Claims for Patent: 12,168,063

Summary for Patent: 12,168,063

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:	US18/640,917
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 12,168,063
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) a somatostatin receptor binding peptide linked to the chelating agent DOTA, and (b) at least one stabilizer(s) against radiolytic degradation that is/are present in a total concentration of 15 mg/mL to 50 mg/mL in the aqueous complex solution; and wherein the aqueous dilution solution comprises at least one stabilizer(s) against radiolytic degradation; and wherein the radionuclide is present in the pharmaceutical aqueous solution in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/mL, and the stabilizer(s) against radiolytic degradation is/are present in the pharmaceutical aqueous solution in a total concentration of 0.5 mg/mL to 10.0 mg/mL; and the pharmaceutical aqueous solution comprises less than 1% ethanol. 2. The process of claim 1, wherein the aqueous dilution solution comprises ascorbic acid or a salt thereof. 3. The process of claim 2, wherein the aqueous dilution solution comprises ascorbic acid or a salt thereof as the only stabilizer against radiolytic degradation. 4. The process of claim 1, wherein the somatostatin receptor binding peptide and the chelating agent form together a molecule selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP, and Satoreotide tetraxetan. 5. The process of claim 4, wherein the somatostatin receptor binding peptide and the chelating agent form together a molecule selected from DOTA-TOC (edotreotide), DOTA-TATE (oxodotreotide) and Satoreotide tetraxetan. 6. The process of claim 5, wherein the somatostatin receptor binding peptide and the chelating agent form together DOTA-TATE. 7. A pharmaceutical aqueous solution manufactured by the process of claim 1. 8. The pharmaceutical aqueous solution of claim 7, wherein the activity of the pharmaceutical aqueous solution is 7.4 GBq±10%. 9. The pharmaceutical aqueous solution of claim 7, wherein 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. 10. The pharmaceutical aqueous solution of claim 7, wherein the stabilizer(s) is/are present in a total concentration of 1.0 mg/mL to 5.0 mg/mL in the pharmaceutical aqueous solution. 11. The pharmaceutical aqueous solution of claim 7, wherein the pharmaceutical aqueous solution comprises 2.0 mg/mL to 5.0 mg/ml of ascorbic acid or a salt thereof. 12. The pharmaceutical aqueous solution of claim 10, wherein the pharmaceutical aqueous solution comprises 2.0 mg/mL to 5.0 mg/ml of ascorbic acid or a salt thereof. 13. The pharmaceutical aqueous solution of claim 7, wherein the pharmaceutical aqueous solution is free of ethanol. 14. The pharmaceutical aqueous solution of claim 12, wherein the pharmaceutical aqueous solution is free of ethanol. 15. The pharmaceutical aqueous solution of claim 9, wherein the pharmaceutical aqueous solution is free of ethanol. 16. The pharmaceutical aqueous solution of claim 7, wherein the pharmaceutical aqueous solution further comprises a sequestering agent. 17. The pharmaceutical aqueous solution of claim 16, wherein the sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof. 18. The pharmaceutical aqueous solution of claim 17, wherein the DPTA or salt thereof is present in an amount to result in a concentration of 0.01 mg/ml to 0.10 mg/mL in the pharmaceutical aqueous solution. 19. The pharmaceutical aqueous solution of claim 7, wherein the pharmaceutical aqueous solution is present in a volume of 10 mL to 50 mL in a dose unit container enclosed within a lead container. 20. The pharmaceutical aqueous solution of claim 7, wherein the pharmaceutical aqueous solution is present in a volume of 10 mL to 50 mL in a stoppered vial enclosed within a lead container. 21. A method of treating a tumor in a patient in need thereof, the method comprising administering to the patient the pharmaceutical aqueous solution of claim 7. 22. The method of claim 21, wherein 10 mL to 50 mL of the pharmaceutical aqueous solution is administered to the patient. 23. The method of claim 21, wherein the tumor is a neuroendocrine tumor (NET). 24. The method of claim 21, 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. 25. The method of claim 21, wherein the tumor is a gastroenteropancreatic neuroendocrine tumor. 26. The method of claim 21, wherein a dose of 7.4 GBq±10% is administered to the patient. 27. The method of claim 21, wherein the administering is by injection or infusion. 28. The method of claim 21, wherein the pharmaceutical aqueous solution is administered to the patient within a period of about 20 minutes to about 30 minutes. 29. The method of claim 23, wherein a dose of 7.4 GBq±10% is administered to the patient. 30. The method of claim 23, wherein the somatostatin receptor binding peptide and the chelating agent form together DOTA-TATE.