Nose to brain delivery of flurbiprofen from a solid lipid nanoparticles-based thermosensitive in-situ gel

Flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), has selective amyloid-lowering characteristics and can be utilized for Alzheimer's disease treatment. Oral flurbiprofen has poor brain bioavailability and high dose-related gastrointestinal adverse effects. To overcome these issues, the study aimed to formulate intranasal flurbiprofen solid lipid nanoparticles (SLN) based thermosensitive in-situ gel. SLN were formulated by the High-speed homogenization method. A 2³ factorial design technique was utilized for optimization, wherein the influence of two independent variables, critical process parameters (X₁ = surfactant concentration, X₂ = D:L ratio) on critical quality attributes (Y₁ = particle size, Y₂=Percent Drug Loading, Y₃=Percent Entrapment Efficiency) was ascertained at three distinct levels. The optimized SLN were then prepared into an SLN-based intranasal thermosensitive in-situ gel with Poloxamer 188 P (1.2% w/v) and Poloxamer 407 P (18% w/v). The in-vitro flurbiprofen release study demonstrated a 100% release of flurbiprofen from the SLN-based thermosensitive in-situ gel at 6 h. The ex-vivo flurbiprofen release study revealed a complete release of flurbiprofen from the SLN-based thermosensitive in-situ gel at 8 h. In the in-vivo tests, the in-situ gel (2 mg/kg) administered intranasally in rats demonstrated nearly three times greater brain bioavailability (C_max = 490.3 ng/ml) than the oral marketed formulation of flurbiprofen, Ansaid® (10 mg/kg) (C_max = 145.1 ng/ml). The plasma concentration obtained with intranasal in-situ gel (C_max = 2.5 μg/ml) was lower than the oral marketed formulation (C_max = 3.4 μg/ml). The time necessary to establish the maximal flurbiprofen concentration (T_max) in the brain was 2 and 0.5 h for oral and intranasal formulations, respectively. Hence, the intranasal formulation could achieve maximal drug concentration in the brain in less time. Thus, flurbiprofen SLN-based thermosensitive in-situ gel can be a potential encouraging safe, non-invasive, and efficacious replacement to oral formulations for achieving direct brain targeting through nose-to-brain drug delivery, thereby treating neuroinflammatory conditions like Alzheimer's disease.