Low-frequency ultrasound for drug delivery in the gastrointestinal tract

The rapid, effective, and safe delivery of a broad range of therapeutics via the gastrointestinal (GI) tract remains a significant challenge in the field of drug delivery. The mucus layer coating the tissue, along with the low pH and wealth of degradative species, largely limit the kinetics and types of therapeutics that may be administered. As a result, technologies beyond formulation-based approaches are needed to enable the delivery of a wide range of therapeutics in a rapid manner. Physical enhancers, such as ultrasound (US), may afford the capacity to achieve ultra-rapid delivery via the GI tract of a wide range of therapeutics currently limited to injection. US is a longitudinal pressure wave with a frequency above the audible range (>20 kHz).[1] US has been investigated for decades for transdermal drug delivery.[2] US, when propagating through a fluid, can spontaneously nucleate voids (bubbles) in the solution, a phenomenon known as cavitation.[1] Research interest first focused on high-frequency (≥1 MHz) US to enhance the permeability of the skin.[3] More recently, research has focused on the use of low-frequency US (≤100 kHz) because of the observation of transient cavitation occurring at these frequencies. At low frequencies, the cavitation bubbles grow over cycles of the US pressure wave through a phenomenon known as rectified diffusion.[4] Eventually, the bubbles become unstable in size and implode, causing the surrounding fluid to rush into that void space, generating a microjet.[1] In transdermal applications, it is these microjets that have been shown to be the dominant mechanism of enhancement in drug delivery.[2] This phenomenon has been shown to enable the delivery of macromolecules, including biologics, such as insulin, via the skin.[5] Since those reports, low-frequency US has been explored extensively with respect to transdermal drug delivery and has been previously reviewed.[1,6] 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. The application of low-frequency US in the GI tract was initially proposed by Kost and Langer in the mid-1980s through their patent application focusing on buccal delivery.[10] However, until recently, there were few reports in the literature investigating this method. Our group recently reported on the use of US in the GI tract (Figure 1). This work was motivated by the significant delivery potential of low-frequency US observed in the vast transdermal literature, the lack of a keratinized barrier in the GI tract, and the potential for modulation of beam profiles, enabling circumferential delivery through a single brief application. As a result, we hypothesized that application of US to the GI tract could provide rapid delivery of small molecules and also facilitate the delivery of macromolecules via the GI tract.