PARACELLULAR AND FOLLICULAR PATHWAYS IMPLICATIONS OF PHYSICAL DIMENSIONS. Philip W. Wertz University of Iowa
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1 PARACELLULAR AND FOLLICULAR PATHWAYS IN TRANSDERMAL DRUG DELIVERY IMPLICATIONS OF PHYSICAL DIMENSIONS Philip W. Wertz University of Iowa Midwest SCC 2011
2 SHOULD COSMETIC INGREDIENTS CROSS THE SC? Cosmetics enhances beauty, superficial Drugs prevent, diagnose or treat disease or modify any structure or function of the body Cosmeceuticals???
3 RJ Schueplein & IH Blank PERMEABILITY OF THE SKIN Physiological Reviews 51: , PATHWAYS ACROSS BARRIER Hair follicles Sweat ducts Intercellular (SC) Transcellular (SC)
4 CONTENT AND COMPOSITION OF PIG EPIDERMAL CELLS GM GRAY & H YARDLEY
5 Ceramide Nomenclature N non-oh FA A alpha-oh FA O omega-oh FA S sphingosine P phytosphingosine H 6-OH-sphingosine E ester-linked FA Motta S et al. Ceramide composition of the psoriatic scale BBA 1993
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12 TRILAMELLAR LIPID STRUCTURES: Broad Narrow Broad d Lucent Bands Transmission electron micrographs displaying three, six, or nine lamellae within the intercellular space of stratum t corneum. Bar = 25 nm. Swartzendruber et al. 1989
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14 Molecular models of the intercellular lipid lamellae from epidermal stratum corneum Biochimica et Biophysica Acta (BBA) Biomembranes Volume 1616, Issue 2, 13 October 2003, Pages J. R. Hill and P. W. Wertz Dows Institute, University of Iowa, Iowa City, IA 52242, USA
15 Densitometer Tracing of the Six Band Pattern of Lamellae from the Intercellular Space of Stratum Corneum Shaded boxes represent the pattern of reduced ruthenium on the micrograph. The first set of tick marks beneath the boxes indicate the centers of the electron dense bands, while the lower set of tick marks indicate the centers of the lucent bands. (Hill & Wertz BBA 2003)
16 Molecular Model for the Three Band Pattern Between the Edges of Adjacent Corneocytes The shaded boxes represent the pattern of reduced ruthenium on a corresponding portion The shaded boxes represent the pattern of reduced ruthenium on a corresponding portion of a transmission electron micrograph. (Hill & Wertz BBA 2003)
17 Molecular Model of the Central Three Bands of the Nine Band dpattern Note the linoleate tails of acylceramide molecules in the central lamella. Shaded boxes represent the pattern of reduced ruthenium on a corresponding portion of a transmission electron micrograph. (Hill & Wertz BBA 2003)
18 Cryo EM of Vitreous Section of Human Skin with permission from Lars Norlen
19 INTERCELLULAR PATHWAY THROUGH STRATUM CORNEUM MK Nemanic & PM Elias In Situ Precipitation: A Novel Technique for Visualization of Permeability Pathways in Mammalian Stratum Corneum J Histochem Cytochem 28: , CA Squier & CA Lesh Penetration pathways of different compounds through epidermis and oral epithelium. J Oral Path 17: , 1988
20 SC EXPECTATIONS Small molecules could diffuse throughtheintercellular the space Vesicles and most particles (>13 nm) should not penetrate t the SC The smallest particles may penetrate into the intercellular spaces of the stratum corneum
21 Characteristics Favorable for Diffusion of Molecules l Across the SC MW 400 P o/w ~ 1 RH G J Hd ftsl ti f D R.H. Guy, J Hadraft Selection of Drug Candidates for Transdermal Drug Delivery Drugs and the Pharmaceutical Sciences 35:59 81, 1989
22 NANOPARTICLES < 100 nm diameter Liposomes Quantum Dots Nanoparticles (polymeric) Nanoemulsions TiO 2
23 LIPOSOMES AD Bangham, MM Standish, JC Watkins Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 13: , 1965 Cambridge Bob bhorne EM Gerald Weissmann lysosomes
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26 LIPOSOMAL DIAMETERS SUV nm LUV nm MLV , nm MVV nm
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29 CONVENTIONAL LIPOSOMES DO NOT PENETRATE SC NFH Ho, GM Ganesan, GL Flynn: Mechanism of topical ldli delivery of liposomallyencapsulated ll l drugs. J Control Release 2:61 65, 1985 S Zellmer, W, Pfeil, J Lasch: Interaction of phosphatidylcholine liposomes with the human stratum corneum. BiochimBiophys h Acta 1237: , 1995 M Kirjavainen, Aurtti, R Valjakka Koskela, J Kiesvaara, J Monkkonen: Liposome skin interactions and their effects on the skin permeation of drugs. Eur J Pharm Sci 7: , 1999
30 FLEXIBLE VESSICLES Transfersomes Niosomes Ethosomes
31 FLEXIBLE VESSICLES Transfersomes Niosomes Ethosomes
32 FLEXIBLE VESSICLES PENETRATE THROUGH THE INTERCELLULAR SPACES OF THE SC A Schatzlein, G Cevc In: G Cevc, F Paltauf (Eds.) Phospholipids h id characterization, i metabolism and novel applications, AOCS Press, Champaigne IL, 1993, pp JA Bouwstra, PL Honeywell Nguyen: Skin structure and mode of action of vesicles. Adv Drug Delivery Rev 54:S41 S55, S55, 2002 HA Benson: Elastic liposomes for transdermal drug HA Benson: Elastic liposomes for transdermal drug delivery. Methods in Molec Biol 605:77 86, 2010
33 JA Bouwstra PL Honeywell Gnuyen Advan Drug JA Bouwstra, PL Honeywell Gnuyen Advan Drug Delivery Rev 54S:S41 S55, 2002
34 NANOPARTICLE INTERACTIONS WITH THE STRATUM CORNEUM X Wu, B Biatry, C Cazeneuve, RH Guy: Drug delivery to the skin from sub micron polymeric particle formulations: influence of particle size and polymer hydrophobicity. Pharm Res 26: , 2009 JP Ryman Rasmussen, R JE Riviere, i NA Montiero Riviere: Penetration by quantum dots with ihdiverse physiochemical h i properties. Toxicol Sci 91: , 2006
35 X Wu, GJ Price, RH Guy Molec Pharmaceutics 6: , 2009
36 X Wu, GJ Price, RH Guy Molec Pharmaceutics 6: , 2009
37 l QUANTUM DOTS Mortensen et al. Nano Letters 8: , 2008
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40 DIAMETER OF HAIR FOLLICLE OPENINGS AT THE SKIN SURFACE Terminal Hair Follicles 172 +/ 70 µm Sebaceous Follicles 86 +/ 37 µm Vogt et al. Exp Dermatol 16: , 2007
41 FOLLICLES EXPECTATIONS Molecules could diffuse into hair follicles Particles or vesicles up to 50 µm Particles or vesicles up to 50 µm could penetrate
42 FOLLICULAR TRANSPORT ROUTE RESDEARCH PROGRESS AND FUTURE PERSPECTIVES F. Knorr, J Lademann, A Patzelt, W Sterry, U Blume Peytavi, A Vogt Eur J Biopharm 71: , 2009
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