Quality by Design-Driven Development and Characterization of an Argan Oil- Based Nanoemulgel for Enhanced Topical Delivery of Dexketoprofen Trometamol

AbstractBackground: Dexketoprofen trometamol (DEX), the pharmacologically active S-(+)-enantiomer ofketoprofen, is a potent non-steroidal anti-inflammatory drug (NSAID) with rapid onset of analgesia.However, its clinical utility is constrained by a short elimination half-life (1–2.5 h) necessitating frequentoral dosing, and significant systemic adverse effects including gastrointestinal ulceration, renalimpairment, and cardiovascular risks. Topical delivery offers a promising alternative for localizedinflammatory pain management, yet conventional formulations achieve limited skin penetration due tothe formidable stratum corneum barrier.Objective: This study aimed to develop and optimize an argan oil-based nanoemulsion and nanoemulgelof DEX using Quality by Design (QbD) principles, thereby enhancing topical delivery, sustaining drugrelease, and minimizing systemic exposure.Methods: Pre-formulation studies including solubility screening, partition coefficient determination, andanalytical method validation were conducted. Pseudo-ternary phase diagrams were constructed toidentify the nanoemulsion region. A Box-Behnken experimental design was employed to optimizeformulation variables (oil concentration, Smix concentration, homogenization pressure) with criticalquality attributes (droplet size, polydispersity index, zeta potential, entrapment efficiency) as responses.The optimized nanoemulsion was incorporated into a Carbopol 934P gel base to form a nanoemulgel.Comprehensive physicochemical characterization, in vitro drug release studies, and stability testing perICH Q1A(R2) guidelines were performed.Results: The optimized nanoemulsion (12.5% w/w argan oil, 40% w/w Smix [Tween 80:PEG 400, 2:1],47.5% w/w aqueous phase) prepared by high-pressure homogenization at 1250 bar for 7 cycles exhibited adroplet size of 86.4 ± 4.6 nm, PDI of 0.168 ± 0.008, zeta potential of −35.2 ± 1.1 mV, and entrapmentefficiency of 90.8 ± 2.3%. The nanoemulgel demonstrated pseudoplastic flow behavior, excellentspreadability (18.5 g·cm/sec), and sustained drug release (58.6% at 8 h; 78.4% at 24 h) followingKorsmeyer-Peppas kinetics (R2 = 0.988, n = 0.52). Stability studies confirmed robust performance underlong-term conditions (25°C/60% RH) with a projected 24-month shelf-life.Conclusion: The QbD-optimized argan oil nanoemulsion/nanoemulgel system represents a promising,clinically translatable strategy for topical NSAID delivery, combining enhanced permeation, sustainedrelease, therapeutic synergy between DEX and argan oil bioactives, and improved safety profile throughreduced systemic exposure.