Mechanistic Analysis of Human Skin Distribution and Follicular Targeting of Adapalene-Loaded Biodegradable Nanospheres With an Insight Into Hydrogel Matrix Influence, In Vitro Skin Irritation, and In Vivo Tolerability

• Published in: Journal of pharmaceutical sciences 2017-10, Vol.106 (10), p.3140-3149
• Main Authors: Sallam, Marwa Ahmed, Marín Boscá, María Teresa
• Format: Article
• Language: English
• Subjects: Acne Vulgaris - drug therapy; adapalene; Adapalene - administration & dosage; Adapalene - chemistry; Animals; Caproates - administration & dosage; Caproates - chemistry; confocal imaging; Delayed-Action Preparations - chemistry; Dermis - metabolism; Draize test; Drug Delivery Systems - methods; Epidermis - metabolism; Hair Follicle - metabolism; Humans; hyaluronic acid; Hyaluronic Acid - chemistry; Hydrogel, Polyethylene Glycol Dimethacrylate - administration & dosage; Hydrogel, Polyethylene Glycol Dimethacrylate - chemistry; Hypromellose Derivatives - chemistry; Lactones - administration & dosage; Lactones - chemistry; Nanospheres; Particle Size; polycaprolactone; Rabbits; Skin Absorption - drug effects
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2017.05.038

This work aimed at the development of a biocompatible, non-oily nanomedicine for follicular delivery of adapalene (AD) ameliorating its irritation potential for convenient localized topical treatment of acne vulgaris. AD was efficiently incorporated into poly-ε-caprolactone nanospheres (NS) with an encapsulation efficiency of 84.73% ± 1.52%, a particle size of 107.5 ± 8.19 nm, and zeta potential of −13.1 mV demonstrating a sustained-release behavior. The AD-NS were embedded in either hydroxypropyl methylcellulose (HPMC) or hyaluronate (HA) gel. The ex vivo human skin dermatokinetics of AD from each system was studied. The nanoparticles dispersion showed significantly higher AD retention in the epidermis and dermis than AD suspension. NS-HPMC decreased whereas NS-HA increased AD retained in all the skin layers. The fate of the NS and the role of the hydrogel in modulating skin distribution was evaluated by confocal laser scanning microscopy (CLSM) imaging of fluorescently labeled NS. CLSM illustrated follicular localization of the florescent NS. HPMC gel restricted the presence of NS to the stratum corneum and epidermis. HA gel enhanced the penetration of NS to all the skin layers. In vitro skin irritation using human dermal fibroblasts and in vivo animal tolerability studies were performed. Accordingly, HA gel–dispersed AD-NS presented a nonirritant compromised cosmeceutical formulation suitable for oily acneic skin.