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Discovery & Development Drug Delivery, Small Molecules

Breaking Through the Barrier

As the largest organ, our skin typically accounts for around 10 percent of our body mass. In terms of drug administration, however, it remains a relatively unexplored frontier. The skin has evolved to be an excellent natural biological barrier, making it challenging for drugs to penetrate it in sufficient quantities to reach therapeutic concentrations (1). 

The skin has a multi-layered composition, so the capacity of a drug to enter and pass through depends on its ability to penetrate both the hydrophobic and hydrophilic layers of the skin. Drugs that are too hydrophilic are unable to pass into the outer layers (the stratum corneum), whilst very lipophilic drugs will be retained in the lipids of the stratum corneum and will not pass into the more aqueous epidermis, limiting permeation. Skin permeability may also be affected by a large number of physiological factors, including the anatomical site, age, ethnicity, gender, and underlying skin disorders (2, 3, 4). Skin is not a homogenous unchanging barrier, which means therapies designed to use the skin as a site of delivery need to be tailored appropriately to be effective.

Despite the challenges, the pharmaceutical industry should not be so hasty in writing off skin-based drug delivery! Topical administration represents a non-invasive, painless and convenient alternative to injection and avoids the first-pass liver metabolism typically encountered by oral drug delivery. Transdermal delivery into subcutaneous tissues and then into the body also has the potential to deliver steady and sustained drug levels over prolonged time periods, thereby reducing side effects associated with the peaks and troughs in drug plasma concentrations that are common with more acute dosing routes, including oral administration (5). 

Clearly, the skin itself is the site of many common diseases and disorders, such as fungal infections, psoriasis, skin cancers, dermatitis, and acne. Here, direct (topical) treatment would logically be the preferred route of administration, as it targets the site of disease directly whilst limiting any unwanted systemic exposure. Indeed, formulations based on nanotechnology should allow the usage of lower doses – as well as shorter treatment times and less frequent applications. 

Nanotechnologies can help tackle many of the challenges presented by skin delivery. Nanocapsules, nanoparticles and liposomes are all viable options (6) – and all of these approaches are characterized as “nanoformulations.” Nanocapsules consist of a lipophilic solid or liquid core enclosing a hydrophilic drug surrounded by a polymeric coating structure. Nanoparticles, on the other hand, are formed using synthetic polymers with high hydrogen binding potential, mixed with the therapeutic molecules or cargo (peptides, nucleic acids, or small molecules), which then rapidly assemble or package into nanoparticles. Finally, liposomes consist of an aqueous center where drugs are surrounded by a hydrophobic membrane in the form of a lipid bilayer. 

In my view, novel delivery systems that can safely and effectively deliver drugs through the skin have the potential to replace conventional therapies. Right now, we’re in a period of evolution rather than a revolution – dermatological conditions are an obvious place to start – but imagine a future when nanoformulations are able to transport a variety of molecules, such as antibodies and proteins, through the skin… When that happens, I believe transdermal will become the go-to mode of drug delivery.

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  1. C Vitorino et al., “Overcoming the Skin Permeation Barrier: Challenges and Opportunities.” Curr Pharm Des, 28, 2698,  (2015). 
  2. KA Walters, “Dermatological and Transdermal Formulations.” 2002. Available from:
  3. KV Roskos, “Percutaneous absorption in the aged.” Dermatol Clin, 4, 455 (1986). 
  4. M Ghannoum and N Isham, “Fungal Nail Infections (Onychomycosis): A Never-Ending Story?” PLoS Pathog.10, (2014).
  5. MB Brown et al., “Dermal and transdermal drug delivery systems: Current and future prospects.” Drug Deliv J Deliv Target Ther Agents, 13,175, (2016).
  6. RK Dhamoonet et al., “Pharmaceutical Nanotechnology Novel Drug Delivery Strategies for the Treatment of Onychomy-cosis.” Pharm Nanotechnol, 7, 24 (2019).
About the Author
Dave Cook

Chief Scientific Officer at Blueberry Therapeutics.

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