Ultrasound-mediated gastrointestinal drug delivery

Abstract

There is a significant clinical need for rapid and efficient delivery of drugs directly to the site of diseased tissues for the treatment of gastrointestinal (GI) pathologies, in particular, Crohn’s and ulcerative colitis. However, complex therapeutic molecules cannot easily be delivered through the GI tract because of physiologic and structural barriers. We report the use of ultrasound as a modality for enhanced drug delivery to the GI tract, with an emphasis on rectal delivery. Ultrasound increased the absorption of model therapeutics inulin, hydrocortisone, and mesalamine two- to tenfold in ex vivo tissue, depending on location in the GI tract. In pigs, ultrasound induced transient cavitation with negligible heating, leading to an order of magnitude enhancement in the delivery of mesalamine, as well as successful systemic delivery of a macromolecule, insulin, with the expected hypoglycemic response. In a rodent model of chemically induced acute colitis, the addition of ultrasound to a daily mesalamine enema (compared to enema alone) resulted in superior clinical and histological scores of disease activity. In both animal models, ultrasound treatment was well tolerated and resulted in minimal tissue disruption, and in mice, there was no significant effect on histology, fecal score, or tissue inflammatory cytokine levels. The use of ultrasound to enhance GI drug delivery is safe in animals and could augment the efficacy of GI therapies and broaden the scope of agents that could be delivered locally and systemically through the GI tract for chronic conditions such as inflammatory bowel disease.

Getting Drugs Across Biological Barriers

“…[110–134] In addition to the SC, physical permeation enhancement has been applied to the blood-brain barrier (BBB, see section 5.4), [135] tumors (see Section 4.2), [113] and the GI tract (see Section 5.3). [136] Table 3 lists a selection of FDA-approved physical means for permeation enhancement.…”

“…US has been used to enhance transport into numerous tissues and anatomic locations, including skin, [149] tumor, [135] the GI tract, [150] cornea, [151] and the BBB. [135, 152] Damage to epithelia from US has been reported, especially with low-frequency US, but seems to be largely reversible.…”

Covert cavitation: Spectral peak suppression in the acoustic emissions from spatially configured nucleations

“…In the particular example presented, the cavitation sub-harmonic at f 0 /2, and its higher harmonics, which are signals widely used to infer the very existence of acoustic cavitation, [1][2][3][4] are significantly suppressed for any detector aligned to the HIFU axis. A windowing function is analytically expressed to predict the frequency values at which peak suppressions will occur for the spectrum of the dual-bubble cavitation activity, in terms of the PSW spectrum from one of the component bubbles.…”

Oral delivery of biologics using drug-device combinations

“…By propelling a jet into the buccal tissue of rabbits, the antibodies pass through the disturbed mucus layer at high levels. Ultrasound has also been shown to enhance permeation of biologics in the GI tract [50,51]. Additionally, needle-free drug delivery systems have been used to deliver APIs in liquid forms by means of spring systems, lasers and energy propelled systems across the skin and to the oral mucosa [52].…”