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Nonlinear absorption kinetics of self-emulsifying drug delivery systems (SEDDS) containing tocotrienols as lipophilic molecules: in vivo and in vitro studies.

ABSTRACT: Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, ?-tocotrienol (?-T3) and ?-tocotrienol (?-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with ?-T3 (90%) and ?-T3 (10%) formulated SEDDS showed bioavailability of 31.5% and 332%, respectively. However, bioavailability showed a progressive decrease with increased treatment dose that displayed nonlinear absorption kinetics. Additional in vitro studies examining cellular uptake studies in Caco 2 cells revealed that the SEDDS formulation increased passive permeability of ?-T3 and ?-T3 by threefold as compared to the commercial capsule formulation. These studies also showed that free surfactants decreased ?-T3 and ?-T3 absorption. Specifically, combined treatment cremophor EL or labrasol with tocotrienols caused a 60-85% reduction in the cellular uptake of ?-T3 and ?-T3 and these effects appear to result from surfactant-induced inhibition of the ?-T3 and ?-T3 transport protein Niemann-Pick C1-like 1 (NPC1L1). In summary, results showed that SEDDS formulation significantly increases the absorption and bioavailability ?-T3 and ?-T3. However, this effect is self-limiting because treatment with increasing doses of SEDDS appears to be associated with a corresponding increase in free surfactants levels that directly and negatively impact tocotrienol transport protein function and results in nonlinear absorption kinetics and a progressive decrease in ?-T3 and ?-T3 absorption and bioavailability.

SUBMITTER: Alqahtani S

PROVIDER: S-EPMC3691427 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

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Nonlinear absorption kinetics of self-emulsifying drug delivery systems (SEDDS) containing tocotrienols as lipophilic molecules: in vivo and in vitro studies.

Alqahtani Saeed S Alayoubi Alaadin A Nazzal Sami S Sylvester Paul W PW Kaddoumi Amal A

The AAPS journal 20130410 3

Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, δ-tocotrienol (δ-T3) and γ-tocotrienol (γ-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with δ-T3 (90%) and γ-T3 (10%) formulated SEDDS showed bioavail ...[more]

PMID: 23572242

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Project description:The development of self-nanoemulsifying drug delivery systems (SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80 (LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides (40% to 75%), Kolliphor® RH40 (5% to 55%), LPC (0 to 40%) and ethanol (0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200?nm. The use of medium-chain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor® RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor® RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor® RH40 as a reference for formulation developers.

Dataset Information

Nonlinear absorption kinetics of self-emulsifying drug delivery systems (SEDDS) containing tocotrienols as lipophilic molecules: in vivo and in vitro studies.

Publications

Nonlinear absorption kinetics of self-emulsifying drug delivery systems (SEDDS) containing tocotrienols as lipophilic molecules: in vivo and in vitro studies.

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