Methods and devices for the direct production of radioisotope-based cancer therapy drugs - Patents.com

Abstract

The present disclosure relates to methods, systems and devices for directly producing radioisotope-based cancer therapy pharmaceuticals from corresponding non-radioactive drug molecule precursors by irradiating the corresponding non-radioactive drug molecule precursors with neutrons generated by an electronic neutron generator array or other neutron generating source. According to some aspects of the present disclosure, the radioisotope-based cancer therapy pharmaceuticals include lutetium-177 (Lu-177) and the corresponding non-radioactive drug molecule precursors include lutetium-176 (Lu-176).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority under 35 U.S.C. § 120 of U.S. patent application Ser. No. 17 / 649,930, entitled “METHOD AND DEVICE FOR DIRECT PRODUCTION OF RADIO-ISOTOPE BASED CANCER TREATMENT PHARMACEUTICALS,” filed Feb. 4, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates generally to methods, systems and devices for the production of radioisotope-based pharmaceuticals, and more particularly to improved methods, systems and devices for the direct production of radioisotope-based cancer therapy pharmaceuticals by irradiating corresponding non-radioactive drug molecule precursors with neutrons generated by an electronic neutron generator array and converting at least a portion of the non-radioactive drug molecule precursors into radioisotope-based pharmaceuticals. Summary of the Invention [Means for solving the problem]

[0003] The following summary is provided to facilitate understanding of some of the innovative features unique to the embodiments disclosed herein and is not intended to be a complete description, with the various embodiments being best understood when taken together in their entirety, including the specification, claims, and abstract.

[0004] In various aspects, the present disclosure provides devices, systems and methods for the direct production of radioisotopic pharmaceuticals from corresponding non-radioactive drug molecule precursors by irradiating the corresponding non-radioactive drug molecule precursors with neutrons generated by an electronic neutron generator array or other neutron emitter such as a Californium-252 (Cf-252) source.

[0005] In various aspects, the present disclosure provides methods for producing a radioisotope-pharmaceutical directly from a corresponding non-radioactive drug molecule precursor, comprising irradiating the non-radioactive drug molecule precursor with neutrons generated by an electronic neutron generator array or other neutron emitter, and converting at least a portion of the non-radioactive drug molecule precursor into a radioisotope-pharmaceutical.

[0006] In various embodiments, the methods include preparing a non-radioactive drug molecule precursor.

[0007] In various embodiments, the radioisotope pharmaceutical comprises a radionuclide or a radioisotope of a metal or metal ion.

[0008] In various aspects, the non-radioactive drug molecule precursor comprises a non-radioactive isotope of the same metal or metal ion as the metal or metal ion of the radioisotopic pharmaceutical. In embodiments, the non-radioactive drug molecule precursor has the same chemical structure as the radioisotopic pharmaceutical, except that the radioactive isotope of the metal or metal ion in the radioisotopic pharmaceutical is replaced with the corresponding non-radioactive isotope of the metal or metal ion.

[0009] In various embodiments, the non-radioactive drug molecule precursor comprises a non-radioactive isotope of a second metal or metal ion that is different from the metal or metal ion in the radioisotope pharmaceutical.

[0010] In various embodiments, the radioisotope pharmaceutical is for the treatment of cancer or tumors, including neuroendocrine tumors (NETs), gastroenteropancreatic neuroendocrine tumors (GEP-NETs), prostate cancer, lung cancer, non-Hodgkin's lymphoma, temporary relief of bone pain, and the like.

[0011] Non-limiting examples of radioisotopeharmaceuticals include Lu-177-based radioisotopeharmaceuticals, such as Lu-177 dotatate, iodine-131 (I-131)-based radioisotopeharmaceuticals, such as I-131 tositumomab, and yttrium-90 (Y-90)-based radioisotopeharmaceuticals, such as Y-90 ibritumomab-tiuxetan.

[0012] In various aspects, the methods of the present disclosure can be applied to manufacture any other radioisotope-based cancer therapy pharmaceuticals that can be prepared by irradiating a non-radioisotope drug molecule precursor with short-term neutron irradiation.

[0013] In various aspects, the radioisotope pharmaceutical is a Lu-177-based radioisotope pharmaceutical, and the non-radioactive drug molecule precursor is a Lu-176 drug molecule precursor.In an embodiment, the Lu-176 drug molecule precursor has the same chemical structure as the Lu-177-based radioisotope pharmaceutical, except that the Lu-177 in the Lu-177-based radioisotope pharmaceutical is replaced with Lu-176.In an embodiment, the Lu-177-based radioisotope pharmaceutical is produced by irradiating the Lu-176 drug molecule precursor with neutrons generated by an electronic neutron generator array, thereby converting at least a portion of the Lu-176 into Lu-177.

[0014] In various aspects, the radioisotope pharmaceutical is Lu-177 Dotatate, and the non-radioactive drug molecule precursor is Lu-176 Dotatate.In an embodiment, Lu-177 Dotatate is directly produced by irradiating Lu-176 Dotatate with neutrons, and converting at least a portion of the Lu-176 in Lu-176 Dotatate to Lu-177.

[0015] In various aspects, the radioisotopeharmaceutical is an I-131-based radioisotopeharmaceutical and the non-radioactive drug molecule precursor is a tellurium (Te) drug molecule precursor. In embodiments, the I-131-based radioisotopeharmaceutical is produced by irradiating a Te drug molecule precursor with neutrons generated by an electronic neutron generator array to convert at least a portion of the Te in the Te drug molecule precursor to I-131.

[0016] In various embodiments, the radioisotope pharmaceutical is I-131 tositumomab and the non-radioactive drug molecule precursor is terulotositumomab. In embodiments, I-131 tositumomab is produced by irradiating terulotositumomab with neutrons.

[0017] In various aspects, the radioisotopeharmaceutical is an yttrium-90 (Y-90) based radioisotopeharmaceutical and the non-radioactive drug molecule precursor is an yttrium-89 (Y-89) drug molecule precursor. In embodiments, the Y-90 based radioisotopeharmaceutical is produced by directly irradiating the Y-89 drug molecule precursor with neutrons generated by an electronic neutron generator array.

[0018] In various embodiments, the radioisotopeharmaceutical is Y-90 ibritumomab-tiuxetan and the non-radioactive drug molecule precursor is Y-89 ibritumomab-tiuxetan. In embodiments, the Y-90 ibritumomab-tiuxetan is produced by directly irradiating Y-89 ibritumomab-tiuxetan with neutrons generated by an electronic neutron generator array.

[0019] In embodiments, the method may not require or eliminate further chemical reactions after conversion.

[0020] In various embodiments, the method further comprises a process of preparing a non-radioactive drug molecule precursor.

[0021] In various embodiments, the radioisotopeharmaceutical comprises or is a first complex of a radionuclide and a target cell receptor binding moiety bound to a chelator.

[0022] In various embodiments, the non-radioactive drug molecule precursor comprises or is a second complex of the corresponding non-radioactive isotope of the radionuclide and a target cell receptor binding moiety bound to a chelator.

[0023] In various embodiments, a process for preparing a non-radioactive drug molecule precursor includes preparing a first aqueous solution containing a corresponding non-radioactive isotope of a radionuclide, preparing a second aqueous solution containing a target cell receptor binding peptide bound to a chelating agent, mixing the first and second aqueous solutions to form a mixture, and heating the mixture to form a reaction solution containing a second complex of the corresponding non-radioactive isotope of the radionuclide and the target cell receptor binding peptide bound to a chelating agent, forming a non-radioactive drug molecule precursor.

[0024] In various embodiments, the process further comprises drying the reaction solution to form a solid or concentrate comprising a second complex of the non-radioactive isotope and the target cell receptor binding moiety bound to a chelator, forming a non-radioactive drug molecule precursor, preferably to form a solid.

[0025] In various embodiments, the process includes treating a reaction solution containing a second complex to obtain the second complex in solid form.

[0026] In various embodiments, the target cell receptor binding moiety is a target cell receptor binding peptide.

[0027] In various embodiments, a method for producing a radioisotopic pharmaceutical comprises irradiating a non-radioactive drug molecule precursor (which comprises or is a second complex) to convert at least a portion of the non-radioactive isotope in the second complex to a radionuclide, thereby forming a radioisotopic pharmaceutical (which comprises or is a first complex).

[0028] In various embodiments, the radioisotope pharmaceutical is a Lu-177-based radioisotope pharmaceutical and the non-radioactive drug molecule precursor is a Lu-176 drug molecule precursor. The process for preparing the Lu-176 drug molecule precursor includes preparing a first aqueous solution containing a non-radioactive Lu-176 isotope, preparing a second aqueous solution containing a target cell receptor binding moiety (such as a peptide) bound to a chelator, mixing the first aqueous solution with the second aqueous solution to form a mixture, and heating the mixture to form a reaction solution containing a complex of Lu-176 and the target cell receptor binding moiety bound to the chelator to form the Lu-176 drug molecule precursor.

[0029] In various embodiments, the radioisotope pharmaceutical is complex Lu-177 dotatate, and the non-radioactive drug molecule precursor is Lu-176 dotatate. The process of preparing Lu-176 dotatate includes: preparing a first aqueous solution containing non-radioactive Lu-176 isotope; preparing a second aqueous solution containing dotatate; mixing the first solution and the second solution to form a mixture; and heating the mixture to form a reaction solution containing complex Lu-176 dotatate.

[0030] In various embodiments, the first aqueous solution comprises LuCl3 (Lu-176) and HCl.

[0031] In various embodiments, the process includes treating a reaction solution containing Lu-176 doutate to form Lu-176 doutate in solid or concentrated form, preferably in solid form.

[0032] In various embodiments, a method for producing Lu-177 dotatate includes irradiating Lu-176 dotatate with neutrons generated by a neutron generator to convert at least a portion of the Lu-176 in the Lu-176 dotatate to Lu-177 to form Lu-177 dotatate.

[0033] In various embodiments, the present disclosure provides devices, systems and methods for directly producing Lu-177-based radioisotopic pharmaceuticals from non-radioactive Lu-176 precursor compounds or complexes using neutrons generated by an electronic neutron generator array or other neutron emitters such as a Californium-252 (Cf-252) source. Lu-177-based radioisotopic pharmaceuticals are used for localized treatment of target cells (such as tumor or cancer cells) that have overexpressed cell receptors compared to normal tissues. Lu-177-based radioisotopic pharmaceuticals include a target cell receptor binding moiety having at least one binding site that binds to a target cell receptor. Thus, after administration to a patient in need thereof, the Lu-177-based radioisotopic pharmaceuticals are specifically delivered to and bound to the patient's target cells (such as tumor or tumor-associated cells) for tumor therapeutic targeting or imaging, while normal cells remain substantially unaffected.

[0034] In various embodiments, disclosed herein is a method for producing a Lu-177-based radioisotope pharmaceutical directly from a Lu-176 complex or compound using neutrons generated by an electronic neutron generator array or other neutron emitter source. The method includes preparing a first aqueous solution containing a non-radioactive Lu-176 isotope, preparing a second aqueous solution containing a target cell receptor binding peptide bound to a chelating agent, mixing the first aqueous solution with the second aqueous solution to form a mixture, heating the mixture to form a reaction solution containing a complex of Lu-176 and the target cell receptor binding peptide bound to a chelating agent, and irradiating the complex to convert at least a portion of the Lu-176 isotope in the complex to the Lu-177 radioisotope and form the Lu-177-based radioisotope pharmaceutical.

[0035] In various embodiments, the method further comprises drying the reaction solution to form a solid or concentrate, preferably a solid, comprising a complex of Lu-176 and the target cell receptor binding peptide conjugated to a chelator, prior to irradiating the complex in step 5).

[0036] In various aspects, the target cell receptor-binding peptide comprises or is a somatostatin receptor-binding peptide.In an embodiment, the somatostatin receptor-binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.In an embodiment, the somatostatin receptor-binding peptide is octreotate.Other target cell receptor-binding peptides are also contemplated by the present disclosure.

[0037] In various aspects, the chelating agent is selected from the group consisting of DOTA, DTPA, NT, EDTA, DO3A, NOC and NOTA. In embodiments, the chelating agent comprises or is DOTA. Other chelating agents are also contemplated by the present disclosure.

[0038] In various embodiments, the target cell receptor binding peptide conjugated to the chelator includes or is selected from the group consisting of DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP.

[0039] In various aspects, the target cell receptor-binding peptide conjugated to the chelator comprises or is DOTA-TATE (dotatate or oxodotreotide) or DOTA-TOC (dotatoc or edotreotide). In embodiments, the target cell receptor-binding peptide conjugated to the chelator comprises or is DOTA-TATE (dotatate or oxodotreotide).

[0040] In various embodiments, the complex comprises or is either Lu-176 dotatoc or Lu-176 dotatate (a drug molecule precursor). In embodiments, the complex comprises or is Lu-176 dotatate.

[0041] In various embodiments, the Lu-177-based radioisotope pharmaceutical comprises or is Lu-177 dotatoc or Lu-177 dotatate (final drug). In an embodiment, the Lu-177-based radioisotope pharmaceutical comprises or is Lu-177 dotatate.

[0042] In various embodiments, the method may exclude the use of any radioisotope intermediate compound. In various embodiments, the method may exclude the use of any Lu-177 intermediate compound.

[0043] In various embodiments, the method may further include adding one or more stabilizers selected from gentisic acid, ascorbic acid, and salts thereof to the reaction solution of step 4) above to improve the stability of the Lu-177-based radioisotope pharmaceutical, such as Lu-177 dotatate.

[0044] In various embodiments, the methods may exclude the use of any stabilizers (such as gentisic acid, ascorbic acid and their salts, and ethanol) in the preparation of Lu-177 radioisotope pharmaceuticals.

[0045] In various aspects, the present disclosure provides a device for directly producing radioisotopic pharmaceuticals from non-radioactive drug molecule precursors by irradiating the non-radioactive drug molecule precursors with neutrons or thermal neutron flux generated by an electronic neutron generator array or other neutron emitter such as a Californium-252 (Cf-252) source. The device comprises: 1) an electronic neutron generator array or at least one neutron emitter source configured to generate neutrons or thermal neutron flux; 2) an irradiation module; and 3) an irradiation module insert. In an embodiment, the device comprises an electronic neutron generator array including at least one electronic neutron generator.

[0046] In various aspects, the irradiation module comprises an irradiation module insertion tube, a deuterium oxide (D2O) moderator module containing D2O of adjustable thickness surrounding and attached to an outer side of the irradiation module insertion tube, a boric acid water module surrounding and attached to an outer side of the D2O moderator module, and a metal shielding module surrounding and attached to an outer side of the boric acid water module. In an embodiment, the irradiation module insertion tube has an insertion port for placing an irradiation module insert into the irradiation module insertion tube.

[0047] In various embodiments, the boric acid water module is configured to contain a boric acid water composition that includes 8-12 wt% (weight percent) sodium borate, 8-40 wt% or preferably 8-20 wt% boric acid, and the balance water. One advantage of using a boric acid water composition is that the borate-rich water can achieve the same shielding effect with a smaller amount of water compared to regular water.

[0048] In various aspects, the at least one electronic neutron generator is arranged in the same plane and configured to direct its neutrons or neutron flux to the center (mid-section) of the irradiation module insertion tube of the irradiation module. In embodiments, the at least one electronic neutron generator is arranged in different planes and configured to direct its neutrons or neutron flux from different angles to the center of the irradiation module insertion tube of the irradiation module.

[0049] In various aspects, the irradiation module insert comprises an insertion rod, a removable nose configured to be removably coupled to the insertion rod, an irradiation chamber housed in the removable nose, an insertion position locking ring configured to be placed on the insertion rod to lock the irradiation module insert in the insertion port and that adjusts the position of the irradiation chamber within the irradiation module insertion tube when the irradiation module insert is inserted into the irradiation module insertion tube, a radiation detector surrounding and / or attached to the irradiation chamber to detect irradiation levels from the irradiation chamber, and a temperature sensor coupled to the irradiation chamber to detect the temperature of the irradiation chamber.

[0050] In various aspects, the device may further comprise a target cooling unit including a liquid coolant, hi embodiments, the target cooling unit is attached to the illumination module and configured to circulate liquid coolant through the illumination module insertion tube to cool the illumination module insertion tube and to cool an illumination chamber of an illumination module insert inserted into the illumination module insertion tube.

[0051] In various aspects, the device may further include a control unit configured to be attached to the illumination module and the illumination module insert.

[0052] In various embodiments, the irradiation module insert further comprises an irradiation detector signal output configured to transmit a first signal of the detected irradiation level from the radiation detector to the control unit, and a temperature sensor signal output configured to transmit a second signal of the sensed temperature from the temperature sensor to the control unit.

[0053] In various embodiments, the irradiation module insert is configured to be placed within the irradiation module insertion tube and maintain the irradiation chamber at the center (middle section) of the irradiation module insertion tube and at the center of the at least one electronic neutron generator, thereby directing all of the neutron flux from the at least one electronic neutron generator into the irradiation chamber.

[0054] In various embodiments, the irradiation module insert is configured to allow placement of an irradiation source (or target) material within an irradiation chamber housed within a removable nose.

[0055] In various aspects, the irradiation chamber is a hollow cylinder for containing the irradiation source (or target) material, and the radiation detector is a hollow cylinder concentric with the irradiation chamber and configured to surround at least a portion or the entire outer side (curved surface) of the irradiation chamber, preferably the entire outer side of the irradiation chamber. In embodiments, the radiation detector may or may not cover the top and bottom circular surfaces of the irradiation chamber.

[0056] In various embodiments, the illumination module insertion tube is configured to be cylindrical in shape so that the illumination module insert can be freely inserted and removed from the illumination module insertion tube.

[0057] In various aspects, the target cooling unit is configured to circulate a coolant through the irradiation module insertion tube when inserted into the irradiation module insertion tube to control the temperature within the irradiation module insertion tube, and thus the temperature of the irradiation chamber of the irradiation module insert.

[0058] In various embodiments, the control unit is configured to receive the first and second signals from the radiation detector and the temperature sensor, adjust parameters of the target cooling unit to control temperatures within the irradiation module insertion tube and the irradiation chamber to be maintained within a predetermined temperature range, determine whether the detected irradiation level reaches a predetermined level, and turn off the at least one electronic neutron generator when the detected irradiation level reaches the predetermined level.

[0059] In various embodiments, the device does not include a target cooling unit. In various embodiments, the device does not include a control unit. In various embodiments, the device is configured to connect to an external target cooling unit and / or an external control unit.

[0060] In various embodiments, the radioisotope pharmaceutical is a radioisotope-based cancer treatment pharmaceutical.Non-limiting examples of radioisotope pharmaceutical include Lu-177-based radioisotope pharmaceutical, such as Lu-177 dotatate, I-131-based radioisotope pharmaceutical, such as I-131 tositumomab, and Y-90-based radioisotope pharmaceutical, such as Y-90 ibritumomab-tiuxetan.

[0061] In various embodiments, the radioisotopeharmaceutical is a Lu-177 based radioisotopeharmaceutical and the non-radioactive drug molecule precursor is a Lu-176 drug molecule precursor.

[0062] In various embodiments, the radioisotope pharmaceutical is Lu-177 Dotatate and the non-radioactive drug molecule precursor is Lu-176 Dotatate.In an embodiment, Lu-177 Dotatate is produced by directly irradiating Lu-176 Dotatate with neutrons generated by an electronic neutron generator array.

[0063] In various aspects, the radioisotopeharmaceutical is an I-131-based radioisotopeharmaceutical, and the non-radioactive drug molecule precursor is a tellurium (Te) drug molecule precursor. In embodiments, the I-131-based radioisotopeharmaceutical is produced by directly irradiating a tellurium drug molecule precursor with neutrons generated by an electronic neutron generator array.

[0064] In various aspects, the radioisotope pharmaceutical is I-131 tositumomab, and the non-radioactive drug molecule precursor is terurutes tositumomab.In an embodiment, I-131 tositumomab is produced by directly irradiating terurutes tositumomab with neutrons generated by an electron neutron generator array.

[0065] In various embodiments, the radioisotopeharmaceutical is a Y-90 based radioisotopeharmaceutical and the non-radioactive drug molecule precursor is an yttrium-89 (Y-89) drug molecule precursor. In embodiments, the Y-90 based radioisotopeharmaceutical is produced by directly irradiating the Y-89 drug molecule precursor with neutrons generated by an electronic neutron generator array.

[0066] In various embodiments, the radioisotopeharmaceutical is Y-90 ibritumomab-tiuxetan and the non-radioactive drug molecule precursor is Y-89 ibritumomab-tiuxetan. In embodiments, the Y-90 ibritumomab-tiuxetan is produced by directly irradiating Y-89 ibritumomab-tiuxetan with neutrons generated by an electronic neutron generator array.

[0067] In various aspects, the present disclosure provides devices for producing Lu-177-based radioisotope pharmaceuticals from non-radioactive irradiated target materials by irradiating the non-radioactive irradiated target materials with neutrons generated by an electronic neutron generator array or other neutron emitter, such as a Californium-252 (Cf-252) source.

[0068] In various embodiments, the present disclosure provides devices for producing Lu-177-based radioisotopharmaceuticals directly from non-radioactive Lu-176 complexes (or compounds) by irradiating the non-radioactive Lu-176 complexes or compounds with neutrons generated by an electronic neutron generator array or other neutron emitters such as a Californium-252 (Cf-252) source.

[0069] In various aspects, the irradiation target material comprises or is either a non-radioactive Lu-176 mixture or a Lu-176 complex precursor. In embodiments, the Lu-176 mixture comprises or is a reaction mixture of a Lu-176 complex and a target cell receptor binding moiety, such as a peptide, conjugated to a chelator, as discussed herein above and elsewhere in this disclosure. In embodiments, the Lu-176 precursor comprises or is a complex of Lu-176 and a target cell receptor binding moiety, such as a peptide, conjugated to a chelator.

[0070] In various aspects, the target cell receptor binding moiety comprises or is a target cell receptor binding antibody (or antibody-derived fragment), peptide, protein, small molecule inhibitor, or DNA / RNA aptamer. In embodiments, the target cell receptor binding moiety comprises or is a target cell receptor binding peptide.

[0071] In various embodiments, the irradiation target material comprises or is Lu-176 dotatate. In various embodiments, the irradiation target material comprises or is a reaction mixture of the Lu-176 compound and dotatate.

[0072] In various embodiments, the present disclosure provides a system for preparing Lu-177-based radioisotope pharmaceuticals. The system includes a device including at least one electronic neutron generator, an irradiation module and an irradiation module insert, a target cooling unit, and a control unit. The device, the target cooling unit, and the control unit are described above and elsewhere in the present disclosure.

[0073] The disclosed methods and devices can advantageously minimize production costs and improve handling safety through the production of Lu-177-based radioisotope pharmaceuticals by directly irradiating non-radioactive drug molecule precursors without handling any radioactive intermediate compounds.

[0074] The disclosed methods and devices can enable the direct production of radioisotopharmaceuticals by directly irradiating non-radioactive drug molecule precursors and converting them into the final radioisotopharmaceuticals without the need for the use of nuclear reactors, thereby enabling radioactive cancer treatment drugs and radioisotopharmaceuticals to be produced in industrial or clinical settings, such as hospitals or cancer treatment centers.

[0075] The methods and devices of the present disclosure allow the neutron energy spectrum to be controlled to maximize desired neutron capture reactions in the irradiated target material.

[0076] The methods and devices of the present disclosure may further advantageously include the ability to control the temperature of the irradiation target material within the irradiation chamber using a coolant temperature and flow supply system, thus minimizing chemical bond disruption of drug molecules caused by thermal effects.

[0077] The methods and devices of the present disclosure can advantageously employ a combination of an aqueous boric acid composition and a low-Z metal radiation shield, such as aluminum, to minimize radiation exposure to the surrounding area of ​​the fabricated device.

[0078] These and other objects, features and characteristics of the present disclosure, as well as the method of operation and function of the associated elements of construction, and the combination of parts and economies of manufacture, will become more apparent from a consideration of the following description and the appended claims, taken in conjunction with the accompanying drawings, all of which form a part hereof, and in which like reference numerals indicate corresponding parts in the various drawings. All aspects and embodiments may be combined in accordance with the present disclosure. It is to be expressly understood, however, that the drawings are for the purposes of illustration and description only, and are not intended to define the limits of the present disclosure.

[0079] The various features of the embodiments described herein are set forth with particularity in the appended claims, however, various aspects, both as to organization and method of operation, together with their advantages, may be understood by reference to the following description taken in conjunction with the accompanying drawings, in which: [Brief description of the drawings]

[0080] [Figure 1] 1 shows a simplified decay scheme of Lu-177 (177Lu), in accordance with at least one embodiment of the present disclosure. [Figure 2A] 2A shows a schematic diagram of a system for preparing a radioisotope pharmaceutical from a non-radioactive drug molecule precursor according to at least one embodiment of the present disclosure. FIG. 2A shows a radial cross-sectional view of an irradiation device having an array of electronic neutron generators arranged in the same plane and configured to direct neutrons to the center of the irradiation module insertion tube (rabbit hole) where the irradiation chamber is located when the irradiation module insert is inserted into the irradiation module insertion tube. [Figure 2B] 2A shows a schematic diagram of a system for preparing a radioisotope pharmaceutical from a non-radioactive drug molecule precursor, according to at least one embodiment of the present disclosure. FIG. 2B shows an axial cross-sectional view of the system along section line AA in FIG. 2A. [Figure 2C] 2A-2C show schematic diagrams of a system for preparing a radioisotope pharmaceutical from a non-radioactive drug molecule precursor, in accordance with at least one embodiment of the present disclosure. [Figure 2D] 2A-2D show schematic diagrams of a system for preparing a radioisotope pharmaceutical from a non-radioactive drug molecule precursor, in accordance with at least one embodiment of the present disclosure. FIG. 2D shows a radial cross-sectional view of an irradiation module insert along section line BB of FIG. 2C. [Figure 3A] 3A shows a schematic diagram of a system for preparing a radioisotope pharmaceutical from a non-radioactive drug molecule precursor according to at least one embodiment of the present disclosure. FIG. 3A shows a radial cross-sectional view of an irradiation device having an array of electronic neutron generators arranged in different planes and configured to direct neutrons from different angles toward the center of the irradiation module insertion tube where the irradiation chamber is located when the irradiation module insert is inserted into the irradiation module insertion tube. [Figure 3B] 3A shows a schematic diagram of a system for preparing a radioisotope pharmaceutical from a non-radioactive drug molecule precursor, according to at least one embodiment of the present disclosure. FIG. 3B shows an axial cross-sectional view of the system along section line AA in FIG. 3A. [Figure 3C] 3A-3C show schematic diagrams of a system for preparing a radioisotope pharmaceutical from a non-radioactive drug molecule precursor, in accordance with at least one embodiment of the present disclosure. [Figure 3D] 3A-3D show schematic diagrams of a system for preparing a radioisotope pharmaceutical from a non-radioactive drug molecule precursor, in accordance with at least one embodiment of the present disclosure. FIG. 3D shows a radial cross-sectional view of the irradiation module insert along section line BB of FIG. 3C. [Figure 4] 2A-2D show examples of the radioactivity of Lu-177 in the Lu-177 Dotatate drug as a function of irradiation time in the system shown in FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0081] The exemplifications set forth herein are illustrative, in one form, of various aspects of the disclosure, and such exemplifications are not to be construed in any way as limiting the scope of the disclosure.

[0082] Before describing the various aspects of the present disclosure in detail, it should be noted that the exemplary embodiments are not limited in application or use to the details disclosed in the accompanying drawings and specification. It should be understood that the exemplary embodiments may be incorporated or incorporated in other embodiments, variations and modifications, and may be practiced or carried out in various ways. Moreover, unless otherwise indicated, the terms and expressions used in this specification have been selected for the convenience of the reader to describe the exemplary embodiments, and are not intended to be limiting thereof.

[0083] In various embodiments, the present disclosure provides devices, systems and methods for producing radioisotope-based cancer therapy pharmaceuticals directly from corresponding non-radioactive drug molecule precursors by irradiating the corresponding non-radioactive drug molecule precursors with neutrons generated by an electronic neutron generator array or other neutron emitters such as Californium 252 (Cf-252) source. The radioisotope pharmaceuticals can be radioisotope-based cancer therapy pharmaceuticals. Non-limiting examples of radioisotope pharmaceuticals include Lu-177-based radioisotope pharmaceuticals such as Lu-177 dotatate, I-131-based radioisotope pharmaceuticals such as I-131 tositumomab, and Y-90-based radioisotope pharmaceuticals such as Y-90 ibritumomab-tiuxetan.

[0084] Different isotopes of metal or metal ion have the same chemical properties. If a radioisotope drug (radioisotope drug molecule) can be produced by a synthetic process, its corresponding non-radioisotope drug molecule precursor (non-radioactive drug molecule precursor) can be produced by the same synthetic process. In order to eliminate the need to handle and process radioisotope material or radioisotope intermediate material during the production of radioisotope drug, thus improving the safety of production and reducing the cost and complexity of production, the present disclosure provides a method, device and system for first preparing a non-radioisotope drug molecule precursor, and then directly irradiating the non-radioisotope drug molecule precursor with neutrons generated by an electronic neutron generator array to produce the final radioisotope drug.

[0085] A wide variety of radioisotope pharmaceuticals are increasingly being used in the clinic or hospital for targeted treatment or imaging of cancer or tumors.

[0086] Tumor targeting is a relatively new but rapidly expanding technology applied to cancer treatment and visualization. Targeted drug delivery generally involves tumor targeting compounds (e.g., antibodies or antibody-derived fragments, proteins, peptides, small molecule inhibitors, or DNA / RNA aptamers) to direct attached drugs, such as radionuclides, to tumor or cancer cells for localized cancer treatment or tumor visualization before or during surgery. Most of these tumor targeting compounds are directed against targetable cell membrane-bound proteins, such as anchoring proteins, receptors, enzymes, and transporter proteins, that are overexpressed in tumors or tumor-associated cells.

[0087] The present disclosure provides targeted drug delivery based on targetable cell receptors that are overexpressed in target cells (i.e., tumor cells or cancer cells) in contrast to non-targeted cells such as normal cells. If a drug has a binding site to these overexpressed cell receptors, it can be delivered to these target cells after administration at high concentration, while not affecting other cells that are not of interest (such as normal cells). For example, if tumor cells are characterized by the overexpression of a specific cell receptor, a drug that has binding affinity to the specific cell receptor will accumulate in high concentration in tumor tissue after intravenous injection, while not affecting normal tissue.

[0088] This concept of targeted drug delivery is also applied to radioisotope medicines, which selectively deliver radionuclides to target cells for diagnostic or therapeutic purposes. In this application, the target cell receptor binding moiety is typically coupled to a chelator that can form a strong complex with the metal ion of the radionuclide. After administration, the radiopharmaceutical drug is delivered to the target cells, and the decay of the radionuclide releases high-energy electrons, positrons, alpha or beta particles, and gamma rays at the target site for localized treatment, which is usually referred to as targeted isotope therapy (TRT).

[0089] An important advantage of TRT over other radiation therapies is that therapeutic radionuclides can be delivered directly to tumors or target cells. This is because some tumors have overexpression of certain cell receptors compared to normal tissues. The radionuclides can be combined with target cell receptor binding moieties, such as peptides or analogs that have binding affinity to cell receptors, to preferentially bind to tumors. With gamma emitters as radionuclides, this technique can be used for imaging with gamma cameras or PET scanners to localize tumors. When combined with alpha or beta emitters, therapeutic effects can be achieved.

[0090] TRT, which uses peptides as the target cell receptor binding moiety of a radioisotope drug, is also called peptide receptor radionuclide therapy (PRRT).

[0091] Lutetium-177 (Lu-177 or 177 Lu) radionuclides have attracted considerable attention and shown great potential in the research, commercial, and clinical communities for use in various peptide receptor radionuclide therapy (PRRT) treatments. 177 Lu) oxodotreotide or Lutathera®) was approved by the FDA in early 2018 for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

[0092] Current methods for preparing Lu-177-based radioisotope pharmaceuticals require the assembly of molecules incorporating highly radioactive Lu-177 atoms during the manufacture of therapeutic vectors, such as Lu-177 dotatates. These methods typically include first preparing the radioisotope Lu-177 by irradiating a source material, for example by direct irradiation of a Lu-176 target via the reaction Lu-176(n,γ)Lu-177, or alternatively by indirect irradiation of a Yb-176 target, such as Yb-176(n,γ)Yb-177, which decays to Lu-177 with a half-life of 1.9 hours, separating the radioactive Lu-177 compound from the irradiated source material, preparing a radioactive Lu-177 reagent, and mixing and reacting the radioactive Lu-177 reagent with a peptide and a chelating agent to form the Lu-177-based radioisotope pharmaceutical.

[0093] One technical problem with current methods for the preparation of Lu-177-based radioisotopic pharmaceuticals is the need to first prepare and then separate the radioisotopic Lu-177 intermediate compound from the irradiated source material, and the need to handle the radioactive Lu-177 intermediate compound during the manufacture of the final drug product. Existing manufacturing methods pose significant safety concerns and also add significant costs to the cancer treatment process, making the treatment problematic, if not impossible, for many patients who need it.

[0094] Furthermore, the radioisotope Lu-177 has a short half-life of about 6.65 days, and decay of the radioisotope Lu-177 to a non-radioactive form occurs constantly during handling of Lu-177 and during the manufacture of the final formulation. This decay of Lu-177 can lead to a decrease in its efficiency in providing a therapeutic effect. Due to the low stability of the radioisotope Lu-177 and its lack of a shelf life, the final Lu-177 radioisotope pharmaceutical product has thus far had to be manufactured in a hospital laboratory as individual patient dose units and administered immediately to patients who must already be there waiting for PRRT at that hospital.

[0095] Lu-177( 177 A simplified decay scheme of Lu is shown in Figure 1. The radioisotope Lu-177 decays in 78% of events (E β(max) =0.497 MeV) and a stable ground state with a half-life of 6.65 days 177 Hf decays to Hf, with 9.7% of events (E β(max) =0.384 MeV) and 12% (E β(max) =0.176 MeV), which are 0.24967 MeV and 0.32132 MeV higher than the ground state, respectively. 177 The Hf decays to an excited state and de-excites to the ground state with the emission of a photon. During these radioactive decay events, 177 Lu is E β(max) It emits beta particles of 497 keV (78.6%), 384 keV (9.1%), and 176 keV (12.2%), and low-energy gamma photons [Eγ = 113 keV (6.6%), 208 keV (11%)].

[0096] Therefore, there is a need for improved methods and systems for producing radioisotopharmaceuticals, e.g., Lu-177-based radioisotopharmaceuticals, that address one or more of the problems of the conventional manufacturing methods discussed above.

[0097] The present disclosure provides improved methods, devices and systems for preparing radioisotope pharmaceuticals that allow the desired radioisotope to be produced directly in the final form of the drug vector from a non-radioactive compound precursor using neutrons generated by an electronic neutron generator, without any radioactive intermediate compound.

[0098] Electronic neutron generators are disclosed in U.S. Provisional Application No. 63 / 166,718, entitled "PRODUCTION OF HIGH ENERGY GAMMA RADIATION USING AN ELECTRONIC NEUTRON GENERATOR FOR FOOD AND MEDICAL DEVICE STERILIZATION," by Heibel et al., and International Application No. PCT / US22 / 71260, entitled "PRODUCTION OF HIGH ENERGY GAMMA RADIATION USING AN ELECTRONIC NEUTRON GENERATOR FOR FOOD AND MEDICAL DEVICE STERILIZATION," the entire contents of which are incorporated herein by reference for all purposes.

[0099] An electronic neutron generator is also disclosed in US Pat. No. 8,737,570 to Firestone et al., which is incorporated herein by reference in its entirety for all purposes.

[0100] The radioisotope pharmaceuticals used in the peptide receptor radionuclide therapy (PRRT) of the present disclosure are composed of three components: a radionuclide (such as Lu-177) that provides the actual therapeutic effect, a target cell receptor binding moiety (such as a peptide or analog thereof) that binds to a cellular receptor overexpressed on tumor or target cells, and a chelator (chelator) that is the essential bond between the radionuclide and the target cell receptor binding moiety. The chelator can form a strong complex with the metal ion of the radionuclide and binds to the target cell receptor binding moiety to form a target cell receptor binding moiety bound to the chelator.

[0101] In embodiments, the radionuclide is Lu-177, I-131, or yttrium-90 (Y-90, or 90 Y). In an embodiment, the radionuclide is Lu-177.

[0102] In embodiments, the target cell receptor binding moiety is selected from the group consisting of an antibody (or antibody-derived fragment), a peptide, a protein, a small molecule inhibitor, or a DNA / RNA aptamer.

[0103] In an embodiment, the target cell receptor binding moiety is a target cell receptor binding peptide.

[0104] In an embodiment, the target cell receptor-binding peptide is a somatostatin receptor-binding peptide. In an embodiment, the somatostatin receptor-binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably octreotide and octreotate.

[0105] In an embodiment, the somatostatin receptor-binding peptide is oxodotreotide.

[0106] In an embodiment, the chelating agent is selected from the group consisting of DOTA, DTPA, NT, EDTA, DO3A, NOC, and NOTA, preferably DOTA.

[0107] In an embodiment, the chelating agent is DOTA, which forms a strong complex with Lu-177 or Lu-176. DOTA is an organic compound of formula (CH2CH2NCH2CO2H)4 and has the chemical structure of Formula I shown below.

[0108] [ka] Formula I

[0109] In an embodiment, the target cell receptor binding moiety conjugated to a chelator is a somatostatin receptor binding peptide conjugated to the chelator DOTA, preferably DOTA-TATE (dotatate or oxodotreotide) or DOTA-TOC (dotatoc or edotreotide), more preferably DOTA-TATE (dotatate or oxodotreotide).

[0110] As used herein, the terms "Dotatate", "DOTA-TATE", "DOTATATE" or oxodotreotide refer to the somatostatin receptor binding peptide octreotate (an eight amino acid long peptide) conjugated to the bifunctional chelator DOTA. Dotatate has the chemical structure of Formula II shown below.

[0111] [ka] Formula II

[0112] In an embodiment, the radioisotopeharmaceutical comprises or is Lu-177 Dotatate, the chemical structure of which is shown as Formula III below.

[0113] [ka] Formula III

[0114] In an embodiment, the non-radioactive Lu-176 drug precursor comprises or is Lu-177 Dotatate. Lu-176 Dotatate may have or include the chemical structure shown as Formula IV below. [ka] Formula IV

[0115] The present disclosure provides a method for preparing Lu-177-based radiopharmaceuticals using a non-radioactive Lu-176 drug precursor, thus eliminating the need to separate the radioactive Lu-177 isotope from irradiated source material and eliminating the need to handle any radioactive Lu-177 intermediate compounds during the manufacture of the Lu-177-based radiopharmaceutical. The method includes preparing a non-radioactive reaction mixture of a Lu-176 compound, a peptide and a chelating agent, or a non-radioactive drug molecule precursor containing Lu-176, and irradiating the non-radioactive reaction mixture or the non-radioactive drug molecule precursor to convert at least a portion of the Lu-176 in the reaction mixture or drug molecule precursor to Lu-177 and form the final Lu-177-based radiopharmaceutical product. Thus, the method of the present disclosure eliminates the formation and handling of any Lu-177 intermediate compounds during the manufacture of the final Lu-177-based radiopharmaceutical.

[0116] In an embodiment, the Lu-177-based radioisotope pharmaceutical comprises or is Lu-177 Dotatate. A method for preparing Lu-177 Dotatate may include preparing a non-radioactive reaction mixture of Lu-176 and Dotatate or a non-radioactive drug molecule precursor Lu-176 Dotatate, and irradiating the reaction mixture or the drug molecule precursor Lu-176 Dotatate to form a Lu-177 Dotatate final product.

[0117] Different isotopes of metals or metal ions have the same chemical properties. If a radioisotope drug (radioisotope drug molecule) can be produced by a synthetic process, its corresponding non-radioisotope drug molecule precursor (non-radioactive drug molecule precursor) can be produced by the same synthetic process. In order to eliminate the need to handle and process radioisotope materials or radioisotope intermediate materials during the production of radioisotope drug, thus improving the safety of production and reducing the cost and complexity of production, the present disclosure provides a method, device and system for first preparing a non-radioisotope drug molecule precursor, and then directly irradiating the non-radioisotope drug molecule precursor with neutrons generated by an electronic neutron generator array to produce the final radioisotope drug.

[0118] Methods for producing Lu-177-based radioisotope pharmaceuticals (such as Lu-177 dotatate) from Lu-177 are disclosed in U.S. Pat. Nos. 10,596,276 and 10,596,278 (the '276 and '278 patents), the entire contents of which are incorporated herein by reference for all purposes.

[0119] Because the non-radioactive Lu-176 isotope has the same chemical properties and reactivity as the Lu-177 radioactive isotope, the corresponding Lu-176 drug molecule precursors, such as Lu-176 Dotatate, can be prepared by methods similar to those disclosed in the '276 and '278 patents.

[0120] The present method advantageously allows for the creation of drug molecules using the non-radioactive isotope Lu-176, thus eliminating the need for preparation of the radioisotope Lu-177, separation of the radioisotope Lu-177 from irradiated source material, and handling of the radioisotope Lu-177 during production of the final Lu-177-based radiopharmaceutical.

[0121] In various embodiments, one or more of the methods are designed to first prepare a non-radioactive drug molecule precursor, which can then be directly irradiated with thermal and epithermal neutrons to form a drug vector molecule (final radioisotope drug) in an environment where temperature and gamma radiation levels can be controlled to ensure minimal degradation of the drug vector molecule due to heat or gamma radiation induced chemical bond cleavage within the drug vector molecule. This approach can be used to produce multiple other radiopharmaceutical drugs, with non-radioactive isotopes that are converted through neutron irradiation into the radioisotopes desired to be included in the drug vector molecule. Other applications of the process described herein include the production of radioactive tracers for material property status monitoring, such as Na-24, and radioactive tracers for medical treatment and diagnostic imaging material creation, such as Cu-64, Ho-166, P-32, and K-42.

[0122] In an embodiment, a method for producing a Lu-177 radioisotope pharmaceutical comprises forming a complex (drug molecule precursor) of non-radioactive Lu-176 and the target cell receptor-binding peptide bound to a chelating agent by 1) preparing an aqueous solution containing non-radioactive Lu-176; 2) preparing an aqueous solution containing a target cell receptor-binding peptide bound to a chelating agent; 3) mixing the aqueous solutions prepared in step 1) and step 2) to form a resultant mixture; and 4) heating the resultant mixture to form a solution containing the complex (drug molecule precursor).

[0123] In embodiments, the method may further include 5) drying the solution containing the complex to form a solid or concentrated irradiation source / target material containing the complex, and 6) irradiating the irradiation source / target material containing the complex to convert at least a portion of the Lu-176 to Lu-177 and form the final drug Lu-177 radioisotope pharmaceutical.

[0124] In an embodiment, the method may further comprise adding a stabilizer against radiolysis or radiolytic degradation, the stabilizer being selected from gentisic acid or a salt thereof, ascorbic acid or a salt thereof, or ethanol. In an embodiment, the stabilizer is selected from gentisic acid or a salt thereof, or ascorbic acid or a salt thereof.

[0125] In embodiments, the method may exclude the addition of stabilizers such as acids or their salts (ie, gentisic acid or ascorbic acid or their salts) or alcohols (ie, ethanol).

[0126] In an embodiment, the irradiation source / target material is a solid that includes the complex.

[0127] In an embodiment, the irradiation source / target material is a concentrate that includes the complex.

[0128] In an embodiment, the method may optionally further comprise purifying the irradiation source / target material prior to irradiation in step 6) to obtain a purified irradiation source / target material.

[0129] In an embodiment, the chelating agent is selected from the group comprising or consisting of DOTA, DTPA, NT, EDTA, DO3A, NOC, and NOTA, preferably DOTA.

[0130] In an embodiment, the target cell receptor-binding peptide comprises or is a somatostatin receptor-binding peptide. In an embodiment, the somatostatin receptor-binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably octreotide and octreotate. In an embodiment, the somatostatin receptor-binding peptide is oxodotreotide.

[0131] In embodiments, the target cell receptor binding peptide conjugated to the chelator comprises or is selected from the group consisting of DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP.

[0132] In an embodiment, the target cell receptor-binding peptide conjugated to the chelator preferably comprises or is preferably either DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), more preferably DOTA-TATE (oxodotreotide).

[0133] In an embodiment, the complex comprises or is either Lu-176 Dotatoc or Lu-176 Dotatate (drug precursor), preferably Lu-176 Dotatate.

[0134] In an embodiment, the final drug Lu-177 radioisotope pharmaceutical comprises or is Lu-177 Dotatoc or Lu-177 Dotatate (final drug), preferably Lu-177 Dotatate.

[0135] As used herein, a chelating agent in the context of this disclosure can be DOTA, which is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DTPA, which is diethylenetriaminepentaacetic acid; NTA, which is nitrilotriacetic acid; EDTA, which is ethylenediaminetetraacetic acid; DO3A, which is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; NOTA, which is 1,4,7-triazacyclononane-1,4,7-triacetic acid; trizoxetane; tetraxetane; or mixtures thereof, preferably DOTA.

[0136] As used herein, the term "target cell receptor binding moiety" can refer to a chemical molecule that binds at least a portion of the chemical molecule to a receptor molecule on the surface of a target cell, such as a tumor or associated cell. The cell receptor binding moiety for which the present disclosure is particularly suited is a somatostatin receptor binding peptide, preferably the somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, pasireotide, iratreotide, pentetreotide, depreotide, satreotide, veldreotide, preferably octreotide and octreotate.

[0137] As used herein, the term "linked" can refer to the cell receptor binding moiety being either directly linked to the chelator or connected via a linker molecule, preferably directly linked. The linking bond can be either a covalent or non-covalent bond between the cell receptor binding moiety (and linker) and the chelator, preferably the bond is a covalent bond.

[0138] The present disclosure provides a device for producing radioisotopharmaceuticals, such as Lu-177, I-131, and Y-90 based radioisotopharmaceuticals. In various embodiments, as shown generally in Figures 2A-2D, the device 200 comprises an array of electronic neutron generators 202 (seven electronic neutron generators in this embodiment) for generating neutron or thermal neutron flux, an irradiation module 250, and an irradiation module insert 216.

[0139] In an embodiment, the device 200 may further comprise a target cooling unit 212 configured to be attached to the irradiation module 250 for controlling a temperature of at least a portion of the irradiation module 250. In an embodiment, the target cooling unit 212 includes a liquid coolant that can be circulated through at least a portion of the irradiation module 250, and thus can control a temperature of at least a portion of the irradiation module 250.

[0140] In an embodiment, the device 200 may further include a control unit attached to the illumination module 250 and the illumination module insert 216. In an embodiment, the control unit may be a control circuit. The control circuit may include a controller with one or more processors (e.g., microprocessors, microcontrollers) connected to at least one memory circuit. The memory circuit stores machine-executable instructions that, when executed by the processor, cause the processor to execute machine instructions for performing various processes described herein. The processor may be any one of a number of single-core or multi-core processors known in the art. The memory circuit may include a volatile storage medium and a non-volatile storage medium. The processor may include an instruction processing unit and an arithmetic unit. The instruction processing unit may be configured to receive instructions from the memory circuit.

[0141] In an embodiment, the illumination module 250 includes an illumination module insertion tube (rabbit hole) 210, a thickness-adjustable heavy water (D2O) moderator module 208 surrounding and attached to the outer side of the illumination module insertion tube 210, a boric acid water module 206 surrounding and attached to the outer side of the D2O moderator module 208, and a metal shielding module 204 surrounding and attached to the outer side of the boric acid water module 206. In an embodiment, the illumination module insertion tube 210 has an insertion port 214 for inserting an illumination module insert 216 into the illumination module insertion tube 210.

[0142] In an embodiment, as shown in FIGS. 2A and 2B, the array of electronic neutron generators 202 is coplanar and configured to direct a flux of neutrons or thermal neutrons toward the center (mid-section) of the irradiation module insertion tube of the irradiation module 250.

[0143] In an embodiment, as shown in FIG. 2C , the irradiation module insert 216 comprises an insertion rod 228, a removable nose 218 configured to be removably coupled to the insertion rod 228, an irradiation chamber 222 housed in the removable nose 218, an insertion position locking ring 230 configured to be attached to the insertion rod 228 to lock the irradiation module insert 216 at the insertion port 214 to adjust the position of the irradiation chamber 222 within the irradiation module insertion tube 210, a radiation detector 220 surrounding and / or attached to the irradiation chamber 222 to detect the irradiation level from the irradiation chamber 222, and a temperature sensor 224 connected to the irradiation chamber 222 to detect the temperature of the irradiation chamber 222.

[0144] In an embodiment, the illumination module insert 216 further comprises an illumination detector signal output 232 configured to transmit a detected illumination signal from the radiation detector 220 to the control unit, and a temperature sensor signal output 234 configured to transmit a sensed temperature signal from the temperature sensor 224 to the control unit. In certain embodiments, the output signals of the radiation detector 220 and / or the temperature sensor 224 may be communicated wirelessly to the control unit using any suitable wireless communication protocol.

[0145] As shown in FIG. 2B , the irradiation module insert 216 is configured to be placed within the irradiation module insertion tube 210 and to hold the irradiation chamber 222 substantially in the center or mid-section of the irradiation module insertion tube 210 and also in the center of the array of electron neutron generators 202 so that all neutron radiation from the electron neutron generators 202 is directed toward the irradiation chamber 222.

[0146] In an embodiment, the irradiation module insert 216 is configured to allow irradiation target material to be placed in an irradiation chamber 222 housed within the removable nose 218 .

[0147] Figure 2D shows a radial cross-section of radiation detector 220 along section line BB in Figure 2C. In an embodiment, as shown in Figure 2D, irradiation chamber 222 is a hollow cylinder for containing irradiation source (or target) material, and radiation detector 220 is a hollow cylinder concentric with irradiation chamber 222 and configured to surround and / or be attached to at least a portion or the entire outer circumferential (curved) surface of irradiation chamber 222, preferably the entire outer circumferential side surface of irradiation chamber 222. Radiation detector 220 may or may not cover the top and bottom circular surfaces of irradiation chamber 222.

[0148] In an embodiment, as shown in FIG. 2B, the target cooling unit 212 is configured to circulate a coolant through the irradiation module insertion tube 210 to control the temperature within the irradiation module insertion tube 210 and, therefore, the temperature of the irradiation chamber 222.

[0149] In an embodiment, the device comprises a control unit (not shown) configured to 1) receive detected irradiation level signals from the cylindrical radiation detector 220 and sensed temperature signals from the temperature sensor 224, 2) adjust parameters of the target cooling unit 212 to control the temperature within the irradiation module insertion tube 210 and the irradiation chamber 222 to be maintained within a predetermined temperature range, 3) determine whether the detected irradiation level reaches a predetermined level, and 4) turn off the array of electronic neutron generators when the detected irradiation level reaches the predetermined level.

[0150] In an embodiment, the device does not include a target cooling unit 212 and does not include a control unit. In an embodiment, the device is configured to connect to an external target cooling unit 212 and / or an external control unit.

[0151] In an embodiment, the irradiation target material comprises or is a non-radioactive Lu-176 mixture or a non-radioactive Lu-176 drug molecule precursor. In an embodiment, the irradiation target material comprises or is Lu-176 dotatate. In an embodiment, the irradiation target material comprises or is a reaction mixture of Lu-176 and dotatate.

[0152] 2A and 2B show a system for preparing radioisotope pharmaceuticals such as Lu-177, I-131, Y-90 and other radioisotope-based pharmaceuticals. The system comprises a device comprising at least one electronic neutron generator 202 (seven electronic neutron generators in this embodiment), an irradiation module 250 and an irradiation module insert 216 as described herein above. The system further comprises a target cooling unit 212. The system further comprises a control unit (not shown).

[0153] By using an array of electronic neutron generators 202 configured as shown diagrammatically in Figures 2A-2D, a container containing either a solid or concentrated liquid form of a drug molecule precursor or other application molecule can be placed in the irradiation chamber 222 and irradiated in a neutron flux field having a neutron energy distribution that can be optimized for neutron absorption resonances in a target material such as a Lu-177 based drug by adjusting the thickness of the moderator module containing deuterium oxide (DO) located in the area between the neutron generator and the irradiation module insertion tube shown in Figures 2A and 2B, and thus the thickness of the moderator DO. These are typically very low energy neutrons, so that there is minimal interaction between the neutrons and chemical bonds that would damage the structure of the molecule.

[0154] For the direct production of drugs such as Lu-177 dotatate, the large neutron capture cross section of Lu-176 and the very small neutron capture cross sections of other substances in the drug molecule ensure the production of relatively large amounts of Lu-177. The temperature of the irradiation target material containing the non-radioactive drug molecule precursor can be controlled by controlling the flow rate and temperature of the coolant flowing around the irradiation module insert 216 having the irradiation chamber 222 that contains the irradiation target / feed material, as shown diagrammatically in FIG. 2B. The radioactivity of the desired radioisotope contained within the irradiation target material can be easily measured by those skilled in the art by measuring the intensity of gamma rays or X-rays emitted from the irradiation target material when neutron capture occurs, using radiation detection equipment configured as shown in FIG. 2C and FIG. 2D. Once the measured radioactivity of the material reaches a desired predetermined level (e.g., saturation equilibrium), the neutron generator 202 can simply be turned off and the resulting irradiated target material, e.g., the final Lu-177 drug, which includes or is Lu-177 Dotatate, can be removed from the irradiation module 250, such as that shown in Figures 2B and 2C, and used directly without the need for further processing.

[0155] 3A-3D show a device 300 for preparing Lu-177-based radioisotope pharmaceuticals similar to the device shown in FIG. 2A-2D. The device 300 comprises at least one electronic neutron generator 302 (10 electronic neutron generators in this embodiment), an irradiation module 350, and an irradiation module insert 316. The device 300 further comprises a target cooling unit 312. The device 300 further comprises a control unit. In an embodiment, the control unit can be a control circuit. The control circuit may comprise a controller with one or more processors (e.g., microprocessors, microcontrollers) connected to at least one memory circuit. The memory circuit stores machine-executable instructions that, when executed by the processor, cause the processor to execute machine instructions for carrying out the various processes described herein. The processor may be any one of a number of single-core or multi-core processors known in the art. The memory circuit may comprise a volatile storage medium and a non-volatile storage medium. The processor may include an instruction processing unit and an arithmetic unit. The instruction processing unit may be configured to receive instructions from the memory circuit.

[0156] In an embodiment, the device 300 is configured such that some of the electronic neutron generators 302 in this embodiment are arranged in the same first plane, and the remaining electronic neutron generators are arranged at different angles, such as 45°, from the first plane, as shown in Fig. 3B. All the electronic neutron generators 302 are configured to direct neutron radiation or thermal neutron flux to the center (middle section) of the irradiation module insertion tube 310, such that the irradiation target material in the irradiation chamber 322 of the irradiation module insert 316 inserted in the irradiation module insertion tube 310 is irradiated by the neutron flux from different angles, as shown in Fig. 3B. All other components of the device 300 are identical to those of the device 200 described above and will be briefly described below.

[0157] In an embodiment, the illumination module 350 comprises an illumination module insertion tube (rabbit hole) 310, a thickness-adjustable heavy water (D2O) moderator module 308 surrounding and attached to the outer side of the illumination module insertion tube 310, a boric acid water module 306 surrounding and attached to the outer side of the D2O moderator module 308, and a metal shielding module 304 surrounding and attached to the outer side of the boric acid water module 306. In an embodiment, the illumination module insertion tube (rabbit hole) 310 has an insertion port 314 for inserting an illumination module insert 316 into the illumination module insertion tube 310.

[0158] As shown in FIG. 3C , the irradiation module insert 316 includes an insertion rod 328, a removable nose 318 configured to be removably coupled to the insertion rod 328, an irradiation chamber 322 housed in the removable nose 318, an insertion position locking ring 330 configured to be attached to the insertion rod 328 to lock the irradiation module insert 316 at the insertion port 314 to adjust the position of the irradiation chamber 322 within the irradiation module insertion tube 310, a radiation detector 320 surrounding and / or attached to the irradiation chamber 322 to detect the irradiation level from the irradiation chamber 322, and a temperature sensor 324 coupled to the irradiation chamber 322 to detect the temperature of the irradiation chamber.

[0159] In an embodiment, as shown in FIG. 3C , the irradiation module insert 316 further comprises an irradiation detector signal output 332 configured to transmit a detected irradiation signal from the radiation detector 320 to the control unit, and a temperature sensor signal output 334 configured to transmit a detected temperature signal from the temperature sensor 324 to the control unit.

[0160] In an embodiment, the boric acid water module 206 of Figures 2A-2D and the boric acid water module 306 of Figures 3A-3D include a boric acid water composition that includes 8-12 wt% sodium borate, 8-20 wt% or more than 20 wt% boric acid, and the balance water. One advantage of using boric acid water is that the borate-rich water can achieve the same shielding effect with a smaller amount of water compared to regular water.

[0161] In various embodiments, the methods and devices of the present disclosure advantageously use a combination of a borated water composition and a low-Z metal radiation shield, such as aluminum, to minimize radiation exposure to the surrounding area of ​​the fabrication device. Borated water is used as a coolant during normal operation of pressurized water reactors (PWRs) and in the emergency core cooling systems (ECCS) of both PWRs and boiling water reactors (BWRs).

[0162] FIG. 4 shows a graph illustrating an example of calculation of the radioactivity of Lu-177 in the Lu-177 Dotatate drug as a function of irradiation time in the system shown in FIG. 2A-2D. The radioactivity quoted by the supplier of the Lu-177 Dotatate drug is 10 mCi / ml of injection solution. The Lu-177 radioactivity corresponding to the results shown in FIG. 2A-2D is about 0.015 mCi per ml at equilibrium. This means that to receive the same dose of Lu-177 as received using 1 ml of currently available drug solution, a patient would need to be injected with about 500 ml of solution. The application of this method irradiates a drug molecule precursor in a substantially solid form, or in a liquid or concentrate form, to produce a radioisotope pharmaceutical. In an embodiment, the drug molecule precursor is in a substantially solid form, and the irradiated target material (irradiated drug molecule precursor) is reconstituted with a solution (such as an aqueous solution) in the appropriate ratio to form the final radioisotope pharmaceutical. In an embodiment, the irradiation target material comprises a drug molecule precursor in liquid form with an appropriate ratio of aqueous solution, which is then irradiated with neutrons to produce a radioisotope drug in a ready-to-use aqueous solution. In an embodiment, the drug molecule precursor is in a concentrate form, and the irradiated target material (irradiated drug molecule precursor) is adjusted with an appropriate ratio of aqueous solution to form a ready-to-use radioisotope drug.

[0163] In an embodiment, the application of this method involves irradiating an essentially solid version of a desired material composition, such as a solid Lu-176 dotatate precursor molecule, and then creating the desired form of the irradiation target from the irradiated solid. For example, by removing the inert liquid in a Lu-177 drug injection solution before irradiation, the Lu-177 in the irradiated material can be increased by orders of magnitude. By incorporating the irradiated material into the solution in the appropriate proportions, a ready-to-use pharmaceutical aqueous solution with the desired radioactivity per ml can be created.

[0164] Alternatively, this method is applied to irradiate a desired material composition (drug molecule precursor) in liquid or concentrate form to produce a radioisotopeharmaceutical, which can be a ready-to-use radioisotopeharmaceutical composition or can be further combined with other components, such as an aqueous solution, to produce a ready-to-use radioisotopeharmaceutical composition.

[0165] Ready-to-use aqueous pharmaceutical solutions of Lu-177 Dotatate are disclosed in US Pat. Nos. 10,596,276 and 10,596,278, the entire contents of which are incorporated herein by reference for all purposes.

[0166] The devices shown in Figures 2A-2D and 3A-3D can also be applied to the production of other radioisotopes used in medical and other commercially valuable activities, such as radiotracers such as Na-24 used in steam generator moisture carryover measurements, and direct irradiation of iodide salts for thyroid cancer treatment. Other therapeutic radioisotopes such as Cu-64, Ho-166, P-32, and K-42 can also be produced using the devices shown in Figures 2A-2D and 3A-3D.

[0167] The method and device shown in this disclosure provide a novel approach to producing highly promising cancer therapeutics that does not require a nuclear reactor to produce the radioisotopes or radionuclides required to be conjugated with the relevant peptides, proteins or antibodies to form the final radioisotope drug molecule that is injected into the patient. In this approach, non-radioactive drug molecule precursors can be constructed prior to use and then irradiated with an electronic neutron generator that minimizes the gamma radiation and heat that the drug molecule receives. This approach allows the final drug to be produced directly in a clinical environment at a much lower cost, allowing for a much more timely patient treatment regime and more efficient use of radioisotopes.

[0168] The method of the present disclosure has another advantage that non-radioactive drug molecule precursors do not decay and therefore have a much longer shelf life than the corresponding radioisotope drug molecules in their final form.Non-radioactive drug molecule precursors can be manufactured in large quantities in advance and stored in hospitals and clinics for multiple applications of PRRT on multiple patients without the need for protective radiation shielding containers or devices.Then, non-radioactive drug molecule precursors can be converted into the corresponding radioisotope drug molecules in their final form just before PRRT.

[0169] The Lu-177 radioisotope pharmaceutical (final drug) may further comprise one or more stabilizers against radiolytic degradation, such as gentisic acid or ascorbic acid or salts thereof, during or after complexation, preferably after complexation.

[0170] The methods of the present disclosure have the further advantage that the Lu-177 radioisotope pharmaceuticals may not require the addition of any stabilizers against radiolytic degradation, such as gentisic acid or ascorbic acid or their salts, or ethanol, which are required for existing Lu-177 radioisotope pharmaceuticals.

[0171] As mentioned above, existing methods for producing Lu-177 radioisotope pharmaceuticals include first preparation, purification, storage and handling before and during the manufacture of the final drug. One of the technical problems of these existing methods is that the decay of radionuclides in intermediate compounds and the final product occurs constantly, for example, before, during and during the manufacture of the drug, and the emitted high energy radiation induces the cleavage of chemical bonds of molecules that form part of the drug. This is often referred to as radiolysis or radiolytic degradation. Radiolytic degradation of the receptor binding portion of the drug can lead to a decrease in efficacy as a diagnostic and / or therapeutic. To address this technical problem, stabilizers against radiolytic degradation are typically added to existing Lu-177 radioisotope pharmaceuticals. However, the addition of stabilizers can be problematic because those chemicals can adversely affect the complexation of the radionuclide to the chelating agent or have limited solubility and can precipitate out of solution. Ethanol has been reported as a stabilizer against radiolysis (WO 2008 / 009444). Although ethanol may not adversely affect complexation or solubility problems, high amounts of ethanol in the infusion solution may be physiologically problematic and may adversely affect drug tolerability. Additionally, gentisic acid or ascorbic acid or their salts have been reported as stabilizers against radiolytic degradation.

[0172] The disclosed method produces Lu-177-based radioisotope pharmaceuticals (final drugs) directly from non-radioactive Lu-176 drug molecule precursors without the use of any radioactive intermediate compounds, thus eliminating the need to prepare, purify, store and handle any radioactive intermediate compounds prior to or during the manufacture of the final drug. Thus, the disclosed Lu-177-based radioisotope pharmaceuticals (final drugs) do not require stabilizers against radiolytic degradation.

[0173] The method, device and system of the present disclosure can also be applied to the production of Y-90 radioisotope pharmaceuticals for treating cancers such as liver cancer. The current method for producing Y-90 radioisotope pharmaceuticals is to first prepare a radioisotope Y-90 compound and then coat the radioactive Y-90 compound on microspheres. In contrast, the method according to the present disclosure produces microspheres coated with non-radioactive isotope Y-89. The Y-89 coated spheres are then irradiated with the device shown in Figures 2A-2D and 3A-3D until the maximum radioactivity of Y-90 is achieved for use in treating patients.

[0174] The methods and devices described in this disclosure allow Applicants to provide current suppliers of drugs such as Lu-177 Dotatate with a means to significantly reduce the costs associated with drug manufacturing and greatly increase the available supply of much needed cancer therapeutics. The Lu-177 manufacturing market is estimated to be $4.25 billion by 2025. Implementation of the manufacturing approach of the present disclosure could allow Applicants to capture a significant portion of the supply market.

[0175] In various aspects, the present disclosure provides a method for producing a radioisotopic pharmaceutical comprising providing a non-radioactive drug molecule precursor and irradiating the non-radioactive drug molecule precursor with a neutron flux to convert at least a portion of the non-radioactive drug molecule precursor into a radioisotopic pharmaceutical.

[0176] In various embodiments, the neutron flux is generated by an electronic neutron generator array having at least one electronic neutron generator.

[0177] In various embodiments, the method further comprises preparing a non-radioisotopic drug molecule precursor.

[0178] In various embodiments, the radioisotopeharmaceutical comprises or is a first complex of a radionuclide and a target cell receptor binding moiety bound to a chelator.

[0179] In various embodiments, the non-radioactive isotope drug molecule precursor comprises or is a second complex of a non-radioactive isotope and a target cell receptor binding moiety bound to a chelator, where the non-radioactive isotope is a radioactive nuclide or a non-radioactive isotope of a different metal or metal ion that can be converted to a radionuclide by irradiating the non-radioactive isotope with a neutron flux.

[0180] In various embodiments, the method further includes preparing a non-radioactive isotope drug molecule precursor by a process including: 1) preparing a first aqueous solution including a non-radioactive isotope; 2) preparing a second aqueous solution including a target cell receptor binding moiety bound to a chelator; 3) mixing the first aqueous solution prepared in step 1) and the second aqueous solution prepared in step 2) to form a mixture; and 4) heating the mixture to form a reaction solution including a second complex, the method including irradiating the reaction solution including the second complex to convert at least a portion of the non-radioactive isotope in the second complex to a radioactive nuclide and form a radioisotope pharmaceutical including the first complex.

[0181] In various embodiments, the process further comprises drying and purifying the reaction solution containing the second complex to form a non-radioisotopic drug molecule precursor in solid form.

[0182] In various embodiments, the target cell receptor binding moiety comprises or is a somatostatin receptor binding peptide selected from the group consisting of octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.

[0183] In various embodiments, the chelator is selected from the group consisting of DOTA, DTPA, NT, EDTA, DO3A, NOC and NOTA.

[0184] In various embodiments, the radioisotopeharmaceutical is selected from the group consisting of a Lu-177-based radioisotopeharmaceutical, an I-131-based radioisotopeharmaceutical, and a Y-90-based radioisotopeharmaceutical.

[0185] In various embodiments, the radioisotopeharmaceutical is selected from the group consisting of Lu-177 dotatate, I-131 tositumomab, and Y-90 ibritumomab-tiuxetan.

[0186] In various embodiments, the non-radioactive drug molecule precursor is selected from the group consisting of a Lu-176 drug molecule precursor, a tellurium drug molecule precursor, and a Y-89 drug molecule precursor.

[0187] In various embodiments, the non-radioactive drug molecule precursor is selected from the group consisting of Lu-176 dotatate, terulotositumomab, and Y-89 ibritumomab-tiuxetan.

[0188] In various embodiments, the radioisotope pharmaceutical is Lu-177 Dotatate and the non-radioactive drug molecule precursor is Lu-176 Dotatate. Lu-177 Dotatate is produced by directly irradiating Lu-176 Dotatate with a neutron flux generated by an electronic neutron generator array.

[0189] In various aspects, the disclosure provides methods for producing a Lu-177-based radioisotope pharmaceutical comprising: 1) preparing a first aqueous solution comprising a non-radioactive Lu-176 isotope; 2) preparing a second aqueous solution comprising a target cell receptor binding peptide conjugated to a chelating agent; 3) mixing the first aqueous solution prepared in step 1) and the second aqueous solution prepared in step 2) to form a mixture; 4) heating the mixture to form a reaction solution comprising a Lu-176 complex of Lu-176 and the target cell receptor binding peptide conjugated to a chelating agent; and 5) irradiating the reaction solution comprising the Lu-176 complex to convert at least a portion of the Lu-176 isotope in the Lu-176 complex to the Lu-177 radioisotope and form the Lu-177-based radioisotope pharmaceutical.

[0190] In various embodiments, the method further comprises drying and / or purifying the reaction solution comprising the Lu-176 complex to form a solid comprising the Lu-176 complex.

[0191] In various embodiments, the method further comprises drying and / or purifying the reaction solution comprising the Lu-176 complex to form a concentrate comprising the Lu-176 complex.

[0192] In various embodiments, the target cell receptor-binding peptide comprises or is a somatostatin receptor-binding peptide.

[0193] In various embodiments, the somatostatin receptor-binding peptide is selected from the group consisting of octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably octreotide and octreotate.

[0194] In various embodiments, the somatostatin receptor-binding peptide is oxodotreotide.

[0195] In various embodiments, the chelator is selected from the group consisting of DOTA, DTPA, NT, EDTA, DO3A, NOC and NOTA.

[0196] In various embodiments, the chelating agent is DOTA.

[0197] In various embodiments, the target cell receptor binding peptide conjugated to the chelator comprises or is Dotatate or Dotatoc.

[0198] In various embodiments, the target cell receptor-binding peptide conjugated to a chelator comprises or is Dotatate.

[0199] In various embodiments, the Lu-176 complex comprises or is either Lu-176 dotatoc or Lu-176 dotatate.

[0200] In various embodiments, the Lu-176 complex comprises or is Lu-176 doutate.

[0201] In various embodiments, the Lu-177-based radioisotopeharmaceutical comprises or is Lu-177 dotatoc or Lu-177 dotatate.

[0202] In various embodiments, the Lu-177-based radioisotopeharmaceutical comprises or is Lu-177 Dotatate.

[0203] In various aspects, the present disclosure provides a device for directly producing radioisotopic pharmaceuticals from non-radioactive drug molecule precursors by irradiating the non-radioactive drug molecule precursors with a neutron flux generated by an electronic neutron generator array. The device includes an electronic neutron generator array having at least one electronic neutron generator configured to generate a neutron flux, an irradiation module insertion tube (rabbit hole) having an insertion port, an irradiation module including a DO moderator module surrounding and attached to the outer side of the irradiation module insertion tube, containing DO and having an adjustable thickness, a boric acid water module surrounding and attached to the outer side of the DO moderator module, and a metal shielding module surrounding and attached to the outer side of the boric acid water module, and an irradiation module insert configured to be inserted into the irradiation module insertion tube through the insertion port and contain an irradiation target material including a non-radioactive drug molecule precursor.

[0204] In various aspects, the irradiation module insert comprises an insertion rod, a removable nose configured to removably couple to the insertion rod, an irradiation chamber housed in the removable nose, and an insertion position locking ring configured to be placed on the insertion rod to lock the irradiation module insert at the insertion port to adjust the position of the irradiation chamber within the irradiation module insertion tube, and the irradiation target material is housed in the irradiation chamber.

[0205] In various aspects, the device further comprises a radiation detector surrounding and attached to the irradiation chamber for detecting the irradiation level from the irradiation chamber, and a temperature sensor coupled to the irradiation chamber for sensing the temperature of the irradiation chamber.

[0206] In various embodiments, the device further comprises a control unit configured to connect to the illumination module and the illumination module insert.

[0207] In various embodiments, the irradiation module insert further comprises an irradiation detector signal output configured to transmit a first signal of the irradiation level detected from the radiation detector to the control unit, and a temperature sensor signal output configured to transmit a second signal of the temperature sensed from the temperature sensor to the control unit.

[0208] In various embodiments, the at least one electronic neutron generator is configured to direct its neutrons or neutron flux toward the center of the irradiation module insertion tube of the irradiation module.

[0209] In various embodiments, the irradiation module insert is configured to be placed within the irradiation module insertion tube and to hold the irradiation chamber substantially in the center of the irradiation module insertion tube and also in the center of the at least one electronic neutron generator such that all neutron flux from the at least one electronic neutron generator is directed toward the irradiation chamber.

[0210] In various aspects, the device further comprises a target cooling unit comprising a liquid coolant, the target cooling unit configured to be attached to the irradiation module to circulate coolant through the irradiation module insertion tube to cool the irradiation module insertion tube and the irradiation module insert inserted into the irradiation module insertion tube so as to control the temperature within the irradiation module insertion tube and thus within the irradiation chamber of the irradiation module insert.

[0211] In various aspects, the irradiation chamber is a hollow cylinder for containing the irradiation target material and has an outer side and upper and lower circular surfaces, and the irradiation detector is a hollow cylinder concentric with the irradiation chamber and configured to surround the entire outer side of the irradiation chamber without covering the upper and lower circular surfaces of the irradiation chamber.

[0212] In various embodiments, the control unit is configured to: 1) receive the second signal, 2) adjust parameters of the target cooling unit to control the temperature in the irradiation module insertion tube and the irradiation chamber to maintain within a predetermined temperature range, 3) receive the first signal, 4) determine whether the detected irradiation level reaches a predetermined level, and 5) turn off the at least one electronic neutron generator when the detected irradiation level reaches the predetermined level.

[0213] In various embodiments, the radioisotopeharmaceutical is selected from the group consisting of a Lu-177-based radioisotopeharmaceutical, an I-131-based radioisotopeharmaceutical, and a Y-90-based radioisotopeharmaceutical.

[0214] In various embodiments, the radioisotopeharmaceutical is selected from the group consisting of Lu-177 dotatate, I-131 tositumomab, and Y-90 ibritumomab-tiuxetan.

[0215] In various embodiments, the non-radioactive drug molecule precursor is selected from the group consisting of a Lu-176 drug molecule precursor, a tellurium drug molecule precursor, and a Y-89 drug molecule precursor.

[0216] In various embodiments, the non-radioactive drug molecule precursor is selected from the group consisting of Lu-176 dotatate, terulotositumomab, and Y-89 ibritumomab-tiuxetan.

[0217] In various embodiments, the non-radioactive drug molecule precursor comprises or is a Lu-176 complex of Lu-176 and a target cell receptor binding moiety bound to a chelator.

[0218] In various embodiments, the non-radioactive drug molecule precursor comprises or is Lu-176 Dotatate.

[0219] In various embodiments, the radioisotopeharmaceutical comprises or is Lu-177 Dotatate.

[0220] In various embodiments, the irradiation target material is a non-radioactive drug molecule precursor.

[0221] All patents, patent applications, publications, or other disclosure materials described herein and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety as if each individual reference was expressly incorporated by reference. All patents and any materials, or portions thereof, that are incorporated herein by reference are incorporated herein only to the extent that the incorporated material does not conflict with existing definitions, descriptions, or other disclosed material set forth in this disclosure. The disclosure expressly set forth herein thus and to the extent necessary, supersedes any conflicting material incorporated herein by reference, and the disclosure expressly set forth in this application is controlling.

[0222] The present disclosure has been described with reference to various typical and exemplary embodiments. It is understood that the embodiments described herein provide exemplary features of various details of the various embodiments of the disclosed disclosure, and therefore, unless otherwise specified, it is understood that, to the extent possible, one or more features, elements, components, ingredients, structures, modules, and / or aspects of the disclosed embodiments may be combined, separated, exchanged, and / or rearranged with one or more other features, elements, components, ingredients, structures, modules, and / or aspects of the disclosed embodiments without departing from the scope of the disclosed disclosure. Thus, one skilled in the art will recognize that various substitutions, modifications, or combinations of any of the exemplary embodiments may be made without departing from the scope of the disclosure. Moreover, one skilled in the art will recognize, upon review of this specification, or will be able to ascertain using no more than routine experimentation, many equivalents to the various embodiments of the disclosure described herein. Thus, the present disclosure is not limited by the description of the various embodiments, but rather by the scope of the claims.

[0223] Those of ordinary skill in the art will recognize that, in general, the terms used herein, and particularly in the appended claims (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," the term "including" should be interpreted as "including, but not limited to," etc.). Where a particular number of prefaced claim recitations are intended, such intent will be expressly set forth in the claim, and in the absence of such recitation, it will be further understood by those of ordinary skill in the art that no such intent exists. For example, to aid in understanding, the following appended claims may include the use of the preface phrases "at least one" and "one or more" to preface the claim recitations. However, the use of such phrases should not be construed as meaning that the preface of a claim recitation with the indefinite article "a" or "an" limits any particular claim that includes a claim recitation so prefaced to a claim that includes only one such recitation, even if that same claim includes the preface phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should typically be construed to mean "at least one" or "one or more"). The same applies to the use of definite articles used to preface claim recitations.

[0224] Moreover, even if a claim explicitly recites a particular number of preambles, one of ordinary skill in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the mere recitation of "two recitations" without other modifiers typically means at least two recitations, or more than two recitations). Furthermore, when a convention similar to "such as at least one of A, B, and C" is used, such configuration is generally intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having A only, B only, C only, A and B, A and C, B and C, and / or A, B, and C, etc.). When a convention similar to "such as at least one of A, B, or C" is used, such configuration is generally intended in the sense that one of skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having A only, B only, C only, A and B, A and C, B and C, and / or A, B, and C, etc.). One of skill in the art will further appreciate that disjunctive words and / or phrases, whether in the specification, claims, or drawings, that typically present two or more alternative terms, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms, unless otherwise indicated by context. For example, the phrase "A or B" will typically be understood to include the possibilities of "A" or "B" or "A and B."

[0225] With respect to the appended claims, one of ordinary skill in the art will appreciate that any operations recited therein may generally be performed in any order. Also, while the claims are presented in a sequence, it should be understood that various operations may be performed in other orders than those recited, or may be performed simultaneously. Examples of such alternative orders may include overlapping, interleaving, interrupting, reordering, incrementing, preparing, supplementing, simultaneous, reverse, or other variant orders, unless the context dictates otherwise. Moreover, terms such as "according to," "related to," or other past tense adjectives are generally not intended to exclude such variants, unless the context dictates otherwise.

[0226] It is worth noting that any reference to "one embodiment," "an embodiment," "various embodiments," "an example," "one example," etc. means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment," "in an embodiment," "in various embodiments," "in an example," "in one example" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0227] As used herein, the singular forms "a," "an," and "the" include the plural forms as well, unless the context clearly indicates otherwise.

[0228] Directional terms used herein, such as, but not limited to, up, down, left, right, lower, upper, front, back, and variations thereof, refer to the orientation of elements as shown in the accompanying drawings and do not limit the scope of the claims, unless expressly stated otherwise.

[0229] The term "about" or "approximately" as used in this disclosure, unless otherwise specified, refers to an acceptable error for a particular value as determined by a person skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 50%, 200%, 105%, 100%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0230] As used herein, unless otherwise indicated, all numerical parameters are understood to be prefaced and modified in all instances by the term "about," with the inherent variability inherent in the underlying measuring techniques employed to determine the numerical value of such parameters. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter set forth herein should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0231] Numerical ranges mentioned herein include all subranges subsumed within the mentioned range. For example, a range of "1 to 100" includes all subranges between (and including) the stated minimum of 1 and the stated maximum of 100, i.e., having a minimum equal to or greater than 1 and a maximum equal to or less than 100. Also, all ranges mentioned herein include the endpoints of the mentioned range. For example, a range of "1 to 100" includes the endpoints 1 and 100. Any maximum numerical limitation mentioned herein is intended to include all lower numerical limitations subsumed therein, and any minimum numerical limitation mentioned herein is intended to include all upper numerical limitations subsumed therein. Accordingly, applicants reserve the right to amend this specification, including the claims, to explicitly recite any subranges subsumed within the expressly recited ranges. All such ranges are inherently described herein.

[0232] The words "comprise" (and any form of compre such as "comprises" and "comprising"), "have" (and any form of having such as "has" and "having"), "include" (and any form of include such as "includes" and "including"), and "contain" (and any form of contain such as "contains" and "containing") are open-ended linking verbs. As a result, a system that "comprises", "has", "includes", or "contains" one or more elements has one or more of those elements, but is not limited to having one or more of those elements. Similarly, a system, device, or apparatus element that "comprises," "has," "includes," or "contains" one or more features possesses those one or more features, but is not limited to possessing only those one or more features.

[0233] In describing aspects and embodiments of the present application, specific terms are used for the sake of clarity. However, the present disclosure is not intended to be limited to the specific terms so selected. Nothing in this specification should be considered as limiting the scope of the present disclosure.

[0234] All examples provided are representative and non-limiting examples. The above aspects and embodiments may be modified or varied without departing from the present disclosure, as will be understood by those skilled in the art in light of the above teachings. It is therefore understood that, within the scope of the claims and their equivalents, the present disclosure may be practiced otherwise than as specifically described.

[0235] Without further elaboration, it is believed that those skilled in the art can utilize the claimed disclosure to its fullest extent using the preceding description. The examples, aspects, and embodiments disclosed herein are to be construed as merely illustrative and in no way limit the scope of the disclosure. It will be apparent to those skilled in the art that various changes and modifications may be made to the details of the above aspects and embodiments without departing from the basic principles discussed. In other words, various modifications and improvements of the aspects and embodiments specifically disclosed in the above description are within the scope of the appended claims. For example, any suitable combination of features of the various aspects and embodiments described is contemplated. It should be noted that elements described in a means-plus-function format are intended to be interpreted in accordance with Section 6 of 35 U.S.C. 112. The scope of the disclosure is therefore defined by the following claims.

Claims

1. 1. A method for producing a radioisotope pharmaceutical comprising: Providing a non-radioactive drug molecule precursor; and exposing said non-radioactive drug molecule precursor to a neutron flux to convert said non-radioactive drug molecule precursor to said radioisotope drug.

2. the radioisotopeharmaceutical comprises a first complex of a radionuclide and a target cell receptor binding moiety bound to a chelator; the non-radioactive drug molecule precursor comprises a second complex of a non-radioactive isotope and the target cell receptor binding moiety bound to the chelator; 2. The method of claim 1, wherein the non-radioactive isotope is the radionuclide or a non-radioactive isotope of a different metal or metal ion that can be converted to the radionuclide by irradiating the non-radioactive isotope with a neutron flux.

3. Providing a first aqueous solution containing the non-radioactive isotope; providing a second aqueous solution comprising the target cell receptor binding moiety bound to the chelating agent; mixing the first aqueous solution and the second aqueous solution to form a mixture; heating the mixture to form a reaction solution comprising the second complex; preparing said non-radioactive drug molecule precursor by a process comprising:

3. The method of claim 2, wherein the method comprises irradiating the reaction solution comprising the second complex to convert the non-radioactive isotope in the second complex to the radionuclide and form the radioisotope pharmaceutical comprising the first complex.

4. 4. The method of claim 3, wherein the process further comprises drying and purifying the reaction solution containing the second complex to form the non-radioactive drug molecule precursor in a solid form.

5. said target cell receptor binding moiety comprises or is a somatostatin receptor binding peptide selected from the group consisting of octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate; 3. The method of claim 2, wherein the chelating agent is selected from the group consisting of DOTA, DTPA, NT, EDTA, DO3A, NOC and NOTA.

6. said radioisotope pharmaceutical is a Lu-177 based radioisotope pharmaceutical; The method comprises: Providing a first aqueous solution containing non-radioactive Lu-176 isotope; Providing a second aqueous solution comprising a target cell receptor binding peptide bound to a chelating agent; mixing the first aqueous solution and the second aqueous solution to form a mixture; heating the mixture to form a reaction solution comprising a Lu-176 complex of the non-radioactive Lu-176 isotope and the target cell receptor binding peptide bound to the chelator; and irradiating the reaction solution containing the Lu-176 complex to convert the non-radioactive Lu-176 isotope in the Lu-176 complex to Lu-177 radioactive isotope and form the Lu-177-based radioisotope.

7. 1. A device for the direct production of radioisotopic pharmaceuticals from non-radioactive drug molecule precursors by irradiating said precursors with a neutron flux generated by an electron neutron generator array, comprising: an electronic neutron generator configured to generate the neutron flux; 1. An illumination module, comprising: an illumination module insertion tube having an insertion port; The illumination module insertion tube is surrounded by an outer side surface thereof and is attached thereto; ２ D, which accommodates O and has an adjustable thickness ２ O moderator module, The above D ２ a boric acid water module surrounding and attached to the outer side of the O moderator module; and The irradiation module includes a metal shielding module attached to and surrounding the outer surface of the boric acid water module; an irradiation module insert configured to be inserted into the irradiation module insertion tube through the insertion port and to receive irradiation target material including the non-radioactive drug molecule precursor.

8. The illumination module insert comprises: An insertion rod; a removable nose configured to removably couple to the insertion rod; an irradiation chamber received in the removable nose for receiving the irradiation target material; 8. The device of claim 7, further comprising: an insertion position locking ring configured to be placed on the insertion rod to lock the irradiation module insert in the insertion port and to adjust the position of the irradiation chamber within the irradiation module insertion tube.

9. a radiation detector surrounding and attached to the irradiation chamber for detecting an irradiation level in the irradiation chamber; a temperature sensor coupled to the irradiation chamber for sensing a temperature of the irradiation chamber; The device of claim 8 further comprising:

10. The device of claim 9 , further comprising a control unit configured to connect to the illumination module and the illumination module insert.

11. The illumination module insert comprises: an irradiation detector signal output configured to send a first signal to the control unit corresponding to the irradiation level detected by the radiation detector; The device of claim 10 , further comprising a temperature sensor signal output configured to send a second signal corresponding to the sensed temperature from the temperature sensor to the control unit.

12. The device of claim 11 , wherein the electronic neutron generator is configured to direct a neutron flux toward a center of the irradiation module insertion tube of the irradiation module.

13. 13. The device of claim 12, wherein the irradiation module insert is configured to be placed within the irradiation module insertion tube and to position the irradiation chamber at a center of the irradiation module insertion tube such that the neutron flux from the electronic neutron generator is directed toward the irradiation chamber.

14. a target cooling unit including a liquid coolant; The device of claim 13 , wherein the targeted cooling unit is configured to attach to the irradiation module to circulate the liquid coolant through the irradiation module insertion tube to cool the irradiation module insertion tube and the irradiation module insert.

15. the irradiation chamber being a hollow cylinder for containing the irradiation target material and having an outer side and upper and lower circular surfaces; 15. The device of claim 14, wherein the radiation detector is a hollow cylinder concentric with the irradiation chamber and configured to surround the outer side of the irradiation chamber without covering the top and bottom circular surfaces of the irradiation chamber.

16. The control unit receiving the second signal; adjusting parameters of the target cooling unit to control the temperature in the irradiation module insertion tube and the irradiation chamber to be maintained within a predetermined temperature range; receiving the first signal; determining whether the detected illumination level has reached a predetermined level; The device of claim 15 configured to turn off the electronic neutron generator when the detected irradiation level reaches the predetermined level.

17. 8. The device of claim 7, wherein the radioisotope pharmaceutical is selected from the group consisting of a Lu-177-based radioisotope pharmaceutical, an I-131-based radioisotope pharmaceutical, and a Y-90-based radioisotope pharmaceutical.

18. 18. The device of claim 17, wherein the non-radioactive drug molecule precursor is selected from the group consisting of a Lu-176 drug molecule precursor, a tellurium drug molecule precursor, and a Y-89 drug molecule precursor.

19. 8. The device of claim 7, wherein the radioisotopeharmaceutical is selected from the group consisting of Lu-177 dotatate, I-131 tositumomab, and Y-90 ibritumomab-tiuxetan.

20. 20. The device of claim 19, wherein said non-radioactive drug molecule precursor is selected from the group consisting of Lu-176 dotatate, terulotositumomab and Y-89 ibritumomab-tiuxetan.

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