Topical application of drugs can be performed for two distinct purposes, either as a localised treatment for dermatological or deeper tissue conditions (dermal) or for systemic delivery (transdermal). There are distinct set of development strategies for both of these two applications, although the first hurdle in both cases is to cross the stratum corneum barrier (Elsabahy and Foldvari 2013). In healthy, uncompromised skin, the physical barrier properties of the skin prevail and prevent most external substances to permeate into the body. The properties of most drugs fall outside the optimum range of permeability (Bos and Meinardi 2000) and hence require some type of an enhancer to be therapeutically useful. The suggested size limit of molecules for passive delivery through the skin is below 500 Da (Bos and Meinardi 2000). Unassisted penetration of molecules above this molecular weight through intact skin is extremely low.

In the past decade, the discovery of new dermal and transdermal technologies with the simultaneous understanding of the physiological pathways in skin layers in much greater detail resulted in the increasing use of the dermal route for delivering not only small drug molecules but also proteins, nucleic acids and vaccine antigens.

Most of the topical or transdermal products on the market were developed for small and lipophilic molecules, resulting in about 30 transdermal products including those intended for local tissue treatment (e.g. clonidine, estradiol, fentanyl, nitroglycerine, nicotine, testosterone, lidocaine, diclofenac sodium).

However, the delivery of most biopharmaceuticals is limited to parenteral administration through IV, IM or SC injections. With increased number of macromolecules (DNA and recombinant proteins) as drugs being discovered and approved, new drug delivery technologies are being explored to deliver these molecules through the skin (Prausnitz and Langer 2008).

One important area of progress involves protein pharmaceuticals. In the past several years, therapeutic opportunities were greatly expanded by using biopharmaceuticals, such as proteins and peptides. Important classes of biopharmaceutical compounds (biodrugs) include interferons and cytokines, blood/clotting factors (erythropoietin), growth hormones/factors, hormones (insulin), enzymes, monoclonal antibodies (mAbs) and vaccines (McCrudden et al. 2013). Biodrugs (new biological entities or NBE) are becoming the most demanded medicines. Evaluate Pharma, for example, shows that seven of the top ten drugs are biopharmaceuticals in 2016. The PhRMA 2013 Annual Report (http://​www.​phrma.​org/​) lists over 900 biologics, including mAbs, vaccines, recombinant proteins, cell therapy, gene therapy and antisense in development from Phase I to III trials and submitted to the US Food and Drug Administration (FDA) for more than 100 diseases. In addition to innovator biodrugs, the ‘generic’ versions, so-called biosimilars (FDA recognises biosimilar and interchangeable biosimilar products) or ‘follow-on biologics’ or ‘biobetters’ (a biologic with a structural modification compared to the original and better performance) are also emerging as important part of the biodrug pipeline. The global market size for biosimilars was $2.5B in 2011, which is expected to grow by 8 % between 2012 and 2016. Currently, more than 40 therapeutic mAbs are approved by EU and FDA, and many more are under review. The market for these is estimated at $58B by 2016 (BCC Research). IMS Health estimated that by 2020, most biologics that make up $64B of global sales will be off patent.

The combination of scientific and commercial factors contributes to the timeliness to introduce improvements in the delivery of biologics, which was previously not opportune.

So far, the only topically applied dermal or transdermal delivery systems available commercially is Regranex^® (becaplermin, recombinant human platelet-derived growth factor, 25 kDa) for lower extremity diabetic ulcers (OMJ Pharmaceuticals/Ortho-McNeil), which is applied on broken skin; hence, localisation of the protein is the main function of the delivery system, and permeability enhancement is not a factor in its efficacy.

Another developing area is gene therapy. Topical delivery of genetic material appears to be promising, in that such delivery could be non-invasive and provide a more continuous supply of the protein within the skin. This approach could have further advantages over the delivery of protein drugs: (i) the DNA is a more stable molecule than the protein, (ii) the continuous expression of protein within the skin after topical administration limits systemic exposure and (iii) topical treatment can be self-administered by the patient. However, these advantages are contingent upon successful delivery of the DNA into the skin.

Current delivery and functional responses after topical application of DNA are only possible on pretreated or damaged skin (use of depilatory lotion, scraping or stripping (Shi et al. 1999; Yu et al. 1999; Watabe et al. 2001)) to remove the stratum corneum, the main permeability barrier layer of the skin. For example, DermaVir, a DNA vaccine by Genetic Immunity, utilises a novel nanoparticle technology, consisting of mannosylated polyethyleneimine-plasmid complex, for topical HIV vaccination, which is applied on the skin after dermabrasion (Lisziewicz et al. 2012). Certain lipid-based delivery systems facilitate DNA uptake into intact skin, both in vitro and in vivo (Birchall et al. 2000; Delepine et al. 2000; Xu et al. 1999), but the efficiency of these systems is still too low to produce therapeutic levels of protein. In the design of effective in vivo systems, the optimum in vitro properties obtained in transfection experiments need to be extended to also include optimum percutaneous permeation-enhancer properties.

Currently, the most effective penetration into and permeation through the skin could be achieved by physical methods (e.g. microneedles (Escobar-Chavez et al. 2011), thermal ablation (Lee et al. 2011)) and electrical methods (e.g. electroporation (Charoo et al. 2010), iontophoresis (Gratieri et al. 2011)). Although the use of physical and electrical methods to enhance the drug permeation through the skin has shown some success in enhancing the delivery of both small and large molecules, there are still significant hurdles to overcome before approval.