CN116785492A

CN116785492A - Liquid embolic agent and preparation method and application thereof

Info

Publication number: CN116785492A
Application number: CN202210246153.9A
Authority: CN
Inventors: 张国艺; 郭远益; 虞鹏; 王亦群
Original assignee: Shenhong Medical Technology Shanghai Co ltd
Current assignee: Shenhong Medical Technology Shanghai Co ltd
Priority date: 2022-03-14
Filing date: 2022-03-14
Publication date: 2023-09-22
Also published as: WO2023174089A1

Abstract

The invention relates to a liquid embolic agent, a preparation method and application thereof, wherein the liquid embolic agent comprises the following components in percentage by mass: 1% -20% of polymer; 10% -50% of a developer, wherein the developer comprises porous developing particles modified by an organic compound; 50-89% of excipient. The developer of the liquid embolic agent contains the porous developing particles modified by the organic compound, so that the suspension stability of the porous developing particles modified by the organic compound is improved, the sedimentation problem of the developing particles is improved, the risk that the developing particles are taken away along with the solvent in the diffusion process is reduced, the liquid embolic agent can accurately reach the disease position, the concentration of the developer is kept high, and a good developing effect is further provided.

Description

Liquid embolic agent and preparation method and application thereof

Technical Field

The invention relates to the technical field of medical instruments, in particular to a liquid embolic agent and a preparation method and application thereof.

Background

The main treatment modes in the prior nerve intervention treatment such as cerebral arteriovenous malformation (AVM), cerebral arteriovenous fistula (DVF), cerebral chronic subdural hematoma (cDSH) and the like are as follows: surgical treatment, interventional embolization, and radiation therapy. In the surgical treatment, according to the condition of the disease, a mode of interventional embolism and then surgical excision is adopted, so that the interventional embolism technology plays an important role in the neural interventional treatment.

The interventional embolic materials used in interventional embolic technology currently fall into two main categories, solid and liquid. Although the embolization process of the solid material is relatively simple, the solid material needs a large-diameter micro-catheter, so that the solid material cannot enter into focus parts such as AVM and the like to perform more accurate embolization, and the problem of reoccurrence easily occurs after particle embolization, so that the solid embolization material is mostly used for preoperative embolization, and the aim of curative embolization is difficult to meet. The liquid embolic agent can be filled into lesion blood vessels uniformly through finer micro-catheters after injection, can realize blocking after solidification, reduces the possibility of vascular recanalization, and realizes accurate and permanent embolism.

The liquid embolic agent widely used in clinic at present is divided into an adhesive liquid embolic agent and a non-adhesive liquid embolic agent. Wherein the adhesive liquid embolic agent is based on cyanoacrylate. The non-adhesive liquid embolic agent is prepared by adding metal powder as developer, such as tantalum powder, tantalum oxide or bismuth trioxide, into DMSO solution of ethylene vinyl alcohol polymer. The most commonly used non-adhesive liquid embolic agent is an Onyx liquid embolic agent, which is mainly prepared by dissolving ethylene vinyl alcohol polymer in dimethyl sulfoxide and adding micron-sized tantalum powder as a developer, wherein the embolic action principle is that metal tantalum powder is stirred or oscillated vigorously for a long time in dimethyl sulfoxide solution of the polymer to form a tantalum powder suspension, and the tantalum powder suspension is injected into pathological blood vessels such as intracranial blood vessels through a microcatheter to form embolic masses so as to block blood vessel passages and achieve the purpose of blocking blood flow.

There are also some techniques to dissolve ethylene vinyl alcohol polymer in mixed solvent of dimethyl sulfoxide and ethanol, and to add micron-sized tantalum powder as developer to prepare liquid embolic agent. However, the liquid embolic agents all use metal powder insoluble in solvent as developer, such as micron-sized tantalum powder, and tantalum is VB group element with atomic number of 73, and have good radiopacity and density of 16.65g/cm ³ The tantalum powder is insoluble in the solvent, so that sedimentation can occur after a long standing time, sedimentation of the tantalum powder is possibly caused in the pushing process, the settled tantalum powder cannot be dispersed to deeper disease parts, the sedimentation of the tantalum powder serving as a developer also can cause concentration change of the developer, and finally poor developing performance of the disease parts is caused.

Disclosure of Invention

Based on this, it is necessary to provide a liquid embolic agent capable of improving the development performance, and a preparation method and application thereof.

The invention is realized by the following technical scheme.

In one aspect of the present invention, there is provided a liquid embolic agent comprising, in mass fractions:

1% -20% of polymer;

10% -50% of a developer, wherein the developer comprises porous developing particles modified by an organic compound; a kind of electronic device with high-pressure air-conditioning system

50-89% of excipient.

In some of these embodiments, the mass fraction of the organic compound modified porous developing particles in the developer is 50% to 100%;

and/or, the organic compound accounts for 0.1-10% of the modified porous developing particles by mass.

In some of these embodiments, the organic compound modified on the porous developing particle is attached to the porous developing particle by a chemical bond;

and/or the organic compound is a small molecular compound or a high molecular compound;

and/or the number of the molecular structure repeating units of the organic compound is 1-1000.

In some embodiments, the organic compound is selected from at least one of polyacrylate, polymethacrylate, polyurethane, polyester, polyether, polysiloxane, polyvinyl acetate, polyprenol, polydopamine, polyamide, and polysaccharide.

In some of these embodiments, the organic compound modified porous developing particles are prepared by surface polymerization or graft coupling methods of the porous developing particles.

In some of these embodiments, the surface of the porous developing particle has porous pores;

and/or, the porous developing particles are hollow particles;

and/or the particle diameter of the porous developing particles is 0.01-150 μm;

and/or the pore size distribution of the porous developing particles is 1 nm-2000 nm;

and/or the porosity of the porous developing particles is 10% -90%.

In some of these embodiments, the porous developing particles are hollow particles and the surface has porous pores, and the hollow structure of the porous developing particles is in communication with at least some of the pores of the surface.

In some embodiments, the porous developing particle surface has porous pores at least partially defined by through-holes.

In some of these embodiments, the porous developing particles contain a developable metal element therein;

and/or the weight average molecular weight of the polymer is 1 to 40 ten thousand;

and/or the polymer is any one of polyolefin, polyolefin alcohol, polyacrylate, polymethacrylate, polyurethane, polyester, polyether, polysiloxane and polyamide, or a copolymer of at least two of the above;

and/or the excipient is at least one of a biocompatible organic solvent, water and a buffer solution.

In some embodiments, the porous developing particles are of a developable metal material, an alloy material containing a developable metal, or a developable metal compound material.

In another aspect of the present invention, a method for preparing a liquid embolic agent is provided, comprising the steps of:

uniformly mixing the components in the liquid embolic agent.

In another aspect of the invention, there is provided the use of a liquid embolic agent as described in any of the preceding claims for the preparation of a medical interventional instrument or an interventional therapy drug.

In another aspect, the present invention provides a medical intervention device, comprising a device body and a reagent disposed within the device body, the reagent comprising a liquid embolic agent according to any of the preceding claims.

In another aspect of the invention, there is provided an interventional drug comprising a liquid embolic agent as described in any of the preceding claims.

Compared with the traditional liquid embolic agent adopting the spherical, blocky or powdery solid non-porous microspheres such as micron-sized tantalum powder and other developers, the liquid embolic agent has the advantages that the porous developing particles modified by the organic compound are contained in the developer, on one hand, the mass of the unit volume of the developer can be reduced due to the porous structure of the porous developing particles, on the other hand, the molecular chains of the organic compound modified on the porous developing particles can be interacted with the polymer with molecular chains in the excipient, which is equivalent to forming a protective layer or buffer layer on the outer surface of the porous developing particles, the sedimentation of the developing particles can be prevented to a certain extent, the suspension stability of the porous developing particles modified by the organic compound is improved from the aspects such as density, intermolecular interaction and the like, the sedimentation problem of the developing particles is improved, the risk that the developing particles are taken away along with the excipient in the diffusion process is reduced, the liquid embolic agent can accurately reach the disease position and the higher concentration of the developer is maintained, and a good developing effect is further provided.

Drawings

FIG. 1 is a schematic diagram showing a mixing state of a liquid embolic agent according to an embodiment of the present invention;

FIG. 2 is a schematic illustration of organic compound modified porous development particles in the liquid embolic agent shown in FIG. 1.

Reference numerals illustrate:

11: a polymer; 12: organic compound modified porous developing particles; 121: a porous developing particle body; 122: an organic compound; 13: and (3) an excipient.

Detailed Description

In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

It will be understood that when an element is referred to as being "fixed to" another element, it can be directly on the other element or intervening elements may also be present. When an element is referred to as being "connected" to another element, it can be directly connected to the other element or intervening elements may also be present.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.

An embodiment of the present invention provides a liquid embolic agent, comprising, in mass fractions: 1 to 20 percent of polymer, 10 to 50 percent of developer and 50 to 89 percent of excipient.

Wherein the developer comprises organic compound modified porous developing particles.

The porous developing particles described above are said to have "developable" properties, by which is meant to be visible under X-rays.

The liquid embolic agent requires thorough mixing of the components prior to use, the mixing of which is shown in fig. 1. In the specific example shown in fig. 1, the organic compound modified porous developing particles 12 are a developer, and the polymer 11 and the organic compound modified porous developing particles 12 in the liquid embolic agent are dispersed in the excipient 13. Referring to fig. 2, the polymer 11 has a good compatibility or uniform dispersibility in the excipient 13, and the molecular chains of the organic compound 122 of which the surface of the porous developing particle body 121 (hereinafter simply referred to as porous developing particle) is modified may have entanglement and intermolecular interactions of the molecular chains of the polymer 11 in the excipient 12.

In addition, conventional embolic agents generally require a long time to thoroughly mix the components of the liquid embolic agent before use in order to improve the dispersive properties, and require a too long operating time. The liquid embolic agent greatly improves the suspension stability of the porous developing particles modified by the organic compound, and compared with the traditional embolic agent, the liquid embolic agent has the advantages of shorter uniform time before use and improved use convenience to a certain extent. And, the porous developing particles with better suspension stability are beneficial to better forward dispersion of the liquid embolic agent during injection, and are beneficial to reducing reflux.

Further, in the liquid embolic agent, the mass fraction of polymer may be 1%, 2%, 3%, 5%, 10%, 13%, 15%, 18%, 20%; the mass fraction of the developer may be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%; the mass fraction of excipient may be 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 89%.

In some of these embodiments, the porous developing particles contain a developable metal element. The developable metal element is at least one of gold (Au), silver (Ag), platinum (Pt), iridium (Ir), chromium (Cr), tantalum (Ta), bismuth (Bi), cobalt (Co), tungsten (W), and barium (Ba). In some embodiments, the developable metal may also include at least one of a lanthanide, actinide metal.

In some of these embodiments, the porous developing particles are of a developable metal material, an alloy material containing a developable metal, or a developable metal compound material.

Further, the metal material is one of the developable metal elements.

Further, the alloy material is an alloy of at least two of the developable metal elements or at least one of the developable metal elements and at least one other metal, i.e., an alloy metal material.

Further, the metal compound is at least one of a metal salt, a metal oxide, a metal carbide and a metal nitride insoluble in the excipient, which is formed from one of developable metal elements. For example, the metal compound material is silver halide, bismuth oxide, tantalum carbide, barium sulfate, tungsten oxide, tantalum nitride, tantalum oxide, or the like.

Further, the metal salts, metal oxides, metal carbides and metal nitrides are water-insoluble and organic solvent-insoluble metal compounds.

In some of these embodiments, the mass fraction of the organic compound modified porous developing particles in the developer is 50% to 100%, e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%. The mass fraction of the porous developing particles modified by the organic compound is 100%, namely the developing agents are all porous developing particles modified by the organic compound. When the mass fraction of the organic compound-modified porous developing particles is less than 100%, other developer such as at least one of solid developing particles and porous developing particles not modified with an organic compound may be further contained in the liquid embolic agent.

Further, in the developer, the mass fraction of the organic compound modified porous developing particles is 70% -90%.

In some of these embodiments, the modified organic compound on the porous developing particle is attached to the porous developing particle by a chemical bond. The porous developing particles are firmly connected through chemical bonds, and can exist stably in the whole dispersion process.

Further, the organic compound accounts for 0.1% -10% of the modified porous developing particles by mass, for example 0.1%, 0.3%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%; preferably, the organic compound comprises 0.5 to 5% by mass of the modified porous developing particles.

Further, the organic compound is a small molecular compound or a high molecular compound, and can contribute to the suspension stability of the porous developing particles in a polymer solution formed of a polymer and an excipient, for example, a polymer. The organic compound is preferably a polymer compound.

Further, the number of the molecular structural repeating units of the organic compound is 1 to 1000. Preferably 1 to 100, and more preferably 2 to 100. For example, an organic compound is a molecular layer having only several repeating units, or a molecular layer formed by connecting several different chemical structures, or a polymer having a certain degree of polymerization. In some embodiments, the number of repeating units of the organic compound molecule is 1-10, and the porous developing particles modified with the organic compound can maintain the suspension stability in the polymer solution, and can not increase the viscosity of the liquid embolic agent as a whole due to the excessive number of repeating units.

Further, the organic compound modified porous developing particles are prepared by a surface polymerization method or a graft coupling method through the porous developing particles.

The surface polymerization method is to perform polymerization reaction on the surface of the porous developing particle, so that a reactive group in the organic compound or a monomer for forming the organic compound is polymerized on the surface of the porous developing particle to obtain a polymer, thereby forming the porous developing particle with the surface modified by the organic compound.

Wherein, the grafting coupling method is as follows: the porous developing particles are subjected to surface activation treatment, and then the porous developing particles subjected to surface activation treatment are subjected to chemical reaction with reactive groups in the organic compound, so that the polymer modified porous developing particles are formed through bonding.

In the step of the polymerization and graft coupling method for the surface of the porous developing particle, the porous developing particle may be treated by a conventional treatment method for metal surface treatment, such as silane coupling, surface initiation, plasma treatment, high-energy radiation treatment, and the like. Wherein, the surface initiation comprises initiator graft polymerization, ultraviolet graft polymerization, ozone initiated graft polymerization and the like; the high-energy radiation treatment includes Y radiation, electron beam radiation, and the like.

In some of these embodiments, the organic compound is selected from at least one of polyacrylates, polymethacrylates, polyurethanes, polyesters, polyethers, polysiloxanes, polyvinyl acetates, polyacenols, polydopamine, polyamides, and polysaccharides. The polymers can be chemically bonded with the developer particles through the modification of functional groups to form ester bonds, urethane bonds, ether bonds and the like, can be obtained through monomer polymers after the surface of the developer particles is modified with an initiator, and also have longer molecular chains, so that the interaction between the polymer and polymer molecules in the liquid embolic agent can be stronger, and the suspension stability of the developer particles can be further improved.

Further, the same porous developing particle may be modified with a plurality of different organic compounds as described above. In a specific example, the polydopamine modified porous development particles may be modified first with polydopamine and then further modified with polyacrylate. More specifically, the method further comprises the step of hydroxylating the surface of the porous developing particles before the polydopamine modification is adopted. The method further comprises the step of initiating modification of the polydopamine modified porous developing particles before further modification of the polydopamine modified porous developing particles with polyacrylate.

In some of these embodiments, the surface of the porous developing particle has porous pores.

Further, the porous developing particles are solid particles having porous holes on the surface. It is understood that solid particles are herein referred to as particles that are relatively hollow, meaning that the particles do not have an internal hollow structure, i.e. the interior as a whole is of a solid structure, but the surface may be porous or non-porous. In other words, solid particles herein include, but are not limited to, particles having an overall solid structure within the interior but no voids on the surface, and particles having both an overall solid structure within the interior and voids on the surface.

In some examples, the solid particles may be made by a polymer template method. The polymer template method is to form a metal layer, an alloy layer or a metal compound layer on the surface of polymer microspheres by taking the polymer microspheres as templates, then not removing the polymer microsphere templates, and reserving the polymer microsphere templates as cores, wherein the obtained solid particles comprise cores of polymer materials and developable shells of metal materials, alloy materials or metal compound materials.

Specifically, the preparation method of the solid particles with porous holes on the surfaces comprises the following steps: polymer microspheres with certain particle size are prepared by adopting emulsion polymerization or self-assembly and other methods, and then a metal layer, an alloy layer or a metal compound layer is formed on the surfaces of the polymer microspheres by adopting a deposition or surface modification method. The polymer microspheres used therein are commercially available as such, for example, microspheres of polyethylene, polystyrene-divinylbenzene, etc. Wherein, the porous holes can be formed in the shell layer by controlling the molecular growth and accumulation process of the metal layer, the alloy layer or the metal compound layer serving as the shell layer.

In some of these embodiments, the porous developing particles are hollow particles. It is understood that hollow particles herein refer to particles having an internal hollow structure, but the surface may be porous or non-porous. In other words, hollow particles herein include, but are not limited to, particles having a hollow structure throughout the interior but no holes on the surface, and particles having a hollow structure throughout the interior and holes on the surface.

The preparation method of the hollow particles can be a polymer template method. Specifically, the polymer template method is to prepare polymer microspheres with a certain particle size by adopting emulsion polymerization or self-assembly and other methods, then deposit a metal layer, an alloy layer or grow and graft on the surface of the polymer microspheres to form a metal compound layer, wherein the metal layer, the alloy layer or the metal compound layer can exist stably and be separated, and the polymer microsphere template in the nucleus is removed by eluting with a specific solvent, or the core polymer microsphere template is removed by calcining or other means at a specific temperature, so that hollow particles are obtained. The polymer microsphere template may also be removed by eluting with a solvent followed by calcination to give hollow particles (or referred to as hollow microspheres).

Further, the volume ratio of the hollow portion of the hollow particles can be controlled by controlling the particle diameter of the polymer microspheres and the thickness of the deposited metal layer or metal compound layer. Further, when the metal layer and the metal compound layer are formed by a solution method, the volume ratio of the hollow portion can be adjusted by adjusting the concentration of the raw materials for forming the metal and the metal compound in the solution, thereby controlling the thickness of the formed metal layer and metal compound layer.

Further, the shell layer can be formed into holes by controlling the molecular growth and accumulation process of the shell layer.

The polymer microsphere can be directly purchased from the market, such as polyethylene, polystyrene-divinylbenzene and the like.

Further, the morphology of the porous developing particles may be spherical, ellipsoidal, or the like.

Further, the porous developing particles are hollow particles and have porous holes on the surface.

In a specific example, the porous developing particles are hollow particles and have porous pores on the surface, and the hollow structure of the porous developing particles communicates with at least part of the pores of the surface.

In a specific example, the porous developing particle surface has at least a portion of the porous pores that are through holes. The through holes are distributed on the two ends of the holes of the particles and are communicated with the outside, and the holes penetrate through the inside of the particles from one end to the other end.

Further, the porous developing particles have a particle diameter of 0.01 μm to 150 μm, for example, 0.01 μm, 0.05 μm, 0.1 μm, 0.2 μm, 0.5 μm, 1 μm, 5 μm, 10 μm, 20 μm, 30 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm; preferably 0.1 μm to 50. Mu.m. It is understood that the porous developing particles may be monodisperse particles of uniform particle size or polydisperse particles of a variety of different particle sizes. For example, the porous developing particles may be particles having a specific particle size distribution obtained by combining them in a certain ratio.

In some examples, the porous developing particles have a pore size distribution of 1nm to 2000nm, with a preferred pore size distribution of 100nm to 1000nm. It is understood that the pore size of the porous developing particles may be uniformly sized pores or polydisperse non-uniformly sized pores. The proper pore size facilitates the penetration of the solution and the modification of the organic compound.

Further, the porosity of the porous developing particles is 10% to 90%, for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, preferably 10% to 70%, more preferably 20% to 50%. Wherein, the porosity refers to the percentage of the pore volume in the porous developing particles to the total volume of the material in a natural state. The higher the porosity, the larger the specific surface area of the particles, the higher the modification ratio of the organic compound, and in addition, the proper density can be obtained by optimizing the porosity of the porous developing particles, and the density can enable the porous developing particles to have better suspension stability in the liquid embolic agent, so that the porous developing particles are easy to disperse and are not easy to settle.

In some embodiments, the polymer is any one of, or a copolymer of at least two of, a polyolefin alcohol, a polyacrylate, a polymethacrylate, a polyurethane, a polyester, a polyether, a polysiloxane, and a polyamide. Among these copolymers include, but are not limited to, non-return copolymers, block copolymers, alternating copolymers, graft copolymers.

Further, the polymer may be at least one of polyacrylamide-polymethyl methacrylate copolymer, polyethylene-vinyl alcohol copolymer, polyethylene glycol-polyacrylate copolymer, and natural polymer which is poorly water-soluble, such as cellulose and its derivatives.

In some embodiments, the weight average molecular weight of the polymer contained in the liquid embolic agent is 1 to 40 tens of thousands; preferably 10 to 30 ten thousand. Further, the molar content of the hydrophobic component of the polymer is greater than 50%, preferably greater than 60%. Wherein the hydrophilic component refers to hydrophilic groups contained in the side chains or main chains of the polymer, and otherwise is a hydrophobic component. The higher the content of the hydrophobic component, the shorter the polymer is in water, buffer or blood, and the smaller the corresponding curing rate, so the curing rate can be controlled by adjusting the proportion of the hydrophilic and hydrophobic components.

In some of these embodiments, the excipient is at least one of the following solvents: a biocompatible organic solvent, water and a buffer solution. These solvents are non-toxic or low toxic and may act as diluents or dispersants in the liquid embolic agent.

Further, the biocompatible organic solvents include, but are not limited to, at least one of dimethyl sulfoxide, N-methyl pyrrolidone (NMP), ethanol, and isopropanol, which have the advantage of low toxicity. It will be appreciated that the solvent may be selected according to the type of polymer, so long as it is capable of forming a uniform system of polymer and solvent. Homogeneous systems are referred to herein as homogeneous clear solutions or homogeneous suspensions.

It is understood that the excipient may be a good solvent for the above-described polymers, i.e., the excipient and the polymer are capable of forming a homogeneous clear solution, or the excipient and the polymer may form a homogeneous system under specific conditions.

The invention also provides a preparation method of the liquid embolic agent, which is to uniformly mix the polymer, excipient and other components.

Further, the mixing may be performed by a conventional method such as stirring or ultrasonic treatment, as long as the liquid embolic agent is allowed to form a uniform system.

Further, the polymer and the excipient may be first mixed to form homogeneous polymer solution via mechanical stirring, etc. and then added with developer, and finally mixed via mechanical stirring to form homogeneous dispersed system.

Further, in the step of forming the polymer solution of a uniform phase, the dissolution can be assisted by heating, cooling, physical dispersion, and the like.

After the liquid embolic agent forms a uniform dispersion system, a conveying or pushing mode can be adopted, and after the liquid embolic agent reaches water or blood, the polymer in the liquid embolic agent is precipitated along with the diffusion of the excipient to form soft embolic groups, and the developer in the embolic groups ensures good developing performance.

The invention also provides an application of the liquid embolic agent in preparing medical interventional instruments or interventional therapeutic drugs.

Another embodiment of the present invention also provides a medical intervention device, a device body and a reagent disposed within the device body, the reagent comprising a liquid embolic agent according to any of the above.

In some of these embodiments, the instrument body is a catheter. Further, the inner diameter of the tube is small, known as a microcatheter. Generally, the inner diameter of the microcatheter is 0.007 to 0.013 inch.

In another embodiment of the invention, an interventional drug is provided, which comprises a liquid embolic agent according to any of the above.

Further, the interventional therapy drug may contain an active ingredient having a therapeutic effect on a disease, in addition to the liquid embolic agent as described above.

Further, the interventional therapy drug may contain other additives in addition to the liquid embolic agent as described in any of the above.

The liquid embolic agent can be used in interventional therapy, such as interventional hemostasis, vascular malformations and malignant tumors, including but not limited to cerebral Arterial Venous Malformations (AVM), hematomas, and interventional embolic therapy of cerebral arterial venous fistulae (DVFs), subdural hematomas, occlusion therapy of blood flow at vascular curves Zhang Zhiliao, tumors, etc., peripheral blood vessels, etc.

The liquid embolic agent reaches the disease position through the pushing injection of the microcatheter, contacts the blood flow, and starts solidifying along with the dispersion of the excipient. In blood flow, the polymer in the liquid embolic agent slowly precipitates and solidifies to form embolic mass, thereby achieving the purposes of blocking vascular access and blocking blood flow.

The liquid embolic agent of the organic compound modified porous developing particles in the liquid embolic agent has excellent suspension stability, can reduce preoperative concussion time, reduce sedimentation risk in the dispersion process, improve dispersion performance and reduce reflux risk in the injection process. Thus, after the liquid embolic agent is pushed from the microcatheter, the microcatheter can be easily withdrawn, reducing the risk of the microcatheter being pulled to the vessel.

In order to make the objects, technical solutions and advantages of the present invention more concise, the present invention will be described in the following specific examples, but the present invention is by no means limited to these examples. The following examples are only preferred embodiments of the present invention, which can be used to describe the present invention, and should not be construed as limiting the scope of the invention. It should be noted that any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

In order to better illustrate the present invention, the following description of the present invention will be given with reference to examples. The following are specific examples.

Example 1:

(1) Preparation of bismuth particles modified by organic compound

1. The bismuth particle surface is first hydroxylated. The method comprises the following specific steps: and respectively ultrasonically cleaning the bismuth particles with the surface subjected to polishing treatment by deionized water, ethanol and acetone for 10min, soaking the bismuth particles in a mixed solution of concentrated sulfuric acid and hydrogen peroxide (30 wt%) (v/v=7/3 of the concentrated sulfuric acid and the hydrogen peroxide) for 50min, filtering, and washing the bismuth particles with deionized water for several times to obtain the hydroxylated bismuth particles.

2. Polydopamine modified bismuth particles. Adding the hydroxylated bismuth particles into dopamine hydrochloride water solution with the concentration of 2mg/mL, adjusting the pH value to be more than 10 by using sodium hydroxide solution, carrying out light-shielding reaction for 24 hours, filtering, and washing with deionized water for several times to obtain polydopamine modified bismuth particles.

3. The bromine initiator modifies the bismuth particles. And (3) adding the polydopamine modified bismuth particles into toluene under anhydrous and anaerobic conditions, adding 2-bromoisobutyryl bromide, stirring at room temperature, reacting for 20 hours, and cleaning for several times by using toluene, ethanol and deionized water respectively after finishing to obtain the bromine initiator modified bismuth particles.

4. And preparing a hydroxyethyl polyacrylate modified layer on the surface of the bismuth particles. Under the anhydrous and anaerobic condition, adding the bismuth particles modified by the bromine initiator into a water/methanol mixed solvent, and adopting CuBr/CuBr ₂ The atom transfer radical copolymerization (ATRP) reaction is carried out by a tetramethyl ethylenediamine (TMEDA) system, then the monomer hydroxyethyl acrylate (HEMA) is added, and the reaction is finished at 60 ℃ for about 10 hours under stirring. Washing with methanol and water for several times to obtain the product, namely the bismuth particles modified by hydroxyethyl Polyacrylate (PHEMA).

(2) Preparation of embolic agent modified with bismuth particles modified with the above organic Compound as developer

And dissolving polyvinyl alcohol in N-methyl pyrrolidone to obtain a polyvinyl alcohol solution, adding the bismuth particles modified by the hydroxyethyl polyacrylate, and mixing to obtain the suspended liquid embolic agent. In the liquid embolic agent, the concentration of the poly (hydroxyethyl acrylate) -modified bismuth particles is 40wt% and the concentration of the poly (vinyl alcohol) is 10wt%.

Example 2

Example 2 is substantially the same as example 1, except that: step 3 and step 4 are omitted, and the polydopamine modified bismuth particles are directly used for preparing the embolic agent serving as the developer.

The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.

The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims

1. A liquid embolic agent, comprising, in mass fractions:

1% -20% of polymer;

50-89% of excipient.

2. The liquid embolic agent of claim 1, wherein in said developer, said organic compound modified porous developing particles have a mass fraction of 50% to 100%;

3. The liquid embolic agent of claim 1, wherein said modified organic compound on said porous developing particle is attached to said porous developing particle by a chemical bond;

4. The liquid embolic agent of claim 1, wherein said organic compound is selected from at least one of polyacrylates, polymethacrylates, polyurethanes, polyesters, polyethers, polysiloxanes, polyvinyl acetate, polyalkylene alcohols, polydopamine, polyamides, and polysaccharides.

5. The liquid embolic agent of claim 1, wherein said organic compound modified porous developing particles are prepared by surface polymerization or graft coupling methods through said porous developing particles.

6. The liquid embolic agent of any of claims 1 to 5, wherein the surface of said porous developing particles has porous pores;

and/or, the porous developing particles are hollow particles;

and/or the porosity of the porous developing particles is 10% -90%.

7. The liquid embolic agent of claim 6, wherein said porous developing particles are hollow particles and have porous pores on a surface, and wherein the hollow structure of said porous developing particles is in communication with at least a portion of the pores of said surface.

8. The liquid embolic agent of claim 6, wherein said porous developing particles have porous pores at least partially defined by through-holes.

9. The liquid embolic agent of any of claims 1 to 5, wherein said porous developing particles contain a developable metallic element therein;

10. The liquid embolic agent of claim 9, wherein said porous developing particles are of a developable metal material, an alloy material containing a developable metal, or a developable metal compound material.

11. A method for preparing a liquid embolic agent, comprising the steps of:

the components of the liquid embolic agent of any of claims 1 to 10 are mixed homogeneously.

12. Use of a liquid embolic agent according to any of claims 1 to 10 for the preparation of a medical interventional instrument or an interventional therapy.

13. A medical intervention device comprising a device body and a reagent disposed within the device body, the reagent comprising a liquid embolic agent according to any of claims 1 to 10.

14. An interventional drug, characterized in that it comprises a liquid embolic agent according to any one of claims 1 to 10.