title: Pharmaceutical development of a parenteral lyophilised dosage form for the novel anticancer agent C1311.
abstract: C1311 (5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo [4,5,1-de]-acridin-6-one-dihydrochloride trihydrate) is the lead compound from the group of imidazoacridinones, a novel group of rationally designed anticancer agents. C1311 shows significant cytotoxic activity in vitro and in vivo toward a range of colon tumours. The aim of the present study is to develop a sterile and stable, injectable pharmaceutical product for C1311 to be used in phase I clinical trials. C1311 drug substance was structurally and analytically characterised by chromatographic, spectrometric, and diffraction techniques. C1311 was freely soluble in water, and its stability was investigated in several liquid and lyophilised formulations with or without the use of buffering, tonicity, and bulking agents. The final product, containing 100 mg/vial C1311 (as anhydrous free base), was stable for at least 3 months under accelerated storage conditions and at the designated long-term storage condition of 5 +/- 3 degrees C in the dark. The drug is currently used in phase I clinical trials.
authors.affiliation: Slotervaart Hospital/The Netherlands Cancer Institute, Department of Pharmacy & Pharmacology, Amsterdam. apmbk@slz.nl
authors.forename: Monique W J
authors.initials: MW
authors.lastname: Den Brok
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Nuijen
authors.forename: J Jantina
authors.initials: JJ
authors.lastname: Kettenes-Van Den Bosch
authors.forename: M J
authors.initials: MJ
authors.lastname: Van Steenbergen
authors.forename: Josie N
authors.initials: JN
authors.lastname: Buluran
authors.forename: Michael D
authors.initials: MD
authors.lastname: Harvey
authors.forename: Charles K
authors.initials: CK
authors.lastname: Grieshaber
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000369:Aged, 80 and over; D000609:Aminoacridines / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D017321:Clinical Trials, Phase I as Topic; D004339:Drug Compounding / Q000379:methods; D004340:Drug Contamination / Q000517:prevention & control; D004355:Drug Stability; D004356:Drug Storage / Q000379:methods; D005612:Freeze Drying / Q000379:methods; D006801:Humans; D007263:Infusions, Parenteral; D019999:Pharmaceutical Solutions; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000609:Aminoacridines; D000970:Antineoplastic Agents; D019999:Pharmaceutical Solutions; C098965:C 1311