Method for preparing a radiopharmaceutical and radium-224 radiopharmaceutical

Abstract

The objective of the present invention is to provide a method for preparing a radiopharmaceutical that can relatively easily prepare the progenitor nuclide Radium 224 from Thorium 232, which exists in relatively large quantities in nature. It is characterized by separating, recovering, and purifying the progenitor nuclide Radium 224 from Thorium 232 by chemical manipulation, and using it as a targeted alpha-ray therapeutic agent.

Description

Technology Field

[0001] The present invention relates to a radiopharmaceutical used in targeted nuclear medicine (α-ray) therapy and a method for preparing the same, and in particular to a technology effective when applied to a radiopharmaceutical using radium 224 as an α-ray source. Background Technology

[0002] Targeted nuclear medicine (α-ray) therapy using radiopharmaceuticals loaded with radionuclides that emit alpha rays (α-rays) on drugs that selectively accumulate in cancer cells (hereinafter also referred to as "targeted α-ray therapy") is expected to be a new cancer treatment method that combines high therapeutic efficacy with low side effects. In particular, since a German scientist cured metastatic prostate cancer in 2016 using a radiopharmaceutical with Actinium 225 (half-life 10.0 days) as an α-ray source, targeted α-ray therapy has attracted worldwide attention, and many researchers are conducting related research and development. However, most α-ray radionuclides are difficult to obtain, and relatively readily available radionuclides are required.

[0003] As background technology in this technical field, there is, for example, technology such as Patent Document 1. Patent Document 1 describes, "for use in the treatment of cancer or inflammation, a) Radium 224 ( 224 Ra) and / or 224 A “formulation relating to a combination of a progeny of Ra and a DNA repair inhibitor” is disclosed.

[0004] In addition, Non-patent Literature 1 discloses the entire phase of targeted alpha radiation therapy and its efficacy.

[0005] In addition, Non-patent document 2 discloses a preparation of a radiopharmaceutical containing lead 212 that emits beta (β) rays. Prior art literature

[0006] Japanese Patent Publication No. 2023-541635

[0007] Young-Seung Kim et al., "An overview of targeted alpha therapy", Tumour Biol., Vol.33, 2012 June, p.573-590 Sara Westrom et al., "Preparation of 212Pb-labeled monoclonal antibody using a novel 224Ra-based generator solution", Nuclear Medicine and Biology, Vol.51, 2017, p.1-9 The problem to be solved

[0008] Actinium 225 is obtained by milking thorium 229, a daughter nuclide of uranium 233 manufactured by countries developing nuclear weapons. Since the number of countries possessing uranium 233 or thorium 229 is limited, research and development to produce actinium 225 in accelerators or nuclear reactors is being conducted in countries around the world as an alternative technology. At this time, radium 226 or thorium 230 are used as raw nuclides, and the low abundance of these nuclides limits the mass production of actinium 225.

[0009] As a method for manufacturing Actinium 225, there is a method that utilizes the nuclear fragmentation reaction of naturally occurring Thorium 232, but an accelerator is required to irradiate the protons.

[0010] Astatine 211 (half-life 7.22 hours) and Radium 223 (half-life 11.4 days) are known as medical alpha nuclides other than Actinium 225, but they are likewise produced as progenitor nuclides of the weapon nuclide Uranium 235 or accelerators, and have the same challenges as Actinium 225. The raw material for Astatine 211 is Bismuth 209, a stable nuclide found in nature, but it requires an accelerator to irradiate helium nuclei (alpha particles), and because of its short half-life, treatment must be performed near the manufacturing site.

[0011] Meanwhile, Radium 224, a daughter nuclide of Thorium 232, has a half-life of 3.66 days, which is a suitable length, so it can be transported even from a remote location and can be manufactured from Thorium 232, which is easily available even to non-nuclear states, without using large-scale devices such as accelerators or nuclear reactors.

[0012] The above patent document 1 is an invention relating to a combination of Radium 224 and various drugs as a radiopharmaceutical used for cancer treatment, and does not contain a technology for a method of preparing (manufacturing) Radium 224.

[0013] In addition, the above-mentioned non-patent document 1 is a paper summarizing the overall picture of targeted alpha-ray therapy, but it does not describe Radium 224. In addition, the above-mentioned non-patent document 2 is a paper concerning a radiopharmaceutical containing lead 212 that emits beta (β) rays, and although lead 212 is prepared from thorium 228, which is a nuclide of radium 224, it does not describe the use of radium 224 as a radiopharmaceutical, nor does it describe a method for preparing (manufacturing) thorium 228, which does not exist in nature.

[0014] In any of the aforementioned documents, the preparation (manufacturing) of Radium 224 becomes a challenge.

[0015] Accordingly, the objective of the present invention is to provide a method for preparing a radiopharmaceutical that can relatively easily prepare the progenitor nuclide Radium 224 from Thorium 232, which exists in relatively large quantities in nature, and a Radium 224 radiopharmaceutical using the same. means of solving the problem

[0016] To solve the above problem, the method for preparing a radiopharmaceutical according to the present invention is characterized by separating, recovering, and purifying the progenitor nuclide Radium 224 from Thorium 232 by chemical manipulation, and using it as a targeted alpha-ray therapeutic agent.

[0017] In addition, the radium 224 radiopharmaceutical of the present invention is characterized by being prepared by the method of preparing the radiopharmaceutical. Effects of the invention

[0018] According to the present invention, a method for preparing a radiopharmaceutical that can relatively easily prepare the progenitor nuclide Radium 224 from Thorium 232, which exists in relatively large quantities in nature, and a Radium 224 radiopharmaceutical using the same can be realized.

[0019] This can contribute to targeted nuclear medicine (α-ray) therapy using radiopharmaceuticals.

[0020] Problems, configurations, and effects other than those mentioned above will become clear from the description of the following embodiments. Brief explanation of the drawing

[0021] Figure 1 is a flowchart illustrating the three-step milking method of the present invention. FIG. 2 is a schematic diagram illustrating a method for preparing Radium 224 according to Example 1 of the present invention. FIG. 3 is a schematic diagram illustrating a method for preparing Radium 224 according to Example 2 of the present invention. Figure 4 is a diagram showing the relationship between the elapsed time, mass, and radioactivity of each nuclide at each stage of Figure 1. Specific details for implementing the invention

[0022] Hereinafter, embodiments of the present invention will be described using the drawings. In addition, in each drawing, the same reference numerals are assigned to identical components, and detailed descriptions of overlapping parts are omitted.

[0023] [Example 1]

[0024] With reference to FIGS. 1, 2, and 4, a method for preparing a radioactive pharmaceutical according to Example 1 of the present invention and a Radium 224 radioactive pharmaceutical using the same will be described.

[0025] FIG. 1 is a flowchart illustrating the three-step milking method of the present invention. FIG. 2 is a schematic diagram illustrating the method for preparing Radium 224 by column chromatography according to the present invention. FIG. 4 is a diagram showing the relationship between the elapsed time, mass, and radioactivity of each nuclide in each step of FIG. 1, with the horizontal axis (time) and the vertical axis (mass and radioactivity) represented as relative values. In this embodiment, a case is described in which the preparation of Radium 224 is realized by column chromatography in which extraction chromatography, leaching, ion exchange, solvent extraction, precipitation, and adsorption methods are carried out on a column.

[0026] As shown in FIG. 1, in the present invention, radium 224 is recovered from thorium 232, which is confirmed to exist in quantities of more than 2 million tons on Earth, through a three-stage milking process. “Milking” is an operation of repeatedly separating and extracting short-lived daughter nuclides from nuclides with long half-lives when a radiometric average is established.

[0027] First, in the first stage (1st) milking M1, Radium 228 with a half-life of 5.75 years is milked from Thorium 232 with a half-life of 14.1 billion years. That is, Radium 228 is separated and recovered from Thorium 232. In the case of Thorium 232, where the separation operation of daughter nuclides has not been performed for a long time, the Radium 228 daughter nuclide becomes radioaveraged, and about 40 MBq of Radium 228 exists in 10 kg of Thorium 232. Furthermore, after separating and recovering Radium 228 from 10 kg of Thorium 232, about 20 MBq of Radium 228 grows after 5.75 years, about 30 MBq after 11.5 years, and about 35 MBq after 23 years.

[0028] In this way, even after radium-228 has been recovered once, it can be recovered repeatedly every few years to decades. If multiple thorium-232s are prepared, the recovery interval can be shortened. For example, if 10 thorium-232s (10 kg / unit) are prepared and radium-228 is recovered in sequence, approximately 20 MBq of radium-228 can be recovered at intervals of about 7 months in the above case.

[0029] Next, in the second milking M2, Radium 228, which was separated and recovered from Thorium 232 in the first stage, is used as the nuclide, and through the daughter nuclide Actinium 228, which has a half-life of 6.13 hours, the grandchild nuclide Thorium 228, which has a half-life of 1.91 years, is recovered. In the second milking M2, since the half-lives of Radium 228 and Thorium 228 are close, the radiation average is not formed, and Thorium 228 grows along with the decay of Radium 228. From 40 MBq of Radium 228, about 5 MBq of Thorium 228 grows in about 5 months, about 10 MBq in about 1 year, and about 20 MBq in about 5 years. The growth of thorium-228 reaches a maximum in 2 to 8 years, then decays, and becomes about 1 MBq after 30 years.

[0030] When thorium 228 is recovered every 5 months, radium 228 is not decaying significantly, so although the amount of thorium 228 recovered gradually decreases, it is possible to recover thorium 228 near the amount mentioned above repeatedly. Also, when thorium 228 is recovered every 5 years, radium 228 decays by about half every 5 years, and about 10 MBq of thorium 228 can be recovered in the second time and about 5 MBq in the third time. Finally (after about 30 years), when radium 228 decays to about 1 MBq or less, radium 228 is supplied by the first milking M1.

[0031] Next, in the third stage (3rd) of the milking M3, the target nuclide, Radium 224 with a half-life of 3.66 days, is separated and recovered from Thorium 228 with a half-life of 1.91 years, which was separated and recovered from Radium 228. Since the half-life of Thorium 228 is two orders of magnitude longer than the half-life of Radium 224 and the half-life of Radium 224 is short, Thorium 228 after separating Radium 224 becomes radiometrically averaged with Radium 224 after about 5 days or more. That is, until about 10 years, when Thorium 228 decays, Radium 224 with the same number of becquerels as Thorium 228 can be recovered at intervals of 5 to 10 days. If the thorium 228 recovered from the second milking M2 is 5 MBq, then radium 224 with a radioactivity of 5 MBq or close to 5 MBq can be recovered from the 5 MBq of thorium 228 at intervals of several days to several tens of days.

[0032] In the above process, Radium 224, which is used as a targeted alpha-ray therapeutic agent, can be separated and recovered from Thorium 232, which exists in relatively large quantities in nature, through chemical manipulation alone without using large devices such as accelerators or nuclear reactors.

[0033] Figure 2 shows a process for realizing three-stage milking by filling or forming a solid phase containing thorium, which is sparingly soluble and highly adsorbent, into a column, and then eluting only radium, which is difficult to form a solid phase due to its relatively easy dissolution.

[0034] First, in step (1), an anion exchange resin (2) adsorbing thorium 232 (half-life 14.1 billion years) containing progenitor nuclides such as radium 228 (half-life 5.75 years) is loaded into the first column (1), and a radium eluent 4 containing radium 228, etc. is eluted with a radium eluent 3, such as nitric acid, having a concentration of about a few moles / liter. While thorium 232 remains adsorbed, progenitor nuclides other than thorium 228 (half-life 1.91 years) are eluted. In this way, radium 228 is completely separated from thorium 232.

[0035] Next, in step (2), after storing the solution containing eluted radium 228, etc. for several days or more, it is injected into a second column (5) filled with an anion exchange resin (6), and a radium eluent (7), such as nitric acid, is passed through it. Thorium 228 grown from radium 228 is adsorbed onto the anion exchange resin (6), and other nuclides (8), such as radium 228, are eluted. In this way, radium 228 is completely removed from thorium 228.

[0036] Finally, in step (3), after removing radium 228 from the thorium 228 adsorbed in step (2), the second column (5) is left as is for at least one day to wait for the growth of radium 224, and a radium eluent (11), such as nitric acid, is passed through the second column (5). By doing so, the intended radium 224 (half-life 3.66 days) (12) grown from thorium 228 is eluted.

[0037] In addition, instead of anion exchange resin (2) or anion exchange resin (6), a material (solid) that adsorbs thorium other than anion exchange resin may be used.

[0038] In addition, in step (3), the anion exchange resin (6) after removing Radium 228 may be transferred to a separate column, in which case a separate column (third column) is required.

[0039] By the above column chromatography, Radium 224, which is used as a targeted alpha-ray therapeutic agent, can be separated and recovered from Thorium 232, which exists in relatively large quantities in nature, through chemical manipulation alone without using large devices such as accelerators or nuclear reactors.

[0040] In addition, in step (1), in addition to the anion exchange resin (2), a material that adsorbs thorium 232, such as UTEVA (registered trademark) resin, may be applied. Also, the thorium 232 loaded into the first column (1) may be in the state of thorium dioxide ThO2. Thorium dioxide ThO2 is stable and does not dissolve in nitric acid, but progenitor nuclides such as radium 228 dissolve and are discharged from the first column (1).

[0041] In addition, in step (2), in addition to the anion exchange resin (6), any material that adsorbs or extracts thorium 228, such as UTEVA resin, or any solid containing thorium 228 can be applied as a material impregnated with the extracting agent. Furthermore, it is acceptable to denitrify the radium 228 nitric acid solution after storing it for several years to form an oxide, or to denitrify the radium 228 nitric acid solution immediately after separation and store it for several years, and then load it into a second column (5) that is not filled with anion exchange resin (6). Thorium dioxide (ThO2) is stable and does not dissolve in nitric acid, but radium 228, etc., dissolve and are discharged from the second column (5).

[0042] After completely removing Radium 228 and allowing more than one day to pass, in step (3), by passing a radium eluent (11), such as nitric acid, the target Radium 224 grown from Thorium 228 can be dissolved and recovered from the second column (5).

[0043] In addition, the first column (1) of step (1) can be stored for a long period (over several years) so that progeny nuclides grow, and thus repeated radium 224 can be obtained by the above procedure.

[0044] By the embodiment described above, thorium 232 (with reserves of 2 million tons or more) which exists in large quantities in nature can be utilized, and radium 224, which is effective as an α-nuclide for radiopharmaceuticals, can be prepared without using large devices such as accelerators or nuclear reactors.

[0045] [Example 2]

[0046] With reference to FIG. 3, a method for preparing a radioactive pharmaceutical according to Example 2 of the present invention and a Radium 224 radioactive pharmaceutical using the same will be described.

[0047] FIG. 3 is a schematic diagram illustrating the preparation of Radium 224 by the solvent extraction method according to the present invention. In this embodiment, a process for realizing three-stage milking by the solvent extraction method is described.

[0048] First, in step (1), thorium 232 containing progenitor nuclides such as radium 228 is dissolved in nitric acid or the like and placed into a solvent extraction device (13) to form a aqueous phase (15). Then, a solvent (organic phase) (14), such as TBP (Tributyl-Phosphate: tribubutyl phosphate), which extracts thorium, is added to this and shaken, so that only thorium is extracted and transferred from the aqueous phase (15) to the organic phase (14). If necessary, extraction with a new solvent is repeated to completely transfer the thorium 232 in the aqueous phase (15) to the organic phase (14).

[0049] Next, in step (2), the organic phase (14) containing thorium 232 is removed from the solvent extraction device (13), and the aqueous phase (17) containing radium 228 is stored for several days or more, and a new solvent (organic phase) (16), such as TBP, is added and shaken. Thorium 228 grown from radium 228 is extracted and transferred from the aqueous phase (17) to the organic phase (16). If necessary, extraction with a new solvent is repeated to transfer as much thorium 228 into the organic phase (16) as possible, while ensuring that radium 228 is not mixed into the organic phase (16).

[0050] Finally, in step (3), the aqueous phase (17) containing radium 228 is removed from the solvent extraction device (13), the organic phase (18) containing thorium 228 is stored for at least one day, and a new solution (aqueous phase) (19), such as nitric acid, is added and shaken. Radium 224 grown from thorium 228 is back-extracted and transferred from the organic phase (18) to the aqueous phase (19).

[0051] By the above solvent extraction operation, Radium 224, which is used as a targeted alpha-ray therapeutic agent, can be separated and recovered from Thorium 232, which exists in relatively large quantities in nature, using only chemical operations without using large devices such as accelerators or nuclear reactors.

[0052] In addition, as the solvent extraction device (13) in Example 2, a separating funnel, a mixer settler, a centrifugal extractor, etc., may be used, and extraction may be performed in multiple stages as well as in a single stage. In addition, a continuous (multi-stage) solvent extraction device such as a pulse column may be used.

[0053] According to each embodiment of the present invention described above, radium 224 can be prepared (manufactured) without using an accelerator or a nuclear reactor by milking thorium 232 existing in nature in three steps.

[0054] The alpha radionuclides used in targeted alpha therapy have half-lives ranging from several hours to tens of days and are prepared (manufactured) from source radionuclides using nuclear reactions. Furthermore, if the source radionuclides do not exist in nature, they are prepared by arbitrary methods. Most alpha radionuclides known to date for targeted alpha therapy use radionuclides that do not exist in nature as source materials, and even if they do exist in nature, they are manufactured using large-scale devices such as accelerators or nuclear reactors. Consequently, there were issues with obtaining source radionuclides, and cancer patients needed to receive treatment in a location close to these large devices.

[0055] In the present invention, the α-nuclide can be prepared using a laboratory-scale device and thorium-232, which is abundant in nature, as the raw material nuclide, thus solving the above-mentioned problem. In particular, once thorium-228 that does not contain radium-228 is prepared, and the second column (5) that adsorbed thorium-228 is taken to a hospital capable of synthesizing radiopharmaceuticals, cancer patients can be treated for about 10 years without supplying radium-224.

[0056] Furthermore, the present invention is not limited to the embodiments described above and includes various modifications. For example, the embodiments described above are detailed to facilitate understanding of the present invention and are not necessarily limited to having all the described configurations. Additionally, it is possible to substitute a part of the configuration of one embodiment with a part of another embodiment, and it is also possible to add a part of another embodiment to a part of one embodiment. Furthermore, it is possible to add, delete, or substitute other configurations for a part of the configuration of each embodiment.

[0057] [Industrial Applicability]

[0058] The present invention has potential for use in the medical field of cancer treatment using radiopharmaceuticals loaded with α-nuclides, the radiochemical field of separating progeny nuclides from natural thorium, the nuclear reprocessing field of removing impurities from irradiated thorium fuel, and the waste treatment field of separating nuclides from radioactive waste. Explanation of the symbols

[0059] 1: Column 1 2, 6, 10: Anion exchange resin 3, 7, 11: Radium eluent 4: Radium eluent 5: Column 2 8: Other nuclides such as Radium-228 12: Radium 224 13: Solvent extraction device 14, 16, 18: Yoo Gi-sang 15, 17, 19: Awards

Claims

Claim 1 A method for preparing a radiopharmaceutical characterized by separating, recovering, and purifying the progenitor nuclide Radium 224 from Thorium 232 by chemical manipulation, and using it as a targeted alpha-ray therapeutic agent. Claim 2 A method for preparing a radiopharmaceutical according to claim 1, wherein the chemical operation comprises at least one of the leaching method, ion exchange method, solvent extraction method, extraction chromatography method, precipitation method, and adsorption method. Claim 3 A method for preparing a radioactive pharmaceutical according to claim 1, characterized by having (a) a step of recovering Radium 228 from Thorium 232 by milking, (b) a step of recovering Thorium 228 from Radium 228 by milking, and (c) a step of recovering Radium 224 from Thorium 228 by milking. Claim 4 A method for preparing a radiopharmaceutical according to claim 3, characterized by having (d) a step of waiting for growth of the radium 228 (half-life 5.75 years) from the thorium 232 (half-life 14.1 billion years) for at least 6 years after step (c), (e) a step of waiting for growth of the thorium 228 (half-life 1.91 years) from the radium 228 for at least 4 days, and (f) a step of waiting for growth of the radium 224 (half-life 3.66 days) from the thorium 228 for at least 1 day. Claim 5 A method for preparing a radiopharmaceutical according to claim 1, characterized in that thorium 228 recovered from thorium 232 by two-stage milking is used as a nuclide, and radium 224 is recovered by a third stage milking. Claim 6 A method for preparing a radiopharmaceutical according to claim 1, characterized by: (g) a step of filling a first column with an oxide of thorium 232 and flowing a radium eluent to recover coexisting radium 228; (h) a step of waiting for thorium 228 to grow from the recovered radium 228, separating the thorium 228 from the radium 228, converting the thorium 228 into an oxide, and then filling it into a second column; and (i) making the thorium 228 a nuclide of radium 224, flowing the radium eluent at intervals of 1 to 10 days, and recovering the radium 224. Claim 7 A method for preparing a radiopharmaceutical according to claim 1, characterized by comprising: (j) a step of filling a first column with a first anion exchange resin that adsorbs thorium 232 containing a progenitor nuclide and flowing a radium eluent to recover coexisting radium 228; (k) a step of waiting for thorium 228 to grow from the recovered radium 228, injecting the thorium 228 into a second column filled with a second anion exchange resin, and flowing the radium eluent to elute and separate the radium 228; and (l) a step of making the thorium 228 after separation of the radium 228 a nuclide for radium 224, flowing the radium eluent at intervals of 1 to 10 days, and recovering the radium 224. Claim 8 A method for preparing a radiopharmaceutical according to any one of claims 1 to 7, characterized in that the radium 224 recovered from the thorium 232 is loaded onto a drug that accumulates in specific cancer cells. Claim 9 Radium 224 radiopharmaceutical characterized by being prepared by the method of preparing a radiopharmaceutical described in any one of claims 1 to 7.

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