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Purpose <p>This research aims to develop Nose-to-Brain Delivery of Dalfampridine (4-Aminopyridine) Chitosan–Lecithin Nanoparticles (DFP-CSLCNPs) to improve DFP delivery to the Central Nervous System in multiple sclerosis (MS).</p> Methods <p>In silico molecular docking studies were performed to evaluate drug-target interactions. Nanoparticles were formulated using a chitosan-lecithin system and optimized through a Box-Behnken experimental design. Key parameters such as particle size, zeta potential, and entrapment efficiency were analyzed. Ex vivo permeation studies were performed using excised nasal mucosa. </p> Results <p>In-silico docking confirmed CNS relevance, with the strongest binding to 6H24 (− 11.2&#xa0;kcal/mol) and favourable Swiss ADME properties. DFP-CSLCNPs were optimized using a 3-factor Box–Behnken experimental design, which predicted an optimal formulation with a particle size of approximately 142&#xa0;nm, zeta potential of + 24 mV, and entrapment efficiency exceeding 80%, supported by statistically significant quadratic models (R² = 0.9759–0.9878). The optimized formulation (F13) was subsequently prepared and experimentally validated, exhibiting a particle size of 182.8 ± 44.2&#xa0;nm, PDI of 0.36 ± 0.01, and zeta potential of + 30.1 mV, confirming nanoscale dimensions and electrostatic stability. In vitro release demonstrated sustained kinetics over 24&#xa0;h, following Korsmeyer–Peppas (R² = 0.9699, <i>n</i> = 0.4183; Fickian diffusion). Ex vivo across excised nasal mucosa, DFP-CSLCNPs achieved higher cumulative permeation (1047.01 vs. 611.46&#xa0;µg/cm²), greater flux <i>Jss</i> (68.18 ± 3.41 vs. 37.22 ± 1.86&#xa0;µg/cm²·h), and higher <i>Papp</i> (68.16 ± 0.36 vs. 37.24 ± 2.12 × 10⁻³ cm/h) than plain solution. Safety evaluations indicated no clinical toxicity over 28 days in Wistar rats. </p> Conclusion <p>The optimized DFP-CSLCNPs show promise as a safe and effective formulation for intranasal nose to brain targeting of potassium channel blockers for the management of MS.</p>

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Optimized Chitosan–Lecithin Nanocarriers for Nose-to-Brain Delivery of Dalfampridine in Multiple Sclerosis: Box–Behnken Design Optimization, and Toxicity Evaluation

  • 期刊论文

  • 发表日期：

    2026年4月12日

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  • Jaghatha Therassama,
  • Justus Oliver Jaslin Edward,
  • Somasundaram Arumugam,
  • Pavazhaviji Pazhani,
  • Jose Prakash Dharmian

摘要

Purpose

This research aims to develop Nose-to-Brain Delivery of Dalfampridine (4-Aminopyridine) Chitosan–Lecithin Nanoparticles (DFP-CSLCNPs) to improve DFP delivery to the Central Nervous System in multiple sclerosis (MS).

Methods

In silico molecular docking studies were performed to evaluate drug-target interactions. Nanoparticles were formulated using a chitosan-lecithin system and optimized through a Box-Behnken experimental design. Key parameters such as particle size, zeta potential, and entrapment efficiency were analyzed. Ex vivo permeation studies were performed using excised nasal mucosa.

Results

In-silico docking confirmed CNS relevance, with the strongest binding to 6H24 (− 11.2 kcal/mol) and favourable Swiss ADME properties. DFP-CSLCNPs were optimized using a 3-factor Box–Behnken experimental design, which predicted an optimal formulation with a particle size of approximately 142 nm, zeta potential of + 24 mV, and entrapment efficiency exceeding 80%, supported by statistically significant quadratic models (R² = 0.9759–0.9878). The optimized formulation (F13) was subsequently prepared and experimentally validated, exhibiting a particle size of 182.8 ± 44.2 nm, PDI of 0.36 ± 0.01, and zeta potential of + 30.1 mV, confirming nanoscale dimensions and electrostatic stability. In vitro release demonstrated sustained kinetics over 24 h, following Korsmeyer–Peppas (R² = 0.9699, n = 0.4183; Fickian diffusion). Ex vivo across excised nasal mucosa, DFP-CSLCNPs achieved higher cumulative permeation (1047.01 vs. 611.46 µg/cm²), greater flux Jss (68.18 ± 3.41 vs. 37.22 ± 1.86 µg/cm²·h), and higher Papp (68.16 ± 0.36 vs. 37.24 ± 2.12 × 10⁻³ cm/h) than plain solution. Safety evaluations indicated no clinical toxicity over 28 days in Wistar rats.

Conclusion

The optimized DFP-CSLCNPs show promise as a safe and effective formulation for intranasal nose to brain targeting of potassium channel blockers for the management of MS.