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<p>Nasal administration provides a route for drug delivery to the brain. This research aimed to formulate and evaluate donepezil hydrochloride (DNP)-loaded nanocomplexes using dextran as a cationic polymer and gellan gum as an anionic polymer, to enhance brain delivery via the intranasal route, avoid its oral enzymatic degradation in the gastric, and enhance its bioavailability. Nanocomplexes were formulated at four different pH levels: 5, 8, 10, and 12. The optimized batch, selected based on physicochemical characteristics, was obtained at pH 10 and exhibited a production yield of 93.18 ± 0.33%, particle size of 155.71 ± 0.55&#xa0;nm, zeta potential of − 26.4 ± 1.20 mV, entrapment efficiency of 89.65 ± 0.62%, and drug content of 74.99 ± 0.12%. Free DNP exhibited 95.63 ± 3.09% drug release within 240&#xa0;min, whereas the DNP-loaded nanocomplex released 63.24 ± 4.95% over 240&#xa0;min, demonstrating the sustained release behavior of the nanocomplex. Fourier-transform infrared spectroscopy confirmed the effective encapsulation of DNP within the nanocomplex, while Differential scanning calorimetry and X-ray diffraction analyses indicated drug–polymer interactions lead to complex formation and the transformation of DNP from a crystalline to an amorphous state. Field-emission scanning electron microscopy analysis revealed that the nanocomplexes are spherical. The optimized nanocomplex exhibited a mucoadhesion efficiency of 70.2 ± 2.1%, while the in vitro drug permeation through a diffusion membrane was 96.83 ± 3.25%. Ex vivo permeation study showed 51.2 ± 2.08% drug permeation from the nanocomplex within 240&#xa0;min, whereas 91.96 ± 1.20% permeation was observed for free DNP within 240&#xa0;min. The pharmacokinetic parameters following nasal administration of the DNP-loaded nanocomplex showed higher C<sub>max</sub>, T<sub>1/2</sub>, and AUC<sub>₀–t</sub> values than those of free DNP. The bioavailability of the DNP nanocomplex was enhanced by around 1.27-fold compared to the free DNP. These results confirm the effectiveness of the nanocomplex in enhancing the nasal bioavailability of DNP in the rat brain.</p>

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Intranasal Administration of a Self-Assembled Donepezil Nanocomplex for Targeted Brain Delivery and Improved Brain Pharmacokinetics in Rats

  • 期刊论文

  • 发表日期：

    2026年5月14日

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  • Purushottam Gangane,
  • Mohammed Kaleem,
  • Neha Kale,
  • Sachin More,
  • Gamal Osman Elhassan,
  • Ameeduzzafar Zafar,
  • Md. Ali Mujtaba,
  • Md. Khalid Anwer

摘要

Nasal administration provides a route for drug delivery to the brain. This research aimed to formulate and evaluate donepezil hydrochloride (DNP)-loaded nanocomplexes using dextran as a cationic polymer and gellan gum as an anionic polymer, to enhance brain delivery via the intranasal route, avoid its oral enzymatic degradation in the gastric, and enhance its bioavailability. Nanocomplexes were formulated at four different pH levels: 5, 8, 10, and 12. The optimized batch, selected based on physicochemical characteristics, was obtained at pH 10 and exhibited a production yield of 93.18 ± 0.33%, particle size of 155.71 ± 0.55 nm, zeta potential of − 26.4 ± 1.20 mV, entrapment efficiency of 89.65 ± 0.62%, and drug content of 74.99 ± 0.12%. Free DNP exhibited 95.63 ± 3.09% drug release within 240 min, whereas the DNP-loaded nanocomplex released 63.24 ± 4.95% over 240 min, demonstrating the sustained release behavior of the nanocomplex. Fourier-transform infrared spectroscopy confirmed the effective encapsulation of DNP within the nanocomplex, while Differential scanning calorimetry and X-ray diffraction analyses indicated drug–polymer interactions lead to complex formation and the transformation of DNP from a crystalline to an amorphous state. Field-emission scanning electron microscopy analysis revealed that the nanocomplexes are spherical. The optimized nanocomplex exhibited a mucoadhesion efficiency of 70.2 ± 2.1%, while the in vitro drug permeation through a diffusion membrane was 96.83 ± 3.25%. Ex vivo permeation study showed 51.2 ± 2.08% drug permeation from the nanocomplex within 240 min, whereas 91.96 ± 1.20% permeation was observed for free DNP within 240 min. The pharmacokinetic parameters following nasal administration of the DNP-loaded nanocomplex showed higher Cmax, T1/2, and AUC₀–t values than those of free DNP. The bioavailability of the DNP nanocomplex was enhanced by around 1.27-fold compared to the free DNP. These results confirm the effectiveness of the nanocomplex in enhancing the nasal bioavailability of DNP in the rat brain.