Development, Central Composite Design Optimization and Pharmacokinetic Evaluation of Lopinavir-Loaded Solid Lipid Nanoparticles for Enhanced Oral Bioavailability (Research Article)

Author(s): Gaurav* and Mukesh Chandra Sharma

Abstract: Background: Lopinavir, a potent HIV protease inhibitor, is classified as a BCS Class II drug with extremely poor aqueous solubility (0.025 mg/mL) and low oral bioavailability (<25% when administered alone). It requires co-administration with ritonavir (a CYP3A4 inhibitor) to achieve therapeutic levels, which introduces additional adverse effects and drug–drug interactions. This study aimed to develop and optimize lopinavir-loaded solid lipid nanoparticles (LPV-SLNs) to enhance oral bioavailability and enable ritonavir-free therapy. Methods: LPV-loaded SLNs (LPV-SLNs) were prepared using the hot-melt emulsion technique, with glyceryl behenate (Compritol 888 ATO) as the lipid matrix and a surfactant blend of Tween 80 and Poloxamer 188 (8:2 ratio). A three-factor Central Composite Design (CCD) with 20 runs (α = 1.682) was employed for optimization. The independent variables were lipid concentration (1.5-3.5 mg/mL), surfactant blend concentration (0.75-1.75% w/v), and homogenization speed (10,000-20,000 rpm). The responses included particle size, encapsulation efficiency (EE%), and cumulative drug release at 12 h (CDR₁₂). The optimized formulation was characterized for particle size, PDI, zeta potential, EE%, DL%, morphology (TEM), thermal behavior (DSC), crystallinity (XRD), in vitro release, stability, and in vivo pharmacokinetics in male Wistar rats (n=6). Results: The optimized LPV-SLN formulation (lipid 3.25 mg/mL, surfactant blend 1.65% w/v, homogenization speed 18,500 rpm) exhibited a particle size of 158.8 ± 4.5 nm, PDI of 0.185 ± 0.012, zeta potential of -34.5 ± 1.6 mV, EE% of 90.2 ± 2.2%, and DL% of 16.05 ± 0.48%. TEM revealed spherical nanoparticles with smooth surface. DSC and XRD confirmed the molecular dispersion of lopinavir in the amorphous state within the lipid matrix. In vitro release demonstrated sustained release (75.5% at 24 hours) with an anomalous transport mechanism (Korsmeyer-Peppas model, n=0.52, R²=0.9895). Stability studies at 25°C/60% RH for 6 months showed a drug content of 95.2%. In vivo pharmacokinetic studies revealed that LPV-SLNs achieved Cmax of 5.68 ± 0.30 μg/mL compared to 1.82 ± 0.18 μg/mL for suspension (3.1-fold increase, p<0.001), Tmax delayed from 2.0 to 6.0 h, AUC₀₋₂₄ increased from 15.85 to 72.45 μg·h/mL (4.57-fold increase), and relative bioavailability of 474.1%. Conclusion: CCD-driven optimization successfully developed LPV-SLNs with high drug loading (16.05%), sustained release characteristics, and exceptional oral bioavailability enhancement (4.7-fold). This formulation has the potential to enable ritonavir-free therapy, simplifying HIV treatment regimens and reducing drug-drug interactions.

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