Low-frequency ultrasound can significantly increase the permeability of human skin to many drugs, including high molecular weight proteins e.g. insulin, g interferon, and erythropoeitin67. This effect is termed sonophoresis. Several hypotheses have been proposed as the mechanism by which sonophoresis enhances transdermal drug absorption. These include thermal effects, generation of convective velocities, and mechanical effects. Confocal microscopy indicates that cavitation occurs in the keratinocytes of the stratum corneum upon ultrasound exposure68; Wu et al69 also reported the formation of large (20 micrometre) pores in stratum corneum after exposure to ultrasound. As the ultrasound shock waves pass through the skin, they tear apart the tissue cohesion and create small vacuum bubbles. It is postulated that collapse of these cavitation bubbles induces disorder in the stratum corneum lipid bilayers, thereby enhancing transdermal transport. This seems to be a rather damaging way of increasing permeability, particularly since the stratum corneum is composed of dead cells and so cannot heal itself. Skin electrical resistance measurements support this model. Since transport through the skin is no longer rate limiting after ultrasound treatment, drug transport then depends directly on the diffusion coefficient, and hence molecular weight, of the drug.
Drug absorption can be enhanced by therapeutic ultrasound (frequency: 1-3 MHz and intensity: 0-2 Wcm-2), although typically by a factor of less than 10. Application of lower frequencies at higher powers causes much larger increases in absorption rate, up to a factor of 100070. The absorption rate also depends on the formulation in which the drug is contained, since the drug must diffuse out of its formulation and there is little point in enhancing drug transport in skin if the device is rate-limiting. For example, insulin and vasopressin71 were better absorbed from saline than from a hydrogel in the presence of an ultrasonic field.
The high powers normally used for sonophoresis may be reduced to therapeutic levels if a permeation enhancer is incorporated in the formulation. Thus Johnson et al72 studied the penetration of a number of model drugs using combinations of therapeutic ultrasound and penetration enhancers, and were able to demonstrate increases in penetration of two orders of magnitude, depending on the drug/enhancer combination used.
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