Box–Behnken design–based comparative optimization and ex vivo evaluation of baricitinib-loaded polymeric nanoparticles and nanostructured lipid carriers for potential dermal delivery in alopecia

Baricitinib (BAR), a selective Janus kinase inhibitor approved for severe alopecia areata, is associated with systemic adverse effects after oral administration, supporting the development of localized dermal and follicle-targeted delivery strategies. BAR-loaded polycaprolactone (PCL) nanoparticles, poly(lactic-co-glycolic acid) (PLGA) nanoparticles, and nanostructured lipid carriers (NLCs) were developed and optimized using a unified three-factor, three-level Box–Behnken design, with particle size, encapsulation efficiency, and loading capacity as responses. Optimized systems showed particle sizes of 57–173 nm, encapsulation efficiencies of 70–90%, and loading capacities of 1.6–14%. Quadratic models (R2 > 0.98) with non-significant lack-of-fit supported design reliability. All formulations exhibited biphasic release; PCL nanoparticles followed Korsmeyer–Peppas kinetics (n = 0.24), whereas PLGA nanoparticles and NLCs were better fitted by the Weibull model. Ex vivo porcine ear skin studies revealed carrier-dependent distribution profiles: NLCs provided the highest transdermal flux (Jss = 0.309 μg/cm2/h), while PCL nanoparticles achieved higher follicular deposition (6.35 ± 0.48 μg) and skin retention (3.74 ± 0.44 μg). During 180-day storage, PLGA nanoparticles showed the most balanced stability, PCL nanoparticles maintained colloidal integrity despite reduced BAR retention, and NLCs required refrigerated storage to limit physical instability. PCL and PLGA nanoparticles were cytocompatible in HaCaT keratinocytes (≥70%, ISO 10993-5), whereas NLCs showed a narrower cytocompatible range. Overall, PCL nanoparticles appeared more suitable for follicle-oriented dermal delivery, NLCs for enhanced transdermal permeation, and PLGA nanoparticles for sustained release with superior storage stability.