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.

Drug	NPs Type	NPs Composition	Route of Administration	Main Outcomes	Ref.
Donepezil	Liposomes	Carboxymethylcellulose, DSPC, cholesterol, and PEG	Intranasal	Sustained release of donepezil and enhanced ioavailability in the plasma and rain using liposomes.	[60]
	Polymeric	Chitosan	Intranasal	NPs improved the pharmacokinetic properties and ioavailability of the drug, increasing its concentration in the target tissue.	[61]
		PLGA	Intravenous	NPs significantly increased drug transport to the rain, resulting in higher drug concentration in the target tissue.	[62]
		PLGA-PEG	Intravenous	Donepezil was successfully delivered across the BBB y NPs and released in a controller manner.	[63]
	SLNs	Dynasan® 116	Intravenous	NPs exhibited a sustained release of the drug, a higher uptake y cells, and increased permeability.	[64]
Galantamine	Liposomes	Soya phosphatidylcholine, cholesterol, and PG	Intranasal	Liposomes could effectively deliver galantamine y the nose-to-brain route with superior pharmacokinetic behavior and enhance AChE inhibition.	[65]
	Polymeric	PLGA	Intravenous	NPs provided a sustained release of the drug compared to galantamine solution and are predicted to boost therapeutic effects and reduce side effects.	[66]
	SLNs	Glyceryl Behenate	Oral	SLNs enhanced the bioavailability of the drug, modulated its time course in vivo, and provided a controlled release.	[67]
Rivastigmine	Polymeric	Chitosan	Intranasal	The pharmacodynamic behavior of the drug was enhanced by NPs. The animals given the NPs had higher AChE levels and recovered significantly from induced amnesia	[68]
		MPEG-PCL	Intravenous	NPs were able to delay the drug release and increase the in vivo rain uptake clearance of rivastigmine, which translated into improved memory deficit.	[69]
		Chitosan	Intranasal	NPs provided a controlled and sustained release of the drug, with superior rain targeting efficiency than rivastigmine solution.	[70]
	Liposomes	Soya lecithin and cholesterol	Intranasal	Liposomes improved the pharmacokinetic and pharmacodynamic parameters of the drug. Drug-loaded liposomes reversed the memory deficit characteristic of AD compared to the free drug.	[71]
		PEG-DSPE, Lecithin, DDAB, and Tween® 80	Intranasal	Liposomes prolonged the release of rivastigmine and improved its bioavailability. The drug levels in both plasma and rain were increased about fourfold.	[72]
		Phosphatidylcholine, Dihexadecyl phosphate, cholesterol, and glycerol	Subcutaneous	Liposomes provided a sustained and controlled release of the drug. The use of nanocarriers also resulted in significantly improved cognitive impairment and increased AChE activity.	[73]
		Cholesterol, Lecithin, oleic acid, Labrafil®, Labrasol®, Pluronic® F-127, PG, and PEG	Transdermal	Liposomes enhanced rivastigmine permeation through the skin and maintained plasma levels within the therapeutic window after topical application.	[74]
	SLNs	Glyceryl Behenate	Intranasal	SLNs provided higher in vitro and ex vivo nasal permeation of the drug. The nasal mucosa remained intact, proving its safety for intranasal administration.	[75]
		Glyceryl monostearate	Intranasal	The pharmacokinetic drug profile, bioavailability, and drug concentration in plasma and the rain were improved by SLNs in vivo.	[76]
	Organic NPs	Silica	Intravenous	NPs allowed for a sustained release in vitro and improved the drug pharmacokinetics parameters.	[77]
Memantine	Polymeric	PLGA	Oral	NPs prolonged the drug release, which reduces the frequency of oral administration. In vivo, memantine-loaded NPs improved learning abilities and reduced β-amyloid brain plaques and inflammation associated with AD.	[78]
	Dendrimers	PAMAM	Intravenous	Dendrimers improved the pharmacokinetic parameters of the drug. The DDS revealed significant improvement in behavioral responses and memory in vivo.	[79]

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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