title: Kolliphor surfactants affect solubilization and bioavailability of fenofibrate. Studies of in vitro digestion and absorption in rats.
abstract: Selection of excipients for drug formulations requires both intellectual and experimental considerations as many of the used excipients are affected by physiological factors, e.g., they may be digested by pancreatic enzymes in the gastrointestinal tract. In the present paper we have looked systematically into the differences between Kolliphor ELP, EL, and RH40 and how they affect the bioavailability of fenofibrate, through pharmacokinetic studies in rats and in vitro lipolysis studies. The study design was made as simple as possible to avoid confounding factors, for which reason the tested formulations only comprised an aqueous micellar solution of the model drug (fenofibrate) in varying concentrations (2-25% (w/v)) of the three tested surfactants. Increased concentrations of Kolliphor ELP and EL led to increased fenofibrate AUC0-24h values. For the Kolliphor RH40 formulations, an apparent fenofibrate absorption optimum was seen at 15% (w/v) surfactant, displaying both the highest AUC0-24h and Cmax. The reduced absorption of fenofibrate from the formulation containing the highest level of surfactant (25% w/v) was thought to be caused by some degree of trapping within Kolliphor RH40 micelles. In vitro, Kolliphor ELP and EL were found to be more prone to digestion than Kolliphor RH40, though not affecting the in vivo results. The highest fenofibrate bioavailability was attained from formulations with high Kolliphor ELP/EL levels (25% (w/v)), indicating that these surfactants are the better choice for solubilizing fenofibrate in order to increase the absorption upon oral administration. Due to drug dependent effects of the different types of Kolliphor, more studies are recommended in order to understand which type of Kolliphor is best suited for a given drug.
authors: †Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
authors: Ragna
authors: R
authors: Berthelsen
authors: †Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.|‡Biologics and Pharmaceutical Science, H. Lundbeck A/S, Valby, Denmark.
authors: René
authors: R
authors: Holm
authors: †Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
authors: Jette
authors: J
authors: Jacobsen
authors: §Ferring Pharmaceuticals A/S, Copenhagen, Denmark.
authors: Jakob
authors: J
authors: Kristensen
authors: Bertil
authors: B
authors: Abrahamsson
authors: †Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.|⊥Bioneer:FARMA, Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
authors: Anette
authors: A
authors: Müllertz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D005079:Excipients; D011345:Fenofibrate / Q000008:administration & dosage*; D007408:Intestinal Absorption; D008055:Lipids; D008066:Lipolysis; D008297:Male; D008823:Micelles; D010316:Particle Size; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013024:Soybean Oil / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D005079:Excipients; D008055:Lipids; D008823:Micelles; D014677:Pharmaceutical Vehicles; D013501:Surface-Active Agents; C022131:cremophor; D011092:Polyethylene Glycols; D013024:Soybean Oil; D011345:Fenofibrate
keywords: Cremophor; IVIVC; Kolliphor EL; Kolliphor ELP; Kolliphor RH40; bioavailability; fenofibrate; in vitro lipolysis; micellar trapping; rats; surfactant digestion