title: Pharmacokinetics of saquinavir after intravenous and oral dosing of saquinavir: hydroxybutenyl-beta-cyclodextrin formulations.
abstract: The current research evaluated the ability of hydroxybutenyl-beta-cyclodextrin (HBenBCD) to enhance saquinavir in vitro solubility and in vivo oral bioavailability; both the base and mesylate salt forms of saquinavir were investigated. HBenBCD was effective and significantly improved saquinavir solubility in aqueous media. In the presence of 10 wt % HBenBCD, saquinavir base solubility in water was increased to ca. 5.5 +/- 0.4 mg/mL and represents a 27-fold increase from that observed in water (207 +/- 5 microg/mL) in the absence of HBenBCD. Saquinavir-HBenBCD formulations were found to have rapid dissolution over a wide pH range (1.2-6.8), and saquinavir solubility in these media was maintained throughout the experiments. When saquinavir-HBenBCD formulations were administered to Wistar-Hannover rats, saquinavir was rapidly absorbed and rapidly eliminated. Rapid saquinavir elimination was particularly pronounced when saquinavir-HBenBCD formulations were given as an oral aqueous gavage. Saquinavir oral bioavailability in rats obtained from saquinavir mesylate capsules (2.0% +/- 0.7%) was increased (9 +/- 4)-fold (18.6% +/- 7.3%) when dosed with saquinavir base-HBenBCD capsules. Clearly, HBenBCD can significantly improve the solubility and oral bioavailability of saquinavir; however, further formulation studies are required to optimize saquinavir oral delivery using this technology.
authors: Eastman Chemical Company, Research Laboratories, P.O. Box 1972, Kingsport, Tennessee 37662, USA. buck@eastman.com
authors: Charles M
authors: CM
authors: Buchanan
authors: Norma L
authors: NL
authors: Buchanan
authors: Kevin J
authors: KJ
authors: Edgar
authors: James L
authors: JL
authors: Little
authors: Michael G
authors: MG
authors: Ramsey
authors: Karen M
authors: KM
authors: Ruble
authors: Vincent J
authors: VJ
authors: Wacher
authors: Michael F
authors: MF
authors: Wempe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D051381:Rats; D017208:Rats, Wistar; D019258:Saquinavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D047392:beta-Cyclodextrins / Q000008:administration & dosage*
chemical_list: D017320:HIV Protease Inhibitors; D047392:beta-Cyclodextrins; C031215:betadex; D019258:Saquinavir