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<p>Alzheimer’s disease is a neurological condition associated with synapse degeneration and abnormal aggregation of proteins leading to the death of neurons. Donepezil, a non-competitive, reversible inhibitor of acetylcholinesterase derived from piperidine, increases cholinergic function by increasing acetylcholine levels. Using a 3<sup>2</sup>-factorial design, this study optimized donepezil-loaded bovine serum albumin (BSA)-based nanoparticles (NPs) by the desolvation method. The effect of BSA concentration and stirring time on particle size (PS) and percentage entrapment efficiency (%EE) was investigated. The optimized NPs were characterized by PS, polydispersity index (PDI), zeta potential (ζ), morphology, %EE, and in vitro drug release. The optimized NPs were incorporated in a hydrogel polymer matrix containing Poloxamer 407 (18% w/v) and Gellan gum (0.8% w/v) to formulate in situ nasal gel. The formulated gel was evaluated for pH, viscosity, gelling time, mucoadhesive strength, nasal ciliotoxicity using sheep nasal mucosa, and ex vivo permeation. Further, in vivo efficacy of the gel formulation was assessed in male Wistar rats through the estimation of pharmacokinetic parameters (<i>AUC</i>, <i>t</i><sub>max</sub>, and <i>C</i><sub>max</sub>). Direct transport percentage (DTP), drug targeting index (DTI), and drug targeting efficiency (DTE) were also determined. The optimized spherical NPs had a PS of 184.30&#xa0;nm, a PDI of 0.193, high %EE (89%), and a <i>ζ</i> of − 39.20&#xa0;mV. NPs remained stable for 90&#xa0;days. The gel formulation exhibited a pH value of 5.6 ± 0.23, a gelling time of 23 ± 5.10&#xa0;s, and an expansion coefficient of 1.4 ± 0.06. Gelling temperature was within the acceptable range. After 8&#xa0;h, NP-loaded gel permeated 89% through sheep nasal mucosa and exhibited no indications of toxicity. The gel formulation showed improved pharmacokinetic parameters. In situ nasal gel formulation had improved DTE (148%), DTI (1.48), and DTP (32.69%) in comparison to the DPZ intranasal solution DTE (148%), DTI (1.09), and DTP (8.43%), respectively. The results indicated that the formulated donepezil-loaded BSA-based NPs containing in situ nasal gel system would be a promising approach for enhancing therapeutic and biopharmaceutical properties of the payload.</p>

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Bovine Serum Albumin-Based Nanoparticles Embedded In Situ Nasal Gel for Brain Delivery of Donepezil: In Vitro and In Vivo Studies

  • 期刊论文

  • 发表日期：

    2025年8月19日

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  • Dyandevi Mathure,
  • Ashish Fulsundar,
  • Yogita Shinde,
  • Rushikesh Jagtap,
  • Hemantkumar Ranpise,
  • Rajendra Awasthi

摘要

Alzheimer’s disease is a neurological condition associated with synapse degeneration and abnormal aggregation of proteins leading to the death of neurons. Donepezil, a non-competitive, reversible inhibitor of acetylcholinesterase derived from piperidine, increases cholinergic function by increasing acetylcholine levels. Using a 32-factorial design, this study optimized donepezil-loaded bovine serum albumin (BSA)-based nanoparticles (NPs) by the desolvation method. The effect of BSA concentration and stirring time on particle size (PS) and percentage entrapment efficiency (%EE) was investigated. The optimized NPs were characterized by PS, polydispersity index (PDI), zeta potential (ζ), morphology, %EE, and in vitro drug release. The optimized NPs were incorporated in a hydrogel polymer matrix containing Poloxamer 407 (18% w/v) and Gellan gum (0.8% w/v) to formulate in situ nasal gel. The formulated gel was evaluated for pH, viscosity, gelling time, mucoadhesive strength, nasal ciliotoxicity using sheep nasal mucosa, and ex vivo permeation. Further, in vivo efficacy of the gel formulation was assessed in male Wistar rats through the estimation of pharmacokinetic parameters (AUC, tmax, and Cmax). Direct transport percentage (DTP), drug targeting index (DTI), and drug targeting efficiency (DTE) were also determined. The optimized spherical NPs had a PS of 184.30 nm, a PDI of 0.193, high %EE (89%), and a ζ of − 39.20 mV. NPs remained stable for 90 days. The gel formulation exhibited a pH value of 5.6 ± 0.23, a gelling time of 23 ± 5.10 s, and an expansion coefficient of 1.4 ± 0.06. Gelling temperature was within the acceptable range. After 8 h, NP-loaded gel permeated 89% through sheep nasal mucosa and exhibited no indications of toxicity. The gel formulation showed improved pharmacokinetic parameters. In situ nasal gel formulation had improved DTE (148%), DTI (1.48), and DTP (32.69%) in comparison to the DPZ intranasal solution DTE (148%), DTI (1.09), and DTP (8.43%), respectively. The results indicated that the formulated donepezil-loaded BSA-based NPs containing in situ nasal gel system would be a promising approach for enhancing therapeutic and biopharmaceutical properties of the payload.