Color developing embolism microspheres and preparation method thereof

Abstract

The application discloses a color-developing embolization microsphere and a preparation method thereof, and belongs to the technical field of embolization microspheres. The method comprises the following steps: obtaining embolization microspheres; preparing active brilliant blue X-BR into a solution and activating the solution; performing heat preservation treatment and pH adjustment on the activated solution, so as to adjust the color of the solution and obtain a dyeing solution; and dyeing the embolization microspheres by using the dyeing solution, so as to obtain color-developing embolization microspheres. The color of the active brilliant blue X-BR is changed by performing heat preservation treatment and pH adjustment on the active brilliant blue X-BR, then the embolization microspheres are dyed, and a color-developing embolization microsphere with other colors and being relatively safe is obtained, and thus it is possible to classify different types of embolization microspheres according to colors.

Description

Technical Field

[0001] This application relates to the field of embolization microsphere technology, and more specifically, to a colorimetric embolization microsphere and its preparation method. Background Technology

[0002] Catheter embolization is an important interventional therapy technique. It involves the controlled injection of artificial embolic materials into the target blood vessels supplying the diseased tissue or organ, causing occlusion and blocking the blood supply. This aims to control bleeding, treat vascular lesions, eliminate diseased organs, and treat tumors.

[0003] Embolizing microspheres, as a novel embolic material, overcome the shortcomings of traditional embolic particles due to their irregular shape (leading to unpredictable embolization levels). Microspheres possess characteristics such as smooth surface, precise size, compressibility, and resistance to clumping, making them easily passable through microcatheters. This allows for better embolization of blood vessels at the tumor's terminal sites, thereby more thoroughly reducing tumor blood supply. Currently, some commercially available embolic microspheres are colorless and transparent spheres, making them difficult for surgeons to observe during surgical preparation and hindering their manipulation.

[0004] To address this issue, some researchers have proposed using reactive blue to stain embolic microspheres. Reactive blue is characterized by its vibrant color, good uniformity, high color fastness, and low cost. This dye binds to the functional groups on the embolic microspheres via covalent bonds, has no toxic side effects on humans in clinical practice, and exhibits extremely low residual levels. However, it can only stain embolic microspheres in one color, making it difficult to classify different types of embolic microspheres by color, resulting in a lack of intuitive differentiation during use. Summary of the Invention

[0005] This application provides a chromogenic embolization microsphere and its preparation method to form a relatively safe chromogenic embolization microsphere of other colors, thereby providing the possibility of classifying different types of embolization microspheres by color.

[0006] In a first aspect, embodiments of this application provide a method for preparing chromogenic embolic microspheres, the method comprising:

[0007] Obtain embolization microspheres;

[0008] Prepare a solution of Reactive Brilliant Blue X-BR and activate it;

[0009] The activated solution was kept at a certain temperature and the pH was adjusted to change the color of the solution, thus obtaining the staining solution;

[0010] Embolism microspheres were stained with a staining solution to obtain chromogenic embolism microspheres.

[0011] In the above implementation process, the color of Reactive Brilliant Blue X-BR was changed by heat preservation treatment and pH adjustment. Then, the embolization microspheres were stained to obtain a relatively safe chromogenic embolization microsphere of other colors, thus providing the possibility of classifying different types of embolization microspheres by color.

[0012] In some embodiments, the temperature for the heat preservation treatment is 60–80°C; and / or

[0013] The heat preservation treatment time is 2-3 hours; and / or

[0014] The target pH value for pH adjustment is below 6.

[0015] In the above implementation process, the color depth of the staining solution can be adjusted by controlling the temperature and time of the heat preservation treatment. By controlling the temperature and time of the heat preservation treatment to 60-80℃ and 2-3h respectively, the prepared chromogenic embolic microspheres can have a deeper color, so that they can be easily observed during operation.

[0016] In some embodiments, the staining temperature is 60–80°C; and / or

[0017] The staining time is 2 to 3 hours.

[0018] In the above process, dyeing at 60-80℃ helps to give the prepared chromogenic embolic microspheres a deeper color.

[0019] In some embodiments, obtaining embolic microspheres includes:

[0020] Water-soluble polymers are formulated into polymer solutions;

[0021] A modified polymer is obtained by mixing and reacting a polymer solution, a water-soluble crosslinking agent, and an acid catalyst.

[0022] A modified polymer, a water-soluble monomer containing ionic functional groups and polymerizable double bonds, and an initiator were formulated into an aqueous phase.

[0023] An aqueous phase is dropped into an oil phase to form a reverse-phase suspension polymerization system, followed by a polymerization reaction to obtain embolization microspheres.

[0024] In some embodiments, the water-soluble polymer includes at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, sodium carboxymethyl cellulose, and water-soluble chitosan; and / or

[0025] The preparation temperature of the polymer solution is 90–100℃; and / or

[0026] Water-soluble crosslinking agents include at least one of N-(2,2-dimethoxy)-2-methacrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylamide, N-(2,2-dimethoxy)-2-acrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylamide, N-(2,2-dimethoxy)-2-methacrylate, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylate, N-(2,2-dimethoxy)-2-acrylate, and N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylate; and / or

[0027] Acid catalysts include at least one of hydrochloric acid, sulfuric acid, nitric acid, and p-toluenesulfonic acid.

[0028] In some embodiments, the ionic functional group of the water-soluble monomer includes at least one of a sulfonic acid group and a carboxyl group; and / or

[0029] Water-soluble monomers include at least one of sodium 2-acrylamido-2-methylpropanesulfonate and sodium allyl sulfonate, sodium methpropylene sulfonate, sodium methacrylate, and sodium acrylate; and / or

[0030] The initiator includes at least one of ammonium persulfate, sodium persulfate, and potassium persulfate.

[0031] In some embodiments, the oil phase comprises an oily solvent and an oil-soluble dispersant; and / or

[0032] Oily solvents include at least one of butyl acetate, ethyl acetate, methyl acetate, and propyl acetate; and / or

[0033] Oil-soluble dispersants include cellulose acetate butyrate.

[0034] In some embodiments, the polymerization reaction temperature is 65–85°C; and / or

[0035] The polymerization reaction takes 10–15 hours.

[0036] Secondly, embodiments of this application provide a chromogenic embolization microsphere, which is prepared using the method provided in the first aspect.

[0037] Thirdly, embodiments of this application provide a method for preparing chromogenic embolic microspheres, the method comprising:

[0038] Obtain embolization microspheres;

[0039] Reactive Brilliant Blue X-BR was prepared into a solution and activated to obtain the first staining solution;

[0040] The activated first staining solution was subjected to heat treatment and pH adjustment to adjust its color, thus obtaining the second staining solution.

[0041] Classification of embolic microspheres;

[0042] The classified embolic microspheres were stained with the first staining solution and the second staining solution respectively to obtain chromogenic embolic microspheres. Attached Figure Description

[0043] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this application and, together with the description, serve to explain the principles of this application.

[0044] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0045] Figure 1 A flowchart illustrating the method provided in the embodiments of this application;

[0046] Figure 2 A color diagram of the chromogenic embolization microspheres provided in Comparative Example 1 of this application;

[0047] Figure 3 This is a color diagram of the chromogenic embolization microspheres provided in Embodiments 1 to 5 of this application;

[0048] Figure 4 This is a color schematic diagram of the chromogenic embolic microspheres provided in Embodiment 6 of this application;

[0049] Figure 5 This is a color diagram of the chromogenic embolization microspheres provided in Embodiment 7 of this application;

[0050] Figure 6 This is a color schematic diagram of the chromogenic embolization microspheres provided in Embodiment 8 of this application;

[0051] Figure 7 This is a color schematic diagram of the chromogenic embolization microspheres provided in Embodiment 9 of this application;

[0052] Figure 8 This is a color schematic diagram of the chromogenic embolization microspheres provided in Embodiment 10 of this application;

[0053] Figure 9 This is a color diagram of the chromogenic embolization microspheres provided in Embodiment 11 of this application. Detailed Implementation

[0054] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application. Unless otherwise specified, all raw materials, reagents, instruments, and equipment used in this application can be purchased on the market or prepared by existing methods.

[0055] The inventors intend to provide an embolization microsphere and its preparation method, introducing photothermal therapy to enhance the anti-tumor therapeutic effect of the embolization microsphere. Furthermore, a material that can expand under photothermal action is used as the skeleton material of the embolization microsphere, enabling the embolization microsphere to expand during photothermal therapy, thereby facilitating the embolization effect of the embolization microsphere and also facilitating the release of chemical drugs, achieving a synergistic effect among embolization therapy, photothermal therapy, and chemical drug therapy.

[0056] Figure 1 A flowchart of the method provided in the embodiments of this application is shown below. Figure 1 As shown in the embodiment of this application, a method for preparing chromogenic embolic microspheres is provided, the method comprising:

[0057] S1. Obtain embolization microspheres;

[0058] The specific preparation process of embolization microspheres can be as follows: a water-soluble polymer is prepared into a polymer solution; the polymer solution, a water-soluble crosslinking agent, and an acid catalyst are mixed and reacted to obtain a modified polymer; the modified polymer, a water-soluble monomer containing ionic functional groups and polymerizable double bonds, and an initiator are prepared into an aqueous phase; the aqueous phase is dropped into an oil phase to form a reverse-phase suspension polymerization system, and then a polymerization reaction is carried out to obtain embolization microspheres.

[0059] The polyhydroxyl-containing water-soluble polymer can be selected from at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, sodium carboxymethyl cellulose, and water-soluble chitosan. Furthermore, the mass percentage of the water-soluble polymer in the polymer solution can be 15% to 25%. For example, the mass percentage of the water-soluble polymer in the polymer solution can be 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%, or any value within the range of 15% to 25%. The preparation temperature of the polymer solution is 90–100°C; in other words, the dissolution temperature of the polymer is 90–100°C. For example, the preparation temperature of the polymer solution can be 90℃, 91℃, 92℃, 93℃, 94℃, 95℃, 96℃, 97℃, 98℃, 99℃ or 100℃, or any value within the range of 90 to 100℃.

[0060] The water-soluble crosslinking agent may be selected from at least one of N-(2,2-dimethoxy)-2-methacrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylamide, N-(2,2-dimethoxy)-2-acrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylamide, N-(2,2-dimethoxy)-2-methacrylate, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylate, N-(2,2-dimethoxy)-2-acrylate and N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylate.

[0061] The mass ratio of water-soluble crosslinking agent to water-soluble polymer can be (0.2-0.6):10. In other words, the mass percentage of water-soluble crosslinking agent in water-soluble polymer can be 2%-6%. For example, the mass percentage of water-soluble crosslinking agent in water-soluble polymer can be 2%, 3%, 4%, 5% or 6%, etc., or any value within the range of 2%-6%.

[0062] Acid catalysts include at least one of hydrochloric acid, sulfuric acid, nitric acid, and p-toluenesulfonic acid.

[0063] The mass ratio of acid catalyst to water-soluble polymer can be (2-4):10, meaning the mass percentage of acid catalyst in water-soluble polymer can be 20%-40%. For example, the mass percentage of acid catalyst in water-soluble polymer can be 20%, 25%, 30%, 35%, or 40%, or any value within the range of 20%-40%. The mixing reaction temperature is 20-30°C. For example, the mixing reaction temperature can be 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C, or any value within the range of 20-30°C.

[0064] The water-soluble monomer can be selected from at least one of olefin compounds with carboxyl groups, olefin compounds with sulfonic acid groups, and olefin compounds with amino groups. Optionally, the water-soluble monomer includes at least one of sodium 2-acrylamido-2-methylpropanesulfonate, sodium allyl sulfonate, sodium methpropylene sulfonate, sodium methacrylate, and sodium acrylate. The mass ratio of the water-soluble monomer to the modified polymer can be (0.5 to 1.5):10, in other words, the mass percentage of the water-soluble monomer in the modified polymer can be 5% to 15%. For example, the mass ratio of the water-soluble monomer to the modified polymer can be 0.5:10, 1:10, or 1.5:10, etc., or any value within the range of (0.5 to 1.5):10.

[0065] The initiator includes at least one of ammonium persulfate, sodium persulfate, and potassium persulfate. The mass ratio of the initiator to the modified polymer can be (0.01 to 0.06):10, in other words, the mass percentage of the initiator in the modified polymer can be 0.1% to 0.6%; for example, the mass ratio of the initiator to the modified polymer can be 0.01:10, 0.02:10, 0.03:10, 0.04:10, 0.05:10, or 0.06:10, etc., or any value within the range of (0.01 to 0.06):10.

[0066] The oil phase comprises an oily solvent and an oil-soluble dispersant. The oily solvent may be selected from at least one of butyl acetate, ethyl acetate, methyl acetate, and propyl acetate. The oil-soluble dispersant may be cellulose acetate butyrate. The mass percentage of the oil-soluble dispersant in the oil phase may be 2% to 6%; for example, the mass percentage of the oil-soluble dispersant in the oil phase may be 2%, 3%, 4%, 5%, or 6%, or any value within the range of 2% to 6%. The oil phase can be prepared by adding the oil-soluble dispersant to the oily solvent and stirring at 30-50°C to dissolve it and form a homogeneous solution, thus obtaining the oil phase.

[0067] The polymerization temperature can be 50–80°C; for example, the polymerization temperature can be 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C, or any value within the range of 50–80°C. The polymerization time can be 5–15 hours; for example, the polymerization time can be 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, or 15 hours, or any value within the range of 5–15 hours. The polymerization reaction can be accompanied by stirring, and the stirring speed can be 200–800 rpm; for example, the stirring speed can be 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm, or 800 rpm, or any value within the range of 200–800 rpm.

[0068] Specifically, in this embodiment, the polymerization process is as follows: Under stirring conditions, an aqueous solution is slowly added dropwise to the oil phase to form a water-in-oil reverse suspension polymerization system. After the addition is complete, the reaction system is heated to 60-70°C, and a certain amount of catalyst is added dropwise to the reaction system. The reverse suspension polymerization reaction begins. After the reaction is completed, stirring and heating are stopped, the reaction system is allowed to stand and separate into layers. The oil phase is separated, the microspheres are collected and repeatedly washed to obtain the initial microsphere product. Microspheres of different sizes can be obtained by sieving using a sieve as needed, such as 40-70μm, 70-100μm, 100-150μm, 150-200μm, 200-300μm, 350-450μm, 480-580μm, 650-750μm, 825-975μm, 1025-1175μm, and 1225-1375μm.

[0069] In some embodiments, the embolization microspheres can also be replaced, specifically by adding the embolization microspheres to a 0.9% sodium chloride solution for replacement twice.

[0070] S2. Prepare a solution of Reactive Brilliant Blue X-BR and activate it.

[0071] In some embodiments, the Reactive Brilliant Blue X-BR can be activated using an alkaline solution. For example, the specific activation operation can be: mixing sodium hydroxide, water, and Reactive Brilliant Blue X-BR evenly.

[0072] S3. The activated solution is kept at a certain temperature and the pH is adjusted to change the color of the solution, thus obtaining the staining solution.

[0073] In some embodiments, the temperature for heat preservation is 60–80°C. Exemplary examples include 60°C, 65°C, 70°C, 75°C, and 80°C, or any value within the range of 60–80°C. The heat preservation time is 2–3 hours. Exemplary examples include 2 hours, 2.2 hours, 2.4 hours, 2.6 hours, 2.8 hours, and 3 hours, or any value within the range of 2–3 hours. The target pH value for pH adjustment is below 6. Exemplary examples include 1, 2, 3, 4, 5, and 6, or any value within the range below 6. By controlling the temperature and time of heat preservation, the color depth of the staining solution can be adjusted. Controlling the temperature and time of heat preservation to 60–80°C and 2–3 hours respectively allows the prepared chromogenic embolic microspheres to have a deeper color, making them easier to observe during operation.

[0074] S4. The embolic microspheres were stained with a staining solution to obtain chromogenic embolic microspheres.

[0075] In some embodiments, the staining temperature is 60–80°C; the staining time is 2–3 hours. Staining at 60–80°C is beneficial for producing chromogenic embolic microspheres with a deeper color.

[0076] This method involves heat treatment and pH adjustment of Reactive Brilliant Blue X-BR to change its color, and then staining the embolic microspheres to obtain a relatively safe chromogenic embolic microsphere of other colors, thus providing the possibility of classifying different types of embolic microspheres by color.

[0077] The specific steps for classifying different types of embolic microspheres by color are as follows: Obtain the embolic microspheres; prepare and activate the reactive brilliant blue X-BR solution to obtain the first staining solution; perform temperature incubation and pH adjustment on a portion of the activated first staining solution to adjust its color, obtaining the second staining solution; classify the embolic microspheres; and stain the classified embolic microspheres using the first and second staining solutions respectively to obtain chromogenic embolic microspheres. Classification methods can include categorization by size, decomposition time, hardness, and elasticity.

[0078] This application also provides a chromogenic embolization microsphere, which is prepared using the method described above.

[0079] The chromogenic embolization microspheres are prepared based on the above method. The specific steps of the method can be referred to the above embodiments. Since the chromogenic embolization microspheres adopt some or all of the technical solutions of the above embodiments, they have at least all the beneficial effects brought about by the technical solutions of the above embodiments, which will not be elaborated here.

[0080] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Experimental methods in the following embodiments that do not specify specific conditions are generally determined according to national standards. If there is no corresponding national standard, then general international standards, conventional conditions, or conditions recommended by the manufacturer are followed.

[0081] Example 1

[0082] This embodiment provides a chromogenic embolic microsphere, which is prepared according to the following method, the method including:

[0083] Step 1: Preparation of modified polymer

[0084] The polymer (polyvinyl alcohol, 100g) was added to water (500mL), heated to 95℃ and stirred to dissolve and form a homogeneous solution; then the water-soluble crosslinking agent ((N-(2,2-dimethoxy)-2-methylacrylamide, 3.00g) was added, stirred evenly, and then the acid catalyst (hydrochloric acid, 30mL) was added. The reaction was carried out at 25℃ for 13h with continuous stirring to obtain a polyvinyl alcohol aqueous solution (i.e., the modified polymer).

[0085] Step 2: Prepare the reverse suspension polymerization oil phase

[0086] Cellulose acetate butyrate (20g) was added to butyl acetate (500mL) and stirred at 35°C to dissolve and form a homogeneous solution, thus obtaining the oil phase.

[0087] Step 3: Prepare the aqueous phase of the reverse-phase suspension polymerization system

[0088] Sodium acrylate (10g), potassium persulfate (0.3g), and the modified polymer from step 1 (100g) were stirred until a homogeneous solution was obtained, thus yielding the aqueous phase.

[0089] Step 4: Reverse suspension polymerization

[0090] Under stirring conditions, the aqueous phase solution from step 3 was slowly added dropwise to the oil phase from step 2 to form a water-in-oil reverse suspension polymerization system. After the addition was complete, a certain amount of the catalyst tetramethylethylenediamine was added dropwise to the reaction system, initiating the reverse suspension polymerization reaction. After the reaction was completed, stirring and heating were stopped, and the reaction system was allowed to stand to separate into layers. The oil phase was separated, and the microspheres were collected and repeatedly washed to obtain the embolic microspheres. The collected microspheres were then replaced twice with a 0.9% sodium chloride solution, and the volume of the microspheres was recorded.

[0091] Step 5: Preparation of staining solution

[0092] Sodium hydroxide, water, and Reactive Brilliant Blue X-BR were mixed evenly and kept in a water bath at 70°C for 2.5 hours. Hydrochloric acid solution was added to adjust the pH of the solution to 7 to obtain the staining solution.

[0093] Step 6: Microsphere staining

[0094] Add the staining solution from step 5 to the microspheres from step 4, incubate in a 70°C water bath for 3 hours, filter through a 500-mesh sieve, collect the embolic microspheres, wash repeatedly to obtain purple chromogenic embolic microspheres.

[0095] Example 2

[0096] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the temperature during the preparation of the staining solution is 60°C.

[0097] Example 3

[0098] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the temperature for maintaining the staining solution is 80°C.

[0099] Example 4

[0100] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the temperature during the preparation of the staining solution is 50°C.

[0101] Example 5

[0102] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the temperature during the preparation of the staining solution is 90°C.

[0103] Example 6

[0104] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the target pH value for pH adjustment in the preparation of the staining solution is 6.

[0105] Example 7

[0106] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the target pH value for pH adjustment in the preparation of the staining solution is 5.

[0107] Example 8

[0108] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the target pH value for pH adjustment in the preparation of the staining solution is 3.

[0109] Example 9

[0110] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the target pH value for pH adjustment in the preparation of the staining solution is 1.

[0111] Example 10

[0112] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the staining temperature during microsphere staining is 50℃.

[0113] Example 11

[0114] This embodiment provides an embolization microsphere, the preparation method of which differs from that of Example 1 in that the staining temperature during microsphere staining is 90℃.

[0115] Comparative Example 1

[0116] This embodiment provides a chromogenic embolic microsphere, which is prepared according to the following method, the method including:

[0117] Step 1: Preparation of modified polymer

[0118] The polymer (polyvinyl alcohol, 100g) was added to water (500mL), heated to 95℃ and stirred to dissolve and form a homogeneous solution; then the water-soluble crosslinking agent ((N-(2,2-dimethoxy)-2-methylacrylamide, 3.00g) was added, stirred evenly, and then the acid catalyst (hydrochloric acid, 30mL) was added. The reaction was carried out at 25℃ for 13h with continuous stirring to obtain a polyvinyl alcohol aqueous solution (i.e., the modified polymer).

[0119] Step 2: Prepare the reverse suspension polymerization oil phase

[0120] Cellulose acetate butyrate (20g) was added to butyl acetate (500mL) and stirred at 35°C to dissolve and form a homogeneous solution, thus obtaining the oil phase.

[0121] Step 3: Prepare the aqueous phase of the reverse-phase suspension polymerization system

[0122] Sodium acrylate (10g), potassium persulfate (0.3g), and the modified polymer from step 1 (100g) were stirred until a homogeneous solution was obtained, thus yielding the aqueous phase.

[0123] Step 4: Reverse suspension polymerization

[0124] Under stirring conditions, the aqueous phase solution from step 3 was slowly added dropwise to the oil phase from step 2 to form a water-in-oil reverse suspension polymerization system. After the addition was complete, a certain amount of the catalyst tetramethylethylenediamine was added dropwise to the reaction system, initiating the reverse suspension polymerization reaction. After the reaction was completed, stirring and heating were stopped, and the reaction system was allowed to stand to separate into layers. The oil phase was separated, and the microspheres were collected and repeatedly washed to obtain the embolic microspheres. The collected microspheres were then replaced twice with a 0.9% sodium chloride solution, and the volume of the microspheres was recorded.

[0125] Step 5: Preparation of staining solution

[0126] Sodium hydroxide, water, and Reactive Brilliant Blue X-BR are mixed thoroughly to obtain the staining solution.

[0127] Step 6: Microsphere staining

[0128] Add the staining solution from step 5 to the microspheres from step 4, incubate at room temperature for 1-3 hours, filter through a 500-mesh sieve, collect the embolized microspheres, wash repeatedly to obtain blue chromogenic embolized microspheres.

[0129] Color detection was performed on the chromogenic embolic microspheres provided in Examples 1 to 15 and Comparative Example 1. The detection results are as follows: Figure 2-9 And as shown in the table below:

[0130]

[0131]

[0132] As shown in the table above, by using the technical solution disclosed in this application and adjusting the dyeing process, microspheres can be dyed purple. Of course, the depth of purple will vary under different parameters. The appropriate parameters can be selected according to actual needs to prepare the required purple microspheres.

[0133] The above are merely specific embodiments of this application, enabling those skilled in the art to understand or implement this application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of this application. Therefore, this application is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A method for preparing chromogenic embolic microspheres, characterized in that, The method includes: Obtain embolization microspheres; The Reactive Brilliant Blue X-BR was prepared into a solution and activated with an alkaline solution; The activated solution is subjected to heat preservation treatment and pH adjustment to adjust the color of the solution and obtain a staining solution. The heat preservation treatment temperature is 60~80℃, the heat preservation treatment time is 2~3h, and the target pH value of the pH adjustment is below 6. The embolic microspheres were stained with the staining solution to obtain chromogenic embolic microspheres. The staining temperature was 60-80℃ and the staining time was 2-3 hours.

2. The method for preparing chromogenic embolic microspheres according to claim 1, characterized in that, The obtained embolization microspheres include: Water-soluble polymers are formulated into polymer solutions; The polymer solution, water-soluble crosslinking agent, and acid catalyst are mixed and reacted to obtain a modified polymer. The modified polymer, a water-soluble monomer containing ionic functional groups and polymerizable double bonds, and an initiator are formulated into an aqueous phase. The aqueous phase is dropped into the oil phase to form a reverse-phase suspension polymerization system, and then a polymerization reaction is carried out to obtain embolization microspheres.

3. The method for preparing chromogenic embolic microspheres according to claim 2, characterized in that, The water-soluble polymer includes at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, sodium carboxymethyl cellulose, and water-soluble chitosan; and / or The preparation temperature of the polymer solution is 90~100℃; and / or The water-soluble crosslinking agent comprises at least one of N-(2,2-dimethoxy)-2-methacrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylamide, N-(2,2-dimethoxy)-2-acrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylamide, N-(2,2-dimethoxy)-2-methacrylate, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylate, N-(2,2-dimethoxy)-2-acrylate, and N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylate; and / or The acid catalyst includes at least one of hydrochloric acid, sulfuric acid, nitric acid, and p-toluenesulfonic acid.

4. The method for preparing chromogenic embolic microspheres according to claim 2, characterized in that, The ionic functional group of the water-soluble monomer includes at least one of a sulfonic acid group and a carboxyl group; and / or The water-soluble monomer includes at least one of sodium 2-acrylamido-2-methylpropanesulfonate and sodium allyl sulfonate, sodium methpropylene sulfonate, sodium methacrylate, and sodium acrylate; and / or The initiator includes at least one of ammonium persulfate, sodium persulfate, and potassium persulfate.

5. The method for preparing chromogenic embolic microspheres according to claim 2, characterized in that, The oil phase includes an oily solvent and an oil-soluble dispersant; and / or The oily solvent includes at least one selected from butyl acetate, ethyl acetate, methyl acetate, and propyl acetate; and / or The oil-soluble dispersant includes cellulose acetate butyrate.

6. The method for preparing chromogenic embolic microspheres according to claim 2, characterized in that, The polymerization reaction is carried out at a temperature of 65-85°C; and / or The polymerization reaction takes 10-15 hours.

7. A colorimetric embolic microsphere, characterized in that, The chromogenic embolic microspheres are prepared by the method described in any one of claims 1 to 6.

8. A method for preparing chromogenic embolic microspheres, characterized in that, The method includes: Obtain embolization microspheres; The Reactive Brilliant Blue X-BR was prepared into a solution and activated with an alkaline solution to obtain the first staining solution; The first staining solution after partial activation is subjected to heat preservation treatment and pH adjustment to adjust the color of the first staining solution to obtain the second staining solution. The heat preservation treatment temperature is 60~80℃, the heat preservation treatment time is 2~3h, and the target pH value of the pH adjustment is below 6. The embolic microspheres were classified; The classified embolic microspheres were stained with the first staining solution and the second staining solution respectively to obtain chromogenic embolic microspheres. The staining temperature was 60~80℃ and the staining time was 2~3h.

Images