Exploring the Depths of Percutaneous Penetration

Jul 3, 2012 | Contact Author | By: Elsa Jungman, Université Paris-Sud
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Title: Exploring the Depths of Percutaneous Penetration
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The Perspectives in Percutaneous Penetration (PPP) conference was held at the Palais des Congrès de La Grande Motte on April 10–14, 2012. For more than two decades, the conference has provided a unique forum for the interchange of ideas on percutaneous penetration among the academic, industrial and regulatory sectors. The event provides an optimized combination of plenary lectures, oral contributions, poster sessions and debates combined with an appropriate experience of local culture. Following are some highlights most relevant to the cosmetics and personal care industry.

Pre-conference Fundamentals

The event opened with a full day pre-conference course on the fundamentals of percutaneous penetration. Michael Roberts, of the University of Queensland, Australia, presented a general overview of skin structure and function. This was followed by a discussion of skin transport mechanisms and permeation enhancement, by Kenneth Walters, PhD, of An-eX Analytical Services Ltd. Various penetration enhancement strategies were presented; from pyrrolidones, anionic and nonionic surfactants, fatty acids and alcohols, to terpenes, a synthetic enhancer: azone, and sunscreens.

Darren M. Green, PhD, also of An-eX, highlighted methods for measuring percutaneous penetration, which for cosmetics, is important for risk assessments and claims substantiation. Green explained there are major limitations of mathematical models because physiological and formulation effects are not taken into account. Further, the theoretical values from the Potts and Guy model do not help to predict permeability coefficients.

Joke Bowstra, PhD, of the Leiden/Amsterdam Center for Drug Research, showed the importance of skin barrier in drug transport and more specifically, the role of epidermal lipids. Finally, Heinz Ahlers of the US Department of Health and Human Services presented on the use of skin notation in the prevention of occupational skin disease.

The first day ended with a welcome reception including a typical French buffet with a nice glass of wine.

Digging Deeper

The official conference opened with a presentation from Tom Franz, the inventor of Franz cells, who discussed the use of in vitro permeation as a bioequivalence tool. He talked about the correlation between in vivo and in vitro data and, from the literature, showed that data from studies conducted with fully harmonized protocols could be totally correlated to in vivo data. Pauls Matts, PhD, of Procter & Gamble, then spoke on the effects of an aqueous British Pharmacoepia-registered (BP) cream on eczema. Such an aqueous cream (AQC) is a light, paraffin-based emulsion that is categorized by the British National Formulary as non-proprietary emollient preparation. It contains the anionic surfactant sodium lauryl sulfate (SLS). However, the recommendation for using AQC as an emollient in atopic skin is surprising, as SLS is a known skin irritant.

Matts described an experiment wherein AQC was applied for one month on the volar forearm of skin. Results showed an increase in desquamatory and inflammatory protease activity, and changes in corneocyte maturity and size, which are also indicative of accelerated skin turnover induced by chronic application of this emollient. These findings question the routine prescription of this preparation as a moisturizer in patients with atopic dermatitis.

Johanna Brandner, PhD, of the University of Hamburg, explained the role of tight junction assembly in the barrier function. Tight junctions, cell-cell junctions localized in the stratum granulosum, are a barrier for ions, water and macromolecules, especially claudine-1. Brandner showed that a decrease of this protein would increase the TEWL, and that an alteration of the tight junction in the epidermis leads to skin diseases such as psoriasis, ichthyosis and atopic dermatitis. The next step would be to study the role of these proteins in exogenous molecule penetration.

Peter Caspers, PhD, of Erasmus MC & River Diagnosis, presented a Raman spectroscopy method to rapidly determine the natural moisturizing factor (NMF) in the stratum corneum of adults and young babies. The new protocols presented offer a direct and non-invasive method to determine early in infants whether there is a deficiency of NMF that could lead to atopic skin.

Cosmeceuticals

The second day opened with two talks on cosmeceuticals. Randy Wickett, PhD, of the University of Cincinnati, and Chris Gummer, PhD, of Cider Solutions Ltd., presented their viewpoints on cosmeceuticals. For Wickett, cosmeceuticals have no legal definition. Cosmeceutical is a term used to describe active cosmetics that have a positive effect on skin beyond cleaning and moisturizing. According to Wickett, the most common cosmeceuticals are retinol, antioxidants, niaciamide, natural anti-aging peptides, etc. All of these compounds aim to decrease fine lines and wrinkles.

For Gummer, cosmeceuticals are an “itch that won’t go away.” As he explained, for him, a product can be either a cosmetic or a medicine; there is no middle ground. Cosmeceuticals are borderline products that are not clear. Gummer explained that the US Food and Drug Administration, and UK and Australia guidelines do not recognize the term cosmeceuticals; only Japan recognizes them as “quasi-drugs.” Some products claim, for example, to work against hair loss with no side effects. However, according to Gummer, this is not possible because if a product works, there are effects; if not, it does not work. So for Gummer, “Cosmeceuticals exist in the advertising world,” because they cannot be defined and regulations need to fast-track these borderlines products. He concluded that it would be in the industry’s best interest “to make cosmeceuticals go away.”

Historical Perspective

A special lecture was presented on the concept of barrier, skin penetration and beyond with a look at concepts presented from 1850–1980 by Robert Scheuplein, PhD, of Keller and Heckman. Scheuplein is an international expert on risk assessment who worked for nearly 20 years at the US FDA. His mentors were Irvin Blank and Albert Kligman, who introduced him to skin permeation and medical/biological research on skin.

Scheuplein explained that between 1850 and the 1860s, the fact that there was a barrier in the epidermis was discovered but it took around one hundred years to locate it in the stratum corneum. Kligman showed that the stratum corneum was stiff by placing it on the top of a bottle full of water, and even with the bottle turned upside-down, the water was contained. In this way, Kligman demonstrated that the stratum corneum was impermeable to water.

Blank demonstrated that water could remain in the stratum through the use of tape-strips. After eight strips, he found transepidermal water loss (TEWL) to increase significantly. The tape-stripping technique was introduced by Wolf, and showed precisely the location of the barrier zone in the stratum corneum.

Two decades of work determined that the principal barrier layer of the skin is the bulk of the stratum corneum. Studies also showed that the skin does not behave like a passive diffusion medium; it was demonstrated that the stratum corneum/epidermis or full thickness skin has the same permeation rate as whole skin. However, this was not the case for the permeation rate of exogenous chemicals. The effect of the vehicle was also a great discovery. Diffusion was tested and an increase in the transepidermal flux with, for example, water or methanol as a vehicle was observed. However, lipophilic solvents tended to decrease the flux.

Scheuplein stated, “To increase penetration, [use] a solvent with the opposite lipophilicity.” He proposed in 1971 a stratum corneum diffusion model that would be related mainly to transcellular diffusion with parallel pathways. Bound water in the keratinocytes provides the primary diffusion resistance. It was not until the 1990s that the first semi-empirical predictive model appeared by Potts and Guy, based on the molecular weight and partition coefficient of the molecule.

The day’s sessions ended with a pleasant dinner and a closing speech by Keith Brain, University of Cardiff.

Nailing Down Nails

On the final day, the morning was focused on nail permeation. Stuart Jones, King’s College, London, explained how the nail is a rich keratin barrier and that 80% of the keratin found in the nail is a hard, hair type of keratin; the remaining 20% is a soft, skin type keratin. This combination gives a rigid structure that is difficult to penetrate, including with drugs, to treat nail diseases. The penetration lag time can last hours but one approach to improve this penetration rate is to manipulate the keratin structure.

The nail environment is different from the skin in that the nail has the ability to be charged, and charged molecules make molecular interactions possible. Four categories of interactions can be developed for improving the drug permeation through the nail. First are solvent-barrier interactions, for example an alcohol-water mixture, which can enhance diffusion; a change of viscosity does not affect water flux. Second are drug-solvent interactions, as supramolecular structures can modify ungual diffusion. Third are drug ion pairs, ions and complexes, which can modify diffusion. Finally, drug-drug interactions; dimer forms have the potential to modify ungual diffusion. This could be a key function; however, it is only in the early stages of development.