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Donepezil and Embelin Loaded Nanostructured Lipid Carriers for Direct Brain Delivery as An Intervention for Alzheimer’s Disease: Formulation Design, Optimization and Evaluation

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Abstract

Donepezil hydrochloride (DPL) and Embelin (EMB) loaded Nanostructured Lipid Carriers (NLCs) have been developed and optimized to achieve optimal drug loading, safer nasal delivery, effective neuronal/cell uptake, enhanced brain accessibility, controlled release, and desired therapeutic effect. Molecular docking studies demonstrated that both drugs bind effectively to AchE with interaction energies of -48.5319 and − 65.7525, respectively, indicating a synergistic approach. The hydrophobic interactions with target proteins facilitate the transportation of drugs through brain hydrophobic channels to provide a desired pharmacological response. N2a cell line investigation advised a 1:1 ratio of DPL and EMB to have the greatest possible synergistic effect based on the MTT assay. NLCs were fabricated by hot emulsification probe sonication method and optimized using QbD-based Central Composite Rotatable Design (CCRD). Optimized NLCs with a diameter of 180.2 nm were suitable for axonal uptake. A low Polydispersity index (PDI) score of 0.37 and Zeta Potential (ZP) of -12 mV indicated a uniform monodisperse system with persistent and stable dispersion properties. The NLCs demonstrated sustained drug release, DPL released at 90.72 ± 1.00%, and EMB at 81.30 ± 0.52% in 24 h. The Korsemeyer-Peppas model proved to be the most accurate fit due to its strong correlation. Ex vivo permeation and CLSM studies revealed superior goat nasal mucosa penetration of NLCs over suspension with a higher fluorescence level, up to 35 μm. NLCs treated nasal mucosa exhibited no erosion or interstitial gaps in the histopathological study. Moreover, NLCs were nontoxic and non-irritating, with a HET CAM score of 0.68 ± 0.05, indicating safe nasal delivery. The cellular uptake study showed a preponderance of the NLCs in the Cell’s cytoplasm, indicating ready uptake by N2a cells. Hence, intranasal therapy with the DPL and EMB-loaded NLCs could be a practical and promising implementation. Further in vivo, and clinical studies will be required to establish the formulation’s efficacy in treating Alzheimer’s disease (AD).

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Acknowledgements

Partially supported by the Distinguished Fellowship program (DSFP), King Saud University, Riyadh, Saudi Arabia. The authors are thankful to Prof. (Dr.) Harun M. Patel, Department of Pharmaceutical Chemistry, R.C. Patel Institute of Pharmaceutical Education, Maharashtra, for his immense support in carrying out Molecular docking investigations. The authors are also grateful to DST-PURSE and DST-FIST for facilities at Jamia Hamdard and AICTE, New Delhi, for the GPAT Scholarship to the first author.

Funding

The financial support to the corresponding author from King Saud University under the Distinguished Fellowship Program is acknowledged. The authors acknowledge DST-PURSE and DST-FIST for facilities at Jamia Hamdard and AICTE, New Delhi, for the GPAT Scholarship to the first author.

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  1. Javed Ali

    Present address: Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India

    Mohd Humair Ali, Asad Ali, Mohd Uzair Ali & Sanjula Baboota

  2. Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India

    Ozair Alam

  3. Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India

    Suhel Parvez

  4. Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia

    Eman Aldosari & Javed Ali

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Mohd Humair Ali: Conceptualization, All investigation, Experimental work, Software, Formal analysis, Writing-original draft. Ozair Alam: Software. Asad Ali: Methodology, Experimental work. Mohd Uzair Ali: Writing- Review and editing. Suhel Parvez: Resources. Eman Aldosari: Funding acquisition. Sanjula Baboota: Data curation, review. Javed Ali: Project administration, Supervision, Funding acquisition.

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Correspondence to Javed Ali.

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Ali, M.H., Alam, O., Ali, A. et al. Donepezil and Embelin Loaded Nanostructured Lipid Carriers for Direct Brain Delivery as An Intervention for Alzheimer’s Disease: Formulation Design, Optimization and Evaluation. J Clust Sci 35, 1021–1044 (2024). https://doi.org/10.1007/s10876-023-02531-7

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