Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps Ex vivo skin permeation and penetration of nonivamide from and in vivo skin tolerability of film-forming formulations containing porous silica Rouven Heck a , Milica Ž. Lukić b , Snežana D. Savić b , Rolf Daniels a , Dominique J. Lunter a,⁎ a Department of Pharmaceutical Technology, Eberhard Karls University, Tuebingen, Germany b Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Serbia ARTICLE INFO Keywords: Chronic pruritus Film-forming formulations Nonivamide Porous silica Skin penetration & permeation ABSTRACT Aim: The purpose of this study was to evaluate skin permeation and penetration of nonivamide which has been formulated in novel film-forming formulations (FFFs). These formulations aim to prolong the availability of capsaicinoids which are used in long-term treatment of chronic pruritus. Methods: An oily solution of nonivamide was loaded into porous silica particles which then were suspended in an aqueous dispersion of a sustained release polymer. Permeation and penetration experiments were performed ex vivo with postauricular porcine skin using modified Franz diffusion cells. The penetrated drug amount was assessed ex vivo by skin surface biopsy followed by cryo-sectioning. Furthermore, in vivo skin irritation experiments were performed to compare the potential skin irritation caused by the FFFs to conventionally used semi-solid formulations. Results: Permeation rates of nonivamide from FFF through the skin are comparable to that from clinically used immediate release formulations. This elucidates the therapeutic safety profile of the novel FFF. Penetration studies confirmed the prolonged drug availability at the site of action. FFFs were found not to irritate the skin of healthy volunteers. Conclusion: FFFs with sustained nonivamide penetration represent safe and easy-to-use formulations. They therefore may improve the treatment of chronic pruritus with capsaicinoids by enhancing patient compliance through a sustained release regime. 1. Introduction Chronic pruritus is a widespread symptom in various skin diseases. Generally, itch is associated with skin diseases such as atopic dermatitis or psoriasis. The challenge of an efficient pruritus therapy is to break the vicious circle of itch and scratching (Stander et al., 2010; Zeidler et al., 2016). Conventionally, itch is treated with antihistamines and local anaesthetics. Severe secondary lesions due to repeated scratching, described as Pruritus nodularis, typically occur in geriatric patients and are treated first-line topically with coritosteroids and pimecrolimus (Zeidler and Stander, 2014). Often, this therapy is inadequate or even fails. In these cases, capsaicinoids represent an alternative in the therapy of chronic pruritus or localized pruritus nodularis (Ellis et al., 1993; Stander et al., 2012, 2001; Staubach and Metz, 2013). Although capsaicinoids may initially induce pain and itch when applied to the skin, long-term topical administration leads to effective relief. The mechanism of action is presumed to involve the vanilloid 1 receptor (TRPV1), a nonselective cation channel expressed on peripheral end- ings of Aδ- and C-fibers in the viable epidermis (Ikoma et al., 2006). Binding of nonivamide to TRPV1 results in release of substance P, calcitonin gene-related peptide (CGRP) and other vasodilative sub- stances inducing neurogenic inflammation and edema (Fang et al., 1999, 1996; Stander et al., 2001). If the application of nonivamide is continued, the persistent influx of cations, mainly calcium, leads to an intracellular calcium overload resulting in a defunctionalization of the nociceptive neurons. Consequently, this is followed by long-lasting relief of pain and pruritus (Anand and Bley, 2011). By eliminating the stimulus for scratching, physiological strain is reduced and skin lesions are given the opportunity to heal. Thus, capsaicinoids represent a suitable drug for the therapy of chronic skin diseases, which are accompanied with itch and pruritus. The synthetic analogue of capsai- cin nonivamide is chemically defined and available highly purified. This is preferable for the development of a novel drug formulation. On this basis, we selected nonivamide as a model drug to be incorporated in the FFFs. Despite the high efficiency of capsaicinoids, no product is author- ized with chronic pruritus as an indication, although a nicoboxil/ nonivamide ointment (Finalgon® Wärmecreme stark, Boehringer http://dx.doi.org/10.1016/j.ejps.2017.05.045 Received 24 February 2017; Received in revised form 4 May 2017; Accepted 20 May 2017 ⁎ Corresponding author at: Department of Pharmaceutical Technology, Auf der Morgenstelle 8, 72076 Tuebingen, Germany. E-mail address: dominique.lunter@uni-tuebingen.de (D.J. Lunter). European Journal of Pharmaceutical Sciences 106 (2017) 34–40 Available online 22 May 2017 0928-0987/ © 2017 Elsevier B.V. All rights reserved. MARK