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. 2014 Nov 26:9:5503-14.
doi: 10.2147/IJN.S73340. eCollection 2014.

Effects of PEGylated lipid nanoparticles on the oral absorption of one BCS II drug: a mechanistic investigation

Xingwang Zhang  1 , Guijiang Chen  1 , Tianpeng Zhang  1 , Zhiguo Ma  1 , Baojian Wu  1
Affiliations

Effects of PEGylated lipid nanoparticles on the oral absorption of one BCS II drug: a mechanistic investigation

Xingwang Zhang et al. Int J Nanomedicine. .

Abstract

Lipid nanocarriers are becoming a versatile platform for oral delivery of lipophilic drugs. In this article, we aimed to explore the gastrointestinal behaviors of lipid nanoparticles and the effect of PEGylation on oral absorption of fenofibrate (FN), a Biopharmaceutics Classification System (BCS) II model drug. FN-loaded PEGylated lipid nanoparticles (FN-PLNs) were prepared by the solvent-diffusion method and characterized by particle size distribution, morphology, Fourier transform infrared spectroscopy, and drug release. Lipolytic experiments were performed to assess the resistance of lipid nanoparticles against pancreatic lipase. Pharmacokinetics was evaluated in rats after oral administration of FN preparations. The obtained FN-PLNs were 186.7 nm in size with an entrapment efficiency of >95%. Compared to conventional lipid nanoparticles, PLNs exhibited slower drug release in the lipase-containing medium, strikingly reduced mucin binding, and suppressed lipolysis in vitro. Further, oral absorption of FN was significantly enhanced using PLNs with relative bioavailability of 123.9% and 157.0% to conventional lipid nanoparticles and a commercial formulation (Lipanthyl(®)), respectively. It was demonstrated that reduced mucin trapping, suppressed lipolysis, and/or improved mucosal permeability were responsible for increased oral absorption. These results facilitated a better understanding of the in vivo fate of lipid nanoparticles, and suggested the potential of PLNs as oral carriers of BCS II drugs.

Keywords: PEGylation; absorption mechanism; fenofibrate; lipid nanoparticles; oral bioavailability.

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Figures

Figure 1
Figure 1
Effects of the ratio of LPG/PM on the particle size, PDI, and entrapment efficiency of FN-PLNs (n=3, mean ± SD). Notes: The left Y-axis represents the particle size of FN-PLNs (black column); the right Y-axis represents the polydispersity index (blue line); and the top X-axis (red digit) denotes the entrapment efficiency of the drug. Abbreviations: FN-PLNs, fenofibrate-loaded PEGylated lipid nanoparticles; LPG, lauroyl polyoxyl-6 glycerides; PDI, polydispersity index; PM, poly (ethylene glycol) monooleate; SD, standard deviation.
Figure 2
Figure 2
Particle size distribution (A) and TEM micrograph (B) of FN-PLNs. Abbreviations: FN-PLNs, fenofibrate-loaded PEGylated lipid nanoparticles; TEM, transmission electron microscopy.
Figure 3
Figure 3
The molecular structure of FN and FTIR spectra of FN (A), LPG (B), PM (C), physical mixture (D), and lyophilized FN-PLNs (E). Abbreviations: FN, fenofibrate; FN-PLNs, fenofibrate-loaded PEGylated lipid nanoparticles; FTIR, Fourier transform infrared spectroscopy; LPG, lauroyl polyoxyl-6 glycerides; PM, poly (ethylene glycol) monooleate.
Figure 4
Figure 4
Release curves of FN from lipid nanoparticles performed based on reverse bulk equilibrium dialysis. Notes: (A) Accumulative release of FN versus time in medium without lipase. (B) Accumulative release of FN versus time in medium containing lipase (n=3, mean ± SD). Abbreviations: FN, fenofibrate; FN-CLNs, fenofibrate-loaded conventional lipid nanoparticles; FN-PLNs, fenofibrate-loaded PEGylated lipid nanoparticles; min, minutes; SD, standard deviation.
Figure 5
Figure 5
Investigation of the interaction between lipid nanoparticles and mucins based on the determination of particle size of the co-incubation system. Notes: The characteristics of ex vivo intestinal fluids and lipid nanoparticle suspensions are summarized in the upper table of the figure. The changes of particle size of the system with incubation time are shown in the bottom. Abbreviations: FN-CLNs, fenofibrate-loaded conventional lipid nanoparticles; FN-PLNs, fenofibrate-loaded PEGylated lipid nanoparticles; min, minutes; PDI, polydispersity index.
Figure 6
Figure 6
Cumulative lipolysis percentage versus time profiles of FN-PLNs and FN-CLNs titrated by NaOH at a constant pH of 6.8. Note: Data expressed as mean ± SD (n=3). Abbreviations: FN-CLNs, fenofibrate-loaded conventional lipid nanoparticles; FN-PLNs, fenofibrate-loaded PEGylated lipid nanoparticles; min, minutes; SD, standard deviation.
Figure 7
Figure 7
Plasma FN concentration–time profiles after oral administration of FN-PLNs, FN-CLNs, and the commercial formulation (Lipanthyl®) to rats at a dose of 25 mg/kg (mean ± SD, n=6). Abbreviations: FN, fenofibrate; FN-CLNs, fenofibrate-loaded conventional lipid nanoparticles; FN-PLNs, fenofibrate-loaded PEGylated lipid nanoparticles; h, hours; SD, standard deviation.
Figure 8
Figure 8
In vitro–in vivo correlation of drug release in lipase-contained medium against drug absorption. Notes: (A) FN-CLNs and (B) FN-PLNs. The data on 0.25, 0.5, 1.0, and 2.0 hours were adopted to linearly fit the equations. Abbreviations: FN-CLNs, fenofibrate-loaded conventional lipid nanoparticles; FN-PLNs, fenofibrate-loaded PEGylated lipid nanoparticles.
Figure 9
Figure 9
Schematic illustration of PEGylated lipid nanoparticles as well as their effects on the oral absorption of delivered drug.
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