WO2023125042A1 - Liquid embolic agent, and preparation method therefor and use thereof - Google Patents

Abstract

The present application relates to a liquid embolic agent, and a preparation method therefor and the use thereof. The liquid embolic agent comprises, by mass fraction: 2-20% of a polymer; 10-50% of developable porous particles, wherein the developable porous particles comprise porous particles of at least one of a metal material, an alloy material and a metal compound material; and 50-78% of a solvent.

Description

Liquid embolic agent and its preparation method and application

This application claims the priority of the Chinese patent application filed on December 31, 2021 with application number 202111679684.9 and titled "Liquid Embolic Agent and Its Preparation Method and Application", which is hereby incorporated by reference in its entirety.

technical field

The present application relates to the technical field of medical devices, in particular to a liquid embolic agent and its preparation method and application.

Background technique

Embolism refers to the phenomenon that abnormal substances insoluble in blood appear in the circulating blood and flow with the blood, thereby blocking the lumen of the blood vessel. The embolic agent is a reagent that has the function of embolizing tumor blood vessels. Its principle of action is to form an embolism in the lumen of the tumor blood vessels, thereby blocking the lumen of the blood vessels, and finally leading to ischemia and necrosis of the tumor.

Embolization, also known as embolization therapy (embolotherapy), is the controlled injection of embolic agents into the supply vessels of diseased organs through arterial or intravenous catheters, causing occlusion and interruption of blood supply, in order to achieve control of bleeding, treatment of tumors and blood vessels. Sexual lesions and the purpose of eliminating the function of diseased organs. Interventional embolization technology is widely used in the clinical treatment of vascular abnormalities such as cerebral arteriovenous malformation (AVM), cerebral arteriovenous fistula (DVF), and subdural hematoma.

At present, there are many types of interventional embolic agents, classified according to their status, including solid embolic agents and liquid embolic agents. After the solid embolic agent (such as coil, gelatin sponge, etc.) enters the target blood vessel, it stays in the blood vessel with similar diameter to form a mechanical embolism. Thrombosis often occurs around the embolus and at the distal end of the embolized blood vessel, resulting in local blood vessels. Flow interruption is mostly used for embolization of small arteries or arteriovenous fistulas, and can also be used for protective embolization when superselective intubation is not possible. In addition, although the embolization process of solid embolic agents is relatively simple, it requires a large-diameter microcatheter, which cannot enter the lesion site close to the AVM for more precise embolization, and the problem of vascular recanalization is prone to occur after particle embolization. Therefore, solid embolic materials are mostly used for preoperative embolization, which is difficult to meet the needs of curative embolization.

Liquid embolic agents have strong fluidity and can be directly injected into the tumor tissue to evenly fill diseased blood vessels through thinner microcatheters. Gaps, so as to achieve complete embolization, to achieve closure after curing, reduce the possibility of blood vessel recanalization, and achieve precise and permanent embolization. Moreover, liquid embolic agents (such as absolute ethanol, sodium morrhuate, iodized oil, etc.) mostly damage the vascular endothelium through chemical destruction, coagulate and destroy the formed components in the blood into mud, and block the capillary bed. Liquid embolic agents stay in the hepatic sinusoids and small arteries for a long time, and cause secondary thrombosis in small arteries, and are mostly used to embolize the vascular bed and arteries of tumors.

Currently, there are two types of liquid embolic agents that are widely used clinically, including adhesive liquid embolic agents and non-adhesive liquid embolic agents. The most commonly used non-adhesive liquid embolic agent is Onyx liquid embolic agent, whose main components include ethylene vinyl alcohol copolymer, dimethyl sulfoxide, and micron-sized tantalum powder as a developer. The embolization principle of Onyx liquid embolic agent is that metal tantalum powder is stirred or shaken violently for a long time in the dimethyl sulfoxide solution of polymer with micron-sized tantalum powder as the developer to form a suspension of tantalum powder, which is passed through micron After the catheter is injected into the blood vessels of intracranial and other lesions, an embolism is formed to block the vascular access and achieve the purpose of blocking blood flow.

However, it has been found in practical applications that metal tantalum powder is used as the developer of the liquid embolic agent, and the liquid embolic agent needs to be mixed for a long time before use, so as to prevent the developer from standing and settling and affecting its performance. In addition, the sedimentation of the developer will inevitably occur during the bolus injection, which will prevent part of the embolic agent from being diffused to the deeper disease site, and at the same time, the sedimentation of part of the developer will cause the concentration of the developer to change, which will eventually lead to the reduction of the developing performance. .

Contents of the invention

Based on this, according to various embodiments of the present application, a liquid embolic agent and its preparation method and application are provided.

This application is achieved through the following technical solutions.

One aspect of the present application provides a liquid embolism, comprising:

Polymer 2% ~ 20%;

10% to 50% of developable porous particles, the developable porous particles include porous particles of at least one of metal material, alloy material and metal compound material; and

Solvent 50%～78%.

In some of the embodiments, the developable porous particles are porous solid particles, and the interior and/or surface of the solid particles have porous pores.

In some embodiments, the developable porous particles have porous pores on their surfaces.

In some embodiments, the developable porous particles are prepared by a polymer template method, and the developable porous particles include a core of polymer material and a shell of developable metal material, alloy material or metal compound material.

In some embodiments, the developable porous particles have porous pores inside and on the surface, at least some of which are through holes.

In some embodiments, the developable porous particles are prepared by sintering or hydrogenation, and the shape of the developable porous particles is spherical, ellipsoidal, polyhedral or coral-like.

In some of these embodiments, the particle size of the developable porous particles is 0.1 μm-200 μm;

And/or, the pore diameter of the developable porous particles is 1nm-500nm;

And/or, the porosity of the developable porous particles is 10%-70%.

In some of these embodiments, the metal material is one of gold, silver, platinum, iridium, chromium, tantalum, bismuth, cobalt, tungsten and barium;

The alloy material is formed of at least two of gold, silver, platinum, iridium, chromium, tantalum, bismuth, cobalt, tungsten and barium;

The material of the metal compound is a metal salt, metal oxide, metal carbide and metal nitrogen insoluble in the solvent formed by one of gold, silver, platinum, iridium, chromium, tantalum, bismuth, cobalt, tungsten and barium. at least one of the compounds.

In some of these embodiments, the polymer has a weight average molecular weight of 10,000 to 400,000;

And/or, the polymer is any one of polyolefins, polyolefin alcohols, polymethacrylates, polyurethanes, polyesters, polyethers, polysiloxanes and polyamides, or at least two of them copolymer;

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

In some of these embodiments, in the liquid embolic agent, by mass fraction, the polymer is 3%-10%, the developable porous particles is 20%-40%, and the solvent is 60%. ~75%.

Another aspect of the present application provides a method for preparing a liquid embolic agent, comprising the steps of:

Mix the components in the liquid embolic agent described in any one of the above evenly.

Another aspect of the present application provides the application of the liquid embolic agent described in any one of the above in the preparation of medical interventional devices or interventional therapy drugs.

Another aspect of the present application provides a medical interventional device, including a device body and the liquid embolism described in any one of the above-mentioned devices disposed in the device body.

Another aspect of the present application provides an interventional therapy drug, which contains the liquid embolic agent as described in any one of the above.

The above-mentioned liquid embolic agent uses the developable porous particles of the above-mentioned specific type of material as the developer. Existence, which reduces the density per unit volume of the developer, and then has a lower average density, so the required buoyancy is reduced, that is, the suspension stability in the same solution is improved, which in turn reduces the sedimentation velocity, which is conducive to lifting the embolic agent. The homogeneity of the developable porous particles in the product can provide a good development effect. Compared with the traditional embolic agent, the homogeneity time required before use is shorter, and the ease of use is improved to a certain extent.

In addition, the developable porous particles with lower average density can play a certain "lubricity" effect in the polymer solution formed by the polymer and the solvent, thereby reducing the viscosity of the polymer solution. Moreover, the developable porous particles with better suspension stability are conducive to the better forward dispersion of the liquid embolic agent during bolus injection, and are conducive to reducing reflux. In this way, the liquid embolic agent can be better pushed from the multi-dimensionality of the liquid embolic agent's uniformity, viscosity, and reflux reduction, thereby improving the development performance of the above-mentioned liquid embolic agent.

Description of drawings

Fig. 1 is the scanning electron micrograph of the metal tantalum porous particle that embodiment 1 makes;

Fig. 2 is the physical photograph of the liquid embolic agent that embodiment 1 and comparative example 1 make;

Fig. 3 is the development photo under X-ray after the liquid embolic agent that embodiment 1 and comparative example 1 make leave standstill 5min;

Fig. 4 is the developing photo under X-ray after the liquid embolic agent that embodiment 1 and comparative example 1 make leave standstill 20min;

Fig. 5 is the variation curve of the brightness value of the liquid embolic agent prepared in Example 1 and Comparative Example 1 under X-ray at the sample 1/2 height with the standing time;

Fig. 6 is the physical photo of the liquid embolism prepared in Example 1 solidified in water.

Detailed ways

In order to facilitate the understanding of the present application, the following will describe the present application more fully and give preferred embodiments of the present application. However, the present application can be embodied in many different forms and is not limited to the embodiments described herein. It should be understood that the purpose of providing these embodiments is to make the understanding of the disclosure of the application more thorough and comprehensive.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this application belongs. The terms used herein in the specification of the application are only for the purpose of describing specific embodiments, and are not intended to limit the application. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

In addition, the terms "first" and "second" are used for descriptive purposes only, and cannot be interpreted as indicating or implying relative importance or implicitly specifying the quantity of indicated technical features. Thus, the features defined as "first" and "second" may explicitly or implicitly include at least one of these features. In the description of the present application, "plurality" means at least two, such as two, three, etc., unless otherwise specifically defined.

One embodiment of the present application provides a liquid embolic agent, which comprises, by mass fraction: 2%-20% of a polymer, 10%-50% of developable porous microparticles and 50%-78% of a solvent.

Wherein, the above-mentioned developable porous particles include porous particles made of at least one of metal, alloy and metal compound materials.

The "developable" of the above-mentioned developable porous particles means that they are visible under X-rays. It can be understood that the metal, alloy or metal compound in the above-mentioned developable porous particles contains a developable metal, and a developable metal refers to a metal visible under X-rays.

It will be appreciated that the liquid embolic agents described above may comprise one or more developable porous particles. When a plurality of developable porous particles are contained, each developable porous particle may be of a different metal material, a different alloy material or a different metal compound material, or contain at least one of the metal material, alloy material and metal compound material. Porous particles of two materials.

The above-mentioned liquid embolic agent uses the developable porous particles of the above-mentioned specific type of material as the developer. Existence, which reduces the density per unit volume of the developer, and then has a lower average density, so the required buoyancy is reduced, that is, the suspension stability in the same solution is improved, which in turn reduces the sedimentation velocity, which is conducive to lifting the embolic agent. The homogeneity of the developable porous particles in the product can provide a good development effect. Compared with the traditional embolic agent, the homogeneity time required before use is shorter, and the ease of use is improved to a certain extent.

In addition, the developable porous particles with lower average density can play a certain "lubricity" effect in the polymer solution formed by the polymer and the solvent, thereby reducing the viscosity of the polymer solution. Moreover, the developable porous particles with better suspension stability are conducive to the better forward dispersion of the liquid embolic agent during bolus injection, and are conducive to reducing reflux. In this way, the liquid embolic agent can be better pushed from the multi-dimensionality of the liquid embolic agent's uniformity, viscosity, and reflux reduction, thereby improving the development performance of the above-mentioned liquid embolic agent.

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

Further, the metal material is gold (Au), silver (Ag), platinum (Pt), iridium (Ir), chromium (Cr), tantalum (Ta), bismuth (Bi), cobalt (Co), tungsten (W) And one of barium (Ba).

Further, the alloy material is gold (Au), silver (Ag), platinum (Pt), iridium (Ir), chromium (Cr), tantalum (Ta), bismuth (Bi), cobalt (Co), tungsten (W) And at least two of barium (Ba), that is, alloy metal material.

Further, the metal compound material is gold (Au), silver (Ag), platinum (Pt), iridium (Ir), chromium (Cr), tantalum (Ta), bismuth (Bi), cobalt (Co), tungsten (W ) and barium (Ba) at least one of metal salts, metal oxides, metal carbides and metal nitrides insoluble in the above solvents. For example, the material of the metal compound is silver halide, bismuth oxide, tantalum carbide, barium sulfate, tungsten oxide, tantalum nitride, tantalum oxide and the like.

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

In some of these embodiments, the surface of the developable porous particles has porous pores.

Further, the developable porous particles are solid particles with porous holes on the surface. It can be understood that the solid particle is relative to the hollow particle herein, and the solid particle means that the particle does not have an internal hollow structure, that is, the internal whole is a solid structure. The porous solid particles herein include, but are not limited to, particles with a solid internal structure but holes on the surface, or particles with a solid internal structure and holes on the surface.

In some examples, the solid particles can be made by polymer templating. The polymer template method refers to the use of polymer microspheres as a template to form a metal layer, alloy layer or metal compound layer on the surface of the polymer microspheres, and then the polymer microsphere templates are not removed, and the polymer microspheres are retained. The template is used as the inner core, and the resulting solid particles include a core of polymer material and a shell of developable metal material, alloy material or metal compound material.

Specifically, the preparation method of the above-mentioned solid particles is as follows: polymer microspheres with a certain particle size are first prepared by emulsion polymerization or self-assembly, and then a metal layer is formed on the surface of the polymer microspheres by deposition or surface modification. Alloy layer or metal compound layer. The polymer microspheres used therein can be directly purchased from the market, such as polyethylene, polystyrene, polystyrene-divinylbenzene and other microspheres. Among them, porous holes can be formed in the shell layer by controlling the molecular growth and accumulation process of the metal layer, alloy layer or metal compound layer as the shell layer.

Further, both the inside and the surface of the developable porous particles may have porous holes, at least some of which are through holes. A through hole means that both ends of the hole distributed in the particle communicate with the outside, and the hole passes through the inside of the particle from one end and penetrates through the other end.

Further, the developable porous particles are prepared by sintering or hydrogenation. For example, metal tantalum porous particles are prepared by high-temperature sintering of high-purity tantalum. The principle is to sinter and melt high-purity tantalum by adding space-occupiers or pore-forming agents at high temperature, and then remove the space-occupiers or pore-forming agents. For example, metal tantalum porous particles are prepared by hydrogenation of tantalum blocks. The principle is to introduce hydrogen gas during the preparation process to control the amount of hydrogen absorbed by the tantalum blocks, and then break and remove hydrogen to form porous pores.

Further, the shape of the developable porous particles is a regular shape such as a sphere, an ellipsoid, a polyhedron, or an irregular shape such as a coral shape.

Compared with traditional liquid embolic agents containing developable metal powders, due to the higher metal density, the larger particle size of developable metal powders will cause them to settle rapidly in solution, thereby blocking the forward diffusion path of subsequent embolic agents , increasing the risk of reflux, the particle size of the developable metal powder is too small and it is easy to be taken away by the solvent diffusion. However, the present application uses developable porous particles with a porous structure. The smaller average density improves its suspension stability in the polymer solution, and the larger volume also reduces the risk of being taken away with solvent diffusion.

Further, the porosity of the developable porous particles is 10%-70%, optionally 20%-50%. Among them, the porosity refers to the percentage of the pore volume in the porous particle to the total volume of the material in the natural state. For the developable porous particles, an appropriate average density can be obtained by optimizing the porosity, and the average density can make the developable porous particles have better suspendability in the liquid embolic agent, be easy to disperse, and not easy to settle.

In some examples, the particle diameter of the developable porous particles is in the range of 0.1-200 μm, optionally 0.5-100 μm. It can be understood that the developable porous particles can be monodisperse particles with uniform particle size, or polydisperse particles with different particle sizes. In some examples, the developable porous particles have a pore size ranging from 1 nm to 500 nm. It can be understood that the pore size of the developable porous particles may be uniform in size or polydisperse inhomogeneous in size.

Further optionally, in the liquid embolic agent, by mass fraction, the polymer content is 3%-10%, the developable porous microparticles content is 20%-40%, and the solvent content is 60%-75%.

When a numerical range is disclosed in this application, the said range is considered continuous and includes the minimum and maximum values of the range and every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum of the range is included. Furthermore, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed in this application are to be understood to encompass any and all subranges subsumed therein.

For example, "2%～20%" can take the numerical range of 2%～20%, and this range is regarded as continuous, and includes the minimum value and maximum value of this range, and every value between such minimum value and maximum value value. Examples include but are not limited to: 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16% , 17%, 18%, 19%, 20%; or any two of these values, as an example, including: 2% to 19%, 2% to 18%, 2% to 17% , 2%~16%, 2%~15%, 2%~14%, 2%~13%, 2%~12%, 2%~11%, 2%~10%, 2%~9%, 2% %～8%, 3%～19%, 4%～19%, 5%～19%, 6%～19%, 7%～19%, 8%～19%, 9%～19%, 10%～ 19%, 3%~18%, 4%~18%, 5%~18%, 6%~18%, 7%~18%, 8%~18%, 9%~18%, 10%~18% , 3% to 19%, 4% to 15%, 5% to 15%, 6% to 15%, 7% to 15%, 8% to 15%, 9% to 15%, 10% to 15%.

For example, "10%～50%" can take the value range of 10%～50%, and the range is regarded as continuous, and includes the minimum value and maximum value of this range, and every value between such minimum value and maximum value For example, including but not limited to: any value in 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%; or the range composed of any two of these values, as Examples include: 10% to 15%, 10% to 19%, 10% to 20%, 10% to 25%, 10% to 30%, 10% to 35%, 10% to 40%, 10% to 45% %, 15%~19%, 15%~20%, 15%~25%, 15%~30%, 15%~35%, 15%~40%, 15%~45%, 15%~50%, 20%～25%, 20%～30%, 20%～35%, 20%～40%, 20%～45%, 20%～50%, 25%～30%, 25%～35%, 25% ～40%, 25%～45%, 25%～50%, 30%～35%, 30%～40%, 30%～45%, 30%～50%, 35%～40%, 35%～45% %, 35% to 50%, 40% to 45%, 45% to 50%.

For example, "50%～78%" can take the value range of 50%～78%. This range is regarded as continuous, and includes the minimum value and maximum value of this range, and every value between such minimum value and maximum value. value. For example, including but not limited to: any value in 50%, 55%, 60%, 65%, 70%, 75%, 76%, 77%, 78%; or a range composed of any two of these values, as an example , including: 50%～55%, 50%～60%, 50%～65%, 50%～70%, 50%～75%, 50%～76%, 50%～77%, 50%～78% , 55%～60%, 55%～65%, 55%～70%, 55%～75%, 55%～76%, 55%～77%, 55%～78%, 60%～65%, 60% %～70%, 60%～75%, 60%～76%, 60%～77%, 60%～78%, 65%～70%, 65%～75%, 65%～76%, 65%～ 77%, 65% to 78%.

It can be understood that the sum of the mass fractions of the components in the liquid embolic agent is 100%.

In some of these embodiments, the polymer is any one of polyolefins, polyolefin alcohols, polymethacrylates, polyurethanes, polyesters, polyethers, polysiloxanes, and polyamides, or at least two of them of copolymers. Further, the above-mentioned copolymer can be polyacrylamide-polymethyl methacrylate, ethylene-vinyl alcohol copolymer, polyethylene glycol-polyacrylate copolymer, etc., and can also be a water-insoluble natural polymer, such as Cellulose and its derivatives, etc. Further, copolymers include but not limited to random copolymers, block copolymers, alternating copolymers and graft copolymers.

Further, the weight average molecular weight of the polymer is 10,000-400,000, optionally 100,000-300,000. Further, the molar content of the hydrophobic component of the polymer is greater than 35%, optionally greater than 45%. Among them, the hydrophilic component is the hydrophilic group contained in the side chain or main chain of the polymer, otherwise it is the hydrophobic component. The higher the content of hydrophobic components, the shorter the precipitation time of the polymer in water, buffer or blood, and the lower the curing rate. The curing rate can be controlled by adjusting the ratio of hydrophilic and hydrophobic components.

In some of these embodiments, the solvent is at least one of a biocompatible organic solvent, water and a buffer. Further, the biocompatible organic solvent includes at least one of dimethyl sulfoxide, N-methylpyrrolidone (NMP), ethanol and isopropanol, and these solvents have the advantage of low toxicity. It can be 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. A homogeneous system here refers to a homogeneous clear solution or a homogeneous suspension.

Further, the solvent can be a good solvent for the above polymer, that is, the solvent and the polymer can form a uniform clear solution, or the solvent and the polymer can form a homogeneous system under certain conditions.

Further, the above-mentioned polymer is a hydrophobic polymer or an amphiphilic polymer, and the solvent is a biocompatible organic solvent.

Another embodiment of the present application also provides a preparation method of the above-mentioned liquid embolic agent, which only needs to mix the above-mentioned polymer, solvent and other components uniformly.

Further, common stirring, ultrasonic and other methods can be used for mixing, as long as the liquid embolic agent can form a homogeneous system.

Further, the polymer and the solvent may be firstly mixed by means of mechanical stirring to form a homogeneous polymer solution, and then the developer is added, and again mixed by means of mechanical stirring to form a uniform dispersion system.

Furthermore, in the step of forming a homogeneous polymer solution, methods such as temperature rise, temperature drop, and physical dispersion can be used to assist in promoting its dissolution.

After 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 solvent, the polymer in the liquid embolic agent precipitates out to form a soft embolism, and the embolism The developer in it ensures its good developing performance.

Another embodiment of the present application also provides the application of the above-mentioned liquid embolic agent in the preparation of medical interventional devices or interventional therapy drugs.

Another embodiment of the present application also provides a medical interventional device, a device body and a reagent disposed in the device body, where the reagent includes any one of the above-mentioned liquid embolic agents.

In some of these embodiments, the device body is a catheter. Furthermore, the inner diameter of the catheter is very small, which is called a micro catheter. Generally, the inner diameter of the microcatheter is 0.007-0.013 inch (inch).

Another embodiment of the present application also provides an interventional therapy drug, the interventional therapy drug comprising any one of the above-mentioned liquid embolic agents.

Furthermore, in addition to any of the above-mentioned liquid embolic agents, the interventional medicine may also contain active ingredients that have a therapeutic effect on diseases.

Furthermore, in addition to any of the above-mentioned liquid embolic agents, the interventional medicine may also contain other additives.

The above-mentioned liquid embolic agent can be used in interventional therapy, for example, in interventional hemostasis, vascular malformation and malignant tumor, including but not limited to cerebral arteriovenous malformation (AVM), hematoma, and cerebral arteriovenous fistula (DVF), subdural hematoma Interventional embolization therapy, treatment of peripheral varicose vessels and blockage of blood flow in tumors and other places.

The above-mentioned liquid embolic agent reaches the lesion area through the push injection of the microcatheter, touches the blood flow, and begins to solidify as the solvent diffuses. In the blood flow, the polymer in the liquid embolic agent slowly precipitates and solidifies to form an embolism, thereby achieving the purpose of blocking the vascular access and blocking the blood flow. In some embodiments, the liquid embolic agent containing developable porous particles has a lower average bulk density and lower viscosity. After the liquid embolic agent is pushed from the microcatheter, the microcatheter can be easily withdrawn, reducing the Risk of being pulled on blood vessels.

In order to make the purpose, technical solutions and advantages of the present application more concise and clear, the present application is described with the following specific examples, but the present application is by no means limited to these examples. The embodiments described below are only preferred embodiments of the present application, which can be used to describe the present application, and should not be construed as limiting the scope of the present application. It should be noted that any modifications, equivalent replacements and improvements made within the spirit and principles of the present application shall be included within the protection scope of the present application.

In order to better illustrate the present application, the content of the present application will be further described below in conjunction with the embodiments. The following are specific examples.

Example 1

The liquid embolic agent of Example 1 uses metal tantalum porous particles as a developer, and its preparation steps are as follows: Weigh 1 g of vinyl alcohol polymer and dissolve it in 20 g of dimethyl sulfoxide, heat and dissolve to obtain a homogeneous vinyl alcohol polymer solution, Take 5 mL of this solution, add 1.5 g of metal tantalum porous particles, and mix for 10 minutes to obtain a developable liquid embolic agent.

Among them, the morphology of the metal tantalum porous particles is shown in Figure 1. The metal tantalum porous particles are coral-like irregular block particles with a large number of holes inside and on the surface, at least some of which are through holes. The pore size is irregular and non-uniform, and the porosity is 40%.

Example 2

Example 2 uses porous tantalum metal particles as a developer, and its preparation method is: weigh 0.5 g of vinyl alcohol polymer and dissolve it in 1.65 g of dimethyl sulfoxide, add 0.6 g of developer, and mix to obtain an embolism.

Example 3

Example 3 uses porous tantalum metal particles as a developer, and its preparation method is: weigh 0.35 g of vinyl alcohol polymer and dissolve it in 1.65 g of dimethyl sulfoxide, add 1.2 g of developer, and mix to obtain an embolism.

Wherein, in terms of mass fraction, the proportions of the components in the liquid embolisms of Examples 1-3 are shown in Table 1.

Table 1

the	polymer(%)	Dimethyl sulfoxide (%)	Metal Tantalum Porous Particles (%)
Example 1	3.3	66.7	30
Example 2	18.2	60	21.8

Comparative example 1

Comparative Example 1 is basically the same as Example 1, except that in Comparative Example 1, metal tantalum powder with a non-porous structure is used to replace the metal tantalum porous particles prepared in step (1) of Example 1, and the quality is the same. Among them, the non-porous metal tantalum powder is a commercial metallurgical tantalum powder.

Fig. 2 shows the physical photos of the liquid embolic agent prepared in Example 1 and Comparative Example 1, wherein a is Example 1, and b is Comparative Example 1.

It can be seen from a and b in Figure 2 that there is no obvious difference between the two under visible light, and both are uniform black suspensions.

Fig. 3 and Fig. 4 show respectively the developing photo under X-ray after the liquid embolic agent that embodiment 1 and comparative example 1 make stand 5min and stand 20min; Wherein a is embodiment 1, b is comparative example 1.

As can be seen from a and b in Figure 3 and Figure 4, under X-rays, the development of the liquid embolic agent prepared in Example 1 of the present application is more obvious, and the outline is clearer; The development of the liquid embolic agent is relatively blurred, and the outline is not clear enough.

After the liquid embolic agents prepared in Example 1 and Comparative Example 1 were left to stand for different periods of time, samples were taken at 1/2 height of the sample under X-rays, and the brightness value of the sampling area was tested. Obtain the change curve of the brightness value of the liquid embolism prepared in Example 1 and Comparative Example 1 at the sample 1/2 height place under X-rays with the standing time, as shown in Figure 5, wherein a is Example 1, and b is Comparative example 1.

As can be seen from a and b in Figure 5, as the standing time prolongs, as shown in curve a, the brightness value of the liquid embolism prepared in Example 1 does not change much, especially when the standing time is 25min within 22 minutes; in contrast, as shown in curve b, the brightness value of the liquid embolic agent prepared in Comparative Example 1 has a larger change range, and it is in the early stage of standing, such as standing time 5min A relatively large increase in the brightness value occurs within a period of time, indicating that more sedimentation occurs during the standing process, resulting in a decrease in the uniformity of the liquid embolic agent, which in turn leads to an increase in the brightness value.

The liquid embolic agent prepared in Example 1 of the present application was injected into water through a syringe, and the liquid embolic agent instantly solidified to form an integrated black solid embolism mass when it came into contact with water, as shown in FIG. 6 . It shows that the liquid embolic agent of the present application has short curing time and high embolization efficiency.

In summary, compared with traditional micron-sized tantalum powder and other developers, due to the existence of porous structure, the suspension stability in the same solution is improved, which in turn reduces the sedimentation velocity and reduces the sedimentation of subsequent embolic agents. The risk of the path of forward diffusion. On the other hand, the porous structure is beneficial to improve the uniformity of the developable porous particles in the embolic agent, so as to maintain a good developing effect while using a small amount of metal developer.

The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, should be considered as within the scope of this specification.

The above-mentioned embodiments only represent several implementation modes of the present application, and the description thereof is relatively specific and detailed, but it should not be construed as limiting the scope of the patent for the invention. It should be noted that for those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, and these all belong to the protection scope of the present application. Therefore, the scope of protection of the patent application shall be based on the appended claims, and the description may be used to interpret the content of the claims.

Claims (13)

1. A liquid embolic agent, characterized in that, by mass fraction, comprising:

   Polymer 2% ~ 20%;

   10% to 50% of developable porous particles, the developable porous particles include porous particles of at least one of metal material, alloy material and metal compound material; and

   Solvent 50%～78%.
2. The liquid embolic agent according to claim 1, wherein the surface of the developable porous particles has porous holes.
3. The liquid embolic agent according to any one of claims 1 to 2, wherein the developable porous microparticles are prepared by a polymer template method, and the developable porous microparticles include an inner core of a polymer material and a developable metal material, alloy material or metal compound material.
4. The liquid embolic agent according to any one of claims 1 to 3, characterized in that the inside and surface of the developable porous particles have porous holes, wherein at least part of the holes are through holes.
5. The liquid embolic agent according to any one of claims 1 to 4, wherein the developable porous particles are prepared by sintering or hydrogenation, and the shape of the developable porous particles is spherical, ellipsoidal, polyhedral or coral shape.
6. The liquid embolic agent according to any one of claims 1 to 5, characterized in that,

   The particle size of the developable porous particles is 0.1 μm to 200 μm;

   And/or, the pore diameter of the developable porous particles is 1nm-500nm;

   And/or, the porosity of the developable porous particles is 10%-70%.
7. The liquid embolic agent according to any one of claims 1 to 6, wherein the metal material is one of gold, silver, platinum, iridium, chromium, tantalum, bismuth, cobalt, tungsten and barium;

   The alloy material is formed of at least two of gold, silver, platinum, iridium, chromium, tantalum, bismuth, cobalt, tungsten and barium;

   The material of the metal compound is a metal salt, metal oxide, metal carbide and metal nitrogen insoluble in the solvent formed by one of gold, silver, platinum, iridium, chromium, tantalum, bismuth, cobalt, tungsten and barium. at least one of the compounds.
8. The liquid embolic agent according to any one of claims 1 to 7, wherein the polymer has a weight average molecular weight of 10,000 to 400,000;

   And/or, the polymer is any one of polyolefins, polyolefin alcohols, polymethacrylates, polyurethanes, polyesters, polyethers, polysiloxanes and polyamides, or at least two of them copolymer;

   And/or, the solvent is at least one of biocompatible organic solvent, water and buffer.
9. The liquid embolic agent according to any one of claims 1 to 8, characterized in that, in the liquid embolic agent, by mass fraction, the polymer is 3% to 10%; the developable porous particles 20% to 40%; the solvent is 65% to 75%.
10. A preparation method of liquid embolic agent, is characterized in that, comprises the steps:

    Mix the components in the liquid embolic agent according to any one of claims 1 to 9 evenly.
11. Application of the liquid embolic agent according to any one of claims 1 to 9 in the preparation of medical interventional equipment or interventional treatment medicine.
12. A medical interventional device, characterized by comprising a device body and the liquid embolic agent according to any one of claims 1 to 9 disposed in the device body.
13. An interventional therapy drug, characterized in that the interventional therapy drug contains the liquid embolic agent according to any one of claims 1-9.

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