In vitro and in vivo evaluation of a sulfobutyl ether β‐cyclodextrin enabled etomidate formulation

Abstract In this study, we report the formulation and in vivo evaluation of etomidate in an aqueous solution using sulfobutyl ether‐7 β‐cyclodextrin (SBE‐CD, Captisol®) as a solubilizing agent. The phase‐solubility behavior of etomidate as a function of SBE‐CD concentration was evaluated, and accelerated solution stability studies of 2 mg/mL etomidate in a 5% w/v SBE‐CD solution were conducted. The intravenous administration of the SBE‐CD etomidate formulation in dogs was compared with Amidate®, the commercial etomidate drug product formulated with propylene glycol as a cosolvent. The etomidate plasma concentration‐time data were fit to a three‐compartment mamillary model and the derived standard pharmacokinetic parameters were not statistically different between the two formulations ( n  = 4, p  > 0.050). Concurrent pharmacodynamic analysis provided statistically equivalent maximum effects and median inhibitory concentrations for the two formulations. In vivo hemolysis after intravenous administration of Amidate® was 10‐fold higher than the SBE‐CD formulation. Whereas Amidate® cannot be given subcutaneously because of the cosolvent in the formulation, a 12 mg/mL aqueous solution of etomidate in 20% (w/v) SBE‐CD was well tolerated by this route. The results suggest that the SBE‐CD formulation is a viable clinical drug product with a reduced side‐effect profile.