Assessment of skin penetration of classical and deformable liposomes

The skin is the largest organ of the human body representing an alternative route of administration by providing an easy and pain-free drug delivery option. Cutaneous drug delivery is not associated with a significant drug loss compared to systemic administration due to low enzymatic degradation and a negligible clearance. Moreover, the systemic toxicity resulting from cutaneous application is limited and side effects are easy to observe and to handle [1]. Thanks to these advantages there is a great interest in using the skin as a route of administration. Besides physical and active methods involving the disruption of the stratum corneum (SC) to increase the penetration of drugs in the underlying layers, passive methods using of non-viral vectors, particularly lipid-based nanovectors, is one of the most attractive method [2]. They were developed to increase topical macromolecules penetration through the SC barrier and to promote the intracellular delivery of large molecules such as nucleic acids. However, it has become obvious that conventional liposomes do not promote the skin penetration without enhancement techniques [3].
The aim of this study is to assess the skin penetration of lipid-based nanocarriers according to their composition. The skin penetration of conventional liposomes was compared to the penetration of deformable liposomes with ethanol and/or edge activators (EA).
25% (w/w) of ethanol was added to conventional liposomes (DOTAP/DOPE) to form ethosomes. Sodium Cholate and Tween®80 were used as EA to develop deformable liposomes. Formulations were characterized in terms of size, polydispersity index and surface charge. Ex vivo skin penetration experiment were performed using pig ear skin on Franz cells. In order to visualize the penetration through the skin using confocal microscopy, nanocarriers were fluorescently labeled with a fluorescent lipid (NBD-PC). A kinetic of application was performed (from 3h to 24h) and each condition was done with or without tape stripping.
In this study, we showed that all the formulations were not able to penetrate the skin, even for deformable formulations. However, when the SC was removed, formulations containing ethanol allowed penetration into the epidermis. Moreover, the addition of an EA seems to encourage deeper penetration.
Acknowledgments: Authors thank the Walloon Region and FEDER for financial supports.
References:
1. Zakrewsky, M., S. Kumar, and S. Mitragotri, Nucleic acid delivery into skin for the treatment of skin disease: Proofs-of-concept, potential impact, and remaining challenges. J Control Release, 2015. 219: p. 445-56.
2. Geusens, B., et al., Lipid-mediated gene delivery to the skin. Eur J Pharm Sci, 2011. 43(4): p. 199-211.
3. Sala, M., et al., Lipid nanocarriers as skin drug delivery systems: Properties, mechanisms of skin interactions and medical applications. Int J Pharm, 2018. 535(1-2): p. 1-17.