Intranasal delivery to the central nervous system: Mechanisms and experimental considerations
Abstract
The blood-brain barrier (BBB) limits the distribution of systemically administered therapeutics to the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neurological and psychiatric diseases and disorders. Intranasal delivery is a noninvasive and convenient method that rapidly targets therapeutics to the CNS, bypassing the BBB and minimizing systemic exposure. This review focuses on the current understanding of the mechanisms underlying intranasal delivery to the CNS, with a discussion of pathways from the nasal cavity to the CNS involving the olfactory and trigeminal nerves, the vasculature, the cerebrospinal fluid, and the lymphatic system. In addition to the properties of the therapeutic, deposition of the drug formulation within the nasal passages and composition of the formulation can influence the pathway a therapeutic follows into the CNS after intranasal administration. Experimental factors, such as head position, volume, and method of administration, and formulation parameters, such as pH, osmolarity, or inclusion of permeation enhancers or mucoadhesives, can influence formulation deposition within the nasal passages and pathways followed into the CNS. Significant research will be required to develop and improve current intranasal treatments and careful consideration should be given to the factors discussed in this review.
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Local delivery strategies such as intra-cerebroventricular or intra-parenchymal injections, intracranial mini-pumps, catheter infusions, focused ultrasound and electromagnetic field-based methodologies are very invasive and risky because of the need for surgical intervention, and many are not suitable for multiple or chronic regimens.
“However, all of these techniques are very invasive and risky, in particular because of the need for surgical intervention [6], and many of them are not suitable in cases of multiple or chronic regimens.”
From Nanoemulsions for “Nose-to-Brain” Drug Delivery (2019) · cites this paper as [6]
The limited number of routes to reach the brain, such as blood-brain barrier and extraneuronal/perineuronal routes along the trigeminal or olfactory nerves, likely explains why only a small amount of intranasal oxytocin reaches the brain.
“This is likely because of the limited number of routes to reach the brain, such as blood-brain barrier and extraneuronal/perineuronal routes along the trigeminal or olfactory nerves.10, 49, 50, 51, 52, 53”
From Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial (2016) · cites this paper as [51]
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“An alternative non-invasive approach to bypass the highly selective BBB features intranasal drug administration, where the therapeutic agent can be delivered across the nasal mucosa along the olfactory or trigeminal nerve pathways directly into the interstitial fluid of the CNS, but may also end up in the olfactory bu…”
Background
- Authors
- Dhuria, S. V., Hanson, L. R., & Frey, W. H.
- Affiliations
- Regions Hospital (US)
- Corresponding author
- Dhuria, Shyeilla V.
- Venue
- Journal of Pharmaceutical Sciences
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 99
- Issue
- 4
- Pages
- 1654-1673
- ISSN
- 0022-3549 (ISSN-L)
- OpenAlex
- W2001525797
- Cited by
- 1,239
- References
- 166
- Citations by year
- 2026: 70 · 2025: 86 · 2024: 78 · 2023: 88 · 2022: 97 · 2021: 97 · 2020: 84 · 2019: 78 · 2018: 94 · 2017: 79 · 2016: 70 · 2015: 68 · 2014: 61 · 2013: 64 · 2012: 58
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmaceutical Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- intranasal drug delivery, brain drug delivery, blood-brain barrier, olfactory pathway, trigeminal pathway, cerebrospinal fluid, penetration enhancers, head position, neurological disorders, mental illness
- MeSH terms
- Administration, Intranasal, Animals, Blood-Brain Barrier, Central Nervous System, Humans, Drug Delivery Systems
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