In Vitro Skin Retention of Crisaborole after Topical Application.

Adriana Fantini,Sara Nicoli,Patrizia Santi,Anna Demurtas,Cristina Padula,Silvia Pescina

doi:10.3390/pharmaceutics12060491

Abstract

Crisaborole, a nonsteroidal phosphodiesterase 4 inhibitor, represents the first nonsteroidal medication approved for the treatment of atopic dermatitis in over a decade. In this work, crisaborole skin permeation and retention was studied in vitro from a 2% ointment using porcine skin as barrier. Crisaborole was also characterized in terms of thermal behavior, solubility, and logP. Control experiments were performed also on tape stripped skin to clarify the role of stratum corneum in drug partitioning and permeation across the skin. The results obtained indicate that crisaborole accumulates into the skin in considerable amounts after application of a topical lipophilic ointment. Crisaborole shows more affinity for the dermis compared to the epidermis despite its relatively high value of partition coefficient; stratum corneum analysis revealed a low affinity of the drug for this skin layer. Skin penetration across hair follicles or sebaceous glands can be a reason for the high dermis retention and is worth further investigation. The comparison with data obtained from a solution in acetonitrile suggests that the formulation plays a certain role in determining the relative distribution of crisaborole in the skin layers and in the receptor compartment.

Highlights

Atopic dermatitis (AD), known as atopic eczema, is a chronic inflammatory condition of the skin [1] which affects up to 5% of adult population and 15%–20% of children [2,3]
The results obtained in the present work indicate that crisaborole accumulates into the skin in considerable amounts after application of a topical lipophilic ointment
Crisaborole shows more affinity for the dermis compared to the epidermis despite its relatively high value of partition coefficient; stratum corneum analysis revealed a low affinity of the drug for this skin layer

Summary

Introduction

Atopic dermatitis (AD), known as atopic eczema, is a chronic inflammatory condition of the skin [1] which affects up to 5% of adult population and 15%–20% of children [2,3]. It is generally accepted that several mechanisms contribute to AD etiology and manifestations [1,6,7]: impairment of epidermal barrier function, deficiency in the structural protein filaggrin, dysbiosis of the skin microbiota (in particular increase of Staphylococcus aureus), systemic immune responses, and neuroinflammation, which is involved in itch. For more severely affected subjects, systemically administered immunosuppressants are often necessary [8,9], whereas topical calcineurin inhibitors (tacrolimus and pimecrolimus) entered the topical treatments for mild AD [10]. Despite their efficacy, the use of both steroids and calcineurin inhibitors is associated with safety concerns due to their side effects [11]. Long-term topical steroid therapy produces skin atrophy and suppression of the hypothalamic–pituitary–adrenal axis, whereas the use of tacrolimus is associated with burning/stinging upon application

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