RU2789366C2 - Stable concentrated solutions of radionuclide complexes - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: present invention relates to an aqueous solution of a radiopharmaceutical product. The proposed solution contains: (a) complex formed with (ai) ¹⁷⁷Lu radionuclide (lutetium-177) and (aii) peptide binding to a somatostatin receptor, connected to DOTA chelate-forming agent, and (b) at least two different stabilizers preventing radiolitic decomposition, where the stabilizer preventing radiolitic decomposition is selected from gentisinic acid and ascorbic acid. At the same time, (bi) gentisinic acid is present at a concentration from 0.5 to 2 mg/ml, preferably from 0.5 to 1 mg/ml, and (bii) ascorbic acid is present at a concentration from 2.0 to 5.0 mg/ml. The specified radionuclide is present at such a concentration, which provides volumetric radioactivity from 250 to 500 MMC/ml. The aqueous solution of the pharmaceutical product contains less than 1% of ethanol. A method for the manufacture of an aqueous solution of a radiopharmaceutical product is also proposed.

EFFECT: invention allows for obtainment of a highly concentrated solution of a radionucleotide complex, which is very chemically and radio-chemically stable, even if it is stored at ambient temperatures or, for a short time, at elevated temperatures, so that it can be produced at an industrial scale and supplied in the form of a ready-to-use radiopharmaceutical product.

28 cl, 2 tbl, 3 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to solutions of radionuclide complexes with high concentration and high chemical and radiochemical stability, which enable their use as a commercial drug product for diagnostic and/or therapeutic purposes.

BACKGROUND OF THE INVENTION

The concept of targeted drug delivery is based on the fact that cellular receptors are overexpressed in the target cell as opposed to non-targeted cells. If the drug has a binding site for these overexpressed cellular receptors, it will deliver the drug after systemic administration in high concentration to these target cells while leaving other non-target cells unaffected. For example, if tumor cells overexpress a particular cellular receptor, a drug with binding affinity for that receptor after intravenous infusion will accumulate in high concentration in the tumor tissue while leaving normal tissue intact.

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

For this radiomedicine application, the target cellular receptor-binding moiety is typically coupled to a chelating agent that is capable of forming a stable complex with radionuclide metal ions. This radiopharmaceutical is then delivered to the target cell and decay of the radionuclide then releases high energy electrons, positrons or alpha particles, and gamma rays at the target site.

One technical problem associated with these radiopharmaceutical drug products is that the decay of the radionuclide occurs constantly, for example also during the manufacture and storage of the drug product, and the high energy radiation emitted causes the chemical bonds of the molecules that form part of the drug product to be broken. This is often referred to as radiolysis or radiolytic decomposition. Radiolytic degradation of a receptor-binding moiety of a drug may reduce its effectiveness as a diagnostic and/or therapeutic agent.

The poor stability of these radiopharmaceutical drug products and the lack of any significant shelf life has required that these drugs have hitherto been made into a single dose dosage form for a particular patient in laboratories in hospitals and administered immediately to a patient who had to be in hospital, already awaiting radiological treatment. To facilitate the production of such drugs in hospital laboratories, "cold" (ie, non-radioactive) freeze-dried kits have been developed that contain a cell receptor-binding moiety linked to a chelating agent without the radionuclide. The freeze-dried contents of the vessels of these kits were then redissolved in the radionuclide solution just prior to administration (Das et al. J Radioanal Nucl Chem 2014, 299, 1389-1398; Das et al. Current Radiopharmaceuticals 2014, 7, 12-19; Luna-Gutierrez et al J Radioanal Nucl Chem 2017, 314, 2181-2188 ). However, these kits are not "off the shelf" as they require a re-dissolution step and additional processing steps (e.g. application of heat to the complexation reaction) as well as purification and sterilization steps before the drug can finally be administered. .

To reduce the radiolysis of radiopharmaceutical drug products and thus improve stability, various strategies have been explored more or less successfully: the drug product can be stored at low temperatures, or prepared at high dilution, or stabilizers can be added.

However, the addition of stabilizers can be problematic because these chemicals can have a negative effect on the complexation of the radionuclide with the chelating agent, or they can have limited solubility and precipitate out of solution. Ethanol has been reported as a stabilizer to prevent radiolysis ( WO 2008/009444 ). Although ethanol may not adversely affect complexation or solubility, large amounts of ethanol in the infusion solution may be physiologically problematic and may have a negative effect on the tolerability of the drug product.

The preparation of a drug product at a high dilution has the disadvantage that patients need to administer large volumes of infusion solutions. For the convenience of patients and for reasons for the tolerance of the drug, it will be very desirable to provide a radiopharmaceutical medicinal product in high concentration. However, these very concentrated solutions are particularly prone to radiolysis. Thus, there are conflicting positions between, on the one hand, by avoiding radiolysis by diluting the drug product, and, on the other hand, avoiding discomfort for the patient in treatment by ensuring a concentrated solution of the drug. Mathur et al. Cancer Biotherapy and Radiopharmaceuticals, 2017, 32 (7), 266-273 reported a product with a high concentration and it was announced as ready for use. However, this composition may have problems in terms of tolerability since it contains large amounts of ethanol.

Thus, the problem remains to provide a ready-to-use radiopharmaceutical drug product that can be produced at an industrial level and delivered as a sufficiently stable and sterile high concentration solution that provides a patient-friendly small volume of solution for infusion and that has a composition with high physiological tolerance. (for example, a composition that does not contain ethanol).

BRIEF DESCRIPTION OF THE INVENTION

The present inventors have found a way to develop and produce a highly concentrated radionuclide complex solution that is chemically and radiochemically very stable, even when stored at ambient temperatures or briefly at elevated temperatures, so that it can be produced on an industrial scale and supplied as a finished product. to the use of a radiopharmaceutical product.

The present invention is presented in various aspects, summarized below.

An aqueous solution of a pharmaceutical agent containing

(a) the complex formed

(ai) a radionuclide and

(aii) a cell receptor-binding organic moiety coupled to a chelating agent; And

(b) at least one stabilizer that prevents radiolytic decomposition;

Where

said radionuclide is present in a concentration that provides a volumetric radioactivity of at least 100 MBq/ml, preferably at least 250 MBq/ml.

Said stabilizer(s) representing component (b) is present at a total concentration of at least 0.2 mg/ml, preferably at least 0.5 mg/ml, more preferably at least 1.0 mg/ml, even more preferably at least 2.7 mg/ml.

An aqueous solution of a pharmaceutical agent containing

(a) the complex formed

(ai) a ¹⁷⁷ lutetium (Lu-177) radionuclide present at a concentration such that a volumetric radioactivity is between 250 and 500 MBq/mL, and

(aii) a chelating somatostatin receptor-binding organic fragment of DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide);

(bi) gentisic acid or a salt thereof as a first anti-radiolytic degradation stabilizer present at a concentration of 0.5 to 1 mg/ml;

(bii) ascorbic acid or a salt thereof as a second stabilizer to prevent radiolytic degradation, present at a concentration of 2.0 to 5.0 mg/ml.

A method for manufacturing said aqueous solution of a pharmaceutical agent as defined above, comprising the steps of the method

(1) formation of a complex of a radionuclide and an organic fragment associated with a chelating agent that binds to a cell receptor through

(1.1) obtaining an aqueous solution containing the radionuclide;

(1.2) obtaining an aqueous solution containing a chelating agent-binding cell receptor organic moiety, a first stabilizer, optionally a second stabilizer; And

(1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture;

(2) diluting the solution of the complex obtained in step (1) with

(2.1) obtaining an aqueous solution for dilution, optionally containing a second stabilizer; And

(2.2.) mixing the solution of the complex obtained in step (1) with the dilution solution obtained in step (2.1).

The present invention provides the following advantages.

High concentration ensures the introduction of a high dose in a short period of time. For example, in the case of ¹⁷⁷ Lu-DOTA-TATE, a high dose of 7.4 GBq can be provided in a small volume of 20.5 to 25.0 ml, allowing completion of the intravenous infusion within approximately 20-30 minutes.

The use of suitable stabilizer(s) according to the present invention, as described herein, provides high stability, at least 95%, 96%, 97%, 98%, 99% or 100% chemical stability relative to chemical purity for binding with a cell receptor molecule after 72 hours at 25°C, even if this molecule is a sensitive peptide molecule. For example, for DOTA-TATE, it was found that after 72 hours at 25°C, and even after 48 hours at 32°C, the chemical purity was 100%. Even under short-term elevated temperature conditions (32° C. for 12 hours and 25° C. for 60 hours), this high stability with respect to chemical purity was found.

In addition, the use of suitable stabilizer(s) according to the present invention, as described herein, provides high stability, at least 95% radiochemical stability relative to the radiochemical purity of the radionuclide complex. For example, for ¹⁷⁷ LU-Dota-Tate, after 72 hours at 25 ° C, a radiochemical cleanliness was found, which makes up at least 95%. Even under conditions of short-term elevated temperature (32° C. for 12 hours and 25° C. for 60 hours), this high stability was found in relation to radiochemical purity.

Although sufficient stability can already be obtained with a single stabilizer, the use of two stabilizers has been found to be particularly suitable in stabilizing solutions of sensitive radiopharmaceuticals. In particular, the presence of one stabilizer during complexation and another stabilizer added after complexation is preferred, as this ensures that already during the complexation reaction, the cell receptor-binding molecule is protected from radiolysis, and the other stabilizer increases the protective effect over time. storage.

In addition, by this sequential application of two stabilizers, it is ensured that only a relatively small amount of stabilizer is present during complexation (which minimizes the potential negative effect of this stabilizer on the complexation reaction), and after complexation, a large amount of a combination of stabilizers is present (which increases the protective effect of stabilizers for subsequent shelf life of the medicinal product).

This sequential use of two stabilizers also reduces the overall heat load on these stabilizers, since one of them is not present in the implementation of the complexation reaction, which involves high temperatures.

In addition, the use of two different stabilizers is particularly preferred, since this combination is more effective in interacting with various radicals, probably formed as a result of radiolysis of the cell receptor-binding molecule, than a single stabilizer alone.

The composition of the radiopharmaceutical solution does not require the presence of ethanol. The solution is fairly stable without ethanol. The absence of ethanol is advantageous in relation to the physiological tolerance of the solution.

A shelf life of at least 3 days is required to ensure that a radiopharmaceutical drug product is manufactured from a centralized pharmaceutical production site to mass production as a ready-to-use drug product.

Thus, due to the high stability (72 h at 25°C), the present invention allows for the centralized production of a pharmaceutical product with the highest quality standards (e.g. cGMP) and on an industrial scale, for example, in a batch size corresponding to 74 GBq or 148 GBq, which provides the drug product in the form of multiple dose units, for example, dose units in an amount sufficient to treat 10-20 patients at a time.

In addition, due to the high stability, there is sufficient time for the present invention to travel from a centralized pharmaceutical production site to remote clinical centers.

In addition, due to high stability, the present invention can be provided as a ready-to-use infusion solution that can be immediately administered to a patient without the need for medical personnel to perform any preparatory work before administration.

The present invention is particularly suitable for somatostatin receptor binding peptides, herein in particular the very sensitive somatostatin analogs octreotide and octreotate, which are highly susceptible to degradation reactions. In addition, the present invention is particularly suitable for the lutetium-177 radionuclide with its specific radioactivity characteristics.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention is described in more detail and illustrated by examples.

In general, the present invention relates to an aqueous solution of a pharmaceutical agent, in particular an aqueous solution of a radiopharmaceutical. The solution is intended for intravenous (IV) use/application/administration. The solution is stable, concentrated and ready to use.

The stability of the solution is ensured by the use of stabilizers that prevent radiolytic decomposition.

In general, the stabilizers used in the present invention may be selected from gentisic acid (2,5-dihydroxybenzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g. sodium ascorbate), methionine, histidine, melatonin, ethanol and Se-methionine. Preferred stabilizers are selected from gentisic acid or salts thereof and ascorbic acid or salts thereof.

Ethanol is considered a less preferred stabilizer due to tolerance issues associated with its presence in high concentrations. Ideally, the presence of ethanol in the solutions of the present invention should be avoided (in other words: does not contain ethanol), at least the amount of ethanol in the solutions of the present invention should be limited, for example, less than 5%, preferably less than 2%, more preferably less than 1% in the final solution, which is intended for injection / infusion. Even more preferably, the solution does not contain ethanol.

According to the present invention, the following embodiments are provided.

1. An aqueous solution of a pharmaceutical agent containing

(a) the complex formed

(ai) a radionuclide and

(aii) a cell receptor-binding organic moiety coupled to a chelating agent; And

(b) at least one stabilizer that prevents radiolytic decomposition;

Where

said radionuclide is present in a concentration that provides a volumetric radioactivity of at least 100 MBq/ml, preferably at least 250 MBq/ml.

2. An aqueous solution of a pharmaceutical agent according to Embodiment 1,

where the specified (specified) stabilizer(s), which is (representing) component (b), is (are present) in a total concentration of at least 0.2 mg/ml, preferably at least 0.5 mg/ml, more preferably at least 1.0 mg/ml, even more preferably at least 2.7 mg/ml.

3. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein said radionuclide is present at a concentration that provides a volumetric radioactivity of 100 to 1000 MBq/ml, preferably 250 to 500 MBq/ml.

4. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein said stabilizer(s) is(are) present in a total concentration of 0.2 to 20.0 mg/mL, preferably 0.5 to 10 .0 mg/ml, more preferably 1.0 to 5.0 mg/ml, even more preferably 2.7 to 4.1 mg/ml.

5. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments,

where component (b) is the only stabilizer that prevents radiolytic decomposition, i.e. only the first stabilizer is present.

6. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments,

where component (b) is at least two anti-radiolytic degradation stabilizers, i.e. at least first and second stabilizers are present, preferably only two stabilizers, i.e. only first and second stabilizers.

7. An aqueous solution of a pharmaceutical agent according to any one of embodiments 5-6, wherein the first stabilizer is present at a concentration of 0.2 to 5 mg/mL, preferably 0.5 to 5 mg/mL, more preferably 0.5 up to 2 mg/ml, even more preferably 0.5 to 1 mg/ml, even more preferably 0.5 to 0.7 mg/ml.

8. An aqueous solution of a pharmaceutical agent according to embodiment 6 or 7, wherein the second stabilizer is present at a concentration of 0.5 to 10 mg/mL, more preferably 1.0 to 8.0 mg/mL, even more preferably 2 0 to 5.0 mg/ml, even more preferably 2.2 to 3.4 mg/ml.

9. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein the stabilizer(s) is(are) selected from gentisic acid (2,5-dihydroxybenzoic acid) or its salts, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (eg sodium ascorbate), methionine, histidine, melatonin, ethanol and Se-methionine, preferably selected from gentisic acid or its salts and ascorbic acid or its salts.

10. An aqueous solution of a pharmaceutical agent according to any one of embodiments 5-9, wherein the first stabilizer is selected from gentisic acid and ascorbic acid, preferably the first stabilizer is gentisic acid.

11. An aqueous solution of a pharmaceutical agent according to any one of embodiments 6-10, wherein the second stabilizer is selected from gentisic acid and ascorbic acid, preferably the second stabilizer is ascorbic acid.

12. An aqueous solution of a pharmaceutical agent according to any one of embodiments 6-8, wherein the first stabilizer is gentisic acid or a salt thereof and the second stabilizer is ascorbic acid or a salt thereof, and wherein the concentration ratio (in mg/mL) of the first stabilizer and the concentration (in mg/ml) of the second stabilizer is 1:3 to 1:7, preferably 1:4 to 1:5.

13. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein the radionuclide is selected from ¹⁷⁷ Lu, ⁶⁸ Ga, ¹⁸ F, ^99m Tc, ²¹¹ At, ⁸² Rb, ¹⁶⁶ Ho, ²²⁵ Ac, ¹¹¹ In, ¹²³ I, ¹³¹ I, ⁸⁹ Zr, ⁹⁰ Y is preferably selected from ¹⁷⁷ Lu and ⁶⁸ Ga, more preferably ¹⁷⁷ Lu.

14. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein the cell receptor binding moiety is a somatostatin receptor binding peptide, preferably said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate.

15. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein the chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, NOC and NOTA, preferably DOTA.

16. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein the cellular receptor binding moiety and the chelating agent together form molecules selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA -LAN and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, are more preferably DOTA-TATE.

17. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein the radionuclide, the cellular receptor binding moiety and the chelating agent together form a ¹⁷⁷ Lu-DOTA-TOC ( ¹⁷⁷ Lu-edotreotide) or ¹⁷⁷ Lu-DOTA-TATE ( ¹⁷⁷ Lu-oxodotreotide) complex. ), preferably ¹⁷⁷ Lu-DOTA-TATE.

18. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, further containing a buffer, preferably said buffer is an acetate buffer, preferably in an amount that provides a concentration of from 0.3 to 0.7 mg/ml (preferably about 0.48 mg /ml) acetic acid and 0.4 to 0.9 mg/ml (preferably about 0.66 mg/ml) sodium acetate.

19. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, further containing a sequestering agent, preferably said sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof, preferably in such an amount that provides a concentration of from 0.01 to 0.10 mg /ml (preferably about 0.05 mg/ml).

20. Aqueous solution of the pharmaceutical agent according to any of the previous embodiments, which is characterized by a shelf life , which is at least 24 hours (h) at at least 48 hours at at least 72 hours ≤ 25°C, 24 h to 120 h at ≤ 25°C, 24 h to 96 h at ≤ 25°C, 24 h to 84 h at ≤ 25°C, 24 h to 72 h at ≤ 25 °C, in particular characterized by a shelf life of 72 hours at ≤ 25°C.

21. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein said solution is obtained by manufacturing on an industrial scale, in particular, obtained with a batch size corresponding to at least 20 GBq, at least 50 GBq, at least 70 GBq.

22a. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, which is ready for use.

22b. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, which is intended for commercial use.

23. An aqueous solution of a pharmaceutical agent containing

(a) the complex formed

(ai) a lutetium-177 ( ¹⁷⁷ Lu) radionuclide present at a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml, and

(aii) a chelating somatostatin receptor-binding organic fragment of DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide);

(bi) gentisic acid or a salt thereof as a first anti-radiolytic degradation stabilizer present at a concentration of 0.5 to 1 mg/ml;

(bii) ascorbic acid or a salt thereof as a second stabilizer to prevent radiolytic degradation, present at a concentration of 2.0 to 5.0 mg/ml.

24. An aqueous solution of a pharmaceutical agent according to embodiment 23, further comprising

(c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/ml.

25. An aqueous solution of a pharmaceutical agent according to embodiments 23 or 24, further comprising

(d) acetic acid at a concentration of 0.3 to 0.7 mg/ml and sodium acetate at a concentration of 0.4 to 0.9 mg/ml.

26. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, wherein the stabilizer(s) is(are) present in the solution during the formation of the complex from components (ai) and (aii).

27. An aqueous solution of a pharmaceutical agent according to any one of embodiments 5-26, where only the first stabilizer is present during the formation of the complex from components (ai) and (aii), preferably in such an amount that provides in the final solution a concentration of from 0.5 to 5 mg/ml, more preferably 0.5 to 2 mg/ml, even more preferably 0.5 to 1 mg/ml, even more preferably 0.5 to 0.7 mg/ml.

28. An aqueous solution of a pharmaceutical agent according to any one of embodiments 6-27, wherein part of the amount of the second stabilizer is already present in solution at the time of complexing of components (ai) and (aii), and another part of the amount of second stabilizer is added after complexing of the components (ai) and (aii).

29. An aqueous solution of a pharmaceutical agent according to any one of embodiments 6-28, wherein the second stabilizer is added after complexation of components (ai) and (aii).

30. An aqueous solution of a pharmaceutical agent according to embodiment 6 or 29, wherein the second stabilizer is added after the complexation of components (ai) and (aii), preferably in such an amount that provides a concentration of 0.5 to 10 mg/ml in the final solution , more preferably 1.0 to 8.0 mg/ml, even more preferably 2.0 to 5.0 mg/ml, even more preferably 2.2 to 3.4 mg/ml.

31. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, further containing a sequestering agent added after the formation of the complex from components (ai) and (aii), to remove any uncomplexed Lu, preferably said sequestering agent is diethylenetriaminepentaacetic acid ( DTPA) or a salt thereof, preferably in such an amount that provides in the final solution a concentration of from 0.01 to 0.10 mg/ml (preferably about 0.05 mg/ml).

32. A method for making an aqueous solution of a pharmaceutical agent as defined in any of the previous embodiments, comprising the steps of the method

(1) formation of a complex of a radionuclide and an organic fragment associated with a chelating agent that binds to a cell receptor through

(1.1) obtaining an aqueous solution containing the radionuclide;

(1.2) obtaining an aqueous solution containing a chelating agent-binding cell receptor organic moiety, a first stabilizer, optionally a second stabilizer; And

(1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture;

(2) diluting the solution of the complex obtained in step (1) with

(2.1) obtaining an aqueous solution for dilution, optionally containing a second stabilizer; And

(2.2.) mixing the solution of the complex obtained in step (1) with the dilution solution obtained in step (2.1).

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

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

35. An aqueous solution of a pharmaceutical agent according to any one of embodiments 32-34, wherein the second stabilizer is added after step (1.3) in step (2.1).

36. Aqueous solution of the pharmaceutical agent according to any of the options for 32-35, where the second stabilizer is added after stage (1.3) at stage (2.1) preferably in such an amount that provides in the final solution a concentration of 0.5 to 10 mg/ml, More preferably from 1.0 to 8.0 mg/ml, even more preferably from 2.0 to 5.0 mg/ml, even more preferably from 2.2 to 3.4 mg/ml.

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

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

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

40. The method according to any one of embodiments 32-39, further comprising the steps of the method

(3) passing the solution obtained in step (2) through a filter with a pore size of 0.2 µm:

(4) dispensing the filtered solution obtained in step (3) into the dose unit containers in the volume necessary to deliver a radioactive dose of 5.0 to 10 MBq, preferably 7.0 to 8.0 MBq, more preferably 7.3 to 7.7 MBq, even more preferably 7.4 to 7.5 MBq, preferably said volume is 10 to 50 ml, more preferably 15 to 30 ml, even more preferably 20 to 25 ml.

41. The method according to any one of embodiments 32-40, wherein the solution in step (1.1) contains LuCl ₃ and HCl.

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

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

44. The method according to any one of embodiments 32-43, wherein the dose unit containers in step (4) are stoppered vials placed in a lead container.

45. An aqueous solution of a pharmaceutical agent obtained (or obtained) using the method defined in any of paragraphs. 32-44.

Additional embodiments of the present invention are described below as "embodiments E".

E1. An aqueous solution of a pharmaceutical agent containing

(a) the complex formed

(ai) radionuclide ¹⁷⁷ Lu (lutetium-177) and

(aii) a somatostatin receptor-binding peptide coupled to a chelating agent DOTA; And

(b) at least two different anti-radiolytic degradation stabilizers;

Where

the specified radionuclide is present in such a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml; And

these stabilizers are present in a total concentration of 0.2 to 20.0 mg/ml.

"Complex formed" can be expressed differently as "complex from".

"Different" in "two different stabilizers" refers to the difference in the chemical structure of these stabilizers. The expression "two different stabilizers" means that the two stabilizers are different chemical compounds, for example, gentisic acid and ascorbic acid are two different stabilizers.

"At least two" means two or more, however, preferably only two stabilizers are present (not three or more). It is also preferred that ethanol is not one of the two stabilizers.

E2. An aqueous solution of a pharmaceutical agent according to embodiment E1,

where the specified component (b) contains stabilizers:

(bi) gentisic acid or a salt thereof, and

(bii) ascorbic acid or a salt thereof.

E3. An aqueous solution of a pharmaceutical agent according to embodiment E2,

Where

(bi) gentisic acid is present at a concentration of 0.5 to 2 mg/ml, preferably 0.5 to 1 mg/ml; And

(bii) ascorbic acid is present at a concentration of 2.0 to 5.0 mg/ml.

In a specific embodiment, the present invention provides for the following.

An aqueous solution of a pharmaceutical agent containing

(a) a complex formed

(ai) a radionuclide ¹⁷⁷ Lu (lutetium-177) in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml, and

(aii) a somatostatin receptor-binding peptide coupled to a chelating agent DOTA; And

(b) stabilizers to prevent radiolytic degradation:

(bi) gentisic acid at a concentration of 0.5 to 1 mg/ml and

(bii) ascorbic acid at a concentration of 2.0 to 5.0 mg/ml.

E4. An aqueous solution of a pharmaceutical agent according to Embodiment E3, further comprising

(c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/ml.

E5. An aqueous solution of a pharmaceutical agent according to embodiments E3 or E4, further comprising

(d) an acetate buffer consisting of

(di) acetic acid at a concentration of 0.3 to 0.7 mg/ml and

(dii) sodium acetate at a concentration of 0.4 to 0.9 mg/ml;

preferably said acetate buffer provides a pH of 4.5 to 6.0, preferably 4.7 to 6.0, more preferably 5.0 to 6.0, even more preferably 5.0 to 5.5.

In a specific embodiment, the present invention provides for the following.

An aqueous solution of a pharmaceutical agent containing

(a) a complex formed

(ai) a radionuclide ¹⁷⁷ Lu (lutetium-177) in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml, and

(aii) a somatostatin receptor-binding peptide coupled to a chelating agent DOTA;

(b) anti-radiolytic degradation stabilizers: (bi) gentisic acid at a concentration of 0.5 to 1 mg/ml and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg/ml;

(c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/ml, and

(d) an acetate buffer consisting of

(di) acetic acid at a concentration of 0.3 to 0.7 mg/ml and

(dii) sodium acetate at a concentration of 0.4 to 0.9 mg/ml;

preferably said acetate buffer provides a pH of 5.0 to 5.5.

The pH values given in this document are the pH values of the final solution. However, the values also represent the pH at the time the solution is made, eg the pH at the time of complex formation.

E6. An aqueous solution of a pharmaceutical agent according to any one of embodiments E1-E5, wherein at least one of the stabilizers is present during complexation of components (ai) and (aii), and at least one of the stabilizers is added after complexation of components (ai ) and (aii).

E7. An aqueous solution of a pharmaceutical agent according to any one of embodiments E1-E5, wherein at least gentisic acid is present during complexation of components (ai) and (aii), and at least ascorbic acid is added after complexation of components (ai) and (aii).

E8. An aqueous solution of a pharmaceutical agent according to any one of embodiments E1-E5, wherein the only stabilizer present during complexation of components (ai) and (aii) is gentisic acid and the only stabilizer added after complexation of components (ai) and (aii) is ascorbic acid.

In a specific embodiment, the present invention provides for the following.

An aqueous solution of a pharmaceutical agent containing

(a) a complex formed

(ai) a radionuclide ¹⁷⁷ Lu (lutetium-177) in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml, and

(aii) a somatostatin receptor-binding peptide coupled to a chelating agent DOTA; And

(b) stabilizers to prevent radiolytic degradation:

(bi) gentisic acid at a concentration of 0.5 to 1 mg/ml (in the final solution) and

(bii) ascorbic acid at a concentration of 2.0 to 5.0 mg/ml (in the final solution);

where gentisic acid is present during the formation of the complex from components (ai) and (aii), and ascorbic acid is added after the formation of the complex from components (ai) and (aii).

In a specific embodiment, the present invention is defined as follows.

An aqueous solution of a pharmaceutical agent containing

(a) a complex formed

(ai) a radionuclide ¹⁷⁷ Lu (lutetium-177) in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml, and

(aii) a somatostatin receptor-binding peptide coupled to a chelating agent DOTA;

(b) anti-radiolytic degradation stabilizers: (bi) gentisic acid at a concentration of 0.5 to 1 mg/ml and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg/ml;

(c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/ml, and

(d) an acetate buffer consisting of

(di) acetic acid at a concentration of 0.3 to 0.7 mg/ml and

(dii) sodium acetate at a concentration of 0.4 to 0.9 mg/ml;

preferably said acetate buffer provides a pH of 5.0 to 5.5;

where gentisic acid is present during the formation of the complex from components (ai) and (aii), and ascorbic acid is added after the formation of the complex from components (ai) and (aii).

E9. An aqueous solution of a pharmaceutical agent according to any one of embodiments E6-E8, wherein the given stabilizer/stabilizers, which/are present at the time of complexation of components (ai) and (aii), is/are present at the time of complexation in total concentrations from 15 to 50 mg/ml, preferably from 20 to 40 mg/ml.

E10. An aqueous solution of a pharmaceutical agent according to embodiment E9, wherein the only stabilizer present during complexation of components (ai) and (aii) is gentisic acid and is present during complexation at a concentration of 20 to 40 mg/mL, preferably from 25 to 35 mg/ml.

In a specific embodiment, the present invention is defined as follows.

An aqueous solution of a pharmaceutical agent containing

(a) a complex formed

(ai) a radionuclide ¹⁷⁷ Lu (lutetium-177) in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml, and

(aii) a somatostatin receptor-binding peptide coupled to a chelating agent DOTA;

(b) anti-radiolytic degradation stabilizers: (bi) gentisic acid at a concentration of 0.5 to 1 mg/ml and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg/ml;

(c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/ml, and

(d) an acetate buffer consisting of

(di) acetic acid at a concentration of 0.3 to 0.7 mg/ml and

(dii) sodium acetate at a concentration of 0.4 to 0.9 mg/ml;

preferably said acetate buffer provides a pH of 5.0 to 5.5;

where gentisic acid is present during the formation of the complex from components (ai) and (aii), and ascorbic acid is added after the formation of the complex from components (ai) and (aii); and wherein the only stabilizer present during complexation of components (ai) and (aii) is gentisic acid and is present during complexation at a concentration of 20 to 40 mg/mL, preferably 25 to 35 mg/mL.

Embodiments E6-E10 may alternatively be defined using the following definitions.

E6. An aqueous solution of a pharmaceutical agent according to any one of embodiments E1-E5, obtained by having at least one of the stabilizers during the formation of the complex from the components (ai) and (aii) and at least one of the stabilizers added after the formation of the complex from the components ( ai) and (aii).

E7. An aqueous solution of a pharmaceutical agent according to any one of embodiments E1-E5, obtained by having at least gentisic acid during complexation of components (ai) and (aii) and adding at least ascorbic acid after complexation of components (ai) and (aii).

E8. An aqueous solution of a pharmaceutical agent according to any one of embodiments E1-E5, obtained by having gentisic acid as the only stabilizer present during complexation of components (ai) and (aii), and ascorbic acid as the only stabilizer added after complexation Of the components (AI) and (AII).

E9. An aqueous solution of a pharmaceutical agent according to any of embodiments E6-E8, obtained by the presence of this/data stabilizer/stabilizers present/present during the formation of the complex from components (ai) and (aii) which/are present/are present during the formation of the complex in a total concentration of 15 to 50 mg/ml, preferably 20 to 40 mg/ml.

E10. An aqueous solution of a pharmaceutical agent according to Embodiment E9 obtained by having gentisic acid as the sole stabilizer present during the complexation of components (ai) and (aii) and present during the complexation at a concentration of 20 to 40 mg/ml, preferably from 25 to 35 mg/ml.

In embodiments of the present invention, in particular in embodiments E9 and E10, the radionuclide may be present at the time of complex formation at a concentration that provides a volumetric radioactivity of not more than 20 GBq/ml, preferably not more than 15 GBq/ml, or from 5 to 20 GBq/ml, preferably 10 to 20 GBq/ml, more preferably 10 to 15 GBq/ml.

In a specific embodiment, the present invention is defined as follows.

An aqueous solution of a pharmaceutical agent containing

(a) a complex formed

(ai) a radionuclide ¹⁷⁷ Lu (lutetium-177) in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml (in the final solution), and

(aii) a somatostatin receptor-binding peptide coupled to a chelating agent DOTA;

(b) anti-radiolytic degradation stabilizers: (bi) gentisic acid at a concentration of 0.5 to 1 mg/ml and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg/ml;

(c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/ml, and

(d) an acetate buffer consisting of

(di) acetic acid at a concentration of 0.3 to 0.7 mg/ml and

(dii) sodium acetate at a concentration of 0.4 to 0.9 mg/ml;

preferably said acetate buffer provides a pH of 5.0 to 5.5;

where gentisic acid is present during the formation of the complex from components (ai) and (aii), and ascorbic acid is added after the formation of the complex from components (ai) and (aii); and while the only stabilizer present during the formation of the complex of components (ai) and (aii) is gentisic acid and is present during the formation of the complex at a concentration of from 20 to 40 mg/ml;

and wherein the radionuclide is present at the time of complex formation at a concentration that provides a volumetric radioactivity of 10 to 20 GBq/mL.

E11. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments E, which has a shelf life of at least 72 hours when stored at ≤ 25°C, in particular at least 72 hours when stored at 25°C.

"Shelf life" has its usual meaning herein in the context of pharmaceutical products. Shelf life is the period of time that a pharmaceutical product can be stored while still meeting the product specification defined during drug development and approved by health authorities.

E12. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments E, for which the radiochemical purity (determined by HPLC) is maintained at ≥ 95% for at least 72 hours when stored at 25°C.

E13. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments E, wherein said solution is produced on an industrial scale, in particular produced in a batch size corresponding to at least 20 GBq, at least 50 GBq, at least 70 GBq.

E14. An aqueous solution of a pharmaceutical agent according to any of the previous embodiments, which is ready for use.

E15. A method for making an aqueous solution of a pharmaceutical agent as defined in any of the previous embodiments E, comprising the steps of the method

(1) complexing the ¹⁷⁷ Lu radionuclide and the somatostatin receptor-binding peptide coupled to the chelating agent DOTA via

(1.1) obtaining an aqueous solution containing the radionuclide;

(1.2) obtaining an aqueous solution containing a somatostatin receptor-binding peptide connected to a chelating agent and at least one anti-radiolytic degradation stabilizer; And

(1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture;

(2) diluting the solution of the complex obtained in step (1) with

(2.1) obtaining an aqueous solution for dilution, optionally containing at least one stabilizer that prevents radiolytic decomposition; And

(2.2.) mixing the solution of the complex obtained in step (1) with the dilution solution obtained in step (2.1) to obtain a final solution;

where if the solution obtained in (1.2) contains only one stabilizer, then the solution obtained in (2.1) contains at least one stabilizer.

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

E17. The method according to embodiment E15, wherein the solution obtained in step (1.2) contains at least a gentisic acid stabilizer and the solution obtained in step (2.1) contains at least an ascorbic acid stabilizer.

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

E19. The method according to any one of embodiments E15-E18, wherein the solution obtained in step (1.2) contains stabilizer(s) in a total concentration of 15 to 50 mg/ml, preferably 20 to 40 mg/ml.

E20. The method according to any one of embodiments E15-E18, wherein the solution obtained in step (1.2) contains only one stabilizer, which is gentisic acid, at a concentration of 20 to 40 mg/ml, preferably 25 to 35 mg/ml.

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

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

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

E24. The method according to any one of embodiments E15-E23, further comprising the steps of the method

(3) passing the solution obtained in step (2) through a filter with a pore size of 0.2 µm:

(4) dispensing the filtered solution obtained in step (3) into the dose unit containers in the volume necessary to deliver a radioactive dose of 5.0 to 10 MBq, preferably 7.0 to 8.0 MBq, more preferably 7.3 to 7.7 MBq, even more preferably 7.4 to 7.5 MBq, preferably said volume is 10 to 50 ml, more preferably 15 to 30 ml, even more preferably 20 to 25 ml.

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

E26. The method according to any of the options for the E15-E25, where the solution at stage (1.2) contains ¹⁷⁷ LU-DOTA-TATE or ¹⁷⁷ LU-Dota-TOC, Gentisic acid, acetic acid and sodium acetate.

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

E28. The method according to any one of embodiments E24-E27, wherein the dose unit containers in step (4) are stoppered vials placed in a lead container.

E29. An aqueous solution of a pharmaceutical agent obtained (or obtained) using the method defined in any of embodiments E15-E28.

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

The present invention also provides an aqueous solution of a pharmaceutical agent as defined herein for use in the treatment of neuroendocrine tumors (NETs).

Alternatively, the present invention provides a method for treating NET in human patients in need of such treatment, which comprises administering an effective amount of an aqueous solution of a pharmaceutical agent as defined herein.

As a further alternative, the present invention contemplates the use of an aqueous solution of a pharmaceutical agent as defined herein for the manufacture/preparation of a medicament for the treatment of NET.

As a further alternative, the present invention provides a drug for the treatment of NET containing an aqueous solution of a pharmaceutical agent as defined herein.

Neuroendocrine tumors (NETs) that can be treated with aqueous solutions of a pharmaceutical agent as defined herein, alone or in combinations according to the present invention, are selected from the group consisting of gastrointestinal neuroendocrine tumor, carcinoid tumor, pheochromocytoma, paraganglioma, medullary thyroid cancer, neuroendocrine tumor of the lung, neuroendocrine tumor of the thymus, carcinoid tumor or neuroendocrine tumor of the pancreas, pituitary adenoma, tumors of the adrenal gland, Merkel cell carcinoma, breast cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, tumor of the head and neck, urothelial carcinoma ( bladder), renal cell carcinoma, hepatocellular carcinoma, GIST, neuroblastoma, bile duct tumor, cervical tumor, Ewing's sarcoma, osteosarcoma, small cell lung cancer (SCLC), prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, soup ratentorial primitive neuroectodermal tumor and esthesioblastoma.

Additional NET tumors that can be treated with aqueous solutions of a pharmaceutical agent as defined herein, alone or in combinations according to the present invention, can be selected from the group consisting of functional carcinoid tumor, insulinoma, gastrinoma, tumor that overexpresses vasoactive intestinal peptide ( VIP), glucagon, serotonin, histamine, ACTHoma, pheochromocytoma, and somatostatin.

The present invention also provides for a combination or combined therapy using a complex formed by radionuclide ¹⁷⁷ LU (Lutetius-177) and associated with a peptide somatostatin receptor connected to a lentor-former determined in this document, a combination or combined therapy with a aqueous solution of a pharmaceutical agent, determined in this document, together with one or more therapeutic agents specified later.

In certain instances, the aqueous solution of the pharmaceutical agent of the present invention is combined with other therapeutic agents such as other anti-cancer agents, anti-allergy agents, anti-nausea (or anti-emetics), analgesics, cytoprotective agents, and combinations thereof.

Common chemotherapeutic agents considered for use in combination therapies include anastrozole (Arimidex ^® ), bicalutamide (Casodex ^® ), bleomycin sulfate (Blenoxane ^® ), busulfan (Myleran ^® ), busulfan injection (Busulfex ^® ), capecitabine (Xeloda ^® ), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin ^® ), carmustine (BiCNU ^® ), chlorambucil (Leukeran ^® ), cisplatin (Platinol ^® ), cladribine (Leustatin ^® ), cyclophosphamide (Cytoxan ^® or Neosar ^® ), cytarabine, cytosine arabinoside (Cytosar-U ^® ), liposomal cytarabine injectable (DepoCyt ^® ), dacarbazine (DTIC-Dome ^® ), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine ^® ), liposomal daunorubicin citrate for injection (DaunoXome ^® ), dexamethasone, docetaxel (Taxotere ^® ), doxorubicin hydrochloride (Adriamycin ^® , Rubex ^® ), etoposide (Vepesid ^® ), fludarabine phosphate (Fludara ^® ), 5-fluorouracil (Adrucil ^® , Efudex ^® ), flutamide ( Eulexin ^® ), Thezacity bin, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea ^® ), idarubicin (Idamycin ^® ), ifosfamide (IFEX ^® ), irinotecan (Camptosar ^® ), L-asparaginase (ELSPAR ^® ), calcium leucovorin, melphalan (Alkeran ^® ), 6- mercaptopurine (Purinethol ^® ), methotrexate (Folex ^® ), mitoxantrone (Novantrone ^® ), mylotarg, paclitaxel (Taxol ^® ), nab-paclitaxel (Abraxane ^® ), phoenix (yttrium 90/MX-DTPA), pentostatin, polyferospan 20 with implant carmustine (Gliadel ^® ), tamoxifen citrate (Nolvadex ^® ), teniposide (Vumon ^® ), 6-thioguanine, thiotepa, tirapazamine (Tirazone ^® ), topotecan hydrochloride injection (Hycamptin ^® ), vinblastine (Velban ^® ), vincristine (Oncovin ^® ) and Vinorerelbin (Navelbine ^® ).

Anti-cancer agents of particular interest for combination with an aqueous solution of a pharmaceutical agent of the present invention include the following.

Tyrosine kinase inhibitors: erlotinib hydrochloride (Tarceva®); linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869 available from Genentech); sunitinib malate (Sutent®); bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-3-carbonitrile, also known as SKI- 606 and described in US Pat. No. 6,780,996); dasatinib (Sprycel®); pazopanib (Votrient®); sorafenib (Nexavar®); zactima (ZD6474); and imatinib or imatinib mesylate (Gilvec® and Gleevec®).

Vascular endothelium factor inhibitors (VEGF): bevacizumab (Avastin®), axitinib (Inlyta®); brivaniba alaninate (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate); sorafenib (Nexavar®); pazopanib (Votrient®); sunitinib malate (Sutent®); cediranib (AZD2171, CAS 288383-20-1); vargatef (BIBF1120, CAS 928326-83-4); foretinib (GSK1363089); telatinib (BAY57-9352, CAS 332012-40-5); apatinib (YN968D1, CAS 811803-05-1); imatinib (Gleevec®); ponatinib (AP24534, CAS 943319-70-8); tivozanib (AV951, CAS 475108-18-0); regorafenib (BAY73-4506, CAS 755037-03-7); vatalanib dihydrochloride (PTK787, CAS 212141-51-0); brivanib (BMS-540215, CAS 649735-46-6); vandetanib (Caprelsa® or AZD6474); motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide described in PCT Publication No. WO 02/066470); dovitinib with lactyl lactic acid (TKI258, CAS 852433-84-2); linfanib (ABT869, CAS 796967-16-3); cabozantinib (XL184, CAS 849217-68-1); lestaurtinib (CAS 111358-88-4); N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38703, CAS 345627-80-7); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3 -ol (BMS690514);N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide (BHG712, CAS 940310-85-0) and aflibercept (Eylea®), sulfatinib, surufatinib.

Platelet growth factor receptor (PDGF) inhibitors: imatinib (Gleevec®); linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869 available from Genentech); sunitinib malate (Sutent®); quisartinib (AC220, CAS 950769-58-1); pazopanib (Votrient®); axitinib (Inlyta®); sorafenib (Nexavar®); vargatef (BIBF1120, CAS 928326-83-4); telatinib (BAY57-9352, CAS 332012-40-5); valatinib dihydrochloride (PTK787, CAS 212141-51-0) and motesaniba diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2 -[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide as described in PCT Application Publication No. WO 02/066470).

Fibroblast growth factor inhibitors (FGFRs): brivaniba alaninate (BMS-582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate); vargatef (BIBF1120, CAS 928326-83-4); dovitinib with lactyl lactic acid (TKI258, CAS 852433-84-2); 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)-phenylamino]pyrimidin-4-yl}-1-methylurea (BGJ398, CAS 872511-34-7); danusertib (PHA-739358) and N-[2-[[4-(diethylamino)butyl]amino]-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]-N' -(1,1-dimethylethyl)urea (PD173074, CAS 219580-11-7), sulfatinib, surufatinib.

Aurora kinase inhibitors: danusertib (PHA-739358);N-[4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino]phenyl]benzamide (ZM447439, CAS 331771-20-1); 4-(2-amino-4-methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phenyl]-2-pyrimidinamine (CYC116, CAS 693228-63-6); tosacertib (VX680 or MK-0457, CAS 639089-54-6); alisertib (MLN8237); (N-{2-[6-(4-cyclobutylamino-5-trifluoromethylpyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazanonaphthalene-9-yl]- 2-oxoethyl}acetamide) (PF-03814735); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid (MLN8054, CAS 869363-13-3); cenisertib (R-763); barasertib (AZD1152) and N-cyclopropyl-N'-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea (AT9283).

Cyclin-dependent kinase (CDK) inhibitors: aloisin A; alvocidib (also known as flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone , and described in US patent No. 5621002); crizotinib (PF-02341066, CAS 877399-52-5); 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R.3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, hydrochloride (P276-00, CAS 920113-03-7); indisulam (E7070); roscovitine (CYC202); 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-ylpyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, hydrochloride (PD0332991); dinacyclib (SCH727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide (BMS 387032, CAS 345627-80-7); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid (MLN8054, CAS 869363-13-3); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322, CAS 837364-57 -5); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS 844442-38-2); 4-[2-methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438,CAS 602306-29-6); palbociclib (PD-0332991) and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfonimidoyl]phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl] hydroxy]-2-butanol (BAY 10000394), ribociclib.

Cell cycle checkpoint kinase (CHK) inhibitors: 7-hydroxystaurosporine (UCN-01); 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinylpyrazolo[1,5-a]pyrimidine-7-amine (SCH900776, CAS 891494-63-6); 5-(3-fluorophenyl)-3-ureidothiophene-2-carboxylic acid N-[(S)-piperidin-3-yl]amide (AZD7762, CAS 860352-01-8); 4-[((3S)-1-azabicyclo[2.2.2]oct-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR 124 , CAS 405168-58-3); 7-aminodactinomycin (7-AAD), isogranulathymide, debromohymenialdizine; N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]phenyl]-N'-(5-methyl-2-pyrazinyl)urea (LY2603618, CAS 911222-45-2); sulforaphane (CAS 4478-93-7, 4-methylsulfinyl butyl isothiocyanate); 9,10,11,12-tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1,3(2H)-dione (SB-218078, CAS 135897-06-2), and TAT-S216A (YGRKKRRQRRRLYRSPAMPENL), and CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr), and ( αR)-α-amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1H-pyrrolo[4,3,2-ef][2 ,3]benzodiazepin-8-yl]cyclohexaneacetamide (PF-0477736).

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

Protein kinase C (PKC) activators: bryostatin I (bryo-1); and sotrastaurin (AEB071).

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

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

Modulators of granulocytic colonialistimulating factor of a person (G-CSF): filgrastim (Neupogen®); sunitinib malate (Sutent®); pegfilgrastim (Neulasta®) and quisartinib (AC220, CAS 950769-58-1).

RET inhibitors: sunitinib malate (Sutent®); vandetanib (Caprelsa®); motesaniba diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide described in PCT Application Publication No. WO 02/066470); sorafenib (BAY 43-9006); regorafenib (BAY73-4506, CAS 755037-03-7) and danusertib (PHA-739358).

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

c-KIT inhibitors: pazopanib (Votrient®); dovitinib with lactyl lactic acid (TKI258, CAS 852433-84-2); motezanib diphosphate (AMG706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide described in PCT Publication No. WO 02/066470); mazitinib (Masivet®); regorafenib (BAY73-4506, CAS 755037-03-7); tivozanib (AV951, CAS 475108-18-0); vatalanib dihydrochloride (PTK787, CAS 212141-51-0); telatinib (BAY57-9352, CAS 332012-40-5); foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); sunitinib malate (Sutent®); quisartinib (AC220, CAS 950769-58-1); axitinib (Inlyta®); dasatinib (BMS-345825) and sorafenib (Nexavar®).

Bcr/Abl kinase inhibitors: imatinib (Gleevec®); inilotinib hydrochloride; nilotinib (Tasigna®); dasatinib (BMS-345825); bosutinib (SKI-606); ponatinib (AP24534); bafetinib (INNO406); danusertib (PHA-739358), AT9283 (CAS 1133385-83-7); saracatinib (AZD0530) andN-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalene-1,4-imin-9-yl]-2-oxoethyl] acetamide (PF-03814735, CAS 942487-16-3).

IGF-1R inhibitors: linsitnib (OSI-906); [7-[trance-3-[(azetidin-1-yl)methyl]cyclobutyl]-5-(3-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (AEW541, CAS 475488-34-7 ); [5-(3-benzyloxyphenyl)-7-[trance-3-[(pyrrolidin-1-yl)methyl]cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine (ADW742 or GSK552602A, CAS 475488-23-4); (2-[[3-bromo-5-(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]propanedinitrile (tyrphostin 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 (BMS754807, CAS 1001350-96-4); picropodophyllotoxin (AXL1717) and nordihydroguaiaretic acid.

Antibodies to IGF-1R: figitumumab (CP751871); cixutumumab (IMC-A12); ganitumab (AMG-479); Robatumumab (SCH-717454); Dalotuzumab (MK0646); R1507 (available from Roche); BIIB022 (available from Biogen) and MEDI-573 (available from MedImmune).

MET inhibitors: cabozantinib (XL184, CAS 849217-68-1); foretinib (GSK1363089, formerly XL880, CAS 849217-64-7); tivantinib (ARQ197, CAS 1000873-98-2); 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458); crizotinib (Xalkori®, PF-02341066); (3Z)-5-(2,3-dihydro-1H-indol-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrole -2-yl}methylene)-1,3-dihydro-2H-indol-2-one (SU11271); (3Z)-N-(3-chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-N- methyl-2-oxoindoline-5-sulfonamide (SU11274); (3Z)-N-(3-chlorophenyl)-3-{[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1H-pyrrol-2-yl]methylene}-N-methyl-2 -oxoindoline-5-sulfonamide (SU11606); 6-[difluoro[6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline (JNJ38877605, CAS 943540- 75-8); 2-[4-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]-1H-pyrazol-1-yl]ethanol ( PF04217903, CAS 956905-27-4); N-((2R)-1,4-dioxan-2-ylmethyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[ 4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide

(MK2461, CAS 917879-39-1); 6-[[6- (1-methyl-1 h -pirazol-4-il) -1,2,4-triazolo [4.3- b ] pyricazin-3-il] tio] chinolin (sgx523, cas 1022150- 57-7) and (3 Z )-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[[3,5-dimethyl-4-[[(2 R )-2-(1- pyrrolidinylmethyl)-1-pyrrolidinyl]carbonyl] -1H- pyrrol-2-yl]methylene]-1,3-dihydro- 2H- indol-2-one (PHA665752, CAS 477575-56-7).

Epidermal growth factor inhibitors (EGFR): erlotinib hydrochloride (Tarceva®), gefitinib (Iressa®); N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)- 2-butenamide (Tovok®); vandetanib (Caprelsa®); lapatinib (Tykerb®); (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3 -ol (BMS690514); canertinib dihydrochloride (CI-1033); 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); mubritinib (TAK165); pelitinib (EKB569); afatinib (BIBW2992); neratinib (HKI-272);N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS599626);N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine (XL647, CAS 781613-23-8) and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI166, CAS 187724-61-4).

Antibodies to EGFR: cetuximab (Erbitux®); panitumumab (Vectibix®); matuzumab (EMD-72000); trastuzumab (Herceptin®); nimotuzumab (hR3); zalutumumab; TheraCIM h-R3; MDX0447 (CAS 339151-96-1) and ch806 (mAb-806, CAS 946414-09-1).

mTOR inhibitors: temsirolimus (Torisel®); ridaphorolimus (formerly known as deferolimus, (1R.2R,4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R.21R, 23S.24E.26E.28Z,thirtyS.32S.35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23, 29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[ 30.3.1.0^4.9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methocyclohexyldimethylphosphinate, also known as AP23573 and MK8669 and described in PCT Publication No. WO 03/064383); everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3); (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trance-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methylpyrido[2,3-d]pyrimidine-7(8H)-one (PF04691502, CAS 1013101-36-4);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-, internal salt (SF1126, CAS 936487-67-1); and N-[4-[[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4-methylbenzamide (XL765, also known as SAR245409); and (1r,4r)-4-(4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl) cyclohexanecarboxylic acid (OSI-027).

Mitogen-activated protein kinase (MEK) inhibitors : XL-518 (also known as GDC-0973, Cas no. 1029872-29-4, available from ACC Corp.); selumetinib (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, also known as AZD6244 or ARRY 142886 described in PCT Publication No. WO2003077914 ) ; 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (also known as CI-1040 or PD184352 and described in PCT Publication No. WO2000035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide (also known as PD0325901 and described in PCT Publication No. WO2002006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]butanedinitrile (also known as U0126 and described in US Pat. No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]cyclopropanesulfonamide (also known as RDEA119 or BAY869766 and described in PCT Publication No. WO2007014011); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecin- 1,7(8H)-dione] (also known as E6201 and described in PCT Publication No. WO2003076424); 2'-amino-3'-methoxyflavone (also known as PD98059, available from Biaffin GmbH & Co., KG, Germany); vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H) -dione (TAK-733, CAS 1035555-63-5); pimacertib (AS-703026, CAS 1204531-26-9); trametinib with dimethyl sulfoxide (GSK-1120212, CAS 1204531-25-80); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330) and 3,4-difluoro- 2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655).

Alkylating agents: oxaliplatin (Eloxatin®); temozolomide (Temodar® and Temodal®); dactinomycin (also known as Actinomycin-D, Cosmegen®); melphalan (also known as L-PAM, L-sarcolysin and phenylalanine mustard, Alkeran®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); carboplatin (Paraplatin®); lomustine (also known as CCNU, CeeNU®); cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); chlorambucil (Leukeran®); cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); ifosfamide (Ifex®); prenumustine; procarbazine (Matulane®); mechlorethamine (also known as nitrogen mustard, mustine and mechlorethamine hydrochloride, Mustargen®); streptozocin (Zanosar®); thiotepa (also known as thiophosfamide, TESPA and TSPA, Thioplex®); cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®) and bendamustine HCl (Treanda®).

Aromatase inhibitors: exemestane (Aromasin®); letrozole (Femara®); and anastrozole (Arimidex®).

Topoisomerase I inhibitors: irinotecan (Camptosar®); topotecan hydrochloride (Hycamtin®); and 7-ethyl-10-hydroxycamptothecin (SN38).

Topoisomerase II inhibitors: etoposide (VP-16 and etoposide phosphate, Toposar®, VePesid® and Etopophos®); teniposide (VM-26, Vumon®) and tafluposide.

DNA synthesis inhibitors: capecitabine (Xeloda®); gemcitabine hydrochloride (Gemzar®); non-larabine ((2R.3S,4R,5R)-2-(2-amino-6-methoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, Arranon® and Atriance®) and sapacitabine (1-(2-cyano-2-deoxy -β-D-arabinofuranosyl)-4-(palmitoylamino)pyrimidine-2(1H)-He).

Folate antagonists or antifolates: trimetrexate glucuronate (Neutrexin®); pyrithrexime isethionate (BW201U); pemetrexed (LY231514); raltitrexed (Tomudex®) and methotrexate (Rheumatrex®, Trexal®).

Immunomodulators: afutuzumab (available from Roche®); Pagfilgrastim (Neulasta®); Lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimide (CC4047) and IRX-2 (human cytokine mixture containing interleukin-1, interleukin-2 and interferon-γ, CAS 951209-71-5, available from IRX Therapeutics).

Somatostatin G-protein coupled receptor inhibitors: octreotide (also known as octreotide acetate, Sandostatin® and Sandostatin LAR®); lanreotide acetate (CAS 127984-74-1); seglitide (MK678); vapreotide acetate (Sanvar®); and cyclo(D-Trp-Lys-Abu-Phe-MeAla-Tyr) (BIM23027).

Interleukin-11 and Synthetic Interleukin-11 (IL-11): oprelvekin (Neumega®).

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

Histone deacetylase (HDAC) inhibitors: voninostat (Zolinza®); romidepsin (Istodax®); treichostatin A (TSA); oxamflatine; vorinostat (Zolinza®, suberoylanilide hydroxamic acid); pyroxamide (siberoyl-3-aminopyridinamide hydroxamic acid); trapoxin A (RF-1023A); trapoxin B (RF-10238); cyclo[(αS.2S)-α-amino-η-oxo-2-oxiranoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-L-prolyl] (Cyl-1); cyclo[(αS.2S)-α-amino-η-oxo-2-oxiranoctanoyl-O-methyl-D-tyrosyl-L-isoleucyl-(2S)-2-piperidinecarbonyl] (Cyl-2); cyclic [L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxyranoctanoyl-D-prolyl] (HC-toxin); cyclo[(αS.2S)-α-amino-η-oxo-2-oxiranoctanoyl-D-phenylalanyl-L-leucyl-(2S)-2-piperidinecarbonyl] (WF-3161); chlamydocin ((S)-cyclic (2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α-aminooxiranoctanoyl);apicidin (cyclo(8-oxo-L-2-aminodecanoyl-1-methoxy-L -tryptophyl-L-isoleucyl-D-2-piperidinecarbonyl); romidepsin (Istodax®, FR-901228); 4-phenylbutyrate; spiruchostatin A; milproin (valproic acid); entinostat (MS-275, N-(2-aminophenyl) -4-[N-(pyridin-3-ylmethoxycarbonyl)aminomethyl]benzamide) and depudecine (4,5:8,9-dianhydro-1,2,6,7,11-pentadeoxy-D-treo-D-ido-undeca-1,6-dienitol).

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

Plant alkaloids: paclitaxel (Taxol and Onxal™); protein-bound paclitaxel (Abraxane®); vinblastine (also known as vinblastine sulfate, vincaleukoblastin and VLB, Alkaban-AQ® and Velban®); vincristine (also known as vincristine sulfate, LCR and VCR, Oncovin® and Vincasar Pfs®) and vinorelbine (Navelbine®).

Taxane antineoplastic agents: paclitaxel (Taxol®); docetaxel (Taxotere®); cabazitaxel (Jevtana®, 1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytax-11-en-2α,4,13α-triyl-4-acetate-2-benzoate-13-[(2R ,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate) and laroxatel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis (acetyloxy)-13-({(2R.3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-en-2-ylbenzoate).

Heat shock protein (HSP) inhibitors: tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA and described in US Pat. No. 4,261,989); retaspimycin (IPI504), ganetespib (STA-9090); [6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-ylmethyl)-9H-purin-2-yl]amine (BIIB021 or CNF2024, CAS 848695-25-0);trance-4-[[2-(aminocarbonyl)-5-[4,5,6,7-tetrahydro-6,6-dimethyl-4-oxo-3-(trifluoromethyl)-1H-indazol-1-yl]phenyl]amino]cyclohexylglycine ester (SNX5422 or PF04929113, CAS 908115-27-5) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG).

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

Demethylating agents: 5-azacytidine (Vidaza®) and decitabine (Dacogen®).

Cytokines: Interlayykin-2 (also known as Aldesleikin and IL-2, ProleUKIN®); interleukin-11 (also known as oprevelkin, Neumega®) and interferon alfa (also known as IFN-alpha, Intron® A and Roferon-A®).

Inhibitors 17 α-hydroxylase/C17.20-lyais (CYP17A1): abiraterone acetate (Zytiga®).

Various cytotoxic agents: arsenic trioxide (Trisenox®); asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, Elspar® and Kidrolase®) and Erwinia Chrysanthemi asparaginase (Erwinaze®).

Antibody to CC chemokine receptor 4 (CCR4): mogamulizumab (Potelligent®).

Antibodies to CD20: rituximab (Riuxan® and MabThera®); and tositumomab (Bexxar®); and ofatumumab (Arzerra®).

Anti-CD20 antibody-drug conjugates: ibritumomab tiuxetan (Zevalin®) and tositumomab.

Anti-CD22 antibody-drug conjugates: inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.).

Conjugates of CD30 mAb-cytotoxin: brentuximab vedotin (Adcetris®).

Anti-CD33 antibody-drug conjugates: gemtuzumab ozogamicin (Mylotarg®).

Antibodies to CD40: dacetuzumab (also known as SGN-40 or huS2C6 available from Seattle Genetics, Inc).

Antibodies to CD52: alemtuzumab (Campath®).

Antibodies to CS1: elotuzumab (HuLuc63, CAS no. 915296-00-3).

Inhibitory antibodies to CTLA-4: tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206) and ipilimumab (anti-CTLA-4 antibody, also known as MDX-010, CAS number 477202-00-9).

TPH inhibitors : telotristat.

PARP (poly-ADP-ribose polymerase) inhibitors : olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zeluja), talazoparib, veliparib.

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-224 (Amplimmune).

PD-L1 inhibitors : durvalumab, atezolizumab, avelumab.

In particular, the present invention provides a combination or combination therapy using a complex formed by the radionuclide ¹⁷⁷ Lu (lutetium-177) and a somatostatin receptor-binding peptide connected to a chelating agent as defined herein, or a combination or combination therapy using an aqueous solution of a pharmaceutical an agent as defined herein together with one or more therapeutic agents selected from the group consisting of octreotide, lanreotide, vaproreotide, pasireotide, satoreotide, everolimus, temozolomide, telotristat, sunitinib, sulfatinib, ribociclib, entinostat, and pazopanib. In specific embodiments, these combinations are for use in the treatment of NET tumors, eg, GEP-NET, lung NET, pNET, lung NET, carcinoid syndrome, SCLC. In specific embodiments, the present invention provides a method of treating a patient with NET tumors, e.g., GEP-NET, lung NET, pNET, lung NET, carcinoid syndrome, SCLC, by administering a therapeutically effective amount of the components of these combinations.

In specific embodiments, the present invention provides a combination or combination therapy using a complex formed by the radionuclide ¹⁷⁷ Lu (lutetium-177) and a somatostatin receptor-binding peptide connected to a chelating agent defined herein, or a combination or combination therapy using an aqueous solution a pharmaceutical agent as defined herein together with one or more immuno-oncological therapeutics selected from the group consisting of PD-1, PD-L1 and CTLA-4 inhibitors, in particular IO therapeutics selected from spartalizumab, nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, avelumab, ipilimumab and tremelimumab. In specific embodiments, these combinations are for use in the treatment of NET tumors, eg, GEP-NET, lung NET, pNET, lung NET, carcinoid syndrome, SCLC. In specific embodiments, the present invention provides a method of treating a patient with NET tumors, e.g., GEP-NET, lung NET, pNET, lung NET, carcinoid syndrome, SCLC, by administering a therapeutically effective amount of the components of these combinations.

DEFINITIONS

The following defines the terms used in this document and their meanings.

The term "about" or "approx." in this document is such that the following value may vary by ±20%, preferably ±10%, more preferably ±5%, even more preferably ±2%, even more preferably ±1%.

Unless otherwise specified, "%" in this document has the meaning of a weight percent (wt. %), also referred to as a percentage on a weight-for-weight basis (wt./wt. %).

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

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

"A complex formed

(ai) radionuclide and

(aii) a cellular receptor-binding organic moiety coupled to a chelating agent":

the radionuclide metal ion forms a non-covalent bond with functional groups of the chelating agent, such as amines or carboxylic acids. The chelating agent contains at least two such complexing functional groups capable of forming a chelate complex.

Chelating agent in the context of the present invention may be

DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,

DTPA: diethylenetriaminepentaacetic acid,

NTA: nitrilotriacetic acid,

EDTA: ethylenediaminetetraacetic acid,

DO3A: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid,

NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid,

Trizoxetane,

Tetraxetane

or mixtures thereof, preferably is DOTA.

"Cellular receptor-binding moiety": A chemical molecule that binds, via at least a portion of its molecule, to a receptor molecule on the surface of a cell. The cell receptor binding moiety for which the present invention is particularly suitable is a somatostatin receptor binding peptide, preferably said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, pasireotide, iltreotide, pentetreotide, depreotide, satoreotide, veldoreotide , preferably selected from octreotide and octreotate.

"Connected": The organic moiety that binds to the cellular receptor is either directly connected to a chelating agent or connected via a linker molecule, preferably directly connected. The link(s) bond(s) is(are) either a covalent(covalent) or non-covalent(non-covalent) bond(s) between the cell receptor-binding organic moiety (and the linker) and the chelating agent, preferably the bond(s) is(are) covalent (covalent).

"Radiolytic Decomposition Stabilizer": A stabilizing agent that protects organic molecules from radiolytic decomposition, for example, when gamma rays emitted by a radionuclide cleave the bonds between atoms of organic molecules and radicals are formed, these radicals are then removed by the stabilizer, which prevents the radicals from passing through - any other chemical reactions that may produce unwanted, potentially ineffective or even toxic molecules. Thus, these stabilizers are also referred to as "free radical scavengers" or "radical scavengers" for short. Other alternative terms for these stabilizers are "irradiation stability enhancers", "radiolytic stabilizers", or simply "quenchers".

"Stabilizer(s) present(s) in solution during complex formation of components (ai) and (aii)": a first stabilizer is present and a second stabilizer is also optionally present, i.e. either the first stabilizer is present alone or in combination with second stabilizer.

"Present during complex formation": the stabilizer(s) is(are) either in the radionuclide solution or in the chelating agent solution prior to the addition of the two solutions and the potential use of elevated temperatures to promote complexation. Preferably, the stabilizer(s) is(are) in a chelate-containing solution.

"Only the first stabilizer is present during the formation of the complex from components (ai) and (aii)":

the first stabilizer is present, the second is absent. In other words, there is only one stabilizer.

"The second stabilizer is added after the complexation of components (ai) and (aii)": Whether or not the second stabilizers were already present at the time of complexation, the second stabilizer is added after the complexation reaction is completed, for example, after the reaction the solution, which may have been heated to an elevated temperature, is cooled back to ambient temperature.

The receptor-binding moiety and the chelating agent can together form the following molecules:

DOTA-OC: [DOTA ⁰ ,D-Phe ¹ ]octreotide,

DOTA-TOC: [DOTA ⁰ ,D-Phe ¹ ,Tyr ³ ]octreotide, edotreotide (INN),

represented using the following formulas:

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

DOTA-TATE: [DOTA ⁰ ,D-Phe ¹ ,Tyr ³ ]octreotate, DOTA-Tyr ³ -octreotate, DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (cyclo 2, 7), oxodotreotide (INN) represented by the following formula:

DOTA-LAN: [DOTA ⁰ ,D-β-Nal ¹ ]lanreotide,

DOTA-VAP: [DOTA ⁰ ,D-Phe ¹ ,Tyr ³ ]vapreotide.

Satoreotide trizoxetane

Satoreotide tetraxetane

Preferred "cell receptor-binding chelating moiety" molecules for the present invention are DOTA-TOC, DOTA-TATE and satoreotide tetraxetane, more preferably the molecule is DOTA-TATE.

For the present invention, a preferred complex formed (or a preferred complex) of a radionuclide and a cell receptor-binding moiety coupled to a chelating agent according to the present invention is ¹⁷⁷ Lu-DOTA-TATE, which is also called lutetium oxodotreotide (177Lu) (INN), i.e. e. hydro[N-{[4,7,10-tris(carboxylate-κ O -methyl)-1,4,7,10-tetraazacyclododecan-1-yl-κ ⁴ N ¹ ,N ⁴ ,N ⁷ ,N ¹⁰ ]acetyl-κ O }-D-phenylalanyl-L-cysteinyltyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoninato cyclic (2→7)-disulfide(4-)](177Lu )luthetate (1-)

and is represented using the following formulas:

"Buffer for pH 4.5 to 6.0": can be an acetate buffer, a citrate buffer (e.g. citrate+HCl or citric acid+disodium hydrogen phosphate) or a phosphate buffer (e.g. sodium dihydrogen phosphate+disodium hydrogen phosphate), preferably as specified the buffer is an acetate buffer, preferably said acetate buffer consists of acetic acid and sodium acetate.

"Sequestering agent", a chelating agent suitable for the formation of complexes with radionuclide metal ions, preferably DTPA:diethylenetriaminepentaacetic acid.

"For commercial use": a drug product, such as an aqueous solution of a pharmaceutical, can (preferably has) received a marketing authorization from a public health authority, such as the US Food and Drug Administration or the European Medicines Agency, by meeting all requirements for the quality and stability of the medicinal product, as required by these health authorities, can be manufactured (preferably manufactured) in or at the place of production of pharmaceuticals on an industrial scale, followed by a quality control testing procedure, and can be supplied (preferably supplied) to remotely located end users e.g. hospitals or patients.

"Combination" refers to either a fixed combination in a single unit dosage form, or combination administration, where a compound of the present invention and a combination partner (e.g., another drug, as explained below, also referred to as a "therapeutic agent" or "co-administered agent" ) may be administered independently at the same time or separately at intervals, especially if such intervals allow the combination partners to demonstrate a cumulative, eg synergistic, effect. Individual components may be packaged as a kit or provided separately. One or both of the components (eg, powders or liquids) may be reconstituted or diluted to the desired dose prior to administration. The terms "co-administration" or "combination administration" or the like as used herein are intended to encompass the administration of a selected combination partner to a single subject in need (e.g., a patient) and is intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product resulting from the mixing or combination of more than one therapeutic agent, which includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents, for example, the compound of the present invention and the combination partner, are administered to the patient simultaneously as a single entity or dose. The term "non-fixed combination" means that the therapeutic agents, e.g., the compound of the present invention and the combination partner, are both administered to the patient as separate entities, either simultaneously, in parallel, or sequentially without specific timing, such administration providing effective therapeutic levels of the two compounds. in the patient's body. The latter also applies to "cocktail therapy", for example the administration of three or more therapeutic agents.

EXAMPLES

Hereinafter, the present invention is described in more detail and specifically with reference to examples, which, however, are not intended to limit the present invention.

Materials:

¹⁷⁷ LuCl ₃ can be obtained from commercial sources such as IDB Holland BV. DOTA ⁰ -Tyr ³ -octreotate can be obtained from commercial sources such as piCHEM Forschungs-und Entwicklungs GmbH, Austria. All other components of the drug product are commercially available from various sources.

Example 1 Drug Product Composition

The drug product ( ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate, 370 MBq/ml, solution for infusion) was developed as a sterile ready-to-use solution for infusion containing ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate as a drug substance with a bulk activity, amounting to the control date and time (calibration time (tc)) 370 MBq/ml. The calibration time (tc) corresponds to the end of production (EOP=t0), which is the time the activity of the first QC vial was measured. The drug product shelf life was defined as 72 hours after the calibration time. The drug product is a single dose vial containing an appropriate amount of solution which, upon injection, delivers 7.4 GBq of radioactivity.

Single doses were received at the site of manufacture, calibrated within the range of 7.4 GBq ± 10%

(200 mCi) after the end of production. Certificates of Analysis indicate both the exact measure of activity obtained and the time at which that activity was achieved. This value is declared as "injection time: {dd-mm-yyyy} {hh:mm} UTC". Considering the variable injection time and the constant degradation of the radionuclide, the fill volume required to obtain an activity of 7.4 GBq at the time of injection was calculated, which can vary from 20.5 to 25.0 ml.

The composition of the medicinal product per ml

property/component Quantity (unit/ml) Function ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate (volumetric activity) 370 MBq/ml at t _c (EOP) medicinal substance X-DOTA ⁰ -Tyr ³ -octreotate 10 µg/ml Total peptide content Specific activity
(GBq/total peptides) ≥ 53 GBq/µmol at EOP Not applicable Excipients
Acetic acid
sodium acetate
Gentisic acid
Ascorbic acid
DTPA
Sodium chloride (NaCl)
Sodium hydroxide (NaOH)
Water for injections 0.48 mg/ml pH regulator 0.66 mg/ml pH regulator 0.63 mg/ml RSE 2.80 mg/ml RSE 0.05 mg/ml sequestering agent 6.85 mg/ml Isotonic remedy 0.64 mg/ml
Up to 1 ml pH regulator
Solvent

EOP - End of production=t ₀ = activity measurement of the first vial = calibration time t _c

RSE - radiation resistance enhancer

Example 2. Manufacturing of a medicinal product

For a batch size of 74 GBq (batch size of 2 Ci), a solution ^{of 177} LuCl ₃ , approximately 74 GBq in HCl, was mixed together with a solution of DOTA-Tyr ³ -octreotate (approximately 2 mg) and a reaction buffer solution containing an antioxidant (and anti-radiolytic degradation stabilizer) (i.e., gentisic acid, approximately 157 mg) and buffer system (i.e., acetate buffer system), which provided a total of approximately 5.5 ml of solution, which was used for radioactive labeling, which occurs at a temperature of from about 90 to about 98°C for less than 15 minutes.

The synthesis was carried out using a disposable replacement cassette in the form of a set of elements installed on the front side of the synthesis module, which contains a fluid channel (tube), a reaction vial and sealed reagent vials.

The resulting mother liquor was diluted with a solution containing a chelating agent (i.e. DTPA), an antioxidant (i.e. ascorbic acid), sodium hydroxide and sodium chloride, and then sterilely passed through a filter with a pore size of 0.2 μm to obtain a ready-to-use the solution described in example 1, with a pH of 4.5-6.0, in particular 5.2-5.3. Finally, the solution was distributed in volumes from 20.5 to 25.0 ml into sterile vials. The vials, sealed with a cork, were placed in lead containers for protective shielding.

The manufacturing process can also be carried out for batch sizes above 74 GBq. In this case, the amount of starting materials (lutetium, peptide and reaction buffer) is increased to ensure the same ratio of starting materials.

Example 3 . Results of stability studies after storage under various temperature conditions.

The following table presents the stability study data for a batch obtained with a batch size corresponding to 74 GBq, according to the method described in example 2.

"But." = not defined; "LOD" = limit of detection

Moments in time t(0) t(0+24h) t(0+48 h) t(0+72 h) Stability at 5 ± 2°C CQ1 11 ml
21.8 ml pH 5.3 n. O. n. O. 5.3
5.3 Chemical purity
(RP-UV-HPLC) Peptide Purity (%) 100.0 n. O. n. O. 100.0
100.0 Radiochemical purity
(RP-γβ-HPLC) ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate (%) 98.37 n. O. n. O. 96.09
96.40 Moments in time t(0) t(0+24h) t(0+48 h) t(0+72 h) Stability at 25 ± 2°C CQ1 5 ml 5 ml 5 ml
24.7 ml pH 5.3 5.3 5.2 5.2
5.3 Chemical purity
(RP-UV-HPLC) Peptide Purity (%) 100.0 100.0 100.0 100.0 Radiochemical purity
(RP-γβ-HPLC) ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate (%) 98.28 96.99 96.29 95.02
95.62 Moments in time t(0) t(0+24h) t(0+48 h) t(0+72 h) Stability at 32 ± 2 ° C CQ1 5.6 ml
22.2 ml 5.6 ml
22.2 ml pH 5.3 n. O. 5.3
5.3 n. O. Chemical purity
(RP-UV-HPLC) Peptide Purity (%) 100.0 100.0
100.0 100.0
100.0 n. O. Radiochemical purity
(RP-γβ-HPLC) ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate (%) 98.37 96.03
96.51 94.45
95.45 n. O. Moments in time t(0) t(0+24h) t(0+48 h) t(0+72 h) Stability at 32 ± 2°C for 12 hours and at 25 ± 2°C for 60 hours CQ1 11 ml Chemical purity
(RP-UV-HPLC) Peptide Purity (%) 100.0 n. O. n. O. 100.0 Radiochemical purity
(RP-γβ-HPLC) ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate (%) 98.28 n. O. n. O. 95.01

Very similar good stability results were obtained for batches made with a batch size corresponding to 148 GBq.

Claims (64)

1. An aqueous solution of a radiopharmaceutical containing (a) the complex formed (ai) radionuclide ¹⁷⁷ Lu (lutetium-177) and (aii) a somatostatin receptor-binding peptide coupled to a chelating agent DOTA; And (b) at least two different anti-radiolytic degradation stabilizers, Where a stabilizer that prevents radiolytic degradation is selected from gentisic acid and ascorbic acid, and (bi) gentisic acid is present at a concentration of 0.5 to 2 mg/ml, preferably 0.5 to 1 mg/ml; And (bii) ascorbic acid is present at a concentration of 2.0 to 5.0 mg/ml, Where the specified radionuclide is present in such a concentration that provides a volumetric radioactivity of 250 to 500 MBq/ml; And said aqueous solution of the pharmaceutical agent contains less than 1% ethanol. 2. An aqueous solution of a pharmaceutical agent according to claim 1, where the specified component (b) contains stabilizers: (bi) gentisic acid and (bii) ascorbic acid. 3. An aqueous solution of a radiopharmaceutical according to claim 1, further containing (c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/ml. 4. An aqueous solution of a radiopharmaceutical agent according to claim 1 or 3, additionally containing (d) an acetate buffer consisting of (di) acetic acid at a concentration of 0.3 to 0.7 mg/ml and (dii) sodium acetate at a concentration of 0.4 to 0.9 mg/ml; preferably said acetate buffer provides a pH of 4.5 to 6.0, preferably 5.0 to 5.5. 5. An aqueous solution of a radiopharmaceutical according to any one of paragraphs. 1-4, wherein at least one of the stabilizers is present during complexation of components (ai) and (aii), and at least one of the stabilizers is added after complexation of components (ai) and (aii). 6. An aqueous solution of a radiopharmaceutical according to any one of paragraphs. 1-4, wherein at least gentisic acid is present during complexation of components (ai) and (aii), and at least ascorbic acid is added after complexation of components (ai) and (aii). 7. An aqueous solution of a radiopharmaceutical according to any one of paragraphs. 1-4, wherein the only stabilizer present during complexation of components (ai) and (aii) is gentisic acid and the only stabilizer added after complexation of components (ai) and (aii) is ascorbic acid . 8. An aqueous solution of a radiopharmaceutical according to any one of paragraphs. 5-7, where this / these stabilizer / stabilizers, which / which are / are present during the formation of the complex from components (ai) and (aii), is / are present during the formation of the complex in a total concentration of 15 to 50 mg / ml, preferably 20 to 40 mg/ml. 9. An aqueous solution of the radiopharmaceutical according to claim 8, wherein the only stabilizer present during complexation of components (ai) and (aii) is gentisic acid and is present during complexation at a concentration of 20 to 40 mg/mL, preferably 25 to 35 mg/ml. 10. An aqueous solution of a radiopharmaceutical according to any one of the preceding claims, which has a shelf life of at least 72 hours when stored at ≤ 25°C, in particular at least 72 hours when stored at 25°C. 11. An aqueous solution of a radiopharmaceutical according to any of the preceding claims, for which the radiochemical purity (determined by HPLC) is maintained at ≥ 95% for at least 72 hours when stored at 25°C. 12. An aqueous solution of a radiopharmaceutical according to any one of the preceding claims, wherein said solution is produced on an industrial scale, in particular produced in a batch size corresponding to at least 20 GBq, at least 50 GBq, at least 70 GBq. 13. An aqueous solution of a radiopharmaceutical according to any one of the preceding claims, which is ready for use. 14. A method for manufacturing an aqueous solution of a radiopharmaceutical according to any one of the preceding claims, comprising the steps of the method (1) complexing the ¹⁷⁷ Lu radionuclide and the somatostatin receptor-binding peptide coupled to the chelating agent DOTA via (1.1) obtaining an aqueous solution containing the radionuclide; (1.2) obtaining an aqueous solution containing a somatostatin receptor-binding peptide connected to a chelating agent and at least one anti-radiolytic degradation stabilizer; And (1.3) mixing the solutions obtained in steps (1.1) and (1.2) and heating the resulting mixture; (2) diluting the solution of the complex obtained in step (1) with (2.1) obtaining an aqueous solution for dilution, optionally containing at least one stabilizer that prevents radiolytic decomposition; And (2.2.) mixing the solution of the complex obtained in step (1) with the dilution solution obtained in step (2.1) to obtain a final solution; where if the solution obtained in (1.2) contains only one stabilizer, then the solution obtained in (2.1) contains at least one stabilizer, Where a stabilizer that prevents radiolytic degradation is selected from gentisic acid and ascorbic acid, and Where said aqueous solution of the pharmaceutical agent contains (bi) gentisic acid at a concentration of 0.5 to 2 mg/ml, preferably 0.5 to 1 mg/ml; And (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg/ml, Where a radio-labeled aqueous solution of a pharmaceutical agent contains less than 1% ethanol. 15. The method of claim 14, wherein the solution obtained in step (1.2) contains at least one stabilizer and the solution obtained in step (2.1) contains at least one stabilizer. 16. The method of claim 14, wherein the solution obtained in step (1.2) contains at least a gentisic acid stabilizer and the solution obtained in step (2.1) contains at least an ascorbic acid stabilizer. 17. The method of claim 14, wherein the solution obtained in step (1.2) contains only one stabilizer, which is gentisic acid, and the solution obtained in step (2.1) contains only one stabilizer, which is ascorbic acid. 18. The method according to any one of paragraphs. 14-17, where the solution obtained in step (1.2) contains the stabilizer(s) in a total concentration of 15 to 50 mg/ml, preferably 20 to 40 mg/ml. 19. The method according to any one of paragraphs. 14-17, where the solution obtained in step (1.2) contains only one stabilizer, which is gentisic acid, at a concentration of 20 to 40 mg/ml, preferably 25 to 35 mg/ml. 20. The method according to any one of paragraphs. 14-19, where the solution in step (1.2) further contains a buffer, preferably an acetate buffer. 21. The method according to any one of paragraphs. 14-20, where in step (1.3) the resulting mixture is heated to a temperature of 70 to 99°C, preferably 90 to 98°C, for 2 to 59 minutes, preferably 10 to 15 minutes. 22. The method according to any one of paragraphs. 14-21, where the solution in step (2.1) further contains diethylenetriaminepentaacetic acid (DTPA) or a salt thereof. 23. The method according to any one of paragraphs. 14-22, further comprising method steps (3) passing the solution obtained in step (2) through a filter with a pore size of 0.2 µm: (4) dispensing the filtered solution obtained in step (3) into the dose unit containers in the volume necessary to deliver a radioactive dose of 5.0 to 10 MBq, preferably 7.0 to 8.0 MBq, more preferably 7.3 to 7.7 MBq, even more preferably 7.4 to 7.5 MBq, preferably said volume is 10 to 50 ml, more preferably 15 to 30 ml, even more preferably 20 to 25 ml. 24. The method according to any one of paragraphs. 14-23, where the solution in step (1.1) contains LuCl ₃ and HCl. 25. The method according to any one of paragraphs. 14-24, where the solution in step (1.2) contains DOTA-TATE or DOTA-TOC, gentisic acid, acetic acid and sodium acetate. 26. The method according to any one of paragraphs. 14-25, where the solution in step (2.1) contains DTPA and ascorbic acid. 27. The method according to any one of paragraphs. 23-26, where the dose unit containers in step (4) are stoppered vials placed in a lead container. 28. An aqueous solution of a radiopharmaceutical obtained using the method according to any one of paragraphs. 14-27.