Embolic microspheres and methods of making and using the same

Abstract

The application provides an embolization microsphere, a preparation method and application thereof, and belongs to the technical field of embolization agent manufacturing. A structural formula of the embolization microsphere is shown in formula I: in formula I, m is an integer selected from any one of 1-8; n is an integer selected from any one of 1-6; k and l are each independently selected from integers greater than or equal to 2; R 1 is selected from H or an alkyl group; R 2 is selected from an alkyl group with a carboxylate or sulfonate; and j is an integer selected from any one of 1-8. Through the embolization microsphere, the strength and elasticity of the embolization microsphere can be improved to improve its tolerance to irradiation sterilization, and meanwhile, effective loading of various types of drugs can be achieved.

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] In the current technology, the embolization microspheres on the market are mainly constructed using polyvinyl alcohol as the main material. This type of embolization microsphere has problems with poor strength and elasticity. In particular, after irradiation sterilization, the particle size, strength and elasticity of the corresponding microspheres will change significantly, which will affect their application and promotion. In addition, this type of embolization microsphere also has the disadvantage of limited drug loading types. It can usually only be used to effectively load anthracycline cationic drugs and it is difficult to effectively load other types of drugs. Summary of the Invention

[0003] The purpose of this application is to provide an embolization microsphere, its preparation method and application, which can improve the strength and elasticity of the embolization microsphere to enhance its resistance to radiation sterilization, and at the same time, can achieve effective loading of various types of drugs.

[0004] The embodiments of this application are implemented as follows:

[0005] In a first aspect, embodiments of this application provide an embolization microsphere, the structural formula of which is shown in Formula I:

[0006]

[0007] In formula I, m is selected from any integer from 1 to 8; n is selected from any integer from 1 to 6; k and l are each independently selected from integers greater than or equal to 2; R 1 Selected from H or alkyl; R 2 Selected from alkyl groups containing carboxylates or sulfonates; j is an integer selected from any one of 1 to 8.

[0008] In the above technical solution, the embolization microspheres contain amide bonds in their structural framework. With the help of the unique physicochemical properties of amide bonds, the framework of the embolization microspheres can have good strength and elasticity, thereby improving their tolerance to radiation sterilization. At the same time, compared with conventional embolization microspheres (i.e., embolization microspheres with polyvinyl alcohol framework), the embolization microspheres with a specific framework provided in this application embodiment can also achieve effective loading of various types of drugs.

[0009] In some alternative implementations, m is selected from any integer from 1 to 4; n is selected from any integer from 1 to 3.

[0010] In the above technical solution, the values ​​of m and n are limited to the range of 1 to 4 and 1 to 3, respectively, so that the entire skeleton has a more suitable size and spatial steric hindrance, thereby making the structure of the entire embolization microsphere more stable.

[0011] In some alternative implementations, R 1 Selected from methyl.

[0012] In the above technical solution, R 1 By setting it to methyl, and taking advantage of its physicochemical properties of having only one carbon atom, the structure of the entire embolization microsphere can be made more stable.

[0013] In some alternative implementations, the embolic microspheres have a structural formula such as Formula II or Formula III:

[0014]

[0015] In equations II and III, m is selected from any integer from 1 to 8; n is selected from any integer from 1 to 6; k and l are each independently selected from integers greater than or equal to 2; R 1 Selected from H or alkyl; j is an integer selected from 1 to 8.

[0016] In the above technical solution, R 2 Setting specific types of functional groups helps drugs bind to embolic microspheres, thereby increasing drug loading.

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

[0018] S1. Preparation of aqueous solution of polymer monomer: The modifier and water-soluble monomer are slowly added to an alkaline aqueous solution and stirred and mixed. The reaction is carried out at room temperature and neutralized with acid after the reaction is completed to obtain a clear aqueous solution of polymer monomer; wherein, the modifier includes alkyl-substituted and / or unsubstituted N-aminoalkyl-2-methylacrylamide, and the water-soluble monomer includes glycidyl ether with an epoxy group at the end.

[0019] S2. Aqueous phase preparation: Ionic monomers and free radical initiators are added to an aqueous solution of polymer monomers and mixed to prepare an aqueous solution.

[0020] S3. Preparation of oil phase: Add 3-5% by mass of surfactant to oil phase solvent and mix to prepare oil phase solution; wherein, oil phase solvent includes at least one of butyl acetate, petroleum ether, n-hexane, cyclohexane or paraffin oil, and surfactant includes at least one of cellulose acetate butyrate, Tween, Span.

[0021] S4. Reverse suspension polymerization: The aqueous solution is slowly added to the oil solution and mixed and stirred to form a water-in-oil reverse suspension polymerization system. Then, tetramethylethylenediamine is added to the polymerization system and crosslinking reaction, purification and collection are carried out in sequence to obtain embolization microspheres.

[0022] Following the above process, embolic microspheres with good strength and elasticity can be prepared, enabling them to exhibit good resistance to radiation sterilization. Furthermore, the prepared embolic microspheres can effectively load various types of drugs. Specifically, the modifier, under the action of a catalyst, can be grafted onto the side chains of the water-soluble monomer to modify it. Further, after forming a water-in-oil reverse suspension polymerization system, the ionic monomers in the system crosslink with the modified water-soluble monomers under the action of a catalyst and initiator, thereby preparing embolic microspheres with amide bond structures in the compound skeleton.

[0023] In some alternative embodiments, the ionic monomer includes at least one of sodium acrylate, sodium methacrylate, and 2-acrylamido-2-methylpropanesulfonic acid; and / or the free radical initiator includes at least one of sodium persulfate, potassium persulfate, ammonium persulfate, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, azobisisobutylammonium valerate, and azobisisopropylimidazoline.

[0024] In the above technical solution, limiting the types of ionic monomers to a specific range makes it easier for the prepared embolization microspheres to bind with drugs, thereby helping to increase the drug loading capacity; at the same time, limiting the types of free radical initiators to a specific range enables the ionic monomers and the modified water-soluble monomers to have a high cross-linking efficiency.

[0025] In some alternative implementations, the preparation method satisfies condition A and / or condition B of the following:

[0026] Modifier A includes Among them, R 1 Selected from H or alkyl; n is an integer selected from 1 to 6.

[0027] Alternatively, the modifier may include at least one of N-(2-aminoethyl)-2-methylacrylamide, N-(3-aminopropyl)-2-methylacrylamide, and N-(4-aminobutyl)-2-methylacrylamide.

[0028] B. Water-soluble monomers include Where m is selected from any integer from 1 to 8.

[0029] Optionally, the water-soluble monomer includes at least one of ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, and tetraethylene glycol diglycidyl ether.

[0030] In the above technical solutions, the types of modifiers and water-soluble monomers are limited to specific ranges, which can better give play to the functions of the corresponding components.

[0031] In some alternative embodiments, the molar ratio of the amount of modifier added to the amount of water-soluble monomer added is 1:(0.8 to 1.2).

[0032] Optionally, the molar ratio of the amount of modifier added to the amount of water-soluble monomer added is 1:1.

[0033] In the above technical solution, limiting the molar ratio of the amount of modifier added to the amount of water-soluble monomer added to a specific range is beneficial to forming long-chain compounds with larger molecular weights, which in turn helps to form high-strength and high-elasticity embolization microspheres in the future.

[0034] Furthermore, by limiting the molar ratio of the modifier to the water-soluble monomer to a more preferred range, embolic microspheres with superior strength and elasticity can be formed.

[0035] In some alternative implementations, the reaction temperature is 50–90°C and the reaction time is not less than 3 hours during the crosslinking reaction.

[0036] In the above technical solution, the crosslinking reaction is carried out under relatively suitable conditions, which helps to improve the crosslinking efficiency.

[0037] 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

[0038] 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.

[0039] Figure 1 This is a photograph of the microspheres provided in Embodiment 1 of this application in a wet-bulb state;

[0040] Figure 2 This is a photograph of the microspheres provided in Embodiment 1 of this application in their dry ball state. Detailed Implementation

[0041] 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.

[0042] 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".

[0043] 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".

[0044] The following is a detailed description of an embolic microsphere, its preparation method, and its application according to an embodiment of this application.

[0045] In a first aspect, embodiments of this application provide an embolization microsphere, the structural formula of which is shown in Formula I:

[0046]

[0047] In formula I, m is selected from any integer from 1 to 8; n is selected from any integer from 1 to 6; K and I are each independently selected from integers greater than or equal to 2; R 1 Selected from H or alkyl; R 2 Selected from alkyl groups containing carboxylates or sulfonates; j is an integer selected from any one of 1 to 8.

[0048] In this application, the embolization microspheres contain amide bonds in their structural framework. The unique physicochemical properties of amide bonds enable the embolization microsphere framework to have good strength and elasticity, thereby improving its resistance to radiation sterilization. At the same time, compared with conventional embolization microspheres (i.e., embolization microspheres with polyvinyl alcohol frameworks), the embolization microspheres with specific frameworks provided in this application embodiment can also achieve effective loading of various types of drugs.

[0049] As an example, k and l are each independently selected from any one of the integers 2, 4, 6, 8, 10, 20, 50, 100, 500, 1000 and 5000, or any one of the two.

[0050] In this implementation, there are many possible values ​​for k and l, which makes it easy to make adaptive adjustments according to actual needs.

[0051] As an example, m is selected from any integer from 1 to 4, for example, any integer from 1, 2, 3 and 4; n is selected from any integer from 1 to 3, for example, any integer from 1, 2 and 3.

[0052] In this embodiment, the values ​​of m and n are limited to the ranges of 1 to 4 and 1 to 3, respectively, so that the entire skeleton has a more suitable size and spatial steric hindrance, thereby making the structure of the entire embolization microsphere more stable.

[0053] As an example, R 1 Selected from methyl.

[0054] In this embodiment, R 1 By setting it to methyl, and taking advantage of its physicochemical properties of having only one carbon atom, the structure of the entire embolization microsphere can be made more stable.

[0055] As an example, the structural formula of the embolization microsphere is as shown in Formula II or Formula III:

[0056]

[0057] In equations II and III, m is selected from any integer from 1 to 8; n is selected from any integer from 1 to 6; k and l are each independently selected from integers greater than or equal to 2; R 1 Selected from H or alkyl; j is an integer selected from 1 to 8.

[0058] In this embodiment, R 2 Setting specific types of functional groups helps drugs bind to embolic microspheres, thereby increasing drug loading.

[0059] As an example, the particle size of the embolization microspheres is 30–1400 μm, for example, but not limited to any point value or any range between 30 μm, 50 μm, 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 800 μm, 1000 μm, 1200 μm and 1400 μm.

[0060] In this embodiment, the particle size range of the embolization microspheres is relatively wide and can be adjusted according to actual needs.

[0061] Secondly, embodiments of this application provide a method for preparing embolic microspheres, comprising the following steps:

[0062] S1. Preparation of aqueous solution of polymer monomer: The modifier and water-soluble monomer are slowly added to an alkaline aqueous solution and stirred and mixed. The reaction is carried out at room temperature and neutralized with acid after the reaction is completed to obtain a clear aqueous solution of polymer monomer; wherein, the modifier includes alkyl-substituted and / or unsubstituted N-aminoalkyl-2-methylacrylamide, and the water-soluble monomer includes glycidyl ether with an epoxy group at the end.

[0063] S2. Aqueous phase preparation: Ionic monomers and free radical initiators are added to an aqueous solution of polymer monomers and mixed to prepare an aqueous solution.

[0064] S3. Preparation of oil phase: Add 3-5% by mass of surfactant to oil phase solvent and mix to prepare oil phase solution; wherein, oil phase solvent includes at least one of butyl acetate, petroleum ether, n-hexane, cyclohexane or paraffin oil, and surfactant includes at least one of cellulose acetate butyrate, Tween, Span.

[0065] S4. Reverse suspension polymerization: The aqueous solution is slowly added to the oil solution and mixed and stirred to form a water-in-oil reverse suspension polymerization system. Then, tetramethylethylenediamine is added to the polymerization system and crosslinking reaction, purification and collection are carried out in sequence to obtain embolization microspheres.

[0066] In this application, the above-described process yields embolic microspheres with good strength and elasticity, enabling them to exhibit good resistance to radiation sterilization. Furthermore, the prepared embolic microspheres can effectively load various types of drugs. Specifically, the modifier, under the action of a catalyst, can be grafted onto the side chains of the water-soluble monomer to modify it. Further, after forming a water-in-oil reverse suspension polymerization system, under stirring and heating conditions, the ionic monomers in the system crosslink with the modified water-soluble monomers under the action of a catalyst and initiator, thereby preparing embolic microspheres with an amide bond structure in the compound skeleton.

[0067] It should be noted that the type of alkaline aqueous solution in S1 is not limited. For example, it can be an aqueous solution of sodium hydroxide or potassium hydroxide. The mass percentage of alkaline substances in the aqueous solution is 5% to 10%, for example, but not limited to any one of 5%, 6%, 7%, 8%, 9% and 10% or any range between two.

[0068] It should be noted that, as is well known in the art, tetramethylethylenediamine is a common reaction aid when a free radical initiator is present in the reaction system, and its amount can be adjusted according to actual needs.

[0069] 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.

[0070] As an example, the ionic monomer includes at least one of sodium acrylate, sodium methacrylate, and 2-acrylamido-2-methylpropanesulfonic acid; and / or the free radical initiator includes at least one of sodium persulfate, potassium persulfate, ammonium persulfate, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, azobisisobutylammonium valerate, and azobisisopropylimidazoline.

[0071] In this embodiment, limiting the types of ionic monomers to a specific range makes it easier for the prepared embolic microspheres to bind with drugs, thereby helping to increase the drug loading capacity; at the same time, limiting the types of free radical initiators to a specific range enables the ionic monomers and the modified water-soluble monomers to have a high crosslinking efficiency.

[0072] As an example, the preparation method satisfies condition A and / or condition B in the following:

[0073] Modifier A includes Among them, R 1 Selected from H or alkyl; m is selected from any integer from 1 to 6.

[0074] As an example, the modifier includes at least one of N-(2-aminoethyl)-2-methylacrylamide, N-(3-aminopropyl)-2-methylacrylamide, and N-(4-aminobutyl)-2-methylacrylamide.

[0075] B. Water-soluble monomers include Where m is selected from any integer from 1 to 8.

[0076] As an example, the water-soluble monomer includes at least one of ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, and tetraethylene glycol diglycidyl ether.

[0077] In this embodiment, the types of modifiers and water-soluble monomers are limited to specific ranges, which can better give play to the functions of the corresponding components.

[0078] As an example, during the crosslinking reaction, the reaction temperature is 50–90°C, for example, but not limited to any one of 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, and 90°C, or any range between two of them; the reaction time is not less than 3 hours, for example, but not limited to any one of 3 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, and 20 hours, or any range between two of them.

[0079] In this embodiment, the crosslinking reaction is carried out under suitable conditions, which helps to improve the crosslinking efficiency.

[0080] It is understandable that the amount of each functional component added is closely related to the performance of the resulting embolic microspheres.

[0081] As an example, the molar ratio of the amount of modifier added to the amount of water-soluble monomer added is 1:(0.8 to 1.2), for example, but not limited to any one of the molar ratios of 1:0.8, 1:0.9, 1:1.0, 1:1.1 and 1:1.2 or any range between the two.

[0082] In this embodiment, limiting the molar ratio of the modifier to the water-soluble monomer to a specific range is beneficial for forming long-chain compounds with larger molecular weights, which in turn helps to form high-strength and high-elasticity embolization microspheres.

[0083] As an example, the molar ratio of the amount of modifier added to the amount of water-soluble monomer added is 1:1.

[0084] In this embodiment, by limiting the molar ratio of the amount of modifier added to the amount of water-soluble monomer added to a more preferred range, embolic microspheres with superior strength and elasticity can be formed.

[0085] As an example, the mass ratio of the amount of water-soluble monomer added to the amount of ionic monomer added is 1:(1.5 to 4), for example, but not limited to any one of the mass ratios of 1:1.5, 1:2, 1:3 and 1:4 or any range between the two.

[0086] As an example, the mass ratio of the amount of free radical initiator added to the amount of water-soluble monomer added is 1:(20 to 65), for example, but not limited to any one of the mass ratios of 1:20, 1:30, 1:40, 1:50, 1:60 and 1:65 or any range between the two.

[0087] It should be noted that for processes or steps not specifically described or limited during preparation, they can be set according to conventional methods in the field.

[0088] To better understand the technical solution, the synthesis process of Formula I is explained here in conjunction with specific reaction equations.

[0089] As an example, the reaction equation flow of Equation I is as follows:

[0090]

[0091] As can be seen from the above reaction equation, under alkaline conditions, the modifier is grafted onto the ring-opening water-soluble monomer. Then, in the water-in-oil reverse suspension polymerization system, the ionic monomer undergoes cross-linking polymerization with the modified water-soluble monomer under the action of free radical initiators and catalysts to form embolizing microspheres.

[0092] 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.

[0093] 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.

[0094] The features and performance of this application will be further described in detail below with reference to the embodiments.

[0095] Example 1

[0096] This application provides a method for preparing embolic microspheres, comprising the following steps:

[0097] S1. Preparation of aqueous solution of polymer monomer: N-(2-aminoethyl)-2-methylacrylamide (modifier) ​​and ethylene glycol diglycidyl ether (water-soluble monomer) are slowly added to an aqueous solution of sodium hydroxide (mass percentage 5%) and stirred and mixed. The mixture is reacted at room temperature and neutralized with hydrochloric acid after the reaction is completed to obtain a clear aqueous solution of polymer monomer; wherein, the molar ratio of the amount of modifier added to the amount of water-soluble monomer added is 1:1.

[0098] S2. Aqueous phase preparation: Sodium acrylate (ionic monomer) and ammonium persulfate (free radical initiator) are added to an aqueous solution of polymer monomer and mixed to prepare an aqueous solution; wherein, the mass ratio of the amount of water-soluble monomer added to the amount of ionic monomer added is 1:2, and the mass ratio of the amount of water-soluble monomer added to the amount of free radical initiator added is 40:1.

[0099] S3. Preparation of oil phase: Add 4% by mass of cellulose acetate butyrate (surfactant) to butyl acetate (oil phase solvent) and mix to prepare an oil phase solution.

[0100] S4. Reverse suspension polymerization: The aqueous phase solution is slowly added to the oil phase solution and mixed and stirred to form a water-in-oil reverse suspension polymerization system. Then, 0.8 mL of tetramethylethylenediamine is added to the polymerization system and crosslinking reaction is carried out sequentially (reaction temperature is 80℃, reaction time is 3.5 h), followed by purification and collection to obtain embolization microspheres.

[0101] To better understand the technical solution, specific reaction equations are provided here for further explanation:

[0102]

[0103] It should be noted that the temperature in the reaction equation is a range because the temperature fluctuates during the reaction process and the reaction time is relatively long. Therefore, the reaction equation uses a range to describe the temperature.

[0104] Example 2

[0105] This application provides a method for preparing embolic microspheres, comprising the following steps:

[0106] S1. Preparation of aqueous solution of polymer monomer: N-(2-aminoethyl)-2-methylacrylamide (modifier) ​​and diethylene glycol diglycidyl ether (water-soluble monomer) are slowly added to an aqueous solution of sodium hydroxide (mass percentage 10%) and stirred and mixed. The mixture is reacted at room temperature and neutralized to neutral with hydrochloric acid after the reaction is completed to prepare a clear aqueous solution of polymer monomer; wherein, the molar ratio of the amount of modifier added to the amount of water-soluble monomer added is 1:1.

[0107] S2. Aqueous phase preparation: Sodium methacrylate (ionic monomer) and sodium persulfate (free radical initiator) are added to an aqueous solution of polymer monomer and mixed to prepare an aqueous solution; wherein, the mass ratio of the amount of water-soluble monomer added to the amount of ionic monomer added is 1:2, and the mass ratio of the amount of water-soluble monomer added to the amount of free radical initiator added is 40:1.

[0108] S3. Preparation of oil phase: Add 3% by mass of cellulose acetate butyrate (surfactant) to butyl acetate (oil phase solvent) and mix to prepare an oil phase solution.

[0109] S4. Reverse suspension polymerization: The aqueous phase solution is slowly added to the oil phase solution and mixed and stirred to form a water-in-oil reverse suspension polymerization system. Then, 0.8 mL of tetramethylethylenediamine is added to the polymerization system and crosslinking reaction is carried out sequentially (reaction temperature is 90℃, reaction time is 4.5 h), followed by purification and collection to obtain embolization microspheres.

[0110] To better understand the technical solution, specific reaction equations are provided here for further explanation:

[0111]

[0112] It should be noted that the temperature in the reaction equation is a range because the temperature fluctuates during the reaction process and the reaction time is relatively long. Therefore, the reaction equation uses a range to describe the temperature.

[0113] Example 3

[0114] This application provides a method for preparing embolic microspheres, comprising the following steps:

[0115] S1. Preparation of aqueous solution of polymer monomer: N-(4-aminobutyl)-2-methylacrylamide (modifier) ​​and tetraethylene glycol diglycidyl ether (water-soluble monomer) were slowly added to an aqueous solution of potassium hydroxide (mass percentage of 8%) and stirred and mixed. The mixture was reacted at room temperature and neutralized to neutral with hydrochloric acid after the reaction was completed to obtain a clear aqueous solution of polymer monomer; wherein, the molar ratio of the amount of modifier added to the amount of water-soluble monomer added was 1:1.

[0116] S2. Aqueous phase preparation: 2-Acrylamido-2-methylpropanesulfonic acid (ionic monomer) and potassium persulfate (free radical initiator) are added to an aqueous solution of polymer monomer and mixed to prepare an aqueous solution; wherein, the mass ratio of the amount of water-soluble monomer added to the amount of ionic monomer added is 1:2, and the mass ratio of the amount of water-soluble monomer added to the amount of free radical initiator added is 40:1.

[0117] S3. Preparation of oil phase: Add 3% by mass of cellulose acetate butyrate (surfactant) to butyl acetate (oil phase solvent) and mix to prepare an oil phase solution.

[0118] S4. Reverse suspension polymerization: The aqueous phase solution is slowly added to the oil phase solution and mixed and stirred to form a water-in-oil reverse suspension polymerization system. Then, 0.8 mL of tetramethylethylenediamine is added to the polymerization system and crosslinking reaction is carried out sequentially (reaction temperature is 85℃, reaction time is 6 h), purification and collection are performed to obtain embolization microspheres.

[0119] To better understand the technical solution, specific reaction equations are provided here for further explanation:

[0120]

[0121] It should be noted that the temperature in the reaction equation is a range because the temperature fluctuates during the reaction process and the reaction time is relatively long. Therefore, the reaction equation uses a range to describe the temperature.

[0122] Comparative Example 1

[0123] This application provides a comparative example of a method for preparing embolization microspheres, comprising the following steps:

[0124] Polyvinyl alcohol was added to a flask containing pure water and stirred until evenly dispersed. The mixture was heated to dissolve the polyvinyl alcohol. After complete dissolution, the mixture was cooled and acrylates or esters were added sequentially. The mixture was stirred to react, and after washing and drying, the desired functionalized macromolecular hydrogel was obtained.

[0125] 2-Acrylamide-2-methylpropanesulfonic acid and potassium persulfate were sequentially added to water, dissolved, and mixed thoroughly. Then, 100g of functionalized macromolecular hydrogel was added and stirred until homogeneous, yielding a polymer monomer solution. Butyl acetate and cellulose acetate were sequentially added to the reaction vessel, while N2 gas was introduced, and the mixture was stirred and heated. Then, the above polymer monomer solution and tetramethylethylenediamine were sequentially added to form an oil-water mixed reaction system, which was then heated and stirred. During this reaction, the stirring speed was controlled at 300 rpm, and the reaction system temperature was controlled at 50℃ when the polymer monomer solution was added. After the reaction was completed, the reaction mixture was filtered to collect microspheres, which were then washed sequentially with butyl acetate, ethyl acetate, and acetone, and finally dried under vacuum to obtain the microspheres.

[0126] Experimental Example 1

[0127] Dry ball swelling rate test

[0128] Test method:

[0129] The embolic microspheres prepared in Examples 1-3 and Comparative Example 1 were prepared into dry spheres and numbered. Specifically, the collected embolic microspheres were dehydrated with acetone multiple times and then dried at 80°C to constant weight to obtain dry granular microspheres. Then, samples corresponding to each number were taken three times, with each amount being 50 mg. The time required for the three groups of samples corresponding to each number to completely swell in pure water, 0.9% NaCl aqueous solution, and 5% glucose aqueous solution was then tested.

[0130] Table 1. Swelling time of microspheres in different solutions

[0131]

[0132] Referring to Table 1, the test results of Examples 1-3 and Comparative Example 1 show that the microspheres prepared in Examples 1-3 have a faster swelling rate.

[0133] Also see Figure 1 and Figure 2 It can be seen that the microspheres prepared in Example 1 have good regularity in the wet-bulb state, and the corresponding dry-bulb photographs are as follows. Figure 2 As shown.

[0134] Experimental Example 2

[0135] Microsphere performance testing before and after irradiation sterilization

[0136] Test method:

[0137] The embolic microspheres prepared in Examples 1-3 and Comparative Example 1 were finely sieved to obtain a size of 100-200 μm (over-limit ratio <5%). After drying, they were sequentially packaged, sealed in vials, and sterilized by electron irradiation. Then, the particle size, strength, and elasticity of the microspheres after irradiation sterilization were tested.

[0138] The standard parameters for irradiation sterilization are: a single cycle irradiation dose of 7 kgy, which can be used to cycle the sample 3 times, accumulating to 21 kgy.

[0139] The particle size testing method is as follows: using an optical microscope, all microspheres in two fields of view are included in the statistics. The total number of microspheres must be greater than 150. If it is less than 150, then microspheres in another field of view are selected. Using the instrument operation software, the particle size of all microspheres included in the statistics is manually tested, the values ​​are recorded, and the average particle size is calculated.

[0140] The strength and elasticity test method is as follows: the test is carried out using the TA.XT.plus C texture analyzer system, with a 6mm probe, a trigger force of 0.1g, the microsphere is compressed and deformed to 50%, and the holding time is 60 seconds.

[0141] Table 2. Results of microsphere performance tests before and after irradiation sterilization

[0142]

[0143] Referring to Table 2, the test results of Examples 1-3 and Comparative Example 1 show that the embolization microspheres prepared by the method provided in the embodiments of this application have higher strength and elasticity than the embolization microspheres prepared by conventional methods. Furthermore, the particle size, strength, and elasticity do not change significantly before and after irradiation sterilization, indicating that they have better irradiation sterilization tolerance.

[0144] Experimental Example 3

[0145] Microsphere drug loading performance test

[0146] Test method:

[0147] Prepare saturated solutions of various drugs (specifically including oxaliplatin, 5-FU, bovine serum albumin, and paclitaxel-liposome type). Take 2 mL of the solution each time and put it into a 10 mL vial. Then add 50 mg of dried microspheres prepared in Examples 1-3. The dried microspheres swell rapidly and absorb the drug solution. Calculate the drug loading of the embolization microspheres based on the absorption volume and drug concentration.

[0148] Table 3. Results of drug loading test for embolization microspheres

[0149] Example 1 30mg 74mg 32mg 6.3mg Example 2 30mg 65mg 41mg 7.7mg Example 3 30mg 47mg 56mg 8.5mg

[0150] Referring to Table 3, the test results of Examples 1 to 3 show that the embolization microspheres prepared by the method provided in the embodiments of this application can effectively load multiple types of drugs, that is, they have good broad-spectrum drug loading function. Compared with single microspheres or microspheres that can only load a certain type of drug, the application range of microspheres is expanded.

[0151] 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 embolic microspheres are composed of the polymer shown in Formula I. Formula I; In Formula I, m is selected from any integer from 1 to 8; n is selected from any integer from 1 to 6; k and l are each independently selected from integers greater than or equal to 2; R 1 Selected from H or alkyl; R 2 Selected from alkyl groups containing carboxylates or sulfonates; j is an integer selected from any one of 1 to 8.

2. The embolic microspheres according to claim 1, characterized in that, The m is selected from any integer from 1 to 4; the n is selected from any integer from 1 to 3.

3. The embolic microspheres according to claim 1, characterized in that, The R 1 Selected from methyl.

4. The embolic microspheres according to any one of claims 1 to 3, characterized in that, The embolic microspheres are composed of polymers represented by Formula II or Formula III. Formula II; Formula III; In Equations II and III, m is selected from any integer from 1 to 8; n is selected from any integer from 1 to 6; k and l are each independently selected from integers greater than or equal to 2; R 1 Selected from H or alkyl; j is selected from any integer from 1 to 8.

5. A method for preparing embolic microspheres, characterized in that, Includes the following steps: S1. Preparation of aqueous solution of polymer monomer: The modifier and water-soluble monomer are slowly added to an alkaline aqueous solution and stirred and mixed. The mixture is reacted at room temperature and neutralized with acid after the reaction is completed to obtain a clear aqueous solution of polymer monomer; wherein, the modifier includes alkyl-substituted and / or unsubstituted N-aminoalkyl-2-methylacrylamide, and the water-soluble monomer includes diglycidyl ether compounds; S2. Aqueous phase preparation: Add ionic monomers and free radical initiators to the aqueous solution of the polymer monomer and mix them, wherein the ionic monomers include at least one of sodium acrylate, sodium methacrylate and 2-acrylamido-2-methylpropanesulfonic acid, to prepare an aqueous phase solution; S3. Oil phase preparation: Add 3-5% by mass of a surfactant to the oil phase solvent and mix to prepare an oil phase solution; wherein, the oil phase solvent includes at least one of butyl acetate, petroleum ether, n-hexane, cyclohexane or paraffin oil, and the surfactant includes at least one of cellulose acetate butyrate, Tween, Span; S4. Reverse suspension polymerization: The aqueous solution is slowly added to the oil solution and mixed and stirred to form a water-in-oil reverse suspension polymerization system. Then, tetramethylethylenediamine is added to the polymerization system and crosslinking reaction, purification and collection are carried out in sequence to obtain embolization microspheres.

6. The preparation method according to claim 5, characterized in that, The free radical initiator includes at least one of sodium persulfate, potassium persulfate, ammonium persulfate, azobisisobutylamidine hydrochloride, azobisisobutylimidazoline hydrochloride, azobisisobutylammonium valerate, and azobisisopropylimidazoline.

7. The preparation method according to claim 5 or 6, characterized in that, The preparation method satisfies condition A and / or B of the following: The modifier A includes , where R 1 Selected from H or alkyl; n is an integer selected from 1 to 6; B. The water-soluble monomers include , where m is any integer from 1 to 8.

8. The preparation method according to claim 7, characterized in that, The modifier includes at least one of N-(2-aminoethyl)-2-methylacrylamide, N-(3-aminopropyl)-2-methylacrylamide, and N-(4-aminobutyl)-2-methylacrylamide.

9. The preparation method according to claim 7, characterized in that, The water-soluble monomer includes at least one of ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, and tetraethylene glycol diglycidyl ether.

10. The preparation method according to claim 5 or 6, characterized in that, The molar ratio of the amount of the modifier to the amount of the water-soluble monomer is 1:(0.8~1.2).

11. The preparation method according to claim 10, characterized in that, The molar ratio of the amount of the modifier to the amount of the water-soluble monomer is 1:

1.

12. The preparation method according to claim 5 or 6, characterized in that, During the crosslinking reaction, the reaction temperature is 50~90℃ and the reaction time is not less than 3 h.

13. The use of an embolic microsphere as described in any one of claims 1 to 4, or an embolic microsphere prepared by any one of claims 5 to 12, in the preparation of an embolic agent.

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