title: Supersaturated self-nanoemulsifying drug delivery systems (Super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug simvastatin in dogs.
abstract: This study investigates the potential of supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) to improve the bioavailability of poorly water-soluble drugs compared to conventional SNEDDS. Conventional SNEDDS contained simvastatin (SIM) at 75% of the equilibrium solubility (S (eq)). Super-SNEDDS containing SIM at 150 and 200% of S (eq) were produced by subjecting the SNEDDS preconcentrates to a heating and cooling cycle. The super-SNEDDS were physically stable over 10 months. During in vitro lipolysis of SNEDDS and super-SNEDDS the SIM concentration in the aqueous phase increased for the first 30 min almost proportional to the drug loads and amounts of preconcentrate employed. The 200% drug-loaded super-SNEDDS generated an amorphous SIM precipitate at the end of in vitro lipolysis. In vivo, the relative bioavailability of SIM from super-SEDDDS increased significantly to 180 ± 53.3% (p = 0.014) compared to the dosing of two capsules of (dose equivalent) 75% drug-loaded SNEDDS. A significant increase in the terminal half-life of elimination was observed for super-SNEDDS (2.3 ± 0.6 h) compared to conventional SNEDDS (1.4 ± 0.3 h) as well as a decreased area under the curve ratio of the SIM metabolite simvastatin acid to the parent compound (0.57 ± 0.20 and 0.90 ± 0.3), possibly due to a combination of saturation effects on presystemic metabolising enzymes and prolonged absorption along the small intestine. In summary, this study demonstrated that super-SNEDDS are a viable formulation option to enhance the bioavailability of poorly water-soluble drugs such as simvastatin while reducing the pill burden by an increased drug load of SNEDDS.
authors.affiliation: School of Pharmacy, University of Otago, 9054, Dunedin, New Zealand.
authors.forename: Nicky
authors.initials: N
authors.lastname: Thomas
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Mats
authors.initials: M
authors.lastname: Garmer
authors.forename: Jens Jakob
authors.initials: JJ
authors.lastname: Karlsson
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
mesh_terms: D000818:Animals; D001682:Biological Availability; D004285:Dogs; D016503:Drug Delivery Systems; D004355:Drug Stability; D004655:Emulsions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D053758:Nanoparticles; D019821:Simvastatin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D004655:Emulsions; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin