The long term goal of this research is to understand the transport mechanisms of transdermal absorption such that more reliable and predictable drug delivery systems may be designed. Because of a continued need for safe and effective agents to regulate fertility, the investigation is focussed on the delivery of contraceptive drugs.
The specific aims of the project are: (1) to evaluate the relationship between drug structure and chemical properties and percutaneous absorption in humans; (2) to determine the rate- limiting process in skin penetration as a function of drug structure and properties; (3) to define the level by which transdermal absorption in vivo may be increased using penetration `enhancers'; (4) to comprehend the mechanism(s) by which skin penetration `enhancers' function. Experiments are performed in vivo in man and in vitro using human skin excised during plastic surgery. Penetration measurements in the presence and absence of `enhancers' utilize novel mass balance and surface disappearance techniques following topical application of radiolabeled drug. Local `enhancer' effects under occlusion are monitored by transepidermal water loss and laser Doppler velocimetry. Drug passage across and localization within the skin is measured by reflectance Fourier-transform infrared spectroscopy (FTIR). Status and perturbations (by the `enhancers') to stratum corneum lipid structure are assessed by FTIR and differential scanning calorimetry. To probe, at a molecular level, the significance of stratum corneum lipid composition and organization, an air-liquid keratinocyte culture is established, manipulated and subjected to examination by physical techniques. Model experiments using closed vesicles prepared from stratum corneum lipids are concurrently undertaken to reinforce the studies in culture. Overall, therefore, the project aims to establish mechanisms of transdermal absorption by the judicious application of biophysical, bioengineering and biochemical techniques to the interpretation of drug penetration and its enhancement through human skin in vivo.
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