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-10596278-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 provides a pharmaceutical aqueous solution containing a complex formed by 177Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA. The solution includes at least two different stabilizers against radiolytic degradation, comprising gentisic acid or a salt thereof and ascorbic acid or a salt thereof, and constrains the radionuclide loading to a volumetric radioactivity of 250 to 500 MBq/mL.
The formulation further limits the pharmaceutical aqueous solution to less than 1% ethanol and requires that the radiochemical purity, determined by HPLC, is maintained at greater than or equal to 95% for at least 72 h when stored at 25°C. Dependent refinements specify DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide), and an embodiment where gentisic acid and ascorbic acid are present in separate specified ranges.
The document also discloses an embodiment in which the solution further comprises DTPA or a salt thereof and an acetate buffer composed of acetic acid and sodium acetate. The solution is presented as a stable high-concentration 177Lu radionuclide complex aqueous drug product formulation for IV use.
Claims Coverage
The document includes two independent claims, clm-00001 and clm-00020, which define a pharmaceutical aqueous solution with a 177Lu/DOTA-somatostatin receptor binding peptide complex, radiolysis stabilizers using gentisic acid and ascorbic acid, and specific constraints for ethanol content and HPLC radiochemical purity over 72 h at 25°C. Across the independent claims, the inventive coverage centers on the combination of the complex identity, stabilizer set, and quantitative formulation constraints ensuring radiochemical stability at 25°C.
DOTA-linked 177Lu somatostatin receptor binding peptide complex with defined volumetric radioactivity
A pharmaceutical aqueous solution comprising a complex formed by 177Lu and a somatostatin receptor binding peptide linked to DOTA, wherein the radionuclide is present in a concentration that provides a volumetric radioactivity of from 250 to 500 MBq/mL.
Two radiolytic stabilizers with total concentration constraint
A pharmaceutical aqueous solution comprising at least two different stabilizers against radiolytic degradation comprising gentisic acid or a salt thereof and ascorbic acid or a salt thereof, wherein the stabilizers are present in a total concentration of from 1.0 to 5.0 mg/mL.
Low ethanol content and maintained HPLC radiochemical purity for at least 72 h at 25°C
A pharmaceutical aqueous solution having less than 1% ethanol, wherein the radiochemical purity, determined by HPLC, is maintained at greater than or equal to 95% for at least 72 h when stored at 25°C.
177Lu complex specifically with DOTA-TATE or DOTA-TOC plus specified gentisic and ascorbic ranges
A pharmaceutical aqueous solution comprising a complex formed by 177Lu in a concentration that provides a volumetric radioactivity of from 250 to 500 MBq/mL and DOTA-TATE or DOTA-TOC; and stabilizers against radiolytic degradation comprising gentisic acid in a concentration of from 0.5 to 1 mg/mL and ascorbic acid in a concentration of from 2.0 to 5.0 mg/mL; wherein the radiochemical purity, determined by HPLC, is maintained at greater than or equal to 95% for at least 72 h when stored at 25°C and ethanol is present at less than 1%.
Inclusion of DTPA and an acetate buffer with acetic acid and sodium acetate
A pharmaceutical aqueous solution further comprising DTPA or a salt thereof in a concentration of from 0.01 to 0.10 mg/mL and an acetate buffer composed of acetic acid and sodium acetate, together with the ethanol limit of less than 1% and the requirement that HPLC radiochemical purity is maintained at greater than or equal to 95% for at least 72 h when stored at 25°C.
Across clm-00001 and clm-00020, the claims cover a high-concentration 177Lu aqueous solution of a DOTA-linked somatostatin receptor binding peptide complex, stabilized against radiolytic degradation using gentisic acid or a salt and ascorbic acid or a salt, while limiting ethanol to less than 1% and maintaining HPLC radiochemical purity of greater than or equal to 95% for at least 72 h at 25°C. clm-00020 additionally specifies quantitative stabilizer ranges, and includes DTPA and an acetate buffer defined by acetic acid and sodium acetate.
Stated Advantages
Maintains radiochemical purity, determined by HPLC, at greater than or equal to 95% for at least 72 h when stored at 25°C.
Limits ethanol content to less than 1%.
Provides a stable high-concentration 177Lu radionuclide complex aqueous drug product formulation for IV use.
Documented Applications
IV use pharmaceutical aqueous drug product formulation containing a stable high-concentration 177Lu radionuclide complex.
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