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-12168063-B2
Publication Date
2024-12-17
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 in which an aqueous complex solution is diluted to form a ready-to-use intravenous (IV) infusion solution. The aqueous complex solution comprises a complex of the radionuclide 177Lu with a somatostatin receptor binding peptide linked to the chelating agent DOTA, and at least one stabilizer against radiolytic degradation present in a defined total concentration range.
After complex formation, the aqueous complex solution is diluted with an aqueous dilution solution that comprises at least one stabilizer against radiolytic degradation, while maintaining substantially less than 1% ethanol in the resulting pharmaceutical aqueous solution. The radionuclide concentration in the pharmaceutical aqueous solution provides a volumetric radioactivity in a defined range, and the stabilizer(s) against radiolytic degradation are present in a defined total concentration range in the final solution.
The described approach aims to provide high-concentration, high-stability radiolabeled DOTA-somatostatin receptor complexes, including embodiments noted for 177Lu-DOTA-TATE/DOTA-TOC and other DOTA-somatostatin analogs. The document further discusses radiolytic stability, chemical and radiochemical purity after storage, and suitability in treating neuroendocrine tumors (NET), including contexts in which such radiolabeled somatostatin-receptor complexes are administered as IV solutions.
Claims Coverage
The independent claim covers a manufacturing process that dilutes an aqueous complex solution containing a 177Lu-DOTA-linked somatostatin receptor binding peptide and radiolytic stabilizers with an aqueous dilution solution containing radiolytic stabilizers, to yield a pharmaceutical aqueous solution with specified volumetric radioactivity, specified stabilizer concentration, and ethanol below 1%. The coverage therefore combines three inventive features.
Dilution to a specified volumetric radioactivity in ethanol-limited pharmaceutical aqueous solution
Diluting an aqueous complex solution with an aqueous dilution solution to form the pharmaceutical aqueous solution, wherein 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.
177Lu-DOTA-somatostatin receptor binding peptide complex with radiolytic stabilizers in complex solution
Providing an aqueous complex solution comprising a complex comprising 177Lu and a somatostatin receptor binding peptide linked to DOTA, and at least one stabilizer against radiolytic degradation present in a total concentration of 15 mg/mL to 50 mg/mL in the aqueous complex solution.
Radiolytic stabilizers also present in aqueous dilution solution with controlled final stabilizer concentration
Using an aqueous dilution solution comprising at least one stabilizer against radiolytic degradation, wherein the stabilizer is present in the pharmaceutical aqueous solution in a total concentration of 0.5 mg/mL to 10.0 mg/mL.
Across the independent claim, the inventive coverage is directed to diluting a specifically defined 177Lu-DOTA-somatostatin receptor binding peptide complex that contains radiolytic stabilizers, using a dilution solution that also contains radiolytic stabilizers, to produce an aqueous IV-ready formulation with specified volumetric radioactivity, specified stabilizer concentration, and ethanol below 1%.
Stated Advantages
Provides radiolytic stability for high-concentration, high-stability radiolabeled somatostatin-receptor complexes.
Maintains chemical and radiochemical purity after storage at 25 to 32°C, as described in the partial content.
Enables formulation as a ready-to-use IV solution with controlled ethanol content (less than 1%).
Documented Applications
Treating neuroendocrine tumors (NET) using radiolabeled somatostatin-receptor complexes formulated as pharmaceutical aqueous solutions for IV use, as described in the partial content.
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