Skin permeabilization for transdermal drug delivery: recent advances and future prospects

Abstract

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 enhancements and developments in the last 5 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.

Figure 1

Histological cross-section of the skin. The outermost layer of the epidermis, the SC, is composed of dead corneocytes locked in a lipid matrix. Below the SC lies the viable epidermis, comprised of keratinocytes. Below this region is the dermis. SC: Stratum corneum.

Figure 2

LTR formation by allura red staining in representative images of skin treated with LFS alone (left) or with dual-frequency US (right). The dotted line indicates the area of the skin exposed to US. LTR: Localized transport region. LFS: Low-frequency sonophoresis. US: Ultrasound.

Figure 3

Images of a flexible MN patch. (A) The MN morphology is highly reproducible (scale bar: 200 μm). The flexibility of the patch is demonstrated in (B) and (C) (scale bar: 1 cm). Reprinted with permission from [41]. MN: Microneedle.

Figure 4

Mechanistic overview of electroporation-faciliated DNA-based vaccine delivery. The DNA material is first injected into the skin (upper left) followed by placement of electrodes. The short electric pulses create transient pores in the cell membrane, facilitating cellular uptake of the DNA (upper right). The cell then begins to produce the antigen encoded for by the DNA, and antigen-presenting cells engulf these antigens and present them to other immune cells to elicit protection. Image courtesy of, and reproduced with permission from, Inovio Pharmaceuticals, Inc.

Figure 5

The cumulative number of drugs approved by the FDA for transdermal administration since 2007. The value for year 2007 was taken from Reference . Data for subsequent years was taken from the FDA Orange Book (Food and Drug Administration, Approved Drug Products with Therapeutic Equivalence Evaluations, 33rd Edition).