A self-emulsifying Omega-3 ethyl ester formulation (AquaCelle) significantly improves eicosapentaenoic and docosahexaenoic acid bioavailability in healthy adults

  • Kristen E. BremmellEmail author
  • David Briskey
  • Tahlia R. Meola
  • Alistair Mallard
  • Clive A. Prestidge
  • Amanda Rao
Original Contribution



Application of intelligent formulation design has the ability to address the poor bioavailability and improve the fasted state bioavailability of fish oils. In this study we assessed the ability of a self-emulsifying drug delivery system (SEDDS), AquaCelle®, as an additive to enhance the oral absorption of Omega-3 ethyl esters (EE) in healthy subjects under low-fat diet conditions.


Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) EE were formulated with AquaCelle®. A single dose (680 mg dose of oil containing 272 mg of EPA EE and 204 mg of DHA EE), randomized, double-blind, study measured uptake of EPA and DHA over 24 h in healthy adults. Participants were randomized into two groups, receiving either the SEDDS AquaCelle® fish oil formulation or the unformulated fish oil EE as control.


The AquaCelle® fish oil EE formulation demonstrated instant and complete emulsification on addition to water to produce an emulsion with an average diameter of 43 μm, compared to the oil alone which did not emulsify. The study revealed a significant difference in absorption (Cmax and AUC0–24h) between the AquaCelle® group and the control group. The AquaCelle® group was capable of increasing maximum plasma concentrations and absorption (AUC0–24h) of total Omega-3 (EPA + DHA) 3.7- and 7.1-fold, respectively, compared to the control.


Formulating Omega-3 EE with a SEDSS concentrate (AquaCelle®) demonstrated a significant improvement in the oral absorption of Omega-3 fatty acids without requiring a high-fat meal.

Graphic abstract


Omega-3 Eicosapentaenoic acid ethyl ester Docosahexaenoic acid ethyl ester Bioavailability Self-emulsifying delivery systems 



This study was funded by Pharmako Biotechnologies, Pty Ltd, Australia.

Compliance with ethical standards

Conflict of interest

The author declares that they have no competing interests.

Ethical standards

The manuscript was written through contribution from all authors who have given approval for the final manuscript.


  1. 1.
    AbuMweis S, Jew S, Tayyem R, Agraib L (2018) Eicosapentaenoic acid and docosahexaenoic acid containing supplements modulate risk factors for cardiovascular disease: a meta-analysis of randomised placebo-control human clinical trials. J Hum Nutr Diet 31(1):67–84. CrossRefPubMedGoogle Scholar
  2. 2.
    Chandra A, Røsjø H, Eide IA, Vigen T, Ihle-Hansen H, Orstad EB, Rønning OM, Lyngbakken MN, Berge T, Schmidt EB, Omland T, Tveit A, Svensson M (2019) Plasma marine n-3 polyunsaturated fatty acids and cardiovascular risk factors: data from the ACE 1950 study. Eur J Nutr. CrossRefPubMedGoogle Scholar
  3. 3.
    Calder PC (2017) Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans 45(5):1105–1115. CrossRefPubMedGoogle Scholar
  4. 4.
    Sinclair AJ, Begg D, Mathai M, Weisinger RS (2007) Omega 3 fatty acids and the brain: review of studies in depression. Asia Pac J Clin Nutr 16(Suppl 1):391–397PubMedGoogle Scholar
  5. 5.
    Mozaffarian D, Wu JHY (2012) (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 142(3):614S–625S. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Davidson MH, Johnson J, Rooney MW, Kyle ML, Kling DF (2012) A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova® compared to Lovaza® in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol 6(6):573–584. CrossRefPubMedGoogle Scholar
  7. 7.
    Shimada H, Nilsson C, Noda Y, Kim H, Lundström T, Yajima T (2017) Effects of food on the pharmacokinetics of Omega-3-carboxylic acids in healthy Japanese male subjects: a phase I, randomized, open-label, three-period, crossover trial. J Atheroscler Thromb 24(9):980–987. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Pouton CW (2006) Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 29(3):278–287. CrossRefPubMedGoogle Scholar
  9. 9.
    McClements DJ, Decker EA, Park Y, Weiss J (2008) Designing food structure to control stability, digestion, release and absorption of lipophilic food components. Food Biophys 3(2):219–228. CrossRefGoogle Scholar
  10. 10.
    Garaiova I, Guschina IA, Plummer SF, Tang J, Wang D, Plummer NT (2007) A randomised cross-over trial in healthy adults indicating improved absorption of omega-3 fatty acids by pre-emulsification. Nutr J 6(1):4. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Chang Y, McClements DJ (2016) Influence of emulsifier type on the in vitro digestion of fish oil-in-water emulsions in the presence of an anionic marine polysaccharide (fucoidan): caseinate, whey protein, lecithin, or Tween 80. Food Hydrocoll 61:92–101. CrossRefGoogle Scholar
  12. 12.
    Joyce P, Gustafsson H, Prestidge CA (2018) Enhancing the lipase-mediated bioaccessibility of omega-3 fatty acids by microencapsulation of fish oil droplets within porous silica particles. J Funct Foods 47:491–502. CrossRefGoogle Scholar
  13. 13.
    Singh B, Bandopadhyay S, Kapil R, Singh R, Katare OP (2009) Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications. Crit Revi Ther Drug Carr Syst 26(5):427–451. CrossRefGoogle Scholar
  14. 14.
    Qin Y, Nyheim H, Haram EM, Moritz JM, Hustvedt SO (2017) A novel self-micro-emulsifying delivery system (SMEDS) formulation significantly improves the fasting absorption of EPA and DHA from a single dose of an omega-3 ethyl ester concentrate. Lipid Health Dis 16(1):204. CrossRefGoogle Scholar
  15. 15.
    Lopez-Toledano MA, Thorsteinsson T, Daak A, Maki KC, Johns C, Rabinowicz AL, Sancilio FD (2017) A novel ω-3 acid ethyl ester formulation incorporating advanced lipid technologiesTM (ALT®) improves docosahexaenoic acid and eicosapentaenoic acid bioavailability compared with lovaza®. Clin Ther 39(3):581–591. CrossRefPubMedGoogle Scholar
  16. 16.
    West AL, Kindberg GM, Hustvedt SO, Calder PC (2018) A novel self-micro-emulsifying delivery system enhances enrichment of eicosapentaenoic acid and docosahexaenoic acid after single and repeated dosing in healthy adults in a randomized trial. J Nutr 148(11):1704–1715. CrossRefPubMedGoogle Scholar
  17. 17.
    Maki KC, Palacios OM, Buggia MA, Trivedi R, Dicklin MR, Maki CE (2018) Effects of a self–micro-emulsifying delivery system formulation versus a standard ω-3 acid ethyl ester product on the bioavailability of eicosapentaenoic acid and docosahexaenoic acid: a study in healthy men and women in a fasted state. Clin Ther 40(12):2065–2076. CrossRefPubMedGoogle Scholar
  18. 18.
    Lopez-Toledano MA, Thorsteinsson T, Daak AA, Maki KC, Johns C, Rabinowicz AL, Sancilio FD (2017) Minimal food effect for eicosapentaenoic acid and docosahexaenoic acid bioavailability from omega-3–acid ethyl esters with an Advanced Lipid TechnologiesTM (ALT)–based formulation. J Clin Lipidol 11:394–405. CrossRefPubMedGoogle Scholar
  19. 19.
    PharmakoBiotechnologies (2019) Accessed 9 April 2019
  20. 20.
    Vasconcelos T, Marques S, Sarmento B (2018) Measuring the emulsification dynamics and stability of self-emulsifying drug delivery systems. Eur J Pharm Biopharm 123:1–8. CrossRefPubMedGoogle Scholar
  21. 21.
    Raatz SK, Johnson LK, Bukowski MR (2016) Enhanced bioavailability of EPA from emulsified fish oil preparations versus capsular triacylglycerol. Lipids 51(5):643–651. CrossRefPubMedGoogle Scholar
  22. 22.
    Sarkar A, Ye A, Singh H (2016) On the role of bile salts in the digestion of emulsified lipids. Food Hydrocoll 60:77–84. CrossRefGoogle Scholar
  23. 23.
    Lawson LD, Hughes BG (1988) Human absorption of fish oil fatty acids as triacylglycerols, free acids, or ethyl esters. Biochem Biophys Res Commun 152(1):328–335. CrossRefPubMedGoogle Scholar
  24. 24.
    National Cholesterol Education Program (NCEP) Expert Panel on Detection E, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002) Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) Final Report. Circulation 106:3143–3421CrossRefGoogle Scholar
  25. 25.
    Neslihan Gursoy R, Benita S (2004) Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 58(3):173–182. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Pharmacy and Medical SciencesUniversity of South AustraliaAdelaideAustralia
  2. 2.ARC Centre of Excellence in Convergent Bio-Nano Science and TechnologyUniversity of South AustraliaMawson LakesAustralia
  3. 3.RDC Clinical Pty LtdBrisbaneAustralia
  4. 4.School of Human Movement and Nutrition SciencesUniversity of QueenslandBrisbaneAustralia

Personalised recommendations