الفهرس 
A novel drug design for bioavailability enhancement
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Abstract
Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor. The claimed mechanism of action of DLX is based on the specific inhibition of both serotonin and norepinephrine reuptake, while it weakly inhibits dopamine reuptake and has no significant affinity for histaminergic, dopaminergic, cholinergic or adrenergic receptors. DLX used in major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy and fibromyalgia. DLX is well absorbed after oral administration with 2 {u2013}hour lag time until absorption begins.DLX suffering from limited bioavailability ({uF0BB} 40%) due to extensive hepatic metabolism. This work aims to formulate and evaluate DLX intranasal thermoreversible cubosomal gels to enhance its bioavailability and ensure efficient brain targeting. The nasal route improves drug bioavailability by bypassing first-pass hepatic metabolism and allows direct delivery to the systemic circulation. The nasal route has privilege in brain targeting by direct drug transfer to the brain through neuronal pathway and avoidance of the blood-brain barrier. The in situ nasal gel prolongs formulation residence time and increase penetration rate with drug absorption improvement. Cubo-gels were prepared by three factors, three levels 33 central composite design to formulate 15 formulations with 5 repetitions of the center point formulation (F8). The three independent factors, lipid ratio (glycerol monooleate: glycerol tripalmitate), Pluronic F127 percent and Pluronic F68 percent. The dependant variables were particle size (PS), gelling temperature (GT), entrapment efficiency (EE %) and in-vitro release. The polydispersity index (PDI) and Zeta potential (ZP) were also measured for the prepared formulations. The PS for the prepared formulation ranged from 145.5nm to 515.9 nm, PDI ranged from 0.3 to 1, ZP ranged from 1.6 to 10.6, GT from 32oc to 80 oc, EE% from 93.1% to 99.7% and Q6 % from 20.3% to 64.5%. The cubo-gel with the highest desirability (0.88) was chosen as the optimized formula using Design Expert® software