Stable, concentrated radionuclide complex solutions
Inventors
de Palo, Francesco • Fugazza, Lorenza • Barbato, Donato • Mariani, Maurizio • Chicco, Daniela • Tesoriere, Giovanni • Brambati, Clementina
Assignees
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Publication Number
US-11904027-B2
Publication Date
2024-02-20
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 a process for manufacturing a pharmaceutical aqueous solution containing a complex of the radionuclide 177Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA. The complex is provided with a first stabilizer against radiolytic degradation and optionally a second stabilizer against radiolytic degradation different from the first stabilizer, and is then diluted with an aqueous dilution solution comprising at least one stabilizer against radiolytic degradation to obtain the pharmaceutical aqueous solution.
A central feature is stabilizer selection and arrangement during formulation. If the solution comprising the complex contains only the first stabilizer and not the second stabilizer, the aqueous dilution solution comprises at least one stabilizer different from the first stabilizer, and the obtained pharmaceutical aqueous solution contains 177Lu at a concentration that provides a volumetric radioactivity from 250 to 500 MBq/mL.
The pharmaceutical aqueous solution further requires the first stabilizer to be present at 0.5 to 2 mg/mL, the concentration ratio between the first and second stabilizers to be between 1:3 and 1:7, and ethanol to be present in a concentration of less than 1%. The disclosed approach supports stable, high-concentration, ready-to-use aqueous products for infusion of radiolabeled peptides such as 177Lu-DOTA-TATE or DOTA-TOC peptide conjugates.
Claims Coverage
The provided content identifies one independent claim. It covers a process for manufacturing a pharmaceutical aqueous solution by diluting a 177Lu-DOTA somatostatin receptor binding peptide complex using radiolysis stabilizers under defined quantitative and composition constraints, including ethanol concentration, volumetric radioactivity, and stabilizer concentration and ratio relationships.
Dilution of a 177lu-dota somatostatin receptor peptide complex with stabilizer-containing aqueous dilution
Providing a solution comprising a complex of the radionuclide 177Lu and a somatostatin receptor binding peptide linked to 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.
Stabilizer selection when only the first stabilizer is present in the complex
Wherein if the solution comprising the complex comprises only the first stabilizer and not the second stabilizer, then the aqueous dilution solution comprises at least one stabilizer that is different from the first stabilizer, and in the obtained pharmaceutical aqueous solution the radionuclide 177Lu is present in a concentration that provides a volumetric radioactivity of from 250 to 500 MBq/mL.
Controlled stabilizer concentrations, ratio, and ethanol limitation in the final aqueous solution
The first stabilizer is present in a concentration of from 0.5 to 2 mg/mL and the concentration ratio between the first and second stabilizers is between 1:3 to 1:7, and ethanol is present in the pharmaceutical aqueous solution in a concentration of less than 1%.
Overall, the claim coverage centers on a dilution-based manufacturing process for a 177Lu-DOTA somatostatin receptor binding peptide radiopharmaceutical, combined with stabilizer selection rules and quantitative constraints for volumetric radioactivity, first stabilizer concentration, stabilizer concentration ratio, and an ethanol concentration below 1%.
Stated Advantages
Enables stable high-concentration radiopharmaceutical aqueous solutions and ready-to-use infusion products.
Provides radionuclide formulations with high chemical and radiochemical purity and stability over defined storage times and temperatures.
Reduces or avoids ethanol in the formulation, with ethanol present at less than 1%.
Allows high volumetric radioactivity enabling short infusion volumes and dosing.
Documented Applications
Ready-to-use infusion products for administration of radiolabeled somatostatin receptor binding peptide complexes such as 177Lu-DOTA-TATE or DOTA-TOC peptide conjugates.
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