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Keywords:

  • bioequivalence;
  • complexation;
  • cyclodextrin;
  • pharmacodynamics;
  • pharmacokinetics

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. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2585–2594, 2004