title: 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.
authors.affiliation: C. U. Shah College of Pharmacy, S.N.D.T. Women's University, Mumbai 400 049, India.
authors.forename: Pallavi V
authors.initials: PV
authors.lastname: Pople
authors.forename: Kamalinder K
authors.initials: KK
authors.lastname: Singh
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001682:Biological Availability; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D006168:Guinea Pigs; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D009824:Ointments; D051381:Rats; D017208:Rats, Wistar; D012869:Skin Absorption; D013045:Species Specificity; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution; D018675:Toxicity Tests
chemical_list: D007166:Immunosuppressive Agents; D008055:Lipids; D009824:Ointments; D016559:Tacrolimus