Skin permeation and penetration of crisaborole when coapplied with emollients

To the Editor: Atopic dermatitis (AD), a chronic inflammatory skin disease characterized by eczematous lesions and pruritus, is prevalent worldwide. 1Weidinger S. Beck L. A. Bieber T. et al. Atopic dermatitis. Nat Rev Dis Primers. 2018; 4: 1Crossref PubMed Scopus (209) Google Scholar Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate AD. 2Eucrisa package insert. Pfizer Labs, New York, NY2017Google Scholar Although moisturizers are often used in combination with topical therapies to reduce xerosis and aid in skin barrier repair, 3Eichenfield L. F. Tom W. L. Berger T. G. et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014; 71: 116-132Abstract Full Text Full Text PDF PubMed Scopus (711) Google Scholar their effect on topical drug permeation and penetration when coapplied is not well understood. The objective of this study was to assess the effect of over-the-counter (OTC) cream and ointment moisturizers on the permeation and penetration of crisaborole. Crisaborole was applied (10 mg/cm2) to ex vivo healthy abdominal human skin (3 donors, 4 replicates, sliced to a thickness of 500 ± 50 μm with a dermatome) either alone, 15 minutes before, immediately after, or 15 minutes after application of OTC cream (Cetaphil; Galderma Inc, Baie d'Urfé, Montréal, Canada) or OTC ointment (Aquaphor; Beiersdorf Inc, Wilton, CT). The skin was mounted in a flow-through diffusion cell, and the receptor solution (phosphate-buffered saline) was collected at 2-hour intervals up to 24 hours. The amount of crisaborole delivered into the skin and through the skin into the receptor solution was determined by liquid chromatography–tandem mass spectrometry. When crisaborole was applied 15 minutes before either OTC cream or ointment, there were no statistical differences in the concentration of crisaborole in the receptor solution or the dermis (Figs 1 and 2). However, when crisaborole was applied immediately after OTC cream, the concentration of crisaborole was significantly decreased by approximately 3-fold in the receptor solution (Fig 1, A) and 2-fold in the dermis (Fig 2, A) compared with crisaborole alone (P <. 05 for both). Similar results were observed for the epidermis. Application of crisaborole 15 minutes after OTC cream resulted in no statistical difference in the concentration of crisaborole in the receptor solution (Fig 1, A) or in the epidermis and dermis (Fig 2, A). When crisaborole was applied immediately after OTC ointment, there was no statistical difference in the concentration of crisaborole in the receptor solution (Fig 1, B) or in the epidermis and dermis (Fig 2, B). However, when crisaborole was applied 15 minutes after OTC ointment, the concentration of crisaborole decreased by approximately 2-fold in both the receptor solution (Fig 1, B) and the epidermis (Fig 2, B) (P <. 05 for both). Fig 2Mean concentration of crisaborole recovered from epidermis and dermis 24 hours after application alone, 15 minutes before, immediately after, and 15 minutes after application of (A) OTC cream and (B) OTC ointment. ∗P <. 05 versus crisaborole alone. OTC, Over the counter. View Large Image Figure ViewerDownload Hi-res image Download (PPT) There are limited data regarding the effect of coapplication of moisturizers and topical treatments. 4Del Rosso J. Q. Lehman P. A. Raney S. G. Impact of order of application of moisturizers on percutaneous absorption kinetics: evaluation of sequential application of moisturizer lotions and azelaic acid gel 15% using a human skin model. Cutis. 2009; 83: 119-124PubMed Google Scholar, 5Ng S. Y. Begum S. Chong S. Y. Does order of application of emollient and topical corticosteroids make a difference in the severity of atopic eczema in children? . Pediatr Dermatol. 2016; 33: 160-164Crossref PubMed Scopus (11) Google Scholar Here, we show, using an ex vivo model, that the time between applications can affect drug penetration and permeation. The current findings in an ex vivo model suggest that crisaborole should be applied at least 15 minutes before OTC ointments and creams to minimize the impact on dermal absorption of crisaborole. The current study was limited by the use of ex vivo skin from patients without AD, although this approach is a suitable tool for demonstrating the bioequivalence of topical dosage forms. 6European Medicines AgencyDraft guideline on quality and equivalence of topical products. https: //www. ema. europa. eu/en/documents/scientific-guideline/draft-guideline-quality-equivalence-topical-productsₑn. pdfDate: 2018Date accessed: August 21, 2019Google Scholar, 7Raney S. G. Franz T. J. Lehman P. A. et al. Pharmacokinetics-based approaches for bioequivalence evaluation of topical dermatological drug products. Clin Pharmacokinet. 2015; 54: 1095-1106Crossref PubMed Scopus (53) Google Scholar The relationship between the results in this ex vivo study and clinical efficacy, as well as the applicability to other OTC moisturizer formulations, requires further investigation.