Stable, concentrated radionuclide complex solution

Abstract

To provide a radionuclide complex solution of high concentration and high chemical stability, that enables the use as a drug product for diagnostic and / or therapeutic purposes.SOLUTION: Provided is stabilization of a radionuclide complex solution by using at least one stabilizer against radiolytic degradation, or two stabilizers introduced during a manufacturing process at different stages. In one aspect, provided is a pharmaceutical aqueous solution comprising: (a) a complex formed by (ai) a radionuclide, and (aii) a cell receptor binding organic moiety linked to a chelating agent; and (b) at least one stabilizer against radiolytic degradation, the radionuclide being present in a concentration that provides a volumetric radioactivity of at least 100 MBq / mL, preferably of at least 250 MBq / mL.SELECTED DRAWING: None

Description

[Technical Field]

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

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

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

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

[0005] The stability of such radiopharmaceutical products is insufficient, limiting any of their significant shelf life. Due to the lack of life expectancy, so far, the drug has only been administered in hospital laboratories as individual patient doses. The drug must be manufactured and administered immediately to patients who are already waiting for radiological treatment. It was necessary to be in the hospital.

[0006] Various strategies have been explored to reduce the radiolysis of radiopharmaceutical products, This has been achieved with more or less success: the drug product can be stored at low temperatures or It may be prepared in dilution or stabilizers may be added.

[0007] However, when stabilizers are added, such chemicals can bind radionuclides to chelating agents. This can be problematic as it can adversely affect the complexation of Summary of the Invention [Problem to be solved by the invention]

[0008] The disadvantage of producing highly diluted drug products is that large volumes of infusion solution must be administered to patients. For patient convenience and drug tolerability reasons, a highly concentrated radiopharmaceutical product is provided. However, such highly concentrated solutions may be highly detrimental to the On the one hand, dilution of pharmaceutical products avoids radiolysis, and on the other hand, concentration The contradictory position of providing a thick drug solution to avoid patient discomfort during treatment is , leaving the design of radiopharmaceutical drug products a technical challenge. [Means for solving the problem]

[0009] The present inventors have now discovered that storage at ambient or short-term elevated temperatures does not result in chemical or radioactive contamination. We have discovered a method for designing and producing highly radiochemically stable high-concentration radionuclide complex solutions. .

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

[0011] (a) Below: (ai) a radionuclide; (aii) a cell receptor-binding organic moiety linked to a chelator; and a complex formed by (b) at least one stabilizer against radiolytic degradation; Including, The radionuclide has a concentration of at least 100MBq / mL, preferably at least 250MBq / mL present at a concentration that provides a volumetric radioactivity of q / mL, Pharmaceutical aqueous solutions.

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

[0013] (a) Below: (ai) A radioactive substance present in a concentration that provides a volumetric activity of 250 to 500 MBq / mL nuclide 177 Lutetium (Lu-177) and (aii) Somatostatin receptor-binding organic moiety DO linked to a chelator TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and a complex formed by (bi) Primary stabilization against radiolytic degradation at concentrations of 0.5-1 mg / mL gentisic acid or a salt thereof as an agent; (bii) Secondary resistance to radiolytic degradation present at concentrations of 2.0 to 5.0 mg / mL ascorbic acid or a salt thereof as a stabilizer; 1. A pharmaceutical aqueous solution comprising:

[0014] (1) The following: (1.1) preparing an aqueous solution containing a radionuclide; (1.2) a cell receptor-binding organic moiety linked to a chelator and a first stable preparing an aqueous solution comprising a stabilizing agent and, optionally, a second stabilizing agent; (1.3) A mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2) and heating the by combining a radionuclide with a cell receptor-binding organic moiety linked to a chelator. a process step of forming a complex; (2) The following: (2.1) preparing an aqueous dilution solution optionally containing a second stabilizer; (2.2.) The complex solution obtained in step (1) and the complex solution obtained in step (2.1) a diluted solution; and a process step of diluting the complex solution obtained in step (1) by A process for producing the pharmaceutical aqueous solution as defined above, comprising:

[0015] The present invention provides the following advantages:

[0016] High concentrations allow for the administration of high doses within a short time frame. For example: 177 Lu-D For OTA-TATE, IV administration should be completed within approximately 20-30 minutes. A high dose of 7.4 GBq can be delivered with a small volume of 25.0 mL.

[0017] Using the preferred stabilizers of the present invention described herein, after 72 hours at 25°C Regarding the chemical purity of the cell receptor-binding molecule, this molecule was a sensitive peptide molecule. At least 95%, 96%, 97%, 98%, 99%, or 100% chemical For example, DOTA-TATE has a high stability at 25°C. 100% chemical purity was found after 72 hours, even after 48 hours at 32°C. Even under short-term elevated temperature conditions (12 h at 32°C and 60 h at 25°C), radiochemical Such high stability in terms of purity was found.

[0018] Furthermore, the use of the preferred stabilizers of the present invention described herein allows for the radionuclide complexes to be High radiochemical stability of at least 95% is ensured for the radiochemical purity of the compound. For example, 177 In the case of Lu-DOTA-TATE, after 72 hours at 25°C, Radiochemical purity of at least 95% was found. Such high stability in terms of radiochemical purity was found even after 60 h at 25°C. Ta.

[0019] Although sufficient stability can already be achieved with one single stabilizer, the use of two stabilizers It has been found that the complex is particularly suitable for stabilizing sensitive radiopharmaceutical solutions. If there is one stabilizer during synthesis and another stabilizer added after complex formation, The complexation reaction protects the cell receptor-binding molecule from radiolysis and also improves storage stability. Advantageously, this ensures that other stabilizers will have an enhancing protective effect over the lifespan.

[0020] Furthermore, this sequential application of two stabilizers results in relatively small amounts of stabilizers being released upon complexation. The presence of a stabilizer minimizes the possibility of its interference with the complexation reaction. (limited to a certain amount), and after complexation, a large amount of the stabilizer combination is present (hence the need for subsequent drug preparation). This ensures that the product is protected (the protection of the stabilizer is enhanced over the product's shelf life).

[0021] Furthermore, this sequential application of two stabilizers allows the complexation reaction to proceed at elevated temperatures. The absence of one of them reduces the overall heat stress of such stabilizers. .

[0022] Furthermore, especially when two different stabilizers are used, this combination is more effective than a single stabilizer. Rather than stabilizers, each compound that may be formed by radiolysis of the cell receptor binding molecule is This is advantageous because the reaction to different types of radicals is efficient.

[0023] To enable the production of radiopharmaceutical drug products from centralized pharmaceutical manufacturing sites and ready-to-use A shelf life of at least 3 days is required to commercialize it as a viable drug product. do.

[0024] Therefore, thanks to its high stability (72 h at 25°C), the invention is able to meet the highest quality standards ( (e.g., cGMP) and industrial scale, e.g., treating 10-20 patients simultaneously. 74GBq or 148GBq to provide pharmaceutical products in multiple dose units, such as dose units sufficient for q batch sizes allow for centralized pharmaceutical manufacturing.

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

[0026] Furthermore, due to its high stability, the present invention requires no preparation by clinical staff prior to administration. A ready-to-use infusion that can be administered to a patient immediately without the need for any work to be performed It can be provided as a solution.

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

[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 a complex formed by (b) at least one stabilizer against radiolytic degradation; Including, The radionuclide has a concentration of at least 100MBq / mL, preferably at least 250MBq / mL present at a concentration that provides a volumetric radioactivity of q / mL, Pharmaceutical aqueous solutions.

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

[0032] 3. The radionuclide is 100 to 1000 MBq / mL, preferably 250 to 500 Any one of embodiments 1 or 2, wherein the radioactivity is present in a concentration providing a volumetric activity of MBq / mL. 10. The pharmaceutical aqueous solution according to claim 9.

[0033] 4. The stabilizer is 0.2 to 20.0 mg / mL, preferably 0.5 to 10.0 mg / mL. g / mL, more preferably 1.0 to 5.0 mg / m, and even more preferably 2.7 to 4. 4. The pharmaceutical aqueous solution of any one of embodiments 1 to 3, wherein the pharmaceutical aqueous solution is present in a total concentration of 1 mg / mL. liquid.

[0034] 5. Component (b) contains only one stabilizer against radiolytic degradation, i.e., the first stabilizer. It is a stabilizer only, 5. The aqueous medicinal solution according to any one of embodiments 1 to 4.

[0035] 6. Component (b) contains at least two stabilizers against radiolytic degradation, namely At least a first and a second stabilizer, preferably only two stabilizers, i.e., a first and a second stabilizer. 2 stabilizers only, 6. The aqueous medicinal solution according to any one of embodiments 1 to 5.

[0036] 7. The first stabilizer is 0.2 to 5 mg / mL, preferably 0.5 to 5 mg / mL, More preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, and even more preferably, it is 0.5 to 2 mg / mL. More preferably, the compound according to any one of embodiments 5 to 6 is present in a concentration of 0.5 to 0.7 mg / mL. The pharmaceutical aqueous solution according to any one of claims 1 to 4.

[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. g / mL, even more preferably 2.0-5.0 mg / mL, even more preferably 2. 7. The pharmaceutical aqueous solution of embodiment 6, wherein the pharmaceutical aqueous solution is present in a concentration of 2 to 3.4 mg / mL.

[0038] 9. The stabilizer is gentisic acid (2,5-dihydroxybenzoic acid) or its salt, aspartame Ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g., sodium ascorbic acid) carbamate), methionine, histidine, melatonin, ethanol, and Se-methionine and preferably selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof. The pharmaceutical aqueous solution according to any one of embodiments 1 to 8, wherein

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

[0040] 11. The second stabilizer is selected from gentisic acid and ascorbic acid, preferably The medicament of any one of embodiments 6 to 10, wherein the second stabilizer is ascorbic acid. Aqueous solution.

[0041] 12. The first stabilizer is gentisic acid or a salt thereof and the second stabilizer is aspartame. corbic acid or its salt, and the concentration of the first stabilizer (in mg / mL) and the concentration of the second stabilizer The ratio of the concentration of the stabilizer (mg / mL unit) is 1:3 to 1:7, preferably 1:4 to 1:5. 9. The aqueous medicinal solution according to any one of embodiments 6 to 8.

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

[0043] 14. The cell receptor binding portion is a somatostatin receptor binding peptide, and preferably Preferably, the somatostatin receptor-binding peptide is octreotide, octreotide, lanreotide, vapreotide, and pasireotide, preferably octotreat. 14. The composition according to any one of embodiments 1 to 13, wherein the compound is selected from octreotide and octreotate. Pharmaceutical aqueous solutions.

[0044] 15. Chelating agents include DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA. 1. The pharmaceutical aqueous solution according to claim 1.

[0045] 16. The cell receptor binding moiety and the chelator together form DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxo dotreotide), DOTA-LAN, and DOTA-VAP, preferably DOTA-TOC and DOTA-TATE are selected, more preferably DOTA-T 16. The pharmaceutical aqueous solution according to any one of embodiments 1 to 15, which forms a molecule that is an ATE. .

[0046] 17. The radionuclide, cell receptor binding moiety, and chelator together form a complex. body 177 Lu-DOTA-TOC( 177 Lu-edotreotide) or 177 Lu-DO TA-TATE( 177 Lu-oxodotreotide), preferably 177 Lu-DOTA 17. The pharmaceutical aqueous solution of any one of embodiments 1 to 16, which forms a TATE.

[0047] 18. The method further comprises the step of: Acetic acid at a concentration of 0.4 to 0.9 mg / mL (preferably about 0.48 mg / mL) and (preferably about 0.66 mg / mL) sodium acetate and an amount of acetate buffer to provide 18. The aqueous medicinal solution according to any one of embodiments 1 to 17.

[0048] 19. Further comprising a sequestering agent, preferably the sequestering agent is or to a concentration of 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL). 19. The method of claim 1, wherein the amount of diethylenetriaminepentaacetic acid (DTPA) or a salt thereof is 10. The pharmaceutical aqueous solution according to any one of the preceding claims.

[0049] 20. At least 24 hours (h) at ≦25℃, at least 48h at ≦25℃, At least 72 hours at 25°C, 24 hours to 120 hours at 25°C or less, 24 hours to 96 hours at 25°C or less, Shelf life is 24-84 hours at 5°C and 24-72 hours at ≦25°C, especially ≦25°C 20. The pharmaceutical aqueous solution of any one of embodiments 1 to 19, having a shelf life of 72 h at RT.

[0050] 21. The solution is produced in a commercial scale, particularly at least 20 GBq, In embodiments 1 to 5, the ion exchange membrane is produced in a batch size of at least 50 GBq, at least 70 GBq. 20. A pharmaceutical aqueous solution according to any one of claims 1 to 20.

[0051] 22a. A ready-to-use aqueous pharmaceutical solution according to any one of embodiments 1 to 21. .

[0052] 22b. A pharmaceutical aqueous solution according to any one of embodiments 1 to 22a, which is for commercial use.

[0053] 23. (a) Below: (ai) A radioactive substance present in a concentration that provides a volumetric activity of 250 to 500 MBq / mL nuclide 177 Lutetium (Lu-177) and (aii) Somatostatin receptor-binding organic moiety DO linked to a chelator TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and a complex formed by (bi) Primary stabilization against radiolytic degradation at concentrations of 0.5-1 mg / mL gentisic acid or a salt thereof as an agent; (bii) Secondary resistance to radiolytic degradation present at concentrations of 2.0 to 5.0 mg / mL ascorbic acid or a salt thereof as a stabilizer; 1. A pharmaceutical aqueous solution comprising:

[0054] 24. (c) Diethylenetriaminepentaacetic acid ( DTPA) or a salt thereof, 24. The pharmaceutical aqueous solution of embodiment 23, further comprising:

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

[0056] 26. A stabilizer is present in solution during the complexation of components (ai) and (aii). 26. The aqueous medicinal solution according to any one of embodiments 1 to 25.

[0057] 27. The first stabilizer alone is preferably present at a concentration of 0.5-5 mg / mL in the final solution, more preferably Preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, even more preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, and more preferably in amounts resulting in a concentration of 0.5 to 0.7 mg / mL of components (ai) and (ai The pharmaceutical aqueous solution according to any one of embodiments 5 to 26, which is present during the formation of the complex i).

[0058] 28. A portion of the amount of the second stabilizer is present during the complexation of components (ai) and (aii). Another part of the amount of the second stabilizer is already present in the solution and is added to the components (ai) and (aii) 28. The pharmaceutical aqueous solution of any one of embodiments 6 to 27, wherein said aqueous solution is added after complexation of

[0059] 29. A method for producing a complex of components (ai) and (aii) in which a second stabilizer is added after the complexation of components (ai) and (aii) The medicinal aqueous solution according to any one of embodiments 6 to 28.

[0060] 30. The second stabilizer is preferably present in a final solution at a concentration of 0.5 to 10 mg / mL, more preferably or 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, More preferably, in an amount resulting in a concentration of 2.2 to 3.4 mg / mL, The pharmaceutical aqueous solution of embodiment 6 or 29, which is added after complexation of (aii).

[0061] 31. Complex forms of components (ai) and (aii) to remove any uncomplexed Lu The method further comprises adding a sequestering agent after synthesis, preferably comprising: Preferably, the final solution is 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL diethylenetriaminepentaacetic acid (DTPA) or a salt thereof in an amount to provide a concentration of 31. The pharmaceutical aqueous solution according to any one of embodiments 1 to 30.

[0062] 32. (1) The following: (1.1) preparing an aqueous solution containing a radionuclide; (1.2) a cell receptor-binding organic moiety linked to a chelator and a first stable preparing an aqueous solution comprising a stabilizing agent and, optionally, a second stabilizing agent; (1.3) A mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2) and heating the by combining a radionuclide with a cell receptor-binding organic moiety linked to a chelator. a process step of forming a complex; (2) The following: (2.1) preparing an aqueous dilution solution optionally containing a second stabilizer; (2.2.) The complex solution obtained in step (1) and the complex solution obtained in step (2.1) a diluted solution; and a process step of diluting the complex solution obtained in step (1) by 32. A process for producing the aqueous pharmaceutical solution of any one of embodiments 1 to 31, comprising:

[0063] 33. The first stabilizer alone is preferably present at a concentration of 0.5-5 mg / mL in the final solution, more preferably Preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, even more preferably, it is 0.5 to 2 mg / mL, even more preferably, it is 0.5 to 1 mg / mL, Preferably, the amount of the compound present in step (1.3) is in an amount that results in a concentration of 0.5 to 0.7 mg / mL. 33. The process of embodiment 32, wherein

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

[0065] 35. The second stabilizer is added in step (2.1) after step (1.3), in an embodiment 35. The aqueous medicinal solution according to any one of aspects 32 to 34.

[0066] 36. The second stabilizer is preferably present in a final solution at a concentration of 0.5-10 mg / mL, more preferably or 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, More preferably, in an amount that results in a concentration of 2.2 to 3.4 mg / mL, 36. The pharmaceutical aqueous solution according to any one of embodiments 32 to 35, which is subsequently added in step (2.1). solution.

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

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

[0069] 39. The solution in step (2.1) contains diethylenetriaminepentaacetic acid (DTPA) or its salts. 39. The process of any one of embodiments 32 to 38, further comprising:

[0070] 40. (3) A process of filtering the solution obtained in step (2) through a 0.2 μm filter The process and (4) The filtered solution obtained in step (3) is added to 5.0 to 10 MBq, preferably 7.0 ~8.0MBq, more preferably 7.3-7.7MBq, even more preferably 7.4- Dispense into dose unit containers in the amount required to deliver a radiation dose of 7.5 MBq. In the process step, the amount is preferably 10 to 50 mL, more preferably 15 to 30 mL. L, and even more preferably 20-25 mL; 40. The process of any one of embodiments 32 to 39, further comprising:

[0071] 41. The method of any one of embodiments 32 to 40, wherein the solution in step (1.1) comprises LuCl3 and HCl. 10. The process according to any one of claims 1 to 9.

[0072] 42. The solution in step (1.2) 177 Lu-DOTA-TATE or 177 Lu- Embodiment 3, comprising DOTA-TOC, gentisic acid, acetic acid, and sodium acetate. 2. The process according to any one of claims 2 to 41.

[0073] 43. Embodiments 32 to 34, wherein the solution in step (2.1) comprises DTPA and ascorbic acid. 42. The process according to any one of claims 1 to 42.

[0074] 44. The dose unit container in step (4) is a stoppered vial sealed in a lead container. 44. The process of any one of embodiments 32 to 43, wherein

[0075] definition The term "about" or "ca." is used herein to mean that the following value is within ±20%, preferably ± 10%, more preferably ±5%, even more preferably ±2%, even more preferably ± This means that it can fluctuate by 1%.

[0076] The following defines the meaning of terms used in this specification.

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

[0078] "(ai) Radionuclides and (aii) a cell receptor-binding organic moiety linked to a chelator; The complex formed by: The radionuclide metal ion is non-covalently coupled to a functional group of the chelator, such as an amine or carboxylic acid. The chelating agent must have at least two bonds that allow it to form a chelate complex. has such a complexing functional group.

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

[0080] Particularly preferred "cell receptor binding moieties" for the present invention are somatostatin receptor binding moieties. Preferably, the somatostatin receptor-binding peptide is an octosteroid. octreotide, lanreotide, vapreotide, and pasireotide. and preferably selected from octreotide and octreotate.

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

[0082] "Stabilizers against radiolytic degradation": Stabilization that protects organic molecules from radiolytic degradation For example, gamma rays emitted from radionuclides cleave the bonds between atoms in organic molecules, When radicals are formed, they are then trapped by the stabilizer, so that Any of these may result in unwanted, potentially ineffective, or even toxic molecules. Therefore, other chemical reactions caused by radicals are also avoided. These stabilizers are also called "free radical scavengers" or simply "radical scavengers." Other alternative terms for such stabilizers are "radiation stabilizing agents" and "radiolytic stabilizers." , or simply "quencher."

[0083] "The stabilizer is present in solution upon complexation of components (ai) and (aii)": and optionally a second stabilizer. That is, the first stabilizer is It is present either alone or in combination with a second stabilizer.

[0084] "Present during complexation": The stabilizer is present in the radionuclide solution or in the chelator-containing solution. The two solutions are then added, possibly to promote complex formation. Elevated temperatures are applied to stabilize the chelating agent. Preferably, the stabilizing agent is in a solution containing the chelating agent.

[0085] "Only the first stabilizer is present when components (ai) and (aii) are complexed": one stabilizer is present and the second is absent. In other words, only one stabilizer is present.

[0086] "The second stabilizer is added after the complexation of components (ai) and (aii)": Complex Form The complex form may or may not have already had a second stabilizer present at the time of synthesis. After the synthesis reaction is complete, for example, the reaction solution that has been heated to an elevated temperature is cooled back down to ambient temperature. Afterwards, a second stabilizer is added.

[0087] The cell receptor binding moiety and the chelator may together form the following molecule: DOTA-OC:[DOTA 0 ,D-Phe 1 ]Octreotide, DOTA-TOC:[DOTA 0 ,D-Phe 1 ,Tyr 3 ]Octreotide and Ed Treotide, DOTA-NOC:[DOTA 0 ,D-Phe 1 ,1-Nal 3 ]Octreotide, DOTA-TATE: [DOTA 0 ,D-Phe 1 ,Tyr 3 ]Octreotate, O oxodotreotide (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] "Buffers with a pH of 4.5 to 6.0": acetate buffers, citrate buffers (e.g., citrate + HCl or citric acid + disodium hydrogen phosphate), or phosphate buffer ( For example, sodium dihydrogen phosphate + disodium hydrogen phosphate) and preferably Preferably, the buffer is an acetate buffer, and preferably, the acetate buffer is a mixture of acetic acid and acetic acid. It is composed of sodium phosphate.

[0090] "sequestering agents", chelating agents suitable for complexing radionuclide metal ions; Preferably DTPA: diethylenetriaminepentaacetic acid.

[0091] "Commercial": A drug product is one that can be licensed for marketing by a health department and is approved for medical use. It can be manufactured on a commercial scale from a pharmaceutical manufacturing site, and can be used at a remote location such as a hospital or patient. It can be supplied to end users. [Example]

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

[0093] material: 177 LuCl3 can be obtained from suppliers such as IDB Holland BV. DOTA 0 -Tyr 3 -Octreotate, piCHEM Forschungs -und Entwicklungs GmbH, Austria and other suppliers. All other components of the drug product are commercially available from various sources.

[0094] Example 1: Composition of pharmaceutical product Pharmaceutical products ( 177 Lu-DOTA 0 -Tyr 3 -Octreotate 370MBq / mL The injection solution) was 370MB at the reference date and reference time (calibration time (tc)). As a pharmaceutical substance with a volumetric radioactivity of q / mL 177 Lu-DOTA 0 -Tyr 3 -Oku It is designed as a sterile, ready-to-use solution for injection containing threotate. The start time (tc) is the end of production (EOP), which is the time of measurement of the radioactivity of the first QC vial. The shelf life of the drug product is assumed to be 72 hours after the calibration time. The drug product is defined as a solution containing a suitable amount of radioactivity that allows delivery of 7.4 GBq of radioactivity upon injection. It is a single dose vial containing a liquid.

[0095] After production, the manufacturing site calibrates the unit to within 7.4 GBq ±10% (200 mCi). A single dose is prepared according to the rated standard. The certificate of analysis provides the exact activity and the time at which this activity is achieved. This value is reported as "Time of injection:{DD MM YYYY}{hh:mm }UTC." Considering the variable injection times and steady decay of radionuclides, The required loading volume for 7.4 GBq of radioactivity at the time of injection is calculated as 20.5-25. The volume may be in the range of 0 mL.

[0096] [Table 1]

[0097] Example 2: Pharmaceutical Product Manufacturing For a 74GBq batch size (2Ci batch size), 177 LuCl3 solution (HCl 74GBq) and DOTA-Tyr 3 -Octreotate solution (2 mg) and reaction buffer The agent solution (antioxidant (i.e., gentisic acid) and buffer system (i.e., acetate buffer system) The radiolabeling is carried out at a temperature of 90-98°C for several minutes. It can be done.

[0098] The synthesis is carried out in a synthesis vessel containing fluid pathways (tubes), reactor vials, and sealed reagent vials. This is done using a single-use disposable kit cassette located at the front of the synthesis module. do.

[0099] The resulting mother solution contained a chelating agent (i.e., DTPA) and an antioxidant (i.e., ascorbic acid). The sample was diluted with a solution containing benzoic acid or gentisic acid, and then filtered through a 0.2 μm filter. Sterile filtered to give the ready-to-use solution described in Example 1.

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

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

[0102] [Table 2]

[0103] Very similar good stability results were obtained for batches manufactured at 148 GBq batch size. was made.

Claims

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 100 MBq / mL, preferably at least 250 MBq / mL q / mL of volumetric radioactivity, Pharmaceutical aqueous solutions.

2. The stabilizer(s), component (b), is / are 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 pharmaceutical aqueous solution is present in a total concentration of at least 2.7 mg / mL. solution.

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

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

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

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

6. The aqueous medicinal solution according to claim 1, wherein the stabilizer is selected from the group consisting of the above.

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

8. The second stabilizer is 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 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 its Salt, ascorbic acid (L-ascorbic acid, vitamin C) or its salts (e.g., sodium melatonin, ethanol, and Se-methionine. thionine, preferably gentisic acid or a salt thereof and ascorbic acid or a salt thereof 9. The pharmaceutical aqueous solution according to claim 1, wherein the compound is selected from the group consisting of hydroxybenzoates, ...

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

11. The second stabilizer is selected from gentisic acid and ascorbic acid, and preferably The medicinal water 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) to the concentration of the second stabilizer is 1:3 to 1:7, preferably 1:4 to 9. The aqueous medicinal solution according to claim 6, wherein the ratio of the ratio of the aqueous medicinal solution to the ratio of ...

13. The radionuclide １７７ Lu, ６８ Ga, 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 aqueous medicinal solution according to any one of claims 1 to 12.

14. The cell receptor binding moiety 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 hydroxylase is selected from the group consisting of hydroxylase, hydroxypropyl methyl methyl ester, hydroxypropyl ... 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 (oxotreotide) dotreotide), DOTA-LAN, and DOTA-VAP, preferably DOTA-TOC and DOTA-TATE, more preferably DOTA-T 16. 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 aqueous pharmaceutical 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 0.3 to 0.7 mg / mL. (preferably about 0.48 mg / mL) of acetic acid and 0.4-0.9 mg / mL (preferably and an acetate buffer in an amount to provide a concentration of sodium acetate (e.g., 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 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL).

19. The compound according to claim 1, which is ethylenetriaminepentaacetic acid (DTPA) or a salt thereof. Item 1. The pharmaceutical aqueous solution according to item 1.

20. At least 24 hours (h) at ≦25°C, at least 48 hours at ≦25°C, at least At most 72 hours, 24 to 120 hours at ≦25℃, 24 to 96 hours at ≦25℃, 24 to 96 hours at ≦25℃ 4 to 84 hours, and a shelf life of 24 to 72 hours at ≦25° C., particularly ≦72 hours 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 50 GBq, at least 70 GBq of any one of claims 1 to 20. 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; 1. 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 pharmaceutical 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 stabilizer(s) are present in solution upon complexation of components (ai) and (aii). The aqueous medicinal solution according to any one of claims 1 to 25.

27. Preferably, the first stabilizing agent alone is present at a concentration of 0.5 to 5 mg / mL in the final solution, more preferably more preferably 0.5 to 2 mg / mL, even more preferably 0.5 to 1 mg / mL), even more preferably Components (ai) and (aii) preferably in amounts to provide a concentration of 0.5 to 0.7 mg / mL 27. The aqueous medicinal solution according to claim 5, wherein the aqueous medicinal solution is present when the complex of

28. A portion of the amount of said second stabilizer is already present at the time of complexation 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 complexation of the hydroxybenzoate and the hydroxybenzoate.

29. 10. The method of claim 9, wherein the second stabilizer is added after the complexation of components (ai) and (aii).

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

30. The second stabilizer is preferably present in a concentration of 0.5 to 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) in amounts that result in 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 to 0.10 mg / mL (preferably about 0.05 mg / mL) in the final solution 10. The compound 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 dilution 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) a diluted solution; and 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. Preferably, the first stabilizing agent alone is present at a concentration of 0.5 to 5 mg / mL in the final solution, more preferably More preferably, the concentration is 0.5 to 2 mg / mL, even more preferably, 0.5 to 1 mg / mL, and even more preferably, 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 said second stabilizer is already present in the solution in step (1.3), and Another part of the amount of the stabilizer in step (2.1) is added after step (1.3).

34. The process of 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 stabilizer is preferably present in a concentration of 0.5 to 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 aqueous pharmaceutical 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 of any one of claims 36 to 36.

38. In step (1.3), the resulting mixture is heated at 70 to 99°C, preferably for 2 to 59 minutes. The process of any one of claims 32 to 37, wherein 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 of 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, even more preferably 20-25 mL; 40. The process of any one of claims 32 to 39, further comprising:

41. The solution in 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, 10. The process of any one of claims 1 to 9.

43. 43. The method according to any one of claims 32 to 42, wherein the solution in step (2.1) contains DTPA and ascorbic acid. The process of any one of claims 1 to 4.

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

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