QUALITY BY DESIGN-DRIVEN DEVELOPMENT AND CHARACTERIZATION OF TOPICAL DELIVERY OF FLURBIPROFEN NANOEMULGEL
Keywords:
Flurbiprofen trometamol, Nanoemulsion, Nanoemulgel, Argan oil, Quality by Design, Topical drug delivery, Anti-inflammatory, Box-Behnken designAbstract
Background: Flurbiprofen 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 frequent oral dosing, and significant systemic adverse effects including gastrointestinal ulceration, renal impairment, and cardiovascular risks. Topical delivery offers a promising alternative for localized inflammatory pain management, yet conventional formulations achieve limited skin penetration due to the formidable stratum corneum barrier.
Objective: This study aimed to develop and optimize an argan oil-based nanoemulsion and nanoemulgel of FBP using Quality by Design (QbD) principles, thereby enhancing topical delivery, sustaining drug release, and minimizing systemic exposure.
Methods: Pre-formulation studies including solubility screening, partition coefficient determination, and analytical method validation were conducted. Pseudo-ternary phase diagrams were constructed to identify the nanoemulsion region. A Box-Behnken experimental design was employed to optimize formulation variables (oil concentration, Smix concentration, homogenization pressure) with critical quality 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 per ICH 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 a droplet size of 86.4 ± 4.6 nm, PDI of 0.168 ± 0.008, zeta potential of −35.2 ± 1.1 mV, and entrapment efficiency of 90.8 ± 2.3%. The nanoemulgel demonstrated pseudoplastic flow behavior, excellent spreadability (18.5 g· cm/sec), and sustained drug release (58.6% at 8 h; 78.4% at 24 h) following Korsmeyer-Peppas kinetics (R² = 0.988, n = 0.52). Stability studies confirmed robust performance under long-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, sustained release, therapeutic synergy between FBP and argan oil bioactives, and improved safety profile through reduced systemic exposure.
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