The Increasing Importance of the Hair Follicle Route in Dermal and Transdermal Drug Delivery

Chapter

Abstract

The enhancement of percutaneous penetration of topically applied substances and drugs is gaining more and more importance as dermal application allows site-specific and dose-adapted therapy bypassing gastrointestinal metabolism and is mostly associated with fewer side effects. In addition to the intercellular penetration pathway, also the advantages of the follicular penetration pathway have been recently revealed. Due to its architectural structure, the hair follicle is predestined as a penetration and reservoir organ as it provides diminished barrier properties in its lower infundibulum allowing fast access for smaller substances into the deeper viable skin layers and thus into the circulation, on the one hand, and storaging capacities of several days for larger substances such as particulate substances, which were shown to penetrate especially deeply into the hair follicles, on the other hand.

Promising new concepts to combine these advantageous follicular attributes involve the application of external or internal stimuli for controlled drug release from particles. The particles only serve to transport the drug deeply into the hair follicle where it is released by a triggered signal and can then penetrate independently into the deeper skin layers through the follicular barrier. The improvement of these approaches will certainly be one of the main focuses of future research on follicular penetration.

Keywords

Follicular penetration Hair follicle Triggered release Infundibulum Particulate substances Transfollicular penetration 
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Notes

Acknowledgments

We would like to thank the Foundation “Skin Physiology” of the Donor Association for German Science and Humanities for financial support. Parts of this work were realized within the BMBF project “Topische Vakzinierung mit funktionalen Nanopartikeln.” The authors acknowledge that this work was supported by a grant funded by the German Ministry of Education and Research (BMBF, grant no, 13N9197). Furthermore, we thank Ulrich Schäfer and Claus-Michael Lehr (University of Saarbrücken) for providing particle preparations and Reinhardt Renneberg (Hong Kong University of Science and Technology) for providing the particles for the triggered release experiments.

References

  1. Barry BW (2002) Drug delivery routes in skin: a novel approach. Adv Drug Deliv Rev 54(Suppl 1):S31–S40PubMedCrossRefGoogle Scholar
  2. Blume-Peytavi U, Vogt A (2011) Human hair follicle: reservoir function and selective targeting. Br J Dermatol 165(Suppl 2):13–17. doi: 10.1111/j.1365-2133.2011.10572.x PubMedCrossRefGoogle Scholar
  3. Blume-Peytavi U, Massoudy L, Patzelt A, Lademann J, Dietz E, Rasulev U, Garcia Bartels N (2010) Follicular and percutaneous penetration pathways of topically applied minoxidil foam. Eur J Pharm Biopharm 76(3):450–453. doi: 10.1016/j.ejpb.2010.06.010 PubMedCrossRefGoogle Scholar
  4. Brazel CS (2009) Magnetothermally-responsive nanomaterials: combining magnetic nanostructures and thermally-sensitive polymers for triggered drug release. Pharm Res 26(3):644–656. doi: 10.1007/s11095-008-9773-2 PubMedCrossRefGoogle Scholar
  5. Caspers PJ, Lucassen GW, Puppels GJ (2003) Combined in vivo confocal Raman spectroscopy and confocal microscopy of human skin. Biophys J 85(1):572–580. doi: 10.1016/S0006-3495(03)74501-9 PubMedCentralPubMedCrossRefGoogle Scholar
  6. Dixit N, Bali V, Baboota S, Ahuja A, Ali J (2007) Iontophoresis – an approach for controlled drug delivery: a review. Curr Drug Deliv 4(1):1–10PubMedGoogle Scholar
  7. Fabin B, Touitou E (1991) Localization of lipophilic molecules penetrating rat skin in vivo by quantitative autoradiography. Int J Pharm 74(1):59–65. doi: 10.1016/0378-5173(91)90408-G CrossRefGoogle Scholar
  8. Helmstadter A (2011) Endermatic, epidermatic, enepidermatic-the early history of penetration enhancers. Int J Pharm 416(1):12–15. doi: 10.1016/j.ijpharm.2011.06.005 PubMedCrossRefGoogle Scholar
  9. Hu SH, Liu TY, Huang HY, Liu DM, Chen SY (2008) Magnetic-sensitive silica nanospheres for controlled drug release. Langmuir 24(1):239–244. doi: 10.1021/la701570z PubMedCrossRefGoogle Scholar
  10. Huang SL (2008) Liposomes in ultrasonic drug and gene delivery. Adv Drug Deliv Rev 60(10):1167–1176. doi: 10.1016/j.addr.2008.03.003 PubMedCrossRefGoogle Scholar
  11. Huang Y, Yu F, Park YS, Wang J, Shin MC, Chung HS, Yang VC (2010) Co-administration of protein drugs with gold nanoparticles to enable percutaneous delivery. Biomaterials 31(34):9086–9091. doi: 10.1016/j.biomaterials.2010.08.046 PubMedCentralPubMedCrossRefGoogle Scholar
  12. Krause K, Foitzik K (2006) Biology of the hair follicle: the basics. Semin Cutan Med Surg 25(1):2–10. doi: 10.1016/j.sder.2006.01.002 PubMedCrossRefGoogle Scholar
  13. Krishnan G, Edwards J, Chen Y, Benson HA (2010) Enhanced skin permeation of naltrexone by pulsed electromagnetic fields in human skin in vitro. J Pharm Sci 99(6):2724–2731. doi: 10.1002/jps.22024 PubMedGoogle Scholar
  14. Labouta HI, Schneider M (2013) Interaction of inorganic nanoparticles with the skin barrier: current status and critical review. Nanomedicine 9(1):39–54. doi: 10.1016/j.nano.2012.04.004 PubMedCrossRefGoogle Scholar
  15. Labouta HI, el-Khordagui LK, Kraus T, Schneider M (2011) Mechanism and determinants of nanoparticle penetration through human skin. Nanoscale 3(12):4989–4999. doi: 10.1039/c1nr11109d PubMedCrossRefGoogle Scholar
  16. Lademann J, Richter H, Schaefer UF, Blume-Peytavi U, Teichmann A, Otberg N, Sterry W (2006) Hair follicles – a long-term reservoir for drug delivery. Skin Pharmacol Physiol 19(4):232–236. doi: 10.1159/000093119 PubMedCrossRefGoogle Scholar
  17. Lademann J, Richter H, Teichmann A, Otberg N, Blume-Peytavi U, Luengo J, Weiss B, Schaefer UF, Lehr CM, Wepf R, Sterry W (2007) Nanoparticles–an efficient carrier for drug delivery into the hair follicles. Eur J Pharm Biopharm 66(2):159–164. doi:10.1016/j.ejpb.2006.10.019 10.1016/j.ejpb.2006.10.019 PubMedCrossRefGoogle Scholar
  18. Lademann J, Patzelt A, Richter H, Antoniou C, Sterry W, Knorr F (2009) Determination of the cuticula thickness of human and porcine hairs and their potential influence on the penetration of nanoparticles into the hair follicles. J Biomed Opt 14(2):021014. doi: 10.1117/1.3078813 PubMedCrossRefGoogle Scholar
  19. Lademann J, Richter H, Meinke M, Sterry W, Patzelt A (2010) Which skin model is the most appropriate for the investigation of topically applied substances into the hair follicles? Skin Pharmacol Physiol 23(1):47–52. doi: 10.1159/000257263 PubMedCrossRefGoogle Scholar
  20. Lai CY, Trewyn BG, Jeftinija DM, Jeftinija K, Xu S, Jeftinija S, Lin VS (2003) A mesoporous silica nanosphere-based carrier system with chemically removable CdS nanoparticle caps for stimuli-responsive controlled release of neurotransmitters and drug molecules. J Am Chem Soc 125(15):4451–4459. doi: 10.1021/ja028650l PubMedCrossRefGoogle Scholar
  21. Lange-Asschenfeldt B, Marenbach D, Lang C, Patzelt A, Ulrich M, Maltusch A, Terhorst D, Stockfleth E, Sterry W, Lademann J (2011) Distribution of bacteria in the epidermal layers and hair follicles of the human skin. Skin Pharmacol Physiol 24(6):305–311. doi: 10.1159/000328728 PubMedCrossRefGoogle Scholar
  22. Lawson LB, Freytag LC, Clements JD (2007) Use of nanocarriers for transdermal vaccine delivery. Clin Pharmacol Ther 82(6):641–643. doi: 10.1038/sj.clpt.6100425 PubMedCrossRefGoogle Scholar
  23. Mak WC, Richter H, Patzelt A, Sterry W, Lai KK, Renneberg R, Lademann J (2011) Drug delivery into the skin by degradable particles. Eur J Pharm Biopharm 79(1):23–27. doi: 10.1016/j.ejpb.2011.03.021 PubMedCrossRefGoogle Scholar
  24. Mak WC, Patzelt A, Richter H, Renneberg R, Lai KK, Ruhl E, Sterry W, Lademann J (2012) Triggering of drug release of particles in hair follicles. J Control Release 160(3):509–514. doi: 10.1016/j.jconrel.2012.04.007 PubMedCrossRefGoogle Scholar
  25. Meidan VM (2010) Methods for quantifying intrafollicular drug delivery: a critical appraisal. Expert Opin Drug Deliv 7(9):1095–1108. doi: 10.1517/17425247.2010.503954 PubMedCrossRefGoogle Scholar
  26. Morgan AJ, Lewis G, Van den Hoven WE, Akkerboom PJ (1993) The effect of zinc in the form of erythromycin-zinc complex (Zineryt lotion) and zinc acetate on metallothionein expression and distribution in hamster skin. Br J Dermatol 129(5):563–570PubMedCrossRefGoogle Scholar
  27. Mortensen LJ, Oberdorster G, Pentland AP, Delouise LA (2008) In vivo skin penetration of quantum dot nanoparticles in the murine model: the effect of UVR. Nano Lett 8(9):2779–2787. doi: 10.1021/nl801323y PubMedCentralPubMedCrossRefGoogle Scholar
  28. Ohyama M (2007) Hair follicle bulge: a fascinating reservoir of epithelial stem cells. J Dermatol Sci 46(2):81–89. doi: 10.1016/j.jdermsci.2006.12.002 PubMedCrossRefGoogle Scholar
  29. Otberg N, Richter H, Knuttel A, Schaefer H, Sterry W, Lademann J (2004a) Laser spectroscopic methods for the characterization of open and closed follicles. Laser Phys Lett 1(1):46–49. doi: 10.1002/lapl.200310011 CrossRefGoogle Scholar
  30. Otberg N, Richter H, Schaefer H, Blume-Peytavi U, Sterry W, Lademann J (2004b) Variations of hair follicle size and distribution in different body sites. J Invest Dermatol 122(1):14–19. doi: 10.1046/j.0022-202X.2003.22110.x PubMedCrossRefGoogle Scholar
  31. Otberg N, Patzelt A, Rasulev U, Hagemeister T, Linscheid M, Sinkgraven R, Sterry W, Lademann J (2008) The role of hair follicles in the percutaneous absorption of caffeine. Br J Clin Pharmacol 65(4):488–492. doi: 10.1111/j.1365-2125.2007.03065.x PubMedCentralPubMedCrossRefGoogle Scholar
  32. Paliwal S, Menon GK, Mitragotri S (2006) Low-frequency sonophoresis: ultrastructural basis for stratum corneum permeability assessed using quantum dots. J Invest Dermatol 126(5):1095–1101. doi: 10.1038/sj.jid.5700248 PubMedCrossRefGoogle Scholar
  33. Papakostas D, Rancan F, Sterry W, Blume-Peytavi U, Vogt A (2011) Nanoparticles in dermatology. Arch Dermatol Res 303(8):533–550. doi: 10.1007/s00403-011-1163-7 PubMedCrossRefGoogle Scholar
  34. Patzelt A, Richter H, Buettemeyer R, Huber HJ, Blume-Peytavi U, Sterry W, Lademann J (2008) Differential stripping demonstrates a significant reduction of the hair follicle reservoir in vitro compared to in vivo. Eur J Pharm Biopharm 70(1):234–238. doi: 10.1016/j.ejpb.2008.02.024 PubMedCrossRefGoogle Scholar
  35. Patzelt A, Richter H, Knorr F, Schafer U, Lehr CM, Dahne L, Sterry W, Lademann J (2011) Selective follicular targeting by modification of the particle sizes. J Control Release 150(1):45–48. doi:10.1016/j.jconrel.2010.11.015 10.1016/j.jconrel.2010.11.015 PubMedCrossRefGoogle Scholar
  36. Pissuwan D, Niidome T, Cortie MB (2011) The forthcoming applications of gold nanoparticles in drug and gene delivery systems. J Control Release 149(1):65–71. doi: 10.1016/j.jconrel.2009.12.006 PubMedCrossRefGoogle Scholar
  37. Ridolfi DM, Marcato PD, Justo GZ, Cordi L, Machado D, Duran N (2012) Chitosan-solid lipid nanoparticles as carriers for topical delivery of tretinoin. Colloids Surf B: Biointerfaces 93:36–40. doi: 10.1016/j.colsurfb.2011.11.051 PubMedCrossRefGoogle Scholar
  38. Rogers GE (2004) Hair follicle differentiation and regulation. Int J Dev Biol 48(2–3):163–170. doi: 10.1387/ijdb.021587gr PubMedCrossRefGoogle Scholar
  39. Rolland A, Wagner N, Chatelus A, Shroot B, Schaefer H (1993) Site-specific drug delivery to pilosebaceous structures using polymeric microspheres. Pharm Res 10(12):1738–1744PubMedCrossRefGoogle Scholar
  40. Schaefer H, Lademann J (2001) The role of follicular penetration. A differential view. Skin Pharmacol Appl Skin Physiol 14(Suppl 1):23–27, doi: 56386PubMedCrossRefGoogle Scholar
  41. Senzui M, Tamura T, Miura K, Ikarashi Y, Watanabe Y, Fujii M (2010) Study on penetration of titanium dioxide (TiO(2)) nanoparticles into intact and damaged skin in vitro. J Toxicol Sci 35(1):107–113PubMedCrossRefGoogle Scholar
  42. Shim J, Seok Kang H, Park WS, Han SH, Kim J, Chang IS (2004) Transdermal delivery of minoxidil with block copolymer nanoparticles. J Control Release 97(3):477–484. doi: 10.1016/j.jconrel.2004.03.028 PubMedCrossRefGoogle Scholar
  43. Teichmann A, Jacobi U, Ossadnik M, Richter H, Koch S, Sterry W, Lademann J (2005) Differential stripping: determination of the amount of topically applied substances penetrated into the hair follicles. J Invest Dermatol 125(2):264–269. doi: 10.1111/j.0022-202X.2005.23779.x PubMedGoogle Scholar
  44. Teichmann A, Otberg N, Jacobi U, Sterry W, Lademann J (2006) Follicular penetration: development of a method to block the follicles selectively against the penetration of topically applied substances. Skin Pharmacol Physiol 19(4):216–223. doi: 10.1159/000093117 PubMedCrossRefGoogle Scholar
  45. Thiboutot D (2004) Regulation of human sebaceous glands. J Invest Dermatol 123(1):1–12. doi: 10.1111/j.1523-1747.2004.t01-2-.x PubMedCrossRefGoogle Scholar
  46. Toll R, Jacobi U, Richter H, Lademann J, Schaefer H, Blume-Peytavi U (2004) Penetration profile of microspheres in follicular targeting of terminal hair follicles. J Invest Dermatol 123(1):168–176. doi: 10.1111/j.0022-202X.2004.22717.x PubMedCrossRefGoogle Scholar
  47. Tsujimoto H, Hara K, Tsukada Y, Huang CC, Kawashima Y, Arakaki M, Okayasu H, Mimura H, Miwa N (2007) Evaluation of the permeability of hair growing ingredient encapsulated PLGA nanospheres to hair follicles and their hair growing effects. Bioorg Med Chem Lett 17(17):4771–4777. doi: 10.1016/j.bmcl.2007.06.057 PubMedCrossRefGoogle Scholar
  48. Ulmer M, Patzelt A, Vergou T, Richter H, Muller G, Kramer A, Sterry W, Czaika V, Lademann J (2012) In vivo investigation of the efficiency of a nanoparticle-emulsion containing polihexanide on the human skin. Eur J Pharm Biopharm. doi: 10.1016/j.ejpb.2012.11.011 PubMedGoogle Scholar
  49. Upadhyay P (2006) Enhanced transdermal-immunization with diphtheria-toxoid using local hyperthermia. Vaccine 24(27–28):5593–5598. doi: 10.1016/j.vaccine.2006.04.039 PubMedCrossRefGoogle Scholar
  50. Vogt A, Hadam S, Heiderhoff M, Audring H, Lademann J, Sterry W, Blume-Peytavi U (2007) Morphometry of human terminal and vellus hair follicles. Exp Dermatol 16(11):946–950. doi: 10.1111/j.1600-0625.2007.00602.x PubMedCrossRefGoogle Scholar
  51. Vogt A, Mahe B, Costagliola D, Bonduelle O, Hadam S, Schaefer G, Schaefer H, Katlama C, Sterry W, Autran B, Blume-Peytavi U, Combadiere B (2008) Transcutaneous anti-influenza vaccination promotes both CD4 and CD8 T cell immune responses in humans. J Immunol 180(3):1482–1489PubMedCrossRefGoogle Scholar
  52. Yamashita S, Fukushima H, Niidome Y, Mori T, Katayama Y, Niidome T (2011) Controlled-release system mediated by a retro Diels-Alder reaction induced by the photothermal effect of gold nanorods. Langmuir 27(23):14621–14626. doi: 10.1021/la2036746 PubMedCrossRefGoogle Scholar
  53. Zhang LW, Monteiro-Riviere NA (2008) Assessment of quantum dot penetration into intact, tape-stripped, abraded and flexed rat skin. Skin Pharmacol Physiol 21(3):166–180. doi: 10.1159/000131080 PubMedCrossRefGoogle Scholar
  54. Zhu Y, Shi J, Shen W, Dong X, Feng J, Ruan M, Li Y (2005) Stimuli-responsive controlled drug release from a hollow mesoporous silica sphere/polyelectrolyte multilayer core-shell structure. Angew Chem Int Ed Engl 44(32):5083–5087. doi:10.1002/anie.200501500 10.1002/anie.200501500 PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Dermatology, Venereology and AllergologyCharité – Universitätsmedizin Berlin, Center of Experimental and Applied Cutaneous PhysiologyBerlinGermany

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