WO2011091736A1 - 一种液体栓塞材料及其制备方法 - Google Patents

一种液体栓塞材料及其制备方法 Download PDF

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Publication number
WO2011091736A1
WO2011091736A1 PCT/CN2011/070451 CN2011070451W WO2011091736A1 WO 2011091736 A1 WO2011091736 A1 WO 2011091736A1 CN 2011070451 W CN2011070451 W CN 2011070451W WO 2011091736 A1 WO2011091736 A1 WO 2011091736A1
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Prior art keywords
cyanoacrylate
compound monomer
embolic material
monomer
plasticizer
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PCT/CN2011/070451
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English (en)
French (fr)
Inventor
谭连江
金巧蓉
李�雨
李晓强
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 WO2011091736A1 publication Critical patent/WO2011091736A1/zh

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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
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • the invention relates to the technical field of interventional therapy, in particular to a liquid embolization material for interventional treatment of an aneurysm or arteriovenous malformation and a preparation method thereof.
  • Transcatheter embolization is an important technique in interventional therapy, with many advantages such as less traumatic and less complications.
  • the principle of transcatheter embolization is to inject the artificial embolization material into the supply vessel or diseased blood vessel of the diseased organ, occlude the blood vessel, interrupt the blood supply, and control bleeding, treat vascular lesions, treat tumors, and eliminate diseased organs. purpose. It can be seen that the choice of embolization material is the key to the success of treatment.
  • 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 embolization material.
  • the liquid embolic material has the advantage of being easy to handle, and can be directly injected into the blood vessel through the microcatheter, so it is an ideal embolic material, and is mostly used in the field of endovascular treatment.
  • the liquid embedding material for clinical application is mainly n-butyl cyanoacrylate.
  • n-butyl cyanoacrylate Due to the double electron-withdrawing effect of cyano group and carboxyl group, the carbon atom is rapidly polymerized by the anion in the blood to achieve the purpose of embolization, while cyanoacrylic acid is positive. Butyl ester is not easily polymerized in a 5% glucose solution, and liquid n-butyl cyanoacrylate can be conveniently injected into a blood vessel. However, n-butyl cyanoacrylate has strong adhesion and is prone to the problem of "sticky tube", that is, the microcatheter adheres to the blood vessel wall, affecting the therapeutic effect, and has certain dangers, and is easy to cause during the embolization process. Catheter adhesions, leading to complications. Summary of the invention
  • the technical problem to be solved by the present invention is to provide a liquid embolic material.
  • the preparation method thereof, the liquid embolic material provided by the invention has moderate viscosity, and the sticking tube problem is not easy to occur.
  • the present invention provides a liquid embolic material comprising a cyanoacrylate compound monomer, a polymerization inhibitor, a developer, a plasticizer and an organic solvent;
  • the cyanoacrylate compound monomer is n-butyl ⁇ -phenylcyanoacrylate or a compound having the structure of the formula (I) or the formula (II):
  • the cyanoacrylate compound monomer is n-hexyl cyanoacrylate or hexyl cyanoacrylate.
  • the cyanoacrylate compound monomer is n-octyl cyanoacrylate.
  • the n satisfies the condition: 8 n 12.
  • the polymerization inhibitor is m-methoxyphenol, hydroquinone, phosphoric acid or sulfur dioxide.
  • the developer is gold powder, platinum powder, tantalum powder, titanium powder, tungsten powder or barium sulfate.
  • the plasticizer is dimethyl phthalate, diethyl phthalate, dibutyl phthalate, butyl benzyl phthalate, benzoate or tricresyl phosphate.
  • the invention also provides a preparation method of a liquid embolic material, comprising: purifying a cyanoacrylate compound monomer by argon gas purging, wherein the cyanoacrylic compound monomer is ⁇ -phenylcyanoacrylic acid Butyl ester or a compound having the structure of formula (I) or formula (II):
  • the liquid embolic material provided by the present invention comprises a cyanoacrylate compound monomer, a polymerization inhibitor, a developer, a plasticizer and an organic solvent, and the cyanoacrylate compound monomer is a n-butyl ⁇ -phenylcyanoacrylate or a cyanoacrylate compound having a fluorenyl chain of 6 or more carbon atoms.
  • the present invention uses a cyanoacrylate having a longer carbon chain structure or a side chain structure, the adhesion is less than n-butyl cyanoacrylate, and the sticking problem is less likely to occur. Meanwhile, the cyanoacrylate compound used in the present invention is less toxic, has better biocompatibility and chemical stability, and is solid in blood vessels. After the formation of a soft sponge-like structure, it can reduce the difficulty of clinical operation and improve the embolization effect. detailed description
  • the present invention provides a liquid embolic material comprising a cyanoacrylate compound monomer, a polymerization inhibitor, a developer, a plasticizer and an organic solvent;
  • the cyanoacrylate compound monomer is n-butyl ⁇ -phenylcyanoacrylate or a compound having the structure of the formula (I) or the formula (II):
  • the main component of the embolic material is a cyanoacrylate compound monomer, and in the cyanoacrylate monomer, a carbon atom is bonded to a polar group such as a cyano group or a carbonyl group, and such a group can induce
  • a polar group such as a cyano group or a carbonyl group
  • the carbon atom has strong electric absorption property, and the polymerization occurs rapidly when the anion in the blood is encountered, so that the density of the double bond electron cloud is lowered, and at the same time, the polymer forms a polypolar center, and a transient polymerization reaction occurs, and the liquid cyanide is generated.
  • the cyanoacrylate compound monomer is a cyanoacrylate monomer having ⁇ -phenylcyanoacrylate or an alkyl group having 6 or more carbon atoms, preferably cyanoacrylate.
  • the embolic material comprises a polymerization inhibitor, and the polymerization inhibitor acts to block the polymerization of the cyanoacrylate monomer, which facilitates the storage of the embolic material; and during the embolization process, due to the blood Rich in anions, making the embolic material fast in the blood vessels Rapid initiation and polymerization, thereby shortening the curing time and improving the embolization effect.
  • the present invention has no particular requirement for the polymerization inhibitor, and is preferably m-methoxyphenol, hydroquinone, phosphoric acid or sulfur dioxide.
  • the mass ratio of the polymerization inhibitor to the cyanoacrylate compound monomer is preferably 1: 10,000 to 500,000, more preferably 1:50,000 to 200,000, and most preferably 1:800 to 120,000.
  • the embolic material includes a plasticizer, and the plasticizer acts to soften the embolic material after curing to form a soft sponge-like structure to enhance the embolization effect.
  • the present invention has no special requirements for plasticizers, and is preferably dimethyl phthalate, diethyl phthalate, dibutyl phthalate, butyl benzyl phthalate, benzoate or phosphoric acid. Tricresol ester.
  • the plasticizer and the cyanoacrylate compound monomer preferably have a mass ratio of 1:10 to 100, more preferably 1:20 to 80, most preferably 1:40 to 60.
  • the embolic material comprises a developer, and the present invention has no particular requirement for the developer, and is preferably a solid developer, more preferably gold powder, platinum powder, tantalum powder, titanium powder, tungsten powder or barium sulfate, most preferably Gold powder.
  • the present invention has no particular requirement for the amount of the developer to be added, and is preferably added in an amount well known to those skilled in the art.
  • the embolic material includes an organic solvent which causes the embolic material to be in a liquid state to exert the advantage of a liquid embolic material.
  • the organic solvent of the present invention is not particularly limited, and is preferably an organic solvent well known to those skilled in the art.
  • the mass ratio of the organic solvent to the cyanoacrylate compound monomer is preferably 1:1-5, more preferably 1:1-3, and most preferably 1:2-3.
  • the cyanoacrylate monomer in the embedding material encounters an anion in the blood to rapidly polymerize and solidify; wherein the polymerization inhibitor acts to shorten the curing time.
  • the curing time is from 10 seconds to 40 seconds, and the addition amount of the polymerization inhibitor can be adjusted to shorten the curing time to 15 seconds to 35 seconds. Due to the action of the plasticizer, the cyanoacrylate monomer is polymerized and cured. It forms a soft, spongy structure that occludes diseased blood vessels or organs and acts as an embolism.
  • the invention also provides a preparation method of a liquid embolic material, comprising:
  • the cyanoacrylic compound monomer is ⁇ -phenylcyanoacrylate n-butyl ester or a compound having the structure of formula (I) or formula (II) :
  • the cyanoacrylate compound monomer is first purged and purified.
  • the purification purification of the present invention is not particularly limited, and is preferably a method well known to those skilled in the art, and more preferably purged under an argon atmosphere. purification.
  • a carbon atom is bonded to a polar group such as a cyano group or a carbonyl group, and such a group can induce an effect, and the carbon atom has a strong electric absorbing property, and encounters an anion in the blood.
  • the cyanoacrylate compound monomer is n-butyl ⁇ -phenylcyanoacrylate or a cyanoacrylate compound having a mercapto group having 6 or more carbon atoms, preferably cyanoacrylate.
  • cyanoacrylate of n-hexyl ester 2-hexyl cyanoacrylate, n-octyl cyanoacrylate or a fluorenyl group having 8 to 12 carbon atoms Monomer.
  • the source of the cyanoacrylate compound monomer of the present invention is not particularly limited, and is preferably obtained by a method well known to those skilled in the art or commercially available.
  • the plasticizer and the polymerization inhibitor are dissolved in an organic solvent, stirred and hooked, and then bubbled with sulfur dioxide to obtain a first mixed solution.
  • the present invention is not particularly limited to the agitating invention, and is preferably a method well known to those skilled in the art.
  • the action of the sulfur dioxide bubbling is to dissolve a trace amount of sulfur dioxide to control the polymerization of the cyanoacrylate.
  • the polymerization inhibitor acts to block the polymerization of the cyanoacrylate monomer, which facilitates the storage of the embolic material.
  • the blood is rich in anions, so that the embolic material is in the blood vessel. It is rapidly initiated and polymerized, thereby shortening the curing time and improving the embolization effect.
  • the present invention has no particular requirement for the polymerization inhibitor, and is preferably m-methoxyphenol, hydroquinone, phosphoric acid or sulfur dioxide.
  • the mass ratio of the polymerization inhibitor to the cyanoacrylate compound monomer is preferably 1: 10,000 to 500,000, more preferably 1:50,000 to 200,000, and most preferably 1:800 to 120,000.
  • the function of the plasticizer is to soften the embolic material after curing to form a soft sponge-like structure and to improve the embolization effect.
  • the present invention has no special requirements for plasticizers, and is preferably dimethyl phthalate, diethyl phthalate, dibutyl phthalate, butyl benzyl phthalate, benzoate or phosphoric acid. Tricresol ester.
  • the plasticizer and the cyanoacrylate compound monomer preferably have a mass ratio of 1:10 to 100, more preferably 1:20 to 80, most preferably 1:40 to 60 organic solvent.
  • the embolic material is brought into a liquid state to take advantage of the liquid embolic material.
  • the organic solvent of the present invention is not particularly limited, and is preferably an organic solvent well known to those skilled in the art, and more preferably acetyl tri-n-butyl citrate.
  • the mass ratio of the organic solvent to the cyanoacrylate compound monomer is preferably 1:1-5, more preferably 1:1-3, and most preferably 1:2-3.
  • the purge-purified cyanoacrylate compound monomer is added to the first mixed solution, and the mixture is homogenized to obtain a second mixed solution.
  • the mixing method of the present invention is not particularly limited, and is preferably a method well known to those skilled in the art, and it is preferred to uniformly mix at normal temperature.
  • the viscosity of the second mixed solution is from 10 centipoise to 30 centipoise.
  • a developer is added to the second mixed solution to obtain a plug material.
  • the present invention has no particular requirement for the developer, and is preferably a solid developer, more preferably gold powder, platinum powder, strontium powder, titanium powder, tungsten powder or barium sulfate, and most preferably gold powder.
  • the present invention has no particular requirement for the amount of the developer, and is preferably an amount well known to those skilled in the art.
  • the embolic material is preferably sealed and stored after being autoclaved, and the embolic material has good stability and can be stored for a long time.
  • the cyanoacrylate compound monomer After the embolic material prepared by the invention is injected into a blood vessel, the cyanoacrylate compound monomer rapidly polymerizes and solidifies when it encounters an anion in the blood; wherein the polymerization inhibitor acts to shorten the curing time and the curing time. For 10 seconds to 40 seconds, adjusting the amount of the polymerization inhibitor added, the curing time can be shortened to 15 seconds - 35 seconds; due to the action of the plasticizer, the cyanoacrylate monomer is polymerized and solidified to form a soft The spongy structure, occluding diseased blood vessels or organs, acts as an embolism.
  • the liquid embolic material provided by the present invention comprises a cyanoacrylate compound monomer, a polymerization inhibitor, a developer, a plasticizer and an organic solvent, and the cyanoacrylate compound monomer is a n-butyl ⁇ -phenylcyanoacrylate or a cyanoacrylate compound monomer having an alkyl chain of 6 or more carbon atoms. Since the present invention uses a cyanoacrylate having a long carbon chain structure or a side chain structure, its viscosity is small and sticking problems are less likely to occur.
  • the cyanoacrylate compound used in the invention has less toxicity, better biocompatibility and chemical stability, and forms a soft sponge-like structure after curing in blood vessels, which can reduce the difficulty of clinical operation and increase embolism. effect.
  • the liquid embolic material provided by the present invention and a method for preparing the same are described below in conjunction with the examples.
  • n-octyl cyanoacrylate monomer 200g was purified by argon gas purging at normal temperature; 3g of cresyl phosphate and 0.002g of hydroquinone were dissolved in 120g of acetyl tri-n-butyl citrate to form a solution. Then, the sulfur dioxide is bubbled to dissolve a small amount of sulfur dioxide, and the obtained solution is uniformly mixed with n-octyl cyanoacrylate at a normal temperature, and the obtained mixture has a viscosity of between 12 centipoise and 24 centipoise; Under the protection of gas, a small amount of gold powder is added to the mixed liquid, sealed in a container, and stored under high temperature sterilization.
  • cyanoacrylate cyanoacrylate monomer 200g was purified by argon gas purging at normal temperature; 3g of dimethyl phthalate and 0.002g of hydroquinone were dissolved in 100g of acetyl tri-n-butyl citrate to form a solution. Stir well, then use sulfur dioxide to bubble to dissolve a small amount of sulfur dioxide, and mix the obtained solution with n-octyl cyanoacrylate at room temperature, and test it. The viscosity of the mixed solution is between 15 centipoise and 25 centipoise; under the protection of argon, a small amount of gold powder is added to the mixed solution, sealed in a container, and stored under high temperature sterilization.
  • n-butyl P-phenylcyanoacrylate monomer 200g was purified by argon gas purging at normal temperature; 4g of dibutyl phthalate and 0.0015g of hydroquinone were dissolved in 100g of acetyl tri-n-butyl citrate Forming a solution, stirring and hooking, then bubbling with sulfur dioxide to dissolve a small amount of sulfur dioxide, and mixing the obtained solution with n-octyl cyanoacrylate at room temperature. After testing, the viscosity of the obtained mixture is 15 centipoise to 25 centistokes. Between the berths; under the protection of argon, a small amount of gold powder is added to the mixture, sealed in a container, and stored under high temperature sterilization.
  • n-octyl cyanoacrylate monomer 200 g was purified by argon gas purging at normal temperature; 4 g of butyl benzyl phthalate and 0.002 g of m-methoxyphenol were dissolved in 100 g of acetyl tri-n-butyl citrate to form a solution. Stir well, then use sulfur dioxide to bubble to dissolve a small amount of sulfur dioxide, and mix the obtained solution with n-octyl cyanoacrylate at room temperature. After testing, the viscosity of the mixture is between 15 centipoise and 25 centipoise. Under the protection of argon, a small amount of gold powder is added to the mixture, sealed in a container, and stored under high temperature sterilization.
  • Example 1 The liquid embolic material prepared in Example 1 was injected into a physiological saline solution of 37 Torr, and the following experimental phenomenon was observed: A white sponge-like precipitate was precipitated immediately, and the precipitate gradually became firm and dense from the inside to the outside. The spongy polymer was taken out and the hand was soft.
  • the experimental results show that the embolic material obtained by the preparation method provided by the present invention can be rapidly cured and formed into a soft sponge-like structure after curing.
  • the description of the above embodiments is only for helping to understand the method of the present invention and its core thinking. miss you. It should be noted that those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the invention.

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Description

一种液体栓塞材料及其制备方法 技术领域
本发明涉及介入疗法技术领域， 尤其涉及一种介入治疗动脉瘤或 动静脉畸形的液体栓塞材料及其制备方法。 背景技术
随着现代医疗技术的发展， 介入疗法来越成熟， 使用的频率也越 来越高。 经导管栓塞术是介入疗法中的重要技术， 具有创伤性小、 并 发症少等多种优点。 经导管栓塞术的治疗原理为： 将人工栓塞材料注 入到病变器官的供应血管或病变血管内， 使血管发生闭塞、 中断供血， 以达到控制出血、 治疗血管性病变、 治疗肿瘤以及消除病变器官的目 的。 由此可见， 栓塞材料的选择是治疗成功与否的关键。 目前， 现有技术已经公开了多种栓塞材料， 其中， 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 是较为理想的栓塞材料， 多用于血管内治疗领域。 目前， 临床应用的 液体栓塞材料主要是氰基丙烯酸正丁酯， 由于氰基和羧基的双重吸电 子作用， 使碳原子受血液中的阴离子催化而迅速聚合， 达到栓塞目的， 同时氰基丙烯酸正丁酯在 5%的葡萄糖溶液中不容易发生聚合， 能够方 便地将液体氰基丙烯酸正丁酯注入到血管内。 但是， 氰基丙烯酸正丁 酯粘附性较强， 容易发生 "粘管" 问题， 即微导管粘附在血管壁上， 影响治疗效果， 并具有一定的危险性， 且在栓塞过程中容易导致导管 粘连， 导致并发症。 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 及其制备方法， 本发明提供的液体栓塞材料粘性适中， 不容易发生粘 管问题。 本发明提供了一种液体栓塞材料， 包括氰基丙烯酸酯类化合物单 体、 阻聚剂、 显影剂、 增塑剂和有机溶剂；
所述氰基丙烯酸酯类化合物单体为 β-苯基氰基丙烯酸正丁酯或具 有式 (I)或式 (II)结构的化合物：
0
if
CH =CH-C— 0— CnH2n+1
CN
(I)
o
II
CH2=C—C— O— CnH2n+1
CN
Figure imgf000003_0001
其中， n≥6。 优选的， 所述氰基丙烯酸酯类化合物单体为氰基丙烯酸正己酯或 2-氰基丙烯酸己酯。 优选的， 所述氰基丙烯酸酯类化合物单体为氰基丙烯酸正辛酯。 优选的， 所述 n满足条件： 8 n 12。 优选的， 所述阻聚剂为间甲氧基苯酚、 对苯二酚、 磷酸或二氧化 硫。 优选的， 所述显影剂为金粉、 铂粉、 钽粉、 钛粉、 钨粉或硫酸钡。 优选的， 所述增塑剂为邻苯二甲酸二甲酯、 邻苯二甲酸二乙酯、 邻苯二甲酸二丁酯、 邻苯二甲酸丁苄酯、 苯甲酸酯或磷酸三甲酚酯。 本发明还提供了一种液体栓塞材料的制备方法， 包括： 将氰基丙烯酸酯类化合物单体通氩气吹洗纯化， 所述氰基丙烯酸 类化合物单体为 β-苯基氰基丙烯酸正丁酯或具有式 (I)或式 (II)结构的化 合物：
Figure imgf000004_0001
(I)
Figure imgf000004_0002
其中， n≥6;
将增塑剂和阻聚剂溶于有机溶剂中， 用二氧化硫鼓泡， 得到第一 混合溶液；
将所述吹洗纯化的氰基丙烯酸酯类化合物单体加入到所述第一混 合溶液中， 混合均匀， 得到第二混合溶液；
向所述第二混合溶液中加入显影剂， 得到栓塞材料。 优选的， 所述 n满足条件： 8 n 12。 优选的， 所述氰基丙烯酸酯类化合物单体为氰基丙烯酸正辛酯。 与现有技术相比， 本发明提供的液体栓塞材料中包括氰基丙烯酸 酯类化合物单体、 阻聚剂、 显影剂、 增塑剂和有机溶剂， 所述氰基丙 烯酸酯类化合物单体为 β-苯基氰基丙烯酸正丁酯或具有 6个以上碳原 子的垸基链的氰基丙烯酸酯类化合物单体。 由于本发明使用了含有较 长碳链结构或含有侧链结构的氰基丙烯酸酯， 其粘附性小于氰基丙烯 酸正丁酯， 不易发生粘管问题。 同时， 本发明使用的氰基丙烯酸酯类 化合物单体毒性较小， 生物相容性和化学稳定性较好， 且在血管中固 化后形成柔软的海绵状结构， 能够降低临床操作难度， 提高栓塞效果。 具体实施方式
本发明提供了一种液体栓塞材料， 包括氰基丙烯酸酯类化合物单 体、 阻聚剂、 显影剂、 增塑剂和有机溶剂；
所述氰基丙烯酸酯类化合物单体为 β-苯基氰基丙烯酸正丁酯或具 有式 (I)或式 (II)结构的化合物：
ο
II
CH =CH-C— 0— CnH2n+1
C
(I)
o
CH2=C-C-0-CnH2n+1
CN
Figure imgf000005_0001
其中， n≥6。 按照本发明， 所述栓塞材料的主要成分是氰基丙烯酸酯类化合物 单体， 氰基丙烯酸酯单体中， 碳原子连着氰基、 羰基等极性基团， 该 类基团能够产生诱导效应， 使碳原子有较强的吸电性， 遇到血液中的 阴离子时迅速发生聚合， 使双键电子云密度降低， 同时使聚合体形成 多极性中心， 产生瞬间聚合反应， 液态的氰基丙烯酸酯单体固化， 形 成柔软的海绵状结构， 使病变血管闭塞， 达到栓塞的目的。 按照本发 明， 所述氰基丙烯酸酯类化合物单体为 β-苯基氰基丙烯酸正丁酯或具 有 6 个以上碳原子的烷基的氰基丙烯酸酯类化合物单体， 优选为氰基 丙烯酸正己酯、 2-氰基丙烯酸己酯、 氰基丙烯酸正辛酯或具有 8-12个 碳原子的烷基的氰基丙烯酸酯类化合物单体。 按照本发明， 所述栓塞材料包括阻聚剂， 所述阻聚剂的作用在于 阻碍氰基丙烯酸酯类化合物单体聚合， 为栓塞材料的储存提供了方便； 而在栓塞过程中， 由于血液中富含阴离子， 使得栓塞材料在血管中迅 速引发并聚合， 从而缩短固化时间， 提高栓塞效果。 本发明对阻聚剂 没有特殊要求， 优选为间甲氧基苯酚、 对苯二酚、 磷酸或二氧化硫。 按照本发明， 所述阻聚剂与所述氰基丙烯酸酯类化合物单体按质量比 优选为 1 : 10000-500000, 更优选为 1 : 50000-200000, 最优选为 1 : 80000-120000。 按照本发明， 所述栓塞材料包括增塑剂， 所述增塑剂的作用在于 使固化后的栓塞材料软化， 形成柔软的海绵状结构， 提高栓塞效果。 本发明对增塑剂没有特殊要求， 优选为邻苯二甲酸二甲酯、 邻苯二甲 酸二乙酯、 邻苯二甲酸二丁酯、 邻苯二甲酸丁苄酯、 苯甲酸酯或磷酸 三甲酚酯。 按照本发明， 所述增塑剂与所述氰基丙烯酸酯类化合物单 体按质量比优选为 1 : 10-100, 更优选为 1 : 20-80, 最优选为 1 : 40-60。 按照本发明， 所述栓塞材料包括显影剂， 本发明对显影剂没有特 殊要求， 优选为固态显影剂， 更优选为金粉、 铂粉、 钽粉、 钛粉、 钨 粉或硫酸钡， 最优选为金粉。 本发明对所述显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。 按照本发明， 所述栓塞材料包括有机溶剂， 有机溶剂使所述栓塞 材料为液体状态， 发挥液体栓塞材料的优势。 本发明对所述有机溶剂 没有特殊限制， 优选为本领域技术人员熟知的有机溶剂。 按照本发明， 所述有机溶剂与所述氰基丙烯酸酯类化合物单体按质量比优选为 1 : 1-5， 更优选为 1 : 1-3， 最优选为 1 : 2-3。 按照本发明， 所述栓塞材料注入血管后， 栓塞材料中的氰基丙烯 酸酯类化合物单体遇到血液中的阴离子而发生迅速聚合、 固化； 其中 的阻聚剂发挥作用， 縮短了固化时间， 使固化时间为 10秒 -40秒， 调 整阻聚剂的添加的量， 能够使固化时间缩短到 15秒 -35秒； 由于增塑 剂的作用， 氰基丙烯酸酯类化合物单体发生聚合、 固化后形成柔软的 海绵状结构， 闭塞病变血管或器官， 起到栓塞作用。 本发明还提供了一种液体栓塞材料的制备方法， 包括：
将氰基丙烯酸酯类化合物单体通氩气吹洗纯化， 所述氰基丙烯酸 类化合物单体为 β-苯基氰基丙烯酸正丁酯或具有式 (I)或式 (II)结构的化 合物：
0
II
CH =CH-C— 0— CnH2n+1
CN
(I)
O
CH2=C— C— 0-CnH2n+1
CN
Figure imgf000007_0001
其中， n≥6;
将增塑剂和阻聚剂溶于有机溶剂中， 用二氧化硫鼓泡， 得到第一 混合溶液；
将所述吹洗纯化的氰基丙烯酸酯类化合物单体加入到所述第一混 合溶液中， 混合均匀， 得到第二混合溶液；
向所述第二混合溶液中加入显影剂， 得到栓塞材料。 按照本发明， 首先将氰基丙烯酸酯类化合物单体吹洗纯化， 本发 明对吹洗纯化没有特殊限制， 优选为本领域技术人员熟知的方法， 更 优选为在通氩气的条件下吹洗纯化。 所述氰基丙烯酸酯单体中， 碳原 子连着氰基、 羰基等极性基团， 该类基团能够产生诱导效应， 使碳原 子有较强的吸电性， 遇到血液中的阴离子时迅速发生聚合， 使双键电 子云密度降低， 同时使聚合体形成多极性中心， 产生瞬间聚合反应， 液态的氰基丙烯酸酯单体固化， 形成柔软的海绵状结构， 使病变血管 闭塞， 达到栓塞的目的。 按照本发明， 所述氰基丙烯酸酯类化合物单 体为 β-苯基氰基丙烯酸正丁酯或具有 6个以上碳原子的垸基的氰基丙 烯酸酯类化合物单体， 优选为氰基丙烯酸正己酯、 2-氰基丙烯酸己酯、 氰基丙烯酸正辛酯或具有 8-12个碳原子的垸基的氰基丙烯酸酯类化合 物单体。 本发明对氰基丙烯酸酯类化合物单体的来源没有特殊限制， 优选为本领域技术人员熟知的方法制备获得或从市场上购得。 按照本发明， 将增塑剂和阻聚剂溶解在有机溶剂中， 搅拌均勾， 然后用二氧化硫鼓泡， 得到第一混合溶液。 本发明对搅拌发明没有特 殊限制， 优选为本领域技术人员熟知的方法。 按照本发明， 二氧化硫 鼓泡的作用在于溶解微量二氧化硫， 控制氰基丙烯酸酯的聚合反应。 按照本发明， 所述阻聚剂的作用在于阻碍氰基丙烯酸酯类化合物单体 聚合， 为栓塞材料的储存提供了方便； 而在栓塞过程中， 由于血液中 富含阴离子， 使得栓塞材料在血管中迅速引发并聚合， 从而缩短固化 时间， 提高栓塞效果。 本发明对阻聚剂没有特殊要求， 优选为间甲氧 基苯酚、 对苯二酚、 磷酸或二氧化硫。 按照本发明， 所述阻聚剂与所 述氰基丙烯酸酯类化合物单体按质量比优选为 1 : 10000-500000, 更优 选为 1： 50000-200000, 最优选为 1： 80000-120000。 所述增塑剂的作 用在于使固化后的栓塞材料软化， 形成柔软的海绵状结构， 提高栓塞 效果。 本发明对增塑剂没有特殊要求， 优选为邻苯二甲酸二甲酯、 邻 苯二甲酸二乙酯、 邻苯二甲酸二丁酯、 邻苯二甲酸丁苄酯、 苯甲酸酯 或磷酸三甲酚酯。 按照本发明， 所述增塑剂与所述氰基丙烯酸酯类化 合物单体按质量比优选为 1 : 10-100， 更优选为 1 : 20-80， 最优选为 1 : 40-60 有机溶剂使所述栓塞材料为液体状态， 发挥液体栓塞材料的优 势。 本发明对所述有机溶剂没有特殊限制， 优选为本领域技术人员熟 知的有机溶剂， 更优选为乙酰柠檬酸三正丁酯。 按照本发明， 所述有 机溶剂与所述氰基丙烯酸酯类化合物单体按质量比优选为 1 : 1-5 , 更 优选为 1 : 1-3 , 最优选为 1 : 2-3。 按照本发明， 将吹洗纯化后的氰基丙烯酸酯类化合物单体加入到 第一混合溶液中， 混合均勾， 得到第二混合溶液。 本发明对所述混合 方法没有特殊限制， 优选为本领域技术人员熟知的方法， 优选为在常 温下混合均匀。 按照本发明， 第二混合溶液的粘度在 10厘泊 -30厘泊。 按照本发明， 向所述第二混合溶液中加入显影剂， 得到栓塞材料。 本发明对显影剂没有特殊要求， 优选为固态显影剂， 更优选为金粉、 铂粉、 钽粉、 钛粉、 钨粉或硫酸钡， 最优选为金粉。 本发明对所述显 影剂的量没有特殊要求， 优选为本领域技术人员熟知的量。 按照本发明， 优选将所述栓塞材料高温灭菌后密封保存， 所述栓 塞材料稳定性较好， 能够保存较长时间。 将本发明制备的栓塞材料注入血管后， 其中的氰基丙烯酸酯类化 合物单体遇到血液中的阴离子而发生迅速聚合、 固化； 其中的阻聚剂 发挥作用， 缩短了固化时间， 使固化时间为 10秒 -40秒， 调整阻聚剂 的添加的量， 能够使固化时间缩短到 15秒 -35秒； 由于增塑剂的作用， 氰基丙烯酸酯类化合物单体发生聚合、 固化后形成柔软的海绵状结构， 闭塞病变血管或器官， 起到栓塞作用。 与现有技术相比， 本发明提供的液体栓塞材料中包括氰基丙烯酸 酯类化合物单体、 阻聚剂、 显影剂、 增塑剂和有机溶剂， 所述氰基丙 烯酸酯类化合物单体为 β-苯基氰基丙烯酸正丁酯或具有 6个以上碳原 子的烷基链的氰基丙烯酸酯类化合物单体。 由于本发明使用了含有较 长碳链结构或含有侧链结构的氰基丙烯酸酯， 其粘性较小， 不易发生 粘管问题。 同时， 本发明使用的氰基丙烯酸酯类化合物单体毒性较小， 生物相容性和化学稳定性较好， 且在血管中固化后形成柔软的海绵状 结构， 能够降低临床操作难度， 提高栓塞效果。 为了进一步了解本发明， 下面结合实施例对本发明提供的液体栓 塞材料及其制备方法进行描述。 实施例 1
按照以下步骤制备液体栓塞材料：
将 200g氰基丙烯酸正辛酯单体在常温下通氩气吹洗纯化； 取 4g 邻苯二甲酸二乙酯和 0.002g对苯二酚溶于 lOOg乙酰柠檬酸三正丁酯中 形成溶液， 搅拌均勾， 然后用二氧化硫鼓泡以溶解微量二氧化硫， 将 得到的溶液与氰基丙烯酸正辛酯在常温下混合均勾， 经检测， 得到的 混合液的粘度在 15厘泊 -25厘泊之间； 在氩气保护下， 向所述混合液 中加入少量金粉， 装入容器中密封、 高温灭菌后存放。 实施例 2
按照以下步骤制备液体栓塞材料- 将 200g氰基丙烯酸正辛酯单体在常温下通氩气吹洗纯化； 取 3g 邻苯二甲酸二丁酯和 0.0015g间甲氧基苯酚溶于 100g乙酰柠檬酸三正 丁酯中形成溶液， 搅拌均匀， 然后用二氧化硫鼓泡以溶解微量二氧化 硫， 将得到的溶液与氰基丙烯酸正辛酯在常温下混合均匀， 经检测， 得到的混合液的粘度在 15厘泊 -25厘泊之间； 在氩气保护下， 向所述 混合液中加入少量金粉， 装入容器中密封、 高温灭菌后存放。 实施例 3
按照以下步骤制备液体栓塞材料：
将 200g氰基丙烯酸正辛酯单体在常温下通氩气吹洗纯化； 取 3g 磷酸三甲酚酯和 0.002g对苯二酚溶于 120g乙酰柠檬酸三正丁酯中形成 溶液， 搅拌均勾， 然后用二氧化硫鼓泡以溶解微量二氧化硫， 将得到 的溶液与氰基丙烯酸正辛酯在常温下混合均匀， 经检测， 得到的混合 液的粘度在 12厘泊 -24厘泊之间； 在氩气保护下， 向所述混合液中加 入少量金粉， 装入容器中密封、 高温灭菌后存放。 实施例 4
按照以下步骤制备液体栓塞材料：
将 200g氰基丙烯酸正葵酯单体在常温下通氩气吹洗纯化； 取 3g 邻苯二甲酸二甲酯和 0.002g对苯二酚溶于 100g乙酰柠檬酸三正丁酯中 形成溶液， 搅拌均匀， 然后用二氧化硫鼓泡以溶解微量二氧化硫， 将 得到的溶液与氰基丙烯酸正辛酯在常温下混合均匀， 经检测， 得到的 混合液的粘度在 15厘泊 -25厘泊之间； 在氩气保护下， 向所述混合液 中加入少量金粉， 装入容器中密封、 高温灭菌后存放。 实施例 5
按照以下步骤制备液体栓塞材料：
将 200gP-苯基氰基丙烯酸正丁酯单体在常温下通氩气吹洗纯化； 取 4g邻苯二甲酸二丁酯和 0.0015g对苯二酚溶于 100g乙酰柠檬酸三正 丁酯中形成溶液， 搅拌均勾， 然后用二氧化硫鼓泡以溶解微量二氧化 硫， 将得到的溶液与氰基丙烯酸正辛酯在常温下混合均匀， 经检测， 得到的混合液的粘度在 15厘泊 -25厘泊之间； 在氩气保护下， 向所述 混合液中加入少量金粉， 装入容器中密封、 高温灭菌后存放。 实施例 6
按照以下步骤制备液体栓塞材料：
将 200g氰基丙烯酸正辛酯单体在常温下通氩气吹洗纯化； 取 4g 邻苯二甲酸丁苄酯和 0.002g间甲氧基苯酚溶于 100g乙酰柠檬酸三正丁 酯中形成溶液， 搅拌均匀， 然后用二氧化硫鼓泡以溶解微量二氧化硫， 将得到的溶液与氰基丙烯酸正辛酯在常温下混合均匀， 经检测， 得到 的混合液的粘度在 15厘泊 -25厘泊之间； 在氩气保护下， 向所述混合 液中加入少量金粉， 装入容器中密封、 高温灭菌后存放。 实施例 7
取实施例 1制备的液体栓塞材料 O.lmL,注入 37Ό的生理盐水中， 观察到如下实验现象： 立即析出白色海绵状沉淀， 沉淀由内向外逐渐 变牢固、 密集。 将所述海绵状聚合物取出， 手感较为柔软。 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 迅速固化， 固化后形成柔软的海绵状结构。 以上实施例的说明只是用于帮助理解本发明的方法及其核心思 想。 应当指出， 对于本技术领域的普通技术人员来说， 在不脱离本发 明原理的前提下， 还可以对本发明进行若干改进和修饰， 这些改进和 修饰也落入本发明权利要求的保护范围内。

Claims

权 利 要 求 书
1. 一种液体栓塞材料， 其特征在于， 包括氰基丙烯酸酯类化合物 单体、 阻聚剂、 显影剂、 增塑剂和有机溶剂；
所述氰基丙烯酸酯类化合物单体为 β-苯基氰基丙烯酸正丁酯或具 有式 (I)或式 (II)结构的化合物：
0
II
CH = CH-C— 0— CnH2n+1
CN
(I)
0
II
CH2=C— C— 0— CiiH2n+i
CN 其中， η≥6。
2. 根据权利要求 1所述的材料， 其特征在于， 所述氰基丙烯酸酯 类化合物单体为氰基丙烯酸正己酯或 2-氰基丙烯酸己酯。
3. 根据权利要求 1所述的材料， 其特征在于， 所述氰基丙烯酸酯 类化合物单体为氰基丙烯酸正辛酯。
4. 根据权利要求 1所述的材料， 其特征在于， 所述 η满足条件： 8 η 12。
5. 根据权利要求 1所述的材料， 其特征在于， 所述阻聚剂为间甲 氧基苯酚、 对苯二酚、 磷酸或二氧化硫。
6. 根据权利要求 1所述的材料，其特征在于，所述显影剂为金粉、 铂粉、 钽粉、 钛粉、 钨粉或硫酸钡。
7. 根据权利要求 1所述的材料， 其特征在于， 所述增塑剂为邻苯 二甲酸二甲酯、 邻苯二甲酸二乙酯、 邻苯二甲酸二丁酯、 邻苯二甲酸 丁苄酯、 苯甲酸酯或磷酸三甲酚酯。
8. —种液体栓塞材料的制备方法， 其特征在于， 包括： 将氰基丙烯酸酯类化合物单体通氩气吹洗纯化， 所述氰基丙烯酸 类化合物单体为 β-苯基氰基丙烯酸正丁酯或具有式 (I)或式 (II)结构的化 合物：
0
II
CH =CH-C— 0— CnH2n+1
CN
(I)
O II
CH2=C— C— O— CnH2n+1
CN
(Π)
其中， n≥6 ;
将增塑剂和阻聚剂溶于有机溶剂中， 用二氧化硫鼓泡， 得到第一 混合溶液；
将所述吹洗纯化的氰基丙烯酸酯类化合物单体加入到所述第一混 合溶液中， 混合均勾， 得到第二混合溶液；
向所述第二混合溶液中加入显影剂， 得到栓塞材料。
9. 根据权利要求 8所述的方法， 其特征在于， 所述 n满足条件： 8 n 12。
10. 根据权利要求 8 所述的方法， 其特征在于， 所述氰基丙烯酸 酯类化合物单体为氰基丙烯酸正辛酯。
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