SONOPHORESIS .2. EXAMINATION OF THE MECHANISM(S) OF ULTRASOUND-ENHANCED TRANSDERMAL DRUG DELIVERY

We have shown previously that high-frequency ultrasound (sonophoresis) can significantly enhance the transdermal delivery of a topically applied drug in vivo and that the augmentation of transport was caused by the action of the ultrasound on the skin. However, these earlier experiments did not reveal (i) the mechanism of sonophoresis, (ii) the pathway of drug permeation under the influence of ultrasound, and (iii) any potentially detrimental effects of the enhancement procedure on skin structure and morphology. In the study reported here, these three key issues have been addressed using electron microscopy to follow the penetration of an electron-dense, colloidal tracer (lanthanum hydroxide; LH). Experiments have again been performed using the hairless guinea pig animal model. Colloidal LH suspensions were applied to skin sites, which were then immediately exposed to ultrasound (at 10 or 16 MHz) for 5 or 20 min. Passive transport of LH under identical conditions (but without ultrasound) provided the control measurements. Tissue processing after the treatment periods utilized standard electron microscopy staining procedures. We found the following: (1) LH does not permeate the skin by passive diffusion; under the influence of ultrasound, on the other hand, it penetrates through the stratum corneum (SC) and the underlying viable epidermal cell layers via an apparently intercellular route. (2) LH transports through the epidermis to the upper dermis, even after only 5 min of ultrasound treatment, a remarkable and unexpected finding. (3) The SC and the cells of the epidermis do not appear to be adversely affected by either (a) ultrasound treatment at 10-MHz frequency (5- or 20-min exposure) or (b) 5 min of sonophoresis at 16 MHz. However, a 20-min treatment with ultrasound at 16 MHz resulted in altered cellular morphology compared to the passive control. The distribution of the tracer in the latter experiments was nonuniform and suggested that cavitational effects may have contributed to the adverse observations. Overall, the results demonstrate that exposure of the skin to ultrasound can induce the considerable and rapid facilitation of LH transport via an intercellular route. Prolonged exposures at high frequencies, however, can alter epidermal morphology, leading us to pose further questions pertaining to the duration and reversibility of ultrasound action on skin.