Developing embolism microsphere and preparation method thereof

Abstract

The embodiment of the invention provides a developing embolism microsphere and a preparation method thereof, and relates to the field of medical instruments. The structural formula of the developing embolism microsphere is # imgabs0 #, m is larger than 0, n is larger than 0, R1 is H or a C1-6 alkyl chain with a sulfo group, and R2 is hydroxyl or an ionic group. According to the developing embolism microsphere and the preparation method thereof, the microsphere has a developing function and is simple in synthesis route and low in cost.

Description

Technical Field

[0001] The present application relates to the field of medical devices, and in particular, to a developing embolic microsphere and a preparation method thereof. Background Art

[0002] Most of the embolic microspheres currently available in China can be penetrated by X-rays, that is, they have no imaging function. Therefore, it is necessary to indirectly judge the direction of the embolic microspheres, the degree of embolism, and whether there is a mistaken embolism by injecting contrast agents (such as Uvitra, iohexol, iopamidol, etc.). However, these vascular contrast agents will quickly disappear with the blood, and it is difficult to determine the position of the embolic microspheres after surgery, and it is difficult to evaluate whether re-embolization is needed. Based on the same idea, it is particularly necessary to develop embolic microspheres that are visible under X-rays, which will reduce the number of contrast agent injections, thereby reducing allergic reactions and potential nephrotoxicity. In addition, the X-ray opaque nature of the embolic microspheres enables interventional physicians to directly observe the position of the embolic microspheres in the blood vessels through X-ray detection equipment (DSA, CBCT, CT, etc.), thereby improving the efficiency and safety of embolism.

[0003] In recent years, great progress has been made in the development of embolic microspheres that are opaque to X-rays by introducing iodine-containing compounds into their structures. However, the current development of embolic microspheres and the synthetic routes of iodine-containing compounds are complicated and costly, which limits the commercial development of embolic microspheres.

[0004] Therefore, it is of great significance to design an embolic microsphere with a simple synthesis route and low cost under the premise of realizing the development function. Summary of the invention

[0005] The purpose of the embodiments of the present application is to provide a developing embolic microsphere and a preparation method thereof. The microsphere has a developing function, and the synthesis route is simple and the cost is low.

[0006] In a first aspect, the present application provides a developing embolic microsphere, the structural formula of which is as follows:

[0007] Where m>0, n>0, R 1 R 2 are hydroxyl groups or ionic groups, respectively.

[0008] In the above technical solution, the microspheres have a developing function, a simple structure, a simple corresponding synthesis route, and a low cost of a corresponding developer.

[0009] In a possible implementation, the ionic group includes a carboxyl group and a sulfonic acid group.

[0010] In a possible implementation, it is a three-dimensional network structure formed by cross-linking a water-soluble copolymer and 2,3-diiodosuccinaldehyde, and the structural formula of the water-soluble copolymer is R 1 is H or a C1-6 alkyl chain with a sulfonic acid group, R 2 It is a hydroxyl group or an ionic group.

[0011] In the above technical solution, the developer 2,3-diiodosuccinaldehyde is used as both a developer and a cross-linking agent, and the developing function can be introduced simultaneously during the cross-linking process. Compared with the existing developing microspheres, the synthesis cycle of the developing microspheres is significantly shortened and the production cost is reduced.

[0012] In a second aspect, the present invention provides a method for preparing the developing embolic microspheres according to the first aspect, wherein a water-soluble copolymer is cross-linked and polymerized with 2,3-diiodosuccinaldehyde, wherein the water-soluble copolymer has a structural formula of x>0,R 1 is H or a C1-6 alkyl chain with a sulfonic acid group, R 2 It is a hydroxyl group or an ionic group.

[0013] In a possible implementation, the following steps are included:

[0014] PVA is first acetal-modified, then sulfonic acid-modified, and then hydrolyzed to obtain sulfonic acid-modified PVA;

[0015] Sulfonic acid group-modified PVA and 2,3-diiodosuccinaldehyde were emulsified and cross-linked to obtain the developing embolic microspheres.

[0016] In a possible implementation, the following steps are included:

[0017] S1. dissolving an aldehyde compound having a hydrophilic group at one end and PVA in deionized water in a certain proportion, adjusting the pH value to 1 to 3 after uniform dissolution, stirring and reacting at a certain temperature for a certain time to obtain a water-soluble PVA acetal;

[0018] S2, dissolving PVA acetal in deionized water, adding sulfonating reagent and NaOH, reacting at a certain temperature for a certain time to obtain sulfonic acid group-modified PVA acetal;

[0019] S3, dissolving the sulfonic acid group-modified PVA acetal in deionized water, adjusting the pH to 3-5, and hydrolyzing at a certain temperature for a certain time to obtain the sulfonic acid group-modified PVA, whose structural formula is x>0, R1 is H or a C1~6 alkyl chain with a sulfonic acid group;

[0020] S4, adding the oil-soluble dispersant to the oil-soluble solvent, stirring and dissolving to form an emulsified cross-linked oil phase;

[0021] S5, preparing the sulfonic acid group-modified PVA into an aqueous solution, then adding 2,3-diiodosuccinaldehyde aqueous solution, and stirring for 10 minutes to form an emulsified cross-linked aqueous phase;

[0022] S6. Mix the emulsified cross-linked oil phase and the emulsified cross-linked water phase, add hydrochloric acid to catalyze the reaction, continue stirring the reaction at a certain temperature for a certain period of time to cross-link the sulfonic acid group-modified PVA with 2,3-diiodosuccinaldehyde, let stand until the reaction system is stratified, separate the oil phase, collect the microspheres and wash them repeatedly to obtain the developed embolic microspheres.

[0023] In a possible implementation, in step S1, the alcoholysis degree of PVA is 0 to 100%;

[0024] The aldehyde compound having a hydrophilic group at one end includes at least one of glyoxylic acid, benzaldehyde-2-sulfonic acid, benzaldehyde-2-sulfonic acid sodium, benzaldehyde-4-sulfonic acid sodium, and p-formylbenzoic acid;

[0025] The molar ratio of the aldehyde compound with a hydrophilic group at one end to PVA is 1:2 to 1:16;

[0026] The reaction temperature of the aldehyde compound with a hydrophilic group at one end and PVA is 15 to 65° C., and the reaction time is 4 to 8 hours;

[0027] and / or, in step S2, the sulfonation reagent comprises at least one of 1,4-butane sultone, 2,4-butane sultone, and 1,3-propane sultone;

[0028] The molar ratio of the sulfonating agent, NaOH and PVA acetal is 1:2:1.3 to 1:2:4;

[0029] The reaction temperature of the PVA acetal and the sulfonation reagent is 50 to 80° C., and the reaction time is 4 to 12 hours;

[0030] and / or, in step S3, the hydrolysis reaction temperature of the sulfonic acid group-modified PVA acetal is 60-80° C., and the reaction time is 4-8 h;

[0031] And / or, in step S4, the oil-soluble dispersant includes at least one of a Span series compound, a Tween series compound, and a modified cellulose series compound;

[0032] The oil-soluble solvent includes at least one of a liquid alkane solvent series compound and an organic solvent;

[0033] The mass proportion of the oil-soluble dispersant in the emulsified cross-linked oil phase is 0.5% to 8%;

[0034] and / or, in step S5, the aqueous solution of the sulfonic acid group-modified PVA is 2.5% to 10%;

[0035] The amount of the 2,3-diiodosuccinaldehyde aqueous solution added is 0.25 to 1 mL;

[0036] And / or, in step S6, the emulsification cross-linking reaction temperature is 20-60° C., and the reaction time is 1-5 hours.

[0037] In a possible implementation, the following steps are included:

[0038] The first monomer and the second monomer are subjected to suspension polymerization to obtain a copolymer, wherein the structural formula of the first monomer is The structural formula of the second monomer is R 4 , R 5 are respectively C1-6 alkyl chains;

[0039] hydrolyzing the copolymer under the action of a base to obtain a water-soluble copolymer;

[0040] The water-soluble copolymer and 2,3-diiodosuccinaldehyde are emulsified and cross-linked to obtain the developing embolic microspheres.

[0041] In a possible implementation, the following steps are included:

[0042] S1, mixing the first monomer and the second monomer and adding an initiator to prepare an oil phase, adding a suspension polymerization dispersant to water to prepare an aqueous phase, slowly dropping the oil phase into the aqueous phase at a certain temperature for a certain period of time to obtain a copolymer;

[0043] S2, adding the copolymer and NaOH into a solvent, and performing a hydrolysis reaction at a certain temperature for a certain time to obtain a water-soluble copolymer;

[0044] S3, adding the oil-soluble dispersant to the oil-soluble solvent, stirring and dissolving to form an emulsified cross-linked oil phase;

[0045] S4, dissolving the water-soluble copolymer in water to prepare an aqueous solution, then adding 2,3-diiodosuccinaldehyde aqueous solution, and stirring evenly to form an emulsified cross-linked aqueous phase;

[0046] S5. Mix the emulsified cross-linked oil phase and the emulsified cross-linked water phase, add hydrochloric acid to catalyze the reaction, continue stirring the reaction for a certain period of time to cross-link the water-soluble copolymer with 2,3-diiodosuccinaldehyde, let stand until the reaction system is stratified, separate the oil phase, collect the microspheres and repeatedly wash them to obtain the developed embolic microspheres.

[0047] In a possible implementation, in step S1, the molar ratio of the first monomer to the second monomer is 1:1 to 1:6;

[0048] The first monomer includes at least one of vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, and vinyl valerate;

[0049] The second monomer comprises at least one of methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, and butyl methacrylate;

[0050] The initiator comprises at least one of benzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, tert-butyl perbenzoate, and dimethyl azobisisobutyrate;

[0051] The amount of the initiator added is 0.1 to 1.5% of the total weight of the monomers;

[0052] The suspension polymer dispersant includes at least one of polyvinyl alcohol, gelatin, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and ethyl hydroxyethyl cellulose;

[0053] The suspension polymerization reaction temperature is 60-80°C and the reaction time is 6-12h;

[0054] and / or, in step S2, the molar ratio of the copolymer to NaOH is 1:3 to 1:5;

[0055] The solvent of the hydrolysis reaction includes deionized water, a mixed solvent with a volume ratio of methanol to deionized water of 1:1 to 1:5, and a mixed solvent with a volume ratio of ethanol to deionized water of 1:1 to 1:5;

[0056] The temperature of the hydrolysis reaction is 60-80°C and the reaction time is 4-12h;

[0057] and / or, in step S3, the mass proportion of the oil-soluble dispersant in the emulsified cross-linked oil phase is 0.5% to 8%;

[0058] and / or, in step S4, the concentration of the aqueous solution of the water-soluble copolymer is 2.5% to 10%;

[0059] The amount of the 2,3-diiodosuccinaldehyde aqueous solution added is 0.25 to 1.0 mL;

[0060] And / or, in step S5, the emulsification cross-linking reaction temperature is 20-60° C., and the reaction time is 1-5 hours. DETAILED DESCRIPTION

[0061] 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.

[0062] The developing embolic microspheres and the preparation method thereof according to the embodiments of the present application are described in detail below.

[0063] In a first aspect, the present application provides a developing embolic microsphere, the structural formula of which is as follows:

[0064] Where m>0, n>0, R 1 R 2 are hydroxyl groups or ionic groups, respectively.

[0065] In a possible implementation, the ionic group includes a carboxyl group and a sulfonic acid group.

[0066] In a possible implementation, it is a three-dimensional network structure formed by cross-linking a water-soluble copolymer and 2,3-diiodosuccinaldehyde, and the structural formula of the water-soluble copolymer is R 1 is H or a C1-6 alkyl chain with a sulfonic acid group, R 2 It is a hydroxyl group or an ionic group.

[0067] In addition, the present invention provides a method for preparing the above-mentioned developing embolic microspheres, wherein a water-soluble copolymer is cross-linked and polymerized with 2,3-diiodosuccinaldehyde, wherein the water-soluble copolymer has a structural formula of x>0,R 1 is H or a C1-6 alkyl chain with a sulfonic acid group, R 2 is a hydroxyl group or an ionic group. The reaction process of the preparation method is as follows:

[0068] I is a water-soluble polymer, and II is the developing embolic microspheres.

[0069] In the present application, the preparation methods can be divided into the following two types: A and B according to the different water-soluble polymers.

[0070] Wherein, the water-soluble polymer in preparation method A is PVA.

[0071] In some embodiments of the present application, preparation method A comprises the following steps:

[0072] PVA is first acetal-modified, then sulfonic acid-modified, and then hydrolyzed to obtain sulfonic acid-modified PVA;

[0073] Sulfonic acid group-modified PVA and 2,3-diiodosuccinaldehyde are emulsified and cross-linked to obtain developing embolic microspheres. The reaction process of the preparation method A is as follows:

[0074] Among them, R3 is a hydrophilic group.

[0075] As an optional embodiment, preparation method A comprises the following steps:

[0076] S1. dissolving an aldehyde compound having a hydrophilic group at one end and PVA in deionized water in a certain proportion, adjusting the pH value to 1 to 3 after uniform dissolution, stirring and reacting at a certain temperature for a certain time to obtain a water-soluble PVA acetal;

[0077] S2, dissolving PVA acetal in deionized water, adding sulfonating reagent and NaOH, reacting at a certain temperature for a certain time to obtain sulfonic acid group-modified PVA acetal;

[0078] S3, dissolving the sulfonic acid group-modified PVA acetal in deionized water, adjusting the pH to 3-5, and hydrolyzing at a certain temperature for a certain time to obtain the sulfonic acid group-modified PVA, whose structural formula is x>0, R1 is H or a C1~6 alkyl chain with a sulfonic acid group;

[0079] S4, adding the oil-soluble dispersant to the oil-soluble solvent, stirring and dissolving to form an emulsified cross-linked oil phase;

[0080] S5, preparing the sulfonic acid group-modified PVA into an aqueous solution, then adding 2,3-diiodosuccinaldehyde aqueous solution, and stirring for 10 minutes to form an emulsified cross-linked aqueous phase;

[0081] S6. Mix the emulsified cross-linked oil phase and the emulsified cross-linked water phase, add hydrochloric acid to catalyze the reaction, continue stirring the reaction at a certain temperature for a certain period of time to cross-link the sulfonic acid group-modified PVA with 2,3-diiodosuccinaldehyde, let stand until the reaction system is stratified, separate the oil phase, collect the microspheres and wash them repeatedly to obtain the developed embolic microspheres.

[0082] In a possible implementation, in step S1, the alcoholysis degree of PVA is 0 to 100%;

[0083] The aldehyde compound having a hydrophilic group at one end includes at least one of glyoxylic acid, benzaldehyde-2-sulfonic acid, benzaldehyde-2-sulfonic acid sodium, benzaldehyde-4-sulfonic acid sodium, and p-formylbenzoic acid;

[0084] The molar ratio of the aldehyde compound with a hydrophilic group at one end to PVA is 1:2 to 1:16;

[0085] The reaction temperature of the aldehyde compound with a hydrophilic group at one end and PVA is 15 to 65° C., and the reaction time is 4 to 8 hours;

[0086] and / or, in step S2, the sulfonation reagent comprises at least one of 1,4-butane sultone, 2,4-butane sultone, and 1,3-propane sultone;

[0087] The molar ratio of the sulfonating agent, NaOH and PVA acetal is 1:2:1.3 to 1:2:4;

[0088] The reaction temperature of the PVA acetal and the sulfonation reagent is 50 to 80° C., and the reaction time is 4 to 12 hours;

[0089] and / or, in step S3, the hydrolysis reaction temperature of the sulfonic acid group-modified PVA acetal is 60-80° C., and the reaction time is 4-8 h;

[0090] And / or, in step S4, the oil-soluble dispersant includes at least one of a Span series compound, a Tween series compound, and a modified cellulose series compound;

[0091] The oil-soluble solvent includes at least one of a liquid alkane solvent series compound and an organic solvent;

[0092] The mass proportion of the oil-soluble dispersant in the emulsified cross-linked oil phase is 0.5% to 8%;

[0093] and / or, in step S5, the aqueous solution of the sulfonic acid group-modified PVA is 2.5% to 10%;

[0094] The amount of the 2,3-diiodosuccinaldehyde aqueous solution added is 0.25 to 1 mL;

[0095] And / or, in step S6, the emulsification cross-linking reaction temperature is 20-60° C., and the reaction time is 1-5 hours.

[0096] Wherein, the water-soluble polymer in the preparation method B is a polymer containing ionic groups.

[0097] In some embodiments of the present application, preparation method B comprises the following steps:

[0098] The first monomer and the second monomer are subjected to suspension polymerization to obtain a copolymer, wherein the structural formula of the first monomer is The structural formula of the second monomer is R 4 , R 5 are respectively C1-6 alkyl chains;

[0099] hydrolyzing the copolymer under the action of a base to obtain a water-soluble copolymer;

[0100] The water-soluble copolymer and 2,3-diiodosuccinaldehyde are emulsified and cross-linked to obtain the developing embolic microspheres. The reaction process of the preparation method B is as follows:

[0101]

[0102] As an optional embodiment, preparation method B comprises the following steps:

[0103] S1, mixing the first monomer and the second monomer and adding an initiator to prepare an oil phase, adding a suspension polymerization dispersant to water to prepare an aqueous phase, slowly dropping the oil phase into the aqueous phase at a certain temperature for a certain period of time to obtain a copolymer;

[0104] S2, adding the copolymer and NaOH into a solvent, and performing a hydrolysis reaction at a certain temperature for a certain time to obtain a water-soluble copolymer;

[0105] S3, adding the oil-soluble dispersant to the oil-soluble solvent, stirring and dissolving to form an emulsified cross-linked oil phase;

[0106] S4, dissolving the water-soluble copolymer in water to prepare an aqueous solution, then adding 2,3-diiodosuccinaldehyde aqueous solution, and stirring evenly to form an emulsified cross-linked aqueous phase;

[0107] S5. Mix the emulsified cross-linked oil phase and the emulsified cross-linked water phase, add hydrochloric acid to catalyze the reaction, continue stirring the reaction for a certain period of time to cross-link the water-soluble copolymer with 2,3-diiodosuccinaldehyde, let stand until the reaction system is stratified, separate the oil phase, collect the microspheres and repeatedly wash them to obtain the developed embolic microspheres.

[0108] In a possible implementation, in step S1, the molar ratio of the first monomer to the second monomer is 1:1 to 1:6;

[0109] The first monomer includes at least one of vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, and vinyl valerate;

[0110] The second monomer comprises at least one of methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, and butyl methacrylate;

[0111] The initiator comprises at least one of benzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, tert-butyl perbenzoate, and dimethyl azobisisobutyrate;

[0112] The amount of the initiator added is 0.1 to 1.5% of the total weight of the monomers;

[0113] The suspension polymer dispersant includes at least one of polyvinyl alcohol, gelatin, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and ethyl hydroxyethyl cellulose;

[0114] The suspension polymerization reaction temperature is 60-80°C and the reaction time is 6-12h;

[0115] and / or, in step S2, the molar ratio of the copolymer to NaOH is 1:3 to 1:5;

[0116] The solvent of the hydrolysis reaction includes deionized water, a mixed solvent with a volume ratio of methanol to deionized water of 1:1 to 1:5, and a mixed solvent with a volume ratio of ethanol to deionized water of 1:1 to 1:5;

[0117] The temperature of the hydrolysis reaction is 60-80°C and the reaction time is 4-12h;

[0118] and / or, in step S3, the mass proportion of the oil-soluble dispersant in the emulsified cross-linked oil phase is 0.5% to 8%;

[0119] and / or, in step S4, the concentration of the aqueous solution of the water-soluble copolymer is 2.5% to 10%;

[0120] The amount of the 2,3-diiodosuccinaldehyde aqueous solution added is 0.25 to 1.0 mL;

[0121] And / or, in step S5, the emulsification cross-linking reaction temperature is 20-60° C., and the reaction time is 1-5 hours.

[0122] The features and performance of the present application are further described in detail below in conjunction with the embodiments.

[0123] Example 1

[0124] This embodiment provides a drug-loaded, X-ray opaque developing embolic microsphere, the preparation method of which comprises the following steps:

[0125] Step 1: Preparation of water-soluble PVA acetal: 0.05 mol of glyoxylic acid and 0.2 mol of polyvinyl alcohol 1788 were dissolved in 100 mL of deionized water. After uniform dissolution, concentrated hydrochloric acid was added to adjust the reaction pH to 1-3. The reaction was stirred at 50° C. for 6 h. After the reaction was completed, the water-soluble PVA glyoxylic acid was obtained by rotary evaporation and drying.

[0126] Step 2: 0.15 mol of PVA glyoxylic acid was dissolved in 150 mL of deionized water, and 2,4-butane sultone and NaOH were added, with the molar ratio of 2,4-butane sultone, NaOH and PVA glyoxylic acid being 1:2:4. The mixture was stirred at 60° C. for 6 h. After the reaction, the solution was acidified to neutrality and dialyzed for desalination, followed by rotary evaporation and drying to obtain sulfonic acid-modified PVA glyoxylic acid.

[0127] Step 3: Dissolve 0.15 mol of sulfonic acid-modified PVA glyoxylic acid in 300 mL of deionized water, adjust the solution pH to 3-5, and hydrolyze at 60°C for 5 h. After the hydrolysis reaction is completed, rotary evaporate and dry to obtain sulfonic acid-modified PVA;

[0128] Step 4: Prepare the emulsified cross-linked oil phase. Add 100 mL of butyl acetate into a four-necked bottle, weigh 0.8 g of cellulose acetate butyrate, and dissolve it in a 60°C constant temperature water bath under stirring until a uniform oil phase system is formed;

[0129] Step 5: Prepare the emulsified cross-linked aqueous phase. First, prepare 20 mL of 10% aqueous solution of sulfonic acid-modified PVA, then add 1 mL of 25% 2,3-diiodosuccinic dialdehyde aqueous solution and stir for 10 minutes;

[0130] Step 6: Emulsification crosslinking. Add hydrochloric acid to catalyze the reaction, crosslink the sulfonic acid group-modified PVA with 2,3-diiodosuccinaldehyde, and react at 60°C for 2h. After the reaction is completed, stop stirring and cool, let stand until the reaction system is separated, separate the oil phase, collect the microspheres and wash them repeatedly to obtain sulfonic acid group-modified PVA developer-loaded microspheres.

[0131] Example 2

[0132] This embodiment provides a drug-loaded, X-ray opaque developing embolic microsphere, the preparation method of which comprises the following steps:

[0133] Step 1: Preparation of water-soluble PVA acetal: 0.05 mol of sodium benzaldehyde-2-sulfonate and 0.2 mol of polyvinyl alcohol 1788 were dissolved in 100 mL of deionized water. After uniform dissolution, concentrated hydrochloric acid was added to adjust the reaction pH to 1-3. The reaction was stirred at 30°C for 6 hours. After the reaction was completed, the water-soluble PVA sodium benzaldehyde-2-sulfonate was obtained by rotary evaporation and drying.

[0134] Step 2: dissolving 0.2 mol of polyvinyl alcohol condensed from sodium benzaldehyde-2-sulfonate in 150 mL of deionized water, adding 1,3-propane sultone and sodium hydroxide, the molar ratio of polyvinyl alcohol condensed from 1,3-propane sultone, sodium hydroxide and sodium benzaldehyde-2-sulfonate is 1:2:2, stirring and reacting at 60° C. for 8 h, and after the reaction is completed, acidifying the solution to neutrality and dialyzing for desalting, followed by rotary evaporation and drying to obtain sulfonic acid-modified PVA sodium benzaldehyde-2-sulfonate;

[0135] Step 3: Dissolve 0.2 mol of sulfonic acid-modified sodium benzaldehyde-2-sulfonate condensed polyvinyl alcohol in 300 mL of deionized water, adjust the solution pH to 3-5, and hydrolyze at 60°C for 6 hours. After the hydrolysis reaction is completed, rotary evaporate and dry to obtain sulfonic acid-modified PVA;

[0136] Step 4: Prepare the emulsified cross-linked oil phase. Add 100 mL of butyl acetate into a four-necked bottle, weigh 2 g of cellulose acetate, and dissolve it in a 60°C constant temperature water bath under stirring until a uniform oil phase system is formed;

[0137] Step 5: Prepare the emulsified cross-linked aqueous phase. First, prepare 20 mL of 8% aqueous solution of sulfonic acid-modified PVA, then add 0.8 mL of 25% 2,3-diiodosuccinic dialdehyde aqueous solution and stir for 10 minutes;

[0138] Step 6: Emulsification crosslinking. Add hydrochloric acid to catalyze the reaction, crosslink the sulfonic acid group-modified PVA with 2,3-diiodosuccinaldehyde, and react at 50°C for 4 hours. After the reaction is completed, stop stirring and cool, let stand until the reaction system is separated, separate the oil phase, collect the microspheres and wash them repeatedly to obtain sulfonic acid group-modified PVA developer-loaded microspheres.

[0139] Example 3

[0140] This embodiment provides a drug-loaded, X-ray opaque developing embolic microsphere, the preparation method of which comprises the following steps:

[0141] Step 1: suspension polymerization: methyl methacrylate and vinyl acetate are mixed in a molar ratio of 1:2 and 1.5% of the total weight of the monomers as initiator AIBN are added to prepare an oil phase, and the dispersant polyvinyl alcohol is added into water and dissolved completely to prepare an aqueous phase, and the oil phase is slowly added dropwise into the aqueous phase at 60° C. to react for 12 hours. After the reaction is completed, the solid product is filtered, collected, washed, and dried to obtain a copolymer of methyl methacrylate and vinyl acetate;

[0142] Step 2: hydrolysis: add the copolymer of methyl methacrylate and vinyl acetate and NaOH in a molar ratio of 1:5 to a mixed solvent of methanol / deionized water in a volume ratio of 1:3, and perform hydrolysis reaction at 70°C for 8 hours. After the reaction, the solution is acidified to neutrality and dialyzed for desalination, followed by rotary evaporation and drying to obtain a water-soluble methacrylic acid-vinyl alcohol copolymer;

[0143] Step 3: Prepare the emulsified cross-linked oil phase. Add 100 mL of butyl acetate into a four-necked bottle, weigh 1.5 g of cellulose acetate butyrate, and dissolve it in a 60°C constant temperature water bath under stirring until a uniform oil phase system is formed;

[0144] Step 4: Prepare the emulsified cross-linked aqueous phase. First, prepare 20 mL of a 7.5% aqueous solution of methacrylic acid-vinyl alcohol copolymer, then add 1 mL of a 25% by mass 2,3-diiodosuccinic dialdehyde aqueous solution and stir for 10 minutes;

[0145] Step 5: Emulsification crosslinking. Add hydrochloric acid to catalyze the reaction, crosslink the methacrylic acid-vinyl alcohol copolymer with 2,3-diiodosuccinaldehyde, and react at 40°C for 6 hours. After the reaction is completed, stop stirring and cool, let stand until the reaction system is stratified, separate the oil phase, collect the microspheres and wash them repeatedly to obtain methacrylic acid-vinyl alcohol copolymer developer drug-loaded microspheres.

[0146] Example 4

[0147] This embodiment provides a drug-loaded, X-ray opaque developing embolic microsphere, the preparation method of which comprises the following steps:

[0148] Step 1: suspension polymerization: methyl acrylate and vinyl acetate are mixed in a molar ratio of 1:3 and 1% of the total weight of the monomers as an initiator BPO is added to prepare an oil phase, and the dispersant hydroxyethyl cellulose is added into water and dissolved completely to prepare an aqueous phase, and the oil phase is slowly added dropwise to the aqueous phase at 65° C. to react for 10 hours. After the reaction is completed, the solid product is filtered, collected, washed, and dried to obtain a copolymer of methyl acrylate and vinyl acetate;

[0149] Step 2: hydrolysis: add the copolymer of methyl acrylate and vinyl acetate and NaOH in a molar ratio of 1:5 into deionized water, and perform hydrolysis reaction at 80°C for 8 hours. After the reaction, acidify the solution to neutrality and dialyze for desalination, then rotary evaporate and dry to obtain a water-soluble acrylic acid-vinyl alcohol copolymer;

[0150] Step 3: Prepare the emulsified cross-linked oil phase. Add 100 mL of liquid paraffin into a four-necked bottle, weigh 2.5 mL of Span 20, and dissolve in a 60°C constant temperature water bath under stirring until a uniform oil phase system is formed;

[0151] Step 4: Prepare the emulsified cross-linked aqueous phase. First, prepare 20 mL of a 6% aqueous solution of acrylic acid-vinyl alcohol copolymer, then add 0.8 mL of a 25% 2,3-diiodosuccinic dialdehyde aqueous solution and stir for 10 minutes;

[0152] Step 5: Emulsification crosslinking. Add hydrochloric acid to catalyze the reaction, crosslink the acrylic acid-vinyl alcohol copolymer with 2,3-diiodosuccinaldehyde, and react at 40°C for 6 hours. After the reaction is completed, stop stirring and cool, let stand until the reaction system is stratified, separate the oil phase, collect the microspheres and wash them repeatedly to obtain acrylic acid-vinyl alcohol copolymer developer drug-loaded microspheres.

[0153] Comparative Example 1

[0154] This comparative example provides a developing embolic microsphere, and the preparation method thereof comprises the following steps:

[0155] Weigh 80g of polyvinyl alcohol and put it into 320g of distilled water, raise the temperature to 95°C until the solution is completely clear and transparent, then cool to room temperature to prepare a polyvinyl alcohol solution. Take 8g of polyvinyl alcohol solution and add 0.762g of triiodobenzaldehyde. After uniform dispersion, add 0.12g of N-(2,2-dimethoxyethyl)-2-acrylamide, 1.08g of 2-acrylamide-2-methylpropanesulfonic acid and 2-acrylamide-2-methylpropanesulfonic acid sodium (mass ratio of 4:1), and stir at 40°C for 4 hours. Add 0.045g of potassium persulfate to the reaction system and stir evenly to obtain an aqueous phase.

[0156] 1.8 g of cellulose acetate butyrate and 100 mL of butyl acetate were added to a three-necked bottle and dissolved at 50° C. to obtain an oil phase.

[0157] The aqueous phase was added to the oil phase, stirred and dispersed evenly for 20 minutes, and then heated to 80°C and reacted for 6 hours. The microspheres obtained after the reaction were washed three times with butyl acetate, acetone, sodium bicarbonate solution, and purified water to obtain developed embolic microspheres.

[0158] 1. Development Experiment

[0159] HU value test method: The developed microspheres obtained in each embodiment and comparative example were subjected to Micro CT test (Bruker skyscan1276), and the results are as follows:

[0160] Example 1 Example 2 Example 3 Example 4 Comparative Example 1 HU value 8749 8571 8284 8385 7561

[0161] 2. Stability Test

[0162] The developed microspheres finally obtained in each embodiment and comparative example were suspended in a Tris buffer solution of pH 7.4 and incubated in a 37° C. water bath. Samples were taken every 24 hours to detect the iodine content in the suspension. The results are shown in the following table:

[0163]

[0164] “—” means not detected.

[0165] Through the above experiments and results, it can be known that compared with the existing development microsphere synthesis technology, the present application can obtain the development function during the cross-linking process of ball formation without the need for additional developer; compared with the iodinated aromatic or iodinated heteroaryl developers commonly used in the existing development microspheres, the developer used in the present application has a stable structure, the prepared embolic microspheres have a stable structure, the synthesis route is simple, the reaction conditions are mild, and the raw materials are inexpensive and widely available.

[0166] In summary, the developing embolic microspheres and the preparation method thereof in the embodiments of the present application have developing functions, and the synthesis route is simple and the cost is low.

[0167] The above description is only an embodiment of the present application and is not intended to limit the protection scope of the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A developing embolic microsphere, characterized in that: Its structural formula is as follows: Wherein, m>0, n>0, R1 is H or a C1~6 alkyl chain with a sulfonic acid group, and R2 is a hydroxyl group or an ionic group.

2. The developing embolic microspheres according to claim 1, characterized in that: The ionic groups include carboxyl groups and sulfonic acid groups.

3. The developing embolic microspheres according to claim 1, characterized in that: It is a three-dimensional network structure formed by cross-linking a water-soluble copolymer and 2,3-diiodosuccinaldehyde. The structural formula of the water-soluble copolymer is R1 is H or a C1-6 alkyl chain with a sulfonic acid group, and R2 is a hydroxyl group or an ionic group.

4. A method for preparing the developing embolic microspheres according to any one of claims 1 to 3, characterized in that: The water-soluble copolymer is cross-linked and polymerized with 2,3-diiodosuccinaldehyde, wherein the structural formula of the water-soluble copolymer is x>0, R1 is H or a C1~6 alkyl chain with a sulfonic acid group, and R2 is a hydroxyl group or an ionic group.

5. The method for preparing the developing embolic microspheres according to claim 4, characterized in that: It includes the following steps: PVA is first acetal-modified, then sulfonic acid-modified, and then hydrolyzed to obtain sulfonic acid-modified PVA; Sulfonic acid group-modified PVA and 2,3-diiodosuccinaldehyde were emulsified and cross-linked to obtain the developing embolic microspheres.

6. The method for preparing the developing embolic microspheres according to claim 5, characterized in that: It includes the following steps: S1. dissolving an aldehyde compound having a hydrophilic group at one end and PVA in deionized water in a certain proportion, adjusting the pH value to 1 to 3 after uniform dissolution, stirring and reacting at a certain temperature for a certain time to obtain a water-soluble PVA acetal; S2, dissolving PVA acetal in deionized water, adding sulfonating reagent and NaOH, reacting at a certain temperature for a certain time to obtain sulfonic acid group-modified PVA acetal; S3, dissolving the sulfonic acid group-modified PVA acetal in deionized water, adjusting the pH to 3-5, and hydrolyzing at a certain temperature for a certain time to obtain the sulfonic acid group-modified PVA, whose structural formula is x>0, R1 is H or a C1~6 alkyl chain with a sulfonic acid group; S4, adding the oil-soluble dispersant to the oil-soluble solvent, stirring and dissolving to form an emulsified cross-linked oil phase; S5, preparing the sulfonic acid group-modified PVA into an aqueous solution, then adding 2,3-diiodosuccinaldehyde aqueous solution, and stirring for 10 minutes to form an emulsified cross-linked aqueous phase; S6. Mix the emulsified cross-linked oil phase and the emulsified cross-linked water phase, add hydrochloric acid to catalyze the reaction, continue stirring the reaction at a certain temperature for a certain period of time to cross-link the sulfonic acid group-modified PVA with 2,3-diiodosuccinaldehyde, let stand until the reaction system is stratified, separate the oil phase, collect the microspheres and wash them repeatedly to obtain the developed embolic microspheres.

7. The method for preparing the developing embolic microspheres according to claim 6, characterized in that: In step S1, the alcoholysis degree of PVA is 0 to 100%; The aldehyde compound having a hydrophilic group at one end includes at least one of glyoxylic acid, benzaldehyde-2-sulfonic acid, benzaldehyde-2-sulfonic acid sodium, benzaldehyde-4-sulfonic acid sodium, and p-formylbenzoic acid; The molar ratio of the aldehyde compound with a hydrophilic group at one end to PVA is 1:2 to 1:16; The reaction temperature of the aldehyde compound with a hydrophilic group at one end and PVA is 15 to 65° C., and the reaction time is 4 to 8 hours; and / or, in step S2, the sulfonation reagent comprises at least one of 1,4-butane sultone, 2,4-butane sultone, and 1,3-propane sultone; The molar ratio of the sulfonating agent, NaOH and PVA acetal is 1:2:1.3 to 1:2:4; The reaction temperature of the PVA acetal and the sulfonation reagent is 50 to 80° C., and the reaction time is 4 to 12 hours; and / or, in step S3, the hydrolysis reaction temperature of the sulfonic acid group-modified PVA acetal is 60-80° C., and the reaction time is 4-8 h; And / or, in step S4, the oil-soluble dispersant includes at least one of a Span series compound, a Tween series compound, and a modified cellulose series compound; The oil-soluble solvent includes at least one of a liquid alkane solvent series compound and an organic solvent; The mass proportion of the oil-soluble dispersant in the emulsified cross-linked oil phase is 0.5% to 8%; and / or, in step S5, the aqueous solution of the sulfonic acid group-modified PVA is 2.5% to 10%; The amount of the 2,3-diiodosuccinaldehyde aqueous solution added is 0.25 to 1 mL; And / or, in step S6, the emulsification cross-linking reaction temperature is 20-60° C., and the reaction time is 1-5 hours.

8. The method for preparing the developing embolic microspheres according to claim 4, characterized in that: It includes the following steps: The first monomer and the second monomer are subjected to suspension polymerization to obtain a copolymer, wherein the structural formula of the first monomer is The structural formula of the second monomer is R4 and R5 are respectively C1-6 alkyl chains; hydrolyzing the copolymer under the action of a base to obtain a water-soluble copolymer; The water-soluble copolymer and 2,3-diiodosuccinaldehyde are emulsified and cross-linked to obtain the developing embolic microspheres.

9. The method for preparing the developing embolic microspheres according to claim 8, characterized in that: It includes the following steps: S1, mixing the first monomer and the second monomer and adding an initiator to prepare an oil phase, adding a suspension polymerization dispersant to water to prepare an aqueous phase, slowly dropping the oil phase into the aqueous phase at a certain temperature for a certain period of time to obtain a copolymer; S2, adding the copolymer and NaOH into a solvent, and performing a hydrolysis reaction at a certain temperature for a certain time to obtain a water-soluble copolymer; S3, adding the oil-soluble dispersant to the oil-soluble solvent, stirring and dissolving to form an emulsified cross-linked oil phase; S4, dissolving the water-soluble copolymer in water to prepare an aqueous solution, then adding 2,3-diiodosuccinic dialdehyde aqueous solution, and stirring evenly to form an emulsified cross-linked aqueous phase; S5. Mix the emulsified cross-linked oil phase and the emulsified cross-linked water phase, add hydrochloric acid to catalyze the reaction, continue stirring the reaction for a certain period of time to cross-link the water-soluble copolymer with 2,3-diiodosuccinaldehyde, let stand until the reaction system is stratified, separate the oil phase, collect the microspheres and repeatedly wash them to obtain the developed embolic microspheres.

10. The method for preparing the developing embolic microspheres according to claim 9, characterized in that: In step S1, the molar ratio of the first monomer to the second monomer is 1:1 to 1:6; The first monomer includes at least one of vinyl formate, vinyl acetate, vinyl propionate, vinyl butyrate, and vinyl valerate; The second monomer comprises at least one of methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, and butyl methacrylate; The initiator comprises at least one of benzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, tert-butyl perbenzoate, and dimethyl azobisisobutyrate; The amount of the initiator added is 0.1 to 1.5% of the total weight of the monomers; The suspension polymer dispersant includes at least one of polyvinyl alcohol, gelatin, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and ethyl hydroxyethyl cellulose; The suspension polymerization reaction temperature is 60-80°C and the reaction time is 6-12h; and / or, in step S2, the molar ratio of the copolymer to NaOH is 1:3 to 1:5; The solvent of the hydrolysis reaction includes deionized water, a mixed solvent with a volume ratio of methanol to deionized water of 1:1 to 1:5, and a mixed solvent with a volume ratio of ethanol to deionized water of 1:1 to 1:5; The temperature of the hydrolysis reaction is 60-80°C and the reaction time is 4-12h; and / or, in step S3, the mass proportion of the oil-soluble dispersant in the emulsified cross-linked oil phase is 0.5% to 8%; and / or, in step S4, the concentration of the aqueous solution of the water-soluble copolymer is 2.5% to 10%; The amount of the 2,3-diiodosuccinaldehyde aqueous solution added is 0.25 to 1.0 mL; And / or, in step S5, the emulsification cross-linking reaction temperature is 20-60° C., and the reaction time is 1-5 hours.

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