Stable, concentrated radionuclide complex solutions
Inventors
Barbato, Donato • Brambati, Clementina • Chicco, Daniela • de Palo, Francesco • Fugazza, Lorenza • Mariani, Maurizio • Tesoriere, Giovanni
Assignees
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Publication Number
US-12161732-B2
Publication Date
2024-12-10
Expiration Date
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.
Core Innovation
The invention relates to stable, high-concentration pharmaceutical aqueous solutions for radiopharmaceutical use. The aqueous complex solution includes a complex comprising the radionuclide 177Lu (Lutetium-177) and a somatostatin receptor binding peptide linked to the chelating agent DOTA, together with at least one stabilizer against radiolytic degradation.
The pharmaceutical aqueous solution is formed by diluting the aqueous complex solution with an aqueous dilution solution that also includes stabilizer(s) against radiolytic degradation. A key aspect is the use of an aqueous dilution solution stabilizer comprising ascorbic acid or a salt thereof, while maintaining radiochemical purity and radiolytic stability.
The radionuclide is present in the pharmaceutical aqueous solution at a concentration providing a volumetric radioactivity of 250 to 500 MBq/mL. The stabilizer(s) against radiolytic degradation are present in a total concentration of 0.5 mg/mL to 10.0 mg/mL, and the pharmaceutical aqueous solution comprises less than 2% ethanol.
Radiochemical purity as determined by HPLC is maintained at 95% or greater for at least 72 hours when stored at 25°C. The overall concept addresses maintaining purity and stability in concentrated aqueous formulations by incorporating radiolytic-stability enhancers in the formulation and dilution approach.
Claims Coverage
The partial content provides one independent claim and several dependent refinements. Across the claim set, the core inventive coverage centers on using a dilution solution containing ascorbic acid or a salt thereof to support radiolytic stability of a 177Lu-DOTA somatostatin receptor binding peptide complex at specified radiochemical purity, stability, concentration, and ethanol limits.
Dilution with an ascorbic-acid stabilizing aqueous dilution solution
Diluting an aqueous complex solution to form the pharmaceutical aqueous solution, wherein the aqueous complex solution comprises 177Lu (Lutetium-177) and a somatostatin receptor binding peptide linked to DOTA and at least one stabilizer against radiolytic degradation, and wherein the aqueous dilution solution comprises at least one stabilizer against radiolytic degradation which comprises ascorbic acid or a salt thereof.
Specified radionuclide concentration and total stabilizer concentration
Providing the radionuclide in the pharmaceutical aqueous solution in a concentration that provides a volumetric radioactivity of 250 to 500 MBq/mL, and having the stabilizer(s against radiolytic degradation) present in the pharmaceutical aqueous solution in a total concentration of 0.5 mg/mL to 10.0 mg/mL.
Maintained HPLC radiochemical purity during storage at 25°C
Maintaining the radiochemical purity of the pharmaceutical aqueous solution as determined by HPLC at 95% or greater for at least 72 hours when stored at 25°C.
Low ethanol content
Configuring the pharmaceutical aqueous solution to comprise less than 2% ethanol.
The independent claim is directed to manufacturing a concentrated aqueous 177Lu-DOTA somatostatin receptor binding peptide radiopharmaceutical solution by diluting with an ascorbic-acid or salt-containing aqueous dilution solution, using specified concentration ranges and stabilizer load, maintaining at least 95% HPLC radiochemical purity for at least 72 hours at 25°C, and limiting ethanol to less than 2%.
Stated Advantages
Radiochemical purity as determined by HPLC can be maintained at 95% or greater for at least 72 hours when stored at 25°C.
The pharmaceutical aqueous solution can be formulated with less than 2% ethanol.
Documented Applications
No documented applications found
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