AAPS PharmSciTech

, Volume 19, Issue 3, pp 1116–1123 | Cite as

Coenzyme Q10-Loaded Fish Oil-Based Bigel System: Probing the Delivery Across Porcine Skin and Possible Interaction with Fish Oil Fatty Acids

  • Mohd Hanif Zulfakar
  • Chan Lee Mei 
  • Khurram Rehman
  • Lam Kok Wai
  • Charles M. Heard
Research Article


Coenzyme Q10 (CoQ10) is a vitamin-like oil-soluble molecule that has anti-oxidant and anti-ageing effects. To determine the most optimal CoQ10 delivery vehicle, CoQ10 was solubilised in both water and fish oil, and formulated into hydrogel, oleogel and bigel. Permeability of CoQ10 from each formulation across porcine ear skin was then evaluated. Furthermore, the effects of the omega-3 fatty eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids from fish oil on skin permeation were investigated by means of nuclear magnetic resonance (NMR) and computerised molecular modelling docking experiments. The highest drug permeation was achieved with the bigel formulation that proved to be the most effective vehicle in delivering CoQ10 across the skin membrane due to a combination of its adhesive, viscous and lipophilic properties. Furthermore, the interactions between CoQ10 and fatty acids revealed by NMR and molecular modelling experiments likely accounted for skin permeability of CoQ10. NMR data showed dose-dependent changes in proton chemical shifts in EPA and DHA. Molecular modelling revealed complex formation and large binding energies between fatty acids and CoQ10. This study advances the knowledge about bigels as drug delivery vehicles and highlights the use of NMR and molecular docking studies for the prediction of the influence of drug–excipient relationships at the molecular level.


nuclear magnetic resonance molecular modelling eicosapentaenoic acid docosahexaenoic acid bigel 



The authors would like to thank the Ministry of Education, Malaysia, for providing research grant ERGS/1/2013/SKK02/UKM/02/3 and Faculty of Pharmacy, Universiti Kebangsaan Malaysia, for the additional support during this study.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Borekova M, Hojerova J, Koprda V, Bauerova K. Nourishing and health benefits of coenzyme Q10. Czech J Food Sci. 2008;26:229–41.CrossRefGoogle Scholar
  2. 2.
    Wen-Chuan L, Tung-Hu T. Preparation and characterization of liposomal coenzyme Q10 for in vivo topical application. Int J Pharm. 2010;395:78–83.CrossRefGoogle Scholar
  3. 3.
    Prahl S, Kueper T, Biernoth T, Wohrmann Y, Munster A, Furstenau M, et al. Aging skin is functionally anaerobic: importance of coenzyme Q10 for anti aging skin care. Biofactors. 2008;32(1-4):245–55. Scholar
  4. 4.
    Muta-Takada K, Terada T, Yamanishi H, Ashida Y, Inomata S, Nishiyama T, et al. Coenzyme Q10 protects against oxidative stress-induced cell death and enhances the synthesis of basement membrane components in der-mal and epidermal cells. Biofactors. 2009;35(5):435–41. Scholar
  5. 5.
    Gokce HE, Korkmaz E, Tanriverdi TS, Dellera E, Sandri G, Bonferonia MC, et al. A comparative evaluation of coenzyme Q10-loaded liposomes and solid lipid nanoparticles as dermal antioxidant carriers. Int J Nanomedicine. 2012;7:5109–17. Scholar
  6. 6.
    Jung SY, Kang EY, Choi YJ, Chun IK, Lee BK, Gwak HS. Formulation and evaluation of ubidecarenone transdermal delivery systems. Drug Dev Ind Pharm. 2009;35(9):1029–34. Scholar
  7. 7.
    Junyaprasert BV, Teeranachaideekul V, Souto BE, Boonme P, Mulller HR. Q10-loaded NLC versus nanoemulsions: stability, rheology and in vitro skin permeation. Int J Pharm. 2009;377(1-2):207–14. Scholar
  8. 8.
    Yue Y, Zhou H, Liu G, Li Y, Yan Z, Duan M. The advantages of a novel CoQ10 delivery system in skin photo-protection. Int J Pharm. 2010;392(1-2):57–63. Scholar
  9. 9.
    Zhang J, Wang S. Topical use of coenzyme Q10-loaded liposomes coated with trimethyl chitosan: tolerance, precorneal retention and anti-cataract effect. Int J Pharm. 2009;372(1-2):66–75. Scholar
  10. 10.
    Smeden J, Janssens M, Gooris GS, Bouwstra JA. The important role of stratum corneum lipids for the cutaneous barrier function. Biochem Biophys Acta. 2014;1841(3):295–313. Scholar
  11. 11.
    Tahara Y, Honda S, Kamiya N, Piao H, Hirata A, Hayakawa E, et al. A solid-in-oil nanodispersion for transcutaneous protein delivery. J Control Release. 2008;131(1):14–28. Scholar
  12. 12.
    Thomas BJ, Finnin BC. The transdermal revolution. Drug Discov Today. 2004;9(16):697–703. Scholar
  13. 13.
    Barry BW. Breaching the skin’s barrier to drugs. Nat Biotechnol. 2004;22(2):165–7. Scholar
  14. 14.
    Choi WI, Lee JH, Kim JC, Kim YH, Tae G. Efficient skin permeation of soluble proteins via flexible and functional nano-carrier. J Control Release. 2012;157(2):272–8. Scholar
  15. 15.
    Rehman K, Zulfakar MH. Recent advances in gel technologies for topical and transdermal drug delivery. Drug Dev Ind Pharm. 2014;40(4):433–40. Scholar
  16. 16.
    Peppas NA, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulation. Eur J Pharm Biopharm. 2000;50(1):27–46. Scholar
  17. 17.
    Rehman K, Tan CM, Zulfakar MH. Development and in-vitro characterization of fish oil oleogels containing benzoyl peroxide and salicylic acid as keratolytic agents. Drug Res. 2014;64:159–65.Google Scholar
  18. 18.
    Lupi FR, Gabriele D, Facciolo D, Baldino N, Seta L, Cindio DB. Effect of organogelator and fat source on rheological properties of olive oil based organogels. Food Res Int. 2012;46(1):177–84. Scholar
  19. 19.
    Rehman K, Amin MCIM, Zulfakar MH. Development and physical characterization of polymer-fish oil bigel (hydrogel/oleogel) system as a transdermal drug delivery vehicle. J Oleo Sci. 2014;63(10):961–70. Scholar
  20. 20.
    Rehman K, Aluwi MFFM, Rullah K, Wai LK, Amin MCIM, Zulfakar MH. Probing the effects of fish oil on the delivery and inflammation-inducing potential of imiquimod. Int J Pharm. 2015;490(1-2):131–41. Scholar
  21. 21.
    Boelsma E, Tanojo H, Bodde H, Ponec M. Assessment of the potential irritancy of oleic acid on human skin: evaluation in vitro and in vivo. Toxicol in Vitro. 1996;10(6):729–42. Scholar
  22. 22.
    Zulfakar MH, Abdelouahab N, Heard CM. Enhanced topical delivery and ex vivo anti-inflammatory activity from a betamethasone dipropionate formulation containing fish oil. Inflam Res. 2010;59(1):23–30. Scholar
  23. 23.
    Heard CM, Gallagher SJ, Harwood J, Maguire PB. The in vitro delivery of NSAIDs across skin was in proportion to the delivery of essential fatty acids in the vehicle—evidence that solutes permeate skin associated with their solvation cages? Int J Pharm. 2003;261(1):165–9. Scholar
  24. 24.
    Huri DF, Shiow NF, Zulfakar MH. Fish oil-based oleogels: physicochemicals characterisation and in vitro release of betamethasone dipropionate. Int J Pharm Pharma Sci. 2013;5(3):458–67.Google Scholar
  25. 25.
    Thomas CP, Heard CM. Probing the skin permeation of eicosapentaenoic acid and ketoprofen: 2. Comparative depth profiling and metabolism of eicosapentaenoic acid. Eur J Pharm Biopharm. 2007;67(1):156–65. Scholar
  26. 26.
    Thomas CP, Platts J, Tatchell T, Heard CM. Probing the skin permeation of fish oil/epa and ketoprofen: 1. NMR spectroscopy and molecular modelling. Int J Pharm. 2007;338(1):207–2. Scholar
  27. 27.
    Kelly JX, Winter R, Riscoe M, Peyton DH. A spectroscopic investigation of the binding interactions between 4,5-dihydroxyanthobne and heme. J Inorg Biochem. 2001;86(2-3):617–25. Scholar
  28. 28.
    Weigmaan HJ, Schanzer S, Patzelt A, Bahaban V, Durat F, Sterry W, et al. Comparison of human and porcine skin for characterization of sunscreens. J Biomed Optics. 2009;14(2):24026–7.CrossRefGoogle Scholar
  29. 29.
    Herkenne C, Naik A, Kalia YN, Hadgraft J, Guy RH. Porcine ear skin ex vivo as a model for in vivo dermatopharmacokinetic studies in man. Pharm Res. 2006;23(8):1850–6. Scholar
  30. 30.
    Hussain Z, Katas H, Amin MCIM, Kumolosasi E, Buang F, Sahudin S. Self-assembled polymeric nanoparticles for percutaneous co-delivery of hydrocortisone/hydroxytyrosol: an ex vivo and in vivo study using an NC/Nga mouse model. Int J Pharm. 2013;444(1-2):109–19. Scholar
  31. 31.
    Sri P, Adimoolam S, Mahmud A. Percutaneous absorption of triacyglycerols (tags), tocols and carotenoids: comparison studies of crude and refined palm oil. Malay J Pharm Sci. 2013;11(1):33–48.Google Scholar
  32. 32.
    Al-Nuri IJ, Rahawi KY, Sharif NB. UV-derivative of spectra of co-enzyme Q0 determination of trace elements. Iraqi Natl J Chem. 2011;43:424–35.Google Scholar
  33. 33.
    Al-Faraji G, Shanshal M. Determination of ubiquinone, 10 in ten different sorts of Iraqi dates “phoenix dactylefra” at different stages of fruit maturation Jordan. J Chem. 2010;5(4):389–400.Google Scholar
  34. 34.
    El-Leithy SE, Abdel-Rashid SR. Validation and application of Vierordt’s spectrophotometric method for simultaneous estimation of tamoxifen/coenzyme Q10 in their binary mixture and pharmaceutical dosage forms. Asian J Pharm Sci. 2016;11:318–25.CrossRefGoogle Scholar
  35. 35.
    Rullah K, Aluwi MFFM, Yamin BM, Abdul BMN, Wei LS, Ahmad S, et al. Inhibition of prostaglandin e2 production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation. Bioorg Med Chem Lett. 2014;24(16):3826–34. Scholar
  36. 36.
    Rullah K, Aluwi MFFM, Yamin BM, Baharuddin MS, Ismail NH, Teruna HY, et al. Molecular characterization, biological activity, and in silico study of 2-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-6-methoxy-4h-chromen-4-one as a novel selective cox-2 inhibitor. J Mol Struct. 2015;1081:51–61. Scholar
  37. 37.
    Wang MY, Yang YY, Heng PWS. Role of solvent in interactions between fatty acids-based formulations and lipids in porcine stratum corneum. J Control Release. 2004;94(1):207–16. Scholar
  38. 38.
    Komata Y, Kaneko A, Fujie T. In Vitro percutaneous absorption of thiamine disulfide through rat skin from a mixture of propylene glycol and fatty acid or its analog. Chem Pharm Bull. 1992;40(8):2173–6. Scholar
  39. 39.
    Komata Y, Kaneko A, Fujie T. Effect of fatty acid on the accumulation thiamine disulfide in rat skin. Biol Pharm Bull. 1994;17(5):705–8. Scholar
  40. 40.
    Pankaj K, Samir M. Enhancement of transdermal drug delivery via synergistic action of chemicals. Biochim Biophys Acta. 2009;1788:2362–73.CrossRefGoogle Scholar
  41. 41.
    Kadir R, Stempler D, Liron Z, Cohen S. Delivery of theophylline into excised human skin from alkanoic acid solutions: a push-pull mechansim. J Pharm Sci. 1987;76(10):774–9. Scholar
  42. 42.
    Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739–49. Scholar
  43. 43.
    Dai Y, Wang Q, Zhang X, Jia S, Zheng H, Feng D, et al. Molecular docking and QSAR study on steroidal compounds as aromatase inhibitors. Eur J Med Chem. 2010;45(12):5612–20. Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  1. 1.Center for Drug Delivery Research, Faculty of PharmacyUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
  2. 2.Lahore Pharmacy College (A Project of Lahore Medical and Dental College)LahorePakistan
  3. 3.Drug and Herbal Research Centre, Faculty of PharmacyUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
  4. 4.School of Pharmacy and Pharmaceutical SciencesCardiff UniversityCardiffUK

Personalised recommendations