Stable, concentrated radionuclide complex solutions

Abstract

The present invention relates to radionuclide complex solutions of high concentration and high chemical stability, which enable said radionuclide complex solutions to be used as pharmaceutical products for diagnostic and / or therapeutic purposes. The stability of the pharmaceutical product is achieved by means of at least one stabilizer that is resistant to radiolytic degradation. It was found that the use of two stabilizers introduced at different stages during the manufacturing process is particularly advantageous.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201880095724.5, filed on September 25, 2018, entitled "Stable, Concentrated Radionuclide Complex Solution". Technical Field

[0002] This invention relates to high-concentration and highly chemically and radiochemically stable solutions of radionuclide complexes, which enable the solutions to be used as commercial pharmaceutical products for diagnostic and / or therapeutic purposes. Background Technology

[0003] The concept of targeted drug delivery is based on cellular receptors that are overexpressed on target cells, unlike untargeted cells. If a drug has a binding site on those overexpressed cellular receptors, it allows for delivery to those target cells after systemic administration at high concentrations, while leaving other non-target cells unaffected. For example, if tumor cells are characterized by the overexpression of specific cellular receptors, a drug with binding affinity to those receptors will accumulate at high concentrations in tumor tissue after intravenous infusion, while leaving normal tissue unaffected.

[0004] This targeted drug delivery concept has also been used in radiation medicine to selectively deliver radionuclides to target cells for diagnostic or therapeutic purposes.

[0005] In this radiomedical application, the target cell receptor-binding portion is typically linked to a chelating agent that forms a strong complex with the metal ions of the radionuclide. The radiopharmaceutical is then delivered to the target cells, and the decay of the radionuclide releases high-energy electrons, positrons or alpha particles, and gamma rays at the target site.

[0006] One technical problem with these radiopharmaceutical products is the continuous decay of radionuclides, occurring, for example, during the manufacturing and storage of the drug product, and the release of high-energy emissions causes the breaking of chemical bonds in molecules that form part of the drug product. This is commonly referred to as radiodegradation or radioactive degradation. Radiodegradation of the receptor-binding portion of the drug can lead to a reduction in its efficacy as a diagnostic and / or therapeutic agent.

[0007] These radiopharmaceutical products are unstable and lack any significant shelf life, thus necessitating their immediate administration in hospital laboratories as dose units for individual patients awaiting radiation therapy. To facilitate the preparation of such drugs in hospital laboratories, “cold” (i.e., non-radioactive) freeze-drying kits have been developed, containing a cell receptor-binding moiety linked to a chelating agent free of radionuclides. The freeze-dried contents of these kit vials are then reconstituted with a radionuclide solution immediately prior to administration (Das et al., J Radioanal Nucl Chem, 2014, 299, 1389-1398; Das et al., Current Radiopharmaceuticals, 2014, 7, 12-19; ​​Luna-Gutierrez et al., J Radioanal Nucl Chem, 2017, 314, 2181-2188). However, these kits are not “ready to use” because they require a reconstitution step and additional processing steps (e.g., applying heat to the complexation reaction) as well as purification and sterilization steps before final drug administration.

[0008] To reduce radioactive decomposition of radiopharmaceutical products and thus improve their stability, various strategies have been explored and have achieved varying degrees of success: the product can be stored at low temperatures, produced at high dilutions, or stabilizers can be added.

[0009] However, adding stabilizers can be problematic because these chemicals may negatively affect the complexation of radionuclides with chelating agents, or they may have limited solubility and precipitate from solution. Ethanol has been reported as a stabilizer against radiodegradation (WO 2008 / 009444). While ethanol may not have negative effects on complexation or solubility, higher amounts of ethanol in the infusion solution may present physiological problems and may negatively impact the tolerability of the drug product.

[0010] A disadvantage of producing drug products at high dilutions is the need for large-volume infusions to be administered to patients. For patient convenience and drug tolerability reasons, there is a strong desire to provide high-concentration radiopharmaceutical products. However, highly concentrated solutions are particularly susceptible to radioactive decomposition. Therefore, there is a contradiction between avoiding radioactive decomposition by diluting the drug product and avoiding patient discomfort during treatment by providing a concentrated drug solution. A high-concentration product, claimed to be ready-to-use, has been reported by Mathur et al. in *Cancer Biotherapy and Radiopharmaceuticals*, 2017, 32(7), 266-273. However, this composition may present tolerability issues due to its high ethanol content.

[0011] Therefore, designing ready-to-use radiopharmaceutical products that can be manufactured on a commercial scale and delivered as sufficiently stable and sterile solutions of high concentrations (resulting in small infusion volumes that are convenient for patients and highly physiologically tolerable, such as compositions that do not contain ethanol) remains a challenge. Summary of the Invention

[0012] The inventors have now found a method for designing and producing high-concentration radionuclide complex solutions that are chemically and radiochemically stable even when stored at ambient temperature or at short-term elevated temperatures, thus enabling them to be produced on a commercial scale and supplied as ready-to-use radiopharmaceutical products.

[0013] The present invention is provided in the following aspects outlined below:

[0014] An aqueous solution of a drug, the aqueous solution of the drug comprising

[0015] (a) A complex formed from the following

[0016] (ai) radioactive nuclides, and

[0017] (aii) the cell receptor-binding organic portion linked to the chelating agent; and

[0018] (b) at least one stabilizer resistant to radioactive degradation;

[0019] in

[0020] The radionuclide is present at a concentration that provides at least 100 MBq / mL, preferably at least 250 MBq / mL of volumetric radioactivity.

[0021] The one or more stabilizers (component (b)) are present at a total concentration of at least 0.2 mg / mL, preferably at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, and even more preferably at least 2.7 mg / mL.

[0022] An aqueous solution of a drug, the aqueous solution of the drug comprising

[0023] (a) A complex formed from the following

[0024] (ai) radionuclides 177 Lutetium (Lu-177) exists at concentrations of volumetric radioactivity ranging from 250 to 500 MBq / mL, and

[0025] (aii) A chelating agent that binds to the organic part of somatostatin receptor DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide);

[0026] (bi) Gentianic acid or its salts, which are present as the first stabilizer against radioactive degradation, at a concentration of 0.5 to 1 mg / mL;

[0027] (bii) ascorbic acid or its salt as a second stabilizer against radioactive degradation, present at a concentration from 2.0 to 5.0 mg / mL.

[0028] A method for manufacturing an aqueous solution of a drug as defined above, the method comprising the following steps:

[0029] (1) A complex of a radionuclide and a chelating agent that binds to a cell receptor is formed as follows.

[0030] (1.1) Prepare an aqueous solution containing the radionuclide;

[0031] (1.2) Prepare an aqueous solution comprising the cell receptor-binding organic moiety of the chelating agent, a first stabilizer, and optionally a second stabilizer; and

[0032] (1.3) Mix the solutions obtained in steps (1.1) and (1.2) and heat the resulting mixture;

[0033] (2) The complex solution obtained in step (1) is diluted as follows.

[0034] (2.1) Prepare an aqueous dilution solution optionally containing a second stabilizer; and

[0035] (2.2.) Mix the complex solution obtained in step (1) with the diluted solution obtained in step (2.1).

[0036] This invention offers the following advantages:

[0037] This high concentration allows for the administration of high doses in a short period of time. For example, in 177 In the case of Lu-DOTA-TATE, a high dose of 7.4 GBq can be delivered in a small volume of 20.5 to 25.0 mL, which allows IV infusion administration to be completed in about 20 to 30 minutes.

[0038] The invention described herein ensures high stability for cell receptor-binding molecules (even sensitive peptide molecules) with at least 95%, 96%, 97%, 98%, 99%, or 100% chemical purity after 72 hours at 25°C. For example, 100% chemical purity was found for DOTA-TATE after 72 hours at 25°C, and even after 48 hours at 32°C. Such high stability with respect to chemical purity was observed even under short-term elevated temperature conditions (12 hours at 32°C and 60 hours at 25°C).

[0039] Furthermore, the present invention, as described herein, ensures high stability by using one or more suitable stabilizers, with a radiochemical stability of at least 95% for radionuclide complexes with respect to radiochemical purity. For example, for 177 Lu-DOTA-TATE was found to have at least 95% radiochemical purity after 72 hours at 25°C. Such high stability regarding radiochemical purity was also observed even under short-term elevated temperature conditions (12 hours at 32°C and 60 hours at 25°C).

[0040] While sufficient stability has been achieved using a single stabilizer, the use of two stabilizers has been found to be particularly suitable for stabilizing sensitive radiopharmaceutical solutions. Specifically, it is advantageous to have one stabilizer present during complex formation and to add another stabilizer after complex formation, because one stabilizer ensures that cell receptor-binding molecules are protected from radioactive degradation during the complexation reaction, and the other stabilizer enhances the protection against degradation over time.

[0041] Furthermore, by administering the two stabilizers sequentially, it is ensured that only a relatively small amount of stabilizer is present during complexation (which minimizes the potential interference of the stabilizer with the complexation reaction) and a large amount of stabilizer combination is present after complexation (which enhances the protective ability of the stabilizer during the subsequent drug storage period).

[0042] The sequential application of these two stabilizers also reduces the total thermal stress of those stabilizers because one of the stabilizers is absent when complexation reactions involving high temperatures occur.

[0043] Furthermore, it is particularly advantageous to use two different stabilizers, as this combination is more effective in reacting with the various groups that may be formed by the radioactive decomposition of cell receptor-binding molecules than a single stabilizer in the aforementioned respects.

[0044] The composition of the radiopharmaceutical solution does not require the presence of ethanol. The solution is sufficiently stable in the absence of ethanol. Regarding the physiological tolerability of the solution, the absence of ethanol is advantageous.

[0045] A shelf life of at least 3 days is required to allow radiopharmaceutical products to be manufactured from centralized drug production sites and commercialized as ready-to-use drug products.

[0046] Therefore, due to its high stability (72 hours at 25°C), the present invention allows for the production of pharmaceuticals at the highest quality standards (e.g., cGMP) and at an industrial scale, such as in batch sizes of 74 GBq or 148 GBq. This provides pharmaceutical products with multiple dose units, such as sufficient dose units to treat 10 to 20 patients simultaneously.

[0047] Furthermore, due to its high stability, the present invention allows sufficient time for transport from centralized drug manufacturing sites to remote clinical centers.

[0048] Furthermore, due to its high stability, the present invention can be provided as a ready-to-use infusion solution that can be administered to patients immediately without any preparation by clinicians prior to administration.

[0049] This invention is particularly applicable to somatostatin receptor-binding peptides, especially the highly sensitive somatostatin analogs octreotide and octreotate, which are particularly prone to degradation. Furthermore, this invention is particularly applicable to the radionuclide lutetium-177, which possesses specific radioactive characteristics. Detailed Implementation

[0050] The invention is described and illustrated in more detail below.

[0051] Generally, this invention relates to aqueous solutions of pharmaceuticals, particularly aqueous solutions of radiopharmaceuticals. The solution is intended for intravenous (IV) use / application / administration. The solution is stable, concentrated, and ready to use.

[0052] The stability of the solution was determined by using a stabilizer resistant to radioactive degradation.

[0053] Typically, the stabilizers used according to the present invention may be selected from gentianic acid (2,5-dihydroxybenzoic 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 gentianic acid or its salts and ascorbic acid or its salts.

[0054] Ethanol is considered a less preferred stabilizer because of associated tolerance issues if present at higher concentrations. Ethanol should ideally be avoided (in other words, ethanol-free) in the solutions of the present invention, or at least the amount of ethanol in the solutions should be limited, for example, to less than 5%, preferably less than 2%, more preferably less than 1%, in the final solution intended for injection / infusion. Even more preferably, the solution is ethanol-free.

[0055] According to the present invention, the following embodiments are provided:

[0056] 1. An aqueous solution of a drug, said aqueous solution comprising...

[0057] (a) A complex formed from the following

[0058] (ai) radioactive nuclides, and

[0059] (aii) the cell receptor-binding organic portion linked to the chelating agent; and

[0060] (b) at least one stabilizer resistant to radioactive degradation;

[0061] in

[0062] The radionuclide is present at a concentration that provides at least 100 MBq / mL, preferably at least 250 MBq / mL of volumetric radioactivity.

[0063] 2. The drug aqueous solution according to Example 1,

[0064] The one or more stabilizers (component (b)) are present at a total concentration of at least 0.2 mg / mL, preferably at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, and even more preferably at least 2.7 mg / mL.

[0065] 3. The drug aqueous solution according to any one of the foregoing embodiments, wherein the radionuclide is present at a concentration providing volumetric radioactivity of 100 to 1000 MBq / mL, preferably from 250 to 500 MBq / mL.

[0066] 4. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the one or more stabilizers are present at a total concentration of 0.2 to 20.0 mg / mL, preferably 0.5 to 10.0 mg / mL, more preferably 1.0 to 5.0 mg / mL, and even more preferably 2.7 to 4.1 mg / mL.

[0067] 5. The aqueous solution of the drug according to any one of the foregoing embodiments,

[0068] Component (b) is a single stabilizer resistant to radioactive degradation, i.e., only the first stabilizer.

[0069] 6. The aqueous solution of the drug according to any one of the foregoing embodiments,

[0070] Component (b) is at least two stabilizers that resist radioactive degradation, i.e., at least the first and second stabilizers, preferably only two stabilizers, i.e. only the first and second stabilizers.

[0071] 7. The aqueous solution of the drug according to any one of Examples 5 to 6, wherein 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, even more preferably 0.5 to 0.7 mg / mL.

[0072] 8. An aqueous solution of a drug according to any one of Examples 6 or 7, wherein the second stabilizer is present at a concentration of 0.5 to 10 mg / mL, more preferably from 1.0 to 8.0 mg / mL, even more preferably from 2.0 to 5.0 mg / mL, even more preferably from 2.2 to 3.4 mg / mL.

[0073] 9. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the one or more stabilizers are selected from gentianic acid (2,5-dihydroxybenzoic 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, preferably selected from gentianic acid or its salts and ascorbic acid or its salts.

[0074] 10. An aqueous solution of a drug according to any one of Examples 5 to 9, wherein the first stabilizer is selected from gentianic acid and ascorbic acid, preferably gentianic acid.

[0075] 11. The aqueous solution of the drug according to any one of Examples 6 to 10, wherein the second stabilizer is selected from gentian acid and ascorbic acid, preferably the second stabilizer is ascorbic acid.

[0076] 12. An aqueous solution of a drug according to any one of Examples 6 to 8, wherein the first stabilizer is gentianic acid or a salt thereof, and the second stabilizer is ascorbic acid or a salt thereof, and the ratio of the concentration of the first stabilizer (in mg / mL) to the concentration of the second stabilizer (in mg / mL) is from 1:3 to 1:7, preferably from 1:4 to 1:5.

[0077] 13. An aqueous solution of a drug according to any one of the foregoing embodiments, wherein the radionuclide is selected from... 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, preferably selected from 177 Lu and 68 Ga, more preferably 177 Lu.

[0078] 14. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the cell receptor binding portion is a somatostatin receptor-binding peptide, preferably the somatostatin receptor-binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, and preferably selected from octreotide and octreotate.

[0079] 15. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, NOC and NOTA, preferably DOTA.

[0080] 16. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the cell receptor binding portion and the chelating agent together form a molecule selected from DOTA-OC, DOTA-TOC (edotroleptide), DOTA-NOC, DOTA-TATE (oxodotroptide), DOTA-LAN, and DOTA-VAP, preferably a molecule selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

[0081] 17. An aqueous solution of a drug according to any one of the foregoing embodiments, wherein the radionuclide, the cell receptor binding moiety, and the chelating agent together form a complex. 177 Lu-DOTA-TOC(177 Lu-edotrepeptide) or 177 Lu-DOTA-TATE 177 Lu-Ossodutratide), preferred 177 Lu-DOTA-TATE.

[0082] 18. The aqueous drug solution according to any one of the foregoing embodiments, wherein the aqueous drug solution further comprises a buffer solution, preferably an acetate buffer solution, preferably in an amount to obtain an acetic acid concentration of 0.3 to 0.7 mg / mL (preferably about 0.48 mg / mL) and an amount of sodium acetate of 0.4 to 0.9 mg / mL (preferably about 0.66 mg / mL).

[0083] 19. The aqueous drug solution according to any one of the foregoing embodiments, wherein the aqueous drug solution further comprises a multivalent chelating agent, preferably diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount to obtain a concentration from 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL).

[0084] 20. The aqueous drug solution according to any one of the foregoing embodiments, wherein the aqueous drug solution has the following properties: at least 24 hours at ≤25°C, at least 48 hours at ≤25°C, at least 72 hours at ≤25°C, from 24 hours to 120 hours at ≤25°C, from 24 hours to 96 hours at ≤25°C, from 24 hours to 84 hours at ≤25°C, and from 24 hours to 72 hours at ≤25°C. Shelf life It has a shelf life of 72 hours at ≤25℃.

[0085] 21. The aqueous solution of a drug according to any one of the foregoing embodiments, wherein the solution is manufactured on a commercial scale, particularly in batch sizes of at least 20 GBq, at least 50 GBq, or at least 70 GBq.

[0086] 22a. The aqueous drug solution according to any one of the foregoing embodiments, wherein the aqueous drug solution is ready for use.

[0087] 22b. An aqueous solution of a drug according to any one of the foregoing embodiments, said aqueous solution being used for commercial purposes.

[0088] 23. An aqueous solution of a drug, said aqueous solution comprising...

[0089] (a) A complex formed from the following

[0090] (ai) radionuclides 177 Lutetium (Lu-177) exists at concentrations of volumetric radioactivity ranging from 250 to 500 MBq / mL, and

[0091] (aii) A chelating agent that binds to the organic part of somatostatin receptor DOTA-TATE (Ossodotritide) or DOTA-TOC (Edotritide);

[0092] (bi) Gentianic acid or its salts, which are present as the first stabilizer against radioactive degradation, at a concentration of 0.5 to 1 mg / mL;

[0093] (bii) Ascorbic acid or its salts, which are present as a second stabilizer against radioactive degradation, at a concentration of 2.0 to 5.0 mg / mL.

[0094] 24. The aqueous drug solution according to Example 23, wherein the aqueous drug solution further comprises:

[0095] (c) Diethylenetriaminepentaacetic acid (DTPA) or its salts at a concentration of 0.01 to 0.10 mg / mL.

[0096] 25. The aqueous drug solution according to Example 23 or 24, wherein the aqueous drug solution further comprises:

[0097] (d) Acetic acid with a concentration of 0.3 to 0.7 mg / mL and sodium acetate with a concentration of 0.4 to 0.9 mg / mL.

[0098] 26. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the one or more stabilizers are present in the solution during the formation of the complex of components (ai) and (aii).

[0099] 27. An aqueous solution of the drug according to any one of Examples 5 to 26, wherein only the first stabilizer is present during the formation of the complex of components (ai) and (aii), preferably in an amount at 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, even more preferably 0.5 to 0.7 mg / mL, to be obtained in the final solution.

[0100] 28. The aqueous solution of the drug according to any one of Examples 6 to 27, wherein a portion of the second stabilizer is already present in the solution during the formation of the complex of components (ai) and (aii), and another portion of the second stabilizer is added after the formation of the complex of components (ai) and (aii).

[0101] 29. An aqueous solution of a drug according to any one of Examples 6 to 28, wherein the second stabilizer is added after the complex of components (ai) and (aii) is formed.

[0102] 30. The aqueous solution of the drug according to Example 6 or 29, wherein the second stabilizer is added after the complex of components (ai) and (aii) is formed, preferably in an amount of concentration from 0.5 to 10 mg / mL, more preferably from 1.0 to 8.0 mg / mL, even more preferably from 2.0 to 5.0 mg / mL, even more preferably from 2.2 to 3.4 mg / mL in the final solution.

[0103] 31. The aqueous drug solution according to any one of the foregoing embodiments, wherein the aqueous drug solution further comprises a multivalent chelating agent added after the formation of the complex of components (ai) and (aii) to remove any uncomplexed Lu, preferably the multivalent chelating agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in an amount at a concentration of from 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL) to be obtained in the final solution.

[0104] 32. A method for producing an aqueous solution of a drug as defined in any of the foregoing embodiments, the method comprising the following steps:

[0105] (1) A complex formed by the following steps to chelate the radionuclide and the organic part of the cell receptor-binding agent.

[0106] (1.1) Prepare an aqueous solution containing the radionuclide;

[0107] (1.2) Prepare an aqueous solution comprising the cell receptor-binding organic moiety of the chelating agent, a first stabilizer, and optionally a second stabilizer; and

[0108] (1.3) Mix the solutions obtained in steps (1.1) and (1.2) and heat the resulting mixture;

[0109] (2) The complex solution obtained in step (1) is diluted as follows.

[0110] (2.1) Prepare an aqueous dilution solution optionally containing a second stabilizer; and

[0111] (2.2.) Mix the complex solution obtained in step (1) with the diluted solution obtained in step (2.1).

[0112] 33. The method according to embodiment 32, wherein in step (1.3) period The first stabilizer is present only, preferably in an amount that yields a final solution at 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, even more preferably 0.5 to 0.7 mg / mL.

[0113] 34. The method according to any one of Examples 32 to 33, wherein during step (1.3), a portion of the second stabilizer is already present in the solution, and in step (1.3) after In step (2.1), another portion of the second stabilizer is added.

[0114] 35. An aqueous solution of the drug according to any one of Examples 32 to 34, wherein in step (1.3) after Add the second stabilizer in step (2.1).

[0115] 36. An aqueous solution of the drug according to any one of Examples 32-35, wherein in step (1.3) after In step (2.1), the second stabilizer is added, preferably in an amount that yields a final solution at a concentration of 0.5 to 10 mg / mL, more preferably from 1.0 to 8.0 mg / mL, even more preferably from 2.0 to 5.0 mg / mL, even more preferably from 2.2 to 3.4 mg / mL.

[0116] 37. The method according to any one of Examples 32 to 36, wherein the solution in step (1.2) further comprises a buffer solution, preferably an acetate buffer solution.

[0117] 38. The method according to any one of Examples 32 to 37, wherein in step (1.3), the resulting mixture is heated to a temperature from 70°C to 99°C, preferably from 90°C to 98°C, for a duration from 2 to 59 minutes.

[0118] 39. The method according to any one of Examples 32 to 38, wherein the solution of step (2.1) further comprises diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

[0119] 40. The method according to any one of Examples 32 to 39, further comprising the following method steps:

[0120] (3) Filter the solution obtained in step (2) through a 0.2 μm filter:

[0121] (4) Dispense the filtered solution obtained in step (3) into a dose unit container in the volume required to deliver the following radioactive dose: from 5.0 to 10 MBq, preferably from 7.0 to 8.0 MBq, more preferably from 7.3 to 7.7 MBq, even more preferably from 7.4 to 7.5 MBq, preferably from 10 to 50 mL, more preferably from 15 to 30 mL, even more preferably from 20 to 25 mL.

[0122] 41. The method according to any one of Examples 32 to 40, wherein the solution in step (1.1) comprises LuCl3 and HCl.

[0123] 42. The method according to any one of Examples 32 to 41, wherein the solution in step (1.2) comprises 177 Lu-DOTA-TATE or 177 Lu-DOTA-TOC, gentian acid, acetic acid, and sodium acetate.

[0124] 43. The method according to any one of Examples 32 to 42, wherein the solution in step (2.1) comprises DTPA and ascorbic acid.

[0125] 44. The method according to any one of Examples 32 to 43, wherein the dose unit container in step (4) is a stoppered vial sealed inside a lead container.

[0126] 45. An aqueous solution of a drug obtained (or obtainable) by the method defined in any one of claims 32 to 44.

[0127] Further embodiments of the invention are described below as “E embodiment”:

[0128] E1. An aqueous solution of a drug, said aqueous solution comprising:

[0129] (a) A complex formed from the following

[0130] (ai) radionuclides 177 Lu (lutetium-177), and

[0131] (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA; and

[0132] (b) at least two different stabilizers resistant to radioactive degradation;

[0133] in

[0134] The radionuclide is present at a concentration that provides volumetric radioactivity from 250 to 500 MBq / mL; and

[0135] The stabilizer is present at a total concentration of 0.2 to 20.0 mg / mL.

[0136] "A complex formed from..." can be alternatively expressed as "...a complex of".

[0137] The "different" in "two different stabilizers" refers to the difference in the chemical entities of these stabilizers. "Two different stabilizers" implies that the two stabilizers are different chemical entities; for example, gentian acid and ascorbic acid are two different stabilizers.

[0138] "At least two" means two or more, however, it is preferred that only two stabilizers are present (not three or more). Further preferred is that ethanol is not one of the two stabilizers. E2. The aqueous solution of the drug according to Example E1,

[0139] The component (b) mentioned above contains a stabilizer:

[0140] (bi) gentic acid or its salt; and

[0141] (bii) Ascorbic acid or its salt.

[0142] E3. The aqueous solution of the drug according to Example E2.

[0143] in

[0144] (bi) Gentianic acid is present at a concentration of 0.5 to 2 mg / mL, preferably 0.5 to 1 mg / mL; and

[0145] (bii) Ascorbic acid exists at concentrations ranging from 2.0 to 5.0 mg / mL.

[0146] In one specific embodiment, the present invention provides:

[0147] An aqueous solution of a drug, the aqueous solution of the drug comprising:

[0148] (a) A complex formed from the following

[0149] (ai) radionuclides 177 Lu (lutetium-177), at concentrations providing it with volumetric radioactivity ranging from 250 to 500 MBq / mL, and

[0150] (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA; and

[0151] (b) Stabilizers resistant to radioactive degradation

[0152] (bi) gentic acid with concentrations ranging from 0.5 to 1 mg / mL and

[0153] (bii) Ascorbic acid at concentrations ranging from 2.0 to 5.0 mg / mL.

[0154] E4. The aqueous drug solution according to Example E3, the aqueous drug solution further comprises:

[0155] (c) Diethylenetriaminepentaacetic acid (DTPA) or its salts at a concentration of 0.01 to 0.10 mg / mL.

[0156] E5. The aqueous drug solution according to Example E3 or E4, the aqueous drug solution further comprises:

[0157] (d) Acetate buffer solution, which consists of the following:

[0158] (di) Acetic acid with a concentration ranging from 0.3 to 0.7 mg / mL; and

[0159] (dii) Sodium acetate with a concentration of 0.4 to 0.9 mg / mL;

[0160] Preferably, the acetate buffer solution provides a pH from 4.5 to 6.0, more preferably from 4.7 to 6.0, more preferably from 5.0 to 6.0, and even more preferably from 5.0 to 5.5.

[0161] In one specific embodiment, the present invention provides:

[0162] An aqueous solution of a drug, the aqueous solution of the drug comprising:

[0163] (a) A complex formed from the following

[0164] (ai) radionuclides 177 Lu (lutetium-177), at concentrations providing it with volumetric radioactivity ranging from 250 to 500 MBq / mL, and

[0165] (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA;

[0166] (b) Stabilizers against radioactive degradation: (bi) gentic 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;

[0167] (c) diethylenetriaminepentaacetic acid (DTPA) or its salts at a concentration from 0.01 to 0.10 mg / mL; and

[0168] (d) Acetate buffer solution, which consists of the following:

[0169] (di) Acetic acid with a concentration ranging from 0.3 to 0.7 mg / mL; and

[0170] (dii) Sodium acetate with a concentration of 0.4 to 0.9 mg / mL;

[0171] Preferably, the acetate buffer solution provides a pH from 5.0 to 5.5.

[0172] The pH value mentioned in this article refers to the final solution pH value. However, it can also be the pH value during solution preparation processes, such as complex formation processes.

[0173] E6. An aqueous solution of a drug according to any one of Examples E1 to E5, wherein at least one of the stabilizers is present during the formation of the complex of components (ai) and (aii), and at least one of the stabilizers is added after the formation of the complex of components (ai) and (aii).

[0174] E7. An aqueous solution of the drug according to any one of Examples E1 to E5, wherein at least gentian acid is present during the formation of the complex of components (ai) and (aii), and at least ascorbic acid is added after the formation of the complex of components (ai) and (aii).

[0175] E8. An aqueous solution of the drug according to any one of Examples E1 to E5, wherein the only stabilizer present during the formation of the complex of components (ai) and (aii) is gentianic acid, and the only stabilizer added after the formation of the complex of components (ai) and (aii) is ascorbic acid.

[0176] In one specific embodiment, the present invention provides:

[0177] An aqueous solution of a drug, the aqueous solution of the drug comprising:

[0178] (a) A complex formed from the following

[0179] (ai) radionuclides 177 Lu (lutetium-177), at concentrations providing it with volumetric radioactivity ranging from 250 to 500 MBq / mL, and

[0180] (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA; and

[0181] (b) Stabilizers resistant to radioactive degradation

[0182] (bi) gentic acid at concentrations ranging from 0.5 to 1 mg / mL (in the final solution) and

[0183] (bii) Ascorbic acid at concentrations ranging from 2.0 to 5.0 mg / mL (in the final solution);

[0184] Gentian acid is present during the formation of the complex of components (ai) and (aii), and ascorbic acid is added after the formation of the complex of components (ai) and (aii).

[0185] In one specific embodiment, the invention is defined as follows:

[0186] An aqueous solution of a drug, the aqueous solution of the drug comprising:

[0187] (a) A complex formed from the following

[0188] (ai) radionuclides 177 Lu (lutetium-177), at concentrations providing it with volumetric radioactivity ranging from 250 to 500 MBq / mL, and

[0189] (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA;

[0190] (b) Stabilizers against radioactive degradation: (bi) gentic 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;

[0191] (c) diethylenetriaminepentaacetic acid (DTPA) or its salts at a concentration from 0.01 to 0.10 mg / mL; and

[0192] (d) Acetate buffer solution, which consists of the following:

[0193] (di) Acetic acid with a concentration ranging from 0.3 to 0.7 mg / mL; and

[0194] (dii) Sodium acetate with a concentration of 0.4 to 0.9 mg / mL;

[0195] Preferably, the acetate buffer solution provides a pH from 5.0 to 5.5;

[0196] Gentian acid is present during the formation of the complex of components (ai) and (aii), and ascorbic acid is added after the formation of the complex of components (ai) and (aii).

[0197] E9. An aqueous solution of a drug according to any one of Examples E6 to E8, wherein one or more of the stabilizers present during the formation of the complex of components (ai) and (aii) are present at a total concentration of from 15 to 50 mg / mL, preferably from 20 to 40 mg / mL, during the formulation of the complex.

[0198] E10. The aqueous solution of the drug according to Example E9, wherein the only stabilizer present during the formation of the complex of components (ai) and (aii) is gentic acid and is present during the preparation of the complex at a concentration of 20 to 40 mg / mL, preferably 25 to 35 mg / mL.

[0199] In one specific embodiment, the invention is defined as follows:

[0200] An aqueous solution of a drug, the aqueous solution of the drug comprising:

[0201] (a) A complex formed from the following

[0202] (ai) radionuclides 177Lu (lutetium-177), at concentrations providing it with volumetric radioactivity ranging from 250 to 500 MBq / mL, and

[0203] (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA;

[0204] (b) Stabilizers against radioactive degradation: (bi) gentic 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;

[0205] (c) diethylenetriaminepentaacetic acid (DTPA) or its salts at a concentration from 0.01 to 0.10 mg / mL; and

[0206] (d) Acetate buffer solution, which consists of the following:

[0207] (di) Acetic acid with a concentration ranging from 0.3 to 0.7 mg / mL; and

[0208] (dii) Sodium acetate with a concentration of 0.4 to 0.9 mg / mL;

[0209] Preferably, the acetate buffer solution provides a pH from 5.0 to 5.5;

[0210] Gentian acid is present during the formation of the complex of components (ai) and (aii), and ascorbic acid is added after the formation of the complex of components (ai) and (aii); and the only stabilizer present during the formation of the complex of components (ai) and (aii) is gentian acid and is present at a concentration of 20 to 40 mg / mL, preferably 25 to 35 mg / mL, during the preparation of the complex.

[0211] Alternatively, embodiments E6 through E10 can be defined using the following terminology:

[0212] E6. An aqueous solution of a drug according to any one of Examples E1 to E5, which is produced by the presence of at least one of the stabilizers during the formation of the complex of components (ai) and (aii), and the addition of at least one of the stabilizers after the formation of the complex of components (ai) and (aii).

[0213] E7. An aqueous solution of a drug according to any one of Examples E1 to E5, which is produced by the presence of at least gentianic acid during the formation of the complex of components (ai) and (aii), and the addition of at least ascorbic acid after the formation of the complex of components (ai) and (aii).

[0214] E8. An aqueous solution of a drug according to any one of Examples E1 to E5, which is produced by the presence of gentianic acid as the sole stabilizer during the formation of the complex of components (ai) and (aii), and the addition of ascorbic acid as the sole stabilizer after the formation of the complex of components (ai) and (aii).

[0215] E9. An aqueous solution of a drug according to any one of Examples E6 to E8, which is produced by one or more of the stabilizers present during the formation of the complex of components (ai) and (aii) at a total concentration of from 15 to 50 mg / mL, preferably from 20 to 40 mg / mL.

[0216] E10. The aqueous solution of the drug according to Example E9, which is produced by the presence of gentian acid as the sole stabilizer during the formation of the complex of components (ai) and (aii) and at a concentration of 20 to 40 mg / mL, preferably 25 to 35 mg / mL, during the preparation of the complex.

[0217] In embodiments of the invention, particularly in Examples E9 and E10, the radionuclide may be present during complex formation at a concentration that provides volumetric radioactivity of up to 20 GBq / mL, preferably up to 15 GBq / mL, or from 5 to 20 GBq / mL, preferably from 10 to 20 GBq / mL, more preferably from 10 to 15 GBq / mL.

[0218] In one specific embodiment, the invention is defined as follows:

[0219] An aqueous solution of a drug, the aqueous solution of the drug comprising:

[0220] (a) A complex formed from the following

[0221] (ai) radionuclides 177 Lu (lutetium-177), at concentrations that provide it with volumetric radioactivity ranging from 250 to 500 MBq / mL (in the final solution), and

[0222] (aii) a somatostatin receptor-binding peptide linked to the chelating agent DOTA;

[0223] (b) Stabilizers against radioactive degradation: (bi) gentic 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;

[0224] (c) diethylenetriaminepentaacetic acid (DTPA) or its salts at a concentration from 0.01 to 0.10 mg / mL; and

[0225] (d) Acetate buffer solution, which consists of the following:

[0226] (di) Acetic acid with a concentration ranging from 0.3 to 0.7 mg / mL; and

[0227] (dii) Sodium acetate with a concentration of 0.4 to 0.9 mg / mL;

[0228] Preferably, the acetate buffer solution provides a pH from 5.0 to 5.5;

[0229] Gentian acid is present during the formation of the complex of components (ai) and (aii), and ascorbic acid is added after the formation of the complex of components (ai) and (aii); and the only stabilizer present during the formation of the complex of components (ai) and (aii) is gentian acid and is present at a concentration of 20 to 40 mg / mL during the preparation of the complex.

[0230] Furthermore, the radionuclide exists at a concentration that provides volumetric radioactivity of 10 to 20 GBq / mL during complex formation.

[0231] E11. The aqueous drug solution according to any one of the preceding E embodiments, wherein the aqueous drug solution has a shelf life of at least 72 hours when stored at ≤25°C, particularly when stored at 25°C.

[0232] The term "shelf life" has its general meaning in the context of pharmaceutical products. Shelf life is the length of time a pharmaceutical product can be stored while its product characteristics still conform to the product specifications defined during the drug development process and approved by health authorities.

[0233] E12. The aqueous solution of the drug according to any one of the preceding E examples, whose radiochemical purity (determined by HPLC) remains ≥95% for at least 72 hours when stored at 25°C.

[0234] E13. An aqueous solution of a drug according to any one of the preceding E embodiments, wherein the solution is produced on a commercial manufacturing scale, particularly in batch sizes of at least 20 GBq, at least 50 GBq, or at least 70 GBq.

[0235] E14. The aqueous solution of the drug according to any one of the foregoing embodiments, wherein the aqueous solution of the drug is ready for use.

[0236] E15. A method for producing an aqueous solution of a drug as defined in any of the preceding E embodiments, the method comprising the following method steps:

[0237] (1) Radionuclides are formed through the following methods 177 A complex of Lu and a somatostatin receptor-binding peptide linked to the chelator DOTA.

[0238] (1.1) Prepare an aqueous solution containing the radionuclide;

[0239] (1.2) Prepare an aqueous solution comprising a somatostatin receptor-binding peptide linked to the chelating agent and at least one stabilizer resistant to radioactive degradation; and

[0240] (1.3) Mix the solutions obtained in steps (1.1) and (1.2) and heat the resulting mixture;

[0241] (2) The complex solution obtained in step (1) is diluted as follows.

[0242] (2.1) Prepare an aqueous dilution solution optionally containing at least one stabilizer resistant to radioactive degradation; and

[0243] (2.2.) The complex solution obtained in step (1) is mixed with the diluted solution obtained in step (2.1) to obtain the final solution;

[0244] If the solution prepared under (1.2) contains only one stabilizer, then the solution prepared under (2.1) contains at least one stabilizer.

[0245] E16. The method according to Example E15, wherein the solution prepared in step (1.2) contains at least one stabilizer, and the solution prepared in step (2.1) contains at least one stabilizer.

[0246] E17. The method according to Example E15, wherein the solution prepared in step (1.2) contains at least the stabilizer gentianic acid, and the solution prepared in step (2.1) contains at least the stabilizer ascorbic acid.

[0247] E18. The method according to Example E15, wherein the solution prepared in step (1.2) contains only one stabilizer, said stabilizer being gentianic acid; and the solution prepared in step (2.1) contains only one stabilizer, said stabilizer being ascorbic acid.

[0248] E19. The method according to any one of Examples E15 to E18, wherein the solution prepared in step (1.2) contains one or more stabilizers with a total concentration of from 15 to 50 mg / mL, preferably from 20 to 40 mg / mL.

[0249] E20. The method according to any one of Examples E15 to E18, wherein the solution prepared in step (1.2) contains only one stabilizer, said stabilizer being gentianic acid with a concentration of 20 to 40 mg / mL, preferably 25 to 35 mg / mL.

[0250] E21. The method according to any one of Examples E15 to E20, wherein the solution in step (1.2) further comprises a buffer solution, preferably an acetate buffer solution.

[0251] E22. The method according to any one of Examples E15 to E21, wherein in step (1.3), the resulting mixture is heated to a temperature from 70°C to 99°C, preferably from 90°C to 98°C, for a duration from 2 to 59 minutes, preferably from 10 to 15 minutes.

[0252] E23. The method according to any one of Examples E15 to E22, wherein the solution of step (2.1) further comprises diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

[0253] E24. The method according to any one of embodiments E15 to E23, wherein the method further comprises the following method steps:

[0254] (3) Filter the solution obtained in step (2) through a 0.2 μm filter:

[0255] (4) Dispense the filtered solution obtained in step (3) into a dose unit container in the volume required to deliver the following radioactive dose: from 5.0 to 10 MBq, preferably from 7.0 to 8.0 MBq, more preferably from 7.3 to 7.7 MBq, even more preferably from 7.4 to 7.5 MBq, preferably from 10 to 50 mL, more preferably from 15 to 30 mL, even more preferably from 20 to 25 mL.

[0256] E25. The method according to any one of Examples E15 to E24, wherein the solution in step (1.1) comprises LuCl3 and HCl.

[0257] E26. The method according to any one of Examples E15 to E25, wherein the solution in step (1.2) comprises 177 Lu-DOTA-TATE or 177 Lu-DOTA-TOC, gentian acid, acetic acid, and sodium acetate.

[0258] E27. The method according to any one of Examples E15 to E26, wherein the solution in step (2.1) comprises DTPA and ascorbic acid.

[0259] E28. The method according to any one of Examples E24 to E27, wherein the dose unit container in step (4) is a stoppered vial sealed inside a lead container.

[0260] E29. An aqueous solution of a drug obtained (or available) by the method defined in any one of Examples E15 to E28.

[0261] In all embodiments described herein, the somatostatin receptor-binding peptide linked to the chelating agent DOTA (component (aii)) is preferably DOTA-TATE (ozodotritide) or DOTA-TOC (edotoritide), more preferably DOTA-TATE (ozodotritide).

[0262] The present invention further provides an aqueous solution of a drug as defined herein for the treatment of neuroendocrine tumors (NETs).

[0263] Alternatively, the present invention provides a method for treating NET in human patients requiring the treatment, the method comprising administering an effective amount of an aqueous solution of a drug as defined herein.

[0264] As another alternative, the present invention provides the use of an aqueous drug solution as defined herein for the manufacture / preparation of a medicament for the treatment of NET.

[0265] As another alternative, the present invention provides a medicament for treating NET, comprising an aqueous solution of a drug as defined herein.

[0266] Neuroendocrine tumors (NETs) that can be treated alone or in combination with other drugs as defined herein are selected from the group consisting of: gastrointestinal and pancreatic neuroendocrine tumors, carcinoid tumors, pheochromocytomas, paragangliomas, medullary thyroid carcinomas, pulmonary neuroendocrine tumors, thymic neuroendocrine tumors, carcinoid tumors or pancreatic neuroendocrine tumors, pituitary adenomas, adrenal tumors, Merkel cell carcinomas, breast cancer, non-Hodgkin lymphomas, Hodgkin lymphomas, head and neck tumors, urothelial carcinomas (bladder), renal cell carcinomas, hepatocellular carcinomas, GIST, neuroblastomas, bile duct tumors, cervical tumors, Ewing sarcoma, osteosarcoma, small cell lung cancer (SCLC), prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, supratentorial primitive neuroectodermal tumors, and olfactory neuroblastomas.

[0267] Other NET tumors that can be treated alone or in combination with the present invention by an aqueous solution of a drug as defined herein are selected from the group consisting of: functional carcinoid tumors, islet tumors, gastrinomas, vasoactive intestinal peptide (VIP) tumors, glucagonomas, serotoninomas, histamine tumors, adrenocorticotropic hormone adenomas (ACTH adenomas (ACTHomas)), pheochromocytomas, and somatostatinomas.

[0268] This invention further provides a method using radioactive nuclides 177A combination or combination therapy of Lu (lutetium-177) and a complex formed with a somatostatin receptor-binding peptide linked to a chelating agent as defined herein, or a combination or combination therapy of an aqueous solution of a drug as defined herein with one or more therapeutic agents as described below:

[0269] In some cases, the aqueous solution of the drug of the present invention may be combined with other therapeutic agents (such as other anticancer agents, anti-allergic agents, anti-nausea agents (or antiemetics), analgesics, cell protectants, and combinations thereof).

[0270] Commonly used chemotherapeutic agents considered for combination therapy include anastrozole ( ), Bicalutamide ), Bleomycin sulfate ( ), Bai Xiaoan ( ), Busulfan Injection ( ), capecitabine ( ), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin ( ), Camustin ( ), chlorambucil ( ), cisplatin ), Kratribine ( ), cyclophosphamide ( or ), cytarabine, cytosine arabinoside ( ), Cytarabine liposome injection ( ), dacarbazine ), actinomycin D (Cosmegan), daunorubicin hydrochloride ( ), Daunorubicin Citrate Liposome Injection ), dexamethasone, docetaxel ( Doxorubicin hydrochloride () , ), etoposide ( ), fludarabine phosphate ( ), 5-fluorouracil ( , Flutamide ), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea ( Idabi Star ( ), ifosfamide ( ), Irinotecan ( L-asparaginase ( ), calcium leucovorin, melphalan ( ), 6-mercaptopurine ( Methotrexate ), Mitoxantrone ( ), gemutumab (mylotarg), paclitaxel ( ), albumin-bound paclitaxel ( Implants containing phoenix (Yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20, and carmustine. ), Tamoxifen citrate ( ), teniposide ( ), 6-thioguanine, thiotepa, telazamine ( Topotecan hydrochloride for injection ( ), Vinpocetine ( ), Vincristine ( ) and Changchun Ruibin ( ).

[0271] Particularly interesting anticancer agents for combination with the aqueous solution of the drug of the present invention include:

[0272] Tyrosine kinase inhibitor: Erlotinib hydrochloride ( Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, is available from Genentech; sunitinib malate ( ); Bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carboxynitrile, also known as SKI-606, and described in U.S. Patent No. 6,780,996); Dasatinib ( ); Pazopanib Sorafenib ( ); vandetanib (ZD6474); and imatinib or imatinib mesylate ( and ).

[0273] Vascular endothelial growth factor (VEGF) receptor inhibitor: bevacizumab ( Axitinib Brivanib alaninate (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-yloxy)propyl-2-yl)2-aminopropionic acid); Sorafenib ); Pazopanib Sunitinib malate ( ); Cediranib (AZD2171, CAS288383-20-1); Vargatef (BIBF1120, CAS 928326-83-4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS 332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib ( Ponatinib (AP24534, CAS 943319-70-8); Tivozanib (AV951, CAS 475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanib dihydrochloride (PTK787, CAS212141-51-0); Brivanib (BMS-540215, CAS 649735-46-6); Vandetanib (… Or AZD6474); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, described in PCT publication WO 02 / 066470); Dovitinib dilactic acid (TKI258, CAS852433-84-2); Linfanib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CAS... 849217-68-1); Lestaurtinib (CAS111358-88-4); N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopentadienzo[c]pyrrolo-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-(3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide (BHG712, CAS 940310-85-0); and Aflibercept ( ), sulfatinib (surufatinib).

[0274] Platelet-derived growth factor (PDGF) receptor inhibitor: Imatinib Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, is available from Genentech; sunitinib malate ( ); Quizartinib (AC220, CAS 950769-58-1); Pazopanib ( Axitinib Sorafenib ( Vargatef (BIBF1120, CAS 928326-83-4); Telatinib (BAY57-9352, CAS 332012-40-5); Vatalanibdihydrochloride (PTK787, CAS212141-51-0); and Motesanibdiphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO 02 / 066470).

[0275] Fibroblast growth factor receptor (FGFR) inhibitors: Brivanib alaninate (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propyl-2-yl)2-aminopropionic acid); Vargatef (BIBF1120, CAS928326-83-4); Dovitinib dilactic acid (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 872511-34-7); Danusertib (PHA-739358); and N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N'-(1,1-dimethylethyl)-urea (PD173074, CAS 219580-11-7). Surufatinib.

[0276] Aurora kinase A 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]-2-pyrimidinylamine (CYC116, CAS 693228-63-6); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); Alisertib (MLN8237); (N-{2-[6-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphth-9-yl]-2-oxo-ethyl}-acetamide)(PF-03814735); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzozazacycloheptatrien-2-yl]amino]-benzoic acid (MLN8054, CAS) 869363-13-3); Cenisertib (R-763); Bareserte (AZD1152); and N-cyclopropyl-N'-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazole-4-yl]-urea (AT9283).

[0277] Cyclin-dependent kinase (CDK) inhibitors: Aloisine A; Alvocidib (also known as flavonoid pyridoxine or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromanone and described in U.S. Patent No. 5,621,002); Crizotinib (PF-02341066, CAS 877399-52-5); 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one hydrochloride (P276-00, CAS 876-00). 920113-03-7); IndiShulan (E7070); Roscovitine (CYC202); 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, hydrochloride (PD 0332991); Dinaciclib (SCH 727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazolyl]piperidin-4-carboxamide (BMS 387032, CAS 10000) 345627-80-7); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzozazonium-2-yl]amino]-benzoic acid (MLN8054, CAS 869363-13-3); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethylamine (AG-024322, CAS837364-57-5); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS 844442-38-2); 4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinylamine (AZD5438, CAS 602306-29-6); palbociclib (PD-0332991); and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfonimino]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol (BAY 10000394), ribociclib.

[0278] Cell cycle checkpoint kinase (CHK) inhibitors: 7-hydroxycryocystine (UCN-01); 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinyl-pyrazol[1,5-a]pyrimidin-7-amine (SCH 900776, CAS 891494-63-6); 5-(3-fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinoline-2(1H)-one (CHIR 124, CAS 405168-58-3); 7-Aminoactinomycin D (7-AAD), Isogranulatimide, debromohymenialdisine; N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2603618, CAS 911222-45-2); Sulforaphane (CAS 4478-93-7,4-methylsulfinylbutyl isothiocyanate); 9,10,11,12-tetrahydro-9,12-epoxy-1H-diindole[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazepine-1,3(2H)-dione (SB-218078, CAS135897-06-2); and TAT-S216A (YGRKKRRQRR) RLYRSPAMPENL), 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]benzodiazepineheptadiene-8-yl]-cyclohexaneacetamide (PF-0477736).

[0279] 3-Phosphatidyl kinase-1 (PDK1 or PDPK1) inhibitors: 7-2-amino-N-[4-[5-(2-phenanthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]acetamide (OSU-03012, CAS 742112-33-0); pyrrolidine-1-carboxylic acid (3-{5-bromo-4-[2-(1H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)-amide (BX912, CAS 702674-56-4); and 4-dodecyl-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (PHT-427, CAS1191951-57-1).

[0280] Protein kinase C (PKC) activators: bryo-1 and somatostatin (AEB071).

[0281] B-RAF inhibitors: Regorafenib (BAY73-4506, CAS 755037-03-7); Tuvizanib (AV951, CAS 475108-18-0); Vemurafenib ( PLX-4032 (CAS 918504-65-1); 5-[1-(2-hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydroindene-1-one oxime (GDC-0879, CAS 905281-76-7); 5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-(4-pyridyl)-1H-imidazol-4-yl]-2,3-dihydro-1H-indene-1-one oxime (GSK2118436 or SB590885); (+ / -)-methyl(5-(2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl)carbamate (also known as XL-281 and BMS908662) and N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (also known as PLX4720).

[0282] C-RAF inhibitors: sorafenib ); 3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-benzamide (ZM336372, CAS208260-29-1); 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).

[0283] Human granulocyte colony-stimulating factor (G-CSF) regulator: Filgrastim Sunitinib malate ( ); Polyethylene glycol filgrastim (Pegilgrastim) ) and quezartinib (AC220, CAS 950769-58-1).

[0284] RET inhibitors: sunitinib malate ( ); Van der Tanis ( Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, described in PCT publication WO 02 / 066470); sorafenib (BAY 43-9006); regorafenib (BAY73-4506, CAS 755037-03-7); and danusertib (PHA-739358).

[0285] FMS-like tyrosine kinase 3 (FLT3) inhibitors or CD135: sunitinib malate ( ); Quizartinib (AC220, CAS 950769-58-1); N-[(1-methyl-4-piperidinyl)methyl]-3-[3-(trifluoromethoxy)phenyl]-imidazo[1,2-b]pyridazine-6-amine sulfate (SGI-1776, CAS1173928-26-1); and Vargatef (BIBF1120, CAS 928326-83-4).

[0286] c-KIT inhibitor: Pazopanib Dovitinib dilacticacid (TKI258, CAS 852433-84-2); Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, described in PCT publication WO 02 / 066470); Masitinib ( ); Regorafenib (BAY73-4506, CAS 755037-03-7); Tevozanib (AV951, CAS 475108-18-0); Vatalanib dihydrochloride (PTK787, CAS212141-51-0); Telatinib (BAY57-9352, CAS 332012-40-5); Foretinib (GSK1363089, formerly known as XL880, CAS 849217-64-7); Sunitinib malate ( ); Quizartinib (AC220, CAS 950769-58-1); Axitinib ( ); dasatinib (BMS-345825); and sorafenib ( ).

[0287] Bcr / Abl kinase inhibitors: Imatinib Inilotinib hydrochloride; Nilotinib ( ); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS1133385-83-7); Saracatinib (AZD0530); and N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthyl-1,4-imino-9-yl]-2-oxoethyl]acetamide (PF-03814735, CAS 942487-16-3).

[0288] IGF-1R inhibitors: Linsitnib (OSI-906); [7-[trans-3-[(azacyclobutan-1-yl)methyl]cyclobutyl]-5-(3-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (AEW541, CAS475488-34-7); [5-(3-benzyloxyphenyl)-7-[trans-3-[(pyrrolo-1-yl)methyl]cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (ADW742 or GSK552602A, CAS 475488-23-4); (2-[[3-bromo-5-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]malonium (tyrosine phosphorylation inhibitor AG1024, CAS...) 65678-07-1); 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[7-methyl-5-(4-morpholinyl)-1H-benzimidazol-2-yl]-2(1H)-pyridone (BMS536924, CAS 468740-43-4); 4-[2-[4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1,2-dihydro-2-oxo-3-pyridyl]-7-methyl-1H-benzimidazol-5-yl]-1-piperazinepropionitrile (BMS554417, CAS 468741-42-6); (2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoro-3-pyridyl)-2-methyl-2-pyrrolidinecarboxamide (BMS754807, CAS1001350-96-4); Picropodophyllotoxin (AXL1717); and Nordihydroguareacetic acid.

[0289] IGF-1R antibody: Figitumumab (CP751871); Cixutumumab (IMC-A12); Ganitumab (AMG-479); Robatumumab (SCH-717454); Dalotuzumab (MK0646); R1507 (available from Roche); BIIB022 (available from Biogen); and MEDI-573 (available from MedImmune).

[0290] MET inhibitors: Cabozantinib (XL184, CAS 849217-68-1); Foretinib (GSK 1363089, formerly known as XL880, CAS 849217-64-7); Tivantinib (ARQ197, CAS1000873-98-2); 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinoline-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458); Cryzotinib ( PF-02341066); (3Z)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrolo-2-yl}methylene)-1,3-dihydro-2H-indol-2-one (SU11271); (3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrolo-2-yl}methylene (3Z)-N-(3-chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrolo-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfonamide (SU11606); 6-[difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazol[4,3-b]pyridazine-3-yl]methyl]quinoline (JNJ) 38877605, CAS 943540-75-8); 2-[4-[1-(quinoline-6-ylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4); N-((2R)-1,4-dioxane-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cycloheptane[1,2-b]pyridin-7-yl]sulfonamide (MK2461, CAS 917879-39-1); 6-[[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazol[4,3-b]pyridazin-3-yl]thio]-quinoline (SGX523, CAS1022150-57-7); and (3Z)-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrrolidinyl]methylene]-1,3-dihydro-2H-indole-2-one (PHA665752, CAS 477575-56-7).

[0291] Epidermal growth factor receptor (EGFR) inhibitor: Erlotinib hydrochloride ( ), Gefitinib ( ); N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3”S”)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butyramide, ); Van der Tanis ( Lapatinib ); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514); cannabinib hydrochloride (CI-1033); 6-[4-[(4-ethyl-1-piperazinyl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788, CAS 497839-62-0); Mubritinib (TAK165); Pelitinib (EKB569); Afatinib (BIBW2992); Neratinib (HKI-272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-yl]-aminomethyl Acids, (3S)-3-morpholinomethyl ester (BMS599626); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopentan[c]pyrrolo-5-yl]methoxy]-4-aminoquinazoline (XL647, CAS781613-23-8); and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI166, CAS 187724-61-4).

[0292] EGFR antibody: Cetuximab Panitumumab () Matuzumab (EMD-72000); Trastuzumab (EMD-72000) ); Nimotuzumab (hR3); Zalutumumab; TheraCIMh-R3; MDX0447 (CAS 339151-96-1); and ch806 (mAb-806, CAS 946414-09-1).

[0293] mTOR inhibitors: Terolimus (Temsirolimus) ); Ridaforolimus (formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxa-11,36-dioxa-4-azatricyclic[30.3.1.0]); 4,9 [[C6-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinic acid ester, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03 / 064383]; Everolimus ( Or RAD001); Rapamycin (AY22989, ); Simapimod (CAS164301-51-3); (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS 1013101-36-4); N 2 -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinon-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-asparticyl-L-serine-, inner salt (SF1126, CAS 936487-67-1); and N-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxolinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methyl-benzamide (XL765, also known as SAR245409); ethyl(1r,4r)-4-(4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexanecarboxylic acid (OSI-027).

[0294] Mitogen-activated protein kinase (MEK) inhibitors: XL-518 (also known as GDC-0973, CAS No. 1029872-29-4, available from ACC Group); sermetinib (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, also known as AZD6244 or ARRY 142886, and described in PCT Publication No. WO2003077914); 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352, and described in PCT Publication No. WO2003077914). 2000035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD 0325901, and described in PCT Publication WO 2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedionitrile (also known as U0126, and described in US Patent No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (also known as RDEA119 or BAY869766, and described in PCT Publication WO 2002006213); 2007014011); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxyheterodecyn-1,7(8H)-dione] (also known as E6201 and described in PCT Publication No. WO 2003076424); 2'-amino-3'-methoxyflavone (also known as PD98059 is available from Biaffin GmbH & Co., Germany).,KG)); Vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS1035555-63-5); Pimasertib (AS-703026, CAS1204531-26-9); 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)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]azolidin-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655).

[0295] Alkylating agent: Oxaliplatin ( ); Temozolomide ( and Actinomycin D (also known as actinomycin D) ); melphalan (also known as L-PAM, L-sarcomain, and phenylalanine mustard) ); Hexamethylmelamine (also known as hexamethylmelamine (HMM)); ); Camustin ( Bendamustine ( ); Bai Xiaoan ( and Carboplatin Lomustine (also known as CCNU) ); Cisplatin (also known as CDDP, and -AQ); Chlorobutyric acid mustard ( ); Cyclophosphamide ( and ); Dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, DTIC- ); Hexamethylmelamine (also known as hexamethylmelamine (HMM)); ); ifosfamide ( Prednumustine; Procarbazine ); dichloromethyldiethylamine (also known as nitrogen mustard, nitrogen mustard hydrochloride, and dichloromethyldiethylamine hydrochloride) ); streptozotocin ( ); Thiotepa (also known as thiophosphoramide, TESPA and TSPA, ); Cyclophosphamide ( , , , , ); and bendamustine hydrochloride ( ).

[0296] Aromatase inhibitor: exemestane ( Letrozole ( ); ); and anastrozole ( ).

[0297] Topoisomerase I inhibitor: Enoxazone ( Topotecan hydrochloride ( ); and 7-ethyl-10-hydroxycamptothecin (SN38).

[0298] Topoisomerase II inhibitors: etoposide (VP-16 and etoposide phosphate, and ); Teniposide (VM-26, ); and tafluposide.

[0299] DNA synthesis inhibitors: capecitabine Gemcitabine hydrochloride ( ); Neraphine ((2R,3S,4R,5R)-2-(2-amino-6-methoxy-purine-9-yl)-5-(hydroxymethyl)oxapentane-3,4-diol, and ); and sasitabine (1-(2-cyano-2-deoxy-β-D-arabinofuryl)-4-(palmitoylamino)pyrimidin-2(1H)-one).

[0300] Folic acid antagonists or antifolate: Trimethyltroxa gluconate ( ); Pyrithione hydroxyethyl sulfonate (BW201U); Pemetrexed (LY231514); Raltitrexed ( ) and methotrexate ( , ).

[0301] Immunomodulatory agents: Atolizumab (available for purchase) ); Polyethylene glycol filgrastim ( Lenalidomide (CC-5013) ); Thalidomide ( Actimid (CC4047); and IRX-2 (a mixture of human cytokines including interleukin-1, interleukin-2, and interferon-γ, CAS 951209-71-5, available from IRXTherapeutics).

[0302] G-protein-coupled somatostatin receptor inhibitor: Octreotide (also known as octreotide acetate) and Sandostatin Lanreotide acetate (CAS127984-74-1); Siglitazone (MK678); Vaportide acetate ( ); and ring (D-Trp-Lys-Abu-Phe-MeAla-Tyr)(BIM23027).

[0303] Interleukin-11 and synthetic interleukin-11 (IL-11): Oprelvekin ( ).

[0304] Erythropoietin and its synthesis: Erythropoietin ( and ); Dapoxetine α ( ); Peggiosapeptide ( ); and EPO covalently linked to polyethylene glycol ( ).

[0305] Histone deacetylase (HDAC) inhibitor: Vorinostat (Voninostat) ); Romidepsin ( ); Treichostatin A (TSA); Oxamflatin; Voronostat ( Vorinostat; Pyroxamide (syberoyl-3-aminopyridine amide isohydroxamic acid); Trapoxin A (RF-1023A); Trapoxin B(RF-10238); Cyclic [(αS,2S)-α-amino-η-oxo-2-epoxyethylene octanoyl-O-methyl-D-tyrosinyl-L-isoleucyl-L-prolyl] (Cyl-1); Cyclic [(αS,2S)-α-amino-η-oxo-2-epoxyethylene octanoyl-O-methyl-D-tyrosinyl-L-isoleucyl-(2S)-2-piperidinyl] (Cyl-2); Cyclic [L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminoepoxyethylene octanoyl-D-prolyl] (HC-toxin); Cyclic [(αS,2S)-α-amino-η-oxo-2-epoxyethylene octanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl](WF-3161); Chlamydocin ((S)-cyclo(2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminoepoxyethylene octanoyl); Apidin (cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L-tryptophanyl-L-isoleucyl-D-2-piperidinecarbonyl); Romidepsin ( FR-901228); 4-Phenylacetic acid; Spiruchostatin A; Mylproin (valproic acid); entinostat (MS-275, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)-amino-methyl]-benzamide); and Depudecin (4,5:8,9-dianhydride-1,2,6,7,11-pentadeoxy-D-threo-D-ido-undecap-1,6-dienol).

[0306] Biological response modifiers: These include therapeutic agents such as interferon, interleukin, colony-stimulating factors, monoclonal antibodies, vaccines (for treatment and prevention), gene therapy, and nonspecific immunomodulators. Interferon α ( , -A); Interferon β; Interferon γ; Interleukin-2 (IL-2 or adeleukin, ); Ferguson ( ); Shagstine ( ); Erythropoietin (Epoetin); Interleukin-11 (Oprein); Imiquimod ( Lenalidomide ( ); Laturoximab ( ); Trastuzumab ( BCG vaccine and BCG); Levamisole ( ); and denileukindiftitox ( ).

[0307] Plant alkaloids: Taxol and Onxol TM ); Paclitaxel-binding protein ( ); Vincristine (also known as vinblastine sulfate, vincristine, and VLB, and Vincristine (also known as vincristine sulfate, LCR, and VCR) and Vincasar ) and Changchun Ruibin ( ).

[0308] Taxane antitumor agents: paclitaxel ( Dorsey ( ) ); Carbapaclitaxel ( 1-Hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytaxo-11-ene-2α,4,13α-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropionate); and lalotaxel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylchloropropionyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-epoxytaxo-11-ene-2-ylbenzoate).

[0309] Heat shock protein (HSP) inhibitors: spiramycin (17-allylamino-17-demethoxygeldromycin, also known as KOS-953 and 17-AAG, available from SIGMA and described in U.S. Patent No. 4,261,989); rispicycin (IPI504), gatspikecillin (STA-9090); [6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purine-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 (SNX5422 or PF04929113, CAS 908115-27-5); and 17-dimethylaminoethylamino-17-demethoxygerdamycin (17-DMAG).

[0310] Thrombopoietin (TpoR) agonists: Eltrombopag (SB497115), and ); and Lomilosteen ( ).

[0311] Demethylating agent: 5-azacytosine nucleoside ) and distillate ( ).

[0312] Cytokines: Interleukin-2 (also known as adefovir and IL-2, Interleukin-11 (also known as Aupre-11 interleukin, ); and α-interferon α (also known as IFN-α, A, and ).

[0313] 17α-hydroxylase / C17,20 lyase (CYP17A1) inhibitor: abiraterone acetate ( ).

[0314] Other cytotoxic agents: Arsenic ( ); Asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, and ); and Cressanase ( ).

[0315] CC chemokine receptor 4 (CCR4) antibody: Mogamulizumab ( )

[0316] CD20 antibody: Retuximab ( and ); and tosimomuzumab ( ) and ophamumab ( ).

[0317] CD20 antibody-drug conjugate: Tettan-Eritumobab ( ); and tosimomidine,

[0318] CD22 antibody drug conjugate: Ointtocilizumab (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

[0319] CD30 mAb-cytotoxin conjugate: Vitin-Brentuximab ( );

[0320] CD33 antibody-drug conjugate: Oxytocin (Ginotumab) ),

[0321] CD40 antibody: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc.);

[0322] CD52 antibody: alentozumab ( ),

[0323] Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS No. 915296-00-3)

[0324] CTLA-4 inhibitor antibodies: Tremelimumab (IgG2 monoclonal antibody, available from Pfizer, formerly known as ticilimumab, CP-675,206); and ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS number 477202-00-9).

[0325] TPH inhibitor: tertristat

[0326] PARP (poly-ADP ribose polymerase) inhibitors: olaparib (Lynparza), rucaparib (Rubraca), nireparib (Zeluja), tazoparib (Tazoparib), veliparib (Viliparib).

[0327] PD-1 inhibitors: Spartalizumab (PDR001, Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co.), Pildilizumab (CureTech), MEDI0680 (Medical Immunology), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (BeiGene), BGB-108 (BeiGene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).

[0328] PD-L1 inhibitors: duvalumab, atelizumab, avelumab

[0329] In particular, the present invention provides a method using radioactive nuclides. 177 A combination or combination therapy of Lu (lutetium-177) and a complex formed with a somatostatin receptor-binding peptide linked to a chelating agent as defined herein, or a combination or combination therapy of an aqueous solution of a drug as defined herein with one or more therapeutic agents selected from the group consisting of: octreotide, lanreotide, valproide, parreotide, satoreotide, everolimus, temozolomide, tertristat, sunitinib malate, surufatinib, libocitric acid, ennostat, and pazopanib. In certain embodiments, those combinations are used to treat NET tumors, such as GEP-NET, lung NET, pNET, lung NET, carcinoid tumor syndrome, and SCLC. In certain embodiments, the present invention provides a method of treating a patient with NET tumors (e.g., GEP-NET, lung NET, pNET, lung NET, carcinoid tumor syndrome, and SCLC) by administering a therapeutically effective amount of the components of those combinations.

[0330] In a particular embodiment, the present invention provides a radionuclide 177A combination or combination therapy of Lu (lutetium-177) and a complex formed with a somatostatin receptor-binding peptide linked to a chelating agent as defined herein, or a combination or combination therapy of an aqueous solution of a drug as defined herein with one or more tumor immunotherapeutic agents selected from the group consisting of PD-1, PD-L1, and CTLA-4 inhibitors, particularly IO therapeutic agents selected from the group consisting of spartazolizumab, nivolumab, pembrolizumab, pildizilzumab, duvalumab, atelizumab, avelumab, ipilimumab, and trimelimumab. In certain embodiments, those combinations are used to treat NET tumors, such as GEP-NET, lung NET, pNET, lung NET, carcinoid tumor syndrome, and SCLC. In certain embodiments, the present invention provides a method of treating a patient with NET tumors (e.g., GEP-NET, lung NET, pNET, lung NET, carcinoid tumor syndrome, and SCLC) by administering a therapeutically effective amount of the components of those combinations.

[0331] definition

[0332] In the following text, the terms used in this article are defined with their meanings.

[0333] The term “about” or “approximately” in this document means that the following values ​​may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, and even more preferably ±1%.

[0334] Unless otherwise defined, “%” in this document means weight percentage (wt%), also known as weight to weight percentage (w / w%).

[0335] "Total concentration": The sum of the concentrations of one or more individuals.

[0336] "Aqueous solution": A solution of one or more dissolved substances in water.

[0337] "The complex is formed through the following: "

[0338] (ai) radioactive nuclides, and

[0339] (aii) cell receptor-binding organic part linked to chelating agents:

[0340] Radioactive nuclide metal ions form non-covalent bonds with the functional groups (e.g., amines or carboxylic acids) of chelating agents. The chelating agent has at least two such complexing functional groups to be able to form a chelate complex.

[0341] In the context of this invention, the chelating agent may be...

[0342] DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

[0343] DTPA: Diethylenetriaminepentaacetic acid.

[0344] NTA: N-diazotriacetic acid,

[0345] EDTA: Ethylenediaminetetraacetic acid (EDTA)

[0346] DO3A: 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid

[0347] NOTA: 1,4,7-Triazacyclononane-1,4,7-triacetic acid

[0348] Trizoxetan

[0349] Tetraxetan

[0350] Or a mixture thereof, preferably DOTA.

[0351] "Cell receptor binding moiety": A chemical molecule whose molecule at least partially binds to a receptor molecule on the cell surface. A particularly suitable cell receptor binding moiety for this invention is a somatostatin receptor-binding peptide, preferably selected from octreotide, octreotate, lanreotide, valproide, parreotide, ilatreotide, pentetreotide, depreotide, sartoreotide, and veldoreotide, with octreotide and octreotate being the most preferred.

[0352] "Link": The cell receptor binding organic moiety is directly linked to the chelating agent or linked via a linker molecule, preferably directly. One or more linking bonds are one or more covalent or non-covalent bonds between the cell receptor binding organic moiety (and linker) and the chelating agent, preferably said one or more bonds are covalent bonds.

[0353] "Radiodegradation resistant stabilizers": These stabilizers protect organic molecules from radiodegradation. For example, when gamma rays emitted from a radionuclide break the bonds formed between atoms and free radicals in an organic molecule, those free radicals are then scavenged by the stabilizer. This prevents the free radicals from undergoing any other chemical reactions that could lead to undesirable, potentially ineffective, or even toxic molecules. Therefore, these stabilizers are also known as "free radical scavengers" or simply "radioactive scavengers." Other alternative terms for these stabilizers are "radiostability enhancers," "radioactive stabilizers," or simply "quenchers."

[0354] "In the formation of complexes of components (ai) and (aii)" period"One or more stabilizers are present": This refers to the presence of a first stabilizer and an optional second stabilizer, i.e., the presence of either the first stabilizer alone or in combination with the second stabilizer.

[0355] "In the formation of complexes" period "Presence": One or more stabilizers are present in the radionuclide solution or in a solution containing a chelating agent before the addition of these two solutions and the application of potentially elevated temperatures to promote complex formation. Preferably, the one or more stabilizers are in a solution containing a chelating agent.

[0356] "In the formation of complexes of components (ai) and (aii)" period "Only the first stabilizer exists": The first stabilizer exists, but the second stabilizer does not. In other words, only one stabilizer exists.

[0357] "Adding a second stabilizer after the formation of the complex of components (ai) and (aii): Regardless of whether the second stabilizer was already present during the complex formation process, the second stabilizer is added after the complex formation reaction is complete, for example, after the reaction solution, which may have been heated to an elevated temperature, is cooled back to ambient temperature.

[0358] The cell receptor binding moiety and the chelating agent can together form the following molecules:

[0359] DOTA-OC: [DOTA] 0 ,D-Phe 1 Octreotide,

[0360] DOTA-TOC: [DOTA] 0 ,D-Phe 1 Tyr 3 Octreotide, Edotreotide (INN),

[0361] It can be expressed by the following formula:

[0362]

[0363] DOTA-NOC: [DOTA] 0 ,D-Phe 1 ,1-Nal 3 Octreotide,

[0364] DOTA-TATE: [DOTA] 0 ,D-Phe 1 Tyr 3 Otto, DOTA-Tyr 3-Octetate, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cycles 2,7), and oxodutratide (INN) are represented by the following formulas:

[0365]

[0366] DOTA-LAN: [DOTA] 0 ,D-β-Nal 1 Lanrui peptide,

[0367] DOTA-VAP: [DOTA] 0 ,D-Phe 1 Tyr 3 [Vaporpeptide]

[0368] Tratan-Sartorepeptide

[0369]

[0370] Titan-Sartorepeptide

[0371]

[0372] Preferred "cell receptor binding moiety linked to chelating agent" molecules used in this invention are DOTA-TOC, DOTA-TATE, and tretan-sartoretide, with DOTA-TATE being more preferred.

[0373] For the present invention, the preferred complex (or preferred complex of a radionuclide and a cell receptor-binding portion linked to a chelating agent) according to the present invention is... 177 Lu-DOTA-TATE, also known as lutetium (177Lu) oxodotate (INN), is hydrogen [N-{[4,7,10-tris(carboxylic acid-κO-methyl)-1,4,7,10-tetraazacyclododecane-1-yl-κ] 4 N 1 N 4 N 7 N 10 Acetyl-κO}-D-phenylalanyl-L-cysteyl-tyrosyl-D-tryptophanyl-L-lysyl-L-threonyl-L-cysteyl-L-threonyl ring (2→7)-disulfide (4-)](177Lu)lutetate (1-)

[0374] And it is expressed by the following formula:

[0375]

[0376] "Buffer solution with pH from 4.5 to 6.0": can be an acetate buffer, a citrate buffer (e.g., citrate + HCl or citric acid + disodium hydrogen phosphate) or a phosphate buffer (e.g., sodium dihydrogen phosphate + disodium hydrogen phosphate), preferably, the buffer solution is an acetate buffer, preferably, the acetate buffer solution is composed of acetic acid and sodium acetate.

[0377] "Sequestering agent" is a chelating agent suitable for complexing radioactive nuclide metal ions, preferably DTPA: diethylenetriaminepentaacetic acid.

[0378] "For commercial use": Pharmaceutical products, such as aqueous solutions of drugs, are able to obtain (preferably have obtained) marketing authorization from health authorities (e.g., US-FDA or EMA) by complying with all pharmaceutical product quality and stability requirements required by such health agencies, are able to be manufactured (preferably have been manufactured) at a commercial scale from or at the pharmaceutical product manufacturing site, and then undergo quality control testing procedures, and are able to be supplied (preferably have been supplied) to end users in remote locations (e.g., hospitals or patients).

[0379] "Combination": The term "combination" refers to a fixed combination in the form of a single dose unit, or combined administration (where the compounds of the present invention and the combination partner (e.g., another drug explained below, also referred to as a "therapeutic agent" or "co-agent")) can be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination partner to exhibit synergistic (e.g., co-effect) effects). Individual components may be packaged in a kit or packaged separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. The terms "co-administration" or "combination administration" as used herein are intended to cover the administration of a selected combination partner to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or simultaneously. As used herein, the term "drug combination" means a product resulting from a mixture or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents (e.g., the compounds of the present invention and the combination partner) are administered simultaneously to the patient in the form of a single entity or dose. The term "non-fixed combination" means that therapeutic agents (e.g., the compounds and combination partners of the present invention) are administered to a patient as separate entities simultaneously, in parallel, or sequentially (without a specific time limit), wherein such administration provides a therapeutically effective level of two compounds in the patient's body. The latter also applies to cocktail therapy, such as the administration of three or more therapeutic agents.

[0380] Example

[0381] The invention will be described in more detail and with specific reference to examples below, but these examples are not intended to limit the invention.

[0382] Material:

[0383] 177 LuCl3 can be obtained from commercial sources, such as the Dutch company IDB (IDBHolland BV). (DOTA) 0 -Tyr 3 -Octrotate can be obtained from commercial sources, for example, by piCHEM Research and Development GmbH (piCHEMForschungs- und Entwicklungs GmbH) in Austria. All other components of the pharmaceutical product are commercially available from various sources.

[0384] Example 1: Composition of pharmaceutical products

[0385] pharmaceutical products ( 177 Lu-DOTA 0 -Tyr 3 -Octetate 370 MBq / mL infusion solution) is designed as a sterile, ready-to-use infusion solution containing 177 Lu-DOTA 0 -Tyr 3 - Octreot, as a pharmaceutical substance, has a volumetric activity of 370 MBq / mL at the reference date and time (calibration time (tc)). The calibration time (tc) corresponds to the end of production (EOP = t0), which is the time when the activity of the first QC vial was measured. The shelf life of the pharmaceutical product is defined as 72 hours after the calibration time. The pharmaceutical product is a single-dose vial containing an appropriate amount of solution that allows for the delivery of 7.4 GBq of radioactivity upon injection.

[0386] A single dose calibrated within 7.4 GBq ± 10% (200 mCi) was prepared at the manufacturing site after production. The exact activity and time to achieve this activity were provided in the analytical certificate report. This value is declared as “Injection Time: {day / month / year}{hour:minute}({DD / MM / YYYY}{hh:mm})UTC”. Taking into account the variable injection time and the constant decay of the radionuclide, the required fill volume for 7.4 GBq activity at the injection time was calculated, ranging from 20.5 to 25.0 mL.

[0387] Drug product composition / mL

[0388]

[0389] EOP: End of Production = t0 = Activity Measurement of the First Vial = Calibration Time t c

[0390] RSE: Radiostability Enhancer

[0391] Example 2: Manufacturing of pharmaceutical products

[0392] For a 74GBq batch size (2Ci batch size), 177 LuCl3 solution (approximately 74 GBq in HCl) and DOTA-Tyr 3 - An octritatate solution (approximately 2 mg) and a reaction buffer solution and buffer system (i.e., an acetate buffer system) containing an antioxidant (and a stabilizer against radioactive degradation) (i.e., gentianic acid, approximately 157 mg) are mixed to produce a total of approximately 5.5 mL of solution for radiolabeling that occurs in less than 15 minutes at a temperature of approximately 90°C to approximately 98°C.

[0393] Synthesis is performed using a single-use, disposable reagent kit installed in front of a synthesis module, which contains a fluid path (pipeline), a reactor vial, and a sealed reagent vial.

[0394] The resulting mother liquor was diluted with a solution containing a chelating agent (i.e., DTPA), an antioxidant (i.e., ascorbic acid), sodium hydroxide, and sodium chloride, and then sterilely filtered through 0.2 μm to give a ready-to-use solution as described in Example 1, with a pH of 4.5–6.0, particularly 5.2–5.3. Finally, the solution was dispensed into sterile vials at volumes of 20.5 to 25.0 mL. The stoppered vials were sealed in lead containers for protective shielding.

[0395] The manufacturing method can also achieve batch sizes greater than 74 GBq. In this case, the amounts of raw materials (lutetium, peptides, and reaction buffer) are multiplied to ensure the same raw material ratio.

[0396] Example 3: Results of stability studies after storage under various temperature conditions.

[0397] The table below provides stability test data for batches produced in 74GBq batches according to the method described in Example 2.

[0398] “nd” = Undetermined; “LOD” = Detection Limit

[0399]

[0400]

[0401] Very similar good stability results were obtained for batches produced in 148GBq batch sizes.

Claims

1. A method for preparing an aqueous solution of a drug, the method comprising diluting an aqueous complex solution with an aqueous diluent to form the aqueous solution of the drug; in, The aqueous complex solution contains: (a) a radioactive nuclide; (ai) a radioactive nuclide. 177 A complex of Lu (lutetium-177) and (aii) with a somatostatin receptor-binding peptide linked to the chelating agent DOTA, and (b) at least one stabilizer resistant to radioactive degradation; and The aqueous diluent contains at least one stabilizer that resists radioactive degradation, including ascorbic acid or a salt thereof. The radionuclide is present in the aqueous drug solution at a concentration providing volumetric radioactivity from 250 to 500 MBq / mL, and the total concentration of the one or more radioactive degradation stabilizers in the aqueous drug solution is from 0.5 mg / mL to 10.0 mg / mL. According to HPLC analysis, the radiochemical purity of the aqueous drug solution, when stored at 25°C, can be maintained at ≥95% for at least 72 hours; and The ethanol content of the aqueous solution of the drug is less than 2%.

2. The method according to claim 1, wherein the aqueous diluent contains ascorbic acid or a salt thereof as the sole anti-radioactive degradation stabilizer.

3. The method according to claim 1, wherein the total amount of the at least one anti-radioactive degradation stabilizer in the aqueous complex solution is from 15 mg / mL to 50 mg / mL.

4. The method according to claim 1, wherein the somatostatin receptor-binding peptide and the chelating agent together form a molecule selected from DOTA-OC, DOTA-TOC (edotoxotritide), DOTA-NOC, DOTA-TATE (ozodeotoxotritide), DOTA-LAN, DOTA-VAP and Satoreotide tetraxetan.

5. The method according to claim 4, wherein the somatostatin receptor-binding peptide and the chelating agent together form a molecule selected from DOTA-TOC, DOTA-TATE, and Satoreotide tetraxetan.

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

7. An aqueous solution of a drug prepared according to the method of claim 1.

8. The aqueous drug solution according to claim 7, wherein the activity of the aqueous drug solution is 7.4 GBq ± 10%.

9. The aqueous drug solution according to claim 7, wherein the total concentration of the one or more stabilizers in the aqueous drug solution is from 1.0 mg / mL to 5.0 mg / mL.

10. The aqueous solution of the drug according to claim 7, wherein the aqueous solution of the drug contains 2.0 mg / mL to 5.0 mg / mL of ascorbic acid or a salt thereof.

11. The aqueous solution of the drug according to claim 9, wherein the aqueous solution of the drug contains 2.0 mg / mL to 5.0 mg / mL of ascorbic acid or a salt thereof.

12. The aqueous drug solution according to claim 7, wherein the aqueous drug solution contains less than 1% ethanol.

13. The aqueous solution of a drug according to claim 9, wherein the aqueous solution of a drug contains less than 1% ethanol.

14. The aqueous drug solution of claim 11, wherein the aqueous drug solution contains less than 1% ethanol.

15. The aqueous drug solution according to claim 7, wherein the aqueous drug solution is a ready-to-use single-dose aqueous drug solution or is provided in multiple-dose units.

16. The aqueous solution of a drug according to claim 12, wherein the aqueous solution of a drug does not contain ethanol.

17. The aqueous drug solution according to claim 7, wherein the aqueous drug solution further comprises a chelating agent.

18. The aqueous solution of the drug according to claim 17, wherein the chelating agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

19. The aqueous solution of a drug according to claim 18, wherein the content of DPTA or a salt thereof is such that the concentration in the aqueous solution of the drug is from 0.01 mg / mL to 0.10 mg / mL.

20. The aqueous drug solution according to claim 7, wherein the aqueous drug solution is contained in a dosage unit container sealed within a lead container in a volume of 10 mL to 50 mL.

21. The aqueous drug solution according to claim 7, wherein the aqueous drug solution is contained in a stoppered vial sealed in a lead container in a volume of 10 mL to 50 mL.

22. The aqueous solution of the drug according to claim 7, used to treat tumors in patients in need.

23. The aqueous solution of the drug for use according to claim 22, wherein administration is by injection or infusion.

24. The aqueous solution of the drug for use according to claim 22, wherein 10 mL to 50 mL of the aqueous solution of the drug is administered to the patient.

25. The aqueous drug solution for use according to claim 22, wherein the aqueous drug solution is administered to the patient over a period of about 20 minutes to about 30 minutes.

26. The aqueous solution of the drug for use according to claim 22, wherein the dose administered to the patient is 7.4 GBq ± 10%.

27. The aqueous solution of the drug according to claim 22, wherein the tumor is a neuroendocrine tumor (NET).

28. The aqueous solution of the drug according to claim 22, wherein the tumor is selected from gastrointestinal and pancreatic neuroendocrine tumors, neuroendocrine carcinoid tumors, neuroendocrine small cell lung cancer, neuroendocrine glioma, neuroendocrine prostate cancer, neuroendocrine meningioma, neuroendocrine neuroblastoma, neuroendocrine paraganglioma, neuroendocrine pheochromocytoma, pulmonary NET, neuroendocrine medullary thyroid carcinoma, neuroendocrine breast cancer, neuroendocrine head and neck tumors, and pancreatic neuroendocrine tumors, neuroendocrine thymic carcinoma, and lung NET.

29. The aqueous solution of the drug according to claim 22, wherein the tumor is a gastrointestinal pancreatic neuroendocrine tumor.

30. The aqueous solution of the drug for use according to claim 29, wherein 10 mL to 50 mL of the aqueous solution of the drug is administered to the patient.

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