A physical mechanism to explain the delivery of chemical penetration enhancers into skin during transdermal sonophoresis — Insight into the observed synergism

Abstract

The synergism between low-frequency sonophoresis (LFS) and chemical penetration enhancers (CPEs), especially surfactants, in transdermal enhancement has been investigated extensively since this phenomenon was first observed over a decade ago. In spite of the identifying that the origin of this synergism is the increased penetration and subsequent dispersion of CPEs in the skin in response to LFS treatment, to date, no mechanism has been directly proposed to explain how LFS induces the observed increased transport of CPEs. In this study, we propose a plausible physical mechanism by which the transport of all CPEs is expected to have significantly increased flux into the localized-transport regions (LTRs) of LFS-treated skin. Specifically, the collapse of acoustic cavitation microjets within LTRs induces a convective flux. In addition, because amphiphilic molecules preferentially adsorb onto the gas/water interface of cavitation bubbles, amphiphiles have an additional adsorptive flux. In this sense, the cavitation bubbles effectively act as carriers for amphiphilic molecules, delivering surfactants directly into the skin when they collapse at the skin surface as cavitation microjets. The flux equations derived for CPE delivery into the LTRs and non-LTRs during LFS treatment, compared to that for untreated skin, explain why the transport of all CPEs, and to an even greater extent amphiphilic CPEs, is increased during LFS treatment. The flux model is tested with a non-amphiphilic CPE (propylene glycol) and both nonionic and ionic amphiphilic CPEs (octyl glucoside and sodium lauryl sulfate, respectively), by measuring the flux of each CPE into untreated skin and the LTRs and non-LTRs of LFS-treated skin. The resulting data shows very good agreement with the proposed flux model.

Applicability and safety of dual-frequency ultrasonic treatment for the transdermal delivery of drugs

“…The custom diffusion top was filled with 300 mL of a solution of 1 wt.% SLS and 0.04 wt.% Allura red dye in PBS. The treatment times tested ranged between 4 and 8 min, which are within the range of commonly-tested treatment times in the literature [16,17]. Thermal effects were determined to be negligible as the temperature increase of the coupling solution was less than 2 °C even at the longest treatment time considered.…”

Recent Advances in Physical Approaches for Transdermal Penetration Enhancement

“…Using nonionic and ionic amphiphilic CPEs, octyl glucoside and sodium lauryl sulfate, a credible physical mechanism for significantly increased flux to localized-transport regions have been proposed. As reported by Polat et al, the collapse of acoustic cavitation microjets within the localized transport regions and additional absorptive flux due to amphiphilic surfactants contribute to the enhanced transdermal flux [91]. Lately this combination strategy of LFS and CPEs has been used to develop non-oral and non-invasive drug delivery modality for the immediate therapeutic effect of muscle relaxants such as tizanidine hydrochloride.…”

Fetal Membrane Transport Enhancement Using Ultrasound for Drug Delivery and Noninvasive Detection

“…For longer permeability experiments (results not shown) the fetal membranes mass transport rate has reversed back to its initial rate (pretreatment) indicating the effect on the fetal membranes is reversible (as with skin). Finally, the greater error bars observed for the US application (during and after) compared to the passive transport may be explained by the known heterogenic nature of US effect on membranes (2,34).…”