Pharmacokinetic and pharmacodynamic evaluation of nasal liposome and nanoparticle based rivastigmine formulations in acute and chronic models of Alzheimer’s disease
Open accessAbstract
With the increasing aging population and progressive nature of the disease, Alzheimer's disease (AD) poses to be an oncoming epidemic with limited therapeutic strategies. It is characterized by memory loss, behavioral instability, impaired cognitive function, predominantly, cognitive inability manifested due to the accumulation of β-amyloid, with malfunctioned cholinergic system. Rivastigmine, a reversible dual cholinesterase inhibitor, is a more tolerable and widely used choice of drug for AD. However, rivastigmine being hydrophilic and undergoing the first-pass metabolism exhibits low CNS bioavailability. Nanoformulations including liposomes and PLGA nanoparticles can encapsulate hydrophilic drugs and deliver them efficiently to the brain. Besides, the nasal route is receiving considerable attention recently, due to its direct access to the brain. Therefore, the present study attempts to evaluate the pharmacokinetic and pharmacodynamic properties of nasal liposomal and PLGA nanoparticle formulations of rivastigmine in acute scopolamine-induced amnesia and chronic colchicine induced cognitive dysfunction animal models, and validate the best formulation by employing pharmacokinetic and pharmacodynamic (PK-PD) modeling. Nasal liposomal rivastigmine formulation showed the best pharmacokinetic features with rapid onset of action (Tmax = 5 min), higher Cmax (1489.5 ± 620.71), enhanced systemic bioavailability (F = 118.65 ± 23.54; AUC = 35,921.75 ± 9559.46), increased half-life (30.92 ± 8.38 min), and reduced clearance rate (Kel (1/min) = 0.0224 ± 0.006) compared to oral rivastigmine (Tmax = 15 min; Cmax = 56.29 ± 27.05; F = 4.39 ± 1.82; AUC = 1663.79 ± 813.54; t1/2 = 13.48 ± 5.79; Kel (1/min) = 0.0514 ± 0.023). Further, the liposomal formulation significantly rescued the memory deficit induced by scopolamine as well as colchicine superior to other formulations as assessed in Morris water maze and passive avoidance tasks. PK-PD modeling demonstrated a strong correlation between the pharmacokinetic parameters and acetylcholinesterase inhibition of liposomal formulation.
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Compared to oral pills, transdermal patches are more pleasant and provide a smaller dosage, leading to fewer side effects.
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- Authors
- Rompicherla, S. K. L., Arumugam, K., Bojja, S. L., Kumar, N., & Rao, C. M.
- Affiliations
- Manipal Academy of Higher Education (IN)
- Corresponding author
- Rao, C. Mallikarjuna
- Venue
- Naunyn-Schmiedeberg s Archives of Pharmacology
- Published
- 2021-06-04
- Volume
- 394
- Issue
- 8
- Pages
- 1737-1755
- ISSN
- 0028-1298 (ISSN-L)
- 1432-1912
- PMC
- PMC8298375
- OpenAlex
- W3130760084
- Cited by
- 86
- References
- 33
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 26 · 2023: 11 · 2022: 12 · 2021: 2
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Naunyn-Schmiedeberg s Archives of Pharmacology (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Manipal Academy of Higher Education, Manipal
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- rivastigmine, Alzheimer's disease, intranasal drug delivery, liposomes, PLGA nanoparticles, nanocarrier formulation, scopolamine-induced amnesia, pharmacokinetic-pharmacodynamic modeling, cholinesterase inhibitors, memory impairment, Morris water maze, passive avoidance, first-pass metabolism, drug repurposing, amyloid-beta
- MeSH terms
- Rivastigmine, Administration, Intranasal, Alzheimer Disease, Animals, Biological Availability, Cholinesterase Inhibitors, Colchicine, Disease Models, Animal, Liposomes, Male, Memory Disorders, Models, Biological, Scopolamine, Rats, Wistar, Maze Learning, Area Under Curve, Rats, Nanoparticles
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