Introduction Transdermal delivery has potential advantages over other routes of administration. It could reduce first-pass metabolism associated with oral delivery and is less painful than injections. However, the outermost layer of the skin, the stratum corneum (SC), limits passive diffusion to small lipophilic molecules. Therefore, methods are needed to safely permeabilize the SC so that ionic and larger molecules may be delivered transdermally. Areas Covered This review focuses on low-frequency sonophoresis, microneedles, electroporation and iontophoresis, and combinations of these methods to permeabilize the SC. The mechanisms of enhancement and developments in the last five years are discussed. Potentially high-impact applications, including protein delivery, vaccination, and sensing, are presented. Finally, commercial interest and clinical trials are discussed. Expert Opinion Not all permeabilization methods are appropriate for all applications. Focused studies into applications utilizing the advantages of each method are needed. The total dose and kinetics of delivery must be considered. Vaccination is one application where permeabilization methods could make an impact. Protein delivery and analyte sensing are also areas of potential impact, although the amount of material that can be delivered (or extracted) is of critical importance. Additional work on the miniaturization of these technologies will help to increase commercial interest.

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.

Both patients and physicians prefer the oral route of drug delivery. The gastrointestinal (GI) tract, though, limits the bioavailability of certain therapeutics because of its protease and bacteria-rich environment as well as general pH variability from pH 1–7. These extreme environments make oral delivery particularly challenging for the biologic class of therapeutics. Here we demonstrate proof-of-concept experiments in swine that microneedle-based delivery has the capacity for improved bioavailability of a biologically-active macromolecule. Moreover, we show that microneedle-containing devices can be passed and excreted from the GI tract safely. These findings strongly support the success of implementation of microneedle technology for use in the GI tract.

Low-frequency ultrasound has been studied extensively due to its ability to enhance skin permeability. In spite of this effort, improvements in enhancing the efficacy of transdermal ultrasound treatments have been limited. Currently, when greater skin permeability is desired at a given frequency, one is limited to increasing the intensity or the duration of the ultrasound treatment, which carries the risk of thermal side effects. Therefore, the ability to increase skin permeability without increasing ultrasound intensity or treatment time would represent a significant and desirable outcome. Here, we hypothesize that the simultaneous application of two distinct ultrasound frequencies, in the range of 20 kHz to 3 MHz, can enhance the efficacy of ultrasound exposure. Aluminum foil pitting experiments showed a significant increase in cavitational activity when two frequencies were applied instead of just one low frequency. Additionally, in vitro tests with porcine skin indicated that the permeability and resulting formation of localized transport regions are greatly enhanced when two frequencies (low and high) are used simultaneously. These results were corroborated with glucose (180 Da) and inulin (5000 Da) transdermal flux experiments, which showed greater permeant delivery both into and through the dual-frequency pre-treated skin.

The skin is a formidable diffusion barrier that restricts passive diffusion to small (<500 Da) lipophilic molecules. Methods used to permeabilize this barrier for the purpose of drug delivery are maturing as an alternative to oral drug delivery and hypodermic injections. Ultrasound can reversibly and non-invasively permeabilize the diffusion barrier posed by the skin. This review discusses the mechanisms of ultrasound-permeability enhancement, and presents technological innovations in equipment miniaturization and recent advances in permeabilization capabilities. Additionally, potentially exciting applications, including protein delivery, vaccination, gene therapy and sensing of blood analytes, are discussed. Finally, the future challenges and opportunities associated with the use of ultrasound are discussed. It is stressed that developing ultrasound for suitable applications is key to ensure commercial success.