Visual embolic microspheres and their processing methods

Abstract

The present application relates to the field of medical materials, and more specifically, to a developing embolic microsphere and a processing method thereof. The developing embolic microsphere is boiled in a saline solution before sterilization, and the ionic strength of the saline solution is: 0.85mol / kg to 3.6mol / kg. By boiling the developing embolic microsphere in a saline solution with an ionic strength of 0.85mol / kg to 3.6mol / kg before sterilization, during the subsequent screening process, even if wet heat sterilization is used for sterilization, the particle size and volume of the microsphere will not shrink significantly during the wet heat sterilization process, thereby not causing the final particle size distribution and volume of the product to deviate from expectations, thereby improving the qualified rate of the developing embolic microsphere product.

Description

Technical Field

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

[0002] Hepatocellular carcinoma has a high mortality rate and postoperative recurrence rate. Most liver cancer patients are already in the advanced stage when they are discovered. Due to the limitations of tumor metastasis, volume, number, etc., they are no longer suitable for surgical treatment. For such liver cancer patients, transcatheter arterial chemoembolization (TACE) is the preferred treatment option in clinical treatment. TACE refers to the selective injection of embolic materials into tumor blood vessels and tumor blood supply arteries through a microcatheter under the monitoring of medical imaging equipment such as CT and MR, cutting off the blood supply to the tumor and releasing chemotherapy drugs at the same time to achieve the purpose of treating the tumor.

[0003] However, when processing the imaging embolic microspheres, under normal circumstances, the microspheres need to be cleaned, screened, and packaged with pure water / physiological saline, and finally sterilized by wet heat sterilization. The microsphere screening process requires precise control of the microsphere particle size distribution, and the sterilization process causes the microspheres to shrink, resulting in the screening process being unable to intuitively control the product particle size distribution, which increases the difficulty of process quality control and product quality risks, and reduces the product qualification rate. Summary of the invention

[0004] The purpose of the embodiments of the present application is to provide a developing embolic microsphere and a processing method thereof.

[0005] In a first aspect, the present application provides a method for processing developing embolic microspheres, comprising:

[0006] The developing embolic microspheres are boiled in a saline solution before sterilization, and the ionic strength of the saline solution is 0.85 mol / kg to 3.6 mol / kg.

[0007] By boiling the developing embolic microspheres in a salt solution with an ionic strength of 0.85 mol / kg to 3.6 mol / kg before sterilization, during the subsequent screening process, even if moist heat sterilization is used, the particle size and volume of the microspheres will not shrink significantly during the moist heat sterilization process, thereby not causing the final particle size distribution and volume of the product to deviate from expectations, thereby improving the qualified rate of the developing embolic microsphere products.

[0008] In other embodiments of the present application, the ionic strength of the above-mentioned salt solution is 0.9 mol / kg to 3.5 mol / kg.

[0009] In other embodiments of the present application, the above-mentioned cooking temperature is 60°C-100°C.

[0010] In other embodiments of the present application, the above-mentioned steaming time is 5 min-30 min.

[0011] In other embodiments of the present application, the cations in the above-mentioned salt solution include: at least one of sodium ions or potassium ions;

[0012] The anions in the above-mentioned salt solution include at least one of carbonate, bicarbonate, hydrogen phosphate, dihydrogen phosphate, acetate, citrate or chloride ion.

[0013] In other embodiments of the present application, the pH of the above-mentioned salt solution is adjusted to 7-10.

[0014] In other embodiments of the present application, the volume of the saline solution is at least one time the volume of the developing embolic microspheres.

[0015] In other embodiments of the present application, the above-mentioned developing embolic microspheres are mainly composed of an iodine-containing developer and polyvinyl alcohol microspheres; the polyvinyl alcohol microspheres and the developer are coupled by covalent bonds;

[0016] Polyvinyl alcohol microspheres are formed by cross-linking polyvinyl alcohol and a water-soluble polymer with sulfonic acid groups.

[0017] In other embodiments of the present application, the above-mentioned developer includes at least one of 1-(dimethoxymethyl)-2,3,5-triiodobenzene, 2,3,5-triiodo N-(2-oxoethyl)benzamide, 2,3,5-triiodo N-(2-oxoethyl, methyl)benzamide or (1H-imidazole-1-yl)(2,3,5-triiodophenyl)methanone.

[0018] In a second aspect, the present application provides a developing embolic microsphere, which is produced by any of the aforementioned developing embolic microsphere processing methods;

[0019] After sterilization, the volume of the developing embolic microspheres shrinks by -2.5% to 2.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] 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.

[0021] Figure 1 This is a graph showing the change in particle size distribution of the developing microspheres prepared in Example 1 of the present application before and after sterilization treatment;

[0022] Figure 2This is a graph showing the volume change of the developing microspheres before and after sterilization treatment of the microspheres prepared in Example 1 of the present application;

[0023] Figure 3 This is a graph showing the change in particle size distribution of the developing microspheres prepared in Comparative Example 1 of the present application before and after sterilization treatment;

[0024] Figure 4 This is a graph showing the volume change of the developing microspheres before and after sterilization treatment of the microspheres prepared in Comparative Example 1 of the present application;

[0025] Figure 5 This is a graph showing the change in particle size distribution of the developing microspheres before and after sterilization treatment of the developing microspheres prepared in Comparative Example 3 of the present application;

[0026] Figure 6 This is a graph showing the volume change of the developing microspheres before and after sterilization treatment of the microspheres prepared in Comparative Example 3 of the present application;

[0027] Figure 7 This is a graph showing the volume change of the developing microspheres prepared in Comparative Example 4 of the present application before and after sterilization. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments.

[0029] Therefore, the following 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 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 creative work are within the scope of protection of the present application.

[0030] The inventors have found that general gel microspheres will change their swelling ability in salt solutions of different concentrations as the salt concentration changes, which is manifested as a change in the diameter or volume of the gel particles. When the degree of cross-linking of the microspheres is low, their volume changes rapidly, and the volume can be quickly shrunk or expanded at room temperature. However, due to the strong surface hydrophobicity and the high degree of cross-linking between surface molecules, the molecular chains are tightly connected and entangled with each other, resulting in that at room temperature, changes in the concentration of the salt solution outside the microspheres are difficult to cause a significant change in the volume of the microspheres. However, during the final moist heat sterilization process, the high temperature and high pressure conditions will promote the movement between the microsphere molecular chains and achieve swelling equilibrium, which is ultimately manifested as changes in the particle size and volume of the microspheres during the moist heat sterilization process.

[0031] Based on the above cognition, the inventors have discovered after long-term research that high-temperature treatment of the microspheres using a salt solution with a specific ionic strength can cause the microspheres to shrink to the expected volume in advance. After cooling to room temperature, the treatment of the microspheres in pure water or salt water, such as screening and purification, will not cause the volume of the microspheres to change again, thereby ensuring the consistency of the particle size distribution and volume of the microspheres before and after sterilization.

[0032] Based on this, the embodiment of the present application provides a method for processing developing embolic microspheres, comprising:

[0033] The developing embolic microspheres are boiled in a saline solution before sterilization, and the ionic strength of the saline solution is 0.85 mol / kg to 3.6 mol / kg.

[0034] By boiling the developing embolic microspheres in a salt solution with an ionic strength of 0.85 mol / kg to 3.6 mol / kg before sterilization, during the subsequent screening process, even if moist heat sterilization is used, the particle size of the microspheres will not shrink during the moist heat sterilization process, thereby preventing the final particle size distribution and volume of the product from deviating from expectations, thereby improving the product's qualification rate.

[0035] Furthermore, in some embodiments of the present application, a process for improving the qualified rate of the developed embolic microsphere products comprises the following steps:

[0036] Step S1, preparing developing embolic microspheres.

[0037] Furthermore, in some embodiments of the present application, the developing embolic microspheres are mainly composed of an iodine-containing developer and polyvinyl alcohol microspheres; the polyvinyl alcohol microspheres are coupled to the developer via covalent bonds.

[0038] Furthermore, the polyvinyl alcohol microspheres are formed by cross-linking polyvinyl alcohol and a water-soluble polymer with a sulfonic acid group.

[0039] Furthermore, in some embodiments of the present application, at least one of 1-(dimethoxymethyl)-2,3,5-triiodobenzene, 2,3,5-triiodo N-(2-oxoethyl)benzamide, 2,3,5-triiodo N-(2-oxoethyl, methyl)benzamide or (1H-imidazole-1-yl)(2,3,5-triiodophenyl)methanone is selected as the developer.

[0040] The polyvinyl alcohol microspheres can be prepared by common preparation methods in the art.

[0041] Furthermore, in some embodiments of the present application, polyvinyl alcohol microspheres are prepared according to the following steps:

[0042] In a 250 ml three-necked flask equipped with an overhead mechanical stirrer, add 100 ml of purified water, add about 15 g of PVA (model 1888), heat to 95 °C to dissolve, and cool to room temperature; add 3.0 g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA), followed by 10 ml of concentrated hydrochloric acid, react at room temperature for 14 hours, and then use 2.5 M sodium hydroxide solution to neutralize to pH = 7 to obtain a macromolecular polyvinyl alcohol monomer solution.

[0043] In a 1L three-necked flask equipped with an overhead mechanical stirrer, add 600mL of butyl acetate, add 18g of cellulose acetate butyrate to dissolve, and obtain an oil phase; dissolve the calculated amount of acrylamide-2-methylpropanesulfonic acid sodium salt (AMPS sodium) in 60ml of water, add 120mL of macromolecular polyvinyl alcohol monomer solution, and add 1.5g of potassium persulfate to obtain an aqueous phase. The speed is set to 400rpm, and the aqueous phase is added dropwise to the oil phase; after the addition is completed, the temperature is raised to 55°C, 2.2ml of tetramethylethylenediamine is added, and the reaction is carried out for 8h. After cooling to 25°C, the product is transferred to a filtration reactor for purification, wherein butyl acetate is filtered off, and then washed with ethyl acetate 5 times and acetone 4 times; vacuum dried at 55°C for 2 hours to remove residual solvents, and polyvinyl alcohol microspheres are obtained.

[0044] Further, in some embodiments of the present application, the polyvinyl alcohol microspheres and the developer are coupled via covalent bonds, which can be carried out according to the following steps:

[0045] Exemplarily, 1-(dimethoxymethyl)-2,3,5-triiodobenzene is selected as the developer: in a 250ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, 8g of 1-(dimethoxymethyl)-2,3,5-triiodobenzene is added, and 120ml of DMSO is added to dissolve it; then 4.0g of dry polyvinyl alcohol microspheres are added; after swelling for 1h, 1ml of methanesulfonic acid is added and reacted at 60°C for 48h, and then washed with DMSO, 10% sodium bicarbonate and brine in sequence to obtain developing microspheres.

[0046] Exemplarily, 2,3,5-triiodo N-(2-oxoethyl)benzamide is selected as a developer: in a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, 6 g of 2,3,5-triiodo N-(2-oxoethyl)benzamide is added, and 120 ml of DMSO is added to dissolve it; then 4.0 g of dry polyvinyl alcohol microspheres are added; after swelling for 1 hour, 1 ml of methanesulfonic acid is added and reacted at 60°C for 48 hours, and then washed with DMSO, 10% sodium bicarbonate and brine in sequence to obtain developing microspheres.

[0047] Exemplarily, 2,3,5-triiodo N-(2-oxoethyl, methyl)benzamide is selected as a developer: in a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, 8 g of 2,3,5-triiodo N-(2-oxoethyl, methyl)benzamide is added, and 120 ml of DMSO is added to dissolve it; then 4.0 g of dry polyvinyl alcohol microspheres are added; after swelling for 1 hour, 1 ml of methanesulfonic acid is added and reacted at 60°C for 48 hours, and then washed with DMSO, 10% sodium bicarbonate and brine in sequence to obtain developing microspheres.

[0048] Exemplarily, (1H-imidazole-1-yl)(2,3,5-triiodophenyl)methanone is selected as a developer: in a 250ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, 10g of (1H-imidazole-1-yl)(2,3,5-triiodophenyl)methanone is added, and 120ml of DMSO is added to dissolve it; then 4.0g of dry polyvinyl alcohol microspheres are added; after swelling for 1h, 2ml of triethylamine is added and reacted at 60°C for 48h, and then washed with DMSO, 10% sodium bicarbonate and brine in sequence to obtain developed microspheres.

[0049] Step S2, preparing a salt solution with an ionic strength of 0.85 mol / kg to 3.6 mol / kg.

[0050] In some embodiments of the present application, the ionic strength of the salt solution is 0.9 mol / kg to 3.5 mol / kg.

[0051] Further optionally, the ionic strength of the salt solution is 0.95 mol / kg to 3.55 mol / kg.

[0052] Illustratively, the ionic strength of the salt solution is 1 mol / kg, 1.5 mol / kg, 2 mol / kg, 2.5 mol / kg, 3 mol / kg, 3.5 mol / kg.

[0053] Furthermore, in some embodiments of the present application, the cations in the salt solution include: at least one of sodium ions or potassium ions.

[0054] Exemplarily, the cations in the salt solution are sodium salt solution, potassium salt solution or a mixed solution of sodium salt and potassium salt.

[0055] Furthermore, in some embodiments of the present application, the anions in the salt solution include at least one of carbonate, bicarbonate, hydrogen phosphate, dihydrogen phosphate, acetate, citrate or chloride ion.

[0056] Exemplarily, the anions in the salt solution are any one of carbonate, bicarbonate, hydrogen phosphate, dihydrogen phosphate, acetate, citrate or chloride; or the anions in the salt solution are carbonate and bicarbonate; or the anions in the salt solution are hydrogen phosphate, dihydrogen phosphate and acetate; or the anions in the salt solution are citrate and chloride, etc.

[0057] It should be noted that in other optional embodiments of the present application, the anions or cations in the above-mentioned salt solution may also be selected from other anions and cations in the art, and only some of the anions and cations are listed here.

[0058] Furthermore, in some embodiments of the present application, the pH of the salt solution is adjusted to 7-10.

[0059] Further optionally, in some embodiments of the present application, the pH of the salt solution is adjusted to 7-10, comprising:

[0060] The pH of the salt solution is adjusted to between 7 and 10 using an acidic or alkaline substance.

[0061] Further optionally, in some embodiments of the present application, the acidic substance includes: at least one of hydrochloric acid or phosphoric acid.

[0062] Further optionally, in some embodiments of the present application, the alkaline substance includes: at least one of sodium carbonate, sodium bicarbonate or sodium hydroxide.

[0063] It should be noted that when the saline solution is used to immerse and boil the developing embolic microspheres, the saline solution may be first adjusted to pH 7 to 10 using the above-mentioned acidic or alkaline substances. Alternatively, after the saline solution and the developing embolic microspheres are mixed, the above-mentioned acidic or alkaline substances may be added to adjust the solution to pH 7 to 10.

[0064] Further optionally, in some embodiments of the present application, the volume of the saline solution is at least one time the volume of the developed embolic microspheres.

[0065] Exemplarily, the volume of the saline solution is two, three, four, five, etc. times the volume of the visualized embolic microspheres.

[0066] Step S3, boiling the developing embolic microspheres obtained in step S1 with the saline solution having an ionic strength of 0.85 mol / kg to 3.6 mol / kg obtained in step S2 before sterilization.

[0067] Further optionally, in some embodiments of the present application, the cooking temperature is 60°C-100°C.

[0068] Further optionally, in some embodiments of the present application, the cooking time is 5 min-30 min.

[0069] Further optionally, in some embodiments of the present application, the developed embolic microspheres prepared in step S1 are immersed in the saline solution with an ionic strength of 0.86 mol / kg to 3.59 mol / kg prepared in step S2 at 61° C. to 99° C. and boiled for 6 min to 29 min.

[0070] Further optionally, in some embodiments of the present application, the developed embolic microspheres prepared in step S1 are immersed in the saline solution with an ionic strength of 0.9 mol / kg to 3.5 mol / kg prepared in step S2 at 65° C. to 95° C. and boiled for 6 min to 29 min.

[0071] Illustratively, the developed embolic microspheres prepared in step S1 are immersed in the saline solution with an ionic strength of 0.92 mol / kg, 0.94 mol / kg, 0.96 mol / kg, 0.98 mol / kg, 1.2 mol / kg, 1.4 mol / kg, 1.6 mol / kg, 1.8 mol / kg, 2.2 mol / kg, 2.4 mol / kg, 2.6 mol / kg, 2.8 mol / kg, 3.2 mol / kg or 3.4 mol / kg prepared in step S2 at 62°C, 64°C, 66°C, 68°C, 70°C, 72°C, 76°C, 78°C, 82°C, 86°C or 96°C and boiled for 8 min, 10 min, 12 min, 15 min, 18 min, 20 min, 22 min, 25 min or 28 min.

[0072] After the processing in step S3, the developed embolic microspheres are shrunk and fixed, so that when the developed embolic microspheres are subsequently screened or sterilized, the particle size distribution and volume will not change significantly.

[0073] Step S4, washing the developed embolic microspheres treated in step S3 to remove the residual salt on the surface of the developed embolic microspheres.

[0074] Some embodiments of the present application provide a developing embolic microsphere, which is manufactured by using the processing method of the developing embolic microsphere provided by any of the aforementioned embodiments.

[0075] Furthermore, after sterilization, the volume shrinkage of the above-mentioned imaging embolic microspheres is between -2.5% and 2.5%. For example, the volume shrinkage is -2.0%, -1.0%, 0, 1% or 2%.

[0076] The features and performance of the present application are further described in detail below in conjunction with the embodiments:

[0077] Example 1

[0078] A method for processing developing embolic microspheres is provided, which is carried out according to the following steps:

[0079] (1) Preparation of polyvinyl alcohol microspheres

[0080] In a 250 ml three-necked flask equipped with an overhead mechanical stirrer, add 100 ml of purified water, add about 15 g of PVA (model 1888), heat to 95 °C to dissolve, and cool to room temperature; add 3.0 g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA), followed by 10 ml of concentrated hydrochloric acid, react at room temperature for 14 hours, and then use 2.5 M sodium hydroxide solution to neutralize to pH = 7 to obtain a macromolecular polyvinyl alcohol monomer solution.

[0081] In a 1L three-necked flask equipped with an overhead mechanical stirrer, add 600mL of butyl acetate, add 18g of cellulose acetate butyrate to dissolve, and obtain an oil phase; dissolve the calculated amount of acrylamide-2-methylpropanesulfonic acid sodium salt (AMPS sodium) in 60ml of water, add 120mL of macromolecular polyvinyl alcohol monomer solution, and add 1.5g of potassium persulfate to obtain an aqueous phase. The speed is set to 400rpm, and the aqueous phase is added dropwise to the oil phase; after the addition is completed, the temperature is raised to 55°C, 2.2ml of tetramethylethylenediamine is added, and the reaction is carried out for 8h. After cooling to 25°C, the product is transferred to a filtration reactor for purification, wherein butyl acetate is filtered off, and then washed with ethyl acetate 5 times and acetone 4 times; vacuum dried at 55°C for 2 hours to remove residual solvents, and polyvinyl alcohol microspheres are obtained.

[0082] (2) Preparation of developing microspheres

[0083] 1-(Dimethoxymethyl)-2,3,5-triiodobenzene was selected as the developer: 8 g of 1-(dimethoxymethyl)-2,3,5-triiodobenzene was added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and dissolved in 120 ml of DMSO; then 4.0 g of dry polyvinyl alcohol microspheres were added; after swelling for 1 hour, 1 ml of methanesulfonic acid was added and reacted at 60°C for 48 hours, and washed with DMSO, 10% sodium bicarbonate and brine in turn to obtain developing microspheres.

[0084] (3) Salt solution treatment

[0085] Prepare a sodium chloride solution with an ionic strength of 0.85 mol / kg, take 1L of pure water, add 100g of sodium chloride, stir to fully dissolve it, test its pH value with a pH meter, adjust its pH to 8.0 with hydrochloric acid and sodium hydroxide, take 500mL of the developed microspheres in pure water, add 1L of sodium chloride solution, heat to boiling with an electric ceramic stove, time for 10 minutes, filter the microspheres with a sieve and rinse with pure water, and the shrinkage process is completed to measure the final volume of the developed microspheres.

[0086] Example 2

[0087] A method for processing developing embolic microspheres is provided, which is carried out according to the following steps:

[0088] Step (1) is the same as in Example 1.

[0089] (2) Preparation of developing microspheres

[0090] 2,3,5-triiodo N-(2-oxoethyl)benzamide was selected as the developer: 6 g of 2,3,5-triiodo N-(2-oxoethyl)benzamide was added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and dissolved in 120 ml of DMSO; then 4.0 g of dry polyvinyl alcohol microspheres were added; after swelling for 1 hour, 1 ml of methanesulfonic acid was added and reacted at 60°C for 48 hours, and washed with DMSO, 10% sodium bicarbonate and brine in turn to obtain developing microspheres.

[0091] (3) Salt solution treatment

[0092] Prepare a phosphate buffer solution with an ionic strength of 2.63 mol / kg. Take 1 L of pure water, add 57.6 g of disodium hydrogen phosphate, 3.8 g of potassium dihydrogen phosphate, and 160 g of sodium chloride, and stir to fully dissolve them. The pH value is 7.4 as tested by a pH meter. Take 500 mL of the developed microspheres in pure water, add 1 L of phosphate buffer, and heat to boiling in an electric ceramic stove for 15 minutes. Filter the microspheres with a sieve and rinse with pure water. The shrinkage process is completed and the final volume of the microspheres is measured.

[0093] Example 3

[0094] A method for processing developing embolic microspheres is provided, which is carried out according to the following steps:

[0095] Step (1) is the same as in Example 1.

[0096] (2) Preparation of developing microspheres

[0097] 2,3,5-triiodo N-(2-oxoethyl, methyl)benzamide was selected as the developer: 8 g of 2,3,5-triiodo N-(2-oxoethyl, methyl)benzamide was added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and dissolved in 120 ml of DMSO; then 4.0 g of dry polyvinyl alcohol microspheres were added; after swelling for 1 hour, 1 ml of methanesulfonic acid was added and reacted at 60°C for 48 hours, and washed with DMSO, 10% sodium bicarbonate and brine in turn to obtain developing microspheres.

[0098] (3) Salt solution treatment

[0099] Prepare a sodium bicarbonate solution with an ionic strength of 3.21 mol / kg (calculated based on complete ionization). Take 1 L of pure water, add 90 g of sodium bicarbonate, stir to fully dissolve it, and test its pH value with a pH meter to 7.9. Take 500 mL of microspheres in pure water, add 1 L of phosphate buffer, heat to boiling in an electric ceramic stove, and time for 15 minutes. Filter the microspheres with a sieve and rinse with pure water. The shrinkage process is completed and the final volume of the microspheres is measured.

[0100] Example 4

[0101] A method for processing developing embolic microspheres is provided, which is carried out according to the following steps:

[0102] Step (1) is the same as in Example 1.

[0103] (2) Preparation of developing microspheres

[0104] (1H-imidazole-1-yl)(2,3,5-triiodophenyl)methanone was selected as the developer: 10 g of (1H-imidazole-1-yl)(2,3,5-triiodophenyl)methanone was added to a 250 ml three-necked round-bottom flask equipped with an overhead stirrer and a thermometer, and dissolved in 120 ml of DMSO; then 4.0 g of dry polyvinyl alcohol microspheres were added; after swelling for 1 hour, 2 ml of triethylamine was added and reacted at 60°C for 48 hours, and washed with DMSO, 10% sodium bicarbonate and brine in turn to obtain developing microspheres.

[0105] (3) Salt solution treatment

[0106] Prepare a sodium carbonate solution with an ionic strength of 3.6 mol / kg. Take 1 L of pure water, add 127 g of sodium carbonate, stir to fully dissolve it, adjust the pH to 10 with hydrochloric acid, take 500 mL of microspheres in pure water, add 1 L of phosphate buffer, heat to boiling with an electric ceramic stove, and time for 15 minutes. Filter the microspheres with a sieve and rinse with pure water. The shrinkage process is completed and the final volume of the microspheres is measured.

[0107] Comparative Example 1

[0108] Provided is a method for processing developing embolic microspheres:

[0109] Steps (1) and (2) are the same as in Example 1.

[0110] (3) Salt solution treatment

[0111] Prepare a potassium chloride solution with an ionic strength of 0.13 mol / kg, take 1L of pure water, add 10g of potassium chloride, stir to fully dissolve it, test its pH value with a pH meter, adjust its pH to 8.0 with hydrochloric acid and sodium hydroxide, take 500mL of developed microspheres in pure water, add 1L of potassium chloride solution, heat to boiling with an electric ceramic stove, time for 10 minutes, filter out the microspheres with a sieve and rinse with pure water, the shrinkage process is completed, and the final volume of the developed microspheres is measured.

[0112] Comparative Example 2

[0113] Provided is a method for processing developing embolic microspheres:

[0114] Steps (1) and (2) are the same as in Example 1.

[0115] (3) Salt solution treatment

[0116] Prepare a sodium chloride solution with an ionic strength of 0.26 mol / kg, take 1L of pure water, add 15g of sodium chloride, stir to fully dissolve it, test its pH value with a pH meter, adjust its pH to 8.0 with hydrochloric acid and sodium hydroxide, take 500mL of the developed microspheres in pure water, add 1L of sodium chloride solution, heat to boiling with an electric ceramic stove, time for 10 minutes, filter the microspheres with a sieve and rinse with pure water, and the shrinkage process is completed to measure the final volume of the developed microspheres.

[0117] Comparative Example 3

[0118] Provided is a method for processing developing embolic microspheres:

[0119] Steps (1) and (2) are the same as in Example 1.

[0120] (3) Salt solution treatment

[0121] Prepare a sodium carbonate solution with an ionic strength of 5.6 mol / kg, take 1 L of pure water, add 200 g of sodium carbonate, stir to fully dissolve it, test its pH value with a pH meter, adjust its pH to 10.0 with hydrochloric acid and sodium hydroxide, take 500 mL of the developed microspheres in pure water, add 1 L of sodium chloride solution, heat to boiling with an electric ceramic stove, time for 10 minutes, filter the microspheres with a sieve and rinse with pure water, and the shrinkage process is completed to measure the final volume of the developed microspheres.

[0122] Comparative Example 4

[0123] Provided is a method for processing developing embolic microspheres:

[0124] Steps (1) and (2) are the same as in Example 1.

[0125] (3) No saline solution treatment (untreated group)

[0126] Experimental Example 1

[0127] The volume shrinkage of the developing embolic microspheres of Examples 1-4 and Comparative Examples 1-4 before and after sterilization was investigated:

[0128] Experimental steps:

[0129] The volumes of the developed embolic microspheres obtained by processing in Examples 1-4 and Comparative Examples 1-4 were sampled and tested, as follows:

[0130] 2.0 mL of the imaging embolic microspheres obtained in Examples 1-4 and Comparative Examples 1-4 were measured with a measuring cylinder, and sterilized by packaging in a physiological saline storage solution; the volume of each imaging embolic microsphere was then measured in a measuring cylinder. The results are shown in Table 1 and Figure 2 , Figure 4 and Figure 6 ;

[0131] Table 1

[0132]

[0133]

[0134] From Table 1 and Figure 2 , Figure 4 and Figure 6 It can be seen that the volume shrinkage rate of the developing embolic microspheres processed in Examples 1-4 after sterilization is very small, ranging from -2.5% to 2.5%, as measured in a measuring cylinder, that is, the developing embolic microspheres hardly undergo significant changes; in particular, the volume of the developing embolic microspheres in Examples 1 and 4 does not change before and after sterilization.

[0135] The developing embolic microspheres obtained in Comparative Examples 1, 2 and 4 had a significant shrinkage of up to 35% during the sterilization process, while the developing embolic microspheres obtained in Comparative Example 3 had a significant expansion of up to 15% during the sterilization process.

[0136] Experimental Example 2

[0137] The particle size distribution of the developing embolic microspheres before and after sterilization of the examples and comparative examples was investigated:

[0138] Experimental steps:

[0139] 2.0 mL of the imaging embolic microspheres obtained in Example 1, Comparative Example 1, Comparative Example 3 and Comparative Example 4 were measured with a measuring cylinder, and the particle size of the imaging embolic microspheres was measured under a microscope. The corresponding statistical results were: Figure 1 , Figure 3 , Figure 5 and Figure 7 shown.

[0140] The particle size distribution of the developing embolic microspheres processed in Example 1 did not change significantly, while the particle size distribution of the developing embolic microspheres in Comparative Examples 1, 3 and 4 changed significantly.

[0141] 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 processing developing embolic microspheres, characterized in that: include: The developed embolic microspheres were boiled in saline solution before packaging and sterilization; The ionic strength of the salt solution is 0.9 mol / kg to 3.5 mol / kg; The cooking temperature is 60℃-100℃; Steaming time: 5min-30min; The cations in the salt solution include: at least one of sodium ions or potassium ions; The anions in the salt solution include at least one of carbonate, bicarbonate, hydrogen phosphate, dihydrogen phosphate, acetate, citrate or chloride; The developing embolic microspheres are mainly composed of an iodine-containing developer and polyvinyl alcohol microspheres; the polyvinyl alcohol microspheres are coupled to the developer via a covalent bond; The polyvinyl alcohol microspheres are formed by cross-linking polyvinyl alcohol and a water-soluble polymer with a sulfonic acid group.

2. The processing method according to claim 1, characterized in that: The pH of the salt solution is adjusted to 7-10.

3. The processing method according to claim 1, characterized in that: The volume of the saline solution is at least one time the volume of the imaging embolic microspheres.

4. The processing method according to claim 1, characterized in that: The developer includes at least one of 1-(dimethoxymethyl)-2,3,5-triiodobenzene, 2,3,5-triiodo-N-(2-oxoethyl)benzamide, 2,3,5-triiodo-N-(2-oxoethyl, methyl)benzamide or (1H-imidazol-1-yl)(2,3,5-triiodophenyl)methanone.

5. A developing embolic microsphere, characterized in that: The microspheres are processed by the processing method of developing embolic microspheres according to any one of claims 1 to 4; After sterilization, the volume of the developing embolic microspheres shrinks by between -2.5% and 2.5%.

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