The long-term objective of the research proposed in this revised Competing Renewal application is to attain a detailed understanding of skin barrier function so that the transdermal delivery of suitable drugs may be enhanced and optimized. Because of a continued need for safe and efficacious agents to regulate fertility, applications of the basic mechanistic studies described will ultimately address the transdermal delivery of contraceptive steroids.
The specific aims of the project are: [1] To determine, in vivo in man, using reflectance infrared (IR) spectroscopy, the dependence of skin (and, particularly, stratum corneum (SC)) permeation on drug structure and properties. [2] To evaluate, (again) in vivo using reflectance IR, the effects of 'penetration enhancers' on SC barrier function and drug permeability. 13] To interpret the IR data, together with other biophysical measurements, to determine the mechanism(s) of enhancer action on the SC. [4] To develop and optimize a human keratinocyte, 'air/liquid', culture system, which mimics epidermal barrier function physically, chemically, and morphologically. [5] To establish that (i) the biophysical properties, and (ii) the permeability, of the SC of the culture are comparable to those of human skin. [6) To study the concurrent transport and metabolism of drugs in the keratinocyte culture system. The principal experimental strategies involve: (a) the use of attenuated total reflectance IR spectroscopy to probe, in vivo, the biophysical basis of SC barrier function, the pathways of drug permeation across the SC, and the mechanism(s) of penetration enhancer action; and (b) the development of an 'epidermal-equivalent' keratinocyte culture system, which resembles the in vivo tissue in morphology, SC lipid composition, biochemistry, metabolism, and barrier function. Studies have been designed, therefore, to examine, determine, and correlate the physical, chemical and biological parameters which define skin (and, specifically, SC) barrier function. Ultimately, the research proposed is intended to answer the following questions: (1) What are the mechanism(s) (pathways) of transdermal penetration? (2) How is the cutaneous barrier to drug permeation constructed? What are the key chemical and biophysical constituents and requirements of a functional barrier? (3) Is it possible to reversibly subvert the SC barrier with penetration enhancers? How do these agents work? (4) Can the basic information derived be applied to solving the important problem of contraceptive steroid delivery by the transdermal route?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD023010-05A2
Application #
3323027
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1987-04-01
Project End
1996-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
5
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
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
Pirot, F; Kalia, Y N; Stinchcomb, A L et al. (1997) Characterization of the permeability barrier of human skin in vivo. Proc Natl Acad Sci U S A 94:1562-7
Tsai, J C; Guy, R H; Thornfeldt, C R et al. (1996) Metabolic approaches to enhance transdermal drug delivery. 1. Effect of lipid synthesis inhibitors. J Pharm Sci 85:643-8
Kalia, Y N; Pirot, F; Guy, R H (1996) Homogeneous transport in a heterogeneous membrane: water diffusion across human stratum corneum in vivo. Biophys J 71:2692-700
Gay, C L; Guy, R H; Golden, G M et al. (1994) Characterization of low-temperature (i.e., < 65 degrees C) lipid transitions in human stratum corneum. J Invest Dermatol 103:233-9
Cullander, C (1994) Imaging in the far-red with electronic light microscopy: requirements and limitations. J Microsc 176:281-6
Higo, N; Naik, A; Bommannan, D B et al. (1993) Validation of reflectance infrared spectroscopy as a quantitative method to measure percutaneous absorption in vivo. Pharm Res 10:1500-6
Bommannan, D; Menon, G K; Okuyama, H et al. (1992) Sonophoresis. II. Examination of the mechanism(s) of ultrasound-enhanced transdermal drug delivery. Pharm Res 9:1043-7
Bommannan, D; Okuyama, H; Stauffer, P et al. (1992) Sonophoresis. I. The use of high-frequency ultrasound to enhance transdermal drug delivery. Pharm Res 9:559-64
Potts, R O; Guy, R H (1992) Predicting skin permeability. Pharm Res 9:663-9

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