Elsevier

Journal of Controlled Release

Volume 268, 28 December 2017, Pages 364-389
Journal of Controlled Release

Review article
Progress in brain targeting drug delivery system by nasal route

https://doi.org/10.1016/j.jconrel.2017.09.001Get rights and content

Abstract

The blood–brain barrier (BBB) restricts the transport of potential therapeutic moieties to the brain. Direct targeting the brain via olfactory and trigeminal neural pathways by passing the BBB has gained an important consideration for delivery of wide range of therapeutics to brain. Intranasal route of transportation directly delivers the drugs to brain without systemic absorption, thus avoiding the side effects and enhancing the efficacy of neurotherapeutics. Over the last several decades, different drug delivery systems (DDSs) have been studied for targeting the brain by the nasal route. Novel DDSs such as nanoparticles (NPs), liposomes and polymeric micelles have gained potential as useful tools for targeting the brain without toxicity in nasal mucosa and central nervous system (CNS). Complex geometry of the nasal cavity presented a big challenge to effective delivery of drugs beyond the nasal valve. Recently, pharmaceutical firms utilized latest and emerging nasal drug delivery technologies to overcome these barriers. This review aims to describe the latest development of brain targeted DDSs via nasal administration.

Chemical compounds studied in this article

Carbopol 934p (PubChem CID: 6581)

Carboxy methylcellulose (PubChem CID: 24748)

Penetratin (PubChem CID: 101111470)

Poly lactic-co-glycolic acid (PubChem CID: 23111554)

Tween 80 (PubChem CID: 5284448)

Introduction

Despite of the tremendous advancement in drug delivery systems (DDSs) for treatment of central nervous system disorders like schizophrenia, migraine, Parkinson's, Alzheimer's disease and brain tumors, still there is need of novel brain targeted DDSs. The major hurdle for targeting the drug to brain is the presence of BBB. BBB is the delicate network of blood vessels having tightly packed endothelial cells which separates the brain from circulatory system. It protects brain from entry of harmful substances such as toxin and bacteria. Hydrophilic substances, charged molecules, proteins and peptides are unable to cross this barrier, whereas lipophillic drugs such as antidepressants, anxiolytics and many hormones can easily cross the endothelial cells [1]. Patients suffering from neurological disorders required chronic dosing, leading to side effects in non targeted organs. It is considered that majority of drugs which are useful to treat the neurological disorders have lost their potential due to the BBB, resulting in limited treatment options for the patients suffering from neurodegenerative diseases and brain cancer [2]. Therefore, non-invasive transport of drug to brain is highly needed for neurological disorders and brain tumors requiring chronic therapy. Olfactory pathway is a reliable alternative to achieve desire therapeutic effects at lower doses for treating chronic diseases while minimizing the side effects. Transmucosal delivery of drug through olfactory or trigeminal pathway to brain by passing the BBB is referred as the direct IN drug transportation to brain. This is the only route through which brain is in connection with the outside environment [3]. This neural connection has gained attention for delivery of wide variety of drug molecules by the formulations ranging from small molecules to large molecules such as nucleotides, peptides and proteins to brain by preventing the enzymatic degradation and enhancing the pharmacological effects without systemic absorption and toxicity to the major peripheral organs. In animal and human studies, it was investigated that different DDSs by improving the nasal permeability, increasing mucoadhesion, providing constant or controlled release of drug or increasing deposition at olfactory epithelium resulted in successful delivery of drug from direct nose to brain [4], [5].

This review highlights literatures regarding pathways and mechanisms of therapeutic agents transporting across nasal mucosa and latest developments on novel DDSs using various formulation strategies to improve the IN drug delivery to brain. Colloidal carriers such as various types of nanocarriers (NPs, micelles, nanogels, nanoemulsions and liposomes) and microspheres as potential DDSs to brain are main focus of discussion. Patented technology based drug delivery devices for efficient nasal delivery of drugs are highlighted in this review. Moreover, limitations as well as future prospects of such brain targeted DDSs are also discussed in details.

Section snippets

Drug delivery strategies for brain targeting

Various drug delivery strategies to disrupt or overcome the BBB and potentiate the transport of drug molecules across this barrier to the CNS have been studied. These strategies are divided into three main categories; invasive and non invasive strategies and recent techniques for BBB disruption (Fig. 1).

Nasal drug delivery to brain

Nasal route has been explored for decades for systemic delivery of drugs which can't be given via oral route but now it has gained attraction and potential for direct IN delivery of neurotherapeutics to brain by circumventing the blood circulation, thus reducing the systemic exposure and hepatic/renal clearance [124], [125]. This pathway involving olfactory and trigeminal nerves is gained an important consideration for delivery of wide range of therapeutic agents even plasmids can be delivered

IN brain targeting novel DDSs

The DDS is designed to transport the drug at particular site in the body, attain desired therapeutic drug level and maintain plasma drug concentration within therapeutic window. The DDSs release the drug at predetermined rate and maintain the drug plasma concentration for desired duration. Colloidal carriers such as NP, liposomes and microspheres have got potential to achieve desired therapeutic level in target tissues for required duration for optimal therapeutic efficacy by controlling the

Nasal drug delivery devices for brain targeting

In addition to DDSs, another strategy for direct transport of drug from nose to brain is to deposit the drug on olfactory epithelium or region of nose innervated by trigeminal nerves so that more drug is transported to brain via olfactory/trigeminal pathway. For this purpose, many effective and efficient novel nasal drug delivery devices were studied by the researchers and some were patented. Among these devices, pressurized olfactory delivery devices, nebulizers, atomizers, pressurized meter

Conclusion

In summary, an analysis of the available literatures has revealed that brain targeting via nasal drug delivery is an attractive approach. Surface modifications of nanocarriers and the introduction of specific ligands provided useful information and progress in this field. Surface modifications of carriers with CPP (NPs, micelles and liposomes) opened a new era of drug delivery systems especially peptides and protein based therapeutic agents to brain. Most research publications focused on

Acknowledgements

This work was supported by the China-Australia Centre for Health Sciences Research (CACHSR no. 2016GJ01).

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