Improving Drug Delivery for Alzheimer’s Disease Through Nose-to-Brain Delivery Using Nanoemulsions, Nanostructured Lipid Carriers (NLC) and in situ Hydrogels

Figures & data

Figure 1 Schematic representation of the systemic process of inflammation in AD neuroinflammation.

Notes: Adapted with permission from: Walker KA, Ficek BN, Westbrook R. Understanding the Role of Systemic Inflammation in Alzheimer’s Disease. ACS Chem Neurosci. 2019;10(8):3340–3342.⁴⁰ Copyright © 2019 American Chemical Society. And from: Focused Ultrasound Foundation. Blood-Brain Barrier Opening. Available at: https://www.fusfoundation.org/mechan isms-of-action/blood-brain-barrier-opening; 2019 [cited 15 July 2020].¹¹³ © 1999–2021 Focused Ultrasound Foundation. Use of the image courtesy of the Focused Ultrasound Foundation.

Figure 2 Main advantages and drawbacks of the nasal drug administration.

Figure 3 Schematic representation of nasal cavity structure and the mechanisms of drug transport through the nasal mucosa to the brain. (A) Direct pathway: direct drug delivery through the olfactory and trigeminal nerves. (B) Indirect pathway: indirect drug delivery through the countercurrent exchange mechanism in the systemic circulation.

Notes: Adapted from Walker KA, Ficek BN, Westbrook R. Understanding the Role of Systemic Inflammation in Alzheimer’s Disease. ACS Chem Neurosci. 2019;10(8):3340–3342.⁴⁰ Copyright © 2019 American Chemical Society.⁴⁰ And from Hong SS, Oh KT, Choi HG, Lim SJ. Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and Future Perspectives. Pharmaceutics. 2019;11(10):540.¹¹⁴ Creative Commons (https://creativecommons.org/licenses/by/4.0/).

Figure 4 Schematic representation of the main characteristics of oil-in-water (O/W) nanoemulsions.

Notes: Adapted from Desfrançois C, Auzély R, Texier I. Lipid nanoparticles and their hydrogel composites for drug delivery: A review. Pharmaceuticals. 2018;11(4):118.⁹⁹ Creative Commons (https://creativecommons.org/licenses/by/4.0/).

Figure 5 Schematic representation of the main characteristics of nanostructured lipid carriers (NLC).

Table 1 Most Relevant Therapeutic Effects of Formulations Containing Nanoemulsions and Nanostructured Lipid Carriers (NLC) for Nose-to-Brain Delivery in the Treatment of Alzheimer’s Disease (AD)

Drug-Loaded Lipid-Based Nanosystem	Excipients	Relevant Outcomes	Therapeutic Effects	Reference
Donepezil-loaded nanoemulsion	● Oil: Labrasol^® ● Emulsifier: Cetyl pyridinium chloride ● Co-emulsifier: Glycerol	● In vitro prolonged drug release ● Absence of cytotoxic effects	● In vivo studies revealed that nanoemulsions allowed a higher uptake of donepezil in the brain than oral and intravenous solutions of donepezil	[^Citation108]
In situ resveratrol-loaded NLC hydrogel	● Solid lipid: Cetyl palmitate ● Liquid lipid: Capmul MCM ● Emulsifier: Poloxamer 188 and Tween^® 80	● According to ANOVA results, the R^2 values for particle size (0.9380), drug loading (0.8752,) and EE (0.9117) indicated that the Placket-Burman design and a two-level three-factor full factorial design were appropriated to evaluate the dependent responses ● Absence of nasal ciliotoxicity	● In vivo pharmacokinetic studies indicated higher drug distribution in the brain after intranasal administration compared to an orally administered resveratrol suspension	[^Citation68]
In situ naringenin-loaded nanoemulsion hydrogel	● Oil: Capmul MCM ● Emulsifiers: Tween^®80 and PEG 400 (4:1) ● Polymers: Poloxame 407 and chitosan	● Ex vivo permeation studies demonstrated that drug permeated slightly more slowly from the in situ naringenin-loaded nanoemulsion hydrogel (92.72 ± 6.41% in 12h) than from the naringenin-loaded nanoemulsion (> 91.0% in 8h) ● No mortality and morphological changes in the microstructure of the brain and in the nasal mucosa	● In vivo studies showed that the in situ naringenin-loaded nanoemulsion hydrogel exhibited higher antioxidant activity and effects in the locomotion of rats compared to the respective nanoemulsion ● In situ naringenin-loaded nanoemulsion hydrogel improved the drug bioavailability in the brain after intranasal administration	[^Citation70]
Memantine-loaded nanoemulsion	● Oil: Labrasol^® ● Emulsifier: cetylpyridinium chloride ● Co-emulsifier: ethylene glycol and propylene glycol	● In vitro drug release of 80% in simulated nasal fluid ● Higher antioxidant potential compared to a placebo nanoemulsion cytotoxicity results showed absence of toxic effects	● In vivo pharmacokinetic studies showed higher uptake of memantine in the brain after intranasal administration compared to an aqueous and an orally and intravenously drug solution	^Citation109
Pioglitazone-loaded NLC	● Solid lipid: tripalmitin ● Liquid lipid: Capmul MCM ● Emulsifiers: Tween^® 80 and Pluronic^® F68.	● According to ANOVA results, the R^2 values obtained for particle size (0.9807) and ZP (0.9890) showed that the Box-Behnken design was adequate to evaluate the dependent responses ● In vitro drug release from the optimized formulation exhibited Higuchi kinetic ● Higher ex vivo permeation after intranasal administration compared to a pioglitazone solution ● Absence of nasal ciliotoxicity	● In vivo biodistribution study indicated enhanced delivery of pioglitazone-loaded NLC into the brain after nasal administration	[^Citation110]
Rivastigmine hydrogen tartrate-loaded NLC	● Solid lipid: Compritol 888 ATO ● Liquid lipid: Triacetin ● Emulsifiers: Sucrose stearate and Poloxamer 188	● According to the ANOVA results, the R^2 values for particle size (93.64%) and EE (92.47%) indicated that the three-factor and three-level Box-Behnken design was suitable to evaluate the dependent responses ● Ex vivo study showed prolonged drug release ● Aldicarb assay indicated greater drug penetration into the brain compared to a rivastigmine solution	● In vivo study indicated an improvement in memory, escape latency, and transfer latency ● Quantitative RT-PCR revealed significantly decreased acetylcholinesterase 1 and 2 expressions when compared to the same dose of a rivastigmine solution	[^Citation111]

Abbreviations: ANOVA, analysis of variance; EE, encapsulation efficiency; NLC, nanostructured lipid carriers; RT-PCR, reverse transcription polymerase chain reaction; ZP, zeta potential.

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