WO2022134409A1 - Radioactive resin microsphere injection, preparation method, and use - Google Patents

Abstract

A radioactive resin microsphere injection, a preparation method, and a use. Each 1 ml of radioactive resin microsphere injection comprises: 0.1 to 300 mg of radioactive resin microspheres and 1 to 0.75 ml of a hydrogel. The injection is used for the preparation of medications that treat tumors, and can be directly injected into a tumor by interventional means, allowing for direct determination, according to the administration volume, of the radioactive dosage of the radioactive resin microspheres. Hydrogel that has reached inside of the tumor can, together with calcium ions, form a gel inside of the tumor, so that the radioactive resin microspheres can be dispersed relatively uniformly and be limited in the tumor. The radioactive resin microspheres provide high-dosage local radiation therapy to implement the treatment of a solid tumor. The present invention has wide application prospect in solid tumor treatment.

Description

A kind of radioactive resin microsphere injection and preparation method and use technical field

The invention relates to the technical field of medicine, in particular to a radioactive resin microsphere injection and a preparation method and application thereof.

Background technique

The radioactive resin microsphere products currently used in clinical mainly include yttrium [ ⁹⁰ Y] resin microspheres SIR-Spheres® (Sirtex Medical Limited) and holmium [ ¹⁶⁶ Ho] resin microspheres QuriemSphere® (Terumo Medical), which is undergoing clinical research. , these two microsphere products are radioactive resin microsphere products dispersed in sterile water for injection or 0.9% sodium chloride injection solution. Because of the rapid sedimentation in the dispersion solution, it is easy to block the needle and make such products unable to pass through. Administration is achieved by direct injection from a syringe. In order to achieve the convenience of administration and the purpose of radiation shielding, the administration needs to use the perfusion administration device shown in Figure 1. This administration method requires 20-60ml of injection solution for flushing and the radioactive microspheres along the The catheter is carried into the body. Although this method can achieve better administration, it has obvious limitations. 1. It cannot be used for intratumoral administration due to the large administration volume and can only be used for intravascular administration; 2. It cannot be achieved according to the administration volume. Radioactive microspheres for radioactive dose dosing purposes. These limitations make SIR-Spheres® and QuriemSphere® only suitable for the treatment of solid tumors with abundant arterial blood supply by means of interventional administration through arterial cannulation, and cannot be used for other solid tumors by direct intratumoral injection The treatment of tumors has limited the expansion of its indications. Therefore, development of new formulations is required.

The density of resin microspheres is generally 1.1-1.6g/cm ³ . In order to achieve the purpose of direct injection of resin microspheres, take non-radioactive resin microsphere products as an example: small molecules and peptides developed at home and abroad. Ball products, such as: risperidone sustained-release microspheres, exenatide sustained-release microspheres, etc. are usually made of sodium carboxymethyl cellulose, Span 80, Tween 80, stearic acid, and sodium dodecylbenzenesulfonate. , fatty acid glycerides, etc. are suspending agents, mainly by adjusting the hydrophobicity and viscosity of the solution to achieve the suspension of resin microspheres in the solution. However, such preparations are non-radioactive microsphere products, which can be administered by direct injection after shaking and mixing during use. The possibility of needle blockage is low, and even if the consequences are not serious. For radioactive microsphere products, it is inconvenient to shake well before administration, and if the needle is blocked, the consequences of radioactive leakage may be serious, so higher requirements are placed on the administration process and product design. In addition, the radioactive microsphere product is equivalent to that the content of the drug has been decreasing due to the decay of the radioactive dose over time, so it is usually necessary to recalculate the radioactive dose at the drug delivery site, and to take and activate the drug according to the calculated amount on site. to obtain accurate radiopharmaceutical doses. This process is cumbersome and has a large radiation safety risk. If the radiopharmaceuticals used are homogeneous, such as solutions, the dose to be administered can be determined directly by volume without the need for on-site activity measurements. However, the currently reported radioactive microsphere products, such as the above-mentioned yttrium [ ⁹⁰ Y] resin microspheres SIR-Spheres® and holmium [ ¹⁶⁶ Ho] resin microspheres (QuriemSphere®), are all heterogeneous and cannot pass through the The drug volume is used to accurately determine the dose of radioactive administration.

SUMMARY OF THE INVENTION

In order to solve the technical problems in the background art, the present invention provides a radioactive resin microsphere injection and a preparation method and application, wherein the radioactive resin microsphere injection has low viscosity and good fluidity, and the radioactive resin microspheres are dispersed in the medium. It is uniform and does not settle for a long time, and can be used for direct injection.

In a first aspect, the present invention also provides a radioactive resin microsphere injection.

The applicant found in the research that a certain concentration of sodium alginate solution has a certain suspending effect on the dispersion of resin microspheres in water, but the resin microspheres dispersed in the sodium alginate solution will completely settle within 10 minutes. Further, sodium alginate is combined with divalent metal ions to form a gel, which can not only disperse the resin microspheres uniformly, but also disperse uniformly for a long time without sedimentation in the gel with the optimized formulation.

Specifically, a radioactive resin microsphere injection, each 1 ml of the radioactive resin microsphere injection includes: 0.1-300 mg of radioactive resin microspheres, and 1-0.75 ml of hydrogel resin microspheres.

Further research found that by optimizing the ratio and dosage of sodium alginate and divalent metal ions, the resin microsphere injection can maintain good fluidity while ensuring that the resin microspheres do not settle, which can be achieved by direct injection. Dosing. By adding a small amount of divalent metal ions, the viscosity of sodium alginate solution decreases significantly. For example, the viscosity of 0.2% sodium alginate solution is about 30 mPa·S. The viscosity of the hydrogel is also different. When the mass ratio of sodium alginate to calcium ion is 1:0.05-0.15, the viscosity of the hydrogel formed is 5-20mPa·S. The decrease in viscosity makes the resistance of the injection process smaller, the needle adaptability is better, the injection becomes easier, the air bubbles in the injection are easier to discharge, and more importantly, the viscosity of the radioactive resin microspheres is reduced in the hydrogel at the same time. The dispersion becomes more uniform and the radioactive resin microspheres do not settle for a long time.

Specifically, the mass ratio of the sodium alginate to the divalent metal ion is 1:(0.02-0.3), preferably 1:(0.05-0.15).

Further, the viscosity of the hydrogel is between 1-100 mPa·S, preferably 5-20 mPa·S.

Further, the divalent metal ion refers to a divalent metal ion with good biocompatibility, which can be combined with the sodium alginate solution to react instantaneously to form a hydrogel, such as calcium ion, strontium ion, preferably calcium ion.

Further, the radionuclide loaded on the radioactive resin microspheres can be any therapeutic and/or imaging nuclide that can be stably loaded on the resin microspheres, including but not limited to: yttrium [ ⁹⁰ Y], Technetium [ ^99m Tc], Lutetium [ ¹⁷⁷ Lu], Holmium [ ¹⁶⁶ Ho], Samarium [ ¹⁵³ Sm], Rhenium [ ¹⁸⁶ Re], Rhenium [ ¹⁸⁸ Re], Zirconium [ ⁸⁹ Zr], Gallium [ ⁶⁸ Ga], Iodine [ ^{or _ _ _ _ _ _ _} variety.

Further research found that the radioactive resin microsphere injection is macroscopically homogeneous, that is, an equal volume of the injection contains substantially the same amount of radioactive resin microspheres and radioactive dose. Therefore, accurate quantitative administration of radioactive resin microspheres can be achieved by controlling the volume of the injection.

Further research found that the dose of radioactivity contained in a unit volume can be adjusted in the range of 0-5GBq/ml, but when the radioactive dose of the radioactive resin microspheres exceeds 5GBq/ml, the hydrogel undergoes radiation degradation in a short time, which makes the The viscosity of the composition dropped significantly and the homogeneity was destroyed.

Specifically, the radioactivity of the radioactive resin microspheres is 0-5 GBq per milliliter of the injection, so that the radioactive concentration of the radioactive resin microspheres can be adjusted within a certain range.

Further research found that the particles of the radioactive resin microspheres with a particle size of less than 1 μm can be uniformly and stably dispersed in an aqueous solution of a macromolecular suspending agent such as sodium carboxymethyl cellulose, while the particles with a particle size of 1-1000 μm in ordinary high Molecular suspending agent solution cannot be uniformly and stably dispersed for a long time, but can be uniformly and stably dispersed for a long time in calcium alginate hydrogel. However, when the particle size of resin microspheres is larger than 300 μm, it is difficult to be administered by direct injection, and the particles with particle size less than 20 μm are easy to migrate to other tissues and organs in the body.

Specifically, the particle size of the radioactive resin microspheres is 1-1000 μm, preferably 20-300 μm, so that the radioactive resin microspheres are uniformly dispersed in the hydrogel system.

Further research found that polystyrene microspheres, polyethylene microspheres, polydivinylbenzene microspheres, polylactic acid microspheres, polyglycolide lactide microspheres, polylactide microspheres, chitosan microspheres The radioactive resin microspheres prepared by using spheres, calcium alginate microspheres, dextran microspheres, and polyalbumin microspheres as carriers can achieve stable and uniform dispersion in the hydrogel.

Further, the radioactive resin microspheres comprise radioactive resin microspheres prepared by any method, including but not limited to: polystyrene microspheres, polyethylene microspheres, polydivinylbenzene microspheres, polylactic acid microspheres, Any one or more of polyglycolide lactide microspheres, polylactide microspheres, chitosan microspheres, calcium alginate microspheres, dextran microspheres, and polyalbumin microspheres.

In the second aspect, the present invention also provides a method for preparing a radioactive resin microsphere injection, including the following two preparation methods:

In a specific embodiment, the radioactive resin microspheres and the hydrogel are directly mixed uniformly, and the specific steps include:

(1) Dissolve a certain amount of sodium alginate in an appropriate amount of sterile water for injection, filter and sterilize the filter membrane, and then add a certain amount of filter-sterilized calcium chloride solution, and mix well to obtain calcium alginate hydrogel , for A1 agent;

(2) Dispense a certain amount of aqueous solution of radioactive resin microspheres and sterilize them with moist heat, which is the B1 agent;

(3) Before use, use a syringe to mix agent A1 and agent B1, mix well, and let stand for a while to remove air bubbles in the preparation.

In order to facilitate clinical use, in another specific embodiment, the radioactive resin microsphere solution containing divalent metal ions and the alginic acid solution are uniformly mixed, and the specific steps include:

(1) Dissolve a certain quality of sodium alginate in an appropriate amount of sterile water for injection, filter and sterilize it, then package and seal to obtain a sterile sodium alginate solution, which is agent A2;

(2) Disperse a certain amount of radioactive resin microspheres in a certain amount of sterile calcium chloride solution, and aseptically subpackage to obtain a sterile calcium ion-containing radioactive resin microsphere solution, which is agent B2;

(3) Use a syringe to inject the A2 agent obtained above into the B2 agent, mix well, and let it stand for a while to remove the air bubbles in the preparation.

In a specific embodiment, the filter membrane is preferably a sterile filter membrane with a pore size of 0.22 μm.

When the present invention is in use, it is preferable to package the A1 agent and the B1 agent together, or to send the A2 agent and the B2 agent combined package as a complete set of products to the hospital to be mixed and formulated by the hospital before use.

The method of the second aspect of the present invention is a method of preparing the radioactive resin microsphere injection of the first aspect of the present invention.

In the third aspect, the present invention also provides the radioactive resin microsphere injection according to the first aspect of the present invention and the radioactive resin microsphere injection prepared by the method according to the second aspect of the present invention, which are used in the preparation of the radioactive resin microsphere injection for the treatment of tumors. application in medicine. The tumors include, but are not limited to, solid tumors such as pancreatic cancer, liver cancer, breast cancer, and prostate cancer.

Further, the drug contains radioactive resin microspheres and hydrogels.

Further, the medicine comprises sodium alginate and radioactive resin microspheres containing divalent metal ions.

Further research found that the calcium alginate hydrogel of the present invention and the calcium ions in the tumor tissue can further react to generate calcium alginate gel. The calcium alginate gel is different from the hydrogel, and its viscosity is much larger than that of the hydrogel. It has no fluidity in the tissue, and it is not easy to move in the tissue after being fixed. This method is beneficial for the radioactive resin microsphere product to be fixed in the solid tumor and not easily transferred to other tissues and organs, which can further reduce the potential safety risk of the radioactive resin microsphere product during the treatment process.

The radioactive resin microsphere injection of the present invention can be administered by direct injection, or can be administered by injection after intervention by a puncture needle.

Specifically, when the tumor is a superficial or superficial tumor, the drug is administered intralesional by direct injection; while deep solid tumors such as pancreatic cancer, liver cancer, and glioma can be guided by ultrasound Under the puncture needle intervention or under the guidance of endoscopic ultrasonography for intratumoral injection. The killing and killing of solid tumors are achieved by local high-dose radioactive radiation to achieve tumor treatment.

The drug can be used for local direct injection of the tumor, and after the drug reaches the lesion site, it can react with calcium ions in the tissue fluid to form a gel, so that the hydrogel gradually loses its fluidity, which is beneficial to fix the radioactive resin microspheres on the site. and reduce the toxic and side effects to other tissues or organs during local radiotherapy.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention significantly reduces the viscosity of the sodium alginate solution by preparing the sodium alginate solution into a hydrogel, so that the injection is not easy to generate bubbles or the bubbles are easily discharged, and the needleability is improved while improving the radioactive resin microspheres in the liquid medium. The dispersion is uniform and does not settle in the liquid phase for a long time. At the same time, the purpose of fixing the radioactive resin microspheres in the tumor is achieved through the further in situ gelation of the hydrogel in the tumor. On the premise of in vivo distribution of the microspheres, the safety risk of its clinical use is reduced.

The radioactive resin microspheres of the present invention are used to prepare a drug for treating tumors, the drug is directly injected into the tumor, and the drug can react with calcium ions in the tissue fluid after reaching the lesion site to form a gel, so that the hydrogel is gradually lost The fluidity is beneficial to fix the radioactive resin microspheres at the lesion site and reduce the toxic and side effects to other tissues or organs during local radiotherapy.

The present invention provides a new and effective suspension system for resin microspheres or radioactive resin microspheres, which can be gelled in situ in tissue, and solves the problem that the radioactive resin microspheres are not easy to be directly injected and the radioactive resin microspheres are not easy to be injected directly. In the process of resin microsphere administration, the radioactive dose cannot be directly quantified by the administration volume.

Description of drawings

Fig. 1 is the perfusion administration device of radioactive microspheres in the background technology;

Fig. 2 is in Example 11 of the present invention, the suspension state comparison diagram of each sample after shaking up and standing for 3 hours;

3 is a PET scan image of the SD rat liver after local injection of the injection in Example 1 for 72 hours in Example 12 of the present invention.

Detailed ways

The specific embodiments of the present invention will be further described below with reference to the embodiments and the accompanying drawings. It should be noted here that the descriptions of these embodiments are used to help the understanding of the present invention, but do not constitute a limitation of the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

Example 1

A method for preparing yttrium [ ⁹⁰ Y] resin microsphere injection, the method comprising the following steps:

Dissolve 20 mg of sodium alginate in 10 ml of sterile water for injection, pass through a 0.22 μm sterile filter membrane, add 10 ml of 0.45 g/L sterile calcium chloride solution, and mix to obtain a viscosity of 16.6 mPa·S (about 20 ℃) calcium alginate hydrogel, which is agent A1; 50 mg of yttrium [ ⁹⁰ Y] resin microspheres are dispersed in 1 ml of sterile water for injection, packaged, and sterilized by moist heat at 121 ℃-15min for use, which is agent B1 ; Add the A1 agent obtained above into the B1 agent, and mix well. The radioactive resin microspheres did not start to settle within 2 hours of the injection.

Example 2

A method for preparing yttrium [ ⁹⁰ Y] resin microsphere injection, the method comprising the following steps:

Dissolve 20 mg of sodium alginate in 10 ml of sterile water for injection, pass through a 0.22 μm sterilizing filter membrane, and encapsulate it for later use as agent A2. Disperse 100 mg of yttrium [ ⁹⁰ Y] resin microspheres in 1 ml of sterile water for injection containing 5 mg of calcium chloride, encapsulate, sterilize with moist heat at 121° C.-15 min, and use it as agent B2. Add the A2 agent obtained above to the B2 agent, and mix well. The radioactive resin microspheres did not start to settle within 2 hours of the injection.

Example 3

A method for preparing holmium [ ¹⁶⁶ Ho] resin microsphere injection, the method comprises the following steps:

Dissolve 20 mg of sodium alginate in 10 ml of sterile water for injection, pass through a 0.22 μm sterilizing filter membrane, and encapsulate it for later use as agent A2. Disperse 300 mg of holmium [ ¹⁶⁶ Ho] resin microspheres in 1 ml of sterile water for injection containing 5 mg of calcium chloride, encapsulate, sterilize with moist heat at 121°C for 15 minutes, and use it as agent B2. Add the A2 agent obtained above to the B2 agent, and mix well. The radioactive resin microspheres did not start to settle within 2 hours of the injection.

Example 4

A method for preparing iodine [ ¹³¹ I] resin microsphere injection, the method comprising the following steps:

Dissolve 20 mg of sodium alginate in 10 ml of sterile water for injection, pass through a 0.22 μm sterile filter membrane, add 10 ml of 0.6 g/L sterile calcium chloride solution, and mix to obtain a viscosity of 8.4 mPa·S (approximately 20°C) calcium alginate hydrogel, as A1 agent. Disperse 100 mg of iodine [ ¹³¹ I] resin microspheres in 1 ml of sterile water for injection, encapsulate, sterilize by moist heat at 121° C.-15 min, and use it as agent B1. Add the A1 agent obtained above to the B1 agent and mix well. The radioactive resin microspheres did not start to settle within 2 hours of the injection.

Example 5

A method for preparing a gallium [ ⁶⁸ Ga] resin microsphere injection, the method comprising the following steps:

Dissolve 20 mg of sodium alginate in 10 ml of sterile water for injection, pass through a 0.22 μm sterile filter membrane, add 10 ml of 0.6 g/L sterile calcium chloride solution, and mix to obtain a viscosity of 8.4 mPa·S (approximately 20°C) calcium alginate hydrogel, as A1 agent. Disperse 200 mg of gallium [ ⁶⁸ Ga] resin microspheres in 1 ml of sterile water for injection, encapsulate, sterilize with moist heat at 121°C for 15 min, and use it as agent B1. Add the A1 agent obtained above to the B1 agent and mix well. The radioactive resin microspheres did not start to settle within 3 hours of the injection.

Example 6

A method for preparing a zirconium [ ⁸⁹ Zr] resin microsphere injection, the method comprising the following steps:

Dissolve 20 mg of sodium alginate in 10 ml of sterile water for injection, pass through a 0.22 μm sterile filter membrane, add 10 ml of 0.6 g/L sterile calcium chloride solution, and mix to obtain a viscosity of 8.4 mPa·S (approximately 20°C) calcium alginate hydrogel, as A1 agent. Disperse 25 mg of zirconium [ ⁸⁹ Zr] resin microspheres in 1 ml of sterile water for injection, encapsulate, sterilize by moist heat at 121°C for 15 minutes, and use it as agent B1. Add the A1 agent obtained above to the B1 agent and mix well. The radioactive resin microspheres did not start to settle within 3 hours of the injection.

Example 7

A method for preparing thorium [ ²²⁷ Th] resin microsphere injection, the method comprises the following steps:

Dissolve 20 mg of sodium alginate in 10 ml of sterile water for injection, pass through a 0.22 μm sterile filter membrane, add 10 ml of 0.5 g/L sterile calcium chloride solution, and mix to obtain a viscosity of 8.0 mPa·S (approx. 20°C) calcium alginate hydrogel, as A1 agent. Disperse 100 mg of thorium [ ²²⁷ Th] resin microspheres in 1 ml of sterile water for injection, encapsulate, sterilize with moist heat at 121°C for 15 minutes, and use it as agent B1. Add the A1 agent obtained above to the B1 agent and mix well. The radioactive resin microspheres did not start to settle within 3 hours of the injection.

Example 8

A method for preparing a diagnosis and treatment integrated radioactive resin microsphere injection, the method comprises the following steps:

Dissolve 20 mg of sodium alginate in 10 ml of sterile water for injection, pass through a 0.22 μm sterile filter membrane, add 10 ml of 0.5 g/L sterile calcium chloride solution, and mix to obtain a viscosity of 8.0 mPa·S (approx. 20°C) calcium alginate hydrogel, as A1 agent. Disperse 100 mg of yttrium [ ⁹⁰ Y] resin microspheres and 20 mg of gallium [ ⁶⁸ Ga] resin microspheres in 1 ml of sterile water for injection, encapsulate, sterilize at 121° C.-15 min with moist heat, and use it as agent B1. Add the A1 agent obtained above to the B1 agent and mix well. The radioactive resin microspheres did not start to settle within 2 hours of the injection.

Other types of radioactive resin microsphere injections can also be obtained by the same or similar methods and processes described above, and will not be described one by one here.

Example 9

To study the injection and needle suitability of different radioactive resin microsphere injection types in tissues:

Take fresh chicken breast meat purchased from the market, cut it into pieces (about 3*3*2cm), use a 1ml syringe to draw 0.5ml of the resin microsphere suspension for injection, insert the needle from the surface (depth 1cm), and insert the syringe vertically , all samples were injected slowly at a single point. Tests show that the dispersion and suspension properties of resin microspheres in sodium carboxymethyl cellulose solution are much better than those of sodium alginate solution with the same concentration. Comparative Study. The injections in Example 1 and Example 2, and the radioactive resin microspheres were dispersed in 0.1% sodium carboxymethyl cellulose solution, 0.2% sodium carboxymethyl cellulose solution, 0.5% sodium carboxymethyl cellulose solution, 1.0% carboxymethyl cellulose sodium solution for various injections of chicken tissue injection administration. During the administration process, the needle suitability was judged according to whether the injection was smooth and the resin microspheres remained on the needle. The results are shown in Table 1.

During the test, it was found that both Example 1 and Example 2 showed good needle suitability, the administration was smooth and the administration resistance was small; the radioactive resin microsphere series dispersed with different concentrations of sodium carboxymethyl cellulose solution also had better performance. Both 0.5% and 1.0% sodium carboxymethyl cellulose have larger concentrations, and the injection is slightly difficult; while 0.1% and 0.2% sodium carboxymethyl cellulose solutions are both Occasional needle blockage occurred, but the administration could be completed after adjusting the injection position.

Table 1. Needle suitability studies and excipient dosage data for different types of injections

.

Example 10

Study on the homogeneity of different radioactive resin microsphere injection types:

Take 10ml of the injections of Examples 1-6 and place them in a 10ml measuring cylinder, then sample 500 μL at 10, 8, 6, 4, and 2ml scales and use a radioactivity meter to measure the activity, and carry out 2 samplings at each scale. Test and take the average. The activities obtained by sampling at different scales are shown in Table 2.

Table 2. Uniformity test of the distribution of radioactive resin microspheres for different injection formulations

.

The results in Table 2 show that the activities of samples and tests in Examples 1-6 are basically the same, and the differences are all within 5%, which proves that the radioactive resin microsphere injection itself is uniform in the examples, and the volume of the liquid medicine can be used. Perform accurate calculations of radioactivity.

Example 11

Study on the sedimentation time of different radioactive resin microsphere injection types:

About 4ml of radioactive resin microspheres of different injection types were placed in a 10ml vial, shaken well and left to stand, and the time when the resin microspheres completely settled on the bottom of the bottle was recorded. Example 1, Example 2 and 100mg of radioactive resin microspheres were dispersed in 10ml of radioactive resin microspheres were respectively studied in 0.1% sodium carboxymethyl cellulose solution, 0.2% sodium carboxymethyl cellulose solution, 0.5 % Sodium carboxymethyl cellulose solution, 1.0% sodium carboxymethyl cellulose solution, shake well and let stand to record the sedimentation time. The results are shown in Table 3. Figure 2 shows the comparison of the dispersion state of each injection after shaking well for a certain period of time. The samples in Figure 2 correspond to the resin microspheres dispersed in the 6 media from top to bottom in Table 3 from left to right.

Table 3. Sedimentation studies and viscosity of radioactive resin microspheres in different solution media

.

It can be seen from the data in Table 3 and Figure 2 that the resin microspheres of the radioactive resin microsphere injection prepared in Example 1 and Example 2 are uniformly dispersed in the liquid medium and do not settle for a long time. The time for uniform dispersion without sedimentation all exceeded 3 hours. The radioactive resin microspheres dispersed in 1.0% carboxymethyl cellulose solution had better suspending properties but would still settle completely within 1 hour. The radioactive resin microsphere injection of the present invention has obvious advantages in the dispersion uniformity and stability of the microspheres.

Example 12

Administration and in vivo distribution of radioactive resin microsphere injection:

Experimental animals: 6 SD rats, half male and half male, weighing 300-430 g. Administration process: The rats were anesthetized and the abdomen was opened, and the hepatic lobe was fixed by lightly pressing the middle lobe margin with a cotton swab. The gauze cutting hole is lightly covered on the injection surface, and the 1ml syringe sucks the radioactive microsphere injection and injects it directly into the liver. Injection of resin microsphere injection of Example 6 100uL (about 60μCi), surgically sutured to close the abdomen. 72 hours after administration, PET examination was performed, placed under the scanning probe, and scanned for 10-15 minutes to observe the distribution of radioactivity. The distribution results of radioactive microspheres are shown in Figure 3.

It can be seen from Fig. 3 that the zirconium [ ⁸⁹ Zr] resin microspheres are concentrated in the liver tissue after being injected into the liver tissue for 72 hours, and there is no metastasis to other organs and tissues. It is proved that the new injection can be concentrated in the organs where the injection site is located after direct injection and is not prone to distant metastasis, which is conducive to the realization of true local treatment in the process of tumor treatment without harming normal tissues and thus ensuring the safety of patients.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand: It is still possible to modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements for some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the technical solutions of the embodiments of the present invention. range.

Claims (16)

1. A radioactive resin microsphere injection, characterized in that each 1 ml of the radioactive resin microsphere injection contains: 0.1-300 mg of radioactive resin microspheres and 1-0.75 ml of hydrogel.
2. The radioactive resin microsphere injection according to claim 1, wherein the radioactivity of the radioactive resin microspheres is 0-5 GBq of radioactive resin microspheres per milliliter of the injection.
3. The radioactive resin microsphere injection according to claim 1 or 2, wherein the radionuclide loaded on the radioactive resin microspheres can be any therapeutic and/or imaging nuclide that can be stably loaded on the resin microspheres The nuclides used include but are not limited to: yttrium [ ⁹⁰ Y], technetium [ ^99m Tc], lutetium [ ¹⁷⁷ Lu], holmium [ ¹⁶⁶ Ho], samarium [ ¹⁵³ Sm], rhenium [ ¹⁸⁶ Re], rhenium [ ¹⁸⁸ Re] ], zirconium [ ⁸⁹ Zr], gallium [ ⁶⁸ Ga], iodine [ ¹³¹ I], iodine [ ¹²⁵ I], phosphorus [ ³² P], copper [ ⁶⁴ Cu], radium [ ²²³ Ra], thorium [ ²²⁷ Th], Any one or more of actinium [ ²²⁵ Ac] and lead [ ²¹² Pb].
4. The radioactive resin microsphere injection according to claim 1, wherein the radioactive resin microspheres include but are not limited to: polystyrene microspheres, polyethylene microspheres, polydivinylbenzene microspheres, polylactic acid microspheres Balls, polyglycolide lactide microspheres, polylactide microspheres, chitosan microspheres, calcium alginate microspheres, dextran microspheres, polyalbumin microspheres.
5. The radioactive resin microsphere injection according to claim 1, wherein the hydrogel is prepared by a mixed reaction of sodium alginate solution and divalent metal ions with good biocompatibility.
6. The radioactive resin microsphere injection according to claim 5, wherein the mass ratio of the sodium alginate to the divalent metal ion is 1:(0.02-0.3), preferably 1:(0.05-0.15).
7. The radioactive resin microsphere injection according to claim 5 or 6, wherein the viscosity of the hydrogel is 1-100 mPa·S, preferably 5-20 mPa·S.
8. A method for preparing a radioactive resin microsphere injection is characterized in that, the method comprises: uniformly mixing the radioactive resin microsphere and the hydrogel.
9. A method for preparing a radioactive resin microsphere injection, characterized in that the method comprises: uniformly mixing a radioactive resin microsphere solution containing divalent metal ions and a sodium alginate solution.
10. A radioactive resin microsphere injection prepared by the method according to claim 8 or 9.
11. The application of the radioactive resin microsphere injection according to any one of claims 1-7 and 10 in the preparation of a medicament for treating tumors.
12. The use of claim 11, wherein the drug comprises radioactive resin microspheres and hydrogels.
13. The application of claim 11, wherein the drug comprises sodium alginate and radioactive resin microspheres containing divalent metal ions.
14. The application according to any one of claims 11-13, wherein when the tumor is a superficial or superficial tumor, the drug is administered intralesional by direct injection, and local high-dose radioactivity is used for intralesional administration. Radiation achieves killing and killing of solid tumors to achieve tumor treatment.
15. The application according to any one of claims 11-13, wherein when the tumor is a deep-body solid tumor, the drug is injected into the tumor through ultrasound-guided puncture needle intervention or endoscopic ultrasound-guided intratumoral injection. Drugs can kill and kill solid tumors through local high-dose radioactive radiation to achieve tumor treatment.
16. The application according to claim 11, wherein the drug can be in situ gelled in the tumor to achieve the function of confining the radioactive resin microspheres in the tumor, avoiding the radioactive resin microspheres during local radiotherapy. The distribution of the ball outside the tumor tissue causes damage to other tissues.