WO2022166568A1

WO2022166568A1 - Suspended particle contrast liquid embolic agent and preparation method therefor

Info

Publication number: WO2022166568A1
Application number: PCT/CN2022/072294
Authority: WO
Inventors: 吕怡然
Original assignee: 艾柯医疗器械(北京)有限公司
Priority date: 2021-02-04
Filing date: 2022-01-17
Publication date: 2022-08-11
Also published as: CN113398320B; CN113398320A

Abstract

The present disclosure relates to a suspended particle contrast liquid embolic agent and a preparation method therefor. The liquid embolic agent of the present disclosure comprises a core-shell structure contrast composite material, a solvent, and an embolic material. The core of the core-shell structure contrast composite material comprises a contrast material, the shell layer of the core-shell structure contrast composite material comprises a polymer material, and the embolic material is dispersed in the solvent to form a solution, wherein the density of the polymer material does not exceed the density of the contrast material. The preparation method for a liquid embolic agent of the present disclosure comprises the following steps: coating a polymer material on the outside of a contrast material to form a core-shell structure contrast composite material; dissolving an embolic material in a solvent to form a solution; and mixing the contrast composite material with the solution. In the liquid embolic agent of the present disclosure, contrast particles can be suspended in the solution for a long time and are not prone to precipitation, so that a doctor can use the contrast particles as needed according to actual situations during operation.

Description

Suspended particle contrast liquid embolic agent and preparation method thereof

technical field

The invention relates to the field of medical devices, in particular to a suspended particle contrast liquid embolic agent and a preparation method thereof.

Background technique

Endovascular embolization is a treatment method that sends catheters or microcatheters to vascular lesions, and injects embolic materials into the diseased blood vessels for embolization to achieve the purpose of treatment. With the rapid development of catheter technology, embolization materials and imaging and the accumulation of experience, endovascular embolization has been widely used and has become one of the important means of treating arterial malformations.

In endovascular embolization therapy, appropriate embolization materials can be selected according to different diseases. Common embolization materials can be divided into two categories: solid embolization materials and liquid embolizing agents. Liquid embolizing agents can enter blood vessels of different sizes and shapes to achieve complete embolization. Suitable for cerebral arteriovenous malformations, cerebral aneurysms, carotid-cavernous fistulas, vertebral arteriovenous fistulas, dural arteriovenous fistulas, Galen venous aneurysms, spinal arteriovenous malformations and fistulas, meningiomas and tumors with rich blood supply at the base of the skull Preoperative supply arterial embolization, etc.

In order to observe the operation process during the operation and determine the effect of the operation, it is usually necessary to add an additional contrast material to the liquid embolic agent. Onyx liquid glue is a typical liquid embolic agent, which is composed of embolic material ethylene-vinyl alcohol polymer (EVOH), solvent dimethyl sulfoxide (DMSO) and contrast material micronized tantalum powder. After the Onyx liquid glue is injected into the blood vessel, DMSO enters the blood and diffuses rapidly, and the ethylene-vinyl alcohol polymer (EVOH) coagulates after contacting the blood to embolize the blood vessel. The injection position of the Onyx liquid glue in the blood vessel and ethylene can be observed by tantalum powder angiography. - the coagulated state of the vinyl alcohol polymer (EVOH).

SUMMARY OF THE INVENTION

The technical problem to be solved by the present disclosure is that the contrast material such as tantalum powder settles at the bottom of the container after being added to the liquid embolic agent. For example, for Onyx liquid glue, it is necessary to shake the Onyx liquid glue for at least 20 minutes before the operation to make the contrast material evenly dispersed, and it needs to be used immediately after the shaking.

The characteristics of the liquid embolic agent that needs to be shaken before use brings many problems to the operation. On the one hand, doctors need to fully evaluate the condition of the lesion, estimate the amount of liquid embolic agent, and perform shock mixing in advance. During the operation, if the doctor estimates that the dosage is small and the prepared liquid embolic agent is insufficient, the embolic agent cannot be temporarily prepared due to the limitation of operation time. Due to incomplete embolization, the patient needs subsequent retreatment, which means more cost and risk of secondary surgery. On the other hand, once the liquid embolic agent stops oscillating, the high-density contrast material will gradually settle, and the content of contrast material in the liquid embolic agent transported to the diseased blood vessel may be greatly reduced, or even lose the contrast effect, resulting in clinicians unable to accurately judge the filling effect. , resulting in ectopic embolism, posing a medical risk. Furthermore, in the treatment of certain diseases, the injection rate of liquid embolic agents is strictly limited. For example, in the treatment of arteriovenous malformations, the injection rate is required to be about 0.16ml/min. When filling, the operation takes a long time (for the operation that requires the injection of 10ml of Onyx liquid glue, it takes about 63 minutes), the sedimentation of tantalum powder in the catheter may cause the catheter to block, and the clinician cannot accurately judge the implementation of the operation through the pressure of the syringe push rod. , causing medical risks such as catheter rupture or ectopic embolism.

The reason for the above technical problems is that contrast materials such as tantalum powder are high-density substances, and their density is greater than that of the solvent in the liquid embolic agent or the solution in which the embolic material is dissolved. Embolic bottom.

In order to solve the above-mentioned technical problems, the present inventor provides a novel contrasting composite material: high-density contrasting particles are coated with low-density polymer materials to form contrasting composites with a core-shell structure, which reduces the sedimentation speed of the contrasting material, so that the The contrast particles can be suspended in the solvent of the liquid embolic agent for a long time. According to the actual situation during the operation, the doctor can take it as needed, and there is no need to frequently oscillate the liquid embolic agent. At the same time, by wrapping the metal material with the polymer material, the metal developing material can not be directly exposed to the body, and the biocompatibility is improved.

Specifically, the present disclosure proposes the following technical solutions:

In one aspect, the present disclosure provides a suspended particulate contrast liquid embolizing agent, comprising a core-shell structure contrast composite material, a solvent and an embolic material, the core of the core-shell structure contrast composite material includes a contrast material, and the core-shell structure contrast composite material The shell layer of the material includes a polymer material, and the embolizing material is dispersed in the solvent to form a solution, wherein the density of the polymer material does not exceed the density of the contrast material.

In the above-mentioned liquid embolic agent, the density of the polymer material does not exceed the density of the solution.

In any of the above-mentioned liquid embolic agents, the polymer material is insoluble in the solvent;

Optionally, the polymer material is selected from one of polyethylene (PE), polypropylene (PP), polymethacrylate (PMMA), polyaryletherketone (PAEK) and polyetheretherketone (PEEK). one or two or more; optionally, the polymer material is selected from one of polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA) and polyether ether ketone (PEEK) or two or more; optionally, the polymer material is selected from polypropylene (PP) and/or polyetheretherketone (PEEK).

In any of the above-mentioned liquid embolic agents, the contrast material is selected from one or more of metals, metal salts, and metal oxides;

Optionally, the metal is selected from one or more of tantalum, platinum, tungsten, titanium, silver, barium, bismuth, gold, iridium and alloys thereof; optionally, the metal is selected from tantalum, platinum , one or more of gold, iridium, tungsten and its alloy; optionally, the alloy is selected from platinum-iridium alloy or platinum-tungsten alloy;

Optionally, the metal salt is selected from one or more of barium sulfate, barium carbonate, bismuth carbonate, bismuth nitrate, bismuth selenide, lanthanum tantalate and yttrium tantalate; selected from barium sulfate;

Optionally, the metal oxide is selected from one or more of tantalum oxide, tungsten oxide, bismuth oxide and titanium oxide;

Optionally, the contrast material is tantalum powder or platinum powder.

In any of the above-mentioned liquid embolic agents, the particle size of the contrast material is 500 nm-5 μm, such as 800 nm-4 μm, 1-3 μm;

Optionally, the particle size of the core-shell structure contrast composite material is 2-20 μm, for example, 3-18 μm, 5-5 μm, 4-13 μm.

In any of the above-mentioned liquid embolic agents, the solvent is selected from one or more of dimethyl sulfoxide (DMSO), N-methyl-pyrrolidone (NMP) and ethanol;

Optionally, the solvent is dimethyl sulfoxide (DMSO) or a mixed solvent of dimethyl sulfoxide (DMSO) and N-methyl-pyrrolidone (NMP);

Optionally, the embolization material is selected from ethylene-vinyl alcohol copolymer (EVOH), n-butyl cyanoacrylate (NBCA), isobutyl cyanoacrylate (IBCA), 2-hydroxyethyl methacrylate One or more of ester, methacrylic acid copolymer and cellulose acetate copolymer (CAP);

Optionally, the plug material is ethylene-vinyl alcohol copolymer (EVOH).

In any of the above liquid embolic agents, the liquid embolic agent contains 35-70 wt.% of the core-shell structure contrast composite material, optionally, the liquid embolic agent contains 45-70 wt.% of the core-shell structure Contrast composite material, optionally, the liquid embolic agent contains 50-65 wt.% of the core-shell structure contrast composite material.

In any of the above-mentioned liquid embolic agents, the embolic material is ethylene-vinyl alcohol copolymer (EVOH), and the solvent is dimethyl sulfoxide (DMSO);

Optionally, the solution contains 3-25 wt.% ethylene-vinyl alcohol copolymer (EVOH); optionally, the solution contains 5-20 wt.% ethylene-vinyl alcohol copolymer (EVOH).

On the other hand, the present disclosure provides a method for preparing any of the above-mentioned liquid embolic agents, comprising the steps of:

Coating the polymer material to the outside of the contrast material to form a core-shell contrast contrast composite material;

Dissolving the embolic material in a solvent to form a solution;

The contrast composite is mixed with the solution.

The contrast material and the polymer material are blended to obtain a blend, and the blend is pulverized and classified to obtain a mixture containing the contrast composite material;

Dissolving the embolic material in a solvent to form a solution;

mixing the contrast composite-containing mixture with the solution;

Optionally, as needed, the mixture containing the contrast composite material is mixed with the solution and allowed to stand to remove floating matter and sediment.

The beneficial effects of the present invention include:

1. The suspended particulate developing liquid embolic agent provided by some embodiments of the present disclosure, the contrast particles can be suspended in the solution for a long time and are not easy to precipitate. Can not be prepared in time, resulting in incomplete embolization or secondary surgery.

2. The suspended particulate developing liquid embolic agent provided by some embodiments of the present disclosure avoids the precipitation of the developing material during the introduction of the blood vessel, causing the tube to be blocked during the operation, and the doctor cannot accurately judge the feel of pushing the syringe, and the pushing force is too large, causing the catheter burst.

3. The suspended particle imaging liquid embolic agent provided by some embodiments of the present disclosure, the imaging material is evenly distributed, and provides accurate information for postoperative evaluation and review.

4. In the suspended particle developing liquid embolic agent provided by some embodiments of the present disclosure, since the contrast particles are encapsulated in a biocompatible polymer material, the contrast particles no longer directly contact blood, which reduces the side effects of the contrast particles on the human body.

Detailed ways

The technical solutions of the present disclosure will be clearly and completely described below. Obviously, based on the specific implementations in the present disclosure, all other implementations obtained by those of ordinary skill in the art without creative efforts fall within the protection scope of the present disclosure.

As described above, the purpose of the present disclosure is to provide a suspension particle contrast liquid embolic agent to solve the technical problems of the current liquid embolic agent that needs to be oscillated to disperse the contrast material before use.

The liquid embolic agent provided by some embodiments of the present disclosure includes a core-shell structure contrast composite material, a solvent, and an embolic material. The core-shell structure contrast composite material has a contrast material as a core and a polymer material as a shell. As used in this disclosure, the term "core-shell structure" includes both structures in which the outer shell completely surrounds the core, and structures in which the outer shell partially surrounds the core. Generally, heavy metal contrast materials such as platinum and tantalum are denser than solvents, while polymer materials such as polyethylene (PE), polypropylene (PP), polytetrafluoroethylene (PTFE), polymethacrylate (PMMA), polyaryletherketone (PAEK) and polyetheretherketone (PEEK), etc., the density is much lower than that of metal materials, so that the density of the core-shell structure contrast composite material is lower than that of the contrast material, thereby slowing down or even avoiding contrast. The material precipitates in solution. When the density of the core-shell structure contrast composite material is equivalent to the density of the solution, the core-shell structure contrast composite material can be suspended in the solution for a long time.

Some embodiments of the present disclosure provide liquid embolic agents in which the density of the polymer material does not exceed the density of the solution, eg, even lower than the density of the solvent, so that the density of the contrast composite material and the solvent are closer together, in Brownian motion together with the embolic material dispersed in the solvent Under the action, the contrast composite material is suspended in the solvent. Alternative polymeric materials such as polyethylene (PE), polypropylene (PP), polymethylmethacrylate (PMMA) and polyetheretherketone (PEEK) can significantly reduce the density of contrast materials. Because the contrast composite material is not easy to precipitate in the liquid embolic agent, the contrast composite material can be suspended in the solution for a long time with slight shaking before the operation, and can be used at any time during the operation. In addition, the contrast-enhancing composite material is not easy to precipitate in the liquid embolic agent, and will not block the catheter and lose the contrast-enhancing effect during use, which simplifies the doctor's operation, facilitates the doctor to accurately judge the intraoperative and postoperative conditions, and reduces medical risks.

In the liquid embolic agent provided by some embodiments of the present disclosure, the particle size of the core contrast material is 500 nm-5 μm, such as 500 nm, 750 nm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm. Core-shell structure contrast materials prepared from contrast materials with different particle sizes are different. In some embodiments of the present disclosure, the particle size of the core-shell structure contrast material is 2-20 μm, such as 2 μm, 2.2 μm, 3 μm, 3.2 μm μm, 4μm, 4.3μm, 5μm, 6μm, 8μm, 8.6μm, 10μm, 12μm, 12.7μm, 13μm, 15μm, 16μm, 17.2μm, 18μm, 20μm.

Some embodiments of the present disclosure provide a liquid embolic agent containing 35-70 wt.% of the core-shell structure contrast composite material. The content of contrast composite material in liquid embolic agent is different, and its developing effect is also different. By adjusting the content of the contrasting composite material, the desired development effect can be obtained, such as 35wt.%, 40wt.%, 45wt.%, 50wt.%, 55wt.%, 60wt.%, 65, wt.%, 70wt.%.

Some embodiments of the present disclosure provide a method for preparing a liquid embolic agent by mixing an embolic material with a solvent to obtain a solution. By adding different amounts of embolization material to the solvent, solutions of different viscosities can be obtained. The polymer material and the contrast material are hot-melt blended, and the contrast material is dispersed into the polymer material by extrusion technology. Then, the polymer material in which the contrast material is dispersed is pulverized by grinding or jet pulverization, and the desired core-shell structure contrast composite material is obtained through classification and screening. Finally, the shell structure contrast composite material is added to the aforementioned solution and mixed to obtain a liquid embolic agent developed by suspended particles. Those skilled in the art understand that the manner of dispersing and encapsulating the contrast material in the polymer material includes, but is not limited to, techniques conventionally used in the art, such as hot melt blending, co-extrusion, and the like. The pulverization method is also not limited to grinding, jet pulverization, or the like.

Some embodiments of the present disclosure provide a method for preparing a liquid embolic agent by mixing an embolic material with a solvent to obtain a solution. The polymer material and the contrast material are mixed and granulated, and then pulverized and classified to obtain ready-to-use powders of different particle sizes. Some embodiments of the present disclosure may be pulverized by a cryogenic mill or a jet mill, etc., and classified by an air classifier. The powder to be used is added to the solution and allowed to stand, and the surface float and bottom sediment of the solution are removed to obtain a liquid embolic agent.

The liquid embolic agent of the present disclosure and the preparation method thereof will be described below through specific examples. The reagents or instruments or operation steps used in the following examples are those that can be routinely determined by those of ordinary skill in the art.

Example 1

The suspended particulate contrast liquid embolic agent of this embodiment contains ethylene-vinyl alcohol copolymer (EVOH) embolization material, DMSO solvent and polyethylene (PE)-coated tantalum powder core-shell structure contrast composite material. The ethylene-vinyl alcohol copolymer (EVOH) embolic material was dissolved in DMSO to obtain a solution. The tantalum powder (with a particle size of about 5 μm) and polyethylene particles are mixed, and the mixture is added to a twin-screw extruder granulator to obtain tantalum powder-polyethylene particles. After the tantalum powder-polyethylene particles are ground by a cryogenic mill, air flow classification is performed to obtain the ready-to-use powder, and the ready-to-use powder is added to the aforementioned solution for 4 hours to remove floating objects and sediments to obtain a contrast-containing composite material. of liquid embolic agents. After the liquid embolic agent was left for 11 hours, it was observed that the contrast composite material particles were suspended in the solution, and no precipitation was found at the bottom of the container.

Example 2

The suspended particulate contrast liquid embolic agent of this embodiment contains ethylene-vinyl alcohol copolymer (EVOH) embolization material, DMSO solvent and polyethylene (PE)-coated tantalum powder core-shell structure contrast composite material. 5.8 g of ethylene-vinyl alcohol copolymer (EVOH) embolic material was dissolved in 100 ml of DMSO to obtain a solution (density 1.16 g/ml). The tantalum powder (particle size is about 4 μm) and polyethylene particles are mixed, and the mixture is added into a twin-screw extruder granulator to obtain tantalum powder-polyethylene particles. After grinding the tantalum powder-polyethylene particles by a cryogenic mill, air classification is performed to obtain the ready-to-use powder. Use dichloroethane and DMSO to prepare a mixed solvent with a density of 1.16g/ml, add the powder to be used in the mixed solvent and let it stand for 4 hours, remove the floating matter and sediment, dry the mixed solvent, wash it with water for several times and then dry it Dried to obtain a contrast composite material. The contrast composite material is added to the above solution and mixed to obtain a liquid embolic agent. After the liquid embolic agent was left for 11 hours, it was observed that the contrast composite material particles were suspended in the solution, and no precipitation was found at the bottom of the container.

Example 3

The suspended particulate contrast liquid embolic agent of the present embodiment contains ethylene-vinyl alcohol copolymer (EVOH) embolic material, DMSO solvent and polyethylene (PE)-coated tantalum powder core-shell contrast composite material. 5.8 g of ethylene-vinyl alcohol copolymer (EVOH) embolic material was dissolved in 100 ml of DMSO to obtain a solution (density 1.16 g/ml). The tantalum powder (with a particle size of about 3 μm) and polyethylene particles are mixed, and the mixture is added to a twin-screw extruder granulator to obtain tantalum powder-polyethylene particles. After the tantalum powder-polyethylene particles are pulverized by a jet mill, the powders to be used are collected in the classification chamber. A sodium chloride aqueous solution with a density of 1.16 g/ml was prepared, the powder to be used was added to the sodium chloride aqueous solution and left to stand for 4 hours, the floating and sediment were removed, dried, and then washed and dried to obtain a contrast-containing composite material. The contrast composite material was added to the EVOH-DMSO solution and mixed to obtain a liquid embolic agent. The liquid embolic agent was left standing for 13 hours and observed, and it was found that the contrast composite material particles were suspended in the solution, and no precipitation was found at the bottom of the container.

Example 4

The suspended particulate contrast liquid embolic agent of this embodiment contains ethylene-vinyl alcohol copolymer (EVOH) embolization material, DMSO solvent and polyethylene (PE)-coated tantalum powder core-shell structure contrast composite material. The ethylene-vinyl alcohol copolymer (EVOH) embolic material was dissolved in DMSO to obtain a solution. The tantalum powder (particle size is about 2 μm) and polyethylene particles are mixed, and the mixture is put into a twin-screw extruder granulator to obtain tantalum powder-polyethylene particles. After the tantalum powder-polyethylene particles are pulverized by a jet mill, the ready-to-use powder is collected in the classification chamber, and the ready-to-use powder is added to water for 4 hours, leaving the precipitation part and drying. The dried precipitate was added to the above solution, mixed and left to stand for 4 hours, and the intermediate suspension, that is, the liquid embolic agent, was intercepted. The liquid embolic agent was left standing for 13 hours and observed, and it was found that the contrast composite material particles were suspended in the solution, and no precipitation was found at the bottom of the container.

Example 5

The suspended particulate contrast liquid embolic agent of this embodiment contains ethylene-vinyl alcohol copolymer (EVOH) embolization material, DMSO solvent and polyethylene (PE)-coated tantalum powder core-shell structure contrast composite material. The ethylene-vinyl alcohol copolymer (EVOH) embolic material was dissolved in DMSO to obtain a solution. The tantalum powder (particle size is about 700 nm) and polyethylene particles are mixed, and the mixture is added to a twin-screw extruder granulator to obtain tantalum powder-polyethylene particles. After the tantalum powder-polyethylene particles are ground by a cryogenic mill, air flow classification is performed to obtain the ready-to-use powder, and the ready-to-use powder is added to the aforementioned solution for 4 hours to remove floating objects and sediments to obtain a contrast-containing composite material. of liquid embolic agents. The liquid embolic agent was left standing for 13 hours and observed, and it was found that the contrast composite material particles were suspended in the solution, and no precipitation was found at the bottom of the container.

Example 6

The suspended particulate contrast liquid embolic agent of this embodiment contains an ethylene-vinyl alcohol copolymer (EVOH) embolization material, a DMSO solvent and a polypropylene (PP)-coated tantalum powder core-shell structure contrast composite material. The ethylene-vinyl alcohol copolymer (EVOH) embolic material was dissolved in DMSO to obtain a solution. The tantalum powder (with a particle size of about 3 μm) and polypropylene particles are mixed, and the mixture is added to a twin-screw extruder granulator to obtain tantalum powder-polypropylene particles. After the tantalum powder-polypropylene particles are ground by a cryogenic mill, air flow classification is performed to obtain the ready-to-use powder, and the ready-to-use powder is added to the aforementioned solution and allowed to stand for 4 hours to remove floating objects and sediments to obtain a contrast-containing composite material. of liquid embolic agents. After the liquid embolic agent was left for 12 hours, it was observed that the contrast composite material was suspended in the solution, and no precipitation was found at the bottom of the container.

Example 7

The suspended particle contrast liquid embolic agent of this embodiment contains ethylene-vinyl alcohol copolymer (EVOH) embolic material, a mixed solvent of dimethyl sulfoxide (DMSO) and N-methyl-pyrrolidone (NMP), and polypropylene (PP) ) coated platinum powder core-shell structure contrast composite material. The ethylene-vinyl alcohol copolymer (EVOH) embolization material was dissolved in a mixed solvent of DMSO and NMP to obtain a solution. The platinum powder (with a particle size of about 2 μm) and polypropylene particles were mixed, and the mixture was added to a twin-screw extruder granulator to obtain platinum powder-polypropylene particles. After the platinum powder-polypropylene particles are ground by a cryogenic mill, air flow classification is performed to obtain the ready-to-use powder, and the ready-to-use powder is added to the aforementioned solution for 4 hours to remove the floating matter and sediment, and obtain a contrast-containing composite material. of liquid embolic agents. After the liquid embolic agent was left standing for 11 hours, it was observed that the contrast composite material was suspended in the solution, and no precipitation was found at the bottom of the container.

Example 8

The suspended particulate contrast liquid embolic agent of this embodiment contains ethylene-vinyl alcohol copolymer (EVOH) embolic material, N-methyl-pyrrolidone (NMP) solvent and polyether ether ketone (PEEK) coated barium sulfate core-shell structure contrast composite Material. The ethylene-vinyl alcohol copolymer (EVOH) embolic material was dissolved in NMP solvent to obtain a solution. The barium sulfate (particle size of about 5 μm) and the polyetheretherketone particles are mixed, and the mixture is added to a twin-screw extruder granulator to obtain barium sulfate-polyetheretherketone particles. After the barium sulfate-polyether ether ketone particles are ground by a cryogenic mill, air flow classification is performed to obtain a ready-to-use powder, and the ready-to-use powder is added to the aforementioned solution and allowed to stand for 4 hours to remove floats and sediments. Composite liquid embolic agents. After the liquid embolic agent was left standing for 10 hours, it was observed that the contrast composite material was suspended in the solution, and no precipitation was found at the bottom of the container.

Example 9

The suspended particulate contrast liquid embolic agent of this embodiment contains an ethylene-vinyl alcohol copolymer (EVOH) embolic material, a DMSO solvent and a polyetheretherketone (PEEK)-coated barium sulfate core-shell structure contrasting composite material. The ethylene-vinyl alcohol copolymer (EVOH) embolic material was dissolved in DMSO solvent to obtain a solution. Barium sulfate (particle size is about 1 μm) and polyetheretherketone particles are mixed, and the mixture is added to a twin-screw extruder granulator to obtain barium sulfate-polyetheretherketone particles. After the barium sulfate-polyether ether ketone particles are ground by a cryogenic mill, air flow classification is performed to obtain a ready-to-use powder, and the ready-to-use powder is added to the aforementioned solution and allowed to stand for 4 hours to remove floats and sediments. Composite liquid embolic agents. After the liquid embolic agent was left standing for 11 hours, it was observed that the contrast composite material was suspended in the solution, and no precipitation was found at the bottom of the container.

Claims

A suspended particle contrast liquid embolizing agent, characterized in that it comprises a core-shell structure contrast composite material, a solvent and an embolizing material, the core of the core-shell structure contrast composite material includes contrast material, and the shell of the core-shell structure contrast composite material The layer includes a polymer material, and the embolic material is dispersed in the solvent to form a solution, wherein the density of the polymer material does not exceed the density of the contrast material.
The liquid embolic agent according to claim 1, wherein the density of the polymer material does not exceed the density of the solution.
The liquid embolic agent according to claim 1 or 2, wherein the polymer material is insoluble in the solvent;

Optionally, the polymer material is selected from polyethylene (PE), polypropylene (PP), polytetrafluoroethylene (PTFE), polymethylmethacrylate (PMMA), polyaryletherketone (PAEK) and poly One or more of ether ether ketone (PEEK); optionally, the polymer material is selected from polyethylene (PE), polypropylene (PP), polymethyl methacrylate (PMMA) and polyether One or more of ether ketone (PEEK); optionally, the polymer material is selected from polypropylene (PP) and/or polyether ether ketone (PEEK).
The liquid embolic agent according to any one of claims 1-3, wherein the contrast material is selected from one or more of metals, metal salts, and metal oxides;

Optionally, the metal is selected from one or more of tantalum, platinum, tungsten, titanium, silver, barium, bismuth, gold, iridium and alloys thereof; optionally, the metal is selected from tantalum, platinum , one or more of gold, iridium, tungsten and its alloy; optionally, the alloy is selected from platinum-iridium alloy or platinum-tungsten alloy;

Optionally, the metal salt is selected from one or more of barium sulfate, barium carbonate, bismuth carbonate, bismuth nitrate, bismuth selenide, lanthanum tantalate and yttrium tantalate; selected from barium sulfate;

Optionally, the metal oxide is selected from one or more of tantalum oxide, tungsten oxide, bismuth oxide and titanium oxide;

Optionally, the contrast material is tantalum powder or platinum powder.
The liquid embolic agent according to any one of claims 1-4, wherein the contrast material has a particle size of 500nm-5μm, such as 800nm-4μm, 1-3μm;

Optionally, the particle size of the core-shell structure contrast composite material is 2-20 μm, for example, 3-18 μm, 5-15 μm, 4-13 μm.
The liquid embolic agent according to any one of claims 1-5, wherein the solvent is selected from one or two of dimethyl sulfoxide (DMSO), N-methyl-pyrrolidone (NMP) and ethanol above;

Optionally, the solvent is dimethyl sulfoxide (DMSO) or a mixed solvent of dimethyl sulfoxide (DMSO) and N-methyl-pyrrolidone (NMP);

Optionally, the embolization material is selected from ethylene-vinyl alcohol copolymer (EVOH), n-butyl cyanoacrylate (NBCA), isobutyl cyanoacrylate (IBCA), 2-hydroxyethyl methacrylate One or more of ester, methacrylic acid copolymer and cellulose acetate copolymer (CAP);

Optionally, the plug material is ethylene-vinyl alcohol copolymer (EVOH).
The liquid embolic agent according to any one of claims 1-6, wherein the liquid embolic agent contains 35-70 wt.% of the core-shell structure contrast composite material, optionally, the liquid embolic agent contains 45-70wt.% of the core-shell structure contrast composite material, optionally, the liquid embolic agent contains 50-65wt.% of the core-shell structure contrast composite material.
The liquid embolic agent according to any one of claims 1-7, wherein the embolic material is ethylene-vinyl alcohol copolymer (EVOH), and the solvent is dimethyl sulfoxide (DMSO);

Optionally, the solution contains 3-25 wt.% ethylene-vinyl alcohol copolymer (EVOH); optionally, the solution contains 5-20 wt.% ethylene-vinyl alcohol copolymer (EVOH).
A preparation method of the liquid embolic agent described in any one of claims 1-8, comprising the steps:

Coating the polymer material to the outside of the contrast material to form a core-shell contrast contrast composite material;

Dissolving the embolic material in a solvent to form a solution;

The contrast composite is mixed with the solution.
A preparation method of the liquid embolic agent described in any one of claims 1-8, comprising the steps:

The contrast material and the polymer material are blended to obtain a blend, and the blend is pulverized and classified to obtain a mixture containing the contrast composite material;

Dissolving the embolic material in a solvent to form a solution;

mixing the contrast composite-containing mixture with the solution;

Optionally, as needed, the mixture containing the contrast composite material is mixed with the solution and allowed to stand to remove floating matter and sediment.