Nose to brain delivery of nanostructured lipid carriers loaded with rivastigmine and nilotinib for treating Alzheimer’s disease: preparation, cell line study, and in vivo evaluation

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative that affects over 55 million people worldwide, a number expected to double by 2050 due to aging populations. This growing prevalence imposes immense societal and economic burdens on healthcare systems and caregivers. AD is challenging to treat with monotherapy, making combination therapy a more effective approach. This study focuses on delivering Rivastigmine tartrate (RIV), and Nilotinib hydrochloride monohydrate (NIL), to the brain to achieve synergistic effects against AD. The optimal ratio of the drug combination was determined using the combination index that was performed using the Neuro2a cells line. It was found to be 1:1, emphasizing the synergistic effect against the cell lines. So, nanostructured lipid carriers (NLCs) were loaded with RIV and NIL, both individually and in combination, developed and optimized in this study. The developed formulations were thoroughly characterized for globule size, polydispersity index (PDI), and entrapment efficiency (EE) for each drug and the combination. The globule size was > 200 nm, PDI > 0.3; EE < 85% in all the developed formulations. On performing an in vitro cell availability study it was found that developed NLCs showed a 1.3 to 1.4-fold increase in the viability of the cells. On conducting an in vivo study, the concentration in the brain following administration of different formulations was in the order of RIV-NIL-NLC > NIL-NLC > RIV-NLC > RIV-NIL SUS > NIL-SUS > RIV-SUS. There was a 3.5 to 5-fold increase in the concentration of RIV and NIL in the brain when administered as RIV-NIL-NLC. So, it can be concluded that the NLCs with combined drugs showed promising results, enhancing drug permeability through the intranasal route, therefore could be used for treating AD.

Introduction

AD is a neurological disorder characterized by cognitive decline, memory loss, abnormal behavior, and loss of functional abilities. The most prevalent form of AD is caused by amyloid-beta peptides (Aβ) building up in the brain’s neocortical and medial temporal lobes, which are the most affected areas [1]. The disease’s prevalence doubles every 10 years. Today, it is projected that over 50 million people universally suffer from AD, and by 2050, this number is expected to surpass 150 million [2]. As of right now, the FDA (Food and Drug Administration) has permitted just four drugs for AD. Among these, memantine (MM) is an antagonist of the N-methyl-d-aspartate (NMDA) receptor, rivastigmine (RIV), galantamine, and donepezil (DPL) are ACh esterase enzyme (AChE) inhibitors [3].

The advantages of these drugs in symptom management are rather slight, though. They also fail to stop the slow deterioration of cognition caused by brain atrophy, neuronal death, or both. Additionally, they are ineffective at halting the gradual decline in cognition caused by neuronal death, brain atrophy, or a combination thereof, primarily focused on symptom management, and often fall short of addressing the underlying disease mechanisms. Among the available drugs, RIV, an ACh esterase inhibitor, has demonstrated efficacy in improving cognitive function, while Nilotinib hydrochloride monohydrate (NIL), a tyrosine kinase inhibitor, has shown promise in reducing neuroinflammation and promoting neuroprotection [4].

Despite their potential benefits, the clinical efficiency of these drugs is inadequate because of their poor bioavailability and ability to cross the blood–brain barrier (BBB). Traditional delivery methods often fail to achieve adequate drug concentrations in the brain, necessitating innovative approaches to enhance therapeutic outcomes [5]. In combination therapy, the unfavorable pharmacodynamics and pharmacokinetics profile of the drug combination is often the cause of therapeutic failure. Inadequate drug physical chemistry (e.g., hydrophobicity), unfavorable biological membrane capture, unfavorable pharmacokinetic parameters (e.g., intense and plasma metabolism), drug variability (photolysis, oxidation, and hydrolysis), and tissue toxicity (e.g., neurotoxicity, kidney toxicity, hepatotoxicity) are the main causes of pharmacotherapy failure [6].

When drugs are combined within nano-formulations, their pharmacokinetics and pharmacodynamics improve, and they often exhibit reduced toxicity. On the one hand, one of the most important aspects of developed nanoformulations is the regulated release of drugs into the brain. Recent advancements in nanotechnology offer promising solutions, particularly the use of nanostructured lipid carriers (NLCs). These carriers not only improve solubility and stability but also facilitate targeted delivery to the central nervous system through non-invasive routes [7].

The intranasal route for administering drugs has garnered increasing interest due to its direct access to the brain, bypassing the BBB. This delivery method can enhance drug absorption and provide a rapid onset of action, making it ideal for AD treatment [8, 9].

The design and assessment of NLC loaded with RIV and NIL, separately and in combination, for the treatment of AD are examined in this work. So, the objective is to examine the feasibility of this dual-drug delivery system in enhancing therapeutic outcomes and to contribute to the advancement of innovative treatment strategies for AD.

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Materials

Rivastigmine Tartrate (RIV) & Nilotinib HCL monohydrate (NIL) was procured as a generous gift from Dr. Reddy’s Laboratories, Hyderabad, India. Gelot™ 64, Gelucire® 50/13, Geleol™ mono and diglyceride NF, Emulcire ™ 61 WL 2659, Gelucire® 43/01, Gelucire® 33/01, Gelucire® 39/01, Tefose® 1500, stearic acid, Glyceryl monostearate, Labrafil® M 2130 CS, Compritol® 888 ATO, Capryol® PGMC, Capmul® MCM, Capryol® 90, Labrafac® WL 1349, Capmul® PG8 NF, Lauroglycol® 90, Labrasol, Captex® 355, Neobee® M20, Captex® 300, Hemp oil, Sesame oil, Labrafil® M1944, wheat germ oil, olive oil, Jojoba oil, castor oil, grape seed oil, Plurol® oleique CC 497, Rice bran oil, Canola oil, Captex® 8000, Tween® 20, Tween® 80, Cremophor® EL, Cremophor® RH 40, Solutol, Poloxamer® 188, Transcutol®, Labrasol®, Span® 80, Span® 20 were obtained as Gift samples from Gattefossè (Saint-Priest, France). Chemicals used in the cell line studies were bought from Sigma Aldrich, USA, and Merck, Germany. The remaining reagents and chemicals were purchased from S.D. Fine Chemicals Ltd. in Mumbai, India. All of the studies were conducted using freshly made buffer solutions.

Khan, S.A., Qamar, Z., Kamboj, S. et al. Nose to brain delivery of nanostructured lipid carriers loaded with rivastigmine and nilotinib for treating Alzheimer’s disease: preparation, cell line study, and in vivo evaluation. Discover Nano 20, 93 (2025). https://doi.org/10.1186/s11671-025-04276-w