Influence of lipolysis and droplet size on tocotrienol absorption from self-emulsifying formulations

https://doi.org/10.1016/j.ijpharm.2004.05.015Get rights and content

Abstract

A single dose comparative bioavailability study was conducted to evaluate the bioavailability of tocotrienols from two self-emulsifying formulations, one of which produced an emulsion that readily lipolysed under in vitro condition (SES-A), while the other produced a finer dispersion with negligible lipolysis (SES-B) in comparison with that of a non-self-emulsifying formulation in soya oil. The study was conducted according to a three-way crossover design using six healthy human volunteers. Statistically significant differences were observed between the logarithmic transformed peak plasma concentration (Cmax) and total area under the plasma concentration–time curve (AUC0–∝) values of both SES-A and -B compared to NSES-C indicating that SES-A and -B achieved a higher extent of absorption compared to NSES-C. Moreover, the 90% confidence interval of the AUC0–∝ values of both SES-A and -B over those of NSES-C were between 2–3 suggesting an increase in bioavailability of about two–three times compared to NSES-C. Both SES-A and -B also achieved a faster onset of absorption. However, both SES-A and -B had comparable bioavailability, despite the fact that SES-B was able to form emulsions with smaller droplet size. Thus, it appeared that both droplet sizes as well as the rate and extent of lipolysis of the emulsion products formed were important for enhancing the bioavailability of the tocotrienols from the self-emulsifying systems.

Introduction

Tocotrienols, which belong to the Vitamin E family, share similar structural features of a chroman head and a 16-carbon phytyl chain with tocopherols. The main difference between the tocopherols and tocotrienols lies in the former having a saturated phytyl chain, while that of the latter is unsaturated, with three double bonds at 3′, 7′ and 11′ positions (Kamal-Eldin and Appelqvist, 1996). In recent years, tocotrienols have generated much interest, as they were reported to possess some biological activities that were not observed with the tocopherols and these include cholesterol lowering activities (Qureshi et al., 1991, Qureshi et al., 1995), anticancer and tumour suppressive activities (Goh et al., 1994, Nesaretnam et al., 1998), antiaggregation of blood platelets (Mahadevappa et al., 1991) and neuroprotective properties (Sen et al., 2000).

We have previously shown that the bioavailability of the tocotrienols was poor and erratic and was markedly increased when taken with food, while their biological half-life values were relatively short, being almost four–five-fold shorter compared to that of α-tocopherol (Yap et al., 2001). In studies using rats, it was also discovered that the absorption of tocotrienols was low and incomplete via the oral route (Yap et al., 2003). There appeared to be biodiscrimination in the oral absorption and disposition among the three tocotrienols. While the absolute bioavailability of α-tocotrienol was approximately 28%, those of δ- and γ-tocotrienol were comparable with a value of approximately 9%. Such poor and erratic bioavailability, which is also influenced by food for enhanced bioavailability makes the tocotrienols suitable candidates for lipid-based formulations, such as self-emulsifying systems to improve their oral bioavailability (Charman, 2000).

Various formulation aspects in the development of self-emulsifying systems have been well discussed and reviewed by Pouton (1997) and more recently by Gershanik and Benita (2000). It was suggested that the droplet sizes of the emulsion products formed by the self-emulsifying systems should be as fine as possible, preferably in colloidal dimensions to facilitate enhanced drug bioavailability. On the other hand, if a lipid formulation is non-self-emulsifying, then its susceptibility to digestion and/or solubilization by mixed micelles of bile salts and phospholipids in the gastrointestinal tract is important to produce the required colloidal dispersion for absorption, on provision that the contained drug is not precipitated during the digestion process (Macgregor et al., 1997, Pouton, 2000). As such, for self-emulsifying systems that produce rather coarse emulsions, subsequent digestion or lipolysis of the oil droplets might be important in their utilization for improving drug bioavailability (Pouton, 2000).

In view of the potential role of digestion/lipolysis in enhancing drug absorption from self-emulsifying systems, the present study was conducted to evaluate the in vivo bioavailability of tocotrienols from two self-emulsifying formulations, one of which produced an emulsion product that readily lipolyzed under in vitro conditions, while the other produced a finer dispersion with negligible lipolysis under the same conditions. Both preparations were evaluated in comparison with a non-self-emulsifying lipid formulation of the tocotrienols using six healthy human volunteers.

Section snippets

Materials

Tocomin® 50%, containing 21.6, 6.4, 10.7 and 10.9% of γ-, δ-, α-tocotrienol and α-tocopherol, respectively, was obtained from Carotech Pte. Ltd. (Ipoh, Malaysia). The rest of the Tocomin® 50% consisted mainly of palm olein, plant squalene and phyto–sterol complex, with trace amounts of phyto carotenoid complex and co-enzyme Q10. Tocotrienol standard kit was purchased from Merck (Darmstadt, Germany). Soya oil was purchased from Yee Lee Edible Oils Pte. Ltd. (Ipoh, Malaysia) while Labrasol (a C8/C

In vitro assessment of self-emulsifying properties and droplet sizes of SES-A and -B and lipolysis of SES-A, -B and NSES-C

Results obtained from the lipolysis experiment conducted on the individual components used in the preparation of the SES are shown in Fig. 1 while the numerical values of the rate and extent of lipolysis calculated are summarized in Table 3. From Fig. 1, it was found that apart from soya oil, the other components in the SES underwent negligible lipolysis. Tween 80 did not lipolyse at all while the extent of lipolysis for both Labrasol and Tocomin® 50% were <5.0%.

Table 3 also shows the visual

Discussion

α-Tocopherol, which is absorbed in the same pathway as other non-polar lipids such as triglycerides and cholesterol, requires the presence of bile salts for emulsification and micelle formation. After absorption it is transported through the lymphatic system, being too lipophilic to be absorbed via the hepatic portal vein (Kayden and Traber, 1993). From the results of our previous study on bioavailability of the tocotrienols under fed and fasted states (Yap et al., 2001), it appears that their

Conclusion

On the basis of the results obtained from the present study, it can be concluded that both SES formulations achieved a faster onset of absorption, with marked increase in the extent of bioavailability of the tocotrienols by two–three-fold compared to the non-self-emulsifying oily solution (NSES-C) under fasted condition. The droplet sizes of the emulsion product formed should be sufficiently fine, preferably in the submicron range to achieve enhanced oral absorption of the contained drug.

Acknowledgements

We wish to thank Carotech Pte. Ltd. for the generous supply of Tocomin® 50%.

References (27)

  • Gibaldi, M., Perrier, D. 1982. Absorption kinetics and bioavailability. In: Pharmacokinetics, second ed. Marcel Dekker,...
  • S.H Goh et al.

    Inhibition of tumour promotion by various palm-oil tocotrienols

    Int. J. Cancer

    (1994)
  • I Ikeda et al.

    Lymphatic transport of α-, γ- and δ-tocotrienols and α-tocopherol in rats

    Int. J. Vit. Nutr. Res.

    (1996)
  • Cited by (85)

    • Self-emulsifying systems for drug delivery: advances and challenges

      2023, Advanced and Modern approaches for Drug Delivery
    • Formulation of oily tocotrienols as a solid self-emulsifying dosage form for improved oral bioavailability in human subjects

      2022, Journal of Drug Delivery Science and Technology
      Citation Excerpt :

      From the results, it is clear that the plasma profiles of the s-SEDDS mixed-tocotrienol preparation were comparable to the commercial liquid self-emulsifying soft gelatin capsules. The commercial liquid formulation, Tocovid Suprabio™, is a patented self-emulsifying system, which has been shown to increase the absorption of tocotrienols by up to 300% compared to a normal oily preparation of the tocotrienols [37,38]. Furthermore, oral supplementation of Tocovid Suprabio™ has been shown in human clinical studies to be taken up efficiently, with increased tocotrienols level detected in blood, adipose tissue, skin, brain, cardiac muscles and liver over time [39].

    • Advancing skin delivery of α-tocopherol and γ-tocotrienol for dermatitis treatment via nanotechnology and microwave technology

      2021, International Journal of Pharmaceutics
      Citation Excerpt :

      The oral absorption efficiency of tocopherols and tocotrienols is hindered by first pass metabolism of therapeutics involving phase I cytochrome p450 3A4 enzyme and their efflux brought about by p-glycoprotein at the gastrointestinal epithelium (Aggarwal et al., 2010; Ikeda et al., 2000; Torres et al., 2008). Low and incomplete oral absorption leads to poor bioavailability for local skin treatment of diseases such as inflammation (Cichewicz et al., 2013; Qureshi et al., 2010; Simon et al., 2016; Yap and Yuen, 2004). With reference to skin inflammatory diseases, direct skin delivery is a promising mode of drug administration.

    View all citing articles on Scopus
    View full text