A radioactive embolism microsphere, a radioactive embolism microsphere preparation, a preparation method thereof and application thereof

Abstract

This invention relates to the field of tumor treatment technology, and particularly to a radioembolization microsphere, a radioembolization microsphere formulation, its preparation method, and its application. The radioembolization microsphere provided by this invention comprises radioactive particles and an organic phase containing iodized oil. The radioactive particles are coated on an interface with the organic phase containing iodized oil as its core. The radioactive particles comprise a radionuclide and an inorganic matrix, with the radionuclide immobilized in the inorganic matrix. The particle size of the radioactive particles is 0.01~10 μm; the particle size of the radioembolization microspheres is 0.01~1000 μm. Applying the radioembolization microspheres of this invention to embolization therapy can maintain long-term retention at the tumor site and reduce radiation damage to non-tumor sites. The iodine component provides X-ray imaging functionality, enabling integrated diagnosis and treatment, radioactive dose tracking, and accurate measurement of radiation dose.

Description

Technical Field

[0001] This invention relates to the field of tumor treatment technology, and in particular to a radioembolization microsphere, a radioembolization microsphere formulation, its preparation method, and its application. Background Technology

[0002] Cancer is one of the major diseases that seriously threaten human health. Radiotherapy is a local treatment method that uses ionizing radiation to inhibit and kill tumor cells, and it is one of the main means of treating malignant tumors in clinical practice. Among them, intratumoral radiotherapy (also known as brachytherapy or internal irradiation therapy) is a treatment method in which a radiation source is directly implanted or delivered into the tumor tissue. Compared with traditional external beam radiotherapy, internal irradiation therapy can precisely concentrate high doses of radiation on the tumor target area while minimizing damage to surrounding normal tissues, thus showing unique advantages in the treatment of various solid tumors.

[0003] For tumors with rich blood supply, such as liver cancer, transarterial radioembolization is an important treatment strategy. This technique utilizes the fact that tumors are primarily supplied by arteries. An embolic agent carrying a radionuclide is injected into the tumor's blood vessels via a catheter. While blocking the tumor's blood supply, the radiation released by the radionuclide (such as alpha or beta rays) kills tumor cells at close range and continuously. This method can achieve extremely high drug and radiation doses locally on the tumor, significantly improving the targeting and effectiveness of treatment.

[0004] Currently, the carriers used clinically for interventional radiotherapy mainly fall into two categories: radioactive iodized oil and radioactive microspheres. Radioactive iodized oil, for example, was previously used... 131 I-labeled iodized oil, although utilizing the affinity of iodized oil for liver tumor tissue, has serious adverse reactions such as easy shedding of radioactive iodine, leading to excessive uptake by the thyroid gland in patients, and easy diffusion to the lungs causing radiation damage. It has been gradually withdrawn from the market.

[0005] Therefore, radioactive microspheres have become the mainstream in current research and application. Existing radioactive microspheres are mainly divided into two types: glass microspheres and resin microspheres. The main disadvantage of glass microspheres is their high specific gravity and density, which makes them prone to sedimentation in the blood and difficult to reach the more peripheral micro-arteries with blood flow. This results in uneven distribution within the tumor, preventing some tumor tissue from receiving effective irradiation and thus affecting the overall therapeutic effect. The main disadvantage of resin microspheres is their lower specific activity, which means that to achieve the same therapeutic dose, a larger number of microspheres need to be injected. This not only increases the complexity of the procedure but also increases the risk of off-target embolism due to blood reflux.

[0006] In summary, existing radioactive carriers used for intratumoral radiotherapy have significant drawbacks. Both glass microspheres and resin microspheres face challenges such as uneven distribution due to density mismatch, potential radioactive material leakage due to unstable mechanical properties, and the difficulty in balancing efficient embolization with uniform radiation. These problems not only limit therapeutic efficacy, reduce effective tumor killing power, and increase the risk of tumor recurrence, but also pose safety risks in clinical application.

[0007] Therefore, there is an urgent need to develop a new type of radioembolization material that possesses high stability and high radiolabeling rate, good biocompatibility and fluidity, and can achieve uniform distribution and firm embolization within tumor vessels, thereby overcoming the shortcomings of existing technologies and providing cancer patients with safer and more effective treatment options. Summary of the Invention

[0008] This invention provides a radioembolization microsphere, a radioembolization microsphere formulation, a preparation method thereof, and its application, in order to solve the aforementioned problems existing in the prior art.

[0009] According to a first aspect of the present invention, the present invention provides a radioactive embolization microsphere comprising radioactive particles and an organic phase containing iodized oil, wherein the radioactive particles are coated on an interface with the organic phase containing iodized oil as a core; the radioactive particles comprise a radionuclide and an inorganic matrix, wherein the radionuclide is fixed in the inorganic matrix; the particle size of the radioactive particles is 0.01~10 μm; and the particle size of the radioactive embolization microsphere is 0.01~1000 μm.

[0010] The radioembolization microspheres provided by this invention encapsulate radioactive particles at the interface of an organic phase core containing iodized oil, constructing a unique core-shell structure. This structure can firmly lock in radioactive materials, significantly reducing the risk of radionuclide leakage and thus improving treatment safety. Simultaneously, the iodized oil core provides X-ray imaging capability, facilitating intraoperative observation and localization. The defined particle size range ensures that the microspheres can effectively embolize tumor-feeding vessels of different diameters, achieving a dual therapeutic effect of physical blockage and internal radioactive irradiation.

[0011] The preferred particle size of the radioactive embolization microspheres is 0.01~0.5μm, 1~10μm, 40~80μm, 100~200μm, or 300~500μm. Such radioactive embolization microspheres can adapt to tumor-feeding vessels of different diameters, achieving effective embolization and sustained retention from main blood vessels to peripheral microvessels. Simultaneously, their semi-solid nature may endow the microspheres with a certain degree of deformability, allowing for more uniform distribution within the blood vessel.

[0012] In this invention, the radionuclide is any α, β, γ, etc., capable of forming stable precipitates / complexes for therapeutic and / or medical imaging, including but not limited to... 43 Sc, 44 Sc, 46 Sc, 47 Sc, 90 Y, 86 Y, 88 Y, 134 La, 135 La, 139 Ce, 141 Ce, 140 Pr, 143 Pr, 149 Pm, 153 Sm, 153 Gd, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 157 Dy, 166 Ho, 165 Er, 169 Er, 167 Tm, 169 Yb, 172 Lu, 177 Lu, 11 C, 14 C, 13 N, 15 O, 18 F, 32 P, 35 S, 34m Cl, 36 Cl, 38 Cl, 39 Cl, 38 K, 42 K, 43 K, 45 Ca 44 Ti, 46 Ti, 48 Cr, 51 Cr, 52 Mn, 52m Mn, 54 Mn, 52 Fe, 55 Fe, 59 Fe, 55 Co, 57 Co, 58 Co, 59 Co, 63 Ni, 60 Cu, 61 Cu,62 Cu, 67 Cu, 64 Cu, 63 Zn, 69m Zn, 65 Zn, 68 Ga, 66 Ga, 67 Ga, 68 Ge, 72 As, 73 As, 74 As, 75 Se, 75 Br, 76 Br, 77 Br, 82 Br, 81 Rb, 82 Rb, 84 Rb, 86 Rb, 89 Sr, 85 Sr, 87 mSr, 90 Sr, 89 Zr, 90 Nb, 95 Nb, 99m Tc, 94m Tc, 95 Tc, 99 Mo, 103 Ru, 103m Rh, 105 Rh, 103 Pd, 109m Ag, 111 Ag, 110m In, 111m In, 113m In, 114m In, 115m In, 117m Sn, 123m Te, 122 I, 123 I, 124 I, 125 I, 131 I, 129 Cs, 134 Cs, 137 Cs, 133m Ba, 127m Ba, 178 Ta, 191m Ir, 192 Ir, 191 Pt, 193m Pt, 195 Pt, 195mPt, 195m Au, 198 Au, 199 Au, 197 Hg, 197m Hg, 203 Hg, 186 Re, 188 Re, 199 Tl, 212 Tl, 203 Pb, 212 Pb, 205 Bi, 212 Bi, 213 Bi, 204 Bi, 206 Bi, 207 Bi, 211 At, 223 Ra, 224 Ra, 226 Ra, 225 Ac, 226 Th, 227 Th, any one or more.

[0013] In some specific embodiments, the radionuclide is preferably... 64 Cu、 90 Y、 177 Lu、 224 Ra.

[0014] According to the radioactive embolization microspheres of the present invention, the inorganic matrix is ​​prepared from a metal salt and a precipitant, wherein the metal ions in the metal salt include Ca. 2+ Y 3+ Lu 3+ Pb 2+ and Ag + One or more of the following, wherein the anion in the precipitant includes PO4. 3- HPO4 2- H2PO4 - CO3 2- C2O4 2- SO4 2- S 2- Cl - and BiO3 - One or more of the following; The molar ratio of the metal ions in the metal salt to the precipitant is 1:(0.5~4.5), preferably 1:(0.5~2.5).

[0015] This invention clarifies the types of metal ions and precipitant anions in metal salts. Through a simple co-precipitation reaction, various therapeutic radionuclides are efficiently and stably immobilized on an inorganic matrix, achieving high labeling rates and good in vivo stability, laying the foundation for the subsequent preparation of highly efficient radioactive microspheres.

[0016] According to the radioactive embolization microspheres of the present invention, the organic phase containing iodized oil is iodized oil or a mixture of iodized oil and other injectable oils; the other injectable oils include one or more of soybean oil, cottonseed oil, corn oil, sesame oil, safflower oil, medium-chain triglycerides, olive oil and fish oil.

[0017] This invention clarifies that the organic phase containing iodized oil is iodized oil or a mixture of it and other injectable oils. On the one hand, this ensures that the microspheres have excellent CT imaging effects as an embolic agent, realizing integrated diagnosis and treatment. On the other hand, by mixing with other injectable oils, the viscosity, flowability and other physical properties of the microspheres can be adjusted, making them better adaptable to different clinical needs, optimizing their delivery and distribution in blood vessels, thereby improving the uniformity and controllability of the embolization effect.

[0018] In some specific embodiments, the organic phase containing iodized oil is a mixed oil phase prepared by iodized oil and other injectable oils in a volume ratio of (1-5):1.

[0019] According to a second aspect of the present invention, the present invention also provides a radioembolization microsphere formulation comprising the above-described radioembolization microspheres.

[0020] In this invention, the radioactive embolization microsphere formulation can be a suspension, gel, emulsion, etc.

[0021] According to the radioembolization microsphere formulation provided by the present invention, the mass percentage of radioactive particles in the radioembolization microsphere formulation is 0.1-10%.

[0022] The radioembolization microsphere formulation provided by the present invention also loads a drug, including one or more of DNA damaging agents, DNA repair inhibitors, cell cycle arrestors, and immunomodulators. For example: (i) Chemotherapy drugs: doxorubicin, epirubicin, paclitaxel, docetaxel, irinotecan, capecitabine, cisplatin, oxaliplatin, fluorouracil, gemcitabine, capecitabine, methotrexate, etc.

[0023] (ii) Immunotherapy drugs: interleukins, interferon-alpha, trastuzumab, bevacizumab, pembrolizumab, nivolumab, ipilimumab, atezolizumab, etc.

[0024] (iii) DNA repair inhibitors: olaparib, rucapanib, nirapanib, pamiparib, AZD6738, M3814.

[0025] This invention incorporates chemotherapy, immunotherapy, and other drugs into a radioembolization microsphere formulation, constructing a multimodal combined treatment platform that enhances the tumor-killing effect through the synergistic effect of radiotherapy with chemotherapy or immunotherapy.

[0026] The radioembolization microsphere formulation provided by the present invention includes a loaded drug comprising a DNA damaging agent, a DNA repair inhibitor, a cell cycle arrestor, and an immunomodulator added to the aqueous or oil phase of the radioembolization microsphere formulation.

[0027] According to a third aspect of the present invention, the present invention also provides a method for preparing the above-mentioned radioactive embolization microsphere formulation, comprising the following steps: (1) A particulate suspension is prepared by reacting soluble radioactive nuclide salts, aqueous solutions containing metal salts and aqueous solutions containing precipitants as raw materials, and the pH value is adjusted to 5.5~9.0, preferably 6.5~8.0; (2) The particulate suspension after pH adjustment is added to the organic phase containing iodized oil and radioactive emulsion is prepared by medical three-way valve, microfluidic chip, membrane emulsification, ultrasonic disruption or high pressure homogenization.

[0028] In the preparation method of this invention, the first step involves a co-precipitation reaction, which stably immobilizes various radionuclides within inorganic particles, achieving efficient radiolabeling and excellent stability, thereby ensuring product safety and therapeutic efficiency. The second step utilizes diverse emulsification techniques (such as medical three-way valves, microfluidic chips, and high-pressure homogenization) to combine drug-loaded particles with an organic phase containing iodized oil. This not only endows the final formulation with excellent CT imaging capabilities for integrated diagnosis and treatment but also allows for flexible and precise control of the embolization microsphere particle size distribution according to clinical needs, ensuring effective targeted embolization of tumor vessels of different sizes. This significantly enhances the industrialization potential and clinical application value of this preparation method.

[0029] According to the preparation method of the radioactive embolization microsphere formulation of the present invention, step (1) is to first mix a soluble radioactive nuclide salt, an aqueous solution containing a metal salt and an aqueous solution containing a precipitant to obtain a coarse particle solution; then, the coarse particle solution is mixed by high-speed stirring, ultrasound (including ultrasound crushing and ordinary ultrasound) or three-way mixing to obtain a radioactive particle suspension.

[0030] In the preparation method of the radioactive embolization microsphere formulation of the present invention, basic radioactive particles are first rapidly generated by simple solution mixing. However, the crude solution of particles obtained by this direct mixing may have problems such as uneven particle size and easy agglomeration. Subsequently, the crude solution is subjected to secondary treatment by physical means such as high-speed stirring, ultrasonic crushing or three-way mixing, which can effectively break up large particles and disperse agglomerates, thereby obtaining a radioactive particle suspension with smaller particle size, more uniform distribution and more stable suspension.

[0031] Preferably, the coarse particle solution is subjected to ultrasound to obtain a radioactive particle suspension; the total power of the ultrasound is 100~800W, preferably 200~300W; the ultrasound time is 1~60min, preferably 2~40min.

[0032] Preferably, the mixing temperature is 10~80℃, more preferably 20~60℃.

[0033] In this invention, the crude solution of radioactive particles is fully dispersed and matured by ultrasound. By adjusting the ultrasound parameters, different components can form radioactive particles with a particle size of 1 to 500 nm.

[0034] According to the preparation method of the radioactive embolization microsphere formulation of the present invention, in step (1), the aqueous solution containing metal salt or the aqueous solution containing precipitant further includes a hydrogel matrix and / or a phosphoric acid additive.

[0035] This invention introduces a hydrogel matrix and / or phosphoric acid additive as a highly efficient stabilizer, which can effectively inhibit the aggregation and sedimentation of radioactive particles during the formation process, thereby significantly improving the stability and uniformity of the particle suspension.

[0036] Preferably, the hydrogel matrix is ​​selected from one or more natural or synthetic polymers such as chitosan, Pronico F127, sodium alginate, and sodium hyaluronate; more preferably, the amount of the hydrogel matrix added is 0.5%-30% of the mass of the aqueous solution containing the metal salt or the aqueous solution containing the precipitant, preferably 1-10%. The hydrogel matrix is ​​beneficial to improving the stability of the microspheres. It can be dissolved in the anionic precipitant first, and then react with the cation to form a precipitate; or it can be added after the precipitate is formed, and the dissolution is accelerated.

[0037] Preferably, the phosphoric acid additive is selected from one or more of hexametaphosphate, polyphosphate, pyrophosphate, ethylenediaminetetra(methylenephosphonic acid), pamidronate, and bisphosphonates; more preferably, the amount of phosphoric acid additive added is 0.1-15% of the mass of the aqueous solution containing the metal salt or the aqueous solution containing the precipitant, preferably 1-2%. The phosphoric acid additive is used to effectively inhibit the aggregation of hydrophilic particles, improve the surface potential of particles, and enhance the suspension and stability of microspheres.

[0038] According to the preparation method of the radioactive embolization microsphere formulation of the present invention, the preparation temperature of step (2) is 10~80℃, preferably 20~40℃; the volume ratio of the particulate suspension and the organic phase containing iodized oil is 1:4~4:1.

[0039] This invention precisely defines the key process parameters (temperature and phase volume ratio) in the emulsification step. By setting a mild and optimized temperature range, it ensures the efficient execution of the emulsification process and the chemical stability of each component (such as radionuclides and iodized oil). The wide range of oil-water volume ratios (1:4 to 4:1) provides a flexible control lever, which allows for the customized preparation of embolic microspheres with specific particle sizes and different radioactive loads according to different clinical needs.

[0040] Preferably, when prepared using a medical three-way valve, the number of shearing cycles is 10 to 300, more preferably 60 to 200.

[0041] Preferably, when fabricated using a microfluidic chip, the flow rate ratio of the external water phase to the internal oil phase is (1.5~3.0):1.0, and the aperture size is 0.5~50μm.

[0042] Preferably, when prepared by membrane emulsification, the rotation speed of the external aqueous phase is 10~500 rpm and the pore size is 0.2~100 μm.

[0043] Preferably, when preparing by ultrasonic disruption, the power range is 150~800W, more preferably 200~500W; the ultrasonic time is 1~30mins, more preferably 5~20mins; the ultrasonic time is 2~5s, and the interval time is 2~5s.

[0044] Preferably, when preparing by high-pressure homogenization, the number of cycles is 2 to 9, more preferably 3 to 7; the homogenization pressure is 20 to 100 MPa, more preferably 40 to 80 MPa.

[0045] The preparation method of the radioactive embolization microsphere formulation according to the present invention further includes the following steps: (3) The radioactive emulsion is mixed with the injection solution to obtain the radioactive embolization microsphere formulation.

[0046] This invention greatly improves the clinical applicability and ease of use of the product by diluting concentrated radioactive emulsion with an injection solution to transform it into a final dosage form that can be directly used for clinical injection.

[0047] Preferably, the volume ratio of the radioactive emulsion to the injection solution is 1:(0.1~100), more preferably 1:(0.1~40).

[0048] Preferably, the injection solution used for dilution is selected from one or more of water for injection, sterile water for injection, physiological saline (0.9% sodium chloride solution), and 5% glucose aqueous solution.

[0049] Preferably, the mixing temperature in step (3) is 15~40°C, and the mixing is carried out in a radiation shielding environment.

[0050] Preferably, the preparation method of the radioactive embolization microsphere formulation according to the present invention includes the following steps: (1) First, a soluble radioactive nuclide salt, an aqueous solution containing a metal salt, and an aqueous solution containing a precipitant are mixed to obtain a coarse particle solution; then, the coarse particle solution is subjected to ultrasound to obtain a radioactive particle suspension, and the pH value is adjusted to 6.5~8.0; the total power of the ultrasound is 200~300W; the ultrasound time is 2~40min; the mixing temperature is 20~60℃; the molar ratio of the metal ion in the metal salt to the precipitant is 1:(0.5~2.5); the metal salt is calcium chloride or yttrium chloride, and the precipitant is trisodium phosphate; (2) The particulate suspension after pH adjustment is added to the organic phase containing iodized oil and prepared into a radioactive emulsion by means of a medical three-way valve; the number of shearing cycles during preparation by means of the medical three-way valve is 60 to 200; the preparation temperature is 20 to 40°C; the volume ratio of the particulate suspension to the organic phase containing iodized oil is 3:(3.5-5); (3) The radioactive emulsion is mixed with the injection solution to obtain the radioactive embolization microsphere preparation. The mixing temperature is 15~40℃.

[0051] According to a fourth aspect of the present invention, the present invention also provides the use of the above-described radioembolization microspheres, the above-described radioembolization microsphere formulations, or the radioembolization microsphere formulations prepared by the above-described preparation method in the preparation of tumor drugs or medical kits.

[0052] The radioactive embolization microspheres provided by this invention can be administered via a classic embolization interventional strategy for liver cancer. After entering the hepatic artery through a catheter, the semi-solid microspheres, with their near-blood density and deformability, easily penetrate the liver cancer microarteries. The larger particle size and viscosity of the mixture confine the microspheres within the gradually narrowing blood vessels of the lesion. Even when flushed by blood, they can stably embolize the tumor vessels, thus achieving uniform distribution within the tumor tissue of the target organ. The mechanically blocked composition generates radiation, while the drug dissolved in the liquid phase diffuses at a concentration gradient to the tumor tissue surrounding the microarteries, thereby enhancing radiation sensitivity or producing a synergistic killing effect. Furthermore, the iodized oil's own X-ray deposition properties can serve as a contrast agent in vivo, allowing for real-time detection and tracking of the drug administration process and dosage.

[0053] The radioactive embolization microspheres provided by this invention have a specific gravity close to that of blood and good deformability, allowing them to penetrate deep into the tiny arteries at the tumor's distal end, just like blood. This overcomes the shortcomings of traditional microspheres, which are prone to settling due to their high density or unable to enter small blood vessels due to their rigidity. As a result, they achieve a deeper and more uniform distribution within the tumor tissue, expanding the effective treatment range.

[0054] The radioactive embolization microspheres provided by this invention utilize the selective deposition characteristics of iodized oil on tumor tissue, allowing the microspheres to be permanently anchored within liver cancer lesions. Simultaneously, their suitable particle size and deformability enable them to effectively embolize blood supply vessels and remain firmly confined within the tumor lesion, making leakage into normal tissue difficult. This achieves long-term therapeutic effects while significantly reducing radiation damage to healthy tissues, thus improving treatment safety.

[0055] The radioembolization microspheres provided by this invention have an iodized oil core component that can absorb X-rays, and the embolization preparation itself is a CT contrast agent. This allows doctors to track the drug delivery process, distribution, and dosage in real time under CT guidance, perfectly combining diagnostic imaging with radiotherapy, and achieving efficient and precise integrated diagnosis and treatment.

[0056] The radioembolization microsphere formulation provided by this invention has a unique oil-water two-phase structure, which enables it to simultaneously load and deliver both hydrophilic and hydrophobic drugs. This makes it a powerful combination therapy platform that can combine local internal radiotherapy with chemotherapy or immunotherapy to exert excellent anti-tumor effects through synergistic effects.

[0057] The method for preparing radioembolization microspheres provided by this invention has a simple process flow and is easy to scale up for production. This preparation method can achieve a radionuclide loading rate of over 96% and ensures that the product has a long-term stable particle size and high radiolabeling rate, thereby improving the safety and efficacy of treatment while ensuring reliable product quality and batch stability. Attached Figure Description

[0058] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0059] Figure 1 This is a scanning electron microscope image of yttrium phosphate nanoparticles in Example 1 provided by the present invention.

[0060] Figure 2 This is a hydrated particle size distribution diagram of yttrium phosphate nanoparticles in Example 1 provided by the present invention.

[0061] Figure 3 This is in Embodiment 1 provided by the present invention. 177 Microscopic image of Lu embolized microspheres.

[0062] Figure 4 The 30 days in Embodiment 1 provided by this invention 177 Lu embolized microspheres inverted microscope image.

[0063] Figure 5 This is in Embodiment 1 provided by the present invention. 177 Lu embolization microspheres and their appearance after 30 days of storage.

[0064] Figure 6 This is the appearance of the semi-solid microsphere sample after adding hydrogel excipients in Example 3 of the present invention.

[0065] Figure 7 This is the ultraviolet absorption characteristic diagram and standard curve of pirarubicin provided in Example 4 of the present invention.

[0066] Figure 8 The images show the appearance of the radioactive emulsion diluted with water at different ratios (1:0, 1:1, 1:10, 1:20, 1:40) in Example 5 of the present invention.

[0067] Figure 9 These are inverted microscope images of different ratios (1:0, 1:1, 1:10, 1:20, 1:40) of water-diluted solutions of radioactive emulsion provided in Example 5 of this invention.

[0068] Figure 10 This is the sedimentation of radioactive emulsion diluted with water at different ratios (1:1, 1:10, 1:20, 1:40) in Example 5 of the present invention.

[0069] Figure 11 This is in embodiment 5 provided by the present invention. 177 Embolism of Lu radioactive emulsion diluted 1:10 in water in capillary tubes.

[0070] Figure 12 This is in Embodiment 1 provided by the present invention. 177 The effect of Lu radioactive emulsion 1:1 injection dilution on rabbit kidney embolism.

[0071] Figure 13 This is in Embodiment 1 provided by the present invention. 177 Tumor distribution in a rabbit VX2 hepatocellular carcinoma model using a 1:1 injection dilution of Lu radioactive emulsion.

[0072] Figure 14 This is in Embodiment 1 provided by the present invention. 64 Cu labeling stability over 36 hours. Detailed Implementation

[0073] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0074] Example 1 This embodiment provides a radioactive embolization microsphere formulation, which is prepared by the following method: (1) According to Table 1, soluble radionuclide salts were mixed with 1.0 ml of aqueous solution containing metal salts using a liquid scintillation counter, gamma counter, or activity meter. 1.0 ml of trisodium phosphate solution was added to obtain a coarse particle solution. The coarse particle solution was sonicated (200 W, 3 mins) at room temperature (25 °C) to obtain a particle suspension. The pH was adjusted to 7.4 using phosphate buffer.

[0075] (2) At room temperature (25°C), iodized oil and particulate suspension were mixed at a volume ratio of 4:3 through a three-way valve, and the aqueous phase was injected into the oil phase. The emulsion was sheared 150 times within 2 minutes to obtain a radioactive emulsion with a uniform appearance.

[0076] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the radioactive preparation vial and shake it simply to obtain a semi-solid embolization microsphere preparation.

[0077] Table 1 No. Soluble radioactive nuclide salts Radiation dose Aqueous solutions containing metal salts Precipitator 1 <![CDATA[Lutetium chloride ( 177 Lu)]]> 35.7μCi Yttrium chloride (0.020 mol / L) Trisodium phosphate (0.024 mol / L) 2 <![CDATA[Yttrium chloride ( 90 Y)]]> 46.2μCi Yttrium chloride (0.020 mol / L) Trisodium phosphate (0.024 mol / L) 3 <![CDATA[Radium chloride ( 224 Ra)]]> 569.9Bq Calcium chloride (0.105 mol / L) Trisodium phosphate (0.077 mol / L) 4 <![CDATA[Copper chloride ( 64 Cu)]]> 1.58mCi Calcium chloride (0.120 mol / L) Trisodium phosphate (0.120 mol / L) Example 2 This embodiment provides a radioactive embolization microsphere formulation, which is prepared by the following method: (1) Take lutetium chloride according to Table 2 ( 177 A solution of Lu was mixed with 1.0 ml of yttrium chloride solution (0.020 mol / L), and 1.0 ml of trisodium phosphate solution (0.024 mol / L) was added to obtain a crude particulate solution. Sodium hexametaphosphate was dissolved in the crude particulate solution (calculated based on 2 ml volume of crude solution, 10 mg was dissolved in the 0.5 wt% group and 20 mg was dissolved in the 1.0 wt% group), and the solution was sonicated (200 W, 3 mins) at room temperature (25 °C) to obtain a particulate suspension, and the pH was adjusted to 7.4 using phosphate buffer.

[0078] (2) At room temperature (25°C), the organic phase listed in Table 2 and the particulate suspension were mixed at a volume ratio of 4:3 through a three-way valve. The aqueous phase was pushed into the oil phase, and the radioactive emulsion with uniform appearance was obtained by shearing 150 times within 2 minutes.

[0079] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the radioactive preparation vial and shake it simply to obtain a semi-solid embolization microsphere preparation.

[0080] Table 2 No Nuclide dose μCi organic phase stabilizer 1 37.6 Iodized oil Sodium hexametaphosphate (crude solution 0.5wt%) 2 38.3 Iodized oil Sodium hexametaphosphate (crude solution 1.0 wt%) 3 35.8 Iodized oil: soybean oil = 2:1 Sodium hexametaphosphate (crude solution 0.5wt%) Example 3 A radioactive embolization microsphere formulation is prepared by the following method: (1) According to Table 3, mix the soluble radionuclide salt solution with 1.0 ml of aqueous solution containing metal salt, and add 1.0 ml of trisodium phosphate solution containing dissolved hydrogel matrix (the amount of hydrogel matrix added is calculated based on the volume of the crude solution of 2 ml) to obtain a crude particle solution. The crude particle solution is sonicated (200 W, 3 mins) at room temperature (25℃) to obtain a particle suspension, and the pH is adjusted to 7.4 using phosphate buffer. Among them, the sodium alginate in group 5 is dissolved in the crude particle solution (the calculation method of the amount added is the same as that of other groups), and then subjected to the process steps of sonication and pH adjustment.

[0081] (2) Under room temperature (25℃) conditions, iodized oil and particulate suspension were mixed through a three-way valve according to the feeding volume ratio in Table 3, and a radioactive emulsion with uniform appearance was obtained by shearing 150 times within 2 minutes.

[0082] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the radioactive preparation vial and shake it simply to obtain a semi-solid embolization microsphere preparation.

[0083] Table 3

[0084] Example 4 A radioactive embolization microsphere formulation is prepared by the following method: (1) Weigh 18 mg of pirarubicin and mix it with 5.0 ml of yttrium chloride solution (0.02 M), and sonicate thoroughly at room temperature (25 °C). Take 1.0 ml of yttrium chloride solution containing pirarubicin (containing 39.71 μCi of lutetium chloride) and add 1.0 ml of trisodium phosphate solution (0.024 M) to obtain a crude particle solution. Sonicate the crude particle solution at room temperature (25 °C) (200 W, 3 mins) to obtain a particle suspension, and adjust the pH to 7.4 using phosphate buffer.

[0085] (2) At room temperature (25°C), iodized oil and particulate suspension were mixed at a volume ratio of 4:3 through a three-way valve, and the aqueous phase was injected into the oil phase. The emulsion was sheared 150 times within 2 minutes to obtain a radioactive emulsion with a uniform appearance.

[0086] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the emulsion vial and shake it simply to obtain a semi-solid embolization microsphere formulation.

[0087] Example 5 A radioactive embolization microsphere formulation is prepared by the following method: (1) Take lutetium chloride according to Table 4 ( 177 Lu) / Radium chloride 224 The Ra solution was mixed with 1.0 ml of yttrium chloride solution (0.02 M) / calcium chloride (0.105 M), and 1.0 ml of trisodium phosphate solution (0.024 M) / (0.077 M) was added to obtain a crude particle solution. The crude particle solution was sonicated (200 W, 3 mins) at room temperature (25 °C) to obtain a particle suspension, and the pH was adjusted to 7.4 using phosphate buffer.

[0088] Method 1: Emulsification under high temperature conditions, with the same dilution factor: (2) Under the conditions of 40℃ / 80℃, the iodized oil and the particulate suspension were mixed at a volume ratio of 4:3 through a three-way valve, the aqueous phase was injected into the oil phase, and the radioactive emulsion with uniform appearance was obtained by shearing 150 times within 2 minutes.

[0089] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the radioactive preparation vial and shake it simply to obtain a semi-solid embolization microsphere preparation.

[0090] Method 2: Emulsification at room temperature, with different dilution ratios: (2) At 25°C, iodized oil and particulate suspension were mixed at a volume ratio of 4:3 through a three-way valve, and the aqueous phase was injected into the oil phase. The emulsion was sheared 150 times within 2 minutes to obtain a radioactive emulsion with a uniform appearance.

[0091] (3) The radioactive emulsion and physiological saline (0.9% sodium chloride solution) were mixed in volume ratios of 1:0, 1:1, 1:10, 1:20 and 1:40. The physiological saline was injected into the radioactive preparation vial with a syringe and shaken simply at room temperature (25°C) to obtain a semi-solid embolization microsphere preparation.

[0092] Table 4 Example 6 This embodiment provides a radioactive embolization microsphere formulation, which is prepared by the following method: (1) Take 42.13 / 42.15 μCi of lutetium chloride ( 177 Lu) was mixed with 1.0 ml of yttrium chloride solution (0.02 M), and 1.0 ml of trisodium phosphate solution (0.024 M) was added to obtain a crude particle solution. The crude particle solution was sonicated (200 W, 3 mins) at room temperature (25 °C) to obtain a particle suspension, and the pH was adjusted to 7.4 using phosphate buffer.

[0093] (2) Iodized oil and particulate suspension were ultrasonically mixed at a volume ratio of 4:3 for 10 minutes under 100W / 200W power conditions to obtain a uniform emulsion.

[0094] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the emulsion vial and shake it simply to obtain a semi-solid embolization microsphere formulation.

[0095] Example 7 This embodiment provides a radioactive embolization microsphere formulation, which is prepared by the following method: (1) Take 40.51 / 40.35 μCi of lutetium chloride ( 177 Lu) was mixed with 1.0 ml of yttrium chloride solution (0.02 M), and 1.0 ml of trisodium phosphate solution (0.024 M) was added to obtain a crude particle solution. The crude particle solution was sonicated (200 W, 3 mins) at room temperature (25 °C) to obtain a particle suspension, and the pH was adjusted to 7.4 using phosphate buffer.

[0096] (2) 10 ml of iodized oil was used as the dispersed phase and 60 ml of particulate suspension was used as the continuous phase. The mixture was then passed through an emulsification membrane. An SPG membrane (pore size 10 μm, 40 μm) was used for emulsification through an external pressure SPG membrane emulsifier MG-20 at a speed of 300 rpm to obtain an emulsion.

[0097] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the emulsion vial and shake it simply to obtain a semi-solid embolization microsphere formulation.

[0098] Example 8 This embodiment provides a radioactive embolization microsphere formulation, which is prepared by the following method: (1) Take 40.67 μCi of lutetium chloride ( 177 Lu) was mixed with 1.0 ml of yttrium chloride solution (0.02 M), and 1.0 ml of trisodium phosphate solution (0.024 M) was added to obtain a crude particle solution. The crude particle solution was sonicated (200 W, 3 mins) at room temperature (25 °C) to obtain a particle suspension, and the pH was adjusted to 7.4 using phosphate buffer.

[0099] (2) Iodized oil and particulate suspension were mixed using a microfluidic chip. The chip was made of polydimethylsiloxane and fabricated using 3D printing technology. The fluid channels were laser-etched and designed with a cross structure. The diameter of the two-phase inlet was 5 μm. The emulsion was obtained by emulsifying the external aqueous phase and the internal oil phase at room temperature with a flow rate ratio of 2:1.

[0100] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the emulsion vial and shake it simply to obtain a semi-solid embolization microsphere formulation.

[0101] Example 9 This embodiment provides a radioactive embolization microsphere formulation, which is prepared by the following method: (1) Take 45.10 / 45.40 μCi of lutetium chloride ( 177 Lu) was mixed with 1.0 ml of yttrium chloride solution (0.02 M), and 1.0 ml of trisodium phosphate solution (0.024 M) was added to obtain a crude particle solution. The crude particle solution was sonicated (200 W, 3 mins) at room temperature (25 °C) to obtain a particle suspension, and the pH was adjusted to 7.4 using phosphate buffer.

[0102] (2) Iodized oil and particulate suspension were fed into a high-pressure homogenizer at a volume ratio of 4:3 and circulated 6 and 10 times. The mixture was emulsified under a pressure of 80 MPa to obtain an emulsion with a uniform appearance.

[0103] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the emulsion vial and shake it simply to obtain a semi-solid embolization microsphere formulation.

[0104] Example 10 This embodiment provides a radioactive embolization microsphere formulation, which is prepared by the following method: (1) Take the radionuclide according to Table 5 and mix it with 1.0 ml of yttrium chloride solution (0.02 M). Add 1.0 ml of trisodium phosphate solution (0.024 M) to obtain a crude particle solution. The crude particle solution is sonicated (200 W, 3 mins) at room temperature (25 °C) to obtain a particle suspension. Adjust the pH to 7.4 using phosphate buffer.

[0105] (2) Iodized oil and particulate solution were ultrasonically broken for 5 minutes under the conditions listed in Table 4 at a volume ratio of 4:3 to obtain an emulsion with uniform appearance.

[0106] (3) Mix the radioactive emulsion with physiological saline (0.9% sodium chloride solution) at a volume ratio of 1:10. Under room temperature (25°C) conditions, use a syringe to push the physiological saline into the emulsion vial and shake it simply to obtain a semi-solid embolization microsphere formulation.

[0107] Table 5 No. Radionuclides Ultrasonic power W Work / Interval Time s 1 <![CDATA[38.70 μCi lutetium chloride ( 177 Lu)]]> 100 2 / 2 2 <![CDATA[38.80 μCi lutetium chloride ( 177 Lu)]]> 250 2 / 2 3 <![CDATA[38.80 μCi lutetium chloride ( 177 Lu)]]> 250 2 / 3 Comparative Example 1 (Patent CN120022390A) This comparative example provides a yttrium [ 90 The preparation method of the Y] microsphere injection solution includes the following steps: S1: Using a 5ml pipette, aspirate the polystyrene sulfonic acid resin microspheres (hereinafter referred to as resin microspheres) five times, mix thoroughly, and then aspirate the entire resin microsphere suspension into a filtration apparatus with a 300ml filter cup / 1000ml receiving bottle. Use a 10μm PC membrane as the filter membrane. Add 100ml of sterile water for injection, stir and rinse for 1 minute, then drain and remove the vacuum pump. Repeat this process three times, draining the solution each time. Remove the rinsed microspheres from the filtration apparatus, weigh 0.5g of resin microspheres, and transfer them to the reaction apparatus. Using a 1ml pipette, add 1ml of 12GBq / ml yttrium chloride solution to a 10ml vial, then add 4ml of 4.0mg / mL yttrium sulfate to the 10ml vial and mix thoroughly. Add the entire mixture from the mixing step to the reaction apparatus, stir and mix for 15 minutes, then drain the liquid using a vacuum pump and remove the vacuum pump. Draw 10 ml of sterile water for injection into a 10 ml syringe, add it to the filtration apparatus, stir and mix for 1 minute, then use a vacuum pump to remove the liquid and release the negative pressure. Repeat the operation twice.

[0108] S2: Draw 5 ml of 30 g / L sodium phosphate solution into the reaction apparatus using a 10 ml syringe, stir and mix for 15 minutes, remove 1.7 ml of supernatant, and then filter the remaining supernatant using a polycarbonate membrane (pore size 0.8 μm). Remove the negative pressure and add the above 1.7 ml of supernatant back into the reaction apparatus.

[0109] S3: Using a 10ml syringe, draw 8ml of a 15g / L sodium dihydrogen phosphate solution and add it to the reaction apparatus. Stir and mix for at least 5 minutes. Remove 3.2ml of the supernatant, then filter the remaining supernatant using a nylon membrane (0.45μm pore size). Remove the negative pressure and add the 3.2ml of supernatant back to the reaction apparatus. Using a 10ml syringe, draw 10ml of sterile water for injection and add it to the reaction apparatus. Stir and mix for 1 minute, then extract the liquid using a vacuum pump. Repeat this process twice. Using a 5ml syringe, draw 5ml of sterile water for injection and add it to the reaction apparatus. Repeat the aspiration and blowing process 5 times to mix the resin and water for injection thoroughly. Transfer the mixture to a 10ml open-top vial using a 1ml pipette, cap the vial, and place it in an activity meter to measure the activity. Place the vial in a lead container, transfer the lead container to an autoclave, open the lid, and set the temperature to 132℃ and the time to 7 minutes.

[0110] Comparative Example 2 (Patent CN119405848A) This comparative example provides a yttrium [ 90 The Y] therapeutic gel is prepared through the following steps: (1) N-isopropylacrylamide (0.15 mol / L), acrylic acid (4 mmol / L), sodium dodecyl sulfate (1 mmol / L), and N,N'-methylenebisacrylamide (4 mmol / L) were added to a three-necked flask equipped with a reflux condenser and a gas delivery device. The flask was dissolved in ultrapure water (the amount of ultrapure water was determined by the concentration of other components and the actual amount of feed) under magnetic stirring. High-purity nitrogen was then introduced into the reaction system for 30 min. The reaction system was heated to 70 °C, and potassium persulfate (1.5 mmol / L) was added as an initiator. The reaction was carried out in a nitrogen atmosphere at 70 °C for 6 h to obtain a white turbid suspension. The suspension was purified by dialysis in ultrapure water and then freeze-dried. The freeze-dried powder was collected to obtain poly(N-isopropylacrylamide-co-acrylic acid) thermosensitive nanogel.

[0111] (2) The above-mentioned temperature-sensitive nanogel, ultrapure water and aqueous phase developer (iodixanol) are mixed in a mass ratio of 6:39:55 and stirred evenly to obtain an aqueous phase.

[0112] (3) Add Na to the glass bottle 131I solution (0.1 ml, 20 mg / ml) was evaporated to dryness and cooled to room temperature. 200 ml of acetone was added and gently shaken. The prepared iodized oil / acetone solution (0.6 ml iodized oil, 3 ml acetone, miscible) was slowly added to a glass bottle. A stir bar was then placed in the bottle, and the mixture was stirred in a 40°C water bath for 1.5 h. After the reaction was complete, the water bath temperature was increased (60-70°C) to evaporate most of the acetone solvent. Then, a small amount of acetone remaining in the iodized oil was evaporated under reduced pressure using a water pump to obtain radioactive iodine-labeled iodized oil (oil phase).

[0113] (4) Use a medical three-way stopcock to mix the above aqueous phase and oil phase evenly in a ratio of 6:4.

[0114] Particle size determination method: After freeze-drying, the particle morphology was photographed using a transmission electron microscope, and the hydrated particle size was determined by dynamic light scattering method. The yttrium phosphate nanoparticles obtained in Example 1 were distributed within a size of 200 nm. Figure 1 The average hydrated particle size is 150 nm. Figure 2 ).

[0115] Methods for determining the quality stability of radioactive emulsions: check the appearance of layering and the size of emulsion droplets.

[0116] Measurement results: (1) The yttrium microspheres have a uniform and stable appearance. The average particle size was calculated to be 40 μm under an inverted microscope by counting. There was no significant change in mass over 30 days. Figures 3-5 ).

[0117] (2) Hydrogel materials exhibit good stability to the appearance of emulsions. Figure 6 ).

[0118] Method for determining radioactive labeling rate: Dilute the embolization preparation with deionized water 3 times, let it stand and settle, and take the supernatant; measure the ratio of total radioactivity and supernatant radioactivity respectively, and calculate the labeling rate of the embolization preparation for radioisotopes.

[0119] The method for determining the comparative proportion is as follows: Comparative Example 1: Detection and Preparation Method for Yttrium Production [ 90 The radioactivity of the Y] microsphere injection solution was then determined using the formula: Labeling rate = Yttrium[ 90 The radioactivity of the microsphere injection solution / the radioactivity of the yttrium chloride solution were used to calculate the yttrium produced in each example and comparative example. 90 Yttrium in microsphere injection 90 The labeling rate of Y].

[0120] Comparative Example 2: 1 ml of the sample was placed in a 2 ml glass bottle and cured in a 50°C constant temperature water bath for 1 hour. The sample separated into a solid phase and a liquid phase. The solid phase was the gelled embolic composition, and the liquid phase was the precipitated aqueous phase. The radioactivity values ​​of the solid and liquid phases after curing were measured separately. The higher the proportion of radioactivity value of the solid phase after curing, the higher the radiostability.

[0121] Measurement results Table 6

[0122] Method for determining the drug loading rate of pirarubicin: The ultraviolet absorption characteristics of pirarubicin aqueous solution (physiological saline) were measured and a standard curve was plotted. Figure 7 After centrifuging the particle suspension from Example 4, 0.5 ml of the supernatant was diluted five times, and 1 ml of the supernatant was used to detect the pirarubicin content. The pirarubicin loading rate of the particles was calculated as follows: Pirarubicin loading rate (%) = ((total pirarubicin content - pirarubicin supernatant content) / total pirarubicin content) × 100%.

[0123] The measurement results are shown in Table 7. Table 7 Example 4 Total content of pirarubicin (mg / ml) Pirarubicin supernatant content (μg / ml) Pirarubicin loading rate <![CDATA[ 177 Lu-yttrium phosphate 0.44 38.39 91.24% The average size of the semi-solid microspheres in the composition was statistically analyzed by diluting the sample with deionized water, observing and counting the particles under an inverted microscope, and then calculating the average particle size.

[0124] Measurement results The components are indicated as different from those in the composition formulation of Example 1; in the example, yttrium phosphate is used as particles adsorbed at the oil-water interface.

[0125] Table 8

[0126] Microsphere mass stability at different dilution ratios: Example 5: The appearance and particle size of the microsphere dilution solutions were observed at dilution ratios of 1:0, 1:1, 1:10, 1:20, and 1:40. The microspheres settled rapidly in the dilution solutions. Figure 10 And there was no obvious sign of dehiscence on the surface. Figure 8 The dilution factor has no effect on the particle size. Figure 9 ).

[0127] Extracorporeal embolization effect: The 1:10 dilution ratio in Example 5 177 Lu embolization microsphere diluents entered capillaries with inner diameters of 40 μm and 1.0 mm respectively via capillary action. The microspheres passed through the 40 μm diameter capillary one by one and were difficult to flow. Figure 11After flowing a certain distance in a 1.0mm tube, it gradually accumulates. Figure 11 ).

[0128] Animal embolism effect: In Example 1 177 Lu radioactive emulsion was diluted with physiological saline at a 1:1 volume ratio to obtain 177 Lu embolization microsphere dilution was introduced into the following animal disease models to observe the embolization effect and CT imaging function: (1) Kidney embolism model: Healthy New Zealand white rabbits were fixed in a supine position on an examination table and anesthetized with an injection of 1 ml / kg of 3% sodium pentobarbital via the marginal ear vein. The skin was prepared and disinfected, exposing both inguinal regions. The puncture point was determined based on the femoral artery pulsation, and a microcatheter was introduced by puncturing the femoral artery using an indwelling intravenous catheter. The tip of the microcatheter was placed at the opening of one renal artery, and the internal radiation composition was slowly injected. The distribution within the rabbit kidney was observed. Figure 12 It can be seen that the composition causes uniform embolization in rabbit kidneys, with clear imaging contours and structures, and the anatomical structures such as the renal cortex and arteries can be distinguished.

[0129] (2) Liver cancer embolization model: New Zealand white rabbits with VX2 liver cancer were fixed in a supine position on an examination table. Anesthesia was achieved by injecting 1 ml / kg of 3% sodium pentobarbital into the ear vein. The skin was prepared and disinfected, exposing the right inguinal region. The right femoral artery was punctured and inserted into the vascular sheath. A microcatheter was inserted through the celiac artery to the left hepatic artery, and the internal radiation composition was slowly injected. The distribution within the liver tumor was observed. Figure 13 As can be seen, the composition exhibits extremely high image density in the tumor treatment area, with significant bright areas. The injected composition shows clear embolization effect without spilling into non-treatment sites.

[0130] Methods for determining the stability of radioactive labeling rate: (1) Semi-solid microspheres: Take the sample from Example 1 64 0.5 ml of Cu radioactive embolization microspheres were added to 5 ml of aqueous solution. After settling, the supernatant was collected. The ratio of total radioactivity to the supernatant was measured, and the labeling rate of the radioactive embolization microspheres to the radioisotope was calculated. Detection time points: 0 h, 12 h, 24 h, 36 h.

[0131] (2) Radioactive particle suspension: Take 200 μl of particle suspension to determine the total activity; centrifuge at 10000 rpm for 5 mins, take the supernatant to determine the activity, calculate the ratio of the total activity of the supernatant to the total activity of the suspension, and calculate the labeling rate of the particle suspension to the radioactive isotope. Detection time points: 0 h, 36 h.

[0132] Depend on Figure 14 It can be seen that, 64During the effective imaging time of Cu (approximately 3 half-lives), the radioactive embolization microsphere formulation... 64 The Cu labeling rate was above 96%, and the inorganic particle matrix was effective against... 64 The Cu labeling rate reached over 98%, and maintained a high labeling rate stably for 36 hours.

[0133] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A radioactive embolization microsphere, characterized in that, The device comprises radioactive particles and an organic phase containing iodized oil, wherein the radioactive particles are coated on an interface with the organic phase containing iodized oil as its core; the radioactive particles comprise radionuclides and an inorganic matrix, wherein the radionuclides are fixed in the inorganic matrix; the particle size of the radioactive particles is 0.01~10μm; and the particle size of the radioactive embolization microspheres is 0.01~1000μm.

2. The radioactive embolization microspheres according to claim 1, characterized in that, The radionuclides include one or more of α, β, and γ radionuclides that can be used for treatment and / or medical imaging. Preferably, the radionuclide includes 43 Sc, 44 Sc, 46 Sc, 47 Sc, 90 Y, 86 Y, 88 Y, 134 La, 135 La, 139 Ce, 141 Ce, 140 Pr, 143 Pr, 149 Pm, 153 Sm, 153 Gd, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 157 Dy, 166 Ho, 165 Er, 169 Er, 167 Tm, 169 Yb, 172 Lu, 177 Lu, 11 C, 14 C, 13 N, 15 O, 18 F, 32 P, 35 S, 34m Cl, 36 Cl, 38 Cl, 39 Cl, 38 K, 42 K, 43 K, 45 Ca 44 Ti, 46 Ti, 48 Cr, 51 Cr, 52 Mn, 52m Mn, 54 Mn, 52 Fe, 55 Fe, 59 Fe, 55 Co, 57 Co, 58 Co, 59 Co, 63 Ni, 60 Cu, 61 Cu, 62 Cu, 67 Cu, 64 Cu, 63 Zn, 69m Zn, 65 Zn, 68 Ga, 66 Ga, 67 Ga, 68 Ge, 72 As, 73 As, 74 As, 75 Se, 75 Br, 76 Br, 77 Br, 82 Br, 81 Rb, 82 Rb, 84 Rb, 86 Rb, 89 Sr, 85 Sr, 87 mSr, 90 Sr, 89 Zr, 90 Nb, 95 Nb, 99m Tc, 94m Tc, 95 Tc, 99 Mo, 103 Ru, 103m Rh, 105 Rh, 103 Pd, 109m Ag, 111 Ag, 110m In, 111m In, 113m In, 114m In, 115m In, 117m Sn, 123m Te, 122 I, 123 I, 124 I, 125 I, 131 I, 129 Cs, 134 Cs, 137 Cs, 133m Ba, 127m Ba, 178 Ta, 191m Ir, 192 Ir, 191 Pt, 193m Pt, 195 Pt, 195m Pt, 195m Au, 198 Au, 199 Au, 197 Hg, 197m Hg, 203 Hg, 186 Re, 188 Re, 199 Tl, 212 Tl, 203 Pb, 212 Pb, 205 Bi, 212 Bi, 213 Bi, 204 Bi, 206 Bi, 207 Bi, 211 At, 223 Ra, 224 Ra, 226 Ra, 225 Ac, 226 Th, 227 One or more of Th; The inorganic matrix is ​​prepared from a metal salt and a precipitant, and the metal ions in the metal salt include Ca. 2+ Y 3+ Lu 3+ Pb 2+ and Ag + One or more of the following, wherein the anion in the precipitant includes PO4. 3- HPO4 2- H2PO4 - CO3 2- C2O4 2- SO4 2- S 2- Cl - and BiO3 - One or more of the following; The molar ratio of the metal ions in the metal salt to the precipitant is 1:(0.5~4.5).

3. The radioactive embolization microspheres according to claim 1 or 2, characterized in that, The organic phase containing iodized oil is iodized oil or a mixture of iodized oil and other injectable oils; the other injectable oils include one or more of soybean oil, cottonseed oil, corn oil, sesame oil, safflower oil, medium-chain triglycerides, olive oil, and fish oil.

4. A radioactive embolization microsphere formulation, characterized in that, Includes the radioactive embolization microspheres according to any one of claims 1-3.

5. A method for preparing the radioactive embolization microsphere formulation according to claim 4, characterized in that, Includes the following steps: (1) A particulate suspension was prepared by reacting soluble radioactive nuclide salts, aqueous solutions containing metal salts and aqueous solutions containing precipitants as raw materials, and the pH value was adjusted to 5.5~9.0; (2) The particulate suspension after pH adjustment is added to the organic phase containing iodized oil and radioactive emulsion is prepared by medical three-way valve, microfluidic chip, membrane emulsification, ultrasonic disruption or high pressure homogenization.

6. The method for preparing the radioactive embolization microsphere formulation according to claim 5, characterized in that, Step (1) involves mixing a soluble radioactive nuclide salt, an aqueous solution containing a metal salt, and an aqueous solution containing a precipitant to obtain a coarse particle solution; then, the coarse particle solution is mixed by high-speed stirring, ultrasound, or a three-way mixing process to obtain a radioactive particle suspension. Preferably, the coarse particle solution is subjected to ultrasound to obtain a radioactive particle suspension; the total power of the ultrasound is 100~800W, and the ultrasound time is 1~60min. Preferably, the mixing temperature is 10~80℃.

7. The method for preparing the radioactive embolization microsphere formulation according to claim 5 or 6, characterized in that, In step (1), the aqueous solution containing metal salt or the aqueous solution containing precipitant further includes a hydrogel matrix and / or a phosphoric acid additive; Preferably, the hydrogel matrix is ​​selected from one or more natural or synthetic polymers; more preferably, the amount of the hydrogel matrix added is 0.5%-30% of the mass of the aqueous solution containing the metal salt or the aqueous solution containing the precipitant. Preferably, the phosphoric acid additive is selected from one or more of hexametaphosphate, polyphosphate, pyrophosphate, ethylenediaminetetra(methylenephosphonic acid), pamidronate and bisphosphonates; more preferably, the amount of phosphoric acid additive added is 0.1 to 15% of the mass of the aqueous solution containing the metal salt or the aqueous solution containing the precipitant.

8. The method for preparing the radioactive embolization microsphere formulation according to any one of claims 5-7, characterized in that, The preparation temperature in step (2) is 10~80℃, preferably 20~40℃; the volume ratio of the particulate suspension to the organic phase containing iodized oil is 1:4~4:

1.

9. The method for preparing the radioactive embolization microsphere formulation according to any one of claims 5-8, characterized in that, It also includes the following steps: (3) The radioactive emulsion is mixed with the injection solution to obtain the radioactive embolization microsphere formulation; Preferably, the volume ratio of the radioactive emulsion to the injection solution is 1:(0.1~100). Preferably, the injection solution is selected from one or more of water for injection, sterile water for injection, physiological saline, and 5% glucose aqueous solution; Preferably, the mixing temperature in step (3) is 15~40°C, and the mixing is carried out in a radiation shielding environment.

10. The use of the radioembolization microspheres according to any one of claims 1-3, the radioembolization microsphere formulation according to claim 4, or the radioembolization microsphere formulation prepared by the preparation method according to any one of claims 5-9 in the preparation of tumor drugs or medical kits.

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