The long-term objective of this research is to extend significantly the range of drugs for which transdermal delivery is a viable administration route. In particular, experiments are described to explore the potential of the skin as a systemic portal for new peptide and protein therapeutic agents emerging from the biotechnology industry. The focus of the proposal is to determine the feasibility and optimization of skin penetration enhancement by iontophoresis - the facilitation of (ionizable drug delivery across the skin by an applied electrical potential.
The specific aims are to address the basic questions: By what mechanism(s) does iontophoresis enhance op iontophoresis dependent upon, and constrained by, penetrant properties? Iontophoresis concentrates attention on drug transport across the stratum corneum (SC, the outermost and least permeable skin layer) via """"""""pores"""""""". The predominantly in vitro work proposed will: (a) use fluorescent probes and confocal microscopy to visualize routes of ionic flow across SC, (b) vectorize ionic transport with the vibrating probe electrode technique, (c) determine basic penetrant structure/properties-iontophoretic enhancement relationships, (d) develop the theoretical understanding of iontophoretic enhancement. Model penetrants for these experiments will be specifically designed peptide derivatives. Overall, a detailed examination of skin transport promotion by electrical means is outlined. In particular, the feasibility and optimization of peptide/small protein delivery, for which few acceptable alternatives exist, will be addressed.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD027839-03
Application #
3329508
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1990-08-01
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hirvonen, J; Guy, R H (1998) Transdermal iontophoresis: modulation of electroosmosis by polypeptide. J Control Release 50:283-9
Langkjaer, L; Brange, J; Grodsky, G M et al. (1998) Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment. J Control Release 51:47-56
Turner, N G; Cullander, C; Guy, R H (1998) Determination of the pH gradient across the stratum corneum. J Investig Dermatol Symp Proc 3:110-3
Turner, N G; Guy, R H (1998) Visualization and quantitation of iontophoretic pathways using confocal microscopy. J Investig Dermatol Symp Proc 3:136-42
Kalia, Y N; Nonato, L B; Lund, C H et al. (1998) Development of skin barrier function in premature infants. J Invest Dermatol 111:320-6
Turner, N G; Kalia, Y N; Guy, R H (1997) The effect of current on skin barrier function in vivo: recovery kinetics post-iontophoresis. Pharm Res 14:1252-7
Turner, N G; Ferry, L; Price, M et al. (1997) Iontophoresis of poly-L-lysines: the role of molecular weight? Pharm Res 14:1322-31
Turner, N G; Guy, R H (1997) Iontophoretic transport pathways: dependence on penetrant physicochemical properties. J Pharm Sci 86:1385-9
Hirvonen, J; Guy, R H (1997) Iontophoretic delivery across the skin: electroosmosis and its modulation by drug substances. Pharm Res 14:1258-63
Prausnitz, M R; Gimm, J A; Guy, R H et al. (1996) Imaging regions of transport across human stratum corneum during high-voltage and low-voltage exposures. J Pharm Sci 85:1363-70

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