Loading profile of topotecan into polyvinyl alcohol microspheres (DC Bead™) over a 7-day period

Abstract

DC Bead™ is successfully used for chemoembolization of various liver cancers. The purpose of this study was to determine the loading capacity of the semi-synthetic topoisomerase-1 inhibitor topotecan into the DC Bead™ microspheres under static or agitated conditions and to assess the physicochemical stability over a period of 7 days. Commercially available topotecan hydrochloride powder (Hycamtin®) was reconstituted with water for injection to yield a nominal concentration of 1 mg/mL topotecan. Polyvinyl alcohol (PVA)-based microspheres (DC Bead™, 300-500 µm, 2 mL/vial) were mixed with 4 mL of the reconstituted topotecan solution. Vials were stored light protected at room temperature under static or agitated conditions for 7 days (n = 3, for each loading condition). At different time intervals, samples were taken from the excess solution and assayed via a stability-indicating HPLC assay. Drug-loading profiles were determined by measuring the remaining topotecan concentration in the excess solution. Under agitated conditions, topotecan was loaded into the microspheres rapidly after mixing. After 5 min 86.4 ± 0.1% of topotecan was loaded. Under static conditions, drug uptake was slower. Only 65.0 ± 0% were loaded after 5 min; 86.6 ± 0.1% drug uptake was achieved not until 1 h. Over a storage period of 7 days, topotecan remained loaded in the DC Bead™ microspheres at a level of >90%. Drug uptake of 4 mg topotecan (1 mg/mL solution) into DC Beads™ was faster under agitated loading conditions. Nevertheless, after 1 h, ∼90% of topotecan was loaded into the DC Bead™ microspheres independent from the type of loading condition. The loading rate remained >90% over the observation period of 7 days and light-protected storage at room temperature. Loading and stability of topotecan-loaded DC Beads™ is suitable and convenient for preparation in a pharmacy-based cytotoxic preparation unit.