Intranasal drug delivery: opportunities and toxicologic challenges during drug development

Keller, Lea-Adriana; Merkel, Olivia M.; Popp, Andreas

doi:10.1007/s13346-020-00891-5

Cited by 271 publications

(226 citation statements)

References 249 publications

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“…Also, the nasal–olfactory artery sends branches from the olfactory bulb into the lamina propria [ 10 , 41 , 49 ]. Although not clearly understood, the perivascular spaces of these blood vessels are considered a potential extracellular pathway to enter the brain [ 39 , 50 , 51 , 52 ]. After reaching the brain, compounds can be distributed throughout the CNS via bulk flow mechanisms and/or more rapidly via the perivascular spaces [ 39 , 53 ].…”

Section: Nasal–cerebral Mechanismmentioning

confidence: 99%

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

et al. 2021

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Pain, particularly chronic pain, remains one of the most debilitating and difficult-to-treat conditions in medicine. Chronic pain is difficult to treat, in part because it is associated with plastic changes in the peripheral and central nervous systems. Polypeptides are linear organic polymers that are highly selective molecules for neurotransmitter and other nervous system receptors sites, including those associated with pain and analgesia, and so have tremendous potential in pain therapeutics. However, delivery of polypeptides to the nervous system is largely limited due to rapid degradation within the peripheral circulation as well as the blood–brain barrier. One strategy that has been shown to be successful in nervous system deposition of polypeptides is intranasal (IN) delivery. In this narrative review, we discuss the delivery of polypeptides to the peripheral and central nervous systems following IN administration. We briefly discuss the mechanism of delivery via the nasal–cerebral pathway. We review recent studies that demonstrate that polypeptides such as oxytocin, delivered IN, not only reach key pain-modulating regions in the nervous system but, in doing so, evoke significant analgesic effects. IN administration of polypeptides has tremendous potential to provide a non-invasive, rapid and effective method of delivery to the nervous system for chronic pain treatment and management.

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Section: Nasal–cerebral Mechanismmentioning

confidence: 99%

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

et al. 2021

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“…The use of biomaterials has been proposed to support macromolecule topical application and to facilitate the body's barriers crossing. For example, nanotherapeutics and nanomaterials improve the biodistribution of drugs throughout the brain for more effective treatments, not only via convection-enhanced delivery, but also via IN delivery (Keller et al, 2021).…”

Section: Biomaterial-assisted Deliverymentioning

confidence: 99%

Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?

et al. 2021

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Nerve growth factor (NGF) was the first-discovered member of the neurotrophin family, a class of bioactive molecules which exerts powerful biological effects on the CNS and other peripheral tissues, not only during development, but also during adulthood. While these molecules have long been regarded as potential drugs to combat acute and chronic neurodegenerative processes, as evidenced by the extensive data on their neuroprotective properties, their clinical application has been hindered by their unexpected side effects, as well as by difficulties in defining appropriate dosing and administration strategies. This paper reviews aspects related to the endogenous production of NGF in healthy and pathological conditions, along with conventional and biomaterial-assisted delivery strategies, in an attempt to clarify the impediments to the clinical application of this powerful molecule.

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“…Excised tissues represent the closest physiological approach in terms of histology, transporter expression and cell type distribution [ 35 , 36 ]. In fact, both excised tissue (organotypic explants) and primary cell cultures are morphologically closer to the airway mucosa, presenting proper tissue architecture and differentiation, but the poor accessibility, the lack of standardization and the existing interspecies differences (nonhuman alternatives) limits their applicability in drug transport and permeability studies [ 30 , 33 , 34 , 37 , 38 ]. In addition, the reproducibility of organotypic explants and primary cell cultures is often challenging due to the genetic variability, inter- and intraindividual differences between the donors, and the uncontrollable environmental variables preceding tissue harvest.…”

Section: In Vitro Cell Models To Evaluate the Effectiveness Of Nasal Formulationsmentioning

confidence: 99%

In Vitro Studies on Nasal Formulations of Nanostructured Lipid Carriers (NLC) and Solid Lipid Nanoparticles (SLN)

et al. 2021

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The nasal route has been used for many years for the local treatment of nasal diseases. More recently, this route has been gaining momentum, due to the possibility of targeting the central nervous system (CNS) from the nasal cavity, avoiding the blood−brain barrier (BBB). In this area, the use of lipid nanoparticles, such as nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN), in nasal formulations has shown promising outcomes on a wide array of indications such as brain diseases, including epilepsy, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and gliomas. Herein, the state of the art of the most recent literature available on in vitro studies with nasal formulations of lipid nanoparticles is discussed. Specific in vitro cell culture models are needed to assess the cytotoxicity of nasal formulations and to explore the underlying mechanism(s) of drug transport and absorption across the nasal mucosa. In addition, different studies with 3D nasal casts are reported, showing their ability to predict the drug deposition in the nasal cavity and evaluating the factors that interfere in this process, such as nasal cavity area, type of administration device and angle of application, inspiratory flow, presence of mucoadhesive agents, among others. Notwithstanding, they do not preclude the use of confirmatory in vivo studies, a significant impact on the 3R (replacement, reduction and refinement) principle within the scope of animal experiments is expected. The use of 3D nasal casts to test nasal formulations of lipid nanoparticles is still totally unexplored, to the authors best knowledge, thus constituting a wide open field of research.

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Intranasal drug delivery: opportunities and toxicologic challenges during drug development

Cited by 271 publications

References 249 publications

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

Intranasal Administration for Pain: Oxytocin and Other Polypeptides

Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?

In Vitro Studies on Nasal Formulations of Nanostructured Lipid Carriers (NLC) and Solid Lipid Nanoparticles (SLN)

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