Targeting tacrolimus to deeper layers of skin with improved safety for treatment of atopic dermatitis—Part II: In vivo assessment of dermatopharmacokinetics, biodistribution and efficacy

Abstract

The objective of present investigation was to study in vivo behavior of tacrolimus-loaded lipid-nanoparticles (T-LN) to understand its targeting potential for treatment of atopic-dermatitis-(AD). T-LN have shown significantly improved drug penetration to deeper epidermal and dermal skin-layers than commercial ointment-Protopic® and effectively reached target dendritic-immune-cells, responsible for immunopathogenesis of AD. Due to enhanced penetrability of T-LN, it became necessary to evaluate the toxicity of the nanocarrier and the drug at non-target tissues. This paper evaluates dermatopharmacokinetics (DPK), biodistribution, efficacy and safety of T-LN in comparison to Protopic® as reference. In vivo DPK in guinea pigs showed 3.02-fold higher bioavailability while γ-scintigraphy in albino-rats demonstrated 1.5-fold rapid penetration of radioactivity in skin for T-LN. Biodistribution in albino-rats revealed restricted localization at the target-skin-area with no general spreading to other body organs suggesting targeting potential of T-LN. In vivo efficacy studies in BALB/c mice showed highly efficient suppression of inflammatory AD-like skin-lesions with T-LN than reference and placebo. Dermal toxicity-studies revealed keratosis and collagenous mass-infiltration with repeated application of reference however interestingly, T-LN treated group showed no evident toxicity demonstrating significantly improved safety. Thus T-LN offered improved penetration to the target site without any toxic-effects and would represent an efficient and commercially viable alternative for AD treatment.