Stable, concentrated radionuclide complex solutions
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.
1. A method of treating a tumor in a patient in need thereof, the method comprising administering to the patient 10 mL to 50 ml of a pharmaceutical aqueous solution comprising:
(a) a complex comprising:
(ai) the radionuclide 177 Lu, and
(aii) a somatostatin receptor binding peptide linked to the chelating agent DOTA; and
(b) at least one stabilizer(s) against radiolytic degradation;
wherein:
the at least one stabilizer(s) against radiolytic degradation is/are present in a total concentration of 0.5 mg/mL to 10.0 mg/mL;
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 pharmaceutical aqueous solution comprises less than 2% ethanol.
2. The method of claim 1 , 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.
3. The method of claim 1 , wherein the at least one stabilizer(s) against radiolytic degradation is/are present in a total concentration of 1.0 mg/mL to 5.0 mg/mL.
4. The method of claim 1 , wherein the at least one stabilizer(s) against radiolytic degradation comprises ascorbic acid or a salt thereof.
5. The method of claim 2 , wherein the at least one stabilizer(s) against radiolytic degradation comprises ascorbic acid or a salt thereof.
6. The method of claim 3 , wherein the at least one stabilizer(s) against radiolytic degradation comprises ascorbic acid or a salt thereof.
7. The method of claim 4 , wherein the ascorbic acid or salt thereof is present in an amount of 2.0 to 5.0 mg/mL.
8. The method 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, DOTA-VAP, and Satoreotide tetraxetan.
9. The method of claim 8 , wherein the somatostatin receptor binding peptide and the chelating agent form together DOTA-TATE (oxodotreotide).
10. The method of claim 1 , wherein the pharmaceutical aqueous solution comprises less than 1% ethanol.
11. The method of claim 2 , wherein the pharmaceutical aqueous solution comprises less than 1% ethanol.
12. The method of claim 3 , wherein the pharmaceutical aqueous solution comprises less than 1% ethanol.
13. The method of claim 4 , wherein the pharmaceutical aqueous solution comprises less than 1% ethanol.
14. The method of claim 5 , wherein the pharmaceutical aqueous solution comprises less than 1% ethanol.
15. The method of claim 1 , wherein the pharmaceutical aqueous solution is free of ethanol.
16. The method of claim 1 , wherein the pharmaceutical aqueous solution further comprises a sequestering agent.
17. The method of claim 16 , wherein the sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof.
18. The method of claim 17 , wherein the DTPA or a salt thereof is present in an amount to result in a concentration of 0.01 mg/mL to 0.10 mg/mL.
19. The method of claim 1 , wherein the administering is by injection or infusion.
20. The method of claim 1 , wherein the administering is by intravenous infusion.
21. The method of claim 1 , wherein the pharmaceutical aqueous solution is administered to the patient within a period of about 20 minutes to about 30 minutes.
22. The method of claim 1 , wherein the tumor is a neuroendocrine tumor (NET).
23. The method of claim 1 , 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.
24. The method of claim 23 , wherein the tumor is a gastroenteropancreatic neuroendocrine tumor.
25. The method of claim 1 , wherein the pharmaceutical aqueous solution is a ready-to-use single dose pharmaceutical aqueous solution.
26. The method of claim 1 , wherein the pharmaceutical aqueous solution is provided in numerous dose units.
27. A method of treating a gastroenteropancreatic neuroendocrine tumor in a patient in need thereof, the method comprising administering to the patient 20.5 mL to 25 mL of a pharmaceutical aqueous solution comprising:
(a) a complex comprising:
(ai) the radionuclide 177 Lu, and
(aii) a somatostatin receptor binding peptide linked to the chelating agent DOTA; and
(b) at least one stabilizer(s) against radiolytic degradation;
wherein:
the at least one stabilizer(s) against radiolytic degradation is/are present in a total concentration of 1.0 mg/mL to 5.0 mg/mL;
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 pharmaceutical aqueous solution comprises less than 1% ethanol.
28. The method of claim 27 , wherein the dose administered to the patient is 7.4 GBq±10%.
29. The method of claim 27 , 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.
30. The method of claim 27 , wherein the somatostatin receptor binding peptide and the chelating agent form together DOTA-TATE (oxodotreotide).