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<p>Epilepsy management remains significantly limited by the blood-brain barrier (BBB), which restricts delivery of antiepileptic drugs like lacosamide (LCM). The drug's poor aqueous solubility (0.027 mg/mL) and variable oral bioavailability (~50%) further complicate treatment. To address these challenges, this study developed chitosan-coated nanostructured lipid carriers (LCM-CT-NLCs) for intranasal administration with the potential to facilitate direct nose-to-brain delivery using a systematic Quality-by-Design (QbD) approach guided by predefined Quality Target Product Profile (QTPP) criteria. The research aimed to optimize LCM-CT-NLCs for intranasal administration, specifically targeting enhanced brain bioavailability and sustained seizure control. Critical QTPP parameters included particle size (100-120 nm), entrapment efficiency (≥80%), sustained release over 8 hours, and mucoadhesive strength (≥0.2 N). Formulation optimization was achieved through Box-Behnken experimental design, evaluating lipid ratios (1:9 to 9:1) and surfactant concentrations (3-5%). Comprehensive characterization involved dynamic light scattering for particle properties, TEM for morphology, and FTIR/DSC/XRD for physicochemical interactions. The optimized formulation (F8) demonstrated excellent alignment with QTPP targets. Uncoated particles measured 99 ± 3.1 nm (PDI &lt;0.2), increasing to 108.8 nm after chitosan coating while maintaining monodispersity. High entrapment efficiency (80.0 ± 1.58%) and sustained drug release (88.39% over 8 hours, Higuchi kinetics R²=0.991) were achieved. The formulation showed strong mucoadhesion (0.22 ± 0.03 N) and significantly enhanced ex vivo permeation (flux 358 ± 13 μg/cm²/h, 1.47-fold higher than LCM solution). Stability studies confirmed robustness at 30°C/60% RH for 90 days with minimal changes in particle size (≤5.6% increase) and drug loading (≤0.1% loss). These results demonstrate that QTPP-driven development successfully produced LCM-CT-NLCs meeting all predefined targets for an intranasal formulation intended for brain delivery.The optimized formulation combines ideal nanocarrier properties with enhanced mucosal retention and permeation characteristics conducive to bypassing the BBB, offering a promising non-invasive alternative for improved epilepsy management. This approach effectively addresses key limitations of conventional LCM therapy while demonstrating excellent stability for potential clinical translation.</p>

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Optimized Lacosamide Nanostructured Lipid Carriers for Enhanced Brain Targeting Via the Intranasal Route

  • 期刊论文

  • 发表日期：

    2025年10月30日

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  • Shruti Khare,
  • Swatantra K. S. Kushwaha,
  • Amit Mishra

摘要

Epilepsy management remains significantly limited by the blood-brain barrier (BBB), which restricts delivery of antiepileptic drugs like lacosamide (LCM). The drug's poor aqueous solubility (0.027 mg/mL) and variable oral bioavailability (~50%) further complicate treatment. To address these challenges, this study developed chitosan-coated nanostructured lipid carriers (LCM-CT-NLCs) for intranasal administration with the potential to facilitate direct nose-to-brain delivery using a systematic Quality-by-Design (QbD) approach guided by predefined Quality Target Product Profile (QTPP) criteria. The research aimed to optimize LCM-CT-NLCs for intranasal administration, specifically targeting enhanced brain bioavailability and sustained seizure control. Critical QTPP parameters included particle size (100-120 nm), entrapment efficiency (≥80%), sustained release over 8 hours, and mucoadhesive strength (≥0.2 N). Formulation optimization was achieved through Box-Behnken experimental design, evaluating lipid ratios (1:9 to 9:1) and surfactant concentrations (3-5%). Comprehensive characterization involved dynamic light scattering for particle properties, TEM for morphology, and FTIR/DSC/XRD for physicochemical interactions. The optimized formulation (F8) demonstrated excellent alignment with QTPP targets. Uncoated particles measured 99 ± 3.1 nm (PDI <0.2), increasing to 108.8 nm after chitosan coating while maintaining monodispersity. High entrapment efficiency (80.0 ± 1.58%) and sustained drug release (88.39% over 8 hours, Higuchi kinetics R²=0.991) were achieved. The formulation showed strong mucoadhesion (0.22 ± 0.03 N) and significantly enhanced ex vivo permeation (flux 358 ± 13 μg/cm²/h, 1.47-fold higher than LCM solution). Stability studies confirmed robustness at 30°C/60% RH for 90 days with minimal changes in particle size (≤5.6% increase) and drug loading (≤0.1% loss). These results demonstrate that QTPP-driven development successfully produced LCM-CT-NLCs meeting all predefined targets for an intranasal formulation intended for brain delivery.The optimized formulation combines ideal nanocarrier properties with enhanced mucosal retention and permeation characteristics conducive to bypassing the BBB, offering a promising non-invasive alternative for improved epilepsy management. This approach effectively addresses key limitations of conventional LCM therapy while demonstrating excellent stability for potential clinical translation.