Stable, concentrated radionuclide complex solutions

Abstract

To provide a process for manufacturing a highly concentrated and chemically stable radionuclide complex solution.SOLUTION: A process includes diluting an aqueous complex solution with a diluent solution to form a pharmaceutical aqueous solution. The aqueous complex solution comprises: a complex comprising (ai) a radionuclide 177 Lu and (aii) a somatostatin receptor binding peptide linked to a chelator DOTA; and (b) at least one stabilizer against radiolytic degradation. Therein: the aqueous diluent solution comprises at least one stabilizer against radiolytic degradation comprising ascorbic acid or a salt thereof; the radionuclide is present in a concentration providing a volumetric activity of 250 to 500 mBq / mL in the pharmaceutical aqueous solution; the stabilizer is present in a total concentration of 0.5 to 10.0 mg / mL; a radiochemical purity (as determined by HPLC) of the pharmaceutical aqueous solution is maintained at a percentage≥95% for at least 72 hours when stored at 25°C; and the pharmaceutical aqueous solution comprises ethanol of 2% or less.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 The act of inducing the cleavage of chemical bonds in molecules that form part of the Radiolytic degradation of the receptor-binding portion of a drug is often called radiolytic degradation. and / or a decrease in its efficacy to act as a therapeutic agent.

[0005] The stability of such radiopharmaceutical products is inadequate, limiting any of their significant shelf life. Due to the lack of life, 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 that I had to be at the hospital.

[0006] Various strategies have been explored to reduce the radiolysis of radiopharmaceutical products, This has been with more or less success: the drug product can be stored at low temperatures or It may be prepared dilute 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 the Summary of the Invention [Problem to be solved by the invention]

[0008] The disadvantage of producing highly dilute drug products is that large volumes of infusion solution must be administered to patients. For patient convenience and drug tolerability reasons, a high concentration radiopharmaceutical drug product is provided. However, such highly concentrated solutions are highly sensitive to radiation. On the one hand, dilution of pharmaceutical products avoids radiolysis, and on the other hand, The contradictory position of providing a thick drug solution to avoid patient discomfort during treatment is , leaving technical challenges in the design of radiopharmaceutical drug products. [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 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.

[0012] The stabilizer (component (b)) should be present in a 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 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) (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 between 0.5 and 1 mg / mL gentisic acid or a salt thereof as an agent; (bii) The second test for radiolytic degradation at concentrations between 2.0 and 5.0 mg / mL Ascorbic acid or a salt thereof as a stabilizer; 13. 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 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 the manufacture of said 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 infusion is completed within approximately 20-30 minutes. A high dose of 7.4 GBq can be delivered in 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, and even after 48 hours at 32°C. Even under short-term elevated temperature conditions (32°C for 12 h and 25°C for 60 h), no radiochemical Such high stability with respect to purity was found.

[0018] Furthermore, the use of the preferred stabilizing agents of the present invention described herein allows for the stabilization of radionuclides complexes. The radiochemical purity of the product is at least 95%. For example, 177 In the case of Lu-DOTA-TATE, after 72 hours at 25°C, A radiochemical purity of at least 95% was found. Such a high stability in terms of radiochemical purity was found even at 20 °C and 25 °C for 60 h. 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 radiation degradation and improves storage stability. Advantageously, this ensures that other stabilizers provide enhanced protective effect over the life span.

[0020] Moreover, this sequential application of two stabilizers results in relatively small amounts of stabilizers being released upon complexation. The presence of a stabilizer (and therefore the possibility of interference with the complexation reaction) is minimized. (limited to the minimum) and after complexation, a large amount of the stabilizer combination is present (hence the subsequent drug preparation This ensures that the protective power of the stabilizer is enhanced over the shelf life of the product.

[0021] In addition, this sequential application of two stabilizers allows the complexation reaction to proceed at elevated temperatures. The absence of one of them when the other is present 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 of the compounds that may be formed by radiolysis of the cell receptor binding molecules is This is advantageous since 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 for use A shelf life of at least 3 days is required to commercialize it as a viable pharmaceutical product. do.

[0024] Thanks to its high stability (72 h at 25 °C), the invention therefore meets the highest quality standards ( (e.g., cGMP) and on an industrial scale, for example, to treat 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 production.

[0025] Furthermore, due to its high stability, the present invention allows for the transfer 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 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 octreotate, 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 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 concentration provides a volumetric activity of MBq / mL. 2. The pharmaceutical aqueous solution according to claim 1 .

[0033] 4. The stabilizer is present in an amount of 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 according to any one of embodiments 1 to 3, which 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 medicinal aqueous 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 2 stabilizers only, 6. The medicinal aqueous solution according to any one of embodiments 1 to 5.

[0036] 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, 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. More preferably, the compound is present in a concentration of 0.5 to 0.7 mg / mL. Medicinal aqueous solution according to any one of claims 1 to 5.

[0037] 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. 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) rubet), 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 medicinal aqueous solution according to any one of embodiments 1 to 8, which is selected from the group consisting of

[0039] 10. The first stabilizer is selected from gentisic acid and ascorbic acid, preferably The pharmaceutical composition according to 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 according to 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 aspartic acid. corbic acid or its salt, and the concentration of the first stabilizer (in mg / mL) and the concentration of the second stabilizer (in mg / mL) The ratio of the concentration of the stabilizer (in mg / mL) is 1:3 to 1:7, preferably 1:4 to 1:5. 9. The medicinal aqueous solution according to any one of embodiments 6 to 8.

[0042] 13. Radioactive nuclides 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 according to any one of embodiments 1 to 12, wherein

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

[0044] 15. Chelating agents are DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA. 10. 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 (oxotate) dotreotide), DOTA-LAN, and DOTA-VAP, preferably DOTA-TOC and DOTA-TATE are preferably selected from DOTA-T 16. The pharmaceutical aqueous solution according to any one of the preceding embodiments, which is an ATE and forms a molecule. .

[0046] 17. The radionuclide, the cell receptor binding moiety, and the 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 steps 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 medicinal aqueous solution according to any one of embodiments 1 to 17.

[0048] 19. The composition further comprises a sequestering agent, preferably the sequestering agent is The concentration is usually about 0.01 to 0.10 mg / mL (preferably about 0.05 mg / mL). 19. The method according to claim 1, wherein the amount of diethylenetriaminepentaacetic acid (DTPA) or a salt thereof is 13. The pharmaceutical aqueous solution according to any one of claims 1 to 12.

[0049] 20. At least 24 hours (h) at ≦25℃, at least 48h at ≦25℃, At least 72h at 25℃, 24h~120h at ≦25℃, 24h~96h at ≦25℃, The shelf life is 24h~84h at 5℃ and 24h~72h at ≦25℃, especially ≦25℃ 20. The pharmaceutical aqueous solution according to any one of the preceding embodiments, having a shelf life of 72 h at 20°C.

[0050] 21. The solution is produced in a commercial scale, particularly at least 20 GBq, In the embodiment 1 to 50 GBq, the batch size is at least 70 GBq. 20. The 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) (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 between 0.5 and 1 mg / mL gentisic acid or a salt thereof as an agent; (bii) The second test for radiolytic degradation at concentrations between 2.0 and 5.0 mg / mL Ascorbic acid or a salt thereof as a stabilizer; 13. A pharmaceutical aqueous solution comprising:

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

[0055] 25. (d) Acetic acid at concentrations of 0.3-0.7 mg / mL and 0.4-0.9 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 complex formation of components (ai) and (aii). 26. The medicinal aqueous solution according to any one of embodiments 1 to 25.

[0057] 27. Only the first stabilizer is present, preferably at 0.5-5 mg / mL in the final solution, more preferably Preferably, the concentration is 0.5 to 2 mg / mL, more preferably, 0.5 to 1 mg / mL, and even more preferably, More preferably, components (ai) and (ai) are added in an amount that results in a concentration of 0.5 to 0.7 mg / mL. 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 already present in the solution is added to the components (ai) and (aii 28. The pharmaceutical aqueous solution according to any one of embodiments 6 to 27, wherein said aqueous solution is added after complex formation of said compound (III).

[0059] 29. A method for the preparation of a complex comprising the steps of: adding a second stabilizer 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 at a concentration of 0.5 to 10 mg / mL in the final solution, more preferably or 1.0 to 8.0 mg / mL, even more preferably 2.0 to 5.0 mg / mL, More preferably, the components (ai) and (ii) are added in an amount that results 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 that results in a concentration of 31. The medicinal 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 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 32. A process for producing the pharmaceutical aqueous solution according to any one of embodiments 1 to 31, comprising:

[0063] 33. Only the first stabilizer is present, preferably at 0.5-5 mg / mL in the final solution, more preferably Preferably, the concentration is 0.5 to 2 mg / mL, more preferably, 0.5 to 1 mg / mL, and even more preferably, More 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,

[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), 35. The medicinal aqueous solution according to any one of aspects 32 to 34.

[0066] 36. The second stabilizer is preferably present at a concentration of 0.5-10 mg / mL in the final solution, 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, step (1.3) The pharmaceutical aqueous solution according to any one of embodiments 32 to 35, which is added later in step (2.1). solution.

[0067] 37. The solution of step (1.2) further comprises a buffer, preferably an acetate buffer. 37. The process according to 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. The process of any one of embodiments 32 to 37, wherein the heating is performed at a temperature of from 2 to 59 minutes.

[0069] 39. The solution in step (2.1) contains diethylenetriaminepentaacetic acid (DTPA) or its salt. 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 diluted with 5.0 to 10 MBq, preferably 7.0 ~8.0MBq, more preferably 7.3-7.7MBq, even more preferably 7.4- Dispense into dose unit containers in the amount required to deliver a radiation dose of 7.5 MBq. In the process, 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. 2. The process according to claim 1 .

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

[0073] 43. The solution of step (2.1) of embodiment 32 to 34 contains 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. The process according to any one of embodiments 32 to 43, wherein

[0075] definition The terms "about" or "ca." are 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] In the following, the meanings of terms used in this specification are defined.

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

[0078] "(ai) A radioactive nuclide, (aii) a cell receptor binding organic moiety linked to a chelator; and 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 carboxyl groups capable of forming a chelate complex. Such a complexing functional group is

[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 octoterene. otide, octreotate, 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 between the cell receptor-binding organic moiety and the (linker) chelator. The bond may be either covalent or non-covalent, preferably the bond is covalent.

[0082] "Stabilizers against radiolytic degradation": Stabilization to protect organic molecules against radiolytic degradation For example, gamma rays emitted from radionuclides break the bonds between atoms in organic molecules, When the 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. Other chemical reactions caused by radicals are also prevented. These stabilizers are also called "free radical scavengers" or simply "radical scavengers". Other alternative terms for such stabilizers are "radiation stability enhancers" 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 complex formation": The stabilizer is present in the radionuclide solution or in the chelating agent-containing solution. The two solutions are then added together, possibly to promote complex formation. Elevated temperature is applied to stabilize the chelating agent.

[0085] "Only the first stabilizer is present during the complexation of components (ai) and (aii)": one stabilizer is present and the second is not present. 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 already have had a second stabilizer present at the time of synthesis. After completion of the synthesis reaction, for example, the reaction solution that was heated to an elevated temperature is cooled back 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 ]Octoleotate, O xodotreotide (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 sale by a health department and has a medical 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 a patient. It can be supplied to end users. EXAMPLES

[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 is a piCHEM Forschungs -und Entwicklungs GmbH, Austria and other suppliers. All other components of the drug product are commercially available from a variety of sources.

[0094] Example 1: Composition of pharmaceutical product Pharmaceutical products ( 177 Lu-DOTA 0 -Tyr 3 -Octreotate 370MBq / mL The injection solution was 370 MB on 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 -Ok 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 when the radioactivity of the first QC vial is measured. The shelf life of the drug product is 72 hours after the calibration time. The drug product is defined as a solution containing a suitable amount of radioactivity that allows the delivery of 7.4 GBq of radioactivity upon injection. It is a single dose vial containing liquid.

[0095] After production, the manufacturing site will be calibrated to within 7.4GBq ±10% (200mCi). A certificate of analysis is provided to determine the exact activity and whether this activity is achieved. This value is reported in the format "Time of injection:{DD MM YYYY}{hh:mm 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 amount of the solution 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 antioxidant solution (i.e., gentisic acid) and the buffer system (i.e., acetate buffer system) The radiolabeling process is carried out at a temperature of 90-98°C for several minutes. It can be.

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

[0099] The resulting mother solution was mixed with a chelating agent (i.e., DTPA) and an antioxidant (i.e., ascorbyl sulfate). The solution was diluted with a solution containing 1,2-dichlorophenyl phthalic acid (nicotinic acid or gentisic acid) and then filtered through a 0.2 μm filter. Sterile filter 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 test data for the batch.

[0102] [Table 2]

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

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 composition 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 claim 6, wherein the ratio of the aqueous solution to the total weight of the pharmaceutical solution 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 Lu The medicinal aqueous 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 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 in 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.

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.

Images