Enhancing 3-acetyl-11-keto-β-boswellic acid skin permeation <i>via</i> nanostructured lipid carriers: integrating quality by design principles for risk estimation and optimization

3-Acetyl-11-keto-β-boswellic acid (AKBA), a bioactive compound derived from <i>Boswellia serrata</i>, exhibits significant anti-inflammatory and antioxidant properties, making it a promising candidate for treating inflammatory skin disorders. Its hydrophobic nature makes topical administration challenging. By developing nanostructured lipid carriers (NLCs), this work sought to enhance the skin penetration of AKBA. Quality-by-design principles were applied for the development of a robust formulation, where AKBA-NLCs were developed using a three-factor, three-level Box-Behnken design. AKBA-NLCs were prepared by the hot homogenization technique. The optimized formulation was further loaded into a gelling system, and its rheological parameters were evaluated. Further evaluation for <i>ex vivo</i> skin permeation and retention, along with other characteristics such as occlusivity, extrudability, and spreadability, was performed. Quality-by-design through <i>p</i>-value assessment highlighted that all three factors significantly affected particle size, and in the case of PDI, only lipid content showed a significant impact, whereas for entrapment efficiency, lipid and surfactant content were the governing factors. Based on the set constraints, the optimized batch of AKBA-NLCs exhibited a particle size of 173.700 ± 1.165 nm, a PDI of 0.323 ± 0.012, a zeta potential of -19.533 ± 0.493 mV, and an entrapment efficiency of 82.349 ± 3.223%. The <i>in vitro</i> release showed a prolonged release profile up to 56 h. When tested for cytotoxicity in the HaCaT cell line, the formulation was observed to be non-cytotoxic. The rheological data of the gel demonstrated a non-Newtonian, pseudo-plastic nature and indicated good structural strength. The <i>ex vivo</i> skin permeation of AKBA-NLCs was found to be 1.34 times higher than that <i>via</i> plain gel. Based on consistent results of viscosity, particle size integrity, and assay after one year of storage, the formulation was found to be stable. The formulation method used was simple and cost-effective, allowing for possible industrial scale-up. According to the findings, the NLC-loaded gel may prove to be a useful delivery strategy for the management of inflammatory skin conditions.