Stable, concentrated radionuclide complex solutions

Abstract

To provide processes for manufacturing a highly concentrated radionuclide complex solution which is chemically and radiochemically very stable, and to provide a pharmaceutical aqueous solution.SOLUTION: A process for manufacturing a pharmaceutical aqueous solution comprises diluting an aqueous complex solution with an aqueous dilution solution. Therein: the aqueous complex solution comprises (a) a complex comprising a radionuclide 177 Lu and a somatostatin receptor binding peptide linked to a chelator DOTA, and (b) at least one stabilizer against radiolytic degradation present at a total concentration of 15-50 mg / mL; the aqueous dilution solution comprises at least one stabilizer against radiolytic degradation; in the pharmaceutical aqueous solution, the radionuclide is present at a concentration providing a volumetric radioactivity of 250-500 MBq / mL and the stabilizer is present at a total concentration of 0.5 to 10.0 mg / mL, and the only stabilizer against radiolytic degradation, which is present in the pharmaceutical aqueous solution, is selected from ascorbic acid or a salt thereof and gentisic acid or a salt thereof.SELECTED DRAWING: None

Description

[Technical field]

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

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

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

[0004] One of the technical problems associated with such radiopharmaceutical drug products is, for example, the manufacturing of the drug product. Decay of radionuclides continues during storage and releases high energy emissions that can cause It is to induce cleavage of chemical bonds of molecules forming a part. This is often called radiolysis or radiolytic degradation. Radiolytic degradation of the receptor-binding portion of a drug may result in a reduction in its efficacy acting as a diagnostic agent and / or therapeutic agent. The stability of such radiopharmaceutical drug products is insufficient and they lack any significant shelf life. Therefore, until now, drugs had to be manufactured in dose units for individual patients in a hospital laboratory and immediately administered to the patients, and the patients had to already be in that hospital waiting for radiological treatment.

[0005]

[0006] Various strategies have been explored to reduce radiolysis of radiopharmaceutical drug products, with more or less success. That is, the drug product can be stored at low temperature, or can be manufactured at high dilution, or stabilizers can be added.

[0007] However, adding stabilizers can be problematic because such chemicals may adversely affect the complexation of radionuclides to chelating agents.

Summary of the Invention

Problems to be Solved by the Invention

[0008] Manufacturing highly diluted drug products creates the drawback that a large amount of infusion solution needs to be administered to the patient. For the convenience of the patient and reasons of drug tolerance, it would be highly desirable to provide highly concentrated radiopharmaceutical drug products. However, such highly concentrated solutions are particularly susceptible to radiolysis. On the one hand, radiolysis is avoided by diluting the drug product, and on the other hand, concentration The contradictory position of avoiding the discomfort of patients during treatment by providing a thick drug solution leaves technical problems in the design of radiopharmaceutical products.

Means for Solving the Problems

[0009] The inventors have now found a method for designing and manufacturing a highly concentrated radionuclide complex solution that is chemically and radiochemically very stable even when stored at ambient temperature or short-term elevated temperature. .

[0010] The present invention is provided in various aspects as outlined below.

[0011] (a) The following: (ai) A radionuclide, (aii) A cell receptor-binding organic moiety linked to a chelating agent, and a complex formed thereby, (b) At least one stabilizer against radiolytic degradation, and the radionuclide is present at a concentration providing a volume radioactivity of at least 100 MBq / mL, preferably at least 250 MB q / mL, an aqueous pharmaceutical solution.

[0012] The stabilizer (component (b)) is present at a total concentration of at least 0.2 mg / mL, preferably at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, even more preferably at least 2.7 mg / mL.

[0013] (a) The following: (ai) A radionuclide present at a concentration providing a volume radioactivity of 250 to 500 MBq / mL 177 lutetium (Lu-177), (aii) The somatostatin receptor-binding organic moiety DO linked to a chelating agent TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and a complex formed thereby, and (bi) Genisteic acid or a salt thereof as a first stabilizer against radiolytic degradation present at a concentration of 0.5 to 1 mg / mL, and and (bii) Ascorbic acid or a salt thereof as a second stabilizer against radiolytic degradation present at a concentration of 2.0 to 5.0 mg / mL, and a pharmaceutical aqueous solution containing .

[0014] (1) The following: (1.1) Preparing an aqueous solution containing a radionuclide, and (1.2) Preparing an aqueous solution containing a cell receptor-binding organic moiety linked to a chelating agent, a first stabilizer, and optionally a second stabilizer, and and (1.3) Heating the mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2), thereby forming a complex of the radionuclide and the cell receptor-binding organic moiety linked to the chelating agent, and a process step; and (2) The following: (2.1) Optionally preparing an aqueous dilution solution containing a second stabilizer, and (2.2) Mixing the complex solution obtained in step (1) and the dilution solution obtained in step (2.1), thereby diluting the complex solution obtained in step (1), and a process step; and a manufacturing process of the pharmaceutical aqueous solution as defined above.

[0015] The present invention provides the following advantages.

[0016] High concentrations enable high-dose administration within a short time frame. For example, 177 Lu-D ​In the case of OTA-TATE, the IV injection can be completed within about 20 to 30 minutes with a small volume of 20.5 to 25.0 mL, which can provide a high dose of 7.4 GBq.

[0017] When using the suitable stabilizer according to the present invention described herein, with respect to the chemical purity of the cell receptor binding molecule after 72 hours at 25°C, even if this molecule is a sensitive peptide molecule, at least 95%, 96%, 97%, 98%, 99%, or 100% chemical stability, a high stability is ensured. For example, in the case of DOTA-TATE, 100% chemical purity was found after 72 hours at 25°C, and even after 48 hours at 32°C. Even under short-term elevated temperature conditions (12 h at 32°C and 60 h at 25°C), such high stability was found with respect to radiochemical purity.

[0018] Furthermore, when using the suitable stabilizer according to the present invention described herein, a high stability of at least 95% radiochemical stability is ensured with respect to the radiochemical purity of the radionuclide complex. For example, in the case of Lu-DOTA-TATE, at least 177 95% radiochemical purity was found after 72 hours at 25°C. Even under short-term elevated temperature conditions (12 h at 32°C and 60 h at 25°C), such high stability was found with respect to radiochemical purity. was found.

[0019] One single stabilizer can already achieve sufficient stability, but the use of two stabilizers was found to be particularly suitable for stabilizing the sensitive radiopharmaceutical solution. Specifically, when there is one stabilizer at the time of complex formation and another one stabilizer added after complex formation, then During the complexation reaction, the cell receptor binding molecule is protected from radiolysis, and during storage it is advantageous because it is ensured that other stabilizers enhance the protective effect over the storage

[0020] Furthermore, by such sequential application of two stabilizers, during complexation, a relatively very small amount of the stabilizer is present (thus minimizing the possibility of interference of the stabilizer with the complexation reaction), and after complexation, a combination of a large amount of stabilizer is present (thus enhancing the protective power of the stabilizer over the subsequent drug product storage period).

[0021] Also, by such sequential application of two stabilizers, when a complexation reaction involving high temperature is carried out, one of them is absent, so the overall thermal stress of such stabilizers is reduced. .

[0022] Furthermore, especially when using two different stabilizers, this combination is more effective in reacting with each type of different radical that may be formed by radiolysis of the cell receptor binding molecule than a single stabilizer, which is advantageous.

[0023] To enable the production of radiopharmaceutical drug products from a centralized pharmaceutical manufacturing site and to commercialize it as an immediately usable drug product, a storage life of at least 3 days is required. .

[0024] Therefore, thanks to the high stability (72 h at 25 °C), the present invention provides drug products in high quality standards (such as cGMP) and on an industrial scale, for example, in a number of dose units sufficient to treat, for example, 10 - 20 patients simultaneously, in a number of dose units such as 74 GBq or 148 GBq. q batch sizes allow for centralized pharmaceutical production.

[0025] Furthermore, due to its high stability, the present invention allows for the production of pharmaceuticals at remote clinical centers from centralized pharmaceutical manufacturing sites. There is enough time to transport it to

[0026] Furthermore, due to its high stability, the present invention does not require preparation by clinical staff prior to administration. A ready-to-use infusion that can be administered immediately to a patient without the need for any work to be performed It can be provided as a solution.

[0027] The present invention relates to somatostatin receptor-binding peptides, In particular, we investigated the extremely sensitive somatostatin analog octreotide, which is particularly susceptible to degradation reactions. In addition, the present invention provides specific radioactive properties. The radionuclide lutetium-177 is particularly suitable. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Hereinafter, the present invention will be described and illustrated in more detail.

[0029] According to the present invention, the following embodiments are provided.

[0030] 1. (a) Below: (ai) a radionuclide; (aii) a cell receptor binding organic moiety linked to a chelator; and and a complex formed by (b) at least one stabilizer against radiolytic degradation; Including, The radionuclide has a concentration of at least 100MBq / mL, preferably at least 250MBq / mL present in a concentration providing a volumetric activity of q / mL, Pharmaceutical aqueous solutions.

[0031] 2. The stabilizer (component (b)) is present at a total concentration of at least 0.2 mg / mL, preferably at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, even more preferably at least 2.7 mg / mL, for the aqueous pharmaceutical solution according to Embodiment 1. The aqueous pharmaceutical solution according to Embodiment 1.

[0032] 3. The radionuclide is present at a concentration providing a volumetric radioactivity of 100 - 1000 MBq / mL, preferably 250 - 500 MBq / mL, for the aqueous pharmaceutical solution according to any one of Embodiments 1 or 2. The aqueous pharmaceutical solution according to any one of Embodiments 1 or 2.

[0033] 4. The stabilizer is present at a total concentration of 0.2 - 20.0 mg / mL, preferably 0.5 - 10.0 m g / mL, more preferably 1.0 - 5.0 mg / m, even more preferably 2.7 - 4. 1 mg / mL, for the aqueous pharmaceutical solution according to any one of Embodiments 1 - 3. The aqueous pharmaceutical solution according to any one of Embodiments 1 - 3.

[0034] 5. Component (b) is only one kind of stabilizer against radiolytic degradation, i.e., only the first stabilizer. The aqueous pharmaceutical solution according to any one of Embodiments 1 - 4.

[0035] 6. Component (b) is at least two kinds of stabilizers against radiolytic degradation, i.e., at least the first and the second stabilizers, preferably only two kinds of stabilizers, i.e., only the first and the second stabilizers. The aqueous pharmaceutical solution according to any one of Embodiments 1 - 5.

[0036] 7. The first stabilizer is at 0.2 - 5 mg / mL, preferably 0.5 - 5 mg / mL, More preferably, it is present at a concentration of 0.5 to 2 mg / mL, even more preferably 0.5 to 1 mg / mL, and even more preferably 0.5 to 0.7 mg / mL, according to any one of Embodiments 5 to 6. The aqueous pharmaceutical solution according to any one of Embodiments 5 to 6, which is present at a concentration of even more preferably 0.5 to 0.7 mg / mL.

[0037] 8. The second stabilizer is present at a concentration of 0.5 to 10 mg / mL, more preferably 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, and even more preferably 2.2 to 3.4 mg / mL, according to Embodiment 6. The aqueous pharmaceutical solution according to Embodiment 6.

[0038] 9. The stabilizer is selected from gentisic acid (2,5-dihydroxybenzoic acid) or a salt thereof, ascorbic acid (L-ascorbic acid, vitamin C) or a salt thereof (for example, sodium ascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine, and is preferably selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 8.

[0039] 10. The first stabilizer is selected from gentisic acid and ascorbic acid, and preferably the first stabilizer is gentisic acid. The aqueous pharmaceutical solution according to any one of Embodiments 5 to 9.

[0040] 11. The second stabilizer is selected from gentisic acid and ascorbic acid, and preferably the second stabilizer is ascorbic acid. The aqueous pharmaceutical solution according to any one of Embodiments 6 to 10.

[0041] 12. The first stabilizer is gentisic acid or a salt thereof, and the second stabilizer is ascorbic acid. ​​​​It is ascorbic acid or a salt thereof, and the ratio of the concentration of the first stabilizer (in mg / mL) to the concentration of the second stabilizer (in mg / mL) is 1:3 to 1:7, preferably 1:4 to 1:5. The aqueous pharmaceutical solution according to any one of Embodiments 6 to 8.

[0042] 13. The radionuclide is 177 Lu, 68 Ga, 18 F, 99m Tc, 211 At, 82 Rb, 166 Ho, 225 Ac, 111 In, 123 I, 131 I, 89 Zr, 90 Y or selected from, preferably 177 Lu and 68 Ga, more preferably 177 L u. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 12.

[0043] 14. The cell receptor binding moiety is a somatostatin receptor binding peptide, preferably the somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably selected from octreotide and octreotate. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 13.

[0044] 15. The chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 14.

[0045] 16. A pharmaceutical aqueous solution according to any one of Embodiments 1 to 15, wherein the cell receptor binding moiety and the chelating agent combine to form a molecule 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, more preferably DOTA-T ATE. ATE.

[0046] 17. A pharmaceutical aqueous solution according to any one of Embodiments 1 to 16, wherein the radionuclide, the cell receptor binding moiety, and the chelating agent combine to form a complex 177 Lu-DOTA-TOC ( 177 Lu-edotreotide) or 177 Lu-DO TA-TATE ( 177 Lu-oxodotreotide), preferably 177 Lu-DOTA -TATE.

[0047] 18. A pharmaceutical aqueous solution according to any one of Embodiments 1 to 17, further comprising a buffer, preferably the buffer is an acetate buffer that provides acetic acid at a concentration of preferably 0.3 to 0.7 m g / mL (preferably about 0.48 mg / mL) and sodium acetate at 0.4 to 0.9 mg / mL (preferably about 0.66 mg / mL).

[0048] 19. A pharmaceutical aqueous solution according to any one of Embodiments 1 to 18, further comprising a metal ion sequestering agent, preferably the metal ion sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof in an amount that provides a concentration of preferably 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL).

[0049] 20. Having a shelf life of at least 24 hours (h) at ≤ 25°C, at least 48 h at ≤ 25°C, at least 72 h at ≤ 25 °C, 24 h to 120 h at ≤ 25°C, 24 h to 96 h at ≤ 25°C, 2 4 h to 84 h at ≤ 25°C, 24 h to 72 h at ≤ 25°C, especially having a shelf life of 72 h at ≤ 25 °C, the aqueous pharmaceutical solution according to any one of Embodiments 1 to 19.

[0050] 21. The solution is manufactured on a commercial scale, especially manufactured in batch sizes of at least 20 GBq, at least 50 GBq, at least 70 GBq, the aqueous pharmaceutical solution according to any one of Embodiments 1 to 20.

[0051] 22a. Immediately available, the aqueous pharmaceutical solution according to any one of Embodiments 1 to 21 .

[0052] 22b. Commercially available, the aqueous pharmaceutical solution according to any one of Embodiments 1 to 22a.

[0053] 23. (a) As follows: (ai) A radionuclide present at a concentration providing a volumetric radioactivity of 250 to 500 MBq / mL Lutetium (Lu-177), and 177 (aii) A complex formed by a somatostatin receptor-binding organic moiety DO TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) linked to a chelating agent, and (bi) Genisteic acid or a salt thereof as a first stabilizer against radiolytic degradation present at a concentration of 0.5 to 1 mg / mL and (bii) Ascorbic acid or a salt thereof as a second stabilizer against radiolytic degradation present at a concentration of 2.0 to 5.0 mg / mL and (bii) Ascorbic acid or a salt thereof as a second stabilizer against radiolytic degradation present at a concentration of 2.0 to 5.0 mg / mL and An aqueous pharmaceutical solution containing

[0054] 24. (c) Diethylenetriaminepentaacetic acid ( DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg / mL, The aqueous pharmaceutical solution according to Embodiment 23, further comprising

[0055] 25. (d) Acetic acid at a concentration of 0.3 to 0.7 mg / mL and sodium acetate at a concentration of 0.4 to 0.9 mg / mL , The aqueous pharmaceutical solution according to Embodiment 23 or 24, further comprising

[0056] 26. The aqueous pharmaceutical solution according to any one of Embodiments 1 to 25, wherein the stabilizer is present in the solution during the complex formation of components (ai) and (aii).

[0057] 27. Only the first stabilizer, preferably at a concentration of 0.5 to 5 mg / mL, more preferably 0.5 to 2 mg / mL, even more preferably 0.5 to 1 mg / mL, and even more preferably 0.5 to 0.7 mg / mL in the final solution, in an amount that results in the concentration, The aqueous pharmaceutical solution according to any one of Embodiments 5 to 26, which is present during the complex formation of components (ai) and (aii).

[0058] 28. A part of the amount of the second stabilizer is present in the solution during the complex formation of components (ai) and (aii), and another part of the amount of the second stabilizer is added after the complex formation of components (ai) and (aii). The aqueous pharmaceutical solution according to any one of Embodiments 6 to 27.

[0058]

[0059]

[0060] 29. The aqueous pharmaceutical solution according to any one of Embodiments 6 to 28, wherein the second stabilizer is added after the complex formation of components (ai) and (aii).

[0060] ​30. The second stabilizer is preferably in a concentration of 0.5 to 10 mg / mL, more preferably 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, and even more preferably 2.2 to 3.4 mg / mL in the final solution, and is added after the complex formation of components (ai) and (aii). The aqueous pharmaceutical solution according to embodiment 6 or 29.

[0061] 31. Further comprising a metal ion sequestering agent added after the complex formation of components (ai) and (aii) to remove any non-complexed Lu, preferably the metal ion sequestering agent is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof in an amount preferably resulting in a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL ) in the final solution. The aqueous pharmaceutical solution according to any one of embodiments 1 to 30.

[0062] 32. (1) The following: (1.1) Preparing an aqueous solution containing a radionuclide; and (1.2) Preparing an aqueous solution containing a cell receptor-binding organic moiety linked to a chelating agent, a first stabilizer, and optionally a second stabilizer; and (1.3) Heating the mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2), thereby forming a process step of forming a complex between the radionuclide and the cell receptor-binding organic moiety linked to the chelating agent; and (2) The following: (2.1) Optionally preparing an aqueous dilution solution containing a second stabilizer; and (2.2) Mixing the complex solution obtained in step (1) and the dilution solution obtained in step (2.1). a process step of diluting the complex solution obtained in step (1); A process for producing an aqueous pharmaceutical solution according to any one of Embodiments 1 to 31, comprising .

[0063] 33. Only the first stabilizer is preferably present in an amount that provides a concentration of 0.5 to 5 mg / mL, more preferably 0.5 to 2 mg / mL, even more preferably 0.5 to 1 mg / mL, even more preferably 0.5 to 0.7 mg / mL at step (1.3), according to the process of Embodiment 32. A process according to Embodiment 32, which is present at step (1.3).

[0064] 34. A part of the amount of the second stabilizer is already present in the solution at step (1.3), and the other part of the amount of the second stabilizer is added in step (2.1) after step (1.3), according to the process according to any one of Embodiments 32 to 33.

[0065] 35. An aqueous pharmaceutical solution according to any one of Embodiments 32 to 34, wherein the second stabilizer is added in step (2.1) after step (1.3). A process according to any one of Embodiments 32 to 34, which is added in step (2.1) after step (1.3).

[0066] 36. The second stabilizer is preferably added in step (2.1) after step (1.3) in an amount that provides a concentration of 0.5 to 10 mg / mL, more preferably 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, even more preferably 2.2 to 3.4 mg / mL in the final solution, according to the aqueous pharmaceutical solution according to any one of Embodiments 32 to 35. A process according to any one of Embodiments 32 to 35, which is added in step (2.1) after step (1.3).

[0067] 37. The solution of step (1.2) further contains a buffer, preferably an acetate buffer, according to the process according to any one of Embodiments 32 to 36.

[0068] 38. The resulting mixture is heated in step (1.3) at a temperature of 70 to 99 °C, preferably 90 to 98 °C, for 2 to 59 minutes, the process according to any one of embodiments 32 to 37.

[0069] 39. The solution of step (2.1) further contains diethylenetriaminepentaacetic acid (DTPA) or a salt thereof the process according to any one of embodiments 32 to 38.

[0070] 40. (3) A process of filtering the solution obtained in step (2) through 0.2 μm step and (4) The filtered solution obtained in step (3) is dispensed into a dose unit container in an amount necessary to deliver a radiation dose of 5.0 to 10 MBq, preferably 7.0 ~8.0 MBq, more preferably 7.3 to 7.7 MBq, even more preferably 7.4 to 7.5 MBq, the process step, preferably the amount being 10 to 50 mL, more preferably 15 to 30 m L, even more preferably 20 to 25 mL, the process step and further comprising the process according to any one of embodiments 32 to 39.

[0071] 41. The solution of step (1.1) contains LuCl3 and HCl, according to embodiments 32 to 40 the process according to any one of them.

[0072] 42. The solution of step (1.2) is 177 Lu-DOTA-TATE or 177 Lu- DOTA-TOC, and gencitic acid, acetic acid, and sodium acetate, the process according to any one of embodiments 3 2 to 41.

[0073] 43. The solution of step (2.1) contains DTPA and ascorbic acid, according to embodiments 32 to ​The process according to any one of 42.

[0074] 44. The dose unit container in step (4) is a vial with a stopper enclosed in a lead container The process according to any one of Embodiments 32 to 43.

[0075] Definition The term "about" or "ca." in this specification means that the following value can vary by ±20%, preferably ± 10%, more preferably ±5%, even more preferably ±2%, even more preferably ± 1%.

[0076] Hereinafter, the meanings of the terms used in this specification are defined.

[0077] "Aqueous solution": A solution of a solute in water.

[0078] "(ai) A radionuclide and, (aii) A cell receptor-binding organic moiety linked to a chelating agent, formed complex": The radionuclide metal ion forms a non-covalent bond with a functional group of a chelating agent such as an amine or a carboxylic acid. The chelating agent has at least two such complexing functional groups so as to form a chelate complex.

[0079] The chelating agents related to the present invention are DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid , DTPA: diethylenetriaminepentaacetic acid, NTA: nitrilotriacetic acid, EDTA: ethylenediaminetetraacetic acid, DO3A: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid, or mixtures thereof, and may preferably be DOTA.

[0080] A "cell receptor binding moiety" particularly suitable for the present invention is a somatostatin receptor binding peptide, and preferably, the somatostatin receptor binding peptide is selected from octre otide, octreotate, lanreotide, vapreotide, and pasireotide, and preferably is selected from octreotide and octreotate.

[0081] "Linked": The cell receptor binding organic moiety is either directly linked to the chelating agent or connected via a linker molecule, and preferably is directly linked. The linking bond is either a covalent or non-covalent bond between the cell receptor binding organic moiety and (the linker and) the chelating agent, and preferably the bond is a covalent bond.

[0082] "Stabilizer against radiolytic degradation": A stabilizer that protects organic molecules from radiolytic degradation. For example, when γ-rays emitted from a radionuclide cleave the bonds between the atoms of an organic molecule and radicals are formed, such radicals are then captured by the stabilizer, so that any other chemical reactions that may lead to undesirable, potentially ineffective, or even toxic molecules are avoided from being caused by the radicals. Therefore, such a stabilizer is also referred to as a "free radical scavenger" or simply a "radical scavenger". Other alternative terms for such stabilizers are "radiation stability improver", "radiolytic stabilizer", or simply a "quencher".

[0083] "The stabilizer is present in the solution during the complex formation of components (ai) and (aii)": First A stabilizer and optionally a second stabilizer are also present. That is, the first stabilizer is present either alone or in combination with the second stabilizer.

[0084] "Present during complex formation": The stabilizer is either in the radionuclide solution or in the chelating agent-containing solution and then these two solutions are added, and in some cases, heating is applied to promote complex formation . Preferably, the stabilizer is in the chelating agent-containing solution.

[0085] "Only the first stabilizer is present during the complex formation of components (ai) and (aii)": First the stabilizer is present and the second is not. In other words, only one kind of stabilizer is present.

[0086] "The second stabilizer is added after the complex formation of components (ai) and (aii)": Regardless of whether the second stabilizer was already present during complex formation, after the completion of the complex formation reaction, for example, after the reaction solution heated up to a certain temperature is cooled again to return to ambient temperature , the second stabilizer is added.

[0087] The cell 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 and ed otreotide, DOTA-NOC: [DOTA 0 , D-Phe 1 , 1-Nal 3 octreotide, DOTA-TATE: [DOTA 0 , D-Phe 1 , Tyr 3 octreotate, octreotide (INN), DOTA-LAN: [DOTA 0 , D-β-Nal 1 lanreotide, DOTA-VAP: [DOTA 0 , D-Phe 1 , Tyr 3 vapreotide.

[0088] Preferred molecules for use in the present invention are DOTA-TOC and DOTA-TATE, more preferably, the molecule is DOTA-TATE.

[0089] "Buffer with a pH of 4.5 to 6.0": It 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), and preferably the buffer is an acetate buffer, and preferably, the acetate buffer is composed of acetic acid and sodium acetate.

[0090] "Metal ion chelator", a chelating agent suitable for complexing radionuclide metal ions, preferably DTPA: diethylenetriaminepentaacetic acid.

[0091] "Commercial": A pharmaceutical product is one that can obtain marketing approval from the health authority, can be manufactured on a commercial scale from a pharmaceutical manufacturing site, and can be supplied to end-users at remote locations such as hospitals and patients.

Examples

[0092] Hereinafter, the present invention will be described in more detail and specifically with reference to examples, but it is not intended to limit the present invention.

[0093] Materials: 177 LuCl3 can be obtained from suppliers such as I.D.B. Holland BV . DOTA 0 -Tyr 3 -octreotate can be obtained from suppliers such as piCHEM Forschungs -und Entwicklungs GmbH, Austria. All other components of the pharmaceutical product are commercially available from various suppliers.

[0094] Example 1: Composition of the pharmaceutical product The pharmaceutical product ( 177 Lu-DOTA 0 -Tyr 3 -octreotate 370 MBq / mL injectable solution) is designed as a sterile ready-to-use injectable solution containing the pharmaceutical substance with a volumetric radioactivity of 370 MBq / mL at the reference date and reference time (calibration time (tc)). The calibration 177 time (tc) corresponds to the time of measurement of the radioactivity of the first QC vial, which is the end of production (EOP = 0 t0). The shelf life of the pharmaceutical product is defined as 72 hours after the calibration time. The pharmaceutical product 3 is a single-dose vial containing a suitable amount of solution to enable delivery of 7.4 GBq of radioactivity upon injection. The production site calibrates within the range of 7.4 GBq ± 10% (200 mCi) after the end of production

[0095] Prepare a rated single dose. The analytical proof reports both the exact radioactivity and the time at which this radioactivity is achieved. This value is specified as "Injection time: {DD MM YYYY}{hh:mm } UTC". Considering the variable injection time and the steady decay of the radionuclide, when calculating the filling volume required to have a radioactivity of 7.4 GBq at the injection time, it can be in the range of 20.5 - 25. 0 mL.

[0096] [Table 1]

[0097] Example 2: Manufacture of Pharmaceutical Product For a 74 GBq batch size (2 Ci batch size), 177 a LuCl3 solution (74 GBq in HCl ), a DOTA-Tyr 3 -octreotate solution (2 mg), and a reaction buffer agent solution (containing an antioxidant (i.e., gentisic acid) and a buffer system (i.e., acetate buffer system)) are mixed and integrated to enable radiolabeling performed at a temperature of 90 - 98 °C for several minutes.

[0098] The synthesis is carried out using a single-use disposable kit cassette installed on the front side of a synthesis module containing a fluid path (tube), a reactor vial, and a seal reagent vial.

[0099] The resulting mother solution is diluted with a solution containing a chelating agent (i.e., DTPA) and an antioxidant (i.e., ascorbic acid or gentisic acid), then passed through a 0.2 μm filter for sterile filtration to give the ready-to-use solution described in Example 1.

[0100] Finally, the solution is dispensed into sterile vials in an amount of 20.5 - 25.0 mL. The vials with stoppers are enclosed in a lead container for protective shielding.

[0101] Example 3: Stability test results after storage under various temperature conditions. The following table provides the stability test data for batches manufactured at a batch size of 74 GBq according to the process described in Example 2.

[0102] [Table 2]

[0103] Very similar good stability results were obtained for batches manufactured at a batch size of 148 GBq. ​

Claims

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

2. The stabilizing agent(s), component (b), is at least 0.2 mg / mL, preferably at least at least 0.5 mg / mL, more preferably at least 1.0 mg / mL, and even more preferably 10. The pharmaceutical aqueous solution of claim 1, wherein the aqueous solution is present in a total concentration of at least 2.7 mg / mL. solution.

3. The radionuclide is 100-1000 MBq / mL, preferably 250-500 MBq 3. The pharmaceutical aqueous solution of claim 1, wherein the solution is present in a concentration providing a volumetric radioactivity of 100 / mL.

4. The stabilizer(s) is / are at a concentration of 0.2-20.0 mg / mL, preferably 0.5-10. 0 mg / mL, more preferably 1.0 to 5.0 mg / mL, even more preferably 2.7 The pharmaceutical composition according to any one of claims 1 to 3, which is present in a total concentration of up to 4.1 mg / mL. sex solution.

5. The component (b) contains only one stabilizer against radiolytic degradation, i.e., the first stabilizer. The medicinal aqueous solution according to any one of claims 1 to 4, wherein the aqueous medicinal solution is the only agent that is a stimulant.

6. The component (b) comprises at least two stabilizers against radiolytic degradation, i.e. at least At least a first and a second stabilizer, preferably only two stabilizers, i.e., a first and a second stabilizer.

6. The pharmaceutical aqueous solution according to claim 1, wherein the stabilizer is selected from the group consisting of 1 and 2.

7. The first stabilizer is present at a concentration of 0.2 to 5 mg / mL, preferably 0.5 to 5 mg / mL, more preferably More preferably, the concentration is 0.5 to 2 mg / mL, even more preferably, the concentration is 0.5 to 1 mg / mL, and even more preferably, the concentration is 0.5 to 2 mg / mL. The method according to claim 5 or 6, more preferably in a concentration of 0.5 to 0.7 mg / mL. Pharmaceutical aqueous solutions.

8. The second stabilizer is preferably present at a concentration of 0.5 to 10 mg / mL, more preferably 1.0 to 8.0 mg / mL. / mL, even more preferably 2.0 to 5.0 mg / mL, even more preferably 2.2 7. The pharmaceutical aqueous solution of claim 6, which is present in a concentration of from about 3.4 mg / mL.

9. The stabilizer(s) may be gentisic acid (2,5-dihydroxybenzoic acid) or Salt, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g. sodium muascorbate), methionine, histidine, melatonin, ethanol, and Se-methionine thionine, preferably gentisic acid or a salt thereof and ascorbic acid or a salt thereof. The pharmaceutical aqueous solution according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of salts.

10. The first stabilizer is selected from gentisic acid and ascorbic acid, preferably 10. The pharmaceutical aqueous solution according to claim 5, wherein the stabilizer is gentisic acid.

11. The second stabilizer is selected from gentisic acid and ascorbic acid, preferably The pharmaceutical solution according to any one of claims 6 to 10, wherein the second stabilizer is ascorbic acid. sex solution.

12. The first stabilizer is gentisic acid or a salt thereof, and the second stabilizer is aspartic acid. corbic acid or a salt thereof, and the concentration of the first stabilizer (in mg / mL) and The ratio of the concentration of the second stabilizer (mg / mL) is 1:3 to 1:7, preferably 1:4 to 9. The pharmaceutical aqueous solution according to any one of claims 6 to 8, wherein the ratio is 1:

5.

13. The radionuclide １７７ Lu, ６８ G.A. １８ F. ９９ mTc, ２１１ At, ８２ Rb , １６６ Ho, ２２５ Ac, １１１ In, １２３ I, １３１ I, ８９ Zr, ９０ selected from Y is selected, preferably １７７ Lu and ６８ Ga, more preferably １７７ In Lu The medicinal aqueous solution according to any one of claims 1 to 12.

14. The cell receptor binding portion is a somatostatin receptor binding peptide, preferably or the somatostatin receptor-binding peptide is octreotide, octreotate, Selected from lanreotide, vapreotide, and pasireotide, preferably octreotide. The medicinal water according to any one of claims 1 to 13, wherein the medicinal water is selected from the group consisting of octreotate and octreotate. sex solution.

15. The chelating agent is DOTA, DTPA, NTA, EDTA, DO3A, NOC, and 15. The method according to claim 1, wherein the nucleotide sequence is selected from NOTA, preferably DOTA. The above medicinal aqueous solution.

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

17. The radionuclide, the cell receptor binding moiety, and the chelator together , complex １７７ Lu-DOTA-TOC ( １７７ Lu-Edotreotide) or １７７ Lu- DOTA-TATE( １７７ Lu-oxodotreotide), preferably １７７ Lu-DO The pharmaceutical aqueous solution of any one of claims 1 to 16, which forms TA-TATE.

18. Further comprising a buffering agent, preferably said buffering agent is preferably at 0.3-0.7 mg / mL (preferably about 0.48 mg / mL) of acetic acid and 0.4 to 0.9 mg / mL (preferably and an acetate buffer in an amount to provide a concentration of sodium acetate (about 0.66 mg / mL).

18. The medicinal aqueous solution according to any one of claims 1 to 17.

19. It further comprises a sequestering agent, preferably said sequestering agent is preferably 0. and an amount of diglyceride to provide a concentration of about 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL). Any one of claims 1 to 18, which is ethylenetriaminepentaacetic acid (DTPA) or a salt thereof. Item 10. The pharmaceutical aqueous solution according to item 10.

20. At least 24 hours (h) at ≦25°C, at least 48 h at ≦25°C, at least At least 72 hours, 24 to 120 hours at ≦25℃, 24 to 96 hours at ≦25℃, 2 4h to 84h, 24h to 72h at ≦25° C., in particular ≦72h at ≦25° C.

20. The pharmaceutical aqueous solution of claim 1, having a shelf life of

21. The solution is produced in a commercial scale production, in particular at least 20 GBq, at least Any of claims 1 to 20, which is produced in batch sizes of at least 50 GBq, at least 70 GBq. The pharmaceutical aqueous solution according to any one of claims 1 to 4.

22. A pharmaceutical aqueous solution according to any one of claims 1 to 21, which is ready to use and / or for commercial use. solution.

23. (a) Below: (ai) Radioactive material present in a concentration providing a volumetric activity of 250-500 MBq / mL Nuclide １７７ Lutetium (Lu-177), (aii) a somatostatin receptor binding organic moiety DO linked to a chelator. TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and a complex formed by (bi) a first stabilization against radiolytic degradation present at a concentration of 0.5 to 1 mg / mL; gentisic acid or a salt thereof as an agent; (bii) a second test for radiolytic degradation present at a concentration of 2.0 to 5.0 mg / mL Ascorbic acid or a salt thereof as a stabilizer; 13. A pharmaceutical aqueous solution comprising:

24. (c) Diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL ) or a salt thereof, 24. The medical aqueous solution of claim 23, further comprising:

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

26. The stabilizing agent(s) are present in solution upon complexation of components (ai) and (aii). The medicinal aqueous solution according to any one of claims 1 to 25.

27. The first stabilizing agent alone is preferably present at a concentration of 0.5-5 mg / mL in the final solution, more preferably More preferably, the concentration is 0.5 to 2 mg / mL, and even more preferably, the concentration is 0.5 to 1 mg / mL. Components (ai) and (aii) preferably in an amount to provide a concentration of 0.5 to 0.7 mg / mL.

27. The pharmaceutical aqueous solution according to claim 5, wherein the aqueous solution is present during complex formation of the compound.

28. A portion of the amount of the second stabilizer is already present at the time of complex formation of components (ai) and (aii). Another part of the amount of the second stabilizer present in the solution is composed of components (ai) and (aii 28. The pharmaceutical aqueous solution according to claim 6, wherein the aqueous solution is added after complex formation of the medicament.

29. The second stabilizer is added after the complexation of components (ai) and (aii).

29. The medicinal aqueous solution according to any one of claims 6 to 28.

30. The second stabilizing agent is preferably present at a concentration of 0.5-10 mg / mL in the final solution, more preferably is 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, and More preferably, components (ai) and (a) are added in an amount to provide a concentration of 2.2 to 3.4 mg / mL.

30. The pharmaceutical aqueous solution of claim 6 or 29, which is added after the complex formation of ii).

31. Added after complexation of components (ai) and (aii) to remove any uncomplexed Lu. Preferably, the sequestering agent is has a concentration of 0.01-0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution 2. The composition according to claim 1, wherein the amount of diethylenetriaminepentaacetic acid (DTPA) or a salt thereof is in an amount that results in 31. The pharmaceutical aqueous solution according to any one of claims 1 to 30.

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

33. The first stabilizing agent alone is preferably present at a concentration of 0.5-5 mg / mL in the final solution, more preferably More preferably, the concentration is 0.5 to 2 mg / mL, even more preferably, the concentration is 0.5 to 1 mg / mL, and even more preferably, the concentration is 0.5 to 2 mg / mL. Preferably present in step (1.3) in an amount resulting in a concentration of 0.5 to 0.7 mg / mL.

33. The process of claim 32.

34. A portion of the amount of the second stabilizer is already present in the solution in step (1.3), and Another part of the amount of the stabilizer of step 2 is added in step (2.1) after step (1.3).

34. The process according to claim 32 or 33.

35. 33. The method of claim 32, wherein the second stabilizer is added in step (2.1) after step (1.3).

35. The pharmaceutical aqueous solution according to any one of claims 1 to 34.

36. The second stabilizing agent is preferably present at a concentration of 0.5-10 mg / mL in the final solution, more preferably is 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, and More preferably, after step (1.3), in an amount that results in a concentration of 2.2 to 3.4 mg / mL. The pharmaceutical aqueous solution according to any one of claims 32 to 35, which is added in step (2.1).

37. 32 to 36, wherein the solution of step (1.2) further comprises a buffer, preferably an acetate buffer.

36. The process according to any one of claims 36 to 38.

38. In step (1.3), the resulting mixture is heated at 70 to 99° C., preferably for 2 to 59 minutes. The process according to any one of claims 32 to 37, wherein the is heated to a temperature of 90 to 98°C. 。

39. The solution of step (2.1) further contains diethylenetriaminepentaacetic acid (DTPA) or a salt thereof. The process according to any one of claims 32 to 38, comprising

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

41. The solution of step (1.1) is ３ and HCl. The process described in paragraph .

42. The solution of step (1.2) １７７ Lu-DOTA-TATE or １７７ Lu-DOTA -TOC, gentisic acid, acetic acid, and sodium acetate.

2. The process according to any one of claims 1 to 11.

43. 43. The method according to claim 32, wherein the solution in step (2.1) contains DTPA and ascorbic acid. The process according to any one of claims 1 to 5.

44. The dose unit container of step (4) is a stoppered vial sealed within a lead container; The process according to any one of claims 32 to 43.

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