WO2012088896A1 - 液体栓塞材料组合物及其制备方法 - Google Patents

液体栓塞材料组合物及其制备方法 Download PDF

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WO2012088896A1
WO2012088896A1 PCT/CN2011/078456 CN2011078456W WO2012088896A1 WO 2012088896 A1 WO2012088896 A1 WO 2012088896A1 CN 2011078456 W CN2011078456 W CN 2011078456W WO 2012088896 A1 WO2012088896 A1 WO 2012088896A1
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nanoparticles
liquid embolic
embolic material
material composition
alkyl cyanoacrylate
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PCT/CN2011/078456
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English (en)
French (fr)
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康亚红
金巧蓉
李�雨
谢志永
罗七一
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微创医疗器械(上海)有限公司
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Publication of WO2012088896A1 publication Critical patent/WO2012088896A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/44Radioisotopes, radionuclides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/06Flowable or injectable implant compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/36Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • Liquid embolic material composition and preparation method thereof The present application claims priority to Chinese Patent Application No. 201010609101.0, entitled “Liquid embolic material composition and preparation method thereof", filed on December 27, 2010. The entire contents of which are incorporated herein by reference.
  • This invention relates to the field of materials, and more particularly to a liquid embolic material composition and a method of making same. Background technique
  • Hemangiomas are formed in arteriovenous blood vessels due to internal and external factors such as mechanical damage, hardening of the arteries, hypertension, proliferation of vascular smooth muscle cells, bacterial or viral infections, induction of venous valve disease, or blood flow impact. Hemangiomas are classified into aneurysms and venous tumors, in which an aneurysm with a convex wall produced in the brain is called a cerebral aneurysm. Cerebral aneurysms are highly susceptible to subarachnoid hemorrhage when ruptured, leading to stroke; even 80% or more of patients die after a recurrent cerebral aneurysm ruptures. Therefore, embolization or occlusion at the earliest stage of cerebral aneurysm is the best cure.
  • embolizing cerebral aneurysms surgical procedures are generally used to block the aneurysms that have been formed, including the cutting and ligation of the aneurysm's mother artery and clamping the aneurysm neck with an aneurysm clip, thereby blocking the blood pair.
  • This method is time consuming and may cause damage to the aneurysm.
  • interventional procedures have been used to block and embolize aneurysms by delivering various embolic materials into cerebral aneurysms, which have gradually replaced traditional surgery.
  • the method using the platinum spring sputum has a low embolization rate, is prone to form a wide range of thrombus, and causes cerebral infarction and the like.
  • embolic materials have been disclosed, mainly divided into solid embolic materials and liquid embolic materials.
  • the liquid embolic material can be directly injected into the aneurysm cavity to adapt to the aneurysm cavity of different shapes and sizes, so that no gap is left between the tumor wall and the embedding material, thereby achieving permanent occlusion.
  • the liquid embolic material has the advantage of being easy to handle and can be directly injected into the blood vessel through the microcatheter. Therefore, liquid embolic material is an ideal embolic material, and is widely used in the field of endovascular treatment including aneurysm and vascular malformation.
  • Liquid embolic materials are generally classified into two types: adhesive liquid embolic materials and non-adhesive liquid embolic materials. Due to the potential vascular toxicity of the organic solvent dimethyl sulfoxide used in non-adhesive liquid embolic materials, the application of non-adhesive liquid embolic materials is affected. Adhesive liquid embolic materials are not vascular and have been widely used. In the prior art, the adhesive liquid embolic material is mainly n-butyl cyanoacrylate, which is not well embedd by microvascular aneurysms and vascular malformations in which complex microcatheters are difficult to fully locate. Summary of the invention
  • the technical problem to be solved by the present invention is to provide a liquid embolic material composition capable of embolizing a microvascular aneurysm and a vascular malformation, and a preparation method thereof.
  • the invention provides a liquid embolic material composition, comprising:
  • Alkyl cyanoacrylate Fe 3 0 4 nanoparticles and contrast agent.
  • the molar ratio of the alkyl cyanoacrylate to the Fe 3 0 4 nanoparticles is 2.5 to 3.5: 0.5 to 1.5.
  • the molar ratio of the alkyl cyanoacrylate to the Fe 3 0 4 nanoparticle is
  • the alkyl group of the alkyl cyanoacrylate has a carbon number of 4 to 10.
  • the contrast agent is one or more of an iodide, a quinone compound, a strontium powder and a gold powder.
  • the present invention also provides a method for preparing a liquid embolic material composition, comprising: dispersing Fe 3 0 4 nanoparticles in an alkyl cyanoacrylate to obtain a suspension; and under argon conditions, suspending the suspension A contrast agent is added to the solution to obtain a liquid embolic material composition.
  • the molar ratio of the alkyl cyanoacrylate to the Fe 3 0 4 nanoparticles is 2.5 to 3.5: 0.5 to 1.5.
  • the alkyl group of the alkyl cyanoacrylate has a carbon number of 4 to 10.
  • the contrast agent is one of iodide, steroid, strontium powder and gold powder or Several.
  • the Fe 3 0 4 nanoparticles are synthesized by a chemical coprecipitation method.
  • the present invention provides a liquid embolic material composition comprising an alkyl cyanoacrylate, Fe 3 0 4 nanoparticles and a contrast agent, and a method of preparing the same. After the liquid embolic material composition is injected into the aneurysm cavity, the Fe 3 0 4 nanoparticles and the alkyl cyanoacrylate form a porous crosslinked body of a multi-crosslinking point by self-assembly to form an embolic body.
  • the porous structure greatly reduces the density of the embolic body, alleviates the problem of the occupying effect caused by the complete embolization of the embolic material and the compression of the peripheral nerve by the aneurysm; and the Fe 3 0 4 nanoparticles form the embolic body.
  • Toughened rubber-like structure, and with its superparamagnetic effect, the liquid embolic material composition can be targeted by external magnetic field, and it is difficult to fully embed a complicated microcatheter. Microvascular aneurysms and vascular malformations. detailed description
  • the invention discloses a liquid embolic material composition, comprising:
  • Alkyl cyanoacrylate Fe 3 0 4 nanoparticles and contrast agent.
  • the alkyl group of the alkyl cyanoacrylate preferably has a carbon number of 4 to 10, more preferably 5 to 8 lake.
  • the molar ratio of the alkyl cyanoacrylate to the Fe 3 0 4 nanoparticle is preferably 2.5-3.5: 0.5-1.5, more preferably 2.8-3.2: 0.8-1.2, most preferably 3:1.
  • the double electron withdrawing action of the cyano group and the carboxyl group in the alkyl cyanoacrylate allows the alkyl cyanoacrylate to be rapidly polymerized by anions in the blood to achieve the purpose of embolization.
  • the Fe 3 0 4 nanoparticle and the alkyl cyanoacrylate form a multi-crosslinked dot polymer as an embolic body by self-assembly, and the Fe 3 0 4 nanoparticle is a magnetic nano particle, and the invention utilizes the nano magnetic particle Superparamagnetic effect, so that it is targeted by external magnetic field.
  • the micro-aneurysm is embolized by the basic targeting of the external magnetic field, and the embolization is more thorough.
  • the liquid embolic material provided by the present invention is introduced into the targeting region through the microcatheter under the action of the external magnetic field, and the liquid embolic material realizes anionic polymerization under the condition of alkaline alkalinity of the plasma, and finally the nanoparticle is used as a cross-linking point by self-assembly.
  • Class of rubber-cured materials The long chain of the polymer formed by the alkyl cyanoacrylate improves the toughness, elasticity and softness of the permanent embolic body after embolization; the alkyl side chain of the alkyl cyanoacrylate makes the embolization Reduce the chance of sticking in the process.
  • the Fe 3 0 4 nanoparticles at the junction not only make the embolic body form a tough material of the self-toughening rubber-like structure, but also embolize the micro-aneurysm and vascular malformation through the basic targeting of the external magnetic field during the embolization process. And the embolization is more thorough.
  • the embolic material provided by the present invention is mixed with an angiographic contrast agent to be suitable for observing arteriovenous embolization during and after surgery, and by mammography.
  • the contrast agent comprises: one or more of an iodide, a quinone compound, a strontium powder and a gold powder, and the iodide preferably comprises 6-triiodoformic acid, sodium 6-triiodobenzoate, iodonium titanate, and a ubiquitin
  • One or more of image acid, iodine acid, iodoic acid, iopakaic acid, iohexol, iodophenol and iodine, and the quinone compound may be antimony trioxide.
  • the present invention has no particular requirement for the amount of the contrast agent to be added, and is preferably added in an amount well known to those skilled in the art.
  • the present invention provides a method for preparing a liquid embolic material composition, comprising: dispersing Fe 3 0 4 nanoparticles in an alkyl cyanoacrylate to obtain a suspension; under argon, the suspension is suspended A contrast agent is added to the solution to obtain a liquid embolic material composition.
  • the Fe 3 0 4 nanoparticles are preferably synthesized by a chemical coprecipitation method.
  • the present invention preferably performs surface chemical modification on the Fe 3 0 4 nanoparticles, specifically:
  • Acrylic acid was added to the suspension of Fe 3 0 4 nanoparticles in toluene, then argon gas was stirred, and after completion of the reaction, the mixture was centrifuged, washed with n-hexane, treated with ethanol, and dried under vacuum at room temperature to obtain a modified Fe 3 0 . 4 nanoparticles.
  • the molar ratio of the alkyl cyanoacrylate to the Fe 3 0 4 nanoparticles is preferably from 2.5 to 3.5: 0.5 to 1.5, more preferably from 2.8 to 3.2: 0.8 to 1.2, most preferably 3:1.
  • the modified Fe 3 0 4 nanoparticles are dispersed in an alkyl cyanoacrylate to form a suspension.
  • the dispersion method of the present invention is not particularly limited, and ultrasonic dispersion is preferably employed.
  • a contrast agent is added to the suspension to obtain a liquid embolic material composition. It is preferably carried out under mechanical stirring.
  • the Fe 3 0 4 nanoparticles may be commercially available Fe 3 0 4 nanoparticles, or may be prepared by themselves.
  • the Fe 3 0 4 nanoparticles of the present invention are preferably Fe 3 0 4 nanoparticles produced by Sigma Corporation.
  • Example 1 In order to further illustrate the technical solutions of the present invention, the preferred embodiments of the present invention are described in the following, but the description of the present invention is not intended to limit the scope of the present invention.
  • Example 1
  • the Fe 3 0 4 nanoparticles are chemically modified, specifically:
  • the suspension was stirred in an argon atmosphere at 40 ° C and 30 g of nano cerium powder was added and stirred until evenly dispersed;
  • the Fe 3 0 4 nanoparticles are chemically modified, specifically:
  • the Fe 3 0 4 nanoparticles are chemically modified, specifically:
  • the Fe 3 0 4 nanoparticles are chemically modified, specifically:
  • the Fe 3 0 4 nanoparticles are chemically modified, specifically:
  • the Fe 3 0 4 nanoparticles are chemically modified, specifically:
  • the Fe 3 0 4 nanoparticles are chemically modified, specifically:
  • the present invention provides a liquid embolic material composition comprising an alkyl cyanoacrylate, Fe 3 0 4 nanoparticles, and a contrast agent, and a method of preparing the same. After the embolic composition is injected into the aneurysm cavity, the Fe 3 0 4 nanoparticles and the alkyl cyanoacrylate form a porous crosslink of the multi-crosslinking point by self-assembly to form an embolic body.
  • the porous structure greatly reduces the density of the embolic body, alleviates the problem of the occupying effect caused by the complete embolization of the embolic material and the compression of the peripheral nerve by the aneurysm; and the Fe 3 0 4 nanoparticles form the embolic body.
  • Toughened rubber-like structure and utilizing its superparamagnetic effect, the liquid embolic material composition can be targeted by external magnetic field Position, very good embolization of complex microcatheters is difficult to fully fit the microvascular aneurysms and vascular malformations.

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Description

液体栓塞材料组合物及其制备方法 本申请要求于 2010 年 12 月 27 日提交中国专利局、 申请号为 201010609101.0、发明名称为"液体栓塞材料组合物及其制备方法"的中国 专利申请的优先权, 其全部内容通过引用结合在本申请中。 技术领域
本发明涉及材料技术领域,更具体地说, 涉及一种液体栓塞材料组合 物及其制备方法。 背景技术
由于机械损伤、 血管硬化、 高血压、 血管平滑肌细胞的增生、 细菌或 病毒感染、静脉瓣疾病的诱导或血流沖击等内外因素的作用,在动静脉血 管中会形成血管瘤。血管瘤分为动脉瘤和静脉瘤, 其中, 产生在颅内的具 有圓凸壁的动脉瘤,被称作大脑动脉瘤。 大脑动脉瘤在破裂时极易诱发蛛 网膜下出血, 从而导致病患中风; 甚至, 80%或者更多的病人在复发大脑 动脉瘤破裂后会死亡。 因此,尽可能的在大脑动脉瘤出现的较早阶段进行 栓塞或者封堵成为最佳的治愈手段。
在栓塞大脑动脉瘤的方法中,一般采用外科手术对已经形成的动脉瘤 进行封堵, 包括针对动脉瘤母动脉的剪断、结扎和采用动脉瘤夹将动脉瘤 颈夹住, 从而阻断血液对动脉瘤的沖击。但是, 这种方法耗时较长且有可 能造成动脉瘤的破损。 近年来, 随着血管影像学的发展, 采用介入手术方 法,通过将各种栓塞材料输送至大脑动脉瘤内以封堵、栓塞动脉瘤已经渐 渐代替了传统的外科手术。 然而, 采用白金弹簧圏的方法的栓塞率较低、 容易形成大范围的血栓而引起大脑梗塞等。
目前已经公开了多种栓塞材料,主要分为固体栓塞材料和液体栓塞材 料两类。液体栓塞材料可以直接注入动脉瘤瘤腔内,适应不同形状和大小 的动脉瘤腔,使瘤壁和栓塞材料之间不留任何空隙,从而达到永久性闭塞。 同时,液体栓塞材料具有易于操作的优点,可以通过微导管直接注入血管, 因此液体栓塞材料是较为理想的栓塞材料,多用于血管内治疗领域包括动 脉瘤及血管畸形等。液体栓塞材料一般分为黏附性液体栓塞材料和非粘附 性液体栓塞材料两种。由于非黏附性液体栓塞材料使用的有机溶剂二甲基 亚砜具有潜在的血管毒性,影响了非黏附性液体栓塞材料的应用。黏附性 液体栓塞材料不具有血管毒性,得到了广泛的应用。现有技术中黏附性液 体栓塞材料主要是氰基丙烯酸正丁酯,该物质不能很好的栓塞复杂的微导 管难以完全到位的微细血管动脉瘤及血管畸形。 发明内容
有鉴于此,本发明要解决的技术问题在于提供一种液体栓塞材料组合 物及其制备方法,该液体栓塞材料组合物能很好的栓塞微细血管动脉瘤及 血管畸形。
本发明提供一种液体栓塞材料组合物, 包括:
氰基丙烯酸烷基酯、 Fe304纳米粒子和造影剂。
优选的, 所述氰基丙烯酸烷基酯与所述 Fe304纳米粒子的摩尔比为 2.5~3.5:0.5~1.5。
优选的, 所述氰基丙烯酸烷基酯与所述 Fe304纳米粒子的摩尔比为
3:1。
优选的, 所述氰基丙烯酸烷基酯中烷基的碳原子数为 4~10。
优选的, 所述造影剂为碘化物、铋类化合物、钽粉和金粉中的一种或 几种。
本发明还提供一种液体栓塞材料组合物的制备方法, 包括: 将 Fe304纳米粒子分散在氰基丙烯酸烷基酯中, 得到悬浊液; 在氩气条件下,向所述悬浊液中加入造影剂,得到液体栓塞材料组合 物。
优选的, 所述氰基丙烯酸烷基酯与所述 Fe304纳米粒子的摩尔比为 2.5~3.5:0.5~1.5。
优选的, 所述氰基丙烯酸烷基酯中烷基的碳原子数为 4~10。
优选的, 所述造影剂为碘化物、铋类化合物、钽粉和金粉中的一种或 几种。
优选的, 所述 Fe304纳米粒子由化学共沉淀法合成。
从上述的技术方案可以看出,本发明提供一种液体栓塞材料组合物及 其制备方法, 该液体栓塞材料组合物包括氰基丙烯酸烷基酯、 Fe304纳米 粒子和造影剂。 该液体栓塞材料组合物被注射至动脉瘤腔后, Fe304纳米 粒子和氰基丙烯酸烷基酯通过自组装的方式形成多交联点的多孔交联体, 从而形成栓塞体。该多孔结构极大地降低了栓塞体的密度,緩解了栓塞材 料完全栓塞固化后引起的占位效应及动脉瘤在惯性下压迫周围神经等问 题; 并且, Fe304纳米粒子使栓塞体形成自增韧的类橡胶结构, 并利用其 具有的超顺磁性作用,使所述液体栓塞材料组合物可以在外界磁场的作用 下可以通过靶向定位,很好的栓塞复杂的微导管难以完全到位的微细血管 动脉瘤及血管畸形。 具体实施方式
下面对本发明实施例中的技术方案进行清楚、 完整地描述, 显然, 所 描述的实施例仅仅是本发明一部分实施例, 而不是全部的实施例。基于本 发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获 得的所有其他实施例, 都属于本发明保护的范围。
本发明公开了一种液体栓塞材料组合物, 包括:
氰基丙烯酸烷基酯、 Fe304纳米粒子和造影剂。
所述氰基丙烯酸烷基酯中烷基的碳原子数优选为 4~10, 更优选为 5-8„ 所述氰基丙烯酸烷基酯与所述 Fe304纳米粒子的摩尔比优选为 2.5-3.5:0.5-1.5 , 更优选为 2.8~3.2:0.8~1.2, 最优选为 3:1。
所述氰基丙烯酸烷基酯中氰基和羧基的双重吸电子作用,使氰基丙烯 酸烷基酯受血液中的阴离子催化而迅速聚合, 达到栓塞目的。 所述 Fe304 纳米粒子与氰基丙烯酸烷基酯通过自组装形成多交联点聚合体作为栓塞 体, 所述 Fe304纳米粒子为磁性纳米粒子, 本发明利用了纳米磁性粒子的 超顺磁性作用 ,使得其在外界磁场的作用下靶向定位。从而在栓塞过程中 , 通过外界磁场的基本靶向, 使得微细动脉瘤得以栓塞, 且栓塞的较彻底。 在外界磁场的作用下通过微导管,将本发明提供的液体栓塞材料导入 靶向区域,该液体栓塞材料在血浆偏碱的条件下实现阴离子聚合,最终通 过自组装得到以纳米粒子为交联点的类橡胶固化材料。所述氰基丙烯酸烷 基酯形成的聚合物长链,使得栓塞后的永久栓塞体韧性、弹性及柔软度得 到很好的改善;所述氰基丙烯酸烷基酯中烷基侧链使得栓塞的过程中降低 粘管现象发生的几率。其连接点的 Fe304纳米粒子不但使得栓塞体形成自 增韧的类橡胶结构的韧性材料, 而且在栓塞过程中,通过外界磁场的基本 靶向, 使得微细动脉瘤及血管畸形得以栓塞, 且栓塞的较彻底。
本发明提供的栓塞材料混合了血管造影术的造影剂,以适于外科手术 期间和之后荧光 X射线照相术、 肉眼可见的观察动静脉瘤栓塞情况。 所 述造影剂包括: 碘化物、 铋类化合物、 钽粉和金粉中的一种或几种, 所述 碘化物优选包括 6-三碘甲酸、 6-三碘苯甲酸钠、 碘钛酸、 甲泛影酸、 碘达 酸、 碘克酸、 碘帕酸、 碘海醇、 碘苯醇和碘曲仑中的一种或几种, 所述铋 类化合物可以为三氧化二铋。 本发明对所述造影剂添加的量没有特殊要 求, 优选为本领域技术人员熟知的添加量。
本发明提供了一种液体栓塞材料组合物的制备方法, 包括: 将 Fe304纳米粒子分散在氰基丙烯酸烷基酯中, 得到悬浊液; 在氩气条件下,向所述悬浊液中加入造影剂,得到液体栓塞材料组合 物。
所述 Fe304纳米粒子优选利用化学共沉淀法合成。本发明优选对所述 Fe304纳米粒子进行表面化学改性, 具体为:
向 Fe304纳米粒子的甲苯悬浮液中加入丙烯酸, 然后通氩气, 搅拌, 待反应完后离心分离, 用正己烷洗涤, 再用乙醇处理, 室温真空干燥, 得 到改性的 Fe304纳米粒子。
所述氰基丙烯酸烷基酯与所述 Fe304纳米粒子的摩尔比优选为 2.5-3.5:0.5-1.5 , 更优选为 2.8~3.2:0.8~1.2, 最优选为 3:1。
所述对改性后的 Fe304纳米粒子分散在氰基丙烯酸烷基酯中,形成悬 浊液, 本发明对其分散方式无特别限制, 优选采用超声分散的方式。
按照本发明,向所述悬浊液中加入造影剂,得到液体栓塞材料组合物 优选在机械搅拌条件下进行。
本发明中 Fe304纳米粒子可以采用市售 Fe304纳米粒子, 也可以为自 行制备。 本发明所述 Fe304纳米粒子优选采用 sigma公司生产的 Fe304纳 米粒子。
为了进一步说明本发明的技术方案,下面结合实施例对本发明优选实 施方案进行描述,但是应当理解,这些描述只是为进一步说明本发明的特 征和优点, 而不是对本发明权利要求的限制。 实施例 1
提供 sigma公司生产的粒径为 10nm的 Fe304纳米粒子, CAS号为: 1317-61-9;
将所述 Fe304纳米粒子进行化学改性, 具体为:
取 250 mL上述 Fe304纳米粒子的甲苯悬浮液,加入 0.5 g丙烯酸, 然 后通 15 min高纯氩气以净化, 密封并在室温下机械搅拌 48 h。 待反应完 后离心分离, 用正己烷洗涤两次, 再用 10 mL的乙醇处理, 室温真空干 燥, 得到改性的 Fe304纳米粒子;
将 1 mol改性的 Fe304纳米粒子分散在 3 mol氰基丙烯酸丙酯的单体, 超声分散, 得到悬浊液;
在 40 °C氩气气氛中将所述悬浊液搅拌并加入 30 g纳米钽粉, 搅拌直 至分散均匀;
装入容器中密封、 灭菌后存放。 实施例 2
提供 sigma公司生产的粒径为 10nm的 Fe304纳米粒子, CAS号为: 1317-61-9;
将所述 Fe304纳米粒子进行化学改性, 具体为:
取 250 mL上述 Fe304纳米粒子的甲苯悬浮液,加入 0.5 g丙烯酸, 然 后通 15 min高纯氩气以净化, 密封并在室温下机械搅拌 48 h, 待反应完 后离心分离, 用正己烷洗涤两次, 再用 10 mL的乙醇处理, 室温真空干 燥, 得到改性的 Fe304纳米粒子;
将 0.7 mol所述改性的 Fe304纳米粒子超声分散在 2 mol氰基丙烯酸 丁酯的单体中, 得到悬浊液;
在 40 °C氩气气氛中搅拌并加入 25 g纳米钽粉, 搅拌直至分散均匀; 装入容器中密封、 灭菌后存放。 实施例 3
提供 sigma公司生产的粒径为 10nm的 Fe304纳米粒子, CAS号为: 1317-61-9;
将所述 Fe304纳米粒子进行化学改性, 具体为:
取 250 mL上述 Fe304纳米粒子的甲苯悬浮液,加入 0.5 g丙烯酸, 然 后通 15 min高纯氩气以净化, 密封并在室温下机械搅拌 48 h。 待反应完 后离心分离, 用正己烷洗涤两次, 再用 10 mL的乙醇处理, 室温真空干 燥, 得到改性的 Fe304纳米粒子;
将 0.4 mol所述改性的 Fe304纳米粒子超声分散 1 mol氰基丙烯酸丁 酯的单体分中, 得到悬浊液;
在 40 °C氩气气氛中搅拌并加入 20 g纳米钽粉, 搅拌直至分散均匀; 装入容器中密封、 灭菌后存放。 实施例 4
提供 sigma公司生产的粒径为 10nm的 Fe304纳米粒子, CAS号为: 1317-61-9;
将所述 Fe304纳米粒子进行化学改性, 具体为:
取 500mL上述 Fe304纳米粒子的甲苯悬浮液, 加入 0.5 g丙婦酸, 然 后通 15 min高纯氩气以净化, 密封并在室温下机械搅拌 48 h。 待反应完 后离心分离, 用正己烷洗涤两次, 再用 10 mL的乙醇处理, 室温真空干 燥, 得到改性的 Fe304纳米粒子;
将 0.7 mol所述改性的 Fe304纳米粒子超声分散在 2 mol氰基丙烯酸 丁酯的单体中, 得到悬浊液; 在 40 °C氩气气氛中搅拌并加入 25 g纳米钽粉, 搅拌直至分散均匀; 装入容器中密封、 灭菌后存放。 实施例 5
提供 sigma公司生产的粒径为 10nm的 Fe304纳米粒子, CAS号为: 1317-61-9;
将所述 Fe304纳米粒子进行化学改性, 具体为:
取 500 mL上述 Fe304纳米粒子的甲苯悬浮液,加入 0.5 g丙烯酸, 然 后通 15 min高纯氩气以净化, 密封并在室温下机械搅拌 48 h。 待反应完 后离心分离, 用正己烷洗涤两次, 再用 10 mL的乙醇处理, 室温真空干 燥, 得到改性的 Fe304纳米粒子;
将 0.4 mol 所述改性的 Fe304纳米粒子超声分散 l mol 氰基丙烯酸丁 酯的单体分中, 得到悬浊液;
在 40 °C氩气气氛中搅拌并加入 20 g纳米钽粉, 搅拌直至分散均匀; 装入容器中密封、 灭菌后存放。 实施例 6
提供 sigma公司生产的粒径为 10nm的 Fe304纳米粒子, CAS号为: 1317-61-9;
将所述 Fe304纳米粒子进行化学改性, 具体为:
取 125mL上述 Fe304纳米粒子的甲苯悬浮液, 加入 0.5 g丙烯酸, 然 后通 15 min高纯氩气以净化, 密封并在室温下机械搅拌 48 h。 待反应完 后离心分离, 用正己烷洗涤两次, 再用 10 mL的乙醇处理, 室温真空干 燥, 得到改性的 Fe304纳米粒子;
将 0.7 mol 所述改性的 Fe304纳米粒子超声分散在 2 mol氰基丙烯酸 丁酯的单体中, 得到悬浊液;
在 40 °C氩气气氛中搅拌并加入 25 g纳米钽粉, 搅拌直至分散均匀; 装入容器中密封、 灭菌后存放。 实施例 7
提供 sigma公司生产的粒径为 10nm的 Fe304纳米粒子, CAS号为: 1317-61-9;
将所述 Fe304纳米粒子进行化学改性, 具体为:
取 125 mL上述 Fe304纳米粒子的甲苯悬浮液,加入 0.5 g丙烯酸, 然 后通 15 min高纯氩气以净化, 密封并在室温下机械搅拌 48 h。 待反应完 后离心分离, 用正己烷洗涤两次, 再用 10 mL的乙醇处理, 室温真空干 燥, 得到改性的 Fe304纳米粒子;
将 0.4 mol 所述改性的 Fe304纳米粒子超声分散 l mol 氰基丙烯酸丁 酯的单体分中, 得到悬浊液;
在 40 °C氩气气氛中搅拌并加入 20 g纳米钽粉, 搅拌直至分散均匀; 装入容器中密封、 灭菌后存放。 将实施例 1~7制备的栓塞材料注入生理盐水中, 30~60s后逐渐由注 射口附近析出黑色海绵状沉淀, 沉淀由内向外逐渐变牢固、 密集; 将生理 盐水置于外加磁场中, 而后在另一端注射该类栓塞材料, 30~60s后在磁 场端观察到黑色沉淀。将所述海绵状聚合物取出,手感较为柔软且具有一 定的弹性, 因此, 实验结果表明, 通过本发明提供的制备方法得到的栓塞 材料能够在外加磁场的作用下定向移动,并能迅速固化,且固化后形成柔 软的海绵状多孔结构。 从上述实施例可以看出,本发明提供一种液体栓塞材料组合物及其制 备方法, 该液体栓塞材料组合物包括氰基丙烯酸烷基酯、 Fe304纳米粒子 和造影剂。 该栓塞组合物被注射至动脉瘤腔后, Fe304纳米粒子和氰基丙 烯酸烷基酯通过自组装的方式形成多交联点的多孔交联体,从而形成栓塞 体。该多孔结构极大地降低了栓塞体的密度,緩解了栓塞材料完全栓塞固 化后引起的占位效应及动脉瘤在惯性下压迫周围神经等问题;并且, Fe304 纳米粒子使栓塞体形成自增韧的类橡胶结构,并利用其具有的超顺磁性作 用,使所述液体栓塞材料组合物可以在外界磁场的作用下可以通过靶向定 位, 很好的栓塞复杂的微导管难以完全到位的微细血管动脉瘤及血管畸 形。
对所公开的实施例的上述说明,使本领域专业技术人员能够实现或使 用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显 而易见的,本文中所定义的一般原理可以在不脱离本发明的精神或范围的 情况下, 在其它实施例中实现。 因此, 本发明将不会被限制于本文所示的 这些实施例,而是要符合与本文所公开的原理和新颖特点相一致的最宽的 范围。

Claims

权 利 要 求
1、 一种液体栓塞材料组合物, 其特征在于, 包括:
氰基丙烯酸烷基酯、 Fe304纳米粒子和造影剂。
2、 根据权利要求 1所述的液体栓塞材料组合物, 其特征在于, 所述 氰基丙烯酸烷基酯与所述 Fe304纳米粒子的摩尔比为 2.5~3.5:0.5~1.5。
3、 根据权利要求 2所述的液体栓塞材料组合物, 其特征在于, 所述 氰基丙烯酸烷基酯与所述 Fe304纳米粒子的摩尔比为 3: 1。
4、 根据权利要求 1所述的液体栓塞材料组合物, 其特征在于, 所述 氰基丙烯酸烷基酯中烷基的碳原子数为 4~10。
5、 根据权利要求 1所述的液体栓塞材料组合物, 其特征在于, 所述 造影剂为碘化物、 铋类化合物、 钽粉和金粉中的一种或几种。
6、 一种液体栓塞材料组合物的制备方法, 其特征在于, 包括: 将 Fe304纳米粒子分散在氰基丙烯酸烷基酯中, 得到悬浊液; 在氩气条件下,向所述悬浊液中加入造影剂,得到液体栓塞材料组合 物。
7、 根据权利要求 6所述的制备方法, 其特征在于, 所述氰基丙烯酸 烷基酯与所述 Fe304纳米粒子的摩尔比为 2.5~3.5:0.5~1.5。
8、 根据权利要求 6所述的制备方法, 其特征在于, 所述氰基丙烯酸 烷基酯中烷基的碳原子数为 4~10。
9、 根据权利要求 6所述的制备方法, 其特征在于, 所述造影剂为碘 化物、 铋类化合物、 钽粉和金粉中的一种或几种。
10、 根据权利要求 6所述的制备方法, 其特征在于, 所述 Fe304纳米 粒子由化学共沉淀法合成。
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