title: In vitro and in vivo performance of monoacyl phospholipid-based self-emulsifying drug delivery systems.
abstract: This study investigates the effect of monoacyl phospholipid incorporation on the in vitro and in vivo performance of self-emulsifying drug delivery systems (SEDDS). Monoacyl phosphatidylcholine (Lipoid S LPC 80 (LPC)) was incorporated into four different fenofibrate (FF)-loaded long-chain SEDDS to investigate the impact of LPC on the emulsion droplet size, extent of digestion, colloidal structure evolution and drug precipitation during in vitro lipolysis simulating human conditions and drug bioavailability in a rat model. The four investigated SEDDS containing long-chain glycerides, polyoxyl 35 castor oil or polyoxyl 8 caprylocaproyl glycerides with or without LPC. In situ synchrotron small/wide-angle X-ray scattering (SAXS/WAXS) was used to simultaneously real-time monitor the kinetics of lamellar phase structure development and FF crystalline precipitation. Adding LPC increased the particle size and polydispersity of the dispersed SEDDS. The two LPC-free SEDDS generated lamellar phase structures (Lα) with d-spacing=4.76nm during digestion. Incorporating LPC into these systems inhibited the formation of lamellar phase structures. The amount of precipitated crystalline FF from the four SEDDS was similar during the first 15min but differed during the last 45min of in vitro digestion. The kinetics of colloidal structure development and FF precipitation was related to the digestion kinetics. The in vivo bioavailability data showed no significant differences between the four SEDDS, which correlates with the in vitro FF precipitation during the first 15min of lipolysis. Thus, the presence of LPC, different emulsion droplet sizes and concentration of lamellar phase structures observed in vitro did not correlate with the FF absorption in rats. The study suggests that later time points of the in vitro lipolysis overestimated FF precipitation in rats because of the high enzyme activity, the lack of gastric and absorption steps, and the low bile salts and phospholipid concentrations of the in vitro model.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Thuy
authors.initials: T
authors.lastname: Tran
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Scheyla D V S
authors.initials: SDVS
authors.lastname: Siqueira
authors.affiliation: Institute of Inorganic Chemistry, Graz University of Technology, Stremayrgasse 9/V, A-8010 Graz, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Amenitsch
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Bioneer: FARMA, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: anette.mullertz@sund.ku.dk.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
mesh_terms: D000818:Animals; D001682:Biological Availability; D002368:Castor Oil / Q000737:chemistry; D011232:Chemical Precipitation; D016503:Drug Delivery Systems; D004655:Emulsions; D011345:Fenofibrate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D005753:Gastric Mucosa / Q000378:metabolism; D005989:Glycerides / Q000737:chemistry; D007408:Intestinal Absorption; D008297:Male; D010316:Particle Size; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley
chemical_list: D004655:Emulsions; D005989:Glycerides; D010713:Phosphatidylcholines; D002368:Castor Oil; C006012:fenofibric acid; D011345:Fenofibrate
keywords: Emulsification; In vitro lipolysis; Monoacyl phospholipid; Pharmacokinetics; Self-emulsifying drug delivery systems; Small-angle X-ray scattering; Wide-angle X-ray scattering