Claims for Patent: 12,415,003

Summary for Patent: 12,415,003

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:	US18/927,047
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, and (b) at least one 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 an amount to result in a concentration of 0.2 to 5 mg/mL in the pharmaceutical aqueous solution; the aqueous dilution solution comprises at least one 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 an amount to result in a concentration of 0.5 to 10 mg/ml in the pharmaceutical aqueous solution; and 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 (±10%) GBq; and the pharmaceutical aqueous solution comprises less than about 5% ethanol. 2. The process of claim 1, wherein the stabilizer(s) against radiolytic degradation in the aqueous complex solution is/are present in an amount to result in a concentration of 0.5 to 5 mg/mL in the pharmaceutical aqueous solution. 3. The process of claim 1, wherein the aqueous complex solution is free of ethanol. 4. The process of claim 1, wherein the stabilizer(s) against radiolytic degradation in the aqueous dilution solution is/are present in an amount to result in a concentration of 1.0 to 8.0 mg/mL in the pharmaceutical aqueous solution. 5. The process of claim 1, wherein the volume of the aqueous dilution solution is from 19.95 to 24.45 mL. 6. The process of claim 1, wherein the stabilizer(s) against radiolytic degradation in the aqueous complex solution is/are present in a concentration of 15 mg/mL to 50 mg/mL in the aqueous complex solution. 7. The process of claim 1, wherein the pharmaceutical aqueous solution contains gentisic acid or a salt thereof in a total concentration from 0.7 mg/mL to 15.0 mg/mL. 8. The process of claim 1, wherein the pharmaceutical aqueous solution contains ascorbic acid or a salt thereof in a total concentration from 0.7 mg/mL to 15.0 mg/mL. 9. The process of claim 1, wherein the pharmaceutical aqueous solution has a volume of 20.5 to 25 mL. 10. The process of claim 1, wherein the pharmaceutical aqueous solution further comprises a sequestering agent. 11. The process of claim 10, wherein the sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof. 12. The process of claim 11, wherein the DTPA or a salt thereof is present in an amount to result in a concentration of about 0.01 mg/mL to about 0.10 mg/mL. 13. 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, and (b) at least one 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 an amount to result in a concentration of 0.2 to 5 mg/mL in the pharmaceutical aqueous solution; the aqueous dilution solution comprises at least one 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 an amount to result in a concentration of 0.5 to 10 mg/ml in the pharmaceutical aqueous solution; and 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 (±10%) GBq; and the pharmaceutical aqueous solution comprises less than about 5% ethanol. 14. The method of claim 13, wherein the administering is by injection or infusion. 15. The method of claim 13, wherein the pharmaceutical aqueous solution contains gentisic acid or a salt thereof in a total concentration from 0.7 mg/mL to 15.0 mg/mL. 16. The method of claim 13, wherein the pharmaceutical aqueous solution is administered to the patient within a period of about 20 minutes to about 30 minutes. 17. The method of claim 13, wherein the tumor is a neuroendocrine tumor (NET). 18. The method of claim 13, 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. 19. The method of claim 13, wherein the tumor is a gastroenteropancreatic neuroendocrine tumor. 20. The process of claim 1, wherein the pharmaceutical aqueous solution comprises less than 5% ethanol. 21. The method of claim 13, wherein the pharmaceutical aqueous solution comprises less than 5% ethanol. 22. The method of claim 13, wherein the stabilizer(s) against radiolytic degradation in the aqueous complex solution is/are present in an amount to result in a concentration of 0.5 to 5 mg/mL in the pharmaceutical aqueous solution. 23. The method of claim 13, wherein the aqueous complex solution is free of ethanol. 24. The method of claim 13, wherein the stabilizer(s) against radiolytic degradation in the aqueous dilution solution is/are present in an amount to result in a concentration of 1.0 to 8.0 mg/mL in the pharmaceutical aqueous solution. 25. The method of claim 13, wherein the volume of the aqueous dilution solution is from 19.95 to 24.45 mL. 26. The method of claim 13, wherein the stabilizer(s) against radiolytic degradation in the aqueous complex solution is/are present in a concentration of 15 mg/mL to 50 mg/mL in the aqueous complex solution. 27. The method of claim 13, wherein the pharmaceutical aqueous solution contains ascorbic acid or a salt thereof in a total concentration from 0.7 mg/mL to 15.0 mg/mL. 28. The method of claim 13, wherein the pharmaceutical aqueous solution has a volume of 20.5 to 25 mL. 29. The method of claim 13, wherein the pharmaceutical aqueous solution further comprises a sequestering agent. 30. The method of claim 29, wherein the sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof.