Amoxapine-Loaded Solid Lipid Nanoparticles with Superior Preclinical Pharmacokinetics for Better Brain Delivery:...

The tricyclic antidepressant amoxapine (AMX) has been reported for a rapid onset of action compared to other cyclic antidepressants. It has very low solubility and bioavailability due to first-pass metabolism. Therefore, we planned to develop solid lipid nanoparticles (SLNs) of AMX using a single emulsification method to increase its solubility and bioavailability. HPLC and LC-MS/MS methods were developed further to quantify AMX in the formulation, plasma, and brain tissue samples. The formulation was studied for entrapment efficiency, loading, and in vitro drug release. Particle size and ζ potential analyses, AFM, SEM, TEM, DSC, and XRD were used for further characterization. In vivo oral pharmacokinetic and brain pharmacokinetic studies were performed using Wistar rats. The entrapment and loading efficiencies of AMX in SLNs were 85.8 ± 3.42 and 4.5 ± 0.45%, respectively. The developed formulation had a mean particle size of 151.5 ± 7.02 nm and a polydispersity index of 0.40 ± 0.11. DSC and XRD results indicated that AMX was incorporated into the nanocarrier system in an amorphous form. SEM, TEM, and AFM studies of AMX-SLNs confirmed the particles' spherical shape and nanoscale size. AMX solubility increased by approx. 2.67 times compared to the pure drug. The developed LC-MS/MS method was successfully applied to the oral and brain pharmacokinetic study of AMX-loaded SLNs in rats. Oral bioavailability was enhanced 1.6 times compared to the pure drug. The peak plasma concentrations of pure AMX and AMX-SLNs were 617.4 ± 137.4 and 1043.5 ± 150.2 (ng/mL), respectively. AMX-SLNs showed more than 5.8 times brain concentration compared to the pure drug. Based on the findings, it appears that utilizing a solid lipid nanoparticle carrier to transport AMX can be a highly effective delivery method with improved pharmacokinetic properties in the brain. This approach may prove valuable for future antidepressant treatment.