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 an iodine-substituted aminobenzoic acid monomer and a glycidyl ether cross-linking agent with an epoxypropane end group. The developing embolism microsphere provided by the invention has good X-ray developing capability, relatively low density, excellent suspension performance and moderate hardness and elasticity, and can be effectively applied to preparation of tumor radiotherapy, chemotherapy and embolism combined treatment medicines and developing diagnostic reagents.

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 both an urgent clinical need and represent the development direction of advanced microsphere materials. They are of extremely high value both in academic and clinical use.

[0003] In existing research, there have been clinical reports on developing embolic microspheres (DC Bead LUMI), which have shown that they have significant clinical use value in precise control of surgical procedures, postoperative evaluation, and combined treatment indicators. However, in the process of realizing the developing function, a large number of highly hydrophobic developer molecules 2,3,5-triiodobenzaldehyde were introduced into the structure of LUMI microspheres, resulting in changes in physical properties such as a significant increase in microsphere density, a decrease in hydrophilicity, and a decrease in elasticity. Therefore, although DC Bead LUMITM has successfully achieved the developing function, other physical properties, such as elasticity, suspension performance, and catheter permeability, have decreased compared to conventional embolic microspheres, which severely limits the scope of clinical application of developing embolic microspheres. 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, so that the developing embolic microsphere has a good developing function while having a low density, excellent suspension performance, and moderate hardness and elasticity, thereby expanding the scope of clinical application of the developing embolic microsphere.

[0005] In a first aspect, an embodiment of the present application provides a developing embolic microsphere, comprising a polymer network structure formed by cross-linking polymerization of an iodine-substituted aminobenzoic acid monomer and a glycidyl ether cross-linking agent having a propylene oxide terminal group.

[0006] In the above technical scheme, by using iodine-substituted aminobenzoic acid compounds and glycidyl ether compounds with propylene oxide terminal groups to undergo epoxy ring-opening addition reaction to form a polymer network structure, the iodine-substituted structure can be introduced at the same time to achieve the development function without adding additional developer molecules. The development embolic microspheres not only have good X-ray development capabilities, but also have low density, excellent suspension performance, low hardness and high elasticity, which facilitates accurate intraoperative embolization and postoperative evaluation. In addition, the development embolic microspheres of the present application also have negatively charged carboxylate groups, so they have drug-carrying functions, can efficiently load a variety of cationic drugs, and are suitable for TACE treatment of a variety of drugs.

[0007] In some embodiments of the present application, the number of iodine-substituted groups in the iodine-substituted aminobenzoic acid monomer is at least three. By controlling the number of iodine-substituted groups, the iodine content of the developed embolic microspheres can be increased, thereby improving the development effect.

[0008] In some embodiments of the present application, the iodine-substituted aminobenzoic acid monomers include at least one of 5-amino-2,4,6-triiodoisophthalic acid, 3-acetylamino-5-amino-2,4,6-triiodobenzoic acid, 5-amino-N-(2-hydroxyethyl)-2,4,6-triiodoisophthalic acid or 3-amino-2,4,6-triiodobenzoic acid. The raw materials of these iodine-substituted aminobenzoic acid monomers are easy to obtain, low in cost, and all have a carboxyl group and three iodine-substituted groups, so that the prepared developing embolic microspheres can achieve efficient drug loading function while having excellent developing function.

[0009] In some embodiments of the present application, the glycidyl ether crosslinking agent having propylene oxide terminal groups has at least three propylene oxide groups. The propylene oxide terminal groups in the glycidyl ether crosslinking agent are located not only at the two ends but also at the side chains. The propylene oxide groups on the side chains are added to the amino groups in the iodine-substituted aminobenzoic acid monomers to form side chains, which is conducive to forming an interpenetrating network with a complex structure, thereby ensuring the hardness and elasticity of the microspheres.

[0010] In some embodiments of the present application, the glycidyl ether crosslinking agent having propylene oxide terminal groups includes at least one of glycerol triglycidyl ether, trimethylolpropane triglycidyl ether or pentaerythritol glycidyl ether. These glycidyl ether crosslinking agents include three or four propylene oxide groups, which are conducive to forming an interpenetrating network with a complex structure.

[0011] In a second aspect, an embodiment of the present application provides a method for preparing developing embolic microspheres, comprising the following steps: preparing an aqueous phase: dissolving an iodine-substituted aminobenzoic acid monomer and a glycidyl ether cross-linking agent having a propylene oxide terminal group in an alkaline catalyst aqueous solution to obtain an aqueous phase solution;

[0012] Preparing the oil phase: mixing the oil-soluble dispersant and the oil-soluble solvent to obtain an oil phase solution;

[0013] Inverse suspension polymerization: Under stirring conditions, the aqueous phase solution is added dropwise to the oil phase solution to form an oil-in-water inverse suspension polymerization system, which is then heated to react to obtain the developing embolic microspheres.

[0014] In the above technical scheme, by using iodine-substituted aminobenzoic acid compounds as water-soluble monomers, glycidyl ether compounds with propylene oxide end groups as cross-linking agents, amino and epoxy groups undergo ring-opening addition reactions to form a polymer network, and the iodine-substituted structure can be introduced while preparing the microspheres, thereby realizing the development function. In addition, the iodine content in the final development embolic microspheres can be controlled by controlling the number of iodine-substituted groups on the iodine-substituted aminobenzoic acid compounds, thereby regulating the development performance of the development embolic microspheres. The preparation method is simple, and no additional developer molecules need to be added. The prepared development embolic microspheres not only have good X-ray development capabilities, but also have lower density, excellent suspension performance, lower hardness and higher elasticity, which facilitates accurate intraoperative embolism and postoperative evaluation. In addition, the development embolic microspheres prepared in the present application also have negatively charged carboxylate groups, and thus have a drug-carrying function, can efficiently load a variety of cationic drugs, and are suitable for TACE treatment of a variety of drugs.

[0015] In some embodiments of the present application, the molar ratio of the iodine-substituted aminobenzoic acid monomer to the glycidyl ether crosslinking agent having propylene oxide terminal groups is 1:(0.5-2). Controlling the molar ratio of the two within a suitable range is conducive to sufficient reaction and crosslinking of the two.

[0016] In some embodiments of the present application, the solute in the alkaline catalyst aqueous solution includes at least one of sodium hydroxide or potassium hydroxide. And / or, the mass concentration of the alkaline catalyst aqueous solution is 15wt% to 25wt%. These alkaline catalysts can efficiently catalyze the epoxy ring-opening addition reaction between the glycidyl ether cross-linking agent and the iodine-substituted aminobenzoic acid monomer, and the reaction conditions are mild.

[0017] In some embodiments of the present application, the oil-soluble dispersant includes at least one of Span series compounds, Tween series compounds, octylphenol polyoxyethylene ether, dodecylphenol polyoxyethylene ether, cellulose acetate or cellulose acetate butyrate.

[0018] In some embodiments of the present application, the oil-soluble dispersant includes Tween 20 and Span 80, and the mass ratio of Tween 20 to Span 80 is (1:1) to (1:4).

[0019] In some embodiments of the present application, the mass concentration of the oil-soluble dispersant in the oil phase solution is 3 wt % to 6 wt %.

[0020] In some embodiments of the present application, the oil-soluble solvent includes at least one of petroleum ether, cyclohexane, liquid paraffin, n-decane, ethyl acetate or butyl acetate.

[0021] In some embodiments of the present application, in the reverse suspension polymerization step, the heating reaction temperature is 80° C. to 120° C., and the time is 18 h to 36 h.

[0022] In some embodiments of the present application, in the reverse phase suspension polymerization step, the stirring rate is 100 rpm to 300 rpm.

[0023] In some embodiments of the present application, the water phase solution accounts for 2 wt % to 20 wt % of the mass of the oil phase solution.

[0024] 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

[0025] 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.

[0026] Figure 1 This is a process flow chart of a method for preparing developing embolic microspheres provided in an embodiment of the present application.

[0027] Figure 2 This is an optical microscope picture of the developed embolic microspheres prepared in Example 1.

[0028] Figure 3 This is an optical microscope picture of the developed embolic microspheres prepared in Example 2.

[0029] Figure 4 This is an optical microscope picture of the developed embolic microspheres prepared in Example 3.

[0030] Figure 5 The in vitro Micro CT development test images of the developing embolic microspheres, iohexol 150 and non-developing microspheres DC Bead prepared in Example 1 are shown.

[0031] Figure 6 It is a test chart showing the change of drug loading rate of doxorubicin hydrochloride of the developing embolic microspheres of Examples 1 to 3 over time.

[0032] Figure 7It is a test graph showing the changes of the drug loading rate of irinotecan hydrochloride of the developing embolic microspheres of Examples 1 to 3 over time.

[0033] Figure 8 This is a test graph showing the changes in the drug loading rate of vinorelbine tartrate of the imaging embolic microspheres of Examples 1 to 3 over time. DETAILED DESCRIPTION

[0034] 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.

[0035] The following is a detailed description of a developing embolic microsphere and a preparation method thereof according to an embodiment of the present application.

[0036] Embolic microspheres, especially those loaded with drugs, have significant clinical value in precise control of surgical procedures, postoperative evaluation, and indicators of combined treatment. However, existing embolic microspheres, such as DC Bead LUMI, which has been clinically reported, are modified by introducing a large number of highly hydrophobic developer molecules into the original polyethylene glycol hydrogel skeleton, resulting in a higher density, poorer elasticity, and poorer hydrophilicity of the microspheres, which results in poor suspension ability, which is not conducive to smooth delivery and precise control during surgery, and is prone to damage blood vessels during delivery.

[0037] Based on this, the embodiment of the present application provides a developing embolic microsphere, Figure 1 For a process flow chart of a method for preparing a developing embolic microsphere provided in the embodiment of the present application, please refer to Figure 1 , the preparation method comprises the following steps:

[0038] S110, preparing an aqueous phase: dissolving an iodine-substituted aminobenzoic acid monomer and a glycidyl ether cross-linking agent having a propylene oxide terminal group in an alkaline catalyst aqueous solution to obtain an aqueous phase solution.

[0039] In some embodiments, the iodine-substituted groups in the iodine-substituted aminobenzoic acid monomer are at least three, for example, three or four. As an example, the iodine-substituted aminobenzoic acid monomer includes at least one of 5-amino-2,4,6-triiodoisophthalic acid, 3-acetylamino-5-amino-2,4,6-triiodobenzoic acid, 5-amino-N-(2-hydroxyethyl)-2,4,6-triiodoisophthalic acid or 3-amino-2,4,6-triiodobenzoic acid.

[0040] In some embodiments, the glycidyl ether crosslinking agent having propylene oxide terminal groups has at least three propylene oxide groups, two of which may be terminal groups and the other propylene oxide groups may be side groups, thereby achieving ring-opening addition on the side chain.

[0041] As an example, the glycidyl ether-based cross-linking agent having a propylene oxide terminal group includes at least one of glycerol triglycidyl ether, trimethylolpropane triglycidyl ether, and pentaerythritol glycidyl ether.

[0042] In some embodiments, the molar ratio of the iodine-substituted aminobenzoic acid monomer to the glycidyl ether cross-linking agent having a propylene oxide terminal group is 1:(0.5-2). As an example, the molar ratio of the iodine-substituted aminobenzoic acid monomer to the glycidyl ether cross-linking agent having a propylene oxide terminal group can be 1:0.7, 1:0.8, 1:1, 1:1.5, 1:2.

[0043] The step of preparing the aqueous phase may include: dissolving the alkaline catalyst in water to prepare an alkaline catalyst aqueous solution with a mass concentration of 15wt% to 25wt%, adding an iodine-substituted aminobenzoic acid monomer and stirring to dissolve, and then adding a glycidyl ether cross-linking agent with a propylene oxide terminal group and stirring for 0.5h to 6h to obtain a uniform aqueous prepolymer solution.

[0044] In some embodiments, the solute in the aqueous alkaline catalyst solution includes at least one of sodium hydroxide or potassium hydroxide.

[0045] As an example, the mass concentration of the alkaline catalyst aqueous solution can be 15wt%, 20wt%, 25wt%; the stirring time can be 0.5h, 2h, 4h, 4.5h, 5h, 6h.

[0046] S120, preparing an oil phase: mixing an oil-soluble dispersant and an oil-soluble solvent to obtain an oil phase solution.

[0047] 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. As an example, the oil-soluble dispersant includes Tween 20 and Span 80, and the mass ratio of Tween 20 to Span 80 is (1:1) to (1:4), for example, 1:1, 1:3, 1:4, etc.

[0048] In some embodiments, the mass concentration of the oil phase dispersant in the oil phase solution is 3 wt % to 6 wt %. As an example, the mass concentration of the oil phase dispersant is 3 wt %, 4 wt %, 5 wt %, or 6 wt %.

[0049] 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.

[0050] S120, reverse suspension polymerization: slowly drop the aqueous phase solution into the oil phase solution under stirring to form an oil-in-water reverse suspension polymerization system, and heat the reaction to obtain the developing embolic microspheres.

[0051] In some embodiments, the temperature of the heating reaction is 80°C to 120°C, and the time is 18h to 36h. As an example, the temperature of the heating reaction is 80°C, 90°C, 100°C, 120°C, and the time is 18h, 20h, 24h, 36h.

[0052] In some embodiments, the stirring rate is 100 rpm to 300 rpm. As an example, the stirring rate can be 100 rpm, 200 rpm, 250 rpm, or 300 rpm.

[0053] In some embodiments, the water phase solution is 2% to 20% of the mass of the oil phase solution. As an example, the water phase solution is 2%, 3%, 10%, 20%, etc., of the mass of the oil phase solution.

[0054] In some embodiments, after the reverse suspension polymerization reaction, the process further comprises: standing, washing, and sieving. For example, stirring and heating are stopped, and the mixture is allowed to stand for separation to separate the layers, and the gel phase microspheres in the lower layer are separated, and the microspheres are 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.

[0055] 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.

[0056] In the present application, polyamino iodine-containing compounds are used as water-soluble monomers, glycidyl ether compounds are used as cross-linking agents, and glycidyl ether cross-linking agents with propylene oxide end groups are subjected to epoxy ring opening in alkaline catalysts, and the amino groups in the aminobenzoic acid monomers can be subjected to addition reaction to form a polymer network, so as to realize the introduction of developer molecules while preparing microspheres, and the preparation method is simple and the reaction conditions are mild. The developed embolic microspheres prepared have high iodine content and low wet bulb density at the same time, so they have good X-ray development ability and excellent suspension performance at the same time, which facilitates accurate intraoperative embolism and postoperative evaluation. In addition, the developed embolic microspheres prepared in the present application also have drug loading function, and can efficiently load a variety of cationic drugs (such as doxorubicin hydrochloride, irinotecan hydrochloride and vinorelbine tartrate, etc.), which are suitable for TACE treatment of various drugs, and are particularly suitable for bronchial artery chemoembolization (Bronchoarterialchemoembolization, referred to as BACE) treatment of lung cancer.

[0057] The features and performance of the technical solution of the present application are further described in detail below in conjunction with the embodiments.

[0058] Example 1

[0059] This embodiment provides a developing embolic microsphere, and its preparation process is represented by a chemical structural formula as shown in formula (I):

[0060]

[0061] The specific preparation method comprises the following steps:

[0062] Prepare the aqueous phase: 2 mL of NaOH aqueous solution (20 wt%), add 1.0 g of 5-amino-2,4,6-triiodoisophthalic acid under stirring, after dissolution, add 300 μL of glycerol triglycidyl ether dropwise, stir for 270 min, and obtain a uniform aqueous phase solution.

[0063] Prepare the oil phase: add 0.75 g of Tween 20 and 2.25 g of Span 80 into 100 mL of liquid paraffin and mix well to obtain an oil phase solution.

[0064] Inverse suspension polymerization: Under stirring conditions at room temperature, slowly drop the aqueous phase solution into the oil phase solution to form an oil-in-water inverse suspension polymerization system. After the dropwise addition is completed, the inverse suspension polymerization system is heated to 100°C, and the stirring and heating state is maintained at a stirring rate of 300 rpm. The reaction is carried out at 100°C for 18 hours, and then the stirring and heating are stopped, and the layers are allowed to stand to separate and obtain the gel microspheres in the lower layer. After washing with petroleum ether, butyl acetate, sodium bicarbonate aqueous solution and ultrapure water in turn, the microspheres are screened through sieves with different apertures to obtain the developing embolic microspheres with different particle size distributions.

[0065] Figure 2 This is an optical microscope picture of the developed embolic microspheres prepared in Example 1. Figure 2 It can be seen that the developed embolic microspheres are round and regular spherical.

[0066] Example 2

[0067] This embodiment provides a developing embolic microsphere, and its preparation process is represented by a chemical structural formula as shown in formula (II):

[0068]

[0069] The specific preparation method comprises the following steps:

[0070] Prepare the aqueous phase: 2 mL of NaOH aqueous solution (25 wt%), add 1.2 g of 5-amino-2,4,6-triiodoisophthalic acid under stirring, after dissolution, add 500 μL of trimethylolpropane triglycidyl ether dropwise, stir for 360 min, and obtain a uniform aqueous phase solution.

[0071] Prepare the oil phase: add 0.75 g of Tween 20 and 2.25 g of Span 80 into 100 mL of cyclohexane and mix well to obtain an oil phase solution.

[0072] Inverse suspension polymerization: Under stirring conditions at room temperature, slowly drop the aqueous phase solution into the oil phase solution to form an oil-in-water inverse suspension polymerization system. After the dropwise addition is completed, the inverse suspension polymerization system is heated to 100°C, and the stirring and heating state is maintained at a stirring rate of 250rpm. The reaction is carried out at 100°C for 18 hours, and then the stirring and heating are stopped, and the layers are allowed to stand to separate and obtain the gel microspheres in the lower layer. After washing with petroleum ether, butyl acetate, sodium bicarbonate aqueous solution and ultrapure water in turn, the microspheres are screened through sieves with different apertures to obtain the developing embolic microspheres with different particle size distributions.

[0073] Figure 3 This is an optical microscope picture of the developed embolic microspheres prepared in Example 2. Figure 3 It can be seen that the developed embolic microspheres are round and regular spherical.

[0074] Example 3

[0075] This embodiment provides a developing embolic microsphere, and its preparation process is represented by a chemical structural formula as shown in formula (III):

[0076]

[0077] The specific preparation method comprises the following steps:

[0078] Prepare the aqueous phase: 2 mL of NaOH aqueous solution (15 wt%), add 1.0 g of 5-amino-2,4,6-triiodoisophthalic acid under stirring, after dissolution, add 350 μL of pentaerythritol glycidyl ether dropwise, stir for 240 min, and obtain a uniform aqueous phase solution.

[0079] Prepare the oil phase: add 6 g of OP-10 into 100 mL of n-decane and mix well to obtain an oil phase solution.

[0080] Inverse suspension polymerization: Under stirring conditions at room temperature, slowly drop the aqueous phase solution into the oil phase solution to form an oil-in-water inverse suspension polymerization system. After the dropwise addition is completed, the inverse suspension polymerization system is heated to 100°C, and the stirring and heating state is maintained at a stirring rate of 350rpm. The reaction is carried out at 100°C for 18 hours, and then the stirring and heating are stopped, and the layers are allowed to stand to separate and obtain the gel microspheres in the lower layer. After washing with petroleum ether, butyl acetate, sodium bicarbonate aqueous solution and ultrapure water in turn, the developed embolic microspheres with different particle size distributions are obtained by sieving through sieves with different apertures.

[0081] Figure 4 This is an optical microscope picture of the developed embolic microspheres prepared in Example 3. Figure 4 It can be seen that the developed embolic microspheres are round and regular spherical.

[0082] Performance testing and result analysis

[0083] 1. Development performance

[0084] The developing embolic microspheres prepared in each embodiment were taken, with a particle size of 100μm to 300μm, and the developing performance was tested by in vitro Micro CT images and HU values. HU value test method: The developing embolic microspheres prepared in each embodiment were subjected to MicroCT testing to evaluate the linear opacity of the developing embolic microsphere samples prepared according to the above method. The beads were suspended in 0.5% agarose gel in a Nunc cryostat vial, and the linear opacity of the developing embolic microspheres was tested using a micro CT imaging system scanner equipped with a tungsten anode and micro-computed tomography technology (micro CT imaging system). The image was then segmented to separate the polymer from the pore structure in order to report the polymer radiation density. The radiation density in HU was then calculated using a water standard obtained on the same day.

[0085] Taking iohexol 150 (i.e., 150 mg of iodine per unit volume of solution) and non-developing microspheres DC Bead (particle size of 100 μm to 300 μm) as comparison, the HU values ​​of each sample are shown in Table 1:

[0086] Table 1 HU values ​​of each sample

[0087] sample HU value Example 1 2342 Example 2 2287 Example 3 2301 Iohexol 150 1685 DC Bead 58

[0088] Figure 5 The in vitro Micro CT imaging test images of the imaging embolic microspheres, iohexol 150 and non-imaging microspheres DC Bead prepared in Example 1. Figure 5 A in the figure is an in vitro Micro CT development test image of the development embolic microspheres prepared in Example 1, Figure 5 B in the figure is the in vitro Micro CT imaging test image of iohexol 150. Figure 5 C in FIG. 1 is a Micro CT imaging test image of non-developing microspheres DCBead in vitro. Figure 5 It can be seen that the HU values ​​of the developing embolic microspheres prepared in Examples 1 to 3 of the present application are all high, and are higher than iohexol 150, and have good X-ray developing ability. The measured HU value of the non-developing microsphere DC Bead is low, no imaging is performed under the CT imaging system, and no X-ray developing ability is achieved.

[0089] 2. Physical properties

[0090] Using the non-developing microspheres DC Bead and the above-listed developing embolic microspheres DC Bead LUMI as comparison, the density, stable suspension time, strength and elasticity of each sample microsphere of the embodiment were tested respectively, and the test method is as follows:

[0091] (1) Density: measured by density gradient column method.

[0092] (2) Stable suspension time: 1 mL of microspheres was placed in a measuring cylinder, 10 mL of saline was added, and the mixture was gently shaken. The time required for the microspheres to settle to 70% of the total amount was measured. This time was the time during which the microspheres could be suspended in the saline.

[0093] (3) Strength / elasticity: The microspheres were spread on the support sheet to form a single layer. The strength and elasticity were measured using a texture analyzer (TAXTplusC). A 6 mm probe was selected and the trigger force was 0.1 g. The microspheres were compressed to 50% and held for 60 seconds. Strength was defined as the maximum force during the 50% compression process, and elasticity was defined as whether the microspheres could recover their spherical shape after being compressed to a certain percentage.

[0094] The above test results are shown in Table 2:

[0095] Table 2 Physical properties of each sample

[0096]

[0097] As shown in Table 2, the developing embolic microspheres prepared by direct cross-linking in Examples 1 to 3 all have lower density, lower strength and higher elasticity, and the stable suspension time in physiological saline is not less than 8 minutes, the strength is greater than 90g, and the elasticity is about 70%. The density, stable suspension time, strength and elasticity of the developing embolic microspheres prepared in the examples of the present application are far superior to those of the developing embolic microspheres DC Bead LUMI that have been marketed.

[0098] 3. Drug loading performance

[0099] Doxorubicin hydrochloride (DOx), irinotecan hydrochloride and vinorelbine tartrate were dissolved in purified water to prepare 20 mg / mL, 25 mg / mL and 10 mg / mL drug solutions, respectively. The drug solution needs to be ultrasonicated before testing to evenly disperse the drugs. In Examples 1 to 3, 1 mL of 100 μm to 300 μm wet bulb was measured in a 10 mL vial, and then 2 mL of drug solution was added and quickly shaken evenly. At the corresponding time point, 20 μL of the upper layer of drug solution was aspirated, and the drug solution was diluted to 1 mL with 980 μL of purified water, and the concentration of the corresponding drug was tested by liquid chromatography to calculate the amount of drug loaded on the embolic microspheres. The test results are shown in Table 3 and Figures 6 to 8 shown.

[0100] Table 3 Drug loading rate of the imaging embolic microspheres in Examples 1 to 3

[0101]

[0102] From Table 3 and Figure 6 , Figure 7 and Figure 8 It can be seen that the imaging embolic microspheres prepared in Examples 1 to 3 can achieve effective and rapid loading of various drugs. The drug loading rate of doxorubicin hydrochloride in the imaging embolic microspheres in Example 3 is as high as 93% in only 1 minute, and each sample can basically complete the drug loading within 5 minutes.

[0103] 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 iodine-substituted aminobenzoic acid monomers and glycidyl ether cross-linking agents having propylene oxide terminal groups.

2. The developing embolic microspheres according to claim 1, characterized in that: The iodine-substituted aminobenzoic acid monomer has at least three iodine-substituted groups; And / or, the iodine-substituted aminobenzoic acid monomer includes at least one of 5-amino-2,4,6-triiodoisophthalic acid, 3-acetylamino-5-amino-2,4,6-triiodobenzoic acid, 5-amino-N-(2-hydroxyethyl)-2,4,6-triiodoisophthalic acid or 3-amino-2,4,6-triiodobenzoic acid.

3. The developing embolic microspheres according to claim 1, characterized in that: The glycidyl ether cross-linking agent having propylene oxide terminal groups has at least three propylene oxide groups; And / or, the glycidyl ether cross-linking agent having propylene oxide terminal groups includes at least one of glycerol triglycidyl ether, trimethylolpropane triglycidyl ether or pentaerythritol glycidyl ether.

4. A method for preparing developing embolic microspheres, characterized in that: The following steps are involved: Prepare the aqueous phase: dissolve the iodine-substituted aminobenzoic acid monomer and the glycidyl ether cross-linking agent having propylene oxide terminal groups in an alkaline catalyst aqueous solution to obtain an aqueous phase solution; Preparing the oil phase: mixing the oil-soluble dispersant and the oil-soluble solvent to obtain an oil phase solution; Inverse suspension polymerization: under stirring conditions, the aqueous phase solution is added dropwise to the oil phase solution to form an oil-in-water inverse suspension polymerization system, and the system is heated for reaction to obtain developing embolic microspheres.

5. The preparation method according to claim 4, characterized in that: The solute in the alkaline catalyst aqueous solution includes at least one of sodium hydroxide or potassium hydroxide; And / or, the mass concentration of the alkaline catalyst aqueous solution is 15wt% to 25wt%.

6. The preparation method according to claim 4, characterized in that: The molar ratio of the iodine-substituted aminobenzoic acid monomer to the glycidyl ether cross-linking agent having propylene oxide terminal groups is 1:(0.5-2).

7. The preparation method according to claim 4, characterized in that: The oil-soluble dispersant includes at least one of a Span series compound, a Tween series compound, octylphenol polyoxyethylene ether, dodecylphenol polyoxyethylene ether, cellulose acetate or cellulose acetate butyrate; And / or, the oil-soluble dispersant comprises Tween 20 and Span 80, and the mass ratio of Tween 20 to Span 80 is (1:1) to (1:4); And / or, the mass concentration of the oil-soluble dispersant in the oil phase solution is 3wt% to 6wt%.

8. The preparation method according to claim 4, characterized in that: The oil-soluble solvent includes at least one of petroleum ether, cyclohexane, liquid paraffin, n-decane, ethyl acetate or butyl acetate.

9. The preparation method according to claim 4, characterized in that: In the reverse phase suspension polymerization step, the heating reaction temperature is 80°C to 120°C and the time is 18h to 36h; And / or, the stirring rate is 100 rpm to 300 rpm; And / or, the water phase solution is 2% to 20% of the mass of the oil phase solution.

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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