N, N-dimethylformamide, add dicyclohexylcarbodiimide and 4-dimethylaminopyridine under stirring conditions , React at room temperature for 24h to obtain hydrophobically modified sodium alginate. The molar ratio of oleic acid to the above-mentioned sodium alginate repeating unit is 0.3:1.
3、磺化改性：将亚硫酸氢钠和亚硝酸钠按照4.25:1(mol:mol)的比例于90℃反应1.5h制备磺化剂，将磺化剂用氢氧化钠调节至pH＝9后与支化疏水改性后的海藻酸钠混合，升温至40℃反应6h，反应完毕后反应液透析72h，浓缩，剩余物40℃干燥2天。磺化剂与上述海藻酸钠重复单元的加入摩尔比例为0.9:1。所述磺化剂为亚硫酸氢钠衍生物，其化学式为：
Figure PCTCN2021087264-appb-000002
3. Sulfonation modification: The sodium bisulfite and sodium nitrite are reacted at 90°C for 1.5 hours at a ratio of 4.25:1 (mol:mol) to prepare a sulfonating agent, and the sulfonating agent is adjusted to pH= with sodium hydroxide. After 9th, it was mixed with branched hydrophobically modified sodium alginate, heated to 40°C for 6h, after the reaction, the reaction solution was dialyzed for 72h, concentrated, and the remainder was dried at 40°C for 2 days. The molar ratio of the sulfonating agent to the sodium alginate repeating unit is 0.9:1. The sulfonating agent is a sodium bisulfite derivative, and its chemical formula is:
Figure PCTCN2021087264-appb-000002
步骤2、3的顺序不限。The order of steps 2 and 3 is not limited.
4、将经上述3步改性获得的改性海藻酸钠配置为质量分数为1％的改性海藻酸钠水溶液，搅拌使改性海藻酸钠充分溶解在水中。4. The modified sodium alginate obtained by the above three-step modification is configured into a 1% aqueous solution of modified sodium alginate, and the modified sodium alginate is fully dissolved in the water by stirring.
5、向改性海藻酸钠水溶液中加入钽粉，使钽粉的含量为8wt％，并在200r/min搅拌30min后，超声分散20min，最后800r/min高速剪切30min至钽粉分散均匀得混合液。5. Add tantalum powder to the modified sodium alginate aqueous solution so that the content of the tantalum powder is 8wt%, and after stirring at 200r/min for 30min, ultrasonically disperse for 20min, and finally 800r/min high-speed shearing for 30min until the tantalum powder is evenly dispersed. Mixture.
6、通过静电液滴发生装置将上述混合液推注到质量浓度为2％的氯化钙水溶液中交联固化24h，获得改性海藻酸钠自显影栓塞微球。6. Inject the above-mentioned mixed liquid into a calcium chloride aqueous solution with a mass concentration of 2% by means of an electrostatic droplet generator for cross-linking and curing for 24 hours to obtain modified sodium alginate auto-imaging embolic microspheres.
具体装置和制备方法记载于文献“两种不同优化方法对静电液滴法制备单分散海藻酸钙微球工艺的比较”(左琴华，何留民，施云峰，谢莎莎，张奕，黄跃新，薛巍。《材料导报》2012年，第2期)，其中铁环直径为10cm，注射器前端距铁环所在平面距离为5cm，铁环与接收液液面距离为15cm，电压15kv，滴液速率为0.5ml/h。The specific device and preparation method are described in the literature "Comparison of two different optimization methods on the preparation of monodisperse calcium alginate microspheres by electrostatic droplet method" (Zuo Qinhua, He Liumin, Shi Yunfeng, Xie Shasha, Zhang Yi, Huang Yuexin, Xue Wei "Material Review" 2012, Issue 2), in which the diameter of the iron ring is 10cm, the distance between the tip of the syringe and the plane of the iron ring is 5cm, the distance between the iron ring and the receiving liquid surface is 15cm, the voltage is 15kv, and the drip rate is 0.5 ml/h.
将固化的改性海藻酸钠自显影栓塞微球按照1g/5ml的比例保存在保养液(浓度为3％的氯化钙溶液)中。The solidified modified sodium alginate auto-imaging plug microspheres were stored in a maintenance solution (a calcium chloride solution with a concentration of 3%) at a ratio of 1 g/5 ml.
7、载药：7. Drug loading:
将含有栓塞微球的保养液吸入10ml注射器中，使注射器中含1.5ml栓塞微球，然后立刻将注射器针头朝上直立静置至微球沉淀在注射器底部，再将注射器内的保养液推出弃掉；之后抽取2ml的0.9％生理盐水到注射器中，摇摆几下注射器后，再将注射器针头朝上静置，直至微球沉淀在注射器底部，将上面的0.9％生理盐水全部推出弃掉。重复上述生理盐水冲洗操作步骤3遍；将盐酸阿霉素配成饱和溶解度80％的生理盐水溶液，将其吸入上述洗好的微球中，间隔4min手动振摇注射器，载药一定时间后将药物溶液推出。Inhale the maintenance solution containing embolic microspheres into a 10ml syringe to make the syringe contain 1.5ml embolic microspheres, then immediately put the syringe needle upright and stand until the microspheres settle on the bottom of the syringe, and then push the maintenance solution in the syringe out of the syringe. Then, draw 2ml of 0.9% saline into the syringe, shake the syringe a few times, and then stand the syringe needle up until the microspheres settle on the bottom of the syringe, push out all the 0.9% saline on the syringe and discard it. Repeat the above normal saline washing operation steps 3 times; mix doxorubicin hydrochloride into a physiological saline solution with a saturated solubility of 80%, and suck it into the washed microspheres. Manually shake the syringe at an interval of 4 minutes. The drug solution is launched.
实施例2-7Example 2-7
本实施例2-7按照实施例1的方法制备改性海藻酸钠自显影栓塞微球并进一步进行载药，区别仅在于制备时的原料及用量、反应条件、显影剂 混合方式和制备电场力电压不完全相同。此外，实施例6-7中将步骤2、3的顺序进行了互换。In Examples 2-7, modified sodium alginate auto-imaging embolic microspheres were prepared according to the method of Example 1 and further loaded with drugs. The only difference lies in the preparation of raw materials and dosage, reaction conditions, developer mixing method and preparation electric field force. The voltages are not exactly the same. In addition, in Examples 6-7, the order of steps 2 and 3 are interchanged.
具体地，实施例2-7在步骤1中海藻酸钠原料、步骤4中改性海藻酸钠水溶液浓度、显影剂含量及载药药物上与实施例1的不同之处见表1，在支化改性时原料用量和反应条件上与实施例1的不同之处见表2，在疏水改性时原料用量和反应条件上与实施例1的不同之处见表3，在磺化改性时原料用量和反应条件上与实施例1的不同之处见表4，在显影剂混合方式上与实施例1的不同之处见表5，实施例2-3的制备电场力电压与实施例1相同，实施例4-7为11kv。Specifically, the differences between Examples 2-7 and Example 1 in the sodium alginate raw material in step 1, the concentration of the modified sodium alginate aqueous solution in step 4, the content of the developer, and the drug-carrying drug are shown in Table 1. See Table 2 for the difference between the amount of raw materials and reaction conditions during chemical modification and Example 1, and see Table 3 for the difference between the amount of raw materials and reaction conditions during hydrophobic modification and Example 1. In sulfonation modification The difference between the amount of raw materials and the reaction conditions in Example 1 is shown in Table 4, the difference between the developer mixing mode and Example 1 is shown in Table 5. 1 is the same, and examples 4-7 are 11kv.
制备过程中未特别说明的部分与实施例1相同。The unspecified parts in the preparation process are the same as in Example 1.
表1Table 1
Figure PCTCN2021087264-appb-000003
Figure PCTCN2021087264-appb-000003
表2Table 2
Figure PCTCN2021087264-appb-000004
Figure PCTCN2021087264-appb-000004
Figure PCTCN2021087264-appb-000005
Figure PCTCN2021087264-appb-000005
表3table 3
Figure PCTCN2021087264-appb-000006
Figure PCTCN2021087264-appb-000006
表4Table 4
Figure PCTCN2021087264-appb-000007
Figure PCTCN2021087264-appb-000007
表5table 5
实施例Example 显影剂混合方式Developer mixing method
22 200r/min搅拌50min后，超声分散20min，最后800r/min高速剪切30minStir at 200r/min for 50min, ultrasonically disperse for 20min, and finally shear at 800r/min for 30min
33 200r/min搅拌50min后，超声分散30min，最后800r/min高速剪切30minAfter stirring at 200r/min for 50min, ultrasonic dispersion for 30min, and finally 800r/min high-speed shearing for 30min
44 260r/min搅拌50min后，超声分散25min，最后1000r/min高速剪切50minAfter stirring at 260r/min for 50min, ultrasonic dispersion for 25min, and finally 1000r/min high-speed shearing for 50min
55 300r/min搅拌40min后，超声分散30min，最后900r/min高速剪切35minAfter stirring at 300r/min for 40min, ultrasonic dispersion for 30min, finally 900r/min high-speed shearing for 35min
66 230r/min搅拌35min后，超声分散25min，最后900r/min高速剪切35minAfter stirring at 230r/min for 35min, ultrasonic dispersing for 25min, and finally high-speed shearing at 900r/min for 35min
77 230r/min搅拌50min后，超声分散25min，最后1000r/min高速剪切50minAfter stirring at 230r/min for 50min, ultrasonic dispersion for 25min, and finally 1000r/min high-speed shearing for 50min
实施例8Example 8
本实施例按照如下方法制备改性海藻酸钠自显影栓塞微球并进一步进行载药：In this example, the modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
1、支化改性：将粘度为110mpa·s的海藻酸钠加入到二溴乙烷的丙酮溶液中，调节溶液pH至11，30℃条件下预反应4h，加入甘油，甘油与海藻酸钠重复单元的摩尔比为0.35：1，100℃下搅拌反应8h，加入过量的丙酮溶液，抽滤，收集沉淀，洗涤后干燥，获得支化改性后的海藻酸钠。1. Branch modification: add sodium alginate with a viscosity of 110mpa·s to the acetone solution of dibromoethane, adjust the pH of the solution to 11, pre-react at 30℃ for 4h, add glycerin, glycerin and sodium alginate The molar ratio of the repeating unit is 0.35:1, and the reaction is stirred at 100°C for 8 hours, an excess of acetone solution is added, and the precipitate is collected by suction filtration, washed and dried to obtain branched modified sodium alginate.
2、疏水改性：2. Hydrophobic modification:
按照0.21:1的摩尔比将丁二酸酐和支化改性后的海藻酸钠加入二氯甲烷中，磁力搅拌下依次加入DMAP，氮气保护下升温至35℃反应5h，抽滤后滤饼35℃鼓风箱干燥。按照0.21:1的摩尔比将N-羟基琥珀酰亚胺和上述干燥产物加入到二氯甲烷中，升温至35℃，保温反应5h，滤后滤饼35℃鼓风箱干燥。按照0.21:1的摩尔比将辛胺与上述产物(辛胺与上述海藻酸钠重复单元的摩尔比0.21：1)溶于碳酸氢钠缓冲液中(pH＝8.5)，常温搅拌反应24h后干燥得疏水改性海藻酸钠。Add succinic anhydride and branched modified sodium alginate to dichloromethane according to the molar ratio of 0.21:1, add DMAP successively under magnetic stirring, and heat up to 35°C under nitrogen protection for 5 hours. After suction filtration, filter cake 35 ℃ blast box drying. Add N-hydroxysuccinimide and the above-mentioned dried product to dichloromethane according to a molar ratio of 0.21:1. The temperature is raised to 35°C, and the reaction is kept for 5h. After filtration, the filter cake is dried in a blast box at 35°C. According to the molar ratio of 0.21:1, octylamine and the above product (the molar ratio of octylamine to the above-mentioned sodium alginate repeating unit 0.21:1) were dissolved in sodium bicarbonate buffer (pH=8.5), stirred and reacted at room temperature for 24 hours and then dried Obtain hydrophobically modified sodium alginate.
3、磺化改性：3. Sulfonation modification:
按照浓硫酸与上述海藻酸钠重复单元的摩尔比1.5:1的比例取98％浓硫酸于一玻璃烧杯中，并按上述比例取适量的支化疏水改性后的海藻酸 钠，快速加入到浓硫酸中，边加边搅拌，于0℃条件下搅拌反应1h，密封静置约2h后，配制1.25moI/L的95％氢氧化钠乙醇溶液，中和反应液至弱碱性(pH＝7.5)以终止反应。According to the molar ratio of concentrated sulfuric acid to the above sodium alginate repeating unit 1.5:1, take 98% concentrated sulfuric acid in a glass beaker, and take an appropriate amount of branched hydrophobically modified sodium alginate according to the above ratio, and quickly add it to In concentrated sulfuric acid, stir while adding, stir at 0℃ for 1h, and after sealing and standing for about 2h, prepare 1.25moI/L 95% sodium hydroxide ethanol solution, and neutralize the reaction solution to weak alkalinity (pH= 7.5) To stop the reaction.
步骤2、3的顺序不限。The order of steps 2 and 3 is not limited.
4、将经上述3步改性获得的改性海藻酸钠配置为质量分数为5％的改性海藻酸钠水溶液，搅拌使改性海藻酸钠充分溶解在水中。4. The modified sodium alginate obtained by the above-mentioned three-step modification is configured into a modified sodium alginate aqueous solution with a mass fraction of 5%, and the modified sodium alginate is fully dissolved in the water by stirring.
5、向改性海藻酸钠水溶液中加入硫酸钡，使硫酸钡的含量为15wt％，并在220r/min搅拌40min后，超声分散25min，最后1000r/min高速剪切40min至硫酸钡分散均匀得混合液。5. Add barium sulfate to the aqueous solution of modified sodium alginate to make the content of barium sulfate 15wt%, and after stirring at 220r/min for 40min, ultrasonic dispersion for 25min, and finally 1000r/min high-speed shearing for 40min until the barium sulfate is evenly dispersed. Mixture.
6、通过实施例1的静电液滴发生装置将上述混合液推注到质量浓度为5％的氯化钡水溶液中交联固化24h，获得改性海藻酸钠自显影栓塞微球。具体制备方法与实施例1相同，区别在于电场力电压为7.5kv。6. Through the electrostatic droplet generating device of Example 1, the above-mentioned mixed liquid was injected into a barium chloride aqueous solution with a mass concentration of 5% for cross-linking and curing for 24 hours to obtain modified sodium alginate auto-imaging embolic microspheres. The specific preparation method is the same as in Example 1, except that the electric field force and voltage are 7.5 kv.
7、载药：本实施例与实施例1的载药方式相同，区别仅在于药物选用表柔比星。7. Drug loading: The drug loading method of this example is the same as that of Example 1, except that the drug is epirubicin.
实施例9Example 9
本实施例按照如下方法制备改性海藻酸钠自显影栓塞微球并进一步进行载药：In this example, the modified sodium alginate auto-imaging embolic microspheres were prepared and further loaded with drugs according to the following method:
1、支化改性：本实施例采用与实施例8相同的支化改性方法，区别仅在于：海藻酸钠的粘度为90mpa·s，以二聚甘油代替甘油，二聚甘油与海藻酸钠重复单元的摩尔比为0.6：1，反应时间为12h。1. Branching modification: This embodiment adopts the same branching modification method as that of Example 8, except that the viscosity of sodium alginate is 90mpa·s, and dipolyglycerol is used instead of glycerin, dipolyglycerol and alginic acid The molar ratio of sodium repeating unit is 0.6:1, and the reaction time is 12h.
2、疏水改性：本实施例采用与实施例8相同的疏水改性方法，区别仅在于：以十二胺代替辛胺，十二胺与上述海藻酸钠重复单元的摩尔比0.4：1。2. Hydrophobic modification: This embodiment uses the same hydrophobic modification method as that of Example 8, except that: dodecylamine is used instead of octylamine, and the molar ratio of dodecylamine to the above-mentioned sodium alginate repeating unit is 0.4:1.
3、磺化改性：3. Sulfonation modification:
按照氯磺酸与上述海藻酸钠重复单元的摩尔比1.2:1的比例将支化疏水改性后的海藻酸钠加入二氯甲烷(除水干燥)中5℃搅拌10min，将氯磺酸加入到二氯甲烷中后滴加到上述海藻酸钠的二氯甲烷溶液中，滴加 20min，滴完后5℃反应3h，对反应液进行抽滤，并取20mL二氯甲烷淋洗滤饼后35℃鼓风干燥。Add the branched hydrophobically modified sodium alginate to dichloromethane (dehydrate and dry) at the molar ratio of chlorosulfonic acid to the above-mentioned sodium alginate repeating unit at a molar ratio of 1.2:1, stir for 10 minutes at 5°C, and add chlorosulfonic acid After adding to the dichloromethane, add dropwise to the above-mentioned sodium alginate in dichloromethane solution, add dropwise for 20 minutes, and react at 5°C for 3 hours after dropping. The reaction solution is suction filtered and 20 mL of dichloromethane is taken to rinse the filter cake Blast drying at 35°C.
步骤2、3的顺序不限。The order of steps 2 and 3 is not limited.
4、将经上述3步改性获得的改性海藻酸钠配置为质量分数为2％的改性海藻酸钠水溶液，搅拌使改性海藻酸钠充分溶解在水中。4. The modified sodium alginate obtained by the above three-step modification is configured into a modified sodium alginate aqueous solution with a mass fraction of 2%, and the modified sodium alginate is fully dissolved in the water by stirring.
5、向改性海藻酸钠水溶液中加入四氧化三铁，使四氧化三铁的含量为15wt％，并在240r/min搅拌38min后，超声分散30min，最后1000r/min高速剪切55min至四氧化三铁分散均匀得混合液。5. Add ferroferric oxide to the modified sodium alginate aqueous solution to make the content of ferroferric oxide 15wt%. After stirring at 240r/min for 38min, ultrasonically disperse for 30min, and finally high-speed shearing at 1000r/min for 55min to four The ferroferric oxide is evenly dispersed to obtain a mixed solution.
6、通过实施例1的静电液滴发生装置将上述混合液推注到质量浓度为12％的氯化铜水溶液中交联固化24h，获得改性海藻酸钠自显影栓塞微球。具体制备方法与实施例1相同，区别在于电场力电压为30kv。6. Through the electrostatic droplet generating device of Example 1, the above-mentioned mixed liquid was injected into a copper chloride aqueous solution with a mass concentration of 12% for cross-linking and curing for 24 hours to obtain modified sodium alginate auto-developing embolic microspheres. The specific preparation method is the same as in Example 1, except that the electric field force and voltage are 30kv.
7、载药：本实施例与实施例8的载药步骤相同。7. Drug loading: The drug loading procedure in this embodiment is the same as that in Example 8.
实施例1-9中改性海藻酸钠经各步制备后的改性取代率数据见表6。The modified substitution rate data of modified sodium alginate prepared in various steps in Examples 1-9 are shown in Table 6.
表6Table 6
实施例Example 支化取代率,％Branch substitution rate,% 疏水取代率,％Hydrophobic substitution rate,% 磺化取代率,％Sulfonation substitution rate,%
11 22twenty two 55 5757
22 22twenty two 1818 5757
33 22twenty two 3232 5757
44 4545 1818 8585
55 4545 1818 121121
66 8181 1818 266266
77 8181 1818 135135
88 3030 21twenty one 8282
99 5252 1515 6868
对比例1Comparative example 1
本对比例按照实施例5的方法制备改性海藻酸钠栓塞微球，区别仅在于不进行磺化改性。In this comparative example, modified sodium alginate embolic microspheres were prepared according to the method of Example 5, except that the sulfonation modification was not performed.
对比例2Comparative example 2
本对比例按照对比例1的方法制备改性海藻酸钠栓塞微球，区别仅在于也不进行疏水改性。In this comparative example, modified sodium alginate embolic microspheres were prepared according to the method of comparative example 1, except that the hydrophobic modification was not carried out.
对比例3Comparative example 3
本对比例按照实施例5的方法制备改性海藻酸钠栓塞微球，区别仅在于：支化单体采用葡萄糖，各步取代率不变。In this comparative example, modified sodium alginate embolization microspheres were prepared according to the method of Example 5. The only difference is that glucose is used as the branching monomer, and the substitution rate of each step is unchanged.
对比例4Comparative example 4
本对比例按照实施例5的方法制备改性海藻酸钠栓塞微球，区别仅在于：疏水改性步骤中：油酸与上述海藻酸钠重复单元的摩尔比0.8：1；疏水取代率60％，其余两步取代率不变。In this comparative example, modified sodium alginate embolic microspheres were prepared according to the method of Example 5. The only difference is: in the hydrophobic modification step: the molar ratio of oleic acid to the above-mentioned sodium alginate repeating unit is 0.8:1; the hydrophobic substitution rate is 60% , The replacement rate of the remaining two steps remains unchanged.
对比例5Comparative example 5
本对比例按照实施例5的方法制备改性海藻酸钠栓塞微球，区别仅在于：磺化改性步骤中：磺化剂与上述海藻酸钠重复单元的加入摩尔比例为0.4:1，磺化取代率32％。In this comparative example, modified sodium alginate embolization microspheres were prepared according to the method of Example 5. The only difference is: in the sulfonation modification step: the molar ratio of the sulfonating agent and the sodium alginate repeating unit is 0.4:1, and the sulfonation The chemical substitution rate is 32%.
对比例6Comparative example 6
本对比例按照实施例5的配方制备改性海藻酸钠，区别在于步骤5加入显影剂的具体方式为：向步骤4获得的改性海藻酸钠水溶液中加入钽粉，使钽粉的含量为15wt％，并在1000r/min搅拌100min进行混合。In this comparative example, modified sodium alginate was prepared according to the formula of Example 5. The difference is that the specific method of adding developer in step 5 is: adding tantalum powder to the modified sodium alginate aqueous solution obtained in step 4 so that the content of tantalum powder is 15wt%, and mixed at 1000r/min for 100min.
实验例1Experimental example 1
本实验例进一步将实施例1-9和对比例1-6的产品进行性能测试。In this experimental example, the products of Examples 1-9 and Comparative Examples 1-6 were further subjected to performance testing.
粒径测试方法为：YY/T 1574-2017中附录B规定的显微镜法；The particle size test method is: the microscope method specified in Appendix B of YY/T 1574-2017;
载药量、24h药物释放量测试方法参见文献“空白及载阿霉素的聚丙烯酸栓塞微球的制备与评价”(郭李盈，刘晓听，邹英华等，北京大学学报(医学版)，2018，50)中的HPLC检测方法。For drug loading and 24h drug release testing methods, please refer to the literature "Preparation and evaluation of blank and adriamycin-loaded polyacrylic acid embolization microspheres" (Guo Liying, Liu Xiaoting, Zou Yinghua, etc., Peking University Journal (Medical Edition), 2018, 50) HPLC detection method.
测试结果见表7。The test results are shown in Table 7.
表7Table 7
Figure PCTCN2021087264-appb-000008
Figure PCTCN2021087264-appb-000008
实验例2Experimental example 2
本实验例进一步将实施例1-9和对比例1-6的产品显影剂分散效果进行测试，具体方法为，显影剂分散完成后取0.5ml分散液(即步骤5中获得的混合液)滴于载玻片上，盖上盖玻片后在显微镜下以20倍物镜进行观察，观察结果见图1。由图1可知，采用常规的分散方式(对比例6)分散效果明显不如本发明所用的方法。This experimental example further tests the developer dispersion effect of the products of Examples 1-9 and Comparative Examples 1-6. The specific method is to take 0.5ml of the dispersion liquid (ie the mixed liquid obtained in step 5) after the developer is dispersed. On a glass slide, cover with a cover glass and observe under a microscope with a 20-fold objective lens. The observation result is shown in Figure 1. It can be seen from Figure 1 that the conventional dispersion method (Comparative Example 6) has a significantly lower dispersion effect than the method used in the present invention.
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的 描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。Although the general description and specific embodiments have been used to describe the present invention in detail above, it is obvious to those skilled in the art that some modifications or improvements can be made on the basis of the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention belong to the scope of the present invention.
工业实用性Industrial applicability
本发明提供一种改性海藻酸钠自显影栓塞微球及其制备方法与应用。本发明的改性海藻酸钠自显影栓塞微球包括：改性海藻酸钠和显影剂；所述改性海藻酸钠为先经支化改性以引入多个羟基后，再进行疏水改性和磺化改性的海藻酸钠，所述支化改性的支化取代率为22-81％；所述疏水改性的疏水取代率为5-32％；所述磺化改性的磺化取代率为57-266％。本发明的栓塞微球在作为药物载体时，既可显著提高带负电的药物的载药量和载药速率，又可延缓药物释放时间，减少药物突释，具有较好的经济价值和应用前景。The invention provides a modified sodium alginate auto-imaging embolic microsphere, and a preparation method and application thereof. The modified sodium alginate auto-imaging embolic microspheres of the present invention include: modified sodium alginate and a developer; the modified sodium alginate is modified by branching to introduce multiple hydroxyl groups, and then hydrophobically modified And sulfonated modified sodium alginate, the branching substitution rate of the branch modification is 22-81%; the hydrophobic substitution rate of the hydrophobic modification is 5-32%; the sulfonated modified sulfonate The chemical substitution rate is 57-266%. When used as a drug carrier, the embolic microspheres of the present invention can not only significantly increase the drug loading and drug loading rate of negatively charged drugs, but also delay drug release time and reduce drug burst release, and have good economic value and application prospects .

Claims (10)

  1. 一种改性海藻酸钠自显影栓塞微球，其特征在于，包括：改性海藻酸钠和显影剂；A modified sodium alginate auto-imaging embolic microsphere, which is characterized in that it comprises: modified sodium alginate and a developer;
    所述改性海藻酸钠为先经支化改性以引入多个羟基后，再进行疏水改性和磺化改性的海藻酸钠，所述支化改性的支化取代率为22-81％；所述疏水改性的疏水取代率为5-32％；所述磺化改性的磺化取代率为57-266％。The modified sodium alginate is sodium alginate that has undergone branching modification to introduce multiple hydroxyl groups, and then hydrophobically modified and sulfonated modified sodium alginate, and the branching substitution rate of the branching modification is 22- 81%; the hydrophobic substitution rate of the hydrophobic modification is 5-32%; the sulfonation substitution rate of the sulfonation modification is 57-266%.
  2. 根据权利要求1所述的栓塞微球，其特征在于，所述支化改性的支化取代率为45％-50％，所述疏水改性的疏水取代率为18-25％，所述磺化改性的磺化取代率为82-121％。The embolic microsphere according to claim 1, wherein the branching substitution rate of the branch modification is 45%-50%, the hydrophobic substitution rate of the hydrophobic modification is 18-25%, and the The sulfonation substitution rate of the sulfonation modification is 82-121%.
  3. 根据权利要求2所述的栓塞微球，其特征在于，所述支化取代率、所述疏水取代率与所述磺化取代率的比值为1:(0.4-0.5):(2.5-2.7)。The embolic microsphere according to claim 2, wherein the ratio of the branch substitution rate, the hydrophobic substitution rate to the sulfonated substitution rate is 1:(0.4-0.5):(2.5-2.7) .
  4. 根据权利要求1-3任一项所述的栓塞微球，其特征在于，所述支化改性的支化改性剂为甘油、季戊四醇、二聚甘油中的一种或多种，优选为季戊四醇；The embolic microsphere according to any one of claims 1 to 3, wherein the branched modified branching modifier is one or more of glycerol, pentaerythritol, and diglycerol, preferably Pentaerythritol
    和/或，所述疏水改性的疏水改性剂为油酸、辛胺、十二胺、十六胺中的一种或多种，优选为油酸；And/or, the hydrophobically modified hydrophobic modifier is one or more of oleic acid, octylamine, dodecylamine, and hexadecylamine, preferably oleic acid;
    和/或，所述磺化改性的磺化剂为亚硫酸盐衍生物、氯磺酸、浓硫酸中的一种或多种，优选为亚硫酸盐衍生物。And/or, the sulfonated modified sulfonating agent is one or more of sulfite derivatives, chlorosulfonic acid, and concentrated sulfuric acid, preferably sulfite derivatives.
  5. 根据权利要求1所述的栓塞微球，其特征在于，所述海藻酸钠的粘度为55-619mpa·s，优选为280-400mpa·s。The embolic microsphere according to claim 1, wherein the viscosity of the sodium alginate is 55-619mpa·s, preferably 280-400mpa·s.
  6. 根据权利要求1所述的栓塞微球，其特征在于，所述显影剂在栓塞微球中的含量为8-30wt％；优选地，所述显影剂为X射线显影剂或MRI显影剂。The embolic microspheres of claim 1, wherein the content of the imaging agent in the embolic microspheres is 8-30 wt%; preferably, the imaging agent is an X-ray imaging agent or an MRI imaging agent.
  7. 根据权利要求1所述的栓塞微球，其特征在于，栓塞微球还负载带正电的药物，优选所述药物为可抗肿瘤的药物；更优选所述药物为盐酸阿霉素、伊立替康、拓扑替康、表柔比星、表阿霉素、博来霉素、顺铂、 卡铂、奥沙利铂、洛铂、氟尿嘧啶、丝裂霉素中的一种或多种。The embolic microspheres according to claim 1, wherein the embolic microspheres also carry positively charged drugs, preferably the drugs are anti-tumor drugs; more preferably, the drugs are doxorubicin hydrochloride, irinote One or more of Kang, topotecan, epirubicin, epirubicin, bleomycin, cisplatin, carboplatin, oxaliplatin, lobaplatin, fluorouracil, and mitomycin.
  8. 一种制备如权利要求1-7任一项所述的栓塞微球的方法，其特征在于，以所述改性海藻酸钠的水溶液与所述显影剂混合后的溶液作为原料液，采用静电液滴法制备。A method for preparing embolic microspheres according to any one of claims 1-7, characterized in that the solution obtained by mixing the aqueous solution of the modified sodium alginate and the developer is used as the raw material liquid, and electrostatic Prepared by droplet method.
  9. 根据权利要求8所述的方法，其特征在于，所述改性海藻酸钠的水溶液的质量分数为1％～15％；The method according to claim 8, wherein the mass fraction of the aqueous solution of modified sodium alginate is 1% to 15%;
    和/或，所述改性海藻酸钠的水溶液与所述显影剂的混合方式为：200-300r/min搅拌30-50min后，超声分散20-30min，最后800-1000r/min高速分散30-50min；优选为，300r/min搅拌40min后，超声分散30min，最后900r/min高速剪切35min。And/or, the mixing method of the aqueous solution of the modified sodium alginate and the developer is: 200-300r/min stirring for 30-50min, ultrasonic dispersion for 20-30min, and finally 800-1000r/min high-speed dispersion for 30- 50min; preferably, after stirring at 300r/min for 40min, ultrasonic dispersion for 30min, and finally high-speed shearing at 900r/min for 35min.
  10. 权利要求1-7任一项所述的栓塞微球或权利要求8或9所述的方法在制备用于血管栓塞术或止血的产品中的应用。The use of the embolic microspheres according to any one of claims 1-7 or the method according to claim 8 or 9 in the preparation of products for vascular embolization or hemostasis.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115211924A (en) * 2022-07-26 2022-10-21 苏州中天医疗器械科技有限公司 Embolic coil, embolic coil assembly and use method thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111481734B (en) * 2020-04-28 2022-04-15 北京诺康达医药科技股份有限公司 Modified sodium alginate self-developing embolism microsphere and preparation method and application thereof
CN111773428A (en) * 2020-08-05 2020-10-16 华中科技大学 Medicine sustained-release alginic acid embolism microsphere and preparation method thereof
CN113730646A (en) * 2021-08-27 2021-12-03 中国海洋大学 High-drug-loading degradable alginic acid sulfate vascular embolization microsphere as well as preparation method and application thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002024248A1 (en) * 2000-09-22 2002-03-28 Kensey Nash Corporation Systems and methods for delivering beneficial agents into targeted tissue of a living being
WO2009017855A2 (en) * 2007-04-27 2009-02-05 Wisconsin Alumni Research Foundation Aneurysm occlusion device containing bioactive and biocompatible copolymer shell and a liquid embolic agent and a biocompatible metallic frame member
CN105816920A (en) * 2016-03-29 2016-08-03 江南大学 Preparation method of modified sodium alginate embolization microspheres
US20170204364A1 (en) * 2014-07-11 2017-07-20 Celenys Method for modifying polysaccharides by grafting polyetheramines, polysaccharides thus modified and preparations comprising same and having heat-sensitive rheological properties
CN109021169A (en) * 2018-08-31 2018-12-18 深圳市比德泰克生物医药科技有限公司 A kind of sodium alginate polymer, novel alga acid natremia pipe embolism chemical therapeutic composition and its preparation method and application
CN111481734A (en) * 2020-04-28 2020-08-04 北京诺康达医药科技股份有限公司 Modified sodium alginate self-developing embolism microsphere and preparation method and application thereof

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005120462A2 (en) * 2004-06-07 2005-12-22 Callisyn Pharmaceuticals, Inc. Biodegradable and biocompatible crosslinked polymer hydrogel prepared from pva and/or peg macromer mixtures
FR2936800B1 (en) * 2008-10-06 2010-12-31 Adocia POLYSACCHARIDE COMPRISING FUNCTIONAL CARBOXYL GROUPS SUBSTITUTED WITH A HYDROPHOBIC ALCOHOL DERIVATIVE
CN103130912B (en) * 2011-12-02 2015-08-12 江南大学 Single stage method prepares covalent cross-linking and hydrophobically modified Sodium Alginate Hydrogel Films
CN104099316A (en) * 2013-04-11 2014-10-15 中国科学院大连化学物理研究所 Amphiphilic structure microsphere based on hydrophobic modified sodium alginate material and preparation and application
CN104877041B (en) * 2014-02-28 2018-05-04 毛文学 A kind of preparation method of hydrophobically modified sodium alginate parents notion colloidal particle
WO2018136012A1 (en) * 2017-01-20 2018-07-26 Agency For Science, Technology And Research A modified alginate copolymer, alginate nanoparticle and applications thereof
CN106620829A (en) * 2017-03-13 2017-05-10 安疗生命科学（武汉）有限公司 Developing embolism material and preparation method thereof
EP3427949A1 (en) * 2017-07-12 2019-01-16 Albert-Ludwigs-Universität Freiburg Mechanically tunable bioinks for bioprinting
CN110680959B (en) * 2019-10-31 2021-12-03 江苏地韵医疗科技有限公司 Hydrogel for repairing multiple cross-linked meniscus and preparation method thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002024248A1 (en) * 2000-09-22 2002-03-28 Kensey Nash Corporation Systems and methods for delivering beneficial agents into targeted tissue of a living being
WO2009017855A2 (en) * 2007-04-27 2009-02-05 Wisconsin Alumni Research Foundation Aneurysm occlusion device containing bioactive and biocompatible copolymer shell and a liquid embolic agent and a biocompatible metallic frame member
US20170204364A1 (en) * 2014-07-11 2017-07-20 Celenys Method for modifying polysaccharides by grafting polyetheramines, polysaccharides thus modified and preparations comprising same and having heat-sensitive rheological properties
CN105816920A (en) * 2016-03-29 2016-08-03 江南大学 Preparation method of modified sodium alginate embolization microspheres
CN109021169A (en) * 2018-08-31 2018-12-18 深圳市比德泰克生物医药科技有限公司 A kind of sodium alginate polymer, novel alga acid natremia pipe embolism chemical therapeutic composition and its preparation method and application
CN111481734A (en) * 2020-04-28 2020-08-04 北京诺康达医药科技股份有限公司 Modified sodium alginate self-developing embolism microsphere and preparation method and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115211924A (en) * 2022-07-26 2022-10-21 苏州中天医疗器械科技有限公司 Embolic coil, embolic coil assembly and use method thereof
CN115211924B (en) * 2022-07-26 2024-04-05 苏州中天医疗器械科技有限公司 Embolic coil, embolic coil assembly and method of use thereof

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