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

Abstract

Low-frequency ultrasound presents an attractive method for transdermal drug delivery. The controlled, yet nonspecific nature of enhancement broadens the range of therapeutics that can be delivered, while minimizing necessary reformulation efforts for differing compounds. Long and inconsistent treatment times, however, have partially limited the attractiveness of this method. Building on recent advances made in this area, the simultaneous use of low- and high-frequency ultrasound is explored in a physiologically relevant experimental setup to enable the translation of this treatment to testing in vivo. Dual-frequency ultrasound, utilizing 20 kHz and 1 MHz wavelengths simultaneously, was found to significantly enhance the size of localized transport regions (LTRs) in both in vitro and in vivo models while decreasing the necessary treatment time compared to 20 kHz alone. Additionally, LTRs generated by treatment with 20 kHz + 1 MHz were found to be more permeable than those generated with 20 kHz alone. This was further corroborated with pore-size estimates utilizing hindered-transport theory, in which the pores in skin treated with 20 kHz + 1 MHz were calculated to be significantly larger than the pores in skin treated with 20 kHz alone. This demonstrates for the first time that LTRs generated with 20 kHz + 1 MHz are also more permeable than those generated with 20 kHz alone, which could broaden the range of therapeutics and doses administered transdermally. With regard to safety, treatment with 20 kHz + 1 MHz both in vitro and in vivo appeared to result in no greater skin disruption than that observed in skin treated with 20 kHz alone, an FDA-approved modality. This study demonstrates that dual-frequency ultrasound is more efficient and effective than single-frequency ultrasound and is well-tolerated in vivo.

Assessment of the efficacy of drug transdermal delivery by electro-phonophoresis in treating tuberculous lymphadenitis

“…The major advantages of this approach include the ease of use, direct effects caused on the focal lesions reduced first-pass drug-degradation, improved drug transportation into the cells and its bioavailability, reduced side effects due to limited circulation via blood, higher efficiency for a long time course, and its utility for various of drugs without any cross infection (Paudel et al, 2010;Prausnitz et al, 2004). The clinical use of this method has verified that the therapeutic doses of ultrasound are safe to human body (Mitragotri, 2005;Schoellhammer et al, 2015;Wiedersberg & Guy, 2014). A series of experiments proved that ultrasonic penetration is effective for many drugs, such as liposomal lidocaine and 5-Aminolevulinate (used for actinic keratosis and other nonmelanoma skin cancers) (Becker et al, 2005;Krishnan et al, 2013;Mitragotri, 2005;Polat et al, 2011;Prausnitz & Langer, 2008;Skarbek-Borowska et al, 2006).…”

Getting Drugs Across Biological Barriers

“…[148] The boosted enhancement by dual treatment is attributed to the simultaneous generation (under high-frequency US) and collapse (under low-frequency US) of bubbles.…”

Low-frequency ultrasound for drug delivery in the gastrointestinal tract

“…Furthermore 3 kDa and 70 kDa dextrans serving as model macromolecules were successfully delivered with US ex vivo and shown to penetrate the entire thickness of the tissue with only one-minute of US treatment. This is in stark contrast to the typical treatment times required for transdermal drug delivery, which can exceed 10 minutes and requires co-administration with surfactants [1], [9]. The efficacy observed with short treatment times in the GI tract to achieve significant enhancement in delivery is thought to be a result of the architecture of the GI epithelium.…”

“…The general findings from the transdermal field include the capacity to deliver nucleic acids [7], peptides [8], proteins [5], [6], as well as significantly enhance the delivery of small molecules [1], [9]. It was this capacity for delivery of a broad range of molecules, which motivated further exploration of this technology for drug delivery to parts of the body other than the skin.…”