Methods for the large scale synthesis of radionuclide complexes.

Abstract

The present disclosure relates to methods for the large scale synthesis of radionuclide complex solutions having high radioactivity for diagnostic and / or therapeutic purposes, their use in the commercial manufacture of radiopharmaceutical substances, and to the respective solutions and containers containing said solutions.

Description

[Technical field]

[0001] The present disclosure relates to methods for the large scale synthesis of radionuclide complex solutions having high radioactivity for diagnostic and / or therapeutic purposes, their use in the commercial production of radiopharmaceutical substances, and to the respective solutions and containers containing said solutions. [Background technology]

[0002] The concept of targeted drug delivery is based on cell receptors or other cell surface markers that are overexpressed in target cells versus non-targeted cells. If a drug has a binding site for these overexpressed cell surface markers, it allows the drug to be delivered to these target cells at high concentrations after systemic administration, while other non-targeted cells remain unaffected. For example, if tumor cells are characterized by the overexpression of specific cell receptors, drugs that have binding affinity for said receptors will accumulate in tumor tissue at high concentrations after intravenous infusion, while normal tissues remain unaffected.

[0003] Targeted drug delivery has also been used in nuclear medicine to selectively deliver radionuclides to target cells for diagnostic or therapeutic purposes. For this nuclear medicine application, the targeting moiety is typically linked to a chelating moiety that can form a strong complex with the metal ion of the radionuclide. This radionuclide complex is then delivered to the target cell, and the decay of the radionuclide then releases high energy electrons, positrons or alpha particles, as well as gamma rays at the target site.

[0004] Radionuclide complexes are preferably produced in a shielded closed system due to their significant radioactivity. In such a shielded closed system, the manufacturing, purification and formulation steps of the drug substance are part of a continuous process. Furthermore, the decay of the radionuclide does not allow enough time for any interruption of the drug substance production process. If not enough time is allowed, the desired radioactivity of the drug will not be achieved and the diagnostic or therapeutic outcome will be jeopardized. Therefore, it may be desirable not to carry out tests at critical stages and synthetic intermediates may not be isolated and controlled during the production process.

[0005] Conventional industrial production methods for pharmaceuticals, such as those described in the applicant's WO 2020 / 079799 A1, including radionuclide complexes, cannot utilize solutions with higher radioactivity of the radionuclides as reactants because they cause a significant degree of radiolysis when mixed with target binding molecules. This limits the supply of certain radiodiagnostic and radiotherapeutic drug substances, but demand is increasing as medical advances in certain fields are established.

[0006] It is therefore desirable to provide a synthetic method for the production of radionuclide complexes at high radioactivity, which substantially avoids radiolysis and therefore allows the production of more pharmaceuticals (patient doses) having radioactivity suitable for administration to a patient per given unit of time. A synthetic method for the production of radiopharmaceutical substances of radionuclide complexes would have the following advantages: - high labeling yields, which correlate with high radiochemical purity; - high labeling yields with minimal levels of free (uncomplexed) radionuclides, -Production of more doses per batch compared to traditional methods. Summary of the Invention

[0007] The present disclosure provides target-binding organic molecules. 177 A reaction solution for radiolabeling with Lu(III) ions, comprising: (1) A unit volume radioactivity of at least 17 GBq / mL 177 Lu(III) ion, (2) a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety suitable for chelating Lu(III) ions; (3) one or more stabilizers against radiolytic degradation.

[0008] The present disclosure also provides 177 1. A mother solution for preparing a dispensing solution comprising a Lu radiolabeled target-binding organic molecule, the mother solution comprising: (1) A unit volume radioactivity of at least 10 GBq / mL 177 Lu(III) ion, (2) a target-binding organic moiety comprising a target-binding organic moiety linked to a chelating moiety; 177 a radionuclide complex formed by Lu(III) ions; (3) one or more stabilizers against radiolytic degradation; (4) An oxygen concentration of less than 50 mg / L, preferably less than 20 mg / L, more preferably less than 10 mg / L, even more preferably less than 5 mg / L, and even more preferably less than 3 mg / L at 25 degrees Celsius.

[0009] The present disclosure also relates to a mother liquor container for collecting solution from a radiolabeling reaction, said container comprising: (1) A mother solution comprising: A unit volume activity of at least 10 GBq / mL 177 Lu(III) ion, b. a target-binding organic moiety comprising a target-binding organic moiety linked to a chelating moiety; 177 a radionuclide complex formed by Lu(III) ions; c. one or more stabilizers against radiolytic degradation; (2) a headspace gas volume above the mother solution, said headspace gas volume containing 10% or less by volume of oxygen.

[0010] The present disclosure also provides a process for producing a radiopharmaceutical solution, comprising: (1) providing a reaction solution; (2) reacting a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety at subatmospheric pressure, optionally in the presence of an inert gas, with the target-binding organic molecule. 177 and reacting the Lu(III) ions with Lu(III) ions to obtain a radionuclide complex in a single vessel for radiolabeling.

[0011] The present disclosure also relates to products obtainable or obtained by the methods described herein.The present disclosure also relates to aqueous solutions comprising radionuclide complexes. [Brief description of the drawings]

[0012] [Figure 1] The MiniAio Kit Cassette for 177Lu-DOTATATE and its kit assembly (Grade C or lower) are shown. [Diagram 2] The MiniAio Kit Cassette for 177Lu-PSMA-617 and its kit assembly (Grade C or lower) are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] definition As used herein, the term "reaction solution" refers to a solution containing a radionuclide ion, a target-binding organic molecule suitable for chelating the radionuclide ion, and one or more stabilizers against radiolytic degradation. The target-binding organic molecule comprises a target-binding organic moiety linked directly or indirectly to a chelating moiety.

[0014] As used herein, the term "mother solution" refers to the solution obtained when the aforementioned reaction solution is reacted to form the radionuclide complex, which has been treated (if applicable) as further described below, and diluted (if applicable) with water for injection (WFI).

[0015] As used herein, the term "dispensing solution" refers to the solution obtained when the aforementioned mother solution is further mixed with a diluent solution. The dispensing solution contains all the components and radioactivity suitable for patient administration. A dispensing solution is a solution that is dispensed into multiple patient doses (vials) and is destined for subsequent administration to patients without further material modification.

[0016] The disclosed method is particularly suitable for the use of metallic radionuclides, which are useful in medicine for diagnostic and / or therapeutic purposes, including radioisotopes of I, In, Tc, Ga, Cu, Zr, Pb, Bi, Ac, Th, Re, Sc, Tb, Y and Lu, in particular: 131 I, 111 In, 99m Tc, 68 Ga, 64 Cu, 67 Cu, 89 Zr, 212 Pb, 213 Bi, 225 Ac, 227 Th, 47 Sc, 188 Re, 161 Tb, 90 Y, 177 Ions of radioisotopes, including but not limited to Lu, form non-covalent bonds with functional groups, such as amino or carboxyl groups, of the chelating agent.

[0017] In a preferred embodiment, the radionuclide ion is lutetium-177( 177 For example, radionuclide ions include 177 It can be derived from LuCl3.

[0018] As used herein, the term "stabilizers against radiolytic degradation" refers to stabilizers that protect organic molecules from radiolysis, e.g., when gamma rays emitted from radionuclides break bonds between atoms of organic molecules to form radicals, these radicals are captured by the stabilizer, preventing them from undergoing chemical reactions that may result in undesirable, potentially ineffective or toxic molecules. These stabilizers are therefore also referred to as "free radical scavengers" or "radical scavengers" for short. Other alternative terms for these stabilizers are "radiostability enhancers", "radiolytic stabilizers" or simply "quenchers".

[0019] The stabilizer present in the solution of the present disclosure may be selected from gentisic acid (2,5-dihydroxybenzoic acid) or a salt thereof, ascorbic acid (L-ascorbic acid, vitamin C) or a salt thereof (e.g., sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine, preferably selected from gentisic acid or a salt thereof, and preferably not selected from ethanol.

[0020] In a specific embodiment, the reaction solution and the mother solution do not contain ascorbic acid, preferably they contain gentisic acid as a stabilizer and do not contain ascorbic acid as a stabilizer. In a specific embodiment, the reaction solution and the mother solution do not contain ethanol as a stabilizer. Preferably, the reaction solution and the mother solution do not contain either ascorbic acid or ethanol as a stabilizer.

[0021] As used herein, when a numerical value is preceded by "about," "about" indicates a deviation of the value or range by only ±20%, preferably ±10%, more preferably ±5%, and potentially ±2% or ±1%.

[0022] Lutetium-177 is accessible via the (n,γ) reaction. 177 There are two ways to produce Lu. 177 Leading to the direct formation of Lu 176However, this method involves the irradiation of metastable 177m This results in the simultaneous formation of the Lu isotope and other lutetium isotopes. Due to the difficulties and challenges involved in separating the isotopes, 177 Lu and 177m Compositions containing Lu, as well as others, may be used. 177 Such compositions containing Lu and related isotopes may be carrier-added. 177 Lu source or 177 This is called the Lu(CA) source.

[0023] The second method is concentrated 176 Short-lived radioisotopes produced by neutron capture in Yb (>99%) targets. 177 It undergoes beta decay of Yb (half-life of 1.9 hours). However, 176 Yb(n,γ) 177 The low thermal neutron cross section of the Yb reaction (2.1 barns) allows for a very small amount of the desired target compared to the total mass of the target. 177 This results in the production of Lu. 176 From Yb 177 The long-term separation of Lu 177 It is feasible to produce a composition containing only the Lu isotope. Such a composition is free of added carriers. 177 Lu, in brief 177 Provide Lu(NCA).

[0024] Target Binding Molecules for Use According to the Present Disclosure As used herein, a target binding molecule comprises (i) a targeting binding organic moiety linked either directly or indirectly via a linker to (ii) a chelating moiety.

[0025] As used herein, the term "target-binding organic moiety" refers to an organic moiety that has specific binding affinity to a target protein, typically a cell surface receptor or a cellular protein. In a specific embodiment, the target-binding receptor moiety is an organic moiety that has specific binding affinity to a somatostatin receptor, such as a somatostatin receptor subtype 2 (SSTR2), or an organic moiety that has binding affinity to a prostate-specific membrane antigen (PSMA). Other target(s)-binding organic moieties may be gastrin releasing peptide receptor (GRPR) antagonists, ligands that target αvβ3 / αvβ5 integrin, and fibroblast activation protein (FAP) inhibitors.

[0026] As used herein, the term "chelating moiety" refers to an organic moiety that contains a functional group that forms a non-covalent bond with a radionuclide during the reaction step of the present method, thereby forming a stable radionuclide complex. The chelating moiety in the context of the present invention may be or may comprise 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane (NODAGA) or mixtures or variants thereof, preferably DOTA.

[0027] Such chelating moieties are either directly linked to the target-binding organic moiety or connected via a linker molecule, preferably it is directly linked. The linking bond is either a covalent or non-covalent bond between the target-binding organic moiety (and linker) and the chelating moiety, preferably the bond is a covalent bond.

[0028] SSTR binding molecule In a specific embodiment, said target binding organic molecule comprises a somatostatin receptor binding peptide. As used herein, the term "somatostatin receptor binding peptide" refers to a peptidic moiety that has specific binding affinity for a somatostatin receptor, e.g., at least the somatostatin receptor subtype 2 (SSTR2).

[0029] In a specific embodiment, said target binding molecule for use as described herein is a compound of formula CSP, wherein: C is a chelating agent capable of chelating a radionuclide, S is an optional spacer covalently bonded between C and P, P is a somatostatin receptor binding peptide that is covalently attached to C, e.g., directly or indirectly via S, through its N-terminus.

[0030] Such somatostatin receptor binding peptides may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, and are preferably selected from octreotide and octreotate.

[0031] As used herein, the term "somatostatin receptor binding peptide" refers to a peptidic moiety having specific binding affinity to a somatostatin receptor. Such somatostatin receptor binding peptides may be selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, and are preferably selected from octreotide and octreotate.

[0032] The somatostatin receptor binding peptide linked to a chelating moiety may comprise a chelating moiety selected from the group including DOTA, DOTAGA, DTPA, NTA, EDTA, DO3A, NOTA, NODAGA. The somatostatin receptor binding peptide linked to a chelating moiety preferably comprises DOTA.

[0033] According to a preferred embodiment, the target-binding organic moiety linked to the chelating moiety which is a somatostatin receptor binding peptide may be selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably selected from DOTA-TATE.

[0034] Thus, the cell receptor binding moiety and the chelator may together form the following molecule: DOTA-OC: [DOTA 0 ,D-Phe 1 ]Octreotide, DOTA-TOC: [DOTA 0 ,D-Phe 1 ,Tyr 3 ]Octreotide, edotreotide (INN), [ka] DOTA-NOC: [DOTA 0 ,D-Phe 1 ,1-Nal 3 ]Octreotide, DOTA-TATE: A compound represented by the following formula: 0 ,D-Phe 1 ,Tyr 3 ]Octreotate, DOTA-Tyr 3 -Octreotate, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo 2,7), oxodotreotide (INN), [ka] DOTA-LAN: [DOTA 0 ,D-β-Nal 1 ]Lanreotide, DOTA-VAP: [DOTA 0,D-Phe 1 ,Tyr 3 ] Vapreotide. Satreotide Trizoxetan [ka] Satreotide Tetraxetan [ka]

[0035] PSMA binding molecule In a specific embodiment, the target-binding organic molecule comprises a PSMA-binding moiety, which may comprise one or more glutamate-urea-lysine moieties.

[0036] The PSMA binding organic molecule may comprise a chelating moiety selected from DOTA, DOTAGA, DTPA, NTA, EDTA, DO3A, NOTA, NODAGA, preferably a chelating moiety selected from DOTA or DOTAGA, more preferably a chelating moiety which is DOTA.

[0037] According to a preferred embodiment, the target-binding organic moiety is preferably PSMA-617, which has the structure [ka] or a variant of PSMA-617 having additional structural features such as an albumin binding moiety; PSMA-I&T, which has the structure [ka] (having and PSMA-R2, where PSMA-R2 has the structure [ka] and wherein the PSMA-binding peptide is selected from The Glu and Lys residues are in the L configuration, and PSMA-617 is preferred.

[0038] A PSMA ligand or PSMA binding organic molecule according to the present disclosure may be selected from the group consisting of PSMA-617, PSMA I&T, PSMA-R2, MIP-1095, MIP-1545, MIP, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, PSMA-7 I&T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, and RPS-074, and is preferably selected from the group consisting of PSMA-617, PSMA I&T, and PSMA-R2, and more preferably selected from PSMA-617.

[0039] Reaction solution The present disclosure relates to a reaction solution comprising reactants that are necessary to form a radionuclide complex through a reaction. Such reactants are a radionuclide and a target-binding organic molecule. The reaction of forming a radionuclide complex from the two reactants is also called radiolabeling. Thus, this reaction solution is used to radiolabel a target-binding organic molecule with a radionuclide and is suitable for radiolabeling. The target-binding organic molecule comprises (i) a targeting-binding organic molecule linked directly or indirectly via a linker to (ii) a chelating moiety, as described above in the previous section.

[0040] The reaction solution further comprises one or more stabilizers against radiolytic degradation.

[0041] The radionuclide is preferably 177 Lutetium-177 in the form of Lu(III) ion ( 177 For example, the radionuclide ion can be 177 The reaction solution may be derived from LuCl3. 177Lu(III) ions are included at a unit volume activity of at least 17 GBq / ml, or 18 GBq / ml, or at least 19 GBq / ml, and more preferably at least 20 GBq / mL, even more preferably at least 25 GBq / mL, even more preferably at least 28 GBq / mL, even more preferably at least 30 GBq / mL. The upper limit for the aforementioned minimum value may be 20, 25, 30, 40, 50 GBq / mL.

[0042] The present disclosure provides target-binding organic molecules. 177 A reaction solution for radiolabeling with Lu(III) ions, comprising: (1) A unit volume radioactivity of at least 17 GBq / mL 177 Lu(III) ion, (2) a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety suitable for chelating Lu(III) ions; (3) one or more stabilizers against radiolytic degradation.

[0043] The reaction solution may contain an oxygen concentration at 25 degrees Celsius of less than 50 mg / L, preferably less than 20 mg / L, more preferably less than 10 mg / L, even more preferably less than 5 mg / L, even more preferably less than 3 mg / L, or may contain an oxygen concentration of 7 mg / L or 6 mg / L, or less than 5 mg / L, preferably less than 4 mg / L, more preferably less than 3 mg / L, more preferably less than 2 mg / L or 1 mg / L (all values ​​at 25 degrees Celsius). Oxygen may be substantially absent in the reaction solution. A low oxygen concentration in the reaction solution reduces radiolytic degradation. A low level / absence of oxygen may be achieved by degassing the reaction solution and / or by flushing the reaction solution with a protective gas such as nitrogen or argon. For a low oxygen concentration, 177Lu(III) ions may be contained in the reaction solution at a unit volume activity of at least 17 GBq / ml, or 18 GBq / ml, preferably 19 GBq / ml and more preferably 20 GBq / ml, even more preferably at least 28 GBq / mL, even more preferably at least 30 GBq / mL. The upper limit for the aforementioned minimum value may be 20, 25, 30, 40, 50 GBq / mL.

[0044] The reaction solution contains one or more stabilizers against radiolytic degradation, which may include gentisic acid or a salt thereof. The concentration of gentisic acid or a salt thereof may be from 5 to 15 mg / mL.

[0045] When the target binding organic moiety linked to the chelating moiety is a somatostatin receptor binding peptide, the concentration of gentisic acid or a salt thereof can be 10-15 mg / mL.

[0046] When the target-binding organic moiety linked to the chelating moiety is a PSMA-binding peptide, the concentration of gentisic acid or a salt thereof is 5-10 mg / mL.

[0047] The reaction solution may contain up to 5% (w / w) ascorbic acid or a salt thereof, preferably up to 2%, even more preferably up to 1%. Most preferably, the reaction solution is free of ascorbic acid, i.e., it is substantially absent (substantially 0%).

[0048] The reaction solution may contain ethanol at 5% (w / w) or less, preferably 2% or less, even more preferably 1% or less. Most preferably, the reaction solution is free of ethanol, i.e., it is substantially absent (substantially 0%). In a preferred embodiment, ascorbic acid or a salt thereof and ethanol are substantially absent from the reaction solution.

[0049] The reaction solution is 177 Lu(III) ions are no carrier added (NCA) 177 Even if derived from a Lu(III) ion source, target-bound organic molecules 177The target-binding organic molecule may be present in a molar excess relative to the Lu(III) ion. 177 The molar ratio between the Lu(III) ions may be at least 1.2, preferably 1.5 to 3.5.

[0050] Carrier Addition (CA) 177 Lu(III) 177 When used as a source of Lu(III) ions, the reaction solution can be used to prepare target-binding organic molecules at the unit volume radioactivity given above for use in the reaction solution of the present invention. 177 present in the composition providing Lu(III) ions, 177 Lu(III) ion, 176 Lu(III) ion, 175 Lu(III) ion and metastable 177m a molar excess relative to the total number of Lu(III) ions in the group, including the Lu(III) ion; 177 Lu(III) ion, 176 Lu(III) ion, 175 Lu(III) ion and metastable 177m The molar ratio between the group of all Lu(III) ions including Lu(III) ions may be at least 1.2, preferably 1.5 to 3.5.

[0051] The reaction solution may include a pharma- ceutically acceptable buffer; 177 The pharmacy provides a pH range of 2 to 8 that is suitable for the reaction between the Lu(III) ions and the target-binding organic molecules. The pharmacy provides a pH range of preferably 4 to 6.

[0052] Pharmaceutically acceptable buffers include acetate buffers, citrate buffers or phosphate buffers. Citrate buffers may include citrate and HCl and / or citric acid. Phosphate buffers may include sodium dihydrogen phosphate and disodium hydrogen phosphate. Pharmaceutically acceptable buffers preferably include phosphate buffers, which are preferably composed of acetic acid and sodium acetate.

[0053] Mother solution The present disclosure relates to a mother solution, which is the solution obtained when the reaction solution described in the preceding section is terminated to form a radionuclide complex, which is treated as further described below and mixed and diluted with water for injection (WFI). Upon termination of the radiolabeling reaction, the mother solution contains radiolabeled target-binding organic molecules, which are radionuclide complexes formed by the target-binding organic moieties and 177Lu(III) ions linked directly or indirectly to the chelating moieties described above.

[0054] The mother solution is used and is suitable for preparing subsequent dispense solutions, which are solutions that are then dispensed, without further material modification, into multiple patient doses (vials) that are to be administered to patients.

[0055] The present disclosure relates to a mother solution for preparing a dispensing solution comprising a 177Lu radiolabeled target-binding organic molecule, the mother solution comprising: (1) A unit volume radioactivity of at least 10 GBq / mL 177 Lu(III) ion, (2) a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety and a radionuclide complex formed by a 177Lu(III) ion; (3) one or more stabilizers against radiolytic degradation; (4) Preferably, the mother solution comprises an oxygen concentration of less than 50 mg / L, preferably less than 20 mg / L, more preferably less than 10 mg / L, even more preferably less than 5 mg / L, even more preferably less than 3 mg / L at 25 degrees Celsius, or an oxygen concentration of less than 7 mg / L, preferably less than 5 mg / L, more preferably less than 4 mg / L, even more preferably less than 3 mg / L, even more preferably less than 2, even more preferably less than 1 mg / L (all values ​​at 25 degrees Celsius) (even more preferably, the mother solution is substantially free of oxygen).

[0056] The mother solution has a unit volume activity of at least 10 GBq / ml, at least 11 GBq / ml, at least 12 GBq / ml, preferably at least 13 GBq / ml, more preferably at least 15 GBq / ml, and most preferably at least 16 GBq / ml. 177 It may contain Lu(III) ions.

[0057] The radionuclide complexes formed by the target-binding organic molecules and the 177Lu(III) ions include target-binding organic molecules as described in the section "Target-binding molecules for use in accordance with the present disclosure."

[0058] The one or more stabilizers against radiolytic degradation and their details are as described above for the reaction solution. The stabilizer may be gentisic acid or a salt thereof in the concentration range as described above for the reaction solution.

[0059] The oxygen concentration and details are as described above for the reaction solution.

[0060] The mother solution may further comprise a nitrogen concentration of up to 20 ml / L at 25 degrees Celsius or an argon concentration of up to 60 ml / L at 25 degrees Celsius. The mother solution may further comprise a nitrogen concentration in the range of 3-20 ml / L at 25 degrees Celsius, preferably 5-15, more preferably 10-15 ml / L at 25 degrees Celsius. Alternatively, the mother solution may further comprise a nitrogen concentration of up to 20 mg / L at 25 degrees Celsius or an argon concentration of up to 60 mg / L at 25 degrees Celsius. Alternatively, the mother solution may comprise a nitrogen concentration in the range of 3-20 mg / L at 25 degrees Celsius, preferably 5-15, more preferably 10-15 mg / L at 25 degrees Celsius. Alternatively, the mother solution may comprise an argon concentration of 3-60 mg / L at 25 degrees Celsius, preferably 10-50, more preferably 20-40 mg / L at 25 degrees Celsius.

[0061] The presence of an inert gas, such as nitrogen or argon, in the mother solution is a result of the steps leading to the formation of the mother solution as part of the process described further below. The concentration of the inert gas in the mother solution reduces the radiolytic degradation of the components of the mother solution.

[0062] Methods for determining oxygen, nitrogen, and argon concentrations and contents in aqueous solutions or gas phases are well known and are described in a wide variety of literature and encyclopedias, for example in Determination of Argon in Air and Water, J. Lasa et al., Chem. Anal. (Warsaw), 47, 839 (2002); HH Willard et al., Instrumental methods of analysis, 6 th ed.D.Van Norstrand,New York,1981,pages 910-912;MLHitchman,Measurement of dissolved oxygen,John Wiley & Sons,New York 1978;Ullmann's Encyclopedia of Industrial Chemistry;S.Uchiyama,Analysis of Dissolved Argon,Oxygen,and Nitrogen in Solutions,Shimadzu Corporation publication,July 2021 is like that.

[0063] In the reaction solution, the descriptions provided above regarding ascorbic acid or a salt thereof and ethanol; the target-binding organic molecule; the molar excess of the target-binding organic molecule relative to the Lu(III) ion; and the pH and pharma- ceutically acceptable buffers apply equally to the mother solution.

[0064] In a specific embodiment, the mother solution comprises: 177 Lu-DOTA-TOC (Lutetium ( 177 Lu) edotreotide) or 177 Lu-DOTA-TATE (Lutetium ( 177 Lu) oxodotreotide) or 177 Lu-PSMA-617([ 177 Lu]Lu-PSMA-617, Lutetium ( 177Lu) bipibotide tetraxetane [INN] or lutetium Lu177 bipibotide tetraxetane [USAN]) or 177 Lu-PSMA-I&T (Lutetium ( 177 Lu)zadabotide and glaxetan) as preferred radionuclide complexes.

[0065] Throughout this disclosure, radionuclide complexes 177 Lu-PSMA-617 (Lutetium ( 177 Lu) bipibotide tetraxetane) is 177 Lu]Lu-PSMA-617, Lutetium ( 177 Lu) bipibotide tetraxetane [INN] or lutetium Lu177 bipibotide tetraxetane [USAN], PLUVICTO, or 2-[4-[2-[[4-[[(2S)-1-[[(5S)-5-carboxy-5-[[(1S)-1,3-dicarboxy-propyl]carbamoylamino]pentyl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]carbamoyl]cyclohexyl]methylamino]-2-oxoethyl]-4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetracyclododec-1-yl]acetate; may also be referred to as lutetium-177(3+). The molecular mass is 1216.06 g / mol and the molecular formula is C 49 H 68 177 LuN9O 16 The chemical structure for lutetium Lu177 bipibotide tetraxetane is shown below: [ka]

[0066] The mother solution is a radionuclide complex. 177 Lu-DOTA-TOC( 177 Lu-Edotreotide) or 177 Lu-DOTA-TATE( 177 Lu-oxodotreotide), preferably 177 Lu-DOTA-TATE( 177Lu-oxodotreotide) at a unit volume radioactivity of 12 GBq / ml to 17 GBq / ml.

[0067] In other specific embodiments, the mother solution is 177 It may contain Lu PSMA-617 at a unit volume radioactivity of 10 to 30, preferably 10 to 25, more preferably 15 to 25, even more preferably 17 to 25, even more preferably 17 to 20, and even more preferably 18 to 19 GBq / ml.

[0068] The mother solution is 177 It may contain Lu-PSMA I&T at a unit volume radioactivity of 10 to 30, preferably 10 to 25, more preferably 15 to 25, even more preferably 17 to 25, even more preferably 17 to 20, even more preferably 18 to 19 GBq / ml.

[0069] Mother Solution Container The present disclosure relates to a mother solution container that is used in a radiolabeling reaction, preferably for collecting the solution formed after completion of the radiolabeling reaction. The mother solution container contains the mother solution described in the preceding section. The mother solution container also contains a headspace gas volume above the mother solution.

[0070] The present disclosure relates to a mother liquor container for collecting a solution formed in a radiolabeling reaction, said container comprising: (1) A mother solution comprising: A unit volume activity of at least 10 GBq / mL 177 Lu(III) ion, b. a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety; 177 a radionuclide complex formed with Lu(III) ions; c. one or more stabilizers against radiolytic degradation; (2) a headspace gas volume above the mother solution, said headspace gas volume containing 10% or less by volume of oxygen.

[0071] The mother solution container comprises a headspace gas volume above the mother solution, said headspace gas volume containing no more than 10% by volume oxygen, preferably no more than 7% by volume, more preferably no more than 5% by volume, and most preferably no more than 3% by volume. The headspace gas volume is substantially free of oxygen (substantially 0% by volume). The low volume percentage of oxygen in the headspace gas volume reduces radiolytic degradation of the components of the mother solution.

[0072] Because the mother liquor container contains the mother liquor described in the preceding section, all of the features and embodiments described above in the mother liquor container apply equally to the mother liquor container.

[0073] In an embodiment, a diluent solution is added to the mother liquor container, the diluent solution including a stabilizer against radiolytic degradation, a sequestering agent, and optionally an isotonicity agent. In such an embodiment, the mother liquor container further includes: (3) a stabilizer against radiolytic degradation; (4) a sequestering agent; and (5) optionally, an isotonic agent.

[0074] The stabilizer against radiolytic degradation may be selected from among any of the stabilizers described herein above, and may preferably be ascorbic acid or a salt thereof. Ethanol may be present in the reaction solution in the concentrations described above, but is preferably substantially absent in the dilute solution.

[0075] As used herein, "sequestering agent" refers to a chelating agent suitable for complexing with free radionuclide metal ions (not complexed with the radiolabeled peptide) in the formulation. The sequestering agent is preferably di-ethylene-triamine-pentaacetic acid (DTPA, also known as pentetic acid).

[0076] The optional isotonicity agent may be any selected from mono- or di-sodium phosphate, sodium chloride, potassium chloride, calcium chloride or magnesium chloride, etc. or mixtures of such salts, preferably sodium chloride.

[0077] In a preferred embodiment, the mother liquor container further comprises: (3) a stabilizer against radiation-induced degradation, preferably ascorbic acid or a salt thereof; (4) a metal sequestering agent, preferably DTPA; (5) Optionally, an isotonicity agent, preferably NaCl.

[0078] In an embodiment, the mother solution container contains the components necessary to construct a dispensing solution that is suitable for dispensing into multiple patient doses (vials) that are scheduled for subsequent administration to patients without further material modification.

[0079] In such an embodiment, the mother liquor container comprises: (A) A radioactivity in the range of 296 to 444 MBq / mL, preferably 333 to 407 MBq / ml, more preferably about 351 to 389 MBq / ml, and most preferably about 370 MBq / mL (10 mCi / mL) 177 Lu-DOTATATE; (B) acetic acid at a concentration in the range of 0.384 to 0.576 mg / ml, preferably 0.432 to 0.528 mg / ml, more preferably 0.456 to 0.504 mg / mL, and most preferably about 0.48 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.528 to 0.792 mg / ml, preferably 0.594 to 0.726 mg / ml, more preferably 0.627 to 0.693 mg / mL, and most preferably about 0.66 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.504 to 0.756 mg / ml, preferably 0.567 to 0.693 mg / ml, more preferably 0.598 to 0.6615 mg / mL, and most preferably about 0.63 mg / mL with respect to the free acid; (E) ascorbic acid or a salt thereof at a concentration in the range of 2.24 to 3.36 mg / mL, preferably 2.52 to 3.08 mg / mL, more preferably 2.66 to 2.94 mg / mL, and most preferably about 2.8 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration in the range of 0.04 to 0.06 mg / mL, preferably 0.045 to 0.055 mg / mL, more preferably 0.048 to 0.053 mg / mL, and most preferably about 0.050 mg / mL with respect to the free acid; (G) sodium chloride at a concentration in the range of 5.55 to 8.15 mg / mL, preferably 6.16 to 7.54 mg / mL, more preferably 6.51 to 7.19 mg / mL, and most preferably about 6.85 mg / mL; (H) optionally sodium hydroxide at a concentration sufficient to provide, together with components (B) and (C), a pH value in the range of 4.5 to 6.0, preferably sodium hydroxide present in a concentration in the range of 0.52 to 0.78 mg / ml, preferably 0.59 to 0.72, more preferably 0.618 to 0.683 mg / mL, and most preferably 0.65 mg / mL.

[0080] In other such embodiments, the mother liquor container comprises: (A) a radioactivity in the range of 800 to 1200 MBq / ml, preferably 900 to 1100 MBq / ml, more preferably 950 to 1050 MBq / ml, and most preferably about 1000 MBq / mL (27 mCi / mL) 177 with Lu-PSMA-617; (B) acetic acid at a concentration in the range of 0.24 to 0.36 mg / mL, preferably 0.27 to 0.33 mg / mL, more preferably 0.285 to 0.315 mg / mL, and most preferably about 0.3 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.33 to 0.49 mg / mL, preferably 0.37 to 0.45 mg / mL, more preferably 0.39 to 0.43 mg / mL, and most preferably about 0.41 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.3 to 1.0 mg / mL, preferably 0.3 to 0.5 mg / mL, more preferably 0.31 to 0.47 mg / mL, even more preferably 0.35 to 0.43 mg / mL, even more preferably 0.37 to 0.41, and most preferably about 0.39 mg / mL with respect to the free acid; (E) with respect to the sodium salt, ascorbic acid or a salt thereof at a concentration in the range of 20 to 52.5 mg / mL, preferably 47.5 to 52.5 mg / mL, more preferably 48 to 52 mg / mL, and most preferably about 50 mg / mL; (F) pentetic acid or a salt thereof at a concentration of 0.08 to 0.12 mg / mL, preferably 0.09 to 0.11 mg / mL, more preferably 0.095 to 0.105 mg / mL, and most preferably about 0.1 mg / mL with respect to the free acid.

[0081] Process for producing radiopharmaceutical solutions The present disclosure also relates to a process for manufacturing a radiopharmaceutical providing a solution and a container, respectively, exhibiting the characteristics described in the preceding sections.

[0082] The process for producing the radiopharmaceutical solution includes: (1) providing a reaction solution; (2) reacting a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety at subatmospheric pressure, optionally in the presence of an inert gas, with the target-binding organic molecule. 177 and reacting with Lu(III) ions to obtain a radionuclide complex in a single vessel for radiolabeling.

[0083] Step (1) relates to a reaction solution as described above in the reaction solution section, and therefore all features and embodiments described above apply equally to the reaction solutions referred to in this section.

[0084] Step (1) of providing a reaction solution may include mixing the individual components described above. In particular, the stabilizer against radiolytic degradation is a compound having a target-binding organic moiety linked to a chelating moiety. 177Before mixing with Lu(III) ions 177 The individual components may be mixed with Lu(III) ions under ambient atmosphere and pressure.

[0085] Alternatively, step (1) may involve mixing the individual components described herein at less than atmospheric pressure to form a reaction solution. Less than atmospheric pressure includes a pressure range that is suitable for removing gaseous components from the vessel and up to removing gaseous components from the solution, but pressures that result in significant evaporation of the solvent (water) should be avoided. The pressure may be at least 150 mbar, 200 mbar, 250 mbar, or 300 mbar below atmospheric pressure, and up to 400 mbar, 500 mbar, 650 mbar, or 700 mbar below atmospheric pressure. The pressure may be at least about 250 mbar below atmospheric pressure, and up to 500 mbar below atmospheric pressure.

[0086] Step (1) may involve degassing solutions of the individual components described herein by bubbling an inert gas through the solution or by purging the headspace above the individual solutions with an inert gas and then mixing the individual solutions under an inert gas atmosphere.

[0087] Step (1) may include degassing solutions of the individual components described herein by bubbling an inert gas through the solution or by purging the headspace above the individual solutions with an inert gas and then mixing the individual solutions at less than atmospheric pressure to form the reaction solution. Less than atmospheric pressure includes the pressures described above.

[0088] Mixing at subatmospheric pressure and / or degassing reduces the oxygen concentration in the reaction solution, thereby reducing radiolytic degradation.

[0089] Step (1) may include providing the reaction solution in a container, which is preferably one single container. Providing the reaction solution in the container may include applying subatmospheric pressure as described above, prior to the step of mixing the individual components in the single container.

[0090] In step (1), the reaction solution may have a radioactivity concentration of at least 5 Ci, preferably 5 to 20 Ci, more preferably 5 to 15 Ci, even more preferably 5 to 12, even more preferably about 5.4 to 12 Ci, even more preferably 7 to 12, even more preferably about 8 to 12 Ci.

[0091] In step (2), the target-binding organic molecule and 177 Lu(III) ions are reacted with each other at subatmospheric pressure to form a target-binding organic molecule and 177 A radionuclide complex composed of Lu(III) ions is obtained. Subatmospheric pressure involves applying pressure as described above in step (1). By carrying out the reaction at subatmospheric pressure, radiolytic degradation is reduced. Step (2) involves carrying out the reaction in one single vessel.

[0092] In step (2), the single container for radiolabeling contains an oxygen concentration of 7 mg / L or 6 mg / L, or less than 5 mg / L, preferably less than 4 mg / L, more preferably less than 3 mg / L, more preferably less than 2 mg / L or 1 mg / L (all values ​​at 25 degrees Celsius). Oxygen may be substantially absent in the single container. The low oxygen concentration in the single container reduces radiolytic degradation. Due to the low oxygen concentration, 177The Lu(III) ions may be contained in a single container with a unit volume radioactivity of at least 17 GBq / ml, or at least 18 GBq / ml, preferably at least 19 GBq / ml and more preferably at least 20 GBq / ml, even more preferably at least 25 GBq / mL, even more preferably at least 30 GBq / mL. The upper limit for the aforementioned minimum value may be 20, 25, 30, 40, 50 GBq / mL.

[0093] In step (2), as described above, the target-binding organic molecule is 177 The Lu(III) ions are reacted in molar excess to ensure high radiochemical labeling yields. In certain preferred embodiments, the process includes a free (non-chelated) ion, such as a tC18 solid phase extraction (SPE) purification step. 177 Does not include any purification step to remove Lu(III) ions. Free (unchelated) 177 The use of tC18 cartridges to perform a solid phase extraction (SPE) purification step to remove Lu(III) ions presents several drawbacks. In particular, the use of this cartridge is not preferred as it may require elution of the product with ethanol (A. Mathur et al., Cancer Biother. Radiopharm. 2017, 32, 266-273). The use of tC18 cartridges may remove stabilizers, which then need to be added again (S. Maus et al., Int. J. Diagnostic imaging, 2014, 1, 5-12).

[0094] The process may include step (3) of recovering the radionuclide complexes formed in step (2) to obtain a mother solution. Step (3) relates to a mother solution as described above in the mother solution section, whereby all features and embodiments described above apply equally to the extent they are applicable to the mother solution referred to in this section.

[0095] Step (3) may include recovering the radionuclide complex at less than atmospheric pressure, the pressure range being as provided above. Step (3) may include recovering the radionuclide complex under an inert gas atmosphere. Preferably, in step (3), recovering the radionuclide complex may be accomplished under an inert gas atmosphere. The inert gas atmosphere may be provided by nitrogen or argon.

[0096] Step (3) of recovering the radionuclide complexes may include introducing or transferring the mother liquor into a single vessel to provide a mother liquor vessel. Step (3) relates to a mother liquor vessel as described above in the Mother Liquor Container section, and therefore all of the features and embodiments described above apply equally to the extent they are applicable to the mother liquor vessel referred to in this section.

[0097] The step (3) of recovering the radionuclide complexes may include purging the mother liquor container with an inert gas prior to and during the introduction or transfer of the mother liquor into the mother liquor container.

[0098] The step (3) of recovering the radionuclide complexes may comprise purging the mother solution with an inert gas at a pressure of at least 250 mbar above atmospheric pressure prior to and during the introduction or transfer of the mother solution to the mother solution container. The pressure may be at least 300 mbar, at least 350 mbar or 400 mbar above atmospheric pressure and up to 450 mbar or 500 mbar above atmospheric pressure.

[0099] Radiolytic degradation of components contained in the mother liquor container is reduced by purging the mother liquor container with an inert gas prior to and during introduction or transfer of the mother liquor into the mother liquor container.

[0100] Transfer from the single vessel in step (2) to the mother liquor vessel in step (3) can be effected by greater than atmospheric pressure or by use of a syringe.

[0101] In step (3), recovering the radionuclide complex may include using water for injection (WFI) for rinsing, i.e., WFI is added to the single vessel of step (2) after completion of the reaction, and the solution formed in the single vessel is introduced or transferred to a mother liquor vessel as described above, thereby ensuring complete (or near complete) transfer of the solution containing the radionuclide complex while maintaining a relatively high unit volume activity.

[0102] In step (3), the mother solution contains a nitrogen concentration of up to 20 ml / L at 25 degrees Celsius or an argon concentration of up to 60 ml / L at 25 degrees Celsius due to purging with nitrogen and argon, respectively. The mother solution may contain a nitrogen concentration in the range of 3-20 ml / L at 25 degrees Celsius, preferably 5-15 ml / L, more preferably 10-15 ml / L at 25 degrees Celsius. The mother solution may contain an argon concentration of 3-60 ml / L at 25 degrees Celsius, preferably 10-50 ml / L, more preferably 20-40 ml / L at 25 degrees Celsius.

[0103] In step (3), the mother solution contains a nitrogen concentration of up to 20 mg / L at 25 degrees Celsius or an argon concentration of up to 60 mg / L at 25 degrees Celsius due to purging with nitrogen and argon, respectively. The mother solution may contain a nitrogen concentration in the range of 3-20 mg / L at 25 degrees Celsius, preferably 5-15 mg / L, more preferably 10-15 mg / L at 25 degrees Celsius. The mother solution may contain an argon concentration of 3-60 mg / L at 25 degrees Celsius, preferably 10-50 mg / L, more preferably 20-40 mg / L at 25 degrees Celsius.

[0104] In step (2), the target-binding organic molecule is reacted at less than atmospheric pressure to obtain a radionuclide complex. 177 The reacting with Lu(III) ions may be carried out over a period of 2 to 15 minutes, preferably 4 to 10 minutes, more preferably 5 minutes ± 0.5 minutes.

[0105] In step (2), the target-binding organic molecule is reacted at less than atmospheric pressure to obtain a radionuclide complex. 177The reacting with Lu(III) ions may be carried out at 80-100 degrees Celsius, preferably 90-98 degrees Celsius, more preferably 94° C.±4° C. Generally, temperatures below 90 degrees Celsius do not ensure quantitative labeling yields.

[0106] The mixture volume in step (2) of reacting the target-binding organic molecule with 177Lu(III) ions at subatmospheric pressure to obtain the radionuclide complex may be 15-19 ml.

[0107] The final volume containing the radionuclide complex after recovering step (3) may be 20-23 ml.

[0108] The disclosed process comprising steps (1), (2) and (3) offers the technical advantage of obtaining a mother solution containing radionuclide complexes at a unit volume activity not previously achieved by prior art methods, while keeping radiolytic degradation to a minimum. The present process facilitates the capture of higher total radioactivity from radionuclide complexes in the same volume of mother solution, for example, as compared to the applicant's published methods. As a result, after formation of the dispensed solution in step (5), a significantly higher number of individual patient doses (for immediate use) are provided by the present process as compared to the prior art. Thus, the process disclosed herein provides a higher number of patient doses per given unit time than the prior art methods. This therefore contributes to meeting the growing global need for radiochemicals used in radiotherapy and radiodiagnosis.

[0109] The processes described herein using DOTATOC or DOTATATE as the target-binding organic molecule facilitate the production of radionuclide complexes with total radioactivity greater than 185 GBq (5 Ci) in a volume of 20-23 ml of mother solution. For example, an embodiment of the process carried out with a radioactivity of 296 GBq (8 Ci) in the same volume: 177 Provides approximately 59-74 patient doses (immediate use) of Lu-DOTATOC or 177Lu-DOTATATE, 177It is believed that a single patient dose (immediate use) of Lu-DOTATOC or 177Lu-DOTATATE typically contains 4-5 GBq (e.g., about 4.7 GBq) of total activity. In contrast, prior art processes that only allow the processing of 148 GBq (4 Ci) of total activity in the same volume would only provide approximately 29-37 patient doses (immediate use).

[0110] As a specific example, for the treatment of somatostatin receptor positive pancreatic and gastrointestinal neuroendocrine tumors, 177 A therapeutic dose of Lu-DOTA-TATE typically contains 7,400 MBq total activity at the time of infusion in a final adjusted volume of 20.5 mL to 25.0 mL. The process disclosed herein when processing 296 GBq (8 Ci) total activity in the mother solution would result in 40 patient doses (immediate use), whereas a prior art process allowing processing of only 148 GBq (4 Ci) total activity in the same volume would provide only 20 patient doses (immediate use).

[0111] As noted above, the process disclosed herein keeps radiolytic degradation to a minimum, thereby meeting radiochemical purity (RCP) requirements, and provides high yields of radiolabeling.

[0112] In an embodiment, the process comprises: (4) diluting the mother solution of step (3) with a diluent to obtain an aliquot solution with a determined unit volume activity; (5) dispensing the aliquots of solution into individual patient dose units.

[0113] The dilute solution is (3) a stabilizer against radiation-induced degradation, preferably ascorbic acid or a salt thereof; (4) a sequestering agent, preferably DTPA; (5) Optionally, an isotonicity agent, preferably NaCl, may be included.

[0114] The characteristics of the stabilizer, sequestering agent and isotonicity agent are as described above in the mother solution container section.

[0115] Steps (4) and (5) provide, without further material modification, an individual patient dose that is then destined to be administered to a patient, the individual patient dose containing the unit volumetric activity required for therapeutic or diagnostic purposes.

[0116] The determined unit volume activity of the dispensed solutions can be adjusted to provide individual patient dose units with a unit volume activity of 1000MBq / mL ± 5% for 177Lu-PSMA-617 and 370MBq / mL ± 5% for 177Lu-DOTA-TATE.

[0117] The process of the present disclosure comprises: 177 Lu-DOTA-TATE( 177 For the synthesis of Lu-oxodotreotide, in particular 177 It can be advantageously used for the production of mother solutions that are used to produce individual patient doses (for immediate use) of Lu-DOTA-TATE.

[0118] In a specific embodiment of the process, the dispensing solution obtained in step (4) above is (A) 177Lu-DOTA-TATE with a radioactivity in the range of 296 to 444 MBq / mL, preferably 333 to 407 MBq / ml, more preferably about 351 to 389 MBq / ml, and most preferably about 370 MBq / mL (10 mCi / mL); (B) acetic acid at a concentration in the range of 0.384 to 0.576 mg / ml, preferably 0.432 to 0.528 mg / ml, more preferably 0.456 to 0.504 mg / mL, and most preferably about 0.48 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.528 to 0.792 mg / ml, preferably 0.594 to 0.726 mg / ml, more preferably 0.627 to 0.693 mg / mL, and most preferably about 0.66 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.504 to 0.756 mg / ml, preferably 0.567 to 0.693 mg / ml, more preferably 0.598 to 0.6615 mg / mL, and most preferably about 0.63 mg / mL with respect to the free acid; (E) ascorbic acid or a salt thereof at a concentration in the range of 2.24 to 3.36 mg / mL, preferably 2.52 to 3.08 mg / mL, more preferably 2.66 to 2.94 mg / mL, and most preferably about 2.8 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration in the range of 0.04 to 0.06 mg / mL, preferably 0.045 to 0.055 mg / mL, more preferably 0.048 to 0.053 mg / mL, and most preferably about 0.050 mg / mL with respect to the free acid; (G) sodium chloride at a concentration in the range of 5.55 to 8.15 mg / mL, preferably 6.16 to 7.54 mg / mL, more preferably 6.51 to 7.19 mg / mL, and most preferably about 6.85 mg / mL; (H) optionally sodium hydroxide at a concentration sufficient to provide, together with components (B) and (C), a pH value in the range of 4.5 to 6.0, preferably sodium hydroxide present in a concentration in the range of 0.52 to 0.78 mg / ml, preferably 0.59 to 0.72, more preferably 0.618 to 0.683 mg / mL, and most preferably 0.65 mg / mL.

[0119] The process of the present disclosure comprises: 177 For the synthesis of Lu-PSMA-617, specifically 177 It can be advantageously used for the production of mother solutions that are used to produce individual patient doses (for immediate use) of Lu-PSMA-617.

[0120] In another specific embodiment of the process, the dispensing solution obtained in step (4) above is (A) Radioactivity in the range of 800 to 1200 MBq / ml, preferably 900 to 1100 MBq / ml, more preferably 950 to 1050 MBq / ml, and most preferably about 1000 MBq / mL (27 mCi / mL) 177with Lu-PSMA-617; (B) acetic acid at a concentration in the range of 0.24 to 0.36 mg / mL, preferably 0.27 to 0.33 mg / mL, more preferably 0.285 to 0.315 mg / mL, and most preferably about 0.3 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.33 to 0.49 mg / mL, preferably 0.37 to 0.45 mg / mL, more preferably 0.39 to 0.43 mg / mL, and most preferably about 0.41 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.3 to 1.0 mg / mL, preferably 0.3 to 0.5 mg / mL, more preferably 0.31 to 0.47 mg / mL, even more preferably 0.35 to 0.43 mg / mL, even more preferably 0.37 to 0.41, and most preferably about 0.39 mg / mL with respect to the free acid; (E) ascorbic acid or a salt thereof at a concentration in the range of 20 to 52.5 mg / mL, preferably 47.5 to 52.5 mg / mL, even more preferably 48 to 52 mg / mL, and most preferably about 50 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration of 0.08 to 0.12 mg / mL, preferably 0.09 to 0.11 mg / mL, more preferably 0.095 to 0.105 mg / mL, and most preferably about 0.1 mg / mL with respect to the free acid.

[0121] Process step implementation The above-mentioned process can be implemented in a closed device with a central pipe section, to which an inlet for an inert gas and an adapter for applying a vacuum to the pipe can be connected. Also connected to the central pipe section are containers containing the above-mentioned reactants and water for injection. Furthermore, containers suitable for receiving the reaction solution and the mother solution are provided and connected to the central pipe section. All connections to the central pipe section are equipped with valves, which allow a directed transfer of the solutions to and from the containers, brought about by application of a vacuum or an inert gas pressure, depending on the particular step. Alternatively, the transfer may be brought about by the use of a syringe, which can be connected to the container and the central pipe section via an adapter. All parts of the device are made of materials compatible with the reagents used in the process.

[0122] The above-described process may be advantageously automated and implemented in a synthesis module utilizing disposable kit cassettes.

[0123] For example, a disposable kit cassette is installed in front of the synthesis module containing the fluid paths (tubing), reactor vials, and sealed reagent vials. The disposable cassette components are made from materials specifically selected to be compatible with the reagents used in the process. In particular, the components are designed to minimize the possibility of surface leakage in contact with the process fluids while maintaining the mechanical performance and integrity of the cassette.

[0124] Preferably, the process is fully automated and carried out within a computer-assisted system.

[0125] A typical kit cassette is: (1) a reaction vial (reactor); (2) connections for inlet and outlet fluids; (3) a spike for connecting a reagent vial; (4) Optionally, a solid phase cartridge.

[0126] One skilled in the art may adapt commercially available kit cassettes used for the preparation of radiopharmaceuticals, such as fluorine-18 labeled radiopharmaceuticals.

[0127] In specific embodiments, the synthesis module (and kit cassette) comprises: (i) at a first position, 177 a needle positioned for insertion at the top of a first vial containing the Lu(III) solution; (ii) at a second position, a needle positioned for insertion at the top of a vial containing a solution comprising a target-binding organic molecule linked to a chelator; (iii) a bag containing water for injection, positioned for the rinsing step, at a third position; (iv) a solution including one or more stabilizers for combating radiolytic degradation disposed at a fourth location; and (v) At another location, a needle may be positioned to insert into the top or tubing of an additional vial (eg, mother solution container) that is installed for transfer from the synthesis module to the dispense isolator.

[0128] Specific examples of synthesis modules and kit cassettes are described in the Examples.

[0129] The product obtained by the manufacturing process The present disclosure also relates to products obtained by the process of manufacture as described above.

[0130] In a specific embodiment, the dispensing solution comprises: (A) 177Lu-DOTA-TATE with a radioactivity in the range of 296 to 444 MBq / mL, preferably 333 to 407 MBq / ml, more preferably about 351 to 389 MBq / ml, and most preferably about 370 MBq / mL (10 mCi / mL); (B) acetic acid at a concentration in the range of 0.384 to 0.576 mg / ml, preferably 0.432 to 0.528 mg / ml, more preferably 0.456 to 0.504 mg / mL, and most preferably about 0.48 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.528 to 0.792 mg / ml, preferably 0.594 to 0.726 mg / ml, more preferably 0.627 to 0.693 mg / mL, and most preferably about 0.66 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.504 to 0.756 mg / ml, preferably 0.567 to 0.693 mg / ml, more preferably 0.598 to 0.6615 mg / mL, and most preferably about 0.63 mg / mL with respect to the free acid; (E) ascorbic acid or a salt thereof, preferably the sodium salt thereof, at a concentration in the range of 2.24 to 3.36 mg / mL, preferably 2.52 to 3.08 mg / mL, more preferably 2.66 to 2.94 mg / mL, and most preferably about 2.8 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration in the range of 0.04 to 0.06 mg / mL, preferably 0.045 to 0.055 mg / mL, more preferably 0.048 to 0.053 mg / mL, and most preferably about 0.050 mg / mL with respect to the free acid; (G) sodium chloride at a concentration in the range of 5.55 to 8.15 mg / mL, preferably 6.16 to 7.54 mg / mL, more preferably 6.51 to 7.19 mg / mL, and most preferably about 6.85 mg / mL; and (H) optionally sodium hydroxide, in combination with components (B) and (C), at a concentration sufficient to provide a pH value in the range of 4.5 to 6.0, preferably sodium hydroxide present at a concentration in the range of 0.52 to 0.78 mg / ml, preferably 0.59 to 0.72, more preferably 0.618 to 0.683 mg / mL, and most preferably 0.65 mg / mL.

[0131] In another specific embodiment, the dispensing solution comprises: (A) Radioactivity in the range of 800 to 1200 MBq / ml, preferably 900 to 1100 MBq / ml, more preferably 950 to 1050 MBq / ml, and most preferably about 1000 MBq / mL (27 mCi / mL) 177 with Lu-PSMA-617; (B) acetic acid at a concentration in the range of 0.24 to 0.36 mg / mL, preferably 0.27 to 0.33 mg / mL, more preferably 0.285 to 0.315 mg / mL, and most preferably about 0.3 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.33 to 0.49 mg / mL, preferably 0.37 to 0.45 mg / mL, more preferably 0.39 to 0.43 mg / mL, and most preferably about 0.41 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.3 to 1.0, preferably 0.3 to 0.5 mg / mL, more preferably 0.31 to 0.47 mg / mL, even more preferably 0.35 to 0.43 mg / mL, even more preferably 0.37 to 0.41, and most preferably about 0.39 mg / mL with respect to the free acid; (E) ascorbic acid or a salt thereof, preferably a sodium salt thereof, at a concentration in the range of 20 to 52.5 mg / mL, preferably 47.5 to 52.5 mg / mL, more preferably 48 to 52 mg / mL, and most preferably about 50 mg / mL with respect to the sodium salt; (F) With respect to the free acid, the product is obtained when it contains pentetic acid or a salt thereof at a concentration in the range of 0.08 to 0.12 mg / mL, preferably 0.09 to 0.11 mg / mL, more preferably 0.095 to 0.105 mg / mL, and most preferably about 0.1 mg / mL.

[0132] Aqueous Pharmaceutical Solutions The present disclosure also relates to aqueous pharmaceutical solutions. In specific embodiments, the present disclosure provides an aqueous solution of: (A) Radioactivity in the range of 800 to 1200 MBq / ml, preferably 900 to 1100 MBq / ml, more preferably 950 to 1050 MBq / ml, and most preferably about 1000 MBq / mL (27 mCi / mL) 177 Lu-PSMA-617; (B+C) Buffers to provide a pH value of the solution in the range of 4.5-7.0; (D) gentisic acid or a salt thereof at a concentration in the range of 0.3 to 1.0, preferably 0.3 to 0.5, more preferably 0.31 to 0.47 mg / mL, even more preferably 0.35 to 0.43 mg / mL, even more preferably 0.37 to 0.41, and most preferably about 0.39 mg / mL with respect to the free acid; (E) ascorbic acid or a salt thereof with respect to the sodium salt, at a concentration in the range of 20 to 52.5 mg / mL, preferably 47.5 to 52.5 mg / mL, even more preferably 48 to 52 mg / mL, and most preferably about 50 mg / mL; (F) Pentetic acid or a salt thereof, with respect to the free acid, at a concentration in the range of 0.08 to 0.12 mg / mL, preferably 0.09 to 0.11 mg / mL, more preferably 0.095 to 0.105 mg / mL, and most preferably about 0.1 mg / mL.

[0133] In another specific embodiment, the present disclosure provides an aqueous solution of: (A) Radioactivity in the range of 800 to 1200 MBq / ml, preferably 900 to 1100 MBq / ml, more preferably 950 to 1050 MBq / ml, and most preferably about 1000 MBq / mL (27 mCi / mL) 177 Lu-PSMA-617; (B) acetic acid at a concentration in the range of 0.24 to 0.36 mg / mL, preferably 0.27 to 0.33 mg / mL, more preferably 0.285 to 0.315 mg / mL, and most preferably about 0.3 mg / mL; (C) acetate, preferably the sodium salt thereof, at a concentration in the range of 0.33 to 0.49 mg / mL, preferably 0.37 to 0.45 mg / mL, more preferably 0.39 to 0.43 mg / mL, and most preferably about 0.41 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.3 to 1.0, preferably 0.3 to 0.5, more preferably 0.31 to 0.47 mg / mL, even more preferably 0.35 to 0.43 mg / mL, even more preferably 0.37 to 0.41, and most preferably about 0.39 mg / mL with respect to the free acid; (E) ascorbic acid or a salt thereof, preferably the hydrochloride salt thereof, with respect to the sodium salt, at a concentration in the range of 20 to 52.5 mg / mL, preferably 47.5 to 52.5 mg / mL, more preferably 48 to 52 mg / mL, and most preferably about 50 mg / mL; (F) Pentetic acid or a salt thereof, with respect to the free acid, at a concentration in the range of 0.08 to 0.12 mg / mL, preferably 0.09 to 0.11 mg / mL, more preferably 0.095 to 0.105 mg / mL, and most preferably about 0.1 mg / mL.

[0134] In certain embodiments, the aqueous solution is about 177 The composition comprises, contains, or consists of Lu-PSMA-617 (about 1,000 MBq / mL, about 27 mCi / mL), acetic acid (about 0.30 mg / mL), sodium acetate (about 0.41 mg / mL), gentisic acid (about 0.39 mg / mL), sodium ascorbate (about 50.0 mg / mL), pentetic acid (about 0.10 mg / mL), and water for injection (e.g., qs to 1 mL), with a pH range of the solution from about 4.5 to about 7.0. The term "about" is used herein to mean ±10% for all components, preferably ±10% for radioactive components, and ±5% for non-radioactive components.

[0135] In more specific embodiments, the present disclosure provides any one of the aqueous solutions of the above embodiments, wherein the radiochemical purity (RCP, as determined by HPLC) is maintained at ≧95% for at least 120 hours when stored at or below 30° C. Thus, the shelf life of the aqueous solution of the present disclosure is preferably about 120 hours or about 5 days from the date and time of calibration, under non-frozen storage conditions below 30° C. (86° F.).

[0136] In more specific embodiments, the present disclosure provides any one of the aqueous solutions of the above embodiments, wherein said solution contains no more than 5% (w / w) ethanol, preferably no more than 1% ethanol, and more preferably is substantially free of any ethanol.

[0137] In a more specific embodiment, the present disclosure provides any one of the aqueous solutions of the above embodiments, wherein said solution comprises a total peptide content of 10-20 micrograms / mL, preferably 13-17 micrograms / mL, more preferably 14-16 micrograms / mL, and most preferably 15 micrograms / mL.

[0138] In certain embodiments, the aqueous solutions of the present invention are provided as sterile, preservative-free, clear, colorless to slightly yellow solutions, hi certain embodiments, the aqueous solutions are provided as ready-to-use solutions.

[0139] The present disclosure further provides individual patient dose units comprising a content of about 7.5 to about 12.5 mL of any one of the aqueous solutions as described in any one of the above embodiments.

[0140] The patient dose unit may be in the form of a vial, e.g., a single-dose vial, e.g., a colorless borosilicate (type I) glass vial, e.g., of about 30 mL size, closed with a bromobutyl rubber stopper (e.g., a stopper with a silicate filler and an inorganic coloring system) and a seal, preferably an aluminum seal, or in the form of a pre-filled syringe or cartridge, e.g., a cartridge that can be loaded into a device for infusion / injection, e.g., a cartridge for a syringe or infusion system. The dose unit may be provided as a lead-shielded container, preferably arranged in a plastic sealed container. The dose unit may be shipped in a Type A packaging system (complying with the corresponding provisions of the International Air Transport Association (IATA) and the International Carriage of Dangerous Goods by Road (ADR)). Type A packaging is designed to meet radiation protection requirements.

[0141] The aqueous solutions of the present disclosure may be first dispensed into vials and then transferred to syringes.

[0142] The aqueous solution of the present disclosure may be injected intravenously (by IV, bolus injection or infusion), or intraarterially, or intratumorally. The aqueous solution of the present disclosure may be administered to a patient by slow intravenous administration (using either a syringe pump or infusion pump, or manually) within approximately 1-10 minutes, for example, via an intravenous catheter prefilled with, for example, 0.9% sterile sodium chloride solution.

[0143] Aqueous solutions of the present disclosure may be administered at a dosage / dose of about 7.4(±10%) GBq (200(±10%) mCi) about every 6 weeks for up to about 6 doses. For example, with respect to management of adverse reactions, administration may be temporarily interrupted (e.g., extending the dosing interval from about every 6 weeks to about every 7, 8, 9, or 10 weeks) or the dosage may be reduced, e.g., by about 20% to about 5.9(±10%) GBq (160(±10%) mCi).

[0144] When referring to a radioactivity-related value, for example a radioactivity of 7.4 GBq (200 mCi), it is preferably the radioactivity at the time of administration that is meant.

[0145] Lutetium-177 for embodiments of the present disclosure may be prepared using two different sources of stable isotopes, either lutetium-176 or ytterbium-176. Lutetium-177 prepared using the stable isotope lutetium-176, also referred to as "carrier-added" (ca, CA), produces a small amount of a long-lived metastable state of lutetium-177 ( 177m Lu). Lutetium-177 prepared using ytterbium-176 is also referred to as "no carrier added" (nca, NCA). In the embodiments of the present disclosure, both the CA and NCA versions of lutetium-177 may be used without qualitatively or quantitatively modifying the other components. Preferably, nca 177 Lu is used. EXAMPLES

[0146] Example 1: 177 Preparation of sterile concentrated aqueous solutions of Lu-DOTA-TATE 1.1 Introduction Radiopharmaceutical substances 177 Lu-DOTA-TATE (hereinafter, 177 Lu-DOTA0-Tyr 3 -octreotate) was prepared as a sterile, concentrated aqueous solution (the so-called mother solution).

[0147] The drug substance synthesis process is automated and remotely controlled by GMP compliant software and is carried out in a self-contained, closed system synthesis module with automatic monitoring and recording of process parameters.

[0148] During each production run of the synthesis module, a single-use disposable kit cassette containing the fluid paths (tubing), reactor vials and sealed reagent vials is used. The synthesis module is protected from manual intervention during production runs. The synthesis module is placed in a lead-shielded hot cell that provides a supply of filtered air.

[0149] Drug Substances ( 177 Lu-DOTA0-Tyr 3 -Octreotate) synthesis and pharmaceuticals ( 177 Lu-DOTA0-Tyr 3 -Octreotate 370 MBq / mL infusion solution) is part of an automated continuous process that does not allow isolation and testing of the drug substance due to its radioactive decay.

[0150] The synthesis of the drug substance is carried out using the MiniAio (Trasis) kit cassette. For the assembly of the kit (under grade C) follow Figure 1. The flow chart below shows the chemical process for the manufacture of the drug substance in 4 Ci and 8 Ci batch sizes in a grade C hot cell.

[0151] [Table 1]

[0152] Labeling (step 7) 177 Lu's DOTA-Tyr 3 -octreotate peptide. This labeling is carried out at 94°C ± 4°C.

[0153] In the reaction mixture, DOTA0-Tyr 3 -Octreotate is 177 It is present in molar excess relative to Lu to ensure acceptable radiochemical labeling yields. 177 Lu-DOTA0-Tyr 3 The chemical reaction to produce -octreotate is illustrated below. [ka]

[0154] The drug product compounding, sterile filtration and dispensing processes are carried out in a Grade A dispensing isolator. The following flow chart details the steps for manufacturing the drug product.

[0155] [Table 2]

[0156] Preparation of starting materials The chemical precursors, radioactive precursors and intermediates of the drug substances used in the manufacturing process are prepared according to Table 1 below.

[0157] [Table 3]

[0158] Details of the reaction buffer lyophilisate are provided in Table 2 below.

[0159] [Table 4]

[0160] Preparation of synthesis modules and kit cassettes The manufacturing process was validated using two different Lu-177 chloride batch sizes, 74.0 GBq ± 20% (2 Ci ± 20%) or 148.0 GBq ± 20% (4 Ci ± 20%).

[0161] The synthesis is carried out using a single-use disposable kit cassette mounted at the front of the synthesis module containing the fluid paths (tubing), reactor vials and sealed reagent vials.

[0162] Kit Cassette for MiniAIO Synthesis Module The kit cassette is ready for immediate use.

[0163] Step 1c: Reaction buffer - Reconstitution of lyophilisate Prior to its use in drug substance synthesis, the Reaction Buffer Lyophilisate (RBL) is reconstituted by the drug substance manufacturing site by dissolving it with Water for Injection (WFI) to obtain the Reaction Buffer Solution.

[0164] The reconstitution occurs immediately prior to the start of the synthesis.

[0165] To dissolve the RBL: For 74 GBq batch size (2 Ci batch size): Reconstitute 1 vial of RBL with 2 mL of WFI using a sterile disposable syringe. For 148 GBq batch size (4 Ci batch size): Reconstitute two vials of RBL with 2 mL of WFI per vial using a sterile disposable syringe. Transfer the contents of one solubilized Reaction Buffer vial to the other vial using a sterile disposable syringe and mix to obtain one vial containing 4 mL of product.

[0166] The composition of the reaction buffer after reconstitution is as described in Table 4.

[0167] [Table 5]

[0168] 1.2 Process 1d:DOTA-Tyr 3 -Dissolution of octreotate (chemical precursor) DOTA-Tyr 3 -Octreotate is provided as a dry powder in vials. Each vial contains 2 mg of DOTA-Tyr 3 -octreotate. Before the synthesis reaction, 3 -Octreotate is dissolved in Water for Injection (WFI).

[0169] DOTA-Tyr 3 -To dissolve octreotate: - For 74GBq batch size (2Ci batch size): DOTA-Tyr 3 -Reconstitute one vial of Octreotate with 2 mL of WFI using a sterile disposable syringe. - For 148GBq batch size (4Ci batch size): DOTA-Tyr 3 -Reconstitute two vials of octreotate with 2 mL of WFI per vial. 3 - The contents of the octreotate vial are transferred to the other vial using a sterile disposable syringe and mixed to obtain one vial containing 4 mL of product.

[0170] Step 5: Placement of starting materials into the kit cassette The reaction buffer solutions, WFI and precursors are placed in the corresponding cassette positions according to the synthesis module to be used. The placement is carried out in a grade C environment.

[0171] Step 6: Lu-177 chloride solution, reaction buffer solution and DOTA-Tyr 3 -Transfer of octreotate solution to reactor The synthesis is started by pressing the "Start Synthesis" button of the synthesis module's PC control software program. The first step of the synthesis consists of the automated transfer of all components required for labeling into a cassette reactor.

[0172] The radioactive and chemical drug substance precursors and reaction buffer solutions are transferred into the reactor in the following order: 1. Lu-177 chloride solution 2. Reaction buffer solution 3.DOTA-Tyr 3 -Octreotate solution

[0173] When valves (positions 5 and 6 on the GE cassette or positions 1 and 2 on the MiniAIO cassette) are opened and negative pressure is applied to the reactor, Lu-177 chloride solution is drawn into the reactor.

[0174] The Lu-177 chloride solution is highly concentrated, and therefore incomplete transfer of the solution to the reactor can affect the labeling yield. For this reason, to ensure complete transfer of the Lu-177 chloride solution, a reaction buffer solution is added to the Lu-177 chloride solution prior to its transfer to the reactor. The reaction buffer is added using a syringe (exactly a 30 mL syringe for the TRACERlab MX synthesis module). 1 Using a 30 mL syringe for the MiniAIO synthesis module and a 30 mL syringe for the MiniAIO synthesis module, the solution (reaction buffer + Lu-177 residue) is transferred into the Lu-177 chloride vial. From this vial, the solution (reaction buffer + Lu-177 residue) is transferred into the reactor by applying negative pressure.

[0175] The final step to initiate the synthesis of the drug substance is the synthesis of DOTA-Tyr. 3 - Transfer of the octreotate solution to the reactor. This is done automatically by negative pressure applied to the reactor.

[0176] 1.10 Step 7: Labeling step The synthetic route is summarized as follows: [ka] DHB = gentisic acid (2,5-benzoic acid) [ka] is used.

[0177] Labeling was performed using DOTA-Tyr with Lu-177. 3 -Octreotate peptide to the DOTA moiety. Labeling was performed at 94°C (± 4°C): - Performed for 5 minutes (± 0.5 minutes) using the MiniAIO (TRASIS) synthesis module.

[0178] In the reactor, DOTA-Tyr 3 -octreotate is present in molar excess relative to Lu-177 to ensure acceptable radiochemical labeling yields (see also Example 2 for process optimization).

[0179] 1.11 Step 8: Drug Substance Transfer and First Filtration (Prefiltration) When the synthesis is completed in the synthesis module, the obtained 177 Lu-DOTA 0 -Tyr 3 -The octreotate mother solution is first sterilized using a sterile filter connected to an extension sterilization cable. During filtration, 177 Lu-DOTA 0 -Tyr 3 -Octreotate mother solution is automatically transferred by nitrogen positive pressure from the synthesis hot cell (grade C) by an extended sterile cable to the dispensing isolator grade A and collected in an intermediate 30 mL sterile vial. Equilibrate the pressure in the intermediate 30 mL sterile vial using a vent filter equipped with a microlance needle.

[0180] Rinse the cassette and reactor three times with 3 mL of water for injection each time to remove any remaining water in the lines. 177 Lu-DOTA 0-Tyr3-octreotate is recovered.

[0181] At the end of the transport process 177 Lu-DOTA 0 The volumes of the -Tyr3-octreotate mother solutions are as follows: For 74GBq batch size (2Ci batch size): ≥ 13.0mL For 148GBq batch size (4Ci batch size): ≥ 19.0mL 8Ci batch size: ≥ 19.0mL

[0182] 177 Lu-DOTA 0 The volume and radioactivity of the -Tyr3-octreotate mother solution are controlled and monitored at the end of the synthesis. The synthesis yield is calculated.

[0183] 1.13 Results

[0184] [Table 6]

[0185] The above table shows that experimental testing during Lutathera 8Ci manufacturing process development demonstrated good results when nitrogen was used to thoroughly degas the mother solution vials and reduce radiolysis over the shelf life of the product. Specifically, during the mother solution vial degassing step, air in the vials containing oxygen, which is believed to be at least partially responsible for radiolysis, is replaced with a nitrogen flush as much as possible.

[0186] The difference in values ​​between the Texp 5 ml and Texp 20 ml data is due to the difference in size of the headspace volume, with the Texp 5 ml experiment having a much larger headspace volume.

[0187] The above results clearly demonstrate that thoroughly degassing the mother solution vials, and optionally keeping the vials under an inert gas atmosphere, results in superior radiochemical purity as measured at the end of the product shelf life.

[0188] Example 2: Preparation of 177Lu-PSMA-617 Synthesis of drug substances at 200 GBq or 400 GBq scale is performed using MiniAio (Trasis) kit cassettes. For kit assembly (under grade C) follow Figure 2. The flow chart below shows the chemical process for the manufacture of drug substances in a grade C hot cell.

[0189] [Table 7]

[0190] Labeling (step 7) 177 Labeling proceeds by chelation of Lu to the DOTA moiety of PSMA-617. Labeling is carried out at 94° C.±4° C. for 5±0.5 min.

[0191] In the reaction mixture, DOTA-PSMA is present in molar excess relative to 177Lu to ensure acceptable radiochemical labeling yields. The chemical reaction for producing the drug substance 177Lu-DOTA-PSMA is shown in the following diagram. [ka]

[0192] Drug compounding, sterile filtration and dispensing are carried out in a Grade A dispensing isolator. The flow chart below details the steps for manufacturing of the drug product.

[0193] [Table 8]

[0194] A dilute solution is prepared by dissolving appropriate amounts of sodium ascorbate and pentetic acid (DTPA) in water for injection (WFI).

[0195] The following tables provide additional experimental information for Examples 1 and 2.

[0196] [Table 9]

[0197] Holding time for handling the mother solution: 60 min.

[0198] Typical yield of the process: 92-95%.

[0199] Bulk Pharmaceuticals 177 The theoretical manufacturing recipe for Lu-PSMA-617 is given in the table below. Regardless of the size of the drug product batch, the ratios of acetic acid, sodium acetate, gentisic acid, sodium ascorbate, pentetic acid and water for injection are maintained.

[0200] Manufacturing formulation for 177Lu-PSMA-617 solution for injection / infusion.

[0201] [Table 10]

[0202] Batch sizes can contain from 1 to 40 customer vials depending on the batch size.

[0203] The composition of the injection / infusion solution of the pharmaceutical agent 177Lu-PSMA-617 per mL of solution is given in the table below.

[0204] [Table 11]

[0205] As a result of the natural decay of the radionuclides, the total radioactivity and radioactivity concentration (unit volume radioactivity) of the drug product will change over time. The composition of the drug product per single dose based on the minimum (7.5 mL) and maximum (12.5 mL) fill volumes is given in the table below.

[0206] [Table 12]

Claims

1. 1. A reaction solution for radiolabeling a target-binding organic molecule with Lu(III) ions, said reaction solution comprising: (1) 177Lu(III) ions with a unit volume radioactivity of at least 17 GBq / mL; (2) a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety suitable for chelating Lu(III) ions; (3) one or more stabilizers against radiolytic degradation.

2. 10. The reaction solution of claim 1, comprising an oxygen concentration of less than 3 mg / L at 25 degrees Celsius.

3. 2. The reaction solution of claim 1, wherein the stabilizer against radiolytic degradation comprises gentisic acid or a salt thereof.

4. The reaction solution according to claim 3, wherein the concentration of gentisic acid or a salt thereof is 5 to 15 mg / mL.

5. 5. The reaction solution of claim 4, wherein the concentration of gentisic acid or a salt thereof is 10 to 15 mg / mL when the target-binding organic moiety is a somatostatin receptor-binding peptide.

6. 5. The reaction solution of claim 4, wherein the concentration of gentisic acid or a salt thereof is 5 to 10 mg / ml when the target-binding organic moiety is a PSMA-binding peptide.

7. 2. The reaction solution of claim 1, wherein the reaction solution contains ascorbic acid or a salt thereof at 5% (w / w) or less, preferably 2% or less, even more preferably 1% or less, and even more preferably contains no ascorbic acid (substantially 0%).

8. 2. The reaction solution of claim 1, wherein the reaction solution comprises ethanol at 5% (w / w) or less, preferably 2% or less, even more preferably 1% or less, and even more preferably no ethanol (substantially 0%).

9. 2. The reaction solution of claim 1, wherein the target-binding organic moiety is a somatostatin receptor-binding peptide.

10. 10. The reaction solution of claim 9, wherein the somatostatin receptor-binding peptide linked to a chelating moiety comprises DOTA.

11. 2. The reaction solution of claim 1, wherein the target-binding organic moiety is a PSMA-binding peptide.

12. 12. The reaction solution of claim 11, wherein the PSMA receptor-binding peptide linked to a chelating moiety comprises DOTA.

13. 2. The reaction solution of claim 1, wherein the target-binding organic molecule is in molar excess relative to the 177Lu(III) ion.

14. 2. The reaction solution of claim 1, wherein the target-binding organic molecule is in molar excess over the group of all Lu(III) ions, including Lu(III) ions, Lu(III) ions, Lu(III), and metastable Lu(III) ions, that are present when carrier-added Lu(III) is used as the source of Lu(III).

15. 14. The reaction solution of claim 13, wherein the molar ratio is at least 1.2, preferably 1.5 to 3.

5.

16. 2. The reaction solution of claim 1, comprising a pharmaceutically acceptable buffer to provide a pH in the range of 2 to 8 suitable for the reaction of the Lu(III) ions with the target-binding organic molecule.

17. 17. The reaction solution of claim 16, wherein the pharmaceutically acceptable buffer provides a pH of 4 to 6.

18. 17. The reaction solution of claim 16, wherein the pharmaceutically acceptable buffer comprises an acetate buffer, a citrate buffer, or a phosphate buffer.

19. 17. The reaction solution of claim 16, wherein the pharmaceutically acceptable buffer comprises an acetate buffer.

20. 1. A mother solution for preparing dispense solutions containing a 177Lu radiolabeled target-binding organic moiety, said mother solution comprising: (1) 177Lu(III) ions with a unit volume radioactivity of at least 10 GBq / mL; (2) a radionuclide complex formed by the Lu(III) ion and a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety; (3) one or more stabilizers against radiolytic degradation; and (4) A mother solution having an oxygen concentration of less than 3 mg / L at 25 degrees Celsius.

21. 21. The mother solution of claim 20, comprising a nitrogen concentration of up to 20 ml / L at 25 degrees Celsius or an argon concentration of up to 60 ml / L at 25 degrees Celsius.

22. 21. The mother solution of claim 20, wherein the stabilizer against radiolytic degradation comprises gentisic acid or a salt thereof.

23. 23. The mother solution according to claim 22, wherein the concentration of gentisic acid or a salt thereof is 5 to 15 mg / mL.

24. 24. The mother solution of claim 23, wherein the concentration of gentisic acid or a salt thereof is 10 to 15 mg / mL when the target-binding organic moiety is a somatostatin receptor-binding peptide.

25. 24. The mother solution of claim 23, wherein the concentration of gentisic acid or a salt thereof is 5 to 10 mg / ml when the target-binding organic moiety is a PSMA-binding peptide.

26. 21. The mother solution of claim 20, wherein the mother solution comprises no more than 5% (w / w) ascorbic acid or a salt thereof, preferably no more than 2%, even more preferably no more than 1%, and even more preferably no ascorbic acid (substantially 0%).

27. 21. The mother solution of claim 20, wherein the mother solution comprises no more than 5% (w / w) ethanol, preferably no more than 2%, even more preferably no more than 1%, and even more preferably no ethanol (substantially 0%).

28. 21. The mother solution of claim 20, wherein the target-binding organic moiety is a somatostatin receptor-binding peptide.

29. 29. The mother solution of claim 28, wherein the somatostatin receptor-binding peptide linked to a chelating moiety comprises DOTA.

30. 21. The mother solution of claim 20, wherein the target-binding organic moiety is a PSMA-binding peptide.

31. 31. The mother solution of claim 30, wherein the PSMA receptor-binding peptide linked to a chelating moiety comprises DOTA.

32. 21. The mother solution of claim 20, wherein the target-binding organic molecule is in molar excess relative to the 177Lu(III) ion.

33. 21. The mother solution of claim 20, wherein the target-binding organic molecule is in molar excess over the group of all Lu(III) ions, including Lu(III) ions, Lu(III) ions, Lu(III), and metastable Lu(III) ions, that are present when carrier-added Lu(III) is used as the source of Lu(III).

34. 33. Mother solution according to claim 32, wherein said molar ratio is at least 1.2, preferably between 1.5 and 3.

5.

35. 22. The mother solution of claim 21, wherein the nitrogen concentration is 3 to 20 ml / L at 25 degrees Celsius.

36. 22. The mother solution of claim 21, wherein the argon concentration is 3 to 60 ml / L at 25 degrees Celsius.

37. 21. The mother solution of claim 20, comprising a pharmaceutically acceptable buffer to provide a pH in the range of 2 to 8 suitable for the reaction of the Lu(III) ions with the target-binding organic molecule.

38. 38. The mother solution of claim 37, wherein the pharmaceutically acceptable buffer provides a pH of 4 to 6.

39. 38. The mother solution of claim 37, wherein the pharmaceutically acceptable buffer comprises an acetate buffer, a citrate buffer, or a phosphate buffer.

40. 38. The mother solution of claim 37, wherein the pharmaceutically acceptable buffer comprises an acetate buffer.

41. The radionuclide complex has a unit volume radioactivity of 12 GBq / ml to 17 GBq / ml. １７７ Lu-DOTA-TOC ( １７７ Lu-edotreotide) or １７７ Lu-DOTA-TATE ( １７７ Lu-oxodotreotide), preferably １７７ Lu-DOTA-TATE ( １７７ 29. The mother solution of claim 28, wherein the hydroxybenzoate is hydroxybenzoate (Hb-oxodotreotide).

42. the radionuclide complex is 177Lu PSMA-617 having a unit volume activity of 18-19 GBq / ml, PSMA-617 having the structure 【Chemistry 1】 31. The mother solution of claim 30, having

43. 1. A mother liquor container for collecting a solution from a radiolabeling reaction, said container comprising: (1) A mother solution comprising: a. 177Lu(III) ions at a unit volume radioactivity of at least 10 GBq / mL; b. a radionuclide complex formed by said 177Lu(III) ion and a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety; c. one or more stabilizers against radiolytic degradation; (2) a headspace gas volume above the mother solution, the headspace gas volume containing no more than 10% by volume of oxygen.

44. 44. The mother liquor container of claim 43, wherein the stabilizer against radiolytic degradation comprises gentisic acid or a salt thereof.

45. 45. The mother solution container of claim 44, wherein the concentration of gentisic acid or a salt thereof is 5 to 15 mg / mL.

46. 46. ​​The mother solution container of claim 45, wherein the concentration of gentisic acid or a salt thereof is 10 to 15 mg / mL when the target-binding organic moiety is a somatostatin receptor-binding peptide.

47. 46. ​​The mother solution container of claim 45, wherein the concentration of gentisic acid or a salt thereof is 5 to 10 mg / ml when the target-binding organic moiety is a PSMA-binding peptide.

48. 44. A mother liquor container as described in claim 43, wherein the mother liquor comprises no more than 5% (w / w) ascorbic acid or a salt thereof, preferably no more than 2%, even more preferably no more than 1%, and even more preferably no ascorbic acid (substantially 0%).

49. 44. A mother liquor container as described in claim 43, wherein the mother liquor contains no more than 5% (w / w) ethanol, preferably no more than 2%, even more preferably no more than 1%, and even more preferably no ethanol (substantially 0%).

50. 44. The mother solution container of claim 43, wherein the target-binding organic moiety is a somatostatin receptor-binding peptide.

51. 51. The mother solution container of claim 50, wherein the somatostatin receptor binding peptide linked to a chelating moiety comprises DOTA.

52. 44. The mother solution container of claim 43, wherein the target-binding organic moiety is a PSMA-binding peptide.

53. 53. The mother solution container of claim 52, wherein the PSMA receptor-binding peptide linked to a chelating moiety comprises DOTA.

54. 44. The mother solution container of claim 43, wherein the target-binding organic molecule is in molar excess relative to the 177Lu(III) ion.

55. 44. The mother solution container of claim 43, wherein the target-binding organic molecule is in molar excess over 177Lu(III) ions and over 176Lu(III) ions and metastable 177mLu(III) ions present when carrier-added 177Lu(III) is used as a source of 177Lu(III).

56. 55. Mother liquor container according to claim 54, wherein the molar ratio is at least 1.2, preferably between 1.5 and 3.

5.

57. 44. A mother liquor container according to claim 43, wherein the headspace gas volume contains no more than 7% volume percent oxygen, preferably no more than 5% volume percent oxygen, preferably no more than 3% volume percent oxygen, preferably no more than 1% volume percent oxygen.

58. 44. The mother liquor container of claim 43, wherein the mother liquor contains an oxygen concentration of less than 3 mg / L at 25 degrees C.

59. 59. The mother liquor container of claim 58, wherein the mother liquor comprises a nitrogen concentration of up to 20 ml / L at 25 degrees Celsius or an argon concentration of up to 60 ml / L at 25 degrees Celsius.

60. 60. The mother liquor container of claim 59, wherein the nitrogen concentration is 20 ml / L at 25 degrees Celsius.

61. 60. The mother liquor container of claim 59, wherein the argon concentration is 6 to 60 ml / L at 25 degrees Celsius.

62. 44. The mother solution container of claim 43, comprising a pharmaceutically acceptable buffer to provide a pH in the range of 2 to 8 suitable for the reaction of the 177Lu(III) ions with the target-binding organic molecule.

63. 63. The mother liquor container of claim 62, wherein the pharmaceutically acceptable buffer provides a pH of 4 to 6.

64. 63. The mother liquor container of claim 62, wherein the pharmaceutically acceptable buffer comprises an acetate buffer, a citrate buffer, or a phosphate buffer.

65. 63. The mother liquor container of claim 62, wherein the pharmaceutically acceptable buffer comprises an acetate buffer.

66. The radionuclide complex has a unit volume radioactivity of 12 GBq / ml to 17 GBq / ml. １７７ Lu-DOTA-TOC ( １７７ Lu-edotreotide) or １７７ Lu-DOTA-TATE ( １７７ Lu-oxodotreotide), preferably １７７ Lu-DOTA-TATE ( １７７ 51. The mother liquor container of claim 50, wherein the hydroxybenzoate is hydroxybenzoate (Hb-oxodotreotide).

67. the radionuclide complex is 177Lu PSMA-617 having a unit volume activity of 18-19 GBq / ml, PSMA-617 having the structure 【Chemistry 2】 53. The mother liquor container of claim 52, having:

68. Furthermore, (3) a stabilizer against radiolytic degradation, preferably ascorbic acid or a salt thereof; (4) a sequestering agent, preferably DTPA; 44. A mother solution container according to claim 43, optionally comprising (5) an isotonic agent, preferably NaCl.

69. (A) 177Lu-DOTATATE with a radioactivity in the range of 296-444 MBq / mL, preferably 333-407 MBq / ml, more preferably about 351-389 MBq / ml, and most preferably about 370 MBq / mL (10 mCi / mL); (B) acetic acid at a concentration ranging from 0.384 to 0.576 mg / ml, preferably 0.432 to 0.528 mg / ml, more preferably 0.456 to 0.504 mg / mL, and most preferably about 0.48 mg / mL; (C) acetate, preferably its sodium salt, at a concentration ranging from 0.528 to 0.792 mg / ml, preferably 0.594 to 0.726 mg / ml, more preferably 0.627 to 0.693 mg / mL, and most preferably about 0.66 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration ranging from 0.504 to 0.756 mg / ml, preferably 0.567 to 0.693 mg / ml, more preferably 0.598 to 0.6615 mg / mL, and most preferably about 0.63 mg / mL, based on the free acid; (E) ascorbic acid or a salt thereof at a concentration ranging from 2.24 to 3.36 mg / ml, preferably 2.52 to 3.08 mg / mL, more preferably 2.66 to 2.94 mg / mL, and most preferably about 2.8 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration ranging from 0.04 to 0.06 mg / mL, preferably 0.045 to 0.055 mg / mL, more preferably 0.048 to 0.053 mg / mL, and most preferably about 0.050 mg / mL, with respect to the free acid; (G) sodium chloride at a concentration ranging from 5.55 to 8.15 mg / mL, preferably 6.16 to 7.54 mg / mL, more preferably 6.51 to 7.19 mg / mL, and most preferably about 6.85 mg / mL; 44. The mother liquor container of claim 43, comprising: (H) optionally sodium hydroxide at a concentration sufficient to provide, together with components (B) and (C), a pH value in the range of 4.5 to 6.0, preferably sodium hydroxide present at a concentration in the range of 0.52 to 0.78 mg / ml, preferably 0.59 to 0.72, more preferably 0.618 to 0.683 mg / mL, and most preferably 0.65 mg / mL.

70. (A) 177Lu-PSMA-617 at a radioactivity in the range of 800-1200 MBq / ml, preferably 900-1100 MBq / ml, more preferably 950-1050 MBq / ml, and most preferably about 1000 MBq / mL (27 mCi / mL); (B) acetic acid at a concentration ranging from 0.24 to 0.36 mg / mL, preferably from 0.27 to 0.33 mg / mL, more preferably from 0.285 to 0.315 mg / mL, and most preferably about 0.3 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.33 to 0.49 mg / mL, preferably 0.37 to 0.45 mg / mL, more preferably 0.39 to 0.43 mg / mL, and most preferably about 0.41 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.3 to 1.0 mg / mL, preferably 0.3 to 0.5 mg / mL, more preferably 0.31 to 0.47 mg / mL, even more preferably 0.35 to 0.43 mg / mL, even more preferably 0.37 to 0.41 mg / mL, and most preferably about 0.39 mg / mL, with respect to the free acid; (E) ascorbic acid or a salt thereof at a concentration ranging from 20 to 52.5 mg / mL, preferably 47.5 to 52.5 mg / mL, more preferably 48 to 52 mg / mL, and most preferably about 50 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration in the range of 0.08 to 0.12 mg / mL, preferably 0.09 to 0.11 mg / mL, more preferably 0.095 to 0.105 mg / mL, and most preferably about 0.1 mg / mL, with respect to the free acid.

71. 1. A process for producing a radiopharmaceutical solution comprising: (1) providing a reaction solution according to any one of claims 1 to 19; (2) reacting a target-binding organic molecule comprising a target-binding organic moiety linked to a chelating moiety with 177Lu(III) ions at subatmospheric pressure to obtain a radionuclide complex in a single vessel for radiolabeling.

72. Furthermore, 72. The process for producing a radiopharmaceutical solution of claim 71, comprising the step of: (3) recovering said radionuclide complex to obtain a mother solution.

73. 73. The process for manufacturing of claim 72, wherein said step (3) of recovering said radionuclide complex comprises recovering under an inert gas atmosphere.

74. 73. The process for manufacturing of claim 72, wherein said step (3) of recovering said radionuclide complexes comprises introducing or transferring said mother solution into a single container to obtain a mother solution container.

75. 75. The process for manufacturing of claim 74, wherein said step (3) of recovering said radionuclide complexes comprises purging said mother liquor container with an inert gas before and during introducing or transferring said mother liquor into said mother liquor container.

76. 76. The process for producing according to claim 75, wherein said step (3) of recovering said radionuclide complexes comprises purging said mother liquor container with an inert gas at a pressure of at least 250 mbar above atmospheric pressure before and during the introduction or transfer of said mother liquor into said mother liquor container.

77. 72. The process for manufacturing of claim 71, wherein said step (2) of obtaining said radionuclide complex in a single container for radiolabeling comprises an oxygen concentration of less than 3 mg / L at 25 degrees Celsius.

78. 74. The process for manufacturing according to claim 73, wherein in step (3), the inert gas atmosphere is provided by nitrogen or argon.

79. 79. The process for manufacturing of claim 78, comprising a nitrogen concentration in the mother solution of up to 20 ml / L at 25 degrees Celsius or an argon concentration of up to 60 ml / L at 25 degrees Celsius.

80. 73. The process for manufacturing of claim 72, wherein said step (3) of recovering said radionuclide complex comprises using water for injection (WFI) for rinsing.

81. The process for manufacturing the product of claim 71, wherein step (1) of providing the reaction solution comprises providing the reaction solution in a container.

82. 72. The process for producing according to claim 71, wherein the reaction solution has a radioactivity of at least 5 Ci, preferably 5 to 20 Ci, more preferably 5 to 15 Ci, even more preferably 5 to 12, even more preferably 5.4 to 12 Ci, even more preferably 7 to 12, even more preferably about 8 to 12 Ci.

83. 72. The process of claim 71, wherein step (2) of reacting the target-binding organic molecule with the 177Lu(III) ion at subatmospheric pressure to obtain the radionuclide complex is carried out for 2 to 15 minutes, preferably 4 to 10 minutes, and more preferably 5 minutes ± 0.5 minutes.

84. 72. The process of claim 71, wherein step (2) of reacting the target-binding organic molecule with the 177Lu(III) ion at sub-atmospheric pressure to obtain the radionuclide complex is carried out at a temperature of 80-100 degrees Celsius, preferably 90-98 degrees Celsius, more preferably 94°C ± 4°C.

85. 72. The process of claim 71, wherein the volume of the mixture in step (2) reacting the target-binding organic molecule with the 177Lu(III) ion at subatmospheric pressure to obtain the radionuclide complex is 15 to 19 ml.

86. 72. The process for manufacturing of claim 71, wherein the final volume containing the radionuclide complex after said recovering step (3) is 20-23 ml.

87. Furthermore, (4) diluting the mother solution with a diluent solution to obtain aliquot solutions with defined unit volume radioactivity; 72. The process for manufacturing a radiopharmaceutical solution of claim 71, comprising the step of: (5) dispensing said dispensing solution into individual patient dose units.

88. The diluted solution is (3) a stabilizer against radiolytic degradation, preferably ascorbic acid or a salt thereof; (4) a sequestering agent, preferably DTPA; 88. The process for manufacturing according to claim 87, optionally comprising (5) an isotonic agent, preferably NaCl.

89. 89. The process for manufacturing of claim 88, wherein the stabilizer against radiolytic degradation comprises ascorbic acid or a salt thereof.

90. 89. The process for manufacturing according to claim 88, wherein the diluted solution contains ethanol at 5% (w / w) or less, preferably 2% or less, even more preferably 1% or less, and even more preferably no ethanol (substantially 0%).

91. 88. The process for manufacturing of claim 87, wherein the defined unit volume activity of the dispensed solutions is adjusted to provide individual patient dose units having a unit volume activity of 1000 MBq / mL ± 5% for 177Lu-PSMA-617 and 370 MBq / mL ± 5% for 177Lu-DOTA-TATE.

92. The dispensing solution is (A) 177Lu-DOTATATE with a radioactivity in the range of 296-444 MBq / mL, preferably 333-407 MBq / ml, more preferably about 351-389 MBq / ml, and most preferably about 370 MBq / mL (10 mCi / mL); (B) acetic acid at a concentration ranging from 0.384 to 0.576 mg / ml, preferably 0.432 to 0.528 mg / ml, more preferably 0.456 to 0.504 mg / mL, and most preferably about 0.48 mg / mL; (C) acetate, preferably its sodium salt, at a concentration ranging from 0.528 to 0.792 mg / ml, preferably 0.594 to 0.726 mg / ml, more preferably 0.627 to 0.693 mg / mL, and most preferably about 0.66 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration ranging from 0.504 to 0.756 mg / ml, preferably 0.567 to 0.693 mg / ml, more preferably 0.598 to 0.6615 mg / mL, and most preferably about 0.63 mg / mL, based on the free acid; (E) ascorbic acid or a salt thereof at a concentration ranging from 2.24 to 3.36 mg / ml, preferably 2.52 to 3.08 mg / mL, more preferably 2.66 to 2.94 mg / mL, and most preferably about 2.8 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration ranging from 0.04 to 0.06 mg / mL, preferably 0.045 to 0.055 mg / mL, more preferably 0.048 to 0.053 mg / mL, and most preferably about 0.050 mg / mL, with respect to the free acid; (G) sodium chloride at a concentration ranging from 5.55 to 8.15 mg / mL, preferably 6.16 to 7.54 mg / mL, more preferably 6.51 to 7.19 mg / mL, and most preferably about 6.85 mg / mL; (H) optionally sodium hydroxide at a concentration sufficient to provide a pH value in the range of 4.5 to 6.0, together with components (B) and (C), preferably present at a concentration in the range of 0.52 to 0.78 mg / ml, preferably 0.59 to 0.72, more preferably 0.618 to 0.683 mg / mL, and most preferably 0.65 mg / mL.

93. The dispensing solution is (A) 177Lu-PSMA-617 at a radioactivity in the range of 800-1200 MBq / ml, preferably 900-1100 MBq / ml, more preferably 950-1050 MBq / ml, and most preferably about 1000 MBq / mL (27 mCi / mL); (B) acetic acid at a concentration ranging from 0.24 to 0.36 mg / mL, preferably from 0.27 to 0.33 mg / mL, more preferably from 0.285 to 0.315 mg / mL, and most preferably about 0.3 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.33 to 0.49 mg / mL, preferably 0.37 to 0.45 mg / mL, more preferably 0.39 to 0.43 mg / mL, and most preferably about 0.41 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.3 to 1.0 mg / mL, preferably 0.3 to 0.5 mg / mL, more preferably 0.31 to 0.47 mg / mL, even more preferably 0.35 to 0.43 mg / mL, even more preferably 0.37 to 0.41 mg / mL, and most preferably about 0.39 mg / mL, with respect to the free acid; (E) ascorbic acid or a salt thereof at a concentration ranging from 20 to 52.5 mg / mL, preferably 47.5 to 52.5 mg / mL, more preferably 48 to 52 mg / mL, and most preferably about 50 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration in the range of 0.08 to 0.12 mg / mL, preferably 0.09 to 0.11 mg / mL, more preferably 0.095 to 0.105 mg / mL, and most preferably about 0.1 mg / mL, based on the free acid.

94. A product obtained or obtainable by the process of claim 71.

95. A product obtained or obtainable by the process of claim 87, wherein the dispensing solution comprises: (A) 177Lu-DOTATATE with a radioactivity in the range of 296-444 MBq / mL, preferably 333-407 MBq / ml, more preferably about 351-389 MBq / ml, and most preferably about 370 MBq / mL (10 mCi / mL); (B) acetic acid at a concentration ranging from 0.384 to 0.576 mg / ml, preferably 0.432 to 0.528 mg / ml, more preferably 0.456 to 0.504 mg / mL, and most preferably about 0.48 mg / mL; (C) acetate, preferably its sodium salt, at a concentration ranging from 0.528 to 0.792 mg / ml, preferably 0.594 to 0.726 mg / ml, more preferably 0.627 to 0.693 mg / mL, and most preferably about 0.66 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration ranging from 0.504 to 0.756 mg / ml, preferably 0.567 to 0.693 mg / ml, more preferably 0.598 to 0.6615 mg / mL, and most preferably about 0.63 mg / mL, based on the free acid; (E) ascorbic acid or a salt thereof at a concentration ranging from 2.24 to 3.36 mg / ml, preferably 2.52 to 3.08 mg / mL, more preferably 2.66 to 2.94 mg / mL, and most preferably about 2.8 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration ranging from 0.04 to 0.06 mg / mL, preferably 0.045 to 0.055 mg / mL, more preferably 0.048 to 0.053 mg / mL, and most preferably about 0.050 mg / mL, with respect to the free acid; (G) sodium chloride at a concentration ranging from 5.55 to 8.15 mg / mL, preferably 6.16 to 7.54 mg / mL, more preferably 6.51 to 7.19 mg / mL, and most preferably about 6.85 mg / mL; (H) optionally sodium hydroxide in a concentration sufficient to provide a pH value in the range of 4.5 to 6.0, in combination with components (B) and (C), preferably present at a concentration in the range of 0.52 to 0.78 mg / ml, preferably 0.59 to 0.72, more preferably 0.618 to 0.683 mg / mL, and most preferably 0.65 mg / mL.

96. A product obtained or obtainable by the process of claim 87, wherein the dispensing solution comprises: (A) 177Lu-PSMA-617 at a radioactivity in the range of 800-1200 MBq / ml, preferably 900-1100 MBq / ml, more preferably 950-1050 MBq / ml, and most preferably about 1000 MBq / mL (27 mCi / mL); (B) acetic acid at a concentration ranging from 0.24 to 0.36 mg / mL, preferably from 0.27 to 0.33 mg / mL, more preferably from 0.285 to 0.315 mg / mL, and most preferably about 0.3 mg / mL; (C) acetate, preferably its sodium salt, at a concentration in the range of 0.33 to 0.49 mg / mL, preferably 0.37 to 0.45 mg / mL, more preferably 0.39 to 0.43 mg / mL, and most preferably about 0.41 mg / mL for the sodium salt; (D) gentisic acid or a salt thereof at a concentration in the range of 0.3 to 1.0 mg / mL, preferably 0.3 to 0.5 mg / mL, more preferably 0.31 to 0.47 mg / mL, even more preferably 0.35 to 0.43 mg / mL, even more preferably 0.37 to 0.41 mg / mL, and most preferably about 0.39 mg / mL, with respect to the free acid; (E) ascorbic acid or a salt thereof at a concentration ranging from 20 to 52.5 mg / mL, preferably 47.5 to 52.5 mg / mL, more preferably 48 to 52 mg / mL, and most preferably about 50 mg / mL for the sodium salt; (F) pentetic acid or a salt thereof at a concentration in the range of 0.08 to 0.12 mg / mL, preferably 0.09 to 0.11 mg / mL, more preferably 0.095 to 0.105 mg / mL, and most preferably about 0.1 mg / mL, with respect to the free acid.

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