Claims for Patent: 12,491,272

Summary for Patent: 12,491,272

Title:	Stable, concentrated radionuclide complex solutions
Abstract:	The present invention relates to radionuclide complex solutions of high concentration and of high chemical stability, that allows their use as drug product for diagnostic and/or therapeutic purposes. The stability of the drug product is achieved by at least one stabilizer against radiolytic degradation. The use of two stabilizers introduced during the manufacturing process at different stages was found to be of particular advantage.
Inventor(s):	Donato Barbato, Clementina Brambati, Daniela Chicco, Francesco de Palo, Lorenza Fugazza, Maurizio Mariani, Giovanni Tesoriere
Assignee:	Advanced Accelerator Applications SA
Application Number:	US18/927,058
Patent Claims:	1. A process for manufacturing a pharmaceutical aqueous solution, the process comprising diluting an aqueous complex solution with an aqueous dilution solution to form the pharmaceutical aqueous solution, wherein the aqueous complex solution comprises: (a) a complex comprising (ai) the radionuclide 177Lu(Lutetium-177) and (aii) DOTA-TATE or DOTA-TOC, and (b) at least one first stabilizer(s) against radiolytic degradation selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof, that is/are present in a total amount to result in a concentration of about 0.5 to about 2.0 mg/mL in the pharmaceutical aqueous solution; wherein the aqueous dilution solution comprises at least one second stabilizer(s) against radiolytic degradation selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof; the radionuclide is present in the pharmaceutical aqueous solution in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/mL, the radiochemical purity of the pharmaceutical aqueous solution as determined by HPLC can be maintained at ≥95% for at least 72 hours when stored at 25° C.; the activity of the pharmaceutical aqueous solution is 7.4 GBq±10%; the pharmaceutical aqueous solution comprises less than about 5% ethanol; and the ratio of the concentration in mg/mL of the first stabilizer(s) against radiolytic degradation to the concentration in mg/mL of the second stabilizer(s) against radiolytic degradation in the pharmaceutical aqueous solution is from 1:3 to 1:7. 2. The process of claim 1, wherein the first stabilizer(s) against radiolytic degradation is/are ascorbic acid or a salt thereof. 3. The process of claim 1, wherein the second stabilizer(s) against radiolytic degradation is/are ascorbic acid or a salt thereof. 4. The process of claim 2, wherein the second stabilizer(s) against radiolytic degradation is/are ascorbic acid or a salt thereof. 5. The process of claim 1, wherein in the pharmaceutical aqueous solution, the ratio of the concentration in mg/mL of the first stabilizer(s) against radiolytic degradation to the concentration in mg/mL of the second stabilizer(s) against radiolytic degradation is from 1:4 to 1:5. 6. The process of claim 1, wherein the aqueous complex solution is free of ethanol. 7. The process of claim 1, wherein the first stabilizer(s) against radiolytic degradation is/are gentisic acid or a salt thereof. 8. The process of claim 1, wherein the volume of aqueous dilution solution is from 19.95 to 24.45 mL. 9. The process of claim 1, wherein the first stabilizer(s) against radiolytic degradation is/are present in a total concentration of 15 mg/mL to 50 mg/mL in the aqueous complex solution. 10. The process of claim 1, wherein the second stabilizer(s) against radiolytic degradation is/are gentisic acid or a salt thereof. 11. The process of claim 1, wherein the the aqueous complex solution comprises DOTA-TATE. 12. The process of claim 1, wherein the pharmaceutical aqueous solution comprises less than 5% ethanol. 13. The process of claim 12, wherein the pharmaceutical aqueous solution has a volume of 20.5 to 25 mL. 14. The process of claim 1, wherein the pharmaceutical aqueous solution further comprises a sequestering agent. 15. The process of claim 14, wherein the sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof. 16. The process of claim 15, wherein the diethylentriaminepentaacetic acid (DTPA) or salt thereof is present in an amount to result in a concentration of from 0.01 mg/mL to 0.10 mg/mL in the pharmaceutical aqueous solution. 17. A method of treating a tumor in a patient in need thereof, the method comprising diluting an aqueous complex solution with an aqueous dilution solution to form a pharmaceutical aqueous solution and administering to the patient the pharmaceutical aqueous solution, wherein the aqueous complex solution comprises: (a) a complex comprising (ai) the radionuclide 177Lu (Lutetium-177) and (aii) DOTA-TATE or DOTA-TOC, and (b) at least one first stabilizer(s) against radiolytic degradation selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof that is/are present in a total amount to result in a concentration of about 0.5 to about 2.0 mg/mL in the pharmaceutical aqueous solution; the aqueous dilution solution comprises at least one second stabilizer(s) against radiolytic degradation selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof; the radionuclide is present in the pharmaceutical aqueous solution in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/mL, the radiochemical purity of the pharmaceutical aqueous solution as determined by HPLC can be maintained at ≥95% for at least 72 hours when stored at 25° C.; the activity of the pharmaceutical aqueous solution is 7.4 GBq±10%; the pharmaceutical aqueous solution comprises less than about 5% ethanol; and the ratio of the concentration (in mg/mL) of the first stabilizer(s) against radiolytic degradation to the concentration (in mg/mL) of the second stabilizer(s) against radiolytic degradation in the pharmaceutical aqueous solution is from 1:3 to 1:7. 18. The method of claim 17, wherein the administering is by injection or infusion. 19. The method of claim 17, wherein the pharmaceutical aqueous solution is administered to the patient within a period of about 20 minutes to about 30 minutes. 20. The method of claim 17, wherein the tumor is a neuroendocrine tumor (NET). 21. The method of claim 17, wherein the tumor is selected from the group consisting of gastroenteropancreatic neuroendocrine tumor, neuroendocrine carcinoid tumor, neuroendocrine small cell lung cancer, neuroendocrine glioma, neuroendocrine prostate cancer, neuroendocrine meningioma, neuroendocrine neuroblastoma, neuroendocrine paraganglioma, neuroendocrine pheochromocytoma, pulmonary NET, neuroendocrine medullary thyroid cancer, neuroendocrine breast cancer, neuroendocrine head & neck tumor and pancreatic NET, neuroendocrine thymic cancer and lung NET. 22. The method of claim 17, wherein the tumor is a gastroenteropancreatic neuroendocrine tumor. 23. The method of claim 17, wherein the aqueous complex solution comprises DOTA- TATE. 24. The method of claim 17, wherein the first stabilizer(s) against radiolytic degradation is/are ascorbic acid or a salt thereof. 25. The method of claim 17, wherein the second stabilizer(s) against radiolytic degradation is/are ascorbic acid or a salt thereof. 26. The method of claim 24, wherein the second stabilizer(s) against radiolytic degradation is/are ascorbic acid or a salt thereof. 27. The method of claim 17, wherein the pharmaceutical aqueous solution comprises less than 5% ethanol. 28. The method of claim 17, wherein the pharmaceutical aqueous solution is free of ethanol. 29. The method of claim 17, wherein the first stabilizer(s) against radiolytic degradation is/are gentisic acid or a salt thereof. 30. The method of claim 17, wherein in the pharmaceutical aqueous solution, the ratio of the concentration in mg/mL of the first stabilizer(s) against radiolytic degradation to the concentration in mg/mL of the second stabilizer(s) against radiolytic degradation is from 1:4 to 1:5.