Rosacea is a debilitating spectrum of disease causing both socially embarrassing erythema
and disfiguring rhinophyma. Treatment is challenging and life-long, often requiring
clinicians to trial multiple medications, such as azelaic acid, metronidazole, or
ivermectin to achieve disease control. The skin of rosacea patients inherently has
impaired skin barrier function, resulting in inflammation and hypersensitivity to most
therapeutics. Thus, many clinicians encourage patients to augment their topical
medications with personal moisturizers to optimize the skin barrier. However, there is
limited data to support that moisturizers do not affect drug epidermal penetrance and
efficacy. To the investigator's knowledge, only a single trial assessing the effect of
moisturizers on skin penetrance of azelaic acid has been published in the English
literature. In the era of evidence-based medicine, it is critical to provide either the
scientific data to support or to refute this medical dogma. The investigator's proposal
addresses this gap in the basic science literature and will provide data to evaluate a
long and widely-held dermatologist recommendation for the treatment of rosacea. The
investigators anticipate that there may be preferred combinations of medication and
moisturizers based upon the matched lipophilicities and other chemical properties of the
occlusive agent and therapeutic drug. Identification of such combinations may lead to
improved outcomes for those struggling with treatment-resistant rosacea and lead to
additional pharmaceutical advances in the treatment of rosacea.
Drug formulation is critical to the successful treatment of dermatologic disease. An
active ingredient must diffuse through the stratum corneum (SC) to reach the dermis to
achieve its therapeutic effect. In addition to the intrinsic chemical properties of the
active compound dictating the kinetics of the diffusion process, chemists tweak a topical
formulation's vehicle, emulsifiers, and polymers to enhance drug SC penetrance and
overcome the skin's evolutionary role as a barrier to the outside world. The combination
of drug with additional topical moisturizers inherently changes the chemical environment
that the active drug must diffuse through to reach the dermis. Moisturizers and other
topical cosmetics are well established to affect dermal drug and toxin absorption. For
example, moisturizers have been demonstrated to enhance dermal penetrance of herbicide
2,4-dichlorophenoxacetic acid in murine models. Similarly, occlusive moisturizers are
often applied over steroids to enhance their anti-inflammatory efficacy, presumably
through improved epidermal penetration. Increased penetrance is a case-by-case scenario,
however, and considerable attention is dedicated to topical formulation to appropriately
modulate therapeutic drug penetrance of the SC during the drug design process.
To the investigator's knowledge, the formulation and timing of moisturizer application on
drug efficacy in rosacea is understudied. An extensive literature review revealed only a
single study addressing this important question for the special case of azelaic acid with
an in vitro Franz cell diffusion assay using donated trunk skin biopsies. In this study,
a 14C radiolabeled 15% azelaic acid gel was applied to epidermis before or after the
application of Dove Lotion, CeraVe Moisturizer Lotion, and Cetaphil Moisturizing Lotion.
The penetrance of azelaic acid into the SC was then assessed up to 48 hours
post-application using liquid scintillation spectrometry. Azelaic acid SC penetration was
not statistically different between the moisturizers or timing of application, although
trends towards decreased penetration was noted in 1 of 3 studied moisturizers. There are
several limitations to this study. First, azelaic acid occupies a unique chemical space
among rosacea therapies. Azelaic acid's lipophilicity (LogP), an important chemical
property affecting epidermal drug penetrance, is 1.6 compared with 5.83, 0.0, -0.3 and
-0.7 for ivermectin, metronidazole, monocycline, and doxycycline, respectively,
suggesting that azelaic acid is between 1.4e2 times more lipophilic to 1.7e4 times less
lipophilic than other therapies. Thus, azelaic acid is a poor standard with which to
assess moisturizers' impact on SC drug penetrance. Second, truncal skin was used to
assess azelaic acid SC penetrance. Consequently, the study's clinical relevance is
limited as rosacea exclusively affects the face, where the skin is much thinner and
transdermal absorption occurs more readily. Finally, although a tritium diffusion control
was implemented to select skin samples with relatively intact barrier function, a Franz
cell diffusion assay inherently utilizes dead, enzymatically inactive skin. Thus, the
results of a Franz cell assay is not necessarily clinically relevant or reflective of
physiologically active skin on patients. Further work is necessary to determine whether
moisturizers affects drug SC penetrance in rosacea patients.
In prior work, the investigators made method advances that overcome many of the
limitations of the Franz cell assay as it relates to clinical relevance. Specifically,
the investigators have established a track record of assessing drug penetrance of
topically delivered medications, e.g. tazarotene, allantoin, ketoconazole, and
betamethasone dipropionate, in the SC using minimally invasive D-squame tape stripes of
human subjects in combination with liquid chromatography mass spectrometry (LC-MS). In
these studies, the investigators are able to assess drug penetrance with physiologically
relevant skin and on skin affected by the disease of interest. Therefore, the methods the
investigators propose for assessing metronidazole SC penetrance in the presence of
moisturizers is now established as an efficient and reliable method for quantitating drug
in the SC in a minimally invasive and clinically relevant context.