Yttrium [90Y] microsphere injection as well as preparation method and application thereof

Abstract

The invention relates to the technical field of radiopharmaceutical preparations, in particular to yttrium [90Y] microsphere injection as well as a preparation method and application thereof. The preparation method of the yttrium [90Y] microsphere injection comprises the following steps: S1, uniformly mixing a radioactive stock solution and an yttrium sulfate solution, stirring and mixing with resin microspheres, and washing to obtain yttrium [90Y] microspheres; s2, stirring and mixing a sodium phosphate solution and the yttrium [90Y] microspheres, taking out 1 / 3 volume of clear liquid, carrying out suction filtration on the residual clear liquid, and mixing the taken clear liquid with the yttrium [90Y] microspheres to obtain mixed liquid; and S3, stirring and mixing the sodium dihydrogen phosphate solution and the mixed liquid, taking out 4 / 10 volume of clear liquid, carrying out suction filtration on the residual clear liquid, mixing the taken clear liquid with yttrium [90Y] microspheres, washing, filling and sealing, and sterilizing to obtain the yttrium [90Y] microsphere injection. The labeling rate of yttrium [90Y] in the produced yttrium [90Y] microsphere injection is high.

Description

Technical Field

[0001] The present invention relates to the technical field of radiopharmaceutical preparations, and in particular to a yttrium[ 90 Y] Microsphere injection and its preparation method and application. Background Art

[0002] yttrium[ 90 Y] microsphere selective internal radiotherapy is one of the important means to treat liver malignancies. 90 Y] Microspheres have the effects of tumor shrinkage, downstaging and transformation, and can transform highly prevalent large liver cancer and giant liver cancer into resectable tumors.

[0003] yttrium[ 90 Y] microsphere injection is a yttrium-containing 90 Y] microsphere injection, which can provide a new and effective treatment for a large number of patients with liver malignancies, create potential surgical resection opportunities, and fill the gap in local treatment of colorectal cancer liver metastasis.

[0004] But yttrium[ 90 Y] microsphere injection is prepared by conventional injection method, and the yttrium [ 90 Yttrium in microsphere injection 90 The labeling rate of yttrium is low and it will cause strong irritation to patients. Therefore, it is urgent to develop a method for producing yttrium[ 90 Y] microsphere injection method, thereby increasing the yttrium [ 90 Yttrium in microsphere injection 90 Y] marking rate. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a yttrium [ 90 Y] microsphere injection and its preparation method and application, the method produces yttrium [ 90 Yttrium in microsphere injection 90 Y] has a high labeling rate and is less irritating to patients. It can significantly reduce local inflammatory reactions and improve the safety of injections. It is also simple to operate and does not require major changes to traditional production equipment.

[0006] To this end, the present invention provides the following technical solutions:

[0007] In a first aspect, the present invention provides an yttrium [ 90 Y] A method for preparing microsphere injection, comprising the following steps:

[0008] S1: Mix the radioactive stock solution and yttrium sulfate solution, stir and mix with the resin microspheres, and rinse to obtain yttrium[ 90 Y] resin microspheres;

[0009] S2: Sodium phosphate solution and the yttrium [ 90 After the microspheres are stirred and mixed, the clear liquid is taken out according to the first volume ratio, and the remaining clear liquid is filtered to leave the yttrium [ 90 Y] resin microspheres, and then the clear solution was mixed with yttrium[ 90 Y] resin microspheres are mixed to obtain a mixed liquid;

[0010] S3: After the sodium dihydrogen phosphate solution and the mixed liquid are stirred and mixed, the clear liquid is taken out according to the second volume ratio, and the remaining clear liquid is filtered to leave the yttrium [ 90 Y] resin microspheres, and then the clear solution was mixed with yttrium[ 90 Y] microspheres are mixed, rinsed, filled, and sterilized to obtain yttrium [ 90 Y] microsphere injection;

[0011] Wherein, in steps S2 and S3, the filter membrane used for filtration is a nylon filter membrane or a polycarbonate filter membrane, the pore size of the nylon filter membrane is 0.45 μm, the pore size of the polycarbonate filter membrane is 0.8 μm, and the resin microspheres are polystyrene sulfonic acid type resin microspheres.

[0012] The present invention is to prepare yttrium by conventional methods. 90 Y] microsphere injection method was improved to improve the production of yttrium [ 90 Yttrium in microsphere injection 90 The marking rate of Y] is high and the operation is simple, without making major changes to traditional production equipment.

[0013] Preferably, the method for preparing the polystyrene sulfonic acid resin microspheres comprises the following steps:

[0014] (1) mixing styrene, divinylbenzene, an initiator and a porogen, dissolving them to obtain an oil phase, injecting the oil phase into an aqueous solution containing a suspending agent, shearing and emulsifying, and heating to react to obtain polystyrene microspheres;

[0015] (2) mixing chloroform and sulfuric acid, cooling the mixture, and then adding acetic anhydride to react to obtain an acetyl sulfonate solution;

[0016] (3) After chloroform and polystyrene microspheres are mixed, the temperature is raised to swell, and then an acetosulfonate solution is added to react to obtain polystyrene sulfonic acid resin microspheres.

[0017] In step (1), the initiator is selected from one or more of benzoyl peroxide (BPO) or azobisisobutyronitrile (AIBN), the porogen is selected from one or more of toluene, n-heptane or xylene, and the suspending agent is selected from one or more of polyvinyl alcohol, hydroxypropyl methylcellulose or polyethylene glycol. The rotation speed of the shear emulsification is 1100 - 1300 r / min, the temperature of the heating reaction is 85 - 95 °C, and the time is 170 - 190 min, preferably 180 min. The mass ratio of styrene, divinylbenzene, initiator, porogen and suspending agent is 1:0.8 - 0.85:0.01 - 0.02:0.90 - 0.95:0.8 - 0.85. Preferably, the mass ratio of styrene, divinylbenzene, benzoyl peroxide, toluene, n-heptane and polyethylene glycol is 1:0.82:0.01:0.51:0.40:0.81.

[0018] In step (2), the temperature for cooling is (-5 °C) - 5 °C, and the reaction time is 60 - 120 min, preferably 60 min. Based on the mass of the polystyrene microspheres, the mass of chloroform is 2.85 - 2.95 times that of the polystyrene microspheres, the mass of sulfuric acid is 2.95 - 3.00 times that of the polystyrene microspheres, and the mass of acetic anhydride is 4.3 - 4.5 times that of the polystyrene microspheres. Preferably, the mass of chloroform is 2.9 times that of the polystyrene microspheres, the mass of sulfuric acid is 2.96 times that of the polystyrene microspheres, and the mass of acetic anhydride is 4.4 times that of the polystyrene microspheres.

[0019] In step (3), the temperature for swelling and heating is 55 - 65 °C, and the time is 120 - 180 min, preferably 180 min. Based on the mass of the polystyrene microspheres, the mass of chloroform is 5.9 - 6.0 times that of the polystyrene microspheres. Preferably, the mass of chloroform is 5.92 times that of the polystyrene microspheres. The reaction temperature is 55 - 65 °C, and the time is 280 - 320 min, preferably 300 min.

[0020] In step (3), after the reaction is completed, it further includes the steps of washing, filtering, drying and screening the polystyrene sulfonic acid resin microspheres.

[0021] Preferably, in step S2, the first volume ratio is one-third of the volume ratio of the solution after mixing the sodium phosphate solution and the yttrium 90 Y] resin microspheres; and / or, in step S3, the second volume ratio is four-tenths of the volume ratio of the solution after mixing the sodium dihydrogen phosphate solution and the mixed liquid.

[0022] Preferably, the mass of the resin microspheres and the volume ratio of the radioactive stock solution are 0.5-1g:0.1-1ml; preferably 0.75g:0.5ml, and / or, the mass of the resin microspheres and the volume ratio of the yttrium sulfate solution are 0.5-1g:3-4ml, preferably 0.75g:3.5ml. The radioactive stock solution is yttrium chloride solution, and the radioactivity is 5-20GBq / ml, preferably 12GBq / ml; and / or, the concentration of the yttrium chloride solution is 2-6mg / ml, preferably 4mg / ml. The mass ratio of the resin microspheres to the volume ratio of the sodium phosphate solution is 0.5-1g:5-7ml, preferably 0.75g:6ml, and the concentration of the sodium phosphate solution is 10-60g / L; and / or, the mass ratio of the resin microspheres to the volume ratio of sodium dihydrogen phosphate is 0.5-1g:7-8ml, preferably 0.75g:7.5ml, and the concentration of the sodium dihydrogen phosphate solution is 2-25g / L.

[0023] In the present invention, the radioactive stock solution can be selected not only from yttrium chloride solution but also from other solutions containing yttrium-90. If the radioactive concentration of the radioactive stock solution is high, it is necessary to dilute the radioactive stock solution with 0.04 mol / L hydrochloric acid solution.

[0024] Preferably, in step S1, the stirring and mixing time is 10-20 minutes, preferably 15 minutes; and / or, in step S2, the stirring and mixing time is 10-20 minutes; preferably 15 minutes, and / or, in step S3, the stirring and mixing time is at least 5 minutes.

[0025] Preferably, before step S1, the resin microspheres are further rinsed for at least 3 times. In step S1, sterile water for injection is used for rinsing; and / or, in step S3, sterile water for injection is used for rinsing and potting.

[0026] In the present invention, the rinsing in step S1 and the rinsing in step S3 are both performed at least twice.

[0027] In a second aspect, the present invention provides an yttrium [ 90 Y] Microsphere injection, prepared by the above preparation method.

[0028] In a third aspect, the present invention provides, in an optional embodiment, a yttrium obtained by the above preparation method [ 90 Y] microsphere injection or the above yttrium [ 90 Y] Application of microsphere injection in the prevention or treatment of liver cancer.

[0029] Compared with the prior art, the present invention has one of the following beneficial effects:

[0030] 1. The yttrium provided by the present invention [ 90 Y] microsphere injection preparation method, the produced yttrium [ 90 Yttrium in microsphere injection 90 Y] has a high labeling rate and is less irritating to patients. It can significantly reduce local inflammatory reactions and improve the safety of injections. It is also simple to operate and does not require major changes to traditional production equipment. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0032] The following is a specific example to illustrate the solution of the present invention.

[0033] In Examples 1-3 and Comparative Examples 1-15, the method for preparing polystyrene sulfonic acid resin microspheres comprises the following steps:

[0034] (1): 1 kg of styrene, 0.82 kg of divinylbenzene, 0.01 kg of dibenzoyl peroxide, 0.51 kg of toluene and 0.40 kg of n-heptane were mixed and dissolved to obtain an oil phase, and the oil phase was injected into an aqueous solution containing 0.81 kg of polyethylene glycol, and sheared and emulsified at a speed of 1200 r / min, and then heated at a temperature of 90° C. for reaction for 180 min to obtain polystyrene microspheres;

[0035] (2) 2.9 kg of chloroform and 2.96 kg of sulfuric acid were mixed, the temperature was lowered to (-5°C)-5°C, and then 4.4 kg of acetic anhydride was added to react for 60 minutes to obtain an acetyl sulfonate solution;

[0036] (3) 5.92 kg of chloroform and 1 kg of polystyrene microspheres were mixed, the temperature was raised to 60° C. for swelling for 180 min, and then an acetosulfonate solution was added to react for 300 min. Finally, the mixture was washed, filtered, dried and sieved to obtain polystyrene sulfonic acid resin microspheres.

[0037] Example 1

[0038] This embodiment provides a yttrium [ 90 Y] A method for preparing microsphere injection, comprising the following steps:

[0039] S1: The raw material polystyrene sulfonic acid resin microspheres (hereinafter referred to as resin microspheres) are sucked 5 times with a 5ml pipette. After mixing, all the resin microsphere suspension is sucked out and added to the filtration device with a specification of 300ml filter cup / 1000ml receiving bottle. The filter membrane is a 10μm PC membrane. Add 100ml sterile injection water, stir and rinse for 1 minute, drain, and remove the negative pressure of the vacuum pump. Repeat the operation three times and drain. Take out the rinsed microspheres from the filtration device, weigh 0.75g of resin microspheres, and transfer them to the reaction device. Use a 1ml pipette to take 0.5ml of 12GBq / ml yttrium chloride solution and put it into a 10ml cillin bottle, then take 3.5ml of 4.0mg / mL yttrium sulfate and add it to the above 10ml cillin bottle and mix thoroughly. Add all the mixed solutions in the mixing step to the reaction device, stir and mix for 15 minutes, drain the liquid by vacuum pump, and remove the negative pressure. Use a 10ml syringe to draw 10ml of sterile water for injection, add it to the suction filter, stir and mix for 1 minute, then use a vacuum pump to drain the liquid and release the negative pressure. Repeat the operation twice.

[0040] S2: Use a 10 ml syringe to draw 6 ml of 30 g / L sodium phosphate solution, add it to the reaction device, stir and mix for 15 minutes, remove 2 ml of the clear liquid, and then filter the remaining clear liquid. The filter membrane used for filtration is a nylon filter membrane (pore size is 0.45 μm), remove the negative pressure, and then add the above 2 ml of clear liquid to the reaction device.

[0041] S3: Use a 10ml syringe to extract 7.5ml of 15g / L sodium dihydrogen phosphate solution, add it to the reaction device, stir and mix for at least 5 minutes, remove 3ml of clear liquid, and then filter the remaining clear liquid. The filter membrane used for filtration is a nylon filter membrane (pore size is 0.45μm), remove the negative pressure, and then add the above 3ml clear night to the reaction device. Use a 10ml syringe to draw 10ml of sterile water for injection, add it to the reaction device, stir and mix for 1 minute, and then extract the liquid through a vacuum pump. Repeat the operation twice. Use a 5ml syringe to take 5ml of sterile water for injection, add it to the reaction device, repeatedly suck and blow 5 times, mix the resin and water for injection, and then transfer it to a 10ml open-top vial with a 1ml pipette, add a stopper and cover, and put the vial with the cover into the activity meter to measure the activity. Put the above vial into a lead can, transfer the lead can to a high-pressure steam sterilizer, open the lid of the lead can, set the temperature: 132℃, and set the time to 7 minutes.

[0042] Example 2

[0043] This embodiment provides a yttrium [ 90 Y] A method for preparing microsphere injection, comprising the following steps:

[0044] S1: The raw material polystyrene sulfonic acid resin microspheres (hereinafter referred to as resin microspheres) are sucked 5 times with a 5ml pipette. After mixing, all the resin microsphere suspension is sucked out and added to the filtration device with a specification of 300ml filter cup / 1000ml receiving bottle. The filter membrane is a 10μm PC membrane. Add 100ml sterile injection water, stir and rinse for 1 minute, drain, and remove the negative pressure of the vacuum pump. Repeat the operation three times and drain. Take out the rinsed microspheres from the filtration device, weigh 1g of resin microspheres, and transfer them to the reaction device. Use a 1ml pipette to take 1ml of 12GBq / ml yttrium chloride solution and put it into a 10ml cillin bottle, then take 3ml of 4.0mg / mL yttrium sulfate and add it to the above 10ml cillin bottle and mix thoroughly. Add all the mixed solutions in the mixing step to the reaction device, stir and mix for 15 minutes, drain the liquid by vacuum pump, and remove the negative pressure. Use a 10ml syringe to draw 10ml of sterile water for injection, add it to the suction filter, stir and mix for 1 minute, then use a vacuum pump to drain the liquid and release the negative pressure. Repeat the operation twice.

[0045] S2: Use a 10 ml syringe to draw 7 ml of 30 g / L sodium phosphate solution, add it to the reaction device, stir and mix for 15 minutes, remove 2.3 ml of clear liquid, and then filter the remaining clear liquid. The filter membrane used for filtration is a nylon filter membrane (pore size is 0.45 μm), remove the negative pressure, and then add the above 2.3 ml of clear liquid to the reaction device.

[0046] S3: Use a 10ml syringe to extract 7ml of sodium dihydrogen phosphate solution with a concentration of 15g / L, add it to the reaction device, stir and mix for at least 5 minutes, remove 2.8ml of clear liquid, and then filter the remaining clear liquid. The filter membrane used for filtration is a polycarbonate filter membrane (pore size is 0.8μm), remove the negative pressure, and then add the above 2.8ml clear night to the reaction device. Use a 10ml syringe to draw 10ml of sterile water for injection, add it to the reaction device, stir and mix for 1 minute, and then extract the liquid through a vacuum pump. Repeat the operation twice. Use a 5ml syringe to take 5ml of sterile water for injection, add it to the reaction device, repeatedly suck and blow 5 times, mix the resin and water for injection, and then transfer it to a 10ml open-top vial with a 1ml pipette, add a stopper and cover, and put the vial with the cover into the activity meter to measure the activity. Put the above vial into a lead can, transfer the lead can to a high-pressure steam sterilizer, open the lid of the lead can, set the temperature: 132℃, and set the time for 7 minutes.

[0047] Example 3

[0048] This embodiment provides a yttrium [ 90 Y] A method for preparing microsphere injection, comprising the following steps:

[0049] S1: The raw material polystyrene sulfonic acid resin microspheres (hereinafter referred to as resin microspheres) are sucked 5 times with a 5ml pipette. After mixing, all the resin microsphere suspension is sucked out and added to the filtration device with a specification of 300ml filter cup / 1000ml receiving bottle. The filter membrane is a 10μm PC membrane. Add 100ml sterile injection water, stir and rinse for 1 minute, drain, and remove the negative pressure of the vacuum pump. Repeat the operation three times and drain. Take out the rinsed microspheres from the filtration device, weigh 0.5g of resin microspheres, and transfer them to the reaction device. Use a 1ml pipette to take 1ml of 12GBq / ml yttrium chloride solution and put it into a 10ml cillin bottle, then take 4ml of 4.0mg / mL yttrium sulfate and add it to the above 10ml cillin bottle and mix thoroughly. Add all the mixed solutions in the mixing step to the reaction device, stir and mix for 15 minutes, drain the liquid through the vacuum pump, and remove the negative pressure. Use a 10ml syringe to draw 10ml of sterile water for injection, add it to the suction filter, stir and mix for 1 minute, then use a vacuum pump to drain the liquid and release the negative pressure. Repeat the operation twice.

[0050] S2: Use a 10 ml syringe to draw 5 ml of a 30 g / L sodium phosphate solution, add it to the reaction device, stir and mix for 15 minutes, remove 1.7 ml of the clear liquid, and then filter the remaining clear liquid using a polycarbonate filter membrane (pore size 0.8 μm). Remove the negative pressure and add the above 1.7 ml of the clear liquid to the reaction device.

[0051] S3: Use a 10ml syringe to extract 8ml of 15g / L sodium dihydrogen phosphate solution, add it to the reaction device, stir and mix for at least 5 minutes, remove 3.2ml of clear liquid, and then filter the remaining clear liquid. The filter membrane used for filtration is a nylon filter membrane (pore size is 0.45μm), remove the negative pressure, and then add the above 3.2ml clear night to the reaction device. Use a 10ml syringe to draw 10ml of sterile water for injection, add it to the reaction device, stir and mix for 1 minute, and then extract the liquid through a vacuum pump. Repeat the operation twice. Use a 5ml syringe to take 5ml of sterile water for injection, add it to the reaction device, repeatedly suck and blow 5 times, mix the resin and water for injection, and then transfer it to a 10ml open-top vial with a 1ml pipette, add a stopper and cap, and put the vial with the cap into the activity meter to measure the activity. Put the above vial into a lead can, transfer the lead can to a high-pressure steam sterilizer, open the lid of the lead can, set the temperature: 132℃, and set the time for 7 minutes.

[0052] Comparative Example 1

[0053] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polyethersulfone filter membrane (pore size is 0.45 μm), and the remaining steps are the same as Example 1.

[0054] Comparative Example 2

[0055] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polyethersulfone filter membrane (pore size is 1.0 μm), and the remaining steps are the same as Example 1.

[0056] Comparative Example 3

[0057] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polyethersulfone filter membrane (pore size is 5.0 μm), and the remaining steps are the same as Example 1.

[0058] Comparative Example 4

[0059] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polytetrafluoroethylene filter membrane (pore size is 0.45 μm), and the remaining steps are the same as Example 1.

[0060] Comparative Example 5

[0061] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polytetrafluoroethylene filter membrane (pore size is 1.0 μm), and the remaining steps are the same as in Example 1.

[0062] Comparative Example 6

[0063] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polytetrafluoroethylene filter membrane (pore size is 5.0 μm), and the remaining steps are the same as in Example 1.

[0064] Comparative Example 7

[0065] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polyvinylidene fluoride filter membrane (pore size is 0.45 μm), and the remaining steps are the same as Example 1.

[0066] Comparative Example 8

[0067] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polyvinylidene fluoride filter membrane (pore size is 1.0 μm), and the remaining steps are the same as Example 1.

[0068] Comparative Example 9

[0069] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polyvinylidene fluoride filter membrane (pore size is 5.0 μm), and the remaining steps are the same as Example 1.

[0070] Comparative Example 10

[0071] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a nylon filter membrane (pore size is 1.0 μm), and the remaining steps are the same as in Example 1.

[0072] Comparative Example 11

[0073] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a nylon filter membrane (pore size is 5.0 μm), and the remaining steps are the same as Example 1.

[0074] Comparative Example 12

[0075] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a nylon filter membrane (pore size is 10.0 μm), and the remaining steps are the same as Example 1.

[0076] Comparative Example 13

[0077] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polycarbonate filter membrane (pore size is 1.2 μm), and the remaining steps are the same as Example 1.

[0078] Comparative Example 14

[0079] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polycarbonate filter membrane (pore size is 5.0 μm), and the remaining steps are the same as Example 1.

[0080] Comparative Example 15

[0081] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the preparation method of Example 1, the difference between this method and the preparation method of Example 1 is that in step S2 and step S3, the filter membrane used for filtration is a polycarbonate filter membrane (pore size is 10.0 μm), and the remaining steps are the same as Example 1.

[0082] Comparative Example 16

[0083] This comparative example provides a yttrium [ 90 Y] A method for preparing microsphere injection. Compared with the method of Example 1, the difference lies in that the method for preparing polystyrene sulfonic acid resin microspheres is different, specifically: (1) Styrene and divinylbenzene are first washed once with a 10% sodium hydroxide aqueous solution, and then washed three times with water for later use.

[0084] (2) Heat polyvinyl alcohol and dissolve it in water to prepare 100 ml of 1% (mass percentage) polyvinyl alcohol aqueous solution, protect with nitrogen, and obtain the water phase. Weigh 2.5 ml of styrene, 1.2 ml of divinylbenzene, 0.02 g of dibenzoyl peroxide, 0.6 ml of toluene and 0.6 ml of n-heptane, mix and dissolve to obtain the oil phase. Inject the oil phase into the water phase and emulsify it by shearing for 5 minutes. Stir at 50°C overnight, and then react at 90°C for 3 hours to obtain polystyrene microspheres. Filter, wash twice with water, wash once with ethanol, and dry.

[0085] (3) Take the dried polystyrene microspheres, add them to 25 mL of concentrated sulfuric acid (98% by mass) at 0°C, disperse them by ultrasonication, heat them to 40°C and react overnight. Filter them by suction, wash them until they are neutral, beat them with hot water at 95°C twice, wash them with ethanol once, dry them, and sieve them to obtain polystyrene sulfonic acid resin microspheres.

[0086] The remaining steps are the same as those in Example 1.

[0087] Experimental example

[0088] 1. The production of yttrium by the preparation method of Examples 1-3 and Comparative Examples 1-16 was detected by an activity meter. 90 Y] microsphere injection solution radioactivity, and then according to the formula: labeling rate = yttrium [ 90The radioactivity of yttrium produced by each embodiment and comparative example is calculated by the radioactivity of yttrium [ 90 Yttrium in microsphere injection 90 Y], the results are shown in Table 1:

[0089] Table 1 Examples 1-3 and Comparative Examples 1-16 Yttrium [ 90 Yttrium in microsphere injection 90 Y]

[0090]

[0091]

[0092] It can be seen from Table 1 that the yttrium produced in Examples 1-3 [ 90 Yttrium in microsphere injection 90 The labeling rate of yttrium [ 90 Yttrium in microsphere injection 90 The labeling rate of Y] is lower than 90%. Therefore, only by strictly following the preparation method of the present invention to produce yttrium [ 90 Y] microsphere injection to obtain a high labeling rate of yttrium [ 90 Y] Microsphere injection.

[0093] 2. Animal Experiments

[0094] Judging and evaluating yttrium[ 90 Y] The irritation level of a single dose of microsphere injection in beagle dogs.

[0095] The experimental animals used were beagle dogs, No. 2233125243, normal grade, male, weighing between 4.5-5.5 kg. A total of 24 dogs were selected and randomly divided into 6 groups, 4 dogs in each group.

[0096] The first group was injected with yttrium from Example 1 [ 90 Y] microsphere injection, the second group was injected with yttrium [ 90 Y] microsphere injection, the third group was injected with yttrium [ 90 Y] microsphere injection, the fourth group was injected with yttrium [ 90 Y] microsphere injection, the fifth group was injected with yttrium [ 90 Y] microsphere injection, the sixth group was injected with yttrium [ 90 Y] Microsphere injection.

[0097] The corresponding yttrium was injected into the midline of the back skin, the left paraspinal muscle and the right paraspinal muscle of each beagle dog. 90Y] microsphere injection (injection volume is injection containing 0.5g resin microsphere). 30 days after injection, each group of beagle dogs were observed, and it was found that no animals were dying or dead during the experiment. Then the beagle dogs were euthanized, and a longitudinal incision was made along the center of the back of the beagle dogs to expose the dorsal muscles and cut them off. The naked eye observation and irritation results were evaluated.

[0098] Visual observation: Check the changes on the animal's body surface to see if there are any abnormalities in glandular secretions, secretions (or exudates), congestion, edema, bleeding, necrosis, etc., and if there are any abnormalities in the shape, size, color, and texture of the organs. Observe the liver surface, cortex, and medulla for any abnormalities; observe the renal capsule, cortex, medulla, and renal pelvis for any abnormalities;

[0099] Results: No relevant macroscopic changes were found.

[0100] Evaluation of irritation results:

[0101] The evaluation method is as follows:

[0102] (1) Evaluate and record the cell and tissue responses of each injection group;

[0103] (2) According to the cell response scores in Table 2 and the tissue response scores in Table 3, score the recorded results accordingly;

[0104] (3) The final reaction score of each group = (the cell reaction score of the corresponding beagle dogs in each group × 2 + the tissue reaction score of the corresponding beagle dogs in each group) / 10.

[0105] Based on the final reaction score, grade the degree of test article injection reaction according to Table 4.

[0106] Table 2 Cellular response scores

[0107]

[0108]

[0109] Table 3 Tissue response scores

[0110]

[0111] Table 4 Grading table of local reaction degree after injection

[0112] Final reaction score Grading 0-2.9 points No irritation or very slight irritation 2.9-3.9 points Mild irritation 3.9-6.7 Moderate stimulation

[0113] The evaluation results of cell response and tissue response in each group are shown in Table 5 and Table 6:

[0114] Table 5 Evaluation results of cell response in each group

[0115]

[0116] Table 6 Tissue response evaluation results of each group

[0117]

[0118]

[0119] According to the above evaluation method, the final reaction score of each group was calculated, and the results are shown in Table 7:

[0120] Table 7 Final reaction scores of each group

[0121] Group Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 score 0.8 0.2 0.6 3.4 6.5 3.7

[0122] It can be seen from Table 7 that the scores of each experimental group are relatively low, all within 2.9, the control group has a strong irritation, and the microsphere injection of the control group will produce irritation or even moderate irritation. Therefore, strictly following the preparation method of the present invention, the yttrium in the microsphere injection can be increased. 90 Y] labeling rate, further significantly reduced the body's local inflammatory response and improved the safety of medication.

[0123] Although the principles of the present invention are described in detail above in conjunction with the preferred embodiments of the present invention, those skilled in the art should understand that the above embodiments are merely explanations of the exemplary implementations of the present invention, and are not intended to limit the scope of the present invention. The details in the embodiments do not constitute limitations on the scope of the present invention, and any obvious changes such as equivalent transformations, simple replacements, etc. based on the technical solution of the present invention, without departing from the spirit and scope of the present invention, fall within the protection scope of the present invention.

Claims

1. A kind of yttrium 90 Y] A method for preparing microsphere injection, characterized in that: The following steps are involved: S1: Mix the radioactive stock solution and yttrium sulfate solution, stir and mix with the resin microspheres, and rinse to obtain yttrium[ 90 Y] resin microspheres; S2: Sodium phosphate solution and the yttrium [ 90 After the microspheres are stirred and mixed, the clear liquid is taken out according to the first volume ratio, and the remaining clear liquid is filtered to leave the yttrium [ 90 Y] resin microspheres, and then the clear solution was mixed with yttrium[ 90 Y] resin microspheres are mixed to obtain a mixed liquid; S3: After the sodium dihydrogen phosphate solution and the mixed liquid are stirred and mixed, the clear liquid is taken out according to the second volume ratio, and the remaining clear liquid is filtered to leave the yttrium [ 90 Y] resin microspheres, and then the clear solution was mixed with yttrium[ 90 Y] microspheres are mixed, rinsed, filled, and sterilized to obtain yttrium [ 90 Y] microsphere injection; Wherein, in steps S2 and S3, the filter membrane used for filtration is a nylon filter membrane or a polycarbonate filter membrane, the pore size of the nylon filter membrane is 0.45 μm, the pore size of the polycarbonate filter membrane is 0.8 μm, and the resin microspheres are polystyrene sulfonic acid type resin microspheres.

2. The yttrium according to claim 1 90 Y] A method for preparing microsphere injection, characterized in that: The preparation method of the polystyrene sulfonic acid resin microspheres comprises the following steps: (1) mixing styrene, divinylbenzene, an initiator and a porogen, dissolving them to obtain an oil phase, injecting the oil phase into an aqueous solution containing a suspending agent, shearing and emulsifying, and heating to react to obtain polystyrene microspheres; (2) mixing chloroform and sulfuric acid, cooling the mixture, and then adding acetic anhydride to react to obtain an acetyl sulfonate solution; (3) After chloroform and polystyrene microspheres are mixed, the temperature is raised to swell, and then an acetosulfonate solution is added to react to obtain polystyrene sulfonic acid resin microspheres.

3. The yttrium according to claim 1 90 Y] A method for preparing microsphere injection, characterized in that: In step S2, the first volume ratio is sodium phosphate solution and yttrium [ 90 Y] one third of the volume ratio of the solution after the resin microspheres are mixed; and / or, In step S3, the second volume ratio is four tenths of the volume ratio of the solution after the sodium dihydrogen phosphate solution and the mixed liquid are mixed.

4. The yttrium according to claim 1 90 Y] A method for preparing microsphere injection, characterized in that: The mass ratio of the resin microspheres to the volume ratio of the radioactive stock solution is 0.5-1 g: 0.1-1 ml; and / or, The mass of the resin microspheres and the volume ratio of the yttrium sulfate solution are 0.5-1g:3-4ml.

5. The yttrium according to claim 1 90 Y] A method for preparing microsphere injection, characterized in that: The radioactive stock solution is a yttrium chloride solution with a radioactivity of 5-20 GBq / ml; and / or, The concentration of the yttrium chloride solution is 2-6 mg / ml.

6. The yttrium according to claim 1 90 Y] A method for preparing microsphere injection, characterized in that: The mass ratio of the resin microspheres to the volume of the sodium phosphate solution is 0.5-1 g:5-7 ml, and the concentration of the sodium phosphate solution is 10-60 g / L; and / or, The mass ratio of the resin microspheres to the volume of sodium dihydrogen phosphate is 0.5-1 g:7-8 ml, and the concentration of the sodium dihydrogen phosphate solution is 2-25 g / L.

7. The yttrium according to claim 1 90 Y] A method for preparing microsphere injection, characterized in that: In step S1, the stirring and mixing time is 10-20 minutes; and / or, In step S2, the stirring and mixing time is 10-20 minutes; and / or, In step S3, the stirring and mixing time is at least 5 minutes.

8. The yttrium according to claim 1 90 Y] A method for preparing microsphere injection, characterized in that: In step S1, the flushing uses sterile water for injection; and / or, In step S3, sterile water for injection is used for flushing and potting.

9. A kind of yttrium 90 Y] microsphere injection, characterized in that The preparation method is described in any one of claims 1 to 8.

10. Yttrium obtained by the preparation method according to any one of claims 1 to 8 90 Y] microsphere injection or the yttrium [ 90 Y] Application of microsphere injection in the prevention or treatment of liver cancer.

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