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 process for manufacturing a pharmaceutical aqueous solution, comprising:
providing a solution comprising a complex of the radionuclide 177 Lu (Lutetium-177) and a somatostatin receptor binding peptide linked to the chelating agent DOTA; a first stabilizer against radiolytic degradation, and optionally a second stabilizer against radiolytic degradation different from the first stabilizer; and
diluting the solution comprising the complex with an aqueous dilution solution comprising at least one stabilizer against radiolytic degradation to obtain the pharmaceutical aqueous solution;
wherein if the solution comprising the complex comprises only the first stabilizer as an stabilizer against radiolytic degradation and not the second stabilizer, then the aqueous dilution solution comprises at least one stabilizer against radiolytic degradation that is different from the first stabilizer, and in the obtained pharmaceutical aqueous solution, the radionuclide 177 Lu is present in a concentration that it provides a volumetric radioactivity of from 250 to 500 MBq/mL and the stabilizers are present in a total concentration of from 1.0 to 5.0 mg/mL, and ethanol is present in a concentration of less than 1%.
2. The process according to claim 1 , comprising:
(1) forming a complex of the radionuclide 177 Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA by
(1.1) providing an aqueous solution comprising the radionuclide;
(1.2) providing an aqueous solution comprising the a somatostatin receptor binding peptide linked to the chelating agent, and a first stabilizer against radiolytic degradation and optionally a second stabilizer against radiolytic degradation different from the first stabilizer; and
(1.3) mixing the solutions provided in steps (1.1) and (1.2) and heating the resulting mixture to form a solution comprising the complex;
(2) diluting the solution comprising the complex obtained by step (1) by
(2.1) providing an aqueous dilution solution comprising at least one stabilizer against radiolytic degradation; and
(2.2.) mixing the solution comprising the complex obtained by step (1) with the dilution solution provided in step (2.1) to obtain the pharmaceutical aqueous solution;
wherein if the solution in step (1.2) comprises only one stabilizer that is the first stabilizer, then the solution in step (2.1) comprise at least one stabilizer that is different from the first stabilizer.
3. The process according to claim 2 , wherein the solution in step (1.2) comprises the first stabilizer and the solution provided in step (2.1) comprises at least one stabilizer.
4. The process according to claim 2 , wherein at least gentisic acid or a salt thereof is provided in step (1.2) and the solution provided in step (2.1) comprises at least ascorbic acid or a salt thereof.
5. The process according to claim 2 , wherein only one stabilizer which is gentisic acid or a salt thereof is provided in step (1.2) and the solution provided in step (2.1) comprises only one stabilizer which is ascorbic acid or a salt thereof.
6. The process according to claim 2 , wherein the stabilizer/stabilizers provided in step (1.2) is/are present during the complex formation in step (1.3) in a total concentration of from 15 to 50 mg/mL.
7. The process according to claim 6 , wherein the stabilizer/stabilizers provided in step (1.2) is/are present during the complex formation in step (1.3) in a total concentration of from 20 to 40 mg/mL.
8. The process according to claim 7 , wherein the only one stabilizer provided in step (1.2) is gentisic acid and the stabilizer is present during the complex formation in step (1.3) in a concentration of from 20 to 40 mg/mL.
9. The process according to claim 8 , wherein the only one stabilizer provided in step (1.2) is gentisic acid and the stabilizer is present during the complex formation in step (1.3) in a concentration of from 25 to 35 mg/mL.
10. The process according to claim 9 , wherein the solution provided in step (1.2) further comprises a buffer.
11. The process according to claim 10 , wherein the buffer is an acetate buffer.
12. The process according to claim 2 , wherein in step (1.3) the resulting mixture is heated to a temperature of from 70 to 99° C., for from 2 to 59 min.
13. The process according to claim 12 , wherein in step (1.3) the resulting mixture is heated to a temperature of from 90 to 98° C. for from 5 to 15 min.
14. The process according to claim 2 , wherein the solution provided in step (2.1) further comprises diethylentriaminepentaacetic acid (DTPA) or a salt thereof.
15. The process according to claim 2 , further comprising the process steps:
(3) filtering the solution obtained by step (2) through 0.2 μm; and
(4) dispensing the filtered solution obtained by step (3) into dose unit containers in a volume required to deliver the radioactive dose of 7.4 GBq±10%.
16. The process according to claim 2 , wherein the solution of step (1.1) comprises LuCl 3 and HCl.
17. The process according to claim 2 , wherein the solution of step (1.2) comprises 177 Lu-DOTA-TATE or 177 Lu-DOTA-TOC, gentisic acid, acetic acid, and sodium acetate.
18. The process according to claim 2 , wherein the solution of step (2.1) comprises DTPA and ascorbic acid.
19. The process according to claim 15 , wherein the dose unit containers in step (4) are stoppered vials, enclosed within a lead container.
20. The pharmaceutical aqueous solution obtained by the process of claim 1 .
21. The pharmaceutical aqueous solution according to claim 20 , which is free of ethanol.
22. The pharmaceutical aqueous solution according to claim 20 , wherein the stabilizers in the obtained pharmaceutical aqueous solution consists essentially of gentisic acid or a salt thereof and ascorbic acid or a salt thereof.
23. The pharmaceutical aqueous solution according to claim 22 , wherein the stabilizers are present in a total concentration of from about 2.7 to about 4.1 mg/mL.
24. The pharmaceutical aqueous solution according to claim 22 , for which the radiochemical purity (determined by HPLC) is maintained at ≥95% for at least 72 h when stored at 25° C.