Preparation method of embolism microspheres

Abstract

The invention discloses a preparation method of embolism microspheres, and belongs to the technical field of medical instruments. The preparation method of the embolism microspheres comprises the following steps: taking a water phase as a dispersion phase and an oil phase as a continuous phase, and preparing the embolism microspheres through a membrane emulsification method. Wherein the water phase comprises a water-soluble high-molecular polymer, a water-soluble monomer, a water-soluble cross-linking agent and an initiator. The oil phase comprises an oily solvent and an oil-soluble dispersant. The preparation method comprises the following steps: by taking a water phase containing a water-soluble high-molecular polymer as a dispersed phase, slowly pressing the dispersed phase into a flowing continuous phase through a membrane hole of a membrane emulsifier under nitrogen pressure by virtue of a membrane emulsification method, so as to form water-in-oil liquid drops with relatively uniform particle size distribution in the continuous phase; the water-soluble high-molecular polymer and the water-soluble monomer in the liquid drops can be cross-linked to form embolism microspheres under the action of an initiator, a cross-linking agent, a catalyst and the like. The embolism microsphere provided by the invention has good particle size distribution uniformity.

Description

Technical Field

[0001] The present application relates to the field of medical device technology, and in particular to a method for preparing embolic microspheres. Background Art

[0002] Embolic microspheres are widely used in the treatment of malignant tumors and vascular malformations such as liver cancer, cerebral aneurysms, and uterine fibroids. Hepatic artery embolization chemotherapy is one of the important means of treating liver cancer. It can not only increase the concentration of chemotherapy drugs in the tumor area and reduce the toxic side effects on healthy tissues, but also effectively block the tumor blood supply artery, prevent tumor growth and spread, and thus improve the treatment effect.

[0003] However, the embolic microspheres prepared by the current process often have the problem of uneven particle size distribution. Microspheres of different sizes are injected into blood vessels through a catheter, which will lead to incomplete embolism and affect the final embolization effect. Summary of the invention

[0004] The purpose of the present application is to provide a method for preparing embolic microspheres to improve the uniformity of particle size distribution of the embolic microspheres.

[0005] The embodiment of the present application is implemented as follows:

[0006] The present application provides a method for preparing embolic microspheres, comprising:

[0007] The embolic microspheres are prepared by membrane emulsification method with water phase as dispersed phase and oil phase as continuous phase, wherein the water phase includes water-soluble polymer, water-soluble monomer, water-soluble crosslinking agent and initiator, and the oil phase includes oily solvent and oil-soluble dispersant.

[0008] In the above technical solution, the aqueous phase containing water-soluble polymer is used as the dispersed phase, and the dispersed phase is slowly pressed into the flowing continuous phase through the membrane pores of the membrane emulsifier by membrane emulsification method, and droplets of oil-in-water structure can be formed in the continuous phase. The water-soluble polymer and water-soluble monomer in these droplets can be cross-linked and cured under the action of initiators, cross-linking agents, catalysts, etc. to form embolic microspheres. The embodiment of the present application can prepare embolic microspheres with uniform particle size distribution by controlling the membrane emulsifier to the oil-in-water reverse suspension system. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below.

[0010] Figure 1 This is a flow chart of the preparation process of embolic microspheres provided in the examples of the present application. DETAILED DESCRIPTION

[0011] 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.

[0012] The embolic microspheres prepared by the current process often have the problem of uneven particle size distribution. Microspheres of different sizes are injected into blood vessels through a catheter, which will lead to incomplete embolism and affect the final embolization effect.

[0013] For example, the embolic microspheres obtained by the current preparation process generally have a particle size of 1 to 1500 μm, and the distribution span of the particle size is relatively large. During use, the prepared embolic microspheres usually need to be screened. However, even after screening by the existing screening technology, the microspheres of various specifications obtained still have large particle size differences. For example, the above-mentioned embolic microspheres are usually screened into 100-300 μm, 300-500 μm, 500-700 μm, 700-900 μm, and 900-1200 μm. The particle size difference in each specification is about 200 μm, which is a large range and poor uniformity.

[0014] Therefore, the present application further improves the preparation process of the embolic microspheres, thereby improving the problem of uneven particle size distribution of the embolic microspheres to a certain extent.

[0015] The present application provides a method for preparing embolic microspheres, comprising:

[0016] The embolic microspheres are prepared by membrane emulsification method with water phase as dispersed phase and oil phase as continuous phase, wherein the water phase includes water-soluble polymer, water-soluble monomer, water-soluble crosslinking agent and initiator, and the oil phase includes oily solvent and oil-soluble dispersant.

[0017] The present application uses a membrane emulsification method to prepare embolic microspheres in an oil-in-water reverse suspension system. The microspheres within the specification have small differences in particle size, are evenly distributed, and have small differences in various properties of the microspheres.

[0018] As an implementation, see Figure 1 The preparation of embolic microspheres by membrane emulsification method includes:

[0019] S1. Under nitrogen pressure, the dispersed phase is pressed into the flowing continuous phase through the membrane pores of the membrane emulsifier to form a mixed solution.

[0020] S2. Heat the mixed solution, add a catalyst, stir the reaction, and collect and wash to obtain the embolic microspheres.

[0021] Membrane emulsification is a method that converts dispersed phase liquid into uniform droplets through the microporous membrane of a membrane emulsifier. Its basic principle is to pass the dispersed phase liquid through the microporous membrane under pressure to form droplets, and then under the flushing of the continuous phase, the droplets peel off from the membrane surface to form an emulsion.

[0022] The embodiment of the present application uses an aqueous phase containing a water-soluble polymer, a water-soluble monomer, a water-soluble cross-linking agent and an initiator as a dispersed phase, and passes the aqueous phase system through a membrane emulsifier to form an oil-in-water structure in the continuous phase of the oil phase system. After a subsequent cross-linking and curing reaction, embolic microspheres formed by water-soluble polymer materials can be obtained.

[0023] The present application uses an aqueous phase as a dispersed phase, wherein the aqueous phase includes a water-soluble polymer, a water-soluble monomer, a water-soluble cross-linking agent and an initiator; specifically, the water-soluble polymer includes at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, sodium hydroxymethyl cellulose and water-soluble chitosan.

[0024] As an example, the water-soluble high molecular polymer is selected from polyvinyl alcohol. The embolic microspheres prepared using polyvinyl alcohol generally have good biocompatibility, degradability or volume stability, etc., and can improve the therapeutic effect and safety.

[0025] In some embodiments, the water-soluble monomer includes at least one of sodium 2-acrylamide-2-methylpropane sulfonate, acrylamide, sodium acrylate, and sodium allyl sulfonate.

[0026] As an example, the water-soluble monomer is selected from sodium acrylate.

[0027] In some embodiments, the water-soluble crosslinking agent includes at least one aldehyde group, acetal group or hemiacetal group and at least one polymerizable double bond. Optionally, the water-soluble crosslinking agent includes at least one of N-(2,2-dimethoxy)-2-methylacrylamide and N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylamide.

[0028] As an example, the water-soluble crosslinking agent is selected from N-(2,2-dimethoxy)-2-methylacrylamide.

[0029] By using N-(2,2-dimethoxy)-2-methylacrylamide and N-(1-hydroxy 2,2-dimethoxyethyl)-2-acrylamide as cross-linking agents, the cross-linking structure inside the microspheres can be enhanced to obtain embolic microspheres with good mechanical properties.

[0030] In some embodiments, the initiator includes at least one of ammonium persulfate, sodium persulfate, and potassium persulfate.

[0031] As an example, the initiator may be selected from potassium persulfate.

[0032] The above-mentioned initiator can be used to initiate a cross-linking reaction among the water-soluble high molecular polymer, the water-soluble monomer and the water-soluble cross-linking agent in the oil-in-water structure, so as to obtain stable embolic microspheres.

[0033] Furthermore, in order to obtain embolic microspheres with good strength, compression elasticity, suspension performance and catheter passability, the content of each component in the aqueous phase can be adjusted.

[0034] In some embodiments, the mass proportion of the water-soluble high molecular polymer in the water phase is 10% to 25%.

[0035] As an example, the mass proportion of the water-soluble polymer in the aqueous phase can be one of 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%, or a range between any two of them.

[0036] As an example, the mass proportion of the water-soluble polymer in the water phase may be 10% to 15%. Alternatively, the mass proportion of the water-soluble polymer in the water phase may be 15% to 20%. Alternatively, the mass proportion of the water-soluble polymer in the water phase may be 20% to 25%.

[0037] In some embodiments, the water-soluble monomer accounts for 5% to 15% by weight in the water phase.

[0038] As an example, the mass proportion of the water-soluble monomer in the aqueous phase can be 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%, or a range between any two of them.

[0039] As an example, the mass proportion of the water-soluble monomer in the water phase may be 5% to 10%. Alternatively, the mass proportion of the water-soluble monomer in the water phase may be 10% to 15%.

[0040] In some embodiments, the mass of the water-soluble cross-linking agent is 2% to 6% of the mass of the water-soluble high molecular polymer.

[0041] As an example, the mass of the water-soluble crosslinking agent is in a range of 2%, 3%, 4%, 5% or 6% of the mass of the water-soluble high molecular weight polymer, or any two thereof.

[0042] The mass of the water-soluble cross-linking agent is 2% to 6% of the mass of the water-soluble high molecular polymer, which can adjust the cross-linking degree of the embolic microspheres, make the embolic microspheres have appropriate strength, and ensure that the embolic microspheres have good catheter permeability.

[0043] In some embodiments, the mass proportion of the initiator in the water phase is 0.1% to 0.6%.

[0044] As an example, the mass proportion of the initiator in the water phase may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5% or 0.6%, or a range between any two of them.

[0045] Furthermore, in some embodiments, when preparing the dispersed phase, the water-soluble high molecular polymer may be first dissolved in water and stirred at elevated temperature to form a uniform polymer aqueous solution, and then a water-soluble crosslinking agent, a water-soluble monomer and an initiator are added respectively and stirred to form a uniform aqueous phase as the dispersed phase.

[0046] Furthermore, in some embodiments, when preparing the dispersed phase, the water-soluble high molecular polymer can be first dissolved in water and heated and stirred to dissolve to form a uniform polymer aqueous solution. Then, a water-soluble crosslinking agent and an acid catalyst are added and stirred to react. After a period of reaction, a water-soluble monomer and an initiator are added in sequence and stirred to form a uniform aqueous phase as the dispersed phase.

[0047] As an example, the acid catalyst includes hydrochloric acid.

[0048] In the present application, the oil phase is used as the continuous phase, wherein the oil phase includes an oily solvent and an oil-soluble dispersant. Specifically, the oil-soluble dispersant is added to the oily solvent, stirred and dissolved at a certain temperature to form a uniform solution to obtain a continuous phase; wherein the dissolution temperature of the oil-soluble dispersant is 30°C to 50°C.

[0049] In some embodiments, the mass proportion of the oil-soluble dispersant in the oil phase is 1% to 6%. If the content of the oil-soluble dispersant in the continuous phase is too much, the viscosity of the continuous phase will be too high, the shear force of the continuous phase will be too large, the size uniformity of the droplets pressed into the continuous phase will be affected, and the qualified rate of the embolic microspheres will be reduced.

[0050] As an example, the mass proportion of the oil-soluble dispersant in the oil phase may be 1%, 2%, 3%, 4%, 5% or 6%, or a range between any two of them.

[0051] The present application can improve the uniformity of the particle size distribution of the embolic microspheres and increase the yield of the embolic microspheres by adjusting the concentration of the oil-soluble dispersant.

[0052] In some embodiments, the oil-soluble dispersant includes at least one of cellulose acetate butyrate, Span, octylphenol polyoxyethylene ether and oleic acid diethanolamide. Optionally, the Span includes Span 20 and Span 80.

[0053] As an example, the oil-soluble dispersant is selected from cellulose acetate butyrate.

[0054] As an example, the oil-soluble dispersant includes a mixture of cellulose acetate butyrate and Span 20.

[0055] As an example, the oil-soluble dispersant includes a mixture of cellulose acetate butyrate and Span 80.

[0056] As an example, the oil-soluble dispersant includes a mixture of octylphenol polyoxyethylene ether and Span 20.

[0057] In the present application, the oil-soluble dispersant plays an emulsifying role in the continuous phase. The addition of the above oil-soluble dispersant greatly improves the stability of the continuous phase system. In the membrane emulsification process, the oil-soluble dispersant can also reduce the interfacial tension of the dispersed phase droplets in the continuous phase, reduce the energy consumption of the preparation, and thus improve the emulsification efficiency. In addition, the oil-soluble dispersant will also affect the size of the prepared microsphere droplets, thereby affecting the uniformity of the particle size of the microspheres.

[0058] In some embodiments, the oily solvent includes at least one of butyl acetate, ethyl acetate, methyl acetate, and propyl acetate.

[0059] In order to further improve the uniformity of the particle size distribution of the embolic microspheres, in some possible embodiments, the membrane of the membrane emulsifier includes a ceramic hydrophilic membrane.

[0060] The use of a ceramic hydrophilic membrane to pass the aqueous phase can improve the wettability of the membrane to the dispersed phase and obtain embolic microspheres with uniform particle size distribution.

[0061] Furthermore, in some embodiments, the pore size of the membrane is 5 to 40 μm. By adjusting the pore size of the membrane, the particle size and particle size distribution uniformity of the prepared embolic microspheres can be adjusted.

[0062] As an example, the pore size of the membrane pores may be in the range of one or any two of 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm or 40 μm.

[0063] As an example, the pore size of the membrane pores may be 5 to 20 μm. Alternatively, the pore size of the membrane pores may be 20 to 40 μm.

[0064] Furthermore, in some embodiments, in step S1, the nitrogen pressure ranges from 8 to 100 mbar. During the membrane emulsification process, adjusting the nitrogen pressure can adjust the droplet growth rate, the droplet detachment time at the membrane pore, and the particle size of the droplet when it detaches from the membrane pore, so as to obtain embolic microspheres with more uniform particle sizes.

[0065] As an example, the nitrogen pressure may be adjusted to one of, or a range between any two of, 8 mbar, 10 mbar, 20 mbar, 30 mbar, 40 mbar, 50 mbar, 60 mbar, 70 mbar, 80 mbar, 90 mbar or 100 mbar.

[0066] As an example, the nitrogen pressure may range from 8 to 25 mbar. Alternatively, the nitrogen pressure may range from 25 to 45 mbar. Alternatively, the nitrogen pressure may range from 45 to 65 mbar. Alternatively, the nitrogen pressure may range from 65 to 85 mbar. Alternatively, the nitrogen pressure may range from 85 to 100 mbar.

[0067] In the present application, the dispersed phase droplets slowly pass through the membrane pores of the membrane emulsifier under nitrogen pressure. At the outlet of the membrane pores, the droplets are subjected to one or more forces such as interfacial tension, membrane pressure, and drag force during water phase stirring. The droplets grow from small to large at the membrane pores and gradually grow into droplets of uniform particle size.

[0068] Furthermore, in step S1, a shear force is formed between the flowing continuous phase and the relatively stationary membrane emulsifier, which affects the particle size uniformity of the oil-in-water structure dripped into the continuous phase under the action of the shear force. The particle size distribution uniformity of the embolic microspheres can be further improved by adjusting the flow rate of the continuous phase.

[0069] In some embodiments, the flow rate of the continuous phase is 100-800 rpm / min. The continuous phase has a suitable flow rate, and embolic microspheres with more uniform particle size distribution can be obtained.

[0070] As an example, the flow rate of the continuous phase can be one of 100 rpm / min, 200 rpm / min, 300 rpm / min, 400 rpm / min, 500 rpm / min, 600 rpm / min, 700 rpm / min or 800 rpm / min, or a range between any two thereof.

[0071] As an example, the flow rate of the continuous phase may be 200 to 700 rpm / min. Alternatively, the flow rate of the continuous phase may be 300 to 600 rpm / min. Alternatively, the flow rate of the continuous phase may be 400 to 500 rpm / min.

[0072] In some embodiments, the continuous phase can be driven to flow by a magnetic stirrer or a stirring paddle.

[0073] Furthermore, in some embodiments, before step S1, step S0 may be performed: immersing the membrane emulsifier in the continuous phase and ultrasonically treating the membrane emulsifier. In the present application, the membrane emulsification rate may be increased by immersing the membrane emulsifier in the continuous phase before the membrane emulsification begins, thereby improving the preparation efficiency.

[0074] As an example, the ultrasonic treatment time may be 30 to 120 minutes.

[0075] After the aqueous dispersed phase is pressed into the flowing continuous phase through a membrane emulsifier, in step S2, the mixed solution can be heated, a catalyst can be added, and after stirring the reaction for a certain period of time, the stirring and heating can be stopped, the reaction system can be allowed to stand to separate layers, the oil phase can be separated, the microspheres can be collected and repeatedly washed and purified to obtain embolic microspheres.

[0076] In some embodiments, in step S2, the mixed solution may be heated to 50-70° C. for reaction.

[0077] As an example, in step S2, the reaction temperature may be one of 50°C, 55°C, 60°C, 65°C or 70°C, or a range between any two of them.

[0078] In some embodiments, in step S2, the stirring rate may be 200-600 rpm / min.

[0079] As an example, the stirring rate can be one of 200rpm / min, 250rpm / min, 300rpm / min, 350rpm / min, 400rpm / min, 450rpm / min, 500rpm / min, 550rpm / min or 600rpm / min, or a range between any two thereof.

[0080] In one embodiment, in step S2, the catalyst may be tetramethylethylenediamine.

[0081] In some embodiments, in step S2, the reaction time may be 8 to 12 hours.

[0082] As an example, the reaction time may be in the range of one or any two of 8 h, 9 h, 10 h, 11 h or 12 h.

[0083] In the present embodiment, the embolic microspheres with relatively uniform particle size can be prepared by controlling the membrane pore size, membrane material, nitrogen pressure, concentration of the oil-soluble dispersant in the continuous phase, and flow rate of the continuous phase of the membrane emulsifier. In addition, the yield of the embolic microspheres can be increased by adjusting the concentration and type of the oil-soluble dispersant in the continuous phase.

[0084] Furthermore, an embodiment of the present application also provides an embolic microsphere prepared according to the above method.

[0085] In the embolic microspheres provided in the examples of the present application, the qualified rate of the target particle size of 75 to 150 μm can reach more than 60%, and the particle size distribution of the prepared embolic microspheres is relatively uniform.

[0086] The qualified rate of the target particle size of 75 to 150 μm refers to the proportion of microspheres with a particle size of 75 to 150 μm in the total amount of embolic microspheres. For example, a qualified rate of 60% means that microspheres with a particle size of 75 to 150 μm account for 60% of the total amount of embolic microspheres.

[0087] The preparation method of the embolic microspheres of the present application is further described in detail below in conjunction with the examples.

[0088] Example 1

[0089] Example 1 provides a method for preparing embolic microspheres, comprising:

[0090] (1) Preparation of dispersed phase:

[0091] Add 50g of polyvinyl alcohol to 500mL of water, heat to 95℃, stir and dissolve to form a uniform solution. Then add a water-soluble crosslinking agent ((N(2,2-dimethoxy)-2-methylacrylamide, 1.5g), stir evenly, add an acid catalyst (hydrochloric acid, 15mL), continue stirring and react at 25℃ for 13h to obtain a polyvinyl alcohol aqueous solution. Then take 100g of the polyvinyl alcohol aqueous solution, add 10g of sodium acrylate and 0.3g of potassium persulfate, stir evenly to a uniform aqueous phase solution, and obtain a dispersed phase.

[0092] (2) Preparation of continuous phase:

[0093] 10 g of cellulose acetate butyrate was added to 500 mL of butyl acetate, and the mixture was stirred and dissolved at 35° C. to form a uniform oil phase solution to obtain a continuous phase.

[0094] (3) Synthetic microspheres:

[0095] Using a membrane emulsifier, under a nitrogen pressure of 20 mbar, the dispersed phase obtained in step (1) is pressed into the continuous phase provided in step (2) through the membrane pores (pore size of 20 μm) of the membrane tube, and the flow rate of the continuous phase is 300 rpm / min. After the dispersed phase is added dropwise, the reaction system is heated to a reaction temperature of 55°C, and a certain amount of catalyst tetramethylethylenediamine is continued to be added dropwise to the reaction system, the reaction stirring rate is 300 rpm, and the reaction is stirred for 10 hours. After the reaction is completed, stirring and heating are stopped, the reaction system is allowed to stand for stratification, the oil phase is separated, the microspheres are collected and repeatedly washed, and polyvinyl alcohol embolization microspheres are obtained.

[0096] Example 2

[0097] Example 2 provides a method for preparing embolic microspheres, which is different from Example 1 in that in step (3), the nitrogen pressure is 40 mbar.

[0098] Example 3

[0099] Example 3 provides a method for preparing embolic microspheres, which is different from Example 1 in that in step (3), the nitrogen pressure is 60 mbar.

[0100] Example 4

[0101] Example 4 provides a method for preparing embolic microspheres, which is different from Example 1 in that: in step (2), the amount of cellulose acetate butyrate is 15 g.

[0102] Example 5

[0103] Example 5 provides a method for preparing embolic microspheres, which is different from Example 1 in that: in step (2), the amount of cellulose acetate butyrate is 20 g.

[0104] Example 6

[0105] Example 6 provides a method for preparing embolic microspheres, which is different from Example 1 in that: in step (2), the amount of cellulose acetate butyrate is 25 g.

[0106] Example 7

[0107] Example 7 provides a method for preparing embolic microspheres, which is different from Example 1 in that in step (2), cellulose acetate butyrate is replaced by cellulose acetate butyrate and Span20.

[0108] Example 8

[0109] Example 8 provides a method for preparing embolic microspheres, which is different from Example 1 in that: in step (2), cellulose butyrate is replaced by cellulose acetate butyrate and Span80.

[0110] Example 9

[0111] Example 9 provides a method for preparing embolic microspheres, which is different from Example 1 in that: in step (2), cellulose acetate butyrate is replaced by octylphenol polyoxyethylene ether and Span20.

[0112] Comparative Example 1

[0113] Comparative Example 1 provides a method for preparing embolic microspheres, comprising:

[0114] (1) Preparation of dispersed phase:

[0115] 10 g of cellulose acetate butyrate was added to 500 mL of butyl acetate, and the mixture was stirred and dissolved at 35° C. to form a uniform oil phase solution to obtain a dispersed phase.

[0116] (2) Preparation of continuous phase:

[0117] Add 50g of polyvinyl alcohol to 500mL of water, heat to 95℃, stir and dissolve to form a uniform solution. Then add a water-soluble crosslinking agent ((N(2,2-dimethoxy)-2-methylacrylamide, 1.5g), stir evenly, add an acid catalyst (hydrochloric acid, 15mL), continue stirring and react at 25℃ for 13h to obtain a polyvinyl alcohol aqueous solution. Then take 100g of the polyvinyl alcohol aqueous solution, add 10g of sodium acrylate and 0.3g of potassium persulfate, stir evenly to a uniform aqueous phase solution, and obtain a continuous phase.

[0118] (3) Synthetic microspheres:

[0119] Using a membrane emulsifier, under a nitrogen pressure of 20 mbar, the dispersed phase of step (1) is pressed into the continuous phase of step (2) through the membrane pores (pore size of 20 μm) of the membrane tube, and the flow rate of the continuous phase is 300 rpm. After the dispersed phase is added dropwise, the reaction system is heated to a reaction temperature of 55° C., and a certain amount of catalyst tetramethylethylenediamine is continuously added dropwise to the reaction system. The reaction stirring rate is 300 rpm and the stirring is performed for 10 hours. After the reaction is completed, stirring and heating are stopped, the reaction system is allowed to stand for stratification, the oil phase is separated, and the precipitate is collected and repeatedly washed.

[0120] Test Case

[0121] (1) The particle size of the embolic microspheres obtained in Examples 1 to 9 and Comparative Example 1 was analyzed, and the qualified rate of the target specification of 75 to 150 μm was counted.

[0122] (2) The mechanical properties of the embolic microspheres obtained in Examples 1 to 9 and Comparative Example 1 were tested.

[0123] Test methods include:

[0124] The embolic microspheres with a particle size range of 75 to 150 μm from Examples 1 to 9 and Comparative Example 1 were respectively taken, spread on a glass slide, placed under the probe of a texture analyzer (TAXT plusC), and the Hold Compression mode was selected for testing.

[0125] The test results of particle size qualification rate and mechanical properties are shown in Table 1.

[0126] Table 1

[0127]

[0128] Result analysis:

[0129] As can be seen from Table 1, the qualified rates of the embolic microspheres provided in Examples 1 to 9 of the present application are all greater than 60%, showing a relatively high qualified rate level. Moreover, after testing, the mechanical properties of the embolic microspheres prepared in the examples of the present application, such as strength, compression elasticity, suspension performance, and catheter passability, have all been tested to be qualified. In the comparative example, after the continuous phase and the dispersed phase were exchanged, the qualified rate of the prepared microspheres was low, and the mechanical properties were poor.

[0130] The particle size distribution range of the embolic microspheres prepared in the embodiment of the present application is narrow and the particle size is highly uniform. When the particle size uniformity of the prepared embolic microspheres is high, the number of microspheres that do not meet the target particle size is small, and thus the yield of the embolic microspheres will also increase accordingly.

[0131] Description: The embodiment of the present application utilizes a membrane emulsification method, with an aqueous phase containing a water-soluble polymer, a water-soluble monomer, a water-soluble cross-linking agent and an initiator as a dispersed phase, and the aqueous dispersed phase is pressed into an oily continuous phase through the membrane pores of a membrane emulsifier under a certain nitrogen pressure. By adjusting the membrane pore size of the membrane emulsifier, the nitrogen pressure, the concentration of the oil-soluble dispersant in the continuous phase and the flow rate of the continuous phase, etc., embolic microspheres with a relatively uniform particle size distribution can be prepared, thereby increasing the yield of embolic microspheres.

[0132] 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 method for preparing embolic microspheres, characterized in that: include: The embolic microspheres are prepared by membrane emulsification method with water phase as dispersed phase and oil phase as continuous phase; wherein the water phase includes water-soluble polymer, water-soluble monomer, water-soluble crosslinking agent and initiator, and the oil phase includes oily solvent and oil-soluble dispersant.

2. The preparation method according to claim 1, characterized in that: The preparation of embolic microspheres by membrane emulsification method comprises: S1. Under nitrogen pressure, the dispersed phase is pressed into the flowing continuous phase through the membrane pores of a membrane emulsifier to form a mixed solution; S2, heating the mixed solution, adding a catalyst, stirring the mixture to react, and collecting and washing the mixture to obtain the embolic microspheres.

3. The preparation method according to claim 2, characterized in that: In step S1, the nitrogen pressure ranges from 8 to 100 mbar; and / or, The membrane of the membrane emulsifier comprises a ceramic hydrophilic membrane; and / or, The pore size of the membrane pores is 5 to 40 μm.

4. The preparation method according to claim 2, characterized in that: In step S1, the flow rate of the continuous phase is 100-800 rpm / min.

5. The preparation method according to claim 2, characterized in that: In step S2, the mixed solution is heated to 50-70° C.; and / or, The stirring reaction has a stirring rate of 200 to 600 rpm / min; and / or, The stirring reaction time is 8 to 12 hours.

6. The preparation method according to claim 2, characterized in that: The preparation method further comprises a step S0 before step S1: immersing the membrane emulsifier in the continuous phase and ultrasonically treating the continuous phase; Optionally, the ultrasonic treatment time is 30 to 120 minutes.

7. The preparation method according to claim 1, characterized in that: The water-soluble high molecular polymer includes at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, sodium hydroxymethyl cellulose and water-soluble chitosan; and / or, The water-soluble monomer includes at least one of sodium 2-acrylamide-2-methylpropane sulfonate, acrylamide, sodium acrylate and sodium allyl sulfonate; and / or, The water-soluble crosslinking agent includes at least one of N(2,2-dimethoxy)2-methacrylamide and N-(1-hydroxy 2,2-dimethoxyethyl)2-acrylamide; and / or, The initiator includes at least one of ammonium persulfate, sodium persulfate and potassium persulfate.

8. The preparation method according to claim 1, characterized in that: The mass proportion of the water-soluble high molecular polymer in the water phase is 10% to 25%; and / or, The water-soluble monomer accounts for 5% to 15% by weight in the water phase; and / or, and / or, the mass of the water-soluble cross-linking agent is 2% to 6% of the mass of the water-soluble high molecular polymer; and / or, The mass proportion of the initiator in the water phase is 0.1% to 0.6%.

9. The preparation method according to claim 1, characterized in that: The mass proportion of the oil-soluble dispersant in the oil phase is 1% to 6%; and / or, the oil-soluble dispersant comprises at least one of cellulose acetate butyrate, Span, octylphenol polyoxyethylene ether and oleic acid diethanolamide; And / or, the oily solvent includes at least one of butyl acetate, ethyl acetate, methyl acetate and propyl acetate.

10. The preparation method according to claim 1, characterized in that: Among the embolic microspheres, microspheres with a particle size of 75 to 150 μm account for more than 60%.

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