Lyophilized Nasal Inserts of Atomoxetine HCl Solid Lipid Nanoparticles for Brain Targeting as a Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD): A Pharmacokinetics Study on Rats

Abstract

The study aims to investigate the ability of lyophilized nasal inserts of nanosized atomoxetine HCl solid lipid nanoparticles (ATM-SLNs) to transport atomoxetine (ATM) directly to the brain and overcome the first-pass metabolism. In this case, 16 formulae of (ATM-SLNs) were prepared using hot melt emulsification, stirring and ultrasonication method technique. A full factorial design was established with 24 trials by optimization of four variables; lipid type (Compritol 888 ATO or stearic acid) (X1), lipid to drug ratio [(1:2) or (2:1)] (X2), span 60: Pluronic f127 ratio [(1:3) or (3:1)] (X3) and probe sonication time (five or ten minutes) (X4). The prepared SLNs were characterized for entrapment efficiency (EE%), in-vitro drug release after 30 min (Q30min), particle size (PS), zeta potential (ZP) and polydispersity index (PDI). Design Expert® software was used to select the optimum two formulae. The morphological examination for the optimum two formulae was carried out using a transmission electron microscope (TEM). Furthermore, eight lyophilized nasal inserts were prepared by using a 23 full factorial design by optimization of three variables: type of (ATM-SLNs) formula (X1), type of polymer (NOVEON AA1 or HPMC K100m) (X2) and concentration of polymer (X3). They were evaluated for nasal inserts’ physicochemical properties. The two optimum inserts were selected by Design Expert® software. The two optimum insets with the highest desirability values were (S4 and S8). They were subjected to DSC thermal stability study and in-vivo study on rats. They were compared with atomoxetine oral solution, atomoxetine (3 mg/kg, intraperitoneal injection) and the pure atomoxetine solution loaded in lyophilized insert. (ATM-SLNs) showed EE% range of (41.14 mg ±1.8% to 90.6 mg ± 2.8%), (Q30min%) of (27.11 ± 5.9% to 91.08 ± 0.15%), ZP of (−8.52 ± 0.75 to −28.4 ± 0.212% mV), PS of (320.9 ± 110.81% nm to 936.7 ± 229.6% nm) and PDI of (0.222 ± 0.132% to 0.658 ± 0.03%). Additionally, the two optimum (ATM-SLNs) formulae chosen, i.e., F7 and F9 showed spherical morphology. Nasal inserts had assay of drug content of (82.5 ± 2.5% to 103.94 ± 3.94%), Q15min% of (89.9 ± 6.4% to 100%) and Muco-adhesion strength of (3510.5 ± 140.21 to 9319.5 ± 39.425). DSC results of S4 and S8 showed compatibility of (ATM) with the other excipients. S8 and S4 also showed higher trans-nasal permeation to the brain with brain targeting efficiency of (211.3% and 177.42%, respectively) and drug transport percentages of (52.7% and 43.64%, respectively). To conclude, lyophilized nasal inserts of (ATM-SLNs) enhanced (ATM) trans-nasal drug targeting permeation and brain targeting efficiency.

Development of Atomoxetine-Loaded NLC In Situ Gel for Nose-to-Brain Delivery: Optimization, In Vitro, and Preclinical Evaluation

“…AXT exhibited a short elimination half-life, resulting in rapid elimination after oral delivery [7]. In the present study, AXT-loaded NLCs were developed, and an optimized The intranasal pathway is the quickest and easiest way to target the brain since it bypasses the BBB.…”

“…The release of AXT from the optimized AXT-NLC in situ gel and pure AXT was determined by the dialysis bag method (MWCO 12 kDa). The pore of the dialysis bag was activated by dipping it in distilled water for 24 h before the study [7]. AXT-NLC in situ gel (equivalent to 5 mg of AXT) and pure AXT formulation (equivalent to 5 mg of AXT) were individually filled into the respected dialysis bag and dipped separately into PBS dissolution medium (250 mL, pH 5.5) at 37 • C. The dissolution medium rotated at 75 rpm on the thermostat's magnetic stirrer.…”

“…The PS of all AXT-NLCs was in the range of 65 nm (AXT-NLC2) to 280 nm (AXT-NLC10). Equation (7) showed that the total lipids (A: olive oil and stearic acid) showed a positive effect while other factors (B: surfactant and C: sonication time) exhibited a negative effect on PC. The PS increased as the concentration of total lipid increased simultaneously.…”

“…We postulated that AXT would have therapeutic effects on endothelial dysfunction and vascular-related dementia. AXT belongs to the BCS class I drug class, exhibiting high water solubility and high intestinal permeability [ 7 ]. It displayed bioavailability of 63% and 94% in its extensive and poor metabolizers, respectively [ 7 ].…”

Crosslinked Chitosan Nanoparticles with Muco-Adhesive Potential for Intranasal Delivery Applications

“…The optimization of mucoadhesion-related properties can be successfully exploited for topical drug administration [ 9 ] and in brain targeting [ 10 ]. The olfactory epithelium and the trigeminal nerve pathways work as a direct route for nose-to-brain delivery [ 3 ], enabling the rapid and efficient absorption of active principles and potentially reducing the adverse effects of systemic administration [ 11 ].…”