Liquid embolism agent as well as preparation method and application method thereof

Abstract

The invention relates to a liquid embolism agent as well as a preparation method and an application method thereof, and belongs to the technical field of medical instruments. The invention discloses a liquid embolism agent which has a developing function and a magnetic hyperthermia function. The liquid embolism agent comprises a polymer, a solvent and carbonyl iron powder, wherein the carbonyl iron powder has a developing function and a magnetic hyperthermia function. The liquid embolism agent is prepared by using the compound carbonyl iron powder which has developing and magnetic hyperthermia effects at the same time, so that when the liquid embolism agent is implanted into a tumor focus area through a microcatheter to embolize tumor blood vessels, the embolism process can be monitored through developing and positioning of the carbonyl iron powder, and meanwhile, under an external alternating magnetic field, the embolism effect can be effectively improved. The carbonyl iron powder generates a magnetocaloric effect under the action of an external magnetic field, so that a focus part is locally heated, and tumor cell regeneration is thoroughly eliminated and eradicated.

Description

Technical Field

[0001] The present application relates to the field of medical device technology, and in particular to a liquid embolic agent and a preparation method and an application method thereof. Background Art

[0002] Endovascular embolization is a minimally invasive surgical method for treating vascular abnormalities in various parts of the body. It can be used to treat clinical diseases including arteriovenous malformations, aneurysms, tumors, and intravascular hemostasis. Its treatment goal is to use biocompatible embolic agents to block the affected blood vessels, reduce blood flow, and reduce the risks and symptoms associated with neurovascular diseases. In recent decades, with the development of intravascular interventional technology, intravascular embolization therapy has become more and more widely used and has become a very important part of the comprehensive treatment plan for neurological and peripheral vascular diseases.

[0003] Embolic materials can be divided into solid embolic agents and liquid embolic agents. Liquid embolic agents generally include microparticles, polymers or in situ gelling biomaterials, which are used to treat diffuse vascular abnormalities and can usually be delivered through catheters. These liquid embolic agents transform into phase functions through in situ coagulation when injected into the blood vessels, and transform from liquid to solid form through processes such as precipitation or polymerization, thereby completely occluding the blood vessels without relying on the formation of thrombi to complete the occlusion. Liquid embolic agents usually need to be added with contrast agents for positioning, which is more conducive to monitoring the surgical embolization process and the postoperative embolization effect. The advantages of liquid embolic agents are: 1) they do not need to rely on activating the body's coagulation function, do not apply radial force to the blood vessel wall, and have no risk of rupture; 2) they can achieve uniform and complete filling of irregularly shaped blood vessels such as arteriovenous malformations; 3) they can penetrate into the distal smaller vascular system, and the penetration depth can be adjusted by adjusting their composition; 4) they form continuous emboli in the blood vessels, are not easy to reflux, and have a lower risk of ectopic embolism. At present, liquid embolic agents have become an ideal choice for the clinical application of intravascular embolization in neurological and peripheral vascular diseases.

[0004] However, the liquid embolic agents currently used in clinical practice only have the function of tumor vascular embolization, the treatment method is single, and the tumor cells after embolization may regenerate and become a threat to human health again. Summary of the invention

[0005] In view of the deficiencies in the prior art, the purpose of the embodiments of the present application includes providing a liquid embolic agent and a preparation method and an application method thereof, so that the embolic agent has both imaging and magnetic hyperthermia functions.

[0006] The embodiment of the present application is implemented as follows:

[0007] In a first aspect, an embodiment of the present application provides a liquid embolic agent, which has a developing function and a magnetic hyperthermia function; the liquid embolic agent comprises: a polymer, a solvent and carbonyl iron powder; wherein the carbonyl iron powder has a developing function and a magnetic hyperthermia function.

[0008] In the above technical scheme, the liquid embolic agent is prepared by using carbonyl iron powder, a compound having both imaging and magnetic hyperthermia effects, so that when the liquid embolic agent is implanted into the tumor lesion area through a microcatheter to embolize the tumor blood vessels, not only can the carbonyl iron powder be used for imaging positioning and monitoring of the embolization process, but also under the external alternating magnetic field, the carbonyl iron powder produces a magnetothermal effect under the action of the external magnetic field, causing the lesion site to be locally heated, thereby completely eliminating and preventing the regeneration of tumor cells.

[0009] In a second aspect, an embodiment of the present application provides a method for preparing the above-mentioned liquid embolic agent, comprising: adding a polymer to a solvent, heating and stirring, to obtain a polymer solution; adding carbonyl iron powder to the polymer solution, stirring and mixing, to obtain a liquid embolic agent.

[0010] In the above technical solution, the polymer is added to the solvent and heated and stirred to form a polymer solution, and then the carbonyl iron powder is added. The steps are clear and easy to operate. The simplified process can improve production efficiency, reduce operation difficulty, and is suitable for large-scale production.

[0011] In a third aspect, an embodiment of the present application provides a method for using the above-mentioned liquid embolic agent, comprising: the liquid embolic agent has a visualization function under digital subtraction angiography; and / or, under a magnetic field strength of 20-60Oe, the temperature is raised to 45°C.

[0012] In the above technical solution, under the external alternating magnetic field, the carbonyl iron powder produces a magnetocaloric effect under the action of the external magnetic field, causing the lesion site to be locally heated up, thereby completely eliminating and preventing the regeneration of tumor cells; therefore, by setting the magnetic field strength, the temperature of the liquid embolic agent can be raised to 45°C, which can effectively expose tumor cells to high temperatures and cause their death. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0014] Figure 1 The digital subtraction angiography (DSA) images of the liquid embolic agents prepared in Examples 1-4 and the comparative example of the present application are shown. DETAILED DESCRIPTION

[0015] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0016] The following is a detailed description of a liquid embolic agent and its preparation method and application method in an embodiment of the present application.

[0017] An embodiment of the present application provides a liquid embolic agent having a developing function and a magnetic hyperthermia function; the liquid embolic agent comprises: a polymer, a solvent and carbonyl iron powder; wherein the carbonyl iron powder has a developing function and a magnetic hyperthermia function.

[0018] Approved by the U.S. Food and Drug Administration (FDA), carbonyl iron powder can be added directly to food as an iron supplement, and carbonyl iron powder will not cause excessive iron intake and poisoning.

[0019] Carbonyl iron powder has good visualization under DSA, and can be used to monitor the embolization process through development positioning; moreover, under the external alternating magnetic field, carbonyl iron powder produces a magnetothermal effect under the action of the external magnetic field, causing the lesion site to heat up locally, which can completely eliminate and prevent tumor cell regeneration.

[0020] Particle size range of carbonyl iron powder: D 50 = 0.5-20 μm, as an example, the particle size D of the carbonyl iron powder 50 Including but not limited to 0.5μm, 1μm, 1.2μm, 1.5μm, 2μm, 2.5μm, 3μm, 4μm, 5μm, 6μm, 7μm, 8μm, 9μm, 10μm, 11μm, 12μm, 13μm, 14μm, 15μm, 16μm, 17μm, 18μm, 19μm, and 20μm.

[0021] The liquid embolic agent in the present application includes carbonyl iron powder, a compound having both imaging and magnetic thermal therapy effects, so that when the liquid embolic agent is implanted into the tumor lesion area through a microcatheter to embolize the tumor blood vessels, not only can the carbonyl iron powder be used for imaging positioning and monitoring of the embolization process, but also a magnetic thermal effect can be generated under the action of an external magnetic field to locally heat up the lesion site, thereby completely killing and preventing the regeneration of tumor cells, thereby achieving a synergistic effect of embolization function and magnetic thermal therapy.

[0022] In an optional embodiment, the polymer of the present application includes ethylene vinyl alcohol copolymer or polyethylene glycol; the solvent includes one or more of dimethyl sulfoxide, ethanol and N-methylpyrrolidone. It should be noted here that the polymer in the present application is in a dry state unless otherwise specified, that is, the water content is less than 0.3%.

[0023] In the embodiment of the present application, the weight percentage includes: 1-25 parts of polymer, 10-50 parts of carbonyl iron powder and 25-89 parts of solvent. The present application can not only ensure that the liquid embolic agent can effectively solidify and exert the effect of embolization after implantation into the human body through the reasonable combination of the mass fractions of the polymer and the carbonyl iron powder; and the reasonable concentration of the carbonyl iron powder can enhance the angiographic imaging intensity in the imaging positioning and monitoring of the embolization process, which is convenient for doctors to observe and detect effectively; in addition, the appropriate concentration of carbonyl iron powder can make the liquid embolic agent controllably heat up under the alternating magnetic field, and avoid damaging normal tissues when the moderate high temperature effectively kills tumor cells.

[0024] In the embodiment of the present application, the carbonyl iron powder includes a first hydrophilic group, and the first hydrophilic group is grafted onto the carbonyl iron powder through a first modifier.

[0025] By using the first modifier to graft the first hydrophilic group onto the surface of the carbonyl iron powder in the form of a covalent bond, the carbonyl iron powder is modified, which can improve the hydrogen bonding between the carbonyl iron powder (developer) and the polymer solution, thereby increasing the suspension stability of the carbonyl iron powder in the polymer solution and reducing the sedimentation rate. On the one hand, the carbonyl iron powder can be evenly dispersed in the polymer, so that the carbonyl iron powder produces a uniform contrast image, thereby making the liquid embolic agent have a good development effect; on the other hand, the carbonyl iron powder evenly dispersed in the polymer generates uniform heat under the action of the alternating magnetic field, thereby avoiding local excessive temperature rise and scalding of tissues.

[0026] The first hydrophilic group includes one or more of a hydroxyl group, a carboxyl group and an amino group.

[0027] The first modifier includes one or more of a halogenated organic acid compound, a hydrophilic amino acid compound and a hydroxycarboxylic acid compound.

[0028] The present application modifies the first hydrophilic group of the carbonyl iron powder by using a first modifier, so that the carbonyl iron powder has better suspension performance as a developer and has excellent visualization effect; the first modifier selected in the present application has good biocompatibility, and the group modified by the developer will degrade in the body to generate substances such as lactic acid and amino acids, which can be reused by the human body, further improving the safety of the liquid embolic agent.

[0029] Optionally, the feed mass ratio of carbonyl iron powder to the first modifier is 1:(0.1-10).

[0030] In another embodiment of the present application, the polymer includes a second hydrophilic group, and the second hydrophilic group is grafted onto the polymer through a second modifier.

[0031] By using a second modifier to graft the second hydrophilic group onto the polymer in the form of a covalent bond, the polymer can be modified, which can strengthen the hydrogen bonding effect between the carbonyl iron powder and the polymer, so that the carbonyl iron powder can be more evenly dispersed in the polymer solution and the sedimentation of the carbonyl iron powder can be avoided, thereby ensuring the improvement of the development effect and the magnetic hyperthermia effect.

[0032] The second hydrophilic group includes one or more of a hydroxyl group, a carboxyl group and an amino group.

[0033] The second modifier includes one or more of a halogenated organic acid compound, a hydrophilic amino acid compound and a hydroxycarboxylic acid compound.

[0034] The feed mass ratio of the polymer to the second modifier is 1:(0.1-4).

[0035] In the present application, the halogenated organic acid compound includes, but is not limited to, one or more of chloroacetic acid, sodium chloroacetate, bromoacetic acid and chloropropionic acid.

[0036] In the present application, the hydrophilic amino acid compound includes one or more of glycine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamic acid and aminoacetyl chloride.

[0037] In the present application, the hydroxycarboxylic acid compound includes one or more of glycolic acid, sodium glycolate and propanoic acid.

[0038] Specifically, in one embodiment of the present application, the first modifier can be modified by only carbonyl iron powder to graft the first hydrophilic group, thereby enhancing the hydrogen bonding effect between the carbonyl iron powder and the polymer, so that the carbonyl iron powder is more evenly dispersed in the polymer solution and the sedimentation of the carbonyl iron powder is avoided.

[0039] In another embodiment of the present application, not only the first modifier is grafted onto the carbonyl iron powder to modify the first hydrophilic group, but also the second modifier is grafted onto the polymer to modify the second hydrophilic group. This can further strengthen the hydrogen bonding effect between the carbonyl iron powder and the polymer, so that the carbonyl iron powder can be evenly and stably dispersed in the polymer solution, avoiding the sedimentation of the carbonyl iron powder, thereby improving the development performance and magnetic hyperthermia performance of the liquid embolic agent.

[0040] The following is an explanation of a method for preparing a liquid embolic agent provided in an embodiment of the present application.

[0041] A method for preparing a liquid embolic agent comprises: adding a polymer into a solvent, heating and stirring, and obtaining a polymer solution; adding carbonyl iron powder into the polymer solution, stirring and mixing, and obtaining a liquid embolic agent.

[0042] The liquid embolic agent prepared by the method of the present application has the dual therapeutic functions of developing function, embolization function and magnetic hyperthermia therapy, and can be used in synergistic tumor treatment.

[0043] In another preparation method of the present application, before adding the carbonyl iron powder to the polymer solution, it also includes: hydroxylating the carbonyl iron powder to obtain hydroxylated carbonyl iron powder; reacting the hydroxylated carbonyl iron powder with a first modifier to graft the first hydrophilic group onto the hydroxylated carbonyl iron powder to obtain carbonyl iron powder modified with the first hydrophilic group; drying the carbonyl iron powder particles modified with the first hydrophilic group and adding them to the polymer solution, stirring and mixing, and obtaining a liquid embolic agent.

[0044] The preparation method of the present application uses a first modifier to graft an organic substance having a first hydrophilic group to the surface of the carbonyl iron powder through a covalent bond, which can improve the hydrogen bonding between the carbonyl iron powder and the polymer solution, so that the carbonyl iron powder has better suspension performance in the polymer solution, and thus the developer has a better visualization effect. Moreover, the modified carbonyl iron powder has good biocompatibility in the human body, and the modified groups of the carbonyl iron powder will degrade in the body to generate substances such as lactic acid and amino acids, which can be reused by the human body, thereby improving the safety of the liquid embolic agent.

[0045] The first hydrophilic group includes one or more of a hydroxyl group, a carboxyl group and an amino group; and the first modifier includes one or more of a halogenated organic acid compound, a hydrophilic amino acid compound and a hydroxycarboxylic acid compound.

[0046] In another preparation method of the present application, before adding the polymer to the solvent, the method further includes: stirring the polymer and the second modifier to react so that the second hydrophilic group is grafted onto the polymer to obtain a polymer modified with the second hydrophilic group; drying the polymer modified with the second hydrophilic group and adding it to the solvent, heating and stirring to obtain a polymer solution; and then adding carbonyl iron powder modified with or without the first hydrophilic group, stirring and mixing to obtain a liquid embolic agent.

[0047] The second hydrophilic group includes one or more of a hydroxyl group, a carboxyl group and an amino group; and the second modifier includes one or more of a halogenated organic acid compound, a hydrophilic amino acid compound and a hydroxycarboxylic acid compound.

[0048] In an optional preparation method, the present application includes modifying the carbonyl iron powder with a first modifier to graft a first hydrophilic group, and modifying the polymer with a second modifier to graft a second hydrophilic group, adding the carbonyl iron powder modified with the first hydrophilic group to the polymer solution modified with the second hydrophilic group, and stirring and mixing to obtain a liquid embolic agent. By modifying the carbonyl iron powder and the polymer at the same time, the strength of the hydrogen bond between the two is further enhanced, which helps the carbonyl iron powder to be evenly and stably dispersed in the polymer, so that the liquid embolic agent maintains a uniform intensity of development performance and a uniform temperature of magnetic hyperthermia performance.

[0049] Optionally, the hydroxylation of carbonyl iron powder in the present application can be prepared by the following method:

[0050] Method 1: heating carbonyl iron powder and hydrogen peroxide solution under reflux conditions; wherein the heating temperature is 80-150° C. and the reflux time is 0.5-24 h.

[0051] Method 2: Mix carbonyl iron powder, hydrogen peroxide solution and concentrated sulfuric acid to react; wherein the mass concentration of the hydrogen peroxide solution is 25-35%, and the mass ratio of the hydrogen peroxide solution to the concentrated sulfuric acid is (3-5):(5-7).

[0052] Optionally, the specific preparation method of modifying the carbonyl iron powder using the first modifier in the embodiment of the present application is as follows:

[0053] When the first hydrophilic group is a hydroxyl group: the hydroxylated carbonyl iron powder and the hydroxycarboxylate can be modified under heating conditions, and after the reaction is completed, the mixture is cooled to room temperature, and titrated with 1 mol / L hydrochloric acid until the pH becomes 5-7, and the modified particles are filtered from the reaction system, and then washed with deionized water and acetone several times in sequence; and then dried in a vacuum dryer for at least 1 day to obtain hydroxyl-modified carbonyl iron powder particles; wherein the concentration of the hydroxycarboxylate is 0.1-10%, and the heating temperature is 50-150°C.

[0054] When the first hydrophilic group is a carboxyl group: the hydroxylated carbonyl iron powder particles are modified with a halogenated organic acid under alkaline conditions. After the reaction is completed, 1 mol / L hydrochloric acid is used for titration until the pH becomes 5-7. After the modified particles are filtered from the reaction system, they are washed several times with deionized water and acetone in sequence; and then dried in a vacuum dryer for at least 1 day to obtain carboxyl-modified carbonyl iron powder, wherein the concentration of the halogenated organic acid is 0.1-10%.

[0055] When the first hydrophilic group is an amino group: the hydroxylated carbonyl iron powder is reacted with a hydrophilic amino acid under a catalyst condition for 0.5-24 hours to carry out modification. After the reaction is completed, the modified particles are filtered from the reaction system and washed several times with deionized water; then dried in a vacuum dryer for at least 1 day to obtain amino-modified carbonyl iron powder; wherein the catalyst includes but is not limited to N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0056] Optionally, the specific preparation method of using the second modifier to modify the polymer in the embodiment of the present application is as follows:

[0057] S1. Dry ethylene-vinyl alcohol copolymer (EVOH) at 105°C to a water content of <0.3%. Put 1 g of the dried EVOH copolymer into a clean three-necked flask, add 100 mL of dried and dehydrated dimethyl sulfoxide (DMSO), heat and stir to dissolve, and cool to room temperature to obtain a polymer solution.

[0058] S2. Under anhydrous and oxygen-free conditions, add 0.5 g of aminoacetyl chloride and 0.2 g of pyridine to the polymer solution in the above step S1, keep the container sealed, react for 1 hour under vigorous stirring, and wash with petroleum ether, ethanol and water several times in succession. After drying, obtain an amino-modified ethylene-vinyl alcohol copolymer.

[0059] Optionally, the method for preparing the modified polymer solution in the embodiment of the present application is as follows:

[0060] The amino-modified ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C to a water content of <0.3%. 0.6 g of the dried EVOH copolymer was placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) was added, and the mixture was stirred and dissolved under heating conditions to obtain a modified polymer solution.

[0061] Optionally, the preparation method of the liquid embolic agent in the embodiment of the present application is as follows:

[0062] Take 3.5 g of hydroxyl-modified carbonyl iron powder particles, add them to the modified polymer solution, stir until the carbonyl iron powder is completely suspended in the polymer solution, and prepare a liquid embolic agent. The liquid embolic agent is sealed in a vial and dry-heat sterilized at 150° C. for 3 h.

[0063] The present application also provides an application method of a liquid embolic agent, comprising: the liquid embolic agent has a visualization function under digital subtraction angiography; and / or, under a magnetic field strength of 20-60Oe, the temperature is raised to 45°C, optionally, the magnetic field strength is 40Oe.

[0064] Carbonyl iron powder has good visualization under digital subtraction angiography (DSA), and the embolization process can be monitored by carbonyl iron powder; by using a liquid embolic agent prepared by a compound carbonyl iron powder having both development and magnetic hyperthermia effects, when the liquid embolic agent is implanted into the tumor lesion area through a microcatheter to embolize the tumor blood vessels, not only can the embolization process be monitored by carbonyl iron powder, but also under the action of an external alternating magnetic field, the carbonyl iron powder produces a magnetothermal effect under the action of an external magnetic field, causing the lesion site to be locally heated, thereby completely eliminating and preventing tumor cell regeneration. Therefore, by setting the magnetic field strength, the liquid embolic agent can be heated to 45°C, which can effectively expose tumor cells to high temperatures and kill them. As an example, the magnetic field strength includes, but is not limited to, 20Oe, 24Oe, 28Oe, 30Oe, 32Oe, 35Oe, 37Oe, 40Oe, 45Oe, 50Oe, 53Oe, 57Oe, and 60Oe.

[0065] The features and performance of the present application are further described in detail below in conjunction with the embodiments.

[0066] Example 1

[0067] This embodiment provides a liquid embolic agent, and the preparation method thereof comprises the following steps:

[0068] (1) Ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C until the water content was less than 0.3%. 0.6 g of the dried EVOH copolymer was placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) was added, and the mixture was stirred and dissolved under heating to obtain a polymer solution.

[0069] (2) Dry the carbonyl iron powder at 105° C. for 5 h, take 3.5 g of the dried carbonyl iron powder, add it to the polymer solution prepared in step (1), and stir until the carbonyl iron powder is completely suspended in the polymer solution to obtain a liquid embolic agent. Fill the liquid embolic agent into a vial and store it after dry heat sterilization at 150° C. for 3 h.

[0070] Example 2

[0071] This embodiment provides a liquid embolic agent, and the preparation method thereof comprises the following steps:

[0072] (1) 4 g of carbonyl iron powder particles were placed in a clean three-necked flask, 100 mL of hydrogen peroxide solution was added, and the mixture was heated to 110° C. and refluxed for 1 h. After the reaction was completed, the mixture was washed several times with deionized water, and the suspension was filtered to collect the hydroxylated carbonyl iron powder particles.

[0073] (2) Add the hydroxylated carbonyl iron powder particles collected in step (1) to 80 mL of 0.5% sodium glycolate solution, heat to 90° C., perform modification reaction, and stir rapidly; after the reaction is completed, cool to room temperature, titrate with 1 mol / L hydrochloric acid until the pH is 6, filter the modified particles obtained from the reaction system, wash with deionized water and acetone several times in sequence, and dry in a vacuum dryer for 2 days to obtain hydroxyl-modified carbonyl iron powder particles.

[0074] (3) Ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C until the water content was less than 0.3%. 0.6 g of the dried EVOH copolymer was placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) was added, and the mixture was stirred and dissolved under heating to obtain a polymer solution.

[0075] (4) Take 3.5 g of the hydroxyl-modified carbonyl iron powder particles prepared in step (2), add them to the polymer solution in step (3), and stir until the carbonyl iron powder is completely suspended in the polymer solution to obtain a liquid embolic agent. The liquid embolic agent is sealed in a vial and dry-heat sterilized at 150° C. for 3 h.

[0076] Example 3

[0077] This embodiment provides a liquid embolic agent, and the preparation method thereof comprises the following steps:

[0078] (1) 4 g of carbonyl iron powder particles were placed in a clean three-necked flask, 100 mL of hydrogen peroxide solution was added, and the mixture was heated to 110° C. and refluxed for 1 h. After the reaction was completed, the mixture was washed several times with deionized water, and the suspension was filtered to collect the hydroxylated carbonyl iron powder particles.

[0079] (2) Add the hydroxylated carbonyl iron powder particles collected in step (1) to 80 mL of 1.5% chloroacetic acid solution, adjust the solution to alkalinity with sodium hydroxide, and stir to react; after the reaction is completed, cool to room temperature, titrate with 1 mol / L hydrochloric acid until the pH is 6, filter the modified particles obtained from the reaction system, and wash them with deionized water and acetone several times in sequence. Dry in a vacuum dryer for 2 days to obtain carboxyl-modified carbonyl iron powder particles.

[0080] (3) Ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C until the water content was less than 0.3%. 0.6 g of the dried EVOH copolymer was placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) was added, and the mixture was stirred and dissolved under heating to obtain a polymer solution.

[0081] (4) Take 3.5 g of the carboxyl-modified carbonyl iron powder particles prepared in step (2), add them to the polymer solution in step (3), and stir until the carbonyl iron powder is completely suspended in the polymer solution to obtain a liquid embolic agent. The liquid embolic agent is sealed in a vial and dry-heat sterilized at 150° C. for 3 h.

[0082] Example 4

[0083] This embodiment provides a liquid embolic agent, and the preparation method thereof comprises the following steps:

[0084] (1) 4 g of carbonyl iron powder particles were placed in a clean three-necked flask, 100 mL of hydrogen peroxide solution was added, and the mixture was heated to 110° C. and refluxed for 1 h. After the reaction was completed, the mixture was washed several times with deionized water, and the suspension was filtered to collect the hydroxylated carbonyl iron powder particles.

[0085] (2) Prepare 80 mL of 2.5% glycine solution, add N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stir at room temperature for 1 hour, add the hydroxylated carbonyl iron powder particles collected in step (1), and react in the dark for 12 hours; after the reaction is completed, cool to room temperature, titrate with 1 mol / L hydrochloric acid until the pH is 6, filter the modified particles obtained from the reaction system, and wash with deionized water and acetone several times in sequence. Dry in a vacuum dryer for 2 days to obtain amino-modified carbonyl iron powder particles.

[0086] (3) Ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C until the water content was less than 0.3%. 0.6 g of the dried EVOH copolymer was placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) was added, and the mixture was stirred and dissolved under heating to obtain a polymer solution.

[0087] (4) Take 3.5 g of the amino-modified carbonyl iron powder particles prepared in step (2), add them to the polymer solution in step (3), and stir until the carbonyl iron powder is completely suspended in the polymer solution to obtain a liquid embolic agent. The liquid embolic agent is sealed in a vial and dry-heat sterilized at 150° C. for 3 h.

[0088] Example 5

[0089] This embodiment provides a liquid embolic agent, and the preparation method thereof comprises the following steps:

[0090] (1) Ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C until the water content was less than 0.3%. 1 g of the dried EVOH copolymer was placed in a clean three-necked flask, and 100 mL of dried and dehydrated dimethyl sulfoxide (DMSO) was added. The mixture was heated and stirred to dissolve, and then cooled to room temperature.

[0091] (2) Under anhydrous and oxygen-free conditions, 0.5 g of aminoacetyl chloride and 0.2 g of pyridine were added to the solution of step (1), the container was kept sealed, and the mixture was reacted for 1 h under vigorous stirring. The mixture was then washed several times with petroleum ether, ethanol and water in sequence, and dried to obtain an amino-modified ethylene-vinyl alcohol copolymer.

[0092] (3) 4 g of carbonyl iron powder particles were placed in a clean three-necked flask, 100 mL of hydrogen peroxide solution was added, and the mixture was heated to 110° C. and refluxed for 1 h. After the reaction was completed, the mixture was washed several times with deionized water, and the suspension was filtered to collect the hydroxylated carbonyl iron powder particles.

[0093] (4) adding the hydroxylated carbonyl iron powder particles collected in step (3) to 80 mL of 2.5% sodium glycolate solution, heating to 90° C., and performing a heated stirring reaction; after the reaction is completed, cooling to room temperature, titrating with 1 mol / L hydrochloric acid until the pH is 6, filtering the modified particles obtained from the reaction system, washing with deionized water and acetone several times in sequence, and then drying in a vacuum dryer for 2 days to obtain hydroxyl-modified carbonyl iron powder particles.

[0094] (5) The amino-modified ethylene-vinyl alcohol copolymer (EVOH) obtained in step (2) is dried at 105° C. until the water content is less than 0.3%. 0.6 g of the dried EVOH copolymer is placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) is added, and the mixture is stirred and dissolved under heating to obtain a polymer solution.

[0095] (6) Take 3.5 g of the hydroxyl-modified carbonyl iron powder particles prepared in step (4), add them to the polymer solution prepared in step (5), and stir until the carbonyl iron powder is completely suspended in the polymer solution to obtain a liquid embolic agent. The liquid embolic agent is filled into a vial and dry-heat sterilized at 150° C. for 3 h.

[0096] Example 6

[0097] This embodiment provides a liquid embolic agent, and the preparation method thereof comprises the following steps:

[0098] (1) Ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C until the water content was less than 0.3%. 1 g of the dried EVOH copolymer was placed in a clean three-necked flask, and 100 mL of dried and dehydrated dimethyl sulfoxide (DMSO) was added. The mixture was heated and stirred to dissolve, and then cooled to room temperature.

[0099] (2) Under anhydrous and oxygen-free conditions, 0.5 g of aminoacetyl chloride and 0.2 g of pyridine were added to the solution of step (1), the container was kept sealed, and the mixture was reacted for 1 h under vigorous stirring. The mixture was then washed several times with petroleum ether, ethanol and water in sequence, and dried to obtain an amino-modified ethylene-vinyl alcohol copolymer.

[0100] (3) 4 g of micronized carbonyl iron powder particles were placed in a clean three-necked flask, 100 mL of hydrogen peroxide solution was added, and the mixture was heated to 110° C. and refluxed for 1 h. After the reaction was completed, the mixture was washed several times with deionized water, and the suspension was filtered to collect the hydroxylated carbonyl iron powder particles.

[0101] (4) adding the hydroxylated carbonyl iron powder particles collected in step (3) to 80 mL of 2.5% chloroacetic acid solution, adjusting the solution to alkalinity with sodium hydroxide, and stirring the reaction; after the reaction is completed, titrating with 1 mol / L hydrochloric acid until the pH is 6, filtering the modified particles obtained from the reaction system, and washing them with deionized water and acetone in sequence for several times; and then drying them in a vacuum dryer for 2 days to obtain carboxyl-modified carbonyl iron powder particles.

[0102] (5) The amino-modified ethylene-vinyl alcohol copolymer (EVOH) obtained in step (2) is dried at 105° C. until the water content is less than 0.3%. 0.6 g of the dried EVOH copolymer is placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) is added, and the mixture is stirred and dissolved under heating to obtain a polymer solution.

[0103] (6) Take 3.5 g of the carboxyl-modified carbonyl iron powder particles prepared in step (4), add them to the polymer solution prepared in step (5), and stir until the carbonyl iron powder is completely suspended in the polymer solution to obtain a liquid embolic agent. The liquid embolic agent is filled into a vial and dry-heat sterilized at 150° C. for 3 h.

[0104] Example 7

[0105] This embodiment provides a liquid embolic agent, and the preparation method thereof comprises the following steps:

[0106] (1) Ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C until the water content was less than 0.3%. 1 g of the dried EVOH copolymer was placed in a clean three-necked flask, and 100 mL of dried and dehydrated dimethyl sulfoxide (DMSO) was added. The mixture was heated and stirred to dissolve, and then cooled to room temperature.

[0107] (2) Under anhydrous and oxygen-free conditions, 0.5 g of aminoacetyl chloride and 0.2 g of pyridine were added to the solution of step (1), the container was kept sealed, and the mixture was reacted for 1 h under vigorous stirring. The mixture was then washed several times with petroleum ether, ethanol and water in sequence, and dried to obtain an amino-modified ethylene-vinyl alcohol copolymer.

[0108] (3) 4 g of carbonyl iron powder particles were placed in a clean three-necked flask, 100 mL of hydrogen peroxide solution was added, and the mixture was heated to 110° C. and refluxed for 1 h. After the reaction was completed, the mixture was washed several times with deionized water, and the suspension was filtered to collect the hydroxylated carbonyl iron powder particles.

[0109] (4) Prepare 80 mL of 2.5% glycine solution, add N-hydroxysuccinimide and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stir at room temperature for 1 hour, add the hydroxylated carbonyl iron powder particles collected in step (3), and react in the dark for 12 hours; after the reaction is completed, cool to room temperature, titrate with 1 mol / L hydrochloric acid until the pH is 6, filter the modified particles obtained from the reaction system, and wash with deionized water and acetone several times in sequence. Dry in a vacuum dryer for 2 days to obtain amino-modified carbonyl iron powder particles.

[0110] (5) The amino-modified ethylene-vinyl alcohol copolymer (EVOH) obtained in step (2) is dried at 105° C. until the water content is less than 0.3%. 0.6 g of the dried EVOH copolymer is placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) is added, and the mixture is stirred and dissolved under heating to obtain a polymer solution.

[0111] (6) Take 3.5 g of the amino-modified carbonyl iron powder particles prepared in step (4), add them to the polymer solution prepared in step (5), and stir until the carbonyl iron powder is completely suspended in the polymer solution to obtain a liquid embolic agent. The liquid embolic agent is filled into a vial and dry-heat sterilized at 150° C. for 3 h.

[0112] Comparative Example

[0113] This comparative example provides a liquid embolic agent, the preparation method of which comprises the following steps:

[0114] (1) Ethylene-vinyl alcohol copolymer (EVOH) was dried at 105°C until the water content was less than 0.3%. 0.6 g of the dried EVOH copolymer was placed in a clean three-necked flask, 9.4 mL of dimethyl sulfoxide (DMSO) was added, and the mixture was stirred and dissolved under heating to obtain a polymer solution.

[0115] (2) Dry the tantalum powder at 105° C. for 5 h, take 3.5 g of the dried tantalum powder, add it to the polymer solution prepared in step (1), and stir until the tantalum powder is completely suspended in the polymer solution to obtain a liquid embolic agent. Fill the liquid embolic agent into a vial and dry-heat sterilize it at 150° C. for 3 h.

[0116] Test Example 1

[0117] In this test example, the visibility of the liquid embolic agents prepared in Examples 1-4 and the comparative example was tested, and the steps were as follows: the liquid embolic agent was first mixed with a vortex mixer for 20 minutes, and then injected into normal saline through a syringe connected to a microcatheter to form a lava-like solid embolus, and the embolus was subjected to a digital subtraction angiography (DSA) development test using an X-ray digital subtraction angiography machine.

[0118] In order to compare the development effects of different contents of carbonyl iron powder on the liquid embolic agent under DSA, the liquid embolic agent was prepared according to the preparation method of Example 1, and the addition amount of carbonyl iron powder was adjusted to 1.0 g, 2.0 g and 3.5 g, respectively. The obtained samples were sample A (1.0 g), sample B (2.0 g) and sample C (3.5 g), respectively.

[0119] In order to compare the development effects of carbonyl iron powders with different modification groups on liquid embolic agents under DSA, liquid embolic agents were prepared according to the methods of Examples 2-4, and the obtained samples were Sample D, Sample E and Sample F, respectively.

[0120] In order to compare the development effect of the above sample with that of the liquid embolic agent using tantalum powder as a developer under DSA, a liquid embolic agent prepared according to the comparative example was obtained to obtain sample G.

[0121] Figure 1 For different liquid embolic agents in digital subtraction angiography (DSA) images, please refer to Figure 1 .pass Figure 1 It can be seen that the carbonyl iron powder has good visualization under digital subtraction angiography (DSA). From the development effects of sample A, sample B and sample C, the amount of carbonyl iron powder added has a significant effect on the visualization. When the amount of carbonyl iron powder added is 3.5 g, the visualization effect of the liquid embolic agent prepared therefrom is the same as that of sample G in the comparative example (a commercial product already on the market), indicating that the liquid embolic agent has good visualization and can meet the visualization requirements for clinical use.

[0122] Comparison of liquid embolic samples D, E and F shows that the visualization effects of liquid embolic samples D, E and F prepared from carbonyl iron powders with three different modified groups are better than that of liquid embolic sample C prepared from unmodified carbonyl iron powder. This is because the modified carbonyl iron powder is more evenly distributed in the liquid embolic agent and has better suspension properties.

[0123] Test Example 2

[0124] In this test example, liquid embolic agents with different concentrations of carbonyl iron powder were placed in a magnetic induction heating system with a constant temperature jacket, and two thermocouples were used for temperature monitoring. The thermocouples were placed in the same environment in advance to test the ambient temperature (37°C ± 1°C), and the test results of the two thermocouples were ensured to be the same. One of the prepared thermocouples was inserted into the liquid embolic agent to test the temperature of the liquid embolic agent; the other was inserted into the constant temperature jacket to test the ambient temperature. The magnetic field current intensity was set to 40Oe, and the temperature rise of liquid embolic agents of different concentrations was recorded. The temperature rise test results are detailed in Table 2.

[0125] Table 2

[0126] Carbonyl iron powder content (mg / ml) Temperature rise end point (℃) Example 1 100 41.5 Example 1 200 43.2 Example 1 350 46.7 Example 2 350 45.6 Example 3 350 45.9 Example 4 350 46.0

[0127] It can be seen from the test results in Table 2 that, under an external alternating magnetic field, the temperature rise of the liquid embolic agent becomes more obvious as the amount of carbonyl iron powder added increases. The results of Examples 2-4 show that the carbonyl iron powder particles modified with hydrophilic groups also have a good magnetothermal effect. The above results show that the modified carbonyl iron powder particles can be used as magnetothermal for tumor treatment.

[0128] Test Example 3

[0129] According to the instructions of the marketed liquid embolic agent product, the liquid embolic agent samples prepared in Examples 1-7 were placed on a vortex mixer and vortexed for 20 minutes, the liquid embolic agent was removed and placed on a digital subtraction angiography (DSA) test platform, and the samples were developed and photographed using an X-ray digital subtraction angiography machine. After waiting for 30 minutes, the samples were developed and photographed again, and the suspension performance of the product was judged by observing the height of the sample sedimentation liquid level. The smaller the sedimentation rate, the better the suspension performance; the sedimentation rate and suspension performance test results are shown in Table 3.

[0130] Table 3

[0131] Sedimentation rate Suspension performance Example 1 30.2％ generally Example 2 18.5％ good Example 3 16.7％ good Example 4 13.3％ good Example 5 11.1％ Excellent Example 6 10.7％ Excellent Example 7 10.4％ Excellent Comparative Example 32.2％ generally

[0132] From the data results in Table 3, it can be seen that the carbonyl iron powder is selected as a developer, and its suspension performance is better than that of the liquid embolic agent that has been marketed, and the sedimentation rate of the modified carbonyl iron powder in the liquid embolic agent is smaller and the suspension performance is better, indicating that the modified carbonyl iron powder has a uniform distribution and better suspension performance in the liquid embolic agent. In addition, the higher the modification ratio of the carbonyl iron powder, the better its suspension performance, which greatly improves the clinical visualization effect.

[0133] The embodiments described above are part of the embodiments of the present application, rather than all of the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents the selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present application.

Claims

1. A liquid embolic agent, characterized in that: The liquid embolic agent has a developing function and a magnetic hyperthermia function; the liquid embolic agent comprises: a polymer, a solvent and carbonyl iron powder; wherein the carbonyl iron powder has the developing function and the magnetic hyperthermia function.

2. The liquid embolic agent according to claim 1, characterized in that: The polymer comprises ethylene vinyl alcohol copolymer or polyethylene glycol; and / or, The solvent includes one or more of dimethyl sulfoxide, ethanol and N-methylpyrrolidone.

3. The liquid embolic agent according to claim 1, characterized in that: In parts by weight, it includes: 1-25 parts of polymer, 10-50 parts of carbonyl iron powder and 25-89 parts of solvent.

4. The liquid embolic agent according to claim 1, characterized in that: The carbonyl iron powder includes a first hydrophilic group, and the first hydrophilic group is grafted onto the carbonyl iron powder through a first modifier; Optionally, the first hydrophilic group includes one or more of a hydroxyl group, a carboxyl group and an amino group; Optionally, the first modifier includes one or more of a halogenated organic acid compound, a hydrophilic amino acid compound, and a hydroxycarboxylic acid compound; Optionally, the mass ratio of the carbonyl iron powder to the first modifier is 1:(0.1-10).

5. The liquid embolic agent according to any one of claims 1 to 4, characterized in that: The polymer includes a second hydrophilic group, and the second hydrophilic group is grafted onto the polymer via a second modifier; Optionally, the second hydrophilic group includes one or more of a hydroxyl group, a carboxyl group and an amino group; Optionally, the second modifier includes one or more of a halogenated organic acid compound, a hydrophilic amino acid compound, and a hydroxycarboxylic acid compound; Optionally, the feed mass ratio of the polymer to the second modifier is 1:(0.1-4).

6. The liquid embolic agent according to claim 5, characterized in that: The halogenated organic acid compound comprises one or more of chloroacetic acid, sodium chloroacetate, bromoacetic acid and chloropropionic acid; and / or, The hydrophilic amino acid compound includes one or more of glycine, serine, threonine, cysteine, tyrosine, aspartic acid, glutamic acid and aminoacetyl chloride; and / or, The hydroxycarboxylic acid compound includes one or more of glycolic acid, sodium glycolate and propanoic acid.

7. A method for preparing the liquid embolic agent according to any one of claims 1 to 6, characterized in that: include: Adding the polymer to the solvent, heating and stirring to obtain a polymer solution; The carbonyl iron powder is added to the polymer solution, and the mixture is stirred and mixed to obtain the liquid embolic agent.

8. The preparation method according to claim 7, characterized in that: Before adding the carbonyl iron powder to the polymer solution, the method further includes: hydroxylating the carbonyl iron powder to obtain hydroxylated carbonyl iron powder; reacting the hydroxylated carbonyl iron powder with a first modifier so that a first hydrophilic group is grafted onto the hydroxylated carbonyl iron powder to obtain carbonyl iron powder modified with the first hydrophilic group; drying the carbonyl iron powder particles modified with the first hydrophilic group, adding the particles to the polymer solution, stirring and mixing the mixture, and obtaining the liquid embolic agent; Optionally, the hydroxylation of the carbonyl iron powder comprises: heating the carbonyl iron powder and hydrogen peroxide solution under reflux conditions; wherein the heating temperature is 80-150° C. and the reflux time is 0.5-24 h; or, mixing the carbonyl iron powder, hydrogen peroxide solution and concentrated sulfuric acid for reaction; wherein the mass concentration of the hydrogen peroxide solution is 25-35%, and the mass ratio of the hydrogen peroxide solution to the concentrated sulfuric acid is (3-5):(5-7); Optionally, the first hydrophilic group includes one or more of a hydroxyl group, a carboxyl group and an amino group; and the first modifier includes one or more of a halogenated organic acid compound, a hydrophilic amino acid compound and a hydroxycarboxylic acid compound.

9. The preparation method according to claim 7 or 8, characterized in that: Before adding the polymer to the solvent, the method further comprises: stirring the polymer and a second modifier to react so that a second hydrophilic group is grafted onto the polymer to obtain a polymer modified with the second hydrophilic group; drying the polymer modified with the second hydrophilic group and adding it to the solvent, heating and stirring to obtain the polymer solution; Optionally, the second hydrophilic group includes one or more of a hydroxyl group, a carboxyl group and an amino group; and the second modifier includes one or more of a halogenated organic acid compound, a hydrophilic amino acid compound and a hydroxycarboxylic acid compound.

10. A method for using the liquid embolic agent according to any one of claims 1 to 6, characterized in that: include: The liquid embolic agent has a visualization function under digital subtraction angiography; and / or, under the condition of a magnetic field strength of 20-60Oe, the temperature is raised to 45°C.

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