A medical microsphere, its preparation method and application

Abstract

The present invention discloses a medical microsphere and its preparation method and application. The medical microsphere includes phenolic resin microspheres and radioactive metal elements loaded on the phenolic resin microspheres; the average particle size of the phenolic resin microspheres is 1 to 150 μm. The medical microsphere in the present invention can not only achieve local cell killing in the blood vessels of a specific part, but also effectively avoid the occurrence of fragmentation; further, the medical microsphere has a good loading rate and an extremely low exudation loss rate, which can meet the loading and safety requirements of radioactive elements; in addition, the preparation method of the medical microsphere is simple.

Description

Technical Field

[0001] The present invention relates to the medical field, and particularly to a medical microsphere, a preparation method thereof, and an application thereof. Background Art

[0002] Malignant tumors are a type of disease that seriously threatens human health. Currently, there are various treatment methods, including chemotherapy, radiotherapy, interventional therapy, biological immunotherapy, etc. As one of the therapies, great progress has been made in providing radioactive materials for cancer patients for localization. The radioactive materials are incorporated into small particles that can be directly implanted into cancer solid tumors, and the α or β rays released by the radioactive elements are used to achieve local cell killing, reducing the impact on normal cells around the tumor cells, and improving safety as much as possible while ensuring the treatment effect.

[0003] In recent years, the developed selective internal radiation therapy (SIRT) technology is to prepare radioactive materials into microspheres with regular sizes and inject them into the arterial blood supply of the target organ. By using the embolism formed by the capillaries and microsphere sizes at specific sites, the radioactive microspheres are fixed to the lesion site, and the rays with extremely short ranges emitted by the radioactive elements are used to kill the surrounding tumor cells, avoiding the side effects caused by the microspheres flowing to unwanted places in the blood.

[0004] Currently, there are various specific applications of the SIRT technology. One of them is glass microspheres, which are prepared by using 89 Y2O3 as a component to prepare glass microspheres, and they need to be bombarded with neutrons in a nuclear reactor to be converted into radioactive 90 Y. There are many problems with this type of microspheres. The density of the glass microspheres is relatively large (3.6 g / ml), significantly higher than the average density of blood (about 1.1 g / mL). Therefore, it is relatively easy to sediment in the blood in advance. During injection, it needs to be injected quickly at one time, and the blood turbulence is used to reduce sedimentation, but the effect is not ideal. At the same time, nuclear reactor resources are difficult to obtain, resulting in unstable raw material supply, and isotopes that release γ rays will be generated after irradiation, causing side effects. Another type is 90 Y-loaded resin microspheres, which use polystyrene-divinylbenzene polymer as a carrier. Its density is relatively close to that of blood, and there is no phenomenon of easy sedimentation. However, there are high technical difficulties in the preparation and loading of resin microspheres, and there may be a situation where Y elements fall off and are lost, with a certain possibility of side effects. Recently, other forms of carrier microspheres such as carbon microspheres and silicon microspheres have also emerged one after another, but they are all in the early development and verification stage, and the technology maturity is unknown.

[0005] Therefore, there is still a need in the art for other forms of microspheres loaded with radioactive elements. Summary of the Invention

[0006] The problem to be solved by the present invention is to overcome the defects of low loading rate of medical microspheres and easy penetration and loss of radioactive elements in the prior art, and to provide a medical microsphere, a preparation method and an application thereof. The medical microsphere in the present invention can not only achieve local cell killing in blood vessels at a specific site, but also effectively avoid fragmentation; further, the medical microsphere has a good loading rate and an extremely low exudation and loss rate, and can meet the loading and safety requirements of radioactive elements; in addition, the preparation method of the medical microsphere is simple.

[0007] In order to achieve the above object, the present invention provides the following technical solutions:

[0008] One of the technical solutions provided by the present invention is: a medical microsphere. The medical microsphere includes a phenolic resin microsphere and a radioactive metal element loaded on the phenolic resin microsphere;

[0009] Wherein, the average particle size of the phenolic resin microsphere is 1-150 μm.

[0010] In the present invention, the average particle size of the phenolic resin microsphere can be 10-100 μm, preferably 15-80 μm, more preferably 20-75 μm, and further preferably 30-50 μm.

[0011] In the present invention, the phenolic resin microsphere is preferably a cation-exchange type phenolic resin microsphere.

[0012] Preferably, the cation-exchange type phenolic resin microsphere is a sulfonated phenolic resin microsphere or a nitrated phenolic resin microsphere.

[0013] Wherein, when the cation-exchange type phenolic resin microsphere is a sulfonated phenolic resin microsphere, the sulfonation degree of the sulfonated phenolic resin microsphere can be 1×10 -3 mmol / mg - 5×10 -1 mmol / mg; preferably 1.5×10 -1 mmol / mg - 5×10 -1 mmol / mg; more preferably 3×10 -1 mmol / mg - 4.8×10 -1 mmol / mg; further preferably 4.2×10 - 1 mmol / mg - 4.8×10 -1 mmol / mg; such as 4.3 mmol / mg, 4.4 mmol / mg, 4.5 mmol / mg, 4.6 mmol / mg or 4.7 mmol / mg.

[0014] Among them, when the cation exchange type phenolic resin microspheres are nitrified phenolic resin microspheres, the nitrification degree of the nitrified phenolic resin microspheres can be 1×10 -3 mmol / mg to 5×10 -1 mmol / mg; preferably 2×10 -1 mmol / mg to 4.8×10 -1 mmol / mg; more preferably 3.5×10 -1 mmol / mg to 4.8×10 -1 mmol / mg; for example, 3.6 mmol / mg, 3.7 mmol / mg, 3.8 mmol / mg, 3.9 mmol / mg, 4.0 mmol / mg, 4.1 mmol / mg, 4.2 mmol / mg, 4.3 mmol / mg, 4.4 mmol / mg, 4.5 mmol / mg, 4.6 mmol / mg or 4.7 mmol / mg.

[0015] In the present invention, the radioactive metal element can be a radioactive metal element capable of releasing α-rays or β-rays that is conventional in the art, preferably a radioactive cationic metal element, and more preferably 67 Cu, 90 Y, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 211 At, 212 Bi, 213 Bi, 223 Ra or 225 Ac.

[0016] In the present invention, preferably, the radioactive metal element is connected to the functional group on the phenolic resin microspheres.

[0017] Among them, the functional group on the phenolic resin microspheres is preferably a sulfonic acid group or a nitrate group.

[0018] When the cation exchange type phenolic resin microspheres are sulfonated phenolic resin microspheres, the radioactive metal element is connected to the sulfonic acid group on the phenolic resin microspheres.

[0019] When the cation exchange type phenolic resin microspheres are nitrified phenolic resin microspheres, the radioactive metal element is connected to the nitrate group on the phenolic resin microspheres.

[0020] In the present invention, according to the convention in the art, the average particle size of the medical microspheres can be equivalent to the average particle size of the phenolic resin microspheres.

[0021] The second technical solution provided by the present invention is: a preparation method of medical microspheres. The preparation method includes the following steps: mixing phenolic resin microspheres with a solution containing a radioactive metal element to load the radioactive metal element on the phenolic resin microspheres;

[0022] Among them, the average particle size of the phenolic resin microspheres is 1-150 μm. In the present invention, the average particle size of the phenolic resin microspheres is preferably 10-100 μm, more preferably 15-80 μm, further preferably 20-75 μm, and still more preferably 30-50 μm.

[0023] In the present invention, the preparation method preferably further includes subjecting the phenolic resin microspheres to a functionalization reaction to prepare cation-exchange phenolic resin microspheres.

[0024] In the present invention, the phenolic resin microspheres are preferably prepared by the following method: reacting a mixed solution of resorcinol, water, an alkaline catalyst, formaldehyde and a dispersant at 60-85 °C for 40-60 h. More preferably, the mixed solution reacts at 85 °C for 48 h.

[0025] Among them, the dosage ratio of resorcinol to water can be conventional in the art, for example, (5-8) g:(20-40) mL, preferably 6.4 g:25 mL.

[0026] Among them, the molar ratio of resorcinol to the alkaline catalyst is preferably 100:(0.001-0.01), more preferably 100:0.005.

[0027] Among them, the alkaline catalyst is preferably selected from one or more of NaOH, KOH, Ca(OH)2, Na2CO3 and K2CO3; more preferably Na2CO3.

[0028] Among them, the molar ratio of resorcinol to formaldehyde is preferably 1:(1.5-5), more preferably 1:(2-4.5), for example 1:3.5 or 1:4.16.

[0029] Among them, the dispersant is preferably selected from one or more of n-heptane, silicone oil, corn oil and olive oil; more preferably silicone oil.

[0030] Among them, after the reaction of the mixed solution is completed, it preferably further includes solid-liquid separation, washing and drying steps. The operations and process conditions of the solid-liquid separation, washing and drying can be conventional in the art.

[0031] In the present invention, the functionalization reaction preferably includes the following steps: reacting the phenolic resin microspheres with a sulfonation reagent to obtain sulfonated phenolic resin microspheres.

[0032] Among them, the sulfonation reagent may be selected from concentrated sulfuric acid, chlorosulfonic acid, sulfur trioxide, sulfamic acid or sulfite, preferably concentrated sulfuric acid.

[0033] Preferably, when the sulfonation reagent is concentrated sulfuric acid, the dosage ratio of the phenolic resin microspheres to the concentrated sulfuric acid may be 1 g:(2 - 15) mL, preferably 1 g:(3 - 12) mL, more preferably 1 g:(4 - 10) mL.

[0034] Among them, the temperature of the reaction may be 30 - 100 °C; preferably 40 - 90 °C, more preferably 50 - 85 °C.

[0035] Among them, the reaction time may be 2 - 9 hours; preferably 4 - 9 hours, more preferably 4 - 8 hours.

[0036] Among them, preferably, the reaction temperature of the phenolic resin microspheres and the sulfonation reagent is 30 - 100 °C, and the reaction time is 2 - 9 hours. More preferably, the reaction temperature of the phenolic resin microspheres and the sulfonation reagent is 40 - 90 °C, and the reaction time is 4 - 9 hours. Further preferably, the reaction temperature of the phenolic resin microspheres and the sulfonation reagent is 50 - 85 °C, and the reaction time is 4 - 8 hours.

[0037] Among them, after the reaction, according to the routine in the art, generally, it also includes the steps of washing and drying. The operations and process conditions of the washing and the drying can be conventional in the art.

[0038] Alternatively, the functionalization reaction preferably includes the following steps: reacting the phenolic resin microspheres with a nitrating reagent to obtain nitrated phenolic resin microspheres.

[0039] Among them, the nitrating reagent may be selected from concentrated nitric acid, fuming nitric acid - acetic acid, fuming nitric acid, concentrated sulfuric acid - potassium nitrate, or concentrated sulfuric acid - concentrated nitric acid, preferably concentrated sulfuric acid - concentrated nitric acid.

[0040] Generally, those skilled in the art can understand that the "fuming nitric acid - acetic acid" is a mixed acid of fuming nitric acid and acetic acid. The "concentrated sulfuric acid - potassium nitrate" is a mixed acid of concentrated sulfuric acid and potassium nitrate. The "concentrated sulfuric acid - concentrated nitric acid" is a mixed acid of concentrated sulfuric acid and concentrated nitric acid.

[0041] Preferably, in the concentrated sulfuric acid - concentrated nitric acid, the molar ratio of concentrated sulfuric acid to concentrated nitric acid can be conventional in the art, such as 1:2.

[0042] When the nitrating reagent is concentrated sulfuric acid - concentrated nitric acid, the dosage ratio of the phenolic resin microspheres to the concentrated sulfuric acid - concentrated nitric acid may be 1 g:(2 - 15) mL, preferably 1 g:(3 - 12) mL, more preferably 1 g:(3 - 10) mL.

[0043] Among them, the temperature of the reaction can be 30 to 100 °C; preferably 40 to 90 °C, more preferably 50 to 85 °C.

[0044] Among them, the time of the reaction can be 2 to 9 hours; preferably 3 to 9 hours, more preferably 4 to 8 hours.

[0045] Among them, preferably, the reaction temperature of the phenolic resin microspheres and the nitrating reagent is 30 to 100 °C, and the reaction time is 2 to 9 hours. More preferably, the reaction temperature of the phenolic resin microspheres and the nitrating reagent is 40 to 90 °C, and the reaction time is 3 to 9 hours. Further preferably, the reaction temperature of the phenolic resin microspheres and the nitrating reagent is 50 to 85 °C, and the reaction time is 4 to 8 hours.

[0046] Among them, after the reaction, according to the routine in the art, generally, it further includes the steps of washing and drying. The operations and process conditions of the washing and the drying can be conventional in the art.

[0047] In the present invention, according to the routine in the art, when the preparation method of the phenolic resin microspheres further includes the step of "reacting the phenolic resin microspheres with a sulfonating reagent" or "reacting the phenolic resin microspheres with a nitrating reagent", the average particle size of the obtained cation exchange type phenolic resin microspheres (sulfonated phenolic resin microspheres, or nitrated phenolic resin microspheres) has no obvious change compared with the average particle size of the aforementioned phenolic resin microspheres, and is all in the range of 1 to 150 μm, preferably 10 to 100 μm, more preferably 15 to 80 μm, further preferably 20 to 75 μm, and still further preferably 30 to 50 μm.

[0048] In the present invention, the solution containing a radioactive metal element can generally be understood as an aqueous solution of a radioactive metal element. Among them, the radioactive metal element is as described above, and preferably 67 Cu, 90 Y, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 211 At, 212 Bi, 213 Bi, 223 Ra or 225 Ac.

[0049] In the present invention, when the radioactive metal element is 90 Y, the concentration of the solution containing the radioactive metal element is preferably 0.002 to 2.5 mg / mL, such as 0.0025 to 2.25 mg / mL, and further such as 0.75 mg / mL.

[0050] In the present invention, when the phenolic resin microspheres are mixed with the solution containing radioactive metal elements, the mixing operation and process conditions can be conventional in the art for ion exchange, and the metal elements are loaded onto the sulfonated phenolic resin microspheres or nitrated phenolic resin microspheres.

[0051] In the present invention, the temperature of the mixing is preferably 25 - 40 °C.

[0052] In the present invention, the mixing time is preferably 2 - 4 h.

[0053] The third technical solution provided by the present invention is: a medical microsphere. The medical microsphere is prepared by the preparation method of the medical microsphere as described above.

[0054] The fourth technical solution provided by the present invention is: an application of the medical microsphere as described above in the preparation of a drug for treating tumors.

[0055] On the basis of conforming to the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0056] The reagents and raw materials used in the present invention are all commercially available.

[0057] The positive and progressive effects of the present invention are as follows:

[0058] (1) The present invention provides a medical microsphere with good performance, whose size conforms to medical uses, can be fixed in the blood vessels at a specific site through embolization, kill surrounding cells by the α or β rays released by the radioactive metal elements loaded thereon, and the intensity meets the requirements, effectively avoiding the occurrence of fragmentation.

[0059] (2) Further, the medical microsphere provided by the present invention can meet the loading and safety requirements of radioactive elements with a good loading rate and an extremely low exudation and loss rate, providing a new technical solution for meeting clinical use; after being soaked in physiological saline for two days, the exudation and loss rate of the metal elements of the medical microsphere in the present invention is lower than 0.05%, and can even be lower than 0.01%.

[0060] (3) The preparation method of the medical microsphere provided by the present invention is simple. Description of the Drawings

[0061] Figure 1 It is the scanning electron microscope (SEM) image of the phenolic resin microspheres in Example 1.

[0062] Figure 2 It is the particle size distribution diagram of the phenolic resin microspheres in Example 1.

[0063] Figure 3It is the infrared spectrum of the sulfonated phenolic resin microspheres in Example 2-01.

[0064] Figure 4 It is the infrared spectrum of the nitrated phenolic resin microspheres in Example 3-01.

[0065] Figure 5 It is the scanning electron microscope (SEM) image of the polystyrene microspheres before sulfonation in Comparative Example 1.

[0066] Figure 6 It is the scanning electron microscope (SEM) image of the polystyrene microspheres after sulfonation in Comparative Example 1.

[0067] Figure 7 It is the optical micrograph of the polystyrene microspheres after sulfonation in Comparative Example 3.

[0068] Figure 8 It is the optical micrograph of the polystyrene microspheres after sulfonation in Comparative Example 5.

[0069] Figure 9 It is the optical micrograph of the sulfonated phenolic resin microspheres in Example 2-01 after stirring at a speed of 2400 r / min for 30 min.

[0070] Figure 10 It is the optical micrograph of the nitrated phenolic resin microspheres in Example 3-01 after stirring at a speed of 2400 r / min for 30 min.

[0071] Figure 11 It is the optical micrograph of the sulfonated polystyrene microspheres in Comparative Example 5 after stirring at a speed of 2400 r / min for 30 min.

[0072] Figure 12 It is the optical micrograph of the nitrated polystyrene microspheres in Comparative Example 7 after stirring at a speed of 2400 r / min for 30 min. Detailed implementation manners

[0073] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0074] Example 1 Preparation of phenolic resin microspheres

[0075] After magnetically stirring 6.4 g of resorcinol, 25 mL of water and 40 mL of silicone oil for 5 min, 5 mL of sodium carbonate aqueous solution (0.0616 g / 1000 mL, the molar ratio of resorcinol to sodium carbonate is 100:0.005) and 9 mL of formaldehyde were added, and then the reaction was carried out for 30 min under the condition of magnetic stirring at 200 rpm / min, and then placed in a reaction kettle and reacted at 85 °C for 48 h. After centrifugally washing with deionized water and absolute ethanol three times each, vacuum drying was carried out at 60 °C for 12 h to obtain phenolic resin microspheres.

[0076] The SEM image of the phenolic resin microspheres is as shown in Figure 1 ; the particle size distribution diagram is as shown in Figure 2 . It can be seen from Figure 2 that the particle size of the phenolic resin microspheres is concentrated in the range of 30 - 50 μm.

[0077] Preparation of sulfonated phenolic resin microspheres in Examples 2 - 01 to 2 - 12

[0078] The phenolic resin microspheres prepared in Example 1 were washed 3 times with absolute ethanol in a centrifuge (4400 r / min, 30 min), dried in an oven at 50 °C for 12 h, and then ultrasonically dispersed in an appropriate amount of concentrated sulfuric acid. After reacting at a certain temperature for a certain time, they were washed and dried. Among them, the reaction temperature and reaction time are shown in Table 1.

[0079] The infrared spectrum of the sulfonated phenolic resin microspheres in Example 2 - 01 is as shown in Figure 3 . It can be seen from Figure 3 that it has a characteristic absorption peak of -SO3H, indicating that after the sulfonation reaction of the phenolic resin microspheres, sulfonic acid groups are introduced on the surface, and it becomes sulfonated phenolic resin microspheres.

[0080] 0.001 g of sulfonated phenolic resin microspheres was ultrasonically dispersed in 50 mL of NaOH solution (0.01 mol / L), 2 drops of phenolphthalein were added as an indicator, and titration was carried out with 0.01 mol / L HCl standard solution to measure the sulfonation degree (the test results are shown in Table 1).

[0081] Table 1

[0082]

[0083] It can be seen from Table 1 that:

[0084] 1. Influence of the amount of concentrated sulfuric acid on the morphology and sulfonation degree of sulfonated phenolic resin microspheres;

[0085] The results show that when using 2 mL of concentrated sulfuric acid for 1 g of microspheres, the amount of concentrated sulfuric acid is so small that it can hardly submerge the microsphere product. After the amount of concentrated sulfuric acid exceeds 10 mL, the sulfonation degree of the microspheres does not increase significantly, but instead increases the cost and may even have an adverse effect on the morphology of the microspheres.

[0086] 2. Influence of Sulfonation Time and Temperature on the Morphology and Sulfonation Degree of Sulfonated Phenolic Resin Microspheres;

[0087] The results show that during the sulfonation process of phenolic resin microspheres, the sulfonation degree of the microspheres increases with the increase of reaction time and temperature. However, after the reaction time exceeds 6 hours and the reaction temperature exceeds 85 °C, continuing to increase the reaction time or reaction temperature does not significantly improve the sulfonation degree, but increases the cost. And after reducing the reaction time or reaction temperature, the sulfonation degree decreases significantly.

[0088] Preparation of Nitrated Phenolic Resin Microspheres in Examples 3-01 to 3-12

[0089] In an ice-water bath, concentrated sulfuric acid was added dropwise to concentrated nitric acid to prepare a mixed acid (the molar ratio of concentrated sulfuric acid to concentrated nitric acid was 1:2). The phenolic resin microspheres were washed 3 times with absolute ethanol in a centrifuge (4400 r / min, 30 min), dried in an oven at 50 °C for 12 h, and then dispersed in an appropriate amount of the mixed acid. After reacting at a certain temperature for a certain time, they were washed and dried. Among them, the reaction temperature and reaction time are shown in Table 2.

[0090] The infrared spectrum of the nitrated phenolic resin microspheres in Example 3-01 is as Figure 4 shown. It can be seen from Figure 4 that it has the characteristic absorption peak of -NO3, indicating that after the phenolic resin microspheres undergo a nitration reaction, nitrate groups are introduced on the surface, becoming nitrated phenolic resin microspheres.

[0091] 0.001 g of nitrated phenolic resin microspheres were ultrasonically dispersed in 50 mL of NaOH solution (0.01 mol / L), 2 drops of phenolphthalein were added as an indicator, and titrated with 0.01 mol / L HCl standard solution to measure the nitration degree (the test results are shown in Table 2).

[0092] Table 2

[0093]

[0094]

[0095] As can be seen from Table 2:

[0096] 1. Influence of the Dosage of Mixed Acid on the Morphology and Nitration Degree of Nitrated Phenolic Resin Microspheres;

[0097] The results show that it is more appropriate to use 3 mL of mixed acid for 1 g of microspheres. Continuing to increase the dosage of the mixed acid does not significantly improve the nitration degree of the microspheres, but instead increases the cost and may even have an adverse effect on the morphology of the microspheres.

[0098] 2. Effects of nitration time and temperature on the morphology and nitration degree of nitrophenolic resin microspheres;

[0099] The results show that during the nitration of phenolic resin microspheres, the nitration degree of the microspheres increases with the increase of reaction time and temperature. However, when the reaction time exceeds 6 hours, further increasing the reaction time does not significantly improve the nitration degree, but increases the cost. After continuously reducing the reaction time, the nitration degree of the microspheres shows a large decrease.

[0100] Preparation of sulfonated polystyrene microspheres in Comparative Examples 1 - 6

[0101] Purchase commercially available crosslinked polystyrene - divinylbenzene polymer microspheres AmberChromTM XT30 with an average particle size of 30 μm from Dupont (hereinafter referred to as "polystyrene microspheres").

[0102] Wash the purchased polystyrene microspheres 3 times with absolute ethanol in a centrifuge (4400 r / min, 30 min), dry them in an oven at 50 °C for 12 h, then ultrasonically disperse them in an appropriate amount of concentrated sulfuric acid, react for 6 hours at a certain temperature, and then wash and dry. Among them, the reaction temperature and reaction time are shown in Table 3.

[0103] Table 3

[0104]

[0105] As can be seen from Table 3, when the ratio of polystyrene microspheres to concentrated sulfuric acid is 1 g:6 mL, even if different reaction temperatures (35 °C, 45 °C, 75 °C) are adjusted, the generated sulfonated polystyrene microspheres are more likely to break. It is necessary to reduce or even cancel stirring to obtain non - broken microspheres, but sulfonation may be uneven, showing the vulnerability of polystyrene microspheres in sulfonation preparation.

[0106] The morphologies of polystyrene microspheres before and after sulfonation in Comparative Example 1 are respectively as Figure 5 and Figure 6 shown.

[0107] The SEM image of the sulfonated polystyrene microspheres in Comparative Example 3 is as Figure 7 shown.

[0108] The SEM image of the sulfonated polystyrene microspheres in Comparative Example 5 is as Figure 8 shown.

[0109] Preparation of nitrated polystyrene microspheres in Comparative Example 7

[0110] Purchase commercially available crosslinked polystyrene - divinylbenzene polymer microspheres AmberChromTM XT30 with an average particle size of 30 μm from Dupont (hereinafter referred to as "polystyrene microspheres").

[0111] 1 g of commercially available polystyrene microspheres was ultrasonically dispersed in 6 mL of a mixed acid (the molar ratio of concentrated sulfuric acid to concentrated nitric acid was 1:2, and the mixture was uniformly mixed in an ice-water bath), reacted at 60 °C for 3 h, cooled to room temperature, and then 60 mL of deionized water was added dropwise in an ice-water bath. After centrifuging 3 times and drying, nitrated polystyrene microspheres were obtained.

[0112] Effect Example 1

[0113] To test the strength of various resin microspheres, the functionalized resin microspheres prepared in Examples 2-01 to 2-12, Examples 3-01 to 3-12, and Comparative Examples 1 to 7 were stirred under the conditions of 2400 r / min for 30 min, and the crushing of the microspheres was observed under a microscope.

[0114] The results showed that: under the conditions of 2400 r / min for 30 min, in Comparative Example 5, sulfonated polystyrene microspheres (as shown in Figure 11 ) and in Comparative Example 7, nitrated polystyrene microspheres (as shown in Figure 12 ) showed more crushing, while in Examples 2-01 to 2-12, sulfonated phenolic resin microspheres (where Example 2-01 is as shown in Figure 9 ) and in Examples 3-01 to 3-12, nitrated phenolic resin microspheres (where Example 3-01 is as shown in Figure 10 ) did not show any crushing, proving that phenolic resin microspheres, as medical microspheres, have more excellent strength and can better avoid side effects caused by crushing in the human body.

[0115] Effect Example 2

[0116] A certain amount of YCl3 was dispersed in 20 mL of deionized water to obtain solutions with different concentrations of Y element, which were mixed uniformly with 0.1 g of resin microspheres and subjected to a loading reaction at a certain temperature for a period of time; the reaction conditions are shown in Table 4.

[0117] Centrifuge 3 times in a centrifuge (4400 r / min, 30 min) to separate the resin microspheres loaded with metal elements from the unloaded metal elements; the separated resin microspheres were washed and soaked in physiological saline for 48 h, and then filtered with deionized water, and the loading rate and leakage rate of the resin microspheres were detected. The results are shown in Table 4 in detail.

[0118] Table 4

[0119]

[0120]

[0121] The results show that for phenolic resin microspheres, after sulfonation or nitration treatment, the loading of metal element Y can generally reach more than 90%, and the leaching loss rate can be well controlled below 0.01%, indicating that the washing process used is sufficient to wash away the free Y element that has not been effectively adsorbed. As the addition amount of Y element decreases, its loading rate further increases, and at the case of 0.025 mg / mL (at this time, the radioactivity that these amounts of loaded elements can carry can still meet the requirements of medical use), the loading rate reaches almost 100%, and at the same time the leaching loss rate is also as low as almost 0%. However, phenolic resin microspheres with too low sulfonation degree or nitration degree have a lower loading rate of Y, and the leaching loss rate also increases.

[0122] For the sulfonated and nitrated polystyrene microspheres in the comparative example, their loading rate of Y can also reach more than 92%, but the corresponding leaching loss rate exceeds 0.1%, and the effect is significantly inferior to that of the sulfonated and nitrated polystyrene microspheres in the examples.

[0123] Effect Example 3

[0124] Disperse a certain amount of CuCl2 in 20 mL of deionized water, mix it evenly with 0.1 g of the sulfonated phenolic resin microspheres in Example 2-06, and carry out the loading reaction at 25 °C for 2 hours; centrifuge 3 times in a centrifuge (4400 r / min, 30 min) to separate the resin microspheres loaded with metal elements from the metal elements that have not been loaded; wash and soak the separated resin microspheres in physiological saline for 48 h, and filter by suction with deionized water. It is detected that the loading rate of the resin microspheres is 91.231%, and the leaching loss rate is lower than 0.01%.

Claims

1. A medical microsphere, characterized in that, The medical microspheres include phenolic resin microspheres and radioactive metal elements loaded on the phenolic resin microspheres; Among them, the phenolic resin microspheres are cation-exchange phenolic resin microspheres; the cation-exchange phenolic resin microspheres are sulfonated phenolic resin microspheres or nitrated phenolic resin microspheres; when the cation-exchange phenolic resin microspheres are sulfonated phenolic resin microspheres, the sulfonation degree of the sulfonated phenolic resin microspheres is 1×10 -3 mmol / mg to 5×10 - 1 mmol / mg; when the cation-exchange phenolic resin microspheres are nitrated phenolic resin microspheres, the nitration degree of the nitrated phenolic resin microspheres is 1×10 -3 mmol / mg to 5×10 -1 mmol / mg; The average particle size of the phenolic resin microspheres is 1 to 150 μm; The radioactive metal element is a radioactive cationic metal element.

2. The medical microsphere according to claim 1, wherein The medical microspheres satisfy one or more of the following conditions a to c: a. The average particle size of the phenolic resin microspheres is 10 to 100 μm; b. The radioactive metal element is 67 Cu, 90 Y, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 211 At, 212 Bi, 213 Bi, 223 Ra or 225 Ac; c. In the medical microspheres, the radioactive metal element is connected to the functional groups on the phenolic resin microspheres; When the cation exchange type phenolic resin microspheres are sulfonated phenolic resin microspheres, the radioactive metal element is connected to the sulfonic acid groups on the phenolic resin microspheres; When the cation exchange type phenolic resin microspheres are nitrated phenolic resin microspheres, the radioactive metal element is connected to the nitrate groups on the phenolic resin microspheres.

3. The medical microsphere according to claim 2, wherein The medical microspheres satisfy one or more of the following conditions a to c: a. The average particle size of the phenolic resin microspheres is 15 to 80 μm; b. When the cation-exchangeable phenolic resin microspheres are sulfonated phenolic resin microspheres, the sulfonation degree of the sulfonated phenolic resin microspheres is 1.5×10 -1 mmol / mg to 5×10 -1 mmol / mg; c. When the cation-exchange phenolic resin microspheres are nitrified phenolic resin microspheres, the nitration degree of the nitrified phenolic resin microspheres is 2×10 -1 mmol / mg to 4.8×10 -1 mmol / mg.

4. The medical microsphere according to claim 3, wherein The medical microspheres satisfy one or more of the following conditions a to c: a. The average particle size of the phenolic resin microspheres is 20 to 75 μm; b. When the cation-exchange phenolic resin microspheres are sulfonated phenolic resin microspheres, the sulfonation degree of the sulfonated phenolic resin microspheres is 3×10 -1 mmol / mg to 4.8×10 -1 mmol / mg; c. When the cation-exchange phenolic resin microspheres are nitrified phenolic resin microspheres, the nitrification degree of the nitrified phenolic resin microspheres is 3.5×10 -1 mmol / mg to 4.8×10 -1 mmol / mg.

5. The medical microspheres according to claim 4, characterized in that, The medical microspheres satisfy one or two of the following conditions a to b: a. The average particle size of the phenolic resin microspheres is 30 to 50 μm; b. When the cation-exchange phenolic resin microspheres are sulfonated phenolic resin microspheres, the sulfonation degree of the sulfonated phenolic resin microspheres is 4.2×10 -1 mmol / mg to 4.8×10 -1 mmol / mg.

6. A method for preparing a medical microsphere, characterized in that, The preparation method of the medical microspheres includes the following steps: mixing the phenolic resin microspheres with a solution containing radioactive metal elements to load the radioactive metal elements on the phenolic resin microspheres; Among them, the average particle size of the phenolic resin microspheres is 1 to 150 μm; The preparation method further includes subjecting the phenolic resin microspheres to a functionalization reaction to prepare cation exchange type phenolic resin microspheres; the functionalization reaction includes the following steps: reacting the phenolic resin microspheres with a sulfonating agent to obtain sulfonated phenolic resin microspheres; or reacting the phenolic resin microspheres with a nitrating agent to obtain nitrated phenolic resin microspheres; When the cation exchange type phenolic resin microspheres are sulfonated phenolic resin microspheres, the sulfonation degree of the sulfonated phenolic resin microspheres is 1×10 -3 mmol / mg to 5×10 -1 mmol / mg; when the cation exchange type phenolic resin microspheres are nitrated phenolic resin microspheres, the nitration degree of the nitrated phenolic resin microspheres is 1×10 -3 mmol / mg to 5×10 - 1 mmol / mg; The radioactive metal element is a radioactive cationic metal element.

7. The preparation method of the medical microspheres according to claim 6, wherein, The preparation method of the phenolic resin microspheres includes the following steps: reacting a mixed solution of resorcinol, water, an alkaline catalyst, formaldehyde and a dispersant at 60 to 85 °C for 40 to 60 h; the dispersant is one or more of n-heptane, silicone oil, corn oil and olive oil.

8. The preparation method of the medical microspheres according to claim 7, characterized in that, The preparation method of the medical microspheres satisfies one or more of the following conditions a to c: a. The mixed solution reacts at 85 °C for 48 h; b. The alkaline catalyst is selected from one or more of NaOH, KOH, Ca(OH)2, Na2CO3 and K2CO3; c. After the reaction of the mixed solution is completed, it further includes solid-liquid separation, washing and drying.

9. The preparation method of the medical microspheres according to claim 8, wherein, The preparation method of the medical microspheres satisfies one or two of the following conditions a to b: a. The alkaline catalyst is selected from Na2CO3; b. The dispersant is silicone oil.

10. The preparation method of the medical microspheres according to claim 6, characterized in that, The preparation method of the medical microspheres satisfies one or more of the following conditions a to d: a. The sulfonating agent is concentrated sulfuric acid, chlorosulfonic acid, sulfur trioxide, sulfamic acid or sulfite; b. The temperature of the reaction is 30 to 100 °C; c. The time of the reaction is 2 to 9 hours; d. After the reaction, it further includes the steps of washing and drying.

11. The preparation method of the medical microspheres according to claim 10, wherein, The preparation method of the medical microspheres satisfies one or more of the following conditions a to c: a. The sulfonation reagent is concentrated sulfuric acid; b. The temperature of the reaction is 40 to 90 °C; c. The time of the reaction is 4 to 9 hours.

12. The preparation method of the medical microspheres according to claim 11, characterized in that, The preparation method of the medical microspheres satisfies one or more of the following conditions a to c: a. When the sulfonation reagent is concentrated sulfuric acid, the dosage ratio of the phenolic resin microspheres to the concentrated sulfuric acid is 1 g : (2 - 15) mL; b. The temperature of the reaction is 50 to 85 °C; c. The time of the reaction is 4 to 8 hours.

13. The preparation method of the medical microspheres according to claim 12, characterized in that, The dosage ratio of the phenolic resin microspheres to the concentrated sulfuric acid is 1 g : (3 - 12) mL.

14. The preparation method of the medical microspheres according to claim 13, characterized in that, The dosage ratio of the phenolic resin microspheres to the concentrated sulfuric acid is 1 g : (4 - 10) mL.

15. The preparation method of the medical microspheres according to claim 6, wherein, The preparation method of the medical microspheres satisfies one or more of the following conditions a to d: a. The nitration reagent is concentrated nitric acid, fuming nitric acid - acetic acid, fuming nitric acid, concentrated sulfuric acid - potassium nitrate, or concentrated sulfuric acid - concentrated nitric acid; b. The temperature of the reaction is 30 to 100 °C; c. The time of the reaction is 2 to 9 hours; d. After the reaction, it further includes the steps of washing and drying.

16. The preparation method of the medical microspheres according to claim 15, wherein, The preparation method of the medical microspheres satisfies one or more of the following conditions a to c: a. The nitration reagent is concentrated sulfuric acid - concentrated nitric acid; b. The temperature of the reaction is 40 to 90 °C; c. The time of the reaction is 3 to 9 hours.

17. The method for preparing the medical microspheres according to claim 16, wherein, The preparation method of the medical microspheres satisfies one or more of the following conditions a to d: a. In the concentrated sulfuric acid - concentrated nitric acid, the molar ratio of concentrated sulfuric acid to concentrated nitric acid is 1 : 2; b. When the nitration reagent is concentrated sulfuric acid - concentrated nitric acid, the dosage ratio of the phenolic resin microspheres to the concentrated sulfuric acid - concentrated nitric acid is 1 g : (2 - 15) mL; c. The temperature of the reaction is 50 to 85 °C; d. The time of the reaction is 4 to 8 hours.

18. The preparation method of the medical microspheres according to claim 17, characterized in that, The dosage ratio of the phenolic resin microspheres to the concentrated sulfuric acid - concentrated nitric acid is 1 g : (3 - 12) mL.

19. The preparation method of the medical microspheres according to claim 18, characterized in that, The dosage ratio of the phenolic resin microspheres to the concentrated sulfuric acid - concentrated nitric acid is 1 g : (3 - 10) mL.

20. The preparation method of the medical microspheres according to claim 6, characterized in that, The solution containing the radioactive metal element is an aqueous solution of the radioactive metal element.

21. The preparation method of the medical microspheres according to claim 20, wherein, The radioactive metal element is 67 Cu, 90 Y, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 211 At, 212 Bi, 213 Bi, 223 Ra or 225 Ac.

22. The preparation method of the medical microspheres according to claim 21, wherein, When the radioactive metal element is 90 Y, the concentration of the solution containing the radioactive metal element is 0.002 to 2.5 mg / mL.

23. The preparation method of the medical microspheres according to claim 22, characterized in that, When the radioactive metal element is 90 Y, the concentration of the solution containing the radioactive metal element is 0.0025 to 2.25 mg / mL.

24. The preparation method of the medical microspheres according to claim 6, characterized in that, The preparation method of the medical microspheres satisfies one or two of the following conditions i to ii: i. The temperature of the mixing is 25 to 40 °C; ii. The time of the mixing is 2 to 4 h.

25. The preparation method of the medical microspheres according to claim 6, wherein, The preparation method of the medical microspheres satisfies one or two of the following conditions a to b: a. When the cation exchange type phenolic resin microsphere is a sulfonated phenolic resin microsphere, the sulfonation degree of the sulfonated phenolic resin microsphere is 1.5×10 -1 mmol / mg to 5×10 -1 mmol / mg; b. When the cation-exchangeable phenolic resin microspheres are nitrified phenolic resin microspheres, the nitration degree of the nitrified phenolic resin microspheres is 2×10 -1 mmol / mg to 4.8×10 -1 mmol / mg.

26. The preparation method of the medical microspheres according to claim 25, wherein, The preparation method of the medical microspheres satisfies one or two of the following conditions a to b: a. When the cation-exchange phenolic resin microspheres are sulfonated phenolic resin microspheres, the sulfonation degree of the sulfonated phenolic resin microspheres is 3×10 -1 mmol / mg to 4.8×10 -1 mmol / mg; b. When the cation-exchange phenolic resin microspheres are nitrified phenolic resin microspheres, the nitrification degree of the nitrified phenolic resin microspheres is 3.5×10 -1 mmol / mg to 4.8×10 -1 mmol / mg.

27. The preparation method of the medical microspheres according to claim 26, characterized in that, When the cation exchange type phenolic resin microspheres are sulfonated phenolic resin microspheres, the sulfonation degree of the sulfonated phenolic resin microspheres is 4.2×10 -1 mmol / mg to 4.8×10 -1 mmol / mg.

28. A medical microsphere, characterized in that, The medical microspheres are prepared by the preparation method of the medical microspheres according to any one of claims 6 - 27.

29. Use of the medical microspheres according to any one of claims 1 - 5 or 28 in the preparation of a drug for treating tumors.

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