title: Incomplete desorption of liquid excipients reduces the in vitro and in vivo performance of self-emulsifying drug delivery systems solidified by adsorption onto an inorganic mesoporous carrier.
abstract: The purpose of the current study was to provide a mechanistic basis for in vitro and in vivo performance differences between lipid-based formulations solidified by adsorption onto a high surface area material and their respective liquid (i.e., nonadsorbed) counterparts. Two self-emulsifying formulations (based on either medium-chain or long-chain lipids) of the poorly water-soluble drug danazol were solidified by adsorption onto Neusilin US2. Liquid and adsorbed lipid-based formulations were subjected to in vitro dispersion-digestion tests, and additional in vitro experiments were performed to elucidate the cause of performance differences. The bioavailability of danazol after oral administration to rats was also assessed. The percentage of the dose solubilized in the aqueous phase during in vitro dispersion-digesting was ∼35%  lower for the adsorbed formulations when compared to their liquid counterparts. This trend was also reflected in vivo, where the bioavailability of danazol after administration of the adsorbed formulations was ∼50% lower than that obtained after administration of the equivalent liquid formulation. Incomplete desorption of the microemulsion preconcentrate from the carrier on dispersion-digestion was identified as the main contributor to the reduced pharmaceutical performance of the adsorbed formulations. The results of the current study indicate that solidification of lipid-based formulations through adsorption onto a high surface area carrier may limit formulation (and drug) release in vivo and thereby reduce oral bioavailability.
authors.affiliation: Laboratory for Pharmacotechnology and Biopharmacy, University of Leuven, Herestraat 49, Box 921, Campus Gasthuisberg ON 2, B-3000 Leuven, Belgium.
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Speybroeck
authors.forename: Hywel D
authors.initials: HD
authors.lastname: Williams
authors.forename: Tri-Hung
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Mette U
authors.initials: MU
authors.lastname: Anby
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000284:Administration, Oral; D000327:Adsorption; D017607:Aluminum Compounds; D000538:Aluminum Silicates / Q000008:administration & dosage; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003613:Danazol / Q000008:administration & dosage / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D004655:Emulsions / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D005079:Excipients / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry*; D008274:Magnesium / Q000008:administration & dosage; D017616:Magnesium Compounds; D008297:Male; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D017640:Silicates; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D017607:Aluminum Compounds; D000538:Aluminum Silicates; D004337:Drug Carriers; D004655:Emulsions; D005079:Excipients; D008055:Lipids; D017616:Magnesium Compounds; D017640:Silicates; D014867:Water; C033065:aluminum magnesium silicate; D008274:Magnesium; D003613:Danazol