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-10596276-B2
Publication Date
2020-03-24
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 177Lu (Lutetium-177) 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. The solution comprising the complex is then diluted with an aqueous dilution solution comprising at least one stabilizer against radiolytic degradation to obtain the pharmaceutical aqueous solution.
When the solution comprising the complex comprises only the first stabilizer and not the second stabilizer, the aqueous dilution solution comprises at least one stabilizer against radiolytic degradation different from the first stabilizer. In the obtained pharmaceutical aqueous solution, 177Lu is present in a concentration providing a volumetric radioactivity of from 250 to 500 MBq/mL, while the stabilizers are present in a total concentration of from 1.0 to 5.0 mg/mL. Ethanol is present in a concentration of less than 1%.
The process is further characterized by formulation and performance constraints for maintaining quality, including radiochemical purity determined by HPLC. The formulation is described as being stabilized against radiolytic degradation, enabling a pharmaceutical aqueous solution suitable for neuroendocrine tumors (NET) treatment as described in the provided partial content. The stabilizer system includes gentisic acid as a first stabilizer and ascorbic acid as a second stabilizer, and the use of DTPA is also described in the provided content.
Claims Coverage
The independent claim defines a manufacturing process for a high-concentration, low-ethanol pharmaceutical aqueous solution containing a 177Lu/DOTA somatostatin receptor binding peptide complex, with radiolytic-degradation stabilization via first and optionally second stabilizers that are handled differently during complex formation versus dilution. Across the dependent claims mentioned, specific stabilizer identities, stabilizer concentration ranges, purity/stability requirements, and downstream filtration/dispensing constraints are further imposed.
DOTA-linked 177Lu complex with stabilizers for radiolytic degradation
Providing a solution comprising a complex of the radionuclide 177Lu (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.
Dilution with stabilizer-containing aqueous dilution solution
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.
Different stabilizer present after dilution when only one stabilizer was used in complex formation
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 against radiolytic degradation different from the first stabilizer, and in the obtained pharmaceutical aqueous solution, 177Lu is present in a concentration providing a volumetric radioactivity of from 250 to 500 MBq/mL, 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%.
Taken together, the claim coverage centers on producing a pharmaceutical aqueous solution with a DOTA-linked 177Lu somatostatin receptor binding peptide complex, using radiolytic-degradation stabilizers while ensuring that the stabilizer composition after dilution provides the required high volumetric radioactivity, total stabilizer concentration, and low ethanol level. Dependent claim refinements mentioned in the provided content include ethanol-free conditions, a gentisic-acid/ascorbic-acid stabilizer pair, a narrowed stabilizer total concentration range, maintained radiochemical purity by HPLC over time and temperature, and filtration through 0.2 µm followed by dose-unit container dispensing under specified numeric constraints.
Stated Advantages
Reduced infusion volume/time as described in the provided content.
Suitability for neuroendocrine tumors (NET) treatment as described in the provided content.
Centralized commercial-scale manufacture as described in the provided content.
Documented Applications
Treatment of neuroendocrine tumors (NET) as described in the provided content.
Combination therapy involving co-therapeutics and IO agents as described in the provided content.
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