Drug Delivery Systems as a Strategy to Improve the Efficacy of FDA-Approved Alzheimer's Drugs

Abstract

Alzheimer's disease (AD) is the most common form of dementia, with a high impact worldwide, accounting for more than 46 million cases. The continuous increase of AD demands the fast development of preventive and curative therapeutic strategies that are truly effective. The drugs approved for AD treatment are classified into acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists. The therapeutic effectiveness of those drugs is hindered by their restricted access to the brain due to the blood-brain barrier, low bioavailability, and poor pharmacokinetic properties. In addition, the drugs are reported to have undesirable side effects. Several drug delivery systems (DDSs) have been widely exploited to address these issues. DDSs serve as drug carriers, combining the ability to deliver drugs locally and in a targeted manner with the ability to release them in a controlled and sustained manner. As a result, the pharmacological therapeutic effectiveness is raised, while the unwanted side effects induced by the unspecific distribution decrease. This article reviews the recently developed DDSs to increase the efficacy of Food and Drug Administration-approved AD drugs.

Keywords: Alzheimer’s disease; donepezil; drug release; galantamine; hydrogel; memantine; nanomaterials; nanoparticle-loaded hydrogel; nanoparticles; rivastigmine.

Figure 1

Chemical structure of AD drugs.

Figure 2

Illustration of BBB constitution.

Figure 3

(A) in vitro release profile and (B) in vitro permeation profile of rivastigmine. Blue and red markers correspond to rivastigmine-loaded liposomes and rivastigmine solution, respectively. Adapted with permission from [72], copyright © 2017, published by Informa UK Limited.

Figure 4

(A) Amyloid plaque counting. Data represent mean ± standard deviation. ** and **** Denotes statistically significant differences (p < 0.01 and p < 0.0001, respectively), and (B) immunohistochemical staining of amyloid plaques (green) and a primary antibody (red) of the cortex of wild-type and transgenic AD mice models. Scale bar: 100 µm. Adapted with permission from [78], copyright © 2018, Springer Nature.

Figure 5

Schematic representation of the hydrogel-forming microneedles’ application and release.

Figure 6

(A) In vivo dissolution of microneedles over time. Scale bar: 500 µm, and (B) in vitro skin irritation of donepezil-loaded hydrogel dissolving microneedles. Scale bar: 2 mm. Adapted with permission from [89], copyright © 2021 MDPI.

Figure 7

Rivastigmine plasma concentrations after in vivo administration in solution and through microparticles (mean ± standard deviation, n = 3). Adapted with permission from [95], copyright © 2021 MDPI.

Figure 8

Schematic representation of the combination of loaded NPs and a hydrogel as DDS.

Figure 9

(A) In vitro release pattern of donepezil, (B) plasma concentration pattern over time, after in vivo administration of donepezil, and (C) skin histology 7 days after in vivo administration. The staining was performed with hematoxylin and eosin (H&E) and Masson’s trichrome (MT). Scale bar: 400 μm. Adapted with permission from [107], copyright © 2021 MDPI.

Figure 10

Schematic distribution of the developed DDS as a strategy to improve the efficacy of FDA-approved Alzheimer’s drugs by their administration routes. The graph was created based on the works reported in this review.