CN103550834B - Embolism material composition as well as preparation method and use thereof - Google Patents

Embolism material composition as well as preparation method and use thereof Download PDF

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CN103550834B
CN103550834B CN201310512955.0A CN201310512955A CN103550834B CN 103550834 B CN103550834 B CN 103550834B CN 201310512955 A CN201310512955 A CN 201310512955A CN 103550834 B CN103550834 B CN 103550834B
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polyvinyl alcohol
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inorganic salt
embolic material
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范田园
卢晓静
孟文静
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Hygea Medical Technology Co Ltd
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Peking University
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Abstract

本发明提供一种栓塞材料组合物及其制备方法和用途,该栓塞材料组合物由反应物原料制成,所述反应物原料包含:生物相容性材料、不透X射线的物质及磁共振成像物质,所述栓塞材料组合物中,不透X射线的物质和磁共振成像物质被生物相容性材料所包裹。本发明的栓塞材料组合物不仅能被X射线影像设备直接检测,而且能被MRI直接检测,便于医生根据患者自身条件及医疗设备条件选择检测方法。

The invention provides an embolic material composition and its preparation method and application. The embolic material composition is made of reactant raw materials, and the reactant raw materials include: biocompatible materials, X-ray-opaque substances and magnetic resonance Imaging substances, in the embolic material composition, X-ray-opaque substances and magnetic resonance imaging substances are wrapped by biocompatible materials. The embolic material composition of the present invention can not only be directly detected by X-ray imaging equipment, but also can be directly detected by MRI, which is convenient for doctors to choose a detection method according to the patient's own conditions and medical equipment conditions.

Description

一种栓塞材料组合物及其制备方法和用途A kind of embolic material composition and its preparation method and application

技术领域technical field

本发明属于介入医学领域,具体涉及一种栓塞材料组合物及其制备方法和用途。The invention belongs to the field of interventional medicine, and in particular relates to an embolic material composition, a preparation method and application thereof.

背景技术Background technique

介入栓塞治疗是指在医学影像设备的引导下,将栓塞剂通过特制的导丝、导管等精密器械,引入人体进行局部治疗。栓塞疗法已经在治疗子宫肌瘤、肝癌、肾癌、血管瘤、血管畸形和止血等方面取得了很好的疗效,成为部分手术治疗的替代疗法。Interventional embolization therapy refers to the introduction of embolic agents into the human body through precision instruments such as special guide wires and catheters for local treatment under the guidance of medical imaging equipment. Embolization therapy has achieved good results in the treatment of uterine fibroids, liver cancer, kidney cancer, hemangioma, vascular malformation and hemostasis, and has become an alternative to partial surgical treatment.

目前临床应用的栓塞剂,如聚乙烯醇不规则颗粒型或微球型栓塞剂、明胶海绵不规则颗粒型或微球型栓塞剂等均不能被X射线影像设备(包括数字剪影造影机(Digital Subtraction Angiography,DSA)和计算机断层扫描(Computed Tomography,CT))以及磁共振成像(Magnetic ResonanceImaging,MRI)直接检测。实际应用中,只能通过DSA检查造影剂的流动而间接推断栓塞剂所在的位置和栓塞终点。最近一项临床研究表明,通过这种方法判断子宫动脉被完全栓塞的病例中,有20%并没有达到完全栓塞,术后的MRI检查显示这些病人的部分子宫动脉仍然有血供。因此,这种间接判断方法并不能及时、准确地判断栓塞剂所在的位置及栓塞终点,影响了栓塞治疗的疗效和安全性。Currently clinically used embolic agents, such as polyvinyl alcohol irregular particles or microspheres, gelatin sponge irregular particles or microspheres, etc., cannot be detected by X-ray imaging equipment (including digital Subtraction Angiography, DSA) and computed tomography (Computed Tomography, CT)) and magnetic resonance imaging (Magnetic Resonance Imaging, MRI) direct detection. In practice, the location of the embolic agent and the end point of embolization can only be inferred indirectly by checking the flow of the contrast agent with DSA. A recent clinical study showed that 20% of the cases where the uterine artery was completely embolized by this method did not achieve complete embolization, and postoperative MRI examinations showed that some of the uterine arteries in these patients still had blood supply. Therefore, this indirect judgment method cannot timely and accurately judge the location of the embolic agent and the end point of embolization, which affects the efficacy and safety of embolization therapy.

为了能够对栓塞剂进行X射线影像设备下的直接检测,现有技术中公开了一些不透X射线的栓塞材料,然而X射线检查存在电离辐射,尤其不利于对年轻女性进行子宫肌瘤的栓塞及复查。In order to be able to directly detect embolic agents under X-ray imaging equipment, some X-ray-opaque embolic materials are disclosed in the prior art, but X-ray examinations have ionizing radiation, which is especially unfavorable for embolization of uterine fibroids in young women and review.

磁共振成像(MRI)是近几十年来发展起来的一种新型医疗诊断手段,是一种安全、快速、准确的临床诊断方法。适用于多种疾病的诊断,包括诊断一些适于栓塞治疗的疾病,如:动静脉畸形、肝癌及子宫肌瘤等。MRI具有较高的空间和时间分辨率,优良的正常组织和病变组织间的对比度,与X射线检测技术相比没有电离辐射,并且已经发展到能够实时采集高分辨率图像的程度。但MRI的缺陷在于不能用于体内装有电、磁及机械有源植入物(如心脏起搏器、神经刺激器、耳蜗植入体或金属义眼等)的患者。Magnetic resonance imaging (MRI) is a new medical diagnostic method developed in recent decades, and it is a safe, fast and accurate clinical diagnosis method. It is suitable for the diagnosis of various diseases, including some diseases suitable for embolization therapy, such as: arteriovenous malformation, liver cancer and uterine fibroids. MRI has high spatial and temporal resolution, excellent contrast between normal tissue and diseased tissue, no ionizing radiation compared with X-ray detection technology, and has been developed to the extent that it can acquire high-resolution images in real time. However, the disadvantage of MRI is that it cannot be used in patients with electrically, magnetically and mechanically active implants in the body (such as cardiac pacemakers, neurostimulators, cochlear implants or metal prosthetic eyes, etc.).

因此,如何提供一种既能被X射线影像设备直接检测又能被MRI直接检测的栓塞材料以便为患者提供更多的选择,成为本领域亟待解决的问题。Therefore, how to provide an embolic material that can be directly detected by both X-ray imaging equipment and MRI so as to provide patients with more choices has become an urgent problem to be solved in this field.

发明内容Contents of the invention

针对上述问题,本发明的一个目的在于提供一种栓塞材料组合物,该栓塞材料组合物不仅能被X射线影像设备直接检测,而且能被MRI直接检测,便于医生根据患者自身条件及医疗设备条件选择检测方法。In view of the above problems, an object of the present invention is to provide an embolic material composition, which can not only be directly detected by X-ray imaging equipment, but also can be directly detected by MRI. Select a detection method.

本发明的另一目的在于提供一种栓塞材料组合物的制备方法。Another object of the present invention is to provide a preparation method of an embolic material composition.

本发明的再一目的在于提供一种栓塞材料组合物的用途。Another object of the present invention is to provide an application of an embolic material composition.

为达到上述目的,本发明提供一种栓塞材料组合物,其由反应物原料制成,所述反应物原料包含:生物相容性材料、不透X射线的物质及磁共振成像物质,所述栓塞材料组合物中,不透X射线的物质和磁共振成像物质被生物相容性材料所包裹。In order to achieve the above object, the present invention provides an embolic material composition, which is made of reactant raw materials, said reactant raw materials include: biocompatible materials, X-ray-opaque substances and magnetic resonance imaging substances, said In the embolic material composition, the X-ray opaque material and the magnetic resonance imaging material are surrounded by a biocompatible material.

进一步地,所述反应物原料包含:1重量份生物相容性材料、0.5-10重量份不透X射线的物质、0.2-5重量份磁共振成像物质及0-6重量份药物;其中,所述药物被生物相容性材料所包裹。Further, the reactant raw materials include: 1 part by weight of biocompatible materials, 0.5-10 parts by weight of X-ray-opaque substances, 0.2-5 parts by weight of magnetic resonance imaging substances, and 0-6 parts by weight of drugs; wherein, The drug is encapsulated by biocompatible material.

进一步地,所述栓塞材料组合物为球形和不规则形状的微粒,优选微囊或微球;Further, the embolic material composition is spherical and irregularly shaped particles, preferably microcapsules or microspheres;

优选地,所述微粒的粒径为10-2000μm,可根据实际需要,选择微粒的粒径为50-100μm、100-300μm、300-500μm、500-700μm、700-900μm、900-1200μm或1200-1500μm等。Preferably, the particle size of the particles is 10-2000 μm, and the particle size of the particles can be selected as 50-100 μm, 100-300 μm, 300-500 μm, 500-700 μm, 700-900 μm, 900-1200 μm or 1200 μm according to actual needs. -1500μm etc.

进一步地,所述生物相容性材料选自聚乙烯醇、海藻酸、海藻酸盐、壳聚糖、明胶、阿拉伯胶、淀粉、淀粉衍生物、纤维素、纤维素衍生物、聚乳酸或由乳酸与羟基乙酸形成的共聚物等中的一种或多种;Further, the biocompatible material is selected from polyvinyl alcohol, alginic acid, alginate, chitosan, gelatin, gum arabic, starch, starch derivatives, cellulose, cellulose derivatives, polylactic acid or One or more of the copolymers of lactic acid and glycolic acid;

优选地,所述不透X射线的物质选自不透X射线的油状液体或不透X射线的固体中的一种或两种,优选不透X射线的油状液体,更优选碘化油或碘苯酯中的一种或两种;所述不透X射线的固体选自钽粉或硫酸钡中的一种或两种;Preferably, the X-ray-opaque substance is selected from one or both of X-ray-opaque oily liquids or X-ray-opaque solids, preferably X-ray-opaque oily liquids, more preferably iodized oil or One or both of iodophenyl esters; the X-ray-opaque solid is selected from one or both of tantalum powder or barium sulfate;

优选地,所述磁共振成像物质选自磁性金属元素铁、钆、锰、镍、钴、钬、铕、铽、镝、铥或镱的化合物中的一种或多种;优选地,所述磁共振成像物质选自磁性金属元素铁、钆、锰、镍、钴、钬、铕、铽、镝、铥或镱的氧化物中的一种或多种,更优选Fe3O4、Fe2O3、MnFe2O4、CoFe2O4、NiFe2O4、DyFe2O4或钬、钆、铕、铽、镝、铥或镱的氧化物中的一种或多种;所述氧化物优选为纳米粒子;更优选地,所述磁共振成像物质选自四氧化三铁或三氧化二铁中的一种或两种,所述三氧化二铁优选γ三氧化二铁。Preferably, the magnetic resonance imaging substance is selected from one or more of the compounds of magnetic metal elements iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium; preferably, the The magnetic resonance imaging substance is selected from one or more of the oxides of magnetic metal elements iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, more preferably Fe 3 O 4 , Fe 2 O 3 , MnFe 2 O 4 , CoFe 2 O 4 , NiFe 2 O 4 , DyFe 2 O 4 or one or more of the oxides of holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium; the oxide The substance is preferably a nanoparticle; more preferably, the magnetic resonance imaging substance is selected from one or both of ferric oxide and ferric oxide, and the ferric oxide is preferably gamma ferric oxide.

进一步地,所述生物相容性材料为聚乙烯醇,优选地,所述聚乙烯醇的平均分子量为1,000-500,000D,优选10,000-150,000D;醇解度为50-100%,优选75-100%;Further, the biocompatible material is polyvinyl alcohol, preferably, the average molecular weight of the polyvinyl alcohol is 1,000-500,000D, preferably 10,000-150,000D; the degree of alcoholysis is 50-100%, preferably 75- 100%;

优选地,所述栓塞材料组合物为聚乙烯醇栓塞微囊,所述聚乙烯醇栓塞微囊的反应物原料包含:1重量份聚乙烯醇、0.5-7.5重量份不透X射线的物质、0.2-5重量份磁共振成像物质、1-5.5重量份无机盐、4-15重量份交联剂、0.9-13.1重量份催化剂及0-3重量份药物;Preferably, the embolic material composition is polyvinyl alcohol embolic microcapsules, and the reactant raw materials of the polyvinyl alcohol embolic microcapsules include: 1 part by weight of polyvinyl alcohol, 0.5-7.5 parts by weight of X-ray-opaque substances, 0.2-5 parts by weight of magnetic resonance imaging substances, 1-5.5 parts by weight of inorganic salts, 4-15 parts by weight of cross-linking agents, 0.9-13.1 parts by weight of catalysts and 0-3 parts by weight of drugs;

优选地,所述栓塞材料组合物为聚乙烯醇栓塞微囊,所述聚乙烯醇栓塞微囊反应物原料包含:1重量份聚乙烯醇、1-6.5重量份不透X射线物质、0.7-4.5重量份磁共振成像物质、2.5-3.5重量份无机盐、6-11重量份交联剂、5.8-13.1重量份催化剂及0.5-1.5重量份药物;Preferably, the embolic material composition is polyvinyl alcohol embolic microcapsules, and the reactant raw materials of the polyvinyl alcohol embolic microcapsules include: 1 part by weight of polyvinyl alcohol, 1-6.5 parts by weight of X-ray opaque substances, 0.7- 4.5 parts by weight of magnetic resonance imaging substances, 2.5-3.5 parts by weight of inorganic salts, 6-11 parts by weight of crosslinking agents, 5.8-13.1 parts by weight of catalysts and 0.5-1.5 parts by weight of drugs;

优选地,所述栓塞材料组合物为聚乙烯醇栓塞微球,所述聚乙烯醇栓塞微球的反应物原料包含:1重量份聚乙烯醇、2-8重量份不透X射线的物质及0.5-4重量份磁共振成像物质、0.015-0.31重量份无机盐、0.6-2.3重量份交联剂、0.5-1.8重量份催化剂、0.1-2.5重量份表面活性剂、5-60重量份与水不互溶的有机溶剂及0-6重量份药物;Preferably, the embolic material composition is polyvinyl alcohol embolic microspheres, and the reactant raw materials of the polyvinyl alcohol embolic microspheres include: 1 part by weight of polyvinyl alcohol, 2-8 parts by weight of X-ray-opaque substances and 0.5-4 parts by weight of magnetic resonance imaging material, 0.015-0.31 parts by weight of inorganic salt, 0.6-2.3 parts by weight of crosslinking agent, 0.5-1.8 parts by weight of catalyst, 0.1-2.5 parts by weight of surfactant, 5-60 parts by weight of water An immiscible organic solvent and 0-6 parts by weight of medicine;

优选地,所述栓塞材料组合物为聚乙烯醇栓塞微球,所述聚乙烯醇栓塞微球的反应物原料包含:1重量份聚乙烯醇、6-8重量份不透X射线的物质、1-4重量份磁共振成像物质、0.15-0.31重量份无机盐、0.6-1.2重量份交联剂、0.8-1.5重量份催化剂、0.6-2重量份表面活性剂、10-50重量份与水不互溶的有机溶剂及2-6重量份药物。Preferably, the embolic material composition is polyvinyl alcohol embolic microspheres, and the reactant raw materials of the polyvinyl alcohol embolic microspheres include: 1 part by weight of polyvinyl alcohol, 6-8 parts by weight of X-ray-opaque substances, 1-4 parts by weight of magnetic resonance imaging material, 0.15-0.31 parts by weight of inorganic salt, 0.6-1.2 parts by weight of crosslinking agent, 0.8-1.5 parts by weight of catalyst, 0.6-2 parts by weight of surfactant, 10-50 parts by weight of water An immiscible organic solvent and 2-6 parts by weight of medicine.

进一步地,所述生物相容性材料为明胶;优选地,所述栓塞材料组合物为明胶栓塞微囊,所述明胶栓塞微囊的反应物原料包含:1重量份明胶、1-9.5重量份不透X射线的物质、0.5-5重量份磁共振成像物质、0.3-1.5重量份交联剂及0-4.5重量份药物;Further, the biocompatible material is gelatin; preferably, the embolic material composition is gelatin embolization microcapsules, and the reactant raw materials of the gelatin embolization microcapsules include: 1 weight part gelatin, 1-9.5 weight parts X-ray-opaque substances, 0.5-5 parts by weight of magnetic resonance imaging materials, 0.3-1.5 parts by weight of cross-linking agents and 0-4.5 parts by weight of drugs;

优选地,所述栓塞材料组合物为明胶栓塞微囊,所述明胶栓塞微囊的反应物原料包含:1重量份明胶、2-3.5重量份不透X射线的物质、0.8-3重量份磁共振成像物质、1.1-1.5重量份交联剂及0.5-4.5重量份药物;Preferably, the embolic material composition is a gelatin embolic microcapsule, and the reactant raw materials of the gelatin embolic microcapsule include: 1 part by weight of gelatin, 2-3.5 parts by weight of X-ray-opaque substances, 0.8-3 parts by weight of magnetic resonance imaging substance, 1.1-1.5 parts by weight of cross-linking agent and 0.5-4.5 parts by weight of drug;

优选地,所述栓塞材料组合物为明胶栓塞微球,所述明胶栓塞微球的反应物原料包含:1重量份明胶、0.8-8重量份不透X射线的物质、0.3-3.5重量份磁共振成像物质、0.1-3.7重量份交联剂、0.1-3.13重量份表面活性剂、5-50重量份与水不互溶的有机溶剂及0-4.5重量份药物;Preferably, the embolic material composition is gelatin embolic microspheres, and the reactant raw materials of the gelatin embolic microspheres include: 1 part by weight of gelatin, 0.8-8 parts by weight of X-ray-opaque substances, 0.3-3.5 parts by weight of magnetic Resonance imaging material, 0.1-3.7 parts by weight of cross-linking agent, 0.1-3.13 parts by weight of surfactant, 5-50 parts by weight of organic solvent immiscible with water, and 0-4.5 parts by weight of drug;

优选地,所述栓塞材料组合物为明胶栓塞微球,所述明胶栓塞微球的反应物原料包含:1重量份明胶、0.8-2.2重量份不透X射线的物质、0.5-3.5重量份磁共振成像物质、0.7-3.7重量份交联剂、0.39-1.87重量份表面活性剂、10-40重量份与水不互溶的有机溶剂及0.5-4.5重量份药物。Preferably, the embolic material composition is gelatin embolic microspheres, and the reactant raw materials of the gelatin embolic microspheres include: 1 part by weight of gelatin, 0.8-2.2 parts by weight of X-ray-opaque substances, 0.5-3.5 parts by weight of magnetic Resonance imaging material, 0.7-3.7 parts by weight of cross-linking agent, 0.39-1.87 parts by weight of surfactant, 10-40 parts by weight of organic solvent immiscible with water and 0.5-4.5 parts by weight of medicine.

进一步地,所述生物相容性材料为壳聚糖和羧甲基纤维素钠的混合物;Further, the biocompatible material is a mixture of chitosan and sodium carboxymethylcellulose;

所述栓塞材料组合物为壳聚糖-羧甲基纤维素栓塞微囊,所述壳聚糖-羧甲基纤维素栓塞微囊的反应物原料包含:1重量份生物相容性材料、4-10重量份不透X射线的油状液体及0.5-5重量份磁共振成像物质、0.2-0.8重量份交联剂及0-4.5重量份药物。The embolic material composition is a chitosan-carboxymethylcellulose embolization microcapsule, and the reactant raw material of the chitosan-carboxymethylcellulose embolization microcapsule comprises: 1 part by weight of a biocompatible material, 4 - 10 parts by weight of an X-ray-opaque oily liquid, 0.5-5 parts by weight of a magnetic resonance imaging substance, 0.2-0.8 parts by weight of a cross-linking agent, and 0-4.5 parts by weight of a drug.

优选地,用于制备聚乙烯醇栓塞微球的无机盐选自水溶性钠盐、钾盐或铵盐中的一种或多种;优选氯化钾、氯化钠或氯化铵等中的一种或多种,更优选氯化钠;用于制备聚乙烯醇栓塞微囊的无机盐选自硫酸盐、磷酸盐、硅酸盐或醋酸盐中的一种或多种,优选硫酸钠、硫酸铝、硫酸铵、三聚磷酸钠等中的一种或两种,更优选硫酸钠;Preferably, the inorganic salt used to prepare polyvinyl alcohol embolization microspheres is selected from one or more of water-soluble sodium salts, potassium salts or ammonium salts; preferably potassium chloride, sodium chloride or ammonium chloride, etc. One or more, more preferably sodium chloride; the inorganic salt used to prepare polyvinyl alcohol embolism microcapsules is selected from one or more of sulfate, phosphate, silicate or acetate, preferably sodium sulfate , one or both of aluminum sulfate, ammonium sulfate, sodium tripolyphosphate, etc., more preferably sodium sulfate;

优选地,所述交联剂选自甲醛、乙醛、丁醛、戊二醛或己二醛等中的一种或多种;所述催化剂选自盐酸、硫酸、磷酸、甲酸或醋酸等中的一种或多种;Preferably, the crosslinking agent is selected from one or more of formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or adipaldehyde; the catalyst is selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid or acetic acid, etc. one or more of

优选地,所述表面活性剂选自司盘类表面活性剂或由司盘类表面活性剂与吐温类表面活性剂组成的混合物中的一种或两种,优选司盘80或司盘85中的一种或两种;Preferably, the surfactant is selected from one or both of Span-type surfactants or a mixture of Span-type surfactants and Tween-type surfactants, preferably Span 80 or Span 85 one or both of

所述栓塞微球在与水不互溶的有机溶剂中制备,所述与水不互溶的有机溶剂选自矿物油、植物油、硅油、烯烃、醇、醛、胺、醚、酮、萜烯烃、卤代烃、杂环化物、含氮化合物或含硫化合物等中的一种或多种,优选液体石蜡或环己烷;The embolization microspheres are prepared in a water-immiscible organic solvent selected from mineral oil, vegetable oil, silicone oil, olefin, alcohol, aldehyde, amine, ether, ketone, terpene hydrocarbon, halogen One or more of substituted hydrocarbons, heterocyclic compounds, nitrogen-containing compounds or sulfur-containing compounds, preferably liquid paraffin or cyclohexane;

优选地,所述药物选自抗肿瘤药物、局麻药物、解热镇痛抗炎药物或抗生素药物等中的一种或多种;Preferably, the drug is selected from one or more of antineoplastic drugs, local anesthetic drugs, antipyretic and analgesic anti-inflammatory drugs or antibiotic drugs;

优选地,所述抗肿瘤药物选自阿霉素、表阿霉素、柔红霉素、丝裂霉素、甲氨喋呤、博来霉素、顺铂、卡铂、伊立替康、紫杉醇、多西紫杉醇、5-氟尿嘧啶、平阳霉素、舒尼替尼(Sunitinib)、索拉非尼(Sorafenib)、吉非替尼(Gefitinib)、伊马替尼(Imatinib)、瓦他拉尼(Vatalanib)或其盐等中的一种或多种;Preferably, the antineoplastic drug is selected from doxorubicin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel , docetaxel, 5-fluorouracil, pingyangmycin, sunitinib, sorafenib, gefitinib, imatinib, vatalanib ( Vatalanib) or its salts, etc.;

优选地,所述局麻药物选自普鲁卡因、氯普鲁卡因、羟普鲁卡因、丁卡因、对乙氧卡因、徒托卡因、二甲卡因、利多卡因、三甲卡因、丙胺卡因、甲哌卡因、布比卡因、罗哌卡因、辛可卡因、达克罗宁、法力卡因、奎尼卡因、非那卡因或其盐等中的一种或多种;Preferably, the local anesthetic is selected from the group consisting of procaine, chloroprocaine, hydroxyprocaine, tetracaine, p-ethoxycaine, tutocaine, methocaine, lidocaine , trimethylcaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, dibucaine, dyclonine, manacaine, quinicaine, phenacaine or its salts, etc. one or more of

优选地,所述解热镇痛抗炎药物选自阿司匹林、水杨酸镁、水杨酸钠、水杨酸胆碱镁、二氟尼柳、双水杨酸酯、布洛芬、吲哚美辛、氟比布洛芬、苯氧基布洛芬、萘普生、萘丁美酮、吡罗昔康、保泰松、对乙酰氨基酚、双氯灭痛、芬洛芬、酮基布洛芬、酮咯酸、四氯芬那酸、舒林酸或托美丁等中的一种或多种;Preferably, the antipyretic, analgesic and anti-inflammatory drugs are selected from aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, salicylate, ibuprofen, indole Maximin, flurbiprofen, phenoxyibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, acetaminophen, diclofenac, fenprofen, ketoprofen, ketoprofen One or more of tetraclofenamic acid, sulindac or tolmetin;

优选地,所述抗生素药物选自β-内酰胺类抗生素(例如青霉素、苯唑西林钠、氨苄西林钠、阿莫西林、头孢哌酮、头孢噻肟钠、氨曲南、克拉维酸或舒巴坦)、四环素类抗生素(例如土霉素、四环素或地美环素)、氨基糖苷类抗生素(链霉素、卡那霉素A、庆大霉素、妥布霉素、西索米星、阿米卡星、地贝卡星、异帕米星、核糖霉素、卡那霉素B、新霉素B或巴龙霉素)、大环内酯类抗生素(例如红霉素、罗红霉素、克拉霉素或阿奇霉素)或其他抗生素(例如氯霉素、环孢素或林可霉素)或其盐等中的一种或多种。Preferably, the antibiotic drug is selected from β-lactam antibiotics (such as penicillin, oxacillin sodium, ampicillin sodium, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid or bactam), tetracyclines (such as oxytetracycline, tetracycline, or demeclocycline), aminoglycosides (streptomycin, kanamycin A, gentamicin, tobramycin, sisomicin , amikacin, dibekacin, isopamicin, ribomycin, kanamycin B, neomycin B, or paromomycin), macrolide antibiotics (such as erythromycin, erythromycin, clarithromycin, or azithromycin) or one or more of other antibiotics (such as chloramphenicol, cyclosporine, or lincomycin) or their salts.

本发明的栓塞材料组合物可以保存在生理盐水或磷酸缓冲液中,或冻干保存。The embolic material composition of the present invention can be stored in physiological saline or phosphate buffer, or freeze-dried.

本发明的栓塞材料组合物的使用方法与普通栓塞剂的使用方法相同。The method of using the embolic material composition of the present invention is the same as that of common embolic agents.

本发明进一步提供上述栓塞材料组合物的制备方法,所述制备方法包括以下步骤:The present invention further provides a preparation method of the above embolic material composition, the preparation method comprising the following steps:

步骤a:将生物相容性材料配制成溶液;Step a: preparing the biocompatible material into a solution;

步骤b:将不透X射线的物质、磁共振成像物质及可选的药物加入到步骤a的溶液中;优选地,当不透X射线的物质为油状液体时,将药物和/或磁共振成像物质分散在不透X射线的物质中,得到混合液,再将该混合液加入到步骤a的溶液中;Step b: adding X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the solution of step a; preferably, when the X-ray-opaque substances are oily liquids, the drugs and/or magnetic resonance The imaging material is dispersed in the X-ray-opaque material to obtain a mixed solution, and then the mixed solution is added to the solution in step a;

步骤c:采用物理化学法、物理机械法或化学法使生物相容性材料发生聚合,得到栓塞材料组合物。Step c: Polymerize the biocompatible material by physical chemical method, physical mechanical method or chemical method to obtain an embolism material composition.

进一步地,所述栓塞材料组合物为聚乙烯醇栓塞微囊,所述聚乙烯醇栓塞微囊采用以下方法制备:Further, the embolic material composition is polyvinyl alcohol embolic microcapsules, and the polyvinyl alcohol embolic microcapsules are prepared by the following method:

步骤a1:称取配方量的聚乙烯醇,配制成0.0035-0.05g/ml,优选0.025-0.04g/ml,更优选0.025g/ml的聚乙烯醇溶液;Step a1: Weigh the polyvinyl alcohol of formula quantity, prepare the polyvinyl alcohol solution of 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, more preferably 0.025g/ml;

步骤b1:将不透X射线的物质、磁共振成像物质及可选的药物加入到步骤a1的聚乙烯醇溶液中,搅拌,得到混合液;Step b1: adding X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the polyvinyl alcohol solution in step a1, and stirring to obtain a mixed solution;

步骤c1:称取配方量的无机盐,配制成0.1-0.4g/ml,优选0.21-0.29g/ml,更优选0.25g/ml的无机盐溶液,在低于该条件下聚乙烯醇溶液的浊点温度,优选低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下将无机盐溶液加入到步骤b1的混合液中,继续搅拌并缓慢升温,当温度升高至浊点温度时,加入交联剂和催化剂,恒温固化15-23h,优选固化21-23h,更优选固化22h,过滤、洗涤后得到聚乙烯醇栓塞微囊;或,Step c1: Take the inorganic salt of formula quantity, be mixed with the inorganic salt solution of 0.1-0.4g/ml, preferably 0.21-0.29g/ml, more preferably 0.25g/ml, under this condition, the polyvinyl alcohol solution Cloud point temperature, preferably at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition, add the inorganic salt solution to the mixed solution in step b1, continue to stir and slowly heat up, when the temperature rises to When the cloud point temperature is reached, add a crosslinking agent and a catalyst, and cure at a constant temperature for 15-23 hours, preferably for 21-23 hours, more preferably for 22 hours, and obtain polyvinyl alcohol embolism microcapsules after filtering and washing; or,

所述聚乙烯醇栓塞微囊采用以下方法制备:The polyvinyl alcohol embolic microcapsules are prepared by the following method:

步骤a2:称取配方量的聚乙烯醇,配制成0.0035-0.05g/ml,优选0.025-0.04g/ml,更优选0.025g/ml的聚乙烯醇溶液;Step a2: Weigh the polyvinyl alcohol of formula quantity, prepare the polyvinyl alcohol solution of 0.0035-0.05g/ml, preferably 0.025-0.04g/ml, more preferably 0.025g/ml;

步骤b2:称取配方量的无机盐,配制成0.1-0.4g/ml,优选0.21-0.29g/ml,更优选0.25g/ml的无机盐溶液,将无机盐溶液与步骤a2中的聚乙烯醇溶液混合,随后加入不透X射线的物质、磁共振成像物质及可选的药物,在低于该条件下聚乙烯醇溶液的浊点温度,优选低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下搅拌,得到混合液;Step b2: Take the inorganic salt of formula quantity, prepare the inorganic salt solution of 0.1-0.4g/ml, preferably 0.21-0.29g/ml, more preferably 0.25g/ml, mix the inorganic salt solution with the polyethylene in step a2 Alcohol solution is mixed, then add X-ray opaque material, magnetic resonance imaging material and optional drug, the cloud point temperature is lower than the polyvinyl alcohol solution under this condition, preferably lower than the cloud point temperature of the polyvinyl alcohol solution under this condition Stir at a water bath temperature with a point temperature of 5-15°C to obtain a mixed solution;

步骤c2:继续搅拌并缓慢升温,当温度升高至浊点温度时,加入交联剂和催化剂,恒温固化15-23h,优选固化21-23h,更优选固化22h,过滤、洗涤后得到聚乙烯醇栓塞微囊。Step c2: Continue to stir and slowly heat up. When the temperature rises to the cloud point temperature, add a crosslinking agent and a catalyst, and cure at a constant temperature for 15-23 hours, preferably 21-23 hours, more preferably 22 hours, and obtain polyethylene after filtration and washing Alcohol embolization microcapsules.

进一步地,所述栓塞材料组合物为聚乙烯醇栓塞微球,所述聚乙烯醇栓塞微球采用以下方法制备:Further, the embolic material composition is polyvinyl alcohol embolic microspheres, and the polyvinyl alcohol embolic microspheres are prepared by the following method:

步骤a3:称取配方量的无机盐,配制成0.0045-0.025g/ml,优选0.017-0.025g/ml,更优选0.02g/ml的无机盐水溶液,将配方量的聚乙烯醇溶解于无机盐水溶液中,得到聚乙烯醇浓度为0.08-0.3g/ml,优选0.21-0.3g/ml,更优选0.21g/ml的溶液;Step a3: Weigh the formulated amount of inorganic salt, prepare an aqueous inorganic salt solution of 0.0045-0.025g/ml, preferably 0.017-0.025g/ml, more preferably 0.02g/ml, and dissolve the formulated amount of polyvinyl alcohol in the inorganic salt In the aqueous solution, the polyvinyl alcohol concentration obtained is 0.08-0.3g/ml, preferably 0.21-0.3g/ml, more preferably 0.21g/ml solution;

步骤b3:室温下将不透X射线的物质、磁共振成像物质及可选的药物加入到步骤a3的溶液中,搅拌,得到混合液;Step b3: adding X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the solution in step a3 at room temperature, and stirring to obtain a mixed solution;

步骤c3:将步骤b3制成的混合液倾入含表面活性剂的与水不互溶的有机溶剂中,制成乳剂,随后加入交联剂和催化剂,在300-1500rpm的搅拌速度和30-65℃水浴温度下固化2-23h,优选在550-650rpm的搅拌速度和30-45℃水浴温度下固化3.5-6h,更优选在600rpm的搅拌速度和30℃水浴温度下固化4h,过滤、洗涤后得到聚乙烯醇栓塞微球;或在步骤b3制成的混合液中加入交联剂和催化剂,搅拌均匀后倾入含表面活性剂的与水不互溶的有机溶剂中,制成乳剂,然后在300-1500rpm的搅拌速度和30-65℃水浴温度下固化2-23h,优选在550-650rpm的搅拌速度和30-45℃水浴温度下固化3.5-6h,更优选在600rpm的搅拌速度和30℃水浴温度下固化4h,过滤、洗涤后得到聚乙烯醇栓塞微球。Step c3: Pour the mixed solution made in step b3 into a water-immiscible organic solvent containing a surfactant to form an emulsion, then add a crosslinking agent and a catalyst at a stirring speed of 300-1500rpm and 30-65 Cure at ℃ water bath temperature for 2-23h, preferably at 550-650rpm stirring speed and 30-45℃ water bath temperature for 3.5-6h, more preferably at 600rpm stirring speed and 30℃ water bath temperature for 4h, after filtering and washing Obtain polyvinyl alcohol embolization microsphere; Or add cross-linking agent and catalyst in the mixed solution that step b3 is made, stir and pour in the water-immiscible organic solvent containing surfactant, make emulsion, then in 300-1500rpm stirring speed and 30-65°C water bath temperature for 2-23h, preferably 550-650rpm stirring speed and 30-45°C water bath temperature for 3.5-6h, more preferably 600rpm stirring speed and 30°C It was cured for 4 hours at the water bath temperature, filtered and washed to obtain polyvinyl alcohol embolism microspheres.

进一步地,所述栓塞材料组合物为明胶栓塞微囊或明胶栓塞微球;所述明胶栓塞微囊采用以下方法制备:Further, the embolic material composition is gelatin embolic microcapsules or gelatin embolic microspheres; the gelatin embolic microcapsules are prepared by the following method:

步骤a4:称取配方量的明胶,将明胶用蒸馏水溶胀后制成0.005-0.1g/ml,优选0.005-0.035g/ml,更优选0.035g/ml的明胶溶液;Step a4: Weigh the gelatin in the formula amount, swell the gelatin with distilled water to make a gelatin solution of 0.005-0.1g/ml, preferably 0.005-0.035g/ml, more preferably 0.035g/ml;

步骤b4:在40-60℃优选53℃水浴条件下,将不透X射线的物质、磁共振成像物质及可选的药物加入到步骤a4的明胶溶液中,搅拌,得到混合液;然后调节混合液的pH值至3.5-4.1,优选滴加0.1g/ml醋酸溶液调节混合液的pH值至3.5-4.1,微囊形成后,加入蒸馏水稀释,得到微囊混悬液;Step b4: Under the condition of 40-60°C, preferably 53°C water bath, add X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the gelatin solution in step a4, stir to obtain a mixed solution; then adjust the mixing The pH value of the solution is 3.5-4.1, preferably dropwise adding 0.1g/ml acetic acid solution to adjust the pH value of the mixed solution to 3.5-4.1. After the microcapsules are formed, distilled water is added to dilute to obtain a microcapsule suspension;

步骤c4:将步骤b4得到的微囊混悬液在冰水浴条件下加入交联剂固化0.5-24h,优选70min或15h,过滤、洗涤后得到明胶栓塞微囊;Step c4: The microcapsule suspension obtained in step b4 is solidified by adding a crosslinking agent in an ice-water bath for 0.5-24 hours, preferably 70 minutes or 15 hours, and then filtering and washing to obtain gelatin plug microcapsules;

当交联剂为甲醛时,上述步骤c4具体包括:将步骤b4得到的微囊混悬液在冰水浴条件下加入甲醛搅拌2-15min,优选10min,调节pH值至8-9,优选滴加0.1g/ml氢氧化钠溶液调节pH值至8-9,固化0.5-24h,优选15h,过滤、洗涤后得到明胶栓塞微囊。When the cross-linking agent is formaldehyde, the above step c4 specifically includes: adding formaldehyde to the microcapsule suspension obtained in step b4 in an ice-water bath and stirring for 2-15min, preferably 10min, adjusting the pH value to 8-9, preferably dropwise Adjust the pH value to 8-9 with 0.1 g/ml sodium hydroxide solution, solidify for 0.5-24 hours, preferably 15 hours, filter and wash to obtain gelatin embolism microcapsules.

所述明胶栓塞微球采用以下方法制备:The gelatin embolization microspheres are prepared by the following method:

步骤a5:称取配方量的明胶,将明胶用蒸馏水溶胀后制成0.08-0.35g/ml,优选0.15-0.30g/ml,更优选0.28g/ml的明胶溶液;Step a5: Weigh the gelatin of the formula amount, swell the gelatin with distilled water to make a gelatin solution of 0.08-0.35g/ml, preferably 0.15-0.30g/ml, more preferably 0.28g/ml;

步骤b5:在35-63℃优选53℃水浴条件下,将不透X射线的物质、磁共振成像物质及可选的药物加入到步骤a5的明胶溶液中,搅拌,得到混合液;Step b5: Add X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the gelatin solution in step a5 under the condition of 35-63°C, preferably 53°C, in a water bath, and stir to obtain a mixed solution;

步骤c5:将步骤b5制成的混合液倾入含表面活性剂的与水不互溶的有机溶剂中,制成乳剂,将乳剂转移到冰水浴中搅拌5-60min,优选30min,加入交联剂,固化0.5-24h,优选70min或15h,过滤、洗涤后得到明胶栓塞微球。Step c5: Pour the mixture prepared in step b5 into a water-immiscible organic solvent containing a surfactant to form an emulsion, transfer the emulsion to an ice-water bath and stir for 5-60 minutes, preferably 30 minutes, and add a crosslinking agent , solidified for 0.5-24h, preferably 70min or 15h, filtered and washed to obtain gelatin embolism microspheres.

当交联剂为甲醛时,上述步骤c5具体包括:将步骤b5制成的混合液倾入含表面活性剂的与水不互溶的有机溶剂中,制成乳剂,将乳剂转移到冰水浴中搅拌5-60min,优选30min,加入甲醛搅拌2-15min,优选10min,调节pH值至8-9,优选滴加0.1g/ml氢氧化钠溶液调节pH值至8-9,固化0.5-24h,优选15h,过滤、洗涤后得到明胶栓塞微球。When the cross-linking agent is formaldehyde, the above-mentioned step c5 specifically includes: pouring the mixed solution prepared in step b5 into a water-immiscible organic solvent containing a surfactant to form an emulsion, and transferring the emulsion to an ice-water bath for stirring 5-60min, preferably 30min, add formaldehyde and stir for 2-15min, preferably 10min, adjust the pH value to 8-9, preferably dropwise add 0.1g/ml sodium hydroxide solution to adjust the pH value to 8-9, solidify for 0.5-24h, preferably After 15 hours, gelatin embolization microspheres were obtained after filtration and washing.

进一步地,所述栓塞材料组合物为壳聚糖-羧甲基纤维素栓塞微囊,所述壳聚糖-羧甲基纤维素栓塞钠微囊采用以下方法制备:Further, the embolic material composition is chitosan-carboxymethylcellulose embolic microcapsules, and the chitosan-carboxymethylcellulose embolic sodium microcapsules are prepared by the following method:

步骤a6:称取配方量的壳聚糖,配制含0.006-0.009g/ml壳聚糖的醋酸溶液,称取配方量的羧甲基纤维素钠,配制0.02-0.056g/ml的羧甲基纤维素钠水溶液,将壳聚糖的醋酸溶液与羧甲基纤维素钠水溶液混合得到混合溶液;Step a6: Take the chitosan of formula quantity, prepare the acetic acid solution containing 0.006-0.009g/ml chitosan, weigh the sodium carboxymethyl cellulose of formula quantity, prepare the carboxymethyl cellulose of 0.02-0.056g/ml Cellulose sodium aqueous solution, the acetic acid solution of chitosan is mixed with carboxymethyl cellulose sodium aqueous solution to obtain mixed solution;

步骤b6:将不透X射线的物质、磁共振成像物质及可选的药物加入到步骤a6的混合溶液中,搅拌,制成混合液,调节混合液的pH值至5.5-6.5,优选用0.1g/ml氢氧化钠溶液调节乳剂的pH值至5.5-6.5,反应5-60min,优选20min;Step b6: Add X-ray-opaque substances, magnetic resonance imaging substances and optional drugs to the mixed solution in step a6, stir to make a mixed solution, adjust the pH value of the mixed solution to 5.5-6.5, preferably 0.1 g/ml sodium hydroxide solution to adjust the pH value of the emulsion to 5.5-6.5, react for 5-60min, preferably 20min;

步骤c6:将步骤b6中的反应液置于冰水浴中,加入交联剂,交联固化0.5-2h优选1h,过滤、洗涤后得到壳聚糖-羧甲基纤维素栓塞微囊。Step c6: Put the reaction solution in step b6 in an ice-water bath, add a crosslinking agent, crosslink and solidify for 0.5-2h, preferably 1h, filter and wash to obtain chitosan-carboxymethylcellulose embolism microcapsules.

本发明进一步提供上述栓塞材料组合物在制备用于治疗肿瘤,例如肝癌、结直肠癌肝转移、肾癌、肺癌、前列腺癌、卵巢癌、子宫肌瘤或乳腺恶性肿瘤,或血管畸形或用于止血等的药物中的用途。The present invention further provides the above-mentioned embolic material composition for the treatment of tumors, such as liver cancer, colorectal cancer liver metastases, kidney cancer, lung cancer, prostate cancer, ovarian cancer, uterine fibroids or malignant breast tumors, or vascular malformations or for Use in drugs such as hemostasis.

与现有技术相比,本发明的栓塞材料组合物至少具有以下优点:Compared with the prior art, the embolic material composition of the present invention has at least the following advantages:

1、本发明通过采用生物相容性材料包裹不透X射线的物质和磁共振成像物质制备具有X射线和磁共振双成像能力的栓塞材料组合物,使栓塞材料组合物具有良好的生物相容性,并能够同时被X射线影像设备和MRI直接检测。与单纯的X射线或MRI显影的栓塞剂相比,本发明的栓塞材料组合物不局限于使用单一设备监测,可以根据医院的设备条件和患者的自身需要任意选择X射线影像设备(如CT、DSA)或MRI进行监测,便于在栓塞术中和术后检查栓塞效果,更方便使用。1. The present invention prepares an embolic material composition with dual imaging capabilities of X-rays and magnetic resonance by using biocompatible materials to wrap X-ray-opaque substances and magnetic resonance imaging substances, so that the embolic material composition has good biocompatibility and can be directly detected by X-ray imaging equipment and MRI at the same time. Compared with pure X-ray or MRI imaging embolic agents, the embolic material composition of the present invention is not limited to monitoring with a single device, and X-ray imaging equipment (such as CT, DSA) or MRI for monitoring, it is convenient to check the effect of embolization during and after embolization, and it is more convenient to use.

2、与不显影的栓塞剂相比,本发明的栓塞材料组合物便于医生在栓塞术中和术后监测栓塞剂所处位置及栓塞终点,提高了治疗的效果与安全性。2. Compared with non-developing embolic agents, the embolic material composition of the present invention is convenient for doctors to monitor the position of the embolic agent and the end point of embolization during and after embolization, improving the efficacy and safety of treatment.

3、可在本发明的栓塞材料组合物中载入药物,并可将载药栓塞材料组合物在X射线影像设备(如CT)或MRI监控下栓塞到特定部位,更好地实现了所载药物的靶向递送;并可实现药物从微粒中的缓慢释放,在栓塞局部长时间维持较高的药物浓度,与灌注治疗相比,可降低药物的全身毒副作用,有利于提高栓塞治疗的疗效。3. Drugs can be loaded into the embolic material composition of the present invention, and the drug-loaded embolic material composition can be embolized to a specific site under the monitoring of X-ray imaging equipment (such as CT) or MRI, so as to better realize the Targeted delivery of drugs; slow release of drugs from microparticles can be achieved, and high drug concentration can be maintained in the embolized area for a long time. Compared with infusion therapy, it can reduce the systemic side effects of drugs and help improve the curative effect of embolization therapy .

4、本发明采用生物相容性材料、不透X射线的物质和磁共振成像物质制备栓塞材料组合物,制备工艺简单,成本低,适合大规模的工业化生产。4. The present invention adopts biocompatible materials, X-ray-opaque substances and magnetic resonance imaging substances to prepare embolic material compositions. The preparation process is simple, the cost is low, and it is suitable for large-scale industrial production.

附图说明Description of drawings

以下,结合附图来详细说明本发明的实施方案,其中:Below, describe embodiment of the present invention in detail in conjunction with accompanying drawing, wherein:

图1为本发明实施例5制备的聚乙烯醇栓塞微球的光学显微镜照片;Fig. 1 is the optical micrograph of the polyvinyl alcohol embolic microsphere that the embodiment of the present invention 5 prepares;

图2为本发明实施例5制备的聚乙烯醇栓塞微球的体外CT检测图像;Fig. 2 is the in vitro CT detection image of the polyvinyl alcohol embolic microspheres prepared in Example 5 of the present invention;

图3为本发明实施例5制备的聚乙烯醇栓塞微球的体外MRI检测图像;3 is an in vitro MRI detection image of polyvinyl alcohol embolization microspheres prepared in Example 5 of the present invention;

图4为本发明实施例5制备的聚乙烯醇栓塞微球在小鼠皮下的CT图像;Fig. 4 is the CT image of the subcutaneous mouse subcutaneous polyvinyl alcohol embolization microspheres prepared in Example 5 of the present invention;

图5为本发明实施例5制备的聚乙烯醇栓塞微球在小鼠皮下的MRI图像;Fig. 5 is the MRI image of the subcutaneous mouse subcutaneous polyvinyl alcohol embolization microspheres prepared in Example 5 of the present invention;

图6为本发明实施例8制备的载紫杉醇聚乙烯醇栓塞微球的体外释药曲线。Fig. 6 is the in vitro drug release curve of paclitaxel-loaded polyvinyl alcohol embolization microspheres prepared in Example 8 of the present invention.

具体实施方式Detailed ways

以下参照具体的实施例来说明本发明。本领域技术人员能够理解,这些实施例仅用于说明本发明,其不以任何方式限制本发明的范围。The present invention will be described below with reference to specific examples. Those skilled in the art can understand that these examples are only used to illustrate the present invention and do not limit the scope of the present invention in any way.

下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的药物原料、试剂、材料等,如无特殊说明,均为市售购买产品。The experimental methods in the following examples are conventional methods unless otherwise specified. The pharmaceutical raw materials, reagents, materials, etc. used in the following examples are all commercially available products unless otherwise specified.

实施例1聚乙烯醇栓塞微囊的制备The preparation of embodiment 1 polyvinyl alcohol embolism microcapsule

1)称取1g聚乙烯醇,配制成0.008g/ml的聚乙烯醇溶液;1) Weigh 1g of polyvinyl alcohol and prepare a 0.008g/ml polyvinyl alcohol solution;

2)将6.5g碘化油、5g四氧化三铁纳米粒子及1.5g紫杉醇混合均匀后加入到步骤1)得到的聚乙烯醇溶液中,搅拌制成水包油(o/w)型乳剂;2) Mix 6.5g iodized oil, 5g iron ferric oxide nanoparticles and 1.5g paclitaxel evenly, then add them to the polyvinyl alcohol solution obtained in step 1), and stir to make an oil-in-water (o/w) emulsion;

3)称取3.0g硫酸钠,配制成0.21g/ml的硫酸钠溶液,在低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下将硫酸钠溶液加入到步骤2)得到的乳剂中,继续搅拌并缓慢升温,当温度升高至浊点温度时,加入11g甲醛和5.8g硫酸,恒温固化20h,静置分层,倾出上清液,过滤、洗涤后得到聚乙烯醇栓塞微囊。3) Weigh 3.0g of sodium sulfate and prepare a 0.21g/ml sodium sulfate solution, and add the sodium sulfate solution to step 2 at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition ) to the obtained emulsion, continue to stir and slowly raise the temperature, when the temperature rises to the cloud point temperature, add 11g formaldehyde and 5.8g sulfuric acid, solidify at constant temperature for 20h, let stand to separate layers, pour out the supernatant, filter and wash to get Polyvinyl alcohol embolization microcapsules.

实施例2聚乙烯醇栓塞微球的制备The preparation of embodiment 2 polyvinyl alcohol embolic microspheres

1)称取0.31g氯化钠,配制0.025g/ml的氯化钠水溶液,将1g聚乙烯醇溶解于氯化钠水溶液中,得到聚乙烯醇浓度为0.08g/ml的溶液;1) Weigh 0.31g of sodium chloride, prepare a 0.025g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.08g/ml;

2)将2g三氧化二铁纳米粒子及6g紫杉醇分散在8g碘化油中,得到混合液,然后在室温下将该混合液加入到步骤1)的聚乙烯醇溶液,搅拌,制成水包油(o/w)型乳剂;2) Disperse 2g of ferric oxide nanoparticles and 6g of paclitaxel in 8g of iodized oil to obtain a mixed solution, then add the mixed solution to the polyvinyl alcohol solution in step 1) at room temperature and stir to make a water-in-packet Oil (o/w) type emulsion;

3)将步骤2)制成的乳剂倾入含2.5g司盘85的60g液体石蜡中,制成油包水包油型(o/w/o)复乳,随后加入0.6g戊二醛和0.5g硫酸,在300rpm的搅拌速度和35℃水浴温度下固化2h,过滤、洗涤后得到聚乙烯醇栓塞微球。3) Pour the emulsion prepared in step 2) into 60g of liquid paraffin containing 2.5g of Span 85 to make an oil-in-water-in-oil type (o/w/o) double emulsion, and then add 0.6g of glutaraldehyde and 0.5 g of sulfuric acid was solidified for 2 hours at a stirring speed of 300 rpm and a water bath temperature of 35° C., filtered and washed to obtain polyvinyl alcohol embolization microspheres.

实施例3明胶栓塞微囊的制备The preparation of embodiment 3 gelatin embolization microcapsules

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.03g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.03g/ml gelatin solution;

2)将0.5g索拉非尼和3g四氧化三铁分散在3.5g碘化油中,得到混合液,在40℃水浴条件下,将得到的混合液加入到步骤1)的明胶溶液中,搅拌,制成水包油(o/w)型乳剂,然后滴加0.1g/ml醋酸溶液调节乳剂的pH值至3.5-4.1,在显微镜下观察到微囊形成后,加入蒸馏水稀释,得到微囊混悬液;2) Disperse 0.5g of sorafenib and 3g of ferric oxide in 3.5g of iodized oil to obtain a mixed solution, and add the obtained mixed solution to the gelatin solution in step 1) in a water bath at 40°C, Stir to make an oil-in-water (o/w) emulsion, then add dropwise 0.1g/ml acetic acid solution to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, add distilled water to dilute, and obtain microcapsules Capsule suspension;

3)将步骤2)得到的微囊混悬液在冰水浴条件下加入1.5g甲醛搅拌2min,滴加0.1g/ml氢氧化钠溶液,调节pH值至8-9,固化15h,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微囊。3) Add 1.5g of formaldehyde to the microcapsule suspension obtained in step 2) and stir for 2 minutes in an ice-water bath, add dropwise 0.1g/ml sodium hydroxide solution, adjust the pH value to 8-9, solidify for 15 hours, and let stand to separate layer, decanting the supernatant, filtering and washing to obtain gelatin embolized microcapsules.

实施例4聚乙烯醇栓塞微球的制备 The preparation of embodiment 4 polyvinyl alcohol embolic microspheres

1)称取0.15g氯化钠,配制0.018g/ml的氯化钠水溶液,将1g聚乙烯醇溶解于氯化钠水溶液中,配制聚乙烯醇浓度为0.12g/ml的溶液;1) Weigh 0.15g of sodium chloride, prepare a 0.018g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and prepare a solution with a polyvinyl alcohol concentration of 0.12g/ml;

2)将4g三氧化二铁纳米粒子和1.5g索拉非尼分散在6g碘苯酯中,得到混合液,然后在室温下将该混合液加入到步骤1)的聚乙烯醇溶液中,搅拌,制成水包油(o/w)型乳剂;2) Disperse 4g of ferric oxide nanoparticles and 1.5g of sorafenib in 6g of iodophenyl ester to obtain a mixed solution, then add the mixed solution to the polyvinyl alcohol solution in step 1) at room temperature, and stir , made into oil-in-water (o/w) emulsion;

3)将步骤2)制成的乳剂倾入含0.4g司盘85的17g蓖麻油中,制成油包水包油(o/w/o)型复乳,随后加入0.8g甲醛和0.6g硫酸,在1500rpm的搅拌速度和45℃水浴温度下固化7h,过滤、洗涤后得到聚乙烯醇栓塞微球。3) Pour the emulsion prepared in step 2) into 17g castor oil containing 0.4g Span 85 to make an oil-in-water-in-oil (o/w/o) type double emulsion, then add 0.8g formaldehyde and 0.6g Sulfuric acid was solidified at a stirring speed of 1500 rpm and a water bath temperature of 45° C. for 7 hours, filtered and washed to obtain polyvinyl alcohol embolism microspheres.

实施例5聚乙烯醇栓塞微球的制备 The preparation of embodiment 5 polyvinyl alcohol embolic microspheres

1)称取0.17g氯化钠,配制0.025g/ml的氯化钠水溶液,将1g聚乙烯醇溶解于氯化钠水溶液中,得到聚乙烯醇浓度为0.15g/ml的溶液;1) Weigh 0.17g of sodium chloride, prepare a 0.025g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.15g/ml;

2)室温下将7g碘化油、1.7g四氧化三铁纳米粒子混合均匀后加入到步骤1)的聚乙烯醇溶液中,搅拌,制成水包油(o/w)型乳剂;2) At room temperature, mix 7g iodized oil and 1.7g iron ferric oxide nanoparticles evenly, then add them to the polyvinyl alcohol solution in step 1), and stir to make an oil-in-water (o/w) emulsion;

3)在步骤2)制成的乳剂中加入0.9g甲醛和0.8g硫酸,迅速搅拌均匀后倾入含2g司盘80的50g液体石蜡中,制成油包水包油(o/w/o)型复乳,在750rpm的搅拌速度和30℃水浴温度下固化4h,过滤、洗涤后得到聚乙烯醇栓塞微球。3) Add 0.9g of formaldehyde and 0.8g of sulfuric acid to the emulsion prepared in step 2), stir it quickly and pour it into 50g of liquid paraffin containing 2g of Span 80 to make oil-in-water-in-oil (o/w/o ) type double emulsion, solidified at a stirring speed of 750 rpm and a water bath temperature of 30°C for 4 hours, filtered and washed to obtain polyvinyl alcohol embolism microspheres.

上述制备的聚乙烯醇栓塞微球在光学显微镜下的形态如图1所示。从图1看出,制备的聚乙烯醇栓塞微球为规则的球形,分散性较好,无粘结和团聚现象。The morphology of the above-prepared polyvinyl alcohol embolization microspheres under an optical microscope is shown in FIG. 1 . It can be seen from Figure 1 that the prepared polyvinyl alcohol embolic microspheres are regular spherical, with good dispersion and no bonding and agglomeration.

实施例6明胶栓塞微球的制备 Embodiment 6 Preparation of gelatin embolization microspheres

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.3g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.3g/ml gelatin solution;

2)在53℃水浴条件下,将0.5g MnFe2O4分散在1.2g碘化油中制成混合液,将混合液加入到步骤1)的明胶溶液中,搅拌,制成水包油(o/w)型乳剂;2) Disperse 0.5g MnFe 2 O 4 in 1.2g iodized oil in a water bath at 53°C to make a mixed solution, add the mixed solution to the gelatin solution in step 1), and stir to make an oil-in-water ( o/w) type emulsion;

3)将步骤2)制成的乳剂倾入含0.39g司盘80的10g环己烷中,制成油包水包油(o/w/o)型乳剂,将乳剂转移到冰水浴中继续搅拌30min,加入0.2g甲醛搅拌2min,滴加0.1g/ml氢氧化钠溶液,调节pH值至8-9,固化10h,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微球。3) Pour the emulsion prepared in step 2) into 10g cyclohexane containing 0.39g Span 80 to make an oil-in-water-in-oil (o/w/o) type emulsion, transfer the emulsion to an ice-water bath to continue Stir for 30 minutes, add 0.2g formaldehyde and stir for 2 minutes, add 0.1g/ml sodium hydroxide solution dropwise, adjust the pH value to 8-9, solidify for 10 hours, let stand to separate layers, pour out the supernatant, filter and wash to obtain a gelatin plug Microspheres.

实施例7壳聚糖-羧甲基纤维素栓塞微囊的制备The preparation of embodiment 7 chitosan-carboxymethyl cellulose embolism microcapsules

1)称取0.1g壳聚糖,制成含0.006g/ml壳聚糖的醋酸溶液,称取0.9g羧甲基纤维素钠,制成0.056g/ml的羧甲基纤维素钠水溶液,将壳聚糖的醋酸溶液与羧甲基纤维素钠水溶液混合得到混合溶液;1) Weigh 0.1g chitosan to make an acetic acid solution containing 0.006g/ml chitosan, weigh 0.9g sodium carboxymethyl cellulose to make a 0.056g/ml sodium carboxymethyl cellulose aqueous solution, The acetic acid solution of chitosan is mixed with the sodium carboxymethyl cellulose aqueous solution to obtain a mixed solution;

2)将4g碘化油及0.5g三氧化二铁纳米粒子混合均匀后加入到步骤1)的混合溶液中,磁力搅拌制成水包油(o/w)型乳剂;用0.1g/ml氢氧化钠溶液调节乳剂的pH值至5.5-6.5,反应5min;2) Mix 4g iodized oil and 0.5g ferric oxide nanoparticles evenly and add them to the mixed solution in step 1), stir magnetically to make an oil-in-water (o/w) emulsion; use 0.1g/ml hydrogen The sodium oxide solution adjusts the pH value of the emulsion to 5.5-6.5, and reacts for 5 minutes;

3)将步骤2)中的反应液置于冰水浴中,加入0.2g戊二醛,交联固化0.5h,静置分层,倾出上清液,过滤、洗涤后得到壳聚糖-羧甲基纤维素栓塞微囊。3) Put the reaction solution in step 2) in an ice-water bath, add 0.2g of glutaraldehyde, cross-link and solidify for 0.5h, let it stand for layers, pour out the supernatant, filter and wash to obtain chitosan-carboxylate Methylcellulose Embolization Microcapsules.

实施例8聚乙烯醇栓塞微球的制备 The preparation of embodiment 8 polyvinyl alcohol embolic microspheres

1)称取0.015g氯化钠,配制0.0045g/ml的氯化钠水溶液,将1g聚乙烯醇溶解于氯化钠水溶液中,得到聚乙烯醇浓度为0.3g/ml的溶液;1) Weigh 0.015g sodium chloride, prepare 0.0045g/ml sodium chloride aqueous solution, dissolve 1g polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.3g/ml;

2)室温下将1.2g紫杉醇、0.8g四氧化三铁纳米粒子分散在2.2g碘化油中制成混合液,将混合液加入到步骤1)的聚乙烯醇溶液中,制成水包油(o/w)型乳剂;2) Disperse 1.2g paclitaxel and 0.8g iron ferric oxide nanoparticles in 2.2g iodized oil at room temperature to make a mixed solution, add the mixed solution to the polyvinyl alcohol solution in step 1) to make oil-in-water (o/w) type emulsion;

3)在步骤2)制成的乳剂中加入2.3g戊二醛和1.8g硫酸,混合均匀后倾入含0.1g司盘85的5g液体石蜡中,在550rpm和55℃水浴温度下固化16h,过滤、洗涤后得到聚乙烯醇栓塞微球。3) Add 2.3g of glutaraldehyde and 1.8g of sulfuric acid to the emulsion prepared in step 2), mix well, pour into 5g of liquid paraffin containing 0.1g of Span 85, and solidify at 550rpm and 55°C water bath temperature for 16h, After filtering and washing, the polyvinyl alcohol embolization microspheres are obtained.

实施例9明胶栓塞微囊的制备The preparation of embodiment 9 gelatin embolization microcapsules

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.1g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.1g/ml gelatin solution;

2)在50℃水浴条件下,将0.8gγ三氧化二铁分散在1g碘化油中,制成混合液,将混合液加入到步骤1)的明胶溶液中,搅拌,制成水包油(o/w)型乳剂;然后滴加0.1g/ml醋酸溶液调节乳剂的pH值至3.5-4.1,在显微镜下观察到微囊形成后,加入蒸馏水稀释,得到微囊混悬液;2) Disperse 0.8g gamma ferric oxide in 1g iodized oil in a water bath at 50°C to make a mixed solution, add the mixed solution to the gelatin solution in step 1), and stir to make oil-in-water ( o/w) type emulsion; then add 0.1g/ml acetic acid solution dropwise to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, dilute with distilled water to obtain a microcapsule suspension;

3)将步骤2)得到的微囊混悬液在冰水浴条件下加入0.3g戊二醛固化70min,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微囊。3) The microcapsule suspension obtained in step 2) was solidified by adding 0.3 g of glutaraldehyde in an ice-water bath for 70 minutes, left to stand for stratification, poured out the supernatant, filtered and washed to obtain gelatin embolism microcapsules.

实施例10聚乙烯醇栓塞微囊的制备 The preparation of embodiment 10 polyvinyl alcohol embolization microcapsules

1)称取1g聚乙烯醇,配制成0.0035g/ml的聚乙烯醇溶液;1) Weigh 1g of polyvinyl alcohol and prepare a 0.0035g/ml polyvinyl alcohol solution;

2)将7g碘化油、0.5g钽粉、4.5g四氧化三铁纳米粒子及3g紫杉醇混合均匀后加入到步骤1)得到的聚乙烯醇溶液中,搅拌制成水包油(o/w)型乳剂;2) Mix 7g of iodized oil, 0.5g of tantalum powder, 4.5g of ferric oxide nanoparticles and 3g of paclitaxel, and then add them to the polyvinyl alcohol solution obtained in step 1), and stir to make oil-in-water (o/w ) type emulsion;

3)称取5.5g硫酸钠,配制成0.1g/ml的硫酸钠溶液,在低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下将硫酸钠溶液加入到步骤2)得到的乳剂中,继续搅拌并缓慢升温,当温度升高至浊点温度时,加入15g甲醛和13.1g硫酸,恒温固化23h,静置分层,倾出上清液,过滤、洗涤后得到聚乙烯醇栓塞微囊。3) Weigh 5.5g of sodium sulfate and prepare 0.1g/ml sodium sulfate solution, and add the sodium sulfate solution to step 2 at a water bath temperature lower than the cloud point temperature of the polyvinyl alcohol solution at 5-15°C under this condition ) to the obtained emulsion, continue to stir and slowly heat up, when the temperature rises to the cloud point temperature, add 15g of formaldehyde and 13.1g of sulfuric acid, solidify at a constant temperature for 23h, let stand to separate layers, pour out the supernatant, filter and wash to get Polyvinyl alcohol embolization microcapsules.

实施例11聚乙烯醇栓塞微囊的制备 Example 11 Preparation of Polyvinyl Alcohol Embolization Microcapsules

1)称取1g聚乙烯醇,配制成0.025g/ml的聚乙烯醇溶液;1) Weigh 1g of polyvinyl alcohol and prepare a 0.025g/ml polyvinyl alcohol solution;

2)称取2.5g硫酸钠,配制成0.29g/ml的硫酸钠溶液,将硫酸钠溶液与步骤1)中的聚乙烯醇溶液混合,随后加入混合均匀的2.1g碘化油和1.7g四氧化三铁纳米粒子,在低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下搅拌,得到水包油型(o/w)乳剂;2) Weigh 2.5g of sodium sulfate and prepare a 0.29g/ml sodium sulfate solution, mix the sodium sulfate solution with the polyvinyl alcohol solution in step 1), then add 2.1g of iodized oil and 1.7g of four Ferric oxide nanoparticles, stirred at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition, to obtain an oil-in-water (o/w) emulsion;

3)继续搅拌并缓慢升温,当温度升高至浊点温度时,加入8g甲醛和1.8g盐酸,恒温固化23h,静置分层,倾出上清液,过滤、洗涤后得到聚乙烯醇栓塞微囊。3) Continue to stir and raise the temperature slowly. When the temperature rises to the cloud point temperature, add 8g of formaldehyde and 1.8g of hydrochloric acid, solidify at constant temperature for 23 hours, let it stand for stratification, pour out the supernatant, filter and wash to obtain polyvinyl alcohol embolism Microcapsules.

实施例12聚乙烯醇栓塞微囊的制备 Example 12 Preparation of Polyvinyl Alcohol Embolization Microcapsules

1)称取1g聚乙烯醇,配制成0.015g/ml的聚乙烯醇溶液;1) Weigh 1g of polyvinyl alcohol and prepare a 0.015g/ml polyvinyl alcohol solution;

2)称取3.5g硫酸钠,配制成0.262g/ml的硫酸钠溶液,将硫酸钠溶液与步骤1)中的聚乙烯醇溶液混合,随后加入混合均匀的3.5g碘化油、2.4g四氧化三铁纳米粒子及1.1g阿霉素,在低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下搅拌,得到水包油型(o/w)乳剂;2) Weigh 3.5g of sodium sulfate and prepare a 0.262g/ml sodium sulfate solution, mix the sodium sulfate solution with the polyvinyl alcohol solution in step 1), then add 3.5g of iodized oil and 2.4g of four Ferric oxide nanoparticles and 1.1g of doxorubicin are stirred at a water bath temperature lower than the cloud point temperature of polyvinyl alcohol solution of 5-15°C under the conditions to obtain an oil-in-water (o/w) emulsion;

3)继续搅拌并缓慢升温,当温度升高至浊点温度时,加入10g甲醛和11g盐酸,恒温固化20h,静置分层,倾出上清液,过滤、洗涤后得到聚乙烯醇栓塞微囊。3) Continue to stir and raise the temperature slowly. When the temperature rises to the cloud point temperature, add 10g of formaldehyde and 11g of hydrochloric acid, solidify at constant temperature for 20h, let stand for stratification, pour out the supernatant, filter and wash to obtain polyvinyl alcohol embolism bag.

实施例13聚乙烯醇栓塞微囊的制备 Example 13 Preparation of Polyvinyl Alcohol Embolization Microcapsules

1)称取1g聚乙烯醇,配制成0.05g/ml的聚乙烯醇溶液;1) Weigh 1g of polyvinyl alcohol and prepare a 0.05g/ml polyvinyl alcohol solution;

2)将0.2g四氧化三铁纳米粒子分散在0.5g碘化油中,得到混合液,再将混合液加入到步骤1)得到的聚乙烯醇溶液中,搅拌制成水包油(o/w)型乳剂;2) Disperse 0.2g of iron ferric oxide nanoparticles in 0.5g of iodized oil to obtain a mixed solution, then add the mixed solution to the polyvinyl alcohol solution obtained in step 1), and stir to make an oil-in-water (o/ w) type emulsion;

3)称取1g三聚磷酸钠,配制成0.25g/ml的三聚磷酸钠溶液,在低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下将三聚磷酸钠溶液加入到步骤2)得到的乳剂中,继续搅拌并缓慢升温,当温度升高至浊点温度时,加入4g甲醛和0.9g硫酸,恒温固化15h,静置分层,倾出上清液,过滤、洗涤后得到聚乙烯醇栓塞微囊。3) Weigh 1g of sodium tripolyphosphate and make it into a 0.25g/ml sodium tripolyphosphate solution. Dissolve sodium tripolyphosphate at a water bath temperature lower than the cloud point temperature of the polyvinyl alcohol solution at 5-15°C under this condition. Add the solution into the emulsion obtained in step 2), continue to stir and slowly raise the temperature, when the temperature rises to the cloud point temperature, add 4g of formaldehyde and 0.9g of sulfuric acid, solidify at a constant temperature for 15h, let stand to separate layers, and pour out the supernatant, After filtering and washing, the polyvinyl alcohol embolism microcapsules are obtained.

实施例14聚乙烯醇栓塞微球的制备 Embodiment 14 Preparation of polyvinyl alcohol embolization microspheres

1)称取0.043g氯化钠,配制0.01g/ml的氯化钠水溶液,将1g聚乙烯醇溶解于氯化钠水溶液中,得到聚乙烯醇浓度为0.23g/ml的溶液;1) Weigh 0.043g of sodium chloride, prepare a 0.01g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.23g/ml;

2)在室温下将2.8g碘化油、1.2g四氧化三铁纳米粒子及1.5g紫杉醇混合均匀后加入到步骤1)的聚乙烯醇溶液中,搅拌,制成水包油(o/w)型乳剂;2) Mix 2.8g iodized oil, 1.2g iron ferric oxide nanoparticles and 1.5g paclitaxel at room temperature and add them to the polyvinyl alcohol solution in step 1), stir to make oil-in-water (o/w ) type emulsion;

3)在步骤2)制成的乳剂中加入1.2g戊二醛和1.1g硫酸,混合均匀后倾入含0.4g司盘85的11g液体石蜡中,在600rpm和65℃水浴温度下固化23h,过滤、洗涤后得到聚乙烯醇栓塞微球。3) Add 1.2g of glutaraldehyde and 1.1g of sulfuric acid to the emulsion prepared in step 2), mix well, pour into 11g of liquid paraffin containing 0.4g of Span 85, and solidify at 600rpm and 65°C water bath temperature for 23h, After filtering and washing, the polyvinyl alcohol embolization microspheres are obtained.

实施例15明胶栓塞微囊的制备The preparation of embodiment 15 gelatin embolization microcapsules

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.035g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.035g/ml gelatin solution;

2)在60℃水浴条件下,将1.5g碘化油、0.5g钽粉、0.5g四氧化三铁纳米粒子及0.5g索拉非尼混合均匀后加入到步骤1)的明胶溶液中,搅拌,制成混合液,然后滴加0.1g/ml醋酸溶液调节乳剂的pH值至3.5-4.1,在显微镜下观察到微囊形成后,加入蒸馏水稀释,得到微囊混悬液;2) Under the condition of 60°C water bath, mix 1.5g iodized oil, 0.5g tantalum powder, 0.5g ferric oxide nanoparticles and 0.5g sorafenib evenly, then add them to the gelatin solution in step 1), and stir , to make a mixed solution, then dropwise add 0.1g/ml acetic acid solution to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, add distilled water to dilute to obtain a microcapsule suspension;

3)将步骤2)得到的微囊混悬液在冰水浴条件下加入0.1g甲醛搅拌15min,滴加0.1g/ml氢氧化钠溶液,调节pH值至8-9,固化10h,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微囊。3) Add 0.1g of formaldehyde to the microcapsule suspension obtained in step 2) and stir for 15 minutes in an ice-water bath, add 0.1g/ml sodium hydroxide solution dropwise, adjust the pH value to 8-9, solidify for 10 hours, and let stand to separate layer, decanting the supernatant, filtering and washing to obtain gelatin embolized microcapsules.

实施例16明胶栓塞微球的制备The preparation of embodiment 16 gelatin embolization microspheres

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.28g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.28g/ml gelatin solution;

2)在45℃水浴条件下,将2g碘化油、0.2g钽粉、1g四氧化三铁纳米粒子及1g紫杉醇混合均匀后加入到步骤1)的明胶溶液中,搅拌,制成混合液;2) Under the condition of water bath at 45°C, mix 2g iodized oil, 0.2g tantalum powder, 1g ferric oxide nanoparticles and 1g paclitaxel evenly, then add them to the gelatin solution in step 1), and stir to make a mixed solution;

3)将步骤2)制成的乳剂倾入含0.51g司盘80的25g液体石蜡中,制成水包油(w/o)型乳剂,将乳剂转移到冰水浴中继续搅拌5min,加入0.7g戊二醛固化70min,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微球。3) Pour the emulsion prepared in step 2) into 25g of liquid paraffin containing 0.51g of Span 80 to make an oil-in-water (w/o) emulsion. Transfer the emulsion to an ice-water bath and continue stirring for 5 minutes. Add 0.7 The g glutaraldehyde was solidified for 70 min, left to separate layers, poured out the supernatant, filtered and washed to obtain gelatin embolism microspheres.

实施例17明胶栓塞微球的制备The preparation of embodiment 17 gelatin embolization microspheres

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.08g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.08g/ml gelatin solution;

2)在63℃水浴条件下,将8g碘化油、3.5g四氧化三铁纳米粒子及4.5g紫杉醇混合均匀后加入到步骤1)的明胶溶液中,搅拌,制成水包油(o/w)型乳剂;2) Under the condition of water bath at 63°C, mix 8g iodized oil, 3.5g iron ferric oxide nanoparticles and 4.5g paclitaxel evenly, then add them to the gelatin solution in step 1), and stir to make oil-in-water (o/ w) type emulsion;

3)将步骤2)制成的乳剂倾入含3.13g司盘80的50g液体石蜡中,制成油包水包油(o/w/o)型乳剂,将乳剂转移到冰水浴中继续搅拌60min,加入3.7g甲醛搅拌10min,滴加0.1g/ml氢氧化钠溶液,调节pH值至8-9,固化15h,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微球。3) Pour the emulsion prepared in step 2) into 50g of liquid paraffin containing 3.13g of Span 80 to make an oil-in-water-in-oil (o/w/o) type emulsion, transfer the emulsion to an ice-water bath and continue stirring 60min, add 3.7g formaldehyde and stir for 10min, add dropwise 0.1g/ml sodium hydroxide solution, adjust the pH value to 8-9, solidify for 15h, let stand to separate layers, pour out the supernatant, filter and wash to obtain gelatin plug microspheres ball.

实施例18明胶栓塞微球的制备The preparation of embodiment 18 gelatin embolization microspheres

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.35g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.35g/ml gelatin solution;

2)在35℃水浴条件下,将0.8g碘化油、0.3g DyFe2O4纳米粒子及0.5g索拉非尼混合均匀后加入到步骤1)的明胶溶液中,搅拌,制成水包油(o/w)型乳剂;2) In a water bath at 35°C, mix 0.8g lipiodol, 0.3g DyFe 2 O 4 nanoparticles and 0.5g sorafenib evenly, add them to the gelatin solution in step 1), stir, and make a water bag Oil (o/w) type emulsion;

3)将步骤2)制成的乳剂倾入含0.1g司盘80的5g液体石蜡中,制成油包水包油(o/w/o)型乳剂,将乳剂转移到冰水浴中继续搅拌20min,加入0.1g甲醛搅拌15min,滴加0.1g/ml氢氧化钠溶液,调节pH值至8-9,固化24h,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微球。3) Pour the emulsion prepared in step 2) into 5g of liquid paraffin containing 0.1g of Span 80 to make an oil-in-water-in-oil (o/w/o) type emulsion, transfer the emulsion to an ice-water bath and continue stirring 20min, add 0.1g formaldehyde and stir for 15min, add dropwise 0.1g/ml sodium hydroxide solution, adjust the pH value to 8-9, solidify for 24h, let stand to separate layers, pour out the supernatant, filter and wash to obtain gelatin plug microspheres ball.

实施例19壳聚糖-羧甲基纤维素栓塞微囊的制备The preparation of embodiment 19 chitosan-carboxymethyl cellulose embolism microcapsules

1)称取0.5g壳聚糖,制成含0.009g/ml壳聚糖的醋酸溶液,称取0.5g羧甲基纤维素钠,制成0.035g/ml的羧甲基纤维素钠水溶液,将壳聚糖的醋酸溶液与羧甲基纤维素钠水溶液混合得到混合溶液;1) Weigh 0.5g chitosan to make an acetic acid solution containing 0.009g/ml chitosan, weigh 0.5g sodium carboxymethyl cellulose to make a 0.035g/ml sodium carboxymethyl cellulose aqueous solution, The acetic acid solution of chitosan is mixed with the sodium carboxymethyl cellulose aqueous solution to obtain a mixed solution;

2)将5g碘化油、2.5g三氧化二铁纳米粒子和2.4g顺铂混合均匀后加入到步骤1)的混合溶液中,磁力搅拌制成水包油(o/w)型乳剂;用0.1g/ml氢氧化钠溶液调节乳剂的pH值至5.5-6.5,反应20min;2) Mix 5g of iodized oil, 2.5g of ferric oxide nanoparticles and 2.4g of cisplatin evenly, then add to the mixed solution in step 1), and stir magnetically to make an oil-in-water (o/w) emulsion; 0.1g/ml sodium hydroxide solution to adjust the pH value of the emulsion to 5.5-6.5, and react for 20 minutes;

3)将步骤2)中的反应液置于冰水浴中,加入0.8g戊二醛,交联固化2h,静置分层,倾出上清液,过滤、洗涤后得到壳聚糖-羧甲基纤维素栓塞微囊。3) Put the reaction solution in step 2) in an ice-water bath, add 0.8g of glutaraldehyde, cross-link and solidify for 2 hours, let stand to separate layers, pour out the supernatant, filter and wash to obtain chitosan-carboxymethyl Cellulose-based embolism microcapsules.

实施例20聚乙烯醇栓塞微囊的制备 Embodiment 20 Preparation of polyvinyl alcohol embolism microcapsules

1)称取1g聚乙烯醇,配制成0.04g/ml的聚乙烯醇溶液;1) Weigh 1g of polyvinyl alcohol and prepare a 0.04g/ml polyvinyl alcohol solution;

2)将1g碘化油、0.7g四氧化三铁纳米粒子及0.2g多西紫杉醇混合均匀后加入到步骤1)得到的聚乙烯醇溶液中,搅拌制成水包油(o/w)型乳剂;2) Mix 1g iodized oil, 0.7g iron ferric oxide nanoparticles and 0.2g docetaxel evenly, then add to the polyvinyl alcohol solution obtained in step 1), stir to make oil-in-water (o/w) type Emulsion;

3)称取2g硫酸铝,配制成0.4g/ml的硫酸铝溶液,在低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下将硫酸铝溶液加入到步骤2)得到的乳剂中,继续搅拌并缓慢升温,当温度升高至浊点温度时,加入6g甲醛和9.5g硫酸,恒温固化21h,静置分层,倾出上清液,过滤、洗涤后得到聚乙烯醇栓塞微囊。3) Weigh 2g of aluminum sulfate and prepare it into a 0.4g/ml aluminum sulfate solution, and add the aluminum sulfate solution to step 2 at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition) In the obtained emulsion, continue to stir and slowly heat up. When the temperature rises to the cloud point temperature, add 6g of formaldehyde and 9.5g of sulfuric acid, solidify at a constant temperature for 21h, leave to separate layers, pour out the supernatant, filter and wash to obtain poly Vinyl alcohol embolization microcapsules.

实施例21聚乙烯醇栓塞微囊的制备 Example 21 Preparation of Polyvinyl Alcohol Embolization Microcapsules

1)称取1g聚乙烯醇,配制成0.035g/ml的聚乙烯醇溶液;1) Weigh 1g of polyvinyl alcohol and prepare a 0.035g/ml polyvinyl alcohol solution;

2)将1.5g碘化油、1g四氧化三铁纳米粒子及0.5g索拉非尼混合均匀后加入到步骤1)得到的聚乙烯醇溶液中,搅拌制成水包油(o/w)型乳剂;2) Mix 1.5g iodized oil, 1g iron ferric oxide nanoparticles and 0.5g sorafenib evenly, then add to the polyvinyl alcohol solution obtained in step 1), and stir to make oil-in-water (o/w) type emulsion;

3)称取1g硫酸铵,配制成0.175g/ml的硫酸铵溶液,在低于该条件下聚乙烯醇溶液的浊点温度5-15℃的水浴温度下将硫酸铵溶液加入到步骤2)得到的乳剂中,继续搅拌并缓慢升温,当温度升高至浊点温度时,加入8g甲醛和3.1g硫酸,恒温固化22h,静置分层,倾出上清液,过滤、洗涤后得到聚乙烯醇栓塞微囊。3) Weigh 1g of ammonium sulfate and prepare ammonium sulfate solution of 0.175g/ml, and add the ammonium sulfate solution to step 2 at a water bath temperature 5-15°C lower than the cloud point temperature of the polyvinyl alcohol solution under this condition) In the obtained emulsion, continue to stir and slowly raise the temperature. When the temperature rises to the cloud point temperature, add 8g of formaldehyde and 3.1g of sulfuric acid, and solidify at a constant temperature for 22h. Let stand to separate layers, pour out the supernatant, filter and wash to obtain poly Vinyl alcohol embolization microcapsules.

实施例22聚乙烯醇栓塞微球的制备 Example 22 Preparation of Polyvinyl Alcohol Embolization Microspheres

1)称取0.081g氯化钠,配制0.017g/ml的氯化钠水溶液,将1g聚乙烯醇溶解于氯化钠水溶液中,得到聚乙烯醇浓度为0.21g/ml的溶液;1) Weigh 0.081g of sodium chloride, prepare a 0.017g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.21g/ml;

2)在室温下将3g碘化油、1g三氧化二铁纳米粒子及2g紫杉醇混合均匀后加入到步骤1)的聚乙烯醇溶液中,搅拌,制成水包油(o/w)型乳剂;2) Mix 3g of iodized oil, 1g of ferric oxide nanoparticles and 2g of paclitaxel at room temperature, then add them to the polyvinyl alcohol solution in step 1), and stir to make an oil-in-water (o/w) emulsion ;

3)将步骤2)制成的乳剂倾入含0.6g司盘85的14g环己烷中,制成油包水包油型(o/w/o)复乳,随后加入1.1g戊二醛和0.9g硫酸,在650rpm的搅拌速度和40℃水浴温度下固化6h,过滤、洗涤后得到聚乙烯醇栓塞微球。3) Pour the emulsion prepared in step 2) into 14g cyclohexane containing 0.6g Span 85 to make an oil-in-water-in-oil type (o/w/o) double emulsion, and then add 1.1g glutaraldehyde and 0.9 g of sulfuric acid, solidified at a stirring speed of 650 rpm and a water bath temperature of 40° C. for 6 h, filtered and washed to obtain polyvinyl alcohol embolism microspheres.

实施例23聚乙烯醇栓塞微球的制备 Example 23 Preparation of Polyvinyl Alcohol Embolization Microspheres

1)称取0.074g氯化钠,配制0.02g/ml的氯化钠水溶液,将1g聚乙烯醇溶解于氯化钠水溶液中,得到聚乙烯醇浓度为0.27g/ml的溶液;1) Weigh 0.074g of sodium chloride, prepare a 0.02g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and obtain a solution with a polyvinyl alcohol concentration of 0.27g/ml;

2)在室温下将2g碘化油、0.5g三氧化二铁纳米粒子及1g紫杉醇混合均匀后加入到步骤1)的聚乙烯醇溶液中,搅拌,制成水包油(o/w)型乳剂;2) Mix 2g of iodized oil, 0.5g of ferric oxide nanoparticles and 1g of paclitaxel at room temperature and add them to the polyvinyl alcohol solution in step 1), stir to make an oil-in-water (o/w) type Emulsion;

3)将步骤2)制成的乳剂倾入含0.7g司盘85的10g液体石蜡中,制成油包水包油型(o/w/o)复乳,随后加入1.4g戊二醛和1.5g硫酸,在900rpm的搅拌速度和45℃水浴温度下固化3.5h,过滤、洗涤后得到聚乙烯醇栓塞微球。3) Pour the emulsion prepared in step 2) into 10g of liquid paraffin containing 0.7g of Span 85 to make an oil-in-water-in-oil type (o/w/o) double emulsion, and then add 1.4g of glutaraldehyde and 1.5 g of sulfuric acid was cured for 3.5 hours at a stirring speed of 900 rpm and a water bath temperature of 45° C., filtered and washed to obtain polyvinyl alcohol embolism microspheres.

实施例24明胶栓塞微囊的制备The preparation of embodiment 24 gelatin embolization microcapsules

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.025g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.025g/ml gelatin solution;

2)在46℃水浴条件下,将2.5g碘化油、1g四氧化三铁纳米粒子及1.5g索拉非尼混合均匀后加入到步骤1)的明胶溶液中,搅拌,制成水包油(o/w)型乳剂,然后滴加0.1g/ml醋酸溶液调节乳剂的pH值至3.5-4.1,在显微镜下观察到微囊形成后,加入蒸馏水稀释,得到微囊混悬液;2) Under the condition of water bath at 46°C, mix 2.5g iodized oil, 1g iron ferric oxide nanoparticles and 1.5g sorafenib evenly, then add them to the gelatin solution in step 1), and stir to make oil-in-water (o/w) type emulsion, then add 0.1g/ml acetic acid solution dropwise to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, dilute with distilled water to obtain a microcapsule suspension;

3)将步骤2)得到的微囊混悬液在冰水浴条件下加入1.1g甲醛搅拌10min,滴加0.1g/ml氢氧化钠溶液,调节pH值至8-9,固化24h,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微囊。3) Add 1.1g of formaldehyde to the microcapsule suspension obtained in step 2) and stir for 10 minutes in an ice-water bath, add dropwise 0.1g/ml sodium hydroxide solution, adjust the pH value to 8-9, solidify for 24 hours, and let stand to separate layer, decanting the supernatant, filtering and washing to obtain gelatin embolized microcapsules.

实施例25明胶栓塞微囊的制备 Embodiment 25 Preparation of gelatin embolization microcapsules

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.005g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.005g/ml gelatin solution;

2)在53℃水浴条件下,将9.5g碘化油、5g四氧化三铁纳米粒子及4.5g索拉非尼混合均匀后加入到步骤1)的明胶溶液中,搅拌,制成水包油(o/w)型乳剂,然后滴加0.1g/ml醋酸溶液调节乳剂的pH值至3.5-4.1,在显微镜下观察到微囊形成后,加入蒸馏水稀释,得到微囊混悬液;2) In a water bath at 53°C, mix 9.5g iodized oil, 5g ferric oxide nanoparticles and 4.5g sorafenib evenly and add them to the gelatin solution in step 1), stir to make oil-in-water (o/w) type emulsion, then add 0.1g/ml acetic acid solution dropwise to adjust the pH value of the emulsion to 3.5-4.1, observe the formation of microcapsules under a microscope, dilute with distilled water to obtain a microcapsule suspension;

3)将步骤2)得到的微囊混悬液在冰水浴条件下加入1.3g戊二醛固化0.5h,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微囊。3) The microcapsule suspension obtained in step 2) was solidified by adding 1.3 g of glutaraldehyde in an ice-water bath for 0.5 h, standing for stratification, decanting the supernatant, filtering and washing to obtain gelatin embolism microcapsules.

实施例26明胶栓塞微球的制备 Embodiment 26 Preparation of gelatin embolization microspheres

1)称取1g明胶,将明胶用蒸馏水溶胀后制成0.15g/ml的明胶溶液;1) Weigh 1g of gelatin, swell the gelatin with distilled water to make a 0.15g/ml gelatin solution;

2)在60℃水浴条件下,将混合均匀的1.6g碘化油、0.7g四氧化三铁纳米粒子及0.7g索拉非尼混合均匀后加入到步骤1)的明胶溶液中,搅拌,制成水包油(o/w)型乳剂;2) Under the condition of 60°C water bath, mix evenly mixed 1.6g iodized oil, 0.7g iron ferric oxide nanoparticles and 0.7g sorafenib and add them into the gelatin solution in step 1), stir to prepare into an oil-in-water (o/w) emulsion;

3)将步骤2)制成的乳剂倾入含1.87g司盘80的40g液体石蜡中,制成油包水包油(o/w/o)型乳剂,将乳剂转移到冰水浴中继续搅拌10min,加入2g戊二醛,固化0.5h,静置分层,倾出上清液,过滤、洗涤后得到明胶栓塞微球。3) Pour the emulsion prepared in step 2) into 40g of liquid paraffin containing 1.87g of Span 80 to make an oil-in-water-in-oil (o/w/o) emulsion, transfer the emulsion to an ice-water bath and continue stirring After 10 min, 2 g of glutaraldehyde was added, solidified for 0.5 h, allowed to stand for stratification, and the supernatant was poured out, filtered and washed to obtain gelatin embolism microspheres.

实施例27壳聚糖-羧甲基纤维素栓塞微囊的制备 Embodiment 27 Preparation of Chitosan-Carboxymethyl Cellulose Embolization Microcapsules

1)称取0.4g壳聚糖,制成含0.007g/ml壳聚糖的醋酸溶液,称取0.6g羧甲基纤维素钠,制成0.02g/ml的羧甲基纤维素钠水溶液,将壳聚糖的醋酸溶液与羧甲基纤维素钠水溶液混合得到混合溶液;1) Weigh 0.4g chitosan to make an acetic acid solution containing 0.007g/ml chitosan, weigh 0.6g sodium carboxymethyl cellulose to make a 0.02g/ml sodium carboxymethyl cellulose aqueous solution, The acetic acid solution of chitosan is mixed with the sodium carboxymethyl cellulose aqueous solution to obtain a mixed solution;

2)将混合均匀的10g碘化油、5g三氧化二铁纳米粒子及4.5g紫杉醇混合均匀后加入到步骤1)的混合溶液中,磁力搅拌制成水包油(o/w)型乳剂;用0.1g/ml氢氧化钠溶液调节乳剂的pH值至5.5-6.5,反应60min;2) Mix evenly mixed 10g iodized oil, 5g ferric oxide nanoparticles and 4.5g paclitaxel, then add them to the mixed solution in step 1), and stir magnetically to make an oil-in-water (o/w) emulsion; Use 0.1g/ml sodium hydroxide solution to adjust the pH value of the emulsion to 5.5-6.5, and react for 60 minutes;

3)将步骤2)中的反应液置于冰水浴中,加入0.5g戊二醛,交联固化1h,静置分层,倾出上清液,过滤、洗涤后得到壳聚糖-羧甲基纤维素栓塞微囊。3) Put the reaction solution in step 2) in an ice-water bath, add 0.5g of glutaraldehyde, cross-link and solidify for 1 hour, let it stand for stratification, pour out the supernatant, filter and wash to obtain chitosan-carboxymethyl Cellulose-based embolism microcapsules.

对比例空白对照聚乙烯醇栓塞微球的制备Preparation of Blank Control Polyvinyl Alcohol Embolization Microspheres

除不加入碘化油及四氧化三铁纳米粒子外,各组分含量及制备工艺均与实施例5相同,具体制备方法如下:Except not adding iodized oil and iron ferric oxide nanoparticles, the content of each component and the preparation process are the same as in Example 5, and the specific preparation method is as follows:

1)称取0.17g氯化钠,配制0.025g/ml的氯化钠水溶液,将1g聚乙烯醇溶解于氯化钠水溶液中,配制聚乙烯醇浓度为0.15g/ml的溶液;1) Weigh 0.17g of sodium chloride, prepare a 0.025g/ml sodium chloride aqueous solution, dissolve 1g of polyvinyl alcohol in the sodium chloride aqueous solution, and prepare a solution with a polyvinyl alcohol concentration of 0.15g/ml;

2)向步骤1)的聚乙烯醇溶液中加入0.9g甲醛和0.8g硫酸,混合均匀,得到混合溶液;将混合溶液倾入含2g司盘80的50g液体石蜡中,制成油包水型(w/o)乳剂,在750rpm的搅拌速度和30℃水浴温度下固化4h,过滤、洗涤后,得到空白对照聚乙烯醇微球。2) Add 0.9g of formaldehyde and 0.8g of sulfuric acid to the polyvinyl alcohol solution in step 1), and mix well to obtain a mixed solution; pour the mixed solution into 50g of liquid paraffin containing 2g of Span 80 to make a water-in-oil type (w/o) The emulsion was solidified at a stirring speed of 750rpm and a water bath temperature of 30°C for 4h, filtered and washed to obtain blank control polyvinyl alcohol microspheres.

测试1栓塞微球的体外CT及MRI检测 Test 1 In vitro CT and MRI detection of embolization microspheres

分别对实施例5制备的聚乙烯醇栓塞微球和对比例制备的空白对照聚乙烯醇栓塞微球进行体外CT及MRI检测。实验过程如下:配制2%琼脂热溶液,倾入培养皿中,使液面厚度为1.5cm,待溶液冷却形成凝胶后,将聚乙烯醇栓塞微球和空白对照聚乙烯醇栓塞微球分别放在琼脂表面,再次倾入厚度为1cm的琼脂热溶液中并冷却,然后将表面皿分别置于CT和3T MRI下进行扫描,CT和3T MRI下的检测结果分别如图2及图3所示:图2及图3中分别示出了聚乙烯醇栓塞微球(右侧)与空白对照聚乙烯醇栓塞微球(左侧)的体外CT和3T MRI检测结果(从上至下两侧微球的数目分别为1、2、3、4、5个),从图2及图3中看出,在CT和3T MRI下,聚乙烯醇磁性微球清晰可见,而空白对照聚乙烯醇栓塞微球基本未被检测到。In vitro CT and MRI detection were performed on the polyvinyl alcohol embolization microspheres prepared in Example 5 and the blank control polyvinyl alcohol embolization microspheres prepared in Comparative Example, respectively. The experimental process is as follows: prepare 2% agar hot solution, pour it into a petri dish, make the liquid surface thickness 1.5cm, after the solution is cooled to form a gel, put the polyvinyl alcohol embolization microspheres and the blank control polyvinyl alcohol embolization microspheres respectively Put it on the surface of agar, pour it into the hot agar solution with a thickness of 1cm again and cool it down, then place the watch glass under CT and 3T MRI for scanning respectively, the detection results under CT and 3T MRI are shown in Figure 2 and Figure 3 respectively Shown: Figure 2 and Figure 3 respectively show the in vitro CT and 3T MRI detection results of polyvinyl alcohol embolization microspheres (right side) and blank control polyvinyl alcohol embolization microspheres (left side). The number of microspheres is 1, 2, 3, 4, 5 respectively), as can be seen from Figure 2 and Figure 3, under CT and 3T MRI, the polyvinyl alcohol magnetic microspheres are clearly visible, while the blank control polyvinyl alcohol Embolization microspheres were largely undetected.

测试2栓塞微球在小鼠皮下的CT及MRI检测 Test 2 CT and MRI detection of embolization microspheres in mice subcutaneous

从实施例5制备的聚乙烯醇栓塞微球中筛分出100-300μm的微球,将2.5ml微球混悬到20ml含1%羧甲基纤维素钠的生理盐水中,取0.15ml注入小鼠皮下。将小鼠置于CT和3T MRI下进行扫描,CT和3T MRI下的检测结果分别如图4和图5所示。图4示出了聚乙烯醇栓塞微球在小鼠皮下的CT图像,白色箭头标示注射部位。图5示出了聚乙烯醇栓塞微球在小鼠皮下的MRI图像,图5中小鼠体外的白色亮点为维生素E胶囊,白色箭头标示注射部位,CT和MRI结果显示,在小鼠皮下注射部位均可检出聚乙烯醇栓塞微球。Sieve out microspheres of 100-300 μm from the polyvinyl alcohol embolization microspheres prepared in Example 5, suspend 2.5ml of microspheres in 20ml of physiological saline containing 1% sodium carboxymethylcellulose, and inject 0.15ml into mice subcutaneously. The mice were scanned under CT and 3T MRI, and the detection results under CT and 3T MRI are shown in Figure 4 and Figure 5, respectively. Figure 4 shows the CT image of the polyvinyl alcohol embolization microspheres subcutaneously in a mouse, and the white arrow marks the injection site. Figure 5 shows the MRI image of polyvinyl alcohol embolization microspheres subcutaneously in mice. In Figure 5, the white bright spots outside the mouse body are vitamin E capsules, and the white arrows indicate the injection site. The results of CT and MRI show that at the mouse subcutaneous injection site Polyvinyl alcohol embolic microspheres can be detected.

测试3栓塞微球体内栓塞 Test 3 In vivo embolization of embolization microspheres

从实施例5制得的聚乙烯醇栓塞微球中筛分出粒径为100-150μm的微球,灭菌后备用。将禁食12h的家兔麻醉后固定于手术台上,分离一侧颈动脉,在数字减影血管造影(DSA)下,经颈动脉用2.8F导管和导丝进行选择性左肾动脉插管,注入0.15ml微球进行肾栓塞,栓塞前后均对左肾进行DSA检查以确定靶血管是否闭塞。术后进行CT和MRI检测,CT和MRI的检测结果均显示微球所在的位置与DSA检查结果一致。The microspheres with a particle size of 100-150 μm were sieved from the polyvinyl alcohol embolization microspheres prepared in Example 5, and sterilized for later use. The 12-hour fasting rabbit was anesthetized and fixed on the operating table, and one side of the carotid artery was separated. Under digital subtraction angiography (DSA), the left renal artery was selectively intubated with a 2.8F catheter and a guide wire through the carotid artery , inject 0.15ml microspheres for renal embolism, DSA examination is performed on the left kidney before and after embolization to determine whether the target vessel is occluded. Postoperatively, CT and MRI were performed, and the results of both CT and MRI showed that the position of the microspheres was consistent with the results of DSA.

测试4载药栓塞微球的释药实验 Test 4 Drug release experiment of drug-loaded embolic microspheres

采用T形管法测定实施例8制备的载紫杉醇聚乙烯醇栓塞微球的体外释放。实验过程如下:向T型管中加入200ml pH7.4的磷酸缓冲液作为释放介质,缓冲液流度为50ml/min,水浴温度为37℃。将1ml上述微球置于T形管的底部,于0.5h、1h、2h、4h、6h、12h和24h,分别取出5ml释放介质并立即补足等温、等体积的新鲜释放介质,在227nm波长下测定吸光度值,根据标准曲线计算释药量。载紫杉醇聚乙烯醇栓塞微球的释药曲线如图6所示。从图6看出,载紫杉醇聚乙烯醇栓塞微球在前4h释药速率较快,4h时累积释药约45%,24h时累积释药约61%。The in vitro release of the paclitaxel-loaded polyvinyl alcohol embolization microspheres prepared in Example 8 was measured by the T-tube method. The experimental process is as follows: add 200ml of pH7.4 phosphate buffer into the T-tube as the release medium, the fluidity of the buffer is 50ml/min, and the temperature of the water bath is 37°C. Put 1ml of the above-mentioned microspheres at the bottom of the T-shaped tube, take out 5ml of the release medium at 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, and immediately make up isothermal and equal-volume fresh release medium. Determine the absorbance value, and calculate the release amount according to the standard curve. The drug release curve of paclitaxel-loaded polyvinyl alcohol embolization microspheres is shown in Figure 6. It can be seen from Figure 6 that the drug release rate of paclitaxel-loaded polyvinyl alcohol embolization microspheres is faster in the first 4 hours, the cumulative drug release is about 45% at 4 hours, and the cumulative drug release is about 61% at 24 hours.

以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明所附权利要求的范围。The above description of the specific embodiments of the present invention does not limit the present invention, and those skilled in the art can make various changes or deformations according to the present invention, as long as they do not depart from the spirit of the present invention, all should belong to the scope of the appended claims of the present invention.

Claims (52)

1. A embolic material composition made from reactant feedstock comprising: the embolization material composition comprises a biocompatible material, an X-ray opaque substance, a magnetic resonance imaging substance and an optional drug, wherein the X-ray opaque substance and the magnetic resonance imaging substance are wrapped by the biocompatible material, and the drug is wrapped by the biocompatible material;
the embolism material composition is polyvinyl alcohol embolism microsphere, and reactant raw materials of the polyvinyl alcohol embolism microsphere comprise: 1 part by weight of polyvinyl alcohol, 2-8 parts by weight of X-ray opaque substance and 0.5-4 parts by weight of magnetic resonance imaging substance, 0.015-0.31 part by weight of inorganic salt, 0.6-2.3 parts by weight of cross-linking agent, 0.5-1.8 parts by weight of catalyst, 0.1-2.5 parts by weight of surfactant, 5-60 parts by weight of water-immiscible organic solvent and 0-6 parts by weight of drug, wherein the X-ray opaque substance is one or two of X-ray opaque oily liquid or X-ray opaque solid, the magnetic resonance material is one or more of magnetic metal elements of iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, the inorganic salt is one or more of water-soluble sodium salt, potassium salt or ammonium salt, and the cross-linking agent is one or more of formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or hexandialdehyde, the catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid or acetic acid, the surfactant is selected from one or two of span surfactants or a mixture consisting of span surfactants and tween surfactants, and the organic solvent immiscible with water is one or more of mineral oil, vegetable oil, silicone oil, olefin, alcohol, aldehyde, amine, ether or ketone;
or,
the embolism material composition is a polyvinyl alcohol embolism microcapsule, and reactant raw materials of the polyvinyl alcohol embolism microcapsule comprise: 1 weight portion of polyvinyl alcohol, 0.5 to 7.5 weight portions of X-ray opaque substance, 0.2 to 5 weight portions of magnetic resonance imaging substance, 1 to 5.5 weight portions of inorganic salt, 4 to 15 weight portions of cross-linking agent, 0.9 to 13.1 weight portions of catalyst and 0 to 3 weight portions of medicine, wherein the X-ray opaque substance is one or both of an X-ray opaque oily liquid or an X-ray opaque solid, the magnetic resonance material is selected from one or more of magnetic metal elements of iron, gadolinium, manganese, nickel, cobalt, holmium, europium, terbium, dysprosium, thulium or ytterbium, the inorganic salt is selected from one or more of sulfate, phosphate, silicate or acetate, the crosslinking agent is selected from one or more of formaldehyde, acetaldehyde, butyraldehyde, glutaraldehyde or hexandialdehyde, and the catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid or acetic acid.
2. The embolic material composition of claim 1, wherein the microspheres or microcapsules have a particle size of 10-2000 μ ι η.
3. The embolic material composition of claim 1, wherein the drug is selected from one or more of an anti-tumor drug, a local anesthetic drug, an antipyretic, analgesic, anti-inflammatory drug, or an antibiotic drug.
4. The embolic material composition of claim 1, wherein the radiopaque substance is an oily liquid radiopaque for X-ray.
5. The embolic material composition of claim 4, wherein the radiopaque substance is one or both of iodized oil or iodophenyl ester.
6. The embolic material composition of claim 1, wherein the magnetic resonance imaging substance is selected from the group consisting of Fe3O4、Fe2O3、MnFe2O4、CoFe2O4、NiFe2O4、DyFe2O4Or one or more oxides of holmium, gadolinium, europium, terbium, dysprosium, thulium or ytterbium.
7. The embolic material composition of claim 6, wherein the oxide is a nanoparticle.
8. The embolic material composition of claim 6, wherein the magnetic resonance imaging substance is selected from one or both of ferroferric oxide and ferric oxide.
9. The embolic material composition of claim 8, wherein the ferric oxide is gamma ferric oxide.
10. The embolic material composition of claim 1, wherein the polyvinyl alcohol has an average molecular weight of 1,000-500,000D.
11. The embolic material composition of claim 10, wherein the polyvinyl alcohol has an average molecular weight of 10,000-150,000D.
12. The embolic material composition of claim 1, wherein the polyvinyl alcohol has a degree of alcoholysis of from 50 to 100%.
13. The embolic material composition of claim 12, wherein the polyvinyl alcohol has an alcoholysis degree of 75-100%.
14. The embolic material composition of claim 1, wherein the embolic material composition is a polyvinyl alcohol embolic microcapsule having reactant materials comprising: 1 weight portion of polyvinyl alcohol, 1 to 6.5 weight portions of X-ray opaque substance, 0.7 to 4.5 weight portions of magnetic resonance imaging substance, 2.5 to 3.5 weight portions of inorganic salt, 6 to 11 weight portions of cross-linking agent, 5.8 to 13.1 weight portions of catalyst and 0.5 to 1.5 weight portions of medicine.
15. The embolic material composition of claim 1, wherein the embolic material composition is a polyvinyl alcohol embolic microsphere having reactant materials comprising: 1 weight portion of polyvinyl alcohol, 6 to 8 weight portions of X-ray opaque substance, 1 to 4 weight portions of magnetic resonance imaging substance, 0.15 to 0.31 weight portion of inorganic salt, 0.6 to 1.2 weight portions of cross-linking agent, 0.8 to 1.5 weight portions of catalyst, 0.6 to 2 weight portions of surfactant, 10 to 50 weight portions of organic solvent which is not mutually soluble with water and 2 to 6 weight portions of medicine.
16. The embolic material composition of claim 1, wherein the inorganic salt used to prepare the polyvinyl alcohol embolic microspheres is selected from one or more of potassium chloride, sodium chloride, or ammonium chloride.
17. The embolic material composition of claim 16, wherein the inorganic salt is sodium chloride.
18. The embolic material composition of claim 1, wherein the inorganic salt used to prepare the polyvinyl alcohol embolic microcapsules is selected from one or two of sodium sulfate, aluminum sulfate, ammonium sulfate, sodium tripolyphosphate.
19. The embolic material composition of claim 18, wherein the inorganic salt is sodium sulfate.
20. The embolic material composition of claim 1, wherein the surfactant is one or both of span 80 or span 85.
21. The embolic material composition of claim 1, wherein the water-immiscible organic solvent is liquid paraffin or cyclohexane.
22. The embolic material composition of claim 3, wherein the anti-tumor drug is selected from one or more of doxorubicin, epirubicin, daunorubicin, mitomycin, methotrexate, bleomycin, cisplatin, carboplatin, irinotecan, paclitaxel, docetaxel, 5-fluorouracil, pingyangmycin, sunitinib, sorafenib, gefitinib, imatinib, vatalanib, or salts thereof.
23. The embolic material composition of claim 3, wherein the local anesthetic drug is selected from one or more of procaine, chloroprocaine, hydroxyprocaine, tetracaine, paraethoxycaine, tetracaine, dicaine, lidocaine, trimecaine, prilocaine, mepivacaine, bupivacaine, ropivacaine, cinchocaine, dyclonine, favicine, quinicaine, phenacaine, or salts thereof.
24. The embolic material composition of claim 3, wherein the antipyretic, analgesic, and anti-inflammatory drug is selected from one or more of aspirin, magnesium salicylate, sodium salicylate, choline magnesium salicylate, diflunisal, salsalate, ibuprofen, indomethacin, flurbiprofen, phenoxyibuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, acetaminophen, diclofenac, fenprophen, ketoprofen, ketorolac, tetrachlorofenamic acid, sulindac, or tolmetin.
25. The embolic material composition of claim 3, wherein the antibiotic drug is selected from one or more of penicillin, oxacillin sodium, ampicillin sodium, amoxicillin, cefoperazone, cefotaxime sodium, aztreonam, clavulanic acid, sulbactam, oxytetracycline, tetracycline, demeclocycline, streptomycin, kanamycin A, gentamicin, tobramycin, sisomicin, amikacin, dibekacin, isepamicin, ribomycin, kanamycin B, neomycin B, paromomycin, erythromycin, roxithromycin, clarithromycin, azithromycin, chloramphenicol, cyclosporine, lincomycin, or salts thereof.
26. The method for producing an embolic material composition according to any of claims 1 to 25,
the embolism material composition is characterized in that the embolism material composition is a polyvinyl alcohol embolism microcapsule, and the polyvinyl alcohol embolism microcapsule is prepared by the following method:
step a 1: weighing polyvinyl alcohol with the formula ratio to prepare 0.0035-0.05g/ml polyvinyl alcohol solution;
step b 1: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional medicines into the polyvinyl alcohol solution obtained in the step a1, and stirring to obtain a mixed solution;
step c 1: weighing inorganic salt with the formula amount, preparing 0.1-0.4g/ml inorganic salt solution, adding the inorganic salt solution into the mixed solution in the step b1 at the water bath temperature lower than the cloud point temperature of the polyvinyl alcohol solution under the condition, continuously stirring and slowly heating, adding a cross-linking agent and a catalyst when the temperature is raised to the cloud point temperature, curing at constant temperature for 15-23h, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
27. The method according to claim 26, wherein in step a1, the polyvinyl alcohol is weighed to obtain a polyvinyl alcohol solution of 0.025-0.04 g/ml.
28. The method according to claim 27, wherein in step a1, the polyvinyl alcohol is weighed out to obtain a polyvinyl alcohol solution of 0.025 g/ml.
29. The method according to claim 26, wherein in step c1, the inorganic salt is weighed to obtain a solution of 0.21-0.29g/ml inorganic salt.
30. The method according to claim 29, wherein in step c1, the inorganic salt is weighed out to obtain a solution of 0.25g/ml inorganic salt.
31. The method of claim 26, wherein in step c1, the inorganic salt solution is added to the mixture of step b1 at a bath temperature of 5-15 ℃ below the cloud point temperature of the polyvinyl alcohol solution under the conditions.
32. The method for preparing the nano particles according to claim 26, wherein in the step c1, the nano particles are solidified for 21-23h at constant temperature.
33. The method for preparing the nano particles according to the claim 32, wherein in the step c1, the nano particles are cured for 22 hours at a constant temperature.
34. The method for preparing an embolic material composition according to any of claims 1 to 25, wherein the embolic material composition is a polyvinyl alcohol embolic microcapsule prepared by:
step a 2: weighing polyvinyl alcohol with the formula ratio to prepare 0.0035-0.05g/ml polyvinyl alcohol solution;
step b 2: weighing inorganic salt with the formula ratio, preparing 0.1-0.4g/ml inorganic salt solution, mixing the inorganic salt solution with the polyvinyl alcohol solution in the step a2, then adding the X-ray opaque substance, the magnetic resonance imaging substance and the optional drug, and stirring at a water bath temperature lower than the cloud point temperature of the polyvinyl alcohol solution under the condition to obtain mixed solution;
step c 2: and (3) continuously stirring and slowly heating, adding a cross-linking agent and a catalyst when the temperature rises to the cloud point temperature, curing for 15-23h at constant temperature, filtering and washing to obtain the polyvinyl alcohol embolism microcapsule.
35. The method according to claim 34, wherein in step a2, the polyvinyl alcohol is weighed to obtain a polyvinyl alcohol solution of 0.025-0.04 g/ml.
36. The method according to claim 35, wherein in step a2, the polyvinyl alcohol is weighed out to obtain a polyvinyl alcohol solution of 0.025 g/ml.
37. The method according to claim 34, wherein in step b2, the inorganic salt is weighed out to obtain a solution of 0.21-0.29g/ml inorganic salt.
38. The method according to claim 37, wherein in step b2, the inorganic salt is weighed out to obtain a solution of 0.25g/ml inorganic salt.
39. The method of claim 34, wherein in step b2, the polyvinyl alcohol solution is stirred at a bath temperature of 5-15 ℃ below the cloud point temperature of the polyvinyl alcohol solution under the conditions.
40. The method for preparing the nano particles as claimed in claim 34, wherein in the step c2, the nano particles are solidified for 21-23h at constant temperature.
41. The method for preparing a nano material according to claim 40, wherein in the step c2, the nano material is cured for 22 hours at a constant temperature.
42. The method for preparing the embolic material composition of any of claims 1 to 25, wherein the embolic material composition is polyvinyl alcohol embolic microspheres prepared by:
step a 3: weighing inorganic salt with a formula amount to prepare an inorganic salt water solution with the concentration of 0.0045-0.025g/ml, and dissolving polyvinyl alcohol with the formula amount in the inorganic salt water solution to obtain a solution with the concentration of 0.08-0.3 g/ml;
step b 3: adding an X-ray opaque substance, a magnetic resonance imaging substance and optional medicines into the solution obtained in the step a3 at room temperature, and stirring to obtain a mixed solution;
step c 3: b3, pouring the mixed solution into an organic solvent which contains a surfactant and is not mutually soluble with water to prepare an emulsion, then adding a cross-linking agent and a catalyst, curing for 2-23h at the stirring speed of 300-1500rpm and the water bath temperature of 30-65 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere; or adding a cross-linking agent and a catalyst into the mixed solution prepared in the step b3, uniformly stirring, pouring into an organic solvent which contains a surfactant and is not mutually soluble with water to prepare an emulsion, curing for 2-23h at the stirring speed of 300-1500rpm and the water bath temperature of 30-65 ℃, filtering and washing to obtain the polyvinyl alcohol embolism microsphere.
43. The method according to claim 42, wherein in step a3, the inorganic salt is weighed to obtain an aqueous solution of 0.017-0.025 g/ml.
44. The method according to claim 43, wherein in step a3, the inorganic salt is weighed out to obtain a formula amount to obtain an aqueous solution of 0.02g/ml inorganic salt.
45. The method according to claim 42, wherein in step a3, the polyvinyl alcohol is dissolved in an aqueous solution of an inorganic salt to obtain a solution having a polyvinyl alcohol concentration of 0.21-0.3 g/ml.
46. The method according to claim 45, wherein in step a3, the polyvinyl alcohol is dissolved in an aqueous solution of an inorganic salt to obtain a solution with a polyvinyl alcohol concentration of 0.21 g/ml.
47. The method as claimed in claim 42, wherein in step c3, the cross-linking agent and the catalyst are added and cured for 3.5-6h at a stirring speed of 550-650rpm and a water bath temperature of 30-45 ℃.
48. The preparation method of claim 47, wherein in the step c3, the cross-linking agent and the catalyst are added, the mixture is solidified for 4 hours at a stirring speed of 600rpm and a water bath temperature of 30 ℃, and the polyvinyl alcohol embolism microspheres are obtained after filtration and washing.
49. The method as claimed in claim 42, wherein in the step c3, the emulsion is prepared and then cured for 3.5-6h at a stirring speed of 550-650rpm and a water bath temperature of 30-45 ℃.
50. The method of claim 49, wherein in step c3, the emulsion is prepared and then cured for 4 hours at a stirring speed of 600rpm and a water bath temperature of 30 ℃.
51. Use of the embolic material composition of any of claims 1 to 25 in the manufacture of a medicament for treating a tumor or vascular malformation or for hemostasis.
52. The use according to claim 51, wherein the tumor is liver cancer, liver metastasis of colorectal cancer, kidney cancer, lung cancer, prostate cancer, ovarian cancer, uterine fibroids or breast malignancy.
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