Enhanced Solubility and Oral Bioavailability of γ‐Tocotrienol Using a Self‐Emulsifying Drug Delivery System (SEDDS)

Abstract

The aim of this study was to evaluate the in vitro and in vivo performance of γ-tocotrienol (γ-T3) incorporated in a self-emulsifying drug delivery system (SEDDS) and to compare its enhanced performance to a commercially available product, namely Tocovid Suprabio™ (hereafter Tocovid), containing tocotrienols. The solubilization of γ-T3 was tested in a dynamic in vitro lipolysis model followed by in vitro cellular uptake study for the lipolysis products. In addition, in vitro uptake studies using Caco2 cells were conducted at different concentrations of γ-T3 prepared as SEDDS, Tocovid, or mixed micelles. γ-T3 incorporated in SEDDS or Tocovid was orally administered to rats at different doses and absolute oral bioavailability from both formulations were determined. The dynamic in vitro lipolysis experiment showed about two fold increase in the solubilization of γ-T3 prepared as SEDDS compared to Tocovid, which correlated with higher cellular uptake in the subsequent uptake studies. In vitro cellular uptake and in vivo oral bioavailability studies have shown a twofold increase in the cellular uptake and oral bioavailability of γ-T3 incorporated in SEDDS compared to Tocovid as a result of improvement in its solubility and passive uptake as confirmed by in vitro studies. In conclusion, incorporation of γ-T3 in SEDDS formulation enhanced γ-T3 solubilization and passive permeability, thus its cellular uptake and oral bioavailability when compared to Tocovid.

Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans

“…A recent study reported the bioavailability of γ-tocotrienol, δ-tocotrienol versus annatto-based γ-tocotrienol (10%) + δ-tocotrienol (90%) dissolved in SEDDS using rats and displayed that γ-tocotrienol (10%) and δ-tocotrienol (90%) showed bioavailability of 332 (0.05 mg/kg) and 31.5 (0.5 mg/kg) for low doses, and bioavailability was 4.5 ± 0.1 (2.5 mg/kg) and 3.0 ± 0.1 (25 mg/kg) at higher doses, due to nonlinear absorption kinetics [ 11 ]. The results of γ- tocotrienol dissolved in SEDDS versus commercial Tocovid were also reported in vitro and in vivo in rats [ 22 ]. The in vitro results showed two-fold increase in the solubilization as well as higher cellular uptake while in vivo studies showed two-fold improvement in oral bioavailabity of γ-tocotrienol in SEDDS formulations compared to Tocovid [ 22 ].…”

Vitamin E Transporters in Cancer Therapy

“…Further studies investigated the incorporation γ-and δ-tocotrienol in self-emulsifying drug-delivery systems (SEDDS) on their bioavailability. Findings of these studies showed a significant increase in the solubility, permeability, and oral bioavailability of γ-and δ-tocotrienols both in vitro and in vivo (67,86). To explain the enhanced intestinal permeability and bioavailability of γ-and δ-tocotrienol delivered as either SLN or SEDDS compared with their delivery as mixed micelles, in vitro mechanistic studies were performed (67,85,86).…”

“…Findings of these studies showed a significant increase in the solubility, permeability, and oral bioavailability of γ-and δ-tocotrienols both in vitro and in vivo (67,86). To explain the enhanced intestinal permeability and bioavailability of γ-and δ-tocotrienol delivered as either SLN or SEDDS compared with their delivery as mixed micelles, in vitro mechanistic studies were performed (67,85,86). Results of these studies revealed that packaging γ-and δ-tocotrienol in SLN or SEDDS delivery systems were able to enhance both isoforms' intestinal permeability and bioavailability as a result of the enhanced passive permeability and reduced contribution of NPC1L1 to the transport of both isoforms (67,85,86).…”

“…To explain the enhanced intestinal permeability and bioavailability of γ-and δ-tocotrienol delivered as either SLN or SEDDS compared with their delivery as mixed micelles, in vitro mechanistic studies were performed (67,85,86). Results of these studies revealed that packaging γ-and δ-tocotrienol in SLN or SEDDS delivery systems were able to enhance both isoforms' intestinal permeability and bioavailability as a result of the enhanced passive permeability and reduced contribution of NPC1L1 to the transport of both isoforms (67,85,86). One of the possible explanations for the increased passive permeability by SLN and SEDDS could be related to the excipients incorporated in these delivery systems and their ability to modulate the fluidity of cell membrane (67,85,86).…”

“…Results of these studies revealed that packaging γ-and δ-tocotrienol in SLN or SEDDS delivery systems were able to enhance both isoforms' intestinal permeability and bioavailability as a result of the enhanced passive permeability and reduced contribution of NPC1L1 to the transport of both isoforms (67,85,86). One of the possible explanations for the increased passive permeability by SLN and SEDDS could be related to the excipients incorporated in these delivery systems and their ability to modulate the fluidity of cell membrane (67,85,86). Similar findings were observed with Yap et al's study (73), who reported the delivery of tocotrienols in SEDDS formulation caused faster onset of absorption with marked increase in the bioavailability of tocotrienols by 2-to 3-fold in humans (87).…”