Embolic microspheres and methods of making and using the same

Abstract

The application provides an embolization microsphere and a preparation method and application thereof, and belongs to the technical field of embolization agent manufacturing. The embolization microsphere is cross-linked and polymerized, and raw materials of the embolization microsphere include inositol and glycidyl ether. The embolization microsphere has the advantages of high drug loading capacity, and is also beneficial to the loading of molecules with rigid structures, large steric hindrance and low flexibility (such as aromatic ring structures).

Description

Technical Field

[0001] This application relates to the field of embolic agent manufacturing technology, and more specifically, to an embolic microsphere, its preparation method, and its application. Background Technology

[0002] Drug-loaded embolized microspheres are the latest type of embolization agent. While embolizing tumor blood supply, they can also deliver higher doses of chemotherapy drugs locally, offering advantages such as lower systemic toxicity and sustained local activity. Compared to traditional iodized oil-based regimens, the use of drug-loaded embolized microspheres significantly reduces the amount of chemotherapy drugs reaching systemic circulation, thus significantly reducing drug-related adverse events.

[0003] Chemotherapy drugs such as 5-fluorouracil are cell cycle drugs. Ideal drug-loaded embolized microspheres need to have a large drug loading capacity, a fast drug loading rate, a small burst release of the drug, and a long sustained release time to prolong the contact time between the tumor drug and the tumor and achieve better therapeutic effects.

[0004] In the existing technology, most of the embolization microspheres on the market are mainly network structures, which have the disadvantage of small drug loading space, and correspondingly, their drug loading capacity is small. At the same time, the structure of this type of embolization microsphere is not conducive to loading molecules with rigid structure, large steric hindrance and low flexibility (such as aromatic ring structure). Summary of the Invention

[0005] The purpose of this application is to provide an embolization microsphere, its preparation method and application, which can improve the drug loading capacity of the embolization microsphere and facilitate the loading of molecules with rigid structure, large steric hindrance and low flexibility (such as aromatic ring structure).

[0006] The embodiments of this application are implemented as follows:

[0007] In one aspect, embodiments of this application provide an embolization microsphere, which is formed by cross-linking polymerization, and the raw materials of the embolization microsphere include inositol and glycidyl ether.

[0008] In the above technical solution, the structural framework of the embolization microspheres contains inositol. The polyhydroxy structure of inositol enables the corresponding embolization microspheres to form a hollow cage structure. Compared with the network structure of embolization microspheres, the hollow cage structure of embolization microspheres has a larger drug loading space, thus having the advantage of a larger drug loading capacity. At the same time, it is also beneficial for loading molecules with rigid structures, large steric hindrance, and low flexibility (such as aromatic ring structures).

[0009] In some alternative embodiments, the glycidyl ether is a glycidyl ether with an alkylene oxide terminal group; optionally, the glycidyl ether includes at least one of ethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, glycerol triglycidyl ether, and pentaerythritol glycidyl ether.

[0010] In the above technical solution, glycidyl ether with propylene oxide end groups is used, and its types are further limited, which has the advantage of high crosslinking efficiency.

[0011] In some alternative embodiments, inositol has a sulfonic acid group; optionally, the sulfonic acid group is obtained by bonding at least one of 1,4-butyrosulactone, 1,3-propanesulfonate, or sodium 2-chloroethylsulfonate to a hydroxyl group on inositol.

[0012] In the above technical solution, inositol with sulfonic acid groups is used, which makes it easier for the prepared embolization microspheres to bind with drugs, thereby helping to increase their drug loading capacity.

[0013] In some alternative implementations, the embolic microspheres have the structural formulas shown in Formula I, Formula II, or Formula III:

[0014]

[0015] In Equations I to III, k, m, and n are each independently selected from integers greater than or equal to 2.

[0016] In the above technical solution, setting the structure of the embolization microspheres to the specific form mentioned above has the advantage of a larger drug loading capacity. At the same time, it is also more conducive to loading molecules with rigid structures, large steric hindrance, and low flexibility (such as aromatic ring structures).

[0017] Secondly, embodiments of this application provide a method for preparing embolic microspheres, comprising the following steps:

[0018] A catalyst, a water-soluble monomer, and a modifier are added to water and reacted under heating and stirring conditions to obtain a modified solution, wherein the water-soluble monomer is inositol; while maintaining stirring and heating, a crosslinking agent is added to the modified solution and mixed to obtain an aqueous solution.

[0019] Under stirring, the aqueous phase solution is added to the oil phase solution to obtain a water-in-oil reverse suspension polymerization system. Then, while maintaining stirring, the water-in-oil reverse suspension polymerization system is heated, purified, and collected sequentially to obtain embolization microspheres.

[0020] Optionally, the modifier is a compound with a sulfonic acid group.

[0021] Optionally, the crosslinking agent is a glycidyl ether with an alkylene oxide terminal group.

[0022] Following the above process, a hollow cage-like structure of embolic microspheres can be prepared. Specifically, the modifier can be branched onto the side chains of inositol under the action of a catalyst to modify inositol. Further, after forming a water-in-oil reverse suspension polymerization system, under stirring and heating conditions, some of the crosslinking agent in the water-in-oil reverse suspension polymerization system polymerizes with the modified inositol to form chain fragments under the action of a catalyst. The remaining crosslinking agent then crosslinks with the formed chain fragments, thereby preparing embolic microspheres with a hollow cage-like structure. Compared with existing preparation processes (which typically produce network-structured embolic microspheres), the hollow cage-like structure of embolic microspheres prepared in this application has a larger drug loading space, and correspondingly, a larger drug loading capacity.

[0023] Furthermore, by setting the modifier to a compound with a sulfonic acid group, the prepared embolic microspheres can more easily bind to the drug, thereby helping to increase the drug loading capacity; at the same time, by setting the crosslinking agent to a glycidyl ether with an end group of glycidyl oxide, it has the advantage of high crosslinking efficiency.

[0024] In some alternative embodiments, the preparation method satisfies at least one of the following conditions A to C:

[0025] Modifier A includes at least one of 1,3-propanesulfonate lactone, 1,4-butanesulfonate lactone, and sodium 2-chloroethylsulfonate.

[0026] B. Crosslinking agent includes at least one of ethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, glycerol triglycidyl ether, and pentaerythritol diglycidyl ether.

[0027] The C catalyst includes at least one of potassium hydroxide and sodium hydroxide.

[0028] In the above technical solutions, the types of modifiers, crosslinking agents and catalysts are limited to specific ranges, which can better give play to the functions of the corresponding components.

[0029] In some alternative implementations, the aqueous solution satisfies at least one of the following conditions D to G:

[0030] The amount of D-inositol added is 5-40% of the mass of the aqueous solution.

[0031] E is based on the molar amount of inositol added, and the molar percentage of the modifier is 25-200%.

[0032] Based on the molar amount of inositol added, the molar percentage of the crosslinking agent is 50-300%.

[0033] The amount of catalyst G added is 5-25% of the mass of the aqueous solution.

[0034] In the above technical solution, the amounts of inositol, modifier, crosslinking agent and catalyst in the aqueous solution are limited to specific ranges so that each functional component has a suitable amount, thereby enabling the preparation of hollow cage-like embolization microspheres with high conversion rate and yield.

[0035] In some alternative implementations, during the sequential heating reaction of the water-in-oil reverse suspension polymerization system, the reaction temperature is 40–100°C and the reaction time is 5–30 h.

[0036] In the above technical solution, the temperature and duration of the heating reaction are limited to specific ranges so that the crosslinking reaction can be carried out under more suitable conditions, thereby helping to improve the crosslinking efficiency.

[0037] In some alternative implementations, the reaction temperature is 60–100°C and the reaction time is 12–20 h.

[0038] In the above technical solution, the temperature and duration of the heating reaction are further limited to a more preferred range so that the crosslinking reaction is carried out under more suitable conditions, thereby helping to further improve the crosslinking efficiency.

[0039] Thirdly, the application of embolic microspheres as provided in the first aspect embodiment or embolic microspheres prepared by the preparation method provided in the second aspect embodiment in the preparation of embolic agents. Attached Figure Description

[0040] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0041] Figure 1 The drug loading performance test results of 5-fluorouracil corresponding to different embolization microspheres provided in the embodiments of this application;

[0042] Figure 2 The test results of the drug loading performance of acetylsalicylic acid for different embolization microspheres provided in the embodiments of this application;

[0043] Figure 3 The test results of the drug loading performance of topotecan for different embolization microspheres provided in the embodiments of this application;

[0044] Figure 4The results of drug release performance tests of 5-fluorouracil corresponding to different embolization microspheres provided in the embodiments of this application;

[0045] Figure 5 The results of drug release performance tests for acetylsalicylic acid corresponding to different embolization microspheres provided in the embodiments of this application;

[0046] Figure 6 The results of drug release performance tests of topotecan for different embolic microspheres provided in the embodiments of this application are shown. Detailed Implementation

[0047] 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.

[0048] It should be noted that the terms "and / or" in this application, such as "feature 1 and / or feature 2", all refer to the three cases of "feature 1" alone, "feature 2" alone, and "feature 1" plus "feature 2".

[0049] In addition, in the description of this application, unless otherwise stated, "one or more" means two or more; the range of "numerical value a to numerical value b" includes the two endpoints "a" and "b"; and "unit of measurement" in "numerical value a to numerical value b + unit of measurement" represents the "unit of measurement" of both "numerical value a" and "numerical value b".

[0050] The following is a detailed description of an embolic microsphere, its preparation method, and its application according to an embodiment of this application.

[0051] In one aspect, embodiments of this application provide an embolization microsphere, which is formed by cross-linking polymerization, and the raw materials of the embolization microsphere include inositol and glycidyl ether.

[0052] In this application, the structural framework of the embolization microspheres contains inositol. The polyhydroxy structure of inositol enables the corresponding embolization microspheres to form a hollow cage-like structure. Compared with the network structure of embolization microspheres, the hollow cage-like structure of embolization microspheres has a larger drug loading space, thus having the advantage of a larger drug loading capacity. At the same time, it is also beneficial for loading molecules with rigid structures, large steric hindrance, and low flexibility (such as aromatic ring structures).

[0053] As an example, glycidyl ethers are glycidyl ethers with an alkylene oxide terminal group.

[0054] As an example, glycidyl ethers include at least one of ethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, glycerol triglycidyl ether, and pentaerythritol glycidyl ether.

[0055] In this embodiment, glycidyl ethers with propylene oxide end groups are used, and their types are further limited, which has the advantage of high crosslinking efficiency.

[0056] As an example, inositol has a sulfonic acid group.

[0057] As an example, the sulfonic acid group is obtained by bonding at least one of 1,4-butyrosulactone, 1,3-propanesulfonate, or sodium 2-chloroethylsulfonate to a hydroxyl group on inositol.

[0058] In this embodiment, inositol with sulfonic acid groups is used, which makes it easier for the prepared embolic microspheres to bind with drugs, thereby helping to increase their drug loading capacity.

[0059] As an example, the structural formula of the embolization microsphere is shown in Formula I, Formula II, or Formula III:

[0060]

[0061]

[0062] In Equations I to III, k, m, and n are each independently selected from integers greater than or equal to 2.

[0063] In this embodiment, setting the structure of the embolization microspheres to the specific form described above has the advantage of a larger drug loading capacity. At the same time, it is also more conducive to loading molecules with rigid structures, large steric hindrance, and low flexibility (such as aromatic ring structures).

[0064] Secondly, embodiments of this application provide a method for preparing embolic microspheres, comprising the following steps:

[0065] A catalyst, a water-soluble monomer, and a modifier were added to water and reacted under heating and stirring conditions to obtain a modified solution, wherein the water-soluble monomer was inositol. While maintaining stirring and heating, a crosslinking agent was added to the modified solution and mixed to obtain an aqueous solution. While stirring, the aqueous solution was added to the oil solution to obtain a water-in-oil reverse suspension polymerization system. Then, while maintaining stirring, the water-in-oil reverse suspension polymerization system was sequentially heated, purified, and collected to obtain embolic microspheres.

[0066] In this application, the above-described process yields embolic microspheres with a hollow cage-like structure. Specifically, the modifier, under the action of a catalyst, can be branched onto the side chains of inositol to modify it. Further, after forming a water-in-oil reverse suspension polymerization system, under stirring and heating conditions, the crosslinking agent in the system undergoes epoxy ring-opening under the action of a catalyst, and then crosslinks with the modified inositol to form embolic microspheres with a hollow cage-like structure. Compared to existing preparation processes (which typically produce embolic microspheres with a network structure), the hollow cage-like structure embolic microspheres prepared in this application have a larger drug-carrying space, and correspondingly, a larger drug loading capacity.

[0067] It is understandable that since the technology of preparing water-in-oil reverse suspension polymerization system by means of aqueous and oil phase solutions, and then using crosslinking agents to prepare embolic microspheres, is a known technology, the corresponding process and steps can be carried out in accordance with the conventional steps in the corresponding field. The embodiments of this application only need to adjust the corresponding process parameters.

[0068] As an example, the process of adding a catalyst, a water-soluble monomer, and a modifier to water and reacting them under heating and stirring conditions to obtain a modified solution includes:

[0069] The catalyst was added to water and mixed to obtain an alkaline aqueous solution; then, the water-soluble monomer and the modifier were added to the alkaline aqueous solution in sequence and reacted under heating and stirring conditions to obtain a modified solution.

[0070] As an example, during the reaction in which water-soluble monomers and modifiers are sequentially added to an alkaline aqueous solution and subjected to heating and stirring, the processing temperature is 50–100°C, for example, but not limited to any one of 50°C, 60°C, 70°C, 80°C, 90°C, and 100°C, or any range between two of these temperatures; the reaction time is 1–180 min, for example, but not limited to any one of 1 min, 5 min, 10 min, 25 min, 50 min, 75 min, 100 min, 120 min, 140 min, 160 min, and 180 min, or any range between two of these times.

[0071] As an example, while maintaining stirring and heating, the crosslinking agent is added to the modified aqueous solution for mixing to obtain an aqueous solution. The stirring and mixing time is 1 to 90 minutes, for example, but not limited to any one of 1 minute, 5 minutes, 10 minutes, 25 minutes, 50 minutes, 70 minutes and 90 minutes or any range between two of them.

[0072] As an example, an oil phase solution includes an oil-soluble dispersant and an oily solvent.

[0073] It is understandable that the homogeneity of the oil phase solution is related to the mass ratio and type of oil-soluble dispersant in it. Therefore, considering the homogeneity of the oil phase solution, the mass and type of oil-soluble dispersant in it can be limited.

[0074] As an example, in the oil phase solution, the mass percentage of the oil-soluble dispersant is 0.5% to 5%, for example, but not limited to any one of 0.5%, 1%, 2%, 3%, 4% and 5% or any range between two.

[0075] As an example, oil-soluble dispersants include mixtures of Tween and Span compounds, specifically, Tween 20 and Span 80.

[0076] As an example, in oil-soluble dispersants, the mass ratio of Tween 20 to Span 80 is (1-5):10.

[0077] As an example, the modifier is a compound with a sulfonic acid group, and the crosslinking agent is a glycidyl ether with an alkylene oxide end group.

[0078] In this embodiment, the modifier is set as a compound with sulfonic acid groups, which makes it easier for the prepared embolic microspheres to bind with drugs, thereby helping to increase the drug loading capacity; at the same time, the crosslinking agent is set as glycidyl ether with glycidyl oxide end groups, which has the advantage of high crosslinking efficiency.

[0079] As an example, the preparation method satisfies at least one of the following conditions A to C:

[0080] Modifier A includes at least one of 1,3-propanesulfonate lactone, 1,4-butanesulfonate lactone, and sodium 2-chloroethylsulfonate.

[0081] B. Crosslinking agent includes at least one of ethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, glycerol triglycidyl ether, and pentaerythritol diglycidyl ether.

[0082] The C catalyst includes at least one of potassium hydroxide and sodium hydroxide.

[0083] In this embodiment, the types of modifiers, crosslinking agents, and catalysts are limited to specific ranges, which can better leverage the functions of the corresponding components.

[0084] As an example, in an aqueous solution, at least one of the following conditions D to G is satisfied:

[0085] The amount of D-inositol added is 5% to 40% of the mass of the aqueous solution, for example, but not limited to any one of 5%, 10%, 20%, 30% and 40% or any range between two.

[0086] E is based on the molar amount of inositol added, and the molar percentage of the modifier is 25% to 200%, for example, but not limited to any one of the molar percentages of 25%, 50%, 100%, 150% and 200% or any range between two.

[0087] F is based on the molar amount of inositol added, and the molar percentage of the crosslinking agent is 50% to 300%, for example, but not limited to any one of the molar percentages of 50%, 100%, 150%, 200%, 250% and 300%, or any range between two.

[0088] The amount of catalyst G added is 5 to 25% of the mass of the aqueous solution, for example, but not limited to any one of 5%, 10%, 15%, 20% and 25% or any range between two.

[0089] It should be noted that since the reaction involving the modifier grafting onto the inositol side chain only occurs in the aqueous solution, and no gas or precipitate is generated in the entire system, the mass of the entire aqueous solution remains constant. Therefore, the amount of each component can be expressed directly by limiting the percentage of the mass of the corresponding component in the aqueous solution.

[0090] In this embodiment, the amounts of inositol, modifier, crosslinking agent and catalyst in the aqueous solution are limited to specific ranges so that each functional component has a suitable amount, thereby enabling the preparation of hollow cage-like embolization microspheres with high conversion rate and yield.

[0091] As an example, during the sequential heating reaction of the water-in-oil reverse suspension polymerization system, the reaction temperature is 40–100°C, for example, but not limited to any one of 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, and 100°C, or any range between any two; the reaction time is 5–30 h, for example, but not limited to any one of 5 h, 10 h, 15 h, 20 h, 25 h, and 30 h, or any range between any two.

[0092] In this embodiment, the temperature and duration of the heating reaction are limited to specific ranges so that the crosslinking reaction can be carried out under more suitable conditions, thereby helping to improve the crosslinking efficiency.

[0093] As an example, the reaction temperature is 60–100°C, for example, but not limited to any one of 60°C, 70°C, 80°C, 90°C, and 100°C, or any range between any two; the reaction time is 12–20 h, for example, but not limited to any one of 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, and 20 h, or any range between any two.

[0094] In this embodiment, the temperature and duration of the heating reaction are further limited to more preferred ranges so that the crosslinking reaction is carried out under more suitable conditions, thereby helping to further improve the crosslinking efficiency.

[0095] As an example, while maintaining stirring, the oil-in-water reverse suspension polymerization system is heated and reacted sequentially, with the stirring speed being 200 to 700 rpm, for example, but not limited to any one of 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm, and 700 rpm, or any range between two of them.

[0096] It should be noted that any processes or steps not specifically described or limited during preparation can be set according to conventional methods in the field.

[0097] It should be noted that the preparation of the aqueous phase solution and the oil phase solution can be carried out simultaneously, or one can be prepared first and then the other.

[0098] Thirdly, the application of embolic microspheres as provided in the first aspect embodiment or embolic microspheres prepared by the preparation method provided in the second aspect embodiment in the preparation of embolic agents.

[0099] It should be noted that the specific type of embolic agent is not limited, that is, the specific type of drug loaded is not limited, and can be set according to the conventional selection in this field.

[0100] The features and performance of this application will be further described in detail below with reference to the embodiments.

[0101] Example 1

[0102] This application provides a method for preparing embolic microspheres, comprising the following steps:

[0103] Preparation of the aqueous solution: NaOH was added to water and mixed to obtain an alkaline aqueous solution; then, inositol and 1,4-butyryl lactone were added to the alkaline aqueous solution in sequence and reacted under heating and stirring conditions to obtain a modified solution, wherein the treatment temperature was 60℃ and the reaction time was 90 min; while maintaining stirring and heating, ethylene glycol diglycidyl ether was added to the modified aqueous solution and mixed to obtain an aqueous solution, wherein the stirring and mixing time was 15 min.

[0104] Specifically, in the aqueous solution, the amount of inositol added accounts for 8.2% of the mass of the aqueous solution, the molar percentage of 1,4-butyryl lactone is 200% based on the molar amount of inositol added, the molar percentage of ethylene glycol diglycidyl ether is 150% based on the molar amount of inositol added, and the amount of catalyst added accounts for 16.5% of the mass of the aqueous solution.

[0105] Preparation of oil phase solution: Tween 20 and Span 80, used as oil-soluble dispersants, are added to liquid paraffin at a mass ratio of 3:10 and stirred to obtain an oil phase solution, wherein the mass percentage of oil-soluble dispersants in the oil phase solution is 4%.

[0106] Under stirring, the aqueous phase solution was added dropwise to the oil phase solution to obtain a water-in-oil reverse suspension polymerization system. Then, while maintaining stirring, the water-in-oil reverse suspension polymerization system was sequentially heated, purified, and collected to obtain embolic microspheres. During the sequential heating and reaction of the water-in-oil reverse suspension polymerization system while maintaining stirring, the stirring speed was 300 rpm, the reaction temperature was 80℃, and the reaction time was 18 h. The purification and collection process to obtain embolic microspheres included stopping stirring and heating after the reaction, allowing the mixture to stand and separate into layers, separating the oil phase, collecting the microspheres, and washing and sieving them to obtain embolic microspheres with different particle size distributions.

[0107] To better understand the technical solution, specific reaction equations are provided here for further explanation:

[0108]

[0109] As can be seen from the above reaction equation, under alkaline conditions, 1,4-butyrosulactone undergoes sulfonate ring-opening and reacts with the hydroxyl groups on inositol, introducing sulfonic acid groups onto inositol; then, in a water-in-oil reverse suspension polymerization system, ethylene glycol diglycidyl ether undergoes epoxy ring-opening under the action of an alkaline catalyst, and then undergoes cross-linking polymerization with the modified inositol to form embolic microspheres.

[0110] To better understand the technical solution, this application provides an approximate skeleton for illustrative purposes, and the skeletons of subsequent embodiments can all refer to Embodiment 1:

[0111]

[0112]

[0113] As can be seen from the above skeletal structure, the skeletal framework of the embolization microspheres is similar to a hollow cuboid, that is, similar to a hollow cage-like structure, and correspondingly, it has a large drug-carrying space.

[0114] Example 2

[0115] This application provides a method for preparing embolic microspheres, comprising the following steps:

[0116] Preparation of the aqueous solution: NaOH was added to water and mixed to obtain an alkaline aqueous solution; then, inositol and 1,4-butyryl lactone were added to the alkaline aqueous solution in sequence and reacted under heating and stirring conditions to obtain a modified solution, wherein the treatment temperature was 60℃ and the reaction time was 90 min; while maintaining stirring and heating, triethylene glycol diglycidyl ether was added to the modified aqueous solution and mixed to obtain an aqueous solution, wherein the stirring and mixing time was 15 min.

[0117] Specifically, in the aqueous solution, the amount of inositol added accounts for 7.7% of the mass of the aqueous solution. Based on the molar amount of inositol added, the molar percentage of 1,4-butyryl lactone is 100%. Based on the molar amount of inositol added, the molar percentage of triethylene glycol diglycidyl ether is 180%. The amount of catalyst added accounts for 15.4% of the mass of the aqueous solution.

[0118] Preparation of oil phase solution: Tween 20 and Span 80, used as oil-soluble dispersants, are added to liquid paraffin at a mass ratio of 3:10 and stirred to obtain an oil phase solution, wherein the mass percentage of oil-soluble dispersants in the oil phase solution is 3%.

[0119] Under stirring, the aqueous phase solution was added dropwise to the oil phase solution to obtain a water-in-oil reverse suspension polymerization system. Then, while maintaining stirring, the water-in-oil reverse suspension polymerization system was sequentially heated, purified, and collected to obtain embolic microspheres. During the sequential heating and reaction of the water-in-oil reverse suspension polymerization system while maintaining stirring, the stirring speed was 300 rpm, the reaction temperature was 80℃, and the reaction time was 18 h. The purification and collection process to obtain embolic microspheres included stopping stirring and heating after the reaction, allowing the mixture to stand and separate into layers, separating the oil phase, collecting the microspheres, and washing and sieving them to obtain embolic microspheres with different particle size distributions.

[0120] To better understand the technical solution, specific reaction equations are provided here for further explanation:

[0121]

[0122] Example 3

[0123] This application provides a method for preparing embolic microspheres, comprising the following steps:

[0124] Preparation of the aqueous solution: NaOH was added to water and mixed to obtain an alkaline aqueous solution; then, inositol and 1,4-butyryl lactone were added to the alkaline aqueous solution in sequence and reacted under heating and stirring conditions to obtain a modified solution, wherein the treatment temperature was 60℃ and the reaction time was 90 min; while maintaining stirring and heating, tetraethylene glycol diglycidyl ether was added to the modified aqueous solution and mixed to obtain an aqueous solution, wherein the stirring and mixing time was 15 min.

[0125] Specifically, in the aqueous solution, the amount of inositol added accounts for 5% of the mass of the aqueous solution, the molar percentage of 1,4-butyryl lactone is 100% based on the molar amount of inositol added, the molar percentage of tetraethylene glycol diglycidyl ether is 125% based on the molar amount of inositol added, and the amount of catalyst added accounts for 10% of the mass of the aqueous solution.

[0126] Preparation of oil phase solution: Tween 20 and Span 80, used as oil-soluble dispersants, are added to liquid paraffin at a mass ratio of 3:10 and stirred to obtain an oil phase solution, wherein the mass percentage of oil-soluble dispersants in the oil phase solution is 3%.

[0127] Under stirring, the aqueous phase solution was added dropwise to the oil phase solution to obtain a water-in-oil reverse suspension polymerization system. Then, while maintaining stirring, the water-in-oil reverse suspension polymerization system was sequentially heated, purified, and collected to obtain embolic microspheres. During the sequential heating and reaction of the water-in-oil reverse suspension polymerization system while maintaining stirring, the stirring speed was 300 rpm, the reaction temperature was 80℃, and the reaction time was 16 h. The purification and collection process to obtain embolic microspheres included stopping stirring and heating after the reaction, allowing the mixture to stand and separate into layers, separating the oil phase, collecting the microspheres, and washing and sieving them to obtain embolic microspheres with different particle size distributions.

[0128] To better understand the technical solution, specific reaction equations are provided here for further explanation:

[0129]

[0130] Example 4

[0131] This application provides a method for preparing embolic microspheres, comprising the following steps:

[0132] Preparation of the aqueous solution: NaOH was added to water and mixed to obtain an alkaline aqueous solution; then, inositol and 1,3-propanesulfonic acid lactone were added to the alkaline aqueous solution in sequence and reacted under heating and stirring conditions to obtain a modified solution, wherein the treatment temperature was 60℃ and the reaction time was 90 min; while maintaining stirring and heating, glycerol triglycidyl ether was added to the modified aqueous solution and mixed to obtain an aqueous solution, wherein the stirring and mixing time was 15 min.

[0133] Specifically, in the aqueous solution, the amount of inositol added accounts for 5.6% of the mass of the aqueous solution, the molar percentage of 1,3-propanesulfonic acid lactone is 150% based on the molar amount of inositol added, the molar percentage of glycerol triglycidyl ether is 120% based on the molar amount of inositol added, and the amount of catalyst added accounts for 10% of the mass of the aqueous solution.

[0134] Preparation of oil phase solution: Tween 20 and Span 80, used as oil-soluble dispersants, are added to liquid paraffin at a mass ratio of 3:10 and stirred to obtain an oil phase solution, wherein the mass percentage of oil-soluble dispersants in the oil phase solution is 3%.

[0135] Under stirring, the aqueous phase solution was added dropwise to the oil phase solution to obtain a water-in-oil reverse suspension polymerization system. Then, while maintaining stirring, the water-in-oil reverse suspension polymerization system was sequentially heated, purified, and collected to obtain embolic microspheres. During the sequential heating and reaction of the water-in-oil reverse suspension polymerization system while maintaining stirring, the stirring speed was 400 rpm, the reaction temperature was 60℃, and the reaction time was 16 h. The purification and collection process to obtain embolic microspheres included stopping stirring and heating after the reaction, allowing the mixture to stand and separate into layers, separating the oil phase, collecting the microspheres, and washing and sieving them to obtain embolic microspheres with different particle size distributions.

[0136] To better understand the technical solution, specific reaction equations are provided here for further explanation:

[0137]

[0138] Example 5

[0139] This application provides a method for preparing embolic microspheres, comprising the following steps:

[0140] Preparation of the aqueous solution: NaOH was added to water and mixed to obtain an alkaline aqueous solution; then, inositol and sodium 2-chloroethylsulfonate were added to the alkaline aqueous solution in sequence and reacted under heating and stirring conditions to obtain a modified solution, wherein the treatment temperature was 60℃ and the reaction time was 90min; while maintaining stirring and heating, pentaerythritol glycidyl ether was added to the modified aqueous solution and mixed to obtain an aqueous solution, wherein the stirring and mixing time was 15min.

[0141] Specifically, in the aqueous solution, the amount of inositol added accounts for 10.1% of the mass of the aqueous solution, the molar percentage of sodium 2-chloroethylsulfonate is 200% based on the molar amount of inositol added, the molar percentage of pentaerythritol glycidyl ether is 80% based on the molar amount of inositol added, and the amount of catalyst added accounts for 20.2% of the mass of the aqueous solution.

[0142] Preparation of oil phase solution: Tween 20 and Span 80, used as oil-soluble dispersants, are added to liquid paraffin at a mass ratio of 3:10 and stirred to obtain an oil phase solution, wherein the mass percentage of the oil-soluble dispersant in the oil phase solution is 5%.

[0143] Under stirring, the aqueous phase solution was added dropwise to the oil phase solution to obtain a water-in-oil reverse suspension polymerization system. Then, while maintaining stirring, the water-in-oil reverse suspension polymerization system was sequentially heated, purified, and collected to obtain embolic microspheres. During the sequential heating and reaction of the water-in-oil reverse suspension polymerization system while maintaining stirring, the stirring speed was 300 rpm, the reaction temperature was 80℃, and the reaction time was 12 h. The purification and collection process to obtain embolic microspheres included stopping stirring and heating after the reaction, allowing the mixture to stand and separate into layers, separating the oil phase, collecting the microspheres, and washing and sieving them to obtain embolic microspheres with different particle size distributions.

[0144] To better understand the technical solution, specific reaction equations are provided here for further explanation:

[0145]

[0146]

[0147] Comparative Example 1

[0148] The comparative example in this application uses Hepasphere embolization microspheres (Merriton Medical Devices (Beijing) Co., Ltd.).

[0149] Experimental Example 1

[0150] Drug loading performance testing of embolization microspheres

[0151] The testing method is as follows:

[0152] Three groups (1 mL each) of embolic microspheres prepared in Examples 1-5 and Comparative Example 1 were taken and numbered. The surface moisture of the microspheres was removed with filter paper. The microspheres were transferred into vials, and 2 mL of 5-fluorouracil solution (20 mg / mL), acetylsalicylic acid solution (10 mg / mL), and topotecan solution (15 mg / mL) were added respectively. The mixture was shaken and the solution concentration was tested at 5 min, 30 min, and 60 min respectively. The drug loading rate of the embolic microspheres was calculated and drug loading curves of each drug corresponding to Examples 1-5 and Comparative Example 1 were plotted.

[0153] Table 1. Statistical Table of Drug Loading Rate Test Results

[0154]

[0155]

[0156] See Table 1 and Figures 1-3 As can be seen from the test results of Examples 1-5 and Comparative Example 1, the hollow cage-like embolization microspheres prepared in this application have a larger drug loading capacity for different drugs compared with the network-like embolization microspheres prepared by conventional processes. In addition, as can be seen from the test results of Examples 1-5, with the increase of crosslinking agent molecular chain segments, the size of the cavity formed by the corresponding embolization microsphere is larger, and it exhibits better drug loading performance.

[0157] Experimental Example 2

[0158] Drug release performance test of embolization microspheres

[0159] The testing method is as follows:

[0160] The drug-loaded microspheres were added to a dialysis bag, which was then placed in a beaker. Physiological saline (20 mL) was added to the beaker, and the bag was sealed. Samples were taken every 5 min, 30 min, and 60 min to determine the drug concentration in the dialysis bag solution. The cumulative release of the drug-loaded embolized microspheres was calculated, and drug release curves for each drug corresponding to Examples 1-5 and Comparative Example 1 were plotted.

[0161] Table 2 Statistical table of drug release rate test results

[0162]

[0163] See Table 2 and Figures 4-6As can be seen from the test results of Examples 1-5 and Comparative Example 1, the hollow cage-like embolization microspheres prepared in the examples of this application have better drug release performance for different drugs compared with the network-like embolization microspheres prepared by conventional processes. In addition, as can be seen from the test results of Examples 1-5, with the increase of crosslinking agent molecular chain segments, the structure of the corresponding embolization microspheres is more porous, and they exhibit better drug release performance.

[0164] The embodiments described above are some, but not all, of the embodiments of this application. The detailed description of the embodiments of this application is not intended to limit the scope of the claimed application, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

Claims

1. An embolic microsphere, characterized in that, The embolization microspheres are formed by cross-linking polymerization, and the raw materials for the embolization microspheres include inositol and glycidyl ether with a functionality of not less than 2.

2. The embolic microspheres according to claim 1, characterized in that, The glycidyl ether includes at least one of ethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, glycerol triglycidyl ether, and pentaerythritol glycidyl ether.

3. The embolic microspheres according to claim 1, characterized in that, The inositol has a sulfonic acid group.

4. The embolic microspheres according to claim 3, characterized in that, The sulfonic acid group is obtained by bonding at least one of 1,4-butyrate lactone, 1,3-propanesulfonate lactone, or sodium 2-chloroethylsulfonate to a hydroxyl group on the inositol.

5. The embolic microspheres according to claim 1, characterized in that, The structural formula of the embolization microspheres is shown in Formula I, Formula II, or Formula III: Formula I; Formula II; Formula III; In Equations I to III, k, m, and n are each independently selected from integers greater than or equal to 2.

6. A method for preparing embolic microspheres, characterized in that, Includes the following steps: A catalyst, a water-soluble monomer, and a modifier are added to water and reacted under heating and stirring conditions to obtain a modified solution, wherein the water-soluble monomer is inositol; while maintaining stirring and heating, a crosslinking agent is added to the modified solution and mixed to obtain an aqueous solution. Under stirring, the aqueous solution is added to the oil phase solution to obtain a water-in-oil reverse suspension polymerization system. Then, while maintaining stirring, the water-in-oil reverse suspension polymerization system is sequentially heated, purified, and collected to obtain embolization microspheres. The modifier is a compound containing a sulfonic acid group; The crosslinking agent is a glycidyl ether with a functionality of not less than 2.

7. The preparation method according to claim 6, characterized in that, The preparation method satisfies at least one of the following conditions A to C: The modifier A includes at least one of 1,3-propanesulfonate lactone, 1,4-butanesulfonate lactone, and sodium 2-chloroethylsulfonate. B. The crosslinking agent includes at least one of ethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, glycerol triglycidyl ether, and pentaerythritol diglycidyl ether; C. The catalyst includes at least one of potassium hydroxide and sodium hydroxide.

8. The preparation method according to claim 6, characterized in that, In the aqueous solution, at least one of the following conditions D to G is satisfied: D. The amount of inositol added is 5-40% of the mass of the aqueous solution; Based on the molar amount of inositol added, the molar percentage of the modifier is 25-200%; Based on the molar amount of inositol added, the molar percentage of the crosslinking agent is 50-300%; G. The amount of catalyst added is 5-25% of the mass of the aqueous solution.

9. The preparation method according to any one of claims 6 to 8, characterized in that, During the process of heating, purifying, and collecting the water-in-oil reverse suspension polymerization system, the reaction temperature is 40~100℃ and the reaction time is 5~30 h.

10. The preparation method according to claim 9, characterized in that, The reaction temperature is 60~100℃, and the reaction time is 12~20 h.

11. The use of an embolic microsphere as described in any one of claims 1 to 5 or an embolic microsphere prepared by any one of claims 6 to 10 in the preparation of an embolic agent.

Images