Preparation method of bimodal developing embolism material
By reacting fluorinated polyvinyl alcohol with an iodine-containing developing agent, an embolic material capable of being developed under NMR and X-rays was prepared, solving the problem that existing embolic materials cannot be developed simultaneously and realizing the ability to be developed under NMR and X-rays.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-19
- Publication Date
- 2026-03-10
AI Technical Summary
Existing embolization materials cannot be simultaneously visualized under NMR and X-ray, thus failing to meet different visualization requirements.
Embolizing materials, including liquid embolic agents and embolic microspheres, are prepared by copolymerizing fluorine-containing monomers with ethylene esters, hydrolyzing them, and then reacting them with iodine-containing contrast agents.
This technology enables the simultaneous development of embolization materials under both NMR and X-ray imaging, meeting diverse development requirements and improving ease of application.
Smart Images
Figure SMS_6 
Figure SMS_7
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the field of embolic materials, in particular, to a preparation method of a dual-modality visualized embolic material. BACKGROUND
[0002] Since the concept of transcatheter arterial embolization (TAE) was proposed more than 40 years ago, selecting appropriate embolic materials is a key link in the development of this technology. The existing embolic materials have no visualizing ability. By introducing iodine compounds, the embolic materials can be visualized under X-ray, but cannot be visualized under nuclear magnetic resonance (NMR).
[0003] Therefore, it is necessary to design an embolic material that can be visualized under NMR and X-ray to solve the problem that the existing embolic materials cannot be visualized under NMR and X-ray. SUMMARY
[0004] The purpose of the embodiments of the present application is to provide a preparation method of a dual-modality visualized embolic material, which can be visualized under NMR and X-ray, and meets different visualizing requirements.
[0005] In a first aspect, the embodiments of the present application provide a preparation method of a dual-modality visualized embolic material, the embolic material being a liquid embolic agent or embolic microspheres, and the preparation method comprising the following steps: copolymerizing a fluorine-containing monomer with vinyl ester, and then hydrolyzing to obtain fluorine-containing polyvinyl alcohol, and the fluorine-containing polyvinyl alcohol is soluble in water and dimethyl sulfoxide; reacting the fluorine-containing polyvinyl alcohol with an iodine-containing contrast agent to obtain a liquid embolic agent, or first preparing the fluorine-containing polyvinyl alcohol into microspheres, and then reacting the microspheres with an iodine-containing compound to obtain embolic microspheres.
[0006] In the above technical solution, F has the NMR visualizing ability. The present application introduces F by a specific method to obtain the embolic material containing F, thereby solving the problem that the existing embolic microspheres cannot be visualized under NMR. Specifically, the fluorine-containing polyvinyl alcohol is obtained by copolymerizing a fluorine-containing monomer with vinyl ester and further hydrolyzing, and the fluorine-containing polyvinyl alcohol can be further modified with iodine or modified with iodine after being formed into a ball to become a dual-modality (NMR+X-ray) embolic material. The fluorine-containing polyvinyl alcohol is reacted with an iodine-containing contrast agent to obtain a liquid embolic agent that can be visualized under X-ray and NMR. The fluorine-containing polyvinyl alcohol is used as a raw material to further prepare microspheres, and the obtained microspheres are reacted with an iodine-containing compound to obtain embolic microspheres that can be visualized under X-ray and NMR.
[0007] In a possible implementation, in the preparation of the fluorine-containing polyvinyl alcohol, the fluorine-containing monomer includes one or more of tetrafluoroethylene, vinylidene fluoride, chlorotrifluoroethylene, and hexafluoropropylene. And / or, the ethylene ester includes vinyl acetate.
[0008] In the above technical solution, F has nuclear magnetic resonance imaging and uses fluorine-containing monomers to modify vinyl acetate (hydrolyzed to PVA).
[0009] In one possible implementation, when preparing the fluorinated polyvinyl alcohol, the mass of the fluorinated monomer is 10% to 20% of the mass of the ethylene ester; And / or, the polyvinyl alcohol content in the fluorinated polyvinyl alcohol obtained is 80-90 wt%.
[0010] In the above technical solution, by controlling the amount of fluorine-containing monomer added, it is possible to ensure that the amount of F introduced is appropriate, so as to achieve NMR imaging and still be soluble in water and DMSO. If the amount of F introduced is insufficient, it is difficult to achieve magnetic imaging. If the amount of F introduced is excessive, it is difficult to dissolve in water or DMSO, and it is difficult to prepare embolization material.
[0011] In one possible implementation, the method for preparing the fluorinated polyvinyl alcohol includes: adding an organic solvent, ethylene ester, and azobisisobutyronitrile to an autoclave, purging with nitrogen, and then introducing a gas containing fluorinated monomers into the autoclave; reacting at 60-80°C for 4-8 hours, precipitating in water, and drying to obtain fluorinated polyvinyl acetate; dissolving the fluorinated polyvinyl acetate in an organic solvent, hydrolyzing under alkaline conditions, and dialysis to obtain the fluorinated polyvinyl alcohol.
[0012] In one possible implementation, the iodine-containing contrast agent, when preparing the liquid embolic agent, comprises triiodobenzaldehyde dimethyl ether; And / or, the mass ratio of the fluorinated polyvinyl alcohol to the iodine-containing developer is 1 to 10:1.
[0013] In one possible implementation, the method for preparing the liquid embolizing agent includes: dissolving fluorinated polyvinyl alcohol in dimethyl sulfoxide, adding an iodine-containing developer and a catalyst, and reacting at 50-70°C for 20-30 hours; precipitating and drying with methanol, and dissolving the resulting polymer in dimethyl sulfoxide to form a liquid embolizing agent.
[0014] In the above technical solution, fluorinated polyvinyl alcohol is combined with an iodine-containing developing agent to obtain a compound that can be rapidly precipitated in water. Since it contains both iodine and fluorine, it can be developed under X-ray and nuclear magnetic resonance.
[0015] In one possible implementation, the method for preparing the embolization microspheres includes: mixing an aqueous solution and an oil solution to form a water-in-oil reverse suspension polymerization system, and reacting the mixture under the action of a catalyst to obtain microspheres; wherein the aqueous solution includes the fluorinated polyvinyl alcohol, a water-soluble monomer, a crosslinking agent, an initiator, and water, and the oil solution contains an organic solvent and a dispersant.
[0016] In the above technical solution, fluorinated polyvinyl alcohol is used to prepare nuclear magnetic resonance imaging microspheres according to the synthesis method of PVA microspheres.
[0017] In one possible implementation, the water-soluble monomer includes one or more of the following: a carboxylic acid compound having both a carboxyl group and a double bond; a carboxylate compound having both a carboxyl group and a double bond; a sulfonic acid compound having both a sulfonate group and a double bond; and a sulfonate compound having both a sulfonate group and a double bond. And / or, the crosslinking agent includes one or more of N,N-methylenebisacrylamide, N-(2,2-dimethoxyethyl)-2-acrylamide, and polyethylene glycol bisacrylamide; And / or, the initiator includes one or more of sodium persulfate, potassium persulfate, ammonium persulfate, benzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, and azodialkylimidazoline salt; And / or, the organic solvent includes one or more of butyl acetate, ethyl acetate, liquid paraffin, dimethyl silicone oil, soybean oil, cycloalkanes, and alkanes; And / or, the dispersant includes one or more of cellulose acetate butyrate, OP dispersants, Span dispersants, Tween dispersants, AEO dispersants, PEG dispersants, and PVA dispersants; And / or, the catalyst comprises one or more of N,N,N',N'-tetramethylethylenediamine and triethylamine.
[0018] In one possible implementation, the iodine-containing compound used in preparing the embolic microspheres includes N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide and 1-(dimethoxymethyl)-2,3,5-triiodobenzamide; And / or, the mass ratio of the microspheres to the iodine-containing compound is 1:1 to 1:3.
[0019] In one possible implementation, the method for preparing the embolization microspheres includes: swelling the microspheres with dimethyl sulfoxide, adding an iodine-containing compound and a catalyst, and reacting at 50-70°C for 36-60 hours to obtain the embolization microspheres.
[0020] In the above technical solution, NMR-reproducible microspheres are reacted with iodine-containing compounds to prepare dual-reproducible microspheres.
[0021] Secondly, embodiments of this application provide a dual-modal radioactive embolization material, which is made using the dual-modal radioactive embolization material provided in the first aspect.
[0022] Thirdly, embodiments of this application provide an application of the dual-modal contrast-enhancing embolization material provided in the second aspect, wherein the dual-modal contrast-enhancing embolization material is used as an embolization material for interventional vascular treatment. Detailed Implementation
[0023] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.
[0024] The preparation method of the dual-modal radioactive embolic material according to the embodiments of this application will be described in detail below.
[0025] Liquid embolic agents and embolic microspheres are two major categories of embolic materials commonly used in interventional vascular therapy. This application provides methods for preparing liquid embolic agents and embolic microspheres that are visualized under MRI and X-ray, respectively, as follows: This application provides a method for preparing a dual-modal radioactive embolic material, wherein the embolic material is a liquid embolic agent, and the preparation method includes the following steps: S1. A fluorinated monomer is copolymerized with ethylene ester and then hydrolyzed to obtain a fluorinated polyvinyl alcohol, which is soluble in water and dimethyl sulfoxide (DMSO).
[0026] In some alternative embodiments of this application, when preparing fluorinated polyvinyl alcohol, the fluorinated monomer includes one or more of tetrafluoroethylene, vinylidene fluoride, trifluorochloroethylene, and hexafluoropropylene (perfluoropropylene); the ethylene ester includes vinyl acetate.
[0027] For example, tetrafluoroethylene and vinyl acetate are copolymerized and further hydrolyzed to obtain polyvinyl alcohol (PTEF-PVA) containing polytetrafluoroethylene.
[0028] In some optional embodiments of this application, when preparing fluorinated polyvinyl alcohol, the mass of the fluorinated monomer is 10% to 20% of the mass of ethylene ester; the polyvinyl alcohol content in the obtained fluorinated polyvinyl alcohol is 80 to 90 wt%.
[0029] In some optional embodiments of this application, the method for preparing fluorinated polyvinyl alcohol includes: adding an organic solvent, ethylene ester, and azobisisobutyronitrile (AIBN) to an autoclave, purging with nitrogen, and then introducing a gas containing fluorinated monomers into the autoclave; reacting at 60-80°C for 4-8 hours, precipitating in water, and drying to obtain fluorinated polyvinyl acetate; dissolving the fluorinated polyvinyl acetate in an organic solvent, hydrolyzing under alkaline conditions, and dialysis to obtain fluorinated polyvinyl alcohol.
[0030] S2. Fluorine-containing polyvinyl alcohol is reacted with an iodine-containing developer to obtain a liquid embolizing agent.
[0031] In some alternative embodiments of this application, the iodine-containing contrast agent used in the preparation of the liquid embolizing agent includes triiodobenzaldehyde dimethyl ether.
[0032] In some optional embodiments of this application, the mass ratio of fluorinated polyvinyl alcohol to iodine-containing developer is 1 to 10:1.
[0033] In some optional embodiments of this application, the method for preparing the liquid embolizing agent includes: dissolving fluorinated polyvinyl alcohol in dimethyl sulfoxide (DMSO), adding an iodine-containing developer and a catalyst, and reacting at 50~70°C for 20~30 h; precipitating and drying with methanol, and dissolving the resulting polymer in dimethyl sulfoxide (DMSO) to form a liquid embolizing agent.
[0034] This application provides a method for preparing a dual-modal radioactive embolic material, wherein the embolic material is embolic microspheres, and the preparation method includes the following steps: S1. A fluorinated monomer is copolymerized with ethylene ester and then hydrolyzed to obtain a fluorinated polyvinyl alcohol, which is soluble in water and dimethyl sulfoxide (DMSO).
[0035] For methods of preparing fluorinated polyvinyl alcohol, please refer to the aforementioned content, which will not be repeated here.
[0036] S2. Fluorine-containing polyvinyl alcohol is first prepared into microspheres, and then reacted with iodine-containing compounds to obtain embolization microspheres.
[0037] In some optional embodiments of this application, the method for preparing embolic microspheres includes: mixing an aqueous solution and an oil solution to form a water-in-oil reverse suspension polymerization system, and reacting the mixture under the action of a catalyst to obtain microspheres; the aqueous solution includes fluorinated polyvinyl alcohol, water-soluble monomers, crosslinking agents, initiators, and water, and the oil solution contains organic solvents and dispersants. Exemplarily, the method for preparing microspheres includes the following steps: (1) Preparation of aqueous solution: Prepare an aqueous solution of water-soluble monomer and water, and neutralize it by slowly adding alkaline solution under ice-water bath. Then add fluorinated polyvinyl alcohol and crosslinking agent. After fully dissolving, a clear and transparent solution is formed. Then add free radical initiator to the clear and transparent solution and mix evenly to obtain an aqueous solution. In some optional embodiments of this application, the water-soluble monomer includes one or more of the following: a carboxylic acid compound having both a carboxyl group and a double bond; a carboxylate compound having both a carboxyl group and a double bond; a sulfonic acid compound having both a sulfonate group and a double bond; and a sulfonate compound having both a sulfonate group and a double bond. Exemplarily, the water-soluble monomer includes: sodium acrylate. Sodium methacrylate Acrylamide, acrylic anhydride, maleic acid, maleic anhydride, itaconic acid, β-(acryloyloxy)propionic acid, 2,4-hexadienoic acid, 2,4-pentadienoic acid, 2-acrylamido-2-methylpropanesulfonic acid (AMPS), sodium 2-acrylamido-2-methylpropanesulfonate One or more of sodium p-styrene sulfonate.
[0038] In the embodiments of this application, unless otherwise specified, "multiple" refers to two or more.
[0039] In some alternative embodiments of this application, the crosslinking agent includes acrylamide-based crosslinking agents, such as N,N-methylenebisacrylamide. One or more of N-(2,2-dimethoxyethyl)-2-acrylamide and polyethylene glycol bisacrylamide.
[0040] In some alternative embodiments of this application, the fluorinated polyvinyl alcohol and the crosslinking agent may be pre-reacted compounds, such as N-(2,2-dimethoxyethyl)-2-acrylamide-modified polyvinyl alcohol (PN). .
[0041] In some alternative embodiments of this application, the initiator includes one or more of sodium persulfate, potassium persulfate, ammonium persulfate, benzoyl peroxide (BPO), azobisisobutyronitrile (AIBN), azobisisoheptanenitrile, and azodialkylimidazoline salt.
[0042] (2) Preparation of oil phase solution: Mix organic solvent and dispersant, and heat appropriately and stir thoroughly to completely dissolve the dispersant to obtain oil phase solution.
[0043] In some alternative embodiments of this application, the organic solvent includes one or more of butyl acetate, ethyl acetate, liquid paraffin, dimethyl silicone oil, soybean oil, cycloalkanes (e.g., cyclohexane), and alkanes (e.g., n-decane, n-heptane, n-hexane).
[0044] In some alternative embodiments of this application, the dispersant includes one or more of the following: cellulose acetate butyrate, OP dispersants (e.g., OP-4, OP-10, OP-20), Span dispersants (e.g., Span-80, Span-60), Tween dispersants (e.g., Tween-60, Tween-80), AEO dispersants (e.g., AEO-7, AEO-9), PEG dispersants (e.g., PEG-400, PEG-8000), and PVA dispersants (e.g., PVA-1788, PVA-1799).
[0045] In some optional embodiments of this application, the amount of dispersant used is 1 to 6 wt% of the organic solvent mass. Exemplarily, the amount of dispersant used is 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt% of the organic solvent mass, or any intermediate value between the two above values.
[0046] (3) Preparation of microspheres: Under stirring conditions, an aqueous solution is added to the oil phase solution, and after uniform dispersion, a catalyst is added. The reaction is continued under stirring and heated for 4-12 hours. The obtained product is washed with an oil phase solvent and boiled with an alkaline solution, then sieved and rinsed to obtain microspheres.
[0047] In some alternative embodiments of this application, the iodine-containing compounds used in the preparation of embolic microspheres include N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide and 1-(dimethoxymethyl)-2,3,5-triiodobenzamide.
[0048] In some alternative embodiments of this application, the mass ratio of microspheres to iodine-containing compounds is 1:1 to 1:3.
[0049] In some optional embodiments of this application, the method for preparing embolization microspheres includes: swelling the microspheres with dimethyl sulfoxide (DMSO), adding an iodine-containing compound and a catalyst, and reacting at 50-70°C for 36-60 h to obtain embolization microspheres.
[0050] This application also provides a dual-modal radioactive embolization material, which is prepared using the dual-modal radioactive embolization material of the aforementioned embodiments. The embolization material is a liquid embolizing agent and / or embolization microspheres.
[0051] This application also provides an application of a dual-modal radiopaque embolization material, which is used as an embolization material for interventional vascular treatment.
[0052] The liquid embolic agents and embolic microspheres of this application differ significantly in terms of physical morphology, embolic mechanism, delivery method, embolic level, controllability, indications, and risk of complications: (1) Physical form: Liquid embolic agents: As the name suggests, they are liquid (or viscous fluid) before or during injection into the vascular system. They typically need to solidify after injection into the target blood vessel (through polymerization, precipitation, chemical reaction, or temperature change).
[0053] Embolization microspheres: These are pre-manufactured solid spherical particles. They are suspended in a liquid carrier (usually physiological saline or a contrast agent mixture) before injection.
[0054] (2) Embolism mechanism: Liquid embolic agents: Their core mechanism is in-situ solidification. The liquid material flows and fills the target blood vessel, then solidifies into a solid embolus or gel, completely blocking blood flow. They can "cast" the shape of the blood vessel lumen.
[0055] Embolic microspheres: Their core mechanism is mechanical obstruction. The microspheres travel with the bloodstream to the target vessel; when the vessel diameter is smaller than the microsphere diameter, the microsphere becomes trapped, physically blocking the vessel. They can also induce local thrombus formation, further enhancing the embolizing effect.
[0056] (3) Conveying method: Liquid embolic agents: These typically require precise delivery to the target area using a microcatheter. Injection speed and pressure need to be carefully controlled to prevent reflux into non-target vessels (the risk of reflux is relatively high). Some require specialized injection techniques (such as the "Sertin technique").
[0057] Embolic microspheres: Injected via microcatheter or conventional catheter. The procedure is relatively simple; the suspension is injected into the target main blood vessel, and the microspheres will distribute to distal branches with blood flow. The risk of reflux is relatively low (but caution is still necessary).
[0058] (4) Level of embolism: Liquid embolic agents: These can embolize very small, tortuous blood vessels (precapillary level). They can penetrate deep into lesions (such as nests of arteriovenous malformations) like "glue."
[0059] Embolic microspheres: The level of embolization depends primarily on the diameter of the microspheres. Different sizes of microspheres can be selected to target and embolize different levels of blood vessels (arterioles, microarteries). The embolization level is typically slightly more "proximal" than with liquid embolic agents (unless very small microspheres are used).
[0060] (5) Controllability and predictability: Liquid embolic agents: Controllability is relatively complex. The solidification rate, blood flow guidance, and injection pressure all affect their distribution. Once polymerization begins, the distribution path is difficult to predict accurately (especially in complex vascular malformations), requiring a high level of operator experience. Some types (such as Onyx) allow for intermittent injection observation.
[0061] Embolic microspheres: Distribution is relatively more predictable, mainly depending on hemodynamics and microsphere size. Once injected, the path is determined by blood flow, making precise "push-stop" observation impossible as with some liquid embolic agents.
[0062] Based on the aforementioned differences between liquid embolizing agents and embolizing microspheres, appropriate embolizing materials can be selected according to actual needs in practical applications, while also meeting the requirements of NMR and X-ray imaging, greatly improving the ease of application.
[0063] The features and performance of this application will be further described in detail below with reference to the embodiments.
[0064] Example 1 This embodiment provides a liquid embolic agent, the preparation process of which is as follows: S1. Add the following organic solvents to a 500mL autoclave: 300mL methanol, 21.5g vinyl acetate, and 0.5g AIBN. Close the autoclave and purge with nitrogen for 30 minutes. Then, charge the autoclave with a fluorinated monomer: tetrafluoroethylene at 20 atmospheres. React at 70℃ for 6 hours. Precipitate in water and dry to obtain a polytetrafluoroethylene-vinyl acetate copolymer. Dissolve the polytetrafluoroethylene-vinyl acetate copolymer in methanol, add an aqueous sodium hydroxide solution, hydrolyze, and dialyze to obtain fluorinated polyvinyl alcohol: polytetrafluoroethylene-containing polyvinyl alcohol (PTEF-PVA).
[0065] The obtained PTEF-PVA was analyzed by NMR: the content of polytetrafluoroethylene was 15wt% and the content of polyvinyl alcohol was 85wt%.
[0066] Add 10g of PTEF-PVA to 100mL of water and stir to determine if it dissolves. The water solubility test shows that it is soluble in water. Add 10g of PTEF-PVA to 100mL of DMSO and stir to determine if it dissolves. The DMSO solubility test shows that it is soluble in DMSO.
[0067] S2. Dissolve 10g of fluorinated polyvinyl alcohol (PTEF-PVA) in DMSO, add 10g of iodine-containing developer (triiodobenzaldehyde dimethyl ether), and add 1ml of methanesulfonic acid as a catalyst. Heat at 60°C. o The reaction was carried out at C for 24 hours; the polymer was dried by precipitation with methanol, and then dissolved in DMSO to form a liquid embolic agent.
[0068] Example 2 This embodiment provides a liquid embolic agent, the preparation process of which is as follows: S1. Add 300 mL of methanol, 21.5 g of vinyl acetate, and 0.5 g of AIBN to a 500 mL autoclave. Close the autoclave and purge with nitrogen for 30 min. Then, pressurize the autoclave with tetrafluoroethylene at 40 atmospheres. React at 70 °C for 6 h. Precipitate in water and dry to obtain polytetrafluoroethylene-vinyl acetate copolymer. Dissolve the polytetrafluoroethylene-vinyl acetate copolymer in methanol, add sodium hydroxide aqueous solution, hydrolyze, and dialyze to obtain polyvinyl alcohol (PTEF-PVA) containing polytetrafluoroethylene.
[0069] The obtained PTEF-PVA was analyzed by NMR: the polytetrafluoroethylene content was 20 wt%, and the polyvinyl alcohol content was 80 wt%.
[0070] Add 10g of PTEF-PVA to 100mL of water and stir to determine if it dissolves. The water solubility test shows that it is soluble in water. Add 10g of PTEF-PVA to 100mL of DMSO and stir to determine if it dissolves. The DMSO solubility test shows that it is soluble in DMSO.
[0071] S2. Dissolve 10g of fluorinated polyvinyl alcohol (PTEF-PVA) in DMSO, add 10g of iodine-containing developer (triiodobenzaldehyde dimethyl ether), and add 1ml of methanesulfonic acid as a catalyst. Heat at 60°C. o The reaction was carried out at C for 24 hours; the polymer was dried by precipitation with methanol, and then dissolved in DMSO to form a liquid embolic agent.
[0072] Example 3 This embodiment provides a liquid embolic agent, the preparation process of which is as follows: S1. Add 300 mL of methanol, 21.5 g of vinyl acetate, and 0.5 g of AIBN to a 500 mL autoclave. Close the autoclave and purge with nitrogen for 30 min. Then, pressurize the autoclave with tetrafluoroethylene at 15 atmospheres. React at 70 °C for 6 h. Precipitate in water and dry to obtain polytetrafluoroethylene-vinyl acetate copolymer. Dissolve the polytetrafluoroethylene-vinyl acetate copolymer in methanol, add sodium hydroxide aqueous solution, hydrolyze, and dialyze to obtain polyvinyl alcohol (PTEF-PVA) containing polytetrafluoroethylene.
[0073] The obtained PTEF-PVA was analyzed by NMR: the content of polytetrafluoroethylene was 10 wt%, and the content of polyvinyl alcohol was 90 wt%.
[0074] Add 10g of PTEF-PVA to 100mL of water and stir to determine if it dissolves. The water solubility test shows that it is soluble in water. Add 10g of PTEF-PVA to 100mL of DMSO and stir to determine if it dissolves. The DMSO solubility test shows that it is soluble in DMSO.
[0075] S2. Dissolve 10g of fluorinated polyvinyl alcohol (PTEF-PVA) in DMSO, add 10g of iodine-containing developer (triiodobenzaldehyde dimethyl ether), and add 1ml of methanesulfonic acid as a catalyst. Heat at 60°C. o The reaction was carried out at C for 24 hours; the polymer was dried by precipitation with methanol, and then dissolved in DMSO to form a liquid embolic agent.
[0076] Example 4 This embodiment provides an embolization microsphere, the preparation process of which is as follows: S1. PTEF-PVA is prepared according to step S1 in Example 1.
[0077] S2. In a 250ml three-necked flask equipped with a top-mounted mechanical stirrer, add 100mL of purified water and approximately 10g of PTEF-PVA. Heat to 95℃ to dissolve, then cool to room temperature. Add 0.7654g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) as a crosslinking agent, followed by 10mL of concentrated hydrochloric acid. The reaction is carried out at room temperature for 14 hours, then neutralized to pH=7 with 2.5M sodium hydroxide solution to obtain a fluorinated macromolecular polyvinyl alcohol monomer solution. Dissolve 8.61g of sodium acrylamide-2-methylpropanesulfonate (AMPS sodium) in 60ml of water, add 160g of the fluorinated macromolecular polyvinyl alcohol monomer solution, and add 1.5g of potassium persulfate as an initiator to obtain an aqueous phase.
[0078] Add 600 mL of butyl acetate as an organic solvent to a 1 L three-necked flask equipped with a top-mounted mechanical stirrer, and add 18 g of cellulose acetate butyrate as a dispersant to dissolve it, thus obtaining the oil phase.
[0079] The rotation speed of the three-necked flask was set to 400 rpm, and the aqueous phase was added dropwise to the oil phase. After the addition was complete, the temperature was raised to 55°C, and 2.2 ml of tetramethylethylenediamine catalyst was added. The reaction was carried out for 8 hours, and after a series of purification and drying processes, microspheres were obtained.
[0080] In a 250ml three-necked round-bottom flask equipped with a top stirrer and thermometer, 4.0g of dry microspheres were added and swollen with 120ml of DMSO; 8g of iodine-containing compound: 1-(dimethoxymethyl)-2,3,5-triiodobenzene was added, and 1ml of methanesulfonic acid was added. The mixture was reacted at 60℃ for 48h to obtain embolization microspheres.
[0081] Example 5 This embodiment provides an embolization microsphere, the preparation process of which is as follows: S1. Following step S1 in Example 2, PTEF-PVA is prepared.
[0082] S2. Using the PTEF-PVA of this embodiment, embolic microspheres are prepared according to step S2 in Example 4.
[0083] Example 6 This embodiment provides an embolization microsphere, the preparation process of which is as follows: S1. Following step S1 in Example 3, PTEF-PVA is prepared.
[0084] S2. Using the PTEF-PVA of this embodiment, embolic microspheres are prepared according to step S2 in Example 4.
[0085] Comparative Example 1 This comparative example provides a polytetrafluoroethylene-containing polyvinyl alcohol (PTEF-PVA), the preparation process of which is as follows: Add 300 mL of methanol, 21.5 g of vinyl acetate, and 0.5 g of AIBN to a 500 mL autoclave. Close the autoclave and purge with nitrogen for 30 min. Then, pressurize the autoclave with tetrafluoroethylene at 60 atmospheres. React at 70 °C for 6 h. Precipitate in water and dry to obtain polytetrafluoroethylene-vinyl acetate copolymer. Dissolve the polytetrafluoroethylene-vinyl acetate copolymer in methanol, add sodium hydroxide aqueous solution, hydrolyze, and dialyze to obtain polyvinyl alcohol (PTEF-PVA) containing polytetrafluoroethylene.
[0086] The obtained PTEF-PVA was analyzed by NMR: the content of polytetrafluoroethylene was 25 wt%, and the content of polyvinyl alcohol was 75 wt%.
[0087] 10g of PTEF-PVA was added to 100mL of water and stirred to determine if it dissolved. The water solubility test showed that it was insoluble in water. 10g of PTEF-PVA was added to 100mL of DMSO and stirred to determine if it dissolved. The DMSO solubility test showed that it was insoluble in DMSO.
[0088] Since this PTEF-PVA is insoluble in both water and DMSO, it is impossible to further prepare liquid embolizing agents and embolizing microspheres.
[0089] Comparative Example 2 This comparative example provides a polytetrafluoroethylene-containing polyvinyl alcohol (PTEF-PVA), the preparation process of which is as follows: Add 300 mL of methanol, 21.5 g of vinyl acetate, and 0.5 g of AIBN to a 500 mL autoclave. Close the autoclave and purge with nitrogen for 30 min. Then, pressurize the autoclave with 5 atmospheres of tetrafluoroethylene. React at 70 °C for 6 h. Precipitate in water and dry to obtain polytetrafluoroethylene-vinyl acetate copolymer. Dissolve the polytetrafluoroethylene-vinyl acetate copolymer in methanol, add sodium hydroxide aqueous solution, hydrolyze, and dialyze to obtain polyvinyl alcohol (PTEF-PVA) containing polytetrafluoroethylene.
[0090] The obtained PTEF-PVA was analyzed by NMR: the content of polytetrafluoroethylene was 5 wt%, and the content of polyvinyl alcohol was 95 wt%.
[0091] 10g of PTEF-PVA was added to 100mL of water and stirred to determine if it dissolved. The water solubility test showed that it was insoluble in water. 10g of PTEF-PVA was added to 100mL of DMSO and stirred to determine if it dissolved. The DMSO solubility test showed that it was insoluble in DMSO.
[0092] Since this PTEF-PVA is insoluble in both water and DMSO, it is impossible to further prepare liquid embolizing agents and embolizing microspheres.
[0093] Comparative Example 3 This comparative example provides an embolization microsphere, the preparation process of which is as follows: In a 250ml three-necked flask equipped with a top-mounted mechanical stirrer, 100mL of purified water was added, followed by approximately 10g of PVA. The mixture was heated to 95℃ to dissolve, then cooled to room temperature. 0.7654g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA) was added, followed by 10mL of concentrated hydrochloric acid. The reaction was carried out at room temperature for 14 hours, then neutralized to pH 7 with 2.5M sodium hydroxide solution to obtain a macromolecular polyvinyl alcohol monomer solution. 8.61g of sodium acrylamide-2-methylpropanesulfonate (AMPS sodium) was dissolved in 60ml of water, and 160g of the macromolecular polyvinyl alcohol monomer solution was added, along with 1.5g of potassium persulfate, to obtain the aqueous phase.
[0094] Add 600 mL of butyl acetate to a 1 L three-necked flask equipped with a top-mounted mechanical stirrer, and then add 18 g of cellulose acetate butyrate to dissolve it, thus obtaining the oil phase.
[0095] The rotation speed of the three-necked flask was set to 400 rpm, and the aqueous phase was added dropwise to the oil phase. After the addition was complete, the temperature was raised to 55°C, 2.2 ml of tetramethylethylenediamine was added, and the reaction was carried out for 8 hours. After a series of purification and drying processes, microspheres were obtained.
[0096] In a 250ml three-necked round-bottom flask equipped with a top stirrer and thermometer, 4.0g of dry microspheres were added and swollen with 120ml of DMSO; 8g of 1-(dimethoxymethyl)-2,3,5-triiodobenzene was added, along with 1ml of methanesulfonic acid and 2g of polytetrafluoroethylene, and the mixture was reacted at 60℃ for 48h to obtain embolization microspheres.
[0097] The imaging performance of the liquid embolizing agents of Examples 1-3 and the embolizing microspheres of Examples 4-6 was verified.
[0098] Development Experiment HU value testing method: The microspheres obtained in each embodiment and comparative example were subjected to Micro CT testing (Bruker Skyscan 1276).
[0099] Table 1
[0100] The strength and elasticity test methods are as follows: the test is carried out using the TA .XT .plus C texture analyzer system, a 6mm probe is selected, the trigger force is 0.1g, the microsphere is compressed and deformed to 50%, and the holding time is 60sec.
[0101] Table 2
[0102] Note: High strength and low elasticity indicate that the microspheres are very brittle and easily break when compressed.
[0103] In summary, the dual-modal imaging embolic material preparation method of this application produces a material that can be developed under NMR and X-ray, meeting different imaging requirements.
[0104] The above description is merely an embodiment of this application and is not intended to limit the scope of protection of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of protection of this application.
Claims
1. A method of preparing a dual modality visualizing embolization material, characterized in that, The embolization material is a liquid embolus or embolization microspheres, and the preparation method comprises the following steps: The fluorine-containing monomer is copolymerized with vinyl acetate, and then hydrolyzed to obtain fluorine-containing polyvinyl alcohol, and the fluorine-containing polyvinyl alcohol is soluble in water and dimethyl sulfoxide; The fluorine-containing polyvinyl alcohol is reacted with an iodine-containing developer to obtain a liquid embolus, or the fluorine-containing polyvinyl alcohol is first prepared into microspheres, and then reacted with an iodine-containing compound to obtain embolization microspheres.
2. The method of claim 1, wherein the bi-modal visualizing embolization material is prepared by the steps of: In the preparation of the fluorine-containing polyvinyl alcohol, the fluorine-containing monomer comprises one or more of tetrafluoroethylene, vinylidene fluoride, chlorotrifluoroethylene and hexafluoropropylene; And / or, the vinyl acetate comprises vinyl acetate.
3. The method of claim 1 or 2, wherein the bi-modal visualization embolization material is prepared by, In the preparation of the fluorine-containing polyvinyl alcohol, the mass of the fluorine-containing monomer is 10% to 20% of the mass of the vinyl acetate; And / or, the content of polyvinyl alcohol in the prepared fluorine-containing polyvinyl alcohol is 80 to 90 wt%.
4. The method of claim 1, wherein the bi-modal visualizing embolization material is prepared by the steps of: The method for preparing the fluorine-containing polyvinyl alcohol comprises: adding an organic solvent, vinyl acetate and azobisisobutyronitrile into an autoclave, purging with nitrogen, and then charging the autoclave with fluorine-containing monomer gas; reacting at 60 to 80°C for 4 to 8 hours, precipitating in water, and drying to obtain fluorine-containing polyvinyl acetate; dissolving the fluorine-containing polyvinyl acetate in an organic solvent, hydrolyzing under alkaline conditions, and dialyzing to obtain the fluorine-containing polyvinyl alcohol.
5. The method of claim 1, wherein the bi-modal visualizing embolization material is prepared by the steps of: In the preparation of the liquid embolus, the iodine-containing developer comprises triiodobenzaldehyde dimethyl ether; And / or, the mass ratio of the fluorine-containing polyvinyl alcohol to the iodine-containing developer is 1 to 10:
1.
6. The method of claim 1 or 5, wherein the bi-modal visualization embolization material is prepared by, The method for preparing the liquid embolus comprises: dissolving the fluorine-containing polyvinyl alcohol in dimethyl sulfoxide, adding an iodine-containing developer and a catalyst, and reacting at 50 to 70°C for 20 to 30 hours; precipitating with methanol, drying, dissolving the obtained polymer in dimethyl sulfoxide to form a liquid embolus.
7. The method of claim 1, wherein the bi-modal visualizing embolization material is prepared by the steps of: In the preparation of the embolization microspheres, the method for preparing microspheres comprises: mixing an aqueous solution and an oil solution to form a water-in-oil reverse-phase suspension polymerization system, and reacting under the action of a catalyst to obtain microspheres; the aqueous solution comprises the fluorine-containing polyvinyl alcohol, a water-soluble monomer, a crosslinking agent, an initiator and water, and the oil solution comprises an organic solvent and a dispersant.
8. The method of claim 7, wherein the bi-modal visualization embolization material is prepared by, The water-soluble monomer comprises one or more of a carboxylic acid compound with both carboxylate and double bond, a carboxylic acid salt compound with both carboxylate and double bond, a sulfonic acid compound with both sulfonate and double bond, and a sulfonic acid salt compound with both sulfonate and double bond; And / or, the crosslinking agent comprises one or more of N,N-methylene bisacrylamide, N-(2,2-dimethoxyethyl)-2-acrylamide and polyethylene glycol bisacrylamide; And / or, the initiator comprises one or more of sodium persulfate, potassium persulfate, ammonium persulfate, dibenzoyl peroxide, azobisisobutyronitrile, azobisisoheptyl nitrile and azobisalkylimidazoline salt; And / or, the organic solvent comprises one or more of butyl acetate, ethyl acetate, liquid paraffin, dimethyl silicone oil, soybean oil, cycloalkane and alkane. And / or, the dispersing agent comprises one or more of cellulose acetate butyrate, OP dispersing agent, Span dispersing agent, Tween dispersing agent, AEO dispersing agent, PEG dispersing agent and PVA dispersing agent; And / or, the catalyst comprises one or more of N,N,N',N'-tetramethyl ethylenediamine and triethylamine.
9. The method of claim 1, wherein the bi-modal visualizing embolization material is prepared by the steps of: In the preparation of the embolism microspheres, the iodine-containing compound comprises N-(2,2-diethoxypropyl)-2,3,5-triiodobenzamide and 1-(dimethoxymethyl)-2,3,5-triiodobenzene; And / or, the mass ratio of the microspheres and the iodine-containing compound is 1:1~1:
3.
10. The method of claim 1 or 9, wherein the bi-modal visualization embolization material is prepared by, The method for preparing the embolism microspheres comprises: swelling the microspheres with dimethyl sulfoxide, adding an iodine-containing compound and a catalyst, and reacting at 50~70℃ for 36~60h to obtain the embolism microspheres.