title: In vitro and in vivo evaluation of a sulfobutyl ether beta-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 beta-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.
authors.affiliation: The Center for Drug Delivery Research, The University of Kansas, 2099 Constant Avenue, Lawrence, KS 66047, USA.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: McIntosh
authors.forename: Nancy
authors.initials: N
authors.lastname: Schwarting
authors.forename: Roger A
authors.initials: RA
authors.lastname: Rajewski
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004355:Drug Stability; D005045:Etomidate / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D006461:Hemolysis; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008954:Models, Biological; D019999:Pharmaceutical Solutions; D019946:Propylene Glycol; D012995:Solubility; D013997:Time Factors; D047392:beta-Cyclodextrins / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000277:Adjuvants, Pharmaceutic; D019999:Pharmaceutical Solutions; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; D019946:Propylene Glycol; D005045:Etomidate