Comparing the efficacy of nanocarriers for cutaneous and follicular delivery of poorly water-soluble molecules: A case study with ciclosporin A

Therapeutic agents approved for the topical treatment of dermatological diseases have diverse physicochemical properties, but they are frequently poorly water-soluble, which makes it a challenge to prepare stable aqueous formulations with good delivery characteristics. Several types of nanocarrier have been reported to facilitate formulation and to enhance cutaneous delivery but there are few direct comparisons of nanocarriers in terms of their ability to deliver a specific molecule to the skin under the same controlled conditions. The present study aimed to address this by developing, optimizing, and comparing different nanocarriers with respect to their ability to deliver ciclosporin A (CsA) to the skin and the hair follicle. Nanoconstructs were categorized as vesicular carriers (micelles and liposomes), emulsion-based systems (microemulsions and nanoemulsions), and nanoparticle systems (e.g. polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers). Formulations were optimized using a design of experiments approach and were characterized with respect to size, morphology and incorporation efficiency. Cutaneous and follicular delivery experiments were performed using porcine skin. CsA deposition, cutaneous biodistribution, follicular delivery and targeting potential (ratio of delivery to skin with and without pilosebaceous units) were assessed. Nanoemulsions, kinetically stable systems with high thermodynamic activity, showed the highest cutaneous delivery of CsA among the nanosystems tested followed by solid lipid nanoparticles and mPEG-dihexPLA micelles - i.e. three different types of nanocarrier. The results confirmed the pivotal role of thermodynamic activity in determining delivery efficiency of a nanocarrier and its greater importance than other routinely studied morphological parameters such as nanocarrier size: the smallest nanocarriers did not yield the highest delivery.