Stable, concentrated radionuclide complex solutions

Abstract

This invention relates to high-concentration and highly chemically stable solutions of radionuclear seed complexes, properties that enable the solutions to be used as pharmaceutical products for diagnostic and / or therapeutic purposes. The stability of the pharmaceutical product is achieved by using at least one stabilizer resistant to radiodegradation. The use of two stabilizers introduced at different stages during the manufacturing process has been found to be particularly advantageous.

Description

Technical Field

[0001] The present invention relates to radioactive nuclide complex solutions with high concentration and high chemical and radiochemical stability, which properties enable the radioactive nuclide complex solutions to be used as commercial pharmaceutical products for diagnostic and / or therapeutic purposes. Prior Art

[0002] The concept of targeted drug delivery is based on cell receptors that are overexpressed in target cells as opposed to non-targeted cells. If a drug has a binding site for those overexpressed cell receptors, it allows the drug to be delivered to those target cells after systemic administration at high concentration while leaving other non-target cells unaffected. For example, if tumor cells are characterized by the overexpression of specific cell receptors, a drug with binding affinity for said receptors will accumulate at high concentration in tumor tissue after intravenous infusion while leaving normal tissue unaffected.

[0003] This concept of targeted drug delivery has also been used in radiomedicine to selectively deliver radionuclides to target cells for diagnostic or therapeutic purposes.

[0004] For this radiomedical application, the target cell receptor-binding moiety is usually linked to a chelating agent that is capable of forming a strong complex with the metal ion of the radionuclide. The radiopharmaceutical is then delivered to the target cells, and the decay of the radionuclide releases high-energy electrons, positrons or alpha particles as well as gamma rays at the target site.

[0005] One technical problem with such radiopharmaceutical products is that the decay of the radionuclide constantly occurs, for example, also during the manufacture and storage of the drug product, and the high-energy emissions released cause the cleavage of chemical bonds of molecules that form part of the drug product. This is commonly referred to as radiolysis or radiolytic degradation. Radiolytic degradation of the receptor-binding moiety of the drug can lead to a reduction in its efficacy as a diagnostic and / or therapeutic agent.

[0006] These radiopharmaceutical products have poor stability and they lack any significant shelf life, so the drugs are required to be manufactured as single patient dose units in the hospital laboratories so far and immediately administered to patients who must be within the hospital and already waiting for radiotherapy. To facilitate the preparation of such drugs in hospital laboratories, "cold" (i.e., non-radioactive) lyophilization kits have been developed, which contain a cell receptor-binding moiety linked to a chelating agent without a radionuclide. Then, immediately before administration, the lyophilized contents of those kit vials are reconstituted with a radionuclide solution (Das et al. J Radioanal Nucl Chem [Journal of Radioanalytical and Nuclear Chemistry] 2014, 299, 1389-1398; Das et al. Current Radiopharmaceuticals [Current Radiopharmaceuticals] 2014, 7, 12-19; Luna-Gutierrez et al. J Radioanal Nucl Chem [Journal of Radioanalytical and Nuclear Chemistry] 2017, 314, 2181-2188). However, these kits are not "ready-to-use" because they require a reconstitution step and additional further processing steps (e.g., applying heat to the complexation reaction) and purification and sterilization steps before the final administration of the drug.

[0007] To reduce the radiolytic decomposition of radiopharmaceutical products and thus improve stability, various strategies have been explored and have met with more or less success: the drug products can be stored at low temperatures, or produced at high dilutions, or stabilizers can be added.

[0008] However, adding stabilizers can be problematic because these chemicals may have a negative impact on the complexation of the radionuclide with the chelating agent, or may have limited solubility and precipitate out of the solution. Ethanol has been reported as a stabilizer against radiolytic decomposition (WO 2008 / 009444). Although ethanol may not have a negative impact on complexation or solubility problems, higher amounts of ethanol in the infusion solution may have physiological problems and may have a negative impact on the tolerance of the drug product.

[0009] The disadvantage of producing pharmaceutical products at high dilutions is that a large volume of infusion solution needs to be administered to the patient. For the convenience of the patient and for reasons of drug tolerance, it is highly desirable to provide highly concentrated radiopharmaceutical products. However, those highly concentrated solutions are particularly prone to radiolytic decomposition. Thus, on the one hand, radiolytic decomposition is avoided by diluting the pharmaceutical product, and on the other hand, discomfort to the patient during treatment is avoided by providing a concentrated pharmaceutical solution, and there is a contradiction between the above two aspects. A highly concentrated product has been reported in Mathur et al., Cancer Biotherapy and Radiopharmaceuticals, 2017, 32(7), 266 - 273, and is claimed to be ready - to - use. However, the composition may have problems with tolerance because it contains a large amount of ethanol.

[0010] Therefore, it remains a challenge to design a ready - to - use radiopharmaceutical product that can be produced on a commercial scale and delivered in the form of a sufficiently stable and sterile solution of a highly concentrated composition (resulting in a convenient small infusion volume for the patient and a highly physiologically tolerable composition, such as a composition without ethanol). Summary of the Invention

[0011] The inventors have now found a method for designing and producing a solution of a highly concentrated radionuclide complex that is chemically and radiochemically very stable even when stored at ambient temperature or at a short - term elevated temperature, and thus it can be produced on a commercial scale and supplied as a ready - to - use radiopharmaceutical product.

[0012] The present invention provides the following aspects: An aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprising (a) a complex formed by (ai) a radionuclide, and (aii) a cell - receptor - binding organic moiety linked to a chelating agent; and (b) at least one stabilizer against radiolytic degradation; wherein the radionuclide is present at a concentration providing a volume radioactivity of at least 100 MBq / mL, preferably at least 250 MBq / mL.

[0013] The one or more stabilizers (component (b)) are present at a total concentration of at least 0.2 mg / mL, preferably at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, and even more preferably at least 2.7 mg / mL.

[0014] An aqueous pharmaceutical solution, said aqueous pharmaceutical solution comprising (a) A complex formed by (ai) The radionuclide lutetium-177 (Lu-177), present at a concentration such that its volumetric radioactivity is from 250 to 500 MBq / mL, and (aii) A chelating agent in which a somatostatin receptor-binding organic moiety DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) is linked; (bi) Gentisic acid or a salt thereof as a first stabilizer against radiolytic degradation, present at a concentration from 0.5 to 1 mg / mL; (bii) Ascorbic acid or a salt thereof as a second stabilizer against radiolytic degradation, present at a concentration from 2.0 to 5.0 mg / mL.

[0015] A method for preparing the aqueous pharmaceutical solution as defined above, said method comprising the following method steps: (1) Forming a complex of a radionuclide and a chelating agent to which a cell receptor-binding organic moiety is linked by (1.1) Preparing an aqueous solution comprising said radionuclide; (1.2) Preparing an aqueous solution comprising a cell receptor-binding organic moiety of a linked chelating agent, a first stabilizer, and optionally a second stabilizer; and (1.3) Mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; (2) Diluting the complex solution obtained by step (1) by (2.1) Preparing an aqueous dilution solution optionally comprising a second stabilizer; and (2.2.) Mixing the complex solution obtained by step (1) with the dilution solution obtained by step (2.1).

[0016] The present invention provides the following advantages: This high concentration allows for high doses to be administered in a short time. For example, in the case of 177Lu-DOTA-TATE, a high dose of 7.4 GBq can be provided in a small volume of 20.5 to 25.0 mL, which allows intravenous infusion to be completed in about 20 to 30 minutes.

[0017] Using one or more suitable stabilizers according to the invention described herein ensures high stability, with at least 95%, 96%, 97%, 98%, 99% or 100% chemical stability with respect to chemical purity for cell receptor binding molecules (even if such molecules are sensitive peptide molecules) after 72 hours at 25 °C. For example, for DOTA-TATE, 100% chemical purity was found after 72 hours at 25 °C, and even 100% chemical purity was found after 48 hours at 32 °C. Even under short-term elevated temperature conditions (12 hours at 32 °C and 60 hours at 25 °C), such high stability was found with respect to chemical purity.

[0018] Furthermore, using one or more suitable stabilizers according to the invention described herein ensures high stability, with at least 95% radiochemical stability with respect to radiochemical purity of the radionuclide complex. For example, for 177Lu-DOTA-TATE, at least 95% radiochemical purity was found after 72 hours at 25 °C. Even under short-term elevated temperature conditions (12 hours at 32 °C and 60 hours at 25 °C), such high stability was found with respect to radiochemical purity.

[0019] Although sufficient stability has been achieved using a single stabilizer, it has been found that using two stabilizers is particularly suitable for stabilizing sensitive radiopharmaceutical solutions. Specifically, it is advantageous to have one stabilizer during complex formation and to add another stabilizer after complex formation, because one stabilizer ensures that the cell receptor binding molecule is already protected from radiolytic decomposition during the complexation reaction and the other stabilizer enhances the protective effect for the shelf life.

[0020] Furthermore, by this sequential application of the two stabilizers, it is ensured that only a relatively small amount of stabilizer is present during complexation (which minimizes the potential interference of the stabilizer with the complexation reaction) and a large combination of stabilizers is present after complexation (which enhances the protective ability of the stabilizer during the subsequent drug storage period).

[0021] This sequential application of the two stabilizers also reduces the total thermal stress of those stabilizers, because when the complexation reaction involving high temperature occurs, one of the stabilizers is absent.

[0022] Furthermore, it is advantageous to use, in particular, two different stabilizers because this combination is more effective than just a single stabilizer in reacting with the various different groups that may be formed by the radiolytic decomposition of the cell receptor-binding molecule in the above respects.

[0023] The composition of the radiopharmaceutical solution does not require the presence of ethanol. The solution is stable enough without ethanol. The absence of ethanol is advantageous with respect to the physiological tolerance of the solution.

[0024] A shelf life of at least 3 days is required to allow the radiopharmaceutical product to be manufactured at a centralized drug production site and commercialized as a ready-to-use drug product.

[0025] Thus, due to the high stability (72 hours at 25 °C), the present invention allows for drug production centralized at the highest quality standards (e.g., cGMP) and on an industrial scale, for example, in batch sizes of 74 GBq or 148 GBq, which provides drug products with multiple dosage units, such as sufficient dosage units to treat 10 to 20 patients simultaneously.

[0026] Furthermore, due to the high stability, the present invention has sufficient time to be transported from a centralized drug production site to distant clinical centers.

[0027] Even further, due to the high stability, the present invention can be provided as a ready-to-use infusion solution that can be immediately administered to a patient without any preparatory work by clinical staff before administration.

[0028] The present invention is particularly suitable for somatostatin receptor-binding peptides, in particular for the very sensitive somatostatin analogs octreotide and octreotate, which are particularly prone to degradation reactions. Furthermore, the present invention is particularly suitable for the radionuclide lutetium-177 having specific radioactive characteristics. Brief Description of the Drawings

[0029] None Embodiments

[0030] The present invention is described and illustrated in more detail below.

[0031] Generally, the present invention relates to aqueous pharmaceutical solutions, particularly aqueous radiopharmaceutical solutions. The solution is for intravenous (IV) use / application / administration. The solution is stable, concentrated, and ready-to-use.

[0032] The stability of the solution is determined by using stabilizers against radiolytic degradation.

[0033] Generally, the stabilizers used according to the present invention can be selected from gentisic acid (2,5-dihydroxybenzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (such as sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine. Preferred stabilizers are selected from gentisic acid or its salts and ascorbic acid or its salts.

[0034] Ethanol is considered to be a less preferred stabilizer because if present in higher concentrations, there are associated tolerance problems. Ethanol should ideally be avoided in the solutions of the present invention (in other words: ethanol-free), or at least the amount of ethanol in the solutions of the present invention should be restricted, for example, less than 5% in the final solution expected to be injected / infused, preferably less than 2%, more preferably less than 1%. Even more preferably, the solution is ethanol-free.

[0035] According to the present invention, the following embodiments are provided: 1. An aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprising (a) a complex formed by (ai) a radionuclide, and (aii) a cell receptor-binding organic moiety linked to a chelating agent; and (b) at least one stabilizer against radiolytic degradation; wherein the radionuclide is present at a concentration providing a volumetric radioactivity of at least 100 MBq / mL, preferably at least 250 MBq / mL.

[0036] 2. The aqueous pharmaceutical solution according to embodiment 1, wherein the one or more stabilizers (component (b)) are present at a total concentration of at least 0.2 mg / mL, preferably at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, even more preferably at least 2.7 mg / mL.

[0037] 3. The aqueous drug solution according to any one of the foregoing embodiments, wherein the radionuclide is present at a concentration providing a volume radioactivity of from 100 to 1000 MBq / mL, preferably from 250 to 500 MBq / mL.

[0038] 4. The aqueous drug solution according to any one of the foregoing embodiments, wherein the one or more stabilizers are present at a total concentration of from 0.2 to 20.0 mg / mL, preferably from 0.5 to 10.0 mg / mL, more preferably from 1.0 to 5.0 mg / mL, even more preferably from 2.7 to 4.1 mg / mL.

[0039] 5. The aqueous drug solution according to any one of the foregoing embodiments, wherein component (b) is only one stabilizer against radiolytic degradation, i.e., only the first stabilizer.

[0040] 6. The aqueous drug solution according to any one of the foregoing embodiments, wherein component (b) is at least two stabilizers against radiolytic degradation, i.e., at least the first and second stabilizers, preferably only two stabilizers, i.e., only the first and second stabilizers.

[0041] 7. The aqueous drug solution according to any one of embodiments 5 to 6, wherein the first stabilizer is present at a concentration of from 0.2 to 5 mg / mL, preferably from 0.5 to 5 mg / mL, more preferably from 0.5 to 2 mg / mL, even more preferably from 0.5 to 1 mg / mL, even more preferably from 0.5 to 0.7 mg / mL.

[0042] 8. The aqueous drug solution according to any one of embodiments 6 or 7, wherein the second stabilizer is present at a concentration of from 0.5 to 10 mg / mL, more preferably from 1.0 to 8.0 mg / mL, even more preferably from 2.0 to 5.0 mg / mL, even more preferably from 2.2 to 3.4 mg / mL.

[0043] 9. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the one or more stabilizers are selected from gentisic acid (2,5-dihydroxybenzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (such as sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine, preferably selected from gentisic acid or its salts and ascorbic acid or its salts.

[0044] 10. The aqueous solution of the drug according to any one of embodiments 5 to 9, wherein the first stabilizer is selected from gentisic acid and ascorbic acid, preferably the first stabilizer is gentisic acid.

[0045] 11. The aqueous solution of the drug according to any one of embodiments 6 to 10, wherein the second stabilizer is selected from gentisic acid and ascorbic acid, preferably the second stabilizer is ascorbic acid.

[0046] 12. The aqueous solution of the drug according to any one of embodiments 6 to 8, wherein the first stabilizer is gentisic acid or its salt, and the second stabilizer is ascorbic acid or its salt, and the ratio of the concentration of the first stabilizer (in mg / mL) to the concentration of the second stabilizer (in mg / mL) is from 1:3 to 1:7, preferably from 1:4 to 1:5.

[0047] 13. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the radionuclide is selected from 177Lu, 68Ga, 18F, 99mTc, 211At, 82Rb, 166Ho, 225Ac, 111In, 123I, 131I, 89Zr, 90Y, preferably selected from 177Lu and 68Ga, more preferably 177Lu.

[0048] 14. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the cell receptor-binding portion is a somatostatin receptor-binding peptide, preferably the somatostatin receptor-binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate.

[0049] 15. The aqueous drug solution according to any one of the foregoing embodiments, wherein the chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA.

[0050] 16. The aqueous drug solution according to any one of the foregoing embodiments, wherein the cell receptor binding moiety and the chelating agent together form a molecule selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (octreotate), DOTA-LAN, and DOTA-VAP, preferably a molecule selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0051] 17. The aqueous drug solution according to any one of the foregoing embodiments, wherein the radionuclide, the cell receptor binding moiety, and the chelating agent together form a complex 177Lu-DOTA-TOC (177Lu-edotreotide) or 177Lu-DOTA-TATE (177Lu-octreotate), preferably 177Lu-DOTA-TATE.

[0052] 18. The aqueous drug solution according to any one of the foregoing embodiments, the aqueous drug solution further comprises a buffer, preferably the buffer is an acetate buffer, preferably in an amount to obtain an acetic acid concentration of from 0.3 to 0.7 mg / mL (preferably about 0.48 mg / mL) and a sodium acetate amount of from 0.4 to 0.9 mg / mL (preferably about 0.66 mg / mL).

[0053] 19. The aqueous drug solution according to any one of the foregoing embodiments, the aqueous drug solution further comprises a multivalent chelating agent, preferably the multivalent chelating agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount to obtain a concentration of from 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL).

[0054] 20. The aqueous drug solution according to any one of the foregoing embodiments has a shelf life of at least 24 hours (h) at ≤ 25 °C, at least 48 h at ≤ 25 °C, at least 72 h at ≤ 25 °C, from 24 h to 120 h at ≤ 25 °C, from 24 h to 96 h at ≤ 25 °C, from 24 h to 84 h at ≤ 25 °C, from 24 h to 72 h at ≤ 25 °C, and particularly has a shelf life of 72 h at ≤ 25 °C.

[0055] 21. The aqueous drug solution according to any one of the foregoing embodiments, wherein the solution is produced on a commercial scale, particularly in batch sizes of at least 20 GBq, at least 50 GBq or at least 70 GBq.

[0056] 22a. The aqueous drug solution according to any one of the foregoing embodiments, which is ready-to-use.

[0057] 22b. The aqueous drug solution according to any one of the foregoing embodiments, which is for commercial use.

[0058] 23. An aqueous drug solution, which comprises (a) a complex formed by (ai) the radionuclide lutetium-177 (Lu-177) present at a concentration providing a volume radioactivity of from 250 to 500 MBq / mL, and (aii) a chelating agent in which a somatostatin receptor-binding organic moiety DOTA-TATE (octreotate) or DOTA-TOC (tedotate) is linked; (bi) gentisic acid or its salt as a first stabilizer against radiolytic degradation, present at a concentration of from 0.5 to 1 mg / mL; (bii) ascorbic acid or its salt as a second stabilizer against radiolytic degradation, present at a concentration of from 2.0 to 5.0 mg / mL.

[0059] 24. The aqueous drug solution according to embodiment 23, which further comprises: (c) diethylenetriaminepentaacetic acid (DTPA) or its salt at a concentration of from 0.01 to 0.10 mg / mL.

[0060] 25. The aqueous drug solution according to Embodiment 23 or 24, wherein the aqueous drug solution further comprises: (d) acetic acid at a concentration of 0.3 to 0.7 mg / mL and sodium acetate at a concentration of 0.4 to 0.9 mg / mL.

[0061] 26. The aqueous drug solution according to any one of the foregoing embodiments, wherein the one or more stabilizers are present in the solution during the formation of the complex of components (ai) and (aii).

[0062] 27. The aqueous drug solution according to any one of Embodiments 5 to 26, wherein only the first stabilizer is present during the formation of the complex of components (ai) and (aii), preferably in an amount such that a concentration of 0.5 to 5 mg / mL, more preferably 0.5 to 2 mg / mL, even more preferably 0.5 to 1 mg / mL, and even more preferably 0.5 to 0.7 mg / mL is obtained in the final solution.

[0063] 28. The aqueous drug solution according to any one of Embodiments 6 to 27, wherein during the formation of the complex of components (ai) and (aii), a partial amount of the second stabilizer is already present in the solution, and another partial amount of the second stabilizer is added after the formation of the complex of components (ai) and (aii).

[0064] 29. The aqueous drug solution according to any one of Embodiments 6 to 28, wherein the second stabilizer is added after the formation of the complex of components (ai) and (aii).

[0065] 30. The aqueous drug solution according to Embodiment 6 or 29, wherein the second stabilizer is added after the formation of the complex of components (ai) and (aii), preferably in an amount such that a concentration of 0.5 to 10 mg / mL, more preferably 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, and even more preferably 2.2 to 3.4 mg / mL is obtained in the final solution.

[0066] 31. The aqueous drug solution according to any one of the foregoing embodiments, wherein the aqueous drug solution further comprises a polyvalent chelating agent, which is added after the formation of the complex of components (ai) and (aii) for removing any uncomplexed Lu. Preferably, the polyvalent chelating agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount such that a concentration of from 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL) is obtained in the final solution.

[0067] 32. A method for preparing an aqueous drug solution as defined in any one of the foregoing embodiments, the method comprising the following method steps: (1) Forming a complex of a radionuclide and a chelating agent linked to a cell receptor-binding organic moiety by: (1.1) Preparing an aqueous solution comprising the radionuclide; (1.2) Preparing an aqueous solution comprising a cell receptor-binding organic moiety linked to a chelating agent, a first stabilizer, and optionally a second stabilizer; and (1.3) Mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; (2) Diluting the complex solution obtained by step (1) by: (2.1) Preparing an aqueous dilution solution optionally comprising a second stabilizer; and (2.2) Mixing the complex solution obtained by step (1) with the dilution solution obtained by step (2.1).

[0068] 33. The method according to embodiment 32, wherein only the first stabilizer is present during step (1.3), preferably in an amount such that a concentration of from 0.5 to 5 mg / mL, more preferably from 0.5 to 2 mg / mL, even more preferably from 0.5 to 1 mg / mL, and even more preferably from 0.5 to 0.7 mg / mL is obtained in the final solution.

[0069] 34. The method according to any one of embodiments 32 to 33, wherein during step (1.3), a partial amount of the second stabilizer is already present in the solution, and another partial amount of the second stabilizer is added in step (2.1) after step (1.3).

[0070] 35. The aqueous drug solution according to any one of Embodiments 32 to 34, wherein the second stabilizer is added in Step (2.1) after Step (1.3).

[0071] 36. The aqueous drug solution according to any one of Embodiments 32 - 35, wherein the second stabilizer is added in Step (2.1) after Step (1.3), preferably in an amount to obtain a concentration in the final solution from 0.5 to 10 mg / mL, more preferably from 1.0 to 8.0 mg / mL, even more preferably from 2.0 to 5.0 mg / mL, and even more preferably from 2.2 to 3.4 mg / mL.

[0072] 37. The method according to any one of Embodiments 32 to 36, wherein the solution of Step (1.2) further comprises a buffer, preferably an acetate buffer.

[0073] 38. The method according to any one of Embodiments 32 to 37, wherein in Step (1.3), the resulting mixture is heated to a temperature from 70 °C to 99 °C, preferably from 90 °C to 98 °C, for a period from 2 to 59 minutes.

[0074] 39. The method according to any one of Embodiments 32 to 38, wherein the solution of Step (2.1) further comprises diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

[0075] 40. The method according to any one of Embodiments 32 to 39, the method further comprising the following method steps: (3) Filtering the solution obtained in Step (2) through 0.2 μm: (4) Dispensing the filtered solution obtained by Step (3) into dose unit containers in a volume required to deliver the following radioactive dose: from 5.0 to 10 MBq, preferably from 7.0 to 8.0 MBq, more preferably from 7.3 to 7.7 MBq, even more preferably from 7.4 - 7.5 MBq, and preferably the volume is from 10 to 50 mL, more preferably from 15 to 30 mL, and even more preferably from 20 to 25 mL.

[0076] 41. The method according to any one of Embodiments 32 to 40, wherein the solution of Step (1.1) comprises LuCl 3 and HCl.

[0077] 42. The method according to any one of embodiments 32 to 41, wherein the solution in step (1.2) comprises 177Lu-DOTA-TATE or 177Lu-DOTA-TOC, gentisic acid, acetic acid and sodium acetate.

[0078] 43. The method according to any one of embodiments 32 to 42, wherein the solution in step (2.1) comprises DTPA and ascorbic acid.

[0079] 44. The method according to any one of embodiments 32 to 43, wherein the dose unit container in step (4) is a stoppered vial enclosed in a lead container.

[0080] 45. An aqueous pharmaceutical solution obtained (or obtainable) by the method defined in any one of embodiments 32 to 44.

[0081] Further embodiments of the present invention are described in the following as "Embodiment E": E1. An aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprising: (a) A complex formed by: (ai) The radionuclide 177Lu (lutetium-177), and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; and (b) At least two different stabilizers against radiolytic degradation; Wherein The radionuclide is present at a concentration providing a volume radioactivity of from 250 to 500 MBq / mL; and The stabilizers are present at a total concentration of from 0.2 to 20.0 mg / mL.

[0082] "A complex formed by..." can alternatively be expressed as: "A complex of...".

[0083] "Different" in "two different stabilizers" means a difference in the chemical entities of such stabilizers. "Two different stabilizers" has the meaning that the two stabilizers are different chemical entities. For example, gentisic acid and ascorbic acid are two different stabilizers.

[0084] "At least two kinds" means two or more kinds. However, it is preferred that there are only two stabilizers (not three or more). Further preferably, ethanol is not one of the two stabilizers.

[0085] E2. The aqueous drug solution according to embodiment E1, wherein the component (b) comprises a stabilizer: (bi) Gentisic acid or its salt; and (bii) Ascorbic acid or its salt.

[0086] E3. The aqueous drug solution according to embodiment E2, where (bi) Gentisic acid is present at a concentration of from 0.5 to 2 mg / mL, preferably from 0.5 to 1 mg / mL; and (bii) Ascorbic acid is present at a concentration of from 2.0 to 5.0 mg / mL.

[0087] In a specific embodiment, the present invention provides: An aqueous drug solution, the aqueous drug solution comprising: (a) A complex formed by (ai) The radionuclide 177Lu (lutetium-177) at a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL, and (aii) A somatostatin receptor binding peptide linked to the chelating agent DOTA; and (b) A stabilizer against radiolytic degradation (bi) Gentisic acid at a concentration of from 0.5 to 1 mg / mL and (bii) Ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL.

[0088] E4. The aqueous drug solution according to embodiment E3, the aqueous drug solution further comprising: (c) Diethylenetriaminepentaacetic acid (DTPA) or its salt at a concentration of from 0.01 to 0.10 mg / mL.

[0089] E5. The aqueous drug solution according to embodiment E3 or E4, the aqueous drug solution further comprising: (d) An acetate buffer solution, which consists of: (di) Acetic acid at a concentration of from 0.3 to 0.7 mg / mL; and (dii) Sodium acetate at a concentration of 0.4 to 0.9 mg / mL; Preferably, the acetate buffer provides a pH of from 4.5 to 6.0, preferably from 4.7 to 6.0, more preferably from 5.0 to 6.0, and even more preferably from 5.0 to 5.5.

[0090] In one specific embodiment, the present invention provides: An aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprising: (a) A complex formed by: (ai) The radionuclide 177Lu (lutetium-177) at a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL, and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; (b) At least two radiolytic degradation-resistant stabilizers, which comprise (bi) gentisic acid at a concentration of from 0.5 to 1 mg / mL and (bii) ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of from 0.01 to 0.10 mg / mL; and (d) An acetate buffer, which consists of: (di) Acetic acid at a concentration of from 0.3 to 0.7 mg / mL; and (dii) Sodium acetate at a concentration of 0.4 to 0.9 mg / mL; Preferably, the acetate buffer provides a pH of from 5.0 to 5.5.

[0091] In one specific embodiment, the present invention provides: An aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprising: (a) A complex formed by: (ai) The radionuclide 177Lu (lutetium-177) at a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL, and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; (b) A stabilizer against radiolytic degradation, which consists of: (bi) gentisic acid with a concentration ranging from 0.5 to 1 mg / mL and (bii) ascorbic acid with a concentration ranging from 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) or its salt with a concentration ranging from 0.01 to 0.10 mg / mL; and (d) An acetate buffer solution, which consists of: (di) acetic acid with a concentration ranging from 0.3 to 0.7 mg / mL; and (dii) sodium acetate with a concentration ranging from 0.4 to 0.9 mg / mL; Preferably, the acetate buffer solution provides a pH ranging from 5.0 to 5.5.

[0092] The pH value indicated herein is the pH value of the final solution. However, it can also be the pH value during the solution manufacturing process, for example, the pH value during the complex formation process.

[0093] E6. The aqueous drug solution according to any one of embodiments E1 to E5, wherein at least one of the stabilizers is present during the complex formation of components (ai) and (aii), and at least one of these stabilizers is added after the complex formation of components (ai) and (aii).

[0094] E7. The aqueous drug solution according to any one of embodiments E1 to E5, wherein gentisic acid is present at least during the complex formation of components (ai) and (aii), and ascorbic acid is added at least after the complex formation of components (ai) and (aii).

[0095] E8. The aqueous drug solution according to any one of embodiments E1 to E5, wherein the only stabilizer present during the complex formation of components (ai) and (aii) is gentisic acid, and the only stabilizer added after the complex formation of components (ai) and (aii) is ascorbic acid.

[0096] In a specific embodiment, the present invention provides: An aqueous drug solution, the aqueous drug solution comprising: (a) A complex formed by the following (ai) The radionuclide 177Lu (lutetium-177), with a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL, and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; and (b) A stabilizer against radiolytic degradation (bi) Gentisic acid at a concentration of from 0.5 to 1 mg / mL (in the final solution) and (bii) Ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL (in the final solution); wherein gentisic acid is present during the complex formation of components (ai) and (aii), and ascorbic acid is added after the complex formation of components (ai) and (aii).

[0097] In a specific embodiment, the present invention is defined as follows: An aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprising: (a) A complex formed by (ai) The radionuclide 177Lu (lutetium-177), with a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL, and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; (b) At least two stabilizers against radiolytic degradation, comprising (bi) gentisic acid at a concentration of from 0.5 to 1 mg / mL and (bii) ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) or its salt at a concentration of from 0.01 to 0.10 mg / mL; and (d) An acetate buffer, which consists of: (di) Acetic acid at a concentration of from 0.3 to 0.7 mg / mL; and (dii) Sodium acetate at a concentration of 0.4 to 0.9 mg / mL; Preferably, the acetate buffer provides a pH of from 5.0 to 5.5; wherein gentisic acid is present during the complex formation of components (ai) and (aii), and ascorbic acid is added after the complex formation of components (ai) and (aii).

[0098] In a specific embodiment, the present invention is defined as follows: An aqueous solution of a drug, the aqueous solution of the drug comprising: (a) A complex formed by: (ai) The radionuclide 177Lu (lutetium-177) at a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL, and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; (b) A stabilizer against radiolytic degradation, consisting of: (bi) gentisic acid at a concentration of from 0.5 to 1 mg / mL and (bii) ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of from 0.01 to 0.10 mg / mL; and (d) An acetate buffer, consisting of: (di) acetic acid at a concentration of from 0.3 to 0.7 mg / mL; and (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL; Preferably, the acetate buffer provides a pH of from 5.0 to 5.5; wherein gentisic acid is present during the formation of the complex of components (ai) and (aii), and ascorbic acid is added after the formation of the complex of components (ai) and (aii).

[0099] E9. The aqueous solution of a drug according to any one of embodiments E6 to E8, wherein the stabilizer or stabilizers present during the formation of the complex of components (ai) and (aii) are present at a total concentration of from 15 to 50 mg / mL, preferably from 20 to 40 mg / mL, during the complex formulation.

[0100] E10. The aqueous solution of a drug according to embodiment E9, wherein the only stabilizer present during the formation of the complex of components (ai) and (aii) is gentisic acid and is present at a concentration of from 20 to 40 mg / mL, preferably from 25 to 35 mg / mL, during the complex formulation.

[0101] In one specific embodiment, the present invention is defined as follows: An aqueous solution of a drug, the aqueous solution of the drug comprising: (a) A complex formed by: (ai) The radionuclide 177Lu (lutetium-177), at a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL, and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; (b) At least two anti-radiolytic degradation stabilizers, comprising (bi) gentisic acid at a concentration of from 0.5 to 1 mg / mL and (bii) ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of from 0.01 to 0.10 mg / mL; and (d) An acetate buffer solution, consisting of: (di) Acetic acid at a concentration of from 0.3 to 0.7 mg / mL; and (dii) Sodium acetate at a concentration of from 0.4 to 0.9 mg / mL; Preferably, the acetate buffer solution provides a pH of from 5.0 to 5.5; Wherein gentisic acid is present during the complex formation of components (ai) and (aii), and ascorbic acid is added after the complex formation of components (ai) and (aii); and wherein the only stabilizer present during the complex formation of components (ai) and (aii) is gentisic acid and is present at a concentration of from 20 to 40 mg / mL, preferably from 25 to 35 mg / mL, during the complex formulation.

[0102] In one specific embodiment, the present invention is defined as follows: An aqueous pharmaceutical solution, said aqueous pharmaceutical solution comprising: (a) A complex formed by (ai) The radionuclide 177Lu (lutetium-177), at a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL, and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; (b) An anti-radiolytic degradation stabilizer, consisting of: (bi) gentisic acid at a concentration of from 0.5 to 1 mg / mL and (bii) ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of from 0.01 to 0.10 mg / mL; and (d) An acetate buffer solution, consisting of: (di) acetic acid at a concentration of from 0.3 to 0.7 mg / mL; and (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL; Preferably, the acetate buffer provides a pH of from 5.0 to 5.5; wherein gentisic acid is present during the complex formation of components (ai) and (aii), and ascorbic acid is added after the complex formation of components (ai) and (aii); and wherein the only stabilizer present during the complex formation of components (ai) and (aii) is gentisic acid and is present at a concentration of from 20 to 40 mg / mL, preferably from 25 to 35 mg / mL, during the complex formulation.

[0103] Alternatively, embodiments E6 to E10 can be defined by the following wording: E6. An aqueous pharmaceutical solution according to any one of embodiments E1 to E5, which is produced by the presence of at least one of the stabilizers during the complex formation of components (ai) and (aii), and the addition of at least one of the stabilizers after the complex formation of components (ai) and (aii).

[0104] E7. An aqueous pharmaceutical solution according to any one of embodiments E1 to E5, which is produced by the presence of at least gentisic acid during the complex formation of components (ai) and (aii), and the addition of at least ascorbic acid after the complex formation of components (ai) and (aii).

[0105] E8. An aqueous pharmaceutical solution according to any one of embodiments E1 to E5, which is produced by the presence of gentisic acid as the only stabilizer during the complex formation of components (ai) and (aii), and the addition of ascorbic acid as the only stabilizer after the complex formation of components (ai) and (aii).

[0106] E9. An aqueous pharmaceutical solution according to any one of embodiments E6 to E8, which is produced by the presence of the stabilizer or stabilizers present during the complex formation of components (ai) and (aii) at a total concentration of from 15 to 50 mg / mL, preferably from 20 to 40 mg / mL, during the complex formation.

[0107] E10. The aqueous solution of the drug according to embodiment E9 is produced by the presence of gentisic acid as the sole stabilizer during the complex formation of components (ai) and (aii) and by its presence at a concentration of from 20 to 40 mg / mL, preferably from 25 to 35 mg / mL, during the complex formulation.

[0108] In an embodiment of the invention, particularly in embodiments E9 and E10, the radionuclide can be present during the complex formation at a concentration providing a volumetric radioactivity of up to 20 GBq / mL, preferably up to 15 GBq / mL, or from 5 to 20 GBq / mL, preferably from 10 to 20 GBq / mL, more preferably from 10 to 15 GBq / mL.

[0109] In a specific embodiment, the invention is defined as follows: An aqueous solution of a drug, the aqueous solution of the drug comprising: (a) A complex formed by: (ai) The radionuclide 177Lu (lutetium-177) at a concentration providing a volumetric radioactivity of from 250 to 500 MBq / mL (in the final solution), and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; (b) At least two stabilizers against radiolytic degradation, comprising (bi) gentisic acid at a concentration of from 0.5 to 1 mg / mL and (bii) ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of from 0.01 to 0.10 mg / mL; and (d) An acetate buffer, which consists of: (di) Acetic acid at a concentration of from 0.3 to 0.7 mg / mL; and (dii) Sodium acetate at a concentration of 0.4 to 0.9 mg / mL; Preferably, the acetate buffer provides a pH of from 5.0 to 5.5; wherein gentisic acid is present during the complex formation of components (ai) and (aii), and ascorbic acid is added after the complex formation of components (ai) and (aii); and wherein the sole stabilizer present during the complex formation of components (ai) and (aii) is gentisic acid and is present at a concentration of from 20 to 40 mg / mL during the complex formulation; and wherein the radionuclide is present at a concentration that provides a volumetric radioactivity of 10 to 20 GBq / mL during complex formation.

[0110] In one specific embodiment, the present invention is defined as follows: An aqueous pharmaceutical solution, the aqueous pharmaceutical solution comprising: (a) A complex formed by: (ai) The radionuclide 177Lu (lutetium-177) at a concentration that provides a volumetric radioactivity of from 250 to 500 MBq / mL (in the final solution), and (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA; (b) A stabilizer against radiolytic degradation, which consists of: (bi) Gentisic acid at a concentration of from 0.5 to 1 mg / mL and (bii) Ascorbic acid at a concentration of from 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of from 0.01 to 0.10 mg / mL; and (d) An acetate buffer, which consists of: (di) Acetic acid at a concentration of from 0.3 to 0.7 mg / mL; and (dii) Sodium acetate at a concentration of from 0.4 to 0.9 mg / mL; Preferably, the acetate buffer provides a pH of from 5.0 to 5.5; wherein gentisic acid is present during the complex formation of components (ai) and (aii), and ascorbic acid is added after the complex formation of components (ai) and (aii); and wherein the only stabilizer present during the complex formation of components (ai) and (aii) is gentisic acid and is present at a concentration of from 20 to 40 mg / mL during complex formulation; and wherein the radionuclide is present at a concentration that provides a volumetric radioactivity of 10 to 20 GBq / mL during complex formation.

[0111] E11. The aqueous pharmaceutical solution according to any one of the foregoing E embodiments has a shelf life of at least 72 hours when stored at ≤25 °C, in particular at least 72 hours when stored at 25 °C.

[0112] "Shelf life" has its ordinary meaning in the context of pharmaceutical products herein. The shelf life is the length of time during which a pharmaceutical product can be stored while its product characteristics still comply with the product specifications defined during the pharmaceutical development process and agreed upon by the health authorities.

[0113] E12. The radiochemical purity (determined by HPLC) of the aqueous pharmaceutical solution according to any one of the foregoing Embodiment E remains ≥ 95% when stored at 25 °C for at least 72 hours.

[0114] E13. The aqueous pharmaceutical solution according to any one of the foregoing Embodiment E, wherein the solution is produced on a commercial manufacturing scale, particularly in batch sizes of at least 20 GBq, at least 50 GBq, or at least 70 GBq.

[0115] E14. The aqueous pharmaceutical solution according to any one of the foregoing embodiments, which is ready-to-use.

[0116] E15. A method for preparing an aqueous pharmaceutical solution as defined in any one of the foregoing Embodiment E, the method comprising the following method steps: (1) Forming a complex of the radionuclide 177Lu and a somatostatin receptor-binding peptide linked to the chelator DOTA as follows (1.1) Preparing an aqueous solution containing the radionuclide; (1.2) Preparing an aqueous solution containing a somatostatin receptor-binding peptide linked to the chelator and at least one stabilizer against radiolytic degradation; and (1.3) Mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; (2) Diluting the complex solution obtained by step (1) as follows (2.1) Preparing an aqueous dilution solution optionally containing at least one stabilizer against radiolytic degradation; and (2.2.) Mixing the complex solution obtained by step (1) with the dilution solution obtained by step (2.1) to obtain a final solution; wherein if the solution prepared in (1.2) contains only one stabilizer, the solution prepared in (2.1) contains at least one stabilizer.

[0117] E16. The method according to embodiment E15, wherein the solution prepared in step (1.2) contains at least one stabilizer, and the solution prepared in step (2.1) contains at least one stabilizer.

[0118] E17. The method according to embodiment E15, wherein the solution prepared in step (1.2) contains at least the stabilizer gentisic acid, and the solution prepared in step (2.1) contains at least the stabilizer ascorbic acid.

[0119] E18. The method according to embodiment E15, wherein the solution prepared in step (1.2) contains only one stabilizer, which is gentisic acid, and the solution prepared in step (2.1) contains only one stabilizer, which is ascorbic acid.

[0120] E19. The method according to any one of embodiments E15 to E18, wherein the solution prepared in step (1.2) contains one or more stabilizers with a total concentration of from 15 to 50 mg / mL, preferably from 20 to 40 mg / mL.

[0121] E20. The method according to any one of embodiments E15 to E18, wherein the solution prepared in step (1.2) contains only one stabilizer, which is gentisic acid with a concentration of from 20 to 40 mg / mL, preferably from 25 to 35 mg / mL.

[0122] E21. The method according to any one of embodiments E15 to E20, wherein the solution of step (1.2) further contains a buffer, preferably an acetate buffer.

[0123] E22. The method according to any one of embodiments E15 to E21, wherein in step (1.3), the resulting mixture is heated to a temperature of from 70 °C to 99 °C (for example, between 80 °C - 99 °C), preferably from 90 °C to 98 °C (for example, 90 °C - 95 °C), for a duration of from 2 to 59 minutes (for example, 2 - 20 minutes, 2 - 15 minutes, 5 - 15 minutes, or 5 - 12 minutes), preferably from 5 - 15 minutes or 10 to 15 minutes.

[0124] E23. The method according to any one of embodiments E15 to E22, wherein the solution in step (2.1) further comprises diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

[0125] E24. The method according to any one of embodiments E15 to E23, the method further comprising the following method steps: (3) Filtering the solution obtained in step (2) through 0.2 μm: (4) Dispensing the filtered solution obtained by step (3) into dose unit containers in a volume required to deliver the following radioactive doses: from 5.0 to 10 MBq, preferably from 7.0 to 8.0 MBq, more preferably from 7.3 to 7.7 MBq, even more preferably from 7.4 - 7.5 Mbq, preferably the volume is from 10 to 50 mL, more preferably from 15 to 30 mL, even more preferably from 20 to 25 mL.

[0126] E25. The method according to any one of embodiments E15 to E24, wherein the solution in step (1.1) comprises LuCl 3 and HCl.

[0127] E26. The method according to any one of embodiments E15 to E25, wherein the solution in step (1.2) comprises 177Lu-DOTA-TATE or 177Lu-DOTA-TOC, gentisic acid, acetic acid and sodium acetate.

[0128] E27. The method according to any one of embodiments E15 to E26, wherein the solution in step (2.1) comprises DTPA and ascorbic acid.

[0129] E28. The method according to any one of embodiments E24 to E27, wherein the dose unit container in step (4) is a stoppered vial enclosed in a lead container.

[0130] E29. An aqueous pharmaceutical solution obtainable (or: obtained) by the method defined in any one of embodiments E15 to E28.

[0131] Further embodiments of the present invention are described in the following as "EE embodiments": EE1. A method for preparing an aqueous pharmaceutical solution, the method comprising: Providing a solution containing a complex of the radionuclide 177Lu (lutetium-177) and a somatostatin receptor-binding peptide linked to the chelator DOTA; a first stabilizer against radiolytic degradation, and optionally a second stabilizer against radiolytic degradation different from the first stabilizer; and Diluting the solution containing the complex with an aqueous dilution solution optionally containing at least one stabilizer against radiolytic degradation to obtain an aqueous pharmaceutical solution; Wherein if the solution containing the complex contains only the first stabilizer and does not contain the second stabilizer, the aqueous dilution solution contains at least one stabilizer different from the first stabilizer, and in the obtained aqueous pharmaceutical solution, the radionuclide 177Lu is present at a concentration providing a volume radioactivity of from 250 to 500 MBq / mL, and the stabilizers are present at a total concentration of from 0.2 to 20.0 mg / mL.

[0132] For example, the first stabilizer is gentisic acid or its salt, and the second stabilizer, when present, is ascorbic acid or its salt. For example, at least one stabilizer in the aqueous dilution solution, when present, is ascorbic acid or its salt.

[0133] EE2. The method according to embodiment EE1, the method comprising the following method steps: (1) Forming a complex of the radionuclide 177Lu and a somatostatin receptor-binding peptide linked to the chelator DOTA by: (1.1) Providing an aqueous solution containing the radionuclide; (1.2) Providing an aqueous solution containing: a somatostatin receptor-binding peptide linked to the chelator, and a first stabilizer against radiolytic degradation, and optionally a second stabilizer against radiolytic degradation different from the first stabilizer; and (1.3) Mixing the solutions provided in steps (1.1) and (1.2), and heating the resulting mixture to form a solution containing the complex; (2) Diluting the solution containing the complex obtained from step (1) by: (2.1) Providing an aqueous dilution solution optionally containing at least one stabilizer against radiolytic degradation; and (2.2.) Mixing the solution containing the complex obtained from step (1) with the dilution solution provided in step (2.1) to obtain the aqueous pharmaceutical solution; Wherein if the solution in step (1.2) contains only one stabilizer, i.e., the first stabilizer, then the solution in step (2.1) contains at least one stabilizer different from the first stabilizer.

[0134] EE3. The method according to embodiment EE1 or EE2, wherein the solution in step (1.2) contains the first stabilizer, and the solution provided in step (2.1) contains at least one stabilizer.

[0135] EE4. The method according to any one of embodiments EE1 to EE3, wherein the solution provided in step (1.2) contains at least gentisic acid or a salt thereof, and the solution provided in step (2.1) contains at least ascorbic acid or a salt thereof.

[0136] EE5. The method according to any one of embodiments EE1 to EE4, wherein the solution provided in step (1.2) contains only one stabilizer, the stabilizer being gentisic acid or a salt thereof, and the solution provided in step (2.1) contains only one stabilizer, the stabilizer being ascorbic acid or a salt thereof.

[0137] EE6. The method according to any one of embodiments EE1 to EE5, wherein the solution provided in step (1.2) contains one or more stabilizers at a total concentration of from 15 to 50 mg / mL.

[0138] EE7. The method according to any one of embodiments EE1 to EE6, wherein the solution provided in step (1.2) contains one or more stabilizers at a total concentration of from 20 to 40 mg / mL.

[0139] EE8. The method according to any one of embodiments EE1 to EE7, wherein the solution provided in step (1.2) contains only one stabilizer, the stabilizer being gentisic acid at a concentration of from 20 to 40 mg / mL.

[0140] EE9. The method according to any one of embodiments EE1 to EE8, wherein the solution provided in step (1.2) contains only one stabilizer, the stabilizer being gentisic acid at a concentration of from 25 to 35 mg / mL.

[0141] EE10. The method according to any one of embodiments EE1 to EE9, wherein the solution provided in step (1.2) further comprises a buffer, such as acetate buffer.

[0142] EE11. The method according to any one of embodiments EE1 to EE10, wherein in step (1.3), the resulting mixture is heated to a temperature ranging from 70 °C to 99 °C (for example, between 80 °C - 99 °C, 90 °C - 98 °C, or between 90 °C - 95 °C).

[0143] EE12. The method according to any one of embodiments EE1 to EE11, wherein in step (1.3), the resulting mixture is heated for 2 to 59 minutes (for example, 2 - 20 minutes, 2 - 15 minutes, 5 - 15 minutes, 5 - 12 minutes, 5 - 15 minutes or 10 to 15 minutes).

[0144] EE13. The method according to any one of embodiments EE1 to EE12, wherein in step (1.3), the resulting mixture is heated to a temperature ranging from 90 °C to 98 °C for 10 to 15 minutes.

[0145] EE14. The method according to any one of embodiments EE1 to EE13, wherein the solution provided in step (2.1) further comprises diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

[0146] EE15. The method according to any one of embodiments EE1 to EE14, the method further comprising the following method steps: (3) Filtering the solution obtained in step (2) through 0.2 μm; and (4) Dispensing the filtered solution obtained by step (3) into dose unit containers in a volume required to deliver the following radioactive dose: from about 5 to about 10 MBq (for example, from about 7 to about 8 MBq, or from 7.3 to 7.7 MBq, or from 7.4 - 7.5 MBq).

[0147] For example, the volume in embodiment EE15 is from about 10 to about 50 mL, such as from about 15 to about 30 mL or from about 20 to about 25 mL.

[0148] EE16. The method according to any one of embodiments EE1 to EE15, wherein the solution in step (1.1) comprises LuCl 3 and HCl.

[0149] EE17. The method according to any one of embodiments EE1 to EE16, wherein the solution in step (1.2) comprises 177Lu-DOTA-TATE or 177Lu-DOTA-TOC, gentisic acid, acetic acid and sodium acetate.

[0150] EE18. The method according to any one of embodiments EE1 to EE17, wherein the solution in step (2.1) comprises DTPA and ascorbic acid.

[0151] EE19. The method according to any one of embodiments EE15 to EE18, wherein the dose unit container in step (4) is a stoppered vial enclosed in a lead container.

[0152] EE20. An aqueous pharmaceutical solution obtainable by the method as defined in any one of embodiments EE1 to E19.

[0153] EE21. The aqueous pharmaceutical solution according to embodiment EE20, which has a shelf life of at least 72 hours when stored at ≤ 25 °C, in particular at least 72 hours when stored at 25 °C.

[0154] EE22. The aqueous pharmaceutical solution according to embodiment EE20 or EE21, the radiochemical purity of which (determined by HPLC) remains ≥ 95% for at least 72 hours when stored at 25 °C.

[0155] EE23. The aqueous pharmaceutical solution according to any one of embodiments EE20 to EE22, wherein the solution is produced in a batch size of at least 20 GBq, at least 50 GBq or at least 70 GBq.

[0156] EE24. The aqueous pharmaceutical solution according to any one of embodiments EE20 to EE23, which is ready-to-use.

[0157] EE25. The aqueous drug solution according to any one of embodiments EE20 to EE24, wherein the aqueous drug solution does not contain ethanol.

[0158] EE26. The aqueous drug solution according to any one of embodiments EE20 to EE25, wherein gentisic acid is present at a concentration of from 0.5 to 2 mg / mL, preferably from 0.5 to 1 mg / mL; and ascorbic acid is present at a concentration of from 2.0 to 5.0 mg / mL.

[0159] EE27. The aqueous drug solution according to any one of embodiments EE20 to EE26, wherein the diethylenetriaminepentaacetic acid (DTPA) or its salt is present at a concentration of from 0.01 to 0.10 mg / mL.

[0160] EE28. The aqueous drug solution according to any one of embodiments EE20 to EE27, wherein the acetate buffer is composed of acetic acid at a concentration of 0.3 to 0.7 mg / mL; and sodium acetate at a concentration of 0.4 to 0.9 mg / mL; preferably, the acetate buffer provides a pH of from 4.5 to 6.0, more preferably from 5.0 to 5.5.

[0161] In all embodiments as described herein, the somatostatin receptor binding peptide linked to the chelating agent DOTA (component (aii)) is preferably DOTA-TATE (octreotate) or DOTA-TOC (tracetide), more preferably DOTA-TATE (octreotate).

[0162] The present invention further provides an aqueous drug solution as defined herein for the treatment of neuroendocrine tumors (NETs).

[0163] Alternatively, the present invention provides a method for treating NETs in a human patient in need thereof, the method comprising administering an effective amount of an aqueous drug solution as defined herein.

[0164] As yet another alternative, the present invention provides the use of an aqueous drug solution as defined herein for the manufacture / preparation of a medicament for the treatment of NETs.

[0165] As yet another alternative, the present invention provides a medicament for the treatment of NETs, which comprises an aqueous drug solution as defined herein.

[0166] Neuroendocrine tumors (NETs) that can be treated by the aqueous solution of the drug as defined herein alone or in combination therapy according to the present invention are selected from the group consisting of: gastroenteropancreatic neuroendocrine tumors, carcinoid tumors, pheochromocytomas, paragangliomas, medullary thyroid carcinoma, pulmonary neuroendocrine tumors, thymic neuroendocrine tumors, carcinoid tumors or pancreatic neuroendocrine tumors, pituitary adenomas, adrenal tumors, Merkel cell carcinoma, breast cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, head and neck tumors, urothelial carcinoma (bladder), renal cell carcinoma, hepatocellular carcinoma, GIST, neuroblastoma, cholangiocarcinoma, cervical tumors, Ewing's sarcoma, osteosarcoma, small cell lung cancer (SCLC), prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, neuroectodermal tumors, and sensitive neuroectodermal tumors.

[0167] Other NET tumors that can be treated by the aqueous solution of the drug as defined herein alone or in combination therapy according to the present invention are selected from the group consisting of: functional carcinoid tumors, insulinomas, gastrinomas, vasoactive intestinal peptide (VIP) tumors, glucagonomas, serotoninoma, histaminoma, adrenocorticotropic hormone adenoma (ACTH adenoma), pheochromocytoma, and somatostatinoma.

[0168] The present invention further provides a combination or combination therapy of a complex formed by the radionuclide 177Lu (lutetium-177) and a somatostatin receptor-binding peptide linked to a chelating agent as defined herein, or a combination or combination therapy of the aqueous solution of the drug as defined herein with one or more therapeutic agents as described below: In certain cases, the aqueous solution of the drug of the present invention is combined with other therapeutic agents such as other anti-cancer agents, anti-allergy agents, anti-nausea agents (or anti-emetics), analgesics, cytoprotective agents, and combinations thereof.

[0169] Consider general chemotherapeutic agents used in combination therapies, including anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposomal injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposomal injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), calcium folinate, melphalan (Alkeran®), 6-mercaptopurine (Purinetol®), methotrexate (Folex(®), mitoxantrone (Novantrone®), gemtuzumab (mylotarg), paclitaxel (Taxol®), albumin-bound paclitaxel (Abraxane®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0170] Anticancer agents of particular interest in combination with the aqueous solution of the drug of the present invention include: [, Tyrosine kinase inhibitor: , ] Erlotinib hydrochloride (Tarceva®); Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperidin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in U.S. Patent No. 6,780,996); Dasatinib (Sprycel®); Pazopanib (Votrient®); Sorafenib (Nexavar®); Vandetanib (ZD6474); and Imatinib or Imatinib mesylate (Gilvec® and Gleevec®).

[0171] [vascular endothelial growth factor (] [VEGF] [)Receptor inhibitors:] Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanib alaninate (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoic acid); Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®); Cediranib (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS 928326-83-4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS 332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®); Ponatinib (AP24534, CAS 943319-70-8); Tivozanib (AV951, CAS 475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanib dihydrochloride (PTK787, CAS 212141-51-0); Brivanib (BMS-540215, CAS 649735-46-6); Vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02 / 066470); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); Linfanib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CAS 849217-68-1); Lestaurtinib (CAS 111358-88-4);N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]trioxan-5-yl)methyl)piperidin-3-ol (BMS690514); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[ c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide (BHG712, CAS 940310-85-0); and Aflibercept (Eylea®), sulfatinib (surufatinib). ;

[0172] [ , Platelet-derived growth factor ( , ] [ , PDGF , ] [ , ) receptor inhibitor:, Imatinib (Gleevec®); Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769-58-1); Pazopanib (Votrient®); Axitinib (Inlyta®); Sorafenib (Nexavar®); Vargatef (BIBF1120, CAS 928326-83-4); Telatinib (BAY57-9352, CAS 332012-40-5); Vatalanib dihydrochloride (PTK787, CAS 212141-51-0); and Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02 / 066470).

[0173] [, Fibroblast growth factor receptor ( , ] [, FGFR , ] [, ) inhibitor:, ]Brivanib alaninate (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]trioxan-6-yloxy)propan-2-yl)2-aminopropionic acid);Vargatef (BIBF1120, CAS 928326-83-4);Dovitinib dilactic acid (TKI258, CAS 852433-84-2); 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperidin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (BGJ398, CAS 872511-34-7); Danusertib (PHA-739358); and N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)-urea (PD173074, CAS 219580-11-7). Sulfatinib (surufatinib).

[0174] [ , Aurora kinase , ] [ , A , ] [ , inhibitor:, ] Danusertib (PHA-739358); N-[4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]phenyl]benzamide (ZM447439, CAS 331771-20-1); 4-(2-amino-4-methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phenyl]-2-pyrimidinamine (CYC116, CAS 693228-63-6); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); Alisertib (MLN8237); (N-{2-[6-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-hydroxyethyl}-acetamide) (PF-03814735); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (MLN8054, CAS 869363-13-3); Cenisertib (R-763); Barasertib (AZD1152); and N-cyclopropyl-N'-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]-urea (AT9283).

[0175] [, Cyclin-dependent kinase ( , ] [, CDK , ] [, ) inhibitor:, ]Aloisine A; Alvocidib (also known as Flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone and described in U.S. Patent No. 5,621,002); Crizotinib (PF-02341066, CAS 877399-52-5); 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one hydrochloride (P276-00, CAS 920113-03-7); E7070; Roscovitine (CYC202); 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperidin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, hydrochloride (PD0332991); Dinaciclib (SCH727965); N-[5-[[(5-tert-butyl-1,3-thiazol-2-yl)methyl]thio]-1,3-thiazol-2-yl]piperidine-4-carboxamide (BMS 387032, CAS 345627-80-7); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (MLN8054, CAS 869363-13-3); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinecarboxamide (AG-024322, CAS 837364-57-5); 4-(2,6-dichlorobenzoyl amino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS 844442-38-2); 4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438, CAS 602306-29-6); Palbociclib (PD-0332991); and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfinyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol (BAY 10000394), ribociclib.

[0176] [, Cell cycle checkpoint kinase ( , ] [, CHK , ] [, ) inhibitor: , ] 7-Hydroxycrossolin (UCN-01); 6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidin-7-amine (SCH900776, CAS 891494-63-6); N-[(S)-piperidin-3-yl]-5-(3-fluorophenyl)-3-ureidothiophene-2-carboxamide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-Aminoactinomycin D (7-AAD), Isogranulatimide, debromohymenialdisine; N-[5-bromo-4-methyl-2-[(2S)-2-pyrrolidinylmethoxy]-phenyl]-N'-(5-methyl-2-pyridinyl)urea (LY2603618, CAS 911222-45-2); Sulforaphane (CAS 4478-93-7, 4-methylsulfinylbutyl isothiocyanate); 9,10,11,12-Tetrahydro-9,12-epoxy-1H-dindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1,3(2H)-dione (SB-218078, CAS 135897-06-2); and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL), and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr); and (αR)-α-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepin-8-yl]-cyclohexaneacetamide (PF-0477736).

[0177] [, 3- , ] [, Phosphatidylinositol , ] [, - , ] [, -dependent kinase , ] [, -1 , ] [ , ( , ] [ , PDK1 , ] [ , or , ] [ , PDPK1 , ] [ , ) inhibitor: , ]7-2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012, CAS 742112-33-0); pyrrolidine-1-carboxylic acid (3-{5-bromo-4-[2-(1H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)-amide (BX912, CAS 702674-56-4); and 4-dodecyl-N-1,3,4-thiadiazol-2-yl-benzenesulfonamide (PHT-427, CAS 1191951-57-1).

[0178] [ , Protein kinase , ] [ , C , ] [ , ( , ] [ , PKC , ] [ , ) activator: , ]Bryo-1 and AEB071.

[0179] [ , B-RAF , ] [ , inhibitor:, Regorafenib (BAY 73-4506, CAS 755037-03-7); Tuvizanib (AV951, CAS 475108-18-0); Vemurafenib (Zelboraf®, PLX-4032, CAS 918504-65-1); 5-[1-(2-Hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydroinden-1-one oxime (GDC-0879, CAS 905281-76-7); 5-[2-[4-[2-(Dimethylamino)ethoxy]phenyl]-5-(4-pyridyl)-1H-imidazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime (GSK2118436 or SB590885); (+ / -)-Methyl (5-(2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl)carbamate (also known as XL-281 and BMS908662) and N-(3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (also known as PLX4720).

[0180] [, C-RAF , ] [, inhibitor: , ] Sorafenib (Nexavar®); 3-(Dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-benzamide (ZM336372, CAS 208260-29-1); and 3-(1-Cyano-1-methylethyl)-N-[3-[(3,4-dihydro-3-methyl-4-oxo-6-quinazolinyl)amino]-4-methylphenyl]-benzamide (AZ628, CAS 1007871-84-2).

[0181] [, Human granulocyte colony-stimulating factor ( , ] [, G-CSF , ] [, ) regulator: , ] Filgrastim (Neupogen®); Sunitinib malate (Sutent®); Pegfilgrastim (Neulasta®) and quizartinib (AC220, CAS 950769-58-1).

[0182] [ , RET , ] [ , inhibitor: , ] Sunitinib malate (Sutent®); Vandetanib (Caprelsa®); Motesanib diphosphate (AMG706, CAS 857876 - 30 - 3, N-(2,3 - dihydro - 3,3 - dimethyl - 1H - indol - 6 - yl)-2-[(4 - pyridylmethyl)amino]-3 - pyridinecarboxamide, as described in PCT Publication No. WO 02 / 066470); Sorafenib (BAY 43 - 9006); Regorafenib (BAY73 - 4506, CAS 755037 - 03 - 7); and Danusertib (PHA - 739358).

[0183] [ , FMS , ] [ , -like tyrosine kinase , ] [ , 3 , ] [ , ( , ] [ , FLT3 , ] [ , ) inhibitor or , ] [ , CD135 , ] [ , : , ] Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769 - 58 - 1); N-[(1 - methyl - 4 - piperidinyl)methyl]-3-[3-(trifluoromethoxy)phenyl]-imidazo[1,2 - b]pyridazin - 6 - amine sulfate (SGI - 1776, CAS 1173928 - 26 - 1); and Vargatef (BIBF1120, CAS 928326 - 83 - 4).

[0184] [ , c-KIT , ] [ , inhibitor:, Pazopanib (Votrient®); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02 / 066470); Masitinib (Masivet®); Regorafenib (BAY73-4506, CAS 755037-03-7); Tivozanib (AV951, CAS 475108-18-0); Vatalanib dihydrochloride (PTK787, CAS 212141-51-0); Telatinib (BAY57-9352, CAS 332012-40-5); Foretinib (GSK1363089, formerly known as XL880, CAS 849217-64-7); Sunitinib malate (Sutent®); Quizartinib (AC220, CAS 950769-58-1); Axitinib (Inlyta®); Dasatinib (BMS-345825); and Sorafenib (Nexavar®).

[0185] [, Bcr / Abl , ] [, kinase inhibitor:, Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7); Saracatinib (AZD0530); and N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalene-1,4-imine-9-yl]-2-sulfooxyethyl]-acetamide (PF-03814735, CAS 942487-16-3).

[0186] [, IGF-1R , ] [, inhibitor:, Linsitinib (OSI-906); [7-[trans-3-[(azetidin-1-yl)methyl]cyclobutyl]-5-(3-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (AEW541, CAS 475488-34-7); [5-(3-benzyloxyphenyl)-7-[trans-3-[(pyrrolidin-1-yl)methyl]cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (ADW742 or GSK552602A, CAS 475488-23-4); (2-[[3-bromo-5-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]propanedinitrile (tyrosine phosphorylation inhibitor AG1024, CAS 65678-07-1); 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[7-methyl-5-(4-morpholinyl)-1H-benzimidazol-2-yl]-2(1H)-pyridone (BMS536924, CAS 468740-43-4); 4-[2-[4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1,2-dihydro-2-oxo-3-pyridinyl]-7-methyl-1H-benzimidazol-5-yl]-1-piperidinepropanenitrile (BMS554417, CAS 468741-42-6); (2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoro-3-pyridinyl)-2-methyl-2-pyrrolidinecarboxamide (BMS754807, CAS 1001350-96-4); Picropodophyllotoxin (AXL1717); and Nordihydroguareacetic acid.

[0187] IGF-1R antibodies: Figitumumab (CP751871); Cixutumumab (IMC-A12); Ganitumumab (AMG-479); Robatumumab (SCH-717454); Dalotuzumab (MK0646); R1507 (available from Roche); BIIB022 (available from Biogen); and MEDI-573 (available from MedImmune).

[0188] [ , MET , ] [ , inhibitor:, Cabozantinib (XL184, CAS 849217-68-1); Foretinib (GSK1363089, formerly known as XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458); Crizotinib (Xalkori®, PF-02341066); (3Z)-5-(2,3-Dihydro-1H-indole-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-1,3-dihydro-2H-indol-2-one (SU11271); (3Z)-N-(3-Chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-methyl-2-oxoindoline-5-sulfonamide (SU11274); (3Z)-N-(3-Chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfonamide (SU11606); 6-[Difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]-quinoline (JNJ38877605, CAS 943540-75-8); 2-[4-[1-(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-1,4-Dioxaspiro[4.5]dec-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfonamide (MK2461, CAS 917879-39-1); 6-[[6-(1-Methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]thio]-quinoline (SGX523, CAS 1022150-57-7);and (3Z)-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrrol-2-yl]methylene]-1,3-dihydro-2H-indol-2-one (PHA665752, CAS 477575-56-7).;

[0189] [, Epidermal growth factor receptor ( , ] [, EGFR , ] [, ) inhibitor: , ] Erlotinib hydrochloride (Tarceva®), Gefitinib (Iressa®); N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butyramide, Tovok®); Vandetanib (Caprelsa®); Lapatinib (Tykerb®); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); Canertinib hydrochloride (CI-1033); 6-[4-[(4-ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); Mubritinib (TAK165); Pelitinib (EKB569); Afatinib (BIBW2992); Neratinib (HKI-272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid, (3S)-3-morpholinylmethyl ester (BMS599626); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-aminoquinazoline (XL647, CAS 781613-23-8); and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (PKI166, CAS 187724-61-4).

[0190] EGFR antibodies: Cetuximab (Erbitux®); Panitumumab (Vectibix®); Matuzumab (EMD-72000); Trastuzumab (Herceptin®); Nimotuzumab (hR3); Zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1).

[0191] [, mTOR , ] [, inhibitor:, Temsirolimus (Torisel®); ridaforolimus (formally deferolimus, (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxa-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03 / 064383); Everolimus (Afinitor® or RAD001); Rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3); (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS 1013101-36-4); N2-[1,4-dioxido-4-[[4-(4-oxido-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-spermidinylglycyl-L-α-aspartyl-L-serine, inner salt (SF1126, CAS 936487-67-1); and N-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinolinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-benzamide (XL765, also known as SAR245409); ethyl (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate (OSI-027).

[0192] [Mitogen-activated protein kinase ( [, MEK , ] [ , ) inhibitor:, XL-518 (also known as GDC-0973, CAS No. 1029872-29-4, available from the ACC Group); Selumetinib (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, also known as AZD6244 or ARRY 142886, and described in PCT Publication No. WO 2003077914); 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352, and described in PCT Publication No. WO 2000035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901, and described in PCT Publication No. WO 2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126, and described in US Patent No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (also known as RDEA119 or BAY869766, and described in PCT Publication No. WO 2007014011); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (also known as E6201, and described in PCT Publication No. WO 2003076424); 2'-amino-3'-methoxyflavone (also known as PD98059 available from Biaffin GmbH & Co., kg)); Vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5); Pimasertib (AS-703026, CAS 1204531-26-9); Dimethyl Sulfoxide Trametinib (GSK-1120212, CAS 1204531-25-80); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330); and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazolidin-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655).

[0193] [, Alkylating agent:, ] Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as Actinomycin-D, Cosmegen®); Melphalan (also known as L-PAM, L-Sarcolysin and Phenylalanine Mustard, Alkeran®); Altretamine (also known as Hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and Imidazole Carboxamide, DTIC-Dome®); Altretamine (also known as Hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Dichloromethyldiethylamine (also known as Nitrogen Mustard, Mustard Hydrochloride and Dichloromethyldiethylamine Hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as Thiophosphoramide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine Hydrochloride (Treanda®).

[0194] [, Aromatase inhibitor: , ] Exemestane (Aromasin®); Letrozole (Femara®); and Anastrozole (Arimidex®).

[0195] [, Topoisomerase , ] [, I , ] [, inhibitor: , ] Irinotecan (Camptosar®); Topotecan Hydrochloride (Hycamtin®); and 7-Ethyl-10-Hydroxycamptothecin (SN38).

[0196] [, Topoisomerase , ] [,II , ] [ , inhibitor: , ] Etoposide (VP-16 and Etoposide phosphate, Toposar®, VePesid®, and Etopophos®); Teniposide (VM-26, Vumon®); and Tafluposide.

[0197] [ , DNA , ] [ , synthesis inhibitor: , ] Capecitabine (Xeloda®); Gemcitabine hydrochloride (Gemzar®); Nelarabine ((2R,3S,4R,5R)-2-(2-amino-6-methoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, Arranon® and Atriance®); and Saxitabine (1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-4-(palmitamido)pyrimidin-2(1H)-one).

[0198] [ , Folic acid antagonist or antifolate: , ] Trimetrexate glucuronate (Neutrexin®); Picotamide hydroxyethyl sulfonate (BW201U); Pemetrexed (LY231514); Raltitrexed (Tomudex®); and Methotrexate (Rheumatrex®, Trexal®).

[0199] [ , Immunomodulator: , ] Atezolizumab (available from Roche®); Pegfilgrastim (Neulasta®); Lenalidomide (CC-5013, Revlimid®); Thalidomide (Thalomid®), Actimid (CC4047); and IRX-2 (a mixture of human cytokines including interleukin 1, interleukin 2, and interferon γ, CAS 951209-71-5, available from IRX Therapeutics).

[0200] [ , G- , ] [ , Protein-coupled somatostatin receptor inhibitor:, ] Octreotide (also known as octreotide acetate, Sandostatin® and Sandostatin LAR®); lanreotide acetate (CAS 127984-74-1); seglitide (MK678); vapreotide acetate (Sanvar®); and cyclo(D-Trp-Lys-Abu-Phe-MeAla-Tyr) (BIM23027).

[0201] [, Interleukin , ] [, -11 , ] [, and synthetic interleukin , ] [, -11 , ] [, ( , ] [, IL-11 , ] [, ): , ] Oprelvekin-11 (Neumega®).

[0202] [, Erythropoietin and synthetic erythropoietin: , ] Erythropoietin (Epogen® and Procrit®); darbepoetin alfa (Aranesp®); peginesatide (Hematide®); and EPO covalently linked to polyethylene glycol (Micera®).

[0203] [, Histone deacetylase ( , ] [, HDAC , ] [, ) inhibitor:, Vorinostat (Zolinza®); Romidepsin (Istodax®); Trichostatin A (TSA); Oxamflatin; Vorinostat (Zolinza®, vorinostat); Pyroxamide (syberoyl-3-aminopyridinecarboxylic acid hydroxamic acid); Trapoxin A (RF-1023A); Trapoxin B (RF-10238); Cyclo[(αS,2S)-α-amino-η-sideoxy-2-epoxyethaneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1); Cyclo[(αS,2S)-α-amino-η-sideoxy-2-epoxyethaneoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl] (Cyl-2); Cyclo[L-alanyl-D-alanyl-(2S)-η-sideoxy-L-α-aminoepoxyethaneoctanoyl-D-prolyl] (HC-toxin); Cyclo[(αS,2S)-α-amino-η-sideoxy-2-epoxyethaneoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl] (WF-3161); Chlamydocin ((S)-cyclo(2-methylalanyl-L-phenylalanyl-D-prolyl-η-sideoxy-L-α-aminoepoxyethaneoctanoyl); Apicidin (cyclo(8-sideoxy-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl); Romidepsin (Istodax®, FR-901228); 4-phenylbutyric acid; Spiruchostatin A; Mylproin (valproic acid); Entinostat (MS-275, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)-amino-methyl]-benzamide); and Depudecin (4,5:8,9-dianhydride-1,2,6,7,11-pentadeoxy-D-threo-D-ido-undeca-1,6-dienol).

[0204] [, Biological response modifier:, ] includes therapeutic agents such as interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines (for treatment and prevention), gene therapy, and non-specific immunomodulators. Interferon alpha (Intron®, Roferson®-A); interferon beta; interferon gamma; interleukin-2 (IL-2 or aldesleukin, Proleukin®); filgrastim (Neupogen®); sargramostim (Leukine®); erythropoietin (epoetin); interleukin-11 (oprelvekin); imiquimod (Aldara®); lenalidomide (Revlimid®); rituximab (Rituxan®); trastuzumab (Herceptin®); Bacillus Calmette-Guérin (theraCys® and TICE® BCG); levamisole (Ergamisol®); and denileukin diftitox (Ontak®).

[0205] [, Plant alkaloid: , ] Paclitaxel (Taxol and Onxal(tm)); paclitaxel protein-bound (Abraxane®); vinblastine (also known as vinblastine sulfate, vincaleukoblastine, and VLB, Alkaban-AQ® and Velban®); vincristine (also known as vincristine sulfate, LCR, and VCR, Oncovin® and Vincasar Pfs®); and vinorelbine (Navelbine®).

[0206] [, Taxane antitumor agent: , ] Paclitaxel (Taxol®); docetaxel (Taxotere®); cabazitaxel (Jevtana®, 1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropionate); and larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylchloropropionyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-ene-2-yl benzoate).

[0207] [, Heat shock protein ( , ] [, HSP, ] [ , ) inhibitor: , ] Tanespimycin (17 - allylamino - 17 - demethoxygeldanamycin, also known as KOS - 953 and 17 - AAG, available from SIGMA and described in U.S. Patent No. 4,261,989); Rispamycin (IPI504), Gataspimycin (STA - 9090); [6 - chloro - 9 - (4 - methoxy - 3,5 - dimethylpyridin - 2 - ylmethyl) - 9H - purin - 2 - yl]amine (BIIB021 or CNF2024, CAS 848695 - 25 - 0); trans - 4 - [[2 - (aminocarbonyl) - 5 - [4,5,6,7 - tetrahydro - 6,6 - dimethyl - 4 - oxo - 3 - (trifluoromethyl) - 1H - indazol - 1 - yl]phenyl]amino]cyclohexylglycinate (SNX5422 or PF04929113, CAS 908115 - 27 - 5); and 17 - dimethylaminoethylamino - 17 - demethoxygeldanamycin (17 - DMAG).

[0208] [ , Thrombopoietin ( , ] [ , TpoR , ] [ , ) agonist: , ] Eltrombopag (SB497115, Promacta® and Revolade®); and Romiplostim (Nplate®).

[0209] [ , Demethylating agent: , ] 5 - Azacytidine (Vidaza®); and Decitabine (Dacogen®).

[0210] [ , Cytokine: , ] Interleukin - 2 (also known as Aldesleukin and IL - 2, Proleukin®); Interleukin - 11 (also known as Oprelvekin, Neumega®); and Alpha interferon alpha (also known as IFN - α, Intron® A, and Roferon - A®).

[0211] [ , 17 α- , ] [ , Hydroxylase , ] [ , / C17,20 , ] [, lyase ( , ] [, CYP17A1 , ] [, ) inhibitor: , ] Abiraterone acetate (Zyitga®).

[0212] [, Other cytotoxic agent: , ] Arsenic trioxide (Trisenox®); Asparaginase (also known as L - Asparaginase, Erwinia L - Asparaginase, Elspar® and Kidrolase®); and Crisantaspase (Erwinaze®).

[0213] [, C-C , ] [, chemokine receptor , ] [, 4 , ] [, ( , ] [, CCR4 , ] [, ) antibody: , ] Mogamulizumab (Potelligent®) [, CD20 , ] [, antibody: , ] Rituximab (Riuxan® and MabThera®); and Tositumomab (Bexxar®); and Ofatumumab (Arzerra®).

[0214] [, CD20 , ] [, antibody-drug conjugate , ] [, : , ] Ibritumomab tiuxetan (Zevalin®); and Tositumomab, [, CD22 , ] [, antibody-drug conjugate , ] [, :, inotuzumab ozogamicin (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.); [, CD30 mAb- , ] [, cytotoxin conjugate: , ] Brentuximab vedotin (Adcetrix®); [, CD33 , ] [, antibody-drug conjugate , ] [, : , ] Gemtuzumab ozogamicin (Mylotarg®), [, CD40 , ] [, antibody: , ] Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); [, CD52 , ] [, antibody: , ] Alemtuzumab (Campath®), [, Anti , ] [, -CS1 , ] [, antibody: , ] Elotuzumab (HuLuc63, CAS No. 915296-00-3) [, CTLA-4 , ] [, inhibitor antibody: , ] Tremelimumab (IgG2 monoclonal antibody, available from Pfizer, previously known as ticilimumab, CP-675,206); and Ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).

[0215] [TPH] [Inhibitor:] Telotristat [PARP] [(Poly] [ADP] [(Poly ADP-ribose polymerase) inhibitors:] Olaparib (Lynparza), Rucaparib (Rubraca), Niraparib (Zeluja), Talazoparib, Veliparib.

[0216] [PD-1] [Inhibitors:] Spartalizumab (PDR001, (Novartis)), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pitolisant (CureTech), MEDI0680 (MedImmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (BeiGene), BGB-108 (BeiGene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

[0217] [PD-L1] [Inhibitors:] Durvalumab, Atezolizumab, Avelumab

[0218] In particular, the present invention provides a combination or combination therapy of a complex formed by the radionuclide 177Lu (lutetium-177) and a somatostatin receptor-binding peptide linked to a chelating agent as defined herein, or a combination or combination therapy of an aqueous solution of a drug as defined herein with one or more therapeutic agents selected from the group consisting of: octreotide, lanreotide, vapreotide, pasireotide, satoreotide, everolimus, temozolomide, tetrasodium etidronate, sunitinib malate, sulfatinib, ribociclib, enasidenib, and pazopanib. In certain embodiments, those combinations are used for the treatment of NET tumors, such as, GEP-NET, lung NET, pNET, lung NET, carcinoid tumor syndrome, SCLC. In certain embodiments, the present invention provides a method of treating a patient suffering from a NET tumor (such as, GEP-NET, lung NET, pNET, lung NET, carcinoid tumor syndrome, SCLC) by administering a therapeutically effective amount of the components of those combinations.

[0219] In certain embodiments, the present invention provides a combination or combination therapy of a complex formed by the radionuclide 177Lu (lutetium-177) and a somatostatin receptor-binding peptide linked to a chelating agent as defined herein, or a combination or combination therapy of an aqueous solution of a drug as defined herein with one or more tumor immunology therapeutic agents selected from the group consisting of PD-1, PD-L1, and CTLA-4 inhibitors, particularly I-O therapeutic agents selected from the group consisting of: spartalizumab, nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, avelumab, ipilimumab, and tremelimumab. In certain embodiments, those combinations are used for the treatment of NET tumors, such as, GEP-NET, lung NET, pNET, lung NET, carcinoid tumor syndrome, SCLC. In certain embodiments, the present invention provides a method of treating a patient suffering from a NET tumor (such as, GEP-NET, lung NET, pNET, lung NET, carcinoid tumor syndrome, SCLC) by administering a therapeutically effective amount of the components of those combinations.

[0220] Definitions Hereinafter, the terms used herein are defined in their meanings.

[0221] Unless otherwise indicated herein or clearly contradicted by the context, the use of the articles "a" and "the" in the specification and claims shall be construed to include both the singular and the plural. Unless otherwise specified, the terms "comprising", "having", "include" (as in, for example, "a complex of a radionuclide and an organic moiety that binds to a cell receptor attached to a chelating agent"), "including" and "containing" are to be construed as open-ended terms (i.e., meaning "including but not limited to"). Additionally, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the intermediate term "consisting essentially of" or the closed term "consisting of" may be used to claim the same embodiment more narrowly.

[0222] The term "about" or "approximately" as used herein means that the following values may vary by ±20%, preferably by ±10%, more preferably by ±5%, even more preferably by ±2%, and even more preferably by ±1%.

[0223] Unless otherwise defined, "%" herein has the meaning of weight percentage (wt%), also known as weight-to-weight percentage (w / w%).

[0224] "Total concentration": the sum of one or more individual concentrations.

[0225] "Aqueous solution": a solution of one or more solutes in water.

[0226] "Complex formed by: (ai) a radionuclide, and (aii) an organic moiety that binds to a cell receptor attached to a chelating agent": The radionuclide metal ion forms a non-covalent bond with a functional group (such as an amine or a carboxylic acid) of the chelating agent. The chelating agent has at least two such complexing functional groups to be able to form a chelate complex.

[0227] The chelating agent in the context of the present invention may be DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DTPA: diethylenetriaminepentaacetic acid, NTA: nitrilotriacetic acid, EDTA: ethylenediaminetetraacetic acid, DO3A: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, NOTE: 1,4,7-triazacyclononane-1,4,7-triacetic acid, Trizoxetan, Tetraxetan or a mixture thereof, preferably DOTA.

[0228] "Cell receptor binding moiety": a chemical molecule at least part of which binds to a receptor molecule on the cell surface. A particularly suitable cell receptor binding moiety for the present invention is a somatostatin receptor binding peptide, preferably, the somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, pasireotide, ilatreotide, pentetreotide, depreotide, satoreotide, veldoreotide, preferably selected from octreotide and octreotate.

[0229] "Linking": the cell receptor binding organic moiety is directly linked to the chelating agent or via a linker molecule, preferably directly linked. One or more linking bonds are one or more covalent or non-covalent bonds between the cell receptor binding organic moiety (and linker) and the chelating agent, preferably the one or more bonds are covalent bonds.

[0230] "Radiolytic degradation stabilizer": a stabilizer that protects an organic molecule from radiolytic degradation, for example, when a bond between an atom and a free radical of an organic molecule is cleaved by a γ-ray emitted from a radionuclide, those free radicals are then scavenged by the stabilizer, which avoids any other chemical reactions that the free radicals might undergo and could lead to undesired, potentially ineffective or even toxic molecules. Therefore, such stabilizers are also referred to as "free radical scavengers" or simply "radical scavengers". Other alternative terms for those stabilizers are "radiostability enhancers", "radiostabilizers" or simply "quenchers".

[0231] "One or more stabilizers are present during the complex formation of components (ai) and (aii)": the first stabilizer present and optionally the second stabilizer, i.e., either the first stabilizer alone or in combination with the second stabilizer "Present during the complex formation": one or more stabilizers are present in the radionuclide solution or in the solution containing the chelating agent before adding the two solutions and applying a possibly elevated temperature to promote the formation of the complex. Preferably, the one or more stabilizers are in the solution containing the chelating agent.

[0232] "Only the first stabilizer is present during the complex formation of components (ai) and (aii)": The first stabilizer is present and the second stabilizer is not present. In other words, only one stabilizer is present.

[0233] "The second stabilizer is added after the complex of components (ai) and (aii) is formed": Regardless of whether the second stabilizer was already present during the complex formation, the second stabilizer is added after the complex formation reaction is completed, for example, after the reaction solution, which may have been heated to an elevated temperature, is cooled back down to ambient temperature.

[0234] The cell receptor binding portion and the chelator can together form the following molecules: DOTA-OC: [DOTA 0,D-Phe 1]octreotide, DOTA-TOC: [DOTA 0,D-Phe 1,Tyr 3]octreotide, edotreotide (INN), represented by the following formula: DOTA-NOC: [DOTA 0, D-Phe 1,1-Nal 3]octreotide, DOTA-TATE: [DOTA 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), osaterotide (INN), represented by the following formula: DOTA-LAN: [DOTA 0,D-β-Nal 1]lanreotide, DOTA-VAP: [DOTA 0,D-Phe 1,Tyr 3]vapreotide.

[0235] Tyrtansomatostatin Titansomatostatin Preferred "cell receptor-binding moiety linked to a chelating agent" molecules for use in the present invention are DOTA-TOC, DOTA-TATE and terutreotide, and more preferably the molecule is DOTA-TATE.

[0236] For the present invention, a preferred complex formed by a radionuclide and a cell receptor-binding moiety linked to a chelating agent (or a preferred complex of a radionuclide and a cell receptor-binding moiety linked to a chelating agent) according to the present invention is 177Lu-DOTA-TATE, which is also known as lutetium (177Lu) octreotate (INN), i.e., hydrogen [N-{[4,7,10-tris(carboxy-κO-methyl)-1,4,7,10-tetraazacyclododecane-1-yl-κ4N1,N4,N7,N10]acetyl-κO}-D-phenylalanyl-L-cysteinyl-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threonyl cyclo(2→7)-disulfide(4-)](177Lu) lutetate(1-) And is represented by the following formula: "Buffer with a pH from 4.5 to 6.0": can be acetate buffer, citrate buffer (such as citrate + HCl or citric acid + disodium hydrogen phosphate) or phosphate buffer (such as sodium dihydrogen phosphate + disodium hydrogen phosphate), preferably, the buffer is acetate buffer, and preferably, the acetate buffer is composed of acetic acid and sodium acetate.

[0237] "Sequestering agent", a chelating agent suitable for complexing radionuclide metal ions, preferably DTPA: diethylenetriaminepentaacetic acid.

[0238] "For commercial use": a pharmaceutical product, such as an aqueous pharmaceutical solution, can be obtained (preferably has been obtained) with marketing authorization from a health authority (such as US-FDA or EMA) by complying with all pharmaceutical product quality and stability requirements required by such health institutions, can be manufactured (preferably has been manufactured) on a commercial scale from or at a pharmaceutical product production site, then undergoes quality control testing procedures, and can be supplied (preferably has been supplied) to end users at remote locations (such as hospitals or patients).

[0239] "Combination": The term "combination" refers to a fixed combination in the form of a dosage unit, or combination administration (wherein the compound of the present invention and a combination partner (e.g., another drug as explained below, also referred to as a "therapeutic agent" or "co-agent") can be administered independently at the same time or separately at time intervals, particularly in cases where such time intervals allow the combination partner to exhibit a cooperative (e.g., synergistic) effect). The individual components can be packaged in a kit or separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dosage before administration. Terms such as "co-administered" or "combination administration" as used herein are intended to encompass the administration of the selected combination partner to a single subject in need (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or simultaneously. As used herein, the term "drug combination" means a product resulting from the mixing or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents (e.g., the compound of the present invention and the combination partner) are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents (e.g., the compound of the present invention and the combination partner) are administered to a patient simultaneously, concurrently, or sequentially as separate entities (without a specific time limit), wherein such administration provides a therapeutically effective level of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents. Examples

[0240] Hereinafter, the present invention will be described in more detail and specifically with reference to examples, but these examples are not intended to limit the present invention.

[0241] Materials: 177LuCl3 can be obtained from commercial sources, for example, I.D.B. Holland BV, Netherlands. DOTA0-Tyr3-octreotate can be obtained from commercial sources, for example, provided by piCHEM Forschungs- und Entwicklungs GmbH, Austria. All other components of the drug product are commercially available from various sources.

[0242] [Examples] [1] [:] Composition of the drug product

[0243] The pharmaceutical product (177Lu-DOTA 0-Tyr 3-octreotate 370 MBq / mL infusion solution) is designed as a sterile ready-to-use infusion solution containing 177Lu-DOTA 0-Tyr 3-octreotate as the drug substance, with a volumetric activity of 370 MBq / mL at the reference date and time (calibration time (tc)). The calibration time (tc) corresponds to the end of production (EOP = t0), which is the measurement time of the activity of the first QC vial. The shelf life of the pharmaceutical product is defined as 72 hours after the calibration time. The pharmaceutical product is a single-dose vial containing an appropriate volume of solution to allow the delivery of 7.4 GBq of radioactivity upon injection.

[0244] The manufacturing site prepares single doses calibrated within the range of 7.4 GBq ± 10% (200 mCi) after the end of production. The certificate of analysis reports the exact activity provided and the time at which this activity is reached. This value is stated as "Time of injection: {day month year} {h:m} ({DD MM YYYY} {hh:mm}) UTC". Considering the variable injection time and the constant decay of the radionuclide, the fill volume required for an activity of 7.4 GBq at the injection time was calculated, which ranges from 20.5 and 25.0 mL.

[0245] Composition of the pharmaceutical product / mL [Properties] [ / ] [Components] [Quantity (unit] [ / mL] [)] [Function] 177Lu-DOTA 0-Tyr 3-octreotate (volumetric activity) 370 MBq / mL at tc (EOP) Drug substance X-DOTA 0-Tyr 3-octreotate 10 µg / mL Total peptide content Specific activity (GBq / total peptide) ≥ 53 GBq / µmol at EOP NA Excipient Acetic acid Sodium acetate Gentisic acid Ascorbic acid DTPA Sodium chloride (NaCl) Sodium hydroxide (NaOH) Water for injection 0.48 mg / mL pH regulator 0.66 mg / mL pH regulator 0.63 mg / mL RSE 2.80 mg / mL RSE 0.05 mg / mL Multivalent chelating agent 6.85 mg / mL Isotonic agent 0.64 mg / mL Add 1 mL pH regulator Solvent EOP: End of production = t0 = Activity measurement of the first vial = Calibration time tc RSE: Radiostability enhancer

[0246] [Example] [2] [:] Manufacture of pharmaceutical products

[0247] For a 74 GBq batch size (2 Ci batch size), mix a 177LuCl3 solution (approx. 74 GBq in HCl) with a solution of DOTA-Tyr3-octreotate (approx. 2 mg) and a reaction buffer solution containing an antioxidant (and a stabilizer against radiolytic degradation) (i.e., gentisic acid, approx. 157 mg) and a buffer system (i.e., acetate buffer system) to produce a total of approx. 5.5 mL of solution, which is used for radiolabeling occurring within less than 15 minutes at a temperature of approx. 90 ºC to approx. 98 ºC.

[0248] Synthesis is carried out using a single-use disposable kit installed in front of the synthesis module, which contains a fluid path (pipeline), a reactor vial, and a sealed reagent vial.

[0249] The resulting mother liquor is diluted with a solution containing a chelating agent (i.e., DTPA), an antioxidant (i.e., ascorbic acid), sodium hydroxide, and sodium chloride, and then sterile filtered through 0.2 μm to give a ready-to-use solution as described in Example 1, with a pH of 4.5 - 6.0, particularly 5.2 - 5.3. Finally, the solution is dispensed into sterile vials in volumes of 20.5 to 25.0 mL. The stoppered vials are packaged inside lead containers for protective shielding.

[0250] The manufacturing method can also achieve batch sizes greater than 74 GBq. In this case, the amounts of the raw materials (lutetium, peptide, and reaction buffer) are multiplied to ensure the same raw material ratio.

[0251] [Example] [3]: Results of stability studies after storage under various temperature conditions.

[0252] The following table provides stability test data for batches produced at a batch size of 74 GBq according to the method described in Example 2.

[0253] 「n.d.」 = not determined; 「LOD」 = limit of detection [, Time point , ] [] [t(0)] [t(0+24h)] [t(0+48h)] [t(0+72h)] [, at , ] [, 5ºC ± 2ºC , ] [, stability , ] [, CQ1 , ] [, , ] [, , ] [ , 11 mL , ] [ , 21.8 mL , ] pH 5.3 n.d. n.d. 5.3 5.3 Chemical purity (RP-UV-HPLC) Peptide purity (%) 100.0 n.d. n.d. 100.0 100.0 Radiochemical purity (RP-γβ-HPLC) 177Lu-DOTA 0-Tyr 3-Octreotate (%) 98.37 n.d. n.d. 96.09 96.40 [ , Time point , ] [ , , ] [t(0)] [t(0+24h)] [t(0+48h)] [t(0+72h)] [ , at , ] [ , 25ºC ± 2ºC , ] [ , stability , ] [ , CQ1 , ] [, 5 mL , ] [, 5mL , ] [, 5 mL , ] [, 24.7 mL , ] pH 5.3 5.3 5.2 5.2 5.3 Chemical purity (RP-UV-HPLC) Peptide purity (%) 100.0 100.0 100.0 100.0 Radiochemical purity (RP-γβ-HPLC) 177Lu-DOTA 0-Tyr 3-Octreotate (%) 98.28 96.99 96.29 95.02 95.62 [, Time point , ] [, , ] [t(0)] [t(0+24h)] [t(0+48h)] [t(0+72h)] [, at , ] [, 32ºC ± 2ºC , ] [, stability , ] [, CQ1 , ] [, 5.6 mL , ] [, 22.2 mL , ] [, 5.6 mL , ] [, 22.2 mL , ] [, , ] pH 5.3 n.d. 5.3 5.3 n.d. Chemical purity (RP-UV-HPLC) Peptide purity (%) 100.0 100.0 100.0 100.0 100.0 n.d. Radiochemical purity (RP-γβ-HPLC) 177Lu-DOTA 0-Tyr 3-Octreotate (%) 98.37 96.03 96.51 94.45 95.45 n.d. [, Time point , ] [, , ] [t(0)] [t(0+24h)] [t(0+48h)] [t(0 + 72h)] [ , at , ] [ , 32ºC ± 2ºC , ] [ , per , ] [ , 12h , ] [ , and at , ] [ , 25ºC ± 2ºC , ] [ , per , ] [ , 60h , ] [ , stability , ] [ , CQ1 , ] [ , , ] [ , , ] [ , 11 mL , ] Chemical purity (RP-UV-HPLC) Peptide purity (%) 100.0 n.d. n.d. 100.0 Radiochemical purity (RP-γβ-HPLC) 177Lu-DOTA 0-Tyr 3-Octreotate (%) 98.28 n.d. n.d. 95.01

[0254] Very similar good stability results were obtained for batches produced in a batch size of 148 GBq.

[0255] None

[0256] None

Claims

1. A method for preparing an aqueous drug solution, the method comprising diluting an aqueous complex solution with an aqueous diluent to form the aqueous drug solution; wherein the aqueous complex solution comprises: (a) a complex comprising (ai) a radioactive nucleus 177Lu (Lysium-177), and (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA; and (b) at least one radioactive degradation stabilizer selected from gentianic acid or a salt thereof and ascorbic acid or a salt thereof, wherein the amount is such that its total concentration in the aqueous drug solution is from 0.5 mg / mL to 2 mg / mL; and wherein the aqueous diluent solution comprises at least one radioactive degradation stabilizer comprising ascorbic acid or a salt thereof, wherein the amount is such that its concentration in the aqueous drug solution is from 2.0 mg / mL to 5.0 mg / mL; wherein the radioactive nucleus is present in the aqueous drug solution at a concentration providing volumetric radioactivity from 250 to 500 MBq / mL; wherein the radiochemical purity of the aqueous drug solution, as determined by HPLC, is maintained at ≥ 1000 MBq / mL when stored at 25ºC. 95% for at least 72 hours; and the aqueous solution of the drug contains less than 2% ethanol.

2. The method as described in claim 1, wherein the aqueous diluent contains ascorbic acid or a salt thereof as the sole stabilizer against radioactive degradation.

3. The method as claimed in claim 1, wherein the at least one radioactive degradation stabilizer is present in the aqueous complex solution at a total concentration of 15 mg / mL to 50 mg / mL.

4. The method as described in claim 1, wherein the somatostatin receptor-binding peptide and the chelating agent together form a molecule selected from the group consisting of: DOTA-OC, DOTA-TOC (edotortide), DOTA-NOC, DOTA-TATE (ozodortide), DOTA-LAN, DOTA-VAP, and Titan-sartoretide.

5. The method as described in claim 4, wherein the somatostatin receptor-binding peptide and the chelating agent together form a molecule selected from: DOTA-TOC (edotortide), DOTA-TATE (ozodortide), and Titan-sartoretide.

6. The method as described in claim 5, wherein the somatostatin receptor-binding peptide and the chelating agent together form DOTA-TATE (ozodotritide).

7. An aqueous solution of a drug produced by the method described in claim 1.

8. The aqueous solution of the drug as described in claim 7, wherein the activity of the aqueous solution of the drug is 7.4 GBq ± 10%.

9. The aqueous solution of the drug as described in claim 7, wherein the aqueous solution of the drug contains less than 1% ethanol.

10. The aqueous solution of a drug as described in claim 7, wherein the aqueous solution of a drug is a ready-to-use single-dose aqueous solution or is provided in multiple dose units.

11. The aqueous solution of the drug as described in claim 9, wherein the aqueous solution of the drug is free of ethanol.

12. The aqueous solution of a drug as claimed in claim 7, wherein the aqueous solution of the drug further comprises a multivalent chelating agent.

13. The aqueous solution of the drug as claimed in claim 12, wherein the multivalent chelating agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

14. An aqueous solution of a drug as claimed in claim 13, wherein the DTPA or its salts are present in the aqueous solution in an amount that yields a concentration from 0.01 mg / mL to 0.10 mg / mL.

15. The aqueous drug solution as claimed in claim 7, wherein the aqueous drug solution is present in a dose unit container sealed within a lead container in a volume of 10 mL to 50 mL.

16. The aqueous solution of a drug as claimed in claim 7, wherein the aqueous solution of the drug is present in a stoppered vial sealed in a lead container in a volume of 10 mL to 50 mL.

17. Use of an aqueous solution of a drug as described in claim 7 in the preparation of a pharmaceutical preparation for treating a patient’s tumor.

18. The use as described in claim 17, wherein the pharmaceutical agent is administered by injection or infusion.

19. The use as described in claim 17, wherein 10 mL to 50 mL of the aqueous solution of the drug is administered to the patient.

20. The use as described in claim 17, wherein the aqueous solution of the drug is administered to the patient over a period of about 20 minutes to about 30 minutes.

21. The use as described in claim 17, wherein a dose of 7.4 GBq ± 10% is administered to the patient.

22. The use as described in claim 17, wherein the tumor is a neuroendocrine tumor (NET).

23. The use as described in claim 17, wherein the tumor is selected from the group consisting of: gastrointestinal and pancreatic neuroendocrine tumors, neuroendocrine small cell lung cancer, neuroendocrine glioma, neuroendocrine prostate cancer, neuroendocrine meningioma, neuroendocrine neuroblastoma, neuroendocrine paraganglioma, neuroendocrine pheochromocytoma, pulmonary neuroendocrine tumors, neuroendocrine medullary thyroid carcinoma, neuroendocrine breast cancer, neuroendocrine head and neck tumors, and pancreatic neuroendocrine tumors and thymic neuroendocrine tumors.

24. The use as described in claim 17, wherein the tumor is a gastrointestinal pancreatic neuroendocrine tumor.

25. The use as described in claim 24, wherein 10 mL to 50 mL of the aqueous solution of the drug is administered to the patient.

26. The use as described in claim 17, wherein the tumor is a neuroendocrine carcinoid tumor.