Automated method and apparatus for producing lead 212 for targeted alpha particle therapy

Abstract

The present disclosure relates to an automated device and method for producing a high purity alpha particle-emitting radioisotope Pb-212 from a column pre-filled with the parent isotope Ra-224 for targeted alpha particle therapy.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 493,139, filed March 30, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to an automated apparatus for producing high-purity Pb-212, a radioactive isotope that emits alpha particles, from a column pre-filled with the parent isotope Ra-224 for use in targeted alpha particle therapy. Background Technology

[0004] Receptor-targeted cancer therapy has been a promising and evolving field, with research focusing on selectively delivering targeted therapies to tumors through chelation of small molecules that recognize tumor-associated receptors, metabolic pathways, transporters, and antigens. These small molecules may include purified radioisotopes that utilize high-energy emission to powerfully target and destroy cancer cells. The ability to diagnose specific cancers and destroy cancer cells with limited impact on surrounding healthy tissue is a promising mechanism that has the potential to significantly advance individual treatment while minimizing toxic side effects.

[0005] Therefore, targeted radionuclide therapy (TRT) has become a highly attractive and rapidly developing treatment option for many diseases, including various types of cancer. While much past research has focused on beta-emitting radionuclides, another form of targeted radionuclide therapy includes targeted alpha-emitting therapy (TAT), an evolving field that aims to purify radioactive materials through alpha decay to target cancerous tissue with high specificity. Alpha-emitting particles have advantages over beta-emitting particles due to their high energy and short range. Furthermore, some cancerous tissues may be resistant to beta emitters, and patients may experience numerous side effects, making alpha-emitting particles a significant advantage for targeted therapy.

[0006] In this field, various methods for producing and purifying radioisotopes have been found to show great potential in TRT and TAT therapies, particularly Pb-212, which has shown promising promise in developing novel therapies that target cancer cells while minimizing impact on healthy tissues. Early studies of Pb-212 as an alpha-emitting nuclide have shown it to be more efficient at killing human ovarian cancer cells than X-ray therapy. Pb-212 has been the focus of numerous clinical trials, including a Phase I clinical trial at the University of Alabama, Birmingham, using Pb-212-TCMC-trastuzumab, which showed extremely low toxicity levels when used to treat ovarian cancer. More recently, a first-in-human dose-escalation clinical trial using targeted alpha emitter therapy (TAT) and Pb-212-DOTAMTATE to treat metastatic neuroendocrine tumors expressing somatostatin receptors (SSTRs) showed that alpha therapy with Pb-212-DOTAMTATE was well-tolerated and significantly effective. A phase II trial is underway to use Pb-212-DOTAMTATE to treat patients with neuroendocrine tumors (NETs) expressing somatostatin receptors with TAT.

[0007] Pb-212 is a daughter product of the Th-228 radioactive family. Th-228 has a half-life of approximately 1.9 years. Ra-224 is in the same radioactive decay chain and has been used as a generator to obtain continuous amounts of Pb-212 via radioactive decay. Typically, this generator is a device containing Ra-224 bound to an ion exchange resin, while Pb-212 is recovered by elution. The eluent containing Pb-212 is acid-digested to remove chemical impurities.

[0008] Current methods for purifying and using such purified Pb-212 have several drawbacks, including the potential accumulation of the radioisotope in the patient's bone marrow and other side effects due to the inherent toxicity of any accumulated free lead. Current methods only achieve a low level of purification, thus requiring the use of low doses of therapeutic agents to avoid unexpected and dangerous side effects. The use of poorly purified radioisotopes in TAT treatment presents a significant disadvantage due to the potential toxicity.

[0009] Therefore, there is an unmet need for improved processes for generating Pb-212 (e.g., reducing the influence of impurities and radioisotope toxicity). Simultaneously, there is a clinical need for efficient processes for generating and purifying Pb-212 to achieve improved and effective targeted alpha particle therapy.

[0010] This invention provides an improved method for purifying and using Pb-212. The invention includes an improved purification system for targeted alpha particle therapy, employing purification resins, higher-activity isotopes, and radiation shielding of the isotope-containing column. This invention provides a more streamlined process for producing alpha emitter therapy, which retains the advantages of previous treatment methods while achieving higher purity and reducing patient toxicity rates. The process of this invention allows for higher activity in both reagents and products, facilitating the large-scale production and commercial manufacturing of Pb-212. Furthermore, this invention provides more effective radiation shielding to improve public safety and facilitate transport. Summary of the Invention

[0011] Various aspects of this disclosure include methods and apparatus for the automated production of Pb-212 from the parent radionuclide Th-228. The produced Pb-212 serves as a radioactive component of radiopharmaceuticals for various targeted alpha particle therapies and is particularly useful in the treatment of a variety of cancers, including but not limited to pancreatic cancer, brain cancer, ovarian cancer, prostate cancer, colon cancer, breast cancer, and neuroendocrine tumors.

[0012] The produced Pb-212 is highly purified and exhibits lower toxicity when labeled with specific ligands and administered to patients in need. It also reduces the accumulation of free lead in the bone marrow and provides better efficacy and fewer adverse effects compared to Pb-212 or other similar β-particle therapies produced by other methods.

[0013] The production process of radionuclides can be implemented sequentially through automated modules to synthesize the desired radionuclides more efficiently.

[0014] The parent radioactive isotope can be selected from Th-228 or directly from Ra-224.

[0015] The radioactive isotopes produced by the method of this invention can be combined with chelating agents and other molecules used for TAT. Chelating agents include those selected from the group consisting of DOTA, DOTAM, TCMC, and their derivatives.

[0016] The purification methods used to produce radionuclides can and will vary because the efficacy of a radionuclide depends on its purity and the amount of ionizing radiation. The purification resins used in the composition can and will vary. In some embodiments, the purification resin used may be selected from Bio-Rad AGMP1, Bio-Rad AMP50, Bio-Rad AG50W, Bio-Rad Chelex 100, Purolite NRW100, Purolite NRW1100, Purolite NRW1160, Purolite NRW1160LS, Purolite NRW150, Purolite NRW160, Purolite NRW160LS, TrisKem Actinide resin, TrisKem DGA resin, TrisKem Guard resin, TrisKem KNiFC-PAN resin, TrisKemLN resin, TrisKem LN2 resin, TrisKem LN3 resin, TrisKem MNO2-PAN resin, TrisKem NI resin, TrisKem PB resin, TrisKem Prefilter resin, TrisKem RE resin, TrisKem The invention comprises the group consisting of SR resin, TrisKem TBP resin, TrisKem TEVA resin, TrisKem TK100 resin, TrisKem TK101 resin, TrisKem TK102 resin, TrisKem TK200 resin, TrisKem TK201 resin, TrisKem TK202 resin, TrisKem TK211 resin, TrisKem TK212 resin, TrisKem TK213 resin, TrisKem TK221 resin, TrisKem TK225 resin, TrisKem TK400 resin, TrisKem TRU resin, TrisKem UTEVA resin, TrisKem WBEC resin, and TrisKem ZR resin. TrisKem resin is also referred to as TK resin. Those skilled in the art will understand the use of various ion exchange resins suitable for this invention.

[0017] The activity levels of the parent isotopes loaded into single-column and multi-column systems can and will vary. In some embodiments, the activity levels range from at least 5 mCi, at least 10 mCi, at least 15 mCi, at least 20 mCi, at least 25 mCi, at least 30 mCi, at least 35 mCi, at least 40 mCi, at least 45 mCi, at least 50 mCi, at least 55 mCi, at least 60 mCi, at least 65 mCi, at least 70 mCi, at least 75 mCi, at least 80 mCi, at least 85 mCi, at least 90 mCi, at least 95 mCi, at least 100 mCi, to... At least 105 mCi, at least 110 mCi, at least 115 mCi, at least 120 mCi, at least 125 mCi, at least 130 mCi, at least 135 mCi, at least 140 mCi, at least 145 mCi, at least 150 mCi, at least 155 mCi, at least 160 mCi, at least 165 mCi, at least 170 mCi, at least 175 mCi, at least 180 mCi, at least 185 mCi, at least 190 mCi, at least 195 mCi, or at least 200 mCi.

[0018] The dosage of the resulting Pb-212 drug can vary and will vary. In some embodiments, the radiopharmaceutical composition contains... 212 The total dose range of Pb can be approximately 1 mCi to 5 mCi, approximately 5 mCi to 10 mCi, approximately 10 mCi to 15 mCi, approximately 15 mCi to 20 mCi, 20 mCi to 30 mCi, approximately 15 mCi to 25 mCi, approximately 25 mCi to 35 mCi, approximately 30 mCi to 40 mCi, approximately 35 mCi to 45 mCi, approximately 40 mCi to 50 mCi, or approximately 45 mCi to 55 mCi. The dose can be approximately 15 mCi, 20 mCi, 25 mCi, 30 mCi, 35 mCi, 40 mCi, 45 mCi, 50 mCi, or 55 mCi.

[0019] Other features and aspects of this disclosure will be described in detail below. Attached Figure Description

[0020] Figure 1 A first embodiment of the apparatus is described, comprising a single multi-port head valve with several valves that control the flow of solvent, eluent, and buffer during the automated production of Pb-212 from the parent radionuclide Ra-224.

[0021] Figure 2A second embodiment of the apparatus is described, which includes a multi-port head valve with several valves that enable further selective control of the flow of solvent, eluent, and buffer solution after eluting Pb-212 from the parent radionuclide Ra-224.

[0022] Figure 3 A third embodiment of the device is described, which includes a multi-port head valve, the valves on the head valve being able to selectively control the flow of solvent, eluent and buffer after purification of Pb-212.

[0023] Figure 4 A schematic layout of the automated sequence for purifying Th-228 and Ra-224 is depicted.

[0024] Figure 5 A schematic diagram illustrating the purification of Pb-212 using a tertiary amine-based resin (e.g., TK resin) is shown.

[0025] Figure 6 Elution curves of Pb-212 fractionated elution from TK resin were plotted.

[0026] Figure 7 The yields (RCY%) of Pb-212 after loading and after elution from the pre-purified column are depicted.

[0027] Figure 8 One implementation of an automated system for purifying Th-228 and Ra-224 is described.

[0028] Figure 9 One implementation of an automated system for Pb-212 elution and purification (or "post-purification") is described.

[0029] Figure 10 The layout of the apparatus housing for Pb-212 elution and purification is depicted: (a) isometric view, (b) side view, (c) top view. Invention Details

[0031] This paper discloses an automated apparatus that produces high-purity, alpha-emitting radioactive isotope Pb-212 from a column pre-filled with the parent isotope Ra-224. The purified Pb-212 can be used for targeted alpha particle therapy.

[0032] The following description includes example apparatuses, methods, techniques, and / or operational instructions embodying the techniques of this subject matter. However, it should be understood that the described embodiments can be practiced without these specific details.

[0033] In describing the elements of various embodiments of this disclosure, the terms "a," "an," "an," "the," "the," and, where no quantifier is used, indicate the presence of one or more elements. The terms "comprising," "including," and "having" are non-exclusive, meaning that there may be other elements besides those listed.

[0034] Unless otherwise stated, the use of a single numerical value is referred to as an approximation, as if the value were preceded by the words “about” or “approximately”. Similarly, unless explicitly stated otherwise, numerical values ​​within the various ranges specified herein are expressed as approximations, as if the minimum and maximum values ​​within the range were preceded by “about” or “approximately”. In this way, variations above and below the range can be used to obtain results substantially the same as those within the range. As used herein, when referring to numerical values, the terms “about” and “approximately” should have their plain and common meaning to those skilled in the art most closely related to the disclosed subject matter or to those skilled in the art in relation to the range or element in question. The amount by which a numerical value is broadened depends on many factors. Some factors that may be considered include the criticality of the element and / or the impact of a variation in a given amount on the performance of the claimed subject matter, as well as other considerations known to those skilled in the art. The use of different significant figures for different numerical values ​​as used herein does not imply any limitation on how the words “about” or “approximately” broaden a specific numerical value or range. Therefore, in general, “about” or “approximately” broadens the numerical value. Furthermore, the disclosure of the range is intended as a continuous range, including every value between the minimum and maximum values, plus the broadening effect provided by the use of the terms "about" or "approximately". Therefore, unless otherwise stated, the description of the range of values ​​herein is intended only as a shorthand method of individually referring to each individual value falling within that range, and each individual value is incorporated into the specification as if it were described individually herein.

[0035] As used herein, the term "half-life" refers to the time required for the physical decay of a radioactive isotope to reach 50% of its initial / initial radioactivity, and for the concentration of a drug in the blood or plasma to decrease by half. This decrease in drug concentration reflects the excretion or elimination of the drug after absorption is complete and distribution reaches equilibrium or quasi-equilibrium. The half-life of a drug in the blood can typically be determined graphically (typically after intravenous administration to a sample population) based on a pharmacokinetic plot of the drug's blood concentration-time curve. Half-life can also be determined using mathematical calculations well known in the art. Furthermore, as used herein, the term "half-life" also includes the "apparent half-life" of a drug. Apparent half-life may be a composite value that encompasses the effects of processes other than elimination, such as absorption, reuptake, or enterohepatic circulation.

[0036] As used herein, the terms “active agent” or “drug” refer to any chemical that, when administered to humans or animals, can elicit a biochemical reaction. A drug may act as a substrate or product of a biochemical reaction, or it may interact with a cell receptor and elicit a physiological response, or it may bind to a receptor and block the receptor, thus eliciting a physiological response.

[0037] The terms “subject” or “patient” are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, humans.

[0038] The terms "pure" or "purity" refer to chemical purity or radiological purity. Radiological purity, in particular, refers to the purity of a radionuclide relative to other radionuclides from which it originates through radioactive decay, and relative to other radionuclides not belonging to its radioactive decay chain.

[0039] The terms “isotope,” “radioactive isotope,” and “radioactive nuclide” are all used to refer to a nuclide that is unstable and will naturally undergo radioactive decay over time.

[0040] The term "parent nuclide" refers to a radionuclide that has not undergone radioactive decay within its known radioactive decay chain to produce a daughter radionuclide.

[0041] The term "daughter nuclide" refers to a radionuclide that originates from a larger parent nuclide and has undergone radioactive decay within its known radioactive decay chain.

[0042] One embodiment of the present invention relates to the use and handling of parent and daughter nuclides. These nuclides may be selected from the group consisting of: 212 Pb, 203 Pb, 84 Cu、 67 Cu、 212 Bi、 68 Ga、212 Bi、 213 Bi、 223 Ra、 224 Ra、 225 Ac、 243 Am、 211 At、 217 At、 154 Dy、 148 Gd, 146 Sm、 147 Sm、 149 Tb, 227 Th、 228 Th、 229 Th、 59 Fe、 60 Cu、 61 Cu、 62 Cu、 61 Ga、 86 Y、 111 In、 153 Gd, 153 Sm and 166 Ho. More specifically, these nuclides can be selected from the nuclides of thorium, radium, actinium, radon, polonium, lead, and bismuth. More specifically, the parent nuclide is composed of Th-228 or Ra-224, and the daughter nuclides are composed of Pb-212 and Bi-212. More specifically, the daughter nuclide is Pb-212.

[0043] The activity levels of the parent radionuclides loaded onto a single column are at least 1 mCi, at least 2 mCi, at least 3 mCi, at least 4 mCi, at least 5 mCi, at least 6 mCi, at least 7 mCi, at least 8 mCi, at least 9 mCi, at least 10 mCi, at least 11 mCi, at least 12 mCi, at least 13 mCi, at least 14 mCi, at least 15 mCi, at least 16 mCi, at least 17 mCi, at least 18 mCi, at least 19 mCi, and at least 20 mCi. mCi, at least 21mCi, at least 22mCi, at least 23mCi, at least 24mCi, at least 25mCi, at least 26mCi, at least 27mCi, at least 28mCi, at least 29mCi, at least 30mCi, at least 31mCi, at least 32mCi, at least 33mCi, at least 34mCi, at least 35mCi, at least 36mCi, at least 37mCi, at least 38mCi, at least 39mCi, at least 40mCi, at least 41 mCi, at least 42mCi, at least 43mCi, at least 44mCi, at least 45mCi, at least 46mCi, at least 47mCi, at least 48mCi, at least 49mCi, at least 50mCi, at least 55mCi, at least 60mCi, at least 65mCi, at least 70mCi, at least 75mCi, at least 80mCi, at least 85mCi, at least 90mCi, at least 95mCi, at least 100mCi, at least 105mCi, at least 110 mCi, at least 115 mCi, at least 120 mCi, at least 125 mCi, at least 130 mCi, at least 135 mCi, at least 140 mCi, at least 145 mCi, at least 150 mCi, at least 155 mCi, at least 160 mCi, at least 165 mCi, at least 170 mCi, at least 175 mCi, at least 180 mCi, at least 185 mCi, at least 190 mCi, at least 195 mCi, or at least 200 mCi. In other embodiments, the activity level of the parent radionuclide is from about 5 mCi to about 100 mCi. In yet another embodiment, the activity level of the parent radionuclide is from about 5 mCi to about 50 mCi. In still another embodiment, the activity level of the parent radionuclide is from about 5 mCi to about 50 mCi.

[0044] One embodiment of the present invention includes a method and apparatus for producing a purified desired daughter nuclide for medical use. One embodiment includes producing the daughter nuclide by radioactive decay of a parent nuclide contained and bound to a first solid medium. Extraction of the daughter nuclide from the first solid medium is performed in the form of an aqueous solution. The method further includes radiochemically and chemically purifying the daughter nuclide in the aqueous solution by passing it through a second solid medium, thereby binding the daughter nuclide and eluting radioactive and chemical impurities. The daughter nuclide is then eluted from the second solid medium to provide the purified daughter nuclide.

[0045] One embodiment of the present invention includes a method and apparatus for producing a purified desired daughter nuclide for medical use by decaying a parent nuclide in an apparatus containing a first solid medium, wherein the first solid medium binds the parent nuclide but not the daughter nuclide.

[0046] A more specific embodiment of the present invention includes a method and apparatus for producing purified Pb-212 for medical use by decaying Th-228 or Ra-224 in an apparatus containing one or more first solid media, wherein the first solid media binds Th-228 or Ra-224 but not Pb-212.

[0047] In one embodiment of the invention, the solid medium incorporating Th-228 or Ra-224 is a column containing a cation exchange resin. More specifically, one embodiment of the invention uses Bio-Rad AGMP1 resin as the cation exchange resin. Another embodiment of the invention uses Bio-Rad AMP50 resin. Yet another embodiment of the invention uses Bio-Rad AG50W resin. Still another embodiment of the invention uses Bio-Rad Chelex100 resin. Yet another embodiment of the invention uses Purolite NRW100 resin. Yet another embodiment of the invention uses Purolite NRW1100 resin. Yet another embodiment of the invention uses Purolite NRW1160 resin. Yet another embodiment of the invention uses Purolite NRW1160LS resin. Yet another embodiment of the invention uses Purolite NRW150 resin. Yet another embodiment of the invention uses Purolite NRW160 resin. Yet another embodiment of the invention uses Purolite NRW160LS resin. Other embodiments of the present invention use TrisKem resin (TK resin). Another embodiment of the present invention uses TrisKem Actinide resin. Yet another embodiment of the present invention uses TrisKem DGA resin. Still another embodiment of the present invention uses TrisKem Guard resin. Yet another embodiment of the present invention uses TrisKem KNiFC-PAN resin. Yet another embodiment of the present invention uses TrisKem LN resin. Yet another embodiment of the present invention uses TrisKem LN2 resin. Yet another embodiment of the present invention uses TrisKem LN3 resin. Yet another embodiment of the present invention uses TrisKem MNO2-PAN resin. Yet another embodiment of the present invention uses TrisKem NI resin. Yet another embodiment of the present invention uses TrisKem PB resin. Yet another embodiment of the present invention uses TrisKem Prefilter resin. Yet another embodiment of the present invention uses TrisKem RE resin. Yet another embodiment of the present invention uses TrisKem SR resin. Yet another embodiment of the present invention uses TrisKem TBP resin. Yet another embodiment of the present invention uses TrisKem TEVA resin. Another embodiment of the present invention uses TrisKem TK100 resin. Yet another embodiment of the present invention uses TrisKem TK101 resin. Yet another embodiment of the present invention uses TrisKem TK102 resin. Yet another embodiment of the present invention uses TrisKem TK200 resin. Yet another embodiment of the present invention uses TrisKem TK201 resin.Another embodiment of the present invention uses TrisKem TK202 resin. Yet another embodiment of the present invention uses TrisKem TK211 resin. Yet another embodiment of the present invention uses TrisKem TK212 resin. Yet another embodiment of the present invention uses TrisKem TK213 resin. Yet another embodiment of the present invention uses TrisKem TK221 resin. Yet another embodiment of the present invention uses TrisKem TK225 resin. Yet another embodiment of the present invention uses TrisKem TK400 resin. Yet another embodiment of the present invention uses TrisKem TRU resin. Yet another embodiment of the present invention uses TrisKem UTEVA resin. Yet another embodiment of the present invention uses TrisKem WBEC resin. Yet another embodiment of the present invention uses TrisKem ZR resin. Those skilled in the art will understand the use of various other ion exchange resins suitable for the present invention.

[0048] In one embodiment of the present invention, when the parent nuclide is bound to the resin, it will produce Pb-212 through radioactive decay, and Pb-212 can be eluted from the resin.

[0049] One specific embodiment of the invention includes using water or an aqueous solution to elute Pb-212 that is not bound to the resin. More specifically, the aqueous solution may be an acidic aqueous solution. For example, the acid may be hydrochloric acid. In another example, the acid may be nitric acid. In another embodiment, the aqueous solution is a buffer solution. For example, the buffer solution may be a sodium acetate buffer solution. In another example, the buffer solution may be an ammonium acetate buffer solution. The concentration may be adjusted or not adjusted to obtain a pH suitable for Pb-212 elution. In embodiments of the invention, the buffer concentration may be from about 0.1M to about 1M, from about 0.1M to about 0.9M, from about 0.2M to about 0.8M, from about 0.3M to about 0.7M, from about 0.3M to about 0.6M, or from about 0.4M to about 0.5M. In one embodiment of the invention, the elution of Pb-212 is carried out at a pH of about 4.5 to about 7.5, about 4.6 to about 7.4, about 4.7 to about 7.3, about 4.8 to about 7.2, about 4.9 to about 7.1, about 5.0 to about 7.0, about 5.1 to about 6.9, about 5.2 to about 6.8, about 5.3 to about 6.7, about 5.4 to about 6.6, about 5.5 to about 6.5, about 5.6 to about 6.4, about 5.7 to about 6.3, 5.8 to about 6.2, about 5.9 to about 6.1, about 6.0 to about 6.1, or about 5.8 to about 6.0. In another embodiment, the pH value is about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5.

[0050] One embodiment of the present invention includes using at least one column in the elution process of Pb-212. For example, one column is used to elute Pb-212. In another example, two columns are used to elute Pb-212. In another example, three columns are used to elute Pb-212. In another example, four columns are used to elute Pb-212. In another example, five columns are used to elute Pb-212. In another example, six columns are used to elute Pb-212. In another example, seven columns are used to elute Pb-212. In another example, eight columns are used to elute Pb-212. In another example, nine columns are used to elute Pb-212. In yet another example, ten columns are used to elute Pb-212.

[0051] One embodiment of the present invention includes a series connection of the columns used in the preceding embodiments. In another embodiment, the columns used in the preceding embodiments are connected in parallel.

[0052] In one embodiment of the invention, one or more pillars used in the preceding embodiments include radiation shielding. In another embodiment, each individual pillar is equipped with radiation shielding. In yet another embodiment, all pillars are collectively equipped with radiation shielding. The radiation shielding comprises materials capable of effectively blocking radiation and ensuring that the radiation received by the user of the invention is at a safe level. The radiation shielding may comprise lead, depleted uranium, antimony, tungsten, tin, bismuth, cerium, or telluride. The radiation shielding may also comprise a material composed of a polymer composite material of lead, depleted uranium, antimony, tungsten, tin, bismuth, cerium, or telluride. The radiation shielding may comprise single-walled carbon nanotubes (SWNTs) or boron nitride nanotubes (BNNTs). The thickness of the radiation shield may be approximately 0.01 mm to approximately 0.04 mm, approximately 0.05 mm to approximately 0.09 mm, approximately 0.10 mm to approximately 0.99 mm, approximately 1.00 mm to approximately 1.99 mm, approximately 2.00 mm to approximately 2.99 mm, approximately 3.00 mm to approximately 3.99 mm, approximately 4.00 mm to approximately 4.99 mm, approximately 5.00 mm to approximately 5.99 mm, approximately 6.00 mm to approximately 6.99 mm, approximately 7.00 mm to approximately 7.99 mm, or approximately 8 mm. Approximately 0.00mm to about 8.99mm, approximately 9.00mm to about 9.99mm, approximately 1.00cm to about 1.99cm, approximately 2.00cm to about 2.99cm, approximately 3.00cm to about 3.99cm, approximately 4.00cm to about 4.99cm, approximately 5.00cm to about 5.99cm, approximately 6.00cm to about 6.99cm, approximately 7.00cm to about 7.99cm, approximately 8.00cm to about 8.99cm, or approximately 9.00cm to about 9.99cm.

[0053] The aqueous solution containing Pb-212 obtained in the preceding embodiments can be further purified using one or more second solid media.

[0054] In one embodiment, the second solid medium may be contained in a column that can retain Pb-212 from the aqueous solution and elute any radioactive and chemical impurities from Pb-212.

[0055] In one embodiment of the invention, the second solid medium is a chromatographic column for purifying Pb-212. More specifically, the second solid medium binding Pb-212 may be a liquid chromatography column for purifying Pb-212. In another embodiment, the liquid chromatography column comprises resin. In a more specific embodiment, the resin is Bio-Rad AGMP1 resin. Another embodiment of the invention uses Bio-Rad AMP50 resin. Yet another embodiment of the invention uses Bio-Rad AG50W resin. Still another embodiment of the invention uses Bio-Rad Chelex 100 resin. Yet another embodiment of the invention uses Purolite NRW100 resin. Yet another embodiment of the invention uses Purolite NRW1100 resin. Yet another embodiment of the invention uses Purolite NRW1160 resin. Yet another embodiment of the invention uses Purolite NRW1160LS resin. Yet another embodiment of the invention uses Purolite NRW150 resin. Another embodiment of the present invention uses Purolite NRW160 resin. Yet another embodiment of the present invention uses Purolite NRW160LS resin. Other embodiments of the present invention use TrisKem resin (TK resin). Yet another embodiment of the present invention uses TrisKem Actinide resin. Another embodiment of the present invention uses TrisKem DGA resin. Yet another embodiment of the present invention uses TrisKem Guard resin. Yet another embodiment of the present invention uses TrisKem KNiFC-PAN resin. Yet another embodiment of the present invention uses TrisKem LN resin. Yet another embodiment of the present invention uses TrisKem LN2 resin. Yet another embodiment of the present invention uses TrisKem LN3 resin. Yet another embodiment of the present invention uses TrisKem MNO2-PAN resin. Yet another embodiment of the present invention uses TrisKem NI resin. Yet another embodiment of the present invention uses TrisKem PB resin. Yet another embodiment of the present invention uses TrisKem Prefilter resin. Yet another embodiment of the present invention uses TrisKem RE resin. Yet another embodiment of the present invention uses TrisKem SR resin. Another embodiment of the present invention uses TrisKem TBP resin. Yet another embodiment of the present invention uses TrisKem TEVA resin. Yet another embodiment of the present invention uses TrisKem TK100 resin. Yet another embodiment of the present invention uses TrisKem TK101 resin. Yet another embodiment of the present invention uses TrisKem TK102 resin.Another embodiment of the present invention uses TrisKem TK200 resin. Another embodiment of the present invention uses TrisKem TK201 resin. Another embodiment of the present invention uses TrisKem TK202 resin. Another embodiment of the present invention uses TrisKem TK211 resin. Another embodiment of the present invention uses TrisKem TK212 resin. Another embodiment of the present invention uses TrisKem TK213 resin. Another embodiment of the present invention uses TrisKem TK221 resin. Another embodiment of the present invention uses TrisKem TK225 resin. Another embodiment of the present invention uses TrisKem TK400 resin. Another embodiment of the present invention uses TrisKem TRU resin. Another embodiment of the present invention uses TrisKem UTEVA resin. Another embodiment of the present invention uses TrisKem WBEC resin. Another embodiment of the present invention uses TrisKem ZR resin. Those skilled in the art will understand the use of various other ion exchange resins suitable for the present invention.

[0056] In one embodiment of the method of the present invention, radiological and chemical impurities that do not bind to the resin can be eluted from the resin by water or an aqueous solution. More specifically, the aqueous solution can be an acidic aqueous solution. For example, the acid can be hydrochloric acid. In another example, the acid can be nitric acid. In another embodiment, the aqueous solution is a buffer solution. For example, the buffer solution can be a sodium acetate buffer solution. In another example, the buffer solution can be an ammonium acetate buffer solution. The concentration can be adjusted or not adjusted to obtain a pH value suitable for eluting radiological and chemical impurities. In embodiments of the present invention, the buffer concentration can be about 0.1M to about 1M, about 0.1M to about 0.9M, about 0.2M to about 0.8M, about 0.3M to about 0.7M, about 0.3M to about 0.6M, or about 0.4M to about 0.5M. In one embodiment of the invention, the elution of radiological and chemical impurities is carried out at pH values ​​of about 4.5 to about 7.5, about 4.6 to about 7.4, about 4.7 to about 7.3, about 4.8 to about 7.2, about 4.9 to about 7.1, about 5.0 to about 7.0, about 5.1 to about 6.9, about 5.2 to about 6.8, about 5.3 to about 6.7, about 5.4 to about 6.6, about 5.5 to about 6.5, about 5.6 to about 6.4, about 5.7 to about 6.3, 5.8 to about 6.2, or about 5.9 to about 6.1, about 6.0 to about 6.1, or about 5.8 to about 6.0. In another embodiment, the pH value is about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. The solid phase of the liquid chromatography column can be washed to elute radioactive and chemical impurities from the bound Pb-212.

[0057] One embodiment of the invention includes using at least one column when eluting radioactive and chemical impurities from Pb-212. For example, one column is used to elute radioactive and chemical impurities. In another example, two columns are used to elute radioactive and chemical impurities. In another example, three columns are used to elute radioactive and chemical impurities. In another example, four columns are used to elute radioactive and chemical impurities. In another example, five columns are used to elute radioactive and chemical impurities. In another example, six columns are used to elute radioactive and chemical impurities. In another example, seven columns are used to elute radioactive and chemical impurities. In another example, eight columns are used to elute radioactive and chemical impurities. In another example, nine columns are used to elute radioactive and chemical impurities. In yet another example, ten columns are used to elute radioactive and chemical impurities.

[0058] In one embodiment of the invention, the columns are connected in series. In another embodiment, the columns are connected in parallel.

[0059] In other embodiments, each individual column is equipped with radiation shielding. In yet another embodiment, each individual column is equipped with radiation shielding. In still another embodiment, all columns are collectively equipped with radiation shielding. The radiation shielding comprises materials capable of effectively blocking radiation and ensuring that the radiation received by the user of the invention is at a safe level. The radiation shielding may comprise lead, depleted uranium, antimony, tungsten, tin, bismuth, cerium, or telluride. The radiation shielding may also comprise a polymer composite material composed of lead, depleted uranium, antimony, tungsten, tin, bismuth, cerium, or telluride. The radiation shielding may comprise single-walled carbon nanotubes (SWNTs) or boron nitride nanotubes (BNNTs). The thickness of the radiation shield may be approximately 0.01 mm to approximately 0.04 mm, approximately 0.05 mm to approximately 0.09 mm, approximately 0.10 mm to approximately 0.99 mm, approximately 1.00 mm to approximately 1.99 mm, approximately 2.00 mm to approximately 2.99 mm, approximately 3.00 mm to approximately 3.99 mm, approximately 4.00 mm to approximately 4.99 mm, approximately 5.00 mm to approximately 5.99 mm, approximately 6.00 mm to approximately 6.99 mm, approximately 7.00 mm to approximately 7.99 mm, or approximately 8 mm. Approximately 0.00mm to about 8.99mm, approximately 9.00mm to about 9.99mm, approximately 1.00cm to about 1.99cm, approximately 2.00cm to about 2.99cm, approximately 3.00cm to about 3.99cm, approximately 4.00cm to about 4.99cm, approximately 5.00cm to about 5.99cm, approximately 6.00cm to about 6.99cm, approximately 7.00cm to about 7.99cm, approximately 8.00cm to about 8.99cm, or approximately 9.00cm to about 9.99cm.

[0060] After removing radioactive and chemical impurities from the liquid chromatography column, the purified Pb-212 can be eluted with water or an aqueous solution. More specifically, the aqueous solution can be an acidic aqueous solution. For example, the acid can be hydrochloric acid. In another example, the acid can be nitric acid. In another embodiment, the aqueous solution is a buffer solution. For example, the buffer solution can be a sodium acetate buffer solution. In another example, the buffer solution can be an ammonium acetate buffer solution. The concentration can be adjusted or not adjusted to obtain a suitable pH value for Pb-212 elution. In embodiments of the invention, the buffer concentration can be from about 0.1M to about 1M, from about 0.1M to about 0.9M, from about 0.2M to about 0.8M, from about 0.3M to about 0.7M, from about 0.3M to about 0.6M, or from about 0.4M to about 0.5M. In one embodiment of the invention, the elution of Pb-212 is carried out at pH values ​​of about 4.5 to about 7.5, about 4.6 to about 7.4, about 4.7 to about 7.3, about 4.8 to about 7.2, about 4.9 to about 7.1, about 5.0 to about 7.0, about 5.1 to about 6.9, about 5.2 to about 6.8, about 5.3 to about 6.7, about 5.4 to about 6.6, about 5.5 to about 6.5, about 5.6 to about 6.4, about 5.7 to about 6.3, 5.8 to about 6.2, or about 5.9 to about 6.1, about 6.0 to about 6.1, or about 5.8 to about 6.0. In another embodiment, the pH value is about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5.

[0061] Preferably, the radiometric purity of Pb-212 produced by the present invention is greater than or equal to about 90%. More preferably, the radiometric purity of Pb-212 produced by the present invention is greater than or equal to about 95%. In another embodiment, the radiometric purity of Pb-212 is greater than or equal to 99.5%. Preferably, the radiometric purity of Pb-212 is greater than or equal to 99.95%. Preferably, the radiometric purity of Pb-212 is greater than or equal to 99.995%.

[0062] Purified Pb-212 may have at least 1 mCi, at least 2 mCi, at least 3 mCi, at least 4 mCi, at least 5 mCi, at least 6 mCi, at least 7 mCi, at least 8 mCi, at least 9 mCi, at least 10 mCi, at least 11 mCi, at least 12 mCi, at least 13 mCi, at least 14 mCi, at least 15 mCi, at least 16 mCi, at least 17 mCi, at least 18 mCi, at least 19 mCi, at least 20 mCi, at least 21 mCi, at least 22 mCi, at least 23 mCi, at least 24 mCi, at least 25 mCi, at least 26 mCi, at least 27 mCi, at least 28 mCi, at least 29 mCi, at least 30 mCi, and at least 31 mCi. The radioactivity concentration (or radioactivity) of Ci, at least 32 mCi, at least 33 mCi, at least 34 mCi, at least 35 mCi, at least 36 mCi, at least 37 mCi, at least 38 mCi, at least 39 mCi, at least 40 mCi, at least 41 mCi, at least 42 mCi, at least 43 mCi, at least 44 mCi, at least 45 mCi, at least 46 mCi, at least 47 mCi, at least 48 mCi, at least 49 mCi, at least 50 mCi, at least 55 mCi, at least 60 mCi, at least 65 mCi, at least 70 mCi, at least 75 mCi, at least 80 mCi, at least 85 mCi, at least 90 mCi, at least 95 mCi, and at least 100 mCi. Preferably, the purified Pb-212 has a radioactivity concentration of about 1-9 mCi, about 10-19 mCi, about 20-29 mCi, about 30-39 mCi, about 40-49 mCi, about 50-59 mCi, about 60-69 mCi, about 70-79 mCi, about 80-89 mCi, about 90-100 mCi, or about 1-100 mCi.

[0063] The resulting dose of Pb-212 can vary and will vary. In some embodiments, the total dose of Pb-212 present in the radiopharmaceutical composition can be at least 1 mCi, at least 2 mCi, at least 3 mCi, at least 4 mCi, at least 5 mCi, at least 6 mCi, at least 7 mCi, at least 8 mCi, at least 9 mCi, at least 10 mCi, at least 11 mCi, at least 12 mCi, at least 13 mCi, at least 14 mCi, at least 15 mCi, at least 16 mCi, at least 17 mCi, at least 18 mCi, at least 19 mCi, at least 20 mCi, at least 21 mCi, at least 22 mCi, at least 23 mCi, at least 24 mCi, at least 25 mCi, or at least 26 mCi. At least 27mCi, at least 28mCi, at least 29mCi, at least 30mCi, at least 31mCi, at least 32mCi, at least 33mCi, at least 34mCi, at least 35mCi, at least 36mCi, at least 37mCi, at least 38mCi, at least 39mCi, at least 40mCi, at least 41mCi, at least 42mCi, at least 43mCi, at least 44mCi, at least 45mCi, at least 46mCi, at least 47mCi, at least 48mCi, at least 49mCi, at least 50mCi, at least 51mCi, at least 52mCi, at least 53mCi, at least 54mCi, at least 55mCi. In some embodiments, the total dose of Pb-212 present in the radiopharmaceutical composition may be in the range of about 0.5 mCi to 5.0 mCi, about 5.0 mCi to 10 mCi, about 10 mCi to 15 mCi, about 20 mCi to 30 mCi, about 15 mCi to 25 mCi, about 25 mCi to 35 mCi, about 30 mCi to 40 mCi, about 35 mCi to 45 mCi, about 40 mCi to 50 mCi, or about 45 mCi to 55 mCi. The dose may be about 15 mCi, 20 mCi, 25 mCi, 30 mCi, 35 mCi, 40 mCi, 45 mCi, 50 mCi, or 55 mCi.

[0064] In one embodiment, the method and apparatus of the present invention are designed to be implemented automatically in a closed system comprising components for eluting Pb-212 from a parent nuclide, components for purifying Pb-212 through one or more liquid chromatography columns, components for collecting the purified Pb-212, and an electronic program for running the automated components for eluting Pb-212 from the parent nuclide, purifying Pb-212, and collecting the purified Pb-212.

[0065] The embodiments of the present invention are as follows: Figures 1 to 3 Further details are provided in the text. Figures 1 to 3The embodiments described herein illustrate the invention's ability to incorporate multiple columns and allow for the simultaneous elution of large quantities of Pb-212 (e.g., up to 100 mCi or more). By accommodating multiple columns loaded with Ra-224, the module can simultaneously elute up to 100 mCi of Pb-212. All solvents and eluents required for each stage of the purification and column regeneration process of this invention can be connected to the system during installation or as needed. Furthermore, potential pathways through which users may be exposed to radiation (e.g., via columns, intermediate bottles, waste bottles, and solution delivery lines) can be shielded using polycarbonate and / or depleted uranium high-density polycarbonate inserts, each employing an effective thickness sufficient to adequately block radiation to keep radiation levels safe for the user. In another embodiment, a radiation detector can be used at any stage of the process or at any location within the apparatus to track the effectiveness of the purification process. The following is a detailed description of several embodiments of the invention. Further embodiments of the invention will be apparent to those skilled in the art.

[0066] In one implementation, such as Figures 1 to 3 The purification apparatus shown includes multi-port valves, such as 101, 201, and 301. In one embodiment, a single multi-port valve may be present. Figure 1 101 in the example). In another embodiment, two multi-port valves may be present ( Figure 2 (202 in the example). In the third embodiment, three multi-port valves may exist ( Figure 3 (303 in the original text). Each multiport valve includes several independent ports that facilitate the flow of liquid within the device. In one embodiment, the multiport valve has at least 6 ports. In another embodiment, the multiport valve has at least 8 ports. In yet another embodiment, the multiport valve has at least 10 ports. In still another embodiment, the multiport valve has at least 12 ports.

[0067] exist Figure 1-3Within the apparatus, liquid can flow through pumps (103, 203, 303) in fluid communication with multi-port valves 101, 201, or 301, and via central tubing 102, 202, or 302 to the chromatography apparatus (104-106, 204-206, or 304-306). Pumps (103, 203, 303) facilitate the movement of liquids, including water (116, 217, 316), buffer solutions (115, 216, 315), and acids (114, 215, 314), through the apparatus. Buffer solutions 115, 216, and 315 may have a suitable pH value that is chemically compatible with the chromatographic resin and apparatus selected by the user. Acids 114, 215, and 314 may be any acid with a suitable pH value and chemically compatible with the chromatographic resin and apparatus selected by the user. The parent nuclide can be introduced into the system in any suitable manner that is obvious to a person skilled in the art. Figure 1-3 In one embodiment, the acid HCl used to elute Pb-212 is from the Ra-224 generator.

[0068] In some embodiments, when the injected liquid flows to Pb-212 columns 104, 204, 304; 105, 205, 305; 106, 206, 306 at output ports 4, 5, or 6 of multi-port valves 101, 201, and 301, respectively, the eluted Pb-212 is injected into input port 12 of the multi-port valves 101, 201, and 301. Unpurified Pb-212 can be loaded onto these columns 104, 204, 304; 105, 205, 305; 106, 206, 306 in series or parallel. Pumps 103, 203, 303 and multi-port valves 101, 201, 301 can directly load these columns with injection volumes from port 12 of modules 101, 201, 301, or dilute the injected Pb-212 with acids 114, 215, 314 drawn from input ports 11 of multi-port valves 101, 201, 301. Another example of introducing the purification target into the device is on-column decay, where a Ra-224 generator binds to appropriate resin within the columns (i.e., columns 104, 204, 304; 105, 205, 305; 106, 206, 306) to decay it into Pb-212 before the device begins the purification process. Another example of loading the purified target Pb-212 onto columns 104, 204, 304; 105, 205, 305; 106, 206, 306 is batch loading, where the purified target is mixed with the chromatographic resin before it is loaded or filled into columns 104, 204, 304; 105, 205, 305; 106, 206, 306. In all examples, the chromatographic resin is pretreated with acids 114, 215, 314, and then equilibrated with acids 114, 215, 314 after the purified target is loaded onto the resin. In another embodiment, the purified target can be added to the column countercurrently, so that when normal flow resumes, the target binds to the most efficient theoretical plate of the column. This reduces the elution volume required to remove the purified target bound to the chromatographic resin and increases the concentration of the purified target in the eluent.

[0069] In use Figure 1In one embodiment of the purification process using the illustrated apparatus, the apparatus utilizes a single multi-port valve 101 to purify Pb-212. In this embodiment, three Pb-212 purification columns 104, 105, and 106 are equilibrated after loading the purification target. The flow-through (FT) after equilibration with acid 114 is directed to waste bottle 113. After equilibration with acid 114, pump 103 and multi-port valve 101 draw water 116 through inlet port 2 of multi-port valve 101 and outlet ports 4, 5, and 6 of multi-port valve 101, then through Pb-212 columns 104, 105, and 106 to adjust the pH. The FT from columns 104, 105, and 106 is directed to waste bottle 113. Next, pump 101 and multi-port valve 103 draw elution buffer 115 (or eluent) through inlet port 1 of multi-port valve 101, outflowing through outlet ports 4, 5, and 6 of the same valve, and then through columns 104, 105, and 106 loaded with Pb-212. The eluent present in columns 104, 105, and 106 causes Pb-212 to dissociate from the chromatographic resin within these columns into the eluent. The Pb-212-containing eluent from each column 104, 105, and 106 is then placed into an intermediate vial 107 equipped with a radiation detector to confirm successful elution; the intermediate vial is optionally equipped with radiation shielding. Elution can be performed using a stepwise or fractional separation method. Pump 103 and multi-port valve 101 then draw the eluent from columns 104, 105, and 106 through multi-port valve 101 via its inlet port 3 and out through the same outlet port 7. This apparatus allows Pb-212 eluent to enter through outlet port 7 of multi-port valve 101, which is then transported to a post-purification column 108, which is generally a purification column made of any suitable resin. Once the Pb-212 eluent is loaded onto the post-purification column 108, which has been pretreated with acid 114, multi-port valve 101 and pump 103 flow water through the post-purification column 108—using the loop from inlet port 2 to outlet port 7 of multi-port valve 101—to neutralize the pH of the post-purification column 108. The FT of this pH adjustment step is directed to waste bottle 113. Pump 103 and multi-port valve 101 then draw in elution buffer 115 through inlet port 1 of multi-port valve 101 and outlet port 7 of the same multi-port valve 101, allowing the eluent to flow onto post-purification column 108. The presence of eluent on column 108 causes Pb-212 to dissociate from the resin of post-purification column 108, and the Pb-212 eluent is then placed into a second intermediate vial, which is also equipped with radiation detector 109 and optionally radiation shielding.Finally, pump 103 and multiport valve 101 draw the final Pb-212 eluent into the inlet line 8 (110) of multiport valve 101 and out through the outlet line 9 (112) of the same multiport valve 101 into the final product bottle 111. After collecting the final product, pump 103 and multiport valve 101 flow acid 114 through columns 104-106, 108 to regenerate all columns, and the FT is disposed in waste bottle 113.

[0070] Another implementation of the purification device ( Figure 2 The diagram shows two multi-port head valves 201 and 208, and at least three initial Pb-212 columns 204, 205, and 206, which are used to achieve the purification of Pb-212. Figure 2The apparatus of the embodiment includes two sets of head valves with interconnected columns in between. Within this purification apparatus, Pb-212 columns are located between a first multi-port head valve 201 and a second multi-port head valve 208. The input end of each column is connected to the first multi-port head valve 201, and the output end of each column is connected to the second multi-port head valve 208. Each Pb-212 purification column 204, 205, and 206 is acid-equilibrated after loading the purification target. The effluent (FT) after equilibration with acid 215 is directed to waste bottle 214. After equilibration with acid 215, pump 203 and multi-port head valve 201 draw water 217 through input port 2 of multi-port head valve 201, and the water flows out through output ports 4, 5, and 6 of multi-port head valve 201, then through Pb-212 columns 204, 205, and 206 to adjust the pH value. Water flowing from Pb-212 columns 204, 205, and 206 enters the input ports 1, 8, and 7 of the second multi-port valve 208 and exits from the output port 2 of the same multi-port valve 208. Subsequently, this water enters the input port 3 of the first multi-port valve 201 and exits from the output port 10 of the same multi-port valve 201, where it is disposed of in waste bottle 214. When the liquid flows from the second multi-port valve 208 to the first multi-port valve 201 after exiting the Pb-212 columns 204, 205, and 206, this circuit 207 can be called the FT circuit 207. When the liquid flows in the opposite direction (from the first multi-port valve 201 to the second multi-port valve 208), 207 can be called the bypass circuit 207. Next, pump 203 and multi-port valve 201 draw in elution buffer 216 (or eluent) through inlet port 1 of multi-port valve 201, through outlet ports 4, 5, and 6 of the same multi-port valve, and through Pb-212 columns 204, 205, and 206. Note that an additional Pb-212 column can be added at outlet port 7 of the first multi-port valve 201 to further increase yield. The eluent within columns 204, 205, and 206 causes Pb-212 to dissociate from the chromatographic resin within these columns, and the Pb-212 eluent from each column flows into inlet ports 1, 8, and 7 of the second multi-port valve 208, respectively. This Pb-212 eluent then flows directly to the post-purification column 209. Using bypass loop 207, elution buffer is allowed to flow into post-purification column 209, causing bound Pb-212 to dissociate from the chromatographic resin within column 209 and subsequently collected into an intermediate vial equipped with radiation detector 210 and optionally radiation shielding. Then, first multiport valve 201 and pump 203 allow the Pb-212 eluent to flow through inlet line 8 of first multiport valve 211 and outlet line 9 of the same multiport valve 213 into final product vial 212. Subsequently, all columns are regenerated using acid 215, and the FT is routed to waste vial 214 using an FT loop.It is also worth noting that, as described herein, the post-purification column 209 is connected to the central line of the second multiport valve 208. However, the input portion of the column 209 can also be easily connected to other ports (e.g., 3-6) of the multiport valve 208, and its output is connected to the main line of the multiport valve 208, for example, if another Pb-212 column is also added.

[0071] In another embodiment of the purification device ( Figure 3 In the second embodiment (previous paragraph), this can be further modified by inserting a third multiport valve 310 between the output of at least one post-purification column 309 and the final product vial 311. This configuration also allows for the addition of an additional post-purification column 309 between the second multiport valve 308 and the third multiport valve 310. In this embodiment, in addition to the waste vial 313 at the output port 10 of the first multiport valve 301, there is a waste vial 312 into which the FT from the third multiport valve 308 can be disposed. This allows at least one post-purification column 309 to be washed using the bypass loop 307 and equilibrated with acid 314 and water 316 before elution with elution buffer 315. Therefore, this embodiment provides a product with higher purity. All purification steps in this embodiment are the same as those in the second embodiment, except for the following: the ability to wash and equilibrate at least one post-purification column as described above; waste bottle 312 downstream of output port 1 of the third multi-port valve 310; washing, equilibration, and elution of at least one post-purification column 309 using bypass circuit 307; and final product bottle 311 downstream of output port 8 of the third multi-port valve 310.

[0072] In another embodiment, the invention includes a housing for the various components of the device. For example, Figure 1-3 Any or all of the devices shown can be housed within a single housing. Figure 11 (a)-(c) depict different views of the housing for the valve port of the present invention.

[0073] The purified Pb-212 of this invention can be used as a radiolabeling agent in radiopharmaceuticals. In one embodiment, Pb-212 can be coordinated with a chelating agent containing a targeting ligand. The chelating agent can be selected from DOTA, DOTAM, TCMC and their derivatives, or other compounds known to those skilled in the art. Example

[0074] Example 1: Purification of Th-228 and Ra-224

[0075] An automated, cartridge-based system was used to purify Th-228 and Ra-224. This 21 CFR-compliant system used AGMP1 and AMP50 resins, respectively, to treat Th-228 and Ra-224. Figure 4 A schematic layout depicting the sequence of purification for Th-228 and Ra-224 is shown. Figure 8 The diagram depicts the apparatus and corresponding connection paths in an automated system, which embodies... Figure 4 The diagram shows the process of generating crude Ra-224 from Th-228, followed by purification of the crude Ra-224 to produce purified Ra-224 suitable for the production of Pb-212.

[0076] Example 2: Detailed description of Pb-212 eluted from a Ra-224 / Pb-212 generator

[0077] Radionuclide analysis of the purity of Pb-212 was performed using a high-resolution gamma-ray spectrometer equipped with an HPGe detector (Canberra) to identify any potential penetration of the daughter isotopes (Bi-212, Tl-208) and the parent isotopes Ra-224 and Th-228.

[0078]

[0079] Table 1. Radionuclide identification of Pb-212

[0080] Example 3: Chemical Characterization of Pb-212

[0081] The chemical purity of Pb-212 eluent was determined using inductively coupled plasma mass spectrometry (ICPMS). Multi-element standard solutions were used to determine the content of the most common stable impurities in Pb-212, which could negatively affect the radiolabeling reaction. Trace metal analysis of Pb-212 showed that the contents of Fe, Cu, and Ni were at moderate to low levels. Key metals that could affect the radiolabeling yield of Pb-212 (Fe-56, Cu-63, Pb-208, Pb-206, and Pb-207) were analyzed, among other elements. The contents of these metals in the eluent were below 7.7–18 μg / L, with iron being the highest value detected. At the detected levels, none of these metals affected radiolabeling. The metal contents were further reduced in the subsequently purified Pb-212. Table 2 below provides more detailed information on trace metal analysis of Pb-212 eluted from Ra-224-AMP50 resin according to the process of the present invention. The metal content of the eluent was monitored throughout the entire service life of the Ra-224 / Pb-212 generator (as shown in Table 2) and during generator use (as shown in Table 3).

[0082]

[0083] Table 2. Trace metal analysis of Pb-212 eluent by inductively coupled plasma mass spectrometry (ICPMS) during the generator's service life.

[0084]

[0085] Table 3. Trace metal analysis of Pb-212 eluent by inductively coupled plasma mass spectrometry (ICPMS) during generator operation.

[0086] Example 4: Purification of Pb-212 using TK201 resin

[0087] Description of TK201 resin (TRISKEM)

[0088] TK201 resin (referred to as "TK resin" in this Example 4) contains a tertiary amine structure and a small amount of long-chain alcohols, which act as free radical scavengers, improving the radiation stability of the TK resin. This resin also functions as a weak ion-pair binder, enabling isotope elution under mild conditions.

[0089] Applications of TK201 resin

[0090] This resin can be used for the separation of various isotopes, including Cu isotopes (Cu has high selectivity for separation relative to Ni, Zn, and Ga), technetium, rhenium, and lead (Pb) isotopes (Pb-203, Pb-212).

[0091] Physical and chemical properties of TK201 resin

[0092] The density of the resin is 0.35 g / mL.

[0093] Procedure for manually purifying Pb-212

[0094] TK resin (60 mg per run) was manually packed into the column and pretreated with 3 bed volumes (BV) of acid (1 M HCl or 2 M HCl) before eluting the generator. Pb-212 chloride eluted from the generator (2-3 ml in 2 M HCl) was loaded onto the resin at a flow rate of approximately 0.5-1 BV / min. The activity of the eluent flowing through the TK resin was measured using a dosimeter to assess the Pb-212 rejection rate. The eluent was then directed to waste. The Pb-212-bound TK resin was washed with 0.5-1 ml of ultrapure, trace metal-free water. The activity of the eluent was counted using a dosimeter and collected in individual vials. The purified Pb-212 was eluted directly from the TK resin into the reaction vessel using 0.4 M sodium acetate or ammonium acetate buffer at pH 6.0 for radiolabeling. Purified Pb-212 can be fractionated to reduce the volume in the labeling reaction. The pH of Pb-212 eluted from TK resin is within the optimal range for labeling (5.9–6.1). After each run, the column packed with TK resin is regenerated by washing / pre-conditioning with 2M HCl. Figure 5 The flowchart in the image illustrates the stepwise purification process of Pb-212.

[0095] Pb-212 was fractionated using manual methods.

[0096] The experiment used 1-8 mCi Pb-212 purified on TK201 resin. Pb-212 was eluted using 0.4-0.5 M sodium acetate buffer (pH 5.8-6.0) or 0.4-0.5 M ammonium acetate buffer (pH 5.8-6.0). Multiple fractions (100-130 μL per vial) were collected. The radioactivity of each fraction was recorded, and the pH of the eluent was determined. The first three fractions were discarded, and all subsequent fractions were collected. The collected fractions were directly used for labeling without further pH adjustment. The highest radioactivity of Pb-212 was observed in fractions 1-3 (see [link to sample sample]). Figure 6 ).

[0097] Post-purification of Pb-212

[0098] Radiochemical yields of Pb-212 retention and elution

[0099] The radiochemical yield (RCY) of Pb-212 retained on TK resin was 85 ± 8%. The elution yield of Pb-212 in 0.4–0.5 N NaOAc or NH4OAc buffer (pH = 6.0) was 86 ± 13%. Table 4 below shows examples of the radiochemical yields (%) of Pb-212 retention and elution during multiple production runs of Ra-224 / Pb-212. The pre-purified column showed good consistency in Pb-212 retention and recovery (see...). Figure 7 ).

[0100]

[0101] Table 4. RCY of Pb-212 retained and eluted from TK1 resin

[0102] Chemical characterization of Pb-212

[0103] The chemical purity of Pb-212 was determined using inductively coupled plasma mass spectrometry (ICPMS). Multi-element standard solutions were used to determine the content of common stable impurities in purified Pb-212, which may negatively affect the radiolabeling reaction. The contents of Fe, Cu, Zn, and Pb were found to be low, and their contents were relatively higher in the first collected fraction. See Table 5 below (see...). Figure 11 This provides an overview of the trace metal analysis of each fraction of Pb-212 (see...). Figure 11 Table 5 shows the ICP-MS trace metal analysis of each fraction of Pb-212. Table 6 below summarizes the trace metal analysis of the crude eluent Pb-212 after post-purification. After post-purification of the crude eluent Pb-212, the detected metal contents decreased by several times (e.g., nickel (Ni-60) content decreased by 1.2 times, and aluminum (Al-27) content decreased by 2281 times).

[0104]

[0105] Table 6. ICP-MS trace metal analysis of Pb-212 eluted from the Ra-224 / Pb-212 generator and ICP-MS analysis of the post-purified fractions of Pb-212. Automated post-purification of Pb-212.

[0106] Pb-212 was eluted from the generator using 2.0M hydrochloric acid (HCl). The TK resin was pretreated before elution from the generator. The Pb-212 eluent was loaded onto the pretreated TK201 resin, and the effluent was directed to waste. The resin was then neutralized with 0.1–0.5 mL of ultrapure, trace metal-free water to adjust the pH of the subsequent Pb-212 fraction. The final purified Pb-212 was eluted directly into a reaction vessel containing the active pharmaceutical ingredient (API) dissolved in a buffer solution at pH 6.0 using 0.4–0.5M sodium acetate or ammonium acetate buffer at pH 5.9–6.1. After each run, the column was regenerated by rinsing with 2 mL of water and 6V of 2M HCl. The Pb-212 elution and purification process layout is as follows: Figure 9 As shown in Table 7, a step-by-step description of the Pb-212 purification process is provided.

[0107]

[0108] Table 7. Step-by-step description of post-purification of Pb-212 using automated methods

[0109] Automated module for Pb-212 production and post-purification

[0110] The RAHA system is a software-controlled automated module for the reproducible production and purification of high-activity Pb-212. This multi-functional system accommodates multiple Ra-224 / Pb-212 generators and supports sequential elution of Pb-212. To reduce radiation exposure risk, the benchtop system is shielded with tungsten and depleted uranium. The system is equipped with three radiation dose detectors to record differential activity during elution from the generator, loading onto TK resin, and transfer to the reaction vessel.

[0111] All references cited herein are incorporated herein by reference. The foregoing is primarily illustrative. Those skilled in the art will readily understand that other pharmaceutical products may be included, and that the components, additives, proportions (shares), formulation methods, methods of use, and other parameters described herein may be further modified or substituted in various ways without departing from the spirit and scope of the invention.

Claims

1. An apparatus for producing Pb-212 from a parent radionuclide, comprising: A first solid medium comprising a parent radionuclide and a resin, wherein the parent radionuclide produces Pb-212 through radioactive decay. as well as A second solid medium comprising Pb-212 and resin, wherein Pb-212 is eluted from the second solid medium to produce purified Pb-212, wherein the purified Pb-212 is 1-100 mCi.

2. The apparatus according to claim 1, wherein the parent nuclide is Th-228 or Ra-224.

3. The apparatus of claim 1, wherein the first solid medium is contained in the first column and the second solid medium is contained in the second column.

4. The apparatus of claim 3, comprising two or more first columns, or two or more second columns.

5. The apparatus according to claim 3 or 4, wherein the first pillar and the second pillar comprise radiation shielding.

6. The apparatus according to claim 3, wherein the first column and the second column are connected in series or in parallel.

7. The apparatus of claim 4, wherein the first column is connected in series or in parallel.

8. The apparatus of claim 4, wherein the second column is connected in series or in parallel.

9. The apparatus of claim 3, wherein the apparatus comprises 1 to 5 first posts and 1 second post.

10. The apparatus of claim 1, further comprising a radiation detector.

11. The apparatus according to claim 1, wherein the resin is a cation exchange resin.

12. The apparatus of claim 1, wherein the resin comprises a tertiary amine.

13. The apparatus according to claim 12, wherein the resin is TK201 resin.

14. The apparatus of claim 1, wherein the purified Pb-212 has a purity greater than about 95.0%.

15. The apparatus of claim 1, wherein the apparatus is automated.

16. The apparatus of claim 15, comprising a multi-port valve, wherein the multi-port valve includes individual ports that facilitate the flow of liquid through the apparatus.

17. The apparatus of claim 16, comprising a pump in fluid communication with the multi-port valve and the first or second solid medium.

18. The apparatus of claim 16, wherein the first solid medium is contained in the first column and the second solid medium is contained in the second column.

19. The apparatus of claim 18, wherein the first pillar and the second pillar comprise radiation shielding.

20. The apparatus of claim 18, wherein the first column and the second column are connected in series or in parallel.

21. The apparatus of claim 18, wherein the second column is connected in series or in parallel.

22. The apparatus of claim 18, further comprising a radiation detector.

23. The apparatus of claim 16, wherein the resin is a cation exchange resin.

24. The apparatus of claim 16, wherein the resin comprises a tertiary amine.

25. The apparatus of claim 24, wherein the resin is TK201 resin.

26. The apparatus of claim 22, further comprising a software-operated automation module that controls the apparatus to produce and purify Pb-212.

27. An apparatus for purifying Ra-224 produced from a second parent radionuclide, comprising: A first solid medium comprising a second parent radionuclide and a resin, wherein the second parent radionuclide produces Ra-224 through radioactive decay; A second solid medium containing Ra-224 is used to elute Ra-224 from the second solid medium to produce purified Ra-224, which can be loaded onto a third solid medium.

28. The apparatus of claim 27, wherein the second parent radionuclide is Th-228.

29. The apparatus of claim 27, wherein the first solid medium is contained in the first column and the second solid medium is contained in the second column.

30. The apparatus of claim 29, comprising two or more first posts or two or more second posts.

31. The apparatus of claim 29 or 30, wherein the columns are connected in series or in parallel.

32. The apparatus of claim 27, wherein the resin is a cation exchange resin.

33. The apparatus of claim 27, wherein the apparatus is automated.

34. A method for purifying Pb-212, comprising the following steps: a. Pretreating the resin with an acidic solution to produce a pretreated resin; b. Load Pb-212 onto the pretreated resin to produce a loaded pretreated resin; c. Wash the loaded pretreated resin with water; d. Elute Pb-212 from the loaded pretreated resin with buffer solution to produce purified Pb-212; and e. Collect the purified Pb-212.

35. The method according to claim 34, wherein the Pb-212 loaded onto the pretreated resin is Pb-212 chloride, and the acidic solution is 1M or 2M HCl.

36. The method of claim 34, wherein the buffer solution is sodium acetate or ammonium acetate buffer.

37. The method of claim 34, wherein the pH of the buffer solution is from 5.8 to about 6.

2.

38. The method of claim 37, wherein the pH is about 6.

0.

39. The method of claim 34, wherein the concentration of the buffer solution is from about 0.3 M to about 0.6 M.

40. The method of claim 39, wherein the concentration of the buffer solution is from about 0.4 M to about 0.5 M.

41. The method of claim 34, wherein the method is automated.

42. An automated method for purifying Pb-212, comprising the following steps: a. To provide the apparatus of claim 17; b. Introduce Pb-212 into the device and the second solid medium; c. Pretreatment with acid and equilibration of the second solid medium; d. Pump the acid through the second solid medium; e. Pump the water through the second solid medium; f. Pumping the buffer solution through the second solid medium to generate an eluent; and g. Collect the purified Pb-212 from the eluent.

43. The method according to claim 42, wherein the buffer solution is sodium acetate or ammonium acetate buffer.

44. The method of claim 42, wherein the pH of the buffer solution is from 5.8 to about 6.

2.

45. The method of claim 44, wherein the pH is about 6.

0.

46. ​​The method of claim 42, wherein the concentration of the buffer solution is from about 0.3 M to about 0.6 M.

47. The method of claim 46, wherein the concentration of the buffer solution is from about 0.4 M to about 0.5 M.

48. The method according to claim 42, wherein the resin is a cation exchange resin.

49. The method according to claim 42, wherein the resin is TK201 resin.

50. The method of claim 42, wherein the purified Pb-212 is about 100 mCi.

51. The method of claim 42, wherein the first solid medium is contained in a first column, the second solid medium is contained in a second column, the first column and the second column contain radiation shielding, the apparatus further includes a radiation detector, and the apparatus further includes a software-operated automation module that controls the apparatus to produce and purify Pb-212.

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