A 177 Method for the preparation of lu-labelled medical glass microspheres

Abstract

The application discloses a kind of 177 Preparation method of Lu labeled medical glass microspheres belongs to the technical field of medicine, the Lu labeled medical glass microspheres disclosed in the application 177 Include nanometer microporous glass microspheres and fluoride of Lutetium, and the Lu labeled medical glass microspheres 177 The fluoride of Lu is adsorbed in the micropore of nanometer microporous glass microspheres, and the preparation method comprises the following steps: (1) nanometer microporous glass cleaning; (2) the Lu containing 177 Dilute acid system is adsorbed with nanometer microporous glass; (3) low-temperature reduced pressure drying, remove liquid; (4) high-temperature decomposition, so that 177 The salt of Lu is changed into 177 The oxide of Lu; (5) hydrofluoric acid treatment, so that 177 The oxide of Lu is changed into 177 The fluoride of Lu; (6) high-temperature calcination obtains 177 Lu labeled medical glass microspheres; the medical glass microspheres obtained by the application have high nuclear purity, uniform particle size distribution, high specific activity, good stability, and the preparation method is simple.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a... 177 Preparation method of Lu-labeled medical glass microspheres. Background Technology

[0002] Surgery, chemotherapy, and radiotherapy are traditional methods for treating cancer. Radiotherapy is widely recognized as more targeted and flexible than chemotherapy, making it a preferred treatment option for cancer patients. It aims to shrink tumors to facilitate surgery or completely eradicate tumor cells. Although cancer cells absorb radiation more readily than normal cells, normal cells are still susceptible to damage. Therefore, the radiation dose in external beam radiotherapy is generally low, insufficient to kill all cancer cells, thus affecting the treatment's effectiveness.

[0003] In the early 1980s, foreign countries began combining radionuclides with specific materials to prepare radioactive microspheres, which were then introduced into tumor sites within the body. Microspheres of a specific particle size can embolize within the tumor capillary bed. The short tissue range and high ionization of the radionuclides provide a large local radiation dose, effectively killing tumor cells and reducing damage to adjacent organs. Currently, two products have been approved for marketing in Europe and the United States, including... 90 Y-glass microspheres and 90 Y-resin microspheres have also been gradually developed in my country. 90 Clinical treatment of Y-microspheres.

[0004] Invention patent CN114504661A discloses a load 177 A method for preparing biodegradable polymer microspheres of Lu. The microspheres consist of a chitosan layer from the inside out, and... 177 Lu-labeled polydopamine layer and polydopamine blocking layer. The microspheres utilize a biodegradable material with good biocompatibility, but still contain a significant amount of [unspecified substance]. 177 Lu is released from the microspheres, and the entire preparation process is quite complex and involves radioactive operations. Summary of the Invention

[0005] This invention aims to solve the problems in the prior art. 177 The technical problems of Lu's easy release from microspheres and the complexity of microsphere preparation methods aim to provide a solution. 177 Preparation method of Lu medical glass microspheres, obtaining 177 Lu-labeled medical glass microspheres have high nuclear purity, uniform particle size distribution, high specific activity, good stability, and a simple preparation method.

[0006] This invention is achieved through the following technical solution:

[0007] A sort of 177The method for preparing Lu-labeled medical glass microspheres, wherein 177 Lu-labeled medical glass microspheres include nanoporous glass microspheres and 177 The fluoride of Lu, the 177 Lu fluorides are adsorbed on the surface and in the micropores of nanoporous glass microspheres.

[0008] The preparation steps include the following:

[0009] (1) Cleaning of nanoporous glass;

[0010] (2) containing 177 Lu undergoes an adsorption reaction with nanoporous glass in a dilute acid system.

[0011] (3) Low-temperature vacuum drying to remove liquid;

[0012] (4) High-temperature decomposition, 177 Lu's salts are transformed into 177 Oxides of Lu;

[0013] (5) Hydrofluoric acid treatment, 177 Lu oxides transform into 177 Fluorides of Lu;

[0014] (6) Obtained after high-temperature calcination 177 Lu-labeled medical glass microspheres.

[0015] The preparation method of this invention involves cleaning the nanoporous glass, 177 The key steps involved in the preparation of Lu were: adsorption of Lu on nanoporous glass, low-temperature vacuum drying, high-temperature decomposition, formation of fluorinated lutetium compounds under hydrofluoric acid, and bonding of lutetium to glass at high temperature. 177 Lu-labeled medical glass microspheres possess high nuclear purity, uniform particle size distribution, moderate specific gravity, high specific activity, and good stability. They can be administered via hepatic artery intervention to achieve arterial embolization of liver cancer areas, and SPECT / CT can be used for in vivo monitoring to assess the distribution and therapeutic effect of the microsphere drugs in vivo.

[0016] The key to this invention lies in using low-concentration hydrofluoric acid for treatment, which effectively reduces... 177 The solubility of Lu in blood is reduced, and then high-temperature calcination is used to firmly bond lutetium fluoride and nanoporous glass, effectively reducing the risk of oxidation. 177 Lu's release.

[0017] Furthermore, in step (1), the nanoporous glass has a particle size of 20-50 μm, a micropore size of 5-400 nm, a porosity of 30-90%, and a specific surface area of ​​30-500 m². 2 / g, with an effective density of 1.5-2.2g / cm³ in aqueous solution.3 .

[0018] Furthermore, in step (2), including 177 Lu's dilute acid system includes hydrochloric acid, nitric acid, or sulfuric acid systems.

[0019] Furthermore, in step (3), low-temperature vacuum drying refers to a pressure of 10-100 mbar and a temperature not exceeding 105℃.

[0020] Furthermore, in step (4), the high-temperature decomposition is carried out at a heating temperature of 600-650℃ for 1-2 hours.

[0021] Furthermore, in step (5), the concentration of the hydrofluoric acid should be between a concentration that can convert the oxide into a fluoride without significantly corroding the glass.

[0022] Furthermore, the concentration of the hydrofluoric acid includes 0.005M.

[0023] Furthermore, in step (6), the high-temperature calcination temperature is 750-800℃.

[0024] Furthermore, the aforementioned 177 The specific activity of Lu-labeled medical glass microspheres is 8-10 Ci / g, and the nuclear purity reaches 100%.

[0025] Furthermore, the aforementioned 177 Lu-labeled medical glass microspheres were administered daily in 0.9% physiological saline solution for the first 19 days. 177 Lu release rate is 0.1%-0.3%, daily over days 20-30. 177 The Lu release rate is 0.45%-0.63%.

[0026] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0027] 1. The preparation method of this invention is simple to operate and can be completed in a common shielding box, yielding... 177 Lu-labeled medical glass microspheres possess high nuclear purity (100%), uniform particle size distribution (20–50 μm >99%), high specific activity (8–10 Ci / g), micropore size of 5–400 nm, porosity of 30–90%, and effective density in aqueous solution of 1.5–2.2 g / cm³. 3 .

[0028] 2. This invention relates to labeled radionuclides. 177 Lu, the glass microspheres themselves do not require irradiation, thus avoiding the generation of radioactive impurities caused by irradiating the glass microspheres themselves.

[0029] 3. The product prepared by this invention177 Lu labeled medical glass microspheres, in 0.9% normal saline, within the first 19 days, daily 177 Lu release rate of 0.1%-0.3%, within the 20th-30th day, daily 177 Lu release rate of 0.45%-0.63%, with 90 Y glass microspheres are equivalent to those described in the published documents, with good stability.

[0030] 5. The present invention uses low concentration of hydrofluoric acid for treatment, effectively reducing 177 Lu solubility in blood, and through high temperature calcination, the Lu fluoride and nano-porous glass are firmly combined in the form of chemical bond and physical wrapping, effectively reducing 177 Lu release. BRIEF DESCRIPTION OF DRAWINGS

[0031] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following will briefly introduce the drawings needed to be used in the embodiments, and it should be understood that the following drawings only show some embodiments of the present invention, and therefore should not be considered as a limitation on the scope, and for those skilled in the art, other related drawings can also be obtained without creative labor. In the drawings:

[0032] Figure 1 The flow chart for preparing 177 Lu labeled medical glass microspheres of the present invention;

[0033] Figure 2 The electron microscope image of 177 Lu labeled medical glass microspheres prepared in Example 1. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solutions and advantages of the present invention more clear and obvious, the following will further describe the present invention in combination with the embodiments and drawings, and the exemplary embodiments of the present invention and the description thereof are only used to explain the present invention, and should not be considered as a limitation on the present invention.

[0035] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, it is apparent to those skilled in the art that the present invention can be practiced without these specific details. In other embodiments, well-known structures, materials or methods are not specifically described in order to avoid obscuring the present invention.

[0036] Throughout this specification, references to "an embodiment," "an example," or "an example" mean that a particular feature, structure, or characteristic described in connection with that embodiment or example is included in at least one embodiment of the invention. Therefore, the phrases "an embodiment," "an example," "an example," or "an example" appearing in various places throughout the specification do not necessarily refer to the same embodiment or example. Furthermore, specific features, structures, or characteristics can be combined in one or more embodiments or examples in any suitable combination and / or sub-combination.

[0037] This invention provides 177 The method for preparing Lu-labeled medical glass microspheres, wherein 177 Lu-labeled medical glass microspheres include nanoporous glass microspheres and 177 The fluoride of Lu, the 177 Fluorides of Lu are adsorbed on the surface and within the pores of nanoporous glass microspheres; the preparation process includes the following steps:

[0038] (1) Cleaning of nanoporous glass;

[0039] (2) containing 177 Lu undergoes an adsorption reaction with nanoporous glass in a dilute acid system.

[0040] (3) Low-temperature vacuum drying to remove liquid;

[0041] (4) High-temperature decomposition, 177 Lu's salts are transformed into 177 Oxides of Lu;

[0042] (5) Hydrofluoric acid treatment, 177 Lu oxides transform into 177 Fluorides of Lu;

[0043] (6) Obtained after high-temperature calcination 177 Lu-labeled medical glass microspheres.

[0044] Preferably, in step (1), the nanoporous glass has a particle size of 20-50 μm, a micropore size of 5-400 nm, a porosity of 30-90%, and a specific surface area of ​​30-500 m². 2 / g, with an effective density of 1.5-2.2g / cm³ in aqueous solution. 3 .

[0045] Preferably, in step (2), the following is included: 177 Lu's dilute acid system includes hydrochloric acid, nitric acid, or sulfuric acid systems.

[0046] As preferred, in step (3), the low-temperature and reduced-pressure drying refers to: the pressure is 10-100 mbar, and the temperature is not higher than 105℃.

[0047] As preferred, in step (4), the high-temperature decomposition refers to: the heating temperature is 600-650℃, and the heating time is 1-2 hours.

[0048] As preferred, in step (5), the concentration of the hydrofluoric acid should be within the range that can convert the oxide into fluoride without obviously corroding the glass.

[0049] As preferred, the concentration of the hydrofluoric acid includes 0.005M.

[0050] As preferred, in step (6), the high-temperature calcination temperature is 750-800℃.

[0051] The radionuclide of the medical glass microspheres of the present application is 177 Lu, with a half-life of 6.7 days, has been developed for the treatment of neuroendocrine tumors and prostate cancer, and has good medical safety and effectiveness. Meanwhile, 177 Lu can not only release β rays for tumor treatment, but also release 208keV γ rays for SPECT / CT monitoring, which is convenient for radio-pharmaceutical distribution and dose monitoring. In addition, 177 The γ ray energy of Lu is low, and the influence on the surrounding environment of the patient is lower, which can better protect the surgical operators and postoperative caregivers.

[0052] The Lu-177 labeled medical glass microspheres of the present application can complete the arterial embolization of the liver cancer region through the hepatic arterial intervention administration mode, and can be monitored in vivo through SPECT / CT to evaluate the distribution and treatment of the microsphere drugs in the body.

[0053] The main material of the medical glass microspheres of the present application is nano-porous glass, which has a lower specific gravity than solid glass and resin, and the injection operation is simple and convenient, and good drug distribution can be achieved in the liver tissue.

[0054] The medical glass microspheres prepared by the present application have no obvious difference in physical and chemical properties from the raw material microspheres, and the main properties are: the particle size is 20-50μm, the pore size is 5 to 400nm, the porosity is 30-90%, the specific surface area is 30-500m 2 / g, the effective density in aqueous solution is 1.5-2.2g / cm 3 , the specific activity of the treated microspheres is 8-10Ci / g, and the nuclear purity can reach 100%.

[0055] Example 1

[0056] A 177 method for preparing Lu labeled medical glass microspheres, comprising the following steps:

[0057] (1) Selection, weighing, and cleaning of nanoporous glass: Accurately weigh 45mg of glass with a particle size of 20-50μm, a micropore size of 5-400 nm, a porosity of 30-90%, and a specific surface area of ​​30-500 m². 2 / g, density in aqueous solution is 1.5-2.2g / cm³ 3 Glass microspheres were prepared. The microspheres were washed three times with distilled water and then dried completely at 105°C.

[0058] (2) 177 Adsorption of Lu on nanoporous glass: Prepare 60 μL of 0.05 M dilute nitric acid solution. 177 The Lu activity was 20 GBq. Glass microspheres were poured into centrifuge tubes, followed by the prepared... 177 Lu's nitric acid solution was added dropwise to a centrifuge tube, the centrifuge tube was closed, and the adsorption reaction was allowed to proceed for 1 hour.

[0059] (3) Drying under low temperature and reduced pressure: Open the centrifuge tube and evaporate the nitric acid for 1 hour under a low pressure of 10 mabr. Then slowly raise the temperature from 60°C to 105°C to remove all the liquid.

[0060] (4) High-temperature decomposition: The microspheres were poured from the centrifuge tube into a ceramic combustion dish, and the temperature was slowly raised to 600°C and maintained for one hour to convert lutetium nitrate into lutetium oxide. After high-temperature treatment, the glass microspheres were slowly cooled at room temperature.

[0061] (5) Formation of lutetium fluoride under hydrofluoric acid: After cooling, the glass microspheres were poured into a new centrifuge tube, washed three times with 1 mL of distilled water, and then centrifuged. The microspheres were dried at 90 °C for one hour. 60 μL of 0.005 M hydrofluoric acid was added to the centrifuge tube, and the mixture was reacted at 10 mbar for 10 minutes. The reaction was then carried out in a constant temperature oven at 30 °C for another 30 minutes. The mixture was then dried at 105 °C until all unreacted hydrofluoric acid was evaporated.

[0062] (6) Bonding of lutetium and glass at high temperature: Glass microspheres were poured into a ceramic combustion dish and heated to 750°C for 2 hours. After thorough heating, the lutetium fluoride and the nanoporous glass bonded tightly together, ultimately yielding 50mg. 177 Lu glass microspheres.

[0063] After cleaning, measurement of indicators such as activity and particle size, and disinfection, the product can be packaged.

[0064] The preparation in this embodiment 177 Lu-labeled medical glass microspheres were administered daily in 0.9% physiological saline solution for the first 19 days. 177 Lu release rate is 0.1%-0.3%, daily over days 20-30.177 Lu release rate is 0.45%-0.63%, compared with 90 The Y-glass microspheres exhibit good stability, as described in the publicly available documentation.

[0065] Example 2

[0066] A sort of 177 The method for preparing Lu-labeled medical glass microspheres includes the following steps:

[0067] (1) Selection, weighing, and cleaning of nanoporous glass: Accurately weigh 38mg of glass with a particle size of 20-50μm, a micropore size of 5-400 nm, a porosity of 30-90%, and a specific surface area of ​​30-500 m². 2 / g, density in aqueous solution is 1.5-2.2g / cm³ 3 Glass microspheres were prepared. The microspheres were washed three times with distilled water and then dried completely at 105°C.

[0068] (2) 177 Adsorption of Lu on nanoporous glass: Prepare 60 μL of 0.05 M dilute nitric acid solution. 177 The Lu activity was 20 GBq. Glass microspheres were poured into centrifuge tubes, followed by the prepared... 177 Lu's hydrochloric acid solution was added dropwise to a centrifuge tube, the centrifuge tube was closed, and the adsorption reaction was allowed to proceed for 1.5 hours.

[0069] (3) Drying under low temperature and reduced pressure: Open the centrifuge tube and evaporate the nitric acid for 1 hour under a low pressure of 40mBr. Then slowly raise the temperature from 60℃ to 105℃ to remove all the liquid.

[0070] (4) High-temperature decomposition: The microspheres were poured from the centrifuge tube into a ceramic combustion dish, and the temperature was slowly raised to 600°C and maintained for one hour to convert lutetium nitrate into lutetium oxide. After high-temperature treatment, the glass microspheres were slowly cooled at room temperature.

[0071] (5) Formation of lutetium fluoride under hydrofluoric acid: After cooling, the glass microspheres were poured into a new centrifuge tube, washed three times with 1 mL of distilled water, and then centrifuged. The microspheres were dried at 90 °C for one hour. 60 μL of 0.005 M hydrofluoric acid was added to the centrifuge tube, and the mixture was reacted at 10 mbar for 10 minutes. The reaction was then carried out in a constant temperature oven at 30 °C for another 30 minutes. The mixture was then dried at 105 °C until all unreacted hydrofluoric acid was evaporated.

[0072] (6) Bonding of lutetium and glass at high temperature: Glass microspheres were poured into a ceramic combustion dish and heated to 750°C for 2 hours. After sufficient heating, the lutetium fluoride and the nanoporous glass were bonded together by chemical bonds and physical encapsulation. 177 Lu will not be released outside the microspheres, thus obtaining177 Lu-labeled medical glass microspheres.

[0073] After cleaning, measurement of indicators such as activity and particle size, and disinfection, the product can be packaged.

[0074] Example 3

[0075] A sort of 177 The method for preparing Lu-labeled medical glass microspheres includes the following steps:

[0076] (1) Selection, weighing, and cleaning of nanoporous glass: Accurately weigh 45mg of glass with a particle size of 20-50μm, a micropore size of 5-400 nm, a porosity of 30-90%, and a specific surface area of ​​30-500 m². 2 / g, density in aqueous solution is 1.5-2.2g / cm³ 3 Glass microspheres were prepared. The microspheres were washed three times with distilled water and then dried completely at 105°C.

[0077] (2) 177 Adsorption of Lu on nanoporous glass: Prepare 60 μL of 0.05 M dilute nitric acid solution. 177 The Lu activity was 20 GBq. Glass microspheres were poured into centrifuge tubes, followed by the prepared... 177 Lu's sulfuric acid solution was added dropwise to a centrifuge tube, the centrifuge tube was closed, and the adsorption reaction was allowed to proceed for 1 hour.

[0078] (3) Drying under low temperature and reduced pressure: Open the centrifuge tube and evaporate the nitric acid for 1 hour under a low pressure of 80mbr. Then slowly raise the temperature from 60℃ to 105℃ to remove all the liquid.

[0079] (4) High-temperature decomposition: The microspheres were poured from the centrifuge tube into a ceramic combustion dish, and the temperature was slowly raised to 650°C and maintained for 1.5 hours to convert lutetium nitrate into lutetium oxide. After high-temperature treatment, the glass microspheres were slowly cooled at room temperature.

[0080] (5) Formation of lutetium fluoride under hydrofluoric acid: After cooling, the glass microspheres were poured into a new centrifuge tube, washed three times with 1 mL of distilled water, and then centrifuged. The microspheres were dried at 90 °C for one hour. 60 μL of 0.005 M hydrofluoric acid was added to the centrifuge tube, and the mixture was reacted at 10 mbar for 10 minutes. The reaction was then carried out in a constant temperature oven at 30 °C for another 30 minutes. The mixture was then dried at 105 °C until all unreacted hydrofluoric acid was evaporated.

[0081] (6) Bonding of lutetium and glass at high temperature: Glass microspheres were poured into a ceramic combustion dish and heated to 800°C for 2 hours. After sufficient heating, the lutetium fluoride and the nanoporous glass were bonded together by chemical bonds and physical encapsulation. 177Lu will not be released to the microspheres outside, get 177 Lu labeled medical glass microspheres.

[0082] After the measurement of the indicators such as washing, activity particle size, etc., it can be sub-packaged after sterilization.

[0083] Comparative example

[0084] The difference between this comparative example and example 1 is that after the hydrofluoric acid treatment in step (5), no high-temperature calcination furnace treatment in step (6) is performed, and the final obtained 177 The Lu glass microspheres have a much higher nuclide release rate in 0.9% normal saline than in 0.1% after high-temperature treatment.

[0085] The above specific embodiments further illustrate the purposes, technical solutions and beneficial effects of the present application. It should be understood that the above description is only a specific embodiment of the present application and is not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, The 177 Lu-labeled medical glass microspheres include nano-porous glass microspheres and 177 fluorides of Lu, which are adsorbed on the surface and micropores of the nano-porous glass microspheres 177 fluorides of Lu, which are adsorbed on the surface and micropores of the nano-porous glass microspheres The preparation process comprises the following steps: (1) cleaning of the nano-porous glass; (2) the acid system containing Lu 177 adsorption reaction of Lu's dilute acid system with nano-porous glass (3) low-temperature and reduced-pressure drying to remove the liquid; (4) pyrolysis, which causes 177 the salt species of Lu to transform into 177 oxides of Lu; (5) hydrofluoric acid treatment, to convert 177 oxides of Lu to 177 fluorides of Lu; (6) 750-800°C high temperature calcination 177 Lu-labelled medical glass microspheres.

2. A method according to claim 1 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, In step (1), the nanoporous glass has a particle size of 20-50 μm, a pore size of 5-400 nm, a porosity of 30-90%, and a specific surface area of 30-500 m 2 / g, and an effective density in aqueous solution of 1.5-2.2 g / cm 3 .

3. A method according to claim 1 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, In step (2), the solution containing 177 The dilute acid system of Lu includes a hydrochloric acid, nitric acid or sulfuric acid system.

4. A method according to claim 1 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, In step (3), the low-temperature and reduced-pressure drying refers to that the pressure is 10-100 mbar and the temperature is not higher than 105℃.

5. A method according to claim 1 wherein the step of forming the glass microspheres comprises the step of: 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, In step (4), the high-temperature decomposition refers to that the heating temperature is 600-650℃ and the heating time is 1-2 hours.

6. A method according to claim 1 wherein the step of forming the glass microspheres comprises the step of: 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, In step (5), the concentration of the hydrofluoric acid should be within a range that can convert the oxide into fluoride without obviously corroding the glass.

7. A method according to claim 6 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, The concentration of the hydrofluoric acid includes 0.005M.

8. A method according to claim 1 wherein the step of forming the glass microspheres comprises the step of: 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, The 177 The specific activity of Lu-labelled medical glass microspheres is 8-10 Ci / g, and the nuclear purity reaches 100%.

9. A method according to claim 1 wherein the glass microspheres are medical grade glass microspheres. 177 A method for preparing Lu-labeled medical glass microspheres, characterized in that, The 177 The Lu labeled medical glass microspheres in 0.9% saline solution, within the first 19 days, had a daily 177 The Lu release rate was 0.1-0.3% within the 20-30 days, daily 177 The Lu release rate was 0.45-0.63%.

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