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In vitro permeation studies of mannitol were conducted across excised hairless mouse skin to determine and compare the enhancing effect of electroporation (EP) or sonophoresis (SP) combined with iontophoresis (IP) on the electroosmotic flow, and to analyze the enhancement mechanism of these combined methods. Mannitol flux was utilized as an index for the electroosmotic flow due to its low molecular weight and no electrorepulsion effect. The combination of SP and IP (SP/IP) resulted in an apparent increase of electroosmotic flow (no effect was sometimes observed by SP/IP), while that of EP and IP (EP/IP) had no synergistic enhancing effect on the electroosmosis. Next, the combined effect of tape-stripping (TS) and IP (TS/IP) was examined in a similar manner to clarify the difference between the SP/IP and EP/IP effects on electroosmosis. When the TS number increased from 0 to 3, the electroosmotic flow increased with the TS number. However, no further increase was observed when the TS number became more than 3, and the flow started to decrease when the TS number became 5. The electric charge of the skin surface was then measured after SP or TS application. When SP was applied, the skin surface charge became much more negative and the electroosmotic flow by SP/IP was markedly increased. Thus, an increase in the electroosmotic flow across the skin during IP application can be obtained not by EP and TS, but by SP. The combined use of SP and IP is a promising means for the enhanced skin delivery of non-electrolyte drugs.Key words sonophoresis; electroporation; iontophoresis; electroosmosis; tape-stripping Recently, advances in development and practical application of physical transdermal drug delivery techniques have been achieved in iontophoresis (IP), sonophoresis (SP) and electroporation (EP). Although conventional transdermal delivery is based on passive diffusion using the concentration gradient of drugs through the skin barrier after topical application, these physical means are characterized by active drug administration based on physical perforation of the skin barrier using external energy sources, and can be used to deliver peptides, proteins and other macromolecular drugs as well as low-molecular-weight organic drugs.Among these techniques, IP 1) and EP 2) are based on electrical energy. IP, involving the application of a weak current for a relatively long period, is a means of using electrical repulsive force (electrorepulsion) and electroosmotic flow (electroosmosis) as driving forces.3) EP, involving the application of a high voltage (100 to 1000 V) for a very short period (100 µs to 100 ms), is used to form new aqueous pathways in the lamellar structure of the stratum corneum.2,4) The EP effect depends on the electric field applied to the skin. 5) SP6) is a skin-penetration-enhancing technique involving the application of a low frequency to the skin surface through media such as aqueous solution.Recently, several combined trials of EP/IP have been reported using insulin, 7) 5-fluorouracil 8) and calcito...

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