A kind of developing embolic microsphere and preparation method thereof

Abstract

A developing embolic microsphere and a preparation method thereof, belonging to the field of medical device technology. The developing embolic microsphere comprises a fluorine-containing compound, a hydroxyl-containing acrylamide monomer, a cross-linking agent containing an epoxy end group, and an ionic monomer containing a double bond, and a network structure formed by cross-linking polymerization. Among them, the fluorine-containing compound contains a silicon-oxygen bond and / or an end group with an epoxy group. The fluorine-containing compound is introduced into the embolic microsphere by chemical reaction. The fluorine-containing compound is not easy to seep out of the embolic microsphere. The fluorine-containing compound can be used as a nuclear magnetic resonance contrast agent, and has the characteristics of low toxicity and high contrast, which can make the embolic microsphere have good developing signal intensity. In addition, the fluorine-containing compound is also hydrophobic. The introduction of the fluorine-containing compound enables the embolic microsphere to have good drug loading and release properties for hydrophobic drugs.

Description

Technical Field

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

[0002] Tumors, especially malignant tumors, have always been a difficult problem in the field of clinical medicine. Conventional methods for treating tumors include surgical resection, radiotherapy, and chemotherapy. Surgical treatment can directly remove the lesion, but the effect is poor when the cancer cells have already metastasized. Tumor resection may not be thorough enough, resulting in secondary cancer cell metastasis.

[0003] In recent years, with the rapid development of minimally invasive interventional technology, transarterial chemoembolization (TACE) has gradually become a popular treatment method. TCAE is an important means of clinical treatment of advanced liver cancer. The embolic material loaded with anti-tumor drugs is injected into the blood supply artery of liver cancer through an arterial or intravenous catheter to block the blood vessels and interrupt the blood supply to achieve the purpose of treating the tumor. Drug-loaded embolic microspheres are a new and good delivery system that can carry drugs accurately to the tumor site, and through local sustained release of drugs, continuous treatment while reducing toxic and side effects.

[0004] At present, commonly used embolic microspheres usually do not have a development function and usually need to be used with contrast agents during application, which puts patients at risk of allergies, as well as the risk of blurred development and misdiagnosis, and is not conducive to postoperative observation. Therefore, it is necessary to provide a drug-loaded embolic microsphere with a development function. Summary of the invention

[0005] The purpose of the present application is to provide a developing embolic microsphere and a preparation method thereof. The developing embolic microsphere has a developing function and can also load hydrophobic drugs.

[0006] The embodiment of the present application is implemented as follows:

[0007] In the first aspect, the embodiment of the present application provides a developing embolic microsphere, comprising a fluorine-containing compound, a hydroxyl-containing acrylamide monomer, a cross-linking agent containing an epoxy terminal group, and an ionic monomer containing a double bond, and a network structure is formed by cross-linking polymerization. The fluorine-containing compound contains a silicon-oxygen bond and / or an epoxy terminal group.

[0008] In the above technical scheme, the hydroxyl-containing acrylamide monomer can undergo an epoxy ring-opening addition reaction with a cross-linking agent containing an epoxy terminal group to form a long-chain segment compound having a hydroxyl group. Since the fluorine-containing material contains a silicon-oxygen bond or an epoxy group at the terminal group, it can be connected to the hydroxyl group of the long-chain segment compound through a chemical covalent bond to obtain a fluorine-containing long-chain segment compound. The fluorine-containing long-chain segment compound can form a mesh-structured embolic microsphere through a double bond addition reaction with an ionic monomer containing a double bond. In addition, the fluorine-containing compound is introduced into the embolic microsphere through a chemical bond, and the fluorine-containing compound is not easy to seep out of the embolic microsphere. The fluorine-containing compound can be used as a nuclear magnetic resonance contrast agent, and the fluorine-containing compound has the characteristics of low toxicity and high contrast, which can make the embolic microsphere have a good development signal intensity. During use, the use of other developers can be reduced, and even other developers do not need to be used additionally. In addition, the present application introduces fluorine-containing compounds into the embolic microspheres by means of chemical bonds. Fluorine-containing compounds are generally hydrophobic. The introduction of fluorine-containing compounds enables the embolic microspheres to have good loading / release properties for hydrophobic drugs.

[0009] In a second aspect, the present application provides a method for preparing developing embolic microspheres, comprising:

[0010] S1. Add a crosslinking agent containing epoxy terminal groups under alkaline solution conditions, then add acrylamide monomer containing hydroxyl groups and a fluorine-containing compound to react to obtain an intermediate compound. The fluorine-containing compound contains a silicon-oxygen bond and / or an epoxy terminal group.

[0011] S2. After adjusting the pH value of the alkaline solution to neutral, add an ionic monomer containing a double bond and an initiator to form an aqueous solution.

[0012] S3, adding the aqueous phase solution dropwise into the oil phase solution to form an oil-in-water reverse suspension polymerization system, stirring, heating and reacting to obtain developing embolic microspheres.

[0013] In the above technical scheme, under alkaline conditions, the hydroxyl-containing acrylamide monomer can undergo an epoxy ring-opening addition reaction with a cross-linking agent containing an epoxy terminal group to form a long-chain segment compound with a hydroxyl group. Since the fluorine-containing material contains a silicon-oxygen bond or an epoxy group at the terminal, it can be connected to the hydroxyl group of the long-chain segment compound through a chemical covalent bond to obtain an intermediate compound of a fluorine-containing long-chain segment. After adjusting the pH to neutral, an ionic monomer containing a double bond and a free radical initiator are added to obtain an aqueous solution. The aqueous solution is added to the oil phase solution to form an oil-in-water reverse suspension polymerization system, which is stirred, heated, and reacted for a certain period of time. The intermediate compound of the fluorine-containing long-chain segment can react with the ionic monomer containing a double bond through a double bond addition reaction to form a network-structured embolic microsphere.

[0014] Fluorinated compounds are introduced into the embolic microspheres through chemical bonds, and the fluorinated compounds are not easy to seep out of the embolic microspheres. Fluorinated compounds can be used as nuclear magnetic resonance contrast agents, and the fluorinated compounds have the characteristics of low toxicity and high contrast, which can make the embolic microspheres have good imaging signal intensity. In the use of the developed embolic microspheres provided in the embodiments of the present application, the use of other developers can be reduced, and even no additional use of other developers is required.

[0015] In addition, the present application introduces fluorine-containing compounds into the embolic microspheres by means of chemical bonds. Fluorine-containing compounds are usually hydrophobic. The introduction of fluorine-containing compounds enables the embolic microspheres to generate a greater force with the hydrophobic drugs, thereby having good loading / release properties for the hydrophobic drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] 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.

[0017] Figure 1 This is a flow chart of the preparation process of the developing embolic microspheres provided in the embodiments of the present application. DETAILED DESCRIPTION

[0018] The embodiments of the present application will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. In the examples, if specific conditions are not specified, they are carried out according to normal 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.

[0019] In recent years, with the rapid development of minimally invasive interventional technology, transarterial chemoembolization (TACE) has gradually become a popular treatment method. TCAE is an important means of clinical treatment of advanced liver cancer. The embolic material loaded with anti-tumor drugs is injected into the blood supply artery of liver cancer through an arterial or intravenous catheter to block the blood vessels and interrupt the blood supply to achieve the purpose of treating the tumor. Drug-loaded embolic microspheres are a new and good delivery system that can carry drugs accurately to the tumor site, and through local sustained release of drugs, continuous treatment while reducing toxic and side effects.

[0020] However, currently used embolic microspheres usually do not have imaging function and usually need to be used with contrast agents during application, which puts patients at risk of allergies, as well as the risk of blurred imaging and misdiagnosis, and is not conducive to postoperative observation. Therefore, it is necessary to provide an embolic microsphere with imaging function that can be loaded with drugs.

[0021] In order to prepare an embolic microsphere with a developing function, attempts have been made to embed developing materials to give the embolic microsphere a developing function. However, the embolic microspheres prepared by embedding developing materials often have a rough microsphere morphology and a risk of leakage of the embedded developing materials.

[0022] In order to further reduce the risk of developer material leakage, attempts have been made to introduce developer materials by chemical methods so that the microspheres have developer functions. However, developer materials introduced by chemical methods are mainly iodine-containing compounds, and the prepared microspheres usually have problems such as high density, high strength, poor suspension, and poor developer signal intensity. Therefore, iodine-containing developer embolization microspheres have certain operational difficulties in practical applications.

[0023] Furthermore, current imaging embolic microspheres can usually only load cationic drugs, and have weak or no loading and release performance for hydrophobic small molecule drugs and non-cationic drugs. Therefore, it is necessary to provide imaging embolic microspheres that can load hydrophobic drugs.

[0024] Based on this, the present application further improves the imaging embolic microspheres, thereby improving the problems of low imaging signal intensity and poor hydrophobic drug loading / release performance of the embolic microspheres to a certain extent. In order to make the purpose, technical solution and advantages of the embodiments of the present application clearer, the technical solution in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application.

[0025] In the first aspect, the embodiment of the present application provides a developing embolic microsphere, comprising a fluorine-containing compound, a hydroxyl-containing acrylamide monomer, a cross-linking agent containing an epoxy terminal group, and an ionic monomer containing a double bond, and a network structure is formed by cross-linking polymerization. The fluorine-containing compound contains a silicon-oxygen bond and / or an epoxy terminal group.

[0026] The developing embolic microspheres provided in the embodiments of the present application include a network structure formed by cross-linking polymerization of fluorinated compounds, hydroxyl-containing acrylamide monomers, epoxy end-group-containing crosslinking agents, and double-bond-containing ionic monomers. The fluorinated compounds are not easy to seep out of the embolic microspheres. The fluorinated compounds can be used as nuclear magnetic resonance contrast agents, and the fluorinated compounds have the characteristics of low toxicity and high contrast, which can make the embolic microspheres have good developing signal intensity. During use, the use of other developers can be reduced, and even other developers do not need to be used additionally. In addition, the present application introduces fluorinated compounds into the embolic microspheres by means of chemical bonds. The fluorinated compounds are usually hydrophobic. The introduction of fluorinated compounds makes the embolic microspheres have good loading / release properties for hydrophobic drugs.

[0027] In the present application, "crosslinking agent containing epoxy terminal groups" means that the terminal groups of the crosslinking agent include epoxy groups.

[0028] In some embodiments, the cross-linking agent containing epoxy terminal groups includes a glycidyl ether compound having a terminal group of propylene oxide.

[0029] As an example, the cross-linking agent containing epoxy terminal groups includes at least one of polyethylene glycol diglycidyl ethers having a degree of polymerization of 1 to 12.

[0030] As an example, the cross-linking agent containing epoxy terminal groups includes at least one of ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, PEG200 diglycidyl ether, or PEG500 diglycidyl ether.

[0031] It is understood that "PEG200 diglycidyl ether" refers to polyethylene glycol diglycidyl ether with a molecular weight of 200. Similarly, "PEG500 diglycidyl ether" refers to polyethylene glycol diglycidyl ether with a molecular weight of 500.

[0032] In some embodiments, the hydroxyl-containing acrylamide monomer includes at least one of N-methylol acrylamide, N-hydroxyethyl acrylamide, N-[tris(hydroxymethyl)methyl]acrylamide, N-(2-hydroxypropyl)acrylamide, N-(hydroxymethyl)methacrylamide, N-(hydroxyethyl)methacrylamide, and N-(2-hydroxypropyl)methacrylamide.

[0033] In the present application, in order to facilitate the introduction of the fluorine-containing compound into the developing embolic microsphere material through chemical bonds, the fluorine-containing compound contains a silicon-oxygen bond and / or an end group with an epoxy group.

[0034] In some embodiments, the fluorine-containing compound includes a fluorine-containing methoxysilane.

[0035] As an example, the fluorine-containing methoxysilane includes at least one of trimethoxy(3,3,3-trifluoropropyl)silane and trimethoxy(1H,1H,2H,2H-heptadecafluorodecane)silane.

[0036] In some embodiments, the fluorine-containing compound includes a fluorine-containing compound having an epoxy group at the terminal, and the fluorine-containing compound having an epoxy group at the terminal includes 1,2-epoxy-3,3,3-trifluoropropane.

[0037] In some embodiments, the double bond-containing ionic monomer includes at least one of sodium itaconate, sodium acrylate, sodium methacrylate, sodium 2-acrylamido-2-methylpropane sulfonate, sodium p-styrene sulfonate, sodium vinyl sulfonate, (3-acrylamidopropyl)trimethylammonium chloride, and (3-methacrylamidopropyl)trimethylammonium chloride.

[0038] As an example, the ionic monomer containing a double bond may be selected from sodium acrylate.

[0039] It can be understood that the amount of each raw material used to form the cross-linked polymerized network structure is closely related to the quality of the developed embolic microspheres. Based on this, the amount of each raw material used can be limited.

[0040] In some embodiments, the molar ratio of the hydroxyl-containing acrylamide monomer to the fluorine-containing compound is (1-5):1.

[0041] As an example, the molar ratio of the hydroxyl-containing acrylamide monomer to the fluorine-containing compound may be in a range between one or any two of 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1 and 5:1.

[0042] As an example, the molar ratio of the hydroxyl-containing acrylamide monomer to the fluorine-containing compound is (1-3):1.

[0043] As an example, the molar ratio of the hydroxyl-containing acrylamide monomer to the fluorine-containing compound is (3-5):1.

[0044] In some embodiments, the molar ratio of the cross-linking agent containing epoxy terminal groups: the acrylamide monomer containing hydroxyl groups: the ionic monomer containing double bonds is 1:(2-4):(1-8).

[0045] As an example, the molar ratio of the crosslinking agent containing epoxy terminal groups to the acrylamide monomer containing hydroxyl groups may be in the range of one or any two of 1:2, 1:2.5, 1:3, 1:3.5 and 1:4.

[0046] As an example, the molar ratio of the crosslinking agent containing epoxy terminal groups to the ionic monomer containing double bonds may range from one or any two of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 and 1:8.

[0047] In the above embodiment, the molar ratio of the hydroxyl-containing acrylamide monomer and the fluorine-containing compound is controlled to be (1-5):1, and the molar ratio of the epoxy end-containing cross-linking agent: the hydroxyl-containing acrylamide monomer: the double-bond-containing ionic monomer is controlled to be 1:(2-4):(1-8). By adjusting the fluorine content of the introduced fluorine-containing compound and the cross-linking degree of the microspheres, not only can the fluorine content in the developing embolic microspheres be regulated, and thus the developing strength of the developing embolic microspheres can be adjusted, but also the drug loading and releasing properties of the developing embolic microspheres for hydrophobic drugs can be adjusted.

[0048] The developing embolic microspheres provided in the embodiments of the present application have good developing strength, good mechanical properties, low density and good loading and releasing properties for hydrophobic drugs.

[0049] In the second aspect, the present application provides a method for preparing developing embolic microspheres, see Figure 1 ,include:

[0050] S1. Add a crosslinking agent containing epoxy terminal groups under alkaline solution conditions, then add acrylamide monomer containing hydroxyl groups and a fluorine-containing compound to react to obtain an intermediate compound. The fluorine-containing compound contains a silicon-oxygen bond and / or an epoxy terminal group.

[0051] S2. After adjusting the pH value of the alkaline solution to neutral, add an ionic monomer containing a double bond and an initiator to form an aqueous solution.

[0052] S3, adding the aqueous phase solution dropwise into the oil phase solution to form an oil-in-water reverse suspension polymerization system, stirring, heating and reacting to obtain developing embolic microspheres.

[0053] In step S1, under alkaline conditions, the hydroxyl-containing acrylamide monomer can undergo an epoxy ring-opening addition reaction with the crosslinking agent containing an epoxy terminal group to form a long-chain segment compound having a hydroxyl group. Since the fluorine-containing compound contains a silicon-oxygen bond or an epoxy group at the terminal, it can be connected to the hydroxyl group of the long-chain segment compound through a chemical covalent bond to obtain an intermediate compound of a fluorine-containing long-chain segment.

[0054] In step S2, after adjusting the pH to neutral, the ionic monomer containing a double bond and the free radical initiator are added to obtain an aqueous solution containing the free radical initiator, the ionic monomer containing a double bond and the intermediate compound containing the fluorine-containing long chain segment.

[0055] In step S3, the aqueous solution obtained in step S2 is added to the oil phase solution to form an oil-in-water reverse suspension polymerization system. After stirring and heating for a certain period of reaction, the intermediate compound containing the fluorine long chain segment can react with the ionic monomer containing the double bond through a double bond addition reaction to form embolic microspheres with a network structure.

[0056] According to the above method, the developing embolic microspheres can be prepared, and fluorine-containing compounds can be introduced into the developing embolic microspheres through chemical bonds. The fluorine-containing compounds can be used as nuclear magnetic resonance contrast agents, and have the characteristics of low toxicity and high contrast, which can make the embolic microspheres have good developing signal intensity. During use, the use of other developing agents can be reduced or even no additional use of other developing agents is required.

[0057] Furthermore, compared with embedding the developing material in the embolic microspheres, the embodiment of the present application introduces the fluorine-containing compound into the embolic microspheres by chemical reaction. The fluorine-containing compound and other materials in the microspheres form the developing embolic microspheres as an organic whole. The fluorine-containing compound is not easy to seep out, which can improve the safety of the developing embolic microspheres and the stability of the developing signal.

[0058] In addition, the present application introduces fluorine-containing compounds into the embolic microspheres by means of chemical bonds. Fluorine-containing compounds are generally hydrophobic. The introduction of fluorine-containing compounds enables the developed embolic microspheres to have good drug loading and release properties for hydrophobic drugs.

[0059] In the above preparation method, the selection range and content of the cross-linking agent containing epoxy end groups, the acrylamide monomer containing hydroxyl groups, the fluorine-containing compound and the ionic monomer containing double bonds can refer to the selection range and content range of the raw materials for developing embolic microspheres provided in the first aspect of the embodiment of the present application, and will not be repeated here.

[0060] In some embodiments, in step S1, the alkaline solution includes a sodium hydroxide solution.

[0061] As an example, the alkaline solution includes 10 wt % to 30 wt % sodium hydroxide solution.

[0062] Furthermore, in some embodiments, in step S1, a cross-linking agent containing epoxy terminal groups can be added to an alkaline solution, and then a hydroxyl-containing acrylamide monomer and a fluorine-containing compound are added in sequence, followed by stirring and reacting.

[0063] In some embodiments, in step S2, after the pH of the alkaline solution is adjusted to neutral, the double-bond-containing ionic monomer and the initiator are added in sequence, and stirred and mixed to form an aqueous solution.

[0064] In some embodiments, in step S2, the initiator may include ammonium persulfate.

[0065] In some embodiments, in step S3, the oil phase solution includes an oil-soluble dispersant and an oily solvent, and the mass percentage of the oil-soluble dispersant to the total mass of the oil phase solution is 0.5% to 8%.

[0066] As an example, the oil-soluble dispersant includes one or more of cellulose acetate butyrate, Tween series compounds, a mixture of Span series compounds, OP series compounds, and AEO series compounds.

[0067] As an example, the oily solvent includes at least one of butyl acetate, petroleum ether, n-hexane, cyclohexane, or paraffin oil.

[0068] As an example, the mass percentage of the oil-soluble dispersant to the total mass of the oil phase solution can be 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5% or 8%, or a range between any two of them.

[0069] Furthermore, in some embodiments, when preparing the oil phase solution, an oil-soluble dispersant can be added to the oily solvent and stirred at a certain temperature to form a uniform oil phase solution.

[0070] Furthermore, in step S3, the aqueous phase solution is slowly added to the oil phase solution under the condition of heating and stirring the oil phase solution to form an oil-in-water reverse suspension polymerization system. Then, the catalyst solution is added, and the stirring and heating reaction is maintained for 4-18 hours, and the lower gel phase is separated, and after swelling, purification and screening, the developing embolic microspheres are prepared.

[0071] As an example, the temperature of the heating and stirring may be 30 to 50°C.

[0072] As an example, the rotation speed of the hotter stirring may be 200 to 500 rpm.

[0073] As an example, the catalyst may include tetramethylethylenediamine.

[0074] As an example, before adding the catalyst, the temperature is raised to 45-55° C., and then the catalyst is added.

[0075] As an example, the heating reaction time may be 6 to 12 hours.

[0076] Furthermore, in some embodiments, after the reaction is completed, the lower gel phase is separated, the microspheres are collected, washed with butyl acetate, sodium bicarbonate aqueous solution and ultrapure water in sequence, and then sieved through sieves with different pore sizes to obtain developing embolic microspheres with different particle size distributions.

[0077] The developing embolic microspheres of the present application are further described in detail below in conjunction with the examples.

[0078] Example 1

[0079] Example 1 provides a developing embolic microsphere, and the preparation method thereof is as follows:

[0080] (1) Preparation of aqueous phase:

[0081] Take 4g of ethylene glycol diglycidyl ether in a flask, add 8mL of 20wt% sodium hydroxide, and stir for 0.5h. Add 16mL of 50% mass fraction N-hydroxyethyl acrylamide aqueous solution and 3.1g of 1,2-epoxy-3,3,3-trifluoropropane to the flask and continue stirring for 2h. Then adjust the pH value to neutral, add 3.3g of sodium acrylate aqueous solution and 0.24g of ammonium persulfate in turn, and repeat the mixing to obtain an aqueous phase solution.

[0082] The molar ratio of ethylene glycol diglycidyl ether: N-hydroxyethyl acrylamide: sodium acrylate is 1:3:2. The molar ratio of N-hydroxyethyl acrylamide to 1,2-epoxy-3,3,3-trifluoropropane is 2.5:1.

[0083] (2) Oil phase preparation:

[0084] Add 2 g of cellulose acetate butyrate to 100 mL of butyl acetate and stir to dissolve at 45°C to form a uniform oil phase solution.

[0085] (3) Inverse suspension polymerization:

[0086] Under stirring conditions of 45°C and 300rpm, the aqueous phase solution prepared in step (1) was slowly added to the oil phase solution prepared in step (2) to form an oil-in-water reverse suspension polymerization system. The mixture was stirred at 45°C for 1 hour, then the temperature was raised to 55°C, and 1.2mL of tetramethylethylenediamine was added to the suspension system and reacted for 8 hours. The gel phase below was separated, and the microspheres were collected. After washing with butyl acetate, sodium bicarbonate aqueous solution and ultrapure water in turn, the microspheres were sieved through sieves of different apertures to obtain development embolization microspheres with different particle size distributions.

[0087] Example 2

[0088] Example 2 provides a developing embolic microsphere, which is different from Example 1 in that:

[0089] In step (1), 3.1 g of 1,2-epoxy-3,3,3-trifluoropropane was replaced with 5 g of trimethoxy(3,3,3-trifluoropropyl)silane.

[0090] Example 3

[0091] Example 3 provides a developing embolic microsphere, which is different from Example 1 in that:

[0092] In step (1), 3.1 g of 1,2-epoxy-3,3,3-trifluoropropane was replaced with 15.8 g of trimethoxy(1H,1H,2H,2H-heptadecafluorodecane)silane.

[0093] The molar ratio of ethylene glycol diglycidyl ether, N-hydroxyethyl acrylamide and sodium acrylate is 1:3:2. The molar ratio of N-hydroxyethyl acrylamide and trimethoxy (1H, 1H, 2H, 2H-heptadecafluorodecane) silane is 2.5:1.

[0094] Example 4

[0095] Example 4 provides a developing embolic microsphere, which is different from Example 1 in that:

[0096] In step (1), 6 g of ethylene glycol diglycidyl ether was placed in a flask, 8 mL of 20 wt% sodium hydroxide was added, and the mixture was stirred for 0.5 h. 16 mL of 50% mass fraction N-hydroxyethyl acrylamide aqueous solution and 3.1 g of 1,2-epoxy-3,3,3-trifluoropropane were added to the flask, and the mixture was stirred for 2 h. The pH value was then adjusted to neutral, and 3.3 g of sodium acrylate aqueous solution and 0.24 g of ammonium persulfate were added in sequence and mixed repeatedly to obtain an aqueous phase solution.

[0097] The molar ratio of ethylene glycol diglycidyl ether, N-hydroxyethyl acrylamide and sodium acrylate is 1.5:3:2. The molar ratio of N-hydroxyethyl acrylamide and 1,2-epoxy-3,3,3-trifluoropropane is 2.5:1.

[0098] Test Example 1

[0099] DC Bead LUMI microspheres were used as comparative example 1.

[0100] The developing performance of the developing embolic microspheres provided in Examples 1 to 4 and the microspheres provided in Comparative Example 1 was tested.

[0101] The test method is as follows:

[0102] T1-weighted imaging (T1WI) scanning with gradient echo sequence was performed using an MRI scanner.

[0103] The test results are shown in Table 1.

[0104] Table 1

[0105] Group Signal Strength Example 1 middle Example 2 Strong Example 3 powerful Example 4 Strong Comparative Example 1 weak

[0106] Result analysis:

[0107] The developing embolic microspheres provided in Examples 1 to 4 of the present application all have good developing signal intensity. By comparing Examples 1 to 3, it can be seen that the fluorine content in the fluorine-containing compounds in Examples 1, 2, and 3 increases successively, resulting in the developing signal intensity of the developing embolic microspheres increasing successively. By comparing Example 1 and Example 4, it can be seen that in Example 4, the cross-linking degree is increased by adjusting the cross-linking agent ratio, thereby increasing the fluorine content in the unit volume of the developing embolic microspheres, thereby further increasing the developing signal intensity of the developing embolic microspheres.

[0108] Test Example 2

[0109] Physical property tests were performed on the developing embolic microspheres provided in Examples 1 to 4 and the microspheres provided in Comparative Example 1. The tests included:

[0110] (1) Mechanical properties test:

[0111] The developing embolic microspheres with a particle size range of 100-300 μm obtained in Examples 1 to 4 and the microspheres with a particle size range of 100-300 μm in Comparative Example 1 were respectively spread on a glass slide, placed under the probe of a texture analyzer (TAXT plusC), and the HoldCompression mode was selected for testing.

[0112] (2) Density test:

[0113] 1 mL of microspheres with a particle size range of 100-300 μm in Examples 1 to 4 and Comparative Example 1 were respectively measured and weighed. The ratio of mass to volume is the density of the microspheres.

[0114] The test results are shown in Table 2.

[0115] Table 2

[0116] Group Strength / g Rebound force / g elasticity(%) Density(g / mL) Example 1 180.2 126.0 69.9 1.07 Example 2 175.4 114.9 65.5 1.06 Example 3 166.9 106.0 63.5 1.04 Example 4 201.7 146.0 72.4 1.10 Comparative Example 1 >1000 >1000 ～0 1.3

[0117] Result analysis:

[0118] As can be seen from Table 2, the developing embolic microspheres provided in Examples 1 to 4 of the present application all have good mechanical properties, providing a basis for the embolic microspheres to have good catheter permeability. Comparative Examples 1 to 3 show that as the spatial structure of the fluorine-containing compound increases, the strength and density of the developing embolic microspheres decrease, mainly because the larger the spatial structure of the fluorine-containing compound, the lower the tightness of the network structure of the developing embolic microspheres, so its mechanical properties and density are smaller. Comparative Example 1 and Example 4 show that as the content of the crosslinking agent increases, the degree of crosslinking of the developing embolic microspheres increases, so its mechanical properties and density are greater.

[0119] Test Example 3

[0120] The drug loading performance of the developing embolic microspheres provided in Examples 1 to 4 and the microspheres provided in Comparative Example 2 was tested. Comparative Example 2 is DC Bead microspheres.

[0121] (1) Wet-bulb drug loading performance test:

[0122] Take 3 groups of 1 ml of the microspheres provided in Examples 1 to 4 and Comparative Example 2, remove the moisture on the surface of the microspheres with filter paper, transfer the microspheres into a vial, add 5 mL of a 10 mg / mL hydrophobic drug gemcitabine solution and a 5 mg / mL hydrophobic drug lenvatinib solution, respectively, mix and shake, and test the solution concentration at 1 min, 5 min, 15 min and 30 min, respectively, and calculate the drug loading rate of the embolic microspheres.

[0123] The test results are shown in Table 3.

[0124] Table 3

[0125]

[0126]

[0127] Result analysis:

[0128] As shown in Table 3, the imaging embolic microspheres provided in Examples 1 to 4 of the present application all exhibit good drug loading performance for hydrophobic drugs, and the drug loading rate can reach 99% within 30 minutes, which is significantly better than the drug loading rate of Comparative Example 2. Comparative Examples 1 to 4 show that the density of the network structure of the imaging embolic microspheres will affect the drug loading rate, and the denser the network structure, the lower the drug loading rate.

[0129] (2) Wet-bulb release performance test:

[0130] The drug-loaded microspheres were added to the dialysis bag, and then the dialysis bag was placed in a beaker. Physiological saline (20 mL) was added to the beaker and the beaker was sealed. Samples were taken every 5 min, 30 min, and 60 min to determine the concentration of the drug in the solution and calculate the cumulative release of the drug-loaded embolic microspheres.

[0131] The test results are shown in Table 4.

[0132] Table 4

[0133]

[0134] Result analysis:

[0135] As can be seen from Table 4, the drug release rate of each group of developing embolic microspheres in Examples 1 to 4 of the present application is significantly lower than that in Comparative Example 2. This is because each example introduces a fluorine-containing compound, and its hydrophobicity increases. Both gemcitabine and lenvatinib have hydrophobic groups, and there is a hydrophobic interaction between the microspheres and the drugs, thereby reducing the release rate of the drugs. Among them, by comparing Example 1 and Example 4, it can be seen that the release rate of the two drugs in Example 4 is lower than that in Example 1. This is because the increase of the cross-linking agent in Example 4 increases the cross-linking degree of the developing embolic microspheres, and the network structure is denser, so the drug release rate is slower.

[0136] The results show that the imaging embolic microspheres provided in the examples of the present application have good imaging signal intensity and also have good drug loading and release properties for drugs with hydrophobic groups.

[0137] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A developing embolic microsphere, characterized in that: A network structure formed by cross-linking polymerization of a fluorine-containing compound, a hydroxyl-containing acrylamide monomer, a cross-linking agent containing an epoxy end group, and an ionic monomer containing a double bond; wherein, The fluorine-containing compound contains a silicon-oxygen bond and / or an epoxy group at the terminal.

2. The developing embolic microspheres according to claim 1, characterized in that: The fluorine-containing compound includes fluorine-containing methoxysilane; optionally, the fluorine-containing methoxysilane includes at least one of trimethoxy (3,3,3-trifluoropropyl) silane and trimethoxy (1H,1H,2H,2H-heptadecafluorodecane) silane; and / or, The fluorine-containing compound includes a fluorine-containing compound with an epoxy group at the terminal, and the fluorine-containing compound with an epoxy group at the terminal includes 1,2-epoxy-3,3,3-trifluoropropane.

3. The developing embolic microspheres according to claim 1, characterized in that: The cross-linking agent containing epoxy end groups includes a glycidyl ether compound with an epoxy propene end group; optionally, the cross-linking agent containing epoxy end groups includes at least one of polyethylene glycol diglycidyl ethers with a degree of polymerization of 1 to 12; optionally, the cross-linking agent containing epoxy end groups includes at least one of ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, PEG200 diglycidyl ether and PEG500 diglycidyl ether; And / or, the hydroxyl-containing acrylamide monomer includes at least one of N-hydroxymethyl acrylamide, N-hydroxyethyl acrylamide, N-[tris(hydroxymethyl)methyl]acrylamide, N-(2-hydroxypropyl)acrylamide, N-(hydroxymethyl)methacrylamide, N-(hydroxyethyl)methacrylamide and N-(2-hydroxypropyl)methacrylamide.

4. The developing embolic microspheres according to claim 1, characterized in that: The double bond-containing ionic monomer includes at least one of sodium itaconate, sodium acrylate, sodium methacrylate, sodium 2-acrylamido-2-methylpropane sulfonate, sodium p-styrene sulfonate, sodium vinyl sulfonate, (3-acrylamidopropyl)trimethylammonium chloride and (3-methacrylamidopropyl)trimethylammonium chloride.

5. The developing embolic microspheres according to claim 1, characterized in that: The molar ratio of the hydroxyl-containing acrylamide monomer to the fluorine-containing compound is (1-5):

1.

6. The developing embolic microspheres according to claim 1, characterized in that: The molar ratio of the cross-linking agent containing epoxy end groups: the acrylamide monomer containing hydroxyl groups: the ionic monomer containing double bonds is 1: (2-4): (1-8).

7. A method for preparing developing embolic microspheres, characterized in that: include: S1. Adding a crosslinking agent containing an epoxy terminal group under alkaline solution conditions, and then adding a hydroxyl-containing acrylamide monomer and a fluorine-containing compound to react to obtain an intermediate compound; the fluorine-containing compound contains a silicon-oxygen bond and / or an epoxy terminal group; S2, after adjusting the pH value of the alkaline solution to neutral, adding a double-bond-containing ionic monomer and an initiator to form an aqueous solution; S3, adding the aqueous phase solution dropwise into the oil phase solution to form an oil-in-water reverse suspension polymerization system, stirring, and heating for reaction to obtain the developing embolic microspheres.

8. The preparation method according to claim 7, characterized in that: The cross-linking agent containing epoxy end groups includes a glycidyl ether compound with an epoxy propene end group; optionally, the cross-linking agent containing epoxy end groups includes at least one of polyethylene glycol diglycidyl ethers with a degree of polymerization of 1 to 12; optionally, the cross-linking agent containing epoxy end groups includes at least one of ethylene glycol diglycidyl ether, diethylene glycol diglycidyl ether, triethylene glycol diglycidyl ether, tetraethylene glycol diglycidyl ether, PEG200 diglycidyl ether and PEG500 diglycidyl ether; and / or, the hydroxyl-containing acrylamide monomer comprises at least one of N-hydroxymethyl acrylamide, N-hydroxyethyl acrylamide, N-[tris(hydroxymethyl)methyl]acrylamide, N-(2-hydroxypropyl)acrylamide, N-(hydroxymethyl)methacrylamide, N-(hydroxyethyl)methacrylamide and N-(2-hydroxypropyl)methacrylamide; And / or, the fluorine-containing compound includes at least one of fluorine-containing methoxysilane and a fluorine-containing compound with an epoxy group at the end; optionally, the fluorine-containing compound includes at least one of trimethoxy (3,3,3-trifluoropropyl) silane, trimethoxy (1H,1H,2H,2H-heptadecafluorodecane) silane and 1,2-epoxy-3,3,3-trifluoropropane; And / or, the double bond-containing ionic monomer includes at least one of sodium itaconate, sodium acrylate, sodium methacrylate, sodium 2-acrylamido-2-methylpropane sulfonate, sodium p-styrene sulfonate, sodium vinyl sulfonate, (3-acrylamidopropyl)trimethylammonium chloride and (3-methacrylamidopropyl)trimethylammonium chloride.

9. The preparation method according to claim 7, characterized in that: The molar ratio of the cross-linking agent containing epoxy terminal groups: the acrylamide monomer containing hydroxyl groups: the ionic monomer containing double bonds is 1: (2-4): (1-8); And / or, the molar ratio of the hydroxyl-containing acrylamide monomer to the fluorine-containing compound is (1-5):

1.

10. The preparation method according to claim 7, characterized in that: In step S1, the alkaline solution includes 10wt% to 30wt% of sodium hydroxide; And / or, in step S3, the oil phase solution comprises an oil-soluble dispersant and an oily solvent, and the mass percentage of the oil-soluble dispersant to the total mass of the oil phase solution is 0.5% to 8%; And / or, in step S3, the heating reaction temperature is 40-70° C. and the time is 4-18 hours.

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