title: Development of an intravenous formulation of SU010382 (prodrug of SU5416, an anti-angiogenesis agent).
abstract: SU5416, the first in a new class of anti-angiogenesis agents, is an insoluble and neutral molecule which requires a formulation containing Cremophor EL, ethanol, and polyethylene glycol. SU010382, a prodrug of SU5416, was designed as N-Mannich base to provide a basic handle that could be exploited to increase the compound's solubility. Though an increase in solubility was obtained, the inherent hydrolytic instability of SU010382 presented a major challenge in formulation development. The aim of this study is to design a stable intravenous formulation of SU010382 at 2 mg/mL equivalent to the 1.5 mg/mL clinical formulation of SU5416 without a high surfactant/co-solvent content. A stable formulation of SU010382 was successfully designed using a combination of adjusted pH and complexation with sulfobutyl-ether-beta-cyclodextrin. This formulation was designed as a lyophilized product to further increase stability. The lyophilized formulation was stable for at least 6 months at 40 degrees C/75% relative humidity, reconstituted completely within 1 min, and was stable for at least 24 h at 25 degrees C following reconstitution.
authors.affiliation: Research Formulations, Pfizer Inc, 10777 Science Center Drive, San Diego, CA 92121, USA. Anand.Sistla@Pfizer.com
authors.forename: Anand
authors.initials: A
authors.lastname: Sistla
authors.forename: Adriana
authors.initials: A
authors.lastname: Kertelj
authors.forename: Narmada
authors.initials: N
authors.lastname: Shenoy
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D005612:Freeze Drying; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry*; D007275:Injections, Intravenous; D008352:Mannich Bases / Q000737:chemistry; D011355:Prodrugs; D011758:Pyrroles / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry; D013696:Temperature; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D008352:Mannich Bases; D011355:Prodrugs; D011758:Pyrroles; C531087:SU 010382; D012997:Solvents; D013501:Surface-Active Agents; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; C116890:Semaxinib