Stable, concentrated radionuclide complex solution

Abstract

To provide radionuclide complex solutions of high concentration and of high chemical stability, that allow their use as drug product for diagnostic and / or therapeutic purposes.SOLUTION: A pharmaceutical aqueous solution is provided, comprising a complex formed by a radionuclide 177 Lu (Lutetium-177) and a somatostatin receptor binding peptide linked to a chelating agent DOTA, and at least two different stabilizers against radiolytic degradation, wherein the radionuclide is present in a concentration that provides a volumetric radioactivity of 250 to 500 MBq / mL, and the stabilizers are present in a total concentration of 0.2 to 20.0 mg / mL.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a radionuclide complex solution having a high concentration that enables use as a commercially available pharmaceutical product for diagnostic and / or therapeutic purposes, and high chemical and radiochemical stability.

Background Art

[0002] The concept of targeted drug delivery is based on cell receptors that are overexpressed in target cells as opposed to non-target cells. If a drug has a binding site to such overexpressed cell receptors, after systemic administration, other non-related cells will remain unaffected, and delivery of a high concentration of the drug to such target cells will be enabled. For example, if tumor cells are characterized by overexpression of specific cell receptors, a drug having a binding affinity to the receptor will accumulate in tumor tissue at a high concentration while leaving normal tissues unaffected after intravenous injection.

[0003] This concept of targeted drug delivery has also been used in radiopharmaceuticals to selectively deliver radionuclides to target cells for diagnostic or therapeutic purposes. In this radiopharmaceutical application, the target cell receptor-binding moiety is typically linked to a chelating agent that can form a strong complex with the metal ion of the radionuclide. The radiopharmaceutical agent is then delivered to the target cells, and then high-energy electrons, positrons, or alpha particles, and further gamma rays are released at the target site due to the decay of the radionuclide.

[0004] One of the technical problems associated with such radiopharmaceutical agent products is that the decay of the radionuclide always occurs, for example, during the manufacture or storage of the agent product, and the released high-energy emissions damage the agent product. ​It is to induce the cleavage of chemical bonds of the molecules forming a part. This is often called radiolysis or radiolytic degradation. Radiolytic degradation of the receptor-binding part of the drug may lead to a decrease in its efficacy acting as a diagnostic agent and / or a therapeutic agent. Since the stability of such radiopharmaceutical drug products is insufficient and they lack any significant shelf life, hitherto, drugs have had to be manufactured in the hospital laboratory as dose units for individual patients and administered to the patients immediately, and the patients have had to already be in that hospital waiting for radiological treatment. To facilitate such drug preparation in the hospital laboratory, "cold" (i.e., non-radioactive) freeze-dried kits containing cell receptor-binding moieties linked to chelating agents without using radionuclides have been developed.

[0005] The freeze-dried contents of such kit vials then have to be reconstituted using a solution of a radionuclide shortly before administration (Das et al. J Radioanal Nucl Chem  2014, 299, 1389 - 1398, Das et al. Current Radiopharmaceuticals 2014, 7, 12 - 1 19, Luna-Gutierrez et al. J Radioanal Nucl Chem 2017, 314, 2181 - 2188). However, such kits are not "ready-to-use" as they require additional processing steps (such as application of heat for complexation reaction) in addition to the reconstitution step, as well as purification and sterilization steps, before the drug can finally be made administrable. To reduce radiolysis and improve the stability of radiopharmaceutical drug products, various strategies have been investigated. However, most of these strategies either have limited effectiveness or are associated with significant drawbacks such as high cost, complexity in synthesis, or potential toxicity. Therefore, there is still a need for new and effective methods to improve the stability of radiopharmaceutical drug products. One approach that has shown promise is the use of stabilizers to protect the drug from radiolysis.

[0006] To reduce radiolysis of radiopharmaceutical drug products and improve their stability, various strategies Teji has been explored and achieved more or less success. That is, pharmaceutical products can be stored at low temperatures or can be manufactured at high dilutions, or stabilizers can be added.

[0007] However, when a stabilizer is added, such chemicals may have an adverse effect on the complexation of radionuclides with chelating agents or may have a problem in that the solubility is limited and precipitation from the solution may occur so there may be a problem. Ethanol has been reported as a stabilizer against radiolysis (WO 2008 / 009444 pamphlet). Ethanol has no adverse effect on complexation or solubility problems, but if the amount of ethanol in the injection solution increases, there may be a physiological problem and it may adversely affect the tolerance of the pharmaceutical product. When manufacturing a highly diluted pharmaceutical product, there is a drawback that a large amount of injection solution needs to be administered to the patient. For the convenience of the patient and reasons of drug tolerance, it would be highly desirable to provide a high-concentration radiopharmaceutical product. However, such high-concentration solutions are particularly susceptible to radiolysis. Therefore, on the one hand, radiolysis is avoided by diluting the pharmaceutical product, and on the other hand, there is a contradictory position of avoiding the discomfort of the patient during treatment by providing a concentrated drug solution. Mathur et al. Cancer Biotherap y and Radiopharmaceuticals, 2017, 32(7), 26

[0008] When manufacturing a highly diluted pharmaceutical product, there is a drawback that a large amount of injection solution needs to be administered to the patient. For the convenience of the patient and reasons of drug tolerance, it would be highly desirable to provide a high-concentration radiopharmaceutical product. However, such high-concentration solutions are particularly susceptible to radiolysis. Therefore, on the one hand, radiolysis is avoided by diluting the pharmaceutical product, and on the other hand, there is a contradictory position of avoiding the discomfort of the patient during treatment by providing a concentrated drug solution. Mathur et al. Cancer Biotherap y and Radiopharmaceuticals, 2017, 32(7), 26 6 - 273 reports and claims that high-concentration products are immediately usable. However since its composition contains a large amount of ethanol, there may be a problem regarding tolerance. while avoiding radiolysis by diluting the pharmaceutical product on the one hand and avoiding the discomfort of the patient during treatment by providing a concentrated drug solution on the other hand, a contradictory position can be seen. Mathur et al. Cancer Biotherap y and Radiopharmaceuticals, 2017, 32(7), 26 6 - 273 reports and claims that high-concentration products are immediately usable. However since its composition contains a large amount of ethanol, there may be a problem regarding tolerance. However, since its composition contains a large amount of ethanol, there is a potential problem regarding tolerance. There is a possibility of becoming a problem.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0009] Therefore, there remains a problem of designing a ready-to-use radiopharmaceutical product that can be manufactured on a commercial scale, provides a small injection volume for the convenience of patients, and can be delivered as a highly stable sterile solution having a high physiological tolerance (for example, a composition not containing ethanol). while having a high physiological tolerance composition (e.g., a composition not containing ethanol) and can be delivered as a highly stable sterile solution with a high concentration, i.e., a ready-to-use radiopharmaceutical agent product.

MEANS FOR SOLVING THE PROBLEMS

[0010] The present inventors have now found a method for designing and manufacturing a highly concentrated radionuclide complex solution that is chemically and radiochemically very stable even when stored at ambient temperature or short-term elevated temperatures so as to be supplyable as a ready-to-use radiopharmaceutical product that can be manufactured on a commercial scale. and can be delivered as a highly stable sterile solution with a high concentration, i.e., a ready-to-use radiopharmaceutical agent product.

[0011] The present invention is provided in various aspects as outlined below.

[0012] (a) The following: (ai) A radionuclide, (aii) A cell receptor-binding organic moiety linked to a chelating agent, and a complex formed thereby, (b) At least one stabilizer against radiolytic degradation, and wherein the radionuclide is present at a concentration providing a volumetric radioactivity of at least 100 MBq / mL, preferably at least 250 MB q / mL, a pharmaceutical aqueous solution.

[0013] The stabilizer (component (b)) is at least 0.2 mg / mL, preferably at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, even more preferably Present in a total concentration of at least 2.7 mg / mL.

[0014] (a) Below: (ai) A radioactive substance present in a concentration that provides a volumetric activity of 250 to 500 MBq / mL nuclide 177 Lutetium (Lu-177) and (aii) Somatostatin receptor-binding organic moiety DO linked to a chelator TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and a complex formed by (bi) Primary stabilization against radiolytic degradation at concentrations of 0.5-1 mg / mL gentisic acid or a salt thereof as an agent; (bii) Secondary resistance to radiolytic degradation present at concentrations of 2.0 to 5.0 mg / mL ascorbic acid or a salt thereof as a stabilizer; 1. A pharmaceutical aqueous solution comprising:

[0015] (1) The following: (1.1) preparing an aqueous solution containing a radionuclide; (1.2) a cell receptor-binding organic moiety linked to a chelator and a first stable preparing an aqueous solution comprising a stabilizing agent and, optionally, a second stabilizing agent; (1.3) A mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2) and heating the by combining a radionuclide with a cell receptor-binding organic moiety linked to a chelator. a process step of forming a complex; (2) The following: (2.1) preparing an aqueous dilution solution optionally containing a second stabilizer; (2.2.) The complex solution obtained in step (1) and the complex solution obtained in step (2.1) Mixing a dilution solution, and A process step of diluting the complex solution obtained in step (1) by The manufacturing process of the pharmaceutical aqueous solution defined above, including

[0016] The present invention provides the following advantages.

[0017] High concentration enables high-dose administration within a short time frame. For example, 177 Lu-D In the case of OTA-TATE, a high dose of 7.4 GBq can be provided in a small amount of 20.5- 25.0 mL, allowing the IV injection to be completed within about 20 to 30 minutes.

[0018] When using the suitable stabilizer according to the present invention described herein, regarding the chemical purity of the cell receptor binding molecule after 72 hours at 25°C, even if this molecule is a sensitive peptide molecule, At least 95%, 96%, 97%, 98%, 99%, or 100% chemical Stability, a high stability, is ensured. For example, in the case of DOTA-TATE, 100% chemical purity was found after 72 hours at 25°C, and was even found After 48 hours at 32°C. Even under short-term elevated temperature conditions (12 h at 32°C and 60 h at 25°C), such high stability Regarding chemical purity was found.

[0019] Furthermore, when using the suitable stabilizer according to the present invention described herein, a high stability of at least 95% radiochemical stability is ensured regarding the radiochemical purity of the radionuclide complex. For example, In the case of Lu-DOTA-TATE, at least 95% radiochemical purity was found after 72 hours at 25°C. Under short-term elevated temperature conditions (12 h at 32°C And 60 h at 25°C), 177 In the case of Lu-DOTA-TATE, at least [[ID=At least 95% radiochemical purity was found after 72 hours at 25°C. Under short-term elevated temperature conditions (12 h at 32°C Even at 25 °C for 60 h, such high stability was found with respect to radiochemical purity. It was.

[0020] One single stabilizer can already achieve sufficient stability, but the use of two stabilizers was found to be particularly suitable for stabilizing sensitive radiopharmaceutical solutions. Specifically, when one stabilizer is present during complex formation and another stabilizer is added after complex formation, it is advantageous because the cell receptor binding molecule is protected from radiolysis during the complexation reaction and the other stabilizer ensures enhanced protective effect over the storage lifetime.

[0021] Furthermore, such sequential application of two stabilizers ensures that a relatively small amount of stabilizer is present during complex formation (thus minimizing the possibility of its interference with the complexation reaction) and a combination of a large amount of stabilizer is present after complex formation (thus enhancing the protective power of the stabilizer over the subsequent drug product storage period).

[0022] Also, such sequential application of two stabilizers reduces the overall thermal stress of such stabilizers because when a complexation reaction involving high temperature is carried out, one of them is absent.

[0023] Furthermore, especially when using two different stabilizers, this combination is advantageous because it is more effective in reacting with each different radical that may be formed by radiolysis of the cell receptor binding molecule than a single stabilizer alone.

[0024] The composition of the radiopharmaceutical solution does not require the presence of ethanol. The solution is ethanol-free. It is sufficiently stable. The absence of ethanol is advantageous with respect to the physiological tolerance of the solution.

[0025] In order to enable the production of radiopharmaceutical drug products from a centralized pharmaceutical manufacturing site and to commercialize it as an immediately usable drug product, a shelf life of at least 3 days is required.

[0026] Thus, thanks to the high stability (72 h at 25 °C), the present invention enables centralized pharmaceutical manufacturing 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 are sufficient for a number of dose units, such as dose units sufficient to treat, for example, 10 - 20 patients simultaneously.

[0027] Furthermore, thanks to the high stability, there is sufficient time in the present invention for transportation from a centralized pharmaceutical manufacturing site to a remote clinical center.

[0028] Moreover, thanks to the high stability, the present invention can be provided as an immediately usable injection solution that can be administered to patients immediately without any need for preparation work by clinical staff before administration.

[0029] The present invention is particularly suitable for somatostatin receptor-binding peptides, and in particular, for octreotide and octreotate, which are extremely sensitive somatostatin analogs that are particularly susceptible to degradation reactions. Furthermore, the present invention is particularly suitable for the radionuclide lutetium - 177 having specific radioactivity characteristics.

DETAILED DESCRIPTION OF THE INVENTION

[0030] Hereinafter, the present invention will be described and illustrated in more detail.​​​​​​​​​​​

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

[0032] The stability of the solution was confirmed by the use of stabilizers against radiolytic degradation.

[0033] Generally, the stabilizers used according to the present invention may be selected from gentisic acid (2,5-dihydro xybenzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g., 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. When ethanol is present at a higher concentration, there are associated tolerance problems, so it

[0034] is not regarded as a more preferred stabilizer. Ethanol should ideally be avoided in the solutions of the present invention (in other words, ethanol-free), and at least the ethanol content of the solutions of the present invention should be limited to, for example, less than 5%, preferably less than 2%, more preferably less than 1% in the final solution expected to be injected / infused. Even more preferably the solution is ethanol-free.

[0035] According to the present invention, the following embodiments are provided.

[0036] 1. (a) The following: (ai) A radionuclide, and (aii) A cell receptor-binding organic moiety linked to a chelating agent, and The complex formed thereby, and (b) at least one stabilizer against radiolytic degradation, and comprising wherein the radionuclide is present at a concentration providing a volumetric radioactivity of at least 100 MBq / mL, preferably at least 250 MB q / mL, An aqueous pharmaceutical solution.

[0037] 2. The stabilizer (component (b)) is 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, The aqueous pharmaceutical solution according to Embodiment 1.

[0038] 3. The radionuclide is present at a concentration providing a volumetric radioactivity of 100 to 1000 MBq / mL, preferably 250 to 500 MBq / mL, of the aqueous pharmaceutical solution according to any one of Embodiments 1 or 2 as described.

[0039] 4. The stabilizer is present at a total concentration of 0.2 to 20.0 mg / mL, preferably 0.5 to 10.0 m g / mL, more preferably 1.0 to 5.0 mg / m, even more preferably 2.7 to 4. 1 mg / mL, of the aqueous pharmaceutical solution according to any one of Embodiments 1 to 3 as described.

[0040] 5. Component (b) is only one stabilizer against radiolytic degradation, i.e., only the first stabilizer only, The aqueous pharmaceutical solution according to any one of Embodiments 1 to 4.

[0041] 6. 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., the first and the second Only the stabilizer of 2 The aqueous pharmaceutical solution according to any one of Embodiments 1 to 5.

[0042] 7. The first stabilizer is present at a concentration of 0.2 to 5 mg / mL, preferably 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, the aqueous pharmaceutical solution according to any one of Embodiments 5 to 6.

[0043] 8. The second stabilizer is present at a concentration of 0.5 to 10 mg / mL, more preferably 1.0 to 8.0 m g / mL, even more preferably 2.0 to 5.0 mg / mL, and even more preferably 2. 2 to 3.4 mg / mL, the aqueous pharmaceutical solution according to Embodiment 6 or 7.

[0044] 9. The stabilizer is selected from gentisic acid (2,5-dihydroxybenzoic acid) or its salt, as corbic acid (L-ascorbic acid, vitamin C) or its salt (e.g., sodium asco rubate), methionine, histidine, melatonin, ethanol, and Se-methionine, preferably selected from gentisic acid or its salt and asco rubic acid or its salt, the aqueous pharmaceutical solution according to any one of Embodiments 1 to 8.

[0045] 10. The first stabilizer is selected from gentisic acid and ascorbic acid, preferably the first stabilizer is gentisic acid, the aqueous pharmaceutical solution according to any one of Embodiments 5 to 9.

[0046] 11. The second stabilizer is selected from gentisic acid and ascorbic acid, preferably ​​​The pharmaceutical according to any one of Embodiments 6 to 10, wherein the second stabilizer is ascorbic acid An aqueous solution.

[0047] 12. The first stabilizer is gentisic acid or a salt thereof, and the second stabilizer is as Ascorbic acid or a salt thereof, and the ratio of the concentration of the first stabilizer (in mg / mL units) to the concentration of the second stabilizer (in mg / mL units) is 1:3 to 1:7, preferably 1:4 to 1:5 There is, the pharmaceutical aqueous solution according to any one of Embodiments 6 to 8.

[0048] 13. The radionuclide is 177 Lu, 68 Ga, 18 F, 99m Tc, 211 At, 82 Rb, 166 Ho, 225 Ac, 111 In, 123 I, 131 I, 89 Zr, 90 Y or Selected from, preferably 177 Lu and 68 Selected from Ga, more preferably 177 L u, the pharmaceutical aqueous solution according to any one of Embodiments 1 to 12.

[0049] 14. The cell receptor binding moiety 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, the pharmaceutical aqueous solution according to any one of Embodiments 1 to 13.

[0050] ​​15. The chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA, according to any one of Embodiments 1 to 14 of the pharmaceutical aqueous solution described.

[0051] 16. The cell receptor binding moiety and the chelating agent together form a molecule selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxo dotreotide), DOTA-LAN, and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-T ATE, of the pharmaceutical aqueous solution according to any one of Embodiments 1 to 15 .

[0052] 17. The radionuclide, the cell receptor binding moiety, and the chelating agent together form a complex body 177 Lu-DOTA-TOC ( 177 Lu-edotreotide) or 177 Lu-DO TA-TATE ( 177 Lu-oxodotreotide), preferably 177 Lu-DOTA -TATE, of the pharmaceutical aqueous solution according to any one of Embodiments 1 to 16.

[0053] 18. Further comprising a buffer, preferably the buffer is preferably an acetate buffer in an amount that provides acetic acid at a concentration of 0.3 to 0.7 m g / mL (preferably about 0.48 mg / mL) and sodium acetate at 0.4 to 0.9 mg / mL (preferably about 0.66 mg / mL), of the pharmaceutical aqueous solution according to any one of Embodiments 1 to 17.

[0054] 19. Further comprising a metal ion sequestering agent, preferably the metal ion sequestering agent is preferably present in an amount that provides a concentration of from 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL) of diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, the pharmaceutical aqueous solution according to any one of Embodiments 1 to 18.

[0055] 20. Having a shelf life of at least ≤ 25 °C for 24 hours (h), ≤ 25 °C for at least 48 h, ≤ 25 °C for at least 72 h, ≤ 25 °C for 24 h to 120 h, ≤ 25 °C for 24 h to 96 h, ≤ 2 5 °C for 24 h to 84 h, ≤ 25 °C for 24 h to 72 h, particularly having a shelf life of ≤ 25 °C for 72 h, the pharmaceutical aqueous solution according to any one of Embodiments 1 to 19.

[0056] 21. The solution is manufactured on a commercial scale, particularly manufactured in batch sizes of at least 20 GBq, at least 50 GBq, at least 70 GBq, the pharmaceutical aqueous solution according to any one of Embodiments 1 to 20.

[0057] 22a. Immediately available, the pharmaceutical aqueous solution according to any one of Embodiments 1 to 21 .

[0058] 22b. Commercially available, the pharmaceutical aqueous solution according to any one of Embodiments 1 to 22a.

[0059] 23. (a) The following: (ai) A radionuclide present at a concentration providing a volumetric radioactivity of 250 to 500 MBq / mL 177 lutetium (Lu-177), and (aii) A somatostatin receptor-binding organic moiety DO linked to a chelating agent TATATE (oxodotreotide) or DOTA-TOC (edotreotide), and a complex formed by (bi) Genisteic acid or a salt thereof as a first stabilizer against radiolytic degradation present at a concentration of 0.5 to 1 mg / mL and, (bii) Ascorbic acid or a salt thereof as a second stabilizer against radiolytic degradation present at a concentration of 2.0 to 5.0 mg / mL and, an aqueous pharmaceutical solution containing the same.

[0060] 24. (c) Diethylenetriaminepentaacetic acid ( DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg / mL further contained in the aqueous pharmaceutical solution according to Embodiment 23.

[0061] 25. (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 further contained in the aqueous pharmaceutical solution according to Embodiment 23 or 24.

[0062] 26. An aqueous pharmaceutical solution according to any one of Embodiments 1 to 25, wherein the stabilizer is present in the solution during the complex formation of components (ai) and (aii).

[0063] 27. An aqueous pharmaceutical solution according to any one of Embodiments 5 to 26, wherein only the first stabilizer is present in an amount that preferably provides 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 in the final solution during the complex formation of components (ai) and (aii).

[0064] ​​​​​​​The aqueous pharmaceutical solution according to any one of Embodiments 6 to 27, which is added after the formation of the complex of (

[0065] 29. The aqueous pharmaceutical 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). 6. The aqueous pharmaceutical 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).

[0066] 30. The second stabilizer is preferably at 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 in the final solution, and is added after the formation of the complex of components (ai) and (aii). The aqueous pharmaceutical solution according to Embodiment 6 or 29. 6. The second stabilizer is preferably at 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 in the final solution, and is added after the formation of the complex of components (ai) and (aii). The aqueous pharmaceutical solution according to Embodiment 6 or 29. 6. The second stabilizer is preferably at 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 in the final solution, and is added after the formation of the complex of components (ai) and (aii). The aqueous pharmaceutical solution according to Embodiment 6 or 29. 6. The second stabilizer is preferably at 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 in the final solution, and is added after the formation of the complex of components (ai) and (aii). The aqueous pharmaceutical solution according to Embodiment 6 or 29.

[0067] 31. Further comprising a metal ion sequestering agent added after the formation of the complex of components (ai) and (aii) to remove any non-complexed Lu, preferably the metal ion sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount that provides a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 30. 6. Further comprising a metal ion sequestering agent added after the formation of the complex of components (ai) and (aii) to remove any non-complexed Lu, preferably the metal ion sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount that provides a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 30. 6. Further comprising a metal ion sequestering agent added after the formation of the complex of components (ai) and (aii) to remove any non-complexed Lu, preferably the metal ion sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount that provides a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 30. 6. Further comprising a metal ion sequestering agent added after the formation of the complex of components (ai) and (aii) to remove any non-complexed Lu, preferably the metal ion sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount that provides a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 30. 6. Further comprising a metal ion sequestering agent added after the formation of the complex of components (ai) and (aii) to remove any non-complexed Lu, preferably the metal ion sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount that provides a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 30.

[0068] 32. (1) The following: (1.1) Preparing an aqueous solution containing a radionuclide; (1.2) Preparing an aqueous solution containing a cell receptor-binding organic moiety linked to a chelating agent, a first stabilizer, and optionally a second stabilizer; (1.3) Heating the mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2);<s (1.4) By which, a radionuclide and a cell receptor-binding organic moiety linked to a chelating agent are obtained. 6. Heating the mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2); 6. By which, a radionuclide and a cell receptor-binding organic moiety linked to a chelating agent are obtained. The process steps for forming the complex, (2) as follows: (2.1) Preparing an aqueous dilution solution optionally containing a second stabilizer; (2.2) Mixing the complex solution obtained in step (1) with the dilution solution obtained in step (2.1), thereby diluting the complex solution obtained in step (1); A process for manufacturing an aqueous pharmaceutical solution according to any one of Embodiments 1 to 31, including the above.

[0069] 33. Only the first stabilizer is preferably present in an amount that provides 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 in the final solution during step (1.3). The process according to Embodiment 32.

[0070] 34. A part of the amount of the second stabilizer is already present in the solution during step (1.3), and another part of the amount of the second stabilizer is added in step (2.1) after step (1.3). The process according to any one of Embodiments 32 to 33.

[0071] 35. The second stabilizer is added in step (2.1) after step (1.3). An aqueous pharmaceutical solution according to any one of Embodiments 32 to 34.

[0072] 36. The second stabilizer is preferably added in step (2.1) after step (1.3) in an amount that provides 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 in the final solution. An aqueous pharmaceutical solution according to any one of Embodiments 32 to 35. ​​​​​​​​​​ Solution.

[0073] 37. The process according to any one of embodiments 32 to 36, wherein the solution of step (1.2) further comprises a buffer, preferably an acetate buffer. The process according to any one of embodiments 32 to 36, wherein the solution of step (1.2) further comprises a buffer, preferably an acetate buffer.

[0074] 38. The process according to any one of embodiments 32 to 37, wherein the obtained mixture is heated at a temperature of 70 to 99 °C, preferably 90 to 98 °C for 2 to 59 minutes in step (1.3). The process according to any one of embodiments 32 to 37, wherein the obtained mixture is heated at a temperature of 70 to 99 °C, preferably 90 to 98 °C for 2 to 59 minutes in step (1.3).

[0075] 39. The process 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. The process 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.

[0076] 40. A process step of filtering the solution obtained in step (2) through 0.2 μm, and a (4) A process step of dispensing the filtered solution obtained in step (3) into a dose unit container in an amount necessary to deliver a radiation dose of 5.0 to 10 MBq, preferably 7.0 to 8.0 MBq, more preferably 7.3 to 7.7 MBq, even more preferably 7.4 to 7.5 MBq, preferably the amount is 10 to 50 mL, more preferably 15 to 30 m L, even more preferably 20 to 25 mL, and a process step, and a process step, further comprising the process according to any one of embodiments 32 to 39. The process according to any one of embodiments 32 to 39, further comprising the process according to any one of embodiments 32 to 39.

[0077] 41. The process according to any one of embodiments 32 to 40, wherein the solution of step (1.1) comprises LuCl3 and HCl. The process according to any one of embodiments 32 to 40, wherein the solution of step (1.1) comprises LuCl3 and HCl.

[0078] 42. The solution of step (1.2) is 177 Lu-DOTA-TATE or 177 Lu- Embodiment 3 comprising DOTA-TOC, gentisic acid, acetic acid, and sodium acetate The process according to any one of 2 to 41.

[0079] 43. The process according to any one of Embodiments 32 to 42, wherein the solution in step (2.1) contains DTPA and ascorbic acid.

[0080] 44. The process 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 .

[0081] 45. An aqueous pharmaceutical solution obtained (or obtainable) by the process according to any one of claims 32 to 44.

[0082] A further embodiment of the present invention is described below as "Embodiment E".

[0083] E1. (a) The following: (ai) A radionuclide 177 Lu (lutetium-177), and (aii) A complex formed by linking 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 volumetric radioactivity of 250 to 500 MBq / mL and and the stabilizers are present at a total concentration of 0.2 to 20.0 mg / mL. An aqueous pharmaceutical solution.

[0084] "A complex formed by ~" can be expressed in alternative words as "a complex of ~".

[0085] ​​The "different" in "two different stabilizers" means the difference in the chemical entities of such stabilizers. "Two different stabilizers" means that the two stabilizers are different chemical entities. For example, genisteic acid and ascorbic acid are two different stabilizers.

[0086] "At least two kinds" means two or more kinds, but preferably exactly two stabilizers are present (not three or more). It is more preferable that ethanol is not one of the two stabilizers.

[0087] E2. Component (b) is a stabilizer: (bi) Genisteic acid or its salt, and (bii) Ascorbic acid or its salt, comprising the aqueous pharmaceutical solution according to embodiment E1.

[0088] E3. (bi) Genisteic acid is present at a concentration of 0.5 - 2 mg / mL, preferably 0.5 - 1 mg / mL, and (bii) Ascorbic acid is present at a concentration of 2.0 - 5.0 mg / mL, the aqueous pharmaceutical solution according to embodiment E2.

[0089] In certain embodiments, the present invention provides (a) the following: (ai) A radionuclide at a concentration providing a volumetric radioactivity of 250 - 500 MBq / mL 17 7 177Lu (lutetium - 177), and (aii) A somatostatin receptor - binding peptide linked to the chelating agent DOTA (b) A stabilizer against radiolytic degradation formed thereby, (bi) Gentisic acid at a concentration of 0.5 to 1 mg / mL, and (bii) Ascorbic acid at a concentration of 2.0 to 5.0 mg / mL, and A pharmaceutical aqueous solution containing is provided.

[0090] E4. (c) Diethylenetriaminepentaacetic acid ( DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg / mL, The pharmaceutical aqueous solution according to embodiment E3, further comprising

[0091] E5. (d) The following: (di) Acetic acid at a concentration of 0.3 to 0.7 mg / mL, and (dii) Sodium acetate at a concentration of 0.4 to 0.9 mg / mL, and An acetate buffer composed of further comprising Preferably, the acetate buffer provides a pH of 4.5 to 6.0, preferably 4.7 to 6.0, more preferably 5.0 to 6.0, even more preferably 5.0 to 5.5, The pharmaceutical aqueous solution according to embodiment E3 or E4.

[0092] In certain embodiments, the present invention provides (a) The following: (ai) A radionuclide at a concentration providing a volume radioactivity of 250 to 500 MBq / mL 17 7 Lu (lutetium - 177), and (aii) A somatostatin receptor - binding peptide linked to the chelating agent DOTA peptide, and a complex formed thereby, and (b) A stabilizer against radiolytic degradation, (bi) Gentisic acid at a concentration of 0.5 to 1 mg / mL and (bii) Ascorbic acid at a concentration of 2.0 to 5.0 mg / mL, and (c) Diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL or a salt thereof, (d) as follows: (di) acetic acid at a concentration of 0.3 - 0.7 mg / mL, (dii) sodium acetate at a concentration of 0.4 - 0.9 mg / mL, an acetate buffer composed of, containing, preferably the acetate buffer provides a pH of 5.0 - 5.5, provides an aqueous pharmaceutical solution.

[0093] The pH values specified in this specification are the pH values of the final solution. However, it is also, the pH during the production of the solution, for example, the pH during complex formation.

[0094] E6. At least one stabilizer is present during the complex formation of components (ai) and (aii) and at least one stabilizer is added after the complex formation of components (ai) and (aii) The aqueous pharmaceutical solution according to any one of Embodiments E1 - E5.

[0095] E7. At least gentiopic acid is present during the complex formation of components (ai) and (aii) and at least ascorbic acid is added after the complex formation of components (ai) and (aii) The aqueous pharmaceutical solution according to any one of Embodiments E1 - E5.

[0096] E8. The only stabilizer present during the complex formation of components (ai) and (aii) is genti opic acid, and the only stabilizer added after the complex formation of components (ai) and (aii) is ascorbic acid. The aqueous pharmaceutical solution according to any one of Embodiments E1 - E5.

[0097] In certain embodiments, the present invention provides (a) as follows: (ai) a radionuclide at a concentration providing a volumetric radioactivity of 250 - 500 MBq / mL17 7 Lutetium-177 (Lu) and, (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA peptide, and a complex formed thereby, and (b) a stabilizer against radiolytic degradation, (bi) genisteic acid at a concentration of 0.5 to 1 mg / mL (in the final solution), and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL (in the final solution), and comprising, genisteic 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), to provide an aqueous pharmaceutical solution.

[0098] In certain embodiments, the invention is defined as follows. That is, (a) The following: (ai) a radionuclide at a concentration providing a volumetric radioactivity of 250 to 500 MBq / mL 17 7 Lutetium-177 (Lu) and, (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA peptide, and a complex formed thereby, and (b) a stabilizer against radiolytic degradation, (bi) genisteic acid at a concentration of 0.5 to 1 mg / mL and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL, and (c) diethylenetriaminepentaacetic acid (DTPA ) or a salt thereof at a concentration of 0.01 to 0.10 mg / mL, and (d) The following: (di) acetic acid at a concentration of 0.3 to 0.7 mg / mL, and (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL, and an acetate buffer composed of comprising preferably, said acetate buffer provides a pH of 5.0 to 5.5, 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), an aqueous pharmaceutical solution.

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

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

[0101] In certain embodiments, the invention is defined as follows. That is, (a) The following: (ai) A radionuclide at a concentration providing a volumetric radioactivity of 250 to 500 MBq / mL 17 7 Lu (lutetium - 177), and (aii) A somatostatin receptor binding peptide linked to the chelating agent DOTA tide, and a complex formed thereby, (b) Stabilizers against radiolytic degradation, (bi) gentisic acid at a concentration of 0.5 to 1 mg / mL and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL, (c) Diethylenetriaminepentaacetic acid (DTPA ) or a salt thereof at a concentration of 0.01 to 0.10 mg / mL, (d) The following: (di) Acetic acid at a concentration of 0.3 to 0.7 mg / mL, and (dii) Sodium acetate at a concentration of 0.4 to 0.9 mg / mL, and An acetate buffer composed of, containing preferably the acetate buffer provides a pH of 5.0 to 5.5, genisteic acid is present during the complex formation of components (ai) and (aii), and component (ai) and ascorbic acid is added after the complex formation of (aii), and the only stabilizer present during the complex formation of components (ai) and (ai i) is genisteic acid, and is present at a concentration of 2 0 to 40 mg / mL, preferably 25 to 35 mg / mL, A pharmaceutical aqueous solution.

[0102] Embodiments E6 to E10 can alternatively be defined by the following expressions.

[0103] E6. At least one stabilizer is present during the complex formation of components (ai) and (aii) and at least one stabilizer is added after the complex formation of components (ai) and (aii), A pharmaceutical aqueous solution according to any one of Embodiments E1 to E5, produced by the above.

[0104] E7. At least genisteic acid is present during the complex formation of components (ai) and (aii) and at least ascorbic acid is added after the complex formation of components (ai) and (aii), A pharmaceutical aqueous solution according to any one of Embodiments E1 to E5, produced by the above.

[0105] E8. Genisteic acid is present as the only stabilizer during the complex formation of components (ai) and (aii) and the only stabilizer after the complex formation of components (ai) and (aii) is Any one of Embodiments E1 to E5 produced by adding ascorbic acid The pharmaceutical aqueous solution described in the above item.

[0106] E9. One or more stabilizers are present during the complex formation of components (ai) and (aii), and are present at a total concentration of 15 to 50 mg / mL, preferably 20 to 40 mg / mL during complex formation. The pharmaceutical aqueous solution according to any one of Embodiments E6 to E8 produced by making it present. described in the above item.

[0107] E10. Gentisic acid is present as the sole stabilizer during the complex formation of components (ai) and (aii), and is present at a concentration of 20 to 40 mg / mL, preferably 25 to 35 mg / mL during complex formulation. The pharmaceutical aqueous solution according to Embodiment E9 produced by making it present. described in the above item.

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

[0109] In certain embodiments, the present invention is defined as follows. That is, (a) The following: (ai) A radionuclide at a concentration providing a volume radioactivity of 250 to 500 MBq / mL (in the final solution) and 177 Lu (lutetium-177), (aii) A somatostatin receptor-binding peptide linked to the chelating agent DOTA and a complex formed by (b) Stabilizer against radiolytic degradation, (bi) genisteic acid at a concentration of 0.5 - 1 mg / mL, (bii) ascorbic acid at a concentration of 2.0 - 5.0 mg / mL, and (c) diethylenetriaminepentaacetic acid (DTPA ) or a salt thereof at a concentration of 0.01 - 0.10 mg / mL, (d) the following: (di) acetic acid at a concentration of 0.3 - 0.7 mg / mL, (dii) sodium acetate at a concentration of 0.4 - 0.9 mg / mL, and an acetate buffer composed of, containing preferably the acetate buffer provides a pH of 5.0 - 5.5, genisteic 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 the only stabilizer present during the complex formation of components (ai) and (ai i) is genisteic acid, and is present at a concentration of 2 0 - 40 mg / mL during complex formulation, and the radionuclide is present at a concentration providing a volume radioactivity of 10 - 20 GBq / mL during complex formation, An aqueous pharmaceutical solution.

[0110] E11. Having a storage life of at least 72 h, especially when stored at 25 °C, having a storage life of at least 72 h, of any one of Embodiments E1 - E10 The aqueous pharmaceutical solution according to any one of the above.

[0111] "Storage life" has its general meaning in relation to pharmaceutical products in this specification. Storage life refers to the length of time during which a pharmaceutical product can be stored while still meeting the product specifications defined during drug development and agreed upon by the health authorities. It is the length of time during which the product characteristics still

[0112] E12. When stored at 25 °C, the radiochemical purity (determined by HPLC) is at least maintained at ≧95% for 72 h, according to any one of Embodiments E1 to E11 of the aqueous pharmaceutical solution described .

[0113] E13. The solution is manufactured on a commercial production scale, in particular at batch sizes of at least 20 GBq, at least 50 GBq, at least 70 GBq, of the aqueous pharmaceutical solution according to any one of Embodiments E 1 to E12

[0114] E14. The aqueous pharmaceutical solution according to any one of Embodiments E1 to E13, which is immediately available for use

[0115] E15. (1) The following: (1.1) Preparing an aqueous solution containing a radionuclide, and (1.2) Preparing an aqueous solution containing a somatostatin receptor-binding peptide linked to a chelating agent 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, thereby forming a complex of the radionuclide Lu and a somatostatin 177 receptor-binding peptide linked to the chelating agent DOTA, and a process step; and (2) The following: (2.1) Optionally preparing an aqueous dilution solution containing at least one stabilizer against radiolytic degradation, and (2.2) Mixing the complex solution obtained in step (1) and the dilution solution obtained in step (2.1) to obtain a final solution, thereby diluting the complex solution obtained in step (1), and a process step . comprising, when the solution prepared under (1.2) contains only one stabilizer, under (2.1) the solution prepared contains at least one stabilizer, The manufacturing process of the aqueous pharmaceutical solution according to any one of Embodiments E1 to E14.

[0116] E16. 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, according to Embodiment E15 The process described.

[0117] E17. 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, the process according to Embodiment E15.

[0118] E18. 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 The process according to Embodiment E15.

[0119] E19. The solution prepared in step (1.2) contains one or more stabilizers at a total concentration of 15 - 50 mg / mL, preferably 2 0 - 40 mg / mL, the process according to any one of Embodiments E15 - E1 8.

[0120] E20. The solution prepared in step (1.2) contains only one stabilizer which is gentisic acid at a concentration of 20 - 40 mg / mL, preferably 2 5 - 35 mg / mL, the process according to any one of Embodiments E 15 - E18.

[0121] The solution in step (1.2) of E21. Process further contains a buffer, preferably an acetate buffer. The process according to any one of embodiments E15 to E20.

[0122] E22. In step (1.3), the resulting mixture is heated to a temperature of 70 - 99 °C, preferably 90 - 98 °C, for 2 - 59 minutes, preferably 10 - 15 minutes. The process according to any one of embodiments E15 - E21. The process according to any one of embodiments E15 - E21. The process according to any one of embodiments E15 - E21.

[0123] E23. The solution in step (2.1) further contains diethylenetriaminepentaacetic acid (DTPA) or a salt thereof. The process according to any one of embodiments E15 - E22. The process according to any one of embodiments E15 - E22.

[0124] E24. (3) A process step of filtering the solution obtained in step (2) through 0.2 μm, and (4) A process step of dispensing the filtered solution obtained in step (3) into a dose unit container in an amount necessary to deliver a radiation dose of 5.0 - 10 MBq, preferably 7.0 - 8.0 MBq, more preferably 7.3 - 7.7 MBq, even more preferably 7.4 - 7.5 MBq, preferably the amount is 10 - 50 mL, more preferably 15 - 30 mL, even more preferably 20 - 25 mL. The process further comprising the above steps, according to any one of embodiments E15 - E23. (4) A process step of dispensing the filtered solution obtained in step (3) into a dose unit container in an amount necessary to deliver a radiation dose of 5.0 - 10 MBq, preferably 7.0 - 8.0 MBq, more preferably 7.3 - 7.7 MBq, even more preferably 7.4 - 7.5 MBq, preferably the amount is 10 - 50 mL, more preferably 15 - 30 mL, even more preferably 20 - 25 mL. The process further comprising the above steps, according to any one of embodiments E15 - E23. ~8.0MBq, more preferably 7.3 - 7.7MBq, even more preferably 7.4 - 7.5MBq of radiation dose, and a process step of dispensing into a dose unit container in an amount necessary to deliver the radiation dose, preferably the amount is 10 - 50mL, more preferably 15 - 30m L, even more preferably 20 - 25mL. The process step further comprising the above steps, according to any one of embodiments E15 - E23. L, even more preferably 20 - 25mL. The process step further comprising the above steps, according to any one of embodiments E15 - E23. The process according to any one of embodiments E15 - E23, further comprising the above steps.

[0125] E25. The solution in step (1.1) contains LuCl3 and HCl. The process according to any one of embodiments E15 - E24. The process according to any one of embodiments E15 - E24.

[0126] E26. The solution in step (1.2) is 177 Lu - DOTA - TATE or 177 Lu Embodiment comprising -DOTA-TOC, gentisic acid, acetic acid, and sodium acetate The process according to any one of E15 to E25.

[0127] E27. Embodiment E1 where the solution in step (2.1) contains DTPA and ascorbic acid The process according to any one of 5 to E26.

[0128] E28. Embodiment where the dose unit container in step (4) is a vial with a stopper enclosed in a lead container The process according to any one of E24 to E27.

[0129] E29. A pharmaceutical aqueous solution obtained ( or obtainable) by the process according to any one of E15 to E28.

[0130] In all embodiments described herein, the somatostatin receptor-binding peptide (component (aii)) linked to the chelating agent DOTA is preferably DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), more preferably DOTA-TATE (oxodotreotide). (oxodotreotide).

[0131] The present invention further provides a pharmaceutical aqueous solution as defined herein for use in the treatment of neuroendocrine tumors (NETs). A pharmaceutical aqueous solution as defined herein for use in the treatment of neuroendocrine tumors (NETs).

[0132] Alternatively, the present invention provides a method for treating NETs in a human patient in need of treatment, comprising administering an effective amount of a pharmaceutical aqueous solution as defined herein. A method for treating NETs in a human patient in need of treatment, comprising administering an effective amount of a pharmaceutical aqueous solution as defined herein.

[0133] As a further alternative, the present invention provides the use of a pharmaceutical aqueous solution as defined herein for the manufacture / preparation of a medicament for treating NETs. The use of a pharmaceutical aqueous solution as defined herein for the manufacture / preparation of a medicament for treating NETs.

[0134] As a further alternative form, the present invention provides a NET therapeutic medicament comprising an aqueous pharmaceutical solution as defined herein.

[0135] Neuroendocrine tumors (NETs) that can be treated according to the present invention alone or in combination with the aqueous pharmaceutical solution as defined herein include gastrointestinal pancreatic neuroendocrine tumors, carcinoid tumors, pheochromocytomas, paragangliomas, medullary thyroid carcinomas, lung neuroendocrine tumors, thymic neuroendocrine tumors, carcinoid tumors or pancreatic neuroendocrine tumors, pituitary adenomas, adrenal tumors, Merkel cell carcinomas, breast cancers, non-Hodgkin lymphomas, Hodgkin lymphomas, head and neck tumors, urothelial carcinomas (bladder), renal cell carcinomas, hepatocellular carcinomas, GI ST, neuroblastomas, cholangiocarcinomas, cervical tumors, Ewing sarcomas, osteosarcomas, small cell lung cancers (SC LC), prostate cancers, melanomas, meningiomas, gliomas, medulloblastomas, hemangioblastomas, primitive neuroectodermal tumors above the tentorium, and sensory neuroblastomas, and are selected from the group consisting of.

[0136] Additional NET tumors that can be treated according to the present invention alone or in combination with the aqueous pharmaceutical solution as defined herein may be selected from the group consisting of functional carcinoid tumors, insulinomas, gastrinomas, vasoactive intestinal peptide (VIP)omas, glucagonomas, serotoninomas, histaminomas, ACTHomas, pheochromocytomas, and somatostatinomas.

[0137] The present invention further provides a combination or combination therapy of a complex formed by 177 Lu (lutetium-177) and a somatostatin receptor-binding peptide linked to a chelating agent as defined herein and, or a combination or combination therapy of an aqueous pharmaceutical solution as defined herein in combination with one or more therapeutic agents outlined below. ​

[0138] In certain cases, the aqueous pharmaceutical solution of the present invention may be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), analgesics, cytoprotective agents, and combinations thereof. be combined.

[0139] Common chemotherapeutic agents that may be considered for use in combination therapy include anastrozole (Ar imidex (registered trademark)), bicalutamide (Casodex (registered trademark)), ble omycin sulfate (Blenoxane (registered trademark)), busulfan (Myleran (registered trademark)), busulfan injection (Busulfex (registered trademark)), capecitabine (Xe loda (registered trademark)), N4-pentyloxycarbonyl-5-deoxy-5-fluorour idine, carboplatin (Paraplatin (registered trademark)), carmustine (BiC NU (registered trademark)), chlorambucil (Leukeran (registered trademark)), cisplatin (Platinol (registered trademark)), cladribine (Leustatin (registered trademark)) , cyclophosphamide (Cytoxan (registered trademark) or Neosar (registered trademark)), cytarabine, cytosine arabinoside (Cytosar-U (registered trademark)), cytarabine li posome injection (DepoCyt (registered trademark)), dacarbazine (DTIC-Dome( registered trademark)), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine (registered trademark)), daunorubicin citrate li posome injection (DaunoXome (registered trademark)), dexamethasone, docetaxel ( Taxotere (registered trademark)), doxorubicin hydrochloride (Adriamycin (registered (trademarks), Rubex (registered trademark), etoposide (Vepesid (registered trademark)), phosphate fludarabine (Fludara (registered trademark)), 5-fluorouracil (Adrucil (registered trademark), Efudex (registered trademark)), flutamide (Eulexin (registered trademark) ), tiazofurin, gemcitabine (difluorodeoxycytidine), hydroxyurea ( Hydrea (registered trademark)), idarubicin (Idamycin (registered trademark)), ifos famide (IFEX (registered trademark)), irinotecan (Camptosar (registered trademark)) , L-asparaginase (ELSPAR (registered trademark)), leucovorin calcium, mel phalan (Alkeran (registered trademark)), 6-mercaptopurine (Purinetho l (registered trademark)), methotrexate (Folex (registered trademark)), mitoxantrone (Novantrone (registered trademark)), Myotarg, paclitaxel (Taxol( registered trademark)), nab-paclitaxel (Abraxane (registered trademark)), phenic (Yttrium90 / MX-DTPA), pentostatin, polypheprosan 20 cal mustine implant (Gliadel (registered trademark)), tamoxifen tosylate (N olvadex (registered trademark)), teniposide (Vumon (registered trademark)), 6-thiogua nin, thiotepa, tirapazamine (Tirazone (registered trademark)), topotecan hydrochloride for injection (Hycamptin (registered trademark)), vinblastine (Velban (registered trademark)) , vincristine (Oncovin (registered trademark)), and vinorelbine (Navelbi ne (registered trademark)) may be mentioned.

[0140] Particularly targeted anticancer agents in combination with the aqueous pharmaceutical solution of the present invention include the following be inhibited

[0141] Tyrosine kinase inhibitors: Erlotinib hydrochloride (Tarceva (registered trademark )), Linifanib (also known as ABT 869 available from Genentech N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2- fluoromethylphenyl)urea), Sunitinib malate (Sutent (registered trademark )), Bosutinib (SKI-606, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy -7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile described in US Patent No. 6,780,996 ), Dasatinib (Sprycel (registered trademark)), Pazopanib (Votrient(registered trademark)), Sorafenib (Nexavar (registered trademark)), Zactima (ZD 6474), and Imatinib or Imatinib mesylate (Gilvec (registered trademark) and Gleevec (registered trademark)). (registered trademark)). 6474), and Imatinib or Imatinib mesylate (Gilvec (registered trademark) and Gleevec (registered trademark)). (registered trademark)).

[0142] Vascular endothelial growth factor (VEGF) receptor inhibitors: Bevacizumab (Avastin (registered trademark )), Axitinib (Inlyta (registered trademark)), Brivanib alaninate (BMS S-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H- indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine -6-yloxy)propan-2-yl)2-aminopropanoate), Sorafenib (Nexavar (registered trademark)), Pazopanib (Votrient (registered trademark)), Sunitinib malate (Sutent (registered trademark)), Cediranib (AZD2171, CAS (registered trademark)). 288383-20-1), BIBF 1120, CAS 928326- 83-4), foretinib (GSK1363089), teratinib (BAY57-935 2, CAS 332012-40-5), apatinib (YN968D1, CAS 811 803-05-1), imatinib (Gleevec (registered trademark)), ponatinib (AP2 4534, CAS 943319-70-8), cibotinib (AV951, CAS 47 5108-18-0), regorafenib (BAY73-4506, CAS 755037 -03-7), pazopanib dihydrochloride (PTK787, CAS 212141- 51-0), brivanib (BMS-540215, CAS 649735-46-6), vandetanib (Caprelsa (registered trademark) or AZD6474), motesanib diphosphate acid (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 International Publication No. 02 / 066470 pamphlet ), dovitinib dilactate (TKI258, CAS 852433-84-2), lymph anib (Linfanib) (ABT869, CAS 796967-16-3), cabo zantinib (XL184, CAS849217-68-1), lestaurtinib (CAS 111358-88-4), N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (B MS38703, CAS 345627-80-7), (3R,4R)-4-amino-1 -((4-((3-Methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]tri azin-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]pyrimi din-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide (BHG712, CAS 940310-85-0), and aflibercept (Eyle a (registered trademark)), sulfatinib, sulfanitinib (sur ufatinib).

[0143] Platelet-derived growth factor (PDGF) receptor inhibitors: imatinib (Gleevec (registered trademark)), lenvatinib (also known as ABT 869 available from Genentech, N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N’- (2-fluoro-5-methylphenyl)urea), sunitinib malate (Sutent ( registered trademark)), quizartinib (AC220, CAS 950769-58-1), pazopa nib (Votrient (registered trademark)), axitinib (Inlyta (registered trademark)), sorafenib (Nexavar (registered trademark)), brivanib (BIBF1120, CAS 928326-83-4), teratinib (BAY57-9352, CAS 33201 2-40-5), brivanib alaninate (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-pyr dinylmethyl)amino]-3-pyridinecarboxamide, as described in PCT International Publication No. 02 / 066 470 pamphlet).

[0144] Fibroblast growth factor receptor (FGFR) inhibitors: alaninate brivanib (BMS- 582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-ind ole-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine -6-yloxy)propan-2-yl)2-aminopropanoate), vargatef (B IBF1120, CAS 928326-83-4), dovitinib dilactate (TKI258 , CAS 852433-84-2), 3-(2,6-dichloro-3,5-dimethoxy- phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino -pyrimidin-4-yl}-1-methyl-urea (BGJ398, CAS 87251 1-34-7), danusertib (PHA-739358), and N-[2-[[4-(di ethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3 -d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)-urea (PD17 3074, CAS 219580-11-7), sulfatinib ), surufatinib.

[0145] Aurora kinase inhibitors: 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 nil]-2-pyrimidineamine (CYC116, CAS 693228-63-6), tor zaciclib (VX680 or MK-0457, CAS 639089-54-6), arie aciclib (MLN8237), (N-{2-[6-(4-cyclobutylamino-5-tr fluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-te trahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-a cetamide) (PF-03814735), 4-[[9-chloro-7-(2,6-diflu orophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]ami no]-benzoic acid (MLN8054, CAS 869363-13-3), seniciclib ( R-763), barasertib (AZD1152), and N-cyclopropyl-N’-[3 -[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H- pyrazol-4-yl]urea (AT9283).

[0146] Cyclin-dependent kinase (CDK) inhibitors: aloisine A, alvocidib (flavopir dol or HMR-1275 also known as 2-(2-chlorophenyl)-5,7-di hydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl] -4-chromenone, as described in U.S. Patent No. 5,621,002), kuli Sunitinib (PF-02341066, CAS 877399-52-5), 2-(2-chloro phenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl )-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P 276-00, CAS 920113-03-7), Indisulam (E7070), R oscovitine (CYC202), 6-acetyl-8-cyclopentyl-5-methyl-2-( 5-piperazin-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pyr imidin-7-one, hydrochloride (PD0332991), Dinaciclib (SCH7279 65), N-[5-[[(5-tert-butyl-oxazol-2-yl)methyl]thio thiazol-2-yl]piperidine-4-carboxamide (BMS387032, CA S 345627-80-7), 4-[[9-chloro-7-(2,6-difluorophenyl )-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzo ic acid (MLN8054, CAS869363-13-3), 5-[3-(4,6-diflu oro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N- ethyl-4-methyl-3-pyridinemethanamine (AG-024322, CAS 837 364-57-5), 4-(2,6-dichlorobenzoylamino)-1H-pyrazole- 3-carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS 8444 42-38-2), 4-[2-methyl-1-(1-methylethyl)-1H-imidazole -5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidineamine (A ZD5438, CAS 602306-29-6), Palbociclib (PD-03329 91), and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropyl sulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyr midinyl]oxy]-2-butanol (BAY 10000394), ribocyclib.

[0147] Checkpoint kinase (CHK) inhibitors: 7-hydroxystaurosporine (UC N-01), 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3 R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidin-7-amine (SCH90 0776, CAS 891494-63-6), 5-(3-fluorophenyl)-3-u rethienyl-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZ D7762, CAS 860352-01-8), 4-[((3S)-1-azabicyclo [2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl l)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 40516 8-58-3), 7-aminodaunomycin (7-AAD), isogranulatimide, de bromohymenialdisine, N-[5-bromo-4-methyl-2-[(2S)-2-morpho linylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2 603618, CAS 911222-45-2), sulforaphane (CAS 447 8-93-7, 4-methylsulfinylbutyl isothiocyanate), 9,10,11, 12-tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3' ,2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-1,3(2H )-Zion (SB-218078, CAS 135897-06-2), and TAT-S 216A (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).

[0148] 3-phosphoinositide-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 7 42112-33-0), 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-4 27, CAS 1191951-57-1).

[0149] Protein kinase C (PKC) activator: Bryostatin I (bryo-1) and Sotrastaurin (AEB071).

[0150] B-RAF inhibitor: Regorafenib (BAY73-4506, CAS 755037- 03-7), Tivozanib (Tuvizanib) (AV951, CAS 475108- ​18-0), vemurafenib (Zelboraf (registered trademark), PLX-4032, CA S 918504-65-1), 5-[1-(2-hydroxyethyl)-3-(pyridine -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-pyridinyl)-1H-imidazole -4-yl]-2,3-dihydro-1H-inden-1-one oxime (GSK21 18436 or SB590885), (+ / -)-methyl (5-(2-(5-chloro-2 -methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindole -1-yl)-1H-benzimidazol-2-yl)carbamate (XL-28 1 and also known as BMS908662), and N-(3-(5-chloro-1H-py rolopyrido[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propa ne-1-sulfonamide (also known as PLX4720).

[0151] C-RAF inhibitors: sorafenib (Nexavar (registered trademark)), 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).

[0152] Human Granulocyte Colony-Stimulating Factor (G-CSF) Modulators: Filgrastim (Ne upogen (registered trademark)), Sunitinib Malate (Sutent (registered trademark)), Pegi lgrastim (Pegilgrastim) (Neulasta (registered trademark)), and Ki zalitinib (AC220, CAS 950769-58-1).

[0153] RET Inhibitors: Sunitinib Malate (Sutent (registered trademark)), Vandetanib (C aprelsa (registered trademark)), Motesanib Diphosphate (AMG706, CAS 8578 76-30-3, N-(2,3-Dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, PC T International Publication No. 02 / 066470 Pamphlet), Sorafenib (BAY 43 -9006), Regorafenib (BAY73-4506, CAS 755037-03- 7), and Danusertib (PHA-739358). 7), and Danusertib (PHA-739358).

[0154] FMS-like Tyrosine Kinase 3 (FLT3) Inhibitors or CD135: Sunitinib Malate (Sutent (registered trademark)), Quizartinib (AC220, CAS 950769-5 8-1), N-[(1-Methyl-4-piperidinyl)methyl]-3-[3-(trifluoro methoxy)phenyl]-imidazo[1,2-b]pyridazin-6-amine sulfate (SG I-1776, CAS 1173928-26-1), and Vargate f (BIBF1120, CAS 928326-83-4).

[0155] c-KIT Inhibitors: Pazopanib (Votrient (registered trademark)), Dovitinib DL (TKI258, CAS 852433-84-2), motesanib diphosphate (AMG70 6, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1 H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridine Carboxamide (described in PCT International Publication No. 02 / 066470), Nib (Masivet®), regorafenib (BAY73-4506, CAS 755037-03-7), tivozanib (AV951, CAS 475108-18- 0), Vatalanib dihydrochloride (PTK787, CAS 212141-51-0), Teratini (BAY57-9352, CAS 332012-40-5), foretinib (GSK 1363089, formerly XL880, CAS 849217-64-7), Malic acid nitrite tinib (Sutent®), quizartinib (AC220, CAS 95076 9-58-1), axitinib (Inlyta®), dasatinib (BMS-3 45825), and sorafenib (Nexavar®).

[0156] Bcr / Abl kinase inhibitors: Imatinib (Gleevec®), Imatinib hydrochloride Nilotinib (Tasigna) trademark), dasatinib (BMS-345825), bosutinib (SKI-606), ponaminib tinib (AP24534), bafetinib (INNO406), danusertib (PHA- 739358), AT9283 (CAS 1133385-83-7), saracatinib ( AZD0530), and N-[2-[(1S,4R)-6-[[4-(cyclobutylamine) [[[5-(Trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydro naphthalen-1,4-imin-9-yl]-2-oxoethyl]-acetamide (PF-03814735, CAS 942487-16-3).

[0157] 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-benzyloxyphe nyl)-7-[trans-3-[(pyrrolidin-1-yl)methyl]cyclobutyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (ADW742 or GSK5 52602A, CAS 475488-23-4), (2-[[3-bromo-5-(1, 1-dimethylethyl)-4-hydroxyphenyl]methylene]-propanedinitrile (ty rohostin AG-1024, CAS 65678-07-1), 4-[[(2S)-2-( (3-chlorophenyl)-2-hydroxyethyl]amino]-3-[7-methyl-5-(4 (morpholinyl)-1H-benzimidazol-2-yl]-2(1H)-pyridinone ( BMS-536924, 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-piperazinepropanenitrile (BMS-554417, 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 (BMS7548 07, CAS 1001350-96-4), picropodophyllotoxin (AXL171 7), and nordihydroguaiaretic acid ic acid).

[0158] IGF-1R antibodies: figitumumab (CP751871), cixutumumab (IMC- A12), ganitumab (AMG-479), robatumumab (SCH-717454), dara tuzumab (MK0646), R1507 (available from Roche), BIIB022 (available from Biogen), and MEDI-573 (possibly available from MedImmune ).

[0159] MET inhibitors: cabozantinib (XL184, CAS 849217-68-1), ph oretinib (GSK1363089, formerly 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 (Xalk ori (registered trademark), PF-02341066), (3Z)-5-(2,3-dihydro- 1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-meth ,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-oxo indoline-5-sulfonamide (SU11274), (3Z)-N-(3-chlorophen yl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H -pyrrol-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfon amide (SU11606), 6-[difluoro[6-(1-methyl-1H-pyrazol- 4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]qui noline (JNJ38877605, CAS 943540-75-8), 2-[4-[1 -(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyra dine-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4), N-((2R)-1,4-dioxan-2-ylme thyl)-N-methyl-N’-[3-(1-methyl-1H-pyrazol-4-yl)-5- oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulf amide (MK2461, CAS 917879-39-1), 6-[[6-(1-meth yl-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).

[0160] Epidermal growth factor receptor (EGFR) inhibitors: erlotinib hydrochloride (Tarceva (registered trademark)), gefitinib (Gefitnib) (Iressa (registered trademark)), N- 4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butanamide, Tovok (registered trademark)), vandetanib (Caprelsa (registered trademark) ), lapatinib (Tykerb (registered trademark)), (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 dihydrochloride (CI1033), 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 ​​​​​​​​Chil ester (BMS599626), N-(3,4-dichloro-2-fluorophenyl )-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclo pentacyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8), and 4-[4-[[(1R)-1-phenylethyl amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (PKI 166, CAS 187724-61-4).

[0161] 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). (mAb-806, CAS 946414-09-1).

[0162] mTOR inhibitors: Temsirolimus (Torisel®), Deforolimus (formally, Deforolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9 S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28 Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-1 5,17,21,23,29,35-hexamethyl-2,3,10,14,20-penta oxo-11,36-dioxa-4-azatricyclo[30.3.1.0 4,9 hexa triaconta-16,24,26,28-tetraene-12-yl]propyl]-2-meth Known as toxicyclohexyl dimethyl phosphinate and also as AP23573 and MK 8669, described in PCT International Publication No. 03 / 064383 pamphlet everolimus (Afinitor® or RAD001), rapamycin (AY22989, Sirolimus®), semapimod (CAS 164 301-51-3), (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-pyridinyl)-4-methyl-pyrido[2, 3-d]pyrimidin-7(8H)-one (PF04691502, CAS 101310 1-36-4), N -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl 2 -4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl] -L-arginylglycyl-L-α-aspartyl L-serine, inner salt (SF112 6, CAS 936487-67-1), and N-[4-[[[3-[(3,5-dimeth oxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3- methoxy-4-methyl-benzamide (XL765, also known as SAR245409 ), and (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indole -2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohex anecarboxylic acid (OSI-027).

[0163] ​Mitogen-activated protein kinase (MEK) inhibitors: XL-518 (GDC-0 973, also known as Cas number 1029872-29-4, available from ACC Corp. Celmetinib (also known as AZD6244 or ARRY142886), 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, as described in PCT International Publication No. WO 2003 / 077914 ), 2-[( (2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4 -difluoro-benzamide (also known as CI-1040 or PD184352, described in PCT International Publication No. WO 2000 / 035436 ), N-[(2R)- 2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]-benzamide (also known as PD0325901, described in PCT International Publication No. WO 2002 / 006213 ), 2,3-bis[amino [(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126, described in U.S. 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 R DEA119 or BAY869766, described in PCT International Publication No. WO 2007 / 014 011), (3S,4R,5Z,8S,9S,11E)-1 4-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9 ​ , 19 - Tetrahydro - 1H - 2 - benzoxacyclotetradecin - 1,7(8H)- dione (also known as E6201 and described in PCT International Publication No. 2003076424 pamphlet let), 2’ - Amino - 3’ - methoxyflavone (also known as PD98059 and available from Biaffin GmbH & Co., KG, Germany ), 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), trametinib dimethyl sulfoxide (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)a mino]-N-(2 - hydroxyethoxy)-5 - [(3 - oxo - [1,2]oxazina n - 2 - yl)methyl]benzamide (Chinese Patent Specification No. 4987655 or Romanian Patent Specification No. 4987655). Alkylating agents: Oxaliplatin (Eloxatin (registered trademark)), Temozolomide(

[0164] Temodar (registered trademark) and Temodal (registered trademark)), Dactinomycin (a ), Cosmegen (registered trademark), also known as actinomycin-D, melphalan (L-PAM, also known as L-sarcolysin and phenylalanine mustard, Alkeran (registered trademark)), altretamine (also known as hexamethylmelamine (HMM), Hexalen (registered trademark)), carmustine (BiCNU (registered trademark) ), bendamustine (Treanda (registered trademark)), busulfan (Busulfex (registered trademark) and Myleran (registered trademark)), carboplatin (Paraplati n (registered trademark)), lomustine (also known as CCNU, CeeNU (registered trademark)) , cisplatin (also known as CDDP, Platinol (registered trademark), and Pl atinol (registered trademark)-AQ), chlorambucil (Leukeran (registered trademark)) , cyclophosphamide (Cytoxan (registered trademark) and Neosar (registered trademark)), dacarbazine (DTIC, DIC, and also known as imidazole carboxamide, DTIC-Dome (registered trademark)), altretamine (also known as hexamethylmelamine (HMM), Hexalen (registered trademark)), ifosfamide (Ifex (registered trademark) ), prednimustine, procarbazine (Matulane (registered trademark)), mechloreta mine (also known as nitrogen mustard, mustard, and mechlorethamine hydrochloride (mechlo roethamine), Mustargen (registered trademark)), stre ptozocin (Zanosar (registered trademark)), thiotepa (also known as thiophosphoramide (thiop hosphoamide), TESPA, and TSPA, Thiopl ex (registered trademark)), cyclophosphamide (Endoxan (registered trademark), Cytoxa n (Registered Trademark), Neosar (Registered Trademark), Procytox (Registered Trademark), Revi mmune (Registered Trademark)), and Bendamustine HCl (Treanda (Registered Trademark)) .

[0165] Aromatase inhibitors: Exemestane (Aromasin (Registered Trademark)), Letrozole (Femara (Registered Trademark)), and Anastrozole (Arimidex (Registered Trademark ).

[0166] Topoisomerase I inhibitors: Irinotecan (Camptosar (Registered Trademark)), Hydrochloric Topotecan (Hycamtin (Registered Trademark)), and 7-Ethyl-10-Hydroxycam ptothecin (SN38).

[0167] Topoisomerase II inhibitors: Etoposide (VP-16 and Etoposide Phosphate, Top osar (Registered Trademark), VePesid (Registered Trademark), and Etopophos (Registered Trademark)), Teniposide (VM-26, Vumon (Registered Trademark)), and Tafuposide.

[0168] DNA synthesis inhibitors: Capecitabine (Xeloda (Registered Trademark)), Gemcitabine Hydrochloride (Gemzar (Registered Trademark)), Nelarabine ((2R,3S,4R,5R)-2-(2-A mino-6-Methoxypurin-9-yl)-5-(Hydroxymethyl)oxolane-3,4 -diol, Arranon (Registered Trademark), and Atriance (Registered Trademark)), and Sapacitabine (1-(2-Cyano-2-deoxy-β-D-Arabinofuranosyl)-4- (Palmitoylamino)pyrimidin-2(1H)-one).

[0169] Folic acid antagonist or anti-folate agent: trimetrexate glucuronate (Neutrex in (registered trademark)), piritexim isethionate (BW201U), pemetrexed LY231514), raltitrexed (Tomudex (registered trademark)), and methotrex ate (Rheumatrex (registered trademark), Trexal (registered trademark)).

[0170] Immunomodulator: alemtuzumab (available from Roche (registered trademark)), pegfil grastim (Neulasta (registered trademark)), lenalidomide (CC-5013, Revlimid (registered trademark)), thalidomide (Thalomid (registered trademark)), a ccimid (CC4047), and IRX-2 (a mixture of human cytokines containing interleukin 1, interleukin 2 and interferon γ, CAS 951209-71 -5, available from IRX Therapeutics).

[0171] G protein-coupled somatostatin receptor inhibitor: octreotide (also known as octreotide acetate. Sandostatin (registered trademark), and Sandos tatin LAR (registered trademark)), lanreotide acetate (CAS 127984-74- 1), seglitide (MK678), vapreotide acetate (Sanvar (registered trademark)), and cyclo(D-Trp-Lys-Abu-Phe-MeAla-Tyr) (BIM230 27).

[0172] Interleukin 11 and synthetic interleukin 11 (IL-11): oprelvekin (Neumega (registered trademark)).

[0173] Erythropoietin and synthetic erythropoietin: Erythropoietin (Epogen (registered trademark) and Procrit (registered trademark)), darbepoetin alfa (Aranesp( registered trademark)), peginesatide (Hematide (registered trademark)), and polyethylene gly col covalently linked EPO (Micera (registered trademark)).

[0174] Histone deacetylase (HDAC) inhibitors: Vorinostat (Zolinza (registered trademark)), Romidepsin (Istodax (registered trademark)), Tr ichostatin A (TSA), Oxamflatin, Bori nostat (Zolinza (registered trademark), suberoylanilide hydroxamic acid), Pyro xamide (syberoyl-3-aminopyridine amide hydroxamic acid ), Trapoxin A (RF-1023A), Trapoxin B (RF-10238), Cycl o[(αS,2S)-α-amino-η-oxo-2-oxiranecanoyl-O-methyl yl-D-tyrosyl-L-isoleucyl-L-prolyl](Cyl-1), Cyclo[(αS ,2S)-α-amino-η-oxo-2-oxiranecanoyl-O-methyl-D-th rosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl](Cyl-2), Sa ick[L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminoox iranecanoyl-D-prolyl](HC-toxin), Cyclo[(αS,2S)-α -amino-η-oxo-2-oxiranecanoyl-D-phenylalanyl-L-leu syl-(2S)-2-piperidinecarbonyl](WF-3161), Clamidosine ((S )-Cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminooxirane octanoyl), apicidin (cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl)), romidepsin (Istodax®, FR-901228), 4-phenylbutyrate, spiruchostatin A, milproin (valproic acid), entinostat (MS-275, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)-amino-methyl]-benzamide), and depsidin (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D-threo-D-ido-undeca-1,6-dienitol). Cyclic(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl), apicidin (cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl)), romidepsin (Istodax®, FR-901228), 4-phenylbutyrate, spiruchostatin A, milproin (valproic acid), entinostat (MS-275, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)-amino-methyl]-benzamide), and depsidin (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D-threo-D-ido-undeca-1,6-dienitol). -2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D- 2-piperidinecarbonyl), romidepsin (Istodax(registered trademark), FR-90 1228), 4-phenylbutyrate, spiruchostatin A, milproin (valproic acid ), entinostat (MS-275, N-(2-aminophenyl)-4-[N-(pyr idin-3-yl-methoxycarbonyl)-amino-methyl]-benzamide), and dep sidin (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D- threo-D-ido-undeca-1,6-dienitol).

[0175] Biological response modifiers: Interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines (therapeutic and prophylactic), gene therapy, non-specific immune modulators and other therapeutic agents. Interferon α (Intron®, Roferon-A), interferon β, interferon γ, interleukin- 2 (IL-2 or aldesleukin, Proleukin®), filgrastim (Neupogen®), sargramostim (Leukine® ), erythropoietin (epoetin), interleukin 11 (oprelvekin), imiquimod (Aldara®), lenalidomide (Revlimid® ), rituximab (Rituxan®), trastuzumab (Hercep tin®), etc. are included. Interferon α (Intron®, Roferon-A), interferon β, interferon γ, interleukin- tin (Registered Trademark)), Bacillus Calmette-Guerin (ther aCys (Registered Trademark) and TICE (Registered Trademark) BCG), Levamisole (Ergami sol (Registered Trademark)), and Denileukin Diftitox (Ontak (Registered Trademark)).

[0176] Plant alkaloids: Paclitaxel (Taxol and Onxal (Trademark)), protein bound paclitaxel (Abraxane (Registered Trademark)), Vinblastine (Vinblastine Sulfate Vinblastine, Vincaleukoblastine, and also known as VLB, Alkaban-A Q (Registered Trademark) and Velban (Registered Trademark)), Vincristine (Vincristine Sulfate, L CR, and also known as VCR, Oncovin (Registered Trademark) and Vincasar Pfs (Registered Trademark)), and Vinorelbine (Navelbine (Registered Trademark)).

[0177] Taxane antineoplastic agents: Paclitaxel (Taxol (Registered Trademark)), Docetaxel (T axotere (Registered Trademark)), Cabazitaxel (Jevtana (Registered Trademark), 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-phenylpropanoate), and Larotaxel ((2α,3ξ,4α,5β,7α ,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)- 3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylprop anoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclo (11E)-11-(4-chlorophenyl)-1,2,2-trimethyl-7-oxo-6,7-dihydro-5H-[1,3]dioxolo[4,5-g]quinoline-3-carboxylic acid

[0178] Heat shock protein (HSP) inhibitors: tanespimycin (KOS-953 and 17 -AAG, also known as 17-allylamino-17-demethoxygeldanamycin, which is available from SIGMA and is described in U.S. Patent No. 4,261,989 ), retaspimycin (IPI504), ganetespib (STA-9090), [6- chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-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]cyclohexylglycine ester (SNX5 422 or PF04929113, CAS 908115-27-5), and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]amino]cyclohexylglycine ester (SNX5 422 or PF04929113, CAS 908115-27-5), and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). 422 or PF04929113, CAS 908115-27-5), and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). 422 or PF04929113, CAS 908115-27-5), and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG).

[0179] Thrombopoietin (TpoR) agonists: eltrombopag (SB497115, Promacta®, and Revolade®), and romiplostim (Nplate®). Promacta®, and Revolade®), and romiplostim (Nplate®).

[0180] Demethylating agents: 5-azacitidine (Vidaza®), and decitabine (D acogen®).

[0181] Cytokines: interleukin-2 (also known as aldesleukin and IL-2 such as Proleukin (registered trademark), interleukin-11 (also known as oprelvekin ), Neumega (registered trademark), and alpha interferon α (IFN -α, also known as Intron (registered trademark) A and Roferon-A (registered trademark ))

[0182] 17α-hydroxylase / C17,20-lyase (CYP17A1) inhibitor: abiraterone acetate (Zyitga (registered trademark))

[0183] A variety of cytotoxic agents: arsenic trioxide (Trisenox (registered trademark)), asparaginase (L-asparaginase, also known as Erwinia L-asparaginase and known as Elspar (registered trademark) and Kidrolase (registered trademark)), and Erwinia Chrysanthemi asparaginase (Erwinaze (registered trademark))

[0184] C-C chemokine receptor 4 (CCR4) antibody: mogamulizumab (Potelige nt (registered trademark))

[0185] CD20 antibody: rituximab (Riuxan (registered trademark) and MabThera (registered trademark)), and tositumomab (Bexxar (registered trademark)), and ofatumumab (Ar zerra (registered trademark))

[0186] CD20 antibody-drug conjugate: ibritumomab tiuxetan (Zevalin (registered trademark )) and tositumomab

[0187] CD22 antibody-drug conjugate: inotuzumab ozogamicin (CMC-544 and ​​​Also known as WAY-207294, available from Hangzhou Sage Chemical Co , Ltd.).

[0188] CD30 mAb-cytotoxin conjugate: Brentuximab vedotin (Adcetr ix (registered trademark)).

[0189] CD33 antibody-drug conjugate: Gemtuzumab ozogamicin (Mylotarg( registered trademark)).

[0190] CD40 antibody: Dacetuzumab (also known as SGN-40 or huS2C6, available from Sea ttle Genetics, Inc).

[0191] CD52 antibody: Alemtuzumab (Campath (registered trademark)).

[0192] Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS number 915296-00-3) .

[0193] CTLA-4 inhibitor antibody: Tremelimumab (an IgG2 monoclonal clonal antibody available from Pfizer and previously known as ticilimumab, CP-675,206 ), and ipilimumab (MDX-010, a CTLA-4 antibody also known as CAS number 477202-00-9 ).

[0194] TPH inhibitor: Telotristat.

[0195] PARP (poly ADP ribose polymerase) inhibitor: Olaparib (Lynparza ), rucaparib (Rubraca), niraparib (Zeluja), talazoparib, veliparib.

[0196] ​PD-1 inhibitors: Spartalizumab (PDR001, Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medimmune ), REGN2810 (Regeneron), TSR-042 (Tesaro), PF -06801591 (Pfizer), BGB-A317 (Beigene), BGB- 108 (Beigene), INCSHR1210 (Incyte), or AMP-22 4 (Amplimmune).

[0197] PD-L1 inhibitors: durvalumab, atezolizumab, avelumab.

[0198] In particular, the present invention relates to a combination or combination therapy of a complex formed by a radionuclide 177 Lu (lutetium-177) and a somatostatin receptor-binding peptide linked to a chelating agent as defined herein, or octreotide, lanreotide, vapreotide, pasireotide, satoreotide, everolimus, temozolomide, telotristat , sunitinib, sulfatinib, ribociclib, enzastaurin, and pazopanib, and a pharmaceutical aqueous solution as defined herein in combination with one or more therapeutic agents selected from the group consisting of provided. In certain embodiments, such combinations are, for example, for the treatment of NET tumors such as GEP-NET, pulmonary NET, pNET, lung NET (lung NET), carcinoid syndrome, SCLC, etc. In certain embodiments, the present invention provides a combination or combination therapy of such a combination of therapeutically effective amounts of components By administering se, for example, a method for treating patients with any NET tumor such as GEP-NET, pulmonary NET, pNET, lung NET, carcinoid syndrome, SCLC, etc. is provided. NET), pNET, lung NET, carcinoid syndrome, SCLC is provided.

[0199] In certain embodiments, the present invention relates to a combination or combination therapy of a complex formed by a radionuclide 177 Lu (lutetium-177) and a somatostatin receptor-binding peptide linked to a chelating agent as defined in the present specification and, or a combination or combination therapy of a pharmaceutical aqueous solution as defined in the present specification in combination with one or more cancer immunotherapeutic agents selected from the group consisting of PD-1, PD-L1, and CTLA-4 inhibitors, particularly, a combination or combination therapy of a pharmaceutical aqueous solution as defined in the present specification in combination with an I-O therapeutic agent selected from the group consisting of sipuleucel-T, nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, avelumab, ipilimumab, and tremelimumab. In certain embodiments, such combinations are for use in the treatment of NET tumors such as GEP-NET, pulmonary NET, pNET, lung NET, carcinoid syndrome, SCLC, etc. In certain embodiments, the present invention provides a method for treating patients with NET tumors such as GEP-NET, pulmonary NET, pNET, lung NET, carcinoid syndrome, SCLC, etc. by administering a therapeutically effective amount of such a combination of components. ulmonary NET), pNET, lung NET, carcinoid syndrome, SCLC, etc. In certain embodiments, the present invention provides a method for treating patients with NET tumors such as GEP-NET, pulmonary NET, pNET, lung NET, carcinoid syndrome, SCLC, etc. by administering a therapeutically effective amount of such a combination of components. ng NET), carcinoid syndrome, SCLC, etc. is provided.

[0200] Definition Hereinafter, the meanings of the terms used in the present specification are defined.

[0201] The term "about" or "ca." as used herein means that the subsequent value may vary by ±20%, preferably ± 10%, more preferably ±5%, even more preferably ±2%, and even more preferably ± 1%.

[0202] Unless otherwise defined, "%" as used herein means weight percent (wt%) and is also referred to as weight / weight percent (w / w%).

[0203] "Total concentration": the sum of one or more individual concentrations.

[0204] "Aqueous solution": a solution of one or more solutes in water.

[0205] "(ai) a radionuclide and (aii) a cell receptor-binding organic moiety linked to a chelating agent," "complex formed thereby": The radionuclide metal ion forms a non-covalent bond with a functional group of a chelating agent such as an amine or a carboxylic acid. The chelating agent has at least two such complexing functional groups capable of forming a chelate complex.

[0206] Chelating agents relevant to the present invention include 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, NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid, trisoxetane, tetrakisoxetane, or a mixture thereof, ​​​It may be, and preferably is, DOTA.

[0207] "Cell receptor binding moiety": A chemical molecule in which at least a part of the molecule binds to a receptor molecule on the surface of a cell. A cell receptor binding moiety particularly suitable for the present invention is a somatostatin receptor binding peptide, and preferably, the somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, pasireotide, ilatreotide, pentetreotide, depeptide, satoreotide, and belotreotide, and preferably is selected from octreotide and octreotate.

[0208] "Linked": The cell receptor binding organic moiety is either directly linked to the chelating agent or connected via a linker molecule, and preferably is directly linked. The linking bond is either a covalent bond or a non-covalent bond between the cell receptor binding organic moiety and (the linker and) the chelating agent, and preferably the bond is a covalent bond.

[0209] "Stabilizer against radiolytic degradation": A stabilizer that protects an organic molecule from radiolytic degradation. For example, when γ-rays emitted from a radionuclide cleave the bonds between the atoms of an organic molecule and form radicals, such radicals are then captured by the stabilizer, so that any other chemical reactions that may lead to undesirable, potentially ineffective, or even toxic molecules are avoided. Therefore, such a stabilizer is also referred to as a "free radical scavenger" or simply a "radical scavenger". Other alternative terms for such stabilizers are "radiation stability improver", "radiolytic stabilizer", ​​​​​​ , or simply "quencher."

[0210] "The stabilizer is present in solution upon complexation of components (ai) and (aii)": and optionally a second stabilizer. That is, the first stabilizer is It is present either alone or in combination with a second stabilizer.

[0211] "Present during complexation": The stabilizer is present in the radionuclide solution or in the chelator-containing solution. The two solutions are then added, possibly to promote complex formation. Elevated temperatures are applied to stabilize the chelating agent. Preferably, the stabilizing agent is in a solution containing the chelating agent.

[0212] "Only the first stabilizer is present when components (ai) and (aii) are complexed": one stabilizer is present and the second is absent. In other words, only one stabilizer is present.

[0213] "The second stabilizer is added after the complexation of components (ai) and (aii)": Complex Form The complex form may or may not have already had a second stabilizer present at the time of synthesis. After the synthesis reaction is complete, for example, the reaction solution that has been heated to an elevated temperature is cooled back down to ambient temperature. Afterwards, a second stabilizer is added.

[0214] The cell receptor binding moiety and the chelator may together form the following molecule: DOTA-OC:[DOTA 0 ,D-Phe 1 ]Octreotide, DOTA-TOC: [DOTA 0 ,D-Phe 1 ,Tyr 3 ] Octreotide and edotreotide (INN): [Chemistry] DOTA-NOC: [DOTA 0 , D-Phe 1 , 1-Nal 3 octreotide, DOTA-TATE: Represented by the following formula [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), oxi Somatostatin (INN): [Chemistry] DOTA-LAN: [DOTA 0 , D-β-Nal 1 lanreotide, DOTA-VAP: [DOTA 0 , D-Phe 1 , Tyr 3 vapreotide.

[0215] Somatostatin trioxetane [Chemistry] Somatostatin tetraoxetane [Chemistry]

[0216] Preferred "cell receptor binding moiety linked to a chelating agent" moieties used in the present invention are DOTA-TOC, DOTA-TATE, and somatostatin tetraoxetane , and more preferably the moiety is DOTA-TATE.

[0217] In the present invention, a preferred complex (or their preferred complexes) formed by a radionuclide and a cell receptor-binding moiety linked to a chelating agent according to the present invention is Lu-DOTA-TATE, which is lutetium (177Lu) oxodotreotide (INN), that is, hydrogen [N-{[4,7,10-tris(carboxylato-κO 177 -methyl)-1,4,7,10-tetraazacyclododecane-1-yl-κ N 4 1 ,N 4 ,N 7 ,N 7 ,N 10 acetyl-κO}-D-phenylalanyl-L-cysteinyl-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threo ninato cyclic(2→7)-disulfide(4-)](177Lu) lutetate(1 -) is also referred to as and is represented by the following formula.

Chemical formula

[0218] "Buffer with a pH of 4.5 to 6.0": It can be an acetate buffer, a citrate buffer (for example, citrate + HCl or citric acid + disodium hydrogen phosphate), or a phosphate buffer ( for example, sodium dihydrogen phosphate + disodium hydrogen phosphate), and preferably, the buffer is an acetate buffer, and preferably, the acetate buffer is composed of acetic acid and sodium acetate.

[0219] "Metal ion sequestering agent", a chelating agent suitable for complexing radionuclide metal ions, preferably DTPA: diethylenetriaminepentaacetic acid.

[0220] "Commercially available": Pharmaceutical products, such as pharmaceutical aqueous solutions, are those that can (preferably have) obtained market approval by a health authority such as the US FDA or EMA by fully meeting the quality and stability requirements of pharmaceutical products required by the health authority, can (preferably are) manufactured on a commercial scale at a pharmaceutical manufacturing site or at that site, and are subsequently subjected to quality control test procedures, and can (preferably are) supplied to end-users at remote locations such as hospitals or patients. "Combination": Either a fixed combination of one dosage unit formulation or the combination of the compound of the present invention and a combination partner (for example, another drug described below ("therapeutic agent" or "co-agent" "also referred to")), either independently and simultaneously or, in the case of a time interval where the combination partner can exhibit a synergistic effect such as a synergistic effect, administered individually within the time interval, meaning either combination administration. The single components can be packaged in a kit or individually. One or both of the components (for example, powder or liquid) can be reconstituted or diluted to the desired dose before administration. Terms such as "co-administration" and "combination administration" used herein are intended to include the administration of the selected combination partners to a single subject (for example, a patient) in need, and are intended to include treatment regimens where the agents are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination" used herein 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" refers to treatment

[0221] Agents, for example, both the compounds and combination partners of the present invention are either a single entity or mean being administered to a patient simultaneously in a dosage form. The term "non-fixed combination" refers to therapeutic agents, for example, both the compounds and combination partners of the present invention, being administered to the patient's body either simultaneously, concurrently, or sequentially, without a specific time limit, as individual entities so as to provide therapeutic effective levels of the two compounds in the body. The latter also applies to cocktail therapies, for example, the administration of three or more therapeutic agents.

Examples

[0222] Hereinafter, the present invention will be described in more detail and specifically with reference to examples, but it is not intended to limit the present invention.

[0223] Materials: 177 LuCl3 can be obtained from suppliers such as I.D.B. Holland BV. DOTA 0 -Tyr 3 -octreotate can be obtained from suppliers such as piCHEM Forschungs -und Entwicklungs GmbH, Austria. All other components of the pharmaceutical product are commercially available from various sources.

[0224] Example 1: Composition of the pharmaceutical product The pharmaceutical product ( 177 Lu-DOTA 0 -Tyr 3 -octreotate 370 MBq / mL injection solution) is a pharmaceutical substance having a volume radioactivity of 370 MB q / mL at the reference date and reference time (calibration time (tc)), and as 177 Lu-DOTA 0 -Tyr 3 -oct​​ It is designed as a sterile ready-to-use solution for injection containing octreotate. The calibration time (tc) corresponds to the end of manufacturing (EOP = t0), which is the time of measurement of the radioactivity 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 a suitable amount of solution to enable delivery of 7.4 GBq of

[0225] radioactivity at the time of injection. The manufacturing site prepares a single dose calibrated within the range of 7.4 GBq ± 10% (200 mCi) after the end of manufacturing. The analytical certificate reports both the exact radioactivity and the time at which this radioactivity is achieved. This value is specified as "Injection time: {DD MM YYYY}{hh:mm } UTC". Considering the variable injection time and the steady decay of the radionuclide, the filling volume required to have 7.4 GBq of radioactivity at the time of injection can be

[0226]

Table 1

[0227] Example 2: Manufacture of the pharmaceutical product For a 74 GBq batch size (2 Ci batch size), 177 a LuCl3 solution (approx. 74 GBq in HCl ), a solution of DOTA-Tyr 3 -octreotate (approx. 2 mg), and a reaction buffer solution (containing an antioxidant (and stabilizer against radiolytic degradation) (i.e., gentisic acid, approx. 157 mg) and a buffer system (i.e., an acetate buffer system)) are mixed together to produce a total solution of approximately 5.5 mL, which is heated at a temperature of about 90 to about 98 °C for less than 15 minutes.It is used for radioactive labeling carried out among them.

[0228] The synthesis is carried out using a single-use disposable kit cassette installed on the front side of a synthesis module containing a fluid path (tube), a reactor vial, and a seal reagent vial. It is carried out using a single-use disposable kit cassette installed on the front side of a synthesis module containing a fluid path (tube), a reactor vial, and a seal reagent vial. It is carried out.

[0229] The obtained mother solution 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, giving a ready-to-use solution as described in Example 1 having a pH of 4.5 - 6.0, particularly 5.2 - 5.3. Finally, the solution is dispensed into sterile vials in an amount of 20.5 - 25.0 mL. The vials with stoppers are enclosed in a lead container for protective shielding. sterile filtered through 0.2 μm, giving a ready-to-use solution as described in Example 1 having a pH of 4.5 - 6.0, particularly 5.2 - 5.3. Finally, the solution is dispensed into sterile vials in an amount of 20.5 - 25.0 mL. The vials with stoppers are enclosed in a lead container for protective shielding. sterile filtered through 0.2 μm, giving a ready-to-use solution as described in Example 1 having a pH of 4.5 - 6.0, particularly 5.2 - 5.3. Finally, the solution is dispensed into sterile vials in an amount of 20.5 - 25.0 mL. The vials with stoppers are enclosed in a lead container for protective shielding. sterile filtered through 0.2 μm, giving a ready-to-use solution as described in Example 1 having a pH of 4.5 - 6.0, particularly 5.2 - 5.3. Finally, the solution is dispensed into sterile vials in an amount of 20.5 - 25.0 mL. The vials with stoppers are enclosed in a lead container for protective shielding. sterile filtered through 0.2 μm, giving a ready-to-use solution as described in Example 1 having a pH of 4.5 - 6.0, particularly 5.2 - 5.3. Finally, the solution is dispensed into sterile vials in an amount of 20.5 - 25.0 mL. The vials with stoppers are enclosed in a lead container for protective shielding.

[0230] The manufacturing process is also achievable with a batch size of more than 74 GBq. In this case, the amounts of raw materials (lutetium, peptide, and reaction buffer) are multiplied several times to ensure the same raw material ratio. The manufacturing process is also achievable with a batch size of more than 74 GBq. In this case, the amounts of raw materials (lutetium, peptide, and reaction buffer) are multiplied several times to ensure the same raw material ratio. The manufacturing process is also achievable with a batch size of more than 74 GBq. In this case, the amounts of raw materials (lutetium, peptide, and reaction buffer) are multiplied several times to ensure the same raw material ratio.

[0231] Example 3: Stability test results after storage under various temperature conditions. The following table provides the stability test data of batches manufactured with a batch size of 74 GBq according to the process described in Example 2. The following table provides the stability test data of batches manufactured with a batch size of 74 GBq according to the process described in Example 2.

[0232]

Table 2

[0233] Very similar good stability results were obtained for batches manufactured with a batch size of 148 GBq. Very similar good stability results were obtained for batches manufactured with a batch size of 148 GBq.

Claims

1. A process for producing a pharmaceutical aqueous solution, said process comprising diluting an aqueous complex solution with an aqueous diluent solution to form said pharmaceutical aqueous solution; The aqueous complex solution is (a) Below: (ai) the radionuclide 177Lu; and (aii) a somatostatin receptor-binding peptide linked to the chelator DOTA; and and a complex comprising (b) at least one stabilizer against radiolytic degradation present in a total concentration of 15 to 50 mg / mL; Including, the aqueous dilution solution comprises at least one stabilizer against radiolytic degradation; In the pharmaceutical aqueous solution, the radionuclide is present in a concentration providing a volumetric activity of 250 to 500 MBq / mL, and the stabilizer is present in a total concentration of 0.5 to 10.0 mg / mL; The process wherein the only stabilizers against radiolytic degradation present in the pharmaceutical aqueous solution are selected from ascorbic acid or its salts and gentisic acid or its salts.

2. The process described in claim 1, wherein the aqueous diluted solution contains ascorbic acid or a salt thereof.

3. The process described in claim 2, wherein the aqueous dilution solution contains ascorbic acid or a salt thereof as the only stabilizer against radiolytic degradation.

4. The process of claim 1, wherein the somatostatin receptor-binding peptide and the chelating agent form a molecule selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, DOTA-VAP, and satoreotide tetraxetan.

5. The process of claim 4, wherein the somatostatin receptor-binding peptide and the chelating agent form a molecule selected from DOTA-TOC (edotreotide), DOTA-TATE (oxodotreotide), and satoreotide tetraxetan.

6. The process of claim 5, wherein the somatostatin receptor-binding peptide and the chelating agent form DOTA-TATE (oxodotreotide).

7. A pharmaceutical aqueous solution produced by the process of claim 1.

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

9. The pharmaceutical aqueous solution of claim 7, wherein the radiochemical purity (determined by HPLC) of the pharmaceutical aqueous solution is maintained at ≥95% for at least 72 hours when stored at 25°C.

10. The pharmaceutical aqueous solution of claim 7, wherein the stabilizer is present in the pharmaceutical aqueous solution at a total concentration of 1.0 to 5.0 mg / mL.

11. The aqueous pharmaceutical solution described in claim 7, wherein the aqueous pharmaceutical solution contains 2.0 to 5.0 mg / mL of ascorbic acid or a salt thereof.

12. The aqueous pharmaceutical solution described in claim 10, wherein the aqueous pharmaceutical solution contains 2.0 to 5.0 mg / mL of ascorbic acid or a salt thereof.

13. The pharmaceutical aqueous solution of claim 7, wherein the pharmaceutical aqueous solution further comprises a sequestering agent.

14. The pharmaceutical aqueous solution of claim 13, wherein the blocking agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

15. The pharmaceutical aqueous solution described in Claim 14, wherein the diethylenetriaminepentaacetic acid (DTPA) or a salt thereof is present in an amount resulting in a concentration of 0.01 to 0.10 mg / mL.

16. The aqueous medicinal solution of claim 7, wherein the aqueous medicinal solution is present in a dose unit container sealed in a lead container in an amount of 10 to 50 mL.

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