Drug delivery to and through the skin

Abstract

Drug delivery technology has advanced significantly over >50 years, and has produced remarkable innovation, countless publications and conferences, and generations of talented and creative scientists. However, a critical review of the current state-of-the-art reveals that the translation of clever and sophisticated drug delivery technologies into products, which satisfy important, unmet medical needs and have been approved by the regulatory agencies, has - given the investment made in terms of time and money - been relatively limited. Here, this point of view is illustrated using a case study of technology for drug delivery into and through the skin and aims: to examine the historical development of this field and the current state-of-the-art; to understand why the translation of drug delivery technologies into products that improve clinical outcomes has been quite slow and inefficient; and to suggest how the impact of technology may be increased and the process of concept to approved product accelerated.

Keywords: Drug delivery technology; Skin barrier function; Skin penetration enhancement – chemical; Skin penetration enhancement – physical; Topical and transdermal drug delivery; Topical formulations and metamorphosis.

Fig. 1

A Common transdermal patch designs used in marketed systems. B Demonstration of how patch area can control and determine drug input across the skin. C Close to zero-order transdermal delivery of oxybutynin over a 3-day period from a single patch. D Clear demonstration of avoidance of hepatic first-pass effect when oxybutynin is administered transdermally

Fig. 2

Indirect measurements of skin penetration enhancement (ER) and irritation potential (IP) are, in general, correlated (data redrawn from [18]). Searching for the ‘sweet spot’ where ER/IP > 1 has yet to bear significant fruit

Fig. 3

Commercialized iontophoretic drug products. LidoSite, Ionsys and Zecurity delivered drugs for local anaesthesia, the treatment of chronic and breakthrough pain, and migraine, respectively. The GlucoWatch, in contrast, used ‘reverse’ iontophoresis to transdermally extract (and the device then detected) glucose for the noninvasive monitoring of blood sugar

Fig. 4

A Schematic diagram of the microneedle ‘concept’, enabling the active pharmaceutical ingredient to access the viable layers of the skin without having to overcome the substantial barrier of the stratum corneum. B Expanded view of the ‘hollow’ type of microneedle. (Created with BioRender.com)

Fig. 5

The stratum corneum is a “brick wall” (10–20 µm thick) with keratin-filled bricks about 0.5 µm across. The space between corneocytes (25–100 nm) is filled with lipid lamellae. How does a 100 nm (or bigger) particle diffuse across this barrier? The micrograph was kindly provided by Dr. Lars Norlén

Fig. 6

Metamorphosis of the calcipotriene and betamethasone dipropionate foam. From the solution in the manufactured product, in which the drugs are dissolved, and upon application and collapse of the foam, the drug’s attain their saturation solubilities (and maximum diving forces for skin penetration), and then create a residual ‘ointment’ film where a transient period of supersaturation may occur and in which thereafter finite amounts of the drugs remain in solution (at saturation) to sustain delivery