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-12151003-B2
Publication Date
2024-11-26
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 radionuclide complex aqueous drug products. The products comprise a complex of the radionuclide 177Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA, together with at least one stabilizer(s) against radiolytic degradation. The aqueous solutions are constrained to remain in pharmaceutical aqueous solution form while achieving high chemical/radiochemical performance.
A central aspect is control of radiolytic degradation by including at least one stabilizer(s) in a total concentration of 0.5 mg/mL to 10.0 mg/mL, in combination with a high activity pharmaceutical aqueous solution of 7.4 GBq ±10%. The solutions have a volume of 10 mL to 50 mL and comprise less than 1% ethanol, enabling ready-to-use small infusion volumes while avoiding or limiting ethanol.
The disclosed formulation supports retention of radiochemical purity over time under specified storage conditions, using HPLC-determined radiochemical purity as a measurable performance criterion. The document describes radiochemical purity at or above 95% for at least 72 hours at 25°C, with additional stability demonstrated at elevated temperatures. This supports use in dose unit formats and administration for treating tumors in patients.
Claims Coverage
The document includes three independent claim groupings covering the pharmaceutical aqueous solution formulation, a dose unit container for that solution, and a tumor-treatment method using that solution. Across the independent claims, the inventive subject matter is defined by the 177Lu/DOTA-linked somatostatin receptor binding peptide complex plus stabilizer(s) against radiolytic degradation, together with quantitative constraints on stabilizer concentration, activity, solution volume, and ethanol content.
177Lu DOTA-linked somatostatin receptor binding peptide complex aqueous solution with radiolysis stabilizer(s)
A pharmaceutical aqueous solution comprising a complex comprising the radionuclide 177Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA, and at least one stabilizer(s) against radiolytic degradation, wherein the stabilizer(s) are present in a total concentration of 0.5 mg/mL to 10.0 mg/mL, the activity is 7.4 GBq ±10%, the volume is 10 mL to 50 mL, and the solution comprises less than 1% ethanol.
Dose unit container containing 10 to 50 mL of 177Lu DOTA-linked somatostatin peptide solution with radiolysis stabilizer(s)
A dose unit container comprising a dose unit comprising 10 to 50 mL of a pharmaceutical aqueous solution, the solution comprising a complex comprising the radionuclide 177Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA, and at least one stabilizer(s) against radiolytic degradation, wherein the stabilizer(s) are present in a total concentration of 0.5 mg/mL to 10.0 mg/mL, the activity is 7.4 GBq ±10%, and the solution comprises less than 1% ethanol.
Tumor-treatment method administering 10 to 50 mL of 177Lu DOTA-linked somatostatin peptide solution with radiolysis stabilizer(s)
A method of treating a tumor in a patient in need thereof, the method comprising administering to the patient 10 mL to 50 mL of a pharmaceutical aqueous solution comprising a complex comprising the radionuclide 177Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA, and at least one stabilizer(s) against radiolytic degradation, wherein the stabilizer(s) are present in a total concentration of 0.5 mg/mL to 10.0 mg/mL, the dose administered is 7.4 GBq ±10%, and the pharmaceutical aqueous solution comprises less than 1% ethanol.
The independent claims define a specific 177Lu/DOTA-linked somatostatin receptor binding peptide aqueous formulation stabilized against radiolytic degradation, a dose unit container holding 10–50 mL of that formulation with defined activity and ethanol limits, and a tumor-treatment method administering that defined dose unit volume and activity while maintaining the radiolysis-stabilized formulation constraints.
Stated Advantages
Stable, high-concentration radionuclide complex aqueous drug products with high chemical/radiochemical performance.
High radiochemical purity maintained over time, including HPLC-determined radiochemical purity maintained at or above 95% for at least 72 hours at 25°C.
Ready-to-use small infusion volumes by limiting solution volume to 10 mL to 50 mL while providing high activity (7.4 GBq ±10%).
Reduced or avoided ethanol by limiting ethanol to less than 1%.
Documented Applications
Treating a tumor in a patient by administering the dose unit from the dose unit container comprising 10 to 50 mL of the pharmaceutical aqueous solution.
Treating a tumor in a patient by administering 10 mL to 50 mL of the pharmaceutical aqueous solution containing the 177Lu/DOTA-linked somatostatin receptor binding peptide complex and radiolysis stabilizer(s).
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