Developing embolism microsphere as well as preparation method and application thereof

Abstract

The invention relates to a developing embolism microsphere as well as a preparation method and application thereof, and belongs to the technical field of embolism microspheres. The developing embolism microsphere comprises a polymer network structure formed by cross-linking polymerization of a modified iodine-containing compound with a sulfonic acid group and polyhydroxy and a cross-linking agent, wherein the cross-linking agent comprises a glycidyl ether compound with an epoxypropane end group; the modified iodine-containing compound is obtained by modifying a polyhydroxy iodine-containing compound with a modifier with a sulfonic acid group, the chemical structure of the iodine-containing compound is as shown in formula (I): # imgabs0 #, R1, R2 and R3 are hydroxyl-containing alkyl or derivatives thereof, and R4 is-H, alkyl or derivatives thereof. The developing embolism microsphere has good developing property and mechanical property, has broad-spectrum drug loading capacity for various types of drugs, and is beneficial to delivery and clinical use of the embolism microsphere and enlargement of the application range of the embolism microsphere.

Description

Technical Field

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

[0002] Embolic microspheres are the most widely used embolic materials in clinical transcatheter arterial embolization (TAE) and transcatheter arterial chemoembolization (TACE) because their various properties are highly compatible with embolic surgery. However, the embolic microspheres currently commonly used in clinical practice cannot be visualized under conventional clinical detection equipment such as CT, ultrasound, and MRI, making it difficult to accurately control their positioning during interventional surgery. Therefore, developing embolic microspheres, especially developing embolic microspheres that can be efficiently loaded with chemotherapy drugs, are not only an urgent clinical need, but also represent the development direction of advanced microsphere materials and new quality productivity. They are of extremely high value both in academic and clinical use.

[0003] At present, some studies have disclosed the use of iodine-containing compounds and monomers with anionic functional groups for cross-linking polymerization to prepare drug-loaded developing embolic microspheres, which can simultaneously achieve the development and drug loading properties of the embolic microspheres. However, the obtained embolic microspheres can often only adsorb drug molecules through ionic interactions, resulting in a single type of drug that can be loaded, which cannot meet the complex and diverse clinical treatment needs of tumors. In addition, in the process of realizing the development function, the developing embolic microspheres in existing studies usually introduce a large number of strongly hydrophobic developer molecules such as 2,3,5-triiodobenzaldehyde, resulting in low elasticity and poor suspension of the microspheres, which is not conducive to the delivery and clinical use of embolic microspheres in practical applications. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present application provides a developing embolic microsphere and a preparation method and application thereof. The developing embolic microsphere has good developing properties and mechanical properties and has a broad-spectrum drug loading capacity for various types of drugs.

[0005] In the first aspect, the embodiment of the present application provides a developing embolic microsphere, comprising a polymer network structure formed by cross-linking polymerization of a modified iodine-containing compound with a sulfonic acid group and a polyhydroxyl group and a cross-linking agent; wherein the cross-linking agent comprises a glycidyl ether compound with a propylene oxide terminal group; the modified iodine-containing compound is an iodine-containing compound with a polyhydroxyl group modified by a modifier with a sulfonic acid group, and the chemical structure of the iodine-containing compound is shown in formula (I):

[0006]

[0007] Among them, R1 , R 2 , R 3 is a hydroxyl-containing alkyl group or its derivative, R 4 is -H, alkyl or its derivative.

[0008] In the above technical solution, the developing embolic microspheres include a polymer network structure formed by cross-linking polymerization of a modified iodine-containing compound with sulfonic acid groups and polyhydroxy groups and a cross-linking agent, and sulfonic acid groups and iodine elements are introduced during cross-linking polymerization, so that the microspheres have both developing properties and drug loading properties. In addition, by using an iodine-containing compound with a benzene ring structure, the benzene ring has a rigid characteristic, so that the obtained microspheres have a relatively rigid pore structure, so that after combining with oppositely charged drugs during the drug loading process, the particle size of the microspheres will not shrink too drastically due to charge neutralization, so that it will not affect the entry of subsequent drugs, so as to obtain a faster drug loading speed and a higher drug loading amount; in addition, the corresponding microspheres obtained by introducing a structure with a benzene ring, because the benzene ring has a certain hydrophobicity, the corresponding microspheres and the hydrophobic drugs can generate a greater force, which is helpful for loading hydrophobic drugs, and at the same time, the hydroxyl group, sulfonic acid group and molecular rigid skeleton structure make the developing embolic microspheres have a broad-spectrum drug loading performance for a variety of drugs.

[0009] In addition, the modified iodine-containing compound with a specific chemical structure and the cross-linking polymerization of the cross-linking agent also make the developing embolic microspheres have good wet ball drug loading and release capacity and good dry ball swelling drug loading capacity, thereby achieving a broad-spectrum drug loading performance for a variety of drugs and good drug sustained release performance. In addition, the special polymer network structure of the developing embolic microspheres also makes them have good mechanical properties, with high strength, high elasticity and low density, which is conducive to delivery and clinical use.

[0010] In some embodiments of the present application, the iodine-containing compound includes at least one of ioversol, iohexol, iodixanol, iomeprol, iopamidol, iopromide, iopentol or iotrolan. The glycidyl ether compound with propylene oxide terminal groups includes at least one of glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether or pentaerythritol glycidyl ether.

[0011] In the above technical scheme, the above iodine-containing compounds and glycidyl ether compounds with propylene oxide terminal groups are selected, and after cross-linking polymerization, developing embolic microspheres with good developability and mechanical properties, as well as broad-spectrum drug loading capacity and drug sustained release capacity can be obtained.

[0012] In some embodiments of the present application, the modifier with a sulfonic acid group includes at least one of the compounds shown in formula (II) or formula (III):

[0013]

[0014] Among them, R 4 is an alkyl group or a derivative thereof; R 5 It is an alkyl group containing a halogen atom or a derivative thereof.

[0015] In the above technical solution, the compounds having the above two chemical structural formulas can react with the hydroxyl groups on the iodine-containing compound, thereby introducing sulfonic acid groups.

[0016] In a second aspect, the present invention provides a method for preparing embolic microspheres, comprising the following steps:

[0017] S1: reacting a polyhydroxy iodine-containing compound and a modifier having a sulfonic acid group in an aqueous solution of an alkaline catalyst to obtain an aqueous solution of a modified iodine-containing compound having a sulfonic acid group and polyhydroxy;

[0018] S2: adding a crosslinking agent to the aqueous solution of the modified iodine-containing compound to obtain an aqueous phase;

[0019] S3: mixing the water phase and the oil phase to form an oil-in-water reverse suspension polymerization system, and obtaining the developing embolic microspheres after the reaction;

[0020] Wherein, the crosslinking agent includes a glycidyl ether compound having an propylene oxide terminal group; the chemical structure of the iodine-containing compound is shown in formula (I):

[0021]

[0022] Among them, R 1 , R 2 , R 3 is a hydroxyl-containing alkyl group or its derivative, R 4 is -H, alkyl or its derivative.

[0023] In the above technical scheme, the modifier with a sulfonic acid group first reacts with the hydroxyl group on the iodine-containing compound under the action of an alkaline catalyst, thereby introducing a sulfonic acid group to obtain a modified iodine-containing compound. Then the modified iodine-containing compound reacts with a cross-linking agent, and the glycidyl ether compound with an propylene oxide terminal group undergoes epoxy ring opening under the action of an alkaline catalyst, reacts with the hydroxyl group on the modified iodine-containing compound, and undergoes cross-linking polymerization with each other to obtain developing embolic microspheres. The entire preparation method is simple, and the developing embolic microspheres obtained by chemical cross-linking bonding have good developing properties. At the same time, the hydroxyl group, sulfonic acid group and rigid skeleton structure enable it to have a broad-spectrum drug loading performance, and can achieve efficient loading of various types of drugs such as doxorubicin hydrochloride, irinotecan hydrochloride, lenvatinib mesylate, carboplatin and oxaliplatin. In addition, the special polymer network structure also gives the developing embolic microspheres good mechanical properties, with high strength, high elasticity and low density. The relatively rigid molecular skeleton enables it to have a faster drug loading efficiency in the wet bulb state, and it also has the ability to sustain drug release, and has excellent drug loading efficiency in the dry bulb state; the higher elasticity and lower density make it conducive to delivery and clinical use in practical applications.

[0024] In some embodiments of the present application, the iodine-containing compound includes at least one of ioversol, iohexol, iodixanol, iomeprol, iopamidol, iopromide, iopentol or iotrolan; the mass percentage of the modified iodine-containing compound in the aqueous phase is 20wt% to 50wt%; the molar ratio of the modified iodine-containing compound to the cross-linking agent is (0.1 to 0.5):1.

[0025] In the above technical solution, by controlling the type, amount and ratio of the iodine-containing compound to the cross-linking agent, the cross-linking degree of the developing embolic microspheres can be further regulated, thereby affecting their mechanical properties and drug loading properties.

[0026] In some embodiments of the present application, the modifier with a sulfonic acid group includes at least one of the compounds shown in formula (II) or formula (III):

[0027]

[0028] Among them, R 4 is an alkyl group or a derivative thereof; R 5 The alkyl group is a halogen-containing alkyl group or a derivative thereof. And / or, the molar ratio of the iodine-containing compound to the modifier having a sulfonic acid group is (0.5-1):1.

[0029] In the above technical solution, the purity of the modified iodine-containing compound can be ensured by controlling the type and amount of the modifier with sulfonic acid group.

[0030] In some embodiments of the present application, the glycidyl ether compound having a propylene oxide terminal group includes at least one of glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether or pentaerythritol glycidyl ether.

[0031] In some embodiments of the present application, the above-mentioned glycidyl ether compounds having propylene oxide terminal groups all have two or more propylene oxide terminal groups and have relatively long molecular chain segments, and can be efficiently cross-linked and polymerized with modified iodine-containing compounds to form developing embolic microspheres having a specific polymer network structure.

[0032] In some embodiments of the present application, the method for preparing the oil phase includes: adding an oil-soluble dispersant to an oil-soluble solvent, stirring and mixing the mixture uniformly to obtain the oil phase.

[0033] In some embodiments of the present application, the mass percentage of the oil-soluble dispersant in the oil phase is 0.5 wt % to 5 wt %.

[0034] In some embodiments of the present application, in step S3, the reaction temperature is 30°C to 90°C, and the reaction time is 5h to 36h.

[0035] In a third aspect, the embodiments of the present application also provide a use of the above-mentioned developing embolic microspheres in the preparation of radiotherapy, chemotherapy and embolization combined treatment drugs and developing diagnostic reagents for tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0037] Figure 1 This is an in vitro Micro CT development test diagram of the developed embolic microspheres and DC Beads in Examples 1 to 4 of the present application.

[0038] Figure 2 The graph is a drug loading curve of doxorubicin hydrochloride for the developed embolic microspheres and DC Beads of Examples 1 to 4 in the wet bulb state.

[0039] Figure 3 The graph is a drug loading curve of irinotecan hydrochloride for the developed embolic microspheres and DC Bead in Examples 1 to 4 in the wet bulb state.

[0040] Figure 4 The graph is a drug loading curve of lenvatinib mesylate for the developed embolic microspheres and DC Beads of Examples 1 to 4 in the wet bulb state.

[0041] Figure 5 The graph is a drug release curve of doxorubicin hydrochloride by the developed embolic microspheres and DC Bead in Examples 1 to 4 in the wet bulb state.

[0042] Figure 6 The graph is a drug release curve of irinotecan hydrochloride from the developing embolic microspheres and DC Bead in Examples 1 to 4 in the wet bulb state.

[0043] Figure 7 The graph shows the drug release curve of lenvatinib mesylate by the developed embolic microspheres and DC Beads of Examples 1 to 4 in the wet bulb state.

[0044] Figure 8 The graph is a drug loading curve of carboplatin for the imaging embolic microspheres and Hepaspheres of Examples 1 to 4 in the dry ball state.

[0045] Fig. 9 The graph is a drug loading curve of oxaliplatin for the developed embolic microspheres and Hepaspheres of Examples 1 to 4 in the dry ball state. DETAILED DESCRIPTION

[0046] 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.

[0047] The following is a detailed description of a developing embolic microsphere and a preparation method thereof according to an embodiment of the present application.

[0048] Embolic microspheres, especially those loaded with drugs, have significant clinical use value in precise control of surgical procedures, postoperative evaluation, and combined treatment indicators. Currently, existing research techniques use iodine-containing compounds and monomers with anionic functional groups to cross-link and polymerize to obtain drug-loaded embolic microspheres, but they can only adsorb drug molecules through ionic interactions, resulting in a single type of drug that can be loaded, which cannot meet the complex and diverse clinical treatment needs of tumors. In addition, in the process of realizing the developing function, the developing embolic microspheres in existing research usually introduce a large number of strongly hydrophobic developer molecules such as 2,3,5-triiodobenzaldehyde, resulting in low elasticity and poor suspension of the prepared microspheres, which is not conducive to the delivery and clinical use of microspheres in practical applications.

[0049] Based on this, the embodiment of the present application provides a developing embolic microsphere and a preparation method thereof, the preparation method comprising the following steps:

[0050] S1, reacting a polyhydroxy iodine-containing compound and a modifier with a sulfonic acid group in an alkaline catalyst aqueous solution to obtain an aqueous solution of a modified iodine-containing compound with sulfonic acid groups and polyhydroxy groups.

[0051] Wherein, the chemical structure of the iodine-containing compound is shown in formula (I):

[0052]

[0053] Among them, R 1 , R 2 , R 3 is a hydroxyl-containing alkyl group or its derivative, R 4 is -H, alkyl or its derivative.

[0054] Preferably, the iodine-containing compound comprises at least one of ioversol, iohexol, iodixanol, iomeprol, iopamidol, iopromide, iopentol or iotrolan.

[0055] The modifier with a sulfonic acid group may include at least one of the compounds shown in formula (II) or formula (III):

[0056]

[0057] Among them, R 4 is an alkyl group or a derivative thereof; R 5 It is an alkyl group containing a halogen atom or a derivative thereof.

[0058] Preferably, the modifier having a sulfonic acid group includes at least one of 1,4-butane sultone, 1,3-propane sultone, sodium 2-chloroethyl sulfonate or tetrafluorosultone.

[0059] In some embodiments, the molar ratio of the iodine-containing compound to the modifier with a sulfonic acid group is (0.5-1): 1. As an example, the molar ratio of the iodine-containing compound to the modifier with a sulfonic acid group can be 0.5:1, 1:1, etc.

[0060] In some embodiments, the conditions for reacting under alkaline conditions in step S1 include: reacting in an alkaline aqueous solution at 30° C. to 100° C. for 1 h to 5 h.

[0061] The alkaline catalyst is at least one of potassium hydroxide (KOH) or sodium hydroxide (NaOH). The mass percentage of the alkaline catalyst in the alkaline catalyst aqueous solution is 10wt% to 30wt%, such as 20wt%, 25wt%, etc.

[0062] S2: adding a crosslinking agent to the above-mentioned aqueous solution of the modified iodine-containing compound to obtain an aqueous phase.

[0063] The cross-linking agent includes a glycidyl ether compound having a propylene oxide terminal group.

[0064] Preferably, the crosslinking agent includes at least one of glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether or pentaerythritol glycidyl ether.

[0065] Further preferably, the cross-linking agent includes at least one of polyethylene glycol diglycidyl ether, glycerol triglycidyl ether or pentaerythritol glycidyl ether.

[0066] In some embodiments, the mass percentage of the modified iodine-containing compound in the aqueous phase is 20 wt % to 50 wt %. For example, the mass percentage of the modified iodine-containing compound in the aqueous phase may be 25 wt %, 30 wt %, 40 wt %, 50 wt %, etc.

[0067] In some embodiments, the molar ratio of the modified iodine-containing compound to the cross-linking agent is (0.1-0.5): 1. By way of example, the molar ratio of the modified iodine-containing compound to the cross-linking agent can be 0.1:1, 0.2:1, 0.3:1, 0.5:1, etc.

[0068] In some embodiments, the mass percentage of the alkaline catalyst in the water phase may be 30 wt % to 60 wt %. For example, the mass percentage of the alkaline catalyst in the water phase may be 25 wt %, 30 wt %, 40 wt %, 50 wt %, etc.

[0069] In some embodiments, after adding the cross-linking agent in step S2, the process further includes stirring the mixture evenly, and the stirring time may be 10 min to 120 min.

[0070] S3: The water phase and the oil phase are mixed to form an oil-in-water reverse suspension polymerization system, and after stirring and reacting for a period of time at a certain temperature, the developing embolic microspheres are obtained.

[0071] The method for preparing the oil phase may include the following steps: adding an oil-soluble dispersant into an oil-soluble solvent, stirring and mixing the mixture to obtain the oil phase.

[0072] In some embodiments, the oil-soluble dispersant includes at least one of a Span series compound, a Tween series compound, octylphenol polyoxyethylene ether, dodecylphenol polyoxyethylene ether (OP-10), cellulose acetate, or cellulose acetate butyrate. Preferably, the oil-soluble dispersant includes Tween 20 and Span 80, and the mass ratio of Tween 20 to Span 80 is (1:5) to (1:10), for example, 1:5, 1:8, 1:10, etc.

[0073] In some embodiments, the mass percentage of the oil phase dispersant in the oil phase is 0.5 wt % to 5 wt %. For example, the mass percentage of the oil phase dispersant can be 0.5 wt %, 1 wt %, 3 wt %, 5 wt %, etc.

[0074] In some embodiments, the oil-soluble solvent includes at least one of petroleum ether, cyclohexane, liquid paraffin, n-decane, ethyl acetate or butyl acetate. Preferably, the oil-soluble solvent is liquid paraffin, cyclohexane or n-decane.

[0075] In some embodiments, the reaction conditions of step S3 may include: slowly adding the aqueous phase solution to the oil phase solution under stirring at room temperature to form an oil-in-water reverse suspension polymerization system; after the addition is completed, the reverse suspension polymerization system is heated to 30°C to 90°C, and the stirring and heating state is maintained. The stirring rate is 100rpm to 500rpm, the reaction time is 5h to 36h, and then the stirring and heating are stopped.

[0076] As an example, the temperature of the reverse suspension polymerization reaction can be 30°C, 50°C, 70°C, 80°C, 90°C, etc.; the stirring rate can be 100rpm, 200rpm, 300rpm, 500rpm, etc.; the reaction time can be 5h, 10h, 16h, 18h, 36h, etc.

[0077] In some embodiments, after the reverse suspension polymerization reaction, the process further includes: standing, washing, and sieving. For example, after stopping stirring and heating, the process is allowed to stand for stratification to separate the gel phase microspheres in the lower layer, which are then washed with petroleum ether, butyl acetate, sodium bicarbonate aqueous solution, and ultrapure water in sequence, and then sieved through sieves with different apertures to obtain developing embolic microspheres with different particle size distributions.

[0078] In addition, the embodiments of the present application also provide an application of developing embolic microspheres in the preparation of radiotherapy, chemotherapy and embolization combined treatment drugs and developing diagnostic reagents for tumors.

[0079] In the preparation method of the developing embolic microspheres provided in the present application, a polyhydroxy iodine-containing compound with a benzene ring structure is used. First, the polyhydroxy iodine-containing compound is modified with sulfonic acid groups through an etherification reaction under alkaline conditions, and then a cross-linking agent is added for pre-cross-linking polymerization to obtain an aqueous phase; finally, the aqueous phase and the oil phase are mixed for a reverse suspension polymerization reaction to obtain the developing embolic microspheres. The entire preparation method is simple, and the developing embolic microspheres obtained by chemical cross-linking bonding have good developing properties. At the same time, the hydroxyl group, sulfonic acid group and rigid molecular skeleton enable it to have a broad-spectrum drug loading performance, and can achieve efficient loading of various types of drugs such as doxorubicin hydrochloride, irinotecan hydrochloride, lenvatinib mesylate, carboplatin and oxaliplatin. In addition, the special polymer network structure also gives the developing embolic microspheres good mechanical properties, with high strength, high elasticity and low density. The relatively rigid molecular skeleton enables it to have a faster drug loading efficiency in the wet bulb state, and it also has the ability to sustain drug release, and has excellent drug loading efficiency in the dry bulb state; the higher elasticity and lower density make it conducive to delivery and clinical use in practical applications.

[0080] The features and performance of the technical solution of the present application are further described in detail below in conjunction with the embodiments.

[0081] Example 1

[0082] This embodiment provides a developing embolic microsphere, and its preparation process is represented by a chemical structural formula as shown in formula (1):

[0083]

[0084] The specific preparation method comprises the following steps:

[0085] Preparation of modified iodine-containing compounds: Prepare a 20wt% NaOH aqueous solution, dissolve iohexol in the solution under stirring conditions for 20 minutes. Then add 1,4-butane sultone, react at 50°C for 3 hours to obtain a modified iohexol aqueous solution; wherein the molar ratio of iohexol to 1,4-butane sultone is 1:1.

[0086] Prepare the aqueous phase: add glycerol triglycidyl ether to the modified iohexol aqueous solution and stir for 20 minutes to obtain a uniform aqueous phase; the mass percentage of the modified iohexol in the aqueous phase is 25wt%, and the molar ratio of the modified iohexol to glycerol triglycidyl ether is 0.12:1.

[0087] Prepare the oil phase: add Tween 20 and Span 80 used as oil-soluble dispersants into liquid paraffin at a ratio of 1:3 (3 wt%), stir and mix well to obtain the oil phase.

[0088] Reverse suspension polymerization: Under stirring conditions at room temperature, the water phase is slowly added dropwise to the oil phase to form an oil-in-water reverse suspension polymerization system. After the addition is completed, the reverse suspension polymerization system is heated to 70°C and maintained in a stirring and heating state at a stirring rate of 300 rpm. After reacting for 16 hours, stirring and heating are stopped, the system is allowed to stand for stratification, the oil phase is separated, the microspheres are collected, and they are washed and sieved to obtain developing embolic microspheres with different particle size distributions.

[0089] Example 2

[0090] This embodiment provides a developing embolic microsphere, and its preparation process is represented by a chemical structural formula as shown in formula (2):

[0091]

[0092] The specific preparation method comprises the following steps:

[0093] Preparation of modified iodine-containing compounds: Prepare a 25wt% NaOH aqueous solution, dissolve iopamidol in the solution under stirring conditions for 30 minutes, then add 1,4-butane sultone, react at 70°C for 1 hour to obtain a modified iopamidol aqueous solution; wherein the molar ratio of iopamidol to 1,4-butane sultone is 1:1.

[0094] Prepare the aqueous phase: add glycerol triglycidyl ether to the modified iopamidol aqueous solution, stir for 30 minutes, and obtain a uniform aqueous phase; the mass percentage of the modified iopamidol in the aqueous phase is 25wt%, and the molar ratio of the modified iopamidol to glycerol triglycidyl ether is 0.12:1.

[0095] Prepare the oil phase: add Tween 20 and Span 80 used as oil-soluble dispersants into liquid paraffin at a ratio of 1:3 (3 wt%), stir and mix well to obtain the oil phase.

[0096] Reverse suspension polymerization: Under stirring conditions at room temperature, the water phase is slowly added dropwise to the oil phase to form an oil-in-water reverse suspension polymerization system. After the addition is completed, the reverse suspension polymerization system is heated to 80°C and maintained in a stirring and heating state at a stirring rate of 300 rpm. After reacting for 18 hours, stirring and heating are stopped, the system is allowed to stand for stratification, the oil phase is separated, the microspheres are collected, and they are washed and sieved to obtain developing embolic microspheres with different particle size distributions.

[0097] Example 3

[0098] This embodiment provides a developing embolic microsphere, and its preparation process is represented by a chemical structural formula as shown in formula (3):

[0099]

[0100] The specific preparation method comprises the following steps:

[0101] Preparation of modified iodine-containing compounds: Prepare a 25 wt% NaOH aqueous solution, dissolve iodixanol in the solution under stirring conditions for 30 minutes, then add 1,4-butane sultone, and react at 30°C for 5 hours to obtain a modified iodixanol aqueous solution; wherein the molar ratio of iodixanol to 1,4-butane sultone is 1:1.

[0102] Prepare the aqueous phase: add glycerol triglycidyl ether to the modified iodixanol aqueous solution and stir for 30 minutes to obtain a uniform aqueous phase; the mass percentage of the modified iodixanol in the aqueous phase is 30wt%, and the molar ratio of the modified iodixanol to glycerol triglycidyl ether is 0.1:1.

[0103] Prepare the oil phase: add Tween 20 and Span 80 used as oil-soluble dispersants into liquid paraffin at a ratio of 1:3 (4 wt%), stir and mix well to obtain the oil phase.

[0104] Reverse suspension polymerization: Under stirring conditions at room temperature, the water phase is slowly added dropwise to the oil phase to form an oil-in-water reverse suspension polymerization system. After the addition is completed, the reverse suspension polymerization system is heated to 80°C and maintained in a stirring and heating state at a stirring rate of 300 rpm. After reacting for 18 hours, stirring and heating are stopped, the system is allowed to stand for stratification, the oil phase is separated, the microspheres are collected, and they are washed and sieved to obtain developing embolic microspheres with different particle size distributions.

[0105] Example 4

[0106] This embodiment provides a developing embolic microsphere, and the preparation method thereof comprises the following steps:

[0107] Preparation of modified iodine-containing compounds: Prepare a 20wt% KOH aqueous solution, dissolve iohexol in the solution under stirring conditions for 20 minutes, then add 1,4-butanesulfone, react at 80°C for 2 hours to obtain a modified iohexol aqueous solution; wherein the molar ratio of iohexol to 1,4-butanesulfone is 1:1.

[0108] Prepare the aqueous phase: add ethylene glycol diglycidyl ether to the modified iohexol aqueous solution and stir for 20 minutes to obtain a uniform aqueous phase; the mass percentage of the modified iohexol in the aqueous phase is 25wt%, and the molar ratio of the modified iohexol to ethylene glycol diglycidyl ether is 0.17:1.

[0109] Preparation of oil phase: Add OP-10 (4 wt %) used as an oil-soluble dispersant into liquid paraffin, stir and mix well to obtain an oil phase.

[0110] Reverse suspension polymerization: Under stirring conditions at room temperature, the water phase is slowly added dropwise to the oil phase to form an oil-in-water reverse suspension polymerization system. After the addition is completed, the reverse suspension polymerization system is heated to 70°C and maintained in a stirring and heating state at a stirring rate of 300 rpm. After reacting for 16 hours, stirring and heating are stopped, the system is allowed to stand for stratification, the oil phase is separated, the microspheres are collected, and they are washed and sieved to obtain developing embolic microspheres with different particle size distributions.

[0111] Comparative Example 1

[0112] This comparative example provides a developing embolic microsphere, and the preparation method thereof comprises the following steps:

[0113] Prepare the aqueous phase: prepare a 10% polyvinyl alcohol aqueous solution under a constant temperature water bath heating condition of 90°C for use; weigh 3.73 g of iohexol and dissolve it in 5 mL of pure water to prepare an iohexol solution, add 0.4 g of acrylamidoacetaldehyde dimethyl acetal, stir evenly and then drop 0.25 mL of concentrated hydrochloric acid, react for 24 hours to generate an olefin aqueous solution of iohexol for use; weigh 0.8 g of 2-acrylamido-2-methylpropanesulfonic acid (AMPS), 0.03 g of N,N-methylenebisacrylamide, and 0.02 g of potassium persulfate and mix and dissolve them in 3 mL of deionized water, mix the AMPS aqueous solution with the olefin aqueous solution of iohexol and 20 mL of polyvinyl alcohol aqueous solution and stir evenly to form a uniform aqueous phase.

[0114] Prepare the oil phase: add 100 ml of butyl acetate into a four-necked bottle, weigh 1.2 g of cellulose acetate butyrate, and dissolve them in a 60°C constant temperature water bath with heating and stirring until a uniform oil phase is formed.

[0115] Reverse suspension polymerization: Under stirring at 130 rpm, slowly add the aqueous phase solution to the oil phase to form an oil-in-water reverse suspension polymerization system. After the addition is completed, the reaction system is heated to 60°C in a water bath, and the reverse suspension polymerization reaction begins. 0.1 mL of 50% glutaraldehyde solution and 0.1 mL of concentrated hydrochloric acid are added to the reaction system, and 0.05 mL of tetramethylethylenediamine is continued to be added to the reaction system. After reacting for 2 hours, 0.2 mL of 50% glutaraldehyde solution is added to the reaction system. After continuing the reaction for 2 hours, 0.3 mL of 50% glutaraldehyde solution is added to the reaction system. After continuing the reaction for 2 hours, the reaction is terminated, the oil phase is separated, the microspheres are collected, and they are washed and sieved to obtain developing embolic microspheres with different particle size distributions.

[0116] Performance testing and result analysis

[0117] 1. Development performance

[0118] Take the developing embolic microspheres prepared in each embodiment and comparative example 1, with a particle size of 100μm to 300μm, and test the developing performance through in vitro Micro CT images and HU values, and compare and illustrate with DC Bead microspheres (Biocompatibles, UK). The test method includes: using a syringe to draw 2mL of the prepared 1.5% agar solution and add it to a centrifuge tube, after solidification, use a 16G needle to create a linear cavity with a diameter of 2 mm in the centrifuge tube containing the agar solution, slowly withdraw the needle along the cavity, and then inject 100μm to 300μm embolic microspheres to fill the cavity to prepare a linear model. Use DSA to test the sample embolic microspheres and the ordinary embolic microsphere linear model to simulate the imaging effect of embolism in the blood vessel after the embolism is completed. Table 1 shows the HU (Hounsfiled Unit) values ​​of each embodiment and comparative example 1 and DC Bead. Figure 1 The in vitro Micro CT development test diagrams of the developed embolic microspheres and DC Bead in Examples 1 to 4 of the present application, from left to right are Example 1, Example 2, Example 3, Example 4 and DC Bead.

[0119] Table 1 HU values ​​of the developing embolic microspheres and DC Bead in Examples 1 to 4 and Comparative Example 1

[0120] Group Example 1 Example 2 Example 3 Example 4 Comparative Example 1 DC Bead HU value 2546 2489 2476 2288 1871 43

[0121] Combination Figure 1 As can be seen from Table 1, the developing embolic microspheres prepared in Examples 1 to 4 of the present application all have good developing properties, the developing embolic microspheres prepared in Comparative Example 1 are slightly worse than those prepared in Examples 1 to 4 of the present application, and the commercially available DC Bead microspheres do not have developing properties.

[0122] 2. Physical properties

[0123] Using non-developing microspheres DC Bead (Biocompatibles, UK) and developing embolic microspheres DC Bead LUMI (Biocompatibles, UK) as comparison, the performance of each sample microsphere in Examples 1 to 4 and Comparative Example 1 was tested, and the test method is as follows:

[0124] (1) Strength / resilience / elasticity: Spread the microspheres onto a slide in a single layer and place them under a texture analyzer (TAXT plus C). Select the Hold Compression mode for testing. Select a 6 mm probe and a trigger force of 0.1 g. Compress the microspheres to 50% and hold for 60 s.

[0125] (2) Density: Measure 1 mL of microspheres with a particle size of 100 μm to 300 μm and weigh the mass. The ratio of mass to volume is the density of the microspheres.

[0126] The above test results are shown in Table 2:

[0127] Table 2 Physical properties of each sample

[0128] Microspheres Strength / g Rebound force / g elasticity(%) Density(g / mL) Example 1 234.5 220.2 77.5 1.12 Example 2 244.3 234.8 68.4 1.12 Example 3 239.6 226.4 75.3 1.11 Example 4 227.3 216.7 65.3 1.14 Comparative Example 1 >1000 >1000 36.8 1.4 DC Bead 113.8 105.1 57.7 1.17 DC Bead LUMI >1000 >1000 ～0 1.3

[0129] As shown in Table 2, the imaging embolic microspheres in Examples 1 to 4 have relatively suitable mechanical strength, high elasticity and low density, and can be transported in the catheter without damage while having good suspension properties, and can meet the needs of complex interventional situations such as catheter bending. However, the imaging embolic microspheres prepared in Comparative Example 1 and the commercially available product DC BeadLUMI have too high strength, too low elasticity, and high density, which are not conducive to practical applications.

[0130] 3. Wet-bulb drug loading performance

[0131] Three groups (each group is 1 mL) of the developed embolic microspheres and DC Bead prepared in Examples 1 to 4 were taken and numbered, and the surface moisture of the microspheres was removed by filter paper. The microspheres were transferred into a vial, and 2 mL of doxorubicin hydrochloride solution (20 mg / mL), irinotecan hydrochloride solution (20 mg / mL) and lenvatinib mesylate solution (10 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 the drug loading curves of each drug corresponding to Examples 1 to 4 and DC Bead were drawn.

[0132] Table 3 Drug loading rate of the imaging embolic microspheres and DC Beads in Examples 1 to 4

[0133]

[0134]

[0135] Figure 2 The drug loading curves of the developed embolic microspheres and DC Beads of Examples 1 to 4 for doxorubicin hydrochloride in the wet bulb state; Figure 3 The drug loading curves of the developing embolic microspheres and DC Beads of Examples 1 to 4 for irinotecan hydrochloride in the wet bulb state; Figure 4 The drug loading curves of the imaging embolic microspheres and DC Beads of Examples 1 to 4 for lenvatinib mesylate in the wet bulb state are shown in Table 3 and Table 4. Figures 2 to 4It can be seen that the developing embolic microspheres of Examples 1 to 4 have excellent loading efficiency for different drugs. The commercially available product DC Bead can also adsorb drugs due to its negative charge, but the rate is significantly lower than that of Examples 1 to 4. This is mainly because the developing embolic microspheres prepared in Examples 1 to 4 have a relatively rigid molecular skeleton due to the presence of benzene rings in the modified iodine-containing compounds. When interacting with drugs, the pores in the microspheres are not easy to collapse, ensuring the smooth flow of drug molecules, so the drug loading speed is faster. The commercially available product DC Bead mainly uses hydrophilic polyvinyl alcohol PVA as the skeleton. As the drug is loaded, the positive and negative charges are neutralized, the volume of the microspheres is reduced, and the pores become smaller, so the drug loading speed is slower.

[0136] 4. Wet-bulb release performance

[0137] The drug-loaded microspheres were added to a dialysis bag, and then the dialysis bag was placed in a beaker, and physiological saline (20 mL) was added to the beaker and sealed; samples were taken every 5 min, 30 min, and 60 min, and the drug concentration in the dialysis bag solution was determined. The cumulative release amount of the drug-loaded embolic microspheres was calculated and the drug release curves of each drug corresponding to Examples 1 to 4 and DC Bead were plotted.

[0138] Table 4 Drug release rate of the developed embolic microspheres and DC Beads in the examples

[0139]

[0140] Figure 5 The graph is a drug release curve of doxorubicin hydrochloride by the developing embolic microspheres and DC Bead in Examples 1 to 4 in a wet bulb state; Figure 6 The graph is a drug release curve of irinotecan hydrochloride by the developing embolic microspheres and DC Bead of Examples 1 to 4 in the wet bulb state; Figure 7 The release curves of lenvatinib mesylate by the imaging embolic microspheres and DC Beads of Examples 1 to 4 in the wet bulb state are shown in Table 4 and Figures 5 to 7 It can be seen that the developing microspheres of Examples 1 to 4 have a sustained release effect on different drugs, and the sustained release effect of the commercially available products on drugs is significantly lower than that of Examples 1 to 4. This is because the polymer network structure of the developing embolic microspheres contains a modified iodine-containing compound containing a benzene ring, which makes the molecular skeleton relatively rigid and has a large steric resistance. These rigid skeletons constitute a "cage" for the drug, so under the dual effects of electrostatic action and steric hindrance, the drug release becomes slower.

[0141] 5. Dry ball drug loading performance

[0142] Three groups (each group, 100 mg) of the developed embolic microspheres and Hepasphere embolic microspheres (Meriton Medical Devices (Beijing) Co., Ltd.) prepared in Examples 1 to 4 were taken and numbered, and the microspheres were transferred into vials. 5 mL of carboplatin solution (10 mg / mL) and oxaliplatin solution (20 mg / mL) were added respectively to allow the microspheres to swell fully. The concentrations of the solutions were tested at 5 min, 30 min and 60 min, respectively. The drug loading rates of the embolic microspheres were calculated, and drug loading curves of each drug corresponding to Examples 1 to 4 and Hepasphere embolic microspheres were plotted.

[0143] Table 5 Drug loading rate of the developed embolic microspheres and Hepaspheres in dry state in Examples 1 to 4

[0144]

[0145] Figure 8 The drug loading curves of carboplatin for the developing embolic microspheres and Hepaspheres of Examples 1 to 4 in the dry ball state; Fig. 9 The drug loading curves of the embolic microspheres and Hepaspheres of Examples 1 to 4 for oxaliplatin in the dry ball state are shown in Table 5. Figure 8 and Fig. 9 It can be seen that the developing microspheres in Examples 1 to 4 have a higher dry ball drug loading efficiency than the Hepasphere embolic microspheres. This is mainly because, in the developing embolic microspheres prepared in Examples 1 to 4, due to the presence of the developer, the molecular skeleton is relatively rigid, and the continuity of the channels in the microspheres can still be maintained in the dry ball state. When the dry ball swells, the pores in the microspheres are not easy to collapse, ensuring the smooth flow of drug molecules, so the loading speed is faster. The commercially available Hepasphere embolic microspheres mainly use hydrophilic polyvinyl alcohol PVA as the skeleton, and the microsphere channels collapse in the dry ball state, and the pores become smaller, so the drug loading speed is slower.

[0146] The embodiments described above are part of the embodiments of the present application, rather than all of the embodiments. The detailed description of the embodiments of the present application is not intended to limit the scope of the present application for protection, but merely represents the selected embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present application.

Claims

1. A developing embolic microsphere, characterized in that: The invention comprises a polymer network structure formed by cross-linking polymerization of a modified iodine-containing compound with a sulfonic acid group and polyhydroxyl groups and a cross-linking agent; wherein the cross-linking agent comprises a glycidyl ether compound with a propylene oxide terminal group; the modified iodine-containing compound is an iodine-containing compound with polyhydroxyl groups modified by a modifier with a sulfonic acid group, and the chemical structure of the iodine-containing compound is shown in formula (I): Among them, R1, R2, and R3 are hydroxyl-containing alkyl groups or their derivatives, and R4 is -H, alkyl groups or their derivatives.

2. The developing embolic microspheres according to claim 1, characterized in that: The iodine-containing compound comprises at least one of ioversol, iohexol, iodixanol, iomeprol, iopamidol, iopromide, iopentol or iotrolan; And / or, the glycidyl ether compound having propylene oxide terminal groups includes at least one of glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether or pentaerythritol glycidyl ether.

3. The developing embolic microspheres according to claim 1, characterized in that: The modifier includes at least one of the compounds shown in formula (II) or formula (III): Wherein, R4 is an alkyl group or a derivative thereof; R5 is an alkyl group containing a halogen atom or a derivative thereof.

4. A method for preparing developing embolic microspheres, characterized in that: The following steps are involved: S1: reacting a polyhydroxy iodine-containing compound and a modifier having a sulfonic acid group in an aqueous solution of an alkaline catalyst to obtain an aqueous solution of a modified iodine-containing compound having a sulfonic acid group and polyhydroxy; S2: adding a crosslinking agent to the aqueous solution of the modified iodine-containing compound to obtain an aqueous phase; S3: mixing the water phase and the oil phase to form an oil-in-water reverse suspension polymerization system, and obtaining developing embolic microspheres after the reaction; Wherein, the cross-linking agent comprises a glycidyl ether compound having an propylene oxide terminal group; the chemical structure of the iodine-containing compound is shown in formula (I): Among them, R1, R2, and R3 are hydroxyl-containing alkyl groups or their derivatives, and R4 is -H, alkyl groups or their derivatives.

5. The preparation method according to claim 4, characterized in that: The iodine-containing compound comprises at least one of ioversol, iohexol, iodixanol, iomeprol, iopamidol, iopromide, iopentol or iotrolan; And / or, the mass percentage of the modified iodine-containing compound in the aqueous phase is 20wt% to 50wt%; And / or, the molar ratio of the modified iodine-containing compound to the cross-linking agent is (0.1-0.5):

1.

6. The preparation method according to claim 4, characterized in that: The modifier includes at least one of the compounds shown in formula (II) or formula (III): Wherein, R4 is an alkyl group or a derivative thereof; R5 is an alkyl group containing a halogen atom or a derivative thereof; And / or, the molar ratio of the iodine-containing compound to the modifier is (0.5-1):

1.

7. The preparation method according to claim 4, characterized in that: The glycidyl ether compound having propylene oxide terminal groups includes at least one of glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether or pentaerythritol glycidyl ether.

8. The preparation method according to claim 4, characterized in that: The method for preparing the oil phase comprises: adding an oil-soluble dispersant into an oil-soluble solvent, stirring and mixing, and obtaining the oil phase; And / or, the mass percentage of the oil-soluble dispersant in the oil phase is 0.5wt% to 5wt%.

9. The preparation method according to claim 4, characterized in that: In step S3, the reaction temperature is 30°C to 90°C, and the reaction time is 5h to 36h.

10. Use of imaging embolic microspheres in the preparation of radiotherapy, chemotherapy and embolic combined therapeutic drugs and imaging diagnostic reagents for tumors, characterized in that: The developing embolic microspheres are the developing embolic microspheres as claimed in any one of claims 1 to 3; Or, the developing embolic microspheres are developing embolic microspheres prepared by the preparation method according to any one of claims 4 to 9.

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