Vanillic acid and avocado oil co-loaded nanostructured lipid carrier gel for topical management of psoriasis: Formulation, characterization, and multi-faceted evaluation through in vitro, <i>ex vivo, in vivo,</i> and <i>in silico</i> studies

Psoriasis is a chronic non-communicable inflammatory skin disease that significantly affects a patient’s well-being and overall quality of life. Because psoriasis is a multifactorial disease involving complex immune and dermatological alterations, and current therapies are often inadequate, it remains challenging to treat effectively. The primary objective of the current study was to prepare a topical gel formulation of nanostructured lipid carriers (NLCs) loaded with vanillic acid and avocado oil for the effective management of psoriasis. Vanillic acid- and avocado oil-loaded NLCs were prepared using the emulsion evaporation–solidification method, with stearic acid serving as the solid lipid (SL) and avocado oil as the liquid lipid (LL). The prepared NLCs were subsequently incorporated into a Carbopol 940 gel base. The formulations were thoroughly evaluated for zeta potential, particle size, drug loading capacity (DL%), entrapment efficiency, as well as in vitro drug release. The NLC-loaded gel was further evaluated for ex vivo skin permeation, skin sensitization, and anti-psoriatic potential. The S7 batch exhibited the highest concentrations of vanillic acid and oleic acid, with values of 21.8 ± 0.098% for vanillic acid and 31.8 ± 0.56% for oleic acid.This batch contained 100 mg each of solid and liquid lipids. The high drug loading was attributed to the 1:1 drug-to-lipid ratio. The entrapment efficiency of vanillic acid ranged from 11.95 ± 0.09% to 65.52 ± 0.70%, whereas that of oleic acid ranged from 53.15 ± 0.74% to 95.74 ± 0.70% across the seven NLC batches. The NLCs exhibited an average particle size ranging from 178.2 ± 4.8 nm to 250.9 ± 6.4 nm, with a zeta potential (ZP) between −18.2 mV and −12.3 mV. The drug release profile was best described by the Higuchi model. These NLCs exhibited excellent permeation properties owing to their capacity to integrate into the lipid matrix of the stratum corneum. Molecular docking and molecular dynamics (MD) simulation of the active ingredients of the formulation i.e. β-sitosterol and vanillic acid exhibited a binding affinity of -9.5 kcal/mol and – 6.2 kcal/mol, forming hydrogen bond at a shortest distance of 2.90Å, the MD simulation has revealed the RMSD of the complex ranged between 0.134 – 0.158Å with stable Vander Waals surface area and radius of gyration under conditions resembling cellular environment. The NLC-loaded gel exhibited controlled drug release and demonstrated promising anti-psoriatic activity in biological evaluations, showing greater efficacy in treating psoriasis compared to the commercial formulation. Further the interaction of bioactive ingredients of the formulation with the proteins of interest has shown stable confirmation with a docking affinity score of -9.5 kcal/mol with stable bonds determined through MD-seed simulations. Phytoactive-loaded NLCs-based gel showed the great potential for phytoactives permeation and offers a promising strategy for the treatment of psoriasis.