Method for producing medical-grade lead-212

Abstract

To provide a method for generating medical-grade lead-212. 【Solution means】The present invention a) generating lead-212 by radioactive decay of radium-224 in at least one first chromatography column containing a first stationary phase to which radium-224 is attached; b) eluting the thus-generated lead-212 from the first stationary phase; c) loading the thus-obtained eluate onto a second chromatography column containing a second stationary phase to attach lead-212 to the second stationary phase; d) performing a washing of the second stationary phase, and e) eluting lead-212 from the second stationary phase In a method for generating medical-grade lead-212, comprising Step b) includes circulating an aqueous solution A1 containing 0.8 mol / L to 1.6 mol / L of chloride, optionally together with up to 200 mmol / L of HCl, through the at least one first chromatography column; Step d) includes circulating an aqueous solution A2 containing 0.01 mol / L to 1 mol / L of chloride through the second chromatography column A method characterized by the above. Use: Manufacture of radiopharmaceuticals based on lead-212 useful in nuclear medicine.

Description

Technical Field

[0001] The present invention is directed to the field of production of radioisotopes, also called radioactive isotopes.

[0002] More specifically, the present invention is directed to a method that enables the production of lead-212 with a very high level of radiation purity and renders lead-212 fully suitable for medical use.

[0003] Thus, this method is likely to find use in the manufacture of lead-212-based radiopharmaceuticals that are useful in nuclear medicine, particularly in alpha radiotherapy targeting cancer treatment.

Background Art

[0004] Lead-212 is a rare radioactive lead isotope that has been the subject of promising research for several years for treatment by targeted alpha therapy, also called targeted radiotherapy, particularly against cancer, especially pancreatic cancer, ovarian cancer, colon cancer, breast cancer, and prostate cancer.

[0005] <00000!9>Lead-212 has also been shown to be of interest in medical imaging diagnostics, particularly for performing examinations by single photon emission computed tomography in combination with a scanner.

[0006] In either case, the use of lead-212 means that lead-212 is injected into a patient in the form of a radiopharmaceutical, which is a product that binds to a molecule, such as a peptide, that can very specifically target the cells that are desired to be destroyed (in the case of targeted alpha therapy) or observed (in the case of medical imaging diagnostics), typically via a chelating agent.

[0007] To achieve this, lead-212 must meet extremely stringent quality requirements, particularly radiation purity, which should ideally be at least 99.95%.

[0008] In this regard, it is stated that the radioactive purity of radioactive isotopes such as lead-212 refers to the purity of this radioactive isotope with respect to the radioactive isotope produced by its radioactive decay (i.e., its parent nuclide) and to other radioactive isotopes that are not part of its radioactive decay series, and does not refer to the purity of the radioactive isotope produced by its own radioactive decay (i.e., its daughter nuclide).

[0009] As shown in Figure 1 attached to the appendix, which represents the radioactive decay series of thorium-232, also known as the decay of thorium-232, lead-212 belongs to the radioactive family of thorium-232 and is its daughter product. It is also a daughter product of thorium-228 and radium-224, which are located between thorium-232 and lead-212 in this series.

[0010] To produce medical-grade lead-212 that meets the aforementioned radioactive purity requirements, methods are provided in the international applications PCT WO-A-2013 / 174949 and WO-A-2017 / 093069, which are references [1] and [2] below, and which are, in general terms, - A process in which lead-212 is produced by the radioactive decay of radium-224 in a generator that includes a stationary phase to which radium-224 is attached, and which will be more simply referred to below as an Ra-224 / Pb-212 generator. - A step of eluting the lead-212 thus generated from the stationary phase of the Ra-224 / Pb-212 generator, followed by - A step to purify the lead-212 that has been eluted in this way by liquid chromatography. Includes.

[0011] These references also describe devices specifically designed for the automated implementation of these methods in a closed system.

[0012] References [1] and [2] both specify eluting lead-212 from the stationary phase of an Ra-224 / Pb-212 generator with an aqueous solution containing 1.5 mol / L to 2.5 mol / L of a strong acid of the hydrochloric acid or nitric acid type, and the acid used in the examples in these references is 2 mol / L hydrochloric acid. This elution yields a strongly acidic eluate, which is loaded into a chromatography column that functions to purify lead-212.

[0013] However, the use of hydrochloric acid at concentrations recommended in references [1] and [2], particularly 2M hydrochloric acid, poses corrosion problems to equipment likely to be used in the production of lead-212, such as automated dissolution equipment containing several acid-sensitive components (e.g., valve bodies, fittings, or bearings), and to adjacent steel surfaces such as the surfaces of glove boxes or shield chains, resulting in higher maintenance rates.

[0014] Furthermore, reference [2] suggests that the method may include a step upstream of lead-212 generation in the Ra-224 / Pb-212 generator, aimed at generating radium-224 itself through the radioactive decay of thorium-228 in the generator. The generator includes a stationary phase to which this thorium adheres, and will hereafter be more simply referred to as a Th-228 / Ra-224 generator. In this case, it is stated that the elution of radium-224 from this stationary phase for the purpose of recovering radium-224 is carried out using an acidic aqueous solution such as hydrochloric acid. Although the hydrochloric acid concentration of this elution solution is not mentioned, it can be inferred from reference [2] that this concentration is between 1 mol / L and 3 mol / L, since the elution solution containing radium-224 used to attach radium-224 to the stationary phase of the Ra-224 / Pb-212 generator has a hydrochloric acid concentration between 1 mol / L and 3 mol / L, preferably 2 mol / L. Therefore, using such eluting solutions leads to the same corrosion problems discussed earlier. Furthermore, the retention curve of thorium-228 using DGA resin (Triskem International), which is recommended for use as the stationary phase in reference [2], shows a very steep slope in 1M to 3M hydrochloric acid media. As a result, even at the smallest approximation of the molar concentration of this acid, there is a high risk of thorium-228 leakage and / or reduction in the generator's lifespan. [Prior art documents] [Patent Documents]

[0015] [Patent Document 1] International application PCT WO-A-2013 / 174949 [Patent Document 2] International application PCT WO-A-2017 / 093069 [Overview of the project] [Problems that the invention aims to solve]

[0016] In view of the foregoing, the present inventors have set the objective of providing a method for producing lead-212 that exhibits the same performance as the methods described in References [1] and [2], particularly in terms of the yield and quality of the lead-212 produced, while being free from the drawbacks discussed above in this specification.

[0017] The present inventors also set the objective of improving the elution performance of lead-212 during purification by liquid chromatography, and more specifically, achieving a reduction in the volume of elution solution required to elute all of the available radioactivity of lead-212.

[0018] The inventors further set the objective that this method can be implemented in an automated manner by, for example, one of the devices described in references [1] and [2]. [Means for solving the problem]

[0019] These objectives are at least, a) A step of producing lead-212 by the radioactive decay of radium-224 present in at least one Ra-224 / Pb-212 generator, that is, in at least one first chromatographic column containing a first stationary phase to which radium-224 is attached, b) A step of eluting the lead-212 thus produced from the first stationary phase to obtain an eluate containing unpurified lead-212, c) The eluate thus obtained is loaded into a second chromatography column containing a second stationary phase, and the lead-212 present in the eluate is attached to the second stationary phase. d) A step of washing the second stationary phase to remove radioactive impurities that are likely to be retained by the second stationary phase without removing lead-212, and e) A method for producing medical-grade lead-212, comprising the step of eluting lead-212 from a second stationary phase to obtain medical-grade lead-212 in an aqueous solution, - Step b) involves circulating an aqueous solution A1 containing 0.8 mol / L to 1.6 mol / L of chloride, either alone or mixed with hydrochloric acid at a maximum of 200 mmol / L, through the at least one first chromatographic column. - Step d) involves circulating an aqueous solution A2 containing 0.01 mol / L to 1 mol / L of chloride through a second chromatographic column. This is satisfied by the present invention which provides a method.

[0020] Therefore, according to the present invention, the aqueous solution used in step b) to elute lead-212 from the stationary phase of the Ra-224 / Pb-212 generator contains chloride and may contain hydrochloric acid, but is an aqueous solution at a concentration far lower than the concentrations encouraged in references [1] and [2]. As a result, the same applies to the eluent loaded into the second chromatographic column in step c).

[0021] Furthermore, the washing of the stationary phase to which lead-212 adheres, or step d, is carried out with an aqueous solution containing chloride rather than an aqueous hydrochloric acid solution as described in the examples of references [1] and [2].

[0022] Therefore, the risk of corrosion of the equipment and adjacent surfaces is eliminated or at least dramatically reduced, and as a result, the maintenance rate is reduced without affecting the level of radiation purity obtained, and thus the production cost of lead-212 is reduced.

[0023] According to the present invention, the first and second stationary phases are preferably of the same type as those used in references [1] and [2] to generate lead-212 in a Ra-224 / Pb-212 generator and then purify this lead respectively, that is: - The first stationary phase is preferably a cation exchange resin that retains radium regardless of its isotope, but does not retain lead in the presence of chloride ions regardless of its isotope, for example, a resin consisting of particles of an organic polymer such as poly(styrene-co-divinylbenzene) grafted with sulfonic acid groups SO3H, available from Bio-Rad under the trade name AG(trademark)MP-50, on the other hand - The second stationary phase is preferably a linear or branched chain C1-C with one or more cyclohexyl or benzyl groups. 12 The extraction resin consists of particles of an inert carrier impregnated with an ether crown such as dicyclohexano-18-crown-6 or dibenzo-18-crown-6, which is substituted with an alkyl group. Therefore, the second stationary phase may be a resin in which the inert carrier is impregnated with 4,4'(5')-di-tert-butylcyclohexane-18-crown-6 in an isodecanol solution, for example, a resin available from Trischem International under the trade name Resin PB.

[0024] The chloride present in aqueous solutions A1 and A2 can be selected from many salts containing at least one chloride anion. In particular, this may be a metallic chloride, especially an alkali metal such as sodium chloride or potassium chloride, or an alkaline earth metal such as calcium chloride or magnesium chloride, or ammonium chloride. Of these salts, magnesium chloride is preferred.

[0025] According to the present invention, aqueous solution A1 preferably contains magnesium chloride in a concentration of 0.8 mol / L to 1.2 mol / L, more preferably 1.0 mol / L, either alone or in a mixture with hydrochloric acid at a maximum concentration of 50 mmol / L, where the acid, if present, is preferably at a concentration of 1 mmol / L.

[0026] Aqueous solution A2 preferably contains 0.1 mol / L to 1 mol / L, more preferably 1 mol / L, of magnesium chloride.

[0027] Given that, like any chromatography column, the second column has two opposing ends called the column head and the column tail, step d) includes circulating a first volume of aqueous solution A2 from the column head to the column tail, and then circulating a second volume of aqueous solution A2, which is the same as or different from the first volume, from the column tail to the column head.

[0028] Step e) comprises circulating aqueous solution A3 through a second chromatography column, the aqueous solution A3 having a pH between 5 and 9, and preferably containing one or more complexing agents or chelating agents (these two terms are considered synonymous herein) and / or antioxidants.

[0029] The complexing agent or chelating agent can be selected from the following in particular: - Ammonium acetate used preferably at a concentration in the range of 0.15 mol / L to 1 mol / L. - Preferably citric acid and its salts used at concentrations in the range of 10 mmol / L to 200 mmol / L, such as alkali metal citrates (e.g., monosodium citrate, disodium citrate, or trisodium citrate), alkaline earth metal citrates (e.g., monocalcium citrate, dicalcium citrate, or tricalcium citrate), or ammonium citrate such as monoammonium citrate, diammonium citrate, or triammonium citrate, with citric acid being preferred. - Chelating agents commonly used in the preparation of nuclear medicine products, particularly cyclone derivatives, namely 1,4,7,10-tetraazacyclododecane, such as DOTA (or 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DOTAM (or 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid amide), save valuable time in the production of lead-212-based radiopharmaceuticals, given their half-lives of only 10.6 hours. When such chelating agents are used, the concentration is preferably 0.2 μmol / L to 200 μmol / L.

[0030] On the other hand, antioxidants can be selected from ascorbic acid and citric acid in particular, and these are preferably used at concentrations of 10 mmol / ~200 mmol / L.

[0031] Advantageously, aqueous solution A3 contains ammonium acetate and citric acid (acting as both a complexing agent and an antioxidant), and / or DOTAM. Therefore, for example, aqueous solution A3 may contain 0.4 mol / L ammonium acetate and 75 mmol / L citric acid, or 0.4 mol / L ammonium acetate, 75 mmol / L citric acid, and 2 μmol / L DOTAM.

[0032] In any case, aqueous solution A3 is preferably circulated through the second chromatography column from the column tail to the column head.

[0033] Advantageously, the method is implemented using m Ra-224 / Pb-212 generators, i.e., m first chromatography columns, each containing a first stationary phase to which radium-224 is attached, where m is an integer at least equal to 2, typically between 2 and 4, and a single second chromatography column.

[0034] In this case, the m first chromatography columns may be arranged in parallel, - Steps a) and b) are performed on each of the m first chromatography columns, thereby obtaining m eluates containing unpurified lead-212, which are collected separately or together to form a mixture of m eluates. - Step c) is carried out by loading the eluate of m or a mixture of the eluates of m thus obtained into a second chromatography column containing a second stationary phase. - Step d) of cleaning the second stationary phase is performed, - Step e) is performed, in which lead-212 is eluted from the second stationary phase.

[0035] Therefore, by loading these m elutes (separately or in the form of a mixture) into a second chromatography column, the amount of unpurified lead-212 adhering to the second stationary phase can be increased, and thus the lead-212 in the aqueous solution derived from the elutes provided in step e) can be concentrated.

[0036] Alternatively, the m first chromatography columns may be connected in series, in which case, - Steps a) and b) are performed in each of the m first chromatography columns, and step b) is performed by continuously circulating aqueous solution A1 through the m first chromatography columns, thereby obtaining an eluate containing unpurified lead-212 as it exits the mth column. - Step c) is performed by loading the eluate thus obtained into a second chromatography column containing a second stationary phase. - Step d) of cleaning the second stationary phase is performed, - Step e) is performed, in which lead-212 is eluted from the second stationary phase.

[0037] Therefore, this alternative configuration has proven to allow lead-212 to be eluted from m Ra-224 / Pb-212 generators using substantially less volume of aqueous solution A1 than required to elute the same amount of lead-212 from m Ra-224 / Pb-212 generators having the same lead-212 loading capacity but not connected in series, ultimately saving reagents and concentrating the unpurified lead-212 in the sole eluate obtained after exiting the mth Ra-224 / Pb-212 generator, thereby allowing this lead to adhere better to the stationary phase of the second chromatography column (because it is present in a smaller volume), and concentrating the lead-212 in the aqueous solution derived from the elution provided in step e).

[0038] Regardless of the alternative configuration, preferably two or three first chromatography columns are used, i.e., m=2 or m=3.

[0039] According to the present invention, the method preferably involves, before step a), i) A step of generating radium-224 by the radioactive decay of thorium-228 in at least one Th-228 / Ra-224 generator, i.e., in at least one third chromatographic column including a third stationary phase to which thorium-228 is attached, and ii) A step of eluting the radium-224 thus generated from a third stationary phase to obtain an eluate containing radium-224, wherein the elution includes circulating an aqueous solution A0 containing 0.4 mol / L to 1 mol / L nitric acid through at least one third chromatography column, and then iii) The eluate thus obtained is loaded into at least one first chromatography column to deposit the radium-224 present in the eluate onto the first stationary phase. It also includes.

[0040] According to the present invention, the third stationary phase is preferably an extraction resin consisting of particles of an organic polymer such as polymethacrylate or poly(styrene-co-divinylbenzene) impregnated with an actinide ligand such as tetraalkylated diglycolamide (e.g., N,N,N',N'-tetraoctyl-diglycolamide or TODGA), dialkyl phosphate (e.g., di(2-ethylhexyl)phosphate or HDEHP), or trialkylphosphine oxide (e.g., trioctylphosphine oxide or TOPO).

[0041] Therefore, the third stationary phase may be a resin in which TODGA is impregnated into a polymer, for example, a resin available from Trischem International under the trade name Resin DGA Normal.

[0042] Preferably, aqueous solution A0 contains 0.5 mol / L to 0.75 mol / L, more preferably 0.5 mol / L, of nitric acid.

[0043] Advantageously, n Th-228 / Ra-224 generators are used, i.e., n third chromatography columns each containing a third stationary phase to which thorium-228 is attached, where n is an integer at least equal to 2, and typically between 2 and 5.

[0044] In this case, the n third chromatography columns may be arranged in parallel, - Steps i) and ii) are performed on each of the n third chromatography columns, thereby obtaining n eluates containing radium-224, which are collected separately or together to form a mixture of n eluates. - Step iii) is carried out by loading the eluate of n or a mixture of the eluates of n thus obtained into the at least one first chromatography column.

[0045] This makes it possible to increase the amount of radium-224 adhering to the stationary phase in at least one first chromatography column in step iii), and therefore increase the amount of lead-212 produced by the radioactive decay of radium-224 in step a).

[0046] Alternatively, the n third chromatography columns may be connected in series, in which case, - Steps i) and ii) are performed in each of the n third chromatography columns, and step ii) is performed by continuously circulating aqueous solution A0 through the n third chromatography columns, thereby obtaining an eluate containing radium-224 as it exits the nth column. - Step iii) is carried out by loading the eluate thus obtained into at least one first chromatography column.

[0047] Here again, this alternative configuration allows for the elution of radium-224 from n Th-228 / Ra-224 generators having the same radium-224 loading capacity but not connected in series, using a volume of aqueous solution A0 significantly less than the volume required to elute the same amount of radium-224 from n Th-228 / Ra-224 generators, ultimately saving reagents and concentrating the radium-224 in the single eluate obtained after exiting the nth Th-228 / Ra-224 generator, thereby allowing this radium to adhere better to the stationary phase of the at least one chromatography column, or in other words, the at least one Ra-224 / Pb-212 generator.

[0048] Regardless of the alternative configuration, preferably two or three third chromatography columns are used, i.e., n=2 or 3.

[0049] Further features and advantages of the method of the present invention will become apparent by reading the following additional description relating to implementations of this method.

[0050] These implementations are provided for illustrative purposes only and are by no means intended to limit the scope of the present invention. [Brief explanation of the drawing]

[0051] [Figure 1] As already mentioned, this is a diagram showing the radioactive decay series of thorium-232. [Figure 2] This figure schematically shows a first implementation embodiment of the method of the present invention. [Figure 3] This figure schematically shows a second implementation embodiment of the method of the present invention. [Modes for carrying out the invention]

[0052] Refer to Figure 2, which schematically shows the different steps 1 to 6 of a first implementation of the method of the present invention, in which a single Th-228 / Ra-224 generator and a single Ra-224 / Pb-212 generator are used.

[0053] Therefore, in this implementation, the starting point of the method is represented by a Th-228 / Ra-224 generator, indicated as 10 in Figure 2. This generator includes a chromatographic column to which thorium-228 is attached, with a stationary phase indicated as 20 consisting of DGA Normal (Triskem International) resin particles.

[0054] When thorium-228 present in generator 10 is caused to decay and produce radium-224, the method proceeds as follows: 1. The radium-224 thus produced is eluted from the stationary phase 20 with an aqueous solution of nitric acid A0 to obtain an eluate E1 containing radium-224. 2. A step to prepare an Ra-224 / Pb-212 generator, indicated as 30, by loading the eluate E1 into a chromatography column whose stationary phase 40 consists of AG(trademark)MP-50 (Bio-Rad) resin particles, thereby allowing the radium-224 present in the eluate to adhere to the stationary phase 40. 3. The radium-224 present in the generator 30 is allowed to decay to produce lead-212, and this lead is eluted from the stationary phase 40 with an aqueous chloride solution A1 in which the lead is alone or in a mixture with very weak concentrated hydrochloric acid to obtain an eluate E2 containing lead-212. 4. The eluate E2 is loaded into a chromatography column labeled 50, where the stationary phase 60 consists of Resin PB (Triskem International) particles, and the lead-212 present in the eluate is deposited onto this stationary phase. 5. A step of performing two consecutive washes of the stationary phase 60 in order to remove trace amounts of radioactive isotopes other than lead-212 that are likely to have been retained in the column in the previous step, wherein each of these washes is performed with an aqueous chloride solution A2, but in opposite directions. 6. Elute lead-212 from stationary phase 60 with aqueous solution A3 having a pH in the range of 5 to 9 and containing one or more complexing agents and / or antioxidants to obtain eluate E3 containing purified lead-212, and collect this eluate in a receptacle indicated as 70, which may be a beaker, flask, or similar type as shown in Figure 2, or a syringe connected to the tail of column 50. Includes.

[0055] All of these processes, detailed below, are performed at room temperature, i.e., between 20°C and 25°C.

[0056] Furthermore, all solutions used are preferably Optima® grade, or prepared from Optima® grade or Trace Metals grade reagents.

[0057] Unless otherwise specified, the aqueous solution circulated through columns 10, 30, and 50 is circulated from the column head to the column tail.

[0058] *Step 1: As previously described, this process involves eluting radium-224, which is produced by the radioactive decay of thorium-228 attached to the stationary phase 20 of the generator 10.

[0059] This generator has, for example, a bed volume or BV in the range of 5 mL to 100 mL and includes a chromatography column packed with, for example, an amount of DGA Normal resin particles ranging from 2 g to 40 g depending on the column's BV.

[0060] This type of resin retains thorium regardless of its isotope, but does not retain radium regardless of its isotope.

[0061] The elution of radium-224 is carried out by circulating a few BV aqueous solution A0 containing 0.5 mol / L to 0.75 mol / L, preferably 0.5 mol / L, nitric acid through the generator 10 at a flow rate of, for example, 0.25 BV / min.

[0062] Therefore, eluate E1 is obtained.

[0063] *Step 2: The generator 30 has dimensions smaller than the chromatography column of the generator 10, and has a BV in the range of, for example, 0.5 mL to 10 mL. The chromatography column is filled with AG(trademark) MP-50 resin particles in an amount ranging from, for example, 300 mg to 5 g, according to the BV of this column, and the eluate E1 is prepared by circulating it through this column.

[0064] In a chloride medium, AG(trademark) MP-50 resin retains radium regardless of its isotope, but does not retain lead regardless of its isotope.

[0065] The loading of eluate E1 into the generator 30 is performed, for example, at a flow rate of 4 BV / min.

[0066] *Step 3: As previously described, this process involves a period during which the generator 30 is allowed to produce lead-212 through the radioactive decay of radium-224 present in the generator, followed by the elution of the thus produced lead-212 from the stationary phase 40.

[0067] To do this, an aqueous solution A1 of several BV is circulated to the generator 30 at a flow rate of, for example, 4 BV / min, and this aqueous solution contains 0.8 mol / L to 1.6 mol / L of chloride, preferably magnesium chloride, and optionally hydrochloric acid, which, if present, has a concentration of up to 200 mmol / L, preferably up to 50 mmol / L, and even better, 1 mmol / L.

[0068] Therefore, eluate E2 is obtained.

[0069] *Step 4: Since the lead-212 present in eluate E2 still does not meet the radioactive purity standards required for medical use, steps 4, 5, and 6 aim to purify the lead-212 with respect to its parent nuclide, particularly radium-224, using a chromatography column packed with resin PB.

[0070] The chromatography column 50 used for this purpose, which is smaller in dimensions than the chromatography column of the generator 30, has a BV in the range of, for example, 0.1 mL to 1 mL and is packed with resin PB particles of 35 mg to 450 mg.

[0071] Loading the eluent E2 into column 50 is performed by circulating the eluent through column 50 at a flow rate of, for example, 4 BV / min.

[0072] *Step 5: The two consecutive washes provided in this process are performed using the same aqueous solution A2, but in opposite directions.

[0073] This aqueous solution contains the same chloride present in aqueous solution A1 used in step 3 above, at a concentration of 25 mmol / L to 75 mmol / L, for example, 50 mmol / L of magnesium chloride.

[0074] The first wash is performed by circulating an aqueous solution A2 of several BV in column 50 from the column head to the column tail at a flow rate of, for example, 6 BV / min, while the second wash is performed by circulating an aqueous solution A2 of preferably the same BV in column 50 at the same flow rate, but from the column tail to the column head.

[0075] *Step 6: The elution of lead-212 from the stationary phase 60 is performed by circulating several BV of aqueous solution A3 from the column tail to the column head of the column 50, where aqueous solution A3 has a pH between 5 and 9 and contains one or more complexing agents and / or antioxidants.

[0076] Aqueous solution A3 is, for example, an aqueous solution with a pH of 6.5 containing 0.4 mol / L ammonium acetate and 75 mmol / L citric acid.

[0077] This is then circulated through column 50 at a flow rate of, for example, 6 BV / min.

[0078] The eluate E3 obtained from the column head is collected in container 70, and the lead-212 present in this eluate has radioactive purity with respect to its parent nuclide and can be used for medical purposes.

[0079] As previously shown, the method described above may also be implemented using n Th-228 / Ra-224 generators arranged in parallel or connected in series, where n is, for example, equal to 3, and m Ra-224 / Pb-212 generators also arranged in parallel or connected in series, where m is, for example, equal to 2.

[0080] Therefore, as shown in Figure 3, which illustrates an implementation using, for example, n Th-228 / Ra-224 generators connected in series and m Ra-224 / Pb-212 generators connected in series, this implementation differs from the implementation shown in Figure 2 only in the following respect: - Since thorium-228 is to decay in n generators 10 to produce radium-224, step 1 is performed by circulating an aqueous solution of nitric acid A0 in succession through these n generators 10, in other words, by introducing this solution into the first of the n generators 10 and circulating it through the next n-1 generators 10, as a result, when it exits the nth generator 10, a single eluate E1 containing radium-224 is obtained. - Step 2 is performed by continuously circulating the eluate E1 thus obtained through m generators 30, in other words, by introducing this eluate into the first of the m generators 30 and circulating it through the next m-1 generator 30, and - Since radium-224 is to decay in m generators 30 to produce lead-212, step 3 is carried out by circulating aqueous solution A1 in succession through these m generators 30, in other words, by introducing this solution into the first of the m generators 30 and circulating it through the next m-1 generators 30, as a result, when it exits the mth generator 30, a single eluate E2 containing unpurified lead-212 is obtained. [Examples]

[0081] (Example 1 - MgCl2 1M / CLG BV 1.25 mL / CLL BV 0.173 mL) Steps 1 to 6 of the first implementation mode described above are as follows: *Step 1: To elute radium-224 from the stationary phase of generator 10 containing 3.7 g of DGA resin, with BV equal to 9.8 mL, prepare 30 mL of aqueous solution A0 containing 0.5 mol / L nitric acid at a flow rate of 5 mL / min. *Step 2: Column 30 is loaded with 0.65 g of AG(trademark) MP-50 resin, with a BV equal to 1.25 mL, and 25.4 mL of eluate E1 obtained in the previous step, at a flow rate of 5 mL / min. This eluate contains 167 MBq of radium-224. *Step 3: After 20 hours, when radium-224 has been allowed to produce lead-212, 10 mL of aqueous solution A1 containing 1 mol / L MgCl2 at a flow rate of 0.5 mL / min, *Step 4: Column 50 containing 73±5 mg of PB resin with a BV equal to 0.173 mL, loaded with eluate E2 obtained in Step 3 at a flow rate of 0.5 mL / min (pre-washed with 1 mL of 1.0 mol / L MgCl2 aqueous solution at a flow rate of 0.5 mL / min), *Step 5: Add 1.5 mL of aqueous solution A2 containing 1.0 mol / L MgCl2 at a flow rate of 0.5 mL / min twice. *Step 6: 1.6 mL of aqueous solution A3 containing 0.4 mol / L ammonium acetate and 75 mmol / L citric acid at a flow rate of 0.5 mL / min. I used [this method] to execute it.

[0082] Thus, an aqueous solution containing 96.8 MBq of lead-212 was obtained.

[0083] This lead-212 had a radioactive purity of over 99.999% with respect to radium-224, as no radium-224 was detected after one week.

[0084] (Example 2 - MgCl2 1M / CLG BV=5.0mL / CLL BV=0.63mL) Steps 1 to 6 of the first implementation mode described above are as follows: *Step 1: To elute radium-224 from the stationary phase of generator 10 containing 3.7 g of DGA resin, with BV equal to 9.8 mL, prepare 30 mL of aqueous solution A0 containing 0.5 mol / L nitric acid at a flow rate of 5 mL / min. *Step 2: Column 30 has a BV of 5 mL, contains 2.43 g of AG(trademark) MP-50 resin, and is loaded with 37.8 mL of eluate E1 obtained in the previous step at a flow rate of 5 mL / min. This eluate contains 116 MBq of radium-224. *Step 3: After 23 hours, when radium-224 has been allowed to produce lead-212, 30 mL of aqueous solution A1 containing 1 mol / L MgCl2 at a flow rate of 3.5 mL / min, *Step 4: Column 50 containing 235±15 mg of PB resin with a BV equal to 0.63 mL, loaded with eluate E2 obtained in Step 3 at a flow rate of 3.5 mL / min (pre-washed with 4 mL of 1 mol / L MgCl2 aqueous solution at a flow rate of 3.5 mL / min), *Step 5: Add 3 mL of aqueous solution A2 containing 1.0 mol / L MgCl2 at a flow rate of 3.5 mL / min twice. *Step 6: 6 mL of aqueous solution A3 containing 0.4 mol / L ammonium acetate and 75 mmol / L citric acid at a flow rate of 3.5 mL / min. It was implemented using [this method].

[0085] Thus, an aqueous solution containing 75.7 MBq of lead-212 was obtained.

[0086] This lead-212 had a radioactive purity of over 99.999% with respect to radium-224, as no radium-224 was detected after one week.

[0087] (Example 3 - MgCl2 1M + 1mM HCl / CLG BV=1.25mL / CLL BV=0.173mL) Steps 3 to 6 of the first implementation method described above are as follows: *Step 3: After 24 hours, when radium-224 has been allowed to produce lead-212, 10 mL of aqueous solution A1 containing 1 mol / L MgCl2 and 1 mmol / L HCl at a flow rate of 0.5 mL / min, *Step 4: Column 50 containing 73±5 mg of PB resin with a BV equal to 0.173 mL, loaded with eluate E2 obtained in Step 3 at a flow rate of 0.5 mL / min (pre-washed with 1 mL of aqueous solution of 1 mol / L MgCl2 and 1 mmol / L HCl at a flow rate of 0.5 mL / min), *Step 5: Add 1.5 mL of aqueous solution A2 containing 1.0 mol / L MgCl2 and 1 mmol / L HCl twice at a flow rate of 0.5 mL / min. *Step 6: 1.6 mL of aqueous solution A3 containing 0.4 mol / L ammonium acetate and 75 mmol / L citric acid at a flow rate of 0.5 mL / min. This was implemented following Example 1 using [the specified method].

[0088] Thus, an aqueous solution containing 77.5 MBq of lead-212 was obtained.

[0089] This lead-212 had a radioactive purity of over 99.999% with respect to radium-224, as no radium-224 was detected after one week.

[0090] (Example 4 - MgCl2 1M + 1mM HCl / CLG BV=5.0mL / CLL BV=0.63mL) Steps 3 to 6 of the first implementation method described above are as follows: *Step 3: After 71 hours, when radium-224 has been allowed to produce lead-212, 30 mL of aqueous solution A1 containing 1 mol / L MgCl2 and 1 mmol / L HCl is added at a flow rate of 3.5 mL / min. *Step 4: Column 50 containing 235 ± 15 mg of PB resin with a BV equal to 0.63 mL, loaded with eluate E2 obtained in Step 3 at a flow rate of 3.5 mL / min (pre-washed with 4 mL of aqueous solutions of 1 mol / L MgCl2 and 1 mmol / L HCl at a flow rate of 3.5 mL / min), *Step 5: Add 3 mL of aqueous solution A2 containing 1.0 mol / L MgCl2 and 1 mmol / L HCl twice at a flow rate of 3.5 mL / min. *Step 6: 6 mL of aqueous solution A3 containing 0.4 mol / L ammonium acetate and 75 mmol / L citric acid at a flow rate of 3.5 mL / min. This was implemented using the method described in Example 2.

[0091] Thus, an aqueous solution containing 51.5 MBq of lead-212 was obtained.

[0092] This lead-212 had a radioactive purity of over 99.999% with respect to radium-224, as no radium-224 was detected after one week.

[0093] In conclusion from Examples 1-4, the yields of collected Pb-212 relative to the lead produced by decay were 88%, 77%, 95%, and 85%, respectively. Since the purity was higher than 99.999% and no Ra-224 was detected, the detection limit was taken into account in the purity calculation.

[0094] Cited references [1]WO-A-2013 / 174949 [2]WO-A-2017 / 093069 [Explanation of symbols]

[0095] 1~6 steps 10 Generator 20 stationary phase 30 Generators 40 stationary phase 50 chromatography columns 60 stationary phase 70 Receptacles A0 aqueous solution A1 Aqueous solution A2 Aqueous solution A3 Aqueous solution E1 eluate E2 eluate E3 eluate

Claims

1. A method for producing a medical-grade lead-212 aqueous solution, wherein this method is at least a) A step of producing lead-212 by the radioactive decay of radium-224 present in at least one first chromatographic column comprising a first stationary phase to which radium-224 is attached, b) A step of eluting the lead-212 thus produced from the first stationary phase to obtain an eluate containing unpurified lead-212, c) The eluate thus obtained is loaded into a second chromatography column containing a second stationary phase, and the lead-212 present in the eluate is attached to the second stationary phase. d) A step of washing the second stationary phase to remove radioactive impurities that are likely to be retained by the second stationary phase without removing lead-212, and e) The process includes the step of eluting lead-212 from a second stationary phase to obtain medical-grade lead-212 in an aqueous solution, Step b) includes circulating an aqueous solution A1 containing 0.8 mol / L to 1.6 mol / L of chloride, either alone or mixed with up to 200 mmol / L of hydrochloric acid, through at least one first chromatography column. Step d) includes circulating an aqueous solution A2 containing 0.01 mol / L to 1 mol / L of chloride through a second chromatography column. A method characterized by the following:

2. The method according to claim 1, wherein the chloride present in aqueous solutions A1 and A2 is an alkali metal chloride, an alkaline earth metal chloride, or ammonium chloride.

3. The method according to claim 2, wherein the chloride is magnesium chloride.

4. The method according to any one of claims 1 to 3, wherein aqueous solution A1 contains 0.8 mol / L to 1.2 mol / L of magnesium chloride, either alone or in a mixture with up to 50 mmol / L of hydrochloric acid.

5. The method according to any one of claims 1 to 4, wherein aqueous solution A1 contains 1.0 mol / L magnesium chloride, either alone or in a mixture with up to 50 mmol / L hydrochloric acid.

6. The method according to any one of claims 1 to 5, wherein aqueous solution A2 contains 0.1 mol / L to 1 mol / L of magnesium chloride.

7. The method according to any one of claims 1 to 6, wherein aqueous solution A2 contains 1 mol / L magnesium chloride.

8. The method according to any one of claims 1 to 7, wherein the second chromatography column has a column head and a column tail, and step d) includes circulating a first volume of aqueous solution A2 from the column head to the column tail, and then circulating a second volume of aqueous solution A2 from the column tail to the column head.

9. The method according to any one of claims 1 to 8, wherein step e) comprises circulating an aqueous solution A3 having a pH between 5 and 9 and containing one or more complexing agents and / or antioxidants through a second chromatography column.

10. The method according to claim 9, wherein aqueous solution A3 comprises ammonium acetate and citric acid and / or DOTAM.

11. The method according to claim 10, wherein aqueous solution A3 contains 0.4 mol / L ammonium acetate and 75 mmol / L citric acid.

12. The method according to any one of claims 9 to 11, wherein the second chromatography column has a column head and a column tail, and aqueous solution A3 circulates within the second chromatography column from the column tail to the column head.

13. m first chromatography columns are used, arranged in parallel, each containing a first stationary phase to which radium-224 is attached, where m is an integer at least equal to 2. Steps a) and b) are performed on each of the m first chromatography columns, thereby obtaining m eluates containing unpurified lead-212, which are collected separately or together to form a mixture of m eluates. Step c) is performed by loading the eluate of m or a mixture of the eluates of m thus obtained into a second chromatography column containing a second stationary phase. Step d) is performed to clean the second stationary phase. Step e) is performed, in which lead-212 is eluted from the second stationary phase. The method according to any one of claims 1 to 12.

14. m first chromatography columns are used, each containing a first stationary phase to which radium-224 is attached, and connected in series, such that m is an integer at least equal to 2. Steps a) and b) are performed in each of the m first chromatography columns, and step b) is performed by continuously circulating aqueous solution A1 through the m first chromatography columns, thereby obtaining an eluate containing unpurified lead-212 as it exits the mth of the m chromatography columns. Step c) is performed by loading the eluate thus obtained into a second chromatography column containing a second stationary phase. Step d) is performed to clean the second stationary phase. Step e) is performed, in which lead-212 is eluted from the second stationary phase. The method according to any one of claims 1 to 12.

15. The method according to claim 13 or claim 14, wherein m is 2 or 3.

16. Before step a), i) A step of generating radium-224 by the radioactive decay of thorium-228 in at least one third chromatographic column including a third stationary phase to which thorium-228 is attached, and ii) A step of eluting the radium-224 thus generated from a third stationary phase to obtain an eluate containing radium-224, wherein the elution includes circulating an aqueous solution A0 containing 0.4 mol / L to 1 mol / L nitric acid through at least one third chromatography column, and then iii) The eluate thus obtained is loaded into at least one first chromatography column to deposit the radium-224 present in the eluate onto the first stationary phase. The method according to any one of claims 1 to 15, further comprising:

17. The method according to claim 16, wherein aqueous solution A0 contains 0.5 mol / L nitric acid.

18. n third chromatography columns are used, arranged in parallel and each containing a third stationary phase to which thorium-228 is attached, where n is an integer at least equal to 2. Steps i) and ii) are performed on each of the n third chromatography columns, thereby obtaining n eluates containing radium-224, which are collected separately or together to form a mixture of n eluates. Step iii) is carried out by loading the eluate of n or a mixture of eluates of n thus obtained into the at least one first chromatography column. The method according to claim 16 or claim 17.

19. n third chromatography columns are used, each connected in series and containing a third stationary phase to which thorium-228 is attached, where n is an integer at least equal to 2. Steps i) and ii) are performed in each of the n third chromatography columns, and step ii) is performed by continuously circulating aqueous solution A0 through the n third chromatography columns, thereby obtaining an eluate containing radium-224 as it exits the nth third chromatography column. Step iii) is performed by loading the eluate thus obtained into the at least one first chromatography column. The method according to claim 16 or claim 17.

20. The method according to claim 18 or claim 19, wherein n is 2 or 3.

Images