Transdermal drug delivery using low-frequency sonophoresis.
OBJECTIVE
Application of therapeutic ultrasound (frequency: 1-3 MHz and intensity: 0-2 W/cm2) enhances transdermal drug transport, although typically by a factor of less than 10. In this paper, we show that application of ultrasound at 20 KHz induces transdermal transport enhancements of up to 1000 times higher than those induced by therapeutic ultrasound.


METHODS
In vitro (human cadaver epidermis) as well as in vivo (hairless rat skin) permeation experiments were performed to assess the effect of low-frequency ultrasound on transdermal transport.


RESULTS
Application of low-frequency ultrasound (20 KHz, 125 mW/cm2, 100 msec pulses applied every second) enhanced transdermal transport of several permeants, including estradiol, salicylic acid, corticosterone, sucrose, aldosterone, water, and butanol, across human cadaver skin by a factor in the range of 3 to 3000 and that of salicylic acid across hairless rat skin in vivo by a factor of up to 300. Low-frequency ultrasound did not induce a long-term loss of the barrier properties of the skin (in vitro) or damage to living skin of hairless rats. At a mechanistic level, it is hypothesized that application of low-frequency ultrasound enhances transdermal transport through aqueous channels in the SC generated by cavitation-induced bilayer disordering. Support for this hypothesis is provided using experimental and theoretical analyses of low-frequency sonophoresis.


CONCLUSIONS
Low-frequency ultrasound enhances transdermal transport of drugs more effectively than that induced by therapeutic ultrasound.
Mitragotri
S
S
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139, USA.
Blankschtein
D
D
Langer
R
R
D000279:Administration, Cutaneous; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008297:Male; D051381:Rats; D012867:Skin / Q000000981:diagnostic imaging / Q000378:metabolism; D012869:Skin Absorption; D014465:Ultrasonics; D014463:Ultrasonography
D008051:Lipid Bilayers