Method for producing Ac-225 solution and method for producing pharmaceuticals using Ac-225 solution

Abstract

225 To provide a highly concentrated solution while suppressing Ac attenuation. [Solution] 226 Step I: irradiating a Ra target with particles to generate RI of two or more types of Ac; Step II: dissolving the target after Step I to obtain Ra-Ac solution 1; Step III: separating the Ra and Ac derived from the target contained in Solution 1 to obtain Ac solution 2 having an increased Ac concentration compared to Solution 1; 225 Step IV is to obtain Ra-Ac solution 3 containing Ra obtained by decaying RI of actinium other than Ac, and to separate Ra and Ac contained in solution 3 and compare them with solution 3. 225 and step V to obtain Ac solution 4 having an increased Ac concentration, which is used to produce the medicine shown below. (a) 225 A pharmaceutical comprising, as an active ingredient, a complex of a chelating agent complexed with Ac and an Nd2 antibody. (b) 225 A drug containing as an active ingredient a complex of a chelating agent complexed with Ac and a targeting agent other than Nd2 antibody.

Description

Technical Field

[0001] One aspect of the present invention relates to 225 a method for producing an Ac solution or a method for producing a pharmaceutical using the solution.

Background Art

[0002] In the field of nuclear medicine, radioisotope (RI) internal radiotherapy is performed, in which a drug containing a radioisotope (RI) is selectively taken up into lesions such as tumors for treatment. Among radiations, alpha rays have a short range and thus have the characteristic of having little influence on unnecessary exposure to surrounding normal cells. 225 Ac, which is one of the alpha-ray-emitting nuclides, is a radioactive nuclide with a half-life of 10 days and has been expected as a therapeutic nuclide in cancer treatment and the like in recent years.

[0003] 225 Ac is produced, for example, by 226 irradiating a Ra target with particles such as protons using an accelerator, and is produced by a (p,2n) nuclear reaction. Patent Document 1 discloses 226 a method for separating and purifying the Ac component from a solution containing Ra ions and 226 Ac ions obtained by dissolving the Ra target after particle irradiation. 225 from the solution containing 225 Ac components.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

[0005] 225 As radioactive isotopes of actinium obtained simultaneously with the production of Ac, 224 Ac (half-life 2.9 days) and 226 Ac (half-life 29 hours) can be mentioned. 224 Ac and 226 Ac have a half-life of225 Since it is shorter than Ac, leave it standing for a certain period of time. 224 and 226 After Ac decays into a metallic allonuclide other than actinium, 225 Ac and 226 Separation of Ra has been attempted. However, in this method, 226 The inventors realized that they had not taken into account the products produced by the fission of Ra.

[0006] 225 During Ac generation, 226 By Ra fission 140 Ba is generated. 140 Ba has a half-life of 12.75 days. 140 In order to transform into La, 224 Ac 226 If we allow a period of time for Ac to decay, 140 La is generated. 140 La and 225 Because it exhibits similar behavior to Ac, it is difficult to separate them, which raises concerns from a quality standpoint.

[0007] 140 Since La has a half-life of 1.7 days, it is possible that it could be eliminated by decay, 140 In the presence of Ba, due to radiative equilibrium... 140 La half-life 140 Since it will be the same as Ba, 140 If we try to eliminate La through decay, ultimately, 224 Ac 226 A longer standing period is required than the decay of Ac. 225 It was discovered that there is a problem of Ac loss.

[0008] One aspect of the present invention is, 225 While suppressing the attenuation of Ac, 225 High quality of Ac concentrate 225 This document provides a method for producing an Ac solution.

[0009] The inventors of this invention have diligently studied methods to solve the above problems and have found that the above problems can be solved by the following configuration example, thereby completing the present invention.

[0010] One aspect of the present invention is, 226 The Ra target is irradiated with at least one particle selected from protons, deuterons, neutrons, and photons, at least 225 A step (I) to produce two or more radioactive isotopes (Ac) of actinium, including Ac, After the above step (I) 226 Dissolve the Ra target, 226 Step (II) to obtain a Ra-Ac solution (1) containing Ra and Ac, The above Ra-Ac solution (1) contains, 226 Ra target derived 226 Step (III) involves separating Ra and Ac to obtain an Ac solution (2) with a higher Ac concentration (especially purity) compared to the above Ra-Ac solution (1), The above Ac solution (2) contains 225 The process (IV) involves decaying radioactive isotopes of actinium other than Ac to obtain a Ra-Ac solution (3) containing the radium isotope (Ra) obtained by decay, The Ra and Ac contained in the above Ra-Ac solution (3) are separated and compared with the above Ra-Ac solution (3). 225 Step (V) to obtain an Ac solution (4) with increased Ac concentration (especially purity), Includes, The above Ac solution (4) is used to manufacture the pharmaceutical product shown in (a) or (b) below. 225 This is a method for producing Ac solution. (a) 225 A pharmaceutical product containing a complex of a chelating agent that has formed a complex with Ac and an Nd2 antibody as an active ingredient. (b) 225 A pharmaceutical product containing a complex of a chelating agent that forms a complex with Ac and a targeting agent (excluding Nd2 antibody) as an active ingredient.

[0011] Another aspect of the present invention is obtained by performing steps (I) to (V) described above.225 Using Ac solution, the above chelating agent 225 The method for producing the above-mentioned pharmaceutical product includes a step (VIa) of forming a complex with Ac.

[0012] According to one aspect of the present invention, 225 While suppressing the attenuation of Ac, 225 High Ac concentration (especially purity) 225 Ac solutions can be produced. [Brief explanation of the drawing]

[0013] [Figure 1] This is a flowchart of Example 2. [Figure 2] These are the gamma spectra of various 225Ac samples. Figure 2(a) is the gamma spectrum of the 225Ac product (primary separation) 4 days after EOB in Example 2, Figure 2(b) is the gamma spectrum of the 225Ac product (secondary separation) 20 days after EOB in Example 2, and Figure 2(c) is the gamma spectrum of commercially available standard 225Ac (manufactured by the generator). [Figure 3] Figure 3(a) shows the α spectrum of the 225Ac product, measured without coating on aliquots of 225Ac (0.37-1.85 kBq) dried on an Al disk. Figure 3(b) shows the α spectrum of the purified 225Ac product 19 days after EOB in Example 2, and Figure 3(b) shows the α spectrum of commercially available standard 225Ac. [Modes for carrying out the invention]

[0014] [ 225 [Method for producing Ac solution] According to one aspect of the present invention 225 The method for producing Ac solution (hereinafter also referred to as "this manufacturing method") is as follows: 226 The Ra target is irradiated with at least one particle selected from protons, deuterons, neutrons, and photons, at least 225 A step (I) to produce two or more radioactive isotopes (Ac) of actinium, including Ac, After process (I) 226Dissolve the Ra target, 226 Step (II) to obtain a Ra-Ac solution (1) containing Ra and Ac, Ra-Ac solution (1) contains, 226 Ra target derived 226 Step (III) involves separating Ra and Ac to obtain an Ac solution (2) with a higher Ac concentration (especially purity) compared to the Ra-Ac solution (1), The contents of Ac solution (2) 225 The process (IV) involves decaying radioactive isotopes of actinium other than Ac to obtain a Ra-Ac solution (3) containing the radium isotope (Ra) obtained by decay, The Ra and Ac contained in Ra-Ac solution (3) were separated and compared with Ra-Ac solution (3). 225 Step (V) to obtain an Ac solution (4) with increased Ac concentration (especially purity), Includes, Ac solution (4) is used to manufacture the pharmaceutical product shown in (a) or (b) below. 225 This is a method for producing Ac solution. (a) 225 A pharmaceutical product containing a complex of a chelating agent that has formed a complex with Ac and an Nd2 antibody as an active ingredient. (b) 225 A pharmaceutical product containing a complex of a chelating agent that forms a complex with Ac and a targeting agent (excluding Nd2 antibody) as an active ingredient.

[0015] In this specification, for example, if you want to specify actinium with a mass number of 225, 225 The term "Ac" is used when there is no particular limitation on the radioactive isotope of actinium. The same applies to radium, etc.

[0016] <Process (I)> In process (I), 226 The Ra target is irradiated with at least one particle selected from protons, deuterons, neutrons, and photons, at least 225 It produces two or more radioactive isotopes (Ac) of actinium, including Ac. 226By irradiating an Ra target with particles, Ac may be generated through decay or other processes. at least 225 Two or more radioactive isotopes of actinium (Ac) including Ac include: 225 Ac and, 224 and 226 This includes at least one selected from Ac.

[0017] 226 As for Ra targets 226 There are no particular restrictions as long as Ra is included. 226 It is preferable that Ra is immobilized on the substrate. 226 As an example of a method for preparing an Ra target, on a silicon carbide (SiC) filter, 226 One method for producing an Ra target with a certain thickness is to precipitate and filter out RaCO3. However, from the viewpoint of efficiently producing an Ra target even in remote operation, an electrodeposition method is preferred, in which free Ra in a solution is electrically solidified onto a substrate. As an example of such an electrodeposition method, Japanese Patent Publication No. 2007-508531 describes the electrodeposition of a radium-containing substance onto an aluminum substrate from a single organic aqueous solution containing radium ions. However, from the viewpoint of increasing electrodeposition efficiency without applying high voltage, a method of electrodeposition using an electrodeposition solution containing a pH buffer is more preferable. An example of such a technology is International Publication No. 2020 / 256066, filed by one of the applicants.

[0018] In the above irradiation, specifically, an accelerator such as a cyclotron or linear accelerator, preferably a cyclotron, is used to accelerate the particles, and the accelerated particles are then... 226 It is preferable to irradiate the Ra target. The particles are preferably protons, deuterons, or photons, with protons being more preferred. For example, when irradiated with protons as particles, 226 Ra(p,2n) 225 A nuclear reaction occurs with Ac, 224 Ac and / or 226Ac is generated as an impurity. Also, when irradiating with photons (γ-rays) as particles, 226 Ra(γ,n) 225 a nuclear reaction of Ra occurs, 225 and Ac is generated by the decay of Ra. When using protons, deuterons or photons as particles, 225 Ac (half-life 27 years) is not generated theoretically, 227 so it is more preferable from the viewpoint of obtaining an 225 Ac solution with a high Ac concentration (especially purity). 225 As conditions for irradiating the particles, there are no particular restrictions as long as the type, energy, irradiation time, etc. of the particles are appropriately adjusted so that two or more actinium radioisotopes (Ac) containing at least Ac are generated, and various conditions can be adopted. 225 When Ac and the particles undergo a nuclear reaction, usually, as a side reaction,

[0019] 225 nuclear fission of Ra occurs, 226 and Ba is generated. 140 Also, 226 it is normal for the raw material of the Ra target to contain 226 Ba in addition to Ra, and a technique for separating 226 Ra and Ba has been developed as in Patent Document 1, 226 but it is difficult to completely remove Ba from the Ra target, 226 132 so when using protons among the above particles, if the Ra target contains Ba, 135 La (half-life 4.8 hours) and 226 La (half-life 19.5 hours) are generated by the nuclear reaction between Ba and protons. In one aspect of the present invention, these radioactive heteronuclei are sequentially removed in each step described later.

[0020] <Step (II)> In Step (II), the 226 Ra target after Step (I) is dissolved to obtain 226 a Ra-Ac solution (1) containing Ra and Ac. The Ra-Ac solution (1) obtained shortly after the completion of step (I) contains, for example, 224 Ac, 225 Ac, 226 Ac, 226 Ra, 140 Ba, 132 La, 135 It includes La.

[0021] 226 When dissolving the Ra target, an acid can be used. This acid may be one type or two or more types. Examples of the above acids include inorganic acids, such as nitric acid, hydrochloric acid, phosphoric acid, sulfuric acid, boric acid, or hydrofluoric acid. Among these, 226 Nitric acid and hydrochloric acid are preferred, and nitric acid is particularly preferred, because they can sufficiently dissolve Ra and Ac and allow the following step (III) to be carried out efficiently.

[0022] 226 In order to dissolve the Ra target, 226 The amount of acid used is preferably 10 times or more, more preferably 20 times or more, preferably 50 times or less, and more preferably 40 times or less, relative to the molar amount of Ra.

[0023] <Process (III)> In step (III), the Ra-Ac solution (1) contains the following: 226 Ra target derived 226 Ra and Ac are separated to obtain Ac solution (2) with a higher Ac concentration (especially purity) compared to the Ra-Ac solution (1) described above. This process (III) allows, for example, 224 Ac, 225 Ac, 226 Ac solution containing Ac (2), 226 Ra, 140 A Ra solution (2) containing Ba can be obtained. In step (III), for example, 224 Ac, 225 Ac, 226 Ac, 226 Ra and 140From a Ra-Ac solution (1) containing Ba, 226 Ra, 140 Because Ba can be separated and removed, Ac solution (2) is a solution with a higher Ac concentration (especially purity) compared to Ra-Ac solution (1).

[0024] If T1 is the time between the completion of process (I) and the start of process (III), then it is preferable that T1 be as short as possible, the lower limit of T1 should be any time during which process (II) can be carried out, and T1 is preferably shorter than 7 days, and more preferably 5 days or less. By setting T1 to the above range, Ac and 140 Because Ba can be separated early, 140 This occurs due to the decay of Ba. 140 A low-La Ac solution (2) can be easily obtained. Furthermore, by setting T1 within the above range, the resulting Ra solution (2) can be reused at an early stage.

[0025] 226 Generated from Ra target 225 Ac is present in trace amounts. 226 Most of the Ra remains unreacted, 226 Since Ra is a valuable radionuclide and disposal is not easy, it is preferable to recover and reuse the Ra solution (2). The Ra solution (2) can be, for example, subjected to a purification process if necessary. 226 It is reused as an electrodeposition solution for manufacturing Ra targets. An example of such technology is International Publication No. 2021 / 002275, filed by one of the applicants.

[0026] In the conventional method, when performing this step (III), 226 Since the amount of Ac needs to be sufficiently reduced, in Ra-Ac solution (1) 226 After the amount of Ac has sufficiently decayed, when Ra and Ac are separated, the resulting Ac fraction contains a considerable amount 140 La is included, this 140 It took even more time to attenuate the amount of La. When it takes this much time, the goal becomes less likely to be achieved as time passes. 225 Because the amount of Ac decreases, in conventional methods, 225 While suppressing the attenuation of Ac, 225 High Ac concentration (especially purity) 225 To manufacture Ac solution, and also 140 The amount of La is small, 225 It achieves both high Ac concentration (especially purity) and high purity. 225 Producing Ac solution was not easy. Also, as mentioned above, most 226 Ra is 225 It is not converted to Ac, 226 Because it remains as Ra, 226 Efficiently recover Ra, 225 Although it is being reused as a raw material for Ac, in conventional methods, 226 Until time has passed for the amount of Ac to decay sufficiently 226 Ra could not be reused. However, in this manufacturing method, 225 High Ac concentration (especially purity) 225 Ac solution can be easily obtained, and immediately after the execution of step (III), 226 Since Ra can be reused, 226 This can improve the efficiency of Ra utilization.

[0027] In process (III), 226 Any technology capable of separating Ra and Ac can be employed, but preferred examples include technologies using solid-phase extractants to capture Ra and technologies for colloidalizing Ac. Preferably, the solid-phase extractant is selected from a cation exchange resin, a solid-phase extractant (a) containing a compound represented by the following formula (A), a solid-phase extractant (b) containing a compound represented by the following formula (B), and a solid-phase extractant (c) containing a compound represented by the following formula (C). Step (III) may involve separating Ra and Ac two or more times. For example, when using a cation exchange resin, the separation may be performed two or more times using the same cation exchange resin, or two or more times using different cation exchange resins, or two or more times using a cation exchange resin and, for example, a solid-phase extractant (a). In this case, the order in which the cation exchange resin and the solid-phase extractant (a) are used is not particularly limited. The same applies when using solid-phase extractants (a), (b), or (c) as when using a cation exchange resin. Furthermore, after separating Ra and Ac, it is preferable to perform a washing step to wash the cation exchange resin and solid-phase extractant.

[0028] Of these, step (III) is preferably a step in which Ra and Ac are separated using a solid-phase extractant (a), and then Ra and Ac are separated using a solid-phase extractant (b), because even with a small amount of solvent used, an Ac solution (2) with high Ac purity can be easily obtained from the Ra-Ac solution (1).

[0029] Alternatively, in step (III), Ra-Ac solution (1) can be alkalized to obtain a solution of Ra solution (2) by filtering the colloidalized actinium hydroxide through a membrane filter or the like and collecting it on the filter, and then dissolving the Ac collected on the filter to obtain Ac solution (2).

[0030] • Cation exchange resin Examples of the cation exchange resins mentioned above include strongly acidic cation exchange resins, and a commercially available example of such a cation exchange resin is "AG 50W" manufactured by Bio-Rad. As the cation exchange resin mentioned above, a resin having the function of selectively adsorbing divalent cations (hereinafter also referred to as "resin (i)") is preferred, in that it can separate Ra and Ac more efficiently.

[0031] A specific example of step (III) when using resin (i) is a method in which Ra-Ac solution (1) is brought into contact with resin (i) under alkaline conditions to adsorb Ra ions onto resin (i), the permeate is obtained as Ac solution (2), and Ra solution (2) is obtained by eluting Ra ions from resin (i) under acidic conditions.

[0032] The resin (i) is preferably capable of forming complexes with metal ions under alkaline conditions and eluting metal ions under acidic conditions, and examples include those having divalent cation exchange groups. Specifically, examples of divalent cation exchange groups include iminodiacetic acid groups, polyamine groups, and methylglycan groups, with iminodiacetic acid groups being preferred. A more preferred example of resin (i) is a styrene-divinylbenzene copolymer that retains iminodiacetic acid groups. Commercially available resins having such iminodiacetic acid groups include the "Chelex" series from Bio-Rad, the "Diaion" series from Mitsubishi Chemical Corporation, and the "Amberlite" series from Dow Chemical, and more specifically, "Chelex100" from Bio-Rad (particle size: 50-100 mesh, ionic type: Na type, Fe type).

[0033] The resin (i) may also be used by filling it into a tube. The tube is not particularly limited as long as it can be filled with the resin (i) and is flexible, but preferably it is a flexible tube made of rubber or resin, and more preferably a medical tube. By using such tubes, the length can be increased compared to conventional glass columns, i.e., the number of theoretical plates can be increased, thereby improving the adsorption efficiency of Ra ions. Furthermore, the resin (i) remaining in the tube after the radioactive material has passed through it can be disposed of easily without contaminating other equipment or instruments with radioactivity.

[0034] • Solid-phase extractant (a) The solid-phase extractant (a) is not particularly limited as long as it contains a compound represented by the following formula (A), and may also contain conventionally known components included in solid-phase extractants. The solid-phase extractant (a) may consist solely of the compound represented by the following formula (A), or it may be a solid-phase extractant containing the compound represented by the following formula (A) and other components (e.g., conventionally known additives, inert supports) (including solid-phase extractants in which the compound represented by the following formula (A) is introduced into the inert support). The solid-phase extractant (a) may contain one compound represented by the following formula (A), or it may contain two or more compounds.

[0035] The solid-phase extractant (a) is preferably an inert support containing a compound represented by the following formula (A), and more preferably a porous silica or organic polymer containing a compound represented by the following formula (A). The pore size of the porous silica is not particularly limited, but a diameter of about 50 to 150 μm is preferred.

[0036] A specific example of step (III) when using a solid-phase extractant (a) is to pass an Ra-Ac solution (1) containing a high concentration of acid (e.g., 0.3 M or higher in the case of nitric acid) through the solid-phase extractant (a) to selectively retain Ac ions in the solid-phase extractant (a), obtain the pass-through solution as Ra solution (2), and obtain Ac solution (2) by passing a low concentration of acid through the solid-phase extractant (a) that retains the Ac ions to elute the retained Ac ions. Thus, because the solid-phase extractant (a) has a high concentration of acid used to separate Ra and Ac (by retaining Ac ions in the solid-phase extractant (a) and allowing Ra ions to pass through), using the solid-phase extractant (a) in this step (III) allows for sufficient separation of Ra ions and Ac ions even with a small amount of solvent used to separate Ac ions from a solution containing Ra ions and Ac ions.

[0037] The high-concentration acid used in the solid-phase extractant (a) can be the same as the acid used in the Ra-Ac solution (1), and the preferred acid is also the same. One or more acids may be used. The concentration of the high-concentration acid used in the solid-phase extractant (a) is preferably 0.3 M or higher, more preferably 0.5 M or higher, and preferably 4.0 M or lower when nitric acid is used, in order to more efficiently separate Ra and Ac (separation with less Ac passage and less Ra retention). When hydrochloric acid is used, it is preferably 1 M or higher, and preferably 8 M or lower.

[0038] When passing the Ra-Ac solution (1) through the solid-phase extractant (a), the flow rate of the Ra-Ac solution (1) is preferably 0.01 mL / min or more, more preferably 0.1 mL / min or more, even more preferably 0.5 mL / min or more, preferably 5 mL / min or less, more preferably 3 mL / min or less, and even more preferably 2 mL / min or less, from the viewpoint that Ra and Ac can be separated more efficiently.

[0039] The low-concentration acid used in the solid-phase extractant (a) can be the same as the acid used in the Ra-Ac solution (1), and the preferred acid is also the same. One or more acids may be used. The concentration of the low-concentration acid used in the solid-phase extractant (a) is not particularly limited as long as it can sufficiently elute the retained Ac ions from the solid-phase extractant (a). However, if the same acid used is the same as the acid used in the Ra-Ac solution (1), a larger concentration difference is preferable. The concentration of the low-concentration acid used in the solid-phase extractant (a) is preferably greater than 0 M, preferably 0.2 M or less, more preferably 0.1 M or less, and even more preferably 0.01 M or less when nitric acid is used as the acid, and preferably greater than 0 M and 0.2 M or less when hydrochloric acid is used as the acid.

[0040] Furthermore, there is a possibility that the acid used in the Ra-Ac solution (1) may remain in the solid-phase extractant (a). In this case as well, it is preferable that the concentration of the high-concentration acid be different from the concentration of the low-concentration acid, and if the concentration of the low-concentration acid is set to 1, the high-concentration acid is preferably 15 or higher.

[0041] The flow rate of the low-concentration acid used in the solid-phase extractant (a) is preferably 0.1 mL / min or more, more preferably 0.5 mL / min or more, preferably 20 mL / min or less, and more preferably 10 mL / min or less, from the standpoint that the retained Ac ions can be sufficiently eluted from the solid-phase extractant (a).

[0042] The solid-phase extractant (a) is not particularly limited, but commercially available products may be used as an example, such as "DGA Resin" and "DGA Branched Resin" manufactured by Eichrom Technologies.

[0043] [ka]

[0044] In formula (A), m and n are independently either 0 or 1, and m and n are preferably 1. In formula (A), R 1 ~R 4 Each of these is independently an alkyl group having 8 to 12 carbon atoms. The alkyl group may be linear or branched. 1 ~R 4 Each of these is independently preferably an octyl group or a 2-ethylhexyl group.

[0045] • Solid-phase extractant (b) The solid-phase extractant (b) is not particularly limited as long as it contains a compound represented by the following formula (B), and may contain conventionally known components included in solid-phase extractants. The solid-phase extractant (b) may consist solely of the compound represented by the following formula (B), or it may be a solid-phase extractant containing the compound represented by the following formula (B) and other components (e.g., conventionally known additives, inert supports) (including solid-phase extractants in which the compound represented by the following formula (B) is introduced into the inert support). The solid-phase extractant (b) may contain one compound represented by the following formula (B), or it may contain two or more compounds.

[0046] The solid-phase extractant (b) is preferably an inert support containing a compound represented by the following formula (B), and more preferably a porous silica or organic polymer containing a compound represented by the following formula (B). The pore size of the porous silica is not particularly limited, but a diameter of about 50 to 150 μm is preferred.

[0047] A specific example of step (III) when using a solid-phase extractant (b) is to pass an Ra-Ac solution (1) containing a low concentration of acid (e.g., 0.2 M or less in the case of nitric acid) through the solid-phase extractant (b) to selectively retain Ac ions in the solid-phase extractant (b), obtain the pass-through solution as Ra solution (2), and obtain Ac solution (2) by passing a high concentration of acid through the solid-phase extractant (b) that retains the Ac ions to elute the retained Ac ions.

[0048] The low-concentration acid used in the solid-phase extractant (b) can be the same acid used in the Ra-Ac solution (1), and the preferred acid is also the same. One or more acids may be used. The concentration of the low-concentration acid used in the solid-phase extractant (b) is preferably greater than 0 M, preferably less than 0.2 M, more preferably 0.1 M or less, and even more preferably 0.01 M or less, when nitric acid is used as the acid, in order to more efficiently separate Ra and Ac (separation with less Ac passage and less Ra retention). When hydrochloric acid is used as the acid, it is preferably greater than 0 M and 0.2 M or less.

[0049] The flow rate when passing the Ra-Ac solution (1) through the solid-phase extractant (b) is preferably 1 mL / min or more, more preferably 1.5 mL / min or more, preferably 30 mL / min or less, and more preferably 20 mL / min or less, from the standpoint that the Ac ions can be sufficiently retained in the solid-phase extractant (b).

[0050] The high-concentration acid used in the solid-phase extractant (b) can be the same as the acid used in the Ra-Ac solution (1), and the preferred acid is also the same. One or more acids may be used. The concentration of the high-concentration acid used in the solid-phase extractant (b) is preferably 0.2 M or higher, more preferably 0.3 M or higher, even more preferably 0.5 M or higher, preferably 4 M or lower, more preferably 2 M or lower, and even more preferably 1 M or lower, when nitric acid is used as the acid, and preferably 0.3 M or higher, and preferably 8 M or lower when hydrochloric acid is used as the acid.

[0051] The flow rate of the high-concentration acid used in the solid-phase extractant (b) is preferably 0.5 mL / min or more, more preferably 1 mL / min or more, even more preferably 2 mL / min or more, preferably 30 mL / min or less, more preferably 25 mL / min or less, and even more preferably 20 mL / min or less, from the viewpoint that the retained Ac ions can be sufficiently eluted from the solid-phase extractant (b).

[0052] The solid-phase extractant (b) is not particularly limited, but commercially available products may be used as an example, such as "Ln Resin," "Ln2 Resin," and "Ln3 Resin" manufactured by Eichrom Technologies.

[0053] [ka]

[0054] In formula (B), R 5 and R 6 Each of these is independently -R' or -OR' (where R' is an 8-C1 alkyl group). The 8-C1 alkyl group in R' may be linear or branched, and preferred examples include an octyl group, a 2-ethylhexyl group, and a 2-methyl-4,4-dimethylpentyl group.

[0055] Suitable examples of compounds represented by formula (B) include the compounds represented by the following formulas (B-1) to (B-3).

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] • Solid-phase extractant (c) The solid-phase extractant (c) is not particularly limited as long as it contains a compound represented by the following formula (C), and may also contain conventionally known components included in solid-phase extractants. The solid-phase extractant (c) may consist only of the compound represented by the following formula (C), or it may consist of the compound represented by the following formula (C) and other components (e.g., R 10 -OH(R 10 The solid-phase extractant may include a compound represented by the following formula (C) (where C is an alkyl group having 4 to 12 carbon atoms, preferably an octyl group), a conventionally known additive, and an inert support (including solid-phase extractants in which a compound represented by the following formula (C) is introduced into the inert support). The solid-phase extractant (c) may contain one compound represented by the following formula (C), or it may contain two or more compounds.

[0060] The solid-phase extractant (c) is preferably an inert support containing a compound represented by the following formula (C), and more preferably a porous silica or organic polymer containing a compound represented by the following formula (C). The pore size of the porous silica is not particularly limited, but a diameter of about 50 to 150 μm is preferred.

[0061] A specific example of step (III) when using a solid-phase extractant (c) is to pass a Ra-Ac solution (1) containing a high concentration of acid through the solid-phase extractant (c), 226Ra ions are selectively retained in the solid-phase extractant (c), and the eluate is obtained as Ac solution (2). 226 By passing a low concentration of acid through a solid-phase extractant (c) that retains Ra ions, the retained Ra ions are obtained. 226 One method is to obtain an Ra solution (2) by eluting Ra ions.

[0062] The high-concentration acid used in the solid-phase extractant (c) can be the same as the acid used in the Ra-Ac solution (1), and the preferred acid is also the same. One or more acids may be used. The concentration of the high-concentration acid used in the solid-phase extractant (c) is preferably greater than 0.1 M, more preferably 1 M or more, preferably 8 M or less, and more preferably 4 M or less, when nitric acid is used as the acid.

[0063] The low-concentration acid used in the solid-phase extractant (c) can be the same as the acid used in the Ra-Ac solution (1), and the preferred acid is also the same. One or more acids may be used. The concentration of the low-concentration acid used in the solid-phase extractant (c) is preferably greater than 0 M, preferably 0.1 M or less, and more preferably 0.05 M or less, when nitric acid is used as the acid.

[0064] The solid-phase extractant (c) is not particularly limited, but a commercially available product may be used as an example, such as "Sr Resin" manufactured by Eichrom Technologies.

[0065] [ka]

[0066] In formula (C), R8 and R9 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group may be linear or branched, and a preferred example is a t-butyl group.

[0067] <Process (IV)> In step (IV), the Ac solution (2) contains 225 Radioactive isotopes of actinium other than Ac are decayed to obtain an Ra-Ac solution (3) containing the radium isotope (Ra) obtained by the decay. This step (IV) preferably 225 Ac, 224 Ra and 226 A Ra-Ac solution containing Ra (3) is obtained.

[0068] Here, 225 "To decay radioactive isotopes of actinium other than Ac" means that the Ac solution (2) contains 225 Radioactive isotopes of actinium other than Ac, specifically, 224 Ac, 226 This refers to the decay of Ac or both to produce the isotope of radium (Ra). 224 Ac is decomposed 224 It produces Ra (half-life 3.66 days). 226 Ac is decomposed 226 Ra and 226 Th (half-life 30.9 minutes) is produced. In process (IV), 224 and 226 It would be fine if only a part of the Ac had decayed, 224 and 226 It is preferable to allow Ac to decay sufficiently.

[0069] If T2 is the time between the completion of process (III) and the start of process (V) described later, it is preferable that T2 is longer than T1, i.e., that the relationship T2 > T1 is satisfied, but it is even more preferable that the relationship T2 ≥ 2 × T1 is satisfied. The lower limit of T2 is, 226 It is preferable to allow sufficient time for Ac to decay. 224 and 226 Isotopes of radium can be produced from Ac, 226 Th can be eliminated. The upper limit for T2 is, 225 It is preferable to set it in a way that minimizes the attenuation of Ac as much as possible. For example, if T2 is 20 days, 226 Ac is 1 × 10 -5 The following is predicted by simulations using the simulation code PHITS. Note that the simulation is performed at the end of irradiation in process (I). 225 This predicts the values ​​of other radioactive heteronuclides after a given time interval, assuming the radioactivity of Ac is set to 1.

[0070] Between process (I) and process (III), 140 Ba 140 If it decays into La, then Ac solution (2) 140 It is possible that La is mixed in. 140 If La affects the quality of the Ac solution (4) obtained in step (V) described later, then step (IV) is performed in the Ac solution (2) 140 This can also be a step to remove La. In this case, T2 is 7 days after the completion of step (V) described later. 140 La content / 225 The amount of Ac is preferably 1 × 10 -5 More preferably 1 × 10 -6 More preferably, 1 × 10 -7 The settings can be configured as follows: In this way, by setting T2, the results generated in process (I) 132 La (half-life 4.8 hours) and 135 It can eliminate the allenucleated species of La (half-life 19.5 hours). Conventional methods, 132 La 135 One way to reduce La is, 226 It is conceivable to reduce the amount of Ba contained in the Ra target, but by setting T2 within the above range, 226 Regardless of the amount of Ba contained in the Ra target, the amount of La is small 225 Ac solution (4) can be obtained. Therefore, according to this manufacturing method in which T2 is within the above range, 226 Ra targets are not restricted, 226 There is a high degree of freedom in selecting Ra targets.

[0071] <Process (V)> In step (V), the Ra and Ac contained in the Ra-Ac solution (3) are separated and compared with the Ra-Ac solution (3). 225 An Ac solution (4) with increased Ac purity is obtained. Ac solution (4) is, for example, 225 Ac, 224 Ra and 226 From the Ra-Ac solution (3) containing Ra, 224 Ra, 226 Because Ra can be separated and removed, compared to Ra-Ac solution (3) 225 This results in a solution with a higher concentration (especially purity) of Ac.

[0072] The specific method for process (V) is the same as that for process (III).

[0073] The period from process (I) to the completion of process (V) can be, for example, one month.

[0074] <Pharmaceuticals> The Ac solution (4) obtained in step (V) above is used to manufacture the pharmaceutical product shown in (a) or (b) below. The above-mentioned pharmaceuticals are (a) 225 A pharmaceutical product containing a complex of a chelating agent complexed with Ac and an Nd2 antibody as an active ingredient, or (b) 225 This pharmaceutical product contains a complex of a chelating agent that forms a complex with Ac and a targeting agent (excluding Nd2 antibody) as its active ingredient.

[0075] The chelating agent mentioned above is, 225 The compounds are not particularly limited as long as they can form complexes with Ac, but examples include the following compounds and compounds containing structures derived from said compounds. ·DOTA(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid) ·DOTMA((1R,4R,7R,10R)-α,α',α'',α'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) ·DOTAM(1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane) ·DOTA-GA(α-(2-Carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) ·DOTP(((1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(methylene))tetraphosphonic acid) ·DOTMP(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid)) ·DOTA-4AMP(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(acetamidomethylenephosphonic acid) ·DO2P(Tetraazacyclododecane dimethanephosphonic acid)

[0076] The above-mentioned Nd2 antibody is not limited to any antibody derived from Nd2, a type of antibody that specifically binds to mucin subtype 5AC. It may be a monoclonal antibody or a polyclonal antibody, and it may be a mouse antibody, a chimeric antibody, or a humanized antibody. Examples of such Nd2 antibodies include the mouse antibody described in Japanese Journal of Cancer Research, 87, 977-984, 199, etc., the chimeric antibody described in Japanese Patent Publication No. Hei 7-203974 and Japanese Patent Publication No. Hei 11-5749, etc., and the humanized antibody described in International Publication No. 2013 / 157102 and International Publication No. 2013 / 157105, etc.

[0077] The above-mentioned targeting agent refers to an agent other than an Nd2 antibody that has a chemical structure that exhibits directivity to a target organ or tissue in the body, or specificity to a target molecule. In this specification, target organs, tissues, or target molecules are collectively referred to as "target sites." Preferably, the targeting agent is one or more selected from the group consisting of chain peptides, cyclic peptides or combinations thereof, proteins, antibodies (except Nd2 antibodies) or their fragments, growth factors, affibodies, unibodies, nanobodies, monosaccharides, polysaccharides, vitamins, antisense nucleic acids, siRNA, miRNA, nucleic acid aptamers, decoy nucleic acids, cPG oligonucleotides, peptide nucleic acids, liposomes, micelles, nanoparticles, and carbon nanotubes, and more preferably a polypeptide. Furthermore, the targeting agent described above is preferably a targeting agent composed of amino acids, and the amino acids constituting the targeting agent may be natural or synthetic, and their molecular weight is not particularly limited.

[0078] A polypeptide can be any peptide consisting of three or more amino acid residues. Specifically, it can be a chain peptide, a cyclic peptide or a combination thereof, a protein, an antibody (excluding Nd2 antibodies) or its fragments. Examples include antibodies (immunoglobulins) of the IgG, IgA, IgM, IgD, and IgE classes, antibody fragments such as Fab fragments and F(ab')2 fragments, and peptide aptamers.

[0079] When the targeting agent is an antibody (excluding Nd2 antibodies), it is preferably a mouse antibody, chimeric antibody, or humanized antibody that has the ability to specifically bind to the antigen, more preferably a humanized antibody, and it is also preferable that it has stable physical properties and excellent accumulation at the target site. The antibody may also be used as its antigen-binding fragment, and this embodiment is also included in one embodiment of the present invention.

[0080] Peptides other than antibodies that can be used as targeting agents (excluding Nd2 antibodies) can be synthesized by conventionally known methods, such as liquid-phase synthesis, solid-phase synthesis, automated peptide synthesis, genetic recombination, phage display, genetic code reprogramming, and RaPID (Random non-standard Peptide Integrated Discovery). When synthesizing various peptides, the functional groups of the amino acids used may be protected as needed.

[0081] To conjugate an Nd2 antibody or targeting agent with a chelating agent, known reactions such as click reactions can be employed. In the complex, the Nd2 antibody and the targeting agent may be directly bound to the chelating agent, or they may be indirectly bound via other known linker structures such as PEG. Furthermore, in the complex, the Nd2 antibody and the targeting agent may be modified to include a reaction group that can bind to other structures, and then combined with the chelating agent. For example, by using the technique described in International Publication No. 2016 / 186206 to conjugate a targeting agent, such as an Nd2 antibody or an IgG antibody, with a chelating agent, the Fc region of the antibody can be modified in a site-specific manner.

[0082] Furthermore, the above compounding is done with a chelating agent and 225 The complex may be prepared by first forming a complex with Ac and then compounding it with an Nd2 antibody or targeting agent, or if the chelating agent is already bound to an Nd2 antibody or targeting agent, the chelating agent and 225 A complex may be prepared by forming a complex with Ac.

[0083] As a method for producing the above complex, for example, the method described in International Publication No. 2021 / 075546, filed by one of the applicants, can be employed. In this method, click-reactive atomic groups are pre-introduced as reaction atomic groups to each of the Nd2 antibody or targeting agent and chelating agent, 225 After coordinating Ac with the chelating agent, a click reaction occurs. 225 A complex is prepared between a chelating agent that has formed a complex with Ac and an Nd2 antibody or a targeting agent. Here, in this specification, "reaction group" refers to a chemical structure in which a reaction directly occurs when one compound is bonded to another.

[0084] Click reactions are reactions that occur, for example, through combinations of alkynes and azides, or dienes and dienophiles. From the viewpoint of simplifying the reaction process, it is preferable that the click reaction-capable atomic groups are those that can be used in metal catalyst-free click reactions. Specific examples of click reactions using such combinations of atomic groups include the Huisgen cycloaddition reaction and the reverse electron-demanded Diels-Alder reaction.

[0085] By introducing an alkyne-containing atomic group into one of the Nd2 antibody or targeting agent and chelating agent, and an azide-containing atomic group into the other, a triazole skeleton can be formed by a click reaction. Furthermore, by introducing a 1,2,4,5-tetrazine-containing atomic group into one of the Nd2 antibody or targeting agent and chelating agent, and an alkene (dienophile)-containing atomic group into the other, a pyridazine skeleton can be formed by a click reaction.

[0086] Specific examples of click-reaction-capable atomic groups include atomic groups containing dibenzocyclooctyne (DBCO) as an alkyne, atomic groups containing an azide group as an azide, atomic groups containing 1,2,4,5-tetrazine as a diene, and atomic groups containing trans-cyclooctene (TCO) as an alkene (dienophile). Click-reaction-capable atomic groups can be introduced using various commercially available reagents. Specifically, when introducing a group containing dibenzocyclooctin (DBCO) as a click-reaction-enabled atomic group, DBCO reagents such as DBCO-C6-Acid, DBCO-Amine, DBCO-Maleimide, DBCO-PEG acid, DBCO-PEG-NHS ester, DBCO-PEG-Alcohol, DBCO-PEG-amine, DBCO-PEG-NH-Boc, Carboxyrhodamine-PEG-DBCO, Sulforhodamine-PEG-DBCO, TAMRA-PEG-DBCO, DBCO-PEG-Biotin, DBCO-PEG-DBCO, DBCO-PEG-Maleimide, TCO-PEG-DBCO, and DBCO-mPEG can be used.

[0087] [Dissolution and purification solution] In another aspect of the present invention, particles (e.g., at least one selected from protons, deuterons, neutrons, and photons) are irradiated. 226 Examples include a purified solution obtained by dissolving an Ra target and purifying the resulting solution. In the dissolved and purified solution one month after irradiation of the particles, 225 relative to Ac amount140 Ratio of La amount ( 140 La content / 225 The amount of Ac is 1 × 10 -5 The following, preferably 1 × 10 -6 More preferably 1 × 10 -7 The following applies: Such dissolving and purifying solutions are 140 The amount of La is small. 225 This is a liquid with a high concentration (especially purity) of Ac. The dissolved and purified solution can specifically be the Ac solution (4) produced by this manufacturing method. Furthermore, it is preferable that the dissolved and purified solution be used specifically to manufacture the pharmaceutical product shown in (a) or (b) above.

[0088] [Methods for manufacturing pharmaceuticals] Another embodiment of the present invention is a method for producing a pharmaceutical product, which includes the following step (VIa). Step (VIa): Obtained by performing this manufacturing method 225 Using Ac solution, the chelating agent 225 Process of forming a complex with Ac

[0089] The above chelating agent 225 The reaction to form a complex with Ac can be carried out in the presence of any solvent, with appropriate heating or other measures. Examples of such reactions are International Publication No. 2021 / 033530 and International Publication No. 2021 / 075546, both filed by one of the applicants.

[0090] Process (VIa) is, 225 The process may further include a step of preparing a complex of a chelating agent that has formed a complex with Ac and an Nd2 antibody or a targeting agent, and it is preferable that this step be included. The process for producing the composite may include steps similar to those described in the section on the manufacturing method.

[0091] Process (VIa) is, 225The formulation process may further include a compounding step for obtaining a pharmaceutical product containing a complex of a chelating agent complexed with Ac and an Nd2 antibody or a targeting agent as an active ingredient. The formulation process may also involve adding various additives as appropriate, such as pH adjusters like citrate buffer, phosphate buffer, or borate buffer, solubilizers like polysorbate, stabilizers, and antioxidants, or diluting with an isotonic solution such as water or physiological saline to adjust the radioactivity concentration. Furthermore, the formulation process may include adding various additives or adjusting their concentrations, followed by sterile filtration using a membrane filter or the like to produce an injectable solution.

[0092] [Other aspects of the present invention] Other aspects of the present invention relate to the following [1] to [7]: 225 Methods for producing Ac solutions and methods for dissolving and purifying Ac solutions are also mentioned.

[0093] [1] 226 The Ra target is irradiated with at least one particle selected from protons, deuterons, neutrons, and photons, at least 225 A step (I) to produce two or more radioactive isotopes (Ac) of actinium, including Ac, After the above step (I) 226 Dissolve the Ra target, 226 Step (II) to obtain a Ra-Ac solution (1) containing Ra and Ac, The above Ra-Ac solution (1) contains, 226 Ra target derived 226 Step (III) involves separating Ra and Ac to obtain an Ac solution (2) with a higher Ac concentration (especially purity) compared to the above Ra-Ac solution (1), The above Ac solution (2) contains 225 The process (IV) involves decaying radioactive isotopes of actinium other than Ac to obtain a Ra-Ac solution (3) containing the radium isotope (Ra) obtained by decay, The Ra and Ac contained in the above Ra-Ac solution (3) are separated and compared with the above Ra-Ac solution (3). 225Step (V) of obtaining an Ac solution (4) with an increased Ac concentration (especially purity), including 225 A method for producing an Ac solution.

[0094] [2] After the completion of the above step (I), when the time until the start of the above step (III) is T1, and when the time until the start of the above step (V) after the completion of the above step (III) is T2, The method for producing an Ac solution according to [1], satisfying the relationship T2 > T1. 225 A method for producing an Ac solution.

[0095] [3] In the above Ac solution (4), 225 The ratio of the amount of La to the amount of Ac ( 140 La amount / 140 Ac amount) is 1 × 10 225 or less at the time 7 days after the completion of the above step (V). The method for producing an Ac solution according to [1] or [2]. -5 225 A method for producing an Ac solution.

[0096] [4] The method for producing an Ac solution according to [2], where the above T1 is a time shorter than 7 days. 225 A method for producing an Ac solution.

[0097] [5] In the above step (III) or the above step (V), using a solid-phase extractant for capturing Ra or including colloidizing Ac. The method for producing an Ac solution according to any one of [1] to [4]. 225 A method for producing an Ac solution.

[0098] [6] The above solid-phase extractant is at least one selected from a cation exchange resin, a solid-phase extractant (a) containing the compound represented by the above formula (A), a solid-phase extractant (b) containing the compound represented by the above formula (B), and a solid-phase extractant (c) containing the compound represented by the above formula (C). The method for producing an Ac solution according to [5]. 225 A method for producing an Ac solution.

[0099] [7] A dissolution and purification liquid of a Ra target irradiated with particles, 226 where One month after the irradiation of the particles, in the dissolution and purification solution, 225 The ratio of 140 the amount of La to 140 the amount of Ac ([La amount] / 225 [Ac amount]) is 1 × 10 -5 or less. The dissolution and purification solution.

Example

[0100] Hereinafter, one aspect of the present invention will be described more specifically based on examples, but the present invention is not limited to these examples at all.

[0101] <Computational chemistry method> Using the simulation code PHITS (Particle and Heavy Ion Transport code System), based on the following assumptions, the amounts of radioactive elements contained in the following respective solutions were calculated by simulation.

[0102] [Simulation 1] 226 It was assumed that a step (I) of irradiating a Ra target (φ20 mm, 226 Ra mass: 50 mg, Ba mass: 50 mg) with protons at an irradiation energy of 16 MeV for 1 hour was performed.

[0103] Immediately after performing step (I), the 226 Ra target obtained in step (I) was dissolved to 226 obtain a Ra-Ac solution (1) containing Ra and Ac in a step (II). In the Ra-Ac solution (1) obtained in this step (II), 225 the radioactivity of Ac ([Ac amount]) was normalized to 1.00 (1.00E+00). In this case, in the obtained Ra-Ac solution (1), 225 the amount of Ac was 5.05E+01, 224 the amount of Ac was 1.07E+00, 226 the amount of Ac was 1.07E+00, 226 derived from the Ra target 226 excluding Ra 226 derived from Ac <{} 226 the amount of Ra was 4.53E-09, 140The amount of Ba is 3.44E-03. 140 The amount of La was calculated to be 2.89E-05.

[0104] The above Ra-Ac solution (1) contains, 226 Ra target derived 226 We assumed that step (III) was performed to separate Ra and Ac to obtain Ac solution (2). The time between the completion of step (I) and the start of step (III) was assumed to be 6 hours (0.25 days). this 226 In separating Ra and Ac, it was assumed that Group 3 elements of the periodic table, lanthanide elements, and actinide elements could not be separated from Ac, while all other elements could be separated 100%. In the Ac solution (2) obtained in this step (III), 225 The amount of Ac is 9.83E-01. 224 The amount of Ac is 1.20E+01. 226 The amount of Ac is 9.31E-01. 226 The Ra quantity is 0.00 (at the start of process (III)). 226 Ra quantity is 5.50E-08), 140 The amount of Ba is 0.00 (at the start of process (III)). 140 The amount of Ba is 3.45E-03), 140 The amount of La was calculated to be 3.67E-04.

[0105] The above Ac solution (2) contains 225 We assumed that the process involved a step (IV) in which radioactive isotopes of actinium other than Ac were decayed to obtain a Ra-Ac solution (3) containing the radium isotope (Ra) obtained by the decay, and a step (V) in which Ra and Ac contained in the obtained Ra-Ac solution (3) were separated to obtain an Ac solution (4). The time from the completion of step (I) to the start of step (V) was assumed to be 504 hours (21 days). In separating Ra and Ac, it was assumed that Group 3 elements of the periodic table, lanthanide elements, and actinide elements could not be separated from Ac, while all other elements could be separated 100%. In the Ac solution (4) obtained in this step (V), 225 The amount of Ac is 2.33E-01.224 The amount of Ac is 0.00. 226 The amount of Ac is 6.30E-06. 226 The Ra quantity is 0.00 (at the start of process (V)). 226 Ra quantity is 3.28E-07), 140 The amount of La was calculated to be 6.96E-08.

[0106] Furthermore, in the Ac solution (4) 7 days after the above process (V) (672 hours (28 days) after the completion of process (I)), 225 The amount of Ac is 1.44E-01. 224 The amount of Ac is 0.00. 226 The amount of Ac is 1.14E-07. 226 The Ra quantity is 2.20E-12. 140 The amount of La was calculated to be 3.86E-09.

[0107] These results are summarized in Table 1 below.

[0108] [Table 1]

[0109] [Comparative Simulation 1] 226 Ra target (φ20mm, 226 We assumed that a process (I) was performed in which protons were irradiated with an irradiation energy of 16 MeV for 1 hour onto Ra (mass: 50 mg, mass: 50 mg) and Ba (mass: 50 mg).

[0110] Immediately after performing process (I), the obtained in process (I) 226 Dissolve the Ra target, 226 We assumed that step (II) was performed to obtain a Ra-Ac solution (1) containing Ra and Ac. In this step (II), the Ra-Ac solution (1) 225 Ac radioactivity ( 225 The amount of Ac was normalized to 1.00 (1.00E+00). In this case, in the obtained Ra-Ac solution (1), 224 The amount of Ac is 5.05E+01. 226 The amount of Ac is 1.07E+00.226 Ra target derived 226 Excluding Ra 226 Acetate-derived 226 The Ra amount was 4.53E-09. 140 The amount of Ba is 3.44E-03. 140 The amount of La was calculated to be 2.89E-05.

[0111] The above Ra-Ac solution (1) contains, 226 Ra target derived 226 We assumed that step (III) was performed to separate Ra and Ac to obtain Ac solution (2). The time between the completion of step (I) and the start of step (III) was assumed to be 504 hours (21 days). this 226 In separating Ra and Ac, it was assumed that Group 3 elements of the periodic table, lanthanide elements, and actinide elements could not be separated from Ac, while all other elements could be separated 100%. In the Ac solution (2) obtained in this step (III), 225 The amount of Ac is 2.33E-01. 224 The amount of Ac is 0.00. 226 The amount of Ac is 6.30E-06. 226 The Ra quantity is 0.00 (at the start of process (III)). 226 The Ra amount is 3.82E-07), 140 The amount of Ba is 0.00 (at the start of process (III)). 140 The amount of Ba is 1.12E-03), 140 The amount of La was calculated to be 1.29E-03.

[0112] Seven days after the above process (III) (672 hours (28 days) after the completion of process (I)), in the Ac solution (2), 225 The amount of Ac is 1.44E-01. 224 The amount of Ac is 0.00. 226 The amount of Ac is 1.14E-07. 226 The Ra quantity is 2.20E-12. 140 The amount of La was calculated to be 7.14E-05.

[0113] These results are summarized in Table 2 below.

[0114] [Table 2]

[0115] <Experimental Chemical Methods> Next, by the following method 225 an Ac solution was prepared.

[0116] [Example 1] · Step (I) Using a cyclotron, a target obtained by electrodepositing 247 μCi of 226 Ra on a gold plate (Φ30) was irradiated with protons under the conditions of 18 MeV, 15 μA, and 0.5 hr ((p, 2n) reaction).

[0117] · Step (II) Three days after the irradiation, the irradiated target was dissolved in 16 mL of 0.7 M nitric acid.

[0118] · Step (III) The obtained solution was passed through a DGA resin (manufactured by Eichrom Technologies) (passing solution (1)). Then, the DGA resin was washed with 5 mL of 0.7 M nitric acid (washing solution (2)). The passing solution (1) and the washing solution (2) were used as 226 a Ra recovery solution and an electrodeposition solution for recycling Ra. Thereafter, the DGA resin was further washed with 15 mL of 0.7 M nitric acid (washing solution (3)). The washing solution (3) was treated as waste liquid. 20 mL of 0.005 M nitric acid was passed through the DGA resin after the above washing, 225 and Ac was eluted. The eluted 225 Ac was passed through an Ln resin (manufactured by Eichrom Technologies) (passing solution (4)). Next, the Ln resin was washed with 10 mL of 0.05 M nitric acid (washing solution (5)). The passing solution (4) and the washing solution (5) were treated as waste liquid. 10 mL of 0.7 M nitric acid was passed through the Ln resin after the above washing, 225 and Ac was eluted ([[:END]] 225 Ac solution (6)). The obtained 225The results of measuring the Ac solution (6) with a germanium semiconductor detector were as follows: 225 Ac was 0.2 μCi when calculated as EOB (end of irradiation).

[0119] ·Process (IV) 225 Seventeen days had passed since obtaining the Ac solution (6).

[0120] ·Process (V) After 17 days have passed as described above, 225 10 mL of Ac solution (6) was passed through the DGA resin (through solution (7)). The DGA resin was washed with 20 mL of 0.7 M nitric acid (washing solution (8)). Through solution (7) and washing solution (8) were discarded. Then, 20 mL of 0.005 M nitric acid is passed through the DGA resin. 225 Ac was leached out. 225 Ac was passed through the Ln resin (permeable solution (9)). Then, the Ln resin was washed with 10 mL of 0.05 M nitric acid (washing solution (10)). Permeable solution (9) and washing solution (10) were treated as waste liquid. After washing as described above, 10 mL of 0.5 M nitric acid is passed through the Ln resin. 225 Ac eluted ( 225 Ac solution (11). 225 The results of measuring the Ac solution (11) with a germanium semiconductor detector showed that 225 Ac was 0.2 μCi when calculated as EOB (end of irradiation).

[0121] [Example 2] • Production of Ac-225 by cyclotron beam irradiation NIRS-AVF-930 cyclotron's 34 MeV H2 + A (ionized molecular hydrogen) beam was used to irradiate the area at a nominal intensity of 10 μA for 3 to 5 hours. H2 +The ions split, yielding a 17 MeV proton beam at approximately 20 μA. The SRIM calculation code estimated that the proton energy incident on the target material would be 15.6 MeV after the beam passed through the vacuum foil (Al, 100 μm), the He cooling layer (30 mm), and the target foil (Nb, 50 μm). 225 To maximize Ac yield, 226 Ra(p,2n) 225 The proton energy in the target material was set to 15.6 MeV to maximize the Ac reaction cross-section. This was chosen by selecting an energy between the result obtained from the ALICE calculation code (15 MeV with a maximum of 700 mb) and the result from the previous study Apostolidis C, Molinet R, McGinley J, Abbas K, Mollenbeck J, Morgenstern A. Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot 2005;62:383-387 (16.8 MeV with a maximum of 710 mb).

[0122] • From the target matrix 225 Separation of Ac Figure 1 shows the separation procedure performed 3-4 days after the end of irradiation (EOB). The cyclotron-irradiated target was dissolved in 3 mL of 0.7 M HNO3, and the resulting solution was passed through a DGA cartridge (N,N,N',N'-tetra-n-octyldiglycolamide, 1 mL, Eichrom Technologies) at a rate of 0.8 mL / min or less. 225 Ac was collected in the cartridge. To improve the recovery of Ac / Ra remaining in the target container, 3 mL of 0.7 M HNO3 was added to the target container twice, and the washing fractions from each step were also passed through the DGA cartridge. 225 Ac was collected in the cartridge.

[0123] This DGA cartridge was washed with 20 mL of 0.7 M HNO3, and the residue remaining in the DGA cartridge 226Ra was washed away. Then, 5 mM HNO3 (20 mL) was passed through the DGA at a rate of 0.8 mL / min or less. 225 Ac was eluted, and the fraction was collected in a vial. Subsequently, crude 225 The Ac fraction is passed through an Ln cartridge (di(2-ethylhexyl) orthophosphate, 2 mL, manufactured by Eichrom Technologies), and this cartridge is washed with 10 mL of 50 mM HNO3 to remove trace amounts of contamination. 226 Ra was removed, and then the area was thoroughly purged. All of the above washing solution fractions were recovered as Ra recovery fractions to be reprocessed in subsequent use. Finally, by passing 0.7M HNO3 (10 mL) through the Ln cartridge, 225 Ac was eluted and collected in another vial.

[0124] Table 3 shows the results of the manufacturing process (3 times) carried out in this embodiment. In Table 3, #1 is the result when T1 was 5 days and T2 was 14 days, #2 is the result when T1 was 4 days and T2 was 21 days, and #3 is the result when T1 was 4 days and T2 was 28 days. Fabricated on the cathode surface by electrodeposition 226 Ra target is 1.0-1.5 mg / cm³ 2 It can be considered a thin target. 226 Ra(p,2n) 225The cross-sectional area (σ) of Ac was estimated to be 353 mb at 15.6 MeV. Previous studies on this nuclear reaction have shown results of approximately 710 mb at 16.8 MeV (Apostolidis C, Molinet R, McGinley J, Abbas K, Mollenbeck J, Morgenstern A. Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot 2005;62:383-387), or 600+ mb at 16.0 MeV (calculated using ALICE code, Apostolidis C, Molinet R, McGinley J, Abbas K, Mollenbeck J, Morgenstern A. Cyclotron production of Ac-225 for targeted alpha therapy. Appl Radiat Isot 2005;62:383-387), and 522 mb at 16.0 MeV (calculated using TENDL-2019, TALYS-based evaluated nuclear data library (TENDL-2019) website). https: / / tendl.web.psi.ch / tendl_2019 / proton_html / Ra / ProtonRa226xs.html (Accessed Sep 4, 2020), and each shows much higher values. However, as mentioned above, the target in this case has about 2 / 3 of its area affected by surface inhomogeneity. 226 It is covered by Ra, and therefore the above σ can be multiplied by, for example, 1.56 (=1 / 0.64). As a result, under the actual conditions in this case 226 Ra(p,2n) 225 and 226 Ra(p,n) 226The values ​​obtained as corrections for the estimated Ac cross-section were 552 mb and 14 mb, respectively (Reference: 34 mb for (p,n) channels at 16 MeV, TALYS-based evaluated nuclear data library (TENDL-2019) website https: / / tendl.web.psi.ch / tendl_2019 / proton_html / Ra / ProtonRa226xs.html Accessed Sep 4, 2020). Ac separation efficiency, beam profile, and Ba / Ra ratio can introduce certain errors into the evaluation, but no quantitative corrections for these potential factors could be applied in this embodiment. Therefore, these uncertainties are not included in the above estimation, but the above corrected cross-sections showed sufficient agreement with the calculated values ​​using the ALICE code and TENDL code, as well as the measured values ​​from previous studies.

[0125] [Table 3]

[0126] ·Separation As shown in Figure 2(a), 226 The presence of Ac and other radioactive allunculi was detected after primary separation. 225 It was detected in the Ac sample. 226 Ac is 226 Like Ra, it is a 4n+2 series radionuclide that produces many daughter nuclides during the cooling period. Therefore, 226 The 4n+2 series impurities released during the decay of Ac can be removed by repeated separation as a secondary purification, resulting in high quality. 225 Ac was generated. Under the above irradiation conditions, 224 Ac(EC:91%, α:9%, T 1 / 2 (=2.8 hours) 226 Ra(p,3n) channel (E TH It should be produced as a by-product via (=13.6MeV), 224 Ac has a very short half-life and could not be detected at the end of the separation process, 4 days after EOB. However, two γ-releasing compounds in the 4n series 224Ac progenitor nuclides, that is, 212 Bi(T 1 / 2 =61 minutes, 727 keV, 6.7%), and, 208 Tl(T 1 / 2 =3.1 min, 2615 keV, 99%) showed a significant distribution in both the washing fraction and each isolate, and furthermore, purification 225 It was also detected in trace amounts in the Ac sample. 224 This was evidence of Ac formation. 225 In the Ac fraction 212 Bi and 208 The presence of Tl was a reasonable result under these separation conditions, as Bi has partial similarity to Ac. On the other hand, 212 The parent nuclide of Bi 212 Pb(T 1 / 2 =10.6 hours, 239 keV, 44%), purification 225 It was not detected in the Ac sample. 212 All 4n series nuclides that could potentially be parent nuclides of Pb ( 224 Ac~ 216 Po( 224 (excluding Ra)) 212 It has a shorter half-life than Pb. 224 Ra is 226 It was removed along with Ra. Therefore, the by-product radionuclides that should be considered during the separation process are mainly those of the 4n+2 series.

[0127] Other notable by-products include, 135 La(EC, T 1 / 2 (=19.5 hours) and 140 La(β, T) 1 / 2 = 1.68 days). The former is derived from natural Ba carriers contained in old Ra sources. 135 It is thought to be produced as a by-product in the Ba(p,n) channel. However, 135 The half-life of La is 225 Its half-life is much shorter than that of Ac, and therefore, it is not necessary to remove the Ba that is mixed in with the extracted Ra. 225 Ac 135 The proportion of La is thought to gradually decrease with appropriate cooling time. On the other hand, the heaviest stable isotope of Ba is 138Because it is Ba, 140 La is thought to have too large an atomic mass to be produced by proton irradiation. That is, 226 In Ra irradiation 226 This suggests that it may have been produced by the fission of Ra. Furthermore, 140 The parent nuclide of La 140 Ba(β, T 1 / 2 It is also possible that it was produced as another fission product (12.6 days). 140 Ba is 225 Because it has a longer half-life than Ac, 140 Ba and its daughter nuclides 140 La 225 A decrease in the ratio to Ac cannot be expected. Therefore, primary separation is performed within a few days after the end of cyclotron irradiation. 226 Its chemical behavior is similar to that of Ra. 140 Ba 226 By primary separation along with Ra 225 Remove from the Ac fraction, 225 In the Ac fraction 140 Only La was used. In fact, 225 Slightly detected in the Ac fraction 140 La decayed with a half-life of 1.67 ± 0.10 days, which is in excellent agreement with its nominal half-life of 1.68 days. Subsequently, after 2-3 weeks of cooling, it decayed to an undetectable level on the gamma spectrum. In other words, by performing primary purification, 140 La 225 The ratio to Ac could be reduced. For example, when the above sample was cooled for 19-20 days after EOB, or 2 weeks after the end of separation, it was found to be produced by a different method. 229 Th / 225 Ac generator (Figure 2(b), Figure 2(c)) 225 A spectrum equivalent to that of Ac was obtained. As shown in Figure 3, this time 225 The α spectrum of the Ac product also shows a similar profile to the reference above, and in particular, 226 Ra(Eα=4.78MeV, 94%) and 210 No detection of Po (Eα=5.30MeV, 100%) was confirmed. Therefore, by separating the sample twice with appropriate cooling periods, 229Th / 225 Derived from an Ac Generator 225 Purification with quality comparable to Ac 225 We concluded that Ac is produced.

[0128] [Example 3] (1-1. Complex formation step) Chelating agents represented by the following formulas (L1 and L2) were used. DOTA-DBCO, represented by formula (L1), was synthesized according to the method described in Wang H et al. Selective in vivo metabolic cell-labeling-mediated cancer targeting. Nat Chem Biol. 13(4): 415-424. (2017). DOTAGA-DBCO, represented by formula (L2), was synthesized according to the method described in Bernhard et al. DOTAGA-Anhydride: A Valuable Building Block for the Preparation of DOTA-Like Chelating Agents, Chem. Eur. J. 18(25): 7834-7841. (2012).

[0129] [ka]

[0130] Chelating agent and obtained according to the method described in Example 1 225 By reacting the Ac solution with sodium acetate buffer (pH 6.0) at 70°C for 90 minutes, 225 A liquid containing a chelating agent that has formed a complex with Ac ( 225 A solution of Ac (compound) was obtained.

[0131] (1-2. Antibody modification step) Separately, a peptide was prepared by the method described in International Publication No. 2017 / 217347 to obtain a peptide containing 17 amino acid residues represented by the following formula (P3). The amino acid sequence of this peptide is identical to the sequence in Sequence ID No. (2) where Xaa2 is a lysine residue, and the amino group at the side chain terminal of the lysine residue is modified in a structure indicated by R1. Furthermore, two cysteine ​​residues are disulfide-bonded to each other, and the N-terminus of the peptide is bonded to an ethyl azide group, which is a reactive atomic group, via a linker structure containing diglycolic acid and eight PEGs.

[0132] [ka] [In formula (P3), Gly represents glycine, Pro represents proline, Asp represents aspartic acid, Cys represents cysteine, Ala represents alanine, Tyr represents tyrosine, His represents histidine, Glu represents glutamic acid, Leu represents leucine, Val represents valine, Trp represents tryptophan, and Phe represents phenylalanine.]

[0133] A mixture of the peptide represented by formula (P3) above and a human IgG antibody (trastuzumab; Roche) in sodium acetate buffer (pH 6) was reacted at room temperature for 30 minutes to obtain a solution containing the peptide-modified antibody. This peptide-modified antibody is one in which the Fc region of the antibody has been site-specifically modified by the above peptide.

[0134] (2. Labeling process) 1-2. Add the peptide-modified antibody obtained in the antibody modification step to the solution obtained in 1-1. the complex formation step. 225 The unpurified Ac complex solution was added and a click reaction was carried out at 37°C for 120 minutes to obtain the complex. Furthermore, the solution of the obtained complex was purified using an ultrafiltration filter (Merck, model number: UFC505096).

[0135] The radiochemical purity and radiochemical yield of the composite were measured as follows. Thin-layer chromatography (Agilent, model number: SGI0001, developing solvent: mixture of acetonitrile and 0.1 mmol / L EDTA solution (pH 5.0) (volume ratio 1:1)) was measured using a scanner-type image analyzer (GE Healthcare, MODEL Typhoon FLA 7000). The radiochemical purity (%) was defined as the percentage of the radioactivity (count) of the peak detected near the origin relative to the total detected radioactivity (count). In addition, the radiochemical yield (%) was defined as the percentage of the radioactivity (count) of the complex obtained after purification in the labeling step relative to the total radioactivity (count) added in the complex formation step, using a gamma-ray spectrometer (ORTEC, MODEL GMX15P4). The measurement results are shown in Table 4.

[0136] [Table 4]

[0137] The resulting complex is diluted with physiological saline solution. 225 To obtain a pharmaceutical product containing a complex of a chelating agent that has formed a complex with Ac and trastuzumab as the active ingredient.

[0138] [Example 4] Commercially available daptomycin (manufactured by Tokyo Chemical Industry Co., Ltd.) was dissolved in dimethylformamide, triethylamine and DOTABnSCN were added, and the mixture was reacted at 50°C for 120 minutes. The resulting reaction solution was separated and purified by reverse-phase silica gel chromatography to obtain DOTA-Daptomycin (formula (L3) below). DOTA-Daptomycin obtained according to the method described in Example 1 225 A complex was obtained by reacting 258 kBq of Ac solution with a mixture of 0.5 mol / L tetramethylammonium acetate buffer (pH 7.8) and an aqueous ethanol solution under heating conditions of 70°C for 1 hour.

[0139] [ka]

[0140] The radiochemical purity of the obtained complex was measured by the following method: thin-layer chromatography (Agilent iTLC-SG, developing solvent: 0.1 mol / L EDTA solution (pH 5.0)) was used to determine the purity of the unreacted components. 225 All, including the Business 225 For AC radioactivity count 225 The radiochemical purity (%) was defined as the percentage of radioactivity count of the chelating agent that formed a complex with Ac. The results showed that the radiochemical purity was 99.9% or higher.

[0141] The resulting complex is diluted with physiological saline solution. 225 To obtain a pharmaceutical product containing a complex of a chelating agent that has formed a complex with Ac and daptomycin as an active ingredient.

Claims

1. 226 The Ra target is irradiated with at least one particle selected from protons, deuterons, neutrons, and photons, and at 225 A step (I) to produce two or more radioactive isotopes (Ac) of actinium, After the above step (I) 226 Dissolve the Ra target, 226 Step (II) to obtain a Ra-Ac solution (1) containing Ra and Ac, The Ra-Ac solution (1) contains, 226 Ra target-derived 226 Step (III) involves separating Ra and Ac to obtain an Ac solution (2) in which the Ac concentration is higher than that of the Ra-Ac solution (1), The Ac solution (2) contains 225 A step (IV) to decay radioactive isotopes of actinium other than Ac to obtain a Ra-Ac solution (3) containing the radium isotope (Ra) obtained by decay, The Ra and Ac contained in the Ra-Ac solution (3) are separated and compared with the Ra-Ac solution (3). 225 The process includes a step (V) of obtaining an Ac solution (4) with an increased Ac concentration, If T1 is the time from the completion of step (I) to the start of step (III), then T1 is less than 5 days. 225 Method for producing an Ac solution.

2. If T2 is the time from the end of step (III) to the start of step (V), The relationship T2 > T1 is satisfied, as described in claim 1. 225 A method for producing Ac solution.

3. In the Ac solution (4), 225 For the amount of Ac 140 Ratio of La amount ( 140 La amount / 225 The amount of Ac is 1 × 10 at 7 days after the completion of the above process (V). -5 The following is the case according to claim 1 or 2 225 A method for producing Ac solution.

4. The radioactivity of 225Ac at the end of irradiation in step (I) is set to 1, and the amount of 226Ac in the Ra-Ac solution (3) at the start of step (V) is 1 × 10⁻⁵ or less, according to any one of claims 1 to 3. 225 A method for producing Ac solution.

5. The method according to any one of claims 1 to 4, wherein step (III) or step (V) includes using a solid-phase extractant that captures Ra or colloidizing Ac. 225 A method for producing Ac solution.

6. The solid-phase extractant is at least one selected from a cation exchange resin, a solid-phase extractant (a) containing a compound represented by the following formula (A), a solid-phase extractant (b) containing a compound represented by the following formula (B), and a solid-phase extractant (c) containing a compound represented by the following formula (C), as described in claim 5. 225 A method for producing Ac solution. 【Chemistry 1】 [In equation (A), m and n are independently either 0 or 1, R 1 ~R 4 Each of these is an alkyl group having 8 to 12 carbon atoms. 【Chemistry 2】 [In formula (B), R 5 and R 6 Each of these is independently an alkyl group having 8 carbon atoms or an alkoxy group having 8 carbon atoms. 【Transformation 3】 [In formula (C), R8 and R9 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.]

7. A dissolving and purifying solution of a 226 Ra target irradiated with particles, A dissolving and purifying solution in which, one month after irradiation of particles, the ratio of the amount of 140 La to the amount of 225 Ac (amount of 140 La / amount of 225 Ac) is 1 × 10⁻⁷ or less.

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