title: Development of separation technology for the removal of radium-223 from decayed thorium-227 in drug formulations. Material screening and method development.
abstract: Targeted thorium conjugates are currently being investigated as a new class of alpha-radiopharmaceuticals. The natural decay of thorium-227 ((227)Th) results in the ingrowth of radium-223 ((223)Ra). Consideration must, therefore, be given to define acceptable limits of (223)Ra in the drug product at the time of dose administration. By effective sequestration of (223)Ra, we aim to improve the radiochemical purity and extend the effective user window of drug products containing (227)Th. (223)Ra is the first progeny of (227)Th and the only one with a long half-life (days). We have, therefore, focused on the removal of this specific species since the progenies of (223)Ra will have a very limited lifetime in the formulation once (223)Ra is removed. In this study, we investigated a multitude of materials for their ability to reduce the (223)Ra level by: (1) passive diffusion or (2) by cartridge filtration on gravity columns. In addition, we probe the compatibility of these materials in the presence of antibody trastuzumab to assess the level of protein binding and estimate the quenching of radiolysis by binding of radionuclides. A screening matrix of organic and inorganic materials was established, i.e. strontium and calcium alginate gel beads, distearoyl phosphatidylglycerol (DSPG) liposomes, ceramic hydroxyapatite, Zeolite UOP type 4A and cation exchange resins AG50W-X8 and SOURCE 30S. First, passive diffusional uptake of (223)Ra by suspended materials present in the formulation was measured as a decrease in sample radioactivity after separation. Second, selected materials were packed on gravity columns in order to evaluate the efficiency of column separation versus diffusional adsorption. The retention of (223)Ra and (227)Th were characterized by measuring the radioactivity in the eluate and on the columns. Finally, the compatibility between trastuzumab, as a selected model antibody, and suspensions of the binding materials was analyzed during storage of the drug product in the presence of adsorbent. The formation of H2O2 was evaluated to measure the influence of radionuclide binding material on radiolysis in the formulation. All the materials bound (223)Ra by passive diffusional uptake ranging from 31% to 95% with DSPG liposomes demonstrating superiority at 95% efficiency. All materials suitable for assessment by gravity column filtration bound (223)Ra almost quantitatively (∼100%) and with minimal variation (relative standard deviation  <1%). The uptake was significantly higher compared to passive diffusional uptake. Alginate gel beads, ceramic hydroxyapatite and SOURCE 30S reduced the antibody concentration in solution to 40-50% while the Zeolite UOP type 4A, AG50W-X8 resin and DSPG liposomes showed ≤10% reduction of antibody concentration. Ceramic hydroxyapatite significantly reduced H2O2 formed by radionuclide initiated radiolysis.
authors.affiliation: a Bayer AS , Oslo , Norway ;
authors.forename: Janne Olsen
authors.initials: JO
authors.lastname: Frenvik
authors.affiliation: b School of Pharmacy, University of Oslo , Oslo , Norway.
authors.forename: Solveig
authors.initials: S
authors.lastname: Kristensen
authors.affiliation: a Bayer AS , Oslo , Norway ;
authors.forename: Olav B
authors.initials: OB
authors.lastname: Ryan
mesh_terms: D000464:Alginates / Q000737:chemistry; D000906:Antibodies / Q000737:chemistry; D002516:Ceramics / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004339:Drug Compounding / Q000379:methods; D017886:Durapatite / Q000737:chemistry; D020723:Glucuronic Acid / Q000737:chemistry; D006207:Half-Life; D006603:Hexuronic Acids / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry*; D011883:Radium / Q000737:chemistry*; D013910:Thorium / Q000737:chemistry*
chemical_list: D000464:Alginates; D000906:Antibodies; D006603:Hexuronic Acids; D008081:Liposomes; D010715:Phosphatidylglycerols; D019275:Radiopharmaceuticals; C084352:distearoyl phosphatidylglycerol; D013910:Thorium; D020723:Glucuronic Acid; D017886:Durapatite; D006861:Hydrogen Peroxide; D011883:Radium
keywords: 223Ra; 227Th; alpha particle; cancer radioimmunotherapy