title: Investigating the correlation between in vivo absorption and in vitro release of fenofibrate from lipid matrix particles in biorelevant medium.
abstract: Lipid matrix particles (LMP) may be used as better carriers for poorly water-soluble drugs than liquid lipid carriers because of reduced drug mobilization in the formulations. However, the digestion process of solid lipid particles and their effect on the absorption of poorly water-soluble drugs are not fully understood. This study aimed at investigating the effect of particle size of LMP on drug release in vitro as well as absorption in vivo in order to get a better understanding on the effect of degradation of lipid particles on drug solubilisation and absorption. Fenofibrate, a model poorly water-soluble drug, was incorporated into LMP in this study using probe ultrasound sonication. The resultant LMP were characterised in terms of particle size, size distribution, zeta potential, entrapment efficiency, in vitro lipolysis and in vivo absorption in rat model. LMP of three different particle sizes i.e. approximately 100 nm, 400 nm, and 10 μm (microparticles) were produced with high entrapment efficiencies. The in vitro lipolysis study showed that the recovery of fenofibrate in the aqueous phase for 100 nm and 400 nm LMP was significantly higher (p<0.05) than that of microparticles after 30 min of lipolysis, suggesting that nano-sized LMP were digested to a larger extent due to greater specific surface area. The 100 nm LMP showed faster initial digestion followed by 400 nm LMP and microparticles. The area under the plasma concentration-time curve (AUC) following oral administration of 100 nm LMP was significantly higher (p<0.01) than that of microparticles and fenofibrate crystalline suspension (control). However, no significant difference was observed between the AUCs of 100 nm and 400 nm LMP. The same rank order on the in vivo absorption and the in vitro response was observed. The recovery (%) of fenofibrate partitioning into the aqueous phase during in vitro lipolysis and the AUC of plasma concentration-time curve of fenofibric acid was in the order of 100 nm LMP>microparticles>control. In summary, the present study demonstrated the particle size dependence of bioavailability of fenofibrate loaded LMP in rat model which correlates well with the in vitro drug release performed in the biorelevant medium.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Nrupa
authors.initials: N
authors.lastname: Borkar
authors.forename: Dengning
authors.initials: D
authors.lastname: Xia
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Yong
authors.initials: Y
authors.lastname: Gan
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.forename: Mingshi
authors.initials: M
authors.lastname: Yang
authors.forename: Huiling
authors.initials: H
authors.lastname: Mu
mesh_terms: D000042:Absorption; D000818:Animals; D019540:Area Under Curve; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D008055:Lipids / Q000737:chemistry*; D008066:Lipolysis / Q000502:physiology; D008297:Male; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D008055:Lipids; D014867:Water; C006012:fenofibric acid; D011345:Fenofibrate
keywords: 4-bromobenzeneboronic acid; ANOVA; AUC; Absorption; BBBA; C(max); FFAs; Fenofibrate; GIT; GMS; HPLC; HPMC; IVIVC; In vitro lipolysis; LMP; Lipid matrix particle; MCT; Particle size; SDS; SEM; SNEDDS; T(max); USP; United States pharmacopeia; analysis of variance; area under curve; free fatty acids; gastro-intestinal tract; glyceryl monostearate; high performance liquid chromatography; hydroxy propyl methylcellulose; in vitro–in vivo correlation; lipid matrix particles; maximal plasma concentration; medium chain triglyceride; self nano-emulsifying drug delivery systems; sodium dodecyl sulfate; standard error of mean; time required for maximal plasma concentration