WO2012025023A1 - 一种栓塞剂及其制备方法 - Google Patents

一种栓塞剂及其制备方法 Download PDF

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WO2012025023A1
WO2012025023A1 PCT/CN2011/078457 CN2011078457W WO2012025023A1 WO 2012025023 A1 WO2012025023 A1 WO 2012025023A1 CN 2011078457 W CN2011078457 W CN 2011078457W WO 2012025023 A1 WO2012025023 A1 WO 2012025023A1
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derivatives
embolic
degradable polymer
embolic agent
polymer
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PCT/CN2011/078457
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English (en)
French (fr)
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李�雨
康亚红
金巧蓉
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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Priority to EP11819398.6A priority Critical patent/EP2614846A4/en
Publication of WO2012025023A1 publication Critical patent/WO2012025023A1/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
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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

  • This invention relates to the field of materials, and more particularly to an embolic agent 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.
  • the impact of an aneurysm is time consuming and may cause damage to the aneurysm.
  • interventional surgery has been used to block and embolize aneurysms by implanting platinum springs into the cerebral aneurysm cavity.
  • the embolization rate of this method has been gradually replaced. Lower, easy to form a wide range of thrombosis and cause cerebral infarction.
  • the liquid embolic material includes a water-insoluble polymer, a cyanoacrylic substance, and the like.
  • 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, can be directly injected into the blood vessel through the microcatheter, and thus is mostly used in the field of endovascular treatment.
  • the embolic material formed by the liquid embolic material disclosed in the prior art has a large density after being solidified in the blood, and causes a large occupying effect when the aneurysm is completely embolized, causing great discomfort to the patient.
  • the technical problem to be solved by the present invention is to provide an embolic agent capable of alleviating the occupancy effect and a preparation method thereof.
  • the present invention provides an embolic agent comprising: a liquid embolic material, a degradable polymer, and a contrast agent.
  • the degradable polymer comprises polylactic acid, polyglycolide, polycaprolactone, polycaprolactone, polyanhydride, poly 1,2-propylene fumarate, polyphosphazene, L - tyrosine-derived polymers, polyorthoesters, amino acid polymers, chitin and its derivatives, chitosan and its derivatives, hyaluronic acid and its derivatives, chondroitin sulfate and its derivatives, collagen One or more of proteins and derivatives thereof, gelatin and its derivatives, agar and its derivatives, fibrin and its derivatives, and silk proteins and derivatives thereof.
  • the degradable polymer is polylactic acid.
  • the molar ratio of the liquid embolic material to the degradable polymer is from 1 to 20:10.
  • the molar ratio of the liquid embolic material to the degradable polymer is from 1 to 10:10.
  • the degradable polymer has a number average molecular weight of 10,000 to 100,000.
  • the number average molecular weight of the degradable polymer is from 50,000 to 80,000.
  • the contrast agent comprises:
  • One or more of iodide, terpenoid, strontium powder and gold powder are present.
  • the invention also provides a preparation method of an embolic agent, comprising:
  • a contrast agent is added to the first solution to obtain an embolic agent.
  • the degradable polymer comprises polylactic acid, polyglycolide, polycaprolactone, polycaprolactone, polyanhydride, poly 1,2-propylene fumarate, polyphosphazene, L - tyrosine-derived polymer, Polyorthoesters, amino acid polymers, chitin and its derivatives, chitosan and its derivatives, hyaluronic acid and its derivatives, chondroitin sulfate and its derivatives, collagen and its derivatives, gelatin and One or more of its derivatives, agar and its derivatives, fibrin and its derivatives, and silk proteins and their derivatives.
  • the present invention provides an embolic agent and a preparation method thereof, the embolic agent comprising a liquid embolic material, a degradable polymer and a contrast agent.
  • the embolic agent After the embolic agent is injected into the aneurysm cavity, it is solidified in the blood and stably filled in a predetermined area, thereby achieving the purpose of embolizing the aneurysm.
  • the embolic body due to the gradual degradation of the degradable polymer, the embolic body forms a porous structure system, which reduces the density of the embolic agent, thereby effectively alleviating the occupancy effect.
  • the resulting porous structure allows tissue cells to attach and grow thereon, promote cell differentiation and proliferation, and accelerate endothelialization of blood vessels, thereby effectively preventing blood recanalization that may occur after embolization.
  • the present invention discloses an embolic agent comprising: a liquid embolic material, a degradable polymer, and a photographic agent.
  • the liquid embolic material can be an adhesive embolic material or a non-adhesive embolic material.
  • the adhesive embolic material preferably includes a cyanoacrylic compound in which the cyanoacrylic compound is polymerized in the blood to form a permanent body to function as an embolism.
  • the non-adhesive liquid embolic material is preferably prepared by dissolving a water-insoluble macromolecular polymer in a water-soluble organic solvent. When contacted with a water-soluble solution, the polymer precipitates and acts as an embolism. effect.
  • the degradable polymer may be a synthetic degradable polymer or a natural degradable polymer, and the degradable polymer preferably includes polylactic acid, polyglycolide, polycaprolactone, polycaprolactone, polyanhydride, Poly(1,2-propylene fumarate), polyphosphazene, L-tyrosine-derived polymer, polyorthoester, amino acid polymer, chitin and its derivatives, chitosan and its derivatives , hyaluronic acid and its derivatives, chondroitin sulfate and its derivatives, collagen and its derivatives, gelatin and its derivatives, One or more of agar and its derivatives, fibrin and its derivatives, and silk proteins and their derivatives.
  • the number average molecular weight of the degradable polymer is preferably from 30,000 to 100,000, more preferably from 50,000 to 80,000, and most preferably from 55,000 to 65,000.
  • the liquid embolic material can be directly injected into the aneurysm cavity, and can be stably filled in a predetermined area after solidification in the blood, thereby achieving the purpose of embolizing the aneurysm.
  • the degradable polymer degrades into carbon dioxide and water, causing the plug to form a porous structure, greatly reducing the density of the plug. Therefore, the embolic agent of the present invention can reduce the density of the embolic body by gradual degradation of the degradable polymer, and alleviate the occupancy effect.
  • the resulting porous structure allows tissue cells to attach and grow thereon, promote cell differentiation and proliferation, and accelerate endothelialization of blood vessels, thereby effectively preventing blood recanalization that may occur after embolization.
  • the molar ratio of the liquid embolic material to the degradable polymer is preferably from 1 to 20:10, more preferably from 1 to 10:10.
  • the embolic agent 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 radio X-ray.
  • 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, 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 invention also provides a preparation method of an embolic agent, comprising:
  • a contrast agent is added to the first solution to obtain an embolic agent.
  • the temperature at which the degradable polymer is physically or chemically bonded to the liquid embolic material is preferably 40 to 80 ° C, more preferably 50 to 70 ° C.
  • the physical doping or chemical bonding of the degradable polymer with the liquid embolic material is preferably carried out under the protection of argon gas, preferably by agitation, and the mixing time is preferably from 1 to 12 h, more preferably from 2 to 10 h.
  • the addition of the contrast agent to the first solution is preferably carried out under the protection of argon gas, preferably by stirring, and the stirring time is not particularly limited, and the mixing is uniform.
  • the embolic agent is preferably placed in a container for sealing, sterilization, and storage.
  • 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
  • EVOL ethylene vinyl alcohol polymer
  • DMSO dimethyl sulfoxide
  • 3 g was added to the above solution.
  • the polylactic acid having a number average molecular weight of 150,000 is stirred at a temperature of 70 ° C in an argon atmosphere for 5 hours to obtain a homogenous solution; 30 g of cerium powder is added to the above-mentioned homogenous solution, and stirred until uniformly dispersed; Sealed and stored after sterilization.
  • DMSO dimethyl sulfoxide
  • Example 3 10 g of a cellulose acetate polymer (CAP) having a number average molecular weight of 60,000 was added to 100 ml of DMSO, and stirred at a temperature of 50 ° C in an argon atmosphere for 2 hours; and 3 g of a number average molecular weight of 150,000 was added to the solution. Ethyl lactide, stirred at a temperature of 70 ° C in an argon atmosphere for 5 hours to obtain a homogenous solution; add 30 g of strontium powder to the above-mentioned homogenous solution, stir until uniform dispersion; seal and extinguish in a container Store after the bacteria.
  • CAP cellulose acetate polymer
  • Example 5 Dispersing 3 g of polycaprolactone having a number average molecular weight of 10,000 in n-butyl cyanoacrylate (NBCA) monomer, stirred at argon atmosphere for 5 hours at 50 ° C to obtain a homogeneous solution; add 30 g of strontium powder to the above-mentioned homogenous solution, stir until dispersed, and sealed in a container Store after sterilization.
  • NBCA n-butyl cyanoacrylate
  • the present invention provides an embolic agent and a method of preparing the same, the embolic agent comprising a liquid embolic material, a degradable polymer, and a contrast agent.
  • Embolization agent into the aneurysm cavity After the inside, it solidifies in the blood and is stably filled in a predetermined area, thereby achieving the purpose of embolizing the aneurysm.
  • the degradable polymer is gradually degraded, the embolic body forms a porous structure system, and the density of the embolic agent is reduced, thereby effectively alleviating the occupancy effect.
  • the resulting porous structure allows tissue cells to attach and grow thereon, promote cell differentiation and proliferation, and accelerate endothelialization of blood vessels, thereby effectively preventing blood recanalization that may occur after embolization.

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Description

一种栓塞剂及其制备方法 本申请要求于 2010 年 8 月 27 日提交中国专利局、 申请号为 201010267116.3、 发明名称为"一种栓塞剂及其制备方法"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， 涉及一种栓塞剂及其制备方 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，通过植入白金弹簧圏至大脑动脉瘤腔内以封堵、栓塞动脉瘤已经渐渐 代替了传统的外科手术， 然而， 该方法栓塞率较低、 容易形成大范围的血 栓而引起大脑梗塞等。
目前，现有技术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。 液体栓塞材料包括非水溶性聚合物和氰基丙烯酸类物质 等。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， 因此多用于血管内治疗领域。然而，现有技术公开的液体栓塞材料在血液 中固化后形成的栓塞体密度较大，在将动脉瘤完全栓塞时造成了巨大的占 位效应， 造成病患极大的不适。 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可緩解占位效应的 栓塞剂及其制备方法。
本发明提供一种栓塞剂， 包括： 液体栓塞材料、 可降解聚合物和造影 剂。
优选的， 所述可降解聚合物包括聚乳酸、 聚乙交酯、 聚己内酯、 聚己 酸内酯、 聚酐、 聚 1,2-亚丙基富马酸酯、 聚膦腈、 L-酪氨酸衍生高分子、 聚原酸酯、 氨基酸类聚合物、 甲壳素及其衍生物、 壳聚糖及其衍生物、 透 明质酸及其衍生物、硫酸软骨素及其衍生物、胶原蛋白及其衍生物、 明胶 及其衍生物、琼脂及其衍生物、纤维蛋白及其衍生物和丝蛋白及其衍生物 中的一种或几种。
优选的， 所述可降解聚合物为聚乳酸。
优选的，所述液体栓塞材料与所述可降解聚合物的摩尔比为 1~20:10。 优选的，所述液体栓塞材料与所述可降解聚合物的摩尔比为 1~10:10。 优选的， 所述可降解聚合物的数均分子量为 10000~100000。
优选的， 所述可降解聚合物的数均分子量为 50000~80000。
优选的， 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。
本发明还提供一种栓塞剂的制备方法， 包括：
将可降解聚合物与液体栓塞材料进行物理掺杂或化学键合,得到第一 溶液；
向所述第一溶液中加入造影剂， 得到栓塞剂。
优选的， 所述可降解聚合物包括聚乳酸、 聚乙交酯、 聚己内酯、 聚己 酸内酯、 聚酐、 聚 1,2-亚丙基富马酸酯、 聚膦腈、 L-酪氨酸衍生高分子、 聚原酸酯、 氨基酸类聚合物、 甲壳素及其衍生物、 壳聚糖及其衍生物、 透 明质酸及其衍生物、硫酸软骨素及其衍生物、胶原蛋白及其衍生物、 明胶 及其衍生物、琼脂及其衍生物、纤维蛋白及其衍生物和丝蛋白及其衍生物 中的一种或几种。
从上述的技术方案可以看出， 本发明提供一种栓塞剂及其制备方法， 栓塞剂包括液体栓塞材料、可降解聚合物和造影剂。栓塞剂注入到动脉瘤 瘤腔内后， 在血液中固化， 稳定地填充在预定区域，从而达到栓塞动脉瘤 的目的。 并且， 由于可降解聚合物的逐步降解， 使栓塞体形成多孔结构体 系， 减少了栓塞剂的密度， 从而有效緩解占位效应。 此外， 这种最终形成 的多孔结构使得组织细胞在其上附着并生长， 促进细胞分化、增殖， 加速 血管内皮化， 从而有效地防止栓塞后可能发生的血液再通现象。 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。
本发明公开了一种栓塞剂， 包括： 液体栓塞材料、 可降解聚合物和造 影剂。
所述液体栓塞材料可以为黏附性栓塞材料或非粘附性栓塞材料。所述 黏附性的栓塞材料优选包括氰基丙烯酸类化合物，其中，所述氰基丙烯酸 类化合物在血液中聚合形成永久体而起到栓塞作用。所述非粘附性液体栓 塞材料优选由非水溶性的大分子聚合物溶于某种水溶性的有机溶剂中配 制而成的， 当与水溶性溶液接触时， 聚合物沉淀析出而起到栓塞作用。
所述可降解聚合物可以为合成可降解聚合物或天然可降解聚合物，所 述可降解聚合物优选包括聚乳酸、 聚乙交酯、 聚己内酯、 聚己酸内酯、 聚 酐、 聚 1,2-亚丙基富马酸酯、 聚膦腈、 L-酪氨酸衍生高分子、 聚原酸酯、 氨基酸类聚合物、 甲壳素及其衍生物、 壳聚糖及其衍生物、透明质酸及其 衍生物、硫酸软骨素及其衍生物、胶原蛋白及其衍生物、明胶及其衍生物、 琼脂及其衍生物、纤维蛋白及其衍生物和丝蛋白及其衍生物中的一种或几 种。 所述可降解聚合物的数均分子量优选为 30000~100000 , 更优选为 50000-80000, 最优选为 55000~65000。
按照本发明，所述液体栓塞材料可以直接注入动脉瘤瘤腔内，在血液 中固化后可稳定地填充在预定区域，从而达到栓塞动脉瘤的目的。可降解 聚合物降解为二氧化碳和水，使栓塞体形成多孔结构，极大地降低了栓塞 体的密度。 因此，本发明所述栓塞剂能够通过可降解聚合物的逐步降解来 减少栓塞体的密度， 緩解了占位效应。 此外， 这种最终形成的多孔结构使 得组织细胞在其上附着并生长， 促进细胞分化、 增殖， 加速血管内皮化， 从而有效地防止栓塞后可能发生的血液再通现象。
所述液体栓塞材料与所述可降解聚合物的摩尔比优选为 1~20: 10, 更 优选为 1~10:10。
本发明提供的栓塞剂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。
本发明还提供一种栓塞剂的制备方法， 包括：
将可降解聚合物与液体栓塞材料进行物理掺杂或化学键合,得到第一 溶液；
向所述第一溶液中加入造影剂， 得到栓塞剂。
按照本发明，所述可降解聚合物与液体栓塞材料物理掺杂或化学键合 的的温度优选为 40~80°C , 更优选为 50~70°C。 所述可降解聚合物与液体 栓塞材料物理掺杂或化学键合优选在氩气保护下进行,优选采用搅拌的方 式达到充分混合的目的， 搅拌时间优选为 l~12h, 更优选为 2~10h。 所述 向所述第一溶液中加入造影剂优选在氩气保护下进行 ,优选采用搅拌的方 式， 对于搅拌时间并无特别限制， 混合均匀即可。 按照本发明，所述得到栓塞剂后优选将栓塞剂装入容器中密封、灭菌 后存放。
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
将 10g数均分子量为 60000 的乙烯乙烯醇聚合物 （EVOL )加入到 100ml二甲亚砜（DMSO )中，在 50°C的温度下、氩气气氛中搅拌 2小时； 在上述溶液中加入 3g数均分子量为 150000的聚乳酸，在 70°C的温度下、 氩气气氛中搅拌 5 小时得到均勾的溶液； 在上述均勾的溶液中加入 30g 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
将 10g数均分子量为 60000 的醋酸纤维素聚合物 （CAP )加入到 lOOmlDMSO中， 在 50°C的温度下、 氩气气氛中搅拌 2小时； 在上述溶液 中加入 3g数均分子量为 150000的聚乙丙交酯， 在 70°C的温度下、 氩气 气氛中搅拌 5小时得到均勾的溶液； 在上述均勾的溶液中加入 30g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
将 10g数均分子量为 60000的甲基丙烯酸共聚物（Eudrsgit-E )加入 到 100ml 无水乙醇和碘普罗胺中， 在 50°C的温度下、 氩气气氛中搅拌 2 小时；在上述溶液中加入 3g数均分子量为 150000的聚羟基乙酸，在 70°C 的温度下、氩气气氛中搅拌 5小时得到均勾的溶液；在上述均勾的溶液中 加入 30g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
将 3g数均分子量为 10000 的聚己酸内酯分散在氰基丙烯酸正丁酯 ( NBCA )单体中， 在 50°C的温度下、 氩气气氛中搅拌 5 小时得到均匀 的溶液； 在上述均勾的溶液中加入 30g钽粉，搅拌直至分散均勾； 装入容 器中密封、 灭菌后存放。 实施例 5
将 2 mol硫酸软骨素加入 10g氰基丙烯酸正戊酯的单体中， 在室温 氩气气氛中搅拌 12 h,后经减压蒸馏， 得到均一的淡黄色溶液， 然后在上 述淡黄色溶液中加入 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 6
将 2 mol聚乙交酯加入 10g氰基丙烯酸正己酯的单体中，在室温氩气 气氛中搅拌 12 h,后经减压蒸馏， 得到均一的淡黄色溶液， 然后在上述淡 黄色溶液中加入 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
将 2 mol 聚乳酸加入 10g氰基丙烯酸正辛酯的单体中， 在室温氩气 气氛中搅拌 12 h,后经减压蒸馏， 得到均一的淡黄色溶液， 然后在上述淡 黄色溶液中加入 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。 将实施例 1~7 制备的栓塞剂注入现取的新鲜血液中， 立即析出海绵 状沉淀， 沉淀由内向外逐渐变牢固、 密集， 并且， 随着可降解聚合物的逐 步降解， 最终形成多孔结构的沉淀物。将所述海绵状聚合物取出， 手感柔 软。 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剂能够 迅速固化， 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，本发明提供一种栓塞剂及其制备方法，栓塞 剂包括液体栓塞材料、可降解聚合物和造影剂。栓塞剂注入到动脉瘤瘤腔 内后， 在血液中固化，稳定地填充在预定区域， 从而达到栓塞动脉瘤的目 的。 并且， 由于可降解聚合物得逐步降解， 使栓塞体形成多孔结构体系， 减少了栓塞剂的密度， 从而有效緩解占位效应。 此外， 这种最终形成的多 孔结构使得组织细胞在其上附着并生长， 促进细胞分化、增殖， 加速血管 内皮化， 从而有效地防止栓塞后可能发生的血液再通现象。
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、 一种栓塞剂， 其特征在于， 包括： 液体栓塞材料、 可降解聚合物 和造影剂。
2、 根据权利要求 1所述的栓塞剂， 其特征在于， 所述可降解聚合物 包括聚乳酸、 聚乙交酯、 聚己内酯、 聚己酸内酯、 聚酐、 聚 1,2-亚丙基富 马酸酯、 聚膦腈、 L-酪氨酸衍生高分子、 聚原酸酯、 氨基酸类聚合物、 甲 壳素及其衍生物、 壳聚糖及其衍生物、透明质酸及其衍生物、硫酸软骨素 及其衍生物、 胶原蛋白及其衍生物、 明胶及其衍生物、 琼脂及其衍生物、 纤维蛋白及其衍生物和丝蛋白及其衍生物中的一种或几种。
3、 根据权利要求 2所述的栓塞剂， 其特征在于， 所述可降解聚合物 为聚乳酸。
4、 根据权利要求 1所述的栓塞剂， 其特征在于， 所述液体栓塞材料 与所述可降解聚合物的摩尔比为 1~20:10。
5、 根据权利要求 4所述的栓塞剂， 其特征在于， 所述液体栓塞材料 与所述可降解聚合物的摩尔比为 1~10:10。
6、 根据权利要求 1~5任意一项所述的栓塞剂， 其特征在于， 所述可 降解聚合物的数均分子量为 10000~100000。
7、 根据权利要求 6所述的栓塞剂， 其特征在于， 所述可降解聚合物 的数均分子量为 50000~80000。
8、 根据权利要求 1~5任意一项所述的栓塞剂， 其特征在于， 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。
9、 一种栓塞剂的制备方法， 其特征在于， 包括：
将可降解聚合物与液体栓塞材料进行物理掺杂或化学键合,得到第一 溶液；
向所述第一溶液中加入造影剂， 得到栓塞剂。
10、根据权利要求 9所述的制备方法， 其特征在于， 所述可降解聚合 物包括聚乳酸、 聚乙交酯、 聚己内酯、 聚己酸内酯、 聚酐、 聚 1,2-亚丙基 富马酸酯、 聚膦腈、 L-酪氨酸衍生高分子、 聚原酸酯、 氨基酸类聚合物、 甲壳素及其衍生物、 壳聚糖及其衍生物、透明质酸及其衍生物、硫酸软骨 素及其衍生物、胶原蛋白及其衍生物、明胶及其衍生物、琼脂及其衍生物、 纤维蛋白及其衍生物和丝蛋白及其衍生物中的一种或几种。
PCT/CN2011/078457 2010-08-27 2011-08-16 一种栓塞剂及其制备方法 WO2012025023A1 (zh)

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