title: EO-9 bladder instillations: formulation selection based on stability characteristics and in vitro simulation studies.
abstract: A bladder instillation of EO-9 (EOquin) is currently used in phase II clinical trials for the treatment of superficial bladder cancer. Three alternative formulations were developed to improve its pharmaceutical properties and clinical acceptability. Freeze-dried products composed of EO-9, 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD), tri(hydroxymethyl) aminomethane (Tris), and sodium bicarbonate (NaHCO(3)) were tested. Selection of one formulation for further development was based on stability studies. These studies comprised stability of the freeze-dried products, stability after reconstitution and dilution and stability during bladder instillation in an experimental set-up. The stability study of the freeze-dried products showed that the formulation composed of EO-9/HPbetaCD/Tris (4/600/1mg/vial) was most stable. After reconstitution and dilution all products were stable for at least 8h. The product composed of EO9/HPbetaCD/NaHCO(3) (4/600/20mg/vial) was the least stable product both as freeze-dried formulation and after reconstitution and dilution. The bladder instillation simulation experiment showed that all products were stable when mixed with urine of pH 8 and unstable in urine of pH 4 and 6. The degradation products formed in urine were EO-5a and EO-9-Cl. Based on these results, the product composed of EO-9/HPbetaCD/Tris (4/600/1mg/vial) was selected for further pharmaceutical development.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. apsvs@slz.nl
authors.forename: S C
authors.initials: SC
authors.lastname: van der Schoot
authors.forename: L D
authors.initials: LD
authors.lastname: Vainchtein
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: A
authors.initials: A
authors.lastname: Gore
authors.forename: D
authors.initials: D
authors.lastname: Mirejovsky
authors.forename: L
authors.initials: L
authors.lastname: Lenaz
authors.forename: B
authors.initials: B
authors.lastname: Nuijen
mesh_terms: D001388:Aziridines / Q000008:administration & dosage* / Q000494:pharmacology; D003198:Computer Simulation; D004355:Drug Stability; D004356:Drug Storage; D045563:Indolequinones / Q000008:administration & dosage* / Q000494:pharmacology; D008954:Models, Biological; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D001388:Aziridines; D045563:Indolequinones; C060817:apaziquone