Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Tocopheryl phosphate mixture (TPM) as a novel lipid-based transdermal drug delivery carrier: formulation and evaluation

Abstract

Transdermal drug delivery is a useful route of administration that avoids first-pass metabolism and more invasive delivery options. However, many drugs require enhancers to enable sufficient drug absorption to reach therapeutic effect. Alpha-tocopheryl phosphate (TP) and di-alpha-tocopheryl phosphate (T2P) are two phosphorylated forms of vitamin E which form tocopheryl phosphate mixture (TPM) when combined, and have been proposed to enhance the dermal and transdermal delivery of actives of interest. Here, we report the physicochemical characteristics and morphological properties of TPM formulations, including particle size, deformability and morphology, and its ability to facilitate the transport of carnosine, vitamin D3, CoEnzyme Q10 and caffeine into, and across, the skin. Results demonstrate that TPM self-assembles to form vesicular structures in hydroethanolic solutions ranging in mean size from 101 to 162 nM depending on the amount of TPM and ethanol present in the formulation. The ratio of TP to T2P in TPM formulations altered vesicle size and elasticity, with vesicles high in TP found to be more deformable than those rich in T2P. TPM produced a significant (p < 0.05) 2.4–3.4-fold increase in the absorption of carnosine, vitamin D3, CoEnzyme Q10 and caffeine into, or through, the skin. The TPM delivery platform was able to deliver a diverse range of actives with differing size and solubility profiles and therefore has significant potential to expand the number and types of drugs available for topical application and transdermal delivery.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. 1.

    Akhtar N. Vesicles: a recently developed novel carrier for enhanced topical drug delivery. Curr Drug Deliv. 2014;11(1):87–97.

  2. 2.

    Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261–8. doi:10.1038/nbt.1504.

  3. 3.

    Jain A, Jain P, Kurmi J, Jain D, Jain R, Chandel S, et al. Novel strategies for effective transdermal drug delivery: a review. Crit Rev Ther Drug Carrier Syst. 2014;31(3):219–72.

  4. 4.

    Honeywell-Nguyen PL, Bouwstra JA. Vesicles as a tool for transdermal and dermal delivery. Drug Discov Today Technol 2005;2(1):67–74. doi:10.1016/j.ddtec.2005.05.003.

  5. 5.

    Paudel KS, Milewski M, Swadley CL, Brogden NK, Ghosh P, Stinchcomb AL. Challenges and opportunities in dermal/transdermal delivery. Ther Deliv. 2010;1(1):109–31.

  6. 6.

    Alexander A, Dwivedi S, Ajazuddin Giri TK, Saraf S, Saraf S et al. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release 2012;164(1):26–40. doi:10.1016/j.jconrel.2012.09.017.

  7. 7.

    Kligman AM. Skin permeability: dermatologic aspects of transdermal drug delivery. Am Heart J. 1984;108(1):200–6.

  8. 8.

    Touitou E, Dayan N, Bergelson L, Godin B, Eliaz M. Ethosomes - novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. Journal of controlled release: official journal of the Controlled Release Society. 2000;65(3):403–18.

  9. 9.

    Benson HA. Transfersomes for transdermal drug delivery. Expert Opin Drug Deliv. 2006;3(6):727–37. doi:10.1517/17425247.3.6.727.

  10. 10.

    Benson HA. Elastic liposomes for topical and transdermal drug delivery. Methods Mol Biol. 2010;605:77–86. doi:10.1007/978-1-60327-360-2_4.

  11. 11.

    Elsayed MM, Abdallah OY, Naggar VF, Khalafallah NM. Deformable liposomes and ethosomes: mechanism of enhanced skin delivery. Int J Pharm. 2006;322(1–2):60–6. doi:10.1016/j.ijpharm.2006.05.027.

  12. 12.

    Elsayed MM, Abdallah OY, Naggar VF, Khalafallah NM. Deformable liposomes and ethosomes as carriers for skin delivery of ketotifen. Die Pharm. 2007;62(2):133–7.

  13. 13.

    Munteanu A, Zingg JM, Ogru E, Libinaki R, Gianello R, West S, et al. Modulation of cell proliferation and gene expression by alpha-tocopheryl phosphates: relevance to atherosclerosis and inflammation. Biochem Biophys Res Commun. 2004;318(1):311–6. doi:10.1016/j.bbrc.2004.04.028.

  14. 14.

    Song YK, Kim CK. Topical delivery of low-molecular-weight heparin with surface-charged flexible liposomes. Biomaterials. 2006;27(2):271–80. doi:10.1016/j.biomaterials.2005.05.097.

  15. 15.

    Srisuk P, Thongnopnua P, Raktanonchai U, Kanokpanont S. Physico-chemical characteristics of methotrexate-entrapped oleic acid-containing deformable liposomes for in vitro transepidermal delivery targeting psoriasis treatment. Int J Pharm. 2012;427(2):426–34. doi:10.1016/j.ijpharm.2012.01.045.

  16. 16.

    Trotta M, Peira E, Carlotti ME, Gallarate M. Deformable liposomes for dermal administration of methotrexate. Int J Pharm. 2004;270(1–2):119–25.

  17. 17.

    Cevc G, Gebauer D, Stieber J, Schatzlein A, Blume G. Ultraflexible vesicles, transfersomes, have an extremely low pore penetration resistance and transport therapeutic amounts of insulin across the intact mammalian skin. Biochim Biophys Acta. 1998;1368(2):201–15.

  18. 18.

    El Maghraby GM, Williams AC, Barry BW. Skin delivery of oestradiol from deformable and traditional liposomes: mechanistic studies. J Pharm Pharmacol. 1999;51(10):1123–34.

  19. 19.

    El Maghraby GM, Williams AC, Barry BW. Skin delivery of oestradiol from lipid vesicles: importance of liposome structure. Int J Pharm. 2000;204(1–2):159–69.

  20. 20.

    Gillet A, Compere P, Lecomte F, Hubert P, Ducat E, Evrard B, et al. Liposome surface charge influence on skin penetration behaviour. Int J Pharm. 2011;411(1–2):223–31. doi:10.1016/j.ijpharm.2011.03.049.

  21. 21.

    Manosroi A, Khanrin P, Lohcharoenkal W, Werner RG, Gotz F, Manosroi W, et al. Transdermal absorption enhancement through rat skin of gallidermin loaded in niosomes. Int J Pharm. 2010;392(1–2):304–10. doi:10.1016/j.ijpharm.2010.03.064.

  22. 22.

    Sinico C, Manconi M, Peppi M, Lai F, Valenti D, Fadda AM. Liposomes as carriers for dermal delivery of tretinoin: in vitro evaluation of drug permeation and vesicle-skin interaction. J Control Release: Off J Control Release Soc. 2005;103(1):123–36. doi:10.1016/j.jconrel.2004.11.020.

  23. 23.

    Traber MG, Sies H. Vitamin E in humans: demand and delivery. Annu Rev Nutr. 1996;16:321–47. doi:10.1146/annurev.nu.16.070196.001541.

  24. 24.

    Gensler HL, Magdaleno M. Topical vitamin E inhibition of immunosuppression and tumorigenesis induced by ultraviolet irradiation. Nutr Cancer. 1991;15(2):97–106. doi:10.1080/01635589109514117.

  25. 25.

    Lopez-Torres M, Thiele JJ, Shindo Y, Han D, Packer L. Topical application of alpha-tocopherol modulates the antioxidant network and diminishes ultraviolet-induced oxidative damage in murine skin. Br J Dermatol. 1998;138(2):207–15.

  26. 26.

    Trevithick JR, Xiong H, Lee S, Shum DT, Sanford SE, Karlik SJ, et al. Topical tocopherol acetate reduces post-UVB, sunburn-associated erythema, edema, and skin sensitivity in hairless mice. Arch Biochem Biophys. 1992;296(2):575–82.

  27. 27.

    Trivedi JS, Krill SL, Fort JJ. Vitamin E as a human skin penetration enhancer. Eur J Pharmaceut Sci. 1995;3:241–3.

  28. 28.

    Gavin P, Griffey A, Gianello R, Kennedy N, Keah HH, Cottrell J, et al. Transdermal delivery of various molecules in vivo using alpha-tocopheryl phosphate. Drug delivery. Technology. 2008;9(9):34–41.

  29. 29.

    Gianello R, Libinaki R, Azzi A, Gavin PD, Negis Y, Zingg JM, et al. Alpha-tocopheryl phosphate: a novel, natural form of vitamin E. Free Radic Biol Med. 2005;39(7):970–6. doi:10.1016/j.freeradbiomed.2005.05.016.

  30. 30.

    Mukherjee S, Lekli I, Das M, Azzi A, Das DK. Cardioprotection with alpha-tocopheryl phosphate: amelioration of myocardial ischemia reperfusion injury is linked with its ability to generate a survival signal through Akt activation. Biochim Biophys Acta. 2008;1782(9):498–503. doi:10.1016/j.bbadis.2008.05.002.

  31. 31.

    Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res. 2004;21(2):201–30.

  32. 32.

    Honeywell-Nguyen PL, Frederik PM, Bomans PH, Junginger HE, Bouwstra JA. Transdermal delivery of pergolide from surfactant-based elastic and rigid vesicles: characterization and in vitro transport studies. Pharm Res. 2002;19(7):991–7.

  33. 33.

    Verma DD, Verma S, Blume G, Fahr A. Liposomes increase skin penetration of entrapped and non-entrapped hydrophilic substances into human skin: a skin penetration and confocal laser scanning microscopy study. Eur J Pharm Biopharm: Off J Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2003;55(3):271–7.

  34. 34.

    Subongkot T, Pamornpathomkul B, Rojanarata T, Opanasopit P, Ngawhirunpat T. Investigation of the mechanism of enhanced skin penetration by ultradeformable liposomes. Int J Nanomedicine. 2014;9:3539–50. doi:10.2147/IJN.S65287.

  35. 35.

    Moghadam SH, Saliaj E, Wettig SD, Dong C, Ivanova MV, Huzil JT, et al. Effect of chemical permeation enhancers on stratum corneum barrier lipid organizational structure and interferon alpha permeability. Mol Pharm. 2013;10(6):2248–60. doi:10.1021/mp300441c.

  36. 36.

    Aungst BJ. Absorption enhancers: applications and advances. AAPS J. 2012;14(1):10–8. doi:10.1208/s12248-011-9307-4.

  37. 37.

    Lopes LB, Garcia MT, Bentley MV. Chemical penetration enhancers. Ther Deliv. 2015;6(9):1053–61. doi:10.4155/tde.15.61.

  38. 38.

    Nakayama S, Katoh EM, Tsuzuki T, Kobayashi S. Protective effect of alpha-tocopherol-6-O-phosphate against ultraviolet B-induced damage in cultured mouse skin. J Invest Dermatol. 2003;121(2):406–11. doi:10.1046/j.1523-1747.2003.12351.x.

  39. 39.

    Ogru E, Libinaki R, Gianello R, West S, Munteanu A, Zingg JM, et al. Modulation of cell proliferation and gene expression by alpha-tocopheryl phosphates: relevance to atherosclerosis and inflammation. Ann N Y Acad Sci. 2004;1031:405–11. doi:10.1196/annals.1331.058.

  40. 40.

    Libinaki R, Tesanovic S, Heal A, Nikolovski B, Vinh A, Widdop RE, et al. Effect of tocopheryl phosphate on key biomarkers of inflammation: implication in the reduction of atherosclerosis progression in a hypercholesterolaemic rabbit model. Clin Exp Pharmacol Physiol. 2010;37(5–6):587–92. doi:10.1111/j.1440-1681.2010.05356.x.

  41. 41.

    Rerek ME, Mills OH, Wood R, Verdicchio R, West S. Disodium Lauriminodipropionate tocopheryl phosphates: a potent new anti-inflammatory. Cosmet Toiletries. 2003;118(7):63–8.

Download references

Acknowledgments

We thank Dr. Nicholas Kennedy, Mr. Giacinto Gaetano and Dr. Billie Nikolovski for the conduct of in vitro permeation studies and Ms. Gisela Ramirez and Mr. Mathew Parsons for the conduct of HPLC analysis. Lynne Waddington (CSIRO, Australia) is also thanked for the provision of cryo-TEM services.

Writing assistance was provided by Gemma Williams, Biosector 2.

Author information

Correspondence to Paul D. Gavin.

Ethics declarations

Conflict of interest

Paul Gavin, Mahmoud El-Tamimy and Hooi Hong Keah are employees of Phosphagenics Limited, a company commercialising TPM for use in transdermal drug delivery.

Ben J. Boyd declares that he has no conflict of interest.

All institutional and national guidelines for the care and use of laboratory animals were followed.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gavin, P.D., El-Tamimy, M., Keah, H.H. et al. Tocopheryl phosphate mixture (TPM) as a novel lipid-based transdermal drug delivery carrier: formulation and evaluation. Drug Deliv. and Transl. Res. 7, 53–65 (2017). https://doi.org/10.1007/s13346-016-0331-x

Download citation

Keywords

  • Transdermal
  • Drug delivery
  • Tocopheryl phosphate mixture
  • TPM
  • Tocopherol
  • Vitamin E