Stable concentrated radionuclide complex solutions

Abstract

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

Description

[Technical Field]

[0001] The present invention provides high concentrations of hydroxybenzoates that allow their use as commercial pharmaceutical products for diagnostic and / or therapeutic purposes. The present invention also relates to a radionuclide complex solution with high chemical and radiochemical stability. [Background technology]

[0002] The concept of targeted drug delivery is based on the discovery of a cellular receptor that is overexpressed in target cells as opposed to non-target cells. Receptor-based drugs have binding sites for such overexpressed cell receptors. If so, after systemic administration, it will target these cells while leaving other unrelated cells unaffected. This allows for the delivery of high concentrations of drugs. For example, when tumor cells overexpress specific cell receptors, If the receptor is characterized by its binding affinity, then the drug having binding affinity to the receptor is After intravenous injection, it will accumulate in high concentrations in tumor tissue, leaving normal tissue unaffected.

[0003] This targeted drug delivery concept also involves selectively delivering radionuclides to target cells for diagnostic or therapeutic purposes. In this radiopharmaceutical application, target cell receptors are activated. The binding moiety is typically a chelating moiety capable of forming a strong complex with the metal ion of the radionuclide. This radiopharmaceutical agent is then delivered to the target cell and then radioactively Decay of nuclides produces high energy electrons, positrons, or alpha particles, as well as gamma rays, at the target site. Release.

[0004] One of the technical problems associated with such radiopharmaceutical drug products is the Decay of radionuclides occurs constantly during storage, and the released high-energy emissions are released into the pharmaceutical product. The act of inducing the cleavage of chemical bonds in molecules that form part of the molecule. This is called radiolysis or radiation. Radiolytic degradation of the receptor-binding portion of a drug is often referred to as radiolytic degradation. and / or may result in a decrease in its efficacy as a therapeutic agent.

[0005] The stability of such radiopharmaceutical products is insufficient, limiting any of their significant shelf life. Due to the lack of life expectancy, so far, the drug has only been administered in hospital laboratories as individual patient doses. The drug must be manufactured and administered immediately to patients who are already waiting for radiological treatment. It was necessary to have the patient present at the hospital. Cell receptor binding moieties linked to chelators without the use of radionuclides to promote "Cold" (i.e., non-radioactive) freeze-dried kits containing The freeze-dried contents of these kit vials are then thawed shortly before administration. The solution must be reconstituted (Das et al. J Radioanal Nucl Chem 2014,299,1389-1398, Das et al. Current Radiopharmaceuticals 2014,7,12-1 9, Luna-Gutierrez et al.J Radioanal Nucl Chem 2017,314,2181-2188). However, such kits Before the drug can finally be administered, it may undergo a reconstitution step as well as further processing steps (e.g., "Ready to use" as it requires purification and sterilization steps (heat application for the complexation reaction) isn't it.

[0006] Various strategies have been developed to reduce radiolysis and improve the stability of radiopharmaceutical products. Therapeutic methods have been explored with more or less success: storing pharmaceutical products at low temperatures; The formulation may be diluted or made at a high dilution or stabilizers may be added.

[0007] However, when stabilizers are added, such chemicals can bind radionuclides to chelating agents. may adversely affect complexation of the This can be problematic as ethanol is a stabilizer against radiolysis. It has been reported as an agent for the treatment of ethanol (International Publication No. WO 2008 / 009444). Although ethanol may not adversely affect complexation or solubility issues, the ethanol in the injection solution Higher doses may be physiologically problematic and may affect the tolerability of the drug product. There is a risk of adverse effects.

[0008] The disadvantage of producing highly diluted drug products is that large volumes of infusion solution must be administered to patients. For patient convenience and drug tolerability reasons, a highly concentrated radiopharmaceutical product is provided. However, such highly concentrated solutions may be highly detrimental to the Therefore, on the one hand, dilution of pharmaceutical products avoids radiolysis. On the other hand, there is a contradiction between providing a concentrated drug solution to avoid patient discomfort during treatment. Mathur et al. Cancer Biotherap y and Radiopharmaceuticals,2017,32(7),26 6-273 reports and claims that the highly concentrated product is ready to use. However, its composition contains a large amount of ethanol, which may cause problems with tolerance. There is a gender. Summary of the Invention [Problem to be solved by the invention]

[0009] Therefore, it can be manufactured on a commercial scale and has small injection volumes for patient convenience. and to develop compositions that are physiologically tolerable (e.g., ethanol-free compositions). A ready-to-use radiopharmaceutical agent deliverable as a highly concentrated, sufficiently stable sterile solution having The challenge remains to design therapeutic products. [Means for solving the problem]

[0010] The present inventors have now discovered a commercially available and ready-to-use radiopharmaceutical. As a product available for supply, it is chemically stable even when stored at ambient temperature or at short-term elevated temperatures. and to find a method for designing and producing a highly radiochemically stable high-concentration radionuclide complex solution. I did.

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

[0012] (a) Below: (ai) a radionuclide; (aii) a cell receptor-binding organic moiety linked to a chelator; and a complex formed by (b) at least one stabilizer against radiolytic degradation; Including, The radionuclide has a concentration of at least 100MBq / mL, preferably at least 250MBq / mL present at a concentration that provides a volumetric radioactivity of q / mL, Pharmaceutical aqueous solutions.

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

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

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

[0016] The present invention provides the following advantages:

[0017] High concentrations allow for the administration of high doses within a short time frame. For example: 177 Lu-D For OTA-TATE, IV administration should be completed within approximately 20-30 minutes. A high dose of 7.4 GBq can be delivered with a small volume of 25.0 mL.

[0018] Using the preferred stabilizers of the present invention described herein, after 72 hours at 25°C Regarding the chemical purity of the cell receptor-binding molecule, this molecule was a sensitive peptide molecule. At least 95%, 96%, 97%, 98%, 99%, or 100% chemical For example, DOTA-TATE has a high stability at 25°C. 100% chemical purity was found after 72 hours, even after 48 hours at 32°C. Even under short-term elevated temperature conditions (12 h at 32°C and 60 h at 25°C), the chemical purity was Such high stability was found for

[0019] Furthermore, the use of the preferred stabilizers of the present invention described herein allows for the radionuclide complexes to be High radiochemical stability of at least 95% is ensured for the radiochemical purity of the compound. For example, 177 In the case of Lu-DOTA-TATE, after 72 hours at 25°C, Radiochemical purity of at least 95% was found. Such high stability in terms of radiochemical purity was found even after 60 h at 25°C. Ta.

[0020] Although sufficient stability can already be achieved with one single stabilizer, the use of two stabilizers It has been found that the complex is particularly suitable for stabilizing sensitive radiopharmaceutical solutions. If there is one stabilizer during synthesis and another stabilizer added after complex formation, The complexation reaction protects the cell receptor-binding molecule from radiolysis and also improves storage stability. Advantageously, this ensures that other stabilizers will have an enhancing protective effect over the lifespan.

[0021] Furthermore, this sequential application of two stabilizers results in relatively small amounts of stabilizers being released upon complexation. The presence of a stabilizer minimizes the possibility of its interference with the complexation reaction. (limited to a certain amount), and after complexation, a large amount of the stabilizer combination is present (hence the need for subsequent drug preparation). This ensures that the product is protected (the protection of the stabilizer is enhanced over the product's shelf life).

[0022] Furthermore, this sequential application of two stabilizers allows the complexation reaction to proceed at elevated temperatures. The absence of one of them reduces the overall heat stress of such stabilizers. .

[0023] Furthermore, especially when two different stabilizers are used, this combination is more effective than a single stabilizer. Rather than stabilizers, each compound that may be formed by radiolysis of the cell receptor binding molecule is This is advantageous because the reaction to different types of radicals is efficient.

[0024] The composition of the radiopharmaceutical solution does not require the presence of ethanol. The absence of ethanol is advantageous with regard to the physiological tolerability of the solution.

[0025] To enable the production of radiopharmaceutical drug products from centralized pharmaceutical manufacturing sites and ready-to-use A shelf life of at least 3 days is required to commercialize it as a viable drug product. do.

[0026] Therefore, thanks to its high stability (72 h at 25°C), the invention is able to meet the highest quality standards ( (e.g., cGMP) and industrial scale, e.g., treating 10-20 patients simultaneously. 74GBq or 148GBq to provide pharmaceutical products in multiple dose units, such as dose units sufficient for q batch sizes allow for centralized pharmaceutical manufacturing.

[0027] Furthermore, due to its high stability, the present invention allows for the delivery of pharmaceuticals from centralized pharmaceutical manufacturing sites to remote clinical centers. There is enough time to transport it to

[0028] Furthermore, due to its high stability, the present invention requires no preparation by clinical staff prior to administration. A ready-to-use infusion that can be administered to a patient immediately without the need for any work to be performed It can be provided as a solution.

[0029] The present invention relates to somatostatin receptor-binding peptides, In particular, we investigated the extremely sensitive somatostatin analogue octreotide, which is particularly susceptible to degradation reactions. Furthermore, the present invention provides specific radioactive properties. The radionuclide lutetium-177 is particularly suitable. DETAILED DESCRIPTION OF THE INVENTION

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

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

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

[0033] Generally, the stabilizer used in accordance with the present invention is gentisic acid (2,5-dihydro ascorbic acid (L-ascorbic acid, vitamin C) or its salts, salts (e.g., sodium ascorbate), methionine, histidine, melatonin, The preferred stabilizer may be selected from gentisic acid, ethanol, and Se-methionine. or a salt thereof and ascorbic acid or a salt thereof.

[0034] Ethanol is not recommended because of the tolerance issues associated with it when present in higher concentrations. Ethanol is not considered a very preferred stabilizer in the solutions of the present invention. should be avoided (in other words, ethanol-free), and at least the ethanol content of the solution of the present invention should be The amount of ethanol in the final solution expected to be injected / infused should be, for example, less than 5%, preferably It should be limited to less than 2%, more preferably less than 1%. , the solution is ethanol-free.

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

[0036] 1. (a) Below: (ai) a radionuclide; (aii) a cell receptor-binding organic moiety linked to a chelator; and a complex formed by (b) at least one stabilizer against radiolytic degradation; Including, The radionuclide has a concentration of at least 100MBq / mL, preferably at least 250MBq / mL present at a concentration that provides a volumetric radioactivity of q / mL, Pharmaceutical aqueous solutions.

[0037] 2. The stabilizer (component (b)) is at least 0.2 mg / mL, preferably at least at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, and even more preferably or present at a total concentration of at least 2.7 mg / mL, 2. The pharmaceutical aqueous solution of embodiment 1.

[0038] 3. The radionuclide is 100 to 1000 MBq / mL, preferably 250 to 500 Any one of embodiments 1 or 2, wherein the radioactivity is present in a concentration providing a volumetric activity of MBq / mL. 10. The pharmaceutical aqueous solution according to claim 9.

[0039] 4. The stabilizer is 0.2 to 20.0 mg / mL, preferably 0.5 to 10.0 mg / mL. g / mL, more preferably 1.0 to 5.0 mg / m, and even more preferably 2.7 to 4. 4. The pharmaceutical aqueous solution of any one of embodiments 1 to 3, wherein the pharmaceutical aqueous solution is present in a total concentration of 1 mg / mL. liquid.

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

[0041] 6. Component (b) contains at least two stabilizers against radiolytic degradation, namely At least a first and a second stabilizer, preferably only two stabilizers, i.e., a first and a second stabilizer. 2 stabilizers only, 6. The aqueous medicinal solution according to any one of embodiments 1 to 5.

[0042] 7. The first stabilizer is 0.2 to 5 mg / mL, preferably 0.5 to 5 mg / mL, More preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, and even more preferably, it is 0.5 to 2 mg / mL. More preferably, the compound according to any one of embodiments 5 to 6 is present in a concentration of 0.5 to 0.7 mg / mL. The pharmaceutical aqueous solution according to any one of claims 1 to 4.

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

[0044] 9. The stabilizer is gentisic acid (2,5-dihydroxybenzoic acid) or its salt, aspartame Ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g., sodium ascorbic acid) ascoorbate), methionine, histidine, melatonin, ethanol and Se-methionine, preferably gentisic acid or a salt thereof and ascorbic acid. 9. The pharmaceutical aqueous solution according to any one of embodiments 1 to 8, wherein the pharmaceutical aqueous solution is selected from the group consisting of benzoic acid and benzoyl carboxylic acid and salts thereof. liquid.

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

[0046] 11. The second stabilizer is selected from gentisic acid and ascorbic acid, preferably The medicament of any one of embodiments 6 to 10, wherein the second stabilizer is ascorbic acid. Aqueous solution.

[0047] 12. The first stabilizer is gentisic acid or a salt thereof and the second stabilizer is aspartame. corbic acid or its salt, and the concentration of the first stabilizer (in mg / mL) and the concentration of the second stabilizer The ratio of the concentration of the stabilizer (mg / mL unit) is 1:3 to 1:7, preferably 1:4 to 1:5. 9. The aqueous medicinal solution according to any one of embodiments 6 to 8.

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

[0049] 14. The cell receptor binding portion is a somatostatin receptor binding peptide, and preferably Preferably, the somatostatin receptor-binding peptide is octreotide, octreotide, lanreotide, vapreotide, and pasireotide, preferably octotreat. 14. The composition according to any one of embodiments 1 to 13, wherein the compound is selected from octreotide and octreotate. Pharmaceutical aqueous solutions.

[0050] 15. Chelating agents include DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA. 1. The pharmaceutical aqueous solution according to claim 1.

[0051] 16. The cell receptor binding moiety and the chelator together form DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxo dotreotide), DOTA-LAN, and DOTA-VAP, preferably DOTA-TOC and DOTA-TATE are selected, more preferably DOTA-T 16. The pharmaceutical aqueous solution according to any one of embodiments 1 to 15, which forms a molecule that is an ATE. .

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

[0053] 18. The method further comprises the step of: Acetic acid at a concentration of 0.4 to 0.9 mg / mL (preferably about 0.48 mg / mL) and (preferably about 0.66 mg / mL) sodium acetate and an amount of acetate buffer to provide 18. The aqueous medicinal solution according to any one of embodiments 1 to 17.

[0054] 19. Further comprising a sequestering agent, preferably the sequestering agent is or to a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL). 19. The method of claim 1, wherein the amount of diethylenetriaminepentaacetic acid (DTPA) or a salt thereof is 10. The pharmaceutical aqueous solution according to any one of the preceding claims.

[0055] 20. At least 24 hours (h) at ≦25℃, at least 48h at ≦25℃, At least 72 hours at 25°C, 24 hours to 120 hours at 25°C or less, 24 hours to 96 hours at 25°C or less, Shelf life is 24-84 hours at 5°C and 24-72 hours at ≦25°C, especially ≦25°C 20. The pharmaceutical aqueous solution of any one of embodiments 1 to 19, having a shelf life of 72 h at RT.

[0056] 21. The solution is produced in a commercial scale, particularly at least 20 GBq, In embodiments 1 to 5, the ion exchange membrane is produced in a batch size of at least 50 GBq, at least 70 GBq. 20. A pharmaceutical aqueous solution according to any one of claims 1 to 20.

[0057] 22a. A ready-to-use aqueous pharmaceutical solution according to any one of embodiments 1 to 21. .

[0058] 22b. A pharmaceutical aqueous solution according to any one of embodiments 1 to 22a, which is for commercial use.

[0059] 23. (a) Below: (ai) A radioactive substance present in a concentration that provides a volumetric activity of 250 to 500 MBq / mL nuclide 177 Lutetium (Lu-177) and (aii) Somatostatin receptor-binding organic moiety DO linked to a chelator TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and a complex formed by (bi) Primary stabilization against radiolytic degradation at concentrations of 0.5-1 mg / mL gentisic acid or a salt thereof as an agent; (bii) Secondary resistance to radiolytic degradation present at concentrations of 2.0 to 5.0 mg / mL ascorbic acid or a salt thereof as a stabilizer; 1. A pharmaceutical aqueous solution comprising:

[0060] 24. (c) Diethylenetriaminepentaacetic acid ( DTPA) or a salt thereof, 24. The pharmaceutical aqueous solution of embodiment 23, further comprising:

[0061] 25. (d) Acetic acid at concentrations of 0.3 to 0.7 mg / mL and 0.4 to 0.9 mg / mL Sodium acetate at a concentration of 25. The pharmaceutical aqueous solution of embodiment 23 or 24, further comprising:

[0062] 26. A stabilizer is present in solution during the complexation of components (ai) and (aii). 26. The aqueous medicinal solution according to any one of embodiments 1 to 25.

[0063] 27. The first stabilizer alone is preferably present at a concentration of 0.5-5 mg / mL in the final solution, more preferably Preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, even more preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, and more preferably in amounts resulting in a concentration of 0.5 to 0.7 mg / mL of components (ai) and (ai The pharmaceutical aqueous solution according to any one of embodiments 5 to 26, which is present during the formation of the complex i).

[0064] 28. A portion of the amount of the second stabilizer is present during the complexation of components (ai) and (aii). Another part of the amount of the second stabilizer is already present in the solution and is added to the components (ai) and (aii) 28. The pharmaceutical aqueous solution of any one of embodiments 6 to 27, wherein said aqueous solution is added after complexation of

[0065] 29. A method for producing a complex of components (ai) and (aii) in which a second stabilizer is added after the complexation of components (ai) and (aii) The medicinal aqueous solution according to any one of embodiments 6 to 28.

[0066] 30. The second stabilizer is preferably present in a final solution at a concentration of 0.5 to 10 mg / mL, more preferably or 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, More preferably, in an amount resulting in a concentration of 2.2 to 3.4 mg / mL, The pharmaceutical aqueous solution of embodiment 6 or 29, which is added after complexation of (aii).

[0067] 31. Complex forms of components (ai) and (aii) to remove any uncomplexed Lu The method further comprises adding a sequestering agent after synthesis, preferably comprising: Preferably, the final solution is 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL diethylenetriaminepentaacetic acid (DTPA) or a salt thereof in an amount to provide a concentration of 31. The pharmaceutical aqueous solution according to any one of embodiments 1 to 30.

[0068] 32. (1) The following: (1.1) preparing an aqueous solution containing a radionuclide; (1.2) a cell receptor-binding organic moiety linked to a chelator and a first stable preparing an aqueous solution comprising a stabilizing agent and, optionally, a second stabilizing agent; (1.3) A mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2) and heating the by combining a radionuclide with a cell receptor-binding organic moiety linked to a chelator. a process step of forming a complex; (2) The following: (2.1) preparing an aqueous dilution solution optionally containing a second stabilizer; (2.2.) The complex solution obtained in step (1) and the complex solution obtained in step (2.1) a diluted solution; and a process step of diluting the complex solution obtained in step (1) by 32. A process for producing the aqueous pharmaceutical solution of any one of embodiments 1 to 31, comprising:

[0069] 33. The first stabilizer alone is preferably present at a concentration of 0.5-5 mg / mL in the final solution, more preferably Preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, even more preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, Preferably, the amount of the compound present in step (1.3) is in an amount that results in a concentration of 0.5 to 0.7 mg / mL. 33. The process of embodiment 32, wherein

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

[0071] 35. The second stabilizer is added in step (2.1) after step (1.3), in an embodiment 35. The aqueous medicinal solution according to any one of aspects 32 to 34.

[0072] 36. The second stabilizer is preferably present in a final solution at a concentration of 0.5-10 mg / mL, more preferably or 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, More preferably, in an amount that results in a concentration of 2.2 to 3.4 mg / mL, 36. The pharmaceutical aqueous solution according to any one of embodiments 32 to 35, which is subsequently added in step (2.1). solution.

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

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

[0075] 39. The solution in step (2.1) contains diethylenetriaminepentaacetic acid (DTPA) or its salts. 39. The process of any one of embodiments 32 to 38, further comprising:

[0076] 40. (3) A process of filtering the solution obtained in step (2) through a 0.2 μm filter The process and (4) The filtered solution obtained in step (3) is diluted with 5.0 to 10 MBq, preferably 7.0 ~8.0MBq, more preferably 7.3-7.7MBq, even more preferably 7.4- Dispense into dose unit containers in the amount required to deliver a radiation dose of 7.5 MBq. In the process step, the amount is preferably 10 to 50 mL, more preferably 15 to 30 mL. L, and even more preferably 20-25 mL; 40. The process of any one of embodiments 32 to 39, further comprising:

[0077] 41. The method of any one of embodiments 32 to 40, wherein the solution in step (1.1) comprises LuCl3 and HCl. 10. The process according to any one of claims 1 to 9.

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

[0079] 43. Embodiments 32 to 34, wherein the solution in step (2.1) comprises DTPA and ascorbic acid. 42. The process according to any one of claims 1 to 42.

[0080] 44. The dose unit container in step (4) is a stoppered vial sealed in a lead container. 44. The process of any one of embodiments 32 to 43, wherein

[0081] 45. A method for producing a compound obtained by (or obtained from) the process according to any one of claims 32 to 44. (possibly a pharmaceutical aqueous solution).

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

[0083] E1. (a) Below: (ai) radionuclide 177 Lu (lutetium-177) and (aii) Somatostatin receptor binding peptide linked to the chelator DOTA Chid and and a complex formed by (b) at least two different stabilizers against radiolytic degradation; Including, the radionuclide is present in a concentration that provides a volumetric activity of 250 to 500 MBq / mL; and the stabilizer is present at a total concentration of 0.2 to 20.0 mg / mL; Pharmaceutical aqueous solutions.

[0084] "A complex formed by" may alternatively be expressed as "a complex of" That is why.

[0085] The term "different" in "two different stabilizers" refers to the chemical entities of such stabilizers. "Two different stabilizers" means that the two stabilizers are different chemical entities. For example, gentisic acid and ascorbic acid are two different It is a stabilizer.

[0086] "At least two" means two or more, but preferably exactly two stabilizers. This means that there are three or more stabilizers present. Ethanol is one of two stabilizers. It is even more preferable that it is not.

[0087] E2. The component (b) is a stabilizer: (bi) gentisic acid or a salt thereof; (bii) ascorbic acid or a salt thereof; Including, The pharmaceutical aqueous solution of embodiment E1.

[0088] E3. (bi) Gentisic acid is 0.5 to 2 mg / mL, preferably 0.5 to 1 mg / mL mL, and (bii) ascorbic acid is present at a concentration of 2.0 to 5.0 mg / mL; The pharmaceutical aqueous solution of embodiment E2.

[0089] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: (a) Below: (ai) A radionuclide at a concentration that provides a volumetric activity of 250 to 500 MBq / mL 17 7 Lu (lutetium-177) and (aii) Somatostatin receptor binding peptide linked to the chelator DOTA Chid and and a complex formed by (b) stabilizers against radiolytic degradation; (bi) gentisic acid at a concentration of 0.5 to 1 mg / mL; (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL; a pharmaceutical aqueous solution comprising to provide.

[0090] E4. (c) Diethylenetriaminepentaacetic acid ( DTPA) or a salt thereof, The pharmaceutical aqueous solution of embodiment E3, further comprising:

[0091] E5. (d) Below: (di) acetic acid at a concentration of 0.3 to 0.7 mg / mL; (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL; an acetate buffer consisting of further comprising Preferably, the acetate buffer has a pH of 4.5 to 6.0, preferably 4.7 to 6.0, more preferably Preferably, the pH is 5.0 to 6.0, and even more preferably 5.0 to 5.5. The pharmaceutical aqueous solution of embodiment E3 or E4.

[0092] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: (a) Below: (ai) A radionuclide at a concentration that provides a volumetric activity of 250 to 500 MBq / mL 17 7 Lu (lutetium-177) and (aii) Somatostatin receptor binding peptide linked to the chelator DOTA Chid and and a complex formed by (b) a stabilizer against radiolytic degradation, (bi) a gen at a concentration of 0.5-1 mg / mL (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL ) or a salt thereof, (d) Below: (di) acetic acid at a concentration of 0.3 to 0.7 mg / mL; (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL; an acetate buffer consisting of Including, Preferably, the acetate buffer provides a pH of 5.0 to 5.5. A medicinal aqueous solution is provided.

[0093] The pH values ​​specified herein are the pH values ​​of the final solution. It is also the pH at the time of preparation of the solution, for example, the pH at the time of complex formation.

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

[0095] E7. At least gentisic acid is present during the complex formation of components (ai) and (aii). and at least ascorbic acid is added after the complexation of components (ai) and (aii). The aqueous medicinal solution of any one of embodiments E1 to E5.

[0096] E8. When components (ai) and (aii) are complexed, the only stabilizer present is gentamicin. The only stabilizing agent added after the complexation of components (ai) and (aii) is a hydroxy acid. The pharmaceutical aqueous solution of any one of embodiments E1-E5, wherein the agent is ascorbic acid.

[0097] In certain embodiments, the present invention provides a method for producing a pharmaceutical composition comprising: (a) Below: (ai) A radionuclide at a concentration that provides a volumetric activity of 250 to 500 MBq / mL17 7 Lu (lutetium-177) and (aii) Somatostatin receptor binding peptide linked to the chelator DOTA Chid and and a complex formed by (b) stabilizers against radiolytic degradation; (bi) gentisic acid at a concentration of 0.5-1 mg / mL (in the final solution); (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL (in the final solution); Including, When components (ai) and (aii) are complexed, gentisic acid is present, and component (ai) and (aii) complexation followed by the addition of ascorbic acid; A medicinal aqueous solution is provided.

[0098] In certain embodiments, the present invention is defined as follows: (a) Below: (ai) A radionuclide at a concentration that provides a volumetric activity of 250 to 500 MBq / mL 17 7 Lu (lutetium-177) and (aii) Somatostatin receptor binding peptide linked to the chelator DOTA Chid and and a complex formed by (b) a stabilizer against radiolytic degradation, (bi) a gen at a concentration of 0.5-1 mg / mL (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL ) or a salt thereof, (d) Below: (di) acetic acid at a concentration of 0.3 to 0.7 mg / mL; (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL; an acetate buffer consisting of Including, Preferably, the acetate buffer provides a pH of 5.0 to 5.5; When components (ai) and (aii) are complexed, gentisic acid is present, and component (ai) and (aii) complexation followed by the addition of ascorbic acid; Pharmaceutical aqueous solutions.

[0099] E9. One or more stabilizers present during the complexation of components (ai) and (aii) However, when the complex is formulated, the total concentration is 15 to 50 mg / mL, preferably 20 to 40 mg / mL. The pharmaceutical aqueous solution of any one of embodiments E6 to E8, wherein

[0100] E10. The only stabilizer present during the complexation of components (ai) and (aii) is gen and when the complex is formulated, the concentration is 20 to 40 mg / mL, preferably 25 to 35 mg / mL. The pharmaceutical aqueous solution of embodiment E9, wherein the pharmaceutical aqueous solution is present in a concentration of 100 mL / min.

[0101] In certain embodiments, the present invention is defined as follows: (a) Below: (ai) A radionuclide at a concentration that provides a volumetric activity of 250 to 500 MBq / mL 17 7 Lu (lutetium-177) and (aii) Somatostatin receptor binding peptide linked to the chelator DOTA Chid and and a complex formed by (b) a stabilizer against radiolytic degradation, (bi) a gen at a concentration of 0.5-1 mg / mL (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL ) or a salt thereof, (d) Below: (di) acetic acid at a concentration of 0.3 to 0.7 mg / mL; (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL; an acetate buffer consisting of Including, Preferably, the acetate buffer provides a pH of 5.0 to 5.5; When components (ai) and (aii) are complexed, gentisic acid is present, and component (ai) After complexation of components (ai) and (aii), ascorbic acid is added, and components (ai) and (ai i) The only stabilizer present during complex formation is gentisic acid, and 2 present at a concentration of 0 to 40 mg / mL, preferably 25 to 35 mg / mL; Pharmaceutical aqueous solutions.

[0102] Embodiments E6-E10 may alternatively be defined by the following expressions:

[0103] E6. The presence of at least one stabilizer when forming the complex of components (ai) and (aii). and after the complexation of components (ai) and (aii), adding at least one stabilizer The aqueous pharmaceutical composition of any one of embodiments E1 to E5, wherein the aqueous pharmaceutical composition is prepared by adding solution.

[0104] E7. When forming the complex of components (ai) and (aii), at least gentisic acid is present. and after the complexation of components (ai) and (aii), at least ascorbic acid is added. The pharmaceutical aqueous solution of any one of embodiments E1 to E5, which is prepared by adding liquid.

[0105] E8. Genticin as the sole stabilizer in the complex formation of components (ai) and (aii) In the presence of an acid, the compound (ai) acts as the only stabilizer after complexation of components (ai) and (aii). and adding ascorbic acid to the mixture. 1. The pharmaceutical aqueous solution according to claim 1.

[0106] E9. The complexation of components (ai) and (aii) is carried out in the presence of one or more stabilizers. At the time of complex formation, the concentration is 15 to 50 mg / mL, preferably 20 to 40 mg / mL. any one of embodiments E6 to E8, wherein the total concentration of A medicinal aqueous solution of.

[0107] E10. Gentism as the only stabilizer in the complexation of components (ai) and (aii) The complex is mixed in the presence of phosphate and at a concentration of 20 to 40 mg / mL, preferably 25 to 35 The pharmaceutical aqueous solution of embodiment E9, wherein the pharmaceutical aqueous solution is prepared by presenting the pharmaceutical aqueous solution at a concentration of 100 mg / mL. liquid.

[0108] In embodiments of the invention, particularly in embodiments E9 and E10, the radionuclide is complexed up to 20 GBq / mL, preferably up to 15 GBq / mL, or 5 to 20 GBq / mL L, preferably 10 to 20 GBq / mL, more preferably 10 to 15 GBq / mL It may be present in a concentration that provides radioactivity.

[0109] In certain embodiments, the present invention is defined as follows: (a) Below: (ai) A concentration that provides a volumetric activity of 250-500 MBq / mL (in the final solution) radionuclides 177 Lu (lutetium-177) and (aii) Somatostatin receptor binding peptide linked to the chelator DOTA Chid and and a complex formed by (b) a stabilizer against radiolytic degradation, (bi) a gen at a concentration of 0.5-1 mg / mL (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL ) or a salt thereof, (d) Below: (di) acetic acid at a concentration of 0.3 to 0.7 mg / mL; (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL; an acetate buffer consisting of Including, Preferably, the acetate buffer provides a pH of 5.0 to 5.5; When components (ai) and (aii) are complexed, gentisic acid is present, and component (ai) After complexation of components (ai) and (aii), ascorbic acid is added, and components (ai) and (ai i) The only stabilizer present during complex formation is gentisic acid, and 2 It exists at a concentration of 0-40mg / mL and the radionuclide has a concentration of 10-20GBq / present in a concentration that provides a volumetric radioactivity of mL, Pharmaceutical aqueous solutions.

[0110] E11. At least 72 hours when stored at ≦25°C, especially when stored at 25°C Any one of embodiments E1 to E10, wherein the composition has a shelf life of at least 72 h. 1. The pharmaceutical aqueous solution according to claim 1.

[0111] "Shelf life" has its ordinary meaning herein in relation to pharmaceutical products. Life means that the product characteristics still meet the product specifications established during drug development and agreed upon by the health authorities. The length of time a pharmaceutical product can be stored under compatible conditions.

[0112] E12. Radiochemical purity (determined by HPLC) of at least 100% when stored at 25°C. any one of embodiments E1 to E11, wherein the IL-16 concentration is maintained at ≧95% for 72 h. Pharmaceutical aqueous solutions.

[0113] E13. The solution is produced on a commercial scale, in particular at least 20 GBq; Manufactured in batch sizes of at least 50 GBq, at least 70 GBq, embodiment E The medicinal aqueous solution according to any one of 1 to E12.

[0114] E14. A ready-to-use pharmaceutical aqueous solution according to any one of embodiments E1 to E13. solution.

[0115] E15. (1) and below: (1.1) preparing an aqueous solution containing a radionuclide; (1.2) a somatostatin receptor-binding peptide linked to a chelator; at least one stabilizer against radiolytic degradation; and , (1.3) Mixing the solutions obtained in steps (1.1) and (1.2) to obtain a mixture. Heating things and By this, radioactive nuclides 177 Lu and somatostatin linked to the chelator DOTA a process step of forming a complex with a receptor-binding peptide; (2) The following: (2.1) Water, optionally containing at least one stabilizer against radiolytic degradation. preparing a dilute solution of (2.2.) The complex solution obtained in step (1) and the complex solution obtained in step (2.1) and a diluted solution to obtain a final solution. a process step of diluting the complex solution obtained in step (1) by Including, If the solution prepared under (1.2) contains only one stabilizer, then under (2.1) The prepared solution comprises at least one stabilizer; A process for producing an aqueous pharmaceutical solution according to any one of embodiments E1 to E14.

[0116] E16. The solution prepared in step (1.2) contains at least one stabilizer, and To embodiment E15, the solution prepared in step (2.1) comprises at least one stabilizer. The process described.

[0117] E17. The solution prepared in step (1.2) contains at least the stabilizer gentisic acid. and the solution prepared in step (2.1) contains at least the stabilizer ascorbic acid. The process according to embodiment E15.

[0118] E18. The solution prepared in step (1.2) contains one stabilizer, gentisic acid. and the solution prepared in step (2.1) contains one stabilizer, which is ascorbic acid. The process of embodiment E15, comprising only the agent.

[0119] E19. The solution prepared in step (1.2) is 15 to 50 mg / mL, preferably 2 Embodiments E15 to E1, comprising one or more stabilizers in a total concentration of 0 to 40 mg / mL. 9. The process according to any one of claims 8 to 8.

[0120] E20. The solution prepared in step (1.2) is 20 to 40 mg / mL, preferably 2 Embodiment E containing only one stabilizer, which is gentisic acid at a concentration of 5 to 35 mg / mL. The process of any one of E15 to E18.

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

[0122] E22. In step (1.3), the mixture obtained is heated for 2 to 59 minutes, preferably 10 to 15 minutes. and heating to a temperature of 70 to 99°C, preferably 90 to 98°C, for 1 minute. The process of any one of 5 to E21.

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

[0124] E24. (3) A process for filtering the solution obtained in step (2) through a 0.2 μm filter. and (4) The filtered solution obtained in step (3) is diluted with 5.0 to 10 MBq, preferably 7.0 ~8.0MBq, more preferably 7.3-7.7MBq, even more preferably 7.4- Dispense into dose unit containers in the amount required to deliver a radiation dose of 7.5 MBq. In the process step, the amount is preferably 10 to 50 mL, more preferably 15 to 30 mL. L, and even more preferably 20-25 mL; The process of any one of embodiments E15 to E23, further comprising:

[0125] E25. Embodiments E15-E, wherein the solution of step (1.1) comprises LuCl3 and HCl. 24. The process according to any one of claims 1 to 24.

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

[0127] E27. Embodiment E1, wherein the solution of step (2.1) comprises DTPA and ascorbic acid. 5 to E26.

[0128] E28. The dose unit container in step (4) is sealed in a lead container with a stoppered via. The process of any one of embodiments E24 to E27, wherein

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

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

[0131] The present invention further provides a method for treating neuroendocrine tumors (NETs) comprising administering to a subject a compound as defined herein. The present invention provides an aqueous pharmaceutical solution.

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

[0133] In a further alternative, the present invention provides a method for the manufacture / preparation of a medicament for the treatment of NETs, ​​comprising: The present invention provides the use of a pharmaceutical aqueous solution as defined above.

[0134] In a further alternative, the present invention provides a NET comprising a pharmaceutical aqueous solution as defined herein. A therapeutic medicament is provided.

[0135] may be treated in accordance with the present invention with the pharmaceutical aqueous solutions defined herein, either alone or in combination. Neuroendocrine tumors (NETs) include gastroenteropancreatic neuroendocrine tumors, carcinoid tumors, pheochromocytomas, Paraganglioma, medullary thyroid carcinoma, pulmonary neuroendocrine tumor, thymic neuroendocrine tumor, carcinoid tumor or pancreatic neuroendocrine tumor, pituitary adenoma, adrenal tumor, Merkel cell carcinoma, breast cancer, non-Hodgkin's Hodgkin's lymphoma, head and neck tumors, urothelial carcinoma (bladder), renal cell carcinoma, hepatocellular carcinoma, GI ST, neuroblastoma, bile duct tumor, neck tumor, Ewing's sarcoma, osteosarcoma, small cell lung cancer (SC LC), prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, supratentorial primitive nerve The tumor is selected from the group consisting of a transectodermal tumor, and an esthesioneuroblastoma.

[0136] may be treated in accordance with the present invention with the pharmaceutical aqueous solutions defined herein, either alone or in combination. Additional NET tumors include functional carcinoid tumors, insulinomas, gastrinomas, and hematologic tumors. vasoactive intestinal peptide (VIP) tumor, glucagonoma, serotoninoma, histaminomas The tumor may be selected from the group consisting of ACTHoma, pheochromocytoma, and somatostatinoma.

[0137] The present invention further provides a method for producing a radionuclide 177 Lu (lutetium-177) as defined herein a somatostatin receptor-binding peptide linked to a chelating agent, combinations or combination therapies of the selected complexes, or in combination with one or more of the therapeutic agents outlined below The present invention provides a combination or combination therapy of pharmaceutical aqueous solutions as defined herein.

[0138] In certain cases, the pharmaceutical aqueous solution of the present invention may contain other therapeutic agents, such as other anti-cancer agents, Antiallergic agents, antinausea (or antiemetic) agents, analgesics, cytoprotective agents, and combinations thereof To be combined.

[0139] Common chemotherapy agents that may be considered for use in combination therapy include anastrozole (Ar); imidex®), bicalutamide (Casodex®), bromine sulfate Omycin (Blenoxane®), busulfan (Myleran®), Busulfan injection (Busulfex®), capecitabine (Xe loda®), N4-pentoxycarbonyl-5-deoxy-5-fluorosilane thiazide, carboplatin (Paraplatin®), carmustine (BiC NU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®) , cyclophosphamide (Cytoxan® or Neosar®), Cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine Injectable vesicle (DepoCyt®), dacarbazine (DTIC-Dome®), Registered Trademark), dactinomycin D (Cosmegan), Daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate DaunoXome (registered trademark), dexamethasone, docetaxel ( Taxotere®), doxorubicin hydrochloride (Adriamycin® (Rubex®), etoposide (Vepesid®), phosphate Fludarabine (Fludara®), 5-fluorouracil (Adrucil (R), Efudex®), flutamide (Eulexin® ), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea ( Hydrea®, Idamycin®, Iphos Famid (IFEX®), irinotecan (Camptosar®) , L-asparaginase (ELSPAR®), leucovorin calcium, Mel Alkeran®, 6-mercaptopurine (Purinetho l (registered trademark), methotrexate (Folex (registered trademark)), mitoxantrone (Novantrone®), Mylotarg, paclitaxel (Taxol®), nab-paclitaxel (Abraxane®), phenytoin (Phenytoin®), (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 cal Mucine implant (Gliadel®), tamoxifen tosylate (N olvadex®), teniposide (Vumon®), 6-thioguaiacol thiazolidine, thiotepa, tirapazamine (Tirazone®), topoteca hydrochloride for injection vinblastine (Velban®), vinblastine (Hycamptin®), , vincristine (Oncovin®), and vinorelbine (Navelbi®) ne (registered trademark).

[0140] Anticancer drugs that are particularly suitable for combination with the aqueous pharmaceutical solution of the present invention include the following: It can be obtained.

[0141] Tyrosine kinase inhibitor: erlotinib hydrochloride (Tarceva®) )), linifanib (also known as ABT 869, available from Genentech N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2- fluoro-5-methylphenyl)urea), sunitinib malate (Sutent® (US Pat. No. 6,780,996), bosutinib (also known as SKI-606) The 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methionine compound described in the specification Oxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carboxy Vonitrile), dasatinib (Sprycel®), pazopanib (Votrie nt (registered trademark), sorafenib (Nexavar (registered trademark), Zactima (ZD 6474), and imatinib or imatinib mesylate (Gilvec® and G leevec (registered trademark).

[0142] Vascular endothelial growth factor (VEGF) receptor inhibitor: Bevacizumab (Avastin) axitinib (Inlyta®), brivanib alanine (BM S-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H- Indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazole (2-aminopropanoic) propan-6-yloxy) propan-2-yl) 2-aminopropanoate), sorafen (Nexavar®), pazopanib (Votrient®), Sunitinib dihydrochloride (Sutent®), cediranib (AZD2171, CAS 288383-20-1), Burgatef (BIBF1120, CAS 928326- 83-4), foretinib (GSK1363089), telatinib (BAY57-935 2, CAS 332012-40-5), apatinib (YN968D1, CAS 811 803-05-1), imatinib (Gleevec®), ponatinib (AP2 4534, CAS 943319-70-8), tivozanib (AV951, CAS 47 5108-18-0), regorafenib (BAY73-4506, CAS 755037 -03-7), Vatalanib dihydrochloride (PTK787, CAS 212141- 51-0), brivanib (BMS-540215, CAS 649735-46-6), Vandetanib (Caprelsa® or AZD6474), motesanib Acid (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3 -dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino] -3-pyridinecarboxamide, PCT International Publication No. 02 / 066470 Dovitinib dilactic acid (TKI258, CAS 852433-84-2), Linfanib (ABT869, CAS 796967-16-3), Cabo Zantinib (XL184, CAS849217-68-1), lestaurtinib (CAS 111358-88-4), N-[5-[[[5-(1,1-dimethylethyl)-2- Oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (B MS38703, CAS 345627-80-7), (3R,4R)-4-amino-1 -((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]to N-(triazin-5-yl)methyl)piperidin-3-ol (BMS690514), 3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β, 6aα)-Octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy ]-4-Quinazolineamine (XL647, CAS 781613-23-8), 4-methyl 3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidinyl] [Diazin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide (BHG712, CAS 940310-85-0), and aflibercept (Eyle a (registered trademark), sulfatinib, sur ufatinib).

[0143] Platelet-derived growth factor (PDGF) receptor inhibitor: Imatinib (Gleevec) (registered trademark), linifanib (also known as ABT 869, available from Genentech) Known as N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'- (2-fluoro-5-methylphenyl)urea), sunitinib malate (Sutent Registered trademark), quizartinib (AC220, CAS 950769-58-1), pazopa nib (Votrient®), axitinib (Inlyta®), Sorafenib (Nexavar®), Bergatef (BIBF1120, CAS 928326-83-4), telatinib (BAY57-9352, CAS 33201 2-40-5), Vatalanib dihydrochloride (PTK787, CAS 212141-51-0) , and motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2 ,3-Dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridyl) (Dimethyl)amino]-3-pyridinecarboxamide, PCT International Publication No. 02 / 066 (See brochure no. 470).

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

[0145] Aurora kinase inhibitor: danusertib (PHA-739358), N-[4-[[6 -Methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino ]phenyl]benzamide (ZM447439, CAS 331771-20-1), 4 -(2-amino-4-methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phenyl] [Nyl]-2-pyrimidinamine (CYC116, CAS 693228-63-6), Zasertib (VX680 or MK-0457, CAS 639089-54-6), Certib (MLN8237), (N-{2-[6-(4-cyclobutylamino-5-trimethylsilyl)amino] Fluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrafluoromethyl-pyrimidin-2-ylamino tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-a cetoamide) (PF-03814735), 4-[[9-chloro-7-(2,6-difluoromethyl) (O-phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amido no]-benzoic acid (MLN8054, CAS 869363-13-3), cenisertib ( R-763), barasertib (AZD1152), and N-cyclopropyl-N'-[3 -[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H- pyrazol-4-yl]urea (AT9283).

[0146] Cyclin-dependent kinase (CDK) inhibitors: Aloisine A, alvocidib (flavopirin) 2-(2-chlorophenyl)-5,7-diol, also known as dol or HMR-1275 Hydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl] 4-chromenone, which is described in U.S. Pat. No. 5,621,002), Zotinib (PF-02341066, CAS 877399-52-5), 2-(2-chloro-2-methyl-2-propanol) (2R,3S)-2-(hydroxymethyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl) 1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P 276-00, CAS 920113-03-7), Indislam (E7070), Scovitin (CYC202), 6-acetyl-8-cyclopentyl-5-methyl-2-( 5-piperazin-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pi Rimidin-7-one, hydrochloride (PD0332991), dinaciclib (SCH7279 65), N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio ]thiazol-2-yl]piperidine-4-carboxamide (BMS387032, CA S 345627-80-7), 4-[[9-chloro-7-(2,6-difluorophenyl) (I)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzo Fragrance acid (MLN8054, CAS869363-13-3), 5-[3-(4,6-difluoromethyl) Oro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N- Ethyl-4-methyl-3-pyridinemethanamine (AG-024322, CAS 837 364-57-5), 4-(2,6-dichlorobenzoylamino)-1H-pyrazole- 3-Carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS 8444 42-38-2), 4-[2-methyl-1-(1-methylethyl)-1H-imidazole -5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (A ZD5438, CAS 602306-29-6, palbociclib (PD-03329 91), and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropyl [phenyl]amino]-5-(trifluoromethyl)-4-pyridyl [midinyl]oxy]-2-butanol (BAY 10000394), ribociclib.

[0147] Checkpoint kinase (CHK) inhibitors: 7-hydroxystaurosporine (UC N-01), 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3 R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidin-7-amine (SCH90 0776, CAS 891494-63-6), 5-(3-fluorophenyl)-3- AZ-112-14-1(N-[(S)-piperidin-3-yl]amide) D7762, CAS 860352-01-8), 4-[((3S)-1-azabicyclo [2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl) (I)-6-chloroquinolin-2(1H)-one (CHIR 124, CAS 40516 8-58-3), 7-aminodactinomycin (7-AAD), isogranulatimide, Bromohymenialdisine, N-[5-bromo-4-methyl-2-[(2S)-2-morpho Linylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2 603618, CAS 911222-45-2), sulforaphane (CAS 447 8-93-7, 4-methylsulfinylbutylisothiocyanate), 9,10,11, 12-Tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3' ,2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1,3(2H )-dione (SB-218078, CAS 135897-06-2), and TAT-S 216A (YGRKKRRQRRRLYRSPAMPENL), and CBP501 ((d -Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr), and (αR)- α-Amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl] )-6-oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepine-8- yl]-cyclohexaneacetamide (PF-0477736).

[0148] 3-Phosphoinositide-Dependent Kinase 1 (PDK1 or PDPK1) Inhibitors: 7-2-Aminobutyrate Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H -pyrazol-1-yl]phenyl]-acetamide (OSU-03012, CAS 7 42112-33-0), pyrrolidine-1-carboxylic acid (3-{5-bromo-4-[2- (1H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}- phenyl)-amide (BX912, CAS 702674-56-4), and 4-dodecyl N-1,3,4-thiadiazol-2-yl-benzenesulfonamide (PHT-4 27, CAS 1191951-57-1).

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

[0150] B-RAF inhibitor: Regorafenib (BAY73-4506, CAS 755037- 03-7), Tuvizanib (AV951, CAS 475108- 18-0), vemurafenib (Zelboraf®, PLX-4032, CA S 918504-65-1), 5-[1-(2-hydroxyethyl)-3-(pyridine -4-yl)-1H-pyrazol-4-yl]-2,3-dihydroinden-1-one Oxime (GDC-0879, CAS 905281-76-7), 5-[2-[4-[2 -(Dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1H-imidazo [4-yl]-2,3-dihydro-1H-inden-1-one oxime (GSK21 18436 or SB590885), (+ / -)-methyl(5-(2-(5-chloro-2 (-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoin (1H-benzoimidazol-1-yl)-1H-benzoimidazol-2-yl)carbamate (XL-28 1 and BMS908662), and N-(3-(5-chloro-1H-pyridinyl)- (2,3-b)pyridine-3-carbonyl-2,4-difluorophenyl)propionate thiazol-1-sulfonamide (also known as PLX4720).

[0151] C-RAF inhibitors: sorafenib (Nexavar®), 3-(dimethylaminobenzoate), amino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]- Benzamide (ZM336372, CAS 208260-29-1), and 3-(1- Cyano-1-methylethyl)-N-[3-[(-3,4-dihydro-3-methyl-4-o 6-quinazolinyl)amino]-4-methylphenyl]-benzamide (AZ628 , CAS 1007871-84-2).

[0152] Human granulocyte colony-stimulating factor (G-CSF) modulator: Filgrastim (Ne upogen®), sunitinib malate (Sutent®), PEG Pegilgrastim (Neulasta®), and Zarutinib (AC220, CAS 950769-58-1).

[0153] RET inhibitors: sunitinib malate (Sutent®), vandetanib (C aprelsa®), motesanib diphosphate (AMG706, CAS 8578 76-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indole-6- (4-pyridinylmethyl)amino)-3-pyridinecarboxamide, PC T WO 02 / 066470 brochure), sorafenib (BAY 43 -9006), regorafenib (BAY73-4506, CAS 755037-03- 7), and danusertib (PHA-739358).

[0154] FMS-like tyrosine kinase 3 (FLT3) inhibitor or CD135: sunitinib malate (Sutent®), quizartinib (AC220, CAS 950769-5 8-1), N-[(1-methyl-4-piperidinyl)methyl]-3-[3-(trifluoromethyl) (trimethoxy)phenyl]-imidazo[1,2-b]pyridazin-6-amine sulfate (SG I-1776, CAS 1173928-26-1, and Vargate f)(BIBF1120, CAS 928326-83-4).

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

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

[0157] IGF-1R inhibitor: Linsitonib (OSI-906), [7 -[trans-3-[(azetidin-1-yl)methyl]cyclobutyl]-5-(3- benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (AEW541, CAS 475488-34-7), [5-(3-benzyloxyphenoxy) (Nyl)-7-[trans-3-[(pyrrolidin-1-yl)methyl]cyclobutyl]- 7H-Pyrrolo[2,3-d]pyrimidin-4-yl]amine (ADW742 or GSK5 52602A, CAS 475488-23-4), (2-[[3-bromo-5-(1, 1-dimethylethyl)-4-hydroxyphenyl]methylene]-propanedinitrile(thi Rofostin 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)-pyridinone( BMS536924, CAS 468740-43-4), 4-[2-[4-[[(2S )-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-1,2-dihydro -2-oxo-3-pyridinyl]-7-methyl-1H-benzimidazol-5-yl] -1-Piperazinepropanenitrile (BMS554417, CAS 468741-42 -6), (2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl) Amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoro (3-pyridinyl)-2-methyl-2-pyrrolidinecarboxamide (BMS7548 07, CAS 1001350-96-4), picropodophyllotoxin (AXL171 7), and nordihydroguareacetic acid ic acid).

[0158] IGF-1R antibodies: figitumumab (CP751871), cixutumumab (IMC- A12), ganitumab (AMG-479), lobatumumab (SCH-717454), Lotuzumab (MK0646), R1507 (available from Roche), BIIB022 (available from Biogen), and MEDI-573 (available from MediImmune Noh).

[0159] MET inhibitors: cabozantinib (XL184, CAS 849217-68-1), Ioletinib (GSK1363089, formerly XL880, CAS 849217-64- 7), tivantinib (ARQ197, CAS 1000873-98-2), 1-(2- Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy) (ii) pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro -1H-pyrazole-4-carboxamide (AMG 458), crizotinib (Xalk ori (registered trademark), PF-02341066), (3Z)-5-(2,3-dihydro- 1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methyl methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-1 ,3-Dihydro-2H-indol-2-one (SU11271), (3Z)-N-(3 -chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazine-1- yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N-methyl-2-oxo Indoline-5-sulfonamide (SU11274), (3Z)-N-(3-chlorophenoxy) nyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H -pyrrol-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfone Amide (SU11606), 6-[difluoro[6-(1-methyl-1H-pyrazole- 4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]ky Nolin (JNJ38877605, CAS 943540-75-8), 2-[4-[1 -(Quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyra [Zin-6-yl]-1H-pyrazol-1-yl]ethanol (PF04217903, CAS 956905-27-4), N-((2R)-1,4-dioxane-2-ylmethyl) ethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5- Oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfur Famid (MK2461, CAS 917879-39-1), 6-[[6-(1-methyl (1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazine -3-yl]thio]-quinoline (SGX523, CAS 1022150-57-7), and (3Z)-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[[ 3,5-dimethyl 4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl 1H-pyrrol-2-yl]carbonyl]methylene]-1,3-dihydro-2H- Indol-2-one (PHA665752, CAS 477575-56-7).

[0160] Epidermal growth factor receptor (EGFR) inhibitor: erlotinib hydrochloride (Tarceva) (Registered Trademark), Gefitnib (Iressa®), N-[ 4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrachlorophenyl Hydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butanol phenamide, Tovok®), vandetanib (Caprelsa®) ), lapatinib (Tykerb®), (3R,4R)-4-amino-1-(( 4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazine (5-methyl)piperidin-3-ol (BMS690514), canertinib Dihydrochloride (CI1033), 6-[4-[(4-ethyl-1-piperazinyl) methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3- d] Pyrimidine-4-amine (AEE788, CAS 497839-62-0), Mbu Litinib (TAK165), pelitinib (EKB569), afatinib (BIBW29 92), neratinib (HKI-272), N-[4-[[1-[(3-fluorophenyl )methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f ][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinyl ethyl ester (BMS599626), N-(3,4-dichloro-2-fluorophenyl) )-6-Methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclohexyl Ropenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8), and 4-[4-[[(1R)-1-phenylethyl ]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol (PKI 166, CAS 187724-61-4).

[0161] EGFR antibodies: cetuximab (Erbitux®), panitumumab (Vec tibix®), matuzumab (EMD-72000), trastuzumab (He rceptin®), nimotuzumab (hR3), zalutumumab, TheraC IM h-R3, MDX0447 (CAS 339151-96-1), and ch806 (mAb-806, CAS 946414-09-1).

[0162] mTOR inhibitors: temsirolimus (Torisel®), ridaforolimus (Formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9 S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28 Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-1 5,17,21,23,29,35-Hexamethyl-2,3,10,14,20-pentamethyl Oxo-11,36-dioxa-4-azatricyclo[30.3.1.0 4,9 ]Hexa Triaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methyl Also known as methylcyclohexyl dimethylphosphinate, AP23573 and MK Also known as 8669 and described in PCT Publication WO 03 / 064383 everolimus (Afinitor® or RAD001), rapamycin (AY22989, Sirolimus®), semapimod (CAS 164 301-51-3), (5-{2,4-bis[(3S)-3-methylmorpholine-4-isocyanate {2,3-d]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055), 2-amino-8-[trans-4-(2-hydroxyethoxy) Cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2, 3-d]pyrimidin-7(8H)-one (PF04691502, CAS 101310 1-36-4), N 2 -[1,4-dioxo-4-[[4-(4-oxo-8-phenyl -4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl] -L-Arginylglycyl-L-α-aspartyl L-serine, -inner salt (SF112 6, CAS 936487-67-1), and N-[4-[[[3-[(3,5-dimeth (2-quinoxalinyl)amino]sulfonyl]phenyl]-3- Methoxy-4-methyl-benzamide (also known as XL765, SAR245409) (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indole) -2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclohexyl Sancarboxylic acid (OSI-027).

[0163] Mitogen-activated protein kinase (MEK) inhibitor: XL-518 (GDC-0 973, also known as Cas No. 1029872-29-4, from ACC Corp. available), selumetinib (also known as AZD6244 or ARRY142886), 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide and described in PCT International Publication No. 2003077914), 2-[( 2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4 -difluoro-benzamide (also known as CI-1040 or PD184352, P CT International Publication No. 2000035436), N-[(2R)- 2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]-benzamide (also known as PD0325901, PCT (described in International Publication No. 2002006213), 2,3-bis[amino [(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126) and described in U.S. Pat. No. 2,779,780), N-[3,4-difluoro b-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]- 1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (R Also known as DEA119 or BAY869766, PCT International Publication No. 2007014 (3S, 4R, 5Z, 8S, 9S, 11E)-1 4-(Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9 ,19-Tetrahydro-1H-2-benzoxacyclotetradecyne-1,7(8H)- Zion] (also known as E6201, PCT International Publication No. 2003076424) 2'-amino-3'-methoxyflavone (described as PD98059) Also known as BIAFFIN GmbH & Co., KG, Germany ), vemurafenib (PLX-4032, CAS 918504-65-1), ( R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4 -iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H ,8H)-dione (TAK-733, CAS 1035555-63-5), Pimaserch (AS-703026, CAS 1204531-26-9), trametinib dimethyl Sulfoxide (GSK-1120212, CAS 1204531-25-80), 2- (2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1, 5-Dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330), and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)a Amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazino

[0023] (Chinese Patent No. 4987655 or Romanian Patent No. 4987655) (Specification of African Patent No. 4987655).

[0164] Alkylating agents: oxaliplatin (Eloxatin®), temozolomide ( Temodar® and Temodal®), dactinomycin (A Also known as methicillin-D (Cosmegen®), melphalan (Also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®), altretamine (as hexamethylmelamine (HMM) also known as Hexalen®), carmustine (BiCNU®), ), bendamustine (Treanda®), busulfan (Busulfex (R) and Myleran®), carboplatin (Paraplatin n®), lomustine (also known as CCNU, CeeNU®) , cisplatin (also known as CDDP, Platinol®, and P1 atinol®-AQ), chlorambucil (Leukeran®) , cyclophosphamide (Cytoxan® and Neosar®), Dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, DTIC Dome®), altretamine (as hexamethylmelamine (HMM) also known as Hexalen®), ifosfamide (Ifex®), ), prednummustine, procarbazine (Matulane®), mechlorethalin Nitrogen mustard, mustine, and mechloroethamine hydrochloride Mustargen®, also known as thiazolinone (proethamine), Putozocin (Zanosar®), thiotepa (thiophosphatamide), Thiopeptide, also known as thiazolinone, ... ex (registered trademark), cyclophosphamide (Endoxan (registered trademark), Cytoxa n(R), Neosar(R), Procytox(R), Reviva mmune®), and bendamustine HCl (Treanda®) .

[0165] Aromatase inhibitors: exemestane (Aromasin®), letrozole (Femara®), and anastrozole (Arimidex®) )).

[0166] Topoisomerase I inhibitors: irinotecan (Camptosar®), hydrochloride Topotecan (Hycamtin®), and 7-ethyl-10-hydroxycan Putothecin (SN38).

[0167] Topoisomerase II inhibitors: Etoposide (VP-16 and etoposide phosphate, Top osar®, VePesid®, and Etopophos®), Teniposide (VM-26, Vumon®), and tafluposide.

[0168] DNA synthesis inhibitors: capecitabine (Xeloda®), gemcitabine hydrochloride ( Gemzar®), nelarabine ((2R,3S,4R,5R)-2-(2-aminobenzoate) (amino-6-methoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4 -diols, Arranon®, and Atriance®), and Sapacitabine (1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-4- (palmitoylamino)pyrimidin-2(1H)-one).

[0169] Folate antagonists or antifolates: trimetrexate glucuronate (Neutrex) in (registered trademark), piritrexim isethionate (BW201U), pemetrexed ( LY231514), raltitrexed (Tomudex®), and methotrexate sate (Rheumatrex®, Trexal®).

[0170] Immune modulators: afutuzumab (available from Roche®), pegf Filgrastim (Neulasta®), lenalidomide (CC-5013, Revlimid®), thalidomide (Thalomid®), Cutimid (CC4047) and IRX-2 (interleukin 1 and interleukin 2 Human cytokine mixture containing interferon gamma and CAS 951209-71 -5, available from IRX Therapeutics).

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

[0172] Interleukin-11 and synthetic interleukin-11 (IL-11): Oprelvekin (Neumega®).

[0173] Erythropoietin and synthetic erythropoietin: Erythropoietin (Epogen (R) and Procrit®), darbepoetin alfa (Aranesp ®), peginesatide (Hematide®), and polyethylene glycol EPO covalently attached to chol (Micera®).

[0174] Histone deacetylase (HDAC) inhibitors: Voninostat ) (Zolinza®), romidepsin (Istodax®), Treichostatin A (TSA), oxamflatin, boli Nostat (Zolinza®, suberoylanilide hydroxamic acid), pyro Syberoyl-3-aminopyridine amide hydroxamic acid ), Trapoxin A (RF-1023A), Trapoxin B (RF-10238), (αS,2S)-α-amino-η-oxo-2-oxiraneoctanoyl-O-methyl α-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1), cyclo[(αS ,2S)-α-amino-η-oxo-2-oxiranoctanoyl-O-methyl-D-thio [Cyl-2], Cyclic [L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxy Silaneoctanoyl-D-prolyl] (HC-toxin), cyclo[(αS,2S)-α -amino-η-oxo-2-oxiraneoctanoyl-D-phenylalanyl-L-roi silyl-(2S)-2-piperidinecarbonyl] (WF-3161), chlamydocin ((S )-Cyclic(2-methylalanyl-L-phenylalanyl-D-prolyl-η-o 8-oxo-L-α-aminooxiranoctanoyl), apicidin (cyclo(8-oxo-L -2-aminodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-D- 2-piperidinecarbonyl), romidepsin (Istodax®, FR-90 1228), 4-phenylbutyrate, Spiruchostatin A, Milproin (Valproic Acid ), entinostat (MS-275, N-(2-aminophenyl)-4-[N-(pyridyl) benzamide), and Dep Decyne (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D- threo-D-ido-undeca-1,6-dienithol).

[0175] Biological response modifiers: interferons, interleukins, colony-stimulating factors, mono Clonal antibodies, vaccines (therapeutic and prophylactic), gene therapy, non-specific immunomodulators Interferon alpha (Intron®, Roferso) n(registered trademark-A), interferon beta, interferon gamma, interleukin- 2 (IL-2 or aldesleukin, Proleukin®), Filgras sargramostim (Neupogen®), sargramostim (Leukine®) )), erythropoietin (epoetin), interleukin 11 (oprelvekin), Imiquimod (Aldara®), lenalidomide (Revlimid®), rituximab (Rituxan®), trastuzumab (Hercep®), tin®), Bacillus Calmette-Guerin aCys® and TICE® BCG), levamisole (Ergami sol®), and denileukin diftitox (Ontak®).

[0176] Plant alkaloids: paclitaxel (Taxol and Onxal™), proteins Substance-bound paclitaxel (Abraxane®), vinblastine (vinblastine sulfate), Alkaban-A, also known as vincaleukoblastine, vincaleukoblastine, and VLB Q® and Velban®), vincristine (vincristine sulfate, L Oncovin® and Vincasar, also known as CR and VCR Pfs®), and vinorelbine (Navelbine®).

[0177] Taxane antineoplastic agents: paclitaxel (Taxol®), docetaxel (T axotere®), cabazitaxel (Jevtana®, 1-hi hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytachis-11 -ene-2α,4,13α-triyl-4-acetate-2-benzoate-13-[( 2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy -3-phenylpropanoate), and larotaxel ((2α,3ξ,4α,5β,7α ,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)- 3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanol (aminoyl)oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-silyl Crotakis-11-en-2-yl benzoate).

[0178] Heat shock protein (HSP) inhibitors: Tanespimycin (KOS-953 and 17 17-allylamino-17-demethoxygeldanamycin, also known as 17-AAG. and is available from SIGMA and is described in U.S. Pat. No. 4,261,989. ), letaspimycin (IPI504), ganetespib (STA-9090), [6- Chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-propanol phospho-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-isothiazolinone Indazol-1-yl]phenyl]amino]cyclohexylglycine ester (SNX5 422 or PF04929113, CAS 908115-27-5), and 17-dimethyl ethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG).

[0179] Thrombopoietin (TpoR) agonist: eltrombopag (SB497115, Promacta® and Revolade®, and Romiplos Chim (Nplate®).

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

[0181] Cytokine: Interleukin-2 (also known as aldesleukin and IL-2) Proleukin (registered trademark), interleukin 11 (as Oplevukin Neumega®), and alpha interferon alpha (IFN Intron® A and Roferon-A (also known as -α) )).

[0182] 17α-hydroxylase / C17,20 lyase (CYP17A1) inhibitors: acetate Biraterone (Zyitga®).

[0183] Miscellaneous cytotoxic agents: arsenic trioxide (Trisenox®), asparagina L-asparaginase, Erwinia L-asparaginase Also known as Elspar® and Kidrolase®), and Erwinia chrysanthemi Aspa Laginase (Erwinaze®).

[0184] CC chemokine receptor 4 (CCR4) antibody: Mogamulizumab (Potellig ent(registered trademark)).

[0185] CD20 antibodies: rituximab (Riuxan® and MabThera®) (Bexxar®), and tositumomab (Ar zerra (registered trademark).

[0186] CD20 antibody-drug conjugate: Ibritumomab tiuxetan (Zevalin®) )), and tositumomab.

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

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

[0189] CD33 antibody drug conjugate: gemtuzumab ozogamicin (Mylotarg Registered trademark).

[0190] CD40 antibody: dacetuzumab (also known as SGN-40 or huS2C6, Sea (Available from Little Genetics, Inc.).

[0191] CD52 antibody: alemtuzumab (Campath®).

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

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

[0194] TPH inhibitor: telotristat.

[0195] PARP (Poly ADP-ribose polymerase) inhibitor: Olaparib (Lynparza) ), rucaparib (Rubraca), niraparib (Zeluja), talazoparib, beri Paribu.

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

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

[0198] In particular, the present invention relates to a method for producing radionuclides 177 Lu (lutetium-177) as defined herein a somatostatin receptor-binding peptide linked to a chelating agent, combinations or combination therapies of the complexes formed, or octreotide, lanreotide, vaprexa Otide, pasireotide, satreotide, everolimus, temozolomide, telotristat , sunitinib, surufatinib, ribociclib, entinostat, and pazopanib A pharmaceutical aqueous solution as defined herein in combination with one or more therapeutic agents selected from the group consisting of In certain embodiments, such combinations include, for example, For example, GEP-NET, pulmonary NET, pNET, pulmonary NET Used to treat NET tumors, including lung NETs, ​​carcinoid syndrome, and SCLC. In certain embodiments, the present invention provides a therapeutically effective amount of such a combination of ingredients. For example, GEP-NET and pulmonary NET (pulmonary NET) can be treated by administering NET), pNET, lung NET, carcinoid syndrome, SCLC, etc. To provide a method for treating patients with NET tumors.

[0199] In certain embodiments, the present invention provides a method for producing a radionuclide 177 Lu (lutetium-177) and A somatostatin receptor-binding peptide linked to a chelator as defined herein. and combination or combination therapy of complexes formed by, or PD-1, PD-L1, and and CTLA-4 inhibitors, in particular, one or more cancer immunotherapeutic agents selected from the group consisting of spa Ibuprofen, nivolumab, pembrolizumab, pidilizumab, durvalumab, and ate IO treatment selected from zolizumab, avelumab, ipilimumab, and tremelimumab and (c) providing a combination or combination therapy of the pharmaceutical aqueous solution as defined herein in combination with a therapeutic agent. In certain embodiments, such combinations include, for example, GEP-NETs, ​​pulmonary NETs (p ulmonary NET, pNET, lung NET, carcinoid The present invention is for use in the treatment of NET tumors, such as SCLC, SCLC, and HER2-associated leukemia syndrome. Now, the present invention provides a method for treating a patient suffering from atopic dermatitis by administering a therapeutically effective amount of such a combination of ingredients, e.g. GEP-NET, pulmonary NET (pulmonary NET), pNET, pulmonary NET (lu The study provides treatment options for patients with NET tumors, including ng NETs, ​​carcinoid syndrome, and SCLC. Provide.

[0200] definition The following defines the meaning of terms used in this specification.

[0201] The term "about" or "ca." is used herein to mean that the following value is within ±20%, preferably ± 10%, more preferably ±5%, even more preferably ±2%, even more preferably ± This means that it can fluctuate by 1%.

[0202] Unless otherwise defined, "%" in this specification means weight percent (wt%). It has a taste and is also referred to as weight / weight percentage (w / w%).

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

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

[0205] "(ai) Radionuclides and (aii) a cell receptor-binding organic moiety linked to a chelator; The complex formed by: The radionuclide metal ion is non-covalently coupled to a functional group of the chelator, such as an amine or carboxylic acid. The chelating agent must have at least two bonds that allow it to form a chelate complex. has such a complexing functional group.

[0206] The chelating agents relevant to the present invention are DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid , DTPA: diethylenetriaminepentaacetic acid; NTA: nitrilotriacetic acid; EDTA: ethylenediaminetetraacetic acid; DO3A: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid; NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid; trizoxetan, tetraxetane, or mixtures thereof, and preferably DOTA.

[0207] "Cell receptor binding portion": At least a portion of a molecule binds to a receptor molecule on the surface of a cell. A particularly preferred cell receptor binding moiety for the present invention is the somatostatin receptor binding chemical molecule. receptor-binding peptides, preferably somatostatin receptor-binding peptides are octreotide, octreotate, lanreotide, vapreotide, pasireotide, From irratereotide, pentetreotide, depreotide, satreotide, and veldreotide It is selected, preferably from octreotide and octreotate.

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

[0209] "Stabilizers against radiolytic degradation": Stabilization that protects organic molecules from radiolytic degradation For example, gamma rays emitted from radionuclides cleave the bonds between atoms in organic molecules, When radicals are formed, they are then trapped by the stabilizer, so that Any of these may result in unwanted, potentially ineffective, or even toxic molecules. Therefore, other chemical reactions caused by radicals are also avoided. These stabilizers are also called "free radical scavengers" or simply "radical scavengers." Other alternative terms for such stabilizers are "radiation stabilizing agents" and "radiolytic stabilizers." , or simply "quencher."

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

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

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

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

[0214] The cell receptor binding moiety and the chelator may together form the following molecule: DOTA-OC:[DOTA 0 ,D-Phe 1 ]Octreotide, DOTA-TOC: [DOTA 0 ,D-Phe 1 ,Tyr 3 ] Octreotide and edotreotide (INN): [ka] DOTA-NOC:[DOTA 0 ,D-Phe 1 ,1-Nal 3 ]Octreotide, DOTA-TATE: A compound represented by the following formula: [DOTA 0 ,D-Phe 1 ,Tyr 3 ]Octreotate, DOTA-Tyr 3 -Octreotate, DOTA-d-Phe- Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr(cyclo2,7), Oxygen Sodotreotide (INN): [ka] DOTA-LAN: [DOTA 0 ,D-β-Nal 1 ]Lanreotide, DOTA-VAP:[DOTA 0 ,D-Phe 1 ,Tyr 3 ]Vapreotide.

[0215] Satreotide Trizoxetan [ka] Satreotide Tetraxetan [ka]

[0216] Preferred "chelator-linked cell receptor binding moieties" molecules provided herein are: The products are DOTA-TOC, DOTA-TATE, and satreotide tetraxetane. More preferably, the molecule is DOTA-TATE.

[0217] The present invention provides a method for the preparation of a radionuclide-linked chelator comprising administering to a subject subject the radionuclide and a cellular receptor linked to a chelator according to the present invention. -binding moiety and a preferred complex formed by (or a preferred complex of) 177 Lu-DOTA-TATE, which is a lutetium (177Lu) oxodotreotide INN, i.e., hydrogen [N-{[4,7,10-tris(carboxylato-κO -methyl)-1,4,7,10-tetraazacyclododecan-1-yl-κ 4 N 1 ,N 4 ,N 7 ,N 10 ]acetyl-κO}-D-phenylalanyl-L-cysteinyl-tyrosine L-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threonyl Ninatocyclic (2→7)-disulfide (4-)](177Lu) lutetate (1 -) and is expressed by the following formula: [ka]

[0218] "Buffers with a pH of 4.5 to 6.0": acetate buffers, citrate buffers (e.g., citrate + HCl or citric acid + disodium hydrogen phosphate), or phosphate buffer ( For example, sodium dihydrogen phosphate + disodium hydrogen phosphate) and preferably Preferably, the buffer is an acetate buffer, and preferably, the acetate buffer is a mixture of acetic acid and acetic acid. It is composed of sodium phosphate.

[0219] "sequestering agents", chelating agents suitable for complexing radionuclide metal ions; Preferably DTPA: diethylenetriaminepentaacetic acid.

[0220] "Commercial": A pharmaceutical product, such as a pharmaceutical aqueous solution, is a pharmaceutical product required by the Department of Health. Compliance with all quality and stability requirements allows for approval by health authorities such as the US FDA or EMA. The product must be (preferably) approved for marketing by the Ministry of Health, Labour and Welfare and must be manufactured by a pharmaceutical manufacturer. can be (and preferably is) manufactured on a commercial scale from or on-site, followed by quality control testing procedure and delivered to the end user at a remote location, such as a hospital or patient. It is possible (and preferably supplied).

[0221] "Combination": A fixed combination in one dosage unit formulation or a combination of compounds of the present invention and a combination thereof. a co-agent (e.g., another drug described below) ")) independently and simultaneously or, in particular, when the combination partners have a synergistic effect, etc. Can be administered separately within a time interval where a synergistic effect may be observed The single components may be packaged in a kit or individually. One or both of the components (e.g., powder or liquid) may be reconstituted to the desired dose prior to administration. As used herein, the terms "co-administration," "administration in combination," and the like The combination partners are administered to a single subject (e.g., a patient) in need thereof. It is intended to encompass both, and the agents do not necessarily have to be administered by the same route or simultaneously. As used herein, "administered" is intended to include therapeutic regimens that are not necessarily administered. The term "pharmaceutical combination" means a product resulting from the mixing or combining of more than one therapeutic agent. The term "fixed combination" includes both fixed and non-fixed combinations of therapeutic agents. The agent, e.g., a compound of the invention and the combination partner, may both be a single entity or The term "non-fixed combination" means that the two or more compounds are administered to a patient simultaneously in the form of a single dosage. Both the therapeutic agent, e.g., a compound of the invention and the combination partner, upon administration, are administered to the patient. either simultaneously, concurrently, or sequentially to provide therapeutically effective levels of the two compounds at is meant to be administered to the patient as a separate entity without any specific time limit. The latter also applies to cocktail therapy, eg the administration of three or more therapeutic agents. [Example]

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

[0223] material: 177 LuCl3 can be obtained from suppliers such as IDB Holland BV. DOTA 0 -Tyr 3 -Octreotate, piCHEM Forschungs -und Entwicklungs GmbH, Austria and other suppliers. All other components of the drug product are commercially available from various sources.

[0224] Example 1: Composition of pharmaceutical product Pharmaceutical products ( 177 Lu-DOTA 0 -Tyr 3 -Octreotate 370MBq / mL The injection solution) was 370MB at the reference date and reference time (calibration time (tc)). As a pharmaceutical substance with a volumetric radioactivity of q / mL 177 Lu-DOTA 0 -Tyr 3 -Oku It is designed as a sterile, ready-to-use solution for injection containing threotate. The start time (tc) is the end of production (EOP), which is the time of measurement of the radioactivity of the first QC vial. The shelf life of the drug product is assumed to be 72 hours after the calibration time. The drug product is defined as a solution containing a suitable amount of radioactivity that allows delivery of 7.4 GBq of radioactivity upon injection. It is a single dose vial containing a liquid.

[0225] After production, the manufacturing site calibrates the unit to within 7.4 GBq ±10% (200 mCi). A single dose is prepared according to the rated standard. The certificate of analysis provides the exact activity and the time at which this activity is achieved. This value is reported as "Time of injection:{DD MM YYYY}{hh:mm }UTC." Considering the variable injection times and steady decay of radionuclides, The required loading volume for 7.4 GBq of radioactivity at the time of injection is calculated as 20.5-25. The volume may be in the range of 0 mL.

[0226] [Table 1]

[0227] Example 2: Pharmaceutical Product Manufacturing For a 74GBq batch size (2Ci batch size), 177 LuCl3 solution (HCl Approximately 74 GBq) and DOTA-Tyr 3 -Octreotate (approximately 2 mg) solution and reaction Buffer solution (antioxidant (and stabilizer against radiolytic degradation) (i.e., gentisic acid 157 mg) and a buffer system (i.e., an acetate buffer system) are mixed together. The resulting solution was heated at a temperature of about 90 to about 98°C for less than 15 minutes. Used for radiolabeling performed during

[0228] The synthesis is carried out in a synthesis vessel containing fluid pathways (tubes), reactor vials, and sealed reagent vials. This is done using a single-use disposable kit cassette located at the front of the synthesis module. do.

[0229] The resulting mother solution contained a chelating agent (i.e., DTPA) and an antioxidant (i.e., ascorbic acid). It is diluted with a solution containing acetic acid, sodium hydroxide, and sodium chloride, and then Sterile filtered through 0.2 μm and has a pH of 4.5 to 6.0, preferably 5.2 to 5.3 A ready-to-use solution as described in Example 1 is obtained. Finally, the solution will be 20.5-25.0 mL The stoppered vials are provided with a protective shield. It is sealed in a lead container.

[0230] The manufacturing process is also feasible for batch sizes above 74 GBq. The amounts of raw materials (lutetium, peptide, and reaction buffer) were adjusted to ensure the same raw material ratio. It will be multiplied several times.

[0231] Example 3: Stability test results after storage at various temperature conditions. The following table shows the results of a 74 GBq batch size produced according to the process described in Example 2. Provide stability testing data for the batch.

[0232] [Table 2]

[0233] Very similar good stability results were obtained for batches manufactured at 148 GBq batch size. was made.

Claims

1. (a) Below: (ai) radioactive nuclide １７７ Lu (lutetium-177), (aii) DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and a complex formed by (b) at least two different stabilizers against radiolytic degradation; Including, the radionuclide is present in a concentration that provides a volumetric activity of 250-500 MBq / mL; The component (b) is a stabilizer: (bi) gentisic acid or a salt thereof at a concentration of 0.5 to 2 mg / mL; (bii) ascorbic acid or a salt thereof at a concentration of 2.0 to 5.0 mg / mL; Including, (d) Below: (di) acetic acid at a concentration of 0.3 to 0.7 mg / mL; (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL; an acetate buffer consisting of further comprising The acetate buffer provides a pH of 4.5 to 6.0; and the pharmaceutical aqueous solution is ethanol-free.

2. (bi) gentisic acid is present at a concentration of 0.5 to 1 mg / mL; and (bii) ascorbic acid is present at a concentration of 2.0 to 5.0 mg / mL; 2. The pharmaceutical aqueous solution of claim 1.

3. (c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg / mL; 3. The pharmaceutical aqueous solution of claim 1 or 2, further comprising:

4. 4. The pharmaceutical aqueous solution according to any one of claims 1 to 3, which has a shelf life of at least 72 h when stored at < 25°C, in particular at least 72 h when stored at 25°C.

5. 5. The pharmaceutical aqueous solution of any one of claims 1 to 4, wherein the radiochemical purity (as determined by HPLC) is maintained at ≥ 95% for at least 72 h when stored at 25°C.

6. 6. The aqueous medicinal solution according to any one of claims 1 to 5, which is ready to use.

7. (1) The following: (1.1) preparing an aqueous solution containing a radionuclide; (1.2) preparing an aqueous solution containing DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) and gentisic acid; (1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the mixture obtained; By this, radioactive nuclides １７７ forming a complex of Lu with DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide); (2) The following: (2.1) preparing a dilute aqueous solution containing ascorbic acid; (2.2.) Mixing the complex solution obtained in step (1) with the diluted solution obtained in step (2.1) to obtain a final solution; a process step of diluting the complex solution obtained in step (1) by Including, A process for producing the aqueous pharmaceutical solution of any one of claims 1 to 6.

8. 8. The process of claim 7, wherein the solution prepared in step (1.2) comprises one or more stabilizers at a total concentration of 15 to 50 mg / mL.

9. 9. The process according to claim 7 or 8, wherein the solution prepared in step (1.2) contains only one stabilizer, which is gentisic acid at a concentration of 20 to 40 mg / mL.

10. 10. The process of any one of claims 7 to 9, wherein the solution of step (1.2) further comprises a buffering agent.

11. 11. The process according to any one of claims 7 to 10, wherein in step (1.3), the resulting mixture is heated to a temperature of 70 to 99°C for a time of 2 to 59 minutes.

12. 12. The process of any one of claims 7 to 11, wherein the solution of step (2.1) further comprises diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

13. (3) filtering the solution obtained in step (2) through a 0.2 μm filter; (4) dispensing the filtered solution obtained from step (3) into dose unit containers in an amount necessary to deliver a radiation dose of 5.0 to 10 MBq. The process of any one of claims 7 to 12, further comprising:

14. The solution in step (1.1) is ３ and HCl.

15. 15. The process of any one of claims 7 to 14, wherein the solution of step (1.2) comprises DOTA-TATE or DOTA-TOC, gentisic acid, acetic acid, and sodium acetate.

16. 16. The process of any one of claims 7 to 15, wherein the solution of step (2.1) comprises DTPA and ascorbic acid.

17. The process according to any one of claims 7 to 16, wherein at least gentisic acid is present in the complex solution obtained in step (1), and at least ascorbic acid is added in step (2).

18. 17. The process of any one of claims 7 to 16, wherein the only stabilizer present in the complex solution obtained in step (1) is gentisic acid, and the only stabilizer added in step (2) is ascorbic acid.

19. 19. The process of any one of claims 7 to 18, wherein the dose unit containers of step (4) are stoppered vials sealed within lead containers.

20. 20. The process of any one of claims 7 to 19, wherein the solution is produced on a commercial manufacturing scale with a batch size of at least 20 GBq.

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