Enhancing, Measuring Skin Penetration

Skin penetration is of great interest to personal care formulators for many reasons—from toxicology concerns to innovative delivery opportunities. With the introduction of nanotechnology to the industry, issues surrounding skin penetration have become more complex. The medical industry has spent much time focused on the mechanisms to increase and decrease skin penetration. Following are a few recent findings related to skin penetration, for your consideration.

According to a report on the University of Irvine, California, Undergraduate Research Opportunities Program Web site, the role of the skin is to provide a barrier to the external environment, which renders the absorption of therapeutic drugs problematic. Preliminary testing has shown that fatty acids such as linoleic acid incorporated into structurally configured polymers can act as penetration enhancers. This modification reportedly alters the barrier properties of the stratum corneum and the migration of topical drugs such as cortisol through human skin. Previous unpublished studies using an amine compound, polyoxyalkyleneamine D 400 (polyamine D 400), have suggested that topical corticosteroid solutions supplemented with novel polymers improve the penetration of therapeutic drugs.

Sets of unique polymers, synthesized at the university’s laboratory, were selected for initial assessment of penetration enhancement using the in vitro Franz diffusion model. The penetration and retention of cortisol into the skin layers were determined by measuring radiolabeled drug levels at the experimental endpoint by liquid scintillation counting. Linoleic acid and polyamine D 400 polymer achieved statistically higher cortisol penetration through the skin when compared to the commercial standard or the vehicle control. In the future, these unique polymers coulud be used as penetration enhancers to improve transdermal delivery of other topical drugs of therapeutic interest. View the complete study (PDF, < 1 MB).

Mid-infrared laser ablation of the stratum corneum is reported to enhance the in vitro percutaneous transport of drugs, according to the Oregon Medical Laser Center. The precise removal of stratum corneum from cadaveric swine skin by a mid-infrared erbium:yttrium scandium gallium garnet laser was assessed by electrical resistance measurements and documented by histology. The effects of stratum corneum removal by laser ablation and by adhesive tape-stripping on the in vitro penetration of 3H-hydrocortisone and 125I-gamma-interferon were determined.

Excised swine skin was irradiated with laser. For skin penetration studies, laser pulses were delivered to discrete 2-mm areas to ablate up to 12.6% of the total 3 cm2 stratum corneum diffusional area. Franz in vitro skin penetration chambers were used to measure the cumulative 48 h penetration of 3H- hydrocortisone and 125I-gamma-interferon in laser-treated and tape-stripped skin. Electrical resistance measurements and histologic studies demonstrated that 10-14 laser pulses at the above energy density were required to abolish skin resistance and selectively ablate stratum corneum without damage to adjacent dermal structures.

Laser ablation of 12.6% of the surface area of stratum corneum produced a 2.8 and 2.1-times increase in permeability constant (kp) for 3H-hydrocortisone and 125I-gamma- interferon, respectively. These studies reportedly demonstrate that a pulsed mid-infrared laser can reliably and precisely remove the stratum corneum, facilitating penetration of large molecules such as 125I-gamma-interferon that cannot penetrate intact skin. This new technique could be useful for basic and clinical investigation of skin barrier properties. For more information, log on to: http://omlc.ogi.edu/.

The Wright State University Boonshoft School of Medicine reports on ways to study skin penetration--both in vitro and in vivo.

In vitro: One of the easiest ways to estimate penetration of drugs or chemicals through the skin is reportedly to take excised human (frequently leftover from surgeries) or laboratory animal (rat, guinea pig or pig) skin and place it between two chambers with the compound of interest in the donor chamber. In such in vitro studies, steady-state flux is determined by measuring the appearance of the compound in the receptor solution in the other chamber. Radioactive compounds are often used to make analysis of the receptor solution easier.

Steady-state flux (mass/time or mass/area/time) is determined from the slope of the linear portion of the cumulative chemical absorbed vs. time plot. Comparing these fluxes across a range of pharmaceutical products with exactly the same method allows acceptable rank-ordering of compounds for their ability to penetrate skin, which can be useful for selection of compounds or development of formulations. Unfortunately, this type of study reportedly does not provide information that is accurate enough for predicting the rate of penetration of a specific chemical in humans for a variety of reasons. Briefly, this is because of the dissimilarity between the environment of the skin in the diffusion cell and the skin on the human body (flux does not extrapolate very well). That said, careful experimentation with diffusion cells can provide fluxes that are “in the ballpark” and the studies are said to be cheaper and easier than whole animal pharmacokinetic studies.

In vivo: Studies of skin penetration in the whole animal have the potential to provide much better information because blood flow, metabolism as well as nervous and hormonal responses of the skin are intact; however, claims the report, they are much more expensive and time consuming. In vivo studies require particularly careful control of the dose applied to the skin. The surface area exposed and the concentration (or mass) on the skin are the driving forces for penetration and unlike diffusion cell studies where the area is carefully controlled and excess chemical is usually applied, these are harder to control in whole animal exposures.

Researchers add that one fascinating problem is how to expose just the skin of whole animals to chemical vapors. Because the respiratory tract is so efficient at absorbing vapors and the skin is not, any of the chemical vapor that can get to the lungs will overwhelm and mask chemical that might come through the skin.

The authors developed and validated a dermal vapor exposure chamber to be able to determine permeability of the skin to organic chemical vapors. The concept was to provide a mask for the rat to breathe fresh air while the rest of the body was exposed to vapor in a chamber. Basically a gas mask was built for rats and they were trained to wear the masks over a three-day period. Their fur was then carefully clipped, they were hooked up in the chamber, and they were provided with positive pressure clean air to breathe; blood samples were drawn during the exposure. According to the report, this system received a US patent (4,582,055) (McDougal et al. 1986a). For more information, visit: http://med.wright.edu/pharm/mcdougal/page1.html.

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