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.

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References

  1. 1.

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

    CAS  Article  PubMed  Google Scholar 

  2. 2.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

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

    CAS  Article  Google Scholar 

  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.

    Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

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

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

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

    CAS  Article  PubMed  Google Scholar 

  37. 37.

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

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Article  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

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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.

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Correspondence to Paul D. Gavin.

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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.

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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

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Keywords

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