TY - JOUR

T1 - Supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug Simvastatin in dogs

AU - Thomas, Nicky

AU - Holm, René

AU - Garmer, Mats

AU - Karlsson, Jens Jakob

AU - Müllertz, Anette

AU - Rades, Thomas

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

U2 - 10.1208/s12248-012-9433-7

DO - 10.1208/s12248-012-9433-7

M3 - Journal article

C2 - 23180162

VL - 15

SP - 219

EP - 227

JO - A A P S Journal

JF - A A P S Journal

SN - 1550-7416

IS - 1

ER -