Preparation method of yttrium-90-loaded magnesium lithium silicate and hydrogel radiotherapy embolization agent

Abstract

The invention discloses a preparation method of yttrium-90 (90Y)-loaded magnesium lithium silicate and a hydrogel radiotherapy embolism agent, relates to the technical field of medical materials, and comprises the preparation method of yttrium-90-loaded magnesium lithium silicate and the hydrogel radiotherapy embolism agent. Lithium magnesium silicate is modified and treated by phosphate, and citric acid is complexed with < 90 > Y < 3 + >, so that interlayer cations of the lithium magnesium silicate are replaced, and < 90 > Y < 3 + > is stably loaded on the lithium magnesium silicate to prepare the < 90 > Y-lithium magnesium silicate compound. Yttrium-90 is a therapeutic nuclide, and a 90Y-magnesium lithium silicate loaded compound can be added into an embolism agent as a thixotropic agent to prepare a hydrogel radiotherapy embolism agent, so that dual effects of internal radiation and vascular embolism are realized.

Description

Technical Field

[0001] The present invention relates to the field of medical materials, and in particular to a preparation method of yttrium-90 loaded lithium magnesium silicate and a hydrogel radiotherapy embolic agent. Background Art

[0002] Lithium magnesium silicate, CAS No. 37220-90-9, molecular formula: Li2Mg2O9Si3, is a synthetic layered silicate clay. It appears as a white powder, is non-toxic and odorless, and has a unique nano-layered structure, high specific surface area and cation exchange capacity. It is widely used in drug delivery, catalysis, environmental remediation and other fields.

[0003] Yttrium-90( 90 As an important therapeutic nuclide in nuclear medicine, beta-ray (Y) plays a key role in tumor treatment due to its unique physical properties. This nuclide precisely irradiates lesions by emitting pure beta rays, with a maximum energy of 2.26 MeV and an average energy of 0.94 MeV. Its average penetration depth in biological tissue is approximately 2.5 mm, and its maximum penetration distance reaches 10.3 mm. This moderate radiation range can effectively kill diseased tissue while maximally protecting surrounding normal cells. It has a wide range of applications in nuclear medicine, including peptide receptor radionuclide therapy (PRRT), radioimmunotherapy (RIT), radiosynovectomy (RSV), and intra-arterial radioembolization.

[0004] Radiotherapy embolic agents are a minimally invasive interventional technique that combines local embolization therapy with targeted radiotherapy. They are primarily used to treat primary or metastatic liver tumors (such as hepatocellular carcinoma (HCC) and colorectal liver metastases). Their core principle is to load radioisotopes onto a carrier and precisely deliver them to tumor vessels via an arterial catheter, achieving the dual effects of localized high-dose radiotherapy and vascular embolization. In the prior art, the carrier is generally in the form of a microsphere. For example, patent CN117503961A discloses a biodegradable yttrium-90 microsphere, its preparation method, and application, for radioembolization therapy of tumor diseases such as liver cancer. Patent CN107715124B discloses medical yttrium-90 carbon microspheres for the treatment of tumors or metastatic tumors. However, the prior art does not yet have an embolic agent that uses yttrium-90 loaded onto lithium magnesium silicate to prepare a hydrogel carrier. Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing yttrium-90 loaded lithium magnesium silicate, which is used to prepare radioactive lithium magnesium silicate.

[0006] Another object of the present invention is to provide a hydrogel radiotherapy embolic agent to fill the gap in the prior art in that there is no radiotherapy embolic agent in which yttrium-90 is loaded onto lithium magnesium silicate to prepare a hydrogel carrier.

[0007] The object of the present application can be achieved by the following technical solutions:

[0008] In a first aspect, the present application discloses a preparation method of yttrium-90 loaded lithium magnesium silicate, comprising the following steps:

[0009] A1, dispersing lithium magnesium silicate in deionized water, adding phosphate, adjusting the pH value to 6.0±0.2, heating, stirring, centrifuging to collect the solid, drying the solid after washing, and obtaining interlayer phosphoric acid modified lithium magnesium silicate;

[0010] A2, dissolving yttrium-90 salt in deionized water, adding citric acid and mixing, adjusting the pH value to 4-5, and obtaining a citric acid- 90 Y 3+ complex solution after standing;

[0011] A3, dispersing the interlayer phosphoric acid modified lithium magnesium silicate in deionized water, ultrasonic treatment, adjusting the pH value to 5-6, adding the citric acid- 90 Y 3+ complex solution dropwise into the phosphoric acid modified lithium magnesium silicate dispersion, stirring, centrifuging to discard the supernatant, washing the solid and drying to obtain 90 Y-lithium magnesium silicate complex.

[0012] More preferably, in step A1, the ratio of millimoles of phosphate to grams of lithium magnesium silicate is 0.1-0.5.

[0013] More preferably, in step A1, the stirring time is 4-10 hours, the stirring speed is 200-1000 rpm, the washing is performed with 60°C hot water, and the washing is performed three times; the drying is vacuum drying at 60°C.

[0014] More preferably, in step A2, the yttrium-90 salt is yttrium chloride-90 or yttrium nitrate-90.

[0015] More preferably, in step A2, the molar ratio of citric acid to 90 Y 3+ is (1-2):1.

[0016] More preferably, in step A3, the stirring is room temperature stirring for 1-3 hours, and the stirring speed is 100-1000 rpm.

[0017] More preferably, in step A3, the ratio of millimoles of 90 Y 3+ to grams of lithium magnesium silicate is 0.05-0.3.

[0018] In a second aspect, the present application discloses a hydrogel radiotherapy embolization agent, raw materials of which include the Yttrium-90 loaded magnesium lithium silicate prepared by the preparation method. The hydrogel radiotherapy embolization agent specifically includes the following components in parts by weight: 60-95 parts of sterile water for injection, 0.1-10 parts of a thixotropic agent, and 5-30 parts of a developing agent.

[0019] More preferably, the preparation method of the hydrogel radiotherapy embolization agent is as follows: the sterile water for injection and the thixotropic agent are stirred uniformly to obtain a mixed solution, the developing agent is added to the mixed solution, and the radiotherapy embolization agent is obtained after uniform stirring.

[0020] More preferably, the thixotropic agent is a mixture of the magnesium lithium silicate and 90 Y

[0021] More preferably, the developing agent is a mixture of one or more of iohexol, iodixanol, iopamidol and tantalum powder.

[0022] The present application has the following beneficial effects:

[0023] 1. The present application modifies the magnesium lithium silicate by phosphate treatment, and the phosphate coordinates with the Mg-OH or Si-OH groups between the layers of the magnesium lithium silicate to form stable coordination bonds. Then, the citric acid is complexed with 90 Y 3+ to stabilize 90 Y 3+ . The affinity of the citric acid to 90 Y 3+ is higher than that of OH-, so that the citric acid preferentially occupies the coordination sites of 90 Y 3+ and prevents the formation of Y(OH)3 precipitate, thereby stabilizing 90 Y 3+ . The stable loading of 90 Y 90 is achieved, and the precipitation of 90 Y 90 is avoided, and the uniformity and stability of the Y loading are increased.

[0024] 2. Yttrium-90 is a therapeutic radionuclide, and the Yttrium-90 loaded magnesium lithium silicate prepared by the present application can be used as a thixotropic agent to prepare a radiotherapy embolization agent, so that the embolization agent has the dual effects of internal radiation and vascular embolization. DETAILED DESCRIPTION

[0025] The technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the present application.

[0026] The experimental methods in the following examples, unless otherwise specified, are conventional methods, which are performed according to the techniques or conditions described in the literature in the art or according to the instructions of the products. The materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels, for example, the types and sources of the raw materials involved in the examples and comparative examples are as shown in Table 1, and Table 1 is as follows:

[0027] Table 1

[0028] Raw Material Source Lithium Magnesium Silicate BYK, Laponite XLG-XR Disodium Hydrogen Phosphate AR (Shanghai test), > 99.0% Yttrium Chloride-90 Nucreta Medical Citric Acid AR (Shanghai test) Gelatin Merck, gel strength 300, Type A Tantalum Powder Ningxia Oriental Tantalum Industry Xanthan Gum USP grade (Vicole)

[0029] Preparation Example 1

[0030] A1, Preparation of interlayer phosphatized magnesium lithium silicate: 1 g of magnesium lithium silicate was dispersed in 100 mL of deionized water, and 0.04 g of disodium hydrogen phosphate was added. The pH was adjusted to 6.0 ± 0.2. The water bath was heated to 60°C, and stirring was performed at 200 rpm for 5 hours. Then the stirred solution was subjected to centrifugal treatment at 15000 rpm for 10 min, the supernatant was discarded, and the solid was collected and washed with 60°C hot water three times. The obtained solid was dried at 60°C under vacuum to obtain interlayer phosphatized magnesium lithium silicate.

[0031] A2, Preparation of citric acid- 90 Y 3+ complex solution: 0.2 g of yttrium chloride-90 was dissolved in 100 mL of deionized water, and 0.3 g of citric acid was added and mixed uniformly. The pH was adjusted to 4-5. After standing for 15 minutes, a citric acid- 90 Y 3+ complex solution was obtained.

[0032] A3, Preparation of 90 Y-magnesium lithium silicate complex: 1 g of interlayer phosphatized magnesium lithium silicate prepared in step A1 was dispersed in 100 mL of deionized water, and ultrasonic treatment was performed for 15 minutes. The pH was adjusted to 5-6. 10 mL of citric acid- 90 Y 3+ complex solution prepared in step A2 was added dropwise to the phosphatized magnesium lithium silicate dispersion, and stirring was performed at room temperature for 2 hours at a stirring speed of 200 rpm. After completion of stirring, centrifugal treatment was performed at 15000 rpm for 10 min, the supernatant was discarded, and the centrifuged solid was washed with deionized water three times and then dried at 60°C under vacuum to obtain 90 Y-magnesium lithium silicate complex.

[0033] Preparation Example 2

[0034] A1, Preparation of 90 Y 3+Solution: 0.2 g of yttrium chloride-90 was dissolved in 100 mL of deionized water, the pH was adjusted to 4-5, and it was stirred uniformly to obtain 90 Y 3+ Solution.

[0035] A2, Preparation 90 Y-magnesium lithium silicate complex: 1 g of magnesium lithium silicate was dispersed in 100 mL of deionized water, ultrasonic treatment was performed for 15 minutes, and the pH was adjusted to 5-6. 10 mL of 90 Y 3+ The solution was added dropwise to the magnesium lithium silicate dispersion, stirred at room temperature for 2 hours at a stirring speed of 200 rpm. After stirring was completed, centrifugation was performed at 15000 rpm for 10 min, the supernatant was discarded, the solid after centrifugation was washed with deionized water 3 times, and vacuum drying was performed at 60°C to obtain 90 Y-magnesium lithium silicate complex.

[0036] Example 1

[0037] In a stirring tank, 62 g of sterile water for injection and 2.5 g of magnesium lithium silicate and 0.5 g of the 90 Y-magnesium lithium silicate complex prepared in Preparation Example 1 were added, the homogenizer speed was set to 1500 rpm, and the dispersion time was 8 min. Then, 16.5 g of tantalum powder was added to the stirring tank, the speed was set to 1500 rpm, and the dispersion time was 5 min, to obtain a hydrogel radiotherapy embolization agent.

[0038] Example 2

[0039] In a stirring tank, 52.2 g of sterile water for injection and 3 g of the 90 Y-magnesium lithium silicate complex prepared in Preparation Example 1 were added, the homogenizer speed was set to 1500 rpm, and the dispersion time was 10 min. Then, 15 g of tantalum powder was added to the stirring tank, the speed was set to 1500 rpm, and the dispersion time was 5 min, to obtain a hydrogel radiotherapy embolization agent.

[0040] Example 3

[0041] In a stirring tank, 61 g of sterile water for injection and 1.2 g of the 90 Y-magnesium lithium silicate complex prepared in Preparation Example 1 were added, the homogenizer speed was set to 1500 rpm, and the dispersion time was 5 min. Then, 15 g of tantalum powder was added to the stirring tank, the speed was set to 1500 rpm, and the dispersion time was 5 min, to obtain a hydrogel radiotherapy embolization agent.

[0042] Comparative Example 1

[0043] In a stirring tank, 62 g of sterile water for injection and 2.5 g of magnesium lithium silicate and 0.5 g of the 90The Y-lithium magnesium silicate complex was prepared by setting the homogenizer speed to 1500 rpm and the dispersion time to 8 minutes. Then, 16.5 g of tantalum powder was added to the stirring tank, and the speed was set to 1500 rpm and the dispersion time to 5 minutes to obtain a hydrogel radiotherapy embolic agent.

[0044] Comparative Example 2

[0045] Add 62g of sterile water for injection and 3g of lithium magnesium silicate to a mixing tank, set the homogenizer speed to 1500rpm, and disperse for 8 minutes. Then, add 16.5g of tantalum powder to the mixing tank, set the speed to 1500rpm, and disperse for 5 minutes to obtain a hydrogel embolic agent.

[0046] Preparation Example 1 and Preparation Example 2 90 The stability of the preparation process of the Y-lithium magnesium silicate composite was evaluated. The test method is as follows: In Example 1, citric acid- 90 Y 3+ The complex solution was added dropwise to the phosphorylated lithium magnesium silicate dispersion; in Comparative Example 1, 90 Y 3+ The solution was directly added dropwise to the unmodified lithium magnesium silicate dispersion, and the occurrence of precipitation in the two systems was observed and recorded throughout the process. 90 The stability performance results of the preparation process of the Y-lithium magnesium silicate composite are as follows.

[0047] In Example 1: Citric acid- 90 Y 3+ No precipitation was observed during the dropwise addition of the complexing solution. 90 Y 3+ The solution was added dropwise and a white precipitate appeared. The precipitate did not dissolve until the stirring was completed. The results showed that the phosphorylation modification of lithium magnesium silicate and the reaction of citric acid with 90 Y 3+ Complexation can avoid 90 Y was precipitated.

[0048] The hydrogel radiotherapy embolic agents of Examples 1-3 and Comparative Examples 1-2 90 The Y load uniformity performance is evaluated. The test method is as follows: Place the sample close to X-ray film, expose it in a dark box for 4 hours, then develop / fix it, and observe the image on the film. 90 Y 3+ The higher the loading, the darker the color on the film. 90 Y 3+ The more uniform the load, the more uniform the color of the film. 90 Y 3+ If there is enrichment, local dark spots will appear on the film. 90 Y3+ The local load is small, and a light color area appears on the film. 90 The results of Y load uniformity are listed in Table 2.

[0049] Table 2

[0050] Sample Name Image Appearance on Film Example 1 The film presents uniform gray color, without local dark spots or light color area. Example 2 The film presents uniform black color, without local dark spots or light color area. Example 3 The film presents uniform gray-black color, without local dark spots or light color area. Comparative Example 1 The film presents non-uniform light gray color, with local dark spots and light color area. Comparative Example 2 The film has no image, presents transparent state.

[0051] From the analysis of the data in Table 2, it can be seen that the Y-magnesium lithium silicate complex prepared in Example 1-3 using the Y synthesized in Preparation Example 1 has no local dark spots or light color areas on the film image, indicating that the phosphatization modification of the magnesium lithium silicate and the complexation with citric acid can achieve 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load. 90 Y 3+ complexation can achieve 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load. 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load. 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load. 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load. 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load. 90 Y 3+ and the stability of the mixture with magnesium lithium silicate is low, and after the formation of precipitates, the Y load uniformity is affected. 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load. 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load. 90 Y load uniformity. Comparative Example 1 uses the Y-magnesium lithium silicate complex synthesized in Example 2, and the result is that the film presents an uneven light gray color with local dark spots and light color areas. Comparative Example 1 and Example 1 have the same amount of Y-magnesium lithium silicate complex added, and the color of the film in Comparative Example 1 is lighter than that in Example 1, indicating that the magnesium lithium silicate that has not been modified by interlayer phosphatization has a lower Y load.

[0052] The above describes one embodiment of the present application in detail, but the content described is only a preferred embodiment of the present application and cannot be considered as limiting the scope of the present application. Any equivalent changes and improvements made within the scope of the present application should still be attributed to the patent coverage of the present application.

Claims

1. A method for preparing lithium magnesium silicate loaded with yttrium-90, characterized in that: The following steps are involved: A1. Disperse lithium magnesium silicate in deionized water, add phosphate, adjust the pH to 6.0±0.2, heat, stir, collect solids by centrifugation, wash the solids, and then dry to obtain interlayer phosphate-modified lithium magnesium silicate; A2. Dissolve yttrium-90 salt in deionized water, add citric acid and mix, adjust the pH value to 4-5, and let it stand to obtain citric acid- 90 Y 3+ complexing solution; A3, disperse the interlayer phosphorylated modified lithium magnesium silicate in deionized water, ultrasonicate, adjust the pH value to 5-6, add citric acid- 90 Y 3+ The complex solution was added dropwise to the phosphorylated modified lithium magnesium silicate dispersion, stirred, centrifuged and the supernatant was discarded, the solid was washed and dried to obtain 90 Y-lithium magnesium silicate complex.

2. The method for preparing yttrium-90 loaded lithium magnesium silicate according to claim 1, wherein: In step A1, the ratio of the millimoles of the phosphate radical to the grams of the lithium magnesium silicate is 0.1-0.

5.

3. The method for preparing yttrium-90 loaded lithium magnesium silicate according to claim 1, characterized in that: In step A1, the stirring time is 4-10 hours, the stirring speed is 200-1000 rpm, the washing is performed three times with 60°C hot water, and the drying is performed at 60°C vacuum drying.

4. The method for preparing yttrium-90 loaded lithium magnesium silicate according to claim 1, wherein: In step A2, the yttrium-90 salt is yttrium-90 chloride or yttrium-90 nitrate.

5. The method for preparing yttrium-90 loaded lithium magnesium silicate according to claim 1, characterized in that: In step A2, citric acid and 90 Y 3+ The molar ratio is (1-2):

1.

6. The method for preparing yttrium-90 loaded lithium magnesium silicate according to claim 1, characterized in that: In step A3, the stirring is carried out at room temperature for 1-3 hours at a stirring speed of 100-1000 rpm.

7. The method for preparing yttrium-90 loaded lithium magnesium silicate according to claim 1, characterized in that: In step A3, the 90 Y 3+ The ratio of millimoles to grams of lithium magnesium silicate is 0.05-0.

3.

8. A hydrogel radiotherapy embolic agent, characterized in that: The raw materials include the yttrium-90 loaded lithium magnesium silicate as described in any one of claims 1 to 7, and specifically include the following components in parts by weight: 60-95 parts of sterile water for injection, 0.1-10 parts of a thixotropic agent, and 5-30 parts of a developer.

9. The hydrogel radiotherapy embolic agent according to claim 8, characterized in that: The preparation method of the hydrogel radiotherapy embolic agent is as follows: sterile water for injection and a thixotropic agent are stirred evenly to obtain a mixed solution, a developer is added to the mixed solution, and the mixture is stirred evenly to obtain the radiotherapy embolic agent.

10. The hydrogel radiotherapy embolic agent according to claim 8, characterized in that: The thixotropic agent is lithium magnesium silicate and 90 A mixture of one or more of Y-lithium magnesium silicate complexes; the developer is a mixture of one or more of iohexol, iodixanol, iopamidol and tantalum powder.