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 - 21 . (canceled)
22 . A pharmaceutical aqueous solution comprising:
(a) a complex comprising
(ai) the radionuclide 177 Lu present in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/mL, and
(aii) a somatostatin receptor binding peptide linked to the chelating agent DOTA; and
(b) at least one stabilizer(s) against radiolytic degradation selected from gentisic acid or a salt thereof, ascorbic acid or a salt thereof, methionine, histidine, melatonine, and Se-methionine present in a total concentration of 0.2 mg/mL to 15.0 mg/mL; and
wherein the activity of the solution is 7.4 GBq±10%,
and wherein the pharmaceutical aqueous solution comprises less than 5% ethanol.
23 . The pharmaceutical aqueous solution of claim 22 , wherein the pharmaceutical aqueous solution is a ready-to-use single dose pharmaceutical aqueous solution.
24 . The pharmaceutical aqueous solution of claim 22 , wherein the pharmaceutical aqueous solution is provided in numerous dose units.
25 . The pharmaceutical aqueous solution of claim 22 , 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.
26 . The pharmaceutical aqueous solution of claim 22 , wherein the at least one stabilizer(s) against radiolytic degradation is/are selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof.
27 . The pharmaceutical aqueous solution of claim 22 , wherein the at least one stabilizer(s) against radiolytic degradation comprises ascorbic acid or a salt thereof.
28 . The pharmaceutical aqueous solution of claim 22 , 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.
29 . The pharmaceutical aqueous solution of claim 28 , 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.
30 . The pharmaceutical aqueous solution of claim 29 , wherein the somatostatin receptor binding peptide and the chelating agent form together DOTA-TATE (oxodotreotide).
31 . The pharmaceutical aqueous solution of claim 22 , further comprising a sequestering agent.
32 . The pharmaceutical aqueous solution of claim 31 , wherein the sequestering agent is diethylentriaminepentaacetic acid (DTPA) or a salt thereof.
33 . The pharmaceutical aqueous solution of claim 32 , wherein the DTPA or salt thereof is present in an amount to result in a concentration of 0.01 mg/mL to 0.10 mg/mL
34 . A dose unit container enclosing the pharmaceutical aqueous solution of claim 22 .
35 . A lead container enclosing the dose unit container of claim 34 .
36 . The dose unit container of claim 34 , wherein the container comprises a stoppered vial comprising the pharmaceutical aqueous solution.
37 . A lead container enclosing the dose unit container of claim 36 .
38 . A method of treating a tumor in a patient in need thereof, the method comprising administering the pharmaceutical aqueous solution of claim 22 to the patient.
39 . The method of claim 38 , wherein the administering is by injection or infusion.
40 . 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 present in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/mL, and
(aii) a somatostatin receptor binding peptide linked to the chelating agent DOTA; and
(b) at least one stabilizer(s) against radiolytic degradation selected from gentisic acid or a salt thereof, ascorbic acid or a salt thereof, methionine, histidine, melatonine, and Se-methionine present in a total concentration of 0.2 mg/mL to 15.0 mg/mL,
wherein the pharmaceutical aqueous solution comprises less than 5% ethanol.
41 . The method of claim 40 , wherein 20.5 mL to 25 mL of the pharmaceutical aqueous solution is administered to the patient.
42 . The method of claim 40 , wherein the dose administered to the patient is 7.4 GBq±10%.
43 . The method of claim 40 , 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.
44 . The method of claim 43 , wherein the somatostatin receptor binding peptide and the chelating agent form together DOTA-TATE (oxodotreotide).
45 . The method of claim 40 , 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.
46 . The method of claim 40 , wherein the tumor is a neuroendocrine tumor (NET).
47 . The method of claim 40 , 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.
48 . The method of claim 40 , wherein the administering is by injection or infusion.
49 . The method of claim 40 , wherein the administering is by intravenous infusion.
50 . The method of claim 40 , wherein the pharmaceutical aqueous solution is administered to the patient within a period of about 20 minutes to about 30 minutes.
51 . The method of claim 44 , wherein the tumor is a neuroendocrine tumor (NET).