<p>Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies</p>

Abstract

Purpose: Duloxetine (DLX) is dual serotonin and norepinephrine reuptake inhibitor suffering from limited bioavailability (≈ 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. Materials and Methods: Cubo-gels were prepared by 3 3 central composite design with three independent factors, lipid ratio (glycerol monooleate: glycerol tripalmitate), Pluronic F127%, and Pluronic F68%. The prepared formulations were evaluated for their particle size (PS), gelling temperature (GT), entrapment efficiency (EE%), and in vitro release. The cubogel with the highest desirability (0.88) was chosen as the optimized formulation. DLX cubogel was evaluated using differential scanning calorimetry, Fourier-transform infrared spectroscopy, X-ray powder diffraction, and transmission electron microscopy. Cytotoxicity study, ex vivo permeation study and in vivo bio-distribution study were conducted to evaluate the safety and efficacy of brain targeting. Results: The optimum cubo-gel was composed of 3.76 lipid ratio, 20% w/v PF127, and 5% w/v PF68. It had PS of 265.13 ± 9.85 nm, GT of 32 ± 0.05°C, EE% of 98.13 ± 0.50%, and showed controlled release behavior where 33% DLX was released within 6 hrs. The plain in situ cubo-gel had a significantly higher IC 50 compared to DLX solution and DLX-loaded in situ cubo-gel. The ex vivo permeation study showed 1.27 enhancement in the drug permeation from DLX in situ cubo-gel. According to the in vivo bio-distribution study in plasma and brain, the intranasal DLX in situ cubo-gel showed a 1.96 fold improvement in brain bioavailability compared to the intranasal solution. Its BTE% and DTP% were 137.77 and 10.5, respectively, indicating efficient brain targeting after intranasal administration. Conclusion: Accordingly, intranasal DLX in situ cubo-gel can be considered as an innovative nano-carrier delivery system for bioavailability enhancement and efficient brain targeting of DLX to maximize its effect.

Sesame Oil-Based Nanostructured Lipid Carriers of Nicergoline, Intranasal Delivery System for Brain Targeting of Synergistic Cerebrovascular Protection

“…Low viscosity of liquid lipids and better drug solubility allow easier diffusion of the drug and faster erosion of the matrix surface [ 54 , 85 ]. In addition, the tendency of Tween 80 to precipitate onto the globular surface also supports this initial burst release [ 58 ]. Over time, slower drug release occurs from the inner core in which the solid lipid is almost homogenous and closely packed; this allows only slow and controlled penetration of the dissolution medium into the deeper lipid layers and drug dissolution.…”

“…The NLC formulations F6, F8, F9, and F15 showed higher EE% for NIC when compared to NLC formulations F1, F4, F10, and F14, respectively, when the SAA concentration increased from 1% to 3% when other factors were kept constant to confirm the main positive effect of SAA concentration on EE%. This effect could be correlated to the solubilizing action of SAA at higher concentration and accumulation of Tween 80 (SAA) interfacial film on the globular surface allowing for the accommodation of additional drug [ 58 , 81 ].…”

“…The release profile of NIC from optimized NLC formulations (F1–F3) in simulated nasal fluid was studied and the average release data were illustrated in Figure 3 . Nicergoline showed retarded slow-release pattern from the prepared NLC formulations over 48 h and reached approximately 72% of the dose, while the unformulated drug reached 71% after 4 h only and completely dissolved within 10 h. This effect is mainly related to the lipophilic nature of the drug that slowing its partitioning out of the lipid core of the NLC systems [ 58 ]. Also, absence of this barrier for drug diffusion at the release membrane surface allows better and faster drug availability in dissolution medium in unformulated form [ 54 ].…”

“…Presence of NIC in plasma with considerable concentrations following IN administration of NLC formula and drug solution was acceptable as systemic absorption is expected through the respiratory epithelium due to the high vascularity nature [ 96 ]. Further investigation of pharmacokinetics data showed that NIC–NLC formula had longer plasma half-life (3.17 h) in comparison to NIC–SOL (1.45 h) following IN administration, the extended circulation time of NIC–NLC formula allows exposure of a larger area of nasal mucosa to the drug for a longer time, which results in extended drug absorption and higher bioavailability [ 58 ].…”

“…In addition, it can be easily functionalized with a specified brain-targeting ligand to guarantee optimum CNS selectivity. Polymeric nanocarriers, nanoemulsions, liposomes, solid lipid nanoparticles, and nanostructured lipid carriers (NLCs) have been recently studied and considered as reliable, promising nose-to-brain delivery systems [ 57 , 58 ].…”