WO2023174089A1 - 液体栓塞剂及其制备方法和应用 - Google Patents

液体栓塞剂及其制备方法和应用 Download PDF

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WO2023174089A1
WO2023174089A1 PCT/CN2023/079840 CN2023079840W WO2023174089A1 WO 2023174089 A1 WO2023174089 A1 WO 2023174089A1 CN 2023079840 W CN2023079840 W CN 2023079840W WO 2023174089 A1 WO2023174089 A1 WO 2023174089A1
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liquid embolic
particles
porous
embolic agent
agent according
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PCT/CN2023/079840
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English (en)
French (fr)
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张国艺
郭远益
虞鹏
王亦群
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神泓医疗科技(上海)有限公司
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Publication of WO2023174089A1 publication Critical patent/WO2023174089A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/18—Materials at least partially X-ray or laser opaque

Definitions

  • the present application relates to the technical field of medical devices, and in particular to a liquid embolic agent and its preparation method and application.
  • the main treatment methods in current neurointerventional treatments for cerebral arteriovenous malformations (AVMs), cerebral arteriovenous fistulas (DVF), and cerebral chronic subdural hematomas (cDSH) include: surgical treatment, interventional embolization, and radiotherapy.
  • surgical treatment interventional embolization and then surgical resection will also be adopted depending on the condition of the disease. Therefore, interventional embolization technology plays an important role in neurointerventional treatment.
  • the interventional embolization materials used in interventional embolization technology currently mainly fall into two categories: solid and liquid.
  • solid embolization materials are mostly used in surgical procedures.
  • Anterior embolization is difficult to achieve the purpose of curative embolization.
  • Liquid embolic agents can pass through thinner microcatheters and evenly fill diseased blood vessels after injection. After solidification, they can be blocked, reducing the possibility of blood vessel recanalization and achieving precise and permanent embolization.
  • liquid embolic agents that are widely used clinically are divided into adhesive liquid embolic agents and non-adhesive liquid embolic agents.
  • the adhesive liquid embolic agent uses cyanoacrylate as the main component.
  • the non-adhesive liquid embolic agent is a DMSO solution of ethylene vinyl alcohol polymer, with metal powder added as a developer, such as tantalum powder, tantalum oxide or bismuth trioxide.
  • the most commonly used non-adhesive liquid embolic agent is Onyx liquid embolic agent, which is mainly composed of ethylene vinyl alcohol polymer dissolved in dimethyl sulfoxide and added with micron-grade tantalum. Powder is made as a developer.
  • Its embolization principle is to stir or shake the metal tantalum powder vigorously for a long time in the dimethyl sulfoxide solution of the polymer to form a tantalum powder suspension.
  • the tantalum powder suspension is injected through a microcatheter. After intracranial blood vessels and other diseased blood vessels, an embolus mass is formed to block the vascular access and achieve the purpose of blocking blood flow.
  • liquid embolic agent including in terms of mass fraction:
  • developer 10% to 50% the developer includes porous developing particles modified with organic compounds.
  • the mass fraction of the organic compound-modified porous developer particles is 50% to 100%.
  • the mass percentage of the organic compound in the modified porous developer particles is 0.01% to 10%.
  • the mass percentage of the organic compound in the modified porous developer particles is 0.1% to 10%.
  • the organic compounds modified on the porous developing particles are passed through Chemical bonds are connected to the porous developer particles.
  • the organic compound is a small molecule compound or a high molecular compound.
  • the number of repeating units in the molecular structure of the organic compound ranges from 1 to 1,000.
  • the organic compound is selected from polyacrylates, polymethacrylates, polyurethanes, polyesters, polyethers, polysiloxanes, polyvinyl acetate, polyenols, polydopamine, polyamides and at least one type of polysaccharide.
  • the organic compound-modified porous developing particles are produced by using the porous developing particles using a surface polymerization method or a graft coupling method.
  • the surface of the porous developer particles has porous holes.
  • the porous developer particles are hollow particles.
  • the particle size of the porous developer particles ranges from 0.01 ⁇ m to 150 ⁇ m.
  • the porous developer particles have a pore size distribution ranging from 1 nm to 2000 nm.
  • the porous developing particles have a porosity of 10% to 90%.
  • the porous developing particles are hollow particles and have porous holes on the surface, and the hollow structure of the porous developing particles is interconnected with at least part of the holes on the surface.
  • At least some of the porous holes on the surface of the porous developing particles are through holes.
  • the porous developer particles contain developable metal elements.
  • the weight average molecular weight of the polymer ranges from 10,000 to 400,000.
  • the polymer is any one of polyolefin, polyalkenol, polyacrylate, polymethacrylate, polyurethane, polyester, polyether, polysiloxane and polyamide, Or a copolymer of at least two of them.
  • the excipient is at least one of a biocompatible organic solvent, water, and a buffer.
  • the porous developing particles are made of a developable metal material, an alloy material containing a developable metal, or a developable metal compound material.
  • Another aspect of the present application provides a method for preparing a liquid embolic agent, including the following steps:
  • Another aspect of the present application provides the use of any of the above liquid embolic agents in the preparation of medical interventional devices or interventional treatment drugs.
  • a medical interventional device which is characterized in that it includes a device body and a reagent provided in the device body, and the reagent includes any of the liquid embolic agents described above.
  • Another aspect of the present application provides an interventional treatment drug, which includes the liquid embolic agent as described in any one of the above.
  • Figure 1 is a schematic diagram of the mixing state of the liquid embolic agent according to one embodiment of the present application
  • Figure 2 is a schematic diagram of porous developing particles modified with organic compounds in the liquid embolic agent shown in Figure 1.
  • liquid embolic agent which includes, in terms of mass fraction: 1% to 20% of polymer, 10% to 50% of developer, and 50% to 89% of excipient.
  • the developer includes porous developing particles modified with organic compounds.
  • porous developing particles have "developable” properties, and "developable” means visible under X-rays.
  • the components need to be thoroughly mixed.
  • the mixing state is shown in Figure 1.
  • the organic compound-modified porous developing particles 12 are the developer, and the polymer 11 in the liquid embolic agent and the organic compound-modified porous developing particles 12 are dispersed in the excipient 13 .
  • polymer 11 has better compatibility or uniform dispersion in excipient 13.
  • the porous developing particles 12 modified with organic compounds include a porous developing particle body 121 (hereinafter referred to as a porous developing particle) and an organic compound 122 modified on the surface of the porous developing particle body 121, and the molecular chain of the organic compound 122 can interact with the polymer 11.
  • the excipient 12 has entanglement of molecular chains and intermolecular interactions.
  • the developer of the above-mentioned liquid embolic agents contains porous developing particles modified with organic compounds.
  • the porous developing particles have a porous structure, which can reduce the mass per unit volume of the developer.
  • the molecular chains of the organic compounds modified on the porous developing particles can interact with the polymer.
  • the compound has the entanglement of molecular chains and intermolecular interactions in the excipient, which is equivalent to forming a protective layer or buffer layer on the outer surface of the porous developing particles, which can prevent the settling of the developing particles to a certain extent, and then
  • the suspension stability of the porous developing particles modified with organic compounds is improved from many aspects such as density and intermolecular interaction, which improves the settling problem of the developing particles and reduces the risk of the developing particles being taken away with the excipients during the diffusion process. , which helps the liquid embolic agent to accurately reach the diseased site and maintain a high developer concentration, thereby providing good development effects.
  • the mass fraction of the polymer can be 1%, 2%, 3%, 5%, 10%, 13%, 15%, 18%, 20%; the mass fraction of the developer can be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%; the mass fraction of excipients can be 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 89%.
  • the porous developer particles contain developable metallic elements.
  • the developable metal elements are gold (Au), silver (Ag), platinum (Pt), iridium (Ir), chromium (Cr), tantalum (Ta), bismuth (Bi), cobalt (Co), tungsten (W) and At least one of barium (Ba).
  • the developable metal may also include at least one of lanthanide and actinide metals.
  • the porous developing particles are made of a developable metal material, an alloy material containing a developable metal, or a developable metal compound material.
  • the metal material is one of the above-mentioned developable metal elements.
  • the porous developer particles may be at least one of gold particles, silver particles, platinum particles, iridium particles, chromium particles, tantalum particles, bismuth particles, cobalt particles, tungsten particles, and barium particles.
  • the alloy material is at least two of the developable metal elements or the developable metal element.
  • An alloy of at least one element and at least one other metal is an alloy metal material.
  • the porous developer particles may be platinum-iridium alloys, cobalt-chromium alloys, cobalt-vanadium alloys, cobalt-based alloys, samarium-cobalt alloys, zirconium-cobalt alloys, tungsten-cobalt alloys, cobalt-chromium-tungsten alloys, chromium-copper alloys, tantalum-based alloys, cobalt-tantalum Zirconium alloy, etc.
  • the metal compound material is at least one of metal salts, metal oxides, metal carbides and metal nitrides formed from one of the developable metal elements and insoluble in the above-mentioned excipient.
  • metal compound materials include silver halide, bismuth oxide, tantalum carbide, barium sulfate, tungsten oxide, tantalum nitride, tantalum oxide, etc.
  • metal salts, metal oxides, metal carbides and metal nitrides are metal compounds that are insoluble in water and inorganic solvents.
  • the mass fraction of the organic compound-modified porous developer particles is 50% to 100%, such as 50%, 55%, 60%, 65%, 70%, 75%, 80% , 85%, 90%, 95%, 100%.
  • the mass fraction of the porous developing particles modified with organic compounds is 100%, that is, the developers are all porous developing particles modified with organic compounds.
  • the liquid embolic agent may also contain other developing agents, such as at least one of solid developing particles and porous developing particles without organic compound modification.
  • the mass fraction of the porous developer particles modified with organic compounds is 70% to 90%.
  • the organic compounds modified on the porous developer particles are connected to the porous developer particles through chemical bonds.
  • the connection with the porous developing particles through chemical bonds is very strong and can exist stably throughout the dispersion process.
  • the mass percentage of the organic compound in the modified porous developing particles is 0.01% to 10%, such as 0.01%, 0.03%, 0.04%, 0.05%, 0.1%, 0.27%, 0.3%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%; in some examples, the mass percentage of the organic compound in the modified porous developing particles is 0.04% to 10% , 0.1 ⁇ 10%, 0.5% ⁇ 5%, 0.04% ⁇ 5%, 0.04% ⁇ 4.5%.
  • the organic compound is a small molecule compound or a high molecular compound, which can be beneficial to Suspension stability of porous developer particles in polymer solutions formed from polymers and excipients, e.g.
  • the organic compound is a polymer compound.
  • the number of repeating units in the molecular structure of the organic compound ranges from 1 to 1,000. In some examples, the number of repeating units in the molecular structure of the organic compound ranges from 1 to 100, and further ranges from 2 to 100.
  • organic compounds are molecular layers with only a few repeating units, or molecular layers connected by several different chemical structures, or polymers with a certain degree of polymerization. In some embodiments, the number of repeating units of the organic compound molecule is 1 to 10.
  • the porous developing particles modified with this organic compound can maintain the stability of suspension in the polymer solution without being affected by the number of repeating units. If it is too large, it will increase the overall viscosity of the liquid embolic agent.
  • porous developing particles modified with organic compounds are produced by surface polymerization or graft coupling of porous developing particles.
  • the surface polymerization method is to perform a polymerization reaction on the surface of the porous developing particles, so that the reactive groups in the organic compounds or the monomers used to form the organic compounds are polymerized on the surface of the porous developing particles to obtain polymers, thereby forming surface organic compounds.
  • Modified porous developer particles are to perform a polymerization reaction on the surface of the porous developing particles, so that the reactive groups in the organic compounds or the monomers used to form the organic compounds are polymerized on the surface of the porous developing particles to obtain polymers, thereby forming surface organic compounds.
  • the graft coupling method is as follows: first perform surface activation treatment on the porous developing particles, and then chemically react the surface-activated porous developing particles with the reactive groups in the organic compounds, and bond to form polymer-modified Porous developing particles.
  • the organic compound is selected from the group consisting of polyacrylates, polymethacrylates, polyurethanes, polyesters, polyethers, polysiloxanes, polyvinyl acetate, polyvinyl alcohols, polydopamine, polyamides, and polysaccharides. at least one of them.
  • These polymers can be chemically bonded through the modification of functional groups to form ester bonds, urethane bonds, ether bonds, etc. between the developer particles, or through the formation of ester bonds in the developer particles.
  • the surface is modified with an initiator and is obtained through a monomer polymer. It also has a longer molecular chain, which will have a stronger interaction with the polymer molecules in the liquid embolic agent itself, further improving the suspension stability of the developing particles.
  • polyacrylates include polyhydroxyethyl (meth)acrylate, polyethylene glycol (meth)acrylate, polyethylene glycol acrylate, polypropylene glycol methacrylate, and polybutylene acrylate, Polyaminoethyl acrylate, polyaminopropyl acrylate, polydiaminobutyl acrylate, polybenzyl glycol acrylate, etc.; in some specific examples, the porous developing particles modified by the above organic compound are bismuth modified by polyhydroxyethyl acrylate.
  • porous developing particles can be modified with a variety of different organic compounds mentioned above.
  • polydopamine may be first used to modify the porous developing particles, and then polyacrylate may be used to further modify the polydopamine-modified porous developing particles. More specifically, before modifying with polydopamine, it also includes the step of hydroxylating the surface of the porous developing particles. Before further modifying the polydopamine-modified porous developing particles with polyacrylate, it also includes the step of modifying the polydopamine-modified porous developing particles with an initiator.
  • the surface of the porous developer particles has porous holes.
  • porous developing particles are solid particles with porous holes on the surface.
  • solid particles in this article are relative to hollow particles.
  • Solid particles refer to particles that do not have an internal hollow structure, that is, the entire interior has a solid structure, but the surface can be porous or non-porous.
  • solid particles in this article include, but are not limited to, particles with a solid interior structure but no holes on the surface, and particles with a solid interior structure and holes on the surface.
  • the solid particles can be produced through polymer template methods.
  • the polymer template method refers to using polymer microspheres as templates to form a metal layer, alloy layer or metal compound layer on the surface of polymer microspheres, and then retaining the polymer microspheres without removing the polymer microsphere template.
  • the template serves as the core, and the resulting solid particles include a core of polymer material and developable metal materials and alloys. material or metal compound.
  • the preparation method of the above-mentioned solid particles with porous holes on the surface is as follows: first prepare polymer microspheres of a certain particle size by emulsion polymerization or self-assembly, and then use deposition or surface modification on the surface of the polymer microspheres. Methods form a metal layer, alloy layer or metal compound layer.
  • the polymer microspheres used can be purchased directly from the market, such as polyethylene, polystyrene, polystyrene-divinylbenzene and other microspheres.
  • porous holes can be formed in the shell layer by controlling the molecular growth and deposition process of the metal layer, alloy layer or metal compound layer as the shell layer.
  • the porous developer particles are hollow particles. It can be understood that hollow particles in this article refer to particles with an internal hollow structure, but the surface may be porous or non-porous. In other words, hollow particles in this article include, but are not limited to, particles with an overall hollow structure inside but no holes on the surface, and particles with an overall hollow structure inside and holes on the surface.
  • the preparation method of the above hollow particles may be a polymer template method.
  • the polymer template method refers to using emulsion polymerization or self-assembly methods to first prepare polymer microspheres of a certain particle size, and then depositing a metal layer, an alloy layer, or a metal layer on the surface of the polymer microspheres. The surface growth is grafted to form a metal compound layer. The metal, alloy or metal compound layer can exist stably and separate.
  • the polymer microsphere template in the core can be removed by elution with a specific solvent, or removed by calcination at a specific temperature or other means.
  • the core polymer microsphere template is used to obtain hollow particles. You can also use solvent to elute first, and then calcine to remove the polymer microsphere template to obtain hollow particles (or hollow microspheres).
  • the volume proportion of the hollow portion of the hollow particles can be controlled by controlling the particle size of the polymer microspheres and the thickness of the deposited metal layer or metal compound layer. Furthermore, when using a solution method to form a metal layer and a metal compound layer, the thickness of the formed metal layer and metal compound layer can be controlled by adjusting the concentration of the raw materials used to form the metal and metal compound layer in the solution to achieve the desired thickness of the hollow part. Adjustment of volume ratio.
  • holes can be formed in the shell layer by controlling the molecular growth and accumulation process of the shell layer.
  • the polymer microspheres can be polymer microspheres purchased directly from the market, such as polyethylene Microspheres such as olefin, polystyrene, polystyrene-divinylbenzene, etc.
  • the shape of the porous developing particles may be spherical, ellipsoid, etc.
  • porous developing particles are hollow particles and have porous holes on their surfaces.
  • the porous developing particles are hollow particles and have porous holes on the surface.
  • the hollow structure of the porous developing particles is interconnected with at least part of the holes on the surface.
  • porous holes on the surface of the porous developing particles are through holes.
  • a through hole means that both ends of the hole distributed in the particle are connected to the outside, and the hole passes through the interior of the particle from one end to the other end.
  • the particle size of the porous developer particles is 0.01 ⁇ m to 150 ⁇ m, such as 0.01 ⁇ m, 0.05 ⁇ m, 0.1 ⁇ m, 0.2 ⁇ m, 0.5 ⁇ m, 1 ⁇ m, 5 ⁇ m, 10 ⁇ m, 20 ⁇ m, 30 ⁇ m, 50 ⁇ m, 60 ⁇ m, 70 ⁇ m, 80 ⁇ m, 90 ⁇ m. , 100 ⁇ m, 110 ⁇ m, 120 ⁇ m, 130 ⁇ m, 140 ⁇ m, 150 ⁇ m; further 0.1 ⁇ m ⁇ 50 ⁇ m.
  • the porous developer particles can be monodisperse particles of uniform particle size, or polydisperse particles of multiple different particle sizes.
  • the porous developing particles may be particles with a specific particle size distribution obtained by combining them in a certain proportion.
  • the pore size distribution of the porous developing particles is 1 nm to 2000 nm. Further, the pore size distribution of the porous developing particles is 100 nm to 1000 nm. It can be understood that the pore diameter of the porous developing particles can be pores of uniform size or polydispersed pores of non-uniform size. Suitable pore sizes facilitate the penetration of solutions and modification of organic compounds.
  • the porous developing particles have a porosity of 10% to 90%, such as 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%; in some examples, porous
  • the porosity of the developed particles is 10% to 70%, further 20% to 50%.
  • porosity refers to the percentage of the pore volume in porous developing particles and the total volume of the material in its natural state. The higher the porosity, the larger the specific surface area of the particles and the higher the proportion of organic compound modifications.
  • a suitable density can be obtained by optimizing the porosity of the porous developing particles. This density can enable the porous developing particles to have a higher performance in liquid embolic agents. Good suspension stability makes it easy to disperse and difficult to settle.
  • the polymer is polyolefin, polyolefin alcohol, polyacrylate, polymethacrylate It can be any one of acrylate, polyurethane, polyester, polyether, polysiloxane and polyamide, or a copolymer of at least two of them.
  • the above-mentioned copolymers include, but are not limited to, random copolymers, block copolymers, alternating copolymers, and graft copolymers.
  • the above-mentioned polymer can be polyacrylamide-polymethylmethacrylate copolymer, polyethylene-vinyl alcohol copolymer, polyethylene glycol-polyacrylate copolymer, water-insoluble natural polymer, such as fiber At least one of the hormones and their derivatives.
  • the weight average molecular weight of the polymer contained in the liquid embolic agent ranges from 10,000 to 400,000; further, the weight average molecular weight ranges from 100,000 to 300,000. Further, the molar content of the hydrophobic component of the polymer is greater than 50%, further still greater than 60%.
  • the hydrophilic component refers to the hydrophilic group contained in the side chain or main chain of the polymer, otherwise it is a hydrophobic component. The higher the content of hydrophobic components, the shorter the time for the polymer to separate out in water, buffer or blood, and the corresponding smaller the curing rate. Therefore, the curing rate can be controlled by adjusting the proportion of hydrophilic and hydrophobic components.
  • the excipient is at least one of the following solvents: biocompatible organic solvents, water, and buffers. These solvents are non-toxic or have low toxicity and can function as diluents or dispersants in liquid embolic agents.
  • biocompatible organic solvents include but are not limited to at least one of dimethyl sulfoxide, N-methylpyrrolidone (NMP), ethanol, and isopropyl alcohol. These solvents have the advantage of low toxicity. It is understood that the solvent can be selected according to the type of the polymer, as long as it can make the polymer and the solvent form a uniform system.
  • the homogeneous system here refers to a homogeneous clear solution or a homogeneous suspension.
  • the excipient can be a good solvent for the above-mentioned polymer, that is, the excipient and the polymer can form a uniform clear solution, or the excipient and the polymer can form a uniform system under specific conditions.
  • Another embodiment of the present application also provides a method for preparing the above-mentioned liquid embolic agent, which involves mixing the above-mentioned polymer, excipients and other other components evenly.
  • the polymer and the excipient can be mixed first by mechanical stirring or other means to form a homogeneous polymer solution, and then the developer can be added and mixed again by mechanical stirring or other means to form a uniformly dispersed system.
  • thermoforming a homogeneous phase of the polymer solution methods such as heating, cooling, and physical dispersion can be used to assist in promoting its dissolution.
  • the liquid embolic agent When the liquid embolic agent forms a uniform dispersion system, it can be transported or pushed. After reaching the water or blood, with the diffusion of the excipient, the polymer in the liquid embolic agent precipitates out, forming a soft embolic mass. The developer in the embolic mass ensures its good developing performance.
  • Another embodiment of the present application also provides the use of the above-mentioned liquid embolic agent in the preparation of medical interventional devices or interventional treatment drugs.
  • Another embodiment of the present application also provides a medical interventional device, a device body and a reagent provided in the device body, where the reagent includes any of the above liquid embolic agents.
  • the device body is a catheter.
  • the inner diameter of the catheter is very small and is called a microcatheter.
  • the inner diameter of the microcatheter is 0.007 to 0.013 inches.
  • Another embodiment of the present application also provides an interventional treatment drug, which includes any of the above liquid embolic agents.
  • the interventional treatment medicine may also contain active ingredients that have a therapeutic effect on the disease.
  • the interventional treatment medicine may also contain other additives.
  • liquid embolic agent can be used in interventional treatments, such as interventional hemostasis, vascular malformations and malignant tumors, including but not limited to cerebral arteriovenous malformations (AVMs), hematomas, cerebral arteriovenous fistulas (DVF), and subdural hematomas.
  • the liquid embolic agent is injected through a microcatheter to reach the diseased site, contacts the blood flow, and begins to solidify as the excipient diffuses.
  • the polymer in the liquid embolic agent slowly precipitates and solidifies.
  • An embolic mass is formed, thereby blocking the vascular passage and blocking blood flow.
  • the above-mentioned liquid embolic agent with organic compound-modified porous developing particles has excellent suspension stability, which can reduce the preoperative shaking time, reduce the risk of settlement during the diffusion process, improve its dispersion performance, and reduce reflux during the injection process. risk. Therefore, after the liquid embolic agent is pushed from the microcatheter, the microcatheter can be easily withdrawn, reducing the risk of the microcatheter being pulled on the blood vessels.
  • Polydopamine modified bismuth particles Add the above hydroxylated bismuth particles to a dopamine hydrochloride aqueous solution with a concentration of 2 mg/mL, adjust the pH value to above 10 with sodium hydroxide solution, react in the dark for 24 hours, filter, and wash several times with deionized water to obtain polydopamine. Modified bismuth particles.
  • Bromine initiator modifies bismuth particles. Under anhydrous and oxygen-free conditions, add the above polydopamine-modified bismuth particles to toluene, add 2-bromoisobutyryl bromide, and react with stirring at room temperature for 20 hours. After completion, wash with toluene, ethanol, and deionized water. Several times, bismuth particles modified with bromine initiator were obtained.
  • the concentration of polyhydroxyethyl acrylate-modified bismuth particles was 40 wt%, and the concentration of polyvinyl alcohol was 10 wt%.
  • the preparation steps are basically the same as those in Example 1.
  • the difference lies in adjusting the reaction time after adding the monomer hydroxyethyl acrylate in step 4 of step (1), controlling the monomer conversion rate, and obtaining bismuth particles with different degrees of modification, that is, different contents.
  • Example 5 is basically the same as Example 1, except that steps 3 and 4 in step (1) are omitted, and polydopamine-modified bismuth particles are directly used as the developer for the preparation of the embolic agent.
  • the concentration of polyhydroxyethyl acrylate-modified bismuth particles was 40 wt%, and the concentration of polyvinyl alcohol was 10 wt%.
  • the polyhydroxyethyl acrylate (PHEMA)-modified bismuth particles prepared in step (1) of Examples 1 to 4 were subjected to thermogravimetric analysis to obtain the PHEMA modification amount as shown in Table 1 below.
  • the polydopamine-modified bismuth particles prepared in Example 5 were subjected to thermogravimetric analysis to obtain the polydopamine modification amount as shown in Table 1 below.
  • the present application uses the above-mentioned modified bismuth particles as the developer to prepare the liquid embolic agent, which can delay the time for delamination to occur when it is left standing.
  • the corresponding The particle suspension stability of the liquid embolic agent is greatly improved, so sufficient operating time is reserved for the user to improve the particle suspension stability of the liquid embolic agent during the pushing process.
  • it helps the liquid embolic agent to accurately reach the diseased site and maintain a high developer concentration, thus providing good imaging effects.

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Abstract

本申请涉及一种液体栓塞剂及其制备方法和应用，该液体栓塞剂按质量分数计，包括：聚合物1％～20％；显影剂10％～50％，所述显影剂包含有机化合物修饰的多孔显影颗粒；及赋形剂50％～89％。

Description

液体栓塞剂及其制备方法和应用
本申请要求于2022年03月14日提交中国专利局、申请号为2022102461539、发明名称为“液体栓塞剂及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请涉及医疗器械技术领域，特别是涉及一种液体栓塞剂及其制备方法和应用。
背景技术
在目前的脑动静脉畸形(AVM)、脑动静脉瘘(DVF)、脑慢性硬膜下血肿(cDSH)等神经介入治疗中主要的治疗方式有：外科手术治疗、介入栓塞，以及放射治疗。而在外科手术治疗中，也会根据病症的情况，会采取先介入栓塞再手术切除的方式，因此，介入栓塞技术在神经介入治疗中有着重要作用。
介入栓塞技术所用的介入栓塞材料目前主要有固体和液体两大类。固体材料虽然栓塞过程相对简单，但其需要大直径的微导管，因此不能进入到接近AVM等病灶部位进行更为精准的栓塞，并且颗粒栓塞后容易出现再通问题，故而固体栓塞材料多用于术前栓塞，难以满足治愈性栓塞的目的。液体栓塞剂则可以通过更细的微导管，注射后可均匀地充满病变血管，固化后实现封堵，降低血管再通可能性，实现精准且永久栓塞。
目前临床运用广泛的液体栓塞剂分为粘附性液体栓塞剂和非粘附性液体栓塞剂。其中粘附性液体栓塞剂是以氰基丙烯酸酯为主要成分。非粘附性液体栓塞剂则是以乙烯乙烯醇聚合物的DMSO溶液，添加金属粉末做显影剂，如钽粉、氧化钽或三氧化铋等。非粘附性液体栓塞剂中最为常用的是Onyx液体栓塞剂，主要由乙烯乙烯醇聚合物溶于二甲亚砜，加入微米级钽 粉作为显影剂制成，其栓塞作用原理是将金属钽粉在聚合物的二甲亚砜溶液中通过长时间的剧烈搅拌或震荡，形成钽粉悬浮液，该钽粉悬浮液通过微导管注入颅内血管等病变血管后，形成栓塞团，封堵血管通路，达到阻断血流的目的。
也有一些技术将乙烯乙烯醇聚合物溶于二甲亚砜和乙醇的混合溶剂中，同样加入微米级钽粉作为显影剂，制成液体栓塞剂。然而上述液体栓塞剂中均以不溶于溶剂的金属粉末为显影剂，例如微米级钽粉，而钽为VB族元素，原子序数73，有良好的不透射线性能，密度16.65g/cm3，不溶于上述溶剂，因此静置时间稍长即会发生沉降，在推送过程中有可能会导致钽粉的沉降，沉降的钽粉不能弥散至更深的病症部位，且作为显影剂的钽粉的沉降还会导致显影剂浓度改变，最终导致病症部位的显影性能不佳。
发明内容
基于此，本申请的一个方面，提供一种液体栓塞剂，按质量分数计，包括：
聚合物1％～20％；
显影剂10％～50％，所述显影剂包含有机化合物修饰的多孔显影颗粒；及
赋形剂50％～89％。
在其中一些实施例中，在所述显影剂中，所述有机化合物修饰的多孔显影颗粒的质量分数为50％～100％。
在其中一些实施例中，所述有机化合物占修饰的多孔显影颗粒中的质量百分比为0.01％～10％。
在其中一些实施例中，所述有机化合物占修饰的多孔显影颗粒中的质量百分比为0.1％～10％。
在其中一些实施例中，所述多孔显影颗粒上修饰的有机化合物通过化 学键与所述多孔显影颗粒连接。
在其中一些实施例中，所述有机化合物为小分子化合物或为高分子化合物。
在其中一些实施例中，所述有机化合物的分子结构重复单元数量为1～1000。
在其中一些实施例中，所述有机化合物选自聚丙烯酸酯、聚甲基丙烯酸酯、聚氨酯、聚酯、聚醚、聚硅氧烷、聚醋酸乙烯酯、聚烯醇、聚多巴胺、聚酰胺及多糖中的至少一种。
在其中一些实施例中，所述有机化合物修饰的多孔显影颗粒通过所述多孔显影颗粒采用表面聚合法或接枝偶联法制得。
在其中一些实施例中，所述多孔显影颗粒的表面具有多孔孔洞。
在其中一些实施例中，所述多孔显影颗粒为空心颗粒。
在其中一些实施例中，所述多孔显影颗粒的粒径为0.01μm～150μm。
在其中一些实施例中，所述多孔显影颗粒的孔径分布为1nm～2000nm。
在其中一些实施例中，所述多孔显影颗粒的孔隙率为10％～90％。
在其中一些实施例中，所述多孔显影颗粒为空心颗粒且表面具有多孔孔洞，所述多孔显影颗粒的空心结构与所述表面的至少部分孔洞相互连通。
在其中一些实施例中，所述多孔显影颗粒表面具有的多孔孔洞中至少部分为通孔。
在其中一些实施例中，所述多孔显影颗粒中含有可显影金属元素。
在其中一些实施例中，所述聚合物的重均分子量为1万～40万。
在其中一些实施例中，所述聚合物为聚烯烃、聚烯烃醇、聚丙烯酸酯、聚甲基丙烯酸酯、聚氨酯、聚酯、聚醚、聚硅氧烷及聚酰胺中的任意一种，或为其中至少两种的共聚物。
在其中一些实施例中，所述赋形剂为生物相容性有机溶剂、水及缓冲液中的至少一种。
在其中一些实施例中，所述多孔显影颗粒为可显影金属材质、含可显影金属的合金材质或可显影金属化合物材质。
本申请的另一个方面，提供一种液体栓塞剂的制备方法，包括如下步骤：
将上述任一项所述的液体栓塞剂中的各组分混合均匀。
本申请的另一个方面，提供上述任一项所述的液体栓塞剂在制备医疗介入器械或介入治疗药物中的应用。
本申请的另一个方面，提供一种医疗介入器械，其特征在于，包括器械本体及设于所述器械本体内的试剂，所述试剂包含有上述任一项所述的液体栓塞剂。
本申请的另一个方面，提供一种介入治疗药物，所述介入治疗药物包含有如上述任一项所述的液体栓塞剂。
本申请的一个或多个实施例的细节在下面的附图和描述中提出。本申请的其它特征、目的和优点将从说明书、附图以及权利要求书变得明显。
附图说明
图1为本申请一实施方式的液体栓塞剂的混合状态示意图；
图2为图1所示的液体栓塞剂中的有机化合物修饰的多孔显影颗粒的示意图。
附图标记说明：
11：聚合物；12：有机化合物修饰的多孔显影颗粒；121：多孔显影颗
粒本体；122：有机化合物；13：赋形剂。
具体实施方式
为了便于理解本申请，下面将参照相关附图对本申请进行更全面的描述。附图中给出了本申请的较佳实施例。但是，本申请可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的 是使对本申请的公开内容的理解更加透彻全面。
需要说明的是，当元件被称为“固定于”另一个元件，它可以直接在另一个元件上或者也可以存在居中的元件。当一个元件被认为是“连接”另一个元件，它可以是直接连接到另一个元件或者可能同时存在居中元件。
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文中在本申请的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本申请。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
本申请一实施方式提供了一种液体栓塞剂，按质量分数计，包括：聚合物1％～20％、显影剂10％～50％及赋形剂50％～89％。
其中，显影剂包含有机化合物修饰的多孔显影颗粒。
上述多孔显影颗粒是具有“可显影”性能，“可显影”是指在X射线下可视。
液体栓塞剂在使用之前，需要将各组分充分混合，其混合状态如图1所示。在如图1所示的具体示例中，有机化合物修饰的多孔显影颗粒12为显影剂，液体栓塞剂中的聚合物11和有机化合物修饰的多孔显影颗粒12分散于赋形剂13中。结合图2，聚合物11在赋形剂13中具有较好的相溶性或均一分散性。有机化合物修饰的多孔显影颗粒12包括多孔显影颗粒本体121(后文简称为多孔显影颗粒)及多孔显影颗粒本体121表面修饰的有机化合物122，且有机化合物122的分子链可与聚合物11在赋形剂12中具有分子链的缠结和分子间的相互作用。
相比于传统采用球状、块状或粉状的无孔实心微球的微米级钽粉等显影剂的液体栓塞剂而言，上述液体栓塞剂的显影剂中包含有机化合物修饰的多孔显影颗粒，一方面由于多孔显影颗粒是多孔结构，可减小显影剂单位体积的质量，另一方面多孔显影颗粒上修饰的有机化合物的分子链可与聚 合物在赋形剂中具有分子链的缠结和分子间的相互作用，相当于在多孔显影颗粒外表面形成了一层保护层或缓冲层，其能够在一定程度阻止显影颗粒的沉降，进而从密度和分子间作用等多个方面提升了有机化合物修饰的多孔显影颗粒的悬浮稳定性，改善了显影颗粒的沉降问题，降低了显影颗粒在扩散过程中随着赋形剂被带走的风险，有利于液体栓塞剂精准到达病症部位并保持较高的显影剂浓度，进而提供良好的显影效果。
此外，一般地为了提高弥散性能，传统栓塞剂在使用前需要较长的时间将液体栓塞剂的各组分充分混合，所需的操作时间太长。上述液体栓塞剂，由于有机化合物修饰的多孔显影颗粒的悬浮稳定性大大提升，相比于传统栓塞剂在使用前所需的均匀时间更短，一定程度改善了使用的简便性。且，悬浮稳定性更佳的多孔显影颗粒有利于液体栓塞剂在推注时更好地向前弥散，有利于减少反流。
进一步地，在液体栓塞剂中，聚合物的质量分数可为1％、2％、3％、5％、10％、13％、15％、18％、20％；显影剂的质量分数可为10％、15％、20％、25％、30％、35％、40％、45％、50％；赋形剂的质量分数可为50％、55％、60％、65％、70％、75％、80％、85％、88％、89％。
在其中一些实施例中，多孔显影颗粒中含有可显影金属元素。可显影金属元素为金(Au)、银(Ag)、铂(Pt)、铱(Ir)、铬(Cr)、钽(Ta)、铋(Bi)、钴(Co)、钨(W)及钡(Ba)中的至少一种。在一些实施方式中，可显影金属也可以包括镧系、锕系金属中的至少一种。
在其中一些实施例中，多孔显影颗粒为可显影金属材质、含可显影金属的合金材质或可显影金属化合物材质。
进一步地，金属材质为上述可显影金属元素中的一种。例如，多孔显影颗粒可为金颗粒、银颗粒、铂颗粒、铱颗粒、铬颗粒、钽颗粒、铋颗粒、钴颗粒、钨颗粒及钡颗粒中的至少一种。
进一步地，合金材质为可显影金属元素中的至少两种或可显影金属元 素中的至少一种与至少一种其他金属的合金，即为合金金属材质。例如，多孔显影颗粒可为铂铱合金、钴铬合金、钴钒合金、钴基合金、钐钴合金、锆钴合金、钨钴合金、钴铬钨合金、铬铜合金、钽基合金、钴钽锆合金等。
进一步地，金属化合物材质为可显影金属元素中的一种形成的不溶于上述赋形剂的金属盐、金属氧化物、金属碳化物及金属氮化物中的至少一种。例如金属化合物材质为卤化银、氧化铋、碳化钽、硫酸钡、氧化钨、氮化钽、氧化钽等。
进一步地，上述金属盐、金属氧化物、金属碳化物及金属氮化物为非水溶且非有机溶剂溶解性的金属化合物。
在其中一些实施例中，在显影剂中，有机化合物修饰的多孔显影颗粒的质量分数为50％～100％，例如50％、55％、60％、65％、70％、75％、80％、85％、90％、95％、100％。有机化合物修饰的多孔显影颗粒的质量分数为100％，即显影剂均为有机化合物修饰的多孔显影颗粒。当有机化合物修饰的多孔显影颗粒的质量分数少于100％时，液体栓塞剂中还可包含其他显影剂，例如实心显影颗粒和未经有机化合物修饰的多孔显影颗粒中的至少一种。
进一步地，在显影剂中，有机化合物修饰的多孔显影颗粒的质量分数为70％～90％。
在其中一些实施例中，多孔显影颗粒上修饰的有机化合物通过化学键与多孔显影颗粒连接。通过化学键与多孔显影颗粒连接非常牢固，能够在整个弥散过程中稳定存在。
进一步地，有机化合物占修饰的多孔显影颗粒中的质量百分比为0.01％～10％，例如0.01％、0.03％、0.04％、0.05％、0.1％、0.27％、0.3％、0.5％、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％；在一些示例中，有机化合物占修饰的多孔显影颗粒中的质量百分比为0.04％～10％、0.1～10％、0.5％～5％、0.04％～5％、0.04％～4.5％。
进一步地，有机化合物为小分子化合物或为高分子化合物，能够有利于 多孔显影颗粒在聚合物和赋形剂形成的聚合物溶液中的悬浮稳定性，例如聚合物。在一些示例中，有机化合物为高分子化合物。
进一步地，有机化合物的分子结构重复单元数量为1～1000。在一些示例中，有机化合物的分子结构重复单元数量为1～100，进一步为2～100。例如有机化合物是仅有几个重复单元的分子层，或是几个不同化学结构连接而成的分子层，或是有一定聚合度的聚合物。在一些实施方式中，有机化合物分子的重复单元数量为1～10个，修饰了这种有机化合物的多孔显影颗粒即能保持其在聚合物溶液中的悬浮稳定性，又可以不因重复单元数量过大而增大液体栓塞剂整体的粘度。
进一步地，有机化合物修饰的多孔显影颗粒通过多孔显影颗粒采用表面聚合法或接枝偶联法制得。
其中，表面聚合法为在多孔显影颗粒的表面进行聚合反应，使得有机化合物中的可反应基团或用于形成有机化合物的单体在多孔显影颗粒表面进行聚合得到聚合物，从而形成表面有机化合物修饰的多孔显影颗粒。
其中，接枝偶联法为：先将多孔显影颗粒先进行表面活化处理，然后将表面活化处理后的多孔显影颗粒与有机化合物中的可反应基团进行化学反应，键合形成聚合物修饰的多孔显影颗粒。
需要说明的是，在对多孔显影颗粒表面进行聚合和接枝偶联方法的步骤中，可采用现有金属表面处理的常用处理方法，如硅烷偶联、表面引发、等离子体处理、高能辐射处理等方式对多孔显影颗粒处理。其中，表面引发包括引发剂接枝聚合、紫外光接枝聚合、臭氧引发接枝聚合等；高能辐射处理包括Y辐射、电子束辐射等。
在其中一些实施例中，有机化合物选自聚丙烯酸酯、聚甲基丙烯酸酯、聚氨酯、聚酯、聚醚、聚硅氧烷、聚醋酸乙烯酯、聚烯醇、聚多巴胺、聚酰胺及多糖中的至少一种。这些聚合物可通过功能化的基团的修饰与显影剂颗粒间形成酯键、氨酯键、醚键等实现化学键合，也可以通过在显影剂颗粒 表面修饰上引发剂后通过单体聚合物得到，而且还具有较长的分子链，与液体栓塞剂中本身的聚合物分子之间的相互作用会更强，进一步提高显影颗粒的悬浮稳定性。
进一步地，聚丙烯酸酯包括聚(甲基)丙烯酸羟乙酯、聚(甲基)丙烯酸乙二醇酯，聚丙烯酸聚乙二醇酯，聚甲基丙烯酸丙二醇酯，聚丙烯酸丁二醇酯，聚丙烯酸氨基乙酯、聚丙烯酸氨基丙酯、聚丙烯酸二氨基丁酯、聚丙烯酸苄二醇酯等；在一些具体示例中，上述有机化合物修饰的多孔显影颗粒为聚丙烯酸羟乙酯修饰的铋颗粒、聚丙烯酸羟乙酯修饰的钽颗粒，聚乙烯醇修饰的铋颗粒，聚乙烯醇修饰的钽颗粒、聚多巴胺修饰的铋颗粒及聚丙烯酸羟乙酯修饰的钽颗粒中的至少一种。
进一步地，可采用上述多种不同有机化合物对同一多孔显影颗粒进行修饰。在一具体示例中，可先采用聚多巴胺修饰多孔显影颗粒，然后再采用聚丙烯酸酯对聚多巴胺修饰的多孔显影颗粒进一步修饰。更具体地，在采用聚多巴胺修饰之前，还包括先将多孔显影颗粒表面羟基化的步骤。在采用聚丙烯酸酯对聚多巴胺修饰的多孔显影颗粒进一步修饰之前，还包括将聚多巴胺修饰的多孔显影颗粒进行引发剂修饰的步骤。
在其中一些实施例中，多孔显影颗粒的表面具有多孔孔洞。
进一步地，多孔显影颗粒为表面具有多孔孔洞的实心颗粒。可理解，本文中实心颗粒是相对空心颗粒来说的，实心颗粒是指颗粒不具有内部空心结构，即内部整体是呈现实心的结构，但表面可以是多孔洞的也可以是无孔洞的。换言之，本文中实心颗粒包括但不限于内部整体呈实心结构但表面不具有孔洞的颗粒，及内部整体呈实心结构和表面同时具有孔洞的颗粒。
在一些示例中，该实心颗粒可通过聚合物模板法制得。聚合物模板法是指以聚合物微球为模板，在聚合物微球的表面形成金属层、合金层或金属化合物层，然后不去除其中的聚合物微球模板，保留其中的聚合物微球模板作为内核，得到的实心颗粒包括聚合物材料的内核和可显影的金属材质、合金 材质或金属化合物材质的外壳。
具体地，上述表面具有多孔孔洞的实心颗粒的制备方法如下：采用乳液聚合或自组装等方法先制备得到一定粒径的聚合物微球，然后在聚合物微球的表面采用沉积或表面修饰的方法形成金属层、合金层或金属化合物层。其中用到的聚合物微球可通过市面直接购买获得，例如聚乙烯、聚苯乙烯、聚苯乙烯-二乙烯基苯等微球。其中，可通过控制作为壳层的金属层、合金层或金属化合物层的分子生长堆积工艺，进而使得壳层中形成多孔孔洞。
在其中一些实施例中，多孔显影颗粒为空心颗粒。可理解，本文中空心颗粒是指具有内部空心结构的颗粒，但表面可以是多孔洞的也可以是无孔洞的。换言之，本文中空心颗粒包括但不限于内部整体呈空心结构但表面不具有孔洞的颗粒，及内部整体呈空心结构和表面同时具有孔洞的颗粒。
上述空心颗粒的制备方法可以为聚合物模板法。具体地，聚合物模板法是指采用乳液聚合或自组装等方法先制备得到一定粒径的聚合物微球，然后在聚合物微球的表面沉积金属层、合金层或在聚合物微球的表面生长接枝形成金属化合物层，该金属、合金或金属化合物层可稳定存在并分离，经特定溶剂洗脱除去除核内的聚合物微球模板，或者通过在特定温度下煅烧或其他手段去除内核聚合物微球模板，得到空心颗粒。也可以先用溶剂洗脱，然后再煅烧去除聚合物微球模板，得到空心颗粒(或称为空心微球)。
进一步地，可通过控制聚合物微球的粒径和沉积的金属层或金属化合物层的厚度来控制空心颗粒的空心部分的体积占比。更进一步地，采用溶液法形成金属层和金属化合物层时，可通过调节溶液中用于形成金属和金属化合物的原料的浓度，进而控制形成的金属层和金属化合物层的厚度，实现空心部分的体积占比的调节。
进一步地，可通过控制壳层的分子生长堆积工艺，进而使得壳层形成孔洞。
其中的聚合物微球可以为通过市面直接购买到的聚合物微球，如聚乙 烯、聚苯乙烯、聚苯乙烯-二乙烯基苯等微球。
进一步地，多孔显影颗粒的形态可为球形、椭球体等。
进一步地，多孔显影颗粒为空心颗粒且表面具有多孔孔洞。
在一具体示例中，多孔显影颗粒为空心颗粒且表面具有多孔孔洞，多孔显影颗粒的空心结构与表面的至少部分孔洞相互连通。
在一具体示例中，多孔显影颗粒表面具有的多孔孔洞中至少部分为通孔。通孔是指分布于微粒的该孔洞的两端均与外部连通，且该孔洞自一端穿过微粒的内部与另一端贯穿。
进一步地，多孔显影颗粒的粒径为0.01μm～150μm，例如0.01μm、0.05μm、0.1μm、0.2μm、0.5μm、1μm、5μm、10μm、20μm、30μm、50μm、60μm、70μm、80μm、90μm、100μm、110μm、120μm、130μm、140μm、150μm；更进一步为0.1μm～50μm。可理解，多孔显影颗粒可为均一粒径的单分散颗粒，或为多种不同粒径的多分散颗粒。例如，多孔显影颗粒可为按照一定比例组合得到的具有特定粒径分布的颗粒。
在一些示例中，多孔显影颗粒的孔径分布为1nm～2000nm，进一步地，多孔显影颗粒的孔径分布为100nm～1000nm。可理解，多孔显影颗粒的孔径可为大小均一的孔洞或为多分散的大小不均一的孔洞。适合的孔径便于溶液的贯通及有机化合物的修饰。
进一步地，多孔显影颗粒的孔隙率为10％～90％，例如10％、20％、30％、40％、50％、60％、70％、80％、90％；在一些示例中，多孔显影颗粒的孔隙率为10％～70％，进一步为20％～50％。其中，孔隙率是指多孔显影颗粒中孔隙体积与材料在自然状态下总体积的百分比。孔隙率高，则颗粒比表面积越大，有机化合物修饰比例更高，此外，可通过优化多孔显影颗粒的孔隙率得到合适的密度，该密度可使得该多孔显影颗粒能够在液体栓塞剂中具有较好的悬浮稳定性，使其易于分散，不易沉降。
在其中一些实施例中，聚合物为聚烯烃、聚烯烃醇、聚丙烯酸酯、聚甲 基丙烯酸酯、聚氨酯、聚酯、聚醚、聚硅氧烷及聚酰胺中的任意一种，或为其中至少两种的共聚物。其中，上述共聚物包括但不限于无归共聚物、嵌段共聚物、交替共聚物、接枝共聚物。
进一步地，上述聚合物可为聚丙烯酰胺-聚甲基丙烯酸甲酯共聚物、聚乙烯-乙烯醇共聚物、聚乙二醇-聚丙烯酸酯共聚物、水难溶性的天然聚合物，如纤维素及其衍生物中的至少一种。
在其中一些实施例中，上述液体栓塞剂中本身含有的聚合物的重均分子量为1万～40万；进一步为10～30万。进一步地，聚合物的疏水组分的摩尔含量大于50％，更进一步为大于60％。其中，亲水组分是指在聚合物的侧链或主链中含有的亲水基团，否则为疏水组分。疏水组分的含量越高，聚合物在水、缓冲液或血液析出时间越短，相应的固化速率越小，故而，可通过调节亲疏水组分比例来控制固化速率。
在其中一些实施例中，赋形剂为如下溶剂中的至少一种：生物相容性有机溶剂、水及缓冲液。这些溶剂无毒或低毒，且在液体栓塞剂中可起到稀释剂或分散剂的作用。
进一步地，生物相容性有机溶剂包括但不限于二甲基亚砜、N甲基吡咯烷酮(NMP)、乙醇及异丙醇中的至少一种，这些溶剂具有低毒的优点。可理解，可根据聚合物的种类选择其溶剂，只要其能够使聚合物与溶剂形成均一体系即可。此处均一体系是指均一的澄清溶液或均一悬浊液。
可理解，赋形剂可为上述聚合物的良溶剂，即赋形剂与该聚合物能够形成均一的澄清溶液，或赋形剂与聚合物可在特定条件下形成均一体系。
本申请另一实施方式还提供了上述液体栓塞剂的制备方法，其将上述聚合物、赋形剂等其他组分混合均匀即可。
进一步地，混合可采用常用的搅拌、超声等方法，只要能够使液体栓塞剂能够形成均匀体系即可。
进一步地，可先将聚合物与赋形剂经机械搅拌等方式混合形成均一相的聚合物溶液，然后再加入显影剂，再次采用机械搅拌等方式混合形成均匀分散体系，即可。
更进一步地，在形成均一相的聚合物溶液的步骤中，可采用升温、降温、物理分散等方式辅助促进其溶解。
待液体栓塞剂形成均一的分散体系，可采用输送或推送的方式，到达水或血液中后，随着赋形剂的扩散，液体栓塞剂中的聚合物沉淀析出，形成柔软的栓塞团，而栓塞团中的显影剂保证了其良好的显影性能。
本申请另一实施方式还提供了上述液体栓塞剂在制备医疗介入器械或介入治疗药物中的应用。
本申请另一实施方式还提供了一种医疗介入器械，器械本体及设于器械本体内的试剂，该试剂包含有如上述任一项的液体栓塞剂。
在其中一些实施例中，器械本体为导管。进一步地，该导管的内径很小，称之为微导管。例如，微导管的内径为0.007～0.013inch(英寸)。
本申请另一实施方式还提供了一种介入治疗药物，该介入治疗药物包含有如上述任一项的液体栓塞剂。
进一步地，该介入治疗药物中除了含有如上述任一项的液体栓塞剂，还可包含有对疾病具有治疗作用的活性成分。
进一步地，该介入治疗药物中除了含有如上述任一项的液体栓塞剂，还可包含有其他添加剂。
上述液体栓塞剂可用于介入治疗中，例如用于介入止血、血管畸形和恶性肿瘤中，包括但不限于脑动静脉畸形(AVM)、血肿、以及脑动静脉瘘(DVF)、硬膜下血肿的介入栓塞治疗、外周等血管曲张治疗及肿瘤等处血流的封堵治疗。
上述液体栓塞剂通过微导管的推注到达病症部位，接触到血流，随着赋形剂的弥散开始固化。在血流中，液体栓塞剂中的聚合物慢慢沉淀析出固化， 形成栓塞团，进而达到封堵血管通路、阻断血流的目的。
上述液体栓塞剂中的有机化合物修饰的多孔显影颗粒的液体栓塞剂具有优良的悬浮稳定性，可减少术前震荡时间，降低弥散过程中的沉降风险，提升其弥散性能，降低注射过程中返流风险。故而，在液体栓塞剂从微导管内推送完成之后，微导管可以很容易被抽出，降低了微导管被拉扯对血管产生的风险。
为了使本申请的目的、技术方案及优点更加简洁明了，本申请用以下具体实施例进行说明，但本申请绝非仅限于这些实施例。以下所描述的实施例仅为本申请较好的实施例，可用于描述本申请，不能理解为对本申请的范围的限制。应当指出的是，凡在本申请的精神和原则之内所做的任何修改、等同替换和改进等，均应包含在本申请的保护范围之内。
为了更好地说明本申请，下面结合实施例对本申请内容作进一步说明。以下为具体实施例。
实施例1：
(1)有机化合物修饰的铋颗粒制备
1、先将铋颗粒表面羟基化。具体步骤为：表面经抛光处理的铋颗粒经去离子水、乙醇、丙酮分别超声清洗10min后，用浓硫酸和双氧水(30wt％)的混合液(浓硫酸和双氧水的v/v＝7/3)浸泡50min，过滤后用去离子水冲洗数遍，得到羟基化铋颗粒。
2、聚多巴胺修饰铋颗粒。将上述羟基化的铋颗粒加入浓度2mg/mL的多巴胺盐酸盐水溶液中，用氢氧化钠溶液调节pH值至10以上，避光反应24h，过滤，用去离子水清洗数遍，得到聚多巴胺修饰的铋颗粒。
3、溴引发剂修饰铋颗粒。在无水无氧条件下，将上述聚多巴胺修饰的铋颗粒加入甲苯中，加入2-溴代异丁酰溴，室温搅拌下反应20小时，结束后用分别用甲苯、乙醇和去离子水清洗数次，得到溴引发剂修饰的铋颗粒。
4、在铋颗粒表面制备聚丙烯酸羟乙酯修饰层。无水无氧条件下，将上述溴引发剂修饰的铋颗粒加入水/甲醇混合溶剂中，采用CuBr/CuBr2/四甲基乙二胺(TMEDA)体系进行原子转移自由基共聚(ATRP)反应，然后加入单体丙烯酸羟乙酯(HEMA)，搅拌下60℃反应10h左右结束。用甲醇、水清洗数次后得到产物，即聚丙烯酸羟乙酯(PHEMA)修饰的铋颗粒。
(2)以上述有机化合物修饰的铋颗粒修饰作为显影剂的栓塞剂的制备
将聚乙烯醇溶于N-甲基吡咯烷酮中，得到聚乙烯醇溶液，加入聚丙烯酸羟乙酯修饰的铋颗粒，混合后得到悬浮的液体栓塞剂。在液体栓塞剂中，聚丙烯酸羟乙酯修饰的铋颗粒的浓度为40wt％，聚乙烯醇的浓度为10wt％。
实施例2～4
制备步骤与实施例1基本相同，区别在于调整步骤(1)中第4步的加入单体丙烯酸羟乙酯后的反应时间，控制单体转化率，得到不同修饰程度的铋颗粒，即不同含量聚丙烯酸羟乙酯(PHEMA)修饰的铋颗粒。
实施例5
实施例5与实施例1基本相同，不同在于：省略了步骤(1)中第3和4步，直接将聚多巴胺修饰的铋颗粒作为显影剂的栓塞剂的制备。
对比例1
以实施例1中表面经抛光处理的未修饰的铋颗粒修饰作为显影剂的栓塞剂的制备。
将聚乙烯醇溶于N-甲基吡咯烷酮中，得到聚乙烯醇溶液，加入铋颗粒，混合后得到悬浮的液体栓塞剂。在液体栓塞剂中，聚丙烯酸羟乙酯修饰的铋颗粒的浓度为40wt％，聚乙烯醇的浓度为10wt％。
将实施例1～4的步骤(1)制得的聚丙烯酸羟乙酯(PHEMA)修饰的铋颗粒通过热重分析得到PHEMA修饰量如下表1所示。将实施例5的制得的聚多巴胺修饰铋颗粒通过热重分析得到聚多巴胺修饰量如下表1所示。
将实施例1～5及对比例1的步骤(2)制得的液体栓塞剂静置后观察， 得到的性能特点如下表1所示。
注：表1中显影剂和聚合物的含量为在液体栓塞剂的总质量中的质量百分含量。
表1
由上述实施例和对比例比较可知，相比于未修饰的铋颗粒，本申请采用上述修饰的铋颗粒作为显影剂制得液体栓塞剂，可以延迟其静置出现分层的时间，换言之对应的液体栓塞剂中颗粒悬浮稳定性大大提升，故而给使用者预留了足够的操作时间，便于提高液体栓塞剂在推送过程中颗粒悬浮稳 定性，有利于液体栓塞剂精准到达病症部位并保持较高的显影剂浓度，进而提供良好的显影效果。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。

Claims (21)

  1. 一种液体栓塞剂，按质量分数计，包括：
    聚合物1％～20％；
    显影剂10％～50％，所述显影剂包含有机化合物修饰的多孔显影颗粒；及
    赋形剂50％～89％。
  2. 如权利要求1所述的液体栓塞剂，其特征在于，在所述显影剂中，所述有机化合物修饰的多孔显影颗粒的质量分数为50％～100％。
  3. 如权利要求1至2任一项所述的液体栓塞剂，其特征在于，所述有机化合物占修饰的多孔显影颗粒中的质量百分比为0.01％～10％。
  4. 如权利要求1至3任一项所述的液体栓塞剂，其特征在于，所述有机化合物占修饰的多孔显影颗粒中的质量百分比为0.1％～10％。
  5. 如权利要求1至4任一项所述的液体栓塞剂，其特征在于，所述多孔显影颗粒上修饰的有机化合物通过化学键与所述多孔显影颗粒连接。
  6. 如权利要求1至5任一项所述的液体栓塞剂，其特征在于，所述有机化合物为小分子化合物或为高分子化合物。
  7. 如权利要求1至6任一项所述的液体栓塞剂，其特征在于，所述有机化合物的分子结构重复单元数量为1～1000。
  8. 如权利要求1至7任一项所述的液体栓塞剂，其特征在于，所述有机化合物选自聚丙烯酸酯、聚甲基丙烯酸酯、聚氨酯、聚酯、聚醚、聚硅氧烷、聚醋酸乙烯酯、聚烯醇、聚多巴胺、聚酰胺及多糖中的至少一种。
  9. 如权利要求1至8任一项所述的液体栓塞剂，其特征在于，所述有机化合物修饰的多孔显影颗粒通过所述多孔显影颗粒采用表面聚合法或接枝偶联法制得。
  10. 如权利要求1至9任一项所述的液体栓塞剂，其特征在于，所述液 体栓塞剂符合以下条件(Ⅰ)至(Ⅴ)中的至少一个：
    (Ⅰ)、所述多孔显影颗粒的表面具有多孔孔洞；
    (Ⅱ)、所述多孔显影颗粒为空心颗粒；
    (Ⅲ)、所述多孔显影颗粒的粒径为0.01μm～150μm；
    (Ⅳ)、所述多孔显影颗粒的孔径分布为1nm～2000nm；
    (Ⅴ)、所述多孔显影颗粒的孔隙率为10％～90％。
  11. 如权利要求1至10任一项所述的液体栓塞剂，其特征在于，所述多孔显影颗粒为空心颗粒且表面具有多孔孔洞，所述多孔显影颗粒的空心结构与所述表面的至少部分孔洞相互连通。
  12. 如权利要求11所述的液体栓塞剂，其特征在于，所述多孔显影颗粒表面具有的多孔孔洞中至少部分为通孔。
  13. 如权利要求1至12任一项所述的液体栓塞剂，其特征在于，所述多孔显影颗粒中含有可显影金属元素。
  14. 如权利要求13所述的液体栓塞剂，其特征在于，所述多孔显影颗粒为可显影金属材质、含可显影金属的合金材质或可显影金属化合物材质。
  15. 如权利要求1至14任一项所述的液体栓塞剂，其特征在于，所述聚合物的重均分子量为1万～40万。
  16. 如权利要求1至15任一项所述的液体栓塞剂，其特征在于，所述聚合物为聚烯烃、聚烯烃醇、聚丙烯酸酯、聚甲基丙烯酸酯、聚氨酯、聚酯、聚醚、聚硅氧烷及聚酰胺中的任意一种，或为其中至少两种的共聚物。
  17. 如权利要求1至16任一项所述的液体栓塞剂，其特征在于，所述赋形剂为生物相容性有机溶剂、水及缓冲液中的至少一种。
  18. 一种液体栓塞剂的制备方法，其特征在于，包括如下步骤：
    将如权利要求1至17任一项所述的液体栓塞剂中的各组分混合均匀。
  19. 如权利要求1至17任一项所述的液体栓塞剂在制备医疗介入器械或介入治疗药物中的应用。
  20. 一种医疗介入器械，其特征在于，包括器械本体及设于所述器械本体内的试剂，所述试剂包含有如权利要求1至17任一项所述的液体栓塞剂。
  21. 一种介入治疗药物，其特征在于，所述介入治疗药物包含有如权利要求1至17任一项所述的液体栓塞剂。
PCT/CN2023/079840 2022-03-14 2023-03-06 液体栓塞剂及其制备方法和应用 WO2023174089A1 (zh)

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