Suspension containing radioactive microspheres as well as preparation method and application of suspension

Abstract

The invention provides a suspension containing radioactive microspheres as well as a preparation method and application of the suspension. The radioactive microsphere comprises a resin microsphere and radionuclide loaded on the resin microsphere, the material of the resin microsphere comprises at least one of polystyrene, polyethylene or polydivinylbenzene or a cross-linked polymer of the polystyrene, the polyethylene or the polydivinylbenzene, the average particle size of the radioactive microsphere is 25-40 [mu] m, and the non-spherical ratio of the radioactive microsphere is controlled within 5%. Therefore, the distribution density of the microspheres in the tumor part is improved, and the tumor killing effect is improved; in addition, the occurrence rate of adverse events can be reduced.

Description

[0001] This patent application is a divisional application of patent application number 2023108208986, the application date of which is July 6, 2023, and the name of the invention is "Suspension containing radioactive microspheres, preparation method and application thereof". Technical Field

[0002] The present application relates to the medical field, and in particular to a suspension containing radioactive microspheres and a preparation method and application thereof. Background Art

[0003] There are currently many treatments for malignant tumors, including chemotherapy, radiotherapy, interventional therapy, biological immunotherapy, etc. Since most patients are already in the middle or late stages of cancer when they are diagnosed, they have lost the opportunity for surgical treatment and are no longer sensitive to chemotherapy drugs after multiple chemotherapy sessions. Therefore, radiotherapy has become a key treatment for some cancers.

[0004] Radioactive microsphere therapy is to prepare radioactive materials into microspheres of regular size, which are injected into the arterial blood supply of the target organ and emit large doses of high-energy beta rays to kill tumor tissue. Due to the limited penetration depth of the radiation tissue, it can also protect nearby healthy tissues. Radioactive microspheres mainly include carriers and radionuclides loaded on the carriers. The radionuclides that have been discovered so far include yttrium [ 90 Y], phosphorus [ 32 P], iodine [ 131 I], iodine[ 125 I], technetium [99m Tc], rhenium [ 188 Re], holmium 166 Ho], etc. The carrier is mainly resin microspheres, which use polystyrene-divinylbenzene polymer as the carrier. Its density is close to that of blood, and there is no easy sedimentation phenomenon. It has been widely used in clinical practice, especially in the treatment of liver cancer (HCC). Recently, other forms of carrier microspheres such as carbon microspheres and silicon microspheres have also appeared, but there is less public information and they are in the early development stage.

[0005] Although radioactive microsphere therapy causes less damage to the patient's normal tissues, some patients will still experience adverse reactions after use. In addition, the existing radioactive microspheres are more effective for small tumors with a volume of <10cc, but the distribution of radioactive microspheres within the boundaries of large tumors with a volume greater than >10cc, especially deep in the tumor, needs to be improved. Summary of the invention

[0006] In view of this, the present application provides a suspension of radioactive microspheres and a preparation method and application thereof, aiming to improve the adverse reactions caused by existing radioactive microspheres and the problem that the therapeutic effect needs to be improved.

[0007] In a first aspect, the present application provides a suspension containing radioactive microspheres, wherein the radioactive microspheres include resin microspheres and radionuclides loaded on the resin microspheres, wherein the material of the resin microspheres includes at least one of polystyrene, polyethylene or polydivinylbenzene, or a cross-linked polymer thereof, and the average particle size of the radioactive microspheres is 25 μm to 40 μm, and the non-spherical ratio is within 5%.

[0008] Optionally, the non-spherical ratio refers to the ratio of the number of non-spherical radioactive microspheres to the total radioactive microspheres in the suspension, and the non-spherical radioactive microspheres refer to radioactive microspheres whose minimum radius is less than 75% of the radius of the original microspheres.

[0009] Optionally, based on the number of the radioactive microspheres, the number of radioactive microspheres with a size of 20 μm to 60 μm in the suspension accounts for more than 85%; and / or the non-spherical ratio of the radioactive microspheres is within 2%; and / or the material of the resin microspheres is selected from cross-linked polystyrene microspheres with a cross-linking degree of 2% to 10%.

[0010] Optionally, the resin microspheres are sulfonated, nitrated or carbonized resin microspheres.

[0011] Optionally, the radionuclide is selected from at least one isotope of yttrium, lutetium, indium, holmium, samarium, iodine, phosphorus, iridium or rhenium.

[0012] Optionally, the radionuclide is selected from yttrium [ 90 Y], the material of the resin microspheres is selected from sulfonated polystyrene partially cross-linked with divinylbenzene, and the suspension also contains water for injection, each 1 mL of yttrium [ 90 Y] activity is 300~700MBq.

[0013] In a second aspect, the present application provides a method for preparing a suspension containing radioactive microspheres, the method comprising: mixing resin microspheres and a radioactive nuclide compound in a solution, and reacting to obtain the suspension containing the radioactive microspheres; the material of the resin microspheres comprises at least one of polystyrene, polyethylene or polydivinylbenzene, or a cross-linked polymer thereof, the average particle size of the radioactive microspheres is 25 μm to 40 μm, and the non-spherical ratio is within 5%.

[0014] Optionally, the resin microspheres are subjected to sulfonation, nitration or carbonization before being mixed with the radionuclide compound.

[0015] In a third aspect, the present application provides use of the suspension described in the first aspect or the suspension prepared by the method described in the second aspect in the preparation of a drug for treating tumors.

[0016] Optionally, the tumor is primary or secondary liver cancer.

[0017] Beneficial effects:

[0018] The present application provides a suspension of radioactive microspheres, which include resin microspheres and radionuclides loaded on the resin microspheres. The material of the resin microspheres includes at least one of polystyrene, polyethylene or polydivinylbenzene, or a cross-linked polymer thereof. The average particle size of the radioactive microspheres is 25 to 40 μm. By controlling the non-spherical ratio of the radioactive microspheres to within 5%, the distribution density of the microspheres in the tumor part is increased, the treatment effect is improved, the incidence of adverse reactions is reduced, and the safety is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for describing the embodiments are briefly introduced below.

[0020] Figure 1 is the minimum radius (R min ) and the original microsphere radius (R), Figure 1 A in the figure is an example of a spherical microsphere, and B, C, and D each represent an example of a non-spherical microsphere.

[0021] Figure 2 This is a microscope photograph of non-spherical radioactive polystyrene microspheres in the examples of the present application.

[0022] Figure 3 Schematic diagram of the implantation position of the test article or control article in the examples of the present application. DETAILED DESCRIPTION

[0023] In order to make the technical problems, technical solutions and technical effects to be solved by the present invention clearer, the present invention will be further described in detail in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0024] The radioactive microspheres existing in the prior art have problems of adverse reactions and therapeutic effects to be improved during the experiment, such as radioactive polystyrene microspheres prepared by commercially available sulfonated polystyrene microspheres or radioactive polystyrene microspheres or carbon microspheres prepared by methods provided by CN202211592412X, CN2022116010239 and CN2022116017505. However, the inventors have found through long-term and extensive research that the non-spherical ratio of the radioactive microspheres finally obtained by the above-mentioned prior art is relatively large, basically greater than 10%. Even if the non-spherical ratio in the sulfonation process is relatively reduced by controlling the stirring speed, there is a phenomenon of uneven sulfonation, and the non-spherical ratio of the finally obtained radioactive microspheres is still greater than 10%. And the prior art does not explore the non-spherical ratio in the suspension containing radioactive microspheres.

[0025] The inventor unexpectedly discovered that when the non-sphericity ratio of the suspension containing radioactive microspheres is controlled within 5%, it can not only increase the distribution density of the microspheres in the tumor, indicating a better killing effect on the tumor; it can also significantly reduce irritation and inflammation, thereby reducing the incidence of adverse reactions such as fever, pain and liver damage. The study found that the non-sphericity ratio of microspheres is one of the key factors affecting the distribution density, which ultimately affects the efficacy and safety.

[0026] In view of this, the present application embodiment first provides a suspension containing radioactive microspheres, which is used for radiotherapy of malignant tumors. The radioactive microspheres include resin microspheres and radionuclides loaded on the resin microspheres, the average particle size of the radioactive microspheres is 25 to 40 μm (micrometers), and the non-sphericity ratio of the radioactive microspheres is within 5%. Compared with the prior art, by controlling the non-sphericity ratio of the radioactive microspheres within this range, not only the treatment effect is improved, but also the safety can be improved.

[0027] In this article, "non-spherical ratio" refers to the ratio of the number of non-spherical microspheres to the total microspheres in the suspension. Non-spherical microspheres refer to microspheres whose minimum radius is less than 75% of the radius of the original microspheres. Correspondingly, "spherical ratio" refers to the ratio of the number of spherical microspheres to the total microspheres in a certain amount of suspension, and the spherical microspheres refer to the microspheres with the minimum radius (R min ) is a microsphere with a radius (R) that is 75% greater than the original microsphere. min It refers to the shortest distance from the center to the edge under the orthographic projection. The center of the circle refers to the center of the two points on the microsphere with the longest straight-line distance under the orthographic projection (if the distance from the center to any point on the edge of the microsphere is equal, non-spherical microspheres are not counted); R refers to the average radius of the microsphere. The average radius is relative to the average diameter. The average diameter refers to the average particle size, and the average radius is half of the average particle size. Figure 1 As shown, Figure 1 The minimum radius of the microsphere (Rmin ) and the original microsphere radius (R), where Figure 1 A is an example of a spherical microsphere, R min is equal to R. B, C, and D represent an example of a non-spherical microsphere, namely R min Less than 0.75 times R. It should also be noted that the sphericity ratio and the average sphericity in this article have different meanings and are calculated in different ways, so the values ​​of the sphericity ratio and the average sphericity of the same microsphere are also different.

[0028] The asphericity ratio can be any value within 5%, for example, 0.1% to 5%, 1% to 4%, 2% to 3%, etc.; for example, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0%, etc.

[0029] The average particle size of the radioactive microspheres can be any value in the range of 25 to 40 μm, such as 30 to 35 μm. Within this range, it is beneficial to the distribution of the microspheres in the target organ, helping to improve the therapeutic effect and reduce side effects. It is understood that the average particle size can be any value in the range of 25 to 40 μm, such as 25 μm, 28 μm, 30 μm, 32.5 μm, 35 μm, 40 μm, etc.

[0030] In some embodiments, in the suspension, the number of radioactive microspheres of 20 μm to 60 μm accounts for more than 85%. For example, more than 90%, and for example more than 95%. Within this range, it is beneficial to the distribution of microspheres in target organs, helping to improve the therapeutic effect and reduce side effects. It is understandable that the number of radioactive microspheres of 20 μm to 60 μm can be any value greater than 85%, such as 85%, 88%, 90%, 95%, 98%, etc. It should be noted that the number of radioactive microspheres of 20 μm to 60 μm refers to the ratio of the number of microspheres with a particle size within this range to the total number of microspheres, where the total number of microspheres includes both spherical microspheres and non-spherical microspheres. Therefore, the microspheres in the range of 20 μm to 60 μm include both spherical microspheres and non-spherical microspheres, and the microspheres outside this range are also spherical and non-spherical.

[0031] In some embodiments, in order to better load radionuclides, the resin microspheres are selected from but not limited to sulfonated, nitrated or carbonized resin microspheres. When the resin microspheres are sulfonated or nitrated resin microspheres, there are sulfonic acid groups or nitric acid groups on their surface, and the radionuclides are connected to the sulfonic acid groups or nitric acid groups and are mostly distributed on the surface of the microspheres. When the resin microspheres are carbonized resin microspheres, they are specifically carbon microspheres. The surface of the carbon microspheres contains mesopores, and the radionuclides are distributed in the pores of the mesopores in the form of complexes. Since carbon microspheres are non-degradable, non-spherical carbon microspheres are more likely to cause inflammatory reactions. Therefore, compared with microspheres of other materials, the non-spherical particles of carbon microspheres are controlled within 5% to reduce irritation and inflammatory reactions, as well as to reduce the incidence of adverse reactions. More significant effect.

[0032] In some embodiments, the material of the resin microspheres is selected from but not limited to at least one of polystyrene, polyethylene or polydivinylbenzene, or a cross-linked polymer thereof. In some embodiments, the material of the resin microspheres includes phenolic resin microspheres. In some embodiments, the resin microspheres are cross-linked polystyrene microspheres, and the degree of cross-linking is 2% to 10%, for example 4%, 6%, 8%. Within this range, the requirements of microsphere strength and loading rate can be taken into account. In some embodiments, the resin microspheres are selected from sulfonated or nitrated cross-linked polystyrene. In some embodiments, the material of the resin microspheres is selected from polystyrene partially cross-linked with divinylbenzene. In some embodiments, the resin microspheres are selected from sulfonated polystyrene partially cross-linked with divinylbenzene.

[0033] In some embodiments, the radionuclide is an isotope of at least one of yttrium, lutetium, indium, holmium, samarium, iodine, phosphorus, iridium, or rhenium. In some embodiments, the radionuclide is yttrium [ 90 Y].

[0034] In some embodiments, the radionuclide is yttrium [ 90 Y], the material of the resin microspheres is selected from sulfonated polystyrene partially cross-linked with divinylbenzene, and the suspension further contains water for injection. In some embodiments, the yttrium-containing [ 90 Y] activity is 300-700MBq, preferably 500-700MBq. In some embodiments, each 1mL of the suspension contains 2-3mg of resin microspheres. In some embodiments, the suspension also contains yttrium chloride and / or yttrium sulfate. In some embodiments, the suspension also contains sulfate, wherein the sulfate is present in a small amount in the aqueous solution. In some embodiments, the sulfate is sodium sulfate. In some embodiments, the suspension also contains a buffer, such as a phosphate buffer.

[0035] The embodiments of the present application also provide a suspension containing radioactive carbon microspheres, wherein the radioactive carbon microspheres include carbon microspheres and radioactive nuclides loaded on the carbon microspheres, wherein the average particle size of the radioactive carbon microspheres is 25 to 40 μm (micrometers), and the non-spherical ratio of the radioactive microspheres is within 5%.

[0036] Accordingly, an embodiment of the present application also provides a method for preparing a suspension of radioactive microspheres, comprising: mixing resin microspheres and radioactive nuclide compounds in a solution, and reacting to obtain the suspension containing the radioactive microspheres; the average particle size of the radioactive microspheres is 25 μm to 40 μm, and the non-spherical ratio is within 5%.

[0037] In some embodiments, the resin microspheres are further subjected to sulfonation, nitration or carbonization treatment before being mixed with the radionuclide compound.

[0038] When the resin microspheres are sulfonated, in some embodiments, the method for preparing a suspension of radioactive microspheres comprises the following steps:

[0039] S10. placing the resin microspheres in concentrated sulfuric acid to undergo a sulfonation reaction to obtain sulfonated resin microspheres.

[0040] S20. Mixing the sulfonated microspheres and the radioactive nuclide compound in a solution, and reacting to obtain the suspension containing the radioactive microspheres.

[0041] In some embodiments, in step S10, the sulfonation reaction is performed under an inert atmosphere or nitrogen, such as nitrogen or argon, so as to prevent the influence of oxidation reaction on the microsphere morphology during the preparation process, which is beneficial to control the non-spherical ratio of the radioactive microspheres.

[0042] In some embodiments, in step S10, the temperature of the sulfonation reaction is 35 to 80°C (degrees Celsius), for example: 35°C, 40°C, 50°C, 60°C, 70°C or 80°C. The time is 3 to 6h (hours), for example: 4h, 5h or 6h. Based on the above embodiments, in some embodiments, the concentrated sulfuric acid is added in batches during the sulfonation reaction. The specific scheme is: first, the resin microspheres are mixed with a small amount of concentrated sulfuric acid, and the temperature is slowly increased to a specific temperature at a heating rate of 1 to 3°C / min (degrees Celsius / minute) while stirring, and then the remaining concentrated sulfuric acid is added for sulfonation. In some embodiments, during the mixing of the microspheres with a small amount of concentrated sulfuric acid, the mass ratio of the resin microspheres to the volume of the concentrated sulfuric acid is 1g: (1.5 to 2) mL. After the remaining concentrated sulfuric acid is added, the mass ratio of the resin microspheres to the volume of the concentrated sulfuric acid is 1g: (3 to 6) mL. In this way, the method of adding concentrated sulfuric acid in batches can not only achieve a better sulfonation effect, but also improve the problem of excessive heat affecting the morphology of microspheres during the sulfonation reaction, thereby controlling the non-spherical ratio of the radioactive microspheres.

[0043] In some embodiments, in step S10, the sulfonation reaction is carried out under an inert atmosphere or nitrogen, and concentrated sulfuric acid is added in batches during the sulfonation reaction. Under this condition, it is beneficial to control the non-spherical ratio of the radioactive microspheres within 5%.

[0044] In some embodiments, in step S20, the concentration of the yttrium chloride solution is 1-3 mg / mL, for example: 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, etc.

[0045] In some embodiments, during the reaction of sulfonated, nitrated or carbonized resin microspheres with radionuclide compounds, the reaction temperature is 25 to 40°C, for example 25°C, 30°C, 35°C, 40°C, and the reaction time is 1 to 2 hours, for example 1 hour, 1.5 hours, 1.8 hours, 2 hours.

[0046] When the resin microspheres are carbonized, in some embodiments, the method for preparing a suspension of radioactive microspheres comprises the following steps:

[0047] S100. In an inert atmosphere or a nitrogen atmosphere, the resin microspheres are calcined to obtain carbon microspheres.

[0048] S200. Mixing the carbon microspheres and the radioactive nuclide compound in a solution, and reacting to obtain the suspension containing the radioactive microspheres.

[0049] In some embodiments, the microsphere calcination temperature in step S100 is 400-800°C, for example: 400°C, 500°C, 600°C, 700°C, 800°C, etc., especially 400-600°C; the time is 3-6h, for example: 3h, 3.5h, 4h, 4.5h, 5h, 6h, etc., especially 3-4h. Based on the above embodiments, in some embodiments, the calcination temperature rise process adopts step-by-step temperature rise, and the specific scheme is: firstly, the temperature is rapidly raised from room temperature to 150°C-200°C at a rate of 4-12°C / min, and then the temperature is slowly raised to a specific calcination temperature at a rate of 1-2°C / min (degrees Celsius / minute) above 150°C-200°C, and then calcined. In another specific embodiment, the temperature is first rapidly raised from room temperature to 150°C to 200°C, then slowly raised to 300°C at a rate of 1.6 to 2°C / min above 150°C to 200°C, and then slowly raised to a specific calcination temperature at a rate of 1 to 1.5°C / min. In this way, the step-by-step heating method is not only conducive to improving production efficiency, but also can control the non-spherical ratio of radioactive microspheres.

[0050] In some embodiments, in step S100, the calcined carbon microspheres are further subjected to a washing step and a drying step. For example, the washing step may be performed by washing with dilute nitric acid and deionized water. The drying step may be performed by vacuum drying or drying in a forced air drying oven.

[0051] In some embodiments, in order to achieve better complexation, a precipitant is added before or after the carbon microspheres and the radionuclide compound are mixed in the solution in step S200. For example, in some specific embodiments, the method for preparing the radioactive carbon microspheres includes any one of the following methods 1 or 2:

[0052] Method 1: After mixing carbon microspheres and a solution containing a radioactive nuclide compound, a solution containing a precipitant is added to obtain radioactive carbon microspheres through reaction.

[0053] Method 2: After mixing the carbon microspheres and a solution containing a precipitant, a solution containing a radioactive nuclide compound is added to obtain radioactive carbon microspheres through reaction.

[0054] In this way, radionuclides can be generated and grown in the mesopores of carbon microspheres, thereby obtaining radioactive carbon microspheres with a higher degree of load firmness. On this basis, the inventors found that the generation rate of radionuclides in the mesopores of carbon microspheres is too fast or the generation amount is too much, which will cause the mesoporous structure to collapse, thereby increasing the non-spherical ratio of carbon microspheres. Therefore, the generation rate and generation amount of radionuclides in mesopores are controlled by controlling the concentration of precipitants and radionuclides. In view of this, in some embodiments, the concentration of the precipitant is 5mg / mL to 10mg / mL (milligrams per milliliter). For example, 5mg / mL, 6mg / mL, 8mg / mL, 10mg / mL, etc. In some embodiments, the concentration of the radionuclide is 3mg / mL to 6mg / mL, such as 3mg / mL, 5mg / mL, 6mg / mL, etc. Controlling the precipitant and radionuclides within this range can not only meet the radionuclide loading, but also slow down the generation rate and generation amount of radionuclides in mesopores, which is conducive to controlling the non-spherical ratio of carbon microspheres.

[0055] In some embodiments, in step S100, the microsphere carbonization process firstly rapidly heats from room temperature to 150°C to 200°C at 4 to 12°C / min, then slowly heats to 400 to 600°C at a rate of 1 to 2°C / min, and calcines for 3 to 4 hours; in step S200, the concentration of the precipitant is 5 mg / mL to 10 mg / mL, and the concentration of the radionuclide is 3 mg / mL to 6 mg / mL. In this way, the non-spherical ratio of the carbon microspheres is controlled within 5%.

[0056] In some embodiments, the radionuclide compound is selected from, but not limited to, yttrium sulfate or yttrium chloride. The precipitant is selected from, but not limited to, at least one of tartaric acid, EDTA, and sodium phosphate, such as one or two. For example:

[0057] When the precipitant is selected from one, such as EDTA, and the radionuclide compound is selected from yttrium chloride, the preparation method of the radioactive carbon microspheres includes: washing the carbon microspheres, mixing them evenly with a YCl3 solution, and then standing for 12 hours, then adding EDTA to the mixture, shaking it in a shaker for 1 hour, washing, and drying to obtain EDTA complex-loaded carbon microspheres.

[0058] When the precipitant is selected from one, such as tartaric acid, and the radionuclide compound is selected from yttrium chloride, the preparation method of the carbon microspheres includes: washing the carbon microspheres, mixing them evenly with a YCl3 solution, and then standing for 12 hours, then adding tartaric acid to the mixture, shaking it in a shaker for 1 hour, washing, and drying to obtain carbon microspheres loaded with a tartaric acid complex.

[0059] When the precipitant is selected from two types, such as tartaric acid and sodium phosphate, and the radionuclide compound is selected from yttrium chloride, the preparation method of carbon microspheres includes: adding porous carbon microspheres loaded with Y-tartaric acid complex to sodium phosphate solution, shaking in a shaker for 1 hour, washing and drying to obtain porous carbon microspheres loaded with Y-PO4 complex.

[0060] The present application also provides a method for preparing a suspension of radioactive carbon microspheres, the method comprising: mixing carbon microspheres and a radioactive nuclide compound in a solution, and reacting to obtain the suspension containing the radioactive carbon microspheres; the average particle size of the radioactive carbon microspheres is 25 μm to 40 μm, and the non-spherical ratio is within 5%.

[0061] Accordingly, the present application also provides the use of the above suspension in the preparation of drugs for treating tumors.

[0062] In some embodiments, the tumor is a vascularized solid tumor. In some embodiments, the tumor is a primary or secondary liver cancer.

[0063] The technical solution of the present disclosure will be more clearly and explicitly described in the following examples in an illustrative manner. It should be understood that these examples are only for illustrative purposes and are by no means intended to limit the scope of protection of the present disclosure. The scope of protection of the present disclosure is limited only by the claims.

[0064] Unless otherwise stated, the reagents and instruments used in the following examples are conventional products that can be obtained commercially. Unless otherwise stated, experiments were carried out under conventional conditions or conditions recommended by the manufacturer. In the following examples, the polystyrene microspheres used for sulfonation treatment were selected from the commercially available cross-linked polystyrene-divinylbenzene polymer microspheres AmberChromTM XT30 with an average particle size of 30 μm and a cross-linking degree in the range of 2% to 10% from Dupont, and the polystyrene microspheres used for carbonization treatment were commercially available cross-linked polystyrene-divinylbenzene polymer microspheres with an average particle size of 50 μm and a cross-linking degree in the range of 2% to 10% from Qingdao Hongpu Biotechnology Co., Ltd. (hereinafter referred to as "polystyrene microspheres"). Sulfonated polystyrene microspheres were selected from the cation exchange resin Aminex 50W-X4 (Biorad, Hercules, CA) with an average particle size of 30 μm. Yttrium chloride [ 90 Y] and yttrium sulfate [ 90 Y] was obtained by the decay of strontium-90. The activity of the radioactive agent was measured by an American Capintec (CRC-55TW) activity meter.

[0065] 1. Preparation Example

[0066] Example 1

[0067] This embodiment provides a radioactive polystyrene microsphere, and the preparation steps are as follows:

[0068] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1 g: 2 mL) in an Ar atmosphere. The temperature was raised to 75 °C at a rate of 1 °C / min under stirring at 300 r / min, and the remaining concentrated sulfuric acid (added to 1 g: 6 mL) was added. The reaction was allowed to proceed for 6 h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0069] (2) Add yttrium chloride solution (yttrium chloride [ 90 The mixture of Y] and yttrium chloride (total 2 mg / mL) was stirred and mixed with 2 g of sulfonated polystyrene microspheres, loaded and reacted at 40°C for 2 h, and then washed and resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0070] Example 2

[0071] This embodiment provides a radioactive polystyrene microsphere, and the preparation steps are as follows:

[0072] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1 g: 2 mL) in an Ar atmosphere. The temperature was raised to 75 °C at a rate of 2 °C / min under stirring at 300 r / min, and then the remaining concentrated sulfuric acid was added (to 1 g: 6 mL). The reaction was continued for 6 h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0073] (2) Add yttrium chloride solution (yttrium chloride [ 90 The mixture of Y] and yttrium chloride (total 2.25 mg / mL) was mixed with 2 g of sulfonated polystyrene microspheres by stirring, and loaded for reaction at 40°C for 2 h. After washing, it was resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0074] Example 3

[0075] This embodiment provides a radioactive polystyrene microsphere, and the preparation steps are as follows:

[0076] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, the microspheres were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1 g: 2 mL) and stirred at 300 r / min. The temperature was then raised to 75°C at a rate of 2°C / min. The remaining concentrated sulfuric acid was added (to 1 g: 6 mL) and reacted for 6 h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0077] (2) Add yttrium chloride solution (yttrium chloride [ 90 The mixture of Y] and yttrium chloride (total 2.25 mg / mL) was mixed with 2 g of sulfonated polystyrene microspheres by stirring, and loaded for reaction at 40°C for 2 h. After washing, it was resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0078] Example 4

[0079] This embodiment provides a radioactive polystyrene microsphere, and the preparation steps are as follows:

[0080] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1 g: 1.5 mL) in a nitrogen atmosphere. The mixture was stirred at 300 r / min and then heated to 80°C at a rate of 3°C / min. The remaining concentrated sulfuric acid was added (to 1 g: 3 mL) and reacted for 6 h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0081] (2) Add yttrium chloride solution (yttrium chloride [ 90A mixture of Y] and yttrium chloride (1 mg / mL in total) was mixed with 2 g of sulfonated polystyrene microspheres by stirring, subjected to loading reaction at 40°C for 2 h, and then washed and resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0082] Example 5

[0083] This embodiment provides a radioactive polystyrene microsphere, and the preparation steps are as follows:

[0084] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1 g: 2 mL) in an Ar atmosphere. The mixture was stirred at 300 r / min and then heated to 80°C at a rate of 1°C / min. The remaining concentrated sulfuric acid was added (to 1 g: 3 mL) and reacted for 3 h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0085] (2) Add yttrium chloride solution (yttrium chloride [ 90 A mixture of Y] and yttrium chloride (total 3 mg / mL) was mixed with 2 g of sulfonated polystyrene microspheres by stirring, loaded and reacted at 40°C for 2 h, and then washed and resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0086] Example 6

[0087] This embodiment provides a radioactive carbon microsphere, and the preparation steps are as follows:

[0088] (1) Polystyrene microspheres were calcined at 400 °C for 4 h in an Ar atmosphere to obtain carbon microspheres (the temperature was increased from room temperature to 200 °C at 10 °C / min, then to 300 °C at 2 °C / min, then to 400 °C at 1 °C / min, maintained for 4 h, and then cooled at a rate of 10 °C / min). The carbon microspheres were then washed twice with 0.3 mol / L dilute nitric acid and deionized water, dried, and sieved.

[0089] (2) 2 g of carbon microspheres were mixed with tartaric acid solution (5 mg / mL) and allowed to stand for 12 h. Then, 5 GBq of yttrium chloride solution (yttrium chloride [ 90 Y] and yttrium chloride mixture, 3 mg / mL) and shaken in a constant temperature shaker at 25°C for 1 h (total solution volume was 20 mL) to obtain radioactive carbon microspheres.

[0090] Example 7

[0091] This embodiment provides a radioactive carbon microsphere, and the preparation steps are as follows:

[0092] (1) Polystyrene microspheres were calcined at 400 °C for 4 h in an Ar atmosphere to obtain carbon microspheres (the temperature was increased from room temperature to 200 °C at a rate of 10 °C / min, then increased to 400 °C at a rate of 2 °C / min, maintained for 4 h, and then cooled at a rate of 10 °C / min). The carbon microspheres were then washed twice with 0.3 mol / L dilute nitric acid and deionized water, dried, and sieved.

[0093] (2) 2 g of carbon microspheres were mixed with tartaric acid solution (10 mg / mL) and allowed to stand for 12 h. Then, 5 GBq of yttrium chloride solution (yttrium chloride [ 90 The mixture of Y] and yttrium chloride, 6 mg / mL) was shaken in a constant temperature shaker at 25°C for 1 h (the total volume of the solution was 20 mL) to obtain radioactive carbon microspheres.

[0094] Example 8

[0095] This embodiment provides a radioactive carbon microsphere, and the preparation steps are as follows:

[0096] (1) Polystyrene microspheres were calcined at 400 °C for 4 h in an Ar atmosphere to obtain carbon microspheres (the temperature was increased from room temperature to 200 °C at a rate of 10 °C / min, then increased to 400 °C at a rate of 2 °C / min, maintained for 4 h, and then cooled at a rate of 10 °C / min). The carbon microspheres were then washed twice with 0.3 mol / L dilute nitric acid and deionized water, dried, and sieved.

[0097] (2) 2 g of carbon microspheres were mixed with tartaric acid solution (25 mg / mL) and allowed to stand for 12 h. Then, 5 GBq of yttrium chloride solution (yttrium chloride [ 90 Y] and yttrium chloride mixture, 12.5 mg / mL) and shaken in a constant temperature shaker at 25°C for 1 h (total solution volume was 20 mL) to obtain radioactive carbon microspheres.

[0098] Example 9

[0099] This embodiment provides a radioactive carbon microsphere, and the preparation steps are as follows:

[0100] (1) Polystyrene microspheres were calcined at 600 °C for 3 h in an Ar atmosphere to obtain carbon microspheres (the room temperature was heated to 150 °C at 10 °C / min, then to 600 °C at 2 °C / min, maintained for 3 h, and then cooled at a rate of 10 °C / min). The carbon microspheres were then washed twice with 0.3 mol / L dilute nitric acid and deionized water, dried, and sieved.

[0101] (2) 2 g of carbon microspheres were mixed with tartaric acid solution (10 mg / mL) and allowed to stand for 12 h. Then, 5 GBq of yttrium chloride solution (yttrium chloride [ 90Y] and yttrium chloride mixture, 5 mg / mL) and shaken in a constant temperature shaker at 25°C for 1 h (total solution volume was 20 mL) to obtain radioactive carbon microspheres.

[0102] Example 10

[0103] This embodiment provides a radioactive carbon microsphere, and the preparation steps are as follows:

[0104] (1) Polystyrene microspheres were calcined at 500 °C for 3 h in an Ar atmosphere to obtain carbon microspheres (the room temperature was heated to 200 °C at a rate of 10 °C / min, then to 500 °C at a rate of 2 °C / min, maintained for 3 h, and then cooled at a rate of 10 °C / min). The carbon microspheres were then washed twice with 0.3 mol / L dilute nitric acid and deionized water, dried, and sieved.

[0105] (2) 2 g of carbon microspheres were mixed with 5 GBq of yttrium chloride solution (yttrium chloride [ 90 The mixture of Y] and yttrium chloride (4 mg / mL) was mixed evenly and allowed to stand for 12 h, and then tartaric acid solution (8 mg / mL) was added to the mixture and shaken in a constant temperature shaker at 25°C for 1 h (the total volume of the solution was 20 mL) to obtain radioactive carbon microspheres.

[0106] Comparative Example 1

[0107] This embodiment provides a radioactive polystyrene microsphere, and the preparation steps are as follows:

[0108] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, the microspheres were ultrasonically dispersed in an appropriate amount of concentrated sulfuric acid (1 g: 6 mL), stirred at a speed of 300 r / min, and reacted at a temperature of 75° C. for 6 h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0109] (2) Add yttrium chloride solution (yttrium chloride [ 90 A mixture of Y] and yttrium chloride, 2.25 mg / mL), was mixed with 2 g of sulfonated polystyrene microspheres by stirring, loaded and reacted at 40°C for 2 h, and then washed and resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0110] Comparative Example 2

[0111] Provided is a radioactive polystyrene microsphere, the preparation steps of which are as follows:

[0112] (1) 2 g of commercially available sulfonated polystyrene microspheres were added to water and then mixed with 5 GBq of yttrium sulfate solution (yttrium chloride [ 90 Y] and yttrium chloride mixture, 2.25 mg / mL in total) were loaded and reacted for 2 h.

[0113] (2) The microspheres were washed with phosphate buffer solution and then resuspended with 10 mL of water to obtain radioactive polystyrene microspheres.

[0114] Comparative Example 3

[0115] Provided is a radioactive carbon microsphere, the preparation steps of which are as follows:

[0116] (1) Polystyrene microspheres were calcined at 400 °C for 4 h in an Ar atmosphere to obtain carbon microspheres (the temperature was increased from room temperature to 200 °C at a rate of 10 °C / min, then increased to 400 °C at a rate of 3 °C / min, maintained for 4 h, and then cooled at a rate of 10 °C / min). The carbon microspheres were then washed twice with 0.3 mol / L dilute nitric acid and deionized water, dried, and sieved.

[0117] (2) 2 g of carbon microspheres were mixed with tartaric acid solution (25 mg / mL) and allowed to stand for 12 h. Then, 5 GBq of yttrium chloride solution (yttrium chloride [ 90 Y] and yttrium chloride mixture, 12.5 mg / mL) and shaken in a constant temperature shaker at 25°C for 1 h (total solution volume was 20 mL) to obtain radioactive carbon microspheres.

[0118] 2. Effect Test Example

[0119] Test Example 1

[0120] Determination of the non-sphericity ratio, particle size and particle size distribution of radioactive microspheres.

[0121] (1) Non-spherical ratio: Observe the morphology of the radioactive microspheres under a microscope and calculate the non-spherical ratio. The specific determination method is as follows:

[0122] Determination method: Take an appropriate amount of the sulfonated polymer in each example on a disposable blood cell counting plate, put the cover on the sample, make the cover grid face down (literally face up) and place it under a trinocular microscope for inspection. On the disposable blood cell counting plate, randomly select four appropriate and equal-sized square areas, observe and photograph them at a magnification of 20 to 40 times, and count the non-spherical microspheres and the total number of microspheres in the selected four areas (including spherical and non-spherical microspheres).

[0123] Calculation method: non-spherical ratio = non-spherical microspheres / total number of microspheres*100% (the final result is the average value of four regions).

[0124] Judgment criteria: Non-spherical microspheres are defined as irregular particles with a minimum radius less than 75% of the original microsphere radius, but excluding concave particles. For details, see Figure 2 , Figure 2 The actual observation result of the microscope of the example containing non-spherical microspheres is shown in FIG. 1 , wherein the framed microspheres represent non-spherical microspheres.

[0125] (2) Particle size and particle size distribution: The determination method is the same as that of the non-spherical ratio. Use a disposable counting plate and a trinocular microscope to observe and photograph, calculate the particle size, and based on the results, count the number of particles in the range of 20 μm to 60 μm and the total number of particles in the four selected areas.

[0126] Calculation method: Percentage of particles in the range of 20 μm to 60 μm = Number of particles in the range of 20 μm to 60 μm / Total number of particles * 100% (the final result is the average of the four regions).

[0127] Judgment criteria: Both non-spherical microspheres and spherical particles are included in the statistics. The particle size of non-spherical microspheres is calculated based on the straight-line distance between the two farthest endpoints on the microsphere.

[0128] (3) Average particle size: The average particle size of the radioactive microspheres was measured using a Malvern laser particle size analyzer (Mastersizer 3000).

[0129] The above tests were all carried out after the radioactive microspheres were completely decayed.

[0130] The final measured results are shown in Table 1. The average particle size of the radioactive polystyrene microspheres and carbon microspheres provided in each embodiment and comparative example is in the range of 25 to 40 μm, and the number of radioactive microspheres in the range of 20 μm to 60 μm accounts for more than 85%. 90 The activities of Y] were all in the range of 500-700 MBq with no significant difference.

[0131] Table 1

[0132] serial number Microsphere Type Asphericity ratio Example 1 Polystyrene 1.4％ Example 2 Polystyrene 5.0％ Example 3 Polystyrene 7.2％ Example 4 Polystyrene 4.6％ Example 5 Polystyrene 2.2％ Example 6 Carbon Microspheres 1.5％ Example 7 Carbon Microspheres 4.8％ Example 8 Carbon Microspheres 9.4％ Example 9 Carbon Microspheres 4.5％ Example 10 Carbon Microspheres 3.4％ Comparative Example 1 Polystyrene 15.2％ Comparative Example 2 Polystyrene 8.0％ Comparative Example 3 Carbon Microspheres 15.1％

[0133] It can be seen from Table 1 that, using the method provided by the present application, the non-sphericity ratio of the radioactive polystyrene microspheres and radioactive carbon microspheres of Examples 1 to 10 can be controlled within 10%. Among them, the non-sphericity ratios of Examples 1 to 2, 4 to 7, and 9 to 10 can be controlled within 5%.

[0134] Test Example 2

[0135] Determine and evaluate whether and to what extent radioactive microspheres retained in tumor microcirculation have irritating effects on mammals.

[0136] Test samples: the radioactive microspheres provided in Examples 1 to 3, Examples 6 to 8, and Comparative Examples 1 and 3.

[0137] Reference material: high density polyethylene film (HDPE) (Hatano Research Institute, FDSC, batch number C-212).

[0138] Experimental animals: New Zealand white rabbits, normal grade, male; body weight: 2.5-3.5 kg.

[0139] Experimental methods:

[0140] (1) The rabbits were divided into 8 groups, each with 3 rabbits, and the 8 groups corresponded to Examples 1 to 3, Examples 6 to 8, and Comparative Examples 1 and 3. Within 24 hours before the test, the hair on both sides of the back of the animals was removed. The anesthetized animals were placed prone on the operating table, and isoflurane was used for anesthesia and maintenance during the operation to prevent the animal's muscle tremors.

[0141] (2) After the sample is left to decay, centrifuge to remove the liquid in the suspension.

[0142] (3) Make a longitudinal incision along the midline of the animal's back skin, separate the fascia and expose the paraspinal muscles. Use a scalpel to make a small incision on the muscle. Use hemostatic forceps to place a certain amount of the treated test sample or control sample (about 0.5 g of resin microspheres and about 0.3 g of carbon microspheres) into the press Figure 3 Four test articles (T1, T2, T3, T4) were implanted into the left paraspinal muscle of each animal, and four control articles (C1, C2, C3, C4) were implanted into the same muscle on the contralateral side.

[0143] (4) The day of implantation is defined as Day 1. All implants are about 25 mm to 50 mm away from the midline and parallel to the midline. The interval between each implant is about 2.5 cm. After implantation, the muscle and skin are sutured with medical sutures. The implantation process ensures aseptic operation, and the implantation period is 13 weeks.

[0144] (5) After the implantation period expires, the animals will be euthanized, and a longitudinal incision will be made down the center of the rabbit's back to expose the paraspinal muscles. The paraspinal muscles that are large enough to wrap the implant and are not affected by the surgery will be cut off. All implantation sites will be collected and fixed, and subjected to macroscopic observation and histopathological evaluation.

[0145] Evaluation criteria:

[0146] The experimental results are mainly evaluated based on the results of histopathological examination. The specific rating process is as follows:

[0147] (1) Evaluate and record the cellular and tissue responses of the local surrounding tissues of each implant.

[0148] (2) Calculate the cellular response (scores in Table 2) and tissue response scores (scores in Table 3) at each implantation site.

[0149] (3) Calculate the total score of each site = total score of cell response × 2 + total score of tissue response.

[0150] (4) Average score of each animal's test article = total score of the animal's test article / number of effective implanted test articles. Add the average scores of each animal's test article and divide by the number of animals to get the total average score of the test article. Calculate the total average score of the control article in the same way.

[0151] (5) Final reaction score = total average score of test sample - total average score of control sample (negative number is recorded as 0).

[0152] Based on the final reaction score, grade the degree of test article implantation reaction according to Table 4.

[0153] Table 2 Histological evaluation system - cell type / response

[0154]

[0155] phf-high power microscope (400×) field of view

[0156] Table 3 Histological evaluation system - tissue response

[0157]

[0158]

[0159] Table 4 Grading table of local reaction after implantation

[0160] Final reaction score Grading 0～2.9 No irritation or very slight irritation 3.0～8.9 Mild irritation 9.0～15.0 Moderate stimulation ＞15.0 Severe stimulation

[0161] The experimental results are as follows:

[0162] No animals were found to be dying or dead during the test. No macroscopic changes related to the test article were found in the planned autopsy.

[0163] The final reaction scores of the test products compared with the control products are shown in Table 5 below.

[0164] Table 5. Implantation experiment results

[0165]

[0166] As can be seen from Table 5, at 13 weeks of implantation, the scores of Examples 1, 2, 6, and 7 were relatively low, all within 2.9, while the scores of Examples 3 and 8 were relatively high, and the scores of Comparative Examples 1 and 3 were even higher, close to 9.0. It can be seen that the score of non-spherical microspheres within 5% was non-irritating, while microspheres beyond 5% would produce irritation or even moderate irritation. It indicates that controlling the non-spherical ratio within 5% can significantly reduce local inflammatory reactions and improve safety.

[0167] Test Example 3

[0168] Determine and evaluate the distribution of microspheres in rabbit liver tumors.

[0169] Test samples: the radioactive microspheres provided in Examples 1 to 3, Examples 6 to 8, and Comparative Examples 1 and 3.

[0170] Experimental animals: New Zealand white rabbits, normal grade, male; body weight: 2.5-3.5 kg.

[0171] Experimental methods:

[0172] (1) Establishing tumor model

[0173] A VX2 rabbit liver transplant cancer model was established using New Zealand white rabbits. A 2mm diameter VX2 tumor mass was implanted at the lower edge of the rabbit liver. A CT scan was performed 7 days later to record the location and size of the tumor mass. The model was successfully established when the maximum diameter of the tumor reached 1-2cm.

[0174] (2) Grouped medication

[0175] Animals were anesthetized before surgery (2.5% sodium pentobarbital, 30 mg / kg). The animal's groin was shaved, the groin skin was cut open, and the femoral artery was bluntly separated; the femoral artery was punctured under direct vision, and a 5F arterial sheath was inserted, and the femoral artery and arterial sheath were fixed with medical absorbable sutures. Under the guidance of a digital subtraction angiography (DSA), a 2.7F microcatheter was inserted into the common hepatic artery, and radioactive microspheres were injected through the microcatheter to avoid microsphere reflux as much as possible. After the embolization was completed, the catheter and arterial sheath were pulled out, the femoral artery puncture site was ligated, and the muscles and skin were sutured layer by layer.

[0176] The rabbits were randomly divided into 8 groups, 3 in each group, and the 8 groups corresponded to Examples 1 to 3, Examples 6 to 8, and Comparative Examples 1 and 3. After 1 GBq of the test sample was left to decay, it was perfused into the liver. After 24 hours, the animals were killed and dissected, and the liver was fixed with formalin, embedded in paraffin, sliced, stained with hematoxylin and eosin, and pathologically examined. The distribution and density of the microspheres were calculated using the following method.

[0177] The observed area is divided into 4 parts:

[0178] 0-1mm outside the tumor boundary, 0-1mm inside the tumor boundary, non-tumor tissue, and deep in the tumor (greater than 1mm inside the tumor boundary).

[0179] In the field of view of the microscope (3 mm × 3 mm), the distribution density of radioactive microspheres in each area was calculated (unit: particles / mm 2 ). The average distribution density of the corresponding area of ​​each test product is calculated as follows:

[0180] Average distribution density = total distribution density in the corresponding area / number of animals.

[0181] The experimental results are shown in Table 6 below.

[0182] Table 6

[0183]

[0184] As can be seen from Table 6, compared with Examples 3 and 8 and Comparative Examples 1 and 3, Examples 1, 2, 6, and 7 have a higher average distribution density in the tumor as a whole. The density of the non-tumor tissue outside the tumor has decreased. For example, the distribution density of the non-tumor tissue of Example 1 is 0.1, while that of Comparative Example 1 is 1.4. The distribution density of the deep part of the tumor of Example 1 is 1.8, while that of Comparative Example 1 is 0.5. This shows that controlling the non-spherical ratio within 5% can increase the distribution density in the tumor while reducing the distribution density outside the tumor boundary.

[0185] Test Example 4

[0186] To determine and evaluate the therapeutic effect of radioactive microspheres on rabbit liver tumors.

[0187] Test substances: the radioactive microspheres provided in Examples 2 and 7, and Comparative Examples 1 and 3.

[0188] Experimental animals: New Zealand white rabbits, normal grade, male; body weight: 2.5-3.5 kg.

[0189] Experimental methods:

[0190] (1) Establishing tumor model

[0191] A VX2 rabbit liver transplant cancer model was established using New Zealand white rabbits. A 2mm diameter VX2 tumor mass was inoculated to the lower edge of the rabbit liver. A CT scan was performed seven days later to record the location and size of the tumor mass. The model was successfully established when the maximum diameter of the tumor reached 1-2cm.

[0192] (2) Grouped medication

[0193] The rabbits were randomly divided into 5 groups, 3 in each group, and the 5 groups corresponded to Examples 2, 7, Comparative Examples 1, 3 and the model group, respectively, among which Examples 2, 7 and Comparative Examples 1, 3 were classified as the treatment group.

[0194] Model group: The animals were anesthetized before surgery (2.5% sodium pentobarbital, 30 mg / kg). The animal's groin was shaved, the groin skin was cut open, and the femoral artery was bluntly separated; the femoral artery was punctured under direct vision, and a 5F arterial sheath was inserted, and the femoral artery and arterial sheath were fixed with medical absorbable sutures. Under the guidance of a digital subtraction angiography (DSA), a 2.7F microcatheter was inserted into the common hepatic artery, and normal saline was injected through the microcatheter to avoid microsphere reflux as much as possible. After the embolization was completed, the catheter and arterial sheath were pulled out, the femoral artery puncture site was ligated, and the muscles and skin were sutured layer by layer.

[0195] A catheter was inserted into the rabbit common hepatic artery, and normal saline was slowly injected through the catheter.

[0196] Treatment group: Each rat was given radioembolic microspheres by surgical intervention, with a dose of 1 GBq, and the intervention method was the same as that of the model group.

[0197] Two weeks after administration, CT scans were performed to record the location and size of the tumor, and the animals were killed, the tumors were removed and weighed, and the tumor growth inhibition rate was calculated. The results are shown in Table 7.

[0198] The tumor growth inhibition rate was calculated according to the following formula:

[0199] Tumor growth inhibition rate = (average tumor weight of animals in the model group - average tumor weight of animals in the treatment group) / average tumor weight of animals in the model group * 100%.

[0200] Table 7

[0201] Group Example 2 Example 7 Comparative Example 1 Comparative Example 3 Tumor growth inhibition rate 85.0％ 81.0％ 61.6％ 58.0％

[0202] As can be seen from Table 7, compared with Comparative Examples 1 and 3, Examples 2 and 7 have a higher tumor growth inhibition rate for liver tumors as a whole. For example, the tumor growth inhibition rate of Example 2 is 85.0%, while the tumor growth inhibition rate of Comparative Example 1 is only 61.6%. This shows that controlling the non-spherical ratio within 5% has a better tumor inhibition effect. This is because the non-spherical ratio is controlled within 5%, which increases the distribution density of microspheres in the tumor, thereby increasing the tumor killing ability.

[0203] The above is a detailed introduction to a suspension containing radioactive microspheres and its preparation method and application provided by the present application. Specific examples are used herein to illustrate the principles and implementation methods of the present application. The description of the above embodiments is only used to help understand the technical solutions and core ideas of the present application; ordinary technicians in this field should understand that they can still modify the technical solutions recorded in the aforementioned embodiments, or replace some of the technical features therein by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A suspension containing radioactive microspheres, characterized in that: The radioactive microspheres include carbon microspheres and radioactive nuclides loaded on the carbon microspheres. The average particle size of the radioactive microspheres is 25 μm to 40 μm, and the non-spherical ratio is within 5%.

2. The suspension according to claim 1, characterized in that The non-spherical ratio refers to the ratio of the number of non-spherical radioactive microspheres to the total radioactive microspheres in the suspension, and the non-spherical radioactive microspheres refer to radioactive microspheres whose minimum radius is less than 75% of the radius of the original microspheres.

3. The suspension according to claim 1, characterized in that The carbon microspheres are carbonized resin microspheres.

4. The suspension according to claim 3, characterized in that The material of the resin microspheres is selected from at least one of polystyrene, polyethylene or polydivinylbenzene, or a cross-linked polymer thereof; and / or the material of the resin microspheres is selected from phenolic resin.

5. The suspension according to claim 1, characterized in that Calculated by the number of the radioactive microspheres, in the suspension, the number of radioactive microspheres with a size of 20 μm to 60 μm accounts for more than 85%; and / or the non-spherical ratio of the radioactive microspheres is within 2%.

6. The suspension according to claim 1, characterized in that The radioactive nuclide is selected from at least one isotope of yttrium, lutetium, indium, holmium, samarium, iodine, phosphorus, iridium or rhenium.

7. The suspension according to claim 1, characterized in that The radionuclide is selected from yttrium [ 90 Y], the carbon microspheres are carbonized resin microspheres, the material of the resin microspheres is selected from polystyrene partially cross-linked with divinylbenzene, and the suspension also contains water for injection, each 1 mL of yttrium [ 90 Y] activity is 300~700MBq.

8. A method for preparing a suspension containing radioactive microspheres, characterized in that: The method comprises: mixing carbon microspheres and radioactive nuclide compounds in a solution, and reacting to obtain the suspension containing the radioactive carbon microspheres; the average particle size of the radioactive carbon microspheres is 25 to 40 μm, and the non-spherical ratio is within 5%.

9. Use of the suspension according to any one of claims 1 to 7 or the suspension prepared by the method according to claim 8 in preparing a drug for treating tumors.

10. The use according to claim 9, characterized in that: The tumor is primary or secondary liver cancer.

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