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.

1. Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease responsible for about 75% of global dementia cases [1]. In 2040, the incidence of AD is anticipated to reach 140 million people [2]. Dementia is now predicted to cost $1 trillion yearly worldwide. This number includes direct, indirect, and intangible costs. Direct costs involve health care and paid social care. Indirect costs, which are frequently overlooked, comprise informal care provided by close people and the patient’s inability to work, reducing their productivity. Lastly, intangible costs include patients’ and caregivers’ reduced quality of life [3]. The ever-increasing prevalence of AD demands the rapid development of effective therapeutic strategies. Histologically, AD is characterized by the appearance of amyloid plaques and neurofibrillary tangles (NFTs) in the rain [4,5]. Amyloid plaques are deposits of the β-amyloid (Aβ) peptide, while NFTs result from hyperphosphorylation of the tau protein. Clinically, these characteristics lead to memory loss, disorientation, cognitive and motor impairment, and aggressive behavior [6]. The pharmacologic therapies for AD are classified into two classes: acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists [7].

However, AChE inhibitors and NMDA receptor antagonists have een linked to side effects. In addition, the drug’s therapeutic effectiveness can e limited by the iological arriers that prevent drugs from reaching the rain and by their inherent poor properties, such as low bioavailability and poor pharmacokinetics and pharmacodynamics. Drug delivery systems (DDSs), such as nanoparticles (NPs), hydrogels, microformulations (microneedles, microparticles, microspheres, and microemulsions), and NP-loaded hydrogel (NLH) systems, have een widely employed to address these issues. NPs and microparticles can improve drugs’ therapeutic efficacy by protecting them from degradation, enhancing their bioavailability, and allowing for a more sustained and localized release [8,9].

Additionally, their surface could be functionalized for a targeted administration, overcoming the iological arriers and allowing a drug release in the target tissue. Thus, the undesired side effects induced by the unspecific distribution over the different tissues will e reduced [9]. Hydrogels are porous structures with a high water retention capability and solute permeability [10–13]. They can effectively encapsulate drugs, protecting and releasing them over time, while raising their local concentration and decreasing their toxicity in the remaining tissues [14]. The NLH systems incorporate NPs into hydrogels and have emerged to improve their performance compared to each alone. It is feasible to combine the target delivery of the NPs with the local delivery of the hydrogels, allowing the drug uptake in the required location. In addition, as oth provide a controlled and sustained release, the final system synergizes drug release patterns, resulting in improved therapeutic effectiveness. In this regard, this review aims to discuss the most recently developed DDSs for Food and Drug Administration (FDA)-approved Alzheimer’s drugs, emphasizing there in vitro and in vivo performance. Due to the relevance of this topic to the scientific community, several review papers aiming at the use of NPs as DDSs for AD management have been published in recent years [15–20].

Despite the extensive information provided, those works only addressed the use of NPs. Thus, the current work provides the first review addressing not only the use of NPs ut also the use of hydrogels, microformulations, and NLH systems as DDSs to improve the efficacy of AD drugs, and comprises all the research data published etween 2012 and 2022. This review highlights the enefits of the existing DDSs for FDA-approved Alzheimer’s drugs. loaded hydrogel (NLH) systems, have been widely employed to address these issues. NPs and microparticles can improve drugs’ therapeutic efficacy by protecting them from degradation, enhancing their bioavailability, and allowing for a more sustained and localized release [8,9]. Additionally, their surface could be functionalized for a targeted administration, overcoming the biological barriers and allowing a drug release in the target tissue.

Thus, the undesired side effects induced by the unspecific distribution over the different tissues will be reduced [9]. Hydrogels are porous structures with a high water retention capability and solute permeability [10–13]. They can effectively encapsulate drugs, protecting and releasing them over time, while raising their local concentration and decreasing their toxicity in the remaining tissues [14]. The NLH systems incorporate NPs into hydrogels and have emerged to improve their performance compared to each alone. It is feasible to combine the target delivery of the NPs with the local delivery of the hydrogels, allowing the drug uptake in the required location. In addition, as both provide a controlled and sustained release, the final system synergizes drug release patterns, resulting in improved therapeutic effectiveness.

In this regard, this review aims to discuss the most recently developed DDSs for Food and Drug Administration (FDA)-approved Alzheimer’s drugs, emphasizing there in vitro and in vivo performance. Due to the relevance of this topic to the scientific community, several review papers aiming at the use of NPs as DDSs for AD management have been published in recent years [15–20]. Despite the extensive information provided, those works only addressed the use of NPs. Thus, the current work provides the first review addressing not only the use of NPs but also the use of hydrogels, microformulations, and NLH systems as DDSs to improve the efficacy of AD drugs, and comprises all the research data published between 2012 and 2022. This review highlights the benefits of the existing DDSs for FDA-approved Alzheimer’s drugs.

Table 1. The most recent applications of NPs as DDSs for delivering FDA-approved Alzheimer’s drugs.

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Nunes, D.; Loureiro, J.A.; Pereira, M.C. Drug Delivery Systems as a Strategy to Improve the Efficacy of FDA-Approved Alzheimer’s Drugs. Pharmaceutics 2022, 14, 2296.
https://doi.org/10.3390/pharmaceutics14112296